A process for the preparation of 5-(difluoromethoxy)pyrazin-2-amine

Abstract

The application discloses a preparation method of 5-(difluoromethoxy)pyrazine-2-amine. The specific steps of the preparation method are as follows: (1) taking compound 1 as a starting material, and preparing compound 2 through a difluoromethylation reaction; and (2) preparing a target product, i.e., the 5-(difluoromethoxy)pyrazine-2-amine, through an Ullmann coupling reaction of the compound 2. The preparation method has the advantages of a short process route, convenient operation, mild and easy-to-control reaction conditions, low cost, suitability for process amplification, easy product purification and high yield.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a preparation method of 5-(difluoromethoxy)pyrazin-2-amine. BACKGROUND

[0002] Fluorine-containing pyrazine molecular building blocks are an important class of organic pharmaceutical intermediates. Research has found that many of these derivatives have good biological activity, and they are also important intermediates for liquid crystal materials and dyes. It is more important to design and synthesize more novel molecular building blocks of this type to develop small molecule drugs with better activity.

[0003] 5-(difluoromethoxy)pyrazin-2-amine is a newly designed derivative of this type, and its synthesis method has not been reported. SUMMARY

[0004] In view of the deficiencies of the prior art, the present application provides a preparation method of 5-(difluoromethoxy)pyrazin-2-amine. The preparation method has a short process route, is easy to operate, has mild and easy-to-control reaction conditions, is low in cost, is suitable for process amplification, is easy to purify the product, and has a high yield.

[0005] The technical scheme of the present application is as follows:

[0006] A preparation method of 5-(difluoromethoxy)pyrazin-2-amine, which is carried out according to the following flowchart:

[0007]

[0008] comprising the following steps:

[0009] (1) Compound 1 is used as a starting material to prepare compound 2 through a difluoromethylation reaction;

[0010] (2) Compound 2 is prepared into the target product, i.e. 5-(difluoromethoxy)pyrazin-2-amine, through a Ullmann coupling reaction.

[0011] Further, in step (1), the specific process of the difluoromethylation reaction is as follows:

[0012] Compound 1 is dissolved in solvent I, then a difluoromethylation reagent and sodium carbonate are added, and the reaction is heated. After the reaction is completed, the reaction is cooled to room temperature, and the crude product is obtained through filtration and concentration, and then compound 2 is prepared through silica gel column chromatography purification.

[0013] Further, the solvent I is at least one selected from acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide; and the concentration of compound 1 in the solvent I is 0.3-0.5 mol / L.

[0014] Further, the difluoromethylation reagent is selected from at least one of 2-bromo-2,2-difluoroethyl acetate, sodium 2-bromo-2,2-difluoroacetate, 2,2-difluoro-2-(fluorosulfonyl)acetic acid; the molar ratio of the compound 1 to the difluoromethylation reagent is 1:1-3; and the molar ratio of the compound 1 to sodium carbonate is 1:2-4.

[0015] Further, the temperature of the reaction is 80-100 DEG C, and the time is 7-12 h.

[0016] Further, in the step (2), the specific process of the Ullmann coupling reaction is as follows:

[0017] Compound 2 is dissolved in solvent II, then copper catalyst and concentrated ammonia are added, and the reaction is carried out under nitrogen protection; after the reaction is completed, it is cooled to room temperature, poured into water for quenching, then extracted, concentrated to obtain a crude product, and the crude product is purified by silica gel column chromatography to obtain the 5-(difluoromethoxy)pyrazine-2-amine.

[0018] Further, the solvent II is selected from at least one of N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide; and the concentration of the compound 2 in the solvent II is 0.4-0.6 mol / L.

[0019] Further, the copper catalyst comprises at least one of cuprous oxide and cuprous iodide; and the molar ratio of the compound 2 to the copper catalyst is 1:0.1-0.2.

[0020] Further, the molar ratio of the compound 2 to the concentrated ammonia is 1:10-20.

[0021] Further, the temperature of the reaction is 70-90 DEG C, and the time is 8-12 h.

[0022] The present application has the beneficial technical effects that:

[0023] The present application introduces difluoromethyl into the pyrazine aromatic ring by using a difluoromethylation reagent, obtains a difluoromethoxy functional group which can significantly enhance the biochemical activity of a molecule, then directly reacts with 28%wt concentrated ammonia under a copper catalyst through halogen on the pyrazine ring to obtain a pyrazine amine molecular building block containing a difluoromethoxy group, and the synthesis method has a good yield.

