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【结 构 式】 
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【分子编号】44260 【品名】1,1,1,3,3,3-hexafluoroacetone 【CA登记号】684-16-2 |
【 分 子 式 】C3F6O 【 分 子 量 】166.0228192 【元素组成】C 21.7% F 68.66% O 9.64% |
合成路线1
该中间体在本合成路线中的序号：(IV)The Grignard condensation of carbaldehyde (I) with methylmagnesium bromide in ethyl ether gives the secondary alcohol (II), which is oxidized with TPAP and NMO in dichloromethane to yield the methyl ketone (III). The aldol reaction of (III) with hexafluoroacetone (IV) by means of LiHMDS in THF affords the hexafluorohydroxy ketone (V), which is reduced with NaBH4 in THF/methanol to provide the diol (VI). The selective acetylation of the secondary OH group of (VI) with Ac2O and pyridine gives the monoacetate (VII), which is treated with Mom-Cl and DIEA in order to protect its tertiary OH group, yielding (VIII). The deacetylation of (VIII) with KOH in methanol affords the secondary alcohol (IX), which is treated with CS2, NaH and Me-I to provide the thionocarbonate (X). The reduction of (X) with Bu3SnH in refluxing toluene gives the protected intermediate (XI), which is finally deprotected by reaction with methanesulfonic acid in methanol to yield the target vitamin D3 derivative.
| 【1】 Ikeda, M.; et al.; Synthesis and biological evaluations of A-ring isomers of 26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3. Bioorg Med Chem 2000, 8, 8, 2157. |
| 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) | 25263 | (3R)-3-[(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]butanal | C35H62O3Si2 | 详情 | 详情 | |
| (II) | 55446 | (4R)-4-{(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}-2-pentanol | C36H66O3Si2 | 详情 | 详情 | |
| (III) | 55447 | (4R)-4-{(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}-2-pentanone | C36H64O3Si2 | 详情 | 详情 | |
| (IV) | 44260 | 1,1,1,3,3,3-hexafluoroacetone | 684-16-2 | C3F6O | 详情 | 详情 |
| (V) | 55448 | (6R)-6-{(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}-1,1,1-trifluoro-2-hydroxy-2-(trifluoromethyl)-4-heptanone | C39H64F6O4Si2 | 详情 | 详情 | |
| (VI) | 55449 | (6R)-6-{(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}-1,1,1-trifluoro-2-(trifluoromethyl)-2,4-heptanediol | C39H66F6O4Si2 | 详情 | 详情 | |
| (VII) | 55450 | 1-((2R)-2-{(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}propyl)-4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butyl acetate | C41H68F6O5Si2 | 详情 | 详情 | |
| (VIII) | 55451 | 1-((2R)-2-{(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}propyl)-4,4,4-trifluoro-3-(methoxymethoxy)-3-(trifluoromethyl)butyl acetate | C43H72F6O6Si2 | 详情 | 详情 | |
| (IX) | 55452 | (6R)-6-{(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}-1,1,1-trifluoro-2-(methoxymethoxy)-2-(trifluoromethyl)-4-heptanol | C41H70F6O5Si2 | 详情 | 详情 | |
| (X) | 55453 | O-[1-((2R)-2-{(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl}propyl)-4,4,4-trifluoro-3-(methoxymethoxy)-3-(trifluoromethyl)butyl] S-methyl carbonodithioa | C43H72F6O5S2Si2 | 详情 | 详情 | |
| (XI) | 55454 | (1R,5S)-3-((Z)-2-{(1R,3aR,7aR)-7a-methyl-1-[(1R)-6,6,6-trifluoro-5-(methoxymethoxy)-1-methyl-5-(trifluoromethyl)hexyl]octahydro-4H-inden-4-ylidene}ethylidene)-5-{[tert-butyl(dimethyl)silyl]oxy}-4-methylenecyclohexyl tert-butyl(dimethyl)silyl ether; [((1R,5S)-3-((Z)-2-{(1R,3aR,7aR)-7a-methyl-1-[(1R)-6,6,6-trifluoro-5-(methoxymethoxy)-1-methyl-5-(trifluoromethyl)hexyl]octahydro-4H-inden-4-ylidene}ethylidene)-5-{[tert-butyl(dimethyl)silyl]oxy}-4-methylenecyclohexyl)oxy](tert-butyl)dimethylsilane | C41H70F6O4Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Synthesis of aldehyde intermediate (IX): The condensation of 1-tert-butoxy-4-chlorobutane (I) with 4-methyl-3-penten-2-one (II) by means of Mg in hot THF gives the 2-octanone (III), which is condensed with hexafluoroacetone (IV) by means of diethyl chlorophosphate and LDA in THF to yield the fluorinated alkynol (V). Hydrogenation of the triple bond of (V) with H2 and Lindlar catalyst affords the cis-alkene (VI), which is deprotected with sulfuric acid to provide the fluorinated diol (VII). Finally, the primary alcohol of (VII) is oxidized to the corresponding aldehyde (VIII) with NaOCl and tempo, which is silylated with Tes-Cl and TEA to afford the desired intermediate (IX).
