WO2017015793A1

WO2017015793A1 - Method for separating diastereoisomer a of bedaquiline

Info

Publication number: WO2017015793A1
Application number: PCT/CN2015/085075
Authority: WO
Inventors: 张福利; 潘林玉; 朱津津; 王新增; 赵立; 任重; 宋颖
Original assignee: 浙江海正药业股份有限公司; 上海医药工业研究院
Priority date: 2015-07-24
Filing date: 2015-07-24
Publication date: 2017-02-02
Also published as: CN107848978A; CN107848978B

Abstract

Disclosed is a method for separating a diastereoisomer A of Bedaquiline. The method comprises the following steps: (1) adding a reversed-phase solvent into a Bedaquiline reaction liquid comprising diastereoisomers A and B, so as to precipitate out the diastereoisomer B; and (2) removing the diastereoisomer B precipitated out in step (1), so as to obtain the diastereoisomer A. The separation method of the present invention is easy to operate and is stable, and has higher industrialization value compared with separation and purification in a conventional column chromatography method, and can resolve the problems of difficulty in purifying and separating Bedaquiline due to the small amount of a product caused by an excessively low conversion rate because preparation condition of Bedaquiline is harsh and the conversion rate is difficult to ensure; raw material residuals can be easily removed, the yield is high, and the purity of the diastereoisomer A is high, which facilitates the split; split can be further carried out to obtain a qualified Bedaquiline product with a purity greater than or equal to 99.0%, wherein the impurities of the diastereoisomers are lower than or equal to 0.1%.

Description

Method for separating bedaquinoline diastereomer A

Technical field

The present invention relates to the field of pharmaceuticals, and more particularly to a method for isolating Bidaquinoline diastereomer A.

Background technique

Bedaquinine is an anti-tuberculosis drug with the structural formula shown in Figure 1:

The chemical name of bedaquinoline is (1R,2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4-dimethylamino-2-(1-naphthyl)-1 -Phenyl-2-butanol, the first drug developed by Johnson & Johnson to inhibit mycobacterial adenosine triphosphate (ATP) synthase, was first marketed in the United States in December 2012 for the treatment of adult multidrug-resistant tuberculosis. The trade name is Sirturo. Bedaquinoline shows strong selectivity for ATP synthase of Mycobacterium tuberculosis, and its new mechanism of action makes it resistant to cross-resistance with other anti-tuberculosis drugs, which will greatly reduce the resistance of Mycobacterium tuberculosis. It shows good activity against multidrug-resistant tuberculosis in macrophages, suggesting that it has the effect of shortening the treatment time.

The synthesis method of bedaquinoline has been reported in the literature, and the specific synthetic route is as follows:

In the patent WO2004011436, it is mentioned that the crude product is separated and purified by column chromatography, but the method is not advantageous for industrialization; in addition, the method for separating and purifying the betatraquinoline diastereomer A is disclosed in the step C of the example of the patent WO2006125769. . However, although the purity of the diastereomer A obtained by the separation and purification method disclosed in the patent is 82%, it is actually possible to achieve only the reaction conversion ratio of more than 80%. The actual research found that due to the difficult control of the reaction conditions for preparing betaxazoline, the control conditions of the reaction on water, temperature and dropping speed are harsh, the reaction is unstable, and the conversion rate cannot be guaranteed to reach more than 80% per batch, usually conversion. When the ratio is between 60-80%, the ratio of diastereomer B to diastereomer A obtained by the method is between 1:1 and 1:3, for the next chiral decomposing. It has an impact; sometimes even the conversion rate is as low as 50%. When the conversion rate is as low as 50%, since the amount of the product in the reaction liquid is small, the separation product can hardly be purified by the method of the patent WO2006125769, even if the product is separated and purified by the purification method disclosed in the patent, the final The purity of the resulting diastereomer A is also very low.

