CN103086877A - Splitting method of 2-hydracrylic acid racemic mixture - Google Patents
Splitting method of 2-hydracrylic acid racemic mixture Download PDFInfo
- Publication number
- CN103086877A CN103086877A CN 201210595382 CN201210595382A CN103086877A CN 103086877 A CN103086877 A CN 103086877A CN 201210595382 CN201210595382 CN 201210595382 CN 201210595382 A CN201210595382 A CN 201210595382A CN 103086877 A CN103086877 A CN 103086877A
- Authority
- CN
- China
- Prior art keywords
- hydroxy
- diphenyl
- propionic acid
- racemic mixture
- propanoic acid
- 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.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 30
- 238000000034 method Methods 0.000 title claims abstract description 27
- -1 2-hydroxyl acrylic acid compound Chemical class 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 230000003287 optical effect Effects 0.000 claims abstract description 16
- VLJNHYLEOZPXFW-BYPYZUCNSA-N L-prolinamide Chemical compound NC(=O)[C@@H]1CCCN1 VLJNHYLEOZPXFW-BYPYZUCNSA-N 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- INQIVJHBJNZHFC-UHFFFAOYSA-N 2-hydroxy-3,3-diphenylbutanoic acid Chemical compound C=1C=CC=CC=1C(C(O)C(O)=O)(C)C1=CC=CC=C1 INQIVJHBJNZHFC-UHFFFAOYSA-N 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 2
- CGZUJOSEECYBRW-UHFFFAOYSA-N 2,3-dihydroxy-3,3-diphenylpropanoic acid Chemical compound C=1C=CC=CC=1C(O)(C(C(O)=O)O)C1=CC=CC=C1 CGZUJOSEECYBRW-UHFFFAOYSA-N 0.000 claims description 2
- RQJWOLFMWKZKCJ-UHFFFAOYSA-N 2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid Chemical group C=1C=CC=CC=1C(C(O)C(O)=O)(OC)C1=CC=CC=C1 RQJWOLFMWKZKCJ-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 239000005864 Sulphur Substances 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 229940118365 Endothelin receptor antagonist Drugs 0.000 abstract description 3
- 239000002308 endothelin receptor antagonist Substances 0.000 abstract description 3
- 208000024172 Cardiovascular disease Diseases 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract 1
- 230000003407 synthetizing effect Effects 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000012065 filter cake Substances 0.000 description 9
- 238000010583 slow cooling Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 4
- 238000003810 ethyl acetate extraction Methods 0.000 description 4
- 238000005194 fractionation Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- CGZUJOSEECYBRW-CYBMUJFWSA-N (2S)-2,3-dihydroxy-3,3-diphenylpropanoic acid Chemical compound O[C@H](C(=O)O)C(C1=CC=CC=C1)(C1=CC=CC=C1)O CGZUJOSEECYBRW-CYBMUJFWSA-N 0.000 description 2
- INQIVJHBJNZHFC-CQSZACIVSA-N (2s)-2-hydroxy-3,3-diphenylbutanoic acid Chemical compound C=1C=CC=CC=1C([C@H](O)C(O)=O)(C)C1=CC=CC=C1 INQIVJHBJNZHFC-CQSZACIVSA-N 0.000 description 2
- RQJWOLFMWKZKCJ-CQSZACIVSA-N (2s)-2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid Chemical compound C=1C=CC=CC=1C([C@H](O)C(O)=O)(OC)C1=CC=CC=C1 RQJWOLFMWKZKCJ-CQSZACIVSA-N 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- BLWYXBNNBYXPPL-YFKPBYRVSA-N methyl (2s)-pyrrolidine-2-carboxylate Chemical class COC(=O)[C@@H]1CCCN1 BLWYXBNNBYXPPL-YFKPBYRVSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000008399 tap water Substances 0.000 description 2
- 235000020679 tap water Nutrition 0.000 description 2
- 239000013543 active substance Substances 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- FEJVSJIALLTFRP-LJQANCHMSA-N darusentan Chemical compound COC1=CC(OC)=NC(O[C@H](C(O)=O)C(OC)(C=2C=CC=CC=2)C=2C=CC=CC=2)=N1 FEJVSJIALLTFRP-LJQANCHMSA-N 0.000 description 1
- 229950008833 darusentan Drugs 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 238000011020 pilot scale process Methods 0.000 description 1
- 239000004476 plant protection product Substances 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical class O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Images
Landscapes
- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a splitting method of 2-hydracrylic acid racemic mixture. The method comprises the following steps of: carrying out optical active alkali reaction on 2-hydracrylic acid racemic mixture and L-prolinamide, separating a single isomer L-prolinamide salt of 2-hydroxyl acrylic acid compound; and taking the single isomer of the 2-hydroxyl acrylic acid compound as important intermediate for synthetizing endothelin receptor antagonist for treating cardiovascular disease. Therefore, the single isomer with high optical purity is separated by the splitting method which is simple to operate and is provided by the invention; and the method is cheap in required material and reagent, and suitable for industrial production, and has good economic benefit.
