|
【结 构 式】 
|
【分子编号】24543 【品名】vinyl acetate 【CA登记号】108-05-4 |
【 分 子 式 】C4H6O2 【 分 子 量 】86.09044 【元素组成】C 55.81% H 7.02% O 37.17% |
合成路线1
该中间体在本合成路线中的序号：(VII)2) The ester (VI) can also be obtained by cyclization of (III) with vinyl acetate (VII) at 110 C.
| 【1】 Micetich, R.G.; et al. (Taiho Pharmaceutical Co., Ltd.); Penicillin derivatives and process for preparation of the same. EP 0097446; ES 523701; ES 538020 . |
| 【2】 Cai, S.X.; Drewe, J.A. (Cytovia, Inc.); Substd. nicotinamides and analogs as activators of caspases and inducers of apoptosis and the use thereof. WO 0155115 . |
| 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) | 24533 | benzhydryl (2S,3R)-3-(chloromethyl)-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C21H20ClNO3S | 详情 | 详情 | |
| (II) | 24534 | benzhydryl (2S,3S)-3-(azidomethyl)-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C21H20N4O3S | 详情 | 详情 | |
| (III) | 24535 | benzhydryl (2S,3S)-3-(azidomethyl)-3-methyl-4,4,7-trioxo-4lambda(6)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C21H20N4O5S | 详情 | 详情 | |
| (VI) | 24539 | benzhydryl (2S,3S)-3-methyl-4,4,7-trioxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4lambda(6)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C23H22N4O5S | 详情 | 详情 | |
| (VII) | 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)8. The enantioselective monoacetylation of isosorbide (I) by means of vinyl acetate (VI) catalyzed by Pig liver esterase in dichloromethane gives isosorbide 2-O-acetate (VII), which is nitrated with HNO3 in acetic anhydride to yield isosorbide 2-O-acetate-5-O-nitrate (VIII). Finally, this compound is deacetylated by means of K2CO3 in methanol. 9. The enantioselective monoacylation of isosorbide (I) by means of vinyl butyrate (IX) catalyzed by Chiraclec-BL in THF or Carlsberg subtilisin in tert-butanol gives isosorbide 2-O-butyrate (X), which is nitrated with HNO3 in acetic anhydride to yield isosorbide 2-O-butyrate-5-O-nitrate (XI). Finally, this compound is deacylated by means of K2CO3 in methanol. 10. The acylation of isosorbide (I) with acetic anhydride and pyridine gives the diacetate (XII), which is enantioselectively monodeacetylated by means of lipase from Pseudomonas fluorescens in THF to yield isosorbide 2-O-acetate (VII). This compound is then nitrated to (VIII) and finally deacetylated as already described. 11. The acylation of isosorbide (I) with HOAc and Ac2O gives (after purification by crystallization) isosorbide 2-O-acetate (VII), which is nitrated to (VIII) and finally deacetylated as already described. 12. The acylation of isosorbide (I) with isobutyric acid (XIII) by means of sulfuric acid in refluxing chlorobenzene/toluene gives isosorbide 2-O-isobutyrate (XIV), which is nitrated with HNO3/H2SO4 to yield isosorbide 2-O-isobutyrate-5-O-nitrate (XV). Finally, this compound is deacylated by means of NaOH in toluene/water. 13. The nitration of isosorbide (I) by means of HNO3 in HOAc/Ac2O gives a 3.5/1 mixture of isosorbide-5-O-nitrate and isosorbide 2-O-nitrate that is separated by column chromatography over alumina. 14. The nitration of isosorbide (I) with HNO3 in benzene/HOAc/Ac2O, followed by a purification step yields the target isosorbide-5-O-nitrate.
| 【1】 Stoss, P.; Process for the preparation of isosorbide-5-nitrate. DE 3102947; EP 0057847; US 4371703 . |
| 【2】 Ito, T.; Ishibashi, K.; Ishiguro, S.; Shimada, F.; A method for the preparation of isosorbide-5-nitrate and sodium isosorbide-5-nitrate hydrate as a precursor thereof. EP 0143507; US 4584391 . |
| 【3】 Dvonch, W.; Alburn, H.E. (Wyeth); Mononitrate esters of 1,4:3,6-dianhydro-d-glucitol. DE 2221080; GB 1356374; US 3886186 . |
| 【4】 Lauer, K.; Kiegel, E. (Boehringer Ingelheim GmbH); Process for the preparation of 1,4:3,6-dianhydro-D-glucite 5-nitrate (isosorbide-5-nitrate). DE 3028873; EP 0045076; US 4431829 . |
| 【5】 Schonafinger, K. (Cassella AG); Process for the preparation of 5-isosorbide nitrate. DE 3117612; EP 0064194; US 4431830 . |
| 【6】 Roberts, S.M.; Marston, R.W.; Quigley, P.F.; Brown, C.M.; Synthesis of isosorbide cpds.. GB 2358859 . |
| 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) | 59337 | (1R,3aS,4S,6aS)octahydro-1,4-pentalenediol | C8H14O2 | 详情 | 详情 | |
| (VI) | 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 |
| (VII) | 59341 | (1S,3aS,4R,6aS)-4-hydroxyoctahydro-1-pentalenyl acetate | C10H16O3 | 详情 | 详情 | |
| (VIII) | 59342 | (1S,3aS,4R,6aS)-4-(nitrooxy)octahydro-1-pentalenyl acetate | C10H15NO5 | 详情 | 详情 | |
| (IX) | 53263 | n-Butyric acid vinyl ester; Vinyl n-butyrate; Vinyl butyrate | 123-20-6 | C6H10O2 | 详情 | 详情 |
