CN1471507A - 用于制备加巴喷丁中间体的改进方法 - Google Patents
用于制备加巴喷丁中间体的改进方法 Download PDFInfo
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- CN1471507A CN1471507A CNA018181899A CN01818189A CN1471507A CN 1471507 A CN1471507 A CN 1471507A CN A018181899 A CNA018181899 A CN A018181899A CN 01818189 A CN01818189 A CN 01818189A CN 1471507 A CN1471507 A CN 1471507A
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- CN
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- Prior art keywords
- preparation
- ammonium hydroxide
- product according
- pimelinketone
- pentylidene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
- 238000000034 method Methods 0.000 title claims abstract description 31
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 title description 23
- 229960002870 gabapentin Drugs 0.000 title description 10
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000000908 ammonium hydroxide Substances 0.000 claims abstract description 11
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims abstract description 11
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000002576 ketones Chemical class 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- YCCUPJCDCSLDPB-UHFFFAOYSA-N CCCCC=C1CC(=O)NC(=O)C1 Chemical compound CCCCC=C1CC(=O)NC(=O)C1 YCCUPJCDCSLDPB-UHFFFAOYSA-N 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims 4
- RCCYSVYHULFYHE-UHFFFAOYSA-N pentanediamide Chemical compound NC(=O)CCCC(N)=O RCCYSVYHULFYHE-UHFFFAOYSA-N 0.000 claims 2
- -1 pentylidene glutaramide Chemical compound 0.000 claims 2
- 239000000243 solution Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 208000018152 Cerebral disease Diseases 0.000 description 1
- 208000006083 Hypokinesia Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000003483 hypokinetic effect Effects 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- ANGDWNBGPBMQHW-UHFFFAOYSA-N methyl cyanoacetate Chemical compound COC(=O)CC#N ANGDWNBGPBMQHW-UHFFFAOYSA-N 0.000 description 1
- 229940072228 neurontin Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 206010042772 syncope Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/20—Spiro-condensed ring systems
-
- 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
- C07D211/86—Oxygen atoms
- C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明涉及一种制备中间体化合物α，α’－二氰基β，β－亚戊基戊二酰亚胺的新方法。该方法包括使酮如环己酮与氰基乙酸乙酯在氢氧化铵存在下进行反应的步骤。
Description
相关申请的交叉参考
本申请根据35 U.S.C.119(e)要求2001年11月2日提交的美国临时申请号60/244891的优先权，其在此引入作为参考。
技术领域
本发明涉及一种在制备加巴喷丁(gabapentin)中用作中间体的化合物，及其制备方法。更具体地，本发明涉及α，α’-二氰基-β，β-亚戊基戊二酰亚胺，及制备α，α’-二氰基-β，β-亚戊基戊二酰亚胺的方法。
