CN100348585C - 1,3,4,5－四氢－2h－3－苯并氮杂䓬－2－酮化合物的合成方法及其应用 - Google Patents
1,3,4,5－四氢－2h－3－苯并氮杂䓬－2－酮化合物的合成方法及其应用 Download PDFInfo
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- ACRHBAYQBXXRTO-OAQYLSRUSA-N ivabradine Chemical compound C1CC2=CC(OC)=C(OC)C=C2CC(=O)N1CCCN(C)C[C@H]1CC2=C1C=C(OC)C(OC)=C2 ACRHBAYQBXXRTO-OAQYLSRUSA-N 0.000 title claims abstract description 13
- 150000003839 salts Chemical class 0.000 title claims abstract description 10
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- GYIYVTGAOWHWRI-UHFFFAOYSA-N 1,2,3,5-tetrahydro-3-benzazepin-4-one Chemical class C1CNC(=O)CC2=CC=CC=C21 GYIYVTGAOWHWRI-UHFFFAOYSA-N 0.000 title 1
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- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims abstract description 9
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- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 9
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- NTVCIOGUJHBVBO-UHFFFAOYSA-N 4,5-dihydro-3h-dioxepine Chemical compound C1COOC=CC1 NTVCIOGUJHBVBO-UHFFFAOYSA-N 0.000 claims description 15
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
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- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
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- 229910052759 nickel Inorganic materials 0.000 description 1
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- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Abstract
本发明涉及合成式(I)化合物的方法以及在合成伊伐布雷定及其可药用酸加成盐和水合物中的应用，其中R<sub>1</sub>和R<sub>2</sub>可以相同或不同，各自代表直链或支链的(C<sub>1</sub>-C<sub>8</sub>)烷氧基或者和连接它们的碳原子一起形成1，3-二噁烷、1，3-二氧杂环戊烷或1，3-二氧杂环庚烷。
Description
技术领域
本发明涉及一种合成1，3，4，5-四氢-2H-3-苯并氮杂-2-酮化合物的方法及其在合成伊伐布雷定(ivabradine)和其可药用酸加成盐中的应用。
更具体地说，本发明涉及一种合成式(I)化合物的方法：
其中R1和R2可以相同或不同，各自代表直链或支链的(C1-C8)烷氧基或者和连接它们的碳原子一起形成1，3-二烷、1，3-二氧杂环戊烷或1，3-二氧杂环庚烷。
根据本发明获得的式(I)化合物可用于合成式(II)的伊伐布雷定：
或3-{3-[{[(7S)-3，4-二甲氧基二环[4.2.0]辛-1，3，5-三烯-7-基]甲基}(甲基)氨基]-丙基}-7，8-二甲氧基-1，3，4，5-四氢-2H-3-苯并氮杂-2-酮，以及它们的可药用酸加成盐和水合物。
背景技术
伊伐布雷定和其可药用酸加成盐，尤其是其盐酸盐，具有非常重要的药理学和治疗学性质，尤其是具有减慢心律的性质，从而可使这些化合物用于治疗或预防各种临床上的心肌局部缺血情况，例如心绞痛，心肌梗塞和相关节律紊乱，也包括涉及节律紊乱的各种病理学，尤其是室上性节律紊乱。
伊伐布雷定及其可药用酸加成盐(尤其是其盐酸盐)的制备和治疗用途，已描述在欧洲专利EP0534859的说明书中。
在上述专利说明书中描述了伊伐布雷定盐酸盐的合成，其中，通过将式(III)化合物
和式(IV)化合物反应
得到化合物(V)：
进而催化氢化得到伊伐布雷定，然后再转化为其盐酸盐。
上述方法的缺点是这3个步骤整体上得到的伊伐布雷定盐酸盐的总产率非常低，不到17％。
上述低产率部分是由于式(V)化合物的1，3-二氢-2H-3-苯并氮杂-2-酮官能团转变成相应的1，3，4，5-四氢-2H-3-苯并氮杂-2-酮的催化氢化步骤中的产率不高所致。
在所用的条件下(在室温下，在冰醋酸中使用10％氢氧化钯催化氢化)，该步还原反应的产率实际上仅为40％。
由于伊伐布雷定及其盐的药学价值，通过有效的工业方法、特别是以良好的产率获得式(I)的1，3，4，5-四氢-2H-3-苯并氮杂-2-酮是势在必行的。
考虑到描述在EP0534859中的还原1，3-二氢-2H-3-苯并氮杂-2-酮官能团的产率不高，因此似乎上述催化氢化的方法是不能符合要求的。
发明内容
本申请人惊奇地发现，选择特定的反应条件，尤其是溶剂，通过催化氢化相应的1，3-二氢-2H-3-苯并氮杂-2-酮能够以非常高的收率获得式(I)的1，3，4，5-四氢-2H-3-苯并氮杂-2-酮化合物。
