CN115385919A

CN115385919A - Synthetic method of sitagliptin

Info

Publication number: CN115385919A
Application number: CN202211046020.3A
Authority: CN
Inventors: 尹强; 何义; 张伸; 徐盛; 陆梦云; 付齐
Original assignee: Jiangsu Alpha Pharmaceutical Co ltd
Current assignee: Jiangsu Alpha Pharmaceutical Co ltd
Priority date: 2022-08-30
Filing date: 2022-08-30
Publication date: 2022-11-25

Abstract

The invention relates to a synthesis method of sitagliptin, belonging to the technical field of drug synthesis. In order to solve the problem of reducing the production cost, the method provides a synthesis method of sitagliptin, which comprises the steps of taking L-aspartic acid-4-ester as a starting material, generating an intermediate compound, reacting the intermediate compound with halide to generate a tri-compound in a formula, reacting the tri-compound with 2,4, 5-trifluorobenzaldehyde to generate an intermediate compound (R) -3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) methyl butyrate, hydrolyzing to obtain a sitagliptin intermediate (R) -3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) butyric acid in a formula, condensing with 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine hydrochloride to obtain tert-butyloxycarbonyl acetal of the sitagliptin, and deprotecting methanol hydrochloride to obtain the sitagliptin; the invention has the advantages of cheap reaction catalyst, low production cost and short reaction route on the whole.

Description

Synthetic method of sitagliptin

Technical Field

The invention relates to a synthetic method of sitagliptin, belonging to the field of medicine preparation.

Background

Sitagliptin (Sitagliptin), developed and developed by american merck company, is a dipeptidyl peptidase-IV inhibitor drug for treating type II diabetes, which increases insulin secretion in the body of a patient when blood sugar rises by improving insulin production capability of islet beta cells of the patient, thereby controlling the blood sugar level of the patient with diabetes, not only having good treatment effect, but also not producing tolerance, and not bringing the risk of hypoglycemia in the treatment process.

The active ingredient is (3R) -3-amino-1- [3- (trifluoromethyl) -5, 6-dihydro-1, 2, 4-triazolo [4,3-a ] pyrazin-7 (8H) -yl ] -4- (2, 4, 5-trifluorophenyl) butan-1-one (formula I), and the structural formula is shown as follows:

at present, the synthesis methods of sitagliptin are more, the steps related to chiral induction and asymmetric hydrogenation are fewer, four steps are five, the steps are more, and more, the steps are ten steps.

For example, in CN102153559B, L-aspartic acid is used as an example of the raw material after modification to react with 2,4, 5-trifluorohalobenzene, but since trifluorohalobenzene is first used as a zinc reagent, expensive palladium catalyst must be used to catalyze the reaction during the reaction process, the production cost is high and the production scale-up is not good, and the route of the synthesis process is as follows:

in patent WO03004498, a synthetic route is reported in which an ester intermediate is subjected to noble metal catalysis to obtain an intermediate, and noble metal rhodium and ferrocenyl diphosphine used in the reaction process are expensive substances, and are not suitable for industrial scale-up production.

Patent WO2010078440 reports a synthesis route of 2,4,5-trifluorophenylacetic acid and magnesium malonate to obtain an ester intermediate, raw materials of the method are also expensive, the production cost is increased, and the industrial production is limited, and the synthesis route is shown as follows:

it can be seen from the above documents that the common disadvantage is high production cost, which limits the industrial production.

Therefore, a synthesis method with low production cost, short reaction route and high product yield is urgently needed.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides a synthesis method of sitagliptin, and solves the problem of how to realize a preparation method which reduces the production cost and shortens the reaction route.

