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【结 构 式】 
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【分子编号】10493 【品名】2-(Benzyloxy)acetyl chloride; Benzyloxyacetyl chloride 【CA登记号】19810-31-2 |
【 分 子 式 】C9H9ClO2 【 分 子 量 】184.62196 【元素组成】C 58.55% H 4.91% Cl 19.2% O 17.33% |
合成路线1
该中间体在本合成路线中的序号：(II)A new partial synthesis of taxol has been described: The esterification of (1S,2R)-2-phenylcyclohexanol (I) with benzyloxyacetyl chloride (II) gives the corresponding chiral ester (III), which is deprotected by hydrogenolysis to the hydroxy ester (IV). Silylation of (IV) with triisopropylsilyl chloride affords the silylated ester (V), which is cyclized with trimethylsilylbenzaldimine (VI) [obtained from benzaldehyde (VII) and hexamethyldisilazane (HMSA)] by means of butyllithium in THF giving (3R,4S)-3-(triisopropylsilyloxy)-4-phenylazetidin-2-one (VIII). The deprotection of (VIII) with tetrabutylammonium fluoride affords (3R,4S)-3-hydroxy-4-phenylazetidin-2-one (IX), which is treated with ethyl vinyl ether to give the 1-ethoxyethyl ether (X). The benzoylation of (X) with benzoyl chloride (XI) by means of dimethylaminopyridine and triethylamine yields (3R,4S)-1-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one (XII), which is condensed with 7-O-(triethylsilyl)baccatin III (XIII) by means of NaH in THF, affording 2'-O-(1-ethoxyethyl)-7-O-(triethylsilyl)taxol (XIV). Finally, this compound is deprotected with HCl in ethanol.
| 【1】 Habus, I.; Zhao, M.; Brigaud, T.; Zucco, M.; Ojima, I.; Sun, C.M.; Park, Y.H.; New and efficient approaches to the semisynthesis of taxol and its C-13 side chain analogs by means of beta-lactam synthon method. Tetrahedron 1992, 48, 34, 6985. |
| 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) | 10492 | (1S,2R)-(+)-trans-2-Phenyl-1-cyclohexanol; (1S,2R)-2-Phenylcyclohexanol | 2362-61-0 | C12H16O | 详情 | 详情 |
| (II) | 10493 | 2-(Benzyloxy)acetyl chloride; Benzyloxyacetyl chloride | 19810-31-2 | C9H9ClO2 | 详情 | 详情 |
| (III) | 10494 | (1S,2R)-2-phenylcyclohexyl 2-(benzyloxy)acetate | C21H24O3 | 详情 | 详情 | |
| (IV) | 10495 | (1S,2R)-2-phenylcyclohexyl 2-hydroxyacetate | C14H18O3 | 详情 | 详情 | |
| (V) | 10496 | (1S,2R)-2-phenylcyclohexyl 2-(triisopropylsilyl)acetate | C23H38O2Si | 详情 | 详情 | |
| (VI) | 10507 | Trimethyl-N-[(E)-benzylidene]silanamine; N-[(E)-Benzylidene]-N-(trimethylsilyl)amine | 17599-61-0 | C10H15NSi | 详情 | 详情 |
| (VII) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (VIII) | 10499 | (3R,4S)-4-Phenyl-3-[(triisopropylsilyl)oxy]-2-azetanone | C18H29NO2Si | 详情 | 详情 | |
| (IX) | 10459 | (3R,4S)-3-Hydroxy-4-phenyl-2-azetanone | C9H9NO2 | 详情 | 详情 | |
| (X) | 10462 | (3R,4S)-3-(1-Ethoxyethoxy)-4-phenyl-2-azetanone | C13H17NO3 | 详情 | 详情 | |
| (XI) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (XII) | 10464 | (3R,4S)-1-Benzoyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetanone | C20H21NO4 | 详情 | 详情 | |
| (XIII) | 10473 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C37H52O11Si | 详情 | 详情 | |
| (XIV) | 10505 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-(1-ethoxyethoxy)-3-phenylpropanoyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C57H73NO15Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVI)The Curtius degradation of carboxylic acid (XIV) with Ph2PON3 and 2-(trimethylsilyl)ethanol (A) gives the carbamate (XV), which is acylated with 2-(benzyloxy)acetyl chloride (XVI) and LiHMDS in THF, yielding the imide (XVII). The condensation of (XVII) with aldehyde (XVIII) by means of TiCl4 and DIEA in dichloromethane affords the expected adduct (XIX), which is oxidized with TFAA and DMSO in dichloromethane/DIEA, providing the beta-ketoimide (XX) as a diastereomeric mixture at the benzyloxy group. The cyclization of (XX) by means of CSA in methanol, followed by separation of the diastereomeric mixture, furnished the hydroxy tetrahydropyran derivative (XXI), which is submitted to a Swern oxidation to give the trahydropyranone (XXII). The reaction of (XXII) with diiodomethane, TiCl4 and Zn yields the exo-methylene compound (XXIII), which is desilylated with TBAF in DMF to afford intermediate (XXIV). Finally, this compound is submitted to a reductive cleavage of the benzyloxy and cyclic carbonate groups with Na/NH3 in THF/ethyl ether to furnish the target compound.
