KR100430575B1 - Method of Preparing Lansoprazole and Its Intermediate - Google Patents

Method of Preparing Lansoprazole and Its Intermediate Download PDF

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KR100430575B1
KR100430575B1 KR10-2001-0008677A KR20010008677A KR100430575B1 KR 100430575 B1 KR100430575 B1 KR 100430575B1 KR 20010008677 A KR20010008677 A KR 20010008677A KR 100430575 B1 KR100430575 B1 KR 100430575B1
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compound
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trifluoroethoxy
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pyridyl
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김경수
박종억
장정민
최재원
김명화
김완주
백용구
유용상
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주식회사 씨트리
한솔케미언스 주식회사
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Priority to EP02700866A priority patent/EP1368338A4/en
Priority to PCT/KR2002/000261 priority patent/WO2002074766A1/en
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    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

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Abstract

본 발명은 하기 화학식 (I)로 표시되는 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸(이하, '란소프라졸(lansoprazole)'이라 함) 및 그 중간체인 하기 화학식 (II)로 표시되는 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸을 제조하는 방법에 관한 것으로, 반응 용매 하에서 2-히드록시메틸-3-메틸-4-(2,2,2-트리플루오로에톡시)피리딘 또는 그의 염과 2-머캅토벤즈이미다졸에 할로겐화제 및 첨가제를 가하여 하기 화학식 (II)의 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸을 고수율로 제조하고, 이를 반응 용매 및 벤젠셀레닌 산 촉매 하에서 과산화수소로 산화시켜 란소프라졸을 제조하기 위한 방법이다.The present invention provides 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole represented by the following general formula (I) 2- (3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl], represented by the following formula (II), and lansoprazole) A method for preparing methylthio-1H-benzimidazole, the method comprising: 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine or a salt thereof in a reaction solvent; Halogenating agent and additive are added to the mercaptobenzimidazole, and 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio- of formula (II) It is a method for preparing lansoprazole by preparing 1H-benzimidazole in high yield and oxidizing it with hydrogen peroxide under a reaction solvent and a benzeneselenic acid catalyst.

Description

란소프라졸 및 그 중간체의 제조방법{Method of Preparing Lansoprazole and Its Intermediate}Method for preparing lansoprazole and its intermediates {Method of Preparing Lansoprazole and Its Intermediate}

본 발명은 위산 분비 억제 및 위점막 보호에 우수한 효과를 나타내는 항-궤양제인 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸 및 그 중간체의 새로운 제조방법에 관한 것이다. 보다 구체적으로 본 발명은 반응용매 하에서 2-히드록시메틸-3-메틸-4-(2,2,2-트리플루오로에톡시)피리딘 또는 그의 염에 2-머캅토벤즈이미다졸을 할로겐화제와 첨가제를 가하여 반응시켜 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸을 고수율(96% 이상)로 제조하고, 이를 벤젠셀레닌 산 촉매 하에서 과산화수소로 산화시켜 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸을 제조하는 방법에 관한 것이다.The present invention is an anti-ulcer agent 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl, which is an anti-ulcer agent having an excellent effect on gastric acid secretion and gastric mucosal protection A novel process for preparing -1H-benzimidazole and its intermediates. More specifically, the present invention relates to halogenated 2-mercaptobenzimidazole in 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine or a salt thereof in a reaction solvent. The reaction was carried out with the addition of an additive to yield 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole in high yield (96% or more). Prepared and oxidized with hydrogen peroxide under benzeneselenine acid catalyst to 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimi The present invention relates to a method for preparing a dozol.

2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸(화학식 I)은 위산 분비 억제 및 위점막 보호에 우수한 효과를 나타내는 항-궤양제로 알려진 화합물이다. 지금까지 알려져 있는 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸과 그 중간체인 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸(화학식 II)의 제조 방법은 대한민국 특허공고 제92-2128호(Takeda), 대한민국 특허공고 제96-0047호(Takeda), 대한민국 특허공고 제97-6299호, 유럽특허 제0,174,726호(Takeda), 유럽특허 제0,446,961호(Takeda), 미국특허 제4,689,333호(Takeda), 미국특허 제5,374,730호, 국제특허공개 WO 제95/12590호, 및 WO 제97/29103호(PDI Research Laboratories)에 개시되어 있다. 또한, 상기 화합물의 제조 방법은 Tetrahedron, 42/17, 5459(1986), Chemical Abstract, 97/5, 547(1982), Chemical Abstract, 68/1, 658 (1968) 등과 같은 여러 학술 문헌에도 기재되어 있다.2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole (Formula I) is used to inhibit gastric acid secretion and gastric mucosal protection. It is a compound known as an anti-ulcer agent that shows excellent effects. 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole and its intermediate 2- [3- Method for preparing methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole (Formula II) is disclosed in Korean Patent Publication No. 92-2128 (Takeda) , Republic of Korea Patent Publication No. 96-0047 (Takeda), Republic of Korea Patent Publication No. 97-6299, European Patent No. 0,174,726 (Takeda), European Patent No. 0,446,961 (Takeda), United States Patent No. 4,689,333 (Takeda), United States Patent 5,374,730, WO 95/12590, and WO 97/29103 (PDI Research Laboratories). In addition, methods for preparing such compounds are also described in various academic documents, such as Tetrahedron, 42/17, 5459 (1986), Chemical Abstract, 97/5, 547 (1982), Chemical Abstract, 68/1, 658 (1968), and the like. have.

상기 문헌에 개시된 제조 방법들을 요약하면 다음과 같다.The manufacturing methods disclosed in the above document are summarized as follows.

상기 화학식 (II)로 표시되는 화합물은 하기 반응식 1에 나타난 바와 같이 화학식 (IV)로 표시되는 2-머캅토벤즈이미다졸과 화학식 (V)로 표시되는 3-메틸-4-(2,2,2-트리플루오로에톡시)피리딘 유도체의 결합 반응을 통하여, 또는 하기 화학식 (VI)으로 표시되는 벤즈이미다졸 유도체와 하기 화학식 (VII)로 표시되는 2-머캅토메틸-3-메틸-4-(2,2,2-트리플루오로에톡시)피리딘의 결합 반응을 통하여 제조될 수 있다(대한민국 특허공고 제92-2128호).The compound represented by formula (II) is 2-mercaptobenzimidazole represented by formula (IV) and 3-methyl-4- (2,2, represented by formula (V) as shown in Scheme 1 below. Through the coupling reaction of 2-trifluoroethoxy) pyridine derivative, or 2-mercaptomethyl-3-methyl-4- represented by the benzimidazole derivative represented by the following general formula (VI) and the following general formula (VII) It can be prepared through the coupling reaction of (2,2,2-trifluoroethoxy) pyridine (Korean Patent Publication No. 92-2128).

상기 반응식에서 X는 이탈기이며, 구체적으로 할로겐 원자, 아릴설포닐옥시기, C1-4알킬설포닐옥시기, 또는 유기 포스포릴옥시기이다.In the above scheme, X is a leaving group, specifically, a halogen atom, an arylsulfonyloxy group, a C 1-4 alkylsulfonyloxy group, or an organic phosphoryloxy group.

상기 방법에서는 반응성을 높이기 위하여 알칼리 금속, 알칼리 금속 수소화물이나 탄산염, 소디움 알콜레이트, 또는 유기 아민과 같은 염기를 사용하며, 반응 용매로 알코올 또는 디메틸포름아미드를 사용한다.In this method, a base such as alkali metal, alkali metal hydride or carbonate, sodium alcoholate, or organic amine is used to increase reactivity, and alcohol or dimethylformamide is used as a reaction solvent.

이 방법의 단점은 첫째, 2-히드록시메틸-3-메틸-4-(2,2,2-트리플루오로에톡시)피리딘(화학식 III)으로부터 화학식 (V)의 화합물을 얻은 다음 화학식 (IV)의 화합물과 결합 반응을 실시하여야 하기 때문에 실질적으로 두 단계의 작업이 필요하다는 점이다. 예를 들어 화학식 (V)에서 X가 염소 원자일 경우 화학식 (III)과 티오닐 클로라이드를 반응시킨 후 잔류하는 티오닐 클로라이드를 제거하기 위하여 분리 작업이나 농축 과정이 필요하다. 둘째, 반응성을 높이기 위하여 염기를 사용하여야 하며, 셋째, 대량 합성에는 부적절한 컬럼 크로마토그래피를 통하여 분리 과정이 진행되며, 넷째, 최종 생성물의 수율(64.5%)이 저조하다는 점이다.Disadvantages of this method are firstly obtained from the compound of formula (V) from 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine (Formula III) It is necessary to carry out the coupling reaction with the compound of), which requires substantially two steps. For example, when X is a chlorine atom in formula (V), a separation operation or a concentration process is necessary to remove the remaining thionyl chloride after reacting formula (III) with thionyl chloride. Second, the base should be used to increase the reactivity. Third, the separation process is performed through column chromatography, which is inappropriate for mass synthesis. Fourth, the yield of the final product (64.5%) is low.

