A method for synthesizing ketoprofen intermediate and loxoprofen intermediate
By converting styrene into ketoprofen or loxoprofen intermediates under the action of nickel catalyst and palladium catalyst, the problem of lengthy and poor selectivity of traditional synthesis steps is solved, and high-efficiency and low-energy-consuming intermediate generation is achieved. It is suitable for the production of high-quality and low-energy-consuming intermediates. Industrialized production.
Patent Information
- Application Number
- CN202310403208.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-04-17
- Publication Date
- 2024-12-20
- Estimated Expiration
- 2043-04-17
AI Technical Summary
The synthesis steps of traditional ketoprofen and loxoprofen are lengthy, with poor selectivity of key steps and low yields, and a simplified process is required to generate ketoprofen intermediates or loxoprofen intermediates from simple and easy-to-get raw materials.
Using styrene as raw material, reacts with hydrogen cyanide under the action of nickel catalyst to form 2-phenylpropionitrile, and then reacts with benzoyl chloride or paraformaldehyde under the action of palladium catalyst and silver salt to form ketoprofen intermediate -Cyanoketoprofen or loxoprofen intermediate 2-(4-bromomethyl-phenyl)propionitrile.
It realizes the efficient and convenient generation of two important intermediates from one raw material, with short process, low energy consumption and pollution-free, and is suitable for large-scale industrial production.
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Abstract
Description
Technical Field
[0001] The invention relates to a ketoprofen intermediate and a new method for synthesizing a loxoprofen intermediate, belonging to the technical field of pharmaceutical intermediate synthesis. Background Art
[0002] Ketoprofen, with the chemical name α-methyl-3-benzoylphenylacetic acid, belongs to the class of 2-arylpropionic acid non-steroidal anti-inflammatory drugs. Its main mechanism of action is to inhibit the biological activity of oxygenase and lipoxygenase in the body, reduce the synthesis of inflammatory substances prostaglandins and leukotrienes, thereby producing good antipyretic, analgesic and anti-inflammatory effects. In clinical practice, ketoprofen is suitable for the treatment of various types of arthritis and postoperative and cancer pain. Compared with similar drugs such as ibuprofen and naproxen, it has significant advantages such as strong efficacy, small dosage, good tolerance, and easy oral absorption, and has a broad market space.
[0003] Among the reported ketoprofen synthesis methods, most of them use benzoic acid substituted with meta-methyl or halogen as the starting material, synthesize the benzophenone skeleton through Friedel-Crafts reaction, and then obtain the nitrile part of the side chain through methylation of the meta-position of the benzene ring or chemical conversion of the halogen. Among them: 1,2-aryl migration method, aniline method, styrene method, and acetophenone method have also become important synthesis strategies for ketoprofen.
[0004] Loxoprofen sodium, whose chemical name is 2-[4-(2-oxocyclopentane-1-ylmethyl)phenyl]propionate sodium dihydrate, belongs to the class of phenylpropionic acid non-steroidal anti-inflammatory drugs. Compared with other drugs of the same type, loxoprofen sodium has stronger analgesic, antipyretic and anti-inflammatory effects, fast absorption and rapid onset of action; it has few adverse reactions and good gastrointestinal tolerance. Since its launch, the drug has had leading sales among non-steroidal anti-inflammatory drugs. Therefore, the synthesis process of loxoprofen sodium is also constantly being updated. Depending on the starting raw materials used, the synthesis of loxoprofen includes the p-methylstyrene method, the ethyl lactate method, the toluene synthesis method, the p-methylacetophenone method, etc. It can be seen from these methods that simple and easily available raw materials are the research direction for process improvement.
