KR101085169B1 - Process for separating the enantiomers of amlodipine - Google Patents
Process for separating the enantiomers of amlodipine Download PDFInfo
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- KR101085169B1 KR101085169B1 KR1020090025351A KR20090025351A KR101085169B1 KR 101085169 B1 KR101085169 B1 KR 101085169B1 KR 1020090025351 A KR1020090025351 A KR 1020090025351A KR 20090025351 A KR20090025351 A KR 20090025351A KR 101085169 B1 KR101085169 B1 KR 101085169B1
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- amlodipine
- methylpyrrolidone
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- 0 CCOC(C([C@@]1c2ccccc2Cl)=C(*)NC(C)=C1C(OC)=O)=O Chemical compound CCOC(C([C@@]1c2ccccc2Cl)=C(*)NC(C)=C1C(OC)=O)=O 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N CN(CCC1)C1=O Chemical compound CN(CCC1)C1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
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- 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
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
본 발명은 N-메틸피롤리돈을 이용하여 암로디핀 라세미 혼합물로부터 광학 이성질체를 높은 광학 순도로 간단하고 효율적으로 분리하는 방법 및 그에 사용되는 중간체에 관한 것이다. 본 발명의 분리방법에 따르면, (R,S)-암로디핀 라세미 혼합물로부터 S-(-)-암로디핀 및 R-(+)-암로디핀 광학 이성질체를 99.5% e.e. 이상의 높은 광학 순도 및 고수율로 제조할 수 있다. The present invention relates to a method for the simple and efficient separation of optical isomers with high optical purity from amlodipine racemic mixtures using N-methylpyrrolidone and intermediates used therein. According to the separation method of the present invention, the 9-% e.e. It can manufacture with high optical purity and high yield of the above.
암로디핀, 광학 이성질체, 분리방법, N-메틸피롤리돈 Amlodipine, Optical Isomers, Separation Method, N-methylpyrrolidone
Description
본 발명은 암로디핀 광학 이성질체의 분리방법에 관한 것이다. 보다 구체적으로 본 발명은 암로디핀 라세미 혼합물로부터 광학 이성질체를 높은 광학 순도로 간단하고 효율적으로 분리하는 방법 및 그에 사용되는 중간체에 관한 것이다.The present invention relates to a method for separating amlodipine optical isomers. More specifically, the present invention relates to a method for the simple and efficient separation of optical isomers from amlodipine racemic mixtures with high optical purity and intermediates used therein.
암로디핀은 장기간 작용하는 칼슘 통로 차단제(long-acting calcium channel blocker)로서, 협심증, 고혈압 등과 같은 심순환계 질환의 치료제로 널리 알려져 있다. 암로디핀을 구조적으로 살펴보면, 하기 화학식 1에 도시된 바와 같이 디히드로피리딘 고리의 4-위치에 비대칭 중심(chiral center)을 가지고 있어 R형 및 S형 두 가지 형태의 광학 이성질체의 라세미 혼합물(racemic mixture)로 존재한다.Amlodipine is a long-acting calcium channel blocker that is long-acting and widely known as a treatment for cardiovascular diseases such as angina pectoris and hypertension. Structurally examining amlodipine, a racemic mixture of two types of optical isomers of R-type and S-type having an asymmetric chiral center in the 4-position of the dihydropyridine ring, as shown in Formula 1 below. Exist).
[화학식 1][Formula 1]
미국특허 제6,057,344호 및 문헌[J. E. Arrowsmith 등, J. Med. Chem. 29, 1696(1986)]에는 순수하게 분리한 S형의 암로디핀이 R형의 암로디핀에 비해 1,000배 이상의 높은 활성을 갖는다고 보고되어 있다. R형의 암로디핀은 칼슘 채널 차단제로서의 활성을 거의 가지고 있지 않지만 약리학적으로 비활성인 것은 아니며, 미국 특허 제6,080,761호에 따르면 민무늬 근육 세포 이동의 강력한 저해제라고 기술되어 있다.U.S. Patent No. 6,057,344 and J. Pat. E. Arrowsmith et al., J. Med. Chem. 29, 1696 (1986)] reported that purely isolated S-type amlodipine has at least 1,000 times higher activity than R-type amlodipine. Type R amlodipine has little activity as a calcium channel blocker but is not pharmacologically inactive and is described as a potent inhibitor of striated muscle cell migration according to US Pat. No. 6,080,761.
