KR100771655B1 - Method of preparing rabeprazole and its intermediate - Google Patents
Method of preparing rabeprazole and its intermediate Download PDFInfo
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- OLBSXXZEMRBFIG-UHFFFAOYSA-N Cc(c(CO)ncc1)c1OCCCOC Chemical compound Cc(c(CO)ncc1)c1OCCCOC OLBSXXZEMRBFIG-UHFFFAOYSA-N 0.000 description 2
- ILXMCFJEWFDAEV-UHFFFAOYSA-N CC(C1)C=Cc([nH]2)c1nc2S(CC1=NC(C)CC(OCCCOC)=C1C)=O Chemical compound CC(C1)C=Cc([nH]2)c1nc2S(CC1=NC(C)CC(OCCCOC)=C1C)=O ILXMCFJEWFDAEV-UHFFFAOYSA-N 0.000 description 1
- QRGIVNKLAWKRHX-UHFFFAOYSA-N Cc(c(C)[n+](cc1)O)c1OCCCOC Chemical compound Cc(c(C)[n+](cc1)O)c1OCCCOC QRGIVNKLAWKRHX-UHFFFAOYSA-N 0.000 description 1
- XPYNCLYLFSMFQE-UHFFFAOYSA-N Cc(c(CCl)ncc1)c1OCCCOC Chemical compound Cc(c(CCl)ncc1)c1OCCCOC XPYNCLYLFSMFQE-UHFFFAOYSA-N 0.000 description 1
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- YHMYGUUIMTVXNW-UHFFFAOYSA-N Sc1nc(cccc2)c2[nH]1 Chemical compound Sc1nc(cccc2)c2[nH]1 YHMYGUUIMTVXNW-UHFFFAOYSA-N 0.000 description 1
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- 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
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- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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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
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- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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Abstract
Description
본 발명은 위산 분비 억제 및 위점막 보호에 우수한 효과를 나타내는 항궤양제인 화학식 (I)로 표시되는 2-4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸술피닐-1H-벤즈이미다졸(이하 '라베프라졸'이라 함) 및 그 중간체의 새로운 제조방법에 관한 것이다. 보다 구체적으로 본 발명은 화학식 (II)로 표시되는 2-히드록시메틸-4-(3-메톡시프로폭시)-3-메틸피리딘 또는 그의 염과 화학식 (IV)로 표시되는 2-메르캅토-1H-벤즈이미다졸을 포스포러스 트리브로마이드(PBr3) 하에서 반응시켜 화학식 (V)로 표시되는 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸을 제조하고, 이를 벤젠셀레닌 산(PhSeO2H)과 트리알킬아민의 혼합촉매 하에서 과산화수소로 산화시켜 화학식 (I)로 표시되는 라베프라졸을 제조하는 방법에 관한 것이다.The present invention relates to 2-4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylsulfinyl represented by formula (I), which is an antiulcer agent exhibiting excellent effects on gastric acid secretion and gastric mucosal protection. 1H-benzimidazole (hereinafter referred to as 'rabbeprazole') and a method for producing the intermediate thereof. More specifically, the present invention relates to 2-hydroxymethyl-4- (3-methoxypropoxy) -3-methylpyridine or salt thereof represented by formula (II) and 2-mercapto- represented by formula (IV). Reaction of 1H-benzimidazole under phosphorus tribromide (PBr 3 ) to 2- [4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylthio] 1H represented by formula (V) -Benzimidazole is prepared and oxidized with hydrogen peroxide under a mixed catalyst of benzene selenic acid (PhSeO 2 H) and trialkylamine to prepare a labeprazole represented by the formula (I).
화학식 (I)로 표시되는 라베프라졸은 그의 구조적 특성으로 인하여 산에 매우 불안정하므로, 이러한 문제를 해결하기 위하여 소듐염의 형태로 만들어진 후 안정하고 저장 가능한 경구 투여 형태(예를 들면, 정제 또는 캡슐)로 사용된다.Rabeprazole represented by formula (I) is very unstable to acids due to its structural properties, so to solve this problem, a stable and storeable oral dosage form (e.g. tablet or capsule) made in the form of sodium salt Used as
라베프라졸의 제조방법은 대한민국특허등록 제46393호, 대한민국특허등록 제559169호, 대한민국특허출원 2002-7013675호, 대한민국특허출원 2003-7010217호, 대한민국특허출원 2002-7011987호 등에 개시되어 있다. The manufacturing method of labeprazole is disclosed in Korea Patent Registration No. 46393, Korea Patent Registration No. 559169, Korea Patent Application 2002-7013675, Korea Patent Application 2003-7010217, Korea Patent Application 2002-7011987.
라베프라졸의 제조방법을 기술하고 있는 최초의 특허출원인 대한민국특허등록 제46393호는 반응식 1에 나타난 바와 같이 라베프라졸의 합성공정을 소개하고 있다. Korea Patent Registration No. 46393, the first patent application describing a method for preparing labeprazole, introduces the synthesis of labeprazole as shown in Scheme 1.
반응식 1Scheme 1
상기 반응식 1에서 제시된 합성방법은 벤즈이미다졸-타입의 프로톤 저해제의 합성에서 가장 흔히 사용되는 방법으로서, 화학식 (II)로 표시되는 2-히드록시메틸-4-(3-메톡시프로폭시)-3-메틸피리딘으로부터 2단계의 반응공정으로 화학식 (V)로 표시되는 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸을 제조하고, 이를 m-클로로퍼벤조산(mcpba)으로 산화시켜 화학식 (I)로 표시되는 라베프라졸을 합성하고 있다. 이 방법에서는 화학식 (III)으로 표시되는 2-클로로메틸-4-(3-메톡시프로폭시)-3-메틸피리딘과 화학식 (IV)로 표시되는 2-메르캅토-1H-벤즈이미다졸의 커플링반응 수율이 90%를 넘지 못하고 있다. 또한 m-클로로퍼벤조산이 위험물로 지정되어 있고, 사용과 보관에 있어서 각별한 주의가 필요하고, 대량으로 취급하기 어려운 문제가 있다. 가격 또한 고가여서 대량생산공정에 사용하기에는 많은 어려움을 가지고 있다. Synthesis method shown in Scheme 1 is the most commonly used in the synthesis of benzimidazole-type proton inhibitor, 2-hydroxymethyl-4- (3-methoxypropoxy)-represented by the formula (II) 2- [4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylthio] 1H-benzimidazole represented by the formula (V) was prepared from a 2-methylpyridine in a two step reaction process. Then, it was oxidized with m-chloroperbenzoic acid (mcpba) to synthesize rabeprazole represented by the formula (I). In this method, a couple of 2-chloromethyl-4- (3-methoxypropoxy) -3-methylpyridine represented by formula (III) and 2-mercapto-1H-benzimidazole represented by formula (IV) Ring reaction yield does not exceed 90%. In addition, m-chloroperbenzoic acid is designated as a dangerous substance, requires special care in use and storage, and has a problem that it is difficult to handle in large quantities. The price is also high, which makes it difficult to use in mass production processes.