[0005] However, the existing processes for the above two products still have lengthy synthesis steps, and the key steps require intermediate raw materials containing specific functional groups. Therefore, it is necessary to develop a method for generating ketoprofen intermediates - cyanoketoprofen or loxoprofen intermediates 2-(4-bromomethyl-phenyl)propionitrile from simple and readily available industrial raw materials through fewer reaction steps, thereby realizing a strategy for converting one raw material into two raw materials. Summary of the invention
[0006] In view of the shortcomings of the traditional ketoprofen or loxoprofen synthesis steps being lengthy, the poor selectivity of the key synthesis steps and the low yield, the present invention provides a new method for synthesizing a ketoprofen intermediate and a loxoprofen intermediate. Using styrene as a raw material, styrene first undergoes an addition reaction with hydrogen cyanide under the action of a nickel catalyst to generate 2-phenylpropionitrile. Then, under the combined action of a palladium catalyst and a silver salt additive, 2-phenylpropionitrile undergoes a cyano-directed meta-carbon-hydrogen bond activation reaction with benzoyl chloride to generate a ketoprofen intermediate-cyanoketoprofen; or 2-phenylpropionitrile is placed in an environment of glacial acetic acid and reacted with paraformaldehyde and hydrobromic acid to generate a loxoprofen intermediate 2-(4-bromomethyl-phenyl)propionitrile. Compared with the traditional preparation method, the synthesis method obtains two important products from a bulk raw material, has an efficient and convenient reaction, a short process, low energy consumption, no pollution, and is easy to operate, and is expected to achieve large-scale workshop production.
[0007] The novel method for synthesizing a ketoprofen intermediate and a loxoprofen intermediate of the present invention realizes the conversion of styrene into a ketoprofen intermediate-cyanoketoprofen or a loxoprofen intermediate 2-(4-bromomethyl-phenyl)propionitrile respectively through a two-step method; the method comprises the following steps:
[0008] In the first step, styrene reacts with hydrogen cyanide in an organic solvent under the action of a nickel catalyst and a ligand to generate 2-phenylpropionitrile;
[0009] In the second step, in the presence of a palladium catalyst and a silver salt additive, 2-phenylpropionitrile reacts with benzoyl chloride in an organic solvent to generate a ketoprofen intermediate - cyanoketoprofen; or 2-phenylpropionitrile reacts with polyformaldehyde in hydrobromic acid and glacial acetic acid to generate a loxoprofen intermediate 2-(4-bromomethyl-phenyl)propionitrile.
[0010] The present invention adopts chemical reaction equation to express as follows:
[0011]
[0012] Furthermore, in the above technical solution, the nickel catalyst in the first step is Ni(PAr3)4, Ni(CO)4 or Ni(cod)2; the ligand is a monophosphine ligand or a diphosphine ligand, and the specific structural formula is as follows:
[0013]
[0014]
[0015] Furthermore, in the above technical solution, the molar ratio of styrene, hydrogen cyanide, nickel catalyst and ligand in the first step is 1:1-5:0.01-0.1:0.01-0.1.
[0016] Furthermore, in the above technical scheme, the organic solvent in the first step is an alkane solvent, an ether solvent or an aromatic solvent (for example: n-hexane, petroleum ether, ethyl ether, toluene, xylene, mesitylene, preferably toluene); the reaction temperature is 0-30°C, and the preferred reaction temperature is 15-30°C.
[0017] Furthermore, in the above technical solution, the palladium catalyst in the second step is PdCl2, Pd(OAc)2, Pd(Allyl)Cl2 or Pd(OPiv)2; the silver salt additive is AgBF4, AgPF6, AgOPiv or AgSbF6. In this process, the selection of specific palladium catalyst and silver salt additive is the key to the effective reaction. Preferably, Pd(OPiv)2 and AgOPiv form a catalytic system.
[0018] Furthermore, in the above technical solution, the molar ratio of 2-phenylpropionitrile, benzoyl chloride, palladium catalyst and silver salt additive in the second step is 1:1-5:0.01-0.20:1.0-4.0.
[0019] Furthermore, in the above technical scheme, in the second step, during the conversion of 2-phenylpropionitrile into cyanoketoprofen, the organic solvent is selected from dichloromethane, 1,2-dichloroethane or 1,2-dibromoethane; the reaction temperature is 60-120°C, preferably 80-100°C.