| (X) | 59343 | (1S,3aS,4R,6aS)-4-hydroxyoctahydro-1-pentalenyl butyrate | C12H20O3 | 详情 | 详情 | |
| (XI) | 59344 | (1S,3aS,4R,6aS)-4-(nitrooxy)octahydro-1-pentalenyl butyrate | C12H19NO5 | 详情 | 详情 | |
| (XII) | 59345 | (1R,3aS,4S,6aS)-4-(acetyloxy)octahydro-1-pentalenyl acetate | C12H18O4 | 详情 | 详情 | |
| (XIII) | 33399 | 2-methylpropionic acid | 79-31-2 | C4H8O2 | 详情 | 详情 |
| (XIV) | 59346 | (1S,3aS,4R,6aS)-4-hydroxyoctahydro-1-pentalenyl 2-methylpropanoate | C12H20O3 | 详情 | 详情 | |
| (XV) | 59347 | (1S,3aS,4R,6aS)-4-(nitrooxy)octahydro-1-pentalenyl 2-methylpropanoate | C12H19NO5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)A new synthesis of didanosine has been described: Treatment of 2'-deoxyadenosine (I) with adenosine deaminase (ADA) in water gives 2'-deoxyinosine (II), which is treated with vinyl acetate (III) and Candida antarctica lipase (CAL) in hot pyridine yielding 5'-O-acetyl-2'-deoxyinosine (IV). The reaction of (IV) with phenyl chlorothionoformate (V) and DMAP in acetonitrile affords the corresponding thiocarbonate (VI), which is treated with tributylstannane and AIBN in hot toluene to provide 5'-O-acetyl-2',3'-dideoxyinosine (VII). Finally, this compound is deacetylated with NH3 in methanol.
| 【1】 Santaniello, E.; Ciuffreda, P.; Casati, S.; Lipase-catalyzed protection of the hydroxy groups of the nucleosides inosine and 2'-deoxyinosine: A new chemoenzymatic synthesis of the antiviral drug 2',3'-dideoxyinosine. Bioorg Med Chem Lett 1999, 9, 11, 1577. |
| 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) | 18061 | (2R,3S,5R)-5-(6-amino-9H-purin-9-yl)-2-(hydroxymethyl)tetrahydro-3-furanol | 958-09-8 | C10H13N5O3 | 详情 | 详情 |
| (II) | 12801 | 9-[(2R,4S,5R)-4-Hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-9H-purin-6-ol | 890-38-0 | C10H12N4O4 | 详情 | 详情 |
| (III) | 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 |
| (IV) | 37609 | [(2R,3S,5R)-3-hydroxy-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-2-furanyl]methyl acetate | C12H14N4O5 | 详情 | 详情 | |
| (V) | 25805 | 1-[(chlorocarbothioyl)oxy]benzene; Phenylchlorothioformate | 1005-56-7 | C7H5ClOS | 详情 | 详情 |
| (VI) | 37610 | [(2R,3S,5R)-5-(6-hydroxy-9H-purin-9-yl)-3-[(phenoxycarbothioyl)oxy]tetrahydro-2-furanyl]methyl acetate | C19H18N4O6S | 详情 | 详情 | |
| (VII) | 37611 | [(2S,5R)-5-(6-hydroxy-9H-purin-9-yl)tetrahydro-2-furanyl]methyl acetate | C12H14N4O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)Reaction of benzaldehyde (I) with dimethyl malonate (II) in refluxing toluene in the presence of piperidine and HOAc provides dimethyl benzylidene malonate (III), which is then hydrogenated over Pd/C to afford dimethyl benzyl malonate (IV). Reduction of (IV) with LiAlH4 in refluxing THF furnishes 2-benzyl-1,3-propanediol (V), which is then subjected to reaction with vinyl acetate (VI) by means of Novozym 435 enzyme to yield diacetate (VII). Enantioselective removal of one acetyl group from (VII) by treatment with Pseudomonas fluorescens Lipase in acetone/phosphate buffer (pH = 7) at 30 C gives 3-acetoxy-2(S)-benzyl-propanol (S)-(VIII), which is then oxidized by means of Jones reagent in acetone/isopropanol to provide carboxylic acid (R)-(IX). The hydrolysis of (IX) with LiOH in THF/H2O gives 2(R)-benzyl-3-hydroxypropanoic acid (R)-(X). Alternatively, intermediate (X) can also be synthesized as follows: Condensation of benzaldehyde (I) with methyl acrylate (XV) by means of diaza-1,4-bicyclo[2.2.2.]octane affords methyl beta-hydroxy-alpha-methylene-benzenepropanoate (XVI), which is then subjected to hydrolysis with KOH in MeOH/H2O to yield carboxylic acid (XVII). Treatment of (XVII) with p-toluenesulfonic acid in refluxing HOAc gives (E)-2-(acetoxymethyl)-3-phenylpropionic acid (XVIII), which is finally converted into (X) by enantioselective hydrogenation in the presence of S-Binap and ruthenium catalyst [CodRu(all)2]. Derivative (R)-(X) is then converted into 3-(acetylsulfanyl)-2(S)-benzylpropionic acid (XI) by means of a Mitsunobu reaction with thioacetic acid, diisopropyl azodicarboxylate (DIAD) and triphenylphosphine (PPh3). Compound (XI) is then subjected to optical purification by formation and isolation of the corresponding salt with (-)-ephedrine and subsequent hydrolysis with HCl to furnish enantiomerically pure (S)-(XII). Finally, carboxylic acid (S)-(XII) is converted into ecadotril by its coupling with benzyl glycinate (XIV), either by means of Et3N, DCC and HOBt in CHCl3, or by first reaction with thionyl chloride to give acid chloride (S)-(XIII) and subsequent coupling with glycinate (XIV) by means of Et3N in CH2Cl2.
