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【结 构 式】 
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【分子编号】24201 【品名】dimethyl 3-methyl-2-oxo-5-octynylphosphonate 【CA登记号】 |
【 分 子 式 】C11H19O4P 【 分 子 量 】246.243222 【元素组成】C 53.65% H 7.78% O 25.99% P 12.58% |
合成路线1
该中间体在本合成路线中的序号：(II)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2
该中间体在本合成路线中的序号：(II)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 |