KR100847635B1 - Salts of Benzimidazole Derivative with Amines - Google Patents

Salts of Benzimidazole Derivative with Amines Download PDF

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KR100847635B1
KR100847635B1 KR1020077002824A KR20077002824A KR100847635B1 KR 100847635 B1 KR100847635 B1 KR 100847635B1 KR 1020077002824 A KR1020077002824 A KR 1020077002824A KR 20077002824 A KR20077002824 A KR 20077002824A KR 100847635 B1 KR100847635 B1 KR 100847635B1
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methoxypropoxy
benzimidazole
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히로유끼 요꼬이
마사노리 미즈노
도요까쯔 하가
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Abstract

본 발명은 (1) 위산 분비 억제제, 항궤양제 등의 의약으로서 유용한 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸의 알칼리 금속염의 제조 방법, 및 (2) 그의 제조 중간체인 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 아민과의 염 및 그의 제조 방법을 제공하는 것을 목적으로 한다. 본 발명에 따르면, 하기 화학식 I로 표시되는 염을 개시한다.

<화학식 I>

Figure 112007010573614-pct00032

식 중, A+는 이소프로필암모늄 이온, sec-부틸암모늄 이온 또는 시클로펜틸암모늄 이온을 나타낸다.

Figure R1020077002824

벤즈이미다졸 유도체, 위산 분비 억제제, 항궤양제.

The present invention relates to (1) 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benz useful as a medicine for gastric acid secretion inhibitors, anti-ulcers and the like. Method for producing alkali metal salt of imidazole, and (2) 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimi It is an object of the present invention to provide a salt of a dozol and an amine and a process for producing the same. According to the present invention, a salt represented by the following formula (I) is disclosed.

<Formula I>

Figure 112007010573614-pct00032

In the formula, A + represents isopropylammonium ion, sec-butylammonium ion or cyclopentylammonium ion.

Figure R1020077002824

Benzimidazole derivatives, gastric acid secretion inhibitors, antiulcers.

Description

벤즈이미다졸 유도체와 아민과의 염{Salts of Benzimidazole Derivative with Amines}Salts of Benzimidazole Derivative with Amines

본 발명은 (1) 위산 분비 억제제, 항궤양제 등의 의약으로서 유용한 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸의 알칼리 금속염의 제조 방법, 및 (2) 그의 제조 중간체인 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 아민과의 염 및 그의 제조 방법에 관한 것이다. The present invention relates to (1) 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benz useful as a medicine for gastric acid secretion inhibitors, anti-ulcers and the like. Method for producing alkali metal salt of imidazole, and (2) 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimi It relates to a salt of a dazol and an amine and a process for producing the same.

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸의 알칼리 금속염은 위산 분비 억제 작용을 갖기 때문에, 항궤양제 등으로서 유용하다는 것이 알려져 있다(예를 들면, 특허 문헌 1 참조). Since the alkali metal salt of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole has a gastric acid secretion inhibitory effect, an antiulcer agent etc. It is known that it is useful as (refer patent document 1).

양성자 펌프 저해제 중 하나인 오메프라졸과 아민의 염은 알려져 있지만(예를 들면, 특허 문헌 2, 3, 4 참조), 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 아민의 염은 알려져 있지 않다. Salts of omeprazole and amine, one of the proton pump inhibitors, are known (see, for example, patent documents 2, 3, 4), but 2-[{4- (3-methoxypropoxy) -3-methylpyridine-2 The salts of -yl} methylsulfinyl] -1H-benzimidazole and amines are unknown.

또한, 오메프라졸 등을 비롯한 여러가지 양성자 펌프 저해 작용을 갖는 화합물과 아민의 염의 결정화 공정이, 불순물 제거 등에 유용하다는 것은 알려져 있지 않다. In addition, it is not known that the crystallization step of a compound having various proton pump inhibitory effects including omeprazole and the like and a salt of an amine is useful for removing impurities.

또한, 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 아민의 염으로부터, 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ알칼리 금속염을 얻는 방법도 알려져 있지 않다. In addition, 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole and a salt of an amine give 2-[{4- (3 A method of obtaining -methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole alkali metal salt is also not known.

한편, 불순물인 (2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술포닐]-1H-벤즈이미다졸)(이하, 간단히 「술폰체」라고 함)의 함량을 0.82 ％ 내지 0.30 ％까지 감소시키는, 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ나트륨염의 제조 방법은 알려져 있다(예를 들면, 특허 문헌 5 참조).On the other hand, (2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfonyl] -1H-benzimidazole) which is an impurity (hereinafter, simply referred to as "sulfone body") ) Of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole sodium salt reducing the content of c) to 0.82% to 0.30%. The manufacturing method is known (for example, refer patent document 5).

특허 문헌 1: 미국 특허 공보 제5,045,552호Patent Document 1: US Patent Publication No. 5,045,552

특허 문헌 2: 국제 특허 공개 공보 WO03/74514호Patent Document 2: International Patent Publication No. WO03 / 74514

특허 문헌 3: 국제 특허 공개 공보 WO94/27988호Patent Document 3: International Patent Publication No. WO94 / 27988

특허 문헌 4: 유럽 특허 공개 공보 제124495호Patent Document 4: European Patent Publication No. 124495

특허 문헌 5: 유럽 특허 공개 공보 제1000943호 Patent Document 5: European Patent Application Publication No. 1000943

항궤양제로서 유용한 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸 제조의 최종 공정에 있어서, 산화제로서 m-클로로과벤조산 등을 이용한 경우, 해당 화합물의 술폰체인 (2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술포닐]-1H-벤즈이미다졸)이 불순물로서 포함되는 경우가 있다.2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole, useful as an anti-ulcer agent, in the final process of preparation, When chloroperbenzoic acid or the like is used, the sulfon chain (2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfonyl] -1H-benzimidazole) of the compound is impurity. It may be included as.

이 술폰체는 분리 정제가 어렵기 때문에, 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸의 회수율이 양호하고, 해당 화합물의 술폰체를 보다 효율적으로 제거할 수 있는 새로운 정제 방법이 요구되고 있다. Since this sulfonate is difficult to separate and purify, the recovery of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole is good. There is a need for a new purification method that can more efficiently remove the sulfone of the compound.

본 발명자들은 정력적으로 연구를 거듭한 결과, 상기 과제인 술폰체를 효율적으로 제거하는 정제 방법 및 이 정제 방법에 유용한 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 아민의 염을 발견하고, 본 발명을 완성하기에 이르렀다.The present inventors have energetically researched, and as a result, the purification method which removes the said sulfone body efficiently, and 2-[{4- (3-methoxypropoxy) -3-methylpyridine-2 useful for this purification method -Yl} methylsulfinyl] -1H-benzimidazole and salts of amines were found and the present invention was completed.

즉, 본 발명의 제1 양태에서는,That is, in the first aspect of the present invention,

[1] 하기 화학식 I로 표시되는 염을 제공한다.[1] A salt represented by the following formula (I) is provided.

Figure 112007010573614-pct00001
Figure 112007010573614-pct00001

식 중, A+는 이소프로필암모늄 이온, sec-부틸암모늄 이온 또는 시클로펜틸암모늄 이온을 나타낸다.In the formula, A + represents isopropylammonium ion, sec-butylammonium ion or cyclopentylammonium ion.

또한, 본 발명의 별도의 양태에서는,Moreover, in another aspect of this invention,

[2] 하기 화학식 II로 표시되는 염과, [2] a salt represented by the following formula (II),

[3] 하기 화학식 III으로 표시되는 염과,[3] a salt represented by the following formula (III),

[4] 하기 화학식 IV로 표시되는 염을 제공한다.[4] A salt represented by the following formula (IV) is provided.

Figure 112007010573614-pct00002
Figure 112007010573614-pct00002

Figure 112007010573614-pct00003
Figure 112007010573614-pct00003

Figure 112007010573614-pct00004
Figure 112007010573614-pct00004

또한, 본 발명의 제2 양태에서는,Moreover, in the 2nd aspect of this invention,

[5] 염형성 공정을 포함하는 염의 제조 방법이며, 하기 화학식 I로 표시되는 염이 생성되도록 상기 염형성 공정을 에스테르 용매, 니트릴 용매, 에테르 용매, 알코올 용매, 케톤 용매, 지방족 탄화수소 용매, 방향족 탄화수소 용매, 물 또는 이들의 혼합 용매 중에서 실행하는 제조 방법과, [5] A salt preparation process comprising a salt formation process, wherein the salt formation process is carried out such that an ester solvent, a nitrile solvent, an ether solvent, an alcohol solvent, a ketone solvent, an aliphatic hydrocarbon solvent or an aromatic hydrocarbon is produced so that a salt represented by the following formula (I) is produced. A production method carried out in a solvent, water or a mixed solvent thereof;

<화학식 I><Formula I>

Figure 112007010573614-pct00005
Figure 112007010573614-pct00005

(식 중, A+는 이소프로필암모늄 이온, sec-부틸암모늄 이온 또는 시클로펜틸암모늄 이온을 나타낸다.)(Wherein A + represents isopropylammonium ion, sec-butylammonium ion or cyclopentylammonium ion.)

[6] 염형성 공정을 포함하는 염의 제조 방법이며, 하기 화학식 I로 표시되는 염이 생성되도록, 상기 염형성 공정을 아세트산 에틸, 아세트산 n-부틸, 탄산디에틸, 아세토니트릴, t-부틸메틸에테르, 이소프로판올, 헥산, 테트라히드로푸란, 톨루엔 또는 이들의 혼합 용매 중에서 실행하는 제조 방법을 제공한다. [6] A method for preparing a salt comprising a salt forming step, wherein the salt forming step is performed to produce a salt represented by the following formula (I): ethyl acetate, n-butyl acetate, diethyl carbonate, acetonitrile, t-butylmethyl ether And isopropanol, hexane, tetrahydrofuran, toluene or a mixed solvent thereof.

<화학식 I><Formula I>

식 중, A+는 이소프로필암모늄 이온, sec-부틸암모늄 이온 또는 시클로펜틸암모늄 이온을 나타낸다.In the formula, A + represents isopropylammonium ion, sec-butylammonium ion or cyclopentylammonium ion.

또한, 본 발명의 제3 양태에서는,Moreover, in the 3rd aspect of this invention,

[7] 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ알칼리 금속염 (V)의 제조 방법이며,[7] A method for producing 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole alkali metal salt (V),

하기 화학식 I로 표시되는 염과 알칼리 금속 함유 염기를 반응시키는 공정을 포함하는 제조 방법을 제공한다. It provides a manufacturing method comprising the step of reacting a salt represented by the following formula (I) with an alkali metal-containing base.

<화학식 I><Formula I>

Figure 112007010573614-pct00007
Figure 112007010573614-pct00007

식 중, A+는 이소프로필암모늄 이온, sec-부틸암모늄 이온 또는 시클로펜틸암모늄 이온을 나타낸다.In the formula, A + represents isopropylammonium ion, sec-butylammonium ion or cyclopentylammonium ion.

[7-1] 본 발명에 관한 (V)의 제조 방법의 바람직한 양태에 따르면, 상기 [7]에 기재된 제조 방법에서는 알칼리 금속 함유 염기와 반응시킨 후, 결정화, 염형성에 의한 침전 또는 동결 건조를 더 행한다. [7-1] According to a preferred embodiment of the production method of (V) according to the present invention, in the production method described in [7], after reacting with an alkali metal-containing base, precipitation or freeze drying by crystallization, salt formation is performed. Do more.

[7-2] 또한, 본 발명에 관한 (V)의 제조 방법의 바람직한 양태에 따르면, 상기 [7]에 기재된 제조 방법에서는 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ알칼리 금속염 (V)의 아세톤 착체를 제조하고, 이어서 가열 건조를 행한다. [7-2] Moreover, according to the preferable aspect of the manufacturing method of (V) which concerns on this invention, in the manufacturing method as described in said [7], 2-[{4- (3-methoxypropoxy) -3-methyl An acetone complex of pyridin-2-yl} methylsulfinyl] -1H-benzimidazole-alkali metal salt (V) is prepared, followed by heat drying.

[7-3] 또한, 상기 [7-2]에 기재된 제조 방법의 바람직한 양태에 따르면, 가열 건조 후, 결정화, 염형성에 의한 침전 또는 동결 건조를 더 행한다. [7-3] Moreover, according to the preferable aspect of the manufacturing method of said [7-2], after heat-drying, precipitation by crystallization, salt formation, or freeze-drying are further performed.

[7-4] 또한, 상기 [7-2] 또는 [7-3]에 기재된 제조 방법의 바람직한 양태에 따르면, 가열 건조의 온도가 30 ℃ 내지 130 ℃이다. [7-4] Moreover, according to the preferable aspect of the manufacturing method as described in said [7-2] or [7-3], the temperature of heat drying is 30 degreeC-130 degreeC.

[7-5] 또한, 상기 [7-2] 또는 [7-3]에 기재된 제조 방법의 바람직한 양태에 따르면, 가열 건조 온도가 100 ℃ 내지 110 ℃이다. [7-5] Moreover, according to the preferable aspect of the manufacturing method as described in said [7-2] or [7-3], heat drying temperature is 100 degreeC-110 degreeC.

[7-6] 또한, 상기 [7-2] 또는 [7-5] 중 어느 하나에 기재된 제조 방법의 바람직한 양태에 따르면, 가열 건조를 감압하에서 행한다. [7-6] Moreover, according to the preferable aspect of the manufacturing method in any one of said [7-2] or [7-5], heat drying is performed under reduced pressure.

또한, 본 발명의 제4 양태에서는,Moreover, in the 4th aspect of this invention,

[8] 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ알칼리 금속염 (V), 및 0.2 ％ 이하의 양의 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술포닐]-1H-벤즈이미다졸 (VI)을 함유하는 위산 분비 억제제, [8] 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole alkali metal salt (V) and an amount of 0.2% or less Gastric acid secretion inhibitor containing 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfonyl] -1H-benzimidazole (VI),

[8-1] 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술포닐]-1H-벤즈이미다졸 (VI)의 함량이 0.2 ％ 이하(화합물 (V) 및 화합물 (VI)의 합계 중량에 기초한 함유율을 나타냄)의 양인, 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ알칼리 금속염 (V), [8-1] The content of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfonyl] -1H-benzimidazole (VI) is 0.2% or less (compound 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H, the amount of (V) and the content based on the total weight of the compound (VI)). -Benzimidazole alkali metal salts (V),

[9] 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ알칼리 금속염 (V), 및 0.2 ％ 이하의 양의 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술포닐]-1H-벤즈이미다졸 (VI)을 함유하는, 위산으로부터 기인하는 질환의 치료 및/또는 예방제, [9] 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole alkali metal salt (V), and an amount of 0.2% or less Treatment of diseases resulting from gastric acid, containing 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfonyl] -1H-benzimidazole (VI) And / or preventive agents,

[10] 상기 [9]에 있어서, 위산으로부터 기인하는 질환이 위궤양, 십이지장궤양, 문합부궤양, 역류성 식도염, 졸린거-엘리슨(Zollinger-Ellison) 증후군, 증후 성 역류성 식도염, 내시경 음성 역류성 식도염, 위 식도 역류증, 인후두 이상, 바레트(Barrett) 식도, NSAID 궤양, 위염, 위 출혈, 소화관 출혈, 소화성 궤양, 출혈성 궤양, 스트레스 궤양, 위과산증, 소화 불량, 위부전, 고령자 궤양, 난치성 궤양, 급성 위점막 병변, 가슴앓이, 이갈이증(tooth grinding), 위통, 속 거북함, 턱 관절증 또는 위 진무름인 치료 및/또는 예방제를 제공한다. [10] The disease of [9], wherein the disease resulting from gastric acid is gastric ulcer, duodenal ulcer, anastomosis ulcer, reflux esophagitis, Zollinger-Ellison syndrome, symptomatic reflux esophagitis, endoscopic negative reflux esophagitis, stomach Esophageal reflux, pharyngeal abnormalities, Barrett's esophagus, NSAID ulcer, gastritis, gastric bleeding, digestive tract bleeding, peptic ulcer, hemorrhagic ulcer, stress ulcer, gastric acidosis, indigestion, gastric insufficiency, elderly ulcer, refractory ulcer, acute gastric mucosa Treatments and / or prophylactic agents are provided that are lesions, heartburn, tooth grinding, stomach pain, stomach ache, jaw arthrosis or stomach erosion.

[11] 상기 [9] 또는 [10]에 기재된 치료 및/또는 예방제의 바람직한 양태에서는, 위산으로부터 기인하는 질환이 위궤양, 십이지장궤양, 문합부궤양, 역류성 식도염, 졸린거-엘리슨 증후군 또는 증후성 역류성 식도염이다.[11] In a preferred embodiment of the treatment and / or prophylactic agent according to the above [9] or [10], the disease resulting from gastric acid is gastric ulcer, duodenal ulcer, anastomosis ulcer, reflux esophagitis, drowsiness-Elison syndrome or symptomatic reflux. Esophagitis.

[12] 상기 [9] 내지 [11] 중 어느 하나에 기재된 치료 및/또는 예방제의 바람직한 양태에서는, 위산으로부터 기인하는 질환이 역류성 식도염 또는 증후성 역류성 식도염이다. [12] In a preferred embodiment of the treatment and / or prophylactic agent according to any one of [9] to [11], the disease resulting from gastric acid is reflux esophagitis or symptomatic reflux esophagitis.

[13] 상기 [9] 내지 [11] 중 어느 하나에 기재된 치료 및/또는 예방제의 바람직한 양태에서는, 위산으로부터 기인하는 질환이 위궤양 또는 십이지장궤양이다. [13] In a preferred embodiment of the treatment and / or prophylactic agent according to any one of [9] to [11], the disease resulting from gastric acid is a gastric ulcer or duodenal ulcer.

또한, 본 발명의 또 다른 양태에서는,In still another aspect of the present invention,

[14] 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ알칼리 금속염 (V), 및 0.2 ％ 이하의 양의 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술포닐]-1H-벤즈이미다졸 (VI)을 함유하는, 위 내 헬리코박터ㆍ파일로리균의 제균제 또는 제균 보조제,[14] 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole alkali metal salt (V), and an amount of 0.2% or less Bacterium bacterium Helicobacter pylori containing 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfonyl] -1H-benzimidazole (VI) Medicinal or antiseptic aids

[15] 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ알칼리 금속염 (V), 및 0.2 ％ 이하의 양의 2-[{4-(3-메톡시프로폭시)-3-메 틸피리딘-2-일}메틸술포닐]-1H-벤즈이미다졸 (VI)을 함유하는, 역류성 식도염 및/또는 증후성 역류성 식도염의 유지 요법제를 제공한다. [15] 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole alkali metal salt (V), and an amount of 0.2% or less Reflux esophagitis and / or symptomatic, containing 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfonyl] -1H-benzimidazole (VI) A maintenance therapy for reflux esophagitis is provided.

또한, 「2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ알칼리 금속염 (V), 및 0.2 ％ 이하의 양의 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술포닐]-1H-벤즈이미다졸 (VI)」에서의 「0.2 ％ 이하의 양의 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술포닐]-1H-벤즈이미다졸 (VI)」이란, 해당 화합물 (VI)이 화합물 (V) 및 화합물 (VI)의 합계 중량에 기초하여 0.2 ％ 이하의 양으로 존재하는 것을 의미한다. Further, "2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole alkali metal salt (V), and an amount of 0.2% or less 2- in an amount of up to 0.2% of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfonyl] -1H-benzimidazole (VI) '' [{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfonyl] -1H-benzimidazole (VI) "means that the compound (VI) is a compound (V) and a compound. It means present in the amount of 0.2% or less based on the total weight of (VI).

상기 [8], [8-1], [9], [14] 또는 [15]에 있어서, 화합물 (V) 및 (VI)의 합계 중량에 기초하여 화합물 (VI)의 함량은 0.2 ％ 이하의 양이지만, 바람직하게는 약 0.15 ％ 이하의 양이고, 보다 바람직하게는 약 0.15 ％ 내지 약 0.01 ％의 양이고, 더욱 바람직하게는 약 0.1 ％ 내지 약 0.01 ％의 양이다. In the above [8], [8-1], [9], [14], or [15], the content of compound (VI) is 0.2% or less based on the total weight of the compound (V) and (VI). Amount, but is preferably in an amount of about 0.15% or less, more preferably in an amount of about 0.15% to about 0.01%, still more preferably in an amount of about 0.1% to about 0.01%.