Description
Technical field
The present invention relates to a kind of method for splitting of 2 hydroxy propanoic acid class racemic mixture
Technical background
2 hydroxy propanoic acid compounds individual isomer is the important intermediate of synthetic plant protection product and medicine; therefore, adopt synthetic method to make racemic intermediate be of great significance through splitting separation preparation high-optical-purity 2 hydroxy propanoic acid compounds individual isomer tool.
WO1996011914 has described the effective endothelin-receptor antagonists that is used for the treatment of cardiovascular disorder 2 heterocyclically substituted group propionic acid compounds conducts, and wherein 2 hydroxy propanoic acid compounds individual isomer is as synthetic these active substances of important intermediate.This disclosure of the invention laboratory scale adopts L-PROLINE methyl esters and (S)-1-(4-nitrophenyl) ethamine to pass through fractionation preparation (S)-2-hydroxy-3-methoxy-3 of racemic mixture, 3-diphenyl-propionic acid, productive rate are 35% (based on racemic mixture), purity 99.8%.
When pointing out in prior art CN1129571C that the reactions steps that will describe in WO1996011914 is amplified to the 100kg scale in proportion, must adopt other operation steps in order to ensure high-optical-purity.The diastereoisomeric salt crystallization difficulty of (S)-2 hydroxy propanoic acid and L-PROLINE methyl esters.Make this diastereoisomeric salt be difficult to separate out in solution, only have after the free crystallization of the diastereoisomeric salt in mother liquor, carry out repeatedly recrystallization in toluene solvant, just can obtain required optical purity.The diastereoisomeric salt crystallization of (S)-2 hydroxy propanoic acid and (S)-1-(4-nitrophenyl) ethamine is also more difficult, is difficult for leaching, and makes a part of mother liquor stay in crystal together with the enantiomorph of opening to be separated.Only have when crystal stirs in still together with the solvent that newly adds in addition, and after the crystal that again leaches is repeatedly washed, just can obtain required optical purity, verified WO1996011914 resolution process exists above not enough really.
WO2000026170 has described at pilot scale and has adopted 1-(4-chloro-phenyl-) ethamine to split preparation (S)-2-hydroxy-3-methoxy-3 as optical active alkali by racemic mixture, 3-diphenyl-propionic acid and (S)-2-hydroxy-3-methyl-3, the 3-diphenyl-propionic acid.The productive rate that obtains in the method is respectively 36.4% (based on racemic mixture), optical purity 99.95% and 38% (based on racemic mixture), purity 99.2%, ee=94%.
