Preparation process of dexketoprofen trometamol

Abstract

The invention belongs to the field of medicine synthesis, and particularly relates to a preparation process of dexketoprofen trometamol. The preparation method comprises the following steps: dissolving 3-benzoyl phenyl acetonitrile in a solvent, adding a catalyst, a chiral ligand, a methylation reagent and alkali, irradiating with a light source for reaction, and after the reaction is completed, filtering and concentrating the dry solvent; adding water, sodium hydroxide and TBAB (Tetrabutylammonium Bromide) to react, and dropwise adding hydrochloric acid until a solid is separated out after the reaction is finished, so as to obtain dexketoprofen; the method comprises the following steps: dissolving dexketoprofen in a solvent, dropwise adding an alcoholic solution of trometamol, and after dropwise adding, cooling, crystallizing and filtering to obtain the product dexketoprofen trometamol. According to the present invention, the chiral center construction of ketoprofen is completed by using the chiral catalysis and photochemistry manner, and the ketoprofen is completely converted into the dexketoprofen, such that the complex route of splitting, racemization and re-splitting in the prior art is avoided, the operation process is simplified, the conversion rate is high, the chiral purity is high, the process is safe, green and environmentally friendly, and the high market competitiveness is provided.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation process of dexketoprofen tromethamine. Background Art

[0002] Dexketoprofen tromethamine tablets are a national Class IV new drug, and are indicated for mild to moderate pain and inflammation, such as rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gouty arthritis, as well as various acute and chronic pains such as dysmenorrhea, toothache, postoperative pain, cancer pain, acute sprains, soft tissue contusion pain, and body pain caused by colds and fever. With low effective doses and few adverse reactions, it is a new type of antipyretic analgesic and non-steroidal anti-inflammatory drug with development prospects.

[0003] Literature reports that ketoprofen is split with optically active anilines (phenylethylamine, amphetamine) and cincotine and other splitting agents to obtain dexketoprofen; dexketoprofen is dissolved in ethanol, an equimolar amount of tromethamine aqueous solution is added, and the salt is formed by stirring at room temperature for half an hour. Then, ethanol and water are evaporated under reduced pressure, and ethanol is required to be carried out with water several times to dryness to obtain a semi-solid viscous material, which is then recrystallized with ethanol-ethyl acetate to obtain dexketoprofen tromethamine.

[0004] The chiral synthesis strategies currently reported in the literature (such as chemical resolution, chromatographic resolution and enzyme-catalyzed biosynthesis) all have significant limitations in the ketoprofen system: traditional chemical resolution requires multi-step resolution using reagents such as chiral phenylethylamine and cinchonidine, the chromatographic resolution method faces the problem of high large-scale production costs, and the bio-enzyme catalysis method has the defect of insufficient substrate adaptability.

[0005] Chinese patent CN 101928214 A discloses a method for synthesizing dexketoprofen tromethamine, wherein the method comprises alkalizing ketoprofen, splitting and separating dexketoprofen crude salt with glucamine, refining and separating dexketoprofen refined salt, adding tromethamine to form salt, and refining dexketoprofen tromethamine; the method of the present invention has high purity of splitting, and realizes the reuse of enantiomers; the method adopts the recycling method to split, racemize, and split again, thereby improving the utilization rate of the precursor drug ketoprofen, and the utilization rate of the precursor drug ketoprofen is increased from the original 60% to 70%; the method adopts a mixed solvent for one-step salt crystallization, thereby improving the product quality, and the yield reaches 70%, which is conducive to industrial production. However, the patent technology adopts the process mode of splitting, racemization, and splitting again, and the operation is complicated. Summary of the invention

[0006] The existing technology of splitting, racemization and re-split process is complicated to operate. In order to overcome the shortcomings of the existing technology, the purpose of the present invention is to provide a preparation process of dexketoprofen trometamol, which adopts a photocatalytic method, has high conversion rate, high chiral purity, simple post-treatment, no impurity generation, can well ensure the quality of the product, and has a safe, environmentally friendly, green and low cost, and has high market competitiveness.

