KR20170105021A - Method for producing pyrazine carboxamide compound, and synthetic intermediate thereof - Google Patents

Abstract

(PROBLEMS) To provide a novel process for producing a pyrazine carboxamide compound as a raw material for producing a medicament or the like, and a synthetic intermediate useful in the production process thereof.
Means for Solving the Problems The present inventors have intensively studied a production method in the industrial production of a pyrazine carboxamide compound. As a result, it has been found that purification by silica gel column chromatography is unnecessary by using a predetermined raw material and a synthetic intermediate , And the pyrazinecarboxamide compound can be produced by a method suitable for industrial production as a pharmaceutical product, in which the yield of the total product is greatly improved, thereby completing the present invention.

Description

METHOD FOR PRODUCING PYRAZINE CARBOXAMIDE COMPOUND, AND SYNTHETIC INTERMEDIATE THEREOF,

The present invention relates to a process for the preparation of 5 - {[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6- (Hereinafter may be referred to as " compound (1) ") and a synthetic intermediate thereof.

We have already reported that the compound (1) or a pharmaceutically acceptable salt thereof is useful as an active ingredient of a pharmaceutical composition for treating cancer (Patent Document 1). In Patent Document 1, the compound (1) is described as Example 54, and the monomethanesulfonic acid salt (9) of the compound (1) is described as Example 261.

[Chemical Formula 1]

The compound (1) (Example 54 of Patent Document 1) and the method for producing the monomethanesulfonic acid salt (9) described in Patent Document 1 are as shown in Reaction Scheme 1. [

(Reaction Scheme 1)

(2)

(Hereinafter sometimes referred to as "compound (8)") and tert-butyl (3R) -3-hydroxypyrrolidine-1 Butyl (3R) -3 - [(5-carboxy-1-yl) -carbamoyl] 6-chloro-3-ethylpyrazin-2-yl) oxy] pyrrolidine-1-carboxylate (hereinafter sometimes referred to as "compound (10)"). Then, the compound (10) and 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] aniline prepared by a known method (3R) -3 - {[5-Carbamoyl-3-ethyl-6 - ({4- [4- (Hereinafter referred to as " compound (4) ") in the presence of a base, such as sodium hydride, sodium hydride, ). Then, the compound (4) was reacted with trifluoroacetic acid in accordance with the method described in Production Example 34 of the same process to obtain 6-ethyl-3- {4- [4- (4- methylpiperazin- Pyridin-3-yloxy] pyrazine-2-carboxamide (hereinafter sometimes referred to as "compound (3)" (1) is prepared by reacting compound (3) with acryloyl chloride and carrying out the reaction according to the method described in Example 1 of the same. Finally, the compound (1) is a method of producing the monomethanesulfonic acid salt (9) of the compound (1) according to the method described in Example 254 of the same document.

However, the method for producing the compound (1) and the monomethanesulfonic acid salt (9) disclosed in Patent Document 1 can be carried out at a low yield of the product, for example, as shown in Table 3 described below, (The first step of the reaction scheme 1), and the total yield to the monomethanesulfonic acid salt of the final target compound (1) is only 5%. In addition, from the point of view that the purification step by the silica gel column chromatography is required (the first step, the third step and the fourth step of the reaction scheme 1), the production method represented by the reaction scheme 1 is an industrial In production, it was a more desirable method.

International Publication No. 2013/108754

There is provided a novel process for producing the compound (1) or a salt thereof, and a useful synthetic intermediate in the process for producing the same.

The inventors of the present invention have made intensive investigations on a production method in the industrial production of the compound (1) or a salt thereof. As a result, it has been found that the purification by silica gel column chromatography is not necessary by using a predetermined raw material and a synthetic intermediate, (1) or a salt thereof can be produced by a method suitable for industrial production as a pharmaceutical product with improved yield, and the present invention has been accomplished.

That is, the present invention relates to a novel synthetic process for producing a compound (1) or a salt thereof and a synthetic intermediate useful in the process for producing the same.

[One]

The compound (2)

(3)

Or a salt thereof is reacted with a base to effect a dehydrochlorination reaction.

[Chemical Formula 1]

Or a salt thereof.

[2]

When the compound (2) or a salt thereof is a compound (3)

[Chemical Formula 4]

Or a salt thereof is reacted with 3-chloropropanoyl chloride to carry out an acylation reaction.

[3]

When the compound (3) or a salt thereof is a compound (4)

[Chemical Formula 5]

Or a salt thereof is subjected to a deprotection reaction. [2] The process according to [2]

[4]

When the compound (4) or its salt is a compound (6)

[Chemical Formula 6]

(5) < / RTI >

(7)

Wherein the aromatic nucleophilic substitution reaction is carried out in the presence of a base.

[5]

When the compound (6) or its salt is a compound (8)

[Chemical Formula 8]

(7) in the presence of a base in 2-butanol in the presence of a base,

[Chemical Formula 9]

Or a salt thereof is reacted with an aromatic nucleus substitution reaction at 80 ° C to 90 ° C.

[6]

A compound (9) characterized in that methanesulfonic acid is allowed to act on the compound (1) or its salt prepared by the method described in any one of [1] to [5] to form a monomethanesulfonic acid salt.

[Chemical formula 10]

≪ / RTI >

[7]

The compound (2)

(3)

Or a salt thereof.

The present invention also relates to a process for producing the following compound (4) or a salt thereof.

