|
【结 构 式】 
|
【分子编号】29693 【品名】Trimethylsulfoxonium iodide 【CA登记号】1774-47-6 |
【 分 子 式 】C3H9IOS 【 分 子 量 】220.07433 【元素组成】C 16.37% H 4.12% I 57.66% O 7.27% S 14.57% |
合成路线1
该中间体在本合成路线中的序号：(III)3-Hydroxybenzaldehyde (I) was protected as the methoxyethoxymethyl ether derivative (II) by treatment with methoxyethoxymethyl chloride and diisopropyl ethyl amine. Subsequent condensation of (II) with dimethyloxosulfonium methylide, generated from oxosulfonium salt (III) and NaH, gave rise to the racemic epoxide (IV). Kinetic resolution by hydrolysis with (R,R)-N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt (III) acetate complex provided the (S)-diol (V) along with the unreacted (R)-epoxide (VI), which were separated by column chromatography. Opening of the desired (R)-epoxide (VI) with methanolic methylamine gave amino alcohol (VII). Finally, removal of the methoxyethoxymethyl group by refluxing in methanolic HCl furnished the title compound.
| 【1】 Gurjar, M.K.; et al.; A practical synthesis of (R)-(-)-phenylephrine hydrochloride. Org Process Res Dev 1998, 2, 6, 422. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 | |
| 40670 | 2-(chloromethoxy)ethyl methyl ether; 1-(chloromethoxy)-2-methoxyethane; (2-methoxyethoxy)methyl chloride | 3970-21-6 | C4H9ClO2 | 详情 | 详情 | |
| (I) | 28537 | 3-hydroxybenzaldehyde | 100-83-4 | C7H6O2 | 详情 | 详情 |
| (II) | 36802 | 3-[(2-methoxyethoxy)methoxy]benzaldehyde | C11H14O4 | 详情 | 详情 | |
| (III) | 29693 | Trimethylsulfoxonium iodide | 1774-47-6 | C3H9IOS | 详情 | 详情 |
| (IV) | 36803 | (2-methoxyethoxy)methyl 3-(2-oxiranyl)phenyl ether; 2-[3-[(2-methoxyethoxy)methoxy]phenyl]oxirane | C12H16O4 | 详情 | 详情 | |
| (V) | 36804 | (1S)-1-[3-[(2-methoxyethoxy)methoxy]phenyl]-1,2-ethanediol | C12H18O5 | 详情 | 详情 | |
| (VI) | 36805 | (2-methoxyethoxy)methyl 3-[(2R)oxiranyl]phenyl ether; (2R)-2-[3-[(2-methoxyethoxy)methoxy]phenyl]oxirane | C12H16O4 | 详情 | 详情 | |
| (VII) | 36806 | (1R)-1-[3-[(2-methoxyethoxy)methoxy]phenyl]-2-(methylamino)-1-ethanol | C13H21NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(A)The reaction of 3beta-hydroxy-15beta,16beta-methylene-5-androsten-17-one (I) with 1-bromo-3,3 dimethoxypropane (II) by means of Li in THF gives the corresponding 3,3-dimethoxypropyl derivative (III), which by cyclization with acetic acid is converted to the lactol (IV). Oxidation of (IV) with cyclohexanone and aluminum isopropoxide in refluxing toluene yields 15beta,16beta-methylene-4-androstene[17(beta-1')-spiro)-5']perhydrofuran-2',3-dione (V), which is dehydrogenated with chloranil in refluxing tert-butanol to the 4,6-androstadiene (VI). Cyclopropanation of (VI) with trimethylsolfoxoniurn iodide (A) and NaH in DMSO affords the 6beta,7beta:15beta,16beta-dimethylene compound (VII), which is finally dehydrogenated by means of 2,3-dichloro-5,6-dicyanobenzoquinone in refluxing dioxane.