[0007] The present invention provides a preparation process of dexketoprofen tromethamine, comprising the following steps:

[0008] (1) dissolving 3-benzoylphenylacetonitrile (Compound 1) in a solvent, adding a catalyst, a chiral ligand, a methylating agent and a base, irradiating with a light source to react, filtering after the reaction is completed, and concentrating the solvent;

[0009] (2) adding water, sodium hydroxide and TBAB to react, and after the reaction is completed, adding hydrochloric acid dropwise until solid precipitates to obtain dexketoprofen;

[0010] (3) dissolving dexketoprofen in a solvent, adding dropwise an alcohol solution of tromethamine, and after completion of the dropwise addition, cooling and crystallizing, filtering, and obtaining the product dexketoprofen tromethamine;

[0011] The reaction equation is as follows:

[0012]

[0013] The core innovation of the present invention is to break through the technical bottleneck of the construction of the chiral center of ketoprofen. The chiral synthesis strategies (such as chemical splitting, chromatographic splitting and enzyme-catalyzed biosynthesis) reported in the literature at present all have significant limitations in the ketoprofen system: traditional chemical splitting needs to rely on chiral phenylethylamine, cincotine and other reagents for multi-step disassembly, chromatographic splitting faces the problem of high cost of large-scale production, and the bio-enzyme catalysis law has the defect of insufficient substrate adaptability. In response to the above challenges, the present invention has pioneered the development of a new synthesis system of chiral catalysis and photochemistry synergy, and successfully achieved the efficient construction of the chiral center of ketoprofen by accurately controlling the multiphase reaction interface of chiral catalysts, methylating agents and alkalis under illumination conditions, simplifying the process and reducing costs.

[0014] Preferably, in step (1), the catalyst is one or more of palladium acetate, tetrakis(triphenylphosphine)palladium, and dichlorobis(triphenylphosphine)palladium; the chiral ligand is S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine ((S)-BINAP); the methylating agent is one or more of CH3Bpin, CH3I, dimethyl carbonate, and dimethyl sulfate; the base is one or more of potassium carbonate, cesium carbonate, and potassium phosphate. The present invention uses the above-mentioned specific catalyst, chiral ligand, methylating agent, and base to achieve the use of chiral catalysis + photochemistry, so that ketoprofen is constructed with a chiral center under the condition of the presence of a catalyst, and is completely converted into dextrorotatory ketoprofen, avoiding the complex route of splitting, racemization, and re-split in the prior art, simplifying the operation process, reducing costs, having a high conversion rate and chiral purity, a yield of more than 72%, and an ee value of more than 87%.

[0015] Preferably, the light source in step (1) is a 254 nm light source. Irradiation with this light source can enhance the activity of the chemical bonds of the compound and ensure the successful construction of the chiral center of ketoprofen.

[0016] Preferably, in step (1), the catalyst is one or more of palladium acetate, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium; the chiral ligand is S-(-)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine)phosphine; the methylating agent is CH3Bpin; and the base is cesium carbonate or potassium carbonate. Using these specific catalysts, chiral ligands, methylating agents and bases, the dexketoprofen prepared has a very high yield and purity, with a yield of more than 82% and an ee value of more than 90%.

[0017] More preferably, in step (1), the catalyst is palladium acetate; the chiral ligand is S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine; the methylating agent is CH3Bpin; and the base is cesium carbonate. Using these specific catalysts, chiral ligands, methylating agents and bases, the dexketoprofen prepared has a very high yield and purity, with a yield of more than 94% and an ee value of more than 99%.

[0018] Preferably, in step (1), the molar ratio of 3-benzoylphenylacetonitrile, catalyst, chiral ligand, methylating agent and base is: 1: 0.01-0.1: 0.02-0.2: 1.0-2.0: 0.5-2.0; preferably: 1: 0.02-0.05: 0.04-0.1: 1.0-2.0: 0.6-1.2.

[0019] Preferably, the solvent in step (1) is acetonitrile, dichloromethane or toluene; the reaction temperature is 20 to 40° C.; and the reaction time is 10 to 30 minutes.

