CN113651717A - Racemization method of optically pure isobutyl succinonitrile - Google Patents
Racemization method of optically pure isobutyl succinonitrile Download PDFInfo
- Publication number
- CN113651717A CN113651717A CN202110898385.8A CN202110898385A CN113651717A CN 113651717 A CN113651717 A CN 113651717A CN 202110898385 A CN202110898385 A CN 202110898385A CN 113651717 A CN113651717 A CN 113651717A
- Authority
- CN
- China
- Prior art keywords
- isobutyl
- succinonitrile
- solid base
- reaction
- base catalyst
- 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.)
- Pending
Links
- 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 33
- 230000006340 racemization Effects 0.000 title abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- 239000003054 catalyst Substances 0.000 claims abstract description 34
- 239000000243 solution Substances 0.000 claims abstract description 31
- 239000007787 solid Substances 0.000 claims abstract description 28
- 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 27
- 238000005406 washing Methods 0.000 claims abstract description 21
- 239000006228 supernatant Substances 0.000 claims abstract description 16
- 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 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims abstract description 4
- 239000011259 mixed solution Substances 0.000 claims abstract description 3
- 239000002585 base Substances 0.000 claims description 25
- 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
- 239000000203 mixture Substances 0.000 claims description 10
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- 229910052783 alkali metal Inorganic materials 0.000 claims description 8
- 150000001340 alkali metals Chemical group 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 239000002808 molecular sieve Substances 0.000 claims description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 2
- 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
- 238000006555 catalytic reaction Methods 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 230000003287 optical effect Effects 0.000 abstract description 2
- 238000004064 recycling Methods 0.000 abstract description 2
- 238000005119 centrifugation Methods 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000004321 preservation Methods 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000000605 extraction Methods 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
- 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
- 238000011534 incubation Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000002994 raw material Substances 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
- 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
- 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
- 230000036506 anxiety Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- PZGIWBPMOSUKEV-JTQLQIEISA-N diethyl 2-[(1r)-1-cyano-3-methylbutyl]propanedioate Chemical compound CCOC(=O)C([C@@H](CC(C)C)C#N)C(=O)OCC PZGIWBPMOSUKEV-JTQLQIEISA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 206010015037 epilepsy Diseases 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
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000007172 homogeneous catalysis Methods 0.000 description 1
- 239000002815 homogeneous catalyst Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 230000001314 paroxysmal effect Effects 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000011949 solid catalyst Substances 0.000 description 1
Images
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
Abstract
The invention relates to a racemization method of optically 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 and washing, recovering the solid base catalyst, combining the centrifuged supernatant and the washing solution, recovering the organic solvent, and obtaining the residual solution, namely racemic isobutyl succinonitrile. The method adopts the solid base catalyst to carry out racemization in the organic solvent, the racemization speed is high, and the racemization yield reaches more than 90 percent; the racemic isobutyl succinonitrile obtained by the method can be further used for enzyme catalytic reaction, the racemic catalyst is easy to separate and can be recycled, and the post-treatment is simple and environment-friendly; the method is simple and easy to operate, and can be applied to a large-scale racemization recycling process of the optical pure isobutyl succinonitrile in the process of synthesizing pregabalin by a nitrilase method.
Description
(I) technical field
The invention relates to a racemization method of optically pure isobutyl succinonitrile.
(II) background of the invention
Pregabalin (Pregabalin), chemically known as (S) -3-aminomethyl-5-methylhexanoic acid, is a structural analog of gamma-aminobutyric acid developed by Pfizer, inc. Pregabalin is one of the best global prescription drugs, and is widely used for treating diseases such as postherpetic neuralgia, paroxysmal epilepsy and anxiety.
The nitrilase method resolution process route is one of the most competitive routes for synthesizing pregabalin, and has the advantages of easily obtained raw materials, high atom economy, less three-waste emission and the like (ZL 201810136409.4). When different selective nitrilases split isobutyl succinonitrile to synthesize optically pure 3-cyano-5-methylhexanoic acid, (R) -or (S) -isobutyl succinonitrile can be obtained, wherein the (S) -3-cyano-5-methylhexanoic acid can be further hydrogenated to synthesize pregabalin.
(S) -or (R) -isobutyl succinonitrile as an ineffective isomer, if the (S) -or (R) -isobutyl succinonitrile cannot be effectively recycled, the production cost and the environmental protection pressure are greatly increased. In order to further improve the utilization rate of raw materials, the development of the racemization technology of (S) -and (R) -isobutyl butanedinitrile is of great significance.
