CN115583935A - Preparation method of 4- (2, 4, 5-trifluorophenyl) -3-oxybutyrate ester - Google Patents
Preparation method of 4- (2, 4, 5-trifluorophenyl) -3-oxybutyrate ester Download PDFInfo
- Publication number
- CN115583935A CN115583935A CN202211366721.5A CN202211366721A CN115583935A CN 115583935 A CN115583935 A CN 115583935A CN 202211366721 A CN202211366721 A CN 202211366721A CN 115583935 A CN115583935 A CN 115583935A
- Authority
- CN
- China
- Prior art keywords
- trifluorophenyl
- hydroxy
- dioxane
- dimethyl
- ethylene
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/03—Preparation of carboxylic acid esters by reacting an ester group with a hydroxy group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
- C07C67/32—Decarboxylation
Abstract
The invention provides a preparation method of 4- (2, 4, 5-trifluorophenyl) -3-oxybutyrate, which specifically comprises the following steps: (1) Dissolving 2,4, 5-trifluoro-phenylacetic acid in a solvent, and then forming 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluoro-phenyl) ethylene ] -1, 3-dioxane-4, 6-diketone by condensation reaction under the action of cyclopropyl (isopropylidene) malonate, a condensing agent and an organic base; (2) 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylidene ] -1, 3-dioxane-4, 6-dione is subjected to reflux decarboxylation in alcohol and esterification to generate 4- (2, 4, 5-trifluorophenyl) -3-oxybutyrate. Wherein the yield of the step (1) can reach 98.2 percent at most. The method does not use pivaloyl chloride and an acid-binding agent which can generate more three wastes, and has the advantages of mild reaction condition, simple operation, suitability for industrial production and the like.
Description
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a preparation method of 4- (2, 4, 5-trifluorophenyl) -3-oxybutyrate.
Background
Sitagliptin phosphate was developed by merck corporation as a drug for the treatment of type two diabetes. The sitagliptin which is taken as the first DPP-4 target point is fully approved in global clinical guidelines by the remarkable characteristics of low incidence rate of hypoglycemia, oral administration, capability of reducing postprandial blood sugar, capability of reducing fasting blood sugar and the like. Sitagliptin phosphate, english name: chemical name of Sitagliptin phosphate monohydrate: the structural formula of monohydrate of 7- [ (3R) -3-amino-1-oxo-4- (2, 4, 5-trifluorophenyl) butyl ] -5,6,7, 8-tetrahydro-3- (trifluoromethyl) -1,2, 4-triazolone [4,3-a ] pyrazine phosphate (1) is shown in formula (1):
the preparation method of intermediate 4- (2, 4, 5-trifluorophenyl) -3-oxybutyrate of sitagliptin phosphate disclosed at home and abroad mainly uses 2,4, 5-trifluorophenylacetic acid and isopropylidene malonate as raw materials, and synthesizes 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylidene ] -1, 3-dioxane-4, 6-diketone with pivaloyl chloride under the action of triethylamine or N, N-diisopropylethylamine; then decarboxylation and esterification are carried out under the action of nucleophilic reagent methanol to generate 4- (2, 4, 5-trifluorophenyl) -3-oxybutyrate. Such as chinese patents CN113666904 and CN108586346; although the method has high reaction yield, because carboxylic acid has weak electrophilicity and can not directly react with the cyclopropyl (ylidene) malonate, pivaloyl chloride is required to be added to prepare acid anhydride to increase the electrophilicity, and the pivaloyl chloride reacts with the carboxylic acid to generate a large amount of hydrochloric acid to inhibit the condensation reaction of the hydrochloric acid with the cyclopropyl (ylidene) malonate, so that an excessive acid-binding agent is required to be added to move the reaction forward, and the defects of more three wastes, poor atom economy and the like are caused. And the best yield for the preparation of 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione 3 by this method was 95%.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a preparation method of 4- (2, 4, 5-trifluorophenyl) -3-oxybutyrate, which avoids the use of pivaloyl chloride and an acid-binding agent, has the advantages of mild reaction conditions, less three wastes, simple operation, high yield and the like, and is suitable for industrial production.
