CN1680323A - 3-hydroxyphthalimidine derivative and synthesis thereof - Google Patents

3-hydroxyphthalimidine derivative and synthesis thereof Download PDF

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CN1680323A
CN1680323A CN 200510023636 CN200510023636A CN1680323A CN 1680323 A CN1680323 A CN 1680323A CN 200510023636 CN200510023636 CN 200510023636 CN 200510023636 A CN200510023636 A CN 200510023636A CN 1680323 A CN1680323 A CN 1680323A
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carbon atoms
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alkyl
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毛振民
徐赟
汤小伟
刘兰芳
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SHANGHAI JINSE MEDICAL TECHNOLOGY DEVELOPMENT Co Ltd
Shanghai Jiaotong University
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SHANGHAI JINSE MEDICAL TECHNOLOGY DEVELOPMENT Co Ltd
Shanghai Jiaotong University
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Abstract

3- hydroxyl(c) pyrroketone derivative, its synthesis are disclosed. It is carried out by dissolving compound into solvent, agitating, adding into CF3COOAg, dripping into Br2, and separating and purifying. It achieves moderate reacting condition and higher efficiency of object product.

Description

3-hydroxybenzene a pair of horses going side by side [c] 2-pyrrolidinone derivative and synthetic method thereof
Technical field
The present invention relates to a kind of 3-hydroxybenzene a pair of horses going side by side [c] 2-pyrrolidinone derivative and synthetic method thereof, belong to the medication preparation field.
Background technology
3-hydroxybenzene a pair of horses going side by side [c] 2-pyrrolidinone derivative [shown in its structural formula following (I)] is the analogue of Thalidomide (Thalidomide).Thalidomide is a glutamic acid derivatives, has antitumor, anti-erythema nodosum and antiphlogistic effect, but also has teratogenecity and neurotoxicity simultaneously.
Wherein: R 1, R 2, R 3And R 4Base, expression H, alkyl, alkoxyl group, ester group, aryl, aryloxy, benzyl, CF 3, OH, N 3, NH 2, NO 2, CN, NHCOR 1', NR 2' R 3', F, Cl, a kind of among the Br; N-R 5Expression N-H, N-alkyl, N-aryl, N-benzyl, N-heterogeneous ring compound, a kind of in amino acid and the amino acid ester thereof.
Find through literature search prior art, J.Med.Chem.2003,46 (18), 3793 publications " Thalidomide Metabolites and Analogues.3.Synthesis and AntiangiogenicActivity of Teratogenic and TNF α-Modulatory Thalidomide Analogue 2-(2; 6-Dioxopiperi-dine-3-yl " (phthalimide Thalidomide metabolite and analogue .3. thalidomide analogs 2-(2 thereof, 6-dioxopiperidine-3-yl) synthetic method of benzene a pair of horses going side by side [c] pyrrolidone with and teratogenesis, the anti-angiogenesis activity research that the regulating effect of tumor necrosis factor-alpha is produced).The synthetic method of 3 hydroxyls of this article report pyrrole ring mainly is that the carbonyl on 3 of the Thalidomide pyrrole rings is carried out this method complicated condition of selective reduction with the aluminium mercury reagent, poor selectivity, synthesis step is more, be difficult for operating, and do not see the report that product evaluation and relevant yield are arranged in the article.
Summary of the invention
The objective of the invention is to solve deficiency of the prior art, a kind of 3-hydroxybenzene a pair of horses going side by side [c] 2-pyrrolidinone derivative and synthetic method thereof are provided, make it have reaction conditions gentleness, the higher characteristics of target product yield.
