CN109809987A

CN109809987A - A kind of new synthetic method of loxoprofen sodium

Info

Publication number: CN109809987A
Application number: CN201711166565.7A
Authority: CN
Inventors: 宫宁瑞
Original assignee: Panjin Gelin Kaimo Technology Co Ltd
Current assignee: Panjin Gelin Kaimo Technology Co Ltd
Priority date: 2017-11-21
Filing date: 2017-11-21
Publication date: 2019-05-28

Abstract

The invention belongs to organic synthesis fields, and in particular to a kind of new synthetic method of loxoprofen sodium.The synthetic method synthetic method is reacted through 4 steps and is made using 2- (4- bromomethyl) phenylpropionic acid as raw material.The present invention uses a kind of new synthetic method of loxoprofen sodium, and yield improves, and industrial prospect is good.

Description

A kind of new synthetic method of loxoprofen sodium

Technical field

The invention belongs to organic synthesis fields, and in particular to a kind of new synthetic method of loxoprofen sodium.

Background technique

Loxoprofen sodium (1oxoprofen sodium) is a kind of important 2- phenylpropionic acid Nonsteroidal anti-inflammatory analgesia Medicine is listed by total company, Japan three in exploitation in 1986, anti-inflammatory, analgesia, refrigeration function with higher, and alimentary canal is bad React small.Compared with clinically similar drugs, feature is mainly reflected in loxoprofen sodium: stronger (clinical effectiveness is good), faster (taking orally 30 minutes plasma concentration, that is, reach to peak values), safer (Small side effects).Another kind of feature is wide indications, clinically can be wide After the general anti-inflammatory and antalgic for being used for rheumatoid arthritis, pain in the loins, scapulohumeral periarthritis, neck shoulder wrist syndrome etc., operation, wound and after extraction Easing pain and diminishing inflammation and the antipyretic-antalgic of acute upper respiratory tract inflammation etc..

Currently, the synthetic route of loxoprofen sodium is mostly more complicated, synthesis yield is low, and bulk pharmaceutical chemicals are expensive and are not easy It obtains.

Summary of the invention

The purpose of the present invention is to provide a kind of new synthetic method of loxoprofen sodium, this method high income, synthesis is simple, It is suitble to industrialized production.

To achieve the goals above, the present invention adopts the following technical scheme: a kind of new synthetic method of loxoprofen sodium, is somebody's turn to do Synthetic method is reacted through 4 steps and is made using 2- (4- bromomethyl) phenylpropionic acid as raw material.

A kind of new synthetic method of loxoprofen sodium, the synthetic method include the following steps:

Step 1: by 24.3 g 2- (4- bromomethyl) phenylpropionic acid, 64 g methanol investment reaction flask, stirring evenly, 0 The 19.6 g concentrated sulfuric acids are added dropwise at~5 DEG C, 50 m L water are added, with 200 m L toluene in 6 h that are added dropwise that the reaction was continued Extraction, layering, organic layer are washed with saturated sodium carbonate solution, are washed to neutrality, dry, are concentrated to dryness, are obtained 25.2 g Compound 2- (4- 2-bromomethylphenyl) methyl propionate (I)；Step 2: by l5.7 g 2- carbethoxyl group cyclopentanone, 50 m L Toluene is put into reaction flask, is stirred evenly, and 5.2 g of potassium carbonate is added, and is warming up to reflux, and the 50 above-mentioned preparations of m L are added dropwise 25.7 g compound I toluene solution, drop finishes, continues to be stirred to react 12 h, be down to room temperature, 50 m L water are added, point Layer, water layer is 3.0-4.0 with 8.0 m olL salt acid for adjusting pH value, is extracted with 50 lnL toluene, and toluene is washed Layer, reduced pressure are evaporated off toluene, obtain 29 g compound 2- [4- (1- carbethoxyl group -2- oxo -1- cyclopentyl-methyl) benzene Base] methyl propionate (II)；Step 3: being 48% hydrobromic acid, 30 mL by 31.8 g compound II, 70 mL mass fractions Glacial acetic acid is put into reaction flask, and 8 h of back flow reaction is cooled to room temperature, and 50 mL water are added, and is extracted with 100 mL toluene, Toluene layer saturated common salt water washing, is concentrated to dryness, with ethyl acetate-hexane (volume ratio 1:2) crystallization, mistake It is sour (III) to obtain 20g loxoprofen for filter, drying；

Step 4: 24.6 g loxoprofens sour (III), 100 mL ethyl alcohol being placed in a reaction flask, 2 mol/L are added dropwise at room temperature Sodium hydrate aqueous solution to pH value be 7.0-8.0, drop finishes, and is stirred at room temperature 3 h, and crystallization, filtering obtains crude product, uses Ethyl alcohol-isopropyl ether recrystallization, obtains loxoprofen sodium.

Compared with prior art, effect of the invention is that: the present invention use loxoprofen sodium new method, not only reduce Cost protects environment, and easy to operate, convenient post-treatment, high income, and synthesis is simple, is suitble to industrialized production.

Specific embodiment

Embodiment 1

Step 1: by 24.3 g 2- (4- bromomethyl) phenylpropionic acid, 64 g methanol investment reaction flask, stirring evenly, 0 The 19.6 g concentrated sulfuric acids are added dropwise at~5 DEG C, 50 m L water are added, with 200 m L toluene in 6 h that are added dropwise that the reaction was continued Extraction, layering, organic layer are washed with saturated sodium carbonate solution, are washed to neutrality, dry, are concentrated to dryness, are obtained 25.2 g Compound 2- (4- 2-bromomethylphenyl) methyl propionate (I) is colourless oil liquid, yield 98%, H PL C detection purity It is 96%.

