A kind of total synthesis method of 1,3,7,9-tetramethyluric acid

A technology of tetramethyl uric acid and dimethyl uric acid, applied in the direction of organic chemistry, etc., can solve the problems of high equipment requirements, cumbersome separation, high risk, etc., and achieves the effects of low equipment requirements, simple post-processing, and high conversion rate.

Active Publication Date: 2018-05-15
SHANGHAI BETTER IN PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Tetramethyluric acid was originally extracted from bitter tea buds and leaves, but the extracted tetramethyluric acid contains caffeine with similar properties, and the separation is cumbersome and costly
[0015] This invention needs to be carried out under high temperature and high pressure conditions. During the production process, the requirements for equipment are high and there is a high risk

Method used

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  • A kind of total synthesis method of 1,3,7,9-tetramethyluric acid
  • A kind of total synthesis method of 1,3,7,9-tetramethyluric acid

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Experimental program
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Effect test

Embodiment 1

[0051] A kind of total synthesis method of 1,3,7,9-tetramethyluric acid, comprises the steps:

[0052] S1: Nitrosylation reaction: use 6-amino-1,3-dimethyluracil as the raw material, as compound I, weigh compound I and dissolve it in ethanol, the mass / volume of compound I and ethanol is 1:8 ~1:20;

[0053] Slowly add the nitrosation reagent dropwise, wherein the mass ratio of compound I to the nitrosation reagent is 3:1 to 3:5, stir at room temperature after the dropwise addition, and monitor the reaction process by HPLC. After the reaction is completed, cool down , filtered, and vacuum-dried to obtain compound II;

[0054] S2: Reduction reaction: Weigh compound II and dissolve it in methanol, the mass / volume of compound II and methanol is 1:3-1:8; add insurance according to the mass ratio of compound II and sodium bicarbonate at 5:3-5:7 powder, fully reacted at room temperature for 12-20h, monitored by HPLC, concentrated after the reaction;

[0055] Add distilled water to ...

Embodiment 2

[0065] A kind of total synthesis method of 1,3,7,9-tetramethyluric acid, comprises the steps:

[0066] S1: Preparation of compound Ⅱ

[0067] ① Weigh 10kg of 6-amino-1,3-dimethyluracil and dissolve it in 120L of ethanol to obtain solution A;

[0068] ② Weigh 7.82kg of isoamyl nitrite, slowly add isoamyl nitrite dropwise to solution A, stir at room temperature after the dropwise addition, and leave overnight;

[0069] ③ HPLC monitoring, after the reaction was completed, the temperature was lowered, filtered, and vacuum-dried to obtain 10.5 kg of red solid, namely compound II, with a yield of 90.0%.

[0070] H NMR spectrum data of compound Ⅱ: 1 H-NMR (CDCl 3 ,400MHz): 2.72(s,6H), 2.12(br,2H).

[0071] S2: Preparation of compound Ⅲ

[0072] ① Weigh 10kg of compound II and dissolve it in 50L of methanol, add 14.1kg of sodium hydrosulfite, fully react at room temperature for 12-20h, monitor by HPLC, and concentrate after the reaction is completed;

[0073] ② Add 20L of distil...

Embodiment 3

[0093] S1: Preparation of compound Ⅱ

[0094] ① Weigh 10kg 6-amino-1,3-dimethyluracil and dissolve it in 100L ethyl acetate to obtain solution A;

[0095] ② Weigh 9.53kg of butyl nitrite, slowly add butyl nitrite dropwise to solution A, stir at room temperature after the dropwise addition, and leave overnight;

[0096] ③ HPLC monitoring, after the reaction was completed, the temperature was lowered, filtered, and vacuum-dried to obtain 10.2 kg of a red solid, which was compound II.

[0097] S2: Preparation of compound Ⅲ

[0098] ①Weigh 10kg of compound II and dissolve it in 80L dimethyl sulfoxide, add 16kg of hydrosulfite, fully react at room temperature for 12-20h, monitor by HPLC, and concentrate after the reaction is completed;

[0099] ② Add 20L of distilled water to the above reactant to dissolve, add 20L of DCM to extract, recover the organic phase, repeat the extraction three times, and combine the organic phase;

[0100] ③ Add 10 L of saturated brine to the above or...

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Abstract

The invention relates to a total synthesis method for theacrine. The total synthesis method comprises the following steps: 6-amino-1,3-dimethyluracil is taken as a raw material and subjected to a nitrosation reaction, and an intermediate 6-amino-1,3-dimethyl-5-nitrosouracil is obtained; 6-amino-1,3-dimethyl-5-nitrosouracil is subjected to a reduction reaction, and an intermediate 1,3-dimethyl-5,6-diaminouracil is obtained; 1,3-dimethyl-5,6-diaminouracil is subjected to a cyclization reaction, and an intermediate 1,3-dimethyluric acid is obtained; 1,3-dimethyluric acid is reacted with a methylation reagent, and a product is obtained. Theacrine prepared with the method can be synthesized massively in industrial application without restriction of raw materials; the conversion rate and the yield are high, the synthesis is convenient, post-processing is simpler, and the method is suitable for large-scale production and can be widely popularized and applied; the method is not needed to be performed under a high pressure condition, has low requirement for equipment and reduces the incidence rate of danger; with adoption of recrystallization for preparing the target product, the product purity is high.

Description

technical field [0001] The invention relates to a synthesis method of a natural product with antidepressant effect in the technical field of medicinal chemistry, in particular to a total synthesis method of the natural product 1,3,7,9-tetramethyluric acid. Background technique [0002] Tetramethyluric acid, the chemical name is 1,3,7,9-tetramethyluric acid, also known as bitter theophylline, is a kind of methylxanthine extracted from the tea group plant bitter tea unique to Honghe Prefecture, Yunnan, my country Alkaloids, similar in structure to theophylline, caffeine, theobromine, etc., the specific structural formula is as follows: [0003] [0004] Recently, it has been reported that tetramethyluric acid (theacrine) has a variety of physiological activities, such as anti-inflammatory, analgesic, antidepressant, sedative and hypnotic effects, and has certain medicinal application value. [0005] 1. Antidepressant [0006] Xie Guo et al. used animal models such as tail ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/14
CPCC07D473/14
Inventor 朱义平孙晋
Owner SHANGHAI BETTER IN PHARMA TECH
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