CN106699559A - Method for preparing loxoprofen sodium - Google Patents

Abstract

The present invention relates to the technical field of organic synthesis, specifically a preparation process of loxoprofen sodium. The present invention provides a compound with the structure of formula 5 and provides its preparation method and application. The loxoprofen sodium prepared by this scheme has high purity and strong industrial operation, so it has a good application prospect.

Description

A kind of preparation technology of loxoprofen sodium

technical field

The invention relates to the technical field of organic synthesis, in particular to a preparation process of loxoprofen sodium.

Background technique

Loxoprofen sodium belongs to phenylpropionic acid non-steroidal anti-inflammatory drugs, first developed by Japan Sankyo Co., Ltd., its chemical name is: 2-[4-(2-oxocyclopentane-1-ylmethyl)benzene Base] sodium propionate, the structural formula is as follows:

Chinese Journal of Medicinal Chemistry 20 (1) 25-28, 2010, using 4-methylacetophenone as raw material, compound I was obtained through sodium borohydride reduction, and compound I was directly chlorinated without purification to obtain compound II, which was obtained through phase transfer Compound III is obtained by cyanidation in the presence of a catalyst, and compound IV is obtained after compound III is heated, hydrolyzed and acidified under basic conditions. Using benzoyl peroxide as an initiator to initiate the bromination reaction, the compound V is prepared, the compound V is esterified with methanol to obtain the compound VI, and the compound VI is condensed with 2-ethoxycarbonylcyclopentanone under alkaline conditions to obtain the compound VII , then use the HBr that mass fraction is 48% to obtain loxoprofen acid in the heating hydrolysis decarboxylation in acetic acid, and then make loxoprofen sodium, its synthetic route is as follows:

Chinese Journal of New Drugs, Volume 9, No. 11, 2000, 765-767 discloses a similar synthetic route:

Chinese Journal of Pharmaceutical Industry 1998, 29 (12), 531-533 prepares compound 2 with the reaction of benzene methane and 2-chloropropionyl chloride, and compound 2 reacts with neopentyl glycol under the catalysis of TsOH to obtain compound 3, and then 2- Compound 4 was obtained under the action of zinc tolylpropionate, compound ₄ reacted with Br2 to obtain compound 5, compound 5 was esterified to obtain compound 6, and then reacted with 2-ethoxycarbonyl cyclopentanone, acidified, and formed into a salt Obtain loxoprofen sodium, its synthetic route is as follows:

The above traditional techniques all take the product obtained by the condensation of p-bromocresyl propionic acid or its ester and 2-ethoxycarbonyl cyclopentanone as a key intermediate, and then through decarboxylation, salify to obtain loxoprofen sodium; in view of loxoprofen The good drug prospect of sodium profen sodium, it is necessary to develop new process route, to overcome shortcomings such as reaction route is long, environmental pollution is big, be unfavorable for suitability for industrialization in the prior art.

Contents of the invention

In order to overcome the technical problems existing in the prior art, the present invention adopts the following technical solutions:

In a first aspect, the present invention provides a compound having the following formula 5 structure:

Wherein R represents a C ₁ -C ₂₀ alkyl group.

Preferred compounds of formula V have the following structure of formula 5:

In a second aspect, the present invention provides a method for preparing a compound having a structure of formula 5: prepared by reacting 1-(4-morpholine) cyclopentene with compound 4:

The 1-(4-morpholine) cyclopentene is obtained from morpholine and cyclopentanone under the catalysis of p-toluenesulfonic acid.

For the preparation of the compound of formula 5, the preferred reaction solvent is well known in the art, such as alkane compound hexane, heptane, cyclohexane, pentane, etc.; aromatic compound benzene, toluene, xylene, etc.; preferred Aromatic compounds, their water separation effect is relatively ideal, which can increase the reaction rate. The preferred reaction temperature is 60-140°C.

The preparation of the compound of formula 4 described therein can be summarized by following reaction equation:

The specific description is as follows:

(1) 1-(1-chloromethyl)-4-methylbenzene is reacted with magnesium and carbon dioxide gas is introduced to obtain the compound of formula 1.

The preferred temperature of the reaction of 1-(1-chloromethyl)-4-methylbenzene and magnesium is -10～60°C; the more preferred reaction temperature is -10～20°C, at this preferred temperature, it can effectively Avoid self-coupling after 1-(1-chloromethyl)-4-methylbenzene forms a Grignard reagent, that is, avoid the generation of the by-product of the following formula A structure:

The preferred reaction solvent of this step reaction is an ether solvent, such as tetrahydrofuran, dimethyltetrahydrofuran, diethyl ether and the like.

