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【结 构 式】 
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【分子编号】34685 【品名】N-(5-chloro-2-pyridinyl)(trifluoro)-N-[(trifluoromethyl)sulfonyl]methanesulfonamide 【CA登记号】145100-51-2 |
【 分 子 式 】C7H3ClF6N2O4S2 【 分 子 量 】392.6870192 【元素组成】C 21.41% H 0.77% Cl 9.03% F 29.03% N 7.13% O 16.3% S 16.33% |
合成路线1
该中间体在本合成路线中的序号：(IX)Synthesis of phosphine oxide (XIV): Epoxidation of l-carvone (I) with H2O2 and LiOH in methanol gives the epoxide (II), which is reduced with L-Selectride in THF to yield the alcohol (III). Oxidation of the isopropenyl group of (III) with OsO4, KIO4, MCPBA and HOAc affords the acetate (IV), which is hydrolyzed to the diol (V) with MeONa in methanol. Protection of the two OH groups of (V) with TBDMS-Cl and imidazole provides the bis-silyl ether (VI), which is oxidized with periodic acid in ethyl ether to give the aldehyde (VII). Compound (VII) is submitted to a Wittig condensation with CBr4, PPh3 and Zn in dichloromethane to yield the dibromovinyl compound (VIII), which is converted into the acetylenic vinyl triflate (X) by treatment with LDA in THF followed by the triflic imide (IX). Cyclization of triflate (X) by means of Pd(OAc)2 and PPh3, followed by carbonylation with CO in methanol provides the methyl ester (XI) as a 2:1 mixture of the Z- and E-isomers. Photoisomerization of this mixture (XIa-b) under the Hoffman-La Roche conditions (presence of 9-fluorenone) gives the Z-isomer (XII) in a high yield. Reduction of ester (XII) with DIBAL in toluene provides the primary alcohol (XIII), which is finally converted into the phosphine oxide (XIV) by known methods.
| 【1】 Mourino, A.; et al.; Efficient and versatile synthesis of A-ring precursors of 1alpha,25-dihydroxyvitamin D3 and analogues. Application to the synthesis of Lythgoe-Roche phosphine oxide. Tetrahedron Lett 1997, 38, 26, 4713. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIa),(XII) | 52149 | methyl 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)acetate | C22H42O4Si2 | 详情 | 详情 | |
| (XIb) | 52150 | methyl 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)acetate | C22H42O4Si2 | 详情 | 详情 | |
| (I) | 13386 | (5R)-5-Isopropenyl-2-methyl-2-cyclohexen-1-one; L-(-)-Carvone | 6485-40-1 | C10H14O | 详情 | 详情 |
| (II) | 52141 | (1R,4R,6R)-4-isopropenyl-1-methyl-7-oxabicyclo[4.1.0]heptan-2-one | C10H14O2 | 详情 | 详情 | |
| (III) | 52142 | (1R,2S,4S,6R)-4-isopropenyl-1-methyl-7-oxabicyclo[4.1.0]heptan-2-ol | C10H16O2 | 详情 | 详情 | |
| (IV) | 52143 | (1R,3S,5S,6S)-5-hydroxy-6-methyl-7-oxabicyclo[4.1.0]hept-3-yl acetate | C9H14O4 | 详情 | 详情 | |
| (V) | 52144 | (1S,2S,4S,6R)-1-methyl-7-oxabicyclo[4.1.0]heptane-2,4-diol | C7H12O3 | 详情 | 详情 | |
| (VI) | 52145 | tert-butyl[((1R,2S,4R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-7-oxabicyclo[4.1.0]hept-2-yl)oxy]dimethylsilane; tert-butyl(dimethyl)silyl (1R,2S,4R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-7-oxabicyclo[4.1.0]hept-2-yl ether | C19H40O3Si2 | 详情 | 详情 | |
| (VII) | 52146 | (3S,5S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-6-oxoheptanal | C19H40O4Si2 | 详情 | 详情 | |
| (VIII) | 52147 | (3S,5R)-8,8-dibromo-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-7-octen-2-one | C20H40Br2O3Si2 | 详情 | 详情 | |
| (IX) | 34685 | N-(5-chloro-2-pyridinyl)(trifluoro)-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | 145100-51-2 | C7H3ClF6N2O4S2 | 详情 | 详情 |
