CN101538253B - 一种制备瑞格列奈中间体的方法 - Google Patents
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
本发明涉及一种制备瑞格列奈中间体式(I)的方法，
Description
技术领域
本发明涉及药物有机合成领域，特别是涉及一种治疗糖尿病的药物瑞格列奈中间体的制备方法。
背景技术
瑞格列奈的化学名为S(+)-2-乙氧基-4-[N-{1-(2-哌啶基苯基)-3-甲基-1-丁基}氨基羰基甲基]苯甲酸，结构式为
可从美国专利(专利号：US5312924)中得知。研究表明，瑞格列奈是有效的对映体，与R(-)-2-乙氧基-4-[N-{1-(2-哌啶基苯基)-3-甲基-1-丁基}氨基羰基甲基]苯甲酸相比，在人体内具有长时间的生物活性，并且更迅速的被消除，它是一种新型的口服降糖药物，能促进胰岛素分泌，具有吸收快、作用时间短的特点，可在II型糖尿病患者中模拟生理性胰岛素分泌，有效控制餐后高血糖，有较高的蛋白结合率，不会在组织中蓄积，安全性良好。瑞格列奈既可以作为一线抗糖尿病药物单独使用，也可以与其他降糖药联合应用增加疗效，为II型糖尿病的治疗提供一种新的手段。
式(I)化合物与式(VIII)化合物经缩合、水解即可制备得到瑞格列奈，同各种文献报道(如US5312924或CN1571769)的方法比较，具有反应时间短、毒性小、环保等优点，因此式(I)化合物是开发瑞格列奈的关键中间体。
因此开发一种新的式(I)化合物的制备方法具有重要的意义和价值。本发明提供了一条新的制备方法，它具有反应时间短，收率高，低毒，低危险，操作简单等优点，是一条具有很好工业化前景的工艺路线。
发明内容
本发明的目的在于提供一种收率高且适合于工业上应用的瑞格列奈中间体的制备方法。
本发明公开了一种制备式(I)所示瑞格列奈中间体的制备方法，
所述方法包括：
(1)邻氯苯甲醛和式(II)所示格氏试剂在金属盐存在下反应，生成式(III)化合物，
(2)式(III)化合物在氧化剂存在下反应，生成式(IV)化合物，
(3)式(IV)化合物在密闭、高温条件下与哌啶缩合反应，生成式(V)化合物，
(4)式(V)化合物与4-甲氧基苄胺在酸催化剂存在下，缩合反应生成式(VI)化合物，在还原剂存在下经还原反应，生成式(VII)化合物，
(5)式(VII)化合物用酸拆分剂拆分，生成式(I)化合物，
其中，对本方案中的步骤进一步优化，在制备式(III)化合物时，所用的金属盐选自卤化亚铜系列，如氯化亚铜、溴化亚铜或碘化亚铜，优选溴化亚铜。
对本方案中的步骤进一步优化，在制备式(IV)化合物时，所用的氧化剂为三氧化铬。
对本方案中的步骤进一步优化，在制备式(V)化合物时，反应在密闭的高压釜中进行，反应的温度控制在100℃～180℃，优选150℃～180℃。
对本方案中的步骤进一步优化，在制备式(VII)化合物时，反应中所用的酸催化剂为对甲苯磺酸，还原剂选自硼氢化锂、硼氢化钠、硼氢化钾或四氢锂铝，优选硼氢化钠。
在本方案中，“酸拆分剂”为光学纯且显酸性的各种拆分剂，如L-酒石酸、L-扁桃酸、N-乙酰-L-谷氨酸等，优选L-扁桃酸。
具体实施方式
为了更详细地说明本发明，给出下述制备实例。但本发明的范围并非限定于此。
实施例一
1-(2-氯苯基)-3-甲基-1-丁醇的制备
方法A
将镁屑(12Kg)、THF(300L)和异丁基溴(7.3L，1.26g/ml)加入到500L反应釜中，加热使反应引发，滴加剩余异丁基溴(80L)，加完后继续回流反应40分钟，冷却，将反应液转移至冷冻釜中，降温至10℃以下，加入六甲基磷酰胺(33L)、溴化亚铜(1.25Kg)，搅拌下滴加邻氯苯甲醛(40Kg)和THF(40L)组成的混合液，保温反应2小时，向反应液中加入稀盐酸调PH＝1～2，用乙酸乙酯提取，合并有机层，水洗，干燥，浓缩干得油状物：56Kg。ESI-MS(m/z)：198.5([M+H])
方法B
采用与方法A相同的制备方法，不同之处在于将异丁基溴改为异丁基氯。
实施例二
1-(2-氯苯基)-3-甲基-1-丁酮的制备
在500L反应釜中加入三氧化铬(84Kg)、冰醋酸(250L)，冷却至0℃左右，滴加例一中间体(56Kg)，滴完后加入10％盐酸(20L)，继续搅拌反应过夜，加水至反应液中，用碳酸钾调PH＝9，用石油醚提取，合并，水洗，干燥，浓缩干得油状物：28Kg。ESI-MS(m/z)：196.5([M+H])