At present, the method for catalyzing racemization of (R) -isobutyl succinonitrile by using a homogeneous catalyst is reported at home and abroad. The company pfeiffe reports that (R) -isobutyl succinonitrile, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) and toluene were mixed, refluxed at high temperature for 2 hours, added with water, and the resulting mixture was extracted with ethyl acetate. The organic extract was washed with 5% HCl and saturated sodium chloride, and racemic isobutyl succinonitrile (CN1942587B) was dried over anhydrous magnesium sulfate. In addition, patent US2005283023 also reports a method for racemizing ethyl (R) -3-cyano-2-carbethoxy-5-methylhexanoate by using sodium ethoxide as a catalyst. Zhangqin et al reported a racemization method of (R) -isobutyl succinonitrile, mixing 20% sodium ethoxide with (R) -isobutyl succinonitrile, heating and refluxing at 45 ℃ for 4h, and rectifying after extraction to obtain racemic isobutyl succinonitrile (Organic Process Research & Development,2019,23, 2042-. However, the homogeneous catalysis racemization method has more defects: the catalyst is difficult to recover, and after racemization, 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 and optically pure racemization method of isobutylsuccinonitrile.
Disclosure of the invention
The object of the present invention is to provide a process for the racemization of optically pure (S) -and (R) -isobutylsuccinonitrile.
The technical scheme adopted by the invention is as follows:
a process for the racemisation of optically pure isobutyl succinonitrile 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 and washing, recovering the solid base catalyst, combining the centrifuged supernatant and a washing solution, recovering the organic solvent, and obtaining the residual solution, namely racemic isobutyl succinonitrile;
the solid base catalyst is alkali metal or alumina, or alkali metal loaded by active carbon, or alkali metal loaded by molecular sieve;
the organic solvent is one of the following or a mixture of two or more of the following: ethanol, n-propanol, n-butanol, isobutanol, isoamyl alcohol and tert-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 butanedinitrile, simultaneously can recycle the racemized solid base catalyst, and avoids generating a large amount of waste acid and waste water by post-treatment.
The (S) -or (R) -isobutyl succinonitrile can be prepared by the following method: nitrilase is used as a biocatalyst, isobutyl succinonitrile is used as a substrate, water is used as a reaction medium, and catalytic reaction is carried out at the temperature of 30 ℃. After the reaction is finished, the obtained conversion solution is centrifuged or filtered, the reaction solution and the biocatalyst are separated, dichloromethane is added into the filtrate, stirring and extraction are carried out, standing and layering are carried out, unreacted substrates are extracted into an organic phase, the organic phase is distilled to remove organic solvent to obtain (S) -or (R) -isobutyl butanedinitrile, and the enantiomeric excess value (ee value) of the isobutyl butanedinitrile is measured by adopting a gas chromatography.
Preferably, the alkali metal catalyst is one of the following or a mixture of two or more thereof: HND-62, HND-63 and HND-64.
The mass ratio of the (S) -isobutyl succinonitrile or the (R) -isobutyl succinonitrile to the solid base catalyst is 1: 0.1-1.
The mass 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 120-600 rpm.
The invention has the following beneficial effects: the invention provides a racemization method of optically pure isobutyl succinonitrile. The method adopts the solid base catalyst to carry out racemization in the organic solvent, the racemization speed is high, and the racemization yield reaches more than 90 percent; the racemic isobutyl succinonitrile obtained by the method can be further used for enzyme catalytic reaction, the racemic catalyst is easy to separate and can be recycled, and the post-treatment is simple and environment-friendly; the method is simple and easy to operate, and can be applied to a 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 isobutylsuccinonitrile.
FIG. 2 is a high performance liquid chromatogram of racemic isobutylsuccinonitrile after racemization by solid base catalyst.
(V) detailed description of the preferred embodiments
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto:
example 1:
adding 0.5g of (R) -isobutyl succinonitrile (ee value is 89.01 percent, and a high performance liquid chromatogram is shown in figure 1) and 10mL of ethanol into a 25mL reaction kettle, preserving the temperature for 30min, adding 0.5g of a solid base catalyst HND-63, reacting for 1h at 35 ℃ and 150rpm, centrifuging the reaction liquid at 8000rpm for 10min, and washing the centrifuged HND-63 with ethanol. The centrifuged supernatant and the washing solution were combined and rotary-evaporated at 70 ℃ for 2 hours to give 0.45g of racemic isobutylsuccinonitrile (ee value 1.78%, yield 90%, HPLC chromatogram shown in FIG. 2).