[8]

Compound (6)

[Chemical Formula 6]

(5) < / RTI >

(7)

(4) < / RTI >

[Chemical Formula 5]

Or a salt thereof.

[9]

Compound (8)

[Chemical Formula 8]

(7) in the presence of a base in 2-butanol in the presence of a base,

[Chemical Formula 9]

(4) or a salt thereof by reacting the compound (5) or a salt thereof and reacting the compound (6) or a salt thereof at 80 ° C to 90 ° C, .

[10]

A production method according to [1], which comprises a step of treating a solution containing a crude product of a compound of formula (1) with activated carbon to remove a part of impurities contained in the preparation .

[11]

[6] The production method according to [6], wherein a mixed solvent of acetone and dimethyl sulfoxide is used as a reaction solvent.

The compound disclosed in the present invention may be either a free acid or a salt. Examples of such salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, And examples thereof include formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, And acid addition salts with organic acids such as sulfonic acid, aspartic acid and glutamic acid.

In addition, the compound disclosed in the present invention may be various hydrates, solvates and crystalline polymorphs of Prince or its salts, and the present invention also includes the substances and the production method using these substances. Further, the compounds disclosed in the present invention may be compounds labeled with various radioactive or non-radioactive isotopes, and the present invention also includes those compounds and methods of using the compounds.

In addition, the compound disclosed in the present invention may form a salt or a salt thereof, or may be various kinds of hydrates and solvates thereof, or may be crystals thereof or amorphous ones.

In addition, the compounds disclosed in the present invention may have tautomers in some cases. In the present specification, there are cases where only one form of the isomers is described, but the present invention encompasses other isomers and methods of production using the other isomers, A preparation method thereof, a mixture of the isomers, and a production method using the mixture.

In the present specification, the compound represented by the formula (1) may be simply referred to as the compound (1), and other numbers may be referred to as the same.

In the present specification, " methanesulfonic acid in the compound (1) or a salt thereof " means that methanesulfonic acid acts on the compound (1) or a salt thereof, or after neutralizing the compound (1) , Methane sulfonic acid may be allowed to act.

In the present specification, "seed crystal" refers to a solid compound which causes seed crystal or crystallization to be promoted.

According to the present invention, it is possible to provide a compound (1), a method for producing the monomethanesulfonic acid salt (9), and a synthetic intermediate useful in the production method, which are preferable for industrial production as a medicine.

Hereinafter, the present invention will be described in detail.

The process for producing the compound (1) of the present invention and its monomethanesulfonic acid salt (9) (Step 1 to Step 6) is shown as Reaction Scheme 2, and will be described in detail below.

(Reaction Scheme 2)

(11)

First step

This step is a step for the preparation of 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] aniline (7) to give an aromatic nucleophilic substitution reaction to give 5-chloro-6-ethyl-3- {4- [4- (4-methylpiperazin- 1- yl) piperidin- 1 -yl] anilino} Pyrazine-2-carboxamide (6). In this reaction, the compound (8) and the compound (7) are used, and the mixture is reacted in a solvent inert to the reaction in the presence of a base under cooling to heating, in an embodiment at 0 ° C to 100 ° C, In another embodiment, stirring is carried out at 80 ° C to 90 ° C, usually for 1 hour to 2 days. Examples of the solvent include, but are not limited to, ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; alcohols such as methanol, ethanol, 2-propanol, 2- N-dimethylformamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethylsulfoxide, acetonitrile and mixtures thereof. - butanol. Examples of the base include, but are not limited to, organic bases such as triethylamine, N, N-diisopropylethylamine and N-methylmorpholine. In one embodiment, N, N-diisopropyl Ethylamine.

Second Step

The present process is a process for the preparation of 5-chloro-6-ethyl-3- {4- [4- (4-methylpiperazin- 1 -yl) piperidin- 1 -yl] anilino} pyrazine- Butyl (3R) -3-hydroxypyrrolidine-1-carboxylate (5) to give tert-butyl (3R) -3 - {[ Yl} phenyl} amino) pyrazin-2-yl] oxy} pyrrolidine-1-carboxylic acid ethyl ester [ 1-carboxylate (4). In this reaction, the compound (6) and the compound (5) are used and the mixture is heated in a solvent inert to the reaction in the presence of a base under cooling to heating, For 1 hour to 2 days. Examples of the solvent to be used here include, but are not limited to, ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, dimethylsulfoxide, acetonitrile, and mixtures thereof. In one embodiment, tetrahydrofuran is exemplified. Examples of the base include, but are not limited to, organic bases such as lithium diisopropylamide, potassium tert-butoxide, and inorganic bases such as sodium hydride. In one embodiment, potassium tert- .

Third step

The present process is a process for the preparation of tert-butyl (3R) -3 - {[5-carbamoyl-3-ethyl-6- ({4- [4- (4-methylpiperazin-1-yl) piperidin- 2-yl] oxy} pyrrolidine-1-carboxylate (4) in an inert solvent such as concentrated hydrochloric acid or trifluoroacetic acid in an inert solvent In one embodiment, heating is carried out at 0 ° C to 100 ° C, usually for 1 hour to 2 days, followed by deprotection reaction to obtain 6-ethyl-3- {4- [4- (4-methylpiperazin- -Yl) piperidin-1-yl] anilino} -5 - [(3R) -pyrrolidin-3- yloxy] pyrazine-2-carboxamide (3). Examples of the solvent used here include, but are not limited to, alcohols such as methanol, ethanol, 2-propanol, 2-butanol, or water, and mixtures thereof. In one embodiment, the functional ethanol or the functional 2-propanol can be mentioned, and in one embodiment, the functional ethanol can be mentioned.

