技术领域technical field
本发明涉及药物化学合成技术领域。具体而言，涉及一种1-(苯乙基氨基)丙烷-2-醇类化合物或其盐的制备方法，还涉及所得的1-(苯乙基氨基)丙烷-2-醇类化合物或其盐用于制备氯卡色林的方法。The invention relates to the technical field of medicinal chemical synthesis. Specifically, it relates to a preparation method of a 1-(phenylethylamino)propane-2-alcohol compound or its salt, and also relates to the obtained 1-(phenethylamino)propane-2-alcohol compound or its The salt is used in the process for the preparation of lorcaserin.
背景技术Background technique
氯卡色林(Lorcaserin，商品名Belviq)是美国FDA13年来首次批准的一种新型减肥药。2012年6月27日，美国食品药品管理局(FDA)正式批准了Arena制药公司的新减肥药盐酸氯卡色林上市。该药获准用于成人体质指数(BMI)≥27的肥胖或超重者，并且患者至少有一项与体重相关的疾病(如高血压、2型糖尿病或高脂血症)。其作用机制是激动丘脑下部的5-羟色胺受体来控制食欲，这一受体的激活可帮助患者吃的更少，且增强饱腹感。与目前市售的其他减肥药如芬氟拉明和芬特明相比，盐酸氯卡色林的优势在于其作用的靶器官只限于脑组织，而不像其他两个药物那样对全身的5-羟色胺受体均有作用，因此不会导致因激动心脏附近的5-羟色胺受体而引起心瓣膜疾病的发生。Lorcaserin (trade name Belviq) is a new type of weight-loss drug approved by the US FDA for the first time in 13 years. On June 27, 2012, the U.S. Food and Drug Administration (FDA) officially approved the listing of the new weight-loss drug lorcaserin hydrochloride of Arena Pharmaceuticals. The drug is approved for obese or overweight adults with a body mass index (BMI) ≥ 27 and who have at least one weight-related disorder (such as hypertension, type 2 diabetes, or hyperlipidemia). Its mechanism of action is to stimulate the serotonin receptors in the hypothalamus to control appetite. The activation of this receptor can help patients eat less and increase the feeling of fullness. Compared with other weight-loss drugs currently on the market such as fenfluramine and phentermine, the advantage of lorcaserin hydrochloride is that its target organ is limited to brain tissue, unlike the other two drugs that affect the body's 5- All serotonin receptors have an effect, so it will not lead to the occurrence of heart valve diseases caused by exciting 5-serotonin receptors near the heart.
制备氯卡色林的关键中间体1-((4-氯苯乙基)氨基)丙烷-2-醇为1-(苯乙基氨基)丙烷-2-醇类化合物，其结构式如下所示，分子量为213.70。The key intermediate 1-((4-chlorophenethyl) amino) propan-2-alcohol of preparation lorcaserin is 1-(phenethylamino) propan-2-alcohol compound, and its structural formula is as follows, The molecular weight is 213.70.
专利文献CN200780045133.9中公开了以1-氨基-2-丙醇和对氯苯乙酸为原料，先合成酰胺化合物，再经还原剂还原得到1-((4-氯苯乙基)氨基)丙烷-2-醇(见下式)。该方法为两步反应，由于还原时用到硼烷或碘，都属于毒性比较大的化学品，对实验人员有一定的危险性和对环境可能造成污染等缺点。The patent document CN200780045133.9 discloses that 1-amino-2-propanol and p-chlorophenylacetic acid are used as raw materials to synthesize amide compounds first, and then reduced by a reducing agent to obtain 1-((4-chlorophenethyl)amino)propane- 2-alcohol (see formula below). The method is a two-step reaction, and because borane or iodine is used in the reduction, both of which are relatively toxic chemicals, which have some disadvantages such as danger to experimenters and possible pollution to the environment.
专利文献WO2010148207是以对氯苯乙醇为原料通过两步反应得到1-((4-氯苯乙基)氨基)丙烷-2-醇(见下式)，总产率有71.7％。但该工艺起始原料对氯苯乙醇的商业价格较高，而且第二步反应长时间高温，能耗较高。Patent document WO2010148207 uses p-chlorophenylethanol as a raw material to obtain 1-((4-chlorophenethyl)amino)propan-2-ol (see the formula below) through two-step reactions, with a total yield of 71.7%. However, the commercial price of p-chlorophenylethanol, the starting material of the process, is relatively high, and the second step reacts at a high temperature for a long time, and the energy consumption is relatively high.
专利文献WO2009111004A1也是以对氯苯乙醇为原料通过两步反应得到1-((4-氯苯乙基)氨基)丙烷-2-醇(见下式)，总产率有67.2％。该工艺起始原料对氯苯乙醇的商业价格较高，而且HBr毒性较大，对实验人员有一定的危险性和对环境可能造成污染。Patent document WO2009111004A1 also uses p-chlorophenylethanol as a raw material to obtain 1-((4-chlorophenethyl)amino)propan-2-ol (see the formula below) through two-step reactions, with a total yield of 67.2%. The commercial price of p-chlorophenylethanol, the starting material of this process, is relatively high, and the toxicity of HBr is relatively high, which is dangerous to experimenters and may cause pollution to the environment.
上述在先文献都没有报道所得1-((4-氯苯乙基)氨基)丙烷-2-醇或其盐的纯度。None of the aforementioned prior documents reported the purity of the obtained 1-((4-chlorophenethyl)amino)propan-2-ol or its salts.
因此，关于1-(苯乙基氨基)丙烷-2-醇类化合物或其盐的已知的制备方法尚存在一定的不足，开发其新的制备方法具有重要的现实意义。Therefore, there are still some deficiencies in the known preparation methods of 1-(phenethylamino)propan-2-ol compounds or salts thereof, and the development of new preparation methods thereof has important practical significance.
发明内容Contents of the invention
针对现有技术的不足，本发明的目的是提供一种1-(苯乙基氨基)丙烷-2-醇类化合物或其盐的新的制备方法，该方法原料易得、反应步骤少、操作简便、收率良好、环境友好、适合工业化生产。For the deficiencies in the prior art, the purpose of this invention is to provide a kind of new preparation method of 1-(phenylethylamino) propane-2-alcohol compound or its salt, and this method raw material is easy to get, reaction steps is few, and operation The method is simple, has good yield, is environmentally friendly and is suitable for industrial production.
本发明提供了一种式Ⅱ所示1-(苯乙基氨基)丙烷-2-醇类化合物或其盐的制备方法，包括以下步骤：使式I化合物与环氧丙烷反应生成所述式II化合物；The present invention provides a preparation method of 1-(phenethylamino)propan-2-alcohol compound represented by formula II or its salt, comprising the following steps: reacting the compound of formula I with propylene oxide to generate said formula II compound;
其中，R1选自H、直链或支链的C1～C4烷基、卤素、甲氧基、硝基或-OH；R2选自H、直链或支链的C1～C4烷基、甲氧基、苄氧羰基、叔丁氧羰基、甲磺酰基、对甲苯磺酰基、苄基或带取代基的苄基，所述取代基选自直链或支链的C1～C4烷基、-OH、直链或支链的C1～C4烷氧基、卤素、4-硝基、4-氨基或4-三氟甲基。Wherein, R1 is selected from H, straight chain or branched C1 ~C4 alkyl, halogen, methoxy, nitro or -OH; R2 is selected from H, straight chain or branched C1 ~C4 Alkyl, methoxy, benzyloxycarbonyl, tert-butoxycarbonyl, methanesulfonyl, p-toluenesulfonyl, benzyl or benzyl witha substituent selected from linear or branched C -C4 alkyl, -OH, straight or branched C1 -C4 alkoxy, halogen, 4-nitro, 4-amino or 4-trifluoromethyl.
所述卤素为氟、氯、溴或碘。The halogen is fluorine, chlorine, bromine or iodine.
优选地，R1为卤素，R2为H。Preferably,R1 is halogen andR2 is H.
更优选地，R1为氯且为对位(即4-氯)，R2为H。More preferably R1 is chloro and is para (ie4- chloro) and R2 is H.
优选地，所述环氧丙烷与所述式I化合物的摩尔比为1～10∶1；反应无溶剂或使用以下溶剂：甲醇、乙醇、丙醇、异丙醇、正丁醇、叔丁醇、异丁醇、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、N-甲基吡咯烷酮、丙酮、丁酮、戊酮、1，4-二氧六环、水、N，N-二甲基甲酰胺、二甲基亚砜或其任意比例的混合物；反应温度为5～189℃；反应时间为2～18小时。Preferably, the molar ratio of the propylene oxide to the compound of formula I is 1 to 10:1; the reaction is solvent-free or the following solvents are used: methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol , isobutanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, N-methylpyrrolidone, acetone, methyl ethyl ketone, pentanone, 1,4-dioxane, water, N,N-dimethylformaldehyde Amide, dimethyl sulfoxide or a mixture thereof in any proportion; the reaction temperature is 5-189° C.; the reaction time is 2-18 hours.
更优选地，所述环氧丙烷与所述式I化合物的摩尔比为1.5～2∶1；反应无溶剂或使用以下溶剂：甲醇、乙醇、水、四氢呋喃、1，4-二氧六环或其任意比例的混合物；反应温度为30～90℃；反应时间为6～16小时。More preferably, the molar ratio of the propylene oxide to the compound of formula I is 1.5 to 2:1; the reaction is solvent-free or the following solvents are used: methanol, ethanol, water, tetrahydrofuran, 1,4-dioxane or It is a mixture in any proportion; the reaction temperature is 30-90° C.; the reaction time is 6-16 hours.
