KR100273765B1 - Method for preparing N- (4-piperidine) benzamide and new active thioester as an intermediate thereof and method for preparing same - Google Patents
Method for preparing N- (4-piperidine) benzamide and new active thioester as an intermediate thereof and method for preparing same Download PDFInfo
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- KR100273765B1 KR100273765B1 KR1019980039547A KR19980039547A KR100273765B1 KR 100273765 B1 KR100273765 B1 KR 100273765B1 KR 1019980039547 A KR1019980039547 A KR 1019980039547A KR 19980039547 A KR19980039547 A KR 19980039547A KR 100273765 B1 KR100273765 B1 KR 100273765B1
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Abstract
본 발명은 위장계통을 자극하는 생리활성을 가지는 다음 일반식(Ⅰ)의 N-(4-피페리딘)벤즈아미드 및 그 약제학적으로 허용되는 부가염의 새로운 제조방법에 관한 것이다. 보다 바람직하게는 다음 일반식(Ⅰ)에서 L이 3-(4-플루오로펜옥시)프로필이고, R이 메틸인 위장 연동운동 촉진제로 사용되는 시사프라이드의 새로운 제조방법에 관한 것이다.The present invention relates to a novel method for preparing N- (4-piperidine) benzamide of the following general formula (I) and a pharmaceutically acceptable addition salt thereof having physiological activity that stimulates the gastrointestinal system. More preferably, it relates to a new process for preparing cisapride, which is used as a gastrointestinal peristalsis promoter in which L is 3- (4-fluorophenoxy) propyl and R is methyl in the following general formula (I).
또한 본 발명은 일반식(Ⅰ)의 N-(4-피페리딘)벤즈아미드 제조에 유용한 구조식(Ⅲ)의 새로운“활성티오에스테르”및 그 제조방법에 관한 것이다.The present invention also relates to novel “active thioesters” of structural formula (III) useful for the preparation of N- (4-piperidine) benzamides of general formula (I) and methods for their preparation.
즉, 본 발명은 구조식(Ⅶ)의 카르복실산 유도체와 일반식(Ⅵ)의 알킬클로로포르메이트를 반응시켜 일반식(Ⅴ)의 중간체를 생성시킨 후 일반식(Ⅴ)의 중간체와 구조식(Ⅳ)의 2-머캅토벤즈이미다졸을 반응시켜 구조식(Ⅲ)의 새로운“활성티오에스테르”를 제조한 다음, 일반식(Ⅱ)의 시스-피페리딘아민 유도체와 반응시켜 목적화합물인 일반식(Ⅰ)의 시스프라이드를 포함하는 벤즈아미드 유도체를 제조하는 방법에 관한 것이다.That is, the present invention reacts the carboxylic acid derivative of formula (VII) with alkylchloroformate of formula (VI) to produce an intermediate of formula (V), and then the intermediate of formula (V) and the formula (IV). 2-mercaptobenzimidazole of) to prepare a new "active thioester" of formula (III), and then react with a cis-piperidinamine derivative of formula (II) A method for producing a benzamide derivative comprising the cispride of I).
상기 식에서 L은 아르알킬 또는 아릴옥시알킬인데, 이때 알킬부분은 C1-C6의 알킬이고, 아릴부분은 할로, C1-C6의 저급알킬 또는C1-C6의 저급알콕시로부터 독립적으로 선택된 3개까지의 치환체로 임의치환된 것이고； R은 C1-C6의 저급알킬이며; R1은 에틸, 이소프로필 또는 이소부틸이다.Inde wherein L is an aralkyl or aryloxyalkyl, wherein the alkyl portion is an alkyl of C 1 -C 6, an aryl portions are independently selected from halo, lower alkoxy of C 1 -C 6 lower alkyl or C 1 -C 6 of Optionally substituted with up to 3 substituents selected from R is C 1 -C 6 lower alkyl; R 1 is ethyl, isopropyl or isobutyl.
Description
본 발명은 위장계통을 자극하는 생리활성을 가지는 다음 일반식(Ⅰ)의 N-(4-피페리딘)벤즈아미드 및 그 약제학적으로 허용되는 부가염의 새로운 제조방법에 관한 것이다.The present invention relates to a novel method for preparing N- (4-piperidine) benzamide of the following general formula (I) and a pharmaceutically acceptable addition salt thereof having physiological activity that stimulates the gastrointestinal system.