1H-NMR (CDCl3): 1.47 (Hz of d, 3H, J=7.5), 3.63 (S, 3H), 3.72 (q, H, J= 7.5 Hz), 4.45 (S, 2H), 7.26 (dd, 2H, J=1.5,6.5 H z), 7.33 (dd, 2H, J=1.5, 6.5 Hz) .Step 2: by l5.7 g 2- carbethoxyl group cyclopentanone, 50 m L toluene investment reaction flask, stir evenly, 5.2 g of potassium carbonate is added, is warming up to reflux, the toluene solution of 25.7 g compound I of the 50 above-mentioned preparations of m L, drop is added dropwise Finish, continue to be stirred to react 12 h, be down to room temperature, 50 m L water, layering, 8.0 m olL hydrochloric acid tune of water layer are added Section pH value is 3.0-4.0, is extracted with 50 mL toluene, and toluene layer is washed, and reduced pressure is evaporated off toluene, obtains 29 g Compound 2- [4- (1- carbethoxyl group -2- oxo -1- cyclopentyl-methyl) phenyl] methyl propionate (II) is yellow oily liquid , it is 92% that yield 9l%, H PLC, which detects purity,；

1H-NMR (CDCl3): 1.25 (Hz of d, 3H, J=7.5), 1.47 (H z of d, 3H, J=7.0), 1.63- 1.65 (m, 1H), 1. 89-1.96 (m, 2H), 2.03~2.O7 (m, 1H), 2.39-2.43 (m, 2H ), 3.o6 (I-Iz of d, 1H, J=14.0), 3.19 (d, 1H ,=l3.5 H z), 3.65 (S, 3H), 3.68 (H z of q, 1H, J=7.5), 4. 16 (H z of q, 2H, J=7.5), 7.09 (d, 2H, J=8.0 H z), 7.18 (H z of d, 2H, J=8.0).

Step 3: being 48% hydrobromic acid, 30 mL glacial acetic acid investment by 31.8 g compound II, 70 mL mass fractions In reaction flask, 8 h of back flow reaction is cooled to room temperature, and 50 mL water are added, and is extracted with 100 mL toluene, and toluene layer is used full And brine It, it is concentrated to dryness, with ethyl acetate-hexane (volume ratio 1:2) crystallization, filters, drying, It is sour (III) to obtain 20g loxoprofen, is white solid, yield 81%, HPLC detection level is 98%, mp108-110 ℃ ；

1H-NMR (CDCl3): 1.49 (H z of d, 3H, J=7.0), 1.51-1.56 (m, 1H), 1.7O-1. 74 (m, 1H), 1.94-1.98 (ITI, 1H), 2.07-2.13 (m, 2H), 2.3l-2.34 (m, 2H), 2.5l (dd, 1H, J=4.0,14.0 H z), 3.13 (dd, 1H, J: 4.0,14.0 H z), 3.70 (q, 1H, J= 7.0 H z), 7.13 (H z of d, 2H, J=8.0), 7.23 (H z of d, 2H, J=8.0).

Step 4: 24.6 g loxoprofens sour (III), 100 mL ethyl alcohol being placed in a reaction flask, 2 are added dropwise at room temperature The sodium hydrate aqueous solution of mol/L to pH value is 7.0-8.0, and drop finishes, and 3 h, crystallization are stirred at room temperature, and filtering obtains slightly Product are recrystallized with ethyl alcohol-isopropyl ether, obtain 25 g of loxoprofen sodium, are white solid, yield 82%, H PLC Detection level is 196-198 DEG C of 99%, mp.

The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.

Claims

1. a kind of new synthetic method of loxoprofen sodium, which is characterized in that the synthetic method is with 2- (4- bromomethyl) phenylpropionic acid For raw material, reacts and be made through 4 steps.

2. a kind of new synthetic method of loxoprofen sodium according to claim 1, which is characterized in that the synthetic method includes Following steps:

Step 1: by 2- (4- bromomethyl) phenylpropionic acid, methanol investment reaction flask, stirring evenly, be added dropwise at 0~5 DEG C The concentrated sulfuric acid, 6 h that are added dropwise that the reaction was continued are added water, are extracted with toluene, is layered, organic layer is washed with saturated sodium carbonate solution It washs, is washed to neutrality, it is dry, it is concentrated to dryness, obtains compound 2- (4- 2-bromomethylphenyl) methyl propionate (I)；

Step 2: by 2- carbethoxyl group cyclopentanone, toluene investment reaction flask, stirring evenly, potassium carbonate is added, is warming up to back The toluene solution of the compound I of above-mentioned preparation is added dropwise in stream, and drop finishes, continues to be stirred to react 12 h, is down to room temperature, and water is added, Layering, water layer is 3.0-4.0 with salt acid for adjusting pH value, is extracted with toluene, and toluene layer is washed, and toluene is evaporated off in reduced pressure, Obtain 29 g compound 2- [4- (1- carbethoxyl group -2- oxo -1- cyclopentyl-methyl) phenyl] methyl propionate (II)；Step 3: by compound II, mass fraction be hydrobromic acid, glacial acetic acid is put into reaction flask, and 8 h of back flow reaction is cooled to room temperature, adds Enter water, extracted with toluene, toluene layer saturated common salt water washing is concentrated to dryness, with ethyl acetate-hexane crystallization, mistake It is sour (III) to obtain loxoprofen for filter, drying；

Step 4: loxoprofen sour (III), ethyl alcohol being placed in a reaction flask, the sodium hydrate aqueous solution being added dropwise at room temperature to pH Value is 7.0-8.0, and drop finishes, and 3 h, crystallization are stirred at room temperature, and filtering obtains crude product, is recrystallized with ethyl alcohol-isopropyl ether, obtains Lip river Suo Luofen sodium.