|
【结 构 式】 
|
【分子编号】18816 【品名】ethyl 2-(diethoxyphosphoryl)propanoate 【CA登记号】3699-66-9 |
【 分 子 式 】C9H19O5P 【 分 子 量 】238.220622 【元素组成】C 45.38% H 8.04% O 33.58% P 13% |
合成路线1
该中间体在本合成路线中的序号：(XI)The silylation of 3(S)-hydroxytetrahydrofuran-2-one (I) with TBDMS-Cl and imidazole gives the silyl ether (II), which is methylated with MeLi in THF yields the 3(S)-(TBDMSO)-5-hydroxy-2-pentanone (IV), through the hemiketal intermediate (III). Simultaneously, the cyclization of 1,3-dichloropropanone (V) with thioacetamide (VI) in refluxing ethanol affords 4-(chloromethyl)-2-methylthiazole (VII), which is treated with tributylphosphine to provide the phosphonium salt (VIII). The condensation of (VIII) with the ketone (IV) gives the unsaturated alcohol (IX), which is oxidized to the corresponding aldehyde (X) by means of oxalyl chloride in DMSO. The condensation of (X) with 2-phosphonopropionic acid triethyl ester (XI) by means of KHMDS gives the dienoic acid ethyl ester (XII), which is reduced with DIBAL in THF yielding the corresponding primary alcohol (XIII). The condensation of (XIII) with the chiral sulfone intermediate (XIV) by means of KHMDS and PPh3 affords the corresponding adduct (XV), which is desulfurized with Na/Hg in THF/methanol giving the silylated diol (XVI). The selective monodesilylation of (XVI) with CSA in methanol/dichloromethane yields the primary alcohol (XVII), which is oxidized with Dess Martin periodinane (DMP) to the aldehyde (XVIII). The condensation of (XVIII) with the intermediate chiral ketone (XIX) by means of LDA in THF affords the hydroxy ketone (XX).
| 【1】 Mulzer, J.; Ohler, E.; Mantoulidis, A. (Schering AG); Method for producing epothilone B and derivs., and intermediate products for this method. WO 0023452 . |
| 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) | 40815 | (3S)-3-hydroxydihydro-2(3H)-furanone | 19444-84-9 | C4H6O3 | 详情 | 详情 |
| (II) | 40816 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]dihydro-2(3H)-furanone | C10H20O3Si | 详情 | 详情 | |
| (III) | 40817 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyltetrahydro-2-furanol | C11H24O3Si | 详情 | 详情 | |
| (IV) | 40818 | (3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-2-pentanone | C11H24O3Si | 详情 | 详情 | |
| (V) | 63907 | 1,3-dichloroacetone | C3H4Cl2O | 详情 | 详情 | |
| (VI) | 19170 | ethanethioamide | 62-55-5 | C2H5NS | 详情 | 详情 |
| (VII) | 40819 | 4-(chloromethyl)-2-methyl-1,3-thiazole | C5H6ClNS | 详情 | 详情 | |
| (VIII) | 40820 | tributyl[(2-methyl-1,3-thiazol-4-yl)methyl]phosphonium chloride | C17H33ClNPS | 详情 | 详情 | |
| (IX) | 40821 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-penten-1-ol | C16H29NO2SSi | 详情 | 详情 | |
| (X) | 40822 | (3S,4E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-(2-methyl-1,3-thiazol-4-yl)-4-pentenal | C16H27NO2SSi | 详情 | 详情 | |
| (XI) | 18816 | ethyl 2-(diethoxyphosphoryl)propanoate | 3699-66-9 | C9H19O5P | 详情 | 详情 |
| (XII) | 40823 | ethyl (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadienoate | C21H35NO3SSi | 详情 | 详情 | |
| (XIII) | 40824 | (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadien-1-ol | C19H33NO2SSi | 详情 | 详情 | |
| (XIV) | 40825 | tert-butyl(dimethyl)[[(2S)-2-methyl-4-(phenylsulfonyl)butyl]oxy]silane; (3S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methylbutyl phenyl sulfone | C17H30O3SSi | 详情 | 详情 | |