상기 식에서 L은 아르알킬 또는 아릴옥시알킬인데 이때 알킬부분은 C1-C6의 알킬이고, 아릴부분은 할로, C1-C6의 저급알킬 또는C1-C6의 저급알콕시로부터 독립적으로 선택된 3개까지의 치환체로 임의치환된 것이며； R은 C1-C6의 저급알킬이다.Inde wherein L is an aralkyl or aryloxy alkyl wherein the alkyl portion is an alkyl of C 1 -C 6, aryl moiety is halo, C 1 -C 6 lower alkyl or C 1 -C 6 selected independently from lower alkoxy of the Optionally substituted with up to 3 substituents; R is C 1 -C 6 lower alkyl.
일반식(Ⅰ)의 대표적인 화합물은 L이 3-(4-플루오로펜옥시)프로필이고 R이 메틸인,위장연동운동 촉진작용이 있는 다음 구조식(Ⅰ´)의 시사프라이드이다.Representative compounds of formula (I) are cisaprides of the following formula (I ′) with gastrointestinal synergism, where L is 3- (4-fluorophenoxy) propyl and R is methyl.
또한 본 발명은 일반식(Ⅰ)의 Ｎ-(4-피페리딘)벤즈아미드의 제조에 유용한 다음 구조식(Ⅲ)의 새로운“활성티오에스테르”및 그 제조방법에 관한 것이다.The present invention also relates to novel “active thioesters” of the following structural formula (III), which are useful for the preparation of N- (4-piperidine) benzamides of the general formula (I), and methods for their preparation.
일반식(Ⅰ)의 시사프라이드를 포함하는 벤즈아미드 유도체는 한국특허공고 제 86-1584호(한국특허공고 제 86-1603호의 분할출원)와 한국특허공고 제 86-1603호에 그 제조방법과 특성들에 관하여 기술되어 있다.Benzamide derivatives containing the cisapride of general formula (I) are prepared according to Korean Patent Publication No. 86-1584 (split application of Korean Patent Publication No. 86-1603) and Korean Patent Publication No. 86-1603. Are described.
위 한국특허공고 제 86-1584호 및 한국특허공고 제 86-1603호에서 기술된 시사프라이드를 포함하는 벤즈아미드 유도체들을 제조하는 방법은 다음의 3가지 방법으로 요약될 수 있다.The method for preparing benzamide derivatives containing cisapride described in Korean Patent Publication No. 86-1584 and Korean Patent Publication No. 86-1603 can be summarized by the following three methods.
상기 식들에서 L 및 R은 위에서 정의한 바와 같다.Where L and R are as defined above.
위의 방법 중에서 방법 B의 경우는 피페리딘환의 3, 4 위치의 두 치환체가 서로 트랜스형태를 이루게 되므로 시사프라이드와 같은 피페리딘환의 치환체가 시스형태를 이루고 있는 화합물 등에 있어서는 적합하지 않다.In the above method, in the case of Method B, the two substituents at the 3 and 4 positions of the piperidine ring are in trans form with each other, and thus, the compound B is not suitable for a compound in which a substituent of the piperidine ring such as cisapride forms a cis form.
방법 C의 경우는 일반적으로 수율이 저조한 것으로 되어 있어 대량생산에 있어서 문제가 되는 방법이다.In the case of Method C, the yield is generally low, which is a problem in mass production.
이들 방법 중에서 방법 A의 카르복실산을 활성기능기로 치환하여 활성기능유도체를 만들고 이를 이용하여 방법 A의 피페리딘아민화합물과 반응시키는 방법 A가 시사프라이드를 포함하는 벤즈아미드 유도체를 제조하는데 실질적이고 유용한 방법으로서 이들 실시예에서도 방법 A가 구체적으로 실시되었다.Among these methods, a method A is substantially useful for preparing a benzamide derivative including cisapride, in which the carboxylic acid of Method A is substituted with an active functional group to form an active functional derivative, and then reacted with the piperidineamine compound of Method A. Method A was specifically carried out in these examples as a useful method.