화학식 (I)로 표시되는 화합물의 제조 방법은 하기 반응식 2에 나타난 바와 같이 화학식 (II)의 화합물을 산화시키는 것으로 다음과 같이 두 가지로 요약될 수 있다.The preparation method of the compound represented by the formula (I) can be summarized in two ways as follows by oxidizing the compound of the formula (II) as shown in Scheme 2 below.

첫 번째 방법은 대한민국 특허공고 제92-2128호에 개시된 바와 같이 반응식 2에서처럼 화학식 (II)로 표시되는 화합물을 산화 반응을 통하여 화학식 (I)로 표시되는 화합물을 합성하는 방법이다. 이때 산화제는 과산, 소디움 브로마이드, 소디움 하이포클로라이드, 또는 과산화수소이며, 반응 용매는 할로겐화 탄화수소, 에테르, 아미드, 알콜, 또는 물이다.The first method is a method of synthesizing the compound represented by the formula (I) through the oxidation reaction of the compound represented by the formula (II) as disclosed in the Republic of Korea Patent Publication No. 92-2128. The oxidant is peracid, sodium bromide, sodium hypochloride, or hydrogen peroxide and the reaction solvent is a halogenated hydrocarbon, ether, amide, alcohol, or water.

이 방법의 단점은 첫째, 산화 반응에서 원하는 화합물인 화학식 (I)만 얻어지는 것이 아니라, 화학식 (I)의 피리딘 환에 존재하는 질소가 산화되어 생성된 하기 화학식 (VIII)의 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸 N-옥사이드가 반응 부산물로 상당량 얻어진다는 점이다.The disadvantages of this method are, firstly, not only the desired compound (I), which is a desired compound in the oxidation reaction, but 2- [3-methyl of formula (VIII) 4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole N-oxide is obtained in significant amounts as a reaction byproduct.

둘째, 반응액의 색상이 진한 보라색으로 변색되어 이로부터 화학식 (I)의 화합물을 분리하여도 상기 색상을 완전히 제거하기 어렵다. 셋째, 생성물의 수율이 77% 정도로 저조하고, 넷째, 컬럼 크로마토그래피를 통하여 분리하므로 대량 합성에 부적절하다.Second, it is difficult to completely remove the color even when the color of the reaction solution is changed to dark purple to separate the compound of formula (I) therefrom. Third, the yield of the product is as low as 77%, and fourth, is separated by column chromatography, which is not suitable for mass synthesis.

화학식 (I)의 두 번째 제조 방법은 대한민국 특허공고 제 96-0047호에 기재되어 있는 방법으로 상기 첫 번째 방법을 좀 더 개량한 방법이다. 촉매로 바나디움 화합물의 존재 하에서 고가의 산화제(m-클로로퍼벤조산) 대신 저가의 산화제인 과산화 수소로 화학식 (II)의 화합물을 산화시켜 화학식 (I)의 화합물을 제조하는 것이다. 이 방법은 기존 방법보다는 생성물의 수율을 높이고 부산물인 화학식 (VIII)의 N-옥사이드 화합물의 생성량을 줄일 수 있는 장점이 있다. 그러나 상기의 방법도 화학식 (I)의 화합물을 합성할 때 반응 완결도가 떨어져서 이를 해결하기 위하여 바나디움 화합물을 증량시켜야 하며, 또한 반응 부산물인 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸 N-옥사이드가 약 4% 정도로 다량 생성된다는 단점이 있다.The second production method of formula (I) is a method described in Korean Patent Publication No. 96-0047, which is a further improvement of the first method. In the presence of a vanadium compound as a catalyst, a compound of formula (I) is prepared by oxidizing a compound of formula (II) with hydrogen peroxide, which is a low-cost oxidant, instead of an expensive oxidant (m-chloroperbenzoic acid). This method has the advantage of increasing the yield of the product and the amount of N-oxide compound of the general formula (VIII) by-products can be reduced than the conventional method. However, in order to solve this problem, the vanadium compound must be increased to synthesize the compound of formula (I), and the reaction by-product, 2- [3-methyl-4- (2,2,2) The disadvantage is that trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole N-oxide is produced in large amounts of about 4%.

본 발명가들은 2-히드록시메틸-3-메틸-4-(2,2,2-트리플루오로에톡시)피리딘으로부터 보다 간편한 방법으로 고품질의 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸을 높은 수율로 제조하고, 이 화합물로부터 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸 N-옥사이드 같은 부산물은 적게 생성되고 원하는 생성물인 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸은 높은 수율로 제조하는 방법을 개발하게 된 것이다. 특히, 하기 화학식 (VIII)의 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸 N-옥사이드 같은 부산물은 최종적으로 원하는 생성물인 하기 화학식 (I)의 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸과 물리적 성질이 비슷하여 재결정과 같은 일반적인 정제방법으로는 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸로부터 제거되기가 어려우므로, 본 발명자들은 반응 단계에서 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸 N-옥사이드가 1% 내외로 적게 생성되는 조건을 찾는데 중점을 두고 연구하였다.The inventors have found that high quality 2- [3-methyl-4- (2,2,2,2,2,2,2,2-trifluoroethoxy) pyridine 2-Trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole was prepared in high yield and 2- [3-methyl-4- (2,2,2-trifluoro) was obtained from this compound. By-products such as loethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole N-oxide are less produced and the desired product is 2- [3-methyl-4- (2,2,2-trifluoro Ethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole has led to the development of a process for high yield. In particular, by-products such as 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole N-oxide of formula (VIII) Is finally the desired product with 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole of formula (I) General purification methods such as recrystallization due to similar physical properties include 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole Since it is difficult to remove from the present inventors, the inventors invented 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole in the reaction step. The research focused on finding conditions that produce less than 1% of N-oxide.

그 결과 본 발명자들은 화학식 (III)의 화합물뿐만 아니라 그 염으로부터 염기의 사용 없이 할로겐화제와 2-머캅토벤즈이미다졸을 가하여 화학식 (II)의 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸을 고수율로 제조하고, 이를 반응 용매 및 벤젠셀레닌 산 촉매 하에서 과산화수소로 산화시켜 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸을 제조하는 방법을 개발하게 되었다.As a result, the present inventors added a halogenating agent and 2-mercaptobenzimidazole from a compound of formula (III) as well as a salt thereof without using a base to prepare 2- [3-methyl-4- (2,2) of formula (II). , 2-Trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole was prepared in high yield, which was oxidized with hydrogen peroxide under a reaction solvent and a benzeneselenic acid catalyst to afford 2- [3-methyl. A method for preparing -4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole has been developed.

따라서, 본 발명에 따르면 염기를 전혀 사용하지 않고도 반응을 효과적으로 진행시킬 수 있으며, 2단계 공정을 거치는 종래의 반응 공정과는 달리 별도의 분리 공정이나 농축 공정이 필요없는 1단계 공정만으로 공지의 방법보다 높은 수율로 화학식 (II)의 화합물을 제조할 수 있으며, 또한 산화 반응은 벤젠셀레닌 산 촉매 하에서 과산화 수소로 진행시켜, 하기 화학식 (VIII)과 같은 부산물이 적게 생성되면서 반응완결도를 높일 수 있어 간편하고 경제적으로 고품질, 고수율의 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸을 제조할 수 있다.Therefore, according to the present invention, it is possible to effectively proceed the reaction without using any base, and unlike the conventional reaction process, which undergoes a two-step process, only a one-step process that does not require a separate separation process or a concentration process than the known method. The compound of formula (II) can be prepared in high yield, and the oxidation reaction can be progressed to hydrogen peroxide under a benzene selenic acid catalyst to increase the reaction completeness while generating less by-products such as formula (VIII). It is possible to prepare high quality, high yield 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole in a simple and economical way. have.

본 발명의 목적은 위산 분비 억제 및 위점막 보호에 우수한 효과를 나타내는항-궤양제인 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸을 제조하는 새로운 방법을 제공하기 위한 것이다.An object of the present invention is an anti-ulcer agent 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl, which has an excellent effect on inhibiting gastric acid secretion and gastric mucosal protection. It is to provide a new method for preparing sulfinyl-1H-benzimidazole.

