有机化学人才网 | 最新人才 | 最新职位 | 有机化学论坛 | 技术交易 | 药物合成 | 企业大全 | CAS大全 注册 | 登陆
   
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 Moxalactam disodium;Latamoxef sodium;S-6059(free acid);LY-127935;Shiomarin;Moxam
Chemical Name (6R,7R)-7-[2-(4-Hydroxyphenyl)-3-oxido-3-oxopropionamido]-7-methoxy-3-(1-methyl-1H-tetrazol-5-ylsulfanylmethyl)-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid disodium salt
CAS 64953-12-4
Related CAS 64952-97-2 (free base)
Formula C20H18N6Na2O9S
Structure
Formula Weight 564.44486
Stage 上市-1982
Company Shionogi (Originator)
Activity/Mechanism Antibiotics, ANTIINFECTIVE THERAPY, Oxacephems
Syn. Route 6
Route 1
6-(tritylamino)penicillanic acid (i) is converted into the azetidinone (ii), which is treated with p-toluenesulfonic acid to yield the tosylate (iii). the chlorination of (iii) with cl2 in carbon tetrachloride affords the 4-chloroazetidinone (iv), which is condensed with propargyl alcohol (v) by means of agbf4 in thf to give the propargyl ether (vi) as a mixture of cis and trans isomers that is separated by chromatography. the acylation of (vi) with phenylacetyl chloride (vii) and pyridine affords the amide (viii).
List of intermediates No.
1-allyl-2-bromopyridinium bromide (v)
n-[2-(hydroxymethyl)thieno[3,2-c]pyridin-4-yl]benzamide (vii)
(2s)-1-[benzyl(isopropyl)amino]-3-chloro-2-propanol (i)
2-[4-([(2s)-3-[benzyl(isopropyl)amino]-2-hydroxypropyl]oxy)phenyl]acetamide (ii)
2,4,5-trifluoro-3-methylbenzoic acid (iii)
2,4,5-trifluoro-3-methyl-6-nitrobenzoic acid (iv)
2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride (vi)
diethyl 2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)malonate (viii)
Reference 1:
    narisada, m.; et al.; synthetic studies on beta-lactam antibiotics. part 5. a synthesis of 7beta-acylamino-3-methyl-1-oxadethia-3-cephem-4-carboxylic acids. heterocycles 1977, 7, 2, 839.
Reference 2:
    nagata, w.; narisada, m. (shionogi & co. ltd.); arylmalonamido-1-oxadethiacephalosporins. us 4180571 .
Reference 3:
    narisada, m.; nagata, w. (shionogi & co. ltd.); arylmalonamido-1-oxadethiacephalosporins. de 2713370; us 4138486 .

Route 2
the partial hydrogenation of (viii) with h2 over pd/(caco3) in methanol gives the allyl ether (ix), which is epoxidized with mcpba in dichloromethane yielding epoxide (x). epoxide cleavage with the lithium salt of 1-methyltetrazole-5-thiol (xi) in thf affords the isopropanol derivative (xii), which is oxidized with cro3/h2so4 in acetone giving the ketone (xiii). the ozonolysis of the isopropylidene group of (xiii) with o3 in dichloromethane affords the alpha ketoester (xiv), which is reduced with zn/acoh to the alpha hydroxyester (xv). the reaction of (xv) with socl2 and pyridine affords the alpha chloroester (xvi), which by reaction with triphenylphosphine in refluxing dichloromethane gives the alpha triphenylphosphoranylidene acetate (xvii). thermal cyclization of (xvii) in refluxing dioxane affords the oxacephem derivative (xviii), which is deacylated by reaction with pcl5 and pyridine providing the 7-beta-amino oxacephem derivative (xix).
List of intermediates No.
diethyl 2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)malonate (viii)
ethyl 3-oxo-3-(2,4,5-trifluoro-3-methyl-6-nitrophenyl)propanoate (ix)
ethyl (z)-3-ethoxy-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)-2-propenoate (x)
ethyl (z)-3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)-2-propenoate (xi)
ethyl 1-cyclopropyl-6,7-difluoro-8-methyl-5-nitro-4-oxo-1,4-dihydro-3-quinolinecarboxylate (xii)
ethyl 5-amino-1-cyclopropyl-6,7-difluoro-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylate (xiii)
5-amino-1-cyclopropyl-6,7-difluoro-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (xiv)
(xv)
n-[(7s)-5-azaspiro[2.4]hept-7-yl]-2,2,2-trifluoroacetamide (xvi)
5-amino-7-[(7s)-7-[(tert-butoxycarbonyl)amino]-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (xvii)
(xviii)
(3as,6ar)-5-methylenehexahydro-1h-cyclopenta[c]furan-1-one (xix)
Reference 1:
    narisada, m.; et al.; synthetic studies on beta-lactam antibiotics. part 10. synthesis of 7beta-[2-carboxy-2-(4-hydroxyphenyl)acetamido]-7alpha-methoxy-3-[[(1-methyl-1h-tetrazol-5-yl)thio]methyl]-1-oxa-1-dethia-3-cephem-4-carboxylic acid disodium salt (6059-s) and its related. j med chem 1979, 22, 7, 757.
Reference 2:
    nagata, w.; narisada, m. (shionogi & co. ltd.); arylmalonamido-1-oxadethiacephalosporins. us 4180571 .
Reference 3:
    narisada, m.; nagata, w. (shionogi & co. ltd.); arylmalonamido-1-oxadethiacephalosporins. de 2713370; us 4138486 .

