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药物详细合成路线

Name Temsirolimus;NSC-683864;CCI-779
Chemical Name [1R,9S,12S[1R(1R,3R,4R)],15R,18R,19R,21R,23S,30S,32S,35R]-1,18-Dihydroxy-12-[2-[4-[3-hydroxy-2-(hydroxymethyl)-2-methylpropionyloxy]-3-methoxycyclohexyl]-1-methylethyl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0(4,9)]hexatriaconta-16(E),24(E),26(E),28(E)-tetraene-2,3,10,14,20-pentaone
CAS 162635-04-3
Related CAS 343261-52-9
Formula C56H87NO16
Structure
Formula Weight 1030.31489
Stage 上市-2007
Company Wyeth Pharmaceuticals (Originator)
Activity/Mechanism Breast Cancer Therapy, Oncolytic Drugs, Prostate Cancer Therapy, Renal Cancer Therapy, Solid Tumors Therapy, Inhibitors of Signal Transduction Pathways, mTOR Inhibitors
Syn. Route 2
Route 1
the reaction of rapamycin (iii) with chlorotrimethylsilane and imidazole in acoet gives 31,42-bis-o-(trimethylsilyl)rapamycin, which, without isolation, is partially deprotected with sulfuric acid to provide 31-o-(trimethylsilyl)rapamycin (v). coupling ether (v) with either 2,2,5-trimethyl-1,3-dioxane-5-carboxylic acid chloride (vi) by means of dmap in ch2cl2/dmf or with carboxylic acid (i) pretreated with 2,4,6-trichlorobenzoyl chloride (ii) and diea by means of dmap in ch2cl2 yields the protected rapamycin 42-ester (vii). removing the trimethylsilyl group of (vii) by treatment with 0.5n sulfuric acid in acetone affords ester (viii), which is finally converted into cci-779 by hydrolysis of the ketal group by means of 2n sulfuric acid in thf.
List of intermediates No.
1-allyl-5-bromo-4-azepanone (iii)
4-[(1-formyl-2-naphthyl)oxy]butyric acid (ii)
(2s,5s)-2-[(benzoyloxy)methyl]-1,3-oxathiolane-5-carboxylic acid (v)
(2r,5s)-2-[(benzoyloxy)methyl]-1,3-oxathiolane-5-carboxylic acid (i)
methyl (2r,5r)-5-(acetyloxy)-1,3-oxathiolane-2-carboxylate (vi)
(e)-1-ethyl-1,4-diphenyl-3-butenylamine; (e)-3,6-diphenyl-5-hexen-3-amine (vii)
(e)-1-ethyl-1,4-diphenyl-3-butenylformamide (viii)
Reference 1:
    sorbera, l.a.; del fresno, m.; castaner, j.; cci-779. drugs fut 2002, 27, 1, 7.
Reference 2:
    skotnicki, j.s.; leone, c.l.; schiehser, g.a. (american home products corp.); rapamycin hydroxyesters. ep 0763039; jp 1997512018; us 5362718; wo 9528406 .

Route 2
2,2-bis(hydroxymethyl)propionic acid isopropylidene ketal (i) is activated by treatment with 2,4,6-trichlorobenzoyl chloride (ii) and triethylamine in anhydrous thf at 0 c. the resulting activated acid is then coupled with rapamycin (iii) by means of dmap in benzene to provide the protected rapamycin derivative (iv). finally, cci-779 is obtained by hydrolysis of the ketal group with hcl in thf.
List of intermediates No.
1-allyl-5-bromo-4-azepanone (iii)
4-[(1-formyl-2-naphthyl)oxy]butyric acid (ii)
(2r,5s)-2-[(benzoyloxy)methyl]-1,3-oxathiolane-5-carboxylic acid (i)
(e)-1-ethyl-1,4-diphenyl-3-butenylformamide (iv)
Reference 1:
    sorbera, l.a.; del fresno, m.; castaner, j.; cci-779. drugs fut 2002, 27, 1, 7.
Reference 2:
    noureldin, r.; fortier, g.; cheal, g.k.; shaw, c.-c.; sellstedt, j.h. (american home products corp.); regioselective synthesis of rapamycin derivs.. wo 0123395 .

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西罗莫司脂化物;英文名Temsirolimus;NSC-683864;CCI-779;CAS[162635-04-3]

 
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