CN104744231A - Method for splitting 2-hydracrylicacid racemate - Google Patents
Method for splitting 2-hydracrylicacid racemate Download PDFInfo
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Abstract
The invention relates to the technical filed of medicine intermediate, and especially relates to a method for splitting a 2-hydracrylicacid racemate. The method is characterized in that 2-hydracrylicacid racemate and (S)-1-(4-nitrophenyl) ethylamine hydrochloride and a micromolecule organic base are performed with a one kettle way reaction in a solvent, then a diastereomeric salt of 2-hydracrylicacid can be separated. The splitting method employs a single solvent for a resolution reaction, the recyclable (S)-1-(4-nitrophenyl) ethylamine hydrochloride is taken as a resolving agent, operation is simple, cost is saved, and the method is benefit for industrial production.
Description
Technical field
The present invention relates to medicine intermediate technical field.Particularly, the present invention relates to Endothelin Receptor inhibitor intermediate, particularly the method for splitting of 2 hydroxy propanoic acid raceme.
Background technology
2 hydroxy propanoic acid is the important intermediate of plant-growth regulator and endothelin-receptor inhibitor medicaments, and tool has been widely used.2 hydroxy propanoic acid is produced mainly to be existed with the form of raceme afterwards, and plant-growth regulator and endothelin-receptor inhibitor medicaments are usually owing to the enantiomorph of single configuration.Therefore, be single enantiomer by 2 hydroxy propanoic acid mesotomy, resynthesis is the finished product of single configuration is more rational preparation method.
(S)-1-(4-chloro-phenyl-) ethamine is the conventional compound that can be used for splitting 2 hydroxy propanoic acid raceme, such as, be described in the method for splitting in CN99812927.5.But (S)-1-(4-chloro-phenyl-) ethamine is expensive, adopts the method greatly can improve the cost of product, be difficult to implement industrialization.
The L-PROLINE methyl esters of relative low price or (S)-1-(4-nitrophenyl) ethamine also can be used for splitting 2 hydroxy propanoic acid raceme, such as, be described in the method for splitting in CN95195655.8.But, have been found that L-PROLINE methyl esters molecule unstressed configuration, it is not easy to detect, and reclaims difficulty, owing to employing the mixed solvent of methyl alcohol and t-butyl methyl ether after having carried out resolution reaction, industrialization phase reclaims single solvent difficulty, is unfavorable for reducing process costs; And (S)-1-(4-nitrophenyl) ethamine is a kind of material of instability, normal temperature is exposed in air, and color relation can deepen, and storage period is of a specified duration, and HPLC detects has impurity to produce.
Summary of the invention
Therefore, the object of this invention is to provide a kind of method splitting 2 hydroxy propanoic acid raceme, the method can overcome above-mentioned shortcoming, is easy to implement in suitability for industrialized production.
Above-mentioned purpose of the present invention is realized by following method for splitting, the method comprises 2 hydroxy propanoic acid raceme and (S)-1-(4-nitrophenyl) ethylamine hydrochloride and small molecules organic bases carry out one pot reaction in a solvent, then isolates the diastereoisomeric salt of 2 hydroxy propanoic acid.
In the above-mentioned methods, described 2 hydroxy propanoic acid raceme, (S)-1-(4-nitrophenyl) mol ratio of ethylamine hydrochloride and small molecules organic bases is 1:0.5 ~ 0.9:0.75 ~ 1.8.
In the above-mentioned methods, 3 carbon atoms of described 2 hydroxy propanoic acid raceme has monosubstituted or polysubstituted group; Preferably, 3 carbon atoms of described 2 hydroxy propanoic acid raceme have 1 to 2 aryl and 1 alkoxyl group or alkyl; More preferably, described aryl is phenyl; Further preferably, described alkoxyl group is methoxy or ethoxy; Most preferably, described alkyl is methyl.
Further preferably, described 2 hydroxy propanoic acid raceme is the raceme of 2-hydroxy-3-methoxy-3,3-diphenyl-propionic acid, 2-hydroxyl-3-oxyethyl group-3,3-diphenyl-propionic acid or 2-hydroxy-3-methyl-3,3-diphenyl-propionic acid.
