ag旗舰厅App
有機化學人才網 | 最新人才 | 最新職位 | 技術交易 | 藥物合成 |
   
全站搜索: |
  您當前位置:網站首頁 >> 藥物合成路線圖解
 

藥物詳細合成路線

Name Latanoprost;XA41;PhXA34 [as 15(R;S)-isomer];PhXA41;Xalatan
Chemical Name (15R)-17-Phenyl-13,14-dihydro-18,19,20-trinor-PGF2alpha isopropyl ester
      [1R-[1alpha(Z),2beta(R),3alpha,5alpha]]-7-[3,5-Dihydroxy-2-(3-hydroxy-5-phenylpentyl)cyclopentyl]-5-heptenoic acid isopropyl ester
      (Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-[3(R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoic acid isopropyl ester
      (Z)-(9S,11R,15R)-9,11,15-Trihydroxy-17-phenyl-18,19,20-trinorprost-5-enoic acid isopropyl ester
CAS 130209-82-4
Related CAS
Formula C26H40O5
Structure
Formula Weight 432.6057
Stage 上市-1996
Company Pfizer (Originator), EyeTech (Marketer)
Activity/Mechanism Antiglaucoma Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, Prostaglandins, Prostanoid FP Agonists
Syn. Route 5
Route 1
the required phosphonate reagent (iv) was prepared by two alternative methods. bromination of benzylacetone (i) in cold methanol afforded 1-bromo-4-phenyl-2-butanone (ii). subsequent displacement of the bromide ion of (ii) with nai in acetone led to the iodo ketone (iii). the desired phosphonate (iv) was then obtained by the arbuzov reaction of (iii) with trimethyl phosphite. alternatively, alkylation of the dianion of dimethyl 2-oxopropyl phosphonate (v) with benzyl bromide led to phosphonate (iv).
List of intermediates No.
(3as,9br)-2-benzyl-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole-8-carbonitrile (ii)
(3r,4r,5s,6s)-6-[(1s)-2-(benzyloxy)-1-methylethyl]-3-(iodomethyl)-2-methoxy-3,5-dimethyltetrahydro-2h-pyran-4-ol (i)
Reference 1:
    gutman, a.; nisnevich, g.; etinger, m.; zaltzman, i.; judovich, l.; pertsikov, b.; a new process for the preparation of latanoprost. wo 0155101 .
Reference 2:
    resul, b.; et al.; phenyl-substituted prostaglandins: potent and selective antiglaucoma agents. j med chem 1993, 36, 2, 243.

Route 2
the title compound was prepared starting from the known bicyclic lactone (vi). oxidation of the primary alcohol function of (vi) to the corresponding aldehyde (vii) was accomplished by either following the pfitzner-moffat method or by means of dess-martin perodinane reagent. aldehyde (vii) was then converted to enone (ix) by wittig reaction with the phosphonium salt (viii) or, in a related method, by wadsworth-emmons condensation of (vii) with phosphonate (iv). stereoselective reduction of enone (ix) with either l-selectride or (-)-b-chlorodiisopinocampheylborane produced the (15s)-allylic alcohol (x) as the major diastereoisomer, which was isolated by flash chromatography. then, catalytic hydrogenation of the double bond of (x) gave the saturated alcohol (xi). reduction of the lactone function employing dibal led to the protected lactol (xii). subsequent removal of the phenylbenzoyl group of (xii) with k2co3 in methanol furnished dihydroxy lactol (xiii). in a variation of this sequence, the phenylbenzoyl group of (xi) was first removed by methanolysis, and the resultant dihydroxy lactone (xiv) was then reduced with dibal to lactol (xiii).
List of intermediates No.
phenyl (3s,6r,7s,8s)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate (vii)
7-hydroxyindole; 7-indolol (vi)
2-nitro-1-propene (ix)
methyl 2-{[3-(2-aminopropyl)-1h-indol-7-yl]oxy}acetate (x)
Reference 1:
    gutman, a.; nisnevich, g.; etinger, m.; zaltzman, i.; judovich, l.; pertsikov, b.; a new process for the preparation of latanoprost. wo 0155101 .
Reference 2:
    kovács, g.; hermecz, i.; szabó, t.; ivanics, j.; ivanics, j.; dalmadi, g.; bahram, r. (chinoin pharmaceutical and chemical works co., ltd.); chemical process. wo 9300329 .
Reference 3:
    resul, b.; et al.; phenyl-substituted prostaglandins: potent and selective antiglaucoma agents. j med chem 1993, 36, 2, 243.

