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【结 构 式】 
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【分子编号】22971 【品名】4-fluorobenzenethiol; 4-fluorophenylhydrosulfide; 4-Fluorothiophenol 【CA登记号】371-42-6 |
【 分 子 式 】C6H5FS 【 分 子 量 】128.1701032 【元素组成】C 56.23% H 3.93% F 14.82% S 25.02% |
合成路线1
该中间体在本合成路线中的序号：(I)1) The reaction of p-fluorothiophenol (I) with p-chloronitrobenzene (II) in 50% aqueous ethanol in the presence of sodium carbonate gives p-fluorophenyl-p-nitrophenyl sulfide (III), which is then oxidized with 30% aqueous hydrogen peroxide in glacial acetic acid to give the corresponding sulfone (IV). The catalytic reduction of the sulfone (IV) with Raney Nickel in p-dioxane affords p-(p-fluorophenylsulfonyl)aniline (V), which is then acetylated with acetic anhydride in tetrahydrofuran to give title compound.
| 【1】 Durr, F.E.; Lang, S.A. Jr.; Shang Wang, B.; Ruszala-Mallon, V.; Lin, Y.-i.; Fields, T.L.; CL-259,763. Drugs Fut 1987, 12, 5, 431. |
| 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) | 22971 | 4-fluorobenzenethiol; 4-fluorophenylhydrosulfide; 4-Fluorothiophenol | 371-42-6 | C6H5FS | 详情 | 详情 |
| (II) | 13909 | 1-Chloro-4-nitrobenzene; p-Nitrochlorobenzene | 100-00-5 | C6H4ClNO2 | 详情 | 详情 |
| (III) | 22973 | 4-fluorophenyl 4-nitrophenyl sulfide; 1-fluoro-4-[(4-nitrophenyl)sulfanyl]benzene | C12H8FNO2S | 详情 | 详情 | |
| (IV) | 22974 | 4-fluorophenyl 4-nitrophenyl sulfone; (4-fluorophenyl)(4-nitrophenyl)dioxo-lambda(6)-sulfane | C12H8FNO4S | 详情 | 详情 | |
| (V) | 22975 | 4-[(4-fluorophenyl)sulfonyl]aniline; 4-[(4-fluorophenyl)sulfonyl]phenylamine | C12H10FNO2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Coupling of methacryloyl chloride (I) with substituted aniline (II) in dimethylacetamide yields amide (III), which is then converted into the epoxy derivative (IV) by oxidation with m-chloroperbenzoic acid (mCPBA) and 4-methyl-2,6-di-tert-butylphenol (A) in refluxing 1,1,1-trichloroethane. Condensation of (IV) with thiol (V) by means of NaH in THF provides fluorophenylthio derivative (VI), which is finally oxidized with mCPBA in CH2Cl2 to furnish the desired compound trichloroethane.
| 【1】 Tucker, H. (AstraZeneca plc); Amide derivs.. EP 0100172; JP 1990131462; US 4636505 . |
| 【2】 Crook, J.W.; Tucker, H.; Chesterson, G.J.; Nonsteroidal antiandrogens. Synthesis and structure-activity relationships of 3-substituted derivatives of 2-hydroxypropionanilides. J Med Chem 1988, 31, 5, 954. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 48072 | 2,6-di(tert-butyl)-4-methylphenol | 128-37-0 | C15H24O | 详情 | 详情 |
| (I) | 33553 | 2-methylacryloyl chloride | 920-46-7 | C4H5ClO | 详情 | 详情 |
| (II) | 18743 | 4-amino-2-(trifluoromethyl)benzonitrile；5-Amino-2-cyanobenzotrifluoride | 654-70-6 | C8H5F3N2 | 详情 | 详情 |
| (III) | 48071 | N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methylacrylamide | C12H9F3N2O | 详情 | 详情 | |
| (IV) | 48074 | N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyl-2-oxiranecarboxamide | C12H9F3N2O2 | 详情 | 详情 | |
| (V) | 22971 | 4-fluorobenzenethiol; 4-fluorophenylhydrosulfide; 4-Fluorothiophenol | 371-42-6 | C6H5FS | 详情 | 详情 |
| (VI) | 48073 | N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfanyl]-2-hydroxy-2-methylpropanamide | C18H14F4N2O2S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Alkylation of 4-fluorothiophenol (I) with 3-chloropropanol (II) in the presence of K2CO3 in DMF provided thioether (III), which was oxidized to sulfone (IV) using Oxone(R). Fluorine displacement in (IV) with phenol and K2CO3 gave phenoxy derivative (V). Subsequent Mitsunobu condensation of (V) with thioacetic acid afforded thioacetate ester (VI), which by further hydrolysis with NaOMe furnished the target thiol.