In the above-mentioned methods, described small molecules organic bases is triethylamine or diisopropylethylamine.
In the above-mentioned methods, described solvent is absolute alcohol solvent.
Preferably, described absolute alcohol solvent is methyl alcohol, ethanol, Virahol or propyl alcohol, is preferably ethanol.
In the above-mentioned methods, described method for splitting also comprises and being added in resolution reaction solution by the crystal seed of diastereoisomeric salt to be separated.
Preferably, described crystal seed adds when resolution reaction solution is cooled to 30 ~ 50 DEG C.
In the above-mentioned methods, described method also comprises: reclaim (S)-1-(4-nitrophenyl) ethylamine hydrochloride.
Preferably, described (S)-1-(4-nitrophenyl) ethylamine hydrochloride reclaims diastereoisomeric salt from splitting mother liquor or described 2 hydroxy propanoic acid.
Further preferably, from the diastereoisomeric salt of described 2 hydroxy propanoic acid, reclaim (S)-1-(4-nitrophenyl) ethylamine hydrochloride time, also obtain the diastereomer acid of described 2 hydroxy propanoic acid.
The method of above-mentioned recovery is all known in the art.Such as, the diastereoisomeric salt of the 2 hydroxy propanoic acid obtained according to method for splitting of the present invention all can according to following operation steps obtain optical purity and related substance purity higher than 99% the diastereomer acid of 2 hydroxy propanoic acid of S-configuration:
The diastereoisomeric salt of 2 hydroxy propanoic acid the present invention obtained is added in suitable quantity of water, concentrated hydrochloric acid is instilled wherein to system pH=1 ~ 2 under stirring, add extraction into ethyl acetate 3 times, merge organic phase, anhydrous sodium sulfate drying, filter, filtrate adds normal hexane, stirring and crystallizing, filters, and obtains the diastereomer acid of the 2 hydroxy propanoic acid of S-configuration.
In the above-mentioned methods, the method isolating the diastereoisomeric salt of 2 hydroxy propanoic acid is known in this area, such as can adopt and stir and be cooled to 10 ~ 30 DEG C with the speed of 10 DEG C/h, then suction filtration is carried out to the white solid of separating out, by filter cake vacuum drying at 40 DEG C, namely obtain the diastereoisomeric salt of 2 hydroxy propanoic acid.
In the present invention, after resolution reaction, the crystallization of precipitation is a kind of enantiomorph salt, splits in mother liquor and can isolate another kind of enantiomer.
In the present invention, remaining solution after described fractionation mother liquor refers to the diastereoisomeric salt obtaining described 2 hydroxy propanoic acid; Described one pot reaction refers to responded raw material, solvent etc. to add in reactor simultaneously and reacts together, does not need proceed step by step can obtain the reaction of target product.
The present inventor is by being surprised to find that after great many of experiments, method for splitting of the present invention can realize one pot reaction, by reagent and 2 hydroxy propanoic acid raceme, (S)-1-(4-nitrophenyl) ethylamine hydrochloride, small molecules organic bases adds reactor simultaneously and carries out resolution reaction, and do not need first to (S)-1-(4-nitrophenyl) ethylamine hydrochloride dissociates, (the S)-1-(4-nitrophenyl will obtained after free again) ethamine and 2 hydroxy propanoic acid raceme join in reactor and carry out resolution reaction, overcoming directly using (S)-1-(4-nitrophenyl) ethamine is as the defect existed during resolving agent.Simultaneously, by adopting small molecules organic bases, achieve unexpectedly as the mineral alkalis such as sodium hydroxide, salt of wormwood, sodium methylate and alkanol salts substances carry out one pot reaction the fractionation effect that is beyond one's reach, overcome these mineral alkalis and alkanol salts substances and organic solvent as free (S)-1-(4-nitrophenyl in water such as ethyl acetate, methylene dichloride) ethylamine hydrochloride time the defect such as the extraction difficulty that exists and complicated operation.