| 【1】 Wirz, B.; Hilpert, H.; Novel versatile approach to an enantiopure 19-nor, des-C,D vitamin D-3 derivative. Tetrahedron 2001, 57, 4, 681. |
| 【2】 Hilpert, H.; Wirz, B. (F. Hoffmann-La Roche AG); New process for the preparation of retiferol derivs.. EP 1094060 . |
| 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) | 49032 | tert-butyl 4-chlorobutyl ether; 1-(tert-butoxy)-4-chlorobutane | C8H17ClO | 详情 | 详情 | |
| (II) | 42266 | 4-methyl-3-penten-2-one | 141-79-7 | C6H10O | 详情 | 详情 |
| (III) | 49033 | 8-(tert-butoxy)-4,4-dimethyl-2-octanone | C14H28O2 | 详情 | 详情 | |
| (IV) | 44260 | 1,1,1,3,3,3-hexafluoroacetone | 684-16-2 | C3F6O | 详情 | 详情 |
| (V) | 49034 | 10-(tert-butoxy)-1,1,1-trifluoro-6,6-dimethyl-2-(trifluoromethyl)-3-decyn-2-ol | C17H26F6O2 | 详情 | 详情 | |
| (VI) | 49035 | (Z)-10-(tert-butoxy)-1,1,1-trifluoro-6,6-dimethyl-2-(trifluoromethyl)-3-decen-2-ol | C17H28F6O2 | 详情 | 详情 | |
| (VII) | 49036 | (Z)-10,10,10-trifluoro-5,5-dimethyl-9-(trifluoromethyl)-7-decene-1,9-diol | C13H20F6O2 | 详情 | 详情 | |
| (VIII) | 49037 | (Z)-10,10,10-trifluoro-9-hydroxy-5,5-dimethyl-9-(trifluoromethyl)-7-decenal | C13H18F6O2 | 详情 | 详情 | |
| (IX) | 49038 | (Z)-10,10,10-trifluoro-5,5-dimethyl-9-[(triethylsilyl)oxy]-9-(trifluoromethyl)-7-decenal | C19H32F6O2Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)The reduction of 4,4-dimethyltetrahydropyran-2-one (I) with iBuAlH in THF gives 4,4-dimethyltetrahydropyran-2-ol (II), which is condensed with phosphorane (III) in refluxing acetonitrile to yield the heptenoic ester (IV). The protection of the OH group of (IV) with Tbdms-Cl and imidazole affords the silyl ether (V), which is reduced at the double bond with H2 over Pd/C in ethyl acetate to provide the heptanoate ester (VI). The reduction of the ester group of (VI) with iBu2AlH in THF gives the primary alcohol (VII), which is protected with dihydropyran and PPTS, yielding the tetrahydropyranyl ether (VIII). The desilylation of (VIII) with TBAF in THF affords the heptanol derivative (IX), which by oxidation with tetrapropylammonium perruthenate (TPAP) in dichloromethane is converted into the aldehyde (X). The condensation of (X) with CBr4 and PPh3 in dichloromethane provides the dibromovinyl compound (XI), which is condensed with hexafluoroacetone (XII) by means of BuLi in THF to give the acetylenic alcohol (XIII). The deprotection of (XIII) with pyridinium p-toluenesulfonate (PPTS) in methanol yields the acetylenic diol (XIV), which is selectively reduced with H2 over Pd/C in ethyl acetate to afford the (Z)-ethylenic diol (XV). The oxidation of the primary alcohol of (XV) with pyridinium dichromate in dichloromethane provides the aldehyde (XVI), which is silylated with Tms-Cl, TEA and DMAP in dichloromethane to give the silylated unsaturated aldehyde (XVII).
