CN1962647A - Preparation process of intermediate 2-cyanpyrazine of pyrazinamide drug - Google Patents

Abstract

The invention discloses a production process of 2-cyanopyrazine, an intermediate of pyrazinamide drugs. It uses N,N-dimethylacetamide as reaction solvent, palladium complex as catalyst, alkali metal carbonate as base, 2-bromopyrazine and alkali metal ferrocyanide under nitrogen protection at 100 React at ~150°C for 1-6 hours, then filter, and fractionate the filtrate under reduced pressure to obtain 2-cyanopyrazine, the molar equivalent ratio of 2-bromopyrazine and alkali metal ferrocyanide is 1:0.15-0.3; catalyst palladium complex The dosage of the compound is 0.1-5% molar equivalent of 2-bromopyrazine; the dosage of alkali metal carbonate is 0.5-2 molar equivalent of 2-bromopyrazine. Compared with the existing synthetic method, the present invention has the following advantages: 1) the reaction conditions are safe and mild, and the yield is high; 2) the reaction process is short; 3) the cyanide is made of cheap and non-toxic alkali metal ferrocyanide Reagent; 4) Feeding and post-treatment are very simple, with little pollution, and easy to realize industrialized large-scale production.

Description

Production technology of pyrazinamide drug intermediate 2-cyanopyrazine

technical field

The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a production process of a pyrazinamide drug intermediate 2-cyanopyrazine.

Background technique

2-cyanopyrazine is an important raw material for the production of pyrazinamide, a drug for treating tuberculosis. Therefore, how to efficiently synthesize 2-cyanopyrazines has attracted great attention. The synthesis of 2-cyanopyrazine has been reported in some literatures. For example, the literature "Fine Chemical Industry" reported the research on the preparation of 2-cyanopyrazine by ammoxidation of 2-methylpyrazine with a special catalyst. The literature Applied Catalsis, 1986, 20: 219-222 reported that ethylenediamine and propylene glycol were dehydrated and dehydrogenated into 2-methylpyrazine under the action of a catalyst, and then catalyzed by high temperature and high pressure for ammoxidation to 2-cyanopyrazine. The document CN1398855 reports that by using 2-methylpyrazine, ammonia and oxygen as raw materials, the reaction temperature is 300-500 ° C, and the reaction pressure is -0.05-0.05 MPa in terms of gauge pressure. The catalytic system and the technical scheme of optional addition of phosphorus and a fluidized bed catalyst bed composed of alkali metals or alkaline earth metals are used in the industrial production of 2-cyanopyrazine. Document CN1408711 reports a catalyst used for synthesizing 2-cyanopyrazine from 2-methylpyrazine. The catalyst uses ammonium metavanadate, vanadium pentoxide, ammonium molybdate, and phosphoric acid to prepare a supported catalyst for the system by impregnation. Document CN1429820 has reported a method for preparing 2-cyanopyrazine by ammoxidation and a special catalyst. It is based on vanadium and titanium as the main catalyst, phosphorus, iron, nickel, cobalt, bismuth, manganese, chromium, molybdenum, copper, Zinc, tin, boron, potassium, lithium, magnesium, etc. are multi-component catalysts as co-catalysts. The preparation of catalysts in the above-mentioned synthesis processes is complex, the reaction process cycle time is long, and the conditions are harsh, or many experimental processes involve high temperature and high pressure conditions, low yield, and complicated post-processing. Therefore, under mild conditions, it is very important and urgent to efficiently solve the synthesis process of 2-cyanopyrazine.

Contents of the invention

The object of the present invention is to provide a kind of production technology of pyrazinamide drug intermediate 2-cyanopyrazine.