가장 심각한 문제점은 이 공정에서 다양한 부산물들이 검출된다는 것이다. 이때 생성되는 대표적인 부산물로는 화학식 (I)로 표시되는 화합물의 피리딘 환에 존재하는 질소가 산화되어 생성된 하기 화학식 (VI)의 2-4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸술피닐-1H-벤즈이미다졸 N-옥사이드나 화학식 (I)로 표시되는 화합물의 설피닐기가 산화된 하기 화학식 (VII)의 2-4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸설포닐-1H-벤즈이미다졸 등이 있다. The most serious problem is that various byproducts are detected in this process. Representative by-products produced at this time include 2-4- (3-methoxypropoxy) -3-methylpyridine of formula (VI), which is formed by oxidation of nitrogen present in the pyridine ring of the compound represented by formula (I). 2-4- (3-methoxypropoxy)-of the following formula (VII) in which the sulfinyl group of 2-ylmethylsulfinyl-1H-benzimidazole N-oxide or a compound represented by formula (I) is oxidized 3-methylpyridin-2-ylmethylsulfonyl-1H-benzimidazole and the like.
또한, 이러한 반응에 가장 보편적으로 사용하는 m-클로로퍼벤조산의 경우 부산물의 생성을 최소화하기 위해 -45℃ 정도의 저온에서 반응을 실시해야 하는 문제점이 있다. 이러한 노력에도 불구하고 상기한 바와 같은 부산물들이 생성되며 이들을 제거하기 위하여 복잡한 정제과정이 추가적으로 요구되고 있다. In addition, in the case of m-chloroperbenzoic acid, which is most commonly used for such a reaction, there is a problem in that the reaction should be carried out at a low temperature of about -45 ° C in order to minimize the generation of by-products. Despite these efforts, by-products as described above are produced and complex purification processes are additionally required to remove them.
대한민국특허등록 제559169호는 반응식 2의 합성공정을 실시예에 구체적으로 제시하고 있으며 이 방법에서는 화학식 (V)로 표시되는 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸의 산화반응에서 m-클로로퍼벤조산 대신에 산무수물 또는 금속촉매의 존재하에 과붕산염을 사용하거나, 염기의 존재하에 N-할로숙신이미드나 1,3-디할로-5,5-디메틸히단토인 등을 사용하고 있다. Korean Patent Registration No. 559169 specifically presents a synthesis process of Scheme 2 in the Examples, in which 2- [4- (3-methoxypropoxy) -3-methylpyridine- is represented by Formula (V). In the oxidation of 2-ylmethylthio] 1H-benzimidazole, perborate is used in the presence of an acid anhydride or a metal catalyst instead of m-chloroperbenzoic acid, or N-halosuccinimide or 1,3- in the presence of a base. Dihalo-5,5-dimethylhydantoin and the like are used.
반응식 2Scheme 2
상기 반응식 2에서 제시된 합성방법이 현재까지 알려진 화학식 (V)로 표시되는 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸의 산화반응 들 중 가장 우수한 방법으로 반응조건에 따라 라베프라졸이 66.6~91.8%의 수율로 얻어진다. Oxidation of 2- [4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylthio] 1H-benzimidazole represented by the general formula (V) Among the reactions, the best method is to obtain a labeprazole in 66.6 ~ 91.8% yield depending on the reaction conditions.
대한민국특허출원 2003-7010217호(테바 파마슈티컬 인더스트리즈 리미티드)에서는 화학식 (V)로 표시되는 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸의 산화반응을 개선하기 위하여 촉매량의 바나듐 아세틸아세토네이트와 t-부틸 히드로페록사이드(TBHP)를 사용하여 화학식 (I)로 표시되는 라베프라졸을 79%의 수율로 얻고 있으나 여전히 불순물이 함께 얻어지는 문제점을 가지고 있다. In Korean Patent Application No. 2003-7010217 (Teva Pharmaceutical Industries Limited), 2- [4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylthio] 1H represented by the formula (V) To improve the oxidation of benzimidazole, the catalytic amount of vanadium acetylacetonate and t-butyl hydroperoxide (TBHP) was used to obtain rabeprazole represented by formula (I) in a yield of 79%, but still impurities This has a problem obtained together.
대한민국특허출원 2002-7011987호(에스티브 퀴미카 에스.에이.)에서도 화학식 (V)로 표시되는 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸을 촉매량의 암모늄몰리브데이트와 과탄산나트륨을 사용하여 화학식 (I)로 표시되는 라베프라졸을 81%의 수율로 제조하고 있으나 이 방법 또한 선행기술들에서의 문제점을 여전히 내포하고 있다. 2- [4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylthio] represented by the general formula (V) also in Korean Patent Application No. 2002-7011987 (Estim Chimica S.A.) Although 1H-benzimidazole is prepared with a catalytic amount of ammonium molybdate and sodium percarbonate, rabeprazole represented by formula (I) in a yield of 81%, but this method still poses a problem in the prior arts. have.
대한민국특허출원 2002-7013675호는 반응식 3과 같이 피리딘 환의 4번 위치에 있는 니트로기를 알콕시기로 변환하여 화학식 (I)로 표시되는 라베프라졸을 제조하는 새로운 방법을 제시하고 있다. 그러나 이 방법은 알콕시기를 도입하는 반응에서 생성물의 수율이 매우 낮다는 문제점이 있다. Korean Patent Application No. 2002-7013675 proposes a novel method for preparing rabeprazole represented by Formula (I) by converting a nitro group at position 4 of the pyridine ring to an alkoxy group as in Scheme 3. However, this method has a problem in that the yield of the product in the reaction for introducing an alkoxy group is very low.
