技术领域technical field
本发明涉及一种治疗耐多药结核病的药物贝达喹啉((1R,2S)-1-(6-溴-2-甲氧基喹啉-3-)-4-二甲氨基-1-苯基-2-(1-萘基)-2-丁醇)消旋体的制备方法。The invention relates to a drug bedaquiline ((1R,2S)-1-(6-bromo-2-methoxyquinoline-3-)-4-dimethylamino-1- Preparation method of phenyl-2-(1-naphthyl)-2-butanol) racemate.
背景技术Background technique
结核病是由结核分枝杆菌引起的一类慢性感染性疾病，可累及全身多器官系统。世界卫生组织统计，全世界每年大约有1/3人口感染结核分枝杆菌且每天约有3800人死于结核病[Curr Opin Immunol,2011,23(4):464-472.]。结核病已成为21世纪严重威胁人类健康的主要疾病之一。Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis, which can affect multiple organ systems throughout the body. According to the statistics of the World Health Organization, about 1/3 of the world's population is infected with Mycobacterium tuberculosis every year and about 3,800 people die of tuberculosis every day [Curr Opin Immunol, 2011,23(4):464-472.]. Tuberculosis has become one of the major diseases that seriously threaten human health in the 21st century.
造成结核病在全球范围内蔓延的主要原因是结核分枝杆菌具有强大的生存能力。事实上，结核分枝杆菌作为最具威胁的一种病原体，已经进化出了一系列机制在每一个可能的途径上来对抗宿主的免疫应答反应(Current Topics in Medicinal Chemistry,2013,13(22),2808-2849)。另一个造成结核病迅速蔓延的重要原因则是耐药性的出现。由于人们对现有抗结核药物的不规范使用，加之流动人口的增加，耐多药结核在全球范围内迅速蔓延。耐多药结核病在许多国家已成为重大的公共卫生问题和全球结核病有效控制的障碍。The main reason for the worldwide spread of tuberculosis is the strong viability of Mycobacterium tuberculosis. In fact, Mycobacterium tuberculosis, as one of the most threatening pathogens, has evolved a series of mechanisms to counteract the host's immune response in every possible way (Current Topics in Medicinal Chemistry, 2013, 13(22), 2808-2849). Another important reason for the rapid spread of tuberculosis is the emergence of drug resistance. Due to the non-standard use of existing anti-tuberculosis drugs and the increase of floating population, MDR-TB is spreading rapidly around the world. MDR-TB has become a major public health problem in many countries and an obstacle to effective global TB control.
1992年6月，美国疾病预防控制中心(CDC)发表的有关耐药结核病的文章中，正式提出“耐多药结核病”(MDR-TB)的概念。即耐多药(multidrug resistance)是指结核杆菌至少对异烟肼、利福平在内的一种一线抗结核药物耐药[American Journal of Health-System Pharmacy,2013,70(22),1984-1994.]。In June 1992, in an article on drug-resistant tuberculosis published by the US Centers for Disease Control and Prevention (CDC), the concept of "multidrug-resistant tuberculosis" (MDR-TB) was formally proposed. That is, multidrug resistance refers to the resistance of Mycobacterium tuberculosis to at least one first-line anti-tuberculosis drug including isoniazid and rifampicin [American Journal of Health-System Pharmacy, 2013, 70(22), 1984- 1994.].
2012年12月28日，美国食品与药物管理局(FDA)通过加速审批程序批准了强生公司旗下的Sirturo(bedaquiline，贝达喹啉)，在无其他替代药物可用时，作为成人耐多药结核(MDR-TB)联合治疗的组成部分。贝达喹啉成为首个被FDA认证通过的抗耐多药结核药物。On December 28, 2012, the U.S. Food and Drug Administration (FDA) approved Johnson & Johnson's Sirturo (bedaquiline, Bedaquiline) through the accelerated approval process, as an adult multidrug-resistant tuberculosis drug when no other alternative drugs are available. (MDR-TB) combination therapy. Bedaquiline became the first anti-multidrug-resistant tuberculosis drug approved by the FDA.
贝达喹啉作为FDA首个批准上市的治疗耐多药结核病药物，由于其作用机制与现有抗结核药物的不同，一出现就被寄予厚望。贝达喹啉全新的作用机制在于它瞄准了结 核病的病原体-结核分枝杆菌的一种酶-ATP合成酶[Science,2005,307(5707),223-227.]。此外，还有文献报道了贝达喹啉在细胞内对结核分枝杆菌的作用，显示贝达喹啉是通过抑制分枝杆菌的ATP合成酶的质子转移链来杀死结核分枝杆菌，这是一种全新的对付结核分枝杆菌的作用途径。这意味着，贝达喹啉与其他抗结核药物不存在交叉耐药性，这将大大降低结核杆菌的抗药性。该文献的研究结果还显示贝达喹啉在巨噬细胞内显示出良好的对抗多药耐药结核病菌的活性，提示它具有缩短治疗时间的作用[Antimicrobial Agents andChemotherapy,2006,50(6),1921-1926.)。Bedaquiline, as the first FDA-approved drug for the treatment of multi-drug-resistant tuberculosis, has high expectations as soon as it appears because its mechanism of action is different from that of existing anti-tuberculosis drugs. The new mechanism of action of bedaquiline is that it targets an enzyme-ATP synthase [Science, 2005, 307 (5707), 223-227.] of the pathogen of tuberculosis-Mycobacterium tuberculosis. In addition, there are literature reports on the effect of bedaquiline on mycobacterium tuberculosis in cells, showing that bedaquiline kills mycobacterium tuberculosis by inhibiting the proton transfer chain of ATP synthase of mycobacteria, which It is a brand-new pathway of action against Mycobacterium tuberculosis. This means that there is no cross-resistance between bedaquiline and other anti-TB drugs, which will greatly reduce the drug resistance of Mycobacterium tuberculosis. The results of this literature also show that bedaquiline shows good activity against multidrug-resistant tuberculosis bacteria in macrophages, suggesting that it has the effect of shortening the treatment time [Antimicrobial Agents and Chemotherapy, 2006, 50 (6), 1921-1926.).
