CN1071733C - Process - Google Patents
Process Download PDFInfo
- Publication number
- CN1071733C CN1071733C CN94106198A CN94106198A CN1071733C CN 1071733 C CN1071733 C CN 1071733C CN 94106198 A CN94106198 A CN 94106198A CN 94106198 A CN94106198 A CN 94106198A CN 1071733 C CN1071733 C CN 1071733C
- Authority
- CN
- China
- Prior art keywords
- enantiomorph
- ibuprofen
- enrichment
- alpha
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention discloses a preparation method. A product of the preparation method is rich in an enantiomer or pharmaceutical salt thereof required by phenylpropionic acid (selected from isobutyl phenylpropyl acid and flurobiphenyl propionic acid). The required enantiomer is optimized into an (S)-enantiomer, and the optimized salt is alpha-methylbenzyl amine salt, lysine salt and sodium salt.
Description
The present invention relates to prepare the pure basically enantiomorph and the pharmacologically acceptable salt thereof of the phenylpropionic acid compounds that is selected from ibuprofen and flurbiprofen, particularly their Alpha-Methyl benzylamine salt, lysine salt and sodium salt.
Chemical name is that the ibuprofen of 2-(4-isobutyl phenenyl) propionic acid and flurbiprofen that chemical name is 2-(2-fluoro-4-xenyl) propionic acid are the well-known medicines with anti-inflammatory, analgesic and analgesic activity.The known applications of ibuprofen and flurbiprofen comprises pain and the inflammation of treatment in flesh and skeletal diseases (for example rheumatism), and the pain of treatment in various other diseases, for example headache, neurodynia and dysmenorrhoea.
Ibuprofen and flurbiprofen all close an independent chiral centre that is positioned at the carbon atom place of asymmetric replacement, so they all exist with two kinds of enantiomeric forms.Known S (+)-ibuprofen is an active agents, and R (-)-ibuprofen can be partially converted to S (+)-ibuprofen in human body.Known S (+)-flurbiprofen also is an active agents.R (-)-flurbiprofen does not change into (S)-enantiomorph in human body, although R (-)-flurbiprofen is considered to have only analgesic activity (International Patent Application WO 92/04018[Paz]).Ibuprofen and flurbiprofen were once sold with the form of racemic mixture before this.Yet a kind of basically enantiomorph of an administration may be favourable in some cases.Therefore need provide improved preparation method, make in the product enrichment the desired the sort of enantiomorph of wanting in the phenylpropionic acid (being selected from ibuprofen and flurbiprofen).
Europe patent application 0362476 (PaZ) has been narrated by with diastereomeric salt selective crystallization in polar solvent, isolates the enantiomeric form of arylpropionic acid compounds.It is more favourable than non-polar solvent that this article has been mentioned the use polar solvent, but do not mention the special solvent mixture that uses in the inventive method.
United States Patent (USP) 5,015,764 (Manimaran) relate to the preparation of (comprising ibuprofen and flurbiprofen) of aliphatic carboxylic acid class, and its practice is to handle their salts solution so that optionally precipitate the less diastereomer of dissolubility with a kind of chirality organic bases.This patent is not mentioned the special solvent mixture that use is used in the methods of the invention.
European patent application 0437369 has been narrated the preparation of (S)-ibuprofen-(S)-lysine salt, its practice contacts with racemic ibuprofen with equimolar amount (S)-Methionin in aqueous ORGANIC SOLVENT MIXTURES, from mixture, isolate the solid of any suspension, with transparent mixture cooling, up to it for (R)-ibuprofen-(S)-lysine salt and (S)-ibuprofen-(S)-all supersaturation of lysine salt, the slurry of this supersaturated solution and (S)-ibuprofen-(S)-lysine salt is contacted, and isolate formed crystalline (S)-ibuprofen-(S)-lysine salt.
International Patent Application WO 92/20334 (Boots) has been narrated the preparation of the sodium salt of (S)-ibuprofen.
The invention provides a kind of preparation method, the desired the sort of enantiomorph of wanting in the phenylpropionic acid (being selected from ibuprofen and flurbiprofen) in enrichment in its product, and this method may further comprise the steps:
(a) splitting step, in this step, prepared the wherein Alpha-Methyl benzylamine salt of the phenylpropionic acid of the desired enantiomorph of enrichment, its practice is as in the toluene of solvent and the methanol mixture a kind of enantiomorph of Alpha-Methyl benzylamine to be contacted with the racemic basically mixture of phenylpropionic acid, and the mol ratio of racemic basically phenylpropionic acid and Alpha-Methyl benzylamine is about 1: 0.25 to about 1: 1;
(b) re-crystallization step, in this step with salt recrystallization in the mixture of methyl alcohol and toluene of formed enrichment, so that make the further enrichment in the Alpha-Methyl benzylamine salt of phenylpropionic acid of desired enantiomorph;
(c) the optional step of disengaging, the phenylpropionic acid of the enantiomorph of wanting that in this step, from the salt of recrystallization, disengaged further enrichment;
(d) Ren Xuan preparation salt step, the solid salt of phenylpropionic acid of the enantiomorph of wanting of in this step, having isolated further enrichment, this solid salt can also randomly be done further enantiomorph enrichment to want enantiomorph.