The model of the gas chromatographic column is BGB-174, and the chromatographic conditions are as follows: the sample introduction amount is 1.0 mu L, the temperature of the sample inlet and the detector is 250 ℃, the column temperature is 120 ℃, the temperature is kept for 15min, and the temperature is increased to 170 ℃ at the temperature of 10 ℃/min. The flow rate was 1.0 mL/min.
Enantiomeric excess value (ee value) calculation reference is made to Rakels et al (Enzyme & microbiological Technology,1993,15, 1051-.
Example 2:
0.5g of (R) -isobutyl succinonitrile (ee value 89.01%) and 10mL of ethanol were added to a 25mL reaction vessel, the mixture was kept warm for 30min, 0.5g of a solid base catalyst HND-63 was added, the reaction was carried out at 40 ℃ and 150rpm for 10h, the reaction mixture was centrifuged at 8000rpm for 10min, the HND-63 obtained by centrifugation was washed with ethanol, the supernatant and the washing solution after centrifugation were combined and rotary-evaporated at 70 ℃ for 2h to obtain 0.45g of racemic isobutyl succinonitrile (ee value 1.08%, yield 90%).
Example 3:
0.5g of (R) -isobutyl succinonitrile (ee value 89.01%) and 10mL of ethanol are added into a 25mL reaction kettle, after heat preservation is carried out for 30min, 0.5g of a solid base catalyst HND-63 is added, after reaction is carried out for 1.5h at 20 ℃ and 150rpm, the reaction solution is centrifuged for 10min at 8000rpm, the HND-63 obtained by centrifugation is washed by ethanol, the supernatant and the washing solution after centrifugation are combined, and the solution is rotary evaporated for 2h at 70 ℃ to obtain 0.47g of racemic isobutyl succinonitrile (ee value 0.68%, yield 94%).
Example 4:
to a 25mL reaction vessel were added 0.5g of (R) -isobutyl succinonitrile (ee value 89.01%) and 10mL of n-propanol, the mixture was incubated for 30min, then 0.5g of a solid base catalyst HND-63 was added, the mixture was reacted at 50 ℃ and 200rpm for 1.5h, the reaction mixture was centrifuged at 8000rpm for 10min, the centrifuged HND-63 was washed with n-propanol, the centrifuged supernatant and the washing solution were combined, and the solution was rotary-evaporated at 70 ℃ for 2h to give 0.45g of racemic isobutyl succinonitrile (ee value 1.18%, yield 90%).
Example 5:
to a 25mL reaction vessel were added 0.5g of (R) -isobutyl succinonitrile (ee value 89.01%) and 10mL of n-butanol, the mixture was kept warm for 30min, then 0.5g of a solid base catalyst HND-63 was added, the reaction mixture was centrifuged at 8000rpm for 10min after 1.5h at 35 ℃ and 600rpm, the HND-63 obtained by the centrifugation was washed with n-butanol, the supernatant and the washing solution after the centrifugation were combined, and the solution was rotary-evaporated at 70 ℃ for 2h to give 0.46g of racemic isobutyl succinonitrile (ee value 1.21%, yield 92%).
Example 6:
a25 mL reaction vessel was charged with 0.5g of (S) -isobutylsuccinonitrile (ee value 75.2%) and 10mL of isobutanol, and after incubation for 30min, 0.5g of a solid base catalyst HND-63 was added, and after reaction at 35 ℃ and 120rpm for 2h, the reaction mixture was centrifuged at 8000rpm for 10min, the HND-63 obtained by centrifugation was washed with isobutanol, and the supernatant and the washing were combined and the solution was rotary-evaporated at 70 ℃ for 2h to give 0.47g of racemic isobutylsuccinonitrile (ee value 0.28%, yield 93.2%).
Example 7:
1g of (S) -isobutyl succinonitrile (ee value: 75.2%) and 20mL of isoamyl alcohol were added to a 25mL reaction vessel, the mixture was kept warm for 30min, 1g of a solid base catalyst HND-63 was added, the reaction solution was centrifuged at 8000rpm for 10min after reacting at 35 ℃ and 200rpm for 2h, the centrifuged HND-63 was washed with isoamyl alcohol, the supernatant and the washing solution after centrifugation were combined, and the solution was rotary-evaporated at 70 ℃ for 2h to give 0.92g of racemic isobutyl succinonitrile (ee value: 0.48%, yield: 92%).