贝达喹啉的合成路线报道较少，主要为原研公司的化合物专利US2005148581和工艺专利CN101180302，主要涉及到两个重要的中间体:6-溴-3-苄基-2-甲氧基喹啉(化合物5)和3-(二甲氨基)-1-(1-萘基)-1-丙酮(化合物6)。化合物5化合物6经缩合反应得到贝达喹啉的消旋体(化合物10)，再经拆分得到贝达喹啉。There are few reports on the synthetic route of bedaquiline, mainly the compound patent US2005148581 of the original research company and the process patent CN101180302, which mainly involve two important intermediates: 6-bromo-3-benzyl-2-methoxyquinoline (Compound 5) and 3-(dimethylamino)-1-(1-naphthyl)-1-propanone (Compound 6). Compound 5 and compound 6 were condensed to obtain the racemate of bedaquiline (compound 10), and then resolved to obtain bedaquiline.
其主要的合成步骤如下：Its main synthetic steps are as follows:
该路线的主要问题是，化合物5和化合物6在LDA的条件下反应的收率很低(26％)。造成收率低有两个原因，其一是化合物6中羰基的α位氢在反应条件下脱除，生成的碳负离子对羰基进攻，发生分子间的多种副反应，导致反应产物很杂；其二是由于化合物6的烯醇化(如下所示)，导致原料不能转化完全。此外，由此所得的贝达喹啉消旋体的纯度不高，严重影响其拆分的效率。The main problem of this route is that the yield of the reaction of compound 5 and compound 6 under the condition of LDA is very low (26%). There are two reasons for the low yield. One is that the α-position hydrogen of the carbonyl group in compound 6 is removed under the reaction conditions, and the generated carbanion attacks the carbonyl group, and various side reactions between molecules occur, resulting in very complicated reaction products; The second is due to the enolization of compound 6 (shown below), resulting in incomplete conversion of the starting material. In addition, the purity of the bedaquiline racemate thus obtained is not high, which seriously affects the efficiency of its resolution.
为了改进文献报道的合成路线的缺陷，减少反应中副产物的生成，提高原料转化率 和贝达喹啉消旋体的纯度，需要开发出一条新的合成路线。In order to improve the defects of the synthetic routes reported in the literature, reduce the generation of by-products in the reaction, improve the conversion rate of raw materials and the purity of the bedaquiline racemate, a new synthetic route needs to be developed.
发明内容Contents of the invention
本发明的目的是提供一种贝达喹啉的制备方法，以克服现有技术存在的缺陷。The purpose of the present invention is to provide a kind of preparation method of bedaquiline, to overcome the defect that prior art exists.
本发明的方法，包括如下步骤：The method of the present invention comprises the steps of:
将化合物(9)在溶剂中，与还原剂反应，反应温度为10～100℃，反应时间为2～24小时，优选的反应温度为20～60℃，反应时间为2～6小时，然后从反应产物中收集贝达喹啉的消旋体；Compound (9) is reacted with a reducing agent in a solvent, the reaction temperature is 10-100°C, the reaction time is 2-24 hours, the preferred reaction temperature is 20-60°C, the reaction time is 2-6 hours, and then from Collect the racemate of bedaquiline in the reaction product;
所述的溶剂选自THF、乙醇、甲醇、1,4-二氧六环或异丙醇；The solvent is selected from THF, ethanol, methanol, 1,4-dioxane or isopropanol;
所述的还原剂选自硼氢化钠、钯碳、铁粉/盐酸、铁粉/醋酸、氯化亚锡、氧化铂或锌粉/氯化铵；The reducing agent is selected from sodium borohydride, palladium carbon, iron powder/hydrochloric acid, iron powder/acetic acid, stannous chloride, platinum oxide or zinc powder/ammonium chloride;
铁粉/盐酸指的是铁粉与盐酸的混合物，其中，铁粉的当量为化合物9的3-10eq，优选3-6eq，盐酸调体系pH值至3-5；Iron powder/hydrochloric acid refers to a mixture of iron powder and hydrochloric acid, wherein the equivalent of iron powder is 3-10eq, preferably 3-6eq, of compound 9, and the hydrochloric acid adjusts the pH value of the system to 3-5;
锌粉/氯化铵的是锌粉与氯化铵的混合物，其中，锌粉的当量为化合物9的3-10eq，优选3-6eq，氯化铵的当量为化合物9的6-10eq，优选6-8eq；Zinc powder/ammonium chloride is a mixture of zinc powder and ammonium chloride, wherein the equivalent of zinc powder is 3-10eq of compound 9, preferably 3-6eq, and the equivalent of ammonium chloride is 6-10eq of compound 9, preferably 6-8eq;
反应式如下：The reaction formula is as follows:
所述的化合物(9)，具有式(9)结构式的化合物或其光学异构体：The compound (9), a compound of formula (9) or an optical isomer thereof:
所述化合物(9)的制备方法，包括如下步骤：The preparation method of described compound (9), comprises the steps:
(1)将化合物(7)与N,N-二甲基甲酰胺二甲基缩醛(DMF-DMA)反应，90-120℃，反应24-48小时，蒸干后得到油状物化合物8；(1) React compound (7) with N,N-dimethylformamide dimethyl acetal (DMF-DMA) at 90-120°C for 24-48 hours, and evaporate to dryness to obtain oil compound 8;
或者，将化合物(7)在含有DMF-DMA的溶剂中反应，90-120℃，反应24-48小时，蒸干后得到油状物化合物8；Alternatively, react compound (7) in a solvent containing DMF-DMA at 90-120°C for 24-48 hours, and evaporate to dryness to obtain oily compound 8;
所述的溶剂选自二甲苯或甲苯，溶剂用量为化合物7重量的2-10倍；The solvent is selected from xylene or toluene, and the amount of the solvent is 2-10 times the weight of compound 7;
DMF-DMA与化合物7的当量为1.2-2eq；The equivalent of DMF-DMA and compound 7 is 1.2-2eq;
反应式如下：The reaction formula is as follows:
(2)将化合物(8)与化合物(5)在四氢呋喃中反应，然后从反应产物中收集获得一对对异构体(9)；(2) react compound (8) and compound (5) in tetrahydrofuran, and then collect a pair of isomers (9) from the reaction product;
化合物(5)和化合物(8)的当量优选1:1.05-1:1.2，化合物5与LDA的当量为1.3-1.5eq，四氢呋喃用量优选化合物(5)的2倍-5倍；温度优选-78°～至-20℃，反应时间为1-12小时；反应式如下：The equivalent of compound (5) and compound (8) is preferably 1:1.05-1:1.2, the equivalent of compound 5 and LDA is 1.3-1.5eq, the amount of tetrahydrofuran is preferably 2 times to 5 times that of compound (5); the temperature is preferably -78 °～to -20°C, the reaction time is 1-12 hours; the reaction formula is as follows:
本发明所用原料和试剂均有市售；The raw materials and reagents used in the present invention are all commercially available;
本发明与已公开报道的方法相比，优势在于：Compared with the method of published report, the present invention has the advantages of:
以化合物(8)为合成子，避免了中间体中的α位氢和烯醇化反应，减少了副反应的发生，提高了较贵原料5的转化率和反应的总收率，大幅度降低成本。所得产物9的纯度高，适合大规模工业化生产。Using compound (8) as a synthon avoids the α-position hydrogen and enolization reaction in the intermediate, reduces the occurrence of side reactions, improves the conversion rate of the more expensive raw material 5 and the total yield of the reaction, and greatly reduces the cost . The obtained product 9 has high purity and is suitable for large-scale industrial production.