本发明提供的所述式II化合物1-(苯乙基氨基)丙烷-2-醇类化合物或其盐的制备方法，进一步包括如下步骤：向所述式II化合物中加入重结晶溶剂，加热回流，然后降温使析出固体来纯化所述式II化合物。优选地，所述重结晶溶剂选自甲醇、乙醇、丙醇、异丙醇、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、乙酸异丙酯、二氯甲烷、丙酮、石油醚、正己烷、环己烷、正庚烷、甲苯、二甲苯、甲基叔丁基醚或其任意比例的混合物；重结晶温度为0～110℃；重结晶时间为2～18小时。更优选地，所述重结晶溶剂选自石油醚、正己烷、正庚烷、乙酸乙酯或其任意比例的混合物；重结晶温度为40～100℃；重结晶时间为1～2小时；降温后的温度为-10～30℃，优选为室温。由此可以得到HPLC纯度＞95％的式II化合物的纯品。The preparation method of the compound of formula II 1-(phenethylamino)propane-2-alcohol compound or its salt provided by the present invention further comprises the steps of: adding a recrystallization solvent to the compound of formula II, and heating to reflux , and then cool down to separate out solids to purify the compound of formula II. Preferably, the recrystallization solvent is selected from methanol, ethanol, propanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, dichloromethane, acetone, petroleum ether, n-hexane, Cyclohexane, n-heptane, toluene, xylene, methyl tert-butyl ether or a mixture thereof in any proportion; the recrystallization temperature is 0-110°C; the recrystallization time is 2-18 hours. More preferably, the recrystallization solvent is selected from petroleum ether, n-hexane, n-heptane, ethyl acetate or a mixture thereof in any proportion; the recrystallization temperature is 40-100°C; the recrystallization time is 1-2 hours; the temperature is lowered The final temperature is -10 to 30°C, preferably room temperature. A pure product of the compound of formula II with an HPLC purity >95% can thus be obtained.
本发明提供的所述式II所示的1-(苯乙基氨基)丙烷-2-醇类化合物或其盐的制备方法，进一步包括如下步骤：使所述式II化合物与酸进行成盐反应得到式II化合物的酸加成盐；其中，所述酸选自盐酸、氢溴酸、乙酸、甲酸、三氟乙酸、二氟乙酸、硫酸、磷酸、硝酸、甲烷磺酸、草酸、柠檬酸、苹果酸或酒石酸。优选地，所述酸选自盐酸、硫酸、草酸、柠檬酸或甲烷磺酸。The preparation method of the 1-(phenethylamino)propane-2-alcohol compound represented by the formula II or its salts provided by the present invention further comprises the following steps: making the compound of the formula II react with an acid to form a salt Obtain the acid addition salt of formula II compound; Wherein, described acid is selected from hydrochloric acid, hydrobromic acid, acetic acid, formic acid, trifluoroacetic acid, difluoroacetic acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, oxalic acid, citric acid, malic acid or tartaric acid. Preferably, the acid is selected from hydrochloric acid, sulfuric acid, oxalic acid, citric acid or methanesulfonic acid.
所述酸与式II化合物的摩尔比是1～3∶1，优选为1～1.5∶1；反应溶剂选自乙酸乙酯、甲苯、二氯甲烷、甲基叔丁基醚、正己烷、石油醚、庚烷、乙醚、甲醇、乙醇、丙醇、异丙醇、正丁醇、叔丁醇、异丁醇、四氢呋喃、2-甲基四氢呋喃、N-甲基吡咯烷酮、丙酮、丁酮、戊酮、1，4-二氧六环、水或其任意比例的混合物，优选为乙酸乙酯、甲醇、二氯甲烷、甲苯、水或其任意比例的混合物；反应温度为0～90℃，优选为0～50℃；反应时间为0.5～12小时，优选为1～4小时。The molar ratio of the acid to the compound of formula II is 1 to 3: 1, preferably 1 to 1.5: 1; the reaction solvent is selected from ethyl acetate, toluene, methylene dichloride, methyl tert-butyl ether, normal hexane, petroleum Ether, heptane, diethyl ether, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isobutanol, tetrahydrofuran, 2-methyltetrahydrofuran, N-methylpyrrolidone, acetone, methyl ethyl ketone, amyl Ketone, 1,4-dioxane, water or a mixture thereof in any proportion, preferably ethyl acetate, methanol, dichloromethane, toluene, water or a mixture in any proportion thereof; the reaction temperature is 0-90°C, preferably 0-50°C; the reaction time is 0.5-12 hours, preferably 1-4 hours.
在本发明制备方法最优选的实施方案中，即R1为4-氯，R2为H时涉及1-((4-氯苯乙基)氨基)丙烷-2-醇或其盐酸的制备方法，具体为：将对氯苯乙胺(化合物1)与环氧丙烷反应生成(1-((4-氯苯乙基)氨基)丙烷-2-醇(化合物2)，化合物2与盐酸成盐得到(1-((4-氯苯乙基)氨基)丙烷-2-醇盐酸盐(化合物3)。In the most preferred embodiment of the preparation method of the present invention, that is, when R is4- chloro, and R is H, it involves a preparation method of 1-((4-chlorophenethyl)amino)propane-2-ol or its hydrochloric acid , specifically: react p-chlorophenethylamine (compound 1) with propylene oxide to generate (1-((4-chlorophenethyl)amino)propan-2-ol (compound 2), compound 2 is salted with hydrochloric acid (1-((4-chlorophenethyl)amino)propan-2-ol hydrochloride (compound 3) was obtained.
进一步地，本发明提供了通过上述方法制备而成的式II所示的1-(苯乙基氨基)丙烷-2-醇类化合物或其盐，Further, the present invention provides 1-(phenethylamino)propan-2-ol compounds or their salts represented by formula II prepared by the above method,
其中，R1和R2的定义与前述的相同。最优选地，所述式Ⅱ化合物为1-((4-氯苯乙基)氨基)丙烷-2-醇或其盐。Wherein , the definitionsof R1 and R2 are the same as above. Most preferably, the compound of formula II is 1-((4-chlorophenethyl)amino)propan-2-ol or a salt thereof.
进一步地，本发明提供一种氯卡色林或其盐的制备方法，其是以上述方法制备得到的1-(苯乙基氨基)丙烷-2-醇类化合物或其盐为原料制备而成的，优选以1-((4-氯苯乙基)氨基)丙烷-2-醇或其盐为原料制备而成。Further, the present invention provides a method for preparing lorcaserin or its salt, which is prepared from the 1-(phenylethylamino)propane-2-ol compound or its salt prepared by the above method as raw material It is preferably prepared from 1-((4-chlorophenethyl)amino)propan-2-ol or its salt.
以下是氯卡色林盐酸盐半水合物的合成路线：The following is the synthetic route of lorcaserin hydrochloride hemihydrate:
化合物2或3通过氯代、F-C关环反应、酒石酸拆分、成盐等反应制备得到氯卡色林盐酸盐半水合物。Lorcaserin hydrochloride hemihydrate was prepared by compound 2 or 3 through chlorination, F-C ring closure reaction, tartaric acid resolution, salt formation and other reactions.
本发明提供了1-(苯乙基氨基)丙烷-2-醇类化合物或其盐的制备方法，使用商业易得的取代或未取代的苯乙胺和环氧丙烷为原料，通过一步反应就可得到1-(苯乙基氨基)丙烷-2-醇类化合物，再通过简单的成盐反应即可得1-(苯乙基氨基)丙烷-2-醇类化合物的盐，成盐后纯度更高，未反应完的原料经简单回收后可套用，总产率良好，简化了操作步骤，降低了生产成本，环境友好，适合工业化生产。另外，本发明制备方法得到的1-(苯乙基氨基)丙烷-2-醇类化合物或其盐作为制备氯卡色林或其盐的中间体具有高纯度，有利于提高产物的质量和稳定性。The invention provides a preparation method of 1-(phenylethylamino)propane-2-alcohol compounds or salts thereof, which uses commercially available substituted or unsubstituted phenethylamine and propylene oxide as raw materials, and undergoes a one-step reaction. 1-(phenylethylamino)propan-2-ol compounds can be obtained, and then the salt of 1-(phenethylamino)propan-2-ol compounds can be obtained through a simple salt-forming reaction, and the purity after salt formation Higher, the unreacted raw materials can be used mechanically after simple recovery, the total yield is good, the operation steps are simplified, the production cost is reduced, the environment is friendly, and it is suitable for industrial production. In addition, the 1-(phenylethylamino)propan-2-ol compound or its salt obtained by the preparation method of the present invention has high purity as an intermediate for preparing lorcaserin or its salt, which is beneficial to improving the quality and stability of the product sex.
具体实施方式detailed description
通过下述实施例将有助于进一步理解本发明，但是不用于限制本发明内容。The following examples will help to further understand the present invention, but are not intended to limit the content of the present invention.
实施例中所使用的各种试剂都是商业购买的。All reagents used in the examples were purchased commercially.
实施例中所述“室温”是指10℃～30℃。The "room temperature" mentioned in the examples refers to 10°C to 30°C.
