A kind of preparation method of diclofenac sodium

Abstract

The invention provides a preparation method of diclofenac sodium, belonging to the field of diclofenac sodium. The preparation method of diclofenac sodium adopts indole as a starting raw material, and obtains diclofenac sodium through a primary reaction step, a secondary reaction step, and a hydrolysis step. The preparation method of diclofenac sodium of the invention does not need to adopt a traditional process route and anhydrous aluminum chloride as a reaction reagent, can prepare diclofenac sodium through conventional commercially available raw materials, has high reaction efficiency, high product yield and purity, mild reaction conditions, low impact on production equipment and working environment, and is conducive to industrial-scale production.

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, in particular to a preparation method of diclofenac sodium. Background Art

[0002] Diclofenac sodium is a third-generation non-steroidal anti-inflammatory drug. It was launched in 1974 and is clinically used for anti-inflammatory, analgesic, antipyretic and anti-rheumatic effects. Diclofenac sodium blocks the conversion of arachidonic acid to prostaglandins by inhibiting the activity of cyclooxygenase (COXs); it can also promote the binding of arachidonic acid to triglycerides and reduce the concentration of free arachidonic acid in cells, thereby indirectly inhibiting the synthesis of leukotrienes, thereby achieving analgesic, anti-inflammatory and antipyretic effects. In the prior art, diclofenac sodium is suitable for the treatment of non-articular soft tissue rheumatic pain, such as shoulder pain, tenosynovitis, bursitis, and myalgia; it can also be used for acute mild and moderate pain, such as postoperative pain, post-traumatic or post-strain pain, dysmenorrhea, toothache, and headache; at the same time, diclofenac sodium can also be used as an adjuvant treatment for severe infectious painful inflammation in otolaryngology (such as pharyngeal tonsillitis and otitis). In addition, diclofenac sodium also has an antipyretic effect on fever in adults and children.

[0003] At present, the more economical synthesis route of diclofenac sodium is to use cyclohexanone as the starting material, synthesize the intermediate 2,6-dichlorodiphenylamine, and then generate N-phenyl-N-(2,6-dichlorophenyl) chloroacetamide under the action of chloroacetyl chloride, and then N-phenyl-N-(2,6-dichlorophenyl) chloroacetamide under the action of anhydrous aluminum chloride to generate 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one through Friedel-Crafts reaction, and finally hydrolyze with sodium hydroxide to obtain diclofenac sodium (China Pharmaceutical Industry Journal, 1995, P145-147). The specific synthesis route is as follows:

[0004] .

[0005] However, in the synthesis of diclofenac sodium, the synthesis of the intermediate 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one uses the Friedel-Crafts reaction, so the purity of the obtained product is low and the production cost is high; and the anhydrous aluminum chloride used has high requirements on the material of the production equipment, which is not conducive to industrial-scale production.

[0006] Therefore, with the gradual expansion of the global annual consumption of diclofenac sodium, the current increase in the price of raw materials and the environmental protection requirements for the production process, it is urgent to optimize the synthesis process of diclofenac sodium. It is of great technical significance to provide a preparation method of diclofenac sodium that does not require the use of traditional process routes and anhydrous aluminum chloride as a reaction reagent, can prepare diclofenac sodium from conventional commercially available raw materials, has high reaction efficiency, high product yield and purity, mild reaction conditions, low impact on production equipment and working environment, and is conducive to industrial-scale production. Summary of the invention

[0007] In order to solve the technical problems existing in the prior art, the present invention provides a preparation method of diclofenac sodium, which does not need to adopt the traditional process route and anhydrous aluminum chloride as a reaction reagent, can prepare diclofenac sodium through conventional commercially available raw materials, has high reaction efficiency, high product yield and purity, mild reaction conditions, low impact on production equipment and working environment, and is conducive to industrial-scale production.

[0008] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0009] A preparation method of diclofenac sodium, using indole as a starting material, and preparing diclofenac sodium through a primary reaction step, a secondary reaction step, and a hydrolysis step;

[0010] The method of the primary reaction step is that 2,6-dichlorophenyl p-toluenesulfonate reacts with indole to obtain 1-(2,6-dichlorophenyl)-1H-indole;

[0011] The method of the secondary reaction step is that 1-(2,6-dichlorophenyl)-1H-indole is subjected to an oxidation reaction in the presence of FeBr2 and hydrogen peroxide to obtain 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one;

[0012] The method of the hydrolysis step is that 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one is hydrolyzed to obtain diclofenac sodium.

[0013] The preparation method of diclofenac sodium, the reaction route is:

[0014] .

