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药物详细合成路线

Name Everolimus;RAD-001;NVP-RAD-001;SDZ-RAD;Certican
Chemical Name [1R,9S,12S[1R(1S,3R,4R)],15R,18R,19R,21R,23S,30S,32S,35R]-1,18-Dihydroxy-12-[2-[4-(2-hydroxyethoxy)-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
      40-O-(2-Hydroxyethyl)rapamycin
      (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-Hexadecahydro-9,27-dihydroxy-3-[2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1(R)-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentaone
CAS 159351-69-6
Related CAS
Formula C53H83NO14
Structure
Formula Weight 958.25076
Stage 上市-2004
Company Novartis (Originator), Guidant (Licensee)
Activity/Mechanism Antiarthritic Drugs, CARDIOVASCULAR DRUGS, IMMUNOMODULATING AGENTS, Immunosuppressants, Oncolytic Drugs, Restenosis Treatment of, Rheumatoid Arthritis, Treatment of, Solid Tumors Therapy, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Treatment of Transplant Rejection, Inhibitors of Signal Transduction Pathways, mTOR Inhibitors, Rapamycins, Rotamase (FKBP12) Inhibitors
Syn. Route 4
Route 1
alkylation of rapamycin (i) with 2-(tert-butyldimethylsilyloxy)ethyl triflate (ii) by means of 2,6-lutidine in hot toluene gives the silylated target compound (iii), which is deprotected by means of 1n hcl in methanol.
List of intermediates No.
1-allyl-5-bromo-4-azepanone (i)
7-chloro-5-(2-chlorophenyl)-1-methyl-2-oxo-2,3-dihydro-1h-1,4-benzodiazepin-4-ium-4-olate (ii)
7-chloro-5-(2-chlorophenyl)-1-methyl-2-oxo-2,3-dihydro-1h-1,4-benzodiazepin-3-yl acetate (iii)
Reference 1:
    casta?er, j.; sorbera, l.a.; leeson, p.a.; sdz-rad. drugs fut 1999, 24, 1, 22.
Reference 2:
    cottens, s.; sedrani, r. (novartis ag; novartis deutschland gmbh); o-alkylated rapamycin derivs. and their use, particularly as immunosuppressants. ep 0663916; ep 0867438; jp 1996502266; jp 1999240884; us 5665772; wo 9409010 .

Route 2
the compound has been obtained biosynthetically by an optimized fermentation process using streptomyces hygroscopicus mutant rsh 1701 with a complex culture medium were [14c]-labeled (1r,3r,4r)-2,3-dichydroxycyclo-hexanecarboxylic acid (i) and [14c]-labeled (s)-pipecolic acid (ii) have been added. this fermentation process yielded [14c]-labeled rapamycin (iii), which was finally selectively o-alkylated at the c-40 position with monosilylated ethylene glycol triflate in dmso/dimethoxyethane.
List of intermediates No.
(1s,2s)-3-amino-1-(2-ethoxyphenoxy)-1-phenyl-2-propanol (ii)
1-allyl-5-bromo-4-azepanone (iii)
(1s,3z,8s,9s,10r,11r)-9-(benzyloxy)-11-[[tert-butyl(dimethyl)silyl]oxy]-8,10,12,12-tetramethyl-1-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-13-oxo-3-tridecenyl acetate (i)
{(2r,3r,5r)-3-(acetyloxy)-4-bromo-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2h)-pyrimidinyl]tetrahydro-2-furanyl}methyl 2-(acetyloxy)-2-methylpropanoate (i)
{(2r,4s,5r)-4-(acetyloxy)-3-bromo-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2h)-pyrimidinyl]tetrahydro-2-furanyl}methyl 2-(acetyloxy)-2-methylpropanoate (ii)
{(2r,3r,5r)-3-(acetyloxy)-4-bromo-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2h)-pyrimidinyl]tetrahydro-2-furanyl}methyl acetate (iii)
Reference 1:
    moenius, t.; et al.; c-14 labelling of nvp rad001 - a new rapamycin derivative. j label compd radiopharm 1999, 42, 1, 29.