In the present step, the compound (3) is isolated without isolating the compound (1) in a predetermined solvent (including, but not limited to, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether and tetrahydrofuran, , Halogenated hydrocarbons such as 1,2-dichloroethane and chloroform, ketones such as 2-butanone and methyl isobutyl ketone, esters such as ethyl acetate and isopropyl acetate, and alcohols such as 2-propanol A mixed solution of methyl isobutyl ketone or methyl isobutyl ketone and 2-propanol may be used as an embodiment, and the separation step may be carried out, and the organic layer may be used as it is to proceed to the next step .

Fourth step

The present process is a process for the preparation of 6-ethyl-3- {4- [4- (4-methylpiperazin- 1 -yl) piperidin- 1 -yl] anilino} -5 - [(3R) -pyrrolidin- 3-yloxy] pyrazine-2-carboxamide (3) was subjected to an acylation reaction by reacting 3-chloropropanoyl chloride to give 5 - {[(3R) -1- (3- chloropropanoyl) Yl) oxy] -6-ethyl-3- {4- [4- (4- methylpiperazin- 1 -yl) piperidin- 1 -yl] anilino} pyrazine- (2). In this reaction, 3-chloropropanoyl chloride is used in a solvent inert to the reaction under cooling to heating, and in one embodiment, stirring is carried out at -10 ° C to 0 ° C, usually for 30 minutes to 2 days. Examples of the solvent to be used here include, but are not limited to, ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane, N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, and mixtures thereof. In one embodiment, a mixture of tetrahydrofuran and N, N-dimethylformamide is exemplified. In this step, the solution of the present reaction can be used to proceed to the next step without isolating the compound (2).

In the present reaction, for example, a methyl isobutyl ketone solution of 3-chloropropanoyl chloride is added to a predetermined solution of the compound (3) obtained without isolating in the third step, In one embodiment, the reaction can be carried out by stirring at 0 ° C to 40 ° C, usually for 30 minutes to 2 days. The predetermined solution may be a mixed solution of methyl isobutyl ketone, methyl isobutyl ketone and 2-propanol described in the third step, or water, and mixtures thereof. Subsequently, separation treatment may be performed without isolating the compound (2), and the aqueous layer may be used as it is to proceed to the next step.

Step 5

The present process is a process for the preparation of 5 - {[(3R) -1- (3-chloropropanoyl) pyrrolidin-3- yl] oxy} -6- Pyrazine-2-carboxamide (2) is subjected to a dehydrochlorination reaction under basic conditions such as an aqueous solution of sodium hydroxide, diazabicyclo-undecene (DBU) and the like Ethyl) -3 - ({4- [4- (4-methylpiperazin-1-yl) piperazin-1- Piperidin-1-yl] phenyl} amino) pyrazine-2-carboxamide (1). In this reaction, an equivalent amount or an excessive amount of DBU is added to a mixture of the compound (2) obtained in the fourth step without isolating in the fourth step, tetrahydrofuran and N, N-dimethylformamide, Under heating, in one embodiment, the mixture is stirred at 0 ° C to 40 ° C, usually for 10 minutes to 2 days.

In the present reaction, for example, a liquid separation operation is carried out without isolation in the fourth step, an aqueous solution of sodium hydroxide of an equal amount or an excessive amount is added to the aqueous solution of the compound (2) obtained as an aqueous layer, The reaction may be carried out by heating at 0 ° C to 40 ° C, typically for 10 minutes to 2 days, under heating.

Step 6

The present process is similar to that described for the synthesis of 5 - {[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6- (3R) -1-acryloylpyrrolidin-3-yl] phenyl} amino) pyrazine-2-carboxamide (1) is reacted with methanesulfonic acid to give 5 - {[ Yl} phenyl} amino) pyrazine-2-carboxamide monomethanesulfonic acid salt < EMI ID = (9). In this reaction, the compound (1) is added to a predetermined solution of methanesulfonic acid, or a predetermined solution of methanesulfonic acid is added to a predetermined solution of the compound (1), and under cooling to heating, Deg.] C to 100 [deg.] C, usually for 1 hour to 2 days. Examples of the solvent used in a predetermined solution of methanesulfonic acid include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, dichloromethane, 1,2- - halogenated hydrocarbons such as dichloroethane and chloroform, alcohols such as methanol, ethanol, 2-propanol and 2-butanol, ketones such as acetone, 2-butanone and methyl isobutyl ketone, ethylacetate, N-dimethylformamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethylsulfoxide, acetonitrile, water and mixtures thereof , In one embodiment water, in another embodiment acetone, and in another embodiment, a mixed solvent of acetone and water. Examples of the solvent used in the predetermined solution of the compound (1) include ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform , Alcohols such as methanol, ethanol, 2-propanol and 2-butanol, ketones such as acetone, 2-butanone and methyl isobutyl ketone, esters such as ethyl acetate and isopropyl acetate, , N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethylsulfoxide, acetonitrile and mixtures thereof. In one embodiment, acetone, acetonitrile or acetone And dimethylsulfoxide. In one embodiment, a mixed solvent of acetone and dimethylsulfoxide may be used.

