CN1325378A - 1-(氨甲基)环己基乙酸的合成方法 - Google Patents
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- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
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- C07C205/51—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
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Abstract
本发明涉及一种新的合成方法,它经由通式(Ⅱ)的新的中间体1-(硝基甲基)环己基乙酸衍生物,来合成通式(Ⅰ)的1-(氨甲基)环己基乙酸,其中R为氢原子、苄基、二苯基甲基或C1-C4烷基或它们的烷氧基芳香环取代的衍生物。
Description
通式(Ⅰ)的1-(氨甲基)环己基乙酸,或者称为加巴喷丁,是GABA(γ-氨基丁酸)拮抗药物的活性组分。文献中已有多种合成这种化合物的方法。
在多数已知的方法中,一种中间体在酸中水解,从形成的加巴喷丁盐酸盐通过离子交换树脂得到加巴喷丁。德国专利No.DE 2460891对这种方法进行了描述,其中1,1-环己基二乙酸酐转化为羟肟酸,而羟肟酸经过洛森降解反应转变为产物的盐酸盐。美国专利No.US 4024175描述了一种方法,而同样的1,1-环己基二乙酸酐用作起始原料。酸酐首先转化为单甲酯单盐,然后从该单甲酯单盐中得到单酸单叠氮化物。从这种叠氮化物经库尔提斯降解反应制备获得加巴喷丁盐酸盐。
同样地,加巴喷丁盐酸盐可用欧洲专利No.EP 414274中描述的方法制得。根据该发明,1-(硝基甲基)乙酸的烷基酯通过催化加氢反应转化为2-氮杂-螺[4,5]癸烷-3-酮衍生物。加巴喷丁盐酸盐可以通过2-氮杂-螺旋[4,5]癸烷-3-酮衍生物的内酰胺衍生物在盐酸中回流制得,加巴喷丁通过离子交换树脂来分离得到。
上面提到的制备方法中的一些不足之处如下。加巴喷丁是以它的盐酸盐形式获得的,而加巴喷丁本身只能通过费力和昂贵的离子交换方法来分离。为避免不需要的内酰胺的形成,副反应也需要耗费人力和昂贵的技术。这些方法更严重的不足在于它们使用有毒的试剂,例如,氰化钾、叠氮化钠和昂贵的耐压装置。
欧洲专利No.EP 414275描述的方法避免了内酰胺化合物和加巴喷丁盐酸盐的生成,这样也就避免了昂贵的离子交换方法的应用。根据该方法,氰基-环己烷-马来酸衍生物与碱一起水解,脱去羧基,最后氰基催化加氢。另一方面,该专利没有描述氰基-环己烷-马来酸衍生物的合成,该合成方法是一种多步骤繁琐的方法。重要的是从环己酮开始合成马来酸酯需要4步反应,这样加巴喷丁的合成总共需要7步反应。和其它描述加巴喷丁合成的专利相比,例如EP 414274,该专利也没有提到获得加巴喷丁的纯化方法。
本发明的目的是建立一种经济的、工业上可用于合成加巴喷丁的方法,它避免了上面提到方法的缺点,使得用很少几步和很高产率的简单合成方法合成非常纯的结构式(Ⅰ)的最终产物成为可能。
本发明的加巴喷丁的合成方法如下所述:
a)通式(Ⅵ)的环亚己基-乙酸烷基酯,其中R2为C1-C4烷基,在碱存在下与硝基甲烷转化为通式(Ⅴ)的1-(硝基甲基)环己基乙酸的烷基酯,其中R2如上面定义。后者在氢氧化钾的含水甲醇溶液中水解,得到通式(Ⅱa)的1-(硝基甲基)环己基乙酸在催化剂存在下在一种溶剂中加氢生成结构式(Ⅰ)的预期产物,或
b)通式(Ⅵ)的环亚己基乙酸烷基酯,其中R2如上面定义,在氢氧化钾的含水甲醇溶液中水解,得到的结构式(Ⅳ)的环亚己基乙酸和通式R1-X试剂反应,其中R1代表苄基、二苯基甲基或在给定条件下为C1-C4烷基或它们的烷氧基芳香环取代的衍生物得到通式(Ⅲ)的合适的环亚己酸衍生物,其中R1如上面定义。该中间体与硝基甲烷一起转化为通式(Ⅱb)的1-(硝基甲基)环己基乙酸衍生物,其中R1如上面定义。后者在催化剂存在下在溶剂中进行加氢反应。
本发明的方法如流程1说明。
本发明基于这样的观察结果,即通式(Ⅱ)的新化合物在常压下还原直接产生纯的预期的最终产物。
令人惊奇地发现,通式(Ⅱ)的化合物在还原步骤中作为起始化合物,不形成内酰胺化合物,但可以直接得到非常纯的加巴喷丁。这在已知的合成技术中是无法预料的,因为这种类型的化合物形成内酰胺的能力在文献中是已知的(如EP 414274)。
用作起始化合物的通式(Ⅵ)的环亚己基乙酸烷基酯可以根据文献通过环己酮和合适的二乙基膦酰乙酸酯的反应制备。
在最后的加氢步骤中,可以使用任何在加氢反应中通常应用的催化剂,稀有金属催化剂,如铑或钯,阮内镍或钴催化剂,在给定条件下在载体上,如碳,优选活性炭上的钯,更优选为待还原化合物的10%。
