Process for the one-pot preparation of sitagliptin intermediates

Abstract

The application belongs to the technical field of preparation of pharmaceutical intermediates, and particularly relates to a one-pot method for preparing a sitagliptin intermediate. The one-pot method for preparing the sitagliptin intermediate comprises the following steps: at room temperature, 2,4,5-trifluorophenylacetic acid is dissolved in an organic solvent A, the temperature is lowered to 0-5 DEG C, thionyl chloride is added dropwise, after the dropwise addition is completed, the temperature is raised to 25-30 DEG C, and reaction is carried out for 2 hours; thin layer chromatography analysis is used for monitoring; vacuum concentration is carried out; an intermediate oil is obtained; solvent B is added; ketene is charged; the temperature is lowered to -78 DEG C to room temperature; reaction is carried out for 3 hours; thin layer chromatography is used for monitoring; after the reaction is completed, the temperature is raised to room temperature; stirring is continuously carried out for 12 hours; water is added; the liquid is left to stand and is separated into layers; the organic phase is collected; extraction is carried out; rotary evaporation is carried out; and the sitagliptin intermediate II is obtained. The preparation method of the sitagliptin intermediate provided by the application has the advantages that raw materials are low in price and easy to obtain, reaction conditions are mild, industrial production can be easily realized, the prepared intermediate is high in purity and high in yield.

Description

Technical Field

[0001] The invention belongs to the technical field of preparation of pharmaceutical intermediates, and particularly relates to a method for preparing a sitagliptin intermediate by a one-pot process. Background Art

[0002] Sitagliptin, also known as (3R)-3-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one, is a novel anti-type 2 diabetes drug and the first dipeptidyl peptidase-IV (DPP-IV) inhibitor indicated for the treatment of type 2 diabetes. It is commonly used in its phosphate form. Sitagliptin can prevent and treat type 2 diabetes, hyperglycemia, insulin resistance, obesity, hypertension, and certain other complications. Currently, sitagliptin phosphate tablets have become the second most popular oral diabetes medication. Clinical studies have shown that sitagliptin is an effective, orally administered drug with promising market prospects. It has a significant blood sugar-lowering effect when used alone or in combination with metformin or pioglitazone. It is also safe, well-tolerated, and has few adverse reactions.

[0003] In the process of synthesizing sitagliptin, intermediate III is the key product. The synthesis routes of intermediate III are mainly as follows: CN201510831495.7 discloses a method of obtaining intermediate III by enzyme catalysis from lipid intermediate II; WO2009064476A1 discloses the most common synthesis method, which uses 2,4,5-trifluorophenylacetic acid and Michaelis acid as raw materials to react to obtain the intermediate, and then adds methanol or ethanol and other solvents to obtain the required lipid intermediate II, and then obtains compound III through chemical synthesis; CN201280027947.0 discloses a method of obtaining intermediate III by metal catalysis from lipid intermediate II. As can be seen from the above, the synthesis of key intermediate III requires the precursor lipid intermediate II,

[0004] In the prior art, there are mainly the following methods for synthesizing intermediate II.

[0005] CN201710462163.5 discloses a method of generating trifluorophenylacetic acid and thionyl chloride to generate trifluorophenylacetyl chloride, and then undergoing Grignard reaction under the conditions of Grignard reagent and cuprous chloride as catalyst to generate sitagliptin intermediate. This method first requires the synthesis of Grignard reagent. The preparation steps are complicated and cuprous iodide is required as a catalyst, which is expensive and has high cost, thus limiting its industrial production. CN201711403311.2 discloses a method for preparing a sitagliptin intermediate, which comprises 2,4,5-trifluorophenylacetonitrile compounds and an organic metal reagent. After the reaction, intermediate II is obtained by hydrochloric acid or activating reagent halogenated silanes. Although the yield is high, the steps are relatively complicated and the reagents used are relatively expensive.

