Synthesis method of sitagliptin

Abstract

The invention relates to the field of chemical synthesis of medicines, and discloses a synthesis method of sitagliptin, which comprises the following steps: carrying out asymmetric hydroamination reaction on (E)-4-(2, 4, 5-trifluorophenyl)-butyl-2-ethyl olefine acid and an ammonia source at room temperature in the presence of a copper (I) catalyst, a chiral ligand, a hydrogen source, a strong base and a solvent to obtain a chiral hydroamination intermediate; carrying out hydrolysis reaction on ethyl ester in the chiral hydroamination intermediate to obtain a hydrolysis intermediate; the hydrolysis intermediate and 3-(trifluoromethyl)-5, 6, 7, 8-tetrahydro-[1, 2, 4] triazolo [4, 3-a] pyrazine are subjected to an amidation reaction in the presence of a condensation reagent, and an amidation intermediate is obtained; and carrying out debenzylation reaction on the amidation intermediate under the action of a catalyst and hydrogen to obtain sitagliptin. By introducing a brand-new catalytic system, the total yield is increased, and the enantioselectivity is remarkably improved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemical synthesis, and more particularly to a method for synthesizing sitagliptin. Background Technology

[0002] Sitagliptin (Formula I) is an important anti-type 2 diabetes drug. As a dipeptidyl peptidase-IV (DPP-IV) inhibitor, its synthesis methods have been reported in various ways.

[0003] In the prior art, patent CN103819475B provides a synthetic route using 2,4,5-trifluorophenylacetic acid as a starting material, which yields sitagliptin through esterification, reduction, oxidation, Wittig reaction, hydroamination, ester hydrolysis, amidation, and debenzylation. The overall yield of this reaction is not high. Summary of the Invention

[0004] The main objective of this invention is to solve the technical problems of high cost and limited efficiency in the synthesis of sitagliptin in the prior art. A method for synthesizing sitagliptin includes the following steps: Ethyl (E)-4-(2,4,5-trifluorophenyl)-but-2-enoate undergoes an asymmetric hydroamination reaction with an ammonia source at room temperature in the presence of a copper (I) catalyst, a chiral ligand, a hydrogen source, a strong base, and a solvent to yield a chiral hydroamination intermediate. The ethyl ester in the chiral hydrogenation intermediate undergoes a hydrolysis reaction to yield the hydrolysis intermediate: The chiral hydroamic intermediate was added to hydrochloric acid and refluxed. The mixture was cooled in an ice-water bath, and the layers separated. The upper water layer was poured off, and the lower oily layer was dissolved in dichloromethane, washed with saturated sodium bicarbonate, separated, and dried to obtain the hydrolysis intermediate.

[0005] The hydrolysis intermediate reacts with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine in the presence of a condensing agent, yielding the amidated intermediate: Under ice-water bath conditions, the hydrolysis intermediate was dissolved in dichloromethane, DIPEA and 1-hydroxybenzotriazole were added, and trimethylacetyl chloride was added dropwise. After reacting for 1-3 hours, 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine was added, and stirring was continued at room temperature for 10-40 hours. The mixture was washed with water and sodium bicarbonate, dried, and recrystallized to obtain the amidated intermediate.

[0006] The amidation intermediate undergoes a debenzylation reaction in the presence of a catalyst and hydrogen to yield sitagliptin: In a hydrogen-filled reactor, the amidation intermediate is dissolved in methanol, a palladium / carbon catalyst and glacial acetic acid are added, the pressure is increased to 30-50 atm, and the reaction is carried out at 40-70°C for 10-50 h. The mixture is then filtered, dissolved in dichloromethane, washed with sodium bicarbonate and evaporated to dryness to obtain sitagliptin.

[0007] The present invention has the following beneficial effects: This invention introduces a novel catalytic system, which significantly improves yield and enantioselectivity, resulting in unexpected technical effects. Detailed Implementation

[0008] The terms “first,” “second,” “third,” “fourth,” etc. (if applicable) in the specification and claims of this invention are used to distinguish similar objects and are not necessarily used to describe a specific order or sequence. It should be understood that such data used can be interchanged where appropriate so that the embodiments described herein can be implemented in orders other than those described. Furthermore, the terms “comprising” or “having,” and any variations thereof, are intended to cover a non-exclusive inclusion; for example, a process, method, system, product, or apparatus that comprises a series of steps or units is not necessarily limited to those steps or units explicitly listed, but may include other steps or units not explicitly listed or inherent to such processes, methods, products, or apparatus.

