A process for the preparation of 2,4-difluorophenylglycine

Abstract

The application provides a preparation method of 2,4-difluorophenyl glycine and relates to the field of compound synthesis. The method uses 2,4-difluorophenyl acetic acid as raw material, and 2,4-difluorophenyl glycine is obtained through bromination reaction and ammoniation reaction; the temperature of the bromination reaction is 60-100 DEG C, and the bromination reaction also needs to add an initiator; the temperature of the ammoniation reaction is 0-50 DEG C, the reaction is carried out in the presence of a solvent, and the solvent is at least one selected from water, methanol, ethanol, acetone and acetonitrile. The target product is obtained through inexpensive and easily available raw materials and mild reaction. The method of the application avoids using a highly toxic reagent, the raw material is inexpensive and easily available, the steps are simple, the overall reaction yield is high, the cost is low, and the method is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of compound synthesis, specifically relating to a method for preparing 2,4-difluorophenylglycine. Background Technology

[0002] 2,4-Difluorophenylglycine is a widely used pharmaceutical intermediate. For example, 2,4-difluorophenylglycine can be used to synthesize novel acid-suppressing drugs such as filsurazine, and has high application value.

[0003] The preparation of 2,4-difluorophenylglycine has been reported in previous literature. For example, Chinese invention patent CN110582482B reports the preparation of 2,4-difluorophenylglycine from 2,4-difluorobenzaldehyde via a Strecker reaction with sodium cyanide and ammonia. The synthetic route is shown below:

[0004]

[0005] Chinese patent CN114702402A discloses a synthetic route for 2,4-difluorophenylglycine, which is obtained by using m-difluorobenzene as a starting material, undergoing Friedel-Crafts acylation with monomethyl oxalate, imidization with benzylamine, followed by hydrogenation catalyzed by palladium or rhodium catalysts, and then hydrolysis. The synthetic route is shown below:

[0006]

[0007] The methods already disclosed have drawbacks such as excessively long reaction routes, the use of expensive catalysts or highly toxic reagents, and low overall yield, making them difficult to implement for industrial production. To address these problems, this technical field urgently needs a new method for preparing 2,4-difluorophenylglycine that is simple to react, low in cost, suitable for industrial production, and yields high purity. Research on such a method is of great significance. Summary of the Invention

[0008] This invention addresses the problems existing in the prior art by providing a method for preparing 2,4-difluorophenylglycine. The method of this invention uses 2,4-difluorophenylacetic acid as raw material, and obtains 2,4-difluorophenylglycine through bromination and amination. The method is simple, low-cost, short in reaction time, and has a high overall yield, making it suitable for industrial production.

[0009] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0010] A method for preparing 2,4-difluorophenylglycine includes the following steps:

[0011]

[0012] (1) Using 2,4-difluorophenylacetic acid as a raw material, a bromination reaction was carried out using a bromination reagent to obtain α-bromo-2,4-difluorophenylacetic acid;

[0013] (2) α-Bromo-2,4-difluorophenylacetic acid reacts with an ammonia reagent to give 2,4-difluorophenylglycine as shown in Formula I.

[0014] Preferably, the brominating agent in step (1) is selected from at least one of bromine, N-bromosuccinimide (NBS), and dibromohydantoin.

[0015] More preferably, the brominating agent is selected from at least one of bromine and NBS.

[0016] Preferably, the bromination reaction in step (1) is carried out at a temperature of 60-100℃ and for a time of 1-3 hours.

[0017] More preferably, the reaction temperature is 80-100℃ and the reaction time is 2h.

[0018] Preferably, the bromination reaction in step (1) is carried out in the presence of a solvent, wherein the solvent is a haloalkane or a halobenzene;

[0019] More preferably, the haloalkane is selected from at least one of dichloromethane, dichloroethane, and chloroform; and the halobenzene is selected from at least one of chlorobenzene and dichlorobenzene.

[0020] Preferably, in step (1), the bromination reaction further includes an initiator.

