CN108059603B

CN108059603B - Refining process of Voglibose impurity N-methyl Jinggang enzyme alcohol amine

Info

Publication number: CN108059603B
Application number: CN201711475501.5A
Authority: CN
Inventors: 张富强; 常森
Original assignee: Shandong Xinhua Pharmaceutical Co Ltd
Current assignee: Shandong Xinhua Pharmaceutical Co Ltd
Priority date: 2017-12-29
Filing date: 2017-12-29
Publication date: 2020-08-14
Anticipated expiration: 2037-12-29
Also published as: CN108059603A

Abstract

The invention relates to a refining process of Voglibose impurity N-methyl Jinggang enzyme alcohol amine, which comprises the following two steps of separation and purification: (1) adsorbing with resin, and gradient eluting with H₂O elution, MeOH/H₂Elution with 20% O and pure MeOH gave H respectively₂O elution MeOH/H₂O ═ 20% elution and pure MeOH elution 3 eluates; (2) concentrating the pure MeOH eluent in the step (1) to obtain an N-methyl-well-sentry enzyme alcohol amine crude product, preparing a liquid phase by adopting HPLC, detecting at 210nm, eluting by using a methanol aqueous solution, separating the eluent, concentrating and freeze-drying to obtain an N-methyl-well-sentry enzyme alcohol amine pure product. The method has the advantages of simple process, high efficiency and high purity, and can obtain a pure product with the content of more than 99.9 percent from the N-methyl-Jinggang-enzyme alcohol amine crude product with the content of 30 percent by the treatment method.

Description

Refining process of Voglibose impurity N-methyl Jinggang enzyme alcohol amine

Technical Field

The invention relates to a refining process of Voglibose impurity N-methyl Jinggang enzyme alcohol amine, belonging to the technical field of drug synthesis.

Background

Voglibose has an inhibitory effect on α -glucosidase, thereby inhibiting hydrolysis of disaccharide and delaying absorption of saccharide. Simultaneously, the medicine can relieve hypertriglyceridemia and hyperinsulinemia.

The voglibose has obvious hypoglycemic effect, the occupancy rate of the voglibose in hypoglycemic drug markets is higher and higher, and the research on the related impurities of the voglibose, such as N-methyljingganganese olamine as an impurity, needs to determine the influence of the alcohol amine on the activity of the voglibose in vivo, so the research on the impurities of the voglibose is very necessary. The invention aims to obtain more than 99.9% of N-methyl Jinggang alcohol amine impurities, so that the methodology of the N-methyl Jinggang alcohol amine impurities can be better researched, and the influence of the N-methyl Jinggang alcohol amine impurities on the metabolism of the Voglibose in the body can be further researched.

At present, no patent or literature report is published.

Disclosure of Invention

The invention aims to provide a refining process of Voglibose impurity N-methyl Jinggang alcohol amine, which has the advantages of simple process, high efficiency and high purity, and the N-methyl Jinggang alcohol amine crude product with the content of 30 percent is processed by the method to obtain a pure product with the content of more than 99.9 percent.

The refining process of the voglibose impurity N-methyl Jinggang alcohol amine comprises two steps of separation and purification:

(1) firstly using resin to adsorb, then using gradient elution to make adsorption,wherein the gradient elution process is H₂O elution, MeOH/H₂Elution with 20% O and pure MeOH gave H respectively₂O elution MeOH/H₂O ═ 20% elution and pure MeOH elution 3 eluates;

(2) concentrating the pure MeOH eluent in the step (1) to obtain an N-methyl-well-sentry enzyme alcohol amine crude product, preparing a liquid phase by adopting HPLC, detecting at 210nm, eluting by using a methanol aqueous solution, separating the eluent, concentrating and freeze-drying to obtain an N-methyl-well-sentry enzyme alcohol amine pure product.

In step (2), the eluent used for preparing the liquid phase is 5% methanol, 10% methanol or 20% methanol.

In the step (1), the resin used is small-pore resin, and the small-pore resin is one of KY2-8 type, 001 × 7 strong-acid styrene cation exchange resin or Dowex50 type.

The small-pore resin is 001 × 7 strong-acid styrene cation exchange resin.

And (2) concentrating the pure MeOH eluent in the step (1), namely washing all the residual organic matters with methanol until no organic matter remains, and concentrating the methanol to obtain the N-methylwellian enzyme alcohol amine crude product.

H₂O eluent and MeOH/H₂The O ═ 20% eluent was a mixture of the trimethyl substitution product quaternary ammonium salt and the dimethyl substitution product, and the pure methanol eluent was the target product N-methylvalienamine.

The first step of separation and purification:

in the first step, the quaternary ammonium salt is removed as much as possible by using a small-pore resin for separation and purification.

Adsorbing with resin, and gradient eluting to obtain H₂O elution, MeOH/H₂Elution with 20% O and pure MeOH gave H respectively₂Eluent O, MeOH/H₂And (3) concentrating the obtained pure methanol eluent to obtain a crude product of the N-methyljingganganese olamine with the purity of more than 80%.

Characterization by Nuclear magnetism H₂O eluent and MeOH/H₂The eluent material with 20 percent of O is mainly trimethyl substitution product quaternary ammonium saltAnd a mixture of dimethyl substitution products; the methanol eluent material is mainly the target product N-methyl valienamine.

And a second step of separation and purification:

and concentrating the methanol eluent obtained in the first step, and preparing a liquid phase to obtain a pure target product.

The eluent used for the preparation of the liquid phase here is 5% methanol, 10% methanol, 20% methanol, preferably 10% methanol.

