CN111187154B - Synthetic method of sitagliptin intermediate 2,4, 5-trifluoro phenylacetic acid - Google Patents

Synthetic method of sitagliptin intermediate 2,4, 5-trifluoro phenylacetic acid Download PDF

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CN111187154B
CN111187154B CN201910404444.4A CN201910404444A CN111187154B CN 111187154 B CN111187154 B CN 111187154B CN 201910404444 A CN201910404444 A CN 201910404444A CN 111187154 B CN111187154 B CN 111187154B
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高照波
张现毅
贺志
王崇
梅义将
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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    • C07C51/38—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by decarboxylation
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Abstract

The invention provides a synthetic method of a sitagliptin intermediate 2,4, 5-trifluoro phenylacetic acid, which comprises the steps of substitution reaction, hydrolysis reaction and decarboxylation reaction, wherein A, a compound of a formula 5 is prepared by the substitution reaction of a compound 4, or the substitution reaction and the hydrolysis reaction of the compound; B. carrying out hydrolysis reaction on the compound shown in the formula 5 to prepare a compound shown in a formula 6; C. the 2,4, 5-trifluoro-phenylacetic acid is prepared by decarboxylation reaction of a compound shown in a formula 6 under the catalysis of a catalyst, wherein the catalyst is a metal oxide. The synthesis process has low cost, high yield and strong applicability in industrial scale-up production, and can be used for preparing the 2,4, 5-trifluoro-phenylacetic acid compound.

Description

Synthetic method of sitagliptin intermediate 2,4, 5-trifluoro phenylacetic acid
Background
The compound 2,4, 5-trifluoro-phenylacetic acid has the following chemical structural formula:
Figure BDA0002060761550000011
the compound is an important intermediate for synthesizing a drug sitagliptin for treating type II diabetes. Sitagliptin is the first DPP-IV inhibitor newly marketed by Merck company, has good curative effect, small side effect, good safety and tolerance for treating type II diabetes, and has wide market prospect.
The compound 2,4, 5-trifluorophenylacetic acid was first disclosed in WO9828268A2 filed in 1997-12-22.
US20040068141 reports 2,4, 5-trifluoro bromobenzene and diethyl malonate as raw materials, which are hydrolyzed to obtain 2,4, 5-trifluoro phenylacetic acid after substitution reaction under alkaline condition. The reaction condition of the route is high in requirement, the yield is low, and the trifluorobromobenzene as the raw material is not easy to obtain and is not suitable for industrial production. The synthetic route is as follows:
Figure BDA0002060761550000012
U.S. Pat. No. 5, 6870067 reports that 2,4, 5-trifluorobromobenzene as a starting material is likewise reacted with magnesium metal to form a Grignard reagent, which is then substituted with allyl bromide to give 1- (2-allyl) -2,4, 5-trifluorobenzene. 1- (2-allyl) -2,4, 5-trifluorobenzene in the presence of RuCl catalyst3And an oxidant NalO4In the presence of (a), to obtain 2,4, 5-trifluorophenylacetic acid. The route has high requirement on anhydrous, and the format reaction intermediate is easy to explode. Furthermore, the catalyst RuCl3And an oxidant NalO4The price of the product is also high, and the product is not suitable for industrial production. The synthetic route is as follows:
Figure BDA0002060761550000013
chinese patent CN106866406A applied by fujianhua chemical limited company in 2016-12-31 discloses a process for preparing 2,4, 5-trifluorophenylacetic acid, the synthetic route is as follows:
Figure BDA0002060761550000021
the starting materials of the route are difficult to obtain, the selectivity of the condensation reaction step is poor, a large number of byproducts are produced, and the decarboxylation reaction is not easy to occur under the acidic condition.
Chinese patent CN1749232 reports that 1,2, 4-trifluorobenzene is used as raw material, and 2,4, 5-trifluorobenzene acetic acid is obtained through chloromethylation, cyanidation and hydrolysis. The chloromethylation reaction of the process has low yield and overlarge three wastes. And the highly toxic sodium cyanide is used, so that the method has greater potential safety hazard in industrial production, and the synthetic route is as follows:
Figure BDA0002060761550000022
chinese patent CN101244994 reports that 1,2, 4-trifluorobenzene is used as a raw material, and 2,4, 5-trifluorobenzene acetic acid is obtained through F-C acylation, Willegerodt-Kindler reaction and hydrolysis. The process has long route and complex operation and generates a large amount of industrial wastewater.
Chinese patent CN1749232 a reports that 1,2, 4-trifluorobenzene is used as raw material, chlorosulfonic acid and zinc chloride are used as chlorinating agents, and reacts with paraformaldehyde through Blanc reaction to prepare 2,4, 5-trifluorobenzyl chloride, then phase transfer catalyst is added into acetonitrile to perform cyanidation reaction, and finally hydrolysis is performed to obtain 2,4, 5-trifluorophenylacetic acid. The chloromethylation reaction of the process has low yield and overlarge three wastes. Chlorosulfonic acid has strong pungent odor, poor safety, difficult recycling of phase transfer catalyst, poor atom economy, greatly improved production cost and poor environmental friendliness, so that chlorosulfonic acid is not suitable for industrial production.
Chinese patent application CN107522609A discloses a method for preparing 2,3, 5-trifluoroaniline by using aniline as a starting material, adding sodium nitrite into glacial acetic acid, and then dropwise adding sodium fluoborate aqueous solution for reaction; adding 2,3, 5-trifluoroaniline and stannic chloride-polystyrene compound into glacial acetic acid, adding liquid bromine, after post-treatment, obtaining 2,3, 5-trifluoro-6-bromoaniline, then adding NaH and ethyl acetate, reacting under the action of cupric bromide at high temperature, acidifying, then adding sodium nitrite and diazotizing to obtain the corresponding product 2,3, 5-trifluorophenylacetic acid. The fluorination reaction in the first step of the process is not determined in product yield, and similar commercial application examples are not seen. The third step of reaction has low yield and no production potential according to the reported literature. The intermediate of the fourth step of removing-NH 2 is easy to lose control and explode, and the raw material liquid bromine and NaH adopted in the reaction process are dangerous substances, so that the safety is poor.
Figure BDA0002060761550000031
In view of the disadvantages of the existing routes, there is a need to further develop a route suitable for commercial production of 2,4, 5-trifluorophenylacetic acid.
