Preparation method of ketoprofen d3
Through the coupling reaction promoted by palladium catalyst and phosphine ligand, combined with weak basic compounds to treat substitution, methylation, and hydrolysis and decarboxylation, the existing ketoprofen-d3 synthesis process is solved, and the efficient and low-cost preparation of ketoprofen-d3 is achieved, which is suitable for industrial production.
Patent Information
- Application Number
- CN202510387852.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2024-06-25
- Filing Date
- 2025-03-31
- Publication Date
- 2025-06-27
AI Technical Summary
The existing ketoprofen-d3 synthesis process has problems such as multi-step cumbersome operations, high energy consumption, high cost, long cycles and intermediate impurities affecting the quality of the final product.
The palladium catalyst and large sterically hindered electron-rich phosphine ligand are used to promote the oxidation and addition of aromatic halides, and the coupling reaction is carried out in combination with weakly basic compounds, and the three-step reactions of substitution, methylation, and hydrolysis and decarboxylation are coordinated to achieve the "one-pot boil" continuous reaction.
The process flow is simplified, energy consumption and cost are reduced, and the total yield and purity of ketoprofen-d3 are improved, making it suitable for large-scale industrial production.
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Figure CN120208774A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of deuterated compound production, and particularly to a preparation method of ketoprofen-d3. Background Art
[0002] Ketoprofen is a non-steroidal anti-inflammatory drug with antipyretic and analgesic effects. The anti-inflammatory effect of ketoprofen is achieved by inhibiting the synthesis of prostaglandins and leukotrienes. It has an anti-bradykinin effect and a stabilizing effect on the cell membrane of lysozyme. The derivative ketoprofen-d3 obtained by deuterium labeling of the methyl group on the propionic acid chain of ketoprofen can be used as an important tool for studying pharmacokinetics, and its chemical structure is as follows: .
[0003] Currently, in the synthesis process of ketoprofen-d3, the synthesis published in existing literature (ChemMedChem, 2021, 16 (5), 869) mostly uses 3-bromobenzophenone as the starting material and undergoes multiple steps such as substitution, methylation, hydrolysis, and decarboxylation to finally obtain ketoprofen-d3. The reaction route is as follows:
[0004] However, each step of this process requires cumbersome post-treatment. In particular, some operation steps require high-temperature vacuum distillation and column chromatography for separation and purification. For example, in step1, NaH is selected as the base, and due to its too strong alkalinity, side products of hydrodehalogenation will be generated, resulting in a low yield and thus further separation and purification are required before proceeding to the next alkylation reaction. Similarly, both the deuteromethylation and hydrolysis decarboxylation steps also have incomplete reactions and low yields. The total yield of the three steps is only about 14%. In addition, problems such as high energy consumption and long cycle time brought about by the concentration and purification required in the whole process not only increase the production cost of enterprises, but also the multiple column separations and purifications will increase the probability of introducing solvent impurities into the intermediate, affecting the final quality of ketoprofen-d3. Therefore, it is necessary to improve the existing technology process. Summary of the Invention
[0005] The purpose of the present invention is to provide an improved preparation method of ketoprofen-d3. This method integrates the three steps of substitution, methylation, and hydrolysis decarboxylation to truly achieve a "one-pot" continuous reaction as a whole, completely eliminating the cumbersome operation steps with high energy consumption, high cost, and long cycle time existing in the whole process, and solving the important problem of large-scale production in the synthesis. This method is simple to operate, low in cost, high in yield, and less polluting. The obtained ketoprofen-d3 has a purity ≧ 99.1% detected by HPLC, and the maximum single impurity is below 0.24%. The total yield of the three steps is greater than 90%, and it is suitable for industrial large-scale production.
