CN110003218B - Preparation method of Allagliptin intermediate - Google Patents

Abstract

The invention provides a preparation method of an Alalogliptin intermediate, which comprises the following steps: (1) performing Vilsmiere reaction on N, N-dimethylformamide (I) and acyl chloride to generate a Vilsmiere reagent, dropwise adding bromoacetic acid (II) into the Vilsmiere reagent, heating for reaction, and hydrolyzing to obtain diformylaldehyde (III); (2) dissolving diformylacetaldehyde (III) and 3-amino-5-methylpyrazole (IV) in an alcohol/sodium alkoxide system, heating, refluxing and stirring to generate 6-formaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V); (3) oxidizing the 6-formaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V) in strong alkali to generate 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (VI). The invention simplifies the reaction steps, has simple and convenient operation, less three wastes and high yield.

Description

Preparation method of Allagliptin intermediate

Technical Field

The invention relates to a preparation method of an Alalogliptin intermediate, belonging to the field of chemical pharmacy.

Background

The chemical name of the alagliptin is N- [2- [ [2- [ (2S) -2-cyano-1-pyrrolidinyl ] -2-oxoethyl ] amino ] -2-methylpropanyl ] -2-methyl-6-pyrazolo [1,5-a ] pyrimidine carboxamide (VIII), the original research unit is Japan Kabushiki Kaisha and chemical research institute, the original research unit is approved by Japan pharmaceutical and medical device integration institute (PMDA) in 9 months of 2012 and is a high-selectivity dipeptidyl peptidase-IV (DPP-4) inhibitor which is used for treating type II diabetes and can enhance the activity of glucagon-like peptide (G L P-1) and Gastric Inhibitory Peptide (GIP) through selectively and continuously inhibiting DPP-4 to play a role in reducing blood sugar.

According to the reports of the literatures (WO2014147640, WO2015104602, Bioorganic & Medicinal Chemistry2011(23), 7221 and the like), the compound (viii) is synthesized from three main fragments of 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (vi), (2S) -N-chloroacetyl-2-cyanotetrahydropyrrole (vii), 2-amino-2-methylpropylamine and the like as a starting material.

The traditional Chinese medicine intermediate for synthesizing the Allagliptin by using the 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (VI) has few synthesis methods and literature reports at present. Patents WO2014147640, IN2013MU00848, CN103819478 and the like all describe a method of obtaining 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid ethyl ester by condensation of 3-amino-5-methylpyrazole and diformylacetic acid ethyl ester under anhydrous, oxygen-free and strong alkaline conditions, and obtaining 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (vi) by hydrolysis:

the method is a synthesis method commonly used for the compound VI at present, wherein the ethyl diformaldehyde acetate is obtained from vinyl ethyl ether and trichloroacetyl chloride through the following steps:

the synthesis method is complicated, waste water and waste gas are more, and dimethyl ethyl acetate is unstable, so that the compound is synthesized in situ by 3, 3-diethoxy ethyl propionate and ethyl formate under the conditions of no water, no oxygen and strong base, and then condensed with 3-amino-5-methylpyrazole, the cost is higher, sodium hydride is used as a strong base acid-binding agent, the reaction is also dangerous, and the market price of the compound VI is high.

Document Bioorganic & Medicinal Chemistry,2011(23),7221 describes the synthesis of 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (vi) by alkaline hydrolysis followed by subsequent acidification, starting from 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxamide:

the method is also prepared by amidating 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid ethyl ester, and has the advantages of high cost, low efficiency and no industrial significance.

Disclosure of Invention

The invention aims to provide a novel preparation method of an Allagliptin intermediate, so as to reduce the manufacturing cost of the Allagliptin intermediate and improve the synthesis efficiency.

The invention adopts the following technical scheme:

the invention aims to provide a synthesis process of an Allagliptin intermediate 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (VI). N, N-dimethylformamide and bromoacetic acid are used as raw materials, and the 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid is synthesized through Vilsmiere reaction, condensation cyclization reaction and oxidation reaction. The process comprises the following steps:

(1) under the condition of low temperature, performing Vilsmiere reaction on N, N-dimethylformamide (I, DMF) and acyl chloride to generate a Vilsmiere reagent, dropwise adding bromoacetic acid (II) into a reaction system, heating for reaction, and hydrolyzing to obtain diformylaldehyde acetaldehyde (III);

(2) dissolving diformylaldehyde (III) and 3-amino-5-methylpyrazole (IV) in alcohol, heating sodium alkoxide as strong base to reflux and stirring to generate 6-formaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V);

(3) oxidizing the 6-formaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V) in strong alkali to generate 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (VI);

in the step (1), the acyl chloride is independently selected from but not limited to phosphorus oxychloride, thionyl chloride, oxalyl chloride, acetyl chloride, propionyl chloride and the like, preferably phosphorus oxychloride; the amount of acid chloride is 100-500%, preferably 250-350% of the amount of the compound II.

