CN113651717B - Racemization method of optical pure isobutyl succinonitrile - Google Patents
Racemization method of optical pure isobutyl succinonitrile Download PDFInfo
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- CN113651717B CN113651717B CN202110898385.8A CN202110898385A CN113651717B CN 113651717 B CN113651717 B CN 113651717B CN 202110898385 A CN202110898385 A CN 202110898385A CN 113651717 B CN113651717 B CN 113651717B
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- KOINRLSRVTULIE-UHFFFAOYSA-N 2-(2-methylpropyl)butanedinitrile Chemical compound CC(C)CC(C#N)CC#N KOINRLSRVTULIE-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 title claims abstract description 34
- 230000006340 racemization Effects 0.000 title abstract description 18
- 230000003287 optical effect Effects 0.000 title abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 51
- 239000000243 solution Substances 0.000 claims abstract description 36
- 239000003054 catalyst Substances 0.000 claims abstract description 35
- 239000007787 solid Substances 0.000 claims abstract description 30
- KOINRLSRVTULIE-QMMMGPOBSA-N (2r)-2-(2-methylpropyl)butanedinitrile Chemical compound CC(C)C[C@@H](C#N)CC#N KOINRLSRVTULIE-QMMMGPOBSA-N 0.000 claims abstract description 25
- 238000005406 washing Methods 0.000 claims abstract description 21
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- KOINRLSRVTULIE-MRVPVSSYSA-N CC(C)C[C@H](C#N)CC#N Chemical compound CC(C)C[C@H](C#N)CC#N KOINRLSRVTULIE-MRVPVSSYSA-N 0.000 claims abstract description 11
- 239000007788 liquid Substances 0.000 claims abstract description 6
- 238000003756 stirring Methods 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims abstract description 4
- 239000011259 mixed solution Substances 0.000 claims abstract description 3
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 5
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 abstract description 8
- 229960001233 pregabalin Drugs 0.000 abstract description 7
- 108090000790 Enzymes Proteins 0.000 abstract description 5
- 102000004190 Enzymes Human genes 0.000 abstract description 5
- 108010033272 Nitrilase Proteins 0.000 abstract description 5
- 230000002194 synthesizing effect Effects 0.000 abstract description 4
- 238000006555 catalytic reaction Methods 0.000 abstract description 3
- 238000004064 recycling Methods 0.000 abstract description 2
- 238000005119 centrifugation Methods 0.000 description 24
- 239000002585 base Substances 0.000 description 20
- 238000004321 preservation Methods 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 150000001340 alkali metals Chemical group 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 239000011942 biocatalyst Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- MGWZYUMZVZMKTN-ZETCQYMHSA-N (3s)-3-cyano-5-methylhexanoic acid Chemical compound CC(C)C[C@H](C#N)CC(O)=O MGWZYUMZVZMKTN-ZETCQYMHSA-N 0.000 description 1
- -1 (R) -3-cyano-2-ethyl-5-methylhexanoic acid ethyl ester Chemical compound 0.000 description 1
- MGWZYUMZVZMKTN-UHFFFAOYSA-N 3-cyano-5-methylhexanoic acid Chemical compound CC(C)CC(C#N)CC(O)=O MGWZYUMZVZMKTN-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000002815 homogeneous catalyst Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000011949 solid catalyst Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a racemization method of optical pure isobutyl succinonitrile. The method comprises the following steps: mixing (S) -isobutyl succinonitrile or (R) -isobutyl succinonitrile with an organic solvent, adding a solid base catalyst, stirring and reacting for 1-10 hours at the temperature of 20-50 ℃, obtaining a reaction mixed solution after the reaction is finished, centrifuging, washing, recovering the solid base catalyst, combining the supernatant and the washing solution after centrifuging, and recovering the organic solvent, wherein the residual liquid is the racemic isobutyl succinonitrile. The method adopts the solid base catalyst to racemize in the organic solvent, the racemization speed is high, and the racemization yield reaches more than 90%; the racemized isobutyl succinonitrile obtained by the method can be further used for enzyme catalytic reaction, and the racemized catalyst is easy to separate and can be reused, and the post-treatment is simple and environment-friendly; the method is simple and easy to operate, and can be applied to the large-scale racemization recycling process of the optical pure isobutyl succinonitrile in the process of synthesizing pregabalin by a nitrilase method.
