WO2021047490A1

WO2021047490A1 - Method for preparing dexibuprofen

Info

Publication number: WO2021047490A1
Application number: PCT/CN2020/113887
Authority: WO
Inventors: 赵平; 刘新; 程志刚; 梁群; 杨宜平; 杨寿松; 孔虎林; 官倩倩; 成森; 周勇; 廖敏杰; 李宁; 张雪芹; 刘玲; 杨慈海
Original assignee: 湖北亨迪药业股份有限公司; 武汉百科药物开发有限公司
Priority date: 2019-09-10
Filing date: 2020-09-08
Publication date: 2021-03-18
Also published as: CN110615735A; AT17930U1

Abstract

Disclosed in the present invention is a method for preparing dexibuprofen, comprising: (1) after adding toluene into a reaction kettle, adding ibuprofen and n-octyl-d-glucamine, heating to 76 to 80°C, keeping the temperature and reacting for 0.5 h or more, transferring the material into an amine salt crystallization kettle, adding purified water, and then cooling and crystallizing; after decreasing the temperature to 18 to 22°C, centrifuging and separating, washing, and drying to obtain the dexibuprofen n-octyl-d-glucamine salt; the feed ratio of ibuprofen : n-octyl-d-glucamine : toluene : purified water is 1 : 0.65 to 0.75 : 7.5 to 8 : 0.01 to 0.02; (2) performing a hydrolysis reaction to precipitate n-octyl-d-glucamine; (3) performing an acidification reaction to precipitate dexibuprofen. The applicant finally determines that the ratio of the volume of purified water to the weight of ibuprofen in the preparation of amine salt is 0.01 to 0.02L : 1 kg, so that the molar yield of dexibuprofen is finally high, and the melting point of dextro amine salt reaches a qualified standard of 135 to 140°C.

Description

A kind of preparation method of dextroibuprofen

Technical field

The invention relates to the technical field of organic synthesis, in particular to a preparation method of dextroprofen.

Background technique

The process of separating the racemate into a pure levorotatory or pure dextrorotatory is called the resolution of the racemate, and chemical resolution is one of the common resolution methods. The chemical method uses a resolving agent to resolve the racemate, and the resolving agent used is usually an organic acid base with optical activity. Dexibuprofen (dexibuprofen) is the right-handed body of ibuprofen. Studies have found that the pharmacological activity of ibuprofen is mainly derived from the dextrorotatory form, which has a higher curative effect than the equal-dose ibuprofen racemate, and a smaller dose can achieve the therapeutic effect. Dexbuprofen has the same effects and uses as ibuprofen, but the doses of the former 150mg and 300mg are equivalent to those of the latter 200mg and 400mg, respectively, and are superior to ibuprofen in terms of safety and pharmacokinetic properties. Therefore, it is necessary to split ibuprofen into right ibuprofen.

Comparative document: The application number is "CN02138434.7" and the name is "Preparation of dextro-ibuprofen". It is disclosed that racemic ibuprofen ((±)I) is used to control the process of host-guest crystallization-reaction kinetics. The method to obtain dextro-ibuprofen ((+)I) by resolution. With meglumine, or α-phenhexylamine, cinchonidine, L-lysine and meglumine ((+)II) as the main body, racemic-ibuprofen ((±)I) as the guest , Ethanol (III) is the solvent, and the salt-forming reaction occurs under normal pressure and temperature of 10～85℃. The salt ((+)I·(+)II) formed by the dextro-ibuprofen ((+)I) and the main resolving agent ((+)II) precipitates out in the form of crystals, while the lev-ibuprofen ( The salt ((-)I·(+)II) produced by (-)I) and the resolving agent ((+)II) is dissolved in the solvent. Separate ((+)I·(+)II) salt, first adjust pH ≥ 10 with NaOH solution in water, filter out solid (+) II, adjust pH 1-2 with hydrochloric acid, and precipitate (+) I. The salt (-)I·(+)II dissolved in the solvent is recovered by racemization ((±)I), and then resolved. Each step of the operation strictly controls the material ratio and temperature, so as to control the resolution and quality of (+)I. The one-time resolution ratio is 27-33%, the mass content of (+)I is ≥99.5%, and the specific optical rotation [α]D is 56-59°. Although the resolution ratio prepared by the reference document is high, the melting point of the dextrorotatory amine salt prepared by the reaction according to the process conditions is seriously low, and the content of dextro-ibuprofen and the levorotary body obtained by hydrolysis and acidification seriously exceeds the qualified standard. How to improve the process so that the molar yield of dextroprofen is high while the melting point of the dextrorotatory amine salt reaches the qualified standard has become a technical problem to be solved urgently.