[0020] Furthermore, in the above technical solution, in the second step, during the conversion of 2-phenylpropionitrile into 2-(4-bromomethyl-phenyl)propionitrile, the hydrobromic acid forms a 10-40wt% solution in acetic acid, preferably with a concentration of 20-35wt%; the reaction temperature is 30-80°C, preferably 40-60°C.
[0021] Furthermore, in the above technical solution, the molar ratio of 2-phenylpropionitrile, hydrogen bromide and paraformaldehyde in the second step is 1:1-10:1.0-2.0.
[0022] Furthermore, in the above technical scheme, the process is divided into two steps of reaction. The first step is: under the joint action of a nickel catalyst and a phosphine ligand, styrene and hydrogen cyanide undergo a Markovnikov addition reaction in an organic solvent to obtain a 2-phenylpropionitrile intermediate; the second step is: under the action of a palladium catalyst and a silver salt catalytic system, 2-phenylpropionitrile and benzoyl chloride undergo an meta-CH bond activation reaction to generate a ketoprofen intermediate - cyanoketoprofen; when glacial acetic acid is used as a reaction solvent, 2-phenylpropionitrile reacts with hydrogen bromide and polyformaldehyde to introduce a bromomethyl functional group at the para position of the phenyl group to generate a loxoprofen intermediate 2-(4-bromomethyl-phenyl)propionitrile.
[0023] Furthermore, in the above technical solution, the specific operation of the synthesis process is:
[0024] The first step: add styrene, nickel catalyst and ligand to a reaction bottle, add organic solvent thereto; dissolve hydrogen cyanide in an organic solvent, add dropwise to the reaction bottle at room temperature; then stir the reaction overnight. The styrene is completely consumed by monitoring by GC, and the reaction is over. Among them, styrene, hydrogen cyanide, nickel catalyst and ligand = 1: 1-5: 0.01-0.1: 0.01-0.1, and the styrene concentration is 0.1-0.2M. After the reaction is over, add saturated NaHCO3 solution to adjust the solution to neutral; extract the aqueous phase with an organic solvent, combine the organic phases, and distill under reduced pressure to obtain the Markov addition product 2-phenylpropionitrile. In this step of the reaction, the organic solvent is an alkane solvent, an ether solvent or an aromatic solvent; the nickel catalytic system requires the nickel catalyst and the ligand to act together.
[0025] Step 2: The step of converting 2-phenylpropionitrile to generate ketoprofen intermediate-cyanoketoprofen (cyano-directed meta-carbon-hydrogen bond activation reaction): 2-phenylpropionitrile, palladium catalyst and silver salt additive are added to the reaction bottle. Add organic solvent, add benzoyl chloride, and heat at 60-120°C. After stirring overnight, the silver salt on the wall of the bottle is shaken into the reaction solution, and heating is continued for a total of 42-48 hours; then it is cooled to room temperature for filtration, washed with organic solvent, and the filtrate is collected and distilled to obtain cyanoketoprofen. Among them, the molar ratio of 2-phenylpropionitrile, benzoyl chloride, palladium catalyst and silver salt additive is 1:1-5:0.01-0.2:1.0-4.0. In this process, specific palladium catalysts and silver additives are the key to the effective reaction. In this step of the reaction, the organic solvent is a halogenated solvent, such as dichloromethane, 1,2-dichloroethane, and chloroform. Ether solvents such as petroleum ether, ethyl ether, and methyl tert-butyl ether are used for post-treatment.
