CN107129501B - 2型糖尿病药物西他列汀制备新方法 - Google Patents

2型糖尿病药物西他列汀制备新方法 Download PDF

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CN107129501B
CN107129501B CN201710358037.5A CN201710358037A CN107129501B CN 107129501 B CN107129501 B CN 107129501B CN 201710358037 A CN201710358037 A CN 201710358037A CN 107129501 B CN107129501 B CN 107129501B
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sitagliptin
diabetes
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刘雄利
田民义
姚震
刘雄伟
张敏
周英
俸婷婷
余章彪
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Guizhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
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    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

本发明公开了一种2型糖尿病药物西他列汀制备新方法。本发明本发明采用价格更便宜的三氟苯做氟代试剂起始原料，通过与L‑天冬氨酸的有效酰基化，成功合成西他列汀的基本骨架，从最初的原料到最终产物，合成路线都完全不同于现有技术公开的方案，并优化了路线,采用原料易得的天然L‑天冬氨酸做手性源，成功合成了光学纯的西他列汀产品，避免了现有技术采用中不对称催化和拆分的复杂性，还有效解决其中三氟苯傅克酰基化反应合成西他列汀基本骨架产率低的问题，提高了产率，而且成本更低，操作更方便，更适合工业化生产，比现有技术合成路线更简单，操作性更强。