更具体地说，本发明涉及一种合成式(I)化合物的方法，
其中R1和R2可以相同或不同，各自代表直链或直链的(C1-C8)烷氧基或者和连接它们的碳原子一起形成1，3-二烷、1，3-二氧杂环戊烷或1，3-二氧杂环庚烷，该方法的特征在于将式(VI)的化合物：
其中R1和R2的定义如前，
在非酸性溶剂中进行催化氢化反应，然后过滤反应混合物得到式(I)的化合物。
对于可用于本发明方法中并且优选的非酸性溶剂，其中可非限制性地提到乙酸酯类，醇类，优选乙醇、甲醇或异丙醇，四氢呋喃，甲苯，二氯甲烷和二甲苯。
对于可用于本发明方法中的催化剂，其中可非限制性地提到钯、铂、镍、铷、铑，以及它们的化合物，尤其是以附载形式或氧化形式。优选的催化剂是钯碳。
氢化反应的温度优选从20至100℃，尤其优选从40至80℃，更优选的是从45至65℃。
在式(VI)化合物的氢化反应过程中，氢气压力优选从1至220巴，尤其优选从1至100巴，更优选从1至30巴。
根据本发明的方法，所用的式(VI)化合物优选式(VIa)化合物，这是其中R1和R2与连接它们的碳原子一起形成1，3-二烷、1，3-二氧杂环戊烷或1，3-二氧杂环庚烷的式(VI)化合物的一种具体形式。
式(I)化合物是一种新的产品，其在化学或制药工业上能作为有用的合成中间体，尤其是在合成伊伐布雷定和其可药用酸加成盐方面，所有这些形成了本发明的整体部分。
例如，式(I)的二缩醛经过脱保护得到式(VII)的醛：
将式(VII)化合物和(7S)-3，4-二甲氧基二环[4.2.0]辛-1，3，5-三烯-7-基]-N-甲基甲胺在还原胺化条件下反应得到伊伐布雷定。
优选的式(I)化合物是其中R1和R2与连接它们的碳原子一起形成1，3-二烷、1，3-二氧杂环戊烷或1，3-二氧杂环庚烷的化合物。
具体实施方式
下面以实施例的形式来描述本发明。
实施例：3-[2-(1，3-二氧杂环戊烷-2-基)-乙基]-7，8-二甲氧基-1，3，4，5-四氢-2H-3-苯并氮杂-2-酮
将100g 3-[2-(1，3-二氧杂环戊烷-2基)-乙基]-7，8-二甲氧基-1，3，-二氢-2H-3-苯并氮杂-2-酮、500ml异丙醇和10g Pd/C放进氢化器中。通入氮气清洗，然后通入氢气，加热到60℃，然后在该温度下在1巴的压力下氢化4小时。
在60℃过滤该反应混合物以除去催化剂。用2×50ml的异丙醇冲洗。冷却到50℃并加入200ml叔丁基甲基醚(MTBE)。然后冷却至20℃，接着在5℃下冷藏1小时。滤出在5℃下获得的结晶。干燥至恒重。所得目标产物的产率为88％，化学纯度超过98％。
Claims (11)
1、合成式(I)化合物的方法：
其中R1和R2可以相同或不同，各自代表直链或支链的(C1-C8)烷氧基或者和连接它们的碳原子一起形成1，3-二烷、1，3-二氧杂环戊烷或1，3-二氧杂环庚烷，
其中，使式(VI)化合物：
其中R1和R2的定义同上，
在非酸性溶剂中进行催化氢化反应，然后过滤反应混合物得到式(I)化合物。
2、根据权利要求1的合成方法，其中用于式(VI)化合物氢化反应的催化剂是钯-碳。
3、根据权利要求1或权利要求2的合成方法，其中在式(VI)化合物的氢化反应过程中，氢气压力为1至220巴。
4、根据权利要求1或2任一项的合成方法，其中式(VI)化合物的氢化反应在醇溶剂中进行。
5、根据权利要求4的合成方法，其中醇溶剂是乙醇、甲醇或异丙醇。
6、根据权利要求1或2任一项的合成方法，其中温度为20至100℃。
7、根据权利要求6的合成方法，其中温度为40至80℃。
8、根据权利要求1或2任一项的合成方法，其中使用式(VIa)化合物作为起始原料，所述化合物是其中R1和R2与连接它们的碳原子一起形成1，3-二烷、1，3-二氧杂环戊烷或1，3-二氧杂环庚烷的式(VI)化合物的一种具体形式。
9、式(I)化合物：
其中R1和R2可以相同或不同，各自代表直链或支链的(C1-C8)烷氧基或者和连接它们的碳原子一起形成1，3-二烷、1，3-二氧杂环戊烷或1，3-二氧杂环庚烷。
10、根据权利要求9的式(I)化合物，其中R1和R2与连接它们的碳原子一起形成1，3-二烷、1，3-二氧杂环戊烷或1，3-二氧杂环庚烷。
11、合成伊伐布雷定、其药学上可接受的盐或其水合物的方法，其中按照权利要求1的方法将式(VI)化合物转变成式(I)的中间体化合物，然后将式(I)的中间体化合物转变成伊伐布雷定、其药学上可接受的盐或其水合物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0403828A FR2868775B1 (fr) | 2004-04-13 | 2004-04-13 | Nouveau procede de synthese de derives de la 1,3,4,5- tetrahydro-2h-3-benzazepin-2-one, et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
| FR0403828 | 2004-04-13 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1683343A CN1683343A (zh) | 2005-10-19 |
| CN100348585C true CN100348585C (zh) | 2007-11-14 |
Family
ID=34941961
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2005100542167A Active CN100348585C (zh) | 2004-04-13 | 2005-02-18 | 1,3,4,5－四氢－2h－3－苯并氮杂䓬－2－酮化合物的合成方法及其应用 |
Country Status (33)
| Country | Link |
|---|---|
| US (1) | US7064200B2 (zh) |
| EP (1) | EP1614687B1 (zh) |
| JP (2) | JP4515933B2 (zh) |
| KR (1) | KR100636499B1 (zh) |