| (X) | 52148 | (2S,4R)-2,4-bis[[tert-butyl(dimethyl)silyl]oxy]-1-methylene-6-heptynyl trifluoromethanesulfonate | C21H39F3O5SSi2 | 详情 | 详情 | |
| (XIII) | 47614 | 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)-1-ethanol | C21H42O3Si2 | 详情 | 详情 | |
| (XIV) | 42574 | [2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide | C33H51O3PSi2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)Addition of 3-methyl-2-butenoic acid (II) to 4-methoxythiophenol (I) in the presence of piperidine at 105 C afforded adduct (III). After conversion of (III) to the corresponding acid chloride (IV) with oxalyl chloride, Friedel-Crafts cyclization using SnCl4 produced thiochromanone (V). Cleavage of the methyl ether of (V) by means of BBr3 gave phenol (VI), which was converted to triflate (VII) with trifluoromethanesulfonic anhydride in pyridine. Coupling of (VII) with trimethylsilyl acetylene (VIII) using a palladium catalyst provided (IX). Subsequent desilylation of (IX) with K2CO3 in MeOH, followed by palladium-catalyzed coupling of the resulting alkyne with ethyl 4-iodobenzoate (X) afforded the diaryl acetylene (XI). Introduction of the 4-aryl group in (XI) was achieved by conversion of (XI) to vinyl triflate (XIII) upon treatment of the sodium enolate with the bis-triflimide reagent (XII), and further condensation with 4-ethyl-phenylzinc chloride (XIV) yielding (XV). Finally, basic hydrolysis of the ethyl ester (XV) furnished the target carboxylic acid.
| 【1】 Standeven, A.M.; Escobar, M.; Wang, L.; Johnson, A.T.; Chandraratna, R.A.S.; Synthesis and biological activity of high-affinity retinoic acid receptor antagonists. Bioorg Med Chem 1999, 7, 1321. |
| 【2】 Klein, E.S.; Chandraratna, R.A.; Teng, M.; Duong, T.T.; Gillett, S.J.; Beard, R.L.; Vuligonda, V.; Johnson, A.T.; Standeven, A.M.; Nagpal, S. (Allergan, Inc.); Benzopyran and benzothiopyran derivs. having retinoid antagonist-like activity. WO 9933821 . |
| 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) | 25639 | 4-methoxyphenylhydrosulfide; 4-methoxybenzenethiol | 34320-82-6 | C7H8OS | 详情 | 详情 |
| (II) | 34677 | 3-methyl-2-butenoic acid | 541-47-9 | C5H8O2 | 详情 | 详情 |
| (III) | 34678 | 3-[(4-methoxyphenyl)sulfanyl]-3-methylbutyric acid | C12H16O3S | 详情 | 详情 | |
| (IV) | 34679 | 3-[(4-methoxyphenyl)sulfanyl]-3-methylbutanoyl chloride | C12H15ClO2S | 详情 | 详情 | |
| (V) | 34680 | 6-methoxy-2,2-dimethyl-2,3-dihydro-4H-thiochromen-4-one | C12H14O2S | 详情 | 详情 | |
| (VI) | 34681 | 6-hydroxy-2,2-dimethyl-2,3-dihydro-4H-thiochromen-4-one | C11H12O2S | 详情 | 详情 | |
| (VII) | 34682 | 2,2-dimethyl-4-oxo-3,4-dihydro-2H-thiochromen-6-yl trifluoromethanesulfonate | C12H11F3O4S2 | 详情 | 详情 | |
| (VIII) | 23897 | ethynyl(trimethyl)silane；trimethylsilyl acetylene | 1066-54-2 | C5H10Si | 详情 | 详情 |
| (IX) | 34683 | 2,2-dimethyl-6-[2-(trimethylsilyl)ethynyl]-2,3-dihydro-4H-thiochromen-4-one | C16H20OSSi | 详情 | 详情 | |
| (X) | 23796 | ethyl 4-iodobenzoate | 51934-41-9 | C9H9IO2 | 详情 | 详情 |
| (XI) | 34684 | ethyl 4-[2-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-thiochromen-6-yl)ethynyl]benzoate | C22H20O3S | 详情 | 详情 | |
| (XII) | 34685 | N-(5-chloro-2-pyridinyl)(trifluoro)-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | 145100-51-2 | C7H3ClF6N2O4S2 | 详情 | 详情 |
| (XIII) | 34686 | ethyl 4-[2-(2,2-dimethyl-4-[[(trifluoromethyl)sulfonyl]oxy]-2H-thiochromen-6-yl)ethynyl]benzoate | C23H19F3O5S2 | 详情 | 详情 | |
| (XIV) | 34687 | chloro(4-ethylphenyl)zinc | C8H9ClZn | 详情 | 详情 | |
