CN106748725B - A kind of preparation method of 4-chloro-2-fluoro-phenylpropionic acid - Google Patents

Abstract

The invention relates to the technical field of chemical synthesis, in particular to a method for preparing 4-chloro-2-fluoro-phenylpropionic acid. By using cheap and easily available 4-chloro-2-fluorotoluene as a raw material, through halogenation, nucleophilic The three-step reaction of substitution, hydrolysis and decarboxylation obtains the target product 4-chloro-2-fluoro-phenylpropionic acid, and the total yield of the target product can reach 74%; and in the treatment process, the intermediate and the final product are extracted , vacuum evaporation, suction filtration, recrystallization and other steps can be purified, compared with column purification, its operation is simple, and it is easy to realize industrial production.

Description

A kind of preparation method of 4-chloro-2-fluoro-phenylpropionic acid

technical field

The invention relates to the technical field of chemical synthesis, in particular to a preparation method of 4-chloro-2-fluoro-phenylpropionic acid.

Background technique

4-Chloro-2-fluoro-phenylpropionic acid is an important organic synthesis and pharmaceutical intermediate, and is widely used in various aspects such as fungicides, ATX inhibitors, NHE3 inhibitors and NMDA receptor antagonists.

After searching the literature, at present, the technological process for the synthesis of 4-chloro-2-fluoro-phenylpropionic acid mainly includes the following:

(1) reported by Musso, David L. etc. take 4-chloro-2-fluorophenol as raw material, obtain target product 4-chloro-2-fluoro-phenylpropane through 4-step reaction with trifluoromethanesulfonic anhydride and ethyl acrylate acid.

(2) Patent document number is 4-chloro-2-fluorocinnamic acid as reported by WO2010025856, WO2001092239 etc. as raw material, platinum dioxide or palladium as catalyst, 4-chloro-2-fluoro-phenylpropane is prepared by hydrogen catalytic reduction reaction acid.

But, whether it is the above-mentioned first synthetic route, or the above-mentioned second synthetic route, the raw material it adopts is expensive, and the reaction time is longer, and the production cost is higher, especially all need to use platinum dioxide or palladium as a catalyst , so that the cost of product preparation is high; and the first synthetic route also needs to be purified by column, and the yield of the obtained product is low, less than 2%.

It can be seen that the synthesis route of 4-chloro-2-fluoro-phenylpropionic acid in the prior art is complicated, with high cost, low yield and high cost.

SUMMARY OF THE INVENTION

In order to solve the above-mentioned technical problems existing in the prior art, the present invention provides a preparation method of 4-chloro-2-fluoro-phenylpropionic acid.

Specifically, this is achieved through the following technical solutions:

The synthetic route of 4-chloro-2-fluoro-phenylpropionic acid is as follows:

Wherein, R ₁ is Cl or Br; R ₂ is methyl and/or ethyl and/or benzyl; (1) is a halogenation reaction; (2) is a nucleophilic substitution reaction; (3) is a hydrolysis decarboxylation reaction.

In this synthetic route, the target product 4-chloro-2-fluoro-phenylpropionic acid is obtained by using cheap and readily available 4-chloro-2-fluorotoluene as raw material, and through three-step reactions of halogenation, nucleophilic substitution, and hydrolysis and decarboxylation, and The total yield of the target product can reach 74%; and during the treatment process, the intermediates and final products can be purified by extraction, evaporation under reduced pressure, suction filtration, recrystallization and other steps. Compared with column purification, The operation is simple and the industrial production is easy to realize.

Specifically in above-mentioned synthetic route, the step that adopts, specifically comprises:

其中，R₁为Cl或Br；通式II为

其中，R₂为甲基和/或乙基和/或苄基。有效的缩短了目标产物的合成路线，降低了合成成本。Using 4-chloro-2-fluorotoluene as raw material, the compound of general formula I is obtained by halogenation reaction, the compound of general formula I is obtained by nucleophilic substitution reaction, the compound of general formula II is obtained by hydrolysis and decarboxylation to obtain the target Product 4-chloro-2-fluoro-phenylpropionic acid; general formula I is:

Wherein, R ₁ is Cl or Br; general formula II is

Wherein, R ₂ is methyl and/or ethyl and/or benzyl. The synthetic route of the target product is effectively shortened, and the synthetic cost is reduced.

