Synthesis method of etoricoxib intermediate
Through a new synthesis method of cocoxib intermediate, 4-methanesulfonylphenylacetic acid is prepared by using compound II through multiple steps, solving the problems of high cost and dangerous processes in the prior art, and achieving safety and controllability and cost-effective synthesis processes.
Patent Information
- Application Number
- CN202411563377.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-05
- Publication Date
- 2025-02-14
AI Technical Summary
The existing synthesis methods based on coxie intermediates have high overall costs and involve dangerous processes, which pose potential safety risks.
Provide a new synthesis method of cocoxib intermediate, by taking Compound II as the starting material, through methylation, halogenation, cyanation, hydrolysis and other steps, 4-methanesulfonylphenylacetic acid is prepared, the material used It is a general chemical for chemical industry, and the process is safe and controllable.
It reduces material costs, avoids dangerous processes, is safe and controllable, and has better cost-effectiveness than existing technologies.
Smart Images
Figure CN119431200A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the field of chemical pharmacy and relates to a preparation method of a pharmaceutical intermediate, and specifically relates to a synthesis method of an etoricoxib intermediate. Background Art
[0002] Etoricoxib is a selective cyclooxygenase-2 (COX-2) inhibitor, mainly used to treat symptoms such as osteoarthritis, rheumatoid arthritis, acute gouty arthritis, primary dysmenorrhea, and acute postoperative pain. It reduces inflammation and pain by inhibiting COX-2 while maintaining the activity of COX-1 to reduce gastrointestinal side effects.
[0003] 4-Methylsulfonylphenylacetic acid is a key intermediate of etoricoxib. The traditional synthesis methods include the following two routes: Route 1 is to use thioanisole as the starting material, and to obtain 4-methylsulfonylphenylacetic acid through FC acylation, Willgerodt-kindler rearrangement, hydrolysis, oxidation, and a total of four steps. Route 2 is to use thioanisole as the starting material, and to obtain 4-methylthiobenzaldehyde after Vilsmeier reaction, which is reacted with methyl α-bromoacetate to generate epoxy ester, which is hydrolyzed and oxidized to obtain 4-methylsulfonylphenylacetic acid.
[0004] Route 1:
[0005]
[0006] Route 2:
[0007]
[0008] The main problems of the existing technical routes are high comprehensive costs, and they all involve dangerous processes: oxidation reactions, which have potential safety risks. In order to reduce material costs and avoid dangerous processes, it is urgent to provide a new synthesis method for etoricoxib intermediates. Summary of the invention
[0009] In view of the above problems existing in the prior art, the present application provides a method for synthesizing an etoricoxib intermediate, which has a safe and controllable process.
[0010] To solve the above problems, the present invention provides the following technical solutions:
[0011] The present application provides a method for synthesizing an etoricoxib intermediate, and the synthetic route is as follows:
[0012]
[0013] Wherein, X=Br or Cl;
[0014] The following steps are involved:
[0015] Using compound II as the starting material, compound III is generated through methylation reaction;
[0016] Compound III undergoes halogenation reaction to generate compound IV;
[0017] Compound IV is subjected to cyanation reaction to generate compound V;
[0018] Compound V is subjected to a hydrolysis reaction with an alkaline compound, and compound I is obtained through extraction, acidification, solid precipitation, filtration, washing and recrystallization.
[0019] In one embodiment of the present application, compound II is used as a starting material and reacted with sodium sulfite and sodium bicarbonate to generate sodium p-toluenesulfinate. Sodium p-toluenesulfinate, sodium bicarbonate and dimethyl sulfate are methylated to generate compound III.
[0020] In one embodiment of the present application, the molar ratio of compound II, sodium sulfite and sodium bicarbonate is 1:2.2:1.1.
[0021] In one embodiment of the present application, the reaction temperature is 60-90° C.; the reaction time is 0.5-2 h.
[0022] In one embodiment of the present application, the reaction temperature is 70-80°C.
[0023] In one embodiment of the present application, when sodium p-toluenesulfinate, sodium bicarbonate and dimethyl sulfate are subjected to methylation reaction, the molar ratio of sodium bicarbonate to dimethyl sulfate is 1.1:1.5.
[0024] In one embodiment of the present application, the temperature of the methylation reaction is 95-102° C.; the time of the methylation reaction is 18-22 hours.
[0025] In one embodiment of the present application, the molar ratio of compound III to chloride or compound III to bromide is 1:1-1.5.
[0026] In one embodiment of the present application, the chloride is selected from sulfonyl chloride.
[0027] In one embodiment of the present application, the bromide is selected from N-bromosuccinimide (NBS).
[0028] In one embodiment of the present application, when compound III and bromide undergo halogenation reaction to generate compound IV, a free radical initiator azobisisobutyronitrile (AIBN) is also added, under the action of which N-bromosuccinimide decomposes to generate bromine free radicals.
[0029] In one embodiment of the present application, compound IV, hexamethylphosphoric triamide and potassium cyanide are added to acetonitrile, the temperature is raised to react, and then water and ethyl acetate are added to dilute, the organic phase is washed, the solid is desolventized and precipitated, and the compound V is obtained by filtration.