以化合物(8)为合成子，较之原专利路线的中间体6、容易制备，所用原料易得，制备成本低。Using the compound (8) as a synthon, compared with the intermediate 6 of the original patent route, it is easier to prepare, the raw materials used are readily available, and the preparation cost is low.
化合物9为未见文献报道的新化合物，本发明以化合物(8)经化合物(9)再制备贝达喹啉消旋体的方法，亦未见文献报道，具有新颖性；所得产物收率大幅度提高(大于47％)，显著大于原专利收率(26％)；所得贝达喹啉消旋体的纯度高，质量稳定可控，有利于后续的拆分反应。Compound 9 is a new compound that has not been reported in the literature. The present invention uses compound (8) to prepare the method of bedaquiline racemate through compound (9), and there is no literature report. It is novel; the resulting product yield is large The range is increased (greater than 47%), which is significantly greater than the original patent yield (26%); the obtained bedaquiline racemate has high purity, stable and controllable quality, and is beneficial to the subsequent resolution reaction.
综上，本发明公开的方法及应用，克服了文献已报道制备方法的缺陷和不足，具有新颖性，较大的积极进步效果和实际应用价值。To sum up, the method and application disclosed in the present invention overcome the defects and deficiencies of the preparation methods reported in the literature, have novelty, great positive progress effect and practical application value.
具体实施方式detailed description
通过下述实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。所述实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention is further illustrated by means of the following examples, but the present invention is not limited to the scope of the examples. For the experimental methods that do not specify specific conditions in the examples, select according to conventional methods and conditions, or according to the product instructions.
实施例1Example 1
3-二甲氨基-2-(1-萘基)-丙-2-烯-1-酮(化合物8)的制备Preparation of 3-dimethylamino-2-(1-naphthyl)-prop-2-en-1-one (compound 8)
1-萘乙酮(170.0g，1.0mol)于室温下加入到DMF-DMA(178.0g，1.5mol)中，加热升温至120℃，24h后，冷却至室温，加入甲苯200ml稀释，然后将溶剂在55℃下减压蒸干，残留物加入甲苯200ml稀释，于55℃下减压蒸干，得到黄色油状物230.1g，粗品收率102％，HPLC纯度98.5％，可直接用于下步反应。1-Naphthyl ethyl ketone (170.0g, 1.0mol) was added to DMF-DMA (178.0g, 1.5mol) at room temperature, heated to 120°C, after 24h, cooled to room temperature, added 200ml of toluene to dilute, and then the solvent Evaporate to dryness under reduced pressure at 55°C, dilute the residue with 200ml of toluene, and evaporate to dryness under reduced pressure at 55°C to obtain 230.1g of a yellow oil, with a crude yield of 102% and a purity of 98.5% by HPLC, which can be directly used in the next reaction .
1H-NMR(CDCl3)δ：2.93-3.14(m,6H)；5.73(d,1H,J＝12.4Hz)；7.38-7.49(m,2H)；7.82(d,1H,J＝12.4Hz)；7.78(m,1H),8.14-3.18(m,2H),8.29(d,2H,J＝8.4Hz),9.45(d,2H,J＝8.8Hz).ESI-MS(m/z)＝226.2[M+H]+1 H-NMR (CDCl3 ) δ: 2.93-3.14 (m, 6H); 5.73 (d, 1H, J = 12.4Hz); 7.38-7.49 (m, 2H); 7.82 (d, 1H, J = 12.4Hz ); 7.78(m, 1H), 8.14-3.18(m, 2H), 8.29(d, 2H, J=8.4Hz), 9.45(d, 2H, J=8.8Hz).ESI-MS(m/z) ＝226.2[M+H]+
实施例2Example 2
3-二甲氨基-2-(1-萘基)-丙-2-烯-1-酮(化合物8)的制备Preparation of 3-dimethylamino-2-(1-naphthyl)-prop-2-en-1-one (compound 8)
1-萘乙酮(150.0g，0.88mol)于室温下加入到DMF-DMA(57.5g，1.5mol)中，加热升温至90℃，24h后，冷却至室温，加入甲苯200ml稀释，然后将溶剂在55℃下减压蒸干，残留物加入甲苯200ml稀释，于55℃下减压蒸干，得到黄色油状物202.5g，粗品收率102％，HPLC纯度98.8％。ESI-MS(m/z)＝226.2[M+H]+1-Naphthylethanone (150.0g, 0.88mol) was added to DMF-DMA (57.5g, 1.5mol) at room temperature, heated to 90°C, after 24h, cooled to room temperature, added 200ml of toluene to dilute, and then the solvent Evaporate to dryness under reduced pressure at 55°C, add 200ml of toluene to the residue to dilute, and evaporate to dryness under reduced pressure at 55°C to obtain 202.5g of yellow oil, crude yield 102%, HPLC purity 98.8%. ESI-MS(m/z)＝226.2[M+H]+
实施例3Example 3
3-二甲氨基-2-(1-萘基)-丙-2-烯-1-酮(化合物8)的制备Preparation of 3-dimethylamino-2-(1-naphthyl)-prop-2-en-1-one (compound 8)
