【结 构 式】 |
【分子编号】63932 【品名】(3aR,5R,6S,6aS)-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-6-fluoro-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole 【CA登记号】 |
【 分 子 式 】C12H19FO5 【 分 子 量 】262.2782632 【元素组成】C 54.95% H 7.3% F 7.24% O 30.5% |
合成路线1
该中间体在本合成路线中的序号:(II)Reaction of 1,2:5,6-di-O-isopropylidene-3-O-tosyl-a-D-allofuranose (I) with KF in acetamide at 210 oC gives 3-deoxy-3-fluoro-1,2:5,6-di-O-isopropylidene-a-D-glucofuranose (II), which is treated with a 1:1 mixture of metha-nol and 0.7% aqueous H2SO4 to yield 3-deoxy-3-fluoro-1,2-isopropylidene-a-D-glucofuranose (III). Selective acylation of the sugar (III) with benzoyl chloride in pyridine affords the 6-O-benzoyl derivative (IV), which is treated with Amberlite IR-100 (H+) ion-exchange resin in hot dioxane to provide 6-O-benzoyl-3-deoxy-3-fluoro-D-glucofuranose (V). The oxidative cleavage of glucofuranose (V) by means of KIO4 in water results in rearrangement to give 5-O-benzoyl-2-deoxy-2-fluoro-3-O-formyl-D- arabinofuranose (VI), which is deformylated by means of NaOMe in methanol to provide 5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranose (VII). Acylation of the arabinofuranose (VII) with acetic anhydride in pyridine affords the 1,3-di-O-acetyl derivative (VIII), which is treated with HBr in AcOH/CH2Cl2 to yield 3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl bromide (IX) (1). Condensation of compound (IX) with 2-chloroadenine (X) by means of potassium tert-butoxide in different solvents gives the acylated 2-chloroadenosine derivative (XI), which is finally deacylated by means of NaOMe in methanol.
【1】 Bauta, W.E.; Schulmeier, B.E.; Cantrell, W.R. Jr.; Lovett, D.; Puente, J. (Ilex Oncology, Inc.); Process for preparing purine nucleosides. US 2003114663; WO 0311877 . |
【2】 Clayton, S.D., Montgomery, J.A., Riordan, J.M., Secrist, J.A. III., Shortnacy-Fowler, A.T.; Synthesis and biologic activity of 2'-fluoro-2-halo derivatives of 9-beta-D-arabinofuranosyladenine. J Med Chem 1992, 35 (2): 397 |
【3】 Castaner, J., Chilman-Blair, K., Mealy, N.E.; Clofarabine. Drugs Fut 2004, 29 (2): 112 |
【4】 Fox, J.J., Reichman, U., Watanabe, K.A.; A practical synthesis of 2-deoxy-2-fluoro-D-arabinofuranose derivatives. Carbohydr Res 1975, 42 (2): 233 |
【5】 Montgomery, J.A., Secrist, J.A. III (Southern Research Institute); 2-Halo-9-(2-deoxy-2-fluoro-B-D-arabinofuranosyl) adenine nucleoside derivs.. JP 1993502014, US 5034518, WO 9014352 |
【6】 Montgomery, J.A., Secrist, J.A. III, Fowler, A.T. (Southern Research Institute); Methods for synthesizing 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-9H-purin-6-amine. WO 0160383, CA 2400470, EP 1261350 |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(X) | 11644 | 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine | 10310-21-1 | C5H4ClN5 | 详情 | 详情 |
(I) | 63931 | (3aR,5R,6S,6aR)-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl 4-methylbenzenesulfonate | C19H26O8S | 详情 | 详情 | |
(II) | 63932 | (3aR,5R,6S,6aS)-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-6-fluoro-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole | C12H19FO5 | 详情 | 详情 | |
(III) | 63933 | (1S)-1-[(3aR,5R,6S,6aS)-6-fluoro-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-1,2-ethanediol | C9H15FO5 | 详情 | 详情 | |
(IV) | 63934 | (2S)-2-[(3aR,5R,6S,6aS)-6-fluoro-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-2-hydroxyethyl benzoate | C16H19FO6 | 详情 | 详情 | |
(V) | 63935 | (2S)-2-[(2R,3R,4S)-3-fluoro-4,5-dihydroxytetrahydro-2-furanyl]-2-hydroxyethyl benzoate | C13H15FO6 | 详情 | 详情 | |
(VI) | 63936 | [(2R,3R,4S)-4-fluoro-3-(formyloxy)-5-hydroxytetrahydro-2-furanyl]methyl benzoate | C13H13FO6 | 详情 | 详情 | |
(VII) | 63937 | [(2R,3R,4S)-4-fluoro-3,5-dihydroxytetrahydro-2-furanyl]methyl benzoate | C12H13FO5 | 详情 | 详情 | |
(VIII) | 63938 | [(2R,3R,4S)-3,5-bis(acetyloxy)-4-fluorotetrahydro-2-furanyl]methyl benzoate | C16H17FO7 | 详情 | 详情 | |
(IX) | 17691 | [(2R,3R,4S)-3-(acetoxy)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl benzoate | C14H14BrFO5 | 详情 | 详情 | |
(XI) | 63940 | [(2R,3R,4S,5R)-3-(acetyloxy)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl benzoate | C19H17ClFN5O5 | 详情 | 详情 | |
(XII) | 25254 | 2,6-dichloro-9H-purine | 5451-40-1 | C5H2Cl2N4 | 详情 | 详情 |
(XIII) | 63941 | [(2R,3R,4S,5R)-3-(acetyloxy)-5-(2,6-dichloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl benzoate | C19H15Cl2FN4O5 | 详情 | 详情 | |
(XIV) | 63942 | (2R,3R,4S,5R)-5-(2-chloro-6-methoxy-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)tetrahydro-3-furanol | C11H12ClFN4O4 | 详情 | 详情 |