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【结 构 式】 
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【药物名称】ZD-4054;Zibotentan 【化学名称】N-(3-Methoxy-5-methylpyrazin-2-yl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]pyridine-3-sulfonamide 【CA登记号】186497-07-4 【 分 子 式 】C19H16N6O4S 【 分 子 量 】424.44117 |
【开发单位】AstraZeneca (Originator), National Cancer Institute (Codevelopment) 【药理作用】Oncolytic Drugs, Prostate Cancer Therapy, Solid Tumors Therapy, Antimitotic Drugs, Endothelin ETA Receptor Antagonists |
合成路线1
In one strategy, condensation of 4-bromobenzohydrazide (I) with HC(OEt)3 in the presence of H2SO4 in refluxing methylated spirit gives 2-(4-bromophenyl)-1,3,4-oxadiazole (II), which upon treatment with (i-PrO)3B in the presence of MeLi and BuLi in THF at –65 °C affords the boronic acid derivative (III). Suzuki coupling between the boronic acid (III) and the chloropyridine derivative (IV) in the presence of Pd(OAc)2, 3,3′,3′′-phosphinidynetris(benzenesulfonic acid) trisodium salt (TPPTS) and NMM in H2O/i-PrOH at 83 °C affords N-protected zibotentan (V). Finally, intermediate (V) is deprotected with ethanolamine in H2O/i-PrOH at 42 °C or with NH3 in H2O/methylated spirit at 60 °C and acidified with AcOH in H2O .
In a second strategy, 4-carboxyphenylboronic acid (VI) is esterified with MeOH in the presence of H2SO4, yielding boronic acid (VII), which undergoes Suzuki coupling with the chloropyridine derivative (IV) in the presence of Pd(PPh3)4 and KF in refluxing toluene/H2O to provide adduct (VIII). Finally, methyl ester (VIII) is converted to hydrazide (IX) by treatment with hydrazine hydrate in refluxing methanol and cyclized by condensation with refluxing HC(OEt)3 .
| 【1】 Brear, C., Hogan, P., Montgomery, F. (AstraZeneca AB). Ethanolamine salt of N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-[1,3,4-oxadiazole-2-yl]phenyl) pyridine3-sulphonamide. WO 2007010235. |
| 【2】 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 |
|---|---|---|---|---|---|---|
| (I) | 69326 | 4-bromobenzohydrazide;(4-Bromobenzoyl)hydrazine;(p-Bromobenzoyl)hydrazine;4-Bromobenzenecarboxylic acid hydrazide;4-Bromobenzhydrazide;4-Bromobenzohydrazide;4-Bromobenzoic acid hydrazide;4-Bromobenzoic hydrazide;4-Bromobenzoyl hydrazide;INHd 16;NSC 60114;p-Bromobenzhydrazide;p-Bromobenzoic acid hydrazide;p-Bromobenzoic hydrazide | 5933-32-4 | C7H7BrN2O | 详情 | 详情 |
| (II) | 69327 | 2-(4-bromophenyl)-1,3,4-oxadiazole；2-(4-bromophenyl)-1,3,4-oxadiazole | C8H5BrN2O | 详情 | 详情 | |
| (III) | 69328 | (4-(1,3,4-oxadiazol-2-yl)phenyl)boronic acid | C8H7BN2O3 | 详情 | 详情 | |
| (IV) | 69329 | isobutyl (2-chloropyridin-3-yl)sulfonyl(3-methoxy-5-methyl-4,5-dihydropyrazin-2-yl)carbamate | C16H21ClN4O5S | 详情 | 详情 | |
| (V) | 69330 | isobutyl (2-(4-(1,3,4-oxadiazol-2-yl)phenyl)pyridin-3-yl)sulfonyl(3-methoxy-5-methylpyrazin-2-yl)carbamate | C24H24N6O6S | 详情 | 详情 | |
| (VI) | 32841 | 4-(dihydroxyboryl)benzoic acid；4-Boronobenzoic acid；4-carboxyphenylboronic acid;4-(Dihydroxyboryl)benzoic acid | 14047-29-1 | C7H7BO4 | 详情 | 详情 |
| (VII) | 64114 | 4-[(methyloxy)carbonyl]phenylboronic acid | C8H9BO4 | 详情 | 详情 | |
| (VIII) | 64116 | methyl 4-{3-[([5-methyl-3-(methyloxy)-2-pyrazinyl]{[(2-methylpropyl)oxy]carbonyl}amino)sulfonyl]-2-pyridinyl}benzoate | C24H26N4O7S | 详情 | 详情 | |
| (IX) | 64117 | 2-[4-(hydrazinocarbonyl)phenyl]-N-[5-methyl-3-(methyloxy)-2-pyrazinyl]-3-pyridinesulfonamide | C18H18N6O4S | 详情 | 详情 |
合成路线2
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 |
合成路线3
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 |