加氢反应在惰性有机溶剂中进行,优选地在C1-C4醇中进行,特别优选地在甲醇中,在10-50℃,1-20千巴压力下,优选地在室温和常压下。
环亚己基乙酸酯和硝基甲烷的迈克尔加成反应在碱存在下进行,优选地在氢氧化钾存在下进行。
烷基酯基团的水解用碱进行,优选地在室温下在氢氧化钾的含水甲醇溶液中进行,然后酸在10%磷酸二氢钾水溶液中释放出来。
过滤除掉催化剂后,产物通过滤液浓缩来离析。得到的产品的浓度为98-99%,产率为50-70%。
该合成方法的优点如下:
——获得的产品非常纯;
——反应步骤比已知方法少;
——不形成非常难被除去的内酰胺化合物;
——既不需特殊的耐压装置也不需昂贵的催化剂;
——不需要使用困难的和复杂的离子交换技术得到最终产物;
——不需要有毒的或危险的物质。
实施例
实施例1
a)1-(硝基甲基)环己基乙酸的合成
4.3克(0.02摩尔)的1-(硝基甲基)环己基乙酸甲酯的溶液,在50毫升甲醇和20毫升10%氢氧化钾水溶液的混合物中,于室温下搅拌24小时,然后甲醇在真空下蒸馏除去。得到的水溶液的pH值用10%磷酸二氢钾水溶液调到7。该溶液用30毫升乙酸乙酯萃取3次,合并有机层,用硫酸钠干燥,浓缩得到3.2克(80%)油状标题化合物。
b)1-(氨甲基)环己基乙酸的合成
2.01克(0.01摩尔)的1-(氨甲基)环己基乙酸,在50毫升甲醇中在0.2克活性炭上的钯存在下于常压下进行加氢反应。过滤除去催化剂,滤液浓缩到10毫升。20毫升四氢呋喃加到残留物中,沉淀的晶体过滤、干燥得到1.3克(80%)的标题化合物。熔点(Mp):164-169℃。
实施例2
1-(氨甲基)环己基乙酸的合成
5克(0.017摩尔)的1-(硝基甲基)环己基乙酸苄酯的50毫升甲醇溶液,加到0.5克10%预加氢的钯活性炭的50毫升甲醇的混合物中。该混合物在室温常压下加氢反应直到消耗掉计算量的氢,然后过滤掉催化剂,滤液浓缩到大约15毫升,加入30毫升四氢呋喃,沉淀出标题化合物。产量:1.5克(51%)。熔点(Mp):168℃。
Claims (9)
1.1-(氨甲基)环己基乙酸及其药学可接受的盐的合成方法,其特征在于:
a)通式(Ⅵ)的环亚己基乙酸烷基酯,其中R2为C1-C4烷基,在碱存在下与硝基甲烷一起转化为通式(Ⅴ)的1-(硝基甲基)环己基乙酸烷基酯,其中R2如上面定义,所得的通式(Ⅴ)的化合物在氢氧化钾的含水甲醇溶液中水解,得到通式(Ⅱa)的1-(硝基甲基)环己基乙酸在催化剂存在下进行加氢反应,在给定条件下,得到的化合物转化为药理学可接受的盐,或
b)通式(Ⅵ)的环亚己基乙酸烷基酯,其中R2为C1-C4烷基,在氢氧化钾的含水甲醇溶液中水解,得到的通式(Ⅳ)的环亚己基乙酸和结构式R1-Ⅹ的试剂反应,其中R1代表苄基、二苯基甲基或在给定条件下为C1-C4烷基或它们的烷氧基芳香环取代的衍生物,Ⅹ为卤原子,给出通式(Ⅲ)的中间体环亚己酸衍生物,其中R1如上面定义,该中间体转化为通式(Ⅱb)的1-(硝基甲基)环己基乙酸衍生物,其中R1如上面定义,后者在催化剂存在下在溶剂中进行加氢反应,在给定条件下,得到的化合物转化为药理学可接受的盐。
2.权利要求1的方法,其中b)的特征在于用苄基卤化物作为结构式R1-Ⅹ的试剂。
3.权利要求1的方法,其中b)的特征在于用二苯基甲基卤化物作为结构式R1-Ⅹ的试剂。
4.权利要求1-3的任一方法,其特征在于加氢反应在惰性有机溶剂中进行。
5.权利要求1-3的任一方法,其特征在于用活性炭上的钯作催化剂。
6.结构式(Ⅱ)的新化合物,其中R代表氢、苄基、二苯基甲基或在给定情况下为C1-C4烷基或它们的烷氧基芳香环取代的衍生物。
7.1-(硝基甲基)环己基-乙酸。
8.1-(硝基甲基)环己基-乙酸苄基酯。
9.1-(硝基甲基)环己基-乙酸二苯基甲基酯。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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HU9803034A HU225502B1 (en) | 1998-12-29 | 1998-12-29 | Process for producing 1-(amino-metyl)-cyclohexene-acetic-acid and intermediates |
HUP9803034 | 1998-12-29 |
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CN1325378A true CN1325378A (zh) | 2001-12-05 |
CN1221525C CN1221525C (zh) | 2005-10-05 |