The technical scheme adopted by the invention for solving the technical problem is as follows: a method for preparing 4- (2, 4, 5-trifluorophenyl) -3-oxybutyrate ester comprises the following steps:
(1) Dissolving 2,4, 5-trifluorophenylacetic acid shown in formula 2 in a solvent, adding isopropylidene malonate, and carrying out condensation reaction under the action of a condensing agent and an organic base to generate 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylidene ] -1, 3-dioxane-4, 6-diketone shown in formula 3;
(2) Refluxing the 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylidene ] -1, 3-dioxane-4, 6-dione obtained in the step (1) in alcohol ROH for decarboxylation and esterification reactions to generate 4- (2, 4, 5-trifluorophenyl) -3-oxybutyrate shown in a formula 4;
the reaction process is as follows:
wherein ROH is the same as R in the formula 4, and R is selected from C 1-6 Alkyl group of (1).
Furthermore, the invention also defines that the condensing agent in the step (1) is one or more of dicyclohexylcarbodiimide, diisopropylcarbodiimide and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, and the feeding molar ratio of the 2,4, 5-trifluorophenylacetic acid to the condensing agent is 1-1.5.
Furthermore, the invention also limits that the organic base in the step (1) is one or two of 4-dimethylamino pyridine and 1-hydroxy benzotriazole, and the feeding molar ratio of the 2,4, 5-trifluoro-phenylacetic acid to the organic base is 1-1.5.
Furthermore, the invention also defines the feeding molar ratio of the 2,4, 5-trifluorophenylacetic acid to the isopropylidene cyclopropane dicarboxylate in the step (1) to be 1.
Further, the invention also limits that the solvent in the step (1) is acetonitrile or dichloromethane, and the mass ratio of the volume of the solvent to the 2,4, 5-trifluoro-phenylacetic acid is 50-70:1, volume unit is mL, and mass unit is g.
Furthermore, the invention also limits the temperature of the condensation reaction in the step (1) to be 0-60 ℃ and the reaction time to be 0.5-3h.
Further, the invention also defines that the alcohol ROH in the step (2) is one of methanol, ethanol and isopropanol.
Further, the invention also limits the reaction temperature in the step (2) to be 50-80 ℃; the reaction time is 2-4 hours.
Further, the present invention also defines that the ratio of the mass of 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione to the alcohol ROH in step (2) is 1.
Compared with the prior art, the invention has the beneficial effects that:
(1) The yield is high: the highest yield of 95 percent is reported in the literature of a method for preparing 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylidene ] -1, 3-dioxane-4, 6-diketone 3 by increasing the electrophilicity of carboxylic acid by using pivaloyl chloride, and the yield of the method is as high as 98 percent;
(2) The dosage of the reagent is less: in the method for increasing the electrophilicity of carboxylic acid by using pivaloyl chloride, as hydrochloric acid generated in the reaction process of pivaloyl chloride and carboxylic acid under the action of an acylation catalyst can inhibit the reaction, a large amount of acid-binding agent needs to be added, and the atom economy is poor; the process described herein requires the addition of only a dehydrating reagent and an organic base.
Detailed Description
The invention is further described below, but the technical parameters involved in the scheme should not be construed as limiting the invention.
Example 1: preparation of 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione
1.9g of 2,4, 5-trifluorophenylacetic acid (0.1 mol), 1.44g of cyclo (ylidene) malonate, and 1.22g of 4-dimethylaminopyridine (0.1 mol) were dissolved in 40mL of dichloromethane and placed in a 100mL three-necked round-bottomed flask at 10 ℃; 2.06g of dicyclohexylcarbodiimide (0.1 mol) was dissolved in 10mL of dichloromethane and added to a constant pressure dropping funnel, the temperature was maintained at 10 ℃ and the dropwise addition of the dicyclohexylcarbodiimide solution was started slowly, after completion of the dropwise addition for 20 minutes and stirring was continued for 1 hour, the precipitate was removed, the pH of the reaction solution was adjusted to 11-12, the reaction solution of the organic layer was separated and cooled to 0-5 ℃, and the precipitated product was filtered, acid-washed and dried under reduced pressure at 45-50 ℃ to give 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione in a yield of 96.8%.
