CN114031621B

CN114031621B - Improved ketorolac preparation method

Info

Publication number: CN114031621B
Application number: CN202111483639.6A
Authority: CN
Inventors: 刘超; 吴昆�; 蔡月皎; 周涛; 王君山; 彭显峰
Original assignee: Sichuan Shengrui Pharmaceutical Co ltd
Current assignee: Sichuan Shengrui Pharmaceutical Co ltd
Priority date: 2021-12-07
Filing date: 2021-12-07
Publication date: 2022-08-26
Anticipated expiration: 2041-12-07
Also published as: CN114031621A

Abstract

The invention discloses an improved ketorolac preparation method, which takes 2-benzoylpyrrole as a main raw material, directly reacts under the catalysis of manganese acetate dihydrate (trivalent), an organic phase directly performs a ring closing reaction after simple liquid separation treatment of a solution after the reaction, and directly performs hydrolysis decarboxylation reaction after the liquid separation treatment, and the reaction solution adjusts acid and alkali to obtain the ketorolac. The method adopts three steps of oxidation condensation, ring closing and hydrolysis deacidification as a one-pot continuous reaction, simplifies the operation, improves the yield and the purity, reduces the production cost and the discharge of three wastes, and is suitable for industrialized production.

Description

Improved ketorolac preparation method

Technical Field

The invention belongs to the field of medicinal chemistry, and particularly relates to an improved preparation method of ketorolac.

Background

Ketorolac tromethamine is a novel injectable nonsteroidal strong analgesic and moderate anti-inflammatory antipyretic drug, the action mechanism of which is to reduce Prostaglandins (PGs) in the periphery and the center of the body by inhibiting the generation of the PGs, and the chemical structure of the main component of ketorolac is as follows:

at present, ketorolac tromethamine is synthesized by taking 2-benzoyl pyrrole as an initial material, and performing oxidative condensation, ring closure and deacidification, and finally forming salt to obtain ketorolac tromethamine, wherein the reaction route is as follows:

the synthesis of ketorolac is particularly important in the step of synthesizing ketorolac tromethamine. However, most of the synthetic procedures disclosed in the prior literature require complicated post-treatment (China journal of pharmaceutical chemistry, 1995,5(3): 223-. In addition, the long-time reduced pressure concentration not only prolongs the production period and increases the production cost, but also increases the probability of generating impurities of intermediates and ketorolac by long-time heating, and influences the final quality of the ketorolac tromethamine. However, since the step 1-step 3 reactions involve the synthesis of a plurality of intermediates, the solvents and reagents used in each step may interfere with the next step, especially in the step of synthesizing M-1, the use of a large amount of manganese ions and acetic acid solvents causes the problems of difficult liquid separation and extraction and difficult removal of high-boiling point acetic acid solvents in the post-treatment process, and the continuous reaction is difficult to achieve the desired purpose. If the acetic acid solvent is enriched in the subsequent synthesis reaction, the cyclization reaction is greatly influenced. Moreover, the problem of a large amount of three wastes caused by a large amount of solvents after each reaction step is finished is also worried, and the problems of high energy consumption, long period and the like caused by concentration are also great challenges for the production cost of enterprises.

Patent CN101143865 optimizes the process of step2 step ring closing reaction and step3 step hydrolysis decarboxylation reaction, and attempts to adopt a "one-pot" method, but does not indicate the source of intermediate M-1, and may involve the problems of a large amount of metal ions and high boiling point solvent acetic acid existing in the step1 step oxidation condensation reaction, and a concentration operation is still adopted in the subsequent treatment process after the step2 step ring closing reaction. CN113603625 and CN101575340 report that ketorolac is susceptible to oxidation. The intermediate of step 1-step 3 has poor stability, and the long-time heating concentration operation can affect the quality of the ketorolac. Therefore, there is a need for improvements to the prior art processes.