| 【1】 Mohr, P.; Barbier, P.; Pirson, W.; Muller, M.; Bauer, F. (F. Hoffmann-La Roche AG); Cyclohexanediole derivs.. EP 1056716; WO 9943646 . |
| 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) | 49051 | 4,4-dimethyltetrahydro-2H-pyran-2-one | C7H12O2 | 详情 | 详情 | |
| (II) | 49052 | 4,4-dimethyltetrahydro-2H-pyran-2-ol | C7H14O2 | 详情 | 详情 | |
| (III) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (IV) | 49053 | ethyl (E)-7-hydroxy-5,5-dimethyl-2-heptenoate | C11H20O3 | 详情 | 详情 | |
| (V) | 49054 | ethyl (E)-7-[[tert-butyl(dimethyl)silyl]oxy]-5,5-dimethyl-2-heptenoate | C17H34O3Si | 详情 | 详情 | |
| (VI) | 49055 | ethyl 7-[[tert-butyl(dimethyl)silyl]oxy]-5,5-dimethylheptanoate | C17H36O3Si | 详情 | 详情 | |
| (VII) | 49056 | 7-[[tert-butyl(dimethyl)silyl]oxy]-5,5-dimethyl-1-heptanol | C15H34O2Si | 详情 | 详情 | |
| (VIII) | 49057 | tert-butyl(dimethyl)silyl 3,3-dimethyl-7-(tetrahydro-2H-pyran-2-yloxy)heptyl ether; tert-butyl[[3,3-dimethyl-7-(tetrahydro-2H-pyran-2-yloxy)heptyl]oxy]dimethylsilane | C20H42O3Si | 详情 | 详情 | |
| (IX) | 49058 | 3,3-dimethyl-7-(tetrahydro-2H-pyran-2-yloxy)-1-heptanol | C14H28O3 | 详情 | 详情 | |
| (X) | 49059 | 3,3-dimethyl-7-(tetrahydro-2H-pyran-2-yloxy)heptanal | C14H26O3 | 详情 | 详情 | |
| (XI) | 49060 | 8,8-dibromo-5,5-dimethyl-7-octenyl tetrahydro-2H-pyran-2-yl ether; 2-[(8,8-dibromo-5,5-dimethyl-7-octenyl)oxy]tetrahydro-2H-pyran | C15H26Br2O2 | 详情 | 详情 | |
| (XII) | 44260 | 1,1,1,3,3,3-hexafluoroacetone | 684-16-2 | C3F6O | 详情 | 详情 |
| (XIII) | 49061 | 1,1,1-trifluoro-6,6-dimethyl-10-(tetrahydro-2H-pyran-2-yloxy)-2-(trifluoromethyl)-3-decyn-2-ol | C18H26F6O3 | 详情 | 详情 | |
| (XIV) | 49062 | 10,10,10-trifluoro-5,5-dimethyl-9-(trifluoromethyl)-7-decyne-1,9-diol | C13H18F6O2 | 详情 | 详情 | |
| (XV) | 49036 | (Z)-10,10,10-trifluoro-5,5-dimethyl-9-(trifluoromethyl)-7-decene-1,9-diol | C13H20F6O2 | 详情 | 详情 | |
| (XVI) | 49037 | (Z)-10,10,10-trifluoro-9-hydroxy-5,5-dimethyl-9-(trifluoromethyl)-7-decenal | C13H18F6O2 | 详情 | 详情 | |
| (XVII) | 49063 | (Z)-10,10,10-trifluoro-5,5-dimethyl-9-(trifluoromethyl)-9-[(trimethylsilyl)oxy]-7-decenal | C16H26F6O2Si | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XII)Alternatively, the intermediate (Z)-ethylenic diol (XV) can also be obtained as follows: The reduction of 5,5-dimethyloxepan-2-one (XX) with iBu2AlH in THF gives 5,5-dimethyloxepan-2-ol (XXI), which is condensed with methyltriphenylphosphonium bromide (XXII) by means of tBu-OK in THF to yield 3,3-dimethyl-6-hepten-1-ol (XXIII). The Swern oxidation of the primary alcohol of (XIII) affords aldehyde (XXIV), which is condensed with CBr4 by means of PPh3 in CH2Cl2 to provide the dibromovinyl compound (XXV). The condensation of (XXV) with hexafluoroacetone (XII) by means of BuLi gives the acetylenic alcohol (XXVI), which is treated with hexylborane in THF to yield the acetylenic diol (XXVII). Finally, this compound is selectively reduced with H2 over Pd/C in EtOAc to afford the desired (Z)-ethylenic diol (XV).