[0020] Preferably, in step (2), the feed ratio of water, sodium hydroxide and TBAB (tetrabutylammonium bromide) is 660-2200 mL: 2.2-3.5 mol: 0.2-0.5 mol, preferably 660-1100 mL: 2.5-3.0 mol: 0.2-0.3 mol.

[0021] Preferably, in step (2), the reaction temperature is 20-40° C., and the reaction time is 2-6 hours; hydrochloric acid is added dropwise until the pH value is 1.5-2.

[0022] Preferably, the solvent in step (3) is methanol, ethanol or isopropanol.

[0023] Preferably, step (3) comprises: adding dexketoprofen to a solvent and heating until completely dissolved; dissolving tromethamine in ethanol to obtain an alcoholic solution of tromethamine, and dripping the alcoholic solution of tromethamine into the dexketoprofen solution, controlling the temperature to 50±2° C., and adding the solution for 1 to 1.5 hours; after the dripping is completed, cooling the solution to -10 to 5° C. at a rate of 0.5 to 1° C. / min, and keeping the temperature for crystallization for 4 to 6 hours; filtering with suction, and drying the filter cake to obtain dexketoprofen tromethamine.

[0024] In step (3), the feed ratio of dexketoprofen and tromethamine is: 1 mol: 1.mol~1.5mol: preferably 1 mol: 1.05~1.2mol.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] (1) The present invention realizes the use of chiral catalysis + photochemistry to construct the chiral center of ketoprofen in the presence of a catalyst, and completely converts it into dextrorotatory ketoprofen, avoiding the complex route of splitting, racemization, and re-split in the prior art, simplifying the operation process, having a high conversion rate, high chiral purity, a safe, green and environmentally friendly process, and low cost, and having high market competitiveness.

[0027] (2) Compared with the prior art, this invention has three significant advantages: (a) Path innovation: abandoning the "split-racemization-resplit" cycle steps in the traditional process, reducing the original multi-step process to a single-step reaction; (b) Performance superiority: the product enantiomeric excess (ee value) and yield have achieved good results; (c) Industrial feasibility: the reaction system does not require harsh conditions such as high pressure / low temperature, and this green synthesis process provides a breakthrough solution for the large-scale production of ketoprofen. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 : The liquid phase diagram of dexketoprofen prepared in Example 1.

[0029] Figure 2: The NMR of the dexketoprofen prepared in Example 1. DETAILED DESCRIPTION

[0030] The present invention is further described below by means of specific examples. The examples described in the present invention are only used to illustrate the present invention and do not limit the scope of the present invention.

[0031] Example 1

[0032] The compound of formula 1 (3-benzoylphenylacetonitrile, 1.0 mol, 221.3 g) was dissolved in acetonitrile, palladium acetate (Pd(OAc)2, 0.05 mol, 11.2 g), (S)-BINAP (0.06 mol, 37.4 g), cesium carbonate (Cs2CO3, 1.0 mol, 325.8 g) were added, and stirred for 10 minutes under argon protection. CH3Bpin (1.2 mol, 204.2 g) was added, and 254 nm ultraviolet light was irradiated for 20 minutes, and the temperature was controlled at 30±2°C. The catalyst was removed by filtration, and the filtrate was concentrated to dryness.

[0033] Add water (5V, 1100mL), sodium hydroxide (2.5mol, 100g), TBAB (0.2mol, 64.5g), and stir at 35℃ for 4 hours. Add hydrochloric acid dropwise until pH=1.5, precipitate solid, filter, and vacuum dry at 50℃ to obtain product dexketoprofen. Yield: 94.3%, enantioselectivity: 99.0%ee (HPLC analysis, chiral column Chiralpak AD-H, the liquid phase diagram of dexketoprofen prepared in Example 1 is shown in Figure 1 , NMR images are shown in Figure 2 ).

