CN106748725B - preparation method of 4-chloro-2-fluoro-phenylpropionic acid - Google Patents
preparation method of 4-chloro-2-fluoro-phenylpropionic acid Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
- C07C51/38—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by decarboxylation
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- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
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- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
Abstract
The invention relates to the technical field of chemical synthesis, in particular to a preparation method of 4-chloro-2-fluoro-phenylpropionic acids, which uses cheap and easily obtained 4-chloro-2-fluorotoluene as a raw material to prepare a target product 4-chloro-2-fluoro-phenylpropionic acid through three steps of reactions of halogenation, nucleophilic substitution and hydrolysis decarboxylation, wherein the total yield of the target product can reach 74 percent, and in the treatment process, an intermediate and a final product can be purified through the steps of extraction, reduced pressure evaporation, suction filtration, recrystallization and the like, and compared with column purification treatment, the preparation method is simple to operate and easy to realize industrial production.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a preparation method of 4-chloro-2-fluoro-phenylpropionic acids.
Background
4-chloro-2-fluoro-phenylpropionic acid is an important organic synthesis and medical intermediate, and is widely applied to various aspects such as bactericides, ATX inhibitors, NHE3 inhibitors, NMDA receptor antagonists and the like by .
According to the search and reference of the literature, at present, the process flow for synthesizing 4-chloro-2-fluoro-phenylpropionic acid mainly comprises the following steps:
(1) musso, David L.et al report that 4-chloro-2-fluorophenol is used as a raw material to react with trifluoromethanesulfonic anhydride and ethyl acrylate for 4 steps to obtain a target product, namely 4-chloro-2-fluoro-phenylpropionic acid.
(2) Patent documents WO2010025856, WO2001092239 and the like report that 4-chloro-2-fluoro cinnamic acid is used as a raw material, platinum dioxide or palladium is used as a catalyst, and 4-chloro-2-fluoro-phenylpropionic acid is prepared through hydrogen catalytic reduction reaction.
However, both the th synthetic route and the second synthetic route have expensive raw materials, long reaction time and high production cost, and particularly, platinum dioxide or palladium dioxide is required to be used as a catalyst, so that the preparation cost of the product is high, and the th synthetic route also requires column purification, so that the yield of the obtained product is low and is less than 2%.
Therefore, the 4-chloro-2-fluoro-phenylpropionic acid in the prior art has complex synthetic route, high cost, low yield and high cost.
Disclosure of Invention
In order to solve the technical problems in the prior art, the invention provides a preparation method of kinds of 4-chloro-2-fluoro-phenylpropionic acid.
The method is realized by the following technical scheme:
the synthetic route of the 4-chloro-2-fluoro-phenylpropionic acid is as follows:
wherein R is1Is Cl or Br; r2Is methyl and/or ethyl and/or benzyl; (1) is a halogenation reaction; (2) is a nucleophilic substitution reaction; (3) is hydrolysis decarboxylation reaction.
The synthesis route uses cheap and easily-obtained 4-chloro-2-fluorotoluene as a raw material, and prepares a target product 4-chloro-2-fluoro-phenylpropionic acid through three-step reactions of halogenation, nucleophilic substitution and hydrolysis decarboxylation, and the total yield of the target product can reach 74%; in the treatment process, the intermediate and the final product can be purified through the steps of extraction, reduced pressure evaporation, suction filtration, recrystallization and the like, and compared with column purification treatment, the method is simple to operate and easy to realize industrial production.
In the above synthetic route, the steps adopted specifically include:
taking 4-chloro-2-fluorotoluene as a raw material, performing a halogenation reaction to obtain a compound shown in a general formula I, performing a nucleophilic substitution reaction on the compound shown in the general formula I to obtain a compound shown in a general formula II, and performing hydrolysis decarboxylation on the compound shown in the general formula II to obtain a target product, namely 4-chloro-2-fluoro-phenylpropionic acid; the general formula I is:
wherein R is1Is Cl or Br; general formula II
Wherein R is2Is methyl and/or ethyl and/or benzyl. Effectively shortens the synthetic route of the target product and reduces the synthetic cost.
Particularly, in the process of halogenation reaction, the adopted halogenating reagent is NCS or NBS; the feeding molar ratio of the halogenated reagent to the 4-chloro-2-fluorotoluene is 1-2: 1. In the reaction process, an initiator and a solvent are added for treatment, wherein the initiator is azobisisobutyronitrile; the solvent is carbon tetrachloride; the feeding molar ratio of the initiator to the 4-chloro-2-fluorotoluene is 0.01-0.02: 1. The time of halogenation is 6-12 h.
