CN102174633B - Method for splitting ibuprofen - Google Patents
Method for splitting ibuprofen Download PDFInfo
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- CN102174633B CN102174633B CN 201110023363 CN201110023363A CN102174633B CN 102174633 B CN102174633 B CN 102174633B CN 201110023363 CN201110023363 CN 201110023363 CN 201110023363 A CN201110023363 A CN 201110023363A CN 102174633 B CN102174633 B CN 102174633B
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Abstract
The invention relates to a method for splitting S(+)-ibuprofen shown in the split formula I. The method comprises the following steps: 1) performing an asymmetric ester exchange reaction with alcohol by taking (R, S)-methyl ibuprofen as a raw material and an immobilized lipase as a catalyst, and performing post-treatment to obtain S(+)-methyl ibuprofen; and 2) hydrolyzing the S(+)-methyl ibuprofen obtained in the step 1) in the catalysis of inorganic acid to obtain S(+)-ibuprofen. The raw materials in the preparation method provided by the invention are easily available, the yield is high, the optical purity of products is high, the pollution is low, and the method is suitable for industrial production.
Description
Technical field
The present invention relates to the method for splitting of a kind of compound Ibuprofen BP/EP [2-(4-isobutyl phenenyl) propionic acid].Belong to chemical industry and chemical field of medicaments.
Background technology
S (+)-Ibuprofen BP/EP [S (+)-ibuprofen] is the popular name of S (+)-2-(4-isobutyl phenenyl) propionic acid, and its structural formula is:
Molecular formula: C
13H
18O
2
Molecular weight: 206.28
Ibuprofen BP/EP is a kind of nonsteroidal antiinflammatory and analgesic medicine, compares with acetylsalicylic acid. have stronger analgesic, anti-inflammatory and analgesic activity, and side effect is then much smaller.Since the late 1970s listing.Ibuprofen BP/EP has obtained to develop rapidly.Now become one of anti inflammation and heat resolution anodyne of turnout and usage quantity maximum.(S)-ibuprofen is the optical isomer of the S configuration of Ibuprofen BP/EP, studies show that in a large number the curative effect of (S)-ibuprofen and Ibuprofen BP/EP is identical, but using dosage is little, and security and pharmacokinetics performance all are better than Ibuprofen BP/EP, and the market of (S)-ibuprofen is expected to further increase in future.At present, the existing report that much splits about Ibuprofen BP/EP, but be to utilize L-Methionin, N-Octylglucamine, meglumine etc. mostly as resolution reagent, in organic solvent, carry out repeatedly recrystallization and prepare (S)-ibuprofen, complex operation, yield is low, and the optical purity of (S)-ibuprofen is difficult to reach desirable level.Therefore, the method for splitting that needs a kind of easy Ibuprofen BP/EP of exploitation.
Summary of the invention
The objective of the invention is to utilize enzyme to make catalyzer, make every effort to obtain a kind of simple to operate, reaction conditions is gentle, be easy to obtain high purity product, can be by the method for the fractionation Ibuprofen BP/EP of industrial amplification production.
The present invention realizes according to following method:
With the racemic ibuprofen methyl esters is raw material, with Novozym 435 is catalyzer, adds certain amount of organic solvent as reaction medium, at 0 ℃ to 70 ℃ following and propyl carbinol reaction 12h to 72h, after reaction finishes, utilize the method for column chromatography to obtain S (+)-Ibuprofen BP/EP methyl esters.
S (+)-Ibuprofen BP/EP methyl esters hydrolysis under the catalysis of mineral acid that the last step obtains obtains S (+)-Ibuprofen BP/EP, and yield is 40%-50%, and optical purity is 90%ee to 93%ee.
