KR19990080735A - Captopril Production Method - Google Patents
Captopril Production Method Download PDFInfo
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- KR19990080735A KR19990080735A KR1019980014188A KR19980014188A KR19990080735A KR 19990080735 A KR19990080735 A KR 19990080735A KR 1019980014188 A KR1019980014188 A KR 1019980014188A KR 19980014188 A KR19980014188 A KR 19980014188A KR 19990080735 A KR19990080735 A KR 19990080735A
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- formula
- proline
- reaction
- thiolactone
- methyl
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- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 title claims abstract description 25
- 229960000830 captopril Drugs 0.000 title claims abstract description 25
- 238000004519 manufacturing process Methods 0.000 title description 4
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims abstract description 46
- 229930182821 L-proline Natural products 0.000 claims abstract description 46
- 229960002429 proline Drugs 0.000 claims abstract description 46
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- 238000000034 method Methods 0.000 claims abstract description 26
- 239000003960 organic solvent Substances 0.000 claims abstract description 17
- 239000000126 substance Substances 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 83
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- 235000017550 sodium carbonate Nutrition 0.000 claims description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 235000011181 potassium carbonates Nutrition 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 3
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- -1 amine salt Chemical class 0.000 claims 2
- 239000002904 solvent Substances 0.000 claims 2
- 150000005323 carbonate salts Chemical class 0.000 claims 1
- 239000000243 solution Substances 0.000 description 16
- 230000002378 acidificating effect Effects 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000001914 filtration Methods 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- VFVHNRJEYQGRGE-UHFFFAOYSA-N 3-acetylsulfanyl-2-methylpropanoic acid Chemical compound OC(=O)C(C)CSC(C)=O VFVHNRJEYQGRGE-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 229960004132 diethyl ether Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 125000004354 sulfur functional group Chemical group 0.000 description 2
- HGNLNELQFWTPKG-OAHLLOKOSA-N (R)-beta-hydroxyisobutyric acid Natural products C[C@@H](C(C=C(CCC1=CC=CC=C1)O)=O)CC=C(C)C HGNLNELQFWTPKG-OAHLLOKOSA-N 0.000 description 1
- DBXBTMSZEOQQDU-GSVOUGTGSA-N (r)-3-hydroxyisobutyric acid Chemical compound OC[C@@H](C)C(O)=O DBXBTMSZEOQQDU-GSVOUGTGSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- ZDGGJQMSELMHLK-UHFFFAOYSA-N m-Trifluoromethylhippuric acid Chemical compound OC(=O)CNC(=O)C1=CC=CC(C(F)(F)F)=C1 ZDGGJQMSELMHLK-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Landscapes
- Pyrrole Compounds (AREA)
Abstract
본 발명은 하기 화학식 7로 표시되는 (R)-α-메틸-β-티이오락톤 및 하기 화학식 5로 표시되는 L-프로린을 반응시켜 하기 화학식 1로 표시되는 캡토프릴을 제조하는 방법에 있어서, 상기 반응을 유기용매내에서 염기촉매 존재하에 수행함을 특징으로 하는 방법에 관한 것이다.The present invention provides a method for preparing a captopril represented by the following Chemical Formula 1 by reacting (R) -α-methyl-β-thiolactone represented by the following Chemical Formula 7 and L-proline represented by the following Chemical Formula 5, The method is characterized in that the reaction is carried out in the presence of a base catalyst in an organic solvent.
화학식 1Formula 1
화학식 7Formula 7
화학식 5Formula 5
Description
본 발명은 고혈압치료제로서 유용한 하기 화학식 1로 표시되는 캡토프릴(captopril)의 제조방법에 관한 것이다.The present invention relates to a method for producing captopril represented by the following Chemical Formula 1 useful as a therapeutic agent for hypertension.
화학식 1Formula 1
세계적인 고혈압 치료제인 캡토프릴은 주로 브리스톨-마이어스스큅(Bristol-Myers Squibb)사에서 생산되고 있는 제품으로 향후 시장규모의 지속적인 성장이 예측되는 품목이다.Captopril, a global antihypertensive drug, is produced mainly by Bristol-Myers Squibb and is expected to continue to grow in the future.
