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【结 构 式】

【分子编号】11723

【品名】4-[[(1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]-2-methyl-2-butanol

【CA登记号】

【 分 子 式 】C38H70O4Si2

【 分 子 量 】647.1424

【元素组成】C 70.53% H 10.9% O 9.89% Si 8.68%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(XI)

1) The microbiological oxidation of 3beta-hydroxyandrost-5-en-17-one (I) gives 1alpha,3beta-dihydroxyandrost-5-en-17-one (II), which is silylated with tert-butyldimethylsilyl (TBS) chloride and imidazole to the bis(silyloxy) compound (III). The dehydrogenation of (III) by bromination with N-bromosuccinimide (NBS) and dehydrobromination with 2,4,6-trimethylpyridine (TMPyr) yields 1alpha,3beta-bis(tert-butyldimethylsilyloxy)androsta-5,7-dien-17-one (IV). The Wittig condensation of (IV) with ethyltriphenylphosphonium bromide (V) by means of NaH in DMS gives the corresponding ethylidene derivative (VI), which is treated first with 9-borabicyclo[3.3.1]nonane (9-BBN) and then with H2O2 and NaOH in THF yielding a mixture of the 20(S)- and 20(R)-isomers of 1alpha,3beta-bis(tert-butyldimethylsilyloxy)pregna-5,7-dien-20-ol that was separated by preparative TLC. The 20(S)-isomer (VII) was condensed with 1-bromo-3-butene (VIII) by means of NaH in refluxing xylene affording 20(S)-(3-butenyloxy)-1alpha,3beta-bis(tert-butyldimethylsilyloxy)pregna-5,7-diene (IX), which is oxidized with O2 gas in DMF/water catalyzed by Cu2Cl2 and PdCl2 to give the corresponding 3-oxobutoxy derivative (X). The Grignard alkylation of (X) with methylmagnesium bromide in THF afforded the 20(S)-(3-hydroxy-3-methylbutoxy) derivative (XI), which was submitted to UV irradiation with a 200 W high-pressure mercury lamp in ethanol yielding the silylated 22-oxavitamin D3 derivative (XII). Finally, this compound is desilylated by a treatment with tetrabutylammonium fluoride (TBAF) in THF. 2) The addition of ethyl acrylate (XIII) to the previously reported pregna-5,7-dien-20(S)-ol (VII) by means of tetrabutylammonium hydroxide/NaOH in water/toluene gives the 2-(ethoxycarbonyl)ethoxy derivative (XIV), which by alkylation of the carbonyl function with methyllithium yields the 3-hydroxy-3-methylbutoxy derivative (XI), already obtained. 3) The addition of N,N-dimethylacrylamide (XV) to the previously reported pregna-5,7-dien-20(S)-ol (VII) by means of NaH gives the corresponding propionamide derivative (XVI), which by a Grignard alkylation with methylmagnesium bromide and CeCl3 is converted into the 3-hydroxy-3-methylbutoxy derivative (XI), already obtained.

