CN101759556A - Synthesis method of ketoprofen - Google Patents

Abstract

The present invention relates to a kind of synthetic method of ketoprofen shown in formula (I), as 3-nitrile ethyl benzophenone shown in formula (II) reacts with sufficient hydrogen chloride gas in alcohols reaction solvent, Produce the intermediate shown in formula (III), add the aqueous solution of 0.1～10mol/L inorganic alkali after reaction finishes and carry out hydrolysis reaction, hydrolysis is finished, after adding acid, adjust pH value to 3～4, reaction liquid separation process obtains as formula ( 1) shown ketoprofen; the present invention has high reaction yield, low cost, mild reaction conditions, no condensation by-products, low energy consumption, easy and convenient operation, and is suitable for industrial production.

Description

A kind of synthetic method of ketoprofen

(1) Technical field

The invention relates to a method for synthesizing ketoprofen, in particular to the method of firstly activating the nitrile group and then hydrolyzing to synthesize ketoprofen.

(2) Background technology

Ketoprofen, whose chemical name is 3-benzoyl-α-methylphenylacetic acid, is a non-steroidal anti-inflammatory analgesic with anti-inflammatory, antipyretic and analgesic effects. The analgesic effect is superior to similar drugs and lasts for a long time, with less toxic and side effects, and good safety and tolerance. It was first listed in France in 1973, and officially entered China in the 1980s. Now it has developed various dosage forms such as oral tablets, patches, and diaphragms, and has been widely used at home and abroad.

Before the present invention was made, most of the chemical synthesis methods of prior art ketoprofen obtained ketoprofen through the hydrolysis of key intermediate 3-nitrile ethyl benzophenone, and hydrolysis can be carried out under acidic conditions and alkaline conditions, such as in 49% sulfuric acid solution 100mL (concentrated sulfuric acid: water = 1: 1), stirred and heated up and kept at 125 ~ 130 ° C reflux for 4-5 hours, then neutralized with alkali, and finally acidified to obtain ketoprofen. This method has high solvent corrosiveness and low operation safety, which brings great inconvenience to industrialization. Or react at high temperature (130° C.) for more than 3 hours in the two-phase system of toluene or xylene and water in the presence of inorganic bases (ZL99116808.9), and obtain ketoprofen after acidification. Above-mentioned method also can produce some impurity that can't remove, affects the purity of ketoprofen.

(3) Contents of the invention

In order to solve the deficiencies in the prior art of high hydrolysis cost, long reaction time, difficult post-treatment and easy pollution of 3-nitrile ethyl benzophenone, the invention provides a method with reasonable process, high reaction yield and short reaction time , low production cost, clean and environment-friendly synthetic method of ketoprofen.

For achieving the purpose of the invention, the technical scheme adopted by the present invention is:

A kind of synthetic method of ketoprofen shown in formula (I): 3-nitrile ethyl benzophenone shown in formula (II) reacts with sufficient hydrogen chloride gas in alcohols reaction solvent, generates such as formula The intermediate shown in (III), after the reaction finishes, add the aqueous solution of 0.1～10mol/L inorganic alkali to carry out hydrolysis reaction, after hydrolysis is completed, after adding acid, the pH value is adjusted to 3～4, and the reaction solution is separated and processed to obtain the formula (I) Ketoprofen shown; usually adjust pH value with hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid aqueous solution; Described inorganic base is potassium hydroxide or sodium hydroxide; Described 3-nitrile ethyl benzophenone and inorganic base The molar ratio of substances is 1:1.0-6.0.

Further, the alcohol reaction solvent is a mixture of one or more of the following in any proportion: methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, ethylene glycol or glycerol . The mass dosage of the alcohol reaction solvent is generally 1-100 times, preferably 5-20 times, the mass of 3-nitrile ethyl benzophenone.

