CN101407487A - Method for preparing racemate of R or S-1-substituent-3-amino pyrrolidine from R or S-1-substituent-3-amino pyrrolidine - Google Patents
Method for preparing racemate of R or S-1-substituent-3-amino pyrrolidine from R or S-1-substituent-3-amino pyrrolidine Download PDFInfo
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- CN101407487A CN101407487A CNA200810136263XA CN200810136263A CN101407487A CN 101407487 A CN101407487 A CN 101407487A CN A200810136263X A CNA200810136263X A CN A200810136263XA CN 200810136263 A CN200810136263 A CN 200810136263A CN 101407487 A CN101407487 A CN 101407487A
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Abstract
The invention relates to a method for preparing raceme thereof from R or S-1-substituent-3-amino pyrrolidine, wherein, the substituent is H, alkyl, naphthenic base, aralkyl, aryl, alkoxycarbonyl, aryl alkoxycarbonyl or aryloxy carbonyl. Firstly, 1-substituent-3-ketoxime pyrrolidine is obtained from R or S-1-substituent-3-amino pyrrolidine through catalytic oxidation; raceme 1-substituent-3-amino pyrrolidine is obtained from the obtained 1-substituent-3-ketoxime pyrrolidine through catalytic hydrogenation, wherein, hydrogen peroxide is adopted in the catalytic hydrogenation reaction as oxidant and the reaction is carried out at the temperature of -10-100 DEG C. The method for preparing raceme thereof from R or S-1-substituent-3-amino pyrrolidine has unique advantages that the reaction can be carried out at relatively low temperature, the raw material is easy to get, the process is simple, requirements for equipment are low; safety is good, the method can be applied to large scale industrialization production and has high yield coefficient and low cost.
Description
Technical field
The present invention relates to the racemization method of optically active amines, particularly relate to and have optically active 1-substituting group-3-amino-pyrrolidine and prepare the method for its racemic modification.
Background technology
Has optically active R or S-1-substituting group-3-amino-pyrrolidine and is the key intermediate of synthetic a large amount of chiral drugs such as Comprecin, carbapenem antibiotic, chemokine conditioning agent etc., but only need a kind of optical antipode wherein usually, another kind of optical antipode is a by product, unwanted by product is not added utilization will cause great waste.The unwanted optical antipode of racemization, preparing needed enantiomorph from racemic modification again is to make one of more cost effective effective way of synthetic drugs.
Publication number is the racemization method that Chiral Amine has been reported in the Chinese invention patent application of CN1330618 and CN1352629, and it is catalyst fixed bed to adopt metal catalyst to prepare, and at 150～270 ℃, reaction makes under the condition of 0.1～10MPa.This method facility investment in early stage is bigger, and inapplicable to heat-labile compound, and therefore, the application of this method has certain limitation.
Summary of the invention
Technical problem to be solved by this invention provides and a kind ofly prepares the method for its racemic modification by R or S-1-substituting group-3-amino-pyrrolidine, and this method is carried out at a lower temperature, and technology is easy, cost is low.
For solving above technical problem, the present invention takes following technical scheme:
A kind ofly prepare the method for its racemic modification by R or S-1-substituting group-3-amino-pyrrolidine, described substituting group is H, alkyl, and cycloalkyl, aralkyl, aryl, carbalkoxy, aralkoxycarbonyl or aryloxy carbonyl, this method comprises the steps:
(1), R or S-1-substituting group-3-amino-pyrrolidine obtains 1-substituting group-3-ketoxime tetramethyleneimine through catalyzed oxidation;
(2), described 1-substituting group-3-ketoxime tetramethyleneimine makes racemize 1-substituting group-3-amino-pyrrolidine through catalytic hydrogenation reduction,
Above-mentioned steps is expressed as follows with chemical equation:
Wherein, X represents described substituting group.
In the step (1), it is oxygenant that catalytic oxidation adopts hydrogen peroxide, carries out under temperature is-10～100 ℃.
