CN104086550A - Synthetic method for tetramethyluric acid - Google Patents
Synthetic method for tetramethyluric acid Download PDFInfo
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- CN104086550A CN104086550A CN201410344230.XA CN201410344230A CN104086550A CN 104086550 A CN104086550 A CN 104086550A CN 201410344230 A CN201410344230 A CN 201410344230A CN 104086550 A CN104086550 A CN 104086550A
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- C07—ORGANIC CHEMISTRY
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- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/14—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with two methyl radicals in positions 1 and 3 and two methyl radicals in positions 7, 8, or 9
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Abstract
The invention discloses a synthetic method for tetramethyluric acid. The method is as follows: I, placing uric acid and a methylation reagent in a high-pressure reaction kettle, introducing a protective gas until pressure in the high-pressure reaction kettle is 0.5MPa-10MPa after replacing the protective gas for three times, heating to 84 DEG C-220 DEG C, and carrying out insulated reaction under a stirring condition; II, cooling the high-pressure reaction kettle by use of condensed water after insulated reaction, opening a gas release valve of the high-pressure reaction kettle for releasing pressure, opening the kettle, discharging after the pressure of the high-pressure reaction kettle is lowered to 0 MPa, pouring the reacted materials into icy water, stirring for separating out crystals, and carrying out suction filtration, thereby obtaining crude products; III, re-crystallizing crude products, and drying to obtain tetramethyluric acid with mass purity not smaller than 95%. According to the synthetic method disclosed by the invention, uric acid is taken as the raw material to obtain the product tetramethyluric acid by virtue of complete methylation reaction of nitrogen on a purine ring under a high-pressure high-temperature condition; the synthetic method has the advantages of being high in conversion rate, high in yield, high in selectivity, short in reaction time, and the like, and is suitable for large-scale synthesis.
Description
Technical field
The invention belongs to that medicine is synthetic, technical field of organic synthesis, be specifically related to a kind of synthetic method of tetramethyl-uric acid.
Background technology
Tetramethyl-uric acid (theacrine) is xanthine alkaloid, and the similar with theophylline, caffeine, Theobromine etc., has multiple physiologically active, as anti-inflammatory, analgesia etc.Research in recent years concentrates on permeability and the nervus centralis effect of its hemato encephalic barrier.Experimental study before shows, this Alkaloid may have provide protection to dopamine neuron in Parkinson disease mice, can prevent or delay it and degenerate, and being expected to very much exploitation becomes the Parkinsonian newtype drug for the treatment of.
Theacrine derives from the herb mixtures tea of southern china, wherein
content in (Theobroma grandiflorum) and Camellia kucha (Camellia assamica var.kucha) is relatively high, and existing method is mainly to obtain by methods such as extraction, column chromatographies.Along with the continuous discovery of the new pharmacologically active of theacrine, existing production method cannot meet its requirement.Therefore, solve source shortage problem to theacrine study deeply, widely and application is very important.
Summary of the invention
Technical problem to be solved by this invention is, for above-mentioned the deficiencies in the prior art, to provide a kind of synthetic method of tetramethyl-uric acid.The method be take uric acid as raw material; on purine skeleton, the reaction of the exhaustive methylation of nitrogen obtains product tetramethyl-uric acid (theacrine) under high pressure, hot conditions; there is the advantages such as high conversion, high yield, highly selective and reaction times is short, be applicable to mass-producing synthetic.
For solving the problems of the technologies described above, the technical solution used in the present invention is: a kind of synthetic method of tetramethyl-uric acid, it is characterized in that, and 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.
The synthetic method of above-mentioned a kind of tetramethyl-uric acid, in step 1, the mol ratio of uric acid and methylating reagent is 1:(5～20).
The synthetic method of above-mentioned a kind of tetramethyl-uric acid, the mol ratio of described uric acid and methylating reagent is 1:10.
The synthetic method of above-mentioned a kind of tetramethyl-uric acid, 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.
The synthetic method of above-mentioned a kind of tetramethyl-uric acid, shielding gas described in step 1 is nitrogen or argon gas.
The synthetic method of above-mentioned a kind of tetramethyl-uric acid, pressure described in step 1 is 2MPa～8MPa.
The synthetic method of above-mentioned a kind of tetramethyl-uric acid, rises to the temperature of autoclave 115 ℃～190 ℃ in step 1, insulation reaction 2.5h～18h under the condition that is 300rpm～1000rpm in stir speed (S.S.).
The synthetic method of above-mentioned a kind of tetramethyl-uric acid, 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.
