CN103086877B - A kind of method for splitting of 2 hydracrylic acid class racemoid - Google Patents
A kind of method for splitting of 2 hydracrylic acid class racemoid Download PDFInfo
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- CN103086877B CN103086877B CN201210595382.8A CN201210595382A CN103086877B CN 103086877 B CN103086877 B CN 103086877B CN 201210595382 A CN201210595382 A CN 201210595382A CN 103086877 B CN103086877 B CN 103086877B
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Abstract
It is used for the method for splitting of 2 hydracrylic acid class racemoids the present invention relates to a kind of, this method reacts 2 hydracrylic acid class racemoids and L prolineamides optical active alkali, and 2 hydracrylic acid class compound individual isomer L prolyl amine salt are subsequently isolated.2 hydracrylic acid class compound individual isomers can be used to treat cardiovascular disease medicine important intermediate as synthesis endothelin-receptor antagonists, therefore a kind of method for splitting easy to operate that this method is provided, the isolated high individual isomer of optical purity, and required raw material and reagent are cheap, suitable industrial production, there is good economic benefits.
Description
Technical field
The present invention relates to a kind of method for splitting of 2 hydroxy propanoic acid class racemoid
Technical background
2 hydroxy propanoic acid class compound individual isomer is the important intermediate for synthesizing plant protection product and medicine, therefore,
Using synthetic method, so that racemic intermediate is through splitting separation, to prepare high-optical-purity 2 hydroxy propanoic acid class compound single different
Structure body tool is of great significance.
WO1996011914 is described in 2 heterocyclically substituted group propionic acid compounds as treating angiocardiopathy
Effective endothelin-receptor antagonists, wherein 2 hydroxy propanoic acid class compound individual isomer synthesizes this as important intermediate
A little active materials.The disclosure of the invention laboratory scale is using L-PROLINE methyl esters and (S) -1- (4- nitrobenzophenones) ethamine by disappearing
The fractionation of rotation thing prepares (S) -2- hydroxy-3-methoxy -3,3- diphenyl-propionic acids, and yield is 35% (being based on racemoid), purity
99.8%.
Pointed out in prior art CN1129571C by the reactions steps described in WO1996011914 scale up to
During 100kg scales, in order to ensure high-optical-purity must use other operating procedure.(S) -2 hydroxy propanoic acid and L-PROLINE
The diastereoisomeric salt crystallization of methyl esters is difficult.So that the diastereoisomeric salt is difficult to separate out in the solution, only will be non-right in mother liquor
Reflect after the free crystallization of body salt, repeated recrystallize is carried out in toluene solvant, required optical purity can be just obtained.(S) -2- hydroxyls
The diastereoisomeric salt crystallization of base propionic acid and (S) -1- (4- nitrobenzophenones) ethamine is also more difficult, is difficult to filter out so that a part is female
Liquid is stayed in crystal together with the enantiomer to be separated opened.Only when crystal is further stirred in kettle together with the solvent newly added
When, and after the crystal filtered out again is repeatedly washed, can just obtain required optical purity, it turned out that WO1996011914
It is not enough that resolution process is implicitly present in the above.
WO2000026170 is described in pilot-scale using 1- (4- chlorphenyls) ethamine as optical active alkali by disappearing
Rotation thing fractionation prepares (S) -2- hydroxy-3-methoxies -3,3- diphenyl-propionic acid and (S) -2- hydroxy-3-methyl -3,3- diphenyl
Propionic acid.The yield obtained in the method is respectively 36.4%, and (being based on racemoid), optical purity 99.95% and 38% (are based on
Racemoid), purity 99.2%, ee=94%.
Use (S) -1- (4- chlorphenyls) ethamine of WO2000026170 descriptions is prepared as the method for optical active alkali
(S) the diastereomer optical purity obtained during -2- hydroxy-3-methyls -3,3- diphenyl-propionic acid only has 94%, it is necessary to will
Diastereoisomeric salt can just obtain the product of high-optical-purity by repeated recrystallize.Yield losses are very big, and operating process is multiple
It is miscellaneous.Optical active alkali (S) -1- (4- nitrobenzophenones) ethamine, 1- (4- chlorphenyls) ethamine market price are higher, are needed in preparation process
A large amount of crystal seeds are added, reclaim difficult, resolution process is complicated, operation inconvenience, industry's enlarging production is with high costs.
