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药物详细合成路线

Name Valganciclovir hydrochloride;TA-9070;Ro-10-79070/194;RS-79070-194;RS-79070(free base);Valcyte;Valcyt;Cymeval
Chemical Name 5-Amino-3-[1-(hydroxymethyl)-2-(L-valyloxy)ethoxymethyl]-6,7-dihydro-3H-imidazo[4,5-d]pyrimidin-7-one hydrochloride
      L-Valine 2-(guanin-9-ylmethoxy)-3-hydroxypropyl ester hydrochloride
CAS 175865-59-5
Related CAS 175865-67-5 ((R)-isomer), 175865-62-0 ((R)-isomer, free base), 175865-63-1 ((R)-isomer, monoacetate
Formula C14H23ClN6O5
Structure
Formula Weight 390.82961
Stage 上市-2001
Company Roche (Originator), Tanabe Seiyaku (Marketer), Recordati (Licensee)
Activity/Mechanism Anti-Cytomegalovirus Drugs, ANTIINFECTIVE THERAPY, Antiviral Drugs, Chemical Delivery Systems, DRUG DELIVERY, Drug Delivery Systems
Syn. Route 6
Route 1
the silylation of ganciclovir (i) with tmscl and imidazole in dmf gives the n2-silylated compound (ii), which by condensation with n-benzyloxycarbonyl-l-valine-n-carboxyanhydride (iii) and subsequent treatment with 3m hcl yields the monoprotected valganciclovir derivative (iv). finally, this compound is submitted to hydrogenolysis with h2 over pd/c in methanol/hcl.
List of intermediates No.
(3-[6-[3-(4-methoxyphenyl)-1,2-diboriran-3-yl]hexaboranyl]-1,2-diboriran-3-yl)methanol (iii)
2-(tert-butyl)-1,3,4-oxadiazole (i)
tert-butyl (1s)-1-formyl-2-methylpropylcarbamate (ii)
tert-butyl (1s)-1-[[5-(tert-butyl)-1,3,4-oxadiazol-2-yl](hydroxy)methyl]-2-methylpropylcarbamate (iv)
Reference 1:
    sorbera, l.a.; casta?er, j.; casta?er, r.m.; valganciclovir hydrochloride. drugs fut 2000, 25, 5, 474.
Reference 2:
    arzeno, h.b.; beard, c.c.; fisher, l.e.; prince, a. (f. hoffmann-la roche ag); process for preparing purine derivs.. wo 9727194 .

Route 2
the condensation of ganciclovir (i) with the activated l-valine derivative (iii) by means of triethylamine in dmf gives the o,o-bis(valyl)ganciclovir derivative (v), which by selective removal of one of the l-valine groups with propylamine in hexane yields the previously reported monoprotected valganciclovir derivative (iv).
List of intermediates No.
(3-[6-[3-(4-methoxyphenyl)-1,2-diboriran-3-yl]hexaboranyl]-1,2-diboriran-3-yl)methanol (iii)
2-(tert-butyl)-1,3,4-oxadiazole (i)
tert-butyl (1s)-1-[[5-(tert-butyl)-1,3,4-oxadiazol-2-yl](hydroxy)methyl]-2-methylpropylcarbamate (iv)
(2s)-2-amino-1-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-3-methyl-1-butanol (v)
Reference 1:
    sorbera, l.a.; casta?er, j.; casta?er, r.m.; valganciclovir hydrochloride. drugs fut 2000, 25, 5, 474.
Reference 2:
    arzeno, h.b. (f. hoffmann-la roche ag); process for preparing purine derivs.. us 5700936; wo 9727195 .

