KR102303635B1 - PROCESS FOR PREPARING (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol AND PHARMACEUTICALLY ACCEPTABLE SALT - Google Patents

Abstract

The present invention relates to a method for manufacturing (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol comprising a method for separating (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol capable of mass production with an economical manufacturing process and high yield, or a pharmaceutically acceptable salt thereof.

Description

(1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol and its Method for preparing a pharmaceutically acceptable salt {PROCESS FOR PREPARING (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl- butan-2-ol AND PHARMACEUTICALLY ACCEPTABLE SALT}

The present invention relates to (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2- It relates to a method for preparing ol and a pharmaceutically acceptable salt thereof. Specifically, the present invention provides (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2- It relates to a method for preparing (1-naphthyl)-1-phenyl-butan-2-ol and a pharmaceutically acceptable salt thereof.

The preparation method according to the present invention is (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl- It includes an economical manufacturing process and a method for isolating butan-2-ol in high yield.

(1R,2S)-1-(6-Bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol is veda It is known as a component name of quiline (bedaquiline) and has a structure of the following formula (A).

<Formula A>

Bedaquiline is a multi-drug-resistant tuberculosis therapeutic agent having a mechanism of specifically inhibiting ATP synthase essential for energy production of Mycobacterium tuberculosis (mycobacteria), and was first disclosed in International Publication No. 2004-011436.

In International Publication No. 2004-011436, 3-benzyl-6-bromo-2-methoxyquinoline is reacted with 3-(dimethylamino)-1-(naphthalen-1-yl)propan-1-one to 1- The following method for preparing (6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol is known has been

1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol has two centers of chirality 4 stereoisomers, namely (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1- Phenyl-butan-2-ol, (1S,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl -Butan-2-ol, (1R,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl- Butan-2-ol, (1S,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane -2-ol is present.

Each of the four stereoisomers has one enantiomer and two diastereomers.

It is one of the four stereoisomers obtained by reacting 3-benzyl-6-bromo-2-methoxyquinoline with 3-(dimethylamino)-1-(naphthalen-1-yl)propan-1-one for the treatment of multidrug-resistant tuberculosis. The substance used is bedaquiline, ie (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1- Since it is phenyl-butan-2-ol, it can be said that a process for effectively removing the remaining three stereoisomers from the reaction mixture is essential.

International Publication No. 2004-011436 discloses a method for obtaining diastereoisomer A from a mixture of diastereoisomer A and diastereoisomer B by column chromatography and crystallization. In addition, (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naph) from diastereoisomer A using chiral column chromatography Methods for isolating thyl)-1-phenyl-butan-2-ol are known. However, the purification method using column chromatography is expensive and not suitable for mass production.

Chemical journal ( J. Am. Chem. Soc. 2010, 132, 7905) uses (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl) using a metal catalyst such as yttrium complex Methods for the stereoselective synthesis of -4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol are known. However, the method has a long synthesis step of 12 steps, and the overall yield is very low at 5%, and the scale is small in mg units, making it difficult to apply to mass production.

International Publication No. 2006-125769 discloses chiral 4-hydroxydinaphtho [2,1-d: 1', 2'-f] [1,3,2] dioxaphosphepine 4-oxide or a derivative thereof (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1- Methods for isolating naphthyl)-1-phenyl-butan-2-ol are known. However, the method requires a seeding method of adding a seed to the reaction mixture for crystallization, and the process is very cumbersome and requires a lot of production time, such as recrystallization to increase purity.

Thus, (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol An effective manufacturing method is required for mass production on a commercial scale.

International Publication No. 2004-011436

The present invention is bedaquiline suitable for commercial mass production because it can be manufactured with high purity and high yield while being manufactured by an economical and simple manufacturing process, that is, (1R,2S)-1-(6-bromo-2-methoxy An object of the present invention is to provide a method for preparing quinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol and a pharmaceutically acceptable salt thereof.

The present invention is bedaquiline suitable for commercial mass production because it can be manufactured with high purity and high yield while being manufactured by an economical and simple manufacturing process, that is, (1R,2S)-1-(6-bromo-2-methoxy It is one object to provide a method for isolating quinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol.

The present invention uses chiral octahydro-4-hydroxy-4-oxide-dynaphtho [2,1-d: 1 ', 2'-f] [1,3,2] dioxaphosphepine as a splitting agent, from a mixture of stereoisomers of 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol ( Optical separation of 1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol of (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol Separation method is provided.

The separation method of one embodiment is a chiral octahydro-4-hydroxy-4-oxide-dynaphtho [2,1-d: 1 ', 2'-f] [1,3,2] dioxaphosphepine as a splitting agent Therefore, a separate seeding process is unnecessary. Therefore, process simplification can be achieved and process costs can be reduced, which is suitable for mass production and economical.