본 발명의 다른 목적은 공지기술과는 달리 별도의 농축 작업이나 분리 공정 없이, 또한 염기를 사용하지 않고 반응액 상태인 산성 조건에서 한 단계 반응으로 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸의 반응 중간체인 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸를 제조하는 방법을 제공하기 위한 것이다.Another object of the present invention, unlike the known art, is 2- [3-methyl-4- (2,2) as a one-step reaction under acidic conditions in a reaction liquid state without a separate concentration operation or separation process and without using a base. 2- [3-methyl-4- (2,2,2-trifluoroethoxy), a reaction intermediate of, 2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole To provide a method for producing 2-pyridyl] methylthio-1H-benzimidazole.

본 발명의 또 다른 목적은 보다 간편하고 경제적으로 고순도의 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸과 그 중간체를 고수율로 제조하는 방법을 제공하기 위한 것이다.Still another object of the present invention is to provide a simpler and more economical way of purifying 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimi It is to provide a method for producing a high yield of the doazole and its intermediates.

본 발명의 또 다른 목적은 분리되기 힘든 반응 부산물인 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸 N-옥사이드를 반응 단계부터 적게 생성하여 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸을 고수율로 제조하는 방법을 제공하기 위한 것이다.Another object of the present invention is 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole, a reaction byproduct that is difficult to separate. Less production of N-oxide from the reaction step yields high yield of 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole To provide a method for producing.

본 발명의 또 다른 목적은 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸을 대량으로 제조하기에 적합한 방법을 제공하기 위한 것이다.It is another object of the present invention to prepare 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole in large quantities. It is to provide a suitable method.

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 하기 화학식 (I)의 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸(이하 '란소프라졸(lansoprazole)'이라 함) 및 그 중간체인 하기 화학식 (II)의 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸을 제조하기 위한 방법에 관한 것이다. 상기 란소프라졸은 하기 화학식 (III)의 2-히드록시메틸-3-메틸-4-(2,2,2-트리플루오로에톡시)피리딘 또는 그의 염 화합물과 하기 화학식 (IV)의 2-머캅토벤즈이미다졸을 반응 용매 및 할로겐화제 하에서 반응시키는 단계, 및 상기 반응에 의하여 생성된 하기 화학식 (II)의 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸 화합물을 반응 용매 및 벤젠셀레닌 산 촉매 하에서 과산화 수소로 산화시키는 단계로 이루어진다. 상기의 산화 단계는 촉매로 벤젠셀레닌 산을 사용하여 반응 완결도를 높이고 부산물의 생성을 최소화하였다.The present invention relates to 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole (hereinafter referred to as' lansoprazole) (lansoprazole) 'and its intermediate 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H- of formula (II) It relates to a process for preparing benzimidazole. The lansoprazole is 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine or a salt compound thereof, and 2-mercapto of formula (IV) Reacting benzimidazole under a reaction solvent and a halogenating agent, and 2- [3-methyl-4- (2,2,2-trifluoroethoxy)-of the formula (II) And oxidizing the 2-pyridyl] methylthio-1H-benzimidazole compound with hydrogen peroxide under a reaction solvent and a benzeneselenic acid catalyst. In the oxidation step, benzene seleninic acid 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.

본 발명에서 화학식 (II)의 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸과 화학식 (I)의 란소프라졸은 하기의 반응식 3에 따라 제조된다.In the present invention, 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole of formula (II) and (I) Lansoprazole is prepared according to Scheme 3 below.

제1단계: 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸의 제조First Step: Preparation of 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole

반응 용매 하에서 상기 화학식 (III)으로 표시되는 2-히드록시메틸-3-메틸-4-(2,2,2-트리플루오로에톡시)피리딘 또는 그의 염 화합물에 할로겐화제와 상기 화학식 (IV)로 표시되는 2-머캅토벤즈이미다졸을 동시에 또는 순차적으로 가하여 반응시켜 란소프라졸의 중간체인 화학식 (II)로 표시되는 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸을 제조한다.In the reaction solvent, a halogenating agent and 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine or a salt compound thereof represented by the above formula (III) and the above formula (IV) 2-mercaptobenzimidazole represented by the above reaction was carried out simultaneously or sequentially to react 2- (3-methyl-4- (2,2,2-trifluoroethoxy) represented by the formula (II) as an intermediate of lansoprazole. ) -2-pyridyl] methylthio-1H-benzimidazole is prepared.

반응에 사용되는 용매는 할로겐화 탄화수소, 예를 들어 디클로로메탄, 클로로포름, 카본 테트라클로라이드; 또는 에테르, 예를 들어 테트라하이드로푸란, 디옥산이 바람직하며, 이 중에서 디클로로메탄 또는 클로로포름이 더욱 바람직하다.Solvents used in the reaction include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride; Or ethers, for example tetrahydrofuran, dioxane, with dichloromethane or chloroform being more preferred.

상기 화학식 (III)의 2-히드록시메틸-3-메틸-4-(2,2,2-트리플루오로에톡시)피리딘은 대한민국 특허공고 제92-2128호(Takeda)에 개시된 바와 같이 2,3-루티딘으로부터 제조될 수 있으며, 화학식 (III)의 화합물은 산과 결합된 그것의 염 형태, 예를 들어 염산 염, 브롬산 염, 또는 요오드산 염 형태로 사용될 수도 있다.2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine of Formula (III) may be prepared as described in Korean Patent Publication No. 92-2128 (Takeda). It can be prepared from 3-lutidine, and the compound of formula (III) can also be used in the form of its salt in combination with an acid, for example in the form of a hydrochloride salt, bromic acid salt, or iodic salt.

상기 반응에 사용되는 화학식 (IV)의 2-머캅토벤즈이미다졸은 2-히드록시메틸-3-메틸-4-(2,2,2-트리플루오로에톡시)피리딘과 등량 또는 그 이상으로 사용되며, 바람직하게는 1∼4당량, 더욱 바람직하게는 1∼1.5당량이 사용된다. 반응 온도는 0℃ 내지 반응 용매의 비점이며, 바람직하게는 20∼85℃이고, 더욱 바람직하게는 35∼60℃이다. 반응 시간은 반응 시작 직후부터 24시간 사이이며, 바람직하게는 10분 내지 3시간이다. 할로젠화제와 2-머캅토벤즈이미다졸을 순차적으로 가하는 경우 적절한 시간 간격은 할로겐화제 투입 직후 내지 8시간이며, 바람직하게는 5분 내지 3시간이다.2-mercaptobenzimidazole of formula (IV) used in the reaction is equivalent to or greater than 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine. Used, preferably 1 to 4 equivalents, more preferably 1 to 1.5 equivalents. 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 10 minutes to 3 hours. When the halogenating agent and 2-mercaptobenzimidazole are added sequentially, an appropriate time interval is from 8 hours immediately after incorporation of the halogenating agent, preferably 5 minutes to 3 hours.

반응에 사용되는 할로겐화제는 할로겐화 포스포러스 화합물, 예를 들어 포스포러스 트리브로마이드(PBr3), 포스포러스 트리클로라이드(PCl3), 포스포러스 펜타브로마이드(PBr5), 포스포러스 펜타클로라이드(PCl5), 포스포러스 옥시브로마이드(POBr3), 포스포러스 옥시클로라이드(POCl3); 또는 이들의 혼합물이며, 바람직하게는 포스포러스 트리할라이드이다. 할로겐화제는 2-히드록시메틸-3-메틸-4-(2,2,2-트리플루오로에톡시)피리딘에 대하여 1당량(몰비로 1/3배)∼15당량(몰비로 5배) 사용되며, 더욱 바람직하게는 2당량∼3당량 사용된다.Halogenating agents used in the reaction are halogenated phosphorus compounds, for example phosphorus tribromide (PBr 3 ), phosphorus trichloride (PCl 3 ), phosphorus pentabromide (PBr 5 ), phosphorus pentachloride (PCl 5 ) , Phosphorus oxybromide (POBr 3 ), phosphorus oxychloride (POCl 3 ); Or mixtures thereof, preferably phosphorus trihalides. The halogenating agent is 1 equivalent (1/3 times in molar ratio) to 15 equivalents (5 times in molar ratio) based on 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine It is used, More preferably, 2 to 3 equivalents are used.