(2) The compound of formula 1 is prepared by free radical reaction with NBS in the presence of azobisisobutyronitrile or benzoyl peroxide to obtain the compound of formula 2.

The preferred reaction temperature of the reaction is 20-80°C, and the more preferred reaction temperature is 35-45°C. Since the benzylic free radical reaction is difficult to control, the reaction at this temperature can effectively suppress the occurrence of side reactions.

The preferred molar ratio of the compound of formula 1 to NBS is 1: (0.7-1.5); more preferably 1: (0.8-0.95), at this molar ratio, although the raw material cannot be completely converted, it can effectively Inhibit the occurrence of dibrominated side reactions, thereby effectively improving the yield and purity of reaction products.

Chinese Journal of New Drugs, Volume 9, No. 11, 2000, 765-767 adopts bromine as a reaction reagent, and the reaction repetition effect is poor, and the repeated yield is 30-40% by the inventor, which restricts the industrial operability of this step.

(3) The compound of formula 2 is reacted with methanol under the catalysis of solid superacid to prepare the compound of formula 3.

Traditional processes mostly use concentrated sulfuric acid as a catalyst, which will produce a large amount of waste acid that cannot be recovered, which is not friendly to the environment. The preparation of compound 3 by using solid superacid as catalyst can be recycled, greatly reducing the discharge of waste, which is more friendly to the environment and belongs to a green synthesis process.

(4) The compound of formula 3 is converted into the compound of formula 4.

The first reaction condition: the compound of formula 3 is reacted with dimethyl sulfoxide in the presence of a base to obtain the compound of formula 4.

Wherein said alkali is preferably sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate.

The molar ratio of the compound of formula 3 to the base is preferably 1: (1-2).

The second reaction condition:

The compound of formula 3 can obtain compound 4 in the presence of sodium periodate or potassium periodate.

The reaction is preferably carried out in the presence of dimethylformamide or dimethylacetamide.

The third reaction condition:

Compound 4 is obtained by reacting the compound of formula 3 with hexamethylenetetramine under an acid catalyst, and then treating with acid.

The acid can be acetic acid, sulfuric acid, trifluoroacetic acid, formic acid, hydrochloric acid, dilute nitric acid, phosphoric acid and the mixed acids of these acids.

The crude products obtained by the first two synthetic methods are not clean and require chromatographic separation. The crude product obtained by the third synthetic method is relatively clean, and can be directly used in the next step reaction without refining, and the preferred acid is hydrochloric acid.

In a third aspect, the present invention provides the use of the compound of formula 5 for the preparation of loxoprofen sodium, which can be summarized by the following reaction equation:

The specific description is as follows:

(5) The compound of formula 5 is hydrogenated by palladium carbon or Raney nickel to obtain the compound of formula 6.

The preferred hydrogen pressure is 0.1-0.5Mpa, the preferred reaction temperature is -10-30°C, and the preferred reaction time is 2-20 hours.

Among them, the reaction selectivity of Raney nickel is higher than that of palladium carbon, the product obtained is cleaner, and the reaction is easy to control.

During the hydrogenation reduction of compound 5, the product 6 will be over-reduced, and react according to the following reaction equation:

resulting in a decrease in productivity. The method adopts low-pressure, low-temperature conditions for reduction. Although the reaction time is long, the occurrence of side reactions is effectively suppressed, and the yield of the product 6 is improved.

(6) The compound of formula 6 can obtain loxoprofen sodium under the action of alkali.

The base may be sodium hydroxide or potassium hydroxide.

Similarly, according to the technical scheme provided above in the present invention, those skilled in the art can easily obtain the following synthetic route 2:

Wherein the definition of R is the same as above.

The loxoprofen sodium product prepared by the technical scheme disclosed in the invention has high purity and strong industrial operation, so it has good application prospects.

detailed description

In order to better understand the content of the present invention, the following will be further described in conjunction with specific examples, but the specific implementation is not a limitation to the content of the present invention.