The invention aims to realize the following technical scheme, and the method for synthesizing sitagliptin comprises the following steps:

s1: taking L-aspartic acid-4-ester as a starting material to generate an intermediate compound (S) -4-p-toluenesulfonyloxy-3-tert-butoxycarbonyl methyl aminobutyric acid;

s2: reacting the intermediate compound obtained in the step S1 with halide to generate a compound shown in the formula III;

s3: reacting the compound obtained in the step S2 with 2,4, 5-trifluorobenzaldehyde to generate an intermediate compound (R) -3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) methyl butyrate;

s4: hydrolyzing the intermediate compound obtained in the step S3 to obtain a sitagliptin intermediate (R) -3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) butyric acid of the compound in the formula II;

s5: condensing sitagliptin intermediate (R) -3-tert-butyloxycarbonylamino-4- (2, 4, 5-trifluorophenyl) butyric acid and 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine hydrochloride to obtain tert-butyloxycarbonyl acetal of sitagliptin;

s6: and (3) deprotecting the acetal product compound obtained in the step (S5) by using hydrochloric acid methanol to obtain the undecaprate compound sitagliptin.

The total synthetic route is as follows:

the synthetic route of a compound of the formula (I) is as follows:

the synthetic route of the compound of the formula III:

synthetic routes to compounds of formula (la):

according to the invention, L-aspartic acid-4-ester is adopted to be modified, a final product halogenated tert-butoxycarbonyl methyl aminobutyric acid obtained through reaction retains a chiral amino structure of L-aspartic acid, the halogenated tert-butoxycarbonyl methyl aminobutyric acid is reacted with 2,4, 5-trifluorobenzaldehyde to synthesize an intermediate compound, a sitagliptin intermediate (formula II) can be obtained only through hydrolysis, the obtained compound of formula II and 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4, 3-alpha ] pyrazine hydrochloride are condensed to generate tert-butyloxycarbonyl acetal of sitagliptin, and the sitagliptin can be obtained through deprotection of methanol hydrochloride.

A compound of the formula:

the compound of formula (II) has the following structural formula:

the compound of formula III has the following structural formula:

wherein X in the compound shown in the formula III is bromine, chlorine or iodine.

In the above synthesis method of sitagliptin intermediate, preferably, the solvent in the step S1 can be one of dichloromethane and dichloroethane, which can better dissolve the intermediate compound. Preferably, dichloromethane is selected as the solution, which is cheap and has a faster reaction rate.

In the above method for synthesizing a sitagliptin intermediate, preferably, the reagent used in the step S2 is one of sodium bromide, potassium chloride and sodium iodide, and an intermediate compound capable of reacting with benzaldehyde is generated. Preferably, sodium bromide is selected as the catalyst, and the reaction is more complete compared with the reaction with faster reaction rate.

In the synthetic method of the sitagliptin intermediate, preferably, the halogenation reaction temperature in the step S2 is 68-80 ℃, so that the reaction rate can be improved. Preferably, the reaction temperature can be set to 75 ℃, which can shorten the reaction time.

In the synthesis method of the sitagliptin intermediate, preferably, the step S3 reaction occurs in an ether solvent, and the ether solvent may be one of tetrahydrofuran and dioxane. The ether solvent is easy to operate, has relatively little pollution to the environment and can reduce the overall production cost. Preferably, tetrahydrofuran is selected as the ether solvent, so that the reaction stability can be improved, the reaction can be better promoted, and the product yield can be improved.

In the above synthesis method of sitagliptin intermediate, the reaction temperature in the step S4 is preferably-70 ℃ to-80 ℃. The reaction process is slowed down at low temperature, and the reaction is more stable. Preferably, the reaction temperature can be set to-78 ℃, so that the stability of the reaction compound and the reaction solvent is improved, and the reaction is facilitated.

In the above synthesis method of sitagliptin intermediate, preferably, the S5 step occurs in an alcoholic solvent, which may be one of methanol, ethanol or propanol. The alcohol solvent has better inclusion and stability, can ensure that the reaction process is carried out stably, and is low in price, thereby being beneficial to reducing the production cost. Preferably, methanol can be used as a reaction solvent, so that the reaction process is more stable.

In the synthesis method of the sitagliptin intermediate, preferably, the catalyst used in the step S6 can be one of diisopropylethylamine and triethylamine, so that the reaction efficiency can be improved. Preferably, the by-product of diisopropylethylamine is used for easier handling.