현재까지 캡토프릴의 생산 공정은 크게 두가지 중간체를 거쳐 만들어지고 있다. 이들 공정은 하기 화학식 2의 메타아크릴산(methacrylic acid)과 하기 화학식 3의 티오아세트산(thiolacetic acid)의 부가 반응 후 만들어진 하기 화학식 4의 3-아세틸머르캅토-2-메틸프로피온산(3-acethylmercapto-2-methylpropionic acid)을 이용하고 있다.To date, the captopril production process is largely made through two intermediates. These processes were prepared after the addition reaction of methacrylic acid of formula 2 and thioacetic acid of formula 3 to 3-acetylmercapto-2-methylpropionic acid of formula 4, wherein 3-acethylmercapto-2- methylpropionic acid).
화학식 2Formula 2
화학식 3Formula 3
화학식 4Formula 4
구체적으로, 첫 번째 스큅(Squibb)사의 공정은 상기 중간체(화학식 4)를 하기 화학식 5의 L-프로린과 축합반응 후 광학 분할하여 캡토프릴을 얻는 것이고, 디에스엠안데노(DSM Andeno)사 방법은 축합반응 전에 중간체(화학식4)를 광학 분할하는 차이가 있다. 두 번째 가네가푸치(Kanekafuchi)사 공정은 발효 공정을 통해 얻어진 화학식 6의 (R)-β-히드록시이소부틸산 (R)-β-hydroxyisobuthyric acid)을 L-프로린(화학식 5)과의 축합반응을 위한 중간체로 이용하는 것이다. 최근에는 3-아세틸머르캅토-2-메틸프로피온산(화학식 4)의 라세미체를 효소적인 방법으로 광학분할함으로서 캡토프릴 합성의 효율을 높이려는 시도가 미쯔비시(Mitsubishi)사 등에 의해 시도되고 있다.Specifically, the first Squibb's process is to optically obtain the captopril by condensation reaction of the intermediate (Formula 4) with L-proline of the formula (5), DSM Andeno (DSM Andeno) method There is a difference in optical division of the intermediate (Formula 4) before the condensation reaction. The second Kanekafuchi process is condensation of (R) -β-hydroxyisobutyric acid (R) -β-hydroxyisobuthyric acid of Formula 6 obtained with a fermentation process with L-proline (Formula 5). It is used as an intermediate for the reaction. Recently, an attempt has been made by Mitsubishi et al to improve the efficiency of captopril synthesis by optically dividing the racemate of 3-acetylmercapto-2-methylpropionic acid (Formula 4) by enzymatic method.
화학식 5Formula 5
화학식 6Formula 6
스큅사 및 안데노사 공정은 황기능기의 반응성으로 인해 캡토프릴을 생산하는 공정중에 보호기를 부가하여 사용해야만 하고 반응후 탈보호기 반응을 진행해야 함으로 공정과정이 늘어나 수율이 낮아지는 원인이 된다. 그리고 마지막 공정에서 황기능기를 도입하는 가네가푸치사 공정은 부산물이 많이 발생하는 문제점이 있다.Due to the reactivity of the sulfur functional group, the Scoop and Andeno yarn processes have to use a protecting group during the captopril production process and the deprotecting group reaction after the reaction, which causes the process to increase in yield. In the last process, the Kanegapuchi company that introduces sulfur functional groups has a problem of generating a lot of by-products.
상기 공정들의 문제점을 개선하기 위한 시도로서 미합중국특허 제 5,128,263호에는 (R)-α-메틸-β-티오락톤을 이용한 축합공정을 제안하고 있다. 그러나 이 특허의 방법에서는 (R)-α-메틸-β-티오락톤을 L-프로린과 반응시키는 개념만 소개하고있을 뿐이고 반응조건, 분리방법, 순도 및 수율에 대한 구체적인 설명이 전혀 기술되어 있지 않다. 따라서 본 발명자는 결과 확인을 위하여 이 특허에서 제시된 조건으로 실험을 수행하여 보았다. 즉 (R)-α-메틸-β-티오락톤과 L-프로린을 일반적인 유기용매의 존재하에서 상온반응으로 7시간 수행한 결과 수율10%, 순도 20%로서 거의 반응이 진행되지 않는 것으로 확인되었다. 따라서 의약품의 원료물질로 이용하는데는 적합하지 못하다.In an attempt to improve the problems of the above processes, US Pat. No. 5,128,263 proposes a condensation process using (R) -α-methyl-β-thiolactone. However, the method of this patent only introduces the concept of reacting (R)-[alpha] -methyl- [beta] -thiolactone with L-proline and does not describe any details about reaction conditions, separation methods, purity and yield. not. Therefore, the present inventors conducted experiments under the conditions set forth in this patent to confirm the results. That is, when (R) -α-methyl-β-thiolactone and L-proline were performed for 7 hours at room temperature in the presence of a general organic solvent, it was confirmed that almost no reaction proceeded with a yield of 10% and a purity of 20%. . Therefore, it is not suitable for use as a raw material for pharmaceuticals.