Disclosure of Invention
The invention provides a synthetic method of a sitagliptin intermediate 2,4, 5-trifluoro phenylacetic acid. The synthesis process can prepare the 2,4, 5-trifluoro-phenylacetic acid compound with low cost and high yield, and has mild production conditions and strong applicability in industrial scale-up production.
In order to realize the technical purpose of the invention, the invention provides the following technical scheme:
firstly, the invention provides an intermediate compound for preparing a sitagliptin intermediate 2,4, 5-trifluoro-phenylacetic acid, which is shown in a formula 2:
Figure BDA0002060761550000032
then, the invention provides a preparation method of the intermediate compound shown in formula 2, which comprises the steps of carrying out hydrolysis reaction on the compound shown in formula 1 under the conditions of water and protonic acid to prepare a compound shown in formula 2;
Figure BDA0002060761550000033
wherein R is an alkyl group, such as a linear or branched alkyl group of methyl, ethyl or propyl, etc.;
the acid in the hydrolysis reaction step is common protonic acid, such as sulfuric acid, phosphoric acid, hydrobromic acid or hydrochloric acid and the like;
the reaction temperature in the hydrolysis reaction step is 100-220 ℃, and preferably 120-150 ℃;
the reaction heat preservation time in the hydrolysis reaction step is 10-40 hours, and preferably 15-30 hours.
The invention further provides a preparation method of the sitagliptin intermediate 2,4, 5-trifluoro-phenylacetic acid, which is prepared by decarboxylation reaction of a compound shown in a formula 2 under the catalysis of a catalyst, wherein the catalyst is a metal oxide:
Figure BDA0002060761550000041
the metal oxide catalyst in the decarboxylation reaction step is silver oxide or cuprous oxide;
the molar equivalent ratio of the reaction catalyst to the raw material in the decarboxylation step is 0.05-5;
the reaction temperature in the decarboxylation step is 120-220 ℃, and preferably 100-150 ℃;
the reaction heat preservation time in the decarboxylation step is 3-15 hours, and preferably 4-12 hours.
The invention further provides a preparation method of the compound of the formula 1, which is characterized in that the compound of the formula 1 is prepared by the substitution reaction of a compound 2,3,5, 6-tetrafluorobenzonitrile and cyanoalkanoate;
Figure BDA0002060761550000042
the substitution reaction step R is alkyl, such as methyl, ethyl or propyl and other straight chain or branched chain alkyl;
the base in the substitution reaction step is common organic base such as triethylamine, pyridine, sodium methoxide or sodium ethoxide and the like, or inorganic base such as sodium carbonate, potassium carbonate, sodium bicarbonate or cesium carbonate and the like.
The invention also provides a precursor compound 5 for preparing the sitagliptin intermediate 2,4, 5-trifluoro phenylacetic acid, which has the following structural formula:
Figure BDA0002060761550000043
R1、R2、R3are respectively-H, -CN, -COOH and-CONH2or-COOR4；
R4Is an alkyl group.
The precursor compound 5 for preparing the sitagliptin intermediate 2,4, 5-trifluoro-phenylacetic acid has the specific structure that:
Figure BDA0002060761550000051
Figure BDA0002060761550000061
Figure BDA0002060761550000071
Figure BDA0002060761550000081
Figure BDA0002060761550000091
the invention further provides a method for preparing a sitagliptin intermediate 2,4, 5-trifluoro phenylacetic acid, which is characterized in that the sitagliptin intermediate is prepared by decarboxylation reaction of a compound shown in a formula 6 under the catalysis of a catalyst, wherein the catalyst is a metal oxide:
Figure BDA0002060761550000101
R7is-H or-COOH;
the decarboxylation reaction steps are specifically as follows: adding the metal oxide into the product 6 obtained in the step (2), heating to 100-220 ℃ for reaction, adjusting the pH after the reaction is finished, extracting the product with ethyl acetate, washing, and carrying out reduced pressure distillation for post-treatment to obtain the 2,4, 5-trifluorophenylacetic acid.
And the metal oxide in the decarboxylation step is silver oxide or cuprous oxide.
The reaction temperature of the decarboxylation reaction step is 120-220 ℃.
The reaction heat preservation time in the decarboxylation step is 3-15 hours, and preferably 4-12 hours.
The invention further provides a preparation method of the intermediate compound shown in the formula 6 for preparing the sitagliptin intermediate 2,4, 5-trifluoro phenylacetic acid, which is characterized in that the precursor compound 5 is subjected to hydrolysis reaction to prepare the compound shown in the formula 6.
Figure BDA0002060761550000102
R1、R2、R3Are respectively-H, -CN, -COOH and-CONH2or-COOR4；
R4Is an alkyl group;
R7is-H or-COOH.
The hydrolysis conditions in the hydrolysis reaction step are water and protonic acid conditions or alkaline conditions, preferably water and protonic acid conditions.
The hydrolysis reaction steps are specifically as follows: adding the product 5 obtained in the step (1) into a common protonic acid aqueous solution, hydrolyzing at 100-200 ℃, and carrying out heat preservation reaction until the reaction of the raw materials is finished.
The acid in the hydrolysis step is a common protic acid.
The hydrolysis reaction temperature in the hydrolysis reaction step is 100-220 ℃, and preferably 120-150 ℃;
the reaction heat preservation time in the hydrolysis reaction step is 10-40 hours, and preferably 15-30 hours.
The invention further provides a method for preparing a precursor compound 5 of the sitagliptin intermediate 2,4, 5-trifluoro phenylacetic acid, which is characterized in that the precursor compound 5 is obtained by a substitution reaction of a compound shown in a formula 4 or the precursor compound 5 is prepared by a hydrolysis reaction of the compound shown in the formula 4 after the substitution reaction:
Figure BDA0002060761550000111
R1、R2、R3are respectively-H, -CN, -COOH and-CONH2or-COOR4；
R4Is an alkyl group;
R5is-H or-CN, -COOH, -COOR6；
R6Is an alkyl group.
The substitution reaction steps are specifically as follows: adding organic base or inorganic base, the compound shown in the formula 4,
Figure BDA0002060761550000112
The nucleophilic substitution reagent shown is reacted, and after the reaction is finished, the precursor compound 5 is obtained after post-treatment.
Further, in the case of a liquid crystal display,
Figure BDA0002060761550000113
nucleophilic substitution reagents as shown include
Figure BDA0002060761550000114
Figure BDA0002060761550000115
Further, the substitution reaction step base is a common organic base such as triethylamine, tripropylamine, tributylamine, diisopropylethylamine, DBU, DABCO, pyridine, sodium methoxide, sodium ethoxide, sodium isopropoxide, potassium isopropoxide, sodium tert-butoxide, potassium tert-butoxide, etc., or an inorganic base such as sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, etc.
