JPWO2016121777A1 - Method for producing pyrazinecarboxamide compound and synthetic intermediate thereof - Google Patents

Abstract

The present invention provides a novel method for producing a pyrazinecarboxamide compound as a raw material for production of pharmaceuticals and the like, and a useful synthetic intermediate in the production method. As a result of intensive studies on the production method in the industrial production of pyrazinecarboxamide compounds, the present inventors do not require purification by silica gel column chromatography by using predetermined raw materials and synthetic intermediates. The present invention has been completed by discovering that a pyrazinecarboxamide compound can be produced by a method suitable for industrial production as a pharmaceutical with greatly improved overall yield. [Selection figure] None

Description

  The present invention relates to 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- [4- (4-methylpiperazin-1-yl) piperidine-1 The present invention relates to a method for producing -yl] phenyl} amino) pyrazine-2-carboxamide (hereinafter sometimes 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, compound (1) is described as Example 54, and monomethanesulfonate (9) of compound (1) is described as Example 261.

The production method of the compound (1) described in Patent Document 1 (Example 54 of Patent Document 1) and its monomethanesulfonate (9) is as shown in Reaction Scheme 1.
(Reaction Scheme 1)

即ち、3,5-ジクロロ-6-エチルピラジン-2-カルボキサミド（以下、「化合物（８）」ということがある）とtert-ブチル (3R)-3-ヒドロキシピロリジン-1-カルボキシラート（以下、「化合物（５）」ということがある）を用いて、同文献の製造例29に記載の方法に準じて反応させることでtert-ブチル (3R)-3-[(5-カルバモイル-6-クロロ-3-エチルピラジン-2-イル)オキシ]ピロリジン-1-カルボキシラート（以下、「化合物（１０）」ということがある）を製造する。次いで化合物（１０）と、公知の方法によって製造された4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]アニリン（以下、「化合物（７）」ということがある）を用いて同文献の製造例31に記載の方法に準じて反応させることでtert-ブチル(3R)-3-{[5-カルバモイル-3-エチル-6-({4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}アミノ)ピラジン-2-イル]オキシ}ピロリジン-1-カルボキシラート（以下、「化合物（４）」ということがある）を製造する。その後化合物（４）にトリフルオロ酢酸を作用させて、同文献の製造例34に記載の方法に準じて反応させることで6-エチル-3-{4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]アニリノ}-5-[(3R)-ピロリジン-3-イルオキシ]ピラジン-2-カルボキサミド（以下、「化合物（３）」ということがある）を製造した後、化合物（３）に塩化アクリロイルを作用させて、同文献の実施例1に記載の方法に準じて反応させることで、目的とする化合物（１）を製造する。最後に化合物（１）を同文献の実施例254に記載の方法に準じて化合物（１）のモノメタンスルホン酸塩（９）を製造する方法である。

That is, 3,5-dichloro-6-ethylpyrazine-2-carboxamide (hereinafter sometimes referred to as “compound (8)”) and tert-butyl (3R) -3-hydroxypyrrolidine-1-carboxylate (hereinafter referred to as “compound (8)”). Tert-butyl (3R) -3-[(5-carbamoyl-6-chloro) by reacting according to the method described in Production Example 29 of the same document. -3-Ethylpyrazin-2-yl) oxy] pyrrolidine-1-carboxylate (hereinafter sometimes referred to as “compound (10)”) is produced. Next, compound (10) and 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] aniline (hereinafter sometimes referred to as “compound (7)”) produced by a known method To give tert-butyl (3R) -3-{[5-carbamoyl-3-ethyl-6-({4- [4- (4 -Methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazin-2-yl] oxy} pyrrolidine-1-carboxylate (hereinafter sometimes referred to as “compound (4)”) is produced. Thereafter, trifluoroacetic acid is allowed to act on the compound (4) and reacted according to the method described in Production Example 34 of the same document to thereby produce 6-ethyl-3- {4- [4- (4-methylpiperazine-1 -Yl) piperidin-1-yl] anilino} -5-[(3R) -pyrrolidin-3-yloxy] pyrazine-2-carboxamide (hereinafter sometimes referred to as “compound (3)”) The target compound (1) is produced by allowing acryloyl chloride to act on (3) and reacting according to the method described in Example 1 of the document. Finally, compound (1) is a method for producing monomethanesulfonate (9) of compound (1) according to the method described in Example 254 of the same document.

  However, the production method of the compound (1) and its monomethanesulfonate (9) disclosed in Patent Document 1 is a process in which the yield of the product is low, for example, as shown in Table 3 below. The step (the first step in Reaction Scheme 1) with a rate of 17% is included, and the total yield of the final target compound (1) to monomethanesulfonate is only 5%. Furthermore, the production method represented by Reaction Scheme 1 is a pharmaceutical product because it includes steps (first step, third step and fourth step of Reaction Scheme 1) that require purification by silica gel column chromatography. As a result, it was a method for which further improvement was desired in industrial production.

International Publication No.2013 / 108754

  A novel production method of compound (1) or a salt thereof, and a useful synthetic intermediate in the production method are provided.

  As a result of intensive studies on the production method in the industrial production of the compound (1) or a salt thereof, the present inventors do not require purification by silica gel column chromatography by using predetermined raw materials and synthetic intermediates. The present invention was completed by discovering that the compound (1) or a salt thereof can be produced by a method suitable