The employing (S) that WO2000026170 describes-1-(4-chloro-phenyl-) ethamine is as method preparation (S)-2-hydroxy-3-methyl-3 of optical active alkali, the diastereomer optical purity that obtains in the process of 3-diphenyl-propionic acid only has 94%, diastereoisomeric salt just can must be obtained the product of high-optical-purity through recrystallization repeatedly.Yield losses is very large, and operating process is complicated.Optical active alkali (S)-1-(4-nitrophenyl) ethamine, 1-(4-chloro-phenyl-) ethamine market price are higher, need add a large amount of crystal seeds in preparation process, reclaim difficulty, and resolution process is complicated, operation inconvenience, and industry's enlarging production is with high costs.
WO2011004402 has also described and has adopted respectively (S)-1-(4-chloro-phenyl-) ethamine analogue, (S)-2,4-dichloro-phenylethylamine, (R)-2,4-dichloro-phenylethylamine, (S)-3-anisole ethamine make respectively 2 hydroxy propanoic acid compounds individual isomer as optical active alkali, this type of resolving agent cost is high, there is no the market competitiveness.
In view of above prior art defective, the optical active alkali that the present invention adopts is the L-prolineamide, and the market price is low, splits the optical purity of products that obtains high, and production cost is low, is easy to implement in technical scale.
Summary of the invention
We find by research, the method that is used for the fractionation of 2 hydroxy propanoic acid racemic mixture by the following stated can realize the object of the invention, the method is with 2 hydroxy propanoic acid class racemic mixture and L-prolineamide optical activity alkali reaction, separate subsequently 2 hydroxy propanoic acid compounds individual isomer L-prolyl amine salt, a kind of new, method for splitting easy and simple to handle is provided, desired raw material and reagent are cheap, and good economic benefits are arranged, suitable industrial production.
2 hydroxy propanoic acid class racemic mixture synthetic be very familiar for those skilled in the art, as be described in CN1923820B, applicable 3 coverlets of the present invention replace or polysubstituted 2 hydroxy propanoic acid, preferably in the fractionation of the racemic mixture of the 2 hydroxy propanoic acid of 3 bit strip phenyl, particularly preferably be defined as follows 2 hydroxy propanoic acid class racemic mixture and split.
Reaction preparation general formula is as follows:
R wherein
1And R
2Be respectively phenyl, can replace by one or more following substituting groups: halogen (as F, Cl, Br or I), OH, NO
2, CN, C
1-C
4Alkyl, C
1-C
4Haloalkyl, C
1-C
4Alkoxyl group, C
1-C
4Halogenated alkoxy, phenoxy group, amino, C
1-C
4Alkylamino or C
1-C
4Dialkyl amido; R3 is-COOH (maybe can be hydrolyzed into-substituting group such as CN, acid amides or the ester group etc. of COOH obtain through hydrolysis) again; R4 is H, any C that replaces
1-C
6Alkyl, the C that replaces arbitrarily
3-C
6Alkenyl, the C that replaces arbitrarily
3-C
6Alkynyl or the C that replaces arbitrarily
3-C
6Cycloalkyl; Z is oxygen or sulphur or a singly-bound.
The preferred embodiment of the inventive method is 2-hydroxy-3-methoxy-3,3-diphenyl-propionic acid, 2-hydroxy-3-methyl-3,3-diphenyl-propionic acid and 2,3-dihydroxyl-3, the fractionation of the racemic mixture of 3-diphenyl-propionic acid.
The mode of implementing the inventive method is generally: the solution of racemize 2 hydroxy propanoic acid compounds is mixed with the optical activity L-prolineamide of its 0.5～0.55 times of molar weight, then isolate a kind of in the diastereoisomeric salt of formation.
The preferred embodiment of the invention with the solution Slow cooling crystallization of diastereoisomeric salt, obtains the higher product of optical purity.If wish to obtain another kind of diastereomer, can be separated from the mother liquor of crystallization and filtration.