The hydrolysis conditions in the hydrolysis reaction step are water and protonic acid or alkaline conditions, preferably water and protonic acid conditions.
The acid in the hydrolysis step is a common protic acid.
The hydrolysis reaction temperature in the hydrolysis reaction step is 100-220 ℃, and preferably 120-150 ℃;
the reaction heat preservation time in the hydrolysis reaction step is 10-40 hours, and preferably 15-30 hours.
The preparation method of the preferable sitagliptin intermediate 2,4, 5-trifluoro-phenylacetic acid provided by the invention specifically comprises the following steps:
(1) adding organic base or inorganic base, a compound shown in a formula 4 and ethyl cyanoacetate into the organic solution, heating for reaction, and performing post-treatment after the reaction is finished to obtain a product 5;
(2) adding the product 5 obtained in the step (1) into a common protonic acid aqueous solution, hydrolyzing at 100-200 ℃, carrying out heat preservation reaction until the reaction of the raw materials is finished, and then washing and drying;
(3) adding metal oxide into the product 6 obtained in the step (2), heating to 100-220 ℃ for reaction, adjusting the pH after the reaction is finished, extracting the product with ethyl acetate, washing, and carrying out reduced pressure distillation and post-treatment to obtain the 2,4, 5-trifluorophenylacetic acid.
The technical scheme for preparing the sitagliptin intermediate 2,4, 5-trifluoro-phenylacetic acid adopted by the invention has the following beneficial effects:
(a) the method has the advantages of low cost, high yield, simple operation and strong applicability in industrial amplification production;
(b) in the substitution step, the reaction condition is milder, the post-treatment mode is simpler, and the yield is high;
(c) in the hydrolysis step, protonic acid is directly used for hydrolysis under an acidic condition, so that three wastes are reduced, and the method is more environment-friendly;
(d) the metal oxide is added in the decarboxylation step, so that the reaction selectivity is better, severe conditions of high temperature and high pressure are not needed, the reaction is safer, the reaction time is greatly shortened, and the efficiency is higher.
Detailed Description
For further understanding of the present invention, the following examples are given to illustrate the synthesis of 2,4, 5-trifluorophenylacetic acid, an intermediate of sitagliptin, in accordance with the present invention. It is to be understood that these examples are described merely to illustrate the features of the present invention in further detail, and not as limitations of the invention or of the scope of the claims appended hereto.
Example 1: synthesis of 2- (carboxymethyl) -3,5, 6-trifluorobenzoic acid (Compound 13)
Figure BDA0002060761550000131
A1000 mL four-necked round bottom flask was charged with 2,3,5, 6-tetrafluoronitrile (40.0g,228mmol), potassium carbonate (63.15g,457 mmol) and acetonitrile (600mL), and mechanical stirring was initiated. Heating to reflux. A mixture of ethyl cyanoacetate (31.0g,274 mmol) and acetonitrile (750mL) was added dropwise over 2 hours. After the completion of the dropwise addition, the reaction was continued. HPLC traces the reaction system, and the reaction is stopped when the raw material 2,3,5, 6-tetrafluorobenzonitrile is less than 5% (area normalization method). Cooling to 20-25 ℃. Filtration and rinsing of the filter cake with acetonitrile (100 mL). And (4) carrying out reduced pressure distillation on the filtrate at 40-45 ℃, and stopping distillation when no fraction is in a condensation tube. Dichloromethane (200mL) was added to the residue, and the mixture was slurried at 20-25 ℃ for 4 hours. Filtering, leaching a filter cake with dichloromethane (100mL), and drying by blowing at 60-65 ℃ under normal pressure. A yellow solid (61.1g,227.8mmol) was obtained, compound 1, in 99.9% molar yield and 99.4% HPLC purity.1H NMR(400MHz，d6-DMSO)δ1.11～1.15(t，3H，J＝6.8Hz)，3.32 (s，1H)，3.90～3.96(q，2H，J＝7.2Hz)，7.58～7.65(m，1H)。MS(ESI)：m/z 291.0346 [M+Na]+
Water (40mL) was added to a 500mL single neck round bottom flask and magnetic stirring was initiated. 98% concentrated sulfuric acid (63.2 g,632mmol) was added dropwise at 30-50 ℃. Compound 1(20g,74.6mmol) was added and the mixture was heated to elevated temperature. The temperature is raised to 140 ℃, and the reaction is kept for 24 hours. And after the reaction is finished, cooling to 30-50 ℃. An aqueous solution of 30% sodium hydroxide (28.4g,710mmol) was added dropwise. After the dropwise addition is finished, reduced pressure distillation is carried out at the temperature of 60-70 ℃, and the distillation is stopped when no fraction is in a condensation tube. Acetonitrile (200mL), 20 was addedPulping for 2 hours at the temperature of 30 ℃. Filtration and rinsing of the filter cake with acetonitrile (50 mL). And (4) carrying out reduced pressure distillation on the filtrate at 40-45 ℃, and stopping distillation when no fraction is in a condensation tube. Dichloromethane (100mL) was added to the residue, and the mixture was slurried at 20-25 ℃ for 3 hours. Filtering, washing a filter cake by using dichloromethane (50mL), and drying at 30-35 ℃ under reduced pressure. An off-white solid (15.7g,67.0mmol) was obtained, compound 13, in 89.9% molar yield and 98.7% HPLC purity.1H NMR(400MHz，CDCL3)δ3.71(s，2H)，7.70～7.77(m，1H)。 MS(ESI)：m/z 257.0015[M+Na]+
Example 2: synthesis of 2- (carboxymethyl) -3,5, 6-trifluorobenzoic acid (Compound 13)
Figure BDA0002060761550000132