实施例中的测试分析仪器和条件：Test analysis instrument and condition in the embodiment:
AV-400核磁共振仪(德国Bruker公司)；AV-400 nuclear magnetic resonance instrument (Germany Bruker company);
LC-20AT型高效液相色谱仪(日本岛津公司)；LC-20AT high performance liquid chromatograph (Shimadzu Corporation of Japan);
LCMS仪器为ThermoLcqFleet2(美国热电公司)。The LCMS instrument is ThermoLcqFleet2 (Thermo Electric Corporation).
HPLC测试条件：色谱柱PrevailTMC18，5μm，4.6mm×250mm；检测时间15min；流动相：乙腈：水(0.01％三氟乙酸)，梯度：时间0min乙腈5％，时间15min乙腈85％。HPLC test conditions: chromatographic column PrevailTM C18, 5 μm, 4.6mm×250mm; detection time 15min; mobile phase: acetonitrile: water (0.01% trifluoroacetic acid), gradient: time 0min acetonitrile 5%, time 15min acetonitrile 85%.
手性测试条件：AgilentAD-H手性柱，流速为1ml/min，流动相为正己烷∶异丙醇∶三氟乙酸∶三乙胺＝950∶50∶2∶1。Chiral test conditions: Agilent AD-H chiral column, flow rate is 1ml/min, mobile phase is n-hexane:isopropanol:trifluoroacetic acid:triethylamine=950:50:2:1.
实施例1Example 1
方法AMethod A
将化合物1对氯苯乙胺(250.00g，1.6mol)和环氧丙烷(93.00g，1.6mol)溶于无水乙醇(1605mL)中，加热至回流反应8～10h。反应结束后，减压除去溶剂，得淡黄色油状液体。向上述油状物加入正己烷(500mL)，升温至回流，保温1h。降温至室温，有固体析出，抽滤，滤饼用少量正己烷洗涤，收集滤饼。干燥。得到白色固体化合物2(1-((4-氯苯乙基)氨基)丙烷-2-醇)，产量158.2g，HPLC＝98.8％。1HNMR(400MHz，CDCl3，δ)：7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，2.88(d，1H)，1.56(d，3H)。LCMS：213.8-215.8(MH)。HPLC保留时间7.8min。滤液回收，减压除去溶剂，减压蒸馏，回收得到未反应的无色液体化合物1对氯苯乙胺94.6g，HPLC＝97％。不计未反应的对氯苯乙胺，产率为74％。Compound 1 p-chlorophenethylamine (250.00g, 1.6mol) and propylene oxide (93.00g, 1.6mol) were dissolved in absolute ethanol (1605mL), heated to reflux for 8-10h. After the reaction, the solvent was removed under reduced pressure to obtain a light yellow oily liquid. Add n-hexane (500 mL) to the above oil, raise the temperature to reflux, and keep it warm for 1 h. After cooling down to room temperature, a solid precipitated out, and it was suction filtered, and the filter cake was washed with a small amount of n-hexane, and the filter cake was collected. dry. A white solid compound 2 (1-((4-chlorophenethyl)amino)propan-2-ol) was obtained with a yield of 158.2 g, HPLC=98.8%.1 HNMR (400MHz, CDCl3 , δ): 7.42(d, 2H), 7.32(d, 2H), 4.58(m, 1H), 3.45(m, 2H), 3.25(m, 2H), 3.02(m, 2H), 2.88(d, 1H), 1.56(d, 3H). LCMS: 213.8-215.8 (MH). HPLC retention time 7.8min. The filtrate was recovered, the solvent was removed under reduced pressure, and distillation under reduced pressure was recovered to obtain 94.6 g of unreacted colorless liquid compound 1 p-chlorophenethylamine, HPLC=97%. Excluding unreacted p-chlorophenethylamine, the yield was 74%.
将化合物21-((4-氯苯乙基)氨基)丙烷-2-醇(93.00g，0.435mol)溶于乙酸乙酯(437.6mL)中，冰浴搅拌，缓慢通入HCl气至呈酸性，使pH＝1～2。加完后搅拌2h，抽滤，滤饼用少量乙酸乙酯洗涤，收集固体，干燥。得到白色固体化合物3(1-((4-氯苯乙基)氨基)丙烷-2-醇盐酸盐)，产量99.4g，产率为91.3％，HPLC＝99.5％。1HNMR(400MHz，DMSOd6，δ)：9.55(s，1H)，9.15(s，1H)，7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，1.56(d，3H)。LCMS：213.8-215.8(MH)。HPLC保留时间5.8min。Compound 21-((4-chlorophenethyl)amino)propan-2-ol (93.00 g, 0.435 mol) was dissolved in ethyl acetate (437.6 mL), stirred in an ice bath, and HCl gas was slowly introduced until it became acidic , make pH=1～2. Stir for 2 hours after the addition, filter with suction, wash the filter cake with a small amount of ethyl acetate, collect the solid and dry it. The white solid compound 3 (1-((4-chlorophenethyl)amino)propan-2-ol hydrochloride) was obtained with a yield of 99.4 g, a yield of 91.3%, HPLC=99.5%.1 HNMR (400MHz, DMSOd6 , δ): 9.55(s, 1H), 9.15(s, 1H), 7.42(d, 2H), 7.32(d, 2H), 4.58(m, 1H), 3.45(m, 2H), 3.25(m, 2H), 3.02(m, 2H), 1.56(d, 3H). LCMS: 213.8-215.8 (MH). HPLC retention time 5.8min.
方法BMethod B
将化合物1对氯苯乙胺(200.00g，1.28mol)和环氧丙烷(96.9g，1.66mol)溶于无水乙醇(1284mL)中，加热至70℃反应8h。反应结束后，减压除去溶剂，得淡黄色油状液体。向上述油状物加入正庚烷(400mL)，升温至回流，保温1h。降温至室温，有固体析出，抽滤，滤饼用少量正庚烷洗涤，收集滤饼。干燥。得到白色固体化合物2(1-((4-氯苯乙基)氨基)丙烷-2-醇)，产量115.7g，HPLC＝98.4％。1HNMR(400MHz，CDCl3，δ)：7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，2.88(d，1H)，1.56(d，3H)。LCMS：213.8-215.8(MH)。HPLC保留时间7.8min。滤液回收，减压除去溶剂，减压蒸馏，回收得到未反应的无色液体化合物1对氯苯乙胺70.3g，HPLC＝96.5％。不计未反应的对氯苯乙胺，产率为65％。Compound 1 p-chlorophenethylamine (200.00g, 1.28mol) and propylene oxide (96.9g, 1.66mol) were dissolved in absolute ethanol (1284mL), heated to 70°C for 8h. After the reaction, the solvent was removed under reduced pressure to obtain a light yellow oily liquid. Add n-heptane (400 mL) to the above oil, raise the temperature to reflux, and keep it warm for 1 h. After cooling down to room temperature, solids were precipitated, filtered with suction, washed the filter cake with a small amount of n-heptane, and collected the filter cake. dry. The white solid compound 2 (1-((4-chlorophenethyl)amino)propan-2-ol) was obtained with a yield of 115.7 g, HPLC=98.4%.1 HNMR (400MHz, CDCl3 , δ): 7.42(d, 2H), 7.32(d, 2H), 4.58(m, 1H), 3.45(m, 2H), 3.25(m, 2H), 3.02(m, 2H), 2.88(d, 1H), 1.56(d, 3H). LCMS: 213.8-215.8 (MH). HPLC retention time 7.8min. The filtrate was recovered, the solvent was removed under reduced pressure, and distillation under reduced pressure was recovered to obtain 70.3 g of unreacted colorless liquid compound 1 p-chlorophenethylamine, HPLC=96.5%. Excluding unreacted p-chlorophenethylamine, the yield was 65%.
将化合物21-((4-氯苯乙基)氨基)丙烷-2-醇(60.00g，0.28mol)溶于乙酸乙酯(282mL)中，冰浴搅拌，缓慢滴加浓盐酸(37％)至呈酸性，使pH＝1～2。加完后搅拌1h，减压除去有机溶剂，剩余物抽滤，收集滤饼，干燥。得到白色固体化合物3(1-((4-氯苯乙基)氨基)丙烷-2-醇盐酸盐)，产量59.7g，产率为85％，HPLC＝99.1％。1HNMR(400MHz，DMSOd6，δ)：9.55(s，1H)，9.15(s，1H)，7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，1.56(d，3H)。LCMS：213.8-215.8(MH)。HPLC保留时间5.8min。Compound 21-((4-chlorophenethyl)amino)propan-2-ol (60.00g, 0.28mol) was dissolved in ethyl acetate (282mL), stirred in an ice bath, and concentrated hydrochloric acid (37%) was slowly added dropwise until acidic, so that pH = 1 ~ 2. Stir for 1 h after the addition, remove the organic solvent under reduced pressure, filter the residue with suction, collect the filter cake and dry it. A white solid compound 3 (1-((4-chlorophenethyl)amino)propan-2-ol hydrochloride) was obtained, yield 59.7 g, yield 85%, HPLC=99.1%.1 HNMR (400MHz, DMSOd6 , δ): 9.55(s, 1H), 9.15(s, 1H), 7.42(d, 2H), 7.32(d, 2H), 4.58(m, 1H), 3.45(m, 2H), 3.25(m, 2H), 3.02(m, 2H), 1.56(d, 3H). LCMS: 213.8-215.8 (MH). HPLC retention time 5.8min.
