CN103087040B - Penicillide derivative, its preparation method and at pharmaceutical usage - Google Patents

Abstract

The invention belongs to pharmaceutical synthesis field, be specifically related to new Penicillide derivative, its preparation method and the pharmaceutical composition containing this derivative and its purposes as therapeutical agent.Penicillide derivative of the present invention is for having the compound of general formula (I), and Penicillide derivative of the present invention can be used as effective constituent pharmaceutical compositions and especially prepares cholestery ester transfer protein inhibitors medicine;wherein: R¹be selected from (1R, 4S)-7-methyl bicyclic [2.2.1] heptane-7-carbonyl, 4-benzoyl bromide, 4-TRIFLUOROMETHYLBENZOYL, 3,5-bis-(trifluoromethyl) benzoyl; R²be selected from hydrogen, methyl, p-methoxyphenyl; R³be selected from hydrogen, methoxyl group.

Description

Translated fromChinese

Penicillide衍生物、其制备方法及其在药用用途Penicillide derivatives, their preparation and their use in medicine

技术领域technical field

本发明属药物合成领域，具体涉及新的Penicillide衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂的用途。The invention belongs to the field of medicine synthesis, and specifically relates to a new penicillide derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent.

背景技术Background technique

1974年由日本科研人员Sassa等人从菌类植物中提取出天然产物Penicillide，并确认了其基本结构(Tetrahedron Lett.1974，15(45)，3941-3942.)，而其绝对构型直到1992年才由Salituro等人确定(Bioorg.Med.Chem.Lett.1993，3(2)，337-340.)。拜耳公司通过对Penicillide进行衍生化，并证实其衍生物具有很好的胆固醇酯转移蛋白抑制活性(拜耳公司的专利WO2004039453；Bioorg.Med.Chem.Lett.2005，15(15)，3611-3614.)。有关天然产物Penicillide其衍生物的研发课题已引发本领域研究者的关注。In 1974, Japanese researchers Sassa and others extracted the natural product Penicillide from fungi, and confirmed its basic structure (Tetrahedron Lett.1974, 15(45), 3941-3942.), and its absolute configuration was not until 1992 The year was determined by Salituro et al. (Bioorg. Med. Chem. Lett. 1993, 3(2), 337-340.). Bayer Corporation derivatizes Penicillide, and confirms that its derivatives have good cholesteryl ester transfer protein inhibitory activity (Patent WO2004039453 of Bayer Corporation; Bioorg.Med.Chem.Lett.2005, 15 (15), 3611-3614. ). The research and development of the natural product Penicillide and its derivatives has attracted the attention of researchers in this field.

发明内容Contents of the invention

本发明的目的是提供新的Penicillide衍生物。The object of the present invention is to provide novel penicillide derivatives.

本发明的Penicillide衍生物为具有通式(I)的化合物：Penicillide derivatives of the present invention are compounds of general formula (I):

其中：in:

R¹选自(1R，4S)-7-甲基二环[2.2.1]庚烷-7-羰基，4-溴苯甲酰基，4-三氟甲基苯甲酰基，3，5-二(三氟甲基)苯甲酰基；R¹ is selected from (1R,4S)-7-methylbicyclo[2.2.1]heptane-7-carbonyl, 4-bromobenzoyl, 4-trifluoromethylbenzoyl, 3,5-di (Trifluoromethyl)benzoyl;

R²选自氢，甲基，对甲氧基苯基；R² is selected from hydrogen, methyl, p-methoxyphenyl;

R³选自氢，甲氧基。R³ is selected from hydrogen, methoxy.

具体的，本发明所述的化合物，分别具有如下化学结构式：Specifically, the compounds described in the present invention respectively have the following chemical structural formulas:

本发明的进一步目的是提供上述Penicillide衍生物的药用用途。具体涉及述Penicillide衍生物在制备含有该衍生物的药物组合物以及其作为治疗剂的用途。A further object of the present invention is to provide the pharmaceutical use of the above-mentioned Penicillide derivatives. It specifically relates to the use of the Penicillide derivatives in the preparation of pharmaceutical compositions containing the derivatives and as therapeutic agents.

本发明所涉及的药物组合物，其含有治疗有效剂量的上述Penicillide衍生物和药学载体。The pharmaceutical composition involved in the present invention contains a therapeutically effective dose of the above-mentioned Penicillide derivatives and a pharmaceutical carrier.

本发明尤其涉及胆固醇酯转移蛋白抑制剂药物，其含有治疗有效剂量的上述Penicillide衍生物和药学载体。换言之，本发明提供了含有药物有效剂量的上述化合物的组合物，以及所述的化合物在制备胆固醇酯转移蛋白抑制剂药物中的用途。In particular, the present invention relates to a cholesteryl ester transfer protein inhibitor drug, which contains a therapeutically effective dose of the above-mentioned Penicillide derivative and a pharmaceutical carrier. In other words, the present invention provides a composition containing the above-mentioned compound in a pharmaceutically effective dose, and the use of the compound in the preparation of a cholesteryl ester transfer protein inhibitor drug.

本发明提供了如具体实施方式所述的上述Penicillide衍生物的合成方法。The present invention provides the synthesis method of the above-mentioned Penicillide derivatives as described in the specific embodiment.

具体实施方式Detailed ways

以下结合实施例用于进一步描述本发明，但这些实施例并非限制本发明的范围。The following examples are used to further describe the present invention, but these examples do not limit the scope of the present invention.

实施例1：制备下述化合物，Embodiment 1: prepare following compound,

1.步骤11. Step 1

250mL干燥的单口瓶中加入NaH(5.8g，144mmol)，THF(72mL)溶解，滴加化合物2，3-二羟基苯甲醛(10.0g，72mmol)的THF(36mL)溶液，室温反应1小时。再缓慢加入溴化苄(12.3g，72mmol)的THF(18mL)溶液，室温反应24小时。再将反应液倒入水(300mL)中，二氯甲烷(3x100mL)萃取，水相用1N盐酸调pH值至2，再用二氯甲烷(3x100mL)萃取，1N盐酸(2x100mL)洗，合并有机相，无水MgSO₄干燥，过滤，浓缩，柱层析PE∶EA＝20∶1(R_f＝0.42，PE∶EA＝10∶1)，后用乙醇重结晶得10.7g化合物1，收率65％。NaH (5.8g, 144mmol) was added to a 250mL dry one-necked bottle, THF (72mL) was dissolved, and a THF (36mL) solution of compound 2,3-dihydroxybenzaldehyde (10.0g, 72mmol) was added dropwise, and reacted at room temperature for 1 hour. A solution of benzyl bromide (12.3 g, 72 mmol) in THF (18 mL) was added slowly, and reacted at room temperature for 24 hours. Then the reaction solution was poured into water (300mL), extracted with dichloromethane (3x100mL), the aqueous phase was adjusted to pH 2 with 1N hydrochloric acid, extracted with dichloromethane (3x100mL), washed with 1N hydrochloric acid (2x100mL), and combined with organic phase, dried over anhydrous MgSO₄ , filtered, concentrated, column chromatography PE: EA = 20: 1 (R_f = 0.42, PE: EA = 10: 1), and recrystallized with ethanol to obtain 10.7g of compound 1, the yield 65%.

¹H-NMR(CDCl₃，300MHz)：δ11.12(s，1H，OH)，9.92(s，1H，CHO)，7.47-7.32(m，5H，Ar-H)，7.20(dd，J＝7.8，1.4Hz，1H，Ar-H)，7.13(d，J＝7.8Hz，1H，Ar-H)，6.90(t，J＝7.8Hz，1H，Ar-H)，5.20(s，2H，CH₂).MS(ESI)：229.1(M+H)⁺.¹ H-NMR (CDCl₃ , 300MHz): δ11.12 (s, 1H, OH), 9.92 (s, 1H, CHO), 7.47-7.32 (m, 5H, Ar-H), 7.20 (dd, J= 7.8, 1.4Hz, 1H, Ar-H), 7.13(d, J=7.8Hz, 1H, Ar-H), 6.90(t, J=7.8Hz, 1H, Ar-H), 5.20(s, 2H, CH₂ ). MS (ESI): 229.1 (M+H)⁺ .

2.步骤22. Step 2

250mL单口瓶中加入化合物1(5.02g，21.9mmol)，加入甲醇(200mL)，冰浴下分批加入NaBH₄(3.34g，88.7mmol)，再在室温下反应4h。减压浓缩，将得到的白色固体溶于3N盐酸，二氯甲烷(3x100mL)萃取，合并有机相，水(3x100mL)洗，无水Na₂SO₄干燥，过滤，浓缩得白色固体4.94g化合物2，收率98％。Compound 1 (5.02g, 21.9mmol) was added to a 250mL single-necked flask, methanol (200mL) was added, NaBH₄ (3.34g, 88.7mmol) was added in batches under ice-cooling, and the reaction was continued at room temperature for 4h. Concentrate under reduced pressure, dissolve the resulting white solid in 3N hydrochloric acid, extract with dichloromethane (3x100mL), combine the organic phases, wash with water (3x100mL), dry over anhydrous Na₂ SO₄ , filter, and concentrate to give 4.94g of compound 2 as a white solid , yield 98%.

¹H-NMR(CDCl₃，300MHz)：δ7.42-7.36(m，5H，Ar-H)，6.91-6.79(m，3H，Ar-H)，6.08(s，1H，OH)，5.11(s，2H，CH₂)，4.74(s，2H，CH₂)，2.33(br s，1H，OH).MS(ESI)：253.0(M+Na)⁺.¹ H-NMR (CDCl₃ , 300MHz): δ7.42-7.36 (m, 5H, Ar-H), 6.91-6.79 (m, 3H, Ar-H), 6.08 (s, 1H, OH), 5.11 ( s, 2H, CH₂ ), 4.74 (s, 2H, CH₂ ), 2.33 (br s, 1H, OH). MS (ESI): 253.0 (M+Na)⁺ .

3.步骤33. Step 3

100mL的单口瓶中加入化合物2(300mg，1.3mmol)，再用干燥的二氯甲烷(5mL)溶解。加入对甲苯磺酸(24mg，0.13mmol)，冰盐浴中搅拌15min后滴加3，4-二氢-2H-吡喃(0.12mL，1.37mmol)，2h后停止反应。加入三乙胺(1mL)淬灭反应，有机相饱和食盐水(10mL)洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝20∶1(R_f＝0.60，PE∶EA＝6∶1)得393mg化合物3，收率96％。Compound 2 (300 mg, 1.3 mmol) was added into a 100 mL single-necked bottle, and then dissolved with dry dichloromethane (5 mL). Add p-toluenesulfonic acid (24mg, 0.13mmol), stir in an ice-salt bath for 15min, then add 3,4-dihydro-2H-pyran (0.12mL, 1.37mmol) dropwise, and stop the reaction after 2h. Triethylamine (1 mL) was added to quench the reaction, the organic phase was washed with saturated brine (10 mL), dried over anhydrous Na₂ SO₄ , filtered, concentrated, column chromatography PE:EA=20:1 (R_f =0.60, PE :EA=6:1) to obtain 393mg of compound 3, yield 96%.

¹H-NMR(CDCl₃，400MHz)：δ7.44-7.33(m，5H，Ar-H)，6.94(dd，J＝7.6，1.2Hz，1H，Ar-H)，6.87(dd，J＝7.8，1.2Hz，1H，Ar-H)，6.80(t，J＝7.8Hz，1H，Ar-H)，6.38(s，1HOH)，5.11(s，2H，CH₂)，4.86(d，J＝12Hz，1H，CH₂)，4.76(t，J＝3.8Hz，1H，CH)，4.63(d，J＝12Hz，1H，CH₂)，3.96-3.93(m，1H，CH₂)，3.58-3.55(m，1H，CH₂)，1.86-1.52(m，6H).MS(ESI)：337.2(M+Na)⁺.¹ H-NMR (CDCl₃ , 400MHz): δ7.44-7.33 (m, 5H, Ar-H), 6.94 (dd, J=7.6, 1.2Hz, 1H, Ar-H), 6.87 (dd, J= 7.8, 1.2Hz, 1H, Ar-H), 6.80(t, J=7.8Hz, 1H, Ar-H), 6.38(s, 1HOH), 5.11(s, 2H,_CH2 ), 4.86(d, J =12Hz, 1H, CH₂ ), 4.76 (t, J=3.8Hz, 1H, CH), 4.63 (d, J=12Hz, 1H, CH₂ ), 3.96-3.93 (m, 1H, CH₂ ), 3.58 -3.55 (m, 1H, CH₂ ), 1.86-1.52 (m, 6H). MS (ESI): 337.2 (M+Na)⁺ .

4.步骤44. Step 4

100mL的单口瓶中加入5-氨基-2-甲基苯酚(1.00g，8.13mmol)，NaHCO₃(2.05g，24.4mmol)，H₂O(33mL)和乙酸乙酯(28mL)，室温搅拌至溶解后加入特戊酰氯(1.05mL，8.54mmol)，1h后停止反应。有机相1N盐酸(1x30mL)洗，无水Na₂SO₄干燥，过滤，浓缩(R_f＝0.75，PE∶EA＝2∶1)得1.84g化合物4，收率97％。Add 5-amino-2-methylphenol (1.00g, 8.13mmol), NaHCO₃ (2.05g, 24.4mmol), H₂ O (33mL) and ethyl acetate (28mL) into a 100mL single-necked bottle, and stir at room temperature until After dissolution, pivaloyl chloride (1.05 mL, 8.54 mmol) was added, and the reaction was stopped after 1 h. The organic phase was washed with 1N hydrochloric acid (1×30 mL), dried over anhydrous Na₂ SO₄ , filtered, and concentrated (R_f =0.75, PE:EA=2:1) to obtain 1.84 g of compound 4 with a yield of 97%.

¹H-NMR(CDCl₃，400MHz)：δ8.57(s，1H)，7.89(s，1H)，7.38(s，1H)，6.99(d，J＝7.8Hz，1H，Ar-H)，6.39(d，J＝7.8Hz，1H，Ar-H)，2.19(s，3H，CH₃)，1.32(s，9H，t-Bu-H).¹³C-NMR(CDCl₃，100MHz)：δ177.6，155.6，136.0，130.3，121.0，110.2，107.4，39.6，27.5(3C)，15.6.MS(ESI)：208.0(M+H)⁺.HRMS(APCI)：Calcd.for C₁₂H₁₈NO₂⁺(M+H)⁺：208.1338，found：208.1349.¹ H-NMR (CDCl₃ , 400MHz): δ8.57(s, 1H), 7.89(s, 1H), 7.38(s, 1H), 6.99(d, J=7.8Hz, 1H, Ar-H), 6.39 (d, J=7.8Hz, 1H, Ar-H), 2.19 (s, 3H, CH₃ ), 1.32 (s, 9H, t-Bu-H).¹³ C-NMR (CDCl₃ , 100MHz): δ177.6, 155.6, 136.0, 130.3, 121.0, 110.2, 107.4, 39.6, 27.5 (3C), 15.6. MS (ESI): 208.0 (M+H)⁺ .HRMS (APCI): Calcd. for C₁₂ H₁₈ NO₂⁺ (M+H)⁺ : 208.1338, found: 208.1349.

5.步骤55. Step 5

50mL单口瓶中加入化合物4(1.00g，4.83mmol)，K₂CO₃(1.67g，12.1mmol)，氩气保护下加入DMF(10mL)，再在室温下加入MeI(0.36mL，5.8mmol)，4h后停止反应。加入H₂O(10mL)，乙酸乙酯萃取(3x20mL)，水(2x50mL)洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝6∶1(R_f＝0.69，PE∶EA＝4∶1)得1.00g化合物5，收率94％。Add compound 4 (1.00g, 4.83mmol), K₂ CO₃ (1.67g, 12.1mmol) to a 50mL single-necked bottle, add DMF (10mL) under argon protection, and then add MeI (0.36mL, 5.8mmol) at room temperature , Stop the reaction after 4h. Add H₂ O (10 mL), extract with ethyl acetate (3x20 mL), wash with water (2x50 mL), dry over anhydrous Na₂ SO₄ , filter, concentrate, column chromatography PE:EA=6:1 (R_f =0.69, PE:EA=4:1) to obtain 1.00 g of compound 5 with a yield of 94%.

¹H-NMR(CDCl₃，300MHz)：δ7.49(s，1H，Ar-H)，7.32(br s，1H，NH)，7.03(d，J＝8.1Hz，1H，Ar-H)，6.73-6.70(m，1H，Ar-H)，3.84(s，3H，OCH₃)，2.17(s，3H，CH₃)，1.32(s，9H，t-Bu-H).MS(ESI)：222.2(M+H)⁺.¹ H-NMR (CDCl₃ , 300MHz): δ7.49 (s, 1H, Ar-H), 7.32 (br s, 1H, NH), 7.03 (d, J=8.1Hz, 1H, Ar-H), 6.73-6.70(m, 1H, Ar-H), 3.84(s, 3H, OCH₃ ), 2.17(s, 3H, CH₃ ), 1.32(s, 9H, t-Bu-H).MS(ESI) : 222.2(M+H)⁺ .

6.步骤66. Step 6

50mL单口瓶中加入化合物5(500mg，2.26mmol)，氩气保护下加入干燥的THF(10mL)，冰盐浴下缓慢滴加n-buLi(4.5mL，7.24mmol，1.6M in THF)。滴加完毕后室温搅拌2h，然后通入CO₂气体2h。随后加入H₂O(30mL)，乙酸乙酯萃取(1x20mL)，水相用1N HCl调pH值至1，再用乙酸乙酯萃取(4x30mL)，合并有机相，无水Na₂SO₄干燥，过滤，浓缩(R_f＝0.24，PE∶EA＝4∶1)得540mg化合物6，收率90％。Compound 5 (500mg, 2.26mmol) was added to a 50mL single-necked bottle, dry THF (10mL) was added under argon protection, and n-buLi (4.5mL, 7.24mmol, 1.6M in THF) was slowly added dropwise in an ice-salt bath. After the dropwise addition, stir at room temperature for 2 h, and then pass CO₂ gas for 2 h. Then H₂ O (30 mL) was added, extracted with ethyl acetate (1×20 mL), the aqueous phase was adjusted to pH 1 with 1N HCl, and then extracted with ethyl acetate (4×30 mL), the organic phases were combined and dried over anhydrous Na₂ SO₄ , Filtration and concentration (R_f =0.24, PE:EA=4:1) yielded 540 mg of compound 6 with a yield of 90%.

¹H-NMR(CDCl₃，300MHz)：δ11.72(s，1H，COOH)，8.63(d，J＝8.7Hz，1H，Ar-H)，7.40(d，J＝8.4Hz，1H，Ar-H)，3.92(s，3H，OCH₃)，2.32(s，3H，CH₃)，1.34(s，9H，t-Bu-H).MS(EI)：265.¹ H-NMR (CDCl₃ , 300MHz): δ11.72(s, 1H, COOH), 8.63(d, J=8.7Hz, 1H, Ar-H), 7.40(d, J=8.4Hz, 1H, Ar -H), 3.92(s, 3H, OCH₃ ), 2.32(s, 3H, CH₃ ), 1.34(s, 9H, t-Bu-H). MS(EI): 265.

7.步骤77. Step 7

100mL的单口瓶中加入化合物6(12.6g，47.6mmol)，甲醇溶解(50mL)，后依次缓慢滴加浓硫酸(5.7mL)，原甲酸三甲酯(5.7mL，52.4mmol)，加热回流，3天后停止反应，冷却，DCM稀释(30mL)，1N盐酸萃取有机相，水相用3N NaOH调pH值至13，后用DCM萃取(3x50mL)，有机相无水Na₂SO₄干燥，过滤，浓缩(R_f＝0.64，PE∶EA＝3∶1)得7.41g化合物7，收率80％。Compound 6 (12.6g, 47.6mmol) was added to a 100mL single-necked bottle, dissolved in methanol (50mL), and then concentrated sulfuric acid (5.7mL) and trimethyl orthoformate (5.7mL, 52.4mmol) were slowly added dropwise successively, heated to reflux, Stop the reaction after 3 days, cool down, dilute with DCM (30mL), extract the organic phase with 1N hydrochloric acid, adjust the pH value of the aqueous phase to 13 with 3N NaOH, then extract with DCM (3x50mL), dry the organic phase with anhydrous Na₂ SO₄ , filter, Concentration (R_f =0.64, PE:EA=3:1) yielded 7.41 g of compound 7 with a yield of 80%.

¹H-NMR(CDCl₃，300MHz)：δ7.03(d，J＝8.4Hz，1H，Ar-H)，6.40(d，J＝8.7Hz，1H，Ar-H)，5.01(br s，2H，NH₂)，3.93(s，3H，OCH₃)，3.74(s，3H，OCH₃)，2.16(s，3H，CH₃).MS(ESI)：196.1(M+H)⁺.¹ H-NMR (CDCl₃ , 300MHz): δ7.03 (d, J=8.4Hz, 1H, Ar-H), 6.40 (d, J=8.7Hz, 1H, Ar-H), 5.01 (br s, 2H, NH₂ ), 3.93 (s, 3H, OCH₃ ), 3.74 (s, 3H, OCH₃ ), 2.16 (s, 3H, CH₃ ). MS (ESI): 196.1 (M+H)⁺ .

8.步骤88. Step 8

250mL的单口瓶中加入化合物7(7.41g，38.0mmol)，HBr(21mL)，H₂O(82mL)，搅拌至溶解，冰盐浴下滴加NaNO₂(2.86g，41.4mmol)的水溶液，搅拌1h。然后缓慢滴加CuBr(7.77g，54.3mmol)的氢溴酸(10mL)溶液，搅拌至没有气泡生成后，油浴80℃反应过夜。停止反应，冷却，DCM(3x100mL)萃取，合并有机相后，饱和NaHCO₃(1x100mL)洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝100∶1(R_f＝0.62，PE∶EA＝20∶1)得7.76g化合物8，收率79％。Compound 7 (7.41g, 38.0mmol), HBr (21mL), H₂ O (82mL) were added to a 250mL single-necked bottle, stirred until dissolved, and an aqueous solution of NaNO₂ (2.86g, 41.4mmol) was added dropwise in an ice-salt bath, Stir for 1h. Then a solution of CuBr (7.77 g, 54.3 mmol) in hydrobromic acid (10 mL) was slowly added dropwise, stirred until no bubbles were formed, and reacted overnight in an oil bath at 80°C. Stop the reaction, cool, extract with DCM (3x100mL), combine organic phases, wash with saturated NaHCO₃ (1x100mL), dry with anhydrous Na₂ SO₄ , filter, concentrate, column chromatography PE:EA=100:1 (R_f = 0.62, PE:EA=20:1) to obtain 7.76g of compound 8, yield 79%.

¹H-NMR(CDCl₃，300MHz)：δ7.23(d，J＝8.4Hz，1H，Ar-H)，7.09(d，J＝8.1Hz，1H，Ar-H)，3.96(s，3H，OCH₃)，3.79(s，3H，OCH₃)，2.26(s，3H，CH₃).MS(ESI)：259.0，261.1(M+H)⁺.¹ H-NMR (CDCl₃ , 300MHz): δ7.23(d, J=8.4Hz, 1H, Ar-H), 7.09(d, J=8.1Hz, 1H, Ar-H), 3.96(s, 3H , OCH₃ ), 3.79 (s, 3H, OCH₃ ), 2.26 (s, 3H, CH₃ ). MS (ESI): 259.0, 261.1 (M+H)⁺ .

9.步骤99. Step 9

50mL的三口瓶中加入NBS(501mg，2.81mmol)，偶氮二异丁腈(28mg，0.18mmol)，氩气保护下加入化合物8(228mg，0.88mmol)的CCl₄溶液(10mL)，加热至回流，反应过夜后停止反应，冷却，过滤，浓缩，直接下一步。50ml含有粗品的反应瓶中缓慢滴加浓硫酸(5mL)，室温搅拌，TLC监测至原料消失时停止反应，将反应液倒入冰水(10mL)中，乙酸乙酯(3x20mL)萃取，饱和NaHCO₃(1x20mL)洗，水(1x30mL)洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝40∶1(R_f＝0.17，PE∶EA＝50∶1)得208mg化合物9，收率87％。Add NBS (501mg, 2.81mmol) and azobisisobutyronitrile (28mg, 0.18mmol) into a 50mL three-necked flask, add compound 8 (228mg, 0.88mmol) under the protection of argon CCl₄ solution (10mL), heat to Reflux, stop the reaction after reacting overnight, cool, filter, concentrate, and go directly to the next step. Slowly add concentrated sulfuric acid (5mL) dropwise to a 50ml reaction flask containing the crude product, stir at room temperature, and stop the reaction when the raw material disappears as monitored by TLC. Pour the reaction solution into ice water (10mL), extract with ethyl acetate (3x20mL), and saturate₃ (1x20mL), washed with water (1x30mL), dried over anhydrous Na₂ SO₄ , filtered, concentrated, column chromatography PE:EA=40:1 (R_f =0.17, PE:EA=50:1) yielded 208mg Compound 9, yield 87%.

¹H-NMR(CDCl₃，300MHz)：δ10.30(s，1H，CHO)，7.78-7.74(m，1H，Ar-H)，7.49-7.46(m 1H，Ar-H)，3.99(s，3H，OCH₃)，3.98(s，3H，OCH₃).MS(ESI)：272.9，274.9(M+H)⁺.¹ H-NMR (CDCl₃ , 300MHz): δ10.30(s, 1H, CHO), 7.78-7.74(m, 1H, Ar-H), 7.49-7.46(m 1H, Ar-H), 3.99(s , 3H, OCH₃ ), 3.98 (s, 3H, OCH₃ ). MS (ESI): 272.9, 274.9 (M+H)⁺ .

10.步骤1010. Step 10

100mL单口瓶中加入化合物3(1.12g，3.55mmol)，化合物9(0.808g，2.96mmol)，Cu(0.474g，7.40mmol)，CuO(0.592g，7.40mmol)，DMAP(1.08g，8.88mmol)，氩气保护下加入CH₃CN(25mL)，再加热至回流，反应17h后停止反应，冷却，DCM稀释(20mL)，过滤，浓缩，柱层析PE∶EA＝6∶1(R_f＝0.11，PE∶EA＝10∶1)得1.10g化合物10，收率73％。Add compound 3 (1.12g, 3.55mmol), compound 9 (0.808g, 2.96mmol), Cu (0.474g, 7.40mmol), CuO (0.592g, 7.40mmol), DMAP (1.08g, 8.88mmol) ), added CH₃ CN (25mL) under argon protection, heated to reflux, stopped the reaction after 17h of reaction, cooled, diluted with DCM (20mL), filtered, concentrated, column chromatography PE:EA=6:1 (R_f =0.11, PE:EA=10:1) to obtain 1.10 g of compound 10 with a yield of 73%.

¹H-NMR(CDCl₃，400MHz)：δ10.22(s，1H，CHO)，7.71(d，J＝4.7Hz，1H，Ar-H)，7.27-7.13(m，7H，Ar-H)，6.99(dd，J＝8.1，1.4Hz，1H，Ar-H)，6.43(d，J＝8.8Hz，1H，Ar-H)，5.02(s，2H，CH₂)，4.73(d，J＝12Hz，1H，CH₂)，4.67-4.66(m，1H，CH)，4.48(d，J＝12Hz，1H，CH₂)，3.99(s，3H，OCH₃)，3.94(s，3H，OCH₃)，3.83-3.76(m，1H，CH₂)，3.51-3.45(m，1H，CH₂)，1.65-1.43(m，6H).MS(ESI)：529.2(M+Na)⁺.¹ H-NMR (CDCl₃ , 400MHz): δ10.22 (s, 1H, CHO), 7.71 (d, J=4.7Hz, 1H, Ar-H), 7.27-7.13 (m, 7H, Ar-H) , 6.99(dd, J=8.1, 1.4Hz, 1H, Ar-H), 6.43(d, J=8.8Hz, 1H, Ar-H), 5.02(s, 2H, CH₂ ), 4.73(d, J =12Hz, 1H, CH₂ ), 4.67-4.66(m, 1H, CH), 4.48(d, J=12Hz, 1H, CH₂ ), 3.99(s, 3H, OCH₃ ), 3.94(s, 3H, OCH₃ ), 3.83-3.76 (m, 1H, CH₂ ), 3.51-3.45 (m, 1H, CH₂ ), 1.65-1.43 (m, 6H). MS (ESI): 529.2 (M+Na)⁺ .

11.步骤1111. Step 11

100mL的单口瓶中加入化合物10(1.01g，2mmol)，对甲苯磺酸(2mg)，后加入异丙醇(9mL)和H₂O(2mL)，加热至回流过夜，停止反应，冷却，加入H₂O(10mL)，乙酸乙酯萃取(3x30mL)，有机相水洗(1x30mL)，无水MgSO₄干燥，过滤，浓缩，柱层析PE∶EA＝3∶1(R_f＝0.14，PE∶EA＝3∶1)得720mg化合物11，收率88％。Add compound 10 (1.01g, 2mmol) and p-toluenesulfonic acid (2mg) into a 100mL single-necked bottle, then add isopropanol (9mL) and H₂ O (2mL), heat to reflux overnight, stop the reaction, cool, add H₂ O (10 mL), extracted with ethyl acetate (3x30 mL), washed the organic phase with water (1x30 mL), dried over anhydrous MgSO₄ , filtered, concentrated, column chromatography PE:EA=3:1 (R_f =0.14, PE: EA=3:1) to obtain 720mg of compound 11, the yield was 88%.

¹H-NMR(CDCl₃，400MHz)：δ10.20(s，1H，CHO)，7.73(d，J＝8.6Hz，1H，Ar-H)，7.26-7.14(m，6H，Ar-H)，7.07(d，J＝7.2Hz，1H，Ar-H)，6.99(d，J＝8.4Hz，1H，Ar-H)，6.43(d，J＝9.0Hz，1H，Ar-H)，5.02(s，2H，CH₂)，4.60(s，2H，CH₂)，3.98(s，3H，OCH₃)，3.94(s，3H，OCH₃)，2.74(br s，1H，OH).¹³C-NMR(CDCl₃，100MHz)：δ187.7，165.5，161.9，160.7，150.5，140.2，136.3，135.3，131.6，128.3(2C)，127.8，126.8(2C)，126.7，123.4，121.3，117.5，114.0，110.0，70.5，64.7，60.5，52.9.MS(EI)：422.HRMS(ESI)：Calcd.for C₂₄H₂₂O₇Na⁺(M+Na)⁺：445.1263，found：445.1262.¹ H-NMR (CDCl₃ , 400MHz): δ10.20 (s, 1H, CHO), 7.73 (d, J=8.6Hz, 1H, Ar-H), 7.26-7.14 (m, 6H, Ar-H) , 7.07(d, J=7.2Hz, 1H, Ar-H), 6.99(d, J=8.4Hz, 1H, Ar-H), 6.43(d, J=9.0Hz, 1H, Ar-H), 5.02 (s, 2H,_CH2 ), 4.60 (s, 2H,_CH2 ), 3.98 (s, 3H,_OCH3 ), 3.94 (s, 3H,_OCH3 ), 2.74 (brs, 1H, OH).¹³ C-NMR (CDCl₃ , 100MHz): δ187.7, 165.5, 161.9, 160.7, 150.5, 140.2, 136.3, 135.3, 131.6, 128.3(2C), 127.8, 126.8(2C), 126.7, 123.4, 121.3, 117.5, 114.0, 110.0, 70.5, 64.7, 60.5, 52.9. MS (EI): 422. HRMS (ESI): Calcd. for C₂₄ H₂₂ O₇ Na⁺ (M+Na)⁺ : 445.1263, found: 445.1262.