반응식 3Scheme 3
한국특허출원 2003-7015941호(얀센 파마슈티카 엔.브이.)는 화학식 (V)로 표시되는 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸을 m-클로로퍼벤조산과 같은 통상의 산화제로 산화시킨 후 화학식 (VII)로 표시되는 부산물을 염기성 수용액으로 추출하여 제거함으로써 라베프라졸을 제조하는 방법을 제시하고 있다. 이 방법으로 화학식 (VII)로 표시되는 부산물을 일부 제거할 수는 있으나, 그 공정이 매우 복잡하고 수율 또한 크게 낮아진다는 문제점이 있다. 결국 이 발명의 내용은 m-클로로퍼벤조산와 같이 통상 사용하는 산화제의 경우 화학식 (V)로 표시되는 화합물의 산화반응에서 얼마나 많은 부산물을 생성하고 결국 얼마나 많은 문제점을 야기하는지를 잘 설명해주고 있다. Korean Patent Application No. 2003-7015941 (Jansen Pharmatica N. V.) is 2- [4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylthio] represented by the formula (V). A method of preparing labeprazole is provided by oxidizing 1H-benzimidazole with a conventional oxidizing agent such as m-chloroperbenzoic acid and then extracting and removing the by-product represented by the formula (VII) with a basic aqueous solution. This method can remove some of the by-product represented by the formula (VII), but the problem is that the process is very complicated and the yield is also significantly lower. After all, the contents of the present invention well explain how many by-products are generated in the oxidation reaction of the compound represented by the formula (V) and eventually cause many problems in the case of a commonly used oxidant such as m-chloroperbenzoic acid.
이에 본 발명자들은 공지된 방법보다 간편한 방법으로 높은 수율로 라베프라졸 및 그의 중간체를 제조하는 방법을 개발하고자 하였다.Therefore, the present inventors have attempted to develop a method for preparing rabeprazole and its intermediates in a high yield in a simpler manner than known methods.
특히 화학식 (VI)으로 표시되는 2-4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸술피닐-1H-벤즈이미다졸 N-옥사이드나 화학식 (VII)로 표시되는 2-4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸설포닐-1H-벤즈이미다졸과 같은 부산물은 최종적으로 원하는 생성물인 화학식 (I)로 표시되는 라베프라졸과 물리적 성질이 비슷하여 재결정과 같은 일반적인 정제방법으로는 제거되기가 어려우므로, 본 발명자들은 반응 단계에서부터 이와 같은 부산물이 적게 생성되는 조건을 찾는데 중점을 두고 연구하였다. In particular 2-4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylsulfinyl-1H-benzimidazole N-oxide represented by formula (VI) or 2 represented by formula (VII) By-products, such as -4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylsulfonyl-1H-benzimidazole, are physically associated with rabeprazole represented by formula (I), which is the final desired product. Since the properties are similar and difficult to remove by a general purification method such as recrystallization, the present inventors focused on finding a condition in which such by-products are produced from the reaction step.
그 결과 본 발명자들은 화학식 (II)으로 표시되는 2-히드록시메틸-4-(3-메톡시프로폭시)-3-메틸피리딘 또는 그 염에 포스포러스 트리브로마이드와 화학식 (IV)로 표시되는 2-메르캅토-1H-벤즈이미다졸을 가하는 경우 염기를 전혀 사용하지 않고도 라베프라졸의 중간체인 화학식 (V)로 표시되는 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸을 고 수율로 얻을 수 있음을 발견하였다. 또한 화학식 (V)로 표시되는 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸을 반응용매 및 벤젠셀레닌 산과 트리알킬아민의 혼합촉매 하에서 과산화수소로 산화시키면 화학식 (I)로 표시되는 라베프라졸이 고 수율로 얻어짐을 알게 되었다. 통상적으로 과산화수소 반응의 촉매로 사용되는 산들이 염기의 존재하에서는 반응이 정상적으로 진행되지 않은 것에 비추어 볼 때 본 기술에서 사용한 벤젠셀레닌 산은 예외적으로 이러한 반응에 적합한 특성을 지니고 있음을 발견할 수 있었다. As a result, the present inventors found that 2-hydroxymethyl-4- (3-methoxypropoxy) -3-methylpyridine or salt thereof represented by formula (II) and phosphorus tribromide represented by formula (IV) When mercapto-1H-benzimidazole is added, 2- [4- (3-methoxypropoxy) -3-methylpyridine represented by the formula (V) which is an intermediate of rabeprazole without using any base. It was found that 2-ylmethylthio] 1H-benzimidazole can be obtained in high yield. In addition, 2- [4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylthio] 1H-benzimidazole represented by the formula (V) may be reacted with a reaction solvent, benzeneselenic acid and trialkylamine. It was found that the oxidation of hydrogen peroxide under a mixed catalyst afforded rabeprazole represented by formula (I) in high yield. In view of the fact that acids normally used as catalysts for hydrogen peroxide reaction did not proceed normally in the presence of a base, it was found that the benzene selenic acid used in the present technology is exceptionally suitable for this reaction.
본 발명에 따르면, 염기를 전혀 사용하지 않고도 반응을 효과적으로 진행시킬 수 있으며, 2단계 공정을 거치는 종래의 반응 공정과는 달리 별도의 분리 공정이 필요 없는 1단계 공정만으로 공지의 방법보다 높은 수율로 화학식 (V)로 표시되는 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸을 제조할 수 있다. 또한, 본 발명에 따르면, 상기 화합물(V)을 벤젠셀레닌 산과 트리알킬아민의 혼합촉매 하에서 과산화수소로 산화시켜 고 수율로 라베프라졸을 제조함으로써, 화학식 (VI)으로 표시되는 2-4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸술피닐-1H-벤즈이미다졸 N-옥사이드나 화학식 (VII)로 표시되는 2-4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸설포닐-1H-벤즈이미다졸과 같은 부산물들이 거의 생성되지 않는 간편하고 경제적인 산화 공정을 실시할 수 있다.According to the present invention, it is possible to effectively proceed the reaction without using any base, and unlike the conventional reaction process that goes through a two-step process, only a one-step process does not require a separate separation process in a higher yield than known methods 2- [4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylthio] 1H-benzimidazole represented by (V) can be prepared. In addition, according to the present invention, the compound (V) is oxidized with hydrogen peroxide under a mixed catalyst of benzene selenic acid and trialkylamine to prepare rabeprazole in high yield. 3-methoxypropoxy) -3-methylpyridin-2-ylmethylsulfinyl-1H-benzimidazole N-oxide or 2-4- (3-methoxypropoxy) -3 represented by formula (VII) A simple and economical oxidation process can be carried out in which little by-products such as -methylpyridin-2-ylmethylsulfonyl-1H-benzimidazole are produced.