Summary of the invention

In order to overcome the deficiencies of the prior art, the present invention provides a method for separating bedaquinoline diastereomer A which is simple in operation and stable in method. Regardless of the reaction conversion rate of the prepared betaxazoline, the method can make the betadarquinoline diastereomer B and the desired diastereomer A The ratio is between 1:8-1:23, thus ensuring the high purity and yield of the desired diastereomer A, which facilitates the next chiral resolution and successfully achieves the non-antagonism of the betaxipaline. Separation of isomer A.

The invention is implemented by the following technical solutions:

The present invention provides a method for isolating bead quinoline diastereomer A comprising the steps of:

(1) adding a reverse phase solvent to the reaction solution of the betaacene containing the diastereomers A and B to precipitate the diastereomer B;

The diastereomer B precipitated in the step (1) is removed to obtain a diastereomer A;

among them,

The diastereomer A is:

The diastereomer B is:

Preferably, in the step (1), the reverse phase solvent is an organic solvent miscible with the solvent of the betadarquinoline reaction solution.

Preferably, the reverse phase solvent is a non-polar or weakly polar solvent.

Further preferably, the reverse phase solvent is a C5-C16 alkane, or a C4-C8 ether solvent, or a mixture of a C5-C16 alkane and a C4-C8 ether solvent.

Preferably, the C5-C16 alkane is n-heptane or n-hexane; the C4-C8 ether solvent is isopropyl ether, petroleum ether or methyl tert-butyl ether.

Preferably, the C5-C16 alkane is n-heptane; the C4-C8 ether solvent is isopropyl ether.

Preferably, the solvent of the bead quinoline reaction solution is tetrahydrofuran; and the betadaquinoline reaction solution is obtained by reacting a reaction raw material with lithium diisopropylamide (LDA) in tetrahydrofuran.

Preferably, in the step (1), the reaction raw materials are 3-benzyl-6-bromo-2-methoxyquinoline and 3-dimethylamino-1-(naphthalen-5-yl)acetone.

Preferably, in the step (1), a weak acid aqueous solution is first added to the bead quinoline reaction solution to remove the residual starting material 3-dimethylamino-1-(naphthalen-5-yl)acetone, and then the anti-addition is added. Phase solvent.

Preferably, in the step (1), the bead quinoline reaction solution is added to the reverse phase solvent to precipitate the diastereomer B, and further subjected to an ice water bath step to further precipitate the diastereomer B. The ice water bath step is carried out at 0-5 °C.

Preferably, in the step (2), a weak acid aqueous solution is added to the solution after removing the diastereomer B precipitated in the step (1) to remove the residual starting material 3-dimethylamino-1-(naphthalene). -5-yl)acetone; then a strong acid aqueous solution was added to remove the residual starting material 3-benzyl-6-bromo-2-methoxyquinoline to give the diastereomer A.

Preferably, in the step (2), after adding a strong acid aqueous solution to remove the raw material 3-benzyl-6-bromo-2-methoxyquinoline, it is made alkaline with an alkaline solution, and added and diastereomeric The organic solvent which is mutually miscible and water-immiscible is extracted and concentrated to obtain diastereomer A; preferably, the alkaline solution is ammonia water or sodium hydroxide, and the diastereomer The organic solvent in which A is mutually soluble and immiscible with water is toluene or dichloromethane.

Preferably, the diastereomer A has a purity of at least 88%; further preferably, the purity is 88-96%.

Preferably, the volume ratio of the reverse phase solvent to the solvent of the betadarquinoline reaction solution is from 1:10 to 10:1; preferably, the volume ratio is from 1:5 to 5:1; further preferably, The volume ratio is from 1:2 to 2:1.

Preferably, the percentage concentration of the weak acid aqueous solution is 10%-60%, the percentage concentration of the strong acid aqueous solution is 5%-40%; further preferably, the weak acid aqueous solution has a percentage concentration of 30%-50%, The percentage concentration of the aqueous strong acid solution is 15%-25%.

