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【结 构 式】 
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【分子编号】49161 【品名】4-Chloroanthranilic acid methyl ester; Methyl 4-chloroanthranilate; Methyl 2-amino-4-chlorobenzoate; 2-Amino-4-chlorobenzoic acid methyl ester 【CA登记号】5900-58-3 |
【 分 子 式 】C8H8ClNO2 【 分 子 量 】185.60976 【元素组成】C 51.77% H 4.34% Cl 19.1% N 7.55% O 17.24% |
合成路线1
该中间体在本合成路线中的序号：(I)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 |
合成路线2
该中间体在本合成路线中的序号：(I)Condensation of methyl 4-chloroanthranilate (I) with dimethyl butynedioate (II), followed by cyclization in the presence of potassium tert-butoxide leads to the quinolone dicarboxylate (III). Partial hydrolysis of diester (III) under basic conditions affords mono-acid (IV), which is converted to acid chloride (V) by treatment with SOCl2. Condensation of acid chloride (V) with pyrrolidine provides the corresponding amide (VI). The methyl ester group of (VI) is subsequently hydrolyzed with NaOH to afford the intermediate acid (VII).
| 【1】 Horchler, C.L.; et al.; Synthesis of 7-chloro-4-hydroxy-2-(3-(aryl/heteroaryl)prop-2-ynyl)1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-diones (PQD I); potent oral glycine antagonists. 28th Natl Med Chem Symp (June 8 2002, San Diego) 2002, Abst 19. |
| 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) | 24551 | Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester | 762-42-5 | C6H6O4 | 详情 | 详情 |
| (III) | 58494 | dimethyl 7-chloro-4-oxo-1,4-dihydro-2,3-quinolinedicarboxylate | C13H10ClNO5 | 详情 | 详情 | |
| (IV) | 58495 | 7-chloro-3-(methoxycarbonyl)-4-oxo-1,4-dihydro-2-quinolinecarboxylic acid | C12H8ClNO5 | 详情 | 详情 | |
| (V) | 58496 | methyl 7-chloro-2-(chlorocarbonyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C12H7Cl2NO4 | 详情 | 详情 | |
| (VI) | 58497 | methyl 7-chloro-4-oxo-2-(1-pyrrolidinylcarbonyl)-1,4-dihydro-3-quinolinecarboxylate | C16H15ClN2O4 | 详情 | 详情 | |
| (VII) | 58498 | 7-chloro-4-oxo-2-(1-pyrrolidinylcarbonyl)-1,4-dihydro-3-quinolinecarboxylic acid | C15H13ClN2O4 | 详情 | 详情 |