A kind of preparation method of diclofenac sodium intermediate
Through the reaction of isatin and 2,6-chlorobenzene diazotetrafluoroborate, combined with the reducing agent step, a high-purity diclofenac sodium intermediate was successfully prepared, solving the low purity of intermediates and the requirements of production equipment in the prior art. High-quality problems have achieved efficient and low-cost industrial scale production.
Patent Information
- Application Number
- CN202411252018.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-09
- Publication Date
- 2024-12-06
- Estimated Expiration
- 2044-09-09
AI Technical Summary
In the existing synthesis process of diclofenac sodium, the intermediate 1-(2,6-dichlorophenyl)-1,3-indolindole-2-one has a low purity, high production cost, and anhydrous three Aluminum chloride has high requirements for equipment material, which is not conducive to industrial scale production.
Using isatin as the starting material, react with 2,6-dichlorobenzene diazottetrafluoroborate through a reaction step to produce 1-(2,6-chlorophenyl)indole-2,3-dione. Then, the secondary reaction was carried out in the presence of a reducing agent to obtain diclofenac sodium intermediate 1-(2,6-chlorophenyl)-1,3-indolindol-2-one, which avoided the traditional process route and anhydrous three Use of aluminum chloride.
It improves the yield and purity of intermediate products, reduces the influence of production equipment and working environment, and has mild reaction conditions, which is suitable for industrial scale production.
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Figure CN118754844B_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the field of organic synthesis, in particular to a method for preparing a diclofenac sodium intermediate. 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. Provide a method for preparing a diclofenac sodium intermediate 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one from conventional commercially available raw materials without using traditional process routes and anhydrous aluminum chloride as a reaction reagent, with high reaction efficiency, high yield and purity of intermediate products, mild reaction conditions, low impact on production equipment and working environment, and conducive to industrial-scale production of diclofenac sodium intermediates, which has important technical significance. 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 a diclofenac sodium intermediate, which does not need to adopt a traditional process route and anhydrous aluminum chloride as a reaction reagent, can prepare the diclofenac sodium intermediate 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one through conventional commercially available raw materials, has high reaction efficiency, high intermediate 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 method for preparing a diclofenac sodium intermediate, using indigo carmine as a starting material, and preparing the diclofenac sodium intermediate 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one through a primary reaction step and a secondary reaction step;
[0010] The method of the primary reaction step is that 2,6-dichlorobenzenediazonium tetrafluoroborate reacts with isatin to obtain 1-(2,6-dichlorophenyl)indole-2,3-dione;
[0011] The method of the secondary reaction step is that 1-(2,6-dichlorophenyl)indole-2,3-dione is subjected to a reduction reaction in the presence of a reducing agent to obtain the diclofenac sodium intermediate 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one;
[0012] The preparation method of the diclofenac sodium intermediate has the following reaction scheme:
[0013] .
[0014] Furthermore, the method of the primary reaction step is to put indigo carmine, potassium carbonate and cuprous chloride into a solvent, then add 2,6-dichlorobenzenediazonium tetrafluoroborate, stir for reaction, filter out the solid, and obtain an extract by extraction; after washing and drying the extract, evaporate to obtain 1-(2,6-dichlorophenyl)indole-2,3-dione.
[0015] Preferably, in the first reaction step, the addition time of 2,6-dichlorobenzenediazonium tetrafluoroborate is no more than 1 hour;
[0016] The molar ratio of isatin to 2,6-dichlorobenzenediazonium tetrafluoroborate is 1:1.1-1.2.
[0017] Furthermore, the method of the secondary reaction step is to add 1-(2,6-dichlorophenyl)indole-2,3-dione to a reducing agent solution, stir and heat to 140°C, keep warm for reaction, and cool to room temperature to obtain a reaction solution; add the reaction solution to ice water, adjust the pH to 2-3, and extract to obtain an extract; after drying the extract, concentrate and crystallize to obtain the diclofenac sodium intermediate 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one.