Embodiment 1: the preparation of 2-(4-methylphenyl) propionic acid (compound 1)

Take a 250ml three-neck flask, add a constant pressure dropping funnel, put magnesium chips (2.70g 112.2mmol) into the reaction flask, and replace it with nitrogen three times for protection. 1-(1-Chloromethyl)-4-methylbenzene (15.76g 102.0mmol) was added into THF (100ml) and mixed evenly, then placed in a constant pressure dropping funnel. Add 1-(1-chloromethyl)-4-methylbenzene/THF (10ml) solution dropwise to the reaction flask at room temperature (20-25°C), turn on magnetic stirring, and the temperature in the reaction flask gradually rises to 50°C. Add the remaining 1-(1-chloromethyl)-4-methylbenzene/THF solution dropwise at 45-50°C. After the dropwise addition is completed, keep the reaction at 45-50°C for 2.0 hours. After the heat preservation is over, lower the temperature to 0°C, and pass carbon dioxide gas into the reaction liquid at 0-5°C until the reaction is complete. After the reaction, add 20ml of water to the reaction bottle to quench the reaction, add concentrated hydrochloric acid strips at 0-5°C, pH=6, separate the organic phase, add 50ml MTBE to the aqueous phase for extraction once, combine the organic phases, add 100ml saturated saline to wash once . Then add 5% NaOH aqueous solution (90ml 112.2mmol) and stir at 20-25°C for 10min, then separate the aqueous phase and discard the organic phase. The aqueous phase was washed with MTBE (50ml), then concentrated hydrochloric acid was added to adjust the pH to 6, and then extracted twice with MTBE (80ml×2), the combined organic phase was washed once with saturated brine (100ml), dried over anhydrous magnesium sulfate, and filtered. Concentrate to dryness to obtain 2-(4-methylphenyl)propionic acid (6.0 g 36.54 mmol) as light yellow oily liquid, with a molar yield of 35.8% and a HPLC purity of 81.3%.

Embodiment 2: the preparation of 2-(4-methylphenyl) propionic acid (compound 1)

Take a 250ml three-neck flask, add a constant pressure dropping funnel, put magnesium chips (3.30g 135.8mmol) into the reaction flask, and replace it with nitrogen three times for protection. 1-(1-Chloromethyl)-4-methylbenzene (20.0g 129.3mmol) was added into THF (150ml) and mixed evenly, then placed in a constant pressure dropping funnel. Add 1-(1-chloromethyl)-4-methylbenzene/THF (10ml) solution dropwise to the reaction flask at room temperature (20-25°C), turn on the magnetic stirring, and gradually increase the temperature in the reaction flask to 35°C Quickly transfer the reaction vial to a low temperature bath to cool down to 10°C. Add the remaining 1-(1-chloromethyl)-4-methylbenzene/THF solution dropwise at 10-15°C. After the dropwise addition is completed, keep the reaction at 10-15°C for 1.5h. After the heat preservation is over, lower the temperature to 0°C, and pass carbon dioxide gas into the reaction liquid at 0-5°C until the reaction is complete. After the reaction, add 30ml of water to the reaction bottle to quench the reaction, add concentrated hydrochloric acid strips at 0-5°C, pH=6, separate the organic phase, add 80ml MTBE to the water phase for extraction once, combine the organic phases, add 150ml saturated saline to wash once . Then add 5% NaOH aqueous solution (114ml 142.23mmol) and stir at 20-25°C for 10min, then separate the aqueous phase and discard the organic phase. The aqueous phase was washed with MTBE (100ml), then concentrated hydrochloric acid was added to adjust the pH to 6, and then extracted twice with MTBE (120ml×2), the combined organic phase was washed once with saturated brine (150ml), dried over anhydrous magnesium sulfate, and filtered. Concentrate to dryness to obtain 2-(4-methylphenyl)propionic acid (14.57g 88.73mmol) as light yellow oily liquid, with a molar yield of 68.6% and an HPLC purity of 89.2%.