In one embodiment, 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol The stereoisomeric mixture is (1R, 2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane-2 -ol, (1S, 2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2- ol, (1R, 2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol and (1S, 2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol may include

Hereinafter, in the present specification (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane- 2-ol and (1S,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane-2 The mixture of -ols is diastereomer A, (1R,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)- 1-phenyl-butan-2-ol and (1S,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1 A mixture of -phenyl-butan-2-ols is defined as diastereomer B. Two compounds contained in diastereomer A are enantiomers of each other, and two compounds contained in diastereomer B are enantiomers of each other. Compounds contained in diastereomer A and compounds contained in diastereomer B are in a diastereomeric relationship with each other.

Diastereomer A may be a racemic mixture. Diastereomer B may be a racemic mixture.

According to one embodiment, in the stereoisomer mixture, the weight ratio of diastereomer A based on the total weight of the stereoisomer mixture may be about 90% by weight or more. However, embodiments are not limited thereto, and may be about 70% by weight or more, or about 80% by weight or more.

In one embodiment, chiral octahydro-4-hydroxy-4-oxide-dinaphtho [2,1-d: 1 ', 2'-f] [1,3,2] dioxaphospepine is represented by Formula 1 can be displayed as

[Formula 1]

In Formula 1, R ₁ to R ₄ are each independently a hydrogen atom, a deuterium atom, a halogen atom, or an unsubstituted or unsubstituted alkyl group having 1 to 5 carbon atoms or an alkyl group substituted or unsubstituted with 6 ring carbon atoms It may be an aryl group of 12 or more. The type of the aryl group substituted with the alkyl group may include an aryl group having 6 to 12 ring carbon atoms, and the type of the alkyl group substituted for the aryl group may include an alkyl group having 1 to 5 carbon atoms.

Examples of the alkyl group having 1 to 5 carbon atoms include methyl group, ethyl group, propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, iso -pentyl group, neo-pentyl group, tert-pentyl group, sec-pentyl group, etc. are mentioned.

Examples of the aryl group having 6 to 12 ring carbon atoms include a phenyl group, a naphthyl group, or a biphenyl group.

The halogen atom may be F, Cl, Br or I.

a and b may each independently be an integer of 1 or more and 2 or less. For example, a and b may be 1. c and d may each independently be an integer of 1 or more and 8 or less. For example, c and d may each independently be an integer of 1 or more and 4 or less, or 1 or more and 2 or less, or 1 may be.

When R ₁ a plurality individual, a plurality of R ₁ s may be the same or different from each other. Even when R ₂ to R ₄ are plural, the same description as that _{of R 1 may be applied.} In one embodiment, the splitting agent is (11bR)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxide-dinaphtho[2,1-d: 1',2'-f][1,3,2]dioxaphospepine, or (11bS)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4 -oxide-dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphospepine. For example, the splitting agent is (11bR)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxide-dinaphtho[2,1-d:1 ',2'-f][1,3,2]dioxaphospepine.

In one embodiment, the separation method comprises (a) the 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1 -Phenylbutan-2-ol stereoisomer mixture and the resolving agent were added to an organic solvent to form (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4- preparing a mixture comprising dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol and a salt of the resolving agent.

In step (a), the organic solvent may include at least one selected from the group consisting of a polar protic solvent, a polar aprotic solvent, and a mixed solvent thereof.

The organic solvent is 1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol and a splitting agent. It may be to show different solubility with respect to the stereoisomers of the salt.

Specifically, the organic solvent is (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane Relatively low solubility in salts of -2-ol and resolving agents, (1S,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2- (1-naphthyl)-1-phenyl-butan-2-ol and salt of resolving agent, (1R,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethyl Salts of amino-2-(1-naphthyl)-1-phenyl-butan-2-ol and splitting agent and (1S,2S)-1-(6-bromo-2-methoxyquinolin-3-yl) -4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol and salts of the splitting agent may each exhibit relatively high solubility.

The polar protic solvent may include at least one selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, t-butyl alcohol, and a mixed solvent thereof.

The polar aprotic solvent is ethyl acetate, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, N-methyl-2-pyrrolidone and It may include at least one selected from the group consisting of these mixed solvents.

For example, the organic solvent may include only the polar protic solvent. For example, the organic solvent may include only methanol. For example, the organic solvent may include the mixed solvent. The mixed solvent may include methanol as a polar protic solvent. The mixed solvent may include at least one selected from tetrahydrofuran, dimethylformamide, and N-methyl-2-pyrrolidone as a polar aprotic solvent. The mixed solvent may include methanol as the polar protic solvent, and at least one selected from tetrahydrofuran, dimethylformamide, and N-methyl-2-pyrrolidone as the polar aprotic solvent. For example, the mixed solvent may include methanol as the polar protic solvent and dimethylformamide as the polar aprotic solvent.

The volume ratio of the polar protic solvent to the polar aprotic solvent in the mixed solvent may be different depending on the type of solvent, but 10:0.5 to 10:2, 10:0.7 to 10:2, 10:0.9 to 10:2, 10:1 to 10:2, 10:0.5 to 10:1.5, 10:0.7 to 10:1.5, 10:0.9 to 10:1.5 or 10:1 to 10:1.5. For example, the volume ratio of the polar protic solvent to the polar aprotic solvent may be about 10:1.

For example, in a mixed solvent containing methanol and dimethylformamide, the volume ratio of methanol and dimethylformamide is 10:0.5 to 10:2, 10:0.7 to 10:2, 10:0.9 to 10:2, 10: 1 to 10:2, 10:0.5 to 10:1.5, 10:0.7 to 10:1.5, 10:0.9 to 10:1.5 or 10:1 to 10:1.5.

Volume (ml) of the polar protic solvent in the mixed solvent versus the 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl) )-1-phenylbutan-2-ol, the ratio of the mass (g) of the mixture of stereoisomers is from 5:1 to 30:1, from 8:1 to 25:1, from 10:1 to 20:1 or from 15:1 to It could be 25:1. For example, the volume (ml) of the polar protic solvent in the mixed solvent versus the 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalene) The ratio of the mass (g) of the mixture of stereoisomers of -1-yl)-1-phenylbutan-2-ol may be 10:1 or 20:1. Volume (ml) of the polar aprotic solvent in the mixed solvent versus the 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalene-1- The ratio of the mass (g) of the mixture of stereoisomers of yl)-1-phenylbutan-2-ol is 0.5:1 to 3:1, 0.8:1 to 2.5:1, 1:1 to 2:1 or 1.5:1 to 2.5:1. Volume (ml) of the polar aprotic solvent in the mixed solvent versus the 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalene-1- The ratio of the mass (g) of the stereoisomeric mixture of yl)-1-phenylbutan-2-ol may be, for example, 1:1 or 2:1. For example, the volume of the polar protic solvent (ml): the volume of the polar aprotic solvent (ml): the 1-(6-bromo-2-methoxyquinolin-3-yl)-4-( The mass (g) of a mixture of stereoisomers of dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol is from 5:0.5:1 to 30:3:1, 8:0.8:1 to 25:2.5:1, 10:1:1 to 20:2:1 or 15:1.5:1 to 25:2.5:1. For example, the volume of the polar protic solvent (ml): the volume of the polar aprotic solvent (ml): the 1-(6-bromo-2-methoxyquinolin-3-yl)-4-( The mass (g) of a mixture of stereoisomers of dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol may be 10:1:1 or 20:2:1.

Volume (ml) of the organic solvent vs. 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutane The ratio of the mass (g) of the mixture of stereoisomers of -2-ol may be 5.5:1 to 33:1, 8.8:1 to 27.5:1, 11:1 to 22:1 or 16.5:1 to 27.5:1 .

In step (a), the (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl- Butan-2-ol and the salt of the splitting agent have low solubility in the organic solvent, and thus may be obtained in a solid state.

(1R,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane in step (a) above Salt of -2-ol and splitting agent, (1S,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1 -Phenyl-butan-2-ol and salts of resolving agents and (1S,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naph Since each of tyl)-1-phenyl-butan-2-ol and the salt of the splitting agent has relatively high solubility in the organic solvent, it can be dissolved in the organic solvent.

Therefore, according to the separation method of one embodiment, the (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)- Salts of 1-phenyl-butan-2-ol and the resolving agent may be optionally isolated. In one embodiment, the resolving agent is (11bR)-8,9,10,11,12,13,14,15. -octahydro-4-hydroxy-4-oxide- dinaphtho[2,1-d:1 ',2'-f][1,3,2]dioxaphospepine.

For example, in step (a), the 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenyl Stereoisomeric mixture of butan-2-ol and (11bR)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxide-dinaphtho[2,1-d :1',2'-f][1,3,2]dioxaphosphepine 10:0.5 to 10:2, 10:0.7 to 10:2, 10:0.9 to 10:2, 10:1 to 10 :2, 10:0.5 to 10:1.5, 10:0.7 to 10:1.5, 10:0.9 to 10:1.5, or 10:1 to 10:1.5 by volume ratio of methanol and dimethylformamide in a mixed solvent of of (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol and (11bR)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxide-dinaphtho[2,1-d:1',2'-f][ 1,3,2] preparing a mixture containing a salt of dioxaphospepine. where, volume of methanol (ml): volume of dimethylformamide (ml): 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalene-1 The mass (g) of a mixture of stereoisomers of -yl)-1-phenylbutan-2-ol is 5:0.5:1 to 30:3:1, 8:0.8:1 to 25:2.5:1, 10:1 :1 to 20:2:1 or 15:1.5:1 to 25:2.5:1, for example 10:1:1 or 20:2:1.

Step (a) may include stirring the mixture. The stirring may be performed at a temperature of about 60° C. or more and about 100° C. or less (eg, about 80° C.) for a time of about 30 minutes or more and about 3 hours or less (eg, about 1 hour).

In one embodiment, the step (a) may further include stirring the mixture, cooling the mixture to 0 or more and 5° C. or less, and stirring for a time of about 30 minutes or more and about 3 hours or less.

Step (a) is the (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl- filtering and washing the butan-2-ol and the salt of the resolving agent.

The separation method of one embodiment is (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane It may further comprise the step of purifying the salt of the -2-ol and the resolving agent.

The purification step was (aa) filtered (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1- The method may further include adding phenyl-butan-2-ol and a salt of the resolving agent to an organic solvent. In the purification step, the organic solvent may be the above-described polar protic solvent, polar aprotic solvent, or mixed solvent. In the step (a) and the purification step, the organic solvent may be the same.

The purification step may include stirring. The stirring may be performed at a temperature of about 60° C. or more and about 100° C. or less (eg, about 80° C.) for a time of about 15 minutes or more and about 1 hour or less (eg, about 30 minutes). In one embodiment, the refining step may further include, after the stirring step, cooling the mixture to 0 or more and 5°C or less, and stirring for about 30 minutes or more and about 3 hours or less.

The purification step is the (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane- filtering and washing the 2-ol and the salt of the resolving agent. (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane- It is possible to increase the purity of the salt of the 2-ol and the splitting agent.

According to one embodiment, in the step (a), the splitting agent is (11bR)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxide-dinaphtho [2,1-d:1',2'-f][1,3,2]dioxaphospepine.

In one embodiment, the separation method comprises (b) (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl) (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-( The method may further include preparing 1-naphthyl)-1-phenyl-butan-2-ol. Step (b) is the (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl- from (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl) from butan-2-ol and salts of the above resolving agents It may be a step of liberating -1-phenyl-butan-2-ol.

In one embodiment, the step (b) comprises the steps of preparing a suspension comprising the crystallized salt; and adding carbonate or phosphate to the suspension.

In one embodiment, the solvent of the suspension in step (b) may include a non-polar organic solvent. For example, the solvent of the suspension may include toluene. In one embodiment, when a non-polar organic solvent such as toluene is used as a solvent of the suspension, the generation of related substances can be reduced.

In one embodiment, the carbonate may be at least one selected from _{K 2} CO ₃ , KHCO ₃ , Na ₂ CO ₃ and NaHCO _{3 .} The phosphate salt may be at least one selected from _{Na 3} PO ₄ and Na ₂ HPO _{4 .} For example, carbonate may be added to the suspension in step (b). For example, K ₂ CO ₃ may be added as carbonate.

The step (b) may include adding and stirring the carbonate or phosphate aqueous solution to the suspension of step (b), and separating the layers to remove the aqueous layer. Thereafter, the steps of adding and stirring a carbonate or phosphate aqueous solution and separating the layers to remove the aqueous layer may be performed at least once more. The step (b) may include washing, dehydrating, filtering and concentrating the organic layer remaining after removing the aqueous layer. Step (b) is (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl) from the concentrate obtained in the concentration step. It may be a step of crystallizing -1-phenyl-butan-2-ol.

According to one embodiment, the present invention is a splitting agent chiral octahydro-4-hydroxy-4-oxide-dinaphtho[2,1-d:1 ',2'-f][1,3,2]dioxa (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1) using phospepine and having high optical purity without a separate seeding process -naphthyl)-1-phenyl-butan-2-ol can be isolated. This simplifies the process and reduces costs, but with high purity (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naph Tyl)-1-phenyl-butan-2-ol can be isolated. In particular, according to the separation method of an embodiment, (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1- Phenyl-butan-2-ol can be mass-produced on a commercial scale. Specifically, according to the separation method of one embodiment, (1R,2S)-1-(6-bromo- having a high purity of 99% or more 2-Methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol can be obtained in high yield.

In one embodiment, the mixture of stereoisomers is prepared by reacting (a1) 3-benzyl-6-bromo-2-methoxyquinoline with a base and 3-(dimethylamino)-1'-propionaphthone followed by an acid. and (b1) crystallizing the reaction mixture obtained in step (a1) to produce crystals.

The step of preparing a stereoisomeric mixture is (c1) from the crystal of step (b1) above (1R,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2- (1-naphthyl)-1-phenyl-butan-2-ol and (1S,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-( The method may further include removing the mixture of 1-naphthyl)-1-phenyl-butan-2-ol to obtain a stereoisomer mixture solution.

In one embodiment, the step (c1) is ethanol; and adding to a mixed solvent containing at least one selected from among ethyl acetate, tetrahydrofuran and dichloromethane.

According to one embodiment, the acid in step (a1) may be acetic acid. In step (a1), the base may be n-butyllithium. In one embodiment, when n-butyllithium is used as the base, excellent yield can be achieved even when applied to mass production.

Step (a1) prepares a reaction solution by dropwise adding a solution containing n-butyllithium to a solution containing 3-benzyl-6-bromo-2-methoxyquinoline at about -80° C. or more and about -70° C. or less adding the reaction solution dropwise to a solution containing 3-(dimethylamino)-1'-propionaphthone at about -80° C. or more and about -70° C. or less and stirring, and stirring the stirring solution at about 0° C. or more It may include the step of stirring by adding an acid after heating to 5 ℃ or less.

