A kind of synthesis method of 2,3-difluoro-5-chloropyridine

Abstract

The invention discloses a synthetic method of 2,3-difluoro-5-chloropyridine, the synthetic method comprising: first heating a first mixed reaction system comprising 2,3-diamino-5-chloropyridine, nitrite and diboric acid ester in a nitrile solvent for boronization reaction to obtain 2,3-diboric acid ester-5-chloropyridine, and then heating a second mixed reaction system comprising the 2,3-diboric acid ester-5-chloropyridine, copper salt and fluorine salt in a nitrile solvent for fluorination reaction to obtain 2,3-difluoro-5-chloropyridine. The synthetic method provided by the present invention uses readily available raw materials, has few reaction steps, few reaction byproducts, and has high purity of the obtained product, and is easy to prepare in large quantities.

Description

Technical Field

[0001] The invention relates to a synthesis method of 2,3-difluoro-5-chloropyridine, and belongs to the field of organic chemical synthesis. Background Art

[0002] Since the fluorine atom has the greatest electronegativity and the atomic radius is small, the carbon-fluorine bond has a large bond energy, and fluorine-containing organic compounds have the characteristics of high stability, high fat solubility and high physiological activity. In the past decade, fluorine-containing pesticides have been rapidly developed and have become the focus of the development of the world's pesticide industry. 2,3-Difluoro-5-chloropyridine is an important pesticide and pharmaceutical intermediate. For example, it is an important raw material for the preparation of the pesticide clodinafop-butyl. As a herbicide, clodinafop-butyl is widely used in crops such as soybeans, rapeseed, and wheat, and has great application prospects. The synthetic routes of 2,3-difluoro-5-chloropyridine are mainly the following:

[0003] (1) Patent US4713109A1 and literature Differding, E.; Frick, W.; Lang, RW; Martin, P.; Schmit, C.; et al. Bulletin des Societes Chimiques Belges, 1990, 99, 647-671 disclose: using 2,4-dichloro-3-fluoropyridine as a raw material and cesium fluoride as a fluorine source, 2,3-difluoro-5-chloropyridine can be synthesized in one step, and the yield of the reaction is up to 87%. However, the main problem of this route is that the raw materials are not easy to obtain. The reaction formula is:

[0004]

[0005] (2) Patent CN103396357A discloses that: trichloroacetaldehyde and acrylonitrile are used as starting materials, and a catalytic ring closure and fluorination reaction are performed to obtain the product 2,3-difluoro-5-chloropyridine, and the reaction yield can reach 78.3%. The reaction formula is:

[0006]

[0007] (3) Patent CN1830963A discloses that 2,3,5-trichloropyridine is used as raw material, ionic liquid is used as solvent, and 2,3-difluoro-5-chloropyridine is synthesized in one step under the condition of alkaline compound as catalyst. In CN101648904B, tetraphenylphosphine bromide or tetrabutylphosphine bromide is used as phase transfer catalyst, and under the protection of inert gas, 180-190°C is kept warm for 5-10 hours, and then 200-210°C is kept warm for 10-15 hours to prepare 2,3-difluoro-5-chloropyridine. In CN102702087A, N-bis(dimethylamino)methylene-1.3-dimethylimidazoline-2-chloroimmonium salt is used as catalyst, and under the condition of inert gas, high temperature reaction is carried out for more than 10 hours to obtain 2,3-difluoro-5-chloropyridine, and the reaction formula thereof is:

[0008]

[0009] In the one-step synthesis route of 2,3,5-trichloropyridine as raw material, the following by-products are generated and difficult to separate and purify. The target product obtained needs further or multi-stage purification to achieve a higher purity. The reaction formula is:

[0010]

[0011] In summary, the reported methods have the following main disadvantages: raw materials are not easily available, expensive reagents are used, reaction temperature is high (high energy consumption), reaction by-products are difficult to separate, etc. Summary of the invention

[0012] The purpose of the present invention is to provide a method for synthesizing 2,3-difluoro-5-chloropyridine to overcome the deficiencies in the prior art.