<발명의 효과>Effect of the Invention

본 발명에 따르면, 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 아민의 염을 사용함으로써, 의약으로서 유용한 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸을 제조할 때, 불순물로서 포함되는 해당 화합물의 술폰체를 효율적으로 제거할 수 있다. According to the invention, it is useful as a medicament by using a salt of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole and an amine When preparing 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole, the sulfone of the compound contained as an impurity is efficiently Can be removed with

<발명을 실시하기 위한 최선의 형태>Best Mode for Carrying Out the Invention

이하의 실시 형태는 본 발명을 설명하기 위한 예시이며, 본 발명을 이 실시 형태로만 한정하는 것은 아니다. 본 발명은 그 요지를 이탈하지 않는 한, 여러가 지 형태로 실시할 수 있다. The following embodiment is an illustration for demonstrating this invention, and does not limit this invention only to this embodiment. The present invention can be implemented in various forms as long as it does not depart from the gist thereof.

본 발명은 위산 분비 억제제, 항궤양제 등의 의약으로서 유용한 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸의 제조시에 부생되는 불순물을 효율적으로 제거하기 위한 염 및 그의 제조 방법을 제공한다. The present invention relates to 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole useful as a medicine for gastric acid secretion inhibitors, anti-ulcers and the like. Provided are a salt and a method for producing the same for efficiently removing by-product impurities produced during production.

화학식 VII로 표시되는 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸은, 하기 화학식 VIIa로 표시되는 화합물, 화학식 VIIb로 표시되는 화합물, 또는 화합물 (VIIa)와 화합물 (VIIb)의 임의의 비율의 혼합물을 의미하고, 바람직하게는 화합물 (VIIa)와 화합물 (VIIb)의 약 1:1의 혼합물이다. 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole represented by the general formula (VII) is a compound represented by the following general formula (VIIa) A compound represented by VIIb or a mixture of compound (VIIa) and any ratio of compound (VIIb), preferably a mixture of about 1: 1 of compound (VIIa) and compound (VIIb).

Figure 112007010573614-pct00008
Figure 112007010573614-pct00008

Figure 112007010573614-pct00009
Figure 112007010573614-pct00009

Figure 112007010573614-pct00010
Figure 112007010573614-pct00010

본 발명에서 사용하는 하기 화학식 I로 표시되는 염은, 화합물 (VII)과 이소프로필아민, sec-부틸아민 및 시클로펜틸아민으로 이루어지는 군으로부터 선택되는 하나의 아민과의 염이고, 상기 화합물 (VII)과 상기 아민이 임의의 비율로 형성하는 염을 의미한다. 바람직하게는, 상기 화합물 (VII)과 상기 아민이 약 1:1의 비로 형성되는 염이다. The salt represented by the following general formula (I) used in the present invention is a salt of compound (VII) with one amine selected from the group consisting of isopropylamine, sec-butylamine and cyclopentylamine, and the compound (VII) And a salt formed by the amine in any ratio. Preferably, the compound (VII) and the amine are salts formed in a ratio of about 1: 1.

<화학식 I><Formula I>

Figure 112007010573614-pct00011
Figure 112007010573614-pct00011

화학식 I로 표시되는 염은, 화합물 (VII)과 이소프로필아민, sec-부틸아민 및 시클로펜틸아민으로 이루어지는 군으로부터 선택되는 하나의 아민과 염을 형성하고 있으면 특별히 제한되지 않지만, 예를 들면 하기 화학식 VIII로 표시되는 염, 하기 화학식 IX로 표시되는 염 등의 태양이다.The salt represented by the formula (I) is not particularly limited as long as it forms a salt with a compound (VII) and one amine selected from the group consisting of isopropylamine, sec-butylamine and cyclopentylamine. And salts represented by VIII and salts represented by the following general formula (IX).

Figure 112007010573614-pct00012
Figure 112007010573614-pct00012

식 중, A+는 이소프로필암모늄 이온, sec-부틸암모늄 이온 또는 시클로펜틸암모늄 이온을 나타낸다.In the formula, A + represents isopropylammonium ion, sec-butylammonium ion or cyclopentylammonium ion.

Figure 112007010573614-pct00013
Figure 112007010573614-pct00013

식 중, A+는 이소프로필암모늄 이온, sec-부틸암모늄 이온 또는 시클로펜틸암모늄 이온을 나타낸다.In the formula, A + represents isopropylammonium ion, sec-butylammonium ion or cyclopentylammonium ion.

본 발명에서 사용하는 용어 「에스테르 용매」란 C3 -7 알킬에스테르 화합물을 의미하고, 구체예로서는 아세트산 메틸, 아세트산 에틸, 아세트산 n-프로필(아세트산 n-프로필에스테르), 아세트산 s-프로필(아세트산 s-프로필에스테르), 아세트산 n-부틸(아세트산 n-부틸에스테르), 탄산디메틸, 탄산디에틸 등이며, 바람직한 예로 서는 아세트산 에틸, 아세트산 n-부틸 등이다. The term "ester solvents" as used in the present invention is C 3 -7 means an alkyl ester compound, and specific examples include methyl acetate, ethyl acetate, n- propyl (ethyl n- propyl ester), propyl acetate s- (ethyl s- Propyl ester), n-butyl acetate (n-butyl ester), dimethyl carbonate, diethyl carbonate and the like, and preferred examples thereof are ethyl acetate, n-butyl acetate and the like.

본 발명에서 사용하는 용어 「니트릴 용매」란 C2 -6 알킬니트릴을 의미하고, 구체예로서는 아세토니트릴 등이다. Means the term "nitrile solvent" which is C 2 -6 alkyl nitriles used in the present invention, and a concrete example acetonitrile.

본 발명에서 사용하는 용어 「에테르 용매」란, 디 C1 -6 알킬에테르 또는 환상 에테르를 의미하고, 구체예로서는 디메틸에테르, t-부틸메틸에테르, 테트라히드로푸란 등이며, 바람직한 예로서는 t-부틸메틸에테르, 테트라히드로푸란 등이다. Means the term "ether solvent" refers to di-C 1 -6 alkyl ether or a cyclic ether to be used in the present invention, and a concrete example dimethyl ether, t- butyl methyl ether, tetra, and the like in tetrahydrofuran, a preferred example t- butyl methyl ether And tetrahydrofuran.

본 발명에서 사용하는 용어 「알코올 용매」란, C1 -6 알킬알코올을 의미하고, 구체예로서는 에탄올, 이소프로판올, n-프로판올 등이며, 바람직한 예로서는 이소프로판올 등이다. The term "alcoholic solvent" as used in the present invention, C 1 -6 examples means an alkyl alcohol, and a sphere, such as ethanol, isopropanol, n- propanol, isopropanol, etc. are preferred examples.

본 발명에서 사용하는 용어 「케톤 용매」란, 디 C1 -6 알킬케톤을 의미하고, 구체예로서는 예를 들면 디메틸케톤, 메틸에틸케톤 등이다. A mean The term "ketone solvent" as used in the invention is, di-C 1 -6 alkyl ketone, and specific examples include, for example, dimethyl ketone, methyl ethyl ketone, and the like.

본 발명에서 사용하는 용어 「지방족 탄화수소 용매」란, C5 -8 알칸을 의미하고, 구체예로서는 헥산, 헵탄 등이며, 바람직한 예로서는 헥산 등이다. Examples meaning the term "aliphatic hydrocarbon solvent" column, C 5 -8 alkane used in the present invention, and concrete, and hexane, heptane and the like, preferred examples are as hexane.

본 발명에서 사용하는 용어 「방향족 탄화수소 용매」란, 치환기(C1 -6 알킬기, C1 -6 알콕시기, 니트릴기, 할로겐 원자 등)를 가질 수도 있는 벤젠을 의미하고, 구체예로서는 톨루엔, 크실렌, 벤젠 등이며, 바람직한 예로서는 톨루엔 등이다. The term "aromatic hydrocarbon solvent" used in the present invention, the substituent means a benzene which may have a (C 1 -6 alkyl, C 1 -6 alkoxy group, a nitrile group, a halogen atom or the like), and specific examples include toluene, xylene, Benzene and the like, and toluene is preferable as an example.

본 발명에서 사용하는 용어 「알칼리 금속염」이란, 알칼리 금속과의 염이라면 특별히 한정되지 않지만, 구체예로서는 나트륨염 또는 칼륨염 등이고, 바람직한 예로서는 나트륨염이다. The term "alkali metal salt" used in the present invention is not particularly limited as long as it is a salt with an alkali metal. Specific examples thereof include sodium salts and potassium salts, and sodium salts are preferred examples.

본 발명에서 사용하는 용어 「알칼리 금속 함유 염기」란, 나트륨, 칼륨 등의 알칼리 금속을 함유하는 염기라면 특별히 한정되지 않지만, 구체예로서는 수산화나트륨, 나트륨에톡시드, 나트륨메톡시드, 수소화나트륨, 수산화칼륨, 칼륨에톡시드, 칼륨메톡시드, 수소화칼륨 또는 이들의 용액, 또는 알칼리 금속염으로 변환하기 위한 이온 교환 수지 등이며, 바람직한 예로서는 수산화나트륨 또는 수산화나트륨 용액이고, 보다 바람직하게는 수산화나트륨, 수산화나트륨 수용액, 수산화나트륨의 메탄올 용액 또는 수산화나트륨의 에탄올 용액이다. The term "alkali metal-containing base" used in the present invention is not particularly limited as long as it contains a base containing an alkali metal such as sodium or potassium. Specific examples thereof include sodium hydroxide, sodium ethoxide, sodium methoxide, sodium hydride and potassium hydroxide. , Potassium ethoxide, potassium methoxide, potassium hydride or a solution thereof, or an ion exchange resin for converting to an alkali metal salt, and the like, and preferred examples thereof are sodium hydroxide or sodium hydroxide solution, and more preferably sodium hydroxide and sodium hydroxide aqueous solution. , Methanol solution of sodium hydroxide or ethanol solution of sodium hydroxide.

본 발명에서 사용하는 용어 「2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ알칼리 금속염의 아세톤 착체」란, 아세톤을 함유하는 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ알칼리 금속염의 결정이라면 특별히 한정되지 않지만, 구체예로서는 국제 공개 공보 WO04/085424호, 유럽 특허 공개 공보 제1000943호에 기재된 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ알칼리 금속염의 아세톤 착체를 의미한다. The term "acetone complex of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole-alkali metal salt" used in the present invention " The crystal is not particularly limited as long as it is a crystal of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole alkali metal salt containing acetone. Examples include 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benz described in WO04 / 085424 and European Patent Publication No. 1000943. It means the acetone complex of imidazole-alkali metal salt.

본 발명에서 사용하는 용어 「위산으로부터 기인하는 질환」이란, 위산의 분비로부터 기인하는 질환이라면 특별히 한정되지 않지만, 구체적으로서는 위궤양, 십이지장궤양, 문합부궤양, 역류성 식도염, 졸린거-엘리슨 증후군, 증후성 역류성 식도염, 내시경 음성 역류성 식도염, 위 식도 역류증, 인후두 이상, 바레트 식도, NSAID 궤양, 위염, 위 출혈, 소화관 출혈, 소화성 궤양, 출혈성 궤양, 스트레스 궤 양, 위과산증, 소화 불량, 위부전, 고령자 궤양, 난치성 궤양, 급성 위점막 병변, 가슴앓이, 이갈이증, 위통, 속 거북함, 턱 관절증 또는 위 진무름 등을 들 수 있고, 바람직한 예로서는 위궤양, 십이지장궤양, 문합부궤양, 역류성 식도염, 졸린거-엘리슨 증후군 또는 증후성 역류성 식도염을 들 수 있으며, 보다 바람직한 예로서는 역류성 식도염, 증후성 역류성 식도염, 위궤양 또는 십이지장궤양을 들 수 있고, 더욱 바람직한 예로서는 (1) 역류성 식도염 또는 증후성 역류성 식도염, 또는 (2) 위궤양 또는 십이지장궤양을 들 수 있다. The term "disease caused by gastric acid" used in the present invention is not particularly limited as long as it is a disease caused by secretion of gastric acid. Specifically, gastric ulcer, duodenal ulcer, anastomosis ulcer, reflux esophagitis, sleepy-Elison syndrome, and symptomatic Reflux esophagitis, endoscopic negative reflux esophagitis, gastroesophageal reflux disease, pharyngeal abnormalities, Barrett's esophagus, NSAID ulcer, gastritis, gastric bleeding, digestive tract bleeding, peptic ulcer, hemorrhagic ulcer, stress ulcer, gastric acidosis, indigestion, stomach failure, elderly ulcer , Refractory ulcers, acute gastric mucosal lesions, heartburn, dizziness, stomach pain, stomach ache, jaw arthropathy or stomach erosion, and the like, and preferred examples include gastric ulcer, duodenal ulcer, anastomosis ulcer, reflux esophagitis, sleepyger-elison Syndrome or symptomatic reflux esophagitis, more preferred examples are reflux esophagitis, symptomatic reverse St. esophagitis, gastric or duodenal ulcers, there may be mentioned, there may be mentioned more preferred examples (1) gastroesophageal reflux disease or symptomatic gastroesophageal reflux disease, or (2) gastric ulcer, or duodenal ulcer.

또한, 본 발명은 상기 화학식 I로 표시되는 염 또는 그의 용매화물을 함유하는 헬리코박터ㆍ파일로리균의 제균제 또는 제균 보조제를 제공한다. 또한, 상기 「예방제」에는 질환의 발증 전에 투여하는 것 외에, 치유 후의 유지 요법제 또는 재발 방지제도 포함된다. 또한, 상기 「제균 보조제」란, 산성 조건하에서는 효과를 발휘하기 어려운 제균제가 효과를 발휘하는 환경을 갖춘 약제를 말한다. The present invention also provides a bactericidal agent or bactericidal aid of Helicobacter pylori containing a salt represented by the formula (I) or a solvate thereof. In addition to the above-mentioned "prophylactic agent", it is administered before the onset of a disease, and also contains the maintenance therapy agent or the recurrence prevention agent after healing. In addition, said "antibacterial adjuvant" means the chemical | medical agent with the environment which the antibacterial agent which is hard to exhibit an effect under acidic conditions exerts an effect.

본 발명에 관한 위산 분비 억제제, 위산으로부터 기인하는 질환의 치료 및/또는 예방제는 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ알칼리 금속염 (V), 및 0.2 ％ 이하의 양의 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술포닐]-1H-벤즈이미다졸 (VI)을 함유시키고, 필요에 따라 공지된 약학적으로 허용할 수 있는 담체(예: 부형제, 결합제, 붕괴제, 활택제, 착색제, 교미 교취제, 안정화제, 유화제, 흡수 촉진제, 계면활성제, pH 조정제, 방부제, 항산화제 등)나, 일반적으로 의약품 제제의 원료로서 사용되는 성분을 배합하여 관용적인 방법에 의해 제제화할 수도 있다. 제제화의 제형으로서는 정제, 산 제, 세립제, 과립제, 캡슐제, 시럽제, 좌제, 주사제 등을 들 수 있다. Gastric acid secretion inhibitors according to the present invention, the treatment and / or prevention of diseases resulting from gastric acid is 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H -Benzimidazole-alkali metal salt (V), and 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfonyl] -1H-benz in an amount of 0.2% or less It contains imidazole (VI) and, if necessary, known pharmaceutically acceptable carriers (e.g. excipients, binders, disintegrants, glidants, colorants, copulation agents, stabilizers, emulsifiers, absorption promoters, surfactants) , pH adjusters, preservatives, antioxidants, and the like), and components generally used as raw materials for pharmaceutical preparations may be blended and formulated by conventional methods. Formulations of the formulation include tablets, powders, granules, granules, capsules, syrups, suppositories, injections and the like.

또한, 본 발명에 관한 위산 분비 억제제와 위산으로부터 기인하는 질환의 치료 및/또는 예방제의 투여 형태는 특별히 한정되지 않지만, 경구적 또는 비경구적으로 투여하는 것이 바람직하다. 본 발명에 관한 위산 분비 억제제, 위산으로부터 기인하는 질환의 치료 및/또는 예방제의 투여량은 증상, 연령 등에 따라 상이하며, 1 내지 500 mg/일이고, 바람직하게는 1 내지 200 mg/일이며, 더욱 바람직하게는 5 내지 135 mg/일이다. In addition, the dosage form of the gastric acid secretion inhibitor and the agent for treating and / or preventing a disease resulting from gastric acid according to the present invention is not particularly limited, but is preferably administered orally or parenterally. The dose of the gastric acid secretion inhibitor, the treatment and / or prophylactic agent for the disease resulting from gastric acid, which varies according to symptoms, age, etc., is 1 to 500 mg / day, preferably 1 to 200 mg / day, More preferably 5 to 135 mg / day.

[일반 제조 방법][General manufacturing method]

제조 방법 AManufacturing Method A

[2-[{4-(3-[2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole 과 and 아민과의With amines 염의 제조 방법 Preparation method of the salt

본 발명에 관한 제조 방법에 있어서, 출발 원료로서 사용하는 화합물 (2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸) (VII)은, 상기 특허 문헌 1에 기재된 방법 또는 해당 방법의 공지된 개량 방법(예를 들면, 일본 특허 공개 공보 (평)11-71370호, 일본 특허 공개 (평)2000-143659호, 국제 특허 공개 공보 WO01/68594호, 유럽 특허 공개 공보 제1,270,555호 등)에 의해 제조할 수 있다. 출발 원료로서 사용하는 상기 화합물 (VII)은 술폰체, (2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술포닐]-1H-벤즈이미다졸) (VI)을 포함할 수도 있고, 포함하지 않을 수도 있다.In the production method according to the present invention, the compound (2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole used as a starting material ) (VII) is a method described in Patent Document 1 or a known improved method (for example, Japanese Patent Laid-Open No. 11-71370, Japanese Patent Laid-Open No. 2000-143659, International Patent publication WO01 / 68594, European Patent Publication No. 1,270,555 and the like). The compound (VII) to be used as a starting material is sulfone, (2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfonyl] -1H-benzimidazole) (VI) may or may not be included.

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸 에 유기 용매와 아민(이소프로필아민, sec-부틸아민 또는 시클로펜틸아민)을 첨가하여 용해한다(이 때, 가열할 수도 있음). 그 후, 30 내지 -40 ℃(바람직하게는 -20 내지 -40 ℃)에서 교반한다. 교반 시간은 특별히 한정되지 않지만, 바람직하게는 1 시간 내지 1 일이고, 보다 바람직하게는 하룻밤(10 내지 12 시간)이다. 냉각하여 교반하는 상기 공정에서 결정이 석출된다.2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole in organic solvents and amines (isopropylamine, sec-butylamine or cyclo Pentylamine) is added and dissolved (at this time, it may be heated). Thereafter, the mixture is stirred at 30 to -40 ° C (preferably -20 to -40 ° C). Although stirring time is not specifically limited, Preferably it is 1 hour-1 day, More preferably, it is overnight (10-12 hours). Crystals precipitate in this step of cooling and stirring.

이 결정 석출 공정에 있어서, 종결정(소량의 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 아민과의 염의 결정)을 첨가할 수도 있고, 첨가하지 않을 수도 있다. 종결정을 첨가하는 온도는 특별히 규정되지 않지만, 바람직하게는 55 ℃ 이하이고, 보다 바람직하게는 35 내지 0 ℃이다. 결정이 석출되기 전 또는 결정이 석출되는 과정에서 헥산, 아세트산 n-부틸에스테르 또는 t-부틸메틸에테르 등의 용매를 적절하게 첨가할 수도 있다.In this crystal precipitation step, seed crystals (a small amount of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole and an amine Salt crystals) may or may not be added. The temperature at which the seed crystals are added is not particularly specified, but is preferably 55 ° C. or lower, more preferably 35 to 0 ° C. A solvent such as hexane, acetic acid n-butyl ester or t-butyl methyl ether may be appropriately added before the crystal is precipitated or during the crystal precipitation.

혼합액 중에 석출된 결정을 여과하여, 목적으로 하는 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 아민과의 염을 얻을 수 있다. The crystals precipitated in the mixed solution were filtered to prepare the desired 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole with an amine. Salts can be obtained.

얻어진 결정은, 필요에 따라 용해에 사용된 용매와 동일한 용매로 세정할 수 있다. 또한, 이 얻어진 결정은 필요에 따라 실온하 또는 가열하에서, 상압하 또는 감압하에 건조할 수 있다. The obtained crystal can be washed with the same solvent as the solvent used for dissolution, if necessary. Moreover, this obtained crystal can be dried under normal pressure or reduced pressure at room temperature or under heating as needed.

