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Preparation method of favipiravir intermediate 2-aminomalonamide

A technology of aminomalonamide and favipiravir, which is applied in the preparation of carboxylic acid amides, organic compounds, cyanide reaction, etc., can solve poisoning inactivation, complicated production process, palladium carbon can not play a role Catalytic hydrogenation and other issues to achieve the effect of not easy to deactivate, reduce production cost, and good tolerance

Pending Publication Date: 2021-06-11
SHANDONG ZOUPING DAZHAN NEW MATERIALS
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

However, there are the following problems in the existing preparation process: due to the existence of some impurities in the intermediate I, such as organic matter containing phosphorus and sulfur, these impurities will cause the phenomenon of "poisoning and deactivation" of palladium carbon during the reaction process , the deactivated palladium carbon will not be able to play the role of catalytic hydrogenation
This complicates the production process

Method used

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  • Preparation method of favipiravir intermediate 2-aminomalonamide
  • Preparation method of favipiravir intermediate 2-aminomalonamide
  • Preparation method of favipiravir intermediate 2-aminomalonamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Prepare 2-amino malonamide as follows:

[0033] (1) Take 150g of diethyl 2-nitrosomalonate, add 400g of methanol, stir and dissolve, add 33g of Raney nickel, replace with hydrogen three times, control the reaction pressure at 0.5-1MPa, and heat up to 40-45°C for reaction;

[0034] (2) Sampling and detection after 6 hours of reaction, the reaction of diethyl 2-nitrosomalonate is complete (there are three main peaks in the reaction solution at this time, respectively RT=6.77, RT=7.33, RT=7.89, the corresponding products dimethyl 2-aminomalonate, ethyl 2-aminomalonate and compound Ⅱ. The reason for the three main peaks is that the reaction solvent is methanol, and the transesterification between methanol and compound Ⅱ generates a single Methyl ester and bismethyl ester products will be transformed into 2-aminomalonamide during the subsequent aminolysis reaction), the temperature is lowered to 20-30°C, and the hydrogenation reaction solution is obtained by filtering;

[0...

Embodiment 2

[0042] Prepare 2-amino malonamide as follows:

[0043] (1) Take 150g of diethyl 2-nitrosomalonate, add 400g of methanol, stir and dissolve, add 33g of Raney nickel, replace with hydrogen three times, control the reaction pressure at 0.5-1MPa, and heat up to 40-45°C for reaction;

[0044] (2) Sampling and testing after 4 hours of reaction, the reaction of diethyl 2-nitrosomalonate was complete, the temperature was lowered to 20-30°C, and the hydrogenation reaction liquid was obtained by filtering;

[0045] (3) Concentrate the hydrogenation reaction solution to obtain 124 g of concentrated solution; sampling is carried out for HPLC detection, and the detection results are shown in Table 2;

[0046] (4) Control the temperature of the concentrated solution to be 10-20°C, add 550ml of saturated ammonia methanol solution dropwise to the concentrated solution, and react at a temperature of 15-20°C; after reacting for 1h, take a sample to detect the content of ammonia in the reaction ...

Embodiment 3

[0052] Prepare 2-amino malonamide as follows:

[0053] (1) Take 150g of diethyl 2-nitrosomalonate, add 400g of methanol, stir and dissolve, add 33g of Raney nickel, replace with hydrogen three times, control the reaction pressure at 0.5-1MPa, and heat up to 40-45°C for reaction;

[0054] (2) Sampling and testing after 4 hours of reaction, the reaction of diethyl 2-nitrosomalonate was complete, the temperature was lowered to 20-30°C, and the hydrogenation reaction liquid was obtained by filtering;

[0055] (3) Concentrate the hydrogenation reaction solution to obtain 130 g of concentrated solution; sampling is carried out for HPLC detection, and the detection results are shown in Table 3;

[0056](4) Control the temperature of the concentrated solution to be 10-20°C, add 550ml of saturated ammonia methanol solution dropwise to the concentrated solution, and react at a temperature of 15-20°C; after reacting for 1h, take a sample to detect the content of ammonia in the reaction s...

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Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a favipiravir intermediate 2-aminomalonamide. According to the method, diethyl 2-nitrosomalonate is used as a starting raw material, Raney nickel is used as a catalyst for hydrogenation reduction to obtain dimethyl 2-aminomalonate, and then aminolysis is performed to obtain 2-aminomalonamide. Raney nickel is used as a catalyst, so that the problem that palladium carbon is easy to inactivate can be effectively avoided. Raney nickel has good tolerance to the raw materials, the inactivation phenomenon is not prone to occurring, and the defect that organic impurities such as phosphorus and sulfur exist in the raw materials can be well overcome. Compared with palladium carbon, Raney nickel is cheaper, and the production cost is reduced to a certain extent through the preparation method.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, in particular to a preparation method of Favipiravir intermediate 2-aminomalonamide. Background technique [0002] Favipiravir, English name Favipiravir, chemical name: 6-fluoro-3-hydroxypyrazine-2-carboxamide, the structural formula is as follows: [0003] [0004] It is mainly used to treat new or re-emergent influenza in adults. 2-Aminomalonamide is an important intermediate for the synthesis of Favipiravir, and the synthesis method is as follows: [0005] [0006] In the process of preparing compound II from compound I, the existing synthesis process uses palladium carbon as a catalyst and prepares it by hydrogenation reduction. However, there are the following problems in the existing preparation process: due to the existence of some impurities in the intermediate I, such as organic matter containing phosphorus and sulfur, these impurities will cause the phenomenon of "pois...

Claims

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Application Information

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IPC IPC(8): C07C231/02C07C237/06
CPCC07C227/04C07C231/02C07C229/24C07C237/06
Inventor 石连胜任传栋林泉生
Owner SHANDONG ZOUPING DAZHAN NEW MATERIALS
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