이미 알려진 암로디핀 광학 이성질체의 분리방법들을 기술하면, 국제특허공개 WO 95/25722호에는 디메틸술폭시드가 함유된 용매중에서 (R,S)-암로디핀을 D-(-)-타르타르 산과 반응시켜 S-(-)-암로디핀-헤미-D-(-)-타르트레이트 디메틸술폭시드 용매화물로 선택적으로 결정화하여 S-(-)-암로디핀을 제조하는 방법이 개시되어 있다. 이외에도 용매로 N,N-디메틸아세트아미드 또는 N,N-디메틸포름아미드를 사용하여 선택적으로 S-(-)-암로디핀을 제조하는 방법이 보고되어 있다[WO 03/035623호 및 WO 2006/043148호]. 또한 대한민국 공개특허 제10-2008-0076009호에는 우레아 및 120℃ 이하의 낮은 비점을 갖는 용매를 사용하여 S-(-)-암로디핀-D-(-)-주석산염 우레아 복합체를 침전시켜 S-(-)-암로디핀을 제조하는 방법이 기술되어 있다. 그 외에 대한민국 공개특허 제10-2006-0061976호에는 D-(-)-주석산 대신 그의 유도체인 O,O'-디벤조일 주석산을 사용하여 광학 이성질체를 분리하는 방법이 개시되어 있다. 그리고, 대한민국 특허출원 제10-2002-0054808호에는 L-(+)-주석산을 이용하여 R-(+)-암로디핀을 제거하고, 여액에 디클로로메탄을 첨가하여 순수한 S-(-)-암로디핀을 분리하는 방법이 보고되어 있다. 하지만, 상기 공지된 기술들을 종합하여 보면, S-(-)-암로디핀을 광학 순도(키랄 HPLC) >99.5% e.e.의 값을 갖도록 하기 위해서는 재처리하는 등의 적어도 1단계 이상의 과정을 거쳐야 하는 문제점이 있었다.Disclosing known methods for separating amlodipine optical isomers, WO 95/25722 discloses the reaction of (R, S) -amlodipine with D-(-)-tartaric acid in a solvent containing dimethyl sulfoxide to give S- ( A method of preparing S-(-)-amlodipine by selectively crystallizing with-)-amlodipine-hemi-D-(-)-tartrate dimethylsulfoxide solvate is disclosed. In addition, a method of selectively preparing S-(-)-amlodipine using N, N-dimethylacetamide or N, N-dimethylformamide as a solvent has been reported [WO 03/035623 and WO 2006/043148]. ]. In addition, Korean Patent Publication No. 10-2008-0076009 discloses S-(-)-amlodipine-D-(-)-tartrate urea complex by using urea and a solvent having a low boiling point of 120 ° C. or lower. A method for preparing amlodipine is described. In addition, Korean Patent Publication No. 10-2006-0061976 discloses a method for separating optical isomers using O, O'-dibenzoyl tartaric acid, which is a derivative thereof, instead of D-(-)-tin acid. In addition, Korean Patent Application No. 10-2002-0054808 discloses the removal of R-(+)-amlodipine using L-(+)-tin acid, and the addition of dichloromethane to the filtrate to provide pure S-(-)-amlodipine. A method of separation has been reported. However, in view of the above known techniques, in order to have S-(-)-amlodipine having an optical purity (chiral HPLC) of> 99.5% ee, it is necessary to undergo at least one step such as reprocessing. there was.
본 발명자들은 (R,S)-암로디핀으로부터 고순도의 S-(-)-암로디핀 및 R-(+)-암로디핀을 용이하고 효율적으로 분리할 수 있는 방법을 개발하기 위해 예의 연구 검토한 결과, 용매로서 N-메틸피롤리돈을 사용하여 광학 순도(키랄 HPLC) >99.5% e.e.의 S-(-)-암로디핀 및 R-(+)-암로디핀을 간단하게 상업적 규모로 분리할 수 있음을 발견하고 본 발명을 완성하게 되었다.The present inventors have studied diligently to develop a method for easily and efficiently separating high purity S-(-)-amlodipine and R-(+)-amlodipine from (R, S) -amlodipine. The invention finds that N-methylpyrrolidone can be used to readily separate S-(-)-amlodipine and R-(+)-amlodipine of optical purity (chiral HPLC)> 99.5% ee on a commercial scale. To complete.
따라서 본 발명의 목적은 (R,S)-암로디핀으로부터 높은 광학 순도의 S-(-)-암로디핀 및 R-(+)-암로디핀을 간단하고 효율적으로 분리하는 방법을 제공하는 것이다.It is therefore an object of the present invention to provide a method for the simple and efficient separation of high optical purity of S-(-)-amlodipine and R-(+)-amlodipine from (R, S) -amlodipine.
본 발명의 다른 목적은 상기 분리방법에 사용되는 신규한 중간체를 제공하는 것이다.Another object of the present invention is to provide a novel intermediate used in the separation method.
