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【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%

与该中间体有关的原料药合成路线共 1 条

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
Extended Information