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【结 构 式】 
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【分子编号】64112 【品名】2-methylpropyl 5-methyl-3-(methyloxy)-2-pyrazinylcarbamate 【CA登记号】 |
【 分 子 式 】C11H17N3O3 【 分 子 量 】239.2744 【元素组成】C 55.22% H 7.16% N 17.56% O 20.06% |
合成路线1
该中间体在本合成路线中的序号：(IV)Bromination of 2-amino-5-methylpyrazine (I) with Br2 in CHCl3 affords the bromopyrazine (II). Subsequent bromide displacement in (II) by means of sodium methoxide gives rise to the methoxypyrazine (III). The amino group of (III) is then protected by acylation with isobutyl chloroformate, to produce carbamate (IV). Diazotization of 3-amino-2-chloropyridine (V), followed by treatment with sulfur dioxide in the presence of CuCl furnishes sulfonyl chloride (VI). Carbamate (IV) is then acylated by means of NaH and sulfonyl chloride (VI) in DMF to furnish the N-sulfonyl carbamate (VII). Esterification of 4-carboxyphenylboronic acid (VIII) with H2SO4 in MeOH gives 4-(methoxycarbonyl)phenylboronic acid (IX). Mitsunobu coupling between boronic acid (IX) and chloropyridine (VII) furnishes adduct (X). Methyl ester (X) is converted into hydrazide (XI) by treatment with hydrazine hydrate in refluxing methanol. Then, cyclization of the acyl hydrazide (XI) with boiling triethyl orthoformate gives rise to the target oxadiazole derivative.
| 【1】 Bradbury, R.H.; Butlin, R.J.; James, R. (AstraZeneca plc); N-Heteroaryl-pyridinesulfonamide derivs. and their use as endothelin antagonists. EP 0832082; JP 1999509175; US 6060475; US 6258817; WO 9640681 . |
| 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) | 64109 | 5-methyl-2-pyrazinamine; 5-methyl-2-pyrazinylamine | C5H7N3 | 详情 | 详情 | |
| (II) | 64110 | 3-bromo-5-methyl-2-pyrazinamine; 3-bromo-5-methyl-2-pyrazinylamine | C5H6BrN3 | 详情 | 详情 | |
| (III) | 64111 | 5-methyl-3-(methyloxy)-2-pyrazinamine; 5-methyl-3-(methyloxy)-2-pyrazinylamine | C6H9N3O | 详情 | 详情 | |
| (IV) | 64112 | 2-methylpropyl 5-methyl-3-(methyloxy)-2-pyrazinylcarbamate | C11H17N3O3 | 详情 | 详情 | |
| (V) | 11160 | 2-Chloro-3-pyridinamine; 2-Chloro-3-pyridinylamine; 3-Amino-2-chloropyridine; 2-Chloro-3-aminopyridine | 6298-19-7 | C5H5ClN2 | 详情 | 详情 |
| (VI) | 64113 | 2-chloro-3-pyridinesulfonyl chloride | C5H3Cl2NO2S | 详情 | 详情 | |
| (VII) | 64115 | 2-methylpropyl (2-chloro-3-pyridinyl)sulfonyl[5-methyl-3-(methyloxy)-2-pyrazinyl]carbamate | C16H19ClN4O5S | 详情 | 详情 | |
| (VIII) | 32841 | 4-(dihydroxyboryl)benzoic acid；4-Boronobenzoic acid；4-carboxyphenylboronic acid;4-(Dihydroxyboryl)benzoic acid | 14047-29-1 | C7H7BO4 | 详情 | 详情 |
| (IX) | 64114 | 4-[(methyloxy)carbonyl]phenylboronic acid | C8H9BO4 | 详情 | 详情 | |
| (X) | 64116 | methyl 4-{3-[([5-methyl-3-(methyloxy)-2-pyrazinyl]{[(2-methylpropyl)oxy]carbonyl}amino)sulfonyl]-2-pyridinyl}benzoate | C24H26N4O7S | 详情 | 详情 | |
| (XI) | 64117 | 2-[4-(hydrazinocarbonyl)phenyl]-N-[5-methyl-3-(methyloxy)-2-pyrazinyl]-3-pyridinesulfonamide | C18H18N6O4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)Bromination of 2-amino-5-methylpyrazine (X) with Br2 in CHCl3 affords the bromopyrazine (XI), which by subsequent bromide displacement by means of sodium methoxide in refluxing methanol gives the methoxypyrazine (XII). Then, the amino group of (XII) is protected by acylation with isobutyl chloroformate (XIII) in the presence of pyridine in CH2Cl2 to provide carbamate (XIV), which finally, after being pretreated with NaH, is sulfonylated with 2-chloropyridine-3-sulfonyl chloride (XV) in DMF. Compound (XV) is prepared from 3-amino-2-chloropyridine (XVI) by diazotization and subsequent treatment with sulfur dioxide in the presence of CuCl in AcOH .
| 【1】 Bradbury, R.H., Butlin, R.J., James, R. (AstraZeneca plc). N-Heteroarylpyridinesulfonamide derivatives and their use as endothelin antagonists. EP 0832082, JP 1999509175, US 6060475, US 6258817, WO 1996040681. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 69329 | isobutyl (2-chloropyridin-3-yl)sulfonyl(3-methoxy-5-methyl-4,5-dihydropyrazin-2-yl)carbamate | C16H21ClN4O5S | 详情 | 详情 | |
| (X) | 64109 | 5-methyl-2-pyrazinamine; 5-methyl-2-pyrazinylamine | C5H7N3 | 详情 | 详情 | |
| (XI) | 64110 | 3-bromo-5-methyl-2-pyrazinamine; 3-bromo-5-methyl-2-pyrazinylamine | C5H6BrN3 | 详情 | 详情 | |
| (XII) | 64111 | 5-methyl-3-(methyloxy)-2-pyrazinamine; 5-methyl-3-(methyloxy)-2-pyrazinylamine | C6H9N3O | 详情 | 详情 | |
| (XIII) | 13423 | 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate | 543-27-1 | C5H9ClO2 | 详情 | 详情 |
| (XIV) | 64112 | 2-methylpropyl 5-methyl-3-(methyloxy)-2-pyrazinylcarbamate | C11H17N3O3 | 详情 | 详情 | |
| (XV) | 64113 | 2-chloro-3-pyridinesulfonyl chloride | C5H3Cl2NO2S | 详情 | 详情 | |
| (XVI) | 11160 | 2-Chloro-3-pyridinamine; 2-Chloro-3-pyridinylamine; 3-Amino-2-chloropyridine; 2-Chloro-3-aminopyridine | 6298-19-7 | C5H5ClN2 | 详情 | 详情 |