In step (1), the reaction temperature is independently selected from 0 to 150 ℃, preferably from 50 to 100 ℃.

In step (2), the alcohol/sodium alkoxide system can be selected from, but not limited to, methanol/sodium methoxide, ethanol/sodium ethoxide, isopropanol/sodium isopropoxide, tert-butanol/sodium tert-butoxide, etc., preferably methanol/sodium methoxide system, and the amount of sodium alkoxide is 100% -400%, preferably 200-300% of the amount of the compound (III).

In step (2), the reaction temperature is independently selected from 0 ℃ to 150 ℃, preferably from 50 ℃ to 100 ℃; after the reaction is finished, the mixture is concentrated, dissolved, washed by water, concentrated, recrystallized, filtered and dried to obtain a compound (V).

In the step (3), the compound (V) is subjected to oxidation reaction to obtain a compound (VI), the oxidant can be selected from one or more of hydrogen peroxide, potassium permanganate, sodium chlorite, sodium bromite, sodium hypochlorite, sodium hypobromite, potassium dichromate and the like, preferably a combination system of sodium chlorite and hydrogen peroxide is adopted, wherein the dosage of the hydrogen peroxide is 50% -150% of the amount of the compound (V), preferably 90% -100%, and the dosage of the sodium chlorite is 50% -150% of the amount of the compound (V), preferably 95% -105%.

In step (3), sodium chlorite is used as the oxidant, and the solvent is selected from but not limited to N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, acetone and the like, preferably dimethyl sulfoxide.

And neutralizing, decoloring, filtering, acidifying, filtering and drying the product of the oxidation reaction to obtain the 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (VI).

Advantageous effects of the invention

Compared with the prior art, the invention has the advantages that the cheap and easily obtained raw materials of N, N-dimethylformamide and bromoacetic acid are used for conveniently synthesizing the 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid through three-step reaction, the complex method for synthesizing the diformylacetic acid ethyl ester is avoided, the dangerous sodium hydride used in the condensation and cyclization process is avoided, the cheap and easily obtained oxidants of sodium chlorite and hydrogen peroxide are used for conveniently and efficiently obtaining the product, the reaction steps are simplified, the operation is simple and convenient, the three wastes are less, and the yield is high. The total yield of the three-step reaction reaches 45-50 percent, which is far higher than the synthesis yield of the intermediate reported in the past literature; moreover, the method has mild reaction conditions, is environment-friendly, has low cost, and is obviously superior to other synthetic technical routes reported in the prior art. The product obtained by the method has stable quality and is very suitable for the industrial production of the Allagliptin.

Drawings

FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of an intermediate 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (VI) according to the invention.

FIG. 2 is a high performance liquid chromatography of intermediate 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (VI) according to the invention.

Detailed Description

The present invention will be described in further detail with reference to examples. It will be apparent to those skilled in the art that equivalent substitutions of reagents and adjustment of specific parameters based on the concept of the present invention are possible within the scope of the present invention.

Example 1:

preparation of diformylacetaldehyde (III)

Adding 300ml of N, N-Dimethylformamide (DMF) into a 500m L four-mouth bottle provided with a mechanical stirring pipe, a condensing pipe and a thermometer, stirring and cooling to 0-5 ℃, keeping the temperature, dropwise adding 45.83g (0.3mol) of phosphorus oxychloride, keeping the temperature and stirring for 0.5 hour after dropwise adding, adding 41.5g (0.3mol) of bromoacetic acid in batches, adding after 20 minutes, heating to 70-75 ℃, stirring for 16 hours, cooling to room temperature, pouring the reaction solution into 200g of ice water, keeping the temperature below 40 ℃, adjusting the pH to 5-6 with sodium hydroxide, stirring for 1 hour at room temperature, adding dichloromethane for extraction (100ml × 3), combining organic phases, drying, filtering, and concentrating to obtain 12.1g of orange solid diformylaldehyde (III), wherein the next reaction can be carried out without refining, and the yield is 40.3%.