| 【1】 Monteil, T.; et al.; New asymmetric synthesis of dexecadotril and ecadotril starting from a single precursor. Synth Commun 2001, 31, 2, 211. |
| 【2】 Duhamel, P.; Duhamel, L.; Danvy, D.; Plaquevent, J.-C.; Giros, B.; Gros, C.; Schwartz, J.-C.; Lecomte, J.-M. (Societe Civile Bioprojet); Enantiomeric derivs. of amino acids, process for their preparation and their pharmaceutical applications. EP 0318377; FR 2623498; JP 1990000161; JP 1996059606; US 5296509; US 5331008 . |
| 【3】 Schwartz, J.-C.; Lecomte, J.-M. (Societe Civile Bioprojet); Novel pharmaceutical compsns. for the treatment of functional colophaties and their process of obtention. EP 0501870; JP 1993105627 . |
| 【4】 Schwartz, J.-C.; Danvy, D.; Lecomte, J.-M.; Duhamel, P.; Duhamel, L.; Monteil, T. (Societe Civile Bioprojet); Method for the asymmetrical synthesis of S-acylated derivs. of 2-mercaptomethyl 3-phenyl propanoic acid, and use thereof for synthesising N-(mercaptoacyl)amino acid derivs.. WO 9729086 . |
| 【5】 Lecomte, J.-M.; Duhamel, P.; Danvy, D.; Schwartz, J.-C.; Duhamel, L.; Monteil, T. (Societe Civile Bioprojet); Process for the synthesis of alpha-substd. acrylic acids and their application. EP 0729936 . |
| 【6】 Henry, J.C.; Genet, J.P.; Dellis, P.; Vidal, V.; Binay, P. (Fournier Industrie et Santé); Preparation of S- and R-isomers of 2-mercaptomethyl-3-aryl propanoic acid by asymmetric reduction of an aryl propenoic acid. FR 2772027 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (S)-(VIII) | 49464 | (2S)-2-benzyl-3-hydroxypropyl acetate | C12H16O3 | 详情 | 详情 | |
| (R)-(IX) | 49465 | (2R)-3-(acetoxy)-2-benzylpropionic acid | C12H14O4 | 详情 | 详情 | |
| (R)-(X) | 49466 | (2R)-2-benzyl-3-hydroxypropionic acid | C10H12O3 | 详情 | 详情 | |
| (XI),(S)-(XII) | 49467 | (2S)-3-(acetylsulfanyl)-2-benzylpropionic acid | C12H14O3S | 详情 | 详情 | |
| (I) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (II) | 19373 | dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester | 108-59-8 | C5H8O4 | 详情 | 详情 |
| (III) | 49460 | Dimethyl benzylidenemalonate | C12H12O4 | 详情 | 详情 | |
| (IV) | 49461 | dimethyl 2-benzylmalonate | C12H14O4 | 详情 | 详情 | |
| (V) | 49462 | 2-Benzylpropane-1,3-diol | C10H14O2 | 详情 | 详情 | |
| (VI) | 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 |
| (VII) | 49463 | 3-(acetoxy)-2-benzylpropyl acetate | C14H18O4 | 详情 | 详情 | |
| (XIII) | 49468 | S-[(2R)-2-benzyl-3-chloro-3-oxopropyl] ethanethioate | C12H13ClO2S | 详情 | 详情 | |
| (XIV) | 49469 | 1-amino-3-phenylacetone | C9H11NO | 详情 | 详情 | |
| (XV) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (XVI) | 49470 | methyl 2-[hydroxy(phenyl)methyl]acrylate | C11H12O3 | 详情 | 详情 | |
| (XVII) | 49471 | 2-[hydroxy(phenyl)methyl]acrylic acid | C10H10O3 | 详情 | 详情 | |
| (XVIII) | 49472 | (E)-2-[(acetoxy)methyl]-3-phenyl-2-propenoic acid | C12H12O4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)The condensation of 4-[2-(cyclopropylmethoxy)ethyl]phenol (I) with epichlorohydrin (II) in pyridine gives the phenol ether (III), which is treated with HCl to open the epoxide ring and yield the racemic chloropropanol (IV). The optical resolution of (IV) by means of Lipase SP 435-L or AK and vinyl acetate (V) gives a mixture of (S)-acetate (S)-(VI) and unreacted (R)-alcohol (R)-(VI) that is easily separated. Finally, the chiral chloropropanol (R)-(VI) is treated with isopropylamine (VII) to afford the target betaxolol. The optical resolution of racemic betaxolol by means of the previously mentioned lipases has also been tried with poor results.