즉, 방법 A에서 시사프라이드를 포함하는 벤즈아미드 유도체를 제조하는데 있어서 핵심중간체라고 할 수 있는 활성기능유도체에 관하여는 위 한국특허공고 제 86-1584호 및 한국특허공고 제 86-1603호에서 다음과 같은 일반식(Ⅶa)의 아실할로겐화물, 일반식(Ⅶb)의 에스테르화합물 및 일반식(Ⅶc)의 무수물을 개시(開示)하였다.That is, the active functional derivatives, which can be said to be the key intermediates in the preparation of benzamide derivatives containing cisapride in Method A, are described in Korean Patent Publication Nos. 86-1584 and 86-1603. The acyl halides of the general formula (VIIa), the ester compounds of the general formula (VIIb) and the anhydrides of the general formula (VIIc) are disclosed.
상기 식에서 X는또는이다.Where X is or to be.
일반식(Ⅶa)와 같은 활성기능유도체를 시사프라이드를 포함하는 벤즈아미드 유도체를 제조하는데 사용할 경우, 소량생산에 있어서는 유용한 방법이지만 대량생산의 경우에 있어서는 까다로우며 다소 위험하다.When active functional derivatives such as general formula (VIIa) are used to prepare benzamide derivatives containing cisapride, they are a useful method for small quantities but are difficult and somewhat dangerous for mass production.
보다 상세하게는 일반식(Ⅶa)와 같은 활성기능유도체를 제조하는데 사용되는 시약은 티오닐클로라이드나 포스겐 등인데 이들은 매우 유독하며 취급이 까다로워 대량생산에 있어서는 일반적으로 적절하지 못하다.More specifically, reagents used to prepare active derivatives such as general formula (VIIa) are thionyl chloride and phosgene, which are very toxic and difficult to handle and are generally not suitable for mass production.
일반식(Ⅶb)와 같은 활성기능유도체는 일반적으로“에스테르”화합물로 불리우며 반응상대인 피페리딘아민류와 반응할 때 그 반응성에 있어서는 매우 약하다고 알려져 있다.Active functional derivatives such as general formula (VIIb) are generally called “ester” compounds and are known to be very weak in their reactivity when reacted with the piperidine amines which are the reaction partners.
일반식(Ⅶc)와 같은 활성기능유도체의 경우에는 먼저 X가인 경우에In the case of active functional derivatives such as general formula in case of
는 부반응이 많이 일어나 수율이 매우 저조한 단점이 있고, X가인 경우에Has a disadvantage in that a lot of side reactions occur and yield is very low. in case of
는 일반적으로“혼합무수물(mixed anhydride)”이라고 불리우는데 이를 제조하기 위하여 사용되는 피발로일클로라이드 등은 활성이 매우 커서 바람직하지 않은 반응이 일어나서 목적물의 순도와 수율에 악영향을 미치는 경우가 있다.Is commonly referred to as “mixed anhydride”, but the pivaloyl chloride used to prepare it has a very high activity, which may adversely affect the purity and yield of the target product.
또한 피발로일클로라이드나 에틸클로로포르메이트로 생성된“혼합무수물”인 경우에는 피페리딘아민화합물과 반응할 때 활성기능유도체 내에 아민기와 반응할 수 있는 카르보닐기가 두군데가 되어 소량의 부반응을 야기할 수 있는 것은 잘 알려져 있다.In addition, in the case of “mixed anhydride” produced from pivaloyl chloride or ethylchloroformate, when reacting with piperidineamine compound, there are two carbonyl groups that can react with amine groups in the active functional derivatives, which may cause a small amount of side reactions. It is well known that it can.
