2-(Chloromethyl)-3,4-dimethoxypyridine; 2-(Chloromethyl)-3-methoxy-4-pyridinyl methyl ether -Drug Synthesis Database

【结构式】

【分子编号】14035

【品名】2-(Chloromethyl)-3,4-dimethoxypyridine; 2-(Chloromethyl)-3-methoxy-4-pyridinyl methyl ether

【CA登记号】72830-09-2

【分子式】C₈H₁₀ClNO₂

【分子量】187.62564

【元素组成】C 51.21% H 5.37% Cl 18.9% N 7.47% O 17.05%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(IV)

A new synthesis of [14C]-labeled pantoprazole has been described: The cyclization of potassium [14C]-ethylxanthate (I) with the diaminobenzene (II) by means of NaOH gives the imidazole (III), which is condensed with 2-(chloromethyl)-3,4-dimethoxypyridine (IV) by means of NaOH in ethanol to afford the sulfide (V). Finally, this compound is oxidized with m-chloroperbenzoic acid (mcpba) in dichloromethane.

参考文献中间体

合成目标

【1】 Saunders, D.; Lawrie, K.W.M.; Crowe, A.M.; Johnston, C.E.A.; The synthesis of [14C]pantoprazole - SK&F 96022Z - An H+/K+ ATP inhibitor. J Label Compd Radiopharm 1992, 31, 5, 409.

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)	14032	Dithiocarbonic acid O-ethyl ester potassium salt		C₃H₅KOS₂	详情	详情
(I)	45190	potassium 1-(carbodithioatooxy)ethane		C₃H₅KOS₂	详情	详情
(II)	14033	4-(Difluoromethoxy)-1,2-benzenediamine; 2-Amino-4-(difluoromethoxy)phenylamine		C₇H₈F₂N₂O	详情	详情
(III)	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
(III)	45191	5-(difluoromethoxy)-1H-benzimidazole-2-thiol; 5-(difluoromethoxy)-1H-benzimidazol-2-ylhydrosulfide		C₈H₆F₂N₂OS	详情	详情
(IV)	14035	2-(Chloromethyl)-3,4-dimethoxypyridine; 2-(Chloromethyl)-3-methoxy-4-pyridinyl methyl ether	72830-09-2	C₈H₁₀ClNO₂	详情	详情
(V)	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
(V)	45192	2-([[5-(difluoromethoxy)-1H-benzimidazol-2-yl]sulfanyl]methyl)-3-methoxy-4-pyridinyl methyl ether; 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfanyl]-1H-benzimidazole		C₁₆H₁₅F₂N₃O₃S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

Using [14C]-labeled (IV) in the preceding synthesis, pantoprazole labeled in the methylene was obtained. Intermediate (IV) labeled in the methylene attached to the pyridine ring can be prepared as follows: The reaction of 2-bromo-3,4-dimethoxypyridine (V) with [14C]-labeled CuCN gives 3,4-dimethoxypyridine-2-carbonitrile (VI), which is hydrolyzed with NaOH and methylated with diazomethane to the methyl ester (VII). Finally, this compound is reduced with LiAlH4 to the corresponding alcohol and treated with SOCl2 to give the chloromethylpyridine (IV*) with the [14C] label. Then this compound is condensed with benzimidazole (III) as usual.

参考文献中间体

合成目标

【1】 Saunders, D.; Lawrie, K.W.M.; Crowe, A.M.; Johnston, C.E.A.; The synthesis of [14C]pantoprazole - SK&F 96022Z - An H+/K+ ATP inhibitor. J Label Compd Radiopharm 1992, 31, 5, 409.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	14035	2-(Chloromethyl)-3,4-dimethoxypyridine; 2-(Chloromethyl)-3-methoxy-4-pyridinyl methyl ether	72830-09-2	C₈H₁₀ClNO₂	详情	详情
(IV)	45195	2-(chloromethyl)-3-methoxy-4-pyridinyl methyl ether; 2-(chloromethyl)-3,4-dimethoxypyridine		C₈H₁₀ClNO₂	详情	详情
(V)	14037	2-Bromo-3-methoxy-4-pyridinyl methyl ether; 2-Bromo-3,4-dimethoxypyridine		C₇H₈BrNO₂	详情	详情
(VI)	14038	3,4-Dimethoxy-2-pyridinecarbonitrile		C₈H₈N₂O₂	详情	详情
(VI)	45193	3,4-dimethoxy-2-pyridinecarbonitrile		C₈H₈N₂O₂	详情	详情
(VII)	14039	methyl 3,4-dimethoxy-2-pyridinecarboxylate		C₉H₁₁NO₄	详情	详情
(VII)	45194	methyl 3,4-dimethoxy-2-pyridinecarboxylate		C₉H₁₁NO₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XIII)

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4

该中间体在本合成路线中的序号：(II)

参考文献中间体

合成目标

【1】 Modi PA, Motiwala JK, Durlabhaji C. 1997. A process for the manufacture of 5-(difluorometboxy)-2- [[ (3,4-dimethoxy-2-pyridinyl methyl] sulfinyl] -lH-benzimidazole, i, e, the antiulcer agent pantoprazole, via oxidation of its thio analog. IN 179805(本专利属于Unichem Laboratories Ltd．India)

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)	66569	5-(difluoromethoxy)-1H-benzo[d]imidazole-2(3H)-thione	97963-62-7	C₈H₆F₂N₂OS	详情	详情
(II)	14035	2-(Chloromethyl)-3,4-dimethoxypyridine; 2-(Chloromethyl)-3-methoxy-4-pyridinyl methyl ether	72830-09-2	C₈H₁₀ClNO₂	详情	详情
(III)	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

Extended Information