CN104016879B - Dibenzoyl amine compound with anti-tumor activity and its preparation method and application - Google Patents

Dibenzoyl amine compound with anti-tumor activity and its preparation method and application Download PDF

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CN104016879B
CN104016879B CN201410242239.XA CN201410242239A CN104016879B CN 104016879 B CN104016879 B CN 104016879B CN 201410242239 A CN201410242239 A CN 201410242239A CN 104016879 B CN104016879 B CN 104016879B
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compound
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benzyloxy
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CN104016879A (en
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张�杰
贺浪冲
张涛
李鹏飞
卢闻
王嗣岑
潘晓艳
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Xian Jiaotong University
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Xian Jiaotong University
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Abstract

The invention discloses a kind of dibenzoyl amine compound with anti-tumor activity and its preparation method and application, the structural formula of this compound is , wherein R 1for hydrogen or halogen, R 2the carbonatoms replaced by tertiary amine groups for end is the alkoxyl group of 1 ~ 4, is connected to the contraposition of acid amides by Sauerstoffatom.This Compound ira vitro has good inhibit activities to tumour cell, can be used for the preparation of antitumor drug, especially medicines resistant to liver cancer and anti-breast cancer medicines.The preparation method of dibenzoyl amine compound provided by the invention, has raw material and is easy to get, and reaction conditions is gentle, and reaction process is simple to operate, the advantage that agents useful for same is cheap.

Description

Dibenzoyl amine compound with anti-tumor activity and its preparation method and application
Technical field
The present invention relates to biomedicine technical field, relate to a kind of antineoplastic compound, particularly a kind of dibenzoyl amine compound with anti-tumor activity and its preparation method and application.
Background technology
Malignant tumour is that current serious affects human health, threatens one of principal disease of human life.The statistical information display of the World Health Organization, the current whole world about has millions of people to die from malignant tumour every year, and it has become the second largest human diseases killer being only second to cardiovascular and cerebrovascular diseases.Chemotherapy, as one of important means for the treatment of tumour, has had huge development and progress at nearly 30 years, has obtained large quantities of clinical antitumor agents with different mechanism of action.But antitumour drug still exists many weak points, such as toxic side effect cannot control, and produce resistance etc. fast, these all cause chemicals cannot reach the result for the treatment of of expection.The research and development of therefore new antitumor drug are one of the focus and difficulties of current pharmaceutical field.
Summary of the invention
The object of the present invention is to provide a kind of dibenzoyl amine compound with anti-tumor activity and its preparation method and application, this dibenzoyl amine compound embodies good anti-tumor activity in vitro, can be applied to the preparation of antitumor drug.
For achieving the above object, the present invention is achieved through the following technical solutions:
There is a dibenzoyl amine compound for anti-tumor activity, there is following structural formula:
Wherein, R 1for hydrogen or halogen, R 2the carbonatoms replaced by tertiary amine groups for end is the alkoxyl group of 1 ~ 4, is connected to the contraposition of acid amides by Sauerstoffatom.
In described tertiary amine groups, nitrogen-atoms is the assorted ring nitrogen of 5 ~ 6 yuan.
Also comprise Sauerstoffatom in described heterocycle, nitrogen-atoms is relative with Sauerstoffatom.
What be connected with nitrogen-atoms in described tertiary amine groups is one or more in straight chained alkyl, cycloalkyl, epoxy alkyl.
Described tertiary amine groups is dimethylamino, diethylin, pyrrolidyl, piperidyl or morpholinyl.
There is the preparation method of the dibenzoyl amine compound of anti-tumor activity, comprise the following steps:
1) 3-bromophenol is obtained by reacting 1-benzyloxy-3-bromobenzene by Benzylation;
2) under catalysis of iodine, 1-benzyloxy-3-bromobenzene and magnesium rod are obtained by reacting 3-benzyloxy-phenyl magnesium bromide by Grignard; 3-benzyloxy-phenyl magnesium bromide and trimethyl borate generation esterification, then obtain 3-benzyloxy phenylo boric acid with saturated ammonium chloride hydrolysis reaction;
3) the binary oxidation system oxidizing reaction of 3-bromobenzaldehyde clorox and hydrogen peroxide obtains 3-bromo-benzoic acid;
4) under the catalysis of palladium carbon, 3-benzyloxy phenylo boric acid and 3-bromo-benzoic acid are obtained by reacting 3 '-benzyloxy biphenyl-3-carboxylic acid by Suzuki;
5) p-NP replaced and tertiary amine side chain generation etherification reaction, then obtain the substituted aniline containing tertiary amine side chain by reduction reaction;
6) 3 '-benzyloxy biphenyl-3-carboxylic acid forms dibenzoyl aminated compounds with the substituted aniline condensation containing tertiary amine side chain, then removes benzyl, obtains target compound.