In the preferred embodiment of the inventive method, desired phenylpropionic acid enantiomorph is (S)-enantiomorph, and:
(a) in splitting step, the mol ratio of used racemic basically phenylpropionic acid and (S)-Alpha-Methyl benzylamine is about 1: 0.35 to about 1: 0.8, for example about 1: 0.4 to about 1: 0.6, in the mixture of methyl alcohol and toluene, be prepared, wherein toluene account for whole volume of mixture at least about 50%, more preferably from about 60% to about 90%, and most preferably from about 70% to about 80%; The temperature of mixture is about 30 ℃ to about 70 ℃, preferred about 40 ℃ to about 60 ℃, so that form supersaturated solution; For example when solution be cooled to temperature for-10 ℃ to about 30 ℃ approximately, preferably about 0 ℃ to about 5 ℃ the time, enrichment the phenylpropionic acid of (the S)-enantiomorph of phenylpropionic acid-(S)-Alpha-Methyl benzylamine salt and is crystallized out from supersaturated solution;
(b) in re-crystallization step, preferred solvent is the mixture of methyl alcohol and toluene, wherein toluene account for whole volume of mixture at least about 25%, more preferably from about 50% to about 80%, most preferably from about 60% to about 70%; For example when solution is cooled to temperature for-10 ℃ to about 30 ℃ approximately, preferred about 0 ℃ to about 5 ℃, further enrichment phenylpropionic acid-(the S)-Alpha-Methyl benzylamine salt of (S)-enantiomorph of phenylpropionic acid crystallize out from solution;
(c) in disengaging step, phenylpropionic acid (the S)-Alpha-Methyl benzylamine salt of the further enrichment that will in re-crystallization step, obtain (S) type enantiomorph with the immiscible solvent of water in acidifying (for example using hydrochloric acid), with the phenylpropionic acid of (S) type that the is rich in enantiomorph that obtains disengaging with the immiscible solvent of water in solution and (S)-aqueous solution of the salt (for example hydrochloride) of Alpha-Methyl benzylamine, can disengage (S)-Alpha-Methyl benzylamine by the latter, thereby can reuse in the splitting step (a) afterwards, for example the solution alkalization and the alkali that will disengage are extracted in the toluene;
(d) choose wantonly in preparation salt step, by the phenylpropionic acid that disengages further enrichment (S) the type enantiomorph that obtains in the step (c) with the immiscible solvent of water in solution can further handle with one or more following methods:
(ⅰ) crystallization and isolate the phenylpropionic acid solid of enrichment (S) type enantiomorph from solution;
(ⅱ) distillation removes and desolvates, to obtain the middle melt that uses of step (ⅴ) below;
(ⅲ) when phenylpropionic acid is ibuprofen, its aqueous solution with the alkali that contains sodium (for example sodium hydroxide) is contacted the aqueous solution with the sodium salt that forms ibuprofen, with it from the immiscible solvent of water separate, aqueous solution acetone diluted then is so that crystallization goes out the ibuprofen sodium salt of further enrichment (S) type enantiomorph; And
(ⅳ) when phenylpropionic acid is ibuprofen, it is contacted with water with (S)-Methionin, wherein ibuprofen with (S)-mol ratio of Methionin is 1: 0.5 to 1: 1, to obtain the aqueous solution of (S)-lysine salt, with it from the immiscible solvent of water isolate, in the aqueous solution, add ethanol then, crystallization the has gone out further enrichment ibuprofen of (S) type enantiomorph-(S)-Methionin.
Above-mentioned steps d (ⅰ) can be used in one or several following further step to the product of d (ⅲ):
(ⅴ) will isolate the solid of above steps d (ⅰ) or the melt of steps d (ⅱ), in aqueous ethanolic solution with (S)-Methionin reaction, wherein phenylpropionic acid with (S)-mol ratio of Methionin is 1: 0.5 to 1: 1, crystallization with separate after obtain (the S)-lysine salt of the phenylpropionic acid of further enrichment (S) type enantiomorph;
(ⅵ) with in the top steps d (ⅲ) further enrichment (S) type enantiomorph ibuprofen sodium with the immiscible solvent of water (for example heptane) in the presence of acidifying, with obtain enrichment (S) type enantiomorph ibuprofen with the immiscible solvent of water in solution, with its separation.Crystallization and isolate the ibuprofen that solid is rich in (S) type enantiomorph then; With
(ⅶ) with the aqueous solution (for example at 60 ℃) acidifying at high temperature of the ibuprofen sodium of further enrichment (S) the type enantiomorph among the top d (ⅲ) to form melt, it is separated with water layer, by top (ⅴ) the described processing.
In the preferred embodiment of the inventive method, phenylpropionic acid is an ibuprofen, and desired enantiomorph is (S) type enantiomorph.In this preferred embodiment:
(a) ibuprofen (the S)-Alpha-Methyl benzylamine salt and first mother liquor of enrichment (S) the type enantiomorph of the generation about 80%-of enantiomeric purity about 90% (weight) in the splitting step, this mother liquor comprises the ibuprofen of enrichment (R) type enantiomorph, it is used in the racemize step (e) to form racemic basically ibuprofen, and this product can be used as the part initiator that uses in the later splitting step (a) and adds;
(b) comprise two steps in the re-crystallization step:
(ⅰ) the first step re-crystallization step comprises the ibuprofen of enrichment (S) the type enantiomorph that generates in will splitting step (a)-(S)-Alpha-Methyl benzylamine recrystallization, with generate enantiomeric purity preferably from about 90% to about 99.9% (weight), be more preferably ibuprofen from about 94% enrichment (S) type enantiomorph-(S)-Alpha-Methyl benzylamine to about 99% (weight), generate second mother liquor of the ibuprofen comprise enrichment (S) type enantiomorph-(S)-Alpha-Methyl benzylamine simultaneously, enantiomeric purity wherein is about 40% to about 70% (weight), more preferably from about 40% to about 60% (weight), and second mother liquor is added as the partial solvent that uses in the splitting step (a) of back; With
(ⅱ) the second step re-crystallization step comprises the ibuprofen of enrichment (S) the type enantiomorph that the first step re-crystallization step (b) is obtained in (ⅰ)-(S)-Alpha-Methyl benzylamine recrystallization, with (S)-ibuprofen of obtaining being essentially pure enantiomorph-(S)-Alpha-Methyl benzylamine, its enantiomeric purity is preferably about 99%, obtain comprising the 3rd mother liquor of the ibuprofen of enrichment (S) type enantiomorph-(S)-Alpha-Methyl benzylamine simultaneously, its enantiomeric purity is about 85% to about 95% (weight), preferred about 88% to about 95% (weight), with the 3rd mother liquor as the first step re-crystallization step (b) of back (ⅰ) in the partial solvent adding of use.