Summary of the invention

The purpose of the present invention is to overcome the defects of the prior art and provide a method for preparing dextroprofen, so that the dextroprofen has a high molar yield and the melting point of the dextro-amine salt reaches the qualified standard.

The present invention is realized as follows:

The purpose of the present invention is to provide a method for preparing dextroibuprofen, the method comprising the following steps:

Step 1. Salt formation reaction to prepare dexibuprofen meglumine salt:

After putting toluene into the reactor, put in ibuprofen and meglumine, stir and heat up to 76～80℃, keep the temperature for more than 0.5h, transfer the materials to the amine salt crystallization kettle, add purified water and then cool down and crystallize, the temperature drops to 18 After ～22°C, centrifugal separation and washing, dexibuprofen meglumine salt is obtained after drying; the feed ratio of ibuprofen: meglumine: toluene: purified water is 1:0.65～0.75:7.5～8 ：0.01～0.02; wherein the unit of ibuprofen and meglumine in the ratio is kg, and the unit of toluene and purified water is L;

Step 2. Hydrolysis reaction to precipitate meglumine: Add the dexibuprofen meglumine salt obtained in step 1 to an alkaline salt solution to carry out a hydrolysis reaction, to precipitate meglumine and remove it;

Step 3. Acidification reaction to precipitate dextroprofen: the material after removing meglucosamine in step 2 is adjusted to pH 1 to 2 with hydrochloric acid, and the wet crude product of dextroprofen is obtained after cooling and centrifugation. After refining, dextroprofen is obtained. Profen finished product.

Compared with the prior art, the present invention has the following advantages and effects: A preparation method of dextroprofen, the applicant adopts a dextroprofen resolution process: toluene is used as a solvent, and meglumine is used as a resolution agent The amine salt is obtained by splitting the ibuprofen, and then hydrolyzed and acidified to obtain dexibuprofen. In the preparation process of dextromethorphan amine salt, when the water content of the three raw materials of meglumine, ibuprofen and toluene is extremely low, and the reaction is carried out according to the process conditions, the melting point of the dextromethorphan salt is seriously low (122℃). ～130℃), after hydrolysis and acidification, the content of dextro-ibuprofen and L-body seriously exceeded the qualified standard. The applicant discovered in an industrial production that the residual moisture after washing in the toluene recycling process unintentionally caused the melting point of the dextrorotatory amine salt to reach the qualified standard. This shows that a small amount of water is required for the separation effect. The applicant found through a large number of innovative experiments that too much water (exceeding 0.02 times the amount of ibuprofen, the unit of water is L, the unit of ibuprofen is kg) will reduce the dissolved amine salt Yield and yield decrease (normally the yield is 92%, the yield of excessive water drops below 88%); the amount of water is too small (less than 0.01 times the feed amount of ibuprofen, the unit of water is L and the unit of ibuprofen is kg) The melting point of the amine salt is seriously low, (the qualified standard is 135～140℃, and the lowest is 125℃). The product is unqualified; we finally determined through experiments that the amount of water required for the preparation of amine salt is: the ratio of the volume of purified water to the weight of ibuprofen It is 0.01～0.02L: 1kg, that is, when the heating reaction of raw materials and auxiliary materials is transferred to crystallization and cooling, the amount of purified water in this proportion is added. Finally, while the molar yield of dextroprofen is high, the melting point of the dextro-amine salt reaches the qualified standard of 135-140°C.

Description of the drawings

Figure 1 is a flow chart of a method for preparing dexibuprofen provided by the present invention;

Figure 2 is an infrared spectrogram of dexibuprofen prepared in Example 1 of the present invention;

Fig. 3 is a chromatogram of dexibuprofen prepared in Example 1 of the present invention;

Fig. 4 is a chromatogram of related substances of dexibuprofen prepared in Example 1 of the present invention.

detailed description

Example 1

A method for preparing dexibuprofen, the method comprising:

1. Preparation of amine salt:

1. Put the process amount of toluene (2448L) in the reactor according to the feed ratio, add about 50L hydrochloric acid solution (14-18%), stir for more than 10 minutes, let stand for more than 10 minutes, divide the hydrochloric acid layer; then add about 200L For drinking water, stir for more than 10 minutes and let stand for more than 10 minutes to separate the water layer.

2. Add 315kg of ibuprofen and 216kg of meglumine according to the ratio, seal the hole cover, stir and heat to increase the temperature to 76-80°C, and keep the temperature for more than 0.5 hours.

3. Transfer the materials to the amine salt crystallization kettle, add about 4.5L of purified water, and then cool down and crystallize. After the temperature drops to 18-22°C, put the materials in a centrifuge to dry (10-15min), and then wash with toluene. Once (30-50L), rinse once (30-40L).

Bag and weigh the materials to obtain the amine salt wet product; put the amine salt wet product into the dryer, control the water temperature at 85～95℃, the vacuum degree ≤-0.09Mpa, dry for 3～6 hours, discharge, bag and weigh . Use a sampling bottle to sample 20～30g and send it for inspection and analysis of melting point. The melting point measured by a melting point tester is 135℃～140℃.

2. Hydrolysis reaction:

1. Add 936L of drinking water, 59.4 kg of potassium hydroxide, and 300 kg of a batch of dexibuprofen meglumine salt prepared in the previous procedure in the hydrolysis reactor according to the feed ratio, and then seal the hole cover.

2. After the temperature is raised to 45-55°C and reacted for 40-60 minutes, the materials are transferred to the hydrolysis freezing kettle, and the ice brine is turned on to cool down to below 20°C.

3. Put the frozen materials into a centrifuge and spin dry, wash with water once (30-50L), pump the centrifugal solution and washing water into the acidification kettle; the centrifugal filter cake is dried by meglumine, and the dryer jacket is controlled Water temperature ≥95℃, vacuum degree ≤-0.09Mpa, drying for more than 8 hours, sampling and testing, discharge and weighing.

3. Acidification reaction:

1. Heat up the contents of the acidification kettle to 45-55°C and then add dropwise hydrochloric acid with a concentration of 14-18% for acidification. The end-point pH value is 1-2, and the reaction temperature is kept for 0.5-1 hour.

2. Cool down to below 30℃, centrifuge and spin dry the discharged materials (8～10min), wash with water to pH=5～7, bag and weigh after drying, the weight of each batch of wet crude products should not be less than 55kg (in amine Salt 135kg), the molar yield should be ≥66%. Yield calculation method: crude product yield ÷ (glucoctamine feed amount × 206.28 ÷ 293.4); in this example, the wet crude product weight is 134 kg, and the molar yield is 88.2%.

3. Sampling 20～30g samples to check the appearance and rt% (HPLC) method, the appearance is off-white to light yellow.

4. Crude product refining:

Put the crude dextroprofen into 80% acetic acid (±2%) into the dissolving kettle, the weight ratio of the crude dextroprofen: 80% acetic acid (±2%) is 1:1.4; this process can be mixed batches , Control the weight of crude product from 330kg to 450kg. Open the manhole cover and put the crude product of ibuprofen and 1~2kg activated carbon in the upper process, then seal, heat up to 45~60℃ and keep for 0.5~1h, then press filter the material into the crystallization kettle, cool it to 0~5℃, and then centrifuge it. dried, and washed with pure water to pH = 5 ~ 7, centrifugal drying (8 ~ 10min) after sampling polyethylene plastic bottle with 20 ~ 30g analysis appearance, cl ^-%, which is white, cl ^-% ≤0.008%. Then put it into the dryer, control the temperature of the dryer to 35～40℃, the vacuum degree ≤-0.09Mpa, dry for more than 24 hours, divide the water every 2～3h, then put the materials into the material box, weigh, and transfer The packing room is crushed, sieved, packed, tied, and packed.

Example 2

A method for preparing dexibuprofen, the method comprising:

1. Preparation of amine salt:

1. Put the process amount of toluene (2362.5L) into the reactor according to the feeding ratio, add about 50L hydrochloric acid solution (14-18%), stir for more than 10 minutes, let stand for more than 10 minutes, divide the hydrochloric acid layer; add about 200L of drinking water, stir for more than 10 minutes, and let stand for more than 10 minutes to separate the water layer.

