A kind of preparation method of ibuprofen

Abstract

The invention discloses a method for preparing ibuprofen, wherein isobutylbenzene is used as a starting material, and a key intermediate 2-(4-isobutylphenyl)propanol is prepared by a Friedel-Crafts reaction with propylene oxide, and the intermediate is directly oxidized to obtain ibuprofen without separation, and the preparation method further includes refining. The route does not require a heavy metal catalyst, the synthesis route has few steps, the materials used are easy to obtain, the operation is simple, the reaction conditions are mild, the environment is friendly, the cost is low, the atomic utilization rate is high, and it is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis and relates to a method for preparing ibuprofen. Specifically, the method comprises a Friedel-Crafts reaction and an oxidation reaction, and further comprises refining. Background Art

[0002] Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) developed by Boots and is the only antipyretic drug for children recommended by WHO and FDA. The compound was discovered by Boots Group in the 1960s and patented in 1961. Its structure is shown in Formula I below: .

[0003] The earlier industrial synthesis route of ibuprofen is the Boots method: it includes 6 steps, using isobutylbenzene as the raw material, undergoing Friedel-Crafts acylation, and reacting with ethyl chloroacetate to generate α, β-epoxy esters. The epoxy esters undergo decarboxylation and hydrolysis to generate unstable free acids, which easily lose carbon dioxide and become enols, and then undergo keto-enol tautomerism to generate aldehydes. Aldehydes react with hydroxylamine to generate oximes, which are then converted into nitrites and hydrolyzed to generate ibuprofen. This method has many synthesis steps, a long reaction cycle, low raw material utilization, and high production costs.

[0004]

[0005] In the 1990s, Hoechst-Celanese and Boots in the United States jointly developed a new method for synthesizing ibuprofen, which achieved industrial production of ibuprofen (called the BHC method) through the carbonylation reaction of 1-(4-isobutylphenyl)ethanol. This method also uses isobutylbenzene as a raw material, and prepares ibuprofen through Friedel-Crafts reaction, catalytic hydrogenation reduction and carbonylation reaction. This synthetic route won the honor of the US Presidential Green Chemistry Challenge Award in 1997. Its atomic economy has been greatly improved from 35% to 80%. After a similar acylation reaction, alcohol is generated using Raney nickel as a catalyst, and then carbonylation is carried out using palladium-catalyzed coupling. The problem with this synthetic method is the separation, recovery and recycling of the precious metal Pd catalyst for the key carbonylation reaction.

[0006]

[0007] To solve the above problems, the present invention provides a simpler, more suitable for industrial production and environmentally friendly synthesis route, the synthesis route has two steps, no heavy metal catalyst, high atomic utilization rate, and easy to obtain reaction materials and reagents. Summary of the invention

[0008] The present invention provides a method for preparing ibuprofen, and the preparation method is as follows: a method for preparing ibuprofen,

[0009]

[0010] The steps include:

[0011] 1) Add Lewis acid and propylene oxide to the reactor, slowly add isobutylbenzene, and after the reaction is completed, add organic solvent I, separate the liquids to obtain an organic layer I;

[0012] 2) Adding acidic solution 1 to the organic layer I in step 1), slowly adding hydrogen peroxide, after the reaction is complete, adding organic solvent II, separating to obtain organic layer II; adding alkaline solution to the obtained organic layer II, separating to obtain a water layer; adding organic solvent III to the obtained water layer, adding acidic solution 2, separating to obtain organic layer III; cooling to crystallize, filtering to obtain ibuprofen.

[0013] The method further comprises step 3) dissolving the ibuprofen obtained in step 2) in organic solvent IV and water, cooling and crystallizing, and filtering to obtain ibuprofen.

[0014] The molar ratio of isobutylbenzene to propylene oxide in step 1) is 1:0.8-1, preferably 1:0.9-1.

[0015] The molar ratio of isobutylbenzene to propylene oxide in step 1) is 1:1-1.2, preferably 1:1-1.1.

[0016] The Lewis acid in step 1) is aluminum trichloride.

[0017] The temperature when adding propylene oxide in step 1) is below 30°C, preferably below 20°C, and more preferably below 10°C.

[0018] After adding propylene oxide in step 1), stir for 0.5h~3h.

[0019] The temperature when adding isobutylbenzene in step 1) is 0-40°C, preferably 5-15°C.

[0020] After the reaction in step 1) is completed, water or brine is added to the reaction solution, and the temperature is controlled below 80°C, preferably below 60°C, and more preferably below 50°C.

[0021] In step 1), the organic solvent I is an aprotic solvent, and the aprotic solvent is selected from petroleum ether, dichloromethane, toluene, xylene or a mixture thereof.

[0022] The organic layer obtained in step 1) is washed with brine, wherein the brine is a sodium chloride solution, the mass fraction of the solution is 10-26.5%, preferably a saturated sodium chloride solution.

[0023] In step 2), the acidic solution 1 is an inorganic acid solution, which is selected from a sulfuric acid solution, a hydrochloric acid solution or a mixture thereof, wherein the mass concentration of the solution is 5% to 50%.

[0024] After the acid solution 1 is added in step 2), the temperature is raised to 40-80°C.

[0025] The mass concentration of hydrogen peroxide in step 2) is 25%~45%.

[0026] The organic solvent II in step 2) is an aprotic solvent, and the aprotic solvent is selected from petroleum ether, dichloromethane, toluene, xylene or a mixture thereof.

[0027] In step 2), after adding organic solvent II, stirring and separating the liquids, the obtained water layer is further extracted with organic solvent II, and the organic layers are combined to obtain organic layer II.

[0028] The alkaline solution in step 2) is an inorganic alkaline solution, and the inorganic alkaline solution is one or more of sodium hydroxide solution, potassium hydroxide solution, lithium hydroxide solution, sodium carbonate solution, potassium carbonate solution, and sodium bicarbonate solution, wherein the mass concentration of the solution is 5% to 40%.

[0029] In step 2), the organic layer II is separated by adding alkaline solution, and the organic layer obtained by separation continues to add alkaline solution, and the aqueous layers are separated and combined.

[0030] The organic solvent III in step 2) is an aprotic solvent, and the aprotic solvent is selected from petroleum ether, dichloromethane, toluene, xylene or a mixture thereof.

[0031] The acidic solution 2 described in step 2) is an inorganic acid solution, and the inorganic acid solution is selected from one of sulfuric acid solution, hydrochloric acid solution, hydrobromic acid solution, hydroiodic acid solution or a mixture thereof, wherein the mass concentration of the solution is 5% to 50%.

[0032] In step 2), an acidic solution 2 is added, the aqueous layer obtained by separation is extracted with an organic solvent III, and the organic layers are combined to obtain an organic layer III.

[0033] The organic layer III obtained in step 2) is washed with brine, wherein the brine is a sodium chloride solution, preferably a saturated sodium chloride solution.

[0034] The crystallization temperature in step 2) is below 20°C, preferably below 10°C, and more preferably 0-5°C.

[0035] After filtering in step 2), drying may be further performed, and the drying temperature is 30°C to 60°C, preferably 30°C to 50°C, and more preferably 35°C to 50°C.

[0036] The organic solvent IV in step 3) is a protic solvent, and the protic solvent is selected from one or a mixture of C1-C5 alcohols, preferably one or more of methanol, ethanol and isopropanol.

[0037] In step 3), ibuprofen is dissolved in an organic solvent IV, and a decolorizing agent may be added. The decolorizing agent is activated carbon, preferably medicinal activated carbon.

[0038] The crystallization temperature in step 3) is below 30°C, preferably below 20°C, and more preferably 0-10°C.

[0039] Wherein step 3) further includes drying after filtration, and the drying method is step-temperature reduced pressure drying, first drying at temperature 1 for a period of time, and then increasing the temperature to temperature 2 to continue drying. The temperature 1 is 20°C to 40°C, preferably 20°C to 30°C, more preferably 20°C to 25°C; the temperature 2 is 45°C to 65°C, preferably 50°C to 60°C.