[0006] The technical solution adopted by the present invention to solve its technical problems is as follows: A preparation method of ketoprofen-d3, comprising the following steps: S1: Add 3-bromobenzophenone, diethyl malonate, a palladium catalyst, a phosphine ligand, and a weak basic compound into an organic solvent, and under nitrogen protection, heat to reflux until the reaction of 3-bromobenzophenone is complete; S2: After the arylation reaction is completed, add CD3I and directly carry out deuteromethylation reaction; S3: After the deuteromethylation reaction is completed, add potassium hydroxide for hydrolysis and decarboxylation reaction. After the reaction is completed, purify to obtain ketoprofen-d3.
[0007] Purification specifically includes: adding 5% aqueous NaHCO3 solution to the reaction product, separating the liquid, washing the aqueous phase with ethyl acetate 1-2 times, acidifying with hydrochloric acid, extracting with ethyl acetate, separating the organic phase, drying, filtering, concentrating, and performing low-temperature recrystallization.
[0008] Preferably, in step S1, the palladium catalyst is Pd2(dba)3.
[0009] Preferably, in step S1, the phosphine ligand is P(t-Bu)3.
[0010] Preferably, in step S1, the weak basic compound is potassium phosphate or sodium tert-butoxide.
[0011] Preferably, in step S1, the organic solvent is tetrahydrofuran, and 9-10 liters of organic solvent are used per kilogram of 3-bromobenzophenone.
[0012] Preferably, the molar ratio of 3-bromobenzophenone: diethyl malonate: palladium catalyst: phosphine ligand: weak basic compound: CD3I = 1: 1~1.4: 0.001~0.02: 0.04~0.2: 3~4.5: 1.5~3.
[0013] Preferably, in step S2, the deuteromethylation reaction conditions are: heating to 75±1°C and reacting for 3 hours.
[0014] Preferably, in step S3, the molar ratio of 3-bromobenzophenone: potassium hydroxide = 1:20.
[0015] Preferably, in step S3, the hydrolysis and decarboxylation reaction conditions are: stirring at room temperature for 12 hours.
[0016] The beneficial effects of the present invention are as follows: The present invention focuses on optimizing the synthesis conditions of the arylation reaction of diethyl malonate in S1. A palladium catalyst and a bulky electron-rich phosphine ligand are used in the reaction to promote the oxidative addition of aromatic halides and the reductive elimination of the corresponding malonate anion complex. Under weakly basic conditions, the arylation of malonate ester is finally achieved by coupling with a high yield. Moreover, the weakly basic compounds (potassium phosphate or sodium tert-butoxide) selected in the present invention are more convenient and safer to use in the laboratory or production compared with NaH used in the literature. Slightly excessive weakly basic compounds can efficiently achieve S2 methylation at the same time, taking into account the synthesis conditions and post-treatment of the S3 hydrolysis and decarboxylation reaction. The three-step reaction is coordinated. Utilizing the advantages of two-phase reaction, after the reaction is completed, the desired product can be separated by simple liquid-liquid extraction, without additional steps such as liquid-solid separation and concentration operations. Other impurities can be removed only by liquid-liquid washing. The "one-pot" continuous reaction is truly realized, completely eliminating the cumbersome operation steps with high energy consumption, high cost and long cycle existing in the whole process, and solving the important problems in the large-scale industrial production of the synthesis. This method has the advantages of simple operation, low cost, high yield and less pollution. The purity (area normalization method) of the obtained ketoprofen-d3 detected by HPLC is greater than or equal to 99.1%, and the single largest impurity is below 0.24%. The total yield of the three steps is greater than 90%, which is suitable for industrial scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS
[0017] Figure 1 It is the MS spectrum of the ketoprofen-d3 obtained in Example 1; Figure 2 It is the NMR spectrum of the ketoprofen-d3 obtained in Example 1. DETAILED DESCRIPTION OF THE INVENTION
[0018] The technical solutions of the present invention will be further specifically described below through specific examples.
[0019] In the present invention, unless otherwise specified, the raw materials and equipment used can be purchased from the market or are commonly used in the art. The methods in the following examples are conventional methods in the art unless otherwise specified.