본 발명의 목적은 위산 분비 억제 및 위점막 보호에 우수한 효과를 나타내는 항궤양제인 라베프라졸을 제조하는 새로운 방법을 제공하기 위한 것이다.It is an object of the present invention to provide a new method for preparing rabeprazole, an anti-ulcer agent which has an excellent effect on gastric acid secretion inhibition and gastric mucosal protection.
본 발명의 다른 목적은 공지기술과는 달리 별도의 분리 공정 없이, 또한 염기를 사용하지 않고 반응액 상태인 산성 조건에서 1 단계 반응으로 라베프라졸의 반응 중간체인 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸을 제조하는 방법을 제공하기 위한 것이다.Another object of the present invention is a 2- [4- (3-method), which is a reaction intermediate of rabeprazole in a one-step reaction under acidic conditions in a reaction liquid state without a separate separation process and without using a base, unlike the known art. To provide a method for preparing oxypropoxy) -3-methylpyridin-2-ylmethylthio] 1H-benzimidazole.
본 발명의 또 다른 목적은 보다 간편하고 경제적으로 라베프라졸을 고 순도 및 고 수율로 제조하는 방법을 제공하기 위한 것이다.Another object of the present invention is to provide a method for producing rabeprazole in high purity and high yield more simply and economically.
본 발명의 또 다른 목적은 라베프라졸을 대량으로 제조하기에 적합한 방법을 제공하기 위한 것이다.It is a further object of the present invention to provide a method suitable for producing large amounts of rabeprazole.
본 발명의 상기 및 기타의 목적들은 하기 설명되는 본 발명에 의하여 모두 달성될 수 있다.The above and other objects of the present invention can be achieved by the present invention described below.
본 발명은 화학식 (I)로 표시되는 라베프라졸 및 그 중간체인 화학식 (V)로 표시되는 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸을 제조하는 방법에 관한 것이다. The present invention relates to rabeprazole represented by formula (I) and its intermediate, 2- [4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylthio] 1H represented by formula (V). It relates to a process for preparing benzimidazole.
본 발명에 따라 라베프라졸을 제조하기 위한 공정은 하기 반응식 4과 같이 나타낼 수 있다. The process for preparing labeprazole according to the present invention can be represented as in Scheme 4 below.
반응식 4Scheme 4
반응식 4에 나타난 바와 같이, 본 발명에 따른 라베프라졸의 제조방법은 화학식 (II)로 표시되는 2-히드록시메틸-4-(3-메톡시프로폭시)-3-메틸피리딘 또는 그의 염과 화학식 (IV)로 표시되는 2-메르캅토-1H-벤즈이미다졸을 반응용매 및 포스포러스 트리브로마이드 하에서 반응시키는 단계, 및 상기 반응에 의하여 생성된 화학식 (V)로 표시되는 화합물을 반응용매 및 벤젠셀레닌 산과 트리알킬아민의 혼합촉매 하에서 과산화수소로 산화시키는 단계로 이루어진다. 상기의 산화 단계는 촉매로 벤젠셀레닌 산과 트리알킬아민의 혼합촉매를 사용하여 반응 완결도를 높이고 부산물의 생성을 최소화하였다.As shown in Scheme 4, the method for preparing labeprazole according to the present invention is 2-hydroxymethyl-4- (3-methoxypropoxy) -3-methylpyridine or a salt thereof represented by Chemical Formula (II). Reacting 2-mercapto-1H-benzimidazole represented by formula (IV) under a reaction solvent and phosphorus tribromide, and reacting the compound represented by formula (V) produced by the reaction with a reaction solvent and benzene Oxidizing with hydrogen peroxide under a mixed catalyst of selenic acid and trialkylamine. In the oxidation step, a mixed catalyst of benzene selenic acid and trialkylamine was used as a catalyst to increase reaction completion and minimize generation of by-products.
이하에서, 본 발명을 더욱 상세히 설명한다.In the following, the present invention is described in more detail.
제1단계: 2-[4-(3-First step: 2- [4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2--2- 일메틸티오Ilmethylthio ]1H-] 1H- 벤즈이미다졸(V)의Of benzimidazole (V) 제조 Produce
반응 용매 하에서 화학식 (II)로 표시되는 2-히드록시메틸-4-(3-메톡시프로 폭시)-3-메틸피리딘 또는 그의 염 화합물에 포스포러스 트리브로마이드와 화학식 (IV)로 표시되는 2-메르캅토-1H-벤즈이미다졸을 동시에 또는 순차적으로 가하여 반응시켜 라베프라졸의 중간체인 화학식 (V)로 표시되는 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸을 제조한다. 2-hydroxymethyl-4- (3-methoxypropoxy) -3-methylpyridine or a salt compound thereof represented by formula (II) under a reaction solvent; Mercapto-1H-benzimidazole was added or reacted simultaneously to react 2- [4- (3-methoxypropoxy) -3-methylpyridine-2- represented by the formula (V) as an intermediate of rabeprazole. Ilmethylthio] 1H-benzimidazole is prepared.
반응에 사용되는 용매는 할로겐화 탄화수소, 예를 들어 디클로로메탄, 클로로포름, 카본 테트라클로라이드; 또는 에테르, 예를 들어 테트라하이드로퓨란, 디옥산이 바람직하며, 이 중에서 디클로로메탄 또는 클로로포름이 가장 바람직하다.Solvents used in the reaction include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride; Or ethers such as tetrahydrofuran, dioxane, with dichloromethane or chloroform being most preferred.
화학식 (IV)로 표시되는 2-메르캅토-1H-벤즈이미다졸은 화학식 (II)으로 표시되는 2-히드록시메틸-4-(3-메톡시프로폭시)-3-메틸피리딘 또는 그의 염 화합물과 등량으로 사용된다. 2-mercapto-1H-benzimidazole represented by formula (IV) is 2-hydroxymethyl-4- (3-methoxypropoxy) -3-methylpyridine or a salt compound thereof represented by formula (II). Used in excess.