| 【1】 Freskos, J.N.; Abbas, Z.S.; Decrescenzo, G.A.; Getman, D.P.; Heintz, R.M.; Mischke, B.V.; McDonald, J.J. (Pharmacia Corp.); Thiol sulfone metalloprotease inhibitors. EP 0939628; WO 9803164 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 | |
| (I) | 22971 | 4-fluorobenzenethiol; 4-fluorophenylhydrosulfide; 4-Fluorothiophenol | 371-42-6 | C6H5FS | 详情 | 详情 |
| (II) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (III) | 27076 | 3-[(4-fluorophenyl)sulfanyl]-1-propanol | C9H11FOS | 详情 | 详情 | |
| (IV) | 27077 | 3-[(4-fluorophenyl)sulfonyl]-1-propanol | C9H11FO3S | 详情 | 详情 | |
| (V) | 27078 | 3-[(4-phenoxyphenyl)sulfonyl]-1-propanol | C15H16O4S | 详情 | 详情 | |
| (VI) | 27079 | S-[3-[(4-phenoxyphenyl)sulfonyl]propyl] ethanethioate | C17H18O4S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Alkylation of 4-fluorothiophenol (I) with 3-chloropropanol (II) in the presence of K2CO3 in DMF provided thioether (III), which was oxidized to sulfone (IV) using Oxone(R). Fluorine displacement in (IV) with thiophenol and K2CO3 gave phenylsulfanyl derivative (V). The hydroxyl group of (V) was converted to mesylate (VI) and then displaced by potassium thioacetate to afford thioacetate ester (VII). Finally, hydrolysis with methanolic NaOMe furnished the target thiol.
| 【1】 Inturrisi, C.E.; Collins, J.J.; Dunkel, I.J.; Portenoy, R.K.; Palmer, L.N.; Lapin, J.; Gupta, S.K.; Weinstein, S.M.; Transdermal fentanyl in children with cancer pain: Feasibility, tolerability, and pharmacokinetic correlates. J Pediatr 1999, 134, 3, 319. |
| 【2】 Freskos, J.N.; Abbas, Z.S.; Decrescenzo, G.A.; Getman, D.P.; Heintz, R.M.; Mischke, B.V.; McDonald, J.J. (Pharmacia Corp.); Thiol sulfone metalloprotease inhibitors. EP 0939628; WO 9803164 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12951 | Benzenethiol; Phenylmercaptan; Phenylhydrosulfide | 108-98-5 | C6H6S | 详情 | 详情 | |
| (I) | 22971 | 4-fluorobenzenethiol; 4-fluorophenylhydrosulfide; 4-Fluorothiophenol | 371-42-6 | C6H5FS | 详情 | 详情 |
| (II) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (III) | 27076 | 3-[(4-fluorophenyl)sulfanyl]-1-propanol | C9H11FOS | 详情 | 详情 | |
| (IV) | 27077 | 3-[(4-fluorophenyl)sulfonyl]-1-propanol | C9H11FO3S | 详情 | 详情 | |
| (V) | 27078 | 3-[(4-phenoxyphenyl)sulfonyl]-1-propanol | C15H16O4S | 详情 | 详情 | |
| (VI) | 27083 | 3-[[4-(phenylsulfanyl)phenyl]sulfonyl]propyl methanesulfonate | C16H18O5S3 | 详情 | 详情 | |
| (VII) | 27084 | S-(3-[[4-(phenylsulfanyl)phenyl]sulfonyl]propyl) ethanethioate | C17H18O3S3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)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6
该中间体在本合成路线中的序号：(III)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 |