Described step 1) concrete operations be: 3-bromophenol is dissolved in dehydrated alcohol, add Anhydrous potassium carbonate, stirring at room temperature is even, add Benzyl Chloride again, heating reflux reaction, after reaction, be cooled to room temperature, suction filtration reaction product, be extracted with ethyl acetate filtrate, organic phase pressure reducing and steaming solvent after washing, drying of extraction, obtains 1-benzyloxy-3-bromobenzene;
Described step 2) concrete operations be: in reaction vessel, add clean magnesium rod and iodine, under nitrogen protection, add the anhydrous tetrahydrofuran solution of 1-benzyloxy-3-bromobenzene, heating reflux reaction, obtain Grignard reagent 3-benzyloxy-phenyl magnesium bromide; The anhydrous tetrahydrofuran solution of trimethyl borate is dripped again wherein at-20 DEG C, room temperature reaction, then add saturated aqueous ammonium chloride and to be hydrolyzed reaction, reaction product is extracted with ethyl acetate, organic phase pressure reducing and steaming solvent after washing, drying of extraction, obtains 3-benzyloxy phenylo boric acid;
Described step 3) concrete operations be: 3-bromobenzaldehyde is dissolved in anhydrous tetrahydro furan, adds water and Sodium phosphate dibasic, under condition of ice bath, drip clorox and hydrogen peroxide solution, drip off rear stirred at ambient temperature reaction; Reaction product is extracted with ethyl acetate, and the pH value regulating the aqueous phase of extraction is 3 ~ 4, and the solid of precipitation is dried to obtain 3-bromo-benzoic acid;
Described step 4) concrete operations be: 3-benzyloxy phenylo boric acid is dissolved in the mixed solution of isopropyl alcohol and water, then adds Anhydrous potassium carbonate and palladium carbon, stirring at room temperature evenly after, add 3-bromo-benzoic acid, back flow reaction under nitrogen protection; Be cooled to room temperature after reaction, filter reaction product, filtrate is extracted with ethyl acetate, and organic phase pressure reducing and steaming solvent after washing, drying of extraction, obtains 3 '-benzyloxy biphenyl-3-carboxylic acid.
Described step 5) concrete operations be: the p-NP of replacement is dissolved in dry DMF, then adds Cs successively 2o 3with the compound with tertiary amine side chain, reacting by heating under nitrogen protection, after reaction terminates, added by reaction solution in frozen water, be extracted with ethyl acetate, organic phase pressure reducing and steaming solvent after washing, drying of extraction, obtains the p-NP of etherificate; The p-NP of etherificate is dissolved in methyl alcohol, adds palladium carbon, pass into hydrogen and at room temperature carry out reduction reaction, the substituted aniline of tertiary amine side chain must be contained;
Described step 6) concrete operations be: 3 '-benzyloxy biphenyl-3-carboxylic acid is dissolved in anhydrous tetrahydro furan, add EDCI, HOBT, DMAP and triethylamine successively again, dropwise rear continuation to stir, then the anhydrous tetrahydrofuran solution of the substituted aniline containing tertiary amine side chain is dripped, dropwise the reaction of rear stirring at room temperature, reaction product is extracted with ethyl acetate, organic phase pressure reducing and steaming solvent afforded crude material after washing, drying of extraction, is separated crude product with chromatography column and obtains Benzylation dibenzoyl amine compound; In Benzylation dibenzoyl amine compound, add methyl alcohol and palladium carbon, room temperature reduction reaction, obtains target compound.
The described dibenzoyl amine compound with anti-tumor activity is preparing the application in antitumor drug.
Described antitumor drug comprises medicines resistant to liver cancer and anti-breast cancer medicines.
Compared with prior art, the present invention has following beneficial effect:
The dibenzoyl amine compound with anti-tumor activity provided by the invention, is a kind of novel compound with anti-tumor activity, can be used for the preparation of antitumor drug.
The preparation method with the dibenzoyl amine compound of anti-tumor activity provided by the invention, has raw material and is easy to get, and reaction conditions is gentle, and reaction process is simple to operate, the advantage that agents useful for same is cheap.
The dibenzoyl amine compound with anti-tumor activity provided by the invention, to its cell-proliferation activity of inhibiting tumour cells comprising breast cancer cell (MCF-7) and liver cancer cell (SMMC-7721), the preparation of antitumor drug can be can be applicable to.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of the dibenzoyl amine compound with anti-tumor activity.
Wherein compound 1 is 3-bromophenol, and compound 2 is 1-benzyloxy-3-bromobenzene, and compound 3 is 3-benzyloxy phenylo boric acid; Compound is 4 is 3-bromobenzaldehyde, compound 5 is 3-bromo-benzoic acid, compound 6 is 3 '-benzyloxy biphenyl-3-carboxylic acid, compound 7 is the p-NP of halogen substiuted, compound 8 is the p-NP of etherificate, compound 9 is the substituted aniline containing tertiary amine side chain, and compound 10 is Benzylation dibenzoyl amine compound, and compound 11 is the dibenzoyl amine target compound BPA1-21 after reduction.
What mark in figure is specially:
(a) BnCl, K 2cO 3, C 2h 5oH, backflow; (b) Mg/I 2, THF, backflow; (c) B (OCH 3) 3, NH 4cl; (d) H 2o 2, NaClO 2, NaH 2pO 4; (e) Pd/C, K 2cO 3, i-PrOH, H 2o, backflow (f) Cs 2cO 3, DMF, backflow; (g) Pd/C, H 2, CH 3oH; (h) EDCI, HOBT, DMAP, THF; (i) Pd/C, H 2, CH 3oH
Embodiment
The invention provides a kind of dibenzoyl amine compound with anti-tumor activity, this dibenzoyl amine compound embodies anti-tumor activity in vitro, can be applied to the preparation of antitumor drug.
