Cizolirtine citrate, E-3710 citrate, E-4018, E-4961((S)-isomer), E-4960((R)-isomer), -Drug Synthesis Database

【结构式】

【药物名称】Cizolirtine citrate, E-3710 citrate, E-4018, E-4961((S)-isomer), E-4960((R)-isomer)

【化学名称】(±)-O-[2-(Dimethylamino)ethyl]-1-methyl-alpha-phenyl-1H-pyrazol-5-methanol citrate
　　　　　　(±)-5-[alpha-[2-(Dimethylamino)ethoxy]benzyl]-1-methyl-1H-pyrazole citrate
　　　　　　(±)-N,N-Dimethyl-2-[1-(1-methyl-1H-pyrazol-5-yl)-1-phenylmethoxy]ethanamine citrate

【CA登记号】142155-44-0, 251375-82-3 ((1:1) salt), 148981-63-9 ((R)-isomer), 148981-65-1 ((S)-isomer), 142155-43-9 (free base), 148981-64-0

【分子式】C₂₁H₂₉N₃O₈

【分子量】451.48058

【开发单位】Esteve (Originator)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Antipyretics, Non-Opioid Analgesics, RENAL-UROLOGIC DRUGS, Urinary Incontinence Therapy

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6

合成路线1

The key compound 5-(alpha-hydroxybenzyl)-1-methyl-1H-pyrazole [(±)-I] was obtained by two related ways: 1) by condensation of N-methylpyrazole with benzonitrile and butyl lithium in tetrahydrofuran and reduction of the obtained ketone with sodium borohydride in methanol or 2) by condensation of N-methylpyrazole with benzaldehyde and butyl lithium in THF/toluene. The alkylation of [(±)-I] with 2-(dimethylamino)ethyl chloride hydrochloride was carried out using phase transfer conditions and reaction with citric acid using propanone as solvent.

参考文献中间体

【1】 Farré, A.J.; Frigola, J.; Cizolirtine Citrate. Drugs Fut 2002, 27, 8, 721.
【2】 Colombo, A.; Pares, J.; Frigola, J. (Laboratorios del Dr. Esteve, SA); Aryl-heteroaryl-carbinol derivs. having an analgesic activity. EP 0289380; FR 2613720; JP 1988267761; US 5017596 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	44234	1-methyl-1H-pyrazole; N-Methylpyrazole	930-36-9	C₄H₆N₂	详情	详情
(rac)-(I)	54583	(1-methyl-1H-pyrazol-5-yl)(phenyl)methanol; 5-(alpha-hydroxybenzyl)-1-methyl-1H-pyrazole		C₁₁H₁₂N₂O	详情	详情

合成路线2

The optical resolution of (±)-cizolirtine was accomplished by recrystallizing diastereoisomeric salts formed with the antipodes of di-p-toluoyltartaric acid in isopropanol.

参考文献中间体

【1】 Farré, A.J.; Frigola, J.; Cizolirtine Citrate. Drugs Fut 2002, 27, 8, 721.
【2】 Frigola-Constansa, J.; Torrens-Jover, A. (Laboratorios del Dr. Esteve, SA); Resolution of amines. EP 1024137; ES 2130079; US 6187930; WO 9902500 .

中间体编号	品名	分子式	供应商	用于合成
54584	N,N-dimethyl-2-[(1-methyl-1H-pyrazol-5-yl)(phenyl)methoxy]-1-ethanamine; N,N-dimethyl-N-{2-[(1-methyl-1H-pyrazol-5-yl)(phenyl)methoxy]ethyl}amine	C₁₅H₂₁N₃O	详情	详情
54585	N,N-dimethyl-2-{[(R)-(1-methyl-1H-pyrazol-5-yl)(phenyl)methyl]oxy}-1-ethanamine; N,N-dimethyl-N-(2-{[(R)-(1-methyl-1H-pyrazol-5-yl)(phenyl)methyl]oxy}ethyl)amine	C₁₅H₂₁N₃O	详情	详情
54586	N,N-dimethyl-2-{[(S)-(1-methyl-1H-pyrazol-5-yl)(phenyl)methyl]oxy}-1-ethanamine; N,N-dimethyl-N-(2-{[(S)-(1-methyl-1H-pyrazol-5-yl)(phenyl)methyl]oxy}ethyl)amine	C₁₅H₂₁N₃O	详情	详情

合成路线3

Resolution of alcohol [(±)-I] as its diastereomeric O-acetylmandelate esters and saponification of each of them in ethanol in the presence of catalytic amounts of sodium cyanide yielded the enantiomerically pure alcohols [(R)-(+)-I] and [(S)-()-I].