Furthermore, the temperature of the hydrolysis reaction between the intermediate represented by the formula (III) and the inorganic base is 20-100°C, preferably 60-100°C. The time of the hydrolysis reaction is 0.1-10 hours, preferably the time of the hydrolysis reaction is 0.5-2 hours.

In the synthesis method of ketoprofen described in the present invention, the reaction temperature of the 3-nitrile ethyl benzophenone and hydrogen chloride gas is -20-100°C, preferably 20-50°C, more preferably room temperature.

Still further, the method for separating and treating the reaction liquid of the present invention is: the reaction liquid is filtered, and the filter cake is recrystallized by a recrystallization solvent to obtain ketoprofen; the recrystallization solvent is a mixture of one or more of the following in any proportion: Water, acetone, methanol or ethanol.

The acid for adjusting the pH value is usually hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid.

Concretely, the synthetic method of synthetic ketoprofen described in the present invention is preferably carried out according to the following steps: 3-nitrile ethyl benzophenone as shown in formula (II) is dissolved in alcoholic solvent, and feeds at room temperature Sufficient amount of HCl gas, TLC to track the reaction, the raw material point disappears after the reaction is completed, add 1-4mol/L inorganic alkali aqueous solution, heat to 60-100°C for hydrolysis reaction, react for 0.5-2 hours, TLC track the reaction, the raw material point disappears That is, after the reaction is finished, the reaction liquid is cooled to room temperature, and the pH value is adjusted to 3 to 4 with hydrochloric acid, filtered, and the filter cake is recrystallized by a recrystallization solvent to obtain ketoprofen; the 3-nitrile ethyl benzophenone and the inorganic base The molar ratio of the substance is 1: 2.0～3.0, and the mass consumption of described reaction solvent is 5～20 times of the quality of 3-nitrile ethyl benzophenone shown in formula (II); Described inorganic base is hydrogen Potassium oxide or sodium hydroxide; The alcohol reaction solvent is the following one or more than two mixed in any proportion: methanol, ethanol, isopropanol, n-butanol, and the recrystallization solvent is the following one or Mixing of two or more in any proportion: water, acetone, methanol or ethanol.

Compared with the prior art, the present invention has beneficial effects embodied in:

1. High reaction yield (basically above 90%)

2. The reaction conditions are mild and the reaction time is short. The reaction time of the traditional process is 8-10 hours, which is long and consumes a lot of energy.

3. Good selectivity, basically no condensation by-products. The active methylene and carbonyl addition condensation products contained in the existing common process products need to be removed with chlorobenzene, and this process does not need to use environmentally unfriendly solvents such as chlorobenzene.

(4) Specific implementation methods

The present invention will be further described below in conjunction with specific examples, but the protection scope of the present invention is not limited thereto.

Example 1

Dissolve 23.5g (0.1mol) of 3-nitrile ethyl benzophenone in 200ml of methanol, pour it into a three-necked flask, feed HCl gas, and react at room temperature for 1.5 hours. TLC will track the reaction. When the raw material point disappears, the reaction ends 8g (0.2mol) NaOH and 100ml water were added to the solution, and the mixture was refluxed at 70°C for 2 hours. The reaction liquid was cooled to room temperature, and the pH value was adjusted to 3.5 with 1 mol/L hydrochloric acid, and a solid was precipitated. Filtrate through filter paper, put the filter cake into an oven to dry, recrystallize the crude product with methanol (300 mL), filter through filter paper, put the filter cake into an oven to dry, and obtain 22.8 g of ketoprofen pure product, which is a white crystal with a melting point of 95 to 96° C. Rate 90%.

Example 2

Dissolve 23.5g (0.1mol) of 3-nitrile ethyl benzophenone in 100ml of methanol, pour it into a three-necked flask, feed HCl gas, react at room temperature for 2 hours, and add 12g (0.3mol l) NaOH and 100ml of water were refluxed at 70°C for 2 hours. The reaction solution was cooled to room temperature, and the pH value was adjusted to about 3.5 with hydrochloric acid, and a solid was precipitated. Filter through filter paper, dry, recrystallize the filter cake with methanol (300 mL), filter through filter paper, put the filter cake into an oven and dry to obtain 23.6 g of pure ketoprofen, which is a white crystal with a melting point of 95 to 96° C. and a yield of 93%.