[0024] The present application optimizes the synthesis route and reaction conditions of 5-(difluoromethoxy)pyrazine-2-amine by screening, improves the yield of the target product, the synthesis method is reported for the first time, raw materials are cheap and easy to obtain, the reaction has good selectivity, less by-products, mild reaction conditions, is easy to operate, has low cost, the obtained product has high purity and good stability, and is suitable for process amplification. Attached Figure Description

[0025] Figure 1 This is a schematic diagram of the reaction process of the present invention.

[0026] Figure 2 The image shows the 1H NMR spectrum of 2-bromo-5-(difluoromethoxy)pyrazine prepared in Example 1 of this invention.

[0027] Figure 3 The image shows the 1H NMR spectrum of 5-(difluoromethoxy)pyrazine-2-amine prepared in Example 1 of this invention. Detailed Implementation

[0028] The present invention will now be described in detail with reference to the accompanying drawings and embodiments.

[0029] Example 1

[0030] A method for preparing 5-(difluoromethoxy)pyrazine-2-amine includes the following steps:

[0031] (1) Add acetonitrile (480 mL, 9.2 mol) to a 1 L single-necked flask, and add compound 1 (5-bromopyrazin-2-ol, 25.0 g, 143.7 mmol, 1 eq) while stirring. Then add ethyl 2-bromo-2,2-difluoroacetate (35.0 g, 173.3 mmol, 1.2 eq) and sodium carbonate (30.0 g, 283.0 mmol, 2 eq) to the flask. React at 80 °C for 12 h, then cool the reaction solution to room temperature, filter, and concentrate the mother liquor to obtain the crude product.

[0032] The crude product was then purified by silica gel column chromatography, eluted with a gradient of petroleum ether:ethyl acetate = 10:1 (volume ratio), and the product eluent was concentrated to obtain 27.0 g of yellow oil, namely compound 2,2-bromo-5-(difluoromethoxy)pyrazine (yield 84%, HPLC purity 95%).

[0033] The structural characterization data of compound 2 are as follows: 1 H NMR (400MHz, Chloroform-d) δ8.27(t,J=1.1Hz,1H),8.18(t,J=1.2Hz,1H),7.51-7.15(t,J=71.8,1H).

[0034] (2) Dimethyl sulfoxide (100 mL, 1.4 mol) was added to a 250 mL stainless steel sealed container. Compound 2 (10.0 g, 44.6 mmol, 1 eq) was added with stirring. After stirring for 5 min, the solution became clear. Cuprous oxide (0.64 g, 4.4 mmol, 0.1 eq) and 28% wt concentrated ammonia (30 mL, 440 mmol, 10 eq) were added to the solution. The reaction was carried out at 70 °C for 12 h under nitrogen protection. The mixture was cooled to room temperature and water was added to quench the reaction. The mixture was then extracted three times with ethyl acetate. The organic phases were combined, washed once with water, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then purified by silica gel column chromatography. The product was eluted with a gradient of petroleum ether:ethyl acetate = 1:1 (volume ratio) to obtain the product eluent. After concentration, 6.2 g of yellow solid was obtained, which is the 5-(difluoromethoxy)pyrazine-2-amine (yield 86%, HPLC purity 99%).

[0035] The structural characterization data of the product 5-(difluoromethoxy)pyrazine-2-amine in this embodiment are as follows: LCMS (ESI): m / z 162 [M+H] + .

[0036] 1 H NMR (400MHz, Chloroform-d) δ7.86 (d, J=1.5Hz, 1H), 7.58 (d, J=1.4Hz, 1H), 7.31-6.95 (t, J=73.2Hz, 1H), 4.39 (br s, 2H).

[0037] Example 2

[0038] A method for preparing 5-(difluoromethoxy)pyrazine-2-amine includes the following steps:

[0039] (1) Add acetonitrile (360 mL, 6.9 mol) to a 1 L single-necked flask, and add compound 1 (5-bromopyrazin-2-ol, 25.0 g, 143.7 mmol, 1 eq) while stirring. Then add sodium 2-bromo-2,2-difluoroacetate (34.1 g, 173.3 mmol, 1.2 eq) and sodium carbonate (30.0 g, 283.0 mmol, 2 eq) to the flask. React at 90 °C for 8 h, then cool the reaction solution to room temperature, filter, and concentrate the mother liquor to obtain the crude product.

[0040] The crude product was then purified by silica gel column chromatography, eluted with a gradient of petroleum ether:ethyl acetate = 10:1 (volume ratio), and the product eluent was concentrated to obtain 26.0 g of yellow oil, namely compound 2,2-bromo-5-(difluoromethoxy)pyrazine (yield 81%, HPLC purity 95%).