Description
Field of the art
The invention relates to a racemization method of optical pure isobutyl succinonitrile.
(II) background art
Pregabalin (Pregabalin), chemical name (S) -3-aminomethyl-5-methylhexanoic acid, is a structural analog of gamma-aminobutyric acid developed by the company Pfizer, inc. Pregabalin is one of the most widely prescribed medicines worldwide and is widely used for treating post-herpetic neuralgia, seizure, anxiety and other diseases.
The nitrilase method resolution process route is one of the most competitive routes for synthesizing pregabalin, and has the advantages of easily available raw materials, high atom economy, less discharge of three wastes and the like (ZL 201810136409.4). The method can obtain (R) -or (S) -isobutyl succinonitrile while synthesizing optically pure 3-cyano-5-methylhexanoic acid by splitting isobutyl succinonitrile with different selective nitrilases, wherein (S) -3-cyano-5-methylhexanoic acid can be synthesized into pregabalin by one-step hydrogenation.
(S) -or (R) -isobutyl succinonitrile as an ineffective isomer, if not effectively recycled, will greatly increase production cost and environmental protection pressure. In order to further improve the utilization rate of raw materials, the development of (S) -and (R) -isobutyl succinonitrile racemization technology has important significance.
At present, a method for catalyzing racemization of (R) -isobutyl succinonitrile by a homogeneous catalyst is reported at home and abroad. The company of the best report that (R) -isobutyl succinonitrile, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) and toluene were mixed, and after refluxing at high temperature for 2 hours, water was added and the resulting mixture was extracted with ethyl acetate. The organic extract was washed with 5% hcl and saturated sodium chloride and the racemic isobutyl succinonitrile (CN 1942587B) was dried over anhydrous magnesium sulfate. In addition, patent US2005283023 reports a method for racemizing (R) -3-cyano-2-ethyl-5-methylhexanoic acid ethyl ester by using sodium ethoxide as a catalyst. Zhang Qin et al report a racemization method of (R) -isobutyl succinonitrile by mixing 20% sodium ethoxide with (R) -isobutyl succinonitrile, refluxing at 45℃for 4 hours, extracting and rectifying to obtain racemic isobutyl succinonitrile (Organic Process Research & Development,2019,23,2042-2049). However, the homogeneous catalytic racemization method has more defects: the catalyst is difficult to recycle, and the racemized isobutyl succinonitrile needs to be separated and purified through multiple steps of extraction, acid washing, filtration, concentration and the like, so that a large amount of waste acid and waste water are generated. Therefore, there is a need to develop a green, efficient, optically pure, isobutyl succinonitrile racemization process.
(III) summary of the invention
The present invention aims at providing a racemization method of optical pure (S) -and (R) -isobutyl succinonitrile.
The technical scheme adopted by the invention is as follows:
A process for racemizing optically pure isobutyl succinonitrile, the process comprising: mixing (S) -isobutyl succinonitrile or (R) -isobutyl succinonitrile with an organic solvent, adding a solid base catalyst, stirring and reacting for 1-10 hours at the temperature of 20-50 ℃, obtaining a reaction mixed solution after the reaction is finished, centrifuging, washing, recovering the solid base catalyst, combining the supernatant and the washing solution after centrifuging, and recovering the organic solvent, wherein the residual liquid is the racemic isobutyl succinonitrile;
The solid base catalyst is alkali metal or alumina, or activated carbon loaded alkali metal, or molecular sieve loaded alkali metal;
The organic solvent is one or a mixture of more than two of the following: ethanol, n-propanol, n-butanol, isobutanol, isoamyl alcohol, t-amyl alcohol.
The invention adopts one or more combined solid base catalysts and one or more organic solvents as media, can effectively racemize (S) -and (R) -isobutyl succinonitrile, and simultaneously can recycle and reuse the racemized solid base catalysts, thereby avoiding the generation of a large amount of waste acid and waste water in post-treatment.