Example 3

Dissolve 23.5g (0.1mol) of 3-nitrile ethyl benzophenone in 100ml of methanol, pour it into a three-necked flask, feed HCl gas, react at room temperature for 1.5 hours, and add 11.2g (0.2mol )KOH and 50ml of water, reflux at 70°C for 2 hours. The reaction solution was cooled to room temperature, and the pH value was adjusted to about 3.5 with hydrochloric acid, and a solid was precipitated. Filter, dry, recrystallize the filter cake with methanol (300 mL), filter, put the filter cake into an oven to dry, and obtain 24.1 g of pure ketoprofen as white crystals, melting point 95-96° C., yield 95%.

Example 4

Dissolve 23.5g (0.1mol) of 3-nitrile ethyl benzophenone in 200ml of methanol, pour it into a three-necked flask, feed HCl gas, react at room temperature for 2 hours, and add 16.8g (0.3mol )KOH and 100ml of water were refluxed at 70°C for 2 hours. The reaction solution was cooled to room temperature, and the pH value was adjusted to about 3.5 with hydrochloric acid, and a solid was precipitated. Filtrate, dry, recrystallize the filter cake with methanol (300 mL), filter, put the filter cake into an oven to dry, and obtain 24.8 g of pure ketoprofen, which is a white crystal with a melting point of 95-96° C. and a yield of 98%.

Example 5

Dissolve 23.5g (0.1mol) of 3-nitrile ethyl benzophenone in 50ml of methanol, pour it into a three-necked flask, feed HCl gas, react at room temperature for 2 hours, and add 11.2g (0.2mol )KOH and 50ml of water, reflux at 70°C for 2 hours. The reaction solution was cooled to room temperature, and the pH value was adjusted to about 3.5 with hydrochloric acid, and a solid was precipitated. Filter, dry, recrystallize the filter cake with methanol (300 mL), filter, put the filter cake into an oven to dry, and obtain 24.1 g of pure ketoprofen as white crystals, melting point 95-96° C., yield 95%.

Example 6

Dissolve 23.5g (0.1mol) of 3-nitrile ethyl benzophenone in 200ml of methanol, pour it into a three-necked flask, feed HCl gas, and react at -10°C for 1.5 hours. After the reaction is complete, add 11.2 g (0.2mol) KOH and 100ml water were refluxed at 70°C for 2 hours. The reaction solution was cooled to room temperature, and the pH value was adjusted to about 3.5 with hydrochloric acid, and a solid was precipitated. Filter, dry, recrystallize the filter cake with methanol (300 mL), filter, put the filter cake into an oven to dry, and obtain 23.1 g of pure ketoprofen as white crystals, with a melting point of 95-96° C. and a yield of 91%.

Example 7

Dissolve 23.5g (0.1mol) of 3-nitrile ethyl benzophenone in 100ml of methanol, pour it into a three-necked flask, feed HCl gas, and react at 50°C for 1.5 hours. After the reaction, add 11.2g of (0.2mol) KOH and 100ml water were refluxed at 70°C for 2 hours. The reaction solution was cooled to room temperature, and the pH value was adjusted to about 3.5 with hydrochloric acid, and a solid was precipitated. Filtrate, dry, recrystallize the filter cake with methanol (300 mL), filter, put the filter cake into an oven to dry, and obtain 24.8 g of pure ketoprofen, which is a white crystal with a melting point of 95-96° C. and a yield of 98%.

Example 8

The reaction solvent was replaced with 200ml ethanol, and other operations and reaction conditions were the same as in Example 4 to obtain 24.6 g of pure ketoprofen as white crystals with a melting point of 95-96° C. and a yield of 97%.