Embodiment 3: Preparation of 2-(4-methylphenyl) propionic acid (compound 1)

Take a 3000ml three-neck flask, add a constant pressure dropping funnel, put magnesium chips (56.6g 2.33mol) and THF (300ml) into the reaction flask, and replace it with nitrogen three times for protection. 1-(1-Chloromethyl)-4-methylbenzene (300.0g 1.94mmol) was added to THF (1500ml) and mixed evenly, then placed in a constant pressure dropping funnel in batches. Add 1-(1-chloromethyl)-4-methylbenzene/THF (30ml) solution dropwise to the reaction flask at room temperature (20～2-*5°C), turn on the mechanical stirring, and the temperature in the reaction flask gradually rises to After 30°C, quickly transfer the reaction bottle to a low-temperature bath to cool down to 0°C. Add the remaining 1-(1-chloromethyl)-4-methylbenzene/THF solution dropwise at -5~5°C. After the dropwise addition was completed, the mixture was incubated at -5 to 5°C for 1.5 hours. After the heat preservation is over, pass carbon dioxide gas into the reaction solution at 0-5°C until the reaction is complete. After the reaction, add 300ml of water to the reaction bottle to quench the reaction, add concentrated hydrochloric acid strips at 0-5°C, pH = 6, separate the organic phase, add 1000ml MTBE to the water phase for extraction once, combine the organic phases, add 1200ml saturated saline to wash once . The organic phase was concentrated under reduced pressure to about 1200ml, then 10% NaOH aqueous solution (860ml 2.14mol) was added, stirred at 20-25°C for 10min, the aqueous phase was separated, and the organic phase was discarded. The aqueous phase was washed with MTBE (800ml), then concentrated hydrochloric acid was added to adjust the pH to 6, and then extracted twice with MTBE (800ml×2), the combined organic phase was washed once with saturated brine (800ml), dried over anhydrous magnesium sulfate, and filtered. Concentrate to dryness to obtain 2-(4-methylphenyl)propionic acid (274.8 g 1.67 mol) as light yellow oily liquid, with a molar yield of 86.0% and an HPLC purity of 97.9%.

¹ H NMR (400MHz, CDCl ₃ ) δ1.48(d, 3H, J=7.2HZ), 2.32(s, 3H), 3.67～3.72(m, 1H), 7.13(d, 2H, J=7.6HZ) , 7.20 (d, 2H, J=8.0HZ).

Embodiment 4: Preparation of 2-(4-bromomethylphenyl) propionic acid (compound 2)

Add 34.02g (0.207mol) 2-(4-methylphenyl) propionic acid, 350ml carbon tetrachloride, 52.41g (0.294mol) N-bromosuccinimide, 0.80g of azobisisobutyronitrile (AIBN), heated to reflux. The reaction was followed by HPLC until the conversion of the starting material was complete. After the reaction was complete, the material was concentrated to dryness. 150 ml of methyl tert-butyl ether was added to the residue, followed by stirring for 2 hours. Suction filtration, filter cake washed with 30ml methyl tert-butyl ether. The filtrate was concentrated to dryness, 10ml of methyl tert-butyl ether and 90ml of hexane were added to the residue, and the slurry was beaten at 20-25°C for 1 hour. After suction filtration, the filter cake was rinsed with 30ml of hexane, and then dried under reduced pressure at 40°C. 15.53 g (0.064 mol) of white solid, namely 2-(4-bromomethylphenyl)propionic acid, was obtained, with a molar yield of 30.9%. HPLC purity 85.32%.

Embodiment 5: Preparation of 2-(4-bromomethylphenyl) propionic acid (compound 2)

Add 34.02g (0.207mol) 2-(4-methylphenyl) propionic acid, 350ml dichloromethane, 52.41g (0.294mol) N-bromosuccinimide, 0.80 g azobisisobutyronitrile (AIBN), heated to reflux. The reaction was followed by HPLC until the conversion of the starting material was complete. After the reaction was complete, the material was concentrated to dryness. 150 ml of methyl tert-butyl ether was added to the residue, followed by stirring for 2 hours. Suction filtration, filter cake washed with 30ml methyl tert-butyl ether. The filtrate was concentrated to dryness, 10ml of methyl tert-butyl ether and 90ml of hexane were added to the residue, and the slurry was beaten at 20-25°C for 1 hour. After suction filtration, the filter cake was rinsed with 30ml of hexane, and then dried under reduced pressure at 40°C. 26.81 g (0.110 mol) of white solid, namely 2-(4-bromomethylphenyl)propionic acid, was obtained, with a molar yield of 53.3%. HPLC purity 94.5%.

