KR20220087933A - Method For Producing Diamine Derivative - Google Patents

Abstract

The present invention relates to a method for preparing FXa (activator factor X) inhibitor edoxaban (Formula 1), a pharmaceutically acceptable salt or hydrate thereof, and novel intermediate compounds (Formulas 7 and 8) therefor. . The manufacturing method of the present invention has the advantage of not using a hydrogenation reaction using a metal catalyst, which is difficult for commercial production applications, or a reaction that must be performed under anhydrous conditions during the reaction, or various kinds of reagents having explosive properties. Therefore, it is possible to stably provide edoxaban with high purity and high yield by the manufacturing method of the present invention.

Description

Method for producing a diamine derivative {Method For Producing Diamine Derivative}

The present invention relates to a method for preparing FXa (activator factor X) inhibitor edoxaban (Formula 1), a pharmaceutically acceptable salt or hydrate thereof, and novel intermediate compounds (Formulas 7 and 8) therefor. .

Edoxaban p-toluenesulfonic acid salt or hydrate thereof is an FXa inhibitor that acts as an anti-blood coagulation factor, and is usefully used as an anticoagulant for the prevention or treatment of thrombosis and embolic diseases. Examples of anticoagulants include Argatroban, Dabigatran, Rivaroxaban, Apixaban, and Edoxaban.

Edoxaban is represented by the following Chemical Formula 1 and the chemical name is N'-(5-chloropyridin-2-yl)-N-{(1S,2R,4S)-4-[(dimethylamino)carbonyl]-2 -[5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]aminocyclohexyl}ethanediamide, its p-toluenesulfonate yl A drug whose main ingredient is hydrate is released under the product name LIXIANA ^® .

[Formula 1]

Edoxaban, used as an anticoagulant as an FXa inhibitor, was first disclosed in International Publication No. WO 2003-000657, and its preparation method can be expressed as <Scheme 1>, <Scheme 2>, and <Scheme 3> .

<Scheme 1>

<Scheme 2>

<Scheme 3>

The preparation method of edoxaban according to <Reaction Scheme 1>, <Reaction Scheme 2>, and <Reaction Scheme 3> uses a hydrogenation reaction using a metal catalyst, a reaction that must be performed under anhydrous conditions during the reaction, and various types of reagents having explosive properties. Therefore, it contains conditions or methods that are very difficult to apply commercially. Therefore, the production of edoxaban by the conventional manufacturing method is difficult to manufacture high-purity edoxaban and is not suitable for mass production in terms of economics as well.

Accordingly, the present inventors have developed a simple manufacturing process of edoxaban that can ensure high purity quality and is suitable for mass production.

International Patent Publication No. WO2003/000657 International Patent Publication No. WO2003/000680

An object of the present invention is to provide a method for manufacturing edoxaban that is significantly advanced than the prior art, and an object of the present invention is to provide a method for manufacturing edoxaban suitable for high-purity, high-yield mass production.

In order to achieve the object of the present invention, the present invention provides a novel method for preparing a compound of Formula 1, a pharmaceutically acceptable salt thereof, or a hydrate thereof, comprising the steps of:

(S-1) reacting a compound of Formula 6 with a compound of Formula 10 to prepare a compound of Formula 7;

(S-2) reacting the compound of Formula 7 with a Mitsunobu reaction to prepare a compound of Formula 8;

(S-3) deprotecting the compound of Formula 8 to prepare a compound of Formula 9; and

(S-4) preparing a compound of Formula 1 by reacting the compound of Formula 9 with a compound of Formula 11.

[Formula 1]

[Formula 6]

[Formula 7]

[Formula 8]

[Formula 9]

[Formula 10]

[Formula 11]

An example of the preparation method of the present invention is provided by Scheme 4 below.

<Scheme 4>

The present invention has the advantage of not using a hydrogenation reaction using a metal catalyst, which is difficult for commercial production applications, or a reaction that must be performed under anhydrous conditions during the reaction, or various kinds of reagents having explosive properties. Therefore, the preparation method of the present invention can stably provide the compound of Formula 1, a pharmaceutically acceptable salt thereof, or a hydrate thereof with high purity and high yield.