[0006] WO2009064476 discloses a common synthesis method, which uses 2,4,5-trifluorophenylacetic acid and Michaelis' acid as raw materials to react, obtaining an intermediate, which is then added to a solvent such as methanol or ethanol to obtain the desired lipid intermediate II. However, this synthesis method is difficult to crystallize the lipid, and the purity is difficult to achieve above 98%. Furthermore, the Michaelis' acid raw material is expensive and difficult to produce. The synthesis formula is:

[0007]

[0008] CN201310732949.6 discloses a method for preparing a sitagliptin intermediate. First, monoethyl malonate, triethylamine, and sewage magnesium chloride are added to anhydrous ethyl acetate. Then, 2,4,5-trifluorophenylacetic acid and N,N'-carbonyldiimidazole are added to ethyl acetate. The two solutions are mixed, and the temperature is lowered after the reaction to adjust the pH. Post-treatment can obtain an intermediate of formula II. Although a low-toxic solvent is selected for the reaction, the reaction steps are complicated, the yield is low, and the purity is also low. Summary of the Invention

[0009] The technical problem to be solved by the present invention is to overcome the above-mentioned defects of the prior art and provide a method for preparing a sitagliptin intermediate. The raw materials are cheap and readily available, the reaction conditions are mild, and industrial production is easy to achieve. The prepared intermediate has high purity and high yield.

[0010] The one-pot method for preparing a sitagliptin intermediate of the present invention comprises the following steps: dissolving 2,4,5-trifluorophenylacetic acid in an organic solvent A at room temperature, cooling the temperature to 0-5°C, adding thionyl chloride dropwise, heating the temperature to 25-30°C for reaction after the addition is complete, determining the reaction by thin-layer chromatography, concentrating under reduced pressure at 45-60°C to obtain 2-(2,4,5-trifluorophenyl)acetyl chloride, adding solvent B, then adding ketene, cooling the temperature to -78°C to room temperature for reaction, determining the completion of the reaction by thin-layer chromatography, heating the temperature to room temperature, continuing stirring for 12-24 hours, adding water, allowing the phase to stand for stratification, collecting the upper organic phase, extracting, and rotary evaporating at 40-50°C to obtain sitagliptin intermediate II;

[0011] The general structural formula of the sitagliptin intermediate II is:

[0012] Wherein R is isopropyl, methyl or ethyl.

[0013] Preferably, the molar ratio of 2,4,5-trifluorophenylacetic acid to thionyl chloride is 1:(1.2-2).

[0014] Preferably, the mass ratio of the charged ketene to the 2,4,5-trifluorophenylacetic acid is (16.6-47)-(50-100).

[0015] Preferably, the organic solvent A is one of dichloromethane, dichloroethane and chloroform.

[0016] Preferably, the volume ratio of the organic solvent A to 2,4,5-trifluorophenylacetic acid is 1 g:(8-12) mL, more preferably 1 g:10 mL.

[0017] Preferably, solvent B is one of methanol, ethanol and isopropanol.

[0018] Preferably, the volume ratio of the mass of solvent B to 2,4,5-trifluorophenylacetic acid is 1 g:(8-12) mL, more preferably 1 g:10 mL.

[0019] Preferably, after standing and separating the layers, only the upper organic phase is collected, and the lower aqueous phase is extracted with ethyl acetate multiple times and then combined with the organic phase.

[0020] Preferably, the extraction is performed using saturated saline solution.

[0021] Specifically, the one-pot method for preparing a sitagliptin intermediate comprises the following steps: dissolving 2,4,5-trifluorophenylacetic acid in an organic solvent A at room temperature, cooling the temperature to 0-5°C, adding thionyl chloride dropwise, raising the temperature to 25-30°C for reaction after the addition is complete, monitoring by thin-layer chromatography, and comparing the raw material trifluorophenylacetic acid spot plate with the raw material trifluorophenylacetic acid spot under ultraviolet light. If the raw material spot disappears and new spots are generated, it means that the raw material reaction is complete, and concentrating under reduced pressure at 45-60°C to obtain an oily substance 2-(2,4,5-trifluorophenyl)acetyl chloride, adding solvent B, and then Add ketene, cool to -78 ° C ~ room temperature conditions, monitor by thin layer chromatography until the trifluorophenylacetyl chloride spot disappears under ultraviolet light and new spots appear, indicating that the reaction is complete, stop cooling, naturally warm to room temperature, continue stirring for 12-24 hours, add water, stop stirring, let stand and separate, collect the upper organic phase, extract the aqueous phase with ethyl acetate several times, combine the organic phases, extract with saturated brine, and evaporate on a rotary evaporator at 40-50 ° C until the solvent is completely evaporated. After removing the solvent, a white solid, i.e., sitagliptin intermediate II, is obtained. Preferably, the reaction formula is as follows:

[0022]

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] (1) The one-pot method for preparing a sitagliptin intermediate of the present invention has a simple synthetic route and is easy to operate.

[0025] (2) The one-pot method for preparing the sitagliptin intermediate of the present invention can obtain the intermediate II with high purity and high yield.

[0026] (3) The one-pot method for preparing sitagliptin intermediates of the present invention uses low-cost, easily available basic raw materials, and has low cost investment.

