AL-6598, -Drug Synthesis Database

【结构式】

【药物名称】AL-6598

【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 isopropyl ester
　　　　　　2-[4-[(1R,2R,3R,5R)-5-Chloro-2-[3(R)-cyclohexyl-3-hydroxypropyl]-3-hydroxycyclopentyl]-2(Z)-butenyloxy]acetic acid isopropyl ester

【CA登记号】170291-06-2

【分子式】C₂₃H₃₉ClO₅

【分子量】431.01728

【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3

合成路线1

The title prostaglandin derivative was synthesized by two methods. 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 subjected to titanium isopropoxide-mediated transesterification to the corresponding isopropyl ester (XII). Conversion of secondary alcohol (XII) into chloride (XIV) was performed via the mesylate (XIII), which was then treated with tetrabutylammonium chloride in hot toluene. Finally, acidic cleavage of the tetrahydropyranyl ether groups of (XIV) led to the title compound.

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)	56291	isopropyl 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		C₃₃H₅₆O₈	详情	详情
(XIII)	56292	isopropyl 2-({(Z)-4-[(1R,2R,3R,5S)-2-[(3R)-3-cyclohexyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-5-[(methylsulfonyl)oxy]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]-2-butenyl}oxy)acetate		C₃₄H₅₈O₁₀S	详情	详情
(XIV)	56293	isopropyl 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		C₃₃H₅₅ClO₇	详情	详情

合成路线3

In a different route, hydrogenation of (R)-3-chloro-1-phenyl-1-propanol (XV) over Rh/Al2O3 gave the cyclohexyl carbinol (XVI), which was protected as the ethoxyethyl ether (XVII) by treatment with ethyl vinyl ether in the presence of pyridinium tosylate. Lithiation of chloride (XVII), followed by exchange with lithium (2-thienyl)cyanocuprate, generated the organocuprate reagent (XVIII), which produced a conjugate addition to enone (XIX) to afford the methylene ketone (XX). Protecting group exchange in (XX) was effected by acidic cleavage of the ethoxyethyl group, followed by silylation with t-butyldimethylsilyl triflate, yielding the bis-silylated compound (XXI). The Z-vinylstannane reagent (XXII) was subjected to a stereospecific transmetalation with Me2Cu(CN)Li2 and the resulting cuprate underwent conjugate addition to enone (XXI) yielding adduct (XXIII). Reduction of ketone (XXIII) with L-Selectride®, followed by acidic cleavage of the ethoxyethyl group, provided diol (XXIV). Alkylation of (XXIV) with tert-butyl bromoacetate (X), followed by transterification as above, furnished the isopropyl ester (XXV). The remaining hydroxyl group of (XXV) was subsequently exchanged by a chloride (XXVI) via the corresponding mesylate. Finally, desilylation of (XXVI) with HF in THF gave rise to the title compound.

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
(X)	17430	2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate	5292-43-3	C₆H₁₁BrO₂	详情	详情
(XV)	37782	(1R)-3-chloro-1-phenyl-1-propanol		C₉H₁₁ClO	详情	详情
(XVI)	56294	(1R)-3-chloro-1-cyclohexyl-1-propanol		C₉H₁₇ClO	详情	详情
(XVII)	56295	(1R)-3-chloro-1-cyclohexylpropyl 2-ethoxyethyl ether; 1-[(1R)-3-chloro-1-(2-ethoxyethoxy)propyl]cyclohexane		C₁₃H₂₅ClO₂	详情	详情
(XVIII)	56296	{[(3R)-3-cyclohexyl-3-(2-ethoxyethoxy)propyl]cuprio}lithium		C₁₃H₂₅CuLiO₂	详情	详情
(XIX)	56297	(4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[(diethylamino)methyl]-2-cyclopenten-1-one		C₁₆H₃₁NO₂Si	详情	详情
(XX)	56298	(3R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-[(3R)-3-cyclohexyl-3-(2-ethoxyethoxy)propyl]-2-methylenecyclopentanone		C₂₅H₄₆O₄Si	详情	详情
(XXI)	56299	(3R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-((3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclohexylpropyl)-2-methylenecyclopentanone		C₂₇H₅₂O₃Si₂	详情	详情
(XXII)	56300	2-ethoxyethyl (Z)-3-(tributylstannyl)-2-propenyl ether; tributyl[(Z)-3-(2-ethoxyethoxy)-1-propenyl]stannane		C₁₉H₄₀O₂Sn	详情	详情
(XXIII)	56301	(2R,3R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-((3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclohexylpropyl)-2-[(Z)-4-(2-ethoxyethoxy)-2-butenyl]cyclopentanone		C₃₄H₆₆O₅Si₂	详情	详情
(XXIV)	56302	(1S,2R,3R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-((3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclohexylpropyl)-2-[(Z)-4-hydroxy-2-butenyl]cyclopentanol		C₃₀H₆₀O₄Si₂	详情	详情
(XXV)	56303	isopropyl 2-({(Z)-4-[(1R,2R,3R,5S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-((3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclohexylpropyl)-5-hydroxycyclopentyl]-2-butenyl}oxy)acetate		C₃₅H₆₈O₆Si₂	详情	详情
(XXVI)	56304	isopropyl 2-({(Z)-4-[(1R,2R,3R,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-((3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclohexylpropyl)-5-chlorocyclopentyl]-2-butenyl}oxy)acetate		C₃₅H₆₇ClO₅Si₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)