实施例2Example 2
方法AMethod A
将化合物1对氯苯乙胺(150.00g，0.963mol)和环氧丙烷(55.90g，0.963mol)溶于无水甲醇(1000mL)中，加热至回流反应10～12h。反应结束后，减压除去溶剂，得淡黄色油状液体。向上述油状物加入石油醚(300mL)，升温至回流，保温1h。降温至室温，有固体析出，抽滤，滤饼用少量石油醚洗涤，收集滤饼。干燥。得到白色固体化合物2(1-((4-氯苯乙基)氨基)丙烷-2-醇)，产量92.6g，HPLC＝98.6％。1HNMR(400MHz，CDCl3，δ)：7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，2.88(d，1H)，1.56(d，3H)。LCMS：213.8-215.8(MH)。HPLC保留时间7.8min。滤液回收，减压除去溶剂，减压蒸馏，回收得到未反应的无色液体化合物1对氯苯乙胺55g，HPLC＝96.8％。不计未反应的对氯苯乙胺，产率为71％。Compound 1 p-chlorophenethylamine (150.00g, 0.963mol) and propylene oxide (55.90g, 0.963mol) were dissolved in anhydrous methanol (1000mL), heated to reflux for 10-12h. After the reaction, the solvent was removed under reduced pressure to obtain a light yellow oily liquid. Petroleum ether (300 mL) was added to the above oil, and the temperature was raised to reflux and kept for 1 h. After cooling down to room temperature, a solid precipitated out, and it was suction filtered, and the filter cake was washed with a small amount of petroleum ether, and the filter cake was collected. dry. A white solid compound 2 (1-((4-chlorophenethyl)amino)propan-2-ol) was obtained with a yield of 92.6 g and HPLC=98.6%.1 HNMR (400MHz, CDCl3 , δ): 7.42(d, 2H), 7.32(d, 2H), 4.58(m, 1H), 3.45(m, 2H), 3.25(m, 2H), 3.02(m, 2H), 2.88(d, 1H), 1.56(d, 3H). LCMS: 213.8-215.8 (MH). HPLC retention time 7.8min. The filtrate was recovered, the solvent was removed under reduced pressure, and distillation under reduced pressure was recovered to obtain 55 g of unreacted colorless liquid compound 1 p-chlorophenethylamine, HPLC=96.8%. Excluding unreacted p-chlorophenethylamine, the yield was 71%.
将化合物21-((4-氯苯乙基)氨基)丙烷-2-醇(38.01g，0.18mol)溶于甲醇(200mL)，降温至0～5℃，滴加草酸(16.06g，0.18mol)的甲醇(60mL)溶液，25～30分钟加完，滴加过程中析出白色固体，加完后室温搅拌1h。减压除去溶剂后加入乙酸乙酯(250mL)，室温搅拌，1h后抽滤，滤饼用少量乙酸乙酯洗涤，收集滤饼，干燥，得到白色固体化合物4(1-((4-氯苯乙基)氨基)丙烷-2-醇草酸盐)，产量47.85g，产率88.6％，HPLC＝99.1％。1HNMR(400MHz，DMSOd6，δ)：10.65(s，1H)，9.55(s，1H)，9.15(s，1H)，7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，1.56(d，3H)。LCMS：213.8-215.8(MH)。HPLC保留时间4.8min。Compound 21-((4-chlorophenethyl)amino)propan-2-ol (38.01g, 0.18mol) was dissolved in methanol (200mL), cooled to 0-5°C, and oxalic acid (16.06g, 0.18mol ) methanol (60mL) solution, the addition was completed in 25 to 30 minutes, a white solid precipitated during the dropwise addition, and stirred at room temperature for 1 hour after the addition was completed. After removing the solvent under reduced pressure, add ethyl acetate (250mL), stir at room temperature, filter with suction after 1h, wash the filter cake with a small amount of ethyl acetate, collect the filter cake, and dry to obtain the white solid compound 4(1-((4-chlorobenzene Ethyl)amino)propan-2-ol oxalate), yield 47.85g, yield 88.6%, HPLC=99.1%.1 HNMR (400MHz, DMSOd6 , δ): 10.65(s, 1H), 9.55(s, 1H), 9.15(s, 1H), 7.42(d, 2H), 7.32(d, 2H), 4.58(m, 1H), 3.45(m, 2H), 3.25(m, 2H), 3.02(m, 2H), 1.56(d, 3H). LCMS: 213.8-215.8 (MH). HPLC retention time 4.8min.
方法BMethod B
将化合物1对氯苯乙胺(5.00g，0.032mol)和环氧丙烷(1.86g，0.032mol)溶于无水甲醇(20mL)中，升温至回流，3h后未完全反应，补加环氧丙烷(0.93g，0.016mol)继续反应6h。反应结束后，减压除去溶剂，得淡黄色油状液体。向上述油状物加入石油醚(10mL)，升温至回流，保温1h。降温至室温，有固体析出，抽滤，滤饼用少量石油醚洗涤，收集滤饼。干燥。得到白色固体化合物2(1-((4-氯苯乙基)氨基)丙烷-2-醇)，产量2.8g，HPLC＝98.4％。1HNMR(400MHz，CDCl3，δ)：7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，2.88(d，1H)，1.56(d，3H)。LCMS：213.8-215.8(MH)。HPLC保留时间7.8min。滤液回收，减压除去溶剂，减压蒸馏，回收得到未反应的无色液体化合物1对氯苯乙胺1.75g，HPLC＝96.5％。不计未反应的对氯苯乙胺，产率为62.7％。Compound 1 p-chlorophenethylamine (5.00g, 0.032mol) and propylene oxide (1.86g, 0.032mol) were dissolved in anhydrous methanol (20mL), and the temperature was raised to reflux. After 3h, the reaction was not complete, and epoxy Propane (0.93g, 0.016mol) continued to react for 6h. After the reaction, the solvent was removed under reduced pressure to obtain a light yellow oily liquid. Petroleum ether (10 mL) was added to the above oil, the temperature was raised to reflux, and the temperature was kept for 1 h. After cooling down to room temperature, a solid precipitated out, and it was suction filtered, and the filter cake was washed with a small amount of petroleum ether, and the filter cake was collected. dry. A white solid compound 2 (1-((4-chlorophenethyl)amino)propan-2-ol) was obtained with a yield of 2.8 g, HPLC=98.4%.1 HNMR (400MHz, CDCl3 , δ): 7.42(d, 2H), 7.32(d, 2H), 4.58(m, 1H), 3.45(m, 2H), 3.25(m, 2H), 3.02(m, 2H), 2.88(d, 1H), 1.56(d, 3H). LCMS: 213.8-215.8 (MH). HPLC retention time 7.8min. The filtrate was recovered, the solvent was removed under reduced pressure, and distilled under reduced pressure to obtain 1.75 g of unreacted colorless liquid compound 1 p-chlorophenethylamine, HPLC=96.5%. Excluding unreacted p-chlorophenethylamine, the yield was 62.7%.
将化合物21-((4-氯苯乙基)氨基)丙烷-2-醇(2.5g，0.012mol)溶于甲醇(10mL)，降温至0～5℃，滴加草酸(1.05g，0.012mol)的水(5mL)溶液，滴加过程中析出白色固体，加完后室温搅拌1h。减压除去有机溶剂，抽滤，收集滤饼，干燥，得到白色固体化合物4(1-((4-氯苯乙基)氨基)丙烷-2-醇草酸盐)，产量2.95g，产率83％，HPLC＝99％。1HNMR(400MHz，DMSOd6，δ)：10.65(s，1H)，9.55(s，1H)，9.15(s，1H)，7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，1.56(d，3H)。LCMS：213.8-215.8(MH)。HPLC保留时间4.5min。Compound 21-((4-chlorophenethyl)amino)propan-2-ol (2.5g, 0.012mol) was dissolved in methanol (10mL), cooled to 0-5°C, and oxalic acid (1.05g, 0.012mol) was added dropwise ) in water (5 mL), a white solid precipitated during the dropwise addition, and stirred at room temperature for 1 h after the addition was complete. The organic solvent was removed under reduced pressure, suction filtered, and the filter cake was collected and dried to obtain a white solid compound 4 (1-((4-chlorophenethyl)amino)propan-2-alcohol oxalate), yield 2.95g, yield 83%, HPLC=99%.1 HNMR (400MHz, DMSOd6 , δ): 10.65(s, 1H), 9.55(s, 1H), 9.15(s, 1H), 7.42(d, 2H), 7.32(d, 2H), 4.58(m, 1H), 3.45(m, 2H), 3.25(m, 2H), 3.02(m, 2H), 1.56(d, 3H). LCMS: 213.8-215.8 (MH). HPLC retention time 4.5min.
