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药物详细合成路线

Name (+)-Fluprostenol isopropyl ester;Travoprost;AL-6221;Travatan
Chemical Name 7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-[3(R)-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1(E)-butenyl]cyclopentyl]-5(Z)-heptenoic acid isopropyl ester
      (+)-16-[3-(Trifluoromethoxy)phenoxy]-17,18,19,20-tetranorprostaglandin F2alpha isopropyl ester
CAS 157283-68-6
Related CAS
Formula C26H35F3O6
Structure
Formula Weight 500.56045
Stage 上市-2001
Company Alcon (Originator)
Activity/Mechanism Antiglaucoma Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, Prostaglandins, Prostanoid FP Agonists
Syn. Route 5
Route 1
the condensation of 2-[3-(trifluoromethyl)phenoxy]acetyl chloride (i) with methylphosphonic acid dimethyl ester (ii) by means of buli in thf gives 2-oxo-3-[3-(trifluoromethyl)phenoxy]propylphosphonic acid dimethyl ester (iii), which is condensed with the known bicyclic aldehyde (iv) by means of buli in dimethoxyethane, yielding the unsaturated ketone (v). the reduction of (v) with zinc borohydride in dimethoxyethane affords the unsaturated alcohol (vi), which is treated with k2co3 to give a diastereomeric mixture of unsaturated diols, resolved by chromatography to yield the chiral unsaturated diol (vii). the protection of (vii) with dihydropyran and tsoh in dichloromethane provides the bis(tetrahydropyranyl) ether (viii), which by reduction of the lactone ring with diisobutylaluminum hydride in thf gives the lactol (ix). the condensation of (ix) with the phosphonium bromide (x) by means of nah in dmso yields the prostenoic acid (xi), which is esterified with isopropyl iodide and 1,8-diazabicyclo[5.4.0]undec-7-ene (dbu) in acetone to afford the corresponding isopropyl ester (xii). finally, this compound is deprotected with acetic acid in hot thf/water.
List of intermediates No.
2-[[3-(phenethyloxy)propyl]sulfonyl]acetaldehyde (ii)
2-bromo-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one (x)
(1s,2s)-2-amino-1-phenyl-1,3-propanediol (xii)
phenyl (3s,6r,7s,8s)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate (iv)
methyl 4-formylbenzoate (i)
methyl 4-[(z)-2-nitro-1-propenyl]benzoate (iii)
methyl 4-(2-oxopropyl)benzoate (v)
methyl 4-((2r)-2-[[(2r)-2-hydroxy-2-phenylethyl]amino]propyl)benzoate (vi)
guanidine (vii)
thiourea (viii)
ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetate (ix)
1-(2-amino-1,3-thiazol-4-yl)-2-(1h-1,2,3-benzotriazol-1-yloxy)-2-oxo-1-ethanone oxime (xi)
1-[((6r,7r)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl]-1-methylpyrrolidinium (xiii)
Reference 1:
    klimko, p.g.; bishop, j.a.; desantis, l. jr.; sallee, v.l. (alcon laboratories, inc.); use of cloprostenol, fluprostenol and their analogues for the manufacture of a medicament for the treatment of glaucoma and ocular hypertension. ep 0639563; jp 1995165703; jp 1998182465; us 5665773 .
Reference 2:
    casta?er, j.; sorbera, l.a.; travoprost. drugs fut 2000, 25, 1, 41.
Reference 3:
    bowler, j.; crossley, n.s. (astrazeneca plc); method of inducing luteolysis using 16-aryloxy-17,18,19,20-tetranor-prostanoic acid derivs. us 4321275 .

