|
【结 构 式】 
|
【分子编号】29284 【品名】4-cyanobenzenesulfonyl chloride 【CA登记号】49584-26-1 |
【 分 子 式 】C7H4ClNO2S 【 分 子 量 】201.633 【元素组成】C 41.7% H 2% Cl 17.58% N 6.95% O 15.87% S 15.9% |
合成路线1
该中间体在本合成路线中的序号：(II)Condensation of the protected aniline derivative (I) with 4-cyanobenzenesulfonyl chloride (II) in the presence of pyridine afforded sulfonamide (III). Subsequent reaction of he nitrile group of (III) with hydroxylamine provided the corresponding amidoxime (IV), which was reacted with 3,4-difluorophenylacetic acid (V) and EDC to produce the oxadiazole (VI). Finally, the Boc protecting group of (VI) was removed by treatment with trifluoroacetic acid.
| 【1】 Biftu, T.; Feng, D.D.; Fisher, M.H.; Kuo, C.-H.; Liang, G.-B.; Weber, A.E.; Naylor, E.M. (Merck & Co., Inc.); Oxadiazole benzenesulfonamides as selective beta3 agonists for the treatment of diabetes and obesity. EP 0906310; US 6034106; WO 9746556 . |
| 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) | 26553 | tert-butyl 4-aminophenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C20H27N3O3 | 详情 | 详情 | |
| (II) | 29284 | 4-cyanobenzenesulfonyl chloride | 49584-26-1 | C7H4ClNO2S | 详情 | 详情 |
| (III) | 29285 | tert-butyl 4-[[(4-cyanophenyl)sulfonyl]amino]phenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C27H30N4O5S | 详情 | 详情 | |
| (IV) | 29286 | tert-butyl 4-[([4-[amino(hydroxyimino)methyl]phenyl]sulfonyl)amino]phenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C27H33N5O6S | 详情 | 详情 | |
| (V) | 29287 | 2-(3,4-difluorophenyl)acetic acid | 658-93-5 | C8H6F2O2 | 详情 | 详情 |
| (VI) | 29288 | tert-butyl 4-[([4-[5-(3,4-difluorobenzyl)-1,2,4-oxadiazol-3-yl]phenyl]sulfonyl)amino]phenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C35H35F2N5O6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Condensation of the protected aniline derivative (I) with 4-cyanobenzenesulfonyl chloride (II) in the presence of pyridine afforded sulfonamide (III). Subsequent reaction of he nitrile group of (III) with hydroxylamine provided the corresponding amidoxime (IV), which was reacted with 4-(trifluoromethoxy)phenylacetic acid (V) and EDC to produce the oxadiazole (VI). Finally, the Boc protecting group of (VI) was removed by treatment with trifluoroacetic acid.
| 【1】 Biftu, T.; Feng, D.D.; Fisher, M.H.; Kuo, C.-H.; Liang, G.-B.; Weber, A.E.; Naylor, E.M. (Merck & Co., Inc.); Oxadiazole benzenesulfonamides as selective beta3 agonists for the treatment of diabetes and obesity. EP 0906310; US 6034106; WO 9746556 . |
| 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) | 26553 | tert-butyl 4-aminophenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C20H27N3O3 | 详情 | 详情 | |
| (II) | 29284 | 4-cyanobenzenesulfonyl chloride | 49584-26-1 | C7H4ClNO2S | 详情 | 详情 |
| (III) | 29285 | tert-butyl 4-[[(4-cyanophenyl)sulfonyl]amino]phenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C27H30N4O5S | 详情 | 详情 | |
| (IV) | 29286 | tert-butyl 4-[([4-[amino(hydroxyimino)methyl]phenyl]sulfonyl)amino]phenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C27H33N5O6S | 详情 | 详情 | |
| (V) | 29289 | 2-[4-(trifluoromethoxy)phenyl]acetic acid | 4315-07-5 | C9H7F3O3 | 详情 | 详情 |
