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【结 构 式】 
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【分子编号】12967 【品名】4-Androstene-3,7-dione; Androstenedione; (8R,9S,10R,13S)-10,13-Dimethyl-7,8,9,10,11,12,13,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione 【CA登记号】63-05-8 |
【 分 子 式 】C19H26O2 【 分 子 量 】286.41424 【元素组成】C 79.68% H 9.15% O 11.17% |
合成路线1
该中间体在本合成路线中的序号：(I)NKS-01 can be obtained by four similar ways: 1) The microbial hydroxylation of 4-androstene-3,17-dione (I) by a culture of Acremonium strictum NN-106 (FERM P-9143) gives 6beta,14alpha-dihydroxy-4-androstene-3,17-dione (II), which is then oxidized, either photochemically with oxygen in CHCl3 under sunlight , with MgO2 at room temperature (2) or with CrO3/H2SO4. 2) The selective microbial hydroxylation of (I) with a culture of Acremonium strictum NN-106 gives 14alpha-hydroxy-4-androstene-3,17-dione (III), which by alkylation of its enolic form is converted into 3-alkoxy-14alpha-hydroxy-3,5-androstadien-17-one (IV) (R = C1-3 alkyl). Finally, (IV) is oxidized with Jones' reagent (CrO3/H2SO4). 3) By oxidation of 3beta,14alpha-dihydroxy-5-androsten-17-one (V) with Jones' reagent (CrO3/H2SO4) in acetone or with K2Cr2O7 in acetic acid. 4) The microbial hydroxylation of (I) by a microorganism of the genus Myrothecium, such as Myrothecium sp. NK-928521 or natural or artificial mutants, gives (II), which is then oxidized with activated MgO2 in CHCl3 at room temperature.
| 【1】 Nakakoshi, M.; Yoshihama, M.; Nakamura, H.; et al. (Snow Brand Milk Products Co., Ltd.); New manufacturing method for 14alpha-hydroxy-4-androsten-3,6,17-trione. JP 9307687 . |
| 【2】 Graul, A.; Castaner, J.; NKS-01. Drugs Fut 1996, 21, 10, 1028. |
| 【3】 Yoshihama, M.; Tamura, K.; Miyata, N.; Nakayama, S.; Nakakoshi, M. (Snow Brand Milk Products Co., Ltd.); Novel androst-4-ene-3,17-dione derivs. and process for their preparation. JP 1988192794; JP 1988192795; JP 1988192796; JP 1988192797; US 4975368; WO 8805781 . |
| 【4】 Seya, M.; Nakamura, H.; Nakakoshi, M. (Snow Brand Milk Products Co., Ltd.); Process for the preparation of 14alpha-hydroxy-4-androsten-3,6,17-trione. JP 1991068596 . |
| 【5】 Nakakoshi, M.; Tamura, K.; Yoshihama, M.; Miyata, N. (Snow Brand Milk Products Co., Ltd.); Process for preparing 14alpha-hydroxy-4-androstene-3,6,17-trione. EP 0382162 . |
| 【6】 Yoshioka, H.; Asada, H.; Fujita, S. (Nippon Kayaku Co., Ltd.); Process for production of 6beta,14alpha-dihydroxy-4-androstene-3,17-dione. EP 0599658 . |
| 【7】 Yoshihama, M.; Nakakoshi, M.; Tamura, K.; Miyata, N.; Kawanishi, G.; Microbial production of two new dihydroxylated androstenedione derivatives by Acremonium strictum. J Ferment Bioeng 1989, 67, 4, 238-43. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IVa) | 12970 | (8R,9S,10R,13S,14R)-14-Hydroxy-3-methoxy-10,13-dimethyl-1,2,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one | C20H28O3 | 详情 | 详情 | |