Preferably, the weak acid aqueous solution is an aqueous formic acid solution, an aqueous solution of acetic acid or an aqueous solution of propionic acid; and the aqueous solution of strong acid is an aqueous solution of sulfonic acid, an aqueous solution of hydrochloric acid, an aqueous solution of sulfuric acid or an aqueous solution of phosphoric acid.

Preferably, the weak acid aqueous solution is an aqueous acetic acid solution; and the strong acid aqueous solution is an aqueous hydrochloric acid solution.

The advantages of the present invention over the prior art are:

First, the separation method used in the present invention has more industrial value than the separation and purification by column chromatography;

Secondly, it has been found through research that the control conditions for preparing bedaquinoline are harsh on the control conditions of moisture, temperature and dropping speed, and the conversion rate is not guaranteed to be above 80%. Usually, the conversion rate is between 60-80%, sometimes It will be as low as about 50%, so the ratio of diastereomer B to diastereomer A obtained by the method disclosed in Example C of the example of WO2006125769 is generally between 1:1 and 1:3. In the meantime, when the reaction conversion rate is low, since the amount of the product in the reaction liquid is small, the separation product can hardly be purified by the method of the patent WO2006125769, even if the product is separated and purified by the purification method disclosed in the patent, and finally The purity of the resulting diastereomer A is also very low. However, in the present invention, the undesired diastereomer B is precipitated from the betaacene racemate by adding a reverse phase solvent to the betadarquinoline reaction solution, regardless of the conversion conversion rate of the prepared betaxazoline. The ratio of the betaactoline diastereomer B to the desired diastereomer A can be between 1:8 and 1:23 to ensure the desired diastereomer. A has higher purity and yield, which is beneficial to the next chiral separation.

Further, in the present invention, by adding a reverse phase solvent to the reaction reaction solution of the bedaquinoline, the bidaquinoline diastereomer B is removed, and then the raw material is removed by pickling, thereby achieving the purpose of further purification, compared with the patent. The ethanol pulping and purifying method used in the step C of the embodiment part of WO2006125769 is more advantageous, on the one hand, the product residue is prevented from causing loss in the beating mother liquor; on the other hand, when the conversion rate of the prepared betaxazoline reaction is not good, the reaction end point is caused. There are always raw material residues, such as purification by ethanol pulping method. The residual raw materials have great influence on the beating yield, and are purified by the method of the present invention. When the conversion rate is not good, the residual raw materials can be easily removed, so the yield is higher. It has advantages over the ethanol pulping method. Finally, the diastereomer A obtained by the method of the present invention is further resolved to obtain a qualified end product of betaxaquinoline having a purity of ≥99.0%, wherein the diastereomer impurity is ≤0.1%. Therefore, the invention has more application value than the prior art in practical applications, and is simple in operation and stable in method.

The diastereomer A isolated by the method of the present invention can be resolved by a prior art method to further obtain the betaxipaquinine of the desired configuration.

The beneficial effects of the invention are:

1. The separation method of the invention has more industrial value than the separation and purification by the conventional column chromatography;

2. The separation method of the present invention can overcome the technical problem that the reaction conditions of the betaxazoline are severe, the conversion rate is difficult to be ensured, and the amount of the product is small when the conversion rate is low, and it is difficult to purify and separate it; The reverse phase solvent is added to precipitate the undesired diastereomer B from the beta-quinoline racemate, and the beta-quinoline diastereomeric can be ensured regardless of the reaction conversion rate of the prepared betaxazoline. The ratio of isomer B to the desired diastereomer A is between 1:8 and 1:23, thereby ensuring that the desired diastereomer A has higher purity and yield, which is advantageous for the next Step chiral splitting;

3. The separation method of the invention can easily remove the residue of the raw material, the yield is high, the purity of the diastereomer A is also high, and the separation is facilitated, and the qualified bedaquinoline can be prepared by further resolution. The product has a purity of ≥99.0%, wherein the diastereomer impurity is ≤0.1%.

