(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 -Drug Synthesis Database

【结构式】

【分子编号】20015

【品名】(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

【CA登记号】

【分子式】C₂₀H₂₈O₃

【分子量】316.44052

【元素组成】C 75.91% H 8.92% O 15.17%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XII)

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

合成目标

【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2

该中间体在本合成路线中的序号：(I)

The condensation of 3,5-dihydroxy-15beta, 16beta-methyleneandrost-6-ene-17-one (I) with propargyl alcohol (II) by means of potassium ethoxide in THF gives 17alpha-(3-hydroxypropynyl)-15beta, 16beta-methyleneandrost-6-ene-3beta,5beta,17beta-triol (III), which is hydrogenated with H2 over RaNi in methanol yielding the 3-hydroxypropyl derivative (IV). The oxidation, with simultaneous cyclization and dehydration of (IV) with pyridine - CrO3, affords 15beta,16beta-methylene-3-oxo-17alpha-pregna-4,6-diene-21,17-carbolactone (V), which is treated with thioacetic acid in methanol - water to give the 7alpha-acetylthio derivative (VI). Finally, this compound is dehydrogenated with dicyano-dichloro-benzoquinone (DDQ) in refluxing benzene.

参考文献中间体

合成目标

【1】 Nickisch, K.; Bittler, D.; Laurent, H.; Losert, W.; Casals-Stenzel, J.; Nishino, Y.; Schillinger, E.; Wiechert, R.; Aldosterone antagonists. 2. New 7alpha-(acetylthio)-15,16-methylene spirolactones. J Med Chem 1987, 30, 8, 1403.

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)	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
(II)	16664	Propargyl Alcohol; 2-propyn-1-ol	107-19-7	C₃H₄O	详情	详情
(III)	20017	(4aR,4bS,6aS,7S,7aS,8aS,8bR,8cR)-7-(3-hydroxy-1-propynyl)-4a,6a-dimethyl-2,3,4,4a,4b,5,6,6a,7,7a,8,8a,8b,8c-tetradecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-2,7,10a(1H)-triol		C₂₃H₃₂O₄	详情	详情
(IV)	20018	(4aR,4bS,6aS,7S,7aS,8aS,8bR,8cR)-7-(3-hydroxypropyl)-4a,6a-dimethyl-2,3,4,4a,4b,5,6,6a,7,7a,8,8a,8b,8c-tetradecahydrocyclopropa[4,5]cyclopenta[1,2-a]phenanthrene-2,7,10a(1H)-triol		C₂₃H₃₆O₄	详情	详情
(V)	20019	3-Oxo-cyclopropa[1',2':15-beta,16-beta]pregna-4,6-diene-21,17-carbolactone		C₂₃H₂₈O₃	详情	详情
(VI)	20020	7-Alpha-(Acetylsulfanyl)-3-oxo-cyclopropa[1',2':15-beta,16-beta]pregn-4-ene-21,17-carbolactone		C₂₅H₃₂O₄S	详情	详情

Extended Information