[0034] Example 2

[0035] The compound of formula 1 (1.0 mol, 221.3 g) was dissolved in toluene (7 V, about 1550 mL), palladium acetate (Pd(OAc)2, 0.05 mol, 11.2 g), (S)-BINAP (0.04 mol, 24.9 g), potassium phosphate (K3PO4, 0.8 mol, 170.2 g) were added, and dimethyl carbonate (DMC, 2.0 mol, 180.2 g) was added after nitrogen replacement. 254 nm ultraviolet light was irradiated for 30 minutes, and the temperature was controlled at 40°C. The catalyst was filtered and the solvent was concentrated to dryness.

[0036] Add water (3V, 660mL), sodium hydroxide (3.0mol, 120g), TBAB (0.3mol, 96.7g), and stir at 25°C for 6 hours. Acidify with hydrochloric acid to pH = 2, crystallize, and dry to obtain the product dexketoprofen. Yield: 72.5%, enantioselectivity: 92.2%ee.

[0037] Example 3

[0038] The compound of formula 1 (1.0 mol, 221.3 g) was dissolved in dichloromethane (6 V, about 1320 mL), and dichlorobis(triphenylphosphine)palladium (PdCl2(PPh3)2, 0.04 mol, 28.1 g), (S)-BINAP (0.08 mol, 49.8 g), and cesium carbonate (Cs2CO3, 1.0 mol, 325.8 g) were added, and stirred for 10 minutes under argon protection. CH3Bpin (1.2 mol, 204.2 g) was added, and 254 nm ultraviolet light was irradiated for 10 minutes, and the temperature was controlled at 30°C. After filtration, the mixture was concentrated to dryness.

[0039] Add water (4V, 880mL), sodium hydroxide (2.8mol, 112g), TBAB (0.25mol, 80.6g), stir at 40°C for 2 hours. Adjust the pH to 1.8 with hydrochloric acid, precipitate solid, and dry to obtain the product dexketoprofen. Yield: 85.6%, enantioselectivity: 96.5%ee.

[0040] Example 4

[0041] The compound of formula 1 (1.0 mol, 221.3 g) was dissolved in dichloromethane (6 V, about 1320 mL), palladium acetate (Pd(OAc)2, 0.05 mol, 11.2 g), (S)-BINAP (0.08 mol, 49.8 g), cesium carbonate (Cs2CO3, 1.0 mol, 325.8 g) were added, and iodomethane (CH3I, 1.5 mol, 213.9 g) was added dropwise under light-proof conditions. The mixture was irradiated with 254 nm ultraviolet light for 10 minutes and the temperature was controlled at 30°C. After filtration, the mixture was concentrated to dryness.

[0042] Add water (4V, 880mL), sodium hydroxide (2.8mol, 112g), TBAB (0.25mol, 80.6g), stir at 40°C for 2 hours. Adjust the pH to 1.8 with hydrochloric acid, precipitate solid, and dry to obtain the product dexketoprofen. Yield: 72.3%, enantioselectivity: 87.1%ee.

[0043] Example 5

[0044] Example 5 is substantially the same as Example 1, except that the cesium carbonate is replaced by the same molar amount of potassium carbonate.

[0045] Results: Yield: 86.7%, ee: 94.0%.

[0046] Example 6

[0047] Example 6 is basically the same as Example 1, with the only difference being that palladium acetate Pd(OAc)2 is replaced by the same molar amount of tetrakis(triphenylphosphine)palladium (Pd(PPh3)4).

[0048] Results: Yield: 82.1%, ee: 90.5%.

[0049] Comparative Example 1

[0050] In Comparative Example 1, no chiral ligand was added.

[0051] Specifically: the compound of formula 1 (3-benzoylphenylacetonitrile, 0.1 mol, 22.13 g) was dissolved in acetonitrile (110 mL), palladium acetate (Pd(OAc)2, 2 mol%, 0.45 g) and cesium carbonate (Cs2CO3, 0.1 mol, 32.58 g) were added. Under argon protection, methyl boric acid pinacol ester (CH3Bpin, 0.12 mol, 20.42 g) was added and stirred to mix evenly. Under 254 nm ultraviolet light, the reaction was stirred at 25-30° C. for 20 minutes. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure. Water (110 mL), sodium hydroxide (2.5 mol, 100 g) and tetrabutylammonium bromide (TBAB, 0.2 mol, 64.5 g) were added and stirred at 35° C. for 4 hours. 1M hydrochloric acid was added dropwise until pH = 1.5, and a white solid was precipitated. The solid was filtered, washed with cold water, and dried under vacuum at 50°C to obtain the product dexketoprofen; the yield was 77.5%, and the ee value was 82.5%.