상기 유기 용매란 특별히 제한되지 않지만, 구체예로서는 에스테르 용매, 니트릴 용매, 에테르 용매, 알코올 용매, 케톤 용매, 지방족 탄화수소 용매, 방향족 탄화수소 용매, 물 또는 이들의 혼합 용매이고, 보다 바람직하게는 아세트산 에틸, 아세트산 n-부틸, 탄산디에틸, 테트라히드로푸란, 아세토니트릴, t-부틸메틸에테르, 헥산, 이소프로판올, 톨루엔으로 이루어지는 군으로부터 선택되는 1종 또는 2종 이상의 용매이다. 유기 용매의 사용량은, 화합물 (VII)이 가열에 의해 용해되는 양을 하한으로 하고, 결정의 수량이 현저하게 저하되지 않는 양을 상한으로 하여 적절하게 선택할 수 있지만, 바람직하게는 화합물 (VII)의 중량에 대한 용량비로 3 내지 30배량(v/w)이고, 보다 바람직하게는 화합물 (VII)의 중량에 대한 용량비로 5 내지 20배량(v/w)이다. Although the said organic solvent is not specifically limited, As an example, it is an ester solvent, a nitrile solvent, an ether solvent, an alcohol solvent, a ketone solvent, an aliphatic hydrocarbon solvent, an aromatic hydrocarbon solvent, water, or a mixed solvent thereof, More preferably, ethyl acetate and acetic acid It is 1 type, or 2 or more types of solvent chosen from the group which consists of n-butyl, diethyl carbonate, tetrahydrofuran, acetonitrile, t-butyl methyl ether, hexane, isopropanol, and toluene. Although the usage-amount of an organic solvent can select suitably the quantity which compound (VII) melt | dissolves by heating as an upper limit, and the quantity which does not significantly reduce the quantity of crystal | crystallization as an upper limit, Preferably it is a compound of (VII) It is 3-30 times (v / w) by volume ratio with respect to weight, More preferably, it is 5-20 times (v / w) by dose ratio with respect to the weight of compound (VII).

아민의 사용량은, 화합물 (VII)의 당량 이상이라면 특별히 제한되지 않지만, 바람직하게는 화합물 (VII)의 몰비로 1 내지 10배이고, 보다 바람직하게는 화합물 (VII)의 몰비로 약 5 내지 10배이며, 더욱 바람직하게는 화합물 (VII)의 몰비로 약 7배이다. The amount of the amine to be used is not particularly limited as long as it is equal to or more than the equivalent of compound (VII). More preferably about 7 times by molar ratio of Compound (VII).

제조 방법 BManufacturing Method B

[2-[{4-(3-[2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole 과 and 아민과의With amines 염으로부터 [2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ알칼리 금속염의 합성] Synthesis of [2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole-alkali metal salt from salt]

본 공정은 유기 화합물의 아민염을 알칼리 금속염으로 변환하는데 있어서 일반적으로 이용되고 있는 방법에 의해 행할 수 있다. 구체적으로는 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 아민의 염을, 톨루엔, 메탄올, 에탄올, 물, 아세톤, 아세트산 에틸, 아세토니트릴, t-부틸메틸에테르, 테트라히드로푸란, 헥산, 이소프로판올로 이루어지는 군으로부터 선택되는 1종 내지 3종의 용매 등에 용해시키고, 이어서 이 혼합액 중에 약 1 당량의 염기(수산화나트륨, 나트륨에톡시드, 나트륨메톡시드, 수소화나트륨, 수산화칼륨, 칼륨에톡시드, 칼륨메톡시드, 수소화칼륨 또는 이들의 용액 등)를 첨가하여 교반한다. 이 혼합액을 용매 증류 제거함으로써 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ알칼리 금속염을 얻을 수 있다. This process can be performed by the method generally used in converting the amine salt of an organic compound into an alkali metal salt. Specifically, the salt of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole and an amine is selected from toluene, methanol, ethanol and water. 1 to 3 solvents selected from the group consisting of acetone, ethyl acetate, acetonitrile, t-butylmethylether, tetrahydrofuran, hexane, isopropanol and the like, and then, in the mixed solution, about 1 equivalent of base (hydroxyl). Sodium, sodium ethoxide, sodium methoxide, sodium hydride, potassium hydroxide, potassium ethoxide, potassium methoxide, potassium hydride or a solution thereof and the like) are added and stirred. The solvent can be distilled off to obtain 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole alkali metal salt.

이 알칼리 금속염은, 상기 혼합액 또는 농축 잔사로부터 결정화, 염형성에 의한 침전, 또는 동결 건조 등에 의해서도 얻을 수 있다. 이 알칼리 금속염은 [2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸의 아세톤 함유 결정(아세톤 착체)의 제조 공정, 및 고온 건조 공정을 각각 적절하게 조합하여 제조할 수도 있다(국제 공개 공보 WO04/085424호, 유럽 특허 공개 공보 제1000943호 기재). This alkali metal salt can also be obtained from crystallization, precipitation by salt formation, freeze drying, or the like from the mixed solution or the concentrated residue. This alkali metal salt is a process for producing acetone-containing crystals (acetone complexes) of [2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole , And a high temperature drying process may be appropriately combined, respectively (International Publication WO04 / 085424, European Patent Publication No. 1000943).

얻어진 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ알칼리 금속염은, 또한 감압 또는 상압하에서 30 내지 60 ℃에서 건조할 수도 있다. 이 건조 공정은 정치하 또는 진동하, 또한 통풍하에서 행할 수도 있다. The obtained 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole alkali metal salt was further reduced at 30 to 60 ° C. under reduced pressure or normal pressure. It may be dry. This drying step can also be performed under stationary or vibration, and under ventilation.

제조 방법 CManufacturing Method C

[2-[{4-(3-[2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole 의 제조 공정]Manufacturing process]

본 발명의 제조 방법에 있어서, 출발 원료로서 사용하는 화합물 (VII)은, 이하에 나타내는 방법에 의해 제조할 수 있다. In the manufacturing method of this invention, the compound (VII) used as a starting raw material can be manufactured by the method shown below.

Figure 112007010573614-pct00014
Figure 112007010573614-pct00014

또한, 상기 화학식 (3x)로 표시되는 화합물(이하, 간단히 「화합물 (3x)」라고 함, 또한 화학식 (4x) 및 (5x)로 표시되는 화합물에 대해서도 동일하게 표기함) 내지 화합물 (5)는 모두 공지된 화합물이다. In addition, the compound represented by the said General formula (3x) (henceforth a "compound (3x)", and also the compound represented by the general formula (4x) and (5x) is the same)-compound (5) are All are known compounds.

(제1x 공정)(1x process)

본 공정은 불활성 용제 중, 화합물 (3x)에 염소화제를 반응시켜 얻어지는 반응 혼합물을 농축함으로써 이루어지는, 조 정제의 화합물 (4x)를 제조하는 공정이다. 본 공정에서 사용하는 불활성 용제에는 원료 화합물을 어느 정도 용해할 수 있고, 본 반응을 저해하지 않는 한 특별히 제한은 없지만, 바람직하게는 예를 들면 벤젠, 톨루엔, 크실렌과 같은 방향족 탄화수소류, 아세트산 메틸, 아세트산 에틸과 같은 유기산 에스테르류, 디에틸에테르, 디이소프로필에테르, 테트라히드로푸란, 디옥산, 디메톡시에탄과 같은 에테르류, 메틸렌클로라이드, 클로로포름, 사염화탄소, 디클로로에탄과 같은 할로겐화 탄화수소류를 사용할 수 있고, 특히 바람직하게는 톨루엔, 아세트산 에틸, 디메톡시에탄 또는 디클로로메탄을 사용한다. This process is a process of manufacturing the compound (4x) of crude purification which consists of concentrating the reaction mixture obtained by making a compound (3x) react with a chlorinating agent in an inert solvent. There is no restriction | limiting in particular in the inert solvent used at this process, unless a raw material compound can be melt | dissolved to some extent and this reaction is not impaired, Preferably, aromatic hydrocarbons, such as benzene, toluene, xylene, methyl acetate, Organic acid esters such as ethyl acetate, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, , Particularly preferably toluene, ethyl acetate, dimethoxyethane or dichloromethane.

본 공정에서 사용하는 염소화제로서는, 예를 들면 삼염화인, 오염화인, 옥시염화인, 염화티오닐 등을 사용할 수 있지만, 바람직하게는 염화티오닐과 같이 용제와 함께 증류 제거될 수 있는 것이 사용된다. As the chlorinating agent used in this step, for example, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, thionyl chloride and the like can be used. Preferably, those which can be distilled off together with a solvent such as thionyl chloride are used. .

본 공정의 반응 온도는 사용하는 용제, 원료 화합물, 염소화제 등에 따라 상이하지만, 통상 -20 내지 50 ℃이고, 바람직하게는 0 내지 30 ℃이다. 본 공정의 반응 시간은 사용하는 용제, 원료 화합물, 염소화제, 반응 온도 등에 따라 상이하지만, 통상 30 분 내지 6 시간이고, 바람직하게는 1 시간 내지 2 시간이다. Although the reaction temperature of this process changes with a solvent, a raw material compound, a chlorinating agent, etc. to be used, it is usually -20-50 degreeC, Preferably it is 0-30 degreeC. Although the reaction time of this process changes with a solvent, a raw material compound, a chlorinating agent, reaction temperature, etc. to be used, it is 30 minutes-6 hours normally, Preferably it is 1 hour-2 hours.

반응 종료 후, (1) 반응 켄칭(quenching), (2) 반응 혼합물의 농축 건조, 및 (3) 정제 등을 적절하게 행한다. 반응의 켄칭으로서, 구체적으로는 반응 혼합물 중에 물이나 저급 알코올(특히, 에탄올)의 적량 첨가를 들 수 있다. After completion of the reaction, (1) reaction quenching, (2) concentrated drying of the reaction mixture, and (3) purification are appropriately performed. Specific examples of the quenching of the reaction include the addition of appropriate amounts of water and lower alcohols (especially ethanol) in the reaction mixture.

반응 혼합물은 반응 켄칭 및 반응 혼합물을 농축 건조하고, 그 후에는 특별히 정제하지 않고 그대로 제2x 공정에 사용할 수 있으며, 바람직하게는 반응 켄칭만으로 반응 혼합물의 농축 건조, 정제를 행하지 않고 그대로 제2x 공정에 사용할 수 있다. The reaction mixture may be concentrated in the reaction quench and the reaction mixture and then used in the 2x process as it is, without any special purification. Preferably, the reaction mixture is concentrated and dried in the 2x process without performing the concentrated drying and purification of the reaction mixture. Can be used.

(제2x 공정)(2x process)

본 공정은 불활성 용제 중, 제1 공정에서 얻어지는 화합물 (4x)에 염기의 존재하에서 2-벤조이미다졸티올을 반응시켜 화합물 (5x)를 제조하는 공정이다. 본 공정에서 사용하는 불활성 용제에는 원료 화합물을 어느 정도 용해할 수 있고, 또한 본 반응을 저해하지 않는 한 특별히 제한은 없지만, 바람직하게는 예를 들면 메탄올, 에탄올, 프로판올, 이소프로판올, 부탄올, tert-부탄올과 같은 알코올류, 벤 젠, 톨루엔, 크실렌과 같은 방향족 탄화수소류, 또는 이들의 혼합 용매를 사용할 수 있다. This step is a step of reacting compound (4x) obtained in the first step with 2-benzoimidazolthiol in the presence of a base in an inert solvent to produce compound (5x). Although there is no restriction | limiting in particular in the inert solvent used at this process, as long as a raw material compound can be melt | dissolved to some extent and this reaction is not inhibited, Preferably it is methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, for example. Alcohols such as, aromatic hydrocarbons such as benzene, toluene, xylene, or a mixed solvent thereof can be used.

본 공정에서 사용하는 염기에는, 용제에 어느 정도 용해되는 것이라면 특별히 제한은 없지만, 바람직하게는 예를 들면 수산화나트륨, 수산화칼륨과 같은 알칼리 금속 수소화물을 사용할 수 있고, 특히 바람직하게는 수산화나트륨을 사용한다. 본 공정의 반응 온도는 사용하는 용제, 원료 화합물, 염기 등에 따라 상이하지만, 통상 -20 내지 70 ℃이고, 바람직하게는 20 내지 70 ℃이다. The base used in the present step is not particularly limited as long as it is dissolved in a solvent to some extent, but alkali metal hydrides such as sodium hydroxide and potassium hydroxide can be preferably used, and sodium hydroxide is particularly preferable. do. Although the reaction temperature of this process changes with a solvent, a raw material compound, a base, etc. to be used, it is usually -20-70 degreeC, Preferably it is 20-70 degreeC.

본 공정의 반응 시간은 사용하는 용제, 원료 화합물, 염기, 반응 온도 등에 따라 상이하지만, 통상 30 분 내지 6 시간이고, 바람직하게는 1 내지 2 시간이다. Although the reaction time of this process changes with the solvent, raw material compound, base, reaction temperature, etc. which are used, it is 30 minutes-6 hours normally, Preferably it is 1-2 hours.

반응 종료 후, 화합물 (5x)는 표준 방법에 따라 반응 혼합물로부터 단리할 수 있다. 예를 들면, 반응 종료 후, 반응 혼합물을 감압 농축하고, 이어서 물 및 물과 혼화되지 않는 유기 용제(예를 들면, 디클로로메탄, 아세트산 에틸, 아세트산 메틸, 아세트산 n-부틸, 톨루엔 등)로 추출하고, 수산화나트륨 수용액 및 물을 사용하여 유기층을 세정 후 농축함으로써, 화합물 (5x)를 제조할 수 있다. 반응 종료 후, 반응 혼합물을 물로 세정한 후, 농축이나 정제를 행하지 않고, 다음 제3x 공정에 사용할 수도 있다.After the end of the reaction, compound (5x) can be isolated from the reaction mixture according to standard methods. For example, after completion of the reaction, the reaction mixture is concentrated under reduced pressure, and then extracted with water and an organic solvent which is not mixed with water (for example, dichloromethane, ethyl acetate, methyl acetate, n-butyl acetate, toluene and the like). Compound (5x) can be prepared by washing and concentrating the organic layer using aqueous sodium hydroxide solution and water. After completion of the reaction, the reaction mixture can be washed with water and then used in the next 3x step without concentration or purification.

특히, 이하와 같은 유기 용제를 사용함으로써, 정제도가 높은 화합물 (5x)를 결정으로서 제조할 수 있다: In particular, by using the following organic solvents, a highly purified compound (5x) can be prepared as a crystal:

디에틸에테르, 디이소프로필에테르, t-부틸메틸에테르, 테트라히드로푸란, 디옥산, 디메톡시에탄과 같은 에테르류(특히, 디이소프로필에테르 또는 t-부틸메틸 에테르);Ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane (particularly diisopropyl ether or t-butylmethyl ether);

아세토니트릴과 같은 니트릴류(특히, 아세토니트릴); Nitriles such as acetonitrile (particularly acetonitrile);

벤젠, 톨루엔, 크실렌과 같은 방향족 탄화수소류(특히, 톨루엔); Aromatic hydrocarbons such as benzene, toluene and xylene (particularly toluene);

메탄올, 에탄올, 프로판올, 이소프로판올과 같은 알코올류(특히, 이소프로판올);Alcohols such as methanol, ethanol, propanol and isopropanol (particularly isopropanol);

아세톤, 메틸에틸케톤과 같은 케톤류(특히, 아세톤); Ketones (especially acetone) such as acetone and methyl ethyl ketone;

아세트산 메틸, 아세트산 에틸, 탄산디메틸, 탄산디에틸과 같은 유기산 에스테르류(특히, 아세트산 에틸, 탄산디에틸); 또는Organic acid esters such as methyl acetate, ethyl acetate, dimethyl carbonate and diethyl carbonate (especially ethyl acetate and diethyl carbonate); or

이들 용제 중 2종 이상을 포함하는 혼합 용제. Mixed solvent containing 2 or more types of these solvents.

또한, 결정화시, 사용하는 용제량은 용제의 종류에 따라 상이하지만, 화합물 (5) 1 g에 대하여 3 내지 40 ㎖이다. In addition, although the amount of solvent used at the time of crystallization changes with kinds of solvent, it is 3-40 ml with respect to 1 g of compound (5).

(제3x 공정)(3x process)

본 공정은 불활성 용제 중, 화합물 (5x)에 산화제를 반응시켜 화합물 (I)을 제조하는 공정이다. 본 공정에서 사용하는 불활성 용제로서는, 원료 화합물을 어느 정도 용해할 수 있고, 또한 본 반응을 저해하지 않는 한 특별히 제한은 없지만, 바람직하게는, 예를 들면 클로로포름, 디클로로메탄, 사염화탄소, 디클로로에탄과 같은 할로겐화 탄화수소류, 벤젠, 톨루엔, 크실렌과 같은 방향족 탄화수소류, 메탄올, 에탄올, 프로판올, 이소프로판올, 부탄올, tert-부탄올과 같은 알코올류, 또는 이들의 혼합 용매를 사용할 수 있고, 특히 바람직하게는 디클로로메탄, 톨루엔, 메탄올, 에탄올 또는 이들의 혼합 용매를 사용할 수 있다. This step is a step of producing compound (I) by reacting an oxidizing agent with compound (5x) in an inert solvent. There is no restriction | limiting in particular as an inert solvent used at this process, unless a raw material compound can be melt | dissolved to some extent and this reaction is inhibited, Preferably, it is preferable, for example, such as chloroform, dichloromethane, carbon tetrachloride, dichloroethane Halogenated hydrocarbons, aromatic hydrocarbons such as benzene, toluene, xylene, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, or a mixed solvent thereof may be used, and particularly preferably dichloromethane, Toluene, methanol, ethanol or a mixed solvent thereof can be used.

본 공정에서 사용하는 산화제로서는 과산화수소, 과아세트산, m-클로로과벤조산, 과요오드산나트륨 등을 사용할 수 있지만, 바람직하게는 m-클로로과벤조산을 사용한다. 화합물 (5x)에 대하여 0.3 내지 1.1 당량을 사용한다. Hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, sodium periodate, etc. can be used as an oxidizing agent used at this process, Preferably, m-chloroperbenzoic acid is used. 0.3 to 1.1 equivalents are used relative to compound (5x).

본 공정의 반응 온도는 사용하는 용제, 원료 화합물, 산화제 등에 따라 상이하지만, 통상 -50 내지 0 ℃이고, 바람직하게는 -40 내지 -10 ℃이다. 본 공정의 반응 시간은 사용하는 용제, 원료 화합물, 산화제, 반응 온도 등에 따라 상이하지만, 통상 30 분 내지 6 시간이고, 바람직하게는 1 내지 2 시간이다. Although the reaction temperature of this process changes with a solvent, a raw material compound, an oxidizing agent, etc. to be used, it is usually -50-0 degreeC, Preferably it is -40-10 degreeC. Although the reaction time of this process changes with the solvent, raw material compound, oxidizing agent, reaction temperature, etc. to be used, it is 30 minutes-6 hours normally, Preferably it is 1-2 hours.

