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 Tirofiban hydrochloride;MK-383;L-700462;Aggrastat
Chemical Name N-(Butylsulfonyl)-4-O-[4-(4-piperidyl)butyl]-L-tyrosine monohydrochloride
CAS 142373-60-2
Related CAS 144494-65-5 (free base), 150915-40-5 (monoH2O)
Formula C22H37ClN2O5S
Structure
Formula Weight 477.06759
Stage 上市-1998
Company Merck & Co. (Originator), Banyu (Licensee), Guilford Pharmaceuticals (Licensee)
Activity/Mechanism Acute Myocardial Infarction, Treatment of, Angina pectoris, Treatment of, Antiplatelet Therapy, CARDIOVASCULAR DRUGS, Cerebrovascular Diseases, Treatment of, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, NEUROLOGIC DRUGS, Stroke, Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Integrin alphaIIbbeta3 (Fibrinogen gpIIb/IIIa) Antagonists
Syn. Route 6
Route 1
4-pyridineacetic acid (i) was hydrogenated to the corresponding piperidine (ii) in the presence of pto2. after protection of (ii) as the n-boc derivative (iii), reduction of its carboxylate group with borane in thf provided alcohol (iv). subsequent swern oxidation of alcohol (iv) furnished aldehyde (v). this was then subjected to a wittig condensation with carbomethoxytriphenylphosphorane to yield the unsaturated ester (vi), which was further hydrogenated to (vii) in the presence of pd/c. after saponification of the methyl ester function of (vii), the resultant carboxylic acid was reduced to alcohol (viii) by means of borane in thf. conversion of alcohol (viii) into the alkyl bromide (ix) was accomplished by treatment with carbon tetrabromide and triphenylphosphine. then, alkylation of the phenolic hydroxyl of n-cbz-l-tyrosine (x) with bromide (ix) in the presence of nah in dmf afforded adduct (xi).
List of intermediates No.
methyl (1s,4s,6r,10r)-15-oxo-5-oxatetracyclo[8.4.1.0(1,6).0(4,6)]pentadec-7-ene-8-carboxylate (i)
(2r)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-(dibenzylamino)-1-propanol (iii)
(x)
methyl (e)-3-[4-(acetyloxy)phenyl]-2-propenoate (iv)
(4s,7s,13r,16r,22r)-13-ethyl-4-(1h-indol-3-ylmethyl)-7-[(4-methoxy-1h-indol-3-yl)methyl]-18,22-dimethyl-16-[(phenylseleninyl)methyl]-24-thia-3,6,9,12,15,18,21,26-octaazabicyclo[21.2.1]hexacosa-1(25),23(26)-diene-2,5,8,11,14,17,20-heptone (ii)
4,8-dimethyl-7-hydroxycoumarin (vi)
4,8-dimethyl-7-(1-methyl-2-oxopropoxy)-2h-chromen-2-one (vii)
Reference 1:
    egbertson, m.s.; laswell, w.l.; hartman, g.d.; duggan, m.e.; halczenko, w. (merck & co., inc.); novel sulfonamide fibrinogen receptor antagonists. ep 0478363; ep 0743302; jp 1992288051; us 5292756 .
Reference 2:
    egbertson, m.s.; hartman, g.d.; halczenko, w.; laswell, w.l.; duggan, m.e. (merck & co., inc.); novel sulfonamide fibrinogen receptor antagonists. wo 9319046 .
Reference 3:
    egbertson, m.s.; chang, c.t.c.; duggan, m.e.; et al.; non-peptide fibrinogen receptor antagonists. 2. optimization of a tyrosine template as a mimic for arg-gly-asp. j med chem 1994, 37, 16, 2537.

Route 2
acid (xi) was converted to the methyl ester (xii) by alkylation with iodomethane in the presence of cs2co3. after removal of the n-cbz group of (xii) by catalytic hydrogenolysis, the resultant amine (xiii) was acylated by butanesulfonyl chloride (xiv) producing sulfonamide (xv). saponification of the ester group of (xv) with lioh gave acid (xvi). the n-boc group of (xvi) was finally cleaved by treatment with hcl in etoac.
List of intermediates No.
2-[(4s)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid (xiv)
Reference 1:
    egbertson, m.s.; hartman, g.d.; halczenko, w.; laswell, w.l.; duggan, m.e. (merck & co., inc.); novel sulfonamide fibrinogen receptor antagonists. wo 9319046 .
Reference 2:
    egbertson, m.s.; laswell, w.l.; hartman, g.d.; duggan, m.e.; halczenko, w. (merck & co., inc.); novel sulfonamide fibrinogen receptor antagonists. ep 0478363; ep 0743302; jp 1992288051; us 5292756 .
Reference 3:
    egbertson, m.s.; chang, c.t.c.; duggan, m.e.; et al.; non-peptide fibrinogen receptor antagonists. 2. optimization of a tyrosine template as a mimic for arg-gly-asp. j med chem 1994, 37, 16, 2537.