Route 3
the reaction of the labeled acylated (+)-bornane-10,2-sultam (iv) with triethyl phosphite gives the phosphonate (v), which is treated with paraformaldehyde, galvinoxyl and k2co3 yielding the acrylate derivative (vi). the cyclization of (vi) with butadiene (vii) by means of diethylaluminum chloride and galvinoxyl (as radical scavenger) affords the cyclohexene-carboxamide derivative (viii), which is hydrolyzed with lioh in thf/water giving the (1r)-3-cyclohexenecarboxylic acid (ix). the oxidation of (ix) with m-chloroperbenzoic acid and triethylamine in ccl4 yielded regioselectively the hydroxylactone (x), which is finally hydrolyzed with hcl to the labeled intermediate (i).
List of intermediates No.
4-hydroxy-1-indanone (x)
(2r)-2-([[(2s)-1-(tert-butoxycarbonyl)pyrrolidinyl]carbonyl]amino)propionic acid (vii)
(2r)-2-([[(2s)-1-((2s)-2-[(tert-butoxycarbonyl)amino]-6-[[(ethylamino)(ethylimino)methyl]amino]hexanoyl)pyrrolidinyl]carbonyl]amino)propionic acid (ix)
(1s,3z,8s,9s,10r,11r)-9-(benzyloxy)-11-[[tert-butyl(dimethyl)silyl]oxy]-8,10,12,12-tetramethyl-1-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-13-oxo-3-tridecenyl acetate (i)
1-isopropoxyvinyl trimethylsilyl ether; [(1-isopropoxyvinyl)oxy](trimethyl)silane (iv)
isopropyl (3s,5r,6r,7s,8s,12z,15s,16e)-15-(acetoxy)-7-(benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-12,16-heptadecadienoate (v)
isopropyl (3s,5r,6s,7s,8s,12z,15s,16e)-15-(acetoxy)-7-(benzyloxy)-3,5-dihydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-12,16-heptadecadienoate (vi)
isopropyl (3s,5r,6s,7s,8s,12z,15s,16e)-15-(acetoxy)-7-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-12,16-heptadecadienoate (viii)
{(2r,3r,5r)-3-(acetyloxy)-4-bromo-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2h)-pyrimidinyl]tetrahydro-2-furanyl}methyl 2-(acetyloxy)-2-methylpropanoate (i)
{(2r,5r)-4-(acetyloxy)-3-bromo-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2h)-pyrimidinyl]tetrahydro-2-furanyl}methyl acetate (iv)
{(2s,5r)-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2h)-pyrimidinyl]-2,5-dihydro-2-furanyl}methyl acetate (v)
{(2s,5r)-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2h)-pyrimidinyl]-2,5-dihydro-2-furanyl}methyl 2-(acetyloxy)-2-methylpropanoate (vi)
2-({(2s,5r)-5-[5-fluoro-2-oxo-4-(1h-1,2,4-triazol-1-yl)-1(2h)-pyrimidinyl]-2,5-dihydro-2-furanyl}methoxy)-1,1-dimethyl-2-propenyl acetate (viii)
2-({(2s,5r)-5-[4-amino-5-fluoro-2-oxo-1(2h)-pyrimidinyl]-2,5-dihydro-2-furanyl}methoxy)-1,1-dimethyl-2-propenyl acetate (ix)
1-(tert-butyl) 3-methyl 5,6-dihydro-1,3(2h)-pyridinedicarboxylate (x)
Reference 1:
    moenius, t.; et al.; c-14 labelling of nvp rad001 - a new rapamycin derivative. j label compd radiopharm 1999, 42, 1, 29.

Route 4
the reaction of the labeled acylated (-)-bornane-10,2-sultam (xi) with benzophenone imine (xii) gives the glycylsultam derivative (xiii), which is alkylated with 4-iodobutyl chloride (xiv) by means of butyllithium and dmpu in thf yielding intermediate (xv). the selective hydrolysis of (xv) with hcl affords the omega-chloro-l-norleucine derivative (xvi), which is cyclized by means of tetrabutylammonium fluoride and diea in hot acetonitrile giving the (2s)-piperidyl derivative (xvii). finally, this compound is hydrolyzed with lioh in thf/water to the labeled intermediate (ii).
List of intermediates No.
(1s,2s)-3-amino-1-(2-ethoxyphenoxy)-1-phenyl-2-propanol (ii)
isopropyl (3s,6r,7s,8s,12z,15s,16e)-15-(acetoxy)-7-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoate (xii)
(3s,6r,7s,8s,12z,15s,16e)-7-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-4,4,6,8,16-pentamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxo-12,16-heptadecadienoic acid (xiii)
(4s,7r,8s,9s,16s)-8-(benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-5,5,7,9-tetramethyl-16-[(e)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxa-13-cyclohexadecene-2,6-dione (xiv)
3-(benzyloxy)-2,2-dimethylpropanal (xv)
(e)-7-(benzyloxy)-6,6-dimethyl-4-hepten-3-one (xvi)
1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone (xvii)
1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone o-methyloxime (xi)
{(2r,4s,5r)-4-(acetyloxy)-3-bromo-5-[5-fluoro-2,4-dioxo-3,4-dihydro-1(2h)-pyrimidinyl]tetrahydro-2-furanyl}methyl 2-(acetyloxy)-2-methylpropanoate (ii)
1-(tert-butyl) 3-methyl 3,6-dihydro-1,3(2h)-pyridinedicarboxylate (xiii)
tert-butyl 3-(hydroxymethyl)-3,6-dihydro-1(2h)-pyridinecarboxylate (xv)
tert-butyl 5-(hydroxymethyl)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (xvi)
(3s,4r,5s)-3-(hydroxymethyl)-5-methyl-4-piperidinol (xvii)
(3r,4r,5r)-5-(hydroxymethyl)-3,4-piperidinediol (xi)
Reference 1:
    moenius, t.; et al.; c-14 labelling of nvp rad001 - a new rapamycin derivative. j label compd radiopharm 1999, 42, 1, 29.

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依维莫司;英文名Everolimus;RAD-001;NVP-RAD-001;SDZ-RAD;Certican;CAS[159351-69-6]

 
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