CN111377920B

CN111377920B - Method for refining quinine compound containing quaternary ammonium group

Info

Publication number: CN111377920B
Application number: CN201811615105.2A
Authority: CN
Inventors: 于文占; 牛晓光; 潘缘媛
Original assignee: YinGu Pharmaceutical Co Ltd
Current assignee: YinGu Pharmaceutical Co Ltd
Priority date: 2018-12-27
Filing date: 2018-12-27
Publication date: 2021-10-26
Anticipated expiration: 2038-12-27
Also published as: CN111377920A

Abstract

The present invention relates to a composition containing quaternary phosphonium represented by the following formula (1)A refining method of an ammonium group quinine compound comprises the steps of mixing a crude compound with an organic solvent-water mixed solution, heating to dissolve the crude compound until the solution is clear, filtering while the solution is hot, and cooling and crystallizing the filtrate. Researches find that the quinine compound containing quaternary ammonium groups is refined by taking the mixed solution of water and an organic solvent as a crystallization solvent, most impurities such as reaction byproducts, inorganic salts, unreacted raw materials and the like can be effectively removed through a recrystallization process, the use of the organic solvent is obviously reduced, the pollution to the environment is avoided or reduced, the product purity is obviously improved, and the obtained product meets the standards of medicinal raw material medicines.

Description

Method for refining quinine compound containing quaternary ammonium group

Technical Field

The invention belongs to the technical field of chemical drugs, and particularly relates to a refining method of a quinine compound containing quaternary ammonium groups.

Background

Pharmacological research shows that quinine compounds containing quaternary ammonium groups shown in the following formula (1) have the activity of blocking cholinergic receptors; the compound has obvious inhibition effect on guinea pig specific allergic asthma. More importantly, the compound cannot penetrate through the blood brain barrier and can not enter the central nervous system, and no central psychomimetic side effect exists; the compound can be used for treating bronchial asthma, chronic obstructive pulmonary disease, common cold, rhinitis, peptic ulcer, dysentery, arrhythmia, etc.

The prior method for preparing quinine compounds containing quaternary ammonium groups as shown in the following formula (1) mainly uses phenyl-R₁Ethylene oxide, quinine alcohol, alkyl halides R₂X is a raw material, and a quaternary ammonium salt structure is formed in a final product. The existing refining method mainly uses acetone as a solvent to recrystallize a crude product of the acetone. However, it has been found that acetone has a poor purification effect on the above-mentioned compounds and it is difficult to remove impurities such as inorganic salts. In addition, the existing process refining method needs to recrystallize the crude product for many times, thus greatly improving the refining efficiencyThe cost of the product is greatly increased and the work-up of the solvent is increased. The defects of economy, environmental protection and the like are inevitable in the industrial implementation of the method.

In view of the above, the present invention is particularly proposed.

Disclosure of Invention

In order to solve the technical problems, the invention provides an economic, environment-friendly and efficient method for refining quinine compounds containing quaternary ammonium groups, which can effectively remove impurities such as reaction byproducts, inorganic salts and the like, can prepare high-purity products, and can also effectively improve the color of the products.

The research of the invention finds that the mixed solution of the organic solvent and water is used as the crystallization solvent to refine the quinine compound containing the quaternary ammonium group, most impurities such as reaction byproducts, inorganic salts, unreacted raw materials and the like can be effectively removed through one-time recrystallization process, the use of the organic solvent is obviously reduced, the pollution to the environment is avoided or reduced, the product purity is obviously improved, and the obtained product meets the standards of medicinal raw material medicines.

Specifically, the invention provides a method for refining a quinine compound containing a quaternary ammonium group, which is shown in the following formula (1), and the method is characterized in that an organic solvent-water mixed solution is used for recrystallizing a crude compound. Mixing the crude compound with an organic solvent-water mixed solution, heating to dissolve the crude compound until the solution is clear, filtering while the solution is hot, and cooling and crystallizing the filtrate to obtain the high-purity quinine compound containing the quaternary ammonium group. The organic solvent is isopropanol or ethanol.

In the formula (1), the reaction mixture is,

R₁、R₂each independently selected from alkyl;

R₃is phenyl; or R₃Is phenyl, optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from alkyl;

x is independently selected from halogen, organic or inorganic acid radical.

Further, the alkyl group means a straight-chain alkyl group, a branched-chain alkyl group or a cyclic alkyl group having 1 to 12 carbon atoms, and specifically includes, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group and the like. Preferably a straight-chain, branched-chain or cyclic alkyl group having 1 to 8 carbon atoms, more preferably a straight-chain, branched-chain or cyclic alkyl group having 3 to 6 carbon atoms.

Further, R₁Independently selected from cyclopropyl, cyclopentyl or cyclohexyl.

Further, R₂Independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

Further, R₃Is phenyl; or R₃Is phenyl, optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from methyl, ethyl, propyl or isopropyl.

Further, X is independently selected from fluorine, chlorine, bromine, iodine, methane sulfonate, p-toluene sulfonate or other acid groups which can be used as medicine.

Further, R₁Is cyclopropyl, cyclopentyl or cyclohexyl; r₂Is methyl; r₃Is phenyl; x is fluorine, chlorine, bromine or iodine.

Furthermore, the quinine compound configuration containing the quaternary ammonium group shown in the formula (1) is a diastereoisomer or a pure optical isomer.

The quinine compound containing the quaternary ammonium group shown in the formula (1) can be prepared by adopting a conventional method in the field, for example, the method disclosed in CN1532196A can be referred to.

Specifically, R₁Is cyclopentyl, R₂Is methyl, R₃Is phenyl, X is bromine; namely, the quinine compound containing the quaternary ammonium group shown in the formula (1) is benzcycloquine ammonium bromide (chemical name: 3- [ (2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy]-1-methyl-bromo-1-azabicyclo [2,2]Octane, the specific structure is shown as the following formula:

the benzcycloquine bromide is an M-receptor blocker, and can be used for lowering blood pressure and treating angina pectoris.

According to the literature, benzenoquine ammonium bromide is synthesized mainly according to the following route:

experiments prove that the method has better refining effect on the benzcycloquine ammonium bromide.

In the above purification method, the ratio of the crude compound to the organic solvent-water mixed solution is not particularly limited, and it is preferable that the crude compound is sufficiently dissolved or a supersaturated solution is obtained. Further research shows that the proportion of the crude compound to the organic solvent-water mixed liquid is preferably 3g (3-30) ml, more preferably 3g (8-10) ml, and in the range, impurities in the product can be removed well, and the loss of the product in recrystallization can be reduced remarkably.

It was found that although there was no significant difference in the purity of the purified compound by using different organic solvents as described above, the difference was significant in the yield, which was much more than expected. Among them, when isopropanol is used, the refining effect is best, i.e. the yield is highest, and ethanol is used secondly.

Further, the volume ratio of the organic solvent to water in the organic solvent-water mixed solution is preferably (95:5) to (80:20), and more preferably 95: 5.

Researches show that when the solution containing the crude quinine compound containing the quaternary ammonium group is heated to the boiling point, especially heated to the temperature 3-7 ℃ higher than the boiling point, most of impurities such as inorganic salt, organic impurities and the like can be effectively removed, and the subsequent steps are facilitated to be rapidly crystallized, so that the purity is improved.

Generally, the purity of the crude quinine compound containing quaternary ammonium groups is more than or equal to 40 percent and usually between 60 and 80 percent, and the purity of the crude quinine compound refined by the method can reach more than 99.80 percent.

For purity, HPLC method can be used for determination, and CN101585835A can be specifically referred to.

The starting materials used in the present invention are commercially available or may be prepared by methods conventional in the art.

On the basis of the common knowledge in the field, the above preferred conditions can be combined with each other to obtain the preferred embodiments of the invention.

The method of the invention takes the organic solvent-water mixed solution as the refined solvent, reduces or avoids the use of organic solvent, reduces the pollution to the environment, avoids the use of organic solvent with higher toxicity such as acetone and the like, and is green and environment-friendly. The method reduces the refining times, simplifies the operation steps, reduces the cost, can prepare the high-purity quinine compound containing the quaternary ammonium group, and can effectively control the content of inorganic salt.

Detailed Description

The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention. The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or instruments used are conventional products available from regular distributors, not indicated by the manufacturer.

