CN113527090B - Synthetic method of p-bromomethyl isophenylpropionic acid - Google Patents

Synthetic method of p-bromomethyl isophenylpropionic acid Download PDF

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CN113527090B
CN113527090B CN202110807425.3A CN202110807425A CN113527090B CN 113527090 B CN113527090 B CN 113527090B CN 202110807425 A CN202110807425 A CN 202110807425A CN 113527090 B CN113527090 B CN 113527090B
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acid
isophenylpropionic
synthesizing
bromomethyl
bromide
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CN113527090A (en
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王光华
陈陆武
陈彦达
易平
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Jiangxi Kaiyuan Biomedicine Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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

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Abstract

The invention provides a method for synthesizing p-bromomethyl isophenylpropionic acid, and relates to the technical field of organic synthesis. The synthesis method comprises the steps of isophenylpropionate synthesis, Vilsmeier reagent preparation, p-aldehyde isophenylpropionate synthesis, p-hydroxymethyl isophenylpropionic acid synthesis, p-bromomethyl isophenylpropionic acid synthesis, separation and purification and the like. The final para-selectivity of the method can reach 90-97%, and the yield of three wastes is greatly reduced, so that the method is more suitable for the development direction of economic and environment-friendly benign industries advocated by the nation.

Description

Synthetic method of p-bromomethyl isophenylpropionic acid
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a synthetic method of p-bromomethyl isophenylpropionic acid.
Background
The loxoprofen sodium is researched and marketed by Sanshu pharmaceutical Co-Ltd in 1986, belongs to novel non-steroidal anti-inflammatory drugs of aryl propionic acid, and is proved to have good analgesic, anti-inflammatory and antirheumatic effects by 30 years of clinical use, so that the loxoprofen sodium is popular in the market. At present, the gene has been marketed in many countries such as Japan and Korean, Europe and America, and the market expansion speed is strong. And the p-bromomethyl isophenylpropionic acid is an important intermediate of the loxoprofen sodium.
In recent years, the research and the production of loxoprofen sodium are started in China, and most of the loxoprofen sodium are prepared by adopting p-bromomethyl isoproylic acid as a raw material and condensing with 2-ethoxycarbonylcyclopentanone through an international traditional route. In the prior art, the p-bromomethyl isophenylpropionic acid is generally synthesized by reacting isophenylpropionic acid, hydrobromic acid solution, paraformaldehyde, concentrated sulfuric acid and the like under certain conditions. The reaction formula is as follows:
Figure BDA0003167124820000011
however, the method has a plurality of adverse factors, mainly including that the selectivity of the bromomethylation reaction is not good enough, the sulfuric acid wastewater cannot be recycled, and the product refining mother liquor is difficult to treat, so that the yield of the p-bromomethyl isophenylpropionic acid is low, and the cost of the loxoprofen sodium is increased.
Disclosure of Invention
In order to solve the problems, the invention provides a method for synthesizing p-bromomethyl isophenylpropionic acid, which can reduce the three-waste treatment cost in the synthesis process of the p-bromomethyl isophenylpropionic acid, improve the yield of the p-bromomethyl isophenylpropionic acid and reduce the cost of loxoprofen sodium.
The synthetic method of the p-bromomethyl isophenylpropionic acid comprises the following synthetic route:
Figure BDA0003167124820000012
Figure BDA0003167124820000021
wherein R is1is-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH(CH3)2or-C (CH)3)3One of (1);
R2is-CH3、-CH2CH3Or
Figure BDA0003167124820000022
One of (1);
R3is-CH3、-CH2CH3or-CH2CH2CH3One of (1);
R4is-Cl, -Br, H, -CH3、-CH2CH3、-OCH3or-NO2One kind of (1).
Further, the synthesis method of the p-bromomethyl isophenylpropionic acid is characterized in that the water-carrying agent is cyclohexane, benzene, toluene, methylcyclohexane or n-heptane.
Furthermore, the amount ratio of the isophenylpropionic acid to the alcohol, the concentrated sulfuric acid and the water-carrying agent is 1.0:1.5-6.0:0.01-0.25: 2.2-4.5.
Further, the acyl chloride is one of phosphorus oxychloride, phosphorus trichloride, sulfuryl chloride, thionyl chloride or phosgene.
Further, the mass ratio of the isophenylpropionate compound to the Vilsmeier reagent is 1.0: 1.1-4.0.
Further, the mass ratio of the p-aldehyde isopropyl benzoate to formaldehyde and sodium hydroxide is 1.0:1.6-4.5: 2.2-6.6; the concentration of sodium hydroxide is 15-55%.
Furthermore, the molecular ratio of the p-hydroxymethyl isophenylpropionic acid to the hydrobromic acid, the bromide salt and the sulfuric acid is 1.0:1.2-2.6:0.2-1.6: 1.5-3.5.