The present invention compared with prior art has the following advantages:
1, the present invention be take uric acid as raw material; on purine skeleton, the reaction of the exhaustive methylation of nitrogen obtains product tetramethyl-uric acid (theacrine) under high pressure, hot conditions; there is the advantages such as high conversion, high yield, highly selective and reaction times is short, be applicable to mass-producing synthetic.
2, the present invention adopts solvent-free reaction, and methylating reagent is reactant, is again reaction medium, in reaction under high pressure, can improve to greatest extent vapor partial pressure, is conducive to improve reaction yield.
3, the present invention adopts high temperature, reaction under high pressure, has shortened the reaction times, has improved to a certain extent efficiency and yield.Speed of reaction, productive rate and selectivity have been taken into account simultaneously.
4, the present invention adopts recrystallization, has improved the separating power to impurity, has improved to a certain extent overall yield.
Below in conjunction with embodiment, technical scheme of the present invention is described in further detail.
Embodiment
Embodiment 1
Step 1, in 500mL autoclave, add 1.6mol methyl iodide and 0.08mol uric acid, inflated with nitrogen is to emptying after 0.5MPa in airtight backward autoclave, in three backward autoclaves of displacement, inflated with nitrogen to high pressure reacting kettle inner pressure is 5MPa continuously, open water of condensation, adjusting stir speed (S.S.) is 180rpm, the temperature of autoclave is risen to 84 ℃, insulation reaction 2h;
Step 2, increase the autoclave cooling of condensate flow after to insulation reaction in step 1, and the air outlet valve pressure release of slowly opening autoclave, until autoclave Pressure Drop, open still discharging during to 0MPa, reacted material is poured in 300mL frozen water and carried out stirring and crystallizing, after suction filtration, obtain crude product;
Step 3, employing ethyl acetate and methyl alcohol carry out recrystallization to crude product described in step 2, the volume ratio of ethyl acetate and methyl alcohol is 5:1,105 ℃ dry obtained tetramethyl-uric acid (1 after 0.5 hour, 3,7,9-tetramethyl-uric acid) 12.4g, productive rate 69.2%, the quality purity that detects tetramethyl-uric acid through HPLC is not less than 95%.
The fusing point of the product tetramethyl-uric acid that after testing, prepared by the present embodiment is 222 ℃～225 ℃; MS:225 (M+H);
1hNMR (CDCl
3): 3.23 (s3H), 3.41 (s3H), 3.52 (s3H), 3.61 (s3H).
Embodiment 2
Step 1, in 500mL autoclave, add 1.6mol methyl-sulfate and 0.16mol uric acid, applying argon gas is to emptying after 0.5MPa in airtight backward autoclave, in three backward autoclaves of displacement, applying argon gas to high pressure reacting kettle inner pressure is 4MPa continuously, open water of condensation, adjusting stir speed (S.S.) is 280rpm, the temperature of autoclave is risen to 180 ℃, insulation reaction 2.5h;
Step 2, increase the autoclave cooling of condensate flow after to insulation reaction in step 1, and the air outlet valve pressure release of slowly opening autoclave, until autoclave Pressure Drop, open still discharging during to 0MPa, reacted material is poured in 400mL frozen water and carried out stirring and crystallizing, after suction filtration, obtain crude product;
Step 3, employing methylene dichloride and methyl alcohol carry out recrystallization to crude product described in step 2, the volume ratio of methylene dichloride and methyl alcohol is 7:1,105 ℃ dry obtained tetramethyl-uric acid (1 after 0.5 hour, 3,7,9-tetramethyl-uric acid) 25.6g, productive rate 71.4%, the quality purity that detects tetramethyl-uric acid through HPLC is not less than 95%.
The fusing point of the product tetramethyl-uric acid that after testing, prepared by the present embodiment is 222 ℃～225 ℃; MS:225 (M+H);
1hNMR (CDCl
3): 3.23 (s3H), 3.41 (s3H), 3.52 (s3H), 3.61 (s3H).
Embodiment 3
Step 1, in 500mL autoclave, add 1.6mol N, dinethylformamide dimethylacetal and 0.16mol uric acid, inflated with nitrogen is to emptying after 0.5MPa in airtight backward autoclave, in three backward autoclaves of displacement, inflated with nitrogen to high pressure reacting kettle inner pressure is 2MPa continuously, open water of condensation, adjusting stir speed (S.S.) is 300rpm, the temperature of autoclave is risen to 190 ℃, insulation reaction 2.5h;
Step 2, increase the autoclave cooling of condensate flow after to insulation reaction in step 1, and the air outlet valve pressure release of slowly opening autoclave, until autoclave Pressure Drop, open still discharging during to 0MPa, reacted material is poured in 500mL frozen water and carried out stirring and crystallizing, after suction filtration, obtain crude product;
Step 3, employing methylene dichloride and acetone carry out recrystallization to crude product described in step 2, the volume ratio of methylene dichloride and acetone is 4:1,105 ℃ dry obtained tetramethyl-uric acid (1 after 0.5 hour, 3,7,9-tetramethyl-uric acid) 28.4g, productive rate 79.2%, the quality purity that detects tetramethyl-uric acid through HPLC is not less than 95%.