As the preferred embodiments of the invention: in the step (1), in the catalytic oxidation mol ratio of R or S-1-substituting group-3-amino-pyrrolidine, catalyzer, hydrogen peroxide be preferably 1: 0.1～1.0: 1.0～20, most preferably 1: 0.6～0.8: 9～11.The solvent of catalytic oxidation is preferably the lower alcohol of C1～C4 and the miscellany of water, and the mass percentage content of alcohol is 10%～90% in the mixture, and most preferably pure content is 40%～60% alcohol-water mixture.Catalytic oxidation preferably carries out under 40～50 ℃ of temperature, and the reaction times is 24～30 hours.
Catalytic oxidation is catalyzer with the sodium wolframate.
The detailed process of step (2) is that 1-substituting group-3-ketoxime tetramethyleneimine is dissolved in lower alcohol, adds Raney's nickel, logical hydrogen, and stirring reaction made described racemic modification in 1～50 hour.Wherein, the pressure that hydrogen feeds preferably carries out under normal pressure between 1～100atm.
Because the enforcement of above technical scheme, the present invention compared with prior art has following advantage:
The present invention can carry out at a lower temperature, and raw material is easy to get, technology is simple, and equipment requirements is low, and security is better, is used for industrialized production and has yield height (total recovery is greater than 82%) and the low unique advantage of cost.
Embodiment
Below be specific embodiments of the invention, technical scheme of the present invention is further described, but the present invention is not limited to these embodiment.
Embodiment 1
Method by S-(-)-3-amino-pyrrolidine preparation (±)-3-amino-pyrrolidine comprises the steps:
(1), S-(-)-3-amino-pyrrolidine generation oxidizing reaction generates 3-ketoxime tetramethyleneimine:
With 50.0g S-(-)-3-amino-pyrrolidine (
) be dissolved in the aqueous ethanolic solution of 1000ml 50%, add the 96.0g sodium wolframate, stirring and dissolving, be heated to 40～50 ℃, drip 300g 30% superoxol, dropwise, back flow reaction 20 hours is cooled to room temperature, stirs 1 hour, there is solid to separate out, filter, use the 100ml water washing, 70 ℃ of dryings 8～10 hours, get faint yellow solid 3-ketoxime tetramethyleneimine 53.0g, yield 91%.
(2), step (1) gained 3-ketoxime tetramethyleneimine generates (±)-3-amino-pyrrolidine through the catalytic hydrogenation reduction:
50.0g 3-ketoxime tetramethyleneimine is dissolved in 500ml ethanol, adds the 10.0g Raney's nickel, normal temperature, normal pressure feed hydrogen down, stirring reaction 30 hours, and reaction finishes, and filters, and it is dried that filtrate decompression is concentrated into, and gets oily matter (±)-3-amino-pyrrolidine 40.9g, yield 95%,
Embodiment 2
Method by R-(+)-3-amino-pyrrolidine preparation (±)-3-amino-pyrrolidine comprises the steps:
(1), R-(+)-3-amino-pyrrolidine generation oxidizing reaction generates 3-ketoxime tetramethyleneimine:
With 50.0g R-(+)-3-amino-pyrrolidine (
) be dissolved in the aqueous ethanolic solution of 1000ml 50%, add the 96.0g sodium wolframate, stirring and dissolving, be heated to 40～50 ℃, drip 300g 30% superoxol, dropwise, back flow reaction 20 hours is cooled to room temperature, stirs 1 hour, there is solid to separate out, filter, use the 100ml water washing, 70 ℃ of dryings 8～10 hours, get faint yellow solid 3-ketoxime tetramethyleneimine 51.5g, yield 88.5%.