Further, the bromide salt is one or more of zinc bromide, iron bromide, tin bromide and copper bromide.
Compared with the prior art, the invention has the beneficial technical effects that:
1. the invention utilizes Vilsmeier reagent and aldehyde group on isopropyl benzoate, the para-position selectivity can reach 90-97%, and the para-position bromomethyl selectivity in the traditional process is only 65-80%.
2. The method has the advantages of high reaction selectivity in each step, greatly reduced yield of three wastes, easy recycling of by-products such as phosphoric acid, sodium formate and the like, and capability of concentrating and recycling diluted waste sulfuric acid after bromomethylation.
3. The synthetic method of the p-bromomethyl isophenylpropionic acid can improve the yield of the p-bromomethyl isophenylpropionic acid, greatly reduce the discharge and treatment of three wastes, and is more suitable for the development direction of economic and environment-friendly benign industries advocated by the state.
Detailed Description
The synthesis of bromomethylisopropiophenoic acid provided by the present invention is further illustrated below with reference to the following examples.
Example 1
1. Synthesis of ethyl isophenylpropionate:
putting 150g of isophenylpropionic acid into a 500ml four-mouth reaction bottle, assembling an ester-water separator, adding 40ml of cyclohexane, 2.8g of concentrated sulfuric acid with the concentration of 98% and 15g of ethanol with the concentration of 95%, heating to 75 ℃, keeping the temperature for 30min, slowly adding 130g of ethanol with the concentration of 95% dropwise into the four-mouth reaction bottle, esterifying, adding generated water and ethanol-cyclohexane ternary azeotrope into the ester-water separator, separating an ethanol-water mixture, returning cyclohexane to the esterification reaction bottle, continuously taking the ethanol-water mixture out until no water is separated out, cooling to 30 ℃, adding powdery calcium carbonate to neutralize sulfuric acid until the pH value is 6.0, filtering, evaporating residual ethanol and cyclohexane from filtrate to obtain 162.3g of isophenylpropionic acid ethyl ester, wherein the gas phase detection content is 99.3%, and the molar yield is 91.2%;
2. preparing a Vilsmeier reagent and p-formyl ethyl isopropionate:
putting 110g of anhydrous N, N-Dimethylformamide (DMF) into a 1000ml four-mouth reaction bottle, cooling to-5 ℃ under stirring, keeping 184g of phosphorus oxychloride slowly dropwise at 3 ℃, keeping the temperature at 8 ℃ for 15min after adding, keeping 178.5g of ethyl isophenylpropionate (1.0mol) dropwise at 10 ℃, keeping the temperature at 18 ℃, 35 ℃ and 55 ℃ for 40min after adding, then keeping the temperature at 85 ℃, and monitoring a liquid phase until the ethyl isophenylpropionate completely reacts; after the reaction is finished, cooling to 30 ℃, adding 100ml of cold water for dilution, separating a water layer, washing with 30ml of saturated saline water for one time, and separating a saline layer to obtain 189g of p-aldehyde ethyl isophenylpropionate, wherein the gas phase content is 98.2 percent, and the molar yield is 90.1 percent;
3. p-hydroxymethyl isophenylpropionic acid synthesis:
adding 60g of 20% formaldehyde and 36g of trioxymethylene into a 1000ml four-mouth reaction bottle, heating to 45 ℃ under stirring, dropwise adding 240g of 50% sodium hydroxide (40 ℃) hot solution, controlling the dropwise adding time to be 2.0-2.5h, keeping the temperature to be 60-65 ℃ after the dropwise adding is finished, and keeping the temperature until the reaction on the aldehyde ethyl isopropionate is complete, wherein the pH value is higher than 12, and simultaneously dropwise adding 210g of p-aldehyde ethyl isopropionate (98.2%, 1.0mol) after the pH value is higher than 12; after the reaction is finished, cooling to 30 ℃, acidifying to pH 3.0 by using hydrochloric acid with the concentration of 30%, extracting the organic phase for three times by using 80g of dichloroethane, and combining the extract liquor, wherein the content of the liquid phase is 98.5%;
4. p-bromomethyl isophenylpropionic acid synthesis:
putting the dichloroethane extract into a 1000ml four-mouth bottle, adding 210g of hydrobromic acid with the concentration of 48% and 25g of zinc bromide, heating to 45 ℃ under stirring, dropwise adding 175g of 85% sulfuric acid, carrying out heat preservation reaction at 75 ℃, and carrying out liquid phase detection until the reaction on the hydroxymethyl isophenylpropionic acid is complete; cooling to 35 ℃ to separate waste acid, adding 50ml of water into the organic phase to wash impurities for 2 times, and finally drying with 30ml of saturated saline water to obtain dichloroethane p-bromomethyl isopropyl benzene acid solution; at 65 deg.C and-0.075 MPa, vacuum distilling off 120g dichloroethane solvent, cooling to 45 deg.C, dripping 130ml n-heptane to precipitate p-bromomethyl isophenylpropionic acid, filtering, and drying to obtain 237.6g p-bromomethyl isophenylpropionic acid with liquid phase content of 98.3%.
The total yield of the above step 3 and step 4 was 96.1%.
Example 2