| 【1】 Roush, W.R.; Pfeifer, L.A.; Total synthesis of mycalamide A and 7-epi-mycalamide A. Org Lett 2000, 2, 6, 859. |
| 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) | 20323 | 2-(trimethylsilyl)-1-ethanol | 2916-68-9 | C5H14OSi | 详情 | 详情 |
| (XIV) | 43443 | (4S,4aR,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxine-4-carboxylic acid | C15H22O9 | 详情 | 详情 | |
| (XV) | 43444 | 2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-ylcarbamate | C20H35NO9Si | 详情 | 详情 | |
| (XVI) | 10493 | 2-(Benzyloxy)acetyl chloride; Benzyloxyacetyl chloride | 19810-31-2 | C9H9ClO2 | 详情 | 详情 |
| (XVII) | 43445 | 2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl[2-(benzyloxy)acetyl]carbamate | C29H43NO11Si | 详情 | 详情 | |
| (XVIII) | 43446 | (3R,4S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methylhexanal | C19H42O3Si2 | 详情 | 详情 | |
| (XIX) | 43447 | 2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl((2R,5R,6S,7R)-2-(benzyloxy)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-6-methyloctanoyl)carbamate | C48H85NO14Si3 | 详情 | 详情 | |
| (XX) | 43448 | 2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl((5R,6S,7R)-2-(benzyloxy)-5,7-bis[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-3-oxooctanoyl)carbamate | C48H83NO14Si3 | 详情 | 详情 | |
| (XXI) | 43449 | 2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl[(2S)-2-(benzyloxy)-2-[(2R,4R,5R,6R)-4-hydroxy-2-methoxy-5,6-dimethyltetrahydro-2H-pyran-2-yl]ethanoyl]ca | C37H57NO14Si | 详情 | 详情 | |
| (XXII) | 43450 | 2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl[(2S)-2-(benzyloxy)-2-[(2R,5S,6R)-2-methoxy-5,6-dimethyl-4-oxotetrahydro-2H-pyran-2-yl]ethanoyl]carbamate | C37H55NO14Si | 详情 | 详情 | |
| (XXIII) | 43451 | 2-(trimethylsilyl)ethyl (4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl[(2S)-2-(benzyloxy)-2-[(2R,5R,6R)-2-methoxy-5,6-dimethyl-4-methylenetetrahydro-2H-pyran-2-yl]ethanoyl]car | C38H57NO13Si | 详情 | 详情 | |
| (XXIV) | 43452 | (2S)-N-((4S,4aS,6R,8S,8aR)-8-methoxy-7,7-dimethyl-6-[[(4S)-2-oxo-1,3-dioxolan-4-yl]methyl]hexahydropyrano[3,2-d][1,3]dioxin-4-yl)-2-(benzyloxy)-2-[(2R,5R,6R)-2-methoxy-5,6-dimethyl-4-methylenetetrahydro-2H-pyran-2-yl]ethanamide | C32H45NO11 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXIX)Synthesis of 250157: Alternatively, the final compound can be obtained by direct condensation of (VI) with chlorotriazolinone (XXVI) in DMF/H2O in the presence of K2CO3 or DIEA. For the obtention of (XXVI), two routes can be followed: 1. Reaction of semicarbazide (XXVII) with orthoester (XXVIII) in MeOH; and 2. Condensation of semicarbazide (XXVII) with benzyloxyacetyl chloride (XXIX) in THF/H2O in the presence of NaOH to provide adduct (XXX), which is then cyclized by means of refluxing NaOH to afford triazolinone (XXXI). Debenzylation of (XXXI) by hydrogenation over Pd/C in MeOH/H2O yields alcohol (XXXII), which is finally treated with thionyl chloride.