1-萘乙酮(250.0g，1.47mol)于室温下加入到DMF-DMA(262.5g，2.20mol)中，加热升温至90℃，48h后，冷却至室温，加入甲苯200ml稀释，然后将溶剂在55℃下减压蒸干，残留物加入甲苯200ml稀释，于55℃下减压蒸干，得到黄色油状物334.2g，粗品收率101％，HPLC纯度98.2％。ESI-MS(m/z)＝226.2[M+H]+1-Naphthyl ethyl ketone (250.0g, 1.47mol) was added to DMF-DMA (262.5g, 2.20mol) at room temperature, heated to 90°C, after 48h, cooled to room temperature, added 200ml of toluene to dilute, and then the solvent Evaporate to dryness under reduced pressure at 55°C, add 200ml of toluene to the residue to dilute, and evaporate to dryness under reduced pressure at 55°C to obtain 334.2g of yellow oil with a crude yield of 101% and an HPLC purity of 98.2%. ESI-MS(m/z)＝226.2[M+H]+
实施例4Example 4
3-二甲氨基-2-(1-萘基)-丙-2-烯-1-酮(化合物8)的制备Preparation of 3-dimethylamino-2-(1-naphthyl)-prop-2-en-1-one (compound 8)
1-萘乙酮(340.0g，2.0mol)于室温下加入到DMF-DMA(286.0g，2.4mol)中，加热升温至90℃，24h后，冷却至室温，加入甲苯200ml稀释，然后将溶剂在55℃下减压蒸干，残留物加入甲苯200ml稀释，于55℃下减压蒸干，得到黄色油状物459.2g，粗品收率102％，HPLC纯度98.5％。ESI-MS(m/z)＝226.2[M+H]+1-Naphthyl ethyl ketone (340.0g, 2.0mol) was added to DMF-DMA (286.0g, 2.4mol) at room temperature, heated to 90°C, after 24h, cooled to room temperature, added 200ml of toluene to dilute, and then the solvent Evaporate to dryness under reduced pressure at 55°C, dilute the residue by adding 200ml of toluene, and evaporate to dryness under reduced pressure at 55°C to obtain 459.2g of yellow oil with a crude yield of 102% and an HPLC purity of 98.5%. ESI-MS(m/z)＝226.2[M+H]+
实施例5Example 5
3-二甲氨基-2-(1-萘基)-丙-2-烯-1-酮(化合物8)的制备Preparation of 3-dimethylamino-2-(1-naphthyl)-prop-2-en-1-one (compound 8)
1-萘乙酮(400.0g，2.35mol)于室温下加入到DMF-DMA(560.0g，4.70mol)中，加热升温至90℃，24h后，冷却至室温，加入甲苯200ml稀释，然后将溶剂在55℃下减压蒸干，残留物加入甲苯200ml稀释，于55℃下减压蒸干，得到黄色油状物545.3g，粗品收率103％，HPLC纯度98.4％。ESI-MS(m/z)＝226.2[M+H]+1-Naphthyl ethyl ketone (400.0g, 2.35mol) was added to DMF-DMA (560.0g, 4.70mol) at room temperature, heated to 90°C, after 24h, cooled to room temperature, added 200ml of toluene to dilute, and then the solvent Evaporate to dryness under reduced pressure at 55°C, dilute the residue by adding 200ml of toluene, and evaporate to dryness under reduced pressure at 55°C to obtain 545.3g of yellow oil with a crude yield of 103% and a purity of 98.4% by HPLC. ESI-MS(m/z)＝226.2[M+H]+
实施例5Example 5
3-二甲氨基-2-(1-萘基)-丙-2-烯-1-酮(化合物8)的制备Preparation of 3-dimethylamino-2-(1-naphthyl)-prop-2-en-1-one (compound 8)
1-萘乙酮(280.0g，1.65mol)于室温下加入到DMF-DMA(294.0g，2.47mol)的甲苯溶液(5.6L)中，加热升温至100℃，24h后，冷却至室温，然后将溶剂在55℃下减压蒸干，残留物加入甲苯1.0L稀释，于55℃下减压蒸干，得到黄色油状物235.2g，粗品收率104％，HPLC纯度98.0％，可直接用于下步反应。ESI-MS(m/z)＝226.2[M+H]+1-Naphthyl ethyl ketone (280.0 g, 1.65 mol) was added to DMF-DMA (294.0 g, 2.47 mol) in toluene solution (5.6 L) at room temperature, heated to 100 ° C, after 24 h, cooled to room temperature, and then The solvent was evaporated to dryness at 55°C under reduced pressure, the residue was diluted with 1.0 L of toluene, and evaporated to dryness under reduced pressure at 55°C to obtain 235.2 g of a yellow oil with a crude yield of 104% and a purity of 98.0% by HPLC, which could be used directly in Next reaction. ESI-MS(m/z)＝226.2[M+H]+
实施例6Example 6
3-二甲氨基-2-(1-萘基)-丙-2-烯-1-酮(化合物8)的制备Preparation of 3-dimethylamino-2-(1-naphthyl)-prop-2-en-1-one (compound 8)
1-萘乙酮(170.0g，1.0mol)于室温下加入到DMF-DMA(178.0g，15mol)的二甲苯溶液(56L)中，加热升温至110℃，24h后，冷却至室温，然后将溶剂在55℃下减压蒸干，残留物加入邻二甲苯1.0ml稀释，于65℃下减压蒸干，得到黄色油状物228.0g，粗品收率101％，HPLC纯度98.8％。ESI-MS(m/z)＝226.2[M+H]+1-Naphthyl ethyl ketone (170.0g, 1.0mol) was added to a xylene solution (56L) of DMF-DMA (178.0g, 15mol) at room temperature, heated to 110°C, after 24h, cooled to room temperature, and then The solvent was evaporated to dryness at 55°C under reduced pressure, and the residue was diluted with 1.0ml of o-xylene, and evaporated to dryness under reduced pressure at 65°C to obtain 228.0g of a yellow oil with a crude yield of 101% and an HPLC purity of 98.8%. ESI-MS(m/z)＝226.2[M+H]+
实施例7Example 7
1-(6-溴-2-甲氧基喹啉-3-基)-4-(二甲基氨基)-2-(萘-1-基)-1-苯基丁-3-烯-2-醇(化合物9)的制备1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalene-1-yl)-1-phenylbut-3-ene-2 - Preparation of Alcohol (Compound 9)
