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【结 构 式】

【分子编号】52288

【品名】1-(1,1-dimethylethyl) 4-ethyl 4-[(4-fluorophenyl)sulfanyl]-1,4-piperidinedicarboxylate

【CA登记号】

【 分 子 式 】C19H26FNO4S

【 分 子 量 】383.4841832

【元素组成】C 59.51% H 6.83% F 4.95% N 3.65% O 16.69% S 8.36%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(V)

Ethyl isonipecotate (I) was protected as the N-Boc derivative (II) employing di-tert-butyl dicarbonate. Sulfenylation of the lithium enolate of ester (II) with the disulfide (IV), generated from the oxidation of 4-fluorothiophenol (III), furnished the phenylsulfanyl derivative (V). Thioether (V) was then oxidized to the corresponding sulfone (VI) by means of meta-chloroperbenzoic acid. After acidic Boc group cleavage in (VI), the resultant piperidine (VII) was alkylated with propargyl bromide (VIII) to produce the N-propargyl piperidine (IX).

1 Becker, D.P.; Hockerman, S.L.; Barta, T.E.; et al.; Design and synthesis of beta-sulfone and alpha-sulfone hydroxamates as potent and orally active MMP inhibitors. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 259.
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) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(II) 49847 1-(tert-butyl) 4-ethyl-1,4-piperidinedicarboxylate; N-Boc-4-Carbethoxypiperidine 142851-03-4 C13H23NO4 详情 详情
(III) 22971 4-fluorobenzenethiol; 4-fluorophenylhydrosulfide; 4-Fluorothiophenol 371-42-6 C6H5FS 详情 详情
(IV) 52287 bis(4-fluorophenyl) disulfide; 1-fluoro-4-[(4-fluorophenyl)disulfanyl]benzene C12H8F2S2 详情 详情
(V) 52288 1-(1,1-dimethylethyl) 4-ethyl 4-[(4-fluorophenyl)sulfanyl]-1,4-piperidinedicarboxylate C19H26FNO4S 详情 详情
(VI) 52289 1-(1,1-dimethylethyl) 4-ethyl 4-[(4-fluorophenyl)sulfonyl]-1,4-piperidinedicarboxylate C19H26FNO6S 详情 详情
(VII) 52290 ethyl 4-[(4-fluorophenyl)sulfonyl]-4-piperidinecarboxylate C14H18FNO4S 详情 详情
(VIII) 11176 3-Bromopropyne; 3-Bromo-1-propyne 106-96-7 C3H3Br 详情 详情
(IX) 56377 ethyl 4-[(4-fluorophenyl)sulfonyl]-1-(2-propynyl)-4-piperidinecarboxylate C17H20FNO4S 详情 详情

合成路线2

该中间体在本合成路线中的序号:(V)

Ethyl nipecotate (I) was protected as the tert-butyl carbamate (II) upon treatment with Boc2O in THF. The lithium enolate of ester (II) was then sulfenylated with the disulfide (IV), prepared by oxidation of 4-fluorothiophenol (III), yielding thioether (V). This was further oxidized to the corresponding sulfone (VI) using meta-chloroperbenzoic acid. Acid cleavage of the Boc protecting group of (VI) gave piperidine (VII), which was converted to the N-cyclopropyl amine (IX) by reductive alkylation with [(1-ethoxycyclopropyl)oxy]trimethylsilane (VIII) in the presence of NaBH3CN. Displacement of the aryl fluoride of (IX) with 4-(trifluoromethoxy)phenol (X) under basic conditions afforded the diaryl ether (XI). After saponification of the ester group of (XI), the resultant carboxylic acid (XII) was coupled to O-(tetrahydropyranyl)hydroxylamine by means of EDC to produce the protected hydroxamate (XIII). Finally, removal of the tetrahydropyranyl protecting group of (XIII) with HCl in dioxan afforded the title compound.

1 Villamil, C.I.; et al.; Design and synthesis of 4,4-disubstituted piperidine alpha-sulphone hydroxamates as potent and selective MMP inhibitors: The discovery of SC-77964. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 258.
2 Aromatic sulfone hydroxamic acid metalloprotease inhibitor. WO 0050396 .
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) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(II) 49847 1-(tert-butyl) 4-ethyl-1,4-piperidinedicarboxylate; N-Boc-4-Carbethoxypiperidine 142851-03-4 C13H23NO4 详情 详情
(III) 22971 4-fluorobenzenethiol; 4-fluorophenylhydrosulfide; 4-Fluorothiophenol 371-42-6 C6H5FS 详情 详情
(IV) 52287 bis(4-fluorophenyl) disulfide; 1-fluoro-4-[(4-fluorophenyl)disulfanyl]benzene C12H8F2S2 详情 详情
(V) 52288 1-(1,1-dimethylethyl) 4-ethyl 4-[(4-fluorophenyl)sulfanyl]-1,4-piperidinedicarboxylate C19H26FNO4S 详情 详情
(VI) 52289 1-(1,1-dimethylethyl) 4-ethyl 4-[(4-fluorophenyl)sulfonyl]-1,4-piperidinedicarboxylate C19H26FNO6S 详情 详情
(VII) 52290 ethyl 4-[(4-fluorophenyl)sulfonyl]-4-piperidinecarboxylate C14H18FNO4S 详情 详情
(VIII) 52291 Cyclopropanone ethyl trimethylsilyl acetal; (1-Ethoxycyclopropoxy)trimethylsilane C8H18O2Si 详情 详情
(IX) 52292 ethyl 1-cyclopropyl-4-[(4-fluorophenyl)sulfonyl]-4-piperidinecarboxylate C17H22FNO4S 详情 详情
(X) 18780 4-(trifluoromethoxy)phenol 828-27-3 C7H5F3O2 详情 详情
(XI) 52293 ethyl 1-cyclopropyl-4-{[4-({4-[(trifluoromethyl)oxy]phenyl}oxy)phenyl]sulfonyl}-4-piperidinecarboxylate C24H26F3NO6S 详情 详情
(XII) 52294 1-cyclopropyl-4-{[4-({4-[(trifluoromethyl)oxy]phenyl}oxy)phenyl]sulfonyl}-4-piperidinecarboxylic acid C22H22F3NO6S 详情 详情
(XIII) 52295 1-cyclopropyl-N-(tetrahydro-2H-pyran-2-yloxy)-4-{[4-({4-[(trifluoromethyl)oxy]phenyl}oxy)phenyl]sulfonyl}-4-piperidinecarboxamide C27H31F3N2O7S 详情 详情
Extended Information