12.步骤1212. Step 12

100mL的单口瓶中加入化合物11(655mg，1.55mmol)，用MeOH溶解(10mL)，加入对甲苯磺酸(55mg，0.32mmol)，室温搅拌1h后，加入NaOH(722mg，18.5mmol)，加热至回流，反应过夜。停止反应，冷却，减压浓缩除去MeOH，用3N HCl调pH值至4，乙酸乙酯萃取(4x30mL)，无水Na₂SO₄干燥，过滤，浓缩，得653mg化合物12粗品。Compound 11 (655mg, 1.55mmol) was added to a 100mL single-necked bottle, dissolved in MeOH (10mL), p-toluenesulfonic acid (55mg, 0.32mmol) was added, stirred at room temperature for 1h, NaOH (722mg, 18.5mmol) was added, and heated to Reflux and react overnight. The reaction was stopped, cooled, concentrated under reduced pressure to remove MeOH, adjusted to pH 4 with 3N HCl, extracted with ethyl acetate (4x30 mL), dried over anhydrous Na₂ SO₄ , filtered, and concentrated to obtain 653 mg of crude compound 12.

MS(ESI)：407.0(M-H)^-.MS(ESI): 407.0(MH)^- .

13.步骤1313. Step 13

将化合物12的粗品(568mg，1.39mmol)和三乙胺(1.55mL，11.1mmol)溶于干燥的CH₃CN(10mL)中，将上述制得的溶液室温下缓慢滴加到由碘化-2-氯-1-甲基吡啶(1.42g，5.57mmol)溶于干燥的CH₃CN(40mL)所配置的溶液中。滴加完毕后，加热回流反应1h。后停止反应，冷却，减压浓缩除去CH₃CN，加入H₂O(20mL)，DCM萃取(3x30mL)，无水Na₂SO₄干燥，过滤，浓缩，柱层析DCM(R_f＝0.67，PE∶EA＝2∶1)得261mg化合物13，两步合计收率55％。The crude compound 12 (568mg, 1.39mmol) and triethylamine (1.55mL, 11.1mmol) were dissolved in dry CH₃ CN (10mL), and the solution prepared above was slowly added dropwise at room temperature to the iodide- 2-Chloro-1-picoline (1.42 g, 5.57 mmol) was dissolved in dry_CH3CN (40 mL). After the dropwise addition was completed, the reaction was heated to reflux for 1 h. After the reaction was stopped, cooled, concentrated under reduced pressure to remove CH₃ CN, added H₂ O (20 mL), extracted with DCM (3x30 mL), dried over anhydrous Na₂ SO₄ , filtered, concentrated, column chromatography DCM (R_f =0.67, PE:EA=2:1) to obtain 261 mg of compound 13, the total yield of the two steps was 55%.

¹H-NMR(CDCl₃，400MHz)：δ10.35(s，1H，CHO)，7.99(d，J＝8.6Hz，1H，Ar-H)，7.50-7.34(m，5H，Ar-H)，7.08-7.01(m，3H，Ar-H)，6.67(d，J＝7.1Hz，1H，Ar-H)，5.22(s，2H，CH₂)，5.18(s，2H，CH₂)，4.12(s，3H，OCH₃).¹³C-NMR(CDCl₃，100MHz)：δ187.7，166.0，161.2，157.6，150.7，145.2，136.4，133.3，128.7(2C)，128.1，127.8，127.2(2C)，127.1，125.2，121.1，120.5，118.7，115.9，71.2，68.9，64.6.MS(ESI)：391.2(M+H)⁺.HRMS(ESI)：Calcd.for C₂₃H₁₈O₆Na⁺(M+Na)⁺：413.1001，found：413.0987.¹ H-NMR (CDCl₃ , 400MHz): δ10.35 (s, 1H, CHO), 7.99 (d, J=8.6Hz, 1H, Ar-H), 7.50-7.34 (m, 5H, Ar-H) , 7.08-7.01 (m, 3H, Ar-H), 6.67 (d, J=7.1Hz, 1H, Ar-H), 5.22 (s, 2H, CH₂ ), 5.18 (s, 2H, CH₂ ),_{(_}^_ 2C), 127.1, 125.2, 121.1, 120.5, 118.7, 115.9, 71.2, 68.9, 64.6. MS (ESI): 391.2 (M+H)⁺ .HRMS (ESI): Calcd.for C₂₃ H₁₈ O₆ Na⁺ (M+Na)⁺ : 413.1001, found: 413.0987.

14.步骤1414. Step 14

新戊基溴化镁的制备：50mL两口瓶中加入Mg(1.045g，43.53mmol)和一粒碘，氩气保护下加入干燥的乙醚溶液(5mL)，加入溴代新戊烷(5mL)的乙醚溶液(1mL)，待反应引发后，加入剩余的溴代新戊烷的乙醚溶液(10mL)，34℃反应12h。后定容后冷却备用。Preparation of neopentylmagnesium bromide: Add Mg (1.045g, 43.53mmol) and a grain of iodine to a 50mL two-necked bottle, add dry ether solution (5mL) under argon protection, add bromoneopentane (5mL) Diethyl ether solution (1 mL), after the reaction was initiated, the remaining diethyl ether solution (10 mL) of bromoneopentane was added, and reacted at 34°C for 12 h. After constant volume, cool for later use.

100mL单口瓶中加入化合物13(136mg，0.35mmol)，氩气保护下，加入干燥的THF(10mL)，冰浴下滴加新戊基溴化镁(0.53mL，1.40mmol)，后自然升温至室温搅拌1h，加入饱和NH₄Cl淬灭反应，乙酸乙酯萃取(3x30mL)，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝5∶1(R_f＝0.38，PE∶EA＝3∶1)得146mg化合物14，收率90％。Compound 13 (136mg, 0.35mmol) was added to a 100mL single-necked bottle, under the protection of argon, dry THF (10mL) was added, and neopentylmagnesium bromide (0.53mL, 1.40mmol) was added dropwise in an ice bath, and then the temperature was naturally raised to Stir at room temperature for 1 h, add saturated NH₄ Cl to quench the reaction, extract with ethyl acetate (3x30 mL), dry over anhydrous Na₂ SO₄ , filter, concentrate, column chromatography PE:EA=5:1 (R_f =0.38, PE :EA=3:1) to obtain 146mg of compound 14, the yield was 90%.

¹H-NMR(CDCl₃，400MHz)：δ7.59(d，J＝8.6Hz，1H，Ar-H)，7.51-7.48(m，2H，Ar-H)，7.42-7.33(m，3H，Ar-H)，7.05-6.95(m，3H，Ar-H)，6.65(d，J＝7.3Hz，1H，Ar-H)，5.22(s，2H，CH₂)，5.19-5.16(m，1H，CH)，5.14(s，2H，CH₂)，3.98(s，3H，OCH₃)，1.87(d，J＝4.8Hz，1H，OH)，1.69-1.59(m，2H，CH₂)，1.03(s，9H，t-Bu-H).¹³C-NMR(CDCl₃，100MHz)：δ167.3，154.1，152.0，150.6，146.3，137.6，136.7，131.0，128.6(2C)，128.0，127.8，127.2(2C)，124.5，121.3，119.4，118.0，116.0，71.4，69.0，66.5，62.7，52.2，30.7，30.1(3C).MS(ESI)：463.1(M+H)⁺.HRMS(ESI)：Calcd.forC₂₈H₂₉O₆^-(M-H)^-：461.1964，found：461.1966.¹ H-NMR (CDCl₃ , 400MHz): δ7.59 (d, J=8.6Hz, 1H, Ar-H), 7.51-7.48 (m, 2H, Ar-H), 7.42-7.33 (m, 3H, Ar-H), 7.05-6.95(m, 3H, Ar-H), 6.65(d, J=7.3Hz, 1H, Ar-H), 5.22(s, 2H, CH₂ ), 5.19-5.16(m, 1H, CH), 5.14 (s, 2H, CH₂ ), 3.98 (s, 3H, OCH₃ ), 1.87 (d, J=4.8Hz, 1H, OH), 1.69-1.59 (m, 2H, CH₂ ) , 1.03(s, 9H, t-Bu-H).¹³ C-NMR (CDCl₃ , 100MHz): δ167.3, 154.1, 152.0, 150.6, 146.3, 137.6, 136.7, 131.0, 128.6(2C), 128.0, 127.8, 127.2(2C), 124.5, 121.3, 119.4, 118.0, 116.0, 71.4, 69.0, 66.5, 62.7, 52.2, 30.7, 30.1(3C).MS(ESI): 463.1(M+H)⁺ .HRMS(ESI ): Calcd.for C₂₈ H₂₉ O₆^- (MH)^- : 461.1964, found: 461.1966.

15.步骤1515. Step 15

50mL单口瓶中加入化合物14(296mg，0.64mmol)，DMSO溶解(10mL)后，加入IBX(358mg，1.28mmol)，室温搅拌过夜，停止反应，加入H₂O(100mL)，DCM萃取(4x40mL)，水洗(1x50mL)，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝4∶1(R_f＝0.51，PE∶EA＝3∶1)得283mg化合物15，收率96％。Add compound 14 (296mg, 0.64mmol) to a 50mL single-necked bottle, after DMSO dissolved (10mL), add IBX (358mg, 1.28mmol), stir at room temperature overnight, stop the reaction, add H₂ O (100mL), DCM extraction (4x40mL) , washed with water (1x50mL), dried over anhydrous Na₂ SO₄ , filtered, concentrated, column chromatography PE:EA=4:1 (R_f =0.51, PE:EA=3:1) gave 283mg of compound 15, yield 96 %.

¹H-NMR(CDCl₃，400MHz)：δ7.60(d，J＝8.6Hz，1H，Ar-H)，7.50-7.48(m，2H，Ar-H)，7.43-7.34(m，3H，Ar-H)，7.06-6.99(m，3H，Ar-H)，6.67(d，J＝7.2Hz，1H，Ar-H)，5.22(s，2H，CH₂)，5.16(s，2H，CH₂)，3.96(s，3H，OCH₃)，2.91(s，2H，CH₂)，1.01(s，9H，t-Bu-H).¹³C-NMR(CDCl₃，100MHz)：δ202.2，166.3，156.5，154.9，150.7，145.7，136.5，133.8，133.7，128.7(2C)，128.1，127.8，127.2(2C)，124.9，121.3，120.8，118.5，116.0，71.3，68.9，63.8，54.8，31.6(3C)，29.8.MS(ESI)：461.0(M+H)⁺.HRMS(ESI)：Calcd.for C₂₈H₂₈O₆Na⁺(M+Na)⁺：483.1784，found：483.1777.¹ H-NMR (CDCl₃ , 400MHz): δ7.60 (d, J=8.6Hz, 1H, Ar-H), 7.50-7.48 (m, 2H, Ar-H), 7.43-7.34 (m, 3H, Ar-H), 7.06-6.99 (m, 3H, Ar-H), 6.67 (d, J=7.2Hz, 1H, Ar-H), 5.22 (s, 2H, CH₂ ), 5.16 (s, 2H, CH₂ ), 3.96(s, 3H, OCH₃ ), 2.91(s, 2H, CH₂ ), 1.01(s, 9H, t-Bu-H).¹³ C-NMR(CDCl₃ , 100MHz): δ202. 2, 166.3, 156.5, 154.9, 150.7, 145.7, 136.5, 133.8, 133.7, 128.7(2C), 128.1, 127.8, 127.2(2C), 124.9, 121.3, 120.8, 118.5, 116.0, 71.3, 68.9, 63.8 31.6 (3C), 29.8. MS (ESI): 461.0 (M+H)^{+ .} HRMS (ESI): Calcd. for_C28H28O6Na⁺ (M+Na)⁺ :_483.1784 , found:_483.1777 .

16.步骤1616. Step 16

50mL单口瓶中，氩气保护下加入(R)-Me-CBS(153μL，0.153mmol)，减压除去其中的甲苯，再加入THF(7.7mL)。降温至-20℃，加入BH₃·THF(0.66mL，0.66mmol，1M in THF)，后缓慢滴加化合物15(237mg，0.51mmol)的THF溶液(7.7mL)，3h滴加完毕。-20℃反应4h后停止反应，加入H₂O(3mL)淬灭反应，乙酸乙酯萃取(3x15mL)，有机相水洗(1x20mL)，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝5∶1得225mg化合物16，收率95％，ee值86％。(手性柱拆分条件：PC-2柱，UV 214nm，正己烷∶异丙醇＝50∶50，0.5mL/min)In a 50 mL single-necked flask, (R)-Me-CBS (153 μL, 0.153 mmol) was added under argon protection, toluene was removed under reduced pressure, and THF (7.7 mL) was added. Cool down to -20°C, add BH₃ ·THF (0.66mL, 0.66mmol, 1M in THF), and then slowly add a THF solution (7.7mL) of compound 15 (237mg, 0.51mmol) dropwise for 3h. Stop the reaction after reacting at -20°C for 4h, add H₂ O (3mL) to quench the reaction, extract with ethyl acetate (3x15mL), wash the organic phase with water (1x20mL), dry over anhydrous Na₂ SO₄ , filter, concentrate, and column chromatography PE:EA=5:1 yielded 225 mg of compound 16 with a yield of 95% and an ee value of 86%. (Chiral column resolution conditions: PC-2 column, UV 214nm, n-hexane:isopropanol=50:50, 0.5mL/min)

[α]_D²⁰＝+36°(C＝0.1，CHCl₃).[α]_D²⁰ =+36° (C=0.1, CHCl₃ ).

17.步骤1717. Step 17

50mL单口瓶中加入化合物16(42mg，0.09mmol)，用EtOH(3mL)和EA(7mL)的混合溶液溶解后加入钯碳(4mg)，通入H₂，TLC监测至原料消失，过滤，浓缩，柱层析PE∶EA＝3∶1(R_f＝0.47，PE∶EA＝2∶1)得29mg化合物17，收率85％。Add compound 16 (42mg, 0.09mmol) to a 50mL single-necked bottle, dissolve it with a mixed solution of EtOH (3mL) and EA (7mL), add palladium carbon (4mg), feed H₂ , monitor by TLC until the raw material disappears, filter, and concentrate , column chromatography PE: EA = 3: 1 (R_f = 0.47, PE: EA = 2: 1) yielded 29 mg of compound 17 with a yield of 85%.

¹H-NMR(CDCl₃，400MHz)：δ7.53(d，J＝8.7Hz，1H，Ar-H)，7.03(d，J＝7.9Hz，1H，Ar-H)，6.97-6.93(m，1H，Ar-H)，6.83(d，J＝8.7Hz，1H，Ar-H)，6.82(s，1H，OH)，6.54(d，J＝7.5Hz，1H，Ar-H)，5.15-5.12(m，3H)，3.97(s，3H，OCH₃)，2.28(br s，1H，OH)，1.64-1.51(m，2H，CH₂)，1.01(s，9H，t-Bu-H).¹³C-NMR(CDCl₃，100MHz)：δ167.8，153.7，150.8，147.9，143.4，138.1，130.9，126.1，124.9，120.2，119.2，117.6，117.3，69.1，66.4，62.4，52.3，30.7，30.0(3C).MS(ESI)：373.0(M+H)⁺.HRMS(ESI)：Calcd.for C₂₁H₂₄O₆Na⁺(M+Na)⁺：395.1471，found：395.1462，[α]_D²⁰＝+23°(C＝0.1，CHCl₃).¹ H-NMR (CDCl₃ , 400MHz): δ7.53(d, J=8.7Hz, 1H, Ar-H), 7.03(d, J=7.9Hz, 1H, Ar-H), 6.97-6.93(m , 1H, Ar-H), 6.83(d, J=8.7Hz, 1H, Ar-H), 6.82(s, 1H, OH), 6.54(d, J=7.5Hz, 1H, Ar-H), 5.15 -5.12(m, 3H), 3.97(s, 3H, OCH₃ ), 2.28(br s, 1H, OH), 1.64-1.51(m, 2H, CH₂ ), 1.01(s, 9H, t-Bu- H).¹³ C-NMR (CDCl₃ , 100MHz): δ167.8, 153.7, 150.8, 147.9, 143.4, 138.1, 130.9, 126.1, 124.9, 120.2, 119.2, 117.6, 117.3, 69.1, 66.4, 62.4, 52.3,_[^__{__}^__ α]_D²⁰ =+23° (C=0.1, CHCl₃ ).

18.步骤1818. Step 18

25mL单口瓶中加入化合物a(500mg，3.24mmol)和干燥的二氯甲烷(4mL)，0℃下后加入1滴DMF，再滴加草酰氯(0.34mL，3.9mmol)，气体不再产生后，在室温下继续搅拌30分钟，再减压浓缩得酰氯b，用干燥的THF定容，直接参与下步反应。Add compound a (500mg, 3.24mmol) and dry dichloromethane (4mL) into a 25mL single-necked bottle, then add 1 drop of DMF at 0°C, then add oxalyl chloride (0.34mL, 3.9mmol) dropwise, after the gas is no longer generated , continue to stir at room temperature for 30 minutes, then concentrate under reduced pressure to obtain the acid chloride b, dilute to volume with dry THF, and directly participate in the next reaction.

25mL单口瓶中加入化合物17(29mg，0.078mmol)和干燥的THF(2mL)，后加入NaH(3.4mg，0.086mmol)，室温搅拌1h，后缓慢滴加酰氯b(17mg，0.10mmol)的THF(2mL)溶液，过夜后停止反应，直接板层析PE∶EA＝3∶1(R_f＝0.42，PE∶EA＝3∶1)得23mg化合物18，收率58％。Add compound 17 (29mg, 0.078mmol) and dry THF (2mL) into a 25mL single-necked bottle, then add NaH (3.4mg, 0.086mmol), stir at room temperature for 1h, then slowly add acid chloride b (17mg, 0.10mmol) in THF (2 mL) solution, stopped the reaction after overnight, direct plate chromatography PE:EA=3:1 (R_f =0.42, PE:EA=3:1) gave 23 mg of compound 18, yield 58%.

¹H-NMR(CDCl₃，400MHz)：δ7.61(d，J＝8.2Hz，1H，Ar-H)，7.09-7.07(m，2H，Ar-H)，7.00(d，J＝8.6Hz，1H，Ar-H)，6.96-6.92(m，1H，Ar-H)，5.18-5.11(m，3H)，3.98(s，3H，OCH₃)，2.33(s，2H)，1.97-1.84(m，5H)，1.70-1.55(m，2H，CH₂)，1.45(s，3H，CH₃)，1.34-1.32(m，4H)，1.03(s，9H，t-Bu-H).¹³C-NMR(CDCl₃，100MHz)：δ175.3，167.1，153.9，151.2，148.4，142.3，138.3，131.1，127.6，127.2，124.5，124.2，119.6，118.3，69.1，66.4，63.0，58.6，52.3，42.0，30.7，30.1，29.4，27.8，17.1.HRMS(APCI)：Calcd.for C₃₀H₃₅O₇^-(M-H)^-：507.2383，found：507.2375，[α]_D²⁰＝+10.8°(C＝1.0，CHCl₃).¹ H-NMR (CDCl₃ , 400MHz): δ7.61 (d, J=8.2Hz, 1H, Ar-H), 7.09-7.07 (m, 2H, Ar-H), 7.00 (d, J=8.6Hz , 1H, Ar-H), 6.96-6.92(m, 1H, Ar-H), 5.18-5.11(m, 3H), 3.98(s, 3H, OCH₃ ), 2.33(s, 2H), 1.97-1.84 (m, 5H), 1.70-1.55 (m, 2H, CH₂ ), 1.45 (s, 3H, CH₃ ), 1.34-1.32 (m, 4H), 1.03 (s, 9H, t-Bu-H).¹³ C-NMR (CDCl₃ , 100MHz): δ175.3, 167.1, 153.9, 151.2, 148.4, 142.3, 138.3, 131.1, 127.6, 127.2, 124.5, 124.2, 119.6, 118.3, 69.1, 66.4, 63.0, 53.6, 52_{.__}^___{_}^_ = 1.0, CHCl₃ ).

实施例2：制备下述化合物，Embodiment 2: prepare following compound,

1.步骤11. Step 1

250mL单口瓶中加入实施例1步骤1所得化合物1(4.00g，17.5mmol)，加入乙腈(90mL)溶解后，再依次加入醋酸铵(137mg，1.75mmol)，NBS(3.28g，18.4mmol)，室温下反应4h。减压浓缩除去乙腈，加水(100mL)稀释，乙酸乙酯(100mL)萃取，有机相无水MgSO₄干燥，过滤，浓缩，柱层析PE∶EA＝20∶1(R_f＝0.35，PE∶DCM＝2∶1)，得4.59g化合物19，收率85％。Compound 1 (4.00g, 17.5mmol) obtained in step 1 of Example 1 was added to a 250mL one-mouth bottle, and after adding acetonitrile (90mL) to dissolve, ammonium acetate (137mg, 1.75mmol) and NBS (3.28g, 18.4mmol) were added in sequence, Reaction at room temperature for 4h. Concentrate under reduced pressure to remove acetonitrile, dilute with water (100 mL), extract with ethyl acetate (100 mL), dry the organic phase over anhydrous MgSO₄ , filter, concentrate, column chromatography PE:EA=20:1 (R_f =0.35, PE: DCM=2:1), to obtain 4.59 g of compound 19, with a yield of 85%.

¹H-NMR(CDCl₃，400MHz)：δ10.96(s，1H，OH)，9.86(s，1H，CHO)，7.46-7.35(m，5H，Ar-H)，7.33(d，J＝2.4Hz，1H，Ar-H)，7.23(d，J＝2.0Hz，1H，Ar-H)，5.16(s，2H，CH₂).MS(ESI)：329.0，331.1(M+Na)⁺.¹ H-NMR (CDCl₃ , 400MHz): δ10.96(s, 1H, OH), 9.86(s, 1H, CHO), 7.46-7.35(m, 5H, Ar-H), 7.33(d, J= 2.4Hz, 1H, Ar-H), 7.23(d, J=2.0Hz, 1H, Ar-H), 5.16(s, 2H,_CH2 ). MS(ESI): 329.0, 331.1(M+Na)⁺ .

2.步骤22. Step 2

50mL单口瓶中加入化合物19(307mg，1mmol)，加入DMF(1mL)溶解后，再加入N，N-二异丙基乙胺(258mg，2mmol)，10min后加入叔丁基二甲基氯硅烷(301mg，2mmol)，室温下反应1h。加水(50mL)淬灭反应，乙酸乙酯(3x50mL)萃取，合并有机相后，水洗，饱和食盐水洗，无水MgSO₄干燥，过滤，浓缩，柱层析PE∶EA＝100∶1(R_f＝0.78，PE∶EA＝15∶1)，得401mg化合物20，收率95％。Add compound 19 (307mg, 1mmol) to a 50mL single-necked bottle, add DMF (1mL) to dissolve, then add N,N-diisopropylethylamine (258mg, 2mmol), and add tert-butyldimethylsilyl chloride after 10min (301mg, 2mmol), react at room temperature for 1h. Add water (50mL) to quench the reaction, extract with ethyl acetate (3x50mL), combine the organic phases, wash with water, wash with saturated brine, dry over anhydrous MgSO₄ , filter, concentrate, column chromatography PE:EA=100:1(R_f =0.78, PE:EA=15:1), to obtain 401mg of compound 20, yield 95%.

¹H-NMR(CDCl₃，400MHz)：δ10.40(s，1H，CHO)，7.52(d，J＝2.4Hz，1H，Ar-H)，7.42-7.41(m，5H，Ar-H)，7.21(d，J＝2.4Hz，1H，Ar-H)，5.03(s，2H，CH₂)，0.92(s，9H，t-Bu-H)，0.07(s，6H，CH₃).¹³C-NMR(CDCl₃，100MHz)：δ188.7，151.3，148.5，135.0，128.9，128.7(2C)，128.4(2C)，121.9，121.1，113.7，71.4，25.7(3C)，18.7，-4.3(2C).MS(ESI)：421.1，423.1(M+H)⁺.¹ H-NMR (CDCl₃ , 400MHz): δ10.40 (s, 1H, CHO), 7.52 (d, J=2.4Hz, 1H, Ar-H), 7.42-7.41 (m, 5H, Ar-H) , 7.21 (d, J=2.4Hz, 1H, Ar-H), 5.03 (s, 2H, CH₂ ), 0.92 (s, 9H, t-Bu-H), 0.07 (s, 6H, CH₃ ).¹³ C-NMR (CDCl₃ , 100MHz): δ188.7, 151.3, 148.5, 135.0, 128.9, 128.7(2C), 128.4(2C), 121.9, 121.1, 113.7, 71.4, 25.7(3C), 18.7, -4.3 (2C). MS (ESI): 421.1, 423.1 (M+H)⁺ .

3.步骤33. Step 3

50mL两口瓶回流装置中，氩气保护下加入化合物20(2.21mg，5.24mmol)，Pd(dppf)Cl₂(58mg，0.08mmol)，无水1，4-二氧六环(15mL)，二甲基锌(5.2mL，6.29mmol，1.2m/L)后，加热回流(110℃)，反应1h。1N盐酸(50mL)淬灭反应，乙酸乙酯(2x50mL)萃取，合并有机相后，水洗，饱和食盐水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝40∶1(R_f＝0.57，PE∶EA＝15∶1)，得1.53g化合物21，收率82％。In the reflux device of a 50mL two-necked flask, compound 20 (2.21mg, 5.24mmol), Pd(dppf)Cl₂ (58mg, 0.08mmol), anhydrous 1,4-dioxane (15mL), and dioxane were added under argon protection. After methylzinc (5.2mL, 6.29mmol, 1.2m/L), heat to reflux (110°C) and react for 1h. Quench the reaction with 1N hydrochloric acid (50 mL), extract with ethyl acetate (2x50 mL), combine the organic phases, wash with water, wash with saturated brine, dry over anhydrous Na₂ SO₄ , filter, concentrate, column chromatography PE:EA=40:1 (R_f =0.57, PE:EA=15:1), 1.53 g of compound 21 was obtained, with a yield of 82%.

¹H-NMR(CDCl₃，400MHz)：δ10.46(s，1H，CHO)，7.44-7.35(m，5H，Ar-H)，7.21(d，J＝1.2Hz，1H，Ar-H)，6.94(d，J＝2.0Hz，1H，Ar-H)，5.05(s，2H，CH₂)，2.28(s，3H，CH₃)，0.94(s，9H，t-Bu-H)，0.08(s，6H，CH₃).¹³C-NMR(CDCl₃，100MHz)：δ190.5，150.1，147.1，136.0，130.9，128.5(2C)，128.3，128.2(2C)，127.7，119.7，119.2，71.0，25.8(3C)，20.9，18.8，-4.3(2C).MS(ESI)：357.2(M+H)⁺.¹ H-NMR (CDCl₃ , 400MHz): δ10.46 (s, 1H, CHO), 7.44-7.35 (m, 5H, Ar-H), 7.21 (d, J=1.2Hz, 1H, Ar-H) , 6.94 (d, J=2.0Hz, 1H, Ar-H), 5.05 (s, 2H, CH₂ ), 2.28 (s, 3H, CH₃ ), 0.94 (s, 9H, t-Bu-H), 0.08(s, 6H, CH₃ ).¹³ C-NMR (CDCl₃ , 100MHz): δ190.5, 150.1, 147.1, 136.0, 130.9, 128.5(2C), 128.3, 128.2(2C), 127.7, 119.7, 119.2 , 71.0, 25.8(3C), 20.9, 18.8, -4.3(2C). MS(ESI): 357.2(M+H)⁺ .

4.步骤44. Step 4

50mL单口瓶中加入化合物21(891mg，2.50mmol)，加入甲醇(25mL)，冰浴下加入NaBH₄(378mg，10.0mmol)，再在室温下反应4h。减压浓缩，将得到的白色固体溶于3N盐酸(50mL)，二氯甲烷(3x50mL)萃取，合并有机相，水(3x50mL)洗，饱和食盐水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝10∶1(R_f＝0.41，PE∶EA＝10∶1)，得812mg化合物22，收率91％。Compound 21 (891mg, 2.50mmol) was added to a 50mL single-necked bottle, methanol (25mL) was added, NaBH₄ (378mg, 10.0mmol) was added under ice-cooling, and the reaction was continued at room temperature for 4h. Concentrate under reduced pressure, dissolve the resulting white solid in 3N hydrochloric acid (50mL), extract with dichloromethane (3x50mL), combine the organic phases, wash with water (3x50mL), wash with saturated brine, dry over anhydrous Na₂ SO₄ , filter, and concentrate , column chromatography PE: EA = 10: 1 (R_f = 0.41, PE: EA = 10: 1), to obtain 812 mg of compound 22 with a yield of 91%.

¹H-NMR(CDCl₃，400MHz)：δ7.42-7.30(m，5H，Ar-H)，6.75(s，1H，Ar-H)，6.68(s，1H，Ar-H)，5.02(s，2H，CH₂)，4.67(s，2H，CH₂)，2.26(s，3H，CH₃)，2.23(s，1H，OH)，0.94(s，9H，t-Bu-H)，0.06(s，6H，CH₃).¹³C-NMR(CDCl₃，100MHz)：δ148.9，140.1，136.5，132.0，130.7，128.4(2C)，128.2(2C)，128.0，121.0，113.1，70.6，61.7，25.9(3C)，21.0，18.6，-4.0(2C).MS(ESI)：381.2(M+Na)⁺.¹ H-NMR (CDCl₃ , 400MHz): δ7.42-7.30 (m, 5H, Ar-H), 6.75 (s, 1H, Ar-H), 6.68 (s, 1H, Ar-H), 5.02( s, 2H, CH₂ ), 4.67 (s, 2H, CH₂ ), 2.26 (s, 3H, CH₃ ), 2.23 (s, 1H, OH), 0.94 (s, 9H, t-Bu-H), 0.06(s, 6H, CH₃ ).¹³ C-NMR (CDCl₃ , 100MHz): δ148.9, 140.1, 136.5, 132.0, 130.7, 128.4(2C), 128.2(2C), 128.0, 121.0, 113.1, 70.6 , 61.7, 25.9 (3C), 21.0, 18.6, -4.0 (2C). MS (ESI): 381.2 (M+Na)⁺ .

5.步骤55. Step 5

25mL单口瓶中加入化合物22(323mg，0.90mmol)，加入四氢呋喃(9mL)，冰浴下加入四丁基氟化铵(471mg，1.80mmol)，后室温下反应0.5h。加水(20mL)稀释，乙酸乙酯(3x20mL)萃取，合并有机相，水洗，饱和食盐水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝4∶1(R_f＝0.26，PE∶EA＝4∶1)，得206mg化合物23，收率94％。Compound 22 (323mg, 0.90mmol) was added to a 25mL single-necked bottle, tetrahydrofuran (9mL) was added, tetrabutylammonium fluoride (471mg, 1.80mmol) was added under ice-cooling, and then reacted at room temperature for 0.5h. Dilute with water (20 mL), extract with ethyl acetate (3x20 mL), combine the organic phases, wash with water, wash with saturated brine, dry over anhydrous Na₂ SO₄ , filter, concentrate, column chromatography PE:EA=4:1 (R_f = 0.26, PE:EA=4:1), to obtain 206mg of compound 23, yield 94%.