2. Add 315kg of ibuprofen and 204.75kg of meglumine according to the ratio, seal the hole cover, stir and heat to increase the temperature to 76-80°C, and keep the temperature for more than 0.5 hours.

3. Transfer the materials to the amine salt crystallization kettle, add about 3.15L of purified water, and then cool down and crystallize. After the temperature drops to 18-22°C, put the materials in a centrifuge to dry (10-15min), and then wash with toluene. Once (30-50L), rinse once (30-40L).

2. Hydrolysis reaction:

1. Add 882.35L of drinking water, 52.9 kg of potassium hydroxide, and 300 kg of a batch of dexibuprofen meglumine salt prepared in the previous procedure in the hydrolysis reactor according to the feed ratio, and then seal the hole cover.

3. Acidification reaction:

2. Cool down to below 30℃, centrifuge and spin dry the discharged materials (8～10min), wash with water to pH=5～7, bag and weigh after drying, the weight of each batch of wet crude products should not be less than 55kg (in amine Salt 135kg), the molar yield should be ≥66%. Yield calculation method: crude product yield ÷ (glucoctamine feed amount × 206.28 ÷ 293.4); in this embodiment, the wet crude product weight is 125 kg, and the molar yield is 86.8%.

4. Crude product refining:

Put the crude dextroprofen into 80% acetic acid (±2%) into the dissolving kettle, the weight ratio of the crude dextroprofen: 80% acetic acid (±2%) is 1:1.4; this process can be mixed batches , Control the weight of crude product from 330kg to 450kg. Open the manhole cover and put the crude product of ibuprofen and 1~2kg activated carbon into the upper process, then seal, heat up to 45~60℃ and keep for 0.5~1h, then press filter the material into the crystallization kettle, cool to 0~5℃, and then centrifuge it. dried, and washed with pure water to pH = 5 ~ 7, centrifugal drying (8 ~ 10min) after sampling polyethylene plastic bottle with 20 ~ 30g analysis appearance, cl ^-%, which is white, cl ^-% ≤0.008%. Then put it into the dryer, control the temperature of the dryer to 35～40℃, the vacuum degree ≤-0.09Mpa, dry for more than 24 hours, divide water every 2～3h, then put the materials into the material box, weigh, and transfer The packing room is crushed, sieved, packed, tied, and packed.

Example 3

A method for preparing dexibuprofen, the method comprising:

1. Preparation of amine salt:

1. Put the process amount of toluene (2520L) in the reactor according to the feed ratio, add about 50L hydrochloric acid solution (14-18%), stir for more than 10 minutes, let stand for more than 10 minutes, separate the hydrochloric acid layer; add about 200L again For drinking water, stir for more than 10 minutes and let stand for more than 10 minutes to separate the water layer.

2. Add 315kg of ibuprofen and 236.25kg of meglumine according to the ratio, seal the hole cover, stir and heat to increase the temperature to 76-80℃, and keep the temperature for more than 0.5 hours.

3. Transfer the materials to the amine salt crystallization kettle, add about 6.3L of purified water, and then cool down and crystallize. After the temperature drops to 18-22°C, put the materials in a centrifuge to dry (10-15min), and then wash with toluene. Once (30-50L), rinse once (30-40L).

2. Hydrolysis reaction:

1. Add 916.7L of drinking water, 58.34kg of potassium hydroxide, and 300kg of a batch of dexibuprofen meglumine salt prepared in the previous procedure in the hydrolysis reactor according to the feed ratio, and then seal the hole cover.

3. Acidification reaction:

2. Cool down to below 30℃, centrifuge and spin dry the discharged materials (8～10min), wash with water to pH=5～7, bag and weigh after drying, the weight of each batch of wet crude products should not be less than 55kg (in amine Salt 135kg), the molar yield should be ≥66%. Yield calculation method: crude product output ÷ (glucoctamine feed amount × 206.28 ÷ 293.4); in this embodiment, the wet crude product weight is 151 kg, and the molar yield is 90.9%.

