CN1490297A - Preparation of dextroilbuprofen - Google Patents
Preparation of dextroilbuprofen Download PDFInfo
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- CN1490297A CN1490297A CNA021384347A CN02138434A CN1490297A CN 1490297 A CN1490297 A CN 1490297A CN A021384347 A CNA021384347 A CN A021384347A CN 02138434 A CN02138434 A CN 02138434A CN 1490297 A CN1490297 A CN 1490297A
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- ibuprofen
- salt
- dextrorotation
- octylglucamine
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Abstract
A process for preparing the d-brufen ((+)A) includes such steps as salting reacting between the glucoctylamine or alpha-benylhexylamine or cinchonidine or L-lysine, and meglucamine ((+)B), and dl-brufen ((+/-)A) in alcohol at 10-85 deg.C, educing out the salt ((+)A.(+)B) in crystal mode, which is generated from (+)A and (+)B, separating it, using NaOH solution to regulate pH to greater than 10 in water, filtering out solid (+)B, using hydrochloric acid to regulate pH to 1-2, and educing out (+)A. Its advantage is high purity (more than 99.5%).
Description
The present invention relates to adopt Subjective and Objective crystallization-reaction kinetics CONTROL PROCESS to split the method that obtains dextrorotation-Ibuprofen BP/EP by the racemize Ibuprofen BP/EP.The salify crystallization in solvent of object racemize Ibuprofen BP/EP and main body N-Octylglucamine generates insoluble salt and two kinds of enantiomers of soluble salt.Insoluble salt obtains dextrorotation-Ibuprofen BP/EP through segregation; Soluble salt obtains the racemize Ibuprofen BP/EP again through racemization, and row splits again.The crystallization of Subjective and Objective salify is controlled by regulating kinetics means such as material proportion and temperature of reaction, thereby is reached once fractionation rate of control 27～33%, quality product content 〉=99.5%, specific rotatory power [α]
D56～59 ° purpose.
About split the research of preparation dextrorotation-Ibuprofen BP/EP by the racemize Ibuprofen BP/EP, also do not report for work.
At home and abroad all also do not have about the patent that splits preparation dextrorotation-Ibuprofen BP/EP by the racemize Ibuprofen BP/EP.
The invention relates to by the racemize Ibuprofen BP/EP adopts Subjective and Objective crystallization-reaction kinetics CONTROL PROCESS to split the method for preparing dextrorotation-Ibuprofen BP/EP.The Subjective and Objective crystallization is the process of a salt-forming reaction, when reacting because of dextrorotation-Ibuprofen BP/EP and left-handed-Ibuprofen BP/EP and N-Octylglucamine, since suffered sterically hindered different, and, make its salify speed different by reaction kinetics control.Wherein, dextrorotation-Ibuprofen BP/EP ((+) I) is fast with N-Octylglucamine ((+) II) salify speed, and the salt dextrorotation-Ibuprofen BP/EP N-Octylglucamine ((+) I (+) II) that generates is insoluble to solvent, and left-handed-Bu Luo ((-) I) and N-Octylglucamine ((+) II) salify speed are slower, and the salt that generates left-handed-Ibuprofen BP/EP N-Octylglucamine ((-) I (+) II) can be dissolved in solvent.The salt that can separate two kinds of different enantiomorphs like this through centrifugation.The salt-forming reaction process can be expressed as follows with chemical reaction equation.In these several materials, the chemical name of material is respectively: racemize Ibuprofen BP/EP, i.e. S (±)-2-(4-isobutyl phenenyl) propionic acid; Dextrorotation-Ibuprofen BP/EP, i.e. S (+)-2-(4-isobutyl phenenyl) propionic acid; Left-handed-Ibuprofen BP/EP, i.e. S (-)-2-(4-isobutyl phenenyl) propionic acid; N-Octylglucamine is the glucose octylame
Dextrorotation-Ibuprofen BP/EP N-Octylglucamine salt ((+) I (+) II), in basic solution, heating can emanate out dextrorotation-Ibuprofen BP/EP ((+) I) and N-Octylglucamine.N-Octylglucamine is separated out in cooling, crystallization, removes in advance, is acidified with acid in mother liquor again, then separates out dextrorotation-Ibuprofen BP/EP.This segregation process can be represented with following reaction equation:
Left-handed-Ibuprofen BP/EP N-Octylglucamine salt ((-) I (+) II) after steaming solvent, adds basic solution and heating, and crystallisation by cooling goes out N-Octylglucamine, removes in advance, is acidified with acid in mother liquor again, then can separate out left-handed-Ibuprofen BP/EP.The reaction equation of this segregation process is the same.