WO2011004402, which is also described, is respectively adopted (S) -1- (4- chlorphenyls) ethamine analog, (S) -2,4- dichloro-benzenes
2 hydroxy propanoic acid class is made as optical active alkali in ethamine, (R) -2,4- dichloro-phenylethylamines, (S) -3- methoxyphenethylamines respectively
Compound individual isomer, such resolving agent cost is high, without the market competitiveness.
In view of above prior art defect, the optical active alkali that the present invention is used is L- prolineamide, and market price is low, tears open
The optical purity of products got is high, and production cost is low, it is easy to implement in commercial scale.
The content of the invention
We are had found by studying, and can be realized by the method for being used for the fractionation of 2 hydroxy propanoic acid racemoid as described below
The object of the invention, this method reacts 2 hydroxy propanoic acid class racemoid and L- prolineamides optical active alkali, and 2- hydroxyls are subsequently isolated
There is provided a kind of new, method for splitting easy to operate, required raw material for base group propionic acid compounds individual isomer L- prolyls amine salt
And reagent is cheap, there is good economic benefits, suitable industrial production.
The synthesis of 2 hydroxy propanoic acid class racemoid is very familiar with for those skilled in the art, is such as described in
In CN1923820B, the present invention be applicable 3 be mono-substituted or polysubstituted Lactic acid preferably 3 bit strip phenyl 2-
The fractionation of the racemoid of hydracrylic acid, is particularly preferably defined as follows the fractionation of 2 hydroxy propanoic acid class racemoid.
It is as follows that reaction prepares formula：
Wherein R1And R2Respectively phenyl, can be replaced by one or more following substituents：Halogen (such as F, Cl, Br or
I), OH, NO2、CN、C1-C4Alkyl, C1-C4Haloalkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, phenoxy group, amino, C1-
C4Alkyl amino or C1-C4Dialkyl amido；R3 is that-COOH (or can be hydrolyzed into-COOH substituent such as CN, acid amides or ester group
Deng again through hydrolysis obtain)；The C that R4 is H, arbitrarily replaced1-C6Alkyl, the C arbitrarily replaced3-C6Alkenyl, the C arbitrarily replaced3-C6
Alkynyl or the C arbitrarily replaced3-C6Cycloalkyl；Z is oxygen or sulphur or a singly-bound.
The preferred embodiment of the inventive method is 2- hydroxy-3-methoxies -3,3- diphenyl-propionic acid, 2- hydroxyls -3-
The fractionation of the racemoid of methyl -3,3- diphenyl-propionic acid and 2,3- dihydroxy -3,3- diphenyl-propionic acid.
Implement the inventive method mode be usually：By the solution of racemic 2 hydroxy propanoic acid class compound and its 0.5~
The optical activity L- prolineamides mixing of 0.55 times of mole, is then demultiplex out one kind in the diastereoisomeric salt to be formed.
The preferred embodiment of the invention, the solution Slow cooling of diastereoisomeric salt is crystallized, and obtains optical purity higher
Product.If it is desired to obtain another diastereomer, it can be separated from the mother liquor of crystallization and filtration.
Racemoid separation preferred solvent of the present invention is alcohol or alcohol and ether or the mixture of alcohol and ester, the preferred C1-C3 of alcohol alcohol
(such as methanol, ethanol, isopropanol or propyl alcohol), ester may be selected from Ethyl formate, ethyl acetate, isopropyl acetate etc., and ether may be selected from first
The ether solvents such as base tertbutyl ether, tetrahydrofuran；It is ethanol, C that racemoid, which separates further preferred solvent,1-C3Alcohols solvent and
Mixed solvent, the C of methyl tertiary butyl ether(MTBE)1-C3Alcohols solvent and ethyl acetate mixed solvent；Particularly preferred ethanol or ethanol and
The mixed solvent of methyl tertiary butyl ether(MTBE) or ethanol and ethyl acetate.
The present invention also provides a kind of 2 hydroxy propanoic acid class compound individual isomer L- prolyl amine salt noval chemical compounds, preferably
Below general formula：
Wherein R1、R2And R4Substituent define to reaction above prepare each corresponding substituent in formula define it is identical.
Offer (S) -2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid L- prolyls amine salt specifically preferred according to the invention, (S) -
2- hydroxy-3-methyl -3,3- diphenyl-propionic acid L- prolyls amine salt and (S) -2,3- dihydroxy -3,3- diphenyl-propionic acid L- dried meat ammonia
Amidic-salt noval chemical compound, for preparing endothelin-receptor antagonists (such as BSF208075, darusentan) important intermediate.