Specifically, in the halogenation reaction process, the halogenation reagent used is NCS or NBS; the molar ratio of the halogenation reagent to 4-chloro-2-fluorotoluene is 1-2:1. In the reaction process, an initiator and solvent treatment are added, wherein the initiator is azobisisobutyronitrile; the solvent is carbon tetrachloride; the molar ratio of the initiator to 4-chloro-2-fluorotoluene is 0.01～ 0.02:1. The time of halogenation reaction is 6-12h.

In the nucleophilic substitution reaction, the nucleophile used is diethyl malonate, dimethyl malonate or dibenzyl malonate; the molar ratio of the nucleophile to the general formula I is 1 to 1.2 : 1; In this reaction, add alkali and solvent, and alkali is sodium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide or sodium ethoxide; Solvent is tetrahydrofuran or N,N-dimethylformamide; Alkali The molar ratio of feed to 4-chloro-2-fluorotoluene is 1-2:1. The time of nucleophilic substitution reaction is 2-5h.

In the hydrolysis decarboxylation reaction, the solvent it adopts is: ethanol, methanol or isopropanol; the alkali is: the aqueous solution of sodium hydroxide, potassium hydroxide or lithium hydroxide; the acid is: concentrated hydrochloric acid; its concrete operation is: General formula II is added into a single-necked bottle, and a solvent and a base are added simultaneously, so that the reaction is refluxed for 2-4h; after the reaction is completed, the solvent is evaporated under reduced pressure, impurities are removed, the water phase is collected, an acid is added, and the reaction is refluxed for 1.5-3h, the reaction After completion, cool, extract, dry, evaporate the solvent under reduced pressure, and recrystallize. The molar ratio of the above-mentioned alkali to the raw material is: 3～9:1; the ratio of the acid to the raw material is: 4～12:1.

The cost of synthesizing 4-chloro-2-fluoro-phenylpropionic acid by the above method is lower and the yield is higher.

Detailed ways

The technical solutions of the present invention will be further limited below in conjunction with specific embodiments, but the scope of protection is not limited to the description.

For "dropwise addition of 4-chloro-2-fluorobenzyl bromide (10.0 g, 44.7 mmol) in tetrahydrofuran (50 mL)" in the following examples means that 10 g of 4-chloro-2-fluorobenzyl bromide was dissolved in 50 mL of tetrahydrofuran to form After the solution was obtained, it was added dropwise.

Example 1

A. Preparation of 4-chloro-2-fluorobenzyl bromide

In a 500 mL eggplant flask, dissolve 4-chloro-2-fluorotoluene (20.0 g, 138.3 mmol), NBS (24.6 g, 138.3 mmol), AIBN (0.3 g, 2.1 mmol) in dry carbon tetrachloride ( 200mL), reflux reaction for 8h. The reaction was completed, filtered, and the filter cake was washed with dichloromethane (60 mL×3), the filtrate was added with water (250 mL), extracted with dichloromethane (100 mL×3), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 4-chloro- 28.2 g of 2-fluorobenzyl bromide, the yield was 91.2%.

B. Preparation of diethyl 2-[(4-chloro-2-fluoro)benzyl]-1,3-malonate

In a 250mL there-necked flask, add diethyl malonate (7.2g, 44.7mmol) and dry tetrahydrofuran (50ml), cool to 0°C, add sodium hydrogen (1.6g, 67.1mmol) in batches under nitrogen protection , stirred for 20 min, and added dropwise a solution of 4-chloro-2-fluorobenzyl bromide (10.0 g, 44.7 mmol) in tetrahydrofuran (50 mL). After the reaction was completed, water (30 mL) was added to quench the reaction, extracted with ethyl acetate (100 mL×3), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 2-[(4-chloro-2-fluoro)benzyl]-1 , 12.2 g of diethyl 3-malonate, a yield of 90.4%.

