3-Oxo-cyclopropa[1',2':15-beta,16-beta]pregan-4,6-diene-21,17-carbolactone -Drug Synthesis Database

【结构式】

【分子编号】11776

【品名】3-Oxo-cyclopropa[1',2':15-beta,16-beta]pregan-4,6-diene-21,17-carbolactone

【CA登记号】

【分子式】C₂₃H₂₈O₃

【分子量】352.47352

【元素组成】C 78.38% H 8.01% O 13.62%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(VI)

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

合成目标

【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

该中间体在本合成路线中的序号：(I)

The synthesis of ZK-91587 has been described: The reaction of 15beta,16beta-methylene-3-oxo-17alpha-pregna-4,6-diene-21,17-carbonolactone (I) with diethylaluminum cyanide in THF or with KCN and NH4Cl in DMF - water gives 7alpha-cyano-15beta,16beta-methylene-3-oxo-17alpha-pregn-21,17-carbonolactone (II), which by partial reduction with diisobutylaluminum hydride in toluene is converted into the corresponding aldehyde (III). The oxidation of (III) with Jones' reagent (CrO3) affords the carboxylic acid (IV), which is finally methylated with diazomethane in dichloromethane.

参考文献中间体

合成目标

【1】 Nishino, Y.; Wiechert, R.; Laurent, H.; Bittler, D.; Losert, W.; Nickisch, K.; Schillinger, E.; Aldosterone antagonists. 3. Synthesis and activities of steroidal 7alpha -(alkoxycarbonyl)-15,16-methylene spirolactones. J Med Chem 1990, 33, 2, 509-13.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	11776	3-Oxo-cyclopropa[1',2':15-beta,16-beta]pregan-4,6-diene-21,17-carbolactone	C₂₃H₂₈O₃	详情	详情
(II)	11777	7-alpha-Cyano-3-oxocyclopropa[1',2':15-beta,16-beta]pregn-4-ene-21,17-carbolactone	C₂₄H₂₉NO₃	详情	详情
(III)	11778	7-alpha-Formyl-3-oxocyclopropa[1',2':15-beta,16-beta]pregn-4-ene-17,21-carbolactone	C₂₄H₃₀O₄	详情	详情
(IV)	11779	7-alpha-Carboxy-3-oxocyclopropa[1',2':15-beta,16-beta]pregn-4-ene-21,17-carbolactone	C₂₄H₃₀O₅	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XVII)

3) Reaction of 3beta-hydroxy-15beta,16beta-methylene-5-androsten-17-one (I) with 1-bromo-3,3-dimethoxypropane (XIII) and lithium in THF gives the 17alpha-(3,3-dimethoxypropyl) derivative (XIV), which by treatment with 70% acetic acid provides the spiro compound (XV). Oxidation of compound (XV) with cyclohexanone in the presence of (i-PrO)3Al and then treatment with 2N H2SO4 affords 15beta,16beta-methylene-3-oxo-17alpha-pregn-4-ene-21,17-carbolactone (XVI). Treatment of (XVI) with chloranil in t-BuOH yields the pregnadiene carbolactone (XVII), which is finally reacted with trimethylsulfoxonium iodide (XVIII) and NaH in DMSO.

参考文献中间体

合成目标

【1】 Norman, P.; Castaner, R.M.; Castaner, J.; Drospirenone. Drugs Fut 2000, 25, 12, 1247.
【2】 Losert, W.; Bittler, D.; Vasals-Stenzel, J.; Wiechert, R.; Kerb, U. (Schering AG); Novel spironolactones and process for their preparation. DE 2652761; US 4129564 .
【3】 Nickisch, K.; Wiechert, R.; Laurent, H.; Petzoldt, K.; Bittler, D. (Schering AG); Process for preparing 3beta,7beta-dihydroxy-DELTA5-steroids. DE 3042136; EP 0051143; JP 1982122798; US 4416985; US 4614616 .

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)	42507	(2S,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
(XIII)	29689	3-bromo-1,1-dimethoxypropane; 3-bromo-1-methoxypropyl methyl ether	36255-44-4	C₅H₁₁BrO₂	详情	详情
(XIV)	42519	(2S,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
(XV)	42520			C₂₃H₃₄O₃	详情	详情
(XVI)	29692	3-Oxo-cyclopropa[1',2':15-beta,16-beta]pregn-4-ene-21,17-carbolactone		C₂₃H₃₀O₃	详情	详情
(XVII)	11776	3-Oxo-cyclopropa[1',2':15-beta,16-beta]pregan-4,6-diene-21,17-carbolactone		C₂₃H₂₈O₃	详情	详情
(XVIII)	29693	Trimethylsulfoxonium iodide	1774-47-6	C₃H₉IOS	详情	详情

Extended Information