| 【1】 Castaner, J.; Silvestre, J.S.; Bayes, M.; Sorbera, L.A.; Aprepitant and L-758298. Drugs Fut 2002, 27, 3, 211. |
| 【2】 Cowden, C.J.; et al.; A new synthesis of 1,2,4-triazolin-5-ones: Application to the convergent synthesis of an NK1 antagonist. Tetrahedron Lett 2000, 41, 44, 8661. |
| 【3】 Cowden, C.J. (Merck Sharp & Dohme Ltd.); Process for the preparation of 1,2,4-triazolin-5-one derivs.. WO 0196315 . |
| 【4】 Dolling, U.H.; Wilson, R.D.; Hands, D.; Cottrell, I.F. (Merck Sharp & Dohme Ltd.); Chemical synthesis of morpholine derivs.. WO 9965900 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 18293 | (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl (2R,3S)-3-(4-fluorophenyl)morpholinyl ether; (2R,3S)-2-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholine | 171482-05-6 | C20H18F7NO2 | 详情 | 详情 |
| (XXVI) | 44196 | 5-(chloromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one | C3H4ClN3O | 详情 | 详情 | |
| (XXVII) | 23944 | 1-Hydrazinecarboxamide | 563-41-7 | CH5N3O | 详情 | 详情 |
| (XXVIII) | 44197 | 2-chloro-1,1-dimethoxyethyl methyl ether; 2-chloro-1,1,1-trimethoxyethane | C5H11ClO3 | 详情 | 详情 | |
| (XXIX) | 10493 | 2-(Benzyloxy)acetyl chloride; Benzyloxyacetyl chloride | 19810-31-2 | C9H9ClO2 | 详情 | 详情 |
| (XXX) | 44193 | 2-[2-(benzyloxy)acetyl]-1-hydrazinecarboxamide | C10H13N3O3 | 详情 | 详情 | |
| (XXXI) | 44194 | 5-[(benzyloxy)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C10H11N3O2 | 详情 | 详情 | |
| (XXXII) | 44195 | 5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one | C3H5N3O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Reaction of benzyloxyacetyl chloride (I) with (-)-trans-2-phenylcyclohexanol (II) afforded chiral ester (III). Subsequent removal of the benzyl group by hydrogenolysis, followed by protection with triisopropylsilyl chloride and imidazole in DMF provided silyl ether (IV). Treatment of (IV) with LDA in THF at -85 C generated the corresponding enolate, which was cyclocondensed with imine (VII), (obtained from 3-methylbutenal (V) and p-anisidine (VI)), to produce azetidinone (VIII). Then, the N-p-methoxyphenyl group was removed by treatment with cerium ammonium nitrate in cold ACN-H2O, and the resulting azetidinone (IX) was coupled with di-tert-butyl dicarbonate in the presence of DMAP and Et3N to yield (X).