The (S) -or (R) -isobutyl succinonitrile can be prepared and obtained by the following method: the nitrilase is used as a biocatalyst, the isobutyl succinonitrile is used as a substrate, water is used as a reaction medium, and the catalytic reaction is carried out at 30 ℃. After the reaction is finished, the obtained conversion solution is centrifuged or filtered, the reaction solution and the biocatalyst are separated, methylene dichloride is added into the filtrate, the mixture is stirred and extracted, the mixture is kept stand for layering, unreacted substrates are extracted into an organic phase, the organic phase is distilled to remove the organic solvent, and the (S) -or (R) -isobutyl succinonitrile is obtained, and the enantiomer excess value (ee value) of the isobutyl succinonitrile is measured by adopting a gas chromatography.
Preferably, the alkali metal catalyst is one or a mixture of more than two of the following: HND-62, HND-63, HND-64.
The mass and dosage ratio of the (S) -isobutyl succinonitrile or the (R) -isobutyl succinonitrile to the solid base catalyst is 1:0.1-1.
The mass and dosage ratio of the (S) -isobutyl succinonitrile or the (R) -isobutyl succinonitrile to the solid base catalyst is 1:1-10.
The reaction is preferably carried out at a stirring speed of 120 to 600 rpm.
The beneficial effects of the invention are mainly as follows: the invention provides a racemization method of optical pure isobutyl succinonitrile. The method adopts the solid base catalyst to racemize in the organic solvent, the racemization speed is high, and the racemization yield reaches more than 90%; the racemized isobutyl succinonitrile obtained by the method can be further used for enzyme catalytic reaction, and the racemized catalyst is easy to separate and can be reused, and the post-treatment is simple and environment-friendly; the method is simple and easy to operate, and can be applied to the large-scale racemization recycling process of the optical pure isobutyl succinonitrile in the process of synthesizing pregabalin by a nitrilase method.
(IV) description of the drawings
FIG. 1 is a high performance liquid chromatogram of optically pure isobutyl succinonitrile.
FIG. 2 is a high performance liquid chromatogram of racemic isobutyl succinonitrile after racemization over a solid base catalyst.
(Fifth) detailed description of the invention
The invention will be further described with reference to the following specific examples, but the scope of the invention is not limited thereto:
example 1:
In a 25mL reaction kettle, 0.5g (R) -isobutyl succinonitrile (ee value 89.01%, high performance liquid chromatogram see figure 1) and 10mL ethanol are added, after heat preservation is carried out for 30min, 0.5g solid base catalyst HND-63 is added, after reaction is carried out for 1h at 35 ℃ and 150rpm, the reaction solution is centrifuged at 8000rpm for 10min, and the HND-63 obtained by centrifugation is washed with ethanol. The supernatant and the washing solution after centrifugation were combined and spin-distilled at 70℃for 2 hours to give 0.45g of racemic isobutyl succinonitrile (ee value 1.78%, yield 90%, high performance liquid chromatography see FIG. 2).
The gas chromatographic column model is BGB-174, and the chromatographic conditions are as follows: the sample injection amount is 1.0 mu L, the temperature of the sample injection port and the detector is 250 ℃, the column temperature is 120 ℃, the temperature is kept for 15min, and the temperature is increased to 170 ℃ at 10 ℃/min. The flow rate was 1.0mL/min.
Calculation of enantiomeric excess values (ee values) reference Rakels et al (Enzyme & Microbial Technology,1993,15,1051-1056).
Example 2:
0.5g (R) -isobutyl succinonitrile (ee value 89.01%) and 10mL ethanol are added into a 25mL reaction kettle, after heat preservation is carried out for 30min, 0.5g solid base catalyst HND-63 is added, after reaction is carried out for 10h at 40 ℃ and 150rpm, the reaction solution is centrifuged at 8000rpm for 10min, HND-63 obtained by centrifugation is washed by ethanol, supernatant and washing solution after centrifugation are combined and rotary evaporation is carried out for 2h at 70 ℃ to obtain 0.45g racemic isobutyl succinonitrile (ee value 1.08 percent, yield 90 percent).
Example 3:
In a 25mL reaction kettle, 0.5g (R) -isobutyl succinonitrile (ee value 89.01%) and 10mL ethanol were added, after heat preservation for 30min, 0.5g solid base catalyst HND-63 was added, after reaction for 1.5h at 20 ℃ and 150rpm, the reaction solution was centrifuged at 8000rpm for 10min, HND-63 obtained by centrifugation was washed with ethanol, and after centrifugation, the supernatant and the washing solution were combined and spin-distilled at 70 ℃ for 2h to obtain 0.47g racemic isobutyl succinonitrile (ee value 0.68%, yield 94%).
