CN1496353A - 氨氯地平的制备方法 - Google Patents
氨氯地平的制备方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims description 27
- 238000003445 Hantzsch reaction Methods 0.000 claims abstract description 9
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- Hydrogenated Pyridines (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
通过以下方法以高收率制备氨氯地平：使吡咯衍生物、氨基巴豆酸甲酯和2－氯苯甲醛进行Hantzsch反应，并通过盐酸羟胺的作用将所得的1，4－二氢吡啶衍生物的吡咯残基转化为胺基团。
Description
技术领域
本发明涉及以高收率制备氨氯地平的合成方法。
背景技术
氨氯地平，式(I)的化合物3-乙基-5-甲基-2-(2-氨基乙氧基-甲基)-4-(2-氯苯基)-6-甲基-1，4-二氢-3，5-吡啶二羧酸酯的通用名，是用于治疗心血管疾病如心绞痛、高血压和充血性心脏停博的长期钙通道阻滞剂。此化合物由于在旋转受限的联芳基轴周围存在两个不同的酯残基而具有不对称性。
已报道了多种用于氨氯地平合成的方法，但这些方法一般存在由于在关键的Hantzsch反应步骤中所观察到的低收率导致的低生产率问题，如以下进一步解释。
例如，韩国专利公开87-909公开了由路线1表示的氨氯地平的制备方法：通过叠氮化合物与氨基巴豆酸甲酯和2-氯苯甲醛进行Hantzsch反应得到1，4-二氢吡啶衍生物，并将其叠氮残基还原。
路线1
其中Et和Me分别代表乙基和甲基。但是，这种方法的收率仅为19％，且由于叠氮化合物的爆炸危险而不适于大规模生产。
韩国专利公开86-1921所公开的方法如以下路线2所示，其中使用具有邻苯二甲酰亚胺胺保护基的衍生物进行Hantzsch反应，然后除去胺保护基，得到氨氯地平。
路线2
其中Et和Me分别代表乙基和甲基。但是，这种方法也存在Hantzsch反应收率很低的问题，如收率为25％。
韩国专利公开87-909公开了一种如以下路线3所示的氨氯地平的制备方法：使用胺基团被两个苄基保护的衍生物进行Hantzsch反应，然后除去苄基。
路线3
其中Bn、Et和Me分别代表苄基、乙基和甲基。此方法也必然伴有低收率10％，而且具有存在需要两步氢化以除去苄基的问题。
美国专利5,389,654描述了由以下路线4表示的苯磺酸(besylate)氨氯地平(氨氯地平苯磺酸酯)的制备方法，其中使用氨基被三苯基甲基保护的衍生物进行Hantzsch反应，然后通过苯磺酸处理除去胺保护基。
路线4
其中Ph、Et和Me分别代表苯基、乙基和甲基。同样，这种复杂的方法也提供极低的收率7％。
根据由以下路线5表示的美国专利6,046,337所公开的方法，使用卤代衍生物进行Hantzsch反应，然后将所得产物的卤素基团转化为胺基团。
路线5
其中Et和Me分别代表乙基和甲基。由于含氯产物在随后的胺取代反应中是非反应性的，因此必须首先将它转化为相应的碘衍生物。因此，不管使用何种卤素衍生物，氨氯地平的总收率均为22％或更低。
因此，这些现有技术方法都存在低收率问题，需要能够以高收率生产氨氯地平的改进的方法。
发明内容
因此，本发明的主要目的是提供以高收率制备氨氯地平的改进的方法。
根据本发明的一个方面，提供了式(I)的氨氯地平的制备方法，所述方法包括：
(a)使式(II)的化合物与式(III)的氨基巴豆酸酯和式(IV)的2-氯苯甲醛进行Hantzsch反应，得到式(V)的化合物；和
(b)在水和有机溶剂的混合物中用盐酸羟胺处理式(V)的化合物：
其中R1和R2独立地为卤素、C1-4烷基或被氢或烷氧基取代的C1-4烷基，Me为甲基，且Et为乙基。
具体实施方式
本发明的方法可以如以下路线6所示：
路线6
其中R1、R2、Et和Me如以上定义。
式(II)的吡咯衍生物为新化合物，且在实施本发明时，R1和R2都优选为甲基。式(II)的吡咯衍生物可以根据[J.Chem.Soc.，Perkin Trans.I，2801，(1984)]中所公开的方法以高收率制备，该方法如本文路线7表示，其中胺残基以吡咯形式被保护。
路线7
其中R1、R2和Et如以上定义。