[0009] The ethyl (E)-4-(2,4,5-trifluorophenyl)-but-2-enoate of the present invention can be synthesized using the synthetic method of patent CN103819475B, or it can be prepared by esterification reaction of commercially available (E)-4-(2,4,5-trifluorophenyl)but-3-enoic acid (CAS#:2226094-64-8) with ethanol.

[0010] All other chemicals used in this invention are commercially available.

[0011] Specifically, in this invention, a method for synthesizing sitagliptin includes the following steps: Ethyl (E)-4-(2,4,5-trifluorophenyl)-but-2-enoate undergoes an asymmetric hydroamination reaction with an ammonia source at room temperature in the presence of a copper (I) catalyst, a chiral ligand, a hydrogen source, a strong base, and a solvent to yield a chiral hydroamination intermediate. In this invention, the nickel catalyst is selected from one or more of nickel acetylacetonate, nickel acetate, nickel dichlorobis(dimethoxyethane) alloy, and nickel bis(1,5-cyclooctadiene) alloy, and the amount used is 5-15 mol.

[0012] In this invention, the chiral ligand is selected from one or more of R-BINAP, S-BINAP, R-Segphos, S-Segphos, R-DTBM-Segphos, S-DTBM-Segphos, R-JosiphosSL-J009-1, S-JosiphosSL-J009-1, and MeO-BIPHEP, and the amount used is 5-15 mol.

[0013] In this invention, the hydrogen source is selected from one or more of polymethylhydrosiloxane, dimethylphenylsilane, diphenylsilane, triethoxysilane, and phenylsilane, and the amount used is 1.5-5.0 equivalents.

[0014] In this invention, the strong base is selected from one or more of lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium hexamethyldisilamide, and sodium hexamethyldisilamide, and the amount used is 2.0-5.0 equivalents.

[0015] In this invention, the ammonia source is selected from one or more of (S)-(+)-N-benzyl-1-phenylethylamine, (S)-(+)-N-(3,5-dinitrobenzoyl)-1-phenylethylamine (69632-31-1), and (S)-(+)-N,N-dimethyl-1-phenylethylamine, and the amount used is 1.0-2.0 equivalents.

[0016] In this invention, the solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, diethyl ether, 1,4-dioxane, n-hexane, cyclohexane, and dichloromethane.

[0017] The ethyl ester in the chiral hydrogenation intermediate undergoes a hydrolysis reaction to yield the hydrolysis intermediate: The chiral hydroamic intermediate was added to hydrochloric acid and refluxed. The mixture was cooled in an ice-water bath, and the layers separated. The upper water layer was poured off, and the lower oily layer was dissolved in dichloromethane, washed with saturated sodium bicarbonate, separated, and dried to obtain the hydrolysis intermediate.

[0018] The hydrolysis intermediate reacts with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine in the presence of a condensing agent, yielding the amidated intermediate: Under ice-water bath conditions, the hydrolysis intermediate was dissolved in dichloromethane, DIPEA and 1-hydroxybenzotriazole were added, and trimethylacetyl chloride was added dropwise. After reacting for 1-3 hours, 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine was added, and the mixture was stirred at room temperature for 10-40 hours. The mixture was washed with water and sodium bicarbonate, dried, and recrystallized to obtain the amidated intermediate.

[0019] The amidation intermediate undergoes a debenzylation reaction in the presence of a catalyst and hydrogen to yield sitagliptin: In a hydrogen-filled reactor, the amidation intermediate is dissolved in methanol, a palladium / carbon catalyst and glacial acetic acid are added, the pressure is increased to 30-50 atm, and the reaction is carried out at 40-70°C for 10-50 h. The mixture is then filtered, dissolved in dichloromethane, washed with sodium bicarbonate and evaporated to dryness to obtain sitagliptin.

