KR100978498B1 - Method for preparing clopidogrel hydrogensulfate - Google Patents
Method for preparing clopidogrel hydrogensulfate Download PDFInfo
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- KR100978498B1 KR100978498B1 KR1020060100787A KR20060100787A KR100978498B1 KR 100978498 B1 KR100978498 B1 KR 100978498B1 KR 1020060100787 A KR1020060100787 A KR 1020060100787A KR 20060100787 A KR20060100787 A KR 20060100787A KR 100978498 B1 KR100978498 B1 KR 100978498B1
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Abstract
본 발명은 하기 화학식 I 로 표현되는 (+)-(S)-α(2-클로로페닐)-4,5,6,7-테트라히드로티에노[3,2-c]피리디닐-5-메틸 아세테이트 황산수소염, 즉 클로피도그렐 황산수소염의 신규한 제조방법에 관한 것이다. The present invention provides (+)-(S) -α (2-chlorophenyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridinyl-5-methyl represented by the formula A novel process for the preparation of acetate hydrogen sulfate, ie clopidogrel hydrogen sulfate.
(화학식 1)(Formula 1)
클로피도그렐, 황산수소염, 포스포니움, 트리페닐포스핀, 우선성 광학활성 Clopidogrel, hydrogen sulfate, phosphonium, triphenylphosphine, preferential optical activity
Description
본 발명은 하기 화학식 1의 구조를 갖는 우선성 광학활성을 가진 클로피도그렐 황산수소염을 고순도, 고효율로 제조하는 신규한 제조방법에 관한 것이다.The present invention relates to a novel process for producing clopidogrel hydrogen sulfate having a preferential optical activity having the structure of formula (1) with high purity and high efficiency.
상기 화학식 1의 (+)-(S)-α-(2-클로로페닐)-4,5,6,7-테트라히드로티에노[3,2-c]피리디닐-5-메틸 아세테이트 황산수소염(클로피도그렐 황산수소염)은 유럽특허 EP 0099802호 및 EP 0281459호 등에 기재되어 있고, 혈소판 응집저해효과 및 항혈전 효과가 있는 유용한 약물로 알려져 있다.(+)-(S) -α- (2-chlorophenyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridinyl-5-methyl acetate hydrogen sulfate of Chemical Formula 1 ( Clopidogrel hydrogen sulfate) is described in European Patent Nos. EP 0099802 and EP 0281459 and the like, and is known as a useful drug having platelet aggregation inhibitory effect and antithrombotic effect.
본 발명에서 참고하고 있는 유럽특허 EP 0281459호에서는 상기의 화학식 1의 우선성 광학 이성질체만이 혈소판 응집저해효과를 나타내며 좌선성 광학이성질체는 항혈전제로써 작용하지 않는 것으로 기술되어 있다. 이러한 이유로 우선성 광학이성질체만을 선택적으로 제조하는 방법에 대해서 유럽특허 EP 0281459, EP 0465358호, 한국특허 KR 0198503호, KR 7017632호 및 미국특허 US 6573381호 등 많은 자료에서 언급되어 있다. European Patent EP 0281459, which is referred to in the present invention, describes that only the preferred optical isomer of Formula 1 exhibits platelet aggregation inhibitory effect, and the left-handed optical isomer does not act as an antithrombotic agent. For this reason, a method for selectively preparing only the preferential optical isomers is mentioned in many data such as European Patent EP 0281459, EP 0465358, Korean Patent KR 0198503, KR 7017632 and US Patent 6573381.
유럽특허 EP 0281459호 및 EP 0465358호 에서는 하기의 반응식 I과 반응식 II와 같이 화학식 a의 라세미체를 제조한 후 적절한 용매중에서 광학적으로 활성인 산과 반응하여 클로피도그렐 라세미체의 염을 형성하고 일정한 광학적 회전력을 갖는 생성물이 얻어질 때까지 그 염의 재결정화를 반복한 후 적절한 염기에 의해 클로피도그렐 라세미체의 염으로부터 우선성 광학이성질체를 유리시키는 것을 기술하고 있다. 이때 활성인 산으로는 화학식 b의 좌선성 캄퍼-10-설폰산을 명시하고 있다. 또한 적절한 용매로는 아세톤을 명시하고 있다. EP 0281459 and EP 0465358 disclose the preparation of racemates of formula a as shown in Schemes I and II below, followed by reaction with an optically active acid in a suitable solvent to form salts of clopidogrel racemates and The recrystallization of the salts is repeated until a product with rotational power is obtained and the release of the preferred optical isomers from the salts of clopidogrel racemate with the appropriate base is described. The active acid at this time specifies the left-handed camphor-10-sulfonic acid of formula (b). In addition, acetone is specified as a suitable solvent.
(반응식 I)Scheme I
(반응식 II)Scheme II
상기의 반응식 I과 반응식 II에 의해서 우선성 광학이성질체의 클로피도그렐을 제조하는 방법은 라세미체의 광학적분할에 의해서 얻어지므로 수율이 많이 저하되어 공업적으로 타당한 방법이 아니다. 반응식 II에서는 화학식 c의 화합물 2-(2-티에닐)에틸아민으로부터 화학식 d의 화합물 4,5,6,7-테트라히드로-[3,2,c]-테에노피리딘을 제조하는 방법을 제시하고 있으나 이에 대한 신규한 제조방법이 많이 알려지고 있을 뿐만 아니라 상업적으로 구매 가능하다. The method for producing the clopidogrel of the preferential optical isomers according to the above schemes I and II is obtained by optical division of the racemate, so that the yield is greatly reduced and is not an industrially valid method. Scheme II provides a process for preparing compound 4,5,6,7-tetrahydro- [3,2, c] -tenenopyridine of formula d from compound 2- (2-thienyl) ethylamine of formula c. However, a number of new manufacturing methods for this are known and commercially available.
이와 같은 문제점을 극복하기 위하여 한국특허 KR 7017632호 및 미국특허 US 6573381호에서는 하기의 반응식 III와 반응식 IV와 같이 광학적 분할의 과정을 거치지 않고 바로 우선성 광학이성질체의 클로피도그렐을 제조하는 방법을 기술하고 있다. 한국특허 KR 7017632호에서는 반응식 III과 같이 화학식 g의 화합물 N,N'-비스-4,5,6,7-테트라히드로-[3,2,c]-테에노피리딜 메탄과 화학식 h의 화합물 (R)-클로로페닐아세트산 유도체를 반응하여 상기의 화학식 1의 화합물을 얻는 방법에 대해 기술하고 있다. 화학식 h의 화합물에서 X는 할로겐원소, OSO2R 그룹, 에스테르 기, 포스파이트기 및 포스페이트기 등을 기술하고 있다. 하지만 이 경우 N,N'-비스-4,5,6,7-테트라히드로-[3,2,c]-테에노피리딜 메탄을 얻기 위하여 화학식 c의 화합물 2-(2-티에닐)에틸아민과 포름알데히드를 반응시켜야 하는 문제점이 있으며, 제조수율도 낮은 것으로 알려져 있다. 또한 수득한 N,N'-비스-4,5,6,7-테트라히드로-[3,2,c]-테에노피리딜 메탄과 (R)-클로로페닐아세트산 유도체의 반응에서도 화학식 1의 목적화합물이 낮은 수율로 얻어져 공업적으로 적용하기에는 타당하지 않은 것으로 알려져 있다. In order to overcome such a problem, Korean Patent KR 7017632 and US Patent 6573381 describe a method for preparing clopidogrel of a preferred optical isomer without undergoing optical division, as shown in Schemes III and IV below. . Korean Patent KR 7017632 discloses the compound N, N'-bis-4,5,6,7-tetrahydro- [3,2, c] -teenopyridyl methane of formula g and formula h as in Scheme III. The method for obtaining the compound of formula 1 by reacting the compound (R) -chlorophenylacetic acid derivative is described. X in the compounds of formula h describes halogen elements, OSO 2 R groups, ester groups, phosphite groups and phosphate groups and the like. In this case, however, compound 2- (2-thienyl) of formula c is obtained to obtain N, N'-bis-4,5,6,7-tetrahydro- [3,2, c] -tenopyridyl methane. There is a problem in that ethylamine and formaldehyde have to be reacted, and production yield is also known to be low. Also in the reaction of the obtained N, N'-bis-4,5,6,7-tetrahydro- [3,2, c] -tenopyridyl methane with (R) -chlorophenylacetic acid derivative, It is known that the target compound is obtained in low yield and is not suitable for industrial application.