| (XV) | 40826 | (1R,3Z,6S,7E)-6-[[tert-butyl(dimethyl)silyl]oxy]-1-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)-3,7-dimethyl-8-(2-methyl-1,3-thiazol-4-yl)-3,7-octadienyl phenyl sulfone; 4-[(1E,3S,5Z,8R,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-8-(phenylsulfonyl)-1,5-undecadienyl]-2-methyl-1,3-thiazole | C36H61NO4S2Si2 | 详情 | 详情 | |
| (XVI) | 40827 | tert-butyl(dimethyl)silyl (1S,3Z,8S)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,8-dimethyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-nonenyl ether; 4-((1E,3S,5Z,10S)-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-1,5-undecadienyl)-2-methyl-1,3-thiazole | C30H57NO2SSi2 | 详情 | 详情 | |
| (XVII) | 40828 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadien-1-ol | C24H43NO2SSi | 详情 | 详情 | |
| (XVIII) | 40829 | (2S,6Z,9S,10E)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,6,10-trimethyl-11-(2-methyl-1,3-thiazol-4-yl)-6,10-undecadienal | C24H41NO2SSi | 详情 | 详情 | |
| (XIX) | 40830 | (5S)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4-dimethyl-3-heptanone | C21H46O3Si2 | 详情 | 详情 | |
| (XX) | 40831 | (7S,10R,11S,12S,16Z,19S)-7-[[tert-butyl(dimethyl)silyl]oxy]-11-hydroxy-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,20-dioxa-3,21-disila-16-tricosen-9-one | C45H87NO5SSi3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)Horner-Emmons reaction of 4-(methylthio)benzaldehyde (XI) with phosphonate (XII) in the presence of Et3N and MgBr2 afforded unsaturated ester (XIII). Oxidation to sulfone (XIV) was effected with H2O2 and a catalytic amount of Na2WO4. Subsequent reduction of the ester group with DIBAL-H in CH2Cl2 at -78 C produced allyl alcohol (XV), which was converted to iodide (XVI) on treatment with I2, Ph3P and imidazole in acetonitrile. Reaction of this iodide with methyl chlorodifluoro-acetate in the presence of KF and CuI in DMF at 90 C yielded trifluoromethyl compound (XVIII). Alternatively, alcohol (XV) could be converted to (XVIII) with chlorodifluoroacetic anhydride followed by conversion of the intermediate ester (XVII) to trifluoroethyl compound in the presence of KF and CuI. Sharpless asymmetric dihydroxylation of olefin (XVIII) with potassium ferricyanide or iodine and a catalytic amount of K3OsO4 as the oxidants and the chiral ligand hydroquinidine 1,4-phthalazinediyl diether ((DHQD)2PHAL) yielded diol (XXI) with a 79% e.e. In a related procedure, diol (XXI) was obtained by reduction of ester (XIII) and treatment of the resulting allyl alcohol (XIX) with chlordifluoroacetic anhydride to give olefin (XX). Sharpless oxidation of (XX) then produced a mixture of diols with a sulfide, sulfoxide and sulfone groups, which was oxidized with H2O2 and Na2WO4 to the sulfone (XXI) with a 82% e.e. Recrystallization from isopropyl acetate-hexane raised the e.e. to > 98%. Then, Swern oxidation of diol (XXI) provided hydroxyketone (VII). Subsequent esterification with 3,4-difluorophenoxyacetic acid (XXII) in the presence of CMC and DMAP gave ester (X), which was cyclized to the target furanone by treatment with DBU using isopropyl trifluoroacetate as a water scavenger.
| 【1】 Tan, L.; et al.; An efficient asymmetric synthesis of a potent COX-2 inhibitor L-784,512. Tetrahedron Lett 1998, 39, 23, 3961. |
| 【2】 Belley, M.; Gauthier, J.Y.; Grimm, E.; Leblanc, Y.; Li, C.-S.; Therien, M.; Lau, C.-K.; Prasit, P.; Roy, P. (Merck Frosst Canada Inc.); (Methylsulfonyl)phenyl-2-(5H)-furanones as COX-2 inhibitors. EP 0863891; JP 1999500146; US 5981576; WO 9714691 . |