The advantage of the invention is that can be pure compared with being produced under the conditions of ease of Use with higher yield in lower cost
The 2 hydroxy propanoic acid class compound of individual isomer, and commercial scale is being amplified to also without any problem.Therefore, save multiple
Miscellaneous operating process, the crystallisation step repeated, substantial amounts of crystal seed consumption, and also L- prolineamides are cheap in itself, so as to drop
Low energy consumption, production cost, considerably improve the operability in production.
Brief description of the drawings
Fig. 1 is the NMR spectra of (S) -2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid L- prolyl amine salt
Embodiment
The following examples describe laboratory and plant-scale the inventive method, and embodiment illustrates the present invention,
But not limit the present invention.
Embodiment 1
(S) -2,3- dihydroxy -3,3- diphenyl-propionic acids are prepared by racemoid fractionation
150g ethanol, 75g ethyl acetate, 20g (77.2mmol) 2,3- dihydroxy -3,3- diphenyl are put into reaction bulb
Propionic acid and 4.8g (42.5mmol) L- prolineamides, are warming up to 56 DEG C, insulated and stirred will after 30 minutes under stirring by the reaction solution
Reaction solution slow cooling is to 0~5 DEG C, and filtering obtains (S) -2,3- dihydroxy -3,3- diphenyl-propionic acid L- prolyl amine salt..
100g ethyl acetate and 100g water are added in filter cake, stirring adjusts solution PH=2~3, and regulation is finished, point liquid, water
Layer is extracted once with 50g ethyl acetate.Merge organic layer, add 50g water washings once, point liquid.Organic layer is concentrated under reduced pressure out
140g ethyl acetate, concentration is finished, by solution slow cooling to 0~5 DEG C.Filtering, filter cake is placed in 40C in vacuum drying oven and dried.
7.1 (S) -2,3- dihydroxy -3,3- diphenyl-propionic acids are obtained, yield 35.5% (is based on racemoid).
HPLC：99.8%
Chiral HPLC：99.5%
Embodiment 2
(S) -2- hydroxy-3-methyl -3,3- diphenyl-propionic acids are prepared by racemoid fractionation
Input 250g methanol and 120g methyl tertiary butyl ether(MTBE)s into reaction bulb, 20g (75.7mmol) 2- hydroxy-3-methyls-
3,3- diphenyl-propionic acids and 4.5g (39.4mmol) L- prolineamides, are warming up to 80.5 DEG C, insulation is stirred under stirring by the reaction solution
Mix reaction solution slow cooling after 30 minutes to 0~5 DEG C, filter, obtain (S) -2- hydroxy-3-methyl -3,3- diphenyl-propionic acids L-
Prolyl amine salt.
100g ethyl acetate and 50g water are added in filter cake, stirring adjusts solution PH=2~3, and regulation is finished, point liquid, water
Layer is extracted once with 50g ethyl acetate.Merge organic layer, add 50g water washings once, point liquid.Organic layer is concentrated under reduced pressure out
140g ethyl acetate, concentration is finished, by solution slow cooling to 0~5 DEG C.Filtering, filter cake is placed in 40 DEG C of drying in vacuum drying oven.
8.4g (S) -2- hydroxy-3-methyl -3,3- diphenyl-propionic acids are obtained, yield 42.0% (is based on racemoid).
HPLC：99.9%
Chiral HPLC：98.3%
Embodiment 3
(S) -2- hydroxy-3-methoxy -3,3- diphenyl-propionic acids are prepared by racemoid fractionation
200g isopropanols are pumped into reactor, then by methoxyl group -3, the 3- diphenyl of 10kg (36.5mmol) 2- hydroxyls -3
In propionic acid and 2.3g (20mmol) L- prolineamides input kettle, the reaction solution is warming up to 75 DEG C, 30 points of insulated and stirred under stirring
By reaction solution slow cooling to 25 DEG C after clock, filtering obtains (S) -2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid L- prolyls
Amine salt.
50g ethyl acetate and 20g water are added in filter cake, stirring adjusts solution PH=2~3, and regulation is finished, point liquid, water layer
Extracted once with 25g ethyl acetate.Merge organic layer, add 10g water washings once, point liquid.Organic layer is concentrated under reduced pressure out 70g second
Acetoacetic ester, concentration is finished, by solution slow cooling to 0~5 DEG C.Rejection filter, filter cake is placed in 40 DEG C of drying in vacuum drying oven.Obtain
Methoxyl group -3, the 3- diphenyl-propionic acid of 3.6g (S) -2- hydroxyls -3, yield 36% (is based on racemoid).