(반응식 III)Scheme III
미국특허 US 6573381호에서는 상기의 화학식 1의 화합물을 얻기 위하여 반응식 IV와 같이 화학식 d의 화합물 4,5,6,7-테트라히드로 티에노 피리딘과 화학식 h의 화합물 (R)-2-클로로 만델산 술포닉 에스테르를 반응하는 것이 기술되어 있다. 화학식 hI의 화합물에서 X는 OSO2R의 술포닐기를 의미한다. 미국특허 US 6573381호에서 언급하고 있는 우선성 광학이성질체의 클로피도그렐을 제조하는 방법은 광학적인 순도측면에서 참고할 만한 제조방법이라 할 수 있다. 하지만 중간체로 사용하 는 (R)-2-클로로 만델산 술포닉 에스테르를 유리하여야 하는 등의 제조상의 어려움으로 공업적으로 적용하기가 쉽지 않다.US Patent No. 6573381 discloses Compound 4,5,6,7-tetrahydro thienopyridine of Formula d and Compound (R) -2-chloromandelic acid of Formula h as in Scheme IV to obtain the compound of Formula 1 above. It is described to react sulfonic esters. In the compound of formula hI X represents the sulfonyl group of OSO 2 R. The method for preparing clopidogrel of the preferred optical isomer mentioned in US Pat. No. 6,657,338 can be referred to as a manufacturing method which can be referred to in terms of optical purity. However, due to manufacturing difficulties, such as (R) -2-chloro-mandelic acid sulfonic ester to be used as an intermediate is difficult to apply industrially.
반응식 IVScheme IV
한국특허 KR 0198503호 및 미국특허 US 6573381호에서는 반응식 V과 같이 화학식 h의 화합물 2-클로로 만델산 술포닉 에스테르 또는 화학식 f의 화합물 2-클로로페닐아세트산 유도체를 화학식 c의 화합물 2-(티엔-2-일)에틸아민과 반응하여 화학식 i의 화합물 α(2(티엔-2-일)에틸아미노)-α-(2-클로로페닐)아세테이트를 제조한 후 산 매질에서 포름알데히드로 고리화 반응하여 화학식 a의 라세믹체의 클로피도그렐 또는 화학식 1의 우선성 광학이성질체의 클로피도그렐을을 제조하는 방법에 대해서 기술하고 있다. 하지만 상기의 제조방법들은 제조공정이 길고 고리화반응등을 진행해야 하는 문제점으로 공업화 하기에는 적절하지 않은 것으로 알려져 있다.Korean Patent KR 0198503 and US Pat. No. 6573381 disclose compound 2-chloro-mandelic acid sulfonic ester of formula h or compound 2-chlorophenylacetic acid derivative of formula f as in Scheme V Reacted with -yl) ethylamine to prepare the compound α (2 (thien-2-yl) ethylamino) -α- (2-chlorophenyl) acetate of formula i, followed by formaldehyde cyclization in an acid medium. A method for producing clopidogrel of the racemic of a or clopidogrel of the preferred optical isomer of formula (1) is described. However, it is known that the above manufacturing methods are not suitable for industrialization due to a long manufacturing process and problems in which a cyclization reaction should be performed.
반응식 VScheme V
이와 같이 광학적으로 순도가 높은 화학식 1의 클로피도그렐을 제조하기 위하여 여러가지 방법이 제안되고 있으나 광학적 분할 또는 난이한 제조공정 등으로 공업화 제법으로 적용하기에는 여러가지 문제점들이 있다.As described above, various methods have been proposed for preparing optically pure clopidogrel of Chemical Formula 1, but there are various problems in applying it to an industrial production method due to optical division or a difficult manufacturing process.
본 발명은 우선성 광회전성을 가진 클로피도그렐 황산수소염을 고순도, 고효율 및 고수율로 제조하는 방법을 제공하는 것을 목적으로 한다.It is an object of the present invention to provide a method for producing clopidogrel hydrogen sulfate having preferential light rotation with high purity, high efficiency and high yield.
본 발명의 일실시예에 따른 제조방법은, 화학식 d의 화합물 4,5,6,7-테트라히드로 티에노[3.2-c] 피리딘과 화학식 2의 (R)-2-클로로 만델산 포스포니움 에스테르 유도체의 반응에 의해 고순도의 화학식 1의 클로피도그렐을 제조하는 것이다. According to one embodiment of the present invention, the compound of formula d, 4,5,6,7-tetrahydro thieno [3.2-c] pyridine and (R) -2-chloro mandelic acid phosphonium of formula (2) By the reaction of the ester derivative to produce a high purity clopidogrel of formula (1).
(화학식 1)(Formula 1)
(상기 화학식 2에서,(In Formula 2,
R은 수소원자 또는 C1-C4의 알킬기이며,R is a hydrogen atom or an alkyl group of C 1 -C 4 ,
X는 OP(R1)3이며, R1은 C1-C4의 알킬기, 페닐과 같은 방향족 고리화합물, 4-니트로페닐, 4-메톡시페닐, 4-클로로페닐기과 같은 치환된 방향족 고리화합물이다.) X is OP (R 1 ) 3 , R 1 is an alkyl group of C 1 -C 4, an aromatic cyclic compound such as phenyl, a substituted aromatic cyclic compound such as 4-nitrophenyl, 4-methoxyphenyl, 4-chlorophenyl group .)
(상기의 화학식 3에서,(In Formula 3,
R은 C1-C4의 알킬기, 페닐과 같은 방향족 고리화합물 또는 4-니트로페닐, 4-메톡시페닐, 4-클로로페닐기과 같은 치환된 방향족 고리화합물이다.) R is an alkyl group of C 1 -C 4, an aromatic cyclic compound such as phenyl or a substituted aromatic cyclic compound such as 4-nitrophenyl, 4-methoxyphenyl, 4-chlorophenyl group.)
(반응식 VI)Scheme VI
(반응식 VII)Scheme VII
(반응식 VIII)Scheme VIII
본 발명을 좀 더 상세하게 설명하면 다음과 같다.The present invention is described in more detail as follows.
상기의 반응식 VI에 기술한 바와 같이 트리페닐포스핀 또는 트리알킬포스틴류와 반응하여 화학식 3의 클로로포스포니움이온을 생성할수 있는 물질로는 사염화 탄소, 헥사클로로아세톤 및 헥사클로로에탄 등이 있으며, 공업적으로 가장 바람직한 것은 헥사클로로에탄이다. 사용하는 포스핀 유도체는 염소 제공 물질에 대해서 0.9~1당량이 적절하며, 바람직하게로는 1당량을 사용하는 것이다. 반응은 -20~20℃ 사이에서 진행할 수 있으나 0 ℃ 이하 에서 진행하는 것이 바람직하며, 반응시간은 1~5시간정도가 가능하나 포스핀 유도체에 따라 1~3시간정도가 바람직하다. 화학식 3의 클로로포스포니움이온은 분리나 정제 및 더 이상의 처리없이 바로 다음공정으로 진행한다. 반응식 VII에 기술한 바와 같이 화학식 j의 화합물 (R)-2-히드록시-2(2-클로로페닐)아세테이트를 투입하여 화학식 II의 포스포니움 에스테르를 제조할 수 있다.As described in Scheme VI, a substance capable of reacting with triphenylphosphine or trialkylphosphines to produce chlorophosphonium ions of Formula 3 includes carbon tetrachloride, hexachloroacetone and hexachloroethane. Most industrially preferred is hexachloroethane. The phosphine derivative to be used is suitably 0.9 to 1 equivalents based on the chlorine providing substance, preferably 1 equivalent. The reaction can be carried out between -20 ~ 20 ℃ but preferably at below 0 ℃, the reaction time is possible for about 1 to 5 hours, but 1 to 3 hours is preferred depending on the phosphine derivative. Chlorophosphonium ions of Formula 3 proceed directly to the next step without separation, purification and further treatment. As described in Scheme VII, the compound (R) -2-hydroxy-2 (2-chlorophenyl) acetate of formula j may be added to prepare a phosphonium ester of formula II.
