Pariprazole sodium, Rabeprazole sodium, LY-307640, E-3810, Aciphex, Pariet, -Drug Synthesis Database

【结构式】

【药物名称】Pariprazole sodium, Rabeprazole sodium, LY-307640, E-3810, Aciphex, Pariet

【化学名称】2-[4-(3-Methoxypropoxy)-3-methylpyridin-2-ylmethylsulfinyl]benzimidazole 1-sodium salt

【CA登记号】117976-90-6, 117976-89-3 (free acid)

【分子式】C₁₈H₂₀N₃NaO₃S

【分子量】381.4322

【开发单位】Eisai (Originator), Janssen (Licensee), Janssen-Cilag (Licensee)

【药理作用】Anti-Helicobacter Pylori Agents, Antiulcer Drugs, Esophageal Diseases, Treatment of, Gastroesophageal Reflux Disease, Agents for, GASTROINTESTINAL DRUGS, H+/K+-ATPase Inhibitors

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5 合成路线6 合成路线7 合成路线8 合成路线9

合成路线1

参考文献中间体

【1】 Zhong HJ．2006．Process for preparation of benzimidazole derivatives.发明专利申请公开说明书．CN 1789251(本专利属于Jiangsu Hansoh Pharmaceutical Co．Ltd，Peop Rep China)

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	12815	4-chloro-2,3-dimethyl-1-pyridiniumolate		C₇H₈ClNO	详情	详情
(II)	66613	1H-benzo[d]imidazole-2(3H)-thione		C₇H₆N₂S	详情	详情
(III)	66614	2-(((4-chloro-3-methylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazole	103312-62-5	C₁₄H₁₂ClN₃S	详情	详情
(IV)	66615	S-1H-benzo[d]imidazol-2-yl 4-chloro-3-methylpyridine-2-carbothioate		C₁₄H₁₀ClN₃OS	详情	详情

合成路线2

参考文献中间体

【1】 Kankan RN, Rao DR, Srinivas PL. 2004. Method for the preparation of pyridinylmethylsulfinylbenzimidazoles which are substantially free of oxidation contaminants for use in pharmaceutical compositions for treaunent of gastric ulcers．W0 2004063188(本专利属于Cipla Limited, Wain, Christopher Paul)

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	45157	1H-benzimidazol-2-yl [4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl sulfoxide; 2-([[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl)-1H-benzimidazole		C₁₈H₂₁N₃O₃S	详情	详情

合成路线3

参考文献中间体

【1】 Avrutov I, Mendelovci M, Frnkelstein N. 2004. Processes for the production of substituted 2-(2-pyridylm-etyl) sulfinyl-lH-benzimidazoles. US 2004138466
【2】 Avrutov I, Mendelovici M. 2002. Processes for the production of substituted 2-(2-pyridinylmethyl) sulfinyl-lH-benzimidazoles using tert-butyl hydmperoxide or oxone. W0 2002062786．(本专利属于Teva Pharmaceutical Industries Ltd. Israel: Teva Pharmaceutical USA, Inc)

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	45157	1H-benzimidazol-2-yl [4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl sulfoxide; 2-([[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl)-1H-benzimidazole		C₁₈H₂₁N₃O₃S	详情	详情

合成路线4

参考文献中间体

【1】 Broeckx RLM, De Smaele D, Leurs SMH. 2003. Improved process for preparing benzimidazole-type compounds, particularly antiulcer agents such as rabeprazole, by oxidation of sulfide analogs aml controlled pH alkaline extraction to remove sulfone impurities. W0 2003008406(本专利属于Janssen Pharmaceutica N, V, Belg)
【2】 Arakawa N. Kumda H.1999. Preparation of pyridinylmethylsulfinylbenzimidazoles. JP 11071370(本专利属于Eisai Co, Ltd, Japan)

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	45157	1H-benzimidazol-2-yl [4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl sulfoxide; 2-([[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl)-1H-benzimidazole		C₁₈H₂₁N₃O₃S	详情	详情

合成路线5

参考文献中间体

【1】 Coppi L,Berenguer MR. 2001. Method for obtaining derivativees of [[(substitmed-pyrulyl) methyl]thio] benzinudazole, useful as intermediates for omepnzole and related antiulcer agents. W0 2001079194(本专利属于Esteve Quimica, SA, Spain)

