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藥物詳細合成路線

Name Ritonavir;A-84538;ABT-538;Norvir
Chemical Name N-[N-(2-Isopropylthiazol-4-ylmethyl)-N-methylcarbamoyl]-L-valine 1(S)-benzyl-3(S)-hydroxy-5-phenyl-4(S)-(thiazol-5-ylmethoxycarbonylamino)pentylamide
CAS 155213-67-5
Related CAS
Formula C37H48N6O5S2
Structure
Formula Weight 720.96031
Stage 上市-1996
Company Abbott (Originator), Dainippon Pharmaceutical (Licensee)
Activity/Mechanism AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, HIV Protease Inhibitors
Syn. Route 5
Route 1
the oxidation of n-(benzyloxycarbonyl)-l-phenylalaninol (i) with oxalyl chloride in dmso gives the corresponding aldehyde (ii), which by dimerization with zn dust in dichloromethane yields (2s,3r,4r,5s)-2,5-bis(benzyloxycarbonylamino)-1,6-diphenylhexane-3,4-diol (iii) [along with the (2s,3s,4s,5s)-isomer]. the reaction of (iii) with alpha-acetoxyisobutyryl bromide (iv) in hexane/dichloromethane affords (2s,3r,4r,5s)-2,5-bis(benzyloxycarbonylamino)-4-bromo-1,6-diphenylhexan-3-ol acetate ester (v), which is converted into the corresponding epoxide (vi) with naoh in dioxane/water. the reduction of the epoxide (vi) with nabh4 in thf affords (2s,3s,5s)-2,5-bis(benzyloxycarbonylamino)-1,6-diphenylhexan-3-ol (vii), which is deprotected with ba(oh)2 in refluxing dioxane/water yielding the corresponding diamine (viii). the cyclization of (viii) with phenylboronic acid (ix) in refluxing toluene gives (4s,6s)-6-[1(s)-amino-2-phenylethyl]-4-benzyl-2-phenyl-1,3,2-oxaazaborinane (x), which is condensed with (5-thiazolylmethyl)(4-nitrophenyl)carbonate (xi) in thf to afford (2s,3s,5s)-5-amino-1,6-diphenyl-2-(5-thiazolylmethoxycarbonylamino) hexan-3-ol (xii). finally, this compound is condensed with n-[n-(2-isopropylthiazol-4-ylmethyl)-n-methylaminocarbonyl]-l-valine (xiii) by means of 1-hydroxybenzotriazole (hbt) and n-[3-(dimethylamino)propyl]-n-ethylcarbodiimide (dec) in thf.
List of intermediates No.
(2s)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid (iv)
(6r,7r)-7-[[2-(2-furyl)-2-(methoxyimino)acetyl]amino]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (i)
4-chlorobenzenesulfonyl isocyanate (ii)
sodium (6r,7r)-3-[[(aminocarbonyl)oxy]methyl]-7-[[2-(2-furyl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (iii)
ethyl 2-(2,5-dimethoxybenzyl)-3-oxobutanoate (v)
2,6-diamino-4-pyrimidinylamine (vi)
2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidin-7(8h)-one (vii)
2-amino-7-chloro-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidin-4-ylamine (viii)
(4ar,6r,7r,7as)-6-(6-amino-9h-purin-9-yl)-2,7-dihydroxytetrahydro-4h-2lambda(5)-furo[3,2-d][1,3,2]dioxaphosphinin-2-one (ix)
1-propoxypropane (x)
(4ar,6r,7r,7ar)-6-[6-(butyrylamino)-9h-purin-9-yl]-2-hydroxy-2-oxotetrahydro-4h-2lambda(5)-furo[3,2-d][1,3,2]dioxaphosphinin-7-yl butyrate (xi)
8-bromo-n-ethyl-3,4-dimethoxy-9-phenanthrenamine (xii)
n-(8-bromo-3,4-dimethoxy-9-phenanthryl)-n-ethylbutanamide (xiii)
Reference 1:
    graul, a.; casta?er, j.; ritonavir. drugs fut 1996, 21, 7, 700.
Reference 2:
    al-razzak, l.; marsh, k.c.; manning, l.p.; kaul, d. (abbott laboratories inc.); pharmaceutical compsns. containing hiv protease inhibitors. ep 0732923; us 5484801; wo 9520384 .
Reference 3:
    kempf, d.j.; norbeck, d.w.; sham, h.l.; zhao, c.; sowin, t.j.; reno, d.s.; haight, a.r.; cooper, a.j. (abbott laboratories inc.); retroviral protease inhibiting cpds. ep 0674513; ep 0727419; jp 1996505844; jp 1997118679; jp 1998087639; wo 9414436 .
Reference 4:
    flentge, c.; kempf, d.; marsh, k.; et al.; symmetry-based inhibitors of hiv protease with high oral bioavailability. 207th acs natl meet (march 13-17, san diego) 1994, abst medi 35.