화학식 2를 제조하는 방법은 상기의 반응식 VI 및 반응식 VII에 따라 양성자성 또는 비양성자성 유기용매의 존재 하에서 유기 또는 무기염기성 시약의 존재하에서 제조할 수 있다. 사용할 수 있는 유기용매로는 메틸렌클로라이드, 클로로포름, 디클로로에탄, 아세토니트릴, 테트라히드로퓨란, 메틸 에틸 케톤, 메틸 이소 부틸 케톤, 이소프로필 아세테이트 및 에틸 아세테이트 등이며, 가장 바람직하게는 메틸렌클로라이드 및 아세토니트릴 이다. 화학식 2를 제조하는 반응은 상기의 유기용매하에서 -10 ~ 5 ℃ 사이에서 진행할 수 있으나 0 ℃ 에서 진행하는 것이 더 바람직하며, 약 0.5 ~ 5 시간의 반응시간이 요구되나 2시간 정도 진행하는 것이 더 바람직하다. 상기 반응 온도가 -10℃ 미만이면 반응에 많은 시간이 요구되며, 5℃를 초과하면 반응 부산물이 많이 생성되어 반응수율이 저하되는 효과가 발생한다. 화학식 2의 화합물은 바람직하게는 (R)-2-(2-클로로페닐)-2-(트리페닐포스포니움)아세트산 메틸 에스테르 클로라이드, (R)-2-(2-클로로페닐)-2-(트리메틸포스포니움)아세트산 메틸 에스테르 클로라이드, (R)-2-(2-클로로페닐)-2-(트리에틸포스포니움)아세트산 메틸 에스테르 클로라이드 또는 (R)-2-(2-클로로페닐)-2-(트리-t-부틸포스포니움)아세트산 메틸 에스테르 클로라이드 이다.The process for preparing Formula 2 may be prepared in the presence of an organic or inorganic basic reagent in the presence of a protic or aprotic organic solvent according to Schemes VI and VII above. Organic solvents that can be used are methylene chloride, chloroform, dichloroethane, acetonitrile, tetrahydrofuran, methyl ethyl ketone, methyl isobutyl ketone, isopropyl acetate and ethyl acetate and the like, most preferably methylene chloride and acetonitrile. . The reaction for preparing Formula 2 may proceed between -10 to 5 ° C. under the organic solvent, but more preferably at 0 ° C., and a reaction time of about 0.5 to 5 hours is required but more preferably about 2 hours. desirable. If the reaction temperature is less than -10 ℃, a lot of time is required for the reaction, if the reaction temperature exceeds 5 ℃ to produce a lot of reaction by-products occur the effect of lowering the reaction yield. The compound of formula (2) is preferably (R) -2- (2-chlorophenyl) -2- (triphenylphosphonium) acetic acid methyl ester chloride, (R) -2- (2-chlorophenyl) -2- (Trimethylphosphonium) acetic acid methyl ester chloride, (R) -2- (2-chlorophenyl) -2- (triethylphosphonium) acetic acid methyl ester chloride or (R) -2- (2-chlorophenyl) 2- (tri-t-butylphosphonium) acetic acid methyl ester chloride.
화학식 2의 화합물을 분리나 정제 없이 바로 화학식 1의 화합물을 제조하는 것이 본 발명의 특징이나 중간체들의 물성 및 광학적인 순도를 측정하기 위하여 분리 및 결정화 작업을 진행하였는데 이때 사용할 수 있는 용매로는 메탄올, 에탄올, 이소프로판올, 또는 이들의 적절한 혼합용매의 사용이 가능하다. 대부분의 화학식 2의 화합물들은 점도가 높은 무색의 액상으로 얻어졌으나 이들을 상기에 언급한 적절한 용매를 이용할 경우 결정화 과정을 진행할 수 있었으며, 메탄올이 가장 바람직하다.The preparation of the compound of Formula 1 without separating or purifying the compound of Formula 2 was performed in the separation and crystallization operation to measure the physical properties and optical purity of the characteristics of the present invention or intermediates. Use of ethanol, isopropanol, or a suitable mixed solvent thereof is possible. Most of the compounds of formula (2) were obtained in a colorless liquid phase with high viscosity, but they could be crystallized using the appropriate solvents mentioned above, and methanol is most preferred.
화학식 2를 제조하기 위하여 사용되는 메틸-(R)-2-클로로 만델레이트는 상업적으로 구매가능한 (R)-2-클로로 만델릭에시드를 황산과 같은 강산조건하에서 메탄올을 이용하여 제조할 수 있다. Methyl- (R) -2-chloro mandelate used to prepare formula (2) can be prepared commercially available (R) -2-chloro mandelic acid using methanol under strong acid conditions such as sulfuric acid.
화학식 2의 화합물과 화학식 d의 화합물 4,5,6,7-테트라히드로 티에노[3,2-c] 피리딘의 반응은 양성자성 또는 비양성자성 유기용매 하에서 진행할 수 있는데 예를 들면, 아세토니트릴, 디메틸포름아미드; 방향족 탄화수소, 바람직하게는 벤 젠, 톨루엔, 크실렌; 염소화 용매, 바람직하게는 메틸렌클로라이드, 클로로포름, 디클로로에탄; 케톤류, 바람직하게는 아세톤, 메틸에틸케톤, 메틸 이소부틸 케톤; 에스테르류, 바람직하게는 이소프로필 아세테이트, 에틸아세테이트; 및 알코올류, 바람직하게는 메탄올, 에탄올, n-프로판올, 부탄올 또는 이들의 혼합용매로부터 선택가능하다. 본 발명에서 가장 바람직하게는 메틸렌클로라이드, 아세톤 및 아세토니트릴이다. The reaction of the compound of formula 2 with compound 4,5,6,7-tetrahydro thieno [3,2-c] pyridine can proceed under protic or aprotic organic solvents, for example, acetonitrile. , Dimethylformamide; Aromatic hydrocarbons, preferably benzene, toluene, xylene; Chlorinated solvents, preferably methylene chloride, chloroform, dichloroethane; Ketones, preferably acetone, methyl ethyl ketone, methyl isobutyl ketone; Esters, preferably isopropyl acetate, ethyl acetate; And alcohols, preferably methanol, ethanol, n-propanol, butanol or a mixed solvent thereof. Most preferred in the present invention are methylene chloride, acetone and acetonitrile.
상기의 반응은 또한 적절한 유기 또는 무기 염기성 시약의 존재하에서 진행할 수 있는데 유기 염기성 시약으로는 트리에틸아민, 디메틸아닐린, 디에틸아닐린 및 테트라메틸구아니딘 등을 사용할 수 있으며, 무기 염기성 시약으로는 알칼리금속 또는 알칼리토금속 카보네이트류를 사용할 수 있는데 바람직하게는 소듐카보네이트, 포타슘카보네이트, 소듐바이카보네이트 및 포타슘바이카보네이트 등이다. 4,5,6,7-테트라히드로 티에노 피리딘은 상기의 화학식 2의 화합물에 대해서 화학양론적 비율로 사용할 수 있으나 바람직하게는 0.4~1 몰비를 사용하는 것이다. The reaction can also proceed in the presence of a suitable organic or inorganic basic reagent. Examples of organic basic reagents include triethylamine, dimethylaniline, diethylaniline, tetramethylguanidine, and the like. Alkaline earth metal carbonates can be used, preferably sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. 4,5,6,7-tetrahydro thienopyridine may be used in a stoichiometric ratio with respect to the compound of Formula 2, but preferably 0.4 to 1 molar ratio.