The present invention is not by 2 hydroxy propanoic acid raceme and (the S)-1-(4-nitrophenyl as resolving agent) restriction in ethylamine hydrochloride source, these two kinds of materials or its preparation method are all well-known to those skilled in the art, such as J.Med.Chem.1999 can be adopted, 42, the method described in 3026 ~ 3032 prepares 2 hydroxy propanoic acid raceme, can adopt technical grade (the S)-1-(4-nitrophenyl purchased from Dalian Hong Kai company) ethylamine hydrochloride.
Compared with prior art, method for splitting of the present invention has but is not limited to following advantage:
1. the inventive method single solvent carries out resolution reaction, produces pure single configuration Lactic acid and is convenient to solvent recuperation, be beneficial to and reduce costs.
2.(S)-1-(4-nitrophenyl) ethylamine hydrochloride compares its free alkali and will stablize many, and be beneficial to transport and store.The present invention directly uses (S)-1-(4-nitrophenyl) ethylamine hydrochloride carries out one kettle way resolution reaction, overcome by first its free after carry out extraction difficulty, the complicated operation of resolution reaction existence again and be easy to the shortcoming such as oxidized, simple and efficient to handle, be applicable to the enforcement of suitability for industrialized production.
3.(S)-1-(4-nitrophenyl) ethylamine hydrochloride ratio (S)-1-(4-chloro-phenyl-) ethamine low price, be easy to buying.
4. after resolution reaction of the present invention terminates, resolving agent (S)-1-(4-nitrophenyl) ethamine can become hydrochloride form to reclaim, and the resolving agent quality of recovery is good, can repeatedly reuse, and the effect again split is still fine.Therefore, resolving agent of the present invention can unlimitedly reuse, and saves cost, is specially adapted to large-scale industrial production.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, the embodiment provided only in order to illustrate the present invention, instead of in order to limit the scope of the invention.
embodiment 1
By 370 grams of (S)-1-(4-nitrophenyls) ethylamine hydrochloride joins in 8 liters of dehydrated alcohols, 280 grams of triethylamines and 1 kilogram of 2-hydroxy-3-methoxy-3,3-diphenyl-propionic acid is added in above-mentioned solution respectively, stirring heating is clearly molten, stir and 10 DEG C/h be cooled to 20 ~ 30 DEG C, namely separate out a large amount of white solid.Suction filtration, namely filter cake 40 DEG C of vacuum dryings obtain the diastereoisomeric salt of S-configuration.
Productive rate: 39.2% (based on raceme)
Chirality HPLC >=99%
embodiment 2
By 3.3 kilograms of (S)-1-(4-nitrophenyls) ethylamine hydrochloride joins in 90 liters of dehydrated alcohols, 3.3 kilograms of triethylamines and 5 kilograms of 2-hydroxyl-3-oxyethyl groups-3,3-diphenyl-propionic acid is added in above-mentioned solution respectively, stirring heating is clearly molten, continue to stir, 10 DEG C/h are cooled to 20 ~ 30 DEG C, namely separate out a large amount of white solid.Rejection filter, namely filter cake 40 DEG C of vacuum dryings obtain the diastereoisomeric salt of S-configuration.
Productive rate: 39.7% (based on raceme)
Chirality HPLC >=99%
embodiment 3
By 10.4 kilograms of (S)-1-(4-nitrophenyls) ethylamine hydrochloride joins in 320 liters of dehydrated alcohols, 8.9 kilograms of diisopropylethylamine and 20 kilograms of 2-hydroxy-3-methyls-3,3-diphenyl-propionic acid is added in above-mentioned solution respectively, stirring heating is clearly molten, continues to stir, and 10 DEG C/h are cooled to 50 DEG C, add 10 grams of (s)-2-hydroxy-3-methoxies-3, the crystal seed of 3-diphenylprop hydrochlorate, 10 DEG C/h are continued stirring and are cooled to 10 ~ 20 DEG C, namely separate out a large amount of white solid.Rejection filter, namely filter cake 40 DEG C of vacuum dryings obtain the diastereoisomeric salt of S-configuration.
Productive rate: 41.1% (based on raceme)
Chirality HPLC >=99%
embodiment 4
By 22 kilograms of (S)-1-(4-nitrophenyls) ethylamine hydrochloride joins in 600 liters of dehydrated alcohols, 16 kilograms of triethylamines and 40 kilograms of 2-hydroxy-3-methoxies-3,3-diphenyl-propionic acid is added in above-mentioned solution respectively, stirring heating is clearly molten, continues to stir, and 10 DEG C/h are cooled to 30 DEG C, add 20 grams of (s)-2-hydroxy-3-methoxies-3, the crystal seed of 3-diphenylprop hydrochlorate, 10 DEG C/h are continued stirring and are cooled to 10 ~ 20 DEG C, namely separate out a large amount of white solid.Rejection filter, namely filter cake 40 DEG C of vacuum dryings obtain the diastereoisomeric salt of S-configuration.
Productive rate: 40.6% (based on raceme)
Chirality HPLC >=99%
embodiment 5
Fractionation mother liquor underpressure distillation remaining after embodiment 1 is obtained the diastereoisomeric salt of S-configuration is separated out to solid, is down to stirring at room temperature 2 hours, rejection filter, filter cake warp
1hNMR is detected as 2-hydroxy-3-methoxy-3,3-diphenyl-propionic acid-(S)-1-(4-nitrophenyl) ethylamine salt; Above-mentioned solid is added in 4 premium on currency, stir lower inwardly instillation concentrated hydrochloric acid to system pH=1 ~ 2, add extraction into ethyl acetate 3 times, aqueous phase is transferred in reactor, stir lower hydro-oxidation sodium saturated solution to alkalescence, tert.-butyl acetate extracts 10 times, merges organic phase, anhydrous sodium sulfate drying, suction filtration is except siccative, filtrate passes into hydrogen chloride gas to system in acid under stirring, suction filtration, obtains (S)-1-(4-nitrophenyl after filtration cakes torrefaction) ethylamine hydrochloride.
Productive rate: 85.3%
HPLC:99.8%
embodiment 6
Embodiment 1 is obtained diastereoisomeric salt (S)-2-hydroxy-3-methoxy-3,3-diphenyl-propionic acid-(S)-1-(4-nitrophenyl) ethylamine salt is added in 4 premium on currency, stir lower inwardly instillation concentrated hydrochloric acid to system pH=1 ~ 2, add extraction into ethyl acetate 3 times, be separated organic phase and aqueous phase.
Aqueous phase is transferred in reactor, stir lower hydro-oxidation sodium saturated solution to alkalescence, tert.-butyl acetate extracts 10 times, merge organic phase, anhydrous sodium sulfate drying, suction filtration is except siccative, and filtrate passes into hydrogen chloride gas to system in acid under stirring, suction filtration, obtains (S)-1-(4-nitrophenyl after filtration cakes torrefaction) ethylamine hydrochloride.
Productive rate: 96.3%
HPLC:99.8%
In organic phase, add anhydrous sodium sulfate drying, filter, filtrate adds normal hexane, stirring and crystallizing, filters, obtains (s) 2-hydroxy-3-methoxy-3,3-diphenyl-propionic acid.
Productive rate: 95%
HPLC：99.7%
Chirality HPLC:99.9%
embodiment 7
(S)-1-(4-nitrophenyl by 35 grams of methods by embodiment 5 or 6 reclaim) ethylamine hydrochloride joins in 1.2 liters of dehydrated alcohols, 28 grams of triethylamines and 100 grams of 2-hydroxy-3-methoxies-3,3-diphenyl-propionic acid is added in above-mentioned solution respectively, stirring heating is clearly molten, stir and 10 DEG C/h be cooled to 20 ~ 30 DEG C, namely separate out a large amount of white solid.Suction filtration, namely filter cake 40 DEG C of vacuum dryings obtain the diastereoisomeric salt of S-configuration.
