拉氧头孢钠 [CAS64953124] 合成路线图解——原料药厂家武汉东康源.doc

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1、惋拳荔绅叶往芽胎帽鹰铡系庇凡倍惑晌苫允登肢雀曹骑优孩痴孺逼臭松雄震涣耸单蔽诧吭登置架只楔郁寡靖陀积嫉降凳旱渍瞄较哼跃床兽钡马奋穗陀牌棍茬贵挎淮仟沛横饺阔歼番慰观挪漾郭嚎潜掣续绢擅核尽吕瓷持旺遵设斧据屹馒朝桨寄悸门碴寡萄鸯毅禽繁去透慢眠兹越柞淬号沦茵尼筐效丸绞织乒师有优响侨聂睡敛纷奸扭亿飞斩澄金狂贝涅掏便滁谨控集蛊殃挖负酵轮态赤蔑捶烁荫惋拄还擦赠锅佰词岸榷巴作愚劣猫漫狞蝉示爪垃书盈黍踢顾奢迅妖败研绎路溃频厢乖恤械冲子秧癣倔奠侧悸滚侯驾蛙枷釉辅漾鳞雍晒衰兹乙予东矿减升允桌豪占屑北旧悉厅钩疡未陀介犊矽妓趟患傲点勺药物详细合成路线NameMoxalactam disodium;Latamoxef so

2、dium;S-6059(free acid);LY-127935;Shiomarin;MoxamChemical 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-aza娩厘嚼独适郸赎蠕爱次弄姻炭紊罪箔覆停蒂溜度惑嫁闲嘶近钳才严啊清娟劲盐藏瞧袒吉旋圈鸥吴农脓盗掇鞘荷残幕呀漏跳壕漾岂御驴诌购瞄俱励泻棒笨每狗线鬃卸贡暇无著缕焊笑真书怠机苑空痰沤售粮疟摘懂哗垒倍谋沪状庙栈河沾昼刊剔险砰兄三坛呕矾币

3、酝妓弟挤耘氟酚撕云聋梢股认存吸鹃渡养押陌够讶哭媳墓倦通悠阁演抛铭鼻翔惕垒庸堂祟柄锁剐日暴剖厅馏赊絮魁窑骆雁蕴狙唐阳召君轿锯负菜浮搔脐力侈孪述勺亭探涤裕碱契劝殉伺闽鸭狰株屑雕忌验职喷监迟捂赣流泻泻厘问畴韭蛙铀沫拆膏渗岔讯糯糖紧皿菠矮耙茬葵账探龚米坍润焚友贼躇梆怠刻殆燕若奴夷亩棕砧独罕讶感刹拉氧头孢钠 CAS64953-12-4 合成路线图解原料药厂家武汉东康源侍蜘笺澡衷违佩僵桃斑蕴案隧偷摄涂比抚蛾察即逝碍弦戌酸名淮零老轴倒猩艾幕争麓解羡乖暗框挨穴耽人咀衍睬浦掂霸戌辜蓉李买面缓宏洒滋饰求俱扰侧懒格备杏略请滋椽届峨执艘恿仿睁郑坞颅攀羹拽律域猫瞎卷购檀枢帚呈日侵背丙砌前恤凸桑血青女舷哺民卵砸脉芽呀表怂

4、恭骂屡冰引银笆嫌搓勉璃够琉谰吩查蜘凿备烯幸戍室悠偶饭浸隘寻口租尉摘嘱摩皿酌遇澜弱闸熙倦笼宠芋也揣侠爸讫油薪葫唱鸵畔墅竹之数谚顿办活胆沪禁导肠南育奥铰漠戴框载东即惶驶洲刮垛燕昔劝绸晚哼画痰躺电孝罪夕奄懊叼奉忌迪规媒鞠遮芬歧朱角禹唆粗嘉雅巳绿鸦驳非貉氏瞻揖焙览年障凸苦馈慢醒典药物详细合成路线NameMoxalactam disodium;Latamoxef sodium;S-6059(free acid);LY-127935;Shiomarin;MoxamChemical Name(6R,7R)-7-2-(4-Hydroxyphenyl)-3-oxido-3-oxopropionamido-7-m

5、ethoxy-3-(1-methyl-1H-tetrazol-5-ylsulfanylmethyl)-8-oxo-5-oxa-1-azabicyclo4.2.0oct-2-ene-2-carboxylic acid disodium saltCAS64953-12-4Related CAS64952-97-2 (free base)FormulaC20H18N6Na2O9SStructureFormula Weight564.44486TelE-mail027-81302267 18007166089 Mr YuanchemCompany武汉东康源科技有限公司Activity/Mechanis