Be described in detail the present invention below in conjunction with accompanying drawing and embodiment, the explanation of the invention is not limited.
The dibenzoyl amine compound with anti-tumor activity provided by the invention, its chemical structural formula is:
Wherein, R 1for hydrogen or halogen, R 2the carbonatoms replaced by tertiary amine groups for end is the alkoxyl group of 1 ~ 4, is connected to the contraposition of acid amides by Sauerstoffatom.
Further, in described tertiary amine groups, nitrogen-atoms is the assorted ring nitrogen of 5 ~ 6 yuan.Also comprise Sauerstoffatom in described heterocycle, nitrogen-atoms is relative with Sauerstoffatom.
What be connected with nitrogen-atoms in described tertiary amine groups is one or more in straight chained alkyl, cycloalkyl, epoxy alkyl.Described tertiary amine groups is dimethylamino, diethylin, pyrrolidyl, piperidyl or morpholinyl.
Preparation and the antitumor activity screening method of biphenyl acid amides target compound is described in detail below in conjunction with the synthetic route shown in Fig. 1 and concrete synthesis example.
Embodiment 1
In the structural formula of this compound, R 1for hydrogen atom, R 2for carbonatoms is the alkoxyl group of 3, end is replaced by dimethylamino, by following steps preparation (see Fig. 1):
1) 3-bromophenol (1) prepares compound 1-benzyloxy-3-bromobenzene (2) by Benzylation reaction
15.57g (90mmol) 3-bromophenol (1) is dissolved in 300mL dehydrated alcohol, add 37.32g (270mmol) Anhydrous potassium carbonate, stirring at room temperature ten minutes, then add 11.50mL (99mmol) Benzyl Chloride, heating reflux reaction 5 hours.After having reacted, be cooled to room temperature suction filtration, decompression filtrate recycling ethanol, then extraction into ethyl acetate is added, organic phase is successively with dilute hydrochloric acid, water, saturated sodium bicarbonate solution, water, saturated nacl aqueous solution washing, last organic phase, again with pressure reducing and steaming solvent after anhydrous sodium sulfate drying, obtains faint yellow 1-benzyloxy-3-bromobenzene crude product (2) 22.02g, productive rate 93%.
2) 1-benzyloxy-3-bromobenzene (2) prepares compound 3-benzyloxy-phenyl magnesium bromide by Gridnard reaction, and 3-benzyloxy-phenyl magnesium bromide prepares compound 3-benzyloxy phenylo boric acid (3) by esterification, hydrolysis reaction
Clean magnesium rod 2.18g (90mmol) is added in the bottle with two necks of 250mL; three iodine; under nitrogen protection; add the anhydrous tetrahydrofuran solution 40mL of 1-benzyloxy-3-bromobenzene (2) 15.79g (60mmol); heating reflux reaction 5 hours, obtains Grignard reagent 3-benzyloxy-phenyl magnesium bromide.
Above-mentioned system is cooled to room temperature, the anhydrous tetrahydrofuran solution of trimethyl borate 9.36g (90mmol) is dripped at subzero 20 degrees Celsius, add rear room temperature reaction 3 hours, add 100mL saturated aqueous ammonium chloride hydrolysis reaction again to spend the night, after having reacted, reclaim under reduced pressure tetrahydrofuran (THF), then 100mL extraction into ethyl acetate is added, organic phase washed with water, saturated nacl aqueous solution wash, last organic phase obtains white 3-benzyloxy phenylo boric acid (3) crude product 7.53g with pressure reducing and steaming solvent after anhydrous sodium sulfate drying again, productive rate 55%.
3) 3-bromobenzaldehyde (4) prepares compound 3-bromo-benzoic acid (5) by oxidizing reaction
3-bromobenzaldehyde (4) 5.55g (30mmol) is dissolved in 100mL anhydrous tetrahydro furan, add 40mL distilled water and 2.16g (18mmol) Sodium phosphate dibasic, drip in advance by the hydrogen peroxide solution 40mL of clorox 8.96g (99mmol) and 6.80mL (66mmol) 30% under condition of ice bath, stirring at room temperature 3h again after dripping off; After having reacted, reclaim under reduced pressure tetrahydrofuran (THF), then 160mL extraction into ethyl acetate is added, organic phase is washed till without absorption with 2mol/LNaOH solution, collect and merge aqueous phase, and to be acidified to pH with concentrated hydrochloric acid be 3 ~ 4, separate out white solid, filtering drying obtains white 3-bromo-benzoic acid (5) 5.73g, productive rate 95%.
4) compound 3-benzyloxy phenylo boric acid (3) and compound 3-bromo-benzoic acid (5) prepare 3 '-benzyloxy biphenyl-3-carboxylic acid (6) by Suzuki linked reaction
3-benzyloxy phenylo boric acid (3) 2.28g (10mmol) is dissolved in Virahol: the volume ratio of water is in the mixed solvent 36mL of 2:1, add Anhydrous potassium carbonate 5.02g (33mmol) again, palladium carbon 0.20g, stirring at room temperature is after 15 minutes, add 3-bromo-benzoic acid (5) 2.01g (10mmol), back flow reaction 12 hours under nitrogen protection; After having reacted, be cooled to room temperature to filter, filtrate decompression reclaims, then 140mL extraction into ethyl acetate is added, organic phase washed with water, saturated nacl aqueous solution washs, and last organic phase obtains white 3 '-benzyloxy biphenyl-3-carboxylic acid (6) crude product 1.37g with pressure reducing and steaming solvent after anhydrous sodium sulfate drying again, productive rate 45%.