Example 4:
In a 25mL reaction kettle, 0.5g (R) -isobutyl succinonitrile (ee value 89.01%) and 10mL of n-propanol were added, after heat preservation for 30min, 0.5g of solid base catalyst HND-63 was added, after reaction for 1.5h at 50℃and 200rpm, the reaction solution was centrifuged at 8000rpm, the HND-63 obtained by centrifugation was washed with n-propanol, the supernatant after centrifugation and the washing solution were combined, and the solution was spin-distilled at 70℃for 2h to obtain 0.45g of racemic isobutyl succinonitrile (ee value 1.18%, yield 90%).
Example 5:
In a 25mL reaction kettle, 0.5g (R) -isobutyl succinonitrile (ee value 89.01%) and 10mL of n-butanol are added, after heat preservation is carried out for 30min, 0.5g of solid base catalyst HND-63 is added, after reaction for 1.5h at 35 ℃ and 600rpm, the reaction solution is centrifuged at 8000rpm for 10min, HND-63 obtained by centrifugation is washed with n-butanol, the supernatant after centrifugation and the washing solution are combined, and the solution is distilled for 2h at 70 ℃ to obtain 0.46g of racemic isobutyl succinonitrile (ee value 1.21%, yield 92%).
Example 6:
In a 25mL reaction kettle, 0.5g (S) -isobutyl succinonitrile (ee value 75.2%) and 10mL isobutanol were added, after heat preservation for 30min, 0.5g solid base catalyst HND-63 was added, after reaction for 2h at 35℃and 120rpm, the reaction solution was centrifuged at 8000rpm for 10min, the HND-63 obtained by centrifugation was washed with isobutanol, and the supernatant after centrifugation and the washing solution were combined and distilled for 2h at 70℃to obtain 0.47g racemic isobutyl succinonitrile (ee value 0.28%, yield 93.2%).
Example 7:
In a 25mL reaction kettle, 1g (S) -isobutyl succinonitrile (ee value 75.2%) and 20mL isoamyl alcohol were added, after heat preservation for 30min, 1g solid base catalyst HND-63 was added, after reaction for 2h at 35 ℃ and 200rpm, the reaction solution was centrifuged at 8000rpm for 10min, HND-63 obtained by centrifugation was washed with isoamyl alcohol, and the supernatant after centrifugation and the washing solution were combined and the solution was distilled off in a rotary manner at 70 ℃ for 2h to obtain 0.92g of racemic isobutyl succinonitrile (ee value 0.48%, yield 92%).
Example 8:
In a 25mL reaction kettle, 1g (S) -isobutyl succinonitrile (ee value 75.2%) and 100mL isoamyl alcohol were added, after heat preservation for 30min, 0.1g of solid base catalyst HND-63 was added, after reaction for 1.5h at 35℃and 150rpm, the reaction solution was centrifuged at 8000rpm for 10min, the HND-63 obtained by centrifugation was washed with isoamyl alcohol, and the supernatant after centrifugation and the washing solution were combined and spin-distilled at 70℃for 2h to obtain 0.9g of racemic isobutyl succinonitrile (ee value 1.94%, yield 90%).
Example 9:
In a 25mL reaction kettle, 1g (S) -isobutyl succinonitrile (ee value 75.2%) and 10mL isoamyl alcohol were added, after heat preservation for 30min, 0.1g solid base catalyst HND-64 was added, after reaction for 4h at 35 ℃ and 150rpm, the reaction solution was centrifuged at 8000rpm for 10min, HND-63 obtained by centrifugation was washed with isoamyl alcohol, and the supernatant after centrifugation and the washing solution were combined and the solution was distilled for 2h at 70 ℃ to obtain 0.93g racemic isobutyl succinonitrile (ee value 1.94%, yield 93%).