S (+)-Ibuprofen BP/EP methyl esters S (+)-Ibuprofen BP/EP
Particularly, the method for S (+)-Ibuprofen BP/EP shown in the split-type I provided by the invention comprises the steps:
1) with (R, S)-the Ibuprofen BP/EP methyl esters is a raw material, is catalyzer with the immobilized lipase, carries out asymmetric transesterification reaction with alcohol, obtains S (+)-Ibuprofen BP/EP methyl esters through aftertreatment then;
2) hydrolysis under the catalysis of mineral acid of the S (+) that step 1 is obtained-Ibuprofen BP/EP methyl esters obtains S (+)-Ibuprofen BP/EP;
Wherein, in the step 1, described immobilized lipase is Novozym 435.
In the step 1, described alcohol is propyl carbinol.
In the step 1, asymmetric transesterification reaction solvent is selected from one or more in dioxane, ether, isopropyl ether, methyl tertiary butyl ether, normal heptane and the sherwood oil, preferred dioxane.
In the asymmetric transesterification reaction described in the step 1, (R, S)-mass ratio of Ibuprofen BP/EP methyl esters and immobilized enzyme is 1: 4～5: 1, is preferably 2: 1.
In the asymmetric transesterification reaction described in the step 1, (R, S)-mol ratio of Ibuprofen BP/EP methyl esters and propyl carbinol is 1: 8～2: 1, preferred 1: 0.8.
In the step 1, described asymmetric transesterification reaction is carried out under 0 ℃～70 ℃, preferred 39 ℃.
In the step 1, the described asymmetric transesterification reaction time is 12h～72h, preferred 20h.
In the step 1, described aftertreatment is for to carry out column chromatography to reaction product.
In the step 2, described mineral acid is dilute sulphuric acid or dilute hydrochloric acid, and preferred volume per-cent is 5% dilute sulphuric acid.
The present invention utilizes the racemic ibuprofen methyl esters to be raw material, is that catalyzer and propyl carbinol carry out asymmetric transesterification reaction with lipase earlier, and wherein, the Ibuprofen BP/EP methyl esters of R configuration is converted into the Ibuprofen BP/EP butyl ester, and transesterification reaction does not take place the Ibuprofen BP/EP of S configuration.To obtain S (+)-Ibuprofen BP/EP methyl esters and be hydrolyzed, and obtain target compound S (+)-Ibuprofen BP/EP at last, the optical purity after once splitting is 93%ee.
Beneficial effect of the present invention is:
1) why the present invention selects transesterification reaction, is because if with Ibuprofen BP/EP and propyl carbinol direct esterification, can discharge big water gaging, water can influence the catalytic activity of enzyme.And transesterification reaction discharges is methyl alcohol, though also can bring disadvantageous effect to the catalytic activity of enzyme, under the lower situation of concentration, enzyme is recycled more than 10 times, and vigor is not obviously reduction still.
2) the present invention utilizes the spatial selectivity of enzyme catalyst, obtains S (+)-Ibuprofen BP/EP by asymmetric transesterification reaction and hydrolysis reaction, and the optical purity after once splitting can reach more than 90%; Used immobilized enzyme Novozym 435 Heat stability is goods are bought easily, and can be recycled, and greatly reduce production cost, have also reduced " three wastes " and have polluted; The reaction yield height, simple to operate, can large-scale industrial production.
Embodiment
Following examples are used to illustrate the present invention, but are not used for limiting the scope of the invention.
Immobilized enzyme Novozym 435 is available from Denmark Novozymes Company company;
The racemic ibuprofen methyl esters is available from lark prestige Science and Technology Ltd. company;
The preparation of embodiment 1 S (+)-Ibuprofen BP/EP methyl esters
22g (100mmol) racemic ibuprofen methyl esters and 5.9g (80mmol) propyl carbinol are dissolved in the 400mL dioxane, add again and jolt reaction 20h under 435,39 ℃ of the 10g Novozym.Reaction back filtering immobilized enzyme.The filtrate distillation is concentrated into 30 to 50mL, and last silicagel column separates (eluent is an isopropyl ether) and obtains S (+)-about 10g of Ibuprofen BP/EP methyl esters, and yield is about 91% (in S (+)-Ibuprofen BP/EP methyl esters).