Route 3
the reaction of the amino group of (xix) with 3,5-di-tert-butyl-4-hydroxybenzaldehyde (xx) gives the imine (xxi), which is dehydrogenated with nickel peroxide to the quinomethane (xxii). addition of methanol to (xxii) yields the 7-alpha-amino compound (xxiii), which is treated with girard reagent t to afford the 7-beta-amino-7-alpha-methoxyoxacepehem compound (xxiv). the acylation of the nh2 group of (xxiv) with 2-(benzyloxycarbonyl)-2-[4-benzyloxy)phenyl)acetyl chloride (xxv) (obtained by reaction of the corresponding acid (xxvi) with oxalyl chloride) gives the expected amide (xxvii), which is finally deprotected with tfa/anisole or alcl3/anisole.
List of intermediates No.
tert-butyl (1r)-1-benzyl-2-(methylamino)-2-oxoethyl(methyl)carbamate (xx)
(3as,6ar)-5-methylenehexahydro-1h-cyclopenta[c]furan-1-one (xix)
4-(1-azepanyl)-2-butyn-1-ol (xxi)
1-(4-chloro-2-butynyl)azepane (xxii)
9-benzylfluorene (xxiii)
methyl 3-methyl-2-([[4-(4-pyridinyloxy)phenyl]sulfonyl]amino)benzoate (xxiv)
methyl 3-methyl-2-(methyl[[4-(4-pyridinyloxy)phenyl]sulfonyl]amino)benzoate (xxv)
3-methyl-2-(methyl[[4-(4-pyridinyloxy)phenyl]sulfonyl]amino)benzoic acid (xxvi)
3-methyl-2-(methyl[[4-(4-pyridinyloxy)phenyl]sulfonyl]amino)benzoyl chloride (xxvii)
Reference 1:
    narisada, m.; et al.; synthetic studies on beta-lactam antibiotics. part 10. synthesis of 7beta-[2-carboxy-2-(4-hydroxyphenyl)acetamido]-7alpha-methoxy-3-[[(1-methyl-1h-tetrazol-5-yl)thio]methyl]-1-oxa-1-dethia-3-cephem-4-carboxylic acid disodium salt (6059-s) and its related. j med chem 1979, 22, 7, 757.
Reference 2:
    nagata, w.; narisada, m. (shionogi & co. ltd.); arylmalonamido-1-oxadethiacephalosporins. us 4180571 .
Reference 3:
    narisada, m.; nagata, w. (shionogi & co. ltd.); arylmalonamido-1-oxadethiacephalosporins. de 2713370; us 4138486 .

