A method for preparing loxoprofen acid

Abstract

This invention provides a method for preparing loxoprofen acid, relating to the field of biomedical technology. The method involves mixing compound 1, 1-(1-pyrrolidine)cyclopentene, and an organic solvent, performing a condensation reaction, and then hydrolyzing the mixture under acidic conditions to obtain loxoprofen acid; wherein X is a halogen, and R includes -CN or -CONH2. This invention uses compound 1 and 1-(1-pyrrolidine)cyclopentene as starting materials, and prepares loxoprofen acid through a condensation reaction followed by hydrolysis under acidic conditions. The product yield is high, the purity is high, and continuous production of loxoprofen acid is possible. The operation is simple, generates little waste, is environmentally friendly, and has low production costs, making it suitable for industrial production. Furthermore, the preparation method provided by this invention concentrates the solvent after the condensation reaction to allow for subsequent hydrolysis, eliminating the need for separation and purification of the intermediate obtained from the condensation reaction, simplifying the operation steps, generating less waste, and being environmentally friendly.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of biological medicine, and particularly relates to a preparation method of loxoprofen acid. BACKGROUND

[0002] Loxoprofen sodium, chemical name 2-[4-[(2-oxocyclopentyl)methyl]phenyl]propanoic acid sodium dihydrate, is developed by Sankyo Company of Japan, and is marketed in Japan in 1986. It is an important 2-phenylpropionic acid non-steroidal analgesic and anti-inflammatory drug, and is widely used for analgesic and anti-inflammatory of rheumatoid arthritis, lumbago, shoulder periarthritis, cervical shoulder wrist syndrome and acute upper respiratory tract inflammation. Its characteristics are strong analgesic effect, fast onset and small adverse reactions.

[0003]

[0004] Japanese patent JP2000327603 discloses that hexanedioate is used as a starting material, and an intermediate 2-oxocyclopentane carboxylate is obtained by cyclization under sodium methoxide. Then, the intermediate is subjected to intermolecular condensation with 2-(4-halogenmethylphenyl)propionate, and the condensate is hydrolyzed in an acidic aqueous solution to obtain loxoprofen acid. The reaction route is as follows:

[0005]

[0006] Japanese patent JP2001081066 discloses an electrochemical method for preparing loxoprofen acid. The method uses p-halogenmethylstyrene as a starting material, and loxoprofen acid is prepared through condensation, hydrolysis, bromination, electrolysis and reduction. The reaction route is as follows:

[0007]

[0008] Chen Fen'er et al. (Chen Fen'er, Liu Anchang et al. Rearrangement synthesis process of loxoprofen sodium, China Medical Industry Journal, 1998, 12, 531-533.) discloses that toluene is used as a starting material, and subjected to a Friedel-Crafts reaction with 2-chloropropionyl chloride. Then, the product is subjected to ketal preparation with neopentyl glycol. The ketal is subjected to rearrangement to obtain 2-(4-methylphenyl)propionic acid, and then subjected to bromination with bromine to obtain a key intermediate 2-(4-bromomethylphenyl)propionic acid. The 2-(4-bromomethylphenyl)propionic acid is subjected to ethyl esterification, intermolecular condensation, hydrolysis and decarboxylation to obtain loxoprofen acid. The reaction route is as follows:

[0009]

[0010] However, the above preparation method has a long reaction route and low yield of product. SUMMARY

[0011] Therefore, the present application aims to provide a preparation method of loxoprofen acid.

[0012] In order to achieve the above-mentioned application purposes, the present application provides the following technical solutions.

[0013] The present application provides a preparation method of loxoprofen acid, comprising the following steps.

[0014] The compound 1, 1-(1-pyrrolidine) cyclopentene and an organic solvent are mixed, and then a condensation reaction is carried out, and then a hydrolysis reaction is carried out under an acidic condition, so as to obtain loxoprofen acid.

[0015]

[0016] In the formula, X is halogen, and R includes -CN or -CONH2.

[0017] Preferably, the molar ratio of the compound 1 to 1-(1-pyrrolidine) cyclopentene is 1:0.7-2.