반응 온도는 0℃ 내지 반응 용매의 비점이며, 바람직하게는 20~85℃이고, 더욱 바람직하게는 35~60℃이다. 반응 시간은 반응 시작 직후부터 24시간 사이이며, 바람직하게는 30분 내지 3시간이다. Reaction temperature is the boiling point of 0 degreeC-reaction solvent, Preferably it is 20-85 degreeC, More preferably, it is 35-60 degreeC. The reaction time is from immediately after the start of the reaction to 24 hours, preferably 30 minutes to 3 hours.
포스포러스 트리브로마이드는 화학식 (II)으로 표시되는 2-히드록시메틸-4-(3-메톡시프로폭시)-3-메틸피리딘 또는 그의 염 화합물에 대하여 1당량(몰비로 1/3배)~15당량(몰비로 5배) 사용되며, 더욱 바람직하게는 2당량~3당량 사용된다.Phosphorus tribromide is from 1 equivalent (1/3 times in molar ratio) to 2-hydroxymethyl-4- (3-methoxypropoxy) -3-methylpyridine or its salt compound represented by the formula (II). 15 equivalents (5 times in molar ratio) are used, More preferably, 2 equivalents-3 equivalents are used.
상기한 바와 같은 반응을 통하여 얻어진 화합물 (V)는 반응액을 냉각한 후 염기화하여 유기층으로 추출하고 농축하여 회수될 수 있으며, 또한 일반적인 정제 방법으로 더 정제될 수 있는데, 예를 들면 에틸 아세테이트와 헥산을 이용하여 더 높은 순도로 정제될 수 있다.Compound (V) obtained through the reaction as described above may be recovered by cooling the reaction solution, basifying it, extracting it into an organic layer, concentrating, and further purifying by a general purification method, for example, with ethyl acetate. Can be purified to higher purity with hexane.
본 발명에 따르면, 화학식 (V)로 표시되는 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸은 화학식 (II)으로 표시되는 2-히드록시메틸-4-(3-메톡시프로폭시)-3-메틸피리딘 또는 그의 염으로부터 92% 이상의 높은 수율과 높은 순도로 제조될 수 있다. 특히, 본 발명은 2단계 공정을 거치는 종래의 공지기술과는 달리 1단계 공정만으로도 화학식 (V)로 표시되는 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸을 별도의 염기 첨가 없이 반응액 상태인 산성 조건 하에서 합성할 수 있다는 데 특징이 있다.According to the invention, 2- [4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylthio] 1H-benzimidazole represented by formula (V) is represented by formula (II) It can be prepared from 2-hydroxymethyl-4- (3-methoxypropoxy) -3-methylpyridine or salt thereof in high yield and high purity of 92% or more. In particular, the present invention is a 2- [4- (3-methoxypropoxy) -3-methylpyridin-2-yl represented by the formula (V) in only one step process, unlike the prior art known through a two step process. Methylthio] 1 H-benzimidazole is characterized in that it can be synthesized under acidic conditions in the reaction state without the addition of a separate base.
제2단계: Second step: 라베프라졸(I)의Of labeprazole (I) 제조 Produce
제2단계에서는 상기 제1단계에서 생성된 화학식 (V)로 표시되는 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸을 반응용매 및 벤젠셀레닌 산과 트리알킬아민의 혼합촉매의 존재 하에서 과산화수소로 산화시켜 화학식 (I)로 표시되는 라베프라졸을 제조한다.In the second step, 2- [4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylthio] 1H-benzimidazole represented by Formula (V) produced in the first step is reacted. Labeprazole represented by the formula (I) is prepared by oxidizing with hydrogen peroxide in the presence of a solvent and a mixed catalyst of benzeneselenic acid and trialkylamine.
본 발명의 제2단계에 사용되는 반응용매는 할로겐화 탄화수소, 예를 들어 디클로로메탄, 클로로포름, 카본 테트라클로라이드; 에테르, 예를 들어 테트라하이드로퓨란, 디옥산; 또는 물이며, 이 중에서 디클로로메탄이나 클로로포름이 바람직하다.The reaction solvent used in the second step of the present invention is a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride; Ethers such as tetrahydrofuran, dioxane; Or water, of which dichloromethane and chloroform are preferred.
반응에 사용되는 촉매는 벤젠셀레닌 산이며, 사용량은 화학식 (V)로 표시되는 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸에 대하여 0.0001~0.2당량, 바람직하게는 0.001~0.1당량, 가장 바람직하게는 0.002~0.01당량이다.The catalyst used in the reaction is benzene seleninic acid, the amount of which is used is 2- [4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylthio] 1H-benzimi represented by the formula (V). 0.0001 to 0.2 equivalent, preferably 0.001 to 0.1 equivalent, and most preferably 0.002 to 0.01 equivalent to dazole.
반응생성물인 라베프라졸이 산에 불안정하기 때문에, 반응액이 산성화되는 것을 방지하기 위하여 벤젠셀레닌 산과 함께 트리알킬아민을 사용한다. 이때 사용되는 트리알킬아민은 1-메틸피롤리딘, N,N-디에틸메틸아민, 1-메틸피페리딘, 트리에틸아민, N,N-디이소프로필메틸아민, N,N-디이소프로필에틸아민 등이며, 가장 바람직하게는 트리에틸아민과 N,N-디이소프로필에틸아민이다. 트리알킬아민의 사용량은 화학식 (V)로 표시되는 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸에 대하여 0.01~1.0당량, 바람직하게는 0.1~0.3당량이다.Since the reaction product, rabeprazole, is unstable in acid, trialkylamine is used together with benzene selenic acid to prevent the reaction from acidifying. The trialkylamines used here are 1-methylpyrrolidine, N, N-diethylmethylamine, 1-methylpiperidine, triethylamine, N, N-diisopropylmethylamine, N, N-diiso Propylethylamine and the like, most preferably triethylamine and N, N-diisopropylethylamine. Trialkylamine is used in an amount of 0.01 to 1.0 equivalents based on 2- [4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylthio] 1H-benzimidazole represented by the formula (V), Preferably it is 0.1-0.3 equivalent.
