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【结 构 式】 
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【药物名称】Cicaprost, ZK-96480 【化学名称】[2-[(2E,3aS,4S,5R,6aS)-Octahydro-5-hydroxy-4-[(3S,4S)-3-hydroxy-4-methyl-1,6-nonadiinyl]-2-pentalenylidene]ethoxy]acetic acid 【CA登记号】95722-07-9 【 分 子 式 】C22H30O5 【 分 子 量 】374.4814 |
【开发单位】Schering AG (Originator) 【药理作用】Antiplatelet Therapy, CARDIOVASCULAR DRUGS, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Hypertension, Treatment of, Oncolytic Drugs, Prostaglandins |
合成路线1
The Wittig condensation of protected bicyclic aldehyde (I) with methyl triphenyl phosphonium bromide and potassium tert-butoxide in THF gives the diene (II), which by hydroboration with disiamyl borane followed by oxidative hydrolysis with NaOH and H2O2 is converted into the alcohol (III). Oxidation of (III) with Collins' reagent followed by treatment with acetic anhydride yields the dienol acetate (IV), which is submitted to a 1,4-catalytic hydrogenation with naphthalene Cr(CO)3-H2 in THF and hydrolysis with K2CO3 to afford the allyl alcohol (V). The condensation of (V) with tert-butyl bromoacetate (VI) by means of tetrabutylammonium bisulfate, followed by partial deprotection with tetrabutylammonium fluoride gives the alcohol (VII), which is oxidized with the SO3-pyridine complex to the aldehyde (VIII). The condensation of (VIII) with 1,1-dibromo-3-methyl-5-octyn-2-one (IX) by means of Zn, diethylaluminum chloride and CuBr in THF yields the B-bromoenone (X), which is reduced stereoselectively with (S)-(-)-2,2'-dihydroxy-1,1'-binaphthyl and LiAlH4 in THF to afford the a bromodienol (XI). Finally, this compound is dehydrominated and saponified with tetrabutylammonium bisulfate and NaOH in ether toluene-water.
| 【1】 Gillum, A.M.; Klem, R.E.; Klasa, R.J.; Frankel, S.R.; Oblimersen Bcl-2 antisense: facilitating apoptosis in anticancer treatment. J Org Chem 1988, 53, 6, 1227. |
| 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) | 13776 | (3aS,5R,6R,6aS)-6-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenecarbaldehyde | C22H38O4Si | 详情 | 详情 | |
| (II) | 23382 | [(2R,3R,3aS,6aS)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-vinyl-1,2,3,3a,4,6a-hexahydro-2-pentalenyl]methyl tetrahydro-2H-pyran-2-yl ether; ([(1R,2R,3aS,6aS)-2-[(tetrahydro-2H-pyran-2-yloxy)methyl]-5-vinyl-1,2,3,3a,6,6a-hexahydro-1-pentalenyl]methoxy)(tert-butyl)dimethylsilane | C23H40O3Si | 详情 | 详情 | |
| (III) | 23383 | 2-[(3aS,5R,6R,6aS)-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]-1-ethanol | C23H42O4Si | 详情 | 详情 | |
| (IV) | 23384 | (E)-2-[(3aS,5R,6R,6aS)-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]ethenyl acetate | C25H42O5Si | 详情 | 详情 | |
| (V) | 23385 | 2-[(3aS,4R,5R,6aR)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]-1-ethanol | C23H42O4Si | 详情 | 详情 | |
| (VI) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (VII) | 23387 | tert-butyl 2-[2-[(3aS,4R,5R,6aR)-4-(hydroxymethyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]ethoxy]acetate | C23H38O6 | 详情 | 详情 | |
| (VIII) | 23388 | tert-butyl 2-[2-[(3aS,4R,5R,6aR)-4-formyl-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]ethoxy]acetate | C23H36O6 | 详情 | 详情 | |
| (IX) | 23389 | tert-butyl 2-[2-[(3aS,4R,5R,6aR)-4-[(Z,4S)-2-bromo-4-methyl-3-oxo-1-nonen-6-ynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]ethoxy]acetate | C32H47BrO6 | 详情 | 详情 | |
| (X) | 23390 | tert-butyl 2-[2-[(3aS,4R,5R,6aR)-4-[(Z,4S)-2-bromo-4-methyl-3-oxo-1-nonen-6-ynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]ethoxy]acetate | C32H47BrO6 | 详情 | 详情 | |
| (XI) | 23391 | tert-butyl 2-[2-[(3aS,4S,5R,6aS)-4-[(Z,3S,4S)-2-bromo-3-hydroxy-4-methyl-1-nonen-6-ynyl]-5-hydroxyhexahydro-2(1H)-pentalenylidene]ethoxy]acetate | C26H39BrO5 | 详情 | 详情 |
合成路线2
1) The Wittig condensation of dimetbyl 3 methyl-2-oxooct-5-inphosphonate (II) with (1R,5S,6R,7R)-3,3-ethylenedioxy 7-benzoyloxy-6-formylbicyclo[3.3.0]octane by means of NaH in dimethoxy ethane, followed by a bromination with N-bromosuccinimide (NBS), gives the brominated condensation product (III), which is reduced with NaBH4 in methanol, debenzoylated with K2CO3 in methanol and protected with dihydropyran and p-toluenesulfonic acid yielding the protected diol (IV). Dehydrobromination of (IV) with potassium tert-butoxide in DMSO THF, followed by hydrolysis with acetic acid, affords the diacetylenic ketone (V), which is submitted to a Wittig condensation with triethyl phosphonoacetate (VI) usino potassium ten butoxide as base, and to a reduction with LiAlH4 in ether yielding the pentalenylideneethanol (VII). The condensation of (VII) with bromoacetic acid (VIII), by means of NaH in THF affords the protected prostaglandin (IX), which is finally deprotected with aceto acid water THF.