4. Crude product refining:

Put the crude dextroprofen into 80% acetic acid (±2%) into the dissolving kettle. The weight ratio of the crude dextroprofen: 80% acetic acid (±2%) is 1:1.4; this process can be mixed batches , Control the weight of crude product from 330kg to 450kg. Open the manhole cover and put the crude product of ibuprofen and 1~2kg activated carbon into the upper process, then seal, heat up to 45~60℃ and keep for 0.5~1h, then press filter the material into the crystallization kettle, cool to 0~5℃, and then centrifuge it. dried, and washed with pure water to pH = 5 ~ 7, centrifugal drying (8 ~ 10min) after sampling polyethylene plastic bottle with 20 ~ 30g analysis appearance, cl ^-%, which is white, cl ^-% ≤0.008%. Then put it into the dryer, control the temperature of the dryer to 35～40℃, the vacuum degree ≤-0.09Mpa, dry for more than 24 hours, divide water every 2～3h, then put the materials into the material box, weigh, and transfer The packing room is crushed, sieved, packed, tied, and packed.

Comparative example 1

This comparative example is the same as in Example 1, except that no purified water is added when the heating reaction of the raw materials and auxiliary materials are transferred to the crystallization and cooling. The salt formation reaction is used to prepare the meglumine salt of dextroibuprofen. , Low.

Experimental example 1

1. The product test of dextroprofen prepared in Example 1 was carried out. The product batch number was "product batch number: C102-1906007M", and the test results are shown in Table 1.

Table 1

1. The infrared spectrum of the dextroprofen prepared in Example 1 is shown in Figure 2. It can be seen from Figure 2 that the infrared absorption spectrum of this product is consistent with that of the conventional dextroprofen reference substance.

2. The ultraviolet spectrum of dextrofen prepared in Example 1 is shown in Figure 3. It can be seen from Figure 3 that there is maximum absorption at 265 and 273nm wavelengths, minimum absorption at 245 and 271nm wavelengths, and 259nm wavelength There is a shoulder.

3. Detection of related substances: Take the finished product obtained in Example 1, add chloroform to make a solution containing 100mg per 1ml, as the test solution; accurately weigh an appropriate amount, add three filters of methane and dilute it to contain per 1ml A 1.0 mg solution was used as a control solution; the chromatogram of related substances is shown in Figure 4. It can be seen from Figure 4 that the retention time of the main peak of the test product under the related substance inspection is consistent with the retention time of the main peak of the conventional right ibuprofen reference substance.

In summary, the present invention successfully prepares dexibuprofen that meets the standard. The dexibuprofen of Example 2-3 also met the standard.

2. The melting point of the dextrorotatory amine salt and the molar yield of dextrofen in Example 1 to Example 3 and Comparative Example 1 are high, as shown in Table 2.

Table 2

组别Group	纯化水的体积：布洛芬重量Volume of purified water: weight of ibuprofen	右旋胺盐的熔点Melting point of dextran salt	摩尔收率Molar yield
实施例1Example 1	0.014：10.014:1	135℃～140℃135℃～140℃	88.2％88.2%
实施例2Example 2	0.010：10.010:1	135℃～140℃135℃～140℃	86.8％86.8%
实施例3Example 3	0.020：10.020:1	135℃～140℃135℃～140℃	90.9％90.9%
对比例1Comparative example 1	00	122℃～130℃122℃～130℃	//

It can be seen from Table 2 that the precise control of the amount of water is very important for the resolution process; in the end, we determined through experiments that the ratio of the volume of purified water added to the weight of ibuprofen during the preparation of the amine salt is 0.01～0.02L: 1kg, that is, the raw materials are heated up. The proportion of purified water is added when the reaction is transferred to crystallization and cooling. Finally, the molar yield of dextrofen is high (the molar yield is 86.8%-90.9%), and the melting point of the dextrorotatory amine salt reaches the qualified standard of 135-140°C.

The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection of the present invention. Within range.

Claims

A preparation method of dexibuprofen, characterized in that the method comprises the following steps:

Step 1. Salt formation reaction to prepare dexibuprofen meglumine salt:

After putting toluene into the reactor, put in ibuprofen and meglumine, stir and heat up to 76～80℃, keep the temperature for more than 0.5h, transfer the materials to the amine salt crystallization kettle, add purified water and then cool down and crystallize, the temperature drops to 18 After ～22°C, centrifugal separation and washing, dexibuprofen meglumine salt is obtained after drying; the feed ratio of ibuprofen: meglumine: toluene: purified water is 1:0.65～0.75:7.5～8 ：0.01～0.02; wherein the unit of the ibuprofen and meglumine in the ratio is kg, and the unit of the toluene and purified water is L.