상기의 반응은 적절한 온도범위에서 진행될 수 있는데 바람직하게는 20~90℃의 온도범위에서 진행한다. 이것은 용매의 비점에 따른 광학적인 순도와의 상관관계 때문이다. 구체적으로, 반응에 사용하는 용매의 종류에 따라 반응시간에 많은 차이가 발생하는데 특히 85℃이상의 온도에서 반응을 진행할 수 있는 톨루엔, 메틸 이소 부틸 케톤 등의 용매에서는 광학적인 순도가 78~85%로 비점이 85℃ 이하로 낮은 용매를 사용할 때보다 조금 떨어지는 결과를 얻었다. 비점이 낮은 메틸렌클로라이드 및 아세토니트릴 같은 용매에서는 광학적인 순도가 95% 이상 되는 화학식 1을 제조할 수 있다. 반응 온도가 20℃ 미만인 경우에는 반응성이 떨어진다. 반응시간은 1 내지 5시간인 것이 바람직하다. 이 반응시간의 범위는 용매의 선택에 의한 비점차이로 인해 결정된 것이다. 비점이 높은 경우는 반응시간이 단축되나 광학순도가 떨어지며, 비점이 낮은 경우는 반대의 효과를 나타낸다. The reaction may proceed in an appropriate temperature range, preferably in the temperature range of 20 ~ 90 ℃. This is due to the correlation of optical purity with the boiling point of the solvent. Specifically, there are many differences in the reaction time depending on the type of solvent used for the reaction. In particular, solvents such as toluene and methyl isobutyl ketone, which can proceed at a temperature of 85 ° C. or higher, have an optical purity of 78 to 85%. The result was that the boiling point was slightly lower than that of using a solvent having a lower temperature of 85 ° C or lower. In solvents such as methylene chloride and acetonitrile having low boiling points, Formula 1 may be prepared having an optical purity of 95% or more. Reactivity is inferior when reaction temperature is less than 20 degreeC. It is preferable that reaction time is 1 to 5 hours. The range of this reaction time is determined due to the difference in boiling point by the choice of solvent. If the boiling point is high, the reaction time is shortened, but the optical purity is lowered. If the boiling point is low, the opposite effect is obtained.
다음의 실시예를 통하여 본 발명을 좀 더 구체적으로 설명하고자 한다.Through the following examples will be described the present invention in more detail.
실시예Example
메틸-(R)-2-클로로 만델레이트는 미국특허 US 6573381호에 개시된 방법을 참조하여 제조하였다.Methyl- (R) -2-chloro mandelate was prepared with reference to the method disclosed in US Pat. No. 6573381.
실시예 1. (R)-2-(2-클로로페닐)-2-(트리페닐포스포니움)아세트산 메틸 에스테르 클로라이드의 제조Example 1.Preparation of (R) -2- (2-chlorophenyl) -2- (triphenylphosphonium) acetic acid methyl ester chloride
트리페닐포스핀 99g(0.38mol)과 헥사클로로에탄 88g(0.38mol)을 메틸렌클로라이드 1000ml에 투입하고 0℃에서 2시간 반응한 후 반응액의 온도를 -10~-5℃로 냉각한 후 메틸-(R)-2-클로로 만델레이트 62.2g(0.31mol)을 메틸렌클로라이드 200ml에 투입하였다. 트리에틸아민 80g을 투입한 후 0℃이하에서 2시간 교반하였다. 반응이 완료되면 증류수 500ml를 가하여 30분간 교반한 후 층분리하여 물층을 폐기하였다. 유기층을 진공하에서 농축을 진행하여 점도가 높은 맑은 액을 얻었다. 농축된 여과액에 메탄올 200ml를 가하여 상온에서 5시간 교반하여 결정을 석출시킨 후 5~10℃로 냉각하여 2시간 교반한 후 여과하였다. 10℃로 냉각된 IPA 30ml로 세척하고 건조하여 목적화합물 178.8g을 수득하였다.99 g (0.38 mol) of triphenylphosphine and 88 g (0.38 mol) of hexachloroethane were added to 1000 ml of methylene chloride and reacted at 0 ° C. for 2 hours. The reaction solution was cooled to -10 to -5 ° C., and then 62.2 g (0.31 mol) of (R) -2-chloro mandelate was added to 200 ml of methylene chloride. After adding 80 g of triethylamine, the mixture was stirred at 0 ° C. or less for 2 hours. After the reaction was completed, 500 ml of distilled water was added thereto, stirred for 30 minutes, and the layers were separated to discard the water layer. The organic layer was concentrated under vacuum to obtain a clear liquid having a high viscosity. 200 ml of methanol was added to the concentrated filtrate, and stirred at room temperature for 5 hours to precipitate crystals. The mixture was cooled to 5-10 ° C., stirred for 2 hours, and filtered. Washed with 30 ml of IPA cooled to 10 ℃ and dried to give 178.8 g of the target compound.
수율 : 98 %Yield: 98%
광학순도 : 99.5%Optical purity: 99.5%
실시예 2. (R)-2-(2-클로로페닐)-2-(트리메틸포스포니움)아세트산 메틸 에스테르 클로라이드의 제조Example 2. Preparation of (R) -2- (2-chlorophenyl) -2- (trimethylphosphonium) acetic acid methyl ester chloride
트리메틸포스핀 28.9g(0.38mol)과 헥사클로로에탄 88g(0.38mol)을 메틸렌클로라이드 1000ml에 투입하고 0℃에서 5시간 반응한 후 반응액의 온도를 -10~-5℃로 냉각한 후 메틸-(R)-2-클로로 만델레이트 62.2g(0.31mol)을 메틸렌클로라이드 200ml에 투입하였다. 트리에틸아민 80g을 투입한 후 0℃이하에서 3시간 교반하였다. 반응이 완료되면 증류수 500ml를 가하여 30분간 교반한 후 층분리하여 물층을 폐기하였다. 유기층을 진공하에서 농축을 진행하면 점도가 높은 맑은 액을 얻었다. 농축된 여과액에 메탄올 200ml를 가하여 상온에서 5시간 교반하여 결정을 석출시킨 후 5~10℃로 냉각하여 2시간 교반한 후 여과하였다. 10℃로 냉각된 IPA 30ml로 세척하고 건조하여 목적화합물 102.7g을 수득하였다.28.9 g (0.38 mol) of trimethylphosphine and 88 g (0.38 mol) of hexachloroethane were added to 1000 ml of methylene chloride and reacted at 0 ° C. for 5 hours, and then the reaction solution was cooled to −10 to −5 ° C., followed by methyl- 62.2 g (0.31 mol) of (R) -2-chloro mandelate was added to 200 ml of methylene chloride. After 80 g of triethylamine was added, the mixture was stirred at 0 ° C or less for 3 hours. After the reaction was completed, 500 ml of distilled water was added thereto, stirred for 30 minutes, and the layers were separated to discard the water layer. The organic layer was concentrated in vacuo to give a clear liquid having a high viscosity. 200 ml of methanol was added to the concentrated filtrate, and stirred at room temperature for 5 hours to precipitate crystals. The mixture was cooled to 5-10 ° C., stirred for 2 hours, and filtered. Washed with 30 ml of IPA cooled to 10 ℃ and dried to give 102.7 g of the target compound.
수율 : 92 %Yield: 92%
광학순도 : 98.1%Optical purity: 98.1%
실시예 3. (R)-2-(2-클로로페닐)-2-(트리에틸포스포니움)아세트산 메틸 에스 테르 클로라이드의 제조Example 3. Preparation of (R) -2- (2-chlorophenyl) -2- (triethylphosphonium) acetic acid methyl ester chloride
트리에틸포스핀 44.9g(0.38mol)과 헥사클로로에탄 88g(0.38mol)을 메틸렌클로라이드 1000ml에 투입하고 0℃에서 3시간 반응한 후 반응액의 온도를 -10~-5℃로 냉각한 후 메틸-(R)-2-클로로 만델레이트 62.2g(0.31mol)을 메틸렌클로라이드 200ml를 투입한다. 트리에틸아민 80g을 투입한 후 0℃이하에서 3시간 교반한다. 반응이 완료되면 증류수 500ml를 가하여 30분간 교반한 후 층분리하여 물층을 폐기한다. 유기층을 진공하에서 농축을 진행하면 점도가 높은 맑은 액을 얻는다. 농축된 여과액에 메탄올 200ml를 가하여 상온에서 5시간 교반하여 결정을 석출시킨 후 5~10℃로 냉각하여 2시간 교반한 후 여과한다. 10℃로 냉각된 IPA 30ml로 세척하고 건조하여 목적화합물 120g을 수득하였다.44.9 g (0.38 mol) of triethylphosphine and 88 g (0.38 mol) of hexachloroethane were added to 1000 ml of methylene chloride and reacted at 0 ° C. for 3 hours, and the reaction solution was cooled to -10 to -5 ° C. 62.2 g (0.31 mol) of-(R) -2-chloro mandelate are charged with 200 ml of methylene chloride. After adding 80 g of triethylamine, the mixture was stirred at 0 ° C. or less for 3 hours. After the reaction is completed, 500 ml of distilled water is added, the mixture is stirred for 30 minutes, and the layers are separated to discard the water layer. The organic layer is concentrated in vacuo to give a clear liquid with high viscosity. 200 ml of methanol was added to the concentrated filtrate and stirred at room temperature for 5 hours to precipitate crystals. The mixture was cooled to 5-10 ° C., stirred for 2 hours, and filtered. Washed with 30 ml of IPA cooled to 10 ℃ and dried to give 120 g of the target compound.