实施例3Example 3
方法AMethod A
将化合物1对氯苯乙胺(5.0g，0.032mol)、环氧丙烷(2.05g，0.035mol)、水(60mL)混合并升温至80℃反应10h，然后加入二氯甲烷(50mL)萃取，合并有机相，旋蒸，得到淡黄色油状物。向上述油状物加入正己烷(10mL)，升温至回流，保温1h。降温至室温，有固体析出，抽滤，滤饼用少量正己烷洗涤，收集滤饼。干燥。得到白色固体化合物2(1-((4-氯苯乙基)氨基)丙烷-2-醇)，产量3.07g，HPLC＝98.7％。1HNMR(400MHz，CDCl3，δ)：7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，2.88(d，1H)，1.56(d，3H)。LCMS：213.8-215.8(MH)。HPLC保留时间7.8min。滤液回收，减压除去溶剂，减压蒸馏，回收得到未反应的无色液体化合物1对氯苯乙胺(1.8g，HPLC＝96.7％)。不计未反应的对氯苯乙胺，产率为70％。Compound 1 p-chlorophenethylamine (5.0 g, 0.032 mol), propylene oxide (2.05 g, 0.035 mol), and water (60 mL) were mixed and heated to 80 ° C for 10 h, then dichloromethane (50 mL) was added for extraction, The organic phases were combined and rotary evaporated to obtain a pale yellow oil. Add n-hexane (10 mL) to the above oil, raise the temperature to reflux, and keep it warm for 1 h. After cooling down to room temperature, a solid precipitated out, and it was suction filtered, and the filter cake was washed with a small amount of n-hexane, and the filter cake was collected. dry. The white solid compound 2 (1-((4-chlorophenethyl)amino)propan-2-ol) was obtained with a yield of 3.07 g, HPLC=98.7%.1 HNMR (400MHz, CDCl3 , δ): 7.42(d, 2H), 7.32(d, 2H), 4.58(m, 1H), 3.45(m, 2H), 3.25(m, 2H), 3.02(m, 2H), 2.88(d, 1H), 1.56(d, 3H). LCMS: 213.8-215.8 (MH). HPLC retention time 7.8min. The filtrate was recovered, the solvent was removed under reduced pressure, and the unreacted colorless liquid compound 1 p-chlorophenethylamine (1.8 g, HPLC=96.7%) was recovered by distillation under reduced pressure. Excluding unreacted p-chlorophenethylamine, the yield was 70%.
降温至20℃以下，将化合物21-((4-氯苯乙基)氨基)丙烷-2-醇(1.0g，0.0047mol)溶于甲醇(7mL)，滴加甲基磺酸(0.45g，0.0047mol)，溶剂减压旋蒸后加入乙酸乙酯(5mL)，滴加石油醚，白色固体析出，2小时后抽滤，得到白色固体化合物5(1-((4-氯苯乙基)氨基)丙烷-2-醇甲磺酸盐)，产量1.27g，产率为87.5％，HPLC＝99.1％。1HNMR(400MHz，DMSOd6，δ)：9.55(s，1H)，9.15(s，1H)，7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.23(s，3H)，3.02(m，2H)，1.56(d，3H)。LCMS：213.8-215.8(MH)。HPLC保留时间4.7min。Cool down to below 20°C, dissolve compound 21-((4-chlorophenethyl)amino)propan-2-ol (1.0g, 0.0047mol) in methanol (7mL), add methanesulfonic acid (0.45g, 0.0047mol), the solvent was evaporated under reduced pressure and ethyl acetate (5mL) was added, and petroleum ether was added dropwise, and a white solid was precipitated. After 2 hours, it was filtered by suction to obtain a white solid compound 5 (1-((4-chlorophenethyl) Amino)propan-2-ol mesylate), yield 1.27g, yield 87.5%, HPLC=99.1%.1 HNMR (400MHz, DMSOd6 , δ): 9.55(s, 1H), 9.15(s, 1H), 7.42(d, 2H), 7.32(d, 2H), 4.58(m, 1H), 3.45(m, 2H), 3.25 (m, 2H), 3.23 (s, 3H), 3.02 (m, 2H), 1.56 (d, 3H). LCMS: 213.8-215.8 (MH). HPLC retention time 4.7min.
方法BMethod B
将化合物1对氯苯乙胺(10.0g，0.064mol)、环氧丙烷(4.47，0.077mol)、水(120mL)混合并升温至80℃反应6h，然后加入二氯甲烷(100mL)萃取，合并有机相，旋蒸，得到淡黄色油状物。向上述油状物加入正己烷(20mL)，升温至回流，保温1h。降温至室温，有固体析出，抽滤，滤饼用少量正己烷洗涤，收集滤饼。干燥。得到白色固体化合物2(1-((4-氯苯乙基)氨基)丙烷-2-醇)，产量5.2g，HPLC＝98.5％。1HNMR(400MHz，CDCl3，δ)：7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，2.88(d，1H)，1.56(d，3H)。LCMS：213.8-215.8(MH)。HPLC保留时间7.8min。滤液回收，减压除去溶剂，减压蒸馏，回收得到未反应的无色液体化合物1对氯苯乙胺3.5g，HPLC＝97.1％。不计未反应的对氯苯乙胺，产率为58.2％。Compound 1 p-chlorophenethylamine (10.0 g, 0.064 mol), propylene oxide (4.47, 0.077 mol), and water (120 mL) were mixed and heated to 80 ° C for 6 h, then added dichloromethane (100 mL) for extraction, and combined The organic phase was rotary evaporated to obtain a light yellow oil. Add n-hexane (20 mL) to the above oil, raise the temperature to reflux, and keep it warm for 1 h. After cooling down to room temperature, a solid precipitated out, and it was suction filtered, and the filter cake was washed with a small amount of n-hexane, and the filter cake was collected. dry. A white solid compound 2 (1-((4-chlorophenethyl)amino)propan-2-ol) was obtained with a yield of 5.2 g, HPLC=98.5%.1 HNMR (400MHz, CDCl3 , δ): 7.42(d, 2H), 7.32(d, 2H), 4.58(m, 1H), 3.45(m, 2H), 3.25(m, 2H), 3.02(m, 2H), 2.88(d, 1H), 1.56(d, 3H). LCMS: 213.8-215.8 (MH). HPLC retention time 7.8min. The filtrate was recovered, the solvent was removed under reduced pressure, and distilled under reduced pressure to obtain 3.5 g of unreacted colorless liquid compound 1 p-chlorophenethylamine, HPLC=97.1%. Excluding unreacted p-chlorophenethylamine, the yield was 58.2%.
降温至20℃以下，将化合物21-((4-氯苯乙基)氨基)丙烷-2-醇(2.0g，0.0094mol)溶于甲醇(15mL)，滴加甲基磺酸(0.9g，0.0094mol)的水(4.5mL)溶液，加完后搅拌1h。减压除去有机溶剂，抽滤，得到白色固体化合物5(1-((4-氯苯乙基)氨基)丙烷-2-醇甲磺酸盐)，产量2.4g，产率为83.2％，HPLC＝99％。1HNMR(400MHz，DMSOd6，δ)：9.55(s，1H)，9.15(s，1H)，7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.23(s，3H)，3.02(m，2H)，1.56(d，3H)。LCMS：213.8-215.8(MH)。HPLC保留时间4.7min。Cool down to below 20°C, dissolve compound 21-((4-chlorophenethyl)amino)propan-2-ol (2.0g, 0.0094mol) in methanol (15mL), add methanesulfonic acid (0.9g, 0.0094mol) in water (4.5mL), and stirred for 1h after the addition was complete. The organic solvent was removed under reduced pressure and suction filtered to obtain white solid compound 5 (1-((4-chlorophenethyl)amino)propan-2-ol methanesulfonate), yield 2.4g, yield 83.2%, HPLC = 99%.1 HNMR (400MHz, DMSOd6 , δ): 9.55(s, 1H), 9.15(s, 1H), 7.42(d, 2H), 7.32(d, 2H), 4.58(m, 1H), 3.45(m, 2H), 3.25 (m, 2H), 3.23 (s, 3H), 3.02 (m, 2H), 1.56 (d, 3H). LCMS: 213.8-215.8 (MH). HPLC retention time 4.7min.
实施例4Example 4
将化合物1对氯苯乙胺(10.0g，0.064mol)、环氧丙烷(3.73g，0.064mol)、THF(80mL)混合并升温至65℃反应11h。反应结束后，减压除去溶剂，得淡黄色油状液体。向上述油状物加入乙酸乙酯(3mL)，石油醚(15ml)升温至回流，保温1h。降温至室温，有固体析出，抽滤，滤饼用少量石油醚洗涤，收集滤饼。干燥。得到白色固体化合物2(1-((4-氯苯乙基)氨基)丙烷-2-醇)，产量4.5g，HPLC＝98.2％。1HNMR(400MHz，CDCl3，δ)：7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，2.88(d，1H)，1.56(d，3H)。LCMS：213.8-215.8(MH)。HPLC保留时间7.8min。滤液回收，减压除去溶剂，减压蒸馏，回收得到未反应的无色液体化合物1对氯苯乙胺3.7g，HPLC＝97％。不计未反应的对氯苯乙胺，产率为52％。Compound 1 p-chlorophenethylamine (10.0 g, 0.064 mol), propylene oxide (3.73 g, 0.064 mol) and THF (80 mL) were mixed and heated to 65° C. for 11 h. After the reaction, the solvent was removed under reduced pressure to obtain a light yellow oily liquid. Ethyl acetate (3 mL) was added to the above oil, and petroleum ether (15 mL) was heated to reflux and kept for 1 h. After cooling down to room temperature, a solid precipitated out, and it was suction filtered, and the filter cake was washed with a small amount of petroleum ether, and the filter cake was collected. dry. A white solid compound 2 (1-((4-chlorophenethyl)amino)propan-2-ol) was obtained with a yield of 4.5 g, HPLC=98.2%.1 HNMR (400MHz, CDCl3 , δ): 7.42(d, 2H), 7.32(d, 2H), 4.58(m, 1H), 3.45(m, 2H), 3.25(m, 2H), 3.02(m, 2H), 2.88(d, 1H), 1.56(d, 3H). LCMS: 213.8-215.8 (MH). HPLC retention time 7.8min. The filtrate was recovered, the solvent was removed under reduced pressure, and distillation under reduced pressure was recovered to obtain 3.7 g of unreacted colorless liquid compound 1 p-chlorophenethylamine, HPLC=97%. Excluding unreacted p-chlorophenethylamine, the yield was 52%.