In the embodiment, the dosage of the phosphorus oxychloride is the molar dosage of the bromoacetic acid: 100 percent

Example 2:

preparation of diformylacetaldehyde (III)

325ml of N, N-Dimethylformamide (DMF) is added into a 500m L four-mouth bottle provided with a mechanical stirring pipe, a condensing pipe and a thermometer, the stirring temperature is reduced to 0-5 ℃, 137.5g (0.9mol) of phosphorus oxychloride is dropwise added at the maintained temperature, the heat preservation stirring is continued for 0.5 hour after the dropwise addition, 41.5g (0.3mol) of bromoacetic acid is added in batches, the addition is finished after 20 minutes, the temperature is increased to 70-75 ℃, the stirring is carried out for 16 hours, the temperature is reduced to the room temperature, the reaction liquid is poured into 200g of ice water, the pH is adjusted to 5-6 by sodium hydroxide at the temperature of below 40 ℃, the stirring is carried out for 1 hour at the room temperature, dichloromethane is added for extraction (100ml × 3), organic phases are combined, dried and filtered, the orange solid diformylacetal (III) 16.3g is obtained by concentration, the next reaction can be carried out.

In the embodiment, the dosage of the phosphorus oxychloride is the molar dosage of the bromoacetic acid: 300 percent

Example 3:

preparation of diformylacetaldehyde (III)

Adding DMF220ml into a 500m L four-necked bottle provided with a mechanical stirring pipe, a condensing pipe and a thermometer, stirring and cooling to 0-5 ℃, dropwise adding oxalyl chloride 57.2g (0.45mol) while keeping the temperature, continuously keeping the temperature and stirring for 0.5 hour after dropwise adding, adding bromoacetic acid 20.8g (0.15mol) in batches, heating to 70-75 ℃ after 20 minutes, stirring for 16 hours while cooling to room temperature, pouring the reaction solution into 100g of ice water, keeping the temperature lower than 40 ℃, adjusting the pH to 5-6 with sodium hydroxide, stirring for 1 hour at room temperature, adding dichloromethane for extraction (50ml × 3), combining organic phases, drying, filtering and concentrating to obtain orange solid (III) 4.6g, wherein the yield is 30.5%.

In the embodiment, the dosage of the phosphorus oxychloride is the molar dosage of the bromoacetic acid: 300 percent

Example 4

Preparation of diformylacetaldehyde (III)

Adding DMF250ml into a 500m L four-mouth bottle provided with a mechanical stirring pipe, a condensing pipe and a thermometer, stirring and cooling to 0-5 ℃, dropwise adding oxalyl chloride 95.3g (0.75mol) while keeping the temperature, continuously keeping the temperature and stirring for 0.5 hour after dropwise adding, adding bromoacetic acid 20.8g (0.15mol) in batches, heating to 140-150 ℃ after 20 minutes, stirring for 16 hours, cooling to room temperature, pouring the reaction solution into 100g of ice water, keeping the temperature lower than 40 ℃, adjusting the pH to 5-6 with sodium hydroxide, stirring for 1 hour at room temperature, adding dichloromethane for extraction (50ml × 3), combining organic phases, drying, filtering, and concentrating to obtain 5.3g of orange solid (III), wherein the yield is 35.1%.

In the embodiment, the dosage of the phosphorus oxychloride is the molar dosage of the bromoacetic acid: 500 percent.

Example 5:

preparation of 6-carboxaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V)

Adding 200ml of methanol, 50g (0.5mol) of diformylacetaldehyde (III) and 49g (0.5mol) of 3-amino-5-methylpyrazole (IV) into a 1000m L four-necked bottle with a mechanical stirring thermometer, stirring and heating to 50 ℃, refluxing, slowly dropwise adding a solution of 27g (0.5mol) of sodium methoxide and 400ml of methanol, dropwise adding after 0.5 hour, keeping the temperature and stirring for 3 hours, distilling a reflux device, evaporating 500-550 ml of methanol, cooling to 0 ℃, adding 300ml of dichloromethane and 200ml of water, stirring for 5 minutes, layering, washing an organic layer with water (50ml × 2), concentrating the organic layer, adding 300ml of methanol, recrystallizing to obtain 49.5g of yellow solid 6-formaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V), wherein the yield is 61.5%, and the melting point is 150-152 ℃.

