Tolterodine tartrate, Kabi-2234, PNU-200583E, Detrol LA, Detrusitol SR, Urotrol, Detrol, Detrusitol, -Drug Synthesis Database

【结构式】

【药物名称】Tolterodine tartrate, Kabi-2234, PNU-200583E, Detrol LA, Detrusitol SR, Urotrol, Detrol, Detrusitol

【化学名称】(+)-(R)-3-(2-Hydroxy-5-methylphenyl)-N,N-diisopropyl-3-phenylpropylamine L-tartrate (1:1)

【CA登记号】124937-52-6, 124937-51-5 (free base)

【分子式】C₂₆H₃₇NO₇

【分子量】475.58729

【开发单位】Pfizer (Originator), Almirall Prodesfarma (Licensee)

【药理作用】RENAL-UROLOGIC DRUGS, Urinary Incontinence Therapy, Muscarinic M3 Antagonists

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线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.

参考文献中间体

【1】 Graul, A.; Martel, A.M.; Castaner, J.; Tolterodine. Drugs Fut 1997, 22, 7, 733.
【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 .
【3】 Kumar, Y.; Prasad, M.; Neela, P.K.; Misra, S. (Ranbaxy Laboratories Ltd.); Process for the preparation of tolterodine. WO 0314060 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	13561	6-Methyl-4-phenyl-2-chromanone		C₁₆H₁₄O₂	详情	详情
(II)	13562	methyl 3-(2-methoxy-5-methylphenyl)-3-phenylpropanoate		C₁₈H₂₀O₃	详情	详情
(III)	13563	3-(2-Methoxy-5-methylphenyl)-3-phenyl-1-propanol		C₁₇H₂₀O₂	详情	详情
(IV)	13564	3-(2-methoxy-5-methylphenyl)-3-phenylpropyl 4-methylbenzenesulfonate		C₂₄H₂₆O₄S	详情	详情
(V)	13565	N-Isopropyl-2-propanamine; Bis(isopropyl)amine; N,N-Diisopropylamine	108-18-9	C₆H₁₅N	详情	详情
(VI)	13566	N,N-Diisopropyl-N-[3-(2-methoxy-5-methylphenyl)-3-phenylpropyl]amine; N,N-Diisopropyl-3-(2-methoxy-5-methylphenyl)-3-phenyl-1-propanamine		C₂₃H₃₃NO	详情	详情
(VII)	13567	2-[3-(Diisopropylamino)-1-phenylpropyl]-4-methylphenol		C₂₂H₃₁NO	详情	详情

合成路线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.

参考文献中间体

【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.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	25113	(4R)-4-phenyl-3-[(E)-3-phenyl-2-propenoyl]-1,3-oxazolidin-2-one	C₁₈H₁₅NO₃	详情	详情
(II)	25114	benzyl 2-bromo-4-methylphenyl ether; 1-(benzyloxy)-2-bromo-4-methylbenzene	C₁₄H₁₃BrO	详情	详情
(III)	25115	(4R)-3-[(3R)-3-[2-(benzyloxy)-5-methylphenyl]-3-phenylpropanoyl]-4-phenyl-1,3-oxazolidin-2-one	C₃₂H₂₉NO₄	详情	详情
(IV)	25116	(3R)-3-[2-(benzyloxy)-5-methylphenyl]-3-phenylpropionic acid	C₂₃H₂₂O₃	详情	详情
(V)	25117	(3R)-3-[2-(benzyloxy)-5-methylphenyl]-3-phenylpropanoyl chloride	C₂₃H₂₁ClO₂	详情	详情
(VI)	25118	(3R)-3-[2-(benzyloxy)-5-methylphenyl]-N,N-diisopropyl-3-phenylpropanamide	C₂₉H₃₅NO₂	详情	详情
(VII)	25119	N-[(3R)-3-[2-(benzyloxy)-5-methylphenyl]-3-phenylpropyl]-N,N-diisopropylamine; (3R)-3-[2-(benzyloxy)-5-methylphenyl]-N,N-diisopropyl-3-phenyl-1-propanamine	C₂₉H₃₇NO	详情	详情

合成路线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.

参考文献中间体

【1】 Gage, J.R.; Cabaj, J.E. (Pharmacia Corp.); Process to prepare tolterodine. US 5992914; WO 9829402 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	37680	(2E)-3-phenyl-2-propenoic acid; trans-Cinnamic acid; trans-3-Phenylacrylic acid	140-10-3	C₉H₈O₂	详情	详情
(II)	37678	p-cresol	106-44-5	C₇H₈O	详情	详情
(III)	13561	6-Methyl-4-phenyl-2-chromanone		C₁₆H₁₄O₂	详情	详情
(IV)	37679	6-methyl-4-phenyl-2-chromanol		C₁₆H₁₆O₂	详情	详情
(V)	13565	N-Isopropyl-2-propanamine; Bis(isopropyl)amine; N,N-Diisopropylamine	108-18-9	C₆H₁₅N	详情	详情
(VI)	13567	2-[3-(Diisopropylamino)-1-phenylpropyl]-4-methylphenol		C₂₂H₃₁NO	详情	详情

合成路线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.

参考文献中间体

【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 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	55510	1-(2-bromo-4-methylphenyl)-1-ethanone		C₉H₉BrO	详情	详情
(II)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(III)	55511	(E)-1-(2-bromo-4-methylphenyl)-3-phenyl-2-propen-1-one		C₁₆H₁₃BrO	详情	详情
(IV)	55512	5-methyl-3-phenyl-1H-inden-1-one		C₁₆H₁₂O	详情	详情
(V)	55513	(3R)-5-methyl-3-phenyl-2,3-dihydro-1H-inden-1-ol		C₁₆H₁₆O	详情	详情
(VI)	55514	(3R)-5-methyl-3-phenyl-2,3-dihydro-1H-inden-1-one		C₁₆H₁₄O	详情	详情
(VII)	55515	(4R)-6-methyl-4-phenyl-3,4-dihydro-2H-chromen-2-one		C₁₆H₁₄O₂	详情	详情
(VIII)	55516	(4R)-6-methyl-4-phenyl-3,4-dihydro-2H-chromen-2-ol		C₁₆H₁₆O₂	详情	详情
(IX)	13565	N-Isopropyl-2-propanamine; Bis(isopropyl)amine; N,N-Diisopropylamine	108-18-9	C₆H₁₅N	详情	详情

合成路线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.

参考文献中间体

【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.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	37678	p-cresol	106-44-5	C₇H₈O	详情	详情
(II)	20597	1-ethynylbenzene	536-74-3	C₈H₆	详情	详情
(III)	56853	4-methyl-2-(1-phenylvinyl)phenol		C₁₅H₁₄O	详情	详情
(IV)	56854	3-(2-hydroxy-5-methylphenyl)-3-phenylpropanal		C₁₆H₁₆O₂	详情	详情
(V)	37679	6-methyl-4-phenyl-2-chromanol		C₁₆H₁₆O₂	详情	详情
(VI)	13565	N-Isopropyl-2-propanamine; Bis(isopropyl)amine; N,N-Diisopropylamine	108-18-9	C₆H₁₅N	详情	详情
(VII)	56855	2-[(E)-3-(diisopropylamino)-1-phenyl-2-propenyl]-4-methylphenol		C₂₂H₂₉NO	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)