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 Cidofovir;GS-0504;GS-504;HPMPC;Forvade;Vistide
Chemical Name (S)-1-(3-Hydroxy-2-phosphonylmethoxypropyl)cytosine
      [(S)-2-[4-Amino-2-oxo-1(2H)-pyrimidinyl]-1-(hydroxymethyl)ethoxymethyl]phosphonic acid
CAS 113852-37-2
Related CAS 149394-66-1 (dihydrate), 120362-37-0 (Na salt)
Formula C8H14N3O6P
Structure
Formula Weight 279.19108
Stage 上市-1996
Company Academy of Sciences of Czech Republic (Originator), Rega Institute for Medical Research (Originator), National Institutes of Health (Not Determined), Gilead (Licensee), Pfizer (Licensee)
Activity/Mechanism Anti-Cytomegalovirus Drugs, Anti-Herpes Simplex Virus Drugs, Anti-Herpes Virus Drugs, ANTIINFECTIVE THERAPY, Antiviral Drugs, DNA Polymerase Inhibitors
Syn. Route 3
Route 1
1) the reaction of 1-[2(s),3-dihydroxypropyl]cytosine (i) with chloromethylphosphoryl dichloride (ii) in triethyl phosphate, followed by hydrolysis with boiling water gives the chloromethylphosphonate (iii), which is then isomerized with aqueous naoh at 80 c.
List of intermediates No.
4-bromophenyl methanesulfonate (i)
4-(6-methoxy-1-benzothiophen-2-yl)phenyl methanesulfonate (ii)
4-(6-hydroxy-1-benzothiophen-2-yl)phenyl methanesulfonate (iii)
Reference 1:
    fromtling, r.a.; castaner, j.; cidofovir. drugs fut 1996, 21, 10, 1003.
Reference 2:
    holy, a.; rosenberg, i.; de clercq, e. (czech academy of sciences; rega institute for medical research); n-phosphonylmethoxyalkyl derivs. of pyrimidine and urine bases, methods for their preparation and pharmaceutical compsns. therefrom with antiviral activity. ep 0253412; jp 1988045289; us 5142051; us 5869467 .

Route 2
2) the reaction of 2(r),3-o-isopropylideneglycerol (iv) with benzyl bromide by means of benzyltriethylammonium bromide (bta) in refluxing aqueous naoh gives (s)-3-o-benzylglycerol (v), which is monotritylated with 4-methoxytriphenylmethyl chloride (vi) and dimethylaminopyridine (dmap) yielding the secondary alcohol (vii). the condensation of (vii) with diethyl tosyloxymethylphosphonate (viii) by means of nah in thf affords the fully protected phosphorylmethoxy derivative (ix), which is detritylated by treatment with aqueous acetic acid at 100 c to give 3-benzyloxy-2(s)-(diethoxyphosphorylmethoxy)-1-propanol (x). the reaction of (x) with methanesulfonyl chloride and triethylamine in dichloromethane yields the corresponding mesylate (xi), which is condensed with cytosine (xii) by means of cesium carbonate in hot dmf affording 1-[3-benzyloxy-2(s)-(diethoxyphosphorylmethoxy)propyl]cytosine (xiii). the debenzylation of (xiii) by treatment with pd(oh)2 on carbon in refluxing ethanol/cyclohexene gives the corresponding alcohol (xiv), which is finally treated with bromotrimethylsilane in acetonitrile to eliminate the ethyl groups of the phosphonate.
List of intermediates No.
4-[6-(benzyloxy)-1-benzothiophen-2-yl]phenyl methanesulfonate (iv)
4-[6-(benzyloxy)-1-benzothiophen-2-yl]phenol (v)
6-(benzyloxy)-2-(4-methoxyphenyl)-1-benzothiophene; benzyl 2-(4-methoxyphenyl)-1-benzothiophen-6-yl ether (vi)
6-(benzyloxy)-3-bromo-2-(4-methoxyphenyl)-1-benzothiophene; benzyl 3-bromo-2-(4-methoxyphenyl)-1-benzothiophen-6-yl ether (vii)
6-(benzyloxy)-3-bromo-2-(4-methoxyphenyl)-1h-1-benzothiophen-1-one (viii)
4-[2-(1-piperidinyl)ethoxy]phenol (ix)
6-(benzyloxy)-2-(4-methoxyphenyl)-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-1h-1-benzothiophen-1-one (x)
benzyl 2-(4-methoxyphenyl)-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-1-benzothiophen-6-yl ether; 1-[2-(4-[[6-(benzyloxy)-2-(4-methoxyphenyl)-1-benzothiophen-3-yl]oxy]phenoxy)ethyl]piperidine (xi)
isonicotinic acid (xii)
p-phthalic acid monomethyl ester chloride; terephthalic acid monomethyl ester chloride; methyl 4-chlorocarbonylbenzoate (xiii)
1,4-diazepane (xiv)
Reference 1:
    martin, j.c.; webb, r.r. ii, wos, j.a.; bronson, j.j.; synthesis of (s)-n1-(3-hydroxy-2-phosphonylmethoxy)propylcytosine, (s)-hpmpc. tetrahedron lett 1988, 29, 5475-8.
Reference 2:
    fromtling, r.a.; castaner, j.; cidofovir. drugs fut 1996, 21, 10, 1003.
Reference 3:
    bronson, j.j.; ghazzouli, i.; hitchcock, m.j.m.; webb, r.r. ii, martin, j.c.; synthesis and antiviral activity of the nucleotide analogue (s)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine. j med chem 1989, 32, 7, 1457-63.
Reference 4:
    martin, j.c.; bronson, j.j.; webb, r.r. ii, hitchcock, m.j.m.; ghazzouli, i.; synthesis and antiherpesvirus activity of (s)-1-((3-hydroxy-2-phosphonylmethoxy)propyl)cytosine (hpmpc) and related nucleotide analogues. nucleosides nucleotides 1989, 8, 5-6, 923-6.