[0020] Example 1 Example 1: Preparation of Ketoprofen-d3
[0021] 1. Add 2.61 g (10 mmol, 1.0 equiv.) of 3-bromobenzophenone (SM), 1.37 mL (9 mmol, 0.9 equiv.) of diethyl malonate, 0.045 g (0.05 mmol, 0.5% equiv.) of Pd2(dba)3, 0.08 g (0.4 mmol, 0.04 equiv.) of P(t-Bu)3, and 9.54 g (45 mmol, 4.5 equiv.) of potassium phosphate into 25 mL of tetrahydrofuran. Under nitrogen protection, heat to reflux overnight, then add an additional 0.76 mL (5 mmol, 0.5 equiv.) of diethyl malonate and react until 3-bromobenzophenone is completely reacted. 2. Add 1.26 mL (20 mmol, 2 equiv.) of CD3I to the reaction system, heat to 75 °C and react for 3 hours to obtain an intermediate containing M-2, denoted as the M-2 solution.
[0022] 3. Directly add 11.22 g (200 mmol, 20 mL, 20.0 equiv.) of potassium hydroxide solution to the above M-2 solution reaction, stir at room temperature for 12 hours, and purify to obtain ketoprofen-d3.
[0023] Purification: Add 5% aqueous NaHCO3 solution (100 mL) to the reaction solution, separate the layers, wash the aqueous phase once with ethyl acetate, acidify with 10 mL of hydrochloric acid, extract with ethyl acetate, separate the organic phase, dry, filter, concentrate, and recrystallize at -20 °C to obtain approximately 2.37 g of ketoprofen-d3, with a total yield of 92% in three steps. Detected by HPLC, the purity is 99.14%, the single largest impurity is 0.24%, and the results are shown in Table 1. The MS spectrum of ketoprofen-d3 is shown in Figure 1 , and the NMR spectrum is shown in Figure 2 .
[0024] Table 1
[0025] Example 2: 1. Add 2.61 g (10 mmol, 1.0 equiv.) of 3-bromobenzophenone (SM), 1.37 mL (9 mmol, 0.9 equiv.) of diethyl malonate, 0.09 g (0.1 mmol, 1% equiv.) of Pd2(dba)3, 0.08 g (0.4 mmol, 0.04 equiv.) of P(t-Bu)3, and 9.54 g (45 mmol, 4.5 equiv.) of potassium phosphate into 25 mL of tetrahydrofuran. Under nitrogen protection, heat under reflux overnight, then add an additional 0.76 mL (5 mmol, 0.5 equiv.) of diethyl malonate and react until 3-bromobenzophenone has completely reacted.
[0026] 2. Add 1.26 mL (20 mmol, 2 equiv.) of CD3I to the reaction system, heat to 75 °C and react for 3 hours to obtain an intermediate containing M-2, denoted as the M-2 solution.
[0027] 3. Directly add 11.22 g (200 mmol, 20 mL, 20.0 equiv.) of potassium hydroxide solution to the above M-2 solution reaction, stir at room temperature until the reaction is complete, and purify to obtain ketoprofen-d3.
[0028] Purification: Add 5% aqueous NaHCO3 solution (100 mL) to the reaction solution, separate the layers, wash the aqueous phase once with ethyl acetate, acidify with 10 mL of hydrochloric acid, extract with ethyl acetate, separate the organic phase, dry, filter, concentrate, and recrystallize at -20 °C to obtain approximately 2.34 g of ketoprofen-d3. The total yield of the three steps is 91%. Detected by HPLC, the purity is 99.15%, and the single largest impurity is 0.23%.
[0029] Example 3: 1. Add 2.61 g (10 mmol, 1.0 equiv.) of 3-bromobenzophenone (SM), 1.37 mL (9 mmol, 0.9 equiv.) of diethyl malonate, 0.045 g (0.05 mmol, 0.5% equiv.) of Pd2(dba)3, 0.08 g (0.4 mmol, 0.04 equiv.) of P(t-Bu)3, and 4.32 g (45 mmol, 4.5 equiv.) of sodium tert-butoxide into 26.1 mL of tetrahydrofuran. Under nitrogen protection, heat under reflux overnight, then add an additional 0.76 mL (5 mmol, 0.5 equiv.) of diethyl malonate and react until 3-bromobenzophenone has completely reacted.