Example 2: preparation of 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione
1.9g2,4, 5-Trifluorophenylacetic acid (0.1 mol), 1.7g of Cycloisopropylidene malonate (0.12 mol), and 1.22g4-dimethylaminopyridine (0.1 mol) were dissolved in 40mL of dichloromethane and placed in a 100mL three-necked round bottom flask at 10 ℃. 2.06g dicyclohexylcarbodiimide (0.1 mol) was dissolved in 10mL dichloromethane and added to a constant pressure dropping funnel, the temperature was maintained at 10 ℃ and slow dropwise addition of the dicyclohexylcarbodiimide solution was started, and after completion of the addition for 20 minutes, stirring was continued for 1 hour. Removing the precipitate, washing with water, adjusting pH of the reaction solution to 11-12, separating the organic layer reaction solution, cooling to 0-5 deg.C, filtering the precipitated product, washing with acid, and drying at 45-50 deg.C under reduced pressure to obtain 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione, with a yield of 97.2%.
Example 3: preparation of 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione
1.9g2,4, 5-Trifluorophenylacetic acid (0.1 mol), 1.87g Cyclo (ylidene) malonate (0.13 mol), and 1.22g 4-dimethylaminopyridine (0.1 mol) were dissolved in 40mL of dichloromethane and placed in a 100mL three-necked round-bottomed flask, maintained at 10 ℃. 2.06g of dicyclohexylcarbodiimide (0.1 mol) was dissolved in 10mL of dichloromethane and added to a constant pressure dropping funnel, the temperature was maintained at 10 ℃ and the slow dropwise addition of the dicyclohexylcarbodiimide solution was started, and after completion of the dropwise addition for 20 minutes, stirring was continued for 1 hour. Removing the precipitate, washing with water, adjusting pH of the reaction solution to 11-12, separating the organic layer reaction solution, cooling to 0-5 deg.C, filtering the precipitated product, acidifying, washing, and drying at 45-50 deg.C under reduced pressure to obtain 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylidene ] -1, 3-dioxane-4, 6-dione, with a yield of 94.4%.
Example 4: preparation of 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione
1.9g2,4, 5-Trifluorophenylacetic acid (0.1 mol), 1.7g of cyclo (methylene) propylmalonate (0.12 mol), and 1.46g4-dimethylaminopyridine (0.12 mol) were dissolved in 40mL of dichloromethane and placed in a 100mL three-necked round-bottomed flask, maintained at 10 ℃. 2.06g of dicyclohexylcarbodiimide (0.1 mol) was dissolved in 10mL of dichloromethane and added to a constant pressure dropping funnel, the temperature was maintained at 10 ℃ and the slow dropwise addition of the dicyclohexylcarbodiimide solution was started, and after completion of the dropwise addition for 20 minutes, stirring was continued for 1 hour. Removing the precipitate, washing with water, adjusting pH of the reaction solution to 11-12, separating the organic layer reaction solution, cooling to 0-5 deg.C, filtering the precipitated product, washing by acidification, and drying at 45-50 deg.C under reduced pressure to obtain 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione, with a yield of 97.7%.
Example 5: preparation of 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione
1.9g2,4, 5-Trifluorophenylacetic acid (0.1 mol), 1.7g of cyclo (methylene) propylmalonate (0.12 mol), and 1.46g4-dimethylaminopyridine (0.12 mol) were dissolved in 40mL of dichloromethane and placed in a 100mL three-necked round-bottomed flask, maintained at 10 ℃. 2.47g of dicyclohexylcarbodiimide (0.12 mol) was dissolved in 10mL of dichloromethane and added to a constant pressure dropping funnel, the temperature was maintained at 10 ℃, and slow dropwise addition of the dicyclohexylcarbodiimide solution was started, and after completion of the dropwise addition for 20 minutes, stirring was continued for 1 hour. Removing the precipitate, washing with water, adjusting pH of the reaction solution to 11-12, separating the organic layer reaction solution, cooling to 0-5 deg.C, filtering the precipitated product, washing by acidification, and drying under reduced pressure at 45-50 deg.C to obtain 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione with a yield of 97.5%.
Example 6: preparation of 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione
1.9g2,4, 5-Trifluoroacetoacetic acid (0.1 mol), 2.2g of Cycloisopropylidene malonate (0.15 mol), and 1.8g4-dimethylaminopyridine (0.15 mol) were dissolved in 40mL of dichloromethane and placed in a 100mL three-necked round-bottomed flask at 10 ℃. 3.1g dicyclohexylcarbodiimide (0.15 mol) was dissolved in 10mL of dichloromethane and added to a constant pressure dropping funnel, the temperature was maintained at 10 ℃ and slow dropwise addition of the dicyclohexylcarbodiimide solution was started, and after completion of the addition for 20 minutes, stirring was continued for 1 hour. Removing the precipitate, washing with water, adjusting pH of the reaction solution to 11-12, separating the organic layer reaction solution, cooling to 0-5 deg.C, filtering the precipitated product, washing by acidification, and drying under reduced pressure at 45-50 deg.C to obtain 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione with a yield of 98.4%.