| 【1】 Mohr, P.; Barbier, P.; Pirson, W.; Muller, M.; Bauer, F. (F. Hoffmann-La Roche AG); Cyclohexanediole derivs.. EP 1056716; WO 9943646 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 44260 | 1,1,1,3,3,3-hexafluoroacetone | 684-16-2 | C3F6O | 详情 | 详情 |
| (XV) | 49036 | (Z)-10,10,10-trifluoro-5,5-dimethyl-9-(trifluoromethyl)-7-decene-1,9-diol | C13H20F6O2 | 详情 | 详情 | |
| (XX) | 49065 | 5,5-dimethyl-2-oxepanone | C8H14O2 | 详情 | 详情 | |
| (XXI) | 49066 | 5,5-dimethyl-2-oxepanol | C8H16O2 | 详情 | 详情 | |
| (XXII) | 30484 | Methyl(triphenyl)phosphonium bromide | 1779-49-3 | C19H18BrP | 详情 | 详情 |
| (XXIII) | 49067 | 3,3-dimethyl-6-hepten-1-ol | C9H18O | 详情 | 详情 | |
| (XXIV) | 49068 | 3,3-dimethyl-6-heptenal | C9H16O | 详情 | 详情 | |
| (XXV) | 49069 | 1,1-dibromo-4,4-dimethyl-1,7-octadiene | C10H16Br2 | 详情 | 详情 | |
| (XXVI) | 49070 | 1,1,1-trifluoro-6,6-dimethyl-2-(trifluoromethyl)-9-decen-3-yn-2-ol | C13H16F6O | 详情 | 详情 | |
| (XXVII) | 49062 | 10,10,10-trifluoro-5,5-dimethyl-9-(trifluoromethyl)-7-decyne-1,9-diol | C13H18F6O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)The dimethylaluminium chloride-catalyzed addition of formaldehyde to the isopropenyl derivative (I) produced the homoallylic alcohol (II). The cyclopropane ring was then constructed over (II) by the Simmons-Smith procedure using diiodomethane and diethylzinc. The resulting cyclopropylethyl alcohol (III) was oxidized to aldehyde (IV) with pyridinium chlorochromate in CH2Cl2, and subsequent addition of diethyl azomethylphosphonate generated the terminal acetylene (V). The lithium acetylide of (V) was then added to hexafluoroacetone (VI), producing the propargylic alcohol (VII). Cleavage of the silyl protecting group with fluorosilicic acid liberated the secondary alcohol (VIII), which was further oxidized to ketone (IX) employing pyridinium dichromate. Condensation of this ketone (IX) with the ylide resulting from phosphine oxide (X) and n-butyllithium at low temperature produced the silylated cholecalciferol analogue (XI). Finally, desilylation with tetrabutylammonium fluoride gave the title compound.