The present invention is achieved by the following technical solutions, the invention provides a kind of 3-hydroxybenzene a pair of horses going side by side [c] 2-pyrrolidinone derivative, and its molecular formula is:
Wherein: R 1, R 2, R 3And R 4Base, expression H, alkyl, alkoxyl group, ester group, aryl, aryloxy, benzyl, CF 3, OH, N 3, NH 2, NO 2, CN, NHCOR 1', NR 2' R 3', F, Cl, a kind of among the Br; N-R 5Be N-H, N-alkyl, N-aryl, N-benzyl, N-heterogeneous ring compound, a kind of in amino acid and the amino acid ester thereof.
R 1, R 2, R 3, R 4, R 5During for alkyl, be straight chain, side chain contain alkyl with cyclic up to 10 carbon atoms; R 1, R 2, R 3, R 4During for alkoxyl group, be the alkoxyl group that contains up to 10 carbon atoms; R 1, R 2, R 3, R 4, R 5During for aryl, be the aryl and the aryl that contains up to 18 carbon atoms that contains up to 14 carbon atoms, it may be replaced by one or more functional groups; R 1, R 2, R 3, R 4During for aryloxy, be the aryloxy and the fragrant-oxyl that contains up to 18 carbon atoms that contains up to 14 carbon atoms, it may be replaced by one or more functional groups; N-R 5During for amino acid ester, its ester is the ester group up to 18 carbon atoms of containing of straight chain, side chain.R 1', R 2', R 3' be the alkyl that contains up to 10 carbon atoms.
The preparation method of the above-mentioned 3-hydroxybenzene of the present invention a pair of horses going side by side [c] 2-pyrrolidinone derivative is specially:
Formula (II) compound is dissolved in the solvent, stirs adding CF down 3COOAg dropwise adds Br 2, after question response finishes product is carried out separation and purification, described formula (II) compound, its molecular formula is:
Figure A20051002363600061
Wherein: R 1, R 2, R 3And R 4Base, expression H, alkyl, alkoxyl group, ester group, aryl, aryloxy, benzyl, CF 3, OH, N 3, NH 2, NO 2, CN, NHCOR 1', NR 2' R 3', F, Cl, a kind of among the Br; N-R 5Expression N-H, N-alkyl, N-aryl, N-benzyl, N-heterogeneous ring compound, a kind of in amino acid and the amino acid ester thereof.
R 1, R 2, R 3, R 4, R 5During for alkyl, be straight chain, side chain contain alkyl with cyclic up to 10 carbon atoms; R 1, R 2, R 3, R 4During for alkoxyl group, be the alkoxyl group that contains up to 10 carbon atoms; R 1, R 2, R 3, R 4, R 5During for aryl, be the aryl and the aryl that contains up to 18 carbon atoms that contains up to 14 carbon atoms, it may be replaced by one or more functional groups; R 1, R 2, R 3, R 4During for aryloxy, be the aryloxy and the fragrant-oxyl that contains up to 18 carbon atoms that contains up to 14 carbon atoms, it may be replaced by one or more functional groups; N-R 5During for amino acid ester, its ester is the ester group up to 18 carbon atoms of containing of straight chain, side chain.R 1', R 2', R 3' be the alkyl that contains up to 10 carbon atoms.
The inventive method can be represented with following reaction formula:
Wherein: R 1, R 2, R 3, R 4, R 5The same.
Described solvent is water and all organic solvents that raw material and product structure are not changed, comprises ether, CH 2Cl 2, CHCl 3, CCl 4, benzene, toluene, dimethylbenzene, dimethyl formamide, N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), 1, a kind of in the 4-dioxane also can use the mixture of above-mentioned two or more solvents.
Wherein: formula (II) compound and Br 2Mol ratio be 1: 0.5～10; Preferred 1: 0.8～2;
Drip Br 2The time temperature of reaction be-20～80 ℃; Preferred 0～5 ℃.