¹H-NMR(CDCl₃，400MHz)：δ7.43-7.37(m，5H，Ar-H)，6.73(s，1H，Ar-H)，6.70(s，1H，Ar-H)，5.91(s，1H，OH)，5.09(s，2H，CH₂)，4.70(s，2H，CH₂)，2.36(s，1H，OH)，2.28(s，3H，CH₃).¹³C-NMR(CDCl₃，100MHz)：δ145.4，141.5，136.3，129.2，128.7(2C)，128.3，127.8(2C)，126.3，121.5，112.6，71.1，61.8，21.0.MS(ESI)：267.1(M+Na)⁺.¹ H-NMR (CDCl₃ , 400MHz): δ7.43-7.37(m, 5H, Ar-H), 6.73(s, 1H, Ar-H), 6.70(s, 1H, Ar-H), 5.91( s, 1H, OH), 5.09 (s, 2H, CH₂ ), 4.70 (s, 2H, CH₂ ), 2.36 (s, 1H, OH), 2.28 (s, 3H, CH₃ ).¹³ C-NMR (CDCl₃ , 100MHz): δ145.4, 141.5, 136.3, 129.2, 128.7(2C), 128.3, 127.8(2C), 126.3, 121.5, 112.6, 71.1, 61.8, 21.0. MS(ESI): 267.1(M+ Na)⁺ .

6.步骤66. Step 6

50mL单口瓶中加入化合物23(892mg，3.66mmol)，后用干燥的二氯甲烷(20mL)溶解，再加入对甲苯磺酸(70mg，0.37mmol)，冰盐浴中搅拌15min后，滴加3，4-二氢-2H-吡喃(0.35mL，3.84mmol)，反应1h。停止反应，加入三乙胺(1mL)淬灭反应，有机相饱和食盐水(10mL)洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝20∶1(R_f＝0.67，PE∶EA＝4∶1)得1.01g化合物24，收率84％。Compound 23 (892mg, 3.66mmol) was added to a 50mL single-necked bottle, and then dissolved with dry dichloromethane (20mL), then p-toluenesulfonic acid (70mg, 0.37mmol) was added, stirred in an ice-salt bath for 15min, and then added dropwise with 3 , 4-dihydro-2H-pyran (0.35 mL, 3.84 mmol), reacted for 1 h. Stop the reaction, add triethylamine (1 mL) to quench the reaction, wash the organic phase with saturated brine (10 mL), dry over anhydrous Na₂ SO₄ , filter, concentrate, column chromatography PE:EA=20:1 (R_f = 0.67, PE:EA=4:1) to obtain 1.01 g of compound 24 with a yield of 84%.

¹H-NMR(CDCl₃，400MHz)：δ7.44-7.34(m，5H，Ar-H)，6.74(s，1H，Ar-H)，6.71(s，1H，Ar-H)，6.23(s，1H，OH)，5.08(s，2H，CH₂)，4.82(d，J＝12Hz，1H，CH₂)，4.75(t，J＝3.3Hz，1H，CH)，4.58(d，J＝12Hz，1H，CH₂)，4.00-3.94(m，1H，CH₂)，3.59-3.56(m，1H，CH₂)，2.26(s，3H，CH₃)，1.88-1.53(m，6H).MS(ESI)：351.1(M+Na)⁺.¹ H-NMR (CDCl₃ , 400MHz): δ7.44-7.34(m, 5H, Ar-H), 6.74(s, 1H, Ar-H), 6.71(s, 1H, Ar-H), 6.23( s, 1H, OH), 5.08 (s, 2H,_CH2 ), 4.82 (d, J = 12Hz, 1H,_CH2 ), 4.75 (t, J = 3.3Hz, 1H, CH), 4.58 (d, J =12Hz, 1H, CH₂ ), 4.00-3.94 (m, 1H, CH₂ ), 3.59-3.56 (m, 1H, CH₂ ), 2.26 (s, 3H, CH₃ ), 1.88-1.53 (m, 6H ). MS (ESI): 351.1 (M+Na)⁺ .

7.步骤77. Step 7

100mL两口瓶回流装置中，加入实施例1步骤9所得化合物9(1.11g，4.08mmol)，化合物24(1.61g，4.89mmol)，Cu(0.653g，10.2mmol)，CuO(0.816g，10.2mmol)，DMAP(1.49g，12.2mmol)，氩气保护下加入CH₃CN(30mL)后加热至回流，反应12h后停止反应，冷却，DCM稀释(20mL)，过滤，浓缩，柱层析PE∶EA＝6∶1(R_f＝0.09，PE∶EA＝10∶1)得1.27g化合物25，收率60％。In the 100mL two-necked flask reflux device, add compound 9 (1.11g, 4.08mmol) obtained in step 9 of Example 1, compound 24 (1.61g, 4.89mmol), Cu (0.653g, 10.2mmol), CuO (0.816g, 10.2mmol ), DMAP (1.49g, 12.2mmol), added CH₃ CN (30mL) under the protection of argon and heated to reflux, stopped the reaction after 12h of reaction, cooled, diluted with DCM (20mL), filtered, concentrated, column chromatography PE: EA=6:1 (R_f =0.09, PE:EA=10:1) yielded 1.27 g of compound 25, yield 60%.

¹H-NMR(CDCl₃，400MHz)：δ10.22(s，1H，CHO)，7.76(d，J＝8.7Hz，1H，Ar-H)，7.28-7.16(m，5H，Ar-H)，6.94(s，1H，Ar-H)，6.83(s，1H，Ar-H)，6.46(d，J＝9.1Hz，1H，Ar-H)，5.00(s，2H，CH₂)，4.69(d，J＝12Hz，1H，CH₂)，4.68-4.67(m，1H，CH)，4.43(d，J＝12Hz，1H，CH₂)，3.99(s，3H，OCH₃)，3.95(s，3H，OCH₃)，3.83-3.76(m，1H，CH₂)，3.51-3.46(m，1H，CH₂)，2.36(s，3H，CH₃)，1.66-1.41(m，6H).¹³C-NMR(CDCl₃，100MHz)：δ187.7，165.3，161.7，161.5，150.1，138.3，136.5，136.4，132,2，131.0，128.2(2C)，127.6，126.7(2C)，122.9，122.5，117.8，114.9，110.3，98.4，70.4，64.7，64.3，61.8，52.6，30.2，25.3，21.4，19.0.MS(ESI)：543.4(M+Na)⁺.HRMS(ESI)：Calcd.for C₃₀H₃₂O₈Na⁺(M+Na)⁺：543.1995，found：543.1968.¹ H-NMR (CDCl₃ , 400MHz): δ10.22 (s, 1H, CHO), 7.76 (d, J=8.7Hz, 1H, Ar-H), 7.28-7.16 (m, 5H, Ar-H) , 6.94 (s, 1H, Ar-H), 6.83 (s, 1H, Ar-H), 6.46 (d, J=9.1Hz, 1H, Ar-H), 5.00 (s, 2H, CH₂ ), 4.69 (d, J=12Hz, 1H, CH₂ ), 4.68-4.67 (m, 1H, CH), 4.43 (d, J=12Hz, 1H, CH₂ ), 3.99 (s, 3H, OCH₃ ), 3.95 ( s, 3H, OCH₃ ), 3.83-3.76 (m, 1H, CH₂ ), 3.51-3.46 (m, 1H, CH₂ ), 2.36 (s, 3H, CH₃ ), 1.66-1.41 (m, 6H) .¹³ C-NMR (CDCl₃ , 100MHz): δ187.7, 165.3, 161.7, 161.5, 150.1, 138.3, 136.5, 136.4, 132, 2, 131.0, 128.2(2C), 127.6, 126.7(2C), 122.9, 122.5, 117.8, 114.9, 110.3, 98.4, 70.4, 64.7, 64.3, 61.8, 52.6, 30.2, 25.3, 21.4, 19.0. MS(ESI): 543.4(M+Na)⁺ .HRMS(ESI): Calcd.for C₃₀ H₃₂ O₈ Na⁺ (M+Na)⁺ : 543.1995, found: 543.1968.

8.步骤88. Step 8

100mL的单口瓶中加入化合物25(1.23g，2.37mmol)，对甲苯磺酸(3mg)，后加入异丙醇(10mL)和H₂O(3mL)，加热回流过夜，停止反应，冷却，加入H₂O(10mL)，乙酸乙酯萃取(3x30mL)，有机相水洗，饱和食盐水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝3∶1(R_f＝0.20，PE∶EA＝3∶1)得960mg化合物26，收率93％。Add compound 25 (1.23g, 2.37mmol), p-toluenesulfonic acid (3mg) into a 100mL single-necked bottle, then add isopropanol (10mL) and H₂ O (3mL), heat and reflux overnight, stop the reaction, cool, add H₂ O (10 mL), extracted with ethyl acetate (3x30 mL), washed the organic phase with water, washed with saturated brine, dried over anhydrous Na₂ SO₄ , filtered, concentrated, column chromatography PE:EA=3:1 (R_f =0.20 , PE:EA=3:1) to obtain 960 mg of compound 26 with a yield of 93%.

¹H-NMR(CDCl₃，400MHz)：δ10.22(s，1H，CHO)，7.74(d，J＝9.0Hz，1H，Ar-H)，7.29-7.16(m，5H，Ar-H)，6.88(s，1H，Ar-H)，6.83(s，1H，Ar-H)，6.46(d，J＝9.0Hz，1H，Ar-H)，5.02(s，2H，CH₂)，4.56(s，2H，CH₂)，3.40(s，3H，OCH₃)，3.96(s，3H，OCH₃)，2.78(br s，1H，OH)，2.35(s，3H，CH₃).¹³C-NMR(CDCl₃，100MHz)：δ187.7，165.6，161.9，160.9，150.2，138.0，136.8，136.3，134.6，131.6，128.3(2C)，127.7，126.7(2C)，123.3，121.9，117.4，114.7，109.9，70.5，64.7，60.7，52.9，21.4.MS(ESI)：459.3(M+Na)⁺.HRMS(ESI)：Calcd.for C₂₅H₂₄O₇Na⁺(M+Na)⁺：459.1420，found：459.1409.¹ H-NMR (CDCl₃ , 400MHz): δ10.22 (s, 1H, CHO), 7.74 (d, J=9.0Hz, 1H, Ar-H), 7.29-7.16 (m, 5H, Ar-H) , 6.88(s, 1H, Ar-H), 6.83(s, 1H, Ar-H), 6.46(d, J=9.0Hz, 1H, Ar-H), 5.02(s, 2H, CH₂ ), 4.56_{13___}^_ C-NMR (CDCl₃ , 100MHz): δ187.7, 165.6, 161.9, 160.9, 150.2, 138.0, 136.8, 136.3, 134.6, 131.6, 128.3(2C), 127.7, 126.7(2C), 123.3, 121.9, 117.4, 114.7, 109.9, 70.5, 64.7, 60.7, 52.9, 21.4. MS (ESI): 459.3 (M+Na)^{+ .} HRMS (ESI): Calcd. for C₂₅ H₂₄ O₇ Na⁺ (M + Na)⁺ : 459.1420, found: 459.1409.

9.步骤99. Step 9

50mL单口瓶中加入化合物26(912mg，2.09mmol)，用MeOH溶解(12mL)，加入对甲苯磺酸(80mg，0.42mmol)，室温搅拌1h后，加入NaOH(940mg，23.5mmol)，加热至回流，反应过夜。停止反应，冷却，减压浓缩除去MeOH，用3N HCl调pH值至3，乙酸乙酯萃取(4x30mL)，无水Na₂SO₄干燥，过滤，浓缩，得837mg化合物27粗品。Add compound 26 (912mg, 2.09mmol) to a 50mL single-necked bottle, dissolve (12mL) with MeOH, add p-toluenesulfonic acid (80mg, 0.42mmol), stir at room temperature for 1h, add NaOH (940mg, 23.5mmol), and heat to reflux , reacted overnight. The reaction was stopped, cooled, concentrated under reduced pressure to remove MeOH, adjusted to pH 3 with 3N HCl, extracted with ethyl acetate (4x30 mL), dried over anhydrous Na₂ SO₄ , filtered, and concentrated to obtain 837 mg of crude compound 27.

¹H-NMR(DMSO，400MHz)：δ10.11(s，1H，CHO)，7.67(d，J＝8.8Hz，1H，Ar-H)，7.25-7.18(m，5H，Ar-H)，7.03(s，1H，Ar-H)，6.98(s，1H，Ar-H)，6.38(d，J＝8.8Hz，1H，Ar-H)，5.08(s，2H，CH₂)，4.37(s，2H，CH₂)，3.97(s，3H，OCH₃)，2.34(s，3H，CH₃).MS(ESI)：421.0(M-H)^-.¹ H-NMR (DMSO, 400MHz): δ10.11 (s, 1H, CHO), 7.67 (d, J=8.8Hz, 1H, Ar-H), 7.25-7.18 (m, 5H, Ar-H), 7.03(s, 1H, Ar-H), 6.98(s, 1H, Ar-H), 6.38(d, J=8.8Hz, 1H, Ar-H), 5.08(s, 2H,_CH2 ), 4.37( s, 2H, CH₂ ), 3.97 (s, 3H, OCH₃ ), 2.34 (s, 3H, CH₃ ). MS (ESI): 421.0 (MH)^- .

10.步骤1010. Step 10

将化合物27的粗品(837mg，1.98mmol)和三乙胺(2.2mL，15.8mmol)溶于干燥的CH₃CN(20mL)中，将上述制得的溶液室温下缓慢滴加到由碘化-2-氯-1-甲基吡啶(2.02g，7.92mmol)溶于干燥的CH₃CN(20mL)所配置的溶液中。滴加完毕后，加热回流反应过夜。停止反应，冷却，减压浓缩除去CH₃CN，加入H₂O(20mL)，DCM萃取(3x30mL)，无水Na₂SO₄干燥，过滤，浓缩，柱层析DCM(R_f＝0.80，PE∶EA＝2∶1)得407mg化合物28，两步合计收率51％。The crude product of compound 27 (837mg, 1.98mmol) and triethylamine (2.2mL, 15.8mmol) were dissolved in dry CH₃ CN (20mL), and the solution prepared above was slowly added dropwise at room temperature to the iodide- 2-Chloro-1-picoline (2.02 g, 7.92 mmol) was dissolved in dry_CH3CN (20 mL). After the dropwise addition was completed, the reaction was heated to reflux overnight. The reaction was stopped, cooled, concentrated under reduced pressure to remove CH₃ CN, added H₂ O (20 mL), extracted with DCM (3x30 mL), dried over anhydrous Na₂ SO₄ , filtered, concentrated, column chromatography DCM (R_f =0.80, PE :EA=2:1) to obtain 407mg of compound 28, the total yield of the two steps was 51%.

¹H-NMR(CDCl₃，400MHz)：δ10.35(d，J＝0.6Hz，1H，CHO)，7.98(d，J＝8.6Hz，1H，Ar-H)，7.51-7.35(m，5H，Ar-H)，7.03(dd，J＝8.6，0.6Hz，1H，Ar-H)，6.89(d，J＝1.5Hz，1H，Ar-H)，6.48(d，J＝1.2Hz，1H，Ar-H)，5.20(s，2H，CH₂)，5.13(s，2H，CH₂)，4.12(s，3H，OCH₃)，2.28(s，3H，CH₃).¹³C-NMR(CDCl₃，100MHz)：δ187.8，166.1，161.2，158.0，150.4，143.2，136.5，135.3，133.3，128.7(2C)，128.1，127.32，127.27(2C)，127.0，121.5，120.6，118.7，116.6，71.3，69.0，64.7，21.2.MS(ESI)：427.0(M+Na)⁺.HRMS(ESI)：Calcd.for C₂₄H₂₀O₆Na⁺(M+Na)⁺：427.1158，found：427.1133.¹ H-NMR (CDCl₃ , 400MHz): δ10.35 (d, J=0.6Hz, 1H, CHO), 7.98 (d, J=8.6Hz, 1H, Ar-H), 7.51-7.35 (m, 5H , Ar-H), 7.03 (dd, J=8.6, 0.6Hz, 1H, Ar-H), 6.89 (d, J=1.5Hz, 1H, Ar-H), 6.48 (d, J=1.2Hz, 1H , Ar-H), 5.20 (s, 2H, CH₂ ), 5.13 (s, 2H, CH₂ ), 4.12 (s, 3H, OCH₃ ), 2.28 (s, 3H, CH₃ ).¹³ C-NMR (CDCl₃ , 100MHz): δ187.8, 166.1, 161.2, 158.0, 150.4, 143.2, 136.5, 135.3, 133.3, 128.7(2C), 128.1, 127.32, 127.27(2C), 127.0, 121.5, 120.6, 1168.7, , 71.3, 69.0, 64.7, 21.2.MS(ESI): 427.0(M+Na)⁺ .HRMS(ESI): Calcd.for C₂₄ H₂₀ O₆ Na⁺ (M+Na)⁺ : 427.1158, found: 427.1133 .

11.步骤1111. Step 11

25mL单口瓶中加入化合物28(262mg，0.65mmol)，氩气保护下，加入干燥的THF(10mL)，冰浴下滴加新戊基溴化镁(1.5mL，3.9mmol)，后自然升温至室温搅拌1h，加入饱和NH₄Cl淬灭反应，EA萃取(3x30mL)，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝5∶1(R_f＝0.44，PE∶EA＝3∶1)得305mg化合物29，收率98％。Compound 28 (262mg, 0.65mmol) was added to a 25mL single-necked bottle, under the protection of argon, dry THF (10mL) was added, and neopentylmagnesium bromide (1.5mL, 3.9mmol) was added dropwise under ice-cooling, and then the temperature was naturally raised to Stir at room temperature for 1 h, add saturated NH₄ Cl to quench the reaction, extract with EA (3x30 mL), dry over anhydrous Na₂ SO₄ , filter, concentrate, column chromatography PE:EA=5:1 (R_f =0.44, PE:EA =3:1) to obtain 305mg of compound 29, the yield was 98%.

¹H-NMR(CDCl₃，400MHz)：δ7.57(d，J＝8.2Hz，1H，Ar-H)，7.51-7.49(m，2H，Ar-H)，7.42-7.31(m，3H，Ar-H)，6.94(d，J＝7.8Hz，1H，Ar-H)，6.85(s，1H，Ar-H)，6.44(s，1H，Ar-H)，5.19(s，2H，CH₂)，5.18-5.14(m，1H，CH)，5.08(s，2H，CH₂)，3.95(s，3H，OCH₃)，2.25(s，3H，CH₃)，2.12(br s，1H，OH)，1.68-1.53(m，2H，CH₂)，1.02(s，9H，t-Bu-H).¹³C-NMR(CDCl₃，100MHz)：δ167.5，153.9，152.0，150.2，144.0，137.5，136.7，134.4，130.9，128.5(2C)，127.9，127.23，127.16(2C)，121.6，119.3，118.0，116.5，71.2，69.0，66.3，62.5，52.1，30.6，30.0(3C)，21.0.MS(ESI)：477.2(M+H)⁺.HRMS(APCI)：Calcd.for C₂₉H₃₃O₆⁺(M+H)⁺：477.2277，found：477.2278.¹ H-NMR (CDCl₃ , 400MHz): δ7.57 (d, J=8.2Hz, 1H, Ar-H), 7.51-7.49 (m, 2H, Ar-H), 7.42-7.31 (m, 3H, Ar-H), 6.94(d, J=7.8Hz, 1H, Ar-H), 6.85(s, 1H, Ar-H), 6.44(s, 1H, Ar-H), 5.19(s, 2H, CH₂ ), 5.18-5.14(m, 1H, CH), 5.08(s, 2H, CH₂ ), 3.95(s, 3H, OCH₃ ), 2.25(s, 3H, CH₃ ), 2.12(br s, 1H , OH), 1.68-1.53 (m, 2H, CH₂ ), 1.02 (s, 9H, t-Bu-H).¹³ C-NMR (CDCl₃ , 100MHz): δ167.5, 153.9, 152.0, 150.2, 144.0, 137.5, 136.7, 134.4, 130.9, 128.5(2C), 127.9, 127.23, 127.16(2C), 121.6, 119.3, 118.0, 116.5, 71.2, 69.0, 66.3, 62.5, 52.1, 30.6, 30.0(3C) .MS(ESI): 477.2(M+H)⁺ .HRMS(APCI): Calcd.for C₂₉ H₃₃ O₆⁺ (M+H)⁺ : 477.2277, found: 477.2278.

12.步骤1212. Step 12

50mL单口瓶中加入化合物29(130mg，0.27mmol)，DMSO溶解(10mL)，后加入IBX(151mg，0.54mmol)，室温搅拌过夜，停止反应，加入H₂O(10mL)，DCM萃取(4x20mL)，有机相水洗(1x50mL)，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝7∶1(R_f＝0.51，PE∶EA＝3∶1)得123mg化合物30，收率96％。Add compound 29 (130mg, 0.27mmol) to a 50mL single-necked bottle, dissolve in DMSO (10mL), then add IBX (151mg, 0.54mmol), stir at room temperature overnight, stop the reaction, add H₂ O (10mL), extract with DCM (4x20mL) , the organic phase was washed with water (1x50mL), dried over anhydrous Na₂ SO₄ , filtered, concentrated, column chromatography PE: EA = 7: 1 (R_f = 0.51, PE: EA = 3: 1) to obtain 123 mg of compound 30, yield The rate is 96%.

¹H-NMR(CDCl₃，400MHz)：δ7.59(d，J＝8.6Hz，1H，Ar-H)，7.50-7.48(m，2H，Ar-H)，7.42-7.33(m，3H，Ar-H)，6.98(d，J＝8.6Hz，1H，Ar-H)，6.87(d，J＝1.2Hz，1H，Ar-H)，6.47(s，1H，Ar-H)，5.19(s，2H，CH₂)，5.11(s，2H，CH₂)，3.94(s，3H，OCH₃)，2.90(s，2H，CH₂)，2.26(s，3H，CH₃)，1.00(s，9H，t-Bu-H).¹³C-NMR(CDCl₃，100MHz)：δ202.2，166.3，156.5，155.1，150.3，143.4，136.6，134.9，133.6，133.5，128.6(2C)，128.0，127.24，127.20(2C)，121.6，120.7，118.4，116.6，71.2，68.9，63.7，54.7，31.6，29.8(3C)，21.1.MS(ESI)：475.3(M+H)⁺.HRMS(APCI)：Calcd.forC₂₉H₃₁O₆⁺(M+H)⁺：475.2121，found：475.2082.¹ H-NMR (CDCl₃ , 400MHz): δ7.59 (d, J=8.6Hz, 1H, Ar-H), 7.50-7.48 (m, 2H, Ar-H), 7.42-7.33 (m, 3H, Ar-H), 6.98(d, J=8.6Hz, 1H, Ar-H), 6.87(d, J=1.2Hz, 1H, Ar-H), 6.47(s, 1H, Ar-H), 5.19( s, 2H, CH₂ ), 5.11 (s, 2H, CH₂ ), 3.94 (s, 3H, OCH₃ ), 2.90 (s, 2H, CH₂ ), 2.26 (s, 3H, CH₃ ), 1.00 ( s, 9H, t-Bu-H).¹³ C-NMR (CDCl₃ , 100MHz): δ202.2, 166.3, 156.5, 155.1, 150.3, 143.4, 136.6, 134.9, 133.6, 133.5, 128.6 (2C), 128.0 , 127.24, 127.20(2C), 121.6, 120.7, 118.4, 116.6, 71.2, 68.9, 63.7, 54.7, 31.6, 29.8(3C), 21.1.MS(ESI): 475.3(M+H)⁺ .HRMS(APCI) : Calcd.forC₂₉ H₃₁ O₆⁺ (M+H)⁺ : 475.2121, found: 475.2082.

13.步骤1313. Step 13

氩气保护下，在50mL单口瓶中加入(R)-Me-CBS(186μL，0.186mmol)，减压除去其中的甲苯，再加入THF(9mL)。降温至-20℃，加入BH₃·THF(0.68mL，0.68mmol，1M in THF)，后缓慢滴加化合物30(294mg，0.62mmol)的THF溶液(9mL)，3h滴加完毕。-20℃反应4h后停止反应，加入H₂O(3mL)淬灭反应，EA萃取(3x15mL)，有机相水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝5∶1得250mg化合物31，收率85％，ee值88％。(手性柱拆分条件：PC-2柱，UV 214nm，正己烷∶异丙醇＝50∶50，0.5mL/min)Under the protection of argon, (R)-Me-CBS (186 μL, 0.186 mmol) was added to a 50 mL single-necked flask, the toluene was removed under reduced pressure, and then THF (9 mL) was added. Cool down to -20°C, add BH₃ ·THF (0.68mL, 0.68mmol, 1M in THF), and then slowly add compound 30 (294mg, 0.62mmol) in THF solution (9mL) dropwise for 3h. Stop the reaction after reacting at -20°C for 4 h, add H₂ O (3 mL) to quench the reaction, extract with EA (3x15 mL), wash the organic phase with water, dry over anhydrous Na₂ SO₄ , filter, concentrate, column chromatography PE:EA=5 : 1 to obtain 250 mg of compound 31 with a yield of 85% and an ee value of 88%. (Chiral column resolution conditions: PC-2 column, UV 214nm, n-hexane:isopropanol=50:50, 0.5mL/min)

[α]_D²⁰＝+7.3°(C＝4.4，CHCl₃).[α]_D²⁰ =+7.3° (C=4.4, CHCl₃ ).

14.步骤1414. Step 14

50mL单口瓶中加入化合物31(165mg，0.35mmol)，用EtOH(3mL)和EA(7mL)的混合溶液溶解后加入钯碳(17mg)，通入H₂，TLC监测至原料消失，过滤，浓缩，柱层析PE∶EA＝3∶1(R_f＝0.42，PE∶EA＝2∶1)得117mg化合物32，收率87％。Add compound 31 (165mg, 0.35mmol) to a 50mL single-necked bottle, dissolve it with a mixed solution of EtOH (3mL) and EA (7mL), add palladium carbon (17mg), feed H₂ , monitor by TLC until the raw material disappears, filter, and concentrate , column chromatography PE: EA = 3: 1 (R_f = 0.42, PE: EA = 2: 1) yielded 117 mg of compound 32, with a yield of 87%.

¹H-NMR(CDCl₃，400MHz)：δ7.52(d，J＝8.7Hz，1H，Ar-H)，6.84(s，1H，Ar-H)，6.81(d，J＝8.7Hz，1H，Ar-H)，6.76(br s，1H，OH)，6.34(s，1H，Ar-H)，5.15-5.04(m，3H)，3.96(s，3H，OCH₃)，2.31(br s，1H，OH)，2.23(s，3H，CH₃)，1.64-1.50(m，2H，CH₂)，1.01(s，9H，t-Bu-H).MS(ESI)：387.0(M+H)⁺.，[α]_D²⁰＝+9.7°(C＝3.2，CHCl₃)¹ H-NMR (CDCl₃ , 400MHz): δ7.52(d, J=8.7Hz, 1H, Ar-H), 6.84(s, 1H, Ar-H), 6.81(d, J=8.7Hz, 1H , Ar-H), 6.76(br s, 1H, OH), 6.34(s, 1H, Ar-H), 5.15-5.04(m, 3H), 3.96(s, 3H, OCH₃ ), 2.31(br s , 1H, OH), 2.23 (s, 3H, CH₃ ), 1.64-1.50 (m, 2H, CH₂ ), 1.01 (s, 9H, t-Bu-H). MS (ESI): 387.0 (M+ H)⁺ ., [α]_D²⁰ =+9.7° (C=3.2, CHCl₃ )

15.步骤1515. Step 15

50mL单口瓶中加入化合物32(161mg，0.42mmol)和干燥的THF(10mL)，后加入NaH(18mg，0.46mmol)，室温搅拌1h，后缓慢滴加对溴苯甲酰氯(101mg，0.46mmol)的THF(10mL)溶液，过夜后停止反应，直接柱层析PE∶EA＝5∶1(R_f＝0.25，PE∶EA＝3∶1)得219mg化合物33，收率92％。Add compound 32 (161mg, 0.42mmol) and dry THF (10mL) into a 50mL single-necked bottle, then add NaH (18mg, 0.46mmol), stir at room temperature for 1h, then slowly add p-bromobenzoyl chloride (101mg, 0.46mmol) dropwise The solution in THF (10 mL) was stopped overnight, and direct column chromatography PE:EA=5:1 (R_f =0.25, PE:EA=3:1) gave 219 mg of compound 33, with a yield of 92%.

¹H-NMR(CDCl₃，400MHz)：δ8.13-8.10(m，2H，Ar-H)，7.69-7.66(m，2H，Ar-H)，7.57(d，J＝8.6Hz，1H，Ar-H)，7.07(s，1H，Ar-H)，6.94(d，J＝8.6Hz，1H，Ar-H)，6.81(s，1H，Ar-H)，5.15-5.11(m，3H)，3.95(s，3H，OCH₃)，2.32(s，3H，CH₃)，1.86(br s，1H，OH)，1.67-1.52(m，2H，CH₂)，1.01(s，9H，t-Bu-H).¹³C-NMR(CDCl₃，100MHz)：δ167.0，164.7，153.9，151.1，145.7，141.9，138.1，134.5，132.0，131.7，131.0，129.2，128.0，127.8，127.2，124.8，119.5，118.2，69.0，66.4，62.9，52.2，30.7，30.0(3C)，20.6.HRMS(APCI)：Calcd.for C₂₉H₂₈BrO₇^-(M-H)^-：567.1019，found：567.1037，[α]_D²⁰＝-3.1°(C＝1.0，CHCl₃).¹ H-NMR (CDCl₃ , 400MHz): δ8.13-8.10 (m, 2H, Ar-H), 7.69-7.66 (m, 2H, Ar-H), 7.57 (d, J=8.6Hz, 1H, Ar-H), 7.07(s, 1H, Ar-H), 6.94(d, J=8.6Hz, 1H, Ar-H), 6.81(s, 1H, Ar-H), 5.15-5.11(m, 3H ), 3.95(s, 3H, OCH₃ ), 2.32(s, 3H, CH₃ ), 1.86(br s, 1H, OH), 1.67-1.52(m, 2H, CH₂ ), 1.01(s, 9H, t-Bu-H).¹³ C-NMR (CDCl₃ , 100MHz): δ167.0, 164.7, 153.9, 151.1, 145.7, 141.9, 138.1, 134.5, 132.0, 131.7, 131.0, 129.2, 128.0, 127.8, 127.2, 124.8, 119.5, 118.2, 69.0, 66.4, 62.9, 52.2, 30.7, 30.0 (3C), 20.6. HRMS (APCI): Calcd. for C₂₉ H₂₈ BrO₇^- (MH)^- : 567.1019, found: 567.1037, [ α]_D²⁰ = -3.1° (C = 1.0, CHCl₃ ).

实施例3：制备下述化合物，Embodiment 3: prepare following compound,

1.步骤11. Step 1

25mL单口瓶中加入实施例2步骤14所得化合物32(30mg，0.078mmol)和干燥的THF(2mL)，后加入NaH(3.4mg，0.086mmol)，室温搅拌1h，后缓慢滴加对三氟甲基苯甲酰氯(13μL，0.086mmol)的THF(2mL)溶液，过夜后停止反应，直接柱层析PE∶EA＝5∶1(R_f＝0.38，PE∶EA＝3∶1)得32mg化合物34，收率73％。Add compound 32 (30mg, 0.078mmol) obtained in Step 14 of Example 2 and dry THF (2mL) into a 25mL single-mouth bottle, then add NaH (3.4mg, 0.086mmol), stir at room temperature for 1h, and then slowly add p-trifluoroform Benzoyl chloride (13μL, 0.086mmol) in THF (2mL) solution, stop the reaction overnight, direct column chromatography PE: EA = 5: 1 (_Rf = 0.38, PE: EA = 3: 1) to give 32 mg of compound 34, yield 73%.