[0052] Comparative Example 2

[0053] Comparative Example 2 is basically the same as Example 1, except that 365 nm ultraviolet light was used for irradiation for 30 minutes. Result: Yield 89.2%, ee value 67.5%.

[0054] Comparative Example 3

[0055] The compound of formula 1 (1.0 mol, 221.3 g) was dissolved in acetonitrile (5 V, 1100 mL), palladium acetate (0.05 mol, 11.2 g), (S)-BINAP (0.06 mol, 37.4 g), cesium carbonate (Cs2CO3, 1.5 mol, 488.7 g) were added, and dimethyl sulfate (1.8 mol, 252.3 g) was added under argon protection. 365 nm ultraviolet light was irradiated for 25 minutes, and the temperature was controlled at 35 ° C. After filtration, the product was concentrated to dryness to obtain dexketoprofen.

[0056] Add water (4V, 880mL), sodium hydroxide (2.8mol, 112g), TBAB: (0.25mol, 80.6g), stir at 40°C for 2 hours. Adjust pH to 1.8 with hydrochloric acid, precipitate solid, and dry. Yield: 70.4%, enantioselectivity: 78.5%ee.

[0057] Example 7

[0058] Dexketoprofen (Formula 2 compound) (1.0mol, 254.28g, molecular weight, 254.28g / mol) prepared in Example 1 was added to ethanol (3V, 762.8mL), heated to 50°C and stirred until completely dissolved. Tromethamine (1.05mol, 127.20g, molecular weight 121.14g / mol) was dissolved in ethanol (100mL), then added dropwise to the dexketoprofen solution, temperature controlled at 50±2°C, and the dropping time was 1 hour. After the dropwise addition was completed, the temperature was lowered to 0-5°C at a rate of 0.5°C / min, and the crystallization was kept warm for 4 hours. Suction filtration, the filter cake was washed with precooled ethanol (50mL), and vacuum dried at 50°C for 12 hours to obtain white crystalline solid dexketoprofen tromethamine. Productivity: 92.5%, chiral purity (ee value): 99.3% (HPLC).

[0059] Example 8

[0060] Dexketoprofen (1.0mol, 254.28g) prepared in Example 1 was dissolved in ethanol (5V, 1271.4mL) and stirred to dissolve. Tromethamine (145.37g) was dissolved in ethanol (200mL) and then added dropwise to the dexketoprofen solution for 1.5 hours. The temperature was lowered to -10°C (cooling rate 1°C / min) and the crystallization was incubated for 6 hours. The filter cake was washed with cold ethanol (100mL) and dried under vacuum at 60°C for 24 hours to obtain white crystalline solid dexketoprofen tromethamine. Yield: 94.8%, chiral purity (ee value): 99.4% (HPLC).

[0061] The reaction conditions and results of Examples 1 to 6 of the present invention and Comparative Examples 1 to 3 are compared as follows:

[0062]

[0063] It can be seen from the results in the above table that the dexketoprofen prepared in Examples 1-6 has a higher yield and an ee value of more than 87.0%.

[0064] Example 2: The methylating agent uses dimethyl carbonate, and the base uses K3PO4. The compatibility of the reagent and the base is adjusted, the yield decreases, and the ee value is still relatively high. Example 3: The catalyst structure is fine-tuned, and the selectivity is slightly reduced. Example 4: The methylating agent uses iodomethane, which has low activity, increased side reactions, and lower yields and ee values. Example 5: The weak base potassium carbonate is used, the transmetallation efficiency is reduced, and the yield and ee values ​​are lowered. Example 6: Tetrakistriphenylphosphine palladium is used, and steric hindrance affects the selectivity.