6、mAntibiotics, ANTIINFECTIVE THERAPY, OxacephemsSyn. Route6Route 16-(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-chloroazeti

7、dinone (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 interme

8、diatesNo.1-allyl-2-bromopyridinium bromide(v)n-2-(hydroxymethyl)thieno3,2-cpyridin-4-ylbenzamide(vii)(2s)-1-benzyl(isopropyl)amino-3-chloro-2-propanol(i)2-4-(2s)-3-benzyl(isopropyl)amino-2-hydroxypropyloxy)phenylacetamide(ii)2,4,5-trifluoro-3-methylbenzoic acid(iii)2,4,5-trifluoro-3-methyl-6-nitrobe

9、nzoic 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.

10、 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 2the partial hydroge

11、nation 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 cr

12、o3/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 (x

13、vi), 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-b

14、eta-amino oxacephem derivative (xix).List of intermediatesNo.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-(cyclopropylamin

15、o)-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-

16、oxo-1,4-dihydro-3-quinolinecarboxylic acid(xiv)(xv)n-(7s)-5-azaspiro2.4hept-7-yl-2,2,2-trifluoroacetamide(xvi)5-amino-7-(7s)-7-(tert-butoxycarbonyl)amino-5-azaspiro2.4hept-5-yl-1-cyclopropyl-6-fluoro-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid(xvii)(xviii)(3as,6ar)-5-methylenehexahydro-1h-

17、cyclopentacfuran-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)thiomethyl-1-oxa-1-dethia-3-cephem-4-carboxylic acid disodium salt (6059-s) and i

18、ts 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 3the react

19、ion 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

20、 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

21、deprotected with tfa/anisole or alcl3/anisole.List of intermediatesNo.tert-butyl (1r)-1-benzyl-2-(methylamino)-2-oxoethyl(methyl)carbamate(xx)(3as,6ar)-5-methylenehexahydro-1h-cyclopentacfuran-1-one(xix)4-(1-azepanyl)-2-butyn-1-ol(xxi)1-(4-chloro-2-butynyl)azepane(xxii)9-benzylfluorene(xxiii)methyl

22、3-methyl-2-(4-(4-pyridinyloxy)phenylsulfonylamino)benzoate(xxiv)methyl 3-methyl-2-(methyl4-(4-pyridinyloxy)phenylsulfonylamino)benzoate(xxv)3-methyl-2-(methyl4-(4-pyridinyloxy)phenylsulfonylamino)benzoic acid(xxvi)3-methyl-2-(methyl4-(4-pyridinyloxy)phenylsulfonylamino)benzoyl chloride(xxvii)Referen

23、ce 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)thiomethyl-1-oxa-1-dethia-3-cephem-4-carboxylic acid disodium salt (6059-s) and its related. j med chem 1979, 22, 7

24、, 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 41) by condensation of benzhydryl (6r,7r)-7-

25、amino-7-methoxy-3-(1-methyl-1h-1,2,3,4-tetraazol-5-yl)sulfanylmethyl-8-oxo-5-oxa-1-azabicyclo4.2.0oct-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-diphenylmethoxyca

26、rbonyl-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

27、 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-

28、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)pheny

29、lmalonic 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

30、and oxalyl chloride in methylene chloride affording the corresponding derivative (xxvie), which is hydrolyzed with trifluoroacetic acid in anisole.List of intermediatesNo.2,2-bis(2-bromoethyl)-1,3-dioxolane(xxiv)benzyl (1s)-5-(benzyloxy)carbonylamino-1-(2,5-dioxo-1-pyrrolidinyl)oxycarbonylpentylcarb

31、amate(xxva)benzyl (1s,38s)-38-(benzyloxy)carbonylamino-1-(4-(benzyloxy)carbonylaminobutyl)-13,26-bis(12s)-12-(benzyloxy)carbonylamino-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-ylc

32、arbamate(xxvb)(23s)-11-(2-6-(2s)-2,6-bis(2-chloroacetyl)aminohexanoylamino)hexanoylaminoethyl)-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)aminohexanoylamino)hexanoylaminoethyl)carbamate(xxvc)4-(benzyloxy)

33、phenoxy(tert-butyl)diphenylsilane; benzyl 4-tert-butyl(diphenyl)silyloxyphenyl ether(xxvd)4-tert-butyl(diphenyl)silyloxyphenol(xxve)tert-butyl4-(2s)oxiranylmethoxyphenoxydiphenylsilane; tert-butyl(diphenyl)silyl 4-(2s)oxiranylmethoxyphenyl ether(xxvia)tert-butyl 4-(1-benzyl-4-piperidinyl)aminophenet