[0013] In order to achieve the above-mentioned object of the invention, the present invention adopts the following technical solutions:

[0014] The present invention provides a method for synthesizing 2,3-difluoro-5-chloropyridine, comprising:

[0015] heating a first mixed reaction system comprising 2,3-diamino-5-chloropyridine, nitrite and diboronate in a nitrile solvent to perform a borylation reaction to obtain 2,3-diboronate-5-chloropyridine;

[0016] The second mixed reaction system comprising the 2,3-diboronate-5-chloropyridine, copper salt and fluoride salt is heated in a nitrile solvent to carry out a fluorination reaction to obtain 2,3-difluoro-5-chloropyridine.

[0017] Compared with the prior art, the beneficial effects of the present invention are at least:

[0018] 1) The present invention uses 2,3-diamino-5-chloropyridine as a raw material, and obtains 2,3-difluoro-5-chloropyridine through one-pot synthesis through boronization and fluorination.

[0019] 2) The method provided by the present invention has the advantages of easy availability of raw materials, few reaction steps, few reaction by-products, high product purity, and easy large-scale preparation. DETAILED DESCRIPTION

[0020] In view of the defects of the prior art, the inventors of this case have proposed the technical solution of the present invention after long-term research and extensive practice. The technical solution of the present invention will be clearly and completely described below. It mainly uses 2,3-diamino-5-chloropyridine as a raw material, and undergoes boronization and fluorination to synthesize 2,3-difluoro-5-chloropyridine.

[0021] The technical solution, its implementation process and principle are further explained as follows. However, it should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here.

[0022] An aspect of an embodiment of the present invention provides a method for synthesizing 2,3-difluoro-5-chloropyridine, comprising:

[0023] heating a first mixed reaction system comprising 2,3-diamino-5-chloropyridine, nitrite and diboronate in a nitrile solvent to perform a borylation reaction to obtain 2,3-diboronate-5-chloropyridine;

[0024] The second mixed reaction system comprising the 2,3-diboronate-5-chloropyridine, copper salt and fluoride salt is heated in a nitrile solvent to carry out a fluorination reaction to obtain 2,3-difluoro-5-chloropyridine.

[0025] In some specific embodiments, the synthesis method of 2,3-difluoro-5-chloropyridine of the present invention comprises:

[0026] Heating 2,3-diamino-5-chloropyridine, nitrite and diboric acid ester in a nitrile solvent to undergo a borylation reaction to obtain a mixed system including 2,3-diboric acid ester-5-chloropyridine;

[0027] Copper salt and fluoride salt are added into the mixed system and heated in a nitrile solvent to carry out fluorination reaction to obtain 2,3-difluoro-5-chloropyridine.

[0028] Specifically, the synthesis route of 2,3-difluoro-5-chloropyridine provided by the present invention comprises two steps, namely, a borylation reaction and a fluorination reaction:

[0029]

[0030] The possible reaction mechanism is as follows: in the first step, 2,3-diamino-5-chloropyridine first reacts with nitrite to obtain a diazonium salt, which can undergo a single electron transfer boronization reaction with a diboric acid ester to obtain 2,3-diboric acid ester-5-chloropyridine; in the second step, a divalent copper salt will form a fluorine-containing divalent copper salt under the reaction conditions, which can undergo a transmetallation reaction with 2,3-diboric acid ester-5-chloropyridine to form a pyridyl fluorine-containing divalent copper salt, and this species undergoes an oxidation reaction in the presence of another molecule of divalent copper salt to obtain a pyridyl fluorine-containing trivalent copper salt, and this species can be reduced and eliminated to obtain 2,3-difluoro-5-chloropyridine.

[0031] In some embodiments, the nitrite includes any one of methyl nitrite, ethyl nitrite, isopropyl nitrite, n-amyl nitrite, isoamyl nitrite, isobutyl nitrite, and tert-butyl nitrite, or a combination of two or more thereof.

[0032] In some embodiments, the borate ester includes any one of pinacol borate and neopentyl glycol borate, or a combination of both.