[0065] Compared with Example 1, Comparative Example 1 has no chiral ligand and the ee value is significantly reduced. Comparative Example 2 uses a long wavelength light source, which is insufficient in activity and the ee value is significantly reduced. Comparative Example 3 uses dimethyl sulfate as the methylation reagent and a long wavelength light source, and dimethyl sulfate has high toxicity and low comprehensive performance.

Claims

1. A preparation technology of dexketoprofen tromethamine, characterized in that: The following steps are involved: (1) dissolving 3-benzoylphenylacetonitrile in a solvent, adding a catalyst, a chiral ligand, a methylating agent and a base, irradiating with a light source to react, filtering after the reaction is completed, and concentrating the solvent; (2) adding water, sodium hydroxide and TBAB to react, and after the reaction is completed, adding hydrochloric acid dropwise until solid precipitates to obtain dexketoprofen; (3) dissolving dexketoprofen in a solvent, adding dropwise an alcohol solution of tromethamine, and after completion of the dropwise addition, cooling and crystallizing, filtering, and obtaining the product dexketoprofen tromethamine; The reaction equation is as follows:

2. The preparation technology of dexketoprofen tromethamine according to claim 1, characterized in that: In step (1), the catalyst is one or more of palladium acetate, tetrakis(triphenylphosphine)palladium, and dichlorobis(triphenylphosphine)palladium; the chiral ligand is S-(-)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine)phosphine; the methylating agent is one or more of CH3Bpin, CH3I, dimethyl carbonate, and dimethyl sulfate; and the base is one or more of potassium carbonate, cesium carbonate, and potassium phosphate.

3. The preparation technology of dexketoprofen tromethamine according to claim 2, characterized in that: In step (1), the catalyst is one or more of palladium acetate, tetrakis(triphenylphosphine)palladium, and dichlorobis(triphenylphosphine)palladium; the chiral ligand is S-(-)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine)phosphine; the methylating agent is CH3Bpin; and the base is cesium carbonate or potassium carbonate.

4. The preparation technology of dexketoprofen tromethamine according to claim 3, characterized in that: In step (1), the catalyst is palladium acetate; the chiral ligand is S-(-)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine); the methylating agent is CH3Bpin; and the base is cesium carbonate.

5. The preparation process of the arbitrary described dexketoprofen tromethamine according to claim 1-4, characterized in that: In step (1), the molar ratio of 3-benzoylphenylacetonitrile, catalyst, chiral ligand, methylating agent and base is 1: 0.01-0.1: 0.02-0.2: 1.0-2.0: 0.5-2.

0.

6. The preparation process of dexketoprofen tromethamine according to claim 1, characterized in that: The light source in step (1) is a 254nm light source.

7. The preparation process of dexketoprofen tromethamine according to claim 1, characterized in that: The solvent in step (1) is acetonitrile, dichloromethane or toluene; the reaction temperature is 20 to 40° C., and the reaction time is 10 to 30 minutes.

8. The preparation process of dexketoprofen tromethamine according to claim 1, characterized in that: In step (2), the feed ratio of water, sodium hydroxide and TBAB is 660-2200 mL: 2.2-3.5 mol: 0.2-0.5 mol.

9. The preparation process of dexketoprofen tromethamine according to claim 1, characterized in that: In step (2), the reaction temperature is 20-40° C. and the reaction time is 2-6 hours; hydrochloric acid is added dropwise until the pH value is 1.5-2.

10. The preparation process of dexketoprofen tromethamine according to claim 1, characterized in that: The step (3) comprises: adding dexketoprofen to a solvent, wherein the solvent is methanol, ethanol or isopropanol, and heating the solvent until the solvent is completely dissolved; dissolving tromethamine in ethanol to obtain an alcohol solution of tromethamine, and dripping the alcohol solution of tromethamine into the dexketoprofen solution, controlling the temperature to 50±2° C., and dripping for 1 to 1.5 hours; after the dripping is completed, cooling the solution to -10 to 5° C. at a rate of 0.5 to 1° C. / min, and keeping the temperature for crystallization for 4 to 6 hours; and filtering the solution by suction, drying the filter cake, and obtaining dexketoprofen tromethamine.

Images