이러한“혼합무수물”들이 가지고 있는 문제점들을 극복하기 위하여 카르복실산의 새로운 활성기능유도체를 개발하기 위한 많은 연구가 진행되었는데 그 결과 요즈음에는“활성에스테르(active ester)”라는 새로운 활성기능유도체가 개발되어 일반적으로 많이 사용되고 있다. (참고 ： Principles of Peptide Synthesis, vol.16 (1984) by M.Bodanszky)In order to overcome the problems of these “mixed anhydrides”, many studies have been conducted to develop a new active functional derivative of carboxylic acid. As a result, a new active functional derivative called “active ester” has been developed. Generally used a lot. (Reference: Principles of Peptide Synthesis, vol. 16 (1984) by M. Bodanszky)
카르복실산 유도체들의 반응성을 높이기 위하여“활성에스테르”형태로 변형시키기 위한 종래의 통상적인 방법은 아래의 반응식에서 볼 수 있는 바와 같이 카르복실산 유도체와 히드록시기가 있는 화합물들을 디시클로헥실카르보디이미드(DCC)와 같은 축합체의 존재 하에서 반응시키는 방법이다.Conventional conventional methods for transforming carboxylic acid derivatives into "active ester" forms to enhance the reactivity of the carboxylic acid derivatives include dicyclohexylcarbodiimide ( Reaction in the presence of a condensate such as DCC).
상기 식에서 R2는 통상의 알킬이고, R3는 다음의 치환체 중에서 선택된다.Wherein R 2 is conventional alkyl, and R 3 is selected from the following substituents.
그러나 이들 종래의 방법에서 사용되는 디시클로헥실카르보디이미드(DCC)는 반응 후 N,N´-디시클로헥실우레아(DCU)로 변형된다.However, the dicyclohexylcarbodiimide (DCC) used in these conventional methods is transformed into N, N'-dicyclohexylurea (DCU) after the reaction.
그런데 변형된 N,N´-디시클로헥실우레아(DCU)는 제거하기가 일반적으로 어려워 이물질이 목적화합물에 잔류하는 경우가 있다.However, modified N, N'-dicyclohexyl urea (DCU) is generally difficult to remove, so that foreign matter may remain in the target compound.
그밖에도“활성에스테르”를 제조하기 위하여 아래와 같은 화합물을 카르복실산 유도체와 반응시키기도 하는데 아래의 화합물들은 대부분 가격면에서 유리하지 못하거나 제조 또는 취급이 까다로운 단점이 있다.In addition, the following compounds may be reacted with carboxylic acid derivatives in order to prepare an "active ester", but most of the following compounds are not advantageous in terms of cost or are difficult to manufacture or handle.
그 외에 다음에 열거된 디설피드화합물들이 트리페닐포스핀의 존재하에서 카르복실산 유도체들과 축합반응을 일으켜“활성티오에스테르”를 형성하는 것이 알려져 있다.In addition, it is known that the disulfide compounds listed below form condensation reactions with carboxylic acid derivatives in the presence of triphenylphosphine to form "active thioesters".
상기 식에서 X는 S 또는 NH이다.Wherein X is S or NH.
이때 축합반응 매개체로 사용되는 트리페닐포스핀은 고가에 속하며 위 트리페닐포스핀을 사용한 축합반응은 부반응이 일어나는 경향이 높아 목적물의 순도에 좋지 않은 영향을 주는 경우가 흔히 있다.At this time, triphenylphosphine used as a condensation reaction medium belongs to a high price, and condensation reaction using the above triphenylphosphine has a high tendency for side reactions to occur, which often adversely affects the purity of a target product.
본 발명에서는 알킬클로로포르메이트와 머캅토벤즈이미다졸을 사용하여 새로운“활성티오에스테르”를 제조하는데 그 목적이 있다.It is an object of the present invention to prepare a new "active thioester" using alkylchloroformate and mercaptobenzimidazole.
또한 본 발명에서는 위에서 제조한 새로운“활성티오에스테르”를 시스-피페리딘아민 유도체와 반응시켜 본 발명의 목적화합물인 시사프라이드를 포함하는 벤즈아미드 유도체를 새로운 방법으로 제조하는데 그 목적이 있다.In addition, in the present invention, the new "active thioester" prepared above is reacted with a cis-piperidineamine derivative to prepare a benzamide derivative including a cisapride which is the target compound of the present invention by a new method.