이에 본 발명자는 (R)-α-메틸-β-티오락톤과 L-프로린의 축합공정에 대해 수많은 연구와 실험을 행한 결과, 유기용매내에서 염기촉매 존재하에 상온부근에서 반응시킴으로써 고순도 및 고수율의 캡토프릴을 경제적으로 제조할 수 있음을 밝혀냈다.Accordingly, the present inventors have conducted a number of studies and experiments on the condensation process of (R) -α-methyl-β-thiolactone and L-proline. It has been found that yields of captopril can be produced economically.
본 발명은 하기 화학식 7로 표시되는 (R)-α-메틸-β-티이오락톤 및 하기 화학식 5로 표시되는 L-프로린을 반응시켜 하기 화학식 1로 표시되는 캡토프릴을 제조하는 방법에 있어서, 상기 반응을 유기용매내에서 염기촉매 존재하에 수행함을 특징으로 하는 방법에 관한 것이다.The present invention provides a method for preparing a captopril represented by the following Chemical Formula 1 by reacting (R) -α-methyl-β-thiolactone represented by the following Chemical Formula 7 and L-proline represented by the following Chemical Formula 5, The method is characterized in that the reaction is carried out in the presence of a base catalyst in an organic solvent.
화학식 1Formula 1
화학식 7Formula 7
화학식 5Formula 5
이하 본 발명을 상세히 설명하면 다음과 같다. 먼저 원료물질인 (R)-α-메틸-β-티오락톤(화학식 7)과 L-프로린(화학식 5)을 유기용매내에서 염기촉매존재하에 반응시키고 반응 종료후 미반응 L-프로린을 여과로 제거한 다음 산성 수용액으로 세척하여 목적화합물인 캡토프릴을 얻는다. 여기서 L-프로린의 사용량은 원료물질(화학식 7) 기준으로 0.9 내지 2.0 당량이 바람직하다.Hereinafter, the present invention will be described in detail. First, raw materials (R) -α-methyl-β-thiolactone (Formula 7) and L-proline (Formula 5) are reacted in the presence of a base catalyst in an organic solvent, and after completion of the reaction, unreacted L-proline is filtered. And then washed with an acidic aqueous solution to obtain the desired compound captopril. Herein, the amount of L-proline is preferably 0.9 to 2.0 equivalents based on the raw material (Formula 7).
유기용매로는 메틸렌클로라이드, 에틸렌디클로라이드, 클로로포름을 포함한 할로겐원자수 1 내지 4개 및 탄소원자수 1 내지 5개의 할로알칸, 에틸에테르, 테트라하이드로퓨란, 디옥산, 아세토니트릴, 그리고 디메틸아미드 등을 사용한다. 바람직하게는 메틸렌클로라이드, 에틸렌디클로라이드, 클로로포름, 디에틸에테르, 디옥산 또는 테트라하이드로퓨란이다. 염기촉매로는 3가의 유기아민 염기 및 무기염기를 사용할 수 있다. 바람직하게, 3가의 유기아민염기로는 트리에틸아민, 피리딘 또는 이미다졸 등을 들 수 있다. 또한 무기염기로는 탄산칼륨, 탄산나트륨, 이탄산칼륨, 이탄산나트륨을 들 수 있다. 그리고 염기의 사용량은 원료물질(화학식 7) 기준으로 0.01 내지 2.5당량, 더욱 바람직하게는 0.05 내지 2.0당량으로 하는 것이 좋다. 반응온도는 저온과 가온반응 모두 가능하나, 바람직하게는 0℃ 내지 100℃의 온도에서 수행한다. 반응온도는 또한 반응시간과 밀접한 관련이 있다. 저온에서는 반응속도가 느리고 고온에서는 반응속도가 빠르게 되지만 상온에서도 비교적 단시간에 반응이 완결된다. 반응시간은 바람직하게는 0.5 내지 24시간이다. 이와 같은 조건에서 순도 99% 이상의 캡토프릴을 거의 정량적인 수율로 얻을 수 있다.As the organic solvent, haloalkanes having 1 to 4 halogen atoms and 1 to 5 carbon atoms including methylene chloride, ethylene dichloride and chloroform, ethyl ether, tetrahydrofuran, dioxane, acetonitrile, and dimethylamide are used. do. Preferably methylene chloride, ethylenedichloride, chloroform, diethylether, dioxane or tetrahydrofuran. Trivalent organic amine base and inorganic base can be used as a base catalyst. Preferably, triethylamine, pyridine, or imidazole etc. are mentioned as a trivalent organic amine base. In addition, examples of the inorganic base include potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate. The amount of base used is preferably 0.01 to 2.5 equivalents, more preferably 0.05 to 2.0 equivalents, based on the raw material (Formula 7). The reaction temperature may be both low temperature and warming reaction, but is preferably performed at a temperature of 0 ℃ to 100 ℃. The reaction temperature is also closely related to the reaction time. At low temperature, the reaction rate is slow, and at high temperature, the reaction rate is high, but the reaction is completed in a relatively short time even at room temperature. The reaction time is preferably 0.5 to 24 hours. Under these conditions, captopril more than 99% pure can be obtained in almost quantitative yield.
이하 본 발명을 실시예를 통해 구체적으로 설명하지만, 하기의 실시예들이 본 발명의 기술적 범주를 한정하는 것은 아니다.Hereinafter, the present invention will be described in detail with reference to Examples, but the following Examples do not limit the technical scope of the present invention.
실시예 1Example 1
(R)-α-메틸-β-티오락톤 1.02g을 메틸렌클로라이드 15g에 녹인 후 트리에틸아민(Et3N)을 0.1당량만큼 부가하였다. 1.2당량의 L-프로린을 반응액에 부가한 다음 상온에서 4.0시간 동안 저어주었다. 반응후 남은 L-프로린은 여과로 일차 제거한 다음 산성 수용액으로 2회 씻어줌으로써 남은 트리에틸아민과 L-프로린을 완전히 제거하였다. 무수황산마그네슘으로 유기용매의 수분을 제거한 다음 감압 농축·건조하여 98%의 수율과 99% 이상의 순도로 캡토프릴 2.13g을 얻었다.1.02 g of (R) -α-methyl-β-thiolactone was dissolved in 15 g of methylene chloride, and then 0.1 equivalent of triethylamine (Et 3 N) was added. 1.2 equivalents of L-proline was added to the reaction solution and then stirred at room temperature for 4.0 hours. The remaining L-proline after the reaction was first removed by filtration and washed twice with an acidic aqueous solution to completely remove the remaining triethylamine and L-proline. Water was removed from the organic solvent with anhydrous magnesium sulfate, and then concentrated under reduced pressure and dried to obtain 2.13 g of captopril with a yield of 98% and a purity of 99% or more.
실시예 2Example 2
(R)-α-메틸-β-티오락톤 1.02g을 메틸렌클로라이드 10g에 녹인 후 탄산칼륨(K2CO3)을 0.1당량만큼 부가하였다. 1.2당량의 L-프로린을 반응액에 부가한 후 상온에서 4.0시간동안 격렬하게 저어주었다. K2CO3와 여분의 L-프로린을 여과하여 제거한 후 산성 수용액으로 2회 씻어주어 남은 L-프로린을 완전히 제거하였다. 무수황산마그네슘으로 유기용매의 수분을 제거한 다음 감압 농축·건조하여 96%의 수율과 99% 이상의 순도로 캡토프릴 2.09g을 얻었다.1.02 g of (R) -α-methyl-β-thiolactone was dissolved in 10 g of methylene chloride, and then 0.1 equivalent of potassium carbonate (K 2 CO 3 ) was added. 1.2 equivalents of L-proline was added to the reaction solution and stirred vigorously at room temperature for 4.0 hours. K 2 CO 3 and excess L-proline were filtered off and washed twice with an acidic aqueous solution to completely remove the remaining L-proline. Water was removed from the organic solvent with anhydrous magnesium sulfate, and then concentrated and dried under reduced pressure to obtain 2.09 g of captopril with a yield of 96% and a purity of 99% or more.