| 【3】 Black, C.; Leger, S.; Prasit, P.; Wang, Z.; Hamel, P.; Han, Y.; Hughes, G. (Merck Frosst Canada Inc.); 3,4-Diaryl-2-hydroxy-2,5-dihydrofurans as prodrugs to Cox-2 inhibitors. EP 0904269; JP 1999500748; US 5698584; WO 9716435 . |
| 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) | 18811 | (2R)-4,4,4-trifluoro-2-hydroxy-2-methyl-1-[4-(methylsulfonyl)phenyl]-1-butanone | C12H13F3O4S | 详情 | 详情 | |
| (X) | 18814 | (1R)-3,3,3-trifluoro-1-methyl-1-[4-(methylsulfonyl)benzoyl]propyl 2-(3,4-difluorophenoxy)acetate | C20H17F5O6S | 详情 | 详情 | |
| (XI) | 18815 | 4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde | 3446-89-7 | C8H8OS | 详情 | 详情 |
| (XII) | 18816 | ethyl 2-(diethoxyphosphoryl)propanoate | 3699-66-9 | C9H19O5P | 详情 | 详情 |
| (XIII) | 18817 | ethyl (E)-2-methyl-3-[4-(methylsulfanyl)phenyl]-2-propenoate | C13H16O2S | 详情 | 详情 | |
| (XIV) | 18818 | ethyl (E)-2-methyl-3-[4-(methylsulfonyl)phenyl]-2-propenoate | C13H16O4S | 详情 | 详情 | |
| (XV) | 18819 | (E)-2-methyl-3-[4-(methylsulfonyl)phenyl]-2-propen-1-ol | C11H14O3S | 详情 | 详情 | |
| (XVI) | 18820 | 4-[(E)-3-iodo-2-methyl-1-propenyl]phenyl methyl sulfone; [4-[(E)-3-iodo-2-methyl-1-propenyl]phenyl](methyl)dioxo-lambda(6)-sulfane | C11H13IO2S | 详情 | 详情 | |
| (XVII) | 18821 | methyl 4-[(E)-4,4,4-trifluoro-2-methyl-1-butenyl]phenyl sulfone; (E)-2-methyl-3-[4-(methylsulfonyl)phenyl]-2-propenyl 2-chloro-2,2-difluoroacetate | C13H13ClF2O4S | 详情 | 详情 | |
| (XVIII) | 18822 | methyl(dioxo)[4-[(E)-4,4,4-trifluoro-2-methyl-1-butenyl]phenyl]-lambda(6)-sulfane | C12H13F3O2S | 详情 | 详情 | |
| (XIX) | 18823 | (E)-2-methyl-3-[4-(methylsulfanyl)phenyl]-2-propen-1-ol | C11H14OS | 详情 | 详情 | |
| (XX) | 18824 | 1-(methylsulfanyl)-4-[(E)-4,4,4-trifluoro-2-methyl-1-butenyl]benzene; methyl 4-[(E)-4,4,4-trifluoro-2-methyl-1-butenyl]phenyl sulfide | C12H13F3S | 详情 | 详情 | |
| (XXI) | 18825 | (1R,2R)-4,4,4-trifluoro-2-methyl-1-[4-(methylsulfonyl)phenyl]-1,2-butanediol | C12H15F3O4S | 详情 | 详情 | |
| (XXII) | 18826 | 2-(3,4-difluorophenoxy)acetic acid | C8H6F2O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The reaction of 5-phenylpentanal (I) with triethyl 2-phosphonopropionate (II) by means of NaOEt in THF gives ethyl 2-methyl-7-phenyl-2(E)-heptenoate (III), which is hydrolyzed with NaOH in methanol/water to the corresponding free acid (IV). The reaction of (IV) with 4-methoxythiophenol (V) in hot piperidine affords 3-(4-methoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid (VI), which by reaction first with oxalyl chloride, then with O-trimethylsilylhydroxylamine (VII) in dichloromethane, and finally with HCl is converted into the hydroxamic acid (VIII). Finally, this compound is oxidized with oxone in methanol/water to provide the target compound as mixture of diastereomeric racemates that is separated by reversed phase HPLC.
| 【1】 Groneberg, R.D.; Neuenschwander, K.W.; Djuric, S.W.; McGeehan, G.M.; Burns, C.J.; Condon, S.M.; Morrissette, M.M.; Salvino, J.M.; Scotese, A.C.; Ullrich, J.W. (Aventis Pharma SA); Substd. (aryl, heteroaryl, arylmethyl or heteroarylmethyl) hydroxamic acid cpds.. EP 0871439; JP 2000503012; WO 9724117 . |
| 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) | 25636 | 5-phenylpentanal | C11H14O | 详情 | 详情 | |
| (II) | 18816 | ethyl 2-(diethoxyphosphoryl)propanoate | 3699-66-9 | C9H19O5P | 详情 | 详情 |
| (III) | 26081 | ethyl (E)-2-methyl-7-phenyl-2-heptenoate | C16H22O2 | 详情 | 详情 | |
| (IV) | 26082 | (E)-2-methyl-7-phenyl-2-heptenoic acid | C14H18O2 | 详情 | 详情 | |
