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【结 构 式】 
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【药物名称】11-9 EM, 9alpha-PGM, U-46619 【化学名称】(15S)-Hydroxy-11alpha,9alpha-(epoxymethano)prosta-5Z,13E-dienoic acid 【CA登记号】56985-40-1 【 分 子 式 】C21H34O4 【 分 子 量 】350.50273 |
【开发单位】Pfizer (Originator) 【药理作用】Antiulcer Drugs, Gastric Antisecretory Drugs, GASTROINTESTINAL DRUGS |
合成路线1
The sylilation of PGE2 methyl ester (I) with hexamethyldisylazane trimethylchlorosylane (A) gives the bis(trimethylsilyl) ether (II), which by reaction with N-methylphenylsulfonimidoylmethyl magnesium chloride in THF followed by a reductive elimination with Al-Hg affords 9-deoxy-9-methylene-PGE2 methyl ester (III) or its his trimethylsilyl ether (IV) depending on the reaction conditions. The selective hydroboration of (IV) with 9-borabicyclo[3.3.1]nonane (B) in THF yields 9-deoxy-9alpha-hydroxymethyl-PGE2 methyl ester (V), which by mesylation with methanesulfonyl chloride and triethylamine in methylene chloride gives the corresponding mesylate (VI). The treatment ot (VI) with 85% phosphoric acid in THF water eliminates the trimethylsilyl groups yielding 9-deoxy-9alpha-mesyloxymethyl-PGE2alpha methyl ester (VII), which is finally cyclized by treatment with NaOH in MeOH - H2O.
| 【1】 Bundy, G.L.; The synthesis of prostaglandin endoperoxide analogs. Tetrahedron Lett 1975, 24, 1957-60. |
| 【2】 Bundy, G.L.; US 3950363 . |
| 【3】 Castaner, J.; Owen, R.T.; U-46619. Drugs Fut 1980, 5, 9, 453. |
| 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) | 39138 | (E)-1,2-bis(trimethylsilyl)diazene | C6H18N2Si2 | 详情 | 详情 | |
| (B) | 39142 | borabicyclo[3.3.1]nonane; 9-borabicyclo[3.3.1]nonane | 280-64-8 | C8H15B | 详情 | 详情 |
| (I) | 39137 | methyl (Z)-7-[(1R,2R,3R)-3-hydroxy-2-[(E,3S)-3-hydroxy-1-octenyl]-5-oxocyclopentyl]-5-heptenoate | C21H34O5 | 详情 | 详情 | |
| (II) | 39139 | methyl (Z)-7-((1R,2R,3R)-5-oxo-3-[(trimethylsilyl)oxy]-2-[(E,3S)-3-[(trimethylsilyl)oxy]-1-octenyl]cyclopentyl)-5-heptenoate | C27H50O5Si2 | 详情 | 详情 | |
| (III) | 39140 | methyl (Z)-7-[(1R,2R,3R)-3-hydroxy-2-[(E,3S)-3-hydroxy-1-octenyl]-5-methylenecyclopentyl]-5-heptenoate | C22H36O4 | 详情 | 详情 | |
| (IV) | 39141 | methyl (Z)-7-((1R,2R,3R)-3-methyl-5-methylene-2-[(E,3S)-3-[(trimethylsilyl)oxy]-1-octenyl]cyclopentyl)-5-heptenoate | C26H46O3Si | 详情 | 详情 | |
| (V) | 39143 | methyl (Z)-7-((1R,2S,3R,5S)-5-(hydroxymethyl)-3-methyl-2-[(E,3S)-3-[(trimethylsilyl)oxy]-1-octenyl]cyclopentyl)-5-heptenoate | C26H48O4Si | 详情 | 详情 | |
| (VI) | 39144 | methyl (Z)-7-((1S,2S,3R,5S)-5-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-3-[(trimethylsilyl)oxy]-2-[(E,3S)-3-[(trimethylsilyl)oxy]-1-octenyl]cyclopentyl)-5-heptenoate | C31H60O5SSi2 | 详情 | 详情 | |
| (VII) | 39145 | methyl (Z)-7-[(1S,2S,3R,5S)-3-hydroxy-2-[(E,3S)-3-hydroxy-1-octenyl]-5-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)cyclopentyl]-5-heptenoate | C25H44O5S | 详情 | 详情 |
合成路线2
