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【结 构 式】 
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【分子编号】16180 【品名】Dimethyl(methylene)-lambda(4)-sulfane; Dimethylsulfonium-methylide 【CA登记号】 |
【 分 子 式 】C3H8S 【 分 子 量 】76.16252 【元素组成】C 47.31% H 10.59% S 42.1% |
合成路线1
该中间体在本合成路线中的序号：(A)1,4-Dihydroestronemethylether (I) was reacted with dimethylsulfonium-methylide (A) in a highly stereoselective manner to give the oxirane (II), which formed the cyanomethyl compound (III) by the addition of sodium cyanide. (III) was hydrolyzed with oxalic acid (B) in methanol and the product (IV) treated with pyridine perbromide hydrobromide to the dibromoketone, which yielded STS-557 after dehydrobromination.
| 【1】 Cook, C.E.; et al.; Synthesis and reactions of oxiranes obtained from 3- and 17-keto steroids. J Org Chem 1968, 33, 2789. |
| 【2】 Hubner, M.; et al.; Ein vereinfachtes Verfahren zur Darstellung von Steroid-Spirooxiranen. J Prakt Chem 1972, 314, 667. |
| 【3】 Ponsold, K.; et al.; Prostagene vom Typ 17alpha-CH2X-substituierter 19-Nortestossteronderivate. Pharmazie 1978, 33, 792. |
| 【4】 Perelman, M.; et al.; A new class of active steroids: the 19-nor-delta(4,9)-3-ketosteroids. J Am Chem Soc 1960, 82, 2402. |
| 【5】 Unterhalt, B.; STS-557. Drugs Fut 1980, 5, 6, 311. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 15713 | Oxalic acid | 144-62-7 | C2H2O4 | 详情 | 详情 |
| (A) | 16180 | Dimethyl(methylene)-lambda(4)-sulfane; Dimethylsulfonium-methylide | C3H8S | 详情 | 详情 | |
| (I) | 32635 | 1,4-Dihydroestronemethylether; (8R,9S,13S,14S)-3-methoxy-13-methyl-1,4,6,7,8,9,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one | C19H26O2 | 详情 | 详情 | |
| (II) | 32637 | 3-Methoxyspiro[estra-2,5(10)-diene-17(S),2'-oxirane] | C20H28O2 | 详情 | 详情 | |
| (III) | 32636 | 2-[(8R,9S,13S,14S,17R)-17-hydroxy-3-methoxy-13-methyl-4,6,7,8,9,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]acetonitrile | C21H29NO2 | 详情 | 详情 | |
| (IV) | 32638 | 2-[(8R,9S,13S,14S,17R)-17-hydroxy-13-methyl-3-oxo-2,3,4,6,7,8,9,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]acetonitrile | C20H27NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(G)The reaction of 7-oxotricyclo[4.2.0.0(2.4)]octane-3-endo-carboxaldehyde neopentylglycol acetal (LIII) with dimethylsulfonium methylide (G) gives the spiroepoxide (LIV), which by isomerization with LiI in THF yields the tricyclononanone (LV). The reduction of (LV) with NaBH4 in ethanol, followed by acetylation with acetic anhydride in pyridine affords the tricyclic acetate (LVI), which is treated with formic acid to eliminate the acetalic residue and form the free aldehyde (LVII). The Wittig reaction of (LVII) with triphenylhexylidenephosphorane (LVIII) affords the tricyclic acetate (LIX), which is hydrolyzed with base and oxidized with Jones reagent to yield the tricyclic ketone (LX). The oxidation of the double bond of (LX) with 0sO4 gives the diol (LXI), which submitted successively to: triethyl orthopropionate (H) in pyridine, to anhydrous formic acid, to aqueous methanolic K2CO3 and to sodium metaperiodate, is converted into the previously obtained dihydroxyketone (XII). This compound can be used in the preceding syntheses or protected with dimethyltert-butylsilyl chloride to afford the bis(silyl) ether (LXII), which by reaction with the sulfoximine (LXIII), and then with AlHg is converted into the protected trialcohol (LXIV).