[0018] Preferably, the organic solvent includes one or more of 1,4 dioxane, tetrahydrofuran and toluene.

[0019] Preferably, the condensation reaction is carried out at a temperature of 50-120℃ for 6-24h.

[0020] Preferably, the acidic condition is provided by an acid, and the acid includes acetic acid and hydrochloric acid.

[0021] Preferably, the molar ratio of the acetic acid to the hydrochloric acid is 1:0.125-8.

[0022] Preferably, the molar ratio of the compound 1 to the acid is 1:2-16.

[0023] Preferably, the hydrolysis reaction is carried out at a temperature of 50-120℃ for 6-24h.

[0024] Preferably, the hydrolysis reaction further comprises a post-treatment, and the post-treatment comprises: cooling the obtained hydrolysis reaction liquid, then extracting, then sequentially performing water washing, recrystallization and solid-liquid separation on the obtained organic phase, and then drying the obtained crystal product.

[0025] Preferably, the extraction agent used for the extraction includes one or more of toluene, ethyl acetate and isopropyl acetate.

[0026] The recrystallization solvent includes one or more of n-heptane, n-hexane, cyclohexane and petroleum ether.

[0027] The present application uses compound 1 and 1-(1-pyrrolidine) cyclopentene as starting materials, and can prepare loxoprofen acid through condensation reaction and hydrolysis reaction under acidic conditions. The product has high yield and high purity, can realize continuous production of loxoprofen acid, has simple operation, less waste, is green and environmentally friendly, has low production cost, and is suitable for industrialized production. As shown in the test results of the examples, the yield of loxoprofen acid is more than 93%, and the purity is more than 99.9%.

[0028] Further, the preparation method provided by the present application can remove the solvent after condensation reaction, and then perform subsequent hydrolysis reaction, without the need of separating and purifying the intermediate obtained through condensation reaction, so that the operation steps are simplified, less waste is produced, and the method is green and environmentally friendly. BRIEF DESCRIPTION OF DRAWINGS

[0029] Figure 1 is the hydrogen spectrum of loxoprofen acid;

[0030] Figure 2 is the HPLC spectrum of loxoprofen acid. DETAILED DESCRIPTION

[0031] The present application provides a preparation method of loxoprofen acid, comprising the following steps:

[0032] Compound 1, 1-(1-pyrrolidine) cyclopentene and an organic solvent are mixed, condensation reaction is performed, and then hydrolysis reaction is performed under acidic conditions to obtain loxoprofen acid;

[0033]

[0034] wherein X is halogen, and R includes -CN or -CONH2.

[0035] Unless otherwise specified, the raw materials used in the present application are all commercially available.

[0036] In the present application, the halogen preferably includes chlorine or bromine. In the present application, the compound 1 preferably includes 2-(4-(bromomethyl)phenyl) propionitrile, 2-(4-(chloromethyl)phenyl) propionitrile, 2-(4-(bromomethyl)phenyl) propionamide or 2-(4-(chloromethyl)phenyl) propionamide.

[0037] In the present application, the molar ratio of the compound 1 to 1-(1-pyrrolidine) cyclopentene is preferably 1:0.7-2, more preferably 1:1-1.8, and further preferably 1:1.2-1.5.

[0038] In the present application, the organic solvent preferably includes one or more of 1,4 dioxane, tetrahydrofuran and toluene, and more preferably 1,4 dioxane. In the present application, the mass ratio of the compound 1 to the organic solvent is preferably 1:1-10, and more preferably 1:3-5.

[0039] In the present application, the temperature of the condensation reaction is preferably 50-120°C, more preferably 80-100°C, and in specific embodiments of the present application, the condensation reaction is preferably carried out under heating reflux condition; the time of the condensation reaction is preferably 6-24h, more preferably 12-16h.

[0040] After the condensation reaction is completed, the present application preferably further comprises post-treatment, which preferably comprises: concentrating the obtained condensation reaction solution to constant weight to obtain the intermediate. The present application does not have special limitations on the concentration method, and the solvent can be removed by a method well known to those skilled in the art, such as reduced pressure distillation.