Route 2
the alkylation of 2-iodo-5-(trifluoromethyl)phenol (i) with ethyl 2-bromoacetate (ii) and k2co3 in acetone gives the phenyl ether (iii), which is condensed with the phosphonate (iv) by means of buli in thf to yield the ketophosphonate (v). the condensation of the corey aldehyde (vi) with phosphonate (v) by means of clli and tea in thf affords the ketonic intermediate (vii), which is reduced with (-)-chlorodiisopinocampheylborane [(-)-dipcl] in thf to produce c-15 hydroxy epimer predominantly with the desired stereochemistry (viii).the hydrolysis of the benzoate group of (viii) with k2co3 in methanol gives the dihydroxylactone (ix), which is protected with dhp and ts-oh in dichloromethane to yield the bis-tetrahydropyranyl ether (x). the lactone group of (x) is reduced with dibal in thf to yield the lactol (xi), which is submitted to a wittig condensation with 4-carboxybutyltriphenylphosphonium bromide (xii) by means of tbu-ok in thf to afford the carboxylic acid (xiii). the esterification of (xiii) with isopropyl iodide and dbu in acetone affords the isopropyl ester (xiv), which is deprotected (elimination of the thp protecting groups) with hcl in methanol/water and purified by chromatography (elimination of the unwanted c15-epimer) to afford the precursor (xv). finally the iodine atom of (xv) is eliminated by hydrogenation with hydrogen over pd/c in ethyl acetate.
List of intermediates No.
2-[[3-(phenethyloxy)propyl]sulfonyl]acetaldehyde (iv)
2-bromo-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one (xii)
[(2r,3s,4s,5r)-5-(6-amino-2-fluoro-9h-purin-9-yl)-3,4-dihydroxytetrahydro-2-furanyl]methyl diethyl phosphate (ii)
(1s)-2-(benzyloxy)-1-[(2r,5r)-5-(1-hydroxy-1-methylethyl)-2-methyltetrahydro-2-furanyl]ethyl acetate (vi)
Reference 1:
    selliah, r.; et al.; synthesis of [phenyl-2-h-3]-travoprost: isopropyl ester prodrug of a selective prostaglandin fp receptor agonist. j label compd radiopharm 2001, 44, 3, 173.

Route 3
the alkylation of 2-iodo-5-(trifluoromethyl)phenol (i) with ethyl 2-bromoacetate (ii) and k2co3 in acetone gives the phenyl ether (iii), which is condensed with the phosphonate (iv) by means of buli in thf to yield the ketophosphonate (v). the condensation of the corey aldehyde (vi) with phosphonate (v) by means of clli and tea in thf affords the ketonic intermediate (vii), which is reduced with (-)-chlorodiisopinocampheylborane [(-)-dipcl] in thf to produce c-15 hydroxy epimer (viii) predominantly with the desired stereochemistry. the hydrolysis of the benzoate group of (viii) with k2co3 in methanol gives the dihydroxylactone (ix), which is protected with dhp and ts-oh in dichloromethane to yield the bis-tetrahydropyranyl ether (x). the lactone group of (x) is reduced with dibal in thf to yield the lactol (xi), which is submitted to a wittig condensation with 4-carboxybutyltriphenylphosphonium bromide (xii) by means of tbu-ok in thf to afford the carboxylic acid (xiii). the esterification of (xiii) with isopropyl iodide and dbu in acetone affords the isopropyl ester (xiv), which is deprotected (elimination of the thp protecting groups) with hcl in methanol/water and purified by chromatography (elimination of the unwanted c15-epimer) to afford the precursor (xv). finally the iodine atom of (xv) is substituted with tritium by hydrogenation with tritium gas over pd/c in ethyl acetate.
List of intermediates No.
2-[[3-(phenethyloxy)propyl]sulfonyl]acetaldehyde (iv)
2-bromo-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one (xii)
[(2r,3s,4s,5r)-5-(6-amino-2-fluoro-9h-purin-9-yl)-3,4-dihydroxytetrahydro-2-furanyl]methyl diethyl phosphate (ii)
(1s)-2-(benzyloxy)-1-[(2r,5r)-5-(1-hydroxy-1-methylethyl)-2-methyltetrahydro-2-furanyl]ethyl acetate (vi)
Reference 1:
    selliah, r.; et al.; synthesis of [phenyl-2-h-3]-travoprost: isopropyl ester prodrug of a selective prostaglandin fp receptor agonist. j label compd radiopharm 2001, 44, 3, 173.