[0030] 2. Add 1.26 mL (20 mmol, 2 equiv.) of CD3I to the reaction system, heat to 75 °C and react for 3 hours to obtain an intermediate containing M-2, denoted as M-2 solution.
[0031] 3. Directly add 11.22 g (200 mmol, 20 mL, 20.0 equiv.) of potassium hydroxide solution to the above M-2 solution reaction, stir at room temperature until the reaction is complete, and purify to obtain ketoprofen-d3.
[0032] Purification: Add 5% aqueous NaHCO3 solution (100 mL) to the reaction solution, separate the layers, wash the aqueous phase with ethyl acetate once, acidify with 10 mL of hydrochloric acid, extract with ethyl acetate, separate the organic phase, dry, filter, concentrate, and recrystallize at -20 °C to obtain about 2.3 g of ketoprofen-d3. The total yield of the three steps is 90%. Detected by HPLC, the purity is 99.0%, and the single largest impurity is 0.25%.
[0033] Example 4: 1. Add 1.3 g (5 mmol, 1.0 equiv.) of 3-bromobenzophenone (SM), 0.7 mL (4.5 mmol, 0.9 equiv.) of diethyl malonate, 0.023 g (0.025 mmol, 0.5% equiv.) of Pd2(dba)3, 0.04 g (0.2 mmol, 0.04 equiv.) of P(t-Bu)3, and 4.77 g (23 mmol, 4.5 equiv.) of potassium phosphate to 11.7 mL of tetrahydrofuran. Under nitrogen protection, heat to reflux overnight, and then add an additional 0.38 mL (2.5 mmol, 0.5 equiv.) of diethyl malonate and react until 3-bromobenzophenone is completely reacted.
[0034] 2. Add 0.95 mL (15 mmol, 3 equiv.) of CD3I to the reaction system, heat to 75 °C and react for 3 hours to obtain an intermediate containing M-2, denoted as M-2 solution.
[0035] 3. Directly add 5.61 g (100 mmol, 10 mL, 20.0 equiv.) of potassium hydroxide solution to the above M-2 solution reaction, stir at room temperature until the reaction is complete, and purify to obtain ketoprofen-d3.
[0036] Purification: Add 5% aqueous NaHCO3 solution (100 mL) to the reaction solution, separate the layers, wash the aqueous layer once with ethyl acetate, acidify with 10 mL of hydrochloric acid, extract with ethyl acetate, separate the organic layer, dry, filter, concentrate, and recrystallize at -20 °C to obtain approximately 1.19 g of ketoprofen-d3 with a total yield of 93% in three steps. The purity is 99.20% as detected by HPLC, and the single largest impurity is 0.15%.
[0037] Example 5: 1. Add 2.61 g (10 mmol, 1.0 equiv.) of 3-bromobenzophenone (SM), 1.37 mL (9 mmol, 0.9 equiv.) of diethyl malonate, 0.045 g (0.001 mmol, 0.1% equiv.) of Pd2(dba)3, 0.08 g (0.4 mmol, 0.04 equiv.) of P(t-Bu)3, and 9.54 g (45 mmol, 4.5 equiv.) of potassium phosphate to 25 mL of tetrahydrofuran. Under nitrogen protection, heat to reflux overnight, and then add an additional 0.76 mL (5 mmol, 0.5 equiv.) of diethyl malonate and react until 3-bromobenzophenone is completely reacted.
[0038] 2. Add 1.26 mL (20 mmol, 2 equiv.) of CD3I to the reaction system, heat to 75 °C and react for 3 hours to obtain an intermediate containing M-2, denoted as the M-2 solution.
[0039] 3. Directly add 11.22 g (200 mmol, 20 mL, 20.0 equiv.) of potassium hydroxide solution to the above reaction of the M-2 solution, stir at room temperature for 12 hours, and purify to obtain ketoprofen-d3.
