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药物详细合成路线

Name Darifenacin;UK-88525-04(hydrobromide);UK-88525;Enablex
Chemical Name (S)-2-[1-[2-(2,3-Dihydrobenzofuran-5-yl)ethyl]pyrrolidin-3-yl]-2,2-diphenylacetamide
CAS 133099-04-4
Related CAS 133099-07-7 (HBr salt)
Formula C28H30N2O2
Structure
Formula Weight 426.5635
Stage 上市-2005
Company Novartis (Proprietary), Pfizer (Originator)
Activity/Mechanism RENAL-UROLOGIC DRUGS, Urinary Incontinence Therapy, Muscarinic M3 Antagonists
Syn. Route 1
Route 1
darifenacin can be obtained by three related ways:1) the decarboxylation of (2s,4r)-4-hydroxypyrrolidine-2-carboxylic acid (i) by heating at 154 c in cyclohexanol/2-cyclohexenone gives 3(r)-hydroxypyrrolidine (ii), which is n-tosylated with p-toluenesulfonyl chloride and pyridine yielding (iii). the reaction of (iii) with methyl p-toluenesulfonate, triphenylphosphine and diethyl azodicarboxylate (dead) in thf affords 1-tosyl-3(s)-(tosyloxy)pyrrolidine (iv), which is condensed with 2,2-diphenylacetonitrile (v) by means of nah in refluxing toluene to give 2,2-diphenyl-2-[1-(p-toluenesulfonyloxy)pyrrolidin-2(s)-yl]acetonitrile (vi). elimination of the tosyl group of (vi) with hbr and phenol in refluxing water yields 2,2-diphenyl-2-[2(s)-pyrrolidinyl]acetonitrile (vii), which by treatment with 95% h2so4 at 100 c is converted into the corresponding acetamide (viii). the condensation of (viii) with 5-(chloroacetyl)-2,3-dihydrobenzofuran (ix) by means of potassium carbonate in industrial methylated spirits affords the ketonic amide (x), which is finally reduced with h2 over pd/c in acetic acid.the intermediate 5-(chloroacetyl)-2,3-dihydrobenzofuran (ix) has been obtained by friedel-crafts condensation of 2,3-dihydrobenzofuran (xi) with chloroacetyl chloride by means of alcl3 in dichloromethane.3) the condensation of 5-(2-bromoethyl)benzofuran (xv), with the previously obtained acetamide (viii) by means of k2co3 in refluxing acetonitrile affords the condensation product (xvi), which is hydrogenated with h2 over pd/c in hot acetic acid.
List of intermediates No.
2-[5-(bis(benzoyloxy)[bis[1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1h-indol-5-yl]]-lambda(5)-bismuthanyl)-1h-indol-1-yl]ethyl tert-butyl(dimethyl)silyl ether (i)
(1r,9s,12s,13r,14s,17r,21s,23s,24r,25s,27r)-12-[(e)-2-((1r,3r,4r)-4-[[1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1h-indol-5-yl]oxy]-3-methoxycyclohexyl)-1-methylethenyl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone (ii)
(1r,9s,12s,13r,14s,17r,21s,23s,24r,25s,27r)-14-[[1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1h-indol-5-yl]oxy]-12-[(e)-2-((1r,3r,4r)-4-[[1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1h-indol-5-yl]oxy]-3-methoxycyclohexyl)-1-methylethenyl]-17-ethyl-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone (iii)
4-(benzyloxy)-2,6-pyridinediamine (iv)
3-formylindole-6-carboxylic acid methyl ester; 3-formyl-1h-indole-6-carboxylic acid methyl ester (v)
methyl 3-methyl-1h-indole-6-carboxylate (vi)
1-(chloromethyl)cyclohexane (vii)
methyl 1-(cyclohexylmethyl)-3-methyl-1h-indole-6-carboxylate (viii)
1-(cyclohexylmethyl)-3-methyl-1h-indole-6-carboxylic acid (ix)
4-amino-3,5-dichloro-1-pyridiniumolate (x)
4-methoxybenzyl 7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (xi)
4-methoxybenzyl 3-[(e)-2-(3-chloro-5-isoxazolyl)ethenyl]-7-([2-(methoxyimino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (xii)
2-bromo-4-fluorophenyl methyl ether (xiii)
(5-fluoro-2-methoxyphenyl)lithium (xiv)
5-fluoro-2-methoxyphenylboronic acid (xv)
methyl 2-bromo-5-nitrobenzoate (xvi)
Reference 1:
    graul, a.; castaner, j.; darifenacin. drugs fut 1996, 21, 11, 1105.
Reference 2:
    cross, p.e.; mackenzie, a.r. (pfizer inc.); pyrrolidine derivs. au 9051402; ep 0388054; jp 1990282360; jp 1995149640; us 5096890 .

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达非那新;英文名Darifenacin;UK-88525-04(hydrobromide);UK-88525;Enablex;CAS[133099-04-4]

 
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