Embodiment 6: Preparation of 2-(4-bromomethylphenyl) propionic acid (compound 2)

Add 34.55g (0.210mol) 2-(4-methylphenyl) propionic acid, 350ml dichloromethane, 33.71g (0.189mol) N-bromosuccinimide, 0.80 g azobisisobutyronitrile (AIBN), heated to reflux. The reaction was tracked by HPLC, and the reaction was stopped when the starting material was <20% (peak area). After the reaction was complete, the material was concentrated to dryness. 150 ml of methyl tert-butyl ether was added to the residue, followed by stirring for 2 hours. Suction filtration, filter cake washed with 30ml methyl tert-butyl ether. The filtrate was concentrated to dryness, 15ml of methyl tert-butyl ether and 90ml of hexane were added to the residue, and the slurry was beaten at 20-25°C for 1 hour. After suction filtration, the filter cake was rinsed with 40ml of hexane, and then dried under reduced pressure at 40°C. 42.05 g (0.173 mol) of white solid, namely 2-(4-bromomethylphenyl)propionic acid, was obtained with a molar yield of 83.6%. HPLC purity 98.7%.

¹ H NMR (400MHz, CDCl ₃ ) δ1.50(d, 3H, J=7.2HZ), 3.71～3.77(m, 1H), 4.48(s, 2H), 7.30(d, 2H, J=8.0HZ) , 7.36 (d, 2H, J=8.4HZ).

Embodiment 7: Preparation of 2-(4-bromomethylphenyl) methyl propionate (compound 3)

2-(4-Bromomethylphenyl)propionic acid (compound 2, 30g, 123.41mmol)) was put into a 250ml three-necked flask, and methanol (90ml) and concentrated sulfuric acid (6.0g) were sequentially added thereto. Stir the reaction at 0-5°C for 16h. After the reaction was completed, sodium carbonate (18.5 g, 17.45 mmol) was added in batches to the reaction liquid, and stirred for 2 hours. When the pH of the reaction solution was 8, filter with suction and wash with methanol (20ml×2). The filtrate was concentrated to dryness under reduced pressure to obtain 30.14 g (117.24 mmol) of methyl 2-(4-bromomethylphenyl)propionate as a pale yellow oily liquid with a molar yield of 95.0% and a HPLC purity of 98.5%.

¹ H NMR (400MHz, CDCl ₃ ) δ1.49(d, 3H, J=7.2HZ), 3.65(d, 3H, J=3.6HZ), 3.71～3.73(m, 1H), 4.48(s, 2H) , 7.27 (d, 2H, J=8.0HZ), 7.35 (d, 2H, J=8.4HZ).

Example 8: Preparation of 2-(4-bromomethylphenyl) methyl propionate (compound 3)

2-(4-bromomethylphenyl)propionic acid (compound 2, 12.16g, 50.02mmol)) was dropped into a 100ml three-necked flask, and methanol (45ml) and solid superacid (1.0g) were added successively thereto. Stir the reaction at 10-15°C for 24 hours. Filter and recover the catalyst. The filtrate was concentrated to dryness under reduced pressure, and 150 ml of ethyl acetate, 1.0 ml of sodium carbonate, and 100 ml of water were added to the residue, and stirred for 5 minutes. Separate layers, take the upper organic phase and discard the lower aqueous phase. The organic phase was concentrated to dryness under reduced pressure to obtain 12.13 g (47.18 mmol) of methyl 2-(4-bromomethylphenyl)propionate as a yellow oily liquid with a molar yield of 94.3% and a HPLC purity of 98.5%.

¹ H NMR (400MHz, CDCl ₃ ) δ1.49(d, 3H, J=7.2HZ), 3.65(d, 3H, J=3.6HZ), 3.71～3.73(m, 1H), 4.48(s, 2H) , 7.27 (d, 2H, J=8.0HZ), 7.35 (d, 2H, J=8.4HZ).

Example 9: Preparation of methyl 2-(4-formylphenyl)propionate (compound 4)

Add 2.70g (10.50mmol) 2-(4-(bromomethyl)phenyl) methyl propionate, 40ml dimethyl sulfoxide, 1.40g (16.67mmol) potassium bicarbonate successively in the 100ml single-neck round bottom flask, Start magnetic stirring. Heat up to 130°C and keep warm for reaction. The reaction was monitored by TLC (developing solvent: ethyl acetate:n-hexane=1:5) until the conversion of the starting material was complete. After the reaction was completed, the reaction feed solution was poured into 100ml of ethyl acetate, 80ml of water was added, and stirred for 5 minutes. Separate layers, take the upper organic phase and discard the lower aqueous phase. The organic phase was washed with 50 ml of 5% aqueous sodium chloride and dried with 0.5 g of magnesium sulfate. Filter and concentrate the filtrate to dryness under reduced pressure. The residue was separated by preparative liquid chromatography to obtain 1.19 g (6.19 mmol) of light yellow oil, ie, methyl 2-(4-formylphenyl)propionate, with a molar yield of 59.0% and an HPLC purity of 81.2%.