| 【1】 Di Bono, G.; Scilimati, A.; Synthesis 1995, 6, 688. |
| 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) | 33330 | 4-[2-(Cyclopropylmethoxy)ethyl]phenol; p-(Cyclopropylmethoxyethyl)phenol | C12H16O2 | 详情 | 详情 | |
| (II) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (III) | 33331 | 2-([4-[2-(Cyclopropylmethoxy)ethyl]phenoxy]methyl)oxirane; 1-[p-(Cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane; 4-[2-(Cyclopropylmethoxy)ethyl]phenyl 2-oxiranylmethyl ether | C15H20O3 | 详情 | 详情 | |
| (IV) | 55675 | 1-chloro-3-{4-[2-(cyclopropylmethoxy)ethyl]phenoxy}-2-propanol | C15H21ClO3 | 详情 | 详情 | |
| (V) | 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 |
| (VI) | 55676 | (2R)-1-chloro-3-{4-[2-(cyclopropylmethoxy)ethyl]phenoxy}-2-propanol | C15H21ClO3 | 详情 | 详情 | |
| (VII) | 55676 | (2R)-1-chloro-3-{4-[2-(cyclopropylmethoxy)ethyl]phenoxy}-2-propanol | C15H21ClO3 | 详情 | 详情 | |
| (VIII) | 23933 | 2-Propanamine; Isopropylamine | 75-31-0 | C3H9N | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(V)The reaction of cyclopentadiene (I) with Br2 gives 1,4-dibromo-2-cyclopentene (II), which is treated with potassium acetate in tert-butanol yielding 1,4-diacetoxy-2-cyclopentene (III). The hydrolysis of (III) with KHCO3 in methanol affords 2-cyclopentene-1,4-diol (IV) as a mixture of the cis and trans isomers. The treatment of (cis/trans) (IV) or (cis) (IV) with pancreatin, vinyl acetate (V) and triethylamine gives (1R,4S)-4-acetoxy-2-cyclopenten-1-ol (VI), which is hydrogenated with H2 over RaNi in ethanol to yield the corresponding saturated (1S,3R)-3-acetoxycyclopentanol (VII). The reaction of (VII) with methanesulfonyl chloride and TEA in dichloromethane affords the corresponding mesylate (VIII), which is condensed with adenine (IX) by means of NaH in hot DMF providing the final intermediate (X). Finally, this compound is deacetylated with HCl in refluxing ethanol.
| 【1】 Borcherding, D.R.; et al.; Carbocyclic nucleosides as inhibitors of human Tumor Necrosis Factor-alpha production: Effects of the stereoisomers of (3-hydroxycyclopentyl)adenines. J Med Chem 1996, 39, 13, 2615. |
| 【2】 Watson, T.J.N.; et al.; Development of the carbocyclic nucleoside MDL 201449A. A tumor necrosis factor-alpha inhibitor. Org Process Res Dev 1998, 2, 6, 357. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (cis/trans)(IV) | 21533 | 4-cyclopentene-1,3-diol | C5H8O2 | 详情 | 详情 | |
| (cis)(IV) | 33168 | (1R,3S)-4-cyclopentene-1,3-diol | C5H8O2 | 详情 | 详情 | |
| (I) | 11183 | 1,3-Cyclopentadiene | C5H6 | 详情 | 详情 | |
| (II) | 33167 | 3,5-dibromo-1-cyclopentene | C5H6Br2 | 详情 | 详情 | |
| (III) | 21534 | 4-(acetoxy)-2-cyclopenten-1-yl acetate | C9H12O4 | 详情 | 详情 | |
| (V) | 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 |
| (VI) | 33169 | (1S,4R)-4-hydroxy-2-cyclopenten-1-yl acetate | C7H10O3 | 详情 | 详情 | |
| (VII) | 33170 | (1R,3S)-3-hydroxycyclopentyl acetate | C7H12O3 | 详情 | 详情 | |
| (VIII) | 33171 | (1R,3S)-3-[(methylsulfonyl)oxy]cyclopentyl acetate | C8H14O5S | 详情 | 详情 | |
| (IX) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (X) | 33172 | (1R,3R)-3-(6-amino-9H-purin-9-yl)cyclopentyl acetate | C12H15N5O2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(V)The rearrangement of furfuryl alcohol (XI) in acidic medium (KH2PO4, H3PO4) gives 4-hydoxy-2-penten-1-one (XII), which is silylated with TBDMS-Cl, Et3N and DMAP in THF yielding the silyl ether (XIII). The reduction of (XIII) with LiAlH4 in toluene affords the (rac)(cis)-4-(tert-butyldimethylsilyloxy)-2-penten-1-ol (XIV), which is submitted to optical resolution by digestion with pancreatin (8xUSP) and vinyl acetate in tert-butyl methyl ether yielding a mixture of (1S,4R)-4-(tert-butyldimethylsilyloxy)-2-cyclopentenyl acetate (XV) and (1R,4S)- 4-(tert-butyldimethylsilyloxy)-2-cyclopenten-1-ol (XVI), which were separated by column chromatography. Both compounds (XV) and (XVI) were used by independent routes to obtain the target compound: a) The desilylation of (XV) with TBAF in THF gives the previously described (1R,4S)-4-acetoxy-2-cyclopenten-1-ol (VI), which is converted into the target compound by the previously described route (VI) - (VII) - (VIII) - (X) - target adenine derivative. b) The hydrogenation of (1R,4S)- 4-(tert-butyldimethylsilyloxy)-2-cyclopenten-1-ol (XVI) with H2 over Ni2B in ethanol gives the corresponding saturated alcohol (XVII), which is treated with methanesulfonyl chloride and triethylamine in tert-butyl methyl ether yielding the mesylate (XVIII). The condensation of (XVIII) with adenine (IX) by means of NaH in hot DMA affords the silylated target compound (XIX), which is finally deprotected with HCl in ethanol.