背景技术
加巴喷丁，1-(氨甲基)-1-环己烷乙酸，具有式I的化学结构：
加巴喷丁用于治疗大脑疾病，如癫痫、晕厥发作、运动功能减退和头盖创伤。Satzinger等人的美国专利4024175，其在此引入作为参考，公开了式(I)的加巴喷丁表现出温热性质，并且在某些情况下，表现出麻醉加强或镇静性质以及保护动物免受cardiozole痉挛的作用。加巴喷丁是Neurontin的活性成分，由Warner Lambert公司出售并由食品和药物管理局审定为抗癫痫、抗(疾病)发作、或抗惊厥药物。为此，需要制备纯的和稳定的加巴喷丁。
在一种制备加巴喷丁的方法中，一种中间体α，α’-二氰基-β，β-亚戊基戊二酰亚胺(式I)
通过Guareschi反应按如下方式生成。在溶于乙醇中的气态氨存在下，环己酮与氰基乙酸乙酯在无水环境下反应。该反应表示如下： 
Guareschi反应效率低，因为完成该反应需要至少48小时，更通常是在48-168小时之间。另外，目前的环境管理使得大规模地制备溶于乙醇中的气态NH3不切实际。
发明概述
本发明涉及一种通过使环己酮和氰基乙酸乙酯在氢氧化铵的存在下反应而制备α，α’-二氰基-β，β-亚戊基戊二酰亚胺(式I)的方法。本发明的方法能够在不到24小时的时间内基本上完成。本发明的反应能够在含水的环境中进行并且可以包括至少一种溶剂。该溶剂可以是甲醇、乙醇或任意的对反应无不利作用的类似溶剂。最重要的是，本发明的反应不需要在无水环境中进行。
发明详述
我们已经发现，与本领域的在先实践相反，Guareschi反应可以在水的存在下进行。因此，在α，α’-二氰基-β，β-亚戊基戊二酰亚胺的反应中，气态NH3可以被例如氢氧化铵的水溶液取代。这种水溶液很明显更容易操作，因为它们避免了许多由处理溶于乙醇中的气态NH3而引起的环境问题。
因此，在本发明的一个实施方案中，酮与氰基乙酸乙酯在氢氧化铵的存在下缩合。在本发明的另一个实施方案中，所述酮为环己酮。
本发明的反应在不到36-48小时的时间内基本上完成。在本发明的一个实施方案中，反应过程在24-36小时内基本上完成。在优选实施方案中，本发明的反应在不到24小时内基本上完成。
在本发明的一个实施方案中，氰基乙酸乙酯∶酮的摩尔比为1∶0.5-4∶2。在本发明的优选实施方案中，氰基乙酸乙酯∶环己酮的摩尔比为2∶1。
Guareschi反应中使用的有机溶剂可以是醇或另一种极性溶剂。在优选实施方案中，溶剂为甲醇和乙醇。另外，在Guareschi反应中，氰基乙酸酯，如氰基乙酸甲酯可用于代替氰基乙酸乙酯。
在如下的实施例中将进一步描述本发明的实施方案。
实施例1
在一个装有回流冷凝器、温度计和搅拌器的三颈圆底烧瓶中加入264.4克氰基乙酸乙酯和312克甲醇。搅拌的同时将溶液冷却到8℃。在8℃下加入2克乙酸铵和1当量环己酮。在1小时内加入60克浓度为25％的氢氧化铵溶液。在加入氢氧化铵的过程中，反应混合物的温度保持在8-11℃。将该溶液在8-11℃下再保持半小时。停止冷却并使得反应混合物的温度在45分钟内升高到25℃。将悬浮液在25℃下保持20小时。20小时后，将悬浮液稍微加热并加入50％的硫酸直到pH为2。在酸化过程中，温度保持在50-55℃。将反应物冷却到12℃，在12℃下将悬浮液搅拌半小时，然后过滤。用甲醇∶水(1∶1重量比)的混合物洗涤滤饼。然后用水洗涤混合物。
干燥后，得到163克α，α’-二氰基-β，β-亚戊基戊二酰亚胺(式I)，分析结果为94％，纯度99.9％。这表示收率为85％。
Claims (22)
1.一种制备式(I)化合物的方法，
包括使酮与氰基乙酸乙酯在氢氧化铵的存在下反应。
2.权利要求1的方法，其中酮为环己酮。
3.权利要求1的方法，其中反应在含水的环境中进行。
4.权利要求1的方法，还包括一种溶剂。
5.权利要求4的方法，其中溶剂为甲醇。
6.权利要求4的方法，其中溶剂为乙醇。
7.权利要求1的方法，其中反应在24小时内基本上完成。
8.权利要求1的方法，还包括加入水。
9.权利要求1的方法，其中氰基乙酸乙酯与环己酮的比例为1∶0.5-3∶2。
10.根据权利要求1的方法制备的产品。
11.一种制备式I化合物的方法，包括使环己酮与氰基乙酸乙酯在氢氧化铵的存在下反应。
12.根据权利要求11的方法制备的产品。
13.一种制备α，α’-二氰基-β，β-亚戊基戊二酰亚胺的方法，包括使环己酮与氰基乙酸乙酯在氢氧化铵的存在下反应。
14.根据权利要求13的方法制备的产品。
15.一种通过在水存在下进行Guareschi反应而形成亚戊基戊二酰胺的方法。
16.根据权利要求15的方法制备的产品。
17.一种通过在氢氧化铵存在下进行Guareschi反应而形成亚戊基戊二酰胺的方法。
18.根据权利要求17的方法制备的产品。
19.一种通过在水存在下进行Guareschi反应而形成戊二酰胺的方法。
20.根据权利要求19的方法制备的产品。
21.一种通过在氢氧化铵存在下进行Guareschi反应而形成戊二酰胺的方法。
22.根据权利要求21的方法制备的产品。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US24489100P | 2000-11-02 | 2000-11-02 | |
| US60/244,891 | 2000-11-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1471507A true CN1471507A (zh) | 2004-01-28 |
Family
ID=22924517
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA018181899A Pending CN1471507A (zh) | 2000-11-02 | 2001-10-26 | 用于制备加巴喷丁中间体的改进方法 |
Country Status (21)
| Country | Link |
|---|---|
| US (2) | US6613904B2 (zh) |
| EP (1) | EP1337506A4 (zh) |
| JP (1) | JP2004530637A (zh) |
| KR (1) | KR20030048105A (zh) |
| CN (1) | CN1471507A (zh) |
| AU (1) | AU2002213506A1 (zh) |
| CA (1) | CA2427237A1 (zh) |
| CZ (1) | CZ20031432A3 (zh) |
| DE (1) | DE01981893T1 (zh) |
| ES (1) | ES2209674T1 (zh) |
| HR (1) | HRP20030443A2 (zh) |
| HU (1) | HUP0303352A3 (zh) |
| IL (1) | IL155733A0 (zh) |
| IS (1) | IS6799A (zh) |
| MX (1) | MXPA03003899A (zh) |
| NO (1) | NO20031927D0 (zh) |
| PL (1) | PL365569A1 (zh) |
| SK (1) | SK6372003A3 (zh) |
| WO (1) | WO2002036545A1 (zh) |
| YU (1) | YU33303A (zh) |
| ZA (1) | ZA200303349B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007019752A1 (fr) * | 2005-08-19 | 2007-02-22 | Nhwa Pharma. Corporation | Procede de fabrication d'hydrochlorure de gabapentine |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050004219A1 (en) * | 2003-07-01 | 2005-01-06 | Medtronic, Inc. | Pump systems including injectable gabapentin compositions |
| US20050090549A1 (en) * | 2003-10-23 | 2005-04-28 | Medtronic, Inc. | Intrathecal gabapentin for treatment of pain |
| US20050090548A1 (en) * | 2003-10-23 | 2005-04-28 | Medtronic, Inc. | Intrathecal gabapentin for treatment of epilepsy |
| US20050187295A1 (en) * | 2004-02-19 | 2005-08-25 | Surendra Kalyan | Processes for the preparation of gabapentin |
| ITMI20040501A1 (it) * | 2004-03-17 | 2004-06-17 | Caffaro Spa Ind Chim | Procedimento per la preparazione della monoaamide dell'acrido ciclosendiacetico |
| ITMI20041271A1 (it) * | 2004-06-24 | 2004-09-24 | Zambon Spa | Processo di preparazione di gabapentina |
| US8495974B2 (en) * | 2009-05-18 | 2013-07-30 | Vito Agosta | Fuel system and method for burning liquid ammonia in engines and boilers |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1142168B (de) * | 1959-07-01 | 1963-01-10 | Warner Lambert Pharmaceutical | Verfahren zur Herstellung von ª‰,ª‰-Penta-methylenbutyrolacton bzw. Salzen der 3, 3-Pentamethylen-4-hydroxybuttersaeure |
| 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 |
| DE3928182A1 (de) | 1989-08-25 | 1991-02-28 | Goedecke Ag | Verfahren zur herstellung von gabapentin |
| NZ331143A (en) | 1996-03-14 | 2001-06-29 | Warner Lambert Co | Substituted cyclic amino acids as pharmaceutical agents |
-
2001
- 2001-10-26 HU HU0303352A patent/HUP0303352A3/hu unknown
- 2001-10-26 EP EP01981893A patent/EP1337506A4/en not_active Withdrawn
- 2001-10-26 YU YU33303A patent/YU33303A/sh unknown
- 2001-10-26 AU AU2002213506A patent/AU2002213506A1/en not_active Abandoned