In the most preferred embodiment of the present invention, first mother liquor in the splitting step (a) is carried out component distillation, so that remove all methyl alcohol substantially avoiding basically forming under the temperature of by product, overhead product is reused in the later splitting step (a) as partial solvent.The resistates that stays after above-mentioned distillation can be obtained the aqueous solution and the organic phase that contains the ibuprofen of enrichment (R) type enantiomorph of (S)-Alpha-Methyl benzylamine salt (for example (S)-Alpha-Methyl benzylamine hydrochloride) by acidifying (for example using hydrochloric acid).Subsequently the aqueous solution is separated and alkalization,, it is extracted in the toluene, be reused for beginning splitting step (a) subsequently with (the S)-Alpha-Methyl benzylamine that in disengaging step, reclaims as resolving agent to obtain free (S)-Alpha-Methyl benzylamine.The organic phase that comprises the ibuprofen of enrichment (R) type enantiomorph can be with any known method racemization in racemize step (e), to form racemic basically ibuprofen, the part of the solvent that its conduct is subsequently used when follow-up splitting step (a) begins adds.
Preferably in each step of the inventive method, can in the step of the front of mother liquor by being used in present method of phenylpropionic acid of the enantiomorph of wanting and circulate wherein not comprising enrichment.Splitting step (a) and re-crystallization step (b) is combined with the step of racemize step (e) and recovery (S)-Alpha-Methyl benzylamine resolving agent, this has the advantage of being avoided handling the multiply mother liquor logistics that each step produces, and owing to save time, energy and starting material have reduced production cost.
Re-crystallization step in aforesaid method can be chosen wantonly and comprises the 3rd and/or follow-up re-crystallization step.
This preferred combined method is described with reference to accompanying drawing, wherein Fig. 1 is the schema of the preferred method of manufacturing of the present invention (S)-ibuprofen, letter representation wherein in aforesaid method, be marked with (a) and (b) (ⅰ), (b) (ⅱ), (c), (d) and each step (e); Numeral 1 to 3 is represented first to the 3rd mother liquor respectively, (S)-Alpha-Methyl benzylamine of numeral 4 expression recirculation, the racemize ibuprofen of numeral 5 expression recirculation.In Fig. 1, dotted line is represented the material of recirculation, the material that solid line representative (S)-ibuprofen increases along direction of arrow enrichment degree.
Splitting step (a) the has generated enrichment ibuprofen of (S) type enantiomorph-(S)-Alpha-Methyl benzylamine product, with it as the first step re-crystallization step (b) initiator (ⅰ).First mother liquor (1) in the splitting step (a) is passed into racemize step (e), by here with racemic ibuprofen (5) recirculation to constitute the part initiator of follow-up splitting step (a), and the then recirculation of (S)-Alpha-Methyl benzylamine (4) of reclaiming splits use with the part as follow-up splitting step (a).Second mother liquor (2) that (ⅰ) is obtained by the first step re-crystallization step (b) then recirculation is used for follow-up splitting step (a).The first step re-crystallization step (b) product (ⅰ) carries out the second step re-crystallization step (b) (ⅱ) to obtain (S)-ibuprofen that enantiomeric purity increases-(S)-Alpha-Methyl benzylamine and the 3rd mother liquor, with this mother liquor recycling, be formed in (ⅰ) part of the middle solvent 4 that uses of follow-up the first step re-crystallization step (b).The product that the second step re-crystallization step (b) is obtained in (ⅱ) is used in and disengages in the step (c) then, to obtain (the S)-ibuprofen of high antimer purity.To disengage (S)-Alpha-Methyl benzylamine (4) recycling that also disengages simultaneously in the step (c), as the part of the resolving agent that is used for follow-up splitting step (a).(the S)-ibuprofen that disengages can be used in the optional preparation salt step (d) subsequently, contains even the salt of (the S)-ibuprofen of high antimer purity (for example sodium salt or (S)-lysine salt) more so that form.
When phenylpropionic acid is an ibuprofen, when desired enantiomorph is (S)-enantiomorph, the product of aforesaid method can be used for preparing (the S)-lysine salt of the ibuprofen of enrichment (S) type enantiomorph, its practice is that the ibuprofen of enrichment (S) the type enantiomorph that disengages is contacted with (S)-Methionin, preferably contact with stoichiometry or (S)-Methionin still less, (S)-lysine salt with the ibuprofen that forms the further enrichment of (S) type enantiomorph, preferred ibuprofen with (S)-mol ratio of Methionin is about 1: 0.5 to about 1: 1, more preferably from about 1: 0.5 to about 1: 0.95.The ibuprofen of the enrichment that disengages (S) enantiomorph can also contact with sodium hydroxide to form the ibuprofen sodium (referring to for example International Patent Application WO 92/20334) of the further enrichment of (S) type enantiomorph.
(the S)-ibuprofen and the salt thereof of high antimer purity in another embodiment preferred of the inventive method, have been provided.
Find also that unexpectedly the flurbiprofen of enrichment (S) type enantiomorph can crystallize out from toluene, remove other enantiomorph simultaneously effectively, form (the S)-flurbiprofen of high antimer purity.
Understand easily, prepare R (-)-ibuprofen, R (-)-flurbiprofen or their pharmacologically acceptable salt if desired, easily above method is improved, replace (S)-Alpha-Methyl benzylamine as the resolving agent in the splitting step (a) of the inventive method with (R)-Alpha-Methyl benzylamine, simultaneously follow-up step is done corresponding improvement, thereby make (R) (-)-ibuprofen, R (-)-flurbiprofen or their pharmacologically acceptable salt.
Now the present invention is described with following embodiment.
The ibuprofen of embodiment 1 by preparation enrichment (S) type enantiomorph-(S)-Alpha-Methyl benzylamine makes ibuprofen split [splitting step (a)]
The racemize ibuprofen (530 kilograms) that recirculation is used is dissolved in the toluene (1335 liters), adds methyl alcohol (900 liters), and mixture under agitation is heated to 66 ℃.In 3 hours, add the solution of (S)-Alpha-Methyl benzylamine (247 kilograms) in toluene (200 liters) that recirculation is used, during to keep temperature be 65-70 ℃.Mixture under agitation is cooled to 0-5 ℃ at last, stirs 1 hour under this temperature.Filter and collect desired product, with toluene (600 liters) washing.Contain (S)-Alpha-Methyl benzylamine salt of the ibuprofen of enrichment (S) type enantiomorph in the product, enantiomeric purity is 89.3% (weight).The reservation mother liquor is used with the similar fashion described in the embodiment 6 and is handled.