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	19482	2,3-dimethyl-4-nitro-1-pyridiniumolate	37699-43-7	C₇H₈N₂O₃	详情	详情
(II)	66616	(3-methyl-4-nitropyridin-2-yl)methyl methanesulfonate		C₈H₁₀N₂O₅S	详情	详情
(III)	66613	1H-benzo[d]imidazole-2(3H)-thione		C₇H₆N₂S	详情	详情
(IV)	66617	2-((2-methyl-3-nitrobenzyl)thio)-1H-benzo[d]imidazole		C₁₅H₁₃N₃O₂S	详情	详情
(V)	45157	1H-benzimidazol-2-yl [4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl sulfoxide; 2-([[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl)-1H-benzimidazole		C₁₈H₂₁N₃O₃S	详情	详情

合成路线6

参考文献中间体

【1】 Cosme Gomez A, Fau de Casa-Juana Munoz M. Gelpi Vintro JM, et aL 2001. Process for the production of 2-(2-pyridinylmethylsulfinyl)-lH-benzimidazoles. W 02001004109(本专利属于Quimica Sintetica,S A, Spain)

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	12815	4-chloro-2,3-dimethyl-1-pyridiniumolate		C₇H₈ClNO	详情	详情
(II)	66618	4-chloro-2-(chloromethyl)-3-methylpyridine		C₇H₇Cl₂N	详情	详情
(III)	66613	1H-benzo[d]imidazole-2(3H)-thione		C₇H₆N₂S	详情	详情
(IV)	66614	2-(((4-chloro-3-methylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazole	103312-62-5	C₁₄H₁₂ClN₃S	详情	详情
(V)	66619	2-((3-chloro-2-methylbenzyl)sulfinyl)-1H-benzo[d]imidazole		C₁₅H₁₃ClN₂OS	详情	详情

合成路线7

参考文献中间体

【1】 Tagami K, Niikawa N, Kayano A. et aL. 1999. Processes for the preparation of pyridine derivatnres. WO 9902521(本专利属于Eisai Co, Ltd, Japan)

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	45157	1H-benzimidazol-2-yl [4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl sulfoxide; 2-([[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl)-1H-benzimidazole		C₁₈H₂₁N₃O₃S	详情	详情

合成路线8

The condensation of 4-chloro-2,3-dimethylpyridine N-oxide (I) with 3-methoxypropanol (II) by means of NaH in DMSO gives 4-(3-methoxypropoxy)-2,3-dimethylpyridine N-oxide (III), which is treated with acetic anhydride at 90 C yielding 2-(acetoxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine (IV). The hydrolysis of (IV) with NaOH in ethanol affords 2-(hydroxymethyl)-4-(3-methoxypropoxy)-3-methylpyridine (V), which by treatment with SOCl2 in dichloromethane is converted into 2-(chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine (VI). The condensation of (VI) with 2-mercaptobenzimidazole (VII) by means of NaOH in ethanol gives 2-[4-(3-methoxypropoxy)-3-methylpyridin-2-ylmethylthio]benzimidazole (VIII), which is oxidized with m-chloroperbenzoic acid in ether - dichloromethane to afford 2-[4-(3-methoxypropoxy)-3-methylpyridin-2-ylsulfinyl]benzimidazole (IX). Finally, this compound is treated wtih aqueous Na2CO3.