Route 4
1) by condensation of benzhydryl (6r,7r)-7-amino-7-methoxy-3-[[(1-methyl-1h-1,2,3,4-tetraazol-5-yl)sulfanyl]methyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (xxiv) with alpha-diphenylmethoxycarbonyl-alpha-(p-hydroxyphenyl)acetic acid (xxva) by means of et3n and oxalyl chloride in methylene chloride gives the 7-[alpha-diphenylmethoxycarbonyl-alpha-(p-hydroxyphenyl)acetamido]-7alpha-methoxy compound (xxvia). finally, all the protecting groups of (xxvia) are eliminated by treatment with trifluoroacetic acid in anisole.2) compound (xxiv) can also be condensed with alpha-(p-benzyloxyphenyl)malonic acid monobenzyl ester (xxvb) by means of et3n and oxalyl chloride in methylene chloride yielding the 7beta-[alpha-(p-benzyloxyphenyl)-alpha-benzyloxycarbonylacetamido]-7alpha-methoxy compound (xxvib), which is hydrolyzed with trifluoroacetic acid in anisole.3) compound (xxiv) can also be condensed with alpha-(p-methoxybenzyl)oxycarbonyl-alpha-[p-(p-methoxybenzyl)oxyphenylacetic acid (xxvc) by means of et3n and oxalyl chloride in methylene chloride giving the corresponding derivative (xxvic), which can be hydrolyzed with trifluoroacetic acid in anisole.4) finally, compound (xxiv) can also be condensed with p-(p-methoxybenzyloxy)phenylmalonic acid (xxvd) by means of et3n and oxalyl chloride in methylene chloride affording compound (xxvid), which is hydrolyzed with trifluoroacetic in anisole.5) compound (xxiv) can also be condensed with alpha-diphenylmethoxycarbonyl-p-(p-methoxybenzyl)oxyphenylacetic acid (xxve) by means of et3n and oxalyl chloride in methylene chloride affording the corresponding derivative (xxvie), which is hydrolyzed with trifluoroacetic acid in anisole.
List of intermediates No.
2,2-bis(2-bromoethyl)-1,3-dioxolane (xxiv)
benzyl (1s)-5-[[(benzyloxy)carbonyl]amino]-1-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]pentylcarbamate (xxva)
benzyl (1s,38s)-38-[[(benzyloxy)carbonyl]amino]-1-(4-[[(benzyloxy)carbonyl]amino]butyl)-13,26-bis((12s)-12-[[(benzyloxy)carbonyl]amino]-4,11,18-trioxo-20-phenyl-19-oxa-3,10,17-triazaicos-1-yl)-2,9,14,25,30,37,44-heptaoxo-46-phenyl-15,18,21,24,45-pentaoxa-3,10,13,26,29,36,43-heptaazahexatetracont-1-ylcarbamate (xxvb)
(23s)-11-(2-[[6-([(2s)-2,6-bis[(2-chloroacetyl)amino]hexanoyl]amino)hexanoyl]amino]ethyl)-30-chloro-23-[(2-chloroacetyl)amino]-10,15,22,29-tetraoxo-3,6,9-trioxa-11,14,21,28-tetraazatriacont-1-yl bis(2-[[6-([(2s)-2,6-bis[(2-chloroacetyl)amino]hexanoyl]amino)hexanoyl]amino]ethyl)carbamate (xxvc)
[4-(benzyloxy)phenoxy](tert-butyl)diphenylsilane; benzyl 4-[[tert-butyl(diphenyl)silyl]oxy]phenyl ether (xxvd)
4-[[tert-butyl(diphenyl)silyl]oxy]phenol (xxve)
tert-butyl[4-[(2s)oxiranylmethoxy]phenoxy]diphenylsilane; tert-butyl(diphenyl)silyl 4-[(2s)oxiranylmethoxy]phenyl ether (xxvia)
tert-butyl 4-[(1-benzyl-4-piperidinyl)amino]phenethylcarbamate (xxvib)
tert-butyl 4-(4-piperidinylamino)phenethylcarbamate (xxvic)
1-isocyanatooctane; octyl isocyanate (xxvid)
tert-butyl 4-([1-[(octylamino)carbonyl]-4-piperidinyl]amino)phenethylcarbamate (xxvie)
Reference 1:
    serradell, m.n.; blancafort, p.; castaner, j.; s-6059. drugs fut 1979, 4, 9, 667.
Reference 2:
    narisada, m.; nagata, w. (shionogi & co. ltd.); arylmalonamido-1-oxadethiacephalosporins. de 2713370; us 4138486 .