| (IVb) | 12971 | (8R,9S,10R,13S,14R)-3-Ethoxy-14-hydroxy-10,13-dimethyl-1,2,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one | C21H30O3 | 详情 | 详情 | |
| (IVc) | 12972 | (8R,9S,10R,13S,14R)-14-Hydroxy-10,13-dimethyl-3-propoxy-1,2,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one | C22H32O3 | 详情 | 详情 | |
| (I) | 12967 | 4-Androstene-3,7-dione; Androstenedione; (8R,9S,10R,13S)-10,13-Dimethyl-7,8,9,10,11,12,13,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione | 63-05-8 | C19H26O2 | 详情 | 详情 |
| (II) | 12968 | (6R,8R,9S,10R,13S,14R)-6,14-Dihydroxy-10,13-dimethyl-7,8,9,10,11,12,13,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione | C19H26O4 | 详情 | 详情 | |
| (III) | 12969 | (8R,9S,10R,13S,14R)-14-Hydroxy-10,13-dimethyl-7,8,9,10,11,12,13,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione | C19H26O3 | 详情 | 详情 | |
| (V) | 12973 | (3S,8R,9S,10R,13S,14R)-3,14-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 |
合成路线2
该中间体在本合成路线中的序号：(XXVII)Microbiological oxidation of androstenedione (XXVII) produced the 11-a hydroxy compound (XXVIII), which was converted to enol ether (XXIX) on treatment with triethyl orthoformate and toluenesulfonic acid. Reaction with trimethyl sulfonium ylide provided epoxide (XXX), and a sequence analogous to Scheme 26146601c then produced lactone (XXXI), decarboxylated compound (XXXII), and enone (XXXIII). This was dehydrogenated to dienone (II), which was converted to the title compound by the synthetic steps described in Scheme 26146601a.
| 【1】 Ng, J.S.; Wang, P.T.; Baez, J.A.; Liu, C.; Anderson, D.K.; Lawson, J.P.; Erb, D.; Wieczorek, J.; Mucciariello, G.; Vanzanella, F.; Kunda, S.A.; Letendre, L.J.; Pozzo, M.J.; Sing, Y.-L.L. (Pharmacia Corp.); Process for preparation of 7 alpha-carboxyl 9,11-epoxy steroids and intermediates useful therein and a general process for the epoxidation of olifinic double bonds. WO 9721720 . |
| 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) | 18028 | 11-Alpha-hydroxy-3-oxo-17-alpha-pregna-4,6-diene-21,17-carbolactone | C22H28O4 | 详情 | 详情 | |
| (XXVII) | 12967 | 4-Androstene-3,7-dione; Androstenedione; (8R,9S,10R,13S)-10,13-Dimethyl-7,8,9,10,11,12,13,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione | 63-05-8 | C19H26O2 | 详情 | 详情 |
| (XXVIII) | 18053 | (8S,9S,10R,11R,13S,14S)-11-hydroxy-10,13-dimethyl-7,8,9,10,11,12,13,14,15,16-decahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione | C19H26O3 | 详情 | 详情 | |
| (XXIX) | 18054 | (8S,9S,10R,11R,13S,14S)-3-ethoxy-11-hydroxy-10,13-dimethyl-1,2,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one | C21H30O3 | 详情 | 详情 | |
| (XXX) | 18055 | 3-Ethoxy-11-alpha-hydroxyspiro[androsta-3,5-diene-17(S),2'-oxirane] | C22H32O3 | 详情 | 详情 | |
| (XXXI) | 18056 | 3-Ethoxy-21-(ethoxycarbonyl)-11-alpha-hydroxypregna-3,5-diene-21,17-carbolactone | C27H38O6 | 详情 | 详情 | |
| (XXXII) | 18057 | 3-Ethoxy-11-alpha-hydroxypregna-3,5-diene-21,17-carbolactone | C24H34O4 | 详情 | 详情 | |
| (XXXIII) | 18058 | 3-Oxo-11-alpha-hydroxypregn-4-ene-21,17-carbolactone | C22H30O4 | 详情 | 详情 |