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藥物詳細合成路線

Name Tolterodine tartrate;Kabi-2234;PNU-200583E;Detrol LA;Detrusitol SR;Urotrol;Detrol;Detrusitol
Chemical Name (+)-(R)-3-(2-Hydroxy-5-methylphenyl)-N,N-diisopropyl-3-phenylpropylamine L-tartrate (1:1)
CAS 124937-52-6
Related CAS 124937-51-5 (free base)
Formula C26H37NO7
Structure
Formula Weight 475.58729
Stage 上市-1997
Company Pfizer (Originator), Almirall Prodesfarma (Licensee)
Activity/Mechanism RENAL-UROLOGIC DRUGS, Urinary Incontinence Therapy, Muscarinic M3 Antagonists
Syn. Route 5
Route 1
the reaction of 6-methyl-4-phenyl-3,4-dihydro-2h-1-benzopyran-2-one (i) with methyl iodide and k2co3 in refluxing acetone/methanol or dimethyl sulfate and naoh gives 3-(2-methoxy-5-phenylphenyl)-3-phenylpropionic acid methyl ester (ii), which is reduced with lialh4 in ether or nabh4 and alcl3 to the corresponding propanol (iii). the reduction of (iii) with tosyl chloride and pyridine yields the expected tosylate (iv), which by condensation with diisopropylamine (v) in hot acetonitrile is converted into the tertiary amine (vi). finally, this compound is treated with bbr3 in dichloromethane or hbr to afford the expected amine (vii) as a racemic mixture, which is resolved with l-(+)-tartaric acid.
List of intermediates No.
5-methoxyindoline; 2,3-dihydro-1h-indol-5-yl methyl ether (i)
benzonitrile (ii)
(5-methoxy-2,3-dihydro-1h-indol-7-yl)(phenyl)methanone (iii)
9-methoxy-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3h)-one (iv)
9-methoxy-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indole-3,4-dione 3-oxime (v)
3-amino-9-methoxy-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3h)-one (vi)
(3r)-3-amino-9-methoxy-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3h)-one (vii)
Reference 1:
    graul, a.; martel, a.m.; castaner, j.; tolterodine. drugs fut 1997, 22, 7, 733.
Reference 2:
    jonsson, n.a.; sparf, b.a.; mikiver, l.; moses, p.; nilvebrant, l.; glas, g. (pharmacia corp.); new amines, their use and preparation. ep 0325571; jp 1991503163; us 5382600; wo 8906644 .
Reference 3:
    kumar, y.; prasad, m.; neela, p.k.; misra, s. (ranbaxy laboratories ltd.); process for the preparation of tolterodine. wo 0314060 .

Route 2
an asymmetric total synthesis of tolterodine has been described: the regioselective addition of 2-benzyloxy-5-methylphenyl bromide (ii) to 4(r)-phenyl-3-[3-phenyl-2(e)-propenoyl]oxazolidin-2-one (i) by means of mg/cubr/dimethylsulfide in thf gives 3-[3(r)-(5-benzyloxy-2-methylphenyl)-3-phenylpropionyl]-4(r)-phenyloxazolidin-2-one (iii), which is hydrolyzed with lioh/h2o2 in thf/water to the corresponding free acid (iv). the reaction of (iv) with socl2/pyridine in benzene yields the acid chloride (v), which is treated with diisopropylamine to afford the corresponding amide (vi). the reduction of (vi) with lialh4 in ethyl ether gives the tertiary amine (vii), which is finally, debenzylated by hydrogenation with h2 over pd/c in methanol.
List of intermediates No.
methyl 2-[(1r,2s,3r,4r)-3-(hydroxymethyl)-2-(2-nitriloethyl)-4-[(tetrahydro-2h-pyran-2-yloxy)methyl]cyclopentyl]acetate (i)
methyl 2-[(1r,2s,3r,4r)-3-formyl-2-(2-nitriloethyl)-4-[(tetrahydro-2h-pyran-2-yloxy)methyl]cyclopentyl]acetate (ii)
methyl 2-[(1r,2s,3s,4r)-2-(2-nitriloethyl)-3-[(e)-3-oxo-1-octenyl]-4-[(tetrahydro-2h-pyran-2-yloxy)methyl]cyclopentyl]acetate (iii)
methyl 2-[(1r,2s,3s,4r)-3-[(e,3s)-3-hydroxy-1-octenyl]-2-(2-nitriloethyl)-4-[(tetrahydro-2h-pyran-2-yloxy)methyl]cyclopentyl]acetate (iv)
methyl 2-((1r,2s,3s,4r)-2-(2-nitriloethyl)-4-[(tetrahydro-2h-pyran-2-yloxy)methyl]-3-[(e,3s)-3-[(tetrahydro-2h-pyran-2-yloxy)methyl]-1-octenyl]cyclopentyl)acetate (v)
methyl 2-((1r,2s,3s,4r)-2-(2-methoxy-2-oxoethyl)-4-[(tetrahydro-2h-pyran-2-yloxy)methyl]-3-[(e,3s)-3-[(tetrahydro-2h-pyran-2-yloxy)methyl]-1-octenyl]cyclopentyl)acetate (vi)
methyl (1r,3ar,4r,5r,6as)-2-oxo-5-[(tetrahydro-2h-pyran-2-yloxy)methyl]-4-[(e,3s)-3-[(tetrahydro-2h-pyran-2-yloxy)methyl]-1-octenyl]octahydro-1-pentalenecarboxylate (vii)
Reference 1:
    andersson, p.g.; et al.; asymmetric total synthesis of (+)-tolterodine, a new muscarinic receptor antagonist, via copper-assisted asymmetric conjugate addition of aryl grignard reagents to 3-phenyl-prop-2-enoyl-oxazolidinones. j org chem 1998, 63, 22, 8067.

