Nileprost, ZK-34798, -Drug Synthesis Database

【结构式】

【药物名称】Nileprost, ZK-34798

【化学名称】(E)-5-Cyano-5-[(1S,5R,6R,7R)-7-hydroxy-6-[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octenyl]-2-oxabicyclo[3.3.0]octan-3-yliden] pentanoic acid
　　　　　　(5E,9alpha,11alpha,13E,15S)-5-Cyano-6,9-epoxy-11,15-dihydroxyprosta-5,13-dien-1-oic acid

【CA登记号】71097-83-1

【分子式】C₂₂H₃₃NO₅

【分子量】391.51201

【开发单位】Schering AG (Originator)

【药理作用】Antiulcer Drugs, Gastric Antisecretory Drugs, GASTROINTESTINAL DRUGS, Prostaglandins

合成路线1 合成路线2

合成路线1

A new synthesis of nileprost has been described: The condensation of the protected lactone (I) with acetonitrile by means of lithium dimethylamide (LDA) gives the cyanomethylene derivative (II), which is condensed with methyl 4-oxobutyrate (III) by means of the same reagent yielding compound (IV). The partial reduction of (IV) with H2 over Pd/C in toluene affords compound (V) with part of the nileprost skeleton. Partial deprotection of (V) with tetrabutylammonium fluoride gives the alcohol (VI), which is oxidized with SO3-pyridine complex to the aldehyde (VII). The Wittig condensation of (VII) with diethyl (2-oxo-3-methylheptyl)phosphonate (VIII) by means of NaH in THF yields the enone (IX), which is deprotected with acetic acid and reduced with diisobutylaluminum hydride in toluene to afford the nileprost methyl ester (X). Finally, this compound is hydrolyzed with NaOH in methanol-water.

参考文献中间体

【1】 Takahashi, A.; Kirio, Y.; Sodeoka, M.; Sasai, H.; Shibasaki, M.; Highly stereoselective synthesis of exocyclic tetrasubstituted enol ethers and olefins. A synthesis of nileprost. J Am Chem Soc 1989, 111, 2, 643.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	21284	(3aR,4S,5R,6aS)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-one	C₂₀H₃₆O₅Si	详情	详情
(II)	21285	2-[(3aR,4S,5R,6aS)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-ylidene]acetonitrile	C₂₂H₃₇NO₄Si	详情	详情
(III)	21286	methyl 4-oxobutanoate	C₅H₈O₃	详情	详情
(IV)	21287	methyl (E)-5-[(3aS,4S,5R,6aS)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-4,5,6,6a-tetrahydro-3aH-cyclopenta[b]furan-2-yl]-5-cyano-4-pentenoate	C₂₇H₄₃NO₆Si	详情	详情
(V)	21288	methyl 5-[(3aR,4S,5R,6aS)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-ylidene]-5-cyanopentanoate	C₂₇H₄₅NO₆Si	详情	详情
(VI)	21289	methyl 5-[(3aR,4S,5R,6aS)-4-(hydroxymethyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-ylidene]-5-cyanopentanoate	C₂₁H₃₁NO₆	详情	详情
(VII)	21290	methyl 5-[(3aR,4S,5R,6aS)-4-formyl-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-ylidene]-5-cyanopentanoate	C₂₁H₂₉NO₆	详情	详情
(VIII)	21291	diethyl 3-methyl-2-oxoheptylphosphonate	C₁₂H₂₅O₄P	详情	详情
(IX)	21292	methyl 5-[(3aR,4R,5R,6aS)-5-hydroxy-4-[(E)-4-methyl-3-oxo-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-ylidene]-5-cyanopentanoate	C₂₃H₃₃NO₅	详情	详情
(X)	21293	methyl 5-[(3aR,4R,5R,6aS)-5-hydroxy-4-[(E,3S)-3-hydroxy-4-methyl-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-ylidene]-5-cyanopentanoate	C₂₃H₃₅NO₅	详情	详情

合成路线2

16-Methylprostaglandin PGF2alpha methyl ester (Ia-b) is cyclized with iodine/sodium bicarbonate to give (IIa-b), which is acetylated with acetic anhydride/pyridine to (IIIa-b). Dehydrohalogenation with DBN generates the protected PGI2 analogue (IVa-b), which reacts smoothly with chlorosulfonyl isocyanate (A) to afford the adduct (Va-b). Without isolation (Va-b) gives on treatment with triethylamine in acetonitrile or solvolysis with N,N-dimethylformamide (DMF) the stable protected 5-cyano analoque (VIa-b), which contains up to ca. 5% Z-isomer, readily removed by chromatography. Finally, saponification affords the free ZK-34,798 (nileprost).