| 【1】 Borcherding, D.R.; et al.; Carbocyclic nucleosides as inhibitors of human Tumor Necrosis Factor-alpha production: Effects of the stereoisomers of (3-hydroxycyclopentyl)adenines. J Med Chem 1996, 39, 13, 2615. |
| 【2】 Watson, T.J.N.; et al.; Development of the carbocyclic nucleoside MDL 201449A. A tumor necrosis factor-alpha inhibitor. Org Process Res Dev 1998, 2, 6, 357. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (rac)(XIV) | 33174 | (1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-ol | C11H22O2Si | 详情 | 详情 | |
| (V) | 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 |
| (VI) | 33169 | (1S,4R)-4-hydroxy-2-cyclopenten-1-yl acetate | C7H10O3 | 详情 | 详情 | |
| (VII) | 33170 | (1R,3S)-3-hydroxycyclopentyl acetate | C7H12O3 | 详情 | 详情 | |
| (VIII) | 33171 | (1R,3S)-3-[(methylsulfonyl)oxy]cyclopentyl acetate | C8H14O5S | 详情 | 详情 | |
| (IX) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (X) | 33172 | (1R,3R)-3-(6-amino-9H-purin-9-yl)cyclopentyl acetate | C12H15N5O2 | 详情 | 详情 | |
| (XI) | 13848 | 2-Furylmethanol; Furfuryl Alcohol | 98-00-0 | C5H6O2 | 详情 | 详情 |
| (XII) | 33173 | 4-hydroxy-2-cyclopenten-1-one | C5H6O2 | 详情 | 详情 | |
| (XIII) | 13805 | (4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one | C11H20O2Si | 详情 | 详情 | |
| (XV) | 33175 | (1S)-2-cyclopenten-1-yl acetate | C7H10O2 | 详情 | 详情 | |
| (XVI) | 64705 | (1R,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopenten-1-ol | C11H22O2Si | 详情 | 详情 | |
| (XVII) | 33176 | (1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]cyclopentanol | C11H24O2Si | 详情 | 详情 | |
| (XVIII) | 33177 | (1R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-yl methanesulfonate | C12H24O4SSi | 详情 | 详情 | |
| (XIX) | 33178 | 9-((1R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]cyclopentyl)-9H-purin-6-amine; 9-((1R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]cyclopentyl)-9H-purin-6-ylamine | C16H27N5OSi | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：An alternative synthesis of the key intermediate (II) in the synthesis of Sch-51048 published in the original monograph has been reported:The reaction of 2-(2,4-difluorophenyl)allyl alcohol (I) with PBr3 in dichloromethane gives the corresponding allyl bromide (II), which is condensed with sodium diethyl malonate (III), yielding the diester (IV). The reduction of (VI) with NaBH4 in ethanol affords the diol (V), which is submitted to an asymmetric acetylation with vinyl acetate catalyzed by the enzyme Novo SP435, giving the chiral monoester (VI). The cyclization of (VI) with I2 and NaHCO3 in acetonitrile affords the tetrahydrofuran derivative (VII), which is allowed to react with the sodium salt of 1,2,4-triazole (VIII) in DMF, yielding the corresponding condensation product (IX). Hydrolysis of (IX) with NaOH in methanol gives the alcohol (X), which is tosylated with tosyl chloride in pyridine.