4. The separation method of the present invention is simple in operation and stable in method.

detailed description

Example 1

Reaction material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) with 3-dimethylamino-1-(naphthalen-5-yl)acetone (10 g) in tetrahydrofuran (80 ml) with LDA (20 g) reaction, one-step reaction to obtain a racemic bedaquinoline reaction solution. The conversion of the reaction was analyzed by HPLC to be 56%. After quenching the reaction, n-heptane (40 ml) was added to the reaction mixture, and the desired diastereomer B was precipitated from ice-water bath at 0 ° C, and filtered to remove diastereomer B. The obtained filtrate was washed with a 50% aqueous acetic acid solution to remove the starting material 3-dimethylamino-1-(naphthalen-5-yl)acetone, and a 15% aqueous hydrochloric acid solution was added to the organic layer to stir to form a salt in the aqueous layer. In the middle of precipitation. Filtration and stratification of the filtrate, at which time the product was transferred to the aqueous layer, and the material, 3-benzyl-6-bromo-2-methoxyquinoline, remained in the organic layer and the organic layer was discarded. The filtered product is combined with the aqueous layer obtained by layering the filtrate with the filtrate, adjusted to basic with aqueous ammonia, extracted with toluene, and the organic layer is washed with water until neutral, and the organic layer is concentrated under reduced pressure to obtain a product. Isomer A (4.9 g), purity 89%.

The obtained diastereomer A was resolved by the method of WO2006125769 to obtain the desired bedaquinoline. The specific method is as follows:

To the obtained diastereomer A (4.9 g) of bedaquinoline, acetone (40 ml), DMSO (4.9 ml) and R-binaphthol phosphate (2.62 g) were added, followed by heating under reflux for 2 hours. Cooling, precipitation of the split salt; filtration at room temperature, washing the filter cake with acetone, vacuum drying at 50-60 ° C to obtain a split salt (2.07 g);

The split salt (2.07 g), toluene (37 ml), potassium carbonate (1.51 g) and water (13 ml) were mixed, heated to 90 ° C and stirred until fully dissolved; hot layered, the organic layer was treated with 10% aqueous potassium carbonate solution ( 5 ml), 1 time, the organic layer was monitored by TLC; washed with purified water until pH was neutral (20 ml × 3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.5 g); The mixture was stirred and stirred at room temperature for 0.5 h to precipitate a solid, which was stirred for 1 hour in ice-water bath, filtered, and the filter cake was washed with ethanol, and dried under vacuum at 50-60 ° C to obtain bedaquinoline (1.07 g) with an HPLC purity of >99%. .

Example 2

Starting material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) with 3-dimethylamino-1-(naphthalen-5-yl)acetone (10 g) in tetrahydrofuran (80 ml) with LDA ( 20 g) reaction, one-step reaction to obtain a racemic bedaquinoline reaction solution. The conversion of the reaction was analyzed by HPLC to be 65%. After quenching at the end of the reaction, isopropyl ether (160 ml) was added to the reaction mixture, and the desired diastereomer B was precipitated in an ice water bath at 5 ° C, and filtered to remove the diastereomer B. The obtained filtrate was washed with a 10% aqueous solution of formic acid to remove the starting material 3-dimethylamino-1-(naphthalen-5-yl)acetone, and a 5% aqueous solution of sulfuric acid was added to the organic layer to stir to form a salt in the aqueous layer. In the middle of precipitation. Filtration and stratification of the filtrate, at which time the product was transferred to the aqueous layer, and the starting material, 3-benzyl-6-bromo-2-methoxyquinoline, remained in the organic layer and the organic layer was discarded. The filtered product is combined with the aqueous layer obtained by layering the filtrate with the filtrate, adjusted to a weak basic with sodium hydroxide, extracted with dichloromethane, and the organic layer is washed with water until neutral, and the organic layer is concentrated under reduced pressure. The product diastereomer A (5.7 g) was obtained with a purity of 92%.