[0026] Step 2: The step of converting 2-phenylpropionitrile to generate the loxoprofen intermediate 2-(4-bromomethyl-phenyl)propionitrile: dissolve 2-phenylpropionitrile in glacial acetic acid and add paraformaldehyde thereto. Dissolve hydrogen bromide in glacial acetic acid to prepare a 31wt% hydrobromic acid / glacial acetic acid solution. Add the hydrobromic acid / glacial acetic acid solution to the reaction solution. Stir at 30-60℃ for 2h. After the reaction is completed, pour the reaction solution into water, and a white solid precipitates. Filter and vacuum dry to obtain a white powder 2-(4-bromomethyl-phenyl)propionitrile. Among them, the molar ratio of 2-phenylpropionitrile, hydrogen bromide and paraformaldehyde is 1:1-10:1.0-2.0; the concentration of 2-phenylpropionitrile is 2mol / L.
[0027] Advantageous Effects of the Invention
[0028] (1) This synthesis method obtains two important API intermediate products from a simple raw material, and the reaction is efficient and convenient; (2) The synthesis process is short, energy-saving, and pollution-free; (3) It is easy to operate and can achieve large-scale industrial production. DETAILED DESCRIPTION
[0029] The following will illustrate the implementation of the present invention through implementation examples, which do not limit the protection scope of the present invention. The nickel catalysts Ni(PAr3)4, Ni(CO)4 and Ni(cod)2; the palladium catalysts PdCl2, Pd(OAc)2, Pd(Allyl)Cl2 and Pd(OPiv)2; the silver salts AgBF4, AgPF6, AgOPiv and AgSbF6 used in the implementation examples are all purchased from chemical reagent companies with a purity of 99%.
[0030] Example 1
[0031] Step 1: Add styrene (52.1 g, 0.5 mol) and Ni[P(Oo-tolyl)3]4 (7.34 g, 0.005 mol) to a reaction flask, and add 300 mL of n-hexane thereto. Dissolve hydrogen cyanide (20.28 g, 0.75 mol) in toluene. At room temperature, add the hydrogen cyanide solution dropwise to the reaction flask. Subsequently, the reaction was stirred overnight at room temperature. The styrene consumption was monitored by GC, and the reaction was stopped when the remaining amount of styrene was less than 0.5%. Then, a saturated NaHCO3 solution was added thereto to adjust the solution to neutral. Phase separation, the aqueous phase was extracted with ether, and the organic phases were combined. By distillation, 45.9 g of Markovnikov addition product 2-phenylpropionitrile was obtained with a yield of 70%, and 6.6 g of chain byproduct 1-phenylpropionitrile was obtained with a yield of 10%.
[0032] Step 2: The step of converting 2-phenylpropionitrile to generate ketoprofen intermediate-cyanoketoprofen (cyano-directed meta-carbon-hydrogen bond activation reaction), 2-phenylpropionitrile (65.59g, 0.5mol), Pd(OPiv)2 (1.55g, 0.005mol) and AgOPiv (250.8g, 1.2mol) were added to the reaction bottle. 300mL of 1,2-dichloroethane was added thereto, and benzoyl chloride (140.6g, 1.0mol) was added and heated at 90°C. After stirring overnight, the silver salt on the bottle wall was shaken into the reaction solution and continued to heat for a total of 42-48h. Subsequently, the reaction was stopped. The reaction solution was cooled to room temperature, filtered, washed with ether, and the filtrate was collected. By distillation, 100g of cyanoketoprofen was obtained with a yield of 85%, HPLC: 99.1%.
[0033] Steps for converting 2-phenylpropionitrile to generate 2-(4-bromomethyl-phenyl)propionitrile, an intermediate of loxoprofen. 2-phenylpropionitrile (65.59 g, 0.5 mol) was dissolved in 250 mL of glacial acetic acid, and paraformaldehyde (31.1 g, 0.5 mol) was added thereto. Hydrogen bromide was dissolved in glacial acetic acid to prepare a 31 wt% hydrobromic acid / glacial acetic acid solution. 100 mL of the hydrobromic acid / glacial acetic acid solution was added to the reaction solution. The reaction was stirred at 50°C for 2 h. After the reaction was completed, the reaction solution was poured into water, and a white solid was precipitated. The white powder was filtered and dried under vacuum to obtain 98.7 g of 2-(4-bromomethyl-phenyl)propionitrile, with a yield of 88%, HPLC: 99.3%.