A1000 mL four-necked round bottom flask was charged with 2,3,5, 6-tetrafluorobenzonitrile (8.8g,50mmol), potassium carbonate (13.8g,100mmol) and acetonitrile (100mL), and mechanical stirring was initiated. Heating to reflux. A mixture of diethyl malonate (8.5g,53mmol) and acetonitrile (50mL) was added dropwise over 1 hour. After the completion of the dropwise addition, the reaction was continued. And (3) tracking the reaction system by HPLC, and stopping the reaction after the raw material 2,3,5, 6-tetrafluorobenzonitrile disappears. Filtration and rinsing of the filter cake with acetonitrile (20 mL). And (4) carrying out reduced pressure distillation on the filtrate at 40-45 ℃, and stopping distillation when no fraction is in a condensation tube. Isopropyl acetate (50mL) was added to the residue, and slurried at 20-25 ℃ for 2 hours. Filtering, washing a filter cake with isopropyl acetate (30mL), and drying by blowing at 50-55 ℃ under normal pressure. A red solid (14.3g,45.5mmol) was obtained as a powder, compound 4, in 88% molar yield and 99.1% HPLC purity. Ms (esi): m/z 338.0631[ M + Na ]]+
A500 mL single neck round bottom flask was charged with Compound 2(21.5g,68.2mmol), 48% aqueous hydrobromic acid (100.0g,592.6 mmol) and magnetic stirring was initiated. Heating to 125 ℃, and reacting for 24 hours under the condition of heat preservation. After the reaction, the reaction mixture was distilled under normal pressure to remove 60.0g of hydrobromic acid, and then isopropanol (50mL) was added thereto, followed by stirring at 20 to 30 ℃ for 2 hours. Filtering, leaching a filter cake with isopropanol (10mL), and drying by blowing at 60-70 ℃ under normal pressure. To give a white solid (14.5g,61.9mmol), Compound 13, in 90.7% molar yieldHPLC purity 98.7%. Ms (esi): m/z 257.0049[ M + Na ]]+
Example 3: synthesis of 2- (carboxymethyl) -3,5, 6-trifluorobenzoic acid (Compound 13)
Figure BDA0002060761550000141
A250 mL four-necked round bottom flask was charged with 2,3,5, 6-tetrafluorobenzonitrile (8.75g,50mmol), potassium carbonate (13.8g,100mmol) and acetonitrile (100mL), and mechanical stirring was initiated. Heating to reflux. A mixture of malononitrile (3.5g,53mmol) and acetonitrile (50mL) was added dropwise over 1 hour. After the completion of the dropwise addition, the reaction was continued. And (3) tracking the reaction system by HPLC, and stopping the reaction after the raw material 2,3,5, 6-tetrafluorobenzonitrile disappears. Filtration and rinsing of the filter cake with acetonitrile (20 mL). And (4) carrying out reduced pressure distillation on the filtrate at 40-45 ℃, and stopping distillation when no fraction is in a condensation tube. Isopropyl acetate (50mL) was added to the residue, and slurried at 20-25 ℃ for 2 hours. Filtering, washing a filter cake with isopropyl acetate (30mL), and drying by blowing at 50-55 ℃ under normal pressure. A red powder solid (9.9g,45mmol) was obtained as compound 3 in 90% molar yield. HPLC purity 98.5%. Ms (esi): m/z 222.0264 [ M + H ]]+。
A500 mL single neck round bottom flask was charged with Compound 3(20g,90.5mmol), 48% aqueous hydrobromic acid (100.0g,592.6 mmol) and magnetic stirring was initiated. Heating to 125 ℃, and reacting for 24 hours under the condition of heat preservation. After the reaction, the reaction mixture was distilled under normal pressure to remove 60.0g of hydrobromic acid, and then isopropanol (50mL) was added thereto, followed by stirring at 20 to 30 ℃ for 2 hours. Filtering, leaching a filter cake with isopropanol (10mL), and drying by blowing at 60-70 ℃ under normal pressure. A white solid (19.3g,82.5mmol) was obtained, compound 13, in 91.2% molar yield. HPLC purity 99.1%. Ms (esi): m/z 235.1344[ M + H ]]+。
Example 4: synthesis of 2- (carboxymethyl) -3,5, 6-trifluoroterephthalic acid (Compound 14)
Figure BDA0002060761550000142
1000ml four-mouth round-bottom flask is added with 2,3,5,6-Tetrafluoroterephthalonitrile (10.0g,50mmol), potassium carbonate (13.8g,100mmol) and acetonitrile (100mL), mechanical stirring was initiated. Heating to reflux. A mixture of ethyl cyanoacetate (6.0g,53mmol) and acetonitrile (50mL) was added dropwise over 1 hour. After the completion of the dropwise addition, the reaction was continued. The reaction system was followed by HPLC, and the reaction was stopped after disappearance of the starting material, 2,3,5, 6-tetrafluoroterephthalonitrile. Filtration and rinsing of the filter cake with acetonitrile (20 mL). And (4) carrying out reduced pressure distillation on the filtrate at the temperature of between 40 and 45 ℃, and stopping distillation when no fraction is in a condensation pipe. Isopropyl acetate- (50mL) was added to the residue and slurried at 20-25 ℃ for 2 hours. Filtering, washing a filter cake with isopropyl acetate (30mL), and drying by blowing at 50-55 ℃ under normal pressure. A red solid (13.2g,45mmol) was obtained as a powder, compound 4, in 90% molar yield and 99.8% HPLC purity.1H NMR(400 MHz，D2O)δ1.24～1.27(t，3H，J＝7.2Hz)，4.11～4.16(q，1H，J＝6.8Hz)，4.79 (s，1H)。MS(ESI)：m/z 294.0512[M+1]+
A500 mL single neck round bottom flask was charged with Compound 4(20g,68.2mmol), 48% aqueous hydrobromic acid (100.0g,592.6 mmol) and magnetic stirring was initiated. Heating to 125 ℃, and reacting for 24 hours under the condition of heat preservation. After the reaction, the reaction mixture was distilled under normal pressure to remove 60.0g of hydrobromic acid, and then isopropanol (50mL) was added thereto, followed by stirring at 20 to 30 ℃ for 2 hours. Filtering, leaching a filter cake with isopropanol (10mL), and drying by blowing at 60-70 ℃ under normal pressure. A white solid (17.9g,64.4mmol) was obtained, compound 14, in 94.4% molar yield and 98.4% HPLC purity.1H NMR(400MHz，CDCL3)δ3.70(s，2H)，11.0 (s，2H)。MS(ESI)：m/z 301.0043[M+Na]+
Example 5: synthesis of 2- (carboxymethyl) -3,5, 6-trifluoroterephthalic acid (Compound 14)
Figure BDA0002060761550000151
A1000 mL four-necked round bottom flask was charged with 2,3,5, 6-tetrafluoroterephthalonitrile (10.0g,50mmol), potassium carbonate (13.8g,100mmol) and acetonitrile (100mL), and mechanical stirring was initiated. Heating to reflux. A mixture of diethyl malonate (8.5g,53mmol) and acetonitrile (50mL) was added dropwise over 1 hour. Completion of the dropwise additionAfter that, the reaction was continued. The reaction system was followed by HPLC, and the reaction was stopped after disappearance of the starting material, 2,3,5, 6-tetrafluoroterephthalonitrile. Filtration and rinsing of the filter cake with acetonitrile (20 mL). And (4) carrying out reduced pressure distillation on the filtrate at 40-45 ℃, and stopping distillation when no fraction is in a condensation pipe. Isopropyl acetate (50mL) was added to the residue and slurried at 20-25 ℃ for 2 hours. Filtering, washing a filter cake with isopropyl acetate (30mL), and drying by blowing at 50-55 ℃ under normal pressure. A red solid (16.0g,47mmol) was obtained as a powder, compound 5, in 94% molar yield and 99.4% HPLC purity. Ms (esi): m/z 363.0579[ M + Na ]]+
A500 mL single neck round bottom flask was charged with Compound 5(23.2g,68.2mmol), 48% aqueous hydrobromic acid (100.0g,592.6 mmol) and magnetic stirring was initiated. Heating to 125 ℃, and reacting for 24 hours under the condition of heat preservation. After the reaction, the reaction mixture was distilled under normal pressure to remove 60.0g of hydrobromic acid, and then isopropanol (50mL) was added thereto, followed by stirring at 20 to 30 ℃ for 2 hours. Filtering, leaching a filter cake with isopropanol (10mL), and drying by blowing at 60-70 ℃ under normal pressure. A white solid (17.7g,63.4mmol) was obtained, compound 14, in 93.0% molar yield and 98.9% HPLC purity. Ms (esi): m/z 301.0043[ M + Na ]]+
Example 6: synthesis of 2- (carboxymethyl) -3,5, 6-trifluoroterephthalic acid (Compound 14)
Figure BDA0002060761550000161
A1000 mL four-necked round bottom flask was charged with 2,3,5, 6-tetrafluoroterephthalonitrile (10.0g,50mmol), potassium carbonate (13.8g,100mmol) and acetonitrile (100mL) and mechanical stirring was initiated. Heating to reflux. A mixture of malononitrile (3.5g,53mmol) and acetonitrile (50mL) was added dropwise over 1 hour. After the completion of the dropwise addition, the reaction was continued. The reaction system was followed by HPLC, and the reaction was stopped after disappearance of the starting material, 2,3,5, 6-tetrafluoroterephthalonitrile. Filter and rinse the filter cake with acetonitrile (20 mL). And (4) carrying out reduced pressure distillation on the filtrate at 40-45 ℃, and stopping distillation when no fraction is in a condensation tube. Isopropyl acetate (50mL) was added to the residue, and slurried at 20-25 ℃ for 2 hours. Filtering, washing a filter cake with isopropyl acetate (30mL), and drying by blowing at 50-55 ℃ under normal pressure. A red powder solid (11.8g,48mmol), Compound 6, was obtained in molar yield96% and 99.6% HPLC purity. Ms (esi): m/z 269.0071[ M + Na ]]+
A500 mL single neck round bottom flask was charged with Compound 3(16.79g,68.2mmol), 48% aqueous hydrobromic acid (100.0g,592.6 mmol) and magnetic stirring was initiated. Heating to 125 ℃, and reacting for 24 hours under the condition of heat preservation. After the reaction, the reaction mixture was distilled under normal pressure to remove 60.0g of hydrobromic acid, and then isopropanol (50mL) was added thereto, followed by stirring at 20 to 30 ℃ for 2 hours. Filtering, leaching a filter cake with isopropanol (10mL), and drying by blowing at 60-70 ℃ under normal pressure. A white solid (17.4g,62.4mmol) was obtained, compound 14, in 91.5% molar yield and 99.0% HPLC purity. Ms (esi): m/z 301.0043[ M + Na ]]+
Example 7: synthesis of 2- (carboxymethyl) -3,5, 6-trifluoroterephthalic acid (Compound 14)
Figure BDA0002060761550000162
A1000 mL four-necked round bottom flask was charged with 2,3,5, 6-tetrafluoro-3-cyanobenzoic acid (11.0g,50mmol), potassium carbonate (13.8g,100mmol), and acetonitrile (100mL) and mechanical stirring was initiated. Heating to reflux. A mixture of ethyl cyanoacetate (6.0g,53mmol) and acetonitrile (50mL) was added dropwise over 1 hour. After the completion of the dropwise addition, the reaction was continued. The reaction system was followed by HPLC and the reaction was stopped after the disappearance of the starting material, 2,3,5, 6-tetrafluoro-3-cyanobenzoic acid. Filtration and rinsing of the filter cake with acetonitrile (20 mL). And (4) carrying out reduced pressure distillation on the filtrate at 40-45 ℃, and stopping distillation when no fraction is in a condensation tube. Isopropyl acetate (50mL) was added to the residue, and slurried at 20-25 ℃ for 2 hours. Filtering, washing a filter cake with isopropyl acetate (30mL), and drying by blowing at 50-55 ℃ under normal pressure. A red solid (14.7g,46.0mmol) was obtained as a powder, compound 7, in 92% molar yield and 99.4% HPLC purity. Ms (esi): m/z 335.0281[ M + Na ]]+
A500 mL single neck round bottom flask was charged with Compound 7(21.29g,68.2mmol), 48% aqueous hydrobromic acid (100.0g,592.6 mmol) and magnetic stirring was initiated. Heating to 125 ℃, and reacting for 24 hours under the condition of heat preservation. After the reaction, the reaction mixture was distilled under normal pressure to remove 60.0g of hydrobromic acid, and then isopropanol (50mL) was added thereto, followed by stirring at 20 to 30 ℃ for 2 hours. Filtering, using different filter cakeAnd (3) rinsing with propanol (10mL), and drying by blowing at 60-70 ℃ under normal pressure. A white solid (17.7g,63.5mmol) was obtained, compound 14, in 93.1% molar yield and 99.2% HPLC purity. Ms (esi): m/z 301.0043[ M + Na ]]+
Example 8: synthesis of 2- (carboxymethyl) -3,5, 6-trifluoroterephthalic acid (Compound 14)
Figure BDA0002060761550000171
A250 mL four-necked round bottom flask was charged with 2,3,5, 6-4-cyano-benzoic acid (11.0g,50mmol), potassium carbonate (13.8g,100mmol) and acetonitrile (100mL) and mechanical stirring was initiated. Heating to reflux. A mixture of malononitrile (3.5g,53mmol) and acetonitrile (50mL) was added dropwise over 1 hour. After the completion of the dropwise addition, the reaction was continued. The reaction system was followed by HPLC and the reaction was stopped after disappearance of the starting material 2,3,5, 6-4-cyano-benzoic acid. Filtration and rinsing of the filter cake with acetonitrile (20 mL). And (4) carrying out reduced pressure distillation on the filtrate at 40-45 ℃, and stopping distillation when no fraction is in a condensation pipe. Isopropyl acetate (50mL) was added to the residue, and slurried at 20-25 ℃ for 2 hours. Filtering, washing a filter cake with isopropyl acetate (30mL), and drying by blowing at 50-55 ℃ under normal pressure. A red powder solid (11.7g,44mmol) was obtained, compound 8, in 88% molar yield. HPLC purity 96.7%. Ms (esi): m/z 266.0172[ M + H ]]+。
A500 mL single neck round bottom flask was charged with Compound 8(20g,75.5mmol), 48% aqueous hydrobromic acid (100.0g,592.6 mmol) and magnetic stirring was initiated. Heating to 125 ℃, and reacting for 24 hours under the condition of heat preservation. After the reaction, the reaction mixture was distilled under normal pressure to remove 60.0g of hydrobromic acid, and then isopropanol (50mL) was added thereto, followed by stirring at 20 to 30 ℃ for 2 hours. Filtering, leaching a filter cake with isopropanol (10mL), and drying by blowing at 60-70 ℃ under normal pressure. A white solid (18.2g,65.5mmol), Compound 14, was obtained in 86.7% molar yield. HPLC purity 98.4%. Ms (esi): m/z 279.0108[ M + H ]]+。
Example 9: synthesis of 2- (carboxymethyl) -3,5, 6-trifluoroterephthalic acid (Compound 14)
Figure BDA0002060761550000172
A1000 mL four-necked round bottom flask was charged with 2,3,5, 6-tetrafluoro-3-cyanobenzoic acid (11.0g,50mmol), potassium carbonate (13.8g,100mmol), and acetonitrile (100mL), and mechanical stirring was initiated. Heating to reflux. A mixture of diethyl malonate (8.5g,53mmol) and acetonitrile (50mL) was added dropwise over 1 hour. After the completion of the dropwise addition, the reaction was continued. The reaction system was followed by HPLC and the reaction was stopped after the disappearance of the starting material, 2,3,5, 6-tetrafluoro-3-cyanobenzoic acid. Filtration and rinsing of the filter cake with acetonitrile (20 mL). And (4) carrying out reduced pressure distillation on the filtrate at 40-45 ℃, and stopping distillation when no fraction is in a condensation tube. Isopropyl acetate (50mL) was added to the residue, and slurried at 20-25 ℃ for 2 hours. Filtering, washing a filter cake with isopropyl acetate (30mL), and drying by blowing at 50-55 ℃ under normal pressure. A red solid (16.2g,45.0mmol) was obtained as a powder, compound 9, in 90% molar yield and 99.7% HPLC purity. Ms (esi): m/z 382.0545[ M + Na ]]+
A500 mL single neck round bottom flask was charged with Compound 9(24.50g,68.2mmol), 48% aqueous hydrobromic acid (100.0g,592.6 mmol) and magnetic stirring was initiated. Heating to 125 ℃, and reacting for 24 hours under the condition of heat preservation. After the reaction, the reaction mixture was distilled under normal pressure to remove 60.0g of hydrobromic acid, and then isopropanol (50mL) was added thereto, followed by stirring at 20 to 30 ℃ for 2 hours. Filtering, leaching a filter cake with isopropanol (10mL), and drying by blowing air at 60-70 ℃ under normal pressure. A white solid (17.5g,63.09mmol) was obtained, compound 14, in 92.5% molar yield and 98.9% HPLC purity. Ms (esi): m/z 301.0043[ M + Na ]]+
Example 10: synthesis of 2- (carboxymethyl) -3,5, 6-trifluoroterephthalic acid (Compound 14)
Figure BDA0002060761550000181
A500 mL four-necked round bottom flask was charged with ethyl 2,3,5, 6-tetrafluoro-4-cyanobenzoate (12.4g,50mmol), potassium carbonate (13.8g,100mmol), and acetonitrile (100mL), and mechanical stirring was initiated. Heating to reflux. A mixture of malononitrile (3.5g,53mmol) and acetonitrile (50mL) was added dropwise over 1 hour. After the completion of the dropwise addition, the reaction was continued. HPLC tracking of the reactionThe reaction was stopped after the disappearance of the starting material ethyl 2,3,5, 6-tetrafluoro-4-cyano-benzoate. Filtration and rinsing of the filter cake with acetonitrile (20 mL). And (4) carrying out reduced pressure distillation on the filtrate at 40-45 ℃, and stopping distillation when no fraction is in a condensation pipe. Isopropyl acetate (50mL) was added to the residue, and slurried at 20-25 ℃ for 2 hours. Filtering, washing a filter cake with isopropyl acetate (30mL), and drying by blowing at 50-55 ℃ under normal pressure. A red powdery solid (11.07g,45mmol) was obtained, compound 10, in 90% molar yield. HPLC purity 96.8%. Ms (esi): m/z 294.0465[ M + H ]]+
A500 mL single neck round bottom flask was charged with Compound 10(20g,68.2mmol), 48% aqueous hydrobromic acid (100.0g,592.6 mmol) and magnetic stirring was initiated. Heating to 125 ℃, and reacting for 24 hours under the condition of heat preservation. After the reaction, the reaction mixture was distilled under normal pressure to remove 60.0g of hydrobromic acid, and then isopropanol (50mL) was added thereto, followed by stirring at 20 to 30 ℃ for 2 hours. Filtering, leaching a filter cake with isopropanol (10mL), and drying by blowing at 60-70 ℃ under normal pressure. A white solid (18.0g,64.7mmol), Compound 14, was obtained in 94.9% molar yield. HPLC purity 97.8%. Ms (esi): m/z 279.0108[ M + H ]]+。
Example 11: synthesis of 2- (carboxymethyl) -3,5, 6-trifluoroterephthalic acid (Compound 14)
Figure BDA0002060761550000182
A500 mL four-necked round bottom flask was charged with ethyl 2,3,5, 6-tetrafluoro-4-cyanobenzoate (12.4g,50mmol), potassium carbonate (13.8g,100mmol), and acetonitrile (100mL), and mechanical stirring was initiated. Heating to reflux. A mixture of diethyl malonate (8.5g,53mmol) and acetonitrile (50mL) was added dropwise over 1 hour. After the completion of the dropwise addition, the reaction was continued. The reaction system was followed by HPLC and the reaction was stopped after the disappearance of the starting material ethyl 2,3,5, 6-tetrafluoro-4-cyano-benzoate. Filter and rinse the filter cake with acetonitrile (20 mL). And (4) carrying out reduced pressure distillation on the filtrate at 40-45 ℃, and stopping distillation when no fraction is in a condensation tube. Isopropyl acetate (50mL) was added to the residue, and slurried at 20-25 ℃ for 2 hours. Filtering, washing a filter cake with isopropyl acetate (30mL), and drying by blowing at 50-55 ℃ under normal pressure. To obtain a red powder solid (18.2g,47mmol), i.e., a compound11, molar yield 94%. HPLC purity 98.8%. Ms (esi): m/z 410.0820[ M + Na ]]+
A500 mL single neck round bottom flask was charged with Compound 11(20g,51.6mmol), 48% aqueous hydrobromic acid (100.0g,592.6 mmol) and magnetic stirring was initiated. Heating to 125 ℃, and reacting for 24 hours under the condition of heat preservation. After the reaction, the reaction mixture was distilled under normal pressure to remove 60.0g of hydrobromic acid, and then isopropanol (50mL) was added thereto, followed by stirring at 20 to 30 ℃ for 2 hours. Filtering, leaching a filter cake with isopropanol (10mL), and drying by blowing at 60-70 ℃ under normal pressure. A white solid (13.7g,49.3mmol) was obtained, compound 14, in 95.5% molar yield. HPLC purity 97.4%. Ms (esi): m/z 279.0108[ M + H ]]+。
Example 12: synthesis of 2- (carboxymethyl) -3,5, 6-trifluoroterephthalic acid (Compound 14)
Figure BDA0002060761550000191
A500 mL four-necked round bottom flask was charged with ethyl 2,3,5, 6-tetrafluoro-4-cyanobenzoate (12.4g,50mmol), potassium carbonate (13.8g,100mmol), and acetonitrile (100mL), and mechanical stirring was initiated. Heating to reflux. A mixture of ethyl cyanoacetate (6.0g,53mmol) and acetonitrile (50mL) was added dropwise over 1 hour. After the completion of the dropwise addition, the reaction was continued. The reaction system was followed by HPLC and the reaction was stopped after the disappearance of the starting material ethyl 2,3,5, 6-tetrafluoro-4-cyano-benzoate. Filtration and rinsing of the filter cake with acetonitrile (20 mL). And (4) carrying out reduced pressure distillation on the filtrate at 40-45 ℃, and stopping distillation when no fraction is in a condensation tube. Isopropyl acetate (50mL) was added to the residue, and slurried at 20-25 ℃ for 2 hours. Filtering, washing a filter cake with isopropyl acetate (30mL), and drying by blowing at 50-55 ℃ under normal pressure. A red powder solid (15.6g,46mmol) was obtained as compound 12 in 92% molar yield. HPLC purity 97.6%. Ms (esi): m/z 363.0551[ M + H ]]+
A500 mL single neck round bottom flask was charged with Compound 12(20g,58.8mmol), 48% aqueous hydrobromic acid (100.0g,592.6 mmol) and magnetic stirring was initiated. Heating to 125 ℃, and reacting for 24 hours under the condition of heat preservation. After the reaction is finished, distilling the reaction product at normal pressure, distilling 60.0g of hydrobromic acid, adding isopropanol (50mL) into the reaction product, and stirring the mixture at 20-30 DEG CFor 2 hours. Filtering, leaching a filter cake with isopropanol (10mL), and drying by blowing at 60-70 ℃ under normal pressure. A white solid (14.1g,50.6mmol), Compound 14, was obtained in 86.1% molar yield. HPLC purity 99.34%. Ms (esi): m/z 279.0108[ M + H ]]+。
Example 13: synthesis of 2- (carboxymethyl) -3,5, 6-trifluorobenzoic acid (Compound 13)
Figure BDA0002060761550000192
A1000 mL four-necked round bottom flask was charged with 2,3,5, 6-tetrafluorobenzonitrile (8.8g,50mmol), potassium carbonate (13.8g,100mmol) and acetonitrile (100mL), and mechanical stirring was initiated. Heating to reflux. A mixture of diethyl malonate (8.5g,53mmol) and acetonitrile (50mL) was added dropwise over 1 hour. After the completion of the dropwise addition, the reaction was continued. And (3) tracking the reaction system by HPLC, and stopping the reaction after the raw material 2,3,5, 6-tetrafluorobenzonitrile disappears. Filtration and rinsing of the filter cake with acetonitrile (20 mL). And (4) carrying out reduced pressure distillation on the filtrate at the temperature of between 40 and 45 ℃, and stopping distillation when no fraction is in a condensation pipe. Isopropyl acetate (50mL) was added to the residue, and slurried at 20-25 ℃ for 2 hours. Filtering, washing a filter cake with isopropyl acetate (30mL), and drying by blowing at 50-55 ℃ under normal pressure. A red solid (14.3g,45.5mmol) was obtained as a powder, compound 4, in 88% molar yield and 99.1% HPLC purity. Ms (esi): m/z 338.0631[ M + Na ]]+
A500 ml autoclave was charged with Compound 2(21.5g,68.2mmol) and 80% aqueous sodium hydroxide (29.6g,592.6 mmol), and magnetic stirring was initiated. Heating to 180 deg.c and maintaining the temperature for reaction for 50 hr. After the reaction, the pH was adjusted to 4-5 with aqueous hydrochloric acid. Adding 50mL of isopropanol, and cooling to 20-25 ℃. Filtering, and drying a filter cake by blowing air at the normal pressure of 60-70 ℃. A white solid (12.33g,52.62mmol) was obtained, compound 13, in 77.10% molar yield and 97.0% HPLC purity. Ms (esi): m/z 257.0049[ M + Na ]]+
Example 14: synthesis of 2- (carboxymethyl) -3,5, 6-trifluorobenzoic acid (Compound 13)
Figure BDA0002060761550000201