본 발명은 (R,S)-암로디핀으로부터 높은 광학 순도의 S-(-)-암로디핀 및 R-(+)-암로디핀을 간단하고 효율적으로 분리하는 방법 및 그에 사용되는 중간체에 관한 것이다.The present invention relates to a method for the simple and efficient separation of high optical purity of S-(-)-amlodipine and R-(+)-amlodipine from (R, S) -amlodipine and the intermediates used therein.
일 태양으로, 본 발명은 (R,S)-암로디핀으부터 S-(-)-암로디핀의 분리방법에 관한 것으로, 본 발명의 분리방법은 In one aspect, the present invention relates to a method for separating S-(-)-amlodipine from (R, S) -amlodipine, the separation method of the present invention
(i) 하기 화학식 1의 (R,S)-암로디핀을 N-메틸피롤리돈 중에서 D-타르타르산과 반응시켜 하기 화학식 2의 (S)-(-)-암로디핀-헤미-D-타르트레이트-모노-N-메틸피롤리돈-용매화물을 수득하는 단계; 및(i) Reacting (R, S) -amlodipine of Formula 1 with D-tartaric acid in N-methylpyrrolidone to (S)-(-)-amlodipine-hemi-D-tartrate-mono of Formula 2 Obtaining an -N-methylpyrrolidone-solvate; And
(ii) 수득된 용매화물을 수용액 중에서 염기로 중화시켜 하기 화학식 3의 S-(-)-암로디핀을 수득하는 단계를 포함한다.(ii) neutralizing the solvate obtained with a base in an aqueous solution to obtain S-(-)-amlodipine of formula (3).
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3](3)
이하, 본 발명의 (R,S)-암로디핀으부터 S-(-)-암로디핀의 분리방법을 보다 상세히 설명하고자 한다. 하기에 기재된 방법은 대표적으로 사용된 방법을 예시한 것일 뿐 단위조작의 순서, 반응시약, 반응조건 등은 경우에 따라 얼마든지 변경될 수 있다.Hereinafter, a method for separating S-(-)-amlodipine from (R, S) -amlodipine of the present invention will be described in more detail. The methods described below are merely illustrative of the methods used, and the sequence of unit operations, reaction reagents, reaction conditions, and the like may be changed as the case may be.
제1단계: (S)-(-)-암로디핀-헤미-D-타르트레이트-모노-N-메틸피롤리돈-용매화물의 제조First step: preparation of (S)-(-)-amlodipine-hemi-D-tartrate-mono-N-methylpyrrolidone-solvate
상기 화학식 2의 (S)-(-)-암로디핀-헤미-D-타르트레이트-모노-N-메틸피롤리돈-용매화물은 상기 화학식 1의 (R,S)-암로디핀을 N-메틸피롤리돈 중에서 D-타르타르산과 반응시켜 생성된 침전물을 여과하여 수득한다.(S)-(-)-amlodipine-hemi-D-tartrate-mono-N-methylpyrrolidone-solvate of Chemical Formula 2 is represented by (R, S) -amlodipine of Chemical Formula 1 as N-methylpyrroli A precipitate obtained by reaction with D-tartaric acid in pigs is obtained by filtration.
상기 N-메틸피롤리돈은 반응용매로서 작용하며, 단독으로 또는 조용매와 혼합하여 사용될 수 있다. The N-methylpyrrolidone acts as a reaction solvent, and may be used alone or in admixture with a co-solvent.
상기 조용매로서는 물, 아세톤, 아세토니트릴, 디메틸술폭시드, 디메틸아세트아미드, 메틸에틸케톤, 테트라히드로푸란, 에틸아세테이트, 디클로로메탄, 디메틸포름아미드, 톨루엔, 메탄올, 에탄올, 이소프로판올, t-부탄올, N,N'-디메틸프로필렌우레아 등을 사용할 수 있다.Examples of the cosolvent include water, acetone, acetonitrile, dimethyl sulfoxide, dimethylacetamide, methyl ethyl ketone, tetrahydrofuran, ethyl acetate, dichloromethane, dimethylformamide, toluene, methanol, ethanol, isopropanol, t-butanol, N , N'-dimethylpropylene urea and the like can be used.
상기 조용매는 전체 반응용매의 50% v/v 이하의 양으로 사용하는 것이 바람직하며, 20% 내지 40% v/v의 양으로 사용하는 것이 보다 바람직하다. The cosolvent is preferably used in an amount of 50% v / v or less of the total reaction solvent, and more preferably in an amount of 20% to 40% v / v.
사용되는 전체 반응용매의 양은 (R,S)-암로디핀 1g에 대하여 3ml 내지 15ml 범위가 바람직하다. The amount of the total reaction solvent used is preferably in the range of 3 ml to 15 ml relative to 1 g of (R, S) -amlodipine.