The present invention is different from traditional synthetic method, and in solvent, formula (II) compound benzene a pair of horses going side by side [c] pyrrolidone and reaction reagent reaction generate target product.Reaction conditions is comparatively gentle, and synthesis step is few, has reduced by product, improves the yield of target product simultaneously.The substituting group in comprising background technology, also will be referred to different positions on the phenyl ring, wider substituting group and pyrrole ring N and go up different substituting groups.The compounds of this invention is the analogue of Thalidomide, has antitumor, anti-erythema nodosum and antiphlogistic effect.
Embodiment
The present invention is described further below by embodiment, so that better understanding invention, but it does not limit protection scope of the present invention.
Embodiment 1
N-(2-methyl propionate base)-3-hydroxybenzene a pair of horses going side by side [c] pyrrolidone
438mg (2mmol) N-(2-methyl propionate base) benzene a pair of horses going side by side [c] pyrrolidone and 442mg (2mmol) trifluoroacetic acid silver are dissolved in 10ml CHCl 3, drip 320mg (2mmo1) Br in-20 ℃ 2(be dissolved in 10mlCHCl 3), dropwise about 1 hour.Stir 3h then under room temperature, filter, filtrate decompression is distilled to dried, purify colourless oil liquid 360mg, yield 76.6%.
Its analyzing test data is as follows:
1HNMR(400MHz，CDCl 3)：δ7.79(d，1H)，7.62(m，2H)，7.52(m，1H)，6.07(s，1H)，5.02(m，1H)，3.76(s，3H)，1.72(d，3H)
MS(M/e)：235，218，176，133。
Embodiment 2
N-(2-ethyl glutarate base)-3-hydroxybenzene a pair of horses going side by side [c] pyrrolidone
Figure A20051002363600081
319mg (1mmol) N-(2-ethyl glutarate base) benzene a pair of horses going side by side [c] pyrrolidone and 112mg (0.5mmol) trifluoroacetic acid silver are dissolved in 10ml benzene, drip 80mg (0.5mmol) Br in 5 ℃ 2(being dissolved in 10ml benzene) dropwised about 1 hour.Stir 2.5h then under room temperature, filter, filtrate decompression is distilled to dried, and purifying gets colourless oil liquid 301mg, yield 89.9%.
Its analyzing test data is as follows:
1HNMR(400MHz，CDCl 3)：δ7.79(d，1H)，7.62(m，2H)，7.52(m，1H)，6.07(s，1H)，4.78(m，1H)，4.23(m，2H)，4.02(m，2H)，2.51(m，4H)，1.28(t，3H)，1.21(t，3H)
MS(M/e)：335，318，244，133。
Embodiment 3
N-(ethyl acetate base)-3-hydroxybenzene a pair of horses going side by side [c] pyrrolidone
438mg (2mmol) N-(ethyl acetate base) benzene a pair of horses going side by side [c] pyrrolidone and 884mg (4mmol) trifluoroacetic acid silver are dissolved among the 15mLDMF, drip 640mg (4mmol) Br in 20 ℃ 2(being dissolved in 10ml DMF) dropwised about 2 hours.Under room temperature, stir 48h then, filter, filtrate through underpressure distillation to doing, purify colourless oil liquid 400mg, yield 85.1%.
Its analyzing test data is as follows:
1HNMR(400MHz，CDCl 3)：δ7.72(d，1H)，7.61(m，2H)，7.50(m，1H)，5.88(s，1H)，4.20(m，2H)，4.18(m，2H)，1.22(t，3H)
MS(M/e)：235，218，162，133。
Embodiment 4
N-(2-dimethyl succinate base)-3-hydroxybenzene a pair of horses going side by side [c] pyrrolidone
1.329g (4.8mmol) N-(2-dimethyl succinate base) benzene a pair of horses going side by side [c] pyrrolidone and 10.603g (48mmol) trifluoroacetic acid silver are dissolved in the 100mL chloroform, drip 7.68g (48mmol) Br in 80 ℃ 2(being dissolved in the 100ml chloroform) dropwised about 2 hours.Under room temperature, stir 48h then, filter, filtrate through underpressure distillation to doing, purify colourless oil liquid 0.992g, yield 70.5%.
Its analyzing test data is as follows:
1HNMR(400MHz，CDCl 3)：δ7.79(d，1H)，7.62(m，2H)，7.52(m，1H)，6.07(s，1H)，4.78(m，1H)，4.23(m，2H)，4.02(m，2H)，2.51(m，4H)，1.28(t，3H)，1.21(t，3H)
MS(M/e)：335，318，244，133。