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CNB998129593A Expired - Fee Related CN1221525C (zh) | 1998-12-29 | 1999-12-23 | 1-(氨甲基)环己基乙酸的合成方法 |
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US (1) | US6765114B1 (zh) |
JP (1) | JP2002533431A (zh) |
CN (1) | CN1221525C (zh) |
AT (1) | ATE250569T1 (zh) |
AU (1) | AU1996300A (zh) |
BG (1) | BG65056B1 (zh) |
CA (1) | CA2349826C (zh) |
CZ (1) | CZ301922B6 (zh) |
DE (1) | DE69911646T2 (zh) |
DK (1) | DK1140793T3 (zh) |
EA (1) | EA003555B1 (zh) |
EE (1) | EE04587B1 (zh) |
ES (1) | ES2207979T3 (zh) |
HU (1) | HU225502B1 (zh) |
PL (1) | PL196854B1 (zh) |
SK (1) | SK287019B6 (zh) |
UA (1) | UA73108C2 (zh) |
WO (1) | WO2000039074A1 (zh) |
Cited By (1)
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CN104974037A (zh) * | 2014-04-13 | 2015-10-14 | 江苏康缘药业股份有限公司 | 一种含羧基多羰基姜黄素衍生物及其制备方法和应用 |
Families Citing this family (3)
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HUP0301919A3 (en) * | 2000-06-16 | 2006-01-30 | Teva Pharma | Stable gabapentin having ph within a controlled range |
EP2038249B1 (en) * | 2006-06-30 | 2013-09-11 | ZaCh System S.p.A. | Process for preparing gabapentin |
US20110190393A1 (en) * | 2008-06-03 | 2011-08-04 | Generics (Uk) Limited | Novel and efficient method for the synthesis of an amino acid |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3253039A (en) * | 1962-02-05 | 1966-05-24 | Engelhard Ind Inc | Catalytic hydrogenation of organic nitrocompounds |
US3594419A (en) * | 1968-04-15 | 1971-07-20 | Gulf Research Development Co | Process for converting nitroparaffins to amines |
US3766271A (en) * | 1971-03-04 | 1973-10-16 | Texaco Inc | Homogeneous catalysts useful in the reduction of nitroparaffins to amines |
DE2460891C2 (de) * | 1974-12-21 | 1982-09-23 | Gödecke AG, 1000 Berlin | 1-Aminomethyl-1-cycloalkanessigsäuren und deren Ester, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel |
US4894476A (en) * | 1988-05-02 | 1990-01-16 | Warner-Lambert Company | Gabapentin monohydrate and a process for producing the same |
DE3928183A1 (de) * | 1989-08-25 | 1991-02-28 | Goedecke Ag | Lactamfreie cyclische aminosaeuren |