| 【1】 Puar, M.S.; Girijavallabhan, V.M.; Saksena, A.K.; Lovey, R.G.; Ganguly, A.K.; Pike, R.E.; Wang, H.Y.; Zaks, A.; Morgan, B.; Highly stereoselective access to novel 2,2,4-trisubstituted tetrahydrofurans by halocyclization: Practical chemoenzymatic synthesis of SCH 51048, a broad-spectrum orally active antifungal agent. Tetrahedron Lett 1995, 36, 11, 1787. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 | |
| (I) | 15491 | 2-(2,4-difluorophenyl)-2-propen-1-ol | C9H8F2O | 详情 | 详情 | |
| (II) | 16335 | 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene | C9H7BrF2 | 详情 | 详情 | |
| (III) | 16336 | [2-ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]sodium | C7H11NaO4 | 详情 | 详情 | |
| (IV) | 16337 | diethyl 2-[2-(2,4-difluorophenyl)-2-propenyl]malonate | C16H18F2O4 | 详情 | 详情 | |
| (V) | 16338 | 2-[2-(2,4-difluorophenyl)-2-propenyl]-1,3-propanediol | C12H14F2O2 | 详情 | 详情 | |
| (VI) | 16339 | (2S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-4-pentenyl acetate | C14H16F2O3 | 详情 | 详情 | |
| (VII) | 16340 | [(3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro-3-furanyl]methyl acetate | C14H15F2IO3 | 详情 | 详情 | |
| (VIII) | 16341 | 1H-1,2,4-triazol-1-ylsodium | C2H2N3Na | 详情 | 详情 | |
| (IX) | 16342 | [(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl acetate | C16H17F2N3O3 | 详情 | 详情 | |
| (X) | 16343 | [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methanol | C14H15F2N3O2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：A new synthesis of Sch-51048 based on a known key intermediate has been described:The reaction of (I) (the final product in Tetrahedron Lett 1995, 36(11): 1787, or intermediate (II) in the synthesis published in the original monograph) with 4-[4-(4-nitrophenyl)piperazin-1-yl]phenol (II) (obtained from the corresponding anisole (III) with 48% HBr) by means of NaOH in DMSO yields the corresponding condensation product (IV). The reduction of the NO2 group of (IV) with H2 over Pd/C in ethanol affords the amine (V), which is acylated with phenyl chloroformate and pyridine to the corresponding carbamate (VI). The reaction of (VI) with hydrazine in dimethoxyethane affords the semicarbazide (VII), which is cyclized with formamidine acetate in 2-methoxyethanol to the triazolinone (VIII). Finally, this compound is alkylated with 3-bromopentane and NaOH in DMSO or DMF.
| 【1】 Girijavallabhan, V.M.; Lovey, R.G.; Saksena, A.K.; et al.; SCH 51048, a novel broad-spectrum orally active antifungal agent: Synthesis and preliminary structure-activity profile. Bioorg Med Chem Lett 1995, 5, 2, 127. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 | |
| (I) | 16311 | [(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-methylbenzenesulfonate | C21H21F2N3O4S | 详情 | 详情 | |
| (II) | 16345 | 4-[4-(4-nitrophenyl)piperazino]phenol | C16H17N3O3 | 详情 | 详情 | |
| (III) | 16314 | methyl 4-[4-(4-nitrophenyl)piperazino]phenyl ether; 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine | C17H19N3O3 | 详情 | 详情 | |
| (IV) | 16347 | [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-[4-(4-nitrophenyl)-1-piperazinyl]phenyl ether | C30H30F2N6O4 | 详情 | 详情 | |
| (V) | 16348 | 4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenylamine; [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-[4-(4-nitrophenyl)-1-piperazinyl]phenyl ether | C30H32F2N6O2 | 详情 | 详情 | |
| (VI) | 16349 | phenyl 4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenylcarbamate | C37H36F2N6O4 | 详情 | 详情 | |
| (VII) | 16350 | N-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-1-hydrazinecarboxamide | C31H34F2N8O3 | 详情 | 详情 | |
| (VIII) | 16351 | 4-[4-[4-(4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy]phenyl)-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C32H32F2N8O3 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：Alternatively, (+)-(XVII) can be obtained as follows: Treatment of (X) with 1-acetoxy-2-bromoethane (XVIII) in DMF in the presence of NaHCO3 yields derivative (XIX), which is then chlorinated by means of SO2Cl2 in CH2Cl2 to provide (XX). Simultaneous hydrolysis and intramolecular cyclization of (XX) by means of Et3N /H2O in THF affords (XXI), which is then converted into butyl ester derivative (XXII) by treatment with refluxing butanol (B). Resolution of the racemic mixture (XXII) by treatment with Lipase PL in vinyl acetate followed by chromatographic separation provides alcohol (-)-(XXIII) and acetoxy (+)-(XXIV). Hydrolysis of (+)-(XXIV) with hot H2SO4/EtOH gives alcohol (+)-(XXV), which is then condensed with 1-methylpiperazine (XVI) in DMF to yield derivative (+)-(XXVI). Finally, treatment with (diethylamino)sulfur trifluoride (DAST) in CH2Cl2 provides fluoro derivative (+)-(XVII). Alternatively, (+)-(XXV) can be obtained by conversion of (XXI) into octyl ester (XXVII) by means of refluxing octanol (A), followed by its enantiomer enzymatic resolution with Liposyme IM in vinyl acetate and chromatographic separation to afford (-)-(XXVIII) and (+)-(XXIX). Finally, hydrolysis of (+)-(XXIX) with hot H2SO4/EtOH yields (+)-(XXV). An analogous procedure comprising enantiomer separation and subsequent hydrolysis can be performed from ethyl esters (XX) or (XXI) by treatment with the corresponding lipases in an appropriate solvent.
