AL-6556, -Drug Synthesis Database

【结构式】

【药物名称】AL-6556

【化学名称】(5Z,9R,11R,15R)-9-Chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanorprosta-5-enoic acid
　　　　　　2-[4-[(1R,2R,3R,5R)-5-Chloro-2-[3(R)-cyclohexyl-3-hydroxypropyl]-3-hydroxycyclopentyl]-2(Z)-butenyloxy]acetic acid

【CA登记号】

【分子式】C₂₀H₃₃ClO₅

【分子量】388.93601

【开发单位】Alcon (Originator)

【药理作用】Antiglaucoma Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, Prostaglandins, Prostanoid DP Agonists

合成路线1 合成路线2

合成路线1

The benzoate ester group of the known lactone precursor (I) was removed by methanolysis in the presence of K2CO3 to afford diol (II), which was further protected as the bis-tetrahydropyranyl ether (III). Catalytic hydrogenation of (III) provided the 13,14-dihydro compound (IV). The lactone function of (IV) was then reduced with LiAlH4 to the corresponding open chain diol, which was subsequently protected as the bis-silyl derivative (V). Regioselective Swern oxidation of the silylated primary hydroxyl of (V) furnished aldehyde (VI). This was subjected to Wadsworth-Emmons olefination with phosphonate (VII) in the presence of tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1) as the K+-complexing agent to yield the Z-unsaturated ester (VIII) as the major isomer. Ester group reduction in (VIII) by means of DIBAL, followed by desilylation with tetrabutylammonium fluoride, provided the allylic alcohol (IX).

参考文献中间体

【1】 Hellberg, M.R.; et al.; 3-Oxa-15-cyclohexyl prostaglandin DP receptor agonists as topical antiglaucoma agents. Bioorg Med Chem 2002, 10, 6, 2031.

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)	56280	(3aR,4R,5R,6aS)-4-[(E,3S)-3-cyclohexyl-3-hydroxy-1-propenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate		C₂₃H₂₈O₅	详情	详情
(II)	56281	(3aR,4R,5R,6aS)-4-[(E,3S)-3-cyclohexyl-3-hydroxy-1-propenyl]-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-one		C₁₆H₂₄O₄	详情	详情
(III)	56282	(3aR,4R,5R,6aS)-4-[(E,3S)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)-1-propenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one		C₂₆H₄₀O₆	详情	详情
(IV)	56283	(3aR,4R,5R,6aS)-4-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one		C₂₆H₄₂O₆	详情	详情
(V)	56284	{(1S,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(triethylsilyl)oxy]cyclopentyl}methyl triethylsilyl ether; ({(1S,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(triethylsilyl)oxy]cyclopentyl}methoxy)(triethyl)silane		C₃₇H₇₂O₆Si₂	详情	详情
(VI)	56285	(1R,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(triethylsilyl)oxy]cyclopentanecarbaldehyde		C₃₁H₅₆O₆Si	详情	详情
(VII)	41856	methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate	88738-78-7	C₇H₉F₆O₅P	详情	详情
(VIII)	56286	methyl (Z)-4-{(1R,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(triethylsilyl)oxy]cyclopentyl}-2-butenoate		C₃₅H₆₂O₇Si	详情	详情
(IX)	56287	(1S,2R,3R,4R)-3-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-2-[(Z)-4-hydroxy-2-butenyl]-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentanol		C₂₈H₄₈O₆	详情	详情

合成路线2

Alkylation of the allylic alcohol (IX) with tert-butyl bromoacetate (X) under phase-transfer conditions afforded ester (XI), which was then converted into chloro derivative (XII) by treatment with a mixture of CH3CN/CCl4/pyridine and then PPh3. Acidic cleavage of the tetrahydropyranyl ether groups of (XII) led to the dihydroxy derivative (XIII), which was finally subjected to saponification with LiOH in MeOH to yield the desired product.

参考文献中间体

【1】 Hellberg, M.R.; et al.; 3-Oxa-15-cyclohexyl prostaglandin DP receptor agonists as topical antiglaucoma agents. Bioorg Med Chem 2002, 10, 6, 2031.

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)	56287	(1S,2R,3R,4R)-3-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-2-[(Z)-4-hydroxy-2-butenyl]-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentanol		C₂₈H₄₈O₆	详情	详情
(X)	17430	2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate	5292-43-3	C₆H₁₁BrO₂	详情	详情
(XI)	56288	tert-butyl 2-({(Z)-4-[(1R,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-2-butenyl}oxy)acetate		C₃₄H₅₈O₈	详情	详情
(XII)	56289	tert-butyl 2-({(Z)-4-[(1R,2R,3R,5R)-5-chloro-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-2-butenyl}oxy)acetate		C₃₄H₅₇ClO₇	详情	详情
(XIII)	56290	tert-butyl 2-[((Z)-4-{(1R,2R,3R,5R)-5-chloro-2-[(3R)-3-cyclohexyl-3-hydroxypropyl]-3-hydroxycyclopentyl}-2-butenyl)oxy]acetate		C₂₄H₄₁ClO₅	详情	详情

Extended Information