선택적으로 상기 반응에 첨가제를 첨가시킬 수 있다. 첨가제로 티오설페이트 화합물을 사용하면 2% 정도의 수율 상승 효과가 있으며, 이때 사용되는 티오설페이트 화합물은 소디움 티오설페이트(Na2S2O3), 포타시움 티오설페이트(K2S2O3), 칼슘 티오설페이트(CaS2O3), 또는 테트라부틸암모니움 티오설페이트((Bu4N)2S2O3)이며, 가장 바람직하게는 소디움 티오설페이트이다. 티오설페이트 화합물은 2-히드록시메틸-3-메틸-4-(2,2,2-트리플루오로에톡시)피리딘에 대하여 0.001당량∼0.5당량 사용되며, 바람직하게는 0.01당량∼0.2당량 사용된다.Optionally, additives can be added to the reaction. When the thiosulfate compound is used as an additive, there is a yield increase effect of about 2%, and the thiosulfate compound used here is sodium thiosulfate (Na 2 S 2 O 3 ), potassium thiosulfate (K 2 S 2 O 3 ), calcium Thiosulfate (CaS 2 O 3 ), or tetrabutylammonium thiosulfate ((Bu 4 N) 2 S 2 O 3 ), most preferably sodium thiosulfate. The thiosulfate compound is used in an amount of 0.001 equivalents to 0.5 equivalents, preferably 0.01 equivalents to 0.2 equivalents, relative to 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine. .

상기와 같이 합성된 화학식 (II)의 화합물은 반응액을 냉각한 후 염기화하여 유기층으로 추출하고 농축하여 회수될 수 있으며, 또한 일반적인 정제 방법 특히, 에틸 아세테이트와 헥산을 이용하여 더 우수한 순도로 정제될 수 있다.The compound of formula (II) synthesized as described above may be recovered by cooling the reaction solution, basifying it, extracting it into an organic layer, and concentrating, and purifying with a higher purity using a general purification method, in particular, ethyl acetate and hexane. Can be.

본 발명의 제조 방법에 따르면 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸은 2-히드록시메틸-3-메틸-4-(2,2,2 -트리플루오로에톡시)피리딘 또는 그의 염으로부터 96% 이상의 높은 수율과 높은 순도로 제조될 수 있다. 특히, 반응과정에서 생성되는 반응 중간체인 하기 화학식 (V)의 2-할로메틸-3-메틸-4-(2,2,2-트리플루오로에톡시)피리딘을 별도의 농축 작업이나 분리 공정 없이, 또한 염기를 사용하지 않고 반응액 상태인 산성 조건에서 한 단계 반응으로 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸의 합성이 가능하다는 특징이 있다.According to the preparation method of the present invention, 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole is 2-hydroxymethyl- It can be prepared from 3-methyl-4- (2,2,2-trifluoroethoxy) pyridine or a salt thereof in high yield and high purity of 96% or more. In particular, 2-halomethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine of the formula (V), which is a reaction intermediate produced during the reaction, is prepared without a separate concentration or separation process. And 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H as a one-step reaction under acidic conditions in a reaction solution state without using a base. It is characterized by the possibility of synthesis of benzimidazole.

상기 화학식에서 X는 할로겐 원자, 즉 브롬이나 염소이다.In the above formula, X is a halogen atom, ie bromine or chlorine.

제2단계: 란소프라졸의 제조Second Step: Preparation of Lansoprazole

본 발명의 상기 제1단계에서 생성된 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸을 반응 용매 및 촉매의 존재 하에서 과산화 수소로 산화시켜 화학식 (I)로 표시되는 란소프라졸을 제조한다.2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole produced in the first step of the present invention is reacted with Lansoprazole represented by the formula (I) is prepared by oxidation with hydrogen peroxide in the presence of a catalyst.

본 발명의 제2단계에 사용되는 반응 용매는 할로겐화 탄화수소, 예를 들어 디클로로메탄, 클로로포름, 카본 테트라클로라이드; 또는 에테르, 예를 들어 테트라하이드로푸란, 디옥산이며, 이 중에서 디클로로메탄이나 클로로포름이 바람직하다.The reaction solvent used in the second step of the present invention may be halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride; Or ethers such as tetrahydrofuran and dioxane, of which dichloromethane and chloroform are preferred.

반응에 사용되는 촉매는 벤젠셀레닌 산(benzeneseleninic acid, PhSeO2H)이며, 사용량은 화학식 (II)의 화합물에 대하여 0.0001∼0.2당량, 바람직하게는 0.001∼0.1당량, 가장 바람직하게는 0.002∼0.01당량이다.The catalyst used in the reaction is benzeneseleninic acid (PhSeO 2 H), and the amount of use is 0.0001 to 0.2 equivalents, preferably 0.001 to 0.1 equivalents, and most preferably 0.002 to 0.01 based on the compound of formula (II). It is equivalent.

과산화 수소는 20∼50% 정도의 수용액을 사용하는 것이 일반적이지만 상기 범위에 한정되는 것은 아니다. 과산화 수소의 사용량은 화학식 (II)의 화합물에 대하여 0.95∼2.0당량, 바람직하게는 0.95∼1.4당량이고, 가장 바람직하게는 1.0∼1.1당량이다.Hydrogen peroxide is generally used in 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 2.0 equivalents, preferably 0.95 to 1.4 equivalents, most preferably 1.0 to 1.1 equivalents based on the compound of formula (II).

반응 온도는 0∼50℃이며, 바람직하게는 5∼35℃, 더욱 바람직하게는 10∼25℃이다. 반응 시간은 5분∼48시간이며, 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 5 minutes to 48 hours, preferably 30 minutes to 10 hours, and more preferably 1 to 6 hours.

위에서 기술된 방법으로 합성된 화학식(I)의 화합물은 일반적인 과산화 수소를 분해시키는 방법(예를 들어 소디움 티오설페이트 수용액을 가하여)으로 산화 반응을 종결시키고, 디클로로메탄과 같은 용매로 추출한 다음 농축하고 아세토니트릴 수용액 또는 에탄올 수용액으로 결정화할 수 있다. 또한 더 좋은 품질의 생성물을 얻기 위하여 에탄올 또는 물 등의 용매를 사용하여 재결정 등의 일반적인 정제 방법으로 정제할 수 있다.Compounds of formula (I) synthesized by the methods described above are terminated by a common method of decomposing hydrogen peroxide (e.g. by addition of aqueous sodium thiosulfate solution), extracted with a solvent such as dichloromethane, concentrated and aceto It can be crystallized with an aqueous solution of nitrile or an aqueous solution of ethanol. Also, in order to obtain a better quality product, it may be purified by a general purification method such as recrystallization using a solvent such as ethanol or water.

상기한 바와 같이 본 발명에 따라, 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸로부터 란소프라졸을 고품질과 고수율(약 90% 이상)로 제조할 수 있다. 특히, 반응 과정에서 부산물로 생성되는 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸 N-옥사이드 양을 1.5% 이하로 현저히 줄일 수 있다. 필요에 따라 하기의 실시예 7-8와 같은 일반적인 정제 과정을 거치면 생성물 중 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸 N-옥사이드 양을 0.1% 이하로 줄일 수 있다.According to the present invention as described above, the lansoprazole from 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole is prepared with high quality and It can be produced in high yield (about 90% or more). In particular, the amount of 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole N-oxide produced as a byproduct during the reaction Can be significantly reduced to less than 1.5%. If necessary, a general purification procedure such as Example 7-8 below may be carried out to form 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl in the product. The amount of -1H-benzimidazole N-oxide can be reduced to 0.1% or less.

본 발명은 하기의 실시예 및 참고예에 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 and reference 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 1-6:2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸의 제조 Example 1-6 Preparation of 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole

실시예 1Example 1

2-히드록시메틸-3-메틸-4-(2,2,2-트리플루오로에톡시)피리딘 23g (0.10mol)을 디클로로메탄 1L에 녹인 후 4℃로 냉각하고, 포스포러스 트리브로마이드(PBr3) 9.9ml(0.10mol)와 2-머캅토벤즈이미다졸 15.6g(0.10mol), 소디움 티오설페이트 3.3g(0.02mol)을 10℃ 이하에서 차례로 투입한 다음 2.5시간 동안 환류시켰다. 반응이 완결된 후 환류 과정에 의하여 승온된 반응액을 실온까지 냉각하고 4N-가성소다를 첨가하여 반응액의 pH를 13.5∼14가 되도록 하였다. 상기 반응액을 20분 동안 강하게 교반시킨 후 유기층을 분리하였다. 분리된 유기층을 무수 황산 마그네슘으로 건조시키고 감압 하에서 농축시켰다. 유기층을 분리한 후 남은 잔류액을 에틸 아세테이트 : 헥산 = 1 : 6 혼합액 630ml로 결정화하여 미백색 결정인 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸 34.2g을 얻었다. 결정의 수율은 93%였다.23 g (0.10 mol) of 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine was dissolved in 1 L of dichloromethane, cooled to 4 ° C, and phosphorus tribromide (PBr 3 ) 9.9 ml (0.10 mol), 2-mercaptobenzimidazole 15.6 g (0.10 mol), and sodium thiosulfate 3.3 g (0.02 mol) were sequentially added at 10 ° C. or lower, and refluxed for 2.5 hours. After the reaction was completed, the reaction solution heated by the reflux process was cooled to room temperature and 4 N -caustic soda was added so that the pH of the reaction solution was 13.5-14. The reaction solution was stirred vigorously for 20 minutes and the organic layer was separated. The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After the organic layer was separated, the remaining solution was crystallized from 630 ml of a mixture of ethyl acetate: hexane = 1: 6, which was a light white crystal, 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-. 34.2 g of pyridyl] methylthio-1H-benzimidazole was obtained. The yield of crystals was 93%.