C. Preparation of 4-chloro-2-fluoro-phenylpropionic acid

In a 250mL single-neck flask, add 2-[(4-chloro-2-fluoro)benzyl]-1,3-malonate diethyl ester (10.0g, 33.0mmol), ethanol (30mL) and 2.5mol/L The aqueous sodium hydroxide solution (containing NaOH 7.9 g, 198.2 mmol) was refluxed for 4 h. After the reaction was completed, the ethanol was evaporated under reduced pressure, the impurities were extracted with ether (50 mL×2), the aqueous phase was collected, concentrated hydrochloric acid (containing HCl 9.6 g, 264.3 mmol) was added, and the reaction was refluxed for 2 h. The reaction was completed, cooled to room temperature, extracted with ethyl acetate (100 mL×3), dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and recrystallized from ethanol twice to obtain 5.9 g of 4-chloro-2-fluoro-phenylpropionic acid. , the yield is 88.3%.

¹ H-NMR (CDCl ₃ ): 2.650-2.688 (t, 2H,); 2.924-2.961 (t, 2H); 7.043-7.076 (q, 2H); 7.135-7.176 (t, 1H).

Example 2

A. Preparation of 4-chloro-2-fluorobenzyl chloride

In a 250 mL eggplant flask, dissolve 4-chloro-2-fluorotoluene (10.0 g, 69.2 mmol), NCS (9.2 g, 69.2 mmol), AIBN (0.2 g, 1.0 mmol) in dry carbon tetrachloride ( 120mL), reflux reaction for 12h. The reaction was completed, filtered, and the filter cake was washed with dichloromethane (30 mL×2), the filtrate was added with water (150 mL), extracted with dichloromethane (60 mL×3), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 4-chloro- 11.0 g of 2-fluorobenzyl chloride, the yield was 89.1%.

B. Preparation of diethyl 2-[(4-chloro-2-fluoro)benzyl]-1,3-malonate

In a 250mL there-necked flask, add diethyl malonate (9.0g, 55.9mmol) and dry N,N-dimethylformamide (50ml), cool to 0°C, add potassium tert-butoxide ( 6.3g, 55.9mmol), stirred for 20min, added dropwise the N,N-dimethylformamide solution (50mL) of 4-chloro-2-fluorobenzyl chloride (10.0g, 55.9mmol), the dropwise addition was completed, and the solution was warmed to room temperature , the reaction 3.5h. After the reaction was completed, water (30 mL) was added to quench the reaction, extracted with ethyl acetate (100 mL×3), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 2-[(4-chloro-2-fluoro)benzyl]-1 , 14.6 g of diethyl 3-malonate, yield 86.6%.

C. Preparation of 4-chloro-2-fluoro-phenylpropionic acid

In a 250mL single-neck flask, add 2-[(4-chloro-2-fluoro)benzyl]-1,3-malonate diethyl ester (10.0g, 33.0mmol), methanol (30mL) and 2.5mol/L The aqueous sodium hydroxide solution (containing NaOH 7.9 g, 198.2 mmol) was refluxed for 3 h. After the reaction was completed, methanol was evaporated under reduced pressure, and the mixture was extracted with ether (50 mL×2), the aqueous phase was collected, concentrated hydrochloric acid (containing HCl 6.0 g, 165.2 mmol) was added, and the reaction was refluxed for 3 h. The reaction was completed, cooled to room temperature, extracted with ethyl acetate (100 mL×3), dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and recrystallized twice with ethanol to obtain 5.8 g of 4-chloro-2-fluoro-phenylpropionic acid. , the yield is 86.7%.

¹ H-NMR (CDCl ₃ ): 2.650-2.688 (t, 2H,); 2.924-2.961 (t, 2H); 7.043-7.076 (q, 2H); 7.135-7.176 (t, 1H).

