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【结 构 式】 
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【分子编号】13746 【品名】3-(Trifluoromethyl)benzoyl chloride 【CA登记号】2251-65-2 |
【 分 子 式 】C8H4ClF3O 【 分 子 量 】208.5670696 【元素组成】C 46.07% H 1.93% Cl 17% F 27.33% O 7.67% |
合成路线1
该中间体在本合成路线中的序号：(XXIII)2) The methylenation of the disilylated 5,6-didehydroprostaglandin E2 (XVIII) with Zn/CH2Br2/TiCl4 as before gives the methylene derivative (XIX), which is converted into the hydroxymethyl derivative (XX) with 9-BBN also as before. The oxidation of (XX) with CrO3/Pyr in dichloromethane yields the corresponding aldehyde (XXI), which is treated with [Ph(Me)2Si]2CuCNLi2 [(PDMS)2CuCNLi2] affording the trisilylated compound (XXII). The esterification of the hydroxy group of (XXII) with 3-(trifluoromethyl)benzoyl chloride (XXIII) by means of DMAP in acetonitrile gives the benzoate (XXIV), which is cyclized by means of N-methylcarbazol (NMC) and magnesium perchlorate in THF/water and irradiation with a 500 W UV-lamp giving the bicyclo[3.3.0]octan-3-ylidene derivative (XXV). The selective desilylation of (XXV) with HClO4 in ether/methanol gives the dihydroxycarbacyclin (XXVI), which is finally desilylated and simultaneously isomerized by a treatment with trifluoroacetic acid in dichloromethane affording the expected clinprost. 3) The cyclization of (XXII) to (XXV) can also be performed by treatment of (XXII) with CS2, CH3I and lithium diisopropylamide in THF to give (XXVII), which is then cyclized to (XXV) by means of Bu3SnH and di-tert-butyl peroxide in hot benzene.
| 【1】 Graul, A.; Leeson, P.; Castaner, J.; Clinprost. Drugs Fut 1997, 22, 6, 608. |
| 【2】 Suzuki, M.; Koyano, H.; Noyori, R.; A controlled synthesis of isocarbacyclin. J Org Chem 1987, 52, 25, 5583-8. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 13741 | methyl 7-[(1R,2R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-5-oxocyclopentyl]-5-heptynoate | C33H60O5Si2 | 详情 | 详情 | |
| (XIX) | 13742 | methyl 7-[(1R,2R,3R)-3-[[tert-utyl(dimethyl)silyl]oxy]-2-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-5-methylenecyclopentyl]-5-heptynoate | C34H62O4Si2 | 详情 | 详情 | |
| (XX) | 13743 | methyl 7-[(1S,2S,3R,5S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-5-(hydroxymethyl)cyclopentyl]-5-heptynoate | C34H64O5Si2 | 详情 | 详情 | |
| (XXI) | 13744 | methyl 7-[(1R,2R,3R,5S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-5-formylcyclopentyl]-5-heptynoate | C34H62O5Si2 | 详情 | 详情 | |
| (XXII) | 13745 | methyl 7-[(1R,2R,3R,5S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-5-[(R)-[dimethyl(phenyl)silyl](hydroxy)methyl]cyclopentyl]-5-heptynoate | C42H74O5Si3 | 详情 | 详情 | |
| (XXIII) | 13746 | 3-(Trifluoromethyl)benzoyl chloride | 2251-65-2 | C8H4ClF3O | 详情 | 详情 |
| (XXIV) | 13747 | (R)-[(1S,2R,3R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-2-(7-methoxy-7-oxo-2-heptynyl)cyclopentyl][dimethyl(phenyl)silyl]methyl 3-(trifluoromethyl)benzoate | C50H77F3O6Si3 | 详情 | 详情 | |
| (XXV) | 13748 | methyl 5-[(1R,3aR,4R,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-1-[dimethyl(phenyl)silyl]hexahydro-2(1H)-pentalenylidene]pentanoate | C42H74O4Si3 | 详情 | 详情 | |
| (XXVI) | 13749 | methyl 5-[(1R,3aR,4R,5R,6aS)-1-[dimethyl(phenyl)silyl]-5-hydroxy-4-[(E,3S)-3-hydroxy-1-octenyl]hexahydro-2(1H)-pentalenylidene]pentanoate | C30H46O4Si | 详情 | 详情 | |
| (XXVII) | 13750 | methyl 7-[(1R,2R,3R,5S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)-5-((R)-[dimethyl(phenyl)silyl][[(methylsulfanyl)carbothioyl]oxy]methyl)cyclopentyl]-5-heptynoate | C44H76O5S2Si3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：The O-silylated 4-hydroxy-delta-caprolactam (XXXIV) was reduced with borane and the resulting piperidine was protected as the N-Boc derivative (XXXV). Lithiation employing sec-butyllithium and TMEDA, followed by addition of aldehyde (XXXIII) produ-ced an inseparable 3:1 mixture of the alcohol epimers (XXXVIIa-b) and the trans-oxazolidinone (XXXVI). Acylation of the mixture with m-(trifluoromethyl)benzoyl chloride afforded a diastereomeric mixture of (trifluoromethyl)benzoates (XXXVIIIa-b), separable by column chromatography. Deprotection of the Boc group from the syn-isomer of (XXXVIII) by means of trimethylsilyl triflate and lutidine gave the free amine (XXXIX). Subsequent cyclization of (XXXIX) with AgNO3 afforded the desired cis-quinolizidine (XL) with very high diastereoselectivity. Reductive cleavage of the (trifluoromethyl)benzoyl group of (XL), followed by treatment of the free alcohol with methanesulfonyl chloride provided mesylate (XLI).