Route 2
the thiazolyl carbonate (xi) has been synthesized as follows:the reaction of formamide (xiv) with p2s5 in ethyl ether gives thioformamide (xv), which is cyclized with 2-chloro-3-oxopropionic acid ethyl ester (xvi) [obtained by condensation of ethyl chloroacetate (xvii) with ethyl formate (xviii) by means of t-buok in thf] yielding thiazol-5-carboxylic acid ethyl ester (xix). the reduction of (xix) with lialh4 in thf affords 5-thiazolylmethanol (xx), which is then esterified with 4-nitrophenyl chloroformate (xxi) by means of 4-methylmorpholine (mph) in dichloromethane to give the desired product (xi).
List of intermediates No.
(4ar,6r,7r,7ar)-6-[6-(butyrylamino)-9h-purin-9-yl]-2-hydroxy-2-oxotetrahydro-4h-2lambda(5)-furo[3,2-d][1,3,2]dioxaphosphinin-7-yl butyrate (xi)
(4r)-5-ethyl-9,10-dimethoxy-4-propyl-4,5-dihydrodibenzo[cd,f]indol-4-ol (xiv)
(4s,5ar)-5-ethyl-10-methoxy-4-propyl-4,5,5a,6-tetrahydrodibenzo[cd,f]indol-9-yl methyl ether (xv)
3,4-dimethoxy-9-phenanthrenecarboxylic acid (xvi)
3,4-dimethoxy-9-phenanthrenamine (xvii)
n-(3,4-dimethoxy-9-phenanthryl)acetamide (xviii)
n-(3,4-dimethoxy-9-phenanthryl)-n-ethylamine (xix)
5-ethyl-9,10-dimethoxydibenzo[cd,f]indol-4(5h)-one (xx)
2-(4-methoxyphenyl)-2-propanol (xxi)
Reference 1:
    graul, a.; casta?er, j.; ritonavir. drugs fut 1996, 21, 7, 700.
Reference 2:
    kempf, d.j.; norbeck, d.w.; sham, h.l.; zhao, c.; sowin, t.j.; reno, d.s.; haight, a.r.; cooper, a.j. (abbott laboratories inc.); retroviral protease inhibiting cpds. ep 0674513; ep 0727419; jp 1996505844; jp 1997118679; jp 1998087639; wo 9414436 .
Reference 3:
    al-razzak, l.; marsh, k.c.; manning, l.p.; kaul, d. (abbott laboratories inc.); pharmaceutical compsns. containing hiv protease inhibitors. ep 0732923; us 5484801; wo 9520384 .
Reference 4:
    flentge, c.; kempf, d.; marsh, k.; et al.; symmetry-based inhibitors of hiv protease with high oral bioavailability. 207th acs natl meet (march 13-17, san diego) 1994, abst medi 35.