Example 8:
1g of (S) -isobutyl succinonitrile (ee value 75.2%) and 100mL of isoamyl alcohol are added into a 25mL reaction kettle, after heat preservation is carried out for 30min, 0.1g of solid base catalyst HND-63 is added, after reaction is carried out for 1.5h under the conditions of 35 ℃ and 150rpm, a reaction solution is centrifuged for 10min under 8000rpm, HND-63 obtained by centrifugation is washed by isoamyl alcohol, supernatant liquid and washing liquid after centrifugation are combined, and the solution is subjected to rotary evaporation for 2h under 70 ℃ to obtain 0.9g of racemic isobutyl succinonitrile (ee value 1.94%, yield 90%).
Example 9:
1g of (S) -isobutyl succinonitrile (ee value 75.2%) and 10mL of isoamyl alcohol are added into a 25mL reaction kettle, after heat preservation is carried out for 30min, 0.1g of solid base catalyst HND-64 is added, after reaction is carried out for 4h under the conditions of 35 ℃ and 150rpm, a reaction solution is centrifuged for 10min under 8000rpm, HND-63 obtained by centrifugation is washed by isoamyl alcohol, supernatant liquid and washing liquid after centrifugation are combined, and the solution is rotary evaporated for 2h under 70 ℃ to obtain 0.93g of racemic isobutyl succinonitrile (ee value 1.94%, yield 93%).
Example 10:
1g of (R) -isobutyl succinonitrile (ee value 89.01%) and 10mL of isoamyl alcohol are added into a 25mL reaction kettle, after heat preservation is carried out for 30min, 0.1g of solid base catalyst HND-62 is added, after reaction is carried out for 4h under the conditions of 35 ℃ and 150rpm, a reaction solution is centrifuged for 10min under 8000rpm, HND-63 obtained by centrifugation is washed by isoamyl alcohol, supernatant liquid and washing liquid after centrifugation are combined, and the solution is rotary evaporated for 2h under 70 ℃ to obtain 0.9g of racemic isobutyl succinonitrile (ee value 0.94%, yield 90%).
Example 11:
1g of (R) -isobutyl succinonitrile (ee value: 89.01%) and 10mL of isoamyl alcohol are added into a 25mL reaction kettle, after heat preservation is carried out for 30min, 0.7g of a solid base catalyst HND-62 is added, after reaction is carried out for 2.0h under the conditions of 35 ℃ and 150rpm, a reaction solution is centrifuged for 10min under 8000rpm, HND-62 obtained by centrifugation is washed by tertiary amyl alcohol, supernatant and washing solution after centrifugation are combined, and the solution is rotary evaporated for 2h under 70 ℃ to obtain 0.91g of isobutyl succinonitrile (ee value: 0.64%, yield: 91%).
Example 12 (comparative):
a25 mL reaction vessel was charged with 0.5g of (R) -isobutyl succinonitrile (ee value: 89.01%) and 10mL of ethyl acetate, and after incubating for 30min, 0.5g of a solid catalyst HND-63 was added, and after reaction at 35 ℃ and 150rpm for 1h, the reaction mixture was centrifuged at 8000rpm for 10min, and the centrifuged HND-63 was washed with ethyl acetate. The centrifuged supernatant and the washings were combined and rotary-evaporated at 70 ℃ for 2 hours to give 0.45g of isobutylsuccinonitrile (ee value 88.98%, yield 90%).
Example 13 (comparative):
a25 mL reaction vessel was charged with 0.5g of (R) -isobutylsuccinonitrile (ee value: 89.01%) and 10mL of ethanol, and after 30min of incubation, 0.5g D201 resin was added, and after 1h of reaction at 35 ℃ and 150rpm, the reaction mixture was centrifuged at 8000rpm for 10min, and the centrifuged D201 resin was washed with ethanol. After centrifugation, the supernatant and the washing solution were combined and rotary-evaporated at 70 ℃ for 2 hours to obtain 0.46g of isobutylsuccinonitrile (ee value 80.18%, yield 91%).
Claims (5)
1. A process for the racemisation of optically pure isobutyl succinonitrile 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 and washing, recovering the solid base catalyst, combining the centrifuged supernatant and a washing solution, recovering the organic solvent, and obtaining the residual solution, namely racemic isobutyl succinonitrile;
the solid base catalyst is alkali metal or alumina, or alkali metal loaded by active carbon, or alkali metal loaded by molecular sieve;
the organic solvent is one of the following or a mixture of two or more of the following: ethanol, n-propanol, n-butanol, isobutanol, isoamyl alcohol and tert-amyl alcohol.
2. The method of claim 1, wherein the alkali metal catalyst is one of the following or a mixture of two or more thereof: HND-62, HND-63 and HND-64.
3. The method according to claim 1, wherein the mass ratio of the (S) -isobutyl butanedinitrile or (R) -isobutyl butanedinitrile to the solid base catalyst is 1: 0.1-1.