[0020] Example 1 In a dry 100 mL three-necked flask, nickel acetylacetonate (0.05 mmol, 10 mol%) and R-BINAP (0.05 mmol, 10 mol%) were added, followed by anhydrous toluene (25 mL). The solution was stirred at room temperature under a nitrogen atmosphere for 15 minutes, and the solution was observed to gradually change from turbid to clear.

[0021] Polymethylhydrosiloxane (10.1 mmol, 2.02 equivalents), potassium tert-butoxide (15.1 mmol, 3.02 equivalents), and (S)-(+)-N-benzyl-1-phenylethylamine (6.05 mmol, 1.21 equivalents) were added sequentially to the reaction system. After stirring at 25°C for 30 minutes, a slight darkening of the reaction solution was observed.

[0022] Ethyl (E)-4-(2,4,5-trifluorophenyl)-but-2-enoate (5.03 mmol) was dissolved in anhydrous toluene (5 mL) and slowly added dropwise to the reaction system over 30 minutes using a constant-pressure dropping funnel. During the addition, the temperature of the reaction solution rose slightly (approximately 2 °C), and the color gradually changed from orange-red to deep red. The reaction was continued to be stirred at 25 °C for 14 hours, and TLC (petroleum ether:ethyl acetate = 4:1) monitoring showed that the starting material spot had essentially disappeared.

[0023] After the reaction was complete, the reaction mixture was transferred to a separatory funnel and carefully quenched with saturated ammonium chloride solution (20 mL). Extraction was performed with dichloromethane (3 × 20 mL), and the organic phases were combined. The organic phases were washed successively with saturated sodium bicarbonate solution (20 mL) and saturated sodium chloride solution (20 mL). After drying with anhydrous sodium sulfate, the mixture was filtered and concentrated under reduced pressure to obtain 1.46 g of a yellow oily substance.

[0024] The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 → 5:1 gradient elution) to give 1.46 g of a pale yellow oily chiral hydroamication intermediate (yield: 60.8%, HPLC purity 97.5%). The product was confirmed by 1H-NMR and HRMS, with an ee value >99% (chiral HPLC analysis, Chiralpak AD-H column, n-hexane:isopropanol = 90:10, 1.0 mL / min, 254 nm).

[0025] Preparation of hydrolysis intermediates In a 250 mL round-bottom flask, the chiral hydroamication intermediate (3.10 mmol) was added to 60 mL of 2 mol / L hydrochloric acid solution. A reflux condenser was installed, and the reaction mixture was heated to vigorous reflux and stirred for 12 hours (monitored by TLC).

[0026] After the reaction was complete, the heat source was removed, and the reaction solution was cooled to room temperature, then further cooled to 0-5°C using an ice-water bath. At this point, a large amount of white solid precipitated from the mixture. This solid was slowly poured into a separatory funnel to separate the upper aqueous phase. The lower oily phase and the solid were extracted together with dichloromethane (3 × 30 mL). The organic phases were combined and carefully washed with saturated sodium bicarbonate solution until no more bubbles were produced (approximately 20 mL), followed by washing with saturated sodium chloride solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a pale yellow, viscous, oily hydrolysis intermediate, which could be used in the next step without further purification. The measured weight was 0.95 g (crude product yield approximately 95%).

[0027] Preparation of amidation intermediates In a 100 mL dry three-necked flask, the hydrolysis intermediate (1.40 mmol) obtained in the previous step was dissolved in anhydrous dichloromethane (10 mL). Under nitrogen protection and cooling in an ice-water bath (0–5 °C), N,N-diisopropylethylamine (DIPEA, 3.50 mmol) and 1-hydroxybenzotriazole (HOBt, 0.14 mmol) were added sequentially. Subsequently, trimethylacetyl chloride (1.75 mmol) was slowly added dropwise over 10 minutes, with slight exothermic reaction during the addition. The mixture was stirred at a low temperature for 30 minutes to form a reactive mixed anhydride.

[0028] Subsequently, 1.54 mmol of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine was added to the reaction system in a single batch. The ice bath was removed, the reaction mixture was allowed to rise to room temperature naturally, and stirring was continued for 30 hours.