In the nucleophilic substitution reaction, the adopted nucleophilic reagent 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; in the reaction, adding alkali and solvent, wherein the alkali is sodium hydride, potassium tert-butoxide, sodium methoxide or sodium ethoxide; the solvent is tetrahydrofuran or N, N-dimethylformamide; the feeding molar ratio of the alkali to the 4-chloro-2-fluorotoluene is 1-2: 1. The time of nucleophilic substitution reaction is 2-5 h.
In the hydrolysis decarboxylation reaction, the adopted solvent is ethanol, methanol or isopropanol; the alkali is: an aqueous solution of sodium hydroxide, potassium hydroxide or lithium hydroxide; the acid is: concentrated hydrochloric acid; the specific operation is as follows: adding the general formula II into a single-mouth bottle, and simultaneously adding a solvent and alkali, so that the reflux reaction is carried out for 2-4 h; after the reaction is finished, decompressing and distilling the solvent out, extracting impurities, collecting the water phase, adding acid, refluxing and reacting for 1.5-3h, cooling, extracting, drying, decompressing and evaporating the solvent to dryness, and recrystallizing to obtain the product. The feeding mol ratio of the alkali to the raw materials is as follows: 3-9: 1; the feeding ratio of acid to raw materials is as follows: 4-12: 1.
The 4-chloro-2-fluoro-phenylpropionic acid synthesized by the method has low cost and high yield.
Detailed Description
The technical solution of the present invention is further defined in step with reference to the specific embodiments, but the scope of the claims is not limited to the description.
In the following examples, "a tetrahydrofuran solution (50mL) of 4-chloro-2-fluorobenzyl bromide (10.0g, 44.7 mmol)" was added dropwise after dissolving 10g of 4-chloro-2-fluorobenzyl bromide in 50mL of tetrahydrofuran to obtain a solution, and then adding dropwise.
Example 1
Preparation of 4-chloro-2-fluorobenzyl bromide
In a 500mL eggplant-shaped bottle, 4-chloro-2-fluorotoluene (20.0g, 138.3mmol), NBS (24.6g, 138.3mmol) and AIBN (0.3g, 2.1mmol) were dissolved in dry carbon tetrachloride (200mL), and the reaction was carried out under reflux for 8 hours. After the reaction, the reaction mixture was filtered, the filter cake was washed with dichloromethane (60 mL. times.3), the filtrate was extracted with water (250mL), dichloromethane (100 mL. times.3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 28.2g of 4-chloro-2-fluorobenzyl bromide with a yield of 91.2%.
Preparation of 2- [ (4-chloro-2-fluoro) benzyl ] -1, 3-malonic acid diethyl ester
Adding diethyl malonate (7.2g, 44.7mmol) and dried tetrahydrofuran (50mL) into a 250mL three-neck flask, cooling to 0 ℃, adding sodium hydrogen (1.6g, 67.1mmol) in batches under the protection of nitrogen, stirring for 20min, dropwise adding a tetrahydrofuran solution (50mL) of 4-chloro-2-fluorobenzyl bromide (10.0g, 44.7mmol), heating to room temperature after dropwise addition, and reacting for 2.5 h. After the reaction, water (30mL) was added to quench the reaction, ethyl acetate (100 mL. times.3) was extracted, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness under reduced pressure to obtain 12.2g of diethyl 2- [ (4-chloro-2-fluoro) benzyl ] -1, 3-malonate in 90.4% yield.
Preparation of C.4-chloro-2-fluoro-phenylpropionic acid
In a 250mL single-necked flask, diethyl 2- [ (4-chloro-2-fluoro) benzyl ] -1, 3-malonate (10.0g, 33.0mmol), ethanol (30mL) and 2.5mol/L aqueous sodium hydroxide solution (containing NaOH 7.9g, 198.2mmol) were added, and the reaction was refluxed for 4 hours. After the reaction, ethanol was distilled off under reduced pressure, and the mixture was extracted with diethyl ether (50 mL. times.2), the aqueous phase was collected, concentrated hydrochloric acid (containing HCl 9.6g, 264.3mmol) was added, and the reaction was refluxed for 2 hours. After the reaction, the mixture is cooled to room temperature, ethyl acetate (100mL multiplied by 3) is extracted, anhydrous sodium sulfate is dried, the solvent is evaporated to dryness under reduced pressure, and ethanol is recrystallized twice to obtain 5.9g of 4-chloro-2-fluoro-phenylpropionic acid with the yield of 88.3 percent.
