Preparation method of 5-(difluoromethoxy) pyrazine-2-amine

Abstract

The invention discloses a preparation method of 5-(difluoromethoxy) pyrazine-2-amine. The 5-(difluoromethoxy) pyrazine-2-amine is used as a raw material. The preparation method comprises the following specific steps: (1) taking a compound 1 as an initial raw material, and carrying out difluoromethylation reaction to prepare a compound 2; and (2) carrying out Ullmann coupling reaction on the compound 2 to prepare a target product, namely the 5-(difluoromethoxy) pyrazine-2-amine. The preparation method provided by the invention is short in process route, convenient to operate, mild in reaction condition, easy to control, relatively low in cost, suitable for process amplification, easy in product purification and relatively high in yield.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical intermediate synthesis, in particular to a method for preparing 5-(difluoromethoxy)pyrazine-2-amine. Background Art

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

[0003] 5-(Difluoromethoxy)pyrazine-2-amine is a newly designed derivative compound of this type, and its synthesis method has not been reported. Summary of the invention

[0004] In view of the deficiencies of the prior art, the present invention provides a method for preparing 5-(difluoromethoxy)pyrazine-2-amine. The preparation method of the present invention has a short process route, convenient operation, mild and easy-to-control reaction conditions, low cost, suitable for process amplification, easy purification of the product, and high yield.

[0005] The technical solution of the present invention is as follows:

[0006] A method for preparing 5-(difluoromethoxy)pyrazine-2-amine, wherein the preparation method is carried out according to the following process:

[0007]

[0008] The steps include:

[0009] (1) Compound 2 is prepared by difluoromethylation reaction using compound 1 as the starting material;

[0010] (2) Compound 2 is subjected to Ullmann coupling reaction to obtain the target product, namely, the 5-(difluoromethoxy)pyrazine-2-amine.

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

[0012] Compound 1 was dissolved in solvent I, and a difluoromethylating agent and sodium carbonate were added, and the mixture was heated to react. After the reaction was completed, the mixture was cooled to room temperature, filtered and concentrated to obtain a crude product, and then purified by silica gel column chromatography to obtain compound 2.

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

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

[0015] Furthermore, the reaction temperature is 80-100° C. and the reaction time is 7-12 hours.

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

[0017] Compound 2 is dissolved in solvent II, and then a copper catalyst and concentrated ammonia water are added to react under nitrogen protection. After the reaction is completed, it is cooled to room temperature and poured into water to quench. Then, the crude product is obtained by extraction and concentration. The crude product is purified by silica gel column chromatography to obtain the 5-(difluoromethoxy)pyrazine-2-amine.

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

[0019] Furthermore, the copper catalyst includes 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] Furthermore, the molar ratio of the compound 2 to concentrated aqueous ammonia is 1:10-20.

[0021] Furthermore, the reaction temperature is 70-90° C. and the reaction time is 8-12 hours.

[0022] The beneficial technical effects of the present invention are:

[0023] The invention adopts a difluoromethylating agent to introduce a difluoromethyl group into a pyrazine aromatic ring, thereby obtaining a difluoromethoxy functional group capable of significantly enhancing the biochemical activity of the molecule, and then directly undergoes an Ullmann coupling reaction between the halogen on the pyrazine ring and 28%wt concentrated ammonia water under a copper catalyst to obtain a pyrazineamine molecular building block containing a difluoromethoxy group. The synthesis method obtains a good yield.

[0024] The invention improves the yield of the target product by screening and optimizing the synthesis route and reaction conditions of 5-(difluoromethoxy)pyrazine-2-amine. The synthesis method of the invention is reported for the first time, and the raw materials are cheap and easy to obtain, the reaction selectivity is good, the by-products are few, the reaction conditions are mild and easy to operate, the cost is low, the obtained product has high purity and good stability, and is suitable for process scale-up. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 It is a schematic diagram of the reaction flow of the present invention.

[0026] Figure 2 This is the H NMR spectrum of 2-bromo-5-(difluoromethoxy)pyrazine prepared in Example 1 of the present invention.

[0027] Figure 3 This is the H NMR spectrum of 5-(difluoromethoxy)pyrazine-2-amine prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0028] The present invention is described in detail below in conjunction with the accompanying drawings and embodiments.