상기 D-타르타르 산은 (R,S)-암로디핀 1 당량에 대하여 0.3 내지 0.5 당량으로 사용하는 것이 바람직하다The D-tartaric acid is preferably used in an amount of 0.3 to 0.5 equivalents based on 1 equivalent of (R, S) -amlodipine.
반응온도는 25℃ 내지 60℃가 바람직하며, 침전물이 생성되기 시작한 후 반응용액을 0℃ 내지 25℃로 냉각시킨 다음 1시간 내지 24시간 동안 교반하여 침전물을 생성시키는 것이 바람직하다. The reaction temperature is preferably 25 ° C. to 60 ° C., and after the precipitate starts to form, the reaction solution is cooled to 0 ° C. to 25 ° C. and then stirred for 1 to 24 hours to generate a precipitate.
제2단계: S-(-)-암로디핀의 제조Second Step: Preparation of S-(-)-Amlodipine
상기 화학식 3의 S-(-)-암로디핀은 상기 화학식 2의 (S)-(-)-암로디핀-헤미-D-타르트레이트-모노-N-메틸피롤리돈-용매화물을 수용액 중에서 염기로 중화시켜 제조한다.S-(-)-amlodipine of Formula 3 neutralizes (S)-(-)-amlodipine-hemi-D-tartrate-mono-N-methylpyrrolidone-solvate of Formula 2 with base in aqueous solution To make it.
바람직하게는, 상기 화학식 2의 용매화물을 디클로로메탄 또는 클로로포름과 같은 유기용매에 현탁시킨 후, pH 7내지 10이 유지되도록 수산화칼륨 또는 수산화나트륨 수용액을 첨가하여 중화시킨 다음 농축시켜 제조한다.Preferably, the solvate of Formula 2 is suspended in an organic solvent such as dichloromethane or chloroform, and then neutralized by addition of aqueous potassium hydroxide or sodium hydroxide solution to maintain a pH of 7 to 10, followed by concentration.
필요에 따라 수득된 (S)-(-)-암로디핀을 적절한 용매, 가장 바람직하게는 헥산 중에서 재결정화할 수도 있다. (S)-(-)-amlodipine obtained as necessary may be recrystallized in a suitable solvent, most preferably hexane.
최종 생성된 (S)-(-)-암로디핀은 키랄 HPLC 분석시 99.5% e.e. (enantiomer exess) 이상의 광학 순도를 갖는다. The final (S)-(-)-amlodipine produced was 99.5% e.e. have an optical purity of at least (enantiomer exess).
다른 태양으로, 본 발명은 (S)-(-)-암로디핀의 분리에 사용되는 신규한 중간체인 하기 화학식 2의 (S)-(-)-암로디핀-헤미-D-타르트레이트-모노-N-메틸피롤리돈 -용매화물에 관한 것이다.In another aspect, the present invention provides a novel intermediate used for the separation of (S)-(-)-amlodipine (S)-(-)-amlodipine-hemi-D-tartrate-mono-N- Methylpyrrolidone-relates to a solvate.
[화학식 2][Formula 2]
상기 본 발명의 (S)-(-)-암로디핀-헤미-D-타르트레이트-모노-N-메틸피롤리돈-용매화물은 1분자의 (S)-(-)-암로디핀, 0.5분자의 D-타르트레이트 및 1분자의 N-메틸피롤리돈이 복합체를 형성하고 있다.The (S)-(-)-amlodipine-hemi-D-tartrate-mono-N-methylpyrrolidone-solvate of the present invention comprises one molecule of (S)-(-)-amlodipine, 0.5 molecule of D Tartrate and one molecule of N-methylpyrrolidone form a complex.
또 다른 태양으로, 본 발명은 하기 화학식 1의 (R,S)-암로디핀을 N-메틸피롤리돈 중에서 D-타르타르산과 반응시키는 것을 특징으로 하는 하기 화학식 2의 (S)-(-)-암로디핀-헤미-D-타르트레이트-모노-N-메틸피롤리돈-용매화물의 제조방법에 관한 것이다. In another embodiment, the present invention provides the reaction of (R, S) -amlodipine of formula (1) with D-tartaric acid in N-methylpyrrolidone (S)-(-)-amlodipine of formula (2). It relates to a process for preparing hemi-D-tartrate-mono-N-methylpyrrolidone-solvate.
[화학식 1][Formula 1]
[화학식 2][Formula 2]
상기 용매화물의 제조방법에 대한 상세한 설명은 (R,S)-암로디핀으부터 S-(-)-암로디핀의 분리방법과 관련하여 상술한 제1단계와 동일하므로, 중복을 피하기 위해 구체적인 설명을 생략한다.Detailed description of the method of preparing the solvate is the same as the first step described above with respect to the separation method of (R, S)-amlodipine from S-(-)-amlodipine, and thus, a detailed description thereof will be omitted. do.