Left-handed-Ibuprofen BP/EP adds in the NaOH solution after making with extra care, and reflux can transform into the racemize Ibuprofen BP/EP and reclaim, and row splits use again.The racemization process of levo form can be represented with following reaction equation
The first step salt-forming reaction is to be solvent with ethanol, also can use methyl alcohol to be solvent, and best solvent is an ethanol.Its usage quantity is a unit with the mole, is 10～60 times of racemic modification, and best usage quantity is 35～45 times.
The main body resolving agent can be used α-benzene hexylamine, Cinchonidune, L-Methionin, N-Octylglucamine and meglumine, but is preferably N-Octylglucamine.
Salt-forming reaction is to carry out under normal pressure and heating condition, and the rate of heating during beginning is controlled at per minute and raises 2～5 ℃, preferably controls 2～3 ℃/minute.After beginning to reflux, temperature reaches 80～85 ℃, can not be too fast to thermal velocity, generally be advisable with medium return velocity.If speed is fast, then understand the mapping salt of doping levo form in the salt of Sheng Chenging, have influence on the quality of dextrorotatory form.The time length of reflux is relevant with rate of heating, and rate of heating is fast, and the time is short, gives heat slow, and the time is long.General control 30～90 minutes is preferably controlled 40～60 minutes.Overlong time can influence the quality of dextrorotation-Ibuprofen BP/EP.
The segregation reaction of the second step salify enantiomorph is with ((+) I (+) II) salt or ((-) I (+) II), puts in a large amount of deionized waters, and the consumption of general water is 20～50 times of amount of salt, and the optimum amount is 30～40 times.50～90 ℃ of Heating temperatures, optimal temperature are 70～75 ℃.Be 20～80 minutes heat-up time, and the optimum time is 30～40 minutes.Available NaOH solution is transferred pH value when temperature reaches 60 ℃, controls certain rate of addition, transfers PH 〉=10, and the most handy 10%NaOH aqueous solution is transferred between the pH value 10～13.When PH 〉=9, promptly there is the solid N-Octylglucamine to separate out.In the solution after removing N-Octylglucamine, transfer pH value, control certain governing speed, when PH≤3, promptly have solid dextrorotation-Ibuprofen BP/EP or left-handed-Ibuprofen BP/EP to separate out with hydrochloric acid.Preferably use 2N HCl acidifying, control PH1～2.
In the 3rd step, the racemization reaction of left-handed-Ibuprofen BP/EP is that levo form is joined in the basic solution, and reflux is used hcl acidifying after for some time, and that separates out is the racemize Ibuprofen BP/EP.Alkaline aqueous solution can directly use the 30%NaOH aqueous solution, also can use 10%～50%NaOH aqueous solution.If use the KOH aqueous solution of suitable concentration, then effect can be better.Racemization reaction under normal pressure, also can carry out adding to depress, and control reaction temperature is 50～120 ℃, generally controls 90～110 ℃.The racemization reaction time is 1～10 hour, generally controls 3～6 hours.When temperature is high, the time that may command is short, on the contrary then long.Reaction is used hcl acidifying after finishing while lowering the temperature.Reduce to room temperature, and transfer PH1～2 o'clock, can separate out racemic modification.
Dextrorotation-Ibuprofen BP/EP, left-handed-Ibuprofen BP/EP or racemization-Ibuprofen BP/EP all can use alcohol, or methyl alcohol makes solvent, operate through recrystallization and purify.The quality of common solvent is 5～20 times of optically active isomer, and sufficient quantity is 10～15 times.Temperature is controlled at 40～60 ℃, and temperature is unsuitable too high, otherwise can destroy optically active isomer.Dextrorotation-Ibuprofen BP/EP mass content 〉=99.5% after purifying, specific rotation [α]
D+ 56～+ 59 ° of (standard values [α]
D59 °)
Example 1
In the 500ml reaction flask, add successively racemic ibuprofen (12g, 60mmol), N-Octylglucamine (16.2g, 55mmol), ethanol (130ml, 95%).Stirring heating refluxed 50 minutes.Slowly cool to 28 ℃, leach crystallization, filtrate for later use.Filter cake is S (+) Ibuprofen BP/EP N-Octylglucamine salt (mp:118～120 ℃).It is dropped in the 120ml deionized water, be heated to 65～72 ℃, transfer PH 〉=10, be cooled to below 25 ℃ the filtering N-Octylglucamine with 10%NaOH solution.Filtrate to PH1～2, is separated out dextrorotation-Ibuprofen BP/EP with hcl acidifying, cools off, filters, is washed to no Cl
-, oven drying at low temperature gets solid 3.7g.Through surveying mp50～52 ℃, [α]
D+ 56～58 ° of (C=2, E
tOH) (literature value mp51～53 ℃).Infared spectrum is consistent with the Ibuprofen BP/EP standard diagram.Once fractionation rate 31%.