Re-crystallization step [re-crystallization step (the b)] embodiment 2 (a) [the first step re-crystallization step (b) (ⅰ)] of (S)-Alpha-Methyl benzylamine salt of the ibuprofen of embodiment 2 enrichments (S) type enantiomorph
To be (2350 liters in the 3rd mother liquor that uses of ibuprofen-(S)-Alpha-Methyl benzylamine (635 kilograms), toluene (598 liters) and the recirculation of enrichment (S) the type enantiomorph of 85.5% (weight) according to the enantiomeric purity that obtains with the similar fashion described in the top embodiment 1, (b) obtains from the following examples 2, it comprises the ibuprofen of enrichment (S) type enantiomorph-(S)-Alpha-Methyl benzylamine (214 kilograms) and methyl alcohol (800 liters)) stir down at 67 ℃, heating and dissolving, being cooled to outlet temperature then is 0 ℃ to 5 ℃.Filter and collect formed solid.Product is ibuprofen-(the S)-Alpha-Methyl benzylamine of enrichment (S) type enantiomorph, and enantiomeric purity is 94.1% (weight).Embodiment 2 (b) [the second step re-crystallization step (b) (ⅱ)]
According to the similar mode of the first step re-crystallization step described in the foregoing description 2 (a), with enantiomeric purity is (629 kilograms of the ibuprofens-(S)-Alpha-Methyl benzylamine of enrichment (S) the type enantiomorph of 91.4% (weight), obtain by the similar fashion described in the top embodiment 2 (a)) recrystallization in toluene (115 liters) and methanol mixture, with toluene (200 liters) washing, its enantiomeric purity is 98.5% (weight).
Embodiment 2 (a) and 2 (b) show, the enantiomeric purity of the ibuprofen of enrichment (S) type enantiomorph-(S)-Alpha-Methyl benzylamine is significantly improved.
Ibuprofen the disengaging in toluene solution [disengaging step (c)] of embodiment 3 (a) enrichment (S) type enantiomorph
With concentrated hydrochloric acid (170 kilograms) stirring of the ibuprofen of enrichment (S) type enantiomorph-(S)-Alpha-Methyl benzylamine salt (485 kilograms), toluene (814 liters), water (300 liters) and proportion 1.18 30 minutes by the preparation of method described in the above embodiment 2 (b).Separate in the lower floor waterbearing stratum that will comprise (S)-Alpha-Methyl benzylamine hydrochloride, merges with the water-bearing mother liquor described in the following embodiment 6, uses by carrying out recirculation described in the top embodiment 1 then.Water (100 liters) washing comprises the upper strata of toluene solution of the ibuprofen of enrichment (S) type enantiomorph, obtains 920 kilogram solution, the ibuprofen of enrichment (S) the type enantiomorph that wherein to contain 300 kilograms of enantiomeric purities be 98.5% (weight).
The purifying of the ibuprofen of embodiment 3 (b) enrichment (S) type enantiomorph
Wash enantiomeric purity with water and be toluene (1221 kilograms) solution of the ibuprofen (180 kilograms) of 98.2% enrichment (S) type enantiomorph.Add entry (220 liters) and aqueous sodium hydroxide solution (47 liters, proportion 1.5),, make its sedimentation 4 hours this mixture heating up to 60 ℃.Tell the lower floor waterbearing stratum, wash toluene layer with water.Aqueous cleaning thing and waterbearing stratum are merged.Remaining toluene is removed in distillation, adds heptane (250 liters) and concentrated hydrochloric acid (78 kilograms, proportion 1.18).Tell heptane layer, wash with water, be cooled to-10 ℃.Filter to collect the ibuprofen of enantiomeric purity, vacuum-drying greater than 99% enrichment (S) type enantiomorph.(166 kilograms of output).
The preparation of the ibuprofen of embodiment 4 (a) enrichment (S) type enantiomorph-(S)-Methionin [preparation salt step (d)]
With reference to table 1 by the following embodiment 4.1 to 4.12 that carries out.The ibuprofen (the 100 gram materials that contain ' a ' % (S) type enantiomorph) of enrichment (S) type enantiomorph is dissolved in the ethanol (900 milliliters) at ambient temperature.The solution of preparation (S)-Methionin monohydrate (' b ' gram) in the mixture of water (' c ' milliliter) and ethanol (' d ' milliliter).Within an hour ibuprofen solution and (S)-lysine solution is added to (S)-ibuprofen-(S)-lysine salt (9.5 gram) in the suspension in water (11 milliliters) and the ethanol (125 milliliters) simultaneously with equimolar ratio, suspension stirred 10 minutes down at 20 ℃ in advance.Then with this mixture at one hour internal cooling to 0 ℃, then be cooled to-10 ℃.Mixture was stirred 2 hours down at-10 ℃.The solid that filter to collect forms with the ethyl acetate washing, 35 ℃ of vacuum-dryings, obtains enantiomeric purity and is the ibuprofen of enrichment (S) the type enantiomorph of ' e ' % (weight)-(S)-lysine salt.
Table 1
Embodiment 4.1-4.12 shows, in the preparation salt step of the inventive method, the enantiomeric purity of the ibuprofen of enrichment (S) type enantiomorph-(S)-lysine salt significantly improved.
| Embodiment | a | b | c | d | e |
| 4.1 | 94.54 | 60.3 | 79 | 55 | 98.9 |
| 4.2 | 99.16 | 60.3 | 79 | 55 | 99.8 |
| 4.3 | 91.1 | 60.3 | 79 | 55 | 98.4 |
| 4.4 | 94.54 | 67.5 | 85.5 | 55 | 98.7 |
| 4.5 | 94.54 | 64 | 82 | 55 | 98.6 |
| 4.6 | 91.1 | 67.5 | 85.5 | 55 | 97.8 |
| 4.7 | 99.16 | 64 | 82 | 55 | 99.7 |
| 4.8 | 99.16 | 67.5 | 85.5 | 55 | 99.7 |
| 4.9 | 91.1 | 64 | 82 | 55 | 97.8 |
| 4.10 | 94.54 | 60.3 | 79 | 55 | 98.5 |
| 4.11 | 94.54 | 64 | 82 | 55 | 98.6 |
| 4.12 | 99.16 | 67.5 | 85.5 | 55 | 99.7 |
The preparation of the ibuprofen of embodiment 4 (b) enrichment (S) type enantiomorph-(S)-Methionin (preparation salt step (d))
With the solution of the ibuprofen of enrichment (S) type enantiomorph (30 gram) in toluene (20 gram) with (S)-Methionin (40 grams, the 50%W/W aqueous solution) and water (20 milliliters) is together 60-70 ℃ of heating.Tell the waterbearing stratum of lower floor, remaining solvent is removed in distillation.Add ethanol (460 milliliters),, be cooled to 0 ℃ to-10 ℃ then mixture heat to 50 ℃-55 ℃, and this temperature maintenance 30 minutes.The ibuprofen of collection crystalline enrichment (S) type enantiomorph-(S)-Methionin, with ethyl acetate (50 milliliters) washing, vacuum-drying.