In summary, compared with the prior art, the invention has the following advantages:

1. the catalyst used in the reaction route of the invention has low price, and compared with expensive catalysts used in other reaction routes, such as palladium catalyst, rhodium catalyst and ferrocenyl diphosphine, the catalyst can reduce the production cost and is beneficial to expanding the production.

The product generated by taking the L-aspartic acid-4-ester as the starting raw material keeps the chiral amino structure of the L-aspartic acid, the complex steps for synthesizing the chiral amino at the later stage are reduced, the obtained intermediate compound can generate a sitagliptin intermediate only by hydrolysis, and the reaction efficiency is further improved.

Drawings

FIG. 1 is a general synthetic route according to the present invention;

FIG. 2 is a scheme for synthesizing a tri-compound of formula (III) according to the present invention;

FIG. 3 is a scheme for the synthesis of two compounds of the present invention;

FIG. 4 is a scheme showing the synthesis of a compound of the formula;

FIG. 5 is a structural formula of a compound of formula (I);

FIG. 6 is a structural formula of a compound of formula (II A);

FIG. 7 shows the structure of the compound of formula III.

Detailed Description

The technical solution of the present invention will be further specifically described below by way of specific examples, but the present invention is not limited to these examples.

Example 1

The first step is as follows: preparation of N-Boc-L-aspartic acid-4-methyl ester:

91.8g of L-aspartic acid-4-methyl ester hydrochloride was dissolved in 1000ml of water, and then 42.0g of sodium hydrogencarbonate was slowly added thereto, followed by stirring for 30 minutes. 750ml of an acetone solution containing 109.1g of Boc anhydride was added dropwise thereto, and the mixture was stirred at room temperature overnight after the addition. After the reaction, filtration was carried out, the filter cake was washed with a small amount of acetone, the filtrates were combined and acetone was distilled off, the aqueous phase was extracted with 500ml of ethyl acetate, the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate for 1 hour, filtered and concentrated to give 105.9g of N-Boc-L-aspartic acid-4-methyl ester as a colorless oily substance with a yield of 85.7%.

The second step is that: preparation of (S) -4-hydroxy-3-tert-butoxycarbonylaminobutyric acid methyl ester

Under the protection of nitrogen, 123.6g of N-Boc-L-aspartic acid-4-methyl ester is dissolved in 1000ml of tetrahydrofuran, the reaction temperature is reduced to-10 ℃, and 50.5g of N-methylmorpholine is added. Controlling the temperature to be minus 10 ℃, starting to dropwise add 54.2g of ethyl chloroformate, and stirring for 10 minutes after the dropwise addition is finished. Adding 18.9g of sodium borohydride in batches, slowly dropping 1000ml of methanol after the sodium borohydride is added, controlling the gas generation speed, controlling the temperature to be below-3 ℃, continuously stirring for 30min after the dropping is finished, evaporating tetrahydrofuran and methanol, adding 100ml of water for dissolving, extracting by ethyl acetate (750 ml multiplied by 3), combining organic phases, washing by potassium bisulfate, 5% of sodium bicarbonate and saturated salt water respectively, drying for 1 hour by anhydrous sodium sulfate, and filtering to obtain 76.9g of light-colored oily product (S) -4-hydroxy-3-tert-butyloxycarbonylaminobutyric acid methyl ester, wherein the yield is 66%.

The third step: preparation of (S) -4-p-toluenesulfonyloxy-3-tert-butoxycarbonylaminobutyric acid methyl ester

Under the protection of nitrogen, 116.6g of (S) -4-hydroxy-3-tert-butoxycarbonyl-aminobutyric acid methyl ester is dissolved in 500ml of dichloromethane, the mixture is cooled to 0 ℃ in an ice water bath, 50.6g of triethylamine is added, then 200ml of dichloromethane solution containing 36.57g of paratoluensulfonyl chloride is added dropwise, and after the dropwise addition is finished, the temperature is raised to room temperature. After the reaction, 100ml of water was added to separate the organic phase, the aqueous phase was extracted with a small amount of methylene chloride, and the organic phase was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate for 1 hour, and filtered to obtain 111.58g of (S) -4-p-toluenesulfonyloxy-3-tert-butoxycarbonylamino methyl butyrate as a pale-colored oily product with a yield of 57.6%.