| 【1】 Petzoldt, K.; Wiechert, R.; Laurent, H.; A new synthesis for aldosterone-antagonistic spirorenone. Angew Chem 1983, 95, 5, 413-414. |
| 【2】 Wiechert, R.; et al. (Schering AG); 6beta,7beta;15,16-Dimethylene-1,4-androstadien-3-ones, their preparation and use as medicinal agents. DE 2922500; EP 0019690; JP 55162799 . |
| 【3】 Serradell, M.N.; Robinson, C.P.; Castaner, J.; Spirorenone. Drugs Fut 1985, 10, 6, 478. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 | |
| 21890 | 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 4,5-dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile | 84-58-2 | C8Cl2N2O2 | 详情 | 详情 | |
| 21891 | 2,3,5,6-Tetrachloro-1,4-benzoquinone; 2,3,5,6-Tetrachlorobenzo-1,4-quinone; p-Chloranil | 118-75-2 | C6Cl4O2 | 详情 | 详情 | |
| (A) | 29693 | Trimethylsulfoxonium iodide | 1774-47-6 | C3H9IOS | 详情 | 详情 |
| (I) | 29688 | (4aR,4bS,6aS,7aS,8aS,8bR,8cR)-2-hydroxy-4a,6a-dimethyl-2,3,4,4a,4b,5,6,6a,7a,8,8a,8b,8c,9-tetradecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7(1H)-one | C20H28O2 | 详情 | 详情 | |
| (II) | 29689 | 3-bromo-1,1-dimethoxypropane; 3-bromo-1-methoxypropyl methyl ether | 36255-44-4 | C5H11BrO2 | 详情 | 详情 |
| (III) | 29690 | (4aR,4bS,6aS,7S,7aS,8aS,8bR,8cR)-7-(3,3-dimethoxypropyl)-4a,6a-dimethyl-1,2,3,4,4a,4b,5,6,6a,7,7a,8,8a,8b,8c,9-hexadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-2,7-diol | C25H40O4 | 详情 | 详情 | |
| (IV) | 29691 | 3-Hydroxycyclopropa[1',2':15-beta,16-beta]pregn-5-ene-21,17-carbolactone | C23H34O3 | 详情 | 详情 | |
| (V) | 29692 | 3-Oxo-cyclopropa[1',2':15-beta,16-beta]pregn-4-ene-21,17-carbolactone | C23H30O3 | 详情 | 详情 | |
| (VI) | 11776 | 3-Oxo-cyclopropa[1',2':15-beta,16-beta]pregan-4,6-diene-21,17-carbolactone | C23H28O3 | 详情 | 详情 | |
| (VII) | 29694 | 3-Oxo-6alpha,7alpha,15alpha,16alpha-tetrahydro-17alpha-dicyclopropa-[6,7:15,16]pregn-4-ene-21,17-carbolactone | C24H30O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)The Friedel-Crafts' condensation of 1,3-difluorobenzene (I) with chloroacetyl chloride (II) by means of AlCl3 yields alpha-chloro-2,4-difluoroacetophenone (III), which is treated with 1,2,4-triazole (IV) and triethylamine in refluxing ethyl acetate giving alpha-(1H-12,4-triazol-1-yl)-2,4-diftuoroacetophenone (V). The reaction of (V) with trimethylsulfoxonium iodide (VI) by means of NaOH in toluene affords 1-[2-(2,4-di fluorophenyl)-2,3-epoxypropyl]-1H-1,2,4-triazole (VII), which is finally treated again with 1,2,4-triazole (IV) and K2CO3 in hot DMF.