To the obtained diastereomer A (5.7 g) of bedaquinoline, acetone (45 ml), DMSO (5.7 ml) and R-binaphthol phosphate (3.04 g) were added, followed by heating under reflux for 2 hours. Cooling, precipitation of the split salt; filtration at room temperature, washing the filter cake with acetone, vacuum drying at 50-60 ° C to obtain a split salt (2.6 g);

The split salt (2.41 g), toluene (39 ml), potassium carbonate (1.58 g) and water (14 ml) were mixed, heated to 90 ° C and stirred until fully dissolved; hot layered, organic layer with 10% aqueous potassium carbonate solution ( Washed once with 5 ml), washed with purified water until the pH was neutral (20 ml × 3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.6 g); toluene (1 ml) The solid was precipitated by stirring at room temperature for 0.5 h, stirred in an ice-water bath for 1 h, filtered, and the filter cake was washed with ethanol, and dried under vacuum at 50-60 ° C to obtain bedaquinoline (1.19 g) with HPLC purity >99%.

Example 3

Starting material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) with 3-dimethylamino-1-(naphthalen-5-yl)acetone (10 g) in tetrahydrofuran (80 ml) with LDA ( 20 g) reaction, one-step reaction to obtain a racemic bedaquinoline reaction solution. The conversion of the reaction was analyzed by HPLC to be 75%. After quenching the reaction, isopropyl ether (400 ml) was added to the reaction mixture, and the desired diastereomer B was precipitated in an ice water bath at 2 ° C, and filtered to remove the diastereomer B. The obtained filtrate was washed with a 60% aqueous solution of propionic acid to remove the starting material 3-dimethylamino-1-(naphthalen-5-yl)acetone, and 40% aqueous methanesulfonic acid was added to the organic layer to stir to form a salt. Precipitated in the water layer. Filtration and stratification of the filtrate, at which time the product was transferred to the aqueous layer, and the material, 3-benzyl-6-bromo-2-methoxyquinoline, remained in the organic layer and the organic layer was discarded. The filtered product is combined with the aqueous layer obtained by layering the filtrate with the filtrate, adjusted to a weak basic with sodium hydroxide, extracted with dichloromethane, and the organic layer is washed with water until neutral, and the organic layer is concentrated under reduced pressure. The product diastereomer A (6.0 g) was obtained with a purity of 94%.

To the obtained diastereomer A (6.0 g) of bedaquinoline, acetone (48 ml), DMSO (6.0 ml) and R-binaphthol phosphate (3.09 g) were added, followed by heating under reflux for 2 hours. Cooling, precipitation of the split salt; filtration at room temperature, washing the filter cake with acetone, vacuum drying at 50-60 ° C to obtain a split salt (2.59 g);

The split salt (2.59g), toluene (40ml), potassium carbonate (1.60g) and water (14ml) were mixed, heated to 90 ° C and stirred until fully dissolved; layered hot, the organic layer was treated with 10% potassium carbonate solution ( Washed once with 5 ml), washed with purified water until the pH was neutral (20 ml × 3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.7 g); toluene (1 ml) Stir at room temperature for 0.5h The solid was precipitated, stirred in an ice water bath for 1 h, filtered, and the filter cake was washed with ethanol, and dried under vacuum at 50-60 ° C to give bedaquinoline (1.20 g) with HPLC purity >99%.