[0033] In some embodiments, the nitrile solvent includes any one of acetonitrile, propionitrile, butyronitrile, or a combination of two or more thereof.

[0034] In some embodiments, the copper salt includes any one of copper chloride, copper fluoride, copper acetate, copper trifluoromethanesulfonate, or a combination of two or more thereof.

[0035] In some embodiments, the fluoride salt includes any one of sodium fluoride, potassium fluoride, and cesium fluoride, or a combination of two or more thereof.

[0036] In some embodiments, the molar ratio of 2,3-diamino-5-chloropyridine to nitrite is 1:1-1:10.

[0037] In some embodiments, the molar ratio of 2,3-diamino-5-chloropyridine to diboron ester is 1:1-1:5.

[0038] In some embodiments, the molar ratio of 2,3-diamino-5-chloropyridine to copper salt is 1:1-1:5.

[0039] In some embodiments, the molar ratio of 2,3-diamino-5-chloropyridine to fluoride salt is 1:1-1:20.

[0040] In some embodiments, the temperature of the borylation reaction is 40° C.-100° C., and the reaction time is 1-4 hours.

[0041] In some embodiments, the fluorination reaction temperature is 40° C.-80° C., and the reaction time is 12-24 hours.

[0042] In some more specific embodiments, the synthesis method of 2,3-difluoro-5-chloropyridine comprises:

[0043] In a reactor, 2,3-diamino-5-chloropyridine, nitrite and diboric acid ester are heated in a nitrile solvent for a certain period of time to obtain 2,3-diboric acid ester-5-chloropyridine. 2,3-diboric acid ester-5-chloropyridine is not purified, copper salt and fluoride salt are added to the system, and then heated for a certain period of time, and then purified to obtain 2,3-difluoro-5-chloropyridine.

[0044] The technical scheme of the present invention is further described in detail below in conjunction with several preferred embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. It should be pointed out that the embodiments described below are intended to facilitate the understanding of the present invention, and do not have any limiting effect on them. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in the field without making creative work belong to the scope of protection of the present invention. The experimental methods for which specific conditions are not specified in the following embodiments are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer.

[0045] Example 1

[0046] The process of synthesizing 2,3-difluoro-5-chloropyridine in this embodiment specifically includes:

[0047] After adding 1 mol of 2,3-diamino-5-chloropyridine, 1 mol of tert-butyl nitrite, 1 mol of biboric acid pinacol ester, propionitrile and magnet into the reactor, the system was heated to 40°C, reacted for 2 hours, cooled, 1 mol of cupric chloride and 1 mol of sodium fluoride were added, heated to 40°C, reacted for 12 hours, cooled, and the organic phase in the system was extracted with ethyl acetate, the organic phases were combined and dried with sodium sulfate for 30 minutes, and then filtered with diatomaceous earth. After the organic phase was concentrated, the product was obtained with a yield of 48%. The obtained product was subjected to nuclear magnetic resonance analysis, and the result was: 1 H NMR (400 MHz, CDCl3) δ7.99 (dd, J=2.4, 2.0 Hz, 1H), 7.62 (ddd, J=8.0, 7.6, 2.0 Hz, 1H), i.e., the obtained product was 2,3-difluoro-5-chloropyridine.

[0048] Example 2

[0049] The process of synthesizing 2,3-difluoro-5-chloropyridine in this embodiment specifically includes:

[0050] Into the reactor, 1 mol of 2,3-diamino-5-chloropyridine (molar ratio of 1), 1.5 mol of isoamyl nitrite, 1.5 mol of biboric acid pinacol ester, acetonitrile and magnet were added, the system was heated to 60°C, reacted for 3 hours, cooled, 2 mol of copper trifluoromethanesulfonate and 2 mol of potassium fluoride were added, heated to 50°C, reacted for 20 hours, cooled, and the organic phase in the system was extracted with ethyl acetate, the organic phases were combined and dried with sodium sulfate for 30 minutes, and then filtered with diatomaceous earth. After the organic phase was concentrated, 2,3-difluoro-5-chloropyridine was obtained with a yield of 93%.