[0015] Furthermore, the method for the primary reaction step is to add 2,6-dichlorophenyl p-toluenesulfonate, indole, cuprous iodide, 8-hydroxyquinoline, and potassium carbonate into a solvent, stir and react at a temperature not lower than 85° C., and then extract to obtain an extract; the extract is washed, dried, concentrated, and purified by column chromatography to obtain 1-(2,6-dichlorophenyl)-1H-indole.

[0016] Furthermore, the method for the secondary reaction step is to add 1-(2,6-dichlorophenyl)-1H-indole, FeBr2, and H2O2 aqueous solution into a solvent, stir the reaction at room temperature and then quench the reaction, and obtain an extract by extraction; the extract is dried and concentrated, and purified by column chromatography to obtain 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one.

[0017] Furthermore, the method of the hydrolysis step is to add 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one, sodium hydroxide solution, and benzyltriethylammonium chloride into a solvent, heat and stir to reflux, keep warm and stir to react, distill to remove the solvent, and then recrystallize and decolorize to obtain diclofenac sodium.

[0018] Preferably, in the primary reaction step, the molar ratio of 2,6-dichlorophenyl p-toluenesulfonate, indole, cuprous iodide, 8-hydroxyquinoline and potassium carbonate is 1:1-1.2:0.01-0.1:0.01-0.1:1.5-2.5.

[0019] Preferably, in the secondary reaction step, the molar ratio of 1-(2,6-dichlorophenyl)-1H-indole, FeBr2, and hydrogen peroxide is 1:0.01-0.1:1.5-2.5.

[0020] Preferably, in the hydrolysis step, the molar ratio of 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one, sodium hydroxide in the sodium hydroxide solution, and benzyltriethylammonium chloride is 1:2-8:0.01-0.1.

[0021] Furthermore, in the first reaction step, the 2,6-dichlorophenyl p-toluenesulfonate used is obtained by reacting 2,6-dichlorophenol with p-toluenesulfonyl chloride.

[0022] Preferably, the molar ratio of 2,6-dichlorophenol to p-toluenesulfonyl chloride is 1:1-1.2.

[0023] Furthermore, the preparation method of 2,6-dichlorophenyl p-toluenesulfonate is as follows: 2,6-dichlorophenol, triethylamine, and 4-(N,N-dimethylamino)pyridine are added to a solvent, and then p-toluenesulfonyl chloride is added, the reaction temperature is controlled to be no higher than 30°C, after reacting at room temperature, the pH is adjusted to 2-3, and an extract is obtained by extraction; the extract is washed, dried, concentrated, and crystallized to obtain 2,6-dichlorophenyl p-toluenesulfonate.

[0024] Furthermore, the overall reaction route of the preparation method of diclofenac sodium is:

[0025] .

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] (1) The preparation method of diclofenac sodium of the present invention uses indole as a starting material, and obtains diclofenac sodium through a primary reaction step, a secondary reaction step, and a hydrolysis step. It does not need to use a traditional process route and anhydrous aluminum chloride as a reaction reagent. It starts with conventional commercially available raw materials and obtains an important intermediate of diclofenac sodium 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one through three steps of chemical reaction. Then, 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one is hydrolyzed to obtain diclofenac sodium. The reaction efficiency is high, the product yield and purity are high, the reaction conditions are mild, the impact on production equipment and working environment is low, and it is conducive to industrial-scale production.

[0028] (2) In the preparation method of diclofenac sodium of the present invention, the reaction efficiency of 2,6-dichlorophenyl p-toluenesulfonate and indole is high, the reaction process is easy to control, the yield and purity of the intermediate product are high, and it is beneficial to the subsequent preparation process.

[0029] (3) The preparation method of diclofenac sodium of the present invention has a high yield of diclofenac sodium, a melting point of 283-285° C., and a high product purity.

[0030] (4) In the preparation method of diclofenac sodium of the present invention, most reactions are carried out under alkaline conditions, which effectively reduces the impact on production equipment and working environment and is conducive to large-scale production.

[0031] (5) The preparation method of diclofenac sodium of the present invention has mild reaction conditions and does not involve reaction processes with excessively high or low temperature or pressure, which is conducive to industrial-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 The hydrogen NMR spectrum of diclofenac sodium prepared in Example 4 of the present invention. DETAILED DESCRIPTION

[0033] In order to have a clearer understanding of the technical features, purposes and effects of the present invention, the specific implementation methods of the present invention are now described.

[0034] Example 1

[0035] Preparation of 2,6-dichlorophenyl p-toluenesulfonate:

[0036] The structure of the 2,6-dichlorophenyl p-toluenesulfonate is shown below:

[0037] .

