CN104086550A - Synthetic method for tetramethyluric acid - Google Patents

Abstract

The invention discloses a method for synthesizing tetramethyluric acid. The method is as follows: 1. Put uric acid and a methylating reagent in a high-pressure reactor, replace the protective gas for three times, and then fill the protective gas until the pressure in the high-pressure reactor is 0.5 MPa～10MPa, heat up to 84°C～220°C, heat preservation reaction under stirring conditions; 2. Use condensed water to cool down the high-pressure reaction kettle after heat preservation reaction, and open the outlet valve of the high-pressure reaction kettle to release the pressure, and wait for the pressure of the high-pressure reaction kettle to drop When it reaches 0MPa, open the kettle and discharge the material, pour the reacted material into ice water for stirring and crystallization, and obtain the crude product after suction filtration; 3. Recrystallize the crude product, and obtain tetramethyluric acid with a mass purity of not less than 95% after drying . The present invention uses uric acid as a raw material to obtain the product tetramethyluric acid under high pressure and high temperature conditions through the complete methylation reaction of nitrogen on the purine ring, which has the advantages of high conversion rate, high yield, high selectivity and short reaction time, and is suitable for synthesized on a large scale.

Description

A kind of synthetic method of tetramethyluric acid

technical field

The invention belongs to the technical fields of drug synthesis and organic synthesis, and in particular relates to a synthesis method of tetramethyluric acid.

Background technique

Tetramethyluric acid (theacrine) is a xanthine alkaloid, which is similar in structure to theophylline, caffeine, and theobromine, and has various physiological activities, such as anti-inflammatory and analgesic. In recent years, studies have focused on the permeability of the blood-brain barrier and the role of the central nervous system. Previous experimental studies have shown that this type of alkaloid may have a protective effect on dopamine neurons in Parkinson's disease model mice, and can prevent or delay its degeneration, and is very promising to be developed as a new drug for the treatment of Parkinson's disease.

Theacrine comes from bitter tea in southern China, where (Theobromagrandiflorum) and Camellia kucha (Camellia assamica var.kucha) are relatively high, and the existing methods are mainly obtained by extraction, column chromatography and other methods. With the continuous discovery of new pharmacological activities of theacrine, the existing production methods have been unable to meet its requirements. Therefore, it is very important for the in-depth and extensive research and application of theacrine to solve the problem of source shortage.

Contents of the invention

The technical problem to be solved by the present invention is to provide a synthetic method for tetramethyluric acid aiming at the above-mentioned deficiencies in the prior art. The method uses uric acid as a raw material to obtain the product tetramethyluric acid (theacrine) under high pressure and high temperature conditions through the complete methylation reaction of nitrogen on the purine ring, which has high conversion rate, high yield, high selectivity and short reaction time. Advantages, suitable for large-scale synthesis.

For solving the problems of the technologies described above, the technical scheme adopted in the present invention is: a kind of synthetic method of tetramethyluric acid, it is characterized in that, this method comprises the following steps:

Step 1. Put uric acid and methylating reagent in the autoclave according to the molar ratio of 1:(1.5~40), replace the autoclave with protective gas three times, and then fill the autoclave with protective gas until the pressure inside the autoclave is 0.5MPa ~10MPa, then raise the temperature of the autoclave to 84°C~220°C, and keep the reaction for 2h~48h under the condition of stirring rate of 180rpm~2000rpm;

Step 2. Use condensed water to cool down the high-pressure reactor after the heat preservation reaction in step 1, and open the outlet valve of the high-pressure reactor to release the pressure. Stir and crystallize in ice water, and obtain the crude product after suction filtration;

Step 3: recrystallize the crude product described in step 2, and obtain tetramethyluric acid with a mass purity of not less than 95% after drying.

In the above-mentioned synthesis method of tetramethyluric acid, the molar ratio of uric acid and methylating reagent in step 1 is 1:(5-20).

The above-mentioned synthetic method of a kind of tetramethyluric acid, the molar ratio of described uric acid and methylation reagent is 1:10.