1H-NMR(CDCl3):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
Preparation of 4-chloro-2-fluorobenzyl chloride
In a 250mL eggplant-shaped bottle, 4-chloro-2-fluorotoluene (10.0g, 69.2mmol), NCS (9.2g, 69.2mmol) and AIBN (0.2g, 1.0mmol) were dissolved in dried carbon tetrachloride (120mL), and the reaction was carried out under reflux for 12 hours. After the reaction, the reaction mixture was filtered, the filter cake was washed with dichloromethane (30 mL. times.2), the filtrate was extracted with water (150mL), dichloromethane (60 mL. times.3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to dryness to give 11.0g of 4-chloro-2-fluorobenzyl chloride, with a yield of 89.1%.
Preparation of 2- [ (4-chloro-2-fluoro) benzyl ] -1, 3-malonic acid diethyl ester
Diethyl malonate (9.0g, 55.9mmol) and dry N, N-dimethylformamide (50mL) are added into a 250mL three-necked flask, the temperature is reduced to 0 ℃, potassium tert-butoxide (6.3g, 55.9mmol) is added in batches, the mixture is stirred for 20min, 4-chloro-2-fluorobenzyl chloride (10.0g, 55.9mmol) in N, N-dimethylformamide (50mL) is added dropwise, and the mixture is heated to room temperature after the dropwise addition, and then the reaction is carried out for 3.5 h. After the reaction, water (30mL) was added to quench the reaction, ethyl acetate (100 mL. times.3) was extracted, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness under reduced pressure to give 14.6g of diethyl 2- [ (4-chloro-2-fluoro) benzyl ] -1, 3-malonate in 86.6% yield.
Preparation of C.4-chloro-2-fluoro-phenylpropionic acid
In a 250mL single-necked flask, diethyl 2- [ (4-chloro-2-fluoro) benzyl ] -1, 3-malonate (10.0g, 33.0mmol), methanol (30mL) and 2.5mol/L aqueous sodium hydroxide solution (containing NaOH 7.9g, 198.2mmol) were added, and the reaction was refluxed for 3 hours. After the reaction, methanol was distilled off under reduced pressure, and the impurities were extracted with diethyl ether (50 mL. times.2), the aqueous phase was collected, concentrated hydrochloric acid (containing 6.0g of HCl, 165.2mmol) was added, and the reaction was refluxed for 3 hours. After the reaction, the mixture is cooled to room temperature, ethyl acetate (100mL multiplied by 3) is extracted, anhydrous sodium sulfate is dried, the solvent is evaporated to dryness under reduced pressure, and ethanol is recrystallized twice to obtain 5.8g of 4-chloro-2-fluoro-phenylpropionic acid with the yield of 86.7 percent.
1H-NMR(CDCl3):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
Preparation of 4-chloro-2-fluorobenzyl bromide
In a 500mL eggplant-shaped bottle, 4-chloro-2-fluorotoluene (20.0g, 138.3mmol), NBS (24.6g, 138.3mmol) and AIBN (0.3g, 2.1mmol) were dissolved in dry carbon tetrachloride (200mL), and the reaction was carried out under reflux for 6 hours. After the reaction, the reaction mixture was filtered, the filter cake was washed with dichloromethane (60 mL. times.3), the filtrate was extracted with water (250mL), dichloromethane (100 mL. times.3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 27.8g of 4-chloro-2-fluorobenzyl chloride in 90.1% yield.
Preparation of 2- [ (4-chloro-2-fluoro) benzyl ] -1, 3-malonic acid diethyl ester
Diethyl malonate (7.2g, 44.7mmol) and dried DMF (50mL) are added into a 250mL three-necked flask, the temperature is reduced to 0 ℃, sodium tert-butoxide (6.5g, 67.1mmol) is added in batches, the mixture is stirred for 20min, a tetrahydrofuran solution (50mL) of 4-chloro-2-fluorobenzyl bromide (10.0g, 55.9mmol) is added dropwise, and after the dropwise addition, the temperature is raised to the room temperature for reaction for 4 h. After the reaction, water (30mL) was added to quench the reaction, ethyl acetate (100 mL. times.3) was extracted, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness under reduced pressure to obtain 12.0g of diethyl 2- [ (4-chloro-2-fluoro) benzyl ] -1, 3-malonate in 88.7% yield.