参考文献中间体

【1】 Lohaus, G.; Nitrilsynthesen mit chlorsulfonylisocyanat. Chem Ber 1967, 100, 2719-29.
【2】 Vorbruggen, H.; Reaktive isocyanate I. Sie direkte einfuehrung von nitrilgruppen in ungesattigte systeme. Eine einfache umwandlung von carbosauren in ihre nitrile. Tetrahedron Lett 1968, 1631-34.
【3】 Tanouchi, T.; Miyake, H.; Igushi, Y.; Hayashi, M.; Iguchi, S.; The synthesis of 16(R)- or 16(S)-methylprostaglandins. J Org Chem 1973, 38, 1250-51.
【4】 Whittaker, N.; A synthesis of prostaglandin sodium salt. Tetrahedron Lett 1977, 2805-08.
【5】 Vorbruggen, H.; Skuballa, W.; Raduchel, B.; Losert, W.; Loge, P.; Muller, B.; Mannesmann, G. (Schering AG); 5-Cyano-prostacyclin derivs.. US 4219479 .
【6】 Hashimoto, S.; Nileprost. Drugs Fut 1982, 7, 9, 643.

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)	14101	Chlorosulfonyl isocyanate	1189-71-5	CClNO₃S	详情	详情
(Ia)	37110	methyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R,4S)-3-hydroxy-4-methyloctyl]cyclopentyl]-5-heptenoate		C₂₂H₄₀O₅	详情	详情
(Ib)	37111	methyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R,4R)-3-hydroxy-4-methyloctyl]cyclopentyl]-5-heptenoate		C₂₂H₄₀O₅	详情	详情
(IIa)	37112	methyl 5-[(3aR,4R,5R,6aS)-5-hydroxy-4-[(E,3S,4S)-3-hydroxy-4-methyl-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-yl]-5-iodopentanoate		C₂₂H₃₇IO₅	详情	详情
(IIb)	37113	methyl 5-[(3aR,4R,5R,6aS)-5-hydroxy-4-[(E,3S,4R)-3-hydroxy-4-methyl-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-yl]-5-iodopentanoate		C₂₂H₃₇IO₅	详情	详情
(IIIa)	37114	methyl 5-[(3aR,4R,5R,6aS)-5-(acetoxy)-4-[(E,3S,4S)-3-(acetoxy)-4-methyl-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-yl]-5-iodopentanoate		C₂₆H₄₁IO₇	详情	详情
(IIIb)	37115	methyl 5-[(3aR,4R,5R,6aS)-5-(acetoxy)-4-[(E,3S,4R)-3-(acetoxy)-4-methyl-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-yl]-5-iodopentanoate		C₂₆H₄₁IO₇	详情	详情
(IVa)	37116	methyl 5-[(3aR,4R,5R,6aS)-5-(acetoxy)-4-[(E,3S,4S)-3-(acetoxy)-4-methyl-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-ylidene]pentanoate		C₂₆H₄₀O₇	详情	详情
(IVb)	37117	methyl 5-[(3aR,4R,5R,6aS)-5-(acetoxy)-4-[(E,3S,4R)-3-(acetoxy)-4-methyl-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-ylidene]pentanoate		C₂₆H₄₀O₇	详情	详情
(Va)	37118	methyl 5-[(3aR,4R,5R,6aS)-5-(acetoxy)-4-[(E,3S,4S)-3-(acetoxy)-4-methyl-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-ylidene]-6-[(chlorosulfonyl)amino]-6-oxohexanoate		C₂₇H₄₀ClNO₁₀S	详情	详情
(Vb)	37119	methyl 5-[(3aR,4R,5R,6aS)-5-(acetoxy)-4-[(E,3S,4R)-3-(acetoxy)-4-methyl-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-ylidene]-6-[(chlorosulfonyl)amino]-6-oxohexanoate		C₂₇H₄₀ClNO₁₀S	详情	详情
(VIa)	37120	methyl 5-[(3aR,4R,5R,6aS)-5-(acetoxy)-4-[(E,3S,4S)-3-(acetoxy)-4-methyl-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-ylidene]-5-cyanopentanoate		C₂₇H₃₉NO₇	详情	详情
(VIb)	37121	methyl 5-[(3aR,4R,5R,6aS)-5-(acetoxy)-4-[(E,3S,4R)-3-(acetoxy)-4-methyl-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-ylidene]-5-cyanopentanoate		C₂₇H₃₉NO₇	详情	详情

Extended Information