Route 3
the reaction of ganciclovir (i) with trityl chloride in dmf in the presence of triethylamine and dmap gives the n,o-bis(trityl) compound (vi), which is condensed with the activated l-valine derivative (iii) by means of triethylamine in dmf/toluene to yield the expected valine ester (vii). finally, the trityl groups of (vii) are removed with tfa in trifluoroethanol to afford the previously reported monoprotected compound (iv). the condensation of the tritylated ganciclovir (vi) with n-(tert-butoxycarbonyl)-l-valine (viii) by means of dcc in dichloromethane gives the expected valine ester (ix), which is finally deprotected with tfa in dichloromethane. the valine ester (ix) can also be obtained by condensation of tritylated ganciclovir (vi) with n-(tert-butoxycarbonyl)-l-valine-n-carboxyanhydride (x) by means of triethylamine in dmf.
List of intermediates No.
3-sulfothiophene-2-carboxylic acid; 3-sulfo-2-thiophenecarboxylic acid (viii)
(3-[6-[3-(4-methoxyphenyl)-1,2-diboriran-3-yl]hexaboranyl]-1,2-diboriran-3-yl)methanol (iii)
2-(tert-butyl)-1,3,4-oxadiazole (i)
tert-butyl (1s)-1-[[5-(tert-butyl)-1,3,4-oxadiazol-2-yl](hydroxy)methyl]-2-methylpropylcarbamate (iv)
2-[5-[[(benzyloxy)carbonyl]amino]-6-oxo-2-phenyl-1(6h)-pyrimidinyl]acetic acid (vi)
benzyl 1-[2-([(1s)-1-[[5-(tert-butyl)-1,3,4-oxadiazol-2-yl](hydroxy)methyl]-2-methylpropyl]amino)-2-oxoethyl]-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinylcarbamate (ix)
benzyl 1-[2-[((1s)-1-[[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]carbonyl]-2-methylpropyl)amino]-2-oxoethyl]-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinylcarbamate (x)
tert-butyl 2-[[imino(phenyl)methyl]amino]acetate (vii)
Reference 1:
    sorbera, l.a.; casta?er, j.; casta?er, r.m.; valganciclovir hydrochloride. drugs fut 2000, 25, 5, 474.
Reference 2:
    arzeno, h.b.; humphreys, e.r. (f. hoffmann-la roche ag); process for preparing purine derivs.. us 5756736; wo 9727196 .

Route 4
the reaction of ganciclovir (i) with trimethyl orthoformate and tfa in dmf gives the cyclic orthoester (xi), which is treated with formic acid in dmf/water to yield ganciclovir o-monoformate (xii). the condensation of (xii) with n-benzyloxycarbonyl-l-valine-n-carboxyanhydride (iii) by means of triethylamine in dmf affords the expected monovalinate (xiii), which is deformylated with hcl in methanol/dichloromethane to give the previously reported monoprotected valganciclovir derivative (iv).the preceding reaction sequence can also be performed by substituting trimethyl orthoformate with other orthoesters such as benzyl orthoformate, ethyl orthoacetate, methyl orthoacetate or ethyl orthopropionate.
List of intermediates No.
(3-[6-[3-(4-methoxyphenyl)-1,2-diboriran-3-yl]hexaboranyl]-1,2-diboriran-3-yl)methanol (iii)
2-(tert-butyl)-1,3,4-oxadiazole (i)
tert-butyl (1s)-1-[[5-(tert-butyl)-1,3,4-oxadiazol-2-yl](hydroxy)methyl]-2-methylpropylcarbamate (iv)
methyl (e)-3-methoxy-2-nitro-2-propenoate (xi)
2-[5-nitro-6-oxo-2-phenyl-1(6h)-pyrimidinyl]acetic acid (xii)
Reference 1:
    sorbera, l.a.; casta?er, j.; casta?er, r.m.; valganciclovir hydrochloride. drugs fut 2000, 25, 5, 474.
Reference 2:
    arzeno, h.b.; humphreys, e.r.; wong, j.-w.; roberts, c.r. (f. hoffmann-la roche ag); process for preparing ganciclovir derivs.. us 5840890; wo 9727197 .