Route 5
the epoxidation of alpha-(3beta-benzamido-4beta-allyloxy-2-oxoazetidin-1-yl)-alpha-isopropylilideneacetic acid diphenylmethyl ester (i) with a peracid gives the corresponding epoxide in the allyl group (ii), which is chlorinated with tert-butyl hypochlorite affording the chloro epoxide (iii). the methoxylation of (iii) with lithium methoxide yields the 3beta-benzamido-3alpha-methoxy derivative (iv), which is condensed with lithium 1-methyltetrazol-5-ylmercaptide (v) to afford the tetrazol derivative (vi). the oxidation of (vi) with cro3 affords the ketonic compound (vii), which is debenzoylated by treatment with pcl5, meoh and triethylamine giving alpha-[3beta-amino-3alpha-methoxy-4beta-[3-(1-methyltetrazol-5-yl)thiomethyl-2-oxopropoxy]-2-oxoazetidine-1-yl]-alpha-isopropylidieneacetic acid diphenylmethyl ester (viii). the condensation of (viii) with alpha-(p-benzyloxyphenyl)-alpha-(benzyloxycarbonyl)acetyl chloride (ix) by means of triethylamine affords the 3beta-[alpha-(benzyloxyphenyl)-alpha-(benzyloxycarbonyl)acetamido] derivative (xx).
List of intermediates No.
methyl 3-methyl-2-(methyl[[4-(4-pyridinyloxy)phenyl]sulfonyl]amino)benzoate (ix)
4-[4-(2-aminoethyl)anilino]-n-octyl-1-piperidinecarboxamide (i)
4-[4-(2-[[(2s)-3-(4-[[tert-butyl(diphenyl)silyl]oxy]phenoxy)-2-hydroxypropyl]amino]ethyl)anilino]-n-octyl-1-piperidinecarboxamide (ii)
3-methoxy-4-(tetrahydro-2h-pyran-2-yloxy)benzaldehyde (iii)
1-hydroxyacetone (iv)
1-(tetrahydro-2h-pyran-2-yloxy)acetone (v)
4-hydroxy-4-[3-methoxy-4-(tetrahydro-2h-pyran-2-yloxy)phenyl]-1-(tetrahydro-2h-pyran-2-yloxy)-2-butanone (vi)
(e)-1-hydroxy-4-(4-hydroxy-3-methoxyphenyl)-3-buten-2-one (vii)
(e)-1-hydroxy-4-[3-methoxy-4-[(trimethylsilyl)oxy]phenyl]-3-buten-2-one (viii)
(e)-3-[3-methoxy-4-[(trimethylsilyl)oxy]phenyl]-2-propenoic acid (x)
Reference 1:
    serradell, m.n.; blancafort, p.; castaner, j.; s-6059. drugs fut 1979, 4, 9, 667.
Reference 2:
    narisada, m.; nagata, w. (shionogi & co. ltd.); arylmalonamido-1-oxadethiacephalosporins. de 2713370; us 4138486 .

Route 6
the isopropylidene group of (x) is oxidized with ozone affording the corresponding diketonic compound (xi), which is reduced selectively with zn and acetic acid yielding the hydroxy ketone (xii). the reaction of (xii) with socl2 affords the corresponding chloro ketone (xiii), which is treated with triphenylphosphine in a basic medium to give alpha-[3beta-[alpha-(p-benzyloxyphenyl)-alpha-(benzyloxycarbonyl)acetamido]-3alpha-methoxy-4beta-[-3-(1-methyltetrazol-5-yl)thiomethyl-2-oxopropoxy]-2-oxoazetidine-1-yl]-alpha-triphenylphosphoranylideneacetic acid diphenylmethyl ester (xiv). finally, this compound is treated with refluxing dioxane affording the protected 1-oxa-dethia-3-cephem compound (xv), which is deprotected with trifluoroacetic acid in anisole.
List of intermediates No.
3-methyl-2-(methyl[[4-(4-pyridinyloxy)phenyl]sulfonyl]amino)benzoyl chloride (xv)
(e)-3-[3-methoxy-4-[(trimethylsilyl)oxy]phenyl]-2-propenoic acid (x)
(e)-4-[3-methoxy-4-[(trimethylsilyl)oxy]phenyl]-2-oxo-3-butenyl (e)-3-[3-methoxy-4-[(trimethylsilyl)oxy]phenyl]-2-propenoate (xi)
sodium (z)-1-cyano-3-ethoxy-3-oxo-1-propen-2-olate (xii)
2-(4-morpholinyl)malononitrile (xiii)
(3,4-dihydroxy-2-methoxyphenyl)(phenyl)methanone (xiv)
Reference 1:
    serradell, m.n.; blancafort, p.; castaner, j.; s-6059. drugs fut 1979, 4, 9, 667.
Reference 2:
    narisada, m.; nagata, w. (shionogi & co. ltd.); arylmalonamido-1-oxadethiacephalosporins. de 2713370; us 4138486 .

 
推荐VIP企业
杭州卢普生物科技有限公司
宁波赛伦化工有限公司
无锡景耀生物科技有限公司
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
2018年第12届韩国国际实验
2017上海国际污泥处理处置设
2017年泰国国际石油天然气展
华中地区醋酐市场行情暂稳
2018年欧洲精细化工展览会(
2018年第十六届俄罗斯国际实
2018年第69届美国匹兹堡实
2017’中国国际石墨烯创新大
广东醋酸丁酯市场平稳运行
华东醋酸丁酯市场整理运行
华北地区醋酐市场行情稳定
2018年埃及国际化工染料展
2017(第十三届)中国国际水
2017上海国际航空航天材料展
2017年欧洲德国制药原料展
2017年第十九届中东迪拜水处
2017中国国际化工科学仪器、
广东醋酸乙酯市场盘整运行
2018上海环保展览会|201
2018沈阳国际润滑油、脂展览
 友情链接
有机化学人才网  有机化学论坛
首页 | 会员级别 | 广告服务 | 建站服务 | 关于我们 | 联系我们 | 版权声明