본 발명에서는 다음의 반응식과 같이 구조식(Ⅶ)의 카르복실산 유도체와 반응 후 쉽게 제거되는 일반식(Ⅵ)의 알킬클로로포르메이트를 반응시켜 일반식(Ⅴ)의 반응중간체를 먼저 생성시킨 다음 일반식(Ⅴ)의 중간체와 구조식(Ⅳ)의 2-머캅토벤즈이미다졸을 반응시켜 구조식(Ⅲ)의 새로운“활성티오에스테르”를 제조한다.In the present invention, the reaction intermediate of Formula (V) is first produced by reacting the alkyl chloroformate of Formula (VI), which is easily removed after the reaction with the carboxylic acid derivative of Structural Formula (VII), as shown in the following scheme: The intermediate of formula (V) and 2-mercaptobenzimidazole of formula (IV) are reacted to produce a new “active thioester” of formula (III).
이어서 구조식(Ⅲ)의“활성티오에스테르”를 일반식(Ⅱ)의 시스-피페리딘아민 유도체와 반응시켜 목적화합물인 일반식(Ⅰ)의 시사프라이드를 포함하는 벤즈아미드 유도체를 제조한다.Subsequently, the "active thioester" of the formula (III) is reacted with the cis-piperidinamine derivative of the general formula (II) to prepare a benzamide derivative including the cisapride of the general formula (I).
일반식(Ⅰ)의 화합물을 제조하는데 있어서 구조식(Ⅲ)의“활성티오에스테르”를 분리하지 않고 계속하여 한 반응기 내에서 시스-피페리딘아민 유도체와 반응시킬 수도 있고 구조식(Ⅲ)의“활성티오에스테르”를 분리한 다음, 시스-피페리딘아민 유도체와 반응시킬 수도 있다.In the preparation of the compound of formula (I), the "active thioester" of formula (III) may be continuously reacted with the cis-piperidinamine derivative in one reactor, and the "activity of formula (III) Thioesters ”can then be reacted with cis-piperidinamine derivatives.
상기 식들에서 L, R은 위에서 정의한 바와 같고 R1은 에틸, 이소프로필 또는 이소부틸이다.Wherein L and R are as defined above and R 1 is ethyl, isopropyl or isobutyl.
위 반응식을 구체적으로 설명하면 구조식(Ⅶ)의 카르복실산 유도체를 산수용체(염기)의 존재하에서 일반식(Ⅵ)의 알킬클로로포르메이트와 10∼25℃의 온화한 조건에서 반응시켜 구조식(Ⅴ)와 같은 활성이 좋은 반응중간체를 생성한다.Specifically, the carboxylic acid derivative of formula (VII) is reacted with alkylchloroformate of formula (VI) under mild conditions of 10 to 25 ° C in the presence of an acid acceptor (base). Produces a good intermediate for the reaction.
이때 산수용체로는 트리에틸아민, N-메틸모르폴린, N-메틸피페리딘, 피리딘 등을 사용함이 바람직하며 반응용매로는 디클로로메탄, 클로로포름, 아세토니트릴, 디메틸포름아미드 등이 바람직하다.At this time, it is preferable to use triethylamine, N-methylmorpholine, N-methylpiperidine, pyridine and the like as the acid acceptor, and dichloromethane, chloroform, acetonitrile, dimethylformamide, etc. are preferable as the reaction solvent.
생성된 일반식(Ⅴ)의 중간체에 구조식(Ⅳ)의 2-머캅토벤즈이미다졸을 첨가하고 0∼25℃에서 온화하게 반응시켜 구조식(Ⅲ)의“활성티오에스테르”를 생성한다.2-mercaptobenzimidazole of formula (IV) is added to the resulting intermediate of formula (V) and reacted mildly at 0-25 ° C. to produce “active thioester” of formula (III).
이 구조식(Ⅲ)의 “활성티오에스테르”는 위 반응식에서도 알 수 있듯이“위치 이성체”가 생성되며 이들“위치 이성체”모두가 일반식(Ⅱ)의 시스-피페리딘아민 유도체와 반응하여 일반식(Ⅰ)의 시사프라이드를 포함하는 벤즈아미드 유도체를 생성하는데 참여한다.As can be seen from the above scheme, the "active thioester" of this structural formula (III) produces "positional isomers" and all of these "positional isomers" react with cis-piperidinamine derivatives of general formula (II). Participate in producing benzamide derivatives comprising the cisapride of (I).