The above-mentioned synthetic method of tetramethyluric acid, the methylating reagent described in step 1 is monohalomethane, dimethyl sulfate, N,N-dimethylformamide, N,N-dimethylformamide Amide dimethyl acetal, tetramethylammonium hydroxide aqueous solution with a mass concentration of 25%, a mixed solution of formaldehyde and formic acid, dimethyl carbonate, trimethyl orthoformate, trimethylchlorosilane or methyl trifluoromethanesulfonate ester.

In the above-mentioned synthetic method of tetramethyluric acid, the protective gas described in step 1 is nitrogen or argon.

In the above synthesis method of tetramethyluric acid, the pressure in step 1 is 2MPa-8MPa.

In the above-mentioned synthesis method of tetramethyluric acid, in step 1, the temperature of the autoclave is raised to 115° C. to 190° C., and the temperature is kept for 2.5 hours to 18 hours at a stirring rate of 300 rpm to 1000 rpm.

The above-mentioned synthetic method of a kind of tetramethyluric acid, the solvent that the recrystallization described in step 3 adopts is a kind of in ethyl acetate, methylene chloride and acetonitrile and alcohols according to the volume ratio of (1～7):1 A mixed mixed solvent, or a mixed solvent mixed with acetone in a volume ratio of 1:(0.25-3) among dichloromethane, n-hexane and alcohols, wherein the alcohols are methanol or ethanol.

Compared with the prior art, the present invention has the following advantages:

1. The present invention uses uric acid as a raw material to obtain the product tetramethyluric acid (theacrine) under high pressure and high temperature conditions through the complete methylation reaction of nitrogen on the purine ring, which has high conversion rate, high yield, high selectivity and reaction time Short and other advantages, suitable for large-scale synthesis.

2. The present invention adopts solvent-free reaction, and the methylating reagent is not only a reactant, but also a reaction medium, which can maximize the steam partial pressure in the high-pressure reaction, which is beneficial to increase the reaction yield.

3. The present invention adopts high temperature and high pressure reaction, which shortens the reaction time and improves the efficiency and yield to a certain extent. At the same time, the reaction rate, yield and selectivity were taken into consideration.

4. The present invention adopts recrystallization, which improves the ability to separate impurities and improves the total yield to a certain extent.

The technical solutions of the present invention will be further described in detail below in conjunction with the embodiments.

Detailed ways

Example 1

Step 1. Add 1.6mol methyl iodide and 0.08mol uric acid into the 500mL autoclave, seal it, fill the autoclave with nitrogen to 0.5MPa, then vent it, replace it three times continuously, and then fill the autoclave with nitrogen into the autoclave The pressure is 5MPa, turn on the condensed water, adjust the stirring rate to 180rpm, raise the temperature of the autoclave to 84°C, and keep it warm for 2h;

Step 2: Increase the flow rate of condensed water to cool down the high-pressure reactor after the heat preservation reaction in step 1, and slowly open the outlet valve of the high-pressure reactor to release the pressure. The material was poured into 300mL ice water and stirred and crystallized, and the crude product was obtained after suction filtration;

Step 3, using ethyl acetate and methanol to recrystallize the crude product described in step 2, the volume ratio of ethyl acetate and methanol is 5:1, after drying at 105°C for 0.5 hour, tetramethyluric acid (1,3,7 , 9-tetramethyluric acid) 12.4g, yield 69.2%, the mass purity of tetramethyluric acid detected by HPLC is not less than 95%.

After testing, the melting point of the product tetramethyluric acid prepared in this example is 222°C-225°C; MS: 225 (M+H); ¹ HNMR (CDCl ₃ ): 3.23 (s3H), 3.41 (s3H), 3.52 ( s3H), 3.61 (s3H).

