octyl (2R,4R)-4-[[(dimethylamino)carbonyl]oxy]-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】47644

【品名】octyl (2R,4R)-4-[[(dimethylamino)carbonyl]oxy]-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylate

【CA登记号】

【分子式】C₃₃H₄₈N₂O₆

【分子量】568.754

【元素组成】C 69.69% H 8.51% N 4.93% O 16.88%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XX)

Synthesis of EN 212779: Deprotection and esterification of pyrrolidine (IX) by first treatment with HCl (gas) in EtOH followed by reaction with ethyl chloroformate (X) and Et3N in acetone/H2O yields carbamate (XI), which is then reduced with LiBH4 in THF to give carbinol (XII). Conversion of alcohol (XII) into cyano derivative (XIII) is then accomplished by first tosylation with p-toluenesulfonic anhydride (Ts2O) and Et3N in dichloromethane followed by reaction with NaCN in DMF. Acidic ethanolysis of nitrile (XIII) by means of HCl in EtOH furnishes ethyl ester (XIV), which is reduced with LiAlH4 in THF to provide ethanol derivative (XV). Treatment of alcohol (XV) with Ts2O and Et3N in dichloromethane affords tosylate (XVI), which is converted into derivative (XVII) by condensation with intermediate (VIII) by means of KOtBu in dimethylacetamide (DMA). Debenzylation of (XVII) by hydrogenation over Pd/C in EtOH yields alcohol (XVIII), which is finally reduced with LiAlH4 in THF and hydrolyzed with HCl in dioxane to give the desired compound. Alternatively, the final product can be obtained by condensation of bromo derivative (XIX) with intermediate (VIII) by means of KOtBu in dimethylacetamide (DMA), furnishing compound (XX), which is finally reduced with LiAlH4 in THF and hydrolyzed with HCl.

参考文献中间体

合成目标

【3】 Fujimoto, K.; Tanaka, N.; Asai, F.; Ito, T.; Koike, H. (Sankyo Co., Ltd.); Phenoxyalkylamines, -pyrrolidines and -piperidines for the treatment and prevention of circulatory diseases and psychosis. EP 0600717; JP 1994234736; JP 1994306025; US 5556864 .
【1】 Ogawa, T.; Sugidachi, A.; Goto, R.; Asai, T.; Tanaka, S.; Ito, R.; Hayakawa, M.; Fujimoto, K.; 2-(omega-Phenylalkyl)phenoxy)alkylamines III: Synthesis and selective serotonin-2 receptor binding (2). Chem Pharm Bull 2000, 48, 11, 1729.
【2】 Tanaka, N.; et al.; Antiplatelets with 5-HT2 receptor antagonistic action - Synthesis and structure-activity relationships of [2-(omega-phenylalkyl)phenoxy]alkylamines. 18th Symp Med Chem (Nov 25 1998, Kyoto) 1998, Abst 2-P-01.

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)	13604	2-(3-Methoxyphenethyl)phenol		C₁₅H₁₆O₂	详情	详情
(IX)	19059	(2R,4S)-4-(benzyloxy)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid	54631-81-1	C₁₇H₂₃NO₅	详情	详情
(X)	11229	1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate	541-41-3	C₃H₅ClO₂	详情	详情
(XI)	47634	diethyl (2S,4R)-4-(benzyloxy)-1,2-pyrrolidinedicarboxylate		C₁₇H₂₃NO₅	详情	详情
(XII)	47635	ethyl (2S,4R)-4-(benzyloxy)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate		C₁₅H₂₁NO₄	详情	详情
(XIII)	47636	ethyl (2R,4R)-4-(benzyloxy)-2-(cyanomethyl)-1-pyrrolidinecarboxylate		C₁₆H₂₀N₂O₃	详情	详情
(XIV)	47637	ethyl (2S,4R)-4-(benzyloxy)-2-(2-ethoxy-2-oxoethyl)-1-pyrrolidinecarboxylate		C₁₈H₂₅NO₅	详情	详情
(XV)	47638	ethyl (2R,4R)-4-(benzyloxy)-2-(2-hydroxyethyl)-1-pyrrolidinecarboxylate		C₁₆H₂₃NO₄	详情	详情
(XVI)	47639	ethyl (2R,4R)-4-(benzyloxy)-2-(2-[[(4-methylphenyl)sulfonyl]oxy]ethyl)-1-pyrrolidinecarboxylate		C₂₃H₂₉NO₆S	详情	详情
(XVII)	47640	ethyl (2S,4R)-4-(benzyloxy)-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylate		C₃₁H₃₇NO₅	详情	详情
(XVIII)	47641	(2S,4R)-4-hydroxy-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylic acid		C₂₂H₂₇NO₅	详情	详情
(XIX)	47643	octyl (2S,4R)-2-(2-bromoethyl)-4-[[(dimethylamino)carbonyl]oxy]-1-pyrrolidinecarboxylate		C₁₈H₃₃BrN₂O₄	详情	详情
(XX)	47644	octyl (2R,4R)-4-[[(dimethylamino)carbonyl]oxy]-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylate		C₃₃H₄₈N₂O₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXI)