Route 4
synthesis of the tricyclic ketone intermediate (vi): optical resolution of racemic bicyclo[3.2.0]hept-2-en-6-one (i) by reaction with so2 and (+)-a-methylbenzylamine (ii) yields a mixture of diastereomeric salts of the a-hydroxysulfonic acid with the chiral amine (ii), which are separated by crystallization. treatment of the purified salt (iii) with aqueous na2co3 results in the pure enantiomer (-)-(i). reaction of (-)-(i) with 1,3-dibromo-5,5-dimethylhydantoin (dbdmh) in acetone/water affords the bromohydrin (iv), which is treated with tbdms-cl and imidazole to provide the silyl ether (v). finally, reaction of the protected bromohydrin (v) with potassium tert-butoxide in toluene gives the target tricyclic ketone intermediate (vi).
List of intermediates No.
2,3,6,7-tetrahydrofuro[2,3-f][1]benzofuran (ii)
methyl (2s)-2-[[(benzyloxy)carbonyl]amino]-2-(hydroxymethyl)-4-pentenoate (--i)
Reference 1:
    boulton, l.t.; brick, d.; fox, m.e.; et al.; synthesis of the potent antiglaucoma agent, travoprost. org process res dev 2002, 6, 2, 138.

Route 5
synthesis of the alkenyl cuprate (xvii): enzymatic acylation of the racemic acetylenic alcohol (vii) with vinyl butyrate (viii) by means of chirazyme l9 gives a mixture of the ester (r)-(ix) and the alcohol (s)-(x). reaction of this mixture with ms-cl and tea yields a mixture of ester (r)-(ix) and the mesylate (s)-(xi). treatment of this mixture with butyric acid and tea results in the acylation of mesylate (s)-(xi) with optical inversion, providing pure ester (r)-(ix). enzymatic hydrolysis of (r)-(ix) with chirazyme l2 affords the enantiomerically pure alcohol (r)-(xiii). silylation of alcohol (xiii) with tbdms-cl and imidazole gives the silyl ether (xiv), which is iodinated with cp2zrcl2 and i2 to yield the iodovinyl derivative (xv). finally, the reaction of compound (xv) with the lithium cuprate (xvi) -prepared by lithiation of thiophene with buli followed by treatment with copper (i) cyanide- affords the alkenyl cuprate (xvii).condensation of the alkenyl cuprate (xvii) with the tricyclic ketone (vi) in toluene provides the bicyclic ketone (xviii), which is submitted to a baeyer-villiger oxidation with peracetic acid to give a mixture of the regioisomeric lactones (xix) and (xx). the minor and unwanted regioisomer (xix) is selectively hydrolyzed by treatment with aqueous na2co3 and separated by crystallization. reduction of lactone (xx) with dibal in toluene gives lactol (xxi), which is submitted to a wittig condensation with (4-carboxybutyl)triphenylphosphonium bromide and t-buok in thf, followed by esterification with isopropyl iodide and dbu, yielding a mixture of the monosilylated compounds (xxiii) and (xxiv) due to migration of the silyl group on the cyclopentane ring. finally, this mixture is deprotected with hcl in isopropanol.
List of intermediates No.
2-bromo-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one (xxii)
Reference 1:
    boulton, l.t.; brick, d.; fox, m.e.; et al.; synthesis of the potent antiglaucoma agent, travoprost. org process res dev 2002, 6, 2, 138.

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曲沃前列素;英文名(+)-Fluprostenol isopropyl ester;Travoprost;AL-6221;Travatan;CAS[157283-68-6]

 
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