[0027] (4) The one-pot method for preparing sitagliptin intermediates of the present invention has mild reaction conditions and is easy to implement industrial production.

[0028] Figures in the specification

[0029] Figure 1 This is the hydrogen spectrum of methyl 2,4,5-trifluorophenylacetoacetate prepared in Example 1.

[0030] Figure 2 This is the fluorine spectrum of methyl 2,4,5-trifluorophenylacetoacetate prepared in Example 1. DETAILED DESCRIPTION

[0031] The present invention will be further described below with reference to specific embodiments.

[0032] The raw materials, solvents, and additives used in the following examples are all commercially available products.

[0033] Example 1

[0034] The one-pot method for preparing methyl 2,4,5-trifluorophenylacetoacetate, an intermediate of sitagliptin, comprises the following steps: dissolving 100 g of 2,4,5-trifluorophenylacetic acid in 1000 mL of chloroform at room temperature, cooling to 0° C., adding 75.1 g of thionyl chloride dropwise, heating to 25° C. and reacting for 2 h. The reaction of the raw materials is observed to be complete by TLC monitoring, and concentrating under reduced pressure at 45° C. for 0.3 h to obtain an oily substance, 2-(2,4,5-trifluorophenyl)acetyl chloride. 1000 ml of methanol is added, and 2 1.3 g of ketene was cooled to -74°C and reacted for 3 hours. TLC monitoring confirmed complete reaction of the starting material. Upon completion of the reaction, cooling was stopped, the mixture was allowed to warm to room temperature, and stirring was continued for 12 hours. 210 mL of pure water was added, stirring was stopped, and the mixture was allowed to stand for separation. The upper organic phase was collected and the aqueous phase was extracted three times with 200 mL of ethyl acetate. The combined organic phases were extracted with saturated brine and the solvent was removed by rotary evaporation at 40°C for 0.3 hours to obtain 115.2 g of methyl 2,4,5-trifluorophenylacetoacetate, a white solid. The purity was 98.9% as determined by liquid chromatography, resulting in a calculated yield of 89%.

[0035] Example 2

[0036] The one-pot method for preparing methyl 2,4,5-trifluorophenylacetoacetate, an intermediate of sitagliptin, comprises the following steps: dissolving 50 g of 2,4,5-trifluorophenylacetic acid in 500 mL of dichloromethane at room temperature, cooling to 0° C., adding 62.6 g of thionyl chloride dropwise, heating to 25° C. and reacting for 2 h. The reaction of the raw materials is observed to be complete by TLC monitoring, and concentrating under reduced pressure at 45° C. for 0.5 h to obtain an oily substance, 2-(2,4,5-trifluorophenyl)acetyl chloride. 500 ml of methanol is added, and 2 2.1 g of ketene was cooled to -75°C and reacted for 3 hours. TLC monitoring confirmed complete reaction of the starting material. Upon completion of the reaction, cooling was stopped, the mixture was allowed to warm to room temperature, and stirring was continued for 12 hours. 110 mL of pure water was added, stirring was stopped, and the mixture was allowed to stand for separation. The upper organic phase was collected and the aqueous phase was extracted three times with 100 mL of ethyl acetate. The combined organic phases were extracted with saturated brine and the solvent was removed by rotary evaporation at 40°C for 0.3 hours to obtain 59.0 g of methyl 2,4,5-trifluorophenylacetoacetate, a white solid. The purity was 98.1% as determined by liquid chromatography, resulting in a calculated yield of 91%.

[0037] Example 3

[0038] The one-pot method for preparing methyl 2,4,5-trifluorophenylacetoacetate, an intermediate of sitagliptin, comprises the following steps: dissolving 50 g of 2,4,5-trifluorophenylacetic acid in 500 mL of dichloroethane at room temperature, cooling to 0° C., adding 50.1 g of thionyl chloride dropwise, heating to 25° C. and reacting for 2 h. The reaction of the raw materials is observed to be complete by TLC monitoring, and concentrating under reduced pressure at 45° C. for 0.5 h to obtain an oily substance, 2-(2,4,5-trifluorophenyl)acetyl chloride. 500 ml of methanol is added, and 1 4.4 g of ketene was cooled to -75°C and reacted for 3 hours. TLC monitoring confirmed complete reaction of the starting material. Upon completion of the reaction, cooling was stopped, the mixture was allowed to warm to room temperature, and stirring was continued for 12 hours. 110 mL of pure water was added, stirring was stopped, and the mixture was allowed to stand for separation. The upper organic phase was collected and the aqueous phase was extracted three times with 100 mL of ethyl acetate. The combined organic phases were extracted with saturated brine and the solvent was removed by rotary evaporation at 40°C for 0.3 hours to obtain 57.1 g of methyl 2,4,5-trifluorophenylacetoacetate, a white solid. The purity was 98.1% as determined by liquid chromatography, and the yield was calculated to be 88%.