The fourth step: preparation of methyl (S) -4-bromo-3-tert-butoxycarbonylaminobutyric acid (formula III)

Under the protection of nitrogen, 193.7g of (S) -4-p-toluenesulfonyloxy-3-tert-butoxycarbonyl methyl aminobutyric acid is dissolved in 1000ml of acetone, 51.4g of sodium bromide is added, then 147.7g of ferric bromide is added, the temperature is raised to 75 ℃, stirring is carried out for 12 hours, after the reaction is finished, partial solvent is evaporated under reduced pressure, 200ml of 5% sodium bisulfite solution is added into the reaction system, the system is extracted by 100ml of ethyl acetate for 2 times, the combined organic phase is washed by water twice, washed by saturated salt water once, dried by anhydrous sodium sulfate for 2 hours, filtered, and the solvent is evaporated under reduced pressure to obtain 164.7g of (S) -4-bromo-3-tert-butoxycarbonyl methyl aminobutyric acid as pale yellow oily liquid, wherein the yield is 96%.

The fifth step: preparation of (R) -3-t-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) butanoic acid (formula II)

171.6g of methyl (S) -4-bromo-3-tert-butoxycarbonylaminobutyric acid was dissolved in 500mL of tetrahydrofuran under a nitrogen atmosphere, and 20.5g of cuprous dimethyl sulfide bromide was added to disperse the solution uniformly. Cooling the reaction system to-78 ℃, adding 88.27g of 2,4, 5-trifluorobenzaldehyde and 500ml of tetrahydrofuran solution, maintaining the temperature at about-78 ℃, keeping the temperature for 30min, slowly raising the temperature to room temperature, stirring overnight, after the reaction is finished, adding 100ml of water, stirring for 1 hour, adding 50ml of ethyl acetate for layering, and drying for 1 hour by using anhydrous sodium sulfate to obtain 143.1g of (R) -3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) methyl butyrate, wherein the yield is 82.4%.

173.6g of methyl (R) -3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) butyrate was dissolved in 500mL of methanol, 100mL of an aqueous solution of 12g of lithium hydroxide was added with stirring to react at room temperature for 2 to 3 hours, after the reaction was completed, an aqueous solution of sodium hydrogensulfate was slowly added, the pH was adjusted to 3 and then stopped, 50mL of ethyl acetate was added to extract 2 times, the combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain 160.8g of (R) -3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) butyrate as a white solid product, with a yield of 96.5%.

Example 2

This example is the preparation of sitagliptin

166.7g of (R) -3- ((R) -tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) butyric acid and 114.3g of 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine hydrochloride were dissolved in 1000ml of dichloromethane solution, cooled to 5 ℃, and then 64.62g of diisopropylethylamine was slowly added dropwise thereto, stirring was carried out while maintaining the temperature for 30min, 67.5g of 1-hydroxybenzotriazole was added to the solution in portions, stirring was continued for 60min while controlling the temperature at 5 ℃, 95.9g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added in portions again, and stirring was carried out overnight at room temperature to obtain 227.58g of intermediate N-tert-butoxycarbonyl-sitagliptin with a yield of 89.7%.

Adding 253.7g of N-tert-butoxycarbonyl-sitagliptin into 1000ml of HCl/MeOH solution at room temperature, stirring for 12 hours at room temperature, pouring the reaction solution into 1000ml of water after the reaction is finished, adding 100ml of ethyl acetate to extract the water phase, drying, and concentrating to obtain 182.06g of final product sitagliptin with the yield of 89.4%.

Example 3

Under the protection of nitrogen, 116.6g of (S) -4-hydroxy-3-tert-butoxycarbonylaminobutyric acid methyl ester is dissolved in 500ml of dichloroethane, the cooled dichloroethane is cooled to 0 ℃ in an ice water bath, 50.6g of triethylamine is added, 200ml of dichloroethane solution containing 36.57g of p-toluenesulfonyl chloride is added dropwise, and after the dropwise addition is finished, the temperature is raised to room temperature. After the reaction, 100ml of water was added to separate the organic phase, the aqueous phase was extracted with a small amount of dichloroethane, the organic phase was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate for 1 hour, and filtered to obtain 100.73g of methyl (S) -4-p-toluenesulfonyloxy-3-tert-butoxycarbonylaminobutyric acid as a pale oily product in 52% yield.

