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 Ziprasidone hydrochloride;CP-88059;CP-88059-01;Geodon;Zeldox
Chemical Name 5-[2-[4-(1,2-Benzisothiazol-3-yl)piperazin-1-yl]ethyl]-6-chloroindolin-2-one hydrochloride hydrate
CAS 138982-67-9
Related CAS 146939-27-7 (anhydrous free base), 118289-78-4 (hemihydrate), 122883-93-6 (monohydrate)
Formula C21H24Cl2N4O2S
Structure
Formula Weight 467.42103
Stage 上市-2000
Company Pfizer (Originator)
Activity/Mechanism Antipsychotic Drugs, Bipolar Disorder, Treatment of, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, 5-HT2A Antagonists, Dopamine D2 Antagonists
Syn. Route 7
Route 1
wolff-kishner reduction of 6-chloroisatin (i) gives 6-chlorooxindole (ii), which is treated with chloroacetyl chloride under friedel-crafts conditions to yield 5-chloroacetyl-6-chlorooxindole (iii). the ketone (iii) is reduced using triethylsilane in trifluoroacetic acid to produce 6-chloro-5-(2-chloroethyl)oxindole (iv). 1,2-benzisothiazolin-3-one (v) is converted to 3-chloro-1,2-benzisothiazole (vi) using phosphorus oxychloride and is then condensed with piperazine to provide 1-(1,2-benzisothiazol-3-yl)piperazine (vii). finally, intermediate (vii) is alkylated by compound (iv) in the presence of sodium carbonate in water and is converted to the salt with aqueous hydrochloric acid.
List of intermediates No.
2,2,2-trifluoro-n-methyl-n-(trimethylsilyl)acetamide
3-amino-2,2-dimethyl-5-phenylpentanoic acid (i)
3-(benzoylamino)-2,2-dimethyl-5-phenylpentanoic acid (ii)
2-amino-4-methyl-3-thiophenecarboxylic acid (iii)
tert-butyl (1s)-1-(5-methyl-4-oxo-4h-thieno[2,3-d][1,3]oxazin-2-yl)ethylcarbamate (iv)
2-[(1s)-1-aminoethyl]-5-methyl-4h-thieno[2,3-d][1,3]oxazin-4-one (v)
(e)-4-oxo-4-phenyl-2-butenoic acid (vi)
3-aminobenzonitrile (vii)
Reference 1:
    lowe, j.a. iii; nagel, a.a. (pfizer inc.); piperazinyl-heterocyclic cpds. us 4831031 .
Reference 2:
    bowles, p. (pfizer inc.); process for preparing aryl piperazinyl-heterocyclic cpds. ep 1029861; jp 1994184143; us 5206366 .
Reference 3:
    howard, h.r. jr.; busch, f.r.; grobin, a.w.; leeman, k.r. (pfizer products inc.); controlled synthesis of ziprasidone and compsns. thereof. wo 0370246 .
Reference 4:
    seeger, t.f.; prakash, c.; howard, h.r.; ziprasidone hydrochloride. drugs fut 1994, 19, 6, 560.

Route 2
a new synthesis for ziprasidone hydrochloride has been reported:the condensation of 6-chloroindolin-2-one (i) with bromoacetic acid (ii) by means of polyphosphoric acid (ppa) gives 5-(bromoacetyl)-6-chloroindolin-2-one (iii), which is reduced with triethylsilane and trifluoroacetic acid to the corresponding 2-bromoethyl derivative (iv). finally, this compound is condensed with 4-(3-benzisothiazolyl)piperazine (v) by means of na2co3 in dmf or isobutyl methyl ketone.
List of intermediates No.
3-(benzoylamino)-2,2-dimethyl-5-phenylpentanoic acid (i)
3-aminobenzonitrile (v)
n-(2-amino-5-cyanophenyl)benzenesulfonamide (iii)
1-bromo-2-isocyanatobenzene (iv)
(4ar,4bs,6as,7s,9as,9bs,11ar)-n,n-diethyl-4a,6a-dimethyl-2-oxohexadecahydro-1h-indeno[5,4-f]quinoline-7-carboxamide (ii)
Reference 1:
    howard, h.r.; lowe, j.a. iii, seeger, t.f.; et al.; 3-benzisothiazolylpiperazine derivatives as potential atypical antipsychotic agents. j med chem 1996, 39, 1, 143.