1. Synthesis of iso-phenylpropionic acid isobutyl ester:
150g of iso-phenylpropionic acid is put into a 500ml four-mouth reaction bottle, an ester-water separator is assembled, 65ml of methylcyclohexane, 5.0g of concentrated sulfuric acid with the concentration of 98 percent and 28g of isobutanol with the concentration of 99 percent are added, the temperature is raised to 95 ℃, the temperature is kept for 30min, 120g of isobutanol with the concentration of 99 percent is slowly dripped into the four-mouth reaction bottle for esterification, generated water and isobutanol-methylcyclohexane ternary azeotrope enter the ester-water separator, a small amount of alcohol mixture is separated out, the methylcyclohexane and the isobutanol return to the esterification reaction bottle until no water is separated out; cooling to 30 ℃, adding powdery calcium carbonate to neutralize sulfuric acid until the pH value is 6.0, filtering, evaporating residual isobutanol and methylcyclohexane from filtrate to obtain 204.0g of iso-butyl phenylpropionate, wherein the gas phase detection content is 99.2%, and the molar yield is 98.18%;
2. preparing Vilsmeier reagent and p-formyl iso-phenylpropionic acid isobutyl ester:
putting 169g of anhydrous N-methyl-N-phenyl formamide (MFA) into a 1000ml four-mouth reaction bottle, cooling to-5 ℃ under stirring, slowly dropping 188.5g of phosphorus oxychloride at 8 ℃, keeping the temperature of the solution at 12 ℃ for 30min after the addition, dropping 208g of iso-phenylpropionic acid isobutyl ester at 15 ℃, keeping the temperature of the solution at 25 ℃, 45 ℃ and 75 ℃ for 1h respectively after the addition, then rising to 105 ℃ for heat preservation, and monitoring a liquid phase until the iso-phenylpropionic acid isobutyl ester is completely reacted; after the reaction is finished, cooling to 40 ℃, adding 130ml of water for dilution, separating a water layer, washing once by using 50ml of saturated saline, and separating a saline layer to obtain 235g of p-formyl iso-phenylpropionic acid isobutyl ester, wherein the gas phase content is 97.2 percent, and the molar yield is 97.6 percent;
3. p-hydroxymethyl isophenylpropionic acid synthesis:
adding 60g of 28% formaldehyde and 36g of trioxymethylene into a 1000ml four-mouth reaction bottle, heating to 45 ℃ under stirring, dropwise adding 260g of 50% sodium hydroxide (40 ℃) hot solution, controlling the dropwise adding time to be 3.0-3.5h after the pH is higher than 12, adding 238.5g of p-formyl iso-phenylpropionic acid isobutyl ester (98.2% and 1.0mol), controlling the dropwise adding time to be 3.0-3.5h, keeping the temperature to be 50-55 ℃ after the addition is finished, and keeping the temperature until the p-formyl iso-phenylpropionic acid isobutyl ester completely reacts; after the reaction is finished, cooling to 30 ℃, acidifying to pH 3.5 by using hydrochloric acid with the concentration of 30%, extracting the organic phase for three times by using 80g of dichloroethane, and combining the extract liquor, wherein the content of the liquid phase is 98.8%;
4. p-bromomethyl isophenylpropionic acid synthesis:
putting the dichloroethane extract into a 1000ml four-mouth bottle, adding 245g of hydrobromic acid with the concentration of 48% and 50g of tin bromide, heating to 35 ℃ while stirring, dropwise adding 295g of sulfuric acid with the concentration of 80%, carrying out heat preservation reaction at 60 ℃, and carrying out liquid phase detection until the reaction on the hydroxymethyl isopropyl benzene sulfonic acid is complete; cooling to 35 ℃ to separate waste acid, adding 50ml of water to wash impurities for 2 times, and finally drying with 30ml of saturated saline water to obtain dichloroethane p-bromomethyl isopropyl benzene acid solution; at 65 deg.C and-0.075 MPa, vacuum distilling off 120g dichloroethane solvent, cooling to 45 deg.C, dripping 150ml n-heptane to precipitate p-bromomethyl isophenylpropionic acid, filtering, drying to obtain 240g p-bromomethyl isophenylpropionic acid with liquid phase content of 98.5%.
The total yield of the above step 3 and step 4 was 97.25%.
From the examples 1-2, it can be seen that the p-aldehyde isopropyl benzoate with high selectivity and high yield can be obtained by selecting a proper alcohol esterification and high activity Vilsmeier reagent; the p-hydroxymethyl-iso-phenylpropionic acid with high yield can be obtained by adopting the conditions of reasonable formaldehyde and sodium hydroxide ratio, dropping speed and the like, and then catalytic acidolysis is carried out to obtain the p-bromomethyl-iso-phenylpropionic acid with total yield of 93.14 percent and liquid phase content of 98.5 percent.
The principles and embodiments of the present invention have been described herein using specific examples, which are provided only to help understand the method and the core concept of the present invention; meanwhile, for a person skilled in the art, according to the idea of the present invention, the specific embodiments and the application range may be changed. In view of the above, the present disclosure should not be construed as limiting the invention.