| 【1】 Uskokovic, M.R.; Manchand, P.S. (F. Hoffmann-La Roche AG); 1,3-Dihydroxy-20,20-dialkyl-vitamin D3 analogs. EP 1015423; WO 9912894 . |
| 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) | 44255 | (1R,3aR,4S,7aR)-1-isopropenyl-7a-methyloctahydro-1H-inden-4-yl tert-butyl(dimethyl)silyl ether; [[(1R,3aR,4S,7aR)-1-isopropenyl-7a-methyloctahydro-1H-inden-4-yl]oxy](tert-butyl)dimethylsilane | C19H36OSi | 详情 | 详情 | |
| (II) | 44256 | 3-((1R,3aR,4S,7aR)-4-[[tert-butyl(dimethyl)silyl]oxy]-7a-methyloctahydro-1H-inden-1-yl)-3-buten-1-ol | C20H38O2Si | 详情 | 详情 | |
| (III) | 44257 | 2-[1-((1R,3aR,4S,7aR)-4-[[tert-butyl(dimethyl)silyl]oxy]-7a-methyloctahydro-1H-inden-1-yl)cyclopropyl]-1-ethanol | C21H40O2Si | 详情 | 详情 | |
| (IV) | 44258 | 2-[1-((1R,3aR,4S,7aR)-4-[[tert-butyl(dimethyl)silyl]oxy]-7a-methyloctahydro-1H-inden-1-yl)cyclopropyl]acetaldehyde | C21H38O2Si | 详情 | 详情 | |
| (V) | 44259 | ([(1R,3aR,4S,7aR)-7a-methyl-1-[1-(2-propynyl)cyclopropyl]octahydro-1H-inden-4-yl]oxy)(tert-butyl)dimethylsilane; (1R,3aR,4S,7aR)-7a-methyl-1-[1-(2-propynyl)cyclopropyl]octahydro-1H-inden-4-yl tert-butyl(dimethyl)silyl ether | C22H38OSi | 详情 | 详情 | |
| (VI) | 44260 | 1,1,1,3,3,3-hexafluoroacetone | 684-16-2 | C3F6O | 详情 | 详情 |
| (VII) | 44261 | 5-[1-((1R,3aR,4S,7aR)-4-[[tert-butyl(dimethyl)silyl]oxy]-7a-methyloctahydro-1H-inden-1-yl)cyclopropyl]-1,1,1-trifluoro-2-(trifluoromethyl)-3-pentyn-2-ol | C25H38F6O2Si | 详情 | 详情 | |
| (VIII) | 44262 | (1R,3aR,4S,7aR)-7a-methyl-1-[1-[5,5,5-trifluoro-4-hydroxy-4-(trifluoromethyl)-2-pentynyl]cyclopropyl]octahydro-1H-inden-4-ol | C19H24F6O2 | 详情 | 详情 | |
| (IX) | 44263 | (1R,3aR,7aR)-7a-methyl-1-[1-[5,5,5-trifluoro-4-hydroxy-4-(trifluoromethyl)-2-pentynyl]cyclopropyl]octahydro-4H-inden-4-one | C19H22F6O2 | 详情 | 详情 | |
| (X) | 30302 | [2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)ethyl(diphenyl)phosphine oxide | C32H51O3PSi2 | 详情 | 详情 | |
| (XI) | 44264 | 5-(1-[(1R,3aS,7aR)-4-[(E)-2-((3R,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]cyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]cyclopropyl)-1,1,1-trifluoro-2-(trifluoromethyl)-3-pentyn-2-ol | C39H62F6O3Si2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)Treatment of aniline (I) with hexafluoroacetone trihydrate (II) and p-toluenesulfonic acid affords derivative (III), which is then derivatized with trifluoroacetic anhydride (IV) to provide trifluoroacetanilide derivative (V). Reduction of (V) by means of LiAlH4 in refluxing THF yields N-trifluoroethylaniline derivative (VI), which is finally converted into the target sulfonamide by reaction with benzenesulfonyl chloride (VII) in pyridine.