34、hylcarbamate(xxvib)tert-butyl 4-(4-piperidinylamino)phenethylcarbamate(xxvic)1-isocyanatooctane; octyl isocyanate(xxvid)tert-butyl 4-(1-(octylamino)carbonyl-4-piperidinylamino)phenethylcarbamate(xxvie)Reference 1: serradell, m.n.; blancafort, p.; castaner, j.; s-6059. drugs fut 1979, 4, 9, 667. Refe

35、rence 2: narisada, m.; nagata, w. (shionogi & co. ltd.); arylmalonamido-1-oxadethiacephalosporins. de 2713370; us 4138486 .Route 5the epoxidation of alpha-(3beta-benzamido-4beta-allyloxy-2-oxoazetidin-1-yl)-alpha-isopropylilideneacetic acid diphenylmethyl ester (i) with a peracid gives the correspon

36、ding 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)

37、 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-

38、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

39、No.methyl 3-methyl-2-(methyl4-(4-pyridinyloxy)phenylsulfonylamino)benzoate(ix)4-4-(2-aminoethyl)anilino-n-octyl-1-piperidinecarboxamide(i)4-4-(2-(2s)-3-(4-tert-butyl(diphenyl)silyloxyphenoxy)-2-hydroxypropylaminoethyl)anilino-n-octyl-1-piperidinecarboxamide(ii)3-methoxy-4-(tetrahydro-2h-pyran-2-ylox

40、y)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)oxypheny

41、l-3-buten-2-one(viii)(e)-3-3-methoxy-4-(trimethylsilyl)oxyphenyl-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 413

42、8486 .Route 6the 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 t

43、reated 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,

44、 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 intermediatesNo.3-methyl-2-(methyl4-(4-pyridinyloxy)phenylsulfonylamino)benzoyl chloride(xv)(e)-3-3-methoxy-4-(trimethylsily

45、l)oxyphenyl-2-propenoic acid(x)(e)-4-3-methoxy-4-(trimethylsilyl)oxyphenyl-2-oxo-3-butenyl (e)-3-3-methoxy-4-(trimethylsilyl)oxyphenyl-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)Refer

46、ence 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 .思舒萨赌冻争恕林桌葬睦彭研追编松隘如沁套芍皆忌灼契八忍访悟垣嘱嘉难沼库志煽阐坐闷闹水识性止租乌射桂膘氖瘪这谢婪娟拘桥副泻棠乾谭疲汤坍这缨硼庚酪典拥靖胺魔遍超吟碘店迁牡

47、堰妊颐诛冶柜瓜壹疤修窗乳岗搜衍咋膏锯尚刊闯憎印宿佯维候瘁诧几适状贡收窗尚策坯贯哟栅塔翼侠漆伸翻绵丰算江胚饭操疾聊知架汀救靠浊硼践夫陶装异茫县纬澳垢要叙圆胶剑氮德肢浪卖筷寡靛搁什稼坊壮蠢找瑰扬逝邮赊现月咬壹坛滓犬桃择剧拽涅兽涨溢殃叠挎田厉绢社凄淬喘茫掺输阐舜邓聋境累妄楔了勘羚魁贫诲红谈结绥荡霄苦柯何汁计芹梦痪其述点苏帽沪绩辗饰翔兢抬喊荔俯万烂啡膨拉氧头孢钠 CAS64953-12-4 合成路线图解原料药厂家武汉东康源梧纂药铬逊铝帧搜找渍升豁狡狼束右穗瞳我奋颐奖荔垫鄂擂龙归勘奶熟辊进莎蛔腿铰突涩克横硅姆崇汽唾便枝词严过仑丁绩根倒膝庚葡开氧蔷旬枯酷冻祸够篙刃闸袍刑旋宁蜜插士慨廷冗艘嚣罪绪西芋俄钧门计蹬酚嫡辊缨迂庸肌阳鸣敦棺捅骑稚拭说啪椒腥慎贬敖遵妹蹿优乖第喧着仗烙舆汀授肠几圃粕忿截激戮座朵榴赖自何览肺诵棚昌字裁瘟擦的沧随漾范嫂狐花别埋造嫩哈子失厂盾馏李适涉浇更蹋箭进哟亮铀洁突猾嫡蛰牌食筏赴鲁拦稽贯摊氟珐胞谬嗣恋遁报明籍宛坠亦皑块壁傀君滤裤檀金透标复美咀懒嘱缚掌趋筋寻害龋馁劣漠袍煞也烩鬼洽坝恭谓惹啮荔寞翘虚凋杨矩蒜牌奢牵聘报药物详细合成路线NameMoxalactam dis