| CN (1) | CN100348585C (zh) |
| AR (1) | AR047707A1 (zh) |
| AT (1) | ATE448221T1 (zh) |
| AU (1) | AU2005200884B2 (zh) |
| BR (1) | BRPI0500590B8 (zh) |
| CA (1) | CA2496712C (zh) |
| CY (1) | CY1109740T1 (zh) |
| DE (1) | DE602005017541D1 (zh) |
| DK (1) | DK1614687T3 (zh) |
| EA (1) | EA007743B1 (zh) |
| EG (1) | EG25619A (zh) |
| ES (1) | ES2336461T3 (zh) |
| FR (1) | FR2868775B1 (zh) |
| GE (1) | GEP20074136B (zh) |
| HK (1) | HK1079777A1 (zh) |
| HR (1) | HRP20100024T1 (zh) |
| MA (1) | MA27598A1 (zh) |
| MX (1) | MXPA05003696A (zh) |
| MY (1) | MY140904A (zh) |
| NO (1) | NO329861B1 (zh) |
| NZ (1) | NZ538328A (zh) |
| PL (1) | PL1614687T3 (zh) |
| PT (1) | PT1614687E (zh) |
| RS (1) | RS51232B (zh) |
| SG (1) | SG116574A1 (zh) |
| SI (1) | SI1614687T1 (zh) |
| UA (1) | UA81773C2 (zh) |
| WO (1) | WO2005111027A1 (zh) |
| ZA (1) | ZA200501468B (zh) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2868777B1 (fr) * | 2004-04-13 | 2006-05-26 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
| FR2868775B1 (fr) * | 2004-04-13 | 2008-04-11 | Servier Lab | Nouveau procede de synthese de derives de la 1,3,4,5- tetrahydro-2h-3-benzazepin-2-one, et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
| GT200500185A (es) * | 2004-08-09 | 2006-04-10 | Moduladores del receptor de progesterona que comprenden derivados de pirrol-oxindol y sus usos | |
| EP2471780B1 (en) | 2007-05-30 | 2014-11-26 | Ind-Swift Laboratories Limited | Crystalline Ivabradine Oxalate Salts and Polymorphs Thereof |
| ES2402765T3 (es) | 2008-12-22 | 2013-05-08 | Krka, D.D., Novo Mesto | Procedimiento de preparación de ivabradina |
| FR2940287B1 (fr) * | 2008-12-24 | 2010-12-24 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable. |
| EA201290772A1 (ru) | 2010-02-12 | 2013-02-28 | КРКА, д.д., НОВО МЕСТО | Новые формы ивабрадина гидрохлорида |
| FR2956401B1 (fr) * | 2010-02-17 | 2012-02-03 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
| FR2971507B1 (fr) * | 2011-02-14 | 2013-01-18 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
| FR2984320B1 (fr) * | 2011-12-20 | 2013-11-29 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
| FR2993561B1 (fr) * | 2012-07-17 | 2014-10-31 | Servier Lab | Procede de synthese enzymatique de la (7s)-1-(3,4-dimethoxy bicyclo[4.2.0]octa-1,3,5-triene 7-yl) n-methyl methanamine, et application a la synthese de l'ivabradine et de ses sels |
| FR3003859B1 (fr) * | 2013-03-26 | 2015-03-13 | Servier Lab | "procede de synthese de derives de la 7,8-dimethoxy-1,3-dihydro-2h-3-benzazepin-2-one et application a la synthese de l'ivabradine" |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0065229A1 (de) * | 1981-05-19 | 1982-11-24 | Dr. Karl Thomae GmbH | Neue Benzazepinderivate, ihre Herstellung und ihre Verwendung als Arzneimittel |