It uses N,N-dimethylacetamide as reaction solvent, palladium complex as catalyst, alkali metal carbonate as base, 2-bromopyrazine and alkali metal ferrocyanide under nitrogen protection at 100 React at ~150°C for 1-6 hours, then filter, and fractionate the filtrate under reduced pressure to obtain 2-cyanopyrazine, the molar equivalent ratio of 2-bromopyrazine and alkali metal ferrocyanide is 1:0.15-0.3; catalyst palladium complex The consumption of compound is 0.1～5% molar equivalent of 2-bromopyrazine; The consumption of alkali metal carbonate is 0.5～2 molar equivalent of 2-bromopyrazine, and reaction formula is:

Described catalyst palladium complex is palladium acetate or two (dibenzylidene aceruvate) palladium; Alkali metal ferrocyanide is sodium ferrocyanide or potassium ferrocyanide; Alkali metal carbonate is sodium carbonate or potassium carbonate. The reaction time is preferably 1 to 5 hours. The reaction temperature is preferably 100 to 140°C. The molar equivalent ratio of 2-bromopyrazine and alkali metal ferrocyanide is preferably 1: 0.15～0.25; The consumption of catalyst palladium complex is 0.1～4% molar equivalent of 2-bromopyrazine; The amount used is preferably 1 to 2 molar equivalents of 2-bromopyrazine.

Compared with existing synthetic methods, the present invention has the following advantages:

1) The reaction conditions are safe and mild, and the yield is high;

2) The reaction process is short;

3) Use cheap, non-toxic alkali metal ferrocyanide as cyanide reagent;

4) The feeding and post-processing are very simple, the pollution is small, and it is easy to realize industrialized large-scale production.

Detailed ways

The molecular formula of 2-cyanopyrazine is:

The concrete reaction steps of the production technology of pyrazinamide drug intermediate 2-cyanopyrazine are as follows:

With N,N-dimethylacetamide as the reaction solvent, palladium complex as the catalyst, alkali metal carbonate as the base, 2-bromopyrazine and alkali metal ferrocyanide under the protection of nitrogen at 100-150 ℃ for 1-6 hours, then filtered, and the filtrate was fractionated under reduced pressure to obtain 2-cyanopyrazine with high yield and high purity. Wherein the molar equivalent ratio of 2-bromopyrazine and alkali metal ferrocyanide is 1: 0.15～0.3; The consumption of catalyst palladium complex is 0.1～5% molar equivalent of 2-bromopyrazine; The consumption of alkali metal carbonate It is 0.5-2 molar equivalents of 2-bromopyrazine. The recommended reaction time is 1 to 5 hours; the recommended reaction temperature is 100 to 140°C; the molar equivalent ratio of 2-bromopyrazine and alkali metal ferrocyanide is recommended to be 1:0.15 to 0.3; the recommended amount of catalyst palladium complex is 0.1-5% molar equivalent of 2-bromopyrazine; the recommended dosage of alkali metal carbonate is 1-2 molar equivalent of 2-bromopyrazine.

The following examples will help to understand the present invention, but are not limited to the content of the present invention:

Example 1

In a 1000 ml three-necked flask, 500 ml of N,N-dimethylacetamide solvent, 48 g (300 mmol) of 2-bromopyrazine, 25 g (60 mmol, 0.2 equivalents) of tris Potassium ferrocyanide hydrate, 680 milligrams (3 millimoles, 0.3mol%) palladium acetate catalyst, 35 grams of sodium carbonate (330 millimoles, 1.1 equivalents), under nitrogen protection at 120 ℃ stirring reaction 2 hours, finish reaction, Then filtered, the filtrate was fractionated under reduced pressure to obtain transparent liquid 2-cyanopyrazine, boiling point: 84-87°C (18-20mmHg), yield 88%, purity 98% (GC).

Example 2

In a 1000 ml three-necked flask, 500 ml of N,N-dimethylacetamide solvent, 48 g (300 mmol) of 2-bromopyrazine, 28 g (66 mmol, 0.22 equivalent) of tris Potassium ferrocyanide hydrate, 340 milligrams (15 millimoles, 5mol%) palladium acetate catalyst, 31.8 gram sodium carbonates (300 millimoles, 1.0 equivalents), under nitrogen protection, stirred reaction at 100 ℃ for 13 hours, ended the reaction, then After filtration, the filtrate was fractionated under reduced pressure to obtain transparent liquid 2-cyanopyrazine with a yield of 90% and a purity of 99%.