Claims (9)

1. A synthetic method of p-bromomethyl isophenylpropionic acid is characterized in that the synthetic route is as follows:
Figure FDA0003167124810000011
wherein R is1is-CH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH(CH3)2or-C (CH)3)3One of (1);
R2is-CH3、-CH2CH3Or
Figure FDA0003167124810000012
One of (1);
R3is-CH3、-CH2CH3or-CH2CH2CH3One of (1);
R4is-Cl, -Br, H, -CH3、-CH2CH3、-OCH3or-NO2One kind of (1).
2. The method for synthesizing p-bromomethylisopropiopropionic acid according to claim 1, wherein the water-carrying agent is cyclohexane, benzene, toluene, methylcyclohexane or n-heptane.
3. The method for synthesizing p-bromomethylisopropiopropionic acid according to claim 1, wherein the sulfuric acid is concentrated sulfuric acid having a concentration of more than 85%.
4. The method for synthesizing p-bromomethylisopropiophenoic acid as claimed in claim 1, wherein the ratio of the amount of the isoprophenoic acid to the amount of the alcohol, the concentrated sulfuric acid and the water-carrying agent is 1.0:1.5-6.0:0.01-0.25: 2.2-4.5.
5. The method for synthesizing p-bromomethylisopropiopropionic acid according to claim 1, wherein the acid chloride is one of phosphorus oxychloride, phosphorus trichloride, sulfuryl chloride, thionyl chloride and phosgene.
6. The method for synthesizing p-bromomethylisopropiophenoic acid as claimed in claim 1, wherein the mass ratio of the isophenylpropionate compound to the Vilsmeier reagent is 1.0: 1.1-4.0.
7. The method for synthesizing p-bromomethylisopropiophenoic acid as claimed in claim 1, wherein the amount ratio of p-aldehydic isophenylpropionate to formaldehyde and sodium hydroxide is 1.0:1.6-4.5: 2.2-6.6; the concentration of sodium hydroxide is 15-55%.
8. The method for synthesizing p-bromomethylisopropiophenoic acid as claimed in claim 1, wherein the molecular ratio of p-hydroxymethylisophenylpropionic acid to hydrobromic acid, bromide salt and sulfuric acid is 1.0:1.2-2.6:0.2-1.6: 1.5-3.5.
9. The method for synthesizing p-bromomethylisopropiophenoic acid as claimed in claim 1, wherein the bromide salt is one or more of zinc bromide, iron bromide, tin bromide and copper bromide.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100817517B1 (en) * 2006-11-29 2008-03-27 (주)위즈켐 A preparation method of 2-[(4-bromomethyl)phenyl]propionic acid
CN106866404A (en) * 2017-01-04 2017-06-20 昆山力田医化科技有限公司 A kind of synthetic method of the different benzenpropanoic acid of 4 bromomethyl
CN111454145A (en) * 2020-05-13 2020-07-28 张明 Preparation method of p-bromomethyl isophenylpropionic acid

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100817517B1 (en) * 2006-11-29 2008-03-27 (주)위즈켐 A preparation method of 2-[(4-bromomethyl)phenyl]propionic acid
CN106866404A (en) * 2017-01-04 2017-06-20 昆山力田医化科技有限公司 A kind of synthetic method of the different benzenpropanoic acid of 4 bromomethyl
CN111454145A (en) * 2020-05-13 2020-07-28 张明 Preparation method of p-bromomethyl isophenylpropionic acid

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