또 다른 태양으로, 본 발명은 (R,S)-암로디핀으부터 R-(+)-암로디핀의 분리방법에 관한 것으로, 본 발명의 분리방법은 In another aspect, the present invention relates to a method for separating R-(+)-amlodipine from (R, S) -amlodipine, wherein the separation method of the present invention
(i') (R,S)-암로디핀을 N-메틸피롤리돈 중에서 L-타르타르산과 반응시켜 (R)-(+)-암로디핀-헤미-D-타르트레이트-모노-N-메틸피롤리돈-용매화물을 수득하는 단계; 및(i ') Reacting (R, S) -amlodipine with L-tartaric acid in N-methylpyrrolidone to (R)-(+)-amlodipine-hemi-D-tartrate-mono-N-methylpyrrolidone Obtaining a solvate; And
(ii') 수득된 용매화물을 수용액 중에서 염기로 중화시켜 R-(+)-암로디핀을 수득하는 단계를 포함한다. (ii ') neutralizing the solvate obtained with a base in an aqueous solution to obtain R-(+)-amlodipine.
상기 분리방법에 대한 상세한 설명은 (R,S)-암로디핀으부터 S-(-)-암로디핀의 분리방법과 관련하여 상술한 내용과 D-타르타르산 대신 L-타르타르산을 사용하는 것을 제외하고는 동일하므로, 역시 중복을 피하기 위해 구체적인 설명을 생략한 다.Detailed description of the separation method is the same as described above with respect to the separation method of S-(-)-amlodipine from (R, S) -amlodipine, except that L-tartaric acid is used instead of D-tartaric acid. Also, detailed descriptions are omitted to avoid duplication.
최종 생성된 (R)-(+)-암로디핀은 키랄 HPLC 분석시 99.5% e.e. (enantiomer exess) 이상의 광학 순도를 갖는다. The final resulting (R)-(+)-amlodipine was 99.5% e.e. have an optical purity of at least (enantiomer exess).
본 발명의 분리방법에 따르면, (R,S)-암로디핀 라세미 혼합물로부터 S-(-)-암로디핀 및 R-(+)-암로디핀 광학 이성질체를 99.5% e.e. 이상의 높은 광학 순도 및 고수율로 간단하고 효율적으로 제조할 수 있다. 본 발명의 분리방법은 간편하고 경제적이므로 상업적으로 높은 광학 순도를 갖는 S-(-)-암로디핀 및 R-(+)-암로디핀을 제조하는데 효과적으로 사용될 수 있다. According to the separation method of the present invention, the 9-% e.e. It can manufacture easily and efficiently with the above high optical purity and high yield. Since the separation method of the present invention is simple and economical, it can be effectively used to prepare S-(-)-amlodipine and R-(+)-amlodipine having commercially high optical purity.
이하, 실시예에 의해 본 발명을 보다 구체적으로 설명하고자 한다. 이들 실시예는 오직 본 발명을 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업자에게 있어서 자명하다.Hereinafter, the present invention will be described in more detail with reference to Examples. It is apparent to those skilled in the art that these examples are only for illustrating the present invention, and the scope of the present invention is not limited to these examples.
본 실시예에 있어 광학 순도는 키랄 HPLC 및 편광계로 측정하였다. 분리에 사용된 HPLC 조건은 다음과 같다: 컬럼(ULTRON ES-OVM 15cm); 유속(0.8㎖/min); 검출파장(360nm); 용출제(제이인산나트륨 완충제(20mM, pH 7.0) : 아세토니트릴 = 80 : 20). 샘플을 아세토니트릴 : 물 = 50 : 50에 0.1㎎/㎖로 용해시켜 측정하였다.Optical purity in this example was measured by chiral HPLC and polarimeter. HPLC conditions used for separation were as follows: column (ULTRON ES-OVM 15 cm); Flow rate (0.8 ml / min); Detection wavelength (360 nm); Eluent (sodium diphosphate buffer (20 mM, pH 7.0): acetonitrile = 80: 20). Samples were measured by dissolving 0.1 mg / ml in acetonitrile: water = 50: 50.
편광계는 Rudolph research analytical사의 Autopol IV 모델을 사용하여 측 정하였다.The polarimeter was measured using an Autopol IV model from Rudolph research analytical.