실시예 3Example 3
(R)-α-메틸-β-티오락톤 1.02g을 메틸렌클로라이드 20g에 녹인 후 이미다졸을 0.2당량만큼 부가하였다. 1.2당량의 L-프로린을 반응액에 부가한 다음 상온에서 6.0시간동안 저어주었다. 반응후 남은 L-프로린을 여과한 다음 산성 수용액으로 2회 씻어줌으로써 유기용매속에 남아있는 이미다졸과 L-프로린을 완전히 제거하였다. 무수황산마그네슘으로 유기용매의 수분을 제거한 다음 감압 농축·건조하여 95%의 수율과 99% 이상의 순도로 캡토프릴 2.06g을 얻었다.1.02 g of (R) -α-methyl-β-thiolactone was dissolved in 20 g of methylene chloride, and 0.2 equivalents of imidazole was added thereto. 1.2 equivalents of L-proline was added to the reaction solution and stirred at room temperature for 6.0 hours. After the reaction, the remaining L-proline was filtered and washed twice with an acidic aqueous solution to completely remove the imidazole and L-proline remaining in the organic solvent. Water was removed from the organic solvent with anhydrous magnesium sulfate, and then concentrated and dried under reduced pressure to obtain 2.06 g of captopril with a yield of 95% and a purity of 99% or more.
실시예 4Example 4
(R)-α-메틸-β-티오락톤 1.02g을 메틸렌클로라이드 15g에 녹인 후 탄산나트륨(Na2CO3)을 0.2당량만큼 부가하였다. 1.2당량의 L-프로린을 반응액에 부가한 다음 상온에서 7.0시간동안 저어주었다. 반응후 남은 L-프로린과 탄산나트륨을 여과하여 제거하고 산성 수용액으로 2회 씻어주었다. 무수황산마그네슘으로 유기용매의 수분을 제거한 다음 감압 농축·건조하여 97%의 수율과 99%이상의 순도로 캡토프릴 2.11g을 얻었다.1.02 g of (R) -α-methyl-β-thiolactone was dissolved in 15 g of methylene chloride, and 0.2 equivalents of sodium carbonate (Na 2 CO 3 ) was added thereto. 1.2 equivalents of L-proline was added to the reaction solution and then stirred at room temperature for 7.0 hours. After the reaction, the remaining L-proline and sodium carbonate were filtered off and washed twice with an acidic aqueous solution. Water was removed from the organic solvent with anhydrous magnesium sulfate, and then concentrated and dried under reduced pressure to obtain 2.11 g of captopril with a yield of 97% and a purity of 99% or more.
실시예 5Example 5
(R)-α-메틸-β-티오락톤 1.02g을 테트라히드로퓨란 15g에 녹인 다음 트리에틸아민을 0.1당량만큼 부가하였다. 1.2당량의 L-프로린을 반응액에 부가한 후 상온에서 5.0시간동안 격렬하게 저어주었다. 반응후 여분의 L-프로린을 여과로 제거하고 반응액에 녹아있는 소량의 L-프로린과 트리에틸아민은 산성 수용액으로 2회 씻어줌으로써 남은 트리에틸아민과 L-프로린을 완전히 제거하였다. 무수황산마그네슘으로 유기용매의 수분을 제거한 다음 감압 농축·건조하여 98%의 수율과 99% 이상의 순도로 캡토프릴 2.13g을 얻었다.1.02 g of (R) -α-methyl-β-thiolactone was dissolved in 15 g of tetrahydrofuran, and then 0.1 equivalent of triethylamine was added. 1.2 equivalents of L-proline was added to the reaction solution and stirred vigorously at room temperature for 5.0 hours. After the reaction, the excess L-proline was removed by filtration, and a small amount of L-proline and triethylamine dissolved in the reaction solution was washed twice with an acidic aqueous solution to completely remove the remaining triethylamine and L-proline. Water was removed from the organic solvent with anhydrous magnesium sulfate, and then concentrated under reduced pressure and dried to obtain 2.13 g of captopril with a yield of 98% and a purity of 99% or more.