수율 : 94 %Yield: 94%
광학순도 : 98.8%Optical purity: 98.8%
실시예 4. (R)-2-(2-클로로페닐)-2-(트리-t-부틸포스포니움)아세트산 메틸 에스테르 클로라이드의 제조Example 4. Preparation of (R) -2- (2-chlorophenyl) -2- (tri-t-butylphosphonium) acetic acid methyl ester chloride
트리-t-부틸포스핀 76.9g(0.38mol)과 헥사클로로에탄 88g(0.38mol)을 메틸렌클로라이드 1000ml에 투입하고 0℃에서 2시간 반응한 후 반응액의 온도를 -10~-5℃로 냉각한 후 메틸-(R)-2-클로로 만델레이트 62.2g(0.31mol)을 메틸렌클로라이드 200ml를 투입하였다. 트리에틸아민 80g을 투입한 후 0℃이하에서 2시간 교반하였다. 반응이 완료되면 증류수 500ml를 가하여 30분간 교반한 후 층분리하여 물층을 폐기하였다. 유기층을 진공하에서 농축을 진행하여 점도가 높은 맑은 액을 얻었다. 농축된 여과액에 메탄올 200ml를 가하여 상온에서 5시간 교반하여 결정을 석출시킨 후 5~10℃로 냉각하여 2시간 교반한 후 여과하였다. 10℃로 냉각된 IPA 30ml로 세척하고 건조하여 목적화합물 159.7g을 수득하였다.76.9 g (0.38 mol) of tri-t-butylphosphine and 88 g (0.38 mol) of hexachloroethane were added to 1000 ml of methylene chloride, and reacted at 0 ° C. for 2 hours. Then, 200 ml of methylene chloride was added to 62.2 g (0.31 mol) of methyl- (R) -2-chloro mandelate. After adding 80 g of triethylamine, the mixture was stirred at 0 ° C. or less for 2 hours. After the reaction was completed, 500 ml of distilled water was added thereto, stirred for 30 minutes, and the layers were separated to discard the water layer. The organic layer was concentrated under vacuum to obtain a clear liquid having a high viscosity. 200 ml of methanol was added to the concentrated filtrate, and stirred at room temperature for 5 hours to precipitate crystals. The mixture was cooled to 5-10 ° C., stirred for 2 hours, and filtered. Washed with 30 ml of IPA cooled to 10 ℃ and dried to give 159.7 g of the target compound.
수율 : 94 %Yield: 94%
광학순도 : 99.1%Optical purity: 99.1%
실시예 5. (R)-2-(2-클로로페닐)-2-(트리페닐포스포니움)아세트산 메틸 에스테르 클로라이드의 제조Example 5 Preparation of (R) -2- (2-chlorophenyl) -2- (triphenylphosphonium) acetic acid methyl ester chloride
트리페닐포스핀 99g(0.38mol)과 사염화탄소 58.5g(0.38mol)을 메틸렌클로라이드 1000ml에 투입하고 0℃에서 3시간 반응한 후 반응액의 온도를 -10~-5℃로 냉각한 후 메틸-(R)-2-클로로 만델레이트 62.2g(0.31mol)을 메틸렌클로라이드 200ml에 투입하였다. 트리에틸아민 80g을 투입한 후 0℃이하에서 2시간 교반하였다. 반응이 완료되었을 때 증류수 500ml를 가하여 30분간 교반한 후 층분리하여 물층을 폐기하였다. 유기층을 진공하에서 농축을 진행하여 점도가 높은 맑은 액을 얻었다. 농축된 여과액에 메탄올 200ml를 가하여 상온에서 5시간 교반하여 결정을 석출시킨 후 5~10℃로 냉각하여 2시간 교반한 후 여과하였다. 10℃로 냉각된 IPA 30ml로 세척하고 건조하여 목적화합물 169.7g을 수득하였다.99 g (0.38 mol) of triphenylphosphine and 58.5 g (0.38 mol) of carbon tetrachloride were added to 1000 ml of methylene chloride and reacted at 0 ° C. for 3 hours, and the reaction solution was cooled to -10 to -5 ° C., followed by 62.2 g (0.31 mol) of R) -2-chloro mandelate was added to 200 ml of methylene chloride. After adding 80 g of triethylamine, the mixture was stirred at 0 ° C. or less for 2 hours. When the reaction was completed, 500ml of distilled water was added thereto, stirred for 30 minutes, and the layers were separated to discard the water layer. The organic layer was concentrated under vacuum to obtain a clear liquid having a high viscosity. 200 ml of methanol was added to the concentrated filtrate, and stirred at room temperature for 5 hours to precipitate crystals. The mixture was cooled to 5-10 ° C., stirred for 2 hours, and filtered. Washed with 30 ml of IPA cooled to 10 ℃ and dried to give 169.7 g of the target compound.
수율 : 93 %Yield: 93%
광학순도 : 99.2%Optical purity: 99.2%
실시예 6. (R)-2-(2-클로로페닐)-2-(트리메틸포스포니움)아세트산 메틸 에스테르 클로라이드의 제조Example 6 Preparation of (R) -2- (2-chlorophenyl) -2- (trimethylphosphonium) acetic acid methyl ester chloride
트리메틸포스핀 28.9g(0.38mol)과 사염화탄소 58.5g(0.38mol)을 메틸렌클로라이드 1000ml에 투입하고 0℃에서 5시간 반응한 후 반응액의 온도를 -10~-5℃로 냉각한 후 메틸-(R)-2-클로로 만델레이트 62.2g(0.31mol)을 메틸렌클로라이드 200ml에 투입하였다. 트리에틸아민 80g을 투입한 후 0℃이하에서 5시간 교반하였다. 반응이 완료되었을 때 증류수 500ml를 가하여 30분간 교반한 후 층분리하여 물층을 폐기하였다. 유기층을 진공하에서 농축을 진행하여 점도가 높은 맑은 액을 얻었다. 농축된 여과액에 메탄올 200ml를 가하여 상온에서 5시간 교반하여 결정을 석출시킨 후 5~10℃로 냉각하여 2시간 교반한 후 여과하였다. 10℃로 냉각된 IPA 30ml로 세척하고 건조하여 목적화합물 98.2g을 수득하였다.28.9 g (0.38 mol) of trimethylphosphine and 58.5 g (0.38 mol) of carbon tetrachloride were added to 1000 ml of methylene chloride and reacted at 0 ° C. for 5 hours, and then the reaction solution was cooled to -10 to -5 ° C. and then methyl- ( 62.2 g (0.31 mol) of R) -2-chloro mandelate was added to 200 ml of methylene chloride. After 80 g of triethylamine was added, the mixture was stirred at 0 ° C or less for 5 hours. When the reaction was completed, 500ml of distilled water was added thereto, stirred for 30 minutes, and the layers were separated to discard the water layer. The organic layer was concentrated under vacuum to obtain a clear liquid having a high viscosity. 200 ml of methanol was added to the concentrated filtrate, and stirred at room temperature for 5 hours to precipitate crystals. The mixture was cooled to 5-10 ° C., stirred for 2 hours, and filtered. Washed with 30 ml of IPA cooled to 10 ℃ and dried to give 98.2 g of the target compound.