5) compound p-NP (7) and N, compound N is prepared in the chloro-1-propylamine reaction of N-dimethyl-3-, N-dimethyl-3-(4-nitrophenoxy)-1-propylamine (8), N, N-dimethyl-3-(4-nitrophenoxy)-1-propylamine (8) reduction reaction generates N, N-dimethyl-3-(4-amino-benzene oxygen)-1-propylamine (9)
P-NP (7) 1.39g (10mmol) is dissolved in 15mL dry DMF, then adds Cs successively 2o 35.29g (15mmol), 2-chloroethyl pyrrole hydrochloride (10mmol), be warming up to 100 DEG C of reactions 4 hours under nitrogen protection, TLC monitors reaction process.After reaction terminates, reaction solution is added 100mL frozen water, be extracted with ethyl acetate three times, merge organic phase, then use saturated sodium carbonate solution successively, water, saturated nacl aqueous solution washs, last organic phase obtains compound N with pressure reducing and steaming solvent after anhydrous sodium sulfate drying again, N-dimethyl-3-(4-nitrophenoxy)-1-propylamine (8) 1.84g, productive rate 82%.
By compound N, N-dimethyl-3-(4-nitrophenoxy)-1-propylamine (8) 1.12g (5mmol) is dissolved in 60mL methyl alcohol, add palladium carbon 0.20g, pass into hydrogen room temperature reduction reaction, TLC monitors reaction process, obtain compound N, N-dimethyl-3-(4-amino-benzene oxygen)-1-propylamine (9) 0.92g, productive rate 95%.
6) compound 3 '-benzyloxy biphenyl-3-carboxylic acid (6) and N, N-dimethyl-3-(4-amino-benzene oxygen)-1-propylamine (9) prepares N-{4-[3-(dimethylamino) propoxy-] phenyl by condensation reaction }-3'-benzyloxy biphenyl-3-methane amide (10), N-{4-[3-(dimethylamino) propoxy-] phenyl }-3'-benzyloxy biphenyl-3-methane amide (10) prepares target compound N-{4-[3-(dimethylamino) propoxy-] phenyl by reduction reaction }-3'-xenol-3-methane amide (BPA-1)
3 '-benzyloxy biphenyl-3-carboxylic acid (6) 1.16g (3.8mmol) is dissolved in 100mL anhydrous tetrahydro furan, add EDCI1.46g (7.6mmol) more successively, HOBT0.77g (5.7mmol), DMAP0.24g, triethylamine 5mL, dropwise rear continuation and stir 15min, then in reaction soln, 0.89g (4.6mmol) N is dripped, the anhydrous tetrahydrofuran solution 30mL of N-dimethyl-3-(4-amino-benzene oxygen)-1-propylamine (9), dropwises rear stirring at room temperature 8 hours.After having reacted, filtrate decompression reclaims, then 140mL extraction into ethyl acetate is added, organic phase washed with water, saturated sodium bicarbonate, saturated nacl aqueous solution washs, and last organic phase obtains white crude with pressure reducing and steaming solvent after anhydrous sodium sulfate drying again, be separated with chromatography column and obtain white solid N-{4-[3-(dimethylamino) propoxy-] phenyl-3'-benzyloxy biphenyl-3-methane amide (10) 1.19g, productive rate 65%.
Compound N-{ 4-[3-(dimethylamino) propoxy-] phenyl }-3'-benzyloxy biphenyl-3-methane amide (10) 1.19g (2.47mmol) adds methyl alcohol 60mL again, palladium carbon 0.20g, room temperature reduction reaction, obtain target compound N-{4-[3-(dimethylamino) propoxy-] phenyl }-3'-xenol-3-methane amide (BPA-1) 0.92g, productive rate 95%.
Gained compound structure is as follows:
Physico-chemical property: m.p.:150-152 DEG C .EI-MS (m/z): 390.3 [M] +.
BPA-1 1HNMR(400MHz,DMSO)δ8.16(s,1H),7.92(d,J＝8.0Hz,1H),7.81(d,J＝8.0Hz,1H),7.68(d,J＝8.0Hz,2H),7.60(t,J＝4.0Hz,1H),7.31(t,J＝4.0Hz,1H),7.18(d,J＝8.0Hz,1H),7.14(s,1H),6.93(d,J＝8.0Hz,2H),6.82(dd,J＝8.0Hz,1H),3.99(t,J＝4.0Hz,2H),2.38(t,J＝4.0Hz,2H),2.17(s,6H),1.87-1.83(m,2H).