In each of the steps in Reaction Scheme 2, there are cases where it is advantageous for the reaction to proceed smoothly by using a seed crystal.

Each compound in Reaction Scheme 2 is isolated as a free compound, a salt thereof (e.g., a pharmaceutically acceptable salt thereof), a hydrate or a solvate thereof, or a hydrate or solvate thereof, or a crystalline polymorph Purified. The pharmaceutically acceptable salt of each compound in Reaction Scheme 2 may be prepared by a salt-forming reaction in a conventional manner.

Isolation and purification are carried out by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.

Example

Hereinafter, the production method of the compound (1) and its monomethanesulfonic acid salt (9) will be described in more detail based on Examples 1 or 2. In addition, Examples 1 and 2 all show a method for producing Compound (1) represented by Reaction Scheme 2 and its monomethanesulfonic acid salt (9). Further, the present invention is not limited to the methods described in the following examples. The termination of the compound used in this embodiment can be produced by the method described in Examples, International Publication No. 2013/108754 and International Patent Publication No. 2010/128659, or a method analogous thereto. The termination of the compound used in Example 2 can also be produced by the method described in Example 1 or a method similar thereto. A known preparation method of the compound (1) represented by the reaction scheme 1 is shown as Reference Example 1.

In the present specification, the following abbreviations may be used.

(Ppm) of the peak in 1H-NMR in dichloromethane, D2: value (ppm) of the peak in 1H-NMR in dimethylsulfoxide-d6 in ppm, ESI + (M / z), s: singlet line (spectrum), d: doublet (spectrum), t: triplet (spectrum) Quadrature line (spectrum), and m: polyline (spectrum). CH ₃ SO ₃ H in the structural formula represents a monomethanesulfonic acid salt, and H ₂ NOC- represents an aminocarbonyl group.

In this specification, naming software such as ACD / Name (registered trademark, Advanced Chemistry Development, Inc.) may be used for naming the compound.

For convenience, the concentration mol / l is expressed as M. For example, 1 M NaOH aqueous solution means 1 mol / L NaOH aqueous solution.

Example 1

First step

Pyrazine-2-carboxamide (Compound (6)) was obtained in the same manner as in Example 1, ) Synthesis of

(17.8 kg) of 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] , And N, N-diisopropylethylamine (15.3 kg) in 2-butanol (105.0 kg) was stirred at 80 ° C to 85 ° C for 1 hour. After adding a seed crystal (2.6 g) of the compound (6), the reaction was carried out at 84 ° C to 88 ° C for 15 hours. After aging at 22 ° C to 30 ° C for 24 hours, the solid was filtered out and washed with 2-butanol. Dried under reduced pressure to give 5-chloro-6-ethyl-3- {4- [4- (4-methylpiperazin- 1 -yl) piperidin- 1 -yl] anilino} pyrazine-2-carboxamide 21.7 kg) was obtained as a solid. In addition, this seedling can be produced by a method of cooling the solution to the room temperature under the same reaction conditions without adding a seed crystal, filtering out the solid, and washing with 2-butanol to obtain the compound (6).

Second Step

butyl (3R) -3 - {[5-carbamoyl-3-ethyl-6- } Amino) pyrazin-2-yl] oxy} pyrrolidine-1-carboxylate (Compound (4))

(17.3 kg), potassium tert-butoxide (10.4 kg) was added to tetrahydrofuran (188.5 kg) and stirred at 24 [deg.] C, . 1-yl] anilino} pyrazine-2-carboxamide (21.2 kg) was added to a solution of 5-chloro-6-ethyl-3- {4- [4- And the mixture was reacted at 55 ° C to 60 ° C for 16 hours. After cooling to 24 占 폚, water (212 L) was added dropwise and the end of compound (4) (4.2 g) was added. Water (212 L) was added dropwise, followed by stirring at 24 ° C to 26 ° C for 21 hours. The solid was filtered, washed with a mixed solvent of tetrahydrofuran and water and dried under reduced pressure to give tert-butyl (3R) -3 - {[5-carbamoyl- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazin-2-yl] oxy} pyrrolidine-1-carboxylate as a solid. In this step, water was added dropwise to the reaction mixture under cooling to room temperature, and the mixture was stirred under ice-cooling. The solid was collected by filtration, washed with a mixed solvent of tetrahydrofuran and water Can be produced by a method of obtaining the compound (4).

The third step, the fourth step and the fifth step (continuous step)

5 - {[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl- -1-yl] phenyl} amino) pyrazine-2-carboxamide (Compound (1))

butyl (3R) -3 - {[5-carbamoyl-3-ethyl-6- Propanol (107.8 kg), water (107 L) and concentrated hydrochloric acid (27.4 kg) at a temperature of 55 < 0 > C to 59 < 0 > C Lt; / RTI > for 3 hours. Methyl isobutyl ketone (106.9 kg) and 2-propanol (41.9 kg) were added and a water (134 L) solution of sodium hydroxide (21.1 kg) and salt (13.4 kg) was added dropwise at 21 ° C to 26 ° C. The residue was purified by silica gel column chromatography to obtain an organic layer and yielded 6-ethyl-3- {4- [4- (4-methylpiperazin-1-yl) piperidin- 1 -yl] anilino} -5- [ 3-yloxy] pyrazine-2-carboxamide (compound (3)) as a mixed solution of methyl isobutyl ketone and 2-propanol (third step).