Route 3
the n-substituted valine (xiii) has been synthesized as follows:the reaction of isobutyramide (xxii) with phosphorus pentasulfide (p4s10) in ethyl ether gives the corresponding thioamide (xxiii), which is cyclized with 1,3-dichloroacetone (xxiv) by means of mgso4 in refluxing acetone yielding 4-(chloromethyl)-2-isopropylthiazole (xxv). the reaction of (xxv) with methylamine in water affords n-(2-isopropylthiazol-4-ylmethyl)-n-methylamine (xxvi), which is condensed with n-(4-nitrophenoxycarbonyl)-l-valine methyl ester (xxvii) by means of 4-(dimethylamino)pyridine (dmap) and triethylamine in refluxing thf to give the thiazol-substituted l-valine ester (xxviii).finally, this compound is converted into the corresponding free acid with lioh in dioxane/water.the n-(4-nitrophenoxycarbonyl)-l-valine methyl ester (xxvii) has been synthesized by reaction of chloroformate (xxi) with l-valine methyl ester (xxix) by means of 4-methylmorpholine (mph) in dichloromethane.
List of intermediates No.
n-(8-bromo-3,4-dimethoxy-9-phenanthryl)-n-ethylbutanamide (xiii)
2-(4-methoxyphenyl)-2-propanol (xxi)
1-methoxy-4-[2-(4-methoxyphenyl)-1,1,2-trimethylpropyl]benzene (xxii)
7-amino[1,8]naphthyridin-2-ol (xxiii)
6-(7-hydroxy[1,8]naphthyridin-2-yl)-2,3-dihydro-5h-[1,4]dithiino[2,3-c]pyrrole-5,7(6h)-dione (xxv)
6-(7-chloro[1,8]naphthyridin-2-yl)-2,3-dihydro-5h-[1,4]dithiino[2,3-c]pyrrole-5,7(6h)-dione (xxvi)
6-(7-chloro[1,8]naphthyridin-2-yl)-7-hydroxy-2,3,6,7-tetrahydro-5h-[1,4]dithiino[2,3-c]pyrrol-5-one (xxvii)
tert-butyl 4-(chlorocarbonyl)-1-piperazinecarboxylate (xxviii)
1-(tert-butyl) 4-[6-(7-chloro[1,8]naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5h-[1,4]dithiino[2,3-c]pyrrol-5-yl] 1,4-piperazinedicarboxylate (xxix)
Reference 1:
    graul, a.; casta?er, j.; ritonavir. drugs fut 1996, 21, 7, 700.
Reference 2:
    kempf, d.j.; norbeck, d.w.; sham, h.l.; zhao, c.; sowin, t.j.; reno, d.s.; haight, a.r.; cooper, a.j. (abbott laboratories inc.); retroviral protease inhibiting cpds. ep 0674513; ep 0727419; jp 1996505844; jp 1997118679; jp 1998087639; wo 9414436 .
Reference 3:
    al-razzak, l.; marsh, k.c.; manning, l.p.; kaul, d. (abbott laboratories inc.); pharmaceutical compsns. containing hiv protease inhibitors. ep 0732923; us 5484801; wo 9520384 .
Reference 4:
    flentge, c.; kempf, d.; marsh, k.; et al.; symmetry-based inhibitors of hiv protease with high oral bioavailability. 207th acs natl meet (march 13-17, san diego) 1994, abst medi 35.

Route 4
a new method for the preparation of a key diaminoalcohol intermediate in the synthesis of ritonavir has been described:the reaction of l-phenylalanine (xxix) with benzyl chloride by means of k2co3 and koh in hot water gives n,n-dibenzyl-l-phenylalanine benzyl ester (xxx), which is condensed first with acetonitrile by means of nanh2 and then with benzylmagnesium chloride, both reactions in methyl tert-butyl ether, yielding 5-amino-2-(dibenzylamino)-1,6-diphenylhex-4-en-3-one (xxxi). the reduction of (xxxi) with nabh4 with an accurate control of the solvent and acidity, results in an enhanced enantioselectivity towards the desired (s,s,s)-enantiomer of 5-amino-2-(dibenzylamino)-1,6-diphenyl-3-hexanol (xxxii). finally, this compound is deprotected by hydrogenation with ammonium formate over pd/c in methanol/water to provide the target chiral diaminoalcohol (viii).
List of intermediates No.
(2s)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoic acid (xxix)
2-amino-7-chloro-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidin-4-ylamine (viii)
benzyl 4-[2-(1,2,3,5-cyclohexatetraen-1-yl)-6-fluoro-1h-indol-3-yl]-3,6-dihydro-1(2h)-pyridinecarboxylate (xxx)
benzyl 4-(6-fluoro-2-phenyl-1h-indol-3-yl)-3-hydroxy-1-piperidinecarboxylate (xxxi)
7,7-dimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl chloride (xxxii)
Reference 1:
    allen, m.s.; stuk, t.l.; haight, a.r.; et al.; reduction of an enaminone: synthesis of the diamino alcohol core of ritonavir. org process res dev 1999, 3, 2, 94.