¹H-NMR(CDCl₃，400MHz)：δ8.39-8.36(m，2H，Ar-H)，7.81-7.78(m，2H，Ar-H)，7.58(d，J＝8.6Hz，1H，Ar-H)，7.09(s，1H，Ar-H)，6.94(d，J＝8.2Hz，1H，Ar-H)，6.83(s，1H，Ar-H)，5.15-5.11(m，3H)，3.95(s，3H，OCH₃)，2.33(s，3H，CH₃)，1.91(br s，1H，OH)，1.67-1.51(m，2H，CH₂)，1.01(s，9H，t-Bu-H).¹³C-NMR(CDCl₃，100MHz)：δ167.0，164.1，153.9，151.0，145.6，141.7，138.2，135.2(q，J＝32Hz)，134.5，132.1，131.0，130.6，128.1，127.2，125.7，124.8，124.7，119.4，118.1，68.9，66.3，62.8，52.2，30.6，30.0(3C)，20.6.¹⁹F-NMR(CDCl₃，376MHz)：δ-63.6.HRMS(APCI)：Calcd.for C₃₀H₂₈F₃O₇^-(M-H)^-：557.1787，found：557.1797，[α]_D²⁰＝-8.4°(C＝1.0，CHCl₃).¹ H-NMR (CDCl₃ , 400MHz): δ8.39-8.36 (m, 2H, Ar-H), 7.81-7.78 (m, 2H, Ar-H), 7.58 (d, J=8.6Hz, 1H, Ar-H), 7.09(s, 1H, Ar-H), 6.94(d, J=8.2Hz, 1H, Ar-H), 6.83(s, 1H, Ar-H), 5.15-5.11(m, 3H ), 3.95(s, 3H, OCH₃ ), 2.33(s, 3H, CH₃ ), 1.91(br s, 1H, OH), 1.67-1.51(m, 2H, CH₂ ), 1.01(s, 9H, t-Bu-H).¹³ C-NMR (CDCl₃ , 100MHz): δ167.0, 164.1, 153.9, 151.0, 145.6, 141.7, 138.2, 135.2 (q, J=32Hz), 134.5, 132.1, 131.0, 130.6 , 128.1, 127.2, 125.7, 124.8, 124.7, 119.4, 118.1, 68.9, 66.3, 62.8, 52.2, 30.6, 30.0 (3C), 20.6.¹⁹ F-NMR (CDCl₃ , 376MHz): δ-63.6.HRMS (APCI ): Calcd.for C₃₀ H₂₈ F₃ O₇^- (MH)^- : 557.1787, found: 557.1797, [α]_D²⁰ = -8.4° (C = 1.0, CHCl₃ ).

实施例4：制备下述化合物，Example 4: Preparation of the following compounds,

1.步骤11. Step 1

25mL单口瓶中加入实施例2步骤14所得化合物32(30mg，0.078mmol)和干燥的THF(2mL)，后加入NaH(3.4mg，0.086mmol)，室温搅拌1h，后缓慢滴加3，5-二(三氟甲基)苯甲酰氯(16μL，0.086mmol)的THF(2mL)溶液，过夜后停止反应，直接柱层析PE∶EA＝5∶1(R_f＝0.45，PE∶EA＝3∶1)得42mg化合物35，收率86％。Add compound 32 (30mg, 0.078mmol) obtained in step 14 of Example 2 and dry THF (2mL) into a 25mL one-mouth bottle, then add NaH (3.4mg, 0.086mmol), stir at room temperature for 1h, and then slowly add 3,5- Bis(trifluoromethyl)benzoyl chloride (16μL, 0.086mmol) in THF (2mL) solution, stop the reaction after overnight, direct column chromatography PE:EA=5:1 (R_f =0.45, PE:EA=3 : 1) 42 mg of compound 35 was obtained, with a yield of 86%.

¹H-NMR(CDCl₃，400MHz)：δ8.70(s，2H，Ar-H)，8.16(s，1H，Ar-H)，7.61(d，J＝8.6Hz，1H，Ar-H)，7.09(s，1H，Ar-H)，6.94(d，J＝8.6Hz，1H，Ar-H)，6.86(s，1H，Ar-H)，5.16-5.12(m，3H)，3.95(s，3H，OCH₃)，2.34(s，3H，CH₃)，1.93(br s，1H，OH)，1.67-1.52(m，2H，CH₂)，1.01(s，9H，t-Bu-H).¹³C-NMR(CDCl₃，100MHz)：δ166.9，162.7，153.9，150.9，145.5，141.3，138.4，134.6，132.5(q，J＝33Hz)，131.1，130.3，128.5，127.3，127.2，124.4，124.0，121.3，119.5，118.0，68.9，66.3，62.9，52.2，30.6，30.0(3C)，20.6.¹⁹F-NMR(CDCl₃，376MHz)：δ-63.4.HRMS(APCI)：Calcd.forC₃₁H₂₇F₆O₇^-(M-H)^-：625.1661，found：625.1649，[α]_D²⁰＝-5.6°(C＝1.0，CHCl₃).¹ H-NMR (CDCl₃ , 400MHz): δ8.70(s, 2H, Ar-H), 8.16(s, 1H, Ar-H), 7.61(d, J=8.6Hz, 1H, Ar-H) , 7.09(s, 1H, Ar-H), 6.94(d, J=8.6Hz, 1H, Ar-H), 6.86(s, 1H, Ar-H), 5.16-5.12(m, 3H), 3.95( s, 3H, OCH₃ ), 2.34 (s, 3H, CH₃ ), 1.93 (br s, 1H, OH), 1.67-1.52 (m, 2H, CH₂ ), 1.01 (s, 9H, t-Bu- H).¹³ C-NMR (CDCl₃ , 100MHz): δ166.9, 162.7, 153.9, 150.9, 145.5, 141.3, 138.4, 134.6, 132.5 (q, J=33Hz), 131.1, 130.3, 128.5, 127.3, 127.2 , 124.4, 124.0, 121.3, 119.5, 118.0, 68.9, 66.3, 62.9, 52.2, 30.6, 30.0 (3C), 20.6.¹⁹ F-NMR (CDCl₃ , 376MHz): δ-63.4. HRMS (APCI): Calcd. forC₃₁ H₂₇ F₆ O₇^- (MH)^- : 625.1661, found: 625.1649, [α]_D²⁰ = -5.6° (C = 1.0, CHCl₃ ).

实施例5：制备下述化合物，Example 5: Preparation of the following compounds,

1.步骤11. Step 1

25mL单口瓶中加入实施例2步骤14所得化合物32(40mg，0.10mmol)和干燥的THF(2mL)，后加入NaH(4.4mg，0.11mmol)，室温搅拌1h，后缓慢滴加实施例1步骤18所得酰氯b(22mg，0.13mmol)的THF(2mL)溶液，过夜后停止反应，直接板层析PE∶EA＝3∶1(R_f＝0.46，PE∶EA＝3∶1)得38mg化合物36，收率73％。Add compound 32 (40mg, 0.10mmol) obtained in step 14 of Example 2 and dry THF (2mL) into a 25mL one-mouth bottle, then add NaH (4.4mg, 0.11mmol), stir at room temperature for 1h, and then slowly add step 1 in Example 1 The THF (2mL) solution of the obtained acid chloride b (22mg, 0.13mmol) obtained in 18 stopped the reaction overnight, and direct plate chromatography PE:EA=3:1 (R_f =0.46, PE:EA=3:1) gave 38mg of the compound 36, yield 73%.

¹H-NMR(CDCl₃，400MHz)：δ7.60(d，J＝8.6Hz，1H，Ar-H)，6.99(d，J＝8.6Hz，1H，Ar-H)，6.88(s，1H，Ar-H)，6.74(s，1H，Ar-H)，5.18-5.14(m，1H，CH)，5.07(s，2H，CH₂)，3.97(s，3H，OCH₃)，2.33(s，2H)，2.28(s，3H，CH₃)，1.98-1.84(m，5H)，1.70-1.55(m，2H，CH₂)，1.45(s，3H，CH₃)，1.34-1.32(m，4H)，1.02(s，9H，t-Bu-H).¹³C-NMR(CDCl₃，100MHz)：δ175.4，167.2，153.8，151.3，146.1，141.8，138.1，134.2，131.1，127.6，127.1，124.7，119.7，118.3，69.1，66.3，62.9，58.6，52.2，41.9，30.7，30.1，29.3，27.7，20.5，17.1.HRMS(APCI)：Calcd.for C₃₁H₃₇O₇^-(M-H)^-：521.2540，found：521.2551，[α]_D²⁰＝+2.4°(C＝1.0，CHCl₃).¹ H-NMR (CDCl₃ , 400MHz): δ7.60(d, J=8.6Hz, 1H, Ar-H), 6.99(d, J=8.6Hz, 1H, Ar-H), 6.88(s, 1H , Ar-H), 6.74 (s, 1H, Ar-H), 5.18-5.14 (m, 1H, CH), 5.07 (s, 2H, CH₂ ), 3.97 (s, 3H, OCH₃ ), 2.33 ( s, 2H), 2.28 (s, 3H, CH₃ ), 1.98-1.84 (m, 5H), 1.70-1.55 (m, 2H, CH₂ ), 1.45 (s, 3H, CH₃ ), 1.34-1.32 ( m, 4H), 1.02 (s, 9H, t-Bu-H).¹³ C-NMR (CDCl₃ , 100MHz): δ175.4, 167.2, 153.8, 151.3, 146.1, 141.8, 138.1, 134.2, 131.1, 127.6 , 127.1, 124.7, 119.7, 118.3, 69.1, 66.3, 62.9, 58.6, 52.2, 41.9, 30.7, 30.1, 29.3, 27.7, 20.5, 17.1. HRMS (APCI): Calcd.for C₃₁ H₃₇ O₇^- (MH )^- : 521.2540, found: 521.2551, [α]_D²⁰ =+2.4° (C = 1.0, CHCl₃ ).

实施例6：制备下述化合物，Example 6: Preparation of the following compounds,

1.步骤11. Step 1

50mL的两口瓶中加入实施例2步骤1所得化合物19(1.04g，3.40mmol)，对甲氧基苯硼酸(620mg，4.08mmol)，Pd(PPh₃)₄(347mg，0.34mmol)，2N K₂CO₃(3.4mL，6.80mmol)，甲醇(15mL)，80℃反应过夜。反应液加硅藻土抽滤，加水稀释后乙酸乙酯萃取，有机相水洗，饱和食盐水洗，无水MgSO₄干燥，过滤，浓缩，柱层析PE∶EA＝10∶1(R_f＝0.16，PE∶EA＝10∶1)得950mg化合物37，收率84％。Compound 19 (1.04g, 3.40mmol) obtained in Step 1 of Example 2, p-methoxyphenylboronic acid (620mg, 4.08mmol), Pd(PPh₃ )₄ (347mg, 0.34mmol), 2N K₂ CO₃ (3.4mL, 6.80mmol), methanol (15mL), react at 80°C overnight. The reaction solution was filtered with diatomaceous earth, diluted with water, extracted with ethyl acetate, washed with water, washed with saturated brine, dried with anhydrous MgSO₄ , filtered, concentrated, column chromatography PE:EA=10:1 (R_f =0.16 , PE:EA=10:1) to obtain 950 mg of compound 37 with a yield of 84%.

¹H-NMR(CDCl₃，400MHz)：δ11.00(s，1H，OH)，9.98(s，1H，CHO)，7.49-7.47(m，2H，Ar-H)，7.41-7.33(m，7H，Ar-H)，6.97-6.95(m，2H，Ar-H)，5.25(s，2H，CH₂)，3.85(s，3H，OCH₃).¹³C-NMR(CDCl₃，100MHz)：δ196.5，159.1，151.1，147.3，136.4，132.8，132.0，128.6(2C)，128.1，127.6(2C)，127.4(2C)，122.9，121.0，119.7，114.3(2C)，71.5，55.3.MS(ESI)：335.2(M+H)⁺.HRMS(APCI)：Calcd.for C₂₁H₁₉O₄⁺(M+H)⁺：335.1283，found：335.1262.¹ H-NMR (CDCl₃ , 400MHz): δ11.00(s, 1H, OH), 9.98(s, 1H, CHO), 7.49-7.47(m, 2H, Ar-H), 7.41-7.33(m, 7H, Ar-H), 6.97-6.95(m, 2H, Ar-H), 5.25(s, 2H, CH₂ ), 3.85(s, 3H, OCH₃ ).¹³ C-NMR (CDCl₃ , 100MHz) : δ196.5, 159.1, 151.1, 147.3, 136.4, 132.8, 132.0, 128.6(2C), 128.1, 127.6(2C), 127.4(2C), 122.9, 121.0, 119.7, 114.3(2C), 71.5, 55.3.MS (ESI): 335.2(M+H)⁺ .HRMS(APCI): Calcd.for C₂₁ H₁₉ O₄⁺ (M+H)⁺ : 335.1283, found: 335.1262.

2.步骤22. Step 2

100mL单口瓶中加入化合物37(950mg，2.84mmol)，加入甲醇(30mL)，冰浴下加入NaBH₄(216mg，5.68mmol)后，室温下反应1h。减压浓缩，将得到的白色固体溶于3N盐酸，乙酸乙酯萃取，有机相水洗，饱和食盐水洗，无水MgSO₄干燥，过滤，浓缩，柱层析PE∶EA＝3∶1(R_f＝0.21，PE∶EA＝3∶1)，得822mg化合物38，收率86％。Compound 37 (950 mg, 2.84 mmol) was added to a 100 mL single-necked bottle, methanol (30 mL) was added, NaBH₄ (216 mg, 5.68 mmol) was added under ice-cooling, and the reaction was carried out at room temperature for 1 h. Concentrate under reduced pressure, dissolve the obtained white solid in 3N hydrochloric acid, extract with ethyl acetate, wash the organic phase with water, wash with saturated brine, dry with anhydrous MgSO₄ , filter, concentrate, column chromatography PE: EA = 3: 1 (R_f =0.21, PE:EA=3:1), to obtain 822mg of compound 38, yield 86%.

¹H-NMR(CDCl₃，400MHz)：δ7.45-7.44(m，7H，Ar-H)，7.08-7.07(m，2H，Ar-H)，6.96-6.94(m，2H，Ar-H)，6.10(s，1H，OH)，5.17(s，2H，CH₂)，4.79(s，2H，CH₂)，3.84(s，3H，OCH₃)，2.40(br s，1H，OH).¹³C-NMR(CDCl₃，100MHz)：δ158.7，145.8，143.0，136.2，133.5，132.9，128.7(2C)，128.4，127.8(2C)，127.7(2C)，126.8，119.5，114.1(2C)，110.5，71.3，61.8，55.3.MS(ESI)：335.2(M-H)^-.HRMS(APCI)：Calcd.for C₂₁H₁₉O₄^-(M-H)^-：335.1284，found：335.1261.¹ H-NMR (CDCl₃ , 400MHz): δ7.45-7.44 (m, 7H, Ar-H), 7.08-7.07 (m, 2H, Ar-H), 6.96-6.94 (m, 2H, Ar-H ), 6.10 (s, 1H, OH), 5.17 (s, 2H, CH₂ ), 4.79 (s, 2H, CH₂ ), 3.84 (s, 3H, OCH₃ ), 2.40 (br s, 1H, OH) .¹³ C-NMR (CDCl₃ , 100MHz): δ158.7, 145.8, 143.0, 136.2, 133.5, 132.9, 128.7(2C), 128.4, 127.8(2C), 127.7(2C), 126.8, 119.5, 114.1(2C ), 110.5, 71.3, 61.8, 55.3. MS (ESI): 335.2 (MH)^{- .} HRMS (APCI): Calcd. for C₂₁ H₁₉ O₄^- (MH)^- : 335.1284, found: 335.1261.

3.步骤33. Step 3

50mL单口瓶中加入化合物38(822mg，2.45mmol)，后用干燥的二氯甲烷(20mL)溶解，再加入对甲苯磺酸(48mg，0.25mmol)，冰盐浴中搅拌15min后，滴加3，4-二氢-2H-吡喃(0.23mL，2.52mmol)，反应1h。停止反应，加入三乙胺(1mL)淬灭反应，有机相饱和食盐水洗，无水MgSO₄干燥，过滤，浓缩，柱层析PE∶EA＝7∶1(R_f＝0.57，PE∶EA＝3∶1)得949mg化合物39，收率92％。Compound 38 (822mg, 2.45mmol) was added to a 50mL single-necked bottle, and then dissolved with dry dichloromethane (20mL), then p-toluenesulfonic acid (48mg, 0.25mmol) was added, and after stirring for 15min in an ice-salt bath, 3 , 4-dihydro-2H-pyran (0.23 mL, 2.52 mmol), reacted for 1 h. Stop the reaction, add triethylamine (1 mL) to quench the reaction, wash the organic phase with saturated brine, dry over anhydrous MgSO₄ , filter, concentrate, column chromatography PE:EA=7:1 (R_f =0.57, PE:EA= 3:1) to obtain 949 mg of compound 39 with a yield of 92%.

¹H-NMR(CDCl₃，400MHz)：δ7.46-7.35(m，7H，Ar-H)，7.12(d，J＝1.6Hz，1H，Ar-H)，7.07(d，J＝2.0Hz，1H，Ar-H)，6.95-6.92(m，2H，Ar-H)，6.40(s，1H，OH)，5.17(s，2H，CH₂)，4.90(d，J＝12Hz，1H，CH₂)，4.79(t，J＝3.5Hz，1H，CH)，4.67(d，J＝12Hz，1H，CH₂)，4.01-3.95(m，1H，CH₂)，3.83(s，3H，OCH₃)，3.60-3.56(m，1H，CH₂)，1.89-1.54(m，6H).¹³C-NMR(CDCl₃，100MHz)：δ158.6，146.2，143.6，136.5，133.7，132.6，128.6(2C)，128.2，127.8(2C)，127.7(2C)，124.0，120.3，114.0(2C)，111.0，98.2，71.3，64.9，62.5，55.3，30.5，25.3，19.5.MS(ESI)：443.2(M+Na)⁺.HRMS(APCI)：Calcd.for C₂₆H₂₇O₅^-(M-H)^-：419.1859，found：419.1823.¹ H-NMR (CDCl₃ , 400MHz): δ7.46-7.35(m, 7H, Ar-H), 7.12(d, J=1.6Hz, 1H, Ar-H), 7.07(d, J=2.0Hz , 1H, Ar-H), 6.95-6.92(m, 2H, Ar-H), 6.40(s, 1H, OH), 5.17(s, 2H, CH₂ ), 4.90(d, J=12Hz, 1H, CH₂ ), 4.79(t, J=3.5Hz, 1H, CH), 4.67(d, J=12Hz, 1H, CH₂ ), 4.01-3.95(m, 1H, CH₂ ), 3.83(s, 3H, OCH₃ ), 3.60-3.56 (m, 1H, CH₂ ), 1.89-1.54 (m, 6H).¹³ C-NMR (CDCl₃ , 100MHz): δ158.6, 146.2, 143.6, 136.5, 133.7, 132.6, 128.6(2C), 128.2, 127.8(2C), 127.7(2C), 124.0, 120.3, 114.0(2C), 111.0, 98.2, 71.3, 64.9, 62.5, 55.3, 30.5, 25.3, 19.5. MS(ESI): 443.2 (M+Na)⁺ .HRMS(APCI): Calcd.for C₂₆ H₂₇ O₅^- (MH)^- : 419.1859, found: 419.1823.

4.步骤44. Step 4

50mL两口瓶回流装置中，加入实施例1步骤9所得化合物9(513mg，1.88mmol)，化合物39(949mg，2.25mmol)，Cu(301mg，4.70mmol)，CuO(376mg，4.70mmol)，DMAP(688mg，5.64mmol)，氩气保护下加入CH₃CN(20mL)后加热至回流，反应12h后停止反应，冷却，加硅藻土过滤，浓缩，柱层析PE∶EA＝5∶1(R_f＝0.32，PE∶EA＝5∶1)得793mg化合物40，收率69％。In the 50mL two-neck bottle reflux device, add compound 9 (513mg, 1.88mmol) obtained in step 9 of Example 1, compound 39 (949mg, 2.25mmol), Cu (301mg, 4.70mmol), CuO (376mg, 4.70mmol), DMAP ( 688mg, 5.64mmol), added CH₃ CN (20mL) under the protection of argon, heated to reflux, stopped the reaction after 12h of reaction, cooled, added diatomaceous earth to filter, concentrated, column chromatography PE: EA = 5: 1 (R_f =0.32, PE:EA=5:1) to obtain 793mg of compound 40, yield 69%.

¹H-NMR(CDCl₃，400MHz)：δ10.23(s，1H，CHO)，7.74(d，J＝8.7Hz，1H，Ar-H)，7.50-7.47(m，2H，Ar-H)，7.31-7.16(m，7H，Ar-H)，7.00-6.97(m，2H，Ar-H)，6.53(d，J＝8.7Hz，1H，Ar-H)，5.08(s，2H，CH₂)，4.77(d，J＝12Hz，1H，CH₂)，4.71-4.70(m，1H，CH)，4.51(d，J＝12Hz，1H，CH₂)，4.00(s，3H，OCH₃)，3.96(s，3H，OCH₃)，3.86(s，3H，OCH₃)，3.84-3.78(m，1H，CH₂)，3.52-3.47(m，1H，CH₂)，1.64-1.42(m，6H).¹³C-NMR(CDCl₃，100MHz)：δ187.8，165.3，161.7，161.3，159.3，150.5，139.6，139.4，136.3，132.9，132.8，131.1，128.3(2C)，128.1(2C)，127.7，126.8(2C)，123.1，120.3，117.9，114.2(2C)，112.6，110.4，98.5，70.6，64.8，64.4，61.8，55.3，52.7，30.2，25.3，19.1.MS(ESI)：635.1(M+Na)⁺.HRMS(ESI)：Calcd.for C₃₆H₃₇O₉⁺(M+H)⁺：613.2438，found：613.2395.¹ H-NMR (CDCl₃ , 400MHz): δ10.23 (s, 1H, CHO), 7.74 (d, J=8.7Hz, 1H, Ar-H), 7.50-7.47 (m, 2H, Ar-H) , 7.31-7.16(m, 7H, Ar-H), 7.00-6.97(m, 2H, Ar-H), 6.53(d, J=8.7Hz, 1H, Ar-H), 5.08(s, 2H, CH₂ ), 4.77(d, J=12Hz, 1H, CH₂ ), 4.71-4.70(m, 1H, CH), 4.51(d, J=12Hz, 1H, CH₂ ), 4.00(s, 3H, OCH₃ ), 3.96 (s, 3H, OCH₃ ), 3.86 (s, 3H, OCH₃ ), 3.84-3.78 (m, 1H, CH₂ ), 3.52-3.47 (m, 1H, CH₂ ), 1.64-1.42 ( m, 6H).¹³ C-NMR (CDCl₃ , 100MHz): δ187.8, 165.3, 161.7, 161.3, 159.3, 150.5, 139.6, 139.4, 136.3, 132.9, 132.8, 131.1, 128.3(2C), 128.1(2C ), 127.7, 126.8(2C), 123.1, 120.3, 117.9, 114.2(2C), 112.6, 110.4, 98.5, 70.6, 64.8, 64.4, 61.8, 55.3, 52.7, 30.2, 25.3, 19.1. MS(ESI): 635.1 (M+Na)⁺ .HRMS(ESI): Calcd. for C₃₆ H₃₇ O₉⁺ (M+H)⁺ : 613.2438, found: 613.2395.

5.步骤55. Step 5

100mL的单口瓶中加入化合物40(993mg，1.62mmol)，对甲苯磺酸(2mg)，后加入异丙醇(8mL)和H₂O(2mL)，加热回流过夜，停止反应，冷却，加入H₂O(10mL)，乙酸乙酯萃取(3x30mL)，有机相水洗，饱和食盐水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝3∶1(R_f＝0.14，PE∶EA＝3∶1)得813mg化合物41，收率95％。Add compound 40 (993mg, 1.62mmol), p-toluenesulfonic acid (2mg) into a 100mL single-necked bottle, then add isopropanol (8mL) and H₂ O (2mL), heat and reflux overnight, stop the reaction, cool, add H₂ O (10 mL), extracted with ethyl acetate (3x30 mL), washed the organic phase with water, washed with saturated brine, dried over anhydrous Na₂ SO₄ , filtered, concentrated, column chromatography PE:EA=3:1 (R_f =0.14, PE:EA=3:1) to obtain 813mg of compound 41, the yield was 95%.

¹H-NMR(CDCl₃，400MHz)：δ10.23(s，1H，CHO)，7.77(d，J＝9.1Hz，1H，Ar-H)，7.49-7.46(m，2H，Ar-H)，7.29-7.16(m，7H，Ar-H)，6.99-6.96(m，2H，Ar-H)，6.53(d，J＝9.1Hz，1H，Ar-H)，5.09(s，2H，CH₂)，4.65(d，J＝5.6Hz，2H，CH₂)，4.01(s，3H，OCH₃)，3.97(s，3H，OCH₃)，3.86(s，3H，OCH₃)，2.74(t，J＝6.5Hz，1H，OH).¹³C-NMR(CDCl₃，100MHz)：δ187.7，165.5，161.9，160.8，159.4，150.7，139.7，139.2，136.2，135.2，132.7，131.6，128.4(2C)，128.1(2C)，127.9，126.9(2C)，123.5，119.8，117.5，114.2(2C)，112.5，110.1，70.7，64.8，61.0，55.3，52.9.MS(ESI)：528.7(M+H)⁺.HRMS(APCI)：Calcd.for C₃₁H₂₉O₈⁺(M+H)⁺：529.1862，found：529.1850.¹ H-NMR (CDCl₃ , 400MHz): δ10.23 (s, 1H, CHO), 7.77 (d, J=9.1Hz, 1H, Ar-H), 7.49-7.46 (m, 2H, Ar-H) , 7.29-7.16(m, 7H, Ar-H), 6.99-6.96(m, 2H, Ar-H), 6.53(d, J=9.1Hz, 1H, Ar-H), 5.09(s, 2H, CH₂ ), 4.65 (d, J=5.6Hz, 2H, CH₂ ), 4.01 (s, 3H, OCH₃ ), 3.97 (s, 3H, OCH₃ ), 3.86 (s, 3H, OCH₃ ), 2.74 ( t, J=6.5Hz, 1H, OH).¹³ C-NMR (CDCl₃ , 100MHz): δ187.7, 165.5, 161.9, 160.8, 159.4, 150.7, 139.7, 139.2, 136.2, 135.2, 132.7, 131.6, 128.4 (2C), 128.1(2C), 127.9, 126.9(2C), 123.5, 119.8, 117.5, 114.2(2C), 112.5, 110.1, 70.7, 64.8, 61.0, 55.3, 52.9. MS(ESI): 528.7(M+ H)⁺ .HRMS(APCI): Calcd.for C₃₁ H₂₉ O₈⁺ (M+H)⁺ : 529.1862, found: 529.1850.

6.步骤66. Step 6

100mL单口瓶中加入化合物41(797mg，1.51mmol)，用MeOH溶解(9mL)，加入对甲苯磺酸(74mg，0.39mmol)，室温搅拌1h后，加入NaOH(846mg，15.1mmol)，加热至回流，反应过夜。停止反应，冷却，减压浓缩除去MeOH，用3N盐酸调pH值至3，乙酸乙酯萃取(4x30mL)，无水Na₂SO₄干燥，过滤，浓缩，得778mg化合物42粗品。Add compound 41 (797mg, 1.51mmol) to a 100mL single-necked bottle, dissolve (9mL) with MeOH, add p-toluenesulfonic acid (74mg, 0.39mmol), stir at room temperature for 1h, add NaOH (846mg, 15.1mmol), and heat to reflux , reacted overnight. The reaction was stopped, cooled, concentrated under reduced pressure to remove MeOH, adjusted to pH 3 with 3N hydrochloric acid, extracted with ethyl acetate (4x30 mL), dried over anhydrous Na₂ SO₄ , filtered, and concentrated to obtain 778 mg of crude compound 42.

MS(ESI)：512.7(M-H)^-.MS(ESI): 512.7(MH)^- .

7.步骤77. Step 7

将化合物42的粗品(778mg，1.51mmol)和三乙胺(1.7mL，12.1mmol)溶于干燥的CH₃CN(30mL)中，将上述制得的溶液室温下缓慢滴加到由碘化-2-氯-1-甲基吡啶(1.54g，6.04mmol)溶于干燥的CH₃CN(30mL)所配置的溶液中。滴加完毕后，加热回流反应过夜。停止反应，冷却，减压浓缩除去CH₃CN，加入H₂O(20mL)，DCM萃取(3x30mL)，无水Na₂SO₄干燥，过滤，浓缩，柱层析DCM(R_f＝0.58，PE∶EA＝2∶1)得138mg化合物43，两步合计收率18％。The crude product of compound 42 (778mg, 1.51mmol) and triethylamine (1.7mL, 12.1mmol) were dissolved in dry CH₃ CN (30mL), and the solution prepared above was slowly added dropwise at room temperature to the iodide- 2-Chloro-1-picoline (1.54 g, 6.04 mmol) was dissolved in dry_CH3CN (30 mL). After the dropwise addition was completed, the reaction was heated to reflux overnight. The reaction was stopped, cooled, concentrated under reduced pressure to remove CH₃ CN, added H₂ O (20 mL), extracted with DCM (3x30 mL), dried over anhydrous Na₂ SO₄ , filtered, concentrated, column chromatography DCM (R_f =0.58, PE :EA=2:1) to obtain 138 mg of compound 43, the total yield of the two steps was 18%.

¹H-NMR(CDCl₃，400MHz)：δ10.37(s，1H，CHO)，8.02(d，J＝8.7Hz，1H，Ar-H)，7.54-7.51(m，2H，Ar-H)，7.45-7.36(m，5H，Ar-H)，7.23(d，J＝2.0Hz，1H，Ar-H)，7.08(dd，J＝8.7，0.8Hz，1H，Ar-H)，6.97-6.94(m，2H，Ar-H)，6.83(d，J＝2.0Hz，1H，Ar-H)，5.28(s，2H，CH₂)，5.23(s，2H，CH₂)，4.14(s，3H，OCH₃)，3.85(s，3H，OCH₃).¹³C-NMR(CDCl₃，100MHz)：δ187.8，166.0，161.2，159.5，157.7，150.8，144.2，138.3，136.4，133.4，132.2，128.7(2C)，128.2，128.0(2C)，127.8，127.4(2C)，127.1，120.6，119.4，118.8，114.4，114.3(2C)，71.5，69.1，64.7，55.3.HRMS(APCI)：Calcd.forC₃₀H₂₅O₇⁺(M+H)⁺：497.1600，found：497.1599.¹ H-NMR (CDCl₃ , 400MHz): δ10.37 (s, 1H, CHO), 8.02 (d, J=8.7Hz, 1H, Ar-H), 7.54-7.51 (m, 2H, Ar-H) , 7.45-7.36 (m, 5H, Ar-H), 7.23 (d, J=2.0Hz, 1H, Ar-H), 7.08 (dd, J=8.7, 0.8Hz, 1H, Ar-H), 6.97- 6.94(m, 2H, Ar-H), 6.83(d, J=2.0Hz, 1H, Ar-H), 5.28(s, 2H, CH₂ ), 5.23(s, 2H, CH₂ ), 4.14(s , 3H, OCH₃ ), 3.85 (s, 3H, OCH₃ ).¹³ C-NMR (CDCl₃ , 100MHz): δ187.8, 166.0, 161.2, 159.5, 157.7, 150.8, 144.2, 138.3, 136.4, 133.4, 132.2, 128.7(2C), 128.2, 128.0(2C), 127.8, 127.4(2C), 127.1, 120.6, 119.4, 118.8, 114.4, 114.3(2C), 71.5, 69.1, 64.7, 55.3.HRMS(APCI): Calcd .for C₃₀ H₂₅ O₇⁺ (M+H)⁺ : 497.1600, found: 497.1599.