本发明的方法的优点特别地在于吡咯基团使得即使在强碱条件下也能以高收率，即90％进行取代反应成为可能。这种碱性条件在采用任何常规胺保护基时都是不适用的。而且，可以通过羟胺的作用将吡咯基容易地转化为胺，而不影响相邻的酯保护基。
在本发明的方法的步骤(a)中，式(V)的化合物的高收率可以通过使式(II)的吡咯衍生物与式(III)的氨基巴豆酸甲酯和2-氯苯甲醛进行Hantzsch反应而得到，所述反应一般通过在有机溶剂中将0.9～1.2∶1∶1当量的量的吡咯衍生物、氨基巴豆酸酯和2-氯苯甲醛回流二十(20)小时而进行。有机溶剂可以是C1-4烷醇如异丙醇和1-丁醇。此反应的收率为约53％，该收率大大高于常规Hantzsch反应的收率。
在步骤(b)中，可以通过以下方法以高收率获得氨氯地平：基于式(V)的化合物的量，在15～25当量，优选20当量的羟胺盐，优选是盐酸羟胺的存在下，在水和有机溶剂的混合物中将式(V)的化合物回流4～5小时的时间。基于1，4-二氢吡啶衍生物的量，当盐酸羟胺与例如10当量的三乙胺一起使用时，可以获得特别高的收率。有机溶剂可以是异丙醇、甲醇、乙醇或1-丁醇，且基于水的体积，它可以与3～5，优选4体积的水混合。
根据本发明，可以获得式(V)的1，4-二氢吡啶衍生物，并以大大高于先前可能的收率的收率被转化为氨氯地平。因此，本发明的方法可以有利地用于大量生产氨氯地平。
在以下实施例中进一步描述本发明，所述实施例仅用于说明目的，而不意在限制本发明的范围。
制备例1：2-(2，5-二甲基吡咯-1-基)乙醇的制备
将30.5g(0.5mol)氨基乙醇、57g(0.5mol)丙酮基丙酮和0.35g(5mmol，催化量)乙酸加入300ml甲苯中，然后，用迪安-斯达克榻分水器将混合物回流3小时。将反应混合物冷却至室温，向其中加入200ml水和100ml乙酸乙酯，并搅拌30分钟。分离有机相，并用硅胶滤垫过滤，减压下将滤液蒸馏，得到66g浅橙色油形式的标题化合物(收率：95％)。
1H-NMR(300MHz，CDCl3)δ(ppm)：5.82(s，2H)，3.94(t，2H，J＝6Hz)，3.78(t，2H，J＝6Hz)，2.28(s，6H)
制备例2：4-[2-(2，5-二甲基吡咯-1-基)乙氧基]乙酰乙酸乙酯的制备
将32g氢化钠(60％油分散体)加入500ml四氢呋喃中，并向其中加入56g(0.4mol)在制备例1中得到的2-(2，5-二甲基吡咯-1-基)乙醇，然后在室温下搅拌1小时。将反应混合物冷却至0℃，在2小时内向其中滴加通过将65.84g(0.4mol)4-氯乙酰乙酸乙酯溶于200ml四氢呋喃而得到的溶液。将混合物于室温下搅拌16小时，然后用3N盐酸调节至pH6～7。加入足量的水以溶解形成的固体沉淀，并分别用600ml和100ml乙酸乙酯将反应混合物萃取两次。用无水硫酸镁干燥合并的乙酸乙酯萃取物，用脱色碳处理，然后减压蒸馏溶剂，得到96.2g标题化合物，为浅黄色油(收率：90％)。
1H-NMR(300MHz，CDCl3)δ(ppm)：5.86(s，2H)，4.19(q，2H，J＝7.1Hz)，4.04(s，2H)，3.98(t，2H，J＝6.0Hz)，3.65(t，2H，J＝6.0Hz)，3.41(s，2H)，2.23(s，6H)，1.27(t，3H，J＝7.1Hz)
实施例1：3-乙基-5-甲基-2-(2-氨基乙氧基-甲基)-4-(2-氯苯基)-6-甲基
-1，4-二氢-3，5-吡啶-二羧酸酯的制备
(步骤a)3-乙基-5-甲基-2-[(2-(2，5-二甲基吡咯-1-基)乙氧基)-甲基]-4-(2-氯苯基)-6-甲基-1，4-二氢-3，5-吡啶-二羧酸酯的制备
将11.4g(42.6mmol)在制备例2中得到的4-[2-(2，5-二甲基吡咯-1-基)乙氧基]乙酰乙酸乙酯、6g(42.6mmol)2-氯苯甲醛和4.9g(42.6mmol)3-氨基巴豆酸甲酯加入100ml异丙醇中，并将混合物回流20小时。将反应混合物冷却至室温，并通过在减压下除去溶剂而浓缩。用柱色谱法纯化残余物，得到11g标题化合物(浅黄色结晶，收率：53％)。
m.p.：46～48℃
质量：m/z＝509.11(M+Na+)，485.94(M+H)+
1H-NMR(300MHz，CDCl3)δ(ppm)：7.07～7.36(m，4H)，6.65(b，1H，NH)，5.86(s，2H)，5.40(s，1H)，4.73(s，2H)，4.03～4.11(m，4H)，3.74(t，2H，J＝5.4Hz)，3.64(s，3H)，2.31(s，6H)，2.27(s，3H)，1.24(t，3H，J＝7.1Hz)
IR(KBr)：3377，2977，2945，1692，1480，1433，1305cm-1
