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药物详细合成路线

Name Atazanavir sulfate;BMS-232632-05;CGP-73547;BMS-232632(free base);Reyataz
Chemical Name N-[2(S)-Hydroxy-3(S)-[N-(methoxycarbonyl)-L-tert-leucylamino]-4-phenylbutyl]-Nalpha-(methoxycarbonyl)-N-[4-(2-pyridyl)benzyl]-L-tert-leucylhydrazide sulfate salt (1:1)
CAS 229975-97-7
Related CAS 198904-31-3 (free base)
Formula C38H54N6O11S
Structure
Formula Weight 802.95168
Stage 上市-2003
Company Bristol-Myers Squibb (Orphan Drug), Novartis (Originator), Bristol-Myers Squibb (Licensee)
Activity/Mechanism AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, HIV Protease Inhibitors
Syn. Route 3
Route 1
1) the reaction of 4-bromobenzaldehyde (i) with trimethylorthoformate (ii) and p-toluenesulfonic acid in methanol gives ketal (iii), which is condensed with 2-pyridylmagnesium bromide in thf, yielding 4-(2-pyridyl)benzaldehyde (iv). the reaction of (iv) with tert-butyl carbazate (v) in refluxing ethanol affords hydrazone (vi), which is reduced with h2 over pd/c in methanol to the hydrazine (vii). the condensation of (vii) with the epoxide (viii) in hot isopropanol gives the expected addition product (ix), which by treatment with hcl or formic acid results in the fully deprotected intermediate (x). finally, this compound is condensed with n-(methoxycarbonyl)-l-tert-leucine (xi) by means of o-(2-oxo-1,2-dihydro-1-pyridyl)-n,n,n,n-tetramethyluronium tetrafluoroborate (tptu) in dichloromethane or dmf.
List of intermediates No.
1-[2-[(4-hydroxyphenyl)sulfanyl]ethyl]-2,5-pyrrolidinedione (v)
1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (i)
(ii)
4-(4-chlorophenyl)-4-piperidinol; 4-(4-chlorophenyl)-4-hydroxypiperidine (iii)
4-(4-chlorophenyl)-1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinol (iv)
1-(4-fluorophenyl)-4-[4-hydroxy-4-[4-(trimethylstannyl)phenyl]-1-piperidinyl]-1-butanone (vi)
(2s,3r,4s,5s,6r,9s,11s)-9-ethyl-4-hydroxy-2-[(2s,3s,6e)-2-hydroxy-3-methyl-7-(tributylstannyl)-6-heptenyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one (vii)
(2s,4s,5s,6r)-6-[(4r,5r,6s)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]-2-ethyl-4-methyl-1,5-heptanediol (viii)
(2s,4s,5s,6r)-6-[(4r,5r,6s)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]-2-ethyl-5-hydroxy-4-methylheptanamide (ix)
(2s,4s,6s)-6-[(4s,5r,6s)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]-2-ethyl-4-methyl-5-oxoheptanamide (x)
(2s,3r,4s,5s,6r,9s,11s)-9-ethyl-4-hydroxy-2-(2-hydroxyethyl)-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one (xi)
Reference 1:
    new aza-dipeptide analogues as potent and orally a. j med chem 1998, 41, 18, 3387.
Reference 2:
    fassler, a.; bold, g.; capraro, h.-g.; lang, m.; khanna, s.c. (novartis ag); antivirally active heterocyclic azahexane derivs.. ep 0900210; jp 1999511177; us 5849911; wo 9740029 .