8.步骤88. Step 8

50mL单口瓶中加入化合物43(136mg，0.27mmol)，氩气保护下，加入干燥的THF(10mL)，冰浴下滴加新戊基溴化镁(0.61mL，1.6mmol)，后自然升温至室温搅拌1h，加入饱和NH₄Cl淬灭反应，乙酸乙酯萃取(3x30mL)，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝5∶1(R_f＝0.30，PE∶EA＝3∶1)得119mg化合物44，收率77％。Compound 43 (136mg, 0.27mmol) was added to a 50mL single-necked bottle, under the protection of argon, dry THF (10mL) was added, and neopentylmagnesium bromide (0.61mL, 1.6mmol) was added dropwise under ice-cooling, and then the temperature was naturally raised to Stir at room temperature for 1 h, add saturated NH₄ Cl to quench the reaction, extract with ethyl acetate (3x30 mL), dry over anhydrous Na₂ SO₄ , filter, concentrate, column chromatography PE:EA=5:1 (R_f =0.30, PE :EA=3:1) to obtain 119mg of compound 44, yield 77%.

¹H-NMR(CDCl₃，400MHz)：δ7.60(d，J＝8.6Hz，1H，Ar-H)，7.54-7.51(m，2H，Ar-H)，7.43-7.34(m，5H，Ar-H)，7.19(d，J＝1.6Hz，1H，Ar-H)，6.99(d，J＝8.6Hz，1H，Ar-H)，6.95-6.92(m，2H，Ar-H)，6.80(d，J＝1.6Hz，1H，Ar-H)，5.27(s，2H，CH₂)，5.19-5.18(s，3H)，3.99(s，3H，OCH₃)，3.83(s，3H，OCH₃)，1.93(br s，1H，OH)，1.70-1.55(m，2H，CH₂)，1.03(s，9H，t-Bu-H).¹³C-NMR(CDCl₃，100MHz)：δ167.3，159.3，154.0，152.0，150.6，145.2，137.6，137.5，136.6，132.3，131.0，128.6(2C)，128.0，127.9(2C)，127.8，127.3(2C)，119.5，119.3，118.0，114.4，114.2(2C)，71.5 69.2，66.4，62.6，55.3，52.2，30.7，30.0(3C).MS(ESI)：568.7(M+H)⁺.HRMS(APCI)：Calcd.forC₃₅H₃₇O₇⁺(M+H)⁺：569.2539，found：569.2534.¹ H-NMR (CDCl₃ , 400MHz): δ7.60 (d, J=8.6Hz, 1H, Ar-H), 7.54-7.51 (m, 2H, Ar-H), 7.43-7.34 (m, 5H, Ar-H), 7.19(d, J=1.6Hz, 1H, Ar-H), 6.99(d, J=8.6Hz, 1H, Ar-H), 6.95-6.92(m, 2H, Ar-H), 6.80(d, J=1.6Hz, 1H, Ar-H), 5.27(s, 2H, CH₂ ), 5.19-5.18(s, 3H), 3.99(s, 3H, OCH₃ ), 3.83(s, 3H , OCH₃ ), 1.93 (br s, 1H, OH), 1.70-1.55 (m, 2H, CH₂ ), 1.03 (s, 9H, t-Bu-H).¹³ C-NMR (CDCl₃ , 100MHz) : δ167.3, 159.3, 154.0, 152.0, 150.6, 145.2, 137.6, 137.5, 136.6, 132.3, 131.0, 128.6(2C), 128.0, 127.9(2C), 127.8, 127.3(2C), 119.5, 119.3, 118. 114.4, 114.2 (2C), 71.5 69.2, 66.4, 62.6, 55.3, 52.2, 30.7, 30.0 (3C). MS (ESI): 568.7 (M+H)^{+ .} HRMS (APCI): Calcd. for C₃₅ H₃₇ O₇⁺ (M+H)⁺ : 569.2539, found: 569.2534.

9.步骤99. Step 9

50mL单口瓶中加入化合物44(108mg，0.19mmol)，DMSO溶解(10mL)，后加入IBX(106mg，0.38mmol)，室温搅拌过夜，停止反应，加入H₂O(10mL)，DCM萃取(4x20mL)，有机相水洗(1x50mL)，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝5∶1(R_f＝0.53，PE∶EA＝3∶1)得104mg化合物45，收率96％。Compound 44 (108mg, 0.19mmol) was added to a 50mL single-necked bottle, dissolved in DMSO (10mL), then IBX (106mg, 0.38mmol) was added, stirred at room temperature overnight, the reaction was stopped, H₂ O (10mL) was added, DCM extraction (4x20mL) , the organic phase was washed with water (1x50mL), dried over anhydrous Na₂ SO₄ , filtered, concentrated, column chromatography PE: EA = 5: 1 (R_f = 0.53, PE: EA = 3: 1) to obtain 104mg of compound 45, yield The rate is 96%.

¹H-NMR(CDCl₃，400MHz)：δ7.61(d，J＝8.6Hz，1H，Ar-H)，7.53-7.51(m，2H，Ar-H)，7.44-7.36(m，5H，Ar-H)，7.21(d，J＝1.6Hz，1H，Ar-H)，7.03(d，J＝8.2Hz，1H，Ar-H)，6.96-6.93(m，2H，Ar-H)，6.82(d，J＝1.6Hz，1H，Ar-H)，5.27(s，2H，CH₂)，5.20(s，2H，CH₂)，3.96(s，3H，OCH₃)，3.84(s，3H，OCH₃)，2.91(s，2H，CH₂)，1.01(s，9H，t-Bu-H).¹³C-NMR(CDCl₃，100MHz)：δ202.1，166.3，159.5，156.6，155.0，150.8，144.7，138.1，136.5，133.8，133.7，132.3，128.7(2C)，128.2，128.0(2C)，127.8，127.4(2C)，120.8，119.6，118.5，114.6，114.3(2C)，71.6，69.1，63.9，55.4，54.8，31.6，29.9(3C).HRMS(APCI)：Calcd.for C₃₅H₃₅O₇⁺(M+H)⁺：567.2383，found：567.2350.¹ H-NMR (CDCl₃ , 400MHz): δ7.61 (d, J=8.6Hz, 1H, Ar-H), 7.53-7.51 (m, 2H, Ar-H), 7.44-7.36 (m, 5H, Ar-H), 7.21(d, J=1.6Hz, 1H, Ar-H), 7.03(d, J=8.2Hz, 1H, Ar-H), 6.96-6.93(m, 2H, Ar-H), 6.82(d, J=1.6Hz, 1H, Ar-H), 5.27(s, 2H, CH₂ ), 5.20(s, 2H, CH₂ ), 3.96(s, 3H, OCH₃ ), 3.84(s, 3H, OCH₃ ), 2.91 (s, 2H, CH₂ ), 1.01 (s, 9H, t-Bu-H).¹³ C-NMR (CDCl₃ , 100MHz): δ202.1, 166.3, 159.5, 156.6, 155.0, 150.8, 144.7, 138.1, 136.5, 133.8, 133.7, 132.3, 128.7(2C), 128.2, 128.0(2C), 127.8, 127.4(2C), 120.8, 119.6, 118.5, 114.6, 114.3, 6C, 7 69.1, 63.9, 55.4, 54.8, 31.6, 29.9 (3C). HRMS (APCI): Calcd. for C₃₅ H₃₅ O₇⁺ (M+H)⁺ : 567.2383, found: 567.2350.

10.步骤1010. Step 10

氩气保护下，在50mL单口瓶中加入(R)-Me-CBS(51μL，0.051mmol)，减压除去其中的甲苯，再加入THF(2.5mL)。降温至-20℃，加入BH₃·THF(0.22mL，0.22mmol，1M in THF)，后缓慢滴加化合物45(94mg，0.17mmol)的THF溶液(2.5mL)，3h滴加完毕。-20℃反应4h后停止反应，加入H₂O(3mL)淬灭反应，乙酸乙酯萃取(3x15mL)，有机相水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝5∶1得72mg化合物46，收率74％。Under the protection of argon, (R)-Me-CBS (51 μL, 0.051 mmol) was added to a 50 mL single-necked flask, the toluene was removed under reduced pressure, and then THF (2.5 mL) was added. Cool down to -20°C, add BH₃ ·THF (0.22mL, 0.22mmol, 1M in THF), and then slowly add compound 45 (94mg, 0.17mmol) in THF solution (2.5mL) dropwise for 3h. Stop the reaction after reacting at -20°C for 4h, add H₂ O (3mL) to quench the reaction, extract with ethyl acetate (3x15mL), wash the organic phase with water, dry over anhydrous Na₂ SO₄ , filter, concentrate, column chromatography PE:EA =5:1 72mg of compound 46 was obtained, the yield was 74%.

[α]_D²⁰＝+19°(C＝0.2，CHCl₃).[α]_D²⁰ =+19° (C=0.2, CHCl₃ ).

11.步骤1111. Step 11

50mL单口瓶中加入化合物46(68mg，0.12mmol)，用EtOH(3mL)和EA(7mL)的混合溶液溶解后加入钯碳(7mg)，通入H₂，TLC监测至原料消失，过滤，浓缩，柱层析PE∶EA＝2∶1(R_f＝0.24，PE∶EA＝2∶1)得53mg化合物47，收率93％，ee值74％。(手性柱拆分条件：PC-2柱，UV 214nm，正己烷∶异丙醇＝20∶30，0.5mL/min)Add compound 46 (68mg, 0.12mmol) to a 50mL single-necked bottle, dissolve it with a mixed solution of EtOH (3mL) and EA (7mL), add palladium carbon (7mg), feed H₂ , monitor by TLC until the raw material disappears, filter, and concentrate , column chromatography PE:EA=2:1 (R_f =0.24, PE:EA=2:1) yielded 53mg of compound 47, yield 93%, ee value 74%. (Chiral column separation conditions: PC-2 column, UV 214nm, n-hexane:isopropanol=20:30, 0.5mL/min)

¹H-NMR(CDCl₃，400MHz)：δ7.55(d，J＝8.2Hz，1H，Ar-H)，7.42-7.39(m，2H，Ar-H)，7.21(d，J＝2.0Hz，1H，Ar-H)，6.95-6.92(m，2H，Ar-H)，6.87(d，J＝8.2Hz，1H，Ar-H)，6.81(br s，1H，OH)，6.71(d，J＝2.0Hz，1H，Ar-H)，5.17-5.14(m，3H)，3.98(s，3H，OCH₃)，3.83(s，3H，OCH₃)，2.24(br s，1H，OH)，1.66-1.52(m，2H，CH₂)，1.02(s，9H，t-Bu-H).¹³C-NMR(CDCl₃，100MHz)：δ167.8，159.3，153.8，151.0，147.9，142.4，138.1，137.9，132.1，131.0，127.9(2C)，126.2，119.2，118.5，117.6，115.4，114.2(2C)，69.3，66.4，62.4，55.3，52.3，30.7，30.1(3C).MS(ESI)：478.9(M+H)⁺.HRMS(APCI)：Calcd.for C₂₈H₃₁O₇⁺(M+H)⁺：479.2070，found：479.2066，[α]_D²⁰＝+55°(C＝0.2，CHCl₃).¹ H-NMR (CDCl₃ , 400MHz): δ7.55 (d, J=8.2Hz, 1H, Ar-H), 7.42-7.39 (m, 2H, Ar-H), 7.21 (d, J=2.0Hz , 1H, Ar-H), 6.95-6.92(m, 2H, Ar-H), 6.87(d, J=8.2Hz, 1H, Ar-H), 6.81(br s, 1H, OH), 6.71(d , J=2.0Hz, 1H, Ar-H), 5.17-5.14 (m, 3H), 3.98 (s, 3H, OCH₃ ), 3.83 (s, 3H, OCH₃ ), 2.24 (br s, 1H, OH ), 1.66-1.52 (m, 2H, CH₂ ), 1.02 (s, 9H, t-Bu-H).¹³ C-NMR (CDCl₃ , 100MHz): δ167.8, 159.3, 153.8, 151.0, 147.9, MS(ESI) ): 478.9 (M+H)⁺ .HRMS (APCI): Calcd.for C₂₈ H₃₁ O₇⁺ (M+H)⁺ : 479.2070, found: 479.2066, [α]_D²⁰ =+55 ° (C = 0.2, CHCl₃ ).

12.步骤1212. Step 12

25mL单口瓶中加入化合物47(7mg，0.015mmol)和干燥的THF(2mL)，后加入NaH(0.7mg，0.017mmol)，室温搅拌1h，后缓慢滴加对三氟甲基苯甲酰氯(3μL，0.017mmol)的THF(2mL)溶液，过夜后停止反应，直接板层析PE∶EA＝3∶1(R_f＝0.24，PE∶EA＝3∶1)得9mg化合物48，收率90％。Add compound 47 (7mg, 0.015mmol) and dry THF (2mL) into a 25mL single-necked bottle, then add NaH (0.7mg, 0.017mmol), stir at room temperature for 1h, then slowly add p-trifluoromethylbenzoyl chloride (3μL , 0.017mmol) in THF (2mL), the reaction was stopped overnight, and direct plate chromatography PE:EA=3:1 (R_f =0.24, PE:EA=3:1) gave 9mg of compound 48, yield 90% .

¹H-NMR(CDCl₃，400MHz)：δ8.42-8.39(m，2H，Ar-H)，7.83-7.80(m，2H，Ar-H)，7.61(d，J＝8.6Hz，1H，Ar-H)，7.47-7.44(m，3H，Ar-H)，7.18(d，J＝2.0Hz，1H，Ar-H)，7.00(d，J＝8.6Hz，1H，Ar-H)，6.98-6.95(m，2H，Ar-H)，5.22(s，2H，CH₂)，5.17-5.15(m，1H，CH)，3.97(s，3H，OCH₃)，3.85(s，3H，OCH₃)，1.86(br s，1H，OH)，1.68-1.53(m，2H，CH₂)，1.02(s，9H，t-Bu-H).¹³C-NMR(CDCl₃，100MHz)：δ166.9，164.1，159.6，154.0，151.0，146.6，142.3，138.4，137.6，135.5，135.1，132.1，131.2，131.1，130.7，128.0，127.8，125.8，125.7，122.3，119.4，118.2，114.3，69.1，66.4，62.9，55.3，52.2，30.7，30.0(3C).¹⁹F-NMR(CDCl₃，376MHz)：δ-63.6.HRMS(APCI)：Calcd.for C₃₆H₃₂F₃O₈^-(M-H)^-：649.2050，found：649.2085，[α]_D²⁰＝+4.9°(C＝1.0，CHCl₃).¹ H-NMR (CDCl₃ , 400MHz): δ8.42-8.39 (m, 2H, Ar-H), 7.83-7.80 (m, 2H, Ar-H), 7.61 (d, J=8.6Hz, 1H, Ar-H), 7.47-7.44 (m, 3H, Ar-H), 7.18 (d, J=2.0Hz, 1H, Ar-H), 7.00 (d, J=8.6Hz, 1H, Ar-H), 6.98-6.95(m, 2H, Ar-H), 5.22(s, 2H, CH₂ ), 5.17-5.15(m, 1H, CH), 3.97(s, 3H, OCH₃ ), 3.85(s, 3H, OCH₃ ), 1.86 (br s, 1H, OH), 1.68-1.53 (m, 2H, CH₂ ), 1.02 (s, 9H, t-Bu-H).¹³ C-NMR (CDCl₃ , 100MHz): δ166.9, 164.1, 159.6, 154.0, 151.0, 146.6, 142.3, 138.4, 137.6, 135.5, 135.1, 132.1, 131.2, 131.1, 130.7, 128.0, 127.8, 125.8, 125.7, 122.3, 169.18.2 66.4, 62.9, 55.3, 52.2, 30.7, 30.0 (3C).¹⁹ F-NMR (CDCl₃ , 376MHz): δ-63.6. HRMS (APCI): Calcd.for C₃₆ H₃₂ F₃ O₈^- (MH)^- : 649.2050, found: 649.2085, [α]_D²⁰ =+4.9°(C=1.0, CHCl₃ ).

实施例7制备下述化合物，Example 7 prepares the following compounds,

1.步骤11. Step 1

25mL单口瓶中加入实施例6步骤11所得化合物47(22mg，0.046mmol)和干燥的THF(2mL)，后加入NaH(2mg，0.051mmol)，室温搅拌1h，后缓慢滴加3，5-二(三氟甲基)苯甲酰氯(12μL，0.066mmol)的THF(2mL)溶液，过夜后停止反应，直接板层析PE∶EA＝3∶1(R_f＝0.67，PE∶EA＝2∶1)得10mg化合物49，收率30％。Add compound 47 (22mg, 0.046mmol) obtained in step 11 of Example 6 and dry THF (2mL) into a 25mL one-mouth bottle, then add NaH (2mg, 0.051mmol), stir at room temperature for 1h, and then slowly add 3,5-di (Trifluoromethyl)benzoyl chloride (12μL, 0.066mmol) in THF (2mL) solution, stop the reaction after overnight, direct plate chromatography PE:EA=3:1 (R_f =0.67, PE:EA=2: 1) 10 mg of compound 49 was obtained, with a yield of 30%.

¹H-NMR(CDCl₃，400MHz)：δ8.73(s，2H，Ar-H)，8.18(s，1H，Ar-H)，7.64(d，J＝8.6Hz，1H，Ar-H)，7.47-7.45(m，3H，Ar-H)，7.21(s，1H，Ar-H)，7.01-6.95(m，3H，Ar-H)，5.22(s，2H，CH₂)，5.18-5.15(m，1H，CH)，3.98(s，3H，OCH₃)，3.85(s，3H，OCH₃)，1.86(br s，1H，OH)，1.69-1.54(m，2H，CH₂)，1.02(s，9H，t-Bu-H).¹³C-NMR(CDCl₃，100MHz)：δ166.8，162.7，159.6，154.1，150.8，146.5，141.9，138.6，137.7，135.5，132.8，132.4，131.2，131.04，131.00，130.4，128.0，127.9，126.1，124.0，122.1，120.8，119.7，118.1，114.4，69.1，66.4，63.0，55.3，52.2，30.7，30.0(3C).¹⁹F-NMR(CDCl₃，376MHz)：δ-63.3.HRMS(APCI)：Calcd.for C₃₇H₃₁F₆O₈^-(M-H)^-：717.1923，found：717.1916，[α]_D²⁰＝+7.0°(C＝1.0，CHCl₃).¹ H-NMR (CDCl₃ , 400MHz): δ8.73 (s, 2H, Ar-H), 8.18 (s, 1H, Ar-H), 7.64 (d, J=8.6Hz, 1H, Ar-H) , 7.47-7.45(m, 3H, Ar-H), 7.21(s, 1H, Ar-H), 7.01-6.95(m, 3H, Ar-H), 5.22(s, 2H, CH₂ ), 5.18- 5.15 (m, 1H, CH), 3.98 (s, 3H, OCH₃ ), 3.85 (s, 3H, OCH₃ ), 1.86 (br s, 1H, OH), 1.69-1.54 (m, 2H, CH₂ ) , 1.02 (s, 9H, t-Bu-H).¹³ C-NMR (CDCl₃ , 100MHz): δ166.8, 162.7, 159.6, 154.1, 150.8, 146.5, 141.9, 138.6, 137.7, 135.5, 132.8, 132.4¹⁹ F-NMR₃ , 376MHz): δ-63.3.HRMS (APCI): Calcd.for C₃₇ H₃₁ F₆ O₈^- (MH)^- : 717.1923, found: 717.1916, [α]_D²⁰ =+7.0° (C = 1.0 , CHCl₃ ).

实施例8：制备下述化合物，Example 8: Preparation of the following compounds,

1.步骤11. Step 1

25mL单口瓶中加入实施例6步骤11所得化合物47(19mg，0.040mmol)和干燥的THF(2mL)，后加入NaH(1.8mg，0.044mmol)，室温搅拌1h，后缓慢滴加实施例1步骤18中酰氯b(9mg，0.052mmol)的THF(2mL)溶液，过夜后停止反应，直接板层析PE∶EA＝3∶1(R_f＝0.37 PE∶EA＝3∶1)得18mg化合物50，收率72％。Add compound 47 (19 mg, 0.040 mmol) obtained in Step 11 of Example 6 and dry THF (2 mL) into a 25 mL single-mouth bottle, then add NaH (1.8 mg, 0.044 mmol), stir at room temperature for 1 h, and then slowly add step 1 in Example 1 Acid chloride b (9mg, 0.052mmol) in THF (2mL) solution in 18, the reaction was stopped after overnight, direct plate chromatography PE:EA=3:1 (R_f =0.37 PE:EA=3:1) gave 18mg of compound 50 , yield 72%.

¹H-NMR(CDCl₃，400MHz)：δ7.63(d，J＝8.6Hz，1H，Ar-H)，7.43-7.40(m，2H，Ar-H)，7.20(s，1H，Ar-H)，7.08(s，1H，Ar-H)，7.04(d，J＝8.6Hz，1H，Ar-H)，6.95-6.93(m，2H，Ar-H)，5.19-5.16(m，3H)，3.99(s，3H，OCH₃)，3.83(s，3H，OCH₃)，2.35(s，2H)，2.00-1.85(m，5H)，1.71-1.56(m，2H，CH₂)，1.48(s，3H，CH₃)，1.35-1.33(m，4H)，1.03(s，9H，t-Bu-H).¹³C-NMR(CDCl₃，100MHz)：δ191.0，175.3，167.1，159.5，153.9，151.3，147.2，142.4，138.3，137.4，131.4，131.2，128.0，127.6，125.3，122.4，118.4，114.3，69.3，66.4，63.0，58.6，55.3，52.3，42.0，30.7，30.1，29.4，27.8，17.2.HRMS(APCI)：Calcd.for C₃₇H₄₁O₈^-(M-H)^-：613.2802，found：613.2816，[α]_D²⁰＝+16.2°(C＝0.5，CHCl₃).¹ H-NMR (CDCl₃ , 400MHz): δ7.63 (d, J=8.6Hz, 1H, Ar-H), 7.43-7.40 (m, 2H, Ar-H), 7.20 (s, 1H, Ar- H), 7.08(s, 1H, Ar-H), 7.04(d, J=8.6Hz, 1H, Ar-H), 6.95-6.93(m, 2H, Ar-H), 5.19-5.16(m, 3H ), 3.99 (s, 3H, OCH₃ ), 3.83 (s, 3H, OCH₃ ), 2.35 (s, 2H), 2.00-1.85 (m, 5H), 1.71-1.56 (m, 2H, CH₂ ), 1.48 (s, 3H, CH₃ ), 1.35-1.33 (m, 4H), 1.03 (s, 9H, t-Bu-H).¹³ C-NMR (CDCl₃ , 100MHz): δ191.0, 175.3, 167.1 , 159.5, 153.9, 151.3, 147.2, 142.4, 138.3, 137.4, 131.4, 131.2, 128.0, 127.6, 125.3, 122.4, 118.4, 114.3, 69.3, 66.4, 63.0, 58.6, 55.3, 52.3, 07.3, 9 , 27.8, 17.2. HRMS (APCI): Calcd. for C₃₇ H₄₁ O₈^- (MH)^- : 613.2802, found: 613.2816, [α]_D²⁰ = +16.2° (C = 0.5, CHCl₃ ).

实施例9：制备下述化合物，Example 9: Preparation of the following compound,

1.步骤11. Step 1

25mL单口瓶中加入实施例1步骤17所得化合物17(30mg，0.081mmol)和干燥的THF(5mL)，后加入NaH(3.2mg，0.081mmol)室温搅拌1h，后缓慢滴加对三氟苯甲酰氯(0.013mL，0.089mmol)，1h后停止反应，加入H₂O(5mL)，EA萃取(3x10mL)，有机相无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝3∶1(R_f＝0.54，PE∶EA＝3∶1)得24mg化合物51，产率55％。Add compound 17 (30mg, 0.081mmol) obtained in step 17 of Example 1 and dry THF (5mL) into a 25mL one-mouth bottle, then add NaH (3.2mg, 0.081mmol) and stir at room temperature for 1h, then slowly add p-trifluorobenzyl Acid chloride (0.013mL, 0.089mmol), stop the reaction after 1h, add H₂ O (5mL), extract with EA (3x10mL), dry the organic phase over anhydrous Na₂ SO₄ , filter, concentrate, column chromatography PE:EA=3 :1 (R_f =0.54, PE:EA=3:1) yielded 24 mg of compound 51, yield 55%.

¹H-NMR(CDCl₃，400MHz)：δ8.39(d，2H，J＝8.2Hz，Ar-H)，7.81(d，2H，J＝8.2Hz，Ar-H)，7.60(d，1H，J＝8.6Hz，Ar-H)，7.30(d，1H，J＝8.2Hz，Ar-H)，7.16(t，1H，J＝7.8Hz，Ar-H)，7.04(d，1H，J＝7.4Hz，Ar-H)，6.96(d，1H，J＝8.6Hz，Ar-H)，5.17-5.15(m，3H)，3.96(s，3H，OCH₃)，1.86(d，1H，J＝4.3Hz，OH)，1.67-1.52(m，2H，CH₂)，1.02(s，9H，t-Bu-H).¹³C-NMR(CDCl₃，100MHz)：δ162.6，159.8，149.7，146.6，143.7，138.0，134.2，127.8，126.8，126.4，123.5，121.5，120.1，115.2，113.9，108.0，64.6，62.1，58.6，48.0，26.4，25.8.HRMS(ESI)：Calcd.for C₂₉H₂₇F₃O₇Na⁺(M+Na)⁺：567.1607，found 567.1593.¹ H-NMR (CDCl₃ , 400MHz): δ8.39(d, 2H, J=8.2Hz, Ar-H), 7.81(d, 2H, J=8.2Hz, Ar-H), 7.60(d, 1H , J=8.6Hz, Ar-H), 7.30(d, 1H, J=8.2Hz, Ar-H), 7.16(t, 1H, J=7.8Hz, Ar-H), 7.04(d, 1H, J =7.4Hz, Ar-H), 6.96(d, 1H, J=8.6Hz, Ar-H), 5.17-5.15(m, 3H), 3.96(s, 3H, OCH₃ ), 1.86(d, 1H, J=4.3Hz, OH), 1.67-1.52 (m, 2H, CH₂ ), 1.02 (s, 9H, t-Bu-H).¹³ C-NMR (CDCl₃ , 100MHz): δ162.6, 159.8, 149.7, 146.6,_143.7 , 138.0, 134.2, 127.8, 126.8, 126.4, 123.5, 121.5, 120.1, 115.2, 113.9, 108.0, 64.6, 62.1, 58.6, 48.0, 26.4, 25.8. H₂₇ F₃ O₇ Na⁺ (M+Na)⁺ : 567.1607, found 567.1593.

实施例10：制备下述化合物，Example 10: Preparation of the following compound,

1.步骤11. Step 1

25mL单口瓶中加入实施例1步骤17所得化合物17(29mg，0.078mmol)和干燥的THF(5mL)，后加入NaH(3.4mg，0.086mmol)室温搅拌1h，后缓慢滴加3，5-二(三氟甲基)苯甲酰氯(0.016mL，0.086mmol)，1h后停止反应，加入H₂O(5mL)，EA萃取(3x10mL)，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝10∶1(R_f＝0.71，PE∶EA＝3∶1)得31mg化合物52，产率65％。Add compound 17 (29mg, 0.078mmol) obtained in step 17 of Example 1 and dry THF (5mL) into a 25mL one-mouth bottle, then add NaH (3.4mg, 0.086mmol) and stir at room temperature for 1h, then slowly add 3,5-di (Trifluoromethyl)benzoyl chloride (0.016mL, 0.086mmol), stop the reaction after 1h, add_H2O (5mL), extract with EA (3x10mL), dry_over anhydrous_Na2SO4 , filter, concentrate, column Analysis of PE: EA = 10: 1 (R_f = 0.71, PE: EA = 3: 1) yielded 31 mg of compound 52 with a yield of 65%.

¹H-NMR(CDCl₃，400MHz)：δ8.71(s，2H，Ar-H)，8.17(s，1H，Ar-H)，7.62(d，1H，J＝8.6Hz，Ar-H)，7.30-7.26(m，1H，Ar-H)，7.18(t，1H，J＝7.8Hz，Ar-H)，7.07(d，1H，J＝7.4Hz，Ar-H)，6.96(d，1H，J＝8.6Hz，Ar-H)，5.17-5.16(m，3H)，3.97(s，3H，OCH₃)，1.84(d，1H，J＝4.3Hz，OH)，1.68-1.53(m，2H，CH₂)，1.02(s，9H，t-Bu-H).¹³C-NMR(CDCl₃，100MHz)：δ162.5，158.4，149.7，146.4，143.6，137.5，134.3，128.5，128.1，126.9，126.7，126.1，123.9，123.6，123.0，120.2，120.0，119.8，117.0，115.2，113.8，64.6，62.1，58.7，48.0，26.4，25.8.HRMS(ESI)：Calcd.for C₃₀H₂₆F₆O₇Na⁺(M+Na)⁺：635.1480，found 635.1473.¹ H-NMR (CDCl₃ , 400MHz): δ8.71 (s, 2H, Ar-H), 8.17 (s, 1H, Ar-H), 7.62 (d, 1H, J=8.6Hz, Ar-H) , 7.30-7.26(m, 1H, Ar-H), 7.18(t, 1H, J=7.8Hz, Ar-H), 7.07(d, 1H, J=7.4Hz, Ar-H), 6.96(d, 1H, J=8.6Hz, Ar-H), 5.17-5.16(m, 3H), 3.97(s, 3H, OCH₃ ), 1.84(d, 1H, J=4.3Hz, OH), 1.68-1.53(m , 2H, CH₂ ), 1.02 (s, 9H, t-Bu-H).¹³ C-NMR (CDCl₃ , 100MHz): δ162.5, 158.4, 149.7, 146.4, 143.6, 137.5, 134.3, 128.5, 128.1 , 126.9, 126.7, 126.1, 123.9, 123.6, 123.0, 120.2, 120.0, 119.8, 117.0, 115.2, 113.8, 64.6, 62.1, 58.7, 48.0, 26.4, 25.8. HRMS (ESI): Calcd.for C₃₀ H₂₆ F₆ O₇ Na⁺ (M+Na)⁺ : 635.1480, found 635.1473.

实施例11：制备下述化合物，Example 11: Preparation of the following compound,

1.步骤11. Step 1

100mL的单口瓶中加入H₂O(14mL)，HBr(3.5mL)，后加入2-氨基-5甲基苯甲酸(1g，6.62mmol)使之溶解。冰盐浴下滴加NaNO₂(0.498g，7.22mmol)的水溶液(2mL)，搅拌1h，缓慢滴加CuBr(1.35g，9.47mmol)的HBr溶液(5mL)。搅拌至不再生成气泡，油浴加热80℃，反应过夜，第二日早停止反应，冷却，过滤，水洗(R_f＝0.33，PE∶EA＝2∶1)得1.325g化合物53，产率93％。Add H₂ O (14 mL), HBr (3.5 mL) into a 100 mL single-necked bottle, and then add 2-amino-5-methylbenzoic acid (1 g, 6.62 mmol) to dissolve it. An aqueous solution (2 mL) of NaNO₂ (0.498 g, 7.22 mmol) was added dropwise in an ice-salt bath, stirred for 1 h, and a HBr solution (5 mL) of CuBr (1.35 g, 9.47 mmol) was slowly added dropwise. Stir until no more bubbles are generated, heat in an oil bath at 80°C, react overnight, stop the reaction early the next day, cool, filter, and wash with water (R_f =0.33, PE:EA=2:1) to obtain 1.325 g of compound 53, the yield 93%.