Example 2

Step 1. Add 1.6mol dimethyl sulfate and 0.16mol uric acid into a 500mL autoclave, seal it, fill the autoclave with argon to 0.5MPa, and then vent it. After three consecutive replacements, fill the autoclave with argon to The pressure in the autoclave is 4MPa, turn on the condensed water, adjust the stirring rate to 280rpm, raise the temperature of the autoclave to 180°C, and keep it warm for 2.5h;

Step 2: Increase the flow rate of condensed water to cool down the high-pressure reactor after the heat preservation reaction in step 1, and slowly open the outlet valve of the high-pressure reactor to release the pressure. The material was poured into 400mL ice water and stirred and crystallized, and the crude product was obtained after suction filtration;

Step 3, using dichloromethane and methanol to recrystallize the crude product described in step 2, the volume ratio of dichloromethane to methanol is 7:1, and after drying at 105°C for 0.5 hour, tetramethyluric acid (1,3,7 , 9-tetramethyluric acid) 25.6g, yield 71.4%, the mass purity of tetramethyluric acid detected by HPLC is not less than 95%.

After testing, the melting point of the product tetramethyluric acid prepared in this example is 222°C-225°C; MS: 225 (M+H); ¹ HNMR (CDCl ₃ ): 3.23 (s3H), 3.41 (s3H), 3.52 ( s3H), 3.61 (s3H).

Example 3

Step 1. Add 1.6mol N,N-dimethylformamide dimethyl acetal and 0.16mol uric acid into a 500mL autoclave, seal it, fill the autoclave with nitrogen to 0.5MPa and then vent it, and replace it three times in a row. Fill the autoclave with nitrogen until the pressure in the autoclave is 2MPa, turn on the condensed water, adjust the stirring rate to 300rpm, raise the temperature of the autoclave to 190°C, and keep it warm for 2.5 hours;

Step 2: Increase the flow rate of condensed water to cool down the high-pressure reactor after the heat preservation reaction in step 1, and slowly open the outlet valve of the high-pressure reactor to release the pressure. The material was poured into 500mL ice water and stirred and crystallized, and the crude product was obtained after suction filtration;

Step 3, using dichloromethane and acetone to recrystallize the crude product described in step 2, the volume ratio of dichloromethane to acetone is 4:1, after drying at 105°C for 0.5 hour, tetramethyluric acid (1,3,7 , 9-tetramethyluric acid) 28.4g, yield 79.2%, the mass purity of tetramethyluric acid detected by HPLC is not less than 95%.

After testing, the melting point of the product tetramethyluric acid prepared in this example is 222°C-225°C; MS: 225 (M+H); ¹ HNMR (CDCl ₃ ): 3.23 (s3H), 3.41 (s3H), 3.52 ( s3H), 3.61 (s3H).

Example 4

Step 1. Add 0.8mol dimethyl carbonate and 0.16mol uric acid into a 500mL autoclave, seal it, fill the autoclave with nitrogen to 0.5MPa and then vent it, replace it three times in a row, then fill the autoclave with nitrogen to react under high pressure The pressure in the autoclave is 8MPa, turn on the condensed water, adjust the stirring rate to 400rpm, raise the temperature of the autoclave to 185°C, and keep the temperature for 5h;

Step 2: Increase the flow rate of condensed water to cool down the high-pressure reactor after the heat preservation reaction in step 1, and slowly open the outlet valve of the high-pressure reactor to release the pressure. The material was poured into 250mL ice water and stirred and crystallized, and the crude product was obtained after suction filtration;

Step 3, using acetone and methanol to recrystallize the crude product described in step 2, the volume ratio of acetone and methanol is 3:1, and after drying at 105°C for 0.5 hour, tetramethyluric acid (1,3,7,9-tetramethyluric acid (1,3,7,9-tetramethyluric acid) is obtained. Methyluric acid) 30.8g, yield 85.9%, the mass purity of tetramethyluric acid detected by HPLC is not less than 95%.

After testing, the melting point of the product tetramethyluric acid prepared in this example is 222°C-225°C; MS: 225 (M+H); ¹ HNMR (CDCl ₃ ): 3.23 (s3H), 3.41 (s3H), 3.52 ( s3H), 3.61 (s3H).