In the present embodiment, the amount of sodium methoxide is the molar amount of diformylacetaldehyde: 100 percent

Example 6:

preparation of 6-carboxaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V)

200ml of methanol, 50g (0.5mol) of diformyl acetaldehyde (III) and 49g (0.5mol) of 3-amino-5-methylpyrazole (IV) are added into a 1000m L four-necked bottle with a mechanical stirring thermometer, the mixture is stirred and heated to 75 ℃ for reflux, a solution of 54g (1.0mol) of sodium methoxide and 400ml of methanol is slowly dropped into the mixture, the dropping is completed within 0.5 hour, the mixture is kept and stirred for 3 hours, a reflux device is changed into distillation, 500 to 550ml of methanol is evaporated, the temperature is reduced to 10 to 15 ℃, 300ml of dichloromethane and 200ml of water are added, the mixture is stirred for 5 minutes and then layered, an organic layer is washed by water (50ml of × 2), the organic layer is concentrated and then added with 300ml of methanol for recrystallization, and yellow solid 6-formaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V) is obtained, the yield is 82.6%, and the melting point is 150 to 152 ℃.

In the present embodiment, the amount of sodium methoxide is the molar amount of diformylacetaldehyde: 200 percent of

Example 7:

preparation of 6-carboxaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V)

150ml of ethanol, 36.0g (0.36mol) of diformylacetaldehyde (III) and 35.3g (0.36mol) of 3-amino-5-methylpyrazole (IV) are added into a 1000m L four-mouth bottle with a mechanical stirring thermometer, the mixture is stirred and heated to 100 ℃ for reflux, 49.0g (0.72mol) of sodium ethoxide and 300ml of ethanol are slowly and dropwise added, the mixture is kept warm and stirred for 3 hours, a reflux device is changed into distillation, 350 to 400ml of ethanol is evaporated, the temperature is reduced to 10 to 15 ℃, 200ml of dichloromethane and 150ml of water are added, the mixture is stirred for 5 minutes and then layered, an organic layer is washed with water (50ml of × 2), the organic layer is concentrated and then added with 200ml of methanol for recrystallization, 46.5g of yellow solid 6-formaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V) is obtained, and the yield is 80.3%.

In this embodiment, the amount of sodium ethoxide is equal to the molar amount of diformylacetaldehyde: 200 percent of

Example 8:

preparation of 6-carboxaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V)

100ml of methanol, 25g (0.25mol) of diformyl acetaldehyde (III) and 24.5g (0.25mol) of 3-amino-5-methylpyrazole (IV) are added into a 1000m L four-necked bottle with a mechanical stirring thermometer, the mixture is stirred and heated to reflux, a solution of 21.6g (0.4mol) of sodium methoxide and 200ml of methanol is slowly dripped, the dropwise addition is finished within 0.5 hour, the mixture is kept at the temperature and stirred for 3 hours, a reflux device is changed into distillation, 250 to 280ml of methanol is evaporated, the temperature is reduced to 10 to 15 ℃, 150ml of dichloromethane and 100ml of water are added, the mixture is stirred for 5 minutes and then layered, an organic layer is washed with water (25ml of × 2), the organic layer is concentrated and then added with 150ml of methanol for recrystallization, and yellow solid 6-methyl-2-methyl-aldehyde [1,5-a ] pyrimidine (V) is obtained, the yield is 65.3%, and the melting point is 150 to 152 ℃.

In the present embodiment, the amount of sodium methoxide is the molar amount of diformylacetaldehyde: 160 percent

Example 9:

preparation of 6-carboxaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V)

100ml of methanol, 25g (0.25mol) of diformylacetaldehyde (III) and 24.5g (0.25mol) of 3-amino-5-methylpyrazole (IV) are added into a 1000m L four-mouth bottle with a mechanical stirring thermometer, the mixture is stirred and heated to 150 ℃ for reflux, 54.0g (1.0mol) of sodium methoxide and 200ml of methanol are slowly dropped into the bottle, the solution is dropped after 0.5 hour, the temperature is kept and stirred for 3 hours, a reflux device is changed into distillation, 250 to 280ml of methanol is evaporated, the temperature is reduced to 15 ℃, 150ml of dichloromethane and 100ml of water are added, the mixture is stirred for 5 minutes and then layered, an organic layer is washed by water (25ml of × 2), the organic layer is concentrated and then added with 150ml of methanol for recrystallization, 47.6g of yellow solid 6-methyl-2-methyl-aldehyde [1,5-a ] pyrimidine (V) is obtained, the yield is 46.7%, and the melting point is 150 to 152 ℃.

