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 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 .

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拉氧头孢钠;英文名Moxalactam disodium;Latamoxef sodium;S-6059(free acid);LY-127935;Shiomarin;Moxam;CAS[64953-12-4]

 
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
华东地区丁二烯市场行情下行
江苏地区丙酮市场弱势下滑
国内甲苯主流出厂价格暂稳
山东地区三氯甲烷价格
江苏地区正丁醇市场最新动态
华南地区醋酸价格稳定
新型杀线虫剂三氟杀线酯成功研发
派姆单抗获 FDA 批准用于原
SDHI类杀菌剂中的潜力股——
啶酰菌胺原药产品登记企业达到2
鲁西地区三氯甲烷企业报价稳定
山东地区丙烷市场行情上涨
燕山周边苯酚市场走势暂稳
山东地区苯酚市场市场暂稳
国内原药市场表现强劲,农药原药
罗氏启动阿尔茨海默病候选药物
华东地区醋酸市场整体稳定
华北地区丁二烯市场维持盘整
山东地区苯酚市场市场稳定
华东地区BDO市场坚挺整理
 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