Example 9

The reaction solvent was replaced with 200ml of n-propanol and 50ml of ethylene glycol, and other operations and reaction conditions were the same as in Example 4 to obtain 24.8g of ketoprofen pure product, which was a white crystal with a melting point of 95-96°C and a yield of 98%.

Example 10

The reaction solvent was replaced with 200ml of isopropanol and 50ml of ethylene glycol, and other operations and reaction conditions were the same as in Example 4 to obtain 24.6g of ketoprofen pure product, which was a white crystal with a melting point of 95-96° C. and a yield of 97%.

Example 11

The reaction solvent was replaced with 200ml of n-butanol and 50ml of ethylene glycol, and other operations and reaction conditions were the same as in Example 4 to obtain 24.1g of ketoprofen pure product, which was a white crystal with a melting point of 95-96° C. and a yield of 95%.

Example 12

The reaction solvent was replaced with 200ml of isobutanol and 50ml of ethylene glycol, and other operations and reaction conditions were the same as in Example 4 to obtain 24.6g of pure ketoprofen as white crystals with a melting point of 95-96° C. and a yield of 97%.

Example 13

The reaction solvent was changed into 1000ml ethylene glycol, and other operations and reaction conditions were the same as in Example 4 to obtain 24.1 g of pure ketoprofen as white crystals with a melting point of 95-96° C. and a yield of 95%.

Example 14

The reaction solvent was replaced with 1000ml glycerol, and other operations and reaction conditions were the same as in Example 4, and 23.6 g of pure ketoprofen was obtained as white crystals with a melting point of 95-96° C. and a yield of 93%.

Example 15

The recrystallization solvent was replaced by ethanol, and the consumption was 500 mL. Other operations and reaction conditions were the same as in Example 4, and 23.8 g of pure ketoprofen was obtained, which was a white crystal with a melting point of 95-96° C. and a yield of 94%.

Example 16

The recrystallization solvent was changed to acetone, and the dosage was 100 mL. Other operations were the same as in Example 4 of the reaction conditions, and 24.6 g of pure ketoprofen was obtained as white crystals with a melting point of 95-96° C. and a yield of 97%.

Example 17

The recrystallization solvent was changed to acetone (100mL) and water (50mL), and other operations and reaction conditions were the same as in Example 4 to obtain 24.6g of pure ketoprofen, which was white crystals with a melting point of 95-96° C. and a yield of 97%.

Comparative example 1

Add 23.5g (0.1mol) 3-nitrile ethyl benzophenone, 4.0g (0.1mol) sodium hydroxide, 100mL water and 200mL methanol , heated to reflux for 2 hours, the reaction solution was cooled to room temperature, the pH value was adjusted to 3.5 with hydrochloric acid, and a solid was precipitated. Filtrate, dry, recrystallize the filter cake with methanol (300 mL), filter, put the filter cake into an oven to dry, and obtain 13.4 g of pure ketoprofen, which is a white crystal with a melting point of 93-95° C. and a yield of 53%.

Comparative example 2

The reflux reaction time was 8 hours, and other operations were the same as in Comparative Example 1 to obtain 18.0 g of pure ketoprofen as white crystals with a melting point of 95-96° C. and a yield of 71%.

Comparative example 3

Reaction solvent is changed into water 200mL, n-butanol 200mL and ethylene glycol 100ml, and the reflux reaction time is 2 hours, and other operations are the same as comparative example 1, obtains ketoprofen pure product 12.7g, is white crystal, and fusing point 93～95 ℃, Yield 50%.

Comparative example 4

Reaction solvent is changed into water 200mL, n-butanol 200mL and ethylene glycol 100ml, and the reflux reaction time is 8 hours, and other operation is the same as comparative example 1, obtains ketoprofen pure product 19.0g, is white crystal, and fusing point 93～95 ℃, Yield 75%.

Comparative example 5

Use 200 ml of acetone for recrystallization, and other operations are the same as in Comparative Example 1 to obtain 14.7 g of pure ketoprofen, which is white crystals with a melting point of 93-95° C. and a yield of 58%.