| 【1】 Narayanaswami, S.; Richardson, K. (Pfizer Inc.); Triazole antifungal agents. EP 0096569; ES 523038 . |
| 【2】 Richardson, K. (Pfizer Inc.); Triazoles. GB 2099818; US 4404216 . |
| 【3】 Fromtling, R.A.; Castaner, J.; Serradell, M.N.; Fluconazole. Drugs Fut 1985, 10, 12, 982. |
| 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) | 13095 | m-Difluorobenzene; 1,3-Difluorobenzene | 372-18-9 | C6H4F2 | 详情 | 详情 |
| (II) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (III) | 16321 | 2-Chloro-2',4'-difluoroacetophenone; 2-Chloro-1-(2,4-difluorophenyl)-1-ethanone | 51336-94-8 | C8H5ClF2O | 详情 | 详情 |
| (IV) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (V) | 15372 | 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)-1-ethanone; 2,4-Difluoro-alpha-(1H-1,2,4-triazolyl)acetophenone | 863867-75-6 | C10H7F2N3O | 详情 | 详情 |
| (VI) | 29693 | Trimethylsulfoxonium iodide | 1774-47-6 | C3H9IOS | 详情 | 详情 |
| (VII) | 29839 | 1-[[2-(2,4-difluorophenyl)-2-oxiranyl]methyl]-1H-1,2,4-triazole | 86386-76-7 | C11H9F2N3O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XVIII)3) Reaction of 3beta-hydroxy-15beta,16beta-methylene-5-androsten-17-one (I) with 1-bromo-3,3-dimethoxypropane (XIII) and lithium in THF gives the 17alpha-(3,3-dimethoxypropyl) derivative (XIV), which by treatment with 70% acetic acid provides the spiro compound (XV). Oxidation of compound (XV) with cyclohexanone in the presence of (i-PrO)3Al and then treatment with 2N H2SO4 affords 15beta,16beta-methylene-3-oxo-17alpha-pregn-4-ene-21,17-carbolactone (XVI). Treatment of (XVI) with chloranil in t-BuOH yields the pregnadiene carbolactone (XVII), which is finally reacted with trimethylsulfoxonium iodide (XVIII) and NaH in DMSO.
| 【1】 Norman, P.; Castaner, R.M.; Castaner, J.; Drospirenone. Drugs Fut 2000, 25, 12, 1247. |
| 【2】 Losert, W.; Bittler, D.; Vasals-Stenzel, J.; Wiechert, R.; Kerb, U. (Schering AG); Novel spironolactones and process for their preparation. DE 2652761; US 4129564 . |
| 【3】 Nickisch, K.; Wiechert, R.; Laurent, H.; Petzoldt, K.; Bittler, D. (Schering AG); Process for preparing 3beta,7beta-dihydroxy-DELTA5-steroids. DE 3042136; EP 0051143; JP 1982122798; US 4416985; US 4614616 . |
| 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) | 42507 | (2S,4aR,4bS,6aS,7aS,8aS,8bR,8cR)-2-hydroxy-4a,6a-dimethyl-2,3,4,4a,4b,5,6,6a,7a,8,8a,8b,8c,9-tetradecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7(1H)-one | C20H28O2 | 详情 | 详情 | |
| (XIII) | 29689 | 3-bromo-1,1-dimethoxypropane; 3-bromo-1-methoxypropyl methyl ether | 36255-44-4 | C5H11BrO2 | 详情 | 详情 |
| (XIV) | 42519 | (2S,4aR,4bS,6aS,7S,7aS,8aS,8bR,8cR)-7-(3,3-dimethoxypropyl)-4a,6a-dimethyl-1,2,3,4,4a,4b,5,6,6a,7,7a,8,8a,8b,8c,9-hexadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-2,7-diol | C25H40O4 | 详情 | 详情 | |
| (XV) | 42520 | C23H34O3 | 详情 | 详情 | ||
| (XVI) | 29692 | 3-Oxo-cyclopropa[1',2':15-beta,16-beta]pregn-4-ene-21,17-carbolactone | C23H30O3 | 详情 | 详情 | |
| (XVII) | 11776 | 3-Oxo-cyclopropa[1',2':15-beta,16-beta]pregan-4,6-diene-21,17-carbolactone | C23H28O3 | 详情 | 详情 | |
| (XVIII) | 29693 | Trimethylsulfoxonium iodide | 1774-47-6 | C3H9IOS | 详情 | 详情 |