Preparation of C.4-chloro-2-fluoro-phenylpropionic acid
In a 250mL single-neck flask, diethyl 2- [ (4-chloro-2-fluoro) benzyl ] -1, 3-malonate (10.0g, 33.0mmol), isopropanol (30mL) and 2.5mol/L aqueous potassium hydroxide solution (containing 11.1g of KOH, 198.2mmol) were added, and the reaction was refluxed for 3 hours. After the reaction, isopropyl alcohol was distilled off under reduced pressure, impurities were extracted with diethyl ether (50 mL. times.2), the aqueous phase was collected, concentrated hydrochloric acid (containing HCl4.8g, 132.1mmol) was added, and the reaction was refluxed for 3 hours. After the reaction, the mixture is cooled to room temperature, ethyl acetate (100mL multiplied by 3) is extracted, anhydrous sodium sulfate is dried, the solvent is evaporated to dryness under reduced pressure, and ethanol is recrystallized twice to obtain 5.7g of 4-chloro-2-fluoro-phenylpropionic acid, wherein the yield is 85.6%.
1H-NMR(CDCl3):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
Preparation of 4-chloro-2-fluorobenzyl bromide
In a 500mL eggplant-shaped bottle, 4-chloro-2-fluorotoluene (20.0g, 138.3mmol), NBS (24.6g, 138.3mmol) and AIBN (0.3g, 2.1mmol) were dissolved in dry carbon tetrachloride (200mL), and the reaction was carried out under reflux for 8 hours. After the reaction, the reaction mixture was filtered, the filter cake was washed with dichloromethane (60 mL. times.3), the filtrate was extracted with water (250mL), dichloromethane (100 mL. times.3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 28.7g of 4-chloro-2-fluorobenzyl bromide with a yield of 92.8%.
Preparation of 2- [ (4-chloro-2-fluoro) benzyl ] -1, 3-propanedioic acid dimethyl ester
In a 250mL three-necked flask, dimethyl malonate (5.9g, 44.7mmol) and dried tetrahydrofuran (50mL) were added, the temperature was reduced to 0 ℃, sodium methoxide (3.6g, 67.1mmol) was added in portions, the mixture was stirred for 20min, a tetrahydrofuran solution (50mL) of 4-chloro-2-fluorobenzyl bromide (10.0g, 44.7mmol) was added dropwise, and after completion of the addition, the mixture was warmed to room temperature and reacted for 5 hours. After the reaction, water (30mL) was added to quench the reaction, ethyl acetate (100 mL. times.3) was extracted, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness under reduced pressure to give 11.0g of dimethyl 2- [ (4-chloro-2-fluoro) benzyl ] -1, 3-propanedioate in 89.6% yield.
Preparation of C.4-chloro-2-fluoro-phenylpropionic acid
In a 250mL single-neck flask, 2- [ (4-chloro-2-fluoro) benzyl ] -1, 3-malonic acid dimethyl ester (10.0g, 36.4mmol), ethanol (30mL) and 2.5mol/L aqueous lithium hydroxide solution (containing LiOH 2.6g, 109.2mmol) were added and the reaction was refluxed for 4 h. After the reaction, ethanol was distilled off under reduced pressure, and the mixture was extracted with diethyl ether (50 mL. times.2), the aqueous phase was collected, concentrated hydrochloric acid (containing HCl 10.6g, 291.3mmol) was added, and the reaction was refluxed for 2 hours. After the reaction, the mixture is cooled to room temperature, ethyl acetate (100mL multiplied by 3) is extracted, anhydrous sodium sulfate is dried, the solvent is evaporated to dryness under reduced pressure, and ethanol is recrystallized twice to obtain 6.4g of 4-chloro-2-fluoro-phenylpropionic acid, wherein the yield is 87.4%.
1H-NMR(CDCl3):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
Preparation of 4-chloro-2-fluorobenzyl bromide
In a 500mL eggplant-shaped bottle, 4-chloro-2-fluorotoluene (20.0g, 138.3mmol), NBS (36.9g, 207.5mmol) and AIBN (0.2g, 1.4mmol) were dissolved in dry carbon tetrachloride (200mL), and the reaction was carried out under reflux for 7 hours. After the reaction, the reaction mixture was filtered, the filter cake was washed with dichloromethane (60 mL. times.3), the filtrate was extracted with water (250mL), dichloromethane (100 mL. times.3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 25.2g of 4-chloro-2-fluorobenzyl bromide with a yield of 81.5%.