| (XV) | 34688 | ethyl 4-[2-[4-(4-ethylphenyl)-2,2-dimethyl-2H-thiochromen-6-yl]ethynyl]benzoate | C30H28O2S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXVIII)The silylation of the acetonide (XVIII) with Tms-Cl and LDA in THF gives dienolate (XIX), which is enantioselectively condensed with acrolein (XX) by means of Carreira's Ti catalyst in ethyl ether to yield the chiral allyl alcohol (XXI). The reaction of (XXI), N,O-dimethylhydroxylamine (XXII) and Me2AlCl affords the amide (XXIII), which is selectively reduced with Me4NBH(OAc)3 in HOAc/acetonitrile to provide the dihydroxyamide (XXIV). The silylation of the OH groups of (XXIV) with Tbdms-Cl and imidazole gives the disilylated compound (XXV), which is submitted to a Grignard reaction with vinylmagnesium bromide (XXVI) in THF to yield the vinyl ketone (XXVII). The Michael addition reaction with Ph2P(O)-Li and simultaneous triflation with (XXVIII) in THF affords the enol triflate (XXIX), which is cyclized by means of Pd(OAc)2, PPh3 and TEA in THF to provide the phosphorane (XXXa-b) as an inseparable mixture of the (Z)- and (E)-isomers. Finally, this mixture is submitted to photochemical isomerization with a medium-pressure UV mercury lamp in the presence of 9-fluorenone, furnishing the target intermediate, the (Z)-isomer (X) with a 95 % yield.
| 【1】 Anné, S.; et al.; Enantioselective syntheses of key A-ring precursors of 1alpha,25-dihydroxyvitamin D3 and analogues. Synlett 1999, 9, 1435. |
| 【2】 Hiyamizu, H.; et al.; A concise enantioselective synthesis of a key A-ring synthon for 1alpha-hydroxyvitamin D3 compounds. Org Lett 2001, 3, 3, 473. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXa),(X) | 42574 | [2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide | C33H51O3PSi2 | 详情 | 详情 | |
| (XXXb) | 53658 | (E)-2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide; (E)-[2-((3S,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane | n/a | C33H51O3PSi2 | 详情 | 详情 |
| (XVIII) | 13327 | 2,2,6-Trimethyl-4H-1,3-dioxin-4-one；2,2,6-trimethyl-1,3-dioxin-4-one；2,2,6-trimethyl-m-Dioxin-4-one;3-(1-hydroxy-1-methylethoxy)-d-lactone Crotonicacid | 5394-63-8 | C7H10O3 | 详情 | 详情 |
| (XIX) | 53651 | [(2,2-dimethyl-4-methylene-4H-1,3-dioxin-6-yl)oxy](trimethyl)silane; 2,2-dimethyl-4-methylene-4H-1,3-dioxin-6-yl trimethylsilyl ether | n/a | C10H18O3Si | 详情 | 详情 |
| (XX) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (XXI) | 53652 | 6-[(2S)-2-hydroxy-3-butenyl]-2,2-dimethyl-4H-1,3-dioxin-4-one | n/a | C10H14O4 | 详情 | 详情 |
| (XXII) | 13361 | (Methoxyamino)methane; N,O-Dimethylhydroxylamine | 1117-97-1 | C2H7NO | 详情 | 详情 |
| (XXIII) | 53653 | (5S)-5-hydroxy-N-methoxy-N-methyl-3-oxo-6-heptenamide | n/a | C9H15NO4 | 详情 | 详情 |
| (XXIV) | 53654 | (3S,5S)-3,5-dihydroxy-N-methoxy-N-methyl-6-heptenamide | n/a | C9H17NO4 | 详情 | 详情 |
| (XXV) | 53655 | (3S,5S)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-N-methoxy-N-methyl-6-heptenamide | n/a | C21H45NO4Si2 | 详情 | 详情 |
| (XXVI) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (XXVII) | 53626 | (4S)-3,3-diethyl-4-{4-[(4-methyl-1-piperazinyl)carbonyl]phenoxy}-2-azetidinone | n/a | C19H27N3O3 | 详情 | 详情 |
| (XXVIII) | 34685 | N-(5-chloro-2-pyridinyl)(trifluoro)-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | 145100-51-2 | C7H3ClF6N2O4S2 | 详情 | 详情 |