1 Murayama, E.; Miyamoto, K.; Kubodera, N.; Mori, T.; Matsunaga, I.; Synthetic studies of vitamin D3 analogues. VIII. Synthesis of 22-oxavitamin D3 analogues. Chem Pharm Bull 1986, 34, 10, 4410-3.
2 Kubodera, N.; Watanabe, H.; Kawanishi, T.; Matsumoto, M.; Synthetic studies of vitamin D analogues. XI. Synthesis and differentiation-inducing activity of 1alpha,25-dihydroxy-22-oxavitamin D3 analogues. Chem Pharm Bull 1992, 40, 6, 1494-9.
3 Leeson, P.A.; Martel, A.M.; Castaner, J.; 22-Oxacalcitriol. Drugs Fut 1996, 21, 12, 1229.
4 Kubodera, N.; Miyamoto, K.; Ochi, K.; Matsunaga, I.; Murayama, E. (Chugai Pharmaceutical Co. Ltd.); Novel vitamin D derivs. and process for producing the same. EP 0184112; JP 1986267548; JP 1986267550 .
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) 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
(II) 11714 (1S,3R,8R,9S,10R,13S,14S)-1,3-Dihydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one C19H28O3 详情 详情
(III) 11715 (1S,8R,9S,10R,13S,14S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one C31H56O3Si2 详情 详情
(IV) 11716 (1S,3R,9S,10R,13S,14S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-1,2,3,4,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one C31H54O3Si2 详情 详情
(V) 11717 Ethyl(triphenyl)phosphonium bromide; (Ethyl)triphenylphosphonium bromide 1530-32-1 C20H20BrP 详情 详情
(VI) 11718 tert-Butyl(dimethyl)silyl (1S,3R,9S,10R,13S,14S)-1-[[tert-butyl(dimethyl)silyl]oxy]-17-[(E)ethylidene]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl ether; tert-Butyl([(1S,3R,9S,10R,13S,14S)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-[(E)ethylidene]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-1-yl]oxy)dimethylsilane C33H58O2Si2 详情 详情
(VII) 11719 (1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)-1-ethanol C33H60O3Si2 详情 详情
(VIII) 11720 4-Bromo-1-butene 5162-44-7 C4H7Br 详情 详情
(IX) 11721 (1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl 3-butenyl ether; [((1S,3R,9S,10R,13S,14S,17S)-17-[(1S)-1-(3-Butenyloxy)ethyl]-3-[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-1-yl)oxy](tert-butyl)dimethylsilane C37H66O3Si2 详情 详情
(X) 11722 4-[[(1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]-2-butanone C37H66O4Si2 详情 详情
(XI) 11723 4-[[(1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]-2-methyl-2-butanol C38H70O4Si2 详情 详情
(XII) 11724 4-[((1S)-1-[(1S,3aS,7aS)-4-[(E)-2-((3S,5R)-3,5-Bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]ethyl)oxy]-2-methyl-2-butanol C38H70O4Si2 详情 详情
(XIII) 10164 ethyl acrylate 140-88-5 C5H8O2 详情 详情
(XIV) 11726 ethyl 3-[[(1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]propanoate C38H68O5Si2 详情 详情
(XV) 11727 N,N-Dimethylacrylamide; N,N-Dimethyl-2-propenamide 2680-03-7 C5H9NO 详情 详情
(XVI) 11728 3-[[(1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]-N,N-dimethylpropanamide C38H69NO4Si2 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XI)

4) The Wittig condensation of the previously reported 1alpha,3beta-bis(tert-butyldimethylsilyloxy)androst-5-en-17-one (III) with ethyltriphenylphosphonium bromide and potassium tert-butoxide gives the corresponding 17-ethylidene derivative (XVII), which is treated first with 9-borabicyclo[3.3.1]nonane (9-BBN) and then with H2O2 and NaOH in THF yielding a mixture of the 20(S)- and 20(R)-isomers of the 1alpha,3beta-bis(tert-butyldimethylsilyloxy)pregn-5-en-20-ol that was separated by preparative TLC. The 20(S)-isomer (XVIII) was condensed with N,N-dimethylacrylamide (XV) by means of NaH affording the propionamide derivative (XIX), which by a Grignard condensation with methylmagnesium bromide catalyzed by CeCl3 is converted into 1alpha,3beta-bis(tert-butyldimethylsilyloxy)-20(S)-(3-hydroxy-3-methylbutoxy)pregn-5-ene (XX). Finally, this compound is dehydrogenated as before by bromination with N-bromosuccinimide (NBS) and dehydrobromination with 2,4,6-trimethylpyridine (TMPyr) to afford the 3-hydroxy-3-methylbutoxy derivative (XI), already obtained.

