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【结 构 式】 
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【分子编号】56595 【品名】(8S,10R,13S,14S)-10,13-dimethyl-7,8,10,12,13,14,15,16-octahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione 【CA登记号】 |
【 分 子 式 】C19H24O2 【 分 子 量 】284.39836 【元素组成】C 80.24% H 8.51% O 11.25% |
合成路线1
该中间体在本合成路线中的序号：(III)Reaction of 9a-hydroxyandrost-4-ene-3,17-dione (I) with benzenesulfinyl chloride and pyridine gives the corresponding sulfinate (II), which by treatment with TsOH in refluxing chloroform yields androsta-4,9(11)-diene-3,17-dione (III). Reaction of the androstadienedione (III) with acetylene by means of potassium tert-butoxide in THF affords the 17a-ethynyl derivative (IV), which is treated with phenylsulfenyl chloride and TEA at 70 C to provide the sulfenate ester (V). Rearrange-ment of sulfenate (V) by warming at 40 C gives the allene sulfoxide (VI), which is treated with sodium methoxide in methanol at 25 C to yield the enol ether sulfoxide (VII). Then, by refluxing in methanol, an equilibrium between sulfoxide (VII) and sulfenate (VIII) occurs. Reaction of the non-isolated sulfenate (VIII) with the thiophile trimethyl phosphite affords the 17a-hydroxy enol ether (IX), which is finally converted to anecortave acetate by either treatment with peracetic acid and NaHCO3 in dichloromethane or bromination with Br2 and pyridine in dichloromethane to give compound (X) followed by treatment with KOAc, KI and AcOH in refluxing acetone.
| 【1】 Van Rheenen, V.; Shephard, K.P.; New synthesis of cortico steroids from 17-keto steroids: Application and stereochemical study of the unsaturated sulfoxide-sulfenate rearrangement. J Org Chem 1979, 44, 9, 1582. |
| 【2】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; Bayes, M.; Anecortave Acetate. Drugs Fut 2002, 27, 11, 1039. |
| 【3】 Shephard, K.P.; Van Rheenen, V.H. (Pharmacia Corp.); Process for the preparation of 17alpha-hydroxyprogesterones and corticoids from androstenes. US 4041055 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 23634 | acetylene | 74-86-2 | C2H2 | 详情 | 详情 | |
| (I) | 28065 | (8S,9R,10S,13S,14S)-9-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 | |
| (II) | 56594 | (8S,10S,13S,14S)-10,13-dimethyl-3,17-dioxo-1,2,3,6,7,8,10,11,12,13,14,15,16,17-tetradecahydro-9H-cyclopenta[a]phenanthren-9-yl benzenesulfinate | C25H30O4S | 详情 | 详情 | |
| (III) | 56595 | (8S,10R,13S,14S)-10,13-dimethyl-7,8,10,12,13,14,15,16-octahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione | C19H24O2 | 详情 | 详情 | |
| (IV) | 56596 | (8S,10R,13S,14S,17R)-17-ethynyl-17-hydroxy-10,13-dimethyl-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H26O2 | 详情 | 详情 | |
| (V) | 56597 | (8S,10R,13S,14S,17R)-17-ethynyl-10,13-dimethyl-3-oxo-2,3,6,7,8,10,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl benzenesulfenate | C27H30O2S | 详情 | 详情 | |
| (VI) | 56598 | (8S,10R,13S,14S)-10,13-dimethyl-17-[2-(phenylsulfinyl)ethenylidene]-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C27H30O2S | 详情 | 详情 | |
| (VII) | 56599 | (8S,10R,13S,14S)-17-[(E)-1-methoxy-2-(phenylsulfinyl)ethylidene]-10,13-dimethyl-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C28H34O3S | 详情 | 详情 | |
| (VIII) | 56600 | (8S,10R,13S,14S,17R)-17-(1-methoxyvinyl)-10,13-dimethyl-3-oxo-2,3,6,7,8,10,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl benzenesulfenate | C28H34O3S | 详情 | 详情 | |
| (IX) | 56601 | (8S,10R,13S,14S,17R)-17-hydroxy-17-(1-methoxyvinyl)-10,13-dimethyl-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C22H30O3 | 详情 | 详情 | |
| (X) | 56602 | (8S,10R,13S,14S,17R)-17-(2-bromoacetyl)-17-hydroxy-10,13-dimethyl-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H27BrO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)Reaction of 4,9(11)-androstadien-3,17-dione (III) with trimethyl orthoformate and TsOH in dioxane gives 3-methoxy-3,5,9(11)-androstatrien-17-one (XI), which is condensed with 1,2-dichloroethylene (XII) by means of MeLi in ethyl ether/THF to yield 17a-(chloroethynyl)-17b-hydroxy-4,9(11)-androstadien-3-one (XIII). Esterification of the OH group of (XIII) with fuming HNO3 and acetic anhydride affords the 17b-(nitrooxy) derivative (XIV), which is treated with formic acid and AgNO3 in N-methylpyrrolidone to provide 21-chloro-17a-(formyloxy)-4,9(11)-pregnadien-3,20-dione (XV). Hydrolysis of the formyloxy group of (XV) by means of KHCO3 in methanol/water gives 21-chloro-17a-hydroxy-4,9(11)-pregnadien-3,20-dione (XVI), which is finally acetylated by means of AcOK and KI in hot DMF.
| 【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; Bayes, M.; Anecortave Acetate. Drugs Fut 2002, 27, 11, 1039. |
| 【2】 Annen, K.; Laurent, H.; Wiechert, R.; Hofmeister, H. (Schering AG); Process for the preparation of pregnane deriv.. DE 3434448; EP 0181442; US 4708823 . |
| 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) | 56595 | (8S,10R,13S,14S)-10,13-dimethyl-7,8,10,12,13,14,15,16-octahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione | C19H24O2 | 详情 | 详情 | |
| (XI) | 18040 | (8S,10R,13S,14S)-3-methoxy-10,13-dimethyl-1,2,7,8,10,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one | C20H26O2 | 详情 | 详情 | |
| (XII) | 28793 | (Z)-1,2-dichloroethene | 156-59-2 | C2H2Cl2 | 详情 | 详情 |
| (XIII) | 56603 | (8S,10R,13S,14S,17S)-17-(2-chloroethynyl)-17-hydroxy-10,13-dimethyl-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H25ClO2 | 详情 | 详情 | |
| (XIV) | 56604 | (8S,10R,13S,14S,17S)-17-(2-chloroethynyl)-10,13-dimethyl-17-(nitrooxy)-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H24ClNO4 | 详情 | 详情 | |
| (XV) | 50605 | allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate | C18H34N2O5SSi | 详情 | 详情 | |
| (XVI) | 56606 | (8S,10R,13S,14S,17R)-17-(2-chloroacetyl)-17-hydroxy-10,13-dimethyl-1,2,6,7,8,10,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H27ClO3 | 详情 | 详情 |