Route 3
a new, one-step commercial process for the preparation of 3-(1-piperazinyl)-1,2-benzisothiazole, a key intermediate in the synthesis of ziprasidone has been developed: the reaction of 2-cyanophenyl disulfide (i) with piperazine (ii) by means of dmso and isopropanol at 120-5 c.
List of intermediates No.
2,2,2-trifluoro-n-methyl-n-(trimethylsilyl)acetamide (ii)
3-[2-[(3-isopropoxy-5-[[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenethyl]oxy]phenoxy)methyl]phenethyl]phenyl tetrahydro-2h-pyran-2-yl ether; 3-(4-[2-[3-isopropoxy-5-([2-[3-(tetrahydro-2h-pyran-2-yloxy)phenethyl]benzyl]oxy)phenoxy]ethyl]phenyl)-5-methyl-1,2,4-oxadiazole (i)
Reference 1:
    sinay, t.g.; fox, d.e.; walinsky, s.w.; lambert, j.f.; new disulfide route to 3-(1-piperazinyl)-1,2-benzisothiazole. nucleus for atypical antipsychotic drugs. org process res dev 1999, 3, 2, 126.

Route 4
the condensation of 1-(1,2-benzoisothiazol-3-yl)piperazine (i) with 6-chloro-5-(2-chloroethyl)-2-indolinone (ii) in refluxing water or refluxing methyl isobutyl ketone gives the target indolinone derivative.
List of intermediates No.
3-aminobenzonitrile (i)
Reference 1:
    lowe, j.a.; nagel, a.a. (pfizer inc.); piperazinyl-heterocyclic cpds.. au 8812537; ep 0281309; jp 1988301861 .
Reference 2:
    bowles, p. (pfizer inc.); process for preparing aryl piperazinyl-heterocyclic cpds. ep 1029861; jp 1994184143; us 5206366 .

Route 5
the friedel crafts condensation of 6-chloroindolin-2-one (i) with 14c labeled 2-chloroacetyl chloride (ii) by means of alcl3 in cs2 gives 6-chloro-5-(2-chloroacetyl)indolin-2-one (iii), which is reduced with trimethylsilane in tfa to yield the labeled chloroethyl derivative (iv). finally, this compound is condensed with 3-(1-piperazinyl)-1,2-benzoisothiazole (v) by means of na2co3 in refluxing water to provide the target radiolabeled compound.
List of intermediates No.
1-(methylamino)-3-tetracyclo[6.6.2.0(2,7).0(9,14)]hexadeca-2,4,6,9,11,13-hexaen-1-yl-2-propanol (ii)
3-(benzoylamino)-2,2-dimethyl-5-phenylpentanoic acid (i)
2-amino-4-methyl-3-thiophenecarboxylic acid (iii)
tert-butyl (1s)-1-(5-methyl-4-oxo-4h-thieno[2,3-d][1,3]oxazin-2-yl)ethylcarbamate (iv)
3-aminobenzonitrile (v)
Reference 1:
    howard, h.r.; shenk, k.d.; smolarek, t.a.; marx, m.h.; windels, j.h.; roth, r.w.; synthesis of h-3- and c-14-labelled cp-88,059: a potent atypical antipsychotic agent. j label compd radiopharm 1994, 34, 2, 117.

