2-methyl-3-pyridinol -Drug Synthesis Database

【结构式】

【分子编号】29609

【品名】2-methyl-3-pyridinol

【CA登记号】1121-25-1

【分子式】C₆H₇NO

【分子量】109.12772

【元素组成】C 66.04% H 6.47% N 12.84% O 14.66%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(VI)

3-Methoxy-2-methylpyridine (VII), prepared by methylation of 2-methyl-3-pyridinol (VI), was converted to the N-oxide (VIII) employing peracetic acid. Nitration of the pyridine N-oxide (VIII) with concentrated nitric acid gave the 4-nitro derivative (IX). Subsequent displacement of the nitro group of (IX) by sodium methoxide led to the dimethoxypyridine N-oxide (X). Rearrangement of the N-oxide group of (X) in hot acetic anhydride produced the acetoxymethyl pyridine (XI). After basic hydrolysis of the acetate ester (XI), the resultant hydroxymethyl pyridine (XII) was chlorinated by SOCl2, yielding chloride (XIII). Condensation between mercapto benzimidazole (V) and the chloromethyl pyridine (XIII) in ethanolic NaOH led to the sulfide adduct (XIV). This was finally oxidized to the desired sulfoxide by using meta-chloroperbenzoic acid in CH2Cl2. The oxidation of sulfide (XIV) has also been performed employing sodium perborate, sodium percarbonate in the presence of ammonium molybdate, or tert-butyl hydroperoxide in the presence of vanadyl acetylacetonate.

参考文献中间体

合成目标

【1】 Coppi, L.; Berenguer Maimó, R. (Laboratorios del Dr. Esteve, SA); Method for obtaining derivs. of [[pyridyl substd.)methyl]thio]benzimidazol. ES 2171116; WO 0179194 .
【2】 Mendelovici, M.; Avrutov, I. (Teva Pharmaceutical Industries Ltd.; Teva Pharmaceuticals USA, Inc.); Processes for the production of substd. 2-(2-pyridylmethyl) sulfinyl-1H-benzimidazoles. WO 0262786 .
【3】 Coppi, L.; Campon Pardo, J.; Berenguer Maimo, R. (Laboratorios del Dr. Esteve, SA); Method for oxidizing a thioether group into a sulfoxide group. ES 2163372; WO 0168594 .
【4】 Brennan, J.P.; Turner, A.T. (Abbott Laboratories Inc.); Chemical process for the production of sulphinyl derivs. by oxidation of the corresponding co-derivs. with perborates. WO 9947514 .
【5】 Kohl, B.; Sturm, E.; Senn-Bilfinger, J.; Simon, W.A.; Krüger, U.; Schaefer, H.; Rainer, G.; Figala, V.; Klemm, K.; (H+,K+)-ATPase inhibiting 2-[(2-pyridylmethyl)sulfinyl]benzimidazoles. 4. A novel series of dimethoxypyridyl-substituted inhibitors with enhanced selectivity. The selection of pantoprazole as a clinical candidate. J Med Chem 1992, 35, 6, 1049.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	14034	5-(Difluoromethoxy)-1H-benzimidazole-2-thiol; 5-(Difluoromethoxy)-1H-benzimidazol-2-ylhydrosulfide; 5-Difluoromethoxy-2-mercapto-1H-benzimidazole	97963-62-7	C₈H₆F₂N₂OS	详情	详情
(VI)	29609	2-methyl-3-pyridinol	1121-25-1	C₆H₇NO	详情	详情
(VII)	56496	3-methoxy-2-methylpyridine; methyl 2-methyl-3-pyridinyl ether		C₇H₉NO	详情	详情
(VIII)	56497	3-methoxy-2-methyl-1-pyridiniumolate		C₇H₉NO₂	详情	详情
(IX)	56498	3-methoxy-2-methyl-4-nitro-1-pyridiniumolate		C₇H₈N₂O₄	详情	详情
(X)	56499	3,4-dimethoxy-2-methyl-1-pyridiniumolate		C₈H₁₁NO₃	详情	详情
(XI)	56500	(3,4-dimethoxy-2-pyridinyl)methyl acetate		C₁₀H₁₃NO₄	详情	详情
(XII)	56501	(3,4-dimethoxy-2-pyridinyl)methanol		C₈H₁₁NO₃	详情	详情
(XIII)	14035	2-(Chloromethyl)-3,4-dimethoxypyridine; 2-(Chloromethyl)-3-methoxy-4-pyridinyl methyl ether	72830-09-2	C₈H₁₀ClNO₂	详情	详情
(XIV)	14036	5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfanyl]-1H-benzimidazole; 2-([[5-(Difluoromethoxy)-1H-benzimidazol-2-yl]sulfanyl]methyl)-3-methoxy-4-pyridinyl methyl ether	102625-64-9	C₁₆H₁₅F₂N₃O₃S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