[0018] Preferably, in the secondary reaction step, the reducing agent in the reducing agent solution is hydrazine hydrate;
[0019] The molar ratio of 1-(2,6-dichlorophenyl)indole-2,3-dione to hydrazine hydrate is 1:10-20.
[0020] Furthermore, the preparation method of the diclofenac sodium intermediate also includes: preparing 2,6-dichlorobenzenediazonium tetrafluoroborate;
[0021] The method for preparing 2,6-dichlorobenzenediazonium tetrafluoroborate is to use 2,6-dichloroaniline as a raw material and perform a diazotization reaction to obtain 2,6-dichlorobenzenediazonium tetrafluoroborate.
[0022] Furthermore, the method for preparing 2,6-dichlorobenzenediazonium tetrafluoroborate is as follows: dissolving 2,6-dichloroaniline in a fluoroboric acid aqueous solution, cooling to 0°C, dropwise adding a sodium nitrite aqueous solution, stirring for reaction, and collecting a thick precipitate; the thick precipitate is washed and dried to obtain 2,6-dichlorobenzenediazonium tetrafluoroborate.
[0023] Preferably, in the step of preparing 2,6-dichlorobenzenediazonium tetrafluoroborate, the molar ratio of 2,6-dichloroaniline to fluoroboric acid in the fluoroboric acid aqueous solution is 1:1-5;
[0024] The molar ratio of 2,6-dichloroaniline to sodium selenite in the sodium nitrite aqueous solution is 1:1.02-1.05.
[0025] Preferably, in the step of preparing 2,6-dichlorobenzenediazonium tetrafluoroborate, the dripping time of the sodium nitrite aqueous solution does not exceed 20 minutes.
[0026] Furthermore, the preparation method of the diclofenac sodium intermediate has the overall reaction route as follows:
[0027] .
[0028] Compared with the prior art, the present invention has the following beneficial effects:
[0029] (1) The preparation method of the diclofenac sodium intermediate of the present invention uses isotonic acid as a starting material, and through a primary reaction step, 2,6-dichlorobenzenediazonium tetrafluoroborate reacts with isotonic acid to obtain 1-(2,6-dichlorophenyl)indole-2,3-dione; then through a secondary reaction step, 1-(2,6-dichlorophenyl)indole-2,3-dione is subjected to a reduction reaction in the presence of a reducing agent to obtain the diclofenac sodium intermediate 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one. The preparation method does not need to use anhydrous aluminum chloride as a reaction reagent in the traditional process route, and can prepare the diclofenac sodium intermediate 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one using conventional commercially available raw materials. The reaction efficiency is high, the yield and purity of the intermediate product 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.
[0030] (2) In the preparation method of the diclofenac sodium intermediate of the present invention, 2,6-dichlorobenzenediazonium tetrafluoroborate is used to participate in the reaction. The condensation reaction rate of the diazonium salt and the nitrogen in isatin is fast, the reaction process is easy to control, and the yield and purity of the intermediate product 1-(2,6-dichlorophenyl)indole-2,3-dione are high, which is beneficial to the subsequent preparation process.
[0031] (3) The method for preparing the diclofenac sodium intermediate of the present invention has a high yield of the diclofenac sodium intermediate 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one, a melting point of 124-125.5°C, and a high product purity; and is conducive to the hydrolysis of the diclofenac sodium intermediate 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one to prepare diclofenac sodium.
[0032] (4) In the preparation method of the diclofenac sodium intermediate 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.
[0033] (5) In the preparation method of the diclofenac sodium intermediate of the present invention, the reaction conditions are mild, and there is no reaction process with too high or too low temperature or pressure, which is conducive to industrial-scale production. BRIEF DESCRIPTION OF THE DRAWINGS
[0034] Figure 1 The figure is the H NMR spectrum of the diclofenac sodium intermediate prepared in Example 3 of the present invention. DETAILED DESCRIPTION
[0035] 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.