| 【1】 Segawa, J.; Matsuoka, M.; Tomii, Y. (Nippon Shinyaku Co., Ltd.); Quinolinecarboxylic acid deriv. and process for producing the same. EP 0675127; WO 9414819 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 | |
| (A) | 12970 | (8R,9S,10R,13S,14R)-14-Hydroxy-3-methoxy-10,13-dimethyl-1,2,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one | C20H28O3 | 详情 | 详情 | |
| (B) | 29766 | butanol; n-butanol; 1-butanol | 71-36-3 | C4H10O | 详情 | 详情 |
| (X) | 42956 | ethyl 4-(benzoyloxy)-6,7-difluoro-2-sulfanyl-3-quinolinecarboxylate | C19H13F2NO4S | 详情 | 详情 | |
| (XVI) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (XVII) | 42961 | ethyl (1R)-6-fluoro-1-(fluoromethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C19H21F2N3O3S | 详情 | 详情 | |
| (XVIII) | 33463 | 2-bromoethyl acetate | 927-68-4 | C4H7BrO2 | 详情 | 详情 |
| (XIX) | 42962 | ethyl 2-[[2-(acetoxy)ethyl]sulfanyl]-4-(benzoyloxy)-6,7-difluoro-3-quinolinecarboxylate | C23H19F2NO6S | 详情 | 详情 | |
| (XX) | 42963 | ethyl 2-[[2-(acetoxy)-1-chloroethyl]sulfanyl]-4-(benzoyloxy)-6,7-difluoro-3-quinolinecarboxylate | C23H18ClF2NO6S | 详情 | 详情 | |
| (XXI) | 42964 | ethyl 1-[(acetoxy)methyl]-6,7-difluoro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C16H13F2NO5S | 详情 | 详情 | |
| (XXII) | 42965 | butyl 6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C16H15F2NO4S | 详情 | 详情 | |
| (XXIII) | 42966 | butyl (1S)-6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C16H15F2NO4S | 详情 | 详情 | |
| (XXIV) | 42967 | butyl (1R)-1-[(acetoxy)methyl]-6,7-difluoro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C18H17F2NO5S | 详情 | 详情 | |
| (XXV) | 42968 | ethyl (1R)-6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C14H11F2NO4S | 详情 | 详情 | |
| (XXVI) | 42969 | ethyl (1R)-6-fluoro-1-(hydroxymethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C19H22FN3O4S | 详情 | 详情 | |
| (XXVII) | 42971 | octyl 2-[6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate | C21H25F2NO4S | 详情 | 详情 | |
| (XXVIII) | 42972 | octyl 2-[(1S)-1-[(acetoxy)methyl]-6,7-difluoro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate | C23H27F2NO5S | 详情 | 详情 | |
| (XXIX) | 42973 | octyl 2-[(1R)-6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate | C21H25F2NO4S | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：Alternatively, (-)-(XVII) can be obtained as follows: Treatment of (X) with 1-acetoxy-2-bromoethane (XVIII) in DMF in the presence of NaHCO3 yields derivative (XIX), which is then chlorinated by means of SO2Cl2 in CH2Cl2 to provide (XX). Simultaneous hydrolysis and intramolecular cyclization of (XX) by means of Et3N /H2O in THF affords (XXI), which is then converted into octyl ester derivative (XXII) by treatment with refluxing octanol (A). Resolution of the racemic mixture (XXII) by treatment with Liposyme IM in vinyl acetate followed by chromatographic separation provides alcohol (+)-(XXIII) and acetoxy (-)-(XXIV). Hydrolysis of (-)-(XXIV) with hot H2SO4/EtOH gives alcohol (-)-(XXV), which then reacts with 1-methylpiperazine (XVI) in DMF to yield derivative (-)-(XXVI). Finally, treatment with (diethylamino)sulfur trifluoride (DAST) in CH2Cl2 provides fluoro derivative (-)-(XVII). Alternatively, (-)-(XXV) can be obtained by conversion of (XXI) into butyl ester (XXVII) by means of refluxing butanol (B), followed by its enantiomer enzymatic resolution with Lipase PL in vinyl acetate and chromatographic separation to afford (+)-(XXVIII) and (-)-(XXIX). Finally, hydrolysis of (-)-(XXIX) with hot H2SO4/EtOH yields (-)-(XXV). An analogous procedure comprising enantiomer separation and subsequent hydrolysis can be performed from ethyl esters (XX) or (XXI) by treatment with the corresponding lipases in an appropriate solvent.