반응 종료 후, 화합물 (I)은 표준 방법에 따라 반응 혼합물로부터 단리할 수 있다. 예를 들면, 이하의 조작을 차례로 행한다: After the reaction is completed, compound (I) can be isolated from the reaction mixture according to standard methods. For example, the following operations are performed in sequence:

(조작 1) 얻어지는 반응 혼합물에 염기성 수용액(예를 들면, 알칼리 금속 수산화물의 수용액, 특히 수산화나트륨 수용액)을 첨가하고, 세차게 교반 또는 세차게 진탕 후 정치하고, 유기층을 분리하여 수층 (a)를 얻고; (Operation 1) A basic aqueous solution (for example, an aqueous solution of an alkali metal hydroxide, in particular, an aqueous sodium hydroxide solution) is added to the reaction mixture obtained, and the mixture is stirred or washed vigorously and left to stand, and the organic layer is separated to obtain an aqueous layer (a);

(조작 2) 수층 (a)에 유기 용제(예를 들면, 클로로포름, 디클로로메탄, 사염화탄소, 디클로로에탄과 같은 할로겐화 탄화수소류, 아세트산 에틸, 아세트산 메틸, 아세트산 n-부틸과 같은 유기산 에스테르류, 톨루엔과 같은 방향족 탄화수소류, 부탄올을 포함하는 알코올류 및 이들의 혼합물)를 첨가하고, 세차게 교반 또는 세차게 진탕 후 정치하고, 유기층을 분리하여 수층 (b)를 얻고; (Operation 2) In the aqueous layer (a), an organic solvent (for example, halogenated hydrocarbons such as chloroform, dichloromethane, carbon tetrachloride, dichloroethane, organic acid esters such as ethyl acetate, methyl acetate, n-butyl acetate, and toluene Aromatic hydrocarbons, alcohols including butanol and mixtures thereof) are added, and the mixture is left to stand after vigorous stirring or vigorous shaking, and the organic layer is separated to obtain an aqueous layer (b);

(조작 3) 수층 (b)에 동일한 유기 용제를 첨가하여 pH 8.0 내지 11.0의 상태로 세차게 교반 또는 세차게 진탕 후 정치하고, 분리하여 유기층 (a)와 수층 (c)를 얻고(이 때, 적절하게 완충 수용액(예를 들면, 아세트산 암모늄 수용액, 아세트산) 을 첨가할 수도 있음); (Operation 3) The same organic solvent was added to the aqueous layer (b), followed by vigorous stirring or vigorous shaking in a state of pH 8.0 to 11.0, followed by separation, to obtain an organic layer (a) and an aqueous layer (c) (at this time, Buffered aqueous solutions (eg, aqueous ammonium acetate solution, acetic acid) may be added);

(조작 4) 수층 (c)에 동일한 유기 용제를 첨가하여 세차게 교반 또는 세차게 진탕 후 정치하고, 분리하여 유기층 (b)를 얻고, 유기층 (a)와 함께 물 또는 중조수(sodium bicarbonate solution)를 더 첨가하여 세차게 교반 또는 세차게 진탕 후 정치하고, 수층을 제거하여 얻어지는 유기층 (c)를 농축한다. (Operation 4) The same organic solvent was added to the aqueous layer (c), followed by vigorous stirring or vigorous shaking, followed by standing. The mixture was separated to obtain an organic layer (b), and water or sodium bicarbonate solution was further added together with the organic layer (a). The mixture is added, stirred vigorously or shaken vigorously, then left to stand, and the organic layer (c) obtained by removing the aqueous layer is concentrated.

특히, 농축 후, 이하와 같은 유기 용제를 사용하여 결정화함으로써, 정제도가 높은 화합물 (I)을 결정으로서 제조할 수 있다: In particular, after concentration, the compound (I) having a high degree of purification can be prepared as crystals by crystallizing using the following organic solvents:

디에틸에테르, 디이소프로필에테르, t-부틸메틸에테르, 테트라히드로푸란, 디옥산, 디메톡시에탄과 같은 에테르류(특히, 디에틸에테르); Ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane and dimethoxyethane (particularly diethyl ether);

아세토니트릴과 같은 니트릴류(특히, 아세토니트릴); Nitriles such as acetonitrile (particularly acetonitrile);

벤젠, 톨루엔, 크실렌과 같은 방향족 탄화수소류(특히, 톨루엔); Aromatic hydrocarbons such as benzene, toluene and xylene (particularly toluene);

메탄올, 에탄올, 프로판올, 이소프로판올, 이소부틸알코올과 같은 알코올류(특히, 이소프로판올); Alcohols (particularly isopropanol) such as methanol, ethanol, propanol, isopropanol and isobutyl alcohol;

아세톤, 메틸에틸케톤과 같은 케톤류(특히, 아세톤); Ketones (especially acetone) such as acetone and methyl ethyl ketone;

아세트산 메틸, 아세트산 에틸, 아세트산 n-부틸, 탄산디메틸, 탄산디에틸과 같은 유기산 에스테르류(특히, 아세트산 n-부틸); 또는Organic acid esters (especially n-butyl acetate) such as methyl acetate, ethyl acetate, n-butyl acetate, dimethyl carbonate and diethyl carbonate; or

이들 용제와의 혼합 용제(특히, 니트릴류와 유기산 에스테르류의 혼합물). Mixed solvents with these solvents (in particular, a mixture of nitriles and organic acid esters).

상기 (조작 1)에서 얻어진 수층 (a), 또는 (조작 1) 및 (조작 2)에서 얻어진 수층 (b)를 농축이나 정제를 행하지 않고, 상기 제조 방법 A에 사용할 수도 있다.The aqueous layer (a) obtained in the above (Operation 1) or the aqueous layer (b) obtained in the (Operation 1) and (Operation 2) may be used in the above-mentioned production method A without performing concentration or purification.

이하, 실시예 및 참고예를 들어, 본 발명을 보다 구체적으로 설명한다. 단, 이들 기재는 예시적인 것이며, 본 발명은 어떠한 경우도 이것으로 한정되는 것이 아니다. Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples. However, these descriptions are exemplary and this invention is not limited to this in any case.

본 발명에서 사용하는 용어 「술폰체 (VI)」이란, 하기 화학식 VI으로 표시되는 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술포닐]-1H-벤즈이미다졸을 의미한다. The term "sulfone (VI)" used in the present invention is 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfonyl]-represented by the following general formula (VI)- 1H-benzimidazole.

Figure 112007010573614-pct00015
Figure 112007010573614-pct00015

하기에 있어서 사용하는 약호의 의미는 이하와 같다:The meaning of the abbreviation used below is as follows:

mcpba: 메타클로로과벤조산, mcpba: metachloroperbenzoic acid,

TLC: 박층 크로마토그래피, TLC: thin layer chromatography,

HPLC: 고속 액체 크로마토그래피.HPLC: high performance liquid chromatography.

<실시예><Example>

2-2- 클로로메틸Chloromethyl -4-(3--4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘의Methylpyridine 합성 synthesis

<참고예 1>Reference Example 1

2-히드록시메틸-4-(3-메톡시프로폭시)-3-메틸피리딘 5.0 g(23.7 mmol)을 톨 루엔 40 ㎖에 용해하고, 여기에 25 ℃를 초과하지 않도록 염화티오닐 4.23 g(35.6 mmol)을 적하하였다. 실온에서 교반한 후, TLC에 의해 원료의 소실을 확인한 후, 감압 농축함으로써 2-클로로메틸-4-(3-메톡시프로폭시)-3-메틸피리딘 6.13 g을 얻었다(수율: 97.3 ％). 5.0 g (23.7 mmol) of 2-hydroxymethyl-4- (3-methoxypropoxy) -3-methylpyridine is dissolved in 40 ml of toluene, and 4.23 g of thionyl chloride is added thereto so as not to exceed 25 ° C. 35.6 mmol) was added dropwise. After stirring at room temperature, disappearance of the raw material was confirmed by TLC, and then concentrated under reduced pressure to obtain 6.13 g of 2-chloromethyl-4- (3-methoxypropoxy) -3-methylpyridine (yield: 97.3%).

<참고예 2>Reference Example 2

2-히드록시메틸-4-(3-메톡시프로폭시)-3-메틸피리딘 5.0 g(23.7 mmol)을 아세트산 에틸 40 ㎖에 용해하고, 여기에 25 ℃를 초과하지 않도록 염화티오닐 4.23 g(35.6 mmol)을 적하하였다. 실온에서 교반한 후, TLC에 의해 원료의 소실을 확인한 후, 감압 농축함으로써 2-클로로메틸-4-(3-메톡시프로폭시)-3-메틸피리딘 6.14 g을 얻었다(수율: 97.4 ％). 5.0 g (23.7 mmol) of 2-hydroxymethyl-4- (3-methoxypropoxy) -3-methylpyridine is dissolved in 40 ml of ethyl acetate, and 4.23 g of thionyl chloride is added thereto so as not to exceed 25 deg. 35.6 mmol) was added dropwise. After stirring at room temperature, disappearance of the raw material was confirmed by TLC, and then concentrated under reduced pressure to obtain 6.14 g of 2-chloromethyl-4- (3-methoxypropoxy) -3-methylpyridine (yield: 97.4%).

<참고예 3>Reference Example 3

2-히드록시메틸-4-(3-메톡시프로폭시)-3-메틸피리딘 5.0 g(23.7 mmol)을 디메톡시에탄 40 ㎖에 용해하고, 여기에 25 ℃를 초과하지 않도록 염화티오닐 4.23 g(35.6 mmol)을 적하하였다. 실온에서 교반한 후, TLC에 의해 원료의 소실을 확인한 후, 감압 농축함으로써 2-클로로메틸-4-(3-메톡시프로폭시)-3-메틸피리딘 6.25 g을 얻었다(수율: 99.2 ％). 5.0 g (23.7 mmol) of 2-hydroxymethyl-4- (3-methoxypropoxy) -3-methylpyridine is dissolved in 40 ml of dimethoxyethane, and 4.23 g of thionyl chloride not to exceed 25 ° C. (35.6 mmol) was added dropwise. After stirring at room temperature, disappearance of the raw material was confirmed by TLC, and then concentrated under reduced pressure to obtain 6.25 g of 2-chloromethyl-4- (3-methoxypropoxy) -3-methylpyridine (yield: 99.2%).

<참고예 4>Reference Example 4

2-히드록시메틸-4-(3-메톡시프로폭시)-3-메틸피리딘 5.0 g(23.7 mmol)을 디클로로메탄 40 ㎖에 용해하고, 여기에 25 ℃를 초과하지 않도록 염화티오닐 4.23 g(35.6 mmol)을 적하하였다. 실온에서 교반한 후, TLC에 의해 원료의 소실을 확인 한 후, 감압 농축함으로써 2-클로로메틸-4-(3-메톡시프로폭시)-3-메틸피리딘 6.23 g을 얻었다(수율: 99.0 ％). 5.0 g (23.7 mmol) of 2-hydroxymethyl-4- (3-methoxypropoxy) -3-methylpyridine are dissolved in 40 ml of dichloromethane, and 4.23 g of thionyl chloride is added thereto so as not to exceed 25 ° C. 35.6 mmol) was added dropwise. After stirring at room temperature, the disappearance of the raw material was confirmed by TLC, and then concentrated under reduced pressure to obtain 6.23 g of 2-chloromethyl-4- (3-methoxypropoxy) -3-methylpyridine (yield: 99.0%) .

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸티오Methylthio ]-1H-] -1H- 벤즈이미다졸의Of benzimidazole 합성 synthesis

<참고예 5-1><Reference Example 5-1>

2-클로로메틸-4-(3-메톡시프로폭시)-3-메틸피리딘 53.2 g(200 mmol), 변성 에탄올 320 ㎖, 2-벤즈이미다졸티올 30.2 g(201 mmol), 수산화나트륨 26.8 g(670 mmol)을 첨가하여 50 ℃에서 약 2 시간 반응시켰다. TLC에 의해 원료의 소실을 확인한 후 감압 농축하고, 아세트산 에틸 430 ㎖ 및 물 340 ㎖를 첨가하여 교반 정치한 후 수층을 분리하였다. 유기층을 10 ％ 수산화나트륨 수용액 110 ㎖, 물 110 ㎖×2로 세정한 후, 감압 농축하여 조 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 69.0 g을 얻었다(HPLC 순도 98.7 ％, 수율 101 ％). 53.2 g (200 mmol) of 2-chloromethyl-4- (3-methoxypropoxy) -3-methylpyridine, 320 ml of denatured ethanol, 30.2 g (201 mmol) of 2-benzimidazolethiol, 26.8 g of sodium hydroxide ( 670 mmol) was added and reacted at 50 ° C. for about 2 hours. After confirming the disappearance of the raw material by TLC, the mixture was concentrated under reduced pressure, and 430 ml of ethyl acetate and 340 ml of water were added thereto, and the mixture was left to stir, and then the aqueous layer was separated. The organic layer was washed with 110 ml of 10% aqueous sodium hydroxide solution and 110 ml × 2 of water, and then concentrated under reduced pressure to give 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio. ] 6H of 1H-benzimidazole were obtained (HPLC purity 98.7%, yield 101%).

조 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 5.00 g을 아세트산 에틸 25 ㎖로 결정화한 후, 여과함으로써 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 4.80 g을 얻었다(HPLC 순도 99.2 ％, 수율 96.0 ％).5.00 g of crude 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was crystallized with 25 ml of ethyl acetate, and then filtered by 4.80 g of [{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was obtained (HPLC purity 99.2%, yield 96.0%).

<참고예 5-2><Reference Example 5-2>

참고예 5-1에서 얻어진 조 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 5.00 g을 tert-부틸(메틸)에테르 30 ㎖로 결정화한 후, 여과함으로써 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미 다졸 4.50 g을 얻었다(HPLC 순도 99.2 ％, 수율 90.0 ％). 5.00 g of crude 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole obtained in Reference Example 5-1 was tert-butyl (methyl) Crystallization with 30 ml of ether followed by filtration gave 4.50 g of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole (HPLC purity) 99.2%, yield 90.0%).

<참고예 5-3><Reference Example 5-3>

참고예 5-1에서 얻어진 조 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 5.00 g을 디이소프로필에테르 200 ㎖로 결정화한 후, 여과함으로써 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 4.94 g을 얻었다(HPLC 순도 99.1 ％, 수율 98.8 ％). 200 ml of diisopropyl ether 5.00 g of crude 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole obtained in Reference Example 5-1 After crystallization with water, 4.94 g of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was obtained (HPLC purity 99.1%, Yield 98.8%).

<참고예 5-4><Reference Example 5-4>

참고예 5-1에서 얻어진 조 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 5.00 g을 톨루엔 30 ㎖로 결정화한 후, 여과함으로써 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 4.56 g을 얻었다(HPLC 순도 99.1 ％, 수율 91.2 ％). 5.00 g of crude 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole obtained in Reference Example 5-1 was crystallized with 30 ml of toluene. After that, 4.56 g of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was obtained by filtration (HPLC purity 99.1%, yield 91.2%). ).

<참고예 5-5><Reference Example 5-5>

참고예 5-1에서 얻어진 조 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 5.00 g을 아세토니트릴 40 ㎖로 결정화한 후, 여과함으로써 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 4.64 g을 얻었다(HPLC 순도 99.1 ％, 수율 92.8 ％). 5.00 g of crude 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole obtained in Reference Example 5-1 was crystallized with 40 ml of acetonitrile. After that, 4.64 g of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was obtained by filtration (HPLC purity 99.1%, yield 92.8). %).

<참고예 5-6><Reference Example 5-6>

참고예 5-1에서 얻어진 조 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 5.00 g을 이소프로필알코올 20 ㎖로 결정화한 후, 여과함으로써 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 4.55 g을 얻었다(HPLC 순도 99.1 ％, 수율 91.0 ％). 5.00 g of crude 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole obtained in Reference Example 5-1 was converted into 20 ml of isopropyl alcohol. After crystallization, 4.55 g of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was obtained (HPLC purity 99.1%, yield). 91.0%).

<참고예 5-7><Reference Example 5-7>

참고예 5-1에서 얻어진 조 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 5.00 g을 아세톤 20 ㎖로 결정화한 후, 여과함으로써 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 4.80 g을 얻었다(HPLC 순도 99.2 ％, 수율 96.0 ％). 5.00 g of crude 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole obtained in Reference Example 5-1 was crystallized with 20 ml of acetone. After that, 4.80 g of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was obtained by filtration (HPLC purity 99.2%, yield 96.0%). ).

<참고예 5-8><Reference Example 5-8>

참고예 5-1에서 얻어진 조 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 5.00 g을 탄신디에틸 90 ㎖로 결정화한 후, 여과함으로써 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 4.85 g을 얻었다(HPLC 순도 99.2 ％, 수율 97.0 ％). 5.00 g of crude 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole obtained in Reference Example 5-1 was diluted with 90 ml of tancindiethyl. After crystallization, 4.85 g of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was obtained (HPLC purity 99.2%, yield). 97.0%).

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸티오Methylthio ]-1H-] -1H- 벤즈이미다졸화Benzimidazole 공정 fair

<참고예 6-1>Reference Example 6-1

2-클로로메틸-4-(3-메톡시프로폭시)-3-메틸피리딘 26.6 g(100 mmol), 변성 에탄올 160 ㎖, 2-벤즈이미다졸티올 15.0 g(100 mmol), 수산화나트륨 13.4 g(335 mmol)을 첨가하여 50 ℃에서 약 2 시간 반응시켰다. TLC에 의해 원료의 소실을 확인한 후 감압 농축하고, 톨루엔 300 ㎖ 및 물 168 ㎖를 첨가하여 교반 정치한 후 수층을 분리하였다. 유기층을 10 ％ 수산화나트륨 수용액 50 ㎖, 물 50 ㎖×2로 세정한 후, 감압 농축하여 조 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티 오]-1H-벤즈이미다졸 34.8 g을 얻었다(HPLC 순도 98.7 ％, 수율 101 ％).26.6 g (100 mmol) of 2-chloromethyl-4- (3-methoxypropoxy) -3-methylpyridine, 160 ml of denatured ethanol, 15.0 g (100 mmol) of 2-benzimidazolethiol, 13.4 g of sodium hydroxide ( 335 mmol) was added and reacted at 50 ° C. for about 2 hours. After confirming the disappearance of the raw materials by TLC, the mixture was concentrated under reduced pressure, 300 ml of toluene and 168 ml of water were added thereto, and the mixture was left still to stir and the aqueous layer was separated. The organic layer was washed with 50 ml of 10% aqueous sodium hydroxide solution and 50 ml × 2 of water, and then concentrated under reduced pressure to obtain crude 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylti 34.8 g of O] -1H-benzimidazole were obtained (HPLC purity 98.7%, yield 101%).

<참고예 6-2>Reference Example 6-2

참고예 6-1에서 얻어진 조 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 3.00 g을 아세트산 에틸 12 ㎖로 결정화한 후, 여과함으로써 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 2.91 g을 얻었다(HPLC 순도 99.3 ％, 수율 97.0 ％). Crystallize 3.00 g of crude 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole obtained in Reference Example 6-1 with 12 ml of ethyl acetate. After that, 2.91 g of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was obtained by filtration (HPLC purity 99.3%, yield 97.0). %).

<참고예 6-3>Reference Example 6-3

참고예 6-1에서 얻어진 조 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 3.00 g을 tert-부틸(메틸)에테르 12 ㎖로 결정화한 후, 여과함으로써 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 2.79 g을 얻었다(HPLC 순도 99.2 ％, 수율 93.0 ％). 3.00 g of crude 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole obtained in Reference Example 6-1 was tert-butyl (methyl) After crystallization with 12 ml of ether, 2.79 g of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was obtained by filtration (HPLC purity). 99.2%, yield 93.0%).

<참고예 6-4>Reference Example 6-4

참고예 6-1에서 얻어진 조 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 3.00 g을 톨루엔 15 ㎖로 결정화한 후, 여과함으로써 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 2.84 g을 얻었다(HPLC 순도 99.1 ％, 수율 94.5 ％). 3.00 g of crude 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole obtained in Reference Example 6-1 was crystallized with 15 ml of toluene. After that, 2.84 g of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was obtained by filtration (HPLC purity 99.1%, yield 94.5%). ).

<참고예 6-5><Reference Example 6-5>

참고예 6-1에서 얻어진 조 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 3.00 g을 아세토니트릴 21 ㎖로 결정화한 후, 여과함으로써 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 2.81 g을 얻었다(HPLC 순도 99.1 ％, 수율 93.5 ％). Crystallize 3.00 g of crude 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole obtained in Reference Example 6-1 with 21 ml of acetonitrile. Then, 2.81 g of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole were obtained by filtration (HPLC purity 99.1%, yield 93.5). %).

<참고예 6-6>Reference Example 6-6

참고예 6-1에서 얻어진 조 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 3.00 g을 디이소프로필알코올 9 ㎖로 결정화한 후, 여과함으로써 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 2.78 g을 얻었다(HPLC 순도 99.4 ％, 수율 92.5 ％). 9 ml of diisopropyl alcohol was added 3.00 g of crude 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole obtained in Reference Example 6-1. After crystallization with water, 2.78 g of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was obtained (HPLC purity 99.4%, Yield 92.5%).

<참고예 6-7>Reference Example 6-7

참고예 6-1에서 얻어진 조 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 3.00 g을 아세톤 9 ㎖로 결정화한 후, 여과함으로써 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 2.91 g을 얻었다(HPLC 순도 99.3 ％, 수율 97.0 ％). 3.00 g of crude 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole obtained in Reference Example 6-1 was crystallized with 9 ml of acetone. After that, 2.91 g of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was obtained by filtration (HPLC purity 99.3%, yield 97.0%). ).

<참고예 6-8><Reference Example 6-8>

참고예 6-1에서 얻어진 조 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 3.00 g을 탄신디에틸 45 ㎖로 결정화한 후, 여과함으로써 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 2.93 g을 얻었다(HPLC 순도 99.3 ％, 수율 97.5 ％). 3.00 g of crude 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole obtained in Reference Example 6-1 with 45 ml of tancindiethyl After crystallization, 2.93 g of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was obtained (HPLC purity 99.3%, yield). 97.5%).

