Preparation method of 2-(difluoromethoxy)-5-bromopyridine

Abstract

The invention discloses a preparation method of 2-(difluoromethoxy)-5-bromopyridine, and belongs to the technical field of organic synthesis.The preparation method comprises the following steps that 2-hydroxy-5-bromopyridine is dissolved in a solvent, sodium difluorochloroacetate and alkali are added while stirring is conducted, then heating continues to conduct a reaction, and a reactant is obtained; and carrying out extraction, concentration and column chromatography on the reactants to obtain the 2-(difluoromethoxy)-5-bromopyridine and the 5-bromo-1-(difluoromethyl) pyridine-2 (1H)-ketone. The preparation process is simple to operate, the raw materials are cheap and easy to obtain, the cost is low, the yield is high, the 2-(difluoromethoxy)-5-bromopyridine with high purity and high yield can be obtained through simple preparation and purification steps, and a small amount of the 5-bromo-1-(difluoromethyl) pyridine-2 (1H)-ketone with high purity can also be obtained. The preparation method effectively solves the problem of high cost or low yield caused by cooperation of other alkalis and solvents in the existing preparation method.

Description

Technical Field

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

[0002] 2-(Difluoromethoxy)-5-bromopyridine and its derivatives are important chemical and pharmaceutical intermediates, and are widely used in the fields of pharmaceutical chemicals and materials as starting materials. For example, integrin receptor antagonists synthesized with 2-(difluoromethoxy)-5-bromopyridine and its derivatives can be used to inhibit bone resorption, treat and prevent osteoporosis, and inhibit vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, wound healing, viral diseases, tumor growth and metastasis. In addition, tert-butyl 4-(6-substituted aminopyridin-3-yl)piperidin-1-carboxylate and 3-chloro-2-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)pyridine are synthesized with 2-(difluoromethoxy)-5-bromopyridine and its derivatives as raw materials. These compounds are widely used in organic synthesis, medicine, pesticides and other fields. In view of the industrial application value of 2-(difluoromethoxy)-5-bromopyridine, it is of great significance to develop a safe and efficient method for preparing 2-(difluoromethoxy)-5-bromopyridine.

[0003] According to the literature Organic Letters (2006), 8(17), 3805-3808, 2-(difluoromethoxy)-5-bromopyridine is synthesized using 2-hydroxy-5-bromopyridine, 2-fluorosulfonyldifluoroacetic acid, sodium sulfate, and acetonitrile as raw materials. However, 2-fluorosulfonyldifluoroacetic acid is expensive, resulting in high product cost and low yield, which limits industrial development.

[0004] According to the document Org.Lett.2021,23,16,6494–6498, 2-(difluoromethoxy)-5-bromopyridine is synthesized from 2-hydroxy-5-bromopyridine, sodium carbonate, difluorobromomethyltrimethylsilane, and acetonitrile as raw materials. Similarly, difluorobromomethyltrimethylsilane is expensive and the reaction yield is low.

[0005] Based on the above research status, how to provide a high-yield, high-purity (difluoromethoxy)-5-bromopyridine to solve the above problems of low yield and high cost has become a technical problem that the present invention urgently needs to solve. Summary of the invention

[0006] In order to solve the above problems, the present invention provides a method for preparing 2-(difluoromethoxy)-5-bromopyridine, which effectively solves the problems of low yield and high cost of the existing preparation process, and the prepared 2-(difluoromethoxy)-5-bromopyridine has high purity and yield.

[0007] The technical solution of the present invention is:

[0008] A method for preparing 2-(difluoromethoxy)-5-bromopyridine comprises the following steps:

[0009] (1) Dissolve 2-hydroxy-5-bromopyridine in a solvent, add sodium difluorochloroacetate and a base while stirring, then raise the temperature to continue the reaction to obtain a reactant; the reaction formula is as follows:

[0010]

[0011] (2) The reactants were extracted, concentrated, and subjected to column chromatography to obtain 2-(difluoromethoxy)-5-bromopyridine and 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one.

[0012] Wherein, in step (1), the base is one or more of sodium carbonate, potassium tert-butoxide, and potassium carbonate.

[0013] Wherein, in step (1), the molar ratio of the 2-hydroxy-5-bromopyridine, the base and the sodium difluorochloroacetate is 1:(1-3):(2-4), preferably, the molar ratio of the 2-hydroxy-5-bromopyridine, sodium carbonate and sodium difluorochloroacetate is 1:(1.5-3):(2.5-4).

[0014] Wherein, in step (1), the solvent is DMF or acetonitrile.