실시예 1: (R,S)-암로디핀으로부터 (S)-(-)-암로디핀-헤미-D-타르트레이트-모노-N-메틸피롤리돈-용매화물의 제조Example 1: Preparation of (S)-(-)-amlodipine-hemi-D-tartrate-mono-N-methylpyrrolidone-solvate from (R, S) -amlodipine
N-메틸피롤리돈 500ml에 (R,S)-암로디핀 50g 및 D-(-)-타르타르산 9.2g (0.5 당량)을 첨가하고, 반응 용액을 60℃로 가온하여 완전히 용해시킨 다음, 상온으로 냉각시키고 철야 교반하였다. 침전물을 여과하고 아세톤 200ml로 세척한 다음 진공 건조기에서 건조하여 (S)-(-)-암로디핀-헤미-D-타르트레이트-모노-N-메틸피롤리돈-용매화물 30.2g (이론적 수율 85%)을 얻었다.To 500 ml of N-methylpyrrolidone, 50 g of (R, S) -amlodipine and 9.2 g (0.5 equivalents) of D-(-)-tartaric acid were added, and the reaction solution was warmed to 60 ° C to completely dissolve and then cooled to room temperature. And stirred overnight. The precipitate was filtered off, washed with 200 ml of acetone and dried in a vacuum dryer to give 30.2 g of (S)-(-)-amlodipine-hemi-D-tartrate-mono-N-methylpyrrolidone-solvate (85% theoretical yield). )
녹는점 : 135~137℃Melting Point: 135 ~ 137 ℃
키랄 HPLC : 99.0% d.e.Chiral HPLC: 99.0% d.e.
1H-NMR (CDCl3) : δ 7.88~6.89 (m, 4H), 5.36 (s, 1H), 4.67 (dd, 2H), 4.38 (s, 1H, 타르타르산 -CH(OH)-), 3.94 (m, 2H), 3.70(s, 2H), 3.48 (s, 3H), 3.39 (t, 2H, N-메틸피롤리돈), 3.14 (s, 2H), 2.80 (s, 3H, N-메틸피롤리돈), 2.33 (t, 2H, N-메틸피롤리돈), 2.25 (s, 3H), 2.13(s, 2H), 1.98(m, 2H, N-메틸피롤리돈), 1.12 (t, 3H) 1 H-NMR (CDCl 3 ): δ 7.88-6.89 (m, 4H), 5.36 (s, 1H), 4.67 (dd, 2H), 4.38 (s, 1H, tartaric acid-C H (OH)-), 3.94 (m, 2H), 3.70 (s, 2H), 3.48 (s, 3H), 3.39 (t, 2H, N-methylpyrrolidone), 3.14 (s, 2H), 2.80 (s, 3H, N-methyl Pyrrolidone), 2.33 (t, 2H, N-methylpyrrolidone), 2.25 (s, 3H), 2.13 (s, 2H), 1.98 (m, 2H, N-methylpyrrolidone), 1.12 (t , 3H)
실시예 2: (R,S)-암로디핀으로부터 (S)-(-)-암로디핀-헤미-D-타르트레이트-모노-N-메틸피롤리돈-용매화물의 제조Example 2: Preparation of (S)-(-)-amlodipine-hemi-D-tartrate-mono-N-methylpyrrolidone-solvate from (R, S) -amlodipine
N-메틸피롤리돈 300ml에 (R,S)-암로디핀 50g 및 D-(-)-타르타르산 9.2g (0.5 당량)을 첨가하고, 디메틸술폭시드 200ml를 첨가하여 완전히 용해 시킨 다음, 상온에서 철야 교반하였다. 침전물을 여과하고 아세톤 200ml로 세척한 다음 진공 건조기에서 건조하여 (S)-(-)-암로디핀-헤미-D-타르트레이트-모노-N-메틸피롤리돈-용매화물 32.4g (이론적 수율 91%)을 얻었다.To 300 ml of N-methylpyrrolidone, 50 g of (R, S) -amlodipine and 9.2 g (0.5 equivalents) of D-(-)-tartaric acid were added, and 200 ml of dimethyl sulfoxide was added to dissolve completely, followed by stirring at room temperature overnight. It was. The precipitate was filtered off, washed with 200 ml of acetone and dried in a vacuum dryer to give 32.4 g of (S)-(-)-amlodipine-hemi-D-tartrate-mono-N-methylpyrrolidone-solvate (theoretical yield 91%) )
녹는점 : 136~137℃Melting Point: 136 ~ 137 ℃
키랄 HPLC : 99.7% d.e.Chiral HPLC: 99.7% d.e.
실시예 3: (R,S)-암로디핀으로부터 (S)-(-)-암로디핀-헤미-D-타르트레이트-모노-N-메틸피롤리돈-용매화물의 제조Example 3: Preparation of (S)-(-)-amlodipine-hemi-D-tartrate-mono-N-methylpyrrolidone-solvate from (R, S) -amlodipine
N-메틸피롤리돈 35ml에 (R,S)-암로디핀 5g 및 D-(-)-타르타르산 0.9g (0.5 당량)을 첨가하고, 이소프로판올 15ml를 첨가하여 완전히 용해 시킨 다음, 상온에서 철야 교반 하였다. 침전물을 여과하고 아세톤 20ml로 세척한 다음 진공 건조기에서 건조하여 (S)-(-)-암로디핀-헤미-D-타르트레이트-모노-N-메틸피롤리돈-용매화물 2.85g (이론적 수율 80%)을 얻었다.5 g of (R, S) -amlodipine and 0.9 g (0.5 equivalents) of D-(-)-tartaric acid were added to 35 ml of N-methylpyrrolidone, and 15 ml of isopropanol was completely dissolved, followed by stirring at room temperature overnight. The precipitate was filtered off, washed with 20 ml of acetone and dried in a vacuum drier 2.85 g of (S)-(-)-amlodipine-hemi-D-tartrate-mono-N-methylpyrrolidone-solvate (theoretical yield 80%) )
키랄 HPLC : 98.6% d.e.Chiral HPLC: 98.6% d.e.
실시예 4: (R,S)-암로디핀으로부터 (S)-(-)-암로디핀-헤미-D-타르트레이트-모노-N-메틸피롤리돈-용매화물의 제조Example 4: Preparation of (S)-(-)-amlodipine-hemi-D-tartrate-mono-N-methylpyrrolidone-solvate from (R, S) -amlodipine
N-메틸피롤리돈 25ml에 (R,S)-암로디핀 5g 및 D-(-)-타르타르산 0.9g (0.5 당량)을 첨가하고, 디메틸포름아미드 10m를 첨가하여 완전히 용해 시킨 다음, 상온에서 철야 교반하였다. 침전물을 여과하고 아세톤 20ml로 세척한 다음 진공 건조기에서 건조하여 (S)-(-)-암로디핀-헤미-D-타르트레이트-모노-N-메틸피롤리돈-용매화물 2.56g (이론적 수율 72%)을 얻었다. To 25 ml of N-methylpyrrolidone, 5 g of (R, S) -amlodipine and 0.9 g (0.5 equivalents) of D-(-)-tartaric acid were added, and 10 m of dimethylformamide was added to dissolve completely, followed by stirring at room temperature overnight. It was. The precipitate was filtered off, washed with 20 ml of acetone and dried in a vacuum dryer to remove 2.56 g of (S)-(-)-amlodipine-hemi-D-tartrate-mono-N-methylpyrrolidone-solvate (theoretical yield 72%). )
키랄 HPLC : 98.5% d.e.Chiral HPLC: 98.5% d.e.
실시예 5: (R,S)-암로디핀으로부터 (S)-(-)-암로디핀의 제조 Example 5 Preparation of (S)-(-)-Amlodipine from (R, S) -Amlodipine
N-메틸피롤리돈 75ml에 (R,S)-암로디핀 15g 및 D-(-)-타르타르산 2.7g (0.5 당량)을 첨가한 다음, 반응 용액에 디메틸술폭시드 75ml를 첨가하고 60℃로 가온하여 완전히 용해시킨 다음, 상온으로 냉각시키고 철야 교반하였다. 침전물을 여과하고 아세톤 50ml로 세척한 다음, 디클로로메탄 150ml 및 증류수 60ml를 넣어 슬러리화하고, 2N-NaOH 수용액 5ml를 첨가하여 유기 용액을 분리한 다음, 유기 용액을 감압 증류하여 디클로로메탄을 제거하였다. 잔류물을 디클로로메탄 5ml에 녹인 후 헥산 150ml에 천천히 첨가하여 교체 슬러리화시켜 (S)-(-)-암로디핀 6.0g (이론적 수율 80%)을 얻었다.To 75 ml of N-methylpyrrolidone was added 15 g of (R, S) -amlodipine and 2.7 g (0.5 equiv) of D-(-)-tartaric acid, and then 75 ml of dimethyl sulfoxide was added to the reaction solution and warmed to 60 ° C. After complete dissolution, the mixture was cooled to room temperature and stirred overnight. The precipitate was filtered and washed with 50 ml of acetone, slurried with 150 ml of dichloromethane and 60 ml of distilled water, and 5 ml of 2N-NaOH aqueous solution was added to separate the organic solution, and the organic solution was distilled under reduced pressure to remove dichloromethane. The residue was dissolved in 5 ml of dichloromethane and slowly added to 150 ml of hexane to make a slurry slurried to give 6.0 g (S)-(-)-amlodipine (80% of theoretical yield).
녹는점 : 109~110℃Melting Point: 109 ~ 110 ℃
키랄 HPLC : 99.6% e.e.Chiral HPLC: 99.6% e.e.