于四口瓶中加入四氢呋喃90ml，冷却至-78℃，加入LDA90ml(2M的环己烷溶液，1.3eq)，然后缓慢滴加化合物5(45.0g溶解于25ml的THF中)，滴加完毕后继续在-78℃下搅拌1h。滴加化合物8(29.4g溶解于20ml的THF溶液中，1.05eq)，滴加完毕后反应6h。将反应液升至-20℃，用2N的冰醋酸THF溶液50ml淬灭反应。反应淬灭后升至室温，加水150ml，分出有机相，水相用乙酸乙酯萃取2次(100*2次)，合并有机相，无水硫酸钠干燥。过滤后，将有机相蒸干，得深色油状物。将深色油状物转移至500ml的单口瓶中，加入200ml无水乙醇，回流打浆，趁热过滤。滤液冷却至室温析晶，过滤得到的固体用100ml无水乙醇重结晶，得类白色固体42.3g，HPLC纯度92.3％，收率55.8％。1H-NMR(CDCl3)δ：1.25-1.28(m,6H)；4.21(s,3H),5.73(d,1H,J＝12.4Hz),5.89(s,3H),6.88-6.89(m,3H),7.12-7.15(m,3H),7.26-7.30(m,1H),7.49-7.50(m,1H),7.55-7.86(m,3H),7.88-7.90(m,2H),7.96(s,1H),8.59(d,2H,J＝8.8Hz),8.89(s,1H).ESI-MS(m/z)＝553.2[M+H]+Add 90ml of tetrahydrofuran into the four-neck flask, cool to -78°C, add 90ml of LDA (2M cyclohexane solution, 1.3eq), then slowly add compound 5 (45.0g dissolved in 25ml of THF) dropwise, after the addition is complete Stirring was continued at -78 °C for 1 h. Compound 8 (29.4g dissolved in 20ml of THF solution, 1.05eq) was added dropwise, and reacted for 6h after the dropwise addition was completed. The reaction solution was raised to -20°C, and the reaction was quenched with 50 ml of 2N glacial acetic acid in THF. After the reaction was quenched, it was raised to room temperature, 150ml of water was added, the organic phase was separated, the aqueous phase was extracted twice with ethyl acetate (100*2 times), the organic phases were combined, and dried over anhydrous sodium sulfate. After filtration, the organic phase was evaporated to dryness to obtain a dark oil. Transfer the dark oil to a 500ml single-necked bottle, add 200ml of absolute ethanol, reflux for beating, and filter while hot. The filtrate was cooled to room temperature for crystallization, and the solid obtained by filtration was recrystallized with 100 ml of absolute ethanol to obtain 42.3 g of an off-white solid with a HPLC purity of 92.3% and a yield of 55.8%. 1H-NMR(CDCl3)δ: 1.25-1.28(m, 6H); 4.21(s, 3H), 5.73(d, 1H, J=12.4Hz), 5.89(s, 3H), 6.88-6.89(m, 3H ),7.12-7.15(m,3H),7.26-7.30(m,1H),7.49-7.50(m,1H),7.55-7.86(m,3H),7.88-7.90(m,2H),7.96(s ,1H),8.59(d,2H,J=8.8Hz),8.89(s,1H).ESI-MS(m/z)=553.2[M+H]+
实施例8Example 8
1-(6-溴-2-甲氧基喹啉-3-基)-4-(二甲基氨基)-2-(萘-1-基)-1-苯基丁-3-烯-2-醇(化合物9)的制备1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalene-1-yl)-1-phenylbut-3-ene-2 - Preparation of Alcohol (Compound 9)
于四口瓶中加入四氢呋喃450ml，冷却至-20℃，加入LDA180ml(2M的环己烷溶液，1.3eq)，然后缓慢滴加化合物5(90.0g溶解于55ml的THF中)，滴加完毕后继续在-20℃下搅拌1h。滴加化合物8(51.5g溶解于50ml的THF溶液中，1.2eq)，滴加完毕后反应1h。按照实施例7的后处理方法得到类白色固体86.2g，HPLC纯度93.5％，收率56.8％。Add 450ml of tetrahydrofuran into the four-necked flask, cool to -20°C, add 180ml of LDA (2M cyclohexane solution, 1.3eq), and then slowly add compound 5 (90.0g dissolved in 55ml of THF) dropwise. Stirring was continued for 1 h at -20 °C. Compound 8 (51.5 g dissolved in 50 ml of THF solution, 1.2 eq) was added dropwise, and reacted for 1 h after the addition was completed. According to the post-treatment method of Example 7, 86.2 g of off-white solid was obtained, the HPLC purity was 93.5%, and the yield was 56.8%.
实施例9Example 9
1-(6-溴-2-甲氧基喹啉-3-基)-4-(二甲基氨基)-2-(萘-1-基)-1-苯基丁-3-烯-2-醇(化合物9)的制备1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalene-1-yl)-1-phenylbut-3-ene-2 - Preparation of Alcohol (Compound 9)
于四口瓶中加入四氢呋喃300ml，冷却至-20℃，加入LDA297ml(2M的环己烷溶液，1.3eq)，然后缓慢滴加化合物5(150.0g溶解于140ml的THF中)，滴加完毕后继续在-20℃下搅拌1h。滴加化合物8(123.5g溶解于110ml的THF溶液中，1.2eq)，滴加完毕后反应12h。按照实施例7的后处理方法得到类白色固体236.5g，HPLC纯度94.6％，收 率56.8％。Add 300ml of tetrahydrofuran into the four-necked flask, cool to -20°C, add 297ml of LDA (2M cyclohexane solution, 1.3eq), and then slowly add compound 5 (150.0g dissolved in 140ml of THF) dropwise. Stirring was continued for 1 h at -20 °C. Compound 8 (123.5g dissolved in 110ml of THF solution, 1.2eq) was added dropwise, and reacted for 12h after the dropwise addition was completed. Obtain 236.5 g of off-white solid according to the aftertreatment method of Example 7, HPLC purity 94.6%, yield 56.8%.