이 반응들에서 사용되는 일반식(Ⅵ)으로 대표되는 에틸클로로포르메이트, 이소프로필클로로포르메이트 또는 이소부틸클로로포르메이트는 값이 매우 저가이고 구조식(Ⅳ)의 2-머캅토벤즈이미다졸은 값이 저가일 뿐만 아니라“활성티오에스테르”제조에 사용된 적이 없으며 본 발명에서 처음으로“활성티오에스테르”제조에 사용된다.Ethylchloroformate, isopropylchloroformate or isobutylchloroformate represented by formula (VI) used in these reactions are very inexpensive and 2-mercaptobenzimidazole of formula (IV) Not only is this low cost, it has never been used in the production of "active thioesters" and is used for the first time in the production of "active thioesters".
생성된 구조식(Ⅲ)의“활성티오에스테르”를 일반식(Ⅱ)의 시스-피페리딘아민 유도체와 0∼25℃에서 온화하게 반응시켜 일반식(Ⅰ)의 시사프라이드를 포함하는 벤즈아미드 유도체를 90％ 정도의 높은 수율로 얻는다.Benzamide derivatives containing cisapride of general formula (I) by gently reacting the resulting "active thioester" of formula (III) with a cis-piperidinamine derivative of general formula (II) at 0-25 ° C In a high yield of about 90%.
실시예 1 :Example 1: 1H-벤조[d]이미다졸-2-일 4-아미노-5-클로로-2-메톡시-1-벤젠카르보티1H-benzo [d] imidazol-2-yl 4-amino-5-chloro-2-methoxy-1-benzenecarboti 오에이트 및 그 이성체(구조식(Ⅲ))의 제조Preparation of Oate and its Isomers (Formula III)
50㎖ 반응기에 4-아미노-5-클로로-2-메톡시벤조산 500㎎과 N,N-디메틸포름아미드 4㎖를 넣은 다음, 트리에틸아민 376㎎과 에틸클로로포르메이트 280㎎을 적가하여 0∼10℃에서 1.5시간 동안 반응시킨 후 실온으로 올려 30분 교반하였다. 계속하여 동일한 반응기에 2-머캅토벤즈이미다졸 396㎎을 가한 후 실온에서 6시간 동안 교반하였다. 반응혼합물에 헥산과 에틸아세테이트 혼합용매를 가하여 생성된트리에틸아민·염산염을 여과하고 여액을 질량 분석을 하여 화합물(Ⅲ)의 분자량을 확인 하였다.500 mg of 4-amino-5-chloro-2-methoxybenzoic acid and 4 ml of N, N-dimethylformamide were added to a 50 ml reactor. Then, 376 mg of triethylamine and 280 mg of ethylchloroformate were added dropwise to add 0 to After reacting at 10 ° C. for 1.5 hours, the mixture was heated to room temperature and stirred for 30 minutes. Subsequently, 396 mg of 2-mercaptobenzimidazole was added to the same reactor, followed by stirring at room temperature for 6 hours. Triethylamine hydrochloride was formed by adding a mixed solvent of hexane and ethyl acetate to the reaction mixture, and the filtrate was subjected to mass spectrometry to confirm the molecular weight of compound (III).