과산화수소는 20~50% 정도의 수용액 형태로 사용하는 것이 일반적이지만 상기 범위에 한정되는 것은 아니다. 과산화수소의 사용량은 화학식 (V)로 표시되는 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸에 대하여 0.95~1.2당량, 바람직하게는 1.0~1.1 당량이다.Hydrogen peroxide is generally used in the form of an aqueous solution of about 20 to 50%, but is not limited to the above range. The amount of hydrogen peroxide used is 0.95 to 1.2 equivalents, preferably relative to 2- [4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylthio] 1H-benzimidazole represented by the formula (V). Is 1.0-1.1 equivalents.
반응 온도는 0~50℃이며, 바람직하게는 5~35℃, 더욱 바람직하게는 10~25℃이다. 반응 시간은 10분~24시간이며, 바람직하게는 30분~10시간이고, 더욱 바람직하게는 1~6시간이다.Reaction temperature is 0-50 degreeC, Preferably it is 5-35 degreeC, More preferably, it is 10-25 degreeC. The reaction time is 10 minutes to 24 hours, preferably 30 minutes to 10 hours, and more preferably 1 to 6 hours.
상기 방법으로 얻어진 생성물은, 일반적인 과산화수소 분해방법(예를 들어, 소디움 티오설페이트 수용액을 가하여)으로 산화 반응을 종결시키고, 디클로로메탄과 같은 용매로 추출한 다음 농축하고 아세톤과 핵산을 사용하여 결정화할 수 있다. 또한, 더 좋은 품질의 생성물을 얻기 위하여 아세톤과 물 등의 용매를 사용하는 재결정 등의 일반적인 정제 방법으로 정제할 수 있다.The product obtained by the above method can be terminated by a general hydrogen peroxide decomposition method (for example, by adding an aqueous sodium thiosulfate solution), extracted with a solvent such as dichloromethane, and then concentrated and crystallized using acetone and nucleic acid. . In addition, it can be purified by a general purification method such as recrystallization using a solvent such as acetone and water in order to obtain a better quality product.
상기한 바와 같이 본 발명에 따라, 화학식 (V)로 표시되는 2-[4-(3-메톡시프 로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸로부터 화학식 (I)로 표시되는 라베프라졸을 고품질과 고수율(88%)로 제조할 수 있다. 특히, 반응 부산물인 화학식 (VI)으로 표시되는 2-4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸술피닐-1H-벤즈이미다졸 N-옥사이드와 화학식 (VII)로 표시되는 2-4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸설포닐-1H-벤즈이미다졸의 생성량을 각기 1.5% 이하로 현저히 줄일 수 있다. 필요에 따라 하기의 실시예 3과 같은 일반적인 정제 과정을 거치면 생성물 중 이들 부산물의 양을 0.1% 이하로 줄일 수 있다.According to the invention as described above, the formula (I) is derived from 2- [4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylthio] 1H-benzimidazole represented by the formula (V). Rabeprazole represented by) can be produced in high quality and high yield (88%). In particular, 2-4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylsulfinyl-1H-benzimidazole N-oxide represented by formula (VI) as a reaction by-product and formula (VII) The production amount of 2-4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylsulfonyl-1H-benzimidazole represented by can be significantly reduced to 1.5% or less, respectively. If necessary, the general purification process as in Example 3 below may reduce the amount of these by-products in the product to 0.1% or less.
본 발명은 하기의 실시예에 의하여 보다 더 잘 이해될 수 있으며, 하기의 실시예는 본 발명을 예시하기 위한 것이며 첨부된 특허청구범위에 의하여 한정되는 보호범위를 제한하고자 하는 것은 아니다.The invention can be better understood by the following examples, which are intended to illustrate the invention and are not intended to limit the scope of protection defined by the appended claims.
실시예Example
실시예 1: 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸(V)의 제조Example 1: Preparation of 2- [4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylthio] 1H-benzimidazole (V)
2-히드록시메틸-4-(3-메톡시프로폭시)-3-메틸피리딘 42.252g (0.20mol)을 디클로로메탄 1.2ℓ에 녹인 후, 포스포러스 트리브로마이드 54.14g(0.20mol)과 2-메르캅토-1H-벤즈이미다졸 30.04g(0.20mol)을 실온에서 차례로 투입한 다음 2.5시간 동안 환류시켰다. 반응이 완결된 후 환류 과정에 의하여 승온된 반응액을 실온까지 냉각하고 4N-가성소다를 서서히 첨가하여 반응액의 pH를 13.5~14가 되도록 하였다. 상기 반응액에 아세톤 200㎖를 가하여 20분 동안 강하게 교반시킨 후 유기층을 분리하고 물층을 디클로로메탄 200㎖로 재추출하였다. 분리된 유기층을 합하여 물 400㎖로 세척한 후 무수 황산 마그네슘으로 건조시키고 감압 하에서 농축시켰다. 용매를 제거하여 남은 오일상의 잔류액을 에틸 아세테이트 200㎖에 현탁시킨 후 헥산 700㎖를 서서히 가하면 미백색 결정인 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸 63.91g을 얻었다. 결정의 수율은 93.0%였다.42.252 g (0.20 mol) of 2-hydroxymethyl-4- (3-methoxypropoxy) -3-methylpyridine was dissolved in 1.2 L of dichloromethane, followed by 54.14 g (0.20 mol) of phosphorus tribromide and 2-mer 30.04 g (0.20 mol) of capto-1H-benzimidazole was sequentially added at room temperature and then refluxed for 2.5 hours. After the reaction was completed, the reaction solution heated by reflux was cooled to room temperature and 4 N -caustic soda was slowly added to make the pH of the reaction solution 13.5-14. 200 ml of acetone was added to the reaction solution, followed by vigorous stirring for 20 minutes. The organic layer was separated, and the water layer was reextracted with 200 ml of dichloromethane. The combined organic layers were combined, washed with 400 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The solvent was removed, the remaining oily residue was suspended in 200 ml of ethyl acetate, and 700 ml of hexane was slowly added to give 2- [4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethyl as a white crystal. 63.91 g of thio] 1H-benzimidazole were obtained. The yield of the crystal was 93.0%.