A novel method for preparing a compound of Formula 1 (edoxaban), a pharmaceutically acceptable salt thereof, or a hydrate thereof according to the present invention includes the following four steps:

(S-1) reacting a compound of Formula 6 with a compound of Formula 10 to prepare a compound of Formula 7;

(S-2) reacting the compound of Formula 7 with a Mitsunobu reaction to prepare a compound of Formula 8;

(S-3) deprotecting the compound of Formula 8 to prepare a compound of Formula 9; and

(S-4) preparing a compound of Formula 1 by reacting the compound of Formula 9 with a compound of Formula 11.

Hereinafter, the manufacturing method of the present invention will be described in detail for each step as follows.

Step S-1

In the preparation method of the present invention, step S-1 is a step of preparing a compound of Formula 7 below by reacting a compound of Formula 6 with a compound of Formula 10. Step S-1 may be specifically performed in the following two ways.

The first method is to prepare the compound of Formula 7 by activating the compound of Formula 10 with a chlorinating agent in the presence of a first organic solvent and then reacting the compound of Formula 6 with the compound of Formula 6 in the presence of a second organic solvent and base. Here, the first organic solvent may be dichloromethane, and the second organic solvent may be toluene, acetonitrile, tetrahydrofuran, dimethylformamide, or a combination thereof. The chlorinating agent may be thionyl chloride (SOCl ₂ ), but is not limited thereto. The base may be triethylamine, diisopropylethylamine, or pyridine, but is not limited thereto.

The second method is a method of preparing a compound of Formula 7 by performing a coupling reaction between a compound of Formula 6 and a compound of Formula 10. Here, hydroxybenzotriazole (HOBt), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), or a combination thereof may be used as the coupling reagents, but is not limited thereto.

The compound of formula (10) is commercially available and can be prepared by methods known in the art.

The present invention provides Example 1 as an example of step S-1, but is not necessarily limited thereto.

[Formula 6]

[Formula 7]

[Formula 10]

Step S-2

In the preparation method of the present invention, step S-2 is a step of preparing the compound of formula 8 by performing a Mitsunobu reaction of the compound of formula 7 prepared in step S-1. Specifically, the Mitsunobu reaction may be a Mitsunobu reaction of the compound of Formula 7 with phthalimide. Documents describing specific conditions for the Mitsunobu reaction are known to those skilled in the art of organic chemistry, and the content of which is incorporated herein by reference.

[Formula 8]

The present invention provides Example 2 as an example of step S-2, but is not necessarily limited thereto.

Step S-3

In the preparation method of the present invention, step S-3 is a step of preparing the compound of formula 9 by deprotection reaction of the compound of formula 8 prepared in step S-2. In step S-3, the reaction may be performed in the presence of an organic solvent, an aqueous solution, or a mixed solvent thereof. As the deprotecting group reagent used in the deprotection reaction, hydrazine or a hydrate thereof may be used, but is not limited thereto. By the deprotection reaction, the compound of Formula 9 in which an amine group is generated is prepared.

[Formula 9]

The present invention provides step 1 of Example 3 as an example of step S-3, but is not necessarily limited thereto.

Step S-4

In the preparation method of the present invention, step S-4 is a step of preparing the compound of formula 1 (edoxaban) by reacting the compound of formula 9 prepared in step S-3 with the compound of formula 11.

[Formula 11]

The compound of formula 11 is commercially available and can be prepared by methods known in the art.

The present invention provides step 2 of Example 3 as an example of step S-4, but is not necessarily limited thereto.

In addition, a pharmaceutically acceptable salt of the compound of Formula 1 or a hydrate thereof (eg, tosylate hydrate of edoxaban) may be prepared through an additional reaction with the compound of Formula 1 (see Example 4).

The present invention also provides novel compounds of Formula 7 and Formula 8 used as intermediates in the novel production method of the present invention.

The manufacturing method according to the present invention does not use expensive metal catalysts or highly explosive reagents used in known prior art, and does not require special reaction equipment such as high-pressure reaction. Therefore, the present invention can manufacture edoxaban of high purity and high yield by a simple and safe manufacturing method of edoxaban.

Hereinafter, the manufacturing method according to the present invention will be described in detail with reference to Examples. However, the present invention is not limited thereto.