Racemic mixture of the present invention separates the mixture that preferred solvent is alcohol or alcohol and ether or alcohol and ester, the alcohol (as methyl alcohol, ethanol, Virahol or propyl alcohol) of the preferred C1-C3 of alcohol, ester can be selected from ethyl formate, ethyl acetate, isopropyl acetate etc., and ether can be selected from the ether solvents such as methyl tertiary butyl ether, tetrahydrofuran (THF); It is ethanol, C that racemic mixture separates further preferred solvent
1-C
3Alcoholic solvent and mixed solvent, the C of methyl tertiary butyl ether
1-C
3Alcoholic solvent and ethyl acetate mixed solvent; The mixed solvent of ethanol or ethanol and methyl tertiary butyl ether or ethanol and ethyl acetate particularly preferably.
The present invention also provides a kind of 2 hydroxy propanoic acid compounds individual isomer L-prolyl amine salt new compound, preferred following general formula:
R wherein
1, R
2And R
4Substituting group definition prepares with top reaction that in general formula, each corresponding substituting group defines identical.
The present invention particularly preferably provides (S)-2-hydroxy-3-methoxy-3,3-diphenyl-propionic acid L-prolyl amine salt, (S)-2-hydroxy-3-methyl-3,3-diphenyl-propionic acid L-prolyl amine salt and (S)-2,3-dihydroxyl-3,3-diphenyl-propionic acid L-prolyl amine salt new compound is for the preparation of endothelin-receptor antagonists (as BSF208075, darusentan etc.) important intermediate.
The invention has the advantages that can be at lower cost, than producing the 2 hydroxy propanoic acid compounds of pure individual isomer under the ease of Use condition with higher productive rate, and is being amplified to technical scale also without any problem.Therefore, save complicated operating process, the crystallisation step of repetition, a large amount of crystal seed consumption, and also L-prolineamide itself is cheap, thus reduced production energy consumption, production cost, improved significantly the operability in producing.
Description of drawings
Fig. 1 is (S)-2-hydroxy-3-methoxy-3, the NMR collection of illustrative plates of 3-diphenyl-propionic acid L-prolyl amine salt
Embodiment
The following examples have been described laboratory and plant-scale the inventive method, and embodiment illustrates the present invention, but and unrestricted the present invention.
Embodiment 1
Split preparation (S)-2,3-dihydroxyl-3,3-diphenyl-propionic acid by racemic mixture
Drop into 150g ethanol in reaction flask, the 75g ethyl acetate, 20g (77.2mmol) 2,3-dihydroxyl-3,3-diphenyl-propionic acid and 4.8g (42.5mmol) L-prolineamide, under stirring, this reaction solution is warming up to 56 ℃, insulated and stirred with reaction solution slow cooling to 0～5 ℃, was filtered after 30 minutes, (S)-2,3-dihydroxyl-3,3-diphenyl-propionic acid L-prolyl amine salt.。
Add 100g ethyl acetate and 100g water in filter cake, stir, regulator solution PH=2～3, regulates complete, separatory, water layer use 50g ethyl acetate extraction once.Merge organic layer, add the 50g water washing once, separatory.The organic layer concentrating under reduced pressure goes out the 140g ethyl acetate, and is concentrated complete, with solution slow cooling to 0～5 ℃.Filter, filter cake is placed in vacuum drying oven 40C oven dry.Obtain 7.1 (S)-2,3-dihydroxyl-3,3-diphenyl-propionic acid, yield 35.5% (based on racemic mixture).
HPLC：99.8％
Chirality HPLC:99.5%
Split preparation (S)-2-hydroxy-3-methyl-3,3-diphenyl-propionic acid by racemic mixture
Drop into 250g methyl alcohol and 120g methyl tertiary butyl ether in reaction flask, 20g (75.7mmol) 2-hydroxy-3-methyl-3,3-diphenyl-propionic acid and 4.5g (39.4mmol) L-prolineamide, under stirring, this reaction solution is warming up to 80.5 ℃, insulated and stirred after 30 minutes with reaction solution slow cooling to 0～5 ℃, filter, get (S)-2-hydroxy-3-methyl-3,3-diphenyl-propionic acid L-prolyl amine salt.