(步骤b)3-乙基-5-甲基-2-(2-氨基乙氧基-甲基)-4-(2-氯苯基)-6-甲基-1，4-二氢-3，5-吡啶-二羧酸酯的制备
将7.9g(16.2mmol)在步骤a中得到的3-乙基-5-甲基-2-[(2-(2，5-二甲基吡咯-1-基)乙氧基)-甲基]-4-(2-氯苯基)-6-甲基-1，4-二氢-3，5-吡啶-二羧酸酯、22.6g(324mmol，20eq)盐酸羟胺和16.4g(162mmol，10eq)三乙胺加入60ml异丙醇和15ml水的混合物中，并将反应混合物回流4.5小时。将反应混合物冷却至室温，在减压下蒸馏出异丙醇。将100ml水加入残余物中，并用3N HCl调节至pH1～2，然后用50ml部分的乙酸乙酯洗涤两次。用1N NaOH将水相调节至pH8～9，然后用100ml部分的乙酸乙酯萃取两次。用饱和盐水洗涤有机相，用无水硫酸镁干燥，然后在减压下蒸馏出溶剂。用柱色谱法纯化残余物，得到5.1g浅黄色泡沫形式的标题化合物(收率：77％)。
1H-NMR(300MHz，CDCl3)δ(ppm)：7.40(br，s，1H，NH)，7.02～7.37(n，4H，ArH)，5.39(s，1H)，4.75(d.d.，2H)，4.02(q，2H)，3.71(m，2H)，3.60(s，3H)，3.12(m，2H)，2.70(br，2H，NH)，2.36(s，3H)，1.19(t，3H)
如上所示，本发明的方法能够以明显高于任何常规方法的收率提供氨氯地平。
虽然根据以上特定实施方案描述了本发明，但是应该认识到，可以由本领域技术人员对本发明进行多种修改和改变，而这些修改和改变都落在所附的权利要求定义的本发明的范围内。
Claims (6)
1.式(I)的氨氯地平的制备方法，所述方法包括：
(a)使式(II)的化合物与式(III)的氨基巴豆酸酯和式(IV)的2-氯苯甲醛进行Hantzsch反应，得到式(V)的化合物；和
(b)在水和有机溶剂的混合物中用盐酸羟胺处理式(V)的化合物，
其中R1和R2独立地为氢、C1-4烷基或被卤素或烷氧基取代的C1-4烷基，Me为甲基，且Et为乙基。
2.权利要求1的方法，其中通过在有机溶剂中将式(II)的化合物、氨基巴豆酸酯和2-氯苯甲醛的0.9～1.2∶1∶1摩尔混合物回流而进行步骤(a)。
3.权利要求1的方法，其中基于式(V)的化合物的量，通过在15～25当量盐酸羟胺的存在下将式(V)的化合物回流而进行步骤(b)。
4.权利要求1的方法，其中基于式(V)的化合物的量，在10当量三乙胺的存在下进行步骤(b)。
5.用于权利要求1的方法的式(II)的吡咯衍生物：
其中R1和R2独立地为氢、C1-4烷基或被卤素或烷氧基取代的C1-4烷基，且Et为乙基。
6.权利要求2的方法，其中R1和R2为甲基。
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| KR10-2001-0012858A KR100374767B1 (ko) | 2001-03-13 | 2001-03-13 | 개선된 암로디핀의 제조 방법 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102659673A (zh) * | 2012-05-07 | 2012-09-12 | 山东新华制药股份有限公司 | 氨氯地平自由碱的制备方法 |
| CN103044316A (zh) * | 2013-01-23 | 2013-04-17 | 石家庄学院 | 一种以咪唑离子液体为催化剂制备1,4-二氢吡啶的方法 |
| CN115536577A (zh) * | 2022-11-09 | 2022-12-30 | 浙江昂利康制药股份有限公司 | 一种氨氯地平碱的制备方法 |
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| JP5678438B2 (ja) * | 2010-03-05 | 2015-03-04 | 国立大学法人名古屋大学 | ピロールの製造方法 |
| CN102070516A (zh) * | 2011-02-22 | 2011-05-25 | 广东东阳光药业有限公司 | 一种制备氨氯地平的方法 |