[0040] Unless otherwise specified, conventional methods were used. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 Example 4 Ibuprofen HPLC purity spectrum DETAILED DESCRIPTION

[0042] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the specific material ratios, process conditions and results described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0043] Example 1 Preparation of Ibuprofen

[0044] Add 298g of anhydrous aluminum chloride to the reactor, add 104g of propylene oxide at a temperature below 20-30°C, stir and react for 0.5h at a temperature below 20-30°C, then drop 300g of isobutylbenzene at 30-40°C, and keep warm at 30-40°C for reaction after the dropwise addition. After the reaction is completed, slowly add 1300g of water, and control the temperature within 80°C. After the addition of water, add 900g of petroleum ether, let stand and separate, wash the organic layer twice with 20% brine, and separate to obtain the organic layer.

[0045] Add 100g of 50% sulfuric acid solution to the above organic layer, heat to 60-70℃, control the temperature at 65-80℃, slowly add 350g of 35% hydrogen peroxide, stir and react for 5h, after the reaction is complete, add 600ml of petroleum ether, stir for 0.5h, stand and separate; continue to add 450ml of petroleum ether for extraction, stand and separate; add 200ml of 20% sodium hydroxide solution, stir for 0.5h, separate; continue to add 200ml of 20% sodium hydroxide solution to the upper layer, stir for 0.5h, separate. Combine the water layers, add 350ml of petroleum ether, slowly add about 250g of hydrochloric acid, stand and separate, add 250ml of petroleum ether to the water layer, extract, separate; combine the petroleum ether layers, wash twice with saturated brine, separate; slowly cool to 0-5℃, stir and react for 3h, filter and dry to obtain ibuprofen, with a yield of 83%.

[0046] Example 2 Preparation of Ibuprofen

[0047] Add 286g of aluminum chloride to the reactor, add 104g of propylene oxide at a temperature below 10-20°C, stir and react for 3h at a temperature below 10-20°C, then add 240g of isobutylbenzene dropwise at 10-20°C, and keep the temperature at 15-25°C for reaction after the addition is complete. After the reaction is completed, slowly add 1700g of water, and control the temperature within 60°C. After the addition of water is completed, add 1000g of dichloromethane, let stand and separate, wash the organic layer twice with 10% brine, and separate to obtain the organic layer.

[0048] To the above organic layer, 100 g of 30% hydrochloric acid solution was added, the temperature was raised to 40-50 ° C, the temperature was controlled at 60-70 ° C, 670 g of 45% hydrogen peroxide was slowly added, and the reaction was stirred. After the reaction was completed, 1000 g of dichloromethane was added, stirred, and the organic layer was allowed to stand for separation to obtain an organic layer. 500 g of 35% potassium hydroxide solution was added to the organic layer, and the aqueous layer was allowed to stand for separation to obtain an aqueous layer. 400 g of toluene was added, and dilute sulfuric acid was slowly added to adjust the pH, and the layers were allowed to stand for separation to obtain a toluene layer, which was washed with a 20% sodium chloride solution and separated; the temperature was slowly lowered to 10 ° C, stirred for crystallization, and filtered to obtain ibuprofen with a yield of 85%.

[0049] Example 3 Preparation of Ibuprofen

[0050] Add 288g (1.21mol) of aluminum chloride to the reactor, add 104g of propylene oxide at a temperature below 0-10°C, stir and react at a temperature below 0-10°C for 1h, then add 264g (1.1mol) of isobutylbenzene dropwise at 5-15°C, and keep the temperature at 5-15°C for reaction after the addition is complete. After the reaction is completed, slowly add 1450g of water, and control the temperature within 50°C. After the addition of water is completed, add 900g of xylene, let stand and separate, wash the organic layer with a saturated sodium chloride solution, and separate to obtain a toluene layer.