The preparation of the ibuprofen sodium salt of embodiment 5 enrichments (S) type enantiomorph (preparation salt step (d))
Be that the ibuprofen (211 kilograms) of 95.5% enrichment (S) type enantiomorph solution and water (300 liters) and the aqueous sodium hydroxide solution (52 liters, proportion 1.5) in toluene (797 kilograms) is heated to 60 ℃ together with enantiomeric purity, make its sedimentation 4 hours.Tell the waterbearing stratum, toluene layer washes with water.Aqueous cleaning thing and waterbearing stratum merge, and remaining toluene is removed in distillation.Add acetone (1684 kilograms), mixture is cooled to 20 ℃.Filter the ibuprofen sodium salt dihydrate (enantiomeric purity is 99.9%) of collecting isolated enrichment (S) type enantiomorph, vacuum-drying.(143.5 kilograms of output).Embodiment 6 handles first mother liquor that obtains in the splitting step
The mixture distillation of first mother liquor that obtains in the splitting step is concentrated, reclaim behind methyl alcohol and the toluene and utilize again subsequently so that remove.Add entry (300 liters) and concentrated hydrochloric acid (170 kilograms, proportion 1.18), stir this mixture.The waterbearing stratum that will contain (S)-Alpha-Methyl benzylamine hydrochloride is told and is merged with (S)-Alpha-Methyl benzylamine hydrochloride aqueous solution among the embodiment 3 (a).With the solution alkalization of aqueous sodium hydroxide solution (340 liters, proportion 1.5) with above-mentioned merging.Add toluene (500 liters), formed (S)-Alpha-Methyl benzylamine solution is according to being used for later splitting step with the similar fashion described in the embodiment 1.
With methyl alcohol (300 liters) and vitriol oil reflux 2 hours.Isolate upper organic phase, with it with methyl alcohol (75 liters) and the vitriol oil (15 liters) reflux 2 hours.Tell the upper strata, it is heated with solid sodium hydroxide (175 kilograms).Methyl alcohol is removed in distillation, the resistates mixture acidifying of concentrated hydrochloric acid (353 kilograms) and water (1750 liters).The top toluene layer that contains racemic ibuprofen washes with water, and by using in the splitting step of preparation afterwards with the similar manner described in the embodiment 1.
The flurbiprofen of embodiment 7 by preparation enrichment (S) type enantiomorph-(S)-Alpha-Methyl benzylamine splits flurbiprofen
Racemic flurbiprofen (61.0 gram) is dissolved in the mixture of methyl alcohol (40 milliliters) and toluene (160 milliliters).With mixture heating up to 60 ℃, in 10 minutes, add 16.9 milliliters of (S)-Alpha-Methyl benzylamines.In reaction mixture, add the crystal seed of (S)-flurbiprofen-(S)-Alpha-Methyl benzylamine, mixture is cooled to 0-5 ℃ then, and under this temperature, kept 1 hour.Filter the collecting precipitation thing, obtain enantiomeric purity and be the flurbiprofen of 92.2% enrichment (S) type enantiomorph-(S)-Alpha-Methyl benzylamine.In the mixture of methyl alcohol (48 milliliters) and toluene (192 milliliters) after the recrystallization, obtained enantiomeric purity and be the flurbiprofen of 98.5% further enrichment (S) type enantiomorph-(S)-Alpha-Methyl benzylamine at throw out.
With mother liquor concentrated hydrochloric acid (10 milliliters) and water (25 milliliters) acidifying that obtains in the re-crystallization step, and under 25 ℃, stirred 15 minutes.Collection contains the lower floor waterbearing stratum of (S)-Alpha-Methyl benzylamine, and reuses.The organic phase on upper strata contains the mixture of flurbiprofen enantiomorph, and S (+) is 41.5%: 58.5% with the weight ratio of R (-).This flurbiprofen is changed into its racemic methyl ester form, make it revert to racemic flurbiprofen with the sodium hydroxide conversion again, join again in the top splitting step.
The preparation of embodiment 8 (R)-flurbiprofen-(R)-Alpha-Methyl benzylamine
Carry out embodiment 8.1 to 8.6 with reference to table 2.The racemic flurbiprofen of (ⅰ) gram is dissolved in the mixture of (ⅱ) ml methanol, (ⅲ) milliliter toluene and any (ⅳ) ml water that adds.Mixture heating up to 55 ℃ to form solution, was added (ⅴ) milliliter (R)-Alpha-Methyl benzylamine in 10 minutes.In being cooled to 25 ℃ mixture, add (R)-flurbiprofen-(R)-Alpha-Methyl benzylamine crystal seed.Filter the collecting precipitation thing, obtain (the R)-Alpha-Methyl benzylamine salt of enantiomeric purity for the flurbiprofen of enrichment (R) the type enantiomorph of (ⅵ) %.In the mixture of methyl alcohol, toluene and water (that uses in ratio and the splitting step is identical) after the recrystallization, obtained enantiomeric purity and be the flurbiprofen of further enrichment (R) the type enantiomorph of (ⅶ) %-(R)-Alpha-Methyl benzylamine solid at throw out.