B.preparation of 2- [ (4-chloro-2-fluoro) benzyl ] -1, 3-malonic acid dibenzyl ester
Adding dibenzyl malonate (15.3g, 53.7mmol) and dried tetrahydrofuran (50mL) into a 250mL three-necked bottle, cooling to 0 ℃, adding sodium ethoxide (6.1g, 89.5mmol) in batches, stirring for 20min, dropwise adding a tetrahydrofuran solution (50mL) of 4-chloro-2-fluorobenzyl bromide (10.0g, 44.7mmol), after dropwise addition, raising the temperature to room temperature, and reacting for 5 h. After the reaction, water (30mL) was added to quench the reaction, ethyl acetate (100 mL. times.3) was extracted, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness under reduced pressure to give 16.9g of dibenzyl 2- [ (4-chloro-2-fluoro) benzyl ] -1, 3-malonate in 88.4% yield.
Preparation of C.4-chloro-2-fluoro-phenylpropionic acid
In a 250mL single-necked flask, 2- [ (4-chloro-2-fluoro) benzyl ] -1, 3-dibenzyl malonate (10.0g, 23.5mmol), ethanol (30mL) and 2.5mol/L aqueous sodium hydroxide solution (containing 5.6g of NaOH, 140.9mmol) are added, and the reaction is refluxed for 3.5 h. After the reaction, ethanol was distilled off under reduced pressure, and the impurities were extracted with diethyl ether (50 mL. times.2), and the aqueous phase was collected and concentrated hydrochloric acid (containing HCl6.9g, 187.9mmol) was added thereto and reacted under reflux for 2 hours. After the reaction, the mixture is cooled to room temperature, ethyl acetate (100mL multiplied by 3) is extracted, anhydrous sodium sulfate is dried, the solvent is evaporated to dryness under reduced pressure, and ethanol is recrystallized twice to obtain 4.2g of 4-chloro-2-fluoro-phenylpropionic acid, wherein the yield is 88.1%.
1H-NMR(CDCl3):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
Preparation of 4-chloro-2-fluorobenzyl bromide
In a 500mL eggplant-shaped bottle, 4-chloro-2-fluorotoluene (20.0g, 138.3mmol), NBS (27.1g, 152.2mmol) and AIBN (0.3g, 2.1mmol) were dissolved in dry carbon tetrachloride (200mL), and the reaction was carried out under reflux for 8 hours. After the reaction, the reaction mixture was filtered, the filter cake was washed with dichloromethane (60 mL. times.3), the filtrate was extracted with water (250mL), dichloromethane (100 mL. times.3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 27.6g of 4-chloro-2-fluorobenzyl bromide with a yield of 89.2%.
Preparation of 2- [ (4-chloro-2-fluoro) benzyl ] -1, 3-malonic acid diethyl ester
Adding diethyl malonate (7.9g, 49.2mmol) and dried tetrahydrofuran (50mL) into a 250mL three-neck flask, cooling to 0 ℃, adding sodium hydrogen (1.6g, 67.1mmol) in batches under the protection of nitrogen, stirring for 20min, dropwise adding a tetrahydrofuran solution (50mL) of 4-chloro-2-fluorobenzyl bromide (10.0g, 44.7mmol), after dropwise addition, raising the temperature to room temperature, and reacting for 2 h. After the reaction, water (30mL) was added to quench the reaction, ethyl acetate (100 mL. times.3) was extracted, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness under reduced pressure to obtain 12.1g of diethyl 2- [ (4-chloro-2-fluoro) benzyl ] -1, 3-malonate in 89.3% yield.
Preparation of C.4-chloro-2-fluoro-phenylpropionic acid
In a 250mL single-neck flask, diethyl 2- [ (4-chloro-2-fluoro) benzyl ] -1, 3-malonate (10.0g, 33.0mmol), methanol (30mL) and 2.5mol/L aqueous potassium hydroxide solution (containing KOH 16.7g, 297.3mmol) were added, and the reaction was refluxed for 2 hours. After the reaction, methanol was distilled off under reduced pressure, and the impurities were extracted with diethyl ether (50 mL. times.2), the aqueous phase was collected, concentrated hydrochloric acid (containing HCl 7.2g, 198.2mmol) was added, and the reaction was refluxed for 2 hours. After the reaction, the mixture is cooled to room temperature, ethyl acetate (100mL multiplied by 3) is extracted, anhydrous sodium sulfate is dried, the solvent is evaporated to dryness under reduced pressure, and ethanol is recrystallized twice to obtain 5.8g of 4-chloro-2-fluoro-phenylpropionic acid, wherein the yield is 86.8%.