Coupling of 3-hydroxypyridine (X) with 2-chloropyridine (XI) afforded the corresponding dipyridyl ether (XII). After reduction of the nitro group of (XII) with SnCl2, the resulting aminopyridine (XIII) was treated with phenyl chloroformate to give the phenyl carbamate (XIV). Finally, condensation of carbamate (XIV) with indoline (IX) produced the title carboxamide.

参考文献中间体

合成目标

【1】 Bromidge, S.M.; Forbes, I.T. (SmithKline Beecham plc); Indoline derivs. useful as 5-HT-2C receptor antagonists. EP 0912554; WO 9748699 .
【2】 Blackburn, T.P. (SmithKline Beecham plc); Pharmaceutical compsn. containing a 5HT2C antagonist and a D2 antagonist. WO 9804289 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	29608	5-methyl-6-(trifluoromethyl)indoline		C₁₀H₁₀F₃N	详情	详情
(X)	29609	2-methyl-3-pyridinol	1121-25-1	C₆H₇NO	详情	详情
(XI)	29610	2-chloro-5-nitropyridine	4548-45-2	C₅H₃ClN₂O₂	详情	详情
(XII)	29611	2-methyl-3-[(5-nitro-2-pyridinyl)oxy]pyridine; 2-methyl-3-pyridinyl 5-nitro-2-pyridinyl ether		C₁₁H₉N₃O₃	详情	详情
(XIII)	29612	6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinamine; 6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinylamine		C₁₁H₁₁N₃O	详情	详情
(XIV)	29613	phenyl 6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinylcarbamate		C₁₈H₁₅N₃O₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

Condensation between 3-amino-6-chloropyridazine (I) and 3-hydroxy-2-methylpyridine (II) in aqueous NaOH at 175 C under pressure afforded the bisaryl ether (III). The phenyl carbamate (IV) was then prepared by treatment of aminopyridazine (III) with phenyl chloroformate. Finally, coupling of carbamate (IV) with 6-chloro-5-methylindoline (V) yielded the title urea derivative.

参考文献中间体

合成目标

【1】 Bromidge, S.M.; Davies, S.; Dabbs, S.; et al.; 1-[2-(Heteroaryloxy)heteroaryl]carbamoy]indolines: Novel and selective 5-HT2C receptor inverse agonists with potential as antidepressant/anxiolytic agents. Bioorg Med Chem Lett 2000, 10, 16, 1863.

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)	43962	6-chloro-3-pyridazinamine; 6-chloro-3-pyridazinylamine	5469-69-2	C₄H₄ClN₃	详情	详情
(II)	29609	2-methyl-3-pyridinol	1121-25-1	C₆H₇NO	详情	详情
(III)	43963	6-[(2-methyl-3-pyridinyl)oxy]-3-pyridazinamine; 6-[(2-methyl-3-pyridinyl)oxy]-3-pyridazinylamine		C₁₀H₁₀N₄O	详情	详情
(IV)	43964	phenyl 6-[(2-methyl-3-pyridinyl)oxy]-3-pyridazinylcarbamate		C₁₇H₁₄N₄O₃	详情	详情
(V)	26798	6-chloro-5-methylindoline		C₉H₁₀ClN	详情	详情

Extended Information