Sulprostone, ZK-57671, SH-B-286, CP-34089, Nalador, -Drug Synthesis Database

【结构式】

【药物名称】Sulprostone, ZK-57671, SH-B-286, CP-34089, Nalador

【化学名称】16-Phenoxy-omega-17,18,19,20-tetranor-PGE2 methylsulfonamide

【CA登记号】60325-46-4

【分子式】C₂₃H₃₁NO₇S

【分子量】465.57002

【开发单位】Schering AG (Originator)

【药理作用】ENDOCRINE DRUGS, Gynecological Disorders, Treatment of , Uterine Stimulants, Uterine Stimulants and Tocolytics

合成路线1 合成路线2

合成路线1

The condensation of methyl phenoxyacetate (I) with dimethyl methylphosphonate (II) by means of butyllithium in THF gives dimethyl 2-oxo-3-phenoxypropylphosphanate (III), which by a Wittig condensation with 2-[3alpha-(p-phenylbenzoyloxy)-5alpha-hydroxy-2beta-formylcyclopentan-1alpha-yl]acetic acid gamma-lactone (IV) by means of butyllithium in hexane yields the keto lactone (V). This compound is reduced with zinc borohydride in dimethoxyethane affording the hydroxylactone (VI), which is hydrolyzed with K2CO3 in methanol giving the dihydroxylactone (VII). The hydroxyl groups of (VII) are protected with dihydropyrane as usual giving (VIII), which is reduced with diisobutylaluminitim hydride in toluene yielding the hemiacetal (IX).

参考文献中间体

【1】 Castaner, J.; Wescott, A.L.; Sulprostone. Drugs Fut 1978, 3, 1, 59.
【2】 Beil, W.; Hoeppener, A.; Wolff, H.J.; Beil, H.; Substituted 16,17,18,19,20-pentanorprostaglandins. DE 2355540; ES 433046; ES 433047; FR 2205335; GB 1456512; JP 49093342; JP 52053841 .

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)	39696	methyl 2-phenoxyacetate	2065-23-8	C₉H₁₀O₃	详情	详情
(II)	39697	dimethyl methylphosphonite	20278-51-7	C₃H₉O₂P	详情	详情
(III)	39698	dimethyl 2-oxo-3-phenoxypropylphosphonite		C₁₁H₁₅O₄P	详情	详情
(IV)	32042	(3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate		C₂₁H₁₈O₅	详情	详情
(V)	32043	(3aR,4R,5R,6aS)-2-oxo-4-[(E)-3-oxo-4-phenoxy-1-butenyl]hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate		C₃₀H₂₆O₆	详情	详情
(VI)	32044	(3aR,4R,5R,6aS)-4-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate		C₃₀H₂₈O₆	详情	详情
(VII)	32045	(3aR,4R,5R,6aS)-5-hydroxy-4-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]hexahydro-2H-cyclopenta[b]furan-2-one		C₁₇H₂₀O₅	详情	详情
(VIII)	32046	(3aR,4S,5R,6aS)-4-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-one		C₂₉H₄₀O₇	详情	详情
(IX)	32047	(3aR,4S,5R,6aS)-4-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-ol		C₂₉H₄₂O₇	详情	详情

合成路线2

A Wittig condensation of [4-(methanesulfonylaminocarbonyl)butyl]triphenylphosphonium bromide (X) [the phosphonium bromide (X) is prepared bv reaction of 5-bromovaleryl chloride (Xl) with methanesulfonamide (XII) at 100 C to give N-methanesulfonyl-5-bromovaleramide (XIII), which is then condensed with triphenylphosphine in refluxing acetonitrile] with hemiacetal (IX) by means of Na in DMSO affords N-methanesulfonyl-9alpha-hydroxy-11alpha,15alpha-bis(tetrahydropyranyloxy)-16-phenoxy-5-cis-13-trans-omega-tetranorprostadienamide (XIV), which is then oxidized with the Jones reagent in acetone to the keto compound (XV). Finally, this compound is deprotected with acetic acid.

参考文献中间体

【1】 Castaner, J.; Wescott, A.L.; Sulprostone. Drugs Fut 1978, 3, 1, 59.
【2】 Beil, W.; Hoeppener, A.; Wolff, H.J.; Beil, H.; Substituted 16,17,18,19,20-pentanorprostaglandins. DE 2355540; ES 433046; ES 433047; FR 2205335; GB 1456512; JP 49093342; JP 52053841 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	32047	(3aR,4S,5R,6aS)-4-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-ol		C₂₉H₄₂O₇	详情	详情
(X)	39699	[5-[(methylsulfonyl)amino]-5-oxopentyl](triphenyl)phosphonium bromide		C₂₄H₂₇BrNO₃PS	详情	详情
(XI)	39700	5-bromopentanoyl chloride	4509-90-4	C₅H₈BrClO	详情	详情
(XII)	39701	methanesulfonamide	3144-09-0	CH₅NO₂S	详情	详情
(XIII)	39702	N-(5-bromopentanoyl)methanesulfonamide		C₆H₁₂BrNO₃S	详情	详情
(XIV)	39703	N-((Z)-7-[(1R,2S,3R,5S)-5-hydroxy-2-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoyl)methanesulfonamide		C₃₅H₅₃NO₉S	详情	详情
(XV)	39704	N-((Z)-7-[(1R,2S,3R)-2-[(E,3R)-3-hydroxy-4-phenoxy-1-butenyl]-5-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoyl)methanesulfonamide		C₂₉H₄₁NO₈S	详情	详情

Extended Information