Tell the ethanolic soln of (S)-ibuprofen N-Octylglucamine salt.After steaming ethanol, add entry, be heated to 65～72 ℃, transfer PH 〉=10 with 10%NaOH solution, be cooled to below 25 ℃, the filtering N-Octylglucamine is applied mechanically after refining again.Filtrate to PH1～2, is separated out left-handed-Ibuprofen BP/EP with hcl acidifying.Left-handed-Ibuprofen BP/EP is added in the 20ml 30%NaOH aqueous solution, and reflux 6h cools off, adds water 15ml, uses hcl acidifying, separates out racemic ibuprofen, gets drying solid 7.7g.Through surveying mp71～72 ℃, [α]
D=0 °, total recovery 95.3%.
Example 2
In the 500ml reaction flask, add successively (±) I (18g, 90mmol), (+) II (24.3g, 81mmol), ethanol (307ml, 95%).Stirring heating refluxed 40 minutes.Be cooled to 30 ℃, crystallization is filtered.Filter cake drops in the 200ml water, is heated to 70～72 ℃, transfers PH=11 with 10%NaOH solution, is cooled to 28 ℃, the elimination N-Octylglucamine.Filtrate is transferred PH=1 with hydrochloric acid, Crystallization Separation.Dry dextrorotatory form 5.1g, mp51.5～52.5 ℃, [α]
D+ 56～59 °, once fractionation rate is 28.6%.
The ethanol mother liquor of isolated (S)-ibuprofen N-Octylglucamine salt, steam ethanol after, imitative example 1 method reclaims N-Octylglucamine, and applies mechanically through refining.Add hcl acidifying and separate out left-handed-Ibuprofen BP/EP.With left-handed-Ibuprofen BP/EP 30%NaOH solution 30ml, reflux 4h, cooling adds water 30ml, uses hcl acidifying, separates out the raceme Ibuprofen BP/EP, gets drying solid 8.4g, total recovery 94.8%.
Example 3
In the 500ml reaction flask, add successively (±) I (12g, 60mmol), meglumine (9.8g, 50mmol), ethanol (125ml, 95%).Stir reflux 60 minutes.Slowly cool to 25 ℃, leach crystallization, mother liquor is standby.Filter cake drops in the 150ml deionized water, is heated to 65～70 ℃, uses 10%NaOH solution, transfers PH=11, is cooled to 26 ℃, the elimination N-Octylglucamine.Filtrate is transferred PH1～2 with hydrochloric acid, crystallization, separation.Dry dextrorotatory form 2.5g, mp48～52 ℃, [α]
D52～57 °, once fractionation rate is 20.8%.
With example 1, reclaim the racemization of meglumine and left-handed-Ibuprofen BP/EP, total recovery 89%.
Example 4
In the 500ml reaction flask, add successively racemic ibuprofen (13g, 65mmol), α-benzene hexylamine (10.6g, 60mmol), ethanol (150ml, 95%).Stir reflux 70 minutes.Slowly cool to 26 ℃, leach crystallization, mother liquor is standby.Filter cake drops in the 130ml deionized water, is heated to 70～75 ℃, transfers PH 〉=10 with 10%NaOH solution, is cooled to 26 ℃, filtering α-benzene hexylamine.Filtrate is used hcl acidifying PH=2, separates out dextrorotatory form.Through separation, purification, dry 3.0g, mp49～52 ℃, [α]
D54～58 °, once fractionation rate 17.2%.
With example 1, reclaim the racemization of α-benzene hexylamine and left-handed Ibuprofen BP/EP and reclaim total recovery 79%.