Description

2型糖尿病药物西他列汀制备新方法
技术领域
本发明涉及化学技术领域，尤其是一种2型糖尿病药物西他列汀制备新方法。
背景技术
西他列汀是一种新型抗2型糖尿病药物,于2006年10月被美国FDA批准上市,西他列汀具有良好的耐受性和安全性，与其他药物相比疗效显著，具有良好的市场前景。2013年磷酸西他列汀销售收入就达到25亿美元。是一种安全、有效、市场前景良好的治疗2型糖尿病的口服药物。由于诺华的竞争产品vidagliptin已经因为肝脏安全性问题元气大伤，所以西他列汀在该类药物中极有可能继续保持领先位置。西他列汀(sitagliptin)磷酸盐(商品名Januvia)作为首个DPP-IV抑制剂被美国FDA批准上市，临床用于治疗2型糖尿病。检索中国专利局，西他列汀专利是2022到期。因此，对西他列汀的仿制具有极其重要的经济意义。
发明内容
本发明的目的是：提供一种2型糖尿病药物西他列汀制备新方法，该方法能有效解决其中三氟苯傅克酰基化反应合成西他列汀基本骨架产率低的问题,提高了产率，而且合成路线简单，成本低廉，操作更方便，操作性更强，更适合工业化生产。
2型糖尿病药物西他列汀制备新方法，由天然L-天冬氨酸苄基酯化反应合成中间体I，中间体I与三聚光气成环化反应合成中间体II，中间体II与氯甲酸甲酯N-酰基保护化反应合成中间体III,中间体III再与三氟苯傅克酰基化反应合成西他列汀基本骨架IV，西他列汀基本骨架IV再通过钯碳与氢气羰基还原成亚甲基与脱苄基化反应，得到中间体V，中间体V与含三氮唑的原料缩合反应得到中间体VI，中间体VI脱Boc反应得到最终的产物西他列汀。
本发明合成路线如下：
由于采用了上技术方案，本发明本发明采用价格更便宜的三氟苯做氟代试剂起始原料，通过与L-天冬氨酸的有效酰基化，成功合成西他列汀的基本骨架，从最初的原料到最终产物，合成路线都完全不同于现有技术公开的方案，并优化了路线,采用原料易得的天然L-天冬氨酸做手性源，成功合成了光学纯的西他列汀产品，避免了现有技术采用中不对称催化和拆分的复杂性，还有效解决其中三氟苯傅克酰基化反应合成西他列汀基本骨架产率低的问题，提高了产率，而且成本更低，操作更方便，更适合工业化生产，比现有技术合成路线更简单，操作性更强。
具体实施方式
为了更好的理解本发明的内容，下面结合具体实施例来做进一步说明，但具体的实施方式并不是本发明的内容所限制。
实施例1：中间体I的制备
在500mL烧杯中加入100mL无水乙醚,再缓慢滴加20mL浓硫酸,边滴加边搅拌,等冷却到室温后,加入150mL苯甲醇,充分搅拌后,减压除掉乙醚,然后分5批加入天冬氨酸共26g至反应瓶中.室温均匀搅拌反应24h,再加入300mL95％的乙醇,并用滴液漏斗逐滴加入80mL吡啶,边滴边剧烈搅拌,然后经冰箱冷冻过夜,抽滤得到固体,固体80℃乙醇搅拌溶解,热过滤,滤液冷藏8h,抽滤.冻干后得到纯净的β-天门冬氨酸苄酯(90％产率).
实施例2：中间体II的制备
在氩气保护下,在500mL的烧瓶中加入4.5g的β-天门冬氨酸苄酯,加入300mL新蒸的无水乙酸乙酯,90℃下回流30min,然后用恒压滴液漏斗将60mL溶有2.7g三光气的新蒸乙酸乙酯缓慢滴加入，90℃继续回流直到溶液变澄清。溶液变清后，用冰盐浴将反应溶液快速冷却(30min),然后用冷的饱和碳酸氢钠溶液快速洗涤3次，接着萃取液用冷的饱和氯化钠溶液快速洗涤2次，再萃取分液，最后将乙酸乙酯溶液用适量无水硫酸镁室温干燥30min。过滤，滤液经浓缩后，用新蒸的无水石油醚沉淀。冷冻抽滤所得白色固体。用乙酸乙酯石油醚混合液进行重结晶，最终得到白色针状晶体(83％产率)。
实施例3：中间体III的制备
在-25℃下，2.5g(10.0mmol)中间体II溶解在30mL干燥的四氢呋喃中，1.3eq的氯甲酸甲酯逐滴加入，1.5eq的N-甲基吗啉(NMM)溶解在5mL四氢呋喃中，在15分钟内逐滴加入至反应体系中，在-25℃下搅拌1h，然后升温至室温搅拌过夜。反应体系继续冷却至-25℃，用含4.0M的HCl二氧六环溶液酸化，直到溶液的pH值接近于3。反应液升温至室温。在氮气保护下，反应液通过干燥的521型硅藻土(3.0g)以及用四氢呋喃做流动相(2×5.0mL)，过滤除掉N-甲基吗啉(NMM)盐酸盐沉淀。滤液浓缩后，用TBME/THF/hexanes作溶剂，在-20℃重结晶过夜。固体收集后保存在真空干燥器中(88％产率)。
实施例4：中间体IV的制备
在氩气保护中，30.7g中间体III和75g 1,2,4-三氟苯溶解在100mL二氯甲烷中，缓慢加入46g AlCl3，加入过程中使整个反应体系保持温度不超过30℃。搅拌5h后，倒入250g冰中，反应液用二氯甲烷(3x200mL)萃取3次，100克无水硫酸镁干燥萃取液，过滤浓缩溶剂，柱层析得到产物中间体IV(78％产率)。
通过在中间体III的氮上成功酰基化保护，有效解决与三氟苯傅克反应产率低的问题,提高了产率。
实施例5：中间体V的制备
