Spirorenone, ZK-35973, Delta-1-MSp, -Drug Synthesis Database

【结构式】

【药物名称】Spirorenone, ZK-35973, Delta-1-MSp

【化学名称】6beta,7beta:15beta,16beta-Dimethylen-1,4-androstadien[17(beta-1')-spiro-5']-perhydrofuran-2',3-dione
　　　　　　17-Hydroxy-6beta,7beta:15beta,16beta-dimethylene-3-oxo-17alpha-pregna-1,4-diene-21-carboxylic acid,gamma-lactone
　　　　　　3-(6,7beta,15,16beta-Dimethylene-3-oxo-1,4-androstadiene-17alpha-yl)propionic acid lactone

【CA登记号】74220-07-8

【分子式】C₂₄H₂₈O₃

【分子量】364.48896

【开发单位】Schering AG (Originator)

【药理作用】Aldosterone Antagonists

合成路线1 合成路线2 合成路线3

合成路线1

The reaction of 3beta-hydroxy-15beta,16beta-methylene-5-androsten-17-one (I) with 1-bromo-3,3 dimethoxypropane (II) by means of Li in THF gives the corresponding 3,3-dimethoxypropyl derivative (III), which by cyclization with acetic acid is converted to the lactol (IV). Oxidation of (IV) with cyclohexanone and aluminum isopropoxide in refluxing toluene yields 15beta,16beta-methylene-4-androstene[17(beta-1')-spiro)-5']perhydrofuran-2',3-dione (V), which is dehydrogenated with chloranil in refluxing tert-butanol to the 4,6-androstadiene (VI). Cyclopropanation of (VI) with trimethylsolfoxoniurn iodide (A) and NaH in DMSO affords the 6beta,7beta:15beta,16beta-dimethylene compound (VII), which is finally dehydrogenated by means of 2,3-dichloro-5,6-dicyanobenzoquinone in refluxing dioxane.

参考文献中间体

【1】 Petzoldt, K.; Wiechert, R.; Laurent, H.; A new synthesis for aldosterone-antagonistic spirorenone. Angew Chem 1983, 95, 5, 413-414.
【2】 Wiechert, R.; et al. (Schering AG); 6beta,7beta;15,16-Dimethylene-1,4-androstadien-3-ones, their preparation and use as medicinal agents. DE 2922500; EP 0019690; JP 55162799 .
【3】 Serradell, M.N.; Robinson, C.P.; Castaner, J.; Spirorenone. Drugs Fut 1985, 10, 6, 478.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	11059	Cyclohexanone	108-94-1	C₆H₁₀O	详情	详情
	21890	2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 4,5-dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile	84-58-2	C₈Cl₂N₂O₂	详情	详情
	21891	2,3,5,6-Tetrachloro-1,4-benzoquinone; 2,3,5,6-Tetrachlorobenzo-1,4-quinone; p-Chloranil	118-75-2	C₆Cl₄O₂	详情	详情
(A)	29693	Trimethylsulfoxonium iodide	1774-47-6	C₃H₉IOS	详情	详情
(I)	29688	(4aR,4bS,6aS,7aS,8aS,8bR,8cR)-2-hydroxy-4a,6a-dimethyl-2,3,4,4a,4b,5,6,6a,7a,8,8a,8b,8c,9-tetradecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7(1H)-one		C₂₀H₂₈O₂	详情	详情
(II)	29689	3-bromo-1,1-dimethoxypropane; 3-bromo-1-methoxypropyl methyl ether	36255-44-4	C₅H₁₁BrO₂	详情	详情
(III)	29690	(4aR,4bS,6aS,7S,7aS,8aS,8bR,8cR)-7-(3,3-dimethoxypropyl)-4a,6a-dimethyl-1,2,3,4,4a,4b,5,6,6a,7,7a,8,8a,8b,8c,9-hexadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-2,7-diol		C₂₅H₄₀O₄	详情	详情
(IV)	29691	3-Hydroxycyclopropa[1',2':15-beta,16-beta]pregn-5-ene-21,17-carbolactone		C₂₃H₃₄O₃	详情	详情
(V)	29692	3-Oxo-cyclopropa[1',2':15-beta,16-beta]pregn-4-ene-21,17-carbolactone		C₂₃H₃₀O₃	详情	详情
(VI)	11776	3-Oxo-cyclopropa[1',2':15-beta,16-beta]pregan-4,6-diene-21,17-carbolactone		C₂₃H₂₈O₃	详情	详情
(VII)	29694	3-Oxo-6alpha,7alpha,15alpha,16alpha-tetrahydro-17alpha-dicyclopropa-[6,7:15,16]pregn-4-ene-21,17-carbolactone		C₂₄H₃₀O₃	详情	详情