The Diels-Alder reaction of butadiene (VIII) with acrylic acid (IX) gives cyclohexene-4-carboxylic acid (X), which by treatment with I2 and KI in water followed by a treatment with 1,5-diazabicyclo[4.3.0]non-5-ene (XI) in benzene is converted to 3-hydroxycyclohexene-5-carboxylic acid lactone (XII). The opening of (XII) with NaOMe in MeOH yields methyl 3-hydroxycyclohexene-5-carboxylate (XIII) as a mixture of isomers, which by treatment with phenylacetyl chloride (A) affords the corresponding phenylacetate (XIV), which by optical resolution and successive racemization of the residue with mercuric trifluoroacetate yields the active methyl 3-hydroxycyclohexene-5-carboxylate (XIIIa). The treatment of (XIIIa) with biphenylyl-4-carbonyl chloride gives the corresponding ester (XV), which is submitted to hydroxylation with OsO4-sodium chlorate yielding the glycol (XVI). Ring opening of (XVI) with sodium periodate in THF-water affords the dialdehyde (XVII), which is cyclized by treatment with pyrrolidine acetate (B) in benzene giving 5-methoxycarbonyl-3-(biphenylylcarbonyloxy)cyclopentene-1-carboxaldehyde (XVIII). The conjugate addition of (XVIII) with the vinyl cuprate (XIX) in HMPT-THF-ether at -78 C gives rise to 2-[3-(1-ethoxyethoxy)-1-octen-1-yl]-3-(4-biphenylylcarbonyloxy)-5-methyloxycarbonylcyclopentane-1-carboxaldehyde (XX), which is converted into the corresponding ethylene ketal (XXI) in the usual way (C).
| 【1】 Trost, B.M.; et al.; An enantioconvergent approach to prostanoids. J Chem Soc Chem Commun 1978, 10, 436-438. |
| 【2】 Castaner, J.; Owen, R.T.; U-46619. Drugs Fut 1980, 5, 9, 453. |
| 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) | 28439 | [1,1'-biphenyl]-4-carbonyl chloride | 14002-51-8 | C13H9ClO | 详情 | 详情 |
| (B) | 39152 | C6H12NO2 | 详情 | 详情 | ||
| (VIII) | 11579 | 1,3-Butadiene; Butadiene | 106-99-0 | C4H6 | 详情 | 详情 |
| (IX) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (X) | 39146 | 3-cyclohexene-1-carboxylic acid；Cyclohex-3-ene-1-carboxylic acid | 4771-80-6 | C7H10O2 | 详情 | 详情 |
| (XI) | 39147 | 2,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrimidine | 3001-72-7 | C7H12N2 | 详情 | 详情 |
| (XII) | 11583 | (1R,5R)-6-Oxabicyclo[3.2.1]oct-3-en-7-one | C7H8O2 | 详情 | 详情 | |
| (XIII) | 11584 | methyl (1R,5R)-5-hydroxy-3-cyclohexene-1-carboxylate | C8H12O3 | 详情 | 详情 | |
| (XIV) | 39148 | methyl (1R,5R)-5-[(2-phenylacetyl)oxy]-3-cyclohexene-1-carboxylate | C16H18O4 | 详情 | 详情 | |
| (XV) | 39149 | (1R,5R)-5-(methoxycarbonyl)-2-cyclohexen-1-yl [1,1'-biphenyl]-4-carboxylate | C21H20O4 | 详情 | 详情 | |
| (XVI) | 39150 | (1R,2R,3R,5R)-2,3-dihydroxy-5-(methoxycarbonyl)cyclohexyl [1,1'-biphenyl]-4-carboxylate | C21H22O6 | 详情 | 详情 | |
| (XVII) | 39151 | (1R,3S)-1-formyl-3-(methoxycarbonyl)-5-oxopentyl [1,1'-biphenyl]-4-carboxylate | C21H20O6 | 详情 | 详情 | |
| (XVIII) | 39153 | (1R,4S)-3-formyl-4-(methoxycarbonyl)-2-cyclopenten-1-yl [1,1'-biphenyl]-4-carboxylate | C21H18O5 | 详情 | 详情 | |
| (XIX) | 39154 | C17H30CuO2 | 详情 | 详情 | ||
| (XX) | 39155 | (1R,2R,3R,4S)-2-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-3-formyl-4-(methoxycarbonyl)cyclopentyl [1,1'-biphenyl]-4-carboxylate | C33H42O7 | 详情 | 详情 | |
| (XXI) | 39157 | (1R,2R,3R,4S)-3-(1,3-dioxolan-2-yl)-2-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-4-(methoxycarbonyl)cyclopentyl [1,1'-biphenyl]-4-carboxylate | C35H46O8 | 详情 | 详情 | |
| (C) | 39156 | 2,2-dimethyl-1,3-dioxolane | 2916-31-6 | C5H10O2 | 详情 | 详情 |
合成路线3
The reduction of ethylene ketal (XXI) with LiAlH4 produces the hydroxymethyl compound (XXII), which by selective tosylation with tosyl chloride yields the tosyloxymethyl compound (XXIII). The cyclization of (XXIII) with NaH in DMF affords the epoxy methane derivative (XXIV), which is deprotected by treatment with piruvic acid (D) in THF to give 2-(3-hydroxy-1-octen-1-yl)-3,5-epoxymethanocyclopentane-1-carboxaldehyde (XXV). The selective protection of the hydroxyl group of (XXV) with ethyl vinyl ether (E) affords the 1-ethoxyethoxy compound (XXVI), which is submitted to homologation in the aldehyde group by treatment with methoxymethylene-triphenylphosphorane (F) and butyllithium in THF, followed by hydrolysis of the non-isolated enol ether with mercuric acetate - water to give the acetaldehyde homolog (XXVII). The Wittig reaction of (XXVII) with 4-carboxybutyltriphenylphosphonium chloride (G) and NaH in DMSO yields 9,11-dideoxy-11alpha,9alpha-epoxymethano-15-(1-ethoxyethoxy)-PGE2 (XXVIII), which is finally deprotected by treatment with acetic acid in THF-water.
| 【1】 Trost, B.M.; et al.; An enantioconvergent approach to prostanoids. J Chem Soc Chem Commun 1978, 10, 436-438. |
| 【2】 Castaner, J.; Owen, R.T.; U-46619. Drugs Fut 1980, 5, 9, 453. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (E) | 18762 | 1-Ethoxyethylene; Ethyl vinyl ether；Ethoxyethene | 109-92-2 | C4H8O | 详情 | 详情 |
| (D) | 24066 | 2-oxopropionic acid | 127-17-3 | C3H4O3 | 详情 | 详情 |
| (F) | 39163 | (methoxymethyl)(triphenyl)phosphonium chloride | 4009-98-7 | C20H20ClOP | 详情 | 详情 |
| (G) | 39165 | (3-carboxypropyl)(triphenyl)phosphonium chloride | C22H22ClO2P | 详情 | 详情 | |
| (XXI) | 39157 | (1R,2R,3R,4S)-3-(1,3-dioxolan-2-yl)-2-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-4-(methoxycarbonyl)cyclopentyl [1,1'-biphenyl]-4-carboxylate | C35H46O8 | 详情 | 详情 | |
| (XXII) | 39158 | (1R,2R,3S,4S)-3-(1,3-dioxolan-2-yl)-2-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-4-(hydroxymethyl)cyclopentanol | C21H38O6 | 详情 | 详情 | |
| (XXIII) | 39159 | [(1S,2S,3R,4R)-2-(1,3-dioxolan-2-yl)-3-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-4-hydroxycyclopentyl]methyl 4-methylbenzenesulfonate | C28H44O8S | 详情 | 详情 | |
| (XXIV) | 39160 | (1S,2E)-3-[(1S,4R,5S,6R)-5-(1,3-dioxolan-2-yl)-2-oxabicyclo[2.2.1]hept-6-yl]-1-pentyl-2-propenyl 1-ethoxyethyl ether; (1S,4R,5S,6R)-5-(1,3-dioxolan-2-yl)-6-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-2-oxabicyclo[2.2.1]heptane | C21H36O5 | 详情 | 详情 | |
| (XXV) | 39161 | (1S,4R,5S,6R)-6-[(E,3S)-3-hydroxy-1-octenyl]-2-oxabicyclo[2.2.1]heptane-5-carbaldehyde | C15H24O3 | 详情 | 详情 | |
| (XXVI) | 39162 | (1S,4R,5S,6R)-6-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-2-oxabicyclo[2.2.1]heptane-5-carbaldehyde | C19H32O4 | 详情 | 详情 | |
| (XXVII) | 39164 | 2-[(1S,4R,5S,6S)-6-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-2-oxabicyclo[2.2.1]hept-5-yl]acetaldehyde | C20H34O4 | 详情 | 详情 | |
| (XXVIII) | 39166 | (Z)-7-[(1S,4R,5S,6S)-6-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-2-oxabicyclo[2.2.1]hept-5-yl]-5-heptenoic acid | C25H42O5 | 详情 | 详情 |