[0034] Example 2
[0035] Step 1: Add styrene (52.1 g, 0.5 mol), Ni(cod)2 (1.4 g, 0.005 mol), and PPh3 (1.4 g, 0.005 mol) to a reaction flask, and add 300 mL of n-hexane thereto. Dissolve hydrogen cyanide (20.28 g, 0.75 mol) in toluene. At room temperature, add the hydrogen cyanide solution dropwise to the reaction flask. Subsequently, the reaction was stirred overnight at room temperature. The styrene consumption was monitored by GC, and the reaction was stopped when the remaining amount of styrene was less than 0.5%. Next, a saturated NaHCO3 solution was added thereto to adjust the solution to neutral. Phase separation, the aqueous phase was extracted with ether, and the organic phases were combined. By distillation, 47.3 g of Markovnikov addition product 2-phenylpropionitrile was obtained with a yield of 72%, and 3.3 g of chain byproduct 1-phenylpropionitrile was obtained with a yield of 5%.
[0036] Step 2: The step of converting 2-phenylpropionitrile to generate ketoprofen intermediate-cyanoketoprofen (cyano-directed meta-carbon-hydrogen bond activation reaction), 2-phenylpropionitrile (65.59g, 0.5mol), Pd(OPiv)2 (1.55g, 0.005mol), AgOPiv (250.8g, 1.2mol) are added to the reaction bottle. 300mL of 1,2-dichloroethane is added thereto, benzoyl chloride (140.6g, 1.0mol) is added, and heated at 90°C. After stirring overnight, the silver salt on the bottle wall is shaken into the reaction solution and continued to heat for a total of 42-48h. Subsequently, the reaction is stopped, the reaction solution is cooled to room temperature, filtered, washed with ether, and the filtrate is collected. By distillation, 100g of cyanoketoprofen is obtained with a yield of 85%, HPLC: 99.1%.
[0037] Steps for converting 2-phenylpropionitrile to generate 2-(4-bromomethyl-phenyl)propionitrile, an intermediate of loxoprofen. 2-phenylpropionitrile (65.59 g, 0.5 mol) was dissolved in 250 mL of glacial acetic acid, and paraformaldehyde (31.1 g, 0.5 mol) was added thereto. Hydrogen bromide was dissolved in glacial acetic acid to prepare a 31 wt% hydrobromic acid / glacial acetic acid solution. 100 mL of the hydrobromic acid / glacial acetic acid solution was added to the reaction solution. The reaction was stirred at 50°C for 2 h. After the reaction was completed, the reaction solution was poured into water, and a white solid was precipitated. The white powder was filtered and dried under vacuum to obtain 96.4 g of 2-(4-bromomethyl-phenyl)propionitrile, with a yield of 86%, HPLC: 99.0%.
[0038] Example 3
[0039] Step 1: Add styrene (52.1 g, 0.5 mol), Ni(cod)2 (1.4 g, 0.005 mol), and P(OPh)3 (1.56 g, 0.005 mol) to a reaction flask, and add 300 mL of n-hexane thereto. Dissolve hydrogen cyanide (20.28 g, 0.75 mol) in toluene. At room temperature, add the hydrogen cyanide solution dropwise to the reaction flask. Subsequently, the reaction was stirred overnight at room temperature. The styrene consumption was monitored by GC, and the reaction was stopped when the remaining amount of styrene was less than 0.5%. Next, a saturated NaHCO3 solution was added thereto to adjust the solution to neutral. Phase separation, the aqueous phase was extracted with ether, and the organic phases were combined. By distillation, 49.2 g of Markovnikov addition product 2-phenylpropionitrile was obtained with a yield of 75%, and 1.4 g of chain byproduct 1-phenylpropionitrile was obtained with a yield of 2%.