The obtained 6-ethyl-3- {4- [4- (4-methylpiperazin-1-yl) piperidin- 1 -yl] anilino} -5 - [(3R) -pyrrolidin- (134 L) was added to a mixed solution of methyl pyruvate-2-carboxamide in methyl isobutyl ketone and 2-propanol, and 3-chloropropanoyl chloride (11.1 kg) was added thereto with stirring at 25 ° C to 28 ° C. Of methyl isobutyl ketone (42.8 kg) was added dropwise. After stirring at 25 ° C to 28 ° C for 30 minutes, a liquid separation and an aqueous layer were obtained, and the organic layer was washed with water (27 L). The obtained aqueous layers were combined to give 5 - {[(3R) -1- (3-chloropropanoyl) pyrrolidin-3- yl] oxy} -6-ethyl-3- {4- [4- 1-yl) piperidin-1-yl] anilino} pyrazine-2-carboxamide (compound (2)) as a hydrogen chloride aqueous solution (fourth step).

The obtained 5 - {[(3R) -1- (3-chloropropanoyl) pyrrolidin-3- yl] oxy} -6-ethyl-3- {4- [4- 2-propanol (209.6 kg) was added to an aqueous solution of hydrogen chloride in pyridine-1-yl) piperidin-1-yl] anilino} pyrazine- Kg) of water (80 L) was added dropwise. After reaction at 25 캜 for 10 minutes, water (187 ℓ) and compound (1) seeds (13.4 g) were added at 26 ° C. The mixture was stirred at 24 ° C to 27 ° C for 2 hours, cooled to 0 ° C to 5 ° C, and stirred for 14 hours. The solid was collected by filtration, washed with a mixed solvent of 2-propanol and water, and then dried under reduced pressure to give 5 - {[(3R) -1-acryloylpyrrolidin-3- yl] oxy} Yl} phenyl} amino) pyrazine-2-carboxamide (20.4 kg) as a solid (Step 5) . In addition, this seedling was subjected to a liquid separation operation in the last step without carrying out the liquid separation operation before the addition of 3-chloropropanoyl chloride under a series of the same reaction conditions carried out without adding a seedling, (1) is obtained by adding water and stirring, stirring the mixture, filtering the solid, and washing with a mixed solvent of 2-propanol and water.

In the third step and the fourth step, the compound (3) and the compound (2) are used in the next step without isolation, but a part thereof is purified by silica gel column chromatography to obtain the target compound Respectively. The physicochemical data of the compounds (3), (2) and (1) are described below.

5 - [(3R) -pyrrolidin-3-yloxy) -pyrrolidin-1-yl] ] Pyrazine-2-carboxamide (silica gel column chromatography, purified product) (compound (3))

3- {4- [4- (4-methylpiperazin-l- (3-chloropyridazinyl) pyrrolidin- Yl) anilino} pyrazine-2-carboxamide (silica gel column chromatography, refined product) (Compound (2))

5 - {[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl- -1-yl] phenyl} amino) pyrazine-2-carboxamide (Compound (1)

Step 6

5 - {[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl- -1-yl] phenyl} amino) pyrazine-2-carboxamide monomethanesulfonate (Compound (9))

(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-ene was added to a mixture of acetone (62.6 kg), purified water (20 L) and methanesulfonic acid (3.05 Kg) Yl) phenyl} amino) pyrazine-2-carboxamide (19.87 kg) was added and dissolved at 46 [deg.] C . The solution was filtered, then a mixed solvent of acetone (12.5 kg) and purified water (4 L) was added, and acetone (140.9 kg) was added dropwise at 45 ° C to 48 ° C. After stirring at 42 ° C to 45 ° C for 1 hour, the end of compound (9) (4.0 g) was added and the mixture was stirred at 44 ° C to 47 ° C for 8 hours. Acetone (140.9 kg) was added dropwise at 46 ° C to 47 ° C, and then stirred at 20 ° C to 30 ° C for 32 hours. The solid was filtered, washed with a mixed solvent of acetone and water, and then washed with acetone. Dried under reduced pressure to give 5 - {[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3- ({4- [4- ) Piperidin-1-yl] phenyl} amino) pyrazine-2-carboxamide monomethanesulfonic acid salt (18.37 kg) as a solid.

Example 2

First step

Pyrazine-2-carboxamide (Compound (6)) was obtained in the same manner as in Example 1, ) Synthesis of

(44.5 Kg), 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] aniline , N, N-diisopropylethylamine (39.9 kg) and 2-butanol (274.7 kg) were stirred at 83 ° C to 86 ° C for 1 hour. After the addition of the seed (7 g) of the compound (6), the reaction was carried out at 85 ° C to 86 ° C for 20 hours. A mixed solvent of 2-butanol (82.4 kg) and dimethylsulfoxide (486.2 kg) was added, and the mixture was stirred at 84 ° C to 85 ° C for 2 hours, cooled, and stirred at 20 ° C to 30 ° C for 19 hours. The solid was filtered out and washed with dimethylsulfoxide and 2-butanol. Dried under reduced pressure to give 5-chloro-6-ethyl-3- {4- [4- (4-methylpiperazin- 1 -yl) piperidin- 1 -yl] anilino} pyrazine-2-carboxamide 55.7 kg) was obtained as a solid.