| 【1】 Ojima, I.; et al.; Syntheses and structure-activity relationships of taxoids derived from 14beta-hydroxy-10-deacetylbaccatin III. J Med Chem 1997, 40, 3, 267. |
| 【2】 Takahashi, N.; et al.; Growth inhibition of gastric cancer cells by troglitazone, a ligand for peroxisome proliferator-activated receptor. Dig Dis Week (May 16 1999, Orlando) 1999, Abst 3684. |
| 【3】 Ojima, I.; Bombardelli, E. (Affymax Technologies, NV; State University of New York, Albany); Anti-tumor cpds., pharmaceutical compsns., methods for preparation thereof and for treatment. US 5705508 . |
| 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) | 10493 | 2-(Benzyloxy)acetyl chloride; Benzyloxyacetyl chloride | 19810-31-2 | C9H9ClO2 | 详情 | 详情 |
| (II) | 10492 | (1S,2R)-(+)-trans-2-Phenyl-1-cyclohexanol; (1S,2R)-2-Phenylcyclohexanol | 2362-61-0 | C12H16O | 详情 | 详情 |
| (III) | 10494 | (1S,2R)-2-phenylcyclohexyl 2-(benzyloxy)acetate | C21H24O3 | 详情 | 详情 | |
| (IV) | 19151 | (1R,2S)-2-phenylcyclohexyl 2-[(triisopropylsilyl)oxy]acetate | C23H38O3Si | 详情 | 详情 | |
| (V) | 19152 | 3-methyl-2-butenal | 107-86-8 | C5H8O | 详情 | 详情 |
| (VI) | 10478 | p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine | 104-94-9 | C7H9NO | 详情 | 详情 |
| (VII) | 19154 | 4-methoxy-N-[(E)-3-methyl-2-butenylidene]aniline; N-(4-methoxyphenyl)-N-[(E)-3-methyl-2-butenylidene]amine | C12H15NO | 详情 | 详情 | |
| (VIII) | 19155 | (3R,4S)-1-(4-methoxyphenyl)-4-(2-methyl-1-propenyl)-3-[(triisopropylsilyl)oxy]-2-azetidinone | C23H37NO3Si | 详情 | 详情 | |
| (IX) | 19156 | (3R,4S)-4-(2-methyl-1-propenyl)-3-[(triisopropylsilyl)oxy]-2-azetidinone | C16H31NO2Si | 详情 | 详情 | |
| (X) | 19157 | tert-butyl (2S,3R)-2-(2-methyl-1-propenyl)-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate | C21H39NO4Si | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)Deprotection of the benzyloxycarbonyl piperazine (I) by catalytic hydrogenolysis provided the secondary amine (II), which was then acylated by benzyloxyacetyl chloride (III) to afford amide (IV). After activation of the hydroxyl group of (IV) as the sulfonate (VI) by treatment with 3-nitrobenzenesulfonyl chloride (V), its displacement with ammonium hydroxide provided the amine (VII). The O-benzyl group of (VII) was then removed by hydrogenolysis, yielding alcohol (VIII). Finally, acylation of the primary amino group of (VIII) with ethyl dithioacetate (IX) in the presence of KOH and NaF gave rise to the title thioacetamide.
| 【1】 Hester, J.B. Jr.; Perricone, S.C.; Nidy, E.G.; Poel, T.-J. (Pharmacia Corp.); Oxazolidinone antibacterial agents having a thiocarbonyl functionality. EP 0984947; JP 2002501530; US 6218413; WO 9854161 . |
| 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) | 18386 | benzyl 4-[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]-1-piperazinecarboxylate | C22H24FN3O5 | 详情 | 详情 | |
| (II) | 55847 | (5R)-3-[3-fluoro-4-(1-piperazinyl)phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one | C14H18FN3O3 | 详情 | 详情 | |
| (III) | 10493 | 2-(Benzyloxy)acetyl chloride; Benzyloxyacetyl chloride | 19810-31-2 | C9H9ClO2 | 详情 | 详情 |
| (IV) | 55848 | (5R)-3-(4-{4-[2-(benzyloxy)acetyl]-1-piperazinyl}-3-fluorophenyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one | C23H26FN3O5 | 详情 | 详情 | |
| (V) | 41948 | 3-nitrobenzenesulfonyl chloride | 121-51-7 | C6H4ClNO4S | 详情 | 详情 |
| (VI) | 55849 | [(5R)-3-(4-{4-[2-(benzyloxy)acetyl]-1-piperazinyl}-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl 3-nitrobenzenesulfonate | C29H29FN4O9S | 详情 | 详情 | |
| (VII) | 55850 | (5S)-5-(aminomethyl)-3-(4-{4-[2-(benzyloxy)acetyl]-1-piperazinyl}-3-fluorophenyl)-1,3-oxazolidin-2-one | C23H27FN4O4 | 详情 | 详情 | |
| (VIII) | 17828 | (5S)-5-(aminomethyl)-3-[3-fluoro-4-(4-glycoloyl-1-piperazinyl)phenyl]-1,3-oxazolidin-2-one | C16H21FN4O4 | 详情 | 详情 | |
| (IX) | 55851 | Ethyl dithioacetate | C4H8S2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XIII)4-Hydroxypiperidine (I) was protected as the N-Boc derivative (II), which was then condensed with 1,2-difluoro-4-nitrobenzene (III) in the presence of potassium tert-butoxide, yielding ether (IV). Reduction of the nitro group of (IV) by transfer hydrogenation, followed by treatment of the resulting aniline (V) with benzyl chloroformate, afforded carbamate (VI). After deprotonation of the carbamate group of (VI) with n-butyllithium, reaction with (R)-glycidyl butyrate (VII) generated the chiral oxazolidinone (VIII). Conversion of (VIII) to mesylate (IX) and subsequent displacement with NaN3 provided azide (X). This was reduced to the corresponding amine, which was acetylated with Ac2O to furnish amide (XI). Cleavage of the Boc protecting group of (XI) with trifluoroacetic acid gave piperidine (XII). This was finally acylated with benzyloxyacetyl chloride (XIII) to provide the title amide.