[0040] Step 2: The step of converting 2-phenylpropionitrile to generate ketoprofen intermediate-cyanoketoprofen (cyano-directed meta-carbon-hydrogen bond activation reaction), 2-phenylpropionitrile (65.59g, 0.5mol), Pd(OPiv)2 (1.55g, 0.005mol), AgOPiv (250.8g, 1.2mol) are added to the reaction bottle. 300mL of 1,2-dichloroethane is added thereto, benzoyl chloride (140.6g, 1.0mol) is added, and heated at 90°C. After stirring overnight, the silver salt on the bottle wall is shaken into the reaction solution and continued to heat for a total of 42-48h. Subsequently, the reaction is stopped, the reaction solution is cooled to room temperature, filtered, washed with ether, and the filtrate is collected. By distillation, 100.0g of cyanoketoprofen is obtained with a yield of 85%, HPLC: 99.1%.
[0041] Steps for converting 2-phenylpropionitrile to generate loxoprofen intermediate 2-(4-bromomethyl-phenyl)propionitrile. Dissolve 2-phenylpropionitrile (65.59g, 0.5mol) in 250mL of glacial acetic acid, and add paraformaldehyde (31.1g, 0.5mol) thereto. Dissolve hydrogen bromide in glacial acetic acid to prepare a 31wt% hydrobromic acid / glacial acetic acid solution. Add 100mL of the hydrobromic acid / glacial acetic acid solution to the reaction solution. The reaction is stirred at 50°C for 2h. After the reaction is completed, pour the reaction solution into water, a white solid precipitates, filter to obtain a white powder, vacuum dry, and obtain 98.6g of 2-(4-bromomethyl-phenyl)propionitrile, with a yield of 88%, HPLC: 99.3%.
[0042] Example 4
[0043] Step 1: Add styrene (52.1 g, 0.5 mol), Ni(cod)2 (1.4 g, 0.005 mol), and bisphosphonite CH2P2(OPh)4 (1.12 g, 0.0025 mol) to a reaction flask, and add 300 mL of n-hexane thereto. Dissolve hydrogen cyanide (20.28 g, 0.75 mol) in toluene. At room temperature, add the hydrogen cyanide solution dropwise to the reaction flask. Subsequently, the reaction was stirred overnight at room temperature. The styrene consumption was monitored by GC, and the reaction was stopped when the remaining amount of styrene was less than 0.5%. Then, a saturated NaHCO3 solution was added thereto to adjust the solution to neutral. Phase separation, the aqueous phase was extracted with ether, and the organic phases were combined. 53.8 g of Markovnikov addition product 2-phenylpropionitrile was obtained by distillation with a yield of 82%, and no chain byproduct 1-phenylpropionitrile was found.
[0044] Step 2: The step of converting 2-phenylpropionitrile to generate ketoprofen intermediate-cyanoketoprofen (cyano-directed meta-carbon-hydrogen bond activation reaction), 2-phenylpropionitrile (65.59g, 0.5mol), Pd(OPiv)2 (1.55g, 0.005mol), AgOPiv (250.8g, 1.2mol) are added to the reaction bottle. 300mL of 1,2-dichloroethane is added thereto, benzoyl chloride (140.6g, 1.0mol) is added, and heated at 90°C. After stirring overnight, the silver salt on the bottle wall is shaken into the reaction solution and continued to heat for a total of 42-48h. Subsequently, the reaction is stopped, the reaction solution is cooled to room temperature, filtered, washed with ether, and the filtrate is collected. By distillation, 101.2g of cyanoketoprofen is obtained with a yield of 86%, HPLC: 99.4%.