[0041] The structural characterization data of compound 2 are as follows:1 H NMR (400 MHz, Chloroform-d) δ 8.27 (t, J = 1.1 Hz, 1H), 8.18 (t, J = 1.2 Hz, 1H), 7.51 - 7.15 (t, J = 71.8, 1H).

[0042] (2) Into a 250 mL stainless steel bomb, dimethyl sulfoxide (100 mL, 1.4 mol) was added, compound 2 (10.0 g, 44.6 mmol, 1 eq) was added under stirring, after 5 min of stirring the solution was clear, cuprous oxide (1.28 g, 8.8 mmol, 0.2 eq), 28% wt concentrated ammonia (30 mL, 440 mmol, 10 eq) was added to it, under nitrogen protection, the reaction was carried out at 70 °C for 12 h, it was brought to room temperature, water was added to quench the reaction, it was extracted with ethyl acetate three times, the organic phase was combined, washed with water once, dried over anhydrous sodium sulfate, filtered, concentrated to get the crude product, the crude product was purified by silica gel column chromatography, eluted with petroleum ether: ethyl acetate = 1:1 (volume ratio) isocratic, the product eluent was obtained, concentrated to get yellow solid 6.0 g, which was the 5-(difluoromethoxy)pyrazin-2-amine (yield 83%, HPLC purity 99%).

[0043] The product of this example, 5-(difluoromethoxy)pyrazin-2-amine, was characterized by the following data: LCMS (ESI): m / z 162 [M+H] + .

[0044] 1 H NMR (400 MHz, Chloroform-d) δ 7.86 (d, J = 1.5 Hz, 1H), 7.58 (d, J = 1.4 Hz, 1H), 7.31 - 6.95 (t, J = 73.2 Hz, 1H), 4.39 (br s, 2H).

[0045] Example 3

[0046] A process for the preparation of 5-(difluoromethoxy)pyrazin-2-amine, comprising the steps of:

[0047] (1) Into a 1 L single necked flask, N,N-dimethylformamide (480 mL, 6.2 mol) was added, compound 1 (5-bromopyrazin-2-ol, 25.0 g, 143.7 mmol, 1 eq) was added under stirring, then 2-bromo-2,2-difluoroacetic acid ethyl ester (58.3 g, 288.8 mmol, 2 eq), sodium carbonate (30.0 g, 283.0 mmol, 2 eq) were added successively, then the reaction was carried out at 100 °C for 7 h, then the reaction was cooled to room temperature, filtered, the mother liquor was concentrated to get the crude product, the crude product was purified by silica gel column chromatography, eluted with petroleum ether: ethyl acetate = 10:1 (volume ratio) isocratic, to get the product eluent, then concentrated to get yellow oil 25.0 g, which was compound 2, 2-bromo-5-(difluoromethoxy)pyrazine (yield 78%, HPLC purity 95%).

[0048] The structural characterization data of compound 2 are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 8.27 (t, J = 1.1 Hz, 1H), 8.18 (t, J = 1.2 Hz, 1H), 7.51-7.15 (t, J = 71.8, 1H).

[0049] (2) Into a 250 mL stainless steel autoclave, N,N-dimethylacetamide (75 mL, 0.8 mol) was added, compound 2 (10.0 g, 44.6 mmol, 1 eq) was added under stirring, the solution was clear after stirring for 5 min, then cuprous iodide (0.84 g, 4.4 mmol, 0.1 eq), 28% wt concentrated ammonia water (30 mL, 440 mmol, 10 eq) were added, the reaction was carried out at 90 °C for 10 h under nitrogen protection, then the reaction was cooled to room temperature, water was added to quench the reaction, then the reaction was extracted with ethyl acetate for 3 times, the organic phase was combined, washed with water once, then dried with anhydrous sodium sulfate, filtered, concentrated to get the crude product, the crude product was purified by silica gel column chromatography, eluted with petroleum ether: ethyl acetate = 1:1 (volume ratio) isocratic, to get the product eluent, then concentrated to get yellow solid 5.5 g, which was 5-(difluoromethoxy)pyrazin-2-amine (yield 76%, HPLC purity 99%).

[0050] The structural characterization data of the product 5-(difluoromethoxy)pyrazin-2-amine of this example are as follows: LCMS (ESI): m / z 162 [M+H] + .

[0051] 1 H NMR (400 MHz, Chloroform-d) δ 7.86 (d, J = 1.5 Hz, 1H), 7.58 (d, J = 1.4 Hz, 1H), 7.31-6.95 (t, J = 73.2 Hz, 1H), 4.39 (br s, 2H).

[0052] Comparative Example 1

[0053] A process for preparing 5-(difluoromethoxy)pyrazin-2-amine was carried out according to the following scheme:

[0054]

[0055] The specific steps are as follows:

[0056] Into a 25 mL single necked flask was added dioxane (15 mL, 0.18 mol), under stirring, the starting material 2-bromo-5-(difluoromethoxy)pyrazine (1.0 g, 4.46 mmol, 1 eq) was added, then diphenylamine (1.2 g, 6.67 mmol, 1.5 eq), cesium carbonate (4.4 g, 13.54 mmol, 3 eq), Xantphos (0.51 g, 0.89 mmol, 0.2 eq) and Pd2(dba)3(0.4 g, 0.44 mmol, 0.1 eq) were added successively, then the reaction was carried out at 100 °C for 15 h under nitrogen protection. LCMS showed about 15% conversion, no further purification was carried out. This method has low conversion.

[0057] Comparative Example 2

[0058] A process for preparing 5-(difluoromethoxy)pyrazin-2-amine was carried out according to the following scheme:

[0059]

[0060] The specific steps are as follows:

[0061] Into a 25 mL single necked flask was added dioxane (15 mL, 0.18 mol), under stirring, the starting material 2-bromo-5-(difluoromethoxy)pyrazine (1.0 g, 4.46 mmol, 1 eq) was added, then diphenylamine (1.2 g, 6.67 mmol, 1.5 eq), cesium carbonate (4.4 g, 13.54 mmol, 3 eq), Xantphos (0.51 g, 0.89 mmol, 0.2 eq) and Pd2(dba)3(0.4 g, 0.44 mmol, 0.1 eq) were added successively, then the reaction was carried out at 100 °C for 15 h under nitrogen protection. LCMS showed about 15% conversion, no further purification was carried out. This method has low conversion.

[0062] The above merely describes the preferred embodiments of the present application, and the present application is not limited to the above embodiments. It can be understood that other improvements and changes directly derived or thought by those skilled in the art without departing from the spirit and concept of the present application shall be considered to be within the protection scope of the present application.

Claims

1. A process for the preparation of 5-(difluoromethoxy)pyrazin-2-amine, characterized in that, The preparation method is carried out according to the following flowchart: The method comprises the following steps: (1) taking compound 1 as a starting material, and preparing compound 2 through a difluoromethylation reaction; (2) preparing a target product, i.e., the 5-(difluoromethoxy)pyrazin-2-amine, through an Ullmann coupling reaction of compound 2; The specific process of the difluoromethylation reaction is as follows: Compound 1 is dissolved in a solvent I, then a difluoromethylation reagent and sodium carbonate are added, and the reaction is heated; after the reaction is completed, the reaction is cooled to room temperature, and the crude product is obtained through filtration and concentration, and then compound 2 is prepared through purification by silica gel column chromatography; The difluoromethylation reagent is at least one selected from 2-bromo-2,2-difluoroacetic acid ethyl ester, 2-bromo-2,2-difluoroacetic acid sodium, and 2,2-difluoro-2-(fluorosulfonyl)acetic acid; the molar ratio of compound 1 to the difluoromethylation reagent is 1:1-3; and the molar ratio of compound 1 to sodium carbonate is 1:2-4; The specific process of the Ullmann coupling reaction is as follows: Compound 2 is dissolved in a solvent II, then a copper catalyst and concentrated ammonia are added, and the reaction is carried out under nitrogen protection; after the reaction is completed, the reaction is cooled to room temperature, and then poured into water for quenching; then the crude product is obtained through extraction and concentration, and then the 5-(difluoromethoxy)pyrazin-2-amine is prepared through purification by silica gel column chromatography.

2. The production method according to claim 1, characterized by, The solvent I is at least one selected from acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide; and the concentration of compound 1 in the solvent I is 0.3-0.5 mol / L.

3. The preparation method according to claim 1, characterized in that, The reaction temperature is 80-100 ℃, and the reaction time is 7-12 h.

4. The method of claim 1, wherein, The solvent II is at least one selected from N,N-dimethylacetamide, N,N-dimethylformamide, and dimethyl sulfoxide; and the concentration of compound 2 in the solvent II is 0.4-0.6 mol / L.

5. The preparation method according to claim 1, characterized in that, The copper catalyst comprises at least one selected from cuprous oxide and cuprous iodide; and the molar ratio of compound 2 to the copper catalyst is 1:0.1-0.

2.

6. The method of claim 1, wherein, The molar ratio of compound 2 to the concentrated ammonia is 1:10-20.

7. The preparation method according to claim 1, characterized in that, The reaction temperature is 70-90 ℃, and the reaction time is 8-12 h.

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