| 【1】 Ha, J.D.; Cha, J.K.; Total synthesis of clavepictines A and B. Diastereoselective cyclization of delta-aminoallenes. J Am Chem Soc 1999, 121, 43, 10012. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 13746 | 3-(Trifluoromethyl)benzoyl chloride | 2251-65-2 | C8H4ClF3O | 详情 | 详情 | |
| (XXXVIIa) | 40267 | tert-butyl (2S,3R,6R)-6-[(1S,7S)-1-hydroxy-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C43H85NO5Si2 | 详情 | 详情 | |
| (XXXVIIb) | 40268 | tert-butyl (2S,3R,6R)-6-[(1R,7S)-1-hydroxy-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienyl]-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C43H85NO5Si2 | 详情 | 详情 | |
| (XXXVIIIa) | 40269 | tert-butyl (2S,3R,6R)-2-methyl-6-[(1S,7S)-1-[[3-(trifluoromethyl)benzoyl]oxy]-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienyl]-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C51H88F3NO6Si2 | 详情 | 详情 | |
| (XXXVIIb) | 40270 | tert-butyl (2S,3R,6R)-2-methyl-6-[(1R,7S)-1-[[3-(trifluoromethyl)benzoyl]oxy]-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienyl]-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C51H88F3NO6Si2 | 详情 | 详情 | |
| (XXXIII) | 40265 | (7S)-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienal | C23H44O2Si | 详情 | 详情 | |
| (XXXIV) | 40278 | (5R,6S)-6-methyl-5-[(triisopropylsilyl)oxy]-2-piperidinone | C15H31NO2Si | 详情 | 详情 | |
| (XXXV) | 40279 | tert-butyl (2S,3R)-2-methyl-3-[(triisopropylsilyl)oxy]-1-piperidinecarboxylate | C20H41NO3Si | 详情 | 详情 | |
| (XXXVI) | 40266 | (1R,5S,6R,8aR)-5-methyl-6-[(triisopropylsilyl)oxy]-1-[(6S)-6-[(triisopropylsilyl)oxy]-3,4-tridecadienyl]hexahydro[1,3]oxazolo[3,4-a]pyridin-3-one | C39H75NO4Si2 | 详情 | 详情 | |
| (XXXIX) | 40271 | (1R,7S)-1-[(2R,5R,6S)-6-methyl-5-[(triisopropylsilyl)oxy]piperidinyl]-7-[(triisopropylsilyl)oxy]-4,5-tetradecadienyl 3-(trifluoromethyl)benzoate | C46H80F3NO4Si2 | 详情 | 详情 | |
| (XL) | 40272 | (1R,4S,6S,7R,9aR)-6-methyl-7-[(triisopropylsilyl)oxy]-4-[(E,3S)-3-[(triisopropylsilyl)oxy]-1-decenyl]octahydro-2H-quinolizin-1-yl 3-(trifluoromethyl)benzoate | C46H80F3NO4Si2 | 详情 | 详情 | |
| (XLI) | 40273 | (1R,4S,6S,7R,9aR)-6-methyl-7-[(triisopropylsilyl)oxy]-4-[(E,3S)-3-[(triisopropylsilyl)oxy]-1-decenyl]octahydro-2H-quinolizin-1-yl methanesulfonate | C39H79NO5SSi2 | 详情 | 详情 |