HPLC：99.8%
Chiral HPLC：97.9%
Embodiment 4
(S) -2- hydroxy-3-methoxy -3,3- diphenyl-propionic acids are prepared by racemoid fractionation
800kg ethanol is pumped into reactor, then by methoxyl group -3, the 3- diphenylprop of 100kg (366mol) 2- hydroxyls -3
In acid and 21.7kg (190mol) L- prolineamides input kettle, the reaction solution is warming up to 75 DEG C, 30 points of insulated and stirred under stirring
By reaction solution slow cooling to 25 DEG C after clock.Magma is separated by centrifuge, filter cake is rinsed with 50kg ethanol, rejection filter to dry,
Obtain (S) -2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid L- prolyl amine salt.
100kg ethyl acetate and 100kg drinking water are added in filter cake, stirring adjusts solution PH=2~3, and regulation is finished,
Divide liquid, water layer is extracted once with 50kg ethyl acetate.Merge organic layer, add 50kg drinking water and washed once, point liquid.Organic layer
Be concentrated under reduced pressure out 120kg ethyl acetate, and concentration is finished, by solution slow cooling to 0~5 DEG C.Rejection filter, filter cake is placed in vacuum drying oven
In 40 DEG C drying.Methoxyl group -3, the 3- diphenyl-propionic acid of 35.8 (S) -2- hydroxyls -3 is obtained, yield 35.8% (is based on racemoid).
HPLC：99.9%
Chiral HPLC：99.9%
Claims (4)
1. a kind of method for splitting for 2 hydroxy propanoic acid class racemoid, it is characterised in that by 2 hydroxy propanoic acid class racemoid and L-
Prolineamide optical active alkali reacts, and 2 hydroxy propanoic acid class compound individual isomer L- prolyl amine salt are subsequently isolated；
Wherein described 2 hydroxy propanoic acid class racemoid be 2- hydroxy-3-methoxy -3,3- diphenyl-propionic acids, 2- hydroxy-3-methyls -
3,3- diphenyl-propionic acids or 2,3- dihydroxy -3,3- diphenyl-propionic acids；
The reaction is carried out in the mixed solution of alcohol or alcohol and ether or alcohol and ester；
The alcohol is selected from methanol, ethanol, isopropanol, propyl alcohol；
The ether is selected from methyl tertiary butyl ether(MTBE), tetrahydrofuran；
The ester is selected from ethyl acetate, Ethyl formate, isopropyl acetate.
2. according to the method described in claim 1, it is characterised in that the reaction in ethanol or ethanol and methyl tertiary butyl ether(MTBE) or
Ethanol is carried out with ethyl acetate in the mixed solvent.
3. according to the isolated 2 hydroxy propanoic acid class compound individual isomer L- prolineamide salt compounds of claim 1.
4. one kind obtains compound according to claim 3, it is characterised in that the 2 hydroxy propanoic acid class compound individual isomer
L- prolyls amine salt is (S) -2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid L- prolyls amine salt, (S) -2- hydroxyl -3- first
Base -3,3- diphenyl-propionic acids L- prolyls amine salt or (S) -2,3- dihydroxy -3,3- diphenyl-propionic acid L- prolyl amine salt.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1325375A (en) * | 1998-10-30 | 2001-12-05 | 巴斯福股份公司 | Method for racemate splitting of 2-hydroxypropionic acids |
| CN101180256A (en) * | 2005-05-24 | 2008-05-14 | 阿斯利康(瑞典)有限公司 | A process for the dynamic resolution of (substituted) (R) - or (S) -mandelic acid |
| CN102180823A (en) * | 2011-03-12 | 2011-09-14 | 浙江华海药业股份有限公司 | Method for refining prolinamide |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1325375A (en) * | 1998-10-30 | 2001-12-05 | 巴斯福股份公司 | Method for racemate splitting of 2-hydroxypropionic acids |
| CN101180256A (en) * | 2005-05-24 | 2008-05-14 | 阿斯利康(瑞典)有限公司 | A process for the dynamic resolution of (substituted) (R) - or (S) -mandelic acid |
| CN102180823A (en) * | 2011-03-12 | 2011-09-14 | 浙江华海药业股份有限公司 | Method for refining prolinamide |
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