[0051] Add 600g of 10% sulfuric acid solution to the above toluene layer, heat to 35-45°C, control the temperature at 50-60°C, slowly add 610g of 25% hydrogen peroxide, stir to react, and after the reaction is complete, add 500ml of xylene, stir, and stand for separation; continue to add 500ml of xylene for extraction, stand for separation; add 800g of 20% sodium carbonate solution, stir, stand for separation; continue to add 800g of 20% sodium carbonate solution to toluene layer by layer, stir, stand for separation. Combine the water layers, add 400g of xylene, slowly add hydrobromic acid to adjust the pH, stand for separation, add xylene to the water layer for extraction, and separate; combine the xylene layers, wash with saturated sodium chloride solution, and separate; slowly cool to 10-15°C, stir for crystallization, filter, and dry to obtain ibuprofen with a yield of 82%.

[0052] Example 4 Ibuprofen Refining

[0053] Take 100 g of ibuprofen prepared according to Example 1, add 200 g of ethanol and 10 g of water, heat to 50° C. and dissolve, filter while hot, cool to 30° C. and stir for a period of time, continue to cool to 10° C. for crystallization, and filter to obtain wet ibuprofen; dry under reduced pressure at 30-40° C. for 5 h, slowly heat to 55-65° C. and dry under reduced pressure for 12 h to obtain ibuprofen, with a yield of 91% and a purity of 99.78%.

[0054] Example 5 Ibuprofen Refining

[0055] Take 100 g of ibuprofen prepared according to Example 2, add 400 g of isopropanol, 25 g of water, add 0.5 g of activated carbon, heat to 50° C. to dissolve, filter while hot, cool to 10° C. to crystallize, and filter to obtain wet ibuprofen; dry under reduced pressure at 20-30° C. for a period of time, slowly heat to 50-60° C. and dry under reduced pressure to obtain ibuprofen, with a yield of 85% and a purity of 99.92%.

[0056] Example 6 Ibuprofen Refining

[0057] Take 100 g of ibuprofen prepared according to Example 3, add 300 g of methanol, 28 g of water, add 1 g of activated carbon, heat to 50° C. and dissolve, filter while hot, cool to 20° C. and stir for a period of time, continue to cool to below 5° C. for crystallization, and filter to obtain wet ibuprofen; dry under reduced pressure at 20-25° C., slowly heat to 45-55° C. and dry under reduced pressure to obtain ibuprofen, with a yield of 90% and a purity of 99.84%.

Claims

1. A method for preparing ibuprofen, characterized in that The steps include: 1) Add aluminum chloride and propylene oxide to a reactor, slowly add isobutylbenzene to react, add water to the reaction solution after the reaction is completed, then add an organic solvent selected from petroleum ether, dichloromethane, and xylene for extraction, and separate to obtain an organic layer I; then directly add an acidic solution 1 to the organic layer I, and slowly add hydrogen peroxide with a mass concentration of 25%-45%, and react at 40°C-80°C. After the reaction is complete, add an organic solvent selected from petroleum ether, dichloromethane, and xylene to the reaction solution, separate to obtain an organic layer II; add an alkaline solution to the obtained organic layer II, separate to obtain a water layer; add an organic solvent selected from petroleum ether, toluene, and xylene to the obtained water layer, and add an acidic solution 2, separate to obtain an organic layer III; cool the obtained organic layer III to crystallize, and filter to obtain a crude ibuprofen; the acidic solution 1 and the acidic solution 2 are aqueous solutions of sulfuric acid or hydrochloric acid with a mass concentration of 5%-50%; the alkaline solution is an aqueous solution of sodium hydroxide or potassium hydroxide; 2) dissolving the obtained crude ibuprofen in a mixed solvent of methanol, ethanol or isopropanol and water, cooling and crystallizing, filtering and drying to obtain ibuprofen; the temperature of cooling and crystallizing is 0°C-10°C; The drying is step temperature drying, and the step temperature drying process is drying at temperature I and then heating up to drying at temperature II; the temperature I is 20°C to 40°C, and the temperature II is 45°C to 65°C.

Images