Route 3
intermediate (xi) was converted to the title compound by an alternative method, reported to provide a higher enantiomeric excess. hydrogenolysis of the n-cbz group of (xi) in the presence of pd/c gave the aminoacid (xv). subsequent acylation of (xv) with butanesulfonyl chloride (xiv) under schotten-baumann conditions furnished sulfonamide (xvi), which was then treated with hcl in etoac to remove the n-boc protecting group.
List of intermediates No.
2-[(4s)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid (xiv)
Reference 1:
    egbertson, m.s.; chang, c.t.c.; duggan, m.e.; et al.; non-peptide fibrinogen receptor antagonists. 2. optimization of a tyrosine template as a mimic for arg-gly-asp. j med chem 1994, 37, 16, 2537.

Route 4
in a different strategy, the lithium derivative of 4-picoline (xvii) was alkylated with 2-(3-bromopropoxy)tetrahydropyran (xviii) to afford (xix). acidic hydrolysis of the tetrahydropyranyl protecting group furnished 4-(4-pyridinyl)butanol (xx). alternatively, lithiation of 4-picoline (xvii), followed by alkylation with 1-bromo-3-chloropropane (xxi) gave rise to 4-(4-pyridinyl)butyl chloride (xxii).
List of intermediates No.
ethyl 2-(3,4-dimethoxyphenyl)-3-[[2-(3,4-dimethoxyphenyl)acetyl]amino]propanoate (xxi)
ethyl (e)-3-[(3ar,6r,6ar)-2,2,6-trimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-4-(benzyloxy)-2-butenoate (xvii)
tert-butyl 2-(benzylamino)acetate (xviii)
Reference 1:
    chung, j.y.l.; zhao, d.; hughes, d.l. (merck & co., inc.); process for preparing fibrinogen receptor antagonists. us 5312923; wo 9316994 .
Reference 2:
    chung, j.y.l.; zhao, d.; hughes, d.l. (merck & co., inc.); process for preparing fibrinogen receptor antagonists. wo 9316995 .
Reference 3:
    chung, j.y.l.; zhao, d.; hughes, d.l.; grabowski, e.e.; a practical synthesis of fibrinogen receptor antagonist mk-383 - selective functionalization of (s)-tyrosine. tetrahedron 1993, 49, 26, 5767.

Route 5
tyrosine methyl ester (xxiii) was acylated with butanesulfonyl chloride (xiv) in the presence of pyridine to produce sulfonamide (xxiv). mitsunobu coupling of pyridinyl butanol (xx) with the phenolic compound (xxiv) furnished ether (xxv). subsequent hydrolysis of the methyl ester group of (xxv) employing lioh afforded acid (xxvi). the title piperidine compound was then obtained by catalytic hydrogenation of the pyridine ring of (xxvi) in the presence of pd/c.
List of intermediates No.
disodium 4-amino-4-[[4,6-bis(3-[[bis(3-amino-3-oxopropyl)amino]sulfonyl]anilino)-1,3,5-triazin-2-yl]amino][1,1-biphenyl]-2,2-disulfonate (xxiii)
2-[(4s)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid (xiv)
Reference 1:
    chung, j.y.l.; zhao, d.; hughes, d.l. (merck & co., inc.); process for preparing fibrinogen receptor antagonists. us 5312923; wo 9316994 .

Route 6
in a variation of this process, l-tyrosine (xxvii) was initially protected as the bis-o-silylated derivative (xxviii) employing n,o-bis(trimethylsilyl) trifluoroacetamide. acylation of (xxviii) with butanesulfonyl chloride (xiv), followed by hydrolysis of the silyl groups, gave rise to n-butanesulfonyl tyrosine (xxix). the phenolic hydroxyl of (xxix) was then alkylated by 4-(4-pyridinyl)butyl chloride (xxii) to produce ether (xxvi). finally, hydrogenation of the pyridine ring furnished the target piperidine derivative, which was isolated as the corresponding hydrochloride salt.
List of intermediates No.
2-[(4s)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid (xiv)
2-hydroxy-6-pentadecylbenzoic acid (xxvii)
Reference 1:
    chung, j.y.l.; zhao, d.; hughes, d.l. (merck & co., inc.); process for preparing fibrinogen receptor antagonists. wo 9316995 .
Reference 2:
    chung, j.y.l.; zhao, d.; hughes, d.l.; grabowski, e.e.; a practical synthesis of fibrinogen receptor antagonist mk-383 - selective functionalization of (s)-tyrosine. tetrahedron 1993, 49, 26, 5767.

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替罗非班;英文名Tirofiban hydrochloride;MK-383;L-700462;Aggrastat;CAS[142373-60-2]

 
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
FDA 批准罗氏肿瘤免疫疗法
带你认识第一款专门治疗产后抑郁
润丰股份致力于打造欧盟农化品活
欧盟批准罗氏血友病药物 Hem
突出重点环节 强化职责落实 努
山东地区辛醇市场保持稳定
华南地区正丁醇市场行情
华东地区BDO市场持续僵持
华北地区丁二烯市场报盘走高
PTA止跌在眼前
华东地区BDO市场平稳整理
华南地区BDO市场商谈出货
江苏地区二氯甲烷价格暂稳
陕西地区醋酸价格
河北地区醋酸价格
华东地区BDO市场商谈整理
华东地区醋酸价格
河北地区醋酸价格
山东地区醋酸价格
江苏地区醋酸价格
 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