¹ H NMR (400MHz, CDCl ₃ ) δ1.54(d, 3H, J=7.2HZ), 3.65～3.68(m, 3H), 3.80～3.85(m, 1H), 7.47(d, 2H, J=8.0 HZ), 7.85 (t, 2H, J1 = 1.6HZ, J2 = 6.8HZ), 10.00 (s, 1H).

Example 10: Preparation of methyl 2-(4-formylphenyl)propionate (compound 4)

Add 26.30g (0.102mol) methyl 2-(4-(bromomethyl)phenyl) propionate, 180ml N, N-dimethylformamide, 22.00g (0.103mol) Sodium periodate, start magnetic stirring. Heat up to 150°C and keep warm for reaction. The reaction was monitored by TLC (developing solvent: ethyl acetate:n-hexane=1:5) until the conversion of the starting material was complete. After the reaction was completed, the reaction feed solution was poured into 400ml of ethyl acetate, 500ml of water was added, and stirred for 10 minutes. Separate the layers and get the upper organic phase; the lower aqueous phase extracts the product with 400ml ethyl acetate. The organic phases were combined and washed with 300 ml of 5% aqueous sodium chloride. The organic phase was concentrated to dryness under reduced pressure. The residue was separated by column chromatography, 14.02 g (0.073 mol) of a yellow oily substance, ie methyl 2-(4-formylphenyl)propionate, the molar yield was 71.5%, and the HPLC purity was 83.7%.

¹ H NMR (400MHz, CDCl ₃ ) δ1.54(d, 3H, J=7.2HZ), 3.65～3.68(m, 3H), 3.80～3.85(m, 1H), 7.47(d, 2H, J=8.0 HZ), 7.85 (t, 2H, J1 = 1.6HZ, J2 = 6.8HZ), 10.00 (s, 1H).

Example 11: Preparation of methyl 2-(4-formylphenyl)propionate (compound 4)

In the 50ml single-neck round bottom flask, add 3.0g (11.67mmol) 2-(4-(bromomethyl) phenyl) methyl propionate, 22ml 95% ethanol, 2.45g (17.48mmol) urotropine (6 methylenetetramine), 5ml water, and start magnetic stirring. Heat to reflux. After reacting under reflux for 3 hours, 4.5ml of 36% concentrated hydrochloric acid was added dropwise, and the reaction was continued for 45 minutes. After the reaction is complete, the material is concentrated under reduced pressure at 45°C, and if no fraction appears in the condenser, the concentration is stopped. Add 10ml of water and 60ml of ethyl acetate, and stir for 5 minutes. Separate layers, take the upper organic phase and discard the lower aqueous phase. The organic phase was washed with 15 ml of 5% aqueous sodium chloride and dried with 0.5 g of magnesium sulfate. Filter and concentrate the filtrate to dryness under reduced pressure. 2.0 g (10.4 mmol) of yellow oily substance, namely methyl 2-(4-formylphenyl)propionate, was obtained, with a molar yield of 89.7% and a HPLC purity of 96.6%.

¹ H NMR (400MHz, CDCl ₃ ) δ1.54(d, 3H, J=7.2HZ), 3.65～3.68(m, 3H), 3.80～3.85(m, 1H), 7.47(d, 2H, J=8.0 HZ), 7.85 (t, 2H, J1 = 1.6HZ, J2 = 6.8HZ), 10.00 (s, 1H).

