有机化学人才网 | 最新人才 | 最新职位 | 技术交易 | 药物合成 |
   
全站搜索: |
  您当前位置:网站首页 >> 药物合成路线图解
 

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]

 
推荐VIP企业
无锡景耀生物科技有限公司
杭州卢普生物科技有限公司
宁波赛伦化工有限公司
苏州昊赛生物科技有限公司
北京嘉盛扬医药科技有限公司
上海泽涵生物医药科技有限公司
河北固安三利化工公司
郑州凯普瑞生物技术有限公司
上海药谷药业有限公司
兰州康寓信生物科技有限公司
湖北朗昕生化药业有限公司
武汉福鑫化工有限公司
嘉兴市英南化工有限公司
苏州迪飞医药科技有限公司
北京富安凯科技有限公司
上海盛中医药化工有限公司
连云港天和化学有限公司
南京晨瑞医药科技有限公司
南京苏如化工有限公司
常州瑞盛化工有限公司
热门文章
面临涨价?6月起部分美国进口的
2018年中国植保市场畅销品牌
江苏地区顺酐市场行情整理
华北地区顺酐市场行情整理
华东地区醋酸价格
华南地区BDO市场行情僵持整理
华东地区苯酚市场稳定
华北地区BDO市场交投清淡
江苏地区二氯甲烷价格下调
华北地区醋酸价格
山东地区辛醇市场走势整理
山东地区醋酸价格
陕西地区醋酸价格
华北地区顺酐市场行情整理
华北地区顺酐市场行情整理
华北地区醋酸价格
华东地区丁二烯市场价格盘整
华东地区甲醛价格持稳
华东地区醋酸价格
华南地区正丁醇市场行情
 友情链接
有机化学人才网  
首页 | 广告服务 | 建站服务 | 关于我们 | 联系我们 | 版权声明