[0015] Wherein, in step (1), the mass volume ratio of the 2-hydroxy-5-bromopyridine to the solvent is 1:(5-20) g / mL.

[0016] The stirring temperature is 20-30°C, the temperature of the reaction is 60-90°C, and the time is 24-36h. Preferably, the stirring temperature of dissolving 2-hydroxy-5-bromopyridine into the solvent and adding sodium difluorochloroacetate and the base is 25°C, the temperature of the reaction is 80°C, and the time is 24h.

[0017] Wherein, in step (2), the extraction agent used in the extraction is ethyl acetate.

[0018] Wherein, the concentration is reduced pressure concentration, and the pressure value is -0.09Mpa.

[0019] The column chromatography conditions are as follows: eluting with pure PE solvent, and concentrating the organic solvent to obtain 2-(difluoromethoxy)-5-bromopyridine; and then eluting with a solvent in a ratio of PE / EA=5 / 1, and concentrating the organic solvent to obtain 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one.

[0020] Compared with the prior art, the technical solution provided by the present invention has the following beneficial effects:

[0021] The present invention uses 2-hydroxy-5-bromopyridine as starting material, uses sodium difluorochloroacetate to coordinate inorganic base, adopts one-pot method to carry out difluoromethylation reaction at high temperature, and then purifies by column chromatography, so as to effectively prepare 2-(difluoromethoxy)-5-bromopyridine. The preparation process is not only simple to operate, the raw materials are cheap and easy to obtain, the cost is low, and the yield is high, through simple preparation and purification steps, that is, high-purity, high-yield 2-(difluoromethoxy)-5-bromopyridine can be obtained, and a small amount of high-purity 5-bromo-1-(difluoromethyl) pyridine-2 (1H)-one can also be obtained. Effectively solve the problem of the low yield caused by the high cost or the coordination of other alkalis and solvents in the preparation method of current 2-(difluoromethoxy)-5-bromopyridine. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 is the 1HNMR spectrum of 2-(difluoromethoxy)-5-bromopyridine;

[0023] Figure 2 is the LC spectrum of 2-(difluoromethoxy)-5-bromopyridine;

[0024] Figure 3 is the 1HNMR spectrum of 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one;

[0025] Figure 4 This is the LC spectrum of 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one. DETAILED DESCRIPTION

[0026] The following embodiments are provided for a better understanding of the present invention, but are not limited to the best mode of implementation, and do not limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained under the inspiration of the present invention or by combining the features of the present invention with other prior arts shall fall within the protection scope of the present invention.

[0027] Example 1

[0028] This embodiment provides a method for preparing 2-(difluoromethoxy)-5-bromopyridine, comprising the following steps:

[0029] (1) Dissolve 50 g of 2-hydroxy-5-bromopyridine in 500 ml of DMF, add 61 g of sodium carbonate and 176.5 g of sodium difluorochloroacetate while stirring at 25°C, and react at 80°C for 30 h. After the reaction is complete as determined by TLC, cool naturally to room temperature, and then pour the reaction solution into water to quench, with a small amount of heat release.

[0030] (2) Ethyl acetate was added to extract the reactant twice, and the organic phase was washed once with saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure at a pressure of -0.09 MPa. Column chromatography gave 61.5 g of 2-(difluoromethoxy)-5-bromopyridine and 2.1 g of 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one.

[0031] The column chromatography conditions are as follows: eluting with pure PE solvent and concentrating the organic solvent to obtain 2-(difluoromethoxy)-5-bromopyridine; then eluting with a solvent in a ratio of PE / EA=5 / 1 and concentrating the organic solvent to obtain 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one.

[0032] In this embodiment, the molar ratio of 2-hydroxy-5-bromopyridine, sodium carbonate and sodium difluorochloroacetate is 1:2:4.

[0033] Example 2

[0034] This embodiment provides a method for preparing 2-(difluoromethoxy)-5-bromopyridine, comprising the following steps:

[0035] (1) Dissolve 50 g of 2-hydroxy-5-bromopyridine in 250 ml of DMF, add 64 g of potassium tert-butoxide and 176.5 g of sodium difluorochloroacetate under stirring at 20° C., and react at 90° C. for 24 h. After the reaction is complete as determined by TLC, cool naturally to room temperature, and then pour the reaction solution into water to quench, with a small amount of heat release.

[0036] (2) Ethyl acetate was added to extract the reactant twice, and the organic phase was washed once with saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure at a pressure of -0.09 MPa. Column chromatography gave 60.8 g of 2-(difluoromethoxy)-5-bromopyridine and 3.6 g of 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one.