In the present embodiment, the amount of sodium methoxide is the molar amount of diformylacetaldehyde: 400 percent

Example 10 was added:

preparation of 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (VI)

100ml of 6-formaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V), 35.2g (0.22mol) of water, 13.95g (0.11mol) of 30% hydrogen peroxide and 9.95g (0.11mol) of sodium chlorite are added into a 500m L four-necked bottle with a mechanical stirring thermometer, the temperature is raised to 50 ℃ for reaction for 1 hour, the temperature is lowered to 20 ℃, T L C shows complete reaction, sodium sulfite is used for adjusting the pH value of a potassium iodide reagent of starch to 2-3, hydrochloric acid is used for adjusting the pH value, the solid is filtered and recrystallized by 200ml of ethanol, 23.3g of white solid 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (VI) is obtained, and the yield is 59.8%.

FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of an intermediate 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (VI) according to the invention.

Compound VI 1H NMR (400MHz, DMSO-d6) 13.54(s,1H),9.32(s,1H),8.78(s,1H),6.61(s,1H),2.43(s, 3H).

In the embodiment, the amount of hydrogen peroxide is the molar amount of the compound V: 50 percent of

The amount of sodium chlorite used in this embodiment is the molar amount of compound V: 50 percent of

FIG. 2 is a high performance liquid chromatography of intermediate 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (VI) according to the invention.

Table 1: parameters in the high performance liquid chromatography in FIG. 1

Name of component	Retention time	Peak height	Peak area	Concentration of	Tailing factor	Theory of the inventionColumn plate
								5.520	3.03	44.324	0.182	1.84	3212
	9.465	1665.05	74310.100	99.818	1.16	1015
							Σ:		1668.08	74354.424	100.000

Example 11:

preparation of 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (VI)

100ml of 6-formaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V), 35.2g (0.22mol) of water, 27.9g (0.22mol) of 30% hydrogen peroxide and 19.9g (0.22mol) of sodium chlorite are added into a 500m L four-necked bottle with a mechanical stirring thermometer, the temperature is raised to 50 ℃ for reaction for 1 hour, the temperature is lowered to 20 ℃, T L C shows complete reaction, sodium sulfite is used for adjusting the pH value of a potassium iodide reagent of starch to 2-3, hydrochloric acid is used for adjusting the pH value, the solid is filtered and recrystallized by 200ml of ethanol, 35.6g of white solid 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (VI) is obtained, and the yield is 91.5%.

In the embodiment, the amount of hydrogen peroxide is the molar amount of the compound V: 100 percent

The amount of sodium chlorite used in this embodiment is the molar amount of compound V: 100 percent

Example 12

Preparation of 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (VI)

100ml of water, 10.0g (0.06mol) of 6-formaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V), 4.5g (0.04mol) of 30% hydrogen peroxide and 3.6g (0.04mol) of sodium chlorite are added into a 500m L four-necked bottle with a mechanical stirring thermometer, the temperature is raised to 50 ℃ for reaction for 1 hour, the temperature is lowered to 20 ℃, sodium sulfite is used for adjusting the pH of a potassium iodide reagent of starch to 2-3, hydrochloric acid is used for adjusting the pH value, filtration is carried out, 100ml of ethanol is used for recrystallization of the solid, 7.8g of white solid 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (VI) is obtained, and the yield is 71.1%.

In the embodiment, the amount of hydrogen peroxide is the molar amount of the compound V: 66 percent

The amount of sodium chlorite used in this embodiment is the molar amount of compound V: 66 percent

Example 13:

preparation of 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (VI)

100ml of 6-formaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V), 35.2g (0.22mol) of water, 41.9g (0.33mol) of 30% hydrogen peroxide and 29.9g (0.33mol) of sodium chlorite are added into a 500m L four-necked bottle with a mechanical stirring thermometer, the temperature is raised to 50 ℃ for reaction for 1 hour, the temperature is lowered to 20 ℃, T L C shows complete reaction, sodium sulfite is used for adjusting the pH value of a potassium iodide reagent of starch to 2-3, hydrochloric acid is used for adjusting the pH value, the solid is filtered and recrystallized by 200ml of ethanol, 29.8g of white solid 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (VI) is obtained, and the yield is 76.7%.