Example 7: preparation of 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione
1.9g2,4, 5-Trifluorophenylacetic acid (0.1 mol), 2.2g of cyclo (methylene) malonate (0.15 mol) and 2.03g 1-hydroxy benzotriazole (0.15 mol) were dissolved in 40mL of dichloromethane and placed in a 100mL three-necked round bottom flask at 10 ℃. 1.89g of diisopropylcarbodiimide (0.15 mol) was dissolved in 10mL of dichloromethane and added to a constant pressure dropping funnel, the temperature was maintained at 10 ℃ and the slow dropwise addition of dicyclohexylcarbodiimide solution was started, and after completion of the dropwise addition for 20 minutes, stirring was continued for 1 hour. Removing the precipitate, washing with water, adjusting the pH of the reaction solution to 11-12, separating the organic layer reaction solution, cooling to 0-5 deg.C, filtering the precipitated product, washing by acidification and drying at 45-50 deg.C under reduced pressure to obtain 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione, with a yield of 95.4%.
Example 8: preparation of 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione
1.9g2,4, 5-trifluorophenylacetic acid (0.1 mol), 2.1g of cyclo (methylene) malonate (0.15 mol) and 2.03g1-hydroxy benzotriazole (0.15 mol) were dissolved in 40mL of dichloromethane and placed in a 100mL three-necked round bottom flask at 10 ℃. 2.88g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (0.15 mol) was dissolved in 10mL of dichloromethane and added to a constant pressure dropping funnel, the temperature was maintained at 10 ℃, and the slow dropwise addition of the dicyclohexylcarbodiimide solution was started, and after completion of the addition for 20 minutes, stirring was continued for 1 hour. Removing the precipitate, washing with water, adjusting pH of the reaction solution to 11-12, separating the organic layer reaction solution, cooling to 0-5 deg.C, filtering the precipitated product, washing by acidification, and drying under reduced pressure at 45-50 deg.C to obtain 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione with a yield of 94.7%.
Example 9: preparation of 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione
1.9g2,4, 5-Trifluorophenylacetic acid (0.1 mol), 2.1g Cycloisopropylidene malonate (0.15 mol), and 1.8g 4-dimethylaminopyridine (0.15 mol) were dissolved in 40mL acetonitrile and placed in a 100mL three-necked round bottom flask at 10 ℃. 3.1g dicyclohexylcarbodiimide (0.15 mol) was dissolved in 10mL acetonitrile and added to a constant pressure dropping funnel, the temperature was maintained at 10 ℃ and slow dropwise addition of the dicyclohexylcarbodiimide solution was started, and after completion of the dropwise addition for 20 minutes, stirring was continued for 1h. Removing the precipitate, washing with water, adjusting pH of the reaction solution to 11-12, separating the organic layer reaction solution, cooling to 0-5 deg.C, filtering the precipitated product, washing by acidification, and drying under reduced pressure at 45-50 deg.C to obtain 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione with a yield of 98.2%.
Example 10: preparation of methyl 4- (2, 4, 5-trifluorophenyl) -3-oxobutanoate
2g of 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione were dissolved in 30mL of methanol solution and reacted with stirring at 65 ℃ for 2 hours. Concentrating the reaction solution, and then distilling under reduced pressure to obtain a light yellow residue, namely a crude product of 4- (2, 4, 5-trifluorophenyl) -3-oxobutyric acid methyl ester, adjusting the pH of the light yellow residue to 7-8 by using a 5% sodium carbonate solution, dissolving the light yellow residue by using dichloromethane after adjusting the pH, adding water for further washing until only a product point is observed on a plate as an organic layer, combining dichloromethane organic layers, and distilling the dichloromethane under reduced pressure to obtain the 4- (2, 4, 5-trifluorophenyl) -3-oxobutyric acid methyl ester, wherein the yield is 95.6%.