[0030] In one embodiment of the present application, the molar ratio of compound IV to potassium cyanide is 1:1.1.
[0031] In one embodiment of the present application, the mass ratio of compound IV to hexamethylphosphoric triamide is 2:1.
[0032] In one embodiment of the present application, the temperature of the temperature-raising reaction is 50-80° C.; and the time of the temperature-raising reaction is 1-20 hours.
[0033] In one embodiment of the present application, the molar ratio of compound V to the basic compound is 1:4.
[0034] In one embodiment of the present application, the temperature of the hydrolysis reaction is 90-110° C.; the time of the hydrolysis reaction is 1-5 h.
[0035] In one embodiment of the present application, the alkaline compound is selected from one of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, and triethylamine.
[0036] In one embodiment of the present application, during acidification, the pH value is adjusted to 1-2.
[0037] Compared with the prior art, the present application provides a novel synthesis method of etoricoxib intermediates, the materials used are all general chemical chemicals, the cost-effectiveness is better than the prior art, and no dangerous processes are involved, and the process is safe and controllable. BRIEF DESCRIPTION OF THE DRAWINGS
[0038] Figure 1 is the HPLC spectrum of 4-methylsulfonylphenylacetic acid;
[0039] Figure 2 4-Methylsulfonylphenylacetic acid 1 HNMR spectrum. DETAILED DESCRIPTION
[0040] The following will provide a clear and complete description of the technical solutions in the embodiments of the present application in conjunction with the drawings in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all of the embodiments.
[0041] The "range" disclosed in this application is defined in the form of a lower limit and an upper limit, and a given range is defined by selecting a lower limit and an upper limit, and the selected lower limit and upper limit define the boundaries of the particular range. The range defined in this way can be inclusive or exclusive of the end values, and can be arbitrarily combined, that is, any lower limit can be combined with any upper limit to form a range.
[0042] Unless otherwise specified, the percentages between liquids and liquids in the present invention are volume / volume percentages; the percentages between liquids and solids in the present invention are volume / weight percentages; the percentages between solids and liquids in the present invention are weight / volume percentages; and the rest are weight / weight percentages.
[0043] Example 1: Synthesis of p-methylsulfonyltoluene
[0044]
[0045] Sodium sulfite (277 g, 2.2 mol, 2.2 eq), sodium bicarbonate (92 g, 1.1 mol, 1.1 eq), and water (382 g, 2 w / w) were added to a reaction flask, heated to 70-80°C, p-toluenesulfonyl chloride (191 g, 1.0 mol, 1.0 eq) was added in batches, and the temperature was kept at 70-80°C for 1 hour. The mixture was slowly cooled to room temperature, solids were precipitated, and the filter cake was sodium p-toluenesulfinate. The obtained sodium p-toluenesulfinate was mixed with sodium bicarbonate (92 g, 1.1 mol, 1.1 eq), dimethyl sulfate (189 g, 1.5 mol, 1.5 eq) and water (191 g, 1 w / w), reacted at 95-102 ° C for 20 hours, cooled to room temperature, and toluene was added to extract the product. The separated toluene phase was washed with water and concentrated under reduced pressure to precipitate a large amount of solid, which was filtered and the filter cake was dried by air to obtain 121 g of the product p-methylsulfonyltoluene with a yield of 71%.
[0046] Example 2: Synthesis of 1-chloromethyl-4-(methylsulfonyl)benzene
[0047]
[0048] Dissolve p-methylsulfonyltoluene (204 g, 1.2 mol, 1.0 eq) in acetonitrile (612 g, 3 w / w) at room temperature, cool to 0-5°C, slowly drop sulfonyl chloride (194 g, 1.44 mol, 1.2 eq), during which a large amount of acidic gas is released. After the dropwise addition is completed, stir at 0-5°C for 1 hour, slowly heat to 45-50°C and distill under reduced pressure to obtain 221 g of 1-chloromethyl-4-(methylsulfonyl chloride)benzene, with a yield of 90%.
[0049] Example 3: Synthesis of 4-methylsulfonylbenzyl bromide
[0050]
[0051] Dissolve p-methylsulfonyltoluene (71 g, 0.42 mol, 1.0 eq) in acetonitrile (284 g, 4 w / w) at room temperature, add AIBN (3.4 g, 0.021 mol, 0.05 eq) and NBS (78.3 g, 0.44 mol, 1.05 eq), heat to reflux, react for 5 hours, add 15% sodium chloride solution for washing, separate the liquids, desolventize the organic phase under reduced pressure, and directly use the residue for the next step reaction. The product 4-methylsulfonylbenzyl bromide 92 g is obtained with a yield of 88%.
[0052] Example 4: Synthesis of 4-(methylsulfonyl)benzyl cyanide
[0053]
[0054] 1-Chloromethyl-4-(methylsulfonyl)benzene (143 g, 0.7 mol, 1.0 eq), hexamethylphosphoric triamide (71.6 g, 0.5 w / w), potassium cyanide (50 g, 0.77 mol, 1.1 eq) were added to acetonitrile (429 g, 3 w / w), the temperature was raised to 75-80 ° C and stirred for reaction for 18 hours, then water and ethyl acetate were added to dilute, the organic phase was washed with sodium bicarbonate solution and brine, the solid was desolventized and precipitated, and the product 4-(methylsulfonyl)benzyl cyanide was filtered to obtain 123 g of the product with a yield of 90%.