Example 4

Starting material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) with 3-dimethylamino-1-(naphthalen-5-yl)acetone (10 g) in tetrahydrofuran (80 ml) with LDA ( 20 g) reaction, one-step reaction to obtain a racemic bedaquinoline reaction solution. The conversion of the reaction was analyzed by HPLC to be 70%. After quenching the reaction, petroleum ether (16 ml) was added to the reaction mixture, and the desired diastereomer B was precipitated in an ice water bath at 3 ° C, and filtered to remove the diastereomer B. The obtained filtrate was washed with a 30% aqueous solution of acetic acid to remove the raw material 3-dimethylamino-1-(naphthalen-5-yl)acetone, and a 25% aqueous phosphoric acid solution was added to the organic layer to stir to form a salt in the aqueous layer. In the middle of precipitation. Filtration and stratification of the filtrate, at which time the product was transferred to the aqueous layer, and the material, 3-benzyl-6-bromo-2-methoxyquinoline, remained in the organic layer and the organic layer was discarded. The filtered product is combined with the aqueous layer obtained by layering the filtrate with the filtrate, adjusted to a weak basic with sodium hydroxide, extracted with dichloromethane, and the organic layer is washed with water until neutral, and the organic layer is concentrated under reduced pressure. The product diastereomer A (5.72 g) was obtained with a purity of 88%.

To the obtained diastereomer A (5.72 g) of bedaquinoline, acetone (45 ml), DMSO (5.7 ml), and R-binaphthol phosphate (3.04 g) were added, followed by heating under reflux for 2 hours. Cooling, precipitation and resolution of the salt; filtration at room temperature, washing the filter cake with acetone, vacuum drying at 50-60 ° C to obtain a split salt (2.43 g);

The split salt (2.43g), toluene (40ml), potassium carbonate (1.60g) and water (14ml) were mixed, heated to 90 ° C and stirred until fully dissolved; hot layered, the organic layer was treated with 10% potassium carbonate solution ( Washed once with 5 ml), washed with purified water until the pH was neutral (20 ml × 3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.5 g); toluene (1 ml) The solid was precipitated by stirring at room temperature for 0.5 h, stirred in an ice-water bath for 1 h, filtered, and the filter cake was washed with ethanol, and dried under vacuum at 50-60 ° C to obtain bedaquinoline (1.16 g) with HPLC purity >99%.

Example 5

Starting material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) with 3-dimethylamino-1-(naphthalen-5-yl)acetone (10 g) in tetrahydrofuran (80 ml) with LDA ( 20 g) reaction, one-step reaction to obtain a racemic bedaquinoline reaction solution. The conversion of the reaction was analyzed by HPLC to be 80%. After quenching the reaction, n-hexane (80 ml) was added to the reaction mixture, and the desired diastereomer B was precipitated in an ice water bath at 1 ° C, and filtered to remove the diastereomer B. The obtained filtrate was washed with a 40% aqueous solution of acetic acid to remove the raw material 3-dimethylamino-1-(naphthalen-5-yl)acetone, and a 20% aqueous hydrochloric acid solution was added to the organic layer to stir to form a salt in the aqueous layer. In the middle of precipitation. Filtration and stratification of the filtrate, at which time the product was transferred to the aqueous layer, and the material, 3-benzyl-6-bromo-2-methoxyquinoline, remained in the organic layer and the organic layer was discarded. The filtered product is combined with the aqueous layer obtained by layering the filtrate with the filtrate, adjusted to a weak basic with sodium hydroxide, extracted with dichloromethane, and the organic layer is washed with water until neutral, and the organic layer is concentrated under reduced pressure. The product diastereomer A (6.1 g) was obtained with a purity of 96%.

To the obtained diastereomer A (6.1 g) of bedaquinoline, acetone (48 ml), DMSO (6.1 ml) and R-binaphthol phosphate (3.09 g) were added, followed by heating under reflux for 2 hours. Cooling, precipitation of the separated salt; filtration at room temperature, washing the filter cake with acetone, vacuum drying at 50-60 ° C to obtain a split salt (2.69 g);

The split salt (2.69 g), toluene (40 ml), potassium carbonate (1.60 g) and water (14 ml) were mixed, heated to 90 ° C and stirred until fully dissolved; hot layered, organic layer with 10% aqueous potassium carbonate solution ( Washed once with 5 ml), washed with purified water until the pH was neutral (20 ml × 3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.8 g); toluene (1 ml) The solid was precipitated by stirring at room temperature for 0.5 h, stirred in an ice water bath for 1 h, filtered, and the filter cake was washed with ethanol, and dried under vacuum at 50-60 ° C to obtain bedaquinoline (1.28 g) with an HPLC purity of >99%.

Claims

A method for separating betaxipolin diastereomer A, characterized in that the method comprises the following steps:

(1) adding a reverse phase solvent to the reaction solution of the betaacene containing the diastereomers A and B to precipitate the diastereomer B;

(2) removing the diastereomer B precipitated in the step (1) to obtain a diastereomer A;

among them,

The diastereomer A is:

The diastereomer B is:
The method according to claim 1, wherein in the step (1), the reverse phase solvent is an organic solvent miscible with the solvent of the betadarquinoline reaction solution; preferably, the reverse phase The solvent is a non-polar or weakly polar solvent; further preferably, the reverse phase solvent is a C5-C16 alkane, or a C4-C8 ether solvent, or a mixture of a C5-C16 alkane and a C4-C8 ether solvent.
The method according to claim 2, wherein the C3-C10 alkane is n-heptane or n-hexane, and the C4-C8 ether solvent is isopropyl ether or methyl tert-butyl ether; preferably, The C3-C10 alkane is n-heptane and the C4-C8 ether solvent is isopropyl ether.
The method according to claim 2, wherein the solvent of the betadarquinoline reaction solution is tetrahydrofuran; and the betadaquinoline reaction solution is obtained by reacting a reaction raw material with lithium diisopropylamide in tetrahydrofuran. .
The method according to claim 4, wherein in the step (1), the The starting materials for the reaction are 3-benzyl-6-bromo-2-methoxyquinoline and 3-dimethylamino-1-(naphthalen-5-yl)acetone.
The method according to claim 5, wherein in the step (1), a weak acid aqueous solution is first added to the bead quinoline reaction solution to remove the residual starting material 3-dimethylamino-1-(naphthalene- 5-Base) Acetone, followed by the addition of a reversed phase solvent.
The method according to any one of claims 1 to 6, wherein in the step (1), after adding the reverse phase solvent to precipitate the diastereomer B, the ice water bath step is further carried out to further precipitate. Diastereomer B; the ice water bath step is carried out at 0-5 °C.
The method according to claim 5, wherein the step (2) is: removing the diastereomer B precipitated in the step (1), in the solution after removing the diastereomer B, Adding a weak acid aqueous solution to remove the residual starting material 3-dimethylamino-1-(naphthalen-5-yl)acetone; then adding a strong acid aqueous solution to remove the residual starting material 3-benzyl-6-bromo-2-methoxyquinoline, Diastereomer A.
The method according to any one of claims 1-8, wherein in the step (2), the purity of the diastereomer A is at least 88%; preferably, the purity is 88. -96%.
The method according to claim 1, wherein the volume ratio of the reverse phase solvent to the solvent of the betadarquinoline reaction solution is from 1:10 to 10:1; preferably, the volume ratio is 1: 5-5:1; further preferably, the volume ratio is from 1:2 to 2:1.
The method according to claim 1, wherein the weak acid aqueous solution has a percentage concentration of 10% to 60%, and the strong acid aqueous solution has a percentage concentration of 5% to 40%; preferably, the percentage of the weak acid aqueous solution The concentration is from 30% to 50%, and the percentage concentration of the strong acid aqueous solution is from 15% to 25%.
The method according to claim 8, wherein the weak acid aqueous solution is an aqueous solution of formic acid, an aqueous solution of acetic acid, or an aqueous solution of propionic acid. Preferably, the aqueous solution of weak acid is an aqueous solution of acetic acid; and the aqueous solution of strong acid is an aqueous solution of sulfonic acid or hydrochloric acid. An aqueous solution, an aqueous solution of sulfuric acid, or an aqueous solution of phosphoric acid, preferably, the aqueous solution of strong acid is an aqueous solution of hydrochloric acid.