• English
  • 简体中文
Login Register
Current Location: Home > Feedback Help Print

【结 构 式】

【药物名称】

【化学名称】2-[5-Amino-2-(4-fluorophenyl)-6-oxo-1,6-dihydropyrimidin-1-yl]-N-(1-benzyl-3,3,3-trifluoro-2-oxopropyl)acetamide

【CA登记号】184709-50-0

【 分 子 式 】C22H18F4N4O3

【 分 子 量 】462.40736

【开发单位】Mitsubishi Pharma (Originator)

【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, RESPIRATORY DRUGS, Chymase Inhibitors

合成路线1

The intermediate pyrimidineacetic acid (X) was prepared as follows. 4-Fluorobenzonitrile (I) was converted to the corresponding imidate (II) by treatment with ethanolic HCl. Reaction of imidate (II) with aminoacetaldehyde diethyl acetal (III) produced amidine (IV), which was condensed with diethyl ethoxymethylenemalonate (V) in boiling EtOH to furnish pyrimidinone (VI). Hydrolysis of the ethyl ester function of (VI) was carried out by treatment with LiI in hot pyridine. The resulting carboxylic acid (VII) was then subjected to a Curtius rearrangement with diphenylphosphoryl azide, and the intermediate isocyanate was subsequently condensed with benzyl alcohol, producing the benzyl carbamate (VIII). Acid hydrolysis of the diethyl acetal group of (VIII) gave aldehyde (IX), which was then oxidized to carboxylic acid (X) by using sodium chlorite.

1 Akahoshi, F.; Yoshimura, T.; Eda, M.; Ashimori, A.; Fukuyama, H.; Nakajima, M.; Imada, T.; Okunishi, H.; Miyazaki, M. (Welfide Corporation); Heterocyclic amide cpds. and medicinal use of the same. EP 0826671; US 5948785; WO 9633974 .
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) 14144 4-Fluorobenzonitrile 1194-02-1 C7H4FN 详情 详情
(II) 49074 ethyl 4-fluorobenzenecarboximidoate C9H10FNO 详情 详情
(III) 10331 2,2-Diethoxy-1-ethanamine; 2,2-Diethoxyethylamine; Aminoacetaldehyde diethyl acetal 645-36-3 C6H15NO2 详情 详情
(IV) 49075 N-(2,2-diethoxyethyl)-4-fluorobenzenecarboximidamide C13H19FN2O2 详情 详情
(V) 14088 Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate 87-13-8 C10H16O5 详情 详情
(VI) 49076 ethyl 1-(2,2-diethoxyethyl)-2-(4-fluorophenyl)-6-oxo-1,6-dihydro-5-pyrimidinecarboxylate C19H23FN2O5 详情 详情
(VII) 49077 1-(2,2-diethoxyethyl)-2-(4-fluorophenyl)-6-oxo-1,6-dihydro-5-pyrimidinecarboxylic acid C17H19FN2O5 详情 详情
(VIII) 49078 benzyl 1-(2,2-diethoxyethyl)-2-(4-fluorophenyl)-6-oxo-1,6-dihydro-5-pyrimidinylcarbamate C24H26FN3O5 详情 详情
(IX) 49079 benzyl 2-(4-fluorophenyl)-6-oxo-1-(2-oxoethyl)-1,6-dihydro-5-pyrimidinylcarbamate C20H16FN3O4 详情 详情
(X) 49080 2-[5-[[(benzyloxy)carbonyl]amino]-2-(4-fluorophenyl)-6-oxo-1(6H)-pyrimidinyl]acetic acid C20H16FN3O5 详情 详情

合成路线2

Acylation of phenylalanine (XI) with benzoyl chloride (XII) under Schotten-Baumann conditions produced the corresponding benzamide (XIII). The cyclization of benzoylphenylalanine (XIII) in the presence of acetic anhydride afforded oxazolone (XIV), which was then reacted with trifluoroacetic anhydride producing the trifluoromethyl ketone (XV). After ketone (XV) reduction to carbinol (XVI) with NaBH4, the acidic hydrolysis of the benzamido group of (XVI) yielded the amino alcohol (XVII) (1). Condensation of acid (X) with amine (XVII) using EDC and HOBt gave amide (XVIII). The hydroxyl group of (XVIII) was then oxidized to ketone (XIX) employing a modified Pfitzner-Moffatt oxidation. Finally, hydrogenolysis of the benzyloxycarbonyl group of (XIX) furnished the desired aminopyrimidinone.

1 Akahoshi, F.; Ashimori, A.; Yoshimura, T.; et al.; Non-peptidic inhibitors of human chymase. Synthesis, structure-activity relationships, and pharmacokinetic profiles of a series of 5-amino-6-oxo-1,6-dihydropyrimidine-containing trifluoromethyl ketones. Bioorg Med Chem 2001, 9, 2, 301.
2 Akahoshi, F.; Yoshimura, T.; Eda, M.; Ashimori, A.; Fukuyama, H.; Nakajima, M.; Imada, T.; Okunishi, H.; Miyazaki, M. (Welfide Corporation); Heterocyclic amide cpds. and medicinal use of the same. EP 0826671; US 5948785; WO 9633974 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 49080 2-[5-[[(benzyloxy)carbonyl]amino]-2-(4-fluorophenyl)-6-oxo-1(6H)-pyrimidinyl]acetic acid C20H16FN3O5 详情 详情
(XI) 26219 Phenylalanine 150-30-1 C9H11NO2 详情 详情
(XII) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(XIII) 49081 N-Benzoyl-DL-phenylalanine 2901-76-0 C16H15NO3 详情 详情
(XIV) 49082 4-Benzyl-2-phenyl-2-oxazolin-5-one 5874-61-3 C16H13NO2 详情 详情
(XV) 49083 N-(1-benzyl-3,3,3-trifluoro-2-oxopropyl)benzamide C17H14F3NO2 详情 详情
(XVI) 49084 N-(1-benzyl-3,3,3-trifluoro-2-hydroxypropyl)benzamide C17H16F3NO2 详情 详情
(XVII) 49085 3-amino-1,1,1-trifluoro-4-phenyl-2-butanol C10H12F3NO 详情 详情
(XVIII) 49086 benzyl 1-[2-[(1-benzyl-3,3,3-trifluoro-2-hydroxypropyl)amino]-2-oxoethyl]-2-(4-fluorophenyl)-6-oxo-1,6-dihydro-5-pyrimidinylcarbamate C30H26F4N4O5 详情 详情
(XIX) 49087 benzyl 1-[2-[(1-benzyl-3,3,3-trifluoro-2-oxopropyl)amino]-2-oxoethyl]-2-(4-fluorophenyl)-6-oxo-1,6-dihydro-5-pyrimidinylcarbamate C30H24F4N4O5 详情 详情
Extended Information