| 【1】 Segawa, J.; Matsuoka, M.; Tomii, Y. (Nippon Shinyaku Co., Ltd.); Quinolinecarboxylic acid deriv. and process for producing the same. EP 0675127; WO 9414819 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 | |
| (A) | 12970 | (8R,9S,10R,13S,14R)-14-Hydroxy-3-methoxy-10,13-dimethyl-1,2,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one | C20H28O3 | 详情 | 详情 | |
| (B) | 29766 | butanol; n-butanol; 1-butanol | 71-36-3 | C4H10O | 详情 | 详情 |
| (X) | 42956 | ethyl 4-(benzoyloxy)-6,7-difluoro-2-sulfanyl-3-quinolinecarboxylate | C19H13F2NO4S | 详情 | 详情 | |
| (XVI) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (XVII) | 42975 | ethyl (1S)-6-fluoro-1-(fluoromethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C19H21F2N3O3S | 详情 | 详情 | |
| (XVIII) | 33463 | 2-bromoethyl acetate | 927-68-4 | C4H7BrO2 | 详情 | 详情 |
| (XIX) | 42962 | ethyl 2-[[2-(acetoxy)ethyl]sulfanyl]-4-(benzoyloxy)-6,7-difluoro-3-quinolinecarboxylate | C23H19F2NO6S | 详情 | 详情 | |
| (XX) | 42963 | ethyl 2-[[2-(acetoxy)-1-chloroethyl]sulfanyl]-4-(benzoyloxy)-6,7-difluoro-3-quinolinecarboxylate | C23H18ClF2NO6S | 详情 | 详情 | |
| (XXI) | 42964 | ethyl 1-[(acetoxy)methyl]-6,7-difluoro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C16H13F2NO5S | 详情 | 详情 | |
| (XXII) | 42971 | octyl 2-[6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate | C21H25F2NO4S | 详情 | 详情 | |
| (XXIII) | 42973 | octyl 2-[(1R)-6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate | C21H25F2NO4S | 详情 | 详情 | |
| (XXIV) | 42972 | octyl 2-[(1S)-1-[(acetoxy)methyl]-6,7-difluoro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate | C23H27F2NO5S | 详情 | 详情 | |
| (XXV) | 42976 | ethyl (1S)-6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C14H11F2NO4S | 详情 | 详情 | |
| (XXVI) | 42977 | ethyl (1S)-6-fluoro-1-(hydroxymethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C19H22FN3O4S | 详情 | 详情 | |
| (XXVII) | 42965 | butyl 6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C16H15F2NO4S | 详情 | 详情 | |
| (XXVIII) | 42967 | butyl (1R)-1-[(acetoxy)methyl]-6,7-difluoro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C18H17F2NO5S | 详情 | 详情 | |
| (XXIX) | 42966 | butyl (1S)-6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate | C16H15F2NO4S | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：2) The 2-(2,4-difluorophenyl)-2-propen-1-ol (IV) is converted into the corresponding propenyl bromide (XXVI), which is condensed with diethyl malonate (X) to afford the malonyl derivative (XXVII). The reduction of (XXVII) with NaBH4 and LiCl yields the 1,3-propanediol derivative (XXVIII), which is enantioselectively acetylated with vinyl acetate and Novozyme 435 in acetonitrile yielding the isomeric (S)-monoacetate (XXIX). The cyclization of (XXIX) with iodine and NaHCO3 in acetonitrile affords (5R-cis)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydrofuran-3-methanol acetate ester (XXX), which is condensed with sodium 1,2,4-triazole (XXXI) to give (5R-cis)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl) tetrahydrofuran-3-methanol acetate ester (XXXII). The hydrolysis of (XXXII) with NaOH yields the corresponding methanol (XXXIII), which is finally tosylated to the tosyl ester (XIV), already obtained previously.
| 【1】 Saksena, A.K.; Girijavallabhan, V.M.; Lovey, R.G.; Bennett, F.; Pike, R.E.; Wang, H.; Pinto, P.; Liu, Y.T.; Patel, N.; Ganguly, A.K.; Novel analogs of SCH 51048: Synthesis and preliminary structure activity relationships. 35th Intersci Conf Antimicrob Agents Chemother (Sept 17-20, San Francisco) 1995, Abst F83.. |
| 【2】 Fromtling, R.A.; Castañer, J.; SCH-56592. Drugs Fut 1996, 21, 2, 160. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 | |
| (IV) | 15491 | 2-(2,4-difluorophenyl)-2-propen-1-ol | C9H8F2O | 详情 | 详情 | |
| (X) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (XXVI) | 16335 | 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene | C9H7BrF2 | 详情 | 详情 | |
| (XXVII) | 16337 | diethyl 2-[2-(2,4-difluorophenyl)-2-propenyl]malonate | C16H18F2O4 | 详情 | 详情 | |
| (XXVIII) | 16338 | 2-[2-(2,4-difluorophenyl)-2-propenyl]-1,3-propanediol | C12H14F2O2 | 详情 | 详情 | |
| (XXIX) | 16339 | (2S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)-4-pentenyl acetate | C14H16F2O3 | 详情 | 详情 | |
| (XXX) | 16340 | [(3S,5R)-5-(2,4-difluorophenyl)-5-(iodomethyl)tetrahydro-3-furanyl]methyl acetate | C14H15F2IO3 | 详情 | 详情 | |
| (XXXI) | 13104 | 1,2,4-Triazole, sodium derivative | 41253-21-8 | C2H2N3Na | 详情 | 详情 |
| (XXXII) | 16342 | [(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl acetate | C16H17F2N3O3 | 详情 | 详情 | |
| (XXXIII) | 16343 | [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methanol | C14H15F2N3O2 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(II)Enantioselective enzyme-catalyzed transesterification of the tricyclic diol (I) with vinyl acetate (II) provides the chiral monoacetate (III). After protection of the free hydroxyl group of (III) as the tert-butyldimethylsilyl ether (IV), alkaline hydrolysis of the acetate ester group yields alcohol (V), which is then oxidized to the corresponding ketone (VI) by means of pyridinium dichromate. Finally, thermal retro-Diels-Alder reaction of (VI) under diminished pressure furnishes the target cyclopentenone derivative.
| 【1】 Liu, Z.-Y.; He, L.; Zheng, H.; Highly enantioselective synthesis of (+) and (-)endo- tricyclo [5.2.1.02,6]deca-4,8-dien-3-one and (-)-4-t-butyldimethylsilyloxy-cyclopentenone by enzyme-catalyzed acetylation. Tetrahedron Asymmetry 1993, 4, 11, 2277. |