수율 : 88 %Yield: 88%
광학순도 : 96.5%Optical purity: 96.5%
실시예 7. (R)-2-(2-클로로페닐)-2-(트리에틸포스포니움)아세트산 메틸 에스테르 클로라이드의 제조Example 7. Preparation of (R) -2- (2-chlorophenyl) -2- (triethylphosphonium) acetic acid methyl ester chloride
트리에틸포스핀 44.9g(0.38mol)과 사염화탄소 58.5g(0.38mol)을 메틸렌클로 라이드 1000ml에 투입하고 0℃에서 5시간 반응한 후 반응액의 온도를 -10~-5℃로 냉각한 후 메틸-(R)-2-클로로 만델레이트 62.2g(0.31mol)을 메틸렌클로라이드 200ml에 투입하였다. 트리에틸아민 80g을 투입한 후 0℃이하에서 3시간 교반하였다. 반응이 완료되었을 때 증류수 500ml를 가하여 30분간 교반한 후 층분리하여 물층을 폐기하였다. 유기층을 진공하에서 농축을 진행하여 점도가 높은 맑은 액을 얻었다. 농축된 여과액에 메탄올 200ml를 가하여 상온에서 5시간 교반하여 결정을 석출시킨 후 5~10℃로 냉각하여 2시간 교반한 후 여과하였다. 10℃로 냉각된 IPA 30ml로 세척하고 건조하여 목적화합물 116.2g을 수득하였다.44.9 g (0.38 mol) of triethylphosphine and 58.5 g (0.38 mol) of carbon tetrachloride were added to 1000 ml of methylene chloride, reacted at 0 ° C. for 5 hours, and the reaction solution was cooled to -10 to -5 ° C. 62.2 g (0.31 mol) of-(R) -2-chloro mandelate were added to 200 ml of methylene chloride. After 80 g of triethylamine was added, the mixture was stirred at 0 ° C or less for 3 hours. When the reaction was completed, 500ml of distilled water was added thereto, stirred for 30 minutes, and the layers were separated to discard the water layer. The organic layer was concentrated under vacuum to obtain a clear liquid having a high viscosity. 200 ml of methanol was added to the concentrated filtrate, and stirred at room temperature for 5 hours to precipitate crystals. The mixture was cooled to 5-10 ° C., stirred for 2 hours, and filtered. Washed with 30 ml of IPA cooled to 10 ℃ and dried to give 116.2 g of the target compound.
수율 : 91 %Yield: 91%
광학순도 : 98.3%Optical purity: 98.3%
실시예 8. (R)-2-(2-클로로페닐)-2-(트리-t-부틸포스포니움)아세트산 메틸 에스테르 클로라이드의 제조Example 8 Preparation of (R) -2- (2-chlorophenyl) -2- (tri-t-butylphosphonium) acetic acid methyl ester chloride
트리-t-부틸포스핀 76.9g(0.38mol)과 사염화탄소 58.5g(0.38mol)을 메틸렌클로라이드 1000ml에 투입하고 0℃에서 3시간 반응한 후 반응액의 온도를 -10~-5℃로 냉각한 후 메틸-(R)-2-클로로 만델레이트 62.2g(0.31mol)을 메틸렌클로라이드 200ml에 투입하였다. 트리에틸아민 80g을 투입한 후 0℃이하에서 3시간 교반하였다. 반응이 완료되었을 때 증류수 500ml를 가하여 30분간 교반한 후 층분리하여 물층을 폐기하였다. 유기층을 진공하에서 농축을 진행하여 점도가 높은 맑은 액을 얻 었다. 농축된 여과액에 메탄올 200ml를 가하여 상온에서 5시간 교반하여 결정을 석출시킨 후 5~10℃로 냉각하여 2시간 교반한 후 여과하였다. 10℃로 냉각된 IPA 30ml로 세척하고 건조하여 목적화합물 148.5g을 수득하였다.76.9 g (0.38 mol) of tri-t-butylphosphine and 58.5 g (0.38 mol) of carbon tetrachloride were added to 1000 ml of methylene chloride and reacted at 0 ° C. for 3 hours, and the reaction solution was cooled to -10 to -5 ° C. 62.2 g (0.31 mol) of methyl- (R) -2-chloro mandelate was added to 200 ml of methylene chloride. After 80 g of triethylamine was added, the mixture was stirred at 0 ° C or less for 3 hours. When the reaction was completed, 500ml of distilled water was added thereto, stirred for 30 minutes, and the layers were separated to discard the water layer. The organic layer was concentrated under vacuum to obtain a clear liquid having a high viscosity. 200 ml of methanol was added to the concentrated filtrate, and stirred at room temperature for 5 hours to precipitate crystals. The mixture was cooled to 5-10 ° C., stirred for 2 hours, and filtered. Washed with 30 ml of IPA cooled to 10 ℃ and dried to give 148.5 g of the target compound.
수율 : 94 %Yield: 94%
광학순도 : 99.2%Optical purity: 99.2%
실시예 9. (+)-(S)-α-(2-클로로페닐)-4,5,6,7-테트라히드로티에노[3,2-c]피리디닐-5-메틸 아세테이트 황산수소염(클로피도그렐 황산수소염)의 제조Example 9 (+)-(S) -α- (2-Chlorophenyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridinyl-5-methyl acetate hydrogen sulfate ( Preparation of Clopidogrel Hydrogen Sulfate)
4,5,6,7-테트라히드로티에노[3,2-c]피리딘 56.6 g ( 0.407 mol)을 아세토니트릴 500ml에 가하여 희석한 후 포타슘 카보네이트 102. 3g(2eq, 0.74 mol)을 투입하였다. 반응 혼합물을 80℃로 가온한 후 아세토니트릴 200ml에 용해한 (R)-2-(2-클로로페닐)-2-(트리페닐포스포니움)아세트산 메틸 에스테르 클로라이드 178g(0.37 mol)을 천천히 가하였다. 투입이 완료된 후 1시간 더 같은 온도에서 반응한 후 20도로 냉각하여 생성된 고체를 여과하고 여액을 농축하였다. 농축된 여액에 에틸아세테이트 1500 ml를 투입한 후 진한황산 39ml를 천천히 가하였다. 진한황산의 투입이 완료되면 가온하여 1시간 동안 환류반응을 진행하였다. 반응액을 20도로 냉각하고 1시간 교반한 후 생성된 고체를 여과하고 건조하여 백색의 목적화합물 142.6 g을 얻었다.56.6 g (0.407 mol) of 4,5,6,7-tetrahydrothieno [3,2-c] pyridine was added to 500 ml of acetonitrile and diluted. 102. 3 g (2eq, 0.74 mol) of potassium carbonate was added thereto. The reaction mixture was warmed to 80 ° C. and then 178 g (0.37 mol) of (R) -2- (2-chlorophenyl) -2- (triphenylphosphonium) acetic acid methyl ester chloride dissolved in 200 ml of acetonitrile were slowly added. After the addition was completed, the reaction was carried out at the same temperature for 1 hour and then cooled to 20 degrees to filter the resulting solid and concentrated the filtrate. 1500 ml of ethyl acetate was added to the concentrated filtrate, and 39 ml of concentrated sulfuric acid was slowly added thereto. When the addition of concentrated sulfuric acid was completed, the mixture was heated to reflux for 1 hour. The reaction solution was cooled to 20 degrees, stirred for 1 hour, and the resulting solid was filtered and dried to yield 142.6 g of a white target compound.
수율 : 92 %Yield: 92%
광학순도 : 99.4 %Optical purity: 99.4%
실시예 10. (+)-(S)-α-(2-클로로페닐)-4,5,6,7-테트라히드로티에노[3,2-c]피리디닐-5-메틸 아세테이트 황산수소염(클로피도그렐 황산수소염)의 제조Example 10. (+)-(S) -α- (2-Chlorophenyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridinyl-5-methyl acetate hydrogen sulfate ( Preparation of Clopidogrel Hydrogen Sulfate)
4,5,6,7-테트라히드로티에노[3,2-c]피리딘 53.4g (0.384 mol)에 아세토니트릴 450ml를 가하여 희석한 후 포타슘 카보네이트 96.7g(2eq, 0.7 mol)을 투입하였다. 반응 혼합물을 80℃로 가온한 후 아세토니트릴 150ml에 용해한 (R)-2-(2-클로로페닐)-2-(트리메틸포스포니움)아세트산 메틸 에스테르 클로라이드 102.7 g(0.35 mol)을 천천히 가하였다. 투입이 완료된 후 3시간 더 같은 온도에서 반응한 후 20도로 냉각하여 생성된 고체를 여과하고 여액을 농축하였다. 농축된 여액에 에틸아세테이트 1200 ml를 투입한 후 진한황산 37ml를 천천히 가하였다. 진한황산의 투입이 완료되면 가온하여 1시간 동안 환류반응을 진행하였다. 반응액을 20도로 냉각하고 1시간 교반한 후 생성된 고체를 여과하고 건조하여 백색의 목적화합물 124.7g을 얻었다.450 ml of acetonitrile was added to 53.4 g (0.384 mol) of 4,5,6,7-tetrahydrothieno [3,2-c] pyridine, followed by dilution, and 96.7 g (2eq, 0.7 mol) of potassium carbonate was added thereto. After the reaction mixture was warmed to 80 ° C., 102.7 g (0.35 mol) of (R) -2- (2-chlorophenyl) -2- (trimethylphosphonium) acetic acid methyl ester chloride dissolved in 150 ml of acetonitrile was slowly added. After the addition was completed, the mixture was reacted at the same temperature for 3 hours, and then cooled to 20 degrees. The resulting solid was filtered and the filtrate was concentrated. 1200 ml of ethyl acetate was added to the concentrated filtrate, and 37 ml of concentrated sulfuric acid was slowly added thereto. When the addition of concentrated sulfuric acid was completed, the mixture was heated to reflux for 1 hour. The reaction solution was cooled to 20 degrees, stirred for 1 hour, and the resulting solid was filtered and dried to yield 124.7 g of a white target compound.
