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【结 构 式】 
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【分子编号】13532 【品名】Bromo(isopentyl)magnesium 【CA登记号】 |
【 分 子 式 】C5H11BrMg 【 分 子 量 】175.35134 【元素组成】C 34.25% H 6.32% Br 45.57% Mg 13.86% |
合成路线1
该中间体在本合成路线中的序号：(X)The cyclization of acetoacetic ester (I) with crotonaldehyde (II) by means of Na and 2-(trimethylsilyl)ethanol (A) in ethyl ether gives the cyclohexenone carboxylic ester (III), which is hydroxylated by means of NaH, Tbdms-OTf and dimethyldioxirane (DMDO) in DMF, yielding the alpha-hydroxy compound (IV). The bromination of (IV) with NBS and AIBN, followed by treatment with Ag2CO3 in acetone/water, affords the diol (V), which is oxidized with DMP to the cyclohexenedione (VI). The cyclization of (VI) with benzocyclobutane (VII) in hot toluene provides the tricyclic dione (VIII), which is aromatized by means of CSA in pyridine/MeOH, furnishing the dihydroanthraquinone (IX). The Grignard condensation of (IX) with isoamylmagnesium bromide (X) in THF gives the adduct (XI), which is finally desilylated by means of TAS-F in THF.
| 【1】 Danishefsky, S.J.; Allen, J.G.; The total synthesis of (±)-rishirilide B. J Am Chem Soc 2001, 123, 2, 351. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 20323 | 2-(trimethylsilyl)-1-ethanol | 2916-68-9 | C5H14OSi | 详情 | 详情 |
| (I) | 45600 | 2-(trimethylsilyl)ethyl 3-oxobutanoate | C9H18O3Si | 详情 | 详情 | |
| (II) | 22517 | (E)-2-butenal | 4170-30-3 | C4H6O | 详情 | 详情 |
| (III) | 45601 | 2-(trimethylsilyl)ethyl 6-methyl-2-oxo-3-cyclohexene-1-carboxylate | 367-57-7 | C13H22O3Si | 详情 | 详情 |
| (IV) | 45602 | 2-(trimethylsilyl)ethyl (1R,6S)-1-hydroxy-6-methyl-2-oxo-3-cyclohexene-1-carboxylate | C13H22O4Si | 详情 | 详情 | |
| (V) | 45603 | 2-(trimethylsilyl)ethyl (1R,6S)-1,5-dihydroxy-6-methyl-2-oxo-3-cyclohexene-1-carboxylate | C13H22O5Si | 详情 | 详情 | |
| (VI) | 45604 | 2-(trimethylsilyl)ethyl (1R,6R)-1-hydroxy-6-methyl-2,5-dioxo-3-cyclohexene-1-carboxylate | C13H20O5Si | 详情 | 详情 | |
| (VII) | 45605 | (7R)-2,8-bis[[tert-butyl(dimethyl)silyl]oxy]bicyclo[4.2.0]octa-1,3,5-trien-7-yl tert-butyl(dimethyl)silyl ether; [((7R)-2,8-bis[[tert-butyl(dimethyl)silyl]oxy]bicyclo[4.2.0]octa-1,3,5-trien-7-yl)oxy](tert-butyl)dimethylsilane | C26H50O3Si3 | 详情 | 详情 | |
| (VIII) | 45606 | 2-(trimethylsilyl)ethyl (2R,3R,4aS,9R,9aR,10S)-8,9,10-tris[[tert-butyl(dimethyl)silyl]oxy]-2-hydroxy-3-methyl-1,4-dioxo-1,2,3,4,4a,9,9a,10-octahydro-2-anthracenecarboxylate | C39H70O8Si4 | 详情 | 详情 | |
| (IX) | 45607 | 2-(trimethylsilyl)ethyl (2R,3R)-8-[[tert-butyl(dimethyl)silyl]oxy]-2-hydroxy-3-methyl-1,4-dioxo-1,2,3,4-tetrahydro-2-anthracenecarboxylate | C27H38O6Si2 | 详情 | 详情 | |
| (X) | 13532 | Bromo(isopentyl)magnesium | C5H11BrMg | 详情 | 详情 | |