降温至20℃以下将化合物21-((4-氯苯乙基)氨基)丙烷-2-醇(2.0g，0.0094mol)溶于甲醇(15mL)，滴加硫酸(0.9g，0.0094mol)，溶剂减压旋蒸后加入乙酸乙酯(10mL)，滴加石油醚，白色固体析出，2小时后抽滤，得到白色固体化合物6(1-((4-氯苯乙基)氨基)丙烷-2-醇硫酸盐)，产量2.24g，产率为80％，HPLC＝98.9％。1HNMR(400MHz，DMSOd6，δ)：9.55(s，1H)，9.15(s，1H)，7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，1.56(d，3H)。LCMS：213.8-215.8(MH)。HPLC保留时间4.9min。The temperature was lowered to below 20°C and the compound 21-((4-chlorophenethyl)amino)propan-2-ol (2.0 g, 0.0094 mol) was dissolved in methanol (15 mL), and sulfuric acid (0.9 g, 0.0094 mol) was added dropwise, After the solvent was evaporated under reduced pressure, ethyl acetate (10 mL) was added, petroleum ether was added dropwise, and a white solid was precipitated. After 2 hours, it was filtered with suction to obtain a white solid compound 6 (1-((4-chlorophenethyl)amino)propane- 2-alcohol sulfate), yield 2.24g, yield 80%, HPLC=98.9%.1 HNMR (400MHz, DMSOd6 , δ): 9.55(s, 1H), 9.15(s, 1H), 7.42(d, 2H), 7.32(d, 2H), 4.58(m, 1H), 3.45(m, 2H), 3.25(m, 2H), 3.02(m, 2H), 1.56(d, 3H). LCMS: 213.8-215.8 (MH). HPLC retention time 4.9min.
实施例5Example 5
将化合物1对氯苯乙胺(10.0g，0.064mol)、环氧丙烷(3.73g，0.064mol)、1，4-二氧六环(75mL)混合并升温至85℃反应10h。反应结束后，减压除去溶剂，得淡黄色油状液体。向上述油状物加入石油醚(20ml)升温至回流，保温1h。降温至室温，有固体析出，抽滤，滤饼用少量石油醚洗涤，收集滤饼。干燥。得到白色固体化合物2(1-((4-氯苯乙基)氨基)丙烷-2-醇)，产量4.8g，HPLC＝98.4％。1HNMR(400MHz，CDCl3，δ)：7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，2.88(d，1H)，1.56(d，3H)。LCMS：213.8-215.8(MH)。HPLC保留时间7.8min。滤液回收，减压除去溶剂，减压蒸馏，回收得到未反应的无色液体化合物1对氯苯乙胺3.8g，HPLC＝97.3％。不计未反应的对氯苯乙胺，产率为56.3％。Compound 1 p-chlorophenethylamine (10.0 g, 0.064 mol), propylene oxide (3.73 g, 0.064 mol), and 1,4-dioxane (75 mL) were mixed and heated to 85° C. for 10 h. After the reaction, the solvent was removed under reduced pressure to obtain a light yellow oily liquid. Petroleum ether (20ml) was added to the above oil and the temperature was raised to reflux, and kept for 1h. After cooling down to room temperature, a solid precipitated out, and it was suction filtered, and the filter cake was washed with a small amount of petroleum ether, and the filter cake was collected. dry. The white solid compound 2 (1-((4-chlorophenethyl)amino)propan-2-ol) was obtained with a yield of 4.8 g, HPLC=98.4%.1 HNMR (400MHz, CDCl3 , δ): 7.42(d, 2H), 7.32(d, 2H), 4.58(m, 1H), 3.45(m, 2H), 3.25(m, 2H), 3.02(m, 2H), 2.88(d, 1H), 1.56(d, 3H). LCMS: 213.8-215.8 (MH). HPLC retention time 7.8min. The filtrate was recovered, the solvent was removed under reduced pressure, and distilled under reduced pressure to obtain 3.8 g of unreacted colorless liquid compound 1 p-chlorophenethylamine, HPLC=97.3%. Excluding unreacted p-chlorophenethylamine, the yield was 56.3%.
降温至20℃以下，将化合物21-((4-氯苯乙基)氨基)丙烷-2-醇(3.0g，0.014mol)溶于甲醇(15mL)，柠檬酸(2.7g，0.014mol)，有白色固体析出，2小时后抽滤，得到白色固体化合物7(1-((4-氯苯乙基)氨基)丙烷-2-醇柠檬酸盐)，产量4.62g，产率为81.2％，HPLC＝99.1％。1HNMR(400MHz，DMSOd6，δ)：9.55(s，1H)，9.15(s，1H)，7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，2.62(m，2H)，2.53(m，2H)，1.56(d，3H)。LCMS：213.8-215.8(MH)。HPLC保留时间5.7min。After cooling down to below 20°C, the compound 21-((4-chlorophenethyl)amino)propan-2-ol (3.0g, 0.014mol) was dissolved in methanol (15mL), citric acid (2.7g, 0.014mol), A white solid was precipitated, and it was filtered after 2 hours to obtain a white solid compound 7 (1-((4-chlorophenethyl)amino)propan-2-ol citrate), with a yield of 4.62 g and a yield of 81.2%. HPLC = 99.1%.1 HNMR (400MHz, DMSOd6 , δ): 9.55(s, 1H), 9.15(s, 1H), 7.42(d, 2H), 7.32(d, 2H), 4.58(m, 1H), 3.45(m, 2H), 3.25(m, 2H), 3.02(m, 2H), 2.62(m, 2H), 2.53(m, 2H), 1.56(d, 3H). LCMS: 213.8-215.8 (MH). HPLC retention time 5.7min.
实施例6Example 6
将化合物1对氯苯乙胺(10.0g，0.064mol)、环氧丙烷(3.73g，0.064mol)，混合并升温至33℃反应16h。反应结束后，向上述反应液中加入石油醚(20ml)升温至回流，保温1h。降温至室温，有固体析出，抽滤，滤饼用少量石油醚洗涤，收集滤饼。干燥。得到白色固体化合物2(1-((4-氯苯乙基)氨基)丙烷-2-醇)，产量4.1g，HPLC＝98.6％。1HNMR(400MHz，CDCl3，δ)：7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，2.88(d，1H)，1.56(d，3H)。LCMS：213.8-215.8(MH)。HPLC保留时间7.8min。滤液回收，减压除去溶剂，减压蒸馏，回收得到未反应的无色液体化合物1对氯苯乙胺4.5g，HPLC＝97.2％。不计未反应的对氯苯乙胺，产率为54.3％。Compound 1 p-chlorophenethylamine (10.0 g, 0.064 mol) and propylene oxide (3.73 g, 0.064 mol) were mixed and heated to 33° C. for 16 h. After the reaction was completed, petroleum ether (20 ml) was added to the above reaction solution and the temperature was raised to reflux, and the temperature was kept for 1 h. After cooling down to room temperature, a solid precipitated out, and it was suction filtered, and the filter cake was washed with a small amount of petroleum ether, and the filter cake was collected. dry. The white solid compound 2 (1-((4-chlorophenethyl)amino)propan-2-ol) was obtained with a yield of 4.1 g, HPLC=98.6%.1 HNMR (400MHz, CDCl3 , δ): 7.42(d, 2H), 7.32(d, 2H), 4.58(m, 1H), 3.45(m, 2H), 3.25(m, 2H), 3.02(m, 2H), 2.88(d, 1H), 1.56(d, 3H). LCMS: 213.8-215.8 (MH). HPLC retention time 7.8min. The filtrate was recovered, the solvent was removed under reduced pressure, and distilled under reduced pressure to obtain 4.5 g of unreacted colorless liquid compound 1 p-chlorophenethylamine, HPLC=97.2%. Excluding unreacted p-chlorophenethylamine, the yield was 54.3%.