또한, 참고예 5-1 내지 참고예 6-8에서의 HPLC 순도는, 이하의 조건으로 구하였다.In addition, HPLC purity in Reference Example 5-1-Reference Example 6-8 was calculated | required under the following conditions.

HPLC 조건HPLC conditions

칼럼: 이너트실(Inertsil) ODS-2(GL 사이언스사 제조)Column: Inertsil ODS-2 (made by GL Science)

이동상: 아세토니트릴:물:아세트산 암모늄=500:500:1Mobile phase: Acetonitrile: Water: Ammonium acetate = 500: 500: 1

유속: 0.7 ㎖/minFlow rate: 0.7 ml / min

칼럼 온도: 35 ℃Column temperature: 35 ℃

검출기: 258 nmDetector: 258 nm

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole 의 합성Synthesis of

<참고예 7>Reference Example 7

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 25.0 g(72.8 mmol)을 디클로로메탄에 용해한 후 냉각하고, mcpba(70.2 ％ 순도) 5.37 g(21.8 mmol)을 내온이 -15 ℃를 초과하지 않도록 조금씩 첨가하였다. 투입 후 10 ％ 수산화나트륨 수용액 70.8 ㎖를 첨가하고, 교반 정치하여 수층을 분리하였다. 분리한 수층을 디클로로메탄 48 ㎖로 2회 세정하였다. 여기에 2 N-아세트산 암모늄 수용액을 투입한 후 디클로로메탄 48 ㎖로 2회 추출하였다. 디클로로메탄층을 물 48 ㎖로 2회 세정한 후 감압 농축하고, 디클로로메탄 14 ㎖ 및 아세토니트릴 92 ㎖로 결정화하고, 여과하여 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸 6.26 g을 얻었다(HPLC 순도 99.7 ％, 수율 23.9 ％). 25.0 g (72.8 mmol) of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was dissolved in dichloromethane and cooled, followed by mcpba ( 70.2% purity) 5.37 g (21.8 mmol) were added in portions so that the internal temperature did not exceed -15 ° C. After the addition, 70.8 ml of a 10% aqueous sodium hydroxide solution was added, and the mixture was left to stir to separate an aqueous layer. The separated aqueous layer was washed twice with 48 ml of dichloromethane. 2 N-ammonium acetate aqueous solution was added thereto, and the mixture was extracted twice with 48 ml of dichloromethane. The dichloromethane layer was washed twice with 48 ml of water and then concentrated under reduced pressure, crystallized with 14 ml of dichloromethane and 92 ml of acetonitrile and filtered to give 2-[{4- (3-methoxypropoxy) -3-methyl 6.26 g of pyridin-2-yl} methylsulfinyl] -1H-benzimidazole were obtained (HPLC purity 99.7%, yield 23.9%).

<참고예 8>Reference Example 8

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 25.0 g(72.8 mmol)을 디클로로메탄에 용해한 후 냉각하고, mcpba(70.2 ％ 순도) 5.37 g(21.8 mmol)을 내온이 -15 ℃를 초과하지 않도록 조금씩 첨가하였다. 투입 후 10 ％ 수산화나트륨 수용액 70.8 ㎖를 첨가하고, 교반 정치하여 수층을 분리하였다. 분리한 수층을 디클로로메탄 48 ㎖로 2회 세정하였다. 여기에 2 N-아세트산 암모늄 수용액을 투입한 후 디클로로메탄 48 ㎖로 2회 추출하였다. 디클로로메탄층을 물 48 ㎖로 2회 세정한 후 감압 농축하고, 아세트산 에틸 66 ㎖로 결정화하고, 여과하여 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸 6.15 g을 얻었다(HPLC 순도 99.8 ％, 수율 23.5 ％). 25.0 g (72.8 mmol) of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was dissolved in dichloromethane and cooled, followed by mcpba ( 70.2% purity) 5.37 g (21.8 mmol) were added in portions so that the internal temperature did not exceed -15 ° C. After the addition, 70.8 ml of a 10% aqueous sodium hydroxide solution was added, and the mixture was left to stir to separate an aqueous layer. The separated aqueous layer was washed twice with 48 ml of dichloromethane. 2 N-ammonium acetate aqueous solution was added thereto, and the mixture was extracted twice with 48 ml of dichloromethane. The dichloromethane layer was washed twice with 48 ml of water, concentrated under reduced pressure, crystallized with 66 ml of ethyl acetate, and filtered to give 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl } 6.15 g of methylsulfinyl] -1H-benzimidazole were obtained (HPLC purity 99.8%, yield 23.5%).

<참고예 9>Reference Example 9

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 25.0 g(72.8 mmol)을 디클로로메탄에 용해한 후 냉각하고, mcpba(70.2 ％ 순도) 7.16 g(29.1 mmol)을 내온이 -15 ℃를 초과하지 않도록 조금씩 첨가하였다. 투입 후 10 ％ 수산화나트륨 수용액 70.8 ㎖를 첨가하고, 교반 정치하여 수층을 분리하였다. 분리한 수층을 디클로로메탄 48 ㎖로 2회 세정하였다. 여기에 2 N-아세트산 암모늄 수용액을 투입한 후 디클로로메탄 48 ㎖로 2회 추출하였다. 디클로로메탄층을 물 48 ㎖로 2회 세정한 후 감압 농축하고, 디클로로메탄 18 ㎖ 및 아세톤 120 ㎖로 결정화하고, 여과하여 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸 8.56 g을 얻었다(HPLC 순도 99.7 ％, 수율 32.7 ％). 25.0 g (72.8 mmol) of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was dissolved in dichloromethane and cooled, followed by mcpba ( 70.2% purity) 7.16 g (29.1 mmol) were added portionwise so that the internal temperature did not exceed -15 ° C. After the addition, 70.8 ml of a 10% aqueous sodium hydroxide solution was added, and the mixture was left to stir to separate an aqueous layer. The separated aqueous layer was washed twice with 48 ml of dichloromethane. 2 N-ammonium acetate aqueous solution was added thereto, and the mixture was extracted twice with 48 ml of dichloromethane. The dichloromethane layer was washed twice with 48 ml of water, concentrated under reduced pressure, crystallized with 18 ml of dichloromethane and 120 ml of acetone, and filtered to give 2-[{4- (3-methoxypropoxy) -3-methylpyridine. 8.56 g of 2-yl} methylsulfinyl] -1H-benzimidazole were obtained (HPLC purity 99.7%, yield 32.7%).

<참고예 10>Reference Example 10

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 25.0 g(72.8 mmol)을 디클로로메탄에 용해한 후 냉각하고, mcpba(70.2 ％ 순도) 7.16 g(29.1 mmol)을 내온이 -15 ℃를 초과하지 않도록 조금씩 첨가하였다. 투입 후 10 ％ 수산화나트륨 수용액 70.8 ㎖를 첨가하고, 교반 정치하여 수층을 분리하였다. 분리한 수층을 디클로로메탄 48 ㎖로 2회 세정하였다. 여기에 2 N-아세트산 암모늄 수용액을 투입한 후 디클로로메탄 48 ㎖로 2회 추출하였다. 디클로로메탄층을 물 48 ㎖로 2회 세정한 후 감압 농축하고, 이소프로필알코올 88 ㎖로 결정화하고, 여과하여 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸 8.29 g을 얻었다(HPLC 순도 99.7 ％, 수율 31.7 ％). 25.0 g (72.8 mmol) of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was dissolved in dichloromethane and cooled, followed by mcpba ( 70.2% purity) 7.16 g (29.1 mmol) were added portionwise so that the internal temperature did not exceed -15 ° C. After the addition, 70.8 ml of a 10% aqueous sodium hydroxide solution was added, and the mixture was left to stir to separate an aqueous layer. The separated aqueous layer was washed twice with 48 ml of dichloromethane. 2 N-ammonium acetate aqueous solution was added thereto, and the mixture was extracted twice with 48 ml of dichloromethane. The dichloromethane layer was washed twice with 48 ml of water, concentrated under reduced pressure, crystallized with 88 ml of isopropyl alcohol, filtered and filtered through 2-[{4- (3-methoxypropoxy) -3-methylpyridine-2- 8.29 g of methyl} methylsulfinyl] -1H-benzimidazoles were obtained (HPLC purity 99.7%, yield 31.7%).

<참고예 11>Reference Example 11

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 25.0 g(72.8 mmol)을 디클로로메탄에 용해한 후 냉각하고, mcpba(70.2 ％ 순도) 7.16 g(29.1 mmol)을 내온이 -15 ℃를 초과하지 않도록 조금씩 첨가하였다. 투입 후 10 ％ 수산화나트륨 수용액 70.8 ㎖를 첨가하고, 교반 정치하여 수층을 분리하였다. 분리한 수층을 디클로로메탄 48 ㎖로 2회 세정하였다. 여기에 2 N-아세트산 암모늄 수용액을 투입한 후 디클로로메탄 48 ㎖로 2회 추출하였다. 디클로로메탄층을 물 48 ㎖로 2회 세정한 후 감압 농축하고, 아세토니트릴 132 ㎖로 결정화하고, 여과하여 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸 8.25 g을 얻었다(HPLC 순도 99.7 ％, 수율 31.5 ％). 25.0 g (72.8 mmol) of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was dissolved in dichloromethane and cooled, followed by mcpba ( 70.2% purity) 7.16 g (29.1 mmol) were added portionwise so that the internal temperature did not exceed -15 ° C. After the addition, 70.8 ml of a 10% aqueous sodium hydroxide solution was added, and the mixture was left to stir to separate an aqueous layer. The separated aqueous layer was washed twice with 48 ml of dichloromethane. 2 N-ammonium acetate aqueous solution was added thereto, and the mixture was extracted twice with 48 ml of dichloromethane. The dichloromethane layer was washed twice with 48 ml of water, concentrated under reduced pressure, crystallized with 132 ml of acetonitrile and filtered to give 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl. } 7.25 g of methylsulfinyl] -1H-benzimidazole were obtained (HPLC purity 99.7%, yield 31.5%).

<참고예 12>Reference Example 12

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 25.0 g(72.8 mmol)을 디클로로메탄에 용해한 후 냉각하고, mcpba(70.2 ％ 순도) 8.95 g(36.4 mmol)을 내온이 -15 ℃를 초과하지 않도록 조금씩 첨가하였다. 투입 후 10 ％ 수산화나트륨 수용액 70.8 ㎖를 첨가하고, 교반 정치하여 수층을 분리하였다. 분리한 수층을 디클로로메탄 48 ㎖로 2회 세정하였다. 여기에 2 N-아세트산 암모늄 수용액을 투입한 후 디클로로메탄 48 ㎖로 2회 추출하였다. 디클로로메탄층을 물 48 ㎖로 2회 세정한 후 감압 농축하고, 아세톤 165 ㎖로 결정화하고, 여과하여 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸 10.8 g을 얻었다(HPLC 순도 99.6 ％, 수율 41.4 ％). 25.0 g (72.8 mmol) of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was dissolved in dichloromethane and cooled, followed by mcpba ( 70.2% purity) 8.95 g (36.4 mmol) was added portionwise so that the internal temperature did not exceed -15 ° C. After the addition, 70.8 ml of a 10% aqueous sodium hydroxide solution was added, and the mixture was left to stir to separate an aqueous layer. The separated aqueous layer was washed twice with 48 ml of dichloromethane. 2 N-ammonium acetate aqueous solution was added thereto, and the mixture was extracted twice with 48 ml of dichloromethane. The dichloromethane layer was washed twice with 48 ml of water, concentrated under reduced pressure, crystallized with 165 ml of acetone, and filtered to give 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl}. 10.8 g of methylsulfinyl] -1H-benzimidazole was obtained (HPLC purity 99.6%, yield 41.4%).

<참고예 13>Reference Example 13

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 25.0 g(72.8 mmol)을 디클로로메탄에 용해한 후 냉각하고, mcpba(70.2 ％ 순도) 8.95 g(36.4 mmol)을 내온이 -15 ℃를 초과하지 않도록 조금씩 첨가하였다. 투입 후 10 ％ 수산화나트륨 수용액 70.8 ㎖를 첨가하고, 교반 정치하여 수층을 분리하였다. 분리한 수층을 디클로로메탄 48 ㎖로 2회 세정하였다. 여기에 2 N-아세트산 암모늄 수용액을 투입한 후 디클로로메탄 48 ㎖로 2회 추출하였다. 디클로로메탄층을 물 48 ㎖로 2회 세정한 후 감압 농축하고, 톨루엔 110 ㎖로 결정화하고, 여과하여 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸 10.6 g을 얻었다(HPLC 순도 99.6 ％, 수율 40.4 ％). 25.0 g (72.8 mmol) of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was dissolved in dichloromethane and cooled, followed by mcpba ( 70.2% purity) 8.95 g (36.4 mmol) was added portionwise so that the internal temperature did not exceed -15 ° C. After the addition, 70.8 ml of a 10% aqueous sodium hydroxide solution was added, and the mixture was left to stir to separate an aqueous layer. The separated aqueous layer was washed twice with 48 ml of dichloromethane. 2 N-ammonium acetate aqueous solution was added thereto, and the mixture was extracted twice with 48 ml of dichloromethane. The dichloromethane layer was washed twice with 48 ml of water, then concentrated under reduced pressure, crystallized with 110 ml of toluene, and filtered to give 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} 10.6 g of methylsulfinyl] -1H-benzimidazole were obtained (HPLC purity 99.6%, yield 40.4%).

<참고예 14>Reference Example 14

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 25.0 g(72.8 mmol)을 디클로로메탄에 용해한 후 냉각하고, mcpba(70.2 ％ 순도) 8.95 g(36.4 mmol)을 내온이 -15 ℃를 초과하지 않도록 조금씩 첨가하였다. 투입 후 10 ％ 수산화나트륨 수용액 70.8 ㎖를 첨가하고, 교반 정치하여 수층을 분리하였다. 분리한 수층을 디클로로메탄 48 ㎖로 2회 세정하였다. 여기에 2 N-아세트산 암모늄 수용액을 투입한 후 디클로로메탄 48 ㎖로 2회 추출하였다. 디클로로메탄층을 물 48 ㎖로 2회 세정한 후 감압 농축하고, 디클로로메탄 28 ㎖ 및 아세트산 에틸 184 ㎖로 결정화하고, 여과하여 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸 10.9 g을 얻었다(HPLC 순도 99.7 ％, 수율 41.7％). 25.0 g (72.8 mmol) of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was dissolved in dichloromethane and cooled, followed by mcpba ( 70.2% purity) 8.95 g (36.4 mmol) was added portionwise so that the internal temperature did not exceed -15 ° C. After the addition, 70.8 ml of a 10% aqueous sodium hydroxide solution was added, and the mixture was left to stir to separate an aqueous layer. The separated aqueous layer was washed twice with 48 ml of dichloromethane. 2 N-ammonium acetate aqueous solution was added thereto, and the mixture was extracted twice with 48 ml of dichloromethane. The dichloromethane layer was washed twice with 48 ml of water and then concentrated under reduced pressure, crystallized with 28 ml of dichloromethane and 184 ml of ethyl acetate, and filtered to give 2-[{4- (3-methoxypropoxy) -3-methyl 10.9 g of pyridin-2-yl} methylsulfinyl] -1H-benzimidazole was obtained (HPLC purity 99.7%, yield 41.7%).

<참고예 15>Reference Example 15

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 25.0 g(72.8 mmol)을 디클로로메탄에 용해한 후 냉각하고, mcpba(70.2 ％ 순도) 10.7 g(43.7 mmol)을 내온이 -15 ℃를 초과하지 않도록 조금씩 첨가하였다. 투입 후 10 ％ 수산화나트륨 수용액 70.8 ㎖를 첨가하고, 교반 정치하여 수층을 분리하였다. 분리한 수층을 디클로로메탄 48 ㎖로 2회 세정하였다. 여기에 2 N-아세트산 암모늄 수용액을 투입한 후 디클로로메탄 48 ㎖로 2회 추출하였다. 디클로로메탄층을 물 48 ㎖로 2회 세정한 후 감압 농축하고, 아세톤 198 ㎖로 결정화하고, 여과하여 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸 12.6 g을 얻었다(HPLC 순도 99.3 ％, 수율 48.3 ％). 25.0 g (72.8 mmol) of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was dissolved in dichloromethane and cooled, followed by mcpba ( 70.2% purity) 10.7 g (43.7 mmol) was added little by little so that internal temperature did not exceed -15 degreeC. After the addition, 70.8 ml of a 10% aqueous sodium hydroxide solution was added, and the mixture was left to stir to separate an aqueous layer. The separated aqueous layer was washed twice with 48 ml of dichloromethane. 2 N-ammonium acetate aqueous solution was added thereto, and the mixture was extracted twice with 48 ml of dichloromethane. The dichloromethane layer was washed twice with 48 ml of water, concentrated under reduced pressure, crystallized with 198 ml of acetone, and filtered to give 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl}. 12.6 g of methylsulfinyl] -1H-benzimidazole were obtained (HPLC purity 99.3%, yield 48.3%).

<참고예 16>Reference Example 16

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 25.0 g(72.8 mmol)을 디클로로메탄에 용해한 후 냉각하고, mcpba(70.2 ％ 순도) 10.7 g(43.7 mmol)을 내온이 -15 ℃를 초과하지 않도록 조금씩 첨가하였다. 투입 후 10 ％ 수산화나트륨 수용액 70.8 ㎖를 첨가하고, 교반 정치하여 수층을 분리하였다. 분리한 수층을 디클로로메탄 48 ㎖로 2회 세정하였다. 여기에 2 N-아세트산 암모늄 수용액을 투입한 후 디클로로메탄 48 ㎖로 2회 추출하였다. 디클로로메탄층을 물 48 ㎖로 2회 세정한 후 감압 농축하고, 디클로로메탄 27 ㎖ 및 에테르 220 ㎖로 결정화하고, 여과하여 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸 14.5 g을 얻었다(HPLC 순도 99.1 ％, 수율 55.4 ％). 25.0 g (72.8 mmol) of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was dissolved in dichloromethane and cooled, followed by mcpba ( 70.2% purity) 10.7 g (43.7 mmol) was added little by little so that internal temperature did not exceed -15 degreeC. After the addition, 70.8 ml of a 10% aqueous sodium hydroxide solution was added, and the mixture was left to stir to separate an aqueous layer. The separated aqueous layer was washed twice with 48 ml of dichloromethane. 2 N-ammonium acetate aqueous solution was added thereto, and the mixture was extracted twice with 48 ml of dichloromethane. The dichloromethane layer was washed twice with 48 ml of water and then concentrated under reduced pressure, crystallized from 27 ml of dichloromethane and 220 ml of ether, filtered and filtered to 2-[{4- (3-methoxypropoxy) -3-methylpyridine 14.5 g of 2-yl} methylsulfinyl] -1H-benzimidazole were obtained (HPLC purity 99.1%, yield 55.4%).

<참고예 17>Reference Example 17

2-히드록시메틸-4-(3-메톡시프로폭시)-3-메틸피리딘 12.02 g(56.9 mmol) 및 톨루엔 96.0 ㎖의 혼합 용액에 25 ℃(내온)을 초과하지 않도록 염화티오닐 8.11 g(68.2 mmol)을 적하하여 실온에서 약 90 분간 교반하였다. 이 혼합 용액에 에탄올 24.0 ㎖를 첨가하여 2-클로로메틸-4-(3-메톡시프로폭시)-3-메틸피리딘 용액을 얻었다. 8.11 g of thionyl chloride in a mixed solution of 12.02 g (56.9 mmol) of 2-hydroxymethyl-4- (3-methoxypropoxy) -3-methylpyridine and 96.0 ml of toluene so as not to exceed 25 ° C (temperature) 68.2 mmol) was added dropwise and stirred at room temperature for about 90 minutes. 24.0 mL of ethanol was added to this mixed solution to obtain a 2-chloromethyl-4- (3-methoxypropoxy) -3-methylpyridine solution.