[0045] Steps for converting 2-phenylpropionitrile to generate 2-(4-bromomethyl-phenyl)propionitrile, an intermediate of loxoprofen. Dissolve 2-phenylpropionitrile (65.59 g, 0.5 mol) in 250 mL of glacial acetic acid, and add paraformaldehyde (31.1 g, 0.5 mol) thereto. Dissolve hydrogen bromide in glacial acetic acid to prepare a 31 wt% hydrobromic acid / glacial acetic acid solution. Add 100 mL of the hydrobromic acid / glacial acetic acid solution to the reaction solution. The reaction was stirred at 50°C for 2 h. After the reaction was completed, the reaction solution was poured into water, and a white solid precipitated. The white powder was filtered and dried under vacuum to obtain 98.6 g of 2-(4-bromomethyl-phenyl)propionitrile, with a yield of 88%, HPLC: 99.3%. .
[0046] Example 5
[0047] Step 1: Add styrene (52.1 g, 0.5 mol), Ni(cod)2 (1.40 g, 0.005 mol), and glucosyl bisphosphine ligand a (3.15 g, 0.0025 mol) to a reaction flask, and add 300 mL of n-hexane thereto. Dissolve hydrogen cyanide (20.28 g, 0.75 mol) in toluene. At room temperature, add the hydrogen cyanide solution dropwise to the reaction flask. Subsequently, the reaction was stirred overnight at room temperature. The styrene consumption was monitored by GC, and the reaction was stopped when the remaining amount of styrene was less than 0.5%. Then, a saturated NaHCO3 solution was added thereto to adjust the solution to neutral. Phase separation, the aqueous phase was extracted with ether, and the organic phases were combined. Markovnikov addition product 2-phenylpropionitrile 60.4 g was obtained by distillation, with a yield of 92%, and no chain byproduct 1-phenylpropionitrile was found.
[0048] Step 2: The step of converting 2-phenylpropionitrile to generate ketoprofen intermediate-cyanoketoprofen (cyano-directed meta-carbon-hydrogen bond activation reaction), 2-phenylpropionitrile (65.59g, 0.5mol), Pd(OPiv)2 (1.55g, 0.005mol), AgOPiv (250.8g, 1.2mol) are added to the reaction bottle. 300mL of 1,2-dichloroethane is added thereto, benzoyl chloride (140.6g, 1.0mol) is added, and heated at 90°C. After stirring overnight, the silver salt on the bottle wall is shaken into the reaction solution and continued to heat for a total of 42-48h. Subsequently, the reaction is stopped, the reaction solution is cooled to room temperature, filtered, washed with ether, and the filtrate is collected. By distillation, 100.0g of cyanoketoprofen is obtained with a yield of 85%, HPLC: 99.1%.
[0049] Steps for converting 2-phenylpropionitrile to generate 2-(4-bromomethyl-phenyl)propionitrile, an intermediate of loxoprofen. 2-phenylpropionitrile (65.59 g, 0.5 mol) was dissolved in 250 mL of glacial acetic acid, and paraformaldehyde (31.1 g, 0.5 mol) was added thereto. Hydrogen bromide was dissolved in glacial acetic acid to prepare a 31 wt% hydrobromic acid / glacial acetic acid solution. 100 mL of the hydrobromic acid / glacial acetic acid solution was added to the reaction solution. The reaction was stirred at 50°C for 2 h. After the reaction was completed, the reaction solution was poured into water, and a white solid was precipitated. The white powder was filtered and dried under vacuum to obtain 97.49 g of 2-(4-bromomethyl-phenyl)propionitrile, with a yield of 87%, HPLC: 99.2%.
[0050] Example 6
[0051] Step 1: Add styrene (52.1 g, 0.5 mol), Ni(cod)2 (1.40 g, 0.005 mol), and glucosyl bisphosphine ligand d (2.07 g, 0.0025 mol) to a reaction flask, and add 300 mL of n-hexane thereto. Dissolve hydrogen cyanide (20.28 g, 0.75 mol) in toluene. At room temperature, add the hydrogen cyanide solution dropwise to the reaction flask. Subsequently, the reaction was stirred overnight at room temperature. The styrene consumption was monitored by GC, and the reaction was stopped when the remaining amount of styrene was less than 0.5%. Next, a saturated NaHCO3 solution was added thereto to adjust the solution to neutral. Phase separation, the aqueous phase was extracted with ether, and the organic phases were combined. 55.76 g of Markovnikov addition product 2-phenylpropionitrile was obtained by distillation with a yield of 85%, and no chain byproduct 1-phenylpropionitrile was found.
