ER-62899, E-2100, -Drug Synthesis Database

【结构式】

【药物名称】ER-62899, E-2100

【化学名称】N-[1-[1-[2-(4-Fluorophenyl)ethyl]piperidin-4-yl]indolin-6-ylmethyl]acetamide

【CA登记号】214611-53-7

【分子式】C₂₄H₃₀FN₃O

【分子量】395.5246

【开发单位】Eisai (Originator)

【药理作用】Antispastic Drugs and Drugs for Muscle Spasms, Muscle Spasms, Drugs for, NEUROLOGIC DRUGS, Smooth Muscle Relaxants, 5-HT1A Antagonists, 5-HT2 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1

Addition of methyl acrylate (II) to 4-fluorophenethylamine (I) afforded diester (III). Dieckmann cyclization of (III) gave the carbomethoxy piperidone (IV), which was decarbomethoxylated to (V) under acidic conditions.

参考文献中间体

【1】 Kimura, T.; Takahashi, K.; Matsunaga, M.; Kawano, K.; Kubota, A.; Kitazawa, N.; Okabe, T.; Ueno, K.; Komatsu, M.; Sasaki, A. (Eisai Co., Ltd.); 1,4-Substd. cyclic amine derivs.. EP 0976732; WO 9843956 .

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)	45818	2-(4-fluorophenyl)-1-ethanamine; 4-fluorophenethylamine		C₈H₁₀FN	详情	详情
(II)	14156	methyl acrylate	96-33-3	C₄H₆O₂	详情	详情
(III)	45819	methyl 3-[(4-fluorophenethyl)(3-methoxy-3-oxopropyl)amino]propanoate		C₁₆H₂₂FNO₄	详情	详情
(IV)	45820	methyl 1-(4-fluorophenethyl)-4-oxo-3-piperidinecarboxylate		C₁₅H₁₈FNO₃	详情	详情
(V)	45821	1-(4-fluorophenethyl)-4-piperidinone		C₁₃H₁₆FNO	详情	详情

合成路线2

Condensation of 2,5-dibromonitrobenzene (VI) with diethyl malonate gave aryl malonate (VII). Reductive cyclization of (VII) in the presence of tin and HCl produced 6-bromooxindole (VIII), which was further reduced to indoline (IX) using borane-dimethyl sulfide complex (1). Reductive alkylation of indoline (IX) with piperidone (V) by means of sodium triacetoxyborohydride furnished the piperidinyl indoline (X).

参考文献中间体

【1】 Kitazawa, N.; Ueno, K.; Sasaki, A.; et al.; Synthesis and evaluation of indoline and indole derivatives as a dual antagonist for 5-HT1A and 5-HT2 receptor. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 97.
【2】 Kimura, T.; Takahashi, K.; Matsunaga, M.; Kawano, K.; Kubota, A.; Kitazawa, N.; Okabe, T.; Ueno, K.; Komatsu, M.; Sasaki, A. (Eisai Co., Ltd.); 1,4-Substd. cyclic amine derivs.. EP 0976732; WO 9843956 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	45821	1-(4-fluorophenethyl)-4-piperidinone		C₁₃H₁₆FNO	详情	详情
(VI)	45805	1,4-dibromo-2-nitrobenzene	3460-18-2	C₆H₃Br₂NO₂	详情	详情
(VII)	45806	diethyl 2-(4-bromo-2-nitrophenyl)malonate		C₁₃H₁₄BrNO₆	详情	详情
(VIII)	45807	6-bromo-1,3-dihydro-2H-indol-2-one		C₈H₆BrNO	详情	详情
(IX)	45808	6-bromoindoline		C₈H₈BrN	详情	详情
(X)	45822	6-bromo-1-[1-(4-fluorophenethyl)-4-piperidinyl]indoline		C₂₁H₂₄BrFN₂	详情	详情

合成路线3

In an alternative method, 3-bromoaniline (XI) was reductively condensed with piperidone (V) to afford the anilino piperidine (XII). Condensation of (XII) with oxalyl chloride, followed by Friedel-Crafts cyclization, gave rise to the N-piperidinyl isatin (XIII). This was sequentially reduced to indole (XIV) with borane in THF, and then to indoline (X) using borane and trifluoroacetic acid.

参考文献中间体

【1】 Kimura, T.; Takahashi, K.; Matsunaga, M.; Kawano, K.; Kubota, A.; Kitazawa, N.; Okabe, T.; Ueno, K.; Komatsu, M.; Sasaki, A. (Eisai Co., Ltd.); 1,4-Substd. cyclic amine derivs.. EP 0976732; WO 9843956 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	45821	1-(4-fluorophenethyl)-4-piperidinone		C₁₃H₁₆FNO	详情	详情
(X)	45822	6-bromo-1-[1-(4-fluorophenethyl)-4-piperidinyl]indoline		C₂₁H₂₄BrFN₂	详情	详情
(XI)	19136	3-bromoaniline; 3-bromophenylamine; 3-bromobenzenamine	591-19-5	C₆H₆BrN	详情	详情
(XII)	45823	N-(3-bromophenyl)-N-[1-(4-fluorophenethyl)-4-piperidinyl]amine; N-(3-bromophenyl)-1-(4-fluorophenethyl)-4-piperidinamine		C₁₉H₂₂BrFN₂	详情	详情
(XIII)	45824	6-bromo-1-[1-(4-fluorophenethyl)-4-piperidinyl]-1H-indole-2,3-dione		C₂₁H₂₀BrFN₂O₂	详情	详情
(XIV)	45825	6-bromo-1-[1-(4-fluorophenethyl)-4-piperidinyl]-1H-indole		C₂₁H₂₂BrFN₂	详情	详情

合成路线4

Introduction of a formyl group into indoline (X) was carried out via lithiation with n-butyllithium, followed by treatment with dimethylformamide. The resulting aldehyde (XV) was converted to oxime (XVI), which was subsequently reduced to amine (XVII) using LiAlH4. Finally, acylation of amine (XVII) with acetyl chloride produced the title amide.

参考文献中间体

【1】 Kitazawa, N.; Ueno, K.; Sasaki, A.; et al.; Synthesis and evaluation of indoline and indole derivatives as a dual antagonist for 5-HT1A and 5-HT2 receptor. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 97.
【2】 Kimura, T.; Takahashi, K.; Matsunaga, M.; Kawano, K.; Kubota, A.; Kitazawa, N.; Okabe, T.; Ueno, K.; Komatsu, M.; Sasaki, A. (Eisai Co., Ltd.); 1,4-Substd. cyclic amine derivs.. EP 0976732; WO 9843956 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(X)	45822	6-bromo-1-[1-(4-fluorophenethyl)-4-piperidinyl]indoline	C₂₁H₂₄BrFN₂	详情	详情
(XV)	45826	1-[1-(4-fluorophenethyl)-4-piperidinyl]-6-indolinecarbaldehyde	C₂₂H₂₅FN₂O	详情	详情
(XVI)	45827	1-[1-(4-fluorophenethyl)-4-piperidinyl]-6-indolinecarbaldehyde oxime	C₂₂H₂₆FN₃O	详情	详情
(XVII)	45828	[1-[1-(4-fluorophenethyl)-4-piperidinyl]-2,3-dihydro-1H-indol-6-yl]methanamine; [1-[1-(4-fluorophenethyl)-4-piperidinyl]-2,3-dihydro-1H-indol-6-yl]methylamine	C₂₂H₂₈FN₃	详情	详情

Extended Information