Synthesis method of 6-chloro-3-fluoro-2-methoxypyridine

Abstract

The invention discloses a synthesis method of 6-chloro-3-fluoro-2-methoxypyridine, which comprises the following steps of: adding 2-chloro-3-fluoro-2-methoxypyridine into a reaction kettle; the synthesis method comprises the following steps: (1) dissolving a compound 1 in methanol, adding alkali under inert gas protection and low-temperature conditions, heating, stirring and reacting to obtain a reaction solution; and (2) after the reaction is completed, carrying out post-treatment on a reaction solution to obtain a target compound 2, namely the 6-chloro-3-fluoro-2-methoxypyridine. According to the synthetic method disclosed by the invention, the compound 2, 6-dichloro-3-fluoropyridine is converted into the compound 6-chloro-3-fluoro-2-methoxypyridine in one step, the reaction conditions are mild, the post-treatment and purification are simple, and the manufacturability amplification can be realized; the compound 6-chloro-3-fluoro-2-methoxypyridine is prepared by adopting a simple and short step, simple and convenient operation, low cost and relatively mild reaction conditions.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing 6-chloro-3-fluoro-2-methoxypyridine. Background Art

[0002] Pyridine compounds are an important class of heterocyclic compounds with strong anti-cancer, anti-viral, cardiotonic, and antihypertensive physiological activities. They are widely used in the research and development of new drugs in the fields of medicine, veterinary drugs, and pesticides. The compound 6-chloro-3-fluoro-2-methoxypyridine is an important pyridine compound and also an important molecular building block. As a key intermediate, in the patent US2012 / 095031 and the article "Synthesis and Evaluation of Novel Radioligands for Positron Emission Tomography Imaging of the Orexin-2 Receptor" published by Norihito Oi et al., 6-chloro-3-fluoro-2-methoxypyridine is used as a key intermediate for the synthesis of orexin receptor antagonists, which can treat insomnia.

[0003] In the prior art, the conventional synthesis route of the compound 6-chloro-3-fluoro-2-methoxypyridine is prepared by using 2-chloro-5-fluoropyridine as a raw material through three steps of reaction. The synthesis process requires the use of peroxide, which is somewhat dangerous. It also requires the use of expensive silver carbonate, and the overall synthesis route is long and the yield is low. Therefore, it is of great significance to develop a new synthesis method of 6-chloro-3-fluoro-2-methoxypyridine. Summary of the invention

[0004] In view of the shortcomings of the prior art, the present invention provides a method for synthesizing 6-chloro-3-fluoro-2-methoxypyridine. The synthetic method of the present invention has the advantages of low cost, short steps, easy operation, relatively mild reaction conditions, low safety risks, and high yield.

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

[0006] A method for synthesizing 6-chloro-3-fluoro-2-methoxypyridine, wherein the method is carried out according to the following process:

[0007]

[0008] The specific steps include:

[0009] (1) dissolving compound 1 in methanol, adding a base under inert gas protection and low temperature conditions, then heating and stirring to react to obtain a reaction solution;

[0010] (2) After the reaction is complete, the reaction solution is post-treated to obtain the target compound 2, i.e., the 6-chloro-3-fluoro-2-methoxypyridine.

[0011] Furthermore, in step (1), the base is selected from one or more of potassium carbonate, sodium carbonate, potassium hydroxide and potassium bicarbonate.

[0012] Furthermore, in step (1), the mass volume ratio of the compound 1 to methanol is 1:5-40 (g / mL).

[0013] Furthermore, in step (1), the molar ratio of the compound 1 to the base is 1:1-3.

[0014] Furthermore, in step (1), the temperature of the low temperature condition is -5 to 10°C.

[0015] Furthermore, in step (1), the reaction temperature is 60 to 200° C. and the reaction time is 10 to 40 hours.

[0016] Furthermore, in step (2), the specific process of the post-processing is:

[0017] After the reaction is complete, the reaction solution is cooled and added to water, extracted with an organic solvent I, and the organic phases are combined and concentrated to obtain a crude product, which is purified to obtain the target compound 2.

[0018] Furthermore, the purification method is selected from one or more of beating, column chromatography, recrystallization or distillation.

[0019] Furthermore, the organic solvent I is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane and dichloroethane.

[0020] The beneficial technical effects of the present invention are:

[0021] The invention provides a method for synthesizing 6-chloro-3-fluoro-2-methoxypyridine. The method comprises taking a compound 2,6-dichloro-3-fluoropyridine as a raw material and reacting it with methanol under the action of a base to obtain a target compound 6-chloro-3-fluoro-2-methoxypyridine.

[0022] The synthesis method of the present invention realizes the one-step conversion of the compound 2,6-dichloro-3-fluoropyridine into the compound 6-chloro-3-fluoro-2-methoxypyridine, and the reaction conditions are mild, the post-treatment and purification are simple, and process scale-up can be achieved; finally, the compound 6-chloro-3-fluoro-2-methoxypyridine is prepared with short steps, simple operation, low cost and relatively mild reaction conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1This is the H NMR spectrum of 6-chloro-3-fluoro-2-methoxypyridine prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0024] The present invention is described in detail below in conjunction with the accompanying drawings and embodiments.

[0025] Example 1

[0026] A method for synthesizing 6-chloro-3-fluoro-2-methoxypyridine comprises the following steps:

[0027] (1) 2,6-Dichloro-3-fluoropyridine (55.22 g, 1.20 mol, 1.20 eq) was dissolved in methanol (2.0 L). Under the protection of inert nitrogen gas, the temperature was lowered to 5°C, and potassium carbonate (333.07 g, 2.41 mol, 2.00 eq) was slowly added. After the addition was complete, the temperature was raised to reflux and the reaction was stirred at 60°C for 12 h.