이 2-클로로메틸-4-(3-메톡시프로폭시)-3-메틸피리딘 용액에, 실온하에서 2-벤즈이미다졸티올 8.71 g(58.0 mmol)을 첨가하고, 이어서 온도(내온)를 65 ℃로 서서히 올리면서 25 ％ 수산화나트륨 수용액 40.6 g을 조금씩 첨가하였다. 반응 혼합물을 65 ℃(내온)에서 약 1 시간 30 분 교반하였다. 반응 혼합물 중에 65 ℃에서 물 60.0 ㎖를 첨가하고, 이어서 25 ％ 수산화나트륨 수용액 0.2 g을 첨가하여 교반하였다. 이 반응 혼합물을 정치하고, 수층을 분리하였다. 유기층을 물 20.0 ㎖로 2회 세정하고, 유기층에 톨루엔 79.6 ㎖, 메탄올 21.5 ㎖를 첨가하여 2-[{4- (3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 용액을 얻었다. To this 2-chloromethyl-4- (3-methoxypropoxy) -3-methylpyridine solution, 8.71 g (58.0 mmol) of 2-benzimidazole thiol was added at room temperature, and then the temperature (internal temperature) was 65 ° C. 40.6 g of 25% sodium hydroxide aqueous solution was added little by little while raising gradually. The reaction mixture was stirred at 65 ° C. (internal temperature) for about 1 hour 30 minutes. 60.0 mL of water was added to the reaction mixture at 65 ° C, and then 0.2 g of 25% aqueous sodium hydroxide solution was added and stirred. The reaction mixture was left to stand and the aqueous layer was separated. The organic layer was washed twice with 20.0 ml of water, and 79.6 ml of toluene and 21.5 ml of methanol were added to the organic layer to give 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio]. A -1H-benzimidazole solution was obtained.

이 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸티오]-1H-벤즈이미다졸 용액을 -30 ℃(외온)로 냉각하고, mcpba(70.2 ％ 순도) 14.39 g(58.5 mmol), 메탄올 12.4 ㎖ 및 톨루엔 10.5 ㎖의 용액을 내온이 -25 ℃를 초과하지 않도록 약 1 시간에 걸쳐 첨가하고, 1 시간 30 분 더 교반하였다. 반응 혼합물에 25 ％ 수산화나트륨 수용액 22.73 g, 물 17.6 ㎖를 첨가하여 교반하였다. 이 반응 혼합물을 정치하고, 유기층을 분리하여 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸을 포함하는 알칼리 수용액을 얻었다. This 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylthio] -1H-benzimidazole solution was cooled to -30 deg. C (outer temperature), and mcpba (70.2% Purity) A solution of 14.39 g (58.5 mmol), 12.4 ml of methanol and 10.5 ml of toluene was added over about 1 hour so that the internal temperature did not exceed -25 ° C, and stirred for another 1 hour 30 minutes. 22.73 g of 25% aqueous sodium hydroxide solution and 17.6 ml of water were added to the reaction mixture, followed by stirring. The reaction mixture is left to stand, and the organic layer is separated to give an aqueous alkaline solution containing 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole. Got.

또한, 참고예 7 내지 참고예 16에서의 HPLC 순도는, 이하의 조건으로 구하였다.In addition, HPLC purity in Reference Examples 7 to 16 was determined under the following conditions.

HPLC 조건HPLC conditions

칼럼: 뉴클레오실(Nucleosil)5c18(켐코사 제조)Column: Nucleosil 5c18 (manufactured by Chemco)

이동상: 메탄올:인산 완충액(pH 7)=3:2Mobile phase: methanol: phosphate buffer (pH 7) = 3: 2

유속: 1.0 ㎖/minFlow rate: 1.0 ml / min

검출기: 290 nmDetector: 290 nm

실시예 1-1 내지 3-1에서의 출발 원료로서 사용하는 화합물 (VII)은, 상기 특허 문헌 1에 기재된 방법 또는 해당 방법의 공지된 개량 방법(예를 들면, 일본 특허 공개 (평)11-71370호, 일본 특허 공개 (평)2000-143659호, 국제 특허 공개 공보 WO01/68594호, 유럽 특허 공개 EP1,2705,55호 등)에 의해 제조할 수 있는, 술폰체 (VI)을 1.61 ％ 포함하고 있는 것, 1.44 ％ 포함하고 있는 것, 0.57 ％ 포함하 고 있는 것, 0.56 ％ 포함하고 있는 것 또는 0.45 ％ 포함하고 있는 것을 사용하였다.Compound (VII) to be used as a starting material in Examples 1-1 to 3-1 is a method described in Patent Document 1 or a known improved method (for example, Japanese Patent Laid-Open No. 11-). 71370, Japanese Patent Laid-Open No. 2000-143659, International Patent Publication No. WO01 / 68594, European Patent Publication No. EP1,2705,55 and the like) include 1.61% of a sulfone body (VI). What contained, what contained 1.44%, what contained 0.57%, what contained 0.56%, or what contained 0.45% was used.

<실시예 1-1><Example 1-1>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole 과 and 이소프로필아민과의With isopropylamine 염의 합성 Synthesis of Salts

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸(3.00 g, 8.35 mmol, 술폰체 (VI) 1.44 ％ 함유)에 아세토니트릴(30 ㎖)을 첨가하여 55 ℃(외온)에서 용해하고, 용해 후 이소프로필아민(4.97 ㎖, 58.4 mmol)을 첨가하였다. 이 혼합액을 30 ℃(외온)로 냉각하고, 그 후 헥산(15 ㎖) 및 미량의 종결정(2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 이소프로필아민과의 염의 결정)을 첨가하여 약 2시간 교반하였다. 이어서, 이 혼합액을 -25 ℃(외온)로 냉각하고, 하룻밤 교반하였다. 혼합액 중에 석출된 결정을 여과하여 -30 ℃에서 냉각한 아세토니트릴(10 ㎖)로 세정하고, 실온하에 감압 건조하여 표기 화합물의 백색 결정 3.30 g(7.88 mmol, 수율 94.5 ％, 술폰체 (VI) 0.02 ％ 함유)을 얻었다. 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole (3.00 g, 8.35 mmol, containing 1.44% of sulfone (VI)) Acetonitrile (30 mL) was added to the resulting solution, which was dissolved at 55 DEG C (outer temperature). After dissolution, isopropylamine (4.97 mL, 58.4 mmol) was added. The mixture was cooled to 30 ° C. (external temperature), and then hexane (15 mL) and a small amount of seed crystals (2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methyl Sulfinyl] -1H-crystals of benzimidazole and isopropylamine) was added and stirred for about 2 hours. Subsequently, this mixed solution was cooled to -25 ° C (outer temperature) and stirred overnight. The precipitated crystals in the mixed solution were filtered, washed with acetonitrile (10 ml) cooled at -30 ° C, dried under reduced pressure at room temperature, and 3.30 g (7.88 mmol, yield 94.5%) of the title compound was obtained. % Content) was obtained.

Figure 112007010573614-pct00016
Figure 112007010573614-pct00016

또한, 술폰체 (VI)의 함량은 이하의 조건의 HPLC(고속 액체 크로마토그래피) 분석으로부터 측정하였다.In addition, the content of sulfone (VI) was measured from HPLC (high speed liquid chromatography) analysis under the following conditions.

[HPLC 분석 조건][HPLC Analysis Conditions]

칼럼; YMC-Pack Pro C18 AS-303 250 mm×4.6 mm I.D.column; YMC-Pack Pro C18 AS-303 250 mm x 4.6 mm I.D.

이동상; MeOH/H2O/AcONH4=550 ㎖/450 ㎖/2 gMobile phase; MeOH / H 2 O / AcONH 4 = 550 mL / 450 mL / 2 g

유속; 1.0 ㎖/minFlow rate; 1.0 ml / min

검출기; UV 290 nm, 칼럼 온도; 35 ℃Detectors; UV 290 nm, column temperature; 35 ℃

<실시예 1-2><Example 1-2>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole 과 and 이소프로필아민과의With isopropylamine 염의 합성 Synthesis of Salts

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸(3.00 g, 8.35 mmol, 술폰체 (VI) 0.56 ％ 함유)에 아세트산 에틸(45 ㎖)을 첨가하여 55 ℃(외온)에서 용해하고, 용해 후 이소프로필아민(4.97 ㎖, 58.4 mmol)을 첨가하였다. 이 혼합액을 서냉하고, 실온에서 약 7 시간 교반하였다. 혼합액 중에 석출된 결정을 여과하여 아세트산 에틸(20 ㎖)로 세정하고, 실온하에 감압 건조하여 표기 화합물의 백색 결정 2.63 g(6.28 mmol, 수율 75.3 ％, 술폰체 (VI) 0.17 ％ 함유)을 얻었다. 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole (3.00 g, 8.35 mmol, containing 0.56% of sulfone (VI)) Ethyl acetate (45 mL) was added to the resulting solution, which was dissolved at 55 ° C. (external temperature). After dissolution, isopropylamine (4.97 mL, 58.4 mmol) was added thereto. This liquid mixture was slow cooled and stirred at room temperature for about 7 hours. The precipitated crystals in the mixed solution were filtered, washed with ethyl acetate (20 mL), and dried under reduced pressure at room temperature to obtain 2.63 g (6.28 mmol, yield 75.3%, and sulfonate (VI) 0.17%) of white crystals of the title compound.

얻어진 염은 NMR 데이타로부터 실시예 1-1과 동일한 것임을 확인하고, 술폰체의 함량에 대해서는 실시예 1-1과 동일한 조건으로 확인하였다. The obtained salt was confirmed to be the same as in Example 1-1 from the NMR data, and the content of sulfone was confirmed under the same conditions as in Example 1-1.

<실시예 1-3><Example 1-3>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole 과 and 이소프로필아민과의With isopropylamine 염의 합성 Synthesis of Salts

원료로서 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸(3.00 g, 8.35 mmol, 술폰체 (VI) 0.57 ％ 함유)을 사용하고, 용매로서 아세트산 에틸(45 ㎖) 대신에 테트라히드로푸란(15 ㎖)을 사용하고, 결정 세정에 있어서 아세트산 에틸(20 ㎖) 대신에 테트라히드로푸란(10 ㎖)을 사용하였다.As a raw material, 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole (3.00 g, 8.35 mmol, sulfone (VI) 0.57% Tetrahydrofuran (15 mL) was used instead of ethyl acetate (45 mL) as a solvent, and tetrahydrofuran (10 mL) was used instead of ethyl acetate (20 mL) in crystal washing.

그 밖에는 실시예 1-2의 방법과 동일하게 행하여 표기 화합물의 백색 결정 2.64 g(6.31 mmol, 수율 75.6 ％, 술폰체 (VI) 0.02 ％ 미만 함유)을 얻었다. Others were carried out similarly to the method of Example 1-2, and obtained 2.64 g (6.31 mmol, 75.6% of yield, less than 0.02% of sulfone bodies (VI)) of the title compound.

얻어진 염은 NMR 데이타로부터 실시예 1-1과 동일한 것임을 확인하고, 술폰체의 함량에 대해서는 실시예 1-1과 동일한 조건으로 확인하였다. The obtained salt was confirmed to be the same as in Example 1-1 from the NMR data, and the content of sulfone was confirmed under the same conditions as in Example 1-1.

<실시예 1-4><Example 1-4>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole 과 and 이소프로필아민과의With isopropylamine 염의 합성 Synthesis of Salts

원료로서 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸(3.00 g, 8.35 mmol, 술폰체 (VI) 1.44 ％ 함유)을 사용하고, 용매로서 아세트산 에틸(45 ㎖) 대신에 아세토니트릴(30 ㎖)을 사용하여 아민 첨가 후의 하룻밤 교반을 0 ℃(외온)에서 행하였다. As a raw material, 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole (3.00 g, 8.35 mmol, sulfonate (VI) 1.44% Containing) and acetonitrile (30 mL) instead of ethyl acetate (45 mL) as a solvent, and stirring overnight after amine addition was performed at 0 degreeC (outer temperature).

그 밖에는 실시예 1-2의 방법과 동일하게 행하여 표기 화합물의 백색 결정 2.90 g(6.93 mmol, 수율 83.0 ％, 술폰체 (VI) 0.02 ％ 미만 함유)을 얻었다. Others were carried out similarly to the method of Example 1-2, and obtained 2.90 g (6.93 mmol, 83.0% of yield, less than 0.02% of sulfone bodies (VI)) of the title compound in the same way.

얻어진 염은 NMR 데이타로부터 실시예 1-1과 동일한 것임을 확인하고, 술폰 체의 함량에 대해서는 실시예 1-1과 동일한 조건으로 확인하였다. The obtained salt was confirmed to be the same as in Example 1-1 from the NMR data, and the content of sulfone was confirmed under the same conditions as in Example 1-1.

<실시예 1-5><Example 1-5>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole 과 and 이소프로필아민과의With isopropylamine 염의 합성 Synthesis of Salts

원료로서 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸(3.00 g, 8.35 mmol, 술폰체 (VI) 1.44 ％ 함유)을 사용하고, 헥산(15 ㎖) 대신에 t-부틸메틸에테르(9 ㎖)를 사용하여 아민 첨가 후의 하룻밤 교반을 0 ℃(외온)에서 행하였다. As a raw material, 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole (3.00 g, 8.35 mmol, sulfonate (VI) 1.44% Containing), and t-butyl methyl ether (9 ml) was used instead of hexane (15 ml), and stirring overnight after amine addition was performed at 0 degreeC (outer temperature).

그 밖에는 실시예 1-1의 방법과 동일하게 행하여 표기 화합물의 백색 결정 2.89 g(6.91 mmol, 수율 82.7 ％, 술폰체 (VI) 0.02 ％ 미만 함유)을 얻었다. Others were carried out similarly to the method of Example 1-1, and obtained 2.89 g (6.91 mmol, yield 82.7%, containing less than 0.02% of sulfone bodies (VI)) of the title compound.

얻어진 염은 NMR 데이타로부터 실시예 1-1과 동일한 것임을 확인하고, 술폰체 (VI)의 함량에 대해서는 실시예 1-1과 동일한 조건으로 확인하였다. The obtained salt was confirmed to be the same as in Example 1-1 from the NMR data, and the content of sulfone body (VI) was confirmed under the same conditions as in Example 1-1.

<실시예 1-6><Example 1-6>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole 과 and 이소프로필아민과의With isopropylamine 염의 합성 Synthesis of Salts

원료로서 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸(3.00 g, 8.35 mmol, 술폰체 (VI) 1.44 ％ 함유)을 사용하여 아민 첨가 후의 하룻밤 교반을 0 ℃(외온)에서 행하고, 그 밖에는 실시예 1-1의 방법과 동일하게 행하여 표기 화합물의 백색 결정 3.17 g(7.57 mmol, 수율 90.6 ％, 술폰체 (VI) 0.02 ％ 미만 함유)을 얻었다. As a raw material, 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole (3.00 g, 8.35 mmol, sulfonate (VI) 1.44% Containing) and stirring overnight after addition of an amine at 0 ° C. (external temperature), and otherwise in the same manner as in Example 1-1, except that 3.17 g (7.57 mmol, 90.6% of a yield) of the title compound was used. VI) containing less than 0.02%).

<실시예 1-7><Example 1-7>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole 과 and 이소프로필아민과의With isopropylamine 염의 합성 Synthesis of Salts

원료로서 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸(3.01 g, 8.37 mmol, 술폰체 (VI) 1.44 ％ 함유)을 사용하고, 이소프로필아민의 사용량을 (4.97 ㎖, 58.4 mmol)로부터 (2.13 ㎖, 25.0 mmol)로 변경하였다.As a raw material, 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole (3.01 g, 8.37 mmol, sulfone (VI) 1.44% Containing), and the amount of isopropylamine used was changed from (4.97 mL, 58.4 mmol) to (2.13 mL, 25.0 mmol).

또한, 헥산의 사용량을 15 ㎖로부터 9 ㎖로 변경하였다. 아민 첨가 후의 하룻밤 교반을 0 ℃(외온)에서 행하고, 그 밖에는 실시예 1-1의 방법과 동일하게 행하여 표기 화합물의 백색 결정 3.16 g(7.55 mmol, 수율 90.2 ％, 술폰체 (VI) 0.03 ％ 함유)을 얻었다. In addition, the usage-amount of hexane was changed into 15 ml from 15 ml. Stirring overnight after amine addition was performed at 0 degreeC (outer temperature), and it carried out similarly to the method of Example 1-1, and contains 3.16 g (7.55 mmol, 90.2% of yield, 90.2% of sulfonates (VI)) of the title compound, and 0.03% of sulfone (VI) )

얻어진 염은 NMR 데이타로부터 실시예 1-1과 동일한 것임을 확인하고, 술폰체의 함량에 대해서는 실시예 1-1과 동일한 조건으로 확인하였다. The obtained salt was confirmed to be the same as in Example 1-1 from the NMR data, and the content of sulfone was confirmed under the same conditions as in Example 1-1.

<실시예 1-8><Example 1-8>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole 과 and 이소프로필아민과의With isopropylamine 염의 합성 Synthesis of Salts

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸(3.00 g, 8.35 mmol, 술폰체 (VI) 1.44 ％ 함유)을 아세토니트릴 28.1 ㎖ 및 이소프로필아민 5.0 ㎖에 30 ℃에서 용해하고, 용해 후 아세트산 n-부틸에스테르 23.0 ㎖ 및 미량의 종결정(2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 이소프로필아민과의 염의 결정)을 첨가하여 1 시간 교반한 후, -25 ℃까지 냉각하여 하룻밤 교반하였다. 석출된 결정을 여과하여 -25 ℃(외온)에서 냉각한 아세토니트릴 5 ㎖로 세정하고, 실온에서 감압 건조하여 표기 화합물의 백색 결정 3.46 g(수율 93.7 ％, 술폰체 (VI) 0.02 ％ 미만 함유)을 얻었다. 술폰체의 함량에 대해서는 실시예 1-1과 동일한 조건으로 확인하였다. 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole (3.00 g, 8.35 mmol, containing 1.44% of sulfone (VI)) Was dissolved in 28.1 ml of acetonitrile and 5.0 ml of isopropylamine at 30 ° C., and after dissolution, 23.0 ml of acetic acid n-butyl ester and a small amount of seed crystals (2-[{4- (3-methoxypropoxy) -3- Methylpyridin-2-yl} methylsulfinyl] -1H-crystal of salt of benzimidazole and isopropylamine) was added and stirred for 1 hour, then cooled to -25 ° C and stirred overnight. The precipitated crystals were filtered off, washed with 5 ml of acetonitrile cooled at -25 ° C (outer temperature), dried under reduced pressure at room temperature, and 3.46 g of white crystals of the title compound (yield 93.7%, containing less than 0.02% of sulfone (VI)). Got. The content of the sulfone was confirmed under the same conditions as in Example 1-1.

Figure 112007010573614-pct00017
Figure 112007010573614-pct00017

<실시예 2-1><Example 2-1>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole 과 and 시클로펜틸아민과의With cyclopentylamine 염의 합성 Synthesis of Salts

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸(3.00 g, 8.35 mmol, 술폰체 (VI) 0.57 ％ 함유)에 톨루엔(60 ㎖)을 첨가하여 55 ℃에서 용해하고, 용해 후 시클로펜틸아민(5.76 ㎖, 58.4 mmol)을 첨가하였다. 이 혼합액을 -10 ℃(외온)에서 냉각하여 하룻밤 교반하였다. 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole (3.00 g, 8.35 mmol, containing 0.57% of sulfone (VI)) Toluene (60 mL) was added thereto and dissolved at 55 ° C. After dissolution, cyclopentylamine (5.76 mL, 58.4 mmol) was added thereto. The mixture was cooled at -10 deg. C (outer temperature) and stirred overnight.

혼합액 중에 석출된 결정을 여과하여 -30 ℃에서 냉각한 톨루엔(10 ㎖)으로 세정하고, 실온하에 감압 건조하여 표기 화합물의 백색 결정 2.97 g(6.68 mmol, 수율 80.0 ％, 술폰체 (VI) 0.06 ％ 함유)을 얻었다. 술폰체의 함량에 대해서는 실시예 1-1과 동일한 조건으로 확인하였다. The precipitated crystals in the mixed solution were filtered, washed with toluene (10 ml) cooled at -30 ° C, dried under reduced pressure at room temperature to give 2.97 g (6.68 mmol, 80.0% yield) of the title compound, and 0.06% sulfonate (VI). Containing). The content of the sulfone was confirmed under the same conditions as in Example 1-1.

Figure 112007010573614-pct00018
Figure 112007010573614-pct00018

<실시예 2-2><Example 2-2>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole 과 and 시클로펜틸아민과의With cyclopentylamine 염의 합성 Synthesis of Salts

원료로서 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸(3.01 g, 8.37 mmol, 술폰체 (VI) 0.57 ％ 함유)을 사용하고, 용매로서 톨루엔(60 ㎖) 대신에 아세트산 에틸(45 ㎖)를 사용하여 아민 첨가 후의 하룻밤 교반을-40 ℃(외온)에서 행하였다.As a raw material, 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole (3.01 g, 8.37 mmol, sulfone (VI) 0.57% Containing), and ethyl acetate (45 mL) was used instead of toluene (60 mL) as a solvent, and the stirring after amine addition was performed at -40 degreeC (outer temperature) overnight.