参考文献中间体

【1】 Souda, S.; Ueda, N.; Miyazawa, S.; Tagami, K.; Nomoto, S.; Okita, M.; Shimomura, N.; Kaneko, T.; Fujimoto, M.; Murakami, M.; Oketani, K.; Fujisaki, H.; Shibata, H.; Wakabayashi, T. (Eisai Co., Ltd.); Pyridine derivs., pharmaceutical compsns. comprising the same, the use of the same for the manufacture of medicaments having therapeutic or preventative value, and a process for preparing the same. AU 8781138; EP 0268956; EP 0475456; EP 0654471; EP 0786461; JP 1989006270; JP 1993247035; JP 1995291967; US 5045552; US 5998445 .
【2】 Castaner, J.; Prous, J.; E-3810. Drugs Fut 1991, 16, 1, 19.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	17888	m-Chloroperbenzoic acid; 3-Chlorobenzenecarboperoxoic acid	937-14-4	C₇H₅ClO₃	详情	详情
(I)	12815	4-chloro-2,3-dimethyl-1-pyridiniumolate		C₇H₈ClNO	详情	详情
(II)	12816	3-Methoxy-1-propanol	1589-49-7	C₄H₁₀O₂	详情	详情
(III)	12817	4-(3-methoxypropoxy)-2,3-dimethyl-1-pyridiniumolate		C₁₁H₁₇NO₃	详情	详情
(IV)	12818	[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl acetate		C₁₃H₁₉NO₄	详情	详情
(V)	12819	[4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]methanol		C₁₁H₁₇NO₃	详情	详情
(VI)	12820	2-(Chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine; 2-(Chloromethyl)-3-methyl-4-pyridinyl 3-methoxypropyl ether	117977-20-5	C₁₁H₁₆ClNO₂	详情	详情
(VII)	12821	2-Mercaptobenzinidiazole; 1H-Benzimidazol-2-ylhydrosulfide; 1H-Benzimidazole-2-thiol; 2-Benzimidazolethiol; o-Phenylenethiourea; 2-Benzimidazolinethione; 1,3-Dihydro-2H-benzimidazole-2-thione	583-39-1	C₇H₆N₂S	详情	详情
(VIII)	12822	2-([[4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfanyl)-1H-benzimidazole; 2-[(1H-Benzimidazol-2-ylsulfanyl)methyl]-3-methyl-4-pyridinyl 3-methoxypropyl ether	117977-21-6	C₁₈H₂₁N₃O₂S	详情	详情
(IX)	12823	2-([[4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl)-1H-benzimidazole; 1H-Benzimidazol-2-yl [4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl sulfoxide		C₁₈H₂₁N₃O₃S	详情	详情

合成路线9

A synthesis for [14C]-labeled E-3810 has been described: The cyclization of o-phenylenediamine (I) with [14C]-labeled carbon disulfide (II) by means of aqueous KOH gives the potassium salt of [14C]-2-mercaptobenzimidazole (III), which is treated with acetic acid to obtain the corresponding thiol (IV). The condensation of (IV) with 2-(chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine (V) by means of NaOH in refluxing ethanol yields [14C]-labeled 2-[4-(3-methoxypropoxy)-3-methylpyridin-3-ylmethylthio]benzimidazole (VI). The oxidation of (VI) with m-chloroperbenzoic acid in dichloromethane affords the corresponding sulfoxide (VIII), which is finally treated with 0.1 N NaOH in ethanol.

参考文献中间体

【1】 Sohda, S.; Tagami, K.; Chiku, S.; Synthesis of 14C-labelled sodium pariprazole (E3810). J Label Compd Radiopharm 1993, 33, 9, 849.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	12824	2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine	95-54-5	C₆H₈N₂	详情	详情
(III)	12825	2-Sulfanyl-1H-benzimidazole potassium salt		C₇H₅KN₂S	详情	详情
(III)	45155	1H-benzimidazol-2-ylsulfide; 1H-benzimidazole-2-thiolate		C₇H₅KN₂S	详情	详情
(IV)	12821	2-Mercaptobenzinidiazole; 1H-Benzimidazol-2-ylhydrosulfide; 1H-Benzimidazole-2-thiol; 2-Benzimidazolethiol; o-Phenylenethiourea; 2-Benzimidazolinethione; 1,3-Dihydro-2H-benzimidazole-2-thione	583-39-1	C₇H₆N₂S	详情	详情
(IV)	45156	1H-benzimidazol-2-ylhydrosulfide; 1H-benzimidazole-2-thiol		C₇H₆N₂S	详情	详情
(V)	12820	2-(Chloromethyl)-4-(3-methoxypropoxy)-3-methylpyridine; 2-(Chloromethyl)-3-methyl-4-pyridinyl 3-methoxypropyl ether	117977-20-5	C₁₁H₁₆ClNO₂	详情	详情
(VI)	12822	2-([[4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfanyl)-1H-benzimidazole; 2-[(1H-Benzimidazol-2-ylsulfanyl)methyl]-3-methyl-4-pyridinyl 3-methoxypropyl ether	117977-21-6	C₁₈H₂₁N₃O₂S	详情	详情
(VI)	45157	1H-benzimidazol-2-yl [4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl sulfoxide; 2-([[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl)-1H-benzimidazole		C₁₈H₂₁N₃O₃S	详情	详情
(VII)	12823	2-([[4-(3-Methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl)-1H-benzimidazole; 1H-Benzimidazol-2-yl [4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl sulfoxide		C₁₈H₂₁N₃O₃S	详情	详情
(VII)	45158	2-([[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfanyl)-1H-benzimidazole; 2-[(1H-benzimidazol-2-ylsulfanyl)methyl]-3-methyl-4-pyridinyl 3-methoxypropyl ether		C₁₈H₂₁N₃O₂S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)