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 Fumagillin;SR-90144;Fugillin;Fumidil
Chemical Name (2E,4E,6E,8E)-Decatetraenedioic acid (3R,4S,5S6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2.5]oct-6-yl monoester
CAS 23110-15-8
Related CAS
Formula C26H34O7
Structure
Formula Weight 458.55668
Stage III 期临床
Company Sanofi-synthélabo (Originator)
Activity/Mechanism Antifungal Agents, ANTIINFECTIVE THERAPY
Syn. Route 7
Route 1
the chiral cyclohexenone intermediate (vii) was prepared as follows. epoxide ring opening of (s)-glycidol (i) with the grignard reagent (ii) produced diol (iii), which was protected as the isopropylidene ketal (iv) by treatment with 2,2-dimethoxypropane. addition of bromine to olefin (iv) and further cyclization of the resultant dibromide in the presence of potassium hexamethyldisilazide gave rise to the spiro cyclopentene (v). ozonolysis of (v), followed by reductive work-up, yielded the keto aldehyde (vi), which upon treatment with koh underwent intramolecular aldol condensation to the target cyclopentenone (vii).
List of intermediates No.
tert-butyl 6-([2-[4-oxo-2-phenethyl-6-phenyl-3(4h)-quinazolinyl]acetyl]amino)hexylcarbamate (i)
Reference 1:
    taber, d.f.; et al.; synthesis of (-)-fumagillin. j am chem soc 1999, 121, 23, 5589.

Route 2
lithiation of dihydrofuran (viii), followed by the addition of tributylstannyllithium, gave an intermediate (ix) that was quenched with methyl iodide to produce alcohol (x). silylation of alcohol (x) with tert-butyl dimethylsilyl chloride then gave silyl ether (xi). copper-catalyzed conjugate addition of the organolithium reagent derived from (xi) to the intermediate enone (vii), with subsequent enolate trapping with triethylsilyl chloride, afforded adduct (xii) as the major diastereoisomer. epoxidation of the silyl enol ether (xii) with m-chloroperbenzoic acid, followed by selective desilylation using tetrabutylammonium fluoride/ammonium chloride, gave rise to hydroxy ketone (xiii). methylation of (xiii) in the presence of silver oxide yielded methyl ether (xiv). then, the keto group of (xiv) was stereoselectively reduced to (xv) employing l-selectride. after protection of the hydroxyl group of (xv) as the benzoate ester, simultaneous deprotection of the ketal and silyl ether functions under acidic conditions provided triol (xvi). oxidative cleavage of the 1,2-diol moiety of (xvi) with naio4 gave ketone (xvii). this was converted to epoxide (xviii) by stereoselective addition of in situ generated trimethylsulfoxonium ylide.
List of intermediates No.
(1r,6s,9s)-2-[(2e,4e)-2,4-hexadienoyl]-5,6,9-trihydroxy-12-[(z,2e,4e)-1-hydroxy-2,4-hexadienylidene]-1,4,6,9-tetramethyltricyclo[6.2.2.0(2,7)]dodec-4-ene-3,10,11-trione (viii)
Reference 1:
    taber, d.f.; et al.; synthesis of (-)-fumagillin. j am chem soc 1999, 121, 23, 5589.

Route 3
the second epoxide function was introduced into (xviii) upon treatment with m-chloroperbenzoic acid, yielding (xix). oxidation of the primary alcohol of (xix) to aldehyde (xx) was effected by means of dess-martin periodinane reagent. subsequent wittig reaction of aldehyde (xx) with isopropylidene triphenylphosphorane furnished olefin (xxi). the chiral fumagillol (-)-(xxii) was then obtained by hydrolysis of the benzoate ester (xxi) in the presence of methanolic k2co3. finally, condensation of alcohol (-)-(xxii) with the acid chloride (xxiii) led to the title compound.
List of intermediates No.
3-cyano-5-methylhexanoic acid (xxii)
Reference 1:
    taber, d.f.; et al.; synthesis of (-)-fumagillin. j am chem soc 1999, 121, 23, 5589.

Route 4
the synthesis of the racemic fumagillol (+/-)-(xxii) has also been reported. regioselective dihydroxylation of 1,3-cyclohexadiene-1-carbaldehyde (xxiv) using n-methylmorpholine-n-oxide in the presence of a catalytic amount of oso4 afforded the cis-diol (xxv), which was further protected as the isopropylidene ketal (xxvi). conjugate addition to (xxvi) of the organocuprate reagent derived from vinyl bromide (xxvii) in the presence of bf3?et2o produced (xxviii) as a mixture of epimers at c-1, which were used without separation. aldehyde (xxviii) was converted to the cyclohexyl nitrone (xxx) upon treatment with n-cyclohexyl hydroxylamine (xxix) and nahco-3. acetylation of (xxx) produced a transitory n-vinyl-o-acetylhydroxylamine (xxxi) which underwent a [3,3] sigmatropic rearrangement to the alpha-acetoxy-n-cyclohexylimine (xxxii). selective hydrolysis of the imine function of (xxxii) using hoac/naoac furnished aldehyde (xxxiii). this was reduced with lialh4, followed by acidic hydrolysis of the isopropylidene ketal to yield the tetraol (xxxiv).
List of intermediates No.
Reference 1:
    vosburg, d.a.; et al.; a concise synthesis of fumagillol. angew chem. int ed 1999, 38, 7, 971.