Route 3
wittig condensation of lactol (xiii) with (carboxybutyl)triphenylphosphonium bromide (xv) in the presence of potassium tert-butoxide produced the z-olefin (xvi). conversion of carboxylic acid (xvi) to the title isopropyl ester was then accomplished by alkylation with 2-iodopropane in the presence of dbu.
List of intermediates No.
2-bromo-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one (xv)
Reference 1:
    kovács, g.; hermecz, i.; szabó, t.; ivanics, j.; ivanics, j.; dalmadi, g.; bahram, r. (chinoin pharmaceutical and chemical works co., ltd.); chemical process. wo 9300329 .
Reference 2:
    resul, b.; et al.; phenyl-substituted prostaglandins: potent and selective antiglaucoma agents. j med chem 1993, 36, 2, 243.

Route 4
a closely related strategy using tetrahydropyranyl protection has been reported. protection of the allylic alcohol (x) with dihydropyran in the presence of p-toluenesulfonic acid yielded the tetrahydropyranyl ether (xvii). catalytic hydrogenation of (xvii) gave rise to (xviii), which was further reduced to lactol (xix) employing dibal in cold toluene. after methanolysis of the phenylbenzoyl group of (xix), the resultant lactol (xx) was subjected to wittig condensation with the phosphonium reagent (xv), yielding olefin (xxi). after conversion of acid (xxi) to the corresponding isopropyl ester(xxii), the tetrahydropyranyl group was removed by means of pyridinium tosylate in meoh.
List of intermediates No.
2-bromo-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one (xv)
methyl 2-{[3-(2-aminopropyl)-1h-indol-7-yl]oxy}acetate (x)
Reference 1:
    gutman, a.; nisnevich, g.; etinger, m.; zaltzman, i.; judovich, l.; pertsikov, b.; a new process for the preparation of latanoprost. wo 0155101 .

Route 5
in an alternative method, the aldehyde lactone (xxiii) was subjected to wadsworth-emmons reaction with phosphonate (iv) to afford enone (xxiv). stereoselective ketone reduction, followed by catalytic hydrogenation of the resultant allylic alcohol (xxv), provided (xxvi). both the benzoate ester and the lactone groups of (xxiv) were hydrolyzed by koh, yielding trihydroxy acid (xxvii), which was further cyclized to lactone (xiv) in boiling toluene. the hydroxyl groups of (xiv) were then protected with ethyl vinyl ether in the presence of trichloroacetic acid to produce the bis-acetal (xxviii). reduction of the lactone function of (xxviii) to the corresponding lactol (xxix), followed by wittig reaction with the phosphorane generated from phosphonium salt (xv) and potassium t-butoxide, furnished olefin (xxx). after acidic hydrolysis of the acetal protecting groups of (xxx), the carboxylate function was converted to the corresponding isopropyl ester by treatment with 2-iodopropane and cesium carbonate.
List of intermediates No.
2-bromo-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one (xv)
(2r,3r,4s,5r)-2-(6-[[(1s,5s)-5-hydroxy-2-cyclopenten-1-yl]amino]-9h-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol (xxiii)
Reference 1:
    henegar, k.e. (pharmacia corp.); process and intermediates to prepare latanoprost. wo 0187816 .

來源:藥化網

作者:藥化小編

摘要:本文合成路線介紹的是藥物中文名拉坦前列腺素;英文名Latanoprost;XA41;PhXA34 [as 15(R;S)-isomer];PhXA41;Xalatan;CAS[130209-82-4]

 
推薦VIP企業
無錫景耀生物科技有限公司
杭州盧普生物科技有限公司
寧波賽倫化工有限公司
蘇州昊賽生物科技有限公司
北京嘉盛揚醫藥科技有限公司
上海澤涵生物醫藥科技有限公司
河北固安三利化工公司
鄭州凱普瑞生物技術有限公司
上海藥谷藥業有限公司
蘭州康寓信生物科技有限公司
湖北朗昕生化藥業有限公司
武漢福鑫化工有限公司
嘉興市英南化工有限公司
蘇州迪飛醫藥科技有限公司
北京富安凱科技有限公司
上海盛中醫藥化工有限公司
連云港天和化學有限公司
南京晨瑞醫藥科技有限公司
南京蘇如化工有限公司
常州瑞盛化工有限公司
熱門文章
中國化學會第六屆全國生物物理化
中國化學會第九屆全國化學推進劑
中國化學會全國二氧化碳資源化利
中國化學會第16屆全國均相催化
54家上市公司年報匯總出爐!4
開創銀屑病長效、便捷治療新模式
有機磷類產品受磷化工污染治理影
江蘇地區順酐市場行情整理
山東地區三氯甲烷價格
華東地區醋酸價格
河南地區醋酸價格
山東地區醋酸價格
浙江地區醋酸價格
華南地區順酐市場行情整理
華北醋酸市場動態
農藥包裝廢棄物監管辦法實施在即
華東地區正丁醇市場行情
江西地區二氯甲烷價格上調
江蘇地區順酐市場行情整理
河北地區醋酸價格
 友情鏈接
有機化學人才網  
首頁 | 廣告服務 | 建站服務 | 關于我們 | 聯系我們 | 版權聲明
ag旗舰厅App