The preparation of embodiment 2 S (+)-Ibuprofen BP/EP methyl esters
22g (100mmol) racemic ibuprofen methyl esters and 5.9g (80mmol) propyl carbinol are dissolved in the 400mL dioxane, add 10g Novozym 435 (embodiment 1 reclaim obtain) again, jolt reaction 22h under 39 ℃.Reaction back filtering immobilized enzyme.The filtrate distillation is concentrated into 30 to 50mL, and last silicagel column separates (eluent is an isopropyl ether) and obtains S (+)-about 10g of Ibuprofen BP/EP methyl esters, and yield is about 91% (in S (+)-Ibuprofen BP/EP methyl esters).
Embodiment 3
22g (100mmol) racemic ibuprofen methyl esters and 59g (800mmol) propyl carbinol are dissolved in the mixed solution (volume ratio is 1: 1) of 500mL methyl tertiary butyl ether and sherwood oil, add again and jolt reaction 72h under 435,0 ℃ of the 10g Novozym.Reaction back filtering immobilized enzyme.The filtrate distillation is concentrated into 30 to 50ml, and last silicagel column separates (eluent is an isopropyl ether) and obtains S (+)-about 8g of Ibuprofen BP/EP methyl esters, and yield is about 92.7% (in S (+)-Ibuprofen BP/EP methyl esters).
Embodiment 4
22g (100mmol) racemic ibuprofen methyl esters and 5.9g (80mmol) propyl carbinol are dissolved in the 500mL isopropyl ether, add again and jolt reaction 5h under 435,70 ℃ of the 80g Novozym.Reaction back filtering immobilized enzyme.The filtrate distillation is concentrated into 30 to 50ml, and last silicagel column separates (eluent is an isopropyl ether) and obtains S (+)-about 10.3g of Ibuprofen BP/EP methyl esters, and yield is about 94% (in S (+)-Ibuprofen BP/EP methyl esters).
The preparation of embodiment 5 S (+)-Ibuprofen BP/EPs
S (+) the Ibuprofen BP/EP methyl esters of 11g (50mmol) is dissolved in the 200mL dioxane, adds the dilute sulphuric acid of 200mL 5% (volume ratio), stir and be heated to 50 ℃, keep 3h.After reaction finishes, add the extraction of 200mL isopropyl ether, organic layer is extremely neutral with the saturated brine washing, drying, evaporate to dryness.Obtain S (+)-Ibuprofen BP/EP 9.3g, yield is 90%, and optical purity is 93%ee, HPLC.
Comparative Examples
According to Xiao Fangqing etc. the preparation of Seractil [J]. Chinese Journal of Pharmaceuticals, 2000,31 (11): 486.
Ibuprofen BP/EP is revolved in cancellation, and (206g 1mol), adds 95% ethanol (2000mL), and after the stirring and dissolving, (146.5g, 0.5mol), temperature rising reflux 0.5h becomes settled solution, is cooled to room temperature, spends the night to add N-Octylglucamine.Filter, with 95% ethanol (200mL) washing, the dry N-Octylglucamine salt (190g is in S (+)-Ibuprofen BP/EP 76%) that gets S (+)-Ibuprofen BP/EP.(190g 0.381mol) joins in the 5%KOH solution (600mL), in 45 ℃ of stirring 0.5h, is chilled to room temperature the N-Octylglucamine salt of S (+)-Ibuprofen BP/EP.Filter, water (200mL) washing, drying must reclaim N-Octylglucamine (110g).Merging filtrate and washing lotion, acidifying is filtered, washing, drying, again with ethyl alcohol recrystallization, 40 ℃ in vacuum dry S (+)-Ibuprofen BP/EP (72g, in S (+)-Ibuprofen BP/EP, a resolution yield 70%, 87%ee, HPLC.
Compare with Comparative Examples, embodiment of the invention 1-5 obtains S (+)-Ibuprofen BP/EP by asymmetric transesterification reaction and hydrolysis reaction, and the optical purity after once splitting can reach more than 90%; Used immobilized enzyme Novozym 435 Heat stability is goods are bought easily, and can be recycled, and greatly reduce production cost, have also reduced " three wastes " and have polluted; The reaction yield height, simple to operate, can large-scale industrial production.