[0036] Example 1
[0037] Preparation of 2,6-dichlorobenzenediazonium tetrafluoroborate:
[0038] The structure of the 2,6-dichlorobenzenediazonium tetrafluoroborate is shown below:
[0039] .
[0040] 2,6-dichloroaniline (8.1 g, 50 mmol) was dissolved in a 40% volume concentration of fluoroboric acid aqueous solution (fluoroboric acid content 200 mmol), cooled to 0°C, and then 15 mL of sodium nitrite aqueous solution (sodium nitrite content 3.6 g, 51 mmol) was added dropwise within 20 min. After stirring at 0°C for 3 h, the thick precipitate was collected and washed with ether (2×10 mL), and dried under vacuum for 10 min to obtain aromatic diazonium tetrafluoroborate, i.e., 2,6-dichlorobenzene diazonium tetrafluoroborate (CAS: 387-41-7), which can be directly used in the preparation of the next step (Example 2) without further purification.
[0041] Example 2
[0042] One reaction step, i.e. preparation of 1-(2,6-dichlorophenyl)indole-2,3-dione:
[0043] The structure of the 1-(2,6-dichlorophenyl)indole-2,3-dione is shown below:
[0044] .
[0045] To a mixture of isatin (1.47 g, 10 mmol), potassium carbonate K2CO3 (1.38 g, 10 mmol), cuprous chloride CuCl (100 mg, 1.0 mmol) and dimethyl sulfoxide DMSO (80 mL) was slowly added 2,6-dichlorobenzenediazonium tetrafluoroborate (3.12 g, 12 mmol) at room temperature, and the addition time of 2,6-dichlorobenzenediazonium tetrafluoroborate was controlled to be no more than 1 h; after the addition of 2,6-dichlorobenzenediazonium tetrafluoroborate was completed, the reaction was stirred for 12 h; after the reaction was completed, the cuprous chloride was filtered off, deionized water (150 mL) was added, and then extracted with ethyl acetate (3×150 mL), and the organic layers were combined to obtain an extract; the extract was washed with a saturated sodium chloride solution, dried, and evaporated under reduced pressure to obtain a red solid, i.e., 1-(2,6-dichlorophenyl)indole-2,3-dione (2.80 g, yield 95%).
[0046] The NMR data of 1-(2,6-dichlorophenyl)indole-2,3-dione prepared in this example:
[0047] 1 H NMR (400MHz, CDCl3) δ7.67(d,J=7.4Hz,1H),7.53-7.43(m,3H),7.36(dd,J=8.9,7.3Hz,1H),7.14(t,J=7.5Hz,1H),6.43(d,J=8.0Hz,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] 1-(2,6-dichlorophenyl)indole-2,3-dione (2.70 g, 9.2 mmol) was dissolved in a hydrazine hydrate solution (concentration 80 wt%, 10 mL, hydrazine hydrate content 160 mmol), stirred and heated to 140°C, kept warm for 4 hours, cooled to room temperature, and then poured into 100 mL of ice water, acidified to pH = 2-3 with 6 mol / L hydrochloric acid, extracted with dichloromethane (3×50 mL), combined organic layers, dried over anhydrous sodium sulfate, filtered, concentrated and crystallized to obtain 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one (2.4 g, yield 92%), melting point mp = 124-125.5°C.
[0053] The NMR data of 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one prepared in this example:
[0054] 1 H NMR (400 MHz, CDCl3) δ 7.52(d,J=7.6Hz,2H),7.42–7.35(m,1H),7.33(dd,J=7.6,0.8Hz,1H),7.21(dd,J =7.6,1.2Hz,1H),7.11(dd,J=7.6,0.8Hz,1H),6.41(d,J=8.0Hz,1H),3.79(s,2H).