실시예 2Example 2

2-히드록시메틸-3-메틸-4-(2,2,2-트리플루오로에톡시)피리딘 23g (0.10mol)을 디클로로메탄 1L에 녹인 후 4℃로 냉각하고, 포스포러스 트리브로마이드(PBr3) 9.9ml(0.10mol)를 10℃ 이하에서 천천히 투입한 다음 1시간 동안 환류시켰다. 환류에 의하여 승온된 반응액을 실온까지 냉각하고 2-머캅토벤즈이미다졸 15.6g(0.10mol)과 소디움 티오설페이트 3.3g(0.02mol)을 투입한 후 2.5시간 동안 환류시켰다. 반응이 완결된 후 반응액을 다시 실온까지 냉각하고 4N-가성소다를 첨가하여 반응액의 pH를 13.5∼14가 되도록 하였다. 상기 반응액을 20분 동안 강하게 교반시킨 후 유기층을 분리하였다. 분리된 유기층을 무수 황산 마그네슘으로 건조시키고 감압 하에서 농축시켰다. 잔류액을 에틸 아세테이트 : 헥산 = 1 : 6 혼합액 630ml로 결정화하여 미백색 결정인 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸 35.3g을 얻었다. 결정의 수율은 96%였다.23 g (0.10 mol) of 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine was dissolved in 1 L of dichloromethane, cooled to 4 ° C, and phosphorus tribromide (PBr 3 ) 9.9 ml (0.10 mol) was slowly added at 10 ° C or less, and then refluxed for 1 hour. The reaction solution heated by reflux was cooled to room temperature, 15.6 g (0.10 mol) of 2-mercaptobenzimidazole and 3.3 g (0.02 mol) of sodium thiosulfate were added thereto, and the mixture was refluxed for 2.5 hours. After the reaction was completed, the reaction solution was cooled to room temperature again and 4N -caustic soda was added to bring the pH of the reaction solution to 13.5-14. The reaction solution was stirred vigorously for 20 minutes and the organic layer was separated. The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from 630 ml of a mixture of ethyl acetate: hexane = 1: 6 to yield a light white crystal, 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio- 35.3 g of 1H-benzimidazole was obtained. The yield of crystals was 96%.

실시예 3Example 3

2-히드록시메틸-3-메틸-4-(2,2,2-트리플루오로에톡시)피리딘 염산 염 26.8g (0.10mol)을 디클로로메탄 1L에 현탁시킨 후 4℃로 냉각하고, 포스포러스 트리브로마이드(PBr3) 9.9ml(0.10mol)와 2-머캅토벤즈이미다졸 15.6g(0.10mol), 소디움 티오설페이트 3.3g(0.02mol)을 10℃ 이하에서 차례로 투입한 다음 2.5시간 동안 환류시켰다. 반응이 완결된 후 반응액을 실온까지 냉각하고 4N-가성소다를 이용하여 반응액의 pH를 13.5∼14가 되도록 하였다. 상기 반응액을 20분 동안 강하게 교반시킨 후 유기층을 분리하였다. 분리된 유기층을 무수 황산 마그네슘으로 건조시키고 감압 하에서 농축시켰다. 잔류액을 에틸 아세테이트 : 헥산 = 1 : 6 혼합액 630ml로 결정화하여 미백색 결정인 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸 33.8g을 얻었다. 결정의 수율은 92.1%였다.26.8 g (0.10 mol) of 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine hydrochloride were suspended in 1 L of dichloromethane and then cooled to 4 ° C., followed by phosphorus 9.9 ml (0.10 mol) of tribromide (PBr 3 ), 15.6 g (0.10 mol) of 2-mercaptobenzimidazole, and 3.3 g (0.02 mol) of sodium thiosulfate were sequentially added at 10 ° C. or below and refluxed for 2.5 hours. . After the reaction was completed, the reaction solution was cooled to room temperature and the pH of the reaction solution was adjusted to 13.5-14 using 4 N -caustic soda. The reaction solution was stirred vigorously for 20 minutes and the organic layer was separated. The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from 630 ml of a mixture of ethyl acetate: hexane = 1: 6 to yield a light white crystal, 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio- 33.8 g of 1H-benzimidazole was obtained. The yield of crystals was 92.1%.

실시예 4Example 4

2-히드록시메틸-3-메틸-4-(2,2,2-트리플루오로에톡시)피리딘 10g (0.0452mol)을 디클로로메탄 400ml에 녹인 후 4℃로 냉각하고, 포스포러스 트리클로라이드(PCl3) 3.94ml(0.0452mol)를 10℃ 이하에서 천천히 투입한 다음 1시간 동안 환류시켰다. 반응액을 실온까지 냉각하고 2-머캅토벤즈이미다졸 6.79g(0.0452mol)과 소디움 티오설페이트 1.43g(0.00904mol)을 투입 후 2.5시간 동안 환류시켰다. 반응이 완결된 후 반응액을 실온까지 냉각하고 4N-가성소다를 첨가하여 반응액의 pH를 13.5∼14가 되도록 하였다. 상기 반응액을 20분 동안 강하게 교반시킨 후 유기층을 분리하였다. 분리된 유기층을 무수 황산 마그네슘으로 건조시키고 감압 하에서 농축시켰다. 잔류액을 에틸 아세테이트 : 헥산 = 1 : 6 혼합액 280ml로 결정화하여 미백색 결정인 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸 4.9g을 얻었다. 결정의 수율은 93%였다.10 g (0.0452 mol) of 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine was dissolved in 400 ml of dichloromethane, cooled to 4 ° C, and phosphorus trichloride (PCl 3 ) 3.94 ml (0.0452 mol) was slowly added at 10 ° C. or lower, and then refluxed for 1 hour. The reaction solution was cooled to room temperature, and 6.79 g (0.0452 mol) of 2-mercaptobenzimidazole and 1.43 g (0.00904 mol) of sodium thiosulfate were refluxed for 2.5 hours. After the reaction was completed, the reaction solution was cooled to room temperature and 4N -caustic soda was added to bring the pH of the reaction solution to 13.5-14. The reaction solution was stirred vigorously for 20 minutes and the organic layer was separated. The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from 280 ml of a mixture of ethyl acetate: hexane = 1: 6 to yield a light white crystal, 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio- 4.9 g of 1H-benzimidazole was obtained. The yield of crystals was 93%.

실시예 5Example 5

2-히드록시메틸-3-메틸-4-(2,2,2-트리플루오로에톡시)피리딘 2.0g (9.04mmol)을 디클로로메탄 80ml에 녹인 후 4℃로 냉각하고, 포스포러스 옥시브로마이드(POBr3) 2.59g(9.04mmol)를 10℃ 이하에서 천천히 투입한 다음 1시간 동안 환류시켰다. 반응액을 실온까지 냉각하고 2-머캅토벤즈이미다졸 1.36g(9.04mmol)과 소디움 티오설페이트 0.29g(1.81mmol)을 투입한 후 2.5시간 동안 환류시켰다. 반응이 완결된 후 반응액을 다시 실온까지 냉각하고 4N-가성소다를 첨가하여 반응액의 pH를 13.5∼14가 되도록 하였다. 상기 반응액을 20분 동안 강하게 교반시킨 후 유기층을 분리하였다. 분리된 유기층을 무수 황산 마그네슘으로 건조시키고 감압 하에서 농축시켰다. 잔류액을 에틸 아세테이트 : 헥산 = 1 : 6 혼합액 56ml로 결정화하여 미백색 결정 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸 2.69g을 얻었다. 결정의 수율은 84.3%였다.2.0 g (9.04 mmol) of 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine was dissolved in 80 ml of dichloromethane, cooled to 4 ° C., and phosphorus oxybromide ( 2.59 g (9.04 mmol) of POBr 3 was slowly added at 10 ° C. or lower, and then refluxed for 1 hour. The reaction solution was cooled to room temperature, 1.36 g (9.04 mmol) of 2-mercaptobenzimidazole and 0.29 g (1.81 mmol) of sodium thiosulfate were added thereto, and the mixture was refluxed for 2.5 hours. After the reaction was completed, the reaction solution was cooled to room temperature again and 4N -caustic soda was added to bring the pH of the reaction solution to 13.5-14. The reaction solution was stirred vigorously for 20 minutes and the organic layer was separated. The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from 56 ml of a mixture of ethyl acetate: hexane = 1: 6 to yield white-white crystals 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H 2.69 g of benzimidazole were obtained. The yield of crystals was 84.3%.