将化合物2(4.5g，1.0eq)、N，N-二甲基乙酰胺(0.55g，0.3eq)加入甲苯(21.5ml)中，换氮气，升温至50-55℃。滴加二氯亚砜(1.98ml，1.5eq)，5-10分钟加完，期间保持温度在50-60℃。加完后升温至60-65℃，过程中进行TLC监测，3h后完全反应。通过1小时降温至15℃左右，甲苯(15ml)加入，搅拌30分钟。抽滤，滤饼用甲苯(10ml×2)洗，收集滤饼，向滤饼中加入异丙醇(11.8ml)和水(1.2ml)中，升温至回流，搅拌1小时后降温，通过2小时左右降至15℃，保温30分钟后，通过30分钟降温至0-5℃，保温1h，抽滤，滤饼用少量异丙醇洗，收集滤饼，干燥。得到白色固体化合物4(5.0g)，产率为88.3％。1HNMR(400MHz，DMSO，δ)：9.55(s，1H)，9.15(s，1H)，7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，1.56(d，3H)。LCMS：232-234(MH)。Add compound 2 (4.5g, 1.0eq), N,N-dimethylacetamide (0.55g, 0.3eq) into toluene (21.5ml), change the nitrogen gas, and raise the temperature to 50-55°C. Thionyl chloride (1.98ml, 1.5eq) was added dropwise over 5-10 minutes while maintaining the temperature at 50-60°C. After the addition, the temperature was raised to 60-65°C, monitored by TLC during the process, and the reaction was complete after 3 hours. The temperature was lowered to about 15° C. over 1 hour, toluene (15 ml) was added, and stirred for 30 minutes. Suction filtration, wash the filter cake with toluene (10ml×2), collect the filter cake, add isopropanol (11.8ml) and water (1.2ml) to the filter cake, heat up to reflux, cool down after stirring for 1 hour, pass through 2 Drop to 15°C in about 1 hour, keep warm for 30 minutes, then cool down to 0-5°C for 30 minutes, keep warm for 1 hour, filter with suction, wash the filter cake with a small amount of isopropanol, collect the filter cake, and dry. Compound 4 (5.0 g) was obtained as a white solid with a yield of 88.3%.1 H NMR (400MHz, DMSO, δ): 9.55(s, 1H), 9.15(s, 1H), 7.42(d, 2H), 7.32(d, 2H), 4.58(m, 1H), 3.45(m, 2H ), 3.25(m, 2H), 3.02(m, 2H), 1.56(d, 3H). LCMS: 232-234 (MH).
化合物4(5.0g，1.0eq)及无水氯化铝(3.74g，1.5eq)加入邻二氯苯(14.4g)中，换氮气，升温至135-140℃，过程中进行TLC监测，反应8-10h。完全反应后降温至30-35℃左右，滴加到水(8g)和硅胶(0.8g)形成的混悬液中，保持温度小于60℃。搅拌15分钟后抽滤，滤饼用50-60℃水(15ml)洗。滤液降温至20-25℃搅拌30分钟，分液，收集水相。邻二氯苯相再用水(15ml)萃取2-3次。合并水相，环己烷(20ml)加入，分液，丢弃环己烷相。水相用30％氢氧化钠溶液调节pH≥13，环己烷(20ml)萃取三次。合并有机相，用水(15ml)洗、饱和食盐水(15ml)洗、干燥，减压除去溶剂，得到油状液体化合物5(3.50g)，产率为96.1％，直接用作下一步反应。Compound 4 (5.0g, 1.0eq) and anhydrous aluminum chloride (3.74g, 1.5eq) were added to o-dichlorobenzene (14.4g), nitrogen was changed, and the temperature was raised to 135-140°C. TLC monitoring was carried out during the reaction. 8-10h. After complete reaction, lower the temperature to about 30-35°C, add dropwise to the suspension formed by water (8g) and silica gel (0.8g), and keep the temperature below 60°C. After stirring for 15 minutes, it was suction filtered, and the filter cake was washed with 50-60° C. water (15 ml). Cool the filtrate to 20-25°C and stir for 30 minutes, separate the liquids, and collect the aqueous phase. The o-dichlorobenzene phase was extracted 2-3 times with water (15 ml). The aqueous phases were combined, cyclohexane (20ml) was added, the layers were separated, and the cyclohexane phase was discarded. The aqueous phase was adjusted to pH ≥ 13 with 30% sodium hydroxide solution, and extracted three times with cyclohexane (20 ml). The organic phases were combined, washed with water (15ml) and saturated brine (15ml), dried, and the solvent was removed under reduced pressure to obtain oily liquid compound 5 (3.50g) with a yield of 96.1%, which was directly used in the next reaction.
将化合物5(3.50g，1.0eq)中加入叔丁醇(12.6g)，室温(25℃)下搅拌。将L-酒石酸(0.55g，0.22eq)溶于水(0.8g)后，滴加到化合物5的叔丁醇溶液中，立即有沉淀生成，10分钟加完。滴加完毕后在20-25℃下搅拌16-18小时。抽滤，滤饼用少量丙酮洗，收集滤饼，得到白色固体(1.9g，Ee＝73.1％)。直接用做下一步。Compound 5 (3.50 g, 1.0 eq) was added with tert-butanol (12.6 g), and stirred at room temperature (25° C.). After L-tartaric acid (0.55g, 0.22eq) was dissolved in water (0.8g), it was added dropwise to the solution of compound 5 in tert-butanol, a precipitate formed immediately, and the addition was completed within 10 minutes. After the dropwise addition, stir at 20-25°C for 16-18 hours. After suction filtration, the filter cake was washed with a small amount of acetone, and the filter cake was collected to obtain a white solid (1.9 g, Ee=73.1%). Use directly for the next step.
将上述所得白色固体(1.9g)加入叔丁醇(13.2g)和水(0.3g)中，升温至76℃回流，滴加水(1.2g)至澄清，保温1h后降温，2.5-3.5小时降至室温25℃，20-25℃下搅拌16-18小时，抽滤，滤饼用少量丙酮洗，收集滤饼，得到白色固体(1.41g，Ee＝89.5％)。直接用做下一步。Add the white solid (1.9g) obtained above to tert-butanol (13.2g) and water (0.3g), raise the temperature to 76°C and reflux, add water (1.2g) dropwise until clarification, keep warm for 1h, then cool down, and cool down for 2.5-3.5 hours. Return to room temperature 25°C, stir at 20-25°C for 16-18 hours, filter with suction, wash the filter cake with a small amount of acetone, collect the filter cake to obtain a white solid (1.41g, Ee=89.5%). Use directly for the next step.
将上述所得白色固体溶于叔丁醇(13g)中，升温至76℃回流，滴加水(1.67g)至澄清，保温1h后降温，2.5-3.5小时降至室温25℃，20-25℃下搅拌16-18小时，抽滤，滤饼用少量丙酮洗，收集滤饼，得到白色固体化合物6(1.2g，Ee＝99.5％)，产率24.1％。Dissolve the white solid obtained above in tert-butanol (13g), raise the temperature to 76°C and reflux, add water (1.67g) dropwise until clarified, keep it warm for 1h, then lower the temperature, and drop it to room temperature 25°C in 2.5-3.5 hours, at 20-25°C Stir for 16-18 hours, filter with suction, wash the filter cake with a small amount of acetone, collect the filter cake to obtain white solid compound 6 (1.2 g, Ee=99.5%), and the yield is 24.1%.
将化合物6(1.2g，1.0eq)加入碳酸钾(0.99g，3.2eq)、水(10g)及乙酸乙酯(10g)中，搅拌0.5h后，分液，收集有机相。水相用乙酸乙酯(10ml)萃取两次。合并有机相，有机相用水(10ml)洗，饱和食盐水(10ml)洗，干燥，减压除去溶剂，得到粘稠液体(0.83g)，溶于乙酸乙酯(8g)和水(0.05g)中，降温至0～5℃，滴加乙酸乙酯(HCl气)至反应液呈酸性pH＝1-2。滴加过程中有白色沉淀析出，加完后0～5℃搅拌1.5h，抽滤，滤饼用少量乙酸乙酯洗，收集滤饼，干燥(35℃下)，得到化合物7(0.8g)，产率78％。1HNMR(400MHz，DMSO)δ9.68(s，2H)，7.24(s，3H)，3.58-3.44(m，1H)，3.32-3.16(m，3H)，3.03(dd，1H)，2.88(dd，2H)，1.36(d，3H)。LCMS：196-197(MH)。Compound 6 (1.2g, 1.0eq) was added to potassium carbonate (0.99g, 3.2eq), water (10g) and ethyl acetate (10g), stirred for 0.5h, separated, and the organic phase was collected. The aqueous phase was extracted twice with ethyl acetate (10ml). Combine the organic phases, wash the organic phase with water (10ml), wash with saturated brine (10ml), dry, and remove the solvent under reduced pressure to obtain a viscous liquid (0.83g), which is dissolved in ethyl acetate (8g) and water (0.05g) , the temperature was lowered to 0-5°C, and ethyl acetate (HCl gas) was added dropwise until the reaction solution was acidic with pH=1-2. During the dropwise addition, a white precipitate precipitated out. After the addition was completed, stir at 0-5°C for 1.5h, filter with suction, wash the filter cake with a small amount of ethyl acetate, collect the filter cake, and dry (at 35°C) to obtain Compound 7 (0.8g) , yield 78%.1 HNMR (400MHz, DMSO) δ9.68(s, 2H), 7.24(s, 3H), 3.58-3.44(m, 1H), 3.32-3.16(m, 3H), 3.03(dd, 1H), 2.88( dd, 2H), 1.36(d, 3H). LCMS: 196-197 (MH).