Add 100g ethyl acetate and 50g water in filter cake, stir, regulator solution PH=2～3, regulates complete, separatory, water layer use 50g ethyl acetate extraction once.Merge organic layer, add the 50g water washing once, separatory.The organic layer concentrating under reduced pressure goes out the 140g ethyl acetate, and is concentrated complete, with solution slow cooling to 0～5 ℃.Filter, filter cake is placed in 40 ℃ of oven dry of vacuum drying oven.Obtain 8.4g (S)-2-hydroxy-3-methyl-3,3-diphenyl-propionic acid, yield 42.0% (based on racemic mixture).
HPLC：99.9％
Chirality HPLC:98.3%
Embodiment 3
Split preparation (S)-2-hydroxy-3-methoxy-3,3-diphenyl-propionic acid by racemic mixture
Suction 200g Virahol in the reactor, again with 10kg (36.5mmol) 2-hydroxyl-3 methoxyl group-3,3-diphenyl-propionic acid and 2.3g (20mmol) L-prolineamide drops in still, under stirring, this reaction solution is warming up to 75 ℃, insulated and stirred after 30 minutes with reaction solution slow cooling to 25 ℃, filter, get (S)-2-hydroxy-3-methoxy-3,3-diphenyl-propionic acid L-prolyl amine salt.
Add 50g ethyl acetate and 20g water in filter cake, stir, regulator solution PH=2～3, regulates complete, separatory, water layer use 25g ethyl acetate extraction once.Merge organic layer, add the 10g water washing once, separatory.The organic layer concentrating under reduced pressure goes out the 70g ethyl acetate, and is concentrated complete, with solution slow cooling to 0～5 ℃.Rejection filter, filter cake are placed in 40 ℃ of oven dry of vacuum drying oven.Obtain 3.6g (S)-2-hydroxyl-3 methoxyl group-3,3-diphenyl-propionic acid, yield 36% (based on racemic mixture).
HPLC：99.8％
Chirality HPLC:97.9%
Embodiment 4
Split preparation (S)-2-hydroxy-3-methoxy-3,3-diphenyl-propionic acid by racemic mixture
Suction 800kg ethanol in the reactor, again with 100kg (366mol) 2-hydroxyl-3 methoxyl group-3,3-diphenyl-propionic acid and 21.7kg (190mol) L-prolineamide drops in still, under stirring, this reaction solution is warming up to 75 ℃, insulated and stirred after 30 minutes with reaction solution slow cooling to 25 ℃.Magma is separated by whizzer, and filter cake gets (S)-2-hydroxy-3-methoxy-3,3-diphenyl-propionic acid L-prolyl amine salt with 50kg ethanol rinsing, rejection filter to doing.
Add 100kg ethyl acetate and 100kg tap water in filter cake, stir, regulator solution PH=2～3, regulates complete, separatory, water layer use 50kg ethyl acetate extraction once.Merge organic layer, add the washing of 50kg tap water once, separatory.The organic layer concentrating under reduced pressure goes out the 120kg ethyl acetate, and is concentrated complete, with solution slow cooling to 0～5 ℃.Rejection filter, filter cake are placed in 40 ℃ of oven dry of vacuum drying oven.Obtain 35.8 (S)-2-hydroxyl-3 methoxyl groups-3,3-diphenyl-propionic acid, yield 35.8% (based on racemic mixture).
HPLC：99.9％
Chirality HPLC:99.9%
Claims (10)
1. a method for splitting that is used for 2 hydroxy propanoic acid class racemic mixture, is characterized in that 2 hydroxy propanoic acid class racemic mixture and L-prolineamide optical activity alkali reaction, separates subsequently 2 hydroxy propanoic acid compounds individual isomer L-prolyl amine salt.