[0052] Step 2: The step of converting 2-phenylpropionitrile to generate ketoprofen intermediate-cyanoketoprofen (cyano-directed meta-carbon-hydrogen bond activation reaction), 2-phenylpropionitrile (65.59g, 5mol), Pd(OPiv)2 (1.55g, 0.005mol), AgOPiv (250.8g, 1.2mol) are added to the reaction bottle. 300mL of 1,2-dichloroethane is added thereto, benzoyl chloride (140.6g, 1.0mol) is added, and heated at 90°C. After stirring overnight, the silver salt on the bottle wall is shaken into the reaction solution and continued to heat for a total of 42-48h. Subsequently, the reaction is stopped, the reaction solution is cooled to room temperature, filtered, washed with ether, and the filtrate is collected. By distillation, 97.65g of cyanoketoprofen is obtained, with a yield of 83%, HPLC: 99.5%.
[0053] Steps for converting 2-phenylpropionitrile to generate loxoprofen intermediate 2-(4-bromomethyl-phenyl)propionitrile. Dissolve 2-phenylpropionitrile (65.59 g, 0.5 mol) in 250 mL of glacial acetic acid, and add paraformaldehyde (31.1 g, 0.5 mol) thereto. Dissolve hydrogen bromide in glacial acetic acid to prepare a 31 wt% hydrobromic acid / glacial acetic acid solution. Add 100 mL of the hydrobromic acid / glacial acetic acid solution to the reaction solution. The reaction was stirred at 50°C for 2 h. After the reaction was completed, the reaction solution was poured into water, and a white solid precipitated. The white powder was filtered and dried under vacuum to obtain 98.6 g of 2-(4-bromomethyl-phenyl)propionitrile, with a yield of 88%, HPLC: 99.3%.
[0054] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.
Claims
1. A method for synthesizing a ketoprofen intermediate, which converts styrene into a ketoprofen intermediate, cyanoketoprofen, by a two-step method, and the reaction equation is as follows: It is characterized in that The steps include: In the first step, styrene reacts with hydrogen cyanide in an organic solvent under the action of a nickel catalyst and a ligand to generate 2-phenylpropionitrile; wherein the nickel and the ligand form Ni[P(Oo-tolyl) 3 ] 4 ; or when the nickel catalyst is Ni(cod) 2 When , the ligand corresponds to the following structure: In the second step, in the presence of a palladium catalyst and a silver salt additive, 2-phenylpropionitrile reacts with benzoyl chloride in an organic solvent to generate a ketoprofen intermediate, cyanoketoprofen; the palladium catalyst is Pd(OPiv) 2 ; The silver salt additive is AgOPiv.
2. The method for synthesizing a ketoprofen intermediate according to claim 1, Features: In the first step, the molar ratio of styrene, hydrogen cyanide, nickel catalyst and ligand is 1:1-5:0.01-0.1:0.01-0.
1.
3. The method for synthesizing a ketoprofen intermediate according to claim 1, Features: In the first step, the organic solvent is an alkane solvent, an ether solvent or an aromatic solvent; and the reaction temperature is 0-30°C.
4. The method for synthesizing a ketoprofen intermediate according to claim 1, Features: In the second step, the molar ratio of the 2-phenylpropionitrile, benzoyl chloride, palladium catalyst and silver salt additive is 1:1-5:0.01-0.20:1.0-4.
0.
5. The method for synthesizing a ketoprofen intermediate according to claim 1, Features: In the second step, during the conversion of 2-phenylpropionitrile into cyanoketoprofen, the organic solvent is selected from dichloromethane, 1,2-dichloroethane or 1,2-dibromoethane; and the reaction temperature is 60-120°C.