Example 3

In a 1000 ml three-necked flask, 500 ml of N,N-dimethylacetamide solvent, 48 g (300 mmol) of 2-bromopyrazine, 20 g (45 mmol, 0.15 equivalent) of tris Sodium ferrocyanide hydrate, 1.5 millimoles (0.5mol%) two (dibenzylidene pyruvate) palladium catalysts, 31.8 grams of sodium carbonate (300 millimoles, 1.0 equivalent), under nitrogen protection, at 120 ℃ stirring reaction 4 Hours, the reaction was terminated, followed by filtration, and the filtrate was fractionated under reduced pressure to obtain a transparent liquid 2-cyanopyrazine with a yield of 80% and a purity of 99%.

Example 4

In a 1000 ml three-necked flask, 500 ml of N,N-dimethylacetamide solvent, 48 g (300 mmol) of 2-bromopyrazine, 28 g (66 mmol, 0.25 equivalent) of tris Potassium ferrocyanide hydrate, 0.3 millimoles (0.1mol%) bis(dibenzylidene pyruvate) palladium catalyst, 66 grams of potassium carbonate (600 millimoles, 2.0 equivalents), stirred reaction at 120 ℃ under nitrogen protection 6 Hours, the reaction was terminated, followed by filtration, and the filtrate was fractionated under reduced pressure to obtain a transparent liquid 2-cyanopyrazine with a yield of 86% and a purity of 97%.

Example 5

In a 1000 ml three-necked flask, 500 ml of N,N-dimethylacetamide solvent, 48 g (300 mmol) of 2-bromopyrazine, 44 g (90 mmol, 0.3 equivalents) of tris Sodium ferrocyanide hydrate, 270 milligrams (1.2 millimoles, 0.4mol%) palladium acetate catalyst, 33 grams of salt of wormwood (300 millimoles, 1.0 equivalent), under the protection of nitrogen at 150 ℃ stirring reaction 3 hours, finish reaction, Then it was filtered, and the filtrate was fractionated under reduced pressure to obtain transparent liquid 2-cyanopyrazine with a yield of 90% and a purity of 99%.

Claims (5)

1. the production technique of a pyrazinoic acid amide class pharmaceutical intermediate 2 cyano pyrazine, it is characterized in that it is with N, the N-N,N-DIMETHYLACETAMIDE is a reaction solvent, with the palladium complex is catalyzer, make alkali with alkaline carbonate, 2-bromo-pyrazine and alkaline ferro prussiate reacted subsequent filtration 1～6 hour at 100～150 ℃ under nitrogen protection, the filtrate decompression fractionation obtains 2 cyano pyrazine, and the molar equivalent ratio of 2-bromo-pyrazine and alkaline ferro prussiate is 1: 0.15～0.3; The consumption of palladium catalyst title complex is 0.1～5% molar equivalent of 2-bromo-pyrazine; The alkaline carbonate consumption is 0.5～2 molar equivalent of 2-bromo-pyrazine, and reaction formula is:

2. the production technique of a kind of pyrazinoic acid amide class pharmaceutical intermediate 2 cyano pyrazine according to claim 1 is characterized in that described palladium catalyst title complex is palladium or two (dibenzalacetone acid) palladium; The alkaline ferro prussiate is yellow prussiate of soda or yellow prussiate of potash; Alkaline carbonate is yellow soda ash or salt of wormwood.

3. the production technique of a kind of pyrazinoic acid amide class pharmaceutical intermediate 2 cyano pyrazine according to claim 1 is characterized in that the described reaction times is 1～5 hour.

4. the production technique of a kind of pyrazinoic acid amide class pharmaceutical intermediate 2 cyano pyrazine according to claim 1 is characterized in that described temperature of reaction is 100～140 ℃.

5. the production technique of a kind of pyrazinoic acid amide class pharmaceutical intermediate 2 cyano pyrazine according to claim 1, the molar equivalent ratio that it is characterized in that described 2-bromo-pyrazine and alkaline ferro prussiate is 1: 0.15～0.25; The consumption of palladium catalyst title complex is 0.1～4% molar equivalent of 2-bromo-pyrazine; The consumption of alkaline carbonate is 1～2 molar equivalent of 2-bromo-pyrazine.