비교실시예 1Comparative Example 1

2-히드록시메틸-3-메틸-4-(2,2,2-트리플루오로에톡시)피리딘 5g (0.0226mol)을 디클로로메탄 200ml에 녹인 후 4℃로 냉각하고, 티오닐 클로라이드(SOCl2) 1.65ml(0.0226mol)와 2-머캅토벤즈이미다졸 3.39g(0.0226 mol)과 소디움 티오설페이트 0.72g(0.00452mol)을 차례로 투입한 후 2.5시간 동안 환류시켰다. 반응이 완결된 후 반응액을 실온까지 냉각하고 4N-가성소다를 첨가하여 반응액의 pH를 13.5∼14가 되도록 하였다. 상기 반응액을 20분 동안 강하게 교반시킨 후 유기층을 분리하였다. 분리된 유기층을 무수 황산 마그네슘으로 건조시키고 감압 하에서 농축시켰다. 잔류액을 에틸 아세테이트 : 헥산 = 1 : 7 혼합액 140ml로 결정화하여 연분홍색 결정인 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸 3.86g을 얻었다. 결정의 수율은 48.3%였다.5 g (0.0226 mol) of 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine was dissolved in 200 ml of dichloromethane, cooled to 4 ° C, and thionyl chloride (SOCl 2 ) 1.65ml (0.0226mol), 2-39-capcapbenzimidazole 3.39g (0.0226mol) and 0.72g (0.00452mol) sodium thiosulfate were added in this order and refluxed for 2.5 hours. After the reaction was completed, the reaction solution was cooled to room temperature and 4N -caustic soda was added to bring the pH of the reaction solution to 13.5-14. The reaction solution was stirred vigorously for 20 minutes and the organic layer was separated. The separated organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from 140 ml of a mixture of ethyl acetate: hexane = 1: 7 to give pale pink crystals of 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio 3.86 g of -1H-benzimidazole were obtained. The yield of crystals was 48.3%.

할로겐화제로서, 일반적으로 사용되는 티오닐 클로라이드를 첨가한 비교실시예 1을 본원발명에 따른 실시예 1-5와 비교하여 보면 생성물 수율에서 현저한 차이가 있음을 확인할 수 있었다.As a halogenating agent, when comparing Comparative Example 1 to which thionyl chloride which is generally used is added compared with Example 1-5 according to the present invention, it was confirmed that there is a significant difference in product yield.

실시예 6: 란소프라졸의 제조Example 6: Preparation of Lansoprazole

상기 실시예 2에서 제조된 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸 1.5g(4.24mmol)을 디클로로메탄 30ml에 현탁시킨 후 벤젠셀레닌 산(PhSeO2H) 2.01mg(0.0106mmol)을 투입하고 현탁액을 10℃로 냉각하였다.tert-부탄올 2ml와 35.7%의 과산화수소 용액 0.376ml(4.46mmol)를 10℃ 이하에서 투입하였다. 반응액의 온도를 15∼20℃로 유지하면서 5시간 동안 교반하여 반응이 완결되면, 반응액을 5℃로 냉각하고 소디움 티오설페이트 0.4g을 물 20ml에 녹인 수용액을 10℃ 이하에서 천천히 적하하고 10℃ 정도에서 30분 동안 강하게 교반하였다. 유기층을 분리하여 물 20ml로 세척하였다. 세척된 유기층을 무수 황산 마그네슘으로 건조시킨 후 감압 하에서 농축하고 결정이 석출되기 전에 에탄올 5ml 정도로 녹인 후 재농축하여 결정화하였다. 결정을 모아 진공 건조하여 연한 베이지 색 고체 생성물 1.51g을 얻었다. 생성물의 수율은 95.1%였다.1.5 g (4.24 mmol) of 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole prepared in Example 2 was prepared. After suspended in 30 ml of dichloromethane, 2.01 mg (0.0106 mmol) of benzene selenic acid (PhSeO 2 H) was added thereto, and the suspension was cooled to 10 ° C. 2 ml of tert -butanol and 0.376 ml (4.46 mmol) of 35.7% hydrogen peroxide solution were added below 10 ° C. After the reaction was completed by stirring for 5 hours while maintaining the temperature of the reaction solution at 15 to 20 ° C., the reaction solution was cooled to 5 ° C. and 0.4 g of sodium thiosulfate dissolved in 20 ml of water was slowly added dropwise at 10 ° C. The mixture was stirred vigorously for about 30 minutes at about ℃. The organic layer was separated and washed with 20 ml of water. The washed organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, dissolved in about 5 ml of ethanol before crystals were precipitated, and then concentrated and recrystallized. The crystals were collected and dried in vacuo to yield 1.51 g of a pale beige solid product. The yield of the product was 95.1%.

참고예 1-2:공지 기술에 의한 란소프라졸의 제조 Reference Example 1-2: Preparation of Lansoprazole by Known Technology

참고예 1Reference Example 1

2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸 1.68g을 디클로로메탄 30ml에 현탁시키고, 15∼20℃에서 바나디움 펜타옥사이드5mg을 함유하는tert-부탄올 (0.2g의 과산화수소에 대해 2.75ml)에 용해시킨 과산화수소 용액을 적하한 후, 20∼25℃에서 약 1시간 동안 반응시켰다. 반응이 완결된 후, 소디움 티오설페이트 수용액(0.5g/30ml)을 반응 혼합물에 가하고 약 10분 동안 격렬하게 교반하고 방치하여 층으로 분리시켰다. 디클로로메탄 층을 물 30ml로 세척하고, 황산 마그네슘으로 건조시킨 다음 감압 하에서 농축하여 결정이 석출되기 전에 에탄올 5ml 정도로 녹인 후 재농축하여 결정화하였다. 결정을 모은 후 진공 건조하여 연한 갈색-보라색 고체의 목적화합물 1.63g을 얻었다(수율 : 93.0%).1.68 g of 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole was suspended in 30 ml of dichloromethane and 15 to 20 ° C. Hydrogen peroxide solution dissolved in tert -butanol (2.75 ml for 0.2 g of hydrogen peroxide) containing 5 mg of vanadium pentaoxide was added dropwise, followed by reaction at 20 to 25 ° C. for about 1 hour. After the reaction was completed, aqueous sodium thiosulfate solution (0.5 g / 30 ml) was added to the reaction mixture, stirred vigorously for about 10 minutes and left to separate into layers. The dichloromethane layer was washed with 30 ml of water, dried over magnesium sulfate, concentrated under reduced pressure, dissolved in about 5 ml of ethanol before crystals were precipitated, and then concentrated and recrystallized. The crystals were collected and dried in vacuo to yield 1.63 g of the target compound as a light brown-purple solid (yield: 93.0%).

참고예 2Reference Example 2

2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸 1.5g을 클로로포름 20ml에 현탁시키고, 5℃로 냉각시키고 5℃ 이하에서 클로로포름 15ml에 m-클로로퍼벤조산 1.0g을 녹인 용액을 30분 동안 천천히 적하 투입하였다. 0∼5℃에서 반응이 완결될 때까지 교반하였다(약 1시간 정도). 반응이 완결된 후, 반응물을 탄산수소나트륨 수용액으로 세척하였다. 분리된 유기층을 황산 마그네슘으로 건조시키고 감압 하에서 농축하여 결정이 석출되기 전에 에탄올 5ml 정도로 녹인 후 재농축하여 결정화하였다. 결정을 모은 후 진공 건조하여 보라색 고체의 목적화합물 1.61g을 얻었다(수율 : 103%).1.5 g of 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole was suspended in 20 ml of chloroform and cooled to 5 ° C. A solution in which 1.0 g of m-chloroperbenzoic acid was dissolved in 15 ml of chloroform at 5 ° C. or lower was slowly added dropwise for 30 minutes. It stirred at 0-5 degreeC until completion of reaction (about 1 hour). After the reaction was completed, the reaction was washed with aqueous sodium hydrogen carbonate solution. The separated organic layer was dried over magnesium sulfate, concentrated under reduced pressure, dissolved in about 5 ml of ethanol before precipitation of crystals, and then concentrated and recrystallized. The crystals were collected and dried in vacuo to yield 1.61 g of the target compound as a purple solid (yield: 103%).