¹H-NMR(CDCl₃，300MHz)：δ7.81(s，1H，Ar-H)，7.57(d，1H，J＝8.1Hz，Ar-H)，7.20(dd，1H，J＝8.1，1.5Hz，Ar-H)，2.36(s，3H，CH₃).¹ H-NMR (CDCl₃ , 300MHz): δ7.81 (s, 1H, Ar-H), 7.57 (d, 1H, J=8.1Hz, Ar-H), 7.20 (dd, 1H, J=8.1, 1.5Hz, Ar-H), 2.36(s, 3H,_CH3 ).

2.步骤22. Step 2

50mL单口瓶中依次加入化合物53(1.228g，5.99mmol)，甲醇(7.04mL)浓硫酸(0.71mL)，加热回流7h。停止反应，冷却，加入饱和NaHCO₃溶液调pH值至7，EA萃取有机相(3x30mL)，水洗(1x30mL)，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝100∶1(R_f＝0.89，PE∶EA＝2∶1)得1.348g化合物54，产率98％。Compound 53 (1.228g, 5.99mmol), methanol (7.04mL) and concentrated sulfuric acid (0.71mL) were sequentially added into a 50mL single-necked bottle, and heated to reflux for 7h. Stop the reaction, cool, add saturated NaHCO₃ solution to adjust the pH to 7, extract the organic phase with EA (3x30mL), wash with water (1x30mL), dry over anhydrous Na₂ SO₄ , filter, concentrate, column chromatography PE:EA=100: 1 (R_f =0.89, PE:EA=2:1) yielded 1.348 g of compound 54, with a yield of 98%.

¹H-NMR(CDCl₃，300MHz)：δ7.60(s，1H，Ar-H)，7.52(d，1H，J＝8.1Hz，Ar-H)，7.21(d，1H，J＝7.8Hz，Ar-H)，3.92(s，3H，OCH₃)，2.33(s，3H，CH₃).¹ H-NMR (CDCl₃ , 300MHz): δ7.60(s, 1H, Ar-H), 7.52(d, 1H, J=8.1Hz, Ar-H), 7.21(d, 1H, J=7.8Hz , Ar-H), 3.92(s, 3H, OCH₃ ), 2.33(s, 3H, CH₃ ).

3.步骤33. Step 3

50mL单口瓶中依次加入NBS(3.26g，18.3mmoL)，AIBN(0.143g，0.873mmol)，氩气保护下加入化合物54的CCl₄(20mL)溶液，加热回流2h，后冷却补加NBS(1.71g，9.6mmol)和AIBN(0.143g，0.873mmol)，加热回流2h。停止反应，冷却，过滤，浓缩。加入浓硫酸(8mL)，室温搅拌，TCL跟踪反应至原料消失，倒入冰水(30mL)中，EA萃取有机相(3x30mL)，饱和NaHCO₃洗(1x30mL)，水洗(1x30mL)，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝30∶1(R_f＝0.55，PE∶EA＝5∶1)得1.131g化合物55，收率53％。Add NBS (3.26g, 18.3mmoL) and AIBN (0.143g, 0.873mmol) to a 50mL single-necked bottle successively, add the CCl₄ (20mL) solution of compound 54 under the protection of argon, heat and reflux for 2h, and add NBS (1.71mL) after cooling. g, 9.6mmol) and AIBN (0.143g, 0.873mmol), heated to reflux for 2h. The reaction was stopped, cooled, filtered and concentrated. Add concentrated sulfuric acid (8mL), stir at room temperature, follow the reaction with TCL until the raw material disappears, pour into ice water (30mL), extract the organic phase with EA (3x30mL), wash with saturated NaHCO₃ (1x30mL), wash with water (1x30mL), anhydrous NaHCO₂ SO₄ dried, filtered, concentrated, column chromatography PE: EA = 30: 1 (R_f = 0.55, PE: EA = 5: 1) to obtain 1.131 g of compound 55, yield 53%.

¹H-NMR(CDCl₃，300MHz)：δ10.02(s，1H，CHO)，8.29(d，1H，J＝1.5Hz，Ar-H)，7.87(d，1H，J＝8.4Hz，Ar-H)，7.83(dd，1H，J＝8.4，1.5Hz，Ar-H)，3.98(s，3H，OCH₃).MS(EI)：244，242.¹ H-NMR (CDCl₃ , 300MHz): δ10.02(s, 1H, CHO), 8.29(d, 1H, J=1.5Hz, Ar-H), 7.87(d, 1H, J=8.4Hz, Ar -H), 7.83 (dd, 1H, J=8.4, 1.5Hz, Ar-H), 3.98 (s, 3H, OCH₃ ). MS (EI): 244, 242.

4.步骤44. Step 4

100mL单口瓶中加入实施例1步骤3所得化合物3(1.258g，4.01mmol)，化合物55(0.811g，3.34mmol)，CuBr(0.239g，1.67mmol)，Cs₂CO₃(2.178g，6.68mmol)，后加入NMP(10mL)，2，2，6，6-四甲基-3，5-庚二酮(0.069mL，0.334mmol)，脱气0.5h，后加热至80℃，反应2h后停止反应，冷却，加入H₂O(1x30mL)，用3N HCl调pH值至4，EA萃取(3x30mL)有机相，水洗(1x50mL)，饱和NH₄Cl洗(1x30mL)，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝15∶1(R_f＝0.12，PE∶EA＝20∶1)得1.14g化合物56，收率72％。Compound 3 (1.258g, 4.01mmol), compound 55 (0.811g, 3.34mmol), CuBr (0.239g, 1.67mmol), Cs₂ CO₃ (2.178g, 6.68mmol) obtained in Step 3 of Example 1 were added to a 100mL one-mouth bottle ), then added NMP (10mL), 2,2,6,6-tetramethyl-3,5-heptanedione (0.069mL, 0.334mmol), degassed for 0.5h, then heated to 80°C, and reacted for 2h Stop the reaction, cool, add H₂ O (1x30mL), adjust the pH to 4 with 3N HCl, extract the organic phase with EA (3x30mL), wash with water (1x50mL), wash with saturated NH₄ Cl (1x30mL), anhydrous Na₂ SO₄ Drying, filtration, concentration, and column chromatography PE:EA=15:1 (R_f =0.12, PE:EA=20:1) yielded 1.14 g of compound 56 with a yield of 72%.

¹H-NMR(CDCl₃，400MHz)：δ9.92(s，1H，CHO)，8.40(d，1H，J＝1.57Hz，Ar-H)，7.84-7.81(m，1H，Ar-H)，7.27-7.15(m，5H，Ar-H)，7.08-7.06(m，2H，Ar-H)，7.01(d，1H，J＝7.8Hz，Ar-H)，6.77(d，1H，J＝9.0Hz，Ar-H)，5.01(s，2H，OCH₂)，4.78(d，1H，J＝12Hz，OCH₂)，4.64(s，1H，OCH)，4.53(d，1H，J＝12Hz，OCH₂)，3.94(s，3H，COOCH₃)，3.76-3.45(m，2H，OCH₂)，1.61-1.40(m，6H，CH₂).¹³C-NMR(CDCl₃，100MHz)：δ190.1，165.3，162.7，150.3，140.9，136.3，134.9，133.3，132.9，130.0，128.3，127.7，126.7，126.3，122.1，120.1，115.9，114.2，98.3，70.6，64.3，61.8，52.3，30.2，25.3.MS(ESI)：499.4(M+Na)⁺.HRMS(ESI)：Calcd.for C₂₈H₂₈O₇Na⁺(M+Na)⁺：499.1733，found：499.1711.¹ H-NMR (CDCl₃ , 400MHz): δ9.92 (s, 1H, CHO), 8.40 (d, 1H, J=1.57Hz, Ar-H), 7.84-7.81 (m, 1H, Ar-H) , 7.27-7.15(m, 5H, Ar-H), 7.08-7.06(m, 2H, Ar-H), 7.01(d, 1H, J=7.8Hz, Ar-H), 6.77(d, 1H, J =9.0Hz, Ar-H), 5.01(s, 2H, OCH₂ ), 4.78(d, 1H, J=12Hz, OCH₂ ), 4.64(s, 1H, OCH), 4.53(d, 1H, J= 12Hz, OCH₂ ), 3.94(s, 3H, COOCH₃ ), 3.76-3.45(m, 2H, OCH₂ ), 1.61-1.40(m, 6H, CH₂ ).¹³ C-NMR(CDCl₃ , 100MHz) : δ190.1, 165.3, 162.7, 150.3, 140.9, 136.3, 134.9, 133.3, 132.9, 130.0, 128.3, 127.7, 126.7, 126.3, 122.1, 120.1, 115.9, 114.2, 98.3, 70.6, 38.3, 2 , 25.3. MS (ESI): 499.4 (M+Na)^{+ .} HRMS (ESI): Calcd. for C₂₈ H₂₈ O₇ Na⁺ (M+Na)⁺ : 499.1733, found: 499.1711.

5.步骤55. Step 5

100mL的单口瓶中依次加入化合物56(1.12g，2.35mmol)，PTSA(3mg)，加入异丙醇(10mL)和H₂O(2.6mL)，加热回流过夜，第二日早停止反应，冷却，加入H₂O(10mL)，EA萃取(3x30mL)，H₂O洗(1x30mL)，无水MgSO₄干燥，过滤，浓缩，柱层析PE∶EA＝3∶1(R_f＝0.14，PE∶EA＝3∶1)得0.871g化合物57，收率95％。Add compound 56 (1.12g, 2.35mmol), PTSA (3mg), isopropanol (10mL) and H₂ O (2.6mL) to a 100mL single-necked bottle in turn, heat and reflux overnight, stop the reaction early the next day, and cool , added H₂ O (10 mL), extracted with EA (3x30 mL), washed with H₂ O (1x30 mL), dried with anhydrous MgSO₄ , filtered, concentrated, column chromatography PE:EA=3:1 (R_f =0.14, PE :EA=3:1) to obtain 0.871 g of compound 57, yield 95%.

¹H-NMR(CDCl₃，300MHz)：δ9.92(s，1H，CHO)，8.41(s，1H，Ar-H)，7.85(d，1H，J＝8.7Hz，Ar-H)，7.24-7.02(m，8H，Ar-H)，6.79(d，1H，J＝8.7Hz，Ar-H)，5.04(s，2H，OCH₂)，4.58(s，2H，OCH₂)，3.96(s，3H，COOCH₃)，2.09(s，1H，OH).HRMS(ESI)：Calcd.for C₂₃H₂₀O₆Na⁺(M+Na)⁺：415.1158，found：415.1154.¹ H-NMR (CDCl₃ , 300MHz): δ9.92 (s, 1H, CHO), 8.41 (s, 1H, Ar-H), 7.85 (d, 1H, J=8.7Hz, Ar-H), 7.24 -7.02 (m, 8H, Ar-H), 6.79 (d, 1H, J=8.7Hz, Ar-H), 5.04 (s, 2H, OCH₂ ), 4.58 (s, 2H, OCH₂ ), 3.96 ( s, 3H, COOCH₃ ), 2.09 (s, 1H, OH). HRMS (ESI): Calcd. for C₂₃ H₂₀ O₆ Na⁺ (M+Na)⁺ : 415.1158, found: 415.1154.

6.步骤66. Step 6

100mL的单口瓶中加入化合物57(0.871g，2.22mmol)，用MeOH溶解(13mL)，加入PTSA(0.19g 1.11mmol)，室温搅拌1h，加入NaOH(0.977g，24.42mmol)，加热回流，反应过夜。第二日早停止反应，冷却，旋转蒸发出MeOH，用3N HCl调pH值至4，EA萃取(4x30mL)，无水Na₂SO₄干燥，过滤，浓缩，得化合物58粗品0.775g。Add compound 57 (0.871g, 2.22mmol) to a 100mL single-necked bottle, dissolve (13mL) with MeOH, add PTSA (0.19g 1.11mmol), stir at room temperature for 1h, add NaOH (0.977g, 24.42mmol), heat to reflux, and react overnight. The next day, the reaction was stopped, cooled, and MeOH was rotovapped, adjusted to pH 4 with 3N HCl, extracted with EA (4x30mL), dried over anhydrous Na₂ SO₄ , filtered, and concentrated to obtain 0.775 g of crude compound 58.

¹H-NMR(DMSO-d₆，300MHz)：δ13.21(s，1H，COOH)，9.94(s，1H，CHO)，8.35(d，1H，J＝1.8Hz，Ar-H)，7.95-7.91(m，1H，Ar-H)，7.33-6.99(m，8H，Ar-H)，6.71(d，1H，J＝8.4Hz，Ar-H)，5.08(s，2H，OCH₂)，4.47(s，2H，OCH₂).MS(ESI)：377.1(M-H)^-.¹ H-NMR (DMSO-d₆ , 300MHz): δ13.21 (s, 1H, COOH), 9.94 (s, 1H, CHO), 8.35 (d, 1H, J=1.8Hz, Ar-H), 7.95 -7.91(m, 1H, Ar-H), 7.33-6.99(m, 8H, Ar-H), 6.71(d, 1H, J=8.4Hz, Ar-H), 5.08(s, 2H, OCH₂ ) , 4.47(s, 2H, OCH₂ ). MS(ESI): 377.1(MH)^- .

7.步骤77. Step 7

将化合物58的粗品(0.775g，2.65mmol)和三乙胺(2.28mL，16.4mmol)溶于干燥的CH₃CN(20mL)中，将上述制得的溶液室温下缓慢滴加到由碘化-2-氯-1-甲基吡啶(2.091g，8.2mmol)溶于干燥的CH₃CN(53mL)所配置的溶液中。滴加完毕后，加热回流反应1h。后停止反应，冷却，旋出CH₃CN，加H₂O(20mL)，DCM萃取(3x30mL)，无水Na₂SO₄干燥，过滤，浓缩，柱层析DCM(R_f＝0.67，PE∶EA＝2∶1)得0.549g化合物59，两步收率合计69％。The crude product of compound 58 (0.775g, 2.65mmol) and triethylamine (2.28mL, 16.4mmol) were dissolved in dry CH₃ CN (20mL), and the solution prepared above was slowly added dropwise to -2-Chloro-1-methylpyridine (2.091 g, 8.2 mmol) was dissolved in dry_CH3CN (53 mL). After the dropwise addition was completed, the reaction was heated to reflux for 1 h. Stop the reaction after cooling, spin out CH₃ CN, add H₂ O (20 mL), extract with DCM (3x30 mL), dry over anhydrous Na₂ SO₄ , filter, concentrate, column chromatography DCM (R_f =0.67, PE: EA=2:1) to obtain 0.549 g of compound 59, the total yield of the two steps was 69%.

¹H-NMR(CDCl₃，400MHz)：δ10.02(s，1H，CHO)，8.13(d，1H，J＝2Hz，Ar-H)，8.07(dd，1H，J＝8.2，2Hz，Ar-H)，7.52-7.36(m，6H，Ar-H)，7.11-7.04(m，2H，Ar-H)，6.79(dd，1H，J＝7.4，2Hz，Ar-H)，5.24(s，2H，OCH₂)，5.13(s，2H，OCH₂).¹³C-NMR(CDCl₃，100MHz)：δ189.7，168.6，156.6，150.7，145.1，136.4，134.5，134.3，131.1，128.7，128.2，127.9，127.5，127.3，125.2，124.5，121.2，115.9，71.3，69.2.HRMS(ESI)：Calcd.for C₂₂H₁₅O₅^-(M-H)^-：359.0920，found：359.0914.¹ H-NMR (CDCl₃ , 400MHz): δ10.02(s, 1H, CHO), 8.13(d, 1H, J=2Hz, Ar-H), 8.07(dd, 1H, J=8.2, 2Hz, Ar -H), 7.52-7.36(m, 6H, Ar-H), 7.11-7.04(m, 2H, Ar-H), 6.79(dd, 1H, J=7.4, 2Hz, Ar-H), 5.24(s , 2H, OCH₂ ), 5.13 (s, 2H, OCH₂ ).¹³ C-NMR (CDCl₃ , 100MHz): δ189.7, 168.6, 156.6, 150.7, 145.1, 136.4, 134.5, 134.3, 131.1, 128.7,_128.2 ,_127.9^,_127.5^, 127.3, 125.2, 124.5, 121.2, 115.9, 71.3, 69.2.

8.步骤88. Step 8

100mL单口瓶中加入化合物59(0.15g，0.385mmol)，氩气保护下，加入干燥的THF(10mL)，冰浴下滴加上述制备好的新戊基溴化镁(0.9mL，2.308mmol)，后自然升温至室温搅拌1h，加入饱和NH₄Cl淬灭反应，EA萃取(3x30mL)，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝3∶1(R_f＝0.13，DCM)得0.173g化合物60，收率97％。Add compound 59 (0.15g, 0.385mmol) to a 100mL single-necked bottle, under the protection of argon, add dry THF (10mL), and add the above-prepared neopentylmagnesium bromide (0.9mL, 2.308mmol) dropwise under ice bath , then naturally warmed to room temperature and stirred for 1 h, quenched the reaction by adding saturated NH₄ Cl, extracted with EA (3x30 mL), dried over anhydrous Na₂ SO₄ , filtered, concentrated, column chromatography PE:EA=3:1 (R_f = 0.13, DCM) to obtain 0.173 g of compound 60, yield 97%.

¹H-NMR(CDCl₃，400MHz)：δ7.57-7.49(m，4H，Ar-H)，7.43-7.38(m，2H，Ar-H)，7.36-7.31(m，1H，Ar-H)，7.20(d，1H，J＝8.2Hz，Ar-H)，7.07-6.97(m，2H，Ar-H)，6.67(dd，1H，J＝7.4，1.2Hz，Ar-H)，5.23(s，2H，OCH₂)，5.10(s，2H，OCH₂)，4.90-4.86(m，1H，OCH)，1.75-1.54(m，2H，CH₂)，1.00(s，9H，t-Bu-H).¹³C-NMR(CDCl₃，100MHz)：δ170.0，151.1，150.6，146.0，145.0，136.7，131.2，128.7，128.1，128.0，127.3，126.3，126.1，124.5，123.4，121.3，116.0，71.5，71.4，69.4，53.2，30.6，30.2.MS(EI)：432，414，361，341，324，293，268，203，147，91，65，57，41.HRMS(ESI)：Calcd.for C₂₇H₂₇O₅^-(M-H)^-：431.1859，found：431.1858.¹ H-NMR (CDCl₃ , 400MHz): δ7.57-7.49 (m, 4H, Ar-H), 7.43-7.38 (m, 2H, Ar-H), 7.36-7.31 (m, 1H, Ar-H ), 7.20 (d, 1H, J=8.2Hz, Ar-H), 7.07-6.97 (m, 2H, Ar-H), 6.67 (dd, 1H, J=7.4, 1.2Hz, Ar-H), 5.23 (s, 2H, OCH₂ ), 5.10 (s, 2H, OCH₂ ), 4.90-4.86 (m, 1H, OCH), 1.75-1.54 (m, 2H, CH₂ ), 1.00 (s, 9H, t- Bu-H).¹³ C-NMR (CDCl₃ , 100MHz): δ170.0, 151.1, 150.6, 146.0, 145.0, 136.7, 131.2, 128.7, 128.1, 128.0, 127.3, 126.3, 126.1, 124.5, 123.4, 121.3, 116.0, 71.5, 71.4, 69.4, 53.2, 30.6, 30.2. Calcd.for C₂₇ H₂₇ O₅^- (MH)^- : 431.1859, found: 431.1858.

9.步骤99. Step 9

100mL单口瓶中加入化合物60(0.056g，0.13mmol)，DMSO溶解(10mL)，后加入IBX(0.073g，0.26mmol)，室温搅拌过夜，第二日早停止反应，加入H2O(10mL)，DCM萃取(4x20mL)，水洗(1x50mL)，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝4∶1(R_f＝0.5，PE∶EA＝3∶1)得0.157g化合物61，收率91％。Compound 60 (0.056g, 0.13mmol) was added to a 100mL single-necked bottle, dissolved in DMSO (10mL), then IBX (0.073g, 0.26mmol) was added, stirred at room temperature overnight, and the reaction was stopped early the next day, and H2O (10mL), DCM Extracted (4x20mL), washed with water (1x50mL), dried over anhydrous Na₂ SO₄ , filtered, concentrated, column chromatography PE:EA=4:1 (R_f =0.5, PE:EA=3:1) yielded 0.157g compound 61, yield 91%.

¹H-NMR(CDCl₃，400MHz)：δ8.17(s，1H，Ar-H)，8.12(d，1H，J＝8.2Hz，Ar-H)，7.51-7.28(m，6H，Ar-H)，7.10-7.02(m，2H，Ar-H)，6.69(d，1H，J＝7.0Hz，Ar-H)，5.24(s，2H，OCH₂)，5.11(s，2H，OCH₂)，2.86(s，2H，COCH₂)，1.07(s，9H，t-Bu-H).¹³C-NMR(CDCl₃，100MHz)：δ198.0，169.1，155.3，150.6，145.3，136.6，136.5，133.8，129.3，128.7，128.1，127.9，127.3，126.6，125.0，123.7，121.2，115.8，71.2，69.2，50.1，31.5，29.3.MS(EI)：430，359，339，309，268，253，212，147，139，91，65.HRMS(EI)：Calcd.for C₂₇H₂₆O₅：430.1780，found：430.1776.¹ H-NMR (CDCl₃ , 400MHz): δ8.17(s, 1H, Ar-H), 8.12(d, 1H, J=8.2Hz, Ar-H), 7.51-7.28(m, 6H, Ar-H) H), 7.10-7.02 (m, 2H, Ar-H), 6.69 (d, 1H, J=7.0Hz, Ar-H), 5.24 (s, 2H, OCH₂ ), 5.11 (s, 2H, OCH₂ ), 2.86 (s, 2H, COCH₂ ), 1.07 (s, 9H, t-Bu-H).¹³ C-NMR (CDCl₃ , 100MHz): δ198.0, 169.1, 155.3, 150.6, 145.3, 136.6, 136.5, 133.8, 129.3, 128.7, 128.1, 127.9, 127.3, 126.6, 125.0, 123.7, 121.2, 115.8, 71.2, 69.2, 50.1, 31.5, 29.3. , 212, 147, 139, 91, 65. HRMS (EI): Calcd. for C₂₇ H₂₆ O₅ : 430.1780, found: 430.1776.

10.步骤1010. Step 10

氩气保护下，在25mL单口瓶中加入(R)-Me-CBS(0.11mL，0.112mmol)，后加入THF(5mL)。降温至-20℃，加入BH₃(0.37mL，0.374mmol，1M in THF)，后缓慢滴加化合物61(0.161g，0.374mmol)的THF溶液(7mL)，3h滴加完毕。-20℃反应4h后停止反应，加入H₂O(5mL)淬灭反应，EA萃取(3x20mL)有机相，水洗(1x20mL)，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝3∶1(R_f＝0.13，PE∶EA＝5∶1)得0.095g化合物62，收率59％，转化率80％，ee值95.5％。(手性柱拆分条件：Chiralcel AD-H柱，正己烷∶异丙醇＝4∶1，0.7mL/min，保留时间：t＝23.19，t＝30.22)Under the protection of argon, (R)-Me-CBS (0.11 mL, 0.112 mmol) was added to a 25 mL single-necked bottle, followed by THF (5 mL). Cool down to -20°C, add BH₃ (0.37mL, 0.374mmol, 1M in THF), and then slowly add compound 61 (0.161g, 0.374mmol) in THF solution (7mL) dropwise, and the dropwise addition was completed within 3h. Stop the reaction after reacting at -20°C for 4h, add H₂ O (5mL) to quench the reaction, extract the organic phase with EA (3x20mL), wash with water (1x20mL), dry over anhydrous Na₂ SO₄ , filter, concentrate, column chromatography PE: EA=3:1 (R_f =0.13, PE:EA=5:1) yielded 0.095 g of compound 62, with a yield of 59%, a conversion of 80%, and an ee value of 95.5%. (Chiral column separation conditions: Chiralcel AD-H column, n-hexane:isopropanol=4:1, 0.7mL/min, retention time: t=23.19, t=30.22)

11.步骤1111. Step 11

100mL单口瓶中加入化合物62(0.095g，0.22mmol)，用EtOH(3mL)和EA(7mL)的混合溶液溶解后加入钯碳(10mg)，通入H₂，TLC监测至原料消失后，过滤，浓缩，得78mg化合物63，收率定量。Add compound 62 (0.095g, 0.22mmol) to a 100mL single-necked bottle, dissolve it with a mixed solution of EtOH (3mL) and EA (7mL), add palladium carbon (10mg), feed H₂ , monitor by TLC until the raw material disappears, and filter , concentrated to obtain 78 mg of compound 63, and the yield was quantitative.

¹H-NMR(CDCl₃，400MHz)：δ7.52-7.49(m，2H，Ar-H)，7.12-7.09(m，1H，Ar-H)，7.07-7.04(m，1H，Ar-H)，6.99-6.94(m，1H，Ar-H)，6.75(br s，1H，Ar-OH)，6.57(dd，1H，J＝7.6，1.4Hz，Ar-H)，5.06(s，2H，OCH₂)，4.87(dd，1H，J＝8.8，2.9Hz，OCH)，1.73-1.50(m，2H，CH₂)，1.00(s，9H，t-Bu-H).¹³C-NMR(CDCl₃，100MHz)：δ170.3，150.0，147.7，145.6，143.2，131.2，126.3，126.2，126.1，124.8，122.9，120.2，117.3，71.4，69.3，53.1，30.6，30.1.HRMS(ESI)：Calcd.for C₂₀H₂₁O₅^-(M-H)^-：341.1389，found：341.1415.¹ H-NMR (CDCl₃ , 400MHz): δ7.52-7.49 (m, 2H, Ar-H), 7.12-7.09 (m, 1H, Ar-H), 7.07-7.04 (m, 1H, Ar-H ), 6.99-6.94 (m, 1H, Ar-H), 6.75 (br s, 1H, Ar-OH), 6.57 (dd, 1H, J=7.6, 1.4Hz, Ar-H), 5.06 (s, 2H , OCH₂ ), 4.87 (dd, 1H, J=8.8, 2.9Hz, OCH), 1.73-1.50 (m, 2H, CH₂ ), 1.00 (s, 9H, t-Bu-H).¹³ C-NMR (CDCl₃ , 100MHz): δ170.3, 150.0, 147.7, 145.6, 143.2, 131.2, 126.3, 126.2, 126.1, 124.8, 122.9, 120.2, 117.3, 71.4, 69.3, 53.1, 30.6, 30.1. HRMS (ESI): Calcd.for C₂₀ H₂₁ O₅^- (MH)^- : 341.1389, found: 341.1415.

12.步骤1212. Step 12

25mL单口瓶中加入化合物63(21mg，0.061mmol)和干燥的THF(5mL)，后加入NaH(2mg，0.077mmol)室温搅拌1h，后缓慢滴加对三氟苯甲酰氯(0.01mL，0.068mmol)，1h后停止反应，加入H₂O(5mL)，EA萃取(3x10mL)，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE∶EA＝3∶1(R_f＝0.76，PE∶EA＝3∶1)得19mg化合物64，产率61％。Add compound 63 (21mg, 0.061mmol) and dry THF (5mL) into a 25mL single-necked bottle, then add NaH (2mg, 0.077mmol) and stir at room temperature for 1h, then slowly add p-trifluorobenzoyl chloride (0.01mL, 0.068mmol ), stop the reaction after 1h, add H₂ O (5mL), extract with EA (3x10mL), dry over anhydrous Na₂ SO₄ , filter, concentrate, column chromatography PE:EA=3:1 (R_f =0.76, PE :EA=3:1) to obtain 19mg of compound 64, the yield was 61%.

¹H-NMR(CDCl₃，400MHz)：δ8.40(d，2H，J＝7.9Hz，Ar-H)，7.81(d，2H，J＝7.9Hz，Ar-H)，7.54-7.50(m，2H，Ar-H)，7.32-7.29(d，1H，J＝7.5Hz，Ar-H)，7.19-7.15(m，2H，Ar-H)，7.06(d，1H，J＝7.1Hz，Ar-H)，5.15(s，2H，OCH₂)，4.89-4.86(m，1H，CH)，1.78(d，1H，J＝3.6Hz，OH)，1.73-1.51(m，2H，CH₂)，1.00(s，9H，t-Bu-H).¹³C-NMR(CDCl₃，100MHz)：δ165.2，159.9，145.7，143.5，141.3，137.9，127.0，126.5，123.5，121.8，121.5，120.2，120.0，119.0，67.1，64.9，48.9，26.3，25.8.HRMS(ESI)：Calcd.for C₂₉H₂₆F₃O₇^-(M-H)^-：513.1525，found：513.1547.¹ H-NMR (CDCl₃ , 400MHz): δ8.40 (d, 2H, J=7.9Hz, Ar-H), 7.81 (d, 2H, J=7.9Hz, Ar-H), 7.54-7.50 (m , 2H, Ar-H), 7.32-7.29(d, 1H, J=7.5Hz, Ar-H), 7.19-7.15(m, 2H, Ar-H), 7.06(d, 1H, J=7.1Hz, Ar-H), 5.15 (s, 2H, OCH₂ ), 4.89-4.86 (m, 1H, CH), 1.78 (d, 1H, J=3.6Hz, OH), 1.73-1.51 (m, 2H, CH₂ ), 1.00 (s, 9H, t-Bu-H).¹³ C-NMR (CDCl₃ , 100MHz): δ165.2, 159.9, 145.7, 143.5, 141.3, 137.9, 127.0, 126.5, 123.5, 121.8, 121.5, 120.2, 120.0, 119.0, 67.1, 64.9, 48.9, 26.3, 25.8. HRMS (ESI): Calcd. for C₂₉ H₂₆ F₃ O₇^- (MH)^- : 513.1525, found: 513.1547.

实施例12：制备下述化合物，Example 12: Preparation of the following compound,

1.步骤11. Step 1

25mL单口瓶中加入化合物63(26mg，0.076mmol)和干燥的THF(5mL)，后加入NaH(2.3mg，0.096mmol)室温搅拌1h，后缓慢滴加3，5-二(三氟甲基)苯甲酰氯(0.015mL，0.084mmol)，1h后停止反应，加入H₂O(5mL)，EA萃取(3x10mL)，无水Na₂SO₄干燥，过滤，浓缩，柱层析DCM(R_f＝0.22，PE∶EA＝3∶1)得16mg化合物65，产率34％，回收原料8mg，转化率52％。Add compound 63 (26mg, 0.076mmol) and dry THF (5mL) into a 25mL single-necked bottle, then add NaH (2.3mg, 0.096mmol) and stir at room temperature for 1h, then slowly add 3,5-bis(trifluoromethyl) Benzoyl chloride (0.015mL, 0.084mmol), stopped the reaction after 1h, added H₂ O (5mL), extracted with EA (3x10mL), dried over anhydrous Na₂ SO₄ , filtered, concentrated, column chromatography DCM (R_f = 0.22, PE: EA = 3: 1) to obtain 16 mg of compound 65 with a yield of 34%, 8 mg of recovered starting material, and a conversion of 52%.