[0041] In the present application, the acidic condition is preferably provided by an acid; the acid preferably comprises acetic acid and hydrochloric acid, the hydrochloric acid is preferably concentrated hydrochloric acid, and the mass fraction of the concentrated hydrochloric acid is preferably 25-38%, more preferably 30-35wt%; the molar ratio of the acetic acid and hydrochloric acid is preferably 1:0.125-8, more preferably 1:0.5-5, and further preferably 1:1-2. In the present application, the acid is preferably used in the form of an acid solution, and the mass fraction of the acid (HAc+HCl) in the acid solution is preferably 50-95%, more preferably 75-90%.

[0042] In the present application, the molar ratio of the compound 1 and the acid is preferably 1:2-16, more preferably 1:3-10, and further preferably 1:5-8.

[0043] In the present application, the temperature of the hydrolysis reaction is preferably 50-120°C, more preferably 80-100°C, and in specific embodiments of the present application, the hydrolysis reaction is preferably carried out under heating reflux condition; the time of the hydrolysis reaction is preferably 6-24h, more preferably 8-12h.

[0044] In the present application, the preparation route of the loxoprofen acid is as follows:

[0045]

[0046] In the present application, the hydrolysis reaction is preferably followed by a post-treatment, which preferably comprises: cooling the obtained hydrolysis reaction solution, then extracting, sequentially washing the obtained organic phase with water, recrystallizing and solid-liquid separating, drying the obtained crystal product to obtain loxoprofen acid. In the present application, the temperature after cooling is preferably -10-30°C, more preferably 5°C. In the present application, the extractant used for extraction preferably comprises one or more of toluene, ethyl acetate and isopropyl acetate; the mass ratio of compound 1 to extractant is preferably 1:0.5-6, more preferably 1:2-3. In the present application, the number of times of washing with water is preferably 1-5, more preferably 2; the mass ratio of compound 1 to water used for single washing is preferably 1:0-5, more preferably 1:1-3. In the present application, the recrystallization solvent preferably comprises one or more of n-heptane, n-hexane, cyclohexane and petroleum ether; the mass ratio of compound 1 to recrystallization solvent is preferably 1:1-8, more preferably 1:2-3. In the present application, the recrystallization preferably comprises sequentially performing temperature-lowering crystallization and temperature-maintaining crystallization; the initial temperature of temperature-lowering crystallization is preferably 30-110°C, more preferably 50-70°C; the final temperature (i.e. the temperature of temperature-maintaining crystallization) is preferably -10-30°C, more preferably 5°C; the time of temperature-maintaining crystallization is preferably 0-24h, more preferably 0.5-2h, wherein the temperature-maintaining crystallization temperature is 0h, the recrystallization is only temperature-lowering crystallization. The present application is not particularly limited to the solid-liquid separation, and any solid-liquid separation method known to those skilled in the art can be used, such as suction filtration, filtration or centrifugal separation. In the present application, the drying temperature is preferably 20-65°C, more preferably 40-50°C; the present application is not particularly limited to the drying time, and drying to constant weight is sufficient.

[0047] The preparation method of loxoprofen acid provided by the present application is described in detail below in combination with examples, but they should not be understood as limitations to the scope of protection of the present application.

[0048] Example 1

[0049] Mix 2-(4-(bromomethyl)phenyl)propionitrile 100g, 1,4 dioxane 500g and 1-(1-pyrrolidine)cyclopentene 73.8g, heat to reflux, react for 12h, remove the solvent under reduced pressure, cool to room temperature, add glacial acetic acid 150g, concentrated hydrochloric acid with a mass fraction of 36% 200g and water 50g, heat to reflux, react for 12h, cool to 40°C, extract with toluene 300g, separate the liquid, wash the obtained organic phase with water 2 times, the amount of water used for single washing is 100g, add n-heptane 300g to the organic phase under stirring, cool to 5°C under stirring, maintain crystallization for 2h, suction filtration, dry at 40°C to constant weight, to obtain loxoprofen acid (white solid, 105g, yield 95.1%, purity 99.95%).