[0051] Example 3

[0052] The process of synthesizing 2,3-difluoro-5-chloropyridine in this embodiment specifically includes:

[0053] After adding 1 mol of 2,3-diamino-5-chloropyridine, 10 mol of isoamyl nitrite, 2 mol of neopentyl glycol diborate, acetonitrile and a magnet into a reactor, the system is heated to 70°C, reacted for 2 hours, cooled, 2 mol of copper fluoride and 4 mol of cesium fluoride are added, heated to 80°C, reacted for 24 hours, cooled, and the organic phase in the system is extracted with ethyl acetate, the organic phases are combined and dried with sodium sulfate for 30 minutes, and then filtered with diatomaceous earth. After the organic phase is concentrated, 2,3-difluoro-5-chloropyridine is obtained with a yield of 85%.

[0054] Example 4

[0055] The process of synthesizing 2,3-difluoro-5-chloropyridine in this embodiment specifically includes:

[0056] After adding 1 mol of 2,3-diamino-5-chloropyridine, 7 mol of isoamyl nitrite, 5 mol of biboric acid pinacol ester, butyronitrile and magnet into the reactor, the system is heated to 100°C, reacted for 3 hours, cooled, 5 mol of copper trifluoromethanesulfonate and 10 mol of potassium fluoride are added, heated to 70°C, reacted for 18 hours, cooled, and the organic phase in the system is extracted with ethyl acetate, the organic phases are combined and dried with sodium sulfate for 30 minutes, and then filtered with diatomaceous earth. After the organic phase is concentrated, 2,3-difluoro-5-chloropyridine is obtained with a yield of 80%.

[0057] Example 5

[0058] The process of synthesizing 2,3-difluoro-5-chloropyridine in this embodiment specifically includes:

[0059] After adding 1 mol of 2,3-diamino-5-chloropyridine, 4 mol of isopropyl nitrite, 3 mol of biboric acid pinacol ester, acetonitrile and magnet into the reactor, the system is heated to 90°C, reacted for 1 hour, cooled, 3 mol of copper trifluoromethanesulfonate and 20 mol of sodium fluoride are added, heated to 75°C, reacted for 20 hours, cooled, and the organic phase in the system is extracted with ethyl acetate, the organic phases are combined and dried with sodium sulfate for 30 minutes, and then filtered with diatomaceous earth. After the organic phase is concentrated, 2,3-difluoro-5-chloropyridine is obtained with a yield of 75%.

[0060] Example 6

[0061] The process of synthesizing 2,3-difluoro-5-chloropyridine in this embodiment specifically includes:

[0062] After adding 1 mol of 2,3-diamino-5-chloropyridine, 2 mol of isoamyl nitrite, 4 mol of biboric acid pinacol ester, acetonitrile and magnet into the reactor, the system is heated to 80°C, reacted for 4 hours, cooled, 4 mol of cupric acetate and 20 mol of sodium fluoride are added, heated to 60°C, reacted for 24 hours, cooled, and the organic phase in the system is extracted with ethyl acetate, the organic phases are combined and dried with sodium sulfate for 30 minutes, and then filtered with diatomaceous earth. After the organic phase is concentrated, 2,3-difluoro-5-chloropyridine is obtained with a yield of 70%.

[0063] Example 7

[0064] The process of synthesizing 2,3-difluoro-5-chloropyridine in this embodiment specifically includes:

[0065] After adding 1 mol of 2,3-diamino-5-chloropyridine, 2 mol of methyl nitrite, 4 mol of biboric acid pinacol ester, acetonitrile and magnet into the reactor, the system is heated to 80°C, reacted for 4 hours, cooled, 4 mol of copper acetate and 20 mol of sodium fluoride are added, heated to 60°C, reacted for 24 hours, cooled, and the organic phase in the system is extracted with ethyl acetate, the organic phases are combined and dried with sodium sulfate for 30 minutes, and then filtered with diatomaceous earth. After the organic phase is concentrated, 2,3-difluoro-5-chloropyridine is obtained.