The inventor of the invention repeatedly searches and researches through bolate trials and experiments, optimizes the synthesis conditions of the oxidation condensation reaction in step1 on the basis of the patent CN113045471, simultaneously considers the synthesis conditions and post-treatment of step2 cyclization and step3 hydrolysis decarboxylation reaction, utilizes the advantages of two-phase reaction of step2 and step3, can separate the required intermediate by simple liquid separation and extraction after the reaction is finished, does not need additional concentration operation steps such as liquid-solid separation and the like, and other impurities are removed only by liquid separation washing, and the three steps of oxidation condensation, cyclization and hydrolysis decarboxylation reaction are comprehensively treated, thereby really realizing 'one-pot' continuous reaction, thoroughly eliminating the fussy operation steps of high energy consumption, high cost, long period and large pollution in the whole process, and solving the important problem of technologized mass production in the synthesis. The method has the advantages of simple operation, low cost, high yield and less pollution, the purity (area normalization method) of the obtained ketorolac is more than or equal to 99.5 percent through HPLC detection, the single maximum impurity is less than 0.15 percent, the total yield in three steps is more than 90 percent, and the method is suitable for industrial mass production. The prepared ketorolac is converted into ketorolac tromethamine through simple decoloration and salification, the purity of the ketorolac tromethamine detected by HPLC is more than or equal to 99.8 percent, and the single maximum impurity is below 0.10 percent, which meets the requirement of medicine (the preparation method refers to CN101143865, which is introduced in full and is not described again).

Disclosure of Invention

The invention aims to provide an improved ketorolac preparation method, which integrates three reactions of oxidative condensation, cyclization and hydrolysis decarboxylation, and truly realizes 'one-pot' continuous reaction on the whole; the method has the advantages of simple operation, low cost, high yield and less pollution, the HPLC detection purity (area normalization method) of the obtained ketorolac is more than or equal to 99.5 percent, the single maximum impurity is less than 0.15 percent, the total yield of the three steps is more than 90 percent, and the method is suitable for industrial mass production. And moreover, the obtained ketorolac is converted into ketorolac tromethamine through simple decoloration and salification, the purity of the ketorolac tromethamine detected by HPLC is more than or equal to 99.8%, and the single maximum impurity is below 0.10%, thus meeting the requirement of medicine.

In one embodiment, the improved preparation method of ketorolac comprises the steps of reacting 2-benzoylpyrrole with triethyl methanetricarboxylate in an organic solvent under the catalysis of manganese acetate dihydrate (trivalent), adding a sodium bisulfite aqueous solution after the reaction is finished, separating an organic phase, directly performing a ring closing reaction in the presence of a phase transfer catalyst without separation, separating the organic phase after the reaction is finished, directly performing hydrolysis and decarboxylation without separation, adjusting the pH value of a reaction solution after the reaction is finished, filtering, and drying to obtain the ketorolac.

In one embodiment, the present invention provides a method for preparing ketorolac, comprising the steps of:

1) adding 2-benzoylpyrrole, triethyl methanetricarboxylate, manganese acetate dihydrate (trivalent), sodium acetate and acetic anhydride into an organic solvent, and heating until the reaction is complete; after the reaction is finished, adding a sodium bisulfite aqueous solution, carrying out liquid separation to obtain an organic phase which is marked as an M-1 solution, and directly carrying out the next step;

2) mixing the M-1 solution with 1, 2-dichloroethane, a phase transfer catalyst, potassium carbonate and a proper amount of water, heating and refluxing until the reaction is complete, adding water for separating liquid, washing the organic phase twice with water to obtain an organic phase which is marked as an M-2 solution, and directly carrying out the next step;

3) mixing the M-2 solution with a phase transfer catalyst and an alkali liquor, heating to 35-45 ℃, reacting completely, separating liquid, washing a water phase with ethyl acetate for 1-2 times, cooling, adjusting the pH value to 1-2 with hydrochloric acid, filtering, washing a filter cake with water, and drying to obtain the ketorolac.

Preferably, in the preparation method of the present invention, the organic solvent is toluene, and the volume amount of the toluene is 9 to 10 times of the mass of the 2-benzoylpyrrole.

Preferably, in the preparation method of the present invention, the phase transfer catalyst is tetrabutylammonium bromide or tetrabutylammonium chloride.