수율 : 85 %Yield: 85%
광학순도 : 98.8 %Optical purity: 98.8%
실시예 11. (+)-(S)-α-(2-클로로페닐)-4,5,6,7-테트라히드로티에노[3,2-c]피리디닐-5-메틸 아세테이트 황산수소염(클로피도그렐 황산수소염)의 제조Example 11. (+)-(S) -α- (2-Chlorophenyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridinyl-5-methyl acetate hydrogen sulfate ( Preparation of Clopidogrel Hydrogen Sulfate)
4,5,6,7-테트라히드로티에노[3,2-c]피리딘 54.6g (0.392 mol)에 아세토니트 릴 500ml를 가하여 희석한 후 포타슘 카보네이트 98.7g(2eq, 0.714mol)을 투입하였다. 반응 혼합물을 80℃로 가온한 후 아세토니트릴 150 ml에 용해한 (R)-2-(2-클로로페닐)-2-(트리에틸포스포니움)아세트산 메틸 에스테르 클로라이드 120g(0.357 mol)을 천천히 가하였다. 투입이 완료된 후 3시간 더 같은 온도에서 반응한 후 20도로 냉각하여 생성된 고체를 여과하고 여액을 농축하였다. 농축된 여액에 에틸아세테이트 1200ml를 투입한 후 진한황산 37.4ml를 천천히 가하였다. 진한황산의 투입이 완료되면 가온하여 1시간 동안 환류반응을 진행하였다. 반응액을 20도로 냉각하고 1시간 교반한 후 생성된 고체를 여과하고 건조하여 백색의 목적화합물 131.6g을 얻었다.500 ml of acetonitrile was added to 54.6 g (0.392 mol) of 4,5,6,7-tetrahydrothieno [3,2-c] pyridine, followed by dilution. 98.7 g (2eq, 0.714 mol) of potassium carbonate was added thereto. The reaction mixture was warmed to 80 ° C. and then 120 g (0.357 mol) of (R) -2- (2-chlorophenyl) -2- (triethylphosphonium) acetic acid methyl ester chloride dissolved in 150 ml of acetonitrile were slowly added. . After the addition was completed, the mixture was reacted at the same temperature for 3 hours, and then cooled to 20 degrees. The resulting solid was filtered and the filtrate was concentrated. 1200 ml of ethyl acetate was added to the concentrated filtrate, and 37.4 ml of concentrated sulfuric acid was slowly added thereto. When the addition of concentrated sulfuric acid was completed, the mixture was heated to reflux for 1 hour. The reaction solution was cooled to 20 degrees, stirred for 1 hour, and the resulting solid was filtered and dried to obtain 131.6 g of a white target compound.
수율 : 88 %Yield: 88%
광학순도 : 99.2 %Optical purity: 99.2%
실시예 12. (+)-(S)-α-(2-클로로페닐)-4,5,6,7-테트라히드로티에노[3,2-c]피리디닐-5-메틸 아세테이트 황산수소염(클로피도그렐 황산수소염)의 제조Example 12. (+)-(S) -α- (2-Chlorophenyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridinyl-5-methyl acetate hydrogen sulfate ( Preparation of Clopidogrel Hydrogen Sulfate)
4,5,6,7-테트라히드로티에노[3,2-c]피리딘 57.9g (0.416 mol)에 아세토니트릴 550ml를 가하여 희석한 후 포타슘 카보네이트 104.4g(2eq, 0.756mol)을 투입하였다. 반응 혼합물을 80℃로 가온한 후 아세토니트릴 200ml에 용해한 (R)-2-(2-클로로페닐)-2-(트리-t-부틸포스포니움)아세트산 메틸 에스테르 클로라이드 159g(0.378 mol)을 천천히 가하였다. 투입이 완료된 후 2시간 더 같은 온도에서 반응한 후 20도로 냉각하여 생성된 고체를 여과하고 여액을 농축하였다. 농축된 여액 에 에틸아세테이트 1500ml를 투입한 후 진한황산 39.6ml를 천천히 가하였다. 진한황산의 투입이 완료되면 가온하여 1시간 동안 환류반응을 진행하였다. 반응액을 20도로 냉각하고 1시간 교반한 후 생성된 고체를 여과하고 건조하여 백색의 목적화합물 144.2g을 얻었다.54.4 g (0.416 mol) of 4,5,6,7-tetrahydrothieno [3,2-c] pyridine was added to dilute 550 ml of acetonitrile, and 104.4 g (2eq, 0.756 mol) of potassium carbonate was added thereto. The reaction mixture was warmed to 80 ° C. and then slowly 159 g (0.378 mol) of (R) -2- (2-chlorophenyl) -2- (tri-t-butylphosphonium) acetic acid methyl ester chloride dissolved in 200 ml of acetonitrile. Was added. After the addition was completed, the reaction was carried out at the same temperature for 2 hours and then cooled to 20 degrees to filter the resulting solid and concentrated the filtrate. 1500 ml of ethyl acetate was added to the concentrated filtrate, and 39.6 ml of concentrated sulfuric acid was added slowly. When the addition of concentrated sulfuric acid was completed, the mixture was heated to reflux for 1 hour. The reaction solution was cooled to 20 degrees, stirred for 1 hour, and the resulting solid was filtered and dried to yield 144.2 g of a white target compound.
수율 : 91 %Yield: 91%
광학순도 : 99.5 %Optical purity: 99.5%
실시예 13. (+)-(S)-α-(2-클로로페닐)-4,5,6,7-테트라히드로티에노[3,2-c]피리디닐-5-메틸 아세테이트 황산수소염(클로피도그렐 황산수소염)의 제조Example 13. (+)-(S) -α- (2-Chlorophenyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridinyl-5-methyl acetate hydrogen sulfate ( Preparation of Clopidogrel Hydrogen Sulfate)
실시예 1에서 얻어진 농축액에 아세토니트릴 200ml를 가하여 맑은 액을 얻었다. 얻어진 액을, 4,5,6,7-테트라히드로티에노[3,2-c]피리딘 56.6 g ( 0.407 mol)과 포타슘 카보네이트 102. 3g(2eq, 0.74 mol)을 아세토니트릴 500ml를 가하여 희석한 후 반응 혼합물을 80℃로 가온한 반응물에 천천히 투입하였다. 투입이 완료된 후 1시간 더 같은 온도에서 반응한 후 20도로 냉각하여 생성된 고체를 여과하고 여액을 농축하였다. 농축된 여액에 에틸아세테이트 1500ml를 투입한 후 진한황산 39ml를 천천히 가하였다. 진한황산의 투입이 완료되면 가온하여 1시간 동안 환류반응을 진행하였다. 반응액을 20도로 냉각하고 1시간 교반한 후 생성된 고체를 여과하고 건조하여 백색의 목적화합물 149.2g을 얻었다.200 ml of acetonitrile was added to the concentrate obtained in Example 1 to obtain a clear solution. The obtained solution was diluted with 56.6 g (0.407 mol) of 4,5,6,7-tetrahydrothieno [3,2-c] pyridine and 102.3 g (2eq, 0.74 mol) of potassium carbonate by adding 500 ml of acetonitrile. The reaction mixture was then slowly added to the reaction, which was warmed to 80 ° C. After the addition was completed, the reaction was carried out at the same temperature for 1 hour and then cooled to 20 degrees to filter the resulting solid and concentrated the filtrate. 1500 ml of ethyl acetate was added to the concentrated filtrate, and 39 ml of concentrated sulfuric acid was slowly added thereto. When the addition of concentrated sulfuric acid was completed, the mixture was heated to reflux for 1 hour. The reaction solution was cooled to 20 degrees, stirred for 1 hour, and the resulting solid was filtered and dried to yield 149.2 g of a white target compound.