| (XI) | 45608 | 2-(trimethylsilyl)ethyl (1R,2R,3R)-8-[[tert-butyl(dimethyl)silyl]oxy]-1,2-dihydroxy-1-isopentyl-3-methyl-4-oxo-1,2,3,4-tetrahydro-2-anthracenecarboxylate | C32H50O6Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)L-654066 has been obtained by three related ways: 1) Reaction of methyl (5alpha)-3-oxo-4-azaandrostene-17beta-carboxylate (I) with potassium hydroxide, followed by treatment with pyridyl disulfide, gives S-(2-pyridyl) (5alpha)-3-oxo-4-azaandrostene-17beta-thiocarboxylate (II). Compound (II) is reacted with isobutylmagnesium chloride (III) in THF to give (5alpha)-23-methyl-4-aza-21-norcholane-3,20-dione (IV), which is finally dehydrogenated using benzeneseleninic anhydride in chlorobenzene. 2) Compound (I) is converted to its dehydro analogue methyl (5alpha)-3-oxo-4-azaandrost-1-ene-17beta-carboxylate (V) with benzeneselenic anhydride, followed by reaction with isobutylmagnesium bromide (VI) in THF in the presence of hexamethyldisilazane. 3) Reaction of (5alpha)-3-oxo-4-azaandrost-1-ene-17beta-carboxylic acid (VII) with carbonyldiimidazole in THF gives 1-[[(5alpha,17beta)-3-oxo-4-azaandrost-1-en-17-yl]carbonyl]-1H-imidazole (VII), which is treated with isobutylmagnesium chloride (III) in THF in the presence of ferric chloride.
| 【1】 Rasmusson, G.H.; Reynolds, G.F. (Merck & Co., Inc.); 17beta-Substd.-4-aza-5alpha-androstenones and their use as 5alpha-reductase inhibitors. AU 8539167; EP 0155096; EP 0314199; ES 8702430; JP 1985222497; JP 1989093600; US 4760071 . |
| 【2】 Rasmusson, G.H.; Reynolds, G.F. (Merck & Co., Inc.); 17beta-Acyl-4-aza-5alpha-androst-1-en-3-ones as 5alpha-reductase inhibitors. EP 0271219; JP 1988139196 . |
| 【3】 Gormley, G.J.; Stoner, E. (Merck & Co., Inc.); Pharmaceutical combination for the treatment of prostatic hyperplasia, containing a 5alpha-reductase inhibitor and an antiandrogen. JP 1994506227; WO 9216213 . |
| 【4】 Bhattacharya, A.; Dolling, U.H.; Amato, J.S.; Williams, J.M. (Merck & Co., Inc.); Methods of synthesizing benign prostatic hypertropic agents and their intermediates. EP 0367502 . |
| 【5】 Williams, J.M. (Merck & Co., Inc.); Process for making 17-beta alkanoyl 3-oxo-4-aza-5-alpha-androst-1-enes. US 5061803 . |
| 【6】 Rasmusson, G.H.; Reynolds, G.F.; Steinberg, N.G.; Walton, E.; Patel, G.F.; Liang, T.; Cascieri, M.A.; Cheung, A.H.; Brooks, J.R.; Berman, C.; Azasteroids: structure-activity relationships for inhibition of 5 alpha-reductase and of androgen receptor binding. J Med Chem 1986, 29, 11, 2298. |
| 【7】 Bhattacharya, A.; Williams, J.M.; Amato, J.S.; Dolling, U.-H.; Grabowski, E.J.J.; Acylimidazolides as versatile synthetic intermediates for the preparation of sterically congested amides and ketones: A practical synthesis of Proscar(R). Synth Commun 1990, 30, 17, 2683. |
| 【8】 Prous, J.; Mealy, N.; Castaner, J.; L-654066. Drugs Fut 1993, 18, 8, 701. |