| 【2】 Boggs, C.M.; et al.; Novel piperidinyloxy-oxazolidinone antimicrobial agents: Effects of position, fluorine substitution, and ring-size on in vitro antimicrobial activity. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 98. |
| 【3】 Boggs, C.; Nelson, E.; Weidner-Wells, M.; Hlasta, D. (Ortho-McNeil Pharmaceutical, Inc.); Piperidinyloxy and pyrrolidinyloxyphenyl oxazolidinones as antibacterials. WO 0146164 . |
| 【1】 Hilliard, J.J.; Montenegro, D.A.; Nelson, E.A.; Goldschmidt, R.M.; Boggs, C.M.; Weidner-Wells, M.A.; Wira, E.; Hlasta, D.J.; Melton, J.; Foleno, B.D.; Bush, K.; Piperidinyloxy substituted oxazolidinones as antibacterial agents. Diversification of the N-substituent. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1828. |
| 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) | 12076 | 4-Piperidinol; 4-Hydroxypiperidine | 5382-16-1 | C5H11NO | 详情 | 详情 |
| (II) | 18625 | tert-butyl 4-hydroxy-1-piperidinecarboxylate | C10H19NO3 | 详情 | 详情 | |
| (III) | 17013 | 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene | 369-34-6 | C6H3F2NO2 | 详情 | 详情 |
| (IV) | 45645 | tert-butyl 4-(2-fluoro-4-nitrophenoxy)-1-piperidinecarboxylate | C16H21FN2O5 | 详情 | 详情 | |
| (V) | 45646 | tert-butyl 4-(4-amino-2-fluorophenoxy)-1-piperidinecarboxylate | 654-01-3 | C16H23FN2O3 | 详情 | 详情 |
| (VI) | 45647 | tert-butyl 4-(4-[[(benzyloxy)carbonyl]amino]-2-fluorophenoxy)-1-piperidinecarboxylate | C24H29FN2O5 | 详情 | 详情 | |
| (VII) | 18385 | (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate | 60456-26-0 | C7H12O3 | 详情 | 详情 |
| (VIII) | 45648 | tert-butyl 4-[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenoxy]-1-piperidinecarboxylate | C20H27FN2O6 | 详情 | 详情 | |
| (IX) | 45649 | tert-butyl 4-[2-fluoro-4-((5R)-5-[[(methylsulfonyl)oxy]methyl]-2-oxo-1,3-oxazolidin-3-yl)phenoxy]-1-piperidinecarboxylate | 22888-70-6 | C21H29FN2O8S | 详情 | 详情 |
| (X) | 45650 | tert-butyl 4-[4-[(5R)-5-(azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenoxy]-1-piperidinecarboxylate | C20H26FN5O5 | 详情 | 详情 | |
| (XI) | 45651 | tert-butyl 4-(4-[(5S)-5-[(acetamido)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenoxy)-1-piperidinecarboxylate | C22H30FN3O6 | 详情 | 详情 | |
| (XII) | 45652 | N-([(5S)-3-[3-fluoro-4-(4-piperidinyloxy)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl)acetamide | 2642-63-9 | C17H22FN3O4 | 详情 | 详情 |
| (XIII) | 10493 | 2-(Benzyloxy)acetyl chloride; Benzyloxyacetyl chloride | 19810-31-2 | C9H9ClO2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XIX)Condensation of ethyl 3-(dimethylamino)acrylate (XVIII) with (benzyloxy)acetyl chloride (XIX) by means of pyridine in CH2Cl2 gives ethyl 2-[(benzyloxy)acetyl]-3-(dimethylamino)-2-propenoate (XX), which by cyclocondensation with ethyl oxalyl chloride (XXI) in the presence of LiHMDS in THF at –78 °C followed by heating with NH4OAc and AcOH affords pyridone derivative (XXII). Alkylation of pyridone (XXII) with bromoacetaldehyde dimethyl acetal (XXIII) and Cs2CO3 in DMF yields diethyl 1-(2,2-dimethoxyethyl)-3-(benzyloxy)-1,4-dihydropyridine-2,5-dicarboxylate (XXIV), which can also be obtained by condensation of diethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (XXV) with 2,2-dimethoxyethylamine (XXVI) in EtOH. Hydrolysis of acetal (XXIV) with H2SO4 and HCOOH in CH2Cl2 yields aldehyde (XXVII), which upon cyclocondensation with 3(R)-amino-1-butanol (XI) by means of AcOH in refluxing MeOH/toluene provides the hexahydropyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazine derivative (XXVIII). Hydrolysis of ester (XXVIII) with NaOH in THF/MeOH/H2O gives the corresponding free acid (XXIX), which is finally condensed with 2,4-difluorobenzylamine (XIV) in the presence of HATU and NMM in DMF .