<Example 1> N-((1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5 Preparation of ,4-c]pyridine-2-carboxamide (Formula 7)

Step 1: Preparation of (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7one

(1S)-Cyclohex-3-ene-1-carboxylic acid (S)-alpha-phenylethylamine salt (2) 10.0 g (40.4 mmol) and 50 ml of dichloromethane were added and stirred, followed by stirring 2.4 g of calcium oxide ( 42.4 mmol) was added. After the reaction solution was cooled to 0-10 °C, 7.5 g (42.4 mmol) of N-bromosuccinimide (NBS) was slowly added thereto. After 20 hours of reaction at room temperature, 50 ml of a 10% aqueous sodium thiosulfate solution was added, stirred for 30 minutes, and the organic layer was separated. The separated organic layer was washed twice with 50 ml of purified water. The separated organic layer was dehydrated using anhydrous sodium sulfate and concentrated. Then, isopropyl alcohol was added to the concentrated reaction product, followed by stirring at room temperature for 2 hours. The resulting solid was filtered and dried under reduced pressure in an oven at 30-40 °C for 3-4 hours to obtain 7.3 g (35.6 mmol, yield 88.0%) of the title compound.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 1.59-1.84 (2H, m), 1.88-2.02 (2H, m), 2.27-2.34 (2H, m), 4.33 (1H, q), 5.02 (1H) , q)

Step 2: Preparation of (1S,3R,4R)-3-amino-4-hydroxy-N,N-dimethylcyclohexane-1-carboxamide

20 g (0.098 mol) of the compound produced in Step 1 of Example 1 and 120 mL of acetonitrile were added to the reactor, and 35.2 g (0.39 mol) of a 50% aqueous dimethylamine solution was added, followed by reaction at 10 ° C. or less for 10 hours. After the reaction solution was concentrated under reduced pressure to remove the solvent, 100 mL of dichloromethane was added to the reaction solution, 24.5 g (0.245 mol) of 40% NaOH sol was added, and the reaction was conducted at room temperature for 4 hours. The reaction solution was concentrated again, aqueous ammonia 125 mL (2.06 mol) was added, and the mixture was stirred at 40° C. for 10 hours. Then, 100 mL of dichloromethane was added to the reaction solution, stirred for 10 minutes, and the organic layer was separated. The separated organic layer was washed twice with 100 mL of purified water, dehydrated using 4 g of anhydrous sodium sulfate, and then concentrated under reduced pressure. 30 mL of n-hexane was added to the concentrated reaction solution for crystallization, and the crystals were filtered and dried under reduced pressure to obtain 14.9 g (0.080 mol, yield 82.0%) of the title compound.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 1.60-1.78 (2H, m), 1.83-1.92 (2H, m), 2.18-2.24 (1H, m), 2.34-2.41 (1H, m), 2.81 -2.90 (1H, m), 2.96 (3H, s), 3.74-3.79 (1H, m), 4.03-4.08 (1H, m)

Step 3-1: N-((1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5 Preparation of ,4-c]pyridine-2-carboxamide (compound of formula 7)

5 g (0.025 mol) of 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid was added to the reactor, and 50 mL of dichloromethane was added to dissolve, and then 10 It was cooled to below °C. To the reaction solution, 3.1 g (0.026 mol) of thionyl chloride was added, stirred at 10° C. or lower for 4 hours, and the reaction solution was concentrated under reduced pressure. To the concentrated reaction solution, 50 mL of acetonitrile and 4.7 g (0.025 mol) of the compound produced in step 2 of Example 1 were added, and 5.3 g (0.052 mol) of triethylamine was slowly added thereto, followed by stirring at room temperature for 6 hours. After concentration under reduced pressure to remove the solvent, 100 mL of purified water was added, stirred at 10° C. or lower for 1 hour, filtered and dried under reduced pressure to obtain 8.4 g (0.023 mol, yield 91.2%) of the title compound.