[0040] Purification: Add 5% aqueous NaHCO3 solution (100 mL) to the reaction solution, separate the layers, wash the aqueous layer once with ethyl acetate, acidify with 10 mL of hydrochloric acid, extract with ethyl acetate, separate the organic layer, dry, filter, concentrate, and recrystallize at -20 °C to obtain approximately 2.29 g of ketoprofen-d3 with a total yield of 89% in three steps. The purity is 99.04% as detected by HPLC, and the single largest impurity is 0.25%.
[0041] Example 6: 1. Add 2.61 g (10 mmol, 1.0 equiv.) of 3-bromobenzophenone (SM), 1.37 mL (9 mmol, 0.9 equiv.) of diethyl malonate, 0.045 g (0.2 mmol, 2% equiv.) of Pd2(dba)3, 0.08 g (0.4 mmol, 0.04 equiv.) of P(t-Bu)3, and 9.54 g (45 mmol, 4.5 equiv.) of potassium phosphate into 25 mL of tetrahydrofuran. Under nitrogen protection, heat to reflux overnight, then add an additional 0.76 mL (5 mmol, 0.5 equiv.) of diethyl malonate and react until the 3-bromobenzophenone is completely reacted.
[0042] 2. Add 1.26 mL (20 mmol, 2 equiv.) of CD3I to the reaction system, heat to 75 °C and react for 3 hours to obtain an intermediate containing M-2, denoted as the M-2 solution.
[0043] 3. Directly add 11.22 g (200 mmol, 20 mL, 20.0 equiv.) of potassium hydroxide solution to the above M-2 solution reaction, stir at room temperature for 12 hours, and purify to obtain ketoprofen-d3.
[0044] Purification: Add 5% aqueous NaHCO3 solution (100 mL) to the reaction solution, separate the layers, wash the aqueous phase with ethyl acetate once, acidify with 10 mL of hydrochloric acid, extract with ethyl acetate, separate the organic phase, dry, filter, concentrate, and recrystallize at -20 °C to obtain approximately 2.32 g of ketoprofen-d3. The total yield of the three steps is 90%. Detected by HPLC, the purity is 99.14%, and the single largest impurity is 0.24%.
[0045] Example 7: 1. Add 2.61 g (10 mmol, 1.0 equiv.) of 3-bromobenzophenone (SM), 1.37 mL (9 mmol, 0.9 equiv.) of diethyl malonate, 0.045 g (0.05 mmol, 0.5% equiv.) of Pd2(dba)3, 0.08 g (0.4 mmol, 0.04 equiv.) of P(t-Bu)3, and 9.54 g (45 mmol, 4.5 equiv.) of potassium phosphate into 25 mL of tetrahydrofuran. Under nitrogen protection, heat to reflux overnight, then add an additional 0.76 mL (5 mmol, 0.5 equiv.) of diethyl malonate and react until the 3-bromobenzophenone is completely reacted.
[0046] 2. Add 0.95 mL (15 mmol, 1.5 equiv.) of CD3I to the reaction system, heat to 75 °C and react for 3 hours to obtain an intermediate containing M-2, denoted as M-2 solution.
[0047] 3. Directly add 11.22 g (200 mmol, 20 mL, 20.0 equiv.) of potassium hydroxide solution to the above M-2 solution reaction, stir at room temperature for 12 hours, and purify to obtain ketoprofen-d3.
[0048] Purification: Add 5% aqueous NaHCO3 solution (100 mL) to the reaction solution, separate the layers, wash the aqueous phase with ethyl acetate once, acidify with 10 mL of hydrochloric acid, extract with ethyl acetate, separate the organic phase, dry, filter, concentrate, and recrystallize at -20 °C to obtain about 2.18 g of ketoprofen-d3, with a total yield of 85% in three steps. Detected by HPLC, the purity is 99.10%, and the single largest impurity is 0.24%.