1H-NMR(CDCl3):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
Preparation of 4-chloro-2-fluorobenzyl bromide
In a 250mL eggplant-shaped bottle, 4-chloro-2-fluorotoluene (10.0g, 69.2mmol), NBS (12.3g, 69.2mmol) and AIBN (0.1g, 0.8mmol) were dissolved in dry carbon tetrachloride (120mL), and the reaction was carried out under reflux for 8 hours. After the reaction, the reaction mixture was filtered, the filter cake was washed with dichloromethane (30 mL. times.2), the filtrate was extracted with water (150mL), dichloromethane (60 mL. times.3), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 14.3g of 4-chloro-2-fluorobenzyl bromide with a yield of 92.4%.
Preparation of 2- [ (4-chloro-2-fluoro) benzyl ] -1, 3-malonic acid diethyl ester
Adding diethyl malonate (7.9g, 49.2mmol) and dried tetrahydrofuran (50mL) into a 250mL three-neck flask, cooling to 0 ℃, adding sodium hydrogen (1.6g, 67.1mmol) in batches under the protection of nitrogen, stirring for 20min, dropwise adding a tetrahydrofuran solution (50mL) of 4-chloro-2-fluorobenzyl bromide (10.0g, 44.7mmol), heating to room temperature after dropwise addition, and reacting for 2.5 h. After the reaction, water (30mL) was added to quench the reaction, ethyl acetate (100 mL. times.3) was extracted, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness under reduced pressure to obtain 12.3g of diethyl 2- [ (4-chloro-2-fluoro) benzyl ] -1, 3-malonate in 90.9% yield.
Preparation of C.4-chloro-2-fluoro-phenylpropionic acid
In a 250mL single-necked flask, diethyl 2- [ (4-chloro-2-fluoro) benzyl ] -1, 3-malonate (10.0g, 33.0mmol), ethanol (30mL) and 2.5mol/L aqueous sodium hydroxide solution (containing NaOH 10.6g, 264.3mmol) were added, and the reaction was refluxed for 3 hours. After the reaction, ethanol was distilled off under reduced pressure, and the mixture was extracted with diethyl ether (50 mL. times.2), the aqueous phase was collected, concentrated hydrochloric acid (containing HCl 14.5g, 396.4mmol) was added, and the reaction was refluxed for 1.5 hours. After the reaction, the mixture is cooled to room temperature, ethyl acetate (100mL multiplied by 3) is extracted, anhydrous sodium sulfate is dried, the solvent is evaporated to dryness under reduced pressure, and ethanol is recrystallized twice to obtain 5.9g of 4-chloro-2-fluoro-phenylpropionic acid with the yield of 88.7%.
1H-NMR(CDCl3):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 adopts cheap and easily available 4-chloro-2-fluorotoluene as raw material, and prepares the target product 4-chloro-2-fluoro-phenylpropionic acid through three steps of halogenation, nucleophilic substitution and hydrolysis decarboxylation, the total yield can reach 74 percent, and the embodiment is only limited by explaining and explaining the technical scheme of the invention, but not limiting the technical scheme of the invention to steps.
Claims (7)
- 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. 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. 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. 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. 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. The method according to claim 5, wherein the molar ratio of the base to 4-chloro-2-fluorotoluene is 1-2: 1.
- 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.
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| CN101591232A (en) * | 2009-06-26 | 2009-12-02 | 湖南斯派克生物化工有限公司 | The preparation method of 3-(3-halogenophenyl) propionic acid |
| CN104592006A (en) * | 2015-01-23 | 2015-05-06 | 郑州大学 | Synthesis method of phenylpropionic acid compound |
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| CN101591232A (en) * | 2009-06-26 | 2009-12-02 | 湖南斯派克生物化工有限公司 | The preparation method of 3-(3-halogenophenyl) propionic acid |
| CN104592006A (en) * | 2015-01-23 | 2015-05-06 | 郑州大学 | Synthesis method of phenylpropionic acid compound |
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| Indanylidenes. 2. Design and Synthesis of (E)-2-(4-Chloro-6-fluoro-1-indanylidene)-N-methylacetamide, a Potent Antiinflammatory and Analgesic Agent without Centrally Acting Muscle Relaxant Activity;David L.等;《J. Med. Chem.》;20021231;第46卷(第3期);第409-416页 * |
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