A250 mL four-necked round bottom flask was charged with 2,3,5, 6-tetrafluorobenzonitrile (8.75g,50mmol), potassium carbonate (13.8g,100mmol) and acetonitrile (100mL) and mechanical stirring was initiated. Heating to reflux. A mixture of malononitrile (3.5g,53mmol) and acetonitrile (50mL) was added dropwise over 1 hour. After the completion of the dropwise addition, the reaction was continued. And (3) tracking the reaction system by HPLC, and stopping the reaction after the raw material 2,3,5, 6-tetrafluorobenzonitrile disappears. Filter and rinse the filter cake with acetonitrile (20 mL). And (4) carrying out reduced pressure distillation on the filtrate at 40-45 ℃, and stopping distillation when no fraction is in a condensation tube. Isopropyl acetate (50mL) was added to the residue and slurried at 20-25 ℃ for 2 hours. Filtering, washing a filter cake with isopropyl acetate (30mL), and drying by blowing at 50-55 ℃ under normal pressure. A red powder solid (9.9g,45mmol) was obtained as compound 3 in 90% molar yield. HPLC purity 98.5%. Ms (esi): m/z 222.0264 [ M + H ]]+。
A500 ml autoclave was charged with Compound 2(21.5g,68.2mmol) and 60% aqueous potassium hydroxide (33.2g,592.6 mmol), and magnetic stirring was initiated. Heating to 160 deg.c and maintaining the temperature for reaction for 35 hr. After the reaction, the pH was adjusted to 4-5 with aqueous hydrochloric acid. Adding 50mL of isopropanol, and cooling to 20-25 ℃. Filtering, and drying a filter cake by blowing air at the normal pressure of 60-70 ℃. A white solid (14.80g,62.71mmol) was obtained, compound 13, in 91.95% molar yield and 99.0% HPLC purity. Ms (esi): m/z 257.0049[ M + Na ]]+
Example 15: synthesis of 2,4, 5-trifluorophenylacetic acid (Compound 15)
Compound 13(10.2g,43.6mmol), cuprous oxide (0.50g), phenanthroline (0.85g), quinoline (20mL) and N-methylpyrrolidone (60mL) were added to a 250mL three-necked round-bottom flask, air in the system was replaced with nitrogen, and magnetic stirring was started. Heating to 170-175 ℃ under the protection of nitrogen, and reacting for 9 hours under heat preservation. After the reaction, water (150mL) was added, and the pH was adjusted to 1 to 2 with a 30% aqueous hydrochloric acid solution (20 mL). The product was extracted with ethyl acetate (200X 2 mL). The organic phases were combined and washed with water (100 mL). And (3) carrying out reduced pressure distillation at 40-45 ℃, and stopping distillation when no fraction is in the condensation pipe. Dichloromethane (50mL) was added to the residue, and the mixture was slurried at 20-25 ℃ for 2 hours. Filtering, leaching a filter cake by using dichloromethane (10mL), and drying by blowing at 40-45 ℃ under normal pressure. A white solid (7.2g,37.9mmol) was obtained, compound 15, in 86.9% molar yield and 99.7% HPLC purity. 1H NMR (400MHz, d 6-DMSO). delta.3.63 (s, 2H), 7.48-7.55 (m, 1H), 12.59 (s, 1H). Ms (esi): m/z 189.0171[ M-H ] -
Example 16: synthesis of 2,4, 5-trifluorophenylacetic acid (Compound 15)
Compound 14(10.2g,36.7mmol), silver oxide (1.50g), phenanthroline (0.85g), quinoline (20mL) and N-methylacetamide (60mL) were added to a 250mL three-necked round-bottom flask, and air in the system was replaced with nitrogen, and magnetic stirring was started. Heating to 150-160 ℃ under the protection of nitrogen, and reacting for 4 hours under heat preservation. After the reaction, water (150mL) was added, and the pH was adjusted to 1 to 2 with a 30% aqueous hydrochloric acid solution (20 mL). The product was extracted with ethyl acetate (200X 2 mL). The organic phases were combined and washed with water (100 mL). And (4) carrying out reduced pressure distillation at 40-45 ℃, and stopping distillation when no fraction is in the condenser pipe. Dichloromethane (50mL) was added to the residue, and the mixture was slurried at 20-25 ℃ for 2 hours. Filtering, washing the filter cake with dichloromethane (10mL), and drying by blowing at 50-60 ℃ under normal pressure. A white solid (7.2g,30.8mmol) was obtained, compound 15, in 83.9% molar yield and 98.7% HPLC purity.1H NMR(400MHz，d6-DMSO)δ3.63(s，2H)，7.48～7.55(m，1H)，12.59 (s，1H)。MS(ESI)：m/z 189.0171[M-H]-。

Claims (5)

1. The method for preparing the sitagliptin intermediate 2,4, 5-trifluoro-phenylacetic acid is characterized in that the sitagliptin intermediate is prepared by decarboxylation reaction of a compound shown in a formula 6 under the catalysis of a catalyst, wherein the catalyst is a metal oxide:
Figure DEST_PATH_IMAGE001
R7is-H or-COOH, and the metal oxide is cuprous oxide or silver oxide;
wherein, the precursor compound 5 is hydrolyzed to prepare the compound shown in the formula 6:
Figure 763439DEST_PATH_IMAGE002
R1is-H, -CN, -COOH or-COOR4，R2、R3Are each-COOR4、-CN；
R4Is an alkyl group;
R7is-H or-COOH;
the hydrolysis step is carried out under conditions of water and protonic acid.
2. The preparation method of sitagliptin intermediate 2,4, 5-trifluoro-phenylacetic acid is characterized in that the sitagliptin intermediate is prepared by decarboxylation reaction of a compound shown in a formula 2 under the catalysis of a catalyst, wherein the catalyst is a metal oxide:
Figure DEST_PATH_IMAGE003
；
the metal oxide catalyst in the decarboxylation step is silver oxide or cuprous oxide;
wherein, the compound of formula 1 is hydrolyzed under the condition of water and protonic acid to prepare the compound of formula 2;
Figure 149421DEST_PATH_IMAGE004
(ii) a R is a straight chain or branched alkyl;
the compound of the formula 1 is prepared by a compound 2,3,5, 6-tetrafluorobenzonitrile and cyanoalkanoate through a substitution reaction;
Figure DEST_PATH_IMAGE005
。
3. the method according to claim 2, wherein the reaction temperature in the hydrolysis step is 100 to 220 ℃.
4. The production method according to claim 2, wherein the molar equivalent ratio of the reaction catalyst to the starting material in the decarboxylation reaction step is 0.05 to 5.
5. The production method according to claim 2, wherein the reaction temperature in the decarboxylation reaction step is 120 to 220 ℃.
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