| 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) | 13527 | methyl (4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxohexadecahydro-1H-indeno[5,4-f]quinoline-7-carboxylate | C20H31NO3 | 详情 | 详情 | |
| (II) | 13528 | S-(2-pyridinyl) (4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxohexadecahydro-1H-indeno[5,4-f]quinoline-7-carbothioate | C24H32N2O2S | 详情 | 详情 | |
| (III) | 13529 | Chloro(isopentyl)magnesium | C5H11ClMg | 详情 | 详情 | |
| (IV) | 13530 | (4aR,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-Dimethyl-7-(3-methylbutanoyl)hexadecahydro-2H-indeno[5,4-f]quinolin-2-one | C23H37NO2 | 详情 | 详情 | |
| (V) | 13009 | methyl (4aS,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxylate | C20H29NO3 | 详情 | 详情 | |
| (VI) | 13532 | Bromo(isopentyl)magnesium | C5H11BrMg | 详情 | 详情 | |
| (VII) | 13533 | (4aS,4bS,6aS,7S,9aS,9bS,11aR)-4a,6a-Dimethyl-2-oxo-2,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-1H-indeno[5,4-f]quinoline-7-carboxylic acid | C19H27NO3 | 详情 | 详情 | |
| (VIII) | 13534 | (4aS,4bS,6aS,7S,9aS,9bS,11aR)-7-(1H-Imidazol-1-ylcarbonyl)-4a,6a-dimethyl-1,4a,4b,5,6,6a,7,8,9,9a,9b,10,11,11a-tetradecahydro-2H-indeno[5,4-f]quinolin-2-one | C22H29N3O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)By condensation of 2(S)-[N-methyl-N-[2-[N-methyl-N-(morpholinocarbonyl)amino]ethyl]carbamoyloxy]-3-phenylpropanoic acid (I) with protected Nalpha-methyl-L-histidine 1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexylamide (II) by means of oxalyl chloride and DMF in dichloromethane. The starting compounds (I) and (II) are obtained as follows: 1) The reaction of morpholinocarbonyl chloride (III) with N-(tert-butoxycarbonyl)-N,N'-dimethylethylenediamine (IV) by means of triethylamine in dichloromethane gives the monoacylated diamine (V), which is deprotected with trifluoroacetic acid to yield N,N'-dimethyl-N-(morpholinocarbonyl)ethylenediamine (VI). The condensation of (VI) with 2(S)-hydroxy-3-phenylpropanoic acid benzyl ester (VII) by means of trichloromethyl chloroformate in refluxing THF affords 2(S)-[N-methyl-N-[2-[N-methyl-N-(morpholinocarbonyl)amino]ethyl]carbamoyloxy]propanoic acid benzyl ester (VIII), which is finally debenzylated by hydrogenation with H2 over Pd/C to give (I). 2) The Grignard reaction of tert-butoxycarbonyl-(3-cyclohexyl)-L-alaninal (IX) with 3-methylbutylmagnesium bromide (X) in THF gives 2(S)-(tert-butoxycarbonylamino)-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (XI), which is deprotected with trifluoroacetic acid to yield the free amine derivative (XII). The condensation of (XII) with Nalpha-(tert-butoxycarbonyl)-Nalpha-methyl-Ntau-tosyl-L-histidine (XIII) by means of N-ethyl-N'-[3-(dimethylamino)propyl]carbodiimide (CDI) in dichloromethane affords the corresponding histidinamide (XIV), which is deprotected with trifluoroacetic acid to afford (II).