1H NMR (CDCl3) δ=2.09(t, J=6.1Hz, 2H), 2.26(s, 3H), 3.35(s, 3H), 3.56(t, J=6.1Hz, 2H), 4.13(t, J=6.1Hz, 2H), 4.37(s, 2H), 6.76(d, J=6.1Hz, 1H), 7.1~7.25(m, 2H), 7.5(br, s, 2H), 8.33(d, J=6.1Hz, 1H) 1 H NMR (CDCl 3 ) δ = 2.09 (t, J = 6.1Hz, 2H), 2.26 (s, 3H), 3.35 (s, 3H), 3.56 (t, J = 6.1Hz, 2H), 4.13 (t , J = 6.1Hz, 2H), 4.37 (s, 2H), 6.76 (d, J = 6.1Hz, 1H), 7.1 ~ 7.25 (m, 2H), 7.5 (br, s, 2H), 8.33 (d, J = 6.1Hz, 1H)
실시예 2: 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸(V)의 제조Example 2: Preparation of 2- [4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylthio] 1H-benzimidazole (V)
2-히드록시메틸-4-(3-메톡시프로폭시)-3-메틸피리딘 염산염 49.544g (0.20mol)을 디클로로메탄 1.2ℓ에 녹인 후, 포스포러스 트리브로마이드 54.14g(0.20mol)과 2-메르캅토-1H-벤즈이미다졸 30.04g(0.20mol)을 실온에서 차례로 투입한 다음 2.5시간 동안 환류시켰다. 반응이 완결된 후 환류 과정에 의하여 승온된 반응액을 실온까지 냉각하고 4N-가성소다를 서서히 첨가하여 반응액의 pH를 13.5~14가 되도록 하였다. 상기 반응액에 아세톤 200㎖를 가하여 20분 동안 강하게 교반시킨 후 유기층을 분리하고 물층을 디클로로메탄 200㎖로 재추출하였다. 분리된 유기층을 합하여 물 400㎖로 세척한 후 무수 황산 마그네슘으로 건조시키고 감압 하에서 농축시켰다. 용매를 제거하여 남은 오일상의 잔류액을 에틸 아세테이트 200㎖에 현탁시킨 후 헥산 700㎖를 서서히 가하면 미백색 결정인 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸 63.52g을 얻었다. 결정의 수율은 92.47%였다.49.544 g (0.20 mol) of 2-hydroxymethyl-4- (3-methoxypropoxy) -3-methylpyridine hydrochloride was dissolved in 1.2 L of dichloromethane, followed by 54.14 g (0.20 mol) of phosphorus tribromide and 2- 30.04 g (0.20 mol) of mercapto-1H-benzimidazole was added sequentially at room temperature and then refluxed for 2.5 hours. After the reaction was completed, the reaction solution heated by reflux was cooled to room temperature and 4 N -caustic soda was slowly added to make the pH of the reaction solution 13.5-14. 200 ml of acetone was added to the reaction solution, followed by vigorous stirring for 20 minutes. The organic layer was separated, and the water layer was reextracted with 200 ml of dichloromethane. The combined organic layers were combined, washed with 400 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The solvent was removed, the remaining oily residue was suspended in 200 ml of ethyl acetate, and 700 ml of hexane was slowly added to give 2- [4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethyl as a white crystal. 63.52 g of thio] 1H-benzimidazole were obtained. The yield of crystals was 92.47%.
1H NMR (CDCl3) δ=2.09(t, J=6.1Hz, 2H), 2.26(s, 3H), 3.35(s, 3H), 3.56(t, J=6.1Hz, 2H), 4.13(t, J=6.1Hz, 2H), 4.37(s, 2H), 6.76(d, J=6.1Hz, 1H), 7.1~7.25(m, 2H), 7.5(br, s, 2H), 8.33(d, J=6.1Hz, 1H) 1 H NMR (CDCl 3 ) δ = 2.09 (t, J = 6.1Hz, 2H), 2.26 (s, 3H), 3.35 (s, 3H), 3.56 (t, J = 6.1Hz, 2H), 4.13 (t , J = 6.1Hz, 2H), 4.37 (s, 2H), 6.76 (d, J = 6.1Hz, 1H), 7.1 ~ 7.25 (m, 2H), 7.5 (br, s, 2H), 8.33 (d, J = 6.1Hz, 1H)
실시예 3: 라베프라졸(I)의 제조Example 3: Preparation of Labeprazole (I)
실시예 1에서 얻어진 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸 30g(87.35mmol)을 디클로로메탄 600㎖에 녹인 후 벤젠셀레닌 산 82mg(0.437mmol)을 투입하고 현탁액을 10℃로 냉각하였다. 트리에틸아민 2.43㎖(17.47mmol)와 35.7%의 과산화수소 용액 8.987g(94.338mmol)을 10℃ 이하에서 투입하였다. 반응액의 온도를 상온으로 서서히 올리면서 5시간 동안 교반하여 반응이 완결되면, 반응액을 5℃로 냉각한 다음 소디움 티오설페이트 8g을 물 400㎖에 녹여 얻어진 수용액을 10℃ 이하에서 천천히 적가하였다. 반응액을 10℃ 정도에서 20분 동안 강하게 교반한 후 유기층을 분리하여 물 400㎖로 세척하였다. 세척된 유기층을 무수 황산 마그네슘으로 건조시킨 후 감압 하에서 농축하여 오일상의 조생성물을 얻었다. 오일상의 조생성물에 아세톤 150㎖를 가하여 녹이고 헥산 300㎖를 서서히 적가한 후 2시간동안 교반하여 결정화하였다. 얻어진 결정을 여과하고 아세톤과 헥산의 1:2 혼합용액 50㎖로 세척한 후 진공 건조하여 29.68g의 흰색 결정을 얻었다. 얻어진 결정을 다시 아세톤 150㎖에 현탁시킨 후 물 50㎖를 서서히 가하여 완전히 녹였다. 다시 물 250㎖를 서서히 적가하면 흰색의 결정이 얻어진다. 얻어진 흰색 결정을 여과하여 물과 아세톤의 1:2 혼합용매 50㎖로 세척한 후 진공 건조하여 27.65g의 흰색 결정을 얻었다. 결정의 수율은 88.06%였다.30 g (87.35 mmol) of 2- [4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylthio] 1H-benzimidazole obtained in Example 1 was dissolved in 600 ml of dichloromethane, and then benzene cell. 82 mg (0.437 mmol) of leninic acid were added and the suspension was cooled to 10 ° C. 2.43 mL (17.47 mmol) of triethylamine and 8.987 g (94.338 mmol) of 35.7% hydrogen peroxide solution were added at 10 占 폚 or lower. When the reaction was completed by stirring for 5 hours while slowly raising the temperature of the reaction solution to room temperature, the reaction solution was cooled to 5 ° C, and 8 g of sodium thiosulfate was dissolved in 400 ml of water, and the resulting aqueous solution was slowly added dropwise at 10 ° C or lower. The reaction solution was stirred vigorously at about 10 ° C. for 20 minutes, and the organic layer was separated and washed with 400 ml of water. The washed organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain an oily crude product. 150 ml of acetone was added to the crude oily product, and 300 ml of hexane was slowly added dropwise, followed by stirring for 2 hours to crystallize. The obtained crystals were filtered, washed with 50 ml of a 1: 2 mixed solution of acetone and hexane, followed by vacuum drying to obtain 29.68 g of white crystals. The obtained crystals were again suspended in 150 ml of acetone, and then 50 ml of water was slowly added to completely dissolve the crystals. When 250 ml of water is slowly added dropwise, white crystals are obtained. The white crystals thus obtained were filtered, washed with 50 ml of a 1: 2 mixed solvent of water and acetone, followed by vacuum drying to obtain 27.65 g of white crystals. The yield of the crystal was 88.06%.
