sodium 5-(triphenylphosphoranylidene)pentanoate -Drug Synthesis Database

【结构式】

【分子编号】29762

【品名】sodium 5-(triphenylphosphoranylidene)pentanoate

【CA登记号】

【分子式】C₂₃H₂₂NaO₂P

【分子量】384.39001

【元素组成】C 71.87% H 5.77% Na 5.98% O 8.32% P 8.06%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(B)

Treatment of the optically pure lactone (I) with lithium dimethyl methylphosphonate in tetrahydrofuran gives hemiacetal (II), which is oxidized to the diketone (III) using Jones' reagent in acetone. Then in the key step, compound (III) cyclizes to enone (IV) using potassium carbonate and 18-crown-6 in warm toluene. Lithium dimethyl cuprate addition to enone (IV) in ether gives ketone (V), which is converted to acid (VI) (a 1:1 mixture of E and Z olefins at C-5) using (4-carboxybutyl)triphenylphosphorane in dimethyl sulfoxide. Cleavage of the alcohol-protecting groups in (VI) with an acetic acid-water-tetrahydrofuran mixture followed by chromatography to remove the 5-E isomer affords 9-methylcarbacyclin (VII). Finally, treatment of (VII) with calcium oxide in tetrahydrofuran gives U-61431F (ciprostene calcium).

参考文献中间体

合成目标

【1】 Aristoff, P.A.; Harrison, A.W.; Johnson, P.D.; Synthesis of 9-subtituted cabacyclin analogues. J Org Chem 1983, 48, 5341.
【2】 Aristoff, P.A.; Practical synthesis of 6a-carbaprostaglandin I2. J Org Chem 1981, 46, 1954.
【3】 Aristoff, P.A. (Pharmacia Corp.); Composition and process. US 4420632 .
【4】 Aistoff, P.A.; Ciprostene Calcium. Drugs Fut 1985, 10, 11, 900.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(A)	29720	[(dimethoxyphosphoryl)methyl]lithium	C₃H₈LiO₃P	详情	详情
(B)	29762	sodium 5-(triphenylphosphoranylidene)pentanoate	C₂₃H₂₂NaO₂P	详情	详情
(I)	29757	(3aR,4S,5R,6aS)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-4-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-one	C₂₇H₄₄O₆	详情	详情
(II)	29758	dimethyl ((3aR,4S,5R,6aS)-2-hydroxy-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-4-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]hexahydro-2H-cyclopenta[b]furan-2-yl)methylphosphonate	C₃₀H₅₃O₉P	详情	详情
(III)	29759	dimethyl 2-oxo-3-((4R,5R)-2-oxo-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-4-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]tetrahydro-3-furanyl)propylphosphonate	C₂₉H₄₉O₁₀P	详情	详情
(IV)	29760	(3aR,4R,5R)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-4-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-3a,4,5,6-tetrahydro-2(3H)-pentalenone	C₂₈H₄₄O₅	详情	详情
(V)	29761	(3aR,5R,6R,6aR)-3a-methyl-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-6-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]hexahydro-2(1H)-pentalenone	C₂₉H₄₈O₅	详情	详情
(VI)	29763	5-[(3aR,5R,6R,6aR)-3a-methyl-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-6-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]hexahydro-2(1H)-pentalenylidene]pentanoic acid	C₃₄H₅₆O₆	详情	详情
(VII)	29764	5-[(3aS,5R,6R,6aR)-5-hydroxy-6-[(E,3S)-3-hydroxy-1-octenyl]-3a-methylhexahydro-2(1H)-pentalenylidene]pentanoic acid	C₂₂H₃₆O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

Reaction of the lactone (I) with lithium ethyl acetate followed by acid catalyzed dehydration and hydrolysis of the ester group with K2CO3 in methanol affords the hydroxy compound (II), which gives after Collins oxidation, treatment with 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and reduction with NaBH4, the ketoester (III). Dealkoxy carbonylation with DABCO in toluene, benzoylation and removal of the silyl group with acetic acid in THF-water yield the ketone (IV). Ketalization of the ketone (IV) with ethylene glycol, Collins oxidation and condensation of the resulting aldehyde with the sodium salt of the phosphonate (V) afford the enone (VI). Reduction of (VI) with NaBH4 in methanol, cleavage of the ketal function with acetic acid-H2O and subsequent tetrahydropyranylation lead to the ketone (VII). Wittig condensation of the ketone (VII) with (VIII) and NaH in DMSO affords after chromatographic separation the acid (IX), which is finally deprotected to (X) (ZK-36374) by treatment with acetic acid in THF-water mixture.

参考文献中间体

合成目标

【1】 Skuballa, W.; Raduechel, B.; Vorbrueggen, H.; Mannesmann, G.; Losert, W.; Casals, J. (Schering AG); Novel prostacyclin derivatives and a process for the preparation thereof.. DE 2845770; ES 485199; US 4692464 .
【2】 Vorbruggen, H.; Schillinger, E.; Ciloprost. Drugs Fut 1981, 6, 11, 676.

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)	11295	Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol	107-21-1	C₂H₆O₂	详情	详情
(IIIa)	32254	ethyl (1R,3aS,4S,5R,6aS)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-hydroxy-2-oxooctahydro-1-pentalenecarboxylate		C₁₈H₃₂O₅Si	详情	详情
(IIIb)	32255	(3aS,4S,5R,6aS)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-hydroxy-1-methylhexahydro-2(1H)-pentalenone		C₁₈H₃₂O₅Si	详情	详情
(VIa)	32257	Benzoic acid (1S,2R,3aR,6aS)-5,5-(ethylenedioxy)-1-(4(S)-methyl-3-oxo-1(E)-octen-6-yn-1-yl)octahydropentalen-2-yl ester		C₂₆H₃₀O₅	详情	详情
(VIb)	32258	Benzoic acid (1S,2R,3aR,6aS)-5,5-(ethylenedioxy)-1-(4(R)-methyl-3-oxo-1(E)-octen-6-yn-1-yl)octahydropentalen-2-yl ester		C₂₆H₃₀O₅	详情	详情
(VIIa)	32259	(3aS,4S,5R,6aR)-4-[(E,3S,4S)-4-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octen-6-ynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenone		C₂₉H₄₄O₅	详情	详情
(VIIb)	32260	(3aS,4S,5R,6aR)-4-[(E,3S,4R)-4-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octen-6-ynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenone		C₂₉H₄₄O₅	详情	详情
(IXa)	32261	5-[(3aS,4S,5R,6aR)-4-[(E,3S,4S)-4-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octen-6-ynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]pentanoic acid		C₃₄H₅₂O₆	详情	详情
(IXb)	32262	5-[(3aS,4S,5R,6aR)-4-[(E,3S,4R)-4-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octen-6-ynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]pentanoic acid		C₃₄H₅₂O₆	详情	详情
(I)	32252	(3aR,4S,5R,6aS)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate		C₂₁H₃₀O₅Si	详情	详情
(II)	32253	ethyl 2-[(3aR,4S,5R,6aS)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-ylidene]acetate		C₁₈H₃₂O₅Si	详情	详情
(IV)	32256	(1S,2R,3aR,6aS)-1-(hydroxymethyl)-5-oxooctahydro-2-pentalenyl benzoate		C₁₆H₁₈O₄	详情	详情
(V)	24482	dimethyl 3-methyl-2-oxo-5-heptynylphosphonate		C₁₀H₁₇O₄P	详情	详情
(VIII)	29762	sodium 5-(triphenylphosphoranylidene)pentanoate		C₂₃H₂₂NaO₂P	详情	详情

Extended Information