Example 4

Under the protection of nitrogen, 193.7g of (S) -4-p-toluenesulfonyloxy-3-tert-butoxycarbonylaminobutyric acid methyl ester is dissolved in 1000ml of acetone, 37.27g of potassium chloride is added, then 147.7g of ferric bromide is added, the temperature is increased to 75 ℃, stirring is carried out for 12 hours, after the reaction is finished, partial solvent is evaporated under reduced pressure, 200ml of 5% sodium bisulfite solution is added into the reaction system, the system is extracted for 2 times by 100ml of ethyl acetate, the combined organic phases are washed twice by water, washed by saturated common salt water, dried for 2 hours by anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure to obtain 146.68g of (S) -4-chloro-3-tert-butoxycarbonylaminobutyric acid methyl ester as a light yellow oily liquid, wherein the yield is 85.5%.

Example 5

Under the protection of nitrogen, 193.7g of (S) -4-p-toluenesulfonyloxy-3-tert-butoxycarbonyl methyl aminobutyric acid is dissolved in 1000ml of acetone, 74.9g of sodium iodide is added, then 147.7g of ferric bromide is added, the temperature is raised to 75 ℃, stirring is carried out for 12 hours, after the reaction is finished, partial solvent is evaporated under reduced pressure, 200ml of 5% sodium bisulfite solution is added into the reaction system, the system is extracted for 2 times by 100ml of ethyl acetate, the combined organic phase is washed twice by water, washed by saturated salt water, dried by anhydrous sodium sulfate for 2 hours, filtered, and the solvent is evaporated under reduced pressure to obtain 134.1g of (S) -4-iodo-3-tert-butoxycarbonyl methyl aminobutyric acid as a light yellow oily liquid, wherein the yield is 78.2%.

Example 6

Under the protection of nitrogen, 193.7g of (S) -4-p-toluenesulfonyloxy-3-tert-butoxycarbonylaminobutyric acid methyl ester is dissolved in 1000ml of acetone, 51.4g of sodium bromide is added, then 147.7g of ferric bromide is added, the temperature is increased to 68 ℃, stirring is carried out for 12 hours, after the reaction is finished, partial solvent is evaporated under reduced pressure, 200ml of 5% sodium bisulfite solution is added into the reaction system, the system is extracted for 2 times by 100ml of ethyl acetate, the combined organic phases are washed twice by water, washed by saturated common salt water, dried for 2 hours by anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure to obtain 152.8g of (S) -4-bromo-3-tert-butoxycarbonylaminobutyric acid methyl ester as pale yellow oily liquid with the yield of 89.1 percent

Example 7

Under the protection of nitrogen, 193.7g of (S) -4-p-toluenesulfonyloxy-3-tert-butoxycarbonyl methyl aminobutyric acid is dissolved in 1000ml of acetone, 51.4g of sodium bromide is added, then 147.7g of ferric bromide is added, the temperature is raised to 80 ℃, stirring is carried out for 12 hours, after the reaction is finished, partial solvent is evaporated under reduced pressure, 200ml of 5% sodium bisulfite solution is added into the reaction system, the system is extracted by 100ml of ethyl acetate for 2 times, the combined organic phase is washed by water twice, washed by saturated salt water once, dried by anhydrous sodium sulfate for 2 hours, filtered, and the solvent is evaporated under reduced pressure to obtain 156.8g of (S) -4-bromo-3-tert-butoxycarbonyl methyl aminobutyric acid as pale yellow oily liquid with the yield of 91.4 percent

Example 8

171.6g of methyl (S) -4-bromo-3-tert-butoxycarbonylaminobutyric acid was dissolved in 500mL of dioxane under nitrogen protection, and 20.5g of cuprous dimethyl sulfide bromide was added to disperse the solution uniformly. Cooling the reaction system to-78 ℃, adding 88.27g of 2,4, 5-trifluorobenzaldehyde and 500ml of dioxane solution, maintaining the temperature at about-78 ℃, keeping the temperature for 30min, slowly raising the temperature to room temperature, stirring overnight, after the reaction is finished, adding 100ml of water, stirring for 1 hour, adding 50ml of ethyl acetate for layering, and drying for 1 hour by anhydrous sodium sulfate to obtain 133.02g of (R) -3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) methyl butyrate, wherein the yield is 76.6%.

Example 9

171.6g of methyl (S) -4-bromo-3-tert-butoxycarbonylaminobutyric acid was dissolved in 500mL of tetrahydrofuran under a nitrogen atmosphere, and 20.5g of cuprous dimethyl sulfide bromide was added to disperse the solution uniformly. Cooling the reaction system to-80 ℃, adding 88.27g of 2,4, 5-trifluorobenzaldehyde and 500ml of tetrahydrofuran solution, maintaining the temperature at about-80 ℃, keeping the temperature for 30min, slowly raising the temperature to room temperature, stirring overnight, after the reaction is finished, adding 100ml of water, stirring for 1 hour, adding 50ml of ethyl acetate for layering, and drying for 1 hour by using anhydrous sodium sulfate to obtain 131.46g of (R) -3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) methyl butyrate, wherein the yield is 75.7%.

Example 10

171.6g of methyl (S) -4-bromo-3-tert-butoxycarbonylaminobutyric acid was dissolved in 500mL of tetrahydrofuran under a nitrogen atmosphere, and 20.5g of cuprous dimethyl sulfide bromide was added to disperse the solution uniformly. Cooling the reaction system to-70 ℃, adding 88.27g of 2,4, 5-trifluorobenzaldehyde and 500ml of tetrahydrofuran solution, maintaining the temperature at about-70 ℃, keeping the temperature for 30min, slowly raising the temperature to room temperature, stirring overnight, after the reaction is finished, adding 100ml of water, stirring for 1 hour, adding 50ml of ethyl acetate for layering, and drying for 1 hour by using anhydrous sodium sulfate to obtain 125.7g of (R) -3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) methyl butyrate, wherein the yield is 72.4%.

Example 11

The temperature is reduced to 5 ℃, 186.4g of methoxymethyltriphenylphosphonium chloride is dissolved in 500ml of dioxane, 24g of sodium hydride is added in batches, the mixture is heated to room temperature and stirred for 6 hours, then 80.5g of 2,4, 5-trifluorobenzaldehyde is added, the mixture is stirred for 12 hours at room temperature and filtered, 80.7g of 1,2, 4-trifluoro-5- (2-methoxyvinyl) benzene is obtained as a light yellow oily substance, and the yield is 85.8%.

94g of 1,2, 4-trifluoro-5- (2-methoxyvinyl) benzene is dissolved in 500ml of dioxane solution, the temperature is reduced to-20-20 ℃,20 ml of concentrated hydrochloric acid is slowly dripped, after the addition, the temperature is raised to 40 ℃, the stirring is carried out for 3 hours, the reaction liquid is poured into water, 50ml of ethyl acetate is added to extract an aqueous phase, a saturated saline solution is used to wash an organic phase, the solvent is pumped out, and 75.75g of light yellow oily matter 2- (2, 4, 5-trifluorophenyl) acetaldehyde is obtained after concentration, and the yield is 87%.

Example 12

173.6g of (R) -methyl 3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) butanoate was dissolved in 500mL of ethanol, and 100mL of an aqueous solution of 12g of lithium hydroxide was added with stirring to react at room temperature for 2 to 3 hours, after the completion of the reaction, an aqueous solution of sodium hydrogensulfate was slowly added, the reaction was stopped after adjusting the pH to 3, 50mL of ethyl acetate was added to extract 2 times, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain 148.3g of (R) -3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) butanoic acid as a white solid product with a yield of 89%.

Example 13

173.6g of methyl (R) -3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) butanoate was dissolved in 500mL of propanol, and 100mL of an aqueous solution of 12g of lithium hydroxide was added with stirring to react at room temperature for 2 to 3 hours, after the completion of the reaction, an aqueous solution of sodium hydrogensulfate was slowly added, the reaction was stopped after adjusting the pH to 3, 50mL of ethyl acetate was added to extract 2 times, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain 145.9g of (R) -3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) butanoic acid as a white solid product with a yield of 87.6%.

Example 14

166.7g of (R) -3- ((R) -tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) butyric acid and 114.3g of 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine hydrochloride were dissolved in 1000ml of dichloromethane solution, cooled to 5 ℃, 50.6g of triethylamine was slowly added dropwise thereto, stirring was carried out while maintaining the temperature for 30min, 67.5g of 1-hydroxybenzotriazole was added to the solution in portions, stirring was continued for 60min while controlling the temperature at 5 ℃, 95.9g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added again in portions, and stirring was carried out overnight at room temperature to obtain 210.3g of intermediate N-tert-butoxycarbonyl-sitagliptin with a yield of 82.9%.

Example 15

This embodiment is an embodiment of the publication document CN102153559A

The first step is as follows: amino protection

20g of L-aspartic acid and 200ml of methanol are added into a three-neck flask provided with a magnetic stirrer and a thermometer, 5ml of thionyl chloride is dropwise added after cooling, the mixture is stirred for 5 hours at room temperature after dropwise addition, and the solid 4-L-aspartic acid methyl ester hydrochloride 40g is obtained by decompression, concentration and desolventization.

20g of 4-L-aspartic acid methyl ester hydrochloride and 20g of sodium bicarbonate are added into a three-neck flask provided with a magnetic stirrer and a thermometer, dissolved in water and 1, 4-dioxane, boc anhydride is added after the dissolution is clear, the mixture is stirred overnight, filtered, 2L of water is added into mother liquor, and the pH value is adjusted by hydrochloric acid. Then, the mixture was extracted with ethyl acetate 3 times, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to remove the solvent to obtain 31g of N-t-butoxycarbonyl-4-L-aspartic acid methyl ester as a pale yellow oily liquid.

The second step is that: esterification

Dissolving 30g of N-tert-butoxycarbonyl-4-L-aspartic acid methyl ester in ethyl acetate, adding 29g of N-hydroxysuccinimide, stirring and dropwise adding 30g of EDCI, dissolving in 100ml of ethyl acetate, stirring, carrying out suction filtration, washing mother liquor twice, drying organic phase anhydrous sodium sulfate, and carrying out reduced pressure concentration and solvent removal to obtain 39g of light yellow oily liquid (3S) -N-tert-butoxycarbonyl-3-amino-4-succinimide oxybutyric acid methyl ester.

The third step: reduction and iodination

Reduction: 1.4g of sodium borohydride is dissolved in 100ml of THF, and is dripped into 20g of (3S) -N-tert-butoxycarbonyl-3-amino-4-iodobutanoic acid methyl ester and 50ml of THF, a large amount of bubbles are generated, the temperature is raised to 30 ℃, the dripping is finished, the reaction is finished, ethyl acetate is extracted for 2 times, anhydrous sodium sulfate is dried, and 5.5g of solvent is removed by decompression and concentration.

Iodination: 9.8g triphenyl phosphine is dissolved in 70ml dichloromethane, 1g imidazole is added after the solution is clear, 2g iodine is added, the temperature is raised to 34 ℃, after 20min reaction, 3.8g of the light yellow oily liquid obtained above is slowly added, the reaction is tracked by a point plate, after the raw material point disappears, the filtration is carried out, the saturated salt water is washed for 2 times, the organic layer is dried by anhydrous sodium sulfate, and the dichloromethane is evaporated under reduced pressure, thus obtaining 3.5g of white solid (3S) -N-tert-butyloxycarbonyl-3-amino-4-iodobutanoic acid methyl ester.