[0029] After the reaction was complete, the reaction solution was diluted with dichloromethane (20 mL) and washed successively with 1M hydrochloric acid (20 mL), saturated sodium bicarbonate solution (20 mL), and saturated sodium chloride solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a pale yellow, foamy crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, gradient elution from 5:1 to 2:1), and then recrystallized from petroleum ether / ethyl acetate (20:1, v / v) to give 0.84 g of a white solid amidated intermediate (yield: 67.3%, HPLC purity 99.2%).

[0030] In a 250 mL high-pressure hydrogenation reactor, the amidation intermediate (1.66 mmol) was dissolved in anhydrous methanol (10 mL), and 5% palladium / carbon (wet basis, 100 mg) and glacial acetic acid (200 mg) were added. The reactor was sealed, and the air inside was purged with hydrogen until the pressure reached 3.5 MPa. The reaction system was heated to 50 °C and stirred for 48 hours.

[0031] After the reaction was complete, the mixture was cooled to room temperature, and residual hydrogen gas was carefully released. The reaction vessel was opened, and the reaction solution was filtered through a diatomaceous earth pad. The catalyst was washed with methanol (3 × 10 mL). The filtrates were combined and concentrated under reduced pressure to remove most of the solvent, yielding a white solid. This solid was dissolved in dichloromethane (30 mL) and washed with saturated sodium bicarbonate solution (20 mL) until the aqueous phase was weakly alkaline. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a white crude solid. The crude product could be recrystallized from ethanol / water (5:1) to give sitagliptin free base, a white crystalline solid of 0.66 g (yield: 96.1%, HPLC purity 99.5%).

[0032] Example 2 The nickel catalyst, chiral ligand, and ammonia source used are as follows: Bis(1,5-cyclooctadiene)nickel S-DTBM-Segphos (S)-(+)-N-benzyl-1-phenylethylamine Example 3 The nickel catalyst, chiral ligand, and ammonia source used are as follows: Bis(1,5-cyclooctadiene)nickel S-DTBM-Segphos (S)-(+)-N-(3,5-dinitrobenzoyl)-1-phenylethylamine (69632-31-1) Example 4 The nickel catalyst, chiral ligand, and ammonia source used are as follows: Nickel acetate S-DTBM-Segphos (S)-(+)-N-(3,5-dinitrobenzoyl)-1-phenylethylamine (69632-31-1) Example 5 The nickel catalyst, chiral ligand, and ammonia source used are as follows: Dichlorobis(dimethoxyethane) nickel S-DTBM-Segphos (S)-(+)-N-(3,5-dinitrobenzoyl)-1-phenylethylamine (69632-31-1) Example 6 The nickel catalyst, chiral ligand, and ammonia source used are as follows: Bis(1,5-cyclooctadiene)nickel S-JosiphosSL-J009-1 (S)-(+)-N-(3,5-dinitrobenzoyl)-1-phenylethylamine (69632-31-1) Example 7 The nickel catalyst, chiral ligand, and ammonia source used are as follows: Bis(1,5-cyclooctadiene)nickel MeO-BIPHEP (S)-(+)-N-(3,5-dinitrobenzoyl)-1-phenylethylamine (69632-31-1) Comparative Example 1 The compounds corresponding to Example 1 were replaced with cuprous acetate, S-DTBM-Segphos, and (S)-(+)-N-(3,5-dinitrobenzoyl)-1-phenylethylamine (69632-31-1).

[0033] Comparative Example 2 Same as in Example 1, but without the addition of R-BINAP (0.05 mmol, 10 mol%).

[0034] The experimental results are shown in Table 1.

[0035] Table 1 Yield (%) HPLC purity (%) ee value (%) Example 1 70.8 97.5 99.6 Example 2 75.3 98.1 99.7 Example 3 86.5 99.2 99.9 Example 4 65.2 96.5 98.5 Example 5 63.1 96.6 98.8 Example 6 68.3 97.8 97.1 Example 7 66.3 96.8 97.3 Comparative Example 1 50.5 90.5 90.7 Comparative Example 2 53.7 95.7 85.4 The above experiments show that the solution of the present invention can obtain high-yield and high-quality sitagliptin.

