Viprostol, CL-115347, -Drug Synthesis Database

【结构式】

【药物名称】Viprostol, CL-115347

【化学名称】15-Deoxy-16-hydroxy-16-vinylprostaglandin E2 methyl ester
　　　　　　Methyl 9-oxo-11alpha,16-dihydroxy-16-vinyl-5-cis,13-trans-prostadienoate
　　　　　　(5Z,11alpha,13E)-16-Ethenyl-11,16-dihydroxy-9-oxo-prosta-5,13-dien-1-oic acid methyl ester

【CA登记号】73621-92-8

【分子式】C₂₃H₃₆O₅

【分子量】392.54037

【开发单位】Wyeth Pharmaceuticals (Originator)

【药理作用】CARDIOVASCULAR DRUGS, DERMATOLOGIC DRUGS, Hair Growth Stimulants, Hypertension, Treatment of

合成路线1 合成路线2

合成路线1

The reaction of 4-hydroxy-1-octyne (I), with chlorotrimethylsilane and imidazole in DMF gives 4-trimethylsilyloxy-1-octyne (II), which is converted into 1-iodo-4-trimethylsilyloxy-trans-1-octene (III) by reaction with bis(3-methyl-2-butyl)borane (A), trimethylamine oxide, NaOH and finally I2. The hydrolysis of (III) with acetic acid in THF affords 1-iodo-4-hydroxy-trans-1-octene (IV), which is oxidized with pyridinium chlorochromate in methylene chloride yielding 1-iodo-4-oxo-trans-1-octene (V). The Grignard reaction of (V) with vinylmagnesium bromide (B) in THF gives 4-hydroxy-4-vinyl-1-iodo-trans-1-octene (VI), which is protected with trimethylsilyl chloride as before yielding 4-trimethylsilyloxy-4-vinyl-1-iodo-trans-1-octene (VII). The reaction of (VII) with tert-butyllithium in ether and then with copper (1)-1-pentyne-tributylphosphine (C) in HMPT affords the copper salt (VIII), which is condensed with 2-(6-trimethylsilyloxycarbonyl-2-cis-hexenyl)-4-trimethylsilyloxycyclopent-2-en-1-one (IX) in ether - THF giving trimethylsilyl-9-oxo-11alpha,16-bistrimethylsilyloxy-16-vinyl-5-cis-13-trans-prostadienoate (X). The hydrolysis of (X) with acetic acid in THF-water yields 9-oxo-11alpha,16-dihydroxy-16-vinyl-5-cis-13-trans-prostadienoic acid (XI), which is finally methylated with diazomethane in ether.

参考文献中间体

【1】 Middlenton, B.F.; Martin, J.W.; Grudzinskas, C.V.; Chen, S.L. (American Cyanamid Co.); Novel prostaglandin compounds. ES 475787; FR 2410648; GB 2009173; US 4198521 .
【2】 Hillier, K.; Blancafort, P.; Serradell, M.N.; Castaner, J.; CL-115,347. Drugs Fut 1983, 8, 4, 307.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	16524	bromo(vinyl)magnesium	1826-67-1	C₂H₃BrMg	详情	详情
(A)	20452	bis(1,2-dimethylpropyl)borane	132509-17-2	C₁₀H₂₃B	详情	详情
(I)	29312	1-octyn-4-ol		C₈H₁₄O	详情	详情
(II)	36018	[(1-butyl-3-butynyl)oxy](trimethyl)silane; 1-butyl-3-butynyl trimethylsilyl ether		C₁₁H₂₂OSi	详情	详情
(III)	36019	(E)-1-butyl-4-iodo-3-butenyl trimethylsilyl ether; [[(E)-1-butyl-4-iodo-3-butenyl]oxy](trimethyl)silane		C₁₁H₂₃IOSi	详情	详情
(IV)	29315	(E)-1-iodo-1-octen-4-ol		C₈H₁₅IO	详情	详情
(V)	29316	(E)-1-iodo-1-octen-4-one		C₈H₁₃IO	详情	详情
(VI)	29317	(5E)-3-butyl-6-iodo-1,5-hexadien-3-ol		C₁₀H₁₇IO	详情	详情
(VII)	36020	(E)-1-butyl-4-iodo-1-vinyl-3-butenyl trimethylsilyl ether; [[(E)-1-butyl-4-iodo-1-vinyl-3-butenyl]oxy](trimethyl)silane		C₁₃H₂₅IOSi	详情	详情
(VIII)	36021	[(1E)-4-butyl-4-[(trimethylsilyl)oxy]-1,5-hexadienyl](1-pentynyl)copper		C₁₈H₃₂CuOSi	详情	详情
(IX)	36022	trimethylsilyl (Z)-7-[(3R)-5-oxo-3-[(trimethylsilyl)oxy]-1-cyclopenten-1-yl]-5-heptenoate		C₁₈H₃₂O₄Si₂	详情	详情
(X)	36023	trimethylsilyl (Z)-7-[(1R,2R,3R)-2-[(1E)-4-butyl-4-[(trimethylsilyl)oxy]-1,5-hexadienyl]-5-oxo-3-[(trimethylsilyl)oxy]cyclopentyl]-5-heptenoate		C₃₁H₅₈O₅Si₃	详情	详情
(XI)	36024	(Z)-7-[(1R,2R,3R)-2-[(1E)-4-butyl-4-hydroxy-1,5-hexadienyl]-3-hydroxy-5-oxocyclopentyl]-5-heptenoic acid		C₂₂H₃₄O₅	详情	详情
(C)	29069	1-pentynylcopper		C₅H₇Cu	详情	详情

