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【结 构 式】 
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【分子编号】14590 【品名】Formic acid 【CA登记号】64-18-6 |
【 分 子 式 】CH2O2 【 分 子 量 】46.02568 【元素组成】C 26.1% H 4.38% O 69.52% |
合成路线1
该中间体在本合成路线中的序号：(II)Thiosemicarbazide (I) is refluxed for 1 h with one equivalent of formic acid (II) in a water solution. It may be recrystallized from water to give needles.
| 【2】 Eastland, G.; AMINOTHIADIAZOLE. Drugs Fut 1988, 13, 8, 711. |
| 【1】 Okada, Y. (Takeda Chemical Industries, Ltd.); 2-Amino-1,3,4-thiadiazole. JP 1972042028 . |
合成路线2
该中间体在本合成路线中的序号：(II)The synthesis of LY-217896 and its [5-14C]- and uniformly labeled [UL-13C]-isotopomers has been described: The cyclization of thiosemicarbazide (I) with formic acid (II) at 80-90 C gives 2-amino-1,3,4-thiadiazole (III), which is protected with benzyl chloride in refluxing isopropanol to yield 3-benzyl-1,3,4-thiadiazol-2(3H)-imine (IV). The reaction of (IV) with cyanogen bromide by means of NaHCO3 in methanol - water affords N-(3-benzyl-1,3,4-thiadiazol-2(3H)-ylidene)cyanamide (V), which is finally deprotected with AlCl3 in dichloromethane. The [5-14C]-isotopomer is obtained using [14C]-labeled formic acid in the first step of the synthesis, and the [UL-13C]-isotopomer is obtained using [13C]-labeled thiosemicarbazide (I) and [13C]-formic acid. [13C]-Labeled (I) is synthesized by reaction of potassium cyanide-[13C] with sulfur, yielding potassium thiocyanate-[13C], which is reacted with hydrazine to give [13C]-thiosemicarbazide.
| 【1】 Wheeler, W.J.; Blanchard, W.B.; The synthesis of 1,3,4-thiadiazol-2-ylcyanamide sodium, a potentially useful anti-influenza agent and its [5-14C] and [UL-13C3] isotopomers. J Label Compd Radiopharm 1992, 31, 7, 495. |
| 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) | 12954 | 1-Hydrazinecarbothioamide; Thiosemicarbazide | 79-19-6 | CH5N3S | 详情 | 详情 |
| (II) | 14590 | Formic acid | 64-18-6 | CH2O2 | 详情 | 详情 |
| (III) | 14591 | 2-Amino-1,3,4-thiadiazole; 1,3,4-Thiadiazol-2-amine; 1,3,4-Thiadiazol-2-ylamine | 4005-51-0 | C2H3N3S | 详情 | 详情 |
| (IV) | 14592 | 3-benzyl-1,3,4-thiadiazol-2(3H)-imine | C9H9N3S | 详情 | 详情 | |
| (V) | 14593 | N-[3-benzyl-1,3,4-thiadiazol-2(3H)-ylidene]cyanamide | C10H8N4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Formylation of 2-methoxy-5-nitroaniline (I) with formic acid (II) in Ac2O/THF yields formamide (III), whose nitro group is then hydrogenated over Pd/C in MeOH to provide aniline (IV). Treatment of (IV) with pentafluorophenylsulfonyl chloride (V) in acetone in the presence of 2,6-lutidine affords sulfonamide (VI), which is then deformylated to hydrochloride (VII) by treatment with acetyl chloride and HCl in EtOH. The target compound is finally obtained by reaction of (VII) with potassium cyanate (KCNO) in H2O/HOAc. An analogous route can be also followed for the synthesis of the target product: Treatment of 3-nitro-4-fluoroaniline (VIII) with sodium methoxide (NaOMe) in refluxing MeOH furnishes 4-methoxy-3-nitroaniline (IX), which is then condensed with pentafluorophenylsulfonyl chloride (V) in MeOH to give sulfonamide (X). Reduction of the nitro moiety of (X) by hydrogenation over Pd/C in EtOH yields aniline (XI), which is finally treated with potassium cyanate (KCNO) in H2O/HOAc.