Example 5
In the 1000ml reaction flask, add successively raceme (±) I (36g, 180mmol), N-Octylglucamine (48g, 163mmol), ethanol (600ml, 95%).Stir reflux 60 minutes.Be cooled to 23 ℃, crystallization is filtered, and mother liquor is standby.Filter cake drops in the 500ml deionized water, is heated to 70 ℃, transfers PH=12 with 10%NaOH, at the uniform velocity is cooled to 25 ℃, the elimination N-Octylglucamine.Filtrate is acidified to PH=2 with refining hydrochloric acid, and Crystallization Separation gets dry dextrorotatory form 11.6g, once fractionation rate 32.2%.
With routine l, reclaim the racemization of N-Octylglucamine and levo form and reclaim total recovery 95%.
The single crystal of dextrorotation-Ibuprofen BP/EP, on the Rigaku-AFC7R four-circle diffractometer, adopt Mok α (to go into=0.071069nm) gamma ray source, scan in ω/2 θ modes, the single-crystal x of receiving-ray diffraction line strength numerical value is reduced into absolute strength through Lp factor correction and K curve.Solve with the MULTAN-80 program at last and many wheel difference Fourier hydrogenation, and, carry out the complete matrix least-squares refinement the coordinate and the anisotropy thermal parameter thereof of whole non-hydrogen atoms.The spatial configuration of molecules that records in view of the above is as shown below.C among the figure (2) is the optical activity center, is the structure of R configuration.
Claims (7)
1. one kind is adopted Subjective and Objective crystallization-reaction kinetics control, and resolution of racemic Ibuprofen BP/EP ((±) I) obtains the method for dextrorotation-Ibuprofen BP/EP ((+) I).It is characterized in that dextrorotation-Ibuprofen BP/EP ((+) I) and main body N-Octylglucamine ((+) II) in the object generates insoluble salt ((+) I. (+) II) and separate out, obtain dextrorotation-Ibuprofen BP/EP through segregation; And left-handed-Ibuprofen BP/EP ((-) I) and N-Octylglucamine ((+) II) generate the salt ((-) I. (+) II) of solubility, through racemization, regenerate racemize Ibuprofen BP/EP ((±) I), through reclaiming row folding branch again.
2. according to the preparation of the described dextrorotation-Ibuprofen BP/EP of claim 1, it is characterized in that the employed main body of salt-forming reaction is a N-Octylglucamine, also can be α-benzene hexylamine, Cinchonidune, L-Methionin and meglumine, object is the racemize Ibuprofen BP/EP, solvent (III) is ethanol or methyl alcohol, and the mole proportioning of material is (±) I: (+) II: (III)=1: 0.6～0.95: 10～60.
3. according to the preparation of the described dextrorotation-Ibuprofen BP/EP of claim 1, the processing condition that it is characterized in that salt-forming reaction are 10～85 ℃ of normal pressure and temperature.The rate of heating of beginning is 2～5 ℃/minute, gives heat even during backflow, keeps moderate return velocity, and the reflux time is 30～90 minutes.
4. according to the preparation of the described dextrorotation-Ibuprofen BP/EP of claim 1, it is characterized in that the insoluble salt that salt-forming reaction generates is dextrorotation-Ibuprofen BP/EP N-Octylglucamine salt.Through centrifugation, wash the back and drop in the deionized water, heating is transferred PH 〉=10 with the NaOH aqueous solution, reduces to room temperature then, separates out N-Octylglucamine, and after removing, transfers PH1～2 with hydrochloric acid, and that separates out is the right side-Ibuprofen BP/EP.The mass ratio of material is a salt: water=1: 20～50.Processing condition are 60～80 ℃ of normal pressure and temperature.Once fractionation rate is 27～33%.
5. according to the preparation of the described dextrorotation-Ibuprofen BP/EP of claim 1, it is characterized in that the soluble salt that salt-forming reaction generates is left-handed-Ibuprofen BP/EP N-Octylglucamine salt.With the mother liquor of isolating behind the solid salt, steam earlier and desolventize, transfer PH 〉=10 with the NaOH aqueous solution again, reduce to room temperature and separate out N-Octylglucamine, reclaimed.Transfer PH1～2 with hydrochloric acid then, can separate out left-handed-Ibuprofen BP/EP, thereby obtain reclaiming.