Second Step

butyl (3R) -3 - {[5-carbamoyl-3-ethyl-6- } Amino) pyrazin-2-yl] oxy} pyrrolidine-1-carboxylate (Compound (4))

(40.2 kg) was added to tert-butyl (3R) -3-hydroxypyrrolidine-1-carboxylate (67.8 kg) and tetrahydrofuran (491.6 kg) Lt; 0 > C for 30 minutes. Subsequently, 5-chloro-6-ethyl-3- {4- [4- (4-methylpiperazin- 1 -yl) piperidin- 1 -yl] anilino} pyrazine- Kg) and tetrahydrofuran (196.6 kg) were added, and the mixture was allowed to react at 55 ° C to 62 ° C for 17 hours. After cooling to 26 ° C, water (277 L) was added dropwise, and the end of the compound (4) (111 g) was added and the mixture was stirred at 25 ° C to 26 ° C for 5 hours. Subsequently, water (691 L) was added dropwise, followed by stirring at 22 ° C to 25 ° C for 21 hours. The solid was filtered out, washed with a mixed solvent of tetrahydrofuran and water and dried under reduced pressure to give the crude tert-butyl (3R) -3 - {[5-carbamoyl- Yl] phenyl} amino) pyrazin-2-yl] oxy} pyrrolidine-1-carboxylate (65.1 kg) as a solid.

The resulting crude tert-butyl (3R) -3 - {[5-carbamoyl-3-ethyl-6- ({4- [4- (4-methylpiperazin- 1 -yl) piperidin- ] Phenyl} amino) pyrazin-2-yl] oxy} pyrrolidine-1-carboxylate (63.4 kg) and 2-butanol (512.3 kg) were stirred at 40 ° C to 47 ° C for 5 hours. And the mixture was stirred at 0 ° C to 5 ° C for 14 hours. The solid was filtered, washed with 2-butanol cooled to 3.5 캜 and dried under reduced pressure to give tert-butyl (3R) -3 - {[5-carbamoyl- Yl] phenyl} amino) pyrazin-2-yl] oxy} pyrrolidine-1-carboxylate (63.2 kg).

Third step

5 - [(3R) -pyrrolidin-3-yloxy) -pyrrolidin-1-yl] ] Pyrazine-2-carboxamide (Compound (3))

butyl (3R) -3 - {[5-carbamoyl-3-ethyl-6- (59.3 kg), ethanol (283.1 kg), 35% -37% hydrochloric acid (61.4 kg) and water (239 L) at 55 [deg.] C- Followed by stirring at 61 DEG C for 5 hours. Cool to 49 [deg.] C and add a solution of sodium hydroxide (23.6 kg) in water (239 L). The pH was adjusted to 11 with 1 M aqueous sodium hydroxide solution, and the end of the compound (3) (120 g) was added and the mixture was stirred at 44 ° C to 45 ° C for 4 hours. Subsequently, water (837 L) was added dropwise, and the mixture was cooled to 30 DEG C and a solution of sodium hydroxide (2.0 kg) in water (60 L) was added and stirred at 23 to 29 DEG C for 3 hours. The solid was filtered out, washed with water and dried under reduced pressure to give 6-ethyl-3- {4- [4- (4-methylpiperazin- 1 -yl) piperidin- 1 -yl] anilino} - [(3R) -pyrrolidin-3-yloxy] pyrazine-2-carboxamide (49.0 kg).

Fourth step and five steps (continuous step)

5 - {[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl- -1-yl] phenyl} amino) pyrazine-2-carboxamide (Compound (1))

5 - [(3R) -pyrrolidin-3-yloxy) -pyrrolidin-1-yl] ] Pyrazine-2-carboxamide (48.4 kg), N, N-dimethylformamide (457.4 kg) and tetrahydrofuran (215.1 kg) were cooled to -8 ° C to give 3-chloropropanoyl chloride (3-chloropropanoyl) pyrrolidin-3-yl] -methanone was added dropwise to the solution at -8 ° C with stirring for 3 hours to give 5 - {[(3R) (Compound (2)) was obtained in the same manner as in (1), except that the compound (2) Of N, N-dimethylformamide and tetrahydrofuran (Step 4).

The obtained 5 - {[(3R) -1- (3-chloropropanoyl) pyrrolidin-3- yl] oxy} -6-ethyl-3- {4- [4- Tetrahydrofuran (107.6 kg) and DBU (49.3 kg) were added to a solution of N, N-dimethylformamide and tetrahydrofuran in tetrahydrofuran-1-yl) piperidin- 1-yl] anilino} pyrazine- And the mixture was stirred at 5 to 11 캜 for 18 hours. (97 g) of Compound (2) was added thereto by heating at 20 DEG C, followed by stirring at 20 DEG C to 23 DEG C for 16 hours . Subsequently, water (920 L) was added and stirred at 22-24 C for 1 hour, then a solution of potassium bicarbonate (32.2 Kg) in water (145 L) Lt; / RTI > The solid was collected by filtration, washed with a mixed solvent of acetone and water, and then dried under reduced pressure to give the crude 5 - {[(3R) -1-acryloylpyrrolidin-3- yl] oxy} -6- Yl} phenyl} amino) pyrazine-2-carboxamide (50.0 kg) was obtained.