合成路线2

The oxidation of 1-hepten-3-ol (XII) with pyridinium chlorochromate gives 1-hepten-3-one (XIII), which by a Grignard condensation with propargylmagnesium bromide (XIV) is converted into 4-hydroxy-4-vinyl-1-octyne (XV). The protection of (XV) with trimethylsilyl chloride and imidazole in DMF yields 4-trimethylsilyloxy-4-vinyl-1-octyne (XVI), which by reaction with tri-n-butyl-stannane and azobisisobutyronitrile at 125 C affords 1-(tri-n-butylstannyl)-4-vinyl-4-(trimethylsilyloxy)-1-octene (XVII). Finally, this compound by reaction with butyllithium and copper -1-pentyne-tributylphosphine (C) in HMPT yields the copper salt (VIII), already obtained.

参考文献中间体

【1】 Grudzinkas, C.V.; Bimbaum, J.E.; Chen. S.L.; Chan, P.S.; Floyd, M.B.; Weiss, M.J.; Cervoni, P.; Prostaglandins and congeners. 29. (16RS)-Rac-15-deoxy-16-hydroxy-16-vivyl-protaglandin E2, an orally and transdermally active hypotensive agent of prolonged duration. J Med Chem 1982, 25, 5, 492-494.
【2】 Hillier, K.; Blancafort, P.; Serradell, M.N.; Castaner, J.; CL-115,347. Drugs Fut 1983, 8, 4, 307.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	36021	[(1E)-4-butyl-4-[(trimethylsilyl)oxy]-1,5-hexadienyl](1-pentynyl)copper		C₁₈H₃₂CuOSi	详情	详情
(XII)	36025	1-hepten-3-ol	4938-52-7	C₇H₁₄O	详情	详情
(XIII)	36026	1-hepten-3-one		C₇H₁₂O	详情	详情
(XIV)	29064	bromo(2-propynyl)magnesium		C₃H₃BrMg	详情	详情
(XV)	29325	3-butyl-1-hexen-5-yn-3-ol		C₁₀H₁₆O	详情	详情
(XVI)	36027	1-butyl-1-vinyl-3-butynyl trimethylsilyl ether; [(1-butyl-1-vinyl-3-butynyl)oxy](trimethyl)silane		C₁₃H₂₄OSi	详情	详情
(XVII)	36028	(E)-1-butyl-4-(tributylstannyl)-1-vinyl-3-butenyl trimethylsilyl ether; [[(E)-1-butyl-4-(tributylstannyl)-1-vinyl-3-butenyl]oxy](trimethyl)silane		C₂₅H₅₂OSiSn	详情	详情
(C)	29069	1-pentynylcopper		C₅H₇Cu	详情	详情

Extended Information