[0021] More preferably, the initiator is an azo initiator or benzoyl peroxide.

[0022] More preferably, the initiator is an azo initiator.

[0023] More preferably, the azo initiator is selected from at least one of azobisisobutyronitrile (AIBN), azobisisoheptanenitrile (ABVN), dimethyl azobisisobutyrate (AIBME), azobisisobutyramidine hydrochloride (AIBA), and azobisisobutyramidine hydrochloride (AIBI).

[0024] Preferably, the ammonia reagent in step (2) is selected from at least one of ammonia water, ammonia gas, and an organic solvent solution of ammonia.

[0025] More preferably, the organic solvent solution of ammonia is selected from at least one of ammonia in methanol, ammonia in ethanol, and ammonia in acetone.

[0026] More preferably, the ammonia reagent is ammonia gas.

[0027] Preferably, the reaction in step (2) is carried out at a temperature of 0-50°C.

[0028] More preferably, the reaction temperature is specifically set as follows: before adding the ammonia reagent, the temperature is kept at 0°C; after adding the ammonia reagent, the reaction is carried out at 0°C for 0.5-2 hours, and then the temperature is raised to 25-30°C to continue the reaction.

[0029] Preferably, the reaction in step (2) is carried out in the presence of a solvent selected from at least one of water, methanol, ethanol, acetone, and acetonitrile.

[0030] More preferably, the solvent is methanol.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] The method for preparing 2,4-difluorophenylglycine described in this invention avoids the use of highly toxic reagents, uses inexpensive and readily available raw materials, has simple steps, high overall reaction yield, low cost, and is suitable for industrial production. Attached Figure Description

[0033] Figure 1 This is the LCMS spectrum of 2,4-difluorophenylglycine prepared in this invention.

[0034] Figure 2 This is the HNMR spectrum of 2,4-difluorophenylglycine prepared by the present invention. Detailed Implementation

[0035] The following non-limiting embodiments are intended to provide a more comprehensive understanding of the invention by those skilled in the art, but do not limit the invention in any way. The following description is merely an exemplary illustration of the scope of protection claimed by the invention. Those skilled in the art can make various changes and modifications to the invention based on the disclosed content, and these should also fall within the scope of protection claimed by the invention. When numerical ranges are given in the embodiments, it should be understood that, unless otherwise stated in the invention, the two endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by those skilled in the art to which this invention pertains.

[0036] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all chemical reagents used in the embodiments of the present invention were obtained through conventional commercial channels. Products from different manufacturers do not significantly affect the effect. In the following embodiments, the 2,4-difluorophenylacetic acid was self-made by Zhejiang Yongtai Technology Co., Ltd.; the NBS was purchased from Aladdin, catalog number B105059; the AIBN was purchased from Maclean's, catalog number A800353; and the bromine was purchased from Shanghai Lingfeng.

[0037] In the following examples, yield = actual weight / theoretical weight × 100%;

[0038] Purity was determined using high-performance liquid chromatography (HPLC), and the instrument was manufactured by Agilent Technologies.

[0039] Examples 1-5 are the reaction formulas for step (1) to prepare α-bromo-2,4-difluorophenylacetic acid:

[0040]

[0041] Examples 6-9 are the reaction formulas for the preparation of 2,4-difluorophenylglycine in step (2):

[0042]

[0043] Example 1

[0044] In a 1L three-necked flask, add 50g of 2,4-difluorophenylacetic acid, 56.9g of NBS, and 500mL of chlorobenzene. Then add 2.4g of AIBN to the mixture. Heat to 80℃ and react for 2 hours (200rpm). After the reaction is complete, cool to room temperature, and add 400mL of a 20% sodium sulfite aqueous solution dropwise at 0℃. The addition is completed within 60 minutes, and the mixture is stirred to separate into layers. The organic phase is evaporated under reduced pressure to remove the solvent, and the residue is recrystallized in n-heptane to give 66.4g of a white solid, with a yield of 91.0%.

[0045] Example 2

[0046] In a 1L three-necked flask, add 50g of 2,4-difluorophenylacetic acid, 56.9g of NBS, and 500mL of chlorobenzene. Then add 0.28g of benzoyl peroxide to the mixture. Heat to 80℃ and react for 2 hours. After the reaction is complete, cool to room temperature, and add 400mL of a 20% sodium sulfite aqueous solution dropwise at 0℃. The addition is completed within 60 minutes, and the mixture is stirred to separate into layers. The organic phase is evaporated under reduced pressure to remove the solvent, and the residue is recrystallized in n-heptane to give 58.8g of a white solid, with a yield of 80.6%.

[0047] Example 3

[0048] In a 1L three-necked flask, add 50g of 2,4-difluorophenylacetic acid, 56.9g of NBS, and 500mL of chloroform. Then add 2.4g of AIBN to the mixture. Heat to reflux and react for 2 hours. After the reaction is complete, cool to room temperature, and add 400mL of a 20% sodium sulfite aqueous solution dropwise at 0°C. The addition is completed over 60 minutes. Stir to separate the layers, evaporate the solvent from the organic phase under reduced pressure, and recrystallize the residue in n-heptane to give 62g of a white solid, yield 85.0%.

[0049] Example 4

[0050] In a 1L three-necked flask, 50g of 2,4-difluorophenylacetic acid, 56.9g of NBS, and 500mL of chlorobenzene were added. The temperature was then raised to 80℃, and the reaction was allowed to proceed for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, and 400mL of a 20% sodium sulfite aqueous solution was added dropwise at 0℃. The addition was completed over 60 minutes, and the mixture was stirred to separate into layers. The organic phase was evaporated under reduced pressure to remove the solvent, and the residue was recrystallized in n-heptane to give 47.8g of a white solid, with a yield of 65.5%.

[0051] Example 5

[0052] In a 1L three-necked flask, 50g of 2,4-difluorophenylacetic acid and 500mL of chlorobenzene were added. 92.8g of bromine was added dropwise at 0°C. After the addition was complete, 2.4g of AIBN was added to the mixture. The temperature was raised to 100°C, and the reaction was allowed to proceed for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, and 400mL of a 20% sodium sulfite aqueous solution was added dropwise at 0°C. The addition was completed within 60 minutes. The mixture was stirred to separate into layers, and the organic phase was evaporated under reduced pressure to remove the solvent. The residue was recrystallized in n-heptane to give 66.4g of a white solid, with a yield of 91.0%.

[0053] Example 6

[0054] In a 1L three-necked flask, 100g of α-bromo-2,4-difluorophenylacetic acid and 500mL of methanol were added. After dissolving, the mixture was cooled to 0°C, and ammonia gas was introduced until saturation. The mixture was stirred for 1 hour (150 rpm) and then allowed to rise to room temperature for 24 hours (150 rpm). Crystals were formed in the reaction system. After filtration, 70.8g of 2,4-difluorophenylglycine was obtained, with a yield of 95.0%.

[0055] ESI-LCMS of product 2,4-difluorophenylglycine: m / z 188.01 (M+H).

[0056] The product 2,4-difluorophenylglycine 1 HNMR (400MHz, DMSO-d6): δ7.96(s,3H), δ7.48(m,1H), δ7.25(td,1H), δ7.10(td,1H), δ4.40(s,1H).

[0057] Example 7

[0058] In a 1L three-necked flask, 100g of α-bromo-2,4-difluorophenylacetic acid and 500mL of methanol were added. After dissolving, 270g of 25% ammonia water was added at 0℃ and stirred for 1 hour. The mixture was then raised to room temperature and reacted for 24 hours. Crystals were formed in the reaction system. After filtration, 63.7g of 2,4-difluorophenylglycine was obtained, with a yield of 85.5%.

[0059] Example 8

[0060] In a 1L three-necked flask, 100g of α-bromo-2,4-difluorophenylacetic acid and 200mL of methanol were added. After dissolving, 285mL of 7M ammonia-methanol solution was added dropwise at 0℃. The mixture was stirred for 1 hour and then allowed to react at room temperature for 24 hours. Crystals were formed in the reaction system. After filtration, 67.2g of 2,4-difluorophenylglycine was obtained, with a yield of 90.2%.

[0061] Example 9

[0062] In a 1L three-necked flask, 100g of α-bromo-2,4-difluorophenylacetic acid and 500mL of acetone were added. After dissolving, the mixture was cooled to 0°C, and ammonia gas was introduced until saturation. The mixture was stirred for 1 hour, and then the reaction was brought to room temperature for 24 hours. Crystals were formed in the reaction system. After filtration, 55.9g of 2,4-difluorophenylglycine was obtained, with a yield of 75.0%.

[0063] Comparative Example 1

[0064] The difference from Example 1 is that the bromination reaction was carried out at a temperature of 40°C; all other aspects are the same as in Example 1.

[0065] In a 1L three-necked flask, add 50g of 2,4-difluorophenylacetic acid, 56.9g of NBS, and 500mL of chlorobenzene. Then add 2.4g of AIBN to the mixture. Heat to 40℃ and react for 2 hours. After the reaction is complete, cool to room temperature, and add 400mL of a 20% sodium sulfite aqueous solution dropwise at 0℃. After the addition is complete, stir to separate the layers, evaporate the solvent from the organic phase under reduced pressure, and recrystallize the residue in n-heptane to give 42.1g of a white solid, yield 57.8%.

[0066] Comparative Example 2

[0067] The difference from Example 6 is that the solvent methanol was replaced with tetrahydrofuran, otherwise it is the same as Example 6.

[0068] In a 1L three-necked flask, 100g of α-bromo-2,4-difluorophenylacetic acid and 500mL of tetrahydrofuran were added. After dissolving, the mixture was cooled to 0°C, and ammonia gas was introduced until saturation. The mixture was stirred for 1 hour, and then the reaction was allowed to proceed to room temperature for 24 hours. Crystals were formed in the reaction system. After filtration, 50.4g of 2,4-difluorophenylglycine was obtained, with a yield of 67.6%.

[0069] Comparative Example 3

[0070] Unlike Example 6, the reaction temperature was different. Specifically, 100g of α-bromo-2,4-difluorophenylacetic acid and 500mL of methanol were added to a 1L three-necked flask. After dissolving, ammonia gas was introduced until saturation, and the mixture was stirred at room temperature for 1 hour. Then, the reaction was carried out at room temperature for 24 hours, and crystals were formed in the reaction system. After filtration, 55.2g of 2,4-difluorophenylglycine was obtained, with a yield of 74.0%.

[0071] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing 2,4-difluorophenylglycine, characterized in that, The specific steps are as follows: (1) Using 2,4-difluorophenylacetic acid as raw material, bromination reaction was carried out in the presence of chlorobenzene or chloroform solvent by using bromination reagent and adding initiator. The reaction temperature was 80-100℃ to obtain α-bromo-2,4-difluorophenylacetic acid. (2) α-Bromo-2,4-difluorophenylacetic acid reacts with an ammonia reagent in the presence of methanol to obtain 2,4-difluorophenylglycine as shown in Formula I; the reaction temperature is specifically set as follows: before adding the ammonia reagent, the temperature is kept at 0℃, and after adding the ammonia reagent, the reaction is carried out at 0℃ for 0.5-2h, and then the temperature is raised to 25-30℃ to continue the reaction.

2. The preparation method according to claim 1, characterized in that, The brominating agent mentioned in step (1) is selected from at least one of bromine and NBS.

3. The preparation method according to claim 1, characterized in that, The initiator is an azo initiator or benzoyl peroxide; the azo initiator is selected from at least one of AIBN, ABVN, AIBME, AIBA, and AIBI.

4. The preparation method according to claim 1, characterized in that, The ammonia reagent mentioned in step (2) is selected from at least one of ammonia water, ammonia gas, and a methanol solution of ammonia.

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