methyl 4-(4-pyridinyl)benzoate -Drug Synthesis Database

【结构式】

【分子编号】58218

【品名】methyl 4-(4-pyridinyl)benzoate

【CA登记号】

【分子式】C₁₃H₁₁NO₂

【分子量】213.23588

【元素组成】C 73.23% H 5.2% N 6.57% O 15.01%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(X)

The cycloaddition reaction between 4-vinylpyridine (VIII) and methyl coumalate (IX) in hot mesitylene gives rise to the pyridyl benzoate (X). After saponification of the ester group of (X), the resultant carboxylic acid (XI) is converted to acid chloride (XII) by treatment with SOCl2. Acylation of amino ester (V) by acid chloride (XII) affords amide (XIII). The pyridine N of (XIII) is then oxidized to the corresponding N-oxide (XIV) employing m-chloroperbenzoic acid. Finally, conversion of the cyano group of (XIV) into the title amidine is accomplished by Pinner reaction, via formation of the intermediate imidate (XV), which is subsequently treated with methanolic ammonia.

参考文献中间体

合成目标

【1】 Guertin, K.R.; et al.; Optimization of the beta-aminoester class of factor Xa inhibitors. Part 2: Identification of FXV673 as a potent and selective inhibitor with excellent in vivo anticoagulant activity. Bioorg Med Chem Lett 2002, 12, 12, 1671.
【2】 Guertin, K.R.; Klein, S.I.; Spada, A.P. (Aventis Pharma SA); Substd. N-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides. EP 0906094; JP 2000502710; US 6080767; WO 9724118 .
【3】 Gong, Y.; Guertin, K.R.; McGarry, D.G.; Pauls, H.W.; Klein, S.I.; Spada, A.P. (Aventis Pharmaceuticals, Inc.); Substd. N-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides. CA 2264556; EP 0931060; WO 9900356 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(V)	38459	methyl (2R,3R)-3-amino-2-(3-cyanobenzyl)butanoate	C₁₃H₁₆N₂O₂	详情	详情
(VIII)	45857	4-vinylpyridine	C₇H₇N	详情	详情
(IX)	58217	methyl 2-oxo-2H-pyran-5-carboxylate; methyl coumalate	C₇H₆O₄	详情	详情
(X)	58218	methyl 4-(4-pyridinyl)benzoate	C₁₃H₁₁NO₂	详情	详情
(XI)	58219	4-(4-pyridinyl)benzoic acid	C₁₂H₉NO₂	详情	详情
(XII)	58220	4-(4-pyridinyl)benzoyl chloride	C₁₂H₈ClNO	详情	详情
(XIII)	58221	methyl (2R,3R)-2-(3-cyanobenzyl)-3-{[4-(4-pyridinyl)benzoyl]amino}butanoate	C₂₅H₂₃N₃O₃	详情	详情
(XIV)	58222	4-[4-({[(1R,2R)-2-(3-cyanobenzyl)-3-methoxy-1-methyl-3-oxopropyl]amino}carbonyl)phenyl]-1-pyridiniumolate	C₂₅H₂₃N₃O₄	详情	详情
(XV)	58223	4-(4-{[((1R,2R)-2-{3-[imino(methoxy)methyl]benzyl}-3-methoxy-1-methyl-3-oxopropyl)amino]carbonyl}phenyl)-1-pyridiniumolate	C₂₆H₂₇N₃O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

The cycloaddition reaction between 4-vinylpyridine (I) and methylcoumalate (II) in hot mesitylene in the presence of Pd/C gives the methyl pyridylbenzoate (III), which is hydrolyzed with NaOH in H2O/MeOH/THF and the resulting carboxylic acid (IV) is converted to the acid chloride (V) upon refluxing with SOCl2 . Acylation of the amino ester (VI) using either pyridylbenzoic acid (IV) by means of TBTU and NMM in DMF or acid chloride (V) in the presence of Et3N in EtOH affords amide (VII), which is then oxidized at the pyridine nitrogen with m-chloroperbenzoic acid or magnesium monoperoxyphthalate in CH2Cl2 to provide the corresponding Noxide (VIII). Finally, nitrile (VIII) is submitted to Pinner reaction with HCl in cold MeOH to afford imidate (IX), followed by heating with methanolic ammonia .

参考文献中间体

合成目标

【1】 Guertin, K.R., Klein, S.I., Spada, A.P. (sanofi-aventis [FR]). Substituted N-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides. EP 0906094, JP 2000502710, US 6080767, WO 1997024118.
【2】 Klein, S.I., Guertin, K.R., McGarry, D.G., Gong, Y., Pauls, H.W., Spada, A.P. (sanofi-aventis US LLC). Substituted N-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides. CA 2264556, EP 0931060, JP 2001500532, WO 1999000356.
【3】 Guertin, K.R., Gardner, C.J., Klein, S.I. et al. Optimization of the betaaminoester class of factor Xa inhibitors. Part 2: Identification of FXV673 as a potent and selective inhibitor with excellent in vivo anticoagulant activity. Bioorg Med Chem Lett 2002, 12(12): 1671-4.
【4】 Teager, D.S., Woodward, R.G. (sanofi-aventis US LLC). Novel crystalline forms of a factor Xa inhibitor. JP 2004521082, US 2003225144, WO 2002028836.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	45857	4-vinylpyridine	C₇H₇N	详情	详情
(II)	58217	methyl 2-oxo-2H-pyran-5-carboxylate; methyl coumalate	C₇H₆O₄	详情	详情
(III)	58218	methyl 4-(4-pyridinyl)benzoate	C₁₃H₁₁NO₂	详情	详情
(IV)	58219	4-(4-pyridinyl)benzoic acid	C₁₂H₉NO₂	详情	详情
(V)	58220	4-(4-pyridinyl)benzoyl chloride	C₁₂H₈ClNO	详情	详情
(VI)	38459	methyl (2R,3R)-3-amino-2-(3-cyanobenzyl)butanoate	C₁₃H₁₆N₂O₂	详情	详情
(VII)	58221	methyl (2R,3R)-2-(3-cyanobenzyl)-3-{[4-(4-pyridinyl)benzoyl]amino}butanoate	C₂₅H₂₃N₃O₃	详情	详情
(VIII)	58222	4-[4-({[(1R,2R)-2-(3-cyanobenzyl)-3-methoxy-1-methyl-3-oxopropyl]amino}carbonyl)phenyl]-1-pyridiniumolate	C₂₅H₂₃N₃O₄	详情	详情
(IX)	58223	4-(4-{[((1R,2R)-2-{3-[imino(methoxy)methyl]benzyl}-3-methoxy-1-methyl-3-oxopropyl)amino]carbonyl}phenyl)-1-pyridiniumolate	C₂₆H₂₇N₃O₅	详情	详情

Extended Information