The fourth step: puppet exercise

1.48g of zinc powder and 2.5ml of DMF are taken, 1ml of 1, 2-dibromoethane is added under the protection of nitrogen at 50 ℃, the stirring reaction is carried out for 20min, the heating is stopped, trimethylchlorosilane is added at 30 ℃, the reaction is weakly exothermic, 1.3g of (3S) -N-tert-butoxycarbonyl-3-amino-4-iodobutanoic acid methyl ester and 10ml of DMF solution are added after 20min, the point plate tracking reaction is carried out, the raw material point disappears after 30min, the catalyst of palladium bis (triphenylphosphine) chloride is added, 1.2g of 2,4, 5-trifluoro iodobenzene is slowly injected by an injector at 30 ℃, the exothermic reaction is completed, the high efficiency liquid phase tracking reaction is carried out, 50ml of ethyl acetate is used for diluting the reaction solution after the raw material point disappears, the mother solution is filtered, the mother solution is washed by saturated common salt water for 2 times, the water washing is carried out for 2 times, anhydrous sodium sulfate is dried, and the reduced pressure concentration is carried out to obtain the product of (3R) -N-tert-butoxycarbonyl-3-amino-4- (2, 4, 5-trifluorophenyl) methyl butyrate.

The fifth step: hydrolysis and amide formation

1.3g of (3R) -N-tert-butoxycarbonyl-3-amino-4- (2, 4, 5-trifluorophenyl) methyl butyrate is added with methanol and 30 percent by mass of lithium hydroxide aqueous solution, after the reaction is completed, the mixture is neutralized and extracted, after drying and concentration, 1.0g of DCC, 1.2g of 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine hydrochloride and 0.5g of triethylamine are added, after the reaction is continued after slowly raising the temperature to the room temperature, the generated N, N' -dicyclohexylurea is removed by filtration, the solvent is removed by rotary evaporation, the residue is dissolved by a small amount of acetic acid ethyl acetate and then is removed by little rotary evaporation, the residue is separated by column chromatography to obtain 1.5g of white foamy solid, and the yield is 55.7%.

By contrast, publication CN102153559A has a short synthetic route but has a lower synthetic efficiency than the present invention.

The specific embodiments described herein are merely illustrative of the spirit of the invention. Various modifications or additions may be made to the described embodiments or alternatives may be employed by those skilled in the art without departing from the spirit or ambit of the invention as defined in the appended claims.

While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

Claims

1. A synthetic method of sitagliptin, which is characterized by comprising the following steps:

s1: taking L-aspartic acid-4-ester as a starting material to generate an intermediate compound (S) -4-p-toluenesulfonyloxy-3-tert-butoxycarbonylaminobutyric acid methyl ester;

s3: reacting the compound obtained in the step S2 with 2,4,5 trifluorobenzaldehyde to generate an intermediate compound (R) -methyl 3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) butyrate;

s5: condensing sitagliptin intermediate (R) -3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) butyric acid and 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine hydrochloride to obtain tert-butyloxycarbonyl acetal of sitagliptin;

s6: and (3) deprotecting the acetal product compound obtained in the step (S5) by using methanol hydrochloride to obtain sitagliptin which is a compound shown as the formula.

2. The method for synthesizing sitagliptin according to claim 1, which is characterized in that: the solvent in the step S1 can be one of dichloromethane and dichloroethane.

3. The method for synthesizing sitagliptin according to claim 1, characterized in that: and the reagent used in the step S2 is one of sodium bromide, potassium chloride and sodium iodide.

4. The method for synthesizing sitagliptin according to claim 1, characterized in that: and the temperature of the halogenation reaction in the step S2 is 68-80 ℃.

5. The method for synthesizing sitagliptin according to claim 1, which is characterized in that: the reaction in the step S3 is carried out in an ether solvent, wherein the ether solvent can be one of tetrahydrofuran and dioxane.

6. The method for synthesizing sitagliptin according to claim 1, which is characterized in that: the esterification reaction temperature in the step S3 is-70 ℃ to-80 ℃.

7. The method for synthesizing sitagliptin according to claim 1, characterized in that: the step S4 takes place in an alcoholic solvent, which may be selected from one of methanol, ethanol or propanol.

8. The method for synthesizing sitagliptin according to claim 1, which is characterized in that: the catalyst used in the step S5 can be one of diisopropylethylamine and triethylamine.