[0055] Example 5: Synthesis of 4-(methylsulfonyl)benzyl cyanide
[0056]
[0057] 4-Methylsulfonylbenzyl bromide (74.7 g, 0.3 mol, 1.0 eq), hexamethylphosphoric triamide (37 g, 0.5 w / w), potassium cyanide (21.5 g, 0.33 mol, 1.1 eq) were added to acetonitrile (224 g, 3 w / w), the temperature was raised to 50-60 ° C and stirred for reaction for 2 hours, then water and ethyl acetate were added to dilute, the organic phase was washed with sodium bicarbonate solution and brine, the solid was desolventized under reduced pressure, and the product 4-(methylsulfonyl)benzylacetonitrile was obtained by filtration 48 g, with a yield of 82%.
[0058] Example 6: Synthesis of 4-methylsulfonylphenylacetic acid
[0059]
[0060] Add 4-(Methylsulfonyl)benzyl cyanide (468g, 2.4mol, 1.0eq) to water (3744g, 8w / w), add potassium hydroxide (539g, 9.6mol, 4.0eq), heat to 98-102°C, and react for 3 hours. Then cool to 25-30°C, and use toluene to extract impurities. Add concentrated hydrochloric acid to the aqueous phase, adjust the pH to 1-2, and a large amount of solids will precipitate. Filter, wash the filter cake with water, dry it with air at 60°C, and recrystallize the product with methanol to obtain 406g of refined 4-methylsulfonylphenylacetic acid, with a yield of 79% and a purity of 99.43%. 1 HNMR (400 MHz, DMSO-d 6 ):7.89-7.91(d,2H),7.56-7.58(d,2H),3.76(s,2H),3.23(s,3H).
[0061] The present application is described in detail above in conjunction with specific implementation methods and exemplary embodiments, but these descriptions cannot be understood as limiting the present application. Those skilled in the art understand that, without departing from the spirit and scope of the present application, the technical solution of the present application and its implementation methods may be subjected to a variety of equivalent substitutions, modifications or improvements, all of which fall within the scope of the present application.
Claims
1. A method for synthesizing an etoricoxib intermediate, characterized in that: Its synthetic route is as follows: Wherein, X=Br or Cl; The following steps are involved: Using compound II as the starting material, compound III is generated through methylation reaction; Compound III undergoes halogenation reaction to generate compound IV; Compound IV is subjected to cyanation reaction to generate compound V; Compound V is subjected to a hydrolysis reaction with an alkaline compound, and compound I is obtained through extraction, acidification, solid precipitation, filtration, washing and recrystallization.
2. The method for synthesizing an etoricoxib intermediate according to claim 1, characterized in that: Compound II is used as a starting material and reacted with sodium sulfite and sodium bicarbonate to generate sodium p-toluenesulfinate. Sodium p-toluenesulfinate, sodium bicarbonate and dimethyl sulfate are subjected to a methylation reaction to generate compound III.
3. The method for synthesizing an etoricoxib intermediate according to claim 2, characterized in that: The molar ratio of compound II, sodium sulfite and sodium bicarbonate is 1:2.2:1.1; the reaction temperature is 60-90°C; the reaction time is 0.5-2h; the molar ratio of sodium bicarbonate to dimethyl sulfate is 1.1:1.5; the methylation reaction temperature is 95-102°C; and the methylation reaction time is 18-22h.
4. The method for synthesizing an etoricoxib intermediate according to claim 1, characterized in that: When compound III undergoes a halogenation reaction to generate compound IV, the molar ratio of compound III to chloride or compound III to bromide is 1:1-1.
5.
5. The method for synthesizing an etoricoxib intermediate according to claim 1, characterized in that: Compound IV, hexamethylphosphoric triamide and potassium cyanide were added to acetonitrile, and the temperature was raised to react. Water and ethyl acetate were then added to dilute the mixture. The organic phase was washed, and the solid was desolventized to precipitate. Compound V was obtained by filtration.
6. The method for synthesizing an etoricoxib intermediate according to claim 5, characterized in that: The molar ratio of compound IV to potassium cyanide is 1:1.1; the mass ratio of compound IV to hexamethylphosphoric triamide is 2:1; the temperature of the temperature-raising reaction is 50-80° C.; and the time of the temperature-raising reaction is 1-20 hours.
7. The method for synthesizing an etoricoxib intermediate according to claim 1, characterized in that: The molar ratio of compound V to the alkaline compound is 1:4; the temperature of the hydrolysis reaction is 90-110° C.; and the time of the hydrolysis reaction is 1-5 hours.
8. The method for synthesizing an etoricoxib intermediate according to claim 7, characterized in that: The alkaline compound is selected from one of sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide and triethylamine.
9. The method for synthesizing an etoricoxib intermediate according to claim 1, characterized in that: When acidifying, adjust the pH to 1-2.