(2), step (1) gained 3-ketoxime tetramethyleneimine generates (±)-3-amino-pyrrolidine through the catalytic hydrogenation reduction:
50.0g 3-ketoxime tetramethyleneimine is dissolved in 500ml ethanol, adds the 10.0g Raney's nickel, normal temperature, normal pressure feed hydrogen down, stirring reaction 30 hours, and reaction finishes, and filters, and it is dried that filtrate decompression is concentrated into, and gets oily matter (±)-3-amino-pyrrolidine 40.9g, yield 95%,
Embodiment 3:
Method by S-(+)-1-phenmethyl-3-amino-pyrrolidine preparation (±)-1-phenmethyl-3-amino-pyrrolidine comprises the steps:
(1), oxidation S-(+)-1-phenmethyl-3-amino-pyrrolidine obtains 1-phenmethyl-3-ketoxime tetramethyleneimine:
10.0g S-(+)-1-phenmethyl-3-amino-pyrrolidine (
) be dissolved in the aqueous ethanolic solution of 500ml 50%, add the 10.0g sodium wolframate, stirring and dissolving, be heated to 40～50 ℃, drip 64g 30% superoxol, dropwise, continue reaction 24 hours, be cooled to room temperature, stirred 1 hour, there is solid to separate out, filter, use the 20ml water washing, 70 ℃ of dryings 8～10 hours, get off-white color solid 1-phenmethyl-3-ketoxime tetramethyleneimine 9.6g, yield 89%.
(2), step (1) gained 1-phenmethyl-3-ketoxime tetramethyleneimine generates (±)-1-phenmethyl-3-amino-pyrrolidine through the catalytic hydrogenation reduction:
9.0g 1-phenmethyl-3-ketoxime tetramethyleneimine is dissolved in 200ml ethanol, adds the 3.0g Raney's nickel, normal temperature, normal pressure feed hydrogen, stirring reaction 24 hours down, reaction finishes, and filters, and filtrate decompression is concentrated into dried, get oily matter (±)-1-phenmethyl-3-amino-pyrrolidine 7.8g, yield 93.6%
Embodiment 4
Method by R-(-)-1-phenmethyl-3-amino-pyrrolidine preparation (±)-1-phenmethyl-3-amino-pyrrolidine comprises the steps:
(1), oxidation R-(-)-1-phenmethyl-3-amino-pyrrolidine obtains 1-phenmethyl-3-ketoxime tetramethyleneimine: with 10.0g R-(-)-1-phenmethyl-3-amino-pyrrolidine (
) be dissolved in the aqueous ethanolic solution of 500ml 50%, add the 10.0g sodium wolframate, stirring and dissolving, be heated to 40～50 ℃, drip 64g 30% superoxol, dropwise, continue reaction 24 hours, be cooled to room temperature, stirred 1 hour, there is solid to separate out, filter, use the 20ml water washing, 70 ℃ of dryings 8～10 hours, get off-white color solid 1-phenmethyl-3-ketoxime tetramethyleneimine 9.4g, yield 87%.
(2), step (1) gained 1-phenmethyl-3-ketoxime tetramethyleneimine generates (±)-1-phenmethyl-3-amino-pyrrolidine through the catalytic hydrogenation reduction:
9.0g 1-phenmethyl-3-ketoxime tetramethyleneimine is dissolved in 200ml ethanol, adds the 3.0g Raney's nickel, normal temperature, normal pressure feed hydrogen, stirring reaction 24 hours down, reaction finishes, and filters, and filtrate decompression is concentrated into dried, get oily matter (±)-1-phenmethyl-3-amino-pyrrolidine 8.0g, yield 96%
Claims (10)
1, a kind ofly prepare the method for its racemic modification by R or S-1-substituting group-3-amino-pyrrolidine, described substituting group is H, alkyl, and cycloalkyl, aralkyl, aryl, carbalkoxy, aralkoxycarbonyl or aryloxy carbonyl is characterized in that: this method comprises the steps:
(1), R or S-1-substituting group-3-amino-pyrrolidine obtains 1-substituting group-3-ketoxime tetramethyleneimine through catalyzed oxidation;
(2), described 1-substituting group-3-ketoxime tetramethyleneimine makes racemize 1-substituting group-3-amino-pyrrolidine through catalytic hydrogenation reduction,
In the step (1), it is oxygenant that catalytic oxidation adopts hydrogen peroxide, carries out under temperature is-10～100 ℃.
