| Loxoprofen sodium’s chemical name is sodium 2-[4-(2-oxocyclopentyl-l-me-thyl)phenyl]propionate dihydrate.Loxoprofen sodium is a non-steroidal anti-infl-ammatory drug of phenylpropionic acid,which has the advantages of good anti-inflammatory effect and small side effects.The market demand for loxoprofen sodium is large,so it is of great significance to explore a green and efficient synthesis process of loxoprofen sodium.The current production process of loxoprofen sodium was mainly produced by process such as 1)methylation and hydrolysis of phenylacetonitrile to for 2-phenylpropionic acid(PPA);2)PPA by bromomethylation to form 2-(4-brom-omethylphenyl)propionic acid(BMPPA);3)BMPPA was esterified,condensed,decarboxylated,and salted to form loxoprofen sodium.There were still many problems in the process route that need to be improved.For example,1)In the preparation of PPA,methylation reagents such as dimethyl sulfate and halomethane were used,which have problems such as high toxicity and generation of halogen salts;2)In the preparation of BMPPA,it was necessary to consume a large amount of sulfuric acid as a catalyst,and it is difficult to apply acid water,which caused a problem of large amount of waste acid;3)Preparation of loxoprofen sodium when the condensation reagent 2-oxocyclopentanecarboxylate was expensive,the process economy as poor.In view of the problems in the above process,this paper has studied it.The main work is as follows:1.Green methylation of phenylacetonitrile was achieved based on a pressurized reaction-rectification technique.Using phenylacetonitrile as a raw material,dimethyl carbonate is also used as a methylating agent and a reaction solvent to react with sodium methoxide to form 2-phenylpropionitrile.By the pressure reaction-rectification coupling technology,the reaction rate is increased by increasing the system pressure to maintain a higher reaction temperature,and at the same time,the appropriate reaction pressure is maintained by the exhaust gas pressure control,and the by-product methanol of the methylation reaction is The carbon dioxide is distilled out of the system,and the dimethyl carbonate having a higher boiling point is distilled out as little as possible to promote the positive movement of the main reaction and increase the conversion rate;after the reaction is completed,the excess dimethyl carbonate is recovered.The obtained 2-phenylpropionitrile was hydrolyzed in an aqueous solution of sodium hydroxide,and then acidified to form PPA.The optimized process conditions are:methylation reaction temperature is 180℃,reaction pressure is 2 MPa,reaction time is 5 h,the molar ratio of phenylacetonitrile:sodium methoxide:dimethyl carbonate is 1:0.2:5,hydrolysis reaction temperature is 100℃,product 2-phenylpropionic acid yield is 84.2%,and purity is 99%.Compared to the literature reported in the process,the reaction time is reduced by 67%and the catalyst usage is reduced by 87%.2.Based on gas phase circulation and reaction-extraction technology,the synthesis process of BMPPA was improved.High-efficiency bromomethylation of PPA was achieved by using hydrobromic acid and paraformaldehyde as bromination methylation reagents and zinc bromide as catalyst.The hydrogen bromide produced by the hydrolysis of phosphorus tribromide and the reaction gas phase were forcedly circulated into the liquid phase of the reactor to promote mass transfer and maintain a higher hydrogen bromide concentration in the reaction system;a suitable extractant,n-heptane,was screened in the reaction.The reactants were well dissolved at the temperature,and the reaction product ends to crystallize the product.The crystallization mother liquor main ingredient was n-heptane,and water phase,were applied to the next round reaction to improve the utilization rate of raw materials and reduce waste liquid discharge.The by-product phosphorous acid which was hydrolyzed by phosphorus tribromide was additionally recovered.The optimized process conditions are:zinc bromide in the reaction system:hydrobromic acid:paraformaldehyde:PPA in a molar ratio of 0.5:2.5:1.5:1,and a reaction temperature of 80℃.Due to the use of gas phase circulation and liquid phase application,the catalyst zinc bromide is basically not consumed,the hydrogen bromide consumption equivalent is generally less than 1.05,the target product yield after purification is 86.7%,the purity is 98%,and the aqueous phase and the organic phase are used more.The product yield is still stable.Compared with the existing process,the waste acid amount of the process is reduced by 80%.3.The process for preparing loxoprofen sodium by enamine alkylation was developed.Esterification of BMPPA with methanol to prepare methyl 2-(4-bromomethylphenyl)propionate,and cyclopentanone with morpholine,azeotrope through toluene water,condensation to form enamine n-(1-cyclopentenyl)morpholine,methyl 2-(4-bromomethylphenyl)propionate and n-(1-cy clopenteny l)morpholine enamine after the alkylation reaction,the product was hydrolyzed by hydrochloric acid,the oil phase was obtained from loxoprofen,and then salt was formed in sodium hydroxide ethanol solution to obtain loxoprofen sodium.After the aqueous phase was neutralized with sodium hydroxide,the morpholine was recovered to recycle.The optimized process conditions are:esterification reaction temperature is 0～10℃(ice bath);morpholine:cyclopentanone molar ratio is 3:1 in the condensation reaction,using toluene as azeotropic water reagent;enamine The reaction temperature was 110℃,the reaction time was 10 h,the yield of loxoprofen sodium is 65.0%,and the purity is 99%.The morpholine recovery rate is 90%.This process realizes the condensation of cyclopentanone with methyl 2-(4-bromomethylphenyl)propionate.Compared with the existing process,the raw materials are cheap and have better economic advantages..The improved process has a total yield of 47.5%for loxoprofen sodium and 99%for loxoprofen sodium.The products of each step are verified by MS,1H NMR and 13C NMR,and the structure is correct.In this paper,the high-efficiency bromomethylation of 2-phenylpropionic acid is realized by the pressure reaction-rectification to realize the methylation of phenylacetonitrile and the reaction-extraction process based on gas phase circulation. |
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