Step 2. Hydrolysis reaction to precipitate meglumine: Add the dexibuprofen meglumine salt obtained in step 1 to an alkaline salt solution to carry out a hydrolysis reaction, to precipitate meglumine and remove it;

Step 3. Acidification reaction to precipitate dextroprofen: the material after removing meglucosamine in step 2 is adjusted to pH 1 to 2 with hydrochloric acid, and the wet crude product of dextroprofen is obtained after cooling and centrifugation. After refining, dextroprofen is obtained. Profen finished product.
The method for preparing dexibuprofen according to claim 1, characterized in that, in the step 1, toluene is put into the reaction kettle, and a hydrochloric acid solution with a concentration of 14-18% is added, stirred for more than 10 minutes, and allowed to stand for more than 10 minutes. Separate the hydrochloric acid layer; add water, stir for more than 10 minutes, and stand for more than 10 minutes to separate the water layer.
The method for preparing dexibuprofen according to claim 1, wherein the specific steps of centrifugal separation and washing in step 1 are: putting the material in a centrifuge to spin dry, and then copy washing with toluene, Then rinse with toluene.
The method for preparing dexibuprofen according to claim 1, wherein the specific steps of drying in the step 1 are: in a dryer, controlling the water temperature at 85-95°C, the vacuum degree ≤ -0.09Mpa, drying Do it for 3 to 6 hours.
The method for preparing dexibuprofen according to claim 1, wherein the specific steps of the hydrolysis reaction in step 2 are: putting the dexibuprofen meglumine salt obtained in step 1 into drinking water, hydroxide In the potassium hydrolysis reactor, heat up to 45～55℃ and react for 40～60min, then transfer the materials into the hydrolysis freezer, turn on the ice salt water to cool to below 20℃, after centrifugation, the solution and washing water are pumped into the acidification reactor and filtered The cake is dried for meglumine.
The method for preparing dextroprofen according to claim 5, characterized in that the addition ratio of the dextroprofen, potassium hydroxide, and drinking water is 170-180 kg: 30-35 kg: 500-550L.
The method for preparing dexibuprofen according to claim 1, wherein the specific steps of the hydrolysis reaction in step 3 are: transferring the material after removing meglucamine in step 2 into an acidification kettle and raising the temperature to 45~ After 55°C, 14-18% hydrochloric acid was added dropwise to acidify, the end pH value was 1~2, and the reaction was kept for 0.5~1h; cooled to below 30°C, the discharged material was centrifuged to dry, and washed with water to pH 5~7, After being dried, a wet crude product of dextroibuprofen was obtained.
The method for preparing dexibuprofen according to claim 1, wherein the step of refining the obtained wet crude dextroprofen in step 3 is: combining the wet crude dexprofen with 78%-82% The acetic acid was put into the dissolving kettle at a weight ratio of 1:1.4, put in an appropriate amount of activated carbon and sealed, heated to 45～60℃ for 0.5～1h, then the material was pressure filtered into the crystallization kettle, cooled to 0～5℃ and centrifuged to dry , And wash with pure water to pH 5-7, centrifuge to dry; then put into the dryer, control the temperature of the dryer to 35-40℃, the vacuum degree ≤ -0.09Mpa, dry for more than 24h, you can get dextroibuprofen Finished product.
The method for preparing dexibuprofen according to claim 1, wherein the toluene mother liquor remaining after the amine salt reaction in step 1 is acid-extracted and alkali-neutralized to obtain meglumine for recycling.
The method for preparing dexibuprofen according to claim 1, wherein the mother liquor of toluene remaining after the amine salt reaction in step 1 is first subjected to acid extraction with 14-18% hydrochloric acid, and then the acid water layer is separated. Add sodium hydroxide to adjust pH=12, cool down, centrifuge and spin-dry, wash with water, PH=8-9, recover meglumine; then add sodium hydroxide and drinking water into the toluene mother liquor to separate the alkaline water layer, and use hydrochloric acid after racemization After adjusting to pH=1～2, extract with toluene, and then centrifuge at cooling to obtain racemic ibuprofen again.