| (V) | 25639 | 4-methoxyphenylhydrosulfide; 4-methoxybenzenethiol | 34320-82-6 | C7H8OS | 详情 | 详情 |
| (VI) | 26083 | 3-[(4-methoxyphenyl)sulfanyl]-2-methyl-7-phenylheptanoic acid | C21H26O3S | 详情 | 详情 | |
| (VII) | 26091 | O-(trimethylsilyl)hydroxylamine; (aminooxy)(trimethyl)silane | 22737-36-6 | C3H11NOSi | 详情 | 详情 |
| (VIII) | 26084 | N-hydroxy-3-[(4-methoxyphenyl)sulfanyl]-2-methyl-7-phenylheptanamide | C21H27NO3S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The Horner-Emmons condensation of 3,5-dimethoxybenzaldehyde (I) with triethyl phosphonopropionate (II) gives the cinnamate ester (III), which is hydrolyzed, treated with SOCl2 and condensed with the chiral auxiliary acylsultam (IV) to yield the adduct (V). The enantioselective methylation of (V) with Me2CuLi gives compound (VI) as the major diastereomer. Subsequent hydrolysis of (VI) with LiOH furnishes carboxylic acid (VII). The reduction of (VII) with LiAlH4 gives alcohol (VIII). The reaction of (VIII) with Ts-Cl and pyridine affords the tosylate (IX), which is condensed with butylmagnesium bromide (X) by means of Li2CuCl4 in THF to provide the adduct (XI). The demethylation of (XI) with BBr3 in dichloromethane gives the resorcinol derivative (XII), which is condensed with 4-hydroxy-myrtenyl pivalate (XIII) by means of BF3-Et2O to yield the cannabinoid pivalate ester (XIV). Finally, the reductive cleavage of the ester group of (XIV) with LiAlH4 yields the target cannabinoid.
| 【1】 Huffman, J.W.; Liddle, J.; Enantioselective synthesis of 11-hydroxy-(1'S,2'R)-dimethylheptyl-DELTA8-THC, a very potent CB1 agonist. Tetrahedron 2001, 57, 36, 7607. |
| 【2】 Duncan, S.G. Jr.; Huffman, J.W.; Synthesis and pharmacology of the 1',2'-dimethylheptyl-DELTA8-THC isomers: Exceptionally potent cannabinoids. Bioorg Med Chem Lett 1997, 7, 21, 2799. |
| 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) | 21720 | 3,5-dimethoxybenzaldehyde | 7311-34-4 | C9H10O3 | 详情 | 详情 |
| (II) | 18816 | ethyl 2-(diethoxyphosphoryl)propanoate | 3699-66-9 | C9H19O5P | 详情 | 详情 |
| (III) | 24400 | ethyl (E)-3-(3,5-dimethoxyphenyl)-2-methyl-2-propenoate | C14H18O4 | 详情 | 详情 | |
| (IV) | 24401 | 1,7,7-Trimethylbicyclo[2,2,1]heptane-1',2-sultam; (1S)-(-)-2,10-Camphorsultam | C10H17NO2S | 详情 | 详情 | |
| (V) | 24402 | 4-[(E)-3-(3,5-dimethoxyphenyl)-2-methyl-2-propenoyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C22H29NO5S | 详情 | 详情 | |
| (VI) | 24403 | 4-[(2S,3S)-3-(3,5-dimethoxyphenyl)-2-methylbutanoyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C23H33NO5S | 详情 | 详情 | |
| (VII) | 24404 | (2S,3S)-3-(3,5-dimethoxyphenyl)-2-methylbutyric acid | C13H18O4 | 详情 | 详情 | |
| (VIII) | 24405 | (2S,3S)-3-(3,5-dimethoxyphenyl)-2-methyl-1-butanol | C13H20O3 | 详情 | 详情 | |
| (IX) | 51421 | (2S,3S)-3-(3,5-dimethoxyphenyl)-2-methylbutyl 4-methylbenzenesulfonate | C20H26O5S | 详情 | 详情 | |
| (X) | 42802 | bromo(butyl)magnesium | 693-03-8 | C4H9BrMg | 详情 | 详情 |
| (XI) | 51422 | 3-[(1S,2R)-1,2-dimethylheptyl]-5-methoxyphenyl methyl ether; 1-[(1S,2R)-1,2-dimethylheptyl]-3,5-dimethoxybenzene | C17H28O2 | 详情 | 详情 | |
| (XII) | 24406 | 5-[(1S,2R)-1,2-dimethylheptyl]-1,3-benzenediol | C15H24O2 | 详情 | 详情 | |
| (XIII) | 24407 | [(1R,5S)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methyl pivalate | C15H24O3 | 详情 | 详情 | |
| (XIV) | 24408 | [(6aR,10aR)-3-[(1S,2R)-1,2-dimethylheptyl]-1-hydroxy-6,6-dimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-9-yl]methyl pivalate | C30H46O4 | 详情 | 详情 |