| (VI) | 29290 | tert-butyl (2R)-2-hydroxy-2-(3-pyridinyl)ethyl(4-[[(4-[5-[4-(trifluoromethoxy)benzyl]-1,2,4-oxadiazol-3-yl]phenyl)sulfonyl]amino]phenethyl)carbamate | C36H36F3N5O7S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)The title compound was prepared by solid-phase synthesis. Resin (II) was treated with 4-nitrophenyl chloroformate (I), and the activated nitrophenyl carbonate resin (III) was coupled to (R)-N-[2-(4-aminophenyl)ethyl]-2-hydroxy-2-(pyrid-3-yl)ethylamine (IV) to furnish the resine-bound aniline (V). After protection of the hydroxyl group as the triethylsilyl ether (VI), reaction with 4-cyanobenzenesulfonyl chloride (VII) in the presence of pyridine provided the resine-bound sulfonamide (VIII). Addition of hydroxylamine to the cyano group of (VIII) afforded the corresponding amidoxime (IX). The required oxadiazole (XI) was obtained by acylation of (IX) with 4-(trifluoromethoxy)phenylacetic acid (X) in the presence of EDC, followed by heating in diglyme to effect the cyclization. Cleavage from the resin and simultaneous desilylation was achieved by treatment with trifluoroacetic acid in dichloromethane.
| 【1】 Biftu, T.; Liang, G.-B.; Feng, D.D.; et al.; Synthesis and SAR of benzyl and phenoxymethylene oxadiazole benzenesulfonamides as selective beta3 adrenergic receptor agonist antiobesity agents. Bioorg Med Chem Lett 2000, 10, 13, 1431. |
| 【2】 Biftu, T.; Feng, D.D.; Fisher, M.H.; Kuo, C.-H.; Liang, G.-B.; Weber, A.E.; Naylor, E.M. (Merck & Co., Inc.); Oxadiazole benzenesulfonamides as selective beta3 agonists for the treatment of diabetes and obesity. EP 0906310; US 6034106; WO 9746556 . |
| 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) | 16605 | 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene | 7693-46-1 | C7H4ClNO4 | 详情 | 详情 |
| (II) | 38837 | 4-nitrophenyl hydrogen carbonate | C7H5NO5 | 详情 | 详情 | |
| (III) | 26652 | tert-butyl (3S,4S)-1-benzyl-4-methoxypyrrolidinylcarbamate | C17H26N2O3 | 详情 | 详情 | |
| (IV) | 42097 | 4-aminophenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamic acid | C16H19N3O3 | 详情 | 详情 | |
| (V) | 42098 | 4-aminophenethyl[(2R)-2-(3-pyridinyl)-2-[(triethylsilyl)oxy]ethyl]carbamic acid | C22H33N3O3Si | 详情 | 详情 | |
| (VI) | 29284 | 4-cyanobenzenesulfonyl chloride | 49584-26-1 | C7H4ClNO2S | 详情 | 详情 |
| (VII) | 42099 | 4-[[(4-cyanophenyl)sulfonyl]amino]phenethyl[(2R)-2-(3-pyridinyl)-2-[(triethylsilyl)oxy]ethyl]carbamic acid | C29H36N4O5SSi | 详情 | 详情 | |
| (VIII) | 42100 | 4-[([4-[amino(hydroxyimino)methyl]phenyl]sulfonyl)amino]phenethyl[(2R)-2-(3-pyridinyl)-2-[(triethylsilyl)oxy]ethyl]carbamic acid | C29H39N5O6SSi | 详情 | 详情 | |
| (IX) | 29289 | 2-[4-(trifluoromethoxy)phenyl]acetic acid | 4315-07-5 | C9H7F3O3 | 详情 | 详情 |
| (X) | 42101 | (2R)-2-(3-pyridinyl)-2-[(triethylsilyl)oxy]ethyl(4-[[(4-[5-[4-(trifluoromethoxy)benzyl]-1,2,4-oxadiazol-3-yl]phenyl)sulfonyl]amino]phenethyl)carbamic acid | C38H42F3N5O7SSi | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VIII)Chlorination of 3-acetylpyridine (I) by means of N-chlorosuccinimide (NCS) and HCl/HOAc in ethyl ether affords chloroacetyl derivative (II), which is then reduced with (-)-B-chlorodiisopinocampheylborane ((-)-DIP-Cl) and Et3N in THF to yield ethanol (III). Alcohol (III) is treated with K2CO3 in refluxing acetone to provide (R)-(3-pyridyl)oxirane (IV), which is then condensed with 4-aminophenethylamine (V) to give derivative (VI). N-Protection of (VI) by means of Boc2O in THF furnishes Boc derivative (VII), which is coupled to benzenesulfonyl chloride (VIII) in CH2Cl2 in the presence of pyridine to afford benzene sulfonamide (IX), which is then treated with H2S and Et3N in pyridine to yield thiocarboxamide derivative (X). Derivative (X) is then condensed in refluxing EtOH with chloromethylketone (XII), which can be obtained by reaction of 4-(trifluoromethyl)benzoyl chloride (XI) first with diazomethane (CH2N2) and then with HCl in ether. Finally, the N-Boc group is removed by means of TFA in CH2Cl2 to provide the target compound.