6.2g中间体IV溶解在60mL绝对无水乙醇中,加入乙醚饱和的HCl溶液10mL以及1gPd/C，充入H2(5atm)室温搅拌反应10h。过滤，浓缩得到黄色油状物。加入12M的浓盐酸10mL，回流30min。加入20mL THF,用LiOH调节至碱性，加入3.0eq的Boc2O,室温搅拌反应8h,用10％的盐酸调节溶液至酸性，迅速二氯甲烷萃取，干燥后浓缩得到一个苍白色固体(66％产率)。1H NMR(DMSO-d6,400MHz)δ:1.32(s,9H),2.63-2.41(m,2H),2.63-2.65(m,1H),2.92(dd,J＝13.8,5.0Hz,1H),4.19-4.07(m,1H),4.92(s,2H),7.17-7.01(m,1H),7.23-7.13(m,1H)；13C NMR(DMSO-d6,100MHz)δ:28.2,32.9,37.8,47.5,79.9,105.4,118.9,121.1,145.3,147.8,150.1,157.1,174.8,176.1；HRMS(ESI-TOF)m/z:Calcd.for C15H18F3NNaO4[M+Na]+:356.1086；Found:356.1083.
实施例6：中间体VI的制备
3.0g中间体V(4.5mmol)溶解在25mL DMF中，加入2.06g EDC.HCl(10.8mmol)和1.46g HOBT(10.8mmol),再加入1.80g原料X(9.0mmol)和1.30mL三乙胺(9.0mmol),室温下搅拌15h,加入水萃灭反应,乙酸乙酯萃取,有机层NaHCO3水溶液和饱和食盐水洗涤,无水Na2SO4干燥.减压蒸除溶剂,柱层析(EtOAc/石油醚＝7:3)得到白色固体产物中间体VI(81％产率)。m.p.＝190-192℃；[α]D 25＝+24.5(c 0.22,CHCl3)。1H NMR(DMSO-d6,400MHz)δ:1.27(s,9H),2.74-2.77(m,3H),2.94-2.99(m,1H),4.09-4.38(m,5H),4.96(s,1H),5.04(br s,1H),7.05-7.12(m,1H),7.18-7.24(m,1H)；13C NMR(DMSO-d6,100MHz)δ:37.7,37.9,38.4,39.5,41.1,41.9,42.1,43.6,44.7,47.6,105.8,117.8,118.7,122.3,144.3,148.7,147.7,150.5,152.2,157.6,170.4,171.5；HRMS(ESI-TOF)m/z:Calcd.forC21H23F6N5NaO3[M+Na]+:530.1603；Found:530.1601.
实施例7：中间体VII的制备
2.54g N-Boc取代的西他列汀(5.0mmol)溶解在100mL MeOH/6N HCl溶液中，室温搅拌6h，浓缩得到白色固体。白色固体加入到1N的NaOH和100mL乙酸乙酯的混合溶液中，搅拌后，用乙酸乙酯萃取，饱和食盐水洗涤，无水Na2SO4干燥。浓缩后柱层析(DCM/MeOH＝10:1)得到无颜色的油状物(-)-(R)-西他列汀(91％产率)。[α]D 25＝-22.5(c 1.0,CHCl3)。1H NMR(CDCl3,400MHz)δ:2.47-2.67(m,4H),2.73(m,1H),2.83(m,1H),3.61(bs,1H),3.86-4.44(m,4H),4.82-5.20(m,2H),6.92(m,1H),7.05-7.22(m,1H)；13C NMR(CDCl3,100MHz)δ:35.9,38.0,39.2,39.7,39.8,41.6,42.5,43.3,43.6,48.6,105.7,117.2,118.9,121.6,143.7,146.6,148.9,149.7,150.4,156.2,170.2,170.5；HRMS(ESI-TOF)m/z:Calcd.forC16H15F6N5NaO[M+Na]+:430.1078；Found:430.1081.

Claims (1)

1.一种2型糖尿病药物西他列汀制备新方法，其特征在于：由天然L-天冬氨酸苄基酯化反应合成中间体I，中间体I与三聚光气成环化反应合成中间体II，中间体II与氯甲酸甲酯N-酰基保护化反应合成中间体III,中间体III再与三氟苯傅克酰基化反应合成西他列汀基本骨架IV，西他列汀基本骨架IV再通过钯碳与氢气羰基还原成亚甲基与脱苄基化反应，得到中间体V，中间体V与含三氮唑的原料缩合反应得到中间体VI，中间体VI脱Boc反应得到最终的产物西他列汀；合成路线如下：
CN201710358037.5A 2017-05-19 2017-05-19 2型糖尿病药物西他列汀制备新方法 Expired - Fee Related CN107129501B (zh)

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