实施例7Example 7
化合物3(110.30g，1.0eq)、N，N-二甲基乙酰胺(11.52g，0.3eq)加入甲苯(450ml)中，换氮气，升温至50-55℃。滴加二氯亚砜(41.5ml，1.5eq)，15-20分钟加完，期间保持温度在50-60℃。加完后升温至60-65℃，过程中进行TLC监测，3h后完全反应。通过1小时降温至15℃左右，甲苯(300ml)加入，搅拌30分钟。抽滤，滤饼用甲苯(200ml×2)洗，收集滤饼(黄白色固体)，向滤饼中加入异丙醇(246ml)和水(24.6ml)中，升温至回流，搅拌1小时后降温，通过2小时左右降至15℃，保温30分钟后，通过30分钟降温至0-5℃，保温1h，抽滤，滤饼用少量异丙醇洗，收集滤饼，干燥。得到白色固体化合物4(101.45g)，产率为85.66％。1HNMR(400MHz，DMSO，δ)：9.55(s，1H)，9.15(s，1H)，7.42(d，2H)，7.32(d，2H)，4.58(m，1H)，3.45(m，2H)，3.25(m，2H)，3.02(m，2H)，1.56(d，3H)。LCMS：232-234(MH)。Add compound 3 (110.30g, 1.0eq), N,N-dimethylacetamide (11.52g, 0.3eq) into toluene (450ml), change the nitrogen gas, and raise the temperature to 50-55°C. Thionyl chloride (41.5ml, 1.5eq) was added dropwise over 15-20 minutes while maintaining the temperature at 50-60°C. After the addition, the temperature was raised to 60-65°C, monitored by TLC during the process, and the reaction was complete after 3 hours. After cooling down to about 15°C for 1 hour, toluene (300 ml) was added and stirred for 30 minutes. Suction filtration, wash the filter cake with toluene (200ml×2), collect the filter cake (yellow-white solid), add isopropanol (246ml) and water (24.6ml) to the filter cake, heat up to reflux, and stir for 1 hour Cool down to 15°C for about 2 hours, keep warm for 30 minutes, then cool down to 0-5°C for 30 minutes, keep warm for 1 hour, filter with suction, wash the filter cake with a small amount of isopropanol, collect the filter cake, and dry. Compound 4 (101.45 g) was obtained as a white solid with a yield of 85.66%.1 H NMR (400MHz, DMSO, δ): 9.55(s, 1H), 9.15(s, 1H), 7.42(d, 2H), 7.32(d, 2H), 4.58(m, 1H), 3.45(m, 2H ), 3.25(m, 2H), 3.02(m, 2H), 1.56(d, 3H). LCMS: 232-234 (MH).
将化合物4(101.45g，1.0eq)及无水氯化铝(75.83g，1.5eq)加入邻二氯苯(292g)中，换氮气，升温至135-140℃。过程中进行TLC监测，反应8-10h。完全反应后降温至30-35℃左右，滴加到水(163g)和硅胶(16.3g)形成的混悬液中，保持温度小于60℃。搅拌15分钟后抽滤，滤饼用50-60℃水(82ml)洗。滤液降温至20-25℃搅拌30分钟，分液，收集水相。邻二氯苯相再用水(100ml)萃取2-3次。合并水相，环己烷(80ml)加入，分液，丢弃环己烷相。水相用30％氢氧化钠溶液调节pH≥13，环己烷(240ml)萃取三次。合并有机相，用水(100ml)洗、饱和食盐水(100ml)洗，干燥，减压除去溶剂，得到油状液体化合物5(73.90g)，产率为100％(有溶剂残留)。直接用作下一步反应。Add compound 4 (101.45g, 1.0eq) and anhydrous aluminum chloride (75.83g, 1.5eq) into o-dichlorobenzene (292g), change nitrogen, and raise the temperature to 135-140°C. TLC monitoring was carried out during the process, and the reaction was carried out for 8-10 hours. After complete reaction, lower the temperature to about 30-35°C, add dropwise to the suspension formed by water (163g) and silica gel (16.3g), and keep the temperature below 60°C. After stirring for 15 minutes, it was suction filtered, and the filter cake was washed with 50-60° C. water (82 ml). Cool the filtrate to 20-25°C and stir for 30 minutes, separate the liquids, and collect the aqueous phase. The o-dichlorobenzene phase was extracted 2-3 times with water (100 ml). The aqueous phases were combined, cyclohexane (80ml) was added, the layers were separated, and the cyclohexane phase was discarded. The aqueous phase was adjusted to pH ≥ 13 with 30% sodium hydroxide solution, and extracted three times with cyclohexane (240 ml). The organic phases were combined, washed with water (100ml) and saturated brine (100ml), dried, and the solvent was removed under reduced pressure to obtain oily liquid compound 5 (73.90g) with a yield of 100% (with solvent residue). directly used in the next reaction.
向上步所得的化合物5中加入叔丁醇(266.33g)，27℃下搅拌。将L-酒石酸(11.56g，0.22eq)溶于水(16.71g)后，滴加到化合物4的叔丁醇溶液中，立即有沉淀生成，15分钟加完。滴加完毕后在20-25℃下搅拌16-18小时。抽滤，滤饼用少量丙酮洗，收集滤饼，得到白色固体(38.16g，Ee＝72.7％)。直接用做下一步。Add tert-butanol (266.33 g) to Compound 5 obtained in the previous step, and stir at 27°C. After L-tartaric acid (11.56g, 0.22eq) was dissolved in water (16.71g), it was added dropwise to the solution of compound 4 in tert-butanol, a precipitate formed immediately, and the addition was completed within 15 minutes. After the dropwise addition, stir at 20-25°C for 16-18 hours. After suction filtration, the filter cake was washed with a small amount of acetone, and the filter cake was collected to obtain a white solid (38.16 g, Ee=72.7%). Use directly for the next step.
将上述所得白色固体(38.16g)加入叔丁醇(265.40g)和水(5.63g)中，升温至76℃回流，滴加水(24.90g)至澄清，保温1h后降温，2.5-3.5小时降至室温25℃，20-25℃下搅拌16-18小时，抽滤，滤饼用少量丙酮洗，收集滤饼，得到白色固体(27.83g，Ee＝89.2％)。直接用做下一步。Add the above-obtained white solid (38.16g) into tert-butanol (265.40g) and water (5.63g), raise the temperature to 76°C and reflux, add water (24.90g) dropwise until clarification, keep warm for 1h, then cool down, and cool down for 2.5-3.5 hours. Return to room temperature 25°C, stir at 20-25°C for 16-18 hours, filter with suction, wash the filter cake with a small amount of acetone, collect the filter cake to obtain a white solid (27.83g, Ee=89.2%). Use directly for the next step.
将上述所得白色固体溶于叔丁醇(264g)中，升温至76℃回流，滴加水(33.26g)至澄清，保温1h后降温，2.5-3.5小时降至室温25℃，20-25℃下搅拌16-18小时，抽滤，滤饼用少量丙酮洗，收集滤饼，得到白色固体化合物6(25.95g，Ee＝99.6％)，产率25％。Dissolve the white solid obtained above in tert-butanol (264g), raise the temperature to 76°C and reflux, add water (33.26g) dropwise until clarified, keep it warm for 1h, then lower the temperature, and drop it to room temperature 25°C in 2.5-3.5 hours, at 20-25°C Stir for 16-18 hours, filter with suction, wash the filter cake with a small amount of acetone, collect the filter cake to obtain white solid compound 6 (25.95 g, Ee=99.6%), and the yield is 25%.
将化合物6(22.36g，1.0eq)加入碳酸钾(18.44g，3.2eq)、水(62.8g)及乙酸乙酯(62.8g)中，搅拌0.5h后，分液，收集有机相。水相用乙酸乙酯(60ml)萃取两次。合并有机相，有机相用水(40ml)洗，饱和食盐水(40ml)洗，干燥，减压除去溶剂，得到粘稠液体(15.50g)，溶于乙酸乙酯(85.04g)和水(0.97g)中，降温至0～5℃，滴加乙酸乙酯(HCl气)至反应液呈酸性pH＝1-2。滴加过程中有白色沉淀析出，加完后0～5℃搅拌1.5h，抽滤，滤饼用少量乙酸乙酯洗，收集滤饼，干燥(35℃下)，得到化合物7(14.9g)，产率80.2％。1HNMR(400MHz，DMSO)δ9.68(s，2H)，7.24(s，3H)，3.58-3.44(m，1H)，3.32-3.16(m，3H)，3.03(dd，1H)，2.88(dd，2H)，1.36(d，3H)。LCMS：196-197(MH)。Compound 6 (22.36g, 1.0eq) was added to potassium carbonate (18.44g, 3.2eq), water (62.8g) and ethyl acetate (62.8g), stirred for 0.5h, separated, and the organic phase was collected. The aqueous phase was extracted twice with ethyl acetate (60ml). Combine the organic phases, wash the organic phase with water (40ml), wash with saturated brine (40ml), dry, and remove the solvent under reduced pressure to obtain a viscous liquid (15.50g), which is dissolved in ethyl acetate (85.04g) and water (0.97g ), the temperature was lowered to 0-5°C, and ethyl acetate (HCl gas) was added dropwise until the reaction solution was acidic with pH=1-2. During the dropwise addition, a white precipitate precipitated out. After the addition was completed, stir at 0-5°C for 1.5h, filter with suction, wash the filter cake with a small amount of ethyl acetate, collect the filter cake, and dry (at 35°C) to obtain Compound 7 (14.9g) , yield 80.2%.1 HNMR (400MHz, DMSO) δ9.68(s, 2H), 7.24(s, 3H), 3.58-3.44(m, 1H), 3.32-3.16(m, 3H), 3.03(dd, 1H), 2.88( dd, 2H), 1.36(d, 3H). LCMS: 196-197 (MH).
本领域技术人员可以理解，在本说明书的教导之下，可以对本发明做出一些修改或变化。这些修改和变化也应当在本发明权利要求所限定的范围之内。Those skilled in the art can understand that some modifications or changes can be made to the present invention under the teaching of this specification. These modifications and changes should also be within the scope defined by the claims of the present invention.
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