[0028] (2) After the reaction is complete, the reaction solution is cooled and added to water (3.0 L), extracted twice with ethyl acetate (1.5 L×2), the organic phases are combined, and the organic phases are concentrated to obtain a crude product, which is purified by column chromatography (eluent: petroleum ether) to obtain the target compound 2, i.e., 6-chloro-3-fluoro-2-methoxypyridine (weight 185.00 g, purity 98%, yield 93%).

[0029] The H NMR spectrum of the obtained compound 2 (6-chloro-3-fluoro-2-methoxypyridine) is as follows Figure 1 The characterization data are as follows:

[0030] 1 H NMR (400MHz, cdcl3) δ7.29 (dd, J=9.3, 8.1Hz, 1H), 6.85 (dd, J=8.1, 2.5Hz, 1H), 4.03 (d, J=1.2Hz, 3H).

[0031] Example 2-3

[0032] The synthesis method of Example 2-3 is basically the same as that of Example 1, except that in step (1) of Example 2-3, 2.41 mol of sodium bicarbonate and 2.41 mol of sodium hydroxide are used to replace the potassium carbonate in Example 1, respectively, and the rest of the contents remain unchanged. The yield of 6-chloro-3-fluoro-2-methoxypyridine in Example 2-3 is shown in Table 1.

[0033] Embodiment 4-5

[0034] The synthesis method of Example 4-5 is basically the same as that of Example 1, except that the molar amounts of potassium carbonate in step (1) of Example 4-5 are 1.20 mol and 3.60 mol, respectively, and the rest remain unchanged. The yield of 6-chloro-3-fluoro-2-methoxypyridine of Example 4-5 is shown in Table 1.

[0035] Embodiment 6-7

[0036] The synthesis method of Example 6-7 is basically the same as that of Example 1, except that the stirring reaction temperature in step (1) of Example 6-7 is 50°C and 70°C respectively, and the rest of the contents remain unchanged. The yield of 6-chloro-3-fluoro-2-methoxypyridine in Example 6-7 is shown in Table 1.

[0037] Embodiment 8-9

[0038] The synthesis method of Example 8-9 is basically the same as that of Example 1, except that the stirring reaction time in step (1) of Example 8-9 is 10 h and 14 h respectively, and the rest of the contents remain unchanged. The yield of 6-chloro-3-fluoro-2-methoxypyridine of Example 8-9 is shown in Table 1.

[0039] Table 1 Synthesis conditions and yield of 6-chloro-3-fluoro-2-methoxypyridine in various examples

[0040]

[0041] It can be seen from the results in Table 1 that in Examples 1-3, potassium carbonate, sodium bicarbonate and sodium hydroxide were used as bases for the reactions, respectively. The reactions were all carried out smoothly, and the yields of the target compound 6-chloro-3-fluoro-2-methoxypyridine were all high. Among them, the reaction yield using potassium carbonate as the base was the highest.

[0042] It can be seen from the results of Example 1 and Examples 4-5 that when the molar ratio of the reaction starting material 2,6-dichloro-3-fluoropyridine to the base is 1.0:1.0-3.0, the yield of the target compound 6-chloro-3-fluoro-2-methoxypyridine is relatively high, among which the product yields when the molar ratio of 2,6-dichloro-3-fluoropyridine to the base is 1.0:2.0 and 1.0:3.0 are basically the same.

[0043] It can be seen from the results of Example 1 and Examples 6-7 that when the reaction is carried out at a temperature of 60°C, the reaction effect is basically optimal.

[0044] It can be seen from the results of Example 1 and Examples 8-9 that the reaction effect is basically optimal when the reaction reaches 12 hours.

[0045] The yield of 6-chloro-3-fluoro-2-methoxypyridine synthesized by the synthesis method of the present invention is 82-93%. Compared with the synthesis method disclosed in the prior art patent US2012 / 095031, the synthesis route is short and the yield is significantly improved.

[0046] 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 synthesizing 6-chloro-3-fluoro-2-methoxypyridine, characterized in that: The synthesis method is carried out according to the following process: The specific steps include: (1) dissolving compound 1 in methanol, adding a base under inert gas protection and low temperature conditions, then heating and stirring to react to obtain a reaction solution; (2) After the reaction is complete, the reaction solution is post-treated to obtain the target compound 2, i.e., the 6-chloro-3-fluoro-2-methoxypyridine.

2. The synthesis method according to claim 1, characterized in that In step (1), the base is selected from one or more of potassium carbonate, sodium carbonate, potassium hydroxide and potassium bicarbonate.

3. The synthesis method according to claim 1, characterized in that In step (1), the mass volume ratio of the compound 1 to methanol is 1:5-40 g / mL.

4. The synthesis method according to claim 1, characterized in that In step (1), the molar ratio of the compound 1 to the base is 1:1-3.

5. The synthesis method according to claim 1, characterized in that In step (1), the temperature of the low temperature condition is -5 to 10°C.

6. The synthesis method according to claim 1, characterized in that In step (1), the reaction temperature is 60 to 200° C. and the reaction time is 10 to 40 hours.

7. The synthesis method according to claim 1, characterized in that In step (2), the specific process of the post-processing is: After the reaction is complete, the reaction solution is cooled and added to water, extracted with an organic solvent I, and the organic phases are combined and concentrated to obtain a crude product, which is purified to obtain the target compound 2.

8. The synthesis method according to claim 7, characterized in that The purification method is selected from one or more of slurrying, column chromatography, recrystallization or distillation.

9. The synthesis method according to claim 7, characterized in that: The organic solvent I is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane and dichloroethane.

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