¹H-NMR(CDCl₃，400MHz)：δ8.72(s，2H，Ar-H)，8.17(s，1H，Ar-H)，7.55-7.52(m，2H，Ar-H)，7.31(d，1H，J＝7.8Hz，Ar-H)，7.21-7.16(m，2H，Ar-H)，7.09(d，1H，J＝7.4Hz，Ar-H)，5.15(s，2H，OCH₂)，4.89(d，1H，J＝8.2Hz，CH)，1.78(d，1H，J＝3.1Hz，OH)，1.77-1.52(m，2H，CH₂)，1.00(s，9H，t-Bu-H).¹³C-NMR(CDCl₃，100MHz)：δ169.4，162.7，149.9，147.7，145.8，141.8，132.8，132.5，131.3，131.1，130.4，128.2，127.9，127.3，126.1，124.4，124.3.124.1，123.2，121.4，71.4，69.2，53.3，30.6，30.1.HRMS(ESI)：Calcd.for C₂₉H₂₄F₆O₆Na⁺(M+Na)⁺：605.1375，found：605.1359.¹ H-NMR (CDCl₃ , 400MHz): δ8.72(s, 2H, Ar-H), 8.17(s, 1H, Ar-H), 7.55-7.52(m, 2H, Ar-H), 7.31( d, 1H, J=7.8Hz, Ar-H), 7.21-7.16(m, 2H, Ar-H), 7.09(d, 1H, J=7.4Hz, Ar-H), 5.15(s, 2H, OCH₂ ), 4.89(d, 1H, J=8.2Hz, CH), 1.78(d, 1H, J=3.1Hz, OH), 1.77-1.52(m, 2H, CH₂ ), 1.00(s, 9H, t -Bu-H).¹³ C-NMR (CDCl₃ , 100MHz): δ169.4, 162.7, 149.9, 147.7, 145.8, 141.8, 132.8, 132.5, 131.3, 131.1, 130.4, 128.2, 127.9, 127.3, 126.1, 124.4 , 124.3.124.1, 123.2, 121.4, 71.4, 69.2, 53.3, 30.6, 30.1. HRMS (ESI): Calcd. for C₂₉ H₂₄ F₆ O₆ Na⁺ (M+Na)⁺ : 605.1375, found: 605.1359.

实施例13：目标物抑制CETP活性测试Example 13: Test of target substance inhibiting CETP activity

实验方法：experimental method:

1.用DMSO溶解所有待测化合物，浓度约为500μM，1. Dissolve all the compounds to be tested in DMSO at a concentration of about 500 μM,

2.按下表制备反应体系，于37℃孵育4小时，2. Prepare the reaction system according to the table below, incubate at 37°C for 4 hours,

混合物1Mixture 1

表1Table 1

3.加入8μL LDL和0.5μL[³H]LDL，用TSE缓冲溶液补足反应体系至600μL，3. Add 8 μL LDL and 0.5 μL [³ H]LDL, make up the reaction system to 600 μL with TSE buffer solution,

4.37℃孵育16小时，Incubate at 4.37°C for 16 hours,

5.加入34.24μL LDL沉淀剂dextran sulfate/MgCl₂，终浓度分别为0.027％和27mM。混匀，静置10分钟，5. Add 34.24 μL LDL precipitant dextran sulfate/MgCl₂ , the final concentrations are 0.027% and 27 mM respectively. Mix well, let stand for 10 minutes,

6.1000g/min离心30分钟，取出后静置10分钟，6. Centrifuge at 1000g/min for 30 minutes, take it out and let it stand for 10 minutes.

7.每管吸取300μL上清液进行闪烁计数。7. Take 300 μL of supernatant from each tube for scintillation counting.

实验结果：Experimental results:

^a未测得有效抑制率。^a No effective inhibition rate was measured.

Claims (1)