[0036] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing sitagliptin, characterized in that, The synthesis method includes the following steps: Ethyl (E)-4-(2,4,5-trifluorophenyl)-but-2-enoate undergoes an asymmetric hydroamination reaction with an ammonia source at room temperature in the presence of a copper (I) catalyst, a chiral ligand, a hydrogen source, a strong base, and a solvent to yield a chiral hydroamination intermediate. The ethyl ester in the chiral hydrogenation intermediate undergoes a hydrolysis reaction to obtain a hydrolysis intermediate; The hydrolysis intermediate was reacted with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine in the presence of a condensing agent to give the amidated intermediate; The amidation intermediate undergoes a debenzylation reaction in the presence of a catalyst and hydrogen to yield sitagliptin.

2. The method for synthesizing sitagliptin according to claim 1, characterized in that, The nickel catalyst is selected from one or more of nickel acetylacetonate, nickel acetate, nickel dichlorobis(dimethoxyethane) alloy, and nickel bis(1,5-cyclooctadiene), and the amount used is 5-15 mol.

3. The method for synthesizing sitagliptin according to claim 1, characterized in that, The chiral ligand is selected from one or more of R-BINAP, S-BINAP, R-Segphos, S-Segphos, R-DTBM-Segphos, S-DTBM-Segphos, R-JosiphosSL-J009-1, S-JosiphosSL-J009-1, and MeO-BIPHEP, and the amount used is 5-15 mol.

4. The method for synthesizing sitagliptin according to claim 1, characterized in that, The hydrogen source is selected from one or more of polymethylhydrosiloxane, dimethylphenylsilane, diphenylsilane, triethoxysilane, and phenylsilane, and the amount used is 1.5-5.0 equivalents.

5. The method for synthesizing sitagliptin according to claim 1, characterized in that, The strong base is selected from one or more of lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium hexamethyldisilamide, and sodium hexamethyldisilamide, and is used in an amount of 2.0-5.0 equivalents.

6. The method for synthesizing sitagliptin according to claim 1, characterized in that, The ammonia source is selected from one or more of (S)-(+)-N-benzyl-1-phenylethylamine, (S)-(+)-N-(3,5-dinitrobenzoyl)-1-phenylethylamine (69632-31-1), and (S)-(+)-N,N-dimethyl-1-phenylethylamine, and the amount used is 1.0-2.0 equivalents.

7. The method for synthesizing sitagliptin according to claim 1, characterized in that, The solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, diethyl ether, 1,4-dioxane, n-hexane, cyclohexane, and dichloromethane.

8. The method for synthesizing sitagliptin according to claim 1, characterized in that, The hydrolysis reaction steps are as follows: The chiral hydroamic intermediate was added to hydrochloric acid and refluxed. The mixture was cooled in an ice-water bath, and the layers separated. The upper water layer was poured off, and the lower oily layer was dissolved in dichloromethane, washed with saturated sodium bicarbonate, separated, and dried to obtain the hydrolysis intermediate.

9. The method for synthesizing sitagliptin according to claim 1, characterized in that, The amidation reaction steps are as follows: Under ice-water bath conditions, the hydrolysis intermediate was dissolved in dichloromethane, DIPEA and 1-hydroxybenzotriazole were added, and trimethylacetyl chloride was added dropwise. After reacting for 1-3 hours, 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine was added, and stirring was continued at room temperature for 10-40 hours. The mixture was washed with water and sodium bicarbonate, dried, and recrystallized to obtain the amidated intermediate.

10. A method for synthesizing sitagliptin according to claim 1, characterized in that, The debenzylation reaction steps are as follows: In a hydrogen-filled reactor, the amidation intermediate is dissolved in methanol, a palladium / carbon catalyst and glacial acetic acid are added, the pressure is increased to 30-50 atm, and the reaction is carried out at 40-70°C for 10-50 h. The mixture is then filtered, dissolved in dichloromethane, washed with sodium bicarbonate and evaporated to dryness to obtain sitagliptin.