CN100393707C - 工业合成取代的噻吩甲酸酯中的中间体 - Google Patents
工业合成取代的噻吩甲酸酯中的中间体 Download PDFInfo
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- CN100393707C CN100393707C CNB2006100073351A CN200610007335A CN100393707C CN 100393707 C CN100393707 C CN 100393707C CN B2006100073351 A CNB2006100073351 A CN B2006100073351A CN 200610007335 A CN200610007335 A CN 200610007335A CN 100393707 C CN100393707 C CN 100393707C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/23—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and carboxyl groups, other than cyano groups, bound to the same unsaturated acyclic carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
工业合成式(I)化合物中所用到的中间体式(VII)化合物。
Description
本发明涉及一种工业合成5-氨基-3-羧甲基-4-氰基-2-噻吩甲酸的甲基二酯的方法和该化合物在工业生产阮内酸(ranelic acid)的二价盐及其水合物中的应用。
更具体地讲，本发明涉及一种工业合成式(I)化合物的新方法：
根据本发明方法得到的式(I)化合物可用于合成阮内酸、式(II)的其锶盐、钙盐或镁盐：
其中M代表锶、钙或镁，
以及所述盐的水合物。
阮内酸的二价盐具有非常有价值的药理学和治疗性能，尤其是显著的抗骨质疏松性能，使得这些化合物可用于治疗骨疾病。
阮内酸的二价盐，更尤其是阮内酸锶，其制备及其治疗用途已公开在欧洲专利说明书EP 0 415 850中。
该专利说明书描述了阮内酸锶由式(III)的乙基四酯开始的合成：
式(III)化合物本身可由式(IV)的乙基二酯开始而得到：
式(IV)中间体的合成已描述在出版物Bull.Soc.Chim.France 1975，pp1786-1792和出版物J.Chem.Tech.Biotechnol.1990，47，pp.39-46中，其通过使3-氧代戊二酸二乙酯、丙二腈和硫在乙醇中在吗啉或二乙基胺存在下相互反应得到。
该方法的优点在于使用容易得到的原料，并且实践简单；然而当应用于几百公斤的规模时，式(IV)化合物不能以大于70％的转化率得到。
考虑到阮内酸锶的药学价值和生产吨位，重要的是能以优异的纯度和至少77％的产率合成5-氨基-3-羧甲基-4-氰基-2-噻吩甲酸的二酯，并且这在工业规模上可再现。
申请人现在已开发出一种能使式(I)的甲基二酯以至少77％的产率和大于97％的纯度得到的有效工业合成方法。
由此得到的式(I)化合物尤其可用于合成阮内酸，其锶盐、钙盐或镁盐以及所述盐的水合物，更尤其是阮内酸锶及其水合物，其中使式(I)化合物与溴乙酸的酯反应，得到相应的四酯，然后将该四酯转化成阮内酸或其锶盐、钙盐或镁盐。
更具体地讲，本发明涉及一种工业合成式(I)化合物的方法，
该方法特征在于使式(V)的3-氧代戊二酸二甲酯：
与式(VI)的丙二腈：
在甲醇中，
在大于0.95mol/mol式(V)化合物的吗啉存在下反应，
得到式(VII)化合物：
然后使式(VII)化合物与大于0.95mol/mol式(V)化合物的硫反应；
然后将反应混合物加热回流；
以及通过在水存在下的沉淀和随后的过滤分离由此得到的式(I)化合物。
因此，通过使用这些非常具体的条件并尤其通过式(VII)化合物(需要的话，可分离出来)的中间体形成而改进的该方法允许式(I)化合物以优异的纯度和至少77％的产率得到，并且这在几百公斤的规模上可再现，由于阮内酸锶的大生产吨位，这大大增加了产量。
甲醇量优选为1-3ml/g式(V)化合物。
式(V)和(VI)化合物之间的反应的温度优选低于50℃。
加入硫后的回流反应时间优选为1小时30分钟到3小时。
式(I)的5-氨基-4-氰基-3-(2-甲氧基-2-氧代乙基)-2-噻吩甲酸甲酯和式(VII)中间体是可在化学或制药工业中，尤其在合成阮内酸锶中用作合成中间体的新化合物，并因而形成本发明的整体部分。
因此，本发明还涉及一种合成阮内酸，其锶盐、钙盐或镁盐以及所述盐的水合物的方法，其由式(I)化合物开始：
使式(I)化合物与溴乙酸的酯反应，得到相应的四酯，然后将该四酯转化成阮内酸或其锶盐、钙盐或镁盐，该方法的特征在于式(I)化合物通过本发明合成式(I)化合物的方法得到。本发明进而尤其涉及一种合成阮内酸锶及其水合物的方法，其由式(I)化合物开始：
使式(I)化合物与溴乙酸的酯反应，得到相应的四酯，然后将该四酯转化成阮内酸锶，该方法的特征在于式(I)化合物通过本发明合成式(I)化合物的方法得到。
下文中的实施例阐述本发明，但绝不限制本发明。
实施例1：5-氨基-4-氰基-3-(2-甲氧基-2-氧代乙基)-2-噻吩甲酸甲酯
向反应器中加入400kg 3-氧代戊二酸二甲酯、158kg丙二腈和560升甲醇，然后在将反应混合物的温度保持在40℃以下的同时加入199.6kg吗啉。
然后加入73.6kg硫，并随后将所得混合物回流。
在反应2小时后，停止回流，并加入水直到发生沉淀。滤除所得沉淀，洗涤并干燥。
由此得到5-氨基-4-氰基-3-(2-甲氧基-2-氧代乙基)-2-噻吩甲酸甲酯，产率为77％，化学纯度为98％。
实施例2：5-氨基-4-氰基-3-(2-甲氧基-2-氧代乙基)-2-噻吩甲酸甲酯
向反应器中加入400kg 3-氧代戊二酸二甲酯、158kg丙二腈和560升甲醇，然后在将反应混合物的温度保持在40℃以下的同时加入199.6kg吗啉。
在将所得混合物冷却后，通过过滤分离由此得到的式(VII)化合物或3-(二氰基亚甲基)-5-羟基-5-甲氧基-4-戊烯酸甲酯与吗啉的加成盐，然后使其与73.6kg硫在甲醇中反应。
然后将所得混合物回流。
在反应2小时后，停止回流，并加入水直到发生沉淀。滤除所得沉淀，洗涤并干燥。
Claims (1)
1.式(VII)化合物：
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0211764 | 2002-09-24 | ||
| FR0211764A FR2844796A1 (fr) | 2002-09-24 | 2002-09-24 | Nouveau procede de synthese industrielle du diester methylique de l'acide 5-amino-3-carboxymethyl-4-cyano-2- thiophenecarboxylique, et application a la synthese des sels bivalents de l'acide ranelique et de leurs hydrates |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB031348076A Division CN1280285C (zh) | 2002-09-24 | 2003-09-24 | 工业合成取代的噻吩甲酸酯的新方法和该化合物的应用 |
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| Publication Number | Publication Date |
|---|---|
| CN1817869A CN1817869A (zh) | 2006-08-16 |
| CN100393707C true CN100393707C (zh) | 2008-06-11 |
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| CNB031348076A Expired - Fee Related CN1280285C (zh) | 2002-09-24 | 2003-09-24 | 工业合成取代的噻吩甲酸酯的新方法和该化合物的应用 |
| CNB2006100073351A Expired - Fee Related CN100393707C (zh) | 2002-09-24 | 2003-09-24 | 工业合成取代的噻吩甲酸酯中的中间体 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB031348076A Expired - Fee Related CN1280285C (zh) | 2002-09-24 | 2003-09-24 | 工业合成取代的噻吩甲酸酯的新方法和该化合物的应用 |
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| Country | Link |
|---|---|
| US (3) | US7105683B2 (zh) |
| EP (1) | EP1403264B1 (zh) |
| JP (1) | JP4136865B2 (zh) |
| KR (1) | KR100551503B1 (zh) |
| CN (2) | CN1280285C (zh) |
| AP (1) | AP1942A (zh) |
| AR (1) | AR041356A1 (zh) |
| AT (1) | ATE286041T1 (zh) |
| AU (2) | AU2003282178A1 (zh) |
| BR (1) | BR0304194A (zh) |
| CA (1) | CA2442875C (zh) |
| DE (1) | DE60300252T2 (zh) |
| DK (1) | DK1403264T3 (zh) |
| EA (1) | EA007496B1 (zh) |
| EC (1) | ECSP055742A (zh) |
| ES (1) | ES2235144T3 (zh) |
| FR (1) | FR2844796A1 (zh) |
| GE (1) | GEP20074140B (zh) |
| HK (2) | HK1061845A1 (zh) |
| HR (1) | HRP20050360B1 (zh) |
| IL (1) | IL167314A (zh) |
| IS (1) | IS2136B (zh) |
| MA (1) | MA26101A1 (zh) |
| ME (1) | ME00451B (zh) |
| MX (1) | MXPA03008645A (zh) |
| MY (1) | MY131939A (zh) |
| NI (1) | NI200500065A (zh) |
| NO (1) | NO328697B1 (zh) |
| NZ (1) | NZ528400A (zh) |
| OA (1) | OA12933A (zh) |
| PL (1) | PL214414B1 (zh) |
| PT (1) | PT1403264E (zh) |
| RS (1) | RS50929B (zh) |
| SG (1) | SG110070A1 (zh) |
| SI (1) | SI1403264T1 (zh) |
| TN (1) | TNSN05089A1 (zh) |
| UA (1) | UA79991C2 (zh) |
| WO (1) | WO2004029035A1 (zh) |
| ZA (1) | ZA200307410B (zh) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2844795B1 (fr) * | 2002-09-24 | 2004-10-22 | Servier Lab | Nouveau procede de synthese industriel du ranelate de strontium et de ses hydrates |
| FR2844796A1 (fr) * | 2002-09-24 | 2004-03-26 | Servier Lab | Nouveau procede de synthese industrielle du diester methylique de l'acide 5-amino-3-carboxymethyl-4-cyano-2- thiophenecarboxylique, et application a la synthese des sels bivalents de l'acide ranelique et de leurs hydrates |