Route 2
2) intermediate (ix) can also be obtained as follows: the cyclization of 4-cyanobenzoic acid methyl ester (xii) with acetylene at 15 atm by means of cobaltocene in toluene at 180 c gives 4-(2-pyridyl)benzoic acid methyl ester (xiii), which is saponified with naoh in methanol to the corresponding acid (xiv). the activation of (xiv) with isobutyl chloroformate yields the mixed anhydride (xv), which is condensed with n-(tert-butoxycarbonyl)-l-phenylalaninal (xvi) and kcn in dichloromethane, affording (xvii). the reaction of (xvii) with tert-butyl carbazate (v) by means of acetic acid in methanol gives hydrazone (xviii), which is reduced to hydrazine (xix) by means of sodium cyanoborohydride in thf. the isomerization of (xix) by means of 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (mtde) in hot diglyme yields hydrazide (xx), which is finally reduced to intermediate (ix) with diisobutylaluminum hydride in dichloromethane/thf.
List of intermediates No.
ethyl 3-cyano-3-[3-(cyclopentyloxy)-4-methoxyphenyl]propanoate (xii)
1-[2-[(4-hydroxyphenyl)sulfanyl]ethyl]-2,5-pyrrolidinedione (v)
bromo(4-isobutylphenyl)magnesium (xvi)
(2s,4s,5s,6r)-6-[(4r,5r,6s)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]-2-ethyl-5-hydroxy-4-methylheptanamide (ix)
(2s,3s,4s,5s,6r,9s,11s)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-((2s,3s)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-pentenyl)-9-ethyl-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one (xiii)
(2r,3s)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-((2s,3s,4s,5s,6r,9s,11s)-4-[[tert-butyl(dimethyl)silyl]oxy]-9-ethyl-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl)-2-methylbutanal (xiv)
(e,4s,5s)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-((2s,3s,4s,5s,6r,9s,11s)-4-[[tert-butyl(dimethyl)silyl]oxy]-9-ethyl-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl)-4-methyl-2-hexenal (xv)
diethyl 1-diazo-2-oxopropylphosphonate (xvii)
3-(6-amino-9h-purin-9-yl)-2-nonanol (xviii)
Reference 1:
    fassler, a.; steiner, h.; bold, g.; capraro, h.-g. (novartis ag); process for the preparation of hydrazine derivs. useful as intermediates for the preparation of peptide analogues. wo 9746514 .

Route 3
the intermediate carbazate (vi) has been obtained as follows. the condensation of phenylboronic acid (i) with 2-bromopyridine (ii) by means of pd(pph3)4 gives 4-(2-pyridyl)benzaldehyde (iii), which is condensed with tert-butyl carbazate (iv) in hot toluene/isopropyl alcohol to yield the benzylidenehydrazone (v). finally, this compound is reduced with sodium formate over pd/c in ethanol to afford the target intermediate; the carbazate (vi).the selective monosilylation of the primary oh group of diol (vii) with tbdms-cl, tea and dmap followed by reaction of the secondary oh group with mscl gives the protected mesylate (viii), which is desilylated with nh4f and acoh yielding the primary alcohol (ix). the epoxidation of (ix) with t-buok in isopropyl alcohol affords the chiral epoxide (x), which is condensed with the intermediate carbazate (vi) in refluxing isopropanol to provide the adduct (xi). elimination of the two boc protecting groups of (xi) with hcl in hot thf gives the diamino compound (xii), which is finally condensed with two moles of n-(methoxycarbonyl)-l-tert-leucine (xiii) by means of wsc, hobt and diea in dichloromethane to provide the target atazanavir.
List of intermediates No.
1-[2-[(4-hydroxyphenyl)sulfanyl]ethyl]-2,5-pyrrolidinedione (iv)
4-(4-chlorophenyl)-1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinol (iii)
1-(4-fluorophenyl)-4-[4-hydroxy-4-[4-(trimethylstannyl)phenyl]-1-piperidinyl]-1-butanone (v)
(2s,3r,4s,5s,6r,9s,11s)-9-ethyl-4-hydroxy-2-[(2s,3s,6e)-2-hydroxy-3-methyl-7-(tributylstannyl)-6-heptenyl]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one (vi)
(2s,4s,5s,6r)-6-[(4r,5r,6s)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]-2-ethyl-4-methyl-1,5-heptanediol (x)
(2s,4s,5s,6r)-6-[(4r,5r,6s)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]-2-ethyl-5-hydroxy-4-methylheptanamide (xi)
(2s,4s,6s)-6-[(4s,5r,6s)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]-2-ethyl-4-methyl-5-oxoheptanamide (xii)
(2s,3r,4s,5s,6r,9s,11s)-9-ethyl-4-hydroxy-2-(2-hydroxyethyl)-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one (xiii)
2-(4-amino-3-[[(1r)-1-methyl-2-(4-morpholinyl)-2-oxoethyl]oxy]benzyl)-1h-isoindole-1,3(2h)-dione (ii)
Reference 1:
    xu, z.; singh, j.; schwinden, m.d.; zheng, b.; kissick, t.p.; patel, b.; humora, m.j.; quiroz, f.; dong, l.; hsieh, d.-m.; heikes, j.e.; pudipeddi, m.; lindrud, m.d.; srivastava, s.k.; kronenthal, d.r.; mueller, r.h.; process research and development for an efficient synthesis of the hiv protease inhibitor bms-232632. org. proc. res. & develop. 2002, 6, 3, 323.

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阿扎那韦硫酸盐;英文名Atazanavir sulfate;BMS-232632-05;CGP-73547;BMS-232632(free base);Reyataz;CAS[229975-97-7]

 
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