Example 10:
In a 25mL reaction kettle, 1g (R) -isobutyl succinonitrile (ee value 89.01%) and 10mL isoamyl alcohol are added, after heat preservation is carried out for 30min, 0.1g solid base catalyst HND-62 is added, after reaction is carried out for 4h at 35 ℃ and 150rpm, the reaction solution is centrifuged at 8000rpm for 10min, HND-63 obtained by washing and centrifuging with isoamyl alcohol is combined, supernatant and washing solution after centrifuging are combined, and the solution is distilled for 2h at 70 ℃ in a rotary way, thus obtaining 0.9g racemic isobutyl succinonitrile (ee value 0.94% and yield 90%).
Example 11:
In a 25mL reaction kettle, 1g (R) -isobutyl succinonitrile (ee value 89.01%) and 10mL isoamyl alcohol were added, after heat preservation for 30min, 0.7g of solid base catalyst HND-62 was added, after reaction for 2.0h at 35 ℃ and 150rpm, the reaction solution was centrifuged at 8000rpm for 10min, the HND-62 obtained by centrifugation was washed with tert-amyl alcohol, and the supernatant after centrifugation and the washing solution were combined and spin-distilled at 70 ℃ for 2h to obtain 0.91g of isobutyl succinonitrile (ee value 0.64%, yield 91%).
Example 12 (comparative):
In a 25mL reaction kettle, 0.5g (R) -isobutyl succinonitrile (ee value 89.01%) and 10mL ethyl acetate were added, after heat preservation for 30min, 0.5g of solid catalyst HND-63 was added, after reaction at 35℃and 150rpm for 1h, the reaction solution was centrifuged at 8000rpm for 10min, and the HND-63 obtained by centrifugation was washed with ethyl acetate. After centrifugation, the supernatant and the washing solution were combined and spin-distilled at 70℃for 2 hours to obtain 0.45g of isobutyl succinonitrile (ee value 88.98%, yield 90%).
Example 13 (comparative):
In a 25mL reaction vessel, 0.5g (R) -isobutyl succinonitrile (ee value 89.01%) and 10mL ethanol were added, the reaction vessel was incubated for 30min, 0.5g of D201 resin was added, the reaction vessel was reacted at 35℃and 150rpm for 1h, the reaction solution was centrifuged at 8000rpm for 10min, and the D201 resin obtained by centrifugation was washed with ethanol. After centrifugation, the supernatant and the washing solution were combined and spin-distilled at 70℃for 2 hours to obtain 0.46g of isobutyl succinonitrile (ee value 80.18%, yield 91%).
Claims (2)
1. A process for racemizing optically pure isobutyl succinonitrile, the process comprising: mixing (S) -isobutyl succinonitrile or (R) -isobutyl succinonitrile with an organic solvent, adding a solid base catalyst, stirring and reacting for 1-10 hours at the temperature of 20-50 ℃, obtaining a reaction mixed solution after the reaction is finished, centrifuging, washing, recovering the solid base catalyst, combining the supernatant and the washing solution after centrifuging, and recovering the organic solvent, wherein the residual liquid is racemic isobutyl succinonitrile;
The solid base catalyst is one or a mixture of more than two of the following: solid base catalyst HND-62, solid base catalyst HND-63, solid base catalyst HND-64; the mass dosage ratio of the (S) -isobutyl succinonitrile or the (R) -isobutyl succinonitrile to the solid base catalyst is 1:0.1-1;
The organic solvent is one or a mixture of more than two of the following: ethanol, n-propanol, n-butanol, isobutanol, isoamyl alcohol, t-amyl alcohol.
2. The method according to claim 1, wherein the reaction is carried out at a stirring speed of 120 to 600 rpm.
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| UA82292C2 (en) * | 2004-04-14 | 2008-03-25 | Пфайзер Продактс Инк. | A method for stereoselective byconversion of aliphatic dinitriles into cyanocarboxylic acids (variants) |
| EA200800909A1 (en) * | 2004-06-21 | 2008-08-29 | УОРНЕР-ЛАМБЕРТ КОМПАНИ ЭлЭлСи | OBTAINING PREGABALIN AND RELATED COMPOUNDS |
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2021
- 2021-08-05 CN CN202110898385.8A patent/CN113651717B/en active Active
Non-Patent Citations (1)
| Title |
|---|
| Efficient Chemoenzymatic Synthesis of Optically Active Pregabalin from Racemic Isobutylsuccinonitrile;Qing Zhang 等;Organic Process Research & Development;第23卷;2042-2049 * |
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