Example 3

A. Preparation of 4-chloro-2-fluorobenzyl bromide

In a 500 mL eggplant flask, dissolve 4-chloro-2-fluorotoluene (20.0 g, 138.3 mmol), NBS (24.6 g, 138.3 mmol), AIBN (0.3 g, 2.1 mmol) in dry carbon tetrachloride ( 200mL), reflux reaction for 6h. The reaction was completed, filtered, and the filter cake was washed with dichloromethane (60 mL×3), the filtrate was added with water (250 mL), extracted with dichloromethane (100 mL×3), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 4-chloro- 27.8 g of 2-fluorobenzyl chloride, the yield was 90.1%.

B. Preparation of diethyl 2-[(4-chloro-2-fluoro)benzyl]-1,3-malonate

In a 250mL three-necked flask, add diethyl malonate (7.2g, 44.7mmol) and dry DMF (50ml), cool to 0°C, add sodium tert-butoxide (6.5g, 67.1mmol) in batches, stir After 20 min, a solution of 4-chloro-2-fluorobenzyl bromide (10.0 g, 55.9 mmol) in tetrahydrofuran (50 mL) was added dropwise, the dropwise addition was completed, the temperature was raised to room temperature, and the reaction was carried out for 4 h. After the reaction was completed, water (30 mL) was added to quench the reaction, extracted with ethyl acetate (100 mL×3), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 2-[(4-chloro-2-fluoro)benzyl]-1 , 12.0 g of diethyl 3-malonate, yield 88.7%.

C. Preparation of 4-chloro-2-fluoro-phenylpropionic acid

In a 250mL single-neck flask, add 2-[(4-chloro-2-fluoro)benzyl]-1,3-malonate diethyl ester (10.0g, 33.0mmol), isopropanol (30mL) and 2.5mol /L potassium hydroxide aqueous solution (containing KOH 11.1 g, 198.2 mmol), refluxed for 3 h. After the reaction was completed, the isopropanol was evaporated under reduced pressure, the impurities were extracted with ether (50 mL×2), the aqueous phase was collected, concentrated hydrochloric acid (containing HCl 4.8 g, 132.1 mmol) was added, and the reaction was refluxed for 3 h. The reaction was completed, cooled to room temperature, extracted with ethyl acetate (100 mL×3), dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and recrystallized from ethanol twice to obtain 5.7 g of 4-chloro-2-fluoro-phenylpropionic acid. , the yield is 85.6%.

¹ H-NMR (CDCl ₃ ): 2.650-2.688 (t, 2H,); 2.924-2.961 (t, 2H); 7.043-7.076 (q, 2H); 7.135-7.176 (t, 1H).

Example 4

A. Preparation of 4-chloro-2-fluorobenzyl bromide

In a 500 mL eggplant flask, dissolve 4-chloro-2-fluorotoluene (20.0 g, 138.3 mmol), NBS (24.6 g, 138.3 mmol), AIBN (0.3 g, 2.1 mmol) in dry carbon tetrachloride ( 200mL), reflux reaction for 8h. The reaction was completed, filtered, and the filter cake was washed with dichloromethane (60 mL×3), the filtrate was added with water (250 mL), extracted with dichloromethane (100 mL×3), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 4-chloro- 28.7 g of 2-fluorobenzyl bromide, the yield was 92.8%.

B. Preparation of dimethyl 2-[(4-chloro-2-fluoro)benzyl]-1,3-malonate

In a 250mL three-necked flask, add dimethyl malonate (5.9g, 44.7mmol) and dry tetrahydrofuran (50ml), cool to 0°C, add sodium methoxide (3.6g, 67.1mmol) in batches, stir for 20min, A solution of 4-chloro-2-fluorobenzyl bromide (10.0 g, 44.7 mmol) in tetrahydrofuran (50 mL) was added dropwise, the dropwise addition was completed, the temperature was raised to room temperature, and the reaction was carried out for 5 h. After the reaction was completed, water (30 mL) was added to quench the reaction, extracted with ethyl acetate (100 mL×3), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 2-[(4-chloro-2-fluoro)benzyl]-1 , 11.0 g of dimethyl 3-malonate, yield 89.6%.