Preferably, in the preparation method of the present invention, the molar ratio of the sodium bisulfite in step 1) to the manganese acetate dihydrate is (0.1-0.3) to 1.0, the phase transfer catalyst in step 2) is tetrabutylammonium bromide, and the molar ratio of the tetrabutylammonium bromide to the 2-benzoylpyrrole is about 0.5:1, step 3) said phase transfer catalyst is tetrabutylammonium bromide, the molar ratio of tetrabutylammonium bromide to 2-benzoylpyrrole is about 0.05: 1.

preferably, in one embodiment, the improved method for preparing ketorolac of the present invention comprises the steps of:

1) adding 2-benzoylpyrrole, triethyl methanetricarboxylate, manganese acetate dihydrate (trivalent), sodium acetate and acetic anhydride into toluene, and heating until the reaction is complete; after the reaction is finished, adding a sodium bisulfite aqueous solution, separating liquid to obtain an organic phase which is marked as an M-1 solution, and directly carrying out the next step;

2) adding M-1 solution, 1, 2-dichloroethane, tetrabutylammonium bromide, potassium carbonate and a proper amount of water, and heating until the reflux reaction is complete; adding water to separate the solution, washing the organic phase twice with water to obtain an organic phase which is marked as an M-2 solution, and directly carrying out the next step;

3) adding an M-2 solution, tetrabutylammonium bromide and a sodium hydroxide aqueous solution, and heating to 35-45 ℃ to completely react; and separating liquid, washing the water phase twice by using ethyl acetate, cooling, adjusting the pH value to 1-2 by using hydrochloric acid, filtering, washing a filter cake by using water, and drying to obtain the ketorolac.

Wherein the molar ratio of the sodium bisulfite in the step 1) to the manganese acetate dihydrate is (0.1-0.3) to 1.0.

Preferably, in the improved method of the present invention, the volume amount of toluene in step 1) is 9 to 10 times of the mass of 2-benzoylpyrrole.

The term "volumetric amount" means the amount of solvent needed per Kg of 2-benzoylpyrrole in volume L, i.e., L/Kg, or ml/g; for example, the toluene solvent has a volume L (ml) of 9 to 10 times that of 2-benzoylpyrrole in kg (g) by 9 to 10 times.

In a preferred embodiment, the present invention provides an improved method for preparing ketorolac, comprising:

1) adding 2-benzoylpyrrole, triethyl methanetricarboxylate, manganese acetate dihydrate (trivalent), sodium acetate and acetic anhydride into toluene with the volume of 10 times, and heating until the reaction is complete; adding a sodium bisulfite aqueous solution with the molar ratio of 0.1 time, separating, and taking the obtained organic phase as an M-1 solution to directly carry out the next step;

In the above preferred embodiment, the ratio of 2-benzoylpyrrole in step 1): triethyl methanetricarboxylate: manganese acetate dihydrate (trivalent): sodium acetate: the molar ratio of acetic anhydride is about 1:1.5:1.5:2.0: 7.5;

in the above preferred embodiment, the ratio of 2-benzoylpyrrole in step 2): 1, 2-dichloroethane: potassium carbonate: tetrabutylammonium bromide is 1: 5.0-10.0: 2.0:0.5, preferably 1: 5.0-8.0: 2.0:0.5, more preferably about 1:6.0:2.0: 0.5;

in the above preferred embodiment, the ratio of 2-benzoylpyrrole in step 3): tetrabutylammonium bromide: the molar ratio of sodium hydroxide is 1:0.05 (4.0-6.0), preferably about 1:0.05: 5.0.

As used herein, "about" means that the feed rates of the various materials in each step are not necessarily exactly integer ratios, and deviations should be tolerated, usually within. + -. 0.1.

The preparation method provided by the invention can be used for obtaining the ketorolac, thoroughly eliminating the complicated operation steps of high energy consumption, high cost, long period and large pollution in the existing process steps, and solving the problem of industrial mass production of ketorolac synthesis. The method has the advantages of simple operation, low cost, less pollution, high purity and high yield. Ketorolac prepared as in the following examples has purity (area normalization method) of 99.5% or more by HPLC detection, single maximum impurity content of 0.15% or less, total yield of more than 90% in three steps, and suitability for industrial mass production. The purity of the obtained ketorolac tromethamine is greater than or equal to 99.8% by HPLC detection, and the single maximum impurity is below 0.10%, which meets the requirement of medicinal use.

Drawings

FIG. 1 is an HPLC chromatogram of ketorolac obtained in example 1.

FIG. 2 is an HPLC chromatogram of ketorolac tromethamine obtained in example 1.

Detailed Description

The following examples are merely exemplary for further illustration and understanding of the present invention, and are not intended to limit the scope of the invention in any way.