본 발명에 따른 실시예 6과 공지 기술(대한민국 특허공고 제96-0047호)에 따른 참고예 1 및 2에 따라 제조된 각 란소프라졸 생성물의 수율, 함량, 및 고성능 액체 크로마토 그래피(HPLC) 분석 결과를 비교하여 하기 표 1에 나타내었다.Yield, content, and high performance liquid chromatography (HPLC) analysis results of the respective lansoprazole products prepared according to Reference Examples 1 and 2 according to Example 6 according to the present invention and known techniques (Korean Patent Publication No. 96-0047) The comparison is shown in Table 1 below.

고성능 액체 크로마토 그래피(HPLC) 분석 조건은 다음과 같다.High performance liquid chromatography (HPLC) analysis conditions are as follows.

사용장치: 영린 하이 퍼포먼스 리퀴드 크로마토그래피 타입 M930(YOUNG-LIN High Performance Liquid Chromatograph Type M930)Equipment used: YOUNG-LIN High Performance Liquid Chromatograph Type M930

컬럼: 크로마실(Kromasil) ODS2(4.6 x 250mm i.d.)Column: Kromasil ODS2 (4.6 x 250 mm i.d.)

검출기: 영린 UV 흡수 광도계 타입 M720Detector: Young UV absorbance photometer type M720

자료 처리 장치: 오토크로-윈(Autochro-Win)Data Processing Unit: Autochro-Win

측정파장: 254nmMeasurement wavelength: 254nm

이동상: 인산을 가함으로써 pH가 7.0으로 조정된 메탄올:물:트리에틸아민의 혼합물(60:40:1)Mobile phase: A mixture of methanol: water: triethylamine adjusted to pH 7.0 by adding phosphoric acid (60: 40: 1)

유속: 0.7ml/분Flow rate: 0.7ml / min

분석에 요구되는 시간: 50분Time required for analysis: 50 minutes

컬럼 온도: 약 25℃의 고정 온도Column temperature: fixed temperature of about 25 ° C

하기 표 1에서 함량은 시판되는 표준품 기준으로 실험 결과 얻어진 생성물 표본의 함량을 나타낸 것으로 하기식에 따라 구하였다:In Table 1, the content represents the content of the product sample obtained as a result of the experiment on the basis of a commercial standard, which was obtained according to the following formula:

함량(%)=[표준품 중량(g)/표본 중량(g)]×[HPLC에서의 표준품 면적/표본 면적]×[표준품 중 수분 중량/표본의 수분 중량]×100Content (%) = [Standard Weight (g) / Sample Weight (g)] × [Standard Product Area / Sample Area in HPLC] × [Water Weight of Sample / Water Weight of Sample] × 100

제조 방법Manufacturing method 실시예 6Example 6 참고예 1Reference Example 1 참고예 2Reference Example 2 수 율a Yield a 95.1%95.1% 93.0%93.0% 103%103% 함 량content 97.5%97.5% 92.1%92.1% 74.4%74.4% 화학식 (II) 화합물b Compound (II) b 1.34%1.34% 1.35%1.35% 1.67%1.67% 화학식 (I) 화합물b Compound (I) b 96.8%96.8% 93.6%93.6% 93.3%93.3% 화학식 (VIII) 화합물b Compound (VIII) b 1.21%1.21% 4.19%4.19% 4.53%4.53%

a : 정제하기 전의 이론적 수율a: theoretical yield before purification

b : 고성능 액체 크로마토그래피에서의 면적률b: area ratio in high performance liquid chromatography

상기 표 1에 나타난 바와 같이 생성물의 이론적 수율은 실시예 6 및 참고예 1-2 사이에 차이가 없었다. 그러나, 외부 표준품 대비 함량, 및 고성능 액체 크로마토그래피에서의 면적률을 비교해 보면 실시예 6의 경우가 공지기술에 따라 실시된 참고예의 경우보다 생성물의 순도 및 실제 수율이 우수함을 알 수 있다. 특히, 고성능 액체 크로마토그래피 분석 결과 실시예 6과 같이 본 발명에 따르면 반응 부산물인 상기 화학식 (VIII)의 N-옥사이드 화합물의 생성량을 1% 내외로 현격하게 줄일 수 있었다.As shown in Table 1 above, the theoretical yield of the product was not different between Example 6 and Reference Examples 1-2. However, comparing the content with respect to the external standard, and the area ratio in high performance liquid chromatography, it can be seen that the case of Example 6 is superior to the purity and actual yield of the product than the case of the reference example carried out according to the known technology. In particular, as a result of high performance liquid chromatography analysis, according to the present invention, the amount of N-oxide compound of the general formula (VIII), which is a reaction byproduct, was significantly reduced to about 1%.

실시예 7-8:란소프라졸의 정제 Example 7-8 Purification of Lansoprazole

실시예 7Example 7

실시예 6에서 얻어진 정제를 거치지 않은 란소프라졸 1.51g에 에탄올 12.1ml를 투입하고 45∼50℃로 가열하여 결정을 완전히 녹였다. 여기에 물 4.03ml를 투입하고 5℃로 서서히 냉각하였다. 5℃를 유지하면서 3시간 동안 방치하여 결정을 완전히 석출시킨 후 얻어진 결정을 여과하고 5℃의 에탄올 : 물 = 3:1 혼합액으로 세척하였다. 결정을 모은 후 진공에서 건조하여 백색 결정인 란소프라졸 1.45g을 얻었다. 결정의 수율은 96.1%였다. 얻어진 결정에 다시 에탄올 11.6ml를 투입하고 45∼50℃로 가열하여 고체를 완전히 용해시켰다. 보온 여과를 통하여 불용성 물질을 제거한 후, 물 1.66ml를 투입하고 5℃로 천천히 냉각하였다. 동일 온도에서 3시간 동안 방치하여 결정을 완전히 석출시킨 다음 얻어진 결정을 여과하고 5℃의 에탄올 : 물 = 7 : 1 혼합액으로 세척하였다. 결정을 모은 후 진공에서 건조하여 백색 결정인 란소프라졸 1.40g 얻었다. 결정의 수율은 96.3%였다.12.1 ml of ethanol was added to 1.51 g of lansoprazole which was not subjected to the purification obtained in Example 6, and heated to 45 to 50 ° C. to completely dissolve the crystals. 4.03 ml of water was added thereto, and the mixture was slowly cooled to 5 ° C. The mixture was left for 3 hours at 5 ° C. to completely precipitate the crystals, and then the obtained crystals were filtered and washed with a 5 ° C. ethanol: water = 3: 1 mixture. The crystals were collected and dried in vacuo to yield 1.45 g of lansoprazole, a white crystal. The yield of the crystal was 96.1%. 11.6 ml of ethanol was further added to the obtained crystals, and the mixture was heated to 45 to 50 ° C to completely dissolve the solid. After the insoluble matters were removed by thermal filtration, 1.66 ml of water was added thereto and slowly cooled to 5 ° C. After standing at the same temperature for 3 hours to completely precipitate the crystals, the obtained crystals were filtered and washed with a ethanol: water = 7: 1 mixture at 5 ° C. The crystals were collected and dried in vacuo to give 1.40 g of lansoprazole as white crystals. The yield of crystals was 96.3%.

실시예 8Example 8

실시예 6에서 얻어진 정제를 거치지 않은 란소프라졸 1.51g에 아세토니트릴 52.9ml를 투입하고 50∼55℃로 가열하여 고체를 완전히 녹였다. 물 5.29ml를 투입하고 실온으로 천천히 냉각한 후 감압 하에서 약 48ml 정도를 농축 제거한다. 5℃에서 3시간 동안 방치하여 결정을 완전히 석출시킨 다음 얻어진 결정을 여과하고 5℃의 아세토니트릴 : 물 = 10 : 1 혼합액으로 세척하였다. 결정을 모은 후 진공에서 건조하여 미백색 결정인 란소프라졸 1.48g 얻었다. 결정의 수율은 98.0%였다. 얻어진 결정에 다시 에탄올 11.8ml를 투입하고 45∼50℃로 가열하여 고체를 완전히 용해시켰다. 보온 여과를 하여 불용성 물질을 제거한 후, 물 1.69ml를 투입하고 5℃로 서서히 냉각하였다. 5℃에서 3시간 동안 방치하여 결정을 완전히 석출시킨 후 얻어진 결정을 여과하고 5℃의 에탄올 : 물 = 7 : 1 혼합액으로 세척하였다. 결정을 모은 후 진공 건조하여 백색 결정인 란소프라졸 1.41g 얻었다. 결정의 수율은 95.0%였다.52.9 ml of acetonitrile was added to 1.51 g of lansoprazole, which was not subjected to the purification obtained in Example 6, and heated to 50 to 55 ° C to completely dissolve the solid. 5.29 ml of water is added, and after cooling slowly to room temperature, about 48 ml are concentrated and removed under reduced pressure. After standing at 5 ° C. for 3 hours to completely precipitate crystals, the obtained crystals were filtered and washed with acetonitrile: water = 10: 1 mixture at 5 ° C. The crystals were collected and dried in vacuo to give 1.48 g of lansoprazole as a white crystal. The yield of the crystal was 98.0%. 11.8 ml of ethanol was further added to the obtained crystals, and the mixture was heated to 45 to 50 ° C to completely dissolve the solid. After thermal filtration to remove the insoluble matter, 1.69 ml of water was added and slowly cooled to 5 ° C. After standing at 5 ° C. for 3 hours to completely precipitate the crystals, the obtained crystals were filtered and washed with 5 ° C. ethanol: water = 7: 1 mixture. The crystals were collected and dried in vacuo to yield 1.41 g of lansoprazole as a white crystal. The yield of the crystal was 95.0%.