The sugar mixture containing trimethyl substitution product quaternary ammonium salt and target product N-methyl valienamine, during the concentration treatment, the trimethyl substitution product quaternary ammonium salt is used as a good methylating agent to destroy the N-methyl valienamine into dimethyl valienamine, so that the separation yield is reduced. The method of fast column passing is used to obtain 80% content of monomethyl product, and then the pure monomethyl product is obtained by preparative liquid phase separation.

After the second step of separation and purification, the purity of the product reaches more than 99.9 percent.

The chemical equation of the invention is as follows:

the process firstly adopts the adsorption of a small-hole adsorption resin, and the elution gradient is set to be H₂O elution, MeOH/H₂And (3) performing elution by 20 percent and pure MeOH, wherein the methanol eluent is mainly the target product N-methyl valienamine and has the purity of over 80 percent. Then preparing a pure product of the target product by using a preparation liquid phase.

Compared with the prior art, the invention has the following beneficial effects:

the refining process of the voglibose impurity N-methyl Jinggang alcohol amine has the advantages of simple process, high efficiency and high purity, and can obtain a pure product with the content of more than 99.9 percent by using the N-methyl Jinggang alcohol amine crude product with the content of 30 percent through the treatment method.

Drawings

FIG. 1 is a nuclear magnetic hydrogen spectrum of N-methyl Kong enzyme alcohol amine;

FIG. 2 is a nuclear magnetic carbon spectrum of N-methyl wellsite alcohol amine;

FIG. 3 is a high resolution mass spectrum of N-methyl Kong enzyme alcohol amine.

Detailed Description

The invention is further described with reference to the following examples, which are not intended to be limiting.

Example 1

Methyl iodide is firstly used for reacting with Jinggang enzyme alcohol amine to obtain a crude product of N-methyl-Jinggang enzyme alcohol amine with the content of about 30 percent.

Taking 1g of crude product, adsorbing with 80ml of KY2-8 type resin for half an hour, and then using 100ml of H₂O elution with 100ml MeOH/H₂Eluting with 20% of O, then eluting with 100ml of pure MeOH, wherein the obtained pure MeOH eluent is mainly the target product N-methylvalienamine, and concentrating the obtained pure MeOH eluent to obtain the crude product of N-methyljingganganese alcohol amine with the purity of 80.22%.

And in the second step, HPLC preparation liquid phase separation is adopted, detection is carried out at 210nm, 5% methanol elution is carried out, a purer target product eluent is separated, concentration and freeze-drying are carried out, and the N-methylwellsite enzymatic hydramine with the content of 175mg of 99.51% is obtained.

Example 2

Collecting 1g crude product, adsorbing with 100ml 001 × 7 strong acid styrene cation exchange resin for half an hour, and adsorbing with 100ml H₂O elution with 100ml MeOH/H₂Eluting with 20% of O, then eluting with 100ml of pure MeOH, wherein the obtained pure MeOH eluent is mainly the target product N-methylvalienamine, and concentrating the obtained pure MeOH eluent to obtain the crude product of N-methyljingganganese alcohol amine with the purity of 85.56%.

And in the second step, HPLC preparation liquid phase separation is adopted, detection is carried out at 210nm, 10% methanol elution is carried out, a relatively pure target product eluent is separated, concentration and freeze-drying are carried out, and 205mg of N-methylwellsite alcohol amine with the content of 99.99% is obtained.

The nuclear magnetic hydrogen spectrogram, nuclear magnetic carbon spectrogram and mass spectrogram of the N-methyl well oil amine are shown in figures 1-3.

Example 3

1g of the crude product is taken and adsorbed for half an hour on 90ml of Dowex50 resin, and then 100ml of H is used₂O elution with 100ml MeOH/H₂Eluting with 20% of O, then eluting with 100ml of pure MeOH, wherein the obtained pure MeOH eluent is mainly the target product N-methylvalienamine, and concentrating the obtained pure MeOH eluent to obtain the crude product of N-methyljingganganese alcohol amine with the purity of 81.23%.

And secondly, preparing liquid phase by HPLC (high performance liquid chromatography), separating, detecting at 210nm, eluting with 20% methanol, separating a relatively pure target product eluent, concentrating, and freeze-drying to obtain 170mg of N-methylwellsite alcohol amine with the content of 99.38%.

Claims

1. A refining process of Voglibose impurity N-methyl Jinggang enzyme alcohol amine is characterized by comprising two steps of separation and purification:

(1) firstly using methyl iodide to react with Jinggang enzyme alcohol amine to obtain a crude product of N-methyl-Jinggang enzyme alcohol amine with the content of 30%, taking the crude product, firstly using 001 × 7 strong acid styrene cation exchange resin to adsorb the crude product, and then carrying out gradient elution, wherein the gradient elution process is H₂O elution, MeOH/H₂Elution with 20% O and pure MeOH gave H respectively₂O elution MeOH/H₂O ═ 20% elution and pure MeOH elution 3 eluates;

2. The process for refining Voglibose impurity N-methyljinggangase alcohol amine according to claim 1, wherein in the step (2), the eluent for preparing the liquid phase is 5% methanol, 10% methanol or 20% methanol.

3. The refining process of voglibose impurity N-methyl wellsite hydramine according to claim 1, characterized in that the pure MeOH eluent in step (1) is concentrated by washing the remaining organic matters with methanol until no organic matters remain, and concentrating the methanol to obtain the crude product of N-methyl wellsite hydramine.

4. The refining process of Voglibose impurity N-methyl wellsite hydramine according to claim 1, characterized in that H₂O eluent and MeOH/H₂The O ═ 20% eluent was a mixture of trimethyl substituted product quaternary ammonium salt and dimethyl substituted product, and pure methanol eluent was the target product N-methylwellsite olamine.