合成路线2

Starting compound (I) is hydroxylated microbiologically by means of Botryodiplodia malorum to 3,7-dihydroxy-15beta,16beta-methylene-5-androsten-17-one (VIII), which is selectively acylated with pivalic anhydride to the monoacyl derivative (IX). Epoxidation of (IX) with tert-butyl hydroperoxide in hot toluene yields the epoxide (X), which by reaction with triphenylphosphine and CCl4 is converted to the chloroepoxide (Xl). The reactive elimination of Cl with Zn-acetic acid followed by hydrolysis with KOH yields 3,5-dihydroxy-15beta,16beta-methylene-6-androsten-17-one (XII), which is submitted to cyclopropanation with methyrene iodide and Zn/Cu in glyme yielding 3,5-dihydroxy-6beta,7beta:15beta,16beta-dimethyleneandrostan-17-one (XIII). The reaction of (XIII) with propargyl alcohol (XIV) by means of potassium ethoxide in THF affords the 17-(3-hydroxy-1-propyn-1-yl) derivative (XV), which is reduced with H2 over Pd/CaCO3 in THF to the corresponding 3-hydroxypropyl derivative (XVI). Finally, this compound is oxidized and cyclized by means of pyridinium dichromate to (VII) ), which is finally dehydrogenated by means of 2,3-dichloro-5,6-dicyanohenzoquinone in refluxing dioxane.

参考文献中间体

【1】 Laurent, H.; Hormeister, H.; Nickisch, K.; Butler, D.; Nickolson, R.; Wischert, R.; Petzoldt, K.; Synthesis of spirorenone. A novel highly active aldosterone antagonist. Angew Chem 1982, 94, 718.
【2】 Serradell, M.N.; Robinson, C.P.; Castaner, J.; Spirorenone. Drugs Fut 1985, 10, 6, 478.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	21890	2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 4,5-dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile	84-58-2	C₈Cl₂N₂O₂	详情	详情
(I)	29688	(4aR,4bS,6aS,7aS,8aS,8bR,8cR)-2-hydroxy-4a,6a-dimethyl-2,3,4,4a,4b,5,6,6a,7a,8,8a,8b,8c,9-tetradecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7(1H)-one		C₂₀H₂₈O₂	详情	详情
(VII)	29694	3-Oxo-6alpha,7alpha,15alpha,16alpha-tetrahydro-17alpha-dicyclopropa-[6,7:15,16]pregn-4-ene-21,17-carbolactone		C₂₄H₃₀O₃	详情	详情
(VIII)	29695	(4aR,4bS,6aS,7aS,8aS,8bS,8cR)-2,9-dihydroxy-4a,6a-dimethyl-2,3,4,4a,4b,5,6,6a,7a,8,8a,8b,8c,9-tetradecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7(1H)-one		C₂₀H₂₈O₃	详情	详情
(IX)	29696	(4aR,4bS,6aS,7aS,8aS,8bS,8cR)-9-hydroxy-4a,6a-dimethyl-7-oxo-1,2,3,4,4a,4b,5,6,6a,7,7a,8,8a,8b,8c,9-hexadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-yl pivalate		C₂₅H₃₆O₄	详情	详情
(X)	29697	(5aR,5bS,7aS,8aS,9aS,9bS,9cR,10aR)-10-hydroxy-5a,7a-dimethyl-8-oxohexadecahydro-2H-cyclopropa[4',5']cyclopenta[1',2':1,2]phenanthro[8a,9-b]oxiren-3-yl pivalate		C₂₅H₃₆O₅	详情	详情
(XI)	29698	(5aR,5bS,7aS,8aS,9aS,9bS,9cR,10aS)-10-chloro-5a,7a-dimethyl-8-oxohexadecahydro-2H-cyclopropa[4',5']cyclopenta[1',2':1,2]phenanthro[8a,9-b]oxiren-3-yl pivalate		C₂₅H₃₅ClO₄	详情	详情
(XII)	20015	(4aR,4bS,6aS,7aS,8aS,8bR,8cR)-2,10a-dihydroxy-4a,6a-dimethyl-2,3,4,4a,4b,5,6,6a,7a,8,8a,8b,8c,10a-tetradecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-7(1H)-one		C₂₀H₂₈O₃	详情	详情
(XIII)	29699	(1aR,5aR,5bS,7aS,8aS,9aS,9bR,9cR,9dR)-1b,3-dihydroxy-5a,7a-dimethyloctadecahydro-8H-cyclopropa[4,5]cyclopenta[1,2-a]cyclopropa[l]phenanthren-8-one		C₂₅H₃₅ClO₄	详情	详情
(XIV)	16664	Propargyl Alcohol; 2-propyn-1-ol	107-19-7	C₃H₄O	详情	详情
(XV)	29700	(1aR,5aR,5bS,7aS,8S,8aS,9aS,9bR,9cR,9dR)-8-(3-hydroxy-1-propynyl)-5a,7a-dimethyloctadecahydro-1bH-cyclopropa[4,5]cyclopenta[1,2-a]cyclopropa[l]phenanthrene-1b,3,8-triol		C₂₄H₃₄O₄	详情	详情
(XVI)	29701	(1aR,5aR,5bS,7aS,8S,8aS,9aS,9bR,9cR,9dR)-8-hydroxy-8-(3-hydroxypropyl)-5a,7a-dimethyl-1,1a,4,5,5a,5b,6,7,7a,8,8a,9,9a,9b,9c,9d-hexadecahydro-3H-cyclopropa[4,5]cyclopenta[1,2-a]cyclopropa[l]phenanthren-3-one		C₂₄H₃₄O₃	详情	详情

