【结 构 式】 |
【药物名称】 【化学名称】4-[2-[2(S)-Azetidinyl]ethoxy]-7-chloro-2-oxo-N-(4-pyrimidinyl)-3-(3,4,5-trimethylphenyl)-1,2-dihydroquinoline-6-carboxamide dihydrochloride 【CA登记号】199861-41-1 (free base) 【 分 子 式 】C28H30Cl3N5O3 【 分 子 量 】590.942 |
【开发单位】Merck & Co. (Originator) 【药理作用】ENDOCRINE DRUGS, Endometriosis Therapy, Gynecological Disorders, Treatment of , ONCOLYTIC DRUGS, GnRH (LHRH) Antagonists |
合成路线1
Treatment of methyl 4-chloroanthranilate (I) with iodine and silver sulfate afforded the 5-iodinated derivative (II). The amino group of (II) was then protected by acylation with acetyl chloride to give amide (III). Carbonylation of the aryl iodide (III) with palladium catalyst under CO atmosphere in DMF/MeOH provided the isophthalate diester (IV). Acid hydrolysis of the acetamido group of (IV), followed by acylation of the resultant amine (V) with 3,4,5-trimethylphenylacetyl chloride, (VI) furnished amide (VII). Quinolone (VIII) was then formed by cyclization of (VII) under basic conditions. Subsequent Mitsunobu coupling of (VIII) with (S)-N-Boc-2-(2-hydroxyethyl)azetidine (IX) provided ether (X). After hydrolysis of the methyl ester of (X) with LiOH, the resulting acid (XI) was coupled with 4-aminopyrimidine (XII) in the presence of EDC to give amide (XIII). The N-Boc group of (XIII) was then deprotected by treatment with trifluoroacetic acid, and the title compound was isolated after conversion to the dihydrochloride salt.
【1】 Walsh, T.F.; Young, J.R.; DeVita, R.J.; et al.; A potent, nonpeptidyl 1H-quinolone antagonist for the gonadotropin-releasing hormone receptor. J Med Chem 2001, 44, 6, 917. |
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) | 49161 | 4-Chloroanthranilic acid methyl ester; Methyl 4-chloroanthranilate; Methyl 2-amino-4-chlorobenzoate; 2-Amino-4-chlorobenzoic acid methyl ester | 5900-58-3 | C8H8ClNO2 | 详情 | 详情 |
(II) | 49162 | methyl 2-amino-4-chloro-5-iodobenzoate | C8H7ClINO2 | 详情 | 详情 | |
(III) | 49163 | methyl 2-(acetamido)-4-chloro-5-iodobenzoate | C10H9ClINO3 | 详情 | 详情 | |
(IV) | 49164 | dimethyl 4-(acetamido)-6-chloroisophthalate | C12H12ClNO5 | 详情 | 详情 | |
(V) | 49165 | dimethyl 4-amino-6-chloroisophthalate | C10H10ClNO4 | 详情 | 详情 | |
(VI) | 49166 | 2-(3,4,5-trimethylphenyl)acetyl chloride | C11H13ClO | 详情 | 详情 | |
(VII) | 49167 | dimethyl 4-chloro-6-[[2-(3,4,5-trimethylphenyl)acetyl]amino]isophthalate | C21H22ClNO5 | 详情 | 详情 | |
(VIII) | 49168 | methyl 7-chloro-4-hydroxy-2-oxo-3-(3,4,5-trimethylphenyl)-1,2-dihydro-6-quinolinecarboxylate | C20H18ClNO4 | 详情 | 详情 | |
(IX) | 49169 | tert-butyl (2S)-2-(2-hydroxyethyl)-1-azetidinecarboxylate | C10H19NO3 | 详情 | 详情 | |
(X) | 49170 | methyl 4-[2-[(2S)-1-(tert-butoxycarbonyl)azetidinyl]ethoxy]-7-chloro-2-oxo-3-(3,4,5-trimethylphenyl)-1,2-dihydro-6-quinolinecarboxylate | C30H35ClN2O6 | 详情 | 详情 | |
(XI) | 49171 | 4-[2-[(2S)-1-(tert-butoxycarbonyl)azetidinyl]ethoxy]-7-chloro-2-oxo-3-(3,4,5-trimethylphenyl)-1,2-dihydro-6-quinolinecarboxylic acid | C29H33ClN2O6 | 详情 | 详情 | |
(XII) | 49172 | 4-Aminopyrimidine | C4H5N3 | 详情 | 详情 | |
(XIII) | 49173 | tert-butyl (2S)-2-(2-[[7-chloro-2-oxo-6-[(4-pyrimidinylamino)carbonyl]-3-(3,4,5-trimethylphenyl)-1,2-dihydro-4-quinolinyl]oxy]ethyl)-1-azetidinecarboxylate | C33H36ClN5O5 | 详情 | 详情 |