6. according to the preparation of the described dextrorotation-Ibuprofen BP/EP of claim 1, it is characterized in that the left-handed-Ibuprofen BP/EP that is reclaimed can obtain the racemize Ibuprofen BP/EP again through refining and racemization.Make with extra care and make solvent recrystallization with ethanol.Mass ratio is (-) I: III=1: 5～30, under 40～60 ℃ of normal pressure and temperature, carry out.Separate out through dissolving, concentrate, lowering the temperature.Racemization be with purified left-handed-Ibuprofen BP/EP joins in 30% the NaOH solution, behind reflux 4～8h, transfers pH value 1～2 with hydrochloric acid, the solid of separating out is (±) I.Processing condition are normal pressure or pressurization, 50～120 ℃ of temperature.
7. according to the preparation of the described dextrorotation-Ibuprofen BP/EP of claim 1, it is characterized in that prepared dextrorotation-Ibuprofen BP/EP can be by carrying out under ethanol～60 ℃.Through dissolving, concentrate, decrease temperature crystalline with separate, washing, drying and get.The mass content of (+) I 〉=99.5%, specific rotation [α]
D+ 56～+ 59.
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| CNA021384347A CN1490297A (en) | 2002-10-15 | 2002-10-15 | Preparation of dextroilbuprofen |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102370615A (en) * | 2010-08-19 | 2012-03-14 | 四川科伦药物研究有限公司 | Ibuprofen injection preparation and preparation method thereof |
| CN102617327A (en) * | 2012-03-02 | 2012-08-01 | 海南灵康制药有限公司 | Dexibuprofen compound and preparation method thereof |
| CN102850204A (en) * | 2011-06-29 | 2013-01-02 | 徐州医学院 | Resolution method of (S)-2-arylpropionic acid non-steroidal anti-inflammatory drug |
| CN109096229A (en) * | 2018-08-29 | 2018-12-28 | 南京正科医药股份有限公司 | A kind of synthetic method of dexketoprofen intermediate |
| CN110615735A (en) * | 2019-09-10 | 2019-12-27 | 湖北百科亨迪药业有限公司 | Preparation method of dexibuprofen |
| CN112125797A (en) * | 2020-09-28 | 2020-12-25 | 苏州第四制药厂有限公司 | Method for preparing dexibuprofen by racemization |
| CN112500283A (en) * | 2020-11-12 | 2021-03-16 | 湖南华纳大药厂手性药物有限公司 | Crystallization process of dexibuprofen |
| CN115286501A (en) * | 2022-08-10 | 2022-11-04 | 浙江新和成股份有限公司 | Comprehensive utilization method of ibuprofen crystallization mother liquor |
-
2002
- 2002-10-15 CN CNA021384347A patent/CN1490297A/en active Pending
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102370615A (en) * | 2010-08-19 | 2012-03-14 | 四川科伦药物研究有限公司 | Ibuprofen injection preparation and preparation method thereof |
| CN102370615B (en) * | 2010-08-19 | 2013-09-04 | 四川科伦药物研究有限公司 | Ibuprofen injection preparation and preparation method thereof |
| CN102850204A (en) * | 2011-06-29 | 2013-01-02 | 徐州医学院 | Resolution method of (S)-2-arylpropionic acid non-steroidal anti-inflammatory drug |
| CN102850204B (en) * | 2011-06-29 | 2015-08-19 | 徐州医学院 | A kind of method for splitting of (S)-2-aryl propionic non-steroid antiphlogistic |
| CN102617327A (en) * | 2012-03-02 | 2012-08-01 | 海南灵康制药有限公司 | Dexibuprofen compound and preparation method thereof |
| CN102617327B (en) * | 2012-03-02 | 2014-04-16 | 海南灵康制药有限公司 | Dexibuprofen compound and preparation method thereof |
| CN109096229A (en) * | 2018-08-29 | 2018-12-28 | 南京正科医药股份有限公司 | A kind of synthetic method of dexketoprofen intermediate |
| CN110615735A (en) * | 2019-09-10 | 2019-12-27 | 湖北百科亨迪药业有限公司 | Preparation method of dexibuprofen |
| WO2021047490A1 (en) * | 2019-09-10 | 2021-03-18 | 湖北亨迪药业股份有限公司 | Method for preparing dexibuprofen |
| CN112125797A (en) * | 2020-09-28 | 2020-12-25 | 苏州第四制药厂有限公司 | Method for preparing dexibuprofen by racemization |
| CN112500283A (en) * | 2020-11-12 | 2021-03-16 | 湖南华纳大药厂手性药物有限公司 | Crystallization process of dexibuprofen |
| CN115286501A (en) * | 2022-08-10 | 2022-11-04 | 浙江新和成股份有限公司 | Comprehensive utilization method of ibuprofen crystallization mother liquor |
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