实施例三
3-甲基-1-[2-(1-哌啶基)苯基]-1-丁酮的制备
将例二中间体(28Kg)、六氢吡啶(70L)、碳酸钾(42Kg)投入到高压釜中，升温至内温180℃，搅拌反应5小时，冷却至室温，用石油醚提取，水相用石油醚反提，合并有机层，水洗，干燥，浓缩干得油状物：33Kg。ESI-MS(m/z)：246.0([M+H])
实施例四
(4-甲氧基苯基)-N-(3-甲基-1-(2-(1-哌啶基)苯基)亚丁基)甲胺的制备
将例三中间体(33Kg)，甲苯(300L)，对甲苯磺酸(3.3Kg)，4-甲氧基苄胺(44.6Kg)投入反应釜中，回流分水反应五小时。加入无水硫酸钠(16Kg)，继续反应过夜。次日，将反应液冷却至室温，冲入饱和碳酸氢钠溶液(200L)中，分层，水层用乙酸乙酯(100L)提取，合并有机层，干燥，浓缩干得油状物：80.8Kg。
TLC：石油醚/乙酸乙酯＝20/1，Rf中间体＝0.7，Rf产物＝0.3
实施例五
N-(4-甲氧基苄基)-3-甲基-1-[2-(1-哌啶基)苯基]-1-丁胺的制备
将例四中间体(80.8Kg)，甲醇(300L)，六水合氯化镍(70Kg)投入反应釜中，冷却到0℃。于0℃以下分批加入硼氢化钠(45.7Kg)。反应液颜色变黑，产生大量气泡，放热明显。加料完毕后自然升温反应五小时。反应液用浓盐酸调PH＝1～2，然后碳酸钾溶液调PH＝9～10，乙酸乙酯(200L×3)提取，合并有机层，无水硫酸镁干燥，浓缩干柱层析得油状物：35.5Kg。ESI-MS(m/z)：367.0([M+H])
展开剂：石油醚/乙酸乙酯＝3/1，Rf中间体＝0.9，Rf产物＝0.6
实施例六
(S)-N-(4-甲氧基苄基)-3-甲基-1-[2-(1-哌啶基)苯基]-1-丁胺制备
将例五中间体(35.5Kg)、L-扁桃酸(14.8Kg)、异丙醇/水(1∶1)的混合溶剂(170L)投入到反应釜中，加热至回流，溶清后，自然放置析晶，过滤，干燥得粗品：31.9Kg；
将上步固体投入到反应釜中，加入甲醇/水(1∶1)的混合溶剂(260L)加热至回流溶清，放冷自然析晶，过滤，干燥，得固体：15.3Kg。
将氢氧化钠(1.2Kg)和纯化水(10L)投入到200L反应釜中，加入甲苯(80L)以及固体(15.Kg)，室温搅拌反应45分钟。
分层，有机层用水(70L×2)洗涤，无水硫酸镁干燥。过滤，滤液浓缩干，得目标化合物。
经过现有技术的鉴定方法，可以得知，本发明实施例所得到的式(I)化合物为目标化合物。
Claims (10)
1. 一种制备式(I)所示瑞格列奈中间体的方法，
包括如下步骤：
(1)邻氯苯甲醛和式(II)所示格氏试剂在金属盐存在下反应，生成式(III)化合物，
(2)式(III)化合物在氧化剂存在下反应，生成式(IV)化合物，
(3)式(IV)化合物在密闭、高温条件下与哌啶缩合反应，生成式(V)化合物，
(4)式(V)化合物与4-甲氧基苄胺在酸催化剂存在下，缩合反应生成式(VI)化合物，在还原剂存在下经还原反应生成式(VII)化合物，
(5)式(VII)化合物用酸拆分剂拆分，得到式(I)化合物，
其中，
X为卤素原子；
金属盐选自氯化亚铜、溴化亚铜或碘化亚铜；
氧化剂选自高锰酸钾或三氧化铬；
还原剂选自硼氢化锂、硼氢化钠、硼氢化钾或四氢锂铝。
2. 根据权利要求1所述的制备方法，其特征在于X为氯原子或溴原子。
3. 根据权利要求2所述的制备方法，其特征在于X为溴原子。
4. 根据权利要求1所述的制备方法，其特征在于在制备式(III)化合物时，金属盐为溴化亚铜。
5. 根据权利要求1所述的制备方法，其特征在于在制备式(IV)化合物时，氧化剂为三氧化铬。
6. 根据权利要求1所述的制备方法，其特征在于在制备式(V)化合物时，反应温度控制在100℃～180℃。
7. 根据权利要求6所述的制备方法，其特征在于所述反应温度为150℃～180℃。
8. 根据权利要求1所述的制备方法，其特征在于在制备式(VII)化合物时，所用的酸催化剂为对甲苯磺酸；还原剂为硼氢化钠。
9. 根据权利要求1的制备方法，其特征在于在制备式(I)化合物时，所用的酸拆分剂选自L-酒石酸或L-扁桃酸。
10. 根据权利要求9所述的制备方法，其特征在于所述酸拆分剂为L-扁桃酸。
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