Table 2
Footnote: 1. second of this embodiment step recrystallization obtains the flurbiprofen of further enrichment (R) type enantiomorph-(R)-Alpha-Methyl benzylamine solid,
| Embodiment | (ⅰ) flurbiprofen/gram | (ⅱ) methyl alcohol/milliliter | (ⅲ) toluene/milliliter | (ⅳ) water/milliliter | (ⅴ) MBA/ milliliter | (ⅵ) enrichment % | (ⅶ) enrichment % |
| 8.1 | 61.0 g | 40.0 ml | 160 ml | - | 17 ml | 91.2％ | 98.8％ |
| 8.2 | 61.0 g | 70.0.m1 | 280 ml | - | 17 ml | 92.0％ | 99.3％ |
| 8.3 | 61.0 g | 40.0 ml | 160 ml | - | 17 ml | 91.8％ | 99.2％ |
| 8.4 | 61.0 g | 40.0 ml | 160 ml | 10.0 ml | 17 ml | 92.4％ | 99.1％ |
| 8.5 | 61.0 g | 40.0 ml | 160 ml | 2 ml | 17 ml | 91.8％ | 99.1％ |
| 8.6 | 43.1 g | 20.0 ml | 180 ml | - | 12 ml | 91.9％ | 99.1％ |
Its enantiomeric purity disengages greater than the flurbiprofen of 99.9% embodiment 9 (a) enrichment (R) type enantiomorph
With enantiomeric purity flurbiprofen-(R)-Alpha-Methyl benzylamine (58.7 grams of 99.1% enrichment (R) type enantiomorph, according to the preparation of similar fashion described in the embodiment 8) heated 15 minutes at 80 ℃ together with the mixture of normal heptane (160 milliliters), water (200 milliliters) and concentrated hydrochloric acid (17 milliliters, proportion 1.18).Tell organic layer, be cooled to 0-5 ℃.The flurbiprofen of enrichment (R) the type enantiomorph that the collection crystallization goes out is with normal heptane washing, vacuum-drying.
Disengaging of the flurbiprofen of embodiment 9 (b) enrichment (S) type enantiomorph
According to the similar fashion described in the embodiment 9 (a), from according to the flurbiprofen that disengages enrichment (S) type enantiomorph the flurbiprofen of enrichment (S) the type enantiomorph that makes with the similar fashion described in the embodiment 7-(S)-Alpha-Methyl benzylamine.
Embodiment 10 (a) carries out the enantiomorph purifying of the flurbiprofen of enrichment (S) type enantiomorph with recrystallization method
The flurbiprofen (47.2 gram) that with enantiomeric purity is 98.9% enrichment (S) type enantiomorph is added in the toluene (132 milliliters), and is heated to 50 ℃.Under 42 ℃ temperature, add (S)-flurbiprofen crystal, the solution order is but arrived-5 ℃.Filter the flurbiprofen solid of collecting enrichment (S) type enantiomorph, find that its enantiomeric purity is 99.8%.
Embodiment 10 (b) carries out the enantiomorph purifying of the flurbiprofen of enrichment (S) type enantiomorph with recrystallization method
The flurbiprofen (13.5 gram) that with enantiomeric purity is 98.4% enrichment (S) type enantiomorph is added in the toluene (26 milliliters), and is heated to 50 ℃.Then solution is cooled to-10 ℃.Filter the flurbiprofen solid of collecting enrichment (S) type enantiomorph, find that its enantiomeric purity is 99.8%.Output 13.0 grams.
Claims (27)
1. one kind prepares the method that desired the sort of enantiomorph in the phenylpropionic acid that is selected from ibuprofen or flurbiprofen in enrichment in the product, and this method may further comprise the steps:
(a) splitting step, in this step, prepared the wherein Alpha-Methyl benzylamine salt of the phenylpropionic acid of the desired enantiomorph of enrichment, its practice is as in the toluene of solvent and the methanol mixture a kind of enantiomorph of Alpha-Methyl benzylamine to be contacted with the racemic basically mixture of phenylpropionic acid, and the mol ratio of racemic basically phenylpropionic acid and Alpha-Methyl benzylamine is about 1: 0.25 to about 1: 1;
(b) re-crystallization step, in this step with salt recrystallization in the mixture of methyl alcohol and toluene of formed enrichment, so that make the further enrichment in the Alpha-Methyl benzylamine salt of phenylpropionic acid of desired enantiomorph;
(c) the optional step of disengaging, the phenylpropionic acid of the enantiomorph of wanting that in this step, from the salt of recrystallization, disengaged further enrichment;
(d) Ren Xuan preparation salt step, the solid salt of phenylpropionic acid of the enantiomorph of wanting of in this step, having isolated further enrichment, this solid salt can also randomly be done further enantiomorph enrichment to want enantiomorph;
Wherein desired phenylpropionic acid enantiomorph is selected from (S)-ibuprofen, (S)-flurbiprofen and (R) flurbiprofen.
2. a kind of method in the claim 1, wherein desired phenylpropionic acid enantiomorph is (S)-enantiomorph, and:
(a) in splitting step, the mol ratio of used racemic basically phenylpropionic acid and (S)-Alpha-Methyl benzylamine is about 1: 0.35 to about 1: 0.8, in the mixture of methyl alcohol and toluene, be prepared, wherein toluene account for whole volume of mixture at least about 50%, the temperature of mixture is about 30 ℃ to about 70 ℃, so that form supersaturated solution; Crystallization goes out the phenylpropionic acid of enrichment (S) type enantiomorph-(S)-Alpha-Methyl benzylamine salt from this supersaturated solution;
(b) in re-crystallization step, solvent is the mixture of methyl alcohol and toluene, wherein toluene account for whole volume of mixture at least about 25%; Crystallization goes out the phenylpropionic acid of further enrichment phenylpropionic acid (S) type enantiomorph-(S)-Alpha-Methyl benzylamine salt from this solution;
(c) in disengaging step, (S)-Alpha-Methyl benzylamine salt of the phenylpropionic acid of further enrichment (S) the type enantiomorph that will in re-crystallization step, obtain with the immiscible solvent of water in acidifying, with the phenylpropionic acid of enrichment (S) the type enantiomorph that obtains disengaging with the immiscible solvent of water in solution and (S)-aqueous solution of Alpha-Methyl benzylamine salt, can disengage (S)-Alpha-Methyl benzylamine by back one solution, thereby it can be used further in the later splitting step (a).
