CN103739547B - The synthetic method of 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid - Google Patents

The synthetic method of 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid Download PDF

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CN103739547B
CN103739547B CN201410001737.5A CN201410001737A CN103739547B CN 103739547 B CN103739547 B CN 103739547B CN 201410001737 A CN201410001737 A CN 201410001737A CN 103739547 B CN103739547 B CN 103739547B
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methoxyl group
dihydro
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CN103739547A (en
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王绍杰
范超
李兆林
陈绍磊
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Ningxia Kang Ya pharmaceutical Limited by Share Ltd
Shenyang Pharmaceutical University
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KANGYA PHARMACEUTICAL INDUSTRY Co Ltd NINGXIA
Shenyang Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4

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  • Organic Chemistry (AREA)
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  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention provides the synthetic method of a kind of 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid.The method comprises: with 1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone for raw material, add trifluoroacetic acid and carry out Fu Ke-acylation reaction through catalyzer, add saturated potassium hydroxide aqueous solution after steaming solvent to neutralize, suction filtration obtains intermediate 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone; With intermediate 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone is raw material, through N-hydrocarbonylation, hydrolysis, condensation reaction synthesis 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid.This synthetic method avoids and uses polyphosphoric acid (PPA) in a large number, technique environmental protection, and is more conducive to suitability for industrialized production.

Description

The synthetic method of 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid
Technical field
The invention belongs to technical field of medicine synthesis, particularly relate to the synthetic method of a kind of 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid.
Background technology
The metabolic syndrome of diabetes to be one group with long term hyperglycemia be principal character.Along with improving constantly of socioeconomic development and people's living standard, diabetes prevalence sharply increases, and has become one of principal disease affecting human body health.By the end of 2003, China became diabetes second big country, had 2,380 ten thousand diabetic subjects.Diabetes are principal character with long term hyperglycemia, and the diabetic complication caused thus is that diabetes disable and lethal major cause.According to statistics, the concurrent blood vessel of more than 1/2 person and DPN is had in diabetic; About have 30% concurrent proliferative retinopathy, wherein 1.2% may be developed to blind; The type 1 diabetes patient of 30% ~ 40% and the diabetes B patient complicated with diabetes ephrosis of 15% ~ 20%, and can by occurring that proteinuria is developed to hypertensive nephropathy syndrome at first.Therefore, treatment and prophylactic agent research especially introduce concern.
At present, researchist finds that the content of usual aldose reductase in the cell of diabetic subject is higher, if can the increase of aldose reductase in T suppression cell, can effectively treat and prevent diabetes, and complication.2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid having research to point out to have following structural formula I can use as aldose reductase inhibitor.
In Chinese patent CN101058558A, disclose a kind of 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid, and give a kind of synthetic method.This synthetic method comprises: with 4-anisidine and ethyl propenoate for Material synthesis 3-(4-anisole amido) propionic acid intermediate; With 3-(4-anisole amido) propionic acid intermediate for raw material, with polyphosphoric acid (PPA) for condensing agent synthesis 6-methoxyl group-2,3-dihydro-4 (1H) quinolinone intermediate; With 6-methoxyl group-2,3-dihydro-4 (1H) quinolinone intermediate for raw material, add ethyl bromoacetate N-alkylation reaction and produce 4-carbonyl-6 methoxyl group-2,3 dihydro-1 (4H)-quinoline acetate intermediates; With 4-carbonyl-6 methoxyl group-2,3 dihydro-1 (4H)-quinoline acetate intermediates are add 2 after raw material hydrolysis, 3-dichlorobenzaldehyde condensation reaction synthesis 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid.The reaction formula of above-mentioned synthetic method is as follows:
Aforesaid method is in synthetic method, at synthetic intermediate " 6-methoxyl group-2, 3-dihydro-4 (1H) quinolinone " time use polyphosphoric acid (PPA) make condensing agent, and the use times amount of polyphosphoric acid is about 20 times of reactant " 3-(4-anisole amido) propionic acid " consumption, so just cause needing when aftertreatment the product of generation just can be made to dissociate out with a large amount of bucks removing polyphosphoric acid, and need high temperature during reaction, the method prepares 6-methoxyl group-2 on a small scale in laboratory, 3-dihydro-4 (1H) even quinolinone time passable, but when producing in a large number in the industry, although yield is higher, but because a large amount of trade effluents produced can cause causing huge pollution to environment, limit suitability for industrialized production.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, provide the synthetic method of a kind of 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid, to reduce environmental pollution.
For this reason, provide the synthetic method of a kind of 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid in the present invention, comprise the following steps:
1) synthesis of 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone:
With 1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone for raw material, add after catalyzer carries out Fu Ke-acylation reaction, steam solvent, add saturated potassium hydroxide aqueous solution and neutralize, suction filtration obtains intermediate 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone;
2) synthesis of 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid:
With intermediate 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone is raw material, through N-hydrocarbonylation, hydrolysis, condensation reaction synthesis 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-1,4-dihydro-1 (4H)-quinolyl] acetic acid, wherein operable catalyzer includes but not limited to one or more of trifluoroacetic acid, boron trifluoride ether solution, aluminum trichloride (anhydrous), tin tetrachloride, preferred trifluoroacetic acid.Steam in the process of solvent different according to adopted catalyzer, the solvent steamed is one or more in trifluoroacetic acid, toluene, tetrahydrofuran (THF), methylene dichloride dimethyl sulfoxide solvent.
Below with reference to embodiment, 2-of the present invention [6-methoxyl group-3-(2 is described step by step, 3-dichlorophenyl) methyl-4-oxo-1,4-dihydro-1 (4H)-quinolyl] synthetic method of acetic acid, wherein mentioned in the feed proportioning process of each step m is quality, and v is volume.
In above-mentioned steps 1) in, intermediate 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone (structure is as shown in the formula middle structural formula (2) Suo Shi) can adopt commercially available prod, also can be that those skilled in the art select suitable mode to prepare under the instruction of the application.In the preferred embodiment of the present invention, synthetic intermediate 6-methoxyl group-2, the method of 3-dihydro-4 (1H)-quinolinone comprises: 1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone (structure is as shown in the formula middle structural formula (1) Suo Shi) and trifluoroacetic acid are mixed in 1: 1 ~ 10 (m/v) ratio, back flow reaction 0.5 ~ 8 hour at 72 ~ 82 DEG C, after reaction terminating, at 40 ~ 50 DEG C, Distillation recovery trifluoroacetic acid under-0.05 ~-0.1MPa, obtains intermediate product A; Can by TLC detection reaction completeness to judge whether reaction stops in above-mentioned reaction.Intermediate product A is cooled to-10 DEG C ~-2, under agitation condition, drips saturated potassium hydroxide aqueous solution, keep temperature of reaction system not higher than 30 DEG C, stop when the PH to reaction system is 9 ~ 10 dripping saturated potassium hydroxide aqueous solution, obtain intermediate product B; Intermediate product B is at room temperature stirred 20 ~ 50min, after suction filtration, the ethanol of 15 ~ 30% is added in 1: 0.5 ~ 5 (m/v) ratio, preferably repeatedly filter cake is washed in the process of suction filtration, more preferably 2 times, 3 times or 5 washing filter cakes, 1 ~ 3h is stirred at 50 ~ 80 DEG C, place 10 ~ 16h, again after suction filtration at 40 ~ 60 DEG C of vacuum-drying 2 ~ 5h, the alcohol flushing filter cake of 15 ~ 30% is preferably repeatedly used in the process of suction filtration, more preferably 2 times, 3 times or 5 flush cake, obtain intermediate product 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone.
The chemical equation of above-mentioned reaction is as follows:
2-[6-methoxyl group-3-(2 provided in the present invention; 3-dichlorophenyl) methyl-4-oxo-1; 4-dihydro-1 (4H)-quinolyl] acetic acid this synthetic method in; with 1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone for raw material; intermediate 6-methoxyl group-2 is obtained by Fu Ke-acyl group reaction; 3-dihydro-4 (1H)-quinolinone; The method avoids and use polyphosphoric acid (PPA) to make condensing agent; decrease the generation of sour water; and decrease the amount of polyphosphoric acid buck used, decrease the pollution to environment.Meanwhile, this reaction, without the need to pyroprocessing, is applicable to scale operation, may be used for suitability for industrialized production.
At above-mentioned 2-[6-methoxyl group-3-(2, 3-dichlorophenyl) methyl-4-oxo-1, 4-dihydro-1 (4H)-quinolyl] synthetic method of acetic acid, step 1) in raw material 1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone that uses directly can adopt commercially available prod, preferably, the synthetic method of this 1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone (structure is as shown in the formula middle structural formula (2) Suo Shi) comprising: by sodium hydride, N-(4-methoxyl group) phenyl-3-halogen propionic acid amide and the first organic solvent are under lucifuge condition, in 1: 1: 1 ~ 10 (m: m: v) ratio mixing, sodium hydride is mixed in 1: 1 ~ 60 (m/v) ratio with the first organic solvent, temperature control-10 ~ 50 DEG C, obtain mixed solution A, by N-(4-methoxyl group) phenyl-3-halogen propionic acid amide and described first organic solvent under lucifuge condition in 1: 5 ~ 10 (m/v) ratio mixed dissolution, obtain mixing solutions B, by mixing solutions B, according to sodium hydride and N-(4-methoxyl group) phenyl-3-halogen propionic acid amide 1: 5 ~ 10, (m: m) drop in mixed solution A, keeps the temperature of reaction system to be-10 ~ 0 DEG C in dropping process, after dropwising, by gained mixing solutions at-10 ~ 50 DEG C of lucifuge reaction 1-6h, after reaction terminating, add in reaction system and stir with the isopyknic water of the first organic solvent, and adjust reaction system pH to 4 ~ 5, the step of adjustment system pH is that 3 ~ 8% dilute hydrochloric acid realize preferably by adding concentration in reaction system, and the water adding the first organic solvent 1 ~ 2 times amount in reaction system stirs, and obtains mixed system A, can by TLC detection reaction completeness to judge whether reaction stops in above-mentioned reaction.Get organic layer in mixed system A, cleaning-drying, preferably first with organic layer washing (1500ml × 4), saturated aqueous common salt (1000ml) is used to clean again, preferred employing anhydrous sodium sulfate drying 10 ~ 16 hours, then ,-0.05 ~ 0.1MPa, solvent is deviate from 20 ~ 30 DEG C of distillations, obtains intermediate product C; Toluene is added in 1: 5 ~ 10 (m/v) ratio in intermediate product C, stirring at room temperature 0.5 ~ 3h, filter, preferred employing toluene repeatedly filter wash cake, such as 2 times, 3 times or more times, then at 40 ~ 60 DEG C of vacuum-drying 0.5 ~ 3h, obtain the synthesis of 1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone.In above-mentioned used N-(4-methoxyl group) phenyl-3-halogen propionic acid amide, halogen is chlorine or bromine; The first above-mentioned used organic solvent preferably includes but is not limited to one or more in methylene dichloride, trichloromethane, N-Methyl pyrrolidone, DMF and dimethyl sulfoxide (DMSO).Preferably, described first organic solvent is that methylene dichloride and DMF are in 1 ~ 5: 1 (v: the v) mixed solvent of ratio mixing.The mode adopting distributed rendering to obtain mixed system A in the above-mentioned methods can avoid the generation of side reaction thing, and makes post-processing operation easy.
The chemical equation of above-mentioned reaction is as follows:
In above-mentioned reaction formula, X is halogen, is more preferably chlorine or bromine.
At above-mentioned 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-1,4-dihydro-1 (4H)-quinolyl] acetic acid synthetic method in, step 1) in 1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone building-up reactions in, N-(4-methoxyl group) phenyl-3-halogen propionic acid amide used can be commercially available prod, and wherein halogen is chlorine or bromine.Preferably, this N-(4-methoxyl group) phenyl-3-halogen propionic acid amide (structure is as shown in the formula middle structural formula (3) Suo Shi) adopts following synthetic method to synthesize, step comprises: by 4-anisidine (structure is as shown in the formula middle structural formula (4) Suo Shi), 3-halogen propionyl chloride (structure is as shown in the formula middle structural formula (5) Suo Shi), in alkaline matter and the second organic solvent 1: 1.5 ~ 3: 1 ~ 2: 2 ~ 8 (m: m: m: v) ratio mixing, at-10 ~ 50 DEG C, reaction times is 0.5 ~ 6h, after reaction terminating, in 4-anisidine in reaction system: water=1: 2 ~ 10 (m/v) ratio adds water stirring, and reaction system pH is adjusted to 4 ~ 5, preferably, the step of adjustment reaction system pH is that 5 ~ 15% dilute hydrochloric acid realize by adding concentration, obtain mixed system B, can by TLC detection reaction completeness to judge whether reaction stops in above-mentioned reaction.Get mixed system B suction filtration, preferred filter cake first repeatedly cleans with water, such as 2 times or 3 times, more repeatedly cleans with toluene, such as 2 times or 3 times.The dry synthesis obtaining N-(4-methoxyl group) phenyl-3-halogen propionic acid amide, preferably dry employing, 40 ~ 60 DEG C of vacuum-drying 0.5 ~ 3h.In above-mentioned 3-halogen propionyl chloride, halogen is chlorine or bromine; Second organic solvent preferably includes but is not limited to one or more of benzene,toluene,xylene; Alkaline matter preferably include but be not limited to sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, saleratus, salt of wormwood, triethylamine one or more.
The chemical equation of above-mentioned reaction is as follows:
In above-mentioned reaction formula, X is halogen, is preferably chlorine or bromine.
At above-mentioned 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-1,4-dihydro-1 (4H)-quinolyl] step 1 of synthetic method of acetic acid) in synthesis N-(4-methoxyl group) phenyl-3-halogen propionic acid amide step in the step that 4-anisidine, 3-halogen propionyl chloride, alkaline matter mix in a second organic solvent is comprised: first 4-anisidine and alkaline matter are dissolved in part second solvent, obtain mixed solution C; 3-halogen propionyl chloride is dissolved in part second solvent, obtains mixing solutions D; Mixing solutions D is dropped in mixed solution C, in dropping process, keeps the temperature of reaction system not higher than 50 DEG C; After dropwising, by gained mixing solutions at-10 ~ 50 DEG C, preferably 20 ~ 30 DEG C of lucifuge reaction 0.5-6h.Adopt and mix various raw material in this way there is convenient post-treatment, and by product is easy to the advantage that removes.
At above-mentioned 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-1,4-dihydro-1 (4H)-quinolyl] the synthetic method step 1 of acetic acid) in, in synthesis N-(4-methoxyl group) phenyl-3-halogen propionic acid amide, the 3-halogen propionyl chloride used can be commercially available prod, and wherein halogen is chlorine or bromine.Preferably, the synthetic method of this 3-halogen propionyl chloride comprises: with N, dinethylformamide is catalyzer, by three halogen propionic acid, sulfur oxychloride, the 3rd organic solvent, DMF by 1: 1 ~ 5: 3 ~ 8: 0.002 ~ 0.1 (m: m: v: v) mix, at 20 ~ 50 DEG C, back flow reaction 10min ~ 6h, after reaction terminating, excess of solvent in reaction system is discharged in distillation, obtains 3-halogen propionyl chloride; 3rd organic solvent is methylene dichloride and/or trichloromethane, and three halogen propionic acid halogens are chlorine or bromine.
At above-mentioned 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid synthetic method in synthesize in the step of 3-halogen propionyl chloride the step that distillation discharges excess of solvent in reaction system and comprise: excess of solvent in the reaction system of 1/4 ~ 2/3 is discharged in air distillation; Excess of solvent in remaining reaction system is discharged by after Pressure Drop to-0.05 ~-0.1MPa.Adopt distillation in this way to discharge solvent and have solvent recuperation amount is increased, the effect reduced costs.
At above-mentioned 2-[6-methoxyl group-3-(2, 3-dichlorophenyl) methyl-4-oxo-1, 4-dihydro-1 (4H)-quinolyl] acetic acid synthetic method in, in step 2) in, with intermediate 6-methoxyl group-4-2, 3-dihydro-4 (1H)-quinolinone is that the step that raw material carries out N-hydrocarbonylation process comprises: by intermediate 6-methoxyl group-2, 3-dihydro-4 (1H)-quinolinone (structure is as shown in the formula middle structural formula (2) Suo Shi), ethyl bromoacetate (structure is as shown in the formula middle structural formula (6) Suo Shi), acid binding agent and the 4th organic solvent are according to 1: 1 ~ 5: 1 ~ 5: 3 ~ 10 (m: m: m: v) ratio mixing, and 2h ~ 40h is reacted at 50 ~ 100 DEG C, after reaction terminating, decompression steams the solvent of 1/4 ~ 2/3, obtain mixed system C, can by TLC detection reaction completeness to judge whether reaction stops in above-mentioned reaction.Mixed system C is poured in the cold water of 0 ~ 5 DEG C under the condition stirred, stirs under 0 ~ 30 DEG C of condition and solid is separated out, preferably stir 20 ~ 50 minutes, by solid precipitate through washing, preferably repeatedly wash, such as 2 times or 3 times, 40 ~ 60 DEG C of vacuum-drying 2 ~ 5h, obtain intermediate product D; Mixed according to 1: 5 ~ 20 (m/v) ratio with mixed solvent E by intermediate product D, 40 ~ 60 DEG C of making beating process 1 ~ 3h, static 10 ~ 16h, suction filtration, preferably uses mixing solutions E many flush cake, such as, rinse 2 times or 3 times.Then clean, 40 ~ 60 DEG C of vacuum-drying 0.5 ~ 3h, obtain 6-methoxyl group-4-carbonyl-2,3 dihydro-1 (4H)-quinoline ethyl acetate (structure is as shown in the formula middle structural formula (7) Suo Shi).The 4th organic solvent used preferably includes but is not limited to one or more in DMF, methyl alcohol, ethanol, methylene dichloride, tetrahydrofuran (THF), acetonitrile; Mixed solvent E is ethyl acetate and sherwood oil volume ratio is the mixing solutions of 1: 2; Acid binding agent preferably includes but is not limited to one or more in Anhydrous potassium carbonate, anhydrous sodium carbonate, potassium hydroxide, sodium hydroxide, saleratus, sodium bicarbonate and triethylamine.
The chemical equation of above-mentioned reaction is as follows:
At above-mentioned 2-[6-methoxyl group-3-(2, 3-dichlorophenyl) methyl-4-oxo-1, 4-dihydro-1 (4H)-quinolyl] acetic acid synthetic method in, in step 2) in, with intermediate 6-methoxyl group-4-carbonyl-2, 3 dihydro-1 (4H)-quinoline ethyl acetate (structure is as shown in the formula middle structural formula (7) Suo Shi) are raw material, through hydrolysis, condensation obtains 2-[6-methoxyl group-3-(2, 3-dichlorophenyl) methyl-4-oxo-1, 4-dihydro-1 (4H)-quinolyl] step of acetic acid (structure is as shown in the formula middle structural formula (I) Suo Shi) comprising: by 6-methoxyl group-4-carbonyl-2, 3 dihydro-1 (4H)-quinoline ethyl acetate are dissolved in the 5th organic solvent, obtain mixing solutions F, in mixing solutions F according to 6-methoxyl group-4-carbonyl-2, 3 dihydro-1 (4H)-quinoline ethyl acetate ratios are 1: 2 ~ 10 (m/v), 1: 3 ~ 8 (m/v) ratio of being preferably adds the aqueous sodium hydroxide solution of 5 ~ 15%, stirring at room temperature hydrolysis 10min ~ 1h, after reaction terminating, according to 6-methoxyl group-4-carbonyl-2, 3 dihydro-1 (4H)-quinoline ethyl acetate ratios are 1: 1 ~ 1: 3 (m/v), be preferably 1: 1 ~ 2 (m/v) and add 2, 3-dichlorobenzaldehyde (structure is as shown in the formula middle structural formula (8) Suo Shi), room temperature condensation reaction 5 ~ 8h, after reaction terminating, preferably by TLC detection reaction completeness to judge whether reaction stops.According to 6-methoxyl group-4-carbonyl-2,3 dihydro-1 (4H)-quinoline ethyl acetate: sodium-chlor=1: 0.5 ~ 4 (m: m) ratio adds sodium-chlor, be warming up to 35 ~ 60 DEG C, stir 15 ~ 30min, after cooling suction filtration, be scattered in water in suction filtration gains 1: 5 ~ 15 (m/v) ratio, heat at lower than 75 DEG C entirely molten, according to 6-methoxyl group-4-carbonyl-2,3 dihydro-1 (4H)-quinoline ethyl acetate: gac 1: 0.01 ~ 0.1 (m/m), stir 15 ~ 45min, filter and obtain filtrate, acetone is added in filtrate, and regulate pH value to 2.8 ~ 3.2 of reaction system at lower than 40 DEG C, stir 30 ~ 90min, cooling suction filtration, preferably by water repeatedly flush cake, such as rinse 2 times or 3 times, at 60 ~ 90 DEG C, vacuum-drying is to constant weight, anhydrous methanol is added in 1: 3 ~ 50 (m/v) ratio in solid product, 1 ~ 2h is stirred at 30 ~ 50 DEG C, static 10 ~ 16h, suction filtration, preferably by methyl alcohol repeatedly flush cake, such as 2 times or 3 times, then vacuum-drying 1 ~ 3h at 40 ~ 60 DEG C, obtain 2-[6-methoxyl group-3-(2, 3-dichlorophenyl) methyl-4-oxo-1, 4-dihydro-1 (4H)-quinolyl] acetic acid, the 5th organic solvent used preferably includes but is not limited to methyl alcohol, ethanol, Virahol, one or more in acetone and tetrahydrofuran (THF).
The chemical equation of above-mentioned reaction is as follows:
Apply 2-of the present invention [6-methoxyl group-3-(2; 3-dichlorophenyl) methyl-4-oxo-1; 4-dihydro-1 (4H)-quinolyl] synthetic method of acetic acid; with 1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone for raw material; intermediate 6-methoxyl group-2 is obtained by Fu Ke-acylation reaction; 3-dihydro-4 (1H)-quinolinone; The method avoids and use polyphosphoric acid (PPA) to make condensing agent; decrease the generation of sour water; and decrease the amount of polyphosphoric acid buck used, decrease the pollution to environment.Meanwhile, this reaction, without the need to pyroprocessing, is applicable to scale operation, may be used for suitability for industrialized production.
Embodiment:
Below in conjunction with specific embodiment 1-3, the present invention is described in detail, and embodiment provided by the present invention is only in order to help to understand technical scheme provided by the present invention, and can not limit protection scope of the present invention; The multitude of different ways that the present invention can be defined by the claims and cover is implemented.
The chemical equation that following embodiment 1 to 3 is reacted is as follows: wherein X is chlorine or bromine.
Embodiment 1
The synthesis of 1.3-bromo propionyl chloro
By three bromo-propionic acids (485g, 3.17mol), sulfur oxychloride (490.3g, 300ml), methylene dichloride (1455ml), N, dinethylformamide (1.2ml), adds in 3000ml reaction flask, finishes, 6 hours are reacted at room temperature stirred at reflux condition, reaction is finished, and first normal pressure steams the solvent of about 1/2, and then reduce pressure (0.1MPa) steams except residual solvent, obtain gold oil liquid, let cool for subsequent use.Yield: 100%.
The synthesis of 2.N-(4-methoxyl group) phenyl-3-bromine propionic acid amide
By 4-anisidine (300g, 2.44mol), sodium bicarbonate (307.5g, 3.66mol), toluene (600ml) adds in 3000ml reaction flask, 3-bromo propionyl chloro (the 543.4g that upper step is obtained is dripped under mechanical stirring, toluene (600ml) solution 3.17mol), drip and finish, stirring at room temperature reacts 2.5 hours, TLC detection reaction completeness, reaction is finished, add water 1000ml, then pH to 4 ~ 5 are adjusted with the hydrochloric acid of 10%, suction filtration, filter cake washing (500ml × 2), toluene is washed (500ml × 2), 50 DEG C of vacuum-drying 2h, obtain white powdery solids 579.7g, yield: 92.2%, mp109.8-110.2 DEG C.
The synthesis of (3.1-4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone
By sodium hydride (55.3g, 1.61mol), methylene dichloride (960ml), DMF (320ml), adds in 3000ml three-necked bottle, maintains the temperature at about-5 DEG C, and lucifuge stirs.By N-(4-methoxyl group) phenyl-3-bromine propionic acid amide (320g, 1.24mol) be dissolved in methylene dichloride 960ml, N, in dinethylformamide (320ml) mixing solutions, and drop to methylene dichloride and the N of above-mentioned sodium hydride further, in dinethylformamide solution, maintain the temperature at about-5 DEG C, drip and finish, be transferred to room temperature, lucifuge reaction 3h, TLC detection reaction completeness, reaction is finished, first drip water 500ml, stir, pH to 4 ~ 5 are adjusted with 5% dilute hydrochloric acid, add water 1000ml again, organic layer washing (1000ml × 2), saturated aqueous common salt (500ml) is washed, anhydrous sodium sulfate drying spends the night.Decompression (0.1MPa, 25 DEG C) is steamed and is desolventized, and adds toluene (120ml) stirring at room temperature 1h, filter, toluene (60ml × 2) filter wash cake, 50 DEG C of vacuum-drying 1h, obtain white powder solid 186.7g, yield: 85.0%, mp103.8-104.2 DEG C.
The synthesis of 4.6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone
By 1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone (218g, 1.23mol), trifluoroacetic acid (1308ml) adds in reaction flask, back flow reaction 4 hours at 70 DEG C, TLC detection reaction completeness, reaction is finished, decompression (0.1MPa, 45 DEG C) steam except trifluoroacetic acid, obtain reddish-brown thick liquid, under being transferred to-5 DEG C of environment, under stirring, slowly add saturated potassium hydroxide water liquid, in maintenance reaction flask, temperature is not higher than 30 DEG C, adjust PH to 9 ~ 10, adjust and finish, stirring at room temperature 30min, suction filtration, washing (100ml × 2) filter cake.With the ethanol 400ml of 25%, at 60 DEG C, stir 1.5h, placement is spent the night, suction filtration, 25% ethanol (80ml × 2) filter wash cake, and 50 DEG C of vacuum-drying 3h, obtain yellow solid 88g, yield: 40.4%.mp112.8-113.2℃。
The synthesis of 5.6-methoxyl group-4-carbonyl-2,3 dihydro-1 (4H)-quinoline ethyl acetate
By 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone (100g, 0.56mo l), ethyl bromoacetate (188.4g, 1.13mol), Anhydrous potassium carbonate (116.7g, 0.85mol) and DMF (500ml) add in 1000ml reaction flask, 80 DEG C of reaction 30h, TLC detection reaction completeness, reaction is finished, and is slowly poured into by reaction solution in the 1000ml cold water under stirring, a large amount of yellow solid is had to separate out, then stirring at room temperature 30min, washing (100ml × 2) filter cake, 50 DEG C of vacuum-drying 3h.By ethyl acetate: sherwood oil (1: 2) 500ml, at 50 DEG C of making beating 1.5h, placement is spent the night, suction filtration, and with both mixed solvent (100ml × 2) filter wash cakes, 50 DEG C of vacuum-drying 1h, obtain bright yellow solid 127.8g, yield: 86.7%.
The synthesis of 6.2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid
6-methoxyl group-4-carbonyl-2,3 dihydro-1 (4H)-quinoline ethyl acetate (500g, 1.9mol) is dissolved in 5000ml ethanol at 40 DEG C, after dissolving, slightly cold, in reaction solution, add the sodium hydroxide solution 3000ml of 10%, stirring at room temperature 30min, TLC detection reaction completeness, reaction is finished, by 2,3-dichlorobenzaldehyde (333g, 1.9mol) add in reaction solution, room temperature reaction 7h, have a large amount of white-yellowish solid to separate out.TLC detection reaction completeness, reaction is finished, add sodium-chlor 250g, be warming up to 40 DEG C, stir 20min, let cool to room temperature, suction filtration, filter cake acetone (400ml × 2) is washed, after be scattered in 5000ml water, at 75 DEG C, be heated to entirely molten, add 40g gac, after stirring 30min, heat filter, filtrate adds 100ml acetone, acid adjustment to 3 at 40 DEG C, a large amount of white solid is had to produce, stir 1h, let cool to room temperature, suction filtration, filter cake water (500ml × 2) is washed, at 80 DEG C, vacuum-drying is to constant weight, use anhydrous methanol 3500ml, 1.5h is stirred at 40 DEG C, placement is spent the night, suction filtration, anhydrous methanol (500ml × 2) filter wash cake, vacuum-drying 2h at 50 DEG C, obtain white solid 108.8g, yield: 73.5%, mp223.4-224.5 DEG C, purity 99.7%.
ESI mass spectrum, infrared analysis and nmr analysis are carried out to 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid prepared by embodiment 1,
Mass spectrum, infrared analysis data:
ESI-MS(m／z)：391[M-1] -；IR(cm -1)3434，1716，1614，1531，1438，1365，1324；
Nmr analysis data:
1H-NMR(DMSO-d 6)6：3.84(s，3H，-OCH 3)，3.90(s，2H，-CH 2-)，5.10(s，2H，-CH 2COOH)，7.25(d，2H，-ArH)，7.34(dd，1H，-ArH)，7.46(d，2H，-ArH)，7.48(m，1H，-ArH)，7.61(d，1H，-ArH)，7.90(s，1H，olefin-H)， 13C-NMR(DMSO-d 6)δ：32.32，53.49，55.87，105.76，117.18，118.59，122.33，126.81，128.20，128.72，129.76，131.58，132.07，135.26，140.94，143.59，155.96，170.14，175.46ppm。
Analytical results: by above-mentioned data is target product 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid through the solid product prepared by aforesaid method.
Embodiment 2
The synthesis of 1.3-bromo propionyl chloro
By three bromo-propionic acids (200.2g, 1.30mol), sulfur oxychloride (1001g, 608ml), methylene dichloride (1600ml), N, dinethylformamide (20ml) adds in 2000ml reaction flask, finish, 50 DEG C of stirred at reflux condition reaction 10mim, reaction is finished, first normal pressure steams the solvent of about 2/3, then (0.05MPa) steaming of reducing pressure, except residual solvent, obtains gold oil liquid, lets cool for subsequent use.Yield: 100%.
The synthesis of 2.N-(4-methoxyl group) phenyl-3-bromine propionic acid amide
By 4-anisidine (123.2g, 1.00mol), Anhydrous potassium carbonate (246.4g, 1.78mol), toluene (300ml) adds in 2000ml reaction flask, 3-bromo propionyl chloro (369.6g is dripped under mechanical stirring, toluene (200ml) solution 2.16mol), drip and finish, stirring reaction 6 hours at-10 DEG C of temperature, TLC detection reaction completeness, reaction is finished, add water 700ml, then pH to 4 ~ 5 are adjusted with the hydrochloric acid of 10%, suction filtration, filter cake washing (200ml × 2), toluene is washed (200ml × 2), 50 DEG C of vacuum-drying 2h, obtain white powdery solids 221.9g, yield: 86.0%, mp109.5-110.8 DEG C.
The synthesis of (3.1-4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone
By sodium hydride (48.4g, 1.20mol), methylene dichloride (2900ml), add in 5000ml three-necked bottle, maintain the temperature at about-0 DEG C, lucifuge stirs, by N-(4-methoxyl group) phenyl-3-bromine propionic acid amide (480g, 1.85mol) be dissolved in methylene dichloride 1800ml, drop in the dichloromethane solution of above-mentioned sodium hydride, maintain the temperature at about-0 DEG C, drip and finish, be transferred to room temperature, lucifuge reaction 2h, TLC detection reaction completeness, reaction is finished, first drip water 300ml, stir, pH to 4 ~ 5 are adjusted with 5% dilute hydrochloric acid, add water 800ml again, organic layer washing (1000ml × 4), saturated aqueous common salt (500ml) is washed, anhydrous sodium sulfate drying spends the night.Decompression (0.1MPa, 25 DEG C) is steamed and is desolventized, and adds toluene (100ml) stirring at room temperature 1h, filter, toluene (40ml × 2) filter wash cake, 60 DEG C of vacuum-drying 4h, obtain white powder solid 123.4g, yield: 81%, mp103.5-104.0 DEG C.
The synthesis of 4.6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone
By 1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone (120.0g, 0.68mol), trifluoroacetic acid (1200ml) adds in reaction flask, 82 DEG C of back flow reaction 0.5 hour, TLC detection reaction completeness, reaction is finished, decompression (0.1MPa, 40 DEG C) steam except trifluoroacetic acid, obtain reddish-brown thick liquid, under being transferred to-10 DEG C of environment, under stirring, slowly add saturated potassium hydroxide solution, temperature in reaction flask is kept to be 30 DEG C, adjust PH to 9 ~ 10, adjust and finish, stirring at room temperature 30min, suction filtration, washing (400ml × 2) filter cake.With the ethanol 100ml of 25%, at 50 DEG C, stir 1.5h, placement is spent the night, suction filtration, 25% ethanol (40ml × 2) filter wash cake, and 50 DEG C of vacuum-drying 5h, obtain yellow solid 54.6g, yield: 45.5%.mp111.2-112.8℃。
The synthesis of 5.6-methoxyl group-4-carbonyl-2,3 dihydro-1 (4H)-quinoline ethyl acetate
By 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone (53.4g, 0.30mol), ethyl bromoacetate (151.9g, 0.91mol), Anhydrous potassium carbonate (82.8g, 0.60mo l) and DMF (300ml) add in 1000ml reaction flask, 80 DEG C of reaction 40h, TLC detection reaction completeness, reaction is finished, and is slowly poured into by reaction solution in the 500ml cold water under stirring, a large amount of yellow solid is had to separate out, then stirring at room temperature 30min, washing (100ml × 2) filter cake, 50 DEG C of vacuum-drying 5h.By ethyl acetate: sherwood oil (1: 2) 100ml, at 50 DEG C of making beating 1.5h, placement is spent the night, suction filtration, and with both mixed solvent (50ml × 2) filter wash cakes, 60 DEG C of vacuum-drying 3h, obtain bright yellow solid 64.8g, yield: 82.0%.
The synthesis of 6.2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid
6-methoxyl group-4-carbonyl-2,3 dihydro-1 (4H)-quinoline ethyl acetate (63.8g, 0.24mol) is dissolved in 800ml ethanol at 40 DEG C, after dissolving, slightly cold, in reaction solution, add the sodium hydroxide solution 240ml of 15%, stirring at room temperature 30min, TLC detection reaction completeness, reaction is finished, by 2,3-dichlorobenzaldehyde (54.6g, 0.31mol) add in reaction solution, room temperature reaction 8h, have a large amount of white-yellowish solid to separate out.TLC detection reaction completeness, reaction is finished, add sodium-chlor 100g, be warming up to 40 DEG C, stir 20min, let cool to room temperature, suction filtration, filter cake acetone (400ml × 2) is washed, after be scattered in 5000ml water, at 75 DEG C, be heated to entirely molten, add 3g gac, after stirring 30min, heat filter, filtrate adds 60ml acetone, acid adjustment to 3 at 40 DEG C, a large amount of white solid is had to produce, stir 1h, let cool to room temperature, suction filtration, filter cake water (100ml × 2) is washed, at 80 DEG C, vacuum-drying is to constant weight, use anhydrous methanol 600ml, 1.5h is stirred at 40 DEG C, placement is spent the night, suction filtration, anhydrous methanol (100ml × 2) filter wash cake, vacuum-drying 4h at 50 DEG C, obtain white solid 78.1g, be target product 2-[6-methoxyl group-3-(2 through ESI mass spectroscopy and this white solid product of nmr analysis, 3-dichlorophenyl) methyl-4-oxo-1, 4-dihydro-1 (4H)-quinolyl] acetic acid.Its yield: 82.9%, mp222.4-224.3 DEG C, purity 99.5%.
Embodiment 3
The synthesis of 1.3-bromo propionyl chloro
By three bromo-propionic acids (800.0g, 5.23mol), sulfur oxychloride (1244.7g, 759ml), methylene dichloride (3000ml), N, dinethylformamide (3ml) adds in 5000ml reaction flask, finish, anti-0.5 hour of 50 DEG C of stirred at reflux condition, reaction is finished, first normal pressure steams the solvent of about 1/4, then (0.3MPa) steaming of reducing pressure, except residual solvent, obtains gold oil liquid, lets cool for subsequent use.Yield: 100%.
The synthesis of 2.N-(4-methoxyl group) phenyl-3-bromine propionic acid amide
By 4-anisidine (360.4g, 2.93mol), sodium carbonate (558.6g, 5.27mol), toluene (1000ml) adds in 5000ml reaction flask, 3-bromo propionyl chloro (the 752.5g that upper step is obtained is dripped under mechanical stirring, toluene (800ml) solution 4.39mol), drip and finish, stirring at room temperature reacts 2.5 hours, TLC detection reaction completeness, reaction is finished, add water 1500ml and then adjust pH to 4 ~ 5 with the hydrochloric acid of 10%, suction filtration, filter cake washing (300ml × 2), toluene is washed (700ml × 2), 60 DEG C of vacuum-drying 4h, obtain white powdery solids 665.9g, yield: 88.1%, mp109.1-110.6 DEG C.
The synthesis of (3.1-4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone
By sodium hydride (148.5g, 3.71mol), methylene dichloride (2000ml), N, dinethylformamide (300ml), add in reaction flask, maintain the temperature at about-3 DEG C, lucifuge stirs, by N-(4-methoxyl group) phenyl-3-bromine propionic acid amide (600.0g, 2.32mol) be dissolved in methylene dichloride 1500ml, N, in dinethylformamide (600ml) mixing solutions, drop to methylene dichloride and the N of above-mentioned sodium hydride, in dinethylformamide solution, maintain the temperature at about-3 DEG C, drip and finish, be transferred to room temperature, lucifuge reaction 3h, TLC detection reaction completeness, reaction is finished, first drip water 600ml, stir, pH to 4 ~ 5 are adjusted with 5% dilute hydrochloric acid, add water 2000ml again, organic layer washing (2000ml × 4), saturated aqueous common salt (1500ml) is washed, anhydrous sodium sulfate drying spends the night.Decompression (0.1MPa, 25 DEG C) is steamed and is desolventized, and adds toluene (500ml) stirring at room temperature 1h, filter, toluene (200ml × 2) filter wash cake, 60 DEG C of vacuum-drying 4h, obtain white powder solid 337.1g, yield: 82.0%, mp103.1-103.9 DEG C.
The synthesis of 4.6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone
By 1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone (239.8g, 1.35mol), trifluoroacetic acid (240ml) adds in reaction flask, 72 DEG C of back flow reaction 4 hours, TLC detection reaction completeness, reaction is finished, decompression (0.1MPa, 45 DEG C) steam except trifluoroacetic acid, obtain reddish-brown thick liquid, under being transferred to 6 DEG C of environment, under stirring, slowly add saturated potassium hydroxide water liquid, keep temperature 20 DEG C in reaction flask, adjust PH to 9 ~ 10, adjust and finish, stirring at room temperature 30min, suction filtration, washing (200ml × 2) filter cake.With the ethanol 500ml of 25%, at 60 DEG C, stir 1.5h, placement is spent the night, suction filtration, 25% ethanol (100ml × 2) filter wash cake, and 50 DEG C of vacuum-drying 5h, obtain yellow solid 103.1g, yield: 43.1%.mp111.8-112.7℃。
The synthesis of 5.6-methoxyl group-4-carbonyl-2,3 dihydro-1 (4H)-quinoline ethyl acetate
By 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone (183.5g, 1.04mol), ethyl bromoacetate (345.8g, 2.07mol), sodium bicarbonate (262.1g, 3.12mol) and DMF (1000ml) add in 3000ml reaction flask, 80 DEG C of reaction 27h, TLC detection reaction completeness, reaction is finished, and is slowly poured into by reaction solution in the 1000ml cold water under stirring, a large amount of yellow solid is had to separate out, then stirring at room temperature 30min, washing (300ml × 2) filter cake, 50 DEG C of vacuum-drying 3h.By ethyl acetate: sherwood oil (1: 2) 480ml, at 50 DEG C of making beating 2h, placement is spent the night, suction filtration, and with both mixed solvent (150ml × 2) filter wash cakes, 60 DEG C of vacuum-drying 6h, obtain bright yellow solid 214.7g, yield: 78.4%.
The synthesis of 6.2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid
6-methoxyl group-4-carbonyl-2,3 dihydro-1 (4H)-quinoline ethyl acetate (150.0g, 0.57mol) is dissolved in 1500ml ethanol at 40 DEG C, after dissolving, slightly cold, in reaction solution, add the sodium hydroxide solution 1500ml of 8%, stirring at room temperature 30min, TLC detection reaction completeness, reaction is finished, by 2,3-dichlorobenzaldehyde (140.0g, 0.80mol) add in reaction solution, room temperature reaction 5h, have a large amount of white-yellowish solid to separate out.TLC detection reaction completeness, reaction is finished, add sodium-chlor 150g, be warming up to 40 DEG C, stir 20min, let cool to room temperature, suction filtration, filter cake acetone (500ml × 2) is washed, after be scattered in 2000ml water, at 75 DEG C, be heated to entirely molten, add 1.5g gac, after stirring 30min, heat filter, filtrate adds 150ml acetone, acid adjustment to 3 at 40 DEG C, a large amount of white solid is had to produce, stir 1h, let cool to room temperature, suction filtration, filter cake water (100ml × 2) is washed, at 80 DEG C, vacuum-drying is to constant weight, use anhydrous methanol 500ml, 1.5h is stirred at 40 DEG C, placement is spent the night, suction filtration, anhydrous methanol (80ml × 2) filter wash cake, vacuum-drying 5h at 60 DEG C, obtain white solid 175.8g, be target product 2-[6-methoxyl group-3-(2 through ESI mass spectroscopy and this white solid product of nmr analysis, 3-dichlorophenyl) methyl-4-oxo-1, 4-dihydro-1 (4H)-quinolyl] acetic acid.Its yield: 80.0%, mp223.7-225.3 DEG C, purity 99.9%.
2-[6-methoxyl group-3-(2 prepared by the method provided by above-described embodiment 1 to 3,3-dichlorophenyl) methyl-4-oxo-1,4-dihydro-1 (4H)-quinolyl] acetic acid, its yield can reach more than 79.0%, and purity can reach more than 98%.And this synthetic method; with 1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone for raw material; intermediate 6-methoxyl group-2 is obtained by Fu Ke-acylation reaction; 3-dihydro-4 (1H)-quinolinone; The method avoids and use polyphosphoric acid (PPA) to make condensing agent; decrease the generation of sour water, and decrease the amount of polyphosphoric acid buck used, decrease the pollution to environment.Meanwhile, this reaction, without the need to pyroprocessing mild condition, is applicable to scale operation, may be used for suitability for industrialized production.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.

Claims (7)

  1. The synthetic method of 1.2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid, is characterized in that, the steps include:
    1) synthesis of 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone:
    1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone and trifluoroacetic acid are mixed in m/v=1: 1 ~ 10 ratios, back flow reaction 0.5 ~ 8 hour, after reaction terminating, at 40 ~ 50 DEG C, Distillation recovery trifluoroacetic acid under-0.05 ~-0.1MPa, obtains intermediate product A;
    Described intermediate product A is cooled to-10 ~-2 DEG C, under agitation condition, drips saturated potassium hydroxide aqueous solution, keep temperature of reaction system not higher than 30 DEG C, stop when the PH to reaction system is 9 ~ 10 dripping described saturated potassium hydroxide aqueous solution, obtain intermediate product B;
    Described intermediate product B is at room temperature stirred 20 ~ 50min, after suction filtration, obtains described intermediate product 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone;
    2) 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-1,4-dihydro-1 (4H)-quinolyl] synthesis of acetic acid: with intermediate 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone is raw material, described 2-[6-methoxyl group-3-(2 is synthesized through N-hydrocarbonylation, hydrolysis, condensation reaction, 3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid;
    Described catalyzer is trifluoroacetic acid;
    I) wherein with intermediate 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone is the step that raw material carries out N-hydrocarbonylation process: by described intermediate 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone, ethyl bromoacetate, acid binding agent and the 4th organic solvent mix in m: m: m: v=1: 1 ~ 5: 1 ~ 5: 3 ~ 10 ratios, and 2h ~ 40h is reacted at 50 ~ 100 DEG C, after reaction terminating, decompression steams the solvent of 1/4 ~ 2/3, obtains mixed system C;
    Pour in the cold water of 0 ~ 5 DEG C by described mixed system C under the condition stirred, stir solid is separated out under 0 ~ 30 DEG C of condition, by solid precipitate through washing, 40 ~ 60 DEG C of vacuum-drying 2 ~ 5h, obtain intermediate product D; Intermediate product D is mixed according to m/v=1: 5 ~ 20 ratios with mixed solvent E, 40 ~ 60 DEG C of making beating process 1 ~ 3h, static 10 ~ 16h, clean after suction filtration, 40 ~ 60 DEG C of vacuum-drying 0.5 ~ 3h, obtain 6-methoxyl group-4-carbonyl-2,3 dihydro-1 (4H)-quinoline ethyl acetate;
    Described 4th organic solvent is one or more in DMF, methyl alcohol, ethanol, methylene dichloride, tetrahydrofuran (THF), acetonitrile;
    Described mixed solvent E is ethyl acetate and sherwood oil volume ratio is the mixing solutions of 1: 2;
    Described acid binding agent is one or more in Anhydrous potassium carbonate, anhydrous sodium carbonate, potassium hydroxide, sodium hydroxide, saleratus, sodium bicarbonate and triethylamine;
    Ii) wherein with intermediate 6-methoxyl group-4-carbonyl-2,3 dihydro-1 (4H)-quinoline ethyl acetate are raw material, 2-[6-methoxyl group-3-(2 is obtained through hydrolysis, condensation, 3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] step of acetic acid is:
    Described 6-methoxyl group-4-carbonyl-2,3 dihydro-1 (4H)-quinoline ethyl acetate is dissolved in the 5th organic solvent, obtains mixing solutions F;
    In described mixing solutions F according to 6-methoxyl group-4-carbonyl-2, 3 dihydro-1 (4H)-quinoline ethyl acetate ratios are the aqueous sodium hydroxide solution that m/v=1: 2 ~ 10 ratios add 5 ~ 15%, 20 ~ 30 DEG C are stirred hydrolysis 10min ~ 1h, after reaction terminating, according to 6-methoxyl group-4-carbonyl-2, 3 dihydro-1 (4H)-quinoline ethyl acetate ratios are that m/v=1: 1 ~ 3 ratios add 2, 3-dichlorobenzaldehyde, room temperature condensation reaction 5 ~ 8h, after reaction terminating, according to 6-methoxyl group-4-carbonyl-2, 3 dihydro-1 (4H)-quinoline ethyl acetate: sodium-chlor is m: m=1: 0.5 ~ 4 add sodium-chlor, be warming up to 35 ~ 60 DEG C, stir 15 ~ 30min, after cooling suction filtration, be scattered in water in suction filtration gains m/v=1: 5 ~ 15 ratio, heat at lower than 75 DEG C entirely molten, by 6-methoxyl group-4-carbonyl-2, 3 dihydro-1 (4H)-quinoline ethyl acetate: gac is m/m=1: 0.01 ~ 0.1 add gac, stir 15 ~ 45min, filtration obtains filtrate,
    Acetone is added in described filtrate, and regulate pH value to 2.8 ~ 3.2 of reaction system at lower than 40 DEG C, stir 30 ~ 90min, cooling suction filtration, at 60 ~ 90 DEG C, vacuum-drying is to constant weight, anhydrous methanol is added in m/v=1: 3 ~ 50 ratios in solid product, 1 ~ 2h is stirred at 30 ~ 50 DEG C, static 10 ~ 16h, vacuum-drying 1 ~ 3h at 40 ~ 60 DEG C after suction filtration, obtains 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-1,4-dihydro-1 (4H)-quinolyl] acetic acid
    Described 5th organic solvent is one or more in methyl alcohol, ethanol, Virahol, acetone and tetrahydrofuran (THF).
  2. 2. synthetic method according to claim 1, it is characterized in that, described step 1) in, after suction filtration step, in suction filtration thing, add the ethanol of 15 ~ 30% further, be warming up to 50 ~ 80 DEG C, stir 1 ~ 3h, place 10 ~ 16h, again after suction filtration at 40 ~ 60 DEG C of vacuum-drying 2 ~ 5h, obtain described intermediate product 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone.
  3. 3. synthetic method according to claim 1, is characterized in that, described step 1) in, the synthetic method of raw material 1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone is:
    Mixed in m/v=1: 1 ~ 60 ratios with the first organic solvent by sodium hydride, temperature control-10 ~ 50 DEG C, obtains mixed solution A;
    By N-(4-methoxyl group) phenyl-3-halogen propionic acid amide and the first organic solvent under lucifuge condition in m/v=1: 5 ~ 10 ratio mixed dissolutions, obtain mixing solutions B;
    Be m: m=1: 5 ~ 10 drop in described mixed solution A by described mixing solutions B according to sodium hydride and N-(4-methoxyl group) phenyl-3-halogen propionic acid amide, in dropping process, keep the temperature of reaction system to be-10 ~ 0 DEG C; After dropwising, by gained mixing solutions at-10 ~ 50 DEG C of lucifuge reaction 1-6h; After reaction terminating, add in reaction system and the isopyknic water of the first organic solvent, stir, after regulating reaction system pH to 3 ~ 6, in reaction system, add the water of the first organic solvent 1 ~ 2 times amount, stir, obtain mixed system A, leave standstill, layering;
    Get organic layer in described mixed system A, after cleaning-drying ,-0.05 ~ 0.1MPa, solvent is deviate from 20 ~ 30 DEG C of distillations, obtains intermediate product C;
    In described intermediate product C, add toluene in m/v=1: 5 ~ 10 ratios, stirring at room temperature 0.5 ~ 3h, in 40 ~ 60 DEG C of vacuum-drying 0.5 ~ 3h after filtration, obtain described 1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone;
    Described first organic solvent is the mixed solvent that methylene dichloride and DMF mix in v: v=1 ~ 5: 1 ratio.
  4. 4. synthetic method according to claim 3, is characterized in that the synthetic method of N-(4-methoxyl group) phenyl-3-halogen propionic acid amide is:
    Mix in 4-anisidine, 3-halogen propionyl chloride, alkaline matter and the second organic solvent in m: m: m: v=1: 1.5 ~ 3: 1 ~ 2: 2 ~ 8 ratios, at-10 ~ 50 DEG C, reaction times is 0.5 ~ 6h, after reaction terminating, in 4-anisidine in reaction system: water is that m/v=1: 2 ~ 10 ratios add water stirring, and the pH of reaction system is adjusted to 4 ~ 5, obtain mixed system B; Get described mixed system B suction filtration cleaning-drying, obtain described N-(4-methoxyl group) phenyl-3-halogen propionic acid amide;
    Described second organic solvent is one or more of benzene,toluene,xylene;
    Described alkaline matter be sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, saleratus, salt of wormwood, triethylamine one or more.
  5. 5. synthetic method according to claim 4, is characterized in that, the described step by the mixing of 4-anisidine, 3-halogen propionyl chloride, alkaline matter and the second organic solvent is:
    Described 4-anisidine and described alkaline matter are dissolved in described second solvent of part, obtain mixed solution C; 3-bromo propionyl chloro is dissolved in described second solvent of part, obtains mixing solutions D;
    Described mixing solutions D is dropped in described mixed solution C, in dropping process, keeps the temperature of reaction system not higher than 50 DEG C.
  6. 6. synthetic method according to claim 5, it is characterized in that, the synthetic method of described 3-halogen propionyl chloride is: take DMF as catalyzer, by three halogen propionic acid, sulfur oxychloride, the 3rd organic solvent, N, dinethylformamide presses m: m: v: v=1: 1 ~ 5: 3 ~ 8: 0.002 ~ 0.1 mixing, at 20 ~ 50 DEG C, back flow reaction 10min ~ 6h, after reaction terminating, excess of solvent in reaction system is discharged in distillation, obtains described 3-halogen propionyl chloride;
    Described 3rd organic solvent is methylene dichloride and/or trichloromethane.
  7. 7. synthetic method according to claim 6, is characterized in that, the step that excess of solvent in reaction system is discharged in distillation is:
    Excess of solvent in the described reaction system of 1/4 ~ 2/3 is discharged in air distillation;
    Excess of solvent in remaining described reaction system will be discharged after Pressure Drop to 0.05 ~ 0.3MPa.
CN201410001737.5A 2014-01-03 2014-01-03 The synthetic method of 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid Active CN103739547B (en)

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