methyl 4-(butyrylamino)-3-methylbenzoate -Drug Synthesis Database

【结构式】

【分子编号】16131

【品名】methyl 4-(butyrylamino)-3-methylbenzoate

【CA登记号】

【分子式】C₁₃H₁₇NO₃

【分子量】235.28292

【元素组成】C 66.36% H 7.28% N 5.95% O 20.4%

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：(III)

The acylation of 4-amino-3-methylbenzoic acid methyl ester (I) with butyryl chloride (II) in hot chlorobenzene gives the corresponding amide (III), which is nitrated with HNO3/H2SO4 yielding 4-butyramido-3-methyl-5-nitrobenzoic acid methyl ester (IV). The hydrogenation of (IV) with H2 over Pd/C in methanol affords the expected amino compound (V), which is cyclized in refluxing acetic acid to 2-propyl-4-methylbenzimidazole-6-carboxylic acid methyl ester (VI). The hydrolysis of (VI) with NaOH in refluxing methanol/water affords the corresponding free acid (VII), which is cyclized with N-methyl-o-phenylenediamine (VIII) by means of polyphosphoric acid (PPA) at 150 C, giving 4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propylbenzimidazole (IX). The condensation of (IX) with 4'-(bromomethyl)biphenyl-4-carboxylic acid tert-butyl ester (X) by means of potassium tert-butoxide in DMSO yields the tert-butyl ester (XI), which is finally hydrolyzed with trifluoroacetic acid.

参考文献中间体

合成目标

【1】 Merlos, M.; Casas, A.; Castaner, J.; Telmisartan. Drugs Fut 1997, 22, 10, 1112.
【2】 Hauel, N.; Narr, B.; Ries, U.; Van Meel, J.; Wienen, W.; Entzeroth, M. (Dr. Karl Thomae GmbH); Benzimidazoles, medicaments containing them and process for their preparation. DE 4103492; DE 4117121; EP 0502314; EP 0543263; JP 1992346978 .
【3】 Ries, U.J.; Mihm, G.; Narr, B.; Hasselbach, K.M.; Wittneben, H.; Entzeroth, M.; van Meel, J.C.A.; Wienen, W.; Hauel, N.H.; 6-Substituted benzimidazoles as new nonpeptide angiotensin II receptor antagonists: Synthesis, biological activity, and structure-activity relationships. J Med Chem 1993, 36, 25, 4040-51.

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)	16129	methyl 4-amino-3-methylbenzoate		C₉H₁₁NO₂	详情	详情
(II)	10792	Butanoyl chloride; Butyryl chloride	141-75-3	C₄H₇ClO	详情	详情
(III)	16131	methyl 4-(butyrylamino)-3-methylbenzoate		C₁₃H₁₇NO₃	详情	详情
(IV)	16132	methyl 4-(butyrylamino)-3-methyl-5-nitrobenzoate		C₁₃H₁₆N₂O₅	详情	详情
(V)	16133	methyl 3-amino-4-(butyrylamino)-5-methylbenzoate		C₁₃H₁₈N₂O₃	详情	详情
(VI)	16134	methyl 4-methyl-2-propyl-1H-benzimidazole-6-carboxylate		C₁₃H₁₆N₂O₂	详情	详情
(VII)	16135	4-methyl-2-propyl-1H-benzimidazole-6-carboxylic acid		C₁₂H₁₄N₂O₂	详情	详情
(VIII)	16136	N-Methyl-1,2-phenylenediamine; N(1)-methyl-1,2-benzenediamine; N-(2-aminophenyl)-N-methylamine	4760-34-3	C₇H₁₀N₂	详情	详情
(IX)	16137	4-Methyl-6-(1-methylbenzaimidazol-2-yl)-2-propyl-1H-benzimidazole		C₁₉H₂₀N₄	详情	详情
(X)	16138	tert-butyl 4'-(bromomethyl)[1,1'-biphenyl]-2-carboxylate	114772-40-6	C₁₈H₁₉BrO₂	详情	详情
(XI)	16139	4'-[4-Methyl-6-(1-methylbenzaimidazol-2-yl)-2-propylbenzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid tert-butyl ester		C₃₇H₃₈N₄O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

L-Proline (I) is protected as its N-Boc derivative (II) with Boc2O/NaOH in a two-phase system. N-Boc-Proline (II) is further converted into diazo ketone (III) via activation with ethyl chloroformate, followed by condensation with diazomethane. Subsequent treatment of diazo ketone (III) with AcOH leads to the acetoxy ketone (IV). Then, acidic N-Boc group cleavage in (IV) furnishes amine (V). On the other side, L-proline (I) is acylated by 4-phenylbutyryl chloride to produce the corresponding amide (VI). Coupling between 2-(acetoxyacetyl)pyrrolidine (V) and N-(phenylbutyryl)proline (VI) via activation with pivaloyl chloride leads to the amide adduct (VII). Finally, methanolysis of the acetate ester group of (VII) provides the target hydroxyacetyl compound.

参考文献中间体

合成目标

【1】 Wallén, E.A.; Christiaans, J.A.M.; Saario, S.M.; Forsberg, M.M.; Venalainen, J.I.; Paso, H.M.; Mannisto, P.T.; Gynther, J.; 4-Phenylbutanoyl-2(S)-acylpyrrolidines and 4-phenylbutanoyl-L-prolyl-2(S)-acylpyrrolidines as prolyl oligopeptidase inhibitors. Bioorg Med Chem 2002, 10, 7, 2199.

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)	16131	methyl 4-(butyrylamino)-3-methylbenzoate		C₁₃H₁₇NO₃	详情	详情
(II)	16734	(2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid		C₁₀H₁₇NO₄	详情	详情
(III)	64266	(L)-2-Diazoacetyl-pyrrolidine-1-carboxylic acid tertiary-butyl ester (L)-2-Diazoacetyl-pyrrolidine-1-carboxylic acid tertiary-butyl ester (L)-2-Diazoacetyl-pyrrolidine-1-carboxylic acid tertiary-butyl ester	101130-03-4	C₁₁H₁₇N₃O₃	详情	详情
(IV)	16736	tert-butyl (2S)-2-[2-(acetoxy)acetyl]tetrahydro-1H-pyrrole-1-carboxylate		C₁₃H₂₁NO₅	详情	详情
(V)	16737	2-oxo-2-[(2S)tetrahydro-1H-pyrrol-2-yl]ethyl acetate		C₈H₁₃NO₃	详情	详情
(VI)	64267	(2S)-1-(4-phenylbutanoyl)-2-pyrrolidinecarboxylic acid		C₁₅H₁₉NO₃	详情	详情
(VII)	64268	2-oxo-2-((2S)-1-{[(2S)-1-(4-phenylbutanoyl)pyrrolidinyl]carbonyl}pyrrolidinyl)ethyl acetate		C₂₃H₃₀N₂O₅	详情	详情

Extended Information