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| DK161312C (da) * | 1982-03-11 | 1991-12-09 | Pfizer | Analogifremgangsmaade til fremstilling af 2-aminoalkoxymethyl-4-phenyl-6-methyl-1,4-dihydropyridin-3,5-dicarboxylsyreestere eller syreadditionssalte deraf samt phthalimidoderivater til anvendelse som udgangsmateriale ved fremgangsmaaden |
| US4515799A (en) * | 1983-02-02 | 1985-05-07 | Pfizer Inc. | Dihydropyridine anti-ischaemic and antihypertensive agents |
| US5389654A (en) * | 1992-11-26 | 1995-02-14 | Lek, Tovarna, Farmacevtskih In Kemicnih . . . | 3-ethyl 5-methyl(±)2-[2-(N-tritylamino)ethoxymethyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-6-methyl-3,5-pyridinedicarboxylate |
| KR100217240B1 (ko) * | 1996-10-31 | 1999-09-01 | 조생현 | 암로디핀 베실레이트의 제조방법 |
| KR200151609Y1 (ko) * | 1996-11-30 | 1999-07-15 | 양재신 | 차량용 컴팩트 디스크 박스 |
| CN100485985C (zh) * | 1997-01-09 | 2009-05-06 | 日亚化学工业株式会社 | 氮化物半导体元器件 |
| HU221810B1 (hu) * | 1997-08-12 | 2003-01-28 | EGIS Gyógyszergyár Rt. | Eljárás amlodipin-bezilát előállítására és az eljárás intermedierjei |
| KR100374767B1 (ko) * | 2001-03-13 | 2003-03-03 | 한미약품공업 주식회사 | 개선된 암로디핀의 제조 방법 |
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| CN102659673A (zh) * | 2012-05-07 | 2012-09-12 | 山东新华制药股份有限公司 | 氨氯地平自由碱的制备方法 |
| CN103044316A (zh) * | 2013-01-23 | 2013-04-17 | 石家庄学院 | 一种以咪唑离子液体为催化剂制备1,4-二氢吡啶的方法 |
| CN115536577A (zh) * | 2022-11-09 | 2022-12-30 | 浙江昂利康制药股份有限公司 | 一种氨氯地平碱的制备方法 |
| CN115536577B (zh) * | 2022-11-09 | 2024-04-30 | 浙江昂利康制药股份有限公司 | 一种氨氯地平碱的制备方法 |
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| EP1368315A4 (en) | 2005-02-09 |
| US6492523B2 (en) | 2002-12-10 |
| EP1368315A1 (en) | 2003-12-10 |
| ES2291443T3 (es) | 2008-03-01 |
| KR20020072847A (ko) | 2002-09-19 |
| US20020132834A1 (en) | 2002-09-19 |
| CN1229348C (zh) | 2005-11-30 |
| DE60223003D1 (de) | 2007-11-29 |
| ATE375979T1 (de) | 2007-11-15 |
| KR100374767B1 (ko) | 2003-03-03 |
| EP1368315B1 (en) | 2007-10-17 |
| DE60223003T2 (de) | 2008-02-07 |
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