CN100546969C - Split the method for 2-methylol-3-phenylpropionic acid optical isomer - Google Patents
Split the method for 2-methylol-3-phenylpropionic acid optical isomer Download PDFInfo
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- CN100546969C CN100546969C CNB2005100297377A CN200510029737A CN100546969C CN 100546969 C CN100546969 C CN 100546969C CN B2005100297377 A CNB2005100297377 A CN B2005100297377A CN 200510029737 A CN200510029737 A CN 200510029737A CN 100546969 C CN100546969 C CN 100546969C
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Abstract
The invention provides the method for a kind of 2-of fractionation methylol-3-phenylpropionic acid optical isomer, by using N-Octylglucamine in certain solvent, to form two diastereomers as the 2-methylol-3-phenylpropionic acid of resolving agent and racemization, separate the diastereomer that obtains less solubleness, obtain by recrystallization, acid or alkali are free again; Used resolution solvent is the mixing solutions of methyl alcohol, ethanol, Virahol, acetone, butanone etc. or itself and water.High and the resolving agent that adopted of the fractionation efficient of the inventive method obtains easily, and is cheap and be easy to reclaim, and is fit to suitability for industrialized production.
Description
Technical field
The present invention relates to split in the chemical field method of optical isomer, be specifically related to split racemization 2-methylol-3-phenylpropionic acid and obtain the method for its optical isomer.
Background technology
As shown in the formula (the R)-2-methylol-3-phenylpropionic acid shown in (1) is renin inhibitor (Chem.Lett, 505-508,1990) and antiviral (J.O.C, 66,3474-52,2001) important intermediate also is synthetic important source material with antihypertensive drug Sinorphan (ecadotril) of ACE/NEP double inhibition effect.
For synthesizing of compound (1), document EP 906900 reports split 2-methylol-3-phenylpropionic acid 2 by Chiral Amine and prepare, and used resolving agent and split result thereof are as shown in table 1:
The split result to racemization 2-methylol-3-phenylpropionic acid of table 1 bibliographical information
In the existing as can be seen reported method, best resolution reagent is cis-1-amino-2-indanol, but this resolving agent raw material itself is not easy to obtain, and costs an arm and a leg; 3-methyl-2-phenyl-1-butylamine is also very expensive, industrialization cost height; Then have the shortcoming that fractionation efficient is low and recycling bothers concurrently with the α-Ben Yian fractionation.
Summary of the invention
The object of the present invention is to provide a kind of 2-methylol-3-phenylpropionic acid that splits racemization to obtain the method for optically active (R)-2-methylol-3-phenylpropionic acid, it splits the efficient height and used resolving agent cheaply is easy to get.
The invention provides the method for a kind of 2-of fractionation methylol-3-phenylpropionic acid, 2-methylol-3-the phenylpropionic acid that is used for splitting racemization obtains optically active (R)-2-methylol-3-phenylpropionic acid, it is characterized in that may further comprise the steps: a, racemization 2-methylol-3-phenylpropionic acid and N-Octylglucamine form two diastereomers in certain solvent; B, separation obtain the diastereomer of less solubleness; C, by the free 2-methylol-3-phenylpropionic acid that obtains (R) configuration of recrystallization, acid or alkali.
According to the present invention, adopt N-Octylglucamine to obtain optically active (R)-2-methylol-3-phenylpropionic acid by the 2-methylol-3-phenylpropionic acid that splits racemization as resolution reagent, its structural formula is as the formula (1).
Wherein the ratio of N-Octylglucamine and racemization 2-methylol-3-phenylpropionic acid can be 0.5～1.5: 1 (mol ratio), but normally waits quantitative response.
Method for splitting of the present invention does not have special restriction to used solvent, can be neutral solvent such as water, alcohols (as ethanol, methyl alcohol, Virahol), ester class (as ethyl acetate), ketone (as acetone, butanone, methyl ethyl ketone) nitrile (as acetonitrile), aromatic hydrocarbon (as toluene, dimethylbenzene) or ethers (as tetrahydrofuran (THF), methyl tertiary butyl ether).Described solvent is preferably from the mixing solutions of methyl alcohol, ethanol, Virahol, acetone, butanone or itself and water.Methyl alcohol in these solvents, second alcohol and water are best, they both can single use also can the two or three mixing solutions use.