[α]D 22 -32.6°(c=1, MeOH)[α] D 22 -32.6 ° (c = 1, MeOH)
실시예 6: (R,S)-암로디핀으로부터 (S)-(-)-암로디핀의 제조 Example 6 Preparation of (S)-(-)-Amlodipine from (R, S) -Amlodipine
N-메틸피롤리돈 105ml에 (R,S)-암로디핀 15g 및 D-(-)-타르타르산 2.7g (0.5 당량)을 첨가한 다음, 반응 용액에 디메틸술폭시드 45ml를 첨가하여 완전히 용해시킨 다음, 상온에서 철야 교반하였다. 침전물을 여과하고 아세톤 50ml로 세척한 다음, 디클로로메탄 300ml 및 증류수 100ml를 넣어 슬러리화하고, 2N-NaOH 수용액 10ml를 첨가하여 유기 용액을 분리한 다음, 유기 용액을 감압 증류하여 디클로로메탄을 제거하였다. 잔류물을 디클로로메탄 5ml에 녹인 후 헥산 150ml에 천천히 첨가하여 교체 슬러리화시켜 (S)-(-)-암로디핀 6.45g (이론적 수율 86%)을 얻었다.15 g of (R, S) -amlodipine and 2.7 g (0.5 equivalents) of D-(-)-tartaric acid were added to 105 ml of N-methylpyrrolidone, and then 45 ml of dimethyl sulfoxide was added to the reaction solution to completely dissolve it. The mixture was stirred overnight at room temperature. The precipitate was filtered and washed with 50 ml of acetone, slurried with 300 ml of dichloromethane and 100 ml of distilled water, and 10 ml of 2N-NaOH aqueous solution was added to separate the organic solution, and the organic solution was distilled under reduced pressure to remove dichloromethane. The residue was taken up in 5 ml of dichloromethane and slowly added to 150 ml of hexane to make slurry slurried to give 6.45 g (S)-(-)-amlodipine (86% of theoretical yield).
녹는점 : 109~110℃Melting Point: 109 ~ 110 ℃
키랄 HPLC : 99.8% e.e.Chiral HPLC: 99.8% e.e.
[α]D 22 -33.0° (c=1, MeOH)[α] D 22 -33.0 ° (c = 1, MeOH)
실시예 7: (R,S)-암로디핀으로부터 (R)-(+)-암로디핀의 제조Example 7 Preparation of (R)-(+)-Amlodipine from (R, S) -Amlodipine
N-메틸피롤리돈 5ml에 (R,S)-암로디핀 1g 및 L-(+)-타르타르산 0.18g (0.5 당량)을 첨가한 다음, 반응 용액에 디메틸술폭시드 5ml를 첨가하여 완전히 용해시킨 다음, 상온에서 철야 교반하였다. 침전물을 여과하고 아세톤 5ml로 세척한 다음, 디클로로메탄 30ml 및 증류수 10ml를 넣어 슬러리화하고, 2N-NaOH 수용액 1ml를 첨가하여 유기 용액을 분리한 다음, 유기 용액을 감압 증류하여 디클로로메탄을 제거하였다. 잔류물을 디클로로메탄 1ml에 녹인 후 헥산 30ml에 천천히 첨가하여 교체 슬러리화시켜 (R)-(+)-암로디핀 0.43g (이론적 수율 86%)을 얻었다.To 5 ml of N-methylpyrrolidone, 1 g of (R, S) -amlodipine and 0.18 g (0.5 equiv) of L-(+)-tartaric acid were added, and then 5 ml of dimethyl sulfoxide was added to the reaction solution to completely dissolve it. The mixture was stirred overnight at room temperature. The precipitate was filtered and washed with 5 ml of acetone, slurried with 30 ml of dichloromethane and 10 ml of distilled water, 1 ml of 2N-NaOH aqueous solution was added thereto to separate the organic solution, and the organic solution was distilled under reduced pressure to remove dichloromethane. The residue was taken up in 1 ml of dichloromethane and slowly added to 30 ml of hexane to make a slurry slurried to give 0.43 g of (R)-(+)-amlodipine (86% of theoretical yield).
녹는점 : 108~110℃Melting Point: 108 ~ 110 ℃
키랄 HPLC : 99.6% e.e.Chiral HPLC: 99.6% e.e.
[α]D 22 +40.0° (c=1, MeOH)[α] D 22 + 40.0 ° (c = 1, MeOH)
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| US20050009887A1 (en) | 2001-10-24 | 2005-01-13 | Sepracor Inc. | Method of resolving amlodipine racemate |
| CN1915974A (en) * | 2005-08-19 | 2007-02-21 | 扬子江药业集团上海海尼药业有限公司 | Method for splitting Amlodipine |
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| US20050009887A1 (en) | 2001-10-24 | 2005-01-13 | Sepracor Inc. | Method of resolving amlodipine racemate |
| CN1915974A (en) * | 2005-08-19 | 2007-02-21 | 扬子江药业集团上海海尼药业有限公司 | Method for splitting Amlodipine |
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