2. method according to claim 1, is characterized in that described 2 hydroxy propanoic acid class racemic mixture is 2-hydroxy-3-methoxy-3,3-diphenyl-propionic acid, 2-hydroxy-3-methyl-3,3-diphenyl-propionic acid or 2,3-dihydroxyl-3,3-diphenyl-propionic acid.
3. method according to claim 1 and 2 is characterized in that described reaction carries out in the mixing solutions of alcohol or alcohol and ether or pure and ester.
4. method according to claim 3, is characterized in that described alcohol is selected from methyl alcohol, ethanol, Virahol, propyl alcohol.
5. method according to claim 3, is characterized in that described ether is selected from methyl tertiary butyl ether, tetrahydrofuran (THF).
6. method according to claim 3, is characterized in that described ester is selected from ethyl acetate, ethyl formate, isopropyl acetate.
7. method according to claim 1 and 2 is characterized in that described reaction carries out in ethanol or ethanol and methyl tertiary butyl ether or ethanol and ethyl acetate mixed solvent.
8. separate according to claim 1 the 2 hydroxy propanoic acid compounds individual isomer L-prolineamide salt compound that obtains.
9. compound according to claim 8 is characterized in that described 2 hydroxy propanoic acid compounds individual isomer L-prolyl amine salt is:
R wherein
1And R
2Be respectively phenyl, can replace by one or more following substituting groups: halogen, OH, NO
2, CN, C
1-C
4Alkyl, C
1-C
4Haloalkyl, C
1-C
4Alkoxyl group, C
1-C
4Halogenated alkoxy, phenoxy group, amino, C
1-C
4Alkylamino or C
1-C
4Dialkyl amido; R4 is H, any C that replaces
1-C
6Alkyl, the C that replaces arbitrarily
3-C
6Alkenyl, the C that replaces arbitrarily
3-C
6Alkynyl or the C that replaces arbitrarily
3-C
6Cycloalkyl; Z is oxygen or sulphur or a singly-bound.
10. according to claim 8 or 9 described compounds, it is characterized in that described 2 hydroxy propanoic acid compounds individual isomer L-prolyl amine salt is (S)-2-hydroxy-3-methoxy-3,3-diphenyl-propionic acid L-prolyl amine salt, (S)-2-hydroxy-3-methyl-3,3-diphenyl-propionic acid L-prolyl amine salt or (S)-2,3-dihydroxyl-3,3-diphenyl-propionic acid L-prolyl amine salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210595382.8A CN103086877B (en) | 2012-12-14 | 2012-12-14 | A kind of method for splitting of 2 hydracrylic acid class racemoid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210595382.8A CN103086877B (en) | 2012-12-14 | 2012-12-14 | A kind of method for splitting of 2 hydracrylic acid class racemoid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103086877A true CN103086877A (en) | 2013-05-08 |
| CN103086877B CN103086877B (en) | 2017-08-25 |
Family
ID=48200069
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210595382.8A Active CN103086877B (en) | 2012-12-14 | 2012-12-14 | A kind of method for splitting of 2 hydracrylic acid class racemoid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103086877B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106699626A (en) * | 2015-11-13 | 2017-05-24 | 辽宁远大诺康生物制药有限公司 | Method for preparing 2-hydroxy-3-methoxy-3,3,-diphenyl propionate racemate |
| CN110204436A (en) * | 2019-06-04 | 2019-09-06 | 斯诺科(杭州)生物科技有限公司 | A kind of method for splitting of naproxen enantiomter |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19850301A1 (en) * | 1998-10-30 | 2000-05-04 | Basf Ag | Process for the resolution of racemates of 2-hydroxypropionic acids |
| GB0510546D0 (en) * | 2005-05-24 | 2005-06-29 | Astrazeneca Ab | New process |
| CN102180823B (en) * | 2011-03-12 | 2016-03-02 | 浙江华海药业股份有限公司 | A kind of method of refining prolinamide |
