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药物详细合成路线

Name (S)-Oxybutynin
Chemical Name (S)-2-Cyclohexyl-2-phenylglycolic acid 4-diethylaminobut-2-ynyl ester
CAS 119618-22-3
Related CAS
Formula C22H31NO3
Structure
Formula Weight 357.49727
Stage III 期临床
Company Sepracor (Originator)
Activity/Mechanism RENAL-UROLOGIC DRUGS, Urinary Incontinence Therapy, Anticholinergics
Syn. Route 3
Route 1
racemic cyclohexylphenyl glycolic acid (chpga) (i) is dissolved with (l)-tyrosine methyl ester (ii) in refluxing acetonitrile/water to yield a mixture of diastereomeric salts, which is resolved by crystallization to afford the desired diastereomeric salt [(s)-chpga-(l)-tme] (iii). finally, the hydrolysis of salt (iii) with hcl or h2so4 at 40-50oc in toluene yields the enantiomer (iv). alternatively intermediate (iv) can be obtained as follows: acetalization of (s)-mandelic acid (v) with pivaldehyde (vi) in pentane and catalytic tfoh provides derivative (vii), which is then treated with lhmds and then condensed with cyclohexanone (viii) in thf to furnish aldol adduct (ix). elimination of tertiary alcohol in (ix) with socl2 and pyridine in thf gives derivative (x), which is then converted into intermediate (iv) either by first hydrolysis of lactone (x) with koh in meoh and subsequent hydrogenation of the obtained derivative (xi) over pd/c in meoh, or by first hydrogenation of (x) over pd/c in meoh to give (xii), followed by hydrolysis with koh in meoh. on turn, derivative (xii) can alternatively be synthesized by treatment of derivative (vii) with lhmds, followed by reaction with 3-bromocyclohexene (xiii) in thf to provide derivative (xiv), which is then hydrogenated over pd/c.
List of intermediates No.
(2r,3s)-1,1,1-trifluoro-4-methyl-3-nitro-2-pentanol (viii)
(4-methoxyphenyl)[5-(methylsulfonyl)-1h-pyrrol-2-yl]methanone (v)
hydroxylamine (vi)
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 (ii)
2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5h-benzo[a]cycloheptene; cyclohexylmethyl 6,7,8,9-tetrahydro-5h-benzo[a]cyclohepten-2-yl ether (xiii)
[(4r)-4-hydroxy-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methyl pivalate (vii)
methyl (2r)-2-{[(4-bromobenzyl)sulfonyl]amino}-3-(tert-butoxy)propanoate (ia)
(2r)-2-{[(4-bromobenzyl)sulfonyl]amino}-3-(tert-butoxy)propanoic acid (ib)
tert-butyl (2s)-2-{[(2r)-2-{[(4-bromobenzyl)sulfonyl]amino}-3-(tert-butoxy)propanoyl]amino}propanoate (iv)
(2s)-2-[((2r)-2-{[(4-bromobenzyl)sulfonyl]amino}-3-hydroxypropanoyl)amino]propanoic acid (iii)
tert-butyl ({4-[(4s,7r)-10-(4-bromophenyl)-7-(hydroxymethyl)-4-methyl-3,6,9,9-tetraoxo-9lambda~6~-thia-2,5,8-triazadec-1-yl]phenyl}imino)[(tert-butoxycarbonyl)amino]methylcarbamate (ix)
bruceolide; methyl 3,10,15,16-tetrahydroxy-9,13-dimethyl-4,11-dioxo-5,18-dioxapentacyclo[12.5.0.0~1,6~.0~2,17~.0~8,13~]nonadec-9-ene-17-carboxylate (x)
1-[4-(methyloxy)phenyl]-1-propanone (xi)
ethyl 3-methyl-4-[4-(methyloxy)phenyl]-2,4-dioxobutanoate (xii)
Reference 1:
    grover, p.t.; et al.; chiral mandelic acid template provides a highly practical solution for (s)-oxybutynin synthesis. j org chem 2000, 65, 19, 6283.
Reference 2:
    senanayake, c.h.; bakale, r.p.; vandenbossche, c.p.; mcconville, f.x.; lopez, j.l. (sepracor inc.); synthesis of optically active cyclohexylphenylglycolic acid and its esters. us 5973182; us 6140529; wo 0023414 .

Route 2
the desired product is finally obtained by first formation of a mixed anhydride (xvi) by reaction of the cyclohexylphenyl glycolic acid (iv) with isobutylchloroformate (xv) in cyclohexane in the presence of et3n, followed by treatment with 4-n,n-diethylamino butynol (xvii) (obtained on turn from reaction of propargyl alcohol (xviii) with diethylamine (xix) in the presence of paraformaldehyde and cucl.
List of intermediates No.
3-(hydroxymethyl)pyrido[3,2-g]quinoline-5,10-dione (xv)
1-allyl-2-bromopyridinium bromide (xviii)
2-(2-hydroxyethoxy)-1h-isoindole-1,3(2h)-dione (xix)
(2r)-2-{[(4-bromobenzyl)sulfonyl]amino}-3-(tert-butoxy)propanoic acid (iv)
ethyl 2-[2-(2,4-dichlorophenyl)hydrazono]-3-methyl-4-[4-(methyloxy)phenyl]-4-oxobutanoate (xvi)
ethyl 1-(2,4-dichlorophenyl)-4-methyl-5-[4-(methyloxy)phenyl]-1h-pyrazole-3-carboxylate (xvii)
Reference 1:
    senanayake, c.h.; bakale, r.p.; vandenbossche, c.p.; mcconville, f.x.; lopez, j.l. (sepracor inc.); synthesis of optically active cyclohexylphenylglycolic acid and its esters. us 5973182; us 6140529; wo 0023414 .

Route 3
the catalytic enantioselective cyanosilylation of the ketone (i) by means of tms-cn catalyzed by gadolinium isopropoxide and the chiral ligand (ii) in thf/propionitrile gives the silylated cyanohydrin (iii), which is reduced by means of dibal in toluene to yield the carbaldehyde (iv). the desilylation of (iv) by means of hcl in aqueous thf affords the hydroxyaldehyde (v), which is finally oxidized by means of naclo2 in tert-butanol/water to provide the target (s)-2-cyclohexyl-2-hydroxy-2-phenylacetic acid intermediate (vi) (see scheme no. 23604001a, intermediate (iv)).
List of intermediates No.
(2r)-2-{[(4-bromobenzyl)sulfonyl]amino}-3-(tert-butoxy)propanoic acid (vi)
Reference 1:
    masumoto, s.; et al.; a practical synthesis of (s)-oxybutynin. tetrahedron lett 2002, 43, 48, 8647.

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(S)-奥昔布宁;英文名(S)-Oxybutynin;CAS[119618-22-3]

 
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