[0049] Example 8: The difference between this example and Example 1 is that: Add 2.61 g (10 mmol, 1.0 equiv.) of 3-bromobenzophenone (SM), 0.76 mL (5 mmol, 0.5 equiv.) of diethyl malonate, 0.045 g (0.05 mmol, 0.5% equiv.) of Pd2(dba)3, 0.08 g (2 mmol, 0.2 equiv.) of P(t-Bu)3, and 2.88 g (30 mmol, 3.0 equiv.) of sodium tert-butoxide to 25 mL of tetrahydrofuran. Under nitrogen protection, heat to reflux overnight, and then add an additional 0.76 mL (5 mmol, 0.5 equiv.) of diethyl malonate and react until 3-bromobenzophenone reacts completely.
[0050] Finally, about 1.28 g of ketoprofen-d3 can be obtained, with a total yield of 50% in three steps. Detected by HPLC, the purity is 98.6%, and the single largest impurity is 0.3%.
[0051] Example 9: The difference between this example and Example 1 is that: Add 2.61 g (10 mmol, 1.0 equiv.) of 3-bromobenzophenone (SM), 0.76 mL (5 mmol, 0.5 equiv.) of diethyl malonate, 0.045 g (0.05 mmol, 0.5% equiv.) of Pd2(dba)3, 0.08 g (2 mmol, 0.2 equiv.) of P(t-Bu)3, and 2.88 g (30 mmol, 3.0 equiv.) of sodium tert-butoxide to 25 mL of tetrahydrofuran. Under nitrogen protection, heat under reflux overnight, and then add an additional 1.37 mL (9 mmol, 0.9 equiv.) of diethyl malonate. React until the 3-bromobenzophenone has completely reacted.
[0052] Finally, approximately 1.79 g of ketoprofen-d3 was obtained, with a total yield of 70% over three steps. As detected by HPLC, the purity was 99.0%, and the single largest impurity was 0.26%.
[0053] The above-described embodiments are merely a preferred solution of the present invention and do not impose any formal limitations on the present invention. There are other variations and modifications without exceeding the technical solutions recited in the claims.
Claims
1. A method for preparing ketoprofen-d3, characterized in that, The following steps are involved: S1: adding 3-bromobenzophenone, diethyl malonate, palladium catalyst, phosphine ligand and weakly basic compound to an organic solvent, and heating under reflux under nitrogen protection until the reaction of 3-bromobenzophenone is complete; S2: After the arylation reaction is completed, CD3I is added to directly carry out the deuterated methylation reaction; S3: After the deuterated methylation reaction is completed, potassium hydroxide is added to carry out a hydrolysis decarboxylation reaction. After the reaction is completed, purification is performed to obtain ketoprofen-d3.
2. The preparation method according to claim 1, characterized in that: In step S1, the palladium catalyst is Pd2(dba)3.
3. The preparation method according to claim 1, characterized in that: In step S1, the phosphine ligand is P(t-Bu)3.
4. The preparation method according to claim 1, characterized in that: In step S1, the weakly alkaline compound is potassium phosphate or sodium tert-butoxide.
5. The preparation method according to claim 1, characterized in that: In step S1, the organic solvent is tetrahydrofuran, and 9-10 liters of the organic solvent are used per kilogram of 3-bromobenzophenone.
6. The preparation method according to claim 1, characterized in that The molar ratio of 3-bromobenzophenone: diethyl malonate: palladium catalyst: phosphine ligand: weakly basic compound: CD3I is 1: 1~1.4: 0.001~0.02: 0.04~0.2: 3~4.5:1.5~3.
7. The preparation method according to claim 1, characterized in that: In step S2, the deuterium methylation reaction conditions are: heating to 75±1° C. and reacting for 3 hours.
8. The preparation method according to claim 1, characterized in that: In step S3, the molar ratio of 3-bromobenzophenone to potassium hydroxide is 1:
20.
9. The preparation method according to claim 1, characterized in that: In step S3, the hydrolysis and decarboxylation reaction conditions are: stirring at room temperature for 12 hours.