1 Kubodera, N.; Active vitamin D analogs. Important and various roles by medicinal chemists during the course of development of promising candidates as useful medicines. Jpn J Org Chem 1996, 54, 2, 139-45.
2 Leeson, P.A.; Martel, A.M.; Castaner, J.; 22-Oxacalcitriol. Drugs Fut 1996, 21, 12, 1229.
3 Kato, M.; Mikami, T.; Ochi, K.; Watanabe, H.; Kubodera, N. (Chugai Pharmaceutical Co. Ltd.); 22-Oxacalciferol deriv. and production thereof. WO 9312083 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 11715 (1S,8R,9S,10R,13S,14S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one C31H56O3Si2 详情 详情
(V) 11717 Ethyl(triphenyl)phosphonium bromide; (Ethyl)triphenylphosphonium bromide 1530-32-1 C20H20BrP 详情 详情
(XI) 11723 4-[[(1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]-2-methyl-2-butanol C38H70O4Si2 详情 详情
(XV) 11727 N,N-Dimethylacrylamide; N,N-Dimethyl-2-propenamide 2680-03-7 C5H9NO 详情 详情
(XVII) 11729 tert-Butyl([(1S,3R,8S,9S,10R,13S,14S)-3-[[tert-butyl(dimethyl)silyl]oxy]-17-[(E)ethylidene]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-1-yl]oxy)dimethylsilane; tert-Butyl(dimethyl)silyl (1S,3R,8S,9S,10R,13S,14S)-1-[[tert-butyl(dimethyl)silyl]oxy]-17-[(E)ethylidene]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl ether C33H60O2Si2 详情 详情
(XVIII) 11730 (1S)-1-((1S,3R,8S,9S,10R,13S,14S,17S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-1-ethanol C33H62O3Si2 详情 详情
(XIX) 11731 3-[[(1S)-1-((1S,3R,8S,9S,10R,13S,14S,17S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]-N,N-dimethylpropanamide C38H71NO4Si2 详情 详情
(XX) 11732 4-[[(1S)-1-((1S,3R,8S,9S,10R,13S,14S,17S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]-2-methyl-2-butanol C38H72O4Si2 详情 详情

合成路线3

该中间体在本合成路线中的序号:(XXIV)

The synthesis of 22-oxacalcitriol labeled with tritium at the 26-methyl group has been performed as follows: The starting compound is the previously obtained 3-oxobutoxy derivative (X), which is submitted to a Grignard alkylation with 3CH3MgI giving the labeled 3-hydroxy-3-methylbutoxy derivative (XXIV). The deprotection of (XXIV) with tetrabutylammonium fluoride affords the triol derivative (XXV), which is finally irradiated with a 400 W high-pressure mercury lamp with a Vycor filter.

1 Leeson, P.A.; Martel, A.M.; Castaner, J.; 22-Oxacalcitriol. Drugs Fut 1996, 21, 12, 1229.
2 Watanabe, H.; Akiyama, M.; Kawanishi, T.; Kubodera, N.; Synthesis of tritiated 1alpha,25-dihydroxy-22-oxavitamin D3. J Label Compd Radiopharm 1995, 36, 7, 645-54.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 11722 4-[[(1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]-2-butanone C37H66O4Si2 详情 详情
(XXIV) 11723 4-[[(1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-Bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]-2-methyl-2-butanol C38H70O4Si2 详情 详情
(XXIV) 45069 4-[[(1S)-1-((1S,3R,9S,10R,13S,14S,17S)-1,3-bis[[tert-butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]-2-methyl-2-butanol C38H70O4Si2 详情 详情
(XXV) 11733 (1S,3R,9S,10R,13S,14S,17S)-17-[(1S)-1-(3-Hydroxy-3-methylbutoxy)ethyl]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-1,3-diol C26H42O4 详情 详情
(XXV) 45070 4-[((1S)-1-[(1S,3aS,7aS)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]ethyl)oxy]-2-methyl-2-butanol C38H70O4Si2 详情 详情
Extended Information