Benzoic acid (1'R,2'R,3'aR,6'aS)-1'-formylspiro[1,3-dioxolane-2,5'-perhydropentalen]-2'-yl ester -Drug Synthesis Database

【结构式】

【分子编号】24200

【品名】Benzoic acid (1'R,2'R,3'aR,6'aS)-1'-formylspiro[1,3-dioxolane-2,5'-perhydropentalen]-2'-yl ester

【CA登记号】

【分子式】C₁₈H₂₀O₅

【分子量】316.3538

【元素组成】C 68.34% H 6.37% O 25.29%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

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.

参考文献中间体

合成目标

【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：(I)

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.

参考文献中间体

合成目标

【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

Extended Information