Example 5

Step 1. Add 4mol trimethylchlorosilane and 0.16mol uric acid into a 500mL autoclave, seal it, fill the autoclave with nitrogen to 0.5MPa, then vent it, replace it three times in a row, and then fill the autoclave with nitrogen to react under high pressure The pressure in the autoclave is 6MPa, turn on the condensed water, adjust the stirring rate to 500rpm, raise the temperature of the autoclave to 115°C, and keep it warm for 18h;

Step 2: Increase the flow rate of condensed water to cool down the high-pressure reactor after the heat preservation reaction in step 1, and slowly open the outlet valve of the high-pressure reactor to release the pressure. The material was poured into 1000mL ice water and stirred and crystallized, and the crude product was obtained after suction filtration;

Step 3, using acetonitrile and ethanol to recrystallize the crude product described in step 2, the volume ratio of acetonitrile and ethanol is 1:1, and after drying at 105°C for 0.5 hours, tetramethyluric acid (1,3,7,9-tetramethyluric acid (1,3,7,9-tetramethyluric acid) is obtained. Methyluric acid) 29.4g, yield 82.0%, the mass purity of tetramethyluric acid detected by HPLC is not less than 95%.

After testing, the melting point of the product tetramethyluric acid prepared in this example is 222°C-225°C; MS: 225 (M+H); ¹ HNMR (CDCl ₃ ): 3.23 (s3H), 3.41 (s3H), 3.52 ( s3H), 3.61 (s3H).

Example 6

Step 1. Add 3.2mol methyl trifluoromethanesulfonate and 0.16mol uric acid into a 500mL autoclave, seal it, fill the autoclave with argon to 0.5MPa, and then empty it. After three consecutive replacements, fill the autoclave with Argon until the pressure in the autoclave is 3MPa, turn on the condensed water, adjust the stirring rate to 1000rpm, raise the temperature of the autoclave to 190°C, and keep it warm for 8h;

Step 2: Increase the flow rate of condensed water to cool down the high-pressure reactor after the heat preservation reaction in step 1, and slowly open the outlet valve of the high-pressure reactor to release the pressure. The material was poured into 600mL ice water and stirred and crystallized, and the crude product was obtained after suction filtration;

Step 3, using n-hexane and acetone to recrystallize the crude product described in step 2, the volume ratio of n-hexane and acetone is 1:1, after drying at 105°C for 0.5 hour, tetramethyluric acid (1,3,7,9 -Tetramethyluric acid) 29.2g, yield 81.5%, the mass purity of tetramethyluric acid detected by HPLC is not less than 95%.

After testing, the melting point of the product tetramethyluric acid prepared in this example is 222°C-225°C; MS: 225 (M+H); ¹ HNMR (CDCl ₃ ): 3.23 (s3H), 3.41 (s3H), 3.52 ( s3H), 3.61 (s3H).

Example 7

Step 1. Add 3.2mol N,N-dimethylformamide and 0.08mol uric acid into the 500mL autoclave, seal it, fill the autoclave with nitrogen to 0.5MPa and then vent it, replace it three times in a row, and put it into the autoclave Fill the autoclave with nitrogen until the pressure in the autoclave is 10MPa, turn on the condensed water, adjust the stirring rate to 1400rpm, raise the temperature of the autoclave to 200°C, and keep it warm for 2 hours;

Step 2: Increase the flow rate of condensed water to cool down the high-pressure reactor after the heat preservation reaction in step 1, and slowly open the outlet valve of the high-pressure reactor to release the pressure. The material was poured into 500mL ice water and stirred and crystallized, and the crude product was obtained after suction filtration;

Step 3, using acetone and methanol to recrystallize the crude product described in step 2, the volume ratio of acetone and methanol is 3:1, and after drying at 105°C for 0.5 hour, tetramethyluric acid (1,3,7,9-tetramethyluric acid (1,3,7,9-tetramethyluric acid) is obtained. Methyluric acid) 15.23g, yield 85.0%, the mass purity of tetramethyluric acid detected by HPLC is not less than 95%.