Liquid chromatograph: shimadzu LC-2030C (3D plus)

A detector: UV + DAD

A chromatographic column: inertsil ODS-3(4.6 x 250mm,5 μm)

Mobile phase: 0.575% ammonium dihydrogen phosphate solution (3.0): tetrahydrofuran 70: 30

Column temperature: 40 deg.C

Flow rate: 1.0ml/min

Wavelength: 313nm

Sample introduction amount: 10 μ l

EXAMPLE 1 preparation of ketorolac

The synthesis route is as follows:

200g (1.17mol, 1.0equiv.) of 2-benzoylpyrrole (SM), 406.9g (1.75mol, 1.5equiv.) of methanetricarboxylic acid, 469.8g (1.75mol, 1.5equiv.) of manganese acetate dihydrate, 191.7g (2.34mol, 2.0equiv.) of sodium acetate and 894.5g (8.76mol, 7.5equiv.) of acetic anhydride are added into 2000mL of toluene, after the reaction is completely heated, about 1000mL of sodium bisulfite solution is added (54.7 g of sodium bisulfite (0.53mol, 0.45equiv.) is added into 1000mL of water for dissolving configuration), and liquid separation is carried out to obtain an organic phase containing the M-1 intermediate, which is recorded as an M-1 solution, and the next step is directly carried out;

heating 693.7g (7.01mol, 6.0equiv.) of the M-1 solution, 188.3g (0.58mol, 0.5equiv.) of tetrabutylammonium bromide, 322.9g (2.34mol, 2.0equiv.) of potassium carbonate and 322.9g of water until the reflux reaction is completed; adding water to separate the solution, washing the organic phase twice with water to obtain an organic phase containing an intermediate M-2, marking as an M-2 solution, and directly carrying out the next step;

mixing the M-2 solution, 18.8g (0.06mol, 0.05equiv.) of tetrabutylammonium bromide and about 1168mL of sodium hydroxide aqueous solution (prepared by dissolving 233.7g of sodium hydroxide (5.84mol, 5.0equiv.) in 1168mL of water), and heating to 35-45 ℃ to completely react; and (3) separating, washing the water phase twice by using ethyl acetate, cooling, adjusting the pH value to 1-2 by using hydrochloric acid, filtering, washing a filter cake by using water, and drying in vacuum to obtain about 278.4g of ketorolac (M-3), wherein the total yield of the three steps is 93.4%. Purity 99.72% by HPLC, single maximum impurity 0.13%. The results are shown in Table 1 and FIG. 1. Ketorolac is converted into ketorolac tromethamine (refer to the preparation method of CN 101143865), and a sample is detected by HPLC, and has the purity of 99.89% and the single maximum impurity of 0.07%. The results are shown in Table 2 and FIG. 2.

Table 1 HPLC test results of ketorolac

Number of peak	Retention time	Area of	Height	Area%	Degree of separation (USP)	Tailing factor	Number of theoretical plate (USP)	RRT
									1	8.620	31854	1698	0.13	--	2.2	6281	0.420
2	10.785	3809	289	0.02	5.7	--	17196	0.526
									3	14.795	3133	155	0.01	9.2	--	11880	0.721
4	15.838	15897	885	0.06	2.1	1.3	18246	0.772
									5	17.932	7001	331	0.03	4.2	--	18236	0.874
6	20.521	24863339	1082328	99.72	4.6	1.2	18718	1.000
									7	42.740	3553	106	0.01	32.3	1.1	48507	2.083
8	46.069	5269	132	0.02	4.4	1.2	60813	2.245
									In total		24933853	1085924	100.00

HPLC detection results of ketorolac tromethamine obtained in Table 2

Peak number	Retention time	Area of	Height	Area%	Degree of separation (USP)	Tailing factor	Theoretical plate number (USP)	RRT
									1	8.633	15950	901	0.07	--	1.7	5704	0.420
2	15.864	4350	253	0.02	16.4	1.0	22164	0.772
									3	20.554	24086076	1047643	99.89	9.1	1.2	18733	1.000
4	46.168	6119	142	0.03	34.2	1.3	42233	2.246
									Total of		24112495	1048939	100.00