[0039] Example 4

[0040] The method for preparing the siglitin intermediate 2,4,5-trifluorophenyl acetic acid ethyl ester in one pot comprises the following steps: at room temperature, 100 g of 2,4,5-trifluorophenyl acetic acid is dissolved in 1000 mL of chloroform, the temperature is lowered to 0°C, 75.1 g of chlorosulfoxide is added dropwise, after the dropwise addition is completed, the temperature is raised to 25°C and the reaction is carried out for 2 hours, the reaction is monitored by TLC, the raw material is observed to be completely reacted, the temperature is lowered to 45°C, and the reaction is concentrated under reduced pressure for 0.3 hours to obtain 2-(2,4,5-trifluorophenyl) acetyl chloride in the form of an oil, 1000 mL of ethanol is added, 21.3 g of ethylene ketone is charged, the temperature is lowered to -75°C, the reaction is carried out for 3 hours, the reaction is monitored by TLC, the raw material is observed to be completely reacted, the reaction is completed, the cooling is stopped, the temperature is naturally raised to room temperature, the stirring is continued for 12 hours, 210 mL of pure water is added, the stirring is stopped, the layers are separated after standing, the upper organic phase is collected, the water phase is extracted with 200 mL of ethyl acetate for 3 times, the organic phases are combined, saturated brine is used for extraction, after the solvent is removed by rotary evaporation at 40°C for 0.3 hours, 117 g of white solid, i.e., 2,4,5-trifluorophenyl acetic acid ethyl ester, is obtained. The purity is detected by liquid chromatography to be 98.3%, and the yield is calculated to be 85.8%.

[0041] Example 5

[0042] The method for preparing the siglitin intermediate 2,4,5-trifluorophenyl acetic acid ethyl ester in one pot comprises the following steps: at room temperature, 100 g of 2,4,5-trifluorophenyl acetic acid is dissolved in 1000 mL of chloroform, the temperature is lowered to 0°C, 75.1 g of chlorosulfoxide is added dropwise, after the dropwise addition is completed, the temperature is raised to 25°C and the reaction is carried out for 2 hours, the reaction is monitored by TLC, the raw material is observed to be completely reacted, the temperature is lowered to 45°C, and the reaction is concentrated under reduced pressure for 0.3 hours to obtain 2-(2,4,5-trifluorophenyl) acetyl chloride in the form of an oil, 1000 mL of ethanol is added, 21.3 g of ethylene ketone is charged, the temperature is lowered to -75°C, the reaction is carried out for 3 hours, the reaction is monitored by TLC, the raw material is observed to be completely reacted, the reaction is completed, the cooling is stopped, the temperature is naturally raised to room temperature, the stirring is continued for 12 hours, 210 mL of pure water is added, the stirring is stopped, the layers are separated after standing, the upper organic phase is collected, the water phase is extracted with 200 mL of ethyl acetate for 3 times, the organic phases are combined, saturated brine is used for extraction, after the solvent is removed by rotary evaporation at 40°C for 0.3 hours, 117 g of white solid, i.e., 2,4,5-trifluorophenyl acetic acid ethyl ester, is obtained. The purity is detected by liquid chromatography to be 98.3%, and the yield is calculated to be 85.8%.

[0043] Example 6

[0044] The method for preparing the siglitin intermediate 2,4,5-trifluorophenyl acetic acid ethyl ester in one pot comprises the following steps: 50 g of 2,4,5-trifluorophenyl acetic acid is dissolved in 500 mL of dichloroethane at room temperature, the temperature is lowered to 0°C, 43.8 g of sulfoxide chloride is added dropwise, after the dropwise addition is completed, the temperature is raised to 25°C and the reaction is carried out for 2 h, the reaction completion is observed by TLC monitoring, the reaction is concentrated at 45°C under reduced pressure for 0.3 h to obtain 2-(2,4,5-trifluorophenyl) acetyl chloride in the form of an oil, 500 mL of ethanol is added, 14.4 g of ketene is charged, the temperature is lowered to -75°C, the reaction is carried out for 3 h, the reaction completion is observed by TLC monitoring, the reaction is stopped, the cooling is stopped, the temperature is naturally raised to room temperature, the stirring is continued for 12 h, 126 mL of pure water is added, the stirring is stopped, the layers are separated after standing, the upper organic phase is collected, the water phase is extracted with 120 mL of ethyl acetate for 3 times, the organic phases are combined, saturated brine is used for extraction, after the solvent is removed by rotary evaporation at 40°C for 0.3 h, 73.6 g of white solid, i.e. 2,4,5-trifluorophenyl acetic acid ethyl ester, is obtained. The purity is detected by liquid chromatography and is 98.3%, and the yield is calculated to be 89.6%.

[0045] Comparative Example 1

[0046] A method for preparing the siglitin intermediate 2,4,5-trifluorophenyl acetic acid methyl ester comprises the following steps: 100 g of 2,4,5-trifluorophenyl acetic acid is dissolved in 1000 mL of chloroform at room temperature, the temperature is lowered to 0°C, 62.6 g of sulfoxide chloride is added dropwise, after the dropwise addition is completed, the temperature is raised to 25°C and the reaction is carried out for 1.5 h, the reaction is concentrated at 45°C under reduced pressure for 0.3 h to obtain 2-(2,4,5-trifluorophenyl) acetyl chloride in the form of an oil, 1000 mL of methanol is added, 22.1 g of ketene is charged, the temperature is lowered to -74°C, the reaction is carried out for 3 h, the reaction is stopped, the cooling is stopped, the temperature is naturally raised to room temperature, the stirring is continued for 12 h, 210 mL of pure water is added, the stirring is stopped, the layers are separated after standing, the upper organic phase is collected, the water phase is extracted with 200 mL of ethyl acetate for 3 times, the organic phases are combined, saturated brine is used for extraction, after the solvent is removed by rotary evaporation at 40°C for 0.3 h, 88.4 g of white solid, i.e. 2,4,5-trifluorophenyl acetic acid methyl ester, is obtained. The purity is detected by liquid chromatography and is 97.8%, and the yield is calculated to be 68.3%.

[0047] As can be seen from the above, when the molar ratio of 2,4,5-trifluorophenyl acetic acid to sulfoxide chloride is adjusted to 1:1 in Comparative Example 1, the yield of the intermediate 2,4,5-trifluorophenyl acetic acid methyl ester is only 69.3%.

Claims

1. A one-pot method for preparing a sitagliptin intermediate, characterized in that: The following steps are involved: At room temperature, 2,4,5-trifluorophenylacetic acid is dissolved in organic solvent A, cooled to 0-5°C, and thionyl chloride is added dropwise. After the addition is complete, the temperature is raised to 25-30°C for reaction. After the reaction is complete as determined by thin-layer chromatography, the temperature is concentrated under reduced pressure at 45-60°C to obtain 2-(2,4,5-trifluorophenyl)acetyl chloride. Solvent B is added, and ketene is added. The temperature is lowered to -78°C to room temperature for reaction. After the reaction is complete as determined by thin-layer chromatography, the temperature is raised to room temperature, and stirring is continued for 12-24 hours. Water is added, and the mixture is allowed to stand for separation. The upper organic phase is collected, extracted, and rotary evaporated at 40-50°C to obtain sitagliptin intermediate II. Solvent B is one of methanol and ethanol. The mass ratio of the charged ketene to the 2,4,5-trifluorophenylacetic acid is (16.6-47): (50-100); Organic solvent A is one of dichloromethane, dichloroethane, and chloroform; The general structural formula of the sitagliptin intermediate II is: , wherein R is methyl or ethyl.

2. The method for preparing a sitagliptin intermediate by a one-pot process according to claim 1, wherein: The molar ratio of 2,4,5-trifluorophenylacetic acid to thionyl chloride is 1:(1.2-2).

3. The method for preparing a sitagliptin intermediate by a one-pot process according to claim 1, wherein: The volume ratio of 2,4,5-trifluorophenylacetic acid to organic solvent A is 1 g:10 mL.

4. The method for preparing a sitagliptin intermediate by a one-pot process according to claim 1, wherein: The mass ratio of 2,4,5-trifluorophenylacetic acid to the volume ratio of solvent B is 1 g:10 mL.

5. The method for preparing a sitagliptin intermediate by a one-pot process according to claim 1, wherein: After standing for stratification, only the upper organic phase was collected, and the lower aqueous phase was extracted with ethyl acetate several times and then combined with the organic phase.

6. The one-pot method for preparing a sitagliptin intermediate according to claim 1, wherein: The extraction was performed using saturated saline solution.

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