After testing, the melting point of the product tetramethyluric acid prepared in this example is 222°C-225°C; MS: 225 (M+H); ¹ HNMR (CDCl ₃ ): 3.23 (s3H), 3.41 (s3H), 3.52 ( s3H), 3.61 (s3H).

Example 8

Step 1. Add 0.15mol trimethyl orthoformate and 0.1mol uric acid into a 500mL autoclave, seal it, fill the autoclave with argon to 0.5MPa, then vent it, replace it three times in a row, and then fill the autoclave with argon When the pressure in the autoclave is 0.5MPa, turn on the condensed water, adjust the stirring rate to 1800rpm, raise the temperature of the autoclave to 220°C, and keep it warm for 48 hours;

Step 2: Increase the flow rate of condensed water to cool down the high-pressure reactor after the heat preservation reaction in step 1, and slowly open the outlet valve of the high-pressure reactor to release the pressure. The material was poured into 500mL ice water and stirred and crystallized, and the crude product was obtained after suction filtration;

Step 3, using acetonitrile and ethanol to recrystallize the crude product described in step 2, the volume ratio of acetonitrile and ethanol is 1:1, and after drying at 105°C for 0.5 hours, tetramethyluric acid (1,3,7,9-tetramethyluric acid (1,3,7,9-tetramethyluric acid) is obtained. Methyluric acid) 17.92g, yield 80%, the mass purity of tetramethyluric acid detected by HPLC is not less than 95%.

After testing, the melting point of the product tetramethyluric acid prepared in this example is 222°C-225°C; MS: 225 (M+H); ¹ HNMR (CDCl ₃ ): 3.23 (s3H), 3.41 (s3H), 3.52 ( s3H), 3.61 (s3H).

Example 9

Step 1. Add a mixed solution of formaldehyde and formic acid (containing 0.64 mol of formaldehyde and 3.2 mol of formic acid) and 0.16 mol of uric acid into a 500mL autoclave. After sealing, fill the autoclave with nitrogen to 0.5MPa and then empty it. After three consecutive replacements Fill the autoclave with nitrogen until the pressure in the autoclave is 10MPa, turn on the condensed water, adjust the stirring rate to 1000rpm, raise the temperature of the autoclave to 100°C, and keep it warm for 24 hours;

Step 2: Increase the flow rate of condensed water to cool down the high-pressure reactor after the heat preservation reaction in step 1, and slowly open the outlet valve of the high-pressure reactor to release the pressure. The material was poured into 500mL ice water and stirred and crystallized, and the crude product was obtained after suction filtration;

Step 3, using dichloromethane and ethanol to recrystallize the crude product described in step 2, the volume ratio of dichloromethane to ethanol is 4:1, after drying at 105°C for 0.5 hour, tetramethyluric acid (1,3,7 , 9-tetramethyluric acid) 29.5g, yield 82.3%, the mass purity of tetramethyluric acid detected by HPLC is not less than 95%.

After testing, the melting point of the product tetramethyluric acid prepared in this example is 222°C-225°C; MS: 225 (M+H); ¹ HNMR (CDCl ₃ ): 3.23 (s3H), 3.41 (s3H), 3.52 ( s3H), 3.61 (s3H).

Example 10

Step 1. Add a 25% aqueous solution of tetramethylammonium hydroxide (containing 1 mol of tetramethylammonium hydroxide) and 0.08 mol of uric acid into a 500 mL autoclave, and fill the autoclave with argon to 0.5 After the MPa is vented, after three consecutive replacements, fill the autoclave with argon until the pressure in the autoclave is 10MPa, turn on the condensed water, adjust the stirring rate to 2000rpm, raise the temperature of the autoclave to 200°C, and keep it warm for 2 hours;

Step 2: Increase the flow rate of condensed water to cool down the high-pressure reactor after the heat preservation reaction in step 1, and slowly open the outlet valve of the high-pressure reactor to release the pressure. The material was poured into 500mL ice water and stirred and crystallized, and the crude product was obtained after suction filtration;

Step 3, using acetone and ethanol to recrystallize the crude product described in step 2, the volume ratio of acetone and ethanol is 2:1, and after drying at 105°C for 0.5 hours, tetramethyluric acid (1,3,7,9-tetramethyluric acid (1,3,7,9-tetramethyluric acid) is obtained. Methyluric acid) 13.44g, yield 75%, the mass purity of tetramethyluric acid detected by HPLC is not less than 95%.