| 【1】 Fisher, M.H.; Naylor, E.M.; Ok, D.; Weber, A.E.; Shih, T.; Ok, H. (Merck & Co., Inc.); Substd. sulfonamides as selective beta3 agonists for the treatment of diabetes and obesity. EP 0757674; JP 1997512275; US 5541197; US 5561142; WO 9529159 . |
| 【3】 Mathvink, R.J.; Parmee, E.R.; Weber, A.E.; Tolman, S. (Merck & Co., Inc.); Thiazole benzenesulfonamides as beta3 agonists for the treatment of diabetes and obesity. EP 0968209; US 6011048; WO 9832753 . |
| 【2】 Mathvink, R.J.; Chitty, D.; Tolman, J.S.; et al.; Potent, selective, and orally bioavailable 3-pyridylethanolamine beta3 adrenergic receptor agonists possessing a thiazole benzenesulfonamide pharmacophore. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 302. |
| 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) | 12027 | 1-(3-Pyridinyl)-1-ethanone; 1-(3-Pyridinyl)ethanone | 350-03-8 | C7H7NO | 详情 | 详情 |
| (II) | 26549 | 2-chloro-1-(3-pyridinyl)-1-ethanone | C7H6ClNO | 详情 | 详情 | |
| (III) | 26550 | (1R)-2-chloro-1-(3-pyridinyl)-1-ethanol | C7H8ClNO | 详情 | 详情 | |
| (IV) | 26551 | 3-[(2R)oxiranyl]pyridine | C7H7NO | 详情 | 详情 | |
| (V) | 18961 | 4-(2-aminoethyl)aniline; 4-(2-aminoethyl)phenylamine | 13472-00-9 | C8H12N2 | 详情 | 详情 |
| (VI) | 26552 | (1R)-2-[(4-aminophenethyl)amino]-1-(3-pyridinyl)-1-ethanol | C15H19N3O | 详情 | 详情 | |
| (VII) | 26553 | tert-butyl 4-aminophenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C20H27N3O3 | 详情 | 详情 | |
| (VIII) | 29284 | 4-cyanobenzenesulfonyl chloride | 49584-26-1 | C7H4ClNO2S | 详情 | 详情 |
| (IX) | 29285 | tert-butyl 4-[[(4-cyanophenyl)sulfonyl]amino]phenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C27H30N4O5S | 详情 | 详情 | |
| (X) | 44829 | tert-butyl 4-([[4-(aminocarbothioyl)phenyl]sulfonyl]amino)phenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C27H32N4O5S2 | 详情 | 详情 | |
| (XI) | 44830 | 4-(trifluoromethyl)benzoyl chloride | 329-15-7 | C8H4ClF3O | 详情 | 详情 |
| (XII) | 44831 | 2-chloro-1-[4-(trifluoromethyl)phenyl]-1-ethanone | C9H6ClF3O | 详情 | 详情 |