Embodiment 2
Wherein R 1for hydrogen atom, R 2for carbonatoms is the alkoxyl group of 2, end is replaced by piperidyl, is prepared by following steps
Step 1) ~ 4) identical with step in embodiment 1, namely compound 3 '-benzyloxy biphenyl-3-carboxylic acid (6) is prepared by initial compounds 3-bromophenol (1), prepare target compound with 1-[2-(4-amino-benzene oxygen) ethyl] piperidines (9) by condensation reaction again, specific embodiment is:
3 '-benzyloxy biphenyl-3-carboxylic acid (6) 1.16g (3.8mmol) is dissolved in 100mL anhydrous tetrahydro furan, add EDCI1.46g (7.6mmol) more successively, HOBT0.77g (5.7mmol), DMAP0.24g, triethylamine 5mL, dropwise rear continuation and stir 15min, then in reaction soln, drip the anhydrous tetrahydrofuran solution 30mL of 1.00g (4.6mmol) 1-[2-(4-amino-benzene oxygen) ethyl] piperidines (9), dropwise rear stirring at room temperature 8 hours.After having reacted, filtrate decompression reclaims, then 140mL extraction into ethyl acetate is added, organic phase washed with water, saturated sodium bicarbonate, saturated nacl aqueous solution washs, and last organic phase obtains white crude with pressure reducing and steaming solvent after anhydrous sodium sulfate drying again, be separated with chromatography column and obtain white solid 3'-benzyloxy-N-[4-(2-piperidin-1-yl oxyethyl group) phenyl]-biphenyl-3-methane amide (10) 1.08g, productive rate 56%.Target compound 3'-hydroxy-n-[4-(2-piperidin-1-yl oxyethyl group) phenyl]-biphenyl-3-methane amide (BPA-5) 0.83g is prepared again, productive rate 94% by reduction reaction.
Gained compound structure is as follows:
Physico-chemical property: m.p.:166-169 DEG C .EI-MS (m/z): 416.3 [M]+.
BPA-51HNMR(400MHz,DMSO)δ8.16(s,1H),7.93(t,J＝4.0Hz,1H),7.81(d,J＝8.0Hz,1H),7.68(d,J＝8.0Hz,2H),7.60(t,J＝4.0Hz,1H),7.31(t,J＝4.0Hz,1H),7.18(d,J＝8.0Hz,1H),7.14(s,1H),6.95(d,J＝8.0Hz,2H),6.82(dd,J＝8.0Hz,1H),4.06(t,J＝4.0Hz,2H),2.65(t,J＝4.0Hz,2H),2.44(s,4H),1.51(d,J＝8.0Hz,4H),1.39(d,J＝8.0Hz,2H).
Embodiment 3
Wherein R 1for fluorine atom, R 2for carbonatoms is the alkoxyl group of 2, end is replaced by diethyl, is prepared by following steps
Step 1) ~ 4) identical with step in embodiment 1, namely compound 3 '-benzyloxy biphenyl-3-carboxylic acid (6) is prepared by initial compounds 3-bromophenol (1), prepare target compound with [2-(4-amino-2-fluorophenoxy) ethyl] diethylamide (9) by condensation reaction again, specific embodiment is:
3 '-benzyloxy biphenyl-3-carboxylic acid (6) 1.16g (3.8mmol) is dissolved in 100mL anhydrous tetrahydro furan, add EDCI1.46g (7.6mmol) more successively, HOBT0.77g (5.7mmol), DMAP0.24g, triethylamine 5mL, dropwise rear continuation and stir 15min, then in reaction soln, drip the anhydrous tetrahydrofuran solution 30mL of 1.04g (4.6mmol) [2-(4-amino-2-fluorophenoxy) ethyl] diethylamide (9), dropwise rear stirring at room temperature 8 hours.After having reacted, filtrate decompression reclaims, then 140mL extraction into ethyl acetate is added, organic phase washed with water, saturated sodium bicarbonate, saturated nacl aqueous solution washs, and last organic phase obtains white crude with pressure reducing and steaming solvent after anhydrous sodium sulfate drying again, be separated with chromatography column and obtain white solid N-{4-[2-(diethylamino) oxyethyl group]-3-fluorophenyl-3'-benzyloxy biphenyl-3-methane amide (10) 1.09g, productive rate 56%.Target compound N-{4-[2-(diethylamino) oxyethyl group]-3-fluorophenyl is prepared again by reduction reaction }-3'-xenol-3-methane amide (BPA-10) 0.84g, productive rate 94%.
Gained compound structure is as follows:
Physico-chemical property: m.p.:135 ~ 137 DEG C .EI-MS (m/z): 413.3 [M]+.
BPA-101HNMR(400MHz,DMSO)δ8.17(d,J＝8.0Hz,1H),7.91(dd,J＝8.0Hz,1H),7.80(d,J＝8.0Hz,2H),7.60(dd,J＝8.0Hz,1H),7.52(s,1H),7.38-7.25(m,1H),7.17(s,3H),6.84(d,J＝8.0Hz,1H),4.08(d,J＝8.0Hz,2H),2.79(d,J＝8.0Hz,2H),1.88(d,J＝8.0Hz,4H),0.98(dd,J＝8.0Hz,6H).
Embodiment 4
Wherein R 1for fluorine atom, R 2for carbonatoms is the alkoxyl group of 2, end is replaced by pyrrolidyl, is prepared by following steps
Step 1) ~ 4) identical with step in embodiment 1, namely compound 3 '-benzyloxy biphenyl-3-carboxylic acid (6) is prepared by initial compounds 3-bromophenol (1), prepare target compound with [the fluoro-4-of 3-(2-pyrrolidin-1-yl oxyethyl group) phenyl] amine (9) by condensation reaction again, specific embodiment is:
3 '-benzyloxy biphenyl-3-carboxylic acid (6) 1.16g (3.8mmol) is dissolved in 100mL anhydrous tetrahydro furan, add EDCI1.46g (7.6mmol) more successively, HOBT0.77g (5.7mmol), DMAP0.24g, triethylamine 5mL, dropwise rear continuation and stir 15min, then in reaction soln, drip the anhydrous tetrahydrofuran solution 30mL of 1.03g (4.6mmol) [the fluoro-4-of 3-(2-pyrrolidin-1-yl oxyethyl group) phenyl] amine (9), dropwise rear stirring at room temperature 8 hours.After having reacted, filtrate decompression reclaims, then 140mL extraction into ethyl acetate is added, organic phase washed with water, saturated sodium bicarbonate, saturated nacl aqueous solution washs, and last organic phase obtains white crude with pressure reducing and steaming solvent after anhydrous sodium sulfate drying again, be separated with chromatography column and obtain white solid N-[the fluoro-4-of 3-(2-pyrrolidin-1-yl oxyethyl group) phenyl]-3'-benzyloxy biphenyl-3-methane amide (10) 1.11g, productive rate 57%.Target compound N-[the fluoro-4-of 3-(2-pyrrolidin-1-yl oxyethyl group) phenyl]-3'-xenol-3-methane amide (BPA-11) 0.84g is prepared again, productive rate 92% by reduction reaction.
Gained compound structure is as follows:
Physico-chemical property: m.p.:110-113 DEG C .EI-MS (m/z): 420.2 [M]+.
BPA-111HNMR(400MHz,DMSO)δ8.17(s,1H),7.94(d,J＝8.0Hz,1H),7.84-7.76(m,2H),7.60(t,J＝4.0Hz,1H),7.53(d,J＝8.0Hz,1H),7.30(t,J＝4.0Hz,1H),7.25-7.16(m,2H),7.15(s,1H),6.86(dd,J＝8.0Hz,1H),6.40(dd,J＝8.0Hz,1H),4.21(t,J＝4.0Hz,2H),3.00(s,2H),2.73(s,4H),1.75(s,4H).
Embodiment 5
Wherein R 1for chlorine atom, R 2for carbonatoms is the alkoxyl group of 2, end is replaced by dimethyl, is prepared by following steps
Step 1) ~ 4) identical with step in embodiment 1, namely compound 3 '-benzyloxy biphenyl-3-carboxylic acid (6) is prepared by initial compounds 3-bromophenol (1), prepare target compound with [3-(4-amino-2-chlorophenoxy) propyl group] dimethyl amine (9) by condensation reaction again, specific embodiment is:
3 '-benzyloxy biphenyl-3-carboxylic acid (6) 1.16g (3.8mmol) is dissolved in 100mL anhydrous tetrahydro furan, add EDCI1.46g (7.6mmol) more successively, HOBT0.77g (5.7mmol), DMAP0.24g, triethylamine 5mL, dropwise rear continuation and stir 15min, then in reaction soln, drip the anhydrous tetrahydrofuran solution 30mL of 1.05g (4.6mmol) [3-(4-amino-2-chlorophenoxy) propyl group] dimethyl amine (9), dropwise rear stirring at room temperature 8 hours.After having reacted, filtrate decompression reclaims, then 140mL extraction into ethyl acetate is added, organic phase washed with water, saturated sodium bicarbonate, saturated nacl aqueous solution washs, and last organic phase obtains white crude with pressure reducing and steaming solvent after anhydrous sodium sulfate drying again, be separated with chromatography column and obtain the chloro-4-of white solid N-{3-[3-(dimethylamino) propoxy-] phenyl-3'-benzyloxy biphenyl-3-methane amide (10) 1.10g, productive rate 56%.The chloro-4-of target compound N-{3-[3-(dimethylamino) propoxy-] phenyl is prepared again by reduction reaction }-3'-xenol-3-methane amide (BPA-15) 0.82g, productive rate 91%.
Gained compound structure is as follows:
Physico-chemical property: m.p.:152-155 DEG C .EI-MS (m/z): 422.9 [M]+.
BPA-151HNMR(400MHz,DMSO)δ8.17(s,1H),7.93(d,J＝8.0Hz,1H),7.80(d,J＝8.0Hz,1H),7.69(d,J＝8.0Hz,2H),7.59(t,J＝4.0Hz,1H),7.30(t,J＝4.0Hz,1H),7.22-7.11(m,2H),6.95(d,J＝8.0Hz,2H),6.84(d,J＝8.0Hz,1H),4.05(t,J＝4.0Hz,2H),2.65(t,J＝4.0Hz,2H),2.24(s,6H),1.89(s,2H).
Embodiment 6
Wherein R1 is chlorine atom, R2 to be carbonatoms be 2 alkoxyl group, end is replaced by morpholinyl, is prepared by following steps
Step 1) ~ 4) identical with step in embodiment 1, namely compound 3 '-benzyloxy biphenyl-3-carboxylic acid (6) is prepared by initial compounds 3-bromophenol (1), prepare target compound with [the chloro-4-of 3-(2-morpholine-4-base oxethyl) phenyl] amine (9) by condensation reaction again, specific embodiment is:
3 '-benzyloxy biphenyl-3-carboxylic acid (6) 1.16g (3.8mmol) is dissolved in 100mL anhydrous tetrahydro furan, add EDCI1.46g (7.6mmol) more successively, HOBT0.77g (5.7mmol), DMAP0.24g, triethylamine 5mL, dropwise rear continuation and stir 15min, then in reaction soln, drip the anhydrous tetrahydrofuran solution 30mL of 1.24g (4.6mmol) [the chloro-4-of 3-(2-morpholine-4-base oxethyl) phenyl] amine (9), dropwise rear stirring at room temperature 8 hours.After having reacted, filtrate decompression reclaims, then 140mL extraction into ethyl acetate is added, organic phase washed with water, saturated sodium bicarbonate, saturated nacl aqueous solution washs, and last organic phase obtains white crude with pressure reducing and steaming solvent after anhydrous sodium sulfate drying again, be separated with chromatography column and obtain white solid N-[the chloro-4-of 3-(2-morpholine-4-base oxethyl) phenyl]-3'-benzyloxy biphenyl-3-methane amide (10) 1.19g, productive rate 56%.Target compound N-[the chloro-4-of 3-(2-morpholine-4-base oxethyl) phenyl]-3'-xenol-3-methane amide (BPA-21) 0.91g is prepared again, productive rate 92% by reduction reaction.
Gained compound structure is as follows:
Physico-chemical property: m.p.:115-117 DEG C .EI-MS (m/z): 479.3 [M]+.
BPA-211HNMR(400MHz,DMSO)δ8.18(s,1H),7.94(t,J＝4.0Hz,1H),7.81(d,J＝8.0Hz,1H),7.69(d,J＝8.0Hz,2H),7.60(t,J＝4.0Hz,1H),7.31(t,J＝4.0Hz,1H),7.21-7.12(m,2H),6.94(d,J＝8.0Hz,2H),6.89-6.80(m,1H),4.00(t,J＝4.0Hz,2H),3.58(dd,J＝8.0Hz,4H),2.51(s,2H),2.42(s,4H),1.89(t,J＝4.0Hz,2H).
Mtt assay is adopted to measure dibenzoyl aminated compounds to the growth inhibitory activity of tumour cell:
Dibenzoyl amine compound provided by the invention has antitumor action, vitro inhibition proliferation activity is had to tumour cell, at breast cancer cell (MCF-7), there is in liver cancer cell (SMMC-7721) proliferation activity of inhibition tumor cell, may be used for the treatment to these cancers; Compared with positive drug BAY 43-9006, individual compound shows higher inhibition tumor cell proliferation activity.
To be in the breast cancer cell (MCF-7) of logarithmic phase, liver cancer cell (SMMC-7721), the trysinization with 0.25% 3 ~ 5 minutes, being diluted to concentration after piping and druming is evenly 5 × 10 3the single cell suspension of individual/mL, is parallelly inoculated in 96 well culture plates, and every hole inoculation volume is 200 μ L; In 37 DEG C, 5%CO 2cultivate 24 hours in incubator;
With the aqueous solution containing 0.25%DMSO (N, N-dimethyl sulfoxide (DMSO)) for negative control, take BAY 43-9006 as positive control, testing sample adds the dibenzoyl amine compound (4 × 10 of 4 different concns -6mol/L; 2 × 10 -5mol/L; 1 × 10 -4mol/L; 5 × 10 -4mol/L), each concentration establishes 3 multiple holes, continues cultivation 48 hours;
Then every hole adds the MTT working fluid 150 μ L of 5mg/mL, mixing, 37 DEG C of incubators are hatched after 4 hours and are taken out, nutrient solution is abandoned in careful suction, every hole adds 150 μ LDMSO, vibration 10min, and euzymelinked immunosorbent assay (ELISA) detector measures 490nm place, each hole ultraviolet absorption value (OD value), then calculate cell inhibitory rate, and obtain IC according to inhibiting rate 50value; The calculation formula of cell inhibitory rate is:
Inhibiting rate %=(positive controls OD value-medication group OD value)/negative control cell OD value × 100%
Detected result shows: compared with negative control group, dibenzoyl amine compound has In-vitro Inhibitory Effect in various degree to above-mentioned 2 kinds of tumour cells.
The inhibit activities result IC of table 1 compd B PA1-21 50(μM)
The suppression of MTT result display section compound on tumor cell is suitable with positive control drug BAY 43-9006, and even have some activity to be better than positive control, this illustrates that the novel proliferation inhibiting effect of dibenzoyl aminated compounds to tumour cell is obvious.
The active compound structure preferably of table 2

Claims (3)

1. there is a preparation method for the dibenzoyl amine compound of anti-tumor activity, it is characterized in that, comprise the following steps:
1) 3-bromophenol is obtained by reacting 1-benzyloxy-3-bromobenzene by Benzylation;
2) under catalysis of iodine, 1-benzyloxy-3-bromobenzene and magnesium rod are obtained by reacting 3-benzyloxy-phenyl magnesium bromide by Grignard; 3-benzyloxy-phenyl magnesium bromide and trimethyl borate generation esterification, then obtain 3-benzyloxy phenylo boric acid with saturated ammonium chloride hydrolysis reaction;
3) the binary oxidation system oxidizing reaction of 3-bromobenzaldehyde clorox and hydrogen peroxide obtains 3-bromo-benzoic acid;
4) under the catalysis of palladium carbon, 3-benzyloxy phenylo boric acid and 3-bromo-benzoic acid are obtained by reacting 3 '-benzyloxy biphenyl-3-carboxylic acid by Suzuki;
5) compound 7 and the compound generation etherification reaction with tertiary amine side chain, obtain compound 8, compound 8 obtains compound 9 by reduction reaction again;
6) 3 '-benzyloxy biphenyl-3-carboxylic acid and compound 9 condensation form dibenzoyl aminated compounds, then remove benzyl, obtain target compound;
Wherein the structural formula of compound 7 is
The structural formula of compound 8 is
The structural formula of compound 9 is
The structural formula of target compound is
R 1for H, F or Cl, R 2for
2. the preparation method with the dibenzoyl amine compound of anti-tumor activity according to claim 1, it is characterized in that: described step 1) concrete operations be: 3-bromophenol is dissolved in dehydrated alcohol, add Anhydrous potassium carbonate, stirring at room temperature is even, then adds Benzyl Chloride, heating reflux reaction, be cooled to room temperature after reaction, suction filtration reaction product, is extracted with ethyl acetate filtrate, organic phase pressure reducing and steaming solvent after washing, drying of extraction, obtains 1-benzyloxy-3-bromobenzene;
Described step 2) concrete operations be: in reaction vessel, add clean magnesium rod and iodine, under nitrogen protection, add the anhydrous tetrahydrofuran solution of 1-benzyloxy-3-bromobenzene, heating reflux reaction, obtain Grignard reagent 3-benzyloxy-phenyl magnesium bromide; The anhydrous tetrahydrofuran solution of trimethyl borate is dripped again wherein at-20 DEG C, room temperature reaction, then add saturated aqueous ammonium chloride and to be hydrolyzed reaction, reaction product is extracted with ethyl acetate, organic phase pressure reducing and steaming solvent after washing, drying of extraction, obtains 3-benzyloxy phenylo boric acid;
Described step 3) concrete operations be: 3-bromobenzaldehyde is dissolved in anhydrous tetrahydro furan, adds water and Sodium phosphate dibasic, under condition of ice bath, drip clorox and hydrogen peroxide solution, drip off rear stirred at ambient temperature reaction; Reaction product is extracted with ethyl acetate, and the pH value regulating the aqueous phase of extraction is 3 ~ 4, and the solid of precipitation is dried to obtain 3-bromo-benzoic acid;
Described step 4) concrete operations be: 3-benzyloxy phenylo boric acid is dissolved in the mixed solution of isopropyl alcohol and water, then adds Anhydrous potassium carbonate and palladium carbon, stirring at room temperature evenly after, add 3-bromo-benzoic acid, back flow reaction under nitrogen protection; Be cooled to room temperature after reaction, filter reaction product, filtrate is extracted with ethyl acetate, and organic phase pressure reducing and steaming solvent after washing, drying of extraction, obtains 3 '-benzyloxy biphenyl-3-carboxylic acid.
3. the preparation method with the dibenzoyl amine compound of anti-tumor activity according to claim 1, is characterized in that: described step 5) concrete operations be: compound 7 is dissolved in dry DMF, then adds Cs successively 2o 3with the compound with tertiary amine side chain, reacting by heating under nitrogen protection, after reaction terminates, added by reaction solution in frozen water, be extracted with ethyl acetate, organic phase pressure reducing and steaming solvent after washing, drying of extraction, obtains compound 8; Compound 8 is dissolved in methyl alcohol, adds palladium carbon, pass into hydrogen and at room temperature carry out reduction reaction, obtain compound 9;
Described step 6) concrete operations be: 3 '-benzyloxy biphenyl-3-carboxylic acid is dissolved in anhydrous tetrahydro furan, add EDCI, HOBT, DMAP and triethylamine successively again, dropwise rear continuation to stir, then the anhydrous tetrahydrofuran solution of compound 9 is dripped, dropwise the reaction of rear stirring at room temperature, reaction product is extracted with ethyl acetate, and organic phase pressure reducing and steaming solvent afforded crude material after washing, drying of extraction, is separated crude product with chromatography column and obtains Benzylation dibenzoyl amine compound; In Benzylation dibenzoyl amine compound, add methyl alcohol and palladium carbon, room temperature reduction reaction, obtains target compound.
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EP1839655A1 (en) * 2005-01-20 2007-10-03 Shionogi Co., Ltd. Ctgf expression inhibitor
WO2008063772A9 (en) * 2006-10-13 2008-08-07 Brigham & Womens Hospital Resolvin d series and protectin d1 mitigate acute kidney injury
WO2009069764A1 (en) * 2007-11-30 2009-06-04 National University Corporation Chiba University Opioid analgesic agent
CN103193647A (en) * 2013-04-01 2013-07-10 史克勇 Cancer pain treatment medicine with high optical purity
CN103254077A (en) * 2013-05-31 2013-08-21 史克勇 Pain disease therapeutic agent

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Publication number Priority date Publication date Assignee Title
EP1839655A1 (en) * 2005-01-20 2007-10-03 Shionogi Co., Ltd. Ctgf expression inhibitor
WO2008063772A9 (en) * 2006-10-13 2008-08-07 Brigham & Womens Hospital Resolvin d series and protectin d1 mitigate acute kidney injury
WO2009069764A1 (en) * 2007-11-30 2009-06-04 National University Corporation Chiba University Opioid analgesic agent
CN103193647A (en) * 2013-04-01 2013-07-10 史克勇 Cancer pain treatment medicine with high optical purity
CN103254077A (en) * 2013-05-31 2013-08-21 史克勇 Pain disease therapeutic agent

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