1H NMR (CDCl3) δ=1.83~2.09(m, 2H), 2.13(s, 3H), 3.34(s, 3H), 3.52(t, J=6.2Hz, 2H), 4.05(t, J=6.2Hz, 2H), 4.79(s, 2H), 6.70(d, J=5.7Hz, 1H), 7.07~7.30(m, 2H), 7.30~7.60(br, s, 2H), 8.27(d, J=5.7Hz, 1H) 1 H NMR (CDCl 3 ) δ = 1.83 to 2.09 (m, 2H), 2.13 (s, 3H), 3.34 (s, 3H), 3.52 (t, J = 6.2 Hz, 2H), 4.05 (t, J = 6.2Hz, 2H), 4.79 (s, 2H), 6.70 (d, J = 5.7Hz, 1H), 7.07 ~ 7.30 (m, 2H), 7.30 ~ 7.60 (br, s, 2H), 8.27 (d, J = 5.7 Hz, 1H)
본 발명은 화학식 (II)으로 표시되는 2-히드록시메틸-4-(3-메톡시프로폭시)-3-메틸피리딘 또는 그의 염과 화학식 (IV)로 표시되는 2-메르캅토-1H-벤즈이미다졸을 포스포러스 트리브로마이드 존재 하에서 반응시켜 화학식 (V)로 표시되는 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸을 고 수율로 제조하고, 이를 벤젠셀레닌 산과 트리알킬아민의 혼합촉매 하에서 과산화수소로 산화시켜 화학식 (I)으로 표시되는 라베프라졸을 용이하게 제조하는 방법을 제공하는 효과를 가진다. 라베프라졸을 제조하는 방법에 관련된 선행기술의 경우 반응공정이 길고, 합성수율이 낮고 최종 생성물에 다수의 불순물이 포함되어 정제가 어렵다는 문제가 있다. 그러나 본 발명은 2-[4-(3-메톡시프로폭시)-3-메틸피리딘-2-일메틸티오]1H-벤즈이미다졸(V)을 얻기 위한 2단계의 공정을 1단계로 줄였을 뿐만 아니라 벤젠셀레닌산과 트리알킬아민의 혼합촉매를 사용함으로써 최종생성물의 수율과 순도를 크게 향상시키고 이에 따라 정제가 용이하다는 장점을 갖는다. The present invention relates to 2-hydroxymethyl-4- (3-methoxypropoxy) -3-methylpyridine or salt thereof represented by formula (II) and 2-mercapto-1H-benz represented by formula (IV). The imidazole is reacted in the presence of phosphorus tribromide to give 2- [4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylthio] 1H-benzimidazole represented by the formula (V). It is produced in a yield, and has the effect of providing a method for easily preparing a rabeprazole represented by the formula (I) by oxidizing it with hydrogen peroxide under a mixed catalyst of benzene selenine acid and trialkylamine. In the prior art related to the method for producing rabeprazole there is a problem that the reaction process is long, the synthesis yield is low and the purification is difficult because a large number of impurities in the final product. However, the present invention reduced the two step process to one step to obtain 2- [4- (3-methoxypropoxy) -3-methylpyridin-2-ylmethylthio] 1H-benzimidazole (V). In addition, by using a mixed catalyst of benzene selenic acid and trialkylamine, it has the advantage of greatly improving the yield and purity of the final product and thus easy to purify.
본 발명의 단순한 변형 내지 변경은 이 분야의 통상의 지식을 가진 자에 의하여 용이하게 이해될 수 있으며, 이러한 변형이나 변경은 모두 본 발명의 영역에 포함되는 것으로 볼 수 있다.Simple modifications and variations of the present invention can be readily understood by those skilled in the art, and all such variations or modifications can be considered to be included within the scope of the present invention.
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| EP0268956A2 (en) * | 1986-11-13 | 1988-06-01 | Eisai Co., Ltd. | Pyridine derivatives, pharmaceutical compositions comprising the same, the use of the same for the manufacture of medicaments having therapeutic or preventative value, and a process for preparing the same |
| KR20020068592A (en) * | 2001-02-21 | 2002-08-28 | 주식회사 씨트리 | Method of Preparing Lansoprazole and Its Intermediate |
| KR100559169B1 (en) | 1997-07-11 | 2006-03-10 | 에자이 가부시키가이샤 | Processes for the preparation of pyridine derivatives |
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| EP0268956A2 (en) * | 1986-11-13 | 1988-06-01 | Eisai Co., Ltd. | Pyridine derivatives, pharmaceutical compositions comprising the same, the use of the same for the manufacture of medicaments having therapeutic or preventative value, and a process for preparing the same |
| KR100559169B1 (en) | 1997-07-11 | 2006-03-10 | 에자이 가부시키가이샤 | Processes for the preparation of pyridine derivatives |
| KR20020068592A (en) * | 2001-02-21 | 2002-08-28 | 주식회사 씨트리 | Method of Preparing Lansoprazole and Its Intermediate |
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