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药物详细合成路线

Name Clofarabine;CAFdA;2-Cl-2-F-araA;Clofarex
Chemical Name 2-Chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine
CAS 123318-82-1
Related CAS
Formula C10H11ClFN5O3
Structure
Formula Weight 303.68227
Stage 上市-2005
Company Bioenvision (Orphan Drug), Ilex Oncology (Orphan Drug), Southern Research Institute (Originator), Bioenvision (Licensee), Ilex Oncology (Licensee), Penn (Distributor)
Activity/Mechanism Leukemia Therapy, Lymphocytic Leukemia Therapy, Myeloid Leukemia Therapy, Oncolytic Drugs, Solid Tumors Therapy, DNA Polymerase Inhibitors, Ribonucleoside-Diphosphate Reductase Inhibitors
Syn. Route 1
Route 1
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.
List of intermediates No.
(1r,4s,5s,6s)-2,5-dioxospiro[imidazolidine-4,4-[2]thiabicyclo[3,1,0]hexane]-6-carboxylic acid ethyl ester (ix)
(2s,3s)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxo-3-azetidinecarbaldehyde (xii)
Reference 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 .
Reference 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
Reference 3:
    castaner, j., chilman-blair, k., mealy, n.e.; clofarabine. drugs fut 2004, 29 (2): 112
Reference 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
Reference 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
Reference 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

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名克罗拉滨;英文名Clofarabine;CAFdA;2-Cl-2-F-araA;Clofarex;CAS[123318-82-1]

 
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