실시예 6Example 6
(R)-α-메틸-β-티오락톤 1.02g을 에틸렌디클로라이드 15g에 녹인 후 트리에틸아민을 0.1당량만큼 부가하였다. 1.2당량의 L-프로린을 반응액에 부가한 후 상온에서 5.0시간동안 격렬하게 저어주었다. 반응후 여분의 L-프로린을 여과로 제거하고 반응액에 녹아있는 소량의 L-프로린과 트리에틸아민은 산성 수용액으로 2회 씻어줌으로써 남은 트리에틸아민과 L-프로린을 완전히 제거하였다. 무수황산마그네슘으로 유기용매의 수분을 제거한 다음 감압 농축·건조하여 98%의 수율과 99% 이상의 순도로 캡토프릴 2.13g을 얻었다.1.02 g of (R) -α-methyl-β-thiolactone was dissolved in 15 g of ethylenedichloride, and then 0.1 equivalent of triethylamine was added. 1.2 equivalents of L-proline was added to the reaction solution and stirred vigorously at room temperature for 5.0 hours. After the reaction, the excess L-proline was removed by filtration, and a small amount of L-proline and triethylamine dissolved in the reaction solution was washed twice with an acidic aqueous solution to completely remove the remaining triethylamine and L-proline. Water was removed from the organic solvent with anhydrous magnesium sulfate, and then concentrated under reduced pressure and dried to obtain 2.13 g of captopril with a yield of 98% and a purity of 99% or more.
실시예 7Example 7
(R)-α-메틸-β-티오락톤 1.02g을 클로로포름 10g에 녹인 후 트리에틸아민을 0.1당량만큼 부가하였다. 1.2당량의 L-프로린을 반응액에 부가한 후 상온에서 5.0시간동안 격렬하게 저어주었다. 반응후 여분의 L-프로린을 여과로 제거하고 반응액에 녹아있는 소량의 L-프로린과 트리에틸아민은 산성 수용액으로 2회 씻어줌으로써 남은 트리에틸아민과 L-프로린을 완전히 제거하였다. 무수황산마그네슘으로 유기용매의 수분을 제거한 다음 감압 농축·건조하여 97%의 수율과 99% 이상의 순도로 캡토프릴 2.11g을 얻었다.1.02 g of (R) -α-methyl-β-thiolactone was dissolved in 10 g of chloroform, and then 0.1 equivalent of triethylamine was added. 1.2 equivalents of L-proline was added to the reaction solution and stirred vigorously at room temperature for 5.0 hours. After the reaction, the excess L-proline was removed by filtration, and a small amount of L-proline and triethylamine dissolved in the reaction solution was washed twice with an acidic aqueous solution to completely remove the remaining triethylamine and L-proline. Water was removed from the organic solvent with anhydrous magnesium sulfate, and then concentrated and dried under reduced pressure to obtain 2.11 g of captopril with a yield of 97% and a purity of 99% or more.
실시예 8Example 8
(R)-α-메틸-β-티오락톤 1.02g을 디에틸에테르 10g에 녹인 후 트리에틸아민을 0.1당량만큼 부가하였다. 1.2당량의 L-프로린을 반응액에 부가한 후 상온에서 6.0시간동안 격렬하게 저어주었다. 반응후 여분의 L-프로린을 여과로 제거하고 반응액에 녹아있는 소량의 L-프로린과 트리에틸아민은 산성 수용액으로 2회 씻어줌으로써 남은 트리에틸아민과 L-프로린을 완전히 제거하였다. 무수황산마그네슘으로 유기용매의 수분을 제거한 다음 감압 농축·건조하여 94%의 수율과 99% 이상의 순도로 캡토프릴 2.04g을 얻었다.1.02 g of (R) -α-methyl-β-thiolactone was dissolved in 10 g of diethyl ether, and then 0.1 equivalent of triethylamine was added. 1.2 equivalents of L-proline was added to the reaction solution and stirred vigorously at room temperature for 6.0 hours. After the reaction, the excess L-proline was removed by filtration, and a small amount of L-proline and triethylamine dissolved in the reaction solution was washed twice with an acidic aqueous solution to completely remove the remaining triethylamine and L-proline. Water was removed from the organic solvent with anhydrous magnesium sulfate, and then concentrated under reduced pressure and dried to obtain 2.04 g of captopril with a yield of 94% and a purity of 99% or more.