[0055] It can be seen from the above examples that the preparation method of the diclofenac sodium intermediate of the present invention uses isotonic acid as a starting material, and through a primary reaction step, 2,6-dichlorobenzenediazonium tetrafluoroborate reacts with isotonic acid to obtain 1-(2,6-dichlorophenyl)indole-2,3-dione; then through a secondary reaction step, 1-(2,6-dichlorophenyl)indole-2,3-dione is subjected to a reduction reaction in the presence of a reducing agent to obtain the diclofenac sodium intermediate 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one; the preparation method does not need to use anhydrous aluminum chloride as a reaction reagent in the traditional process route, and can prepare the diclofenac sodium intermediate 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one through conventional commercially available raw materials, has high reaction efficiency, high intermediate product yield and purity, mild reaction conditions, low impact on production equipment and working environment, and is conducive to industrial-scale production.
[0056] Unless otherwise specified, all percentages used in the present invention are by mass.
[0057] 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 a diclofenac sodium intermediate, characterized in that: Using indigo carmine as a starting material, through a primary reaction step and a secondary reaction step, a diclofenac sodium intermediate 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one is prepared; The method of the primary reaction step is to put indigo carmine, potassium carbonate and cuprous chloride into a solvent, then add 2,6-dichlorobenzenediazonium tetrafluoroborate, stir for reaction, filter out solids, and extract to obtain an extract; after washing and drying the extract, evaporate to obtain 1-(2,6-dichlorophenyl)indole-2,3-dione; The method of the secondary reaction step is as follows: putting 1-(2,6-dichlorophenyl)indole-2,3-dione into a reducing agent solution, stirring and heating to 140°C, keeping the temperature for reaction, cooling to room temperature, and obtaining a reaction solution; putting the reaction solution into ice water, adjusting the pH to 2-3, and extracting to obtain an extract; the extract is dried, concentrated, and crystallized to obtain the diclofenac sodium intermediate 1-(2,6-dichlorophenyl)-1,3-dihydroindole-2-one; The reducing agent in the reducing agent solution is hydrazine hydrate; The preparation method of the diclofenac sodium intermediate has the following reaction scheme: 。 2. The method for preparing a diclofenac sodium intermediate according to claim 1, characterized in that: In the first reaction step, the addition time of 2,6-dichlorobenzenediazonium tetrafluoroborate is no more than 1 hour; The molar ratio of isatin to 2,6-dichlorobenzenediazonium tetrafluoroborate is 1:1.1-1.
2.
3. The method for preparing a diclofenac sodium intermediate according to claim 1, characterized in that: In the secondary reaction step, the molar ratio of 1-(2,6-dichlorophenyl)indole-2,3-dione to hydrazine hydrate is 1:10-20.
4. The method for preparing a diclofenac sodium intermediate according to claim 1, characterized in that: The invention also includes: a step of preparing 2,6-dichlorobenzenediazonium tetrafluoroborate; The method for preparing 2,6-dichlorobenzenediazonium tetrafluoroborate is to use 2,6-dichloroaniline as a raw material and perform a diazotization reaction to obtain 2,6-dichlorobenzenediazonium tetrafluoroborate.
5. The method for preparing a diclofenac sodium intermediate according to claim 4, characterized in that: The method for preparing 2,6-dichlorobenzenediazonium tetrafluoroborate comprises dissolving 2,6-dichloroaniline in a fluoroboric acid aqueous solution, cooling to 0° C., dripping a sodium nitrite aqueous solution, stirring for reaction, and collecting a thick precipitate; washing and drying the thick precipitate to obtain 2,6-dichlorobenzenediazonium tetrafluoroborate.
6. The method for preparing a diclofenac sodium intermediate according to claim 5, characterized in that: In the step of preparing 2,6-dichlorobenzenediazonium tetrafluoroborate, the molar ratio of 2,6-dichloroaniline to fluoroboric acid in the fluoroboric acid aqueous solution is 1:1-5; The molar ratio of 2,6-dichloroaniline to sodium nitrite in the sodium nitrite aqueous solution is 1:1.02-1.
05.
7. The method for preparing a diclofenac sodium intermediate according to claim 5, characterized in that: In the step of preparing 2,6-dichlorobenzenediazonium tetrafluoroborate, the sodium nitrite aqueous solution is added dropwise for no more than 20 minutes.