The fusing point of the product tetramethyl-uric acid that after testing, prepared by the present embodiment is 222 ℃～225 ℃; MS:225 (M+H);
1hNMR (CDCl
3): 3.23 (s3H), 3.41 (s3H), 3.52 (s3H), 3.61 (s3H).
Embodiment 4
Step 1, in 500mL autoclave, add 0.8mol methylcarbonate and 0.16mol uric acid, inflated with nitrogen is to emptying after 0.5MPa in airtight backward autoclave, in three backward autoclaves of displacement, inflated with nitrogen to high pressure reacting kettle inner pressure is 8MPa continuously, open water of condensation, adjusting stir speed (S.S.) is 400rpm, the temperature of autoclave is risen to 185 ℃, insulation reaction 5h;
Step 2, increase the autoclave cooling of condensate flow after to insulation reaction in step 1, and the air outlet valve pressure release of slowly opening autoclave, until autoclave Pressure Drop, open still discharging during to 0MPa, reacted material is poured in 250mL frozen water and carried out stirring and crystallizing, after suction filtration, obtain crude product;
Step 3, employing acetone and methyl alcohol carry out recrystallization to crude product described in step 2, the volume ratio of acetone and methyl alcohol is 3:1,105 ℃ dry obtained tetramethyl-uric acid (1 after 0.5 hour, 3,7,9-tetramethyl-uric acid) 30.8g, productive rate 85.9%, the quality purity that detects tetramethyl-uric acid through HPLC is not less than 95%.
The fusing point of the product tetramethyl-uric acid that after testing, prepared by the present embodiment is 222 ℃～225 ℃; MS:225 (M+H);
1hNMR (CDCl
3): 3.23 (s3H), 3.41 (s3H), 3.52 (s3H), 3.61 (s3H).
Embodiment 5
Step 1, in 500mL autoclave, add 4mol trimethylchlorosilane and 0.16mol uric acid, inflated with nitrogen is to emptying after 0.5MPa in airtight backward autoclave, in three backward autoclaves of displacement, inflated with nitrogen to high pressure reacting kettle inner pressure is 6MPa continuously, open water of condensation, adjusting stir speed (S.S.) is 500rpm, the temperature of autoclave is risen to 115 ℃, insulation reaction 18h;
Step 2, increase the autoclave cooling of condensate flow after to insulation reaction in step 1, and the air outlet valve pressure release of slowly opening autoclave, until autoclave Pressure Drop, open still discharging during to 0MPa, reacted material is poured in 1000mL frozen water and carried out stirring and crystallizing, after suction filtration, obtain crude product;
Step 3, employing acetonitrile and ethanol carry out recrystallization to crude product described in step 2, the volume ratio of acetonitrile and ethanol is 1:1,105 ℃ dry obtained tetramethyl-uric acid (1 after 0.5 hour, 3,7,9-tetramethyl-uric acid) 29.4g, productive rate 82.0%, the quality purity that detects tetramethyl-uric acid through HPLC is not less than 95%.
The fusing point of the product tetramethyl-uric acid that after testing, prepared by the present embodiment is 222 ℃～225 ℃; MS:225 (M+H);
1hNMR (CDCl
3): 3.23 (s3H), 3.41 (s3H), 3.52 (s3H), 3.61 (s3H).
Embodiment 6
Step 1, in 500mL autoclave, add 3.2mol trifluoromethanesulfonic acid methyl esters and 0.16mol uric acid, applying argon gas is to emptying after 0.5MPa in airtight backward autoclave, in three backward autoclaves of displacement, applying argon gas to high pressure reacting kettle inner pressure is 3MPa continuously, open water of condensation, adjusting stir speed (S.S.) is 1000rpm, the temperature of autoclave is risen to 190 ℃, insulation reaction 8h;
Step 2, increase the autoclave cooling of condensate flow after to insulation reaction in step 1, and the air outlet valve pressure release of slowly opening autoclave, until autoclave Pressure Drop, open still discharging during to 0MPa, reacted material is poured in 600mL frozen water and carried out stirring and crystallizing, after suction filtration, obtain crude product;
Step 3, employing normal hexane and acetone carry out recrystallization to crude product described in step 2, the volume ratio of normal hexane and acetone is 1:1,105 ℃ dry obtained tetramethyl-uric acid (1 after 0.5 hour, 3,7,9-tetramethyl-uric acid) 29.2g, productive rate 81.5%, the quality purity that detects tetramethyl-uric acid through HPLC is not less than 95%.