In the embodiment, the amount of hydrogen peroxide is the molar amount of the compound V: 150 percent

The amount of sodium chlorite used in this embodiment is the molar amount of compound V: 150 percent

Example 14:

preparation of 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (VI)

Adding 1000ml of 5% potassium permanganate solution and 2g of potassium hydroxide into a 2000m L four-necked bottle with a mechanical stirring thermometer, keeping the temperature at 10-15 ℃, adding 35g (0.22mol) of 6-formaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V) at one time, stirring for 30min at 10-15 ℃ after the addition is finished, filtering, adjusting the water phase to be not discolored by using sodium sulfite as a starch potassium iodide reagent, adding 0.5g of activated carbon, stirring and decoloring for 30min, filtering, adjusting the pH of the filtrate to be 2-3 by using concentrated hydrochloric acid, filtering, and recrystallizing the solid by using 200ml of ethanol to obtain 17.8g of white-like solid 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (VI), wherein the yield is 45.8%.

Claims (10)

1. A preparation method of an Alalogliptin intermediate is characterized by comprising the following steps:

(1) performing Vilsmiere reaction on N, N-dimethylformamide (I) and acyl chloride to generate a Vilsmiere reagent, dropwise adding bromoacetic acid (II) into the Vilsmiere reagent, heating for reaction, and hydrolyzing to obtain diformylaldehyde (III);

(2) dissolving diformylacetaldehyde (III) and 3-amino-5-methylpyrazole (IV) in an alcohol/sodium alkoxide system, heating, refluxing and stirring to generate 6-formaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V);

(3) oxidizing the 6-formaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V) in strong alkali to generate 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (VI).

2. The process for the preparation of the alagliptin intermediate of claim 1, which comprises:

in the step (1), the Vilsmiere reaction of N, N-dimethylformamide (I) and acyl chloride is carried out at the reaction temperature of 0-150 ℃, and the molar amount of the acyl chloride is 100-500% of the molar amount of bromoacetic acid.

3. The process for the preparation of the alagliptin intermediate of claim 1, which comprises:

in the step (1), the Vilsmiere reaction temperature of the N, N-dimethylformamide (I) and the acyl chloride is 50-100 ℃, and the molar amount of the acyl chloride is 250-350% of that of the bromoacetic acid.

4. The process for the preparation of the alagliptin intermediate of claim 1, which comprises:

in the step (2), the alcohol/sodium alkoxide system is selected from one group of methanol/sodium methoxide, ethanol/sodium ethoxide, isopropanol/sodium isopropoxide or tert-butyl alcohol/sodium tert-butoxide, and the using amount of the sodium alkoxide is 100-400% of the amount of the diformylaldehyde acetaldehyde (III) substance.

5. The process for the preparation of the alagliptin intermediate of claim 1, which comprises:

in the step (2), the reaction temperature is 0-150 ℃, and after the reaction is finished, 6-formaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V) is obtained by concentration, dissolution, water washing, concentration, recrystallization, filtration and drying.

6. The process for the preparation of the alagliptin intermediate of claim 1, which comprises:

in the step (3), the 6-formaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V) is subjected to oxidation reaction to obtain 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (VI), and the oxidant is selected from one or a combination of at least two of hydrogen peroxide, potassium permanganate, sodium chlorite, sodium bromite, sodium hypochlorite, sodium hypobromite and potassium dichromate.

7. The process for the preparation of the alagliptin intermediate of claim 1, which comprises:

in the step (3), the 6-formaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V) is subjected to oxidation reaction to obtain 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (VI), and the oxidant is a sodium chlorite and hydrogen peroxide combined system, wherein the dosage of the hydrogen peroxide is 50% -150% of the dosage of the 6-formaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V) substance, and the dosage of the sodium chlorite is 50% -150% of the dosage of the 6-formaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V) substance.

8. The process for the preparation of the alagliptin intermediate of claim 1, which comprises:

in the step (3), the 6-formaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V) is subjected to oxidation reaction to obtain 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (VI), and the oxidant is a sodium chlorite and hydrogen peroxide combined system, wherein the dosage of the hydrogen peroxide is 90-100% of the dosage of the 6-formaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V), and the dosage of the sodium chlorite is 95-105% of the dosage of the 6-formaldehyde-2-methyl-pyrazolo [1,5-a ] pyrimidine (V).

9. The process for the preparation of the alagliptin intermediate of claim 7, which comprises:

in the step (3), when sodium chlorite is used as the oxidizing agent, the solvent is one selected from N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran and acetone.

10. The process for the preparation of the alagliptin intermediate of claim 7, which comprises:

and neutralizing, decoloring, filtering, acidifying, filtering and drying the product of the oxidation reaction to obtain the 2-methyl-pyrazolo [1,5-a ] pyrimidine-6-carboxylic acid (VI).

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