[0038] 2,6-Dichlorophenol (16.3 g, 0.1 mol) was dissolved in 200 mL of dichloromethane, and then triethylamine (17 mL, 0.12 mol) and 4-(N,N-dimethylamino)pyridine DMAP (0.2 g, 1.6 mmol) were added, and then p-toluenesulfonyl chloride (21 g, 0.12 mol) was slowly added; during the addition of p-toluenesulfonyl chloride, the reaction temperature was kept below 30 °C by controlling the addition rate of p-toluenesulfonyl chloride; after the addition of p-toluenesulfonyl chloride, the reaction was carried out at room temperature for 3 h, and then thin plate chromatography was performed. After the reaction is complete, 1 mol / L hydrochloric acid is added to adjust the pH to 2-3. After separation, the aqueous layer is extracted twice with dichloromethane, each time with 100 mL of dichloromethane; the dichloromethane layers (i.e., the extracts) are combined and washed with deionized water (100 mL), and then washed with a saturated sodium bicarbonate aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered to remove the solids, concentrated, and crystallized in ethanol to obtain 2,6-dichlorophenyl p-toluenesulfonate (30.1 g, yield 95%); melting point mp = 72-73 ° C.

[0039] The NMR data of 2,6-dichlorophenyl p-toluenesulfonate prepared in this example:

[0040] 1 H NMR (400MHz, CDCl3) δ7.70 (dd, J=8.0, 2.3Hz, 2H), 7.45 (dd, J=8.0, 2.3Hz, 2H), 7.13-7.02 (m, 3H), 2.44 (s, 3H).

[0041] Example 2

[0042] One reaction step, namely, preparation of 1-(2,6-dichlorophenyl)-1H-indole:

[0043] The structure of the 1-(2,6-dichlorophenyl)-1H-indole is shown below:

[0044] .

[0045] 2,6-Dichlorophenyl p-toluenesulfonate (3.17 g, 10 mmol), indole (1.4 g, 12 mmol), cuprous iodide CuI (40 mg, 0.2 mmol), 8-hydroxyquinoline (60 mg, 0.4 mmol), potassium carbonate (3.45 g, 25 mmol) and 20 mL of dimethyl sulfoxide DMSO were stirred in a single-mouth reaction bottle at 90°C for 24 h. After the reaction was completed, the reaction solution was cooled and 50 mL of ethyl acetate and water were added. After separation, the aqueous phase was extracted once with ethyl acetate, and the organic layers were combined to obtain an extract; the extract was washed with saturated sodium bicarbonate aqueous solution and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 1-(2,6-dichlorophenyl)-1H-indole (2.36 g, yield 90%).

[0046] The NMR data of 1-(2,6-dichlorophenyl)-1H-indole prepared in this example:

[0047] 1 H NMR (500MHz, CDCl3) δ7.80(m,1H),7.56(d,J=8.1Hz,2H),7.40(t,J=8.1Hz,1H),7.28(m,2H),7.19(d,J=3.3Hz,1H),7.06–7.01(m,1H),6.84(d,J=3.4Hz,1H).

[0048] Example 3

[0049] Secondary reaction step, i.e. preparation of 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one:

[0050] The structure of the 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one is shown below:

[0051] .

[0052] Under stirring conditions, FeBr2 (90 mg, 0.4 mmol) was added to a solution of 1-(2,6-dichlorophenyl)-1H-indole (1.05 g, 4 mmol) in tetrahydrofuran / water (THF to H2O volume ratio of 10:1, 22 mL), and then a 30 wt% H2O2 aqueous solution (1 mL, 9 mmol) was added. After the addition was completed, the mixture was stirred at room temperature for 3 h, and then a Na2S2O3 aqueous solution (0.1 mol / L, 100 mL) and ethyl acetate (200 mL) were added to quench the reaction. After separation, the aqueous layer was extracted with ethyl acetate (2×100 mL), and the organic layers were combined to obtain an extract; the extract was dried over anhydrous sodium sulfate, filtered to remove the solid, and then concentrated under reduced pressure, and purified by column chromatography to obtain 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one (1.03 g, yield 93%); melting point mp = 123-125°C.

[0053] The NMR data of 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one prepared in this example:

[0054] 1 H NMR (400MHz, CDCl3) δ7.51(d,J=7.6Hz,2H),7.41–7.36(m,1H),7.34(dd,J=7.6,0.8Hz,1H),7.21(td,J =7.6,1.2Hz,1H),7.10(td,J=7.6,0.8Hz,1H),6.40(d,J=8.0Hz,1H),3.78(s,2H).