Propenoate (XX) can also be prepared by condensation of ethyl 4-chloroacetoacetate (XXX) with PhCH2OH in the presence of t-AmONa to give benzyl ether (XXXI), which then reacts with N,N-dimethylformamide dimethyl acetal (XXXII) in toluene .
| 【1】 Sumino, Y., Okamoto, K., Masui, M., Yamada, D., Ikarashi, F. (Shionogi & Co., Ltd.). Process for preparing compound having HIV integrase inhibitory activity. WO 2012018065. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 68577 | 3(R)-amino-1-butanol;(R)-3-aminobutan-1-ol | 61477-39-2 | C4H11NO | 详情 | 详情 |
| (XIV) | 68578 | 2,4-difluorobenzylamine | 72235-52-0 | C7H7F2N | 详情 | 详情 |
| (XV) | 68579 | (4R,12aS)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide | C27H25F2N3O5 | 详情 | 详情 | |
| (XVIII) | 16000 | ethyl (E)-3-(dimethylamino)-2-propenoate; Ethyl trans-3-dimethylaminoacrylate | 1117-37-9 | C7H13NO2 | 详情 | 详情 |
| (XIX) | 10493 | 2-(Benzyloxy)acetyl chloride; Benzyloxyacetyl chloride | 19810-31-2 | C9H9ClO2 | 详情 | 详情 |
| (XX) | 68583 | (E)-ethyl 4-(benzyloxy)-2-((dimethylamino)methylene)-3-oxobutanoate | C16H21NO4 | 详情 | 详情 | |
| (XXI) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (XXII) | 68584 | diethyl 3-(benzyloxy)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate | C18H19NO6 | 详情 | 详情 | |
| (XXIII) | 13183 | 2-Bromo-1,1-dimethoxyethane; 2-Bromo-1-methoxyethyl methyl ether; Bromoacetaldehyde dimethyl acetal | 7252-83-7 | C4H9BrO2 | 详情 | 详情 |
| (XXIV) | 68585 | 1-(2,2-dimethoxyethyl)-3-(benzyloxy)-1,4-dihydropyridine-2,5-dicarboxylate diethyl；diethyl 3-(benzyloxy)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate | C22H27NO8 | 详情 | 详情 | |
| (XXV) | 68586 | diethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate | C18H18O7 | 详情 | 详情 | |
| (XXVI) | 34158 | aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine | 22483-09-6 | C4H11NO2 | 详情 | 详情 |
| (XXVII) | 68587 | diethyl 3-(benzyloxy)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2,5-dicarboxylate | C20H21NO7 | 详情 | 详情 | |
| (XXVIII) | 68588 | (4R,12aS)-ethyl 7-(benzyloxy)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylate | C22H24N2O6 | 详情 | 详情 | |
| (XXIX) | 68589 | (4R,12aS)-7-(benzyloxy)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid | C20H20N2O6 | 详情 | 详情 | |
| (XXX) | 23541 | ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate | 638-07-3 | C6H9ClO3 | 详情 | 详情 |
| (XXXI) | 68590 | ethyl 4-(benzyloxy)-3-oxobutanoate | C13H16O4 | 详情 | 详情 | |
| (XXXII) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |