CN103739547A - Synthesis method of 2-[6-methoxy-3-(2,3-dichlorophenyl)methyl-4-oxo-1,4-dihydro-1(4H)-quinolyl] acetic acid - Google Patents
Synthesis method of 2-[6-methoxy-3-(2,3-dichlorophenyl)methyl-4-oxo-1,4-dihydro-1(4H)-quinolyl] acetic acid Download PDFInfo
- Publication number
- CN103739547A CN103739547A CN201410001737.5A CN201410001737A CN103739547A CN 103739547 A CN103739547 A CN 103739547A CN 201410001737 A CN201410001737 A CN 201410001737A CN 103739547 A CN103739547 A CN 103739547A
- Authority
- CN
- China
- Prior art keywords
- dihydro
- methoxyl group
- reaction
- mixed
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Quinoline Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a synthesis method of 2-[6-methoxy-3-(2,3-dichlorophenyl)methyl-4-oxo-1,4-dihydro-1(4H)-quinolyl] acetic acid. The method comprises the following steps: with 1-(4-methoxyphenyl)azacyclobutyl-2-one as a raw material, adding trifluoroacetic acid and performing a Friedel-Crafts acylation reaction by use of a catalyst; after the solvent is steamed out, adding a saturated aqueous solution of potassium hydroxide for neutralizing; performing suction filtration to obtain an intermediate 6-methoxy-2,3-dihydro-4(1H)-quinolinone; and with the intermediate 6-methoxy-2,3-dihydro-4(1H)-quinolinone as a raw material, performing N-hydrocarbonylation, hydrolysis and condensation reaction to synthesize the 2-[6-methoxy-3-(2,3-dichlorophenyl)methyl-4-oxo-1,4-dihydro-1(4H)-quinolyl] acetic acid. The synthesis method avoids a large dosage of polyphosphoric acid (PPA) and is environment-friendly in process and better for industrial production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, relate in particular to a kind of 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] synthetic method of acetic acid.
Background technology
Diabetes are one group and take the metabolic syndrome that long-term hyperglycemia is principal character.Along with improving constantly of socioeconomic development and people's living standard, diabetes prevalence sharply increases, and has become and has affected one of principal disease of human body health.By the end of 2003, China became diabetes the second big country, had 2,380 ten thousand diabetic subjects.Diabetes be take long-term hyperglycemia as principal character, and the diabetic complication causing is thus that diabetes disable and lethal major cause.According to statistics, in diabetic, there are the concurrent blood vessel of 1/2 above person and DPN; Approximately have 30% concurrent proliferative retinopathy, wherein 1.2% may be developed to blind; 30%～40% type 1 diabetes patient and 15%～20% diabetes B patient complicated with diabetes ephrosis, and can be by occurring that at first proteinuria is developed to hypertensive nephropathy syndrome.Therefore, treatment and prophylactic agent research are especially introduced and are paid close attention to.
At present, researchist finds that in diabetic subject's cell, the content of aldose reductase is higher conventionally, if can suppress the increase of aldose reductase in cell, can effectively treat and prevent diabetes, and complication.Having research to point out to have 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl of following structural formula I] acetic acid can use as aldose reductase inhibitor.
A kind of 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl is disclosed in Chinese patent CN101058558A] acetic acid, and provided a kind of synthetic method.This synthetic method comprises: take 4-anisidine and ethyl propenoate as synthetic 3-(4-anisole amido) the propionic acid intermediate of raw material; 3-(4-anisole amido) the propionic acid intermediate of take is raw material, take polyphosphoric acid (PPA) as the synthetic 6-of condensing agent methoxyl group-2,3-dihydro-4 (1H) quinolinone intermediate; With 6-methoxyl group-2,3-dihydro-4 (1H) quinolinone intermediate is raw material, adds ethyl bromoacetate N-alkylation reaction to produce methoxyl group-2,4-carbonyl-6,3 dihydro-1 (4H)-quinoline ethyl acetate intermediate; With methoxyl group-2,4-carbonyl-6,3 dihydro-1 (4H)-quinoline ethyl acetate intermediate is to add 2 after raw material hydrolysis, 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl is synthesized in the condensation reaction of 3-dichlorobenzaldehyde] acetic acid.The reaction formula of above-mentioned synthetic method is as follows:
Aforesaid method is in synthetic method, in synthetic intermediate " 6-methoxyl group-2, 3-dihydro-4 (1H) quinolinone " time use polyphosphoric acid (PPA) to make condensing agent, and the use of polyphosphoric acid is doubly measured and is about 20 times of reactant " 3-(4-anisole amido) propionic acid " consumption, with regard to causing need to removing polyphosphoric acid with a large amount of bucks when the aftertreatment, just can make the product generating dissociate out like this, and during reaction, need high temperature, the method is prepared 6-methoxyl group-2 on a small scale in laboratory, 3-dihydro-4 (1H) are even can during quinolinone, but while producing in a large number in industry, although yield is higher, but because a large amount of trade effluents that produce can cause environment to cause huge pollution, limited suitability for industrialized production.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, a kind of 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl be provided] synthetic method of acetic acid, to reduce environmental pollution.
For this reason, provide in the present invention a kind of 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] synthetic method of acetic acid, comprise the following steps:
1) 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone synthetic:
1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone of take is raw material, add catalyzer to carry out, after Fu Ke-acylation reaction, steaming solvent, add saturated potassium hydroxide aqueous solution to neutralize, suction filtration obtains intermediate 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone;
2) 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid synthetic:
With intermediate 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone is raw material, through N-hydrocarbonylation, hydrolysis, the synthetic 2-[6-methoxyl group-3-(2 of condensation reaction, 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 differently according to adopted catalyzer, the solvent steaming is one or more in trifluoroacetic acid, toluene, tetrahydrofuran (THF), methylene dichloride dimethyl sulfoxide solvent.
Below with reference to embodiment, 2-[6-methoxyl group-3-(2 of the present invention is described step by step, 3-dichlorophenyl) methyl-4-oxo-1,4-dihydro-1 (4H)-quinolyl] synthetic method of acetic acid, wherein in the feed proportioning process of each step, mentioned m is quality, 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 shown in middle structural formula (2)) can adopt commercially available prod, can be also under the application's instruction, and those skilled in the art select suitable mode to prepare.In a kind of preferred implementation 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 shown in middle structural formula (1)) and trifluoroacetic acid are mixed in 1: 1～10 (m/v) ratio, at 72～82 ℃, back flow reaction is 0.5～8 hour, after reaction terminating, at 40～50 ℃, Distillation recovery trifluoroacetic acid under-0.05～-0.1MPa, obtains intermediate product A; In above-mentioned reaction, can with judgement reaction, whether stop by TLC detection reaction completeness.Intermediate product A is cooled to-10 ℃～-2, under agitation condition, drips saturated potassium hydroxide aqueous solution, keep temperature of reaction system not higher than 30 ℃, stop dripping saturated potassium hydroxide aqueous solution at 9～10 o'clock to the PH of reaction system, obtain intermediate product B; Intermediate product B is at room temperature stirred to 20～50min, after suction filtration, 15～30% ethanol is added in 1: 0.5～5 (m/v) ratio, in the process of suction filtration, preferably repeatedly wash filter cake, more preferably 2 times, 3 times or 5 washing filter cakes, at 50～80 ℃, stir 1～3h, place 10～16h, again after suction filtration at 40～60 ℃ of vacuum-drying 2～5h, in the process of suction filtration, preferably repeatedly use 15～30% alcohol flushing filter cake, 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 of providing in the present invention; 3-dichlorophenyl) methyl-4-oxo-1; 4-dihydro-1 (4H)-quinolyl] in this synthetic method of acetic acid; 1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone of take is raw material; by the reaction of Fu Ke-acyl group, obtain intermediate 6-methoxyl group-2; 3-dihydro-4 (1H)-quinolinone; this method has avoided use polyphosphoric acid (PPA) to make condensing agent; reduced the generation of sour water; and reduced the amount of removing polyphosphoric acid buck used, reduced the pollution to environment.Meanwhile, this reacts without pyroprocessing, is applicable to scale operation, can be 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) the raw material 1-using in (4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone can directly 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 shown in middle structural formula (2)) 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 is mixed, sodium hydride is mixed in 1: 1～60 (m/v) ratio with the first organic solvent, temperature control-10～50 ℃, obtain mixed solution A, by N-(4-methoxyl group) phenyl-3-halogen propionic acid amide and described the 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, keep the temperature of reaction system to be-10～0 ℃ in dropping process, after dropwising, gained mixing solutions is reacted to 1-6h-10～50 ℃ of lucifuges, after reaction terminating, in reaction system, add and the isopyknic water stirring of the first organic solvent, and adjust reaction system pH to 4～5, the step of adjustment system pH is preferably that 3～8% dilute hydrochloric acid are realized by add concentration in reaction system, in reaction system, adds the water of 1～2 times of amount of the first organic solvent to stir, and obtains mixed system A, in above-mentioned reaction, can with judgement reaction, whether stop by TLC detection reaction completeness.Get organic layer in mixed system A, cleaning-drying, preferably first with organic layer washing (1500ml * 4), use again saturated aqueous common salt (1000ml) to clean, preferably adopt anhydrous sodium sulfate drying 10～16 hours, then ,-0.05～0.1MPa, solvent is deviate from 20～30 ℃ of distillations, obtains intermediate product C; In intermediate product C, in 1: 5～10 (m/v) ratio, add toluene, stirring at room 0.5～3h, filter, preferably adopt repeatedly filter wash cake of toluene, for example 2 times, 3 times or more times, then at 40～60 ℃ of vacuum-drying 0.5～3h, obtain the synthetic 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 the first organic solvent be methylene dichloride and DMF in 1～5: 1 (v: the mixed solvent that v) ratio is mixed.The mode that adopts the mixing that distributes to obtain mixed system A in aforesaid method can be avoided 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, 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] in the synthetic method of acetic acid, in the building-up reactions of the 1-step 1) (4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone, the N-using (4-methoxyl group) phenyl-3-halogen propionic acid amide 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 shown in middle structural formula (3)) adopts following synthetic method synthetic, step comprises: by 4-anisidine (structure is as shown in the formula shown in middle structural formula (4)), 3-halogen propionyl chloride (structure is as shown in the formula shown in middle structural formula (5)), 1: 1.5～3: 1～2: 2～8 (m: m: m: v) ratio is mixed in alkaline matter and the second organic solvent, at-10～50 ℃, reaction times is 0.5～6h, after reaction terminating, to in reaction system in 4-anisidine: water=1: 2～10 (m/v) ratio adds water and stirs, and reaction system pH is adjusted to 4～5, preferably, the step of adjusting reaction system pH is that 5～15% dilute hydrochloric acid are realized by adding concentration, obtain mixed system B, in above-mentioned reaction, can with judgement reaction, whether stop by TLC detection reaction completeness.Get mixed system B suction filtration, preferably the first water of filter cake repeatedly cleans, and for example 2 times or 3 times, then with toluene, repeatedly clean for example 2 times or 3 times.Dry the synthetic of N-(4-methoxyl group) phenyl-3-halogen propionic acid amide, preferred dry employing, 40～60 ℃ of vacuum-drying 0.5～3h of obtaining.In above-mentioned 3-halogen propionyl chloride, halogen is chlorine or bromine; The second organic solvent preferably includes but is not limited to one or more of benzene,toluene,xylene; Alkaline matter preferably includes but is not limited to one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, saleratus, salt of wormwood, triethylamine.
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 the step of 4-anisidine, 3-halogen propionyl chloride, alkaline matter being mixed in the second organic solvent in the step of synthetic N-(4-methoxyl group) phenyl-3-halogen propionic acid amide comprise: first 4-anisidine and alkaline matter are dissolved in part the second solvent, obtain mixed solution C; 3-halogen propionyl chloride is dissolved in part the second solvent, obtains mixing solutions D; Mixing solutions D is dropped in mixed solution C, in dropping process, keep the temperature of reaction system not higher than 50 ℃; After dropwising, by gained mixing solutions, at-10～50 ℃, preferably 20～30 ℃ of lucifuges are reacted 0.5-6h.Adopt and mix in this way various raw materials and there is convenient post-treatment, and the by product advantage that is easy to remove.
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 synthetic N-(4-methoxyl group) phenyl-3-halogen propionic acid amide, the 3-halogen propionyl chloride using 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, three halogen propionic acid, sulfur oxychloride, the 3rd organic solvent, DMF are pressed to 1: 1～5: 3～8: 0.002～0.1 (m: m: v: v) mix, at 20～50 ℃, back flow reaction 10min～6h, after reaction terminating, unnecessary solvent in reaction system is discharged in distillation, obtains 3-halogen propionyl chloride; The 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] in the step of synthetic 3-halogen propionyl chloride, unnecessary solvent in reaction system is discharged in distillation in the synthetic method of acetic acid step comprises: unnecessary solvent in 1/4～2/3 reaction system is discharged in air distillation; Pressure Drop is discharged to unnecessary solvent in remaining reaction system to-0.05～-0.1MPa.Adopt distillation discharge solvent in this way and there is the increase of the solvent recuperation of making amount, the effect reducing costs.
At above-mentioned 2-[6-methoxyl group-3-(2, 3-dichlorophenyl) methyl-4-oxo-1, 4-dihydro-1 (4H)-quinolyl] in the synthetic method of acetic acid, 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 processing comprises: by intermediate 6-methoxyl group-2, 3-dihydro-4 (1H)-quinolinone (structure is as shown in the formula shown in middle structural formula (2)), ethyl bromoacetate (structure is as shown in the formula shown in middle structural formula (6)), acid binding agent and the 4th organic solvent are according to 1: 1～5: 1～5: 3～10 (m: m: m: v) ratio is mixed, and react 2h～40h at 50～100 ℃, after reaction terminating, decompression steams 1/4～2/3 solvent, obtain mixed system C, in above-mentioned reaction, can with judgement reaction, whether stop by TLC detection reaction completeness.Mixed system C is poured under the condition stirring in the cold water of 0～5 ℃, under 0～30 ℃ of condition, stir solid is separated out, preferably stir 20～50 minutes, solid precipitate, through washing, is preferably repeatedly washed to for example 2 times or 3 times, 40～60 ℃ of vacuum-drying 2～5h, obtain intermediate product D; Intermediate product D is mixed according to 1: 5～20 (m/v) ratio with mixed solvent E, and 1～3h is processed in 40～60 ℃ of making beating, static 10～16h, and suction filtration, preferably uses many flush cake of mixing solutions E, for example, rinse 2 times or 3 times.Then clean, 40～60 ℃ 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 shown in middle structural formula (7)).The 4th organic solvent using preferably includes but is not limited to one or more in DMF, methyl alcohol, ethanol, methylene dichloride, tetrahydrofuran (THF), acetonitrile; Mixed solvent E is the mixing solutions that ethyl acetate and sherwood oil volume ratio are 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] in the synthetic method of acetic acid, 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 shown in middle structural formula (7)) is 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 shown in middle structural formula (I)) comprising: by 6-methoxyl group-4-carbonyl-2, 3 dihydro-1 (4H)-quinoline ethyl acetate is dissolved in the 5th organic solvent, obtain mixing solutions F, to in mixing solutions F according to 6-methoxyl group-4-carbonyl-2, 3 dihydro-1 (4H)-quinoline ethyl acetate ratio is 1: 2～10 (m/v), being preferably 1: 3～8 (m/v) ratio adds 5～15% aqueous sodium hydroxide solution, stirring at room hydrolysis 10min～1h, after reaction terminating, according to 6-methoxyl group-4-carbonyl-2, 3 dihydro-1 (4H)-quinoline ethyl acetate ratio is 1: 1～1: 3 (m/v), being preferably 1: 1～2 (m/v) add 2, 3-dichlorobenzaldehyde (structure is as shown in the formula shown in middle structural formula (8)), room temperature condensation reaction 5～8h, after reaction terminating, preferably by TLC detection reaction completeness, with judgement reaction, whether stop.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 ℃, stir 15～30min, after cooling suction filtration, in suction filtration gains 1: 5～15 (m/v) ratio, be scattered in water, heating is entirely molten at lower than 75 ℃, 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, in filtrate, add acetone, and regulate pH value to 2.8～3.2 of reaction system at lower than 40 ℃, stir 30～90min, cooling suction filtration, preferred water is flush cake repeatedly, for example rinse 2 times or 3 times, at 60～90 ℃, vacuum-drying is to constant weight, in solid product, in 1: 3～50 (m/v) ratio, add anhydrous methanol, at 30～50 ℃, stir 1～2h, static 10～16h, suction filtration, preferably by methyl alcohol flush cake repeatedly, for example 2 times or 3 times, then vacuum-drying 1～3h at 40～60 ℃, obtain 2-[6-methoxyl group-3-(2, 3-dichlorophenyl) methyl-4-oxo-1, 4-dihydro-1 (4H)-quinolyl] acetic acid, the 5th organic solvent using 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-[6-methoxyl group-3-(2 of the present invention; 3-dichlorophenyl) methyl-4-oxo-1; 4-dihydro-1 (4H)-quinolyl] synthetic method of acetic acid; 1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone of take is raw material; by Fu Ke-acylation reaction, obtain intermediate 6-methoxyl group-2; 3-dihydro-4 (1H)-quinolinone; this method has avoided use polyphosphoric acid (PPA) to make condensing agent; reduced the generation of sour water; and reduced the amount of removing polyphosphoric acid buck used, reduced the pollution to environment.Meanwhile, this reacts without pyroprocessing, is applicable to scale operation, can be 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 understanding 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 of following embodiment 1 to 3 reaction is as follows: wherein X is chlorine or bromine.
Embodiment 1
Synthesizing 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, under room temperature reflux conditions, stirring reaction is 6 hours, reaction is finished, and first normal pressure steams approximately 1/2 solvent, and then decompression (0.1MPa) is steamed except residual solvent, obtain golden yellow oily liquids, let cool standby.Yield: 100%.
Synthesizing 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, under mechanical stirring, drip the 3-bromo propionyl chloro (543.4g that upper step makes, toluene 3.17mol) (600ml) solution, drip and finish, stirring at room reaction 2.5 hours, TLC detection reaction completeness, reaction is finished, add water 1000ml, then with 10% hydrochloric acid, adjust pH to 4～5, suction filtration, filter cake washing (500ml * 2), toluene is washed (500ml * 2), 50 ℃ of vacuum-drying 2h, obtain white powder solid 579.7g, yield: 92.2%, mp109.8-110.2 ℃.
3.1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone is synthetic
By sodium hydride (55.3g, 1.61mol), methylene dichloride (960ml), DMF (320ml), adds in 3000ml three-necked bottle, maintains the temperature at-5 ℃ of left and right, 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 further drop to methylene dichloride and the N of above-mentioned sodium hydride, in dinethylformamide solution, maintain the temperature at-5 ℃ of left and right, drip and finish, be transferred to room temperature, lucifuge reaction 3h, TLC detection reaction completeness, reaction is finished, first drip water 500ml, stir, with 5% dilute hydrochloric acid, adjust pH to 4～5, add again water 1000ml, organic layer washing (1000ml * 2), saturated aqueous common salt (500ml) is washed, anhydrous sodium sulfate drying spends the night.Decompression (0.1MPa, 25 ℃) is steamed and is desolventized, and adds toluene (120ml) stirring at room 1h, filter, and toluene (60ml * 2) filter wash cake, 50 ℃ of vacuum-drying 1h, obtain white powder solid 186.7g, yield: 85.0%, mp103.8-104.2 ℃.
4.6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone synthetic
By 1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone (218g, 1.23mol), trifluoroacetic acid (1308ml) adds in reaction flask, at 70 ℃, back flow reaction is 4 hours, TLC detection reaction completeness, reaction is finished, decompression (0.1MPa, 45 ℃) steam except trifluoroacetic acid, obtain reddish-brown thick liquid, be transferred under-5 ℃ of environment, under stirring, slowly add saturated potassium hydroxide water liquid, keep the interior temperature of reaction flask not higher than 30 ℃, adjust PH to 9～10, adjust and finish, stirring at room 30min, suction filtration, washing (100ml * 2) filter cake.Ethanol 400ml with 25% stirs 1.5h at 60 ℃, and placement is spent the night, suction filtration, and 25% ethanol (80ml * 2) filter wash cake, 50 ℃ of vacuum-drying 3h, obtain yellow solid 88g, yield: 40.4%.mp112.8-113.2℃。
5.6-methoxyl group-4-carbonyl-2,3 dihydro-1 (4H)-quinoline ethyl acetate synthetic
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 ℃ of reaction 30h, TLC detection reaction completeness, reaction is finished, and reaction solution is slowly poured in the 1000ml cold water under stirring, there are a large amount of yellow solids to separate out, then stirring at room 30min, washes (100ml * 2) filter cake, 50 ℃ of vacuum-drying 3h.By ethyl acetate: sherwood oil (1: 2) 500ml, at 50 ℃ of making beating 1.5h, placement is spent the night, suction filtration, with both mixed solvents (100ml * 2) filter wash cake, 50 ℃ of vacuum-drying 1h, obtain glassy yellow solid 127.8g, yield: 86.7%.
6.2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid synthetic
By 6-methoxyl group-4-carbonyl-2,3 dihydro-1 (4H)-quinoline ethyl acetate (500g, 1.9mol) is dissolved in 5000ml ethanol at 40 ℃, after dissolving, slightly cold, to the sodium hydroxide solution 3000ml that adds 10% in reaction solution, stirring at room 30min, TLC detection reaction completeness, reaction is finished, by 2,3-dichlorobenzaldehyde (333g, 1.9mol) add in reaction solution, room temperature reaction 7h, has 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 ℃, stir 20min, let cool to room temperature, suction filtration, acetone for filter cake (400ml * 2) is washed, after be scattered in 5000ml water, at 75 ℃, be heated to entirely molten, add 40g gac, stir after 30min, heat filter, filtrate adds 100ml acetone, acid adjustment to 3 at 40 ℃, there are a large amount of white solids to produce, stir 1h, let cool to room temperature, suction filtration, filter cake water (500ml * 2) is washed, at 80 ℃, vacuum-drying is to constant weight, use anhydrous methanol 3500ml, at 40 ℃, stir 1.5h, placement is spent the night, suction filtration, anhydrous methanol (500ml * 2) filter wash cake, vacuum-drying 2h at 50 ℃, obtain white solid 108.8g, yield: 73.5%, mp223.4-224.5 ℃, purity 99.7%.
To embodiment 1 prepared 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid carries out ESI mass spectrum, infrared analysis and nmr analysis,
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, be target product 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl through the prepared solid product of aforesaid method] acetic acid.
Embodiment 2
Synthesizing 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, stirring reaction 10mim under 50 ℃ of reflux conditionss, reaction is finished, first normal pressure steams approximately 2/3 solvent, then decompression (0.05MPa) is steamed except residual solvent, obtains golden yellow oily liquids, lets cool standby.Yield: 100%.
Synthesizing 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, under mechanical stirring, drip 3-bromo propionyl chloro (369.6g, toluene 2.16mol) (200ml) solution, drip and finish, at-10 ℃ of temperature, stirring reaction is 6 hours, TLC detection reaction completeness, reaction is finished, add water 700ml, then with 10% hydrochloric acid, adjust pH to 4～5, suction filtration, filter cake washing (200ml * 2), toluene is washed (200ml * 2), 50 ℃ of vacuum-drying 2h, obtain white powder solid 221.9g, yield: 86.0%, mp109.5-110.8 ℃.
3.1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone is synthetic
By sodium hydride (48.4g, 1.20mol), methylene dichloride (2900ml), add in 5000ml three-necked bottle, maintain the temperature at-0 ℃ of left and right, 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-0 ℃ of left and right, drip and finish, be transferred to room temperature, lucifuge reaction 2h, TLC detection reaction completeness, reaction is finished, first drip water 300ml, stir, with 5% dilute hydrochloric acid, adjust pH to 4～5, add again water 800ml, organic layer washing (1000ml * 4), saturated aqueous common salt (500ml) is washed, anhydrous sodium sulfate drying spends the night.Decompression (0.1MPa, 25 ℃) is steamed and is desolventized, and adds toluene (100ml) stirring at room 1h, filter, and toluene (40ml * 2) filter wash cake, 60 ℃ of vacuum-drying 4h, obtain white powder solid 123.4g, yield: 81%, mp103.5-104.0 ℃.
4.6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone synthetic
By 1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone (120.0g, 0.68mol), trifluoroacetic acid (1200ml) adds in reaction flask, 82 ℃ of back flow reaction 0.5 hour, TLC detection reaction completeness, reaction is finished, decompression (0.1MPa, 40 ℃) steam except trifluoroacetic acid, obtain reddish-brown thick liquid, be transferred under-10 ℃ of environment, under stirring, slowly add saturated potassium hydroxide solution, keeping temperature in reaction flask is 30 ℃, adjust PH to 9～10, adjust and finish, stirring at room 30min, suction filtration, washing (400ml * 2) filter cake.Ethanol 100ml with 25% stirs 1.5h at 50 ℃, and placement is spent the night, suction filtration, and 25% ethanol (40ml * 2) filter wash cake, 50 ℃ of vacuum-drying 5h, obtain yellow solid 54.6g, yield: 45.5%.mp111.2-112.8℃。
5.6-methoxyl group-4-carbonyl-2,3 dihydro-1 (4H)-quinoline ethyl acetate synthetic
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 ℃ of reaction 40h, TLC detection reaction completeness, reaction is finished, and reaction solution is slowly poured in the 500ml cold water under stirring, there are a large amount of yellow solids to separate out, then stirring at room 30min, washes (100ml * 2) filter cake, 50 ℃ of vacuum-drying 5h.By ethyl acetate: sherwood oil (1: 2) 100ml, at 50 ℃ of making beating 1.5h, placement is spent the night, suction filtration, with both mixed solvents (50ml * 2) filter wash cake, 60 ℃ of vacuum-drying 3h, obtain glassy yellow solid 64.8g, yield: 82.0%.
6.2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid synthetic
By 6-methoxyl group-4-carbonyl-2,3 dihydro-1 (4H)-quinoline ethyl acetate (63.8g, 0.24mol) is dissolved in 800ml ethanol at 40 ℃, after dissolving, slightly cold, to the sodium hydroxide solution 240ml that adds 15% in reaction solution, stirring at room 30min, TLC detection reaction completeness, reaction is finished, by 2,3-dichlorobenzaldehyde (54.6g, 0.31mol) add in reaction solution, room temperature reaction 8h, has 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 ℃, stir 20min, let cool to room temperature, suction filtration, acetone for filter cake (400ml * 2) is washed, after be scattered in 5000ml water, at 75 ℃, be heated to entirely molten, add 3g gac, stir after 30min, heat filter, filtrate adds 60ml acetone, acid adjustment to 3 at 40 ℃, there are a large amount of white solids to produce, stir 1h, let cool to room temperature, suction filtration, filter cake water (100ml * 2) is washed, at 80 ℃, vacuum-drying is to constant weight, use anhydrous methanol 600ml, at 40 ℃, stir 1.5h, placement is spent the night, suction filtration, anhydrous methanol (100ml * 2) filter wash cake, vacuum-drying 4h at 50 ℃, obtain white solid 78.1g, through ESI mass spectroscopy and this white solid product of nmr analysis, be target product 2-[6-methoxyl group-3-(2, 3-dichlorophenyl) methyl-4-oxo-1, 4-dihydro-1 (4H)-quinolyl] acetic acid.Its yield: 82.9%, mp222.4-224.3 ℃, purity 99.5%.
Embodiment 3
Synthesizing 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, stir anti-0.5 hour under 50 ℃ of reflux conditionss, reaction is finished, first normal pressure steams approximately 1/4 solvent, then decompression (0.3MPa) is steamed except residual solvent, obtains golden yellow oily liquids, lets cool standby.Yield: 100%.
Synthesizing 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, under mechanical stirring, drip the 3-bromo propionyl chloro (752.5g that upper step makes, toluene 4.39mol) (800ml) solution, drip and finish, stirring at room reaction 2.5 hours, TLC detection reaction completeness, reaction is finished, add water 1500ml and then with 10% hydrochloric acid, adjust pH to 4～5, suction filtration, filter cake washing (300ml * 2), toluene is washed (700ml * 2), 60 ℃ of vacuum-drying 4h, obtain white powder solid 665.9g, yield: 88.1%, mp109.1-110.6 ℃.
3.1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone is synthetic
By sodium hydride (148.5g, 3.71mol), methylene dichloride (2000ml), N, dinethylformamide (300ml), add in reaction flask, maintain the temperature at-3 ℃ of left and right, 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-3 ℃ of left and right, drip and finish, be transferred to room temperature, lucifuge reaction 3h, TLC detection reaction completeness, reaction is finished, first drip water 600ml, stir, with 5% dilute hydrochloric acid, adjust pH to 4～5, add again water 2000ml, organic layer washing (2000ml * 4), saturated aqueous common salt (1500ml) is washed, anhydrous sodium sulfate drying spends the night.Decompression (0.1MPa, 25 ℃) is steamed and is desolventized, and adds toluene (500ml) stirring at room 1h, filter, and toluene (200ml * 2) filter wash cake, 60 ℃ of vacuum-drying 4h, obtain white powder solid 337.1g, yield: 82.0%, mp103.1-103.9 ℃.
4.6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone synthetic
By 1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone (239.8g, 1.35mol), trifluoroacetic acid (240ml) adds in reaction flask, 72 ℃ of back flow reaction 4 hours, TLC detection reaction completeness, reaction is finished, decompression (0.1MPa, 45 ℃) steam except trifluoroacetic acid, obtain reddish-brown thick liquid, be transferred under 6 ℃ of environment, under stirring, slowly add saturated potassium hydroxide water liquid, keep 20 ℃ of the interior temperature of reaction flask, adjust PH to 9～10, adjust and finish, stirring at room 30min, suction filtration, washing (200ml * 2) filter cake.Ethanol 500ml with 25% stirs 1.5h at 60 ℃, and placement is spent the night, suction filtration, and 25% ethanol (100ml * 2) filter wash cake, 50 ℃ of vacuum-drying 5h, obtain yellow solid 103.1g, yield: 43.1%.mp111.8-112.7℃。
5.6-methoxyl group-4-carbonyl-2,3 dihydro-1 (4H)-quinoline ethyl acetate synthetic
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 ℃ of reaction 27h, TLC detection reaction completeness, reaction is finished, and reaction solution is slowly poured in the 1000ml cold water under stirring, there are a large amount of yellow solids to separate out, then stirring at room 30min, washes (300ml * 2) filter cake, 50 ℃ of vacuum-drying 3h.By ethyl acetate: sherwood oil (1: 2) 480ml, at 50 ℃ of making beating 2h, placement is spent the night, suction filtration, with both mixed solvents (150ml * 2) filter wash cake, 60 ℃ of vacuum-drying 6h, obtain glassy yellow solid 214.7g, yield: 78.4%.
6.2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid synthetic
By 6-methoxyl group-4-carbonyl-2,3 dihydro-1 (4H)-quinoline ethyl acetate (150.0g, 0.57mol) is dissolved in 1500ml ethanol at 40 ℃, after dissolving, slightly cold, to the sodium hydroxide solution 1500ml that adds 8% in reaction solution, stirring at room 30min, TLC detection reaction completeness, reaction is finished, by 2,3-dichlorobenzaldehyde (140.0g, 0.80mol) add in reaction solution, room temperature reaction 5h, has 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 ℃, stir 20min, let cool to room temperature, suction filtration, acetone for filter cake (500ml * 2) is washed, after be scattered in 2000ml water, at 75 ℃, be heated to entirely molten, add 1.5g gac, stir after 30min, heat filter, filtrate adds 150ml acetone, acid adjustment to 3 at 40 ℃, there are a large amount of white solids to produce, stir 1h, let cool to room temperature, suction filtration, filter cake water (100ml * 2) is washed, at 80 ℃, vacuum-drying is to constant weight, use anhydrous methanol 500ml, at 40 ℃, stir 1.5h, placement is spent the night, suction filtration, anhydrous methanol (80ml * 2) filter wash cake, vacuum-drying 5h at 60 ℃, obtain white solid 175.8g, through ESI mass spectroscopy and this white solid product of nmr analysis, be target product 2-[6-methoxyl group-3-(2, 3-dichlorophenyl) methyl-4-oxo-1, 4-dihydro-1 (4H)-quinolyl] acetic acid.Its yield: 80.0%, mp223.7-225.3 ℃, purity 99.9%.
The prepared 2-[6-methoxyl group-3-(2 of method being 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; 1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone of take is raw material; by Fu Ke-acylation reaction, obtain intermediate 6-methoxyl group-2; 3-dihydro-4 (1H)-quinolinone; this method has avoided use polyphosphoric acid (PPA) to make condensing agent; reduce the generation of sour water, and reduced the amount of removing polyphosphoric acid buck used, reduced the pollution to environment.Meanwhile, this reacts without pyroprocessing mild condition, is applicable to scale operation, can be 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 modification of doing, be equal to replacement, improvement etc., within all should being included in protection scope of the present invention.
Claims (9)
1.2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] synthetic method of acetic acid, it is characterized in that, comprise the following steps:
1) 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone synthetic:
1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone of take is raw material, add catalyzer to carry out, after Fu Ke-acylation reaction, steaming solvent, add saturated potassium hydroxide aqueous solution to neutralize, suction filtration obtains intermediate 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone;
2) 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid synthetic:
With intermediate 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone is raw material, through N-hydrocarbonylation, hydrolysis, synthetic described 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (the 4H)-quinolyl of condensation reaction] acetic acid;
Described catalyzer is one or more of trifluoroacetic acid, boron trifluoride ether solution, aluminum trichloride (anhydrous), tin tetrachloride, preferred trifluoroacetic acid.
2. synthetic method according to claim 1, is characterized in that, described step 1) in, synthetic intermediate 6-methoxyl group-2, the method for 3-dihydro-4 (1H)-quinolinone comprises:
1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone and trifluoroacetic acid are mixed in 1: 1～10 (m/v) ratio, back flow reaction 0.5～8 hour, after reaction terminating, at 40～50 ℃, Distillation recovery trifluoroacetic acid under-0.05～-0.1MPa, obtains intermediate product A;
Described intermediate product A is cooled to-10～-2 ℃, under agitation condition, drips saturated potassium hydroxide aqueous solution, keep temperature of reaction system not higher than 30 ℃, stop dripping described saturated potassium hydroxide aqueous solution at 9～10 o'clock to the PH of reaction system, obtain intermediate product B;
Described intermediate product B is at room temperature stirred to 20～50min, after suction filtration, obtain described intermediate product 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone, preferably further after suction filtration step to the ethanol that adds 15～30% in suction filtration thing, be warming up to 50～80 ℃, stir 1～3h, place 10～16h, again after suction filtration at 40～60 ℃ of vacuum-drying 2～5h, obtain described intermediate product 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone.
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 comprises:
Described sodium hydride is mixed in 1: 1～60 (m/v) ratio with described the first organic solvent, and temperature control-10～50 ℃, obtain mixed solution A;
By described N-(4-methoxyl group) phenyl-3-halogen propionic acid amide and described the first organic solvent under lucifuge condition in 1: 5～10 (m/v) ratio mixed dissolution, obtain mixing solutions B;
By described 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 described mixed solution A, keep the temperature of reaction system to be-10～0 ℃ in dropping process; After dropwising, gained mixing solutions is reacted to 1-6h-10～50 ℃ of lucifuges; After reaction terminating, in reaction system, add and the isopyknic water of the first organic solvent, stir, regulate behind reaction system pH to 3～6, the water to adding 1～2 times of amount of the first organic solvent in reaction system, stirs, and obtains mixed system A, standing, layering;
Get organic layer in described mixed system A, after cleaning-drying ,-0.05～0.1MPa, solvent is deviate from 20～30 ℃ of distillations, obtains intermediate product C;
In described intermediate product C, in 1: 5～10 (m/v) ratio, add toluene, stirring at room 0.5～3h, in 40～60 ℃ of vacuum-drying 0.5～3h, obtains described 1-(4-p-methoxy-phenyl) nitrogen heterocyclic din-2-ketone after filtration;
Described the first organic solvent is methylene dichloride, trichloromethane, N-Methyl pyrrolidone, N, one or more in dinethylformamide and dimethyl sulfoxide (DMSO), preferably, described the first organic solvent be methylene dichloride and DMF in 1～5: 1 (v: the mixed solvent that v) ratio is mixed.
4. synthetic method according to claim 3, is characterized in that, described step 1) in, the synthetic method of N-(4-methoxyl group) phenyl-3-halogen propionic acid amide comprises:
By in 4-anisidine, 3-halogen propionyl chloride, alkaline matter and the second organic solvent in 1: 1.5～3: 1～2: 2～8 (m: m: m: v) ratio is mixed, at-10～50 ℃, reaction times is 0.5～6h, after reaction terminating, to in reaction system in 4-anisidine: water=1: 2～10 (m/v) ratio adds water and stirs, 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;
One or more that described the second organic solvent is benzene,toluene,xylene;
Described alkaline matter is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, saleratus, salt of wormwood, triethylamine.
5. synthetic method according to claim 4, is characterized in that, the described step that 4-anisidine, 3-halogen propionyl chloride, alkaline matter and the second organic solvent are mixed comprises:
Described 4-anisidine and described alkaline matter are dissolved in described the second solvent of part, obtain mixed solution C;
3-bromo propionyl chloro is dissolved in described the second solvent of part, obtains mixing solutions D;
Described mixing solutions D is dropped in described mixed solution C, in dropping process, keep the temperature of reaction system not higher than 50 ℃; After dropwising, gained mixing solutions, at-10～50 ℃, is reacted to 0.5～6h.
6. synthetic method according to claim 5, is characterized in that, the synthetic method of described 3-halogen propionyl chloride comprises:
With N, dinethylformamide is catalyzer, by three halogen propionic acid, sulfur oxychloride, the 3rd organic solvent, N, dinethylformamide is by 1: 1～5: 3～8: 0.002～0.1 (m: m: v: v) mix, at 20～50 ℃, back flow reaction 10min～6h, after reaction terminating, unnecessary solvent in reaction system is discharged in distillation, obtains described 3-halogen propionyl chloride;
Described the 3rd organic solvent is methylene dichloride and/or trichloromethane.
7. synthetic method according to claim 4, is characterized in that, the step that unnecessary solvent in reaction system is discharged in distillation comprises:
Unnecessary solvent in the described reaction system of air distillation discharge 1/4～2/3;
Unnecessary solvent in remaining described reaction system will be discharged after Pressure Drop to 0.05～0.3MPa.
8. synthetic method according to claim 1, is characterized in that, described step 2) in, with intermediate 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone is that the step that raw material carries out N-hydrocarbonylation processing comprises:
By described intermediate 6-methoxyl group-2,3-dihydro-4 (1H)-quinolinone, ethyl bromoacetate, acid binding agent and the 4th organic solvent are in 1: 1～5: 1～5: 3～10 (m: m: m: v) ratio is mixed, and react 2h～40h at 50～100 ℃, after reaction terminating, decompression steams 1/4～2/3 solvent, obtains mixed system C;
Described mixed system C is poured under the condition stirring in the cold water of 0～5 ℃, under 0～30 ℃ of condition, stir solid is separated out, by solid precipitate, through washing, 40～60 ℃ of vacuum-drying 2～5h, obtain intermediate product D; Intermediate product D is mixed according to 1: 5～20 (m/v) ratio with mixed solvent E, and 1～3h, static 10～16h are processed in 40～60 ℃ of making beating, after suction filtration, clean, 40～60 ℃ of vacuum-drying 0.5～3h, obtain 6-methoxyl group-4-carbonyl-2,3 dihydro-1 (4H)-quinoline ethyl acetate
Described the 4th organic solvent is one or more in DMF, methyl alcohol, ethanol, methylene dichloride, tetrahydrofuran (THF), acetonitrile;
Described mixed solvent E is the mixing solutions that ethyl acetate and sherwood oil volume ratio are 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.
9. synthetic method according to claim 8, it is characterized in that, with intermediate 6-methoxyl group-4-carbonyl-2,3 dihydro-1 (4H)-quinoline ethyl acetate is raw material, through hydrolysis, condensation, obtain 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] step of acetic acid comprises:
By 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;
To in described mixing solutions F according to 6-methoxyl group-4-carbonyl-2, 3 dihydro-1 (4H)-quinoline ethyl acetate ratio is that 1: 2～10 (m/v) ratio adds 5～15% aqueous sodium hydroxide solution, 20～30 ℃ are stirred hydrolysis 10min～1h, after reaction terminating, according to 6-methoxyl group-4-carbonyl-2, 3 dihydro-1 (4H)-quinoline ethyl acetate ratio is that 1: 1～3 (m/v) ratio adds 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=1: 0.5～4 (m: m) add sodium-chlor, be warming up to 35～60 ℃, stir 15～30min, after cooling suction filtration, in suction filtration gains 1: 5～15 (m/v) ratio, be scattered in water, heating is entirely molten at lower than 75 ℃, press 6-methoxyl group-4-carbonyl-2, 3 dihydro-1 (4H)-quinoline ethyl acetate: gac=1: 0.01～0.1 (m/m) adds gac, stir 15～45min, filtration obtains filtrate,
In described filtrate, add acetone, and regulate pH value to 2.8～3.2 of reaction system at lower than 40 ℃, stir 30～90min, cooling suction filtration, at 60～90 ℃, vacuum-drying is to constant weight, in solid product, in 1: 3～50 (m/v) ratio, add anhydrous methanol, at 30～50 ℃, stir 1～2h, static 10～16h, vacuum-drying 1～3h at 40～60 ℃ after suction filtration, obtains 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-1,4-dihydro-1 (4H)-quinolyl] acetic acid
Described the 5th organic solvent is one or more in methyl alcohol, ethanol, Virahol, acetone and tetrahydrofuran (THF).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410001737.5A CN103739547B (en) | 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 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410001737.5A CN103739547B (en) | 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 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103739547A true CN103739547A (en) | 2014-04-23 |
| CN103739547B CN103739547B (en) | 2015-09-02 |
Family
ID=50496635
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410001737.5A Active CN103739547B (en) | 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 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103739547B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113372268A (en) * | 2021-07-06 | 2021-09-10 | 宁夏康亚药业股份有限公司 | 4-oxo-6-methoxy-3- (2, 3-dichlorophenyl) methyl-1 (4H) quinolineacetic acid metabolites |
| CN116273169A (en) * | 2021-12-20 | 2023-06-23 | 安庆莱霆光电科技有限公司 | Supported catalyst and preparation method thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0464823A1 (en) * | 1990-07-06 | 1992-01-08 | Kyorin Pharmaceutical Co., Ltd. | (6,7-Substituted-8-alkoxy-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid-O3,O4)bis(acyloxy-O)borates and the salts thereof, and methods for their manufacture |
