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【结 构 式】 
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【分子编号】53082 【品名】1-(Bromomethyl)-2-chlorobenzene; 2-Chloro-alpha-bromotoluene; 2-Chlorobenzyl bromide; Alpha-Bromo-2-chlorotoluene; o-Chlorobenzyl bromide 【CA登记号】611-17-6 |
【 分 子 式 】C7H6BrCl 【 分 子 量 】205.48134 【元素组成】C 40.92% H 2.94% Br 38.89% Cl 17.25% |
合成路线1
该中间体在本合成路线中的序号：(IX)Protection of 2-amino-4-methoxycarbonylphenyl triflate (I) with benzyl chloroformate provided carbamate (II). Stille coupling of aryl triflate (II) with 1-pentynyl (tributyl)stannane (III) furnished adduct (IV), which was further cyclized to the indole derivative (V) upon treatment with gold(III)sodium chloride. The N-benzyloxycarbonyl group of (V) was then removed by catalytic hydrogenolysis, yielding indole (VI). Friedel-Crafts acylation of (VI) with isobutyryl chloride (VII) produced the 3-isobutyryl indole (VIII). Subsequent alkylation of the indole N of (VIII) with 2-chlorobenzyl bromide (IX) in the presence of NaH gave the N-benzyl derivative (X). The methyl ester group of (X) was then hydrolyzed to the carboxylic acid (XI) under basic conditions. Finally, conversion of acid (XI) to the title amide was carried out via activation with EDC/HOBt, followed by quenching with ammonium hydroxide.
| 【1】 Oku, T.; Sawada, K.; Kuroda, A.; Ohne, K.; Nomoto, A.; Hosogai, N.; Nakajima, Y.; Nagashima, A.; Sogabe, K.; Tamura, K.; Kobayashi, M. (Fujisawa Pharmaceutical Co., Ltd.); Indole derivs. as cGMP-PDE inhibitors. EP 0820441; JP 1999503445; WO 9632379 . |
| 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) | 53075 | methyl 3-amino-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate | n/a | C9H8F3NO5S | 详情 | 详情 |
| (II) | 53076 | methyl 3-{[(benzyloxy)carbonyl]amino}-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate | n/a | C17H14F3NO7S | 详情 | 详情 |
| (III) | 53077 | tributyl(1-pentynyl)stannane | n/a | C17H34Sn | 详情 | 详情 |
| (IV) | 53078 | methyl 3-{[(benzyloxy)carbonyl]amino}-4-(1-pentynyl)benzoate | n/a | C21H21NO4 | 详情 | 详情 |
| (V) | 53079 | 1-benzyl 6-methyl 2-propyl-1H-indole-1,6-dicarboxylate | n/a | C21H21NO4 | 详情 | 详情 |
| (VI) | 53080 | methyl 2-propyl-1H-indole-6-carboxylate | n/a | C13H15NO2 | 详情 | 详情 |
| (VII) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (VIII) | 53081 | methyl 3-isobutyryl-2-propyl-1H-indole-6-carboxylate | n/a | C17H21NO3 | 详情 | 详情 |
| (IX) | 53082 | 1-(Bromomethyl)-2-chlorobenzene; 2-Chloro-alpha-bromotoluene; 2-Chlorobenzyl bromide; Alpha-Bromo-2-chlorotoluene; o-Chlorobenzyl bromide | 611-17-6 | C7H6BrCl | 详情 | 详情 |
| (X) | 53083 | methyl 1-(2-chlorobenzyl)-3-isobutyryl-2-propyl-1H-indole-6-carboxylate | n/a | C24H26ClNO3 | 详情 | 详情 |
| (XI) | 53084 | 1-(2-chlorobenzyl)-3-isobutyryl-2-propyl-1H-indole-6-carboxylic acid | n/a | C23H24ClNO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)Iodination of 5-amino-4,6-dichloropyrimidine (VI) by means of NaI in concentrated HI affords the diiodopyridine (VII). Sequential alkylation of aminopyrimidine (VII) with 2-chlorobenzyl bromide (VIII) to produce (IX), and further N-methylation with iodomethane and NaH, lead to the tertiary amine (X). Ammonolysis of the diiodopyrimidine (X) with ethanolic ammonia in a sealed tube at 80 C yields amine (XI). Finally, Sonogashira coupling between acetylene (V) and iodopyrimidine (XI) in the presence of Pd(PPh3)2Cl2 and CuI furnishes the target diaryl acetylene
| 【1】 Gomtsyan, A.; et al.; Design, synthesis, and structure-activity relationship of 6-alkynylpyrimidines as potent adenosine kinase inhibitors. J Med Chem 2002, 45, 17, 3639. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 60888 | 4-(5-ethynyl-2-pyridinyl)morpholine | C11H12N2O | 详情 | 详情 | |
| (VI) | 22845 | 5-Amino-4,6-dichloropyrimidine; 4,6-dichloro-5-pyrimidinylamine; 4,6-dichloro-5-pyrimidinamine | 5413-85-4 | C4H3Cl2N3 | 详情 | 详情 |
| (VII) | 60889 | 4,6-diiodo-5-pyrimidinamine; 4,6-diiodo-5-pyrimidinylamine | C4H3I2N3 | 详情 | 详情 | |
| (VIII) | 53082 | 1-(Bromomethyl)-2-chlorobenzene; 2-Chloro-alpha-bromotoluene; 2-Chlorobenzyl bromide; Alpha-Bromo-2-chlorotoluene; o-Chlorobenzyl bromide | 611-17-6 | C7H6BrCl | 详情 | 详情 |
| (IX) | 60890 | N-(2-chlorobenzyl)-4,6-diiodo-5-pyrimidinamine; N-(2-chlorobenzyl)-N-(4,6-diiodo-5-pyrimidinyl)amine | C11H8ClI2N3 | 详情 | 详情 | |
| (X) | 60891 | N-(2-chlorobenzyl)-4,6-diiodo-N-methyl-5-pyrimidinamine; N-(2-chlorobenzyl)-N-(4,6-diiodo-5-pyrimidinyl)-N-methylamine | C12H10ClI2N3 | 详情 | 详情 | |
| (XI) | 60892 | N-(4-amino-6-iodo-5-pyrimidinyl)-N-(2-chlorobenzyl)-N-methylamine; N~5~-(2-chlorobenzyl)-6-iodo-N~5~-methyl-4,5-pyrimidinediamine | C12H12ClIN4 | 详情 | 详情 |