-
2012
- 2012-12-14 CN CN201210595382.8A patent/CN103086877B/en active Active
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106699626A (en) * | 2015-11-13 | 2017-05-24 | 辽宁远大诺康生物制药有限公司 | Method for preparing 2-hydroxy-3-methoxy-3,3,-diphenyl propionate racemate |
| CN106699626B (en) * | 2015-11-13 | 2019-08-16 | 辽宁远大诺康生物制药有限公司 | A kind of preparation method of 2- hydroxy-3-methoxy -3,3- diphenylprop hydrochlorate raceme |
| CN110204436A (en) * | 2019-06-04 | 2019-09-06 | 斯诺科(杭州)生物科技有限公司 | A kind of method for splitting of naproxen enantiomter |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103086877B (en) | 2017-08-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108129288B (en) | Synthesis method of trans-3-hydroxycyclobutylformic acid | |
| EA018227B1 (en) | A method for the preparation of dabigatran and its intermediates | |
| CN102617542B (en) | Method for preparing and purifying olmesartan intermediate | |
| CN101891649A (en) | Novel 3-cyano methyl benzoate preparing method | |
| CN104086439B (en) | A kind of recovery method of pregabalin intermediate resolving agent (R)-(+)-α-phenylethylamine | |
| US6559338B1 (en) | Method for racemate splitting of 2-hydroxypropionic acids | |
| CN102020584A (en) | Method for synthesizing intermediate L-2-aminobutyrylamide hydrochloride of chiral drug levetiracetam | |
| CN113999142A (en) | Preparation method of chiral N-Boc-trans-1, 2-cyclohexanediamine | |
| CN103864748A (en) | Purification method of 4-chloromethyl-5-methyl-1,3-dioxole-2-ketone | |
| JP6137185B2 (en) | (R) -1,1,3-Trimethyl-4-aminoindane production method | |
| CN103086877A (en) | Splitting method of 2-hydracrylic acid racemic mixture | |
| CN104529935B (en) | Method for synthesizing ethyl 2-(3-aldehyde-4-isobutyloxyphenyl)-4-methylthiazole-5-formate | |
| CN101735085A (en) | Method for preparing D-serine by kinetic resolution | |
| CN105907832B (en) | A kind of method of Enzymatic Resolution Chinese mugwort Saperconazole intermediate | |
| CN103086959A (en) | Novel process for producing 3,5,6-sodium trichloropyrindinol | |
| CN104860980A (en) | Ezetimibe synthesis intermediate and preparation method and application thereof | |
| CN108947919A (en) | A kind of novel processing step and its key intermediate of gout suppressant Lesinurad | |
| CN104098462A (en) | Resolution method of 2-hydroxy-3-methoxy-3,3-dibenzylpropionic acid racemate | |
| CN101875603B (en) | Preparation method for synthesizing intermediate mutilin from pleuromutilin antibiotics | |
| CN105175361A (en) | Improved production process for repaglinide | |
| CN105130794A (en) | Method for preparing S-4-methoxymandelic acid through splitting S-1-phenylethylamine | |
| CN103467350A (en) | Method for preparing (S)-azetidine-2-carboxylic acid | |
| CN111518861B (en) | Novel process for preparing D-calcium pantothenate | |
| CN108947908B (en) | New intermediate of brivaracetam with imidazole ring and synthesis method and application thereof | |
| CN103242291A (en) | Mass production process of polycrystalline high-content benzoic acid alogliptin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20181203 Address after: 317024 Flood Bridge, Linhai City, Zhejiang Province Co-patentee after: Universal Bailey biological medicine research and development (Shanghai) Co., Ltd. Patentee after: Zhejiang Huahai Pharmaceutical Co., Ltd. Address before: 317024 Xunqiao Development Zone, Linhai City, Zhejiang Province Patentee before: Zhejiang Huahai Pharmaceutical Co., Ltd. |
|
| TR01 | Transfer of patent right |