The step (b1) may include adding water to the reaction mixture obtained in step (a1) and stirring, separating the organic layer, dehydrating and concentrating, and adding an organic solvent to the concentrate and stirring. . The step of stirring by adding an organic solvent (for example, a mixed solvent of ethyl acetate and ethanol) to the concentrate includes heating and stirring to about 50 ℃ or more and 90 ℃ or less (eg, about 75 ℃ or more and 80 ℃ or less). It may include a first stirring step and a second stirring step of stirring by cooling to room temperature (eg, about 15 ℃ to about 30 ℃ or less, or about 25 ℃).

In step (c1), the crystal of step (b1) is suspended in a solvent containing tetrahydrofuran, adding ethanol to the suspension, stirring, and filtering after stirring to obtain a stereoisomeric mixture solution may include the step of

In one embodiment, (1R,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane- 2-ol and (1S,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane-2 Since crystals containing a mixture of -ols are removed, (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl) -1-phenyl-butan-2-ol and (1S,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)- A mixture of stereoisomers with a high proportion of the mixture of 1-phenyl-butan-2-ol can be obtained. Thus, (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naph) in higher purity and higher yield from the stereoisomeric mixture Tyl)-1-phenyl-butan-2-ol can be isolated.

According to one embodiment, in the step (c1), the diastereomer (1R,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1- Naphthyl)-1-phenyl-butan-2-ol and (1S,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naph The removal ratio of the mixture of tyl)-1-phenyl-butan-2-ol is determined by the (1R,2R)-1-(6-bromo-2-methoxyquinoline included in the crystal obtained in step (b1) above. -3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol and (1S,2S)-1-(6-bromo-2-methoxyquinoline- 3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol, based on the total weight of the mixture, may be at least about 80% by weight or at least about 90% by weight.

The separation method of an embodiment may further include (d1) crystallizing the stereoisomer mixture contained in the stereoisomer mixture solution obtained in step (c1). The separation method of an embodiment may include filtering the crystallized stereoisomer mixture obtained in step (d1), and drying the filtered crystals. The obtained crystal may contain 80 wt% or more or 90 wt% or more of the diastereomer A based on the total weight of the crystal.

The crystallization step of step (b1) and step (d1) is ethanol; Alternatively, it may be a step of using a mixed solvent of ethyl acetate and ethanol.

Diastereomer A may have relatively high solubility in the organic solvent used in step (c1), and diastereomer B may have relatively low solubility in the organic solvent used in step (c1). For example, the organic solvent used in step (c1) is ethanol; And it may be a mixed solvent comprising at least one selected from ethyl acetate, tetrahydrofuran and dichloromethane. For example, the organic solvent used in step (c1) may be a mixed solvent of ethanol and tetrahydrofuran. That is, according to an embodiment, 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2- When preparing a stereoisomeric mixture of ol, diastereomer A may be dissolved in a large number in the mixed solvent and diastereomer B may remain in a majority crystalline state. Thereafter, the remaining crystals are removed and the stereoisomer mixture containing the diastereomer A remaining in the mixed solvent is recrystallized to obtain a stereoisomeric mixture having a high ratio of the diastereomer A. Accordingly, since a separate seeding process is not required, a stereoisomer mixture having a high ratio of diastereomer A can be obtained while simplifying the process step.

(1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl according to an embodiment of the present invention -Butan-2-ol, or a method for preparing a pharmaceutically acceptable salt thereof is chiral octahydro-4-hydroxy-4-oxide-dinaphtho [2,1-d: 1 ', 2'-f] 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalene-1- (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1) from a mixture of stereoisomers of yl)-1-phenylbutan-2-ol optical separation of -naphthyl)-1-phenyl-butan-2-ol.

In one embodiment, the same description as the above-described separation step may be applied to the optical separation step.

For example, the splitting agent is (11bR)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxide-dinaphtho[2,1-d:1 ',2'-f][1,3,2]dioxaphospepine.

The optical separation step is, (a) the 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenyl (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino in a solid state by adding the stereoisomeric mixture of butan-2-ol and the resolving agent to an organic solvent preparing a mixture comprising -2-(1-naphthyl)-1-phenyl-butan-2-ol and a salt of the resolving agent. In step (a), the organic solvent may include methanol, or methanol and dimethylformamide. In step (a), the volume ratio of the methanol and the dimethylformamide may be the same as described above. For example, the volume ratio of the methanol and the dimethylformamide may be 10:0.5 to 10:2.

The preparation method is (b) (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl- (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl) from butan-2-ol and salts of the above resolving agents The method may further include preparing -1-phenyl-butan-2-ol. Step (b) is the (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl- (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl) from butan-2-ol and salts of the above resolving agents It may be a step of liberating -1-phenyl-butan-2-ol.

The preparation method is (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane-2 - It may further comprise the step of reacting an ol with an acid.

The step of reacting with the acid is the free (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1- The method may include adding phenyl-butan-2-ol to an organic solvent (eg, isopropyl alcohol) and stirring, then adding an acid to reflux and stirring.

In one embodiment, the acid is an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid; organic carboxylic acids such as acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid or malic acid, sulfonic acid such as methanesulfonic acid or para-toluenesulfonic acid; or other various acids known to form pharmaceutically acceptable salts. For example, the acid may be fumaric acid.

The solution reacted with the acid was filtered, washed, cooled and stirred, the solid was filtered and dried (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino A salt of -2-(1-naphthyl)-1-phenyl-butan-2-ol can be obtained.

In one embodiment, non-limiting examples of the pharmaceutically acceptable salt include a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid; Salts with organic carboxylic acids such as acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid or malic acid, or sulfonic acids such as methanesulfonic acid or para-toluenesulfonic acid ; or salts with various acids known to form other pharmaceutically acceptable salts.

In one embodiment, the pharmaceutically acceptable salt is (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl) )-1-phenyl-butan-2-ol fumarate.

(1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane-2 according to the invention The production method of -ol and a pharmaceutically acceptable salt thereof is economical and convenient, and the generation of related substances is reduced, and at the same time, it can be prepared with high purity and high yield, so it is suitable for commercial mass production.

(1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane-2 according to the invention - The separation method of ol is economical and simple, and the generation of related substances is reduced, and at the same time, it can be manufactured with high purity and high yield, so it is suitable for commercial mass production.

Hereinafter, to help the understanding of the present invention, examples will be described in detail. However, the following examples are merely illustrative of the contents of the present invention, and the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art.

<Measuring method>

The following measuring methods are commonly applied to each Example according to the present invention.

1. Purity analysis

The purity of the compounds was determined by high performance liquid chromatography (HPLC) using an Agilent Technologies 1260 Infinity. A stationary phase (Agilent SB-CN C18, 250 x 4.6 mm, 5 μm), a mobile phase A (0.1% aqueous phosphoric acid solution) and a mobile phase B (methanol: acetonitrile: isopropanol = 45: 45: 10) were used.

2. Optical Purity Analysis

The optical purity of the compound was determined by high performance liquid chromatography (HPLC) using an Agilent Technologies 1260 Infinity. A stationary phase (Cyclobond I RSP-250 x 4.6 mm, 5 μm) and a mobile phase adjusted to pH 7 with acetic acid (methanol: water: ammonium acetate = 60 mL: 40 mL: 0.154 g) were used.

<Example 1> 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol Preparation of stereoisomeric mixtures

3-(dimethylamino)-1'-propionaphthone hydrochloride (50.6 g; 192 mmol) was dissolved in water (60 mL), diluted with toluene (500 mL), and stirred at room temperature to prepare a reaction solution A . Sodium hydroxide (8.23 g; 206 mmol) was dissolved in water (60 mL), cooled to room temperature, added to reaction solution A, and stirred for 30 minutes. The organic layer was separated, washed with water (60 mL), and dehydrated over anhydrous sodium sulfate (25 g). The dehydrated solution was filtered under reduced pressure and concentrated under reduced pressure at an external temperature of 45°C. The concentrate was vacuum dried at room temperature for 2 hours to obtain a product A.

Tetrahydrofuran (300 mL) was added to the first reaction part filled with nitrogen, diethylamine (12.6 mL; 122 mmol) and N,N,N',N'-tetramethylethylenediamine (18.2 mL; 122 mmol) ), cooled to -20 °C, n-butyllithium (1.6 M, 76 mL; 122 mmol) was added, stirred for 30 minutes, and cooled to -70 ~ -80 °C to prepare a reagent. After adding 3-benzyl-6-bromo-2-methoxyquinoline (30 g; 91 mmol) to the second reaction part, tetrahydrofuran (300 mL) was added to dissolve it, and then heated to -70 to -80°C under a nitrogen atmosphere. After cooling, a reaction solution B was prepared. The reagent prepared in the first reaction part was slowly added dropwise to the reaction solution B and stirred for 1 hour to prepare a reaction solution C. The obtained product A was diluted by adding toluene (300 mL), cooled to -70 ~ -80°C under a nitrogen atmosphere, and then slowly added dropwise to the reaction solution C and stirred for 24 hours to obtain a reaction solution D. Then, after heating the reaction solution D to 0 ~ 5 ℃ acetic acid (13.1 mL; 229 mmol) diluted in tetrahydrofuran (15 mL) was slowly added and stirred at the same temperature for 1 hour. Then, water (150 mL) was added and the mixture was stirred at 0-5° C. for 1 hour. After separating the organic layer, it was dehydrated with anhydrous sodium sulfate (45 g) and concentrated under reduced pressure at an external temperature of 45° C. to obtain a concentrate A. Ethanol (90 mL) was added to Concentrate A and further concentrated at the same temperature to obtain Concentrate B. After dilution by adding ethyl acetate (30 mL) to Concentrate B, ethanol (270 mL) was added thereto, followed by heating and stirring for 1 hour at an external temperature of 75 to 80° C. under a nitrogen atmosphere. After cooling to room temperature, the mixture was stirred at the same temperature for 2 hours to produce crystals containing diastereomer A and diastereomer B. The resulting crystals were filtered under reduced pressure, washed with ethanol (90 mL), and dehydrated. The washed and dehydrated crystals were vacuum-dried overnight at an internal temperature of 30°C. After adding tetrahydrofuran (480 mL) to the dried crystals to suspend them, ethanol (480 mL) was added and stirred for 1 hour at room temperature under a nitrogen atmosphere, the crystals were filtered under reduced pressure, washed with ethanol (90 mL), and the filtrate was removed from the outside. Concentrated under reduced pressure at a temperature of 45°C. Ethyl acetate (32 mL) was added to the concentrate to suspend it, and ethanol (320 mL) was added thereto, followed by stirring at room temperature under a nitrogen atmosphere for 1 hour to produce crystals containing diastereomer A in a high proportion. The resulting crystals were filtered under reduced pressure, washed with ethanol (90 mL), and dehydrated. Thereafter, the obtained crystals were vacuum dried overnight at an internal temperature of 30° C. to obtain 18.8 g of a white powder. Yield: 37%, diastereomer A: 93.9% (w/w), diastereomer B 4.2% (w/w).

<Example 2> 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane-2 from a stereoisomeric mixture -separation of ol

A. (1R,2S)-1-(6-Bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol and salt preparation of splitting agent

The powder (2.8g; 5.04mmol) obtained in Example 1 was added to the reaction unit, and methanol (56mL) and dimethylformamide (5.6mL) were added thereto, followed by stirring. (11bR)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxide-dinaphtho[2,1-d:1',2'-f][ After adding 1,3,2] dioxaphospepine, the temperature was raised to 80° C. and stirred for 1 hour. Thereafter, after cooling to room temperature, the mixture was cooled to 0-5° C. and stirred for 90 minutes. The solid was filtered and washed with methanol (14 mL). The washed solid was suspended in methanol (21 mL) and dimethylformamide (2.1 mL), and the temperature was raised to 80° C. and stirred for 30 minutes. The mixture was cooled to room temperature and then cooled to 0-5° C. and stirred for 90 minutes. The solid was filtered and washed with methanol (10 mL). The washed solid was dried under vacuum at 30° C. (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1 -phenyl-butan-2-ol and (11bR)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxide-dinaphtho[2,1-d: 1.96 g of a salt of 1',2'-f][1,3,2]dioxaphospepine was obtained. Yield: 43%, purity: 93.3%, optical purity: 99.9%.

B. (1R,2S)-1-(6-Bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol and (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane from the salt of the resolving agent -2-ol vitrification

The solid obtained in step A (1.9 g; 2.08 mmol) was added to the reaction unit, and toluene (38 mL) was added thereto, followed by stirring. Potassium carbonate (0.86 g; 6.25 mmol) was dissolved in water (38 mL) and added to the reaction unit, followed by stirring for 10 minutes. The layers were separated to remove the aqueous layer, and the organic layer was washed with water (38 mL) and brine (38 mL) in that order. After dehydration and filtration over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure at 55°C. Ethyl acetate (1 mL) and methanol (10 mL) were added to the concentrate, followed by stirring at 50° C. for 1 hour. After cooling to room temperature, the mixture was cooled to 0-5° C. and stirred for 90 minutes. The solid was filtered and washed with methanol (5 mL). Drying under vacuum at 30°C (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane 0.78 g of -2-ol was obtained. Yield: 67%, purity: 97.6%.

<Example 3> (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane- Preparation of 2-ol fumarate

The solid (0.75 g; 1.35 mmol) obtained in step B of Example 2 was added to the reaction unit, and isopropyl alcohol (15 mL) was added thereto and stirred. After adding fumaric acid (0.17 g; 1.43 mmol), the mixture was stirred under reflux for 1 hour. The mixture was filtered and washed with isopropyl alcohol (3.8 mL). The mixture was cooled to 0-5 °C and stirred for 2 hours. The solid was filtered and washed with isopropyl alcohol (3.8 mL). Drying under vacuum at 30°C (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane 0.78 g of -2-ol fumarate was obtained. Yield: 86%, purity: 99.9%, optical purity: 100%.

As the specific parts of the present invention have been described in detail above, for those of ordinary skill in the art, it is clear that these specific descriptions are only preferred embodiments, and the scope of the present invention is not limited thereby. will be. Accordingly, it is intended that the substantial scope of the present invention be defined by the appended claims and their equivalents.