Route 5
the reaction of n-(tert-butoxycarbonyl)-l-phenylalanine methyl ester (i) with trimethylphosphonate lithium salt (ii) in thf gives the dimethyl l-phenylalanylmethylphosphonate (iii), which is condensed with 2-phenylacetaldehyde (iv) by means of na2co3 in ethanol yielding the diphenylhexenone (v). the reduction of the carbonyl group of (v) with nabh4 in methanol affords a diastereomeric mixture of alcohols (vi) and (vii) from which the desired major isomer (vii) is separated by column chromatography.. the epoxidation of the double bond of (vii) with mcpba in dichloromethane gives the epoxide (viii) (1), which is cleaved with red-al in thf providing the diol (ix). the reaction of (ix) with ms-cl and diea yields the intermediate dimesylate (x) which, without isolation, affords oxazolidinone (xi). the reaction of (xi) with sodium azide and 18-c-6 in dmso gives the azide (xii), which is treated with nah and boc2o in thf in order to cleave the oxazolidine ring and furnish the protected aminoalcohol (xiii). finally the azido group of (xiii) is hydrogenate with h2 over pd/c in methanol to afford the monoprotected diaminoalcohol (xiv) the target compound.
List of intermediates No.
tert-butyl (2r,4r)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(4-formylphenyl)-1-pyrrolidinecarboxylate (iv)
(4as,4bs,5as,6as,7r,9as,9bs,11r)-7-[2-(acetoxy)acetyl]-3-bromo-11-fluoro-4a,6a-dimethyl-2-oxo-2,4a,5a,6,6a,7,8,9,9a,9b,10,11-dodecahydrocyclopenta[7,8]phenanthro[4b,5-b]oxiren-7-yl acetate (i)
5-methyl-2-nitrophenol (ii)
(6s,8s,9s)-6,11,11-triethyl-9-{(1s)-1-[(4s,5s)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl}-2,2,8-trimethyl-3,3-diphenyl-4,10-dioxa-3,11-disilatridecane; tert-butyl(diphenyl)silyl (2s,4s,5s,6s)-2-ethyl-6-[(4s,5s)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-4-methyl-5-[(triethylsilyl)oxy]heptyl ether (iii)
(2r,3r,4s,5s,6s,8s)-8-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-5-[(triethylsilyl)oxy]decanal (v)
(5s,8s,9s,10s,11s,12s,13s,15s)-15-({[tert-butyl(diphenyl)silyl]oxy}methyl)-8-hydroxy-10-[(4-methoxybenzyl)oxy]-5,9,11,13-tetramethyl-12-[(triethylsilyl)oxy]-1-(trimethylsilyl)-1-heptadecyn-6-one (vi)
(2s,4s,5s,6r,7r,8r)-8-{(4s,6s)-2,2-dimethyl-6-[(1s)-1-methyl-4-pentynyl]-1,3-dioxan-4-yl}-2-ethyl-7-[(4-methoxybenzyl)oxy]-4,6-dimethyl-1,5-nonanediol (vii)
(2s,4s,5s,6r,7r,8r)-8-{(4s,6s)-2,2-dimethyl-6-[(1s)-1-methyl-4-pentynyl]-1,3-dioxan-4-yl}-2-ethyl-5-hydroxy-7-[(4-methoxybenzyl)oxy]-4,6-dimethylnonyl pivalate (viii)
(2s,4s,5s,6s,7s,8r)-8-{(4s,6s)-2,2-dimethyl-6-[(1s)-1-methyl-4-pentynyl]-1,3-dioxan-4-yl}-2-ethyl-7-[(4-methoxybenzyl)oxy]-4,6-dimethyl-5-[(triethylsilyl)oxy]-1-nonanol (ix)
methyl (2s,4s,5s,6s,7s,8r)-8-{(4s,6s)-2,2-dimethyl-6-[(1s)-1-methyl-4-pentynyl]-1,3-dioxan-4-yl}-2-ethyl-7-[(4-methoxybenzyl)oxy]-4,6-dimethyl-5-[(triethylsilyl)oxy]nonanoate (x)
(2s,4s,5s,6s,7s,8r)-8-{(4s,6s)-2,2-dimethyl-6-[(1s)-1-methyl-4-pentynyl]-1,3-dioxan-4-yl}-2-ethyl-7-[(4-methoxybenzyl)oxy]-4,6-dimethyl-5-[(triethylsilyl)oxy]nonanamide (xi)
(2s,4s,6s,7s,8r)-8-{(4s,6s)-2,2-dimethyl-6-[(1s)-1-methyl-4-pentynyl]-1,3-dioxan-4-yl}-2-ethyl-7-[(4-methoxybenzyl)oxy]-4,6-dimethyl-5-oxononanamide (xii)
(2s,3r,4s,5s,6r,9s,11s)-9-ethyl-2-[(2s,3s)-2-hydroxy-3-methyl-6-heptynyl]-4-[(4-methoxybenzyl)oxy]-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one (xiii)
(2s,3ar,6r,7s,7ar)-6-(acetyloxy)-2-methyl-2-(propylsulfanyl)tetrahydro-3ah-[1,3]dioxolo[4,5-b]pyran-7-yl acetate (xiv)
Reference 1:
    norbedo, s.; benedetti, f.; epoxyalcohol route to hydroxyethylene dipeptide isosteres: a new synthesis of the diaminoalcohol core of hiv-protease inhibitor abt-538 (ritonavir). chem commun (london) 2001, 2, 203.
Reference 2:
    benedetti, f.; et al.; versatile and stereoselective synthesis of diamino diol dipeptide isosteres, core units of pseudopeptide hiv protease inhibitors. j org chem 1997, 62, 26, 9348.

來源:藥化網

作者:藥化小編

摘要:本文合成路線介紹的是藥物中文名利托那韋;英文名Ritonavir;A-84538;ABT-538;Norvir;CAS[155213-67-5]

 
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