[0050] The NMR spectrum of loxoprofen acid is shown in Figure 1 Figure 2 and Table 1. The NMR data are as follows: 1 H-NMR (500 MHz, DMSO-d6) δ: 12.25 (1H, s), 7.20 (4H, m), 3.66 (1H, dd), 2.98 (1H, m), 2.47 (2H, d), 2.27 (1H, m), 2.12 (1H, m), 1.97 (2H, m), 1.72 (1H, m), 1.53 (1H, m), 1.48 (3H, d).

[0051] Table 1 HPLC chromatographic peak information of loxoprofen acid

[0052] Retention time / min Area Width / min Height Separation Theoretical plates Tailing factor Area / % Label 16.956 15.02 1.42 0.49 7218 1.00 0.022 BB 18.735 13.32 1.94 0.42 2.27 9393 1.23 0.019 BB 24.912 68301.54 7.99 1608.23 6.73 8801 0.84 99.948 BB 36.225 2.55 0.48 0.30 17.72 455282 1.22 0.004 BB 37.325 4.42 0.52 0.66 5.92 904692 1.13 0.006 BB Total 68336.85

[0053] Example 2

[0054] Loxoprofen acid was prepared according to the method of Example 1, with the only difference from Example 1 being that 2-(4-(bromomethyl)phenyl)propionitrile was replaced by 2-(4-(chloromethyl)phenyl)propionitrile. Loxoprofen acid (off-white solid, 127.4 g, yield 93%, purity 99.77%). The NMR data of loxoprofen acid were consistent with those of Example 1.

[0055] Example 3

[0056] Loxoprofen acid was prepared according to the method of Example 1, with the only difference from Example 1 being that 2-(4-(bromomethyl)phenyl)propionitrile was replaced by 2-(4-(chloromethyl)phenyl)propionitrile. Loxoprofen acid (off-white solid, 127.4 g, yield 93%, purity 99.77%). The NMR data of loxoprofen acid were consistent with those of Example 1.

[0057] Example 4

[0058] Loxoprofen acid was prepared according to the method of Example 1, with the only difference from Example 1 being that 2-(4-(bromomethyl)phenyl)propionitrile was replaced by 2-(4-(chloromethyl)phenyl)propionitrile. Loxoprofen acid (off-white solid, 127.4 g, yield 93%, purity 99.77%). The NMR data of loxoprofen acid were consistent with those of Example 1. ​

[0059] The above merely describes the preferred embodiments of the present application, and it should be pointed out that those skilled in the art can make several improvements and refinements without departing from the principles of the present application, and these improvements and refinements should also be considered as falling within the protection scope of the present application.

Claims

1. A method for preparing loxoprofen acid, characterized in that, Includes the following steps: Compound 1, 1-(1-pyrrolidine)cyclopentene, and an organic solvent were mixed and subjected to a condensation reaction, followed by hydrolysis under acidic conditions to obtain loxoprofen acid. ； Where X is a halogen and R is -CN or -CONH2; The molar ratio of compound 1 to 1-(1-pyrrolidine)cyclopentene is 1:1 to 1.8; The organic solvent is one or more of 1,4-dioxane, tetrahydrofuran, and toluene; The condensation reaction is carried out at a temperature of 50~120℃ for 12~16 hours. The acidic conditions are provided by an acid, which is acetic acid and hydrochloric acid, and the molar ratio of acetic acid to hydrochloric acid is 1:0.5~5; The molar ratio of compound 1 to acid is 1:8~16; The hydrolysis reaction is carried out at a temperature of 50~120℃ for 8~12 hours.

2. The preparation method according to claim 1, characterized in that, The hydrolysis reaction is followed by post-treatment, which includes: cooling and extracting the obtained hydrolysis reaction solution, washing the obtained organic phase with water, recrystallizing and separating the solid and liquid phases in sequence, and drying the obtained crystalline product.

3. The preparation method according to claim 2, characterized in that, The extractant used for extraction is one or more of toluene, ethyl acetate and isopropyl acetate; The solvent used for recrystallization is one or more of n-heptane, n-hexane, cyclohexane, and petroleum ether.

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