Translated fromChinese

1.Penicillide衍生物的制备方法，其特征在于，按如下合成路线和步骤制备化合物18：1. The preparation method of Penicillide derivatives is characterized in that compound 18 is prepared according to the following synthetic route and steps:步骤1：step 1:干燥的单口瓶中加入NaH 144mmol，THF溶解，滴加化合物2,3-二羟基苯甲醛72mmol的THF溶液，室温反应1小时，再缓慢加入溴化苄72mmol的THF溶液，室温反应24小时；再将反应液倒入水中，二氯甲烷萃取，水相用1N盐酸调pH值至2，再用二氯甲烷萃取，1N盐酸洗，合并有机相，无水MgSO₄干燥，过滤，浓缩，柱层析PE：EA＝20:1，R_f＝0.42,PE:EA＝10:1，后用乙醇重结晶得化合物1；Add 144 mmol of NaH to the dry single-necked bottle, dissolve in THF, add dropwise a THF solution of 72 mmol of compound 2,3-dihydroxybenzaldehyde, react at room temperature for 1 hour, then slowly add 72 mmol of benzyl bromide in THF solution, and react at room temperature for 24 hours; Pour the reaction solution into water, extract with dichloromethane, adjust the pH value of the aqueous phase to 2 with 1N hydrochloric acid, then extract with dichloromethane, wash with 1N hydrochloric acid, combine the organic phases, dry over anhydrous MgSO₄ , filter, concentrate, and column layer Analysis of PE: EA=20:1, R_f =0.42, PE:EA=10:1, and then recrystallized with ethanol to obtain compound 1;步骤2：Step 2:单口瓶中加入化合物1 21.9mmol，加入甲醇，冰浴下分批加入NaBH₄88.7mmol，再在室温下反应4h；减压浓缩，将得到的白色固体溶于3N盐酸，二氯甲烷萃取，合并有机相，水洗，无水Na₂SO₄干燥，过滤，浓缩得化合物2；Add 21.9mmol of compound 1 to a single-necked flask, add methanol, add NaBH₄ 88.7mmol in batches under ice bath, and react at room temperature for 4h; concentrate under reduced pressure, dissolve the obtained white solid in 3N hydrochloric acid, extract with dichloromethane, and combine The organic phase was washed with water, dried over anhydrous Na₂ SO₄ , filtered, and concentrated to obtain compound 2;步骤3：Step 3:单口瓶中加入化合物2 1.3mmol，再用干燥的二氯甲烷溶解，加入对甲苯磺酸0.13mmol，冰盐浴中搅拌后滴加3,4-二氢-2H-吡喃1.37mmol，2h后停止反应；加入三乙胺淬灭反应，有机相饱和食盐水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝20:1，R_f＝0.60,PE:EA＝6:1，得化合物3；Add 1.3mmol of compound 2 to the single-necked bottle, dissolve it in dry dichloromethane, add 0.13mmol of p-toluenesulfonic acid, stir in an ice-salt bath, add 1.37mmol of 3,4-dihydro-2H-pyran dropwise, after 2h Stop the reaction; add triethylamine to quench the reaction, wash the organic phase with saturated brine, dry over anhydrous Na₂ SO₄ , filter, concentrate, column chromatography PE:EA=20:1, R_f =0.60, PE:EA=6 : 1, to obtain compound 3;步骤4：Step 4:单口瓶中加入5-氨基-2-甲基苯酚8.13mmol，NaHCO₃24.4mmol，H₂O和乙酸乙酯，室温搅拌至溶解后加入特戊酰氯8.54mmol，1h后停止反应；有机相1N盐酸洗，无水Na₂SO₄干燥，过滤，浓缩，R_f＝0.75,PE:EA＝2:1，得化合物4；Add 8.13mmol of 5-amino-2-methylphenol, 24.4mmol of NaHCO₃ , H₂ O and ethyl acetate into a single-necked bottle, stir at room temperature until dissolved, then add 8.54mmol of pivaloyl chloride, and stop the reaction after 1h; the organic phase is 1N hydrochloric acid Washed, dried over anhydrous Na₂ SO₄ , filtered, concentrated, R_f =0.75, PE:EA=2:1, to obtain compound 4;步骤5：Step 5:单口瓶中加入化合物4 4.83mmol，K₂CO₃12.1mmol，氩气保护下加入DMF，再在室温下加入MeI 5.8mmol，4h后停止反应，加入H₂O，乙酸乙酯萃取，水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝6:1，R_f＝0.69,PE:EA＝4:1，得化合物5；Add 4.83mmol of compound 4 and 12.1mmol of K₂ CO₃ to a single-necked flask, add DMF under the protection of argon, then add 5.8mmol of MeI at room temperature, stop the reaction after 4h, add H₂ O, extract with ethyl acetate, wash with water, no Dry over Na₂ SO₄ , filter, concentrate, column chromatography PE:EA=6:1, R_f =0.69, PE:EA=4:1, to obtain compound 5;步骤6：Step 6:单口瓶中加入化合物5 2.26mmol，氩气保护下加入干燥的THF，冰盐浴下缓慢滴加n-buLi,7.24mmol,1.6M in THF，滴加完毕后室温搅拌2h，然后通入CO₂气体2h，随后加入H₂O，乙酸乙酯萃取，水相用1N HCl调pH值至1，再用乙酸乙酯萃取，合并有机相，无水Na₂SO₄干燥，过滤，浓缩，R_f＝0.24,PE:EA＝4:1，得化合物6；Add 2.26mmol of compound 5 into the single-necked flask, add dry THF under the protection of argon, slowly add n-buLi, 7.24mmol, 1.6M in THF dropwise in the ice-salt bath, stir at room temperature for 2h after the dropwise addition, and then introduce CO₂ Gas for 2h, then add H₂ O, extract with ethyl acetate, adjust the pH value of the aqueous phase to 1 with 1N HCl, then extract with ethyl acetate, combine the organic phases, dry over anhydrous Na₂ SO₄ , filter, concentrate, R_f =0.24, PE:EA=4:1, compound 6 was obtained;步骤7：Step 7:单口瓶中加入化合物6 47.6mmol，甲醇溶解，后依次缓慢滴加浓硫酸，原甲酸三甲酯52.4mmol，加热回流，3天后停止反应，冷却，DCM稀释，1N盐酸萃取有机相，水相用3NNaOH调pH值至13，后用DCM萃取，有机相无水Na₂SO₄干燥，过滤，浓缩，R_f＝0.64,PE:EA＝3:1，得化合物7；Add 47.6mmol of compound 6 to the single-necked bottle, dissolve in methanol, then slowly add concentrated sulfuric acid and 52.4mmol of trimethyl orthoformate dropwise, heat to reflux, stop the reaction after 3 days, cool, dilute with DCM, extract the organic phase with 1N hydrochloric acid, and use Adjust the pH value to 13 with 3NNaOH, then extract with DCM, dry the organic phase over anhydrous Na₂ SO₄ , filter, concentrate, R_f =0.64, PE:EA=3:1, and compound 7 is obtained;步骤8：Step 8:单口瓶中加入化合物7 38.0mmol，HBr，H₂O，搅拌至溶解，冰盐浴下滴加NaNO₂41.4mmol的水溶液，搅拌1h，然后缓慢滴加CuBr,54.3mmol的氢溴酸溶液，搅拌至没有气泡生成后，油浴80℃反应过夜，停止反应，冷却，DCM萃取，合并有机相后，饱和NaHCO₃洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝100:1，R_f＝0.62,PE:EA＝20:1，得化合物8；Add 38.0mmol of compound 7, HBr, H₂ O into the single-necked bottle, stir until dissolved, drop NaNO₂ 41.4mmol aqueous solution under ice-salt bath, stir for 1h, then slowly add CuBr, 54.3mmol hydrobromic acid solution dropwise, stir After no bubbles are formed, react overnight in an oil bath at 80°C, stop the reaction, cool, extract with DCM, combine the organic phases, wash with saturated NaHCO₃ , dry with anhydrous Na₂ SO₄ , filter, concentrate, and perform column chromatography PE:EA= 100:1, R_f =0.62, PE:EA=20:1, compound 8 was obtained;步骤9：Step 9:三口瓶中加入NBS,2.81mmol，偶氮二异丁腈,0.18mmol，氩气保护下加入化合物80.88mmol的CCl₄溶液，加热至回流，反应过夜后停止反应，冷却，过滤，浓缩，直接下一步；l含有粗品的反应瓶中缓慢滴加浓硫酸，室温搅拌，TLC监测至原料消失时停止反应，将反应液倒入冰水中，乙酸乙酯萃取，饱和NaHCO₃洗，水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝40:1，R_f＝0.17,PE:EA＝50:1，得化合物9；Add NBS, 2.81mmol, azobisisobutyronitrile, 0.18mmol into the three-necked flask, add compound 80.88mmol CCl₄ solution under the protection of argon, heat to reflux, stop the reaction after reacting overnight, cool, filter, concentrate, and directly download One step; l slowly add concentrated sulfuric acid dropwise to the reaction flask containing the crude product, stir at room temperature, stop the reaction when the raw material disappears as monitored by TLC, pour the reaction solution into ice water, extract with ethyl acetate, wash with saturated NaHCO₃ , wash with water, anhydrous Na₂ SO₄ dried, filtered, concentrated, column chromatography PE:EA=40:1, R_f =0.17, PE:EA=50:1, compound 9 was obtained;步骤10：Step 10:单口瓶中加入化合物3 3.55mmol，化合物9 2.96mmol，Cu,7.40mmol，CuO,7.40mmol，DMAP,8.88mmol，氩气保护下加入CH₃CN，再加热至回流，反应17h后停止反应，冷却，DCM稀释，过滤，浓缩，柱层析PE:EA＝6:1，R_f＝0.11,PE:EA＝10:1，得化合物10；Add compound 3 3.55mmol, compound 9 2.96mmol, Cu, 7.40mmol, CuO, 7.40mmol, DMAP, 8.88mmol, add CH₃ CN under the protection of argon, then heat to reflux, stop the reaction after 17h, cool , diluted with DCM, filtered, concentrated, column chromatography PE:EA=6:1, R_f =0.11, PE:EA=10:1, to obtain compound 10;步骤11：Step 11:单口瓶中加入化合物10,2mmol，对甲苯磺酸，后加入异丙醇和H₂O，加热至回流过夜，停止反应，冷却，加入H₂O，乙酸乙酯萃取，有机相水洗，无水MgSO₄干燥，过滤，浓缩，柱层析PE:EA＝3:1，R_f＝0.14,PE:EA＝3:1，得化合物11；Add compound 10,2mmol, p-toluenesulfonic acid to a single-necked flask, then add isopropanol and H₂ O, heat to reflux overnight, stop the reaction, cool, add H₂ O, extract with ethyl acetate, wash the organic phase with water, anhydrous MgSO₄ was dried, filtered, concentrated, column chromatography PE:EA=3:1, R_f =0.14, PE:EA=3:1, to obtain compound 11;步骤12：Step 12:单口瓶中加入化合物11,1.55mmol，用MeOH溶解，加入对甲苯磺酸,0.32mmol，室温搅拌1h后，加入NaOH,18.5mmol，加热至回流，反应过夜，停止反应，冷却，减压浓缩除去MeOH，用3N HCl调pH值至4，乙酸乙酯萃取，无水Na₂SO₄干燥，过滤，浓缩，得化合物12粗品；Add compound 11, 1.55mmol, into a one-necked bottle, dissolve it with MeOH, add p-toluenesulfonic acid, 0.32mmol, stir at room temperature for 1h, add NaOH, 18.5mmol, heat to reflux, react overnight, stop the reaction, cool, and concentrate under reduced pressure to remove MeOH, adjusted the pH value to 4 with 3N HCl, extracted with ethyl acetate, dried over anhydrous Na₂ SO₄ , filtered, and concentrated to obtain the crude compound 12;步骤13：Step 13:将化合物12的粗品,1.39mmol和三乙胺,11.1mmol溶于干燥的CH₃CN中，将上述制得的溶液室温下缓慢滴加到由碘化-2-氯-1-甲基吡啶,5.57mmol溶于干燥的CH₃CN所配置的溶液中，滴加完毕后，加热回流反应1h，后停止反应，冷却，减压浓缩除去CH₃CN，加入H₂O,DCM萃取，无水Na₂SO₄干燥，过滤，浓缩，柱层析DCM，R_f＝0.67,PE:EA＝2:1，得化合物13；The crude product of compound 12, 1.39mmol, and triethylamine, 11.1mmol were dissolved in dry CH₃ CN, and the solution prepared above was slowly added dropwise at room temperature to the iodine-2-chloro-1-picoline, 5.57mmol was dissolved in the solution prepared by dry CH₃ CN. After the dropwise addition, heated to reflux for 1h, then stopped the reaction, cooled, concentrated under reduced pressure to remove CH₃ CN, added H₂ O, extracted with DCM, anhydrous Na₂ SO₄ dried, filtered, concentrated, column chromatography DCM, R_f =0.67, PE:EA=2:1, to obtain compound 13;步骤14：Step 14:制备新戊基溴化镁：两口瓶中加入Mg,43.53mmol和一粒碘，氩气保护下加入干燥的乙醚溶液，加入溴代新戊烷的乙醚溶液，待反应引发后，加入剩余的溴代新戊烷的乙醚溶液，34℃反应12h，后定容后冷却备用；Preparation of neopentylmagnesium bromide: add Mg, 43.53mmol and a grain of iodine into a two-necked bottle, add dry ether solution under argon protection, add bromoneopentane ether solution, after the reaction is triggered, add the remaining bromine Diethyl ether solution of neopentane, react at 34°C for 12h, and then cool down after constant volume;单口瓶中加入化合物13,0.35mmol，氩气保护下，加入干燥的THF，冰浴下滴加新戊基溴化镁,1.40mmol，后自然升温至室温搅拌1h，加入饱和NH₄Cl淬灭反应，乙酸乙酯萃取，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝5:1，R_f＝0.38,PE:EA＝3:1，得化合物14；Add compound 13, 0.35mmol, into a single-necked flask, add dry THF under the protection of argon, add neopentylmagnesium bromide, 1.40mmol dropwise under ice-cooling, then naturally warm to room temperature and stir for 1h, add saturated NH₄ Cl to quench Reaction, extraction with ethyl acetate, drying over anhydrous Na₂ SO₄ , filtration, concentration, column chromatography PE:EA=5:1, R_f =0.38, PE:EA=3:1, to obtain compound 14;步骤15：Step 15:单口瓶中加入化合物14,0.64mmol，DMSO溶解后，加入IBX 1.28mmol，室温搅拌过夜，停止反应，加入H₂O，DCM萃取，水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝4:1，R_f＝0.51,PE:EA＝3:1，得化合物15；Add compound 14, 0.64mmol, into a single-necked bottle, after DMSO dissolves, add 1.28mmol of IBX, stir overnight at room temperature, stop the reaction, add H₂ O, extract with DCM, wash with water, dry with anhydrous Na₂ SO₄ , filter, concentrate, column layer Analyze PE:EA=4:1,_Rf =0.51, PE:EA=3:1, obtain compound 15;步骤16：Step 16:单口瓶中，氩气保护下加入(R)-Me-CBS,0.153mmol，减压除去其中的甲苯，再加入THF，降温至-20℃，加入BH₃·THF,0.66mmol,1M in THF，后缓慢滴加化合物150.51mmol的THF溶液，3h滴加完毕，-20℃反应4h后停止反应，加入H₂O淬灭反应，乙酸乙酯萃取，有机相水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝5:1得化合物16；In a single-necked flask, add (R)-Me-CBS, 0.153mmol under the protection of argon, remove the toluene in it under reduced pressure, then add THF, cool down to -20°C, add BH₃ ·THF, 0.66mmol, 1M in THF, Afterwards, compound 150.51 mmol THF solution was slowly added dropwise, and the dropwise addition was completed in 3 hours. After reacting at -20°C for 4 hours, the reaction was stopped, and H₂ O was added to quench the reaction, extracted with ethyl acetate, the organic phase was washed with water, and dried with anhydrous Na₂ SO₄ . Filtration, concentration, column chromatography PE:EA=5:1 to obtain compound 16;步骤17：Step 17:单口瓶中加入化合物16 0.09mmol，用EtOH和EA的混合溶液溶解后加入钯碳，通入H₂，TLC监测至原料消失，过滤，浓缩，柱层析PE:EA＝3:1，R_f＝0.47,PE:EA＝2:1，得化合物17；Add 0.09 mmol of compound 16 to a single-necked bottle, dissolve it with a mixed solution of EtOH and EA, add palladium carbon, feed H₂ , monitor by TLC until the raw material disappears, filter, concentrate, column chromatography PE:EA=3:1, R_f =0.47, PE:EA=2:1, compound 17 was obtained;步骤18：Step 18:单口瓶中加入化合物a,3.24mmol和干燥的二氯甲烷，0℃下后加入1滴DMF，再滴加草酰氯,3.9mmol，气体不再产生后，在室温下继续搅拌30分钟，再减压浓缩得酰氯b，用干燥的THF定容，直接参与下步反应；Add compound a, 3.24mmol and dry dichloromethane into the single-necked bottle, then add 1 drop of DMF at 0°C, then add oxalyl chloride, 3.9mmol dropwise, after the gas is no longer generated, continue stirring at room temperature for 30 minutes, then reduce Concentrate under pressure to obtain acid chloride b, dilute to volume with dry THF, and directly participate in the next step reaction;单口瓶中加入化合物17,0.078mmol和干燥的THF，后加入NaH,0.086mmol，室温搅拌1h，后缓慢滴加酰氯b,0.10mmol的THF溶液，过夜后停止反应，直接板层析PE:EA＝3:1，R_f＝0.42,PE:EA＝3:1，得化合物18；Add compound 17, 0.078mmol and dry THF to the single-necked bottle, then add NaH, 0.086mmol, stir at room temperature for 1h, then slowly add acid chloride b, 0.10mmol THF solution, stop the reaction overnight, and direct plate chromatography PE:EA =3:1, R_f =0.42, PE:EA=3:1, compound 18 was obtained;或，or,按如下合成路线和步骤制备化合物33Compound 33 was prepared according to the following synthetic route and steps步骤1：step 1:单口瓶中加入上述制备化合物18的步骤1所得化合物1,17.5mmol，加入乙腈溶解后，再依次加入醋酸铵,1.75mmol，NBS,18.4mmol，室温下反应4h，减压浓缩除去乙腈，加水稀释，乙酸乙酯萃取，有机相无水MgSO₄干燥，过滤，浓缩，柱层析PE:EA＝20:1，R_f＝0.35,PE:DCM＝2:1，得化合物19；Add compound 1, 17.5mmol obtained in step 1 of the preparation of compound 18 above, into a one-mouth bottle, add acetonitrile to dissolve, then add ammonium acetate, 1.75mmol, NBS, 18.4mmol, react at room temperature for 4h, concentrate under reduced pressure to remove acetonitrile, dilute with water , extracted with ethyl acetate, the organic phase was dried over anhydrous MgSO₄ , filtered, concentrated, column chromatography PE:EA=20:1, R_f =0.35, PE:DCM=2:1, compound 19 was obtained;步骤2：Step 2:单口瓶中加入化合物19,1mmol，加入DMF溶解后，再加入N，N-二异丙基乙胺,2mmol，加入叔丁基二甲基氯硅烷,2mmol，室温下反应1h，加水淬灭反应，乙酸乙酯萃取，合并有机相后，水洗，饱和食盐水洗，无水MgSO₄干燥，过滤，浓缩，柱层析PE:EA＝100:1，R_f＝0.78,PE:EA＝15:1，得化合物20；Add compound 19, 1mmol, into a single-necked bottle, add DMF to dissolve, then add N,N-diisopropylethylamine, 2mmol, add tert-butyldimethylsilyl chloride, 2mmol, react at room temperature for 1h, add water to quench the reaction , extracted with ethyl acetate, combined organic phases, washed with water, washed with saturated brine, dried over anhydrous MgSO₄ , filtered, concentrated, column chromatography PE:EA=100:1,_Rf =0.78, PE:EA=15:1 , to obtain compound 20;步骤3：Step 3:两口瓶回流装置中，氩气保护下加入化合物20,5.24mmol，Pd(dppf)Cl₂,0.08mmol，无水1,4-二氧六环，二甲基锌,6.29mmol后，加热回流，反应1h，1N盐酸淬灭反应，乙酸乙酯萃取，合并有机相后，水洗，饱和食盐水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝40:1，R_f＝0.57,PE:EA＝15:1，得化合物21；In the reflux device of the two-neck flask, add compound 20, 5.24mmol, Pd(dppf)Cl₂ , 0.08mmol, anhydrous 1,4-dioxane, dimethyl zinc, 6.29mmol under argon protection, and heat to reflux. Reaction for 1 h, quenched with 1N hydrochloric acid, extracted with ethyl acetate, combined organic phases, washed with water, washed with saturated brine, dried with anhydrous Na₂ SO₄ , filtered, concentrated, column chromatography PE:EA=40:1, R_f =0.57, PE:EA=15:1, compound 21 was obtained;步骤4：Step 4:单口瓶中加入化合物21,2.50mmol，加入甲醇，冰浴下加入NaBH₄,10.0mmol，再在室温下反应4h，减压浓缩，将得到的白色固体溶于3N盐酸，二氯甲烷萃取，合并有机相，水洗，饱和食盐水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝10:1，R_f＝0.41,PE:EA＝10:1，得化合物22；Add compound 21, 2.50mmol, methanol to the single-necked flask, add NaBH₄ , 10.0mmol under ice bath, react at room temperature for 4h, concentrate under reduced pressure, dissolve the obtained white solid in 3N hydrochloric acid, extract with dichloromethane, combine The organic phase was washed with water, washed with saturated brine, dried over anhydrous Na₂ SO₄ , filtered, concentrated, column chromatography PE:EA=10:1, R_f =0.41, PE:EA=10:1, and compound 22 was obtained;步骤5step 5单口瓶中加入化合物22,0.90mmol，加入四氢呋喃，冰浴下加入四丁基氟化铵,1.80mmol，后室温下反应0.5h，加水稀释，乙酸乙酯萃取，合并有机相，水洗，饱和食盐水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝4:1，R_f＝0.26,PE:EA＝4:1，得化合物23；Add compound 22, 0.90 mmol, tetrahydrofuran to a one-necked bottle, add tetrabutylammonium fluoride, 1.80 mmol, under ice-cooling, react at room temperature for 0.5 h, dilute with water, extract with ethyl acetate, combine organic phases, wash with water, and use saturated salt Washed with water, dried over anhydrous Na₂ SO₄ , filtered, concentrated, column chromatography PE:EA=4:1, R_f =0.26, PE:EA=4:1, to obtain compound 23;步骤6：Step 6:单口瓶中加入化合物23,3.66mmol，后用干燥的二氯甲烷溶解，再加入对甲苯磺酸,0.37mmol，冰盐浴中搅拌后，滴加3，4-二氢-2H-吡喃,3.84mmol，反应1h，停止反应，加入三乙胺淬灭反应，有机相饱和食盐水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝20:1，R_f＝0.67,PE:EA＝4:1，得化合物24；Add compound 23, 3.66mmol, into a single-necked bottle, and then dissolve it with dry dichloromethane, then add p-toluenesulfonic acid, 0.37mmol, stir in an ice-salt bath, add 3,4-dihydro-2H-pyran dropwise, 3.84mmol, react for 1h, stop the reaction, add triethylamine to quench the reaction, wash the organic phase with saturated brine, dry over anhydrous Na₂ SO₄ , filter, concentrate, column chromatography PE:EA=20:1, R_f =0.67 ,PE:EA=4:1, compound 24 is obtained;步骤7：Step 7:两口瓶回流装置中加入上述制备化合物18的步骤9所得化合物9,4.08mmol，化合物244.89mmol，Cu,10.2mmol，CuO,10.2mmol，DMAP,12.2mmol，氩气保护下加入CH₃CN后加热至回流，反应12h后停止反应，冷却，DCM稀释，过滤，浓缩，柱层析PE:EA＝6:1，R_f＝0.09,PE:EA＝10:1，得化合物25：Add compound 9, 4.08mmol, compound 244.89mmol, Cu, 10.2mmol, CuO, 10.2mmol, DMAP, 12.2mmol obtained in step 9 of the preparation of compound 18 above into the two-neck flask reflux device, add CH₃ CN under argon protection and heat to Reflux, stop the reaction after 12h, cool, dilute with DCM, filter, concentrate, column chromatography PE:EA=6:1, R_f =0.09, PE:EA=10:1, to obtain compound 25:步骤8：Step 8:单口瓶中加入化合物25,2.37mmol，对甲苯磺酸,后加入异丙醇和H₂O，加热回流过夜，停止反应，冷却，加入H₂O，乙酸乙酯萃取，有机相水洗，饱和食盐水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝3:1，R_f＝0.20,PE:EA＝3:1，得化合物26；Add compound 25, 2.37mmol, p-toluenesulfonic acid into a single-necked flask, then add isopropanol and H₂ O, heat and reflux overnight, stop the reaction, cool, add H₂ O, extract with ethyl acetate, wash the organic phase with water, and wash with saturated brine , dried over anhydrous Na₂ SO₄ , filtered, concentrated, column chromatography PE:EA=3:1, R_f =0.20, PE:EA=3:1, compound 26 was obtained;步骤9：Step 9:单口瓶中加入化合物26,2.09mmol，用MeOH溶解，加入对甲苯磺酸,0.42mmol，室温搅拌1h后，加入NaOH,23.5mmol，加热至回流，反应过夜，停止反应，冷却，减压浓缩除去MeOH，用3N HCl调pH值至3，乙酸乙酯萃取，无水Na₂SO₄干燥，过滤，浓缩，得化合物27粗品；Add compound 26, 2.09mmol, into a one-necked bottle, dissolve it with MeOH, add p-toluenesulfonic acid, 0.42mmol, stir at room temperature for 1h, add NaOH, 23.5mmol, heat to reflux, react overnight, stop the reaction, cool, and concentrate under reduced pressure to remove MeOH, adjusted the pH value to 3 with 3N HCl, extracted with ethyl acetate, dried over anhydrous Na₂ SO₄ , filtered, and concentrated to obtain the crude compound 27;步骤10：Step 10:将化合物27的粗品g,1.98mmol和三乙胺,15.8mmol溶于干燥的CH₃CN中，将上述制得的溶液室温下缓慢滴加到由碘化-2-氯-1-甲基吡啶7.92mmol溶于干燥的CH₃CN所配置的溶液中，滴加完毕后，加热回流反应过夜，停止反应，冷却，减压浓缩除去CH₃CN，加入H₂O，DCM萃取，无水Na₂SO₄干燥，过滤，浓缩，柱层析DCM，R_f＝0.80,PE:EA＝2:1，得化合物28；The crude product g, 1.98mmol and triethylamine, 15.8mmol of compound 27 were dissolved in dry CH₃ CN, and the solution prepared above was slowly added dropwise at room temperature by iodine-2-chloro-1-picoline 7.92mmol was dissolved in the solution prepared by dry CH₃ CN. After the dropwise addition, heated and refluxed overnight, stopped the reaction, cooled, concentrated under reduced pressure to remove CH₃ CN, added H₂ O, extracted with DCM, anhydrous Na₂ SO₄ dried, filtered, concentrated, column chromatography DCM, R_f =0.80, PE:EA=2:1, to obtain compound 28;步骤11：Step 11:单口瓶中加入化合物28,0.65mmol，氩气保护下，加入干燥的THF，冰浴下滴加新戊基溴化镁,3.9mmol，后自然升温至室温搅拌1h，加入饱和NH₄Cl淬灭反应，EA萃取，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝5:1，R_f＝0.44,PE:EA＝3:1，得化合物29；Add compound 28, 0.65mmol, into a single-necked flask, add dry THF under the protection of argon, add neopentylmagnesium bromide, 3.9mmol dropwise under ice-cooling, then naturally warm to room temperature and stir for 1h, add saturated NH₄ Cl to quench Reaction, extraction with EA, drying over anhydrous Na₂ SO₄ , filtration, concentration, column chromatography PE:EA=5:1, R_f =0.44, PE:EA=3:1, compound 29 was obtained;步骤12：Step 12:单口瓶中加入化合物29,0.27mmol，DMSO溶解，后加入IBX,0.54mmol，室温搅拌过夜，停止反应，加入H₂O，DCM萃取，有机相水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝7:1，R_f＝0.51,PE:EA＝3:1，得化合物30；Add compound 29, 0.27mmol, to dissolve in DMSO, then add IBX, 0.54mmol, stir overnight at room temperature, stop the reaction, add H₂ O, extract with DCM, wash the organic phase with water, dry with anhydrous Na₂ SO₄ , filter and concentrate , column chromatography PE:EA=7:1, R_f =0.51, PE:EA=3:1, compound 30 was obtained;步骤13：Step 13:氩气保护下，在单口瓶中加入(R)-Me-CBS,0.186mmol，减压除去其中的甲苯，再加入THF，降温至-20℃，加入BH₃·THF,0.68mmol,1M in THF，后缓慢滴加化合物30,0.62mmol的THF溶液，3h滴加完毕，-20℃反应4h后停止反应，加入H₂O淬灭反应，EA萃取，有机相水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝5:1得化合物31；Under the protection of argon, add (R)-Me-CBS, 0.186mmol into a single-necked bottle, remove the toluene in it under reduced pressure, then add THF, cool down to -20°C, add BH₃ ·THF, 0.68mmol, 1M in THF , then slowly add compound 30, 0.62mmol THF solution dropwise, the dropwise addition is completed in 3h, stop the reaction after reacting at -20°C for 4h, add H₂ O to quench the reaction, extract with EA, wash the organic phase with water, and dry with anhydrous Na₂ SO₄ , filtered, concentrated, column chromatography PE:EA=5:1 to obtain compound 31;步骤14：Step 14:单口瓶中加入化合物31,0.35mmol，用EtOH和EA的混合溶液溶解后加入钯碳，通入H₂，TLC监测至原料消失，过滤，浓缩，柱层析PE:EA＝3:1，R_f＝0.42,PE:EA＝2:1，得化合物32；Add compound 31, 0.35 mmol, into a single-necked bottle, dissolve it with a mixed solution of EtOH and EA, add palladium carbon, feed H₂ , monitor by TLC until the raw material disappears, filter, concentrate, column chromatography PE:EA=3:1, R_f =0.42, PE:EA=2:1, compound 32 was obtained;步骤15：Step 15:单口瓶中加入化合物32,0.42mmol和干燥的THF，后加入NaH,0.46mmol，室温搅拌1h，后缓慢滴加对溴苯甲酰氯,0.46mmol的THF溶液，过夜后停止反应，直接柱层析PE:EA＝5:1，R_f＝0.25,PE:EA＝3:1，得化合物33；Add compound 32, 0.42mmol and dry THF to the one-necked bottle, then add NaH, 0.46mmol, stir at room temperature for 1h, then slowly add p-bromobenzoyl chloride, 0.46mmol THF solution dropwise, stop the reaction overnight, and perform direct column chromatography PE:EA=5:1, R_f =0.25, PE:EA=3:1, compound 33 was obtained;或，or,按如下合成路线和步骤制备化合物34Compound 34 was prepared according to the following synthetic route and steps单口瓶中加入上述制备化合物33的步骤步骤14所得化合物32,0.078mmol和干燥的THF，后加入NaH,0.086mmol，室温搅拌1h，后缓慢滴加对三氟甲基苯甲酰氯,0.086mmol的THF溶液，过夜后停止反应，直接柱层析PE:EA＝5:1，R_f＝0.38,PE:EA＝3:1，得g化合物34；Add compound 32, 0.078mmol and dry THF obtained in the step 14 of the above-mentioned preparation of compound 33 into a one-mouth bottle, then add NaH, 0.086mmol, stir at room temperature for 1h, and then slowly add p-trifluoromethylbenzoyl chloride, 0.086mmol THF solution, stopped the reaction after overnight, direct column chromatography PE:EA=5:1, R_f =0.38, PE:EA=3:1, and g compound 34 was obtained;或，or,按如下合成路线和步骤制备化合物35Compound 35 was prepared according to the following synthetic route and steps单口瓶中加入上述所得化合物320.078mmol和干燥的THF，后加入NaH,0.086mmol，室温搅拌1h，后缓慢滴加3,5-二(三氟甲基)苯甲酰氯,0.086mmol的THF溶液，过夜后停止反应，直接柱层析PE:EA＝5:1，R_f＝0.45,PE:EA＝3:1，得化合物35；Add 320.078mmol of the compound obtained above and dry THF into the single-necked bottle, then add NaH, 0.086mmol, stir at room temperature for 1h, then slowly add 3,5-bis(trifluoromethyl)benzoyl chloride, 0.086mmol THF solution dropwise, The reaction was stopped overnight, and direct column chromatography PE:EA=5:1, R_f =0.45, PE:EA=3:1, yielded compound 35;或，or,按如下合成路线和步骤制备化合物36，Compound 36 was prepared according to the following synthetic route and steps,单口瓶中加入所得化合物32,0.10mmol和干燥的THF，后加入NaH,0.11mmol，室温搅拌1h，后缓慢滴加所得酰氯b,0.13mmol的THF溶液，过夜后停止反应，直接板层析PE:EA＝3:1，R_f＝0.46,PE:EA＝3:1，得化合物36；Add the obtained compound 32, 0.10mmol and dry THF into a single-necked bottle, then add NaH, 0.11mmol, stir at room temperature for 1h, then slowly add the obtained acid chloride b, 0.13mmol THF solution dropwise, stop the reaction after overnight, direct plate chromatography PE :EA=3:1, R_f =0.46, PE:EA=3:1, compound 36 was obtained;或，or,按如下合成路线和步骤制备化合物48，Compound 48 was prepared according to the following synthetic route and steps,步骤1：step 1:两口瓶中加入所得化合物19 3.40mmol，对甲氧基苯硼酸,4.08mmolPd(PPh₃)₄,0.34mmol，2N K₂CO₃,6.80mmol，甲醇，80℃反应过夜，反应液加硅藻土抽滤，加水稀释后乙酸乙酯萃取，有机相水洗，饱和食盐水洗，无水MgSO₄干燥，过滤，浓缩，柱层析PE:EA＝10:1，R_f＝0.16,PE:EA＝10:1，得化合物37；Add 3.40mmol of the obtained compound 19, p-methoxyphenylboronic acid, 4.08mmol Pd(PPh₃ )₄ , 0.34mmol, 2N K₂ CO₃ , 6.80mmol, methanol to the two-necked flask, react overnight at 80°C, add diatomaceous earth to the reaction solution Suction filtration, dilute with water, extract with ethyl acetate, wash the organic phase with water, wash with saturated brine, dry over anhydrous MgSO₄ , filter, concentrate, column chromatography PE:EA=10:1, R_f =0.16, PE:EA=10 : 1, to obtain compound 37;步骤2：Step 2:单口瓶中加入化合物37,2.84mmol，加入甲醇，冰浴下加入NaBH₄,5.68mmol后，室温下反应1h，减压浓缩，将得到的白色固体溶于3N盐酸，乙酸乙酯萃取，有机相水洗，饱和食盐水洗，无水MgSO₄干燥，过滤，浓缩，柱层析PE:EA＝3:1，R_f＝0.21,PE:EA＝3:1，得化合物38；Add compound 37, 2.84mmol, methanol to a single-necked bottle, add NaBH₄ , 5.68mmol under ice-cooling, react at room temperature for 1h, concentrate under reduced pressure, dissolve the obtained white solid in 3N hydrochloric acid, extract with ethyl acetate, organic phase Washed with water, washed with saturated brine, dried over anhydrous MgSO₄ , filtered, concentrated, column chromatography PE:EA=3:1, R_f =0.21, PE:EA=3:1, to obtain compound 38;步骤3：Step 3:单口瓶中加入化合物38,2.45mmol，后用干燥的二氯甲烷溶解，再加入对甲苯磺酸0.25mmol，冰盐浴中搅拌后，滴加3，4-二氢-2H-吡喃,2.52mmol，反应1h，停止反应，加入三乙胺淬灭反应，有机相饱和食盐水洗，无水MgSO₄干燥，过滤，浓缩，柱层析PE:EA＝7:1，R_f＝0.57,PE:EA＝3:1，得化合物39；Add compound 38, 2.45mmol, into a single-necked bottle, and then dissolve it with dry dichloromethane, then add 0.25mmol of p-toluenesulfonic acid, stir in an ice-salt bath, add dropwise 3,4-dihydro-2H-pyran, 2.52 mmol, reacted for 1 h, stopped the reaction, added triethylamine to quench the reaction, washed the organic phase with saturated brine, dried over anhydrous MgSO₄ , filtered, concentrated, column chromatography PE:EA=7:1,_Rf =0.57, PE: EA=3:1, compound 39 was obtained;步骤4：Step 4:两口瓶回流装置中，加入所得化合物9 1.88mmol，化合物39,2.25mmol，Cu 4.70mmol，CuO,4.70mmol，DMAP,5.64mmol，氩气保护下加入CH₃CN后加热至回流，反应12h后停止反应，冷却，加硅藻土过滤，浓缩，柱层析PE:EA＝5:1，R_f＝0.32,PE:EA＝5:1，得化合物40；In the reflux device of the two-neck flask, add the obtained compound 9 1.88mmol, compound 39, 2.25mmol, Cu 4.70mmol, CuO, 4.70mmol, DMAP, 5.64mmol, add CH₃ CN under the protection of argon, heat to reflux, stop after 12h of reaction React, cool, add diatomaceous earth to filter, concentrate, column chromatography PE:EA=5:1, R_f =0.32, PE:EA=5:1, to obtain compound 40;步骤5：Step 5:单口瓶中加入化合物40 1.62mmol，对甲苯磺酸,后加入异丙醇和H₂O，加热回流过夜，停止反应，冷却，加入H₂O，乙酸乙酯萃取，有机相水洗，饱和食盐水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝3:1，R_f＝0.14,PE:EA＝3:1，得化合物41；Add 1.62 mmol of compound 40, p-toluenesulfonic acid, and then add isopropanol and H₂ O to the single-necked flask, heat and reflux overnight, stop the reaction, cool, add H₂ O, extract with ethyl acetate, wash the organic phase with water, and wash with saturated brine. Dry over anhydrous Na₂ SO₄ , filter, concentrate, column chromatography PE:EA=3:1, R_f =0.14, PE:EA=3:1, to obtain compound 41;步骤6：Step 6:L单口瓶中加入化合物41,1.51mmol，用MeOH溶解，加入对甲苯磺酸,0.39mmol，室温搅拌1h后，加入NaOH,15.1mmol，加热至回流，反应过夜，停止反应，冷却，减压浓缩除去MeOH，用3N盐酸调pH值至3，乙酸乙酯萃取，无水Na₂SO₄干燥，过滤，浓缩，得化合物42粗品；Add compound 41, 1.51mmol, to an L single-necked flask, dissolve in MeOH, add p-toluenesulfonic acid, 0.39mmol, stir at room temperature for 1h, add NaOH, 15.1mmol, heat to reflux, react overnight, stop the reaction, cool, and concentrate under reduced pressure Remove MeOH, adjust the pH value to 3 with 3N hydrochloric acid, extract with ethyl acetate, dry over anhydrous Na₂ SO₄ , filter, and concentrate to obtain the crude compound 42;步骤7：Step 7:将化合物42的粗品1.51mmol和三乙胺,12.1mmol溶于干燥的CH₃CN中，将上述制得的溶液室温下缓慢滴加到由碘化-2-氯-1-甲基吡啶,6.04mmol溶于干燥的CH₃CN所配置的溶液中，滴加完毕后，加热回流反应过夜，停止反应，冷却，减压浓缩除去CH₃CN，加入H₂O，DCM萃取，无水Na₂SO₄干燥，过滤，浓缩，柱层析DCM，R_f＝0.58,PE:EA＝2:1，得化合物43；Dissolve 1.51mmol of the crude product of compound 42 and triethylamine, 12.1mmol in dry CH₃ CN, and slowly add the solution prepared above to the solution prepared by iodine-2-chloro-1-methylpyridine, 6.04 Dissolve mmol in the solution prepared by dry CH₃ CN. After the dropwise addition, heat to reflux for overnight reaction, stop the reaction, cool, concentrate under reduced pressure to remove CH₃ CN, add H₂ O, extract with DCM, anhydrous Na₂ SO₄ was dried, filtered, concentrated, column chromatography DCM, R_f =0.58, PE:EA=2:1, to obtain compound 43;步骤8：Step 8:单口瓶中加入化合物43 0.27mmol氩气保护下，加入干燥的THF，冰浴下滴加新戊基溴化镁1.6mmol，后自然升温至室温搅拌1h，加入饱和NH₄Cl淬灭反应，乙酸乙酯萃取，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝5:1，R_f＝0.30,PE:EA＝3:1得化合物44；Add 0.27 mmol of compound 43 to the single-necked flask under the protection of argon, add dry THF, dropwise add 1.6 mmol of neopentylmagnesium bromide under ice bath, then naturally warm up to room temperature and stir for 1 h, add saturated NH₄ Cl to quench the reaction, acetic acid Extracted with ethyl ester, dried over anhydrous Na₂ SO₄ , filtered, concentrated, column chromatography PE:EA=5:1, R_f =0.30, PE:EA=3:1 to obtain compound 44;步骤9：Step 9:单口瓶中加入化合物44,0.19mmol，DMSO溶解，后加入IBX,0.38mmol，室温搅拌过夜，停止反应，加入H₂O，DCM萃取，有机相水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝5:1，R_f＝0.53,PE:EA＝3:1，得化合物45；Add compound 44, 0.19mmol, into a single-necked bottle, dissolve in DMSO, then add IBX, 0.38mmol, stir overnight at room temperature, stop the reaction, add H₂ O, extract with DCM, wash the organic phase with water, dry with anhydrous Na₂ SO₄ , filter, and concentrate , column chromatography PE:EA=5:1, R_f =0.53, PE:EA=3:1, compound 45 was obtained;步骤10：Step 10:氩气保护下，在单口瓶中加入(R)-Me-CBS,0.051mmol，减压除去其中的甲苯，再加入THF，降温至-20℃，加入BH₃·THF,0.22mmol,1M in THF，后缓慢滴加化合物45,0.17mmol的THF溶液，3h滴加完毕，-20℃反应4h后停止反应，加入H₂O淬灭反应，乙酸乙酯萃取，有机相水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝5:1得化合物46；Under the protection of argon, add (R)-Me-CBS, 0.051mmol into a single-necked bottle, remove the toluene in it under reduced pressure, then add THF, cool down to -20°C, add BH₃ ·THF, 0.22mmol, 1M in THF , then slowly add compound 45, 0.17mmol THF solution dropwise, the dropwise addition is completed in 3h, stop the reaction after reacting at -20°C for 4h, add H₂ O to quench the reaction, extract with ethyl acetate, wash the organic phase with water, anhydrous Na₂ SO₄ dried, filtered, concentrated, column chromatography PE:EA=5:1 to obtain compound 46;步骤11：Step 11:单口瓶中加入化合物46,0.12mmol，用EtOH和EA的混合溶液溶解后加入钯碳，通入H₂，TLC监测至原料消失，过滤，浓缩，柱层析PE:EA＝2:1，R_f＝0.24,PE:EA＝2:1，得化合物47；Add compound 46, 0.12 mmol, into a single-necked bottle, dissolve it with a mixed solution of EtOH and EA, add palladium carbon, feed H₂ , monitor by TLC until the raw material disappears, filter, concentrate, column chromatography PE:EA=2:1, R_f =0.24, PE:EA=2:1, compound 47 was obtained;步骤12：Step 12:单口瓶中加入化合物47,0.015mmol和干燥的THF，后加入NaH,0.017mmol，室温搅拌1h，后缓慢滴加对三氟甲基苯甲酰氯,0.017mmol的THF溶液，过夜后停止反应，直接板层析PE:EA＝3:1，R_f＝0.24,PE:EA＝3:1，得化合物48；Add compound 47, 0.015mmol and dry THF to the single-necked bottle, then add NaH, 0.017mmol, stir at room temperature for 1h, then slowly add p-trifluoromethylbenzoyl chloride, 0.017mmol THF solution, stop the reaction overnight, and directly Plate chromatography PE:EA=3:1, R_f =0.24, PE:EA=3:1, compound 48 was obtained;或，or,按如下合成路线和步骤制备化合物49，Compound 49 was prepared according to the following synthetic route and steps,单口瓶中加入所得化合物47,0.046mmol和干燥的THF，后加入NaH,0.051mmol，室温搅拌1h，后缓慢滴加3,5-二(三氟甲基)苯甲酰氯,0.066mmol的THF溶液，过夜后停止反应，直接板层析PE:EA＝3:1，R_f＝0.67,PE:EA＝2:1，得化合物49；Add the obtained compound 47, 0.046mmol and dry THF into the single-necked bottle, then add NaH, 0.051mmol, stir at room temperature for 1h, then slowly add 3,5-bis(trifluoromethyl)benzoyl chloride, 0.066mmol THF solution dropwise , stop the reaction after overnight, direct plate chromatography PE:EA=3:1, R_f =0.67, PE:EA=2:1, to obtain compound 49;或，or,按如下合成路线和步骤制备化合物50，Compound 50 was prepared according to the following synthetic route and steps,单口瓶中加入所得化合物47,0.040mmol和干燥的THF，后加入NaH,0.044mmol，室温搅拌1h，后缓慢滴加所述的酰氯b,0.052mmol的THF溶液，过夜后停止反应，直接板层析PE:EA＝3:1，R_f＝0.37PE:EA＝3:1，得化合物50；Add the obtained compound 47, 0.040mmol and dry THF into the single-necked bottle, then add NaH, 0.044mmol, stir at room temperature for 1h, then slowly add the above-mentioned acid chloride b, 0.052mmol THF solution, stop the reaction overnight, and directly plate Analyze PE:EA=3:1,_Rf =0.37PE:EA=3:1, obtain compound 50;或，or,按如下合成路线和步骤制备化合物51，Compound 51 was prepared according to the following synthetic route and steps,单口瓶中加入所得化合物17,0.081mmol和干燥的THF，后加入NaH,0.081mmol室温搅拌1h，后缓慢滴加对三氟苯甲酰氯,0.089mmol，1h后停止反应，加入H₂O，EA萃取，有机相无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝3:1，R_f＝0.54,PE:EA＝3:1，得化合物51；Add the obtained compound 17, 0.081mmol and dry THF into the single-necked bottle, then add NaH, 0.081mmol and stir at room temperature for 1h, then slowly add p-trifluorobenzoyl chloride, 0.089mmol, stop the reaction after 1h, add H₂ O, EA Extraction, the organic phase was dried over anhydrous Na₂ SO₄ , filtered, concentrated, column chromatography PE:EA=3:1, R_f =0.54, PE:EA=3:1, to obtain compound 51;或，or,按如下合成路线和步骤制备化合物52，Compound 52 was prepared according to the following synthetic route and steps,单口瓶中加入所得化合物17 0.078mmol和干燥的THF，后加入NaH,0.086mmol室温搅拌1h，后缓慢滴加3,5-二(三氟甲基)苯甲酰氯,0.086mmol，1h后停止反应，加入H₂O，EA萃取，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝10:1，R_f＝0.71,PE:EA＝3:1，得化合物52；Add 0.078mmol of the obtained compound 17 and dry THF to the single-necked bottle, then add NaH, 0.086mmol and stir at room temperature for 1h, then slowly add 3,5-bis(trifluoromethyl)benzoyl chloride, 0.086mmol dropwise, and stop the reaction after 1h , added H₂ O, extracted with EA, dried over anhydrous Na₂ SO₄ , filtered, concentrated, column chromatography PE:EA=10:1, R_f =0.71, PE:EA=3:1, to obtain compound 52;或，or,按如下合成路线和步骤制备化合物64，Compound 64 was prepared according to the following synthetic route and steps,步骤1：step 1:单口瓶中加入H₂O，HBr，后加入2-氨基-5甲基苯甲酸,6.62mmol使之溶解，冰盐浴下滴加NaNO₂,7.22mmol的水溶液，搅拌1h，缓慢滴加CuBr,9.47mmol的HBr溶液，搅拌至不再生成气泡，油浴加热80℃，反应过夜，第二日早停止反应，冷却，过滤，水洗，R_f＝0.33,PE:EA＝2:1，得化合物53；Add H₂ O and HBr to the single-necked bottle, then add 2-amino-5-methylbenzoic acid, 6.62mmol to dissolve it, add NaNO₂ , 7.22mmol aqueous solution dropwise in ice-salt bath, stir for 1h, slowly add CuBr dropwise, 9.47 mmol of HBr solution, stirred until no more bubbles are generated, heated in an oil bath at 80°C, reacted overnight, stopped the reaction early the next day, cooled, filtered, washed with water, R_f = 0.33, PE:EA = 2:1, and the compound was obtained 53;步骤2：Step 2:单口瓶中依次加入化合物53 5.99mmol，甲醇，浓硫酸，加热回流7h，停止反应，冷却，加入饱和NaHCO₃溶液调pH值至7，EA萃取有机相，水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝100:1，R_f＝0.89,PE:EA＝2:1，得化合物54；Add 5.99 mmol of compound 53, methanol, and concentrated sulfuric acid to the single-necked flask in sequence, heat and reflux for 7 h, stop the reaction, cool, add saturated NaHCO₃ solution to adjust the pH value to 7, extract the organic phase with EA, wash with water, and dry with anhydrous Na₂ SO₄ . Filtration, concentration, column chromatography PE:EA=100:1, R_f =0.89, PE:EA=2:1, yielded compound 54;步骤3：Step 3:单口瓶中依次加入NBS,18.3mmoL，AIBN,0.873mmol，氩气保护下加入化合物54的CCl₄溶液，加热回流2h，后冷却补加NBS,9.6mmol和AIBN,0.873mmol加热回流2h，停止反应，冷却，过滤，浓缩。加入浓硫酸，室温搅拌，TCL跟踪反应至原料消失，倒入冰水中，EA萃取有机相，饱和NaHCO₃洗，水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝30:1，R_f＝0.55,PE:EA＝5:1，得化合物55；Add NBS, 18.3mmol, AIBN, 0.873mmol to the single-necked bottle in turn, add the CCl₄ solution of compound 54 under the protection of argon, heat and reflux for 2h, then cool and add NBS, 9.6mmol and AIBN, 0.873mmol, heat and reflux for 2h, stop the reaction , cooled, filtered and concentrated. Add concentrated sulfuric acid, stir at room temperature, follow the reaction with TCL until the raw materials disappear, pour into ice water, extract the organic phase with EA, wash with saturated NaHCO₃ , wash with water, dry with anhydrous Na₂ SO₄ , filter, concentrate, column chromatography PE:EA= 30:1, R_f =0.55, PE:EA=5:1, compound 55 was obtained;步骤4：Step 4:单口瓶中加入所得化合物3 4.01mmol，化合物55,3.34mmol，CuBr,1.67mmol，Cs₂CO₃,6.68mmol，后加入NMP，2,2,6,6-四甲基-3,5-庚二酮,0.334mmol，脱气0.5h，后加热至80℃，反应2h后停止反应，冷却，加入H₂O，用3N HCl调pH值至4，EA萃取有机相，水洗，饱和NH₄Cl洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝15:1，R_f＝0.12,PE:EA＝20:1，得化合物56；Add the obtained compound 3 4.01mmol, compound 55, 3.34mmol, CuBr, 1.67mmol, Cs₂ CO₃ , 6.68mmol into the single-necked bottle, and then add NMP, 2,2,6,6-tetramethyl-3,5-heptane Diketone, 0.334mmol, degassed for 0.5h, then heated to 80°C, stopped the reaction after 2h, cooled, added H₂ O, adjusted the pH value to 4 with 3N HCl, extracted the organic phase with EA, washed with water, saturated NH₄ Cl Wash, dry with anhydrous Na₂ SO₄ , filter, concentrate, column chromatography PE:EA=15:1, R_f =0.12, PE:EA=20:1, to obtain compound 56;步骤5：Step 5:单口瓶中依次加入化合物56,2.35mmol，PTSA，加入异丙醇和H₂O，加热回流过夜，第二日早停止反应，冷却，加入H₂O，EA萃取，H₂O洗，无水MgSO₄干燥，过滤，浓缩，柱层析PE:EA＝3:1，R_f＝0.14,PE:EA＝3:1，得化合物57；Add compound 56, 2.35mmol, PTSA, isopropanol and H₂ O to the single-necked flask in turn, heat and reflux overnight, stop the reaction early the next day, cool, add H₂ O, extract with EA, wash with H₂ O, anhydrous MgSO₄ was dried, filtered, concentrated, column chromatography PE:EA=3:1, R_f =0.14, PE:EA=3:1, to obtain compound 57;步骤6：Step 6:单口瓶中加入化合物57 2.22mmol，用MeOH溶解，加入PTSA 1.11mmol，室温搅拌1h，加入NaOH,24.42mmol，加热回流，反应过夜。第二日早停止反应，冷却，旋转蒸发出MeOH，用3N HCl调pH值至4，EA萃取，无水Na₂SO₄干燥，过滤，浓缩，得化合物58粗品；Add 2.22mmol of compound 57 to the single-necked flask, dissolve it with MeOH, add 1.11mmol of PTSA, stir at room temperature for 1h, add NaOH, 24.42mmol, heat to reflux, and react overnight. The next day, the reaction was stopped early, cooled, and the MeOH was rotary evaporated, and the pH value was adjusted to 4 with 3N HCl, extracted with EA, dried over anhydrous Na₂ SO₄ , filtered, and concentrated to obtain the crude compound 58;步骤7：Step 7:将化合物58的粗品,2.65mmol和三乙胺,16.4mmol溶于干燥的CH₃CN中，将上述制得的溶液室温下缓慢滴加到由碘化-2-氯-1-甲基吡啶,8.2mmol溶于干燥的CH₃CN所配置的溶液中，滴加完毕后，加热回流反应1h，后停止反应，冷却，旋出CH₃CN，加H₂O，DCM萃取，无水Na₂SO₄干燥，过滤，浓缩，柱层析DCM，R_f＝0.67,PE:EA＝2:1，得化合物59；The crude product of compound 58, 2.65mmol and triethylamine, 16.4mmol were dissolved in dry CH₃ CN, and the solution prepared above was slowly added dropwise at room temperature to the iodine-2-chloro-1-picoline, 8.2mmol was dissolved in the solution prepared by dry CH₃ CN, after the dropwise addition, heated to reflux for 1h, then stopped the reaction, cooled, spin out CH₃ CN, added H₂ O, extracted with DCM, anhydrous Na₂ SO₄ was dried, filtered, concentrated, column chromatography DCM, R_f =0.67, PE:EA=2:1, to obtain compound 59;步骤8：Step 8:单口瓶中加入化合物59,0.385mmol，氩气保护下，加入干燥的THF，冰浴下滴加制备的新戊基溴化镁,2.308mmol，后自然升温至室温搅拌1h，加入饱和NH₄Cl淬灭反应，EA萃取，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝3:1，R_f＝0.13,DCM，得化合物60；Add compound 59, 0.385mmol, into a single-necked flask, add dry THF under the protection of argon, add the prepared neopentylmagnesium bromide, 2.308mmol, dropwise under ice-cooling, then naturally warm up to room temperature and stir for 1h, add saturated NH₄ Cl Quench the reaction, extract with EA, dry over anhydrous Na₂ SO₄ , filter, concentrate, column chromatography PE:EA=3:1, R_f =0.13, DCM, to obtain compound 60;步骤9：Step 9:单口瓶中加入化合物60,0.13mmol，DMSO溶解，后加入IBX,0.26mmol，室温搅拌过夜，第二日早停止反应，加入H₂O，DCM萃取，水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝4:1，R_f＝0.5,PE:EA＝3:1，得化合物61；Add compound 60, 0.13mmol, into the single-necked bottle, dissolve in DMSO, then add IBX, 0.26mmol, stir overnight at room temperature, stop the reaction early the next day, add H₂ O, extract with DCM, wash with water, dry with anhydrous Na₂ SO₄ , filter , concentrated, column chromatography PE:EA=4:1, R_f =0.5, PE:EA=3:1, compound 61 was obtained;步骤10：Step 10:氩气保护下，在单口瓶中加入(R)-Me-CBS,0.112mmol，后加入THF，降温至-20℃，加入BH₃,0.374mmol,1M in THF，后缓慢滴加化合物61,0.374mmol的THF溶液，3h滴加完毕，-20℃反应4h后停止反应，加入H₂O淬灭反应，EA萃取有机相，水洗，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝3:1，R_f＝0.13,PE:EA＝5:1，得化合物62；Under the protection of argon, add (R)-Me-CBS, 0.112mmol, then add THF, cool down to -20°C, add BH₃ , 0.374mmol, 1M in THF, and then slowly add compound 61, 0.374 The THF solution in mmol was added dropwise for 3 hours, and the reaction was stopped after 4 hours at -20°C. The reaction was quenched by adding H₂ O, the organic phase was extracted with EA, washed with water, dried with anhydrous Na₂ SO₄ , filtered, concentrated, and subjected to column chromatography PE :EA=3:1,_Rf =0.13, PE:EA=5:1, compound 62 was obtained;步骤11：Step 11:单口瓶中加入化合物62 0.22mmol，用EtOH和EA的混合溶液溶解后加入钯碳，通入H₂，TLC监测至原料消失后，过滤，浓缩，得化合物63；Add 0.22 mmol of compound 62 to a single-necked bottle, dissolve it with a mixed solution of EtOH and EA, add palladium carbon, and inject H₂ , monitor by TLC until the raw material disappears, filter and concentrate to obtain compound 63;步骤12：Step 12:单口瓶中加入化合物63 0.061mmol和干燥的THF，后加入NaHg,0.077mmol室温搅拌1h，后缓慢滴加对三氟苯甲酰氯,0.068mmol，1h后停止反应，加入H₂O，EA萃取，无水Na₂SO₄干燥，过滤，浓缩，柱层析PE:EA＝3:1，R_f＝0.76,PE:EA＝3:1，得化合物64；Add 0.061mmol of compound 63 and dry THF to the single-necked bottle, then add NaHg, 0.077mmol, stir at room temperature for 1h, then slowly add p-trifluorobenzoyl chloride, 0.068mmol, stop the reaction after 1h, add H₂ O, extract with EA, Dry over anhydrous Na₂ SO₄ , filter, concentrate, column chromatography PE:EA=3:1, R_f =0.76, PE:EA=3:1, to obtain compound 64;或，or,按如下合成路线和步骤制备化合物65，Compound 65 was prepared according to the following synthetic route and steps,单口瓶中加入化合物63 0.076mmol和干燥的THF，后加入NaH,0.096mmol室温搅拌1h，后缓慢滴加3,5-二(三氟甲基)苯甲酰氯,0.084mmol，1h后停止反应，加入H₂O，EA萃取，无水Na₂SO₄干燥，过滤，浓缩，柱层析DCM，R_f＝0.22,PE:EA＝3:1，得化合物65。Add 0.076mmol of compound 63 and dry THF to the single-necked bottle, then add NaH, 0.096mmol and stir at room temperature for 1h, then slowly drop 3,5-bis(trifluoromethyl)benzoyl chloride, 0.084mmol, and stop the reaction after 1h. Add H₂ O, extract with EA, dry over anhydrous Na₂ SO₄ , filter, concentrate, column chromatography in DCM, R_f =0.22, PE:EA=3:1, to obtain compound 65.