Step 3-2: N-((1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5 Preparation of ,4-c]pyridine-2-carboxamide (compound of formula 7)

4.7 g (0.025 mol) of the compound produced in step 2 of Example 1 and 35 mL of acetonitrile were added to the reactor, and the mixture was cooled and stirred at 10° C. or less. In the reaction solution, 10.1 g (0.100 mol) of triethylamine, 5.4 g (0.027 mol) of 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid, and hydro 4.1 g (0.030 mol) of oxybenzotriazole and 5.8 g (0.030 mol) of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride were sequentially added, followed by stirring at 20° C. for 20 hours. The reaction solution was cooled to 10° C., 65 mL of purified water was added, stirred for 1 hour, filtered, washed with 10 mL of purified water, and dried under reduced pressure to obtain 8.1 g (0.022 mol, yield 89.3%) of the title compound.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 1.47-1.73 (4H, m), 2.01-2.15 (2H, t), 2.26 (3H, s), 2.38 (1H, m), 2.76-2.83 (4H) , m),2.98 (6H, s), 3.37 (2H, s), 3.54 (1H, m), 4.16 (1H, m), 5.37 (1H, s), 8.32 (1H, s)

<Example 2> N-((1R,2S,5S)-5-(dimethylcarbamoyl)-2-(1,3-dioxoisoindolin-2-yl)cyclohexyl)-5-methyl-4, Preparation of 5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide (Formula 8)

After adding 40 mL of tetrahydrofuran and 10 g (0.027 mol) of the final compound prepared in Example 1 to the reactor, 4.7 g (0.032 mol) of phthalimide and 8.4 g (0.032 mol) of triphenylphosphine were added. The reaction solution was cooled to 10° C. or less, and DEAD 7.1 g (0.041 mol) was added thereto. After stirring at room temperature for 2 hours, the temperature was raised to 45°C, and the mixture was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, 50 mL of dichloromethane and 50 mL of purified water were added to the reactor, and the organic layer was separated and concentrated under reduced pressure. Into the concentrated reaction solution, 60 mL of ethanol was added, dissolved by heating to 60 °C, cooled to 10 °C, stirred, filtered, and dried under reduced pressure to obtain 10.9 g (0.022 mol, yield 80.0%) of the title compound.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 1.73-1.80 (4H, m), 2.02 (2H, t), 2.26 (3H, s), 2.38 (1H, m), 2.76-2.83 (4H, m) ), 2.98 (6H, s), 3.37 (2H, s), 4.16~4.18 (2H, m), 7.84-7.92 (4H, m), 8.32 (1H, s)

<Example 3> N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-(dimethylcarbamoyl)-2-(5-methyl-4,5,6, Preparation of 7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl)oxalamide (Formula 1)

Step 1: N-((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4- c] Preparation of pyridine-2-carboxamide

11 g (0.022 mol) of the final compound prepared in Example 2, 1100 mL of methyl alcohol, and 7.0 g (0.220 mol) of hydrazine were added to the reactor, the temperature was raised to 30 ° C., and stirred for 1 hour. Then, the temperature was raised to 65 ° C. and stirred for 5 hours. did. After cooling the reaction solution to 20°C, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, 180 mL of tetrahydrofuran was added, the temperature was raised to 60°C to dissolve, and then cooled to 10°C again and filtered. The filtered wet body was dried under reduced pressure to obtain 7.3 g (0.020 mol, yield 91.1%) of the title compound.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 1.48-1.79 (4H, m), 2.02 (2H, m), 2.26 (3H, s), 2.38 (1H, m), 2.76-2.83 (4H, m) ), 2.98 (6H, s), 3.19 (1H, m), 3.37 (2H, s), 3.49 (1H, m), 8.32 (1H, s)

Step 2: N1-(5-Chloropyridin-2-yl)-N2-((1S,2R,4S)-4-(dimethylcarbamoyl)-2-(5-methyl-4,5,6,7- Preparation of tetrahydrothiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl)oxalamide

8.3 g (0.083 mol) of triethylamine, 12 g (0.033 mol) of the compound prepared in step 1 of Example 3, and 50 mL of acetonitrile were added to the reactor. The reaction solution was heated to 60°C, ethyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate monohydrochloride 9.5 g (0.036 mol) was slowly added, stirred while maintaining 60°C, and stirred for 4 hours at 20°C was cooled and stirred for 10 hours. 200 mL of purified water was added to the reaction solution, stirred at 5° C. for 1 hour, filtered, and dried under reduced pressure to obtain 15.9 g (0.029 mol, yield 89.2%) of the title compound.