Route 6
the bromination of 3-chloro-1,2-benzoisothiazole (i) with br2 in acoh using fecl3 as catalyst gives a mixture of 3,5-dibromo-1,2-benzoisothiazole (ii) and 3,7-dibromo-1,2-benzoisothiazole (iii) that are separated by flash chromatography. the desired isomer (iii) is condensed with piperazine (iv) in refluxing diglyme to yield 7-bromo-3-(1-piperazinyl)-1,2-benzoisothiazole (v), which is condensed with 6-chloro-5-(2-chloroethyl)indolin-2-one (vi) by means of na2co3 in refluxing water to afford the brominated adduct (vii). finally, this compound is debrominated with tritium gas over a pd/baso4 catalyst in thf to provide the target radiolabeled compound.
List of intermediates No.
2,2,2-trifluoro-n-methyl-n-(trimethylsilyl)acetamide (iv)
tert-butyl (1s)-1-(5-methyl-4-oxo-4h-thieno[2,3-d][1,3]oxazin-2-yl)ethylcarbamate (vi)
(e)-4-oxo-4-phenyl-2-butenoic acid (i)
Reference 1:
    howard, h.r.; shenk, k.d.; smolarek, t.a.; marx, m.h.; windels, j.h.; roth, r.w.; synthesis of h-3- and c-14-labelled cp-88,059: a potent atypical antipsychotic agent. j label compd radiopharm 1994, 34, 2, 117.

Route 7
the nitration of 2,5-dichlorotoluene (i) with hno3 in h2so4/acoh gives 2,5-dichloro-4-methylnitrobenzene (ii), which is treated with t-butoxybis(dimethylamino)methane (iii) in refluxing thf to yield 2,5-dichloro-4-[2-(dimethylamino)vinyl]nitrobenzene (iv). the condensation of (iv) with 1-(1,2-benzoisothiazol-3-yl)piperazine (v) in acoh affords the disubstituted piperazine (vi), whose double bond is reduced by means of nabh(oac)3 in dichloroethane/acoh to provide the saturated compound (vii). the condensation of (vii) with dimethyl malonate (viii) by means of koh in nmp gives the alkylated malonic ester (ix), which is hydrolyzed and monodecarboxylated with refluxing 3n hcl to yield the phenylacetic acid (x). the esterification of (x) with socl2 and methanol affords the methyl ester (xi), which is finally cyclized to the target indolone by reduction of its nitro group with sodium hydrosulfite in refluxing thf/ethanol.alternatively, compound (vii) can be condensed with methyl cyanacetate (xii) by means of koh in nmp to give the alkylated cyanacetic ester (xiii), which is hydrolyzed with refluxing 3n hcl to afford the already reported phenylacetic acid (x).
List of intermediates No.
3-aminobenzonitrile (v)
[(1r,2r)-7-chloro-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1h-3-benzazepin-2-yl]methanol (viii)
2-[benzyl(methyl)amino]ethyl 3-oxobutanoate (iii)
2-(2-phenyl-1h-indol-3-yl)-1-ethanamine; 2-(2-phenyl-1h-indol-3-yl)ethylamine (xii)
Reference 1:
    urban, f.j.; et al.; a novel synthesis of the antipsychotic agent ziprasidone. synth commun 1996, 26, 8, 1629.
Reference 2:
    urban, f.j. (pfizer inc.); processes and intermediates for the preparation of 5-[2-(4-(benzoisothiazol-3-yl)-piperazin-1-yl)ethyl]-6-chloro-1,3-dihydro-indol-2-one. wo 9500510 .

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盐酸齐拉西酮;英文名Ziprasidone hydrochloride;CP-88059;CP-88059-01;Geodon;Zeldox;CAS[138982-67-9]

 
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
唐山盛源泽兴化工有限公司
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
久易农业、托球股份、快达农化、
菜青虫和小菜蛾绿色防控技术
飞防应用场景为导向的制剂研究
泰禾旗下公司拟投建年产1万吨2
中农立华原药价格指数20200
印度发布农药禁令,或重塑全球供
未来已至,只是分布不均
南京农大在杀菌剂调控赤霉病菌D
跨国巨头原药供应商之一——长青
中化助力新疆“大国棉仓”升级!
中农联合完成上市辅导,再冲IP
农业农村部种植业管理司:这10
红太阳全球首家拥有敌草快二氯盐
山东华阳农药拟投建1500t/
先正达在意大利推出杀虫剂Min
当今现代物理农业的四个高端技术
国际农药分析协作委员会的农药与
巴西对252种已登记的制剂产品
透过颖泰生物2019年报看行业
开发“专利到期”农药,也要重视
 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