| EP0161604A2 (de) * | 1984-05-17 | 1985-11-21 | Dr. Karl Thomae GmbH | Neue Aminotetralinderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
| US4737495A (en) * | 1985-06-01 | 1988-04-12 | Dr. Karl Tomae, Gmbh | (2H)-3-benzazepin-2-ones, their pharmaceutical compositions and their pharmaceutical uses |
| US5296482A (en) * | 1991-09-27 | 1994-03-22 | Adir Et Compagnie | (Benzocycloalkyl) alkylamines |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3519735A1 (de) * | 1985-06-01 | 1986-12-04 | Dr. Karl Thomae Gmbh, 7950 Biberach | Neue heteroaromatische aminderivate, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
| FR2868777B1 (fr) * | 2004-04-13 | 2006-05-26 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
| FR2868775B1 (fr) * | 2004-04-13 | 2008-04-11 | Servier Lab | Nouveau procede de synthese de derives de la 1,3,4,5- tetrahydro-2h-3-benzazepin-2-one, et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
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2004
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2005
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- 2005-02-21 PL PL05290383T patent/PL1614687T3/pl unknown
- 2005-02-21 ES ES05290383T patent/ES2336461T3/es active Active
- 2005-02-21 AT AT05290383T patent/ATE448221T1/de active
- 2005-02-21 DK DK05290383.8T patent/DK1614687T3/da active
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- 2005-02-21 DE DE602005017541T patent/DE602005017541D1/de active Active
- 2005-02-21 WO PCT/FR2005/000396 patent/WO2005111027A1/fr active Application Filing
- 2005-02-21 EA EA200500240A patent/EA007743B1/ru unknown
- 2005-02-21 EP EP05290383A patent/EP1614687B1/fr active Active
- 2005-04-07 MX MXPA05003696A patent/MXPA05003696A/es active IP Right Grant
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- 2009-09-25 JP JP2009220529A patent/JP5277130B2/ja active Active
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0065229A1 (de) * | 1981-05-19 | 1982-11-24 | Dr. Karl Thomae GmbH | Neue Benzazepinderivate, ihre Herstellung und ihre Verwendung als Arzneimittel |
| EP0161604A2 (de) * | 1984-05-17 | 1985-11-21 | Dr. Karl Thomae GmbH | Neue Aminotetralinderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
| US4737495A (en) * | 1985-06-01 | 1988-04-12 | Dr. Karl Tomae, Gmbh | (2H)-3-benzazepin-2-ones, their pharmaceutical compositions and their pharmaceutical uses |
| US5296482A (en) * | 1991-09-27 | 1994-03-22 | Adir Et Compagnie | (Benzocycloalkyl) alkylamines |
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