参考文献中间体

【1】 Hueso, J.; Frigola, J.; Farré, A.; Berrocal, J.; Gutierrez, B.; Preparation of the enantiomers of the analgesic E-3710. Bioorg Med Chem Lett 1993, 3, 2, 269.
【2】 Farré, A.J.; Frigola, J.; Cizolirtine Citrate. Drugs Fut 2002, 27, 8, 721.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(rac)-(I)	54583	(1-methyl-1H-pyrazol-5-yl)(phenyl)methanol; 5-(alpha-hydroxybenzyl)-1-methyl-1H-pyrazole	C₁₁H₁₂N₂O	详情	详情
(R)-(+)-(I)	54587	(R)-(1-methyl-1H-pyrazol-5-yl)(phenyl)methanol	C₁₁H₁₂N₂O	详情	详情
(S)-(-)-(I)	54588	(S)-(1-methyl-1H-pyrazol-5-yl)(phenyl)methanol	C₁₁H₁₂N₂O	详情	详情

合成路线4

The transesterification of [(±)-I] with vinyl acetate enzymatically catalyzed (lipase) allowed the selective recovery of the enatiomer [(R)-(+)-I] and the hydrolysis and racemization of the undesired enantiomer [(S)-()-II] with hydrochloric acid.

参考文献中间体

【1】 Farré, A.J.; Frigola, J.; Cizolirtine Citrate. Drugs Fut 2002, 27, 8, 721.
【2】 Frigola Constansa, J.; Cuberes Altisent, M.R.; Berrocal Romero, J.M.; Gotor Santamaria, V. (Laboratorios del Dr. Esteve, SA); Method for separating carbinols. ES 2128959; FR 2742147; US 5849931; WO 9720817 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(rac)-(I)	54583	(1-methyl-1H-pyrazol-5-yl)(phenyl)methanol; 5-(alpha-hydroxybenzyl)-1-methyl-1H-pyrazole	C₁₁H₁₂N₂O	详情	详情
(R)-(+)-(I)	54587	(R)-(1-methyl-1H-pyrazol-5-yl)(phenyl)methanol	C₁₁H₁₂N₂O	详情	详情
(S)-(-)-(III)	54589	(S)-(1-methyl-1H-pyrazol-5-yl)(phenyl)methyl acetate	C₁₃H₁₄N₂O₂	详情	详情

合成路线5

Asymmetric reduction of ketone (III) with catecholborane or boranemethyl sulfide complex and CBS-oxazaborolidene as catalyst afforded [(R)-(+)-I] or [(S)-()-I].

参考文献中间体

【1】 Farré, A.J.; Frigola, J.; Cizolirtine Citrate. Drugs Fut 2002, 27, 8, 721.
【2】 Frigola-Constansa, J.; Torrens-Jover, A. (Laboratorios del Dr. Esteve, SA); Process for obtaining enantiomers of cizolirtine. EP 1029852; ES 2130083; US 6118009; WO 9907684 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	20631	(R)-Methyl oxazaborolidine; (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole	112022-83-0	C₁₈H₂₀BNO	详情	详情
(R)-(+)-(I)	54587	(R)-(1-methyl-1H-pyrazol-5-yl)(phenyl)methanol		C₁₁H₁₂N₂O	详情	详情
(III)	54590	(1-methyl-1H-pyrazol-5-yl)(phenyl)methanone		C₁₁H₁₀N₂O	详情	详情

合成路线6

Ethyl (R)-mandelate [(R)-IV] was protected as its tert-butyldimethylsilyl ether and reduced with DIBAL to [(R)-V], which was treated with ethoxycarbonylmethyl-enetriphenylphosphorane, followed by reduction to give [(R)-VI]. Subsequent oxidation to [(R)-VII] and cyclization by reaction with methylhydrazine afforded a mixture of pyrazolines [(R)-VIII]. Oxidation to pyrazole and deprotection yielded [(R)-(+)-I].

参考文献中间体

【1】 Farré, A.J.; Frigola, J.; Cizolirtine Citrate. Drugs Fut 2002, 27, 8, 721.
【2】 Hueso, J.; Frigola, J.; Farré, A.; Berrocal, J.; Gutierrez, B.; Preparation of the enantiomers of the analgesic E-3710. Bioorg Med Chem Lett 1993, 3, 2, 269.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(R)-(+)-(I)	54587	(R)-(1-methyl-1H-pyrazol-5-yl)(phenyl)methanol	C₁₁H₁₂N₂O	详情	详情
(R)-(IV)	54591	ethyl (2R)-2-hydroxy-2-phenylethanoate	C₁₀H₁₂O₃	详情	详情
(R)-(V)	54592	(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-phenylethanal	C₁₄H₂₂O₂Si	详情	详情
(R)-(VI)	54593	(E,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-4-phenyl-2-buten-1-ol	C₁₆H₂₆O₂Si	详情	详情
(R)-(VII)	54594	(E,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-4-phenyl-2-butenal	C₁₆H₂₄O₂Si	详情	详情
(R)-(VIII)	54595	tert-butyl(dimethyl)silyl (R)-(1-methyl-4,5-dihydro-1H-pyrazol-5-yl)(phenyl)methyl ether; 5-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]-1-methyl-4,5-dihydro-1H-pyrazole	C₁₇H₂₈N₂OSi	详情	详情

Extended Information