Route 3
3) the reaction of 2(s),3-o-isopropylideneglycerol (xv) with methanesulfonyl chloride and triethylamine in dichloromethane gives the corresponding mesylate (xvi), which is condensed with cytosine (xii) by means of cesium carbonate as before yielding 1-[2(s),3-(isopropylidenedioxy)propyl]cytosine (xvii). the deprotection of (xvii) with aqueous acetic acid at 100 c affords the corresponding diol (xviii), which is treated with trityl chloride, dmap and triethylamine in dmf to give the monotrityl compound (xix). the condensation of (xix) with diethyl tosyloxymethylphosphonate (viii) [obtained by reaction of diethylphosphite (xx) with paraformaldehyde, followed by tosylation with tosyl chloride] by a previous treatment of (xx) with dmf dimethylacetal, then condensation by means of nah in dmf, and a final hydrolysis with hot aqueous acetic acid yields the 1-[2(s)-(diethoxyphosphorylmethoxy)-3-hydroxypropyl]cytosine (xiv) (already obtained), which is finally treated with bromotrimethylsilane as before.4) the reaction of the acetonide (xvi) with n4-benzoylcytosine (xxi) by means of potassium tert-butoxide or cesium carbonate gives the condensation product (xxii), which is deprotected with hcl in acetic acid yielding the diol (xxiii). the reaction of (xxiii) with trityl chloride and dmap in refluxing pyridine affords the monotritylated compound (xxiv), which is condensed with the phosphonate (viii) by means of nah in dmf to give the fully protected hpmpc compound (xxv).the successive deprotections of (xxv), first with hcl in dichloromethane to eliminate the trityl group yielding (xxvi), then with bromotrimethylsilane to obtain the free phosphono group giving (xxvii), and finally with concentrated aqueous nh4oh to eliminate the benzoyl group affords cidofovir.5) the benzoylation of acetonide derivative (xvii) with benzoyl anhydride in refluxing pyridine gives the benzoyl citosine derivative (xxii) already obtained.
List of intermediates No.
4-bromophenyl methanesulfonate (xviii)
6-(benzyloxy)-3-bromo-2-(4-methoxyphenyl)-1h-1-benzothiophen-1-one (viii)
isonicotinic acid (xii)
1,4-diazepane (xiv)
diethyl n-(4-aminobenzoyl)glutamate; diethyl 2-[(4-aminobenzoyl)amino]pentanedioate (xv)
2-amino-1,3-benzothiazole-6-carboxylic acid (xvi)
4-amino-3-sulfanylbenzoic acid hydrochloride (xvii)
methyl 4-[(4-methylphenyl)sulfonyl]-3,4-dihydro-2h-1,4-benzothiazine-7-carboxylate (xix)
4-[(4-methylphenyl)sulfonyl]-3,4-dihydro-2h-1,4-benzothiazine-7-carboxylic acid (xx)
dimethyl 2-[([4-[(4-methylphenyl)sulfonyl]-3,4-dihydro-2h-1,4-benzothiazin-7-yl]carbonyl)amino]hexanedioate (xxi)
4-ethylbenzaldehyde (xxii)
6-(4-ethylstyryl)-2,4-pteridinediamine (xxiii)
butyric anhydride (xxiv)
n-[2-(butyrylamino)-6-(4-ethylstyryl)-4-pteridinyl]butanamide (xxv)
n-[2-(butyrylamino)-6-formyl-4-pteridinyl]butanamide (xxvi)
n-[2-(butyrylamino)-6-(hydroxymethyl)-4-pteridinyl]butanamide (xxvii)
Reference 1:
    fromtling, r.a.; castaner, j.; cidofovir. drugs fut 1996, 21, 10, 1003.
Reference 2:
    bronson, j.j.; ferrara, l.m.; howell, h.g.; brodfuehrer, p.r.; martin, j.c.; a new synthesis of the potent and selective anti-herpesvirus agent (s)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine. nucleosides nucleotides 1990, 9, 6, 745-69.

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西多福韦;英文名Cidofovir;GS-0504;GS-504;HPMPC;Forvade;Vistide;CAS[113852-37-2]

 
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
山东地区醋酸价格
陕西地区醋酸价格
江苏地区醋酸价格
浙江地区醋酸价格
山东地区醋酸价格
华北地区醋酸价格
河北地区醋酸价格
华北地区BDO市场低位整理
华东地区BDO市场偏弱运行
江苏地区醋酸价格
华北地区顺酐市场行情整理
河南地区醋酸价格
华北地区醋酸价格
华北地区醋酸价格
江苏地区醋酸价格
华北地区BDO市场低位整理
河北地区醋酸价格
江苏地区醋酸价格
浙江地区醋酸价格
华南地区BDO市场走势偏弱
 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