| 【1】 Shan, B. (Tularik Inc.); Compsns. and methods for raising HDL cholesterol levels. WO 0103705 . |
| 【2】 Liu, J.; Li, L.; Cutler, S.T.; Zhu, L.; Shan, B.; Medina, J.C.; Hasegawa, H.; Lustig, K. (Tularik Inc.); LXR modulators. EP 1161233; WO 0054759 . |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 44260 | 1,1,1,3,3,3-hexafluoroacetone | 684-16-2 | C3F6O | 详情 | 详情 |
| (III) | 50005 | 2-(4-Aminophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; 4-(Hexafluoro-2-hydroxyisopropyl)aniline | 722-92-9 | C9H7F6NO | 详情 | 详情 |
| (IV) | 33862 | trifluoroacetic anhydride | 407-25-0 | C4F6O3 | 详情 | 详情 |
| (V) | 50006 | 2,2,2-trifluoro-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]acetamide | C11H6F9NO2 | 详情 | 详情 | |
| (VI) | 50007 | 1,1,1,3,3,3-hexafluoro-2-[4-[(2,2,2-trifluoroethyl)amino]phenyl]-2-propanol | C11H8F9NO | 详情 | 详情 | |
| (VII) | 14713 | benzenesulfonyl chloride | 98-09-9 | C6H5ClO2S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XI)Lithiation of thiazole (X) with butyllithium, and then addition to hexafluoroacetone (XI) in cold Et2O gives the carbinol adduct (XII), which is subsequently protected with 2-(trimethylsilyl)ethoxymethyl chloride (XIII), yielding the SEM ether (XIV). A further metalation of (XIV) with butyllithium, followed by addition to aldehyde (IX) provides alcohol (XV). Bromination of (XV), with simultaneous SEM group cleavage to afford (XVI), is accomplished by treatment with thionyl bromide and pyridine. Alkylation of the potassium enolate of ethyl 3-pyridylacetate N-oxide (XVII) with bromide (XVI) gives ester (XVIII). Finally, decarboethoxylation of (XVIII) by means of LiOH, followed by resolution of the racemic mixture using chiral HPLC furnishes the title enantiomer.
| 【1】 Girard, M.; Frenette, R.; Hamel, P.; Guay, D.; Ducharme, Y.; Blouin, M.; Friesen, R.; Cote, B.; Martins, E.; Laliberte, S. (Merck Frosst Canada Inc.); Tri-aryl-substd.-ethane PDE4 inhibitors. EP 1272488; US 6399636; WO 0170738 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 59749 | 3-(cyclopropyloxy)-4-(difluoromethoxy)benzaldehyde | C11H10F2O3 | 详情 | 详情 | |
| (X) | 23000 | 1,3-thiazole | 288-47-1 | C3H3NS | 详情 | 详情 |
| (XI) | 44260 | 1,1,1,3,3,3-hexafluoroacetone | 684-16-2 | C3F6O | 详情 | 详情 |
| (XII) | 59750 | 1,1,1,3,3,3-hexafluoro-2-(1,3-thiazol-2-yl)-2-propanol | C6H3F6NOS | 详情 | 详情 | |
| (XIII) | 27243 | [2-(chloromethoxy)ethyl](trimethyl)silane | 76513-69-4 | C6H15ClOSi | 详情 | 详情 |
| (XIV) | 59751 | 2-(2,2,2-trifluoro-1-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)-1,3-thiazole; [2,2,2-trifluoro-1-(1,3-thiazol-2-yl)-1-(trifluoromethyl)ethoxy]methyl 2-(trimethylsilyl)ethyl ether | C12H17F6NO2SSi | 详情 | 详情 | |
| (XV) | 59752 | [3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl][2-(2,2,2-trifluoro-1-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)-1,3-thiazol-5-yl]methanol | C23H27F8NO5SSi | 详情 | 详情 | |
| (XVI) | 59753 | 2-(5-{bromo[3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl]methyl}-1,3-thiazol-2-yl)-1,1,1,3,3,3-hexafluoro-2-propanol | C17H12BrF8NO3S | 详情 | 详情 | |
| (XVII) | 59754 | 3-(2-ethoxy-2-oxoethyl)-1-pyridiniumolate | C9H11NO3 | 详情 | 详情 | |
| (XVIII) | 59755 | 3-(2-[3-(cyclopropyloxy)-4-(difluoromethoxy)phenyl]-1-(ethoxycarbonyl)-2-{2-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1,3-thiazol-5-yl}ethyl)-1-pyridiniumolate | C26H22F8N2O6S | 详情 | 详情 |