Route 5
the primary alcohol group of (xxxiv) was selectively converted to mesylate (xxxv), which was subsequently treated with methanolic naoh to afford the spiro-epoxide (xxxvi). sharpless epoxidation of diene (xxxvi) in the presence of tert-butyl hydroperoxide and vanadyl acetylacetonate gave rise to the bis-epoxide (xxxvii) as the major diastereoisomer. finally, regioselective hydroxyl group alkylation in (xxxvii) under williamsons synthesis conditions furnished the racemic fumagillol (+/-)-(xxii).
List of intermediates No.
3-cyano-5-methylhexanoic acid (xxii)
Reference 1:
    vosburg, d.a.; et al.; a concise synthesis of fumagillol. angew chem. int ed 1999, 38, 7, 971.

Route 6
the cyclization of the chiral diene (i) with acrolein (ii) by means of bf3/et2o in dichloromethane gives the chiral cyclohexene (iii), which is dihydroxylated under upjohn conditions (oso4) yielding the dihydroxy compound (iv). the reaction of (iv) with acetone (v) and tsoh affords the isopropylidene derivative (vi), which is treated with naoh in thf/water to eliminate the chiral auxiliary to yield the cyclohexene carbaldehyde (vii). the regio- and diastereoselective condensation of (vii) with bromide (viii) by means of t-buli and bf3/et2o affords the adduct (ix), which is treated with n-cyclohexyl-hydroxylamine (x) to provide the nitrone (xi). the reaction of (xi) with acetyl chloride gives the alpha-acetoxy-n-cyclohexylimine (xiii), through the intermediate (xii). the hydrolysis of (xiii) with acoh and naoac yields the carbaldehyde (xiv), which is reduced with lialh4 in ethanol to afford the hydroxymethyl derivative (xv). the hydrolysis of the acetoxy and isopropylidene groups of (xv) by means of hcl in thf provides the tetrahydroxy derivative (xvi), which is converted into the epoxide (xvii) by a treatment with mscl, tea, dmap and naoh in dichloromethane. a new epoxidation of (xvii) by means of vo(acac)2 and t-buooh in benzene gives the bis-epoxide compound (xviii), which is finally monomethylated by means of t-buona and mei in thf to yield the target intermediate fumagillol (xix).
List of intermediates No.
3-cyano-5-methylhexanoic acid (xix)
tert-butyl 1-[(1-amino-6-isoquinolinyl)methyl]-2-oxo-2-(1-piperidinyl)ethylcarbamate (ii)
2-[[([(2s,3s,5r)-3-azido-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2h)-pyrimidinyl]tetrahydro-2-furanyl]methoxy)(oxo)phosphoranyl]oxy]-1-[(palmitoyloxy)methyl]ethyl palmitate (v)
Reference 1:
    vosburg, d.a.; et al.; concise stereocontrolled routes to fumagillol, fumagillin, and tnp-470. chirality 2003, 15, 2, 156.

Route 7
the horner-wadsworth-emmons condensation of (e,e)-muconaldehyde (i) with triethyl phosphonoacetate (ii) by means of ba(oh)2 in thf/water gives (e,e,e,e)-decatetraenedioic acid diethyl ester (iii), which is hydrolyzed with lioh to provide the target intermediate; the (e,e,e,e)-decatetraenedioic acid (iv).
List of intermediates No.
4-(benzyloxy)-3-[[tert-butyl(dimethyl)silyl]oxy]phenylboronic acid (ii)
Reference 1:
    vosburg, d.a.; et al.; concise stereocontrolled routes to fumagillol, fumagillin, and tnp-470. chirality 2003, 15, 2, 156.

 
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
河北加氢苯市场稳定
华北地区丁二烯市场延续推涨
华南地区BDO市场商谈横盘
华北地区醋酐市场行情维稳
华东醋酸市场稳定
华东地区MTBE行情平稳
华东地区丁二烯市场报盘走高
华东地区二氯甲烷市场稳定
江苏地区甲苯市场重心上探
华中地区醋酐市场行情暂稳
华东地区醋酐市场行情暂稳
华北醋酸市场盘整
广东醋酸市场盘整
东北地区粗苯市场弱势整理
东北地区粗苯市场弱势整理
山东加氢苯市场盘整
江苏地区二甲苯价格走高
广东地区甲苯二甲苯市场重心探涨
东北地区MTBE行情平稳
山西地区粗苯市场稳定
 友情链接
有机化学人才网  有机化学论坛
首页 | 广告服务 | 建站服务 | 关于我们 | 联系我们 | 版权声明