The obtained crude 5 - {[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl- Pyridine-2-carboxamide (49.7 kg), acetone (58.7 kg) and tetrahydrofuran (331.4 kg) were dissolved at 47 占 폚. Activated carbon (5.0 kg) and acetone (39.2 kg) were added, and the mixture was stirred at 48 ° C to 50 ° C for 1 hour. Acetone (58.7 kg), tetrahydrofuran (22.1 kg), water (149 L) and a seedling (99 g) of Compound (1) were added to the filtrate. Lt; / RTI > Subsequently, water (746 L) was added dropwise, and the mixture was stirred at 44 ° C to 45 ° C for 1 hour. Followed by cooling and stirring at 23 ° C to 30 ° C for 13 hours. The solid was filtered out, washed with a mixed solvent of acetone and water, and dried under reduced pressure to give 5 - {[(3R) -1-acryloylpyrrolidin-3- yl] oxy} Yl} phenyl} amino) pyrazine-2-carboxamide (47.7 kg) was obtained (Step 5).

Compound (2) is used in the next step without isolation in the fourth step, but it is confirmed that the compound is the target compound according to the retention time of high performance liquid chromatography (HPLC). (Retention time = 21 min; retention time of compound (2) obtained in Example 1 = 21 min) " HPLC measurement conditions: detector (ultraviolet absorption spectrophotometer, measurement wavelength: 210 nm) (45 m mol / l perchloric acid aqueous solution), mobile phase B (acetonitrile), mobile phase B (acetonitrile), and mobile phase B (acetonitrile) (0 to 29 minutes: mobile phase A 85 → 55% mobile phase B 15 → 45%, 29 to 37 minutes: mobile phase A 55 → 10% mobile phase B 45 → 90% B 90%, 39-40 min: mobile phase A 10 → 85% mobile phase B 90 → 15%, 40-45 min: mobile phase A 85% mobile phase B 15%

Step 6

5 - {[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl- -1-yl] phenyl} amino) pyrazine-2-carboxamide monomethanesulfonate (Compound (9))

5 - {[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl- Yl) phenyl} amino) pyrazine-2-carboxamide (42.4 kg), acetone (968.9 kg) and dimethylsulfoxide (209.9 kg) were dissolved at 53 占 폚. After filtration of the solution, an acetone (66.8 kg) solution of acetone (66.8 kg) and methanesulfonic acid (7.02 kg) was added to 20% of the solution, followed by addition of 42 g of the compound (9). Subsequently, an acetone solution of the remaining methanesulfonic acid was added dropwise, and acetone (33.4 kg) was added thereto, followed by stirring at 55 캜 for 30 minutes. Followed by cooling and stirring at 22 ° C to 30 ° C for 1 hour. The solid was filtered, washed with acetone and dried under reduced pressure to give 5 - {[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6- Yl] phenyl} amino) pyrazine-2-carboxamide monomethanesulfonic acid salt (47.4 kg) was obtained.

Reference Example 1

First step

Synthesis of tert-butyl (3R) -3 - [(5-carbamoyl-6-chloro-3-ethylpyrazin-2-yl) oxy] pyrrolidine-1-carboxylate

To a mixture of tert-butyl (3R) -3-hydroxypyrrolidine-1-carboxylate (2600 mg) and N, N-dimethylformamide (60 mL) was added under ice- And the mixture was stirred for 1 hour and a half. 3,5-Dichloro-6-ethylpyrazine-2-carboxamide (3000 mg) was added to the reaction solution under ice-cooling, and the mixture was further stirred for 30 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate). The resulting solid was washed with diisopropyl ether to give tert-butyl (3R) -3- [(5-carbamoyl-6-chloro-3-ethylpyrazin-2-yl) oxy] pyrrolidine- (855 mg) as a solid.

Second Step

butyl (3R) -3 - {[5-carbamoyl-3-ethyl-6- } Amino) pyrazin-2-yl] oxy} pyrrolidine-1-carboxylate (Compound (4))

pyrrolidine-1-carboxylate (90 mg), 4- [4- (4-fluorophenyl) (210 mg), N, N-diisopropylethylamine (140 μl) and N-methylpyrrolidone (500 μl) were added to a solution of (4-methylpiperazin-1-yl) piperidin- The mixture was reacted at 150 DEG C for 2 hours using a microwave reactor (Viotage). After the reaction mixture was cooled, water and diisopropyl ether were added and the insoluble material was filtered to obtain tert-butyl (3R) -3 - {[5-carbamoyl- Phenyl] amino) pyrazin-2-yl] oxy} pyrrolidine-1-carboxylate (101 mg) was obtained as a solid .

Third step

5 - [(3R) -pyrrolidin-3-yloxy) -pyrrolidin-1-yl] ] Pyrazine-2-carboxamide (Compound (3))

butyl (3R) -3 - {[5-carbamoyl-3-ethyl-6- Trifluoroacetic acid (4 ml) was added at 0 占 폚 to a dichloromethane (5 ml) solution of 4-amino-3- (2- trifluoromethylphenyl) amino) pyrazin-2-yl] oxy} pyrrolidine- Respectively. The solvent was distilled off, and chloroform and a saturated aqueous solution of sodium hydrogencarbonate were added to the residue, and liquid separation operations were carried out. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol / 28% ammonia water) to give 6-ethyl-3- {4- [4- (3R) -pyrrolidin-3-yloxy] pyrazine-2-carboxamide (174 mg) was added to a solution of (4-methylpiperazin-1 -yl) piperidin- .