[0029] Example 1

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

[0031] (1) Add acetonitrile (480 mL, 9.2 mol) to a 1 L single-necked flask, add compound 1 (5-bromopyrazin-2-ol, 25.0 g, 143.7 mmol, 1 eq) under 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) successively, and then react at 80° C. for 12 h, then cool the reaction solution to room temperature, filter, and concentrate the mother liquor to obtain a crude product.

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

[0033] The structural characterization data of compound 2 are: 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 can, and compound 2 (10.0 g, 44.6 mmol, 1 eq) was added under stirring. After stirring for 5 min, the solution became clear, and cuprous oxide (0.64 g, 4.4 mmol, 0.1 eq) and 28% wt concentrated ammonia (30 mL, 440 mmol, 10 eq) were added thereto. Under nitrogen protection, the mixture was reacted at 70° C. for 12 h, cooled to room temperature, and water was added to quench the reaction. The mixture was extracted with ethyl acetate three times, the organic phases were combined, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was then purified by silica gel column chromatography, eluted with petroleum ether:ethyl acetate = 1:1 (volume ratio) isocratic gradient to obtain the product eluate, which was concentrated to obtain 6.2 g of a yellow solid, i.e., 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 example 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 comprises the following steps:

[0039] (1) Add acetonitrile (360 mL, 6.9 mol) to a 1 L single-necked flask, add compound 1 (5-bromopyrazin-2-ol, 25.0 g, 143.7 mmol, 1 eq) under 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) successively, and then react at 90° C. for 8 h, then cool the reaction solution to room temperature, filter, and concentrate the mother liquor to obtain a crude product.

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

[0041] The structural characterization data of compound 2 are: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).

[0042] (2) Dimethyl sulfoxide (100 mL, 1.4 mol) was added to a 250 mL stainless steel can, and compound 2 (10.0 g, 44.6 mmol, 1 eq) was added under stirring. After stirring for 5 min, the solution became clear, and cuprous oxide (1.28 g, 8.8 mmol, 0.2 eq) and 28% wt concentrated ammonia (30 mL, 440 mmol, 10 eq) were added thereto. Under nitrogen protection, the mixture was reacted at 70° C. for 12 h, cooled to room temperature, and water was added to quench the reaction. The mixture was extracted with ethyl acetate three times, the organic phases were combined, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was then purified by silica gel column chromatography, eluted with petroleum ether:ethyl acetate = 1:1 (volume ratio) isocratic gradient to obtain the product eluate, which was concentrated to obtain 6.0 g of a yellow solid, namely, the 5-(difluoromethoxy)pyrazine-2-amine (yield 83%, HPLC purity 99%).

[0043] The structural characterization data of the product 5-(difluoromethoxy)pyrazine-2-amine in this example are as follows: LCMS (ESI): m / z 162 [M+H] + .

[0044] 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).

[0045] Example 3

[0046] A method for preparing 5-(difluoromethoxy)pyrazine-2-amine comprises the following steps:

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

[0048] The structural characterization data of compound 2 are: 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).

[0049] (2) N, N-dimethylacetamide (75 mL, 0.8 mol) was added to a 250 mL stainless steel can, and compound 2 (10.0 g, 44.6 mmol, 1 eq) was added under stirring. After stirring for 5 min, the solution became clear, and cuprous iodide (0.84 g, 4.4 mmol, 0.1 eq) and 28% wt concentrated ammonia (30 mL, 440 mmol, 10 eq) were added thereto. Under nitrogen protection, the mixture was reacted at 90° C. for 10 h, cooled to room temperature, and water was added to quench the reaction. The mixture was extracted with ethyl acetate three times, the organic phases were combined, washed once with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was then purified by silica gel column chromatography, eluted with petroleum ether:ethyl acetate = 1:1 (volume ratio) isocratic gradient to obtain the product eluate, which was concentrated to obtain 5.5 g of a yellow solid, namely, the 5-(difluoromethoxy)pyrazine-2-amine (yield 76%, HPLC purity 99%).

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

[0051] 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).

[0052] Comparative Example 1

[0053] A method for preparing 5-(difluoromethoxy)pyrazine-2-amine is carried out according to the following process:

[0054]

[0055] The specific steps are:

[0056] Add dioxane (15 mL, 0.18 mol) to a 25 mL single-necked flask, add the raw material 2-bromo-5-(difluoromethoxy)pyrazine (1.0 g, 4.46 mmol, 1 eq) under stirring, then add tert-butylcarbamate (0.78 g, 6.67 mmol, 1.5 eq), sodium tert-butoxide (1.3 g, 13.54 mmol, 3 eq) and X-phos-Pd-G2 (0.35 g, 0.44 mmol, 0.1 eq) successively, then react at 90 ° C for 12 h, concentrate the reaction solution to obtain a crude product, and then purify it by silica gel column chromatography, use petroleum ether: ethyl acetate = 10: 1 (volume ratio) isocratic elution to obtain the product eluate, and after concentration, obtain 0.2 g of off-white solid, that is, the compound (5-(difluoromethoxy)pyrazine-2-yl)carbamic acid tert-butyl ester (yield 17%, HPLC purity 95%). This method has a low yield.

[0057] Comparative Example 2

[0058] A method for preparing 5-(difluoromethoxy)pyrazine-2-amine is carried out according to the following process:

[0059]

[0060] The specific steps are:

[0061] Add dioxane (15 mL, 0.18 mol) to a 25 mL single-necked flask, add the raw material 2-bromo-5-(difluoromethoxy)pyrazine (1.0 g, 4.46 mmol, 1 eq) under stirring, then add dibenzylamine (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) successively, protect with nitrogen, and then react at 100 ° C for 15 h. LCMS shows that the conversion rate is about 15%, and no further purification is performed. This method has a low conversion rate.

[0062] The above is only a preferred embodiment of the present invention, and the present invention is not limited to the above embodiments. It is understood that other improvements and changes directly derived or associated by those skilled in the art without departing from the spirit and concept of the present invention should be considered to be included in the protection scope of the present invention.

Claims

1. A method for preparing 5-(difluoromethoxy)pyrazine-2-amine, characterized in that: The preparation method is carried out according to the following process: The steps include: (1) Compound 2 is prepared by difluoromethylation reaction using compound 1 as the starting material; (2) Compound 2 is subjected to Ullmann coupling reaction to obtain the target product, namely, the 5-(difluoromethoxy)pyrazine-2-amine.

2. The preparation method according to claim 1, characterized in that: In step (1), the specific process of the difluoromethylation reaction is: Compound 1 was dissolved in solvent I, and a difluoromethylating agent and sodium carbonate were added, and the mixture was heated to react. After the reaction was completed, the mixture was cooled to room temperature, filtered and concentrated to obtain a crude product, and then purified by silica gel column chromatography to obtain compound 2.

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

4. The preparation method according to claim 2, characterized in that: The difluoromethylation agent is selected from at least one of ethyl 2-bromo-2,2-difluoroacetate, sodium 2-bromo-2,2-difluoroacetate, and 2,2-difluoro-2-(fluorosulfonyl)acetic acid; the molar ratio of the compound 1 to the difluoromethylation agent is 1:1-3; the molar ratio of the compound 1 to sodium carbonate is 1:2-4.

5. The preparation method according to claim 2, characterized in that: The reaction temperature is 80-100° C. and the reaction time is 7-12 hours.

6. The preparation method according to claim 1, characterized in that: In step (2), the specific process of the Ullmann coupling reaction is: Compound 2 is dissolved in solvent II, and then a copper catalyst and concentrated ammonia water are added to react under nitrogen protection. After the reaction is completed, it is cooled to room temperature and poured into water to quench. Then, the crude product is obtained by extraction and concentration. The crude product is purified by silica gel column chromatography to obtain the 5-(difluoromethoxy)pyrazine-2-amine.

7. The preparation method according to claim 6, characterized in that: The solvent II is selected from at least one of N,N-dimethylacetamide, N,N-dimethylformamide and dimethyl sulfoxide; the concentration of the compound 2 in the solvent II is 0.4-0.6 mol / L.

8. The preparation method according to claim 6, characterized in that: The copper catalyst includes at least one of cuprous oxide and cuprous iodide; the molar ratio of the compound 2 to the copper catalyst is 1:0.1-0.

2.

9. The preparation method according to claim 6, characterized in that: The molar ratio of the compound 2 to concentrated aqueous ammonia is 1:10-20.

10. The preparation method according to claim 6, characterized in that: The reaction temperature is 70-90° C. and the reaction time is 8-12 hours.

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