Embodiment 12: Preparation of Compound 5

Add 4.36g (50.00mmol) morpholine, 90ml toluene, 4.42g (52.54mmol) cyclopentanone, and 0.40g p-toluenesulfonic acid to a 250ml three-neck round bottom flask successively, install a water separator and a condenser, and start mechanical stirring . The temperature was raised to reflux, and the reaction was carried out for 4 hours. Cool down to 80°C, add 9.61g (50.00mmol) of methyl 2-(4-formylphenyl)propionate (compound 4), and raise the temperature to reflux. The reaction was continued for 4 hours. After the reaction was completed, the temperature was lowered to 30°C. 7ml of 36% concentrated hydrochloric acid was added dropwise, and stirred for 30 minutes. The layers were separated, and the upper organic phase was taken; the lower aqueous phase was extracted with 50ml of toluene. The organic phases were combined, washed with 50 ml of 5% aqueous sodium chloride, and dried with 2.5 g of magnesium sulfate. Filter and concentrate the filtrate to dryness under reduced pressure. 5ml of ethyl acetate and 40ml of hexane were added to the residue, and the slurry was beaten at 25°C for 2 hours. After filtering, the filter cake was rinsed with 10 ml of hexane, and dried under reduced pressure at 40°C. Obtained 11.27g (43.63mmol) light yellow powder, i.e. (E)-2-(4-((2-oxocyclopentylethylene)methyl)phenyl)propionic acid methyl ester, molar yield 87.26%, HPLC 99.1% purity.

¹ H NMR (400MHz, CDCl ₃ ) δ1.52(d, 3H, J=7.2HZ), 2.00～2.07(m, 2H), 2.41(t, 2H, J1=7.6HZ, J2=8.0HZ), 2.95 ～2.99(m, 2H), 3.67(s, 3H), 3.73～3.78(m, 1H), 7.34～7.37(m, 2H), 7.50(d, 2H, J=8.4HZ).

Embodiment 13: Preparation of compound 6

Add 10g (38.71mmol) (E)-2-(4-((2-oxocyclopentylethylene)methyl)phenyl)propionate methyl ester (compound 5) into a 250ml stainless steel autoclave, and then add ethanol (100 mL) and 5% palladium on carbon (2 g), and seal the apparatus. The air in the kettle was continuously replaced with hydrogen three times. Afterwards, fill in hydrogen, make the pressure inside the kettle P=1Mpa, and react at 70-80°C for 6 hours. The reaction was monitored by TLC (developer ethyl acetate:n-hexane=1:3) until the conversion of the starting material was complete. After the reaction, filter and wash the filter cake with methanol (30ml×2). The filtrate was concentrated to dryness under reduced pressure. The residue was subjected to column chromatography to obtain methyl 2-(4-((2-oxocyclopentyl)methyl)phenyl)propionate (compound 6, 7.24g, 27.8mmol) as a colorless transparent oily liquid. The molar yield is 68.30%, and the HPLC purity is 79.8%.

Embodiment 14: Preparation of Compound 6

Add 10g (38.71mmol) (E)-2-(4-((2-oxocyclopentylethylene)methyl)phenyl)propionate methyl ester (compound 5) into a 250ml stainless steel autoclave, and then add ethanol (100 mL) and 5% palladium on carbon (2 g), and seal the apparatus. The air in the kettle was continuously replaced with hydrogen three times. Afterwards, fill in hydrogen, make the pressure inside the kettle P=1Mpa, and react at 30°C for 8 hours. The reaction was monitored by TLC (developing solvent ethyl acetate:n-hexane=1:3) until the conversion of the starting material was complete. After the reaction, filter and wash the filter cake with methanol (30ml×2). The filtrate was concentrated to dryness under reduced pressure. The residue was subjected to column chromatography to obtain methyl 2-(4-((2-oxocyclopentyl)methyl)phenyl)propionate (compound 6, 7.89 g, 30.3 mmol) as a colorless transparent oily liquid. The molar yield is 78.4%, and the HPLC purity is 87.2%.

Embodiment 15: Preparation of compound 6

Add 10g (38.71mmol) (E)-2-(4-((2-oxocyclopentylethylene)methyl)phenyl)propionate methyl ester (compound 5) into a 250ml stainless steel autoclave, followed by methanol (100 mL) and 5% palladium on carbon (2 g), and seal the apparatus. The air in the kettle was continuously replaced with hydrogen three times. Afterwards, fill in hydrogen, make the pressure inside the kettle P=0.15Mpa, and react at 10-15°C for 14 hours. The reaction was monitored by TLC (developer ethyl acetate:n-hexane=1:3) until the conversion of the starting material was complete. After the reaction, filter and wash the filter cake with methanol (30ml×2). The filtrate was concentrated to dryness under reduced pressure. The residue was subjected to column chromatography to obtain methyl 2-(4-((2-oxocyclopentyl)methyl)phenyl)propionate (compound 6, 9.1 g, 34.96 mmol) as a colorless transparent oily liquid. The molar yield is 90.30%, and the HPLC purity is 97.9%.