Claims (10)

1. the synthetic method of the Ketoprofen shown in the formula (I), it is characterized in that described method is: suc as formula the 3-nitrile ethyl benzophenone shown in (II) in the alcohols reaction solvent and the hydrogen chloride gas precursor reactant of capacity, generation is suc as formula intermediate shown in (III), reaction finishes the reaction that is hydrolyzed of the aqueous solution that the back adds 0.1～10mol/L mineral alkali, hydrolysis finishes, add the acid back and transfer pH value to 3～4, the reaction solution separating treatment obtains suc as formula the Ketoprofen shown in (I); Described mineral alkali is potassium hydroxide or sodium hydroxide; The amount of substance ratio of described 3-nitrile ethyl benzophenone and mineral alkali is 1: 1.0～6.0;

2. the synthetic method of Ketoprofen as claimed in claim 1 is characterized in that described alcohols reaction solvent is following one or more mixing by arbitrary proportion: methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, ethylene glycol or glycerol.

3. the synthetic method of Ketoprofen as claimed in claim 1, the quality consumption that it is characterized in that described alcohols reaction solvent is 1～100 times of 3-nitrile ethyl benzophenone quality.

4. the method for synthesizing ketoprofen as claimed in claim 1 is characterized in that described temperature suc as formula intermediate shown in (III) and mineral alkali hydrolysis reaction is 20～100 ℃.

5. the synthetic method of Ketoprofen as claimed in claim 1, the time that it is characterized in that described hydrolysis reaction is 0.1～10 hour.

6. the synthetic method of Ketoprofen as claimed in claim 1 is characterized in that the temperature of described 3-nitrile ethyl benzophenone and hcl reaction is-20～100 ℃.

7. the synthetic method of Ketoprofen as claimed in claim 1 is characterized in that the temperature of described 3-nitrile ethyl benzophenone and hcl reaction is a room temperature.

8. the synthetic method of Ketoprofen as claimed in claim 1 is characterized in that described reaction solution method for separating and processing is: reacting liquid filtering, and filter cake obtains Ketoprofen through the recrystallization solvent recrystallization; Described recrystallization solvent is following one or more mixing by arbitrary proportion: water, acetone, methyl alcohol or ethanol.

9. the synthetic method of Ketoprofen as claimed in claim 1 is characterized in that hydrolysis reaction finishes, and transfers PH to 3～4 with hydrochloric acid, sulfuric acid, phosphoric acid or aqueous acetic acid.

10. the synthetic method of synthesizing ketoprofen as claimed in claim 1, it is characterized in that described method carries out according to following steps: will be dissolved in alcoholic solvent suc as formula the 3-nitrile ethyl benzophenone shown in (II), feed capacity HCl gas under the room temperature, TLC follows the tracks of reaction, after the disappearance of raw material point is promptly reacted and is finished, the aqueous solution that adds 1～4mol/L mineral alkali, be heated to 60～100 ℃ of hydrolysis reaction, reacted 0.5～2 hour, TLC follows the tracks of reaction, and raw material point disappears after the i.e. reaction end, reaction solution is cooled to room temperature, with salt acid for adjusting pH value to 3～4, filter, filter cake obtains Ketoprofen through the recrystallization solvent recrystallization; The throwing amount of substance ratio of described 3-nitrile ethyl benzophenone and mineral alkali is 1: 2.0～3.0, and the quality consumption of described reaction solvent is 5～20 times suc as formula the 3-nitrile ethyl benzophenone quality shown in (II); Described mineral alkali is potassium hydroxide or sodium hydroxide; Described alcohols reaction solvent is following one or more mixing by arbitrary proportion: methyl alcohol, ethanol, Virahol, propyl carbinol,, described recrystallization solvent is following one or more mixing by arbitrary proportion: water, acetone, methyl alcohol or ethanol.