The fusing point of the product tetramethyl-uric acid that after testing, prepared by the present embodiment is 222 ℃～225 ℃; MS:225 (M+H);
1hNMR (CDCl
3): 3.23 (s3H), 3.41 (s3H), 3.52 (s3H), 3.61 (s3H).
Embodiment 7
Step 1, in 500mL autoclave, add 3.2mol N, dinethylformamide and 0.08mol uric acid, inflated with nitrogen is to emptying after 0.5MPa in airtight backward autoclave, in three backward autoclaves of displacement, inflated with nitrogen to high pressure reacting kettle inner pressure is 10MPa continuously, open water of condensation, adjusting stir speed (S.S.) is 1400rpm, the temperature of autoclave is risen to 200 ℃, insulation reaction 2h;
Step 2, increase the autoclave cooling of condensate flow after to insulation reaction in step 1, and the air outlet valve pressure release of slowly opening autoclave, until autoclave Pressure Drop, open still discharging during to 0MPa, reacted material is poured in 500mL frozen water and carried out stirring and crystallizing, after suction filtration, obtain crude product;
Step 3, employing acetone and methyl alcohol carry out recrystallization to crude product described in step 2, the volume ratio of acetone and methyl alcohol is 3:1,105 ℃ dry obtained tetramethyl-uric acid (1 after 0.5 hour, 3,7,9-tetramethyl-uric acid) 15.23g, productive rate 85.0%, the quality purity that detects tetramethyl-uric acid through HPLC is not less than 95%.
The fusing point of the product tetramethyl-uric acid that after testing, prepared by the present embodiment is 222 ℃～225 ℃; MS:225 (M+H);
1hNMR (CDCl
3): 3.23 (s3H), 3.41 (s3H), 3.52 (s3H), 3.61 (s3H).
Embodiment 8
Step 1, in 500mL autoclave, add 0.15mol trimethyl orthoformate and 0.1mol uric acid, applying argon gas is to emptying after 0.5MPa in airtight backward autoclave, in three backward autoclaves of displacement, applying argon gas to high pressure reacting kettle inner pressure is 0.5MPa continuously, open water of condensation, adjusting stir speed (S.S.) is 1800rpm, the temperature of autoclave is risen to 220 ℃, insulation reaction 48h;
Step 2, increase the autoclave cooling of condensate flow after to insulation reaction in step 1, and the air outlet valve pressure release of slowly opening autoclave, until autoclave Pressure Drop, open still discharging during to 0MPa, reacted material is poured in 500mL frozen water and carried out stirring and crystallizing, after suction filtration, obtain crude product;
Step 3, employing acetonitrile and ethanol carry out recrystallization to crude product described in step 2, the volume ratio of acetonitrile and ethanol is 1:1,105 ℃ dry obtained tetramethyl-uric acid (1 after 0.5 hour, 3,7,9-tetramethyl-uric acid) 17.92g, productive rate 80%, the quality purity that detects tetramethyl-uric acid through HPLC is not less than 95%.
The fusing point of the product tetramethyl-uric acid that after testing, prepared by the present embodiment is 222 ℃～225 ℃; MS:225 (M+H);
1hNMR (CDCl
3): 3.23 (s3H), 3.41 (s3H), 3.52 (s3H), 3.61 (s3H).
Embodiment 9
Step 1, to adding in 500mL autoclave the mixing solutions of formaldehyde and formic acid (containing formaldehyde 0.64mol, formic acid 3.2mol) and 0.16mol uric acid, inflated with nitrogen is to emptying after 0.5MPa in airtight backward autoclave, in three backward autoclaves of displacement, inflated with nitrogen to high pressure reacting kettle inner pressure is 10MPa continuously, open water of condensation, adjusting stir speed (S.S.) is 1000rpm, the temperature of autoclave is risen to 100 ℃, insulation reaction 24h;
Step 2, increase the autoclave cooling of condensate flow after to insulation reaction in step 1, and the air outlet valve pressure release of slowly opening autoclave, until autoclave Pressure Drop, open still discharging during to 0MPa, reacted material is poured in 500mL frozen water and carried out stirring and crystallizing, after suction filtration, obtain crude product;
Step 3, employing methylene dichloride and ethanol carry out recrystallization to crude product described in step 2, the volume ratio of methylene dichloride and ethanol is 4:1,105 ℃ dry obtained tetramethyl-uric acid (1 after 0.5 hour, 3,7,9-tetramethyl-uric acid) 29.5g, productive rate 82.3%, the quality purity that detects tetramethyl-uric acid through HPLC is not less than 95%.