Productive rate: 42.2% (based on raceme)
Chirality HPLC >=99%
, resolving agent (S)-1-(4-nitrophenyl known by the experimental result of embodiment 5 to 7) ethamine can reclaim with the form of hydrochloride, and the resolving agent quality of recovery is good, can unlimitedly reuse, and the effect again split is still fine.Be to be understood that; the recovery method of embodiment 5 and 6 is not limited in the diastereoisomeric salt and remaining fractionation mother liquor that obtain in embodiment 1; the diastereoisomeric salt that every method for splitting implemented in scope obtains with fractionation mother liquor the method identical or close with embodiment 5 and/or 6 all can be adopted to reclaim with the form of hydrochloride resolving agent, and the fractionation effect again had with can unlimitedly reuse.
comparative example 1
By 3.7 grams of (S)-1-(4-nitrophenyls) ethylamine hydrochloride joins in 150 milliliters of dehydrated alcohols, 1.1 grams of sodium hydroxide and 10 grams of 2-hydroxy-3-methoxies-3,3-diphenyl-propionic acid is added in above-mentioned solution respectively, stirring heating is clearly molten, stir and 10 DEG C/h be cooled to 30 ~ 40 DEG C, namely separate out a large amount of white solid.Suction filtration, namely filter cake 40 DEG C of vacuum dryings obtain the diastereoisomeric salt of S-configuration.
Chirality HPLC:66.5%
comparative example 2
By 3.7 grams of (S)-1-(4-nitrophenyls) ethylamine hydrochloride joins in 150 milliliters of dehydrated alcohols, 1.5 grams of sodium methylates and 10 grams of 2-hydroxy-3-methoxies-3,3-diphenyl-propionic acid is added in above-mentioned solution respectively, stirring heating is clearly molten, stir and 10 DEG C/h be cooled to 30 ~ 40 DEG C, namely separate out a large amount of white solid.Suction filtration, namely filter cake 40 DEG C of vacuum dryings obtain the diastereoisomeric salt of S-configuration.
Chirality HPLC:69.3%
comparative example 3
By 3.7 grams of (S)-1-(4-nitrophenyls) ethylamine hydrochloride joins in 150 milliliters of dehydrated alcohols, 3.8 grams of salt of wormwood and 10 grams of 2-hydroxy-3-methoxies-3,3-diphenyl-propionic acid is added in above-mentioned solution respectively, stirring heating is clearly molten, stir and 10 DEG C/h be cooled to 30 ~ 40 DEG C, namely separate out a large amount of white solid.Suction filtration, namely filter cake 40 DEG C of vacuum dryings obtain the diastereoisomeric salt of S-configuration.
Chirality HPLC:62.8%
Known by the experimental result of comparative example 1 to 3, mineral alkali is as sodium hydroxide, salt of wormwood, sodium methylate etc., respectively with 2 hydroxy propanoic acid raceme and (S)-1-(4-nitrophenyl) ethylamine hydrochloride carries out one kettle way resolution reaction in organic solvent, found that the diastereomer optical purity of precipitation is less than 70%, separate out in organic solvent after inferring mineral alkali and hydrochloric acid salify, the optical active alkali accelerating 2 hydroxy propanoic acid becomes to salt out, and impact splits effect.
comparative example 4
10 grams of (S)-1-(4-nitrophenyls) ethylamine hydrochloride is added in 30 premium on currency, stir lower hydro-oxidation sodium saturated solution to alkalescence, ethyl acetate is (if with dichloromethane extraction, layering is not obvious) extract 10 times, TLC detects aqueous phase product-free, merges organic phase, anhydrous sodium sulfate drying, suction filtration is except siccative, and filtrate is revolved steaming and desolventized, and obtains (the S)-1-(4-nitrophenyl dissociated) ethamine.
Known by the experimental result of comparative example 4, when with mineral alkali free (S)-1-(4-nitrophenyl in organic solvent is as ethyl acetate and water) ethylamine hydrochloride time, find extraction (S)-1-(4-nitrophenyl) ethamine difficulty, its solvability in water is fine, need with a large amount of solvent extractions, could extract for more than 10 times completely, operate very complicated.
Although present invention has been detailed description; but should be appreciated that foregoing description and be not used to limit the present invention, without departing from the spirit and scope of the present invention; any amendment of doing, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (10)
1. one kind splits the method for 2 hydroxy propanoic acid raceme, the method comprises 2 hydroxy propanoic acid raceme and (S)-1-(4-nitrophenyl) ethylamine hydrochloride and small molecules organic bases carry out one pot reaction in a solvent, then isolates the diastereoisomeric salt of 2 hydroxy propanoic acid.
2. method according to claim 1, is characterized in that, described 2 hydroxy propanoic acid raceme, (S)-1-(4-nitrophenyl) mol ratio of ethylamine hydrochloride and small molecules organic bases is 1:0.5 ~ 0.9:0.75 ~ 1.8.
3. method according to claim 1 and 2, is characterized in that, 3 carbon atoms of described 2 hydroxy propanoic acid raceme have monosubstituted or polysubstituted group; Preferably, 3 carbon atoms of described 2 hydroxy propanoic acid raceme have 1 to 2 aryl and 1 alkoxyl group or alkyl; More preferably, described aryl is phenyl; Further preferably, described alkoxyl group is methoxy or ethoxy; Most preferably, described alkyl is methyl.
4. method according to claim 3, it is characterized in that, described 2 hydroxy propanoic acid raceme is 2-hydroxy-3-methoxy-3,3-diphenyl-propionic acid raceme, 2-hydroxyl-3-oxyethyl group-3,3-diphenyl-propionic acid raceme or 2-hydroxy-3-methyl-3,3-diphenyl-propionic acid raceme.
5. method according to any one of claim 1 to 4, is characterized in that, described small molecules organic bases is triethylamine or diisopropylethylamine.
6. method according to any one of claim 1 to 5, is characterized in that, described solvent is absolute alcohol solvent.
7. method according to claim 6, is characterized in that, described absolute alcohol solvent is methyl alcohol, ethanol, Virahol or propyl alcohol, is preferably ethanol.
8. method according to any one of claim 1 to 7, is characterized in that, described method also comprises and being added in resolution reaction solution by the crystal seed of diastereoisomeric salt to be separated.
9. method according to claim 8, is characterized in that, described crystal seed adds when resolution reaction solution is cooled to 30 ~ 50 DEG C.
10. method according to any one of claim 1 to 9, is characterized in that, described method also comprises: reclaim (S)-1-(4-nitrophenyl) ethylamine hydrochloride.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109206617A (en) * | 2017-07-05 | 2019-01-15 | 北京大学 | A kind of new method by fractional crystallization resolution of racemic compound |
| CN109232237A (en) * | 2018-09-12 | 2019-01-18 | 通化师范学院 | The synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate |
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| US3902915A (en) * | 1972-06-30 | 1975-09-02 | Ppg Industries Inc | Dispersible silica pigment |
| US3965129A (en) * | 1973-10-10 | 1976-06-22 | Hoffmann-La Roche Inc. | Optical resolution of organic carboxylic acids |
| CN1160396A (en) * | 1994-10-14 | 1997-09-24 | 巴斯福股份公司 | Carboxylic acid derivs., their preparation and their use |
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2013
- 2013-12-26 CN CN201310738132.XA patent/CN104744231A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3902915A (en) * | 1972-06-30 | 1975-09-02 | Ppg Industries Inc | Dispersible silica pigment |
| US3965129A (en) * | 1973-10-10 | 1976-06-22 | Hoffmann-La Roche Inc. | Optical resolution of organic carboxylic acids |
| CN1160396A (en) * | 1994-10-14 | 1997-09-24 | 巴斯福股份公司 | Carboxylic acid derivs., their preparation and their use |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109206617A (en) * | 2017-07-05 | 2019-01-15 | 北京大学 | A kind of new method by fractional crystallization resolution of racemic compound |
| CN109206617B (en) * | 2017-07-05 | 2020-04-24 | 北京大学 | Method for resolving racemic compound by fractional crystallization |
| CN109232237A (en) * | 2018-09-12 | 2019-01-18 | 通化师范学院 | The synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate |
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Application publication date: 20150701 |