Example 11: preparation of methyl 4- (2, 4, 5-trifluorophenyl) -3-oxobutanoate
2g of 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione were dissolved in 30mL of methanol solution and reacted with stirring at 50 ℃ for 4 hours. Concentrating the reaction solution, and then distilling under reduced pressure to obtain a light yellow residue, namely a crude product of 4- (2, 4, 5-trifluorophenyl) -3-oxobutyric acid methyl ester, adjusting the pH of the light yellow residue to 7-8 by using a 5% sodium carbonate solution, dissolving the light yellow residue by using dichloromethane after adjusting the pH, adding water for further washing until only a product point is observed on a plate as an organic layer, combining dichloromethane organic layers, and distilling the dichloromethane under reduced pressure to obtain the 4- (2, 4, 5-trifluorophenyl) -3-oxobutyric acid methyl ester, wherein the yield is 92.5%.
Example 12: preparation of methyl 4- (2, 4, 5-trifluorophenyl) -3-oxobutanoate
2g of 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione were dissolved in 40m methanol solution and reacted with stirring at 65 ℃ for 2h. Concentrating the reaction solution, and distilling under reduced pressure to obtain a light yellow crude product of methyl 4- (2, 4, 5-trifluorophenyl) -3-oxobutyrate. The pale yellow residue was further treated with 5% sodium carbonate solution to adjust the pH to 7-8. After adjusting the pH, the light yellow residue was dissolved with dichloromethane and the combined dichloromethane organic layers were further washed with water. Methylene chloride was distilled under reduced pressure to give methyl 4- (2, 4, 5-trifluorophenyl) -3-oxobutanoate in a yield of 96.2%.
Example 13: preparation of ethyl 4- (2, 4, 5-trifluorophenyl) -3-oxobutanoate
2g2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione were dissolved in 40mL ethanol solution and reacted with stirring at 65 ℃ for 2h. Concentrating the reaction solution, and distilling under reduced pressure to obtain a light yellow crude product of ethyl 4- (2, 4, 5-trifluorophenyl) -3-oxobutyrate. The pale yellow residue was further treated with 5% sodium carbonate solution to adjust the pH to 7-8. After adjusting the pH, the light yellow residue was dissolved with dichloromethane and the combined dichloromethane organic layers were further washed with water. Methylene chloride was distilled under reduced pressure to give ethyl 4- (2, 4, 5-trifluorophenyl) -3-oxobutanoate in a yield of 95.2%.
Example 14: preparation of isopropyl 4- (2, 4, 5-trifluorophenyl) -3-oxobutyrate
2g2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione was dissolved in 40mL isopropanol solution and reacted with stirring at 80 ℃ for 2h. Concentrating the reaction solution, and distilling under reduced pressure to obtain a light yellow crude product of isopropyl 4- (2, 4, 5-trifluorophenyl) -3-oxybutyrate. The pale yellow residue was further treated with 5% sodium carbonate solution to adjust the pH to 7-8. After adjusting the pH, the light yellow residue was dissolved with dichloromethane and the dichloromethane organic layer was further washed and combined with water. Methylene chloride was distilled under reduced pressure to give isopropyl 4- (2, 4, 5-trifluorophenyl) -3-oxobutyrate in a yield of 94.8%.
Claims (9)
1. A method for preparing 4- (2, 4, 5-trifluorophenyl) -3-oxybutyrate ester, characterized by comprising the steps of:
(1) Dissolving 2,4, 5-trifluorophenylacetic acid shown in formula 2 in a solvent, adding isopropylidene malonate, and carrying out condensation reaction under the action of a condensing agent and an organic base to generate 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-diketone shown in formula 3;
(2) Refluxing the 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylidene ] -1, 3-dioxane-4, 6-diketone obtained in the step (1) in an alcohol ROH for decarboxylation and esterification to generate a 4- (2, 4, 5-trifluorophenyl) -3-oxybutyrate shown in a formula 4;
the reaction process is as follows:
wherein ROH is the same as R in formula 4, and R is selected from C 1-6 Alkyl group of (1).
2. The method for preparing 4- (2, 4, 5-trifluorophenyl) -3-oxobutanoate according to claim 1, characterized in that the condensing agent in step (1) is one or more of dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, and the molar ratio of the 2,4, 5-trifluorophenylacetic acid to the condensing agent is 1-1.5.
3. The method for preparing 4- (2, 4, 5-trifluorophenyl) -3-oxobutyrate according to claim 1, characterized in that the organic base in the step (1) is one or two of 4-dimethylaminopyridine and 1-hydroxy benzotriazole, and the feeding molar ratio of the 2,4, 5-trifluorophenylacetic acid to the organic base is 1.