| 【1】 Hemmi, K.; Neya, M.; Marusawa, H.; Imai, K.; Kayakiri, N.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); New amino acid derivs. processes for the preparation thereof and pharmaceutical compsns. containing the same. AU 8818190; EP 0300189; JP 1989019071; US 4921855; US 5223489 . |
| 【2】 Prous, J.; Castaner, J.; FK-906. Drugs Fut 1993, 18, 4, 312. |
| 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) | 15845 | (2S)-2-[[(methyl[2-[methyl(morpholinocarbonyl)amino]ethyl]amino)carbonyl]oxy]-3-phenylpropionic acid | C19H27N3O6 | 详情 | 详情 | |
| (II) | 15846 | (2S)-N-[(1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-5-methylhexyl]-2-(methylamino)-3-[1-[(4-methylphenyl)sulfonyl]-1H-imidazol-4-yl]propanamide | C28H44N4O4S | 详情 | 详情 | |
| (III) | 15847 | 4-morpholinecarbonyl chloride; Morpholine-4-carbonyl chloride | 15159-40-7 | C5H8ClNO2 | 详情 | 详情 |
| (IV) | 15848 | tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate | C9H20N2O2 | 详情 | 详情 | |
| (V) | 15849 | tert-butyl N-methyl-N-[2-[methyl(morpholinocarbonyl)amino]ethyl]carbamate | C14H27N3O4 | 详情 | 详情 | |
| (VI) | 15850 | N-methyl-N-[2-(methylamino)ethyl]-4-morpholinecarboxamide | C9H19N3O2 | 详情 | 详情 | |
| (VII) | 15851 | Benzyl (s)-(-)-2-hydroxy-3-phenylpropionate; benzyl (2S)-2-hydroxy-3-phenylpropanoate | 7622-21-1 | C16H16O3 | 详情 | 详情 |
| (VIII) | 15852 | benzyl (2S)-2-[[(methyl[2-[methyl(morpholinocarbonyl)amino]ethyl]amino)carbonyl]oxy]-3-phenylpropanoate | C26H33N3O6 | 详情 | 详情 | |
| (IX) | 15853 | tert-butyl N-[(1S)-2-cyclohexyl-1-formylethyl]carbamate | C14H25NO3 | 详情 | 详情 | |
| (X) | 13532 | Bromo(isopentyl)magnesium | C5H11BrMg | 详情 | 详情 | |
| (XI) | 15855 | tert-butyl N-[(1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-5-methylhexyl]carbamate | C19H37NO3 | 详情 | 详情 | |
| (XII) | 15856 | (2S,3S)-2-amino-1-cyclohexyl-6-methyl-3-heptanol | C14H29NO | 详情 | 详情 | |
| (XIII) | 15857 | (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-[1-[(4-methylphenyl)sulfonyl]-1H-imidazol-4-yl]propionic acid | C19H25N3O6S | 详情 | 详情 | |
| (XIV) | 15858 | tert-butyl (1S)-2-[[(1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-5-methylhexyl]amino]-1-([1-[(4-methylphenyl)sulfonyl]-1H-imidazol-4-yl]methyl)-2-oxoethyl(methyl)carbamate | C33H52N4O6S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXIV)Synthesis of the cholestane aglycone (XXXII): The condensation of the commercial dehydroisoandrosterone (XVIII) with ethyl triphenylphosphonium bromide (XIX) and potassium tert-butoxide in refluxing THF gives the ethylidene derivative (XX), which is silylated at the 3-OH group with Tbdps-Cl and imidazole to yield the silyl ether (XXI). The reaction of (XXI) with paraformaldehyde in the presence of catalytic BF3/Et2O affords the desired homoallylic alcohol (XXII) stereoselectively. Oxidation of alcohol (XXII) with DMP in dichloromethane provides the corresponding aldehyde (XXIII), which when treated with the Grignard reagent (XXIV) of the 1-bromo-3-methyl butane in ether furnishes the adduct (XXV). The oxidation of the secondary alcohol of (XXV) with PDC in DMF/dichloromethane gives the expected ketone (XXVI), which is protected as the spiroketal (XXVIII) by reaction with ethyleneglycol (XXVII), TsOH and triethyl orthoformate. The Tbdps protecting group of (XXVIII) was now converted into the Tbdms group by desilylation with TBAF and resilylation with Tbdms-Cl and imidazole to give (XXIX). The oxidation of (XXIX) with OsO4 and pyridine in ether yields the 16alpha,17alpha-diol (XXX), which is oxidized with oxalyl chloride to afford the ketone (XXXI). The reduction of (XXXI) with NaBH4 and CeCl3 in THF provides the target 16beta,17alpha-diol (XXXII).