The purity (HPLC) of the crude benzcycloquine ammonium bromide used below is 60.0%, and the benzcycloquine ammonium bromide can be prepared by the method in the reference CN 1257903C.

The following 95% aqueous isopropanol solution refers to a 95:5 ratio by volume of isopropanol to water.

Example 1

Adding 500ml of 95% isopropanol aqueous solution and 150g of benzoquinoline ammonium bromide crude product into a reaction bottle, refluxing to dissolve the solid, carrying out hot filtration, and cooling and crystallizing the filtrate. And (3) carrying out suction filtration and drying to constant weight to obtain white solid powder: 88.2g, yield: 98%, purity: 99.81% (HPLC), residue on ignition: 0.010%.

Example 2

400ml of 80% isopropanol aqueous solution and 120g of benzoquinoline ammonium bromide crude product are added into a reaction bottle, the mixture is refluxed to dissolve solids, the solid is filtered while the mixture is hot, and the filtrate is cooled and crystallized. And (3) carrying out suction filtration and drying to constant weight to obtain white solid powder: 68.4g, yield: 95%, purity: 99.80% (HPLC), residue on ignition: 0.013%.

Example 3

Adding 200ml of 95% ethanol aqueous solution and 60g of crude bencycloquine ammonium bromide into a reaction bottle, refluxing to dissolve the solid, filtering while the solution is hot, and cooling and crystallizing the filtrate. And (3) carrying out suction filtration, and drying to constant weight to obtain white solid powder: 32g, yield: 90%, purity: 99.89% (HPLC), residue on ignition: 0.010%.

Example 4

Adding 200ml of 80% ethanol solution and 60g of crude benzcycloquine ammonium bromide into a reaction bottle, refluxing to dissolve the solid, filtering while the solution is hot, and cooling and crystallizing the filtrate. And (3) carrying out suction filtration and drying to constant weight to obtain white solid powder: 32g, yield: 88%, purity: 99.85% (HPLC), residue on ignition: 0.011 percent.

Comparative example 1

130ml of distilled water and 50g of the crude benzcycloquine bromide are added into a reaction bottle, the mixture is refluxed to dissolve the solid, the solid is filtered while the mixture is hot, and the filtrate is cooled and crystallized. And (3) carrying out suction filtration and drying to constant weight to obtain white solid powder: 23.4g, yield: 78%, purity: 99.82% (HPLC), residue on ignition: 0.012 percent.

Furthermore, documents CN1532196A, CN1769286A, CN101585835A are incorporated herein in their entirety, as part hereof or as references herein.

Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.

Claims

1. A refining method of quinine compounds containing quaternary ammonium groups as shown in the following formula (1) is characterized by comprising the steps of mixing a crude product of the compound with an organic solvent-water mixed solution, heating to dissolve the crude product until the solution is clear, filtering while the solution is hot, and cooling and crystallizing filtrate; the organic solvent is isopropanol; the volume ratio of the organic solvent to the water in the organic solvent-water mixed solution is (95:5) - (80: 20); the proportion of the crude compound shown in the formula (1) to the organic solvent-water mixed solution is 3g (8-10) ml; the purity of the crude compound shown in the formula (1) is 60-80%;

(1)

R₁independently selected from cyclopropyl, cyclopentyl or cyclohexyl;

R₂independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl;

R₃is phenyl;

x is independently selected from fluorine, chlorine, bromine, iodine.

2. The method according to claim 1, wherein the compound represented by formula (1) is benzcycloquine bromide.

3. The method according to claim 1 or 2, wherein the configuration of the compound of formula (1) is diastereomer or pure optical isomer.

4. The method according to claim 1 or 2, wherein the volume ratio of the organic solvent to water in the organic solvent-water mixture is 95: 5.

5. The process of claim 1 or 2, wherein the solution containing the crude quinine compound containing quaternary ammonium groups is heated to boiling point.

6. The process of claim 5, wherein the solution containing the crude quinine compound containing quaternary ammonium groups is heated to a temperature of 3-7 ℃ above the boiling point.

7. The method according to any one of claims 1, 2 and 6, wherein the purity of the crude compound represented by the formula (1) is 60%.