TS-951, -Drug Synthesis Database

【结构式】

【药物名称】TS-951

【化学名称】endo-N-[8-(3-Hydroxypropyl)-8-azabicyclo[3.2.1]oct-3-yl]-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide

【CA登记号】174486-39-6

【分子式】C₂₃H₃₁N₃O₃

【分子量】397.52182

【开发单位】Taisho (Originator)

【药理作用】Gastric Emptying Disorders,Treatment of of, GASTROINTESTINAL DRUGS, Prokinetic Agents, 5-HT4 Agonists

合成路线1 合成路线2 合成路线3

合成路线1

Reductive ring closure of diethyl 2-nitrobenzylidenemalonate (I) afforded quinolone (II). Subsequent N-alkylation of (II) with isopropyl iodide gave (III). Carboxylic acid (IV) was then obtained by basic hydrolysis of the ethyl ester (III). In a related procedure, reductive alkylation of 2-aminobenzyl alcohol (V) with acetone in the presence of NaBH4 gave the N-isopropyl derivative (VI). Oxidation of (VI) using activated MnO2 in toluene yielded aldehyde (VII). Further Knoevenagel condensation of (VII) with diethyl malonate in the presence of piperidine and AcOH produced the previously described quinolone ester (III). Alternatively, condensation of (VII) with malonic acid directly produced the previously described quinolonecarboxylic acid (IV). Acid chloride (VIII) was then prepared by treatment of (IV) with thionyl chloride in hot toluene.

参考文献中间体

【1】 Yokomori, S.; Muramatsu, M.; Suzuki, M.; Ito, C.; Asanuma, H.; Isobe, Y.; Ohuchi, Y.; Kaneko, T.; Synthesis and evaluation of novel 2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives as potent and selective serotonin 5-HT4 receptor agonists. Chem Pharm Bull 2001, 49, 1, 29.
【2】 Ohuchi, Y.; Suzuki, M.; Asanuma, H.; Yokomori, S.; Hatayama, K. (Taisho Pharmaceutical Co., Ltd.); Quinolinecarboxylic acid deriv.. EP 0710662; JP 1996034784; US 5753673; WO 9531455 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	16829	Diethyl malonate	105-53-3	C₇H₁₂O₄	详情	详情
(I)	36330	diethyl 2-(2-nitrobenzylidene)malonate		C₁₄H₁₅NO₆	详情	详情
(II)	36331	ethyl 2-oxo-1,2-dihydro-3-quinolinecarboxylate		C₁₂H₁₁NO₃	详情	详情
(III)	36332	ethyl 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate		C₁₅H₁₇NO₃	详情	详情
(IV)	36333	1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid		C₁₃H₁₃NO₃	详情	详情
(V)	18619	(2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol	5344-90-1	C₇H₉NO	详情	详情
(VI)	36334	[2-(isopropylamino)phenyl]methanol；2-(isopropylamino)benzyl alcohol;(2-(isopropylamino)phenyl)methanol		C₁₀H₁₅NO	详情	详情
(VII)	36335	2-(isopropylamino)benzaldehyde		C₁₀H₁₃NO	详情	详情
(VIII)	36336	1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarbonyl chloride		C₁₃H₁₂ClNO₂	详情	详情

合成路线2

Condensation of acid chloride (VIII) 3-aminotropane (IX) provided amide (X). N-Demethylation of (X) was then achieved by treatment with 1-chloroethyl chloroformate, followed by hydrolysis and decarboxylation of the intermediate carbamate (XI) with MeOH. The resulting secondary amine (XII) was then alkylated with 3-bromopropanol (XIII) to afford the target hydroxypropyl derivative.

参考文献中间体

【1】 Yokomori, S.; Muramatsu, M.; Suzuki, M.; Ito, C.; Asanuma, H.; Isobe, Y.; Ohuchi, Y.; Kaneko, T.; Synthesis and evaluation of novel 2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives as potent and selective serotonin 5-HT4 receptor agonists. Chem Pharm Bull 2001, 49, 1, 29.
【2】 Ohuchi, Y.; Suzuki, M.; Asanuma, H.; Yokomori, S.; Hatayama, K. (Taisho Pharmaceutical Co., Ltd.); Quinolinecarboxylic acid deriv.. EP 0710662; JP 1996034784; US 5753673; WO 9531455 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	22014	1-chloro-1-[(chlorocarbonyl)oxy]ethane	50893-53-3	C₃H₄Cl₂O₂	详情	详情
(VIII)	36336	1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarbonyl chloride		C₁₃H₁₂ClNO₂	详情	详情
(IX)	12412	(1R,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-amine; (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]oct-3-ylamine		C₈H₁₆N₂	详情	详情
(X)	36337	1-isopropyl-N-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-2-oxo-1,2-dihydro-3-quinolinecarboxamide		C₂₁H₂₇N₃O₂	详情	详情
(XI)	36338	1-chloroethyl (1R,5S)-3-[[(1-isopropyl-2-oxo-1,2-dihydro-3-quinolinyl)carbonyl]amino]-8-azabicyclo[3.2.1]octane-8-carboxylate		C₂₃H₂₈ClN₃O₄	详情	详情
(XII)	36339	N-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide		C₂₀H₂₅N₃O₂	详情	详情
(XIII)	12573	3-Bromo-1-propanol; 3-Bromopropanol	627-18-9	C₃H₇BrO	详情	详情

合成路线3

Condensation between 2,5-dimethoxytetrahydrofuran (XIV), acetone-1,3-dicarboxylic acid (XV) and 3-amino-1-propanol (XVI), followed by acid decarboxylation of the intermediate adduct (XVII) furnished the tropinone analogue (XVIII). After conversion of (XVIII) to the corresponding oxime (XIX), its hydrogenation over PtO2 gave amine (XX). This was finally coupled with acid chloride (VIII) to give the title amide.

参考文献中间体

【1】 Yokomori, S.; Muramatsu, M.; Suzuki, M.; Ito, C.; Asanuma, H.; Isobe, Y.; Ohuchi, Y.; Kaneko, T.; Synthesis and evaluation of novel 2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives as potent and selective serotonin 5-HT4 receptor agonists. Chem Pharm Bull 2001, 49, 1, 29.
【2】 Ohuchi, Y.; Suzuki, M.; Asanuma, H.; Yokomori, S.; Hatayama, K. (Taisho Pharmaceutical Co., Ltd.); Quinolinecarboxylic acid deriv.. EP 0710662; JP 1996034784; US 5753673; WO 9531455 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	36336	1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarbonyl chloride		C₁₃H₁₂ClNO₂	详情	详情
(XIV)	12132	2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether	696-59-3	C₆H₁₂O₃	详情	详情
(XV)	15530	1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid	542-05-2	C₅H₆O₅	详情	详情
(XVI)	18522	3-amino-1-propanol	156-87-6	C₃H₉NO	详情	详情
(XVII)	36340	(1R,5S)-8-(3-hydroxypropyl)-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylic acid		C₁₂H₁₇NO₆	详情	详情
(XVIII)	36341	(1R,5S)-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]octan-3-one		C₁₀H₁₇NO₂	详情	详情
(XIX)	36342	(1R,5S)-8-(3-hydroxypropyl)-8-azabicyclo[3.2.1]octan-3-one oxime		C₁₀H₁₈N₂O₂	详情	详情
(XX)	36343	3-[(1R,5S)-3-amino-8-azabicyclo[3.2.1]oct-8-yl]-1-propanol		C₁₀H₂₀N₂O	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)