[0037] Wherein, the column chromatography conditions are: eluting with pure PE solvent, concentrating the organic solvent to obtain 2-(difluoromethoxy)-5-bromopyridine; then eluting with a solvent with a ratio of PE / EA=5 / 1, concentrating the organic solvent to obtain 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one. In this embodiment, the molar ratio of 2-hydroxy-5-bromopyridine, potassium tert-butoxide, and sodium difluorochloroacetate is 1:2:4.

[0038] Example 3

[0039] This embodiment provides a method for preparing 2-(difluoromethoxy)-5-bromopyridine, comprising the following steps:

[0040] (1) Dissolve 50 g of 2-hydroxy-5-bromopyridine in 1000 ml of DMF, add 46 g of sodium carbonate and 109.6 g of sodium difluorochloroacetate while stirring at 30°C, and react at 60°C for 36 hours. After the reaction is complete as determined by TLC, cool naturally to room temperature, and then pour the reaction solution into water to quench, with a small amount of heat release.

[0041] (2) Ethyl acetate was added to extract the reactant twice, and the organic phase was washed once with saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure at a pressure of -0.09 MPa. Column chromatography gave 59.6 g of 2-(difluoromethoxy)-5-bromopyridine and 5.8 g of 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one.

[0042] The column chromatography conditions are as follows: eluting with pure PE solvent and concentrating the organic solvent to obtain 2-(difluoromethoxy)-5-bromopyridine; then eluting with a solvent in a ratio of PE / EA=5 / 1 and concentrating the organic solvent to obtain 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one.

[0043] In this embodiment, the molar ratio of 2-hydroxy-5-bromopyridine, sodium carbonate and sodium difluorochloroacetate is 1:1.5:2.5.

[0044] Example 4

[0045] This embodiment provides a method for preparing 2-(difluoromethoxy)-5-bromopyridine, comprising the following steps:

[0046] (1) Dissolve 50 g of 2-hydroxy-5-bromopyridine in 750 ml of ACN, add 91.4 g of sodium carbonate and 176.5 g of sodium difluorochloroacetate while stirring at 25°C, and react at 70°C for 36 hours. After the reaction is complete as determined by TLC, cool naturally to room temperature, and then pour the reaction solution into water to quench, with a small amount of heat release.

[0047] (2) The reactant was extracted twice with ethyl acetate, and the organic phase was washed once with saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure at a pressure of -0.09 MPa. Column chromatography gave 61.2 g of 2-(difluoromethoxy)-5-bromopyridine and 4.6 g of 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one.

[0048] The column chromatography conditions are as follows: eluting with pure PE solvent and concentrating the organic solvent to obtain 2-(difluoromethoxy)-5-bromopyridine; then eluting with a solvent in a ratio of PE / EA=5 / 1 and concentrating the organic solvent to obtain 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one.

[0049] In this embodiment, the molar ratio of 2-hydroxy-5-bromopyridine, sodium carbonate and sodium difluorochloroacetate is 1:3:4.

[0050] Example 5

[0051] This embodiment provides a method for preparing 2-(difluoromethoxy)-5-bromopyridine, comprising the following steps:

[0052] (1) Dissolve 50 g of 2-hydroxy-5-bromopyridine in 500 ml of DMF, add 39.7 g of potassium carbonate and 87.7 g of sodium difluorochloroacetate while stirring at 25°C, and react at 80°C for 24 h. After the reaction is complete as determined by TLC, cool naturally to room temperature, and then pour the reaction solution into water to quench, with a small amount of heat release.

[0053] (2) Ethyl acetate was added to extract the reactant twice, the organic phase was washed once with saturated brine, the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure, the pressure value was -0.09 MPa, and column chromatography obtained 59.9 g of 2-(difluoromethoxy)-5-bromopyridine and 1.9 g of 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one. In this embodiment, the reaction temperature was 60° C. and the reaction time was 36 h.

[0054] The column chromatography conditions are as follows: eluting with pure PE solvent and concentrating the organic solvent to obtain 2-(difluoromethoxy)-5-bromopyridine; then eluting with a solvent in a ratio of PE / EA=5 / 1 and concentrating the organic solvent to obtain 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one.

[0055] In this embodiment, the molar ratio of 2-hydroxy-5-bromopyridine, potassium carbonate and sodium difluorochloroacetate is 1:1:2.

[0056] Comparative Example

[0057] This embodiment provides a method for preparing 2-(difluoromethoxy)-5-bromopyridine. In step (1) of this embodiment, sodium carbonate is not added, and the other added materials and process steps are the same as those in Example 1, which will not be repeated here.

[0058] This example yielded 37.8 g of 2-(difluoromethoxy)-5-bromopyridine and 10.0 g of 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one.

[0059] Experimental example

[0060] The 2-(difluoromethoxy)-5-bromopyridine and 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one prepared in Example 1 were subjected to nuclear magnetic resonance analysis. The obtained nuclear magnetic resonance 1HNMR spectrum is as follows: Figure 1 and Figure 3 As shown. Figure 1 It can be seen that the present invention successfully prepared the target main product 2-(difluoromethoxy)-5-bromopyridine; Figure 3 It is known that the present invention also obtains 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one as a by-product.

[0061] The yield and purity (purity test using liquid chromatography) of 2-(difluoromethoxy)-5-bromopyridine and 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one prepared in Examples 1-5 were analyzed. The yield ratio of the main product 2-(difluoromethoxy)-5-bromopyridine to the by-product 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one also changed under different reaction conditions. The results are shown in Table 1. Among them, the LC spectrum of 2-(difluoromethoxy)-5-bromopyridine prepared in Example 1 is shown in Figure 2 As shown, the LC spectrum of 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one prepared in Example 1 is as follows Figure 4 shown.

[0062] Table 1 Product yield and purity

[0063]

[0064] Depend on Figure 2 As shown in Table 1, the preparation method of 2-(difluoromethoxy)-5-bromopyridine provided by the present invention, with 2-hydroxy-5-bromopyridine as starting material, sodium difluorochloroacetate is used to coordinate inorganic base, and difluoromethylation reaction is carried out at high temperature by one-pot method, and then purified by column chromatography, so as to effectively prepare 2-(difluoromethoxy)-5-bromopyridine. The low yield and high cost problems of the preparation method of current 2-(difluoromethoxy)-5-bromopyridine are effectively solved, and the preparation of 2-(difluoromethoxy)-5-bromopyridine has extremely strong application value, and the industrial application of 2-(difluoromethoxy)-5-bromopyridine can also be further promoted.

[0065] The above descriptions are only preferred specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Other embodiments obtained by those skilled in the art without creative work should all fall within the protection scope of the present invention.

Claims

1. A method for preparing 2-(difluoromethoxy)-5-bromopyridine, characterized in that: The following steps are involved: (1) Dissolve 2-hydroxy-5-bromopyridine in a solvent, add sodium difluorochloroacetate and a base while stirring, then raise the temperature to continue the reaction to obtain a reactant; the reaction formula is as follows: (2) The reactants were extracted, concentrated, and subjected to column chromatography to obtain 2-(difluoromethoxy)-5-bromopyridine and 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one.

2. The method for preparing 2-(difluoromethoxy)-5-bromopyridine according to claim 1, characterized in that: In step (1), the base is one or more of sodium carbonate, potassium tert-butoxide, and potassium carbonate.

3. The method for preparing 2-(difluoromethoxy)-5-bromopyridine according to claim 1, characterized in that: In step (1), the molar ratio of 2-hydroxy-5-bromopyridine, base and sodium difluorochloroacetate is 1:(1-3):(2-4).

4. The method for preparing 2-(difluoromethoxy)-5-bromopyridine according to claim 1, characterized in that: In step (1), the solvent is DMF or acetonitrile.

5. The method for preparing 2-(difluoromethoxy)-5-bromopyridine according to claim 1, characterized in that: In step (1), the mass volume ratio of the 2-hydroxy-5-bromopyridine to the solvent is 1:(5-20) g / mL.

6. The method for preparing 2-(difluoromethoxy)-5-bromopyridine according to any one of claims 1 to 6, characterized in that: The stirring temperature is 20-30°C, the heating reaction temperature is 60-90°C, and the time is 24-36h.

7. The method for preparing 2-(difluoromethoxy)-5-bromopyridine according to any one of claims 1 to 6, characterized in that: In step (2), the extraction agent used in the extraction is ethyl acetate.

8. The method for preparing 2-(difluoromethoxy)-5-bromopyridine according to any one of claims 1 to 6, characterized in that: The concentration is reduced pressure concentration, and the pressure value is -0.09Mpa.

9. The method for preparing 2-(difluoromethoxy)-5-bromopyridine according to any one of claims 1 to 6, characterized in that: The column chromatography conditions are as follows: eluting with pure PE solvent, and concentrating the organic solvent to obtain 2-(difluoromethoxy)-5-bromopyridine; and then eluting with a solvent in a ratio of PE / EA=5 / 1, and concentrating the organic solvent to obtain 5-bromo-1-(difluoromethyl)pyridin-2(1H)-one.

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