Fourth step

5 - {[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl- -1-yl] phenyl} amino) pyrazine-2-carboxamide (Compound (1))

5 - [(3R) -pyrrolidin-3-yloxy) -pyrrolidin-1-yl] ] Pyrazine-2-carboxamide (174 mg) in chloroform (20 mL) was added N, N-diisopropylethylamine (390 μL) and acryloyl chloride (130 μL) under ice- Lt; / RTI > Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol / 28% ammonia water) to obtain 5 - {[(3R) -1- acryloylpyrrolidin- Yl} phenyl} amino) pyrazine-2-carboxamide (159 mg) was added to a solution of 4- (4- {4- [4- .

Step 5

5 - {[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl- -1-yl] phenyl} amino) pyrazine-2-carboxamide monomethanesulfonate (Compound (9))

3-yl] oxy} -6-ethyl-3 - ({4- [4- (4- methylpiperazin- Yl) phenyl} amino) pyrazine-2-carboxamide (100 mg) was heated to 50 占 폚, and 2M methanesulfonic acid aqueous solution (80 占 퐇) was added. The mixture was stirred at 50 占 폚 for 30 minutes and then at room temperature for 20 hours. The precipitated solid was collected by filtration and dried under reduced pressure at 50 DEG C for 6 hours to obtain 5 - {[(3R) -1-acryloylpyrrolidin-3-yl] oxy} Yl] phenyl} amino) pyrazine-2-carboxamide monomethanesulfonic acid salt (97 mg) was obtained as a solid.

The effects of the present invention are shown below.

Table 1 shows the yields and the total yields of the respective steps in Example 1.

Table 2 shows the yields and the total yields of the respective steps in Example 2.

Table 3 shows the yields and the total yields of the respective steps in Reference Example 1.

The production method of the present invention (Example 1 and Example 2 in Reaction Scheme 2) is different from the known production method (Reference Example 1 in Reaction Scheme 1), and purification by silica gel column chromatography From the fact that the process is not included, it is expected that it is preferable for industrial production as a medicine. Particularly, in Reference Example 1, by using acryloyl chloride as the acylating agent in the fourth step, compound (11) in which one molecule compound (3) is already added to compound (1) Compound (11) was required to be removed by silica gel column chromatography. However, in the present invention, by using 3-chloropropanoyl chloride instead of acryloyl chloride, generation of by-products was avoided and purification by silica gel column chromatography Lt; / RTI > Therefore, it is expected that not only a complicated operation by using silica gel column chromatography can be avoided, but also an excellent manufacturing method in terms of cost.

[Chemical Formula 12]

In the production method of the present invention (Example 2), the compound (3) which has been carried out by the continuous reaction up to now is obtained by changing the reaction solvent from 2-propanol used in Example 1 to ethanol in the third step It became possible to isolate easily. In addition, in the fifth step, in the purification operation of the compound (1), once the crude product is dissolved in acetone and tetrahydrofuran, activated carbon is added, and stirring and filtration are performed, It has become possible to remove impure impurities. Compound (9) was obtained in a higher yield than in Example 1 by using acetone and dimethyl sulfoxide in place of acetone and water as solvents in the sixth step.

It was also confirmed that the production method of the present invention (Examples 1 and 2) was remarkably higher than that of the known production method (Reference Example 1). In particular, introduction of the compound (5) to be carried out in the first step of Reference Example 1 can be carried out by introducing the compound (5) into the compound (8), introducing the compound (7) It was confirmed that it became possible to obtain a high yield.

From the above, it is expected that the production method of the present invention can be an industrially excellent production method as compared with known production methods. Particularly, it is expected that by the production method of the present invention, it becomes possible to achieve a high total yield.

Industrial availability

According to the present invention, there can be provided a compound (1), a method for producing the monomethanesulfonic acid salt thereof, and a synthetic intermediate useful in the method for producing the compound (1), which is preferable for industrial production as a medicine with high yield and low cost.

Claims (9)

Equation (2)
(3)

(1), wherein a compound of the formula (1) or a salt thereof is subjected to a dehydrochlorination reaction by the action of a base,
[Chemical Formula 1]

Or a salt thereof. The method according to claim 1,
The compound of the formula (2)
[Chemical Formula 4]

Wherein the acylation reaction is carried out by reacting a compound of the formula (I) or a salt thereof with 3-chloropropanoyl chloride. 3. The method of claim 2,
The compound of the formula (3) or a salt thereof is represented by the formula (4)
[Chemical Formula 5]

Or a salt thereof is subjected to a deprotection reaction. The method of claim 3,
The compound of the formula (4) or a salt thereof is represented by the formula (6)
[Chemical Formula 6]

(5), or a salt thereof,
(7)

Or a salt thereof is reacted with an aromatic nucleus substitution reaction. 5. The method of claim 4,
When the compound of the formula (6) or a salt thereof is a compound represented by the formula (8)
[Chemical Formula 8]

(7) in 2-butanol in the presence of a base,
[Chemical Formula 9]

Or a salt thereof is reacted with an aromatic nucleus substitution reaction at 80 ° C to 90 ° C. A process for producing a compound represented by the formula (9), which comprises reacting a compound of the formula (1) prepared by the process according to any one of claims 1 to 5 or a salt thereof with methanesulfonic acid to form a monomethanesulfonic acid salt ≪ / RTI >
[Chemical formula 10]

Equation (2)
(3)

Or a salt thereof. The production method according to claim 1, comprising a step of treating a solution containing the preparation of the compound of formula (1) with activated carbon to remove a part of the impurities contained in the preparation.  A production method according to claim 6, wherein a mixed solvent of acetone and dimethyl sulfoxide is used as a reaction solvent.