|
【结 构 式】 
|
【药物名称】 【化学名称】11alpha,15alpha-Dihydroxy-16-(3-methoxymethylphenyl)-9-oxo-17,18,19,20-tetranor-5-thia-13(E)-prostenoic acid 【CA登记号】256382-23-7 【 分 子 式 】C23H32O6S 【 分 子 量 】436.57189 |
【开发单位】Ono (Originator) 【药理作用】IMMUNOMODULATING AGENTS, Immunomodulators, Prostaglandins, Prostanoid EP4 Agonists |
合成路线1
Treatment of 3-bromobenzyl bromide (I) with sodium methoxide gives 1-bromo-3-(methoxymethyl)benzene (II). After conversion of aryl bromide (II) into the corresponding Grignard reagent (III), addition to epoxide (IV) in the presence of CuI affords the chiral alcohol (V). Removal of the O-trityl protecting group of (V) under acidic conditions provides diol (VI), which is selectively acylated at the primary hydroxyl group by means of acetyl chloride and 2,4,6-collidine to produce the mono-acetate (VII). After protection of the secondary hydroxyl group of (VII) as the tetrahydropyranyl ether (VIII), alkaline hydrolysis of the acetate ester group leads to the primary alcohol (IX). Subsequent Swern oxidation of alcohol (IX) provides aldehyde (X). Condensation of aldehyde (X) with tetrabromomethane in the presence of triphenylphosphine furnishes the gem-dibromoolefin (XI). This is then converted to the terminal alkyne (XII) by treatment with butyllithium in cold THF.
| 【2】 Ohuchida, S.; Maruyama, T. (Ono Pharmaceutical Co., Ltd.); 5-Thia-omega-substd. phenyl-prostaglandin E derivs., process for producing the same and drugs containing the same as the active ingredient. EP 1097922; JP 2001089444; US 6462081; WO 0003980 . |
| 【1】 Maruyama, T.; et al.; Design and synthesis of a selective EP4-receptor agonist. Part 3: 16-Phenyl-5-thiaPGE1 and 9-beta-halo derivatives with improved stability. Bioorg Med Chem 2002, 10, 6, 1743. |
| 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) | 20466 | 1-bromo-3-(bromomethyl)benzene | 823-78-9 | C7H6Br2 | 详情 | 详情 |
| (II) | 56397 | 3-bromobenzyl methyl ether; 1-bromo-3-(methoxymethyl)benzene | C8H9BrO | 详情 | 详情 | |
| (III) | 57226 | bromo[3-(methoxymethyl)phenyl]magnesium | C8H9BrMgO | 详情 | 详情 | |
| (IV) | 41006 | (2S)-oxiranylmethyl trityl ether; (2S)-2-[(trityloxy)methyl]oxirane | C22H20O2 | 详情 | 详情 | |
| (V) | 56398 | (2S)-1-[3-(methoxymethyl)phenyl]-3-(trityloxy)-2-propanol | C30H30O3 | 详情 | 详情 | |
| (VI) | 56399 | (2S)-3-[3-(methoxymethyl)phenyl]-1,2-propanediol | C11H16O3 | 详情 | 详情 | |
| (VII) | 56400 | (2S)-2-hydroxy-3-[3-(methoxymethyl)phenyl]propyl acetate | C13H18O4 | 详情 | 详情 | |
| (VIII) | 56401 | (2S)-3-[3-(methoxymethyl)phenyl]-2-(tetrahydro-2H-pyran-2-yloxy)propyl acetate | C18H26O5 | 详情 | 详情 | |
| (IX) | 56402 | (2S)-3-[3-(methoxymethyl)phenyl]-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanol | C16H24O4 | 详情 | 详情 | |
| (X) | 56403 | (2S)-3-[3-(methoxymethyl)phenyl]-2-(tetrahydro-2H-pyran-2-yloxy)propanal | C16H22O4 | 详情 | 详情 | |
| (XI) | 56404 | (1S)-3,3-dibromo-1-[3-(methoxymethyl)benzyl]-2-propenyl tetrahydro-2H-pyran-2-yl ether; 2-({(1S)-3,3-dibromo-1-[3-(methoxymethyl)benzyl]-2-propenyl}oxy)tetrahydro-2H-pyran | C17H22Br2O3 | 详情 | 详情 | |
| (XII) | 56405 | (1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl tetrahydro-2H-pyran-2-yl ether; 2-({(1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl}oxy)tetrahydro-2H-pyran | C17H22O3 | 详情 | 详情 |
合成路线2