4. The process for preparing 4- (2, 4, 5-trifluorophenyl) -3-oxobutanoate according to claim 1, characterized in that the feeding molar ratio of 2,4, 5-trifluorophenylacetic acid and cyclopropane-cyclo (isopropylidene) malonate in step (1) is 1.
5. The method for preparing 4- (2, 4, 5-trifluorophenyl) -3-oxobutanoate according to claim 1, characterized in that the solvent in step (1) is acetonitrile or dichloromethane, the mass ratio of the volume of the solvent to 2,4, 5-trifluorophenylacetic acid is 50-70:1, volume unit is mL, and mass unit is g.
6. The process for producing 4- (2, 4, 5-trifluorophenyl) -3-oxobutanoate according to claim 1, characterized in that the temperature of the condensation reaction in step (1) is 0-60 ℃ and the reaction time is 0.5-3h.
7. The method for producing 4- (2, 4, 5-trifluorophenyl) -3-oxobutanoate according to claim 1, characterized in that the alcohol ROH in step (2) is one of methanol, ethanol, isopropanol.
8. The method for producing 4- (2, 4, 5-trifluorophenyl) -3-oxobutanoate according to claim 1, characterized in that the reaction temperature in step (2) is 50-80 ℃; the reaction time is 2-4 hours.
9. The process for producing 4- (2, 4, 5-trifluorophenyl) -3-oxobutanoate according to claim 1, characterized in that the volume ratio of the mass of 2, 2-dimethyl-5- [ 1-hydroxy-2- (2, 4, 5-trifluorophenyl) ethylene ] -1, 3-dioxane-4, 6-dione to the alcohol ROH in step (2) is 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211366721.5A CN115583935A (en) | 2022-11-03 | 2022-11-03 | Preparation method of 4- (2, 4, 5-trifluorophenyl) -3-oxybutyrate ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211366721.5A CN115583935A (en) | 2022-11-03 | 2022-11-03 | Preparation method of 4- (2, 4, 5-trifluorophenyl) -3-oxybutyrate ester |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115583935A true CN115583935A (en) | 2023-01-10 |
Family
ID=84782660
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211366721.5A Pending CN115583935A (en) | 2022-11-03 | 2022-11-03 | Preparation method of 4- (2, 4, 5-trifluorophenyl) -3-oxybutyrate ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115583935A (en) |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101417999A (en) * | 2007-10-25 | 2009-04-29 | 上海恒瑞医药有限公司 | Piperazines derivates, preparation method thereof and application thereof in medicine |
| CN101468988A (en) * | 2007-12-26 | 2009-07-01 | 上海恒瑞医药有限公司 | Piperazine derivative, preparation thereof and use thereof in medicine |
| CN101824036A (en) * | 2009-03-05 | 2010-09-08 | 上海恒瑞医药有限公司 | Salt of tetrahydroimidazo [1,5-a] pyrazine derivative, preparation method and pharmaceutical application thereof |
| CN102212015A (en) * | 2010-04-12 | 2011-10-12 | 上海源力生物技术有限公司 | Method for preparing chiral beta-amino arylbutyric acid derivatives |
| CN102503829A (en) * | 2011-10-08 | 2012-06-20 | 山东铂源化学有限公司 | Preparation methods for sitagliptin intermediates |
| CN102574856A (en) * | 2009-05-11 | 2012-07-11 | 基因里克斯(英国)有限公司 | Sitagliptin synthesis |
| CN105218371A (en) * | 2015-09-24 | 2016-01-06 | 上海交通大学 | The preparation method of optically pure 3-hydroxyl-4-(2,4,5-trifluorophenyl) ethyl butyrate |
| CN107501112A (en) * | 2017-09-15 | 2017-12-22 | 苏州爱玛特生物科技有限公司 | A kind of Chiral Synthesis of chiral beta amino acids and the synthetic method of medicine intermediate |
| CN108586346A (en) * | 2018-05-10 | 2018-09-28 | 中国国际医药卫生有限公司 | A kind of method that living things catalysis synthesizes sitagliptin and its intermediate |
| CN113666904A (en) * | 2020-05-14 | 2021-11-19 | 浙江医药股份有限公司新昌制药厂 | Preparation method of sitagliptin phosphate intermediate |
-
2022
- 2022-11-03 CN CN202211366721.5A patent/CN115583935A/en active Pending