C. Preparation of 4-chloro-2-fluoro-phenylpropionic acid

In a 250mL single-neck flask, add 2-[(4-chloro-2-fluoro)benzyl]-1,3-malonate dimethyl ester (10.0g, 36.4mmol), ethanol (30mL) and 2.5mol/L The aqueous lithium hydroxide solution (containing LiOH 2.6 g, 109.2 mmol) was refluxed for 4 h. After the reaction was completed, the ethanol was evaporated under reduced pressure, the impurities were extracted with ether (50 mL×2), the aqueous phase was collected, concentrated hydrochloric acid (containing HCl 10.6 g, 291.3 mmol) was added, and the reaction was refluxed for 2 h. The reaction was completed, cooled to room temperature, extracted with ethyl acetate (100 mL×3), dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and recrystallized from ethanol twice to obtain 6.4 g of 4-chloro-2-fluoro-phenylpropionic acid. , the yield is 87.4%.

¹ H-NMR (CDCl ₃ ): 2.650-2.688 (t, 2H,); 2.924-2.961 (t, 2H); 7.043-7.076 (q, 2H); 7.135-7.176 (t, 1H).

Example 5

A. Preparation of 4-chloro-2-fluorobenzyl bromide

In a 500 mL eggplant flask, dissolve 4-chloro-2-fluorotoluene (20.0 g, 138.3 mmol), NBS (36.9 g, 207.5 mmol), AIBN (0.2 g, 1.4 mmol) in dry carbon tetrachloride ( 200mL), reflux reaction for 7h. The reaction was completed, filtered, and the filter cake was washed with dichloromethane (60 mL×3), the filtrate was added with water (250 mL), extracted with dichloromethane (100 mL×3), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 4-chloro- 25.2 g of 2-fluorobenzyl bromide, the yield was 81.5%.

B. Preparation of Dibenzyl 2-[(4-Chloro-2-fluoro)benzyl]-1,3-malonate

In a 250mL there-necked flask, add dibenzyl malonate (15.3g, 53.7mmol) and dry tetrahydrofuran (50ml), cool to 0°C, add sodium ethoxide (6.1g, 89.5mmol) in batches, stir for 20min, A solution of 4-chloro-2-fluorobenzyl bromide (10.0 g, 44.7 mmol) in tetrahydrofuran (50 mL) was added dropwise, the dropwise addition was completed, the temperature was raised to room temperature, and the reaction was carried out for 5 h. After the reaction was completed, water (30 mL) was added to quench the reaction, extracted with ethyl acetate (100 mL×3), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 2-[(4-chloro-2-fluoro)benzyl]-1 , 16.9 g of dibenzyl 3-malonate, a yield of 88.4%.

C. Preparation of 4-chloro-2-fluoro-phenylpropionic acid

In a 250mL single-neck flask, add 2-[(4-chloro-2-fluoro)benzyl]-1,3-malonate dibenzyl (10.0g, 23.5mmol), ethanol (30mL) and 2.5mol/L The aqueous sodium hydroxide solution (containing NaOH 5.6g, 140.9mmol) was refluxed for 3.5h. After the reaction was completed, the ethanol was evaporated under reduced pressure, the impurities were extracted with ether (50 mL×2), the aqueous phase was collected, concentrated hydrochloric acid (containing HCl 6.9 g, 187.9 mmol) was added, and the reaction was refluxed for 2 h. The reaction was completed, cooled to room temperature, extracted with ethyl acetate (100 mL×3), dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and recrystallized from ethanol twice to obtain 4.2 g of 4-chloro-2-fluoro-phenylpropionic acid. , the yield is 88.1%.

¹ H-NMR (CDCl ₃ ): 2.650-2.688 (t, 2H,); 2.924-2.961 (t, 2H); 7.043-7.076 (q, 2H); 7.135-7.176 (t, 1H).

Example 6

A. Preparation of 4-chloro-2-fluorobenzyl bromide

In a 500 mL eggplant flask, dissolve 4-chloro-2-fluorotoluene (20.0 g, 138.3 mmol), NBS (27.1 g, 152.2 mmol), AIBN (0.3 g, 2.1 mmol) in dry carbon tetrachloride ( 200mL), reflux reaction for 8h. The reaction was completed, filtered, and the filter cake was washed with dichloromethane (60 mL×3), the filtrate was added with water (250 mL), extracted with dichloromethane (100 mL×3), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 4-chloro- 27.6 g of 2-fluorobenzyl bromide, the yield was 89.2%.

B. Preparation of diethyl 2-[(4-chloro-2-fluoro)benzyl]-1,3-malonate

In a 250mL there-necked flask, add diethyl malonate (7.9g, 49.2mmol) and dry tetrahydrofuran (50ml), cool to 0°C, add sodium hydrogen (1.6g, 67.1mmol) in batches under nitrogen protection , stirred for 20 min, and added dropwise a solution of 4-chloro-2-fluorobenzyl bromide (10.0 g, 44.7 mmol) in tetrahydrofuran (50 mL). After the reaction was completed, water (30 mL) was added to quench the reaction, extracted with ethyl acetate (100 mL×3), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 2-[(4-chloro-2-fluoro)benzyl]-1 , 12.1 g of diethyl 3-malonate, a yield of 89.3%.

C. Preparation of 4-chloro-2-fluoro-phenylpropionic acid

In a 250mL single-neck flask, add 2-[(4-chloro-2-fluoro)benzyl]-1,3-malonate diethyl ester (10.0g, 33.0mmol), methanol (30mL) and 2.5mol/L The aqueous potassium hydroxide solution (containing KOH 16.7 g, 297.3 mmol) was refluxed for 2 h. After the reaction was completed, methanol was evaporated under reduced pressure, and the mixture was extracted with ether (50 mL×2). The aqueous phase was collected, concentrated hydrochloric acid (containing HCl 7.2 g, 198.2 mmol) was added, and the reaction was refluxed for 2 h. The reaction was completed, cooled to room temperature, extracted with ethyl acetate (100 mL×3), dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and recrystallized twice with ethanol to obtain 5.8 g of 4-chloro-2-fluoro-phenylpropionic acid. , the yield is 86.8%.

¹ H-NMR (CDCl ₃ ): 2.650-2.688 (t, 2H,); 2.924-2.961 (t, 2H); 7.043-7.076 (q, 2H); 7.135-7.176 (t, 1H).

Example 7

A. Preparation of 4-chloro-2-fluorobenzyl bromide

In a 250 mL eggplant flask, dissolve 4-chloro-2-fluorotoluene (10.0 g, 69.2 mmol), NBS (12.3 g, 69.2 mmol), AIBN (0.1 g, 0.8 mmol) in dry carbon tetrachloride ( 120mL), reflux reaction for 8h. The reaction was completed, filtered, and the filter cake was washed with dichloromethane (30 mL×2), the filtrate was added with water (150 mL), extracted with dichloromethane (60 mL×3), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 4-chloro- 14.3 g of 2-fluorobenzyl bromide, the yield was 92.4%.

B. Preparation of diethyl 2-[(4-chloro-2-fluoro)benzyl]-1,3-malonate

In a 250mL there-necked flask, add diethyl malonate (7.9g, 49.2mmol) and dry tetrahydrofuran (50ml), cool to 0°C, add sodium hydrogen (1.6g, 67.1mmol) in batches under nitrogen protection , stirred for 20 min, and added dropwise a solution of 4-chloro-2-fluorobenzyl bromide (10.0 g, 44.7 mmol) in tetrahydrofuran (50 mL). After the reaction was completed, water (30 mL) was added to quench the reaction, extracted with ethyl acetate (100 mL×3), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 2-[(4-chloro-2-fluoro)benzyl]-1 , 12.3 g of diethyl 3-malonate, a yield of 90.9%.

C. Preparation of 4-chloro-2-fluoro-phenylpropionic acid

In a 250mL single-neck flask, add 2-[(4-chloro-2-fluoro)benzyl]-1,3-malonate diethyl ester (10.0g, 33.0mmol), ethanol (30mL) and 2.5mol/L The aqueous sodium hydroxide solution (containing NaOH 10.6 g, 264.3 mmol) was refluxed for 3 h. After the reaction was completed, the ethanol was evaporated under reduced pressure, the impurities were extracted with ether (50 mL×2), the aqueous phase was collected, concentrated hydrochloric acid (containing HCl 14.5 g, 396.4 mmol) was added, and the reaction was refluxed for 1.5 h. The reaction was completed, cooled to room temperature, extracted with ethyl acetate (100 mL×3), dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and recrystallized from ethanol twice to obtain 5.9 g of 4-chloro-2-fluoro-phenylpropionic acid. , the yield is 88.7%.

¹ H-NMR (CDCl ₃ ): 2.650-2.688 (t, 2H,); 2.924-2.961 (t, 2H); 7.043-7.076 (q, 2H); 7.135-7.176 (t, 1H).

The invention creates the target product 4-chloro-2-fluoro-phenylpropionic acid by using cheap and easy-to-obtain 4-chloro-2-fluorotoluene as a raw material, and through three-step reactions of halogenation, nucleophilic substitution, and hydrolysis and decarboxylation, The total yield can reach 74%, and the above-mentioned embodiment is only limited to explain and illustrate the technical solution created by the present invention, and is not a further limitation to the technical solution created by the present invention. Those skilled in the art make on this basis. Non-prominent substantive features and non-significant progress improvements belong to the protection scope of the present invention.

Claims (7)

1. The preparation method of kinds of 4-chloro-2-fluoro-phenylpropionic acid is characterized in that the synthetic route is as follows:

   

   wherein R1 is Cl or Br; r2 is methyl and/or ethyl and/or benzyl; (1) is a halogenation reaction; (2) is a nucleophilic substitution reaction; (3) in order to carry out the hydrolysis decarboxylation reaction,

   the preparation method of the 4-chloro-2-fluoro-phenylpropionic acid comprises the specific preparation steps of taking 4-chloro-2-fluorotoluene as a raw material, performing halogenation reaction to obtain the compound with the general formula I, and performing nucleophilic substitution on the compound with the general formula I to obtain the compound with the general formula IObtaining a compound of a general formula II, and hydrolyzing and decarboxylating the compound of the general formula II to obtain a target product 4-chloro-2-fluoro-phenylpropionic acid; the general formula I is:

   

   wherein R1 is Cl or Br; general formula II

   

   Wherein R2 is methyl and/or ethyl and/or benzyl.
2. 2. The process for the preparation of 4-chloro-2-fluoro-phenylpropionic acid as claimed in claim 1, wherein the halogenation reaction is carried out using a halogenating agent NCS or NBS; the feeding molar ratio of the halogenated reagent to the 4-chloro-2-fluorotoluene is 1-2: 1.
3. 3. The process for the preparation of 4-chloro-2-fluoro-phenylpropionic acid as claimed in claim 1, wherein the halogenation reaction is carried out in the presence of an initiator and a solvent, the initiator being azobisisobutyronitrile; the solvent is carbon tetrachloride.
4. 4. A process for the preparation of 4-chloro-2-fluoro-benzenepropanoic acid as claimed in claim 1, wherein said nucleophilic substitution reaction employs a nucleophile which is diethyl malonate, dimethyl malonate or dibenzyl malonate; the feeding molar ratio of the nucleophilic reagent to the general formula I is 1-1.2: 1.
5. 5. The process for preparing 4-chloro-2-fluoro-phenylpropionic acid according to claim 1, wherein the nucleophilic substitution reaction further comprises adding a base and a solvent during the reaction, wherein the base is sodium hydride, potassium tert-butoxide, sodium methoxide or sodium ethoxide; the solvent is tetrahydrofuran or N, N-dimethylformamide.
6. 6. The method according to claim 5, wherein the molar ratio of the base to 4-chloro-2-fluorotoluene is 1-2: 1.
7. 7. The process for the preparation of 4-chloro-2-fluoro-phenylpropionic acid as claimed in claim 1, wherein the hydrolysis decarboxylation reaction is carried out using ethanol, methanol or isopropanol as a solvent; the alkali used is sodium hydroxide solution, potassium hydroxide solution or lithium hydroxide solution.