[0055] Example 4

[0056] The hydrolysis step, i.e. the preparation of diclofenac sodium:

[0057] 1-(2,6-Dichlorophenyl)-1,3-dihydroindole-2-one (3.5 g, 12.6 mmol), 30 wt% sodium hydroxide solution (8 mL, 60 mmol), benzyltriethylammonium chloride (0.2 g) and xylene (8 mL) were placed in a single-necked reaction bottle, heated with stirring and refluxed for 5 h, azeotropic dehydration was followed by adding 25 mL of deionized water, and distillation was continued to remove excess xylene. The residue was recrystallized with water and decolorized with activated carbon to obtain a white crystalline powder, i.e., diclofenac sodium (3.2 g, yield 80%), with a melting point of mp = 283-285 °C.

[0058] The nuclear magnetic resonance data of diclofenac sodium prepared in this example:

[0059] 1H NMR (DMSO-d6):10.47(s,1H),7.44(d,J=8.0Hz,2H),7.05(d,J=7.2Hz,1H),7.03(m,1H),6.91(m,1H),6.72(m,1H),6.22(m,1H),3.37(s,2H).

[0060] It can be seen from the above examples that the preparation method of diclofenac sodium of the present invention uses indole as a starting material, and obtains diclofenac sodium through a primary reaction step, a secondary reaction step, and a hydrolysis step; there is no need to use a traditional process route and anhydrous aluminum chloride as a reaction reagent, and the important intermediate 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one of diclofenac sodium is obtained through three-step chemical reactions starting from conventional commercially available raw materials; 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one is hydrolyzed to obtain diclofenac sodium, and the reaction efficiency is high, the product yield and purity are high, the reaction conditions are mild, the impact on production equipment and working environment is low, and it is conducive to industrial-scale production. In a single reaction step, the reaction efficiency of 2,6-dichlorophenyl p-toluenesulfonate and indole is high, the reaction process is easy to control, the yield and purity of the intermediate product are high, and the subsequent preparation process is beneficial; the preparation method of diclofenac sodium has a high yield of diclofenac sodium, a melting point of 283-285° C., and a high product purity.

[0061] Unless otherwise specified, all percentages used in the present invention are by mass.

[0062] Finally, it should be noted that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing diclofenac sodium, characterized in that, Indole is used as a starting material, and diclofenac sodium is prepared through a primary reaction step, a secondary reaction step, and a hydrolysis step; The method of the primary reaction step is to add 2,6-dichlorophenyl p-toluenesulfonate, indole, cuprous iodide, 8-hydroxyquinoline and potassium carbonate into a solvent, stir and react at a temperature not lower than 85° C., and then extract to obtain an extract; the extract is washed, dried, concentrated, and purified by column chromatography to obtain 1-(2,6-dichlorophenyl)-1H-indole; The method of the secondary reaction step is to put 1-(2,6-dichlorophenyl)-1H-indole, FeBr2, and H2O2 aqueous solution into a solvent, stir the reaction at room temperature, quench the reaction, and obtain an extract by extraction; the extract is dried and concentrated, and purified by column chromatography to obtain 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one; The method of the hydrolysis step is that 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one is hydrolyzed to obtain diclofenac sodium.

2. The method for preparing diclofenac sodium according to claim 1, characterized in that The method of the hydrolysis step is to put 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one, sodium hydroxide solution and benzyltriethylammonium chloride into a solvent, heat and stir until reflux, keep the temperature and stir to react, distill and remove the solvent, and then recrystallize and decolorize to obtain diclofenac sodium.

3. The method for preparing diclofenac sodium according to claim 1, characterized in that: In the primary reaction step, the molar ratio of 2,6-dichlorophenyl p-toluenesulfonate, indole, cuprous iodide, 8-hydroxyquinoline and potassium carbonate is 1:1-1.2:0.01-0.1:0.01-0.1:1.5-2.

5.

4. The method for preparing diclofenac sodium according to claim 1, characterized in that: In the secondary reaction step, the molar ratio of 1-(2,6-dichlorophenyl)-1H-indole, FeBr2, and hydrogen peroxide is 1:0.01-0.1:1.5-2.

5.

5. The method for preparing diclofenac sodium according to claim 2, characterized in that: In the hydrolysis step, the molar ratio of 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one, sodium hydroxide in the sodium hydroxide solution, and benzyltriethylammonium chloride is 1:2-8:0.01-0.

1.

6. The method for preparing diclofenac sodium according to claim 1, characterized in that: In the first reaction step, the 2,6-dichlorophenyl p-toluenesulfonate used is obtained by reacting 2,6-dichlorophenol with p-toluenesulfonyl chloride.

7. The method for preparing diclofenac sodium according to claim 6, characterized in that: The molar ratio of the 2,6-dichlorophenol to p-toluenesulfonyl chloride is 1:1-1.2.

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