| 【1】 Morton, D.R.Jr.; DE 2904655 . |
| 【2】 Brokaw, F.C.; Morton, D.R.Jr.; Total synthesis of 6a-carboprostaglandin I2 and related isomers. J Org Chem 1979, 44, 16, 2880-87. |
| 【3】 Castaner, J.; Hillier, K.; Carbacyclin. Drugs Fut 1981, 6, 12, 753. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (G) | 16180 | Dimethyl(methylene)-lambda(4)-sulfane; Dimethylsulfonium-methylide | C3H8S | 详情 | 详情 | |
| (H) | 37557 | 1-ethoxypropyl ethyl ether; 1,1-diethoxypropane | 4744-08-5 | C7H16O2 | 详情 | 详情 |
| (XII) | 37504 | (3aS,4S,5R,6aR)-5-hydroxy-4-[(E,3S)-3-hydroxy-1-octenyl]hexahydro-2(1H)-pentalenone | C16H26O3 | 详情 | 详情 | |
| (LIII) | 37548 | (1R,2S,4S,6S)-3-(5,5-dimethyl-1,3-dioxan-2-yl)tricyclo[4.2.0.0(2,4)]octan-7-one | C14H20O3 | 详情 | 详情 | |
| (LIV) | 37549 | C15H22O3 | 详情 | 详情 | ||
| (LV) | 37550 | (1aR,1bS,4aR,5aS)-1-(5,5-dimethyl-1,3-dioxan-2-yl)octahydro-3H-cyclopropa[a]pentalen-3-one | C15H22O3 | 详情 | 详情 | |
| (LVI) | 37551 | (1aR,1bS,4aR,5aS)-1-(5,5-dimethyl-1,3-dioxan-2-yl)octahydro-1H-cyclopropa[a]pentalen-3-yl acetate | C17H26O4 | 详情 | 详情 | |
| (LVII) | 37552 | (1aR,1bS,4aR,5aS)-1-formyloctahydro-1H-cyclopropa[a]pentalen-3-yl acetate | C12H16O3 | 详情 | 详情 | |
| (LVIII) | 37553 | hexylidene(triphenyl)phosphorane | C24H27P | 详情 | 详情 | |
| (LIX) | 37554 | (1aS,1bS,4aR,5aS)-1-[(E)-1-heptenyl]octahydro-1H-cyclopropa[a]pentalen-3-yl acetate | C18H28O2 | 详情 | 详情 | |
| (LX) | 37555 | (1aS,1bS,4aR,5aS)-1-[(E)-1-heptenyl]octahydro-3H-cyclopropa[a]pentalen-3-one | C16H24O | 详情 | 详情 | |
| (LXI) | 37556 | (1aR,1bS,4aR,5aS)-1-[(1R,2S)-1,2-dihydroxyheptyl]octahydro-3H-cyclopropa[a]pentalen-3-one | C16H26O3 | 详情 | 详情 | |
| (LXII) | 37558 | (3aS,4S,5R,6aR)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)hexahydro-2(1H)-pentalenone | C28H54O3Si2 | 详情 | 详情 | |
| (LXIII) | 37559 | bromo[1-[methyl(phenyl)sulfonimidoyl]-6-(tetrahydro-2H-pyran-2-yloxy)hexyl]magnesium | C18H28BrMgNO3S | 详情 | 详情 | |
| (LXIV) | 37560 | [((1S,2E)-3-[(1S,2R,3aS,6aS)-2-[[tert-butyl(dimethyl)silyl]oxy]-5-[(E)-6-(tetrahydro-2H-pyran-2-yloxy)hexylidene]octahydro-1-pentalenyl]-1-pentyl-2-propenyl)oxy](tert-butyl)dimethylsilane; 6-[(3aS,4S,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)hexahydro-2(1H)-pentalenylidene]hexyl tetrahydro-2H-pyran-2-yl ether | C39H74O4Si2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)1) The reaction of dimethyl sulfate (I) with dimethyl sulfide (II) by means of sodium methoxide in acetonitrile gives dimethyl (methylene)-lambda4-sulfane (III), which, without isolation, is condensed with benzo[b]thiophene-5-carbaldehyde (IV) in the same solvent to yield 2-(benzo[b]thiophen-5-yl)oxirane (V) (1). The reaction of (V) with 2-(dimethylamino)ethanol (VI) by means of potassium tert-butoxide in hot DMSO (1, 2), or hot DMF (3) affords (±)-1-(benzo[b]thiophen-5-yl)-2-[2-(diethylamino)ethoxy]ethanol (racemic T-588) (VII), which is submitted to optical resolution first by treatment with acetic anhydride in refluxing toluene to give the corresponding acetate (VIII), and then by reaction of (VIII) with D-dibenzoyltartaric acid (IX) in ethyl acetate/acetone/water followed by fractionated crystallization of the resulting salt to yield the D-dibenzoyltartrate salt of the (R)-isomer (X). Finally, (X) is deacetylated with sodium methoxide in methanol and salified with ethanolic hydrochloric acid.