Claims (24)

Using chiral octahydro-4-hydroxy-4-oxide-dynaphtho [2,1-d: 1 ', 2'-f] [1,3,2] dioxaphospepine as a splitting agent, 1- ( From a mixture of stereoisomers of 6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol (1R,2S Optical separation of )-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol (1R Separation of ,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol.
According to claim 1,
The splitting agent is a separation method represented by the following formula (1):
[Formula 1]

In Formula 1,
R ₁ to R ₄ are each independently a hydrogen atom, a deuterium atom, a halogen atom, an alkyl group having 1 or more and 5 or less carbon atoms substituted or unsubstituted with an aryl group, or an alkyl group substituted or unsubstituted with 6 or more ring carbon atoms and not more than 12 carbon atoms an aryl group,
a and b are each independently an integer of 1 or more and 2 or less,
c and d are each independently an integer of 1 or more and 8 or less.
According to claim 1,
The splitting agent is (11bR)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxide-dynaphtho[2,1-d:1 ',2' -f][1,3,2] Dioxaphospepine Isolation method.
According to claim 1,
The separation method is (a) the 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutane-2 (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2- in a solid state by adding the stereoisomeric mixture of -ol and the resolving agent to an organic solvent A separation method comprising the step of preparing a mixture comprising (1-naphthyl)-1-phenyl-butan-2-ol and a salt of a resolving agent.
5. The method of claim 4,
In the step (a), the organic solvent comprises at least one selected from the group consisting of a polar protic solvent, a polar aprotic solvent, and a mixed solvent thereof,
The polar protic solvent comprises at least one selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, t-butyl alcohol, and a mixed solvent thereof,
The polar aprotic solvent is ethyl acetate, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, N-methyl-2-pyrrolidone and Separation method comprising at least one selected from the group consisting of a mixed solvent thereof.
6. The method of claim 5,
The organic solvent includes methanol or a mixed solvent of methanol and the polar aprotic solvent,
The polar aprotic solvent is a separation method comprising at least one selected from tetrahydrofuran, dimethylformamide and N-methyl-2-pyrrolidone.
7. The method of claim 6,
The volume ratio of the methanol to the polar aprotic solvent in the mixed solvent is 10:0.5 to 10:2.
5. The method of claim 4,
The splitting agent is (11bR)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxide-dynaphtho[2,1-d:1 ',2' -f][1,3,2] Dioxaphospepine Isolation method.
5. The method of claim 4,
The separation method is (b) the (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl) from salts of -butan-2-ol and resolving agent Separation method further comprising the step of preparing -1-phenyl-butan-2-ol.
10. The method of claim 9,
The step (b) is
preparing a suspension of the salt; and
Separation method comprising the step of adding at least one of carbonate or phosphate to the suspension.
11. The method of claim 10,
In step (b), the solvent of the suspension is a non-polar organic solvent.
According to claim 1,
(1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-( 1-Naphthyl)-1-phenyl-butan-2-ol and (1S,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1 -Naphthyl)-1-phenyl-butan-2-ol in a weight ratio of 90% by weight or more.
According to claim 1,
The mixture of stereoisomers is
(a1) reacting 3-benzyl-6-bromo-2-methoxyquinoline with a base and 3-(dimethylamino)-1'-propionaphthone, followed by addition of an acid; and
(b1) a separation method obtained by a method for preparing a stereoisomeric mixture comprising the step of crystallizing the reaction mixture obtained in step (a1) to produce crystals.
14. The method of claim 13,
The method for preparing the stereoisomeric mixture is (c1) (1R,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2 from the crystal in step (b1). -(1-naphthyl)-1-phenyl-butan-2-ol and (1S,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2- The separation method further comprising the step of removing the mixture of (1-naphthyl)-1-phenyl-butan-2-ol to obtain a mixture of stereoisomers.
15. The method of claim 14,
The step (c1) is ethanol; and adding to a mixed solvent comprising at least one selected from ethyl acetate, tetrahydrofuran and dichloromethane.
15. The method of claim 14,
(d1) The separation method further comprising the step of crystallizing the stereoisomer mixture contained in the stereoisomer mixture solution obtained in step (c1).
17. The method of claim 16,
The crystallization step of step (b1) and step (d1) is ethanol; Or a separation method using a mixed solvent of ethyl acetate and ethanol.
Using chiral octahydro-4-hydroxy-4-oxide-dynaphtho [2,1-d: 1 ', 2'-f] [1,3,2] dioxaphospepine as a splitting agent, 1- ( From a mixture of stereoisomers of 6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol (1R,2S optical separation of )-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol; (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol comprising , or a method for preparing a pharmaceutically acceptable salt thereof.
19. The method of claim 18,
The splitting agent is (11bR)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxide-dynaphtho[2,1-d:1 ',2' -f] [1,3,2] dioxaphospephine production method
19. The method of claim 18,
The optical separation step is (a) 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutane- (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2 in a solid state by adding the stereoisomeric mixture of 2-ol and the resolving agent to an organic solvent -(1-naphthyl)-1-phenyl-butan-2-ol and a preparation method comprising the step of preparing a mixture comprising a salt of the resolving agent.
21. The method of claim 20,
In step (a), the organic solvent includes methanol, or methanol and dimethylformamide,
The volume ratio of the methanol and the dimethylformamide is 10:0.5 to 10:2.
21. The method of claim 20,
The preparation method is (b) (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl- (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)- from salts of butan-2-ol and resolving agent The method further comprising the step of liberating 1-phenyl-butan-2-ol.
19. The method of claim 18,
(1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol The method further comprising the step of reacting with an acid.
19. The method of claim 18,
The pharmaceutically acceptable salt is (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl -Butan-2-ol fumarate production method.