实施例10Example 10
1-(6-溴-2-甲氧基喹啉-3-基)-4-(二甲基氨基)-2-(萘-1-基)-1-苯基丁-3-烯-2-醇(化合物9)的制备1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalene-1-yl)-1-phenylbut-3-ene-2 - Preparation of Alcohol (Compound 9)
于四口瓶中加入四氢呋喃600ml，冷却至-78℃，加入LDA594ml(2M的环己烷溶液，1.3eq)，然后缓慢滴加化合物5(300g溶解于280ml的THF中)，滴加完毕后继续在-20℃下搅拌1h。滴加化合物8(257.0g溶解于250ml的THF溶液中，1.2eq)，滴加完毕后反应6h。按照实施例7的后处理方法得到类白色固体473.0g，HPLC纯度93.5％，收率56.3％。Add 600ml of tetrahydrofuran into the four-neck flask, cool to -78°C, add 594ml of LDA (2M cyclohexane solution, 1.3eq), then slowly add compound 5 (300g dissolved in 280ml of THF) dropwise, and continue to Stir at -20 °C for 1 h. Compound 8 (257.0 g dissolved in 250 ml of THF solution, 1.2 eq) was added dropwise, and reacted for 6 h after the addition was completed. According to the post-processing method of Example 7, 473.0 g of off-white solid was obtained, the HPLC purity was 93.5%, and the yield was 56.3%.
实施例11Example 11
1-(6-溴-2-甲氧基喹啉-3-基)-4-(二甲基氨基)-2-(萘-1-基)-1-苯基丁-3-烯-2-醇(化合物9)的制备1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalene-1-yl)-1-phenylbut-3-ene-2 - Preparation of Alcohol (Compound 9)
于四口瓶中加入四氢呋喃600ml，冷却至-78℃，加入LDA594ml(2M的环己烷溶液，1.5eq)，然后缓慢滴加化合物5(500g溶解于490ml的THF中)，滴加完毕后继续在-20℃下搅拌1h。滴加化合物8(411.6g溶解于400ml的THF溶液中，1.2eq)，滴加完毕后反应6h。按照实施例7的后处理方法得到类白色固体474.6g，HPLC纯度92.8％，收率56.0％。Add 600ml of tetrahydrofuran into the four-necked flask, cool to -78°C, add 594ml of LDA (2M cyclohexane solution, 1.5eq), and then slowly add compound 5 (500g dissolved in 490ml of THF) dropwise, continue to Stir at -20 °C for 1 h. Compound 8 (411.6g dissolved in 400ml of THF solution, 1.2eq) was added dropwise, and reacted for 6h after the dropwise addition was completed. According to the post-treatment method of Example 7, 474.6 g of off-white solid was obtained, the HPLC purity was 92.8%, and the yield was 56.0%.
实施例12Example 12
1-(6-溴-2-甲氧基喹啉-3-基)-4-(二甲基氨基)-2-(萘-1-基)-1-苯基丁-2-醇(贝达喹啉的消旋体)的制备1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalene-1-yl)-1-phenylbutan-2-ol (bei The preparation of the racemate of daquinoline)
将化合物9(300.0g，0.54mol)溶解于1.5L的THF中，室温下依次加入单质碘69.0g，硼氢化钠40.0g，升温至65℃回流，2h后TLC显示原料反应完全，冷却至室温，滴加甲醇500ml淬灭反应。溶剂蒸干后所得白色固体用二氯甲烷600ml悬浮，10％的氢氧化钠100ml洗涤有机相，分层后分出有机相，水相用二氯甲烷200ml再萃取一次，合并有机相，无水硫酸钠干燥，蒸干有机相后所得固体用无水乙醇重结晶一次，得白色固体240.0g，纯度95.6％，收率85％。1H-NMR(CDCl3)δ：1.28-1.30(m,6H),1.85-1.89(m,2H),2.43-2.46(m,2H),4.26(s,3H),5.74(d,1H,J＝12.4Hz),5.93(s,3H),6.89-90(m,3H),7.13-7.17(m,3H),7.26-7.30(m,1H),7.49-7.50(m,1H),7.55-7.86(m,3H),7.89-7.91(m,3H),7.96(s,1H),8.59(d,2H,J＝8.8Hz),8.89(s,1H).ESI-MS(m/z)＝553.2[M+H]+Compound 9 (300.0 g, 0.54 mol) was dissolved in 1.5 L of THF, 69.0 g of elemental iodine and 40.0 g of sodium borohydride were added successively at room temperature, and the temperature was raised to 65°C for reflux. After 2 hours, TLC showed that the reaction of the raw materials was complete, and cooled to room temperature , 500ml of methanol was added dropwise to quench the reaction. After the solvent was evaporated to dryness, the resulting white solid was suspended with 600ml of dichloromethane, and the organic phase was washed with 100ml of 10% sodium hydroxide. Dry over sodium sulfate, evaporate the organic phase to dryness, and recrystallize the obtained solid once with absolute ethanol to obtain 240.0 g of white solid with a purity of 95.6% and a yield of 85%. 1H-NMR (CDCl3) δ: 1.28-1.30 (m, 6H), 1.85-1.89 (m, 2H), 2.43-2.46 (m, 2H), 4.26 (s, 3H), 5.74 (d, 1H, J= 12.4Hz), 5.93(s, 3H), 6.89-90(m, 3H), 7.13-7.17(m, 3H), 7.26-7.30(m, 1H), 7.49-7.50(m, 1H), 7.55-7.86 (m,3H),7.89-7.91(m,3H),7.96(s,1H),8.59(d,2H,J＝8.8Hz),8.89(s,1H).ESI-MS(m/z)＝ 553.2[M+H]+
实施例13Example 13
1-(6-溴-2-甲氧基喹啉-3-基)-4-(二甲基氨基)-2-(萘-1-基)-1-苯基丁-2-醇的制备Preparation of 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalene-1-yl)-1-phenylbutan-2-ol
将化合物9(500.0g，0.9mol)溶解于1.5L的THF中，室温下加入10％Pd/C30.0g，空气置换后室温催化氢化，12小时后反应完全，将钯碳滤除后，蒸干有机相，所得固体用无水乙醇重结晶一次，得白色固体40.0g，纯度96.3％，收率88％。Dissolve compound 9 (500.0 g, 0.9 mol) in 1.5 L of THF, add 10% Pd/C 30.0 g at room temperature, replace the air with catalytic hydrogenation at room temperature, and complete the reaction after 12 hours. The organic phase was dried, and the resulting solid was recrystallized once with absolute ethanol to obtain 40.0 g of a white solid with a purity of 96.3% and a yield of 88%.