DE3928182A1 (de) * | 1989-08-25 | 1991-02-28 | Goedecke Ag | Verfahren zur herstellung von gabapentin |
FI905584A (fi) | 1989-11-16 | 1991-05-17 | Lonza Ag | Foerfarande foer framstaellning av 1-(aminometyl)cyklohexanaettikssyra. |
BR9813284B1 (pt) | 1997-10-27 | 2012-08-21 | aminoácidos cìclicos e derivados dos mesmos úteis como agentes farmacêuticos e composição farmacêutica. |
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1998
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- 1999-12-23 WO PCT/HU1999/000102 patent/WO2000039074A1/en active IP Right Grant
- 1999-12-23 SK SK937-2001A patent/SK287019B6/sk not_active IP Right Cessation
- 1999-12-23 CN CNB998129593A patent/CN1221525C/zh not_active Expired - Fee Related
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN104974037A (zh) * | 2014-04-13 | 2015-10-14 | 江苏康缘药业股份有限公司 | 一种含羧基多羰基姜黄素衍生物及其制备方法和应用 |
CN104974037B (zh) * | 2014-04-13 | 2019-04-30 | 江苏康缘药业股份有限公司 | 一种含羧基多羰基姜黄素衍生物及其制备方法和应用 |
Also Published As
Publication number | Publication date |
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EE04587B1 (et) | 2006-02-15 |
CA2349826C (en) | 2009-05-12 |
BG65056B1 (bg) | 2007-01-31 |
HU9803034D0 (en) | 1999-02-01 |
SK9372001A3 (en) | 2002-01-07 |
CZ301922B6 (cs) | 2010-07-28 |
DE69911646D1 (de) | 2003-10-30 |
UA73108C2 (en) | 2005-06-15 |
ATE250569T1 (de) | 2003-10-15 |
DE69911646T2 (de) | 2004-07-08 |
AU1996300A (en) | 2000-07-31 |
EA200100723A1 (ru) | 2001-12-24 |
EE200100295A (et) | 2002-12-16 |
PL348461A1 (en) | 2002-05-20 |
CN1221525C (zh) | 2005-10-05 |
WO2000039074A1 (en) | 2000-07-06 |
ES2207979T3 (es) | 2004-06-01 |
BG105491A (en) | 2001-12-29 |
EA003555B1 (ru) | 2003-06-26 |
HUP9803034A2 (hu) | 2001-02-28 |
CA2349826A1 (en) | 2000-07-06 |
JP2002533431A (ja) | 2002-10-08 |
CZ20012070A3 (cs) | 2001-09-12 |
DK1140793T3 (da) | 2004-02-02 |
HU225502B1 (en) | 2007-01-29 |
SK287019B6 (sk) | 2009-09-07 |
PL196854B1 (pl) | 2008-02-29 |
US6765114B1 (en) | 2004-07-20 |
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