그 밖에는 실시예 2-1의 방법과 동일하게 행하여 표기 화합물의 백색 결정 3.21 g(7.22 mmol, 수율 86.4 ％, 술폰체 (VI) 0.26 ％ 함유)을 얻었다. Others were carried out similarly to the method of Example 2-1, and 3.21 g (7.22 mmol, yield 86.4%, containing 0.26% of sulfone bodies (VI)) of the title compound were obtained.

얻어진 염은 NMR 데이타로부터 실시예 2-1과 동일한 것임을 확인하고, 술폰체의 함량에 대해서는 실시예 1-1과 동일한 조건으로 확인하였다. The obtained salt was confirmed to be the same as in Example 2-1 from the NMR data, and the content of sulfone was confirmed under the same conditions as in Example 1-1.

<실시예 2-3><Example 2-3>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole 과 and 시클로펜틸아민과의With cyclopentylamine 염의 합성 Synthesis of Salts

원료로서 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸(3.00 g, 8.35 mmol, 술폰체 (VI) 0.57 ％ 함유)을 사용하고, 용매로서 톨 루엔(60 ㎖) 대신에 이소프로판올(21 ㎖)을 사용하여 아민 첨가 후의 하룻밤 교반을 -40 ℃(외온)에서 행하였다. As a raw material, 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole (3.00 g, 8.35 mmol, sulfone (VI) 0.57% Containing), and isopropanol (21 ml) was used instead of toluene (60 ml) as a solvent, and stirring overnight after amine addition was performed at -40 degreeC (outer temperature).

그 밖에는 실시예 2-1의 방법과 동일하게 행하여 표기 화합물의 백색 결정 3.30 g(7.42 mmol, 수율 88.9 ％, 술폰체 (VI) 0.26 ％ 함유)을 얻었다. Others were carried out similarly to the method of Example 2-1 to obtain 3.30 g (7.42 mmol, yield 88.9%, sulfonate (VI) containing 0.26%) of white crystals of the title compound.

얻어진 염은 NMR 데이타로부터 실시예 2-1과 동일한 것임을 확인하고, 술폰체의 함량에 대해서는 실시예 1-1과 동일한 조건으로 확인하였다. The obtained salt was confirmed to be the same as in Example 2-1 from the NMR data, and the content of sulfone was confirmed under the same conditions as in Example 1-1.

<실시예 2-4><Example 2-4>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole 과 and 시클로펜틸아민과의With cyclopentylamine 염의 합성 Synthesis of Salts

원료로서 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸(3.00 g, 8.35 mmol, 술폰체 (VI) 0.45 ％ 함유)을 아세토니트릴 28.1 ㎖ 및 시클로펜틸아민 5.7 ㎖에 용해하고, 아세트산 n-부틸에스테르 23.0 ㎖를 첨가하여 10 ℃로 냉각한 후, 미량의 종결정(2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 시클로펜틸아민과의 염의 결정)을 첨가하여 1 시간 교반한 후, -25 ℃까지 냉각하여 하룻밤 교반하였다. 석출된 결정을 여과하여 -25 ℃(외온)에서 냉각한 아세토니트릴 5 ㎖로 세정하고, 실온에서 감압 건조하여 표기 화합물의 백색 결정 3.35 g(수율 90.3 ％, 술폰체 (VI) 0.06 ％ 함유)을 얻었다. 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole (3.00 g, 8.35 mmol, sulfonate (VI) 0.45% as a starting material ) Was dissolved in 28.1 ml of acetonitrile and 5.7 ml of cyclopentylamine, and 23.0 ml of acetic acid n-butyl ester was added and cooled to 10 ° C., followed by trace seed crystals (2-[{4- (3-methoxy). Propoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-crystals of benzimidazole and cyclopentylamine) was added thereto, stirred for 1 hour, cooled to -25 ° C and stirred overnight. . The precipitated crystals were filtered off, washed with 5 ml of acetonitrile cooled at -25 ° C (outer temperature), and dried under reduced pressure at room temperature to yield 3.35 g of a white crystal of the title compound (yield 90.3%, sulfonate (VI) containing 0.06%). Got it.

얻어진 염은 NMR 데이타로부터 실시예 2-1과 동일한 것임을 확인하고, 술폰체의 함량에 대해서는 실시예 1-1과 동일한 조건으로 확인하였다. The obtained salt was confirmed to be the same as in Example 2-1 from the NMR data, and the content of sulfone was confirmed under the same conditions as in Example 1-1.

<실시예 3-1><Example 3-1>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole 과 and secsec -- 부틸아민과의With butylamine 염의 합성 Synthesis of Salts

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸(3.00 g, 8.35 mmol, 술폰체 (VI) 0.57 ％ 함유)에 아세트산 에틸(45 ㎖)을 첨가하여 55 ℃에서 용해하고, 용해 후 sec-부틸아민(5.90 ㎖, 58.4 mmol)을 첨가하였다. 이 혼합액을 -40 ℃(외온)에서 냉각하여 하룻밤 교반하였다. 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole (3.00 g, 8.35 mmol, containing 0.57% of sulfone (VI)) Ethyl acetate (45 mL) was added to the resulting solution, which was dissolved at 55 ° C. After dissolution, sec-butylamine (5.90 mL, 58.4 mmol) was added thereto. The mixture was cooled at -40 ° C (external temperature) and stirred overnight.

혼합액 중에 석출된 결정을 여과하여 -30 ℃에서 냉각한 아세트산 에틸(10 ㎖)로 세정하고, 실온하에 감압 건조하여 표기 화합물의 백색 결정 3.14 g(7.26 mmol, 수율 86.9 ％, 술폰체 (VI) 0.02 ％ 미만 함유)을 얻었다. 술폰체의 함량에 대해서는 실시예 1-1과 동일한 조건으로 확인하였다. The precipitated crystals in the mixture were filtered, washed with ethyl acetate (10 ml) cooled at -30 ° C, dried under reduced pressure at room temperature, and 3.14 g (7.26 mmol, 86.9% yield) of the title compound was obtained. Less than%)). The content of the sulfone was confirmed under the same conditions as in Example 1-1.

Figure 112007010573614-pct00019
Figure 112007010573614-pct00019

<실시예 3-2><Example 3-2>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole 과 and secsec -- 부틸아민과의With butylamine 염의 합성 Synthesis of Salts

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸(3.00 g, 8.35 mmol, 술폰체 (VI) 0.45 ％ 함유)을 아세토니트릴 51.0 ㎖, sec-부틸 아민 5.93 ㎖에 용해하고, 용해 후 15 ℃로 냉각한 후, 미량의 종결정(2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 sec-부틸아민과의 염의 결정)을 첨가하여 1 시간 교반한 후, -25 ℃까지 냉각하여 하룻밤 교반하였다. 석출된 결정을 여과하여 -25 ℃(외온)에서 냉각한 아세토니트릴 5 ㎖로 세정하고, 실온에서 감압 건조하여 표기 화합물의 백색 결정 3.15 g(수율 87.1 ％, 술폰체 (VI) 0.02 ％ 미만 함유)을 얻었다. 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole (3.00 g, 8.35 mmol, containing 0.45% of sulfone (VI)) Was dissolved in 51.0 ml of acetonitrile and 5.93 ml of sec-butyl amine, and after dissolution was cooled to 15 ° C., a trace amount of seed crystals (2-[{4- (3-methoxypropoxy) -3-methylpyridine- 2-yl} methylsulfinyl] -1H-benzimidazole and crystals of a salt of sec-butylamine) were added and stirred for 1 hour, and then cooled to -25 ° C and stirred overnight. The precipitated crystals were filtered off, washed with 5 ml of acetonitrile cooled at -25 ° C (external temperature), dried under reduced pressure at room temperature, and 3.15 g of white crystals of the title compound (yield 87.1%, containing less than 0.02% of sulfone (VI)). Got.

얻어진 염은 NMR 데이타로부터 실시예 3-1과 동일한 것임을 확인하고, 술폰체의 함량에 대해서는 실시예 1-1과 동일한 조건으로 확인하였다. The obtained salt was confirmed to be the same as in Example 3-1 from the NMR data, and the content of sulfone was confirmed under the same conditions as in Example 1-1.

<실시예 3-3><Example 3-3>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole 과 and secsec -- 부틸아민과의With butylamine 염의 합성 Synthesis of Salts

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸(3.00 g, 8.35 mmol, 술폰체 (VI) 1.61 ％ 함유)을 아세토니트릴 28.1 ㎖ 및 sec-부틸아민 5.9 ㎖에 용해하고, 용해 후 탄산디에틸 23.0 ㎖를 첨가하여 15 ℃로 냉각한 후, 미량의 종결정(2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 sec-부틸아민과의 염의 결정)을 첨가하여 1 시간 교반한 후, -25 ℃까지 냉각하여 하룻밤 교반하였다. 석출된 결정을 여과하여 -25 ℃(외온)에서 냉각한 아세토니트릴 5 ㎖로 세정하고, 실온에서 감압 건조하여 표기 화합물의 백색 결정 3.23 g(수율 89.4 ％, 술폰체 (VI) 0.02 ％ 미만 함유)을 얻었다. 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole (3.00 g, 8.35 mmol, containing 1.61% of sulfone (VI)) Was dissolved in 28.1 ml of acetonitrile and 5.9 ml of sec-butylamine. After dissolution, 23.0 ml of diethyl carbonate was added, followed by cooling to 15 ° C., followed by trace seed crystals (2-[{4- (3-methoxyprop). Foxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-crystals of benzimidazole and sec-butylamine) was added and stirred for 1 hour, then cooled to -25 ° C and stirred overnight. . The precipitated crystals were filtered off, washed with 5 ml of acetonitrile cooled at -25 ° C (outer temperature), dried under reduced pressure at room temperature, and 3.23 g of white crystals of the title compound (yield 89.4%, containing less than 0.02% of sulfone (VI)). Got.

얻어진 염은 NMR 데이타로부터 실시예 3-1과 동일한 것임을 확인하고, 술폰 체의 함량에 대해서는 실시예 1-1과 동일한 조건으로 확인하였다. The obtained salt was confirmed to be the same as in Example 3-1 from the NMR data, and the content of sulfone was confirmed under the same conditions as in Example 1-1.

하기 실시예 1X-1, 2X-1, 3X-1에서의 출발 원료인 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸을 포함하는 알칼리 용액은, 상기 참고예 7 내지 17, 또는 일본 특허 공개 (평)11-71370호(실시예 1)와 동일한 방법으로 얻어지는, 화합물 (VII)의 수산화나트륨 수용액(반응 후의 수산화나트륨 수용액에 의한 추출액)을 사용하였다.2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H- which is a starting material in Examples 1X-1, 2X-1, and 3X-1 below An alkaline solution containing benzimidazole is an aqueous sodium hydroxide solution of compound (VII) obtained by the same method as in Reference Examples 7 to 17 or JP-A-11-71370 (Example 1). Extract with an aqueous sodium hydroxide solution).

<실시예 1X-1><Example 1X-1>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole 과 and 이소프로필아민과의With isopropylamine 염의 합성 Synthesis of Salts

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸 7.37 g을 포함하는 알칼리 용액 41.77 g(술폰체 (VI) 1.75 ％ 함유)에 물 64.4 ㎖, 톨루엔 69.4 ㎖ 및 1-부탄올 3.7 ㎖를 첨가하여 교반하고, 이어서 아세트산 1.74 g을 첨가하여 pH를 9.0으로 조정하였다. 이 혼합 용액을 톨루엔층과 수층으로 분리하고, 수층은 톨루엔 54.0 ㎖로 다시 추출하여 먼저 추출한 톨루엔층과 합쳤다. 이 톨루엔층을 물 15.4 ㎖로 세정하고, 이어서 이소프로필아민 5.7 ㎖를 첨가하여 감압 농축하였다. 얻어진 잔사에 아세토니트릴 58.0 ㎖, 이소프로필아민 1.9 ㎖를 첨가하여 다시 감압 농축하였다. 농축 잔사에 아세토니트릴 62.3 ㎖ 및 이소프로필아민 10.2 ㎖를 첨가하여 30 ℃에서 교반한 후, 아세트산 n-부틸에스테르 54.6 ㎖ 및 미량의 종결정(2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 이소프로필아민과의 염)을 첨가하고, 그 후 -25 ℃(외온)까지 냉각하여 하룻밤 교반하였다. 석출물을 여과하여 -25 ℃(외온)에서 냉각한 아세토니트릴 15 ㎖로 세정한 후, 실온에서 약 6 시간 감압 건조하여 표기 화합물의 백색 결정 7.94 g(수율 92.5 ％, 술폰체 (VI) 0.02 ％ 미만 함유)을 얻었다. 술폰체의 함량에 대해서는 실시예 1-1과 동일한 조건으로 확인하였다. 41.77 g of an alkaline solution containing 7.37 g of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole (sulfonate (VI) 1.75 %), 64.4 ml of water, 69.4 ml of toluene and 3.7 ml of 1-butanol were added and stirred, and then 1.74 g of acetic acid was added to adjust the pH to 9.0. The mixed solution was separated into a toluene layer and an aqueous layer, and the aqueous layer was extracted again with 54.0 ml of toluene and combined with the first extracted toluene layer. The toluene layer was washed with 15.4 ml of water, and then 5.7 ml of isopropylamine was added and concentrated under reduced pressure. 58.0 ml of acetonitrile and 1.9 ml of isopropylamine were added to the obtained residue, and the resultant was further concentrated under reduced pressure. 62.3 ml of acetonitrile and 10.2 ml of isopropylamine were added to the concentrated residue, followed by stirring at 30 DEG C, followed by 54.6 ml of acetic acid n-butyl ester and a small amount of seed crystals (2-[{4- (3-methoxypropoxy)). -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole and a salt of isopropylamine) were added, and then cooled to -25 ° C (outer temperature) and stirred overnight. The precipitate was filtered, washed with 15 ml of acetonitrile cooled at -25 ° C (external temperature), and dried under reduced pressure at room temperature for about 6 hours to obtain 7.94 g of a white crystal of the title compound (yield 92.5%, sulfonate (VI) less than 0.02% Containing). The content of the sulfone was confirmed under the same conditions as in Example 1-1.

Figure 112007010573614-pct00020
Figure 112007010573614-pct00020

<실시예 1X-2><Example 1X-2>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole ㆍ나트륨염의 아세톤 ㆍ Acetone of Sodium Salt 착제의Complex 합성 synthesis

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 이소프로필아민과의 염 2.51 g(6.0 mmol, 술폰체 (VI) 0.02 ％ 미만 함유)에 에탄올 26.1 ㎖, 아세트산 에틸 26.1 ㎖를 첨가하여 실온에서 용해하였다. 이 용액에 5 mol/L의 수산화나트륨 수용액 1.11 ㎖를 첨가하여 감압 농축하였다. 얻어진 잔사에 아세트산 에틸 50.4 ㎖, 아세톤 2.5 ㎖를 첨가하여 다시 감압 농축하였다. 얻어진 건조물에 아세트산 에틸 18.0 ㎖, 아세톤 12.0 ㎖를 첨가하여 용해하였다. 이 혼합 용액 중으로 미량의 종결정(2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ나트륨염의 아세톤 착체)을 첨가하여 실온에서 하룻밤 교반하였다. 석출물을 여과하여 아세톤 7 ㎖로 세정한 후, 실온에서 감압 건조 하여 표기 화합물의 백색 결정 2.35 g(5.3 mmol, 수율 89.2 ％)을 얻었다. 2.51 g (6.0 mmol of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole with isopropylamine, 6.0 mmol, sulfone ( VI) containing less than 0.02%), 26.1 ml of ethanol and 26.1 ml of ethyl acetate were added to dissolve at room temperature. To this solution was added 1.11 ml of a 5 mol / L aqueous sodium hydroxide solution, followed by concentration under reduced pressure. 50.4 ml of ethyl acetate and 2.5 ml of acetone were added to the obtained residue, and the resultant was concentrated under reduced pressure again. 18.0 ml of ethyl acetate and 12.0 ml of acetone were added and dissolved in the obtained dried material. A small amount of seed crystals (acetone complex of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole-sodium salt) was added to the mixed solution. Add and stir overnight at room temperature. The precipitate was filtered, washed with 7 ml of acetone, and dried under reduced pressure at room temperature to obtain 2.35 g (5.3 mmol, yield 89.2%) of white crystals of the title compound.

<실시예 1X-3><Example 1X-3>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole ㆍ나트륨염의 합성ㆍ Synthesis of Sodium Salt

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ나트륨염의 아세톤 착체 2.35 g을 사용하고, WO2004-085424호의 실시예 6과 동일한 방법을 행하여 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ나트륨염 2.07 g(술폰체 (VI) 0.02 ％ 미만 함유)을 얻었다. 술폰체의 함량에 대해서는 실시예 1-1과 동일한 조건으로 확인하였다. Implementation of WO2004-085424 using 2.35 g of acetone complex of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole sodium salt 2.07 g of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole sodium salt in the same manner as in Example 6 (sulfone ( VI) containing less than 0.02%). The content of the sulfone was confirmed under the same conditions as in Example 1-1.

Figure 112007010573614-pct00021
Figure 112007010573614-pct00021

<실시예 1X-4><Example 1X-4>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole ㆍ나트륨염의 합성ㆍ Synthesis of Sodium Salt

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 이소프로필아민과의 염 2.00 g(4.8 mmol, 술폰체 (VI) 0.02 ％ 미만 함유), 물 5.0 ㎖, 5 mol/L의 수산화나트륨 수용액 0.89 ㎖를 첨가하여 교반 용해한 후, 물 1.0 ㎖로 수세하여 동결 건조하였다. 그 후, 50 ℃에서 약 21 시간 감압 건조하여 표기 화합물의 백색 고체 1.79 g(4.7 mmol, 수율 98.0 ％, 술폰체 (VI) 0.02 ％ 미 만 함유)을 얻었다. 술폰체의 함량에 대해서는 실시예 1-1과 동일한 조건으로 확인하였다. 2.00 g (4.8 mmol of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole with isopropylamine (4.8 mmol, sulfonate ( VI) containing less than 0.02%), 5.0 ml of water and 0.89 ml of a 5 mol / L sodium hydroxide aqueous solution were added to dissolve and stirred, and then washed with 1.0 ml of water and lyophilized. Then, it dried under reduced pressure at 50 degreeC for about 21 hours, and 1.79 g (4.7 mmol, yield of 98.0%, containing less than 0.02% of sulfone bodies (VI)) of the title compound were obtained. The content of the sulfone was confirmed under the same conditions as in Example 1-1.

Figure 112007010573614-pct00022
Figure 112007010573614-pct00022

<실시예 2X-1><Example 2X-1>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole 과 and 시클로펜틸아민과의With cyclopentylamine 염의 합성 Synthesis of Salts

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸 7.38 g을 포함하는 알칼리 용액 41.66 g(술폰체 (VI) 1.66 ％ 함유)에 물 64.4 ㎖, 톨루엔 69.4 ㎖ 및 1-부탄올 3.7 ㎖를 첨가하여 교반하고, 이어서 아세트산 1.98 g 및 5 mol/L의 수산화나트륨 수용액 0.36 g을 첨가하여 pH를 9.0으로 조정하였다. 이 혼합 용액을 톨루엔층과 수층으로 분리하고, 수층은 톨루엔 54.0 ㎖로 다시 추출하여 먼저 추출한 톨루엔층과 합쳤다. 이 톨루엔층을 물 25.9 ㎖로 세정하고, 이어서 시클로펜틸아민 5.9 ㎖를 첨가하여 감압 농축하였다. 얻어진 잔사에 아세토니트릴 58.0 ㎖, 시클로펜틸아민 2.0 ㎖를 첨가하여 다시 감압 농축하였다. 농축 잔사에 아세토니트릴 62.3 ㎖ 및 시클로펜틸아민 11.8 ㎖, 아세트산 n-부틸에스테르 54.6 ㎖를 첨가하여 2 ℃에서 교반하였다. 미량의 종결정(2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 시클로펜틸아민과의 염)을 첨가하여 결정 석출을 확인한 후, 30 ℃(외온)에서 60 분간 교반하고, -25 ℃( 외온)까지 냉각하였다. 석출물을 여과하여 -25 ℃(외온)에서 냉각한 아세토니트릴 10 ㎖로 세정한 후, 실온에서 약 3 시간 감압 건조하여 표기 화합물의 백색 결정 8.23 g(수율 90.2 ％, 술폰체 (VI) 0.10 ％ 함유)을 얻었다. 술폰체의 함량에 대해서는 실시예 1-1과 동일한 조건으로 확인하였다. 41.66 g of an alkaline solution containing 7.38 g of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole (sulfonate (VI) 1.66 %), 64.4 mL of water, 69.4 mL of toluene and 3.7 mL of 1-butanol were added and stirred, and then the pH was adjusted to 9.0 by adding 1.98 g of acetic acid and 0.36 g of 5 mol / L aqueous sodium hydroxide solution. The mixed solution was separated into a toluene layer and an aqueous layer, and the aqueous layer was extracted again with 54.0 ml of toluene and combined with the first extracted toluene layer. The toluene layer was washed with 25.9 ml of water, and then concentrated under reduced pressure by adding 5.9 ml of cyclopentylamine. 58.0 ml of acetonitrile and 2.0 ml of cyclopentylamine were added to the obtained residue, and the resultant was further concentrated under reduced pressure. 62.3 ml of acetonitrile, 11.8 ml of cyclopentylamine, and 54.6 ml of acetic acid n-butyl ester were added to the concentrated residue, and the mixture was stirred at 2 ° C. Trace seed crystals (2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole and a cyclopentylamine salt) After confirming crystal precipitation, the mixture was stirred at 30 ° C. (external temperature) for 60 minutes and cooled to −25 ° C. (external temperature). The precipitate was filtered, washed with 10 ml of acetonitrile cooled at -25 ° C (external temperature), dried under reduced pressure at room temperature for about 3 hours, and contained 8.23 g of a white crystal of the title compound (yield 90.2%, sulfonate (VI) 0.10%). ) The content of the sulfone was confirmed under the same conditions as in Example 1-1.