수율 : 95 %Yield: 95%
광학순도 : 99.8 %Optical purity: 99.8%
실시예 14. (+)-(S)-α-(2-클로로페닐)-4,5,6,7-테트라히드로티에노[3,2-c]피리디닐-5-메틸 아세테이트 황산수소염(클로피도그렐 황산수소염)의 제조Example 14 (+)-(S) -α- (2-Chlorophenyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridinyl-5-methyl acetate hydrogen sulfate ( Preparation of Clopidogrel Hydrogen Sulfate)
실시예 2에서 얻어진 농축액에 아세토니트릴 150ml를 가하여 맑은 액을 얻었다. 얻어진 액을, 4,5,6,7-테트라히드로티에노[3,2-c]피리딘 53.4 g ( 0.384 mol)과 포타슘 카보네이트 96.7g(2eq, 0.7mol)을 아세토니트릴 500ml에 가하여 희석한 후 반응 혼합물을 80℃로 가온한 반응물에 천천히 투입하였다. 투입이 완료된 후 3시간 더 같은 온도에서 반응한 후 20도로 냉각하여 생성된 고체를 여과하고 여액을 농축하였다. 농축된 여액에 에틸아세테이트 1200ml를 투입한 후 진한황산 37ml를 천천히 가하였다. 진한황산의 투입이 완료되면 가온하여 1시간 동안 환류반응을 진행하였다. 반응액을 20도로 냉각하고 1시간 교반한 후 생성된 고체를 여과하고 건조하여 백색의 목적화합물 130.4g을 얻었다.150 ml of acetonitrile was added to the concentrate obtained in Example 2 to obtain a clear solution. The resulting solution was diluted by adding 53.4 g (0.384 mol) of 4,5,6,7-tetrahydrothieno [3,2-c] pyridine and 96.7 g (2eq, 0.7 mol) of potassium carbonate to 500 ml of acetonitrile. The reaction mixture was slowly added to the reaction, which was warmed to 80 ° C. After the addition was completed, the mixture was reacted at the same temperature for 3 hours, and then cooled to 20 degrees. The resulting solid was filtered and the filtrate was concentrated. 1200 ml of ethyl acetate was added to the concentrated filtrate, and 37 ml of concentrated sulfuric acid was added slowly. When the addition of concentrated sulfuric acid was completed, the mixture was heated to reflux for 1 hour. The reaction solution was cooled to 20 degrees, stirred for 1 hour, and the resulting solid was filtered and dried to obtain 130.4 g of a white target compound.
수율 : 89 %Yield: 89%
광학순도 : 99.2 %Optical purity: 99.2%
실시예 15. (+)-(S)-α-(2-클로로페닐)-4,5,6,7-테트라히드로티에노[3,2-c]피리디닐-5-메틸 아세테이트 황산수소염(클로피도그렐 황산수소염)의 제조Example 15. (+)-(S) -α- (2-Chlorophenyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridinyl-5-methyl acetate hydrogen sulfate ( Preparation of Clopidogrel Hydrogen Sulfate)
실시예 3에서 얻어진 농축액에 아세토니트릴 150ml를 가하여 맑은 액을 얻었다. 얻어진 액을, 4,5,6,7-테트라히드로티에노[3,2-c]피리딘 54.6 g ( 0.392 mol)과 포타슘 카보네이트 98.7g(2eq, 0.714mol)을 아세토니트릴 500ml에 가하여 희석 한 후 반응 혼합물을 80℃로 가온한 반응물에 천천히 투입하였다. 투입이 완료된 후 3시간 더 같은 온도에서 반응한 후 20도로 냉각하여 생성된 고체를 여과하고 여액을 농축하였다. 농축된 여액에 에틸아세테이트 1200ml를 투입한 후 진한황산 37.4ml를 천천히 가하였다. 진한황산의 투입이 완료되면 가온하여 1시간 동안 환류반응을 진행하였다. 반응액을 20도로 냉각하고 1시간 교반한 후 생성된 고체를 여과하고 건조하여 백색의 목적화합물 137.6g을 얻었다.150 ml of acetonitrile was added to the concentrate obtained in Example 3 to obtain a clear solution. The obtained solution was diluted by adding 54.6 g (0.392 mol) of 4,5,6,7-tetrahydrothieno [3,2-c] pyridine and 98.7 g (2eq, 0.714 mol) of potassium carbonate to 500 ml of acetonitrile. The reaction mixture was slowly added to the reaction, which was warmed to 80 ° C. After the addition was completed, the mixture was reacted at the same temperature for 3 hours, and then cooled to 20 degrees. The resulting solid was filtered and the filtrate was concentrated. 1200 ml of ethyl acetate was added to the concentrated filtrate, and 37.4 ml of concentrated sulfuric acid was slowly added thereto. When the addition of concentrated sulfuric acid was completed, the mixture was heated to reflux for 1 hour. The reaction solution was cooled to 20 degrees, stirred for 1 hour, and the resulting solid was filtered and dried to obtain 137.6 g of a white target compound.
수율 : 92 %Yield: 92%
광학순도 : 99.4 %Optical purity: 99.4%
실시예 16. (+)-(S)-α-(2-클로로페닐)-4,5,6,7-테트라히드로티에노[3,2-c]피리디닐-5-메틸 아세테이트 황산수소염(클로피도그렐 황산수소염)의 제조Example 16. (+)-(S) -α- (2-Chlorophenyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridinyl-5-methyl acetate hydrogen sulfate ( Preparation of Clopidogrel Hydrogen Sulfate)
실시예 4에서 얻어진 농축액에 아세토니트릴 150ml를 가하여 맑은 액을 얻었다. 얻어진 액을, 4,5,6,7-테트라히드로티에노[3,2-c]피리딘 57.9 g ( 0.416 mol)과 포타슘 카보네이트 104.4g(2eq, 0.756mol)을 아세토니트릴 500ml에 가하여 희석한 후 반응 혼합물을 80℃로 가온한 반응물에 천천히 투입하였다. 투입이 완료된 후 2시간 더 같은 온도에서 반응한 후 20도로 냉각하여 생성된 고체를 여과하고 여액을 농축하였다. 농축된 여액에 에틸아세테이트 1500ml를 투입한 후 진한황산 39.7ml를 천천히 가하였다. 진한황산의 투입이 완료되면 가온하여 1시간 동안 환류반응을 진행하였다. 반응액을 20도로 냉각하고 1시간 교반한 후 생성된 고체를 여과하고 건조하여 백색의 목적화합물 150.5g을 얻었다.150 ml of acetonitrile was added to the concentrate obtained in Example 4 to obtain a clear solution. The resulting solution was diluted by adding 57.9 g (0.416 mol) of 4,5,6,7-tetrahydrothieno [3,2-c] pyridine and 104.4 g (2eq, 0.756 mol) of potassium carbonate to 500 ml of acetonitrile. The reaction mixture was slowly added to the reaction, which was warmed to 80 ° C. After the addition was completed, the reaction was carried out at the same temperature for 2 hours and then cooled to 20 degrees to filter the resulting solid and concentrated the filtrate. 1500 ml of ethyl acetate was added to the concentrated filtrate, and 39.7 ml of concentrated sulfuric acid was added slowly. When the addition of concentrated sulfuric acid was completed, the mixture was heated to reflux for 1 hour. The reaction solution was cooled to 20 degrees, stirred for 1 hour, and the resulting solid was filtered and dried to yield 150.5 g of a white target compound.
수율 : 95 %Yield: 95%
광학순도 : 99.8 %Optical purity: 99.8%
본 발명은 신규한 중간체인 화학식 2의 화합물을 이용하여 고순도로 우선성 클로피도그렐 황산수소염을 제조할 수 있는 신규한 방법으로 산업적 효용가치가 매우 우수하다.The present invention is a novel method for producing a preferred clopidogrel hydrogen sulphate with high purity by using a compound of formula (2) as a novel intermediate, the industrial utility value is very excellent.
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| EP0465358A1 (en) * | 1990-07-04 | 1992-01-08 | Sanofi | 2-Thienylglycidic acid derivative, process for its preparation and its use as synthetic intermediate |
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| EP0465358A1 (en) * | 1990-07-04 | 1992-01-08 | Sanofi | 2-Thienylglycidic acid derivative, process for its preparation and its use as synthetic intermediate |
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