Claims (8)

1, a kind of 3-hydroxybenzene a pair of horses going side by side [c] 2-pyrrolidinone derivative is characterized in that molecular formula is:
Figure A2005100236360002C1
Wherein: R 1, R 2, R 3And R 4Base, expression H, alkyl, alkoxyl group, ester group, aryl, aryloxy, benzyl, CF 3, OH, N 3, NH 2, NO 2, CN, NHCOR 1', NR 2' R 3', F, Cl, a kind of among the Br; N-R 5Be N-H, N-alkyl, N-aryl, N-benzyl, N-heterogeneous ring compound, a kind of in amino acid and the amino acid ester thereof.
2,3-hydroxybenzene a pair of horses going side by side according to claim 1 [c] 2-pyrrolidinone derivative is characterized in that R 1, R 2, R 3, R 4, R 5During for alkyl, be straight chain, side chain contain alkyl with cyclic up to 10 carbon atoms; R 1, R 2, R 3, R 4During for alkoxyl group, be the alkoxyl group that contains up to 10 carbon atoms; R 1, R 2, R 3, R 4, R 5During for aryl, be the aryl and the aryl that contains up to 18 carbon atoms that contains up to 14 carbon atoms, it may be replaced by one or more functional groups; R 1, R 2, R 3, R 4During for aryloxy, be the aryloxy and the fragrant-oxyl that contains up to 18 carbon atoms that contains up to 14 carbon atoms, it may be replaced by one or more functional groups; N-R 5During for amino acid ester, its ester is the ester group up to 18 carbon atoms of containing of straight chain, side chain.
3, as 3-hydroxybenzene a pair of horses going side by side [c] 2-pyrrolidinone derivative as described in claim 1 or 2, it is characterized in that R 1', R 2', R 3' be the alkyl that contains up to 10 carbon atoms.
4, the synthetic method of a kind of 3-hydroxybenzene a pair of horses going side by side [c] 2-pyrrolidinone derivative is characterized in that, (II) compound is dissolved in the solvent, stirs to add CF down 3COOAg dropwise adds Br 2, after question response finishes product is carried out separation and purification, described formula (II) compound, its molecular formula is:
Wherein: R 1, R 2, R 3And R 4Base, expression H, alkyl, alkoxyl group, ester group, aryl, aryloxy, benzyl, CF 3, OH, N 3, NH 2, NO 2, CN, NHCOR 1', NR 2' R 3', F, Cl, a kind of among the Br; N-R 5Expression N-H, N-alkyl, N-aryl, N-benzyl, N-heterogeneous ring compound, a kind of in amino acid and the amino acid ester thereof.
5, the synthetic method of 3-hydroxybenzene a pair of horses going side by side according to claim 4 [c] 2-pyrrolidinone derivative is characterized in that R 1, R 2, R 3, R 4, R 5During for alkyl, be straight chain, side chain contain alkyl with cyclic up to 10 carbon atoms; R 1, R 2, R 3, R 4During for alkoxyl group, be the alkoxyl group that contains up to 10 carbon atoms; R 1, R 2, R 3, R 4, R 5During for aryl, be the aryl and the aryl that contains up to 18 carbon atoms that contains up to 14 carbon atoms, it may be replaced by one or more functional groups; R 1, R 2, R 3, R 4During for aryloxy, be the aryloxy and the fragrant-oxyl that contains up to 18 carbon atoms that contains up to 14 carbon atoms, it may be replaced by one or more functional groups; N-R 5During for amino acid ester, its ester is the ester group up to 18 carbon atoms of containing of straight chain, side chain.
6, as the synthetic method of claim 4 or 5 described 3-hydroxybenzene a pair of horses going side by side [c] 2-pyrrolidinone derivatives, it is characterized in that R 1', R 2', R 3' be the alkyl that contains up to 10 carbon atoms.
7, the synthetic method of 3-hydroxybenzene a pair of horses going side by side as claimed in claim 4 [c] 2-pyrrolidinone derivative is characterized in that, in solvent, uses Br 2And CF 3COOAg is as reaction reagent;
Wherein: formula (II) compound and Br 2Mol ratio be 1: 0.5～10;
Temperature of reaction is-20～80 ℃.
8, as the synthetic method of claim 4 or 7 described 3-hydroxybenzene a pair of horses going side by side [c] 2-pyrrolidinone derivatives, it is characterized in that, described solvent, all organic solvents that are meant water and raw material and product structure are not changed comprise ether, CH 2Cl 2, CHCl 3, CCl 4, benzene, toluene, dimethylbenzene, dimethyl formamide, N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), 1,4-dioxane a kind of perhaps uses the mixture of above-mentioned two or more solvents.
CN 200510023636 2005-01-27 2005-01-27 3-hydroxyphthalimidine derivative and synthesis thereof Pending CN1680323A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101225070B (en) * 2008-01-31 2010-04-14 上海交通大学 Antineoplastic medicament
CN101703507B (en) * 2008-01-31 2011-08-31 上海交通大学 Antineoplastic medicament
CN105348058A (en) * 2015-10-29 2016-02-24 付思涵 Synthetic method of carbonyl alcohol compounds

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101225070B (en) * 2008-01-31 2010-04-14 上海交通大学 Antineoplastic medicament
CN101703507B (en) * 2008-01-31 2011-08-31 上海交通大学 Antineoplastic medicament
CN105348058A (en) * 2015-10-29 2016-02-24 付思涵 Synthetic method of carbonyl alcohol compounds
CN105348058B (en) * 2015-10-29 2017-11-21 金溪斯普瑞药业有限公司 A kind of synthetic method of carbonyl alcohol compound

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