Figure 112007010573614-pct00023
Figure 112007010573614-pct00023

<실시예 2X-2><Example 2X-2>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole ㆍ나트륨염의 아세톤 ㆍ Acetone of Sodium Salt 착체의Complex 합성 synthesis

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 시클로펜틸아민과의 염 2.51 g(5.6 mmol, 술폰체 (VI) 0.10 ％ 함유)에 에탄올 25.1 ㎖, 아세트산 에틸 25.1 ㎖를 첨가하여 실온에서 용해하였다. 이 용액에 5 mol/L의 수산화나트륨 수용액 1.11 ㎖를 첨가하여 감압 농축하였다. 얻어진 잔사에 아세트산 에틸 50.2 ㎖, 아세톤 2.5 ㎖를 첨가하여 다시 감압 농축하였다. 얻어진 건조물에 아세트산 에틸 18.0 ㎖, 아세톤 12.0 ㎖를 첨가하여 용해하였다. 이 혼합 용액 중으로 미량의 종결정(2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ나트륨염의 아세톤 착체)을 첨가하여 실온에서 하룻밤 교반하였다. 석출물을 여과하여 아세톤 7 ㎖로 세정한 후, 실온에서 감압 건조 하여 표기 화합물의 백색 결정 2.32 g(5.3 mmol, 수율 93.7 ％)을 얻었다. 2.51 g (5.6 mmol of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole with cyclopentylamine (5.6 mmol, sulfonate ( 25.1 mL of ethanol and 25.1 mL of ethyl acetate were added to the solution (VI) containing 0.10%) and dissolved at room temperature. To this solution was added 1.11 ml of a 5 mol / L aqueous sodium hydroxide solution, followed by concentration under reduced pressure. 50.2 ml of ethyl acetate and 2.5 ml of acetone were added to the obtained residue, and the resultant was concentrated under reduced pressure again. 18.0 ml of ethyl acetate and 12.0 ml of acetone were added and dissolved in the obtained dried material. A small amount of seed crystals (acetone complex of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole-sodium salt) was added to the mixed solution. Add and stir overnight at room temperature. The precipitate was filtered off, washed with 7 ml of acetone, and dried under reduced pressure at room temperature to obtain 2.32 g (5.3 mmol, yield: 93.7%) of white crystals of the title compound.

<실시예 2X-3><Example 2X-3>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole ㆍ나트륨염의 합성ㆍ Synthesis of Sodium Salt

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ나트륨염의 아세톤 착체 2.32 g을 사용하고, WO2004-085424호의 실시예 6과 동일한 방법을 행하여 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ나트륨염 2.04 g(술폰체 (VI) 0.08 ％ 함유)을 얻었다. Implementation of WO2004-085424 using 2.32 g of acetone complex of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole sodium salt 2.04 g of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole sodium salt in the same manner as in Example 6 (sulfone ( VI) containing 0.08%).

얻어진 염은 NMR 데이타로부터 실시예 1X-3과 동일한 것임을 확인하고, 술폰체의 함량에 대해서는 실시예 1-1과 동일한 조건으로 확인하였다. The obtained salt was confirmed to be the same as in Example 1X-3 from the NMR data, and the content of sulfone was confirmed under the same conditions as in Example 1-1.

<실시예 2X-4><Example 2X-4>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole ㆍ나트륨염의 합성ㆍ Synthesis of Sodium Salt

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 시클로펜틸아민과의 염 2.00 g(4.5 mmol, 술폰체 (VI) 0.10 ％ 함유), 물 5.0 ㎖, 5 mol/L의 수산화나트륨 수용액을 첨가하여 교반 용해한 후, 물 1.0 ㎖로 수세하여 동결 건조하였다. 그 후, 50 ℃에서 약 21 시간 감압 건조하여 표기 화합물의 백색 고체 1.81 g(4.7 mmol, 수율 105.2 ％, 술폰체 (VI) 0.11 ％ 함유)을 얻었다. 2.00 g (4.5 mmol of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole with cyclopentylamine (4.5 mmol, sulfonate ( VI) 0.10%), 5.0 mL of water, and 5 mol / L sodium hydroxide aqueous solution were added, it melt | dissolved, and it stirred with 1.0 mL of water, and lyophilized. Then, it dried under reduced pressure at 50 degreeC for about 21 hours, and obtained 1.81 g (4.7 mmol, yield 105.2%, and sulfonate (VI) containing 0.11%) of white solid of the title compound.

얻어진 염은 NMR 데이타로부터 실시예 1X-4와 동일한 것임을 확인하고, 술폰 체의 함량에 대해서는 실시예 1-1과 동일한 조건으로 확인하였다. The obtained salt was confirmed to be the same as in Example 1X-4 from the NMR data, and the content of sulfone was confirmed under the same conditions as in Example 1-1.

<실시예 3X-1><Example 3X-1>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole 과 and secsec -- 부틸아민과의With butylamine 염의 합성 Synthesis of Salts

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸 7.38 g을 포함하는 알칼리 용액 41.66 g(술폰체 (VI) 1.66 ％ 함유)에 물 64.4 ㎖, 톨루엔 69.4 ㎖ 및 1-부탄올 3.7 ㎖를 첨가하여 교반하고, 이어서 아세트산 1.90 g을 첨가하여 pH를 9.0으로 조정하였다. 이 혼합 용액을 톨루엔층과 수층으로 분리하고, 수층은 톨루엔 54.0 ㎖로 다시 추출하여 먼저 추출한 톨루엔층과 합쳤다. 이 톨루엔층을 물 25.9 ㎖로 세정하고, 이어서 sec-부틸아민 6.0 ㎖를 첨가하여 감압 농축하였다. 얻어진 잔사에 아세토니트릴 58.0 ㎖, sec-부틸아민 2.0 ㎖를 첨가하여 다시 감압 농축하였다. 농축 잔사에 아세토니트릴 62.3 ㎖ 및 sec-부틸아민 12.3 ㎖, 아세트산 n-부틸에스테르 54.6 ㎖를 첨가하여 12 ℃에서 교반하였다. 미량의 종결정(2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 sec-부틸아민과의 염)을 첨가하여 -15 ℃(외온)까지 냉각하여 결정 석출을 확인한 후, 20 ℃(외온)에서 20 분간 교반하고, -25 ℃(외온)까지 냉각하였다. 석출물을 여과하여 -25 ℃(외온)에서 냉각한 아세토니트릴 10 ㎖로 세정한 후, 실온에서 약 3.5 시간 감압 건조하여 표기 화합물의 백색 결정 8.10 g(수율 91.3 ％, 술폰체 (VI) 0.02 ％ 미만 함유)을 얻었다. 술폰체의 함량에 대해서는 실시예 1-1과 동일한 조건으로 확인하였다. 41.66 g of an alkaline solution containing 7.38 g of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole (sulfonate (VI) 1.66 %), 64.4 mL of water, 69.4 mL of toluene, and 3.7 mL of 1-butanol were added and stirred, and then 1.90 g of acetic acid was added to adjust the pH to 9.0. The mixed solution was separated into a toluene layer and an aqueous layer, and the aqueous layer was extracted again with 54.0 ml of toluene and combined with the first extracted toluene layer. The toluene layer was washed with 25.9 ml of water, and then 6.0 ml of sec-butylamine was added and concentrated under reduced pressure. 58.0 ml of acetonitrile and 2.0 ml of sec-butylamine were added to the obtained residue, and the resultant was further concentrated under reduced pressure. 62.3 ml of acetonitrile, 12.3 ml of sec-butylamine, and 54.6 ml of acetic acid n-butyl ester were added to the concentrated residue, and the mixture was stirred at 12 ° C. Trace seed crystals (2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole and sec-butylamine salt) are added After cooling to -15 ° C (outer temperature) to confirm the precipitation of crystals, the mixture was stirred at 20 ° C (outer temperature) for 20 minutes and cooled to -25 ° C (outer temperature). The precipitate was filtered, washed with 10 ml of acetonitrile cooled at -25 ° C (outer temperature), and dried under reduced pressure at room temperature for about 3.5 hours to give 8.10 g of a white crystal of the title compound (yield 91.3%, sulfonate (VI) less than 0.02% Containing). The content of the sulfone was confirmed under the same conditions as in Example 1-1.

Figure 112007010573614-pct00024
Figure 112007010573614-pct00024

<실시예 3X-2><Example 3X-2>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole ㆍ나트륨염의 아세톤 ㆍ Acetone of Sodium Salt 착제의Complex 합성 synthesis

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 sec-부틸아민과의 염 2.61 g(6.0 mmol, 술폰체 (VI) 0.02 ％ 미만 함유)에 에탄올 26.1 ㎖, 아세트산 에틸 26.1 ㎖를 첨가하여 실온에서 용해하였다. 이 용액에 5 mol/L의 수산화나트륨 수용액 1.14 ㎖를 첨가하여 감압 농축하였다. 얻어진 잔사에 아세트산 에틸 52.2 ㎖, 아세톤 2.6 ㎖를 첨가하여 다시 감압 농축하였다. 얻어진 건조물에 아세트산 에틸 18.0 ㎖, 아세톤 12.0 ㎖를 첨가하여 용해하였다. 이 혼합 용액 중으로 미량의 종결정(2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ나트륨염의 아세톤 착체)을 첨가하여 실온에서 하룻밤 교반하였다. 석출물을 여과하여 아세톤 6 ㎖로 세정한 후, 실온에서 감압 건조하여 표기 화합물의 백색 결정 2.36 g(5.4 mmol, 수율 88.9 ％)을 얻었다. 2.61 g (6.0 mmol, sulfone) of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole with sec-butylamine (VI) containing less than 0.02%), 26.1 ml of ethanol and 26.1 ml of ethyl acetate were added and dissolved at room temperature. 5.14 ml of 5 mol / L sodium hydroxide aqueous solution was added to this solution, and it concentrated under reduced pressure. To the obtained residue, 52.2 ml of ethyl acetate and 2.6 ml of acetone were added, and the resultant was further concentrated under reduced pressure. 18.0 ml of ethyl acetate and 12.0 ml of acetone were added and dissolved in the obtained dried material. A small amount of seed crystals (acetone complex of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole-sodium salt) was added to the mixed solution. Add and stir overnight at room temperature. The precipitate was filtered off, washed with 6 ml of acetone, and dried under reduced pressure at room temperature to obtain 2.36 g (5.4 mmol, 88.9%) of white crystals of the title compound.

<실시예 3X-3><Example 3X-3>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole ㆍ나트륨염의 합성ㆍ Synthesis of Sodium Salt

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ나트륨염의 아세톤 착체 2.36 g을 사용하고, WO2004-085424호의 실시예 6과 동일한 방법을 행하여 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸ㆍ나트륨염 2.08 g(술폰체 (VI) 0.02 ％ 미만 함유)을 얻었다. Implementation of WO2004-085424 using 2.36 g of acetone complex of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole sodium salt 2.08 g of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole sodium salt in the same manner as in Example 6 (sulfonate ( VI) containing less than 0.02%).

얻어진 염은 NMR 데이타로부터 실시예 1X-3과 동일한 것임을 확인하고, 술폰체의 함량에 대해서는 실시예 1-1과 동일한 조건으로 확인하였다. The obtained salt was confirmed to be the same as in Example 1X-3 from the NMR data, and the content of sulfone was confirmed under the same conditions as in Example 1-1.

<실시예 3X-4><Example 3X-4>

2-[{4-(3-2-[{4- (3- 메톡시프로폭시Methoxypropoxy )-3-) -3- 메틸피리딘Methylpyridine -2-일}-2 days} 메틸술피닐Methylsulfinyl ]-1H-] -1H- 벤즈이미다졸Benzimidazole ㆍ나트륨염의 합성ㆍ Synthesis of Sodium Salt

2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 sec-부틸아민의 염 2.00 g(4.6 mmol, 술폰체 (VI) 0.02 ％ 미만 함유), 물 5.0 ㎖, 5 mol/L의 수산화나트륨 수용액 0.87 ㎖를 첨가하여 교반 용해한 후, 물 1.0 ㎖로 수세하여 동결 건조하였다. 그 후, 50 ℃에서 약 21 시간 감압 건조하여 표기 화합물의 백색 고체 1.75 g(4.6 mmol, 수율 99.3 ％, 술폰체(VI) 0.02 ％ 미만 함유)을 얻었다. 2.00 g (4.6 mmol of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole and sec-butylamine VI) containing less than 0.02%), 5.0 ml of water, and 0.87 ml of 5 mol / L aqueous sodium hydroxide solution were added to dissolve and stirred, followed by washing with 1.0 ml of water and freeze-drying. Then, it dried under reduced pressure at 50 degreeC for about 21 hours, and 1.75 g (4.6 mmol, yield 99.3%, containing less than 0.02% of sulfone bodies (VI)) of the title compound were obtained.

얻어진 염은 NMR 데이타로부터 실시예 1X-4와 동일한 것임을 확인하고, 술폰체의 함량에 대해서는 실시예 1-1과 동일한 조건으로 확인하였다. The obtained salt was confirmed to be the same as in Example 1X-4 from the NMR data, and the content of sulfone was confirmed under the same conditions as in Example 1-1.

분말 X선 회절 패턴의 측정Measurement of Powder X-Ray Diffraction Patterns

각 실시예에서 얻어진 염의 분말 X선 회절 측정은, 일본 약전의 일반 시험법에 기재된 분말 X선 회절 측정법에 따라, 이하의 측정 조건으로 행하였다. The powder X-ray diffraction measurement of the salt obtained in each Example was performed on the following measurement conditions according to the powder X-ray diffraction measurement method described in the general test method of the Japanese Pharmacopoeia.

(장치)(Device)

이학 X선 DTA 시스템: RINT-2000(가부시끼가이샤 리가꾸 제조)Science X-ray DTA system: RINT-2000 (manufactured by Rigaku Co., Ltd.)

(조작 방법)(Operation method)

시료에 대하여 마노(agate) 유발로 분쇄한 후 유리판에 샘플링하고, 이하의 조건으로 측정을 행하였다. The sample was ground by agate induction, sampled on a glass plate, and measured under the following conditions.

사용 X선: CuKα선Use X-ray: CuKα ray

관 전압: 40 kVTube voltage: 40 kV

관 전류: 20 mATube Current: 20 mA

발산 슬릿: 1 degDivergence Slit: 1 deg

수광(受光) 슬릿: 0.15 mmLight receiving slit: 0.15 mm

산란 슬릿: 1 degScattering Slit: 1 deg

주사 속도: 2°/분Scanning speed: 2 ° / min

주사 스텝: 0.02°Scan Step: 0.02 °

측정 범위(2θ): 5 내지 40° Measuring range (2θ): 5 to 40 °

도 1은 실시예 1X-1에서 얻어진 염의 분말 X선 회절 패턴을 나타내고, 도 2는 실시예 2X-1에서 얻어진 염의 분말 X선 회절 패턴을 나타내고, 도 3은 실시예 3X-1에서 얻어진 염의 분말 X선 회절 패턴을 나타낸다. 도 1 내지 도 3에 나타낸 분말 X선 회절 패턴의 결과로부터 명확한 바와 같이, 도 1 내지 도 3에서는 X선 회절 피크가 존재하기 때문에, 각 실시예에서의 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 이소프로필아민, 시클로펜틸아민 및 sec-부틸아민과의 염은 비정질 상태가 아니며, 결정 상태의 염으로서 합성된 것임을 알 수 있다. 1 shows a powder X-ray diffraction pattern of the salt obtained in Example 1X-1, FIG. 2 shows a powder X-ray diffraction pattern of the salt obtained in Example 2X-1, and FIG. 3 shows a powder of the salt obtained in Example 3X-1. An X-ray diffraction pattern is shown. As is clear from the results of the powder X-ray diffraction pattern shown in Figs. 1 to 3, since X-ray diffraction peaks exist in Figs. 1 to 3, 2-[{4- (3-methoxy in each example). Propoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole and salts of isopropylamine, cyclopentylamine and sec-butylamine are not amorphous and are salts in the crystalline state. It can be seen that it is synthesized.

본 발명에 따르면, 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸과 아민과의 염을 사용함으로써, 의약으로서 유용한 2-[{4-(3-메톡시프로폭시)-3-메틸피리딘-2-일}메틸술피닐]-1H-벤즈이미다졸을 제조할 때, 불순물로서 포함되는 해당 화합물의 술폰체를 효율적으로 제거할 수 있다. According to the present invention, by using a salt of 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole with an amine, When preparing useful 2-[{4- (3-methoxypropoxy) -3-methylpyridin-2-yl} methylsulfinyl] -1H-benzimidazole, the sulfonates of the compounds involved as impurities are It can be removed efficiently.

도 1은 본 발명의 실시예 1X-1에서 얻어진 염의 분말 X선 회절 패턴을 나타낸다.1 shows a powder X-ray diffraction pattern of the salt obtained in Example 1X-1 of the present invention.

도 2는 본 발명의 실시예 2X-1에서 얻어진 염의 분말 X선 회절 패턴을 나타낸다.2 shows a powder X-ray diffraction pattern of the salt obtained in Example 2X-1 of the present invention.

도 3은 본 발명의 실시예 3X-1에서 얻어진 염의 분말 X선 회절 패턴을 나타낸다. Figure 3 shows a powder X-ray diffraction pattern of the salt obtained in Example 3X-1 of the present invention.

Claims (10)

하기 화학식 I로 표시되는 염.Salt represented by the following formula (I). <화학식 I><Formula I>
Figure 112007010573614-pct00025
Figure 112007010573614-pct00025
 식 중, A+는 이소프로필암모늄 이온, sec-부틸암모늄 이온 또는 시클로펜틸암모늄 이온을 나타낸다.In the formula, A + represents isopropylammonium ion, sec-butylammonium ion or cyclopentylammonium ion. 하기 화학식 II로 표시되는 염.Salt represented by the following formula (II). <화학식 II><Formula II>
Figure 112007010573614-pct00026
Figure 112007010573614-pct00026
 하기 화학식 III으로 표시되는 염.Salt represented by the following general formula (III). <화학식 III><Formula III>
Figure 112007010573614-pct00027
Figure 112007010573614-pct00027
 하기 화학식 IV로 표시되는 염.Salt represented by the following formula (IV). <화학식 IV><Formula IV>
Figure 112007010573614-pct00028
Figure 112007010573614-pct00028
 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete 삭제delete
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0674272B2 (en) * 1986-11-13 1994-09-21 エーザイ株式会社 Pyridine derivative and ulcer therapeutic agent containing the same
WO1994027988A1 (en) * 1993-05-28 1994-12-08 Astra Aktiebolag Optically pure salts of pyridinylmethyl sulfinyl-ih-benzimidazole compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0674272B2 (en) * 1986-11-13 1994-09-21 エーザイ株式会社 Pyridine derivative and ulcer therapeutic agent containing the same
WO1994027988A1 (en) * 1993-05-28 1994-12-08 Astra Aktiebolag Optically pure salts of pyridinylmethyl sulfinyl-ih-benzimidazole compounds

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