¹ H-NMR (500 MHz, CDCl ₃ ): δ 1.60-1.98 (3H, m), 2.00-2.16 (3H, m), 2.52 (3H,s), 2.78-2.90 (3H, m), 2.92-2.98 (2H, m), 2.95 (3H, s), 3.06 (3H, s), 3.69 (1H, d), 3.75 (1H, d), 4.07-4.15 (1H, m), 4.66-4.72 (1H, m) ) 7.40 (1H, m), 7.68 (1H, m), 8.03 (1H, d), 8.16 (1H, m), 8.30 (1H, m), 9.72 (1H, s)

<Example 4> N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-(dimethylcarbamoyl)-2-(5-methyl-4,5,6, Preparation of 7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl)oxalamide tosylate monohydrate

12 g (0.022 mol) of the compound of Example 3 was put into the reactor, 72 mL of ethyl alcohol and 24 mL of purified water were added, 4.4 g (0.023 mol) of p-toluenesulfonic acid monohydrate was added, and the reaction solution was heated to 70° C. It heated up and stirred for 2 hours. The reaction solution was cooled to 20 °C, stirred for 1 hour, filtered, and dried under reduced pressure to obtain 15.5 g (0.021 mol, yield 97.2%) of the title compound.

¹ H-NMR (500 MHz, DMSO): δ 1.48-1.74 (4H, m), 2.38 (2H, m), 2.26 (3H, s), 2.38 (1H, m), 2.43 (3H, s), 2.76 -2.83 (4H, m), 2.98 (6H, s), 3.37 (2H, s), 4.15-4.23 (2H, m), 7.47 (2H, m), 7.70-7.75 (3H, m), 8.02 (1H) , m), 8.28-8.31 (2H, m), 8.05 (1H, s), 8.80 (1H, s), 11.23 (1H, s)

Claims (14)

(S-1) reacting a compound of Formula 6 with a compound of Formula 10 to prepare a compound of Formula 7;
(S-2) reacting the compound of Formula 7 with a Mitsunobu reaction to prepare a compound of Formula 8;
(S-3) deprotecting the compound of Formula 8 to prepare a compound of Formula 9; and
(S-4) preparing a compound of Formula 1 by reacting the compound of Formula 9 with a compound of Formula 11
A method for preparing a compound of Formula 1, a pharmaceutically acceptable salt thereof, or a hydrate thereof, comprising:
[Formula 1]

[Formula 6]

[Formula 7]

[Formula 8]

[Formula 9]

[Formula 10]

[Formula 11]

The method of claim 1, wherein step (S-1)
(i) activating the compound of Formula 10 with a chlorinating agent in a first organic solvent; and
(ii) reacting the activated compound of formula (10) with a compound of formula (6) in a second organic solvent and a base to prepare a compound of formula (7)
A manufacturing method comprising a. The method according to claim 2, wherein the first organic solvent is dichloromethane. The method according to claim 2, wherein the second organic solvent is toluene, acetonitrile, tetrahydrofuran, dimethylformamide, or a combination thereof. The method according to claim 2, wherein the chlorinating agent is thionyl chloride (SOCl ₂ ). The method according to claim 2, wherein the base is triethylamine, diisopropylethylamine, pyridine, or a combination thereof. The method of claim 1, wherein step (S-1)
Preparing the compound of formula 7 by coupling the compound of formula 6 and the compound of formula 10 with hydroxybenzotriazole (HOBt), EDCI (1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide), or a combination thereof
A manufacturing method comprising a. The method according to claim 1, wherein the Mitsunobu reaction in step (S-2) is performed together with phthalimide. The method according to claim 1, wherein the deprotection reaction in step (S-3) is performed in the presence of an organic solvent, an aqueous solution, or a mixed solvent thereof. The method according to claim 1, wherein the deprotection reaction of step (S-3) is performed with hydrazine, a hydrate thereof, or a combination thereof. A compound of formula 7
[Formula 7]

12. The compound of claim 11, which is prepared by reacting a compound of formula (6) with a compound of formula (10).
[Formula 6]

[Formula 10]

A compound of formula 8:
[Formula 8]

14. The compound of Formula 8 according to claim 13, which is prepared by subjecting the compound according to claim 11 to a Mitsunobu reaction.