¹ H NMR (400MHz, CDCl ₃ ) δ1.23(d, 3H, J=19.6HZ), 1.47～1.58(m, 1H), 1.66～1.77(m, 1H), 1.93～2.00(m, 1H), 2.04～2.16(m, 2H), 2.29～2.37(m, 2H), 2.48～2.53(m, 1H), 3.13(dd, 1H, J＝4.0, 5.2HZ), 3.66(s, 3H), 3.70( d, 1H, J=8.0HZ), 7.12 (d, 2H, J=8.0HZ), 7.21 (d, 2H, J=8.4HZ).

Embodiment 16: the preparation of loxoprofen sodium

Methyl 2-(4-((2-oxocyclopentyl)methyl)phenyl)propionate (compound 6, 38g, 154.28mmol) was put into a 500ml three-necked flask, ethanol (200ml) was added, and the temperature was raised to reflux . Sodium hydroxide solution (20.9 g, mass fraction 30%) was slowly added dropwise, and the drop was completed within 1 hour. After dropping, the material was concentrated to dryness under reduced pressure, and the residue was recrystallized from ethanol-methyl tert-butyl ether to obtain a white powder solid (35.36 g, 131.80 mmol), with a molar yield of 85.43% and an HPLC purity of 99.7%.

Embodiment 17: the preparation of loxoprofen sodium

10g (38.71mmol) (E)-2-(4-((2-oxocyclopentylethylene) methyl) phenyl) methyl propionate (compound 5) was added in a 250ml single-necked round bottom flask, and then Ethyl acetate (130 mL) and Raney Ni (2 g, model A-7F63) were added, and the kettle was purged with hydrogen for three consecutive times. Cool down to -5~0°C, hydrogenation reaction under normal pressure. The reaction was monitored by TLC (developer ethyl acetate:n-hexane=1:5) until the conversion of starting material 5 was complete. After the reaction was completed, it was filtered, and the filter cake was rinsed with ethyl acetate (40ml). The filtrate was concentrated to dryness under reduced pressure to obtain 10.03 g of methyl 2-(4-((2-oxocyclopentyl)methyl)phenyl)propionate of compound 6 as a colorless oil, with a yield of 99.5% and a purity of 99.8% by HPLC.

¹ H NMR (400MHz, CDCl ₃ ) δ1.23(d, 3H, J=19.6HZ), 1.47～1.58(m, 1H), 1.66～1.77(m, 1H), 1.93～2.00(m, 1H), 2.04～2.16(m, 2H), 2.29～2.37(m, 2H), 2.48～2.53(m, 1H), 3.13(dd, 1H, J＝4.0, 5.2HZ), 3.66(s, 3H), 3.70( d, 1H, J=8.0HZ), 7.12 (d, 2H, J=8.0HZ), 7.21 (d, 2H, J=8.4HZ).

Claims (10)

1. a kind of compound with the structure of formula 5：

2. a kind of preparation method of the compound with the structure of formula 5, is prepared by 1- (4- morpholines) cyclopentene with the reaction of compound 4：

3. preparation method according to claim 2, further includes the step of compound of formula 3 is converted into 4 compound of formula：

4. preparation method according to claim 3, the compound of formula 3 reacts with hexa, then with acid treatment after, obtain The described compound of formula 4.

5. the preparation method according to claim 3 or 4, further include the compound of formula 2 under solid superacid as catalyst with methyl alcohol The step of reaction is converted into 3 compound of formula：

6. preparation method according to claim 3, further includes that the compound of formula 1 is deposited in azodiisobutyronitrile or benzoyl peroxide The step of lower and NBS generations radical reaction prepares 2 compound of formula：

7. preparation method according to claim 5, dioxy is passed through after further including 1- (1- chloromethyls) -4- methylbenzenes and reactive magnesium The step of change carbon gas obtains 1 compound of formula：

8. preparation method according to claim 7,1- (1- chloromethyls) -4- methylbenzenes with magnesium are entered under the conditions of temperature -10~10 DEG C Row reaction.

9. a kind of purposes of the compound of formula 5, the compound of formula 6 is obtained through palladium carbon or Raney Ni catalytic hydrogenation.

10. the purposes of compound according to claim 9, further includes that the compound of formula 6 obtains loxoprofen under alkali effect The step of sodium：