4. The use according to claim 1, wherein the ratio of the mass amount of (S) -isobutylsuccinonitrile or (R) -isobutylsuccinonitrile to the mass amount of solid base catalyst is 1:1 to 10.
5. The method of claim 1, wherein the reaction is carried out at a stirring speed of 120 to 600 rpm.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110898385.8A CN113651717A (en) | 2021-08-05 | 2021-08-05 | Racemization method of optically pure isobutyl succinonitrile |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110898385.8A CN113651717A (en) | 2021-08-05 | 2021-08-05 | Racemization method of optically pure isobutyl succinonitrile |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113651717A true CN113651717A (en) | 2021-11-16 |
Family
ID=78478516
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110898385.8A Pending CN113651717A (en) | 2021-08-05 | 2021-08-05 | Racemization method of optically pure isobutyl succinonitrile |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113651717A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050283023A1 (en) * | 2004-06-21 | 2005-12-22 | Shanghui Hu | Preparation of pregabalin and related compounds |
| CN1942587A (en) * | 2004-04-14 | 2007-04-04 | 辉瑞产品公司 | Stereoselective bioconversion of aliphatic dinitriles into cyano carboxylic acids |
-
2021
- 2021-08-05 CN CN202110898385.8A patent/CN113651717A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1942587A (en) * | 2004-04-14 | 2007-04-04 | 辉瑞产品公司 | Stereoselective bioconversion of aliphatic dinitriles into cyano carboxylic acids |
| US20050283023A1 (en) * | 2004-06-21 | 2005-12-22 | Shanghui Hu | Preparation of pregabalin and related compounds |
Non-Patent Citations (1)
| Title |
|---|
| QING ZHANG 等: "Efficient Chemoenzymatic Synthesis of Optically Active Pregabalin from Racemic Isobutylsuccinonitrile", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 23, pages 2042 - 2049 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112368262B (en) | Method for preparing pregabalin intermediate (R) -3- (carbamoylmethyl) -5-methylhexanoic acid | |
| US5008192A (en) | Enzymatic process for the preparation of optically active cyanohydrins | |
| EA015418B1 (en) | Preparation of pregabalin and related compounds | |
| CN111662898A (en) | New lipase immobilization technology and method for applying same to enantiomer resolution | |
| Eleveld et al. | Enantioselective deprotonation of two racemic cyclic carbonyl compounds by a chiral lithium amide | |
| CN102260721A (en) | Process for preparing (S)-2-aminobutanamide by using enzyme method | |
| WO2024078646A1 (en) | Method for preparing (r)-tebuconazole by means of enzyme chemical process | |
| CN103966275B (en) | Bioanalysis prepares high-purity S-Leucine | |
| CN109161577B (en) | Levo Corey lactone diol intermediate, preparation method and pharmaceutical application thereof | |
| CN1680565A (en) | Preparation of chiral epichlorohydrin | |
| CN102250976A (en) | Synthesis method of chiral tert-leucine and final product obtained in method | |
| US5658796A (en) | Optical resolution of alkyl chroman-2-carboxylates | |
| CN113651717A (en) | Racemization method of optically pure isobutyl succinonitrile | |
| CN109295152B (en) | Method for catalyzing, esterifying and splitting 2-phenylpropionic acid enantiomer by Novozym435 lipase | |
| CN111686809A (en) | Carbonyl reductase/isopropanol dehydrogenase co-immobilized catalyst and preparation method and application thereof | |
| CN101260085A (en) | Catalytic asymmetric hydrogenation synthesis method for chiral gamma-sultam | |
| CN106636241B (en) | Method for preparing esmollin intermediate by enzyme method | |
| CN102465159A (en) | Synthesis process for preparing eslicarbazepine with microbial method | |
| CN101012181B (en) | Resolution method of DL-p-chlorophenylalanine | |
| CA2315837A1 (en) | Microbial production of levodione | |
| CN100376681C (en) | Process for preparing (R)-mandelic acid by microbial asymmetric reduction | |
| CN114921507B (en) | Resolution method of prostaglandin chiral intermediate 2-oxabicyclo- [3.3.0] oct-6-en-3-one | |
| CN100391934C (en) | Method for preparing L-glutamic acid | |
| CN117844876A (en) | Method for synthesizing 3-cyanopropionic acid derivative based on dynamic kinetic resolution, 3-cyanopropionic acid derivative and gamma-aminobutyric acid derivative | |
| CN114478446B (en) | Method for preparing chromogen III by converting D-acetamido glucose |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |