CN110183337A - A kind of chiral separation method being used to prepare high-purity single configuration leucinol - Google Patents
A kind of chiral separation method being used to prepare high-purity single configuration leucinol Download PDFInfo
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- CN110183337A CN110183337A CN201910383652.0A CN201910383652A CN110183337A CN 110183337 A CN110183337 A CN 110183337A CN 201910383652 A CN201910383652 A CN 201910383652A CN 110183337 A CN110183337 A CN 110183337A
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- leucinol
- chiral
- ethyl acetate
- single configuration
- separation method
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/30—Preparation of optical isomers
- C07C227/34—Preparation of optical isomers by separation of optical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The present invention relates to a kind of chiral separation method for being used to prepare high-purity single configuration leucinol, specific steps include: a) with (1R,2R) -1,2- cyclohexanediamine is precursor, prepares catenanes chiral resolving agent through multistep derivative；B) raceme leucinol is dissolved in ethanol/water mixed solution, and is mixed with the chiral resolving agent of single configuration leucinol equimolar amounts and copper chloride, there is solid precipitation；C) vacuum rotary steam removes the ethyl alcohol in mixed solution, is extracted with ethyl acetate, and filtrate is concentrated, obtains optically pure dextrorotation leucinol, and ee value is up to 98.0% or more；D) solid is precipitated in step c and is dissolved in deionized water, be extracted with ethyl acetate, filtrate is concentrated, obtains optically pure left-handed leucinol, ee value is up to 99.0% or more.The beneficial effects of the present invention are: catenanes chiral resolving agent synthetic method is simple, chiral resolution high income, isolated leucinol optical purity is high, is easy to scale chiral resolution.
Description
Technical field
The present invention relates to a kind of chiral separation methods for being used to prepare high-purity single configuration leucinol, belong to a kind of chemical industry neck
The separation method in domain.
Background technique
Chiral amino alcohol is a kind of important organic molecule with optical activation, is widely used to medicine, pesticide, change
The fields such as work.May have entirely different pharmacology, physicochemical property in view of the chiral molecules of the various configuration of enantiomer, therefore,
The single configuration amino alcohol molecule of preparation high-purity has great importance.In the existing method, to the height of racemic mixture
It is a kind of effective way for obtaining single configuration chiral molecules that effect, which is split,.Currently, developed method has crystallization Split Method, chromatography
Method, biological resolution method and chemical resolution method etc..However, either all there is some shortcomings for which kind of method.Such as: utilize chromatography
Method carries out fractionation higher cost to enantiomer, needs to use expensive chiral column, and is unfavorable for scale fractionation；Crystallization is torn open
Point-score, which exists, splits low efficiency, is not easy to obtain the isomers of purity is high.Therefore, foundation fractionation is high-efficient, is easy to scale fractionation
Chiral Separation method be present industrial urgent need to resolve one of problem.
Leucinol is a kind of amino acid (leucine) derivative, is commonly used for medicine, pesticide intermediate.In order to realize to bright ammonia
The efficient separating of alcohol, it is general by be added the higher organic acid of optical purity and its at salt to generate precipitating.But this method
Have the defects that very important: product optics product purity obtained is lower and splitting condition is not easy to control.Currently, scale
Leucinol is split still without finding suitable method.Therefore, it is realized by preparing the novel chiral resolving agent of one kind to leucinol
Efficient separating have great importance.
Summary of the invention
The purpose of the invention is to provide a kind of chiral separation methods for being used to prepare high-purity single configuration leucinol.It will
After the catenanes chiral resolving agent of preparation is mixed with leucinol raceme, selective coordination occurs under the coordination of copper ion
Complex-precipitation, to obtain higher left-handed, the dextrorotation leucinol of optical purity.
A kind of chiral separation method being used to prepare high-purity single configuration leucinol, comprising the following steps:
A, it prepares chiral resolving agent precursor: weighing 228mg dextrorotation cyclohexanediamine and be added in 80-100mL acetonitrile, 0oIt is stirred under C,
600mg2- bromine ethyl isocyanate is added dropwise into above-mentioned solution, there is white solid production, after reacting 6-8h, chloroform is used in centrifugal filtration
Wash obtained solid product, vacuum drying；
B, it prepares catenanes chiral resolving agent: weighing the above-mentioned product of 207mg and be dissolved in 40-60mL ethyl alcohol, 78mg4 is added, 4'- joins pyrrole
Pyridine and 180mg dibenzo-18-crown-6 (DB18C6), magnetic agitation, and 85oC heating, after reaction 48-60 hours, vacuum rotary steam is removed
Solvent, with ethanol washing, vacuum drying；
C, it splits preparation dextrorotation leucinol: weighing 40mg raceme leucinol and be dissolved in 20-30mL water/alcohol mixed solution, add
Enter the chiral resolving agent and copper chloride with single configuration leucinol equimolar amounts, there is solid precipitation, high speed centrifugation, vacuum rotary steam removes
Ethyl alcohol in mixed solution, ethyl acetate extraction are removed water with anhydrous sodium sulfate is dry simultaneously, and vacuum rotary steam removes ethyl acetate, very
Sky is dry, obtains optically pure dextrorotation leucinol；
D, it splits and prepare left-handed leucinol: the step c solid being precipitated is dissolved in deionized water, ethyl acetate extracts while with anhydrous
The dry water removal of sodium sulphate, vacuum rotary steam remove ethyl acetate, and vacuum drying obtains optically pure left-handed leucinol.
Further, in step a magnetic stirring speed be 200-250r/min, centrifugal rotational speed 8000-10000r/min,
It is 30-50mL that chloroform volume used is washed in purifying.
Further, magnetic stirring speed is 200-250r/min in step b, and it is 25- that ethyl alcohol volume used is washed in purifying
50mL。
Further, centrifugal rotational speed is 8000-10000r/min in step c, and extracting ethyl acetate volume used is 30-
50mL, anhydrous sodium sulfate quality are 10-20g.
Further, deionized water volume is 10-15mL in step d, and extracting ethyl acetate volume used is 30-50mL,
Anhydrous sodium sulfate quality is 10-20g.
The beneficial effects of the present invention are: catenanes chiral resolving agent synthetic method is simple, chiral resolution high income, separates
To leucinol optical purity it is high, be easy to scale chiral resolution.
Detailed description of the invention
This experiment is further illustrated with reference to the accompanying drawing.
Fig. 1 is the chemical structural drawing of the catenanes chiral resolving agent prepared in embodiment one.
Specific embodiment
Presently in connection with specific embodiment, the present invention will be further described, following embodiment be intended to illustrate invention rather than
Limitation of the invention further.
The optical purity of the present invention for splitting obtained leucinol is identified as follows:
ee=(CS-CR)/(CS-CR)
In formula, ee indicates the excessive value of S type enantiomer, CSAnd CRRespectively indicate the concentration of S- leucinol and R- leucinol.
Embodiment one:
The preparation of chiral resolving agent includes following two step:
(1) 2.28g (1 is weighedR,2R) -1,2- cyclohexanediamine is added in 150mL acetonitrile, and 0oIt is stirred under C, in Xiang Shangshu solution
6.0g2- bromine ethyl isocyanate is added dropwise, there is white solid precipitation, after reacting 8h, centrifugal filtration produces obtained by 100mL chloroform
Object is dried in vacuo to get the reacting precursor 7.78g for preparing chiral resolving agent, yield 94%.
(2) it weighs the above-mentioned product of 4.14g and is dissolved in 100mL ethyl alcohol, 1.56g4,4'- bipyridyl and 1.80g dibenzo-is added
Crown ether -6 18-, magnetic agitation, and 85oC heating, after reaction 60 hours, vacuum rotary steam removes solvent, is washed with 100mL ethyl alcohol
Wash, be dried in vacuo as shown in Figure 1 to get the catenanes chiral resolving agent 6.75g(molecular structure), yield 90%.
Embodiment two:
It weighs 236mg raceme compound leucinol and is dissolved in 20mL water/alcohol mixed solution (volume ratio 1:1), be added and list
The chiral resolving agent (0.75g) and copper chloride (0.135g) of configuration leucinol equimolar amounts, there is blue solid precipitation, at a high speed from
Solution revolving after fractionation is removed ethyl alcohol therein, is extracted with 30mL ethyl acetate, it is anhydrous that 10g is added in organic extractant phase liquid by the heart
Sodium sulphate is dry, is evaporated under reduced pressure, and vacuum drying obtains the dextrorotation leucinol 116mg of high-purity, measures ee value greater than 98%.It will be blue
Color solid is dissolved in 20mL deionized water, is extracted with 30mL ethyl acetate, and the drying of 10g anhydrous sodium sulfate is added in organic extractant phase liquid,
Vacuum rotary steam removes ethyl acetate, and vacuum drying obtains the left-handed rotation leucinol 110mg of high-purity, measures ee value greater than 99%.
Embodiment three:
It weighs 2.36g raceme compound leucinol and is dissolved in 500mL water/alcohol mixed solution (volume ratio 1:1), be added and list
The chiral resolving agent (7.5g) and copper chloride (1.35g) of configuration leucinol equimolar amounts, there is a blue solid precipitation, high speed centrifugation,
Solution revolving removes ethyl alcohol therein after splitting, and is extracted with 100mL ethyl acetate, and the anhydrous sulphur of 25g is added in organic extractant phase liquid
Sour sodium is dry, is evaporated under reduced pressure, and vacuum drying obtains the dextrorotation leucinol 1.08g of high-purity, measures ee value greater than 98%.It will be blue
Solid is dissolved in 100mL deionized water, is extracted with 150mL ethyl acetate, and the drying of 30g anhydrous sodium sulfate is added in organic extractant phase liquid,
Vacuum rotary steam removes ethyl acetate, and vacuum drying obtains the left-handed rotation leucinol 1.09g of high-purity, measures ee value greater than 99%.
Claims (5)
1. a kind of chiral separation method for being used to prepare high-purity single configuration leucinol, steps are as follows:
A, it prepares chiral resolving agent precursor: weighing 228mg dextrorotation cyclohexanediamine and be added in 80-100mL acetonitrile, 0oIt is stirred under C,
600mg2- bromine ethyl isocyanate is added dropwise into above-mentioned solution, there is white solid production, after reacting 6-8h, chloroform is used in centrifugal filtration
Wash obtained solid product, vacuum drying；
B, it prepares catenanes chiral resolving agent: weighing the above-mentioned product of 207mg and be dissolved in 40-60mL ethyl alcohol, 78mg4 is added, 4'- joins pyrrole
Pyridine and 180mg dibenzo-18-crown-6 (DB18C6), magnetic agitation, and 85oC heating, after reaction 48-60 hours, vacuum rotary steam is removed
Solvent, with ethanol washing, vacuum drying；
C, it splits preparation dextrorotation leucinol: weighing 40mg raceme leucinol and be dissolved in 20-30mL water/alcohol mixed solution, add
Enter the chiral resolving agent and copper chloride with single configuration leucinol equimolar amounts, there is solid precipitation, high speed centrifugation, vacuum rotary steam removes
Ethyl alcohol in mixed solution, ethyl acetate extraction are removed water with anhydrous sodium sulfate is dry simultaneously, and vacuum rotary steam removes ethyl acetate, very
Sky is dry, obtains optically pure dextrorotation leucinol；
D, it splits and prepare left-handed leucinol: the step c solid being precipitated is dissolved in deionized water, ethyl acetate extracts while with anhydrous
The dry water removal of sodium sulphate, vacuum rotary steam remove ethyl acetate, and vacuum drying obtains optically pure left-handed leucinol.
2. a kind of chiral separation method for being used to prepare high-purity single configuration leucinol according to claim 1, it is characterized in that:
Magnetic stirring speed is 200-250r/min, centrifugal rotational speed 8000-10000r/min in the step a, is purified used in washing
Chloroform volume is 30-50mL.
3. a kind of chiral separation method for being used to prepare high-purity single configuration leucinol according to claim 1, it is characterized in that:
Magnetic stirring speed is 200-250r/min in the step b, and it is 25-50mL that ethyl alcohol volume used is washed in purifying.
4. a kind of chiral separation method for being used to prepare high-purity single configuration leucinol according to claim 1, it is characterized in that:
Centrifugal rotational speed is 8000-10000r/min in the step c, and extracting ethyl acetate volume used is 30-50mL, anhydrous sodium sulfate
Quality is 10-20g.
5. a kind of chiral separation method for being used to prepare high-purity single configuration leucinol according to claim 1, it is characterized in that:
Deionized water volume is 10-15mL in the step d, and extracting ethyl acetate volume used is 30-50mL, anhydrous sodium sulfate quality
For 10-20g.
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| CN2019101274957 | 2019-02-20 | ||
| CN201910127495 | 2019-02-20 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110591105A (en) * | 2019-09-05 | 2019-12-20 | 常州大学 | Preparation and application of rotaxane molecule with electrochemical activity |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001002663A (en) * | 1999-06-23 | 2001-01-09 | Agency Of Ind Science & Technol | Compound containing rotaxane structure in main chain and its intermediate, and method for producing the same |
| JP2009067699A (en) * | 2007-09-11 | 2009-04-02 | Tokyo Institute Of Technology | Rotaxane and method for producing the same |
| CN104177384A (en) * | 2013-05-24 | 2014-12-03 | 邱胜贤 | Pseudorotaxane, rotaxane and catenane structures guided by metal ions |
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2019
- 2019-05-09 CN CN201910383652.0A patent/CN110183337A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001002663A (en) * | 1999-06-23 | 2001-01-09 | Agency Of Ind Science & Technol | Compound containing rotaxane structure in main chain and its intermediate, and method for producing the same |
| JP2009067699A (en) * | 2007-09-11 | 2009-04-02 | Tokyo Institute Of Technology | Rotaxane and method for producing the same |
| CN104177384A (en) * | 2013-05-24 | 2014-12-03 | 邱胜贤 | Pseudorotaxane, rotaxane and catenane structures guided by metal ions |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110591105A (en) * | 2019-09-05 | 2019-12-20 | 常州大学 | Preparation and application of rotaxane molecule with electrochemical activity |
| CN110591105B (en) * | 2019-09-05 | 2021-11-30 | 常州大学 | Preparation method of electrochemical-active rotaxane molecule for chiral recognition |
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Application publication date: 20190830 |