实施例14Example 14
1-(6-溴-2-甲氧基喹啉-3-基)-4-(二甲基氨基)-2-(萘-1-基)-1-苯基丁-2-醇的制备Preparation of 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalene-1-yl)-1-phenylbutan-2-ol
将化合物9(400.0g，0.72mol)溶解于1.2L的乙醇中，室温下加入还原铁粉200.0g，浓盐酸100ml，加热至回流，2小时后反应完全，将铁粉趁热滤除后，蒸干有机相，所得固体用无水乙醇重结晶一次，得白色固体340.2g，纯度98.4％，收率85％。Dissolve compound 9 (400.0 g, 0.72 mol) in 1.2 L of ethanol, add 200.0 g of reduced iron powder and 100 ml of concentrated hydrochloric acid at room temperature, heat to reflux, and the reaction is complete after 2 hours. After the iron powder is filtered off while hot, The organic phase was evaporated to dryness, and the resulting solid was recrystallized once with absolute ethanol to obtain 340.2 g of a white solid with a purity of 98.4% and a yield of 85%.
实施例15Example 15
1-(6-溴-2-甲氧基喹啉-3-基)-4-(二甲基氨基)-2-(萘-1-基)-1-苯基丁-2-醇的制备Preparation of 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalene-1-yl)-1-phenylbutan-2-ol
将化合物9(800.0g，0.14mol)溶解于2.4L的乙醇中，室温下加入还原铁粉400.0g，冰醋酸3.0ml，加热至回流，2小时后反应完全，将铁粉趁热滤除后，蒸干有机相，所得固体用无水乙醇重结晶一次，得白色固体6.9g，纯度96.5％，收率86％。Dissolve compound 9 (800.0g, 0.14mol) in 2.4L of ethanol, add 400.0g of reduced iron powder and 3.0ml of glacial acetic acid at room temperature, heat to reflux, the reaction is complete after 2 hours, and filter off the iron powder while hot , the organic phase was evaporated to dryness, and the resulting solid was recrystallized once with absolute ethanol to obtain 6.9 g of a white solid with a purity of 96.5% and a yield of 86%.
实施例16Example 16
1-(6-溴-2-甲氧基喹啉-3-基)-4-(二甲基氨基)-2-(萘-1-基)-1-苯基丁-2-醇的制备Preparation of 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalene-1-yl)-1-phenylbutan-2-ol
将化合物9(650.0g，0.12mol)溶解于2.4L的乙醇中，室温下加入氯化亚锡447.0g，浓盐酸100ml，加热至回流，2小时后反应完全，将反应中生成的固体滤除后，蒸干有机相，所得固体用无水乙醇重结晶一次，得白色固体559.0g，纯度97.3％，收率86％。Dissolve compound 9 (650.0g, 0.12mol) in 2.4L of ethanol, add 447.0g of stannous chloride and 100ml of concentrated hydrochloric acid at room temperature, heat to reflux, the reaction is complete after 2 hours, and the solid generated in the reaction is filtered off Afterwards, the organic phase was evaporated to dryness, and the obtained solid was recrystallized once with absolute ethanol to obtain 559.0 g of a white solid with a purity of 97.3% and a yield of 86%.
实施例17Example 17
1-(6-溴-2-甲氧基喹啉-3-基)-4-(二甲基氨基)-2-(萘-1-基)-1-苯基丁-2-醇)的制备1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalene-1-yl)-1-phenylbutan-2-ol) preparation
将化合物9(500.0g，0.9mol)溶解于2.5L的乙醇中，室温下加入锌粉294.0g，氯化铵95.0g，加热至回流，2小时后反应完全，将锌粉趁热滤除后，蒸干有机相，所得固 体用无水乙醇重结晶一次，得白色固体559.0g，纯度97.3％，收率86％。Dissolve compound 9 (500.0g, 0.9mol) in 2.5L of ethanol, add 294.0g of zinc powder and 95.0g of ammonium chloride at room temperature, heat to reflux, the reaction is complete after 2 hours, and filter the zinc powder while hot , the organic phase was evaporated to dryness, and the obtained solid was recrystallized once with absolute ethanol to obtain 559.0 g of a white solid with a purity of 97.3% and a yield of 86%.
实施例18Example 18
1-(6-溴-2-甲氧基喹啉-3-基)-4-(二甲基氨基)-2-(萘-1-基)-1-苯基丁-2-醇)的制备1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalene-1-yl)-1-phenylbutan-2-ol) preparation
将化合物9(750.0g，1.125mol)溶解于2.5L的甲醇中，室温下加入氧化铂2.55g，室温催化氢化，2小时后反应完全，将氧化铂滤除后，蒸干有机相，所得固体用甲醇重结晶一次，得白色固体838.5g，纯度98.2％，收率85.6％。Compound 9 (750.0 g, 1.125 mol) was dissolved in 2.5 L of methanol, 2.55 g of platinum oxide was added at room temperature, and catalytic hydrogenation was carried out at room temperature. After 2 hours, the reaction was complete. After the platinum oxide was filtered off, the organic phase was evaporated to dryness to obtain a solid Recrystallized once with methanol to obtain 838.5 g of white solid with a purity of 98.2% and a yield of 85.6%.