Route 5
the condensation of 2-(acetoxymethoxy)-1,3-bis(benzyloxy)propane (xiv) with n2-acetylguanine (xv) by means of hexamethyldisilazane (hmds) and trifluoromethanesulfonic acid gives the n2-acetyl-o,o-dibenzylganciclovir (xvi), which is selectively monodebenzylated with either h2 over pd/c in methanol or cyclohexene and pd(oh)2 in refluxing ethanol, yielding intermediate (xvii), which by deacetylation with nh4oh in methanol affords mono-o-benzylganciclovir (xviii). the condensation of (xviii) with n-benzyloxycarbonyl-l-valine (xix) by means of dcc in dichloromethane gives the expected valine ester (xx), which is finally debenzylated with h2 over pd/c in methanol as before.
List of intermediates No.
2-iodoisophthalic acid (xix)
7-[(1,1-dimethyl-2-propynyl)oxy]-4-methyl-2(1h)-quinolinone (xiv)
tert-butyl 4,8,8-trimethyl-2-oxo-2h-pyrano[2,3-h]quinoline-1(8h)-carboxylate (xvi)
tert-butyl (9r,10r)-9,10-dihydroxy-4,8,8-trimethyl-2-oxo-9,10-dihydro-2h-pyrano[2,3-h]quinoline-1(8h)-carboxylate (xv)
2-[[imino(phenyl)methyl]amino]acetic acid (xvii)
n-allylbenzenecarboximidamide (xviii)
3-allyl-5-nitro-2-phenyl-4(3h)-pyrimidinone (xx)
Reference 1:
    nestor, j.j.; womble, s.w.; maag, h. (f. hoffmann-la roche ag); 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol deriv.. ca 2154721; ep 0694547; es 2083348; jp 1996041061; us 5840891; us 6083953 .
Reference 2:
    sorbera, l.a.; casta?er, j.; casta?er, r.m.; valganciclovir hydrochloride. drugs fut 2000, 25, 5, 474.
Reference 3:
    dvorak, c.a.; beard, c.c.; wren, d.l.; axt, s.d.; han, y.-k.; fatheree, p.r.; nguyen, s.l.; lund, j.p.; fisher, l.e.; arzeno, h.b.; humphreys, e.r. (f. hoffmann-la roche ag); process for preparing purine derivs.. us 6040446; wo 9727198 .

Route 6
the condensation of 1-acetoxy-2-(acetoxymethoxy)-3-(benzyloxy) propane (xxi) with guanine (xxii) by means of hmds and trifluoromethanesulfonic acid gives o-acetyl-o-benzylganciclovir (xxiii), which is deacetylated with naoh in methanol to yield the previously reported mono-o-benzylganciclovir (xviii).the preceding reaction sequence can also be performed by using 1-(benzyloxy)-2-(propionyloxymethoxy)-3-(propionyloxy)propane (xxiv) instead of compound (xxi), yielding intermediate (xxv) and finally the previously reported mono-o-benzylganciclovir (xviii).
List of intermediates No.
n,n-dipropylamine; n-propyl-1-propanamine (xxii)
n-allylbenzenecarboximidamide (xviii)
n-(2-furylmethyl)benzenecarboximidamide (xxi)
3-(2-furylmethyl)-5-nitro-2-phenyl-4(3h)-pyrimidinone (xxiii)
n-(2,2-dimethoxyethyl)benzenecarboximidamide (xxiv)
3-(2,2-dimethoxyethyl)-5-nitro-2-phenyl-4(3h)-pyrimidinone (xxv)
Reference 1:
    sorbera, l.a.; casta?er, j.; casta?er, r.m.; valganciclovir hydrochloride. drugs fut 2000, 25, 5, 474.
Reference 2:
    dvorak, c.a.; beard, c.c.; wren, d.l.; axt, s.d.; han, y.-k.; fatheree, p.r.; nguyen, s.l.; lund, j.p.; fisher, l.e.; arzeno, h.b.; humphreys, e.r. (f. hoffmann-la roche ag); process for preparing purine derivs.. us 6040446; wo 9727198 .

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缬更昔洛韦盐酸盐;英文名Valganciclovir hydrochloride;TA-9070;Ro-10-79070/194;RS-79070-194;RS-79070(free base);Valcyte;Valcyt;Cymeval;CAS[175865-59-5]

 
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