合成路线3

3beta-Hydroxy-5-androsten-17-one (XVII) is dihydroxylated microbiologically by means of Colletotrichum lini to 3beta,7alpha,15alpha-trihydroxy-5-androsten-17-one (XVIII), which is treated with acetone and boron trifluoride etherate yielding the acetonide (XIX). Hydrolysis of (XIX) with HCl in methanol affords the 3beta,7beta,15alpha-isomer (XX), which is also obtained from (XVIII) by isomerization with perchloric acid in methylisobutylketone. Selective acylation of (XX) with pivaloyl chloride affords the 3beta,15alpha-dipivaloyloxy compound (XXI), which is submitted to cyclopropanation with trimethylsulfoxonium iodide and NaOH as before yielding (IX).

参考文献中间体

【1】 Losert, W.; Bittler, D.; Vasals-Stenzel, J.; Wiechert, R.; Kerb, U. (Schering AG); Novel spironolactones and process for their preparation. DE 2652761; US 4129564 .
【2】 Serradell, M.N.; Robinson, C.P.; Castaner, J.; Spirorenone. Drugs Fut 1985, 10, 6, 478.

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)	29663	1-(3-methoxyphenyl)acetone	3027-13-2	C₁₀H₁₂O₂	详情	详情
(IX)	29696	(4aR,4bS,6aS,7aS,8aS,8bS,8cR)-9-hydroxy-4a,6a-dimethyl-7-oxo-1,2,3,4,4a,4b,5,6,6a,7,7a,8,8a,8b,8c,9-hexadecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthren-2-yl pivalate		C₂₅H₃₆O₄	详情	详情
(XVII)	29705	(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		C₁₉H₂₈O₂	详情	详情
(XVIII)	29702	(7S,8R,9S,10R,13S,14S,15S)-3,7,15-trihydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one		C₁₉H₂₈O₄	详情	详情
(XIX)	29703	(2aS,5aS,10aR,10bS,12aS,12bS,12cR)-8-hydroxy-4,4,10a,12a-tetramethyl-2,2a,5a,7,8,9,10,10a,10b,11,12,12a,12b,12c-tetradecahydro-1H-benzo[h]indeno[1,7,6-def][1,3]benzodioxepin-1-one		C₂₂H₃₂O₄	详情	详情
(XX)	29706	(8R,9S,10R,13S,14S,15S)-3,7,15-trihydroxy-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one		C₁₉H₂₈O₄	详情	详情
(XXI)	29704	(8R,9S,10R,13S,14S,15S)-15-[(2,2-dimethylpropanoyl)oxy]-7-hydroxy-10,13-dimethyl-17-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl pivalate		C₂₉H₄₄O₆	详情	详情

Extended Information