实施例19Example 19
1-(6-溴-2-甲氧基喹啉-3-基)-4-(二甲基氨基)-2-(萘-1-基)-1-苯基丁-2-醇)的制备1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalene-1-yl)-1-phenylbutan-2-ol) preparation
将化合物9(300.0g，1.125mol)溶解于1.6L的异丙醇中，室温下加入10％Pd/C3.0g，室温催化氢化，6小时后反应完全，将Pd/C滤除后，蒸干有机相，所得固体用异丙醇重结晶一次，得白色固体265.0g，纯度98.5％，收率86.1％。Dissolve compound 9 (300.0 g, 1.125 mol) in 1.6 L of isopropanol, add 3.0 g of 10% Pd/C at room temperature, and perform catalytic hydrogenation at room temperature. After 6 hours, the reaction is complete. After filtering off Pd/C, distill The organic phase was dried, and the resulting solid was recrystallized once with isopropanol to obtain 265.0 g of a white solid with a purity of 98.5% and a yield of 86.1%.
实施例20Example 20
(1R,2S)-1-(6-溴-2-甲氧基喹啉-3-)-4-二甲氨基-1-苯基-2-(1-萘基)-2-丁醇(贝达喹啉)的制备(1R,2S)-1-(6-bromo-2-methoxyquinoline-3-)-4-dimethylamino-1-phenyl-2-(1-naphthyl)-2-butanol ( Bedaquiline) preparation
第一步：成盐，拆分。将化合物10(91.3g，0.15mol)于室温下悬浮于240ml丙酮中，滴加拆分剂(R)-(-)-联萘酚磷酸酯(52.8g，0.15mol)的DMSO溶液35ml。滴加完毕后，溶液变澄清，反应液在室温搅拌1h后升温回流1h，然后缓慢冷却至室温，搅拌2h后过滤，所得白色固体用丙酮洗涤2次。将抽滤所得的固体用220ml丙酮回流打浆2h，然后缓慢冷却至室温后抽滤，所得固体用丙酮50ml洗涤一次，干燥后得白色块状固体165.0g。The first step: into salt, split. Compound 10 (91.3 g, 0.15 mol) was suspended in 240 ml of acetone at room temperature, and 35 ml of a DMSO solution of (R)-(-)-binaphthol phosphate (52.8 g, 0.15 mol) was added dropwise. After the dropwise addition, the solution became clear. The reaction solution was stirred at room temperature for 1 h, then heated to reflux for 1 h, then slowly cooled to room temperature, stirred for 2 h, and then filtered. The resulting white solid was washed twice with acetone. The solid obtained by suction filtration was beaten with 220ml of acetone under reflux for 2h, then slowly cooled to room temperature and filtered with suction, the obtained solid was washed once with 50ml of acetone, and dried to obtain 165.0g of white blocky solid.
第二步：游离。将第一步得到的白色固体悬浮于150ml甲苯中，然后加入10％碳酸钾溶液40ml，然后将混合物加热至回流，冷却至室温后分层，分出有机相后用水50ml在80℃洗涤2次，分出的甲苯层不经干燥直接在56℃下减压浓缩至干。蒸干后的白色固体用150ml乙醇回流打浆1h，然后缓慢冷却至0℃，并在低温下搅拌1h，过滤，滤饼用50ml乙醇洗涤，然后70℃真空干燥得白色固体35.6g，收率39％，HPLC纯度99.6％，ee值99.8％。1HNMR(300MHz,CDCl3):δ＝8.89(s,1H),8.61d,J＝8.6Hz,1H,),7.96(d,J＝2.0Hz,1H),7.92(d,J＝7.4Hz,1H),7.87(d,J＝8.1Hz,1H),7.72(d,J＝8.8Hz,1H),7.68–7.56(m,3H,H7,H16),7.48(t,J＝7.6Hz,1H),7.30(t,J＝7.7Hz,1H),7.17–7.10(m, 2H),6.93–6.83(m,3H),5.89(s,1H),4.21(s,3H),2.60–2.51(m,1H),2.18–2.02(m,2H),1.99(s,6H),1.95–1.85(m,1H).HRMS(ESI)calcd.forC32H32BrN2O2[M+H]+55.1642；found555.1671。The second step: free. Suspend the white solid obtained in the first step in 150ml of toluene, then add 40ml of 10% potassium carbonate solution, then heat the mixture to reflux, cool to room temperature and separate the layers, separate the organic phase and wash twice with 50ml of water at 80°C , the separated toluene layer was directly concentrated to dryness at 56° C. under reduced pressure without drying. The evaporated white solid was refluxed with 150ml of ethanol for beating for 1h, then slowly cooled to 0°C, stirred at low temperature for 1h, filtered, the filter cake was washed with 50ml of ethanol, and then vacuum-dried at 70°C to obtain 35.6g of white solid with a yield of 39% %, HPLC purity 99.6%, ee value 99.8%.1 HNMR (300MHz, CDCl3 ): δ＝8.89(s, 1H), 8.61d, J＝8.6Hz, 1H,), 7.96(d, J＝2.0Hz, 1H), 7.92(d, J＝7.4Hz ,1H),7.87(d,J=8.1Hz,1H),7.72(d,J=8.8Hz,1H),7.68–7.56(m,3H,H7,H16),7.48(t,J=7.6Hz, 1H),7.30(t,J＝7.7Hz,1H),7.17–7.10(m,2H),6.93–6.83(m,3H),5.89(s,1H),4.21(s,3H),2.60–2.51 (m,1H),2.18–2.02(m,2H),1.99(s,6H),1.95–1.85(m,1H).HRMS(ESI)calcd.forC32H32BrN2O2[M+ H]+55.1642;found555.1671.
| Application Number | Priority Date | Filing Date | Title |
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| CN201410190912.XACN105085395B (en) | 2014-05-07 | 2014-05-07 | Shellfish reaches the preparation method of quinoline |
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| CN201410190912.XACN105085395B (en) | 2014-05-07 | 2014-05-07 | Shellfish reaches the preparation method of quinoline |
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| CN201410190912.XAActiveCN105085395B (en) | 2014-05-07 | 2014-05-07 | Shellfish reaches the preparation method of quinoline |
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