| WO2002079198A1 (en) * | 2001-03-30 | 2002-10-10 | Pfizer Products Inc. | Pyridazinone aldose reductase inhibitors |
| WO2005035520A1 (en) * | 2003-10-03 | 2005-04-21 | Portola Pharmaceuticals, Inc. | Substituted isoquinolinones |
| CN101058558A (en) * | 2007-05-28 | 2007-10-24 | 沈阳药科大学 | 4-Oxy-1(4H)-quinoline carboxylic acids compound and composition with aldose reductase inhibition activity and preparation method thereof |
| CN101443327A (en) * | 2004-11-24 | 2009-05-27 | 艾博特公司 | Chromanylurea compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor and uses thereof |
| CN101497589A (en) * | 2009-02-26 | 2009-08-05 | 沈阳药科大学 | Method for synthesizing 2-(3-cyano-4- isobutoxy phenyl)-4-methyl-carboxylate |
-
2014
- 2014-01-03 CN CN201410001737.5A patent/CN103739547B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0464823A1 (en) * | 1990-07-06 | 1992-01-08 | Kyorin Pharmaceutical Co., Ltd. | (6,7-Substituted-8-alkoxy-1-cyclopropyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid-O3,O4)bis(acyloxy-O)borates and the salts thereof, and methods for their manufacture |
| WO2002079198A1 (en) * | 2001-03-30 | 2002-10-10 | Pfizer Products Inc. | Pyridazinone aldose reductase inhibitors |
| WO2005035520A1 (en) * | 2003-10-03 | 2005-04-21 | Portola Pharmaceuticals, Inc. | Substituted isoquinolinones |
| CN101443327A (en) * | 2004-11-24 | 2009-05-27 | 艾博特公司 | Chromanylurea compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor and uses thereof |
| CN101058558A (en) * | 2007-05-28 | 2007-10-24 | 沈阳药科大学 | 4-Oxy-1(4H)-quinoline carboxylic acids compound and composition with aldose reductase inhibition activity and preparation method thereof |
| CN101497589A (en) * | 2009-02-26 | 2009-08-05 | 沈阳药科大学 | Method for synthesizing 2-(3-cyano-4- isobutoxy phenyl)-4-methyl-carboxylate |
Non-Patent Citations (3)
| Title |
|---|
| DONA CHIANELLI等: "Application of a Novel Design Paradigm to Generate General Nonpeptide Combinatorial Scaffolds Mimicking Beta Turns: Synthesis of Ligands for Somatostatin Receptors", 《BIOORGANIC & MEDICINAL CHEMISTRY》, vol. 11, 31 December 2003 (2003-12-31) * |
| ROBERT G. SCHMIDT等: "Chroman and tetrahydroquinoline ureas as potent TRPV1 antagonists", 《BIOORGANIC & MEDINCINAL CHEMISTRY LETTERS》, vol. 21, 21 January 2011 (2011-01-21), pages 1340 - 4 * |
| 王绍杰等: "甲基喹啉酮乙酸类化合物的合成及其醛糖还原酶抑制活性", 《中国药物化学杂志》, vol. 19, no. 1, 28 February 2007 (2007-02-28), pages 7 - 14 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113372268A (en) * | 2021-07-06 | 2021-09-10 | 宁夏康亚药业股份有限公司 | 4-oxo-6-methoxy-3- (2, 3-dichlorophenyl) methyl-1 (4H) quinolineacetic acid metabolites |
| CN113372268B (en) * | 2021-07-06 | 2023-10-17 | 宁夏康亚药业股份有限公司 | 4-oxo-6-methoxy-3- (2, 3-dichlorophenyl) methyl-1 (4H) quinolineacetic acid metabolites |
| CN116273169A (en) * | 2021-12-20 | 2023-06-23 | 安庆莱霆光电科技有限公司 | Supported catalyst and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103739547B (en) | 2015-09-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103058993B (en) | Chlorantraniliprole preparation method | |
| CN102010405B (en) | 4-(benzofuran-5-yl)-2-benzal aminothiazole and application of 4-(benzofuran-5-base)-2-benzal aminothiazole as antineoplastic agent | |
| CN103936694A (en) | Preparation method of antidepressant vortioxetine | |
| CN101245065B (en) | Method for producing benzo isoxazole derivative and its intermediate | |
| CN112321602A (en) | Preparation method of Ruogeli drug intermediate | |
| CN106699570A (en) | Synthesis method for (2-chloro-5-iodophenyl)(4-fluorophenyl)ketone | |
| CN1321121C (en) | Preparation and post-treatment method of levofloxacin | |
| CN103739547B (en) | The synthetic method of 2-[6-methoxyl group-3-(2,3-dichlorophenyl) methyl-4-oxo-Isosorbide-5-Nitrae-dihydro-1 (4H)-quinolyl] acetic acid | |
| CN104650093B (en) | Synthesis method of sildenafil analog | |
| CN103896858B (en) | The preparation technology of cytosine | |
| CN104072426B (en) | A kind of preparation method of cancer therapy drug | |
| CN105037236A (en) | Ribociclib intermediate and preparation method thereof | |
| CN108840868B (en) | The preparation method and application of trypoline ketone compounds with anti-tumor activity | |
| CN106905234B (en) | A method of the synthesis chloro- 6- amino -7- ethoxyquinoline of linatinib intermediate 3- cyano -4- | |
| CN105461640A (en) | Preparation method of tyrosine kinase inhibitor | |
| CN111393423A (en) | Epipiprazole impurity compound and preparation method thereof | |
| CN110078718A (en) | A kind of preparation method of Afatinib degradation cyclisation impurity | |
| CN102911125B (en) | A kind of preparation method of Gefitinib intermediate | |
| CN107698501A (en) | The preparation technology of the hydroxy niacin of 5,6 dimethyl 2 | |
| CN107155325B (en) | Novel amino-phenyl-sulfonyl-acetic ester derivative and application thereof | |
| CN108409648B (en) | Preparation method of sorafenib tosylate related intermediate | |
| CN103204810B (en) | A kind of tolvaptan intermediate and preparation method thereof | |
| CN1603324A (en) | Leavo halogenated salt and its preparation process and use | |
| CN104098521A (en) | Preparation method for diclazuril and isotope interior label D4-diclazuril | |
| CN104513231A (en) | Synthetic method for lapatinib and lapatinib intermediates |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 110016 Shenhe province Shenyang District Cultural Road, No. 103, No. Co-patentee after: Ningxia Kang Ya pharmaceutical Limited by Share Ltd Patentee after: Shenyang Pharmaceutical University Address before: 110016 Shenhe province Shenyang District Cultural Road, No. 103, No. Co-patentee before: Kangya Pharmaceutical Industry Co., Ltd., Ningxia Patentee before: Shenyang Pharmaceutical University |