[0066] Example 8

[0067] The process of synthesizing 2,3-difluoro-5-chloropyridine in this embodiment specifically includes:

[0068] After adding 1 mol of 2,3-diamino-5-chloropyridine, 2 mol of ethyl nitrite, 4 mol of biboric acid pinacol ester, acetonitrile and magnet into the reactor, the system is heated to 80°C, reacted for 4 hours, cooled, 4 mol of copper acetate and 20 mol of sodium fluoride are added, heated to 60°C, reacted for 24 hours, cooled, and the organic phase in the system is extracted with ethyl acetate, the organic phases are combined and dried with sodium sulfate for 30 minutes, and then filtered with diatomaceous earth. After the organic phase is concentrated, 2,3-difluoro-5-chloropyridine is obtained.

[0069] Example 9

[0070] The process of synthesizing 2,3-difluoro-5-chloropyridine in this embodiment specifically includes:

[0071] After adding 1 mol of 2,3-diamino-5-chloropyridine, 2 mol of n-pentyl nitrite, 4 mol of biboric acid pinacol ester, acetonitrile and magnet into the reactor, the system is heated to 80°C, reacted for 4 hours, cooled, 4 mol of copper acetate and 20 mol of sodium fluoride are added, heated to 60°C, reacted for 24 hours, cooled, and the organic phase in the system is extracted with ethyl acetate, the organic phases are combined and dried with sodium sulfate for 30 minutes, and then filtered with diatomaceous earth. After the organic phase is concentrated, 2,3-difluoro-5-chloropyridine is obtained.

[0072] In addition, the inventors of this case also referred to the aforementioned embodiments and conducted experiments with other raw materials, process operations, and process conditions described in this specification, and obtained relatively ideal results.

[0073] It should be understood that the technical solution of the present invention is not limited to the above-mentioned specific implementation cases. Any technical deformation made according to the technical solution of the present invention without departing from the scope of protection of the purpose of the present invention and the claims shall fall within the protection scope of the present invention.

Claims

1. A method for synthesizing 2,3-difluoro-5-chloropyridine, characterized in that: include: The first mixed reaction system comprising 2,3-diamino-5-chloropyridine, nitrite and biboric acid ester is heated in a nitrile solvent for boration reaction to obtain 2,3-diboric acid ester-5-chloropyridine, wherein the biboric acid ester is selected from any one of biboric acid pinacol ester and biboric acid neopentyl glycol ester or a combination of two thereof, the molar ratio of the 2,3-diamino-5-chloropyridine to the nitrite is 1:1-1:10, the molar ratio of the 2,3-diamino-5-chloropyridine to the biboric acid ester is 1:1-1:5, the temperature of the boration reaction is 40°C-100°C, the reaction time is 1-4 hours, and the nitrite is selected from any one of methyl nitrite, ethyl nitrite, isopropyl nitrite, n-amyl nitrite, isoamyl nitrite, isobutyl nitrite and tert-butyl nitrite or a combination of two or more thereof; The second mixed reaction system comprising the 2,3-diboric acid ester-5-chloropyridine, a copper salt and a fluoride salt is heated in a nitrile solvent for a fluorination reaction to obtain 2,3-difluoro-5-chloropyridine, wherein the molar ratio of the 2,3-diamino-5-chloropyridine to the copper salt is 1:1-1:5, and the molar ratio of the 2,3-diamino-5-chloropyridine to the fluoride salt is 1:1-1:

20. The temperature of the fluorination reaction is 40°C-80°C, and the reaction time is 12-24 hours. The copper salt is selected from any one of copper chloride, copper fluoride, copper acetate, and copper trifluoromethanesulfonate, or a combination of two or more thereof. The fluoride salt is selected from any one of sodium fluoride, potassium fluoride, and cesium fluoride, or a combination of two or more thereof.

2. The synthesis method according to claim 1, characterized in that: The nitrile solvent is selected from any one of acetonitrile, propionitrile and butyronitrile or a combination of two or more thereof.

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