The mixture of the normally every gram of the volume of solvent for use 2-methylol-3-phenylpropionic acid and N-Octylglucamine needs 3～50ml solvent.
For the less salt of solubleness in the feasible diastereomer that forms is separated out from solvent, 2-methylol-3-phenylpropionic acid (2) and N-Octylglucamine can be dissolved in rarer solvent reconcentration to separating out crystallization, perhaps the two is dissolved in the solvent crystallisation by cooling again under heating condition, makes and salt out thereby also can in above-mentioned solution, add the solvent that can reduce solubleness.
The salt of separating out adopts the solid-liquid isolation technique such as suction filtration and centrifugal obtaining with certain solvent recrystallization.
Salt behind the recrystallization dissociates with acid or alkali and obtains optically active 2-methylol-3-phenylpropionic acid and corresponding N-Octylglucamine.Free with the acidic aqueous solution example hydrochloric acid aqueous solution particularly, obtain optically active 2-methylol-3-phenylpropionic acid with organic solvent such as ethyl acetate, dichloromethane extraction again.Obtain separating by recrystallization after the water that contains N-Octylglucamine adds alkali such as sodium hydroxide, perhaps use organic solvent such as ethyl acetate, dichloromethane extraction and then recycling.
The result who obtains is as shown in the table:
Table 2 N-Octylglucamine is to the fractionation effect of (2)
| N-Octylglucamine consumption (eq) | Solvent | Salify yield (%) | Fusing point (℃) | [α] D 20 (c＝1，CHCl 3 ) | Primary crystallization optical purity (%) | Secondary crystal optical purity (%) |
| 1 | Ethanol | 115.3 | +2.8 | 20.4 | ||
| 1 | Methyl alcohol | 76.2 | 122 | +13.1 | 94.2 | ＞99 |
| 0.6 | Methyl alcohol | 120 | +12.9 | 92.8 | 96.4 |
The invention has the advantages that splitting with N-Octylglucamine has good fractionation efficient, than with prior art in cheap phenylethylamine make the fractionation efficient height of resolving agent; And it is suitable with expensive cis-1-amino-2-indanol with 3-methyl-2-phenyl-1-butylamine fractionation effect.Contrast table 1 and table 2 can be found out this point at an easy rate.
The present invention be advantageous in that the resolution reagent that is adopted is cheap, be easy to reclaim, be fit to very much suitability for industrialized production.
Embodiment
The present invention is further elaborated below in conjunction with embodiment, but these embodiment do not constitute any restriction to the present invention.
Fusing point is measured with capillary tube technique, and thermometer is not proofreaied and correct; Varian Inova type nuclear magnetic resonance analyser (interior mark TMS, solvent C DCl3); Finnign-MAT212 type mass spectrograph; Polarimeter341 type polarimeter.
Embodiment one:
10.0g (55.6mmol) 2-methylol-3-phenylpropionic acid, 16.3g N-Octylglucamine add in the 250ml single port bottle, add 120ml ethanol, reflux and naturally cool to room temperature after 10 minutes, leave standstill 2 days, filter solid 10.0g.Use the 100ml ethyl alcohol recrystallization again 1 time, get solid 9.4g.
Solid adds in the 50ml water, stirs down and regulates pH9 with the 10%NaOH aqueous solution, filters, and filtrate is regulated pH2 with 10% dilute hydrochloric acid again, uses the 80ml ethyl acetate extraction, and organic phase is dry to be concentrated.Add the crystallization of 100ml petroleum ether and stirring and get white solid 3.6g (yield 36%, mp 68-69 ℃).
1HNMR(CDCl
3)：7.19-7.31(5H，m)，5.91(1H，br)，3.71-3.81(2H，m)，2.92-3.12(1H，m)，2.84-2.92(2H，m)
[α]
D 20＝+13.1°(c＝1，CHCl
3)
Embodiment two:
18g (100mmol) 2-methylol-3-phenylpropionic acid, 29.3g (100mmol) N-Octylglucamine are added in the 100ml single port bottle, add 150ml Virahol and 10nl water, stir down in 80 ℃ and to naturally cool to room temperature in 10 minutes, left standstill 24 hours, filter solid 21.7g.Use the 30ml ethyl alcohol recrystallization again 2 times, get solid 19.8g.