Synthesis of EN 296245: Deprotection and esterification of pyrrolidine (IX) by first treatment with HCl (gas) in EtOH followed by reaction with ethyl chloroformate (X) and Et3N in acetone/H2O, yields carbamate (XI), which is then reduced with LiBH4 in THF to give derivative (XII). Conversion of alcohol (XII) into cyano derivative (XIII) is then accomplished by first tosylation with p-toluenesulfonic anhydride (Ts2O) and Et3N in dichloromethane, followed by reaction with NaCN in DMF. Acidic ethanolysis of nitrile (XIII) by means of HCl in EtOH furnishes ethyl ester (XIV), which is reduced with LiAlH4 in THF to provide derivative (XV). Treatment of alcohol (XV) with Ts2O and Et3N in dichloromethane affords tosylate (XVI), which is converted into derivative (XVII) by condensation with intermediate (VIII) by means of KOtBu in dimethylacetamide (DMA). Debenzylation of (XVII) by hydrogenation over Pd/C in EtOH yields alcohol (XVIII), which is converted into alcohol (XIX) by treatment with LiAlH4 in THF, followed by hydrolysis with HCl in dioxane. Alternatively, derivative (XIX) can be obtained by condensation of bromo derivative (XX) with intermediate (VIII) by means of KOtBu in dimethylacetamide (DMA) to furnish compound (XXI), followed by reduction with LiAlH4 in THF and hydrolysis with HCl. Finally, esterification of (XIX) with lauric anhydride (XXII) by means of DMAP in pyridine yields the target product.

参考文献中间体

合成目标

【1】 Ogawa, T.; Sugidachi, A.; Goto, R.; Asai, T.; Tanaka, S.; Ito, R.; Hayakawa, M.; Fujimoto, K.; 2-(omega-Phenylalkyl)phenoxy)alkylamines III: Synthesis and selective serotonin-2 receptor binding (2). Chem Pharm Bull 2000, 48, 11, 1729.
【2】 Tanaka, N.; et al.; Antiplatelets with 5-HT2 receptor antagonistic action - Synthesis and structure-activity relationships of [2-(omega-phenylalkyl)phenoxy]alkylamines. 18th Symp Med Chem (Nov 25 1998, Kyoto) 1998, Abst 2-P-01.
【4】 Asai, F.; Fujimoto, K. (Sankyo Co., Ltd.); Compsn. containing diarylalkane deriv. as the active ingredient for treating or preventing pancreatitis. JP 1998212232; WO 9823271 .
【3】 Fujimoto, K.; Tanaka, N.; Asai, F.; Ito, T.; Koike, H. (Sankyo Co., Ltd.); Phenoxyalkylamines, -pyrrolidines and -piperidines for the treatment and prevention of circulatory diseases and psychosis. EP 0600717; JP 1994234736; JP 1994306025; US 5556864 .

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)	13604	2-(3-Methoxyphenethyl)phenol		C₁₅H₁₆O₂	详情	详情
(IX)	19059	(2R,4S)-4-(benzyloxy)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid	54631-81-1	C₁₇H₂₃NO₅	详情	详情
(X)	11229	1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate	541-41-3	C₃H₅ClO₂	详情	详情
(XI)	47634	diethyl (2S,4R)-4-(benzyloxy)-1,2-pyrrolidinedicarboxylate		C₁₇H₂₃NO₅	详情	详情
(XII)	47635	ethyl (2S,4R)-4-(benzyloxy)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate		C₁₅H₂₁NO₄	详情	详情
(XIII)	47636	ethyl (2R,4R)-4-(benzyloxy)-2-(cyanomethyl)-1-pyrrolidinecarboxylate		C₁₆H₂₀N₂O₃	详情	详情
(XIV)	47637	ethyl (2S,4R)-4-(benzyloxy)-2-(2-ethoxy-2-oxoethyl)-1-pyrrolidinecarboxylate		C₁₈H₂₅NO₅	详情	详情
(XV)	47638	ethyl (2R,4R)-4-(benzyloxy)-2-(2-hydroxyethyl)-1-pyrrolidinecarboxylate		C₁₆H₂₃NO₄	详情	详情
(XVI)	47639	ethyl (2R,4R)-4-(benzyloxy)-2-(2-[[(4-methylphenyl)sulfonyl]oxy]ethyl)-1-pyrrolidinecarboxylate		C₂₃H₂₉NO₆S	详情	详情
(XVII)	47640	ethyl (2S,4R)-4-(benzyloxy)-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylate		C₃₁H₃₇NO₅	详情	详情
(XVIII)	47641	(2S,4R)-4-hydroxy-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylic acid		C₂₂H₂₇NO₅	详情	详情
(XIX)	47642	(3R,5S)-5-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-methyl-3-pyrrolidinol		C₂₂H₂₉NO₃	详情	详情
(XX)	47643	octyl (2S,4R)-2-(2-bromoethyl)-4-[[(dimethylamino)carbonyl]oxy]-1-pyrrolidinecarboxylate		C₁₈H₃₃BrN₂O₄	详情	详情
(XXI)	47644	octyl (2R,4R)-4-[[(dimethylamino)carbonyl]oxy]-2-[2-[2-(3-methoxyphenethyl)phenoxy]ethyl]-1-pyrrolidinecarboxylate		C₃₃H₄₈N₂O₆	详情	详情
(XXII)	47645	dodecanoic anhydride		C₂₄H₄₆O₃	详情	详情

Extended Information