3. a kind of method in the claim 2, wherein:
(d) in preparation salt step, by the phenylpropionic acid that disengages further enrichment (S) the type enantiomorph that obtains in the step (c) with the immiscible solvent of water in solution can further handle with one or more following methods:
(ⅰ) crystallization and isolate the phenylpropionic acid solid of enrichment (S) type enantiomorph from solution;
(ⅱ) distillation removes and desolvates, to obtain a kind of melt;
(ⅲ) when phenylpropionic acid is ibuprofen, its aqueous solution with the alkali that contains sodium is contacted, the aqueous solution with the sodium salt that forms ibuprofen, with it from the immiscible solvent of water separate, aqueous solution acetone diluted then is so that crystallization goes out the ibuprofen sodium salt of further enrichment (S) type enantiomorph; Perhaps
(ⅳ) when phenylpropionic acid is ibuprofen, it is contacted with water with (S)-Methionin, wherein ibuprofen with (S)-mol ratio of Methionin is 1: 0.5 to 1: 1, to obtain the aqueous solution of (S)-lysine salt, with it from the immiscible solvent of water isolate, in the aqueous solution, add ethanol then, crystallization the has gone out further enrichment ibuprofen of (S) enantiomorph-(S)-Methionin.
4. claimed in the claim 1-kind of method, wherein the racemic basically phenylpropionic acid that uses in splitting step (a) and the mol ratio of Alpha-Methyl benzylamine are 1: 0.4 to 1: 0.6.
5. claimed a kind of method in the claim 1, wherein the methyl alcohol that uses in splitting step (a) and the mixture of toluene comprise the toluene that accounts for whole volume of mixture about 60% to about 90%.
6. claimed a kind of method in the claim 5, wherein the mixture that uses in splitting step (a) comprises the toluene that accounts for whole volume of mixture about 70% to about 80%.
7. claimed a kind of method in the claim 1, wherein the initial temperature of the mixture that uses in splitting step (a) is about 40 ℃ to about 60 ℃.
8. 1 claimed a kind of method in the claim wherein is cooled to the mixture in the splitting step (a) temperature and is-10 ℃ to about 30 ℃ approximately.
9. claimed a kind of method in the claim 8, wherein the mixture in the splitting step (a) being cooled to temperature is about 0 ℃ to about 5 ℃.
10. claimed a kind of method in the claim 1, wherein the mixture that uses in re-crystallization step (b) comprises the toluene that accounts for whole volume of mixture about 50% to about 80%.
11. claimed a kind of method in the claim 10, wherein the mixture that uses in re-crystallization step (b) comprises the toluene that accounts for whole volume of mixture about 60% to about 70%.
12. claimed a kind of method in the claim 1 wherein will be cooled to temperature at the solution in the re-crystallization step (b) and be-10 ℃ to about 30 ℃ approximately.
13. claimed a kind of method in the claim 12, wherein will be cooled to temperature at the solution in the re-crystallization step (b) is about 0 ℃ to about 5 ℃.
14. claimed a kind of method in the claim 1; wherein in disengaging step (c); the salt of the phenylpropionic acid of further enrichment (S) the type enantiomorph that will obtain from re-crystallization step (b) with hydrochloric acid carries out acidifying; to obtain the aqueous solution of (S)-Alpha-Methyl benzylamine hydrochloride; with its alkalization; this alkali is extracted in the toluene, in the postpose again splitting step of this toluene extract (a).
15. claim 3 or claim 4 to 14 claimed a kind of method in any one wherein when being attached to claim 4; the steps d (ⅴ) that comprises further preparation salt in this method; wherein will prepare the melt that solid that salt steps d (ⅰ) obtains or preparation salt steps d (ⅱ) obtain separates; and in aqueous ethanolic solution with (S)-Methionin reaction; phenylpropionic acid with (S)-mol ratio of Methionin is about 1: 0.5 to about 1: 1 so that crystallization with separate after obtain (the S)-lysine salt of the phenylpropionic acid of the further enrichment of (S) type enantiomorph.
16. claim 3 or claim 4 to 14 claimed a kind of method in any one wherein when being attached to claim 4; this method comprises the steps d (ⅵ) of further preparation salt; wherein will prepare the ibuprofen sodium that obtains in the salt steps d (ⅲ) with the immiscible solvent of water in the presence of acidifying; with the ibuprofen that obtains the further enrichment of (S) type enantiomorph with the immiscible solvent of water in solution; with its separation, crystallization and isolate the ibuprofen solid of enrichment (S) type enantiomorph then.
17. claimed a kind of method in the claim 16, wherein in steps d (ⅵ), use with the immiscible solvent of water be heptane.
18. claim 3 or claim 4 to 14 claimed a kind of method in any one wherein when being attached to claim 3; this method comprises a further steps d (ⅶ) of preparation salt; in this step with the aqueous solution acidifying at high temperature of the ibuprofen sodium of the further enrichment of (S) type enantiomorph that obtains in the steps d (ⅲ) to form melt; it is isolated from water layer, then crystallization and isolate the ibuprofen solid of enrichment (S) type enantiomorph.
19. claimed a kind of method in the claim 18, high temperature wherein is about 60 ℃.
20. claimed a kind of method in the claim 1, wherein phenylpropionic acid is an ibuprofen, and desired enantiomorph is (S)-enantiomorph, and:
(a) generate enantiomeric purity in the splitting step and be about 80% (S)-Alpha-Methyl benzylamine salt and first mother liquor that comprises the ibuprofen of enrichment (R) type enantiomorph to about 95% (weight), this mother liquor is used in the racemize step (e) to form racemic basically ibuprofen, with its part initiator adding as use in follow-up splitting step (a);
(b) comprised for two steps in the re-crystallization step:
(ⅰ) the first step re-crystallization step comprises the ibuprofen of enrichment (S) the type enantiomorph that generates in will splitting step (a)-(S)-Alpha-Methyl benzylamine recrystallization, generate the ibuprofen that enantiomeric purity preferably is about enrichment (S) the type enantiomorph of 90%-99.9% (weight)-(the S)-Alpha-Methyl benzylamine and second mother liquor, comprise the ibuprofen that enantiomeric purity is about 40% enrichment to about 70% (weight) (S) type enantiomorph-(S)-Alpha-Methyl benzylamine in second mother liquor, this second mother liquor is as the partial solvent adding of using in follow-up splitting step (a);
(ⅱ) the second step re-crystallization step comprises the ibuprofen of enrichment (S) the type enantiomorph that produces in will the first step re-crystallization step b (ⅰ)-(S)-Alpha-Methyl benzylamine recrystallization, preferably be about 99% (the S)-ibuprofen that is essentially pure enantiomorph-(S)-Alpha-Methyl benzylamine and the 3rd mother liquor to generate enantiomeric purity, comprise the ibuprofen that enantiomeric purity is about 85% enrichment to about 95% (weight) (S) type enantiomorph-(S)-Alpha-Methyl benzylamine in this mother liquor, this 3rd mother liquor is as the partial solvent adding of using in (ⅰ) in follow-up the first step re-crystallization step (b).