The fusing point of the product tetramethyl-uric acid that after testing, prepared by the present embodiment is 222 ℃～225 ℃; MS:225 (M+H);
1hNMR (CDCl
3): 3.23 (s3H), 3.41 (s3H), 3.52 (s3H), 3.61 (s3H).
Embodiment 10
Step 1, to adding mass concentration in 500mL autoclave, be 25% tetramethylammonium hydroxide aqueous solution (containing Tetramethylammonium hydroxide 1mol) and 0.08mol uric acid, applying argon gas is to emptying after 0.5MPa in airtight backward autoclave, in three backward autoclaves of displacement, applying argon gas to high pressure reacting kettle inner pressure is 10MPa continuously, open water of condensation, adjusting stir speed (S.S.) is 2000rpm, the temperature of autoclave is risen to 200 ℃, insulation reaction 2h;
Step 2, increase the autoclave cooling of condensate flow after to insulation reaction in step 1, and the air outlet valve pressure release of slowly opening autoclave, until autoclave Pressure Drop, open still discharging during to 0MPa, reacted material is poured in 500mL frozen water and carried out stirring and crystallizing, after suction filtration, obtain crude product;
Step 3, employing acetone and ethanol carry out recrystallization to crude product described in step 2, the volume ratio of acetone and ethanol is 2:1,105 ℃ dry obtained tetramethyl-uric acid (1 after 0.5 hour, 3,7,9-tetramethyl-uric acid) 13.44g, productive rate 75%, the quality purity that detects tetramethyl-uric acid through HPLC is not less than 95%.
The fusing point of the product tetramethyl-uric acid that after testing, prepared by the present embodiment is 222 ℃～225 ℃; MS:225 (M+H);
1hNMR (CDCl
3): 3.23 (s3H), 3.41 (s3H), 3.52 (s3H), 3.61 (s3H).
The above; it is only preferred embodiment of the present invention; not the present invention is done to any restriction, every any simple modification of above embodiment being done according to invention technical spirit, change and equivalent structure change, and all still belong in the protection domain of technical solution of the present invention.
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.
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| CN106046004A (en) * | 2016-06-06 | 2016-10-26 | 上海佰特因医药科技有限公司 | Total synthesis method for theacrine |
| CN107326053A (en) * | 2017-06-19 | 2017-11-07 | 湖州恒睿营养健康科技有限公司 | Two step enzyme methods prepare 1,3,7,9 tetramethyluric acids |
| CN108912121A (en) * | 2018-08-08 | 2018-11-30 | 南京纽邦生物科技有限公司 | Preparation method, the preparation method of intermediate and intermediate of three kinds of methyl-uric acid class compounds |
| CN115536598A (en) * | 2022-09-15 | 2022-12-30 | 青岛科技大学 | Novel synthesis method of 1,4-dimethyl-2,5-piperazinedione compound |
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| CN111620872B (en) * | 2020-05-19 | 2021-02-09 | 南京纽邦生物科技有限公司 | Synthetic method of tetramethyluric acid and special catalyst thereof |
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| CN106046004A (en) * | 2016-06-06 | 2016-10-26 | 上海佰特因医药科技有限公司 | Total synthesis method for theacrine |
| CN106046004B (en) * | 2016-06-06 | 2018-05-15 | 上海佰特因医药科技有限公司 | A kind of total synthesis method of 1,3,7,9- tetramethyluric acids |
| CN107326053A (en) * | 2017-06-19 | 2017-11-07 | 湖州恒睿营养健康科技有限公司 | Two step enzyme methods prepare 1,3,7,9 tetramethyluric acids |
| CN107326053B (en) * | 2017-06-19 | 2019-10-08 | 浙江华睿生物技术有限公司 | Two step enzyme methods prepare 1,3,7,9- tetramethyluric acid |
| CN108912121A (en) * | 2018-08-08 | 2018-11-30 | 南京纽邦生物科技有限公司 | Preparation method, the preparation method of intermediate and intermediate of three kinds of methyl-uric acid class compounds |
| CN115536598A (en) * | 2022-09-15 | 2022-12-30 | 青岛科技大学 | Novel synthesis method of 1,4-dimethyl-2,5-piperazinedione compound |
| CN115536598B (en) * | 2022-09-15 | 2024-04-02 | 青岛科技大学 | New synthesis method of 1, 4-dimethyl-2, 5-piperazine dione compound |
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