| 【1】 Haberey, M.; Raduchel, B.; Schillinger, E.; Skuballa, W.; Sturzebecher, C.-S.; Town, M.H.; Vorbruggen, H. (Schering AG); Novel carbacyclins, processes for their preparation and their use as medicinal agents. EP 0119949; US 5013758 . |
| 【2】 Castaner, J.; Prous, J.; Cicaprost. Drugs Fut 1986, 11, 11, 913. |
| 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) | 24200 | Benzoic acid (1'R,2'R,3'aR,6'aS)-1'-formylspiro[1,3-dioxolane-2,5'-perhydropentalen]-2'-yl ester | C18H20O5 | 详情 | 详情 | |
| (II) | 24201 | dimethyl 3-methyl-2-oxo-5-octynylphosphonate | C11H19O4P | 详情 | 详情 | |
| (III) | 24202 | Benzoic acid (2'R,3'aR,6'aS)-1'-(2-Bromo-4(S)-methyl-3-oxonon-1(E)-en-6-yn-1-yl)-spiro[1,3-dioxolane-2,5'-perhydropentalen]-2'-yl ester | C27H31BrO5 | 详情 | 详情 | |
| (IV) | 24203 | 2-Bromo-4(S)-methyl-1-[(2'(R),3'a(R),6'a(S))-2'-(tetrahydropyranyloxy)spiro[1,3-dioxolane-2,5'-perhydropentalen]-1-yl]non-1(E)-en-6-yn-3-one | C21H29BrO3 | 详情 | 详情 | |
| (V) | 24204 | (3aS,5R,6aR)-4-[(3S,4S)-4-methyl-3-(tetrahydro-2H-pyran-2-yloxy)-1,6-nonadiynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenone | C29H42O5 | 详情 | 详情 | |
| (VI) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (VII) | 24206 | 2-[(3aS,4R,5R,6aR)-4-[(3S,4S)-4-methyl-3-(tetrahydro-2H-pyran-2-yloxy)-1,6-nonadiynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]-1-ethanol | C31H46O5 | 详情 | 详情 | |
| (VIII) | 23666 | (2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-[((2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propanoyl)oxy]butyric acid | C27H32N2O8 | 详情 | 详情 | |
| (IX) | 24208 | 2-[2-[(3aS,4R,5R,6aR)-4-[(3S,4S)-4-methyl-3-(tetrahydro-2H-pyran-2-yloxy)-1,6-nonadiynyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2(1H)-pentalenylidene]ethoxy]acetic acid | C33H48O7 | 详情 | 详情 |
合成路线3
2) The reduction of (III) with NaBH4 followed by debenzoylation with NaOH and deprotection with acetic acid gives the dihydroxy ketone (X), which by silviation with dimethyl-tert-butylsilyl chloride in DMF is converted to the disilylated ketone (XI). A Horner Wittig reaction of ketone (XI) with phosphonate (VI), followed by reduction with LiAlH4 as before affords the pentalenylideneethanol (XII), which is etherified with ten butyl bromoacetate (XIII) in aqueous NaOH - toluene and tetrabutylammonium sulfate with simultaneous hydrolysis of the tert-butyl group yielding the silylated prostaglandin (XIV). Finally, this compound is deprotected with tetrabutylammonium fluoride in THF.
| 【1】 Skuballa, W.; et al.; Synthesis of a new chemically and metabolically stable prostacyclin analogue with high and long-lasting oral activity. J Med Chem 1986, 29, 3, 313. |
| 【2】 Castaner, J.; Prous, J.; Cicaprost. Drugs Fut 1986, 11, 11, 913. |
| 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) | 24200 | Benzoic acid (1'R,2'R,3'aR,6'aS)-1'-formylspiro[1,3-dioxolane-2,5'-perhydropentalen]-2'-yl ester | C18H20O5 | 详情 | 详情 | |
| (II) | 24201 | dimethyl 3-methyl-2-oxo-5-octynylphosphonate | C11H19O4P | 详情 | 详情 | |
| (III) | 24202 | Benzoic acid (2'R,3'aR,6'aS)-1'-(2-Bromo-4(S)-methyl-3-oxonon-1(E)-en-6-yn-1-yl)-spiro[1,3-dioxolane-2,5'-perhydropentalen]-2'-yl ester | C27H31BrO5 | 详情 | 详情 | |
| (VI) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (X) | 24212 | (3aS,5R,6aR)-5-hydroxy-4-[(3S,4S)-3-hydroxy-4-methyl-1,6-nonadiynyl]hexahydro-2(1H)-pentalenone | C18H24O3 | 详情 | 详情 | |
| (XI) | 24213 | (3aS,5R,6aR)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-((3S,4S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-1,6-nonadiynyl)hexahydro-2(1H)-pentalenone | C30H52O3Si2 | 详情 | 详情 | |
| (XII) | 24215 | 2-[(3aS,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-((3S,4S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-1,6-nonadiynyl)hexahydro-2(1H)-pentalenylidene]-1-ethanol | C32H56O3Si2 | 详情 | 详情 | |
| (XIII) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (XIV) | 24216 | 2-[2-[(3aS,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-((3S,4S)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-1,6-nonadiynyl)hexahydro-2(1H)-pentalenylidene]ethoxy]acetic acid | C34H58O5Si2 | 详情 | 详情 |