- 2001-10-26 KR KR10-2003-7006056A patent/KR20030048105A/ko not_active Application Discontinuation
- 2001-10-26 MX MXPA03003899A patent/MXPA03003899A/es active IP Right Grant
- 2001-10-26 JP JP2002539305A patent/JP2004530637A/ja not_active Withdrawn
- 2001-10-26 CA CA002427237A patent/CA2427237A1/en not_active Abandoned
- 2001-10-26 CZ CZ20031432A patent/CZ20031432A3/cs unknown
- 2001-10-26 PL PL01365569A patent/PL365569A1/xx not_active Application Discontinuation
- 2001-10-26 SK SK637-2003A patent/SK6372003A3/sk unknown
- 2001-10-26 DE DE0001337506T patent/DE01981893T1/de active Pending
- 2001-10-26 IL IL15573301A patent/IL155733A0/xx unknown
- 2001-10-26 ES ES01981893T patent/ES2209674T1/es active Pending
- 2001-10-26 WO PCT/US2001/042783 patent/WO2002036545A1/en not_active Application Discontinuation
- 2001-10-26 CN CNA018181899A patent/CN1471507A/zh active Pending
- 2001-10-26 US US09/984,058 patent/US6613904B2/en not_active Expired - Fee Related
-
2003
- 2003-04-29 NO NO20031927A patent/NO20031927D0/no not_active Application Discontinuation
- 2003-04-30 ZA ZA200303349A patent/ZA200303349B/en unknown
- 2003-04-30 IS IS6799A patent/IS6799A/is unknown
- 2003-06-02 HR HR20030443A patent/HRP20030443A2/hr not_active Application Discontinuation
- 2003-06-06 US US10/455,314 patent/US6881843B2/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007019752A1 (fr) * | 2005-08-19 | 2007-02-22 | Nhwa Pharma. Corporation | Procede de fabrication d'hydrochlorure de gabapentine |
| US7667071B2 (en) | 2005-08-19 | 2010-02-23 | Nhwa Pharma Corporation | Process for the preparation of gabapentin hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1337506A1 (en) | 2003-08-27 |
| CA2427237A1 (en) | 2002-05-10 |
| SK6372003A3 (en) | 2003-12-02 |
| MXPA03003899A (es) | 2005-02-17 |
| DE01981893T1 (de) | 2004-05-19 |
| US20030195358A1 (en) | 2003-10-16 |
| US6881843B2 (en) | 2005-04-19 |
| HUP0303352A3 (en) | 2005-04-28 |
| CZ20031432A3 (cs) | 2003-12-17 |
| YU33303A (sh) | 2006-05-25 |
| ES2209674T1 (es) | 2004-07-01 |
| PL365569A1 (en) | 2005-01-10 |
| KR20030048105A (ko) | 2003-06-18 |
| US20020107395A1 (en) | 2002-08-08 |
| AU2002213506A1 (en) | 2002-05-15 |
| IS6799A (is) | 2003-04-30 |
| JP2004530637A (ja) | 2004-10-07 |
| EP1337506A4 (en) | 2005-05-04 |
| NO20031927L (no) | 2003-04-29 |
| NO20031927D0 (no) | 2003-04-29 |
| IL155733A0 (en) | 2003-11-23 |
| HUP0303352A2 (hu) | 2004-01-28 |
| US6613904B2 (en) | 2003-09-02 |
| WO2002036545A1 (en) | 2002-05-10 |
| HRP20030443A2 (en) | 2005-04-30 |
| ZA200303349B (en) | 2005-06-09 |
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