CN110256261B

CN110256261B - Chiral resolution method for preparing levo 2-amino-1-butanol

Info

Publication number: CN110256261B
Application number: CN201910384086.5A
Authority: CN
Inventors: 吴大同
Original assignee: Changzhou University
Current assignee: Changzhou University
Priority date: 2019-02-20
Filing date: 2019-05-09
Publication date: 2022-06-24
Anticipated expiration: 2039-05-09
Also published as: CN110256261A

Abstract

The invention relates to a chiral resolution method for preparing levo 2-amino-1-butanol, which comprises the following specific steps: a) preparing a target chiral resolving agent by taking (1S,2S) -1, 2-cyclohexanediamine as a precursor through multi-step derivatization; b) dissolving a racemate compound 2-amino-1-butanol in an ethanol/water mixed solution, and mixing with an equimolar amount of a chiral resolving agent and copper chloride to precipitate a blue solid; c) removing ethanol in the mixed solution by rotary evaporation under reduced pressure, extracting with ethyl acetate, concentrating the filtrate, and vacuum drying to obtain optically pure levorotatory compound 2-amino-1-butanol with ee value of more than 99.0%. The invention has the beneficial effects that: the chiral resolving agent has the advantages of simple synthesis method, mild reaction conditions, high optical purity of the product obtained by separation, cost saving and suitability for industrial resolution.

Description

Chiral resolution method for preparing levo 2-amino-1-butanol

Technical Field

The invention relates to a chiral resolution method for preparing levo 2-amino-1-butanol, belonging to a separation method in the chemical field.

Background

Chirality, i.e., two molecules that are mirror-symmetric to each other, is a feature that is ubiquitous in nature. For example, proteins constituting the basic unit of a living body are all composed of L-type amino acids, and saccharides are all composed of D-type monosaccharides; in the macroscopic world, neither the tendrils of the plants nor the threads of the shells are chiral. Existing studies indicate that chiral molecules of different configurations may have distinct physicochemical properties. Therefore, high purity resolution of racemic compounds is of great importance. At present, a crystallization resolution method, a chromatography method, a biological resolution method, a chemical resolution method and the like are common chiral resolution methods. However, these methods have some disadvantages and are difficult to apply to industrial production. For example, chromatographic methods for chiral resolution are not suitable for industrial applications and are relatively expensive. Therefore, the development of a resolution method for obtaining an enantiomer with high optical purity is one of the problems that the industry needs to solve urgently.

2-amino-1-butanol is a common pharmaceutical intermediate, which is useful, for example, in the preparation of ethambutol, an antituberculous drug. At present, the resolution commonly adopted in industrial production is that high-purity single-configuration mandelic acid (or tartaric acid and glutamic acid) is added into 2-amino-1-butanol racemic modification to form salt with one configuration enantiomer selectively. However, this method has a not negligible problem: the obtained product has low optical product purity. Therefore, the preparation of a novel chiral resolving agent has important significance for realizing the efficient resolution of the 2-amino-1-butanol.

Disclosure of Invention

The invention aims to provide a chiral resolution method for preparing levo 2-amino-1-butanol. The prepared chiral resolving agent is mixed with the 2-amino-1-butanol racemate, and selective coordination complexing precipitation is carried out under the coordination action of copper ions, so that the 2-amino-1-butanol racemate is efficiently resolved.

A chiral resolution process for the preparation of l-2-amino-1-butanol comprising the steps of:

a. preparation of chiral resolving agent precursor: weighing 114mg of (1S,2S) -1, 2-cyclohexanediamine, adding into 50mL of acetonitrile, stirring in ice bath, dropwise adding 300mg of 2-bromoethyl isocyanate into the solution, reacting for 4 hours, centrifuging, filtering, washing the obtained product with dichloromethane, and drying in vacuum;

b. preparing a chiral resolving agent: weighing 207mg of the product, dissolving the product in 40mL of ethanol, adding 78mg of 4,4' -bipyridine, magnetically stirring, heating at 85 ℃, reacting for 36 hours, distilling under reduced pressure to remove the solvent, washing with ethyl acetate, and drying in vacuum to obtain the target chiral resolving agent;

c. resolving to prepare L-2-amino-1-butanol: weighing 40mg of racemate 2-amino-1-butanol, dissolving the racemate in 20mL of water/ethanol mixed solution, adding equimolar chiral resolving agent and copper chloride, separating out blue solid, performing high-speed centrifugation, performing reduced pressure rotary evaporation to remove ethanol in the mixed solution, extracting with ethyl acetate, removing water with anhydrous sodium sulfate, and performing vacuum drying to obtain optically pure levo-2-amino-1-butanol.

Further, in the step a, the magnetic stirring speed is 150-200r/min, the centrifugal rotation speed is 8000r/min, and the volume of the dichloromethane used for purification and washing is 30-50 mL.

Further, the magnetic stirring speed in step b is 150-200r/min, and the volume of ethyl acetate used for purification washing is 30-50 mL.

Further, in the step c, the centrifugal rotating speed is 8000r/min, the volume of ethyl acetate used for extraction is 30-50mL, and the mass of anhydrous sodium sulfate is 4-8 g.

The invention has the beneficial effects that: the chiral resolving agent has the advantages of simple synthesis method, mild reaction conditions, high resolving yield, high optical purity of the product obtained by separation, cost saving and suitability for industrial production.

Drawings

The experiment is further described below with reference to the accompanying drawings.

Fig. 1 is a chemical structural diagram of a chiral resolving agent prepared in example one.

Detailed Description

The invention will now be further illustrated by reference to specific examples, which are intended to be illustrative of the invention and are not intended to be a further limitation of the invention.

The optical purity of the levo-2-amino-1-butanol obtained by the resolution of the invention is calculated according to the following method:

ee＝(C_R-C_S)/(C_R+C_S)

in the formula, ee represents the percentage of the levorotatory enantiomeric excess, C_RAnd C_SRespectively represent the concentrations of L-2-amino-1-butanol and D-2-amino-1-butanol.

The first embodiment is as follows:

the preparation of the chiral resolving agent comprises the following two steps:

(1) weighing 1.14g of (1S,2S) -1, 2-cyclohexanediamine, adding the weighed materials into 150mL of acetonitrile, stirring in an ice bath, dropwise adding 3.0g of 2-bromoethyl isocyanate into the solution, separating out white solid, reacting for 4 hours, centrifuging, filtering, washing with 100mL of dichloromethane, and drying in vacuum to obtain 3.98g of an intermediate product for preparing the chiral resolving agent, wherein the yield is 96%;

(2) weighing 2.07g of the product prepared in the step 1, dissolving in 100mL of ethanol, adding 0.78g of 4,4' -bipyridine, magnetically stirring, heating at 80 ℃, reacting for 36h, removing the solvent by reduced pressure distillation, washing with 100mL of ethyl acetate, and vacuum drying to obtain 2.65g of the target chiral resolving agent (the molecular structure is shown in figure 1), wherein the yield is 93%.

Example two:

weighing 300mg of racemate compound 2-amino-1-butanol, dissolving the racemate compound in 30mL of water/ethanol mixed solution (the volume ratio is 1:1), adding equimolar chiral resolving agent (1.92g) and copper chloride (0.455g), separating out blue solid, centrifuging, performing rotary evaporation on the solution after resolution to remove ethanol, extracting with 60mL of ethyl acetate, adding 15g of anhydrous sodium sulfate into organic phase extract, drying, performing reduced pressure distillation to obtain 148mg of high-purity levo 2-amino-1-butanol, and measuring the ee value to be more than 99%.

Example three:

weighing 10g of racemic compound 2-amino-1-butanol, dissolving in 800mL of water/ethanol mixed solution (volume ratio is 1:1), adding equimolar chiral resolving agent (64g) and copper chloride (15.1g), separating out blue solid, centrifuging, carrying out reduced pressure rotary evaporation on the resolved solution to remove ethanol, extracting with 300mL of ethyl acetate, adding 35g of anhydrous sodium sulfate into organic phase extract, drying, carrying out reduced pressure distillation to obtain 4.92g of high-purity levo 2-amino-1-butanol, and measuring the ee value to be more than 99%.

Claims

1. A chiral resolution method for preparing levo 2-amino-1-butanol comprises the following steps:

a. preparation of chiral resolving agent precursor: weighing 114mg of (1S,2S) -1, 2-cyclohexanediamine, adding into 50mL of acetonitrile, stirring in an ice bath, dropwise adding 300mg of 2-bromoethyl isocyanate into the solution, reacting for 4 hours, centrifuging, filtering, washing the obtained product with dichloromethane, and drying in vacuum;

b. preparing a chiral resolving agent: weighing 207mg of the product, dissolving the product in 40mL of ethanol, adding 78mg of 4,4' -bipyridyl, magnetically stirring, heating at 85 ℃, reacting for 36 hours, distilling under reduced pressure to remove the solvent, washing with ethyl acetate, and drying in vacuum to obtain a target chiral resolving agent;

c. resolving to prepare L-2-amino-1-butanol: weighing 40mg of racemate 2-amino-1-butanol, dissolving in 20mL of water/ethanol mixed solution, adding equimolar chiral resolving agent and copper chloride, separating out blue solid, centrifuging at high speed, removing ethanol in the mixed solution by reduced pressure rotary evaporation, extracting with ethyl acetate, removing water by anhydrous sodium sulfate, removing ethyl acetate by reduced pressure rotary evaporation, and drying in vacuum to obtain optically pure levo-2-amino-1-butanol.

2. The chiral resolution method for preparing L-2-amino-1-butanol according to claim 1, which is characterized in that: in the step a, the magnetic stirring speed is 150-.

3. The chiral resolution process for the preparation of L-2-amino-1-butanol according to claim 1, characterized in that: the magnetic stirring speed in the step b is 150-.

4. The chiral resolution method for preparing L-2-amino-1-butanol according to claim 1, which is characterized in that: in the step c, the centrifugal rotating speed is 8000r/min, the volume of ethyl acetate used for extraction is 30-50mL, and the mass of anhydrous sodium sulfate is 4-8 g.