실시예 9Example 9
(R)-α-메틸-β-티오락톤 1.02g을 디옥산 7g에 녹인 후 트리에틸아민을 0.1당량만큼 부가하였다. 1.2당량의 L-프로린을 반응액에 부가한 후 상온에서 4.0시간동안 격렬하게 저어주었다. 반응후 여분의 L-프로린을 여과로 제거하고 반응액에 녹아있는 소량의 L-프로린과 트리에틸아민은 산성 수용액으로 2회 씻어줌으로써 남은 트리에틸아민과 L-프로린을 완전히 제거하였다. 무수황산마그네슘으로 유기용매의 수분을 제거한 다음 감압 농축·건조하여 97%의 수율과 99% 이상의 순도로 캡토프릴 2.11g을 얻었다.1.02 g of (R) -α-methyl-β-thiolactone was dissolved in 7 g of dioxane, and then 0.1 equivalent of triethylamine was added. 1.2 equivalents of L-proline was added to the reaction solution and stirred vigorously at room temperature for 4.0 hours. After the reaction, the excess L-proline was removed by filtration, and a small amount of L-proline and triethylamine dissolved in the reaction solution was washed twice with an acidic aqueous solution to completely remove the remaining triethylamine and L-proline. Water was removed from the organic solvent with anhydrous magnesium sulfate, and then concentrated and dried under reduced pressure to obtain 2.11 g of captopril with a yield of 97% and a purity of 99% or more.
실시예 10Example 10
(R)-α-메틸-β-티오락톤 1.02g을 아세토니트릴 25g에 녹인 후 트리에틸아민을 0.1당량만큼 부가하였다. 1.2당량의 L-프로린을 반응액에 부가한 후 상온에서 4.0시간동안 격렬하게 저어주었다. 반응액에 녹아있는 소량의 L-프로린과 트리에틸아민은 산성 수용액으로 2회 씻어줌으로써 남은 트리에틸아민과 L-프로린을 완전히 제거하였다. 무수황산마그네슘으로 유기용매의 수분을 제거한 다음 감압 농축·건조하여 95%의 수율과 99% 이상의 순도로 캡토프릴 2.06g을 얻었다.1.02 g of (R) -α-methyl-β-thiolactone was dissolved in 25 g of acetonitrile, and triethylamine was added by 0.1 equivalent. 1.2 equivalents of L-proline was added to the reaction solution and stirred vigorously at room temperature for 4.0 hours. Small amounts of L-proline and triethylamine dissolved in the reaction solution were washed twice with an acidic aqueous solution to completely remove the remaining triethylamine and L-proline. Water was removed from the organic solvent with anhydrous magnesium sulfate, and then concentrated and dried under reduced pressure to obtain 2.06 g of captopril with a yield of 95% and a purity of 99% or more.
실시예 11-31Example 11-31
하기 표 1에 나타낸 반응조건으로 상기 실시예와 동일한 방법을 수행하여 실시예 11-31의 캡토프릴을 얻었다. 표 1에서 시약들의 사용량은 (R)-메틸-β-티오락톤 1.02g(0.01몰)을 기준으로 표시하였다.The captopril of Example 11-31 was obtained by performing the same method as the above-described example under the reaction conditions shown in Table 1. The amount of reagents used in Table 1 is expressed based on 1.02 g (0.01 mol) of (R) -methyl-β-thiolactone.
표 1.Table 1.
1 : 트리에틸아민1: triethylamine
2 : 메틸렌클로라이드2: methylene chloride
3 : 에틸렌디클로라이드3: ethylenedichloride
4 : 테트라하이드로퓨란4: tetrahydrofuran
본발명에 따르면, 반응조건이 온화하고 부산물의 발생이 거의 없고 또한 분리방법이 간단하므로 고순도 및 고수율의 캡토프릴을 경제적으로 제조할 수 있다.According to the present invention, since the reaction conditions are mild, there is little generation of by-products, and the separation method is simple, high purity and high yield of captopril can be economically produced.
Claims (10)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019980014188A KR19990080735A (en) | 1998-04-21 | 1998-04-21 | Captopril Production Method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019980014188A KR19990080735A (en) | 1998-04-21 | 1998-04-21 | Captopril Production Method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR19990080735A true KR19990080735A (en) | 1999-11-15 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019980014188A Ceased KR19990080735A (en) | 1998-04-21 | 1998-04-21 | Captopril Production Method |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR19990080735A (en) |
-
1998
- 1998-04-21 KR KR1019980014188A patent/KR19990080735A/en not_active Ceased
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