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101417999A (en) * | 2007-10-25 | 2009-04-29 | 上海恒瑞医药有限公司 | Piperazines derivates, preparation method thereof and application thereof in medicine |
| CN101468988A (en) * | 2007-12-26 | 2009-07-01 | 上海恒瑞医药有限公司 | Piperazine derivative, preparation thereof and use thereof in medicine |
| CN101824036A (en) * | 2009-03-05 | 2010-09-08 | 上海恒瑞医药有限公司 | Salt of tetrahydroimidazo [1,5-a] pyrazine derivative, preparation method and pharmaceutical application thereof |
| CN102574856A (en) * | 2009-05-11 | 2012-07-11 | 基因里克斯(英国)有限公司 | Sitagliptin synthesis |
| CN102212015A (en) * | 2010-04-12 | 2011-10-12 | 上海源力生物技术有限公司 | Method for preparing chiral beta-amino arylbutyric acid derivatives |
| CN102503829A (en) * | 2011-10-08 | 2012-06-20 | 山东铂源化学有限公司 | Preparation methods for sitagliptin intermediates |
| CN105218371A (en) * | 2015-09-24 | 2016-01-06 | 上海交通大学 | The preparation method of optically pure 3-hydroxyl-4-(2,4,5-trifluorophenyl) ethyl butyrate |
| CN107501112A (en) * | 2017-09-15 | 2017-12-22 | 苏州爱玛特生物科技有限公司 | A kind of Chiral Synthesis of chiral beta amino acids and the synthetic method of medicine intermediate |
| CN108586346A (en) * | 2018-05-10 | 2018-09-28 | 中国国际医药卫生有限公司 | A kind of method that living things catalysis synthesizes sitagliptin and its intermediate |
| CN113666904A (en) * | 2020-05-14 | 2021-11-19 | 浙江医药股份有限公司新昌制药厂 | Preparation method of sitagliptin phosphate intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR20170040278A (en) | Method for the preparation of (4s)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carbox-amide and the purification thereof for use as an active pharmaceutical ingredient | |
| CN111285760B (en) | Synthesis method and intermediate of pipadiric acid | |
| US8507716B2 (en) | Process for preparing pemetrexed disodium and its intermediate, 4-(4-carbomethoxyphenyl) butanal | |
| CN101462974A (en) | Process for synthesizing 5-aminovaleric acid hydrochloride | |
| CN110183445B (en) | Synthetic method of moxifloxacin and derivatives thereof | |
| CN108358799B (en) | Preparation method of pregabalin | |
| CN115583935A (en) | Preparation method of 4- (2, 4, 5-trifluorophenyl) -3-oxybutyrate ester | |
| RU2756507C2 (en) | Method for preparing 1-(4-methanesulfonyl-2-trifluoromethylbenzyl)-2-methyl-1h-pyrrolo[2,3-b]pyridine-3-yl-acetic acid | |
| JP2013166752A (en) | Industrial process for preparation of 1,2-dihydroquinoline derivative or salt thereof, and intermediate for preparation thereof | |
| CN113336703A (en) | Synthesis of 1,3,4, 5-tetrasubstituted 1H-pyrazole derivatives | |
| JP5463051B2 (en) | Method for producing 1,4-dihydropyridine derivative | |
| CN111574463A (en) | Riagliptin intermediate compound IV | |
| TWI551592B (en) | Preparation of 3,5-dioxo hexanoate ester in two steps | |
| CN115677456B (en) | Preparation method of cannabidiol | |
| CN1197854C (en) | Lactonization processing method in preparing Tating compounds | |
| CN114394908B (en) | Method for preparing 2-hydroxy-3-aminoacetophenone | |
| CN114560845B (en) | Crystal form alpha of quinoline compound, and preparation method and application thereof | |
| CN112592323B (en) | Process for preparing odaterol and salts thereof | |
| CN111978327B (en) | Preparation method of ticagrelor | |
| JP6572399B1 (en) | Method for purifying 2,15-hexadecanedione and method for producing 3-methylcyclopentadecenones | |
| CN110003218B (en) | Preparation method of Allagliptin intermediate | |
| JP2003528869A (en) | Method for producing simvastatin | |
| CN117720504A (en) | Preparation method of ticagrelor intermediate | |
| CN116178376A (en) | Synthesis method of Pevonedistit intermediate | |
| KR100448640B1 (en) | Method for producing phenyl propionic acid derivatives with high yield and purity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |