阅读说明：本技术 一种手性固膜及其在手性拆分中的应用 (Chiral solid membrane and application thereof in chiral resolution ) 是由 袁黎明 李丹 段爱红 章俊辉 于 2020-06-12 设计创作，主要内容包括：一种手性固膜及其在手性拆分中的应用,手性固膜为R-(3,3’-二苯基-1,1’-二萘基)-20-冠-6手性固膜,是由R-(3,3’-二苯基-1,1’-二萘基)-20-冠-6与高分子聚合物混合后溶解于有机溶剂中制得；采用所述制得的R-(3,3’-二苯基-1,1’-二萘基)-20-冠-6手性固膜应用于在所述苯甘氨酸、对羟基苯甘氨酸两种氨基酸外消旋体光学拆分中。本发明的优点为：获得的对映体纯度相对较高、成本低、节能、环保、易于连续操作和大规模工业生产。(A chiral solid film and its application in chiral resolution, the chiral solid film is R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 chiral solid film, is prepared by dissolving R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 and high molecular polymer in organic solvent after mixing; the prepared R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 chiral solid film is applied to optical resolution of two amino acid racemates of phenylglycine and p-hydroxyphenylglycine. The invention has the advantages that: the obtained enantiomer has relatively high purity, low cost, energy conservation, environmental protection, easy continuous operation and large-scale industrial production.)

1. A chiral solid film and its application in chiral resolution, wherein the chiral solid film is R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 chiral solid film, is prepared by dissolving R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 and high molecular polymer in organic solvent after mixing; wherein: the R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 chiral solid film is prepared by the following steps:

a. dissolving dried commercial polyethersulfone as a matrix in dry N, N-dimethylformamide;

b. stirring for 24h for dissolution, performing ultrasonic treatment for 1h, removing aggregated particle molecules, standing for 24h for deaeration;

c. adding 12% R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 into the solution, stirring for 24h, and standing for 24h to form uniform casting solution;

d. pouring the casting film liquid on smooth and clean non-woven fabric at room temperature, and scraping the non-woven fabric into a film with the thickness of 0.05-0.2 mm by using a film scraping knife;

e. volatilizing for 10min, soaking in 0 deg.C deionized water for 5 hr, and keeping in deionized water;

the R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 chiral solid film is applied to optical resolution of two amino acid racemates of phenylglycine and p-hydroxyphenylglycine.

2. The chiral solid film of claim 1 and its application in chiral resolution, wherein: the solid film material is a multifunctional high molecular substance of polysulfones, polyesters, polyamides, cellulose derivatives or crustaceans and R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6.

3. The chiral solid film of claim 1 and its application in chiral resolution, wherein: the application is that R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 with chiral recognition ability is used as a chiral selective recognition agent of the membrane to prepare a separation solid membrane through solution, and the separation solid membrane is used for resolution of phenylglycine and p-hydroxyphenylglycine racemates.

4. The chiral solid film according to claim 1 or 3 and the application thereof in chiral resolution, wherein the application is R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 chiral solid film resolution of phenylglycine and p-hydroxyphenylglycine raceme comprises the following steps:

a. dissolving dried commercial polyethersulfone as a matrix in dry N, N-dimethylformamide;

b. stirring for 24h for dissolution, performing ultrasonic treatment for 1h, removing aggregated particle molecules, standing for 24h for deaeration;

c. adding 12% R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 into the solution, stirring for 24h, and standing for 24h to form uniform casting solution;

d. pouring the casting film liquid on smooth and clean non-woven fabric at room temperature, and scraping the non-woven fabric into a film with the thickness of 0.05-0.2 mm by using a film scraping knife;

e. volatilizing for 10min, soaking in 0 deg.C deionized water for 5h, and keeping in deionized water;

f. and (2) putting the prepared R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 chiral solid membrane into a conventional dialysis device, adopting a membrane process driven by concentration difference, taking the concentration difference of 0.2-0.8 mg/mL as a driving force, respectively splitting aqueous solutions of racemes of phenylglycine and p-hydroxyphenylglycine, wherein the concentration of the aqueous solutions is 0.2-0.8 mg/mL, the pH value of the aqueous solutions is perchloric acid with the pH value of 2, and dialyzing for 4-15 days at 25 ℃ and 25 ℃ at room temperature.

Technical Field

The invention belongs to a polymer membrane chiral separation technology, and particularly relates to an application of an R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 chiral polymer solid membrane in resolution of phenylglycine and p-hydroxyphenylglycine racemates.

Background

Chirality is one of the essential attributes of nature, for example, nucleic acids, proteins, enzymes, polysaccharides that form organisms are all naturally occurring chiral substances in nature. The chiral problem relates to a plurality of fields such as agriculture, food, medicine, materials and the like, and is closely related to the daily life of people. Of the nearly 2000 commonly used drugs, about 500 exist as racemates. Racemic drugs, usually a stereoisomer, are pharmacologically active, whereas its mirror molecule often has no pharmacological activity and may even have toxic side effects. The "seal malformation baby" event, as in the 20 th century, is caused by the S configuration in the chiral drug "thalidomide". The R configuration in thalidomide can prevent vomiting symptoms occurring in the pregnancy, but people do not know that the thalidomide with the S configuration can make pregnant women have a blocking effect on blood supply of fetuses to cause infant malformation, and due to the tragic training, people pay more attention to acquisition of the single-chiral medicine.

At present, three methods of natural source, asymmetric synthesis and racemate resolution are mainly used for preparing the single chiral isomer. However, the natural chiral isomers are limited at present, and racemization often occurs in the generation process; some single chiral drugs obtained by asymmetric synthesis have technical problems and economic problems, such as higher cost, lower enantiomeric excess (e.e.%), and narrower total use range; although the chiral resolution technology comprises a mechanical resolution method, a chemical resolution method, a molecularly imprinted polymer resolution method, a chromatographic resolution method, a membrane resolution method and the like, the chiral resolution technology belongs to the chiral polymer membrane resolution method with the advantages of comprehensive scale production, environmental protection, energy conservation, low cost and the like.

Phenylglycine and p-hydroxyphenylglycine are important drug synthesis intermediates and are commonly used for producing beta-lactam antibiotics such as cefaclor, cefepime, piperacillin, ampicillin sodium, cefotrozine, amoxicillin, cefadroxil, and phenimidazole penicillin. Because they have optical activity and the two dextro-and levorotatory isomers have different effects, one enantiomer is commonly used in medicine for pharmaceutical production. China is a country with great production and demand for antibiotic medicines, and semi-synthetic cephalosporin and semi-synthetic penicillin medicines have become key and hot spots for the development of pharmaceutical industry. Therefore, it is important to separate the single isomer from the racemic mixtures of phenylglycine and p-hydroxyphenylglycine. To date, no literature report on the use of R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 as a chiral solid film has been found.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provides a preparation method of an R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 polyether sulfone solid membrane and application thereof in resolution of phenylglycine and p-hydroxyphenylglycine racemates.

The above object of the present invention is achieved by the following technical solutions:

a chiral solid film and its application in chiral resolution, the chiral solid film is R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 chiral solid film, is prepared by mixing R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 with high molecular polymer, and dissolving in organic solvent; wherein: the R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 chiral solid film is prepared by the following steps:

a. dissolving dried commercial polyethersulfone as a matrix in dry N, N-dimethylformamide;

b. stirring for 24h for dissolution, performing ultrasonic treatment for 1h to remove bubbles, removing aggregated particle molecules, and standing for 24h for defoaming;

c. adding 12% R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 into the solution, stirring for 24h, and standing for 24h to form uniform casting solution;

d. pouring the casting film liquid on smooth and clean non-woven fabric at room temperature, and scraping the casting film liquid into a film with the thickness of 0.05-0.2 mm by using a film scraping knife;

e. volatilizing for 10min, soaking in 0 deg.C deionized water for 5 hr, and keeping in deionized water;

the R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 chiral solid film is applied to optical resolution of two amino acid racemates of phenylglycine and p-hydroxyphenylglycine.

The invention relates to an application of R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 chiral solid membranes in the resolution of phenylglycine and p-hydroxyphenylglycine racemates respectively.

The solid film material is a multifunctional high molecular substance of polysulfones, polyesters, polyamides, cellulose derivatives or crustaceans and R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6.

The application of the invention is that R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 with chiral recognition ability is used as a chiral selective recognition agent of the membrane to prepare a separation solid membrane through solution, and the separation solid membrane is used for resolution of phenylglycine and p-hydroxyphenylglycine racemates.

The application of the invention is that R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 chiral solid membrane resolution phenylglycine and p-hydroxyphenylglycine raceme comprises the following steps:

a. dissolving dried commercial polyethersulfone as a matrix in dry N, N-dimethylformamide;

b. stirring for 24h for dissolution, performing ultrasonic treatment for 1h, removing aggregated particle molecules, standing for 24h for deaeration;

c. adding 12% R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 into the solution, stirring for 24h, and standing for 24h to form uniform casting solution;

d. pouring the casting film liquid on smooth and clean non-woven fabric at room temperature, and scraping the non-woven fabric into a film with the thickness of 0.05-0.2 mm by using a film scraping knife;

e. volatilizing for 10min, soaking in 0 deg.C deionized water for 5h, and keeping in deionized water;

f. and (2) putting the prepared R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 chiral solid membrane into a conventional dialysis device, adopting a membrane process driven by concentration difference, taking the concentration difference of 0.2-0.8 mg/mL as a driving force, respectively splitting aqueous solutions of racemes of phenylglycine and p-hydroxyphenylglycine, wherein the concentration of the aqueous solutions is 0.2-0.8 mg/mL, the pH value of the aqueous solutions is perchloric acid with the pH value of 2, and dialyzing for 4-15 days at 25 ℃ and 25 ℃ at room temperature.

Compared with the prior art, the invention has the following advantages:

1. the enantiomer purity (e.e.%) obtained by resolving the phenylglycine racemate by using the R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 chiral solid membrane reaches more than 76 percent, and the separation of the enantiomer with higher purity can be realized; the purity (e.e.%) of enantiomer obtained by resolving racemic p-hydroxyphenylglycine is more than 24%, and the basic separation of enantiomer can be realized;

2. the film splitting process is carried out at normal temperature, no phase change occurs, and the driving force is concentration difference, so the energy consumption is low;

3. no new chemical reagent is added in the process of membrane splitting, so the method is environment-friendly and has low cost;

4. the membrane separation is easy to operate continuously and is easy to carry out large-scale industrial production.

Drawings

FIG. 1 is a molecular structural formula of R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6;

FIG. 2 is a diagram of a dialysis apparatus for R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 chiral solid membrane;

wherein, 1, a raw material liquid pool; 2. a film; 3. a receiving liquid pool;

FIG. 3 is a scanning electron micrograph of the chiral solid film of R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 of example 1;

FIG. 4 is a chromatogram of example 2 using different thicknesses of R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 chiral solid films of the present invention;

FIG. 5 is a chromatogram of example 3 using different dialysis times for R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 chiral solid membranes of the present invention;

FIG. 6 is a chromatogram of different concentrations obtained by dialysis of example 4 using R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 chiral solid membranes of the present invention;

FIG. 7(a) is a chromatogram of selective dialysis of phenylglycine for example 5 using R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 chiral solid film of the present invention; FIG. 7(b) is a chromatogram of selective dialysis of p-hydroxyphenylglycine for example 5 using R- (3,3 '-diphenyl-1, 1' -dinaphthyl) -20-crown-6 chiral solid membranes of the present invention.

Detailed Description

The substance of the present invention will be described in further detail with reference to the accompanying drawings and examples, but the present invention is not limited thereto.