Mespirenone, ZK-94679, SH-467, -Drug Synthesis Database

【结构式】

【药物名称】Mespirenone, ZK-94679, SH-467

【化学名称】15alpha,16alpha-Dihydro-17-hydroxy-7alpha-mercapto-3-oxo-3'H-cyclopropa[15,16]-17alpha-pregna-1,4,15-triene-21-carboxylic acid,gamma-lactone acetate

【CA登记号】87952-98-5

【分子式】C₂₅H₃₀O₄S

【分子量】426.57945

【开发单位】Schering AG (Originator)

【药理作用】Diuretics, RENAL-UROLOGIC DRUGS, Aldosterone Antagonists

合成路线1 合成路线2

合成路线1

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

【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

合成路线2

The acylation of spiro[pregnane-17,2'-tetrahydrofuran]-4,6,15-triene-3,5'-dione (I) with thioacetic acid in refluxing methanol gives the 7-acetylthio derivative (II), which is methylenated with trimethylsulfoxonium iodide and NaH in refluxing DMSO, yielding the 15beta,16beta-methylene derivative (III). Finally, this compound is dehydrogenated with 2,3-dichloro-5,6-dicyanobenzoquinone (IV) in refluxing benzene.

参考文献中间体

【1】 Bittler, D.; Laurent, H.; Losert, W.; Nickisch, K.; Wiechert, R. (Schering AG); 7alpha-Acylthio-15,16-methylene-3-oxo-17alpha-pregna-1,4-diene-21,17-carbonolactones, their preparation and use as medicinal agents. DE 3227598; US 4500522 .
【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】 Prous, J.; Castaner, J.; Mespirenone. Drugs Fut 1987, 12, 1, 27.

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)	22987	3-Oxopregn-4,6,15-triene-21,17-carbolactone		C₂₂H₂₆O₃	详情	详情
(II)	22988	7-Alpha-(acetylsulfanyl)-3-oxopregna-4,15-diene-21,17-carbolactone		C₂₄H₃₀O₄S	详情	详情
(III)	22989	7-Alpha-(Acetylsulfanyl)-3-oxo-cyclopropa[1',2':15-beta,16-beta]pregn-4-ene-21,17-carbolactone		C₂₅H₃₂O₄S	详情	详情
(IV)	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

Extended Information