| EP1534305B9 (en) * | 2003-05-07 | 2007-03-07 | Osteologix A/S | Treating cartilage / bone conditions with water-soluble strontium salts |
| PT2266584E (pt) * | 2003-05-07 | 2012-12-19 | Osteologix As | Composição com estrôncio e vitamina d para a profilaxia/tratamento de patologias da cartilagem e/ou do osso |
| US20050085531A1 (en) * | 2003-10-03 | 2005-04-21 | Hodge Carl N. | Thiophene-based compounds exhibiting ATP-utilizing enzyme inhibitory activity, and compositions, and uses thereof |
| EP1732575B1 (en) * | 2004-02-26 | 2010-12-29 | Osteologix A/S | Strontium-containing compounds for use in the prevention or treatment of necrotic bone conditions |
| AU2005256317B2 (en) | 2004-06-25 | 2011-09-15 | Mokwalo Spf S.A. | Compositions comprising strontium and vitamin D and uses thereof |
| FR2875807B1 (fr) * | 2004-09-30 | 2006-11-17 | Servier Lab | Forme cristalline alpha du ranelate de strontium, son procede de preparation, et les compositions pharmaceutiques qui la contiennent |
| US20070292529A1 (en) * | 2006-06-19 | 2007-12-20 | Tabbiner Philip S | Strontium compositions and methods of treating osteoporotic conditions |
| CN101665483B (zh) * | 2008-09-01 | 2013-01-23 | 河北医科大学 | 一种雷尼酸锶中间体化合物ⅱ的合成方法 |
| WO2011110597A1 (de) | 2010-03-11 | 2011-09-15 | Azad Pharmaceutical Ingredients Ag | Verfahren zur herstellung von strontiumranelat |
| CN103319454B (zh) * | 2013-06-14 | 2014-06-18 | 广东众生药业股份有限公司 | 一种高纯度雷尼酸四乙酯及其中间体的制备方法 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5128367A (en) * | 1989-09-01 | 1992-07-07 | Adir Et Compagnie | Divalent metal salts of 2-[N-N-di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR415850A (fr) | 1909-07-22 | 1910-10-05 | Gustave Auguste Ferrie | Dispositif de mesure permettant de lire directement la valeur d'une grandeur fonction de deux variables |
| FR2844797B1 (fr) * | 2002-09-24 | 2004-10-22 | Servier Lab | Nouveau procede de synthese industriel des tetraesters de l'acide 5-[bis (carboxymethyl)]-3-carboxymethyl-4-cyano-2- thiophenecarboxylique, et application a la synthese des sels bivalents de l'acide ranelique et de leurs hydrates |
| FR2844796A1 (fr) * | 2002-09-24 | 2004-03-26 | Servier Lab | Nouveau procede de synthese industrielle du diester methylique de l'acide 5-amino-3-carboxymethyl-4-cyano-2- thiophenecarboxylique, et application a la synthese des sels bivalents de l'acide ranelique et de leurs hydrates |
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| US5128367A (en) * | 1989-09-01 | 1992-07-07 | Adir Et Compagnie | Divalent metal salts of 2-[N-N-di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid |
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| Synthesis of 2-azo-3-cyano-5-carbethoxythiophene derivatives and their application on polyester fibres. Ram W. Sabnis, et al.J. CHEM. TECH. BIOTECNOL.,Vol.47 . 1990 * |
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