Route 3
a new process for the preparation of tolterodine has been described:the cyclization of trans-cinnamic acid (i) with p-cresol (ii) by means of hot sulfuric acid gives 6-methyl-4-phenyl-3,4-dihydro-2h-1-benzopyran-2-one (iii), which is reduced with dibal in toluene, yielding 6-methyl-4-phenyl-3,4-dihydro-2h-1-benzopyran-2-ol (iv). the reductocondensation of (iv) with diisopropylamine (v) by means of h2 over pd/c in methanol affords racemic tolterodine (vi), which is finally submitted to optical resolution with l-tartaric acid in dichloromethane/water.
List of intermediates No.
5-methoxyindoline; 2,3-dihydro-1h-indol-5-yl methyl ether (iii)
9-methoxy-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indole-3,4-dione 3-oxime (v)
(3r)-3-amino-9-methoxy-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3h)-one (vi)
4-imidazo[1,2-a]pyridin-2-ylphenol (ii)
2-[4-(4-chlorobutoxy)phenyl]imidazo[1,2-a]pyridine; 4-chlorobutyl 4-imidazo[1,2-a]pyridin-2-ylphenyl ether (iv)
myristaldehyde; myristyl aldehyde; tetradecanal; myristic aldehyde trimer; tetradecyl aldehyde (i)
Reference 1:
    gage, j.r.; cabaj, j.e. (pharmacia corp.); process to prepare tolterodine. us 5992914; wo 9829402 .

Route 4
the condensation of 2-bromo-4-methylacetophenone (i) with benzaldehyde (ii) by means of naome in methanol gives the propenone (iii), which is cyclized by means of pdcl2, pph3 and k2co3 in dmf, yielding 5-methyl-3-phenyl-1-indenone (iv). the enantioselective reduction of (iv) by means of borane/me2s complex and (r)-3,3-diphenyl-1-methyltetrahydro-1h,3h-pyrrolo[1,2-c][1,3,2]oxazaborole [(r)-mecbs] as chiral catalyst in thf affords 5-methyl-3(s)-phenylindan-1-ol (v), which is oxidized with 1,4-diazabicyclo[2,2,2]octane (dabco) in refluxing thf/tea to provide the corresponding indanone (vi). the oxidation of (vi) with mcpba in dichloromethane gives 6-methyl-4(s)-phenyl-3,4-dihydro-2h-1-benzopyran-2-one (vii), which is reduced with dibal in toluene to yield 6-methyl-4(s)-phenyl-3,4-dihydro-2h-1-benzopyran-2-ol (viii). finally, this compound is reductocondensed with diisopropylamine (ix) by means of h2 over pd/c in methanol to afford the target compound.
List of intermediates No.
methyl 3-[5-(2-chlorophenyl)-2-oxo-2,3-dihydro-1h-thieno[2,3-e][1,4]diazepin-7-yl]propanoate (ii)
9-methoxy-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indole-3,4-dione 3-oxime (ix)
Reference 1:
    andersson, p.g.; hedberg, c. (pharmacia & upjohn ab); process of preparing tolterodine and analogues there of as well as intermediates prepared in the process. wo 0149649 .

Route 5
the condensation of p-cresol (i) with phenylacetylene (ii) by means of acid activated alumina in refluxing dichlorobenzene gives 4-methyl-2-(1-phenylvinyl)phenol (iii), which is hydroformylated with co, h2 and a rh catalyst in hot toluene to yield 3-(2-hydroxy-5-methylphenyl)-3-phenylpropionaldehyde (iv), mostly in the hemiacetalic form (v). the reaction of (v) with diisopropylamine (vi) in hot toluene catalyzed by molecular sieves gives the enamine (vii), which is finally hydrogenated with h2 over pto2 in refluxing toluene to afford the target racemic tolterodine.alternatively, the reductocondensation of hemiacetal (v) with diisopropylamine (vi) by means of h2 over pd/c in hot methanol provides directly the target racemic tolterodine.
List of intermediates No.
9-methoxy-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indole-3,4-dione 3-oxime (vi)
7-chloro-1-(2-methyl-4-nitrobenzoyl)-1,2,3,4-tetrahydro-5h-1-benzazepin-5-one (ii)
4-imidazo[1,2-a]pyridin-2-ylphenol (i)
2-[4-(4-chlorobutoxy)phenyl]imidazo[1,2-a]pyridine; 4-chlorobutyl 4-imidazo[1,2-a]pyridin-2-ylphenyl ether (v)
Reference 1:
    paganelli, s.; piccolo, o.; botteghi, c.; marchetti, m.; corrias, t.; a new efficient route to tolterodine. org process res dev 2002, 6, 7, 379.

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酒石酸托特羅定;英文名Tolterodine tartrate;Kabi-2234;PNU-200583E;Detrol LA;Detrusitol SR;Urotrol;Detrol;Detrusitol;CAS[124937-52-6]

 
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