diethyl 2-(4-bromo-2-nitrophenyl)malonate -Drug Synthesis Database

【结构式】

【分子编号】45806

【品名】diethyl 2-(4-bromo-2-nitrophenyl)malonate

【CA登记号】

【分子式】C₁₃H₁₄BrNO₆

【分子量】360.1613

【元素组成】C 43.35% H 3.92% Br 22.19% N 3.89% O 26.65%

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：(VII)

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

合成目标

【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2

该中间体在本合成路线中的序号：(II)

Condensation of 2,5-dibromonitrobenzene (I) with diethyl malonate gave aryl malonate (II). Reductive cyclization of (II) in the presence of tin and HCl produced 6-bromooxindole (III), which was further reduced to indoline (IV) using borane-dimethyl sulfide complex. Reductive alkylation of indoline (IV) with piperidone (V) by means of sodium triacetoxyborohydride furnished the piperidinyl indoline (VI). Introduction of a formyl group into indoline (VI) was carried out via lithiation with n-butyllithium, followed by treatment with dimethylformamide. The resulting aldehyde (VII) was reduced to alcohol (VIII) using NaBH4. Conversion to the corresponding chloride by treatment with HCl, followed by reaction with NaCN, furnished nitrile (IX). Hydrolysis of nitrile (IX) with aqueous H2SO4 gave carboxylic acid (X), which, after activation with carbonyldiimidazole, was coupled with methylamine to yield amide (XI). Finally, indoline (XI) was oxidized to the title indole with MnO2 in CHCl3. Alternatively, Stille coupling of bromoindoline (VI) with ethyl tributylstannylacetate gave indolineacetate (XII), which was further oxidized to indole (XIII) with MnO2. Saponification of the ester group of (XIII), followed by condensation with methylamine furnished the title compound.

参考文献中间体

合成目标

【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
(I)	45805	1,4-dibromo-2-nitrobenzene	3460-18-2	C₆H₃Br₂NO₂	详情	详情
(II)	45806	diethyl 2-(4-bromo-2-nitrophenyl)malonate		C₁₃H₁₄BrNO₆	详情	详情
(III)	45807	6-bromo-1,3-dihydro-2H-indol-2-one		C₈H₆BrNO	详情	详情
(IV)	45808	6-bromoindoline		C₈H₈BrN	详情	详情
(V)	45809	1-(2-fluorophenethyl)-4-piperidinone		C₁₃H₁₆FNO	详情	详情
(VI)	45810	6-bromo-1-[1-(2-fluorophenethyl)-4-piperidinyl]indoline		C₂₁H₂₄BrFN₂	详情	详情
(VII)	45811	1-[1-(2-fluorophenethyl)-4-piperidinyl]-6-indolinecarbaldehyde		C₂₂H₂₅FN₂O	详情	详情
(VIII)	45812	[1-[1-(2-fluorophenethyl)-4-piperidinyl]-2,3-dihydro-1H-indol-6-yl]methanol		C₂₂H₂₇FN₂O	详情	详情
(IX)	45813	2-[1-[1-(2-fluorophenethyl)-4-piperidinyl]-2,3-dihydro-1H-indol-6-yl]acetonitrile	285-69-8	C₂₃H₂₆FN₃	详情	详情
(X)	45814	2-[1-[1-(2-fluorophenethyl)-4-piperidinyl]-2,3-dihydro-1H-indol-6-yl]acetic acid		C₂₃H₂₇FN₂O₂	详情	详情
(XI)	45815	2-[1-[1-(2-fluorophenethyl)-4-piperidinyl]-2,3-dihydro-1H-indol-6-yl]-N-methylacetamide		C₂₄H₃₀FN₃O	详情	详情
(XII)	45816	ethyl 2-[1-[1-(2-fluorophenethyl)-4-piperidinyl]-2,3-dihydro-1H-indol-6-yl]acetate		C₂₅H₃₁FN₂O₂	详情	详情
(XIII)	45817	ethyl 2-[1-[1-(2-fluorophenethyl)-4-piperidinyl]-1H-indol-6-yl]acetate		C₂₅H₂₉FN₂O₂	详情	详情

Extended Information