The tetrahydropyranyl protecting group of (XII) is removed under acidic conditions, and the resultant alcohol (XIII) is then reprotected as the silyl ether (XIV) by treatment with tert-butyldimethylsilyl chloride and imidazole. Alkyne (XIV) is converted into the vinyl iodide (XV) employing zirconocene chloride hydride and iodine. Metalation of (XV) with tert-butyllithium and 2-(thienyl)cyanocuprate, followed by Michael addition to cyclopentenone (XVI) produces the intermediate enol adduct (XVII), which is further condensed with aldehyde (XVIII) to furnish the hydroxy ketone (XIX). Dehydration of (XIX) to enone (XX) is accomplished by treatment with methanesulfonyl chloride and 4-(dimethylamino)pyridine. Selective reduction of the conjugated olefin of (XX) with tributyltin hydride and tert-butyl peroxide leads to the saturated ketone (XXI). Then, desilylation of (XXI) with HF in pyridine produces diol (XXII). The methyl ester group of (XXII) is finally hydrolyzed to the target carboxylic acid by using pig liver esterase (PLE) in a buffered medium.
| 【2】 Ohuchida, S.; Maruyama, T. (Ono Pharmaceutical Co., Ltd.); 5-Thia-omega-substd. phenyl-prostaglandin E derivs., process for producing the same and drugs containing the same as the active ingredient. EP 1097922; JP 2001089444; US 6462081; WO 0003980 . |
| 【1】 Maruyama, T.; et al.; Design and synthesis of a selective EP4-receptor agonist. Part 3: 16-Phenyl-5-thiaPGE1 and 9-beta-halo derivatives with improved stability. Bioorg Med Chem 2002, 10, 6, 1743. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 56405 | (1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl tetrahydro-2H-pyran-2-yl ether; 2-({(1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl}oxy)tetrahydro-2H-pyran | C17H22O3 | 详情 | 详情 | |
| (XIII) | 56406 | (2S)-1-[3-(methoxymethyl)phenyl]-3-butyn-2-ol | C12H14O2 | 详情 | 详情 | |
| (XIV) | 56407 | tert-butyl(dimethyl)silyl (1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl ether; tert-butyl({(1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl}oxy)dimethylsilane | C18H28O2Si | 详情 | 详情 | |
| (XV) | 56408 | tert-butyl(dimethyl)silyl (1S,2E)-3-iodo-1-[3-(methoxymethyl)benzyl]-2-propenyl ether; tert-butyl({(1S,2E)-3-iodo-1-[3-(methoxymethyl)benzyl]-2-propenyl}oxy)dimethylsilane | C18H29IO2Si | 详情 | 详情 | |
| (XVI) | 13805 | (4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one | C11H20O2Si | 详情 | 详情 | |
| (XVII) | 56986 | lithium (3R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-{(E,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(methoxymethyl)phenyl]-1-butenyl}-1-cyclopenten-1-olate | C29H49LiO4Si2 | 详情 | 详情 | |
| (XVIII) | 56410 | methyl 4-[(2-oxoethyl)sulfanyl]butanoate | C7H12O3S | 详情 | 详情 | |
| (XIX) | 56411 | methyl 4-{[2-((2R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentyl)-2-hydroxyethyl]sulfanyl}butanoate | C36H62O7SSi2 | 详情 | 详情 | |
| (XX) | 56412 | methyl 4-{[2-((2R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentylidene)ethyl]sulfanyl}butanoate | C36H60O6SSi2 | 详情 | 详情 | |
| (XXI) | 56413 | methyl 4-{[2-((1R,2R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentyl)ethyl]sulfanyl}butanoate | C36H62O6SSi2 | 详情 | 详情 | |
| (XXII) | 56987 | methyl 4-{[2-((1R,2R,3R)-3-hydroxy-2-{(E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentyl)ethyl]sulfanyl}butanoate | C24H34O6S | 详情 | 详情 |
合成路线3
In an alternative method, oxidation of the lactone alcohol (I) using DMSO in the presence of SO3-pyridine complex gives aldehyde (II). Horner-Emmons condensation of aldehyde (II) with phosphonate (III) affords enone (IV). Stereoselective reduction of (IV) with LiAlH4 in the presence of (S)-BINOL provides the (S)-alcohol (V), which is further protected with dihydropyran in the presence of p-toluenesulfonic acid to yield the bis-tetrahydropyranyl ether (VI). Lactone ring opening in (VI) under reductive conditions leads to diol (VII). Selective mesylation of the primary alcohol of (VII), followed by protection of the secondary hydroxyl with chlorotrimethylsilane produces the intermediate mesylate (VIII), which is then displaced with potassium thioacetate to yield the thioacetate ester (IX).
| 【1】 Maruyama, T.; et al.; Design and synthesis of a selective EP4-receptor agonist. Part 4: Practical synthesis and biological evaluation of a novel highly selective EP4-receptor agonist. Bioorg Med Chem 2002, 10, 7, 2103. |
| 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) | 56988 | (3aR,4S,5R,6aS)-4-(hydroxymethyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one | C13H20O5 | 详情 | 详情 | |
| (II) | 56989 | (3aR,4R,5R,6aS)-2-oxo-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-4-carbaldehyde | C13H18O5 | 详情 | 详情 | |
| (III) | 56990 | dimethyl 3-[3-(methoxymethyl)phenyl]-2-oxopropylphosphonate | C13H19O5P | 详情 | 详情 | |
| (IV) | 56991 | (3aR,4R,5R,6aS)-4-{(E)-4-[3-(methoxymethyl)phenyl]-3-oxo-1-butenyl}-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one | C24H30O6 | 详情 | 详情 | |
| (V) | 56992 | (3aR,4R,5R,6aS)-4-{(E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one | C24H32O6 | 详情 | 详情 | |
| (VI) | 56993 | (3aR,4R,5R,6aS)-4-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one | C29H40O7 | 详情 | 详情 | |
| (VII) | 56994 | (1S,2R,3R,4R)-2-(2-hydroxyethyl)-3-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentanol | C29H44O7 | 详情 | 详情 | |
| (VIII) | 56995 | 2-{(1R,2R,3R,5S)-2-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(trimethylsilyl)oxy]cyclopentyl}ethyl methanesulfonate | C33H54O9SSi | 详情 | 详情 | |
| (IX) | 56996 | S-(2-{(1R,2R,3R,5S)-2-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(trimethylsilyl)oxy]cyclopentyl}ethyl) ethanethioate | C34H54O7SSi | 详情 | 详情 |
合成路线4
Methanolysis of the thioacetate and silyl ether groups of (IX), with concomitant S-alkylation by methyl 4-iodobutyrate (X) lead to thioether (XI). The deprotected alcohol function of (XI) is then oxidized to ketone (XII) under modified Swern conditions. Subsequent acidic hydrolysis of the tetrahydropyranyl ether groups of (XII) provide diol (XIII). Finally, hydrolysis of ester (XIII) to the target carboxylic acid is performed employing pig liver esterase.
| 【1】 Maruyama, T.; et al.; Design and synthesis of a selective EP4-receptor agonist. Part 4: Practical synthesis and biological evaluation of a novel highly selective EP4-receptor agonist. Bioorg Med Chem 2002, 10, 7, 2103. |
| 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) | 56996 | S-(2-{(1R,2R,3R,5S)-2-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(trimethylsilyl)oxy]cyclopentyl}ethyl) ethanethioate | C34H54O7SSi | 详情 | 详情 | |
| (X) | 13816 | Methyl 4-iodobutyrate; Methyl 4-iodobutanoate | 14273-85-9 | C5H9IO2 | 详情 | 详情 |
| (XI) | 56997 | methyl 4-({2-[(1R,2R,3R,5S)-5-hydroxy-2-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]ethyl}sulfanyl)butanoate | C34H52O8S | 详情 | 详情 | |
| (XII) | 56998 | methyl 4-({2-[(1R,2R,3R)-2-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-5-oxo-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]ethyl}sulfanyl)butanoate | C34H50O8S | 详情 | 详情 | |
| (XIII) | 56987 | methyl 4-{[2-((1R,2R,3R)-3-hydroxy-2-{(E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentyl)ethyl]sulfanyl}butanoate | C24H34O6S | 详情 | 详情 |