| (XXIX) | 53657 | (3S,5S)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-1-[(E)-2-(diphenylphosphoryl)ethylidene]-6-heptenyl trifluoromethanesulfonate | n/a | C34H52F3O6PSSi2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)The intermediate phosphine oxide (XIV) has been obtained as follows: The epoxidation of l-carvone (I) with H2O2 and LiOH in methanol gives the epoxide (II), which is reduced with L-Selectride in THF to yield the alcohol (III). The oxidation of the isopropenyl group of (III) with OsO4, KIO4, MCPBA and HOAc affords the acetate (IV), which is hydrolyzed to the diol (V) with NaOMe in methanol. The protection of the two OH groups of (V) with Tbdms-Cl and imidazole provides the bis-silyl ether (VI), which is oxidized with periodic acid in ethyl ether to give the ketoaldehyde (VII). The aldehyde group of (VII) is subjected to a Wittig condensation with CBr4, PPh3 and Zn in dichloromethane to yield the dibromovinyl compound (VIII), which by treatment with LDA and the triflic imide (IX) in THF affords the acetylenic vinyl triflate (X). The cyclization of (X) by means of Pd(OAc)2 and PPH3, followed by carbonylation in methanol, provides the methyl ester (XI) as a 2:1 mixture of the (Z)- and (E)-isomers. The photoisomerization of this mixture under the Hoffmann-La Roche conditions (presence of 9-fluorenone) gives a high yield of the (Z)-isomer (XII), which is reduced with DIBAL in toluene to give the primary alcohol (XIII). Finally, this compound is converted into the target phosphine oxide (XIV) is performed by known methods.
| 【1】 Mourino, A.; et al.; Efficient and versatile synthesis of A-ring precursors of 1alpha,25-dihydroxyvitamin D3 and analogues. Application to the synthesis of Lythgoe-Roche phosphine oxide. Tetrahedron Lett 1997, 38, 26, 4713. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIa),(XII) | 52149 | methyl 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)acetate | C22H42O4Si2 | 详情 | 详情 | |
| (XIb) | 52150 | methyl 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)acetate | C22H42O4Si2 | 详情 | 详情 | |
| (I) | 13386 | (5R)-5-Isopropenyl-2-methyl-2-cyclohexen-1-one; L-(-)-Carvone | 6485-40-1 | C10H14O | 详情 | 详情 |
| (II) | 52141 | (1R,4R,6R)-4-isopropenyl-1-methyl-7-oxabicyclo[4.1.0]heptan-2-one | C10H14O2 | 详情 | 详情 | |
| (III) | 52550 | 1-methyl-4-(1-methylethenyl)-7-oxabicyclo[4.1.0]heptan-2-ol | C10H16O2 | 详情 | 详情 | |
| (IV) | 52143 | (1R,3S,5S,6S)-5-hydroxy-6-methyl-7-oxabicyclo[4.1.0]hept-3-yl acetate | C9H14O4 | 详情 | 详情 | |
| (V) | 52144 | (1S,2S,4S,6R)-1-methyl-7-oxabicyclo[4.1.0]heptane-2,4-diol | C7H12O3 | 详情 | 详情 | |
| (VI) | 52145 | tert-butyl[((1R,2S,4R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-7-oxabicyclo[4.1.0]hept-2-yl)oxy]dimethylsilane; tert-butyl(dimethyl)silyl (1R,2S,4R,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-7-oxabicyclo[4.1.0]hept-2-yl ether | C19H40O3Si2 | 详情 | 详情 | |
| (VII) | 52146 | (3S,5S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-6-oxoheptanal | C19H40O4Si2 | 详情 | 详情 | |
| (VIII) | 52147 | (3S,5R)-8,8-dibromo-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-7-octen-2-one | C20H40Br2O3Si2 | 详情 | 详情 | |
| (IX) | 34685 | N-(5-chloro-2-pyridinyl)(trifluoro)-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | 145100-51-2 | C7H3ClF6N2O4S2 | 详情 | 详情 |
| (X) | 52148 | (2S,4R)-2,4-bis[[tert-butyl(dimethyl)silyl]oxy]-1-methylene-6-heptynyl trifluoromethanesulfonate | C21H39F3O5SSi2 | 详情 | 详情 | |
| (XIII) | 47614 | 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)-1-ethanol | C21H42O3Si2 | 详情 | 详情 | |
| (XIV) | 42574 | [2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide | C33H51O3PSi2 | 详情 | 详情 |