ESI (M+1) : 334.2ESI (M + 1): 334.2
실시예 2 :Example 2: 시스-2-메톡시-4-아미노-5-클로로-N-[1-[3-(4-플루오로펜옥시)프로Cis-2-methoxy-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) prop 필]-3-메톡시-4-피페리디닐]벤즈아미드(시사프라이드)·일수화물Phil] -3-methoxy-4-piperidinyl] benzamide (cisapride) monohydrate 의 제조(일반식(Ⅰ))Preparation (General Formula (Ⅰ))
50㎖ 반응기에 4-아미노-5-클로로-2-메톡시벤조산 500㎎과 N,N-디메틸포름아미드 4㎖를 넣은 다음, 트리에틸아민 376㎎과 에틸클로로포르메이트 280㎎을 적가하여 0∼10℃에서 1.5시간 동안 반응시킨 후 실온으로 올려 30분 교반하였다. 계속하여 동일한 반응기에 2-머캅토벤즈이미다졸 396㎎을 가한 후 실온에서 6시간 동안 교반하였다. 반응혼합물에 시스-4-아미노-3-메톡시-1-[3-(4-플루오로펜옥시)프로필]피페리딘 630㎎을 N,N-디메틸포름아미드 1㎖에 녹인 용액을 적가하고 실온에서 5시간 동안 교반하였다. 반응 후, 반응혼합물에 정제수 25㎖를 넣고 실온에서 1시간 교반한 후 여과하였다. 여과한 고체를 1N-NaOH 수용액(5㎖)과 이소프로판올(5㎖)의 혼합액을 넣고 40∼45℃에서 2시간 동안 교반한 후, 실온으로 냉각하여 고체를 여과한 후 50％ 이소프로판올 수용액과 이소프로판올로 차례로 세척하고 건조시켜 목적화합물 963㎎을 얻었다. (수율 : 89.2％)500 mg of 4-amino-5-chloro-2-methoxybenzoic acid and 4 ml of N, N-dimethylformamide were added to a 50 ml reactor. Then, 376 mg of triethylamine and 280 mg of ethylchloroformate were added dropwise to add 0 to After reacting at 10 ° C. for 1.5 hours, the mixture was heated to room temperature and stirred for 30 minutes. Subsequently, 396 mg of 2-mercaptobenzimidazole was added to the same reactor, followed by stirring at room temperature for 6 hours. To the reaction mixture was added dropwise a solution of 630 mg of cis-4-amino-3-methoxy-1- [3- (4-fluorophenoxy) propyl] piperidine in 1 ml of N, N-dimethylformamide. Stir at room temperature for 5 hours. After the reaction, 25 ml of purified water was added to the reaction mixture, which was stirred at room temperature for 1 hour and filtered. The filtered solid was mixed with a mixed solution of 1N-NaOH aqueous solution (5 ml) and isopropanol (5 ml), stirred at 40 to 45 ° C. for 2 hours, cooled to room temperature, filtered to solid, and filtered with 50% isopropanol aqueous solution and isopropanol. It was washed sequentially and dried to obtain 963 mg of the target compound. (Yield 89.2%)
종래의 "활성에스테르"를 제조함에 있어서는 반응식 1과 같이 축합제로 디시클로헥실카르보디이미드(DCC)를 필요로 하는데 이 DCC는 반응후 N,N'-디시클로헥실우레아(DCU)로 변형되고 이 DCU는 제거하기가 어려우며, 또한 종래의 "활성티오에스테르"를 제조함에 있어서는 디설피드화합물과 다소 고가인 트리페닐포스핀을 사용하는데 이 반응은 부반응이 일어나는 경향이 많아 시사프라이드를 포함하는 목적화합물에 잔류하여 목적화합물의 순도에 좋지 않은 영향을 미치나 본 발명의 "활성티오에스테르"를 제조함에 있어서는 일반식(V)의 중간체와 구조식(IV)의 2-머캅토벤즈이미다졸을 축합하는데 축합제를 사용하지 않으므로 위와같은 단점들이 제거되었고 일반식(V)의 중간체는 반응후 부산물로 제거하기가 쉬운 알코올류를 방출하므로 "활성티오에스테르" 뿐만아니라 시사프라이드를 포함하는 목적화합물의 순도에도 매우 좋은 영향을 미친다.In preparing a conventional "active ester", dicyclohexylcarbodiimide (DCC) is required as a condensing agent as in Scheme 1, and this DCC is transformed into N, N'-dicyclohexyl urea (DCU) after the reaction. DCU is difficult to remove, and in the preparation of the conventional "active thioester", a disulfide compound and a relatively expensive triphenylphosphine are used. This reaction tends to cause side reactions, and thus to a target compound containing cisapride. The remaining contaminants adversely affect the purity of the target compound, but in the preparation of the "active thioester" of the present invention, a condensing agent is used to condense the intermediate of formula (V) and 2-mercaptobenzimidazole of formula (IV). Since these disadvantages are eliminated because they are not used, the intermediate of formula (V) releases alcohols that are easy to remove as by-products after the reaction. "It also has a very good effect on the purity of the target compound, including cisapride.
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