After testing, the melting point of the product tetramethyluric acid prepared in this example is 222°C-225°C; MS: 225 (M+H); ¹ HNMR (CDCl ₃ ): 3.23 (s3H), 3.41 (s3H), 3.52 ( s3H), 3.61 (s3H).

The above are only preferred embodiments of the present invention, and do not limit the present invention in any way. All simple modifications, changes and equivalent structural changes made to the above embodiments according to the technical essence of the invention still belong to the technical solution of the present invention. within the scope of protection.

Claims (8)

1. a synthetic method for tetramethyl-uric acid, is characterized in that, the method comprises the following steps:

Step 1, according to 1:(1.5～40) mol ratio uric acid and methylating reagent are placed in autoclave, after autoclave is replaced to three times with shielding gas, filling shielding gas to high pressure reacting kettle inner pressure is 0.5MPa～10MPa, then the temperature of autoclave is risen to 84 ℃～220 ℃, insulation reaction 2h～48h under the condition that is 180rpm～2000rpm in stir speed (S.S.);

Step 2, the autoclave cooling after adopting water of condensation to insulation reaction in step 1, and the air outlet valve pressure release of opening autoclave, until autoclave Pressure Drop, open still discharging during to 0MPa, reacted material is poured in frozen water and carried out stirring and crystallizing, after suction filtration, obtain crude product;

Step 3, crude product described in step 2 is carried out to recrystallization, obtain quality purity after dry to be not less than 95% tetramethyl-uric acid.

2. the synthetic method of a kind of tetramethyl-uric acid according to claim 1, is characterized in that, in step 1, the mol ratio of uric acid and methylating reagent is 1:(5～20).

3. the synthetic method of a kind of tetramethyl-uric acid according to claim 2, is characterized in that, the mol ratio of described uric acid and methylating reagent is 1:10.

4. according to the synthetic method of a kind of tetramethyl-uric acid described in claim 1,2 or 3, it is characterized in that, methylating reagent described in step 1 is a methyl halide, methyl-sulfate, N, the mixing solutions of tetramethylammonium hydroxide aqueous solution, formaldehyde and formic acid that dinethylformamide, DMF dimethylacetal, mass concentration are 25%, methylcarbonate, trimethyl orthoformate, trimethylchlorosilane or trifluoromethanesulfonic acid methyl esters.

5. according to the synthetic method of a kind of tetramethyl-uric acid described in claim 1,2 or 3, it is characterized in that, shielding gas described in step 1 is nitrogen or argon gas.

6. the synthetic method of a kind of tetramethyl-uric acid according to claim 1, is characterized in that, pressure described in step 1 is 2MPa～8MPa.

7. the synthetic method of a kind of tetramethyl-uric acid according to claim 1, is characterized in that, the temperature of autoclave is risen to 115 ℃～190 ℃, insulation reaction 2.5h～18h under the condition that is 300rpm～1000rpm in stir speed (S.S.) in step 1.

8. the synthetic method of a kind of tetramethyl-uric acid according to claim 1, it is characterized in that, the solvent that recrystallization described in step 3 adopts is a kind of and alcohols in ethyl acetate, methylene dichloride and acetonitrile according to (1～7): the mixed solvent that 1 volume ratio is mixed, or be that a kind of and acetone in methylene dichloride, normal hexane and alcohols is according to 1:(0.25～3) the mixed solvent that mixes of volume ratio, wherein alcohols is methyl alcohol or ethanol.