| 【1】 Ono, S.; Yamafuji, T.; Chaki, H.; Todo, Y.; Maekawa, M.; Kitamura, K.; Kimura, T.; Nakada, Y.; Mozumi, K.; Narita, H.; A new cognition-enhancing agent, (R)-(-)-1-(benzo[b]thiophen-5-yl)-2-[2-(N,N-diethylamino)ethoxy]ethanol hydrochloride. Effects on memory impairment in rats generated by cerebral embolization and basal forebrain lesions. Biol Pharm Bull 1995, 18, 12, 1779-83. |
| 【2】 Ono, S.; Yamafuji, T.; Chaki, H.; Morita, H.; Todo, Y.; Okada, N.; Maekawa, M.; Kitamura, K.; Tai, M.; Narita, H.; Studies on cognitive enhancing agents. III. Antiamnestic and antihypoxic activities of a series of 1-bicycloaryl-2-(omega-aminoalkoxy)ethanols. Chem Pharm Bull 1995, 43, 9, 1492-6. |
| 【3】 Martel, A.M.; Prous, J.; Castaner, J.; T-588. Drugs Fut 1997, 22, 4, 386. |
| 【4】 Ono, S.; Yamafuji, T.; Chaki, H.; Maekawa, M.; Todo, Y.; Narita, H. (Toyama Chemical Co., Ltd.); 1,2-Ethanediol deriv. and salt thereof, process for producing the same, and cerebral function-improving agent comprising them. EP 0383281; EP 0587193; EP 0587194; EP 0589484; FR 2643079; JP 1991047158; JP 1991197422; US 5280032; US 5472984; US 5612381; US 5658904 . |
| 【5】 Ono, T.; Yamafuji, T.; Chaki, H.; Maekawa, M.; Fujido, Y.; Narita, H. (Toyama Chemical Co., Ltd.); 1,2-Ethanediol derivs. and their salts. JP 1992095070 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 16179 | Dimethyl sulfide; (Methylsulfanyl)methane | 75-18-3 | C2H6S | 详情 | 详情 |
| (III) | 16180 | Dimethyl(methylene)-lambda(4)-sulfane; Dimethylsulfonium-methylide | C3H8S | 详情 | 详情 | |
| (IV) | 16181 | 1-benzothiophene-5-carbaldehyde | C9H6OS | 详情 | 详情 | |
| (V) | 16182 | 2-(1-benzothiophen-5-yl)oxirane | C10H8OS | 详情 | 详情 | |
| (VI) | 16183 | Diethylaminoethanol; 2-(diethylamino)-1-ethanol | 100-37-8 | C6H15NO | 详情 | 详情 |
| (VII) | 16184 | 1-(1-benzothiophen-5-yl)-2-[2-(diethylamino)ethoxy]-1-ethanol | C16H23NO2S | 详情 | 详情 | |
| (VIII) | 16185 | 1-(1-benzothiophen-5-yl)-2-[2-(diethylamino)ethoxy]ethyl acetate | C18H25NO3S | 详情 | 详情 | |
| (IX) | 16186 | (2R,3R)-2,3-bis(benzoyloxy)butanedioic acid | C18H14O8 | 详情 | 详情 | |
| (X) | 16187 | (1R)-1-(1-benzothiophen-5-yl)-2-[2-(diethylamino)ethoxy]ethyl acetate | C18H25NO3S | 详情 | 详情 |