본 발명은 반응 단계를 줄이고 저가의 산화제를 사용함으로써 공지기술보다 간편하고 경제적인 방법으로 고순도 및 고수율로 위산 분비 억제 및 위점막 보호에 우수한 효과를 나타내는 항-궤양제인 란소프라졸과 그 중간체를 대량으로 제조하는 방법을 제공하는 효과를 가진다.The present invention provides a large amount of lansoprazole and its intermediates, which are anti-ulcer agents that exhibit superior effects on gastric acid secretion inhibition and gastric mucosa protection with high purity and yield in a simpler and more economical way than the prior art by reducing the reaction step and using a low-cost oxidant. It has the effect of providing the manufacturing method.

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.

Claims (10)

하기 화학식 (III)의 2-히드록시메틸-3-메틸-4-(2,2,2-트리플루오로에톡시)피리딘 또는 그의 염 화합물과 하기 화학식 (IV)의 2-머캅토벤즈이미다졸을 반응 용매, 할로겐화 포스포러스 화합물, 및 티오설페이트 화합물 하에서 반응시키는 단계; 및2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine or its salt compound of formula (III) and 2-mercaptobenzimidazole of formula (IV) Reacting under a reaction solvent, a halogenated phosphorus compound, and a thiosulfate compound; And 상기 반응에 의하여 생성된 하기 화학식 (II)의 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸 화합물을 반응 용매 및 벤젠셀레닌 산 촉매 하에서 과산화 수소로 산화시키는 단계;2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole compound of formula (II) Oxidizing with hydrogen peroxide under a reaction solvent and a benzeneselenic acid catalyst; 로 이루어지는 하기 화학식 (I)의 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸설피닐-1H-벤즈이미다졸(란소프라졸)의 제조 방법.Preparation of 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylsulfinyl-1H-benzimidazole (lansoprazole) having the following formula (I) Way. 하기 화학식 (III)의 2-히드록시메틸-3-메틸-4-(2,2,2-트리플루오로에톡시)피리딘 또는 그의 염 화합물과 하기 화학식 (IV)의 2-머캅토벤즈이미다졸을 반응 용매, 할로겐화 포스포러스 화합물, 및 티오설페이트 화합물 하에서 반응시켜 하기 화학식 (II)의 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸 화합물을 제조하는 방법.2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine or its salt compound of formula (III) and 2-mercaptobenzimidazole of formula (IV) Is reacted under a reaction solvent, a halogenated phosphorus compound, and a thiosulfate compound to yield 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] of formula (II) A process for preparing a methylthio-1H-benzimidazole compound. 제2항에 따라 생성된 2-[3-메틸-4-(2,2,2-트리플루오로에톡시)-2-피리딜]메틸티오-1H-벤즈이미다졸을 반응 용매 및 벤젠셀레닌 산 촉매 하에서 과산화 수소로 산화시켜 하기 화학식 (I)의 란소프라졸을 제조하는 방법.The 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methylthio-1H-benzimidazole produced according to claim 2 is reacted with a reaction solvent and benzeneselenin. A process for preparing lansoprazole of formula (I) by oxidation with hydrogen peroxide under an acid catalyst. 제1항 내지 제3항 중 어느 한 항에 있어서, 상기 반응 용매는 할로겐화 탄화수소 또는 에테르인 것을 특징으로 하는 제조 방법.The process according to any one of claims 1 to 3, wherein the reaction solvent is a halogenated hydrocarbon or ether. 제1항 또는 제2항에 있어서, 상기 2-머캅토벤즈이미다졸은 2-히드록시메틸-3-메틸-4-(2,2,2-트리플루오로에톡시)피리딘에 대하여 1∼4당량 사용되는 것을 특징으로 하는 제조 방법.The method according to claim 1 or 2, wherein the 2-mercaptobenzimidazole is 1 to 4 relative to 2-hydroxymethyl-3-methyl-4- (2,2,2-trifluoroethoxy) pyridine. The equivalent method is used, The manufacturing method characterized by the above-mentioned. 제1항 또는 제2항에 있어서, 상기 화학식 (II)의 화합물 제조 단계에서의 티오설페이트 화합물은 소디움 티오설페이트(Na2S2O3), 포타시움 티오설페이트(K2S2O3), 칼슘 티오설페이트(CaS2O3), 및 테트라부틸암모니움 티오설페이트((Bu4N)2S2O3)로 이루어진 군으로부터 선택되고, 상기 화학식 (III)의 화합물에 대하여 0.001∼0.5당량 사용되는 것을 특징으로 하는 제조 방법.The method of claim 1 or 2, wherein the thiosulfate compound in the step of preparing the compound of formula (II) is sodium thiosulfate (Na 2 S 2 O 3 ), potassium thiosulfate (K 2 S 2 O 3 ), calcium Thiosulfate (CaS 2 O 3 ), and tetrabutylammonium thiosulfate ((Bu 4 N) 2 S 2 O 3 ), which is used in an amount of 0.001 to 0.5 equivalents based on the compound of formula (III) The manufacturing method characterized by the above-mentioned. 제1항 또는 제2항에 있어서, 상기 할로겐화 포스포러스 화합물은 포스포러스 트리브로마이드(PBr3), 포스포러스 트리클로라이드(PCl3), 포스포러스 펜타브로마이드(PBr5), 포스포러스 펜타클로라이드(PCl5), 포스포러스 옥시브로마이드(POBr3), 포스포러스 옥시클로라이드(POCl3), 및 이들의 혼합물로 이루어진 군으로부터 선택되고, 상기 화학식 (III)의 화합물에 대하여 1당량(몰비로 1/3배)∼15당량(몰비로 5배) 사용되는 것을 특징으로 하는 제조 방법.According to claim 1 or 2, wherein the halogenated phosphorus compound is phosphorus tribromide (PBr 3 ), phosphorus trichloride (PCl 3 ), phosphorus pentabromide (PBr 5 ), phosphorus pentachloride (PCl 5 ), phosphorus oxybromide (POBr 3), phosphorus oxychloride (POCl 3), and is selected from the group consisting of a mixture thereof, to 1 equivalent of one-third times (molar ratio of a compound represented by the above formula (III)) The manufacturing method characterized by using 15 equivalent (5 times molar ratio). 제1항에 있어서, 상기 할로겐화 포스포러스 화합물은 포스포러스 트리브로마이드(PBr3)이고, 상기 티오설페이트 화합물은 소디움 티오설페이트(Na2S2O3)인 것을 특징으로 하는 제조 방법.The method of claim 1, wherein the halogenated phosphorus compound is phosphorus tribromide (PBr 3 ), and the thiosulfate compound is sodium thiosulfate (Na 2 S 2 O 3 ). 제1항 또는 제3항에 있어서, 상기 벤젠셀레닌 산은 상기 화학식 (II)의 화합물에 대하여 0.0001∼0.2당량 사용되는 것을 특징으로 하는 제조 방법.The method according to claim 1 or 3, wherein the benzene selenine acid is used in an amount of 0.0001 to 0.2 equivalents based on the compound of formula (II). 제1항 또는 제3항에 있어서, 상기 과산화 수소는 상기 화학식 (II)의 화합물에 대하여 0.95∼2.0당량 사용되는 것을 특징으로 하는 제조 방법.The method according to claim 1 or 3, wherein the hydrogen peroxide is used in an amount of 0.95 to 2.0 equivalents based on the compound of formula (II).
KR10-2001-0008677A 2001-02-21 2001-02-21 Method of Preparing Lansoprazole and Its Intermediate KR100430575B1 (en)

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