| 【1】 Houze, J.; Medina, J.; Gergely, J.; et al.; T900607: Design and evaluation of a second-generation irreversible binder of beta-tubulin. Clin Cancer Res 2000, 6, Suppl., Abst 562. |
| 【2】 Houze, J.B. (Tularik Inc.); Arylsulfonanilide ureas. EP 1115701; US 6214880; WO 0017159 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII), (XI) | 46684 | N-(3-amino-4-methoxyphenyl)-2,3,4,5,6-pentafluorobenzenesulfonamide | C13H9F5N2O3S | 详情 | 详情 | |
| (I) | 46680 | 2-methoxy-5-nitrophenylamine; 2-methoxy-5-nitroaniline | 99-59-2 | C7H8N2O3 | 详情 | 详情 |
| (II) | 14590 | Formic acid | 64-18-6 | CH2O2 | 详情 | 详情 |
| (III) | 46681 | 2-methoxy-5-nitrophenylformamide | C8H8N2O4 | 详情 | 详情 | |
| (IV) | 46682 | 5-amino-2-methoxyphenylformamide | C8H10N2O2 | 详情 | 详情 | |
| (V) | 20482 | 2,3,4,5,6-pentafluorobenzenesulfonyl chloride | 832-53-1 | C6ClF5O2S | 详情 | 详情 |
| (VI) | 46683 | 2,3,4,5,6-pentafluoro-N-[3-(formylamino)-4-methoxyphenyl]benzenesulfonamide | C14H9F5N2O4S | 详情 | 详情 | |
| (VIII) | 24710 | 4-fluoro-3-nitroaniline | 364-76-1 | C6H5FN2O2 | 详情 | 详情 |
| (IX) | 46685 | 4-methoxy-3-nitroaniline; 4-methoxy-3-nitrophenylamine | C7H8N2O3 | 详情 | 详情 | |
| (X) | 46686 | 2,3,4,5,6-pentafluoro-N-(4-methoxy-3-nitrophenyl)benzenesulfonamide | C13H7F5N2O5S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XII)The condensation of 4-(trifluoromethoxy)phenol (I) with 4-fluorophenyl(methyl)sulfone (II) by means of K2CO3 in hot DMSO gives the diphenyl ether (III), which is condensed with 2,2-dimethyl-1,3-dioxolane-(R)-carboxylic acid methyl ester (IV) by means of BuLi in THF to afford the ethanone (V). The reduction of (V) with NaBH4 in ethanol yields the ethanol derivative (VI), which is dehydrated to the ethylene (VII) by means of MsCl, TEA and NaHCO3. The addition of hydroxylamine to the double bond of (VII) provides the hydroxyamine derivative (VIII) as a diastereomeric mixture that is separated by flash chromatography, affording the desired enantiomer (IX). Finally, this compound is formylated by treatment with 2,2,2-trifluoroethyl formate (X) (obtained by reaction of 2,2,2-trifluoroethanol (XI) with hot formic acid (XII)) in refluxing MTBE.
| 【1】 Curtin, M.L.; Wada, C.K.; Holms, J.H.; et al.; Phenoxyphenyl sulfone N-forylhydroxylamines (retrohydroxamates) as potent, selective, orally bioavailable matrix metalloproteinase inhibitors. J Med Chem 2002, 45, 1, 219. |
| 【2】 Curtin, M.L.; Davidsen, S.K.; Michaelides, M.R.; Steinman, D.H.; Dai, Y.; Heyman, H.R.; Holmes, J.H. (Abbott Laboratories Inc.); Reverse hydroxamate inhibitors of matrix metalloproteinases. WO 0044739 . |
| 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) | 18780 | 4-(trifluoromethoxy)phenol | 828-27-3 | C7H5F3O2 | 详情 | 详情 |
| (II) | 46256 | 4-fluorophenyl methyl sulfone; (4-fluorophenyl)(methyl)dioxo-lambda(6)-sulfane | C7H7FO2S | 详情 | 详情 | |
| (III) | 46241 | methyl(dioxo)[4-[4-(trifluoromethoxy)phenoxy]phenyl]-lambda(6)-sulfane; methyl 4-[4-(trifluoromethoxy)phenoxy]phenyl sulfone | C14H11F3O4S | 详情 | 详情 | |
| (IV) | 20917 | methyl (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxylate | 52373-72-5 | C7H12O4 | 详情 | 详情 |
| (V) | 46257 | 1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)-1-ethanone | C20H19F3O7S | 详情 | 详情 | |
| (VI) | 46258 | (1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)-1-ethanol | C20H21F3O7S | 详情 | 详情 | |
| (VII) | 46259 | (Z)-2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethenyl 4-[4-(trifluoromethoxy)phenoxy]phenyl sulfone; (4S)-2,2-dimethyl-4-[(Z)-2-([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)ethenyl]-1,3-dioxolane | C20H19F3O6S | 详情 | 详情 | |
| (VIII) | 46260 | (4S)-4-[1-(hydroxyamino)-2-([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)ethyl]-2,2-dimethyl-1,3-dioxolane; N-[1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)ethyl]hydroxylamine | C20H22F3NO7S | 详情 | 详情 | |
| (IX) | 46261 | N-[(1S)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)ethyl]hydroxylamine; (4S)-4-[(1S)-1-(hydroxyamino)-2-([4-[4-(trifluoromethoxy)phenoxy]phenyl]sulfonyl)ethyl]-2,2-dimethyl-1,3-dioxolane | C20H22F3NO7S | 详情 | 详情 | |
| (X) | 46245 | 2,2,2-trifluoroethyl formate | C3H3F3O2 | 详情 | 详情 | |
| (XI) | 19483 | 2,2,2-trifluoro-1-ethanol | 75-89-8 | C2H3F3O | 详情 | 详情 |
| (XII) | 14590 | Formic acid | 64-18-6 | CH2O2 | 详情 | 详情 |