Example 2

206g (1.20mol, 1.0equiv.) of 2-benzoylpyrrole, 419.2g (1.81mol, 1.5equiv.) of methanetricarboxylic acid, 483.9g (1.81mol, 1.5equiv.) of manganese acetate dihydrate (trivalent), 197.4g (2.41mol, 2.0equiv.) of sodium acetate, 921.4g (9.03mol, 7.5equiv.) of acetic anhydride are added into 1850mL of toluene, after complete reaction by heating, about 1030mL of sodium bisulfite aqueous solution is added (41.3 g of sodium bisulfite (0.40mol, 0.33equiv.) is added into 1030mL of water for dissolution configuration), and liquid separation is carried out to obtain an organic phase which is taken as the M-1 solution, and the next step is directly carried out;

heating 952.7g (9.63mol, 8.0equiv.) of the M-1 solution, 167.2g (0.60mol, 0.5equiv.) of tetrabutyl ammonium chloride, 332.6g (2.41mol, 2.0equiv.) of potassium carbonate and 332.6g of water until the reflux reaction is completed; adding water to separate the solution, washing the organic phase twice with water to obtain an organic phase which is marked as an M-2 solution, and directly carrying out the next step;

mixing the M-2 solution, 17.8g (0.06mol, 0.05equiv.) of tetrabutylammonium chloride and about 963mL of sodium hydroxide aqueous solution (dissolving 192.5g of sodium hydroxide (4.81mol, 4.0equiv.) in 963mL of water), and heating to 35-45 ℃ to completely react; and (3) separating liquid, washing the water phase twice with ethyl acetate, cooling, adjusting the pH value to 1-2 with hydrochloric acid, filtering, washing a filter cake with water, and drying in vacuum to obtain about 282.1g of ketorolac, wherein the total yield of the three steps is 91.8%. Purity 99.67% by HPLC, single maximum impurity 0.12%. The prepared ketorolac is converted into ketorolac tromethamine (refer to the preparation method of CN 101143865), and a sample is detected by HPLC, wherein the purity is 99.84 percent, and the single maximum impurity is 0.06 percent.

Example 3

183g (1.07mol, 1.0equiv.) of 2-benzoylpyrrole, 372.4g (1.60mol, 1.5equiv.), 429.9g (1.60mol, 1.5equiv.) of triethyl methanetricarboxylate, 175.4g (2.14mol, 2.0equiv.) of sodium acetate, 818.5g (8.02mol, 7.5equiv.) of acetic anhydride were added to 1800mL of toluene, and after completion of the reaction by heating, about 915mL of an aqueous sodium bisulfite solution was added (50.1 g of sodium bisulfite (0.48mol, 0.45equiv.) was dissolved in mL of water), followed by liquid separation to obtain an organic phase M-1 solution, which was directly used for the next step;

heating 528.9g (5.34mol, 5.0equiv.) of the M-1 solution, 172.3g (0.53mol, 0.5equiv.) of tetrabutylammonium bromide, 295.5g (2.14mol, 2.0equiv.) of potassium carbonate and 295.5g of water until the reflux reaction is completed; adding water to separate the solution, washing the organic phase twice with water to obtain an organic phase which is marked as an M-2 solution, and directly carrying out the next step;

dissolving the M-2 solution, 15.8g (0.05mol, 0.05equiv.) of tetrabutylammonium chloride and about 1499mL of potassium hydroxide aqueous solution (299.8 g of potassium hydroxide (5.34mol, 5.0equiv.) is added into 1499mL of water for preparation), and heating to 35-45 ℃ for complete reaction; and (3) separating liquid, washing the water phase twice by using ethyl acetate, cooling, adjusting the pH value to 1-2 by using hydrochloric acid, filtering, washing a filter cake by using water, and drying in vacuum to obtain about 249.2g of ketorolac, wherein the total yield of the three steps is 91.3%. Purity 99.64% by HPLC, single maximum impurity 0.14%.

Example 4

215g (1.26mol, 1.0equiv.) of 2-benzoylpyrrole, 437.5g (1.88mol, 1.5equiv.) of methanetricarboxylic acid, 505.1g (1.88mol, 1.5equiv.) of manganese acetate dihydrate, 206.1g (2.51mol, 2.0equiv.) of sodium acetate, 961.6g (9.42mol, 7.5equiv.) of acetic anhydride are added into 2150mL of toluene, after the reaction is completely heated, about 1075mL of sodium bisulfite solution is added (52.3 g of sodium bisulfite (0.50mol, 0.40equiv.) is added into 1075mL of water for dissolution configuration), the liquid separation is carried out, the obtained organic phase is recorded as M-1 solution, and the next step is directly carried out;