Though above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, this modification of this that made or improvement without departing from theon the basis of the spirit of the present invention all belongs to the scope of protection of present invention.
Claims (9)
1. the method for S (+)-Ibuprofen BP/EP shown in the split-type I comprises the steps:
1) with (R, S)-the Ibuprofen BP/EP methyl esters is a raw material, is catalyzer with the immobilization esterase, carries out asymmetric transesterification reaction with alcohol, obtains S (+)-Ibuprofen BP/EP methyl esters through aftertreatment then;
Be specially: with the racemic ibuprofen methyl esters is raw material, with Novozym435 is catalyzer, adds organic solvent as reaction medium, at 0 ℃ to 70 ℃ following and propyl carbinol reaction 12h to 72h, after reaction finishes, utilize the method for column chromatography to obtain S (+)-Ibuprofen BP/EP methyl esters;
2) hydrolysis under the catalysis of mineral acid of the S (+) that step 1) is obtained-Ibuprofen BP/EP methyl esters obtains S (+)-Ibuprofen BP/EP
In the step 1), asymmetric transesterification reaction solvent is selected from one or more in dioxane, ether, isopropyl ether, methyl tertiary butyl ether, normal heptane and the sherwood oil;
Step 2) in, described mineral acid is dilute sulphuric acid or dilute hydrochloric acid.
2. method for splitting according to claim 1 is characterized in that, in the step 1), asymmetric transesterification reaction solvent is a dioxane.
3. method for splitting according to claim 1 is characterized in that, in the asymmetric transesterification reaction described in the step 1), (R, S)-mass ratio of Ibuprofen BP/EP methyl esters and immobilization esterase is 1:4～5:1.
Method for splitting 4. according to claim 3 is characterized in that, described (R, S)-mass ratio of Ibuprofen BP/EP methyl esters and immobilization esterase is 2:1.
5. method for splitting according to claim 1 is characterized in that, in the asymmetric transesterification reaction described in the step 1), (R, S)-mol ratio of Ibuprofen BP/EP methyl esters and propyl carbinol is 1:8～2:1.
Method for splitting 6. according to claim 5 is characterized in that, described (R, S)-mol ratio of Ibuprofen BP/EP methyl esters and propyl carbinol is 1:0.8.
7. method for splitting according to claim 1 is characterized in that, in the step 1), described asymmetric transesterification reaction is carried out under 39 ℃.
8. method for splitting according to claim 1 is characterized in that, in the step 1), the described asymmetric transesterification reaction time is 20h.
9. method for splitting according to claim 1 is characterized in that step 2) in, described mineral acid is that volume percent is 5% dilute sulphuric acid.
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| CN 201110023363 CN102174633B (en) | 2011-01-20 | 2011-01-20 | Method for splitting ibuprofen |
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| CN 201110023363 CN102174633B (en) | 2011-01-20 | 2011-01-20 | Method for splitting ibuprofen |
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| CN102174633B true CN102174633B (en) | 2013-07-24 |
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| CN103319327A (en) * | 2013-07-12 | 2013-09-25 | 四川省惠达药业有限公司 | Ibuprofen compound, and pharmaceutical composition and preparation method thereof |
| CN108642119B (en) * | 2018-03-24 | 2021-09-07 | 湖南理工学院 | Method for resolution of 2- (4-methylphenyl) propionic acid enantiomer by stereoselective enzyme catalytic esterification |
| CN113088553A (en) * | 2021-03-30 | 2021-07-09 | 东华理工大学 | Method for preparing S-ibuprofen by enzymatic resolution-chemical racemization tandem |
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| CN101104861B (en) * | 2007-04-28 | 2012-01-18 | 北京化工大学 | Method for preparing S-ibuprofen and S-ibuprofen ester by biological catalysis |
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