21. claimed a kind of method in the claim 20, wherein the enantiomeric purity of the ibuprofen of enrichment (S) the type enantiomorph that obtains in (ⅰ) in the first step re-crystallization step (b)-(S)-Alpha-Methyl benzylamine is about 94% to about 99% (weight).
22. claimed a kind of method in the claim 20, wherein second mother liquor comprises the ibuprofen that enantiomeric purity is about 40% enrichment to about 60% (weight) (S) type enantiomorph-(S)-Alpha-Methyl benzylamine.
23. claimed a kind of method in any one in the claim 20 to 22, wherein the 3rd mother liquor comprises the ibuprofen that enantiomeric purity is about 88% enrichment to about 95% (weight) (S) type enantiomorph-(S)-Alpha-Methyl benzylamine.
24. claimed a kind of method in the claim 1; wherein first mother liquor that obtains in the splitting step (a) is carried out component distillation avoiding basically forming under the temperature of by product; to remove all methyl alcohol basically, overhead product re-uses as the partial solvent that uses in follow-up splitting step (a).
25. claimed a kind of method in the claim 24, wherein with the remaining resistates acidifying in first mother liquor distillation back, obtain the aqueous solution and the organic phase that comprises the ibuprofen of enrichment (R) type enantiomorph of (S)-Alpha-Methyl benzylamine salt, tell the aqueous solution and alkalinisation treatment, obtain free (S)-Alpha-Methyl benzylamine, it is extracted in the toluene, begins as (S)-Alpha-Methyl benzylamine that resolving agent reclaiming in follow-up splitting step (a) in disengaging step (c) and use; Organic phase racemization in racemize step (e) that will comprise the ibuprofen of enrichment (R) type enantiomorph to obtain racemic basically ibuprofen, adds it then as the partial solvent that uses when follow-up splitting step (a) begins.
26. claimed a kind of method in the claim 25, the resistates acidifying that will stay after wherein will distilling with hydrochloric acid generates (S)-Alpha-Methyl benzylamine hydrochloride aqueous solution.
27. claimed a kind of method in the claim 1, wherein re-crystallization step (b) comprises three steps or more re-crystallization step.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB929225202A GB9225202D0 (en) | 1992-12-02 | 1992-12-02 | Process |
| CN94106198A CN1071733C (en) | 1992-12-02 | 1994-06-01 | Process |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB929225202A GB9225202D0 (en) | 1992-12-02 | 1992-12-02 | Process |
| CN94106198A CN1071733C (en) | 1992-12-02 | 1994-06-01 | Process |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1113908A CN1113908A (en) | 1995-12-27 |
| CN1071733C true CN1071733C (en) | 2001-09-26 |
Family
ID=37075770
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94106198A Expired - Fee Related CN1071733C (en) | 1992-12-02 | 1994-06-01 | Process |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1071733C (en) |
| GB (1) | GB9225202D0 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107954857A (en) * | 2017-11-21 | 2018-04-24 | 潍坊新益制药技术有限公司 | A kind of brufen resolution process and the purification process based on the resolution process |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5248813A (en) * | 1992-10-14 | 1993-09-28 | Ethyl Corporation | Enantiomeric resolution |
| US5260482A (en) * | 1992-10-14 | 1993-11-09 | Ethyl Corporation | Enantiomeric resolution |
-
1992
- 1992-12-02 GB GB929225202A patent/GB9225202D0/en active Pending
-
1994
- 1994-06-01 CN CN94106198A patent/CN1071733C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5248813A (en) * | 1992-10-14 | 1993-09-28 | Ethyl Corporation | Enantiomeric resolution |
| US5260482A (en) * | 1992-10-14 | 1993-11-09 | Ethyl Corporation | Enantiomeric resolution |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1113908A (en) | 1995-12-27 |
| GB9225202D0 (en) | 1993-01-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU672269B2 (en) | Process for preparing substantially pure enantiomers of phenylpropionic acids | |
| US5380867A (en) | Selective precipitation of α-aryl carboxylic acid salts | |
| US5332834A (en) | Racemization of an enantomerically enriched α-aryl carboxylic acid | |
| JP3299747B2 (en) | Preparation of optically active aliphatic carboxylic acids | |
| JPH11511742A (en) | Chiral acid separation process with 1-aminoindan-2-ol | |
| CN1071733C (en) | Process | |
| CN1022482C (en) | Optical resolution method of (+/-) -cis or (+/-) -trans-dichlorochrysanthemic acid | |
| US5235095A (en) | Preparation of optically active aliphatic carboxylic acids | |
| US5220053A (en) | Preparation of optically active aliphatic carboxylic acids | |
| EP0036265B1 (en) | Method of optical resolution of (+/-)-2-amino-1-butanol and/or (+/-) -mandelic acid | |
| CN1204337A (en) | Production of salt clavulanic acid | |
| US5235101A (en) | Preparation by flotation of optically active aliphatic carboxylic acids | |
| JPH10506384A (en) | Separation of bicyclic lactam enantiomers | |
| CN1155553C (en) | Process for preparing antimer of 2-fluo-alpha-methyl-[1,1'-diphenyl]-4-acetic acid | |
| JPS6142A (en) | Manufacture of optically active alpha substituted phenylacetic acids | |
| CN1051725A (en) | Glutaric acid derivatives and preparation method thereof | |
| JPH059171A (en) | Distillation of optically active carboxylic acid | |
| JPH0472824B2 (en) | ||
| FR2536391A1 (en) | New carnitinenitrile salts and process for their preparation. | |
| ITMI972257A1 (en) | PROCESS FOR PREPARATION OF PROPIONIC 2- (4-ISOBUTYLPHENYL) ACID | |
| JPS62175446A (en) | Optical resolution of (+-)-1-(1-naphthyl)ethylamine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20010926 Termination date: 20130601 |