Solid adds 50ml water, stirs down and regulates pH to 2 with 10% dilute hydrochloric acid, and filtration drying gets white solid 7.2g (yield 40.3%)
Embodiment three:
13.6g (75.6mmol) 2-methylol-3-phenylpropionic acid, 13.3g (45.4mmol) N-Octylglucamine are added in the 100ml single port bottle, add 50ml methyl alcohol, reflux and naturally cool to room temperature after 10 minutes, left standstill 2 days, filter solid 15.6g.Use the 30ml ethyl alcohol recrystallization again 2 times, get solid 14.2g.Solid adds 50ml water, stirs down and regulates pH to 2 with 10% dilute hydrochloric acid, uses the 80ml ethyl acetate extraction, and anhydrous sodium sulfate drying concentrates.With the crystallization of 100ml petroleum ether and stirring, get white solid 5.4g (yield 39.8%)
More than show and described ultimate principle of the present invention and principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; that describes in the foregoing description and the specification sheets just illustrates principle of the present invention; the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (7)
1. method that splits 2-methylol-3-phenylpropionic acid, the 2-methylol-3-phenylpropionic acid that is used for splitting racemization obtains optically active (R)-2-methylol-3-phenylpropionic acid, shown in (1):
It is characterized in that may further comprise the steps:
A, racemization 2-methylol-3-phenylpropionic acid and N-Octylglucamine form two diastereomers in solvent, described solvent is selected from: water, ethanol, methyl alcohol, Virahol, ethyl acetate, acetone, butanone, methyl ethyl ketone, acetonitrile, toluene, dimethylbenzene, tetrahydrofuran (THF) or methyl tertiary butyl ether;
B, separation obtain the diastereomer of less solubleness;
C, by recrystallization and acid or the free 2-methylol-3-phenylpropionic acid that obtains (R) configuration of alkali.
2, the method for claim 1, wherein the volume of step a solvent for use is mixture needs 3～50ml solvent of every gram 2-methylol-3-phenylpropionic acid and N-Octylglucamine.
3, the method for claim 1, wherein the method that the less salt of solubleness is separated out from solvent in the feasible diastereomer that forms of step b is, 2-methylol-3-phenylpropionic acid and N-Octylglucamine are dissolved in rarer solvent reconcentration to separating out crystallization, perhaps the two is dissolved in the solvent crystallisation by cooling again under heating condition, makes and salt out thereby perhaps in above-mentioned solution, add the solvent that can reduce solubleness.
4, the method for claim 1, wherein step c to resulting salt with acid or alkali free method is, and is free with acidic aqueous solution earlier, obtains optically active 2-methylol-3-phenylpropionic acid with organic solvent extraction again; After adding alkali, the water that contains N-Octylglucamine obtains separating by filtration and recrystallization.
5, method as claimed in claim 4, wherein said acidic aqueous solution are aqueous hydrochloric acid.
6, method as claimed in claim 4, wherein said organic solvent are ethyl acetate, methylene dichloride.
7, method as claimed in claim 4, wherein said alkali are sodium hydroxide.
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| CN106349144B (en) * | 2016-08-30 | 2019-05-24 | 山东默得森生物制药有限公司 | A kind of preparation method of (S)-oxiracetam intermediate |
| CN109232220B (en) * | 2017-09-15 | 2021-09-10 | 上海健康医学院 | Chemical resolution method of 3-hydroxy-3-phenylpropionic acid compound |
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Non-Patent Citations (3)
| Title |
|---|
| 2-芳基丙酸类药物的拆分研究进展. 微生物学通报，第(22)卷第2期. 1995 |
| 徐诗伟等 |
| 徐诗伟等；2-芳基丙酸类药物的拆分研究进展. 微生物学通报，第(22)卷第2期. 1995 * |
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