| 【1】 Deng, S.; et al.; First total synthesis of an exceptionally potent antitumor saponin, OSW-1. J Org Chem 1999, 64, 1, 202. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 11713 | Dehydroepiandrosterone;prasterone；(3S,8R,9S,10R,13S,14S)-3-Hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one | 53-43-0 | C19H28O2 | 详情 | 详情 |
| (XIX) | 11717 | Ethyl(triphenyl)phosphonium bromide; (Ethyl)triphenylphosphonium bromide | 1530-32-1 | C20H20BrP | 详情 | 详情 |
| (XX) | 48980 | (3S,10R,13S)-17-[(Z)ethylidene]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-3-ol | C21H32O | 详情 | 详情 | |
| (XXI) | 48981 | tert-butyl([(3S,10R,13S)-17-[(Z)ethylidene]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-3-yl]oxy)diphenylsilane; tert-butyl(diphenyl)silyl (3S,10R,13S)-17-[(Z)ethylidene]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-3-yl ether | C37H50OSi | 详情 | 详情 | |
| (XXII) | 48982 | (2S)-2-((3S,10R,13S)-3-[[tert-butyl(diphenyl)silyl]oxy]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)-1-propanol | C38H52O2Si | 详情 | 详情 | |
| (XXIII) | 48983 | (2S)-2-((3S,10R,13S)-3-[[tert-butyl(diphenyl)silyl]oxy]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)propanal | C38H50O2Si | 详情 | 详情 | |
| (XXIV) | 13532 | Bromo(isopentyl)magnesium | C5H11BrMg | 详情 | 详情 | |
| (XXV) | 48984 | (2S,3S)-2-((3S,10R,13S)-3-[[tert-butyl(diphenyl)silyl]oxy]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)-6-methyl-3-heptanol | C43H62O2Si | 详情 | 详情 | |
| (XXVI) | 48985 | (2S)-2-((3S,10R,13S)-3-[[tert-butyl(diphenyl)silyl]oxy]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)-6-methyl-3-heptanone | C43H60O2Si | 详情 | 详情 | |
| (XXVII) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (XXVIII) | 48986 | tert-butyl([(3S,10R,13S)-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy)diphenylsilane; tert-butyl(diphenyl)silyl (3S,10R,13S)-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl ether | C45H64O3Si | 详情 | 详情 | |
| (XXIX) | 48987 | tert-butyl([(3S,10R,13S)-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy)dimethylsilane; tert-butyl(dimethyl)silyl (3S,10R,13S)-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl ether | C35H60O3Si | 详情 | 详情 | |
| (XXX) | 48988 | (3S,10R,13S,16R,17S)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-16,17-diol | C35H62O5Si | 详情 | 详情 | |
| (XXXI) | 48963 | (3S,10R,13S,17S)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-hydroxy-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,17-tetradecahydro-16H-cyclopenta[a]phenanthren-16-one | C35H60O5Si | 详情 | 详情 | |
| (XXXII) | 48964 | (3S,10R,13S,16S,17S)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-[(1S)-1-(2-isopentyl-1,3-dioxolan-2-yl)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-16,17-diol | C35H62O5Si | 详情 | 详情 |