heating 745.7g (7.54mol, 6.0equiv.) of the M-1 solution, 202.4g (0.63mol, 0.5equiv.) of tetrabutylammonium bromide, 347.1g (2.51mol, 2.0equiv.) of potassium carbonate and 347.1g of water until the reflux reaction is completed; adding water to separate the solution, washing the organic phase twice with water to obtain an organic phase which is marked as an M-2 solution, and directly carrying out the next step;

heating the M-2 solution, 18.6g (0.06mol, 0.05equiv.) of tetrabutylammonium chloride and about 1507mL of sodium hydroxide aqueous solution (301.4 g of sodium hydroxide (7.54mol, 6.0equiv.) are added into 1507mL of water for dissolving and configuration), and heating to 35-45 ℃ to completely react; and (3) separating liquid, washing the water phase twice by using ethyl acetate, cooling, adjusting the pH value to 1-2 by using hydrochloric acid, filtering, washing a filter cake by using water, and drying in vacuum to obtain about 298.9g of ketorolac, wherein the total yield of the three steps is 93.2%. Purity 99.69% by HPLC, single maximum impurity 0.12%.

The above examples are merely exemplary, and any simple modifications and variations made within the spirit of the present invention are within the scope of the present invention.

Claims

1. An improved method for preparing ketorolac, comprising the following steps:

1) adding 2-benzoylpyrrole, triethyl methanetricarboxylate, manganese acetate dihydrate (trivalent), sodium acetate and acetic anhydride into toluene, and heating until the reaction is complete; after the reaction is finished, adding a sodium bisulfite aqueous solution, separating, recording the obtained organic phase as an M-1 solution, and directly carrying out the next step, wherein the 2-benzoylpyrrole: triethyl methanetricarboxylate: manganese acetate dihydrate (trivalent): sodium acetate: the molar ratio of acetic anhydride is 1:1.5:1.5:2.0: 7.5;

2) mixing the M-1 solution with 1, 2-dichloroethane, a phase transfer catalyst, potassium carbonate and a proper amount of water, heating and refluxing until the reaction is complete, adding water for separating liquid, washing the organic phase twice with water to obtain an organic phase which is marked as an M-2 solution, and directly carrying out the next step, wherein the phase transfer catalyst is tetrabutylammonium bromide;

3) mixing the M-2 solution with a phase transfer catalyst and an alkali liquor, heating to 35-45 ℃, reacting completely, separating liquid, washing a water phase with ethyl acetate for 1-2 times, cooling, adjusting the pH value to 1-2 with hydrochloric acid, filtering, washing a filter cake with water, and drying to obtain ketorolac, wherein the phase transfer catalyst is tetrabutylammonium bromide, and the alkali liquor is an aqueous sodium hydroxide solution.

2. The process according to claim 1, wherein the toluene in step 1) is contained in an amount of 9 to 10 times by mass based on the mass of 2-benzoylpyrrole, and the amount is expressed in terms of L/kg.

3. The preparation method according to claim 1, wherein the molar ratio of the sodium bisulfite to the manganese acetate dihydrate (trivalent) in step 1) is (0.1-0.3): 1.0.

4. The method of claim 1, wherein the molar ratio of tetrabutylammonium bromide to 2-benzoylpyrrole in step 2) is 0.5: 1.

5. The process according to claim 1, wherein the molar ratio of tetrabutylammonium bromide to 2-benzoylpyrrole in step 3) is 0.05: 1.

6. The process according to claim 1, wherein in step 2) the ratio of 2-benzoylpyrrole: 1, 2-dichloroethane: potassium carbonate: tetrabutylammonium bromide =1: 5.0-10.0: 2.0: 0.5.

7. The process according to claim 6, wherein in step 2) the ratio of 2-benzoylpyrrole: 1, 2-dichloroethane: potassium carbonate: tetrabutylammonium bromide =1: 5.0-8.0: 2.0: 0.5.

8. The process according to claim 6, wherein in step 2) the ratio of 2-benzoylpyrrole: 1, 2-dichloroethane: potassium carbonate: tetrabutylammonium bromide =1:6.0:2.0: 0.5.

9. The process according to claim 5, wherein the ratio of 2-benzoylpyrrole: tetrabutylammonium bromide: the molar ratio of the sodium hydroxide is 1:0.05, (4.0-6.0).

10. The process according to claim 5, wherein the ratio of 2-benzoylpyrrole: tetrabutylammonium bromide: the molar ratio of sodium hydroxide was 1:0.05: 5.0.