2, according to claim 1ly prepare the method for its racemic modification by R or S-1-substituting group-3-amino-pyrrolidine, it is characterized in that: in the step (1), the mol ratio of R or S-1-substituting group-3-amino-pyrrolidine, catalyzer, hydrogen peroxide is 1: 0.1～1.0: 1.0～20 in the catalytic oxidation.
3, according to claim 2ly prepare the method for its racemic modification by R or S-1-substituting group-3-amino-pyrrolidine, it is characterized in that: in the step (1), the mol ratio of R or S-1-substituting group-3-amino-pyrrolidine, catalyzer, hydrogen peroxide is 1: 0.6～0.8: 9～11 in the catalytic oxidation.
4, according to claim 1ly prepare the method for its racemic modification by R or S-1-substituting group-3-amino-pyrrolidine, it is characterized in that: in the step (1), the solvent of catalytic oxidation is the lower alcohol of C1～C4 and the miscellany of water, and the mass percentage content of alcohol is 10%～90% in the mixture.
5, according to claim 4ly prepared the method for its racemic modification, be it is characterized in that by R or S-1-substituting group-3-amino-pyrrolidine: the mass percentage content of alcohol is 40%～60% in the described mixture.
6, according to claim 1ly prepared the method for its racemic modification, be it is characterized in that by R or S-1-substituting group-3-amino-pyrrolidine: in the step (1), catalytic oxidation carries out under 40～50 ℃ of temperature, and the reaction times is 24～30 hours.
7, prepared the method for its racemic modification, be it is characterized in that by R or S-1-substituting group-3-amino-pyrrolidine according to above-mentioned any claim is described: in the step (1), catalytic oxidation is catalyzer with the sodium wolframate.
8, according in the claim 1～6 any one describedly prepare the method for its racemic modification by R or S-1-substituting group-3-amino-pyrrolidine, it is characterized in that: the detailed process of step (2) is that 1-substituting group-3-ketoxime tetramethyleneimine is dissolved in lower alcohol, add Raney's nickel, logical hydrogen, stirring reaction made described racemic modification in 1～50 hour.
9, according to claim 8ly prepared the method for its racemic modification, be it is characterized in that by R or S-1-substituting group-3-amino-pyrrolidine: in the step (2), the pressure that hydrogen feeds is 1～100atm.
10, according to claim 9ly prepared the method for its racemic modification, be it is characterized in that by R or S-1-substituting group-3-amino-pyrrolidine: described catalytic hydrogenation is carried out under normal pressure.
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| CN200810136263XA CN101407487B (en) | 2008-11-19 | 2008-11-19 | Method for preparing racemate of R or S-1-substitued-3-amino pyrrolidine from R or S-1-substituent-3-amino pyrrolidine |
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| CN200810136263XA CN101407487B (en) | 2008-11-19 | 2008-11-19 | Method for preparing racemate of R or S-1-substitued-3-amino pyrrolidine from R or S-1-substituent-3-amino pyrrolidine |
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| CN101407487B CN101407487B (en) | 2011-04-06 |
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Owner name: ABA CHEMICALS CO., LTD Free format text: FORMER NAME: ABA CHEMICALS (SUZHOU) CO., LTD. |
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Address after: 215433, No. 18 Dongfang East Road, petrochemical District, Taicang Port Development Zone, Taicang, Jiangsu Patentee after: Aba Chemicals Corporation Address before: 215433, No. 18 Dongfang East Road, petrochemical District, Taicang Port Development Zone, Taicang, Jiangsu Patentee before: ABA Chemicals (Suzhou) Co., Ltd. |