methyl 4-(acetamido)-2-hydroxybenzoate -Drug Synthesis Database

【结构式】

【分子编号】12330

【品名】methyl 4-(acetamido)-2-hydroxybenzoate

【CA登记号】

【分子式】C₁₀H₁₁NO₄

【分子量】209.20168

【元素组成】C 57.41% H 5.3% N 6.7% O 30.59%

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：(I)

The starting compounds (IV) and (VII) are obtained as follows: a) Methyl 4-acetylamino-2-hydroxybenzoate (I) is converted to the 2-ethoxy derivative (II) with ethyl iodide, and then chlorination of (II) with N-chlorosuccinimide followed by alkaline hydrolysis of (III) gives benzoic acid (IV). b) The reaction of 2-[(4-fluorobenzyl)amino]ethanol (V) with N-(2,3-epoxypropyl)phthalimide (VI), followed by treatment with concentrated sulfuric acid, affords intermediate (VII). The condensation of 4-Amino-5-chloro-2-ethoxybenzoic acid (IV) with 4-(4-fluorobenzyl)-2-(methylamino) morpholine (VII) by means of ethyl chloroformate and triethylamine in CHCl3 gives 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl] benzamide, which is converted to mosapride citrate, by treatment with citric acid.

参考文献中间体

合成目标

【1】 Kato, S.; Yoshida, N.; Ito, T.; Mosapride Citrate. Drugs Fut 1993, 18, 6, 513.
【2】 Kato, S.; Morie, T.; Hino, K.; Kon, T.; Naruto, S.; Yoshida, N.; Karasawa, T.; Matsumoto, J.; Novel benzamides as selective and potent gastrokinetic agents. 1. Synthesis and structure-activity relationships of N[4-(2-morpholinyl)alkyl]benzamides. J Med Chem 1990, 33, 5, 1406-13.
【3】 Kato, S.; Morie, T.; Hino, K.; Kon, T.; Naruto, S.; Yoshida, N.; Karasawa, T.; Matsumoto, J.; Novel benzamides as selective and potent gastrokinetic agents. 1. Synthesis and structure-activity relationships of N[4-(2-morpholinyl)alkyl]benzamides. J Med Chem 1990, 33, 5, 1406-13.

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)	12330	methyl 4-(acetamido)-2-hydroxybenzoate		C₁₀H₁₁NO₄	详情	详情
(II)	12331	Methyl 4-acetamido-2-ethoxybenzoate; methyl 4-(acetamido)-2-ethoxybenzoate	59-06-3	C₁₂H₁₅NO₄	详情	详情
(III)	12332	methyl 4-(acetamido)-5-chloro-2-ethoxybenzoate		C₁₂H₁₄ClNO₄	详情	详情
(IV)	12333	4-Amino-5-chloro-2-ethoxybenzoic acid		C₉H₁₀ClNO₃	详情	详情
(V)	12334	2-[(4-Fluorobenzyl)amino]-1-ethanol		C₉H₁₂FNO	详情	详情
(VI)	12335	2-(2-Oxiranylmethyl)-1H-isoindole-1,3(2H)-dione; N-(2,3-Epoxypropyl)phtalimide	5455-98-1	C₁₁H₉NO₃	详情	详情
(VII)	12336	[4-(4-Fluorobenzyl)-1,4-oxazinan-2-yl]methylamine; [4-(4-Fluorobenzyl)-1,4-oxazinan-2-yl]methanamine; 2-Aminomethyl-4-(4-fluorobenzyl)morpholine	112914-13-3	C₁₂H₁₇FN₂O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Alkylation of methyl 4-(acetylamino)-2-hydroxybenzoate (I) with propargyl bromide (II) in the presence of K2CO3 in refluxing acetonitrile gave propargyl ether (III), and subsequent chlorination with N-chlorosuccinimide in DMF yielded (IV). Then, a Claisen-type rearrangement of (IV) in boiling diphenyl ether furnished the benzopyran (V), which was hydrogenated over Pt/C to give dihydrobenzopyran (VI). Subsequent treatment of (VI) with 4 N KOH produced the hydrolysis of both ester and amide functions, affording acid (VII). Treatment of dicyclopropyl ketone (VIII) with HCl gas provided 1,7-dichloro-4-heptanone (IX). Cyclization of (IX) with cyanoacetic acid in a two-phase system of aqueous ammonia and n-hexane gave bicyclic intermediate (X), which upon decarboxylation yielded nitrile (XI). Subsequent hydrogenation in the presence of Raney-Ni and NaOH furnished 5-(2-aminoethyl)-1-azabicyclo[3.3.0]octane (XII) (3). The title compound was then obtained by coupling of acid (VII) with amine (XII) using carbonyldiimidazole (CDI), followed by conversion to the hemifumarate salt.

参考文献中间体

合成目标

【1】 Kakigami, T.; et al.; Synthesis and structure-activity relationship of 3-substituted benzamide, benzo[b]furan-7-carboxamide, 2,3-dihydrobenzo[b]furan-7-carboxamide, and indole-5-carboxamide derivatives as selective serotonin 5-HT4 receptor agonists. Chem Pharm Bull 1998, 46, 1, 42.
【2】 Suzuki, T.; et al.; N-[2-(1-Azabicyclo[3.3.0]octan-5-yl)ethyl]-2-nitroaniline, a potent muscarinic agonist. Chem Pharm Bull 1997, 45, 7, 1218.
【3】 Kakigami, T.; et al.; A 3D-quantitative structure-activity relationship study of benzamide type serotonin 5-HT4 receptor agonists based on a comparative molecular field analysis model, and the design and synthesis of potent agonists. Chem Pharm Bull 1998, 46, 12, 1881.

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)	12330	methyl 4-(acetamido)-2-hydroxybenzoate		C₁₀H₁₁NO₄	详情	详情
(II)	11176	3-Bromopropyne; 3-Bromo-1-propyne	106-96-7	C₃H₃Br	详情	详情
(III)	19907	methyl 4-(acetamido)-2-(2-propynyloxy)benzoate		C₁₃H₁₃NO₄	详情	详情
(IV)	19908	methyl 4-(acetamido)-5-chloro-2-(2-propynyloxy)benzoate		C₁₃H₁₂ClNO₄	详情	详情
(V)	19909	methyl 5-(acetamido)-6-chloro-2H-chromene-8-carboxylate		C₁₃H₁₂ClNO₄	详情	详情
(VI)	19910	methyl 5-(acetamido)-6-chloro-8-chromanecarboxylate		C₁₃H₁₄ClNO₄	详情	详情
(VII)	19911	5-amino-6-chloro-8-chromanecarboxylic acid		C₁₀H₁₀ClNO₃	详情	详情
(VIII)	19912	Dicyclopropylmethanone; Dicyclopropyl ketone	1121-37-5	C₇H₁₀O	详情	详情
(IX)	19913	1,7-dichloro-4-heptanone	40624-07-5	C₇H₁₂Cl₂O	详情	详情
(X)	19914	2-cyano-2-tetrahydro-1H-pyrrolizin-7(5H)-ylacetic acid		C₁₀H₁₄N₂O₂	详情	详情
(XI)	19915	2-tetrahydro-1H-pyrrolizin-7(5H)-ylacetonitrile		C₉H₁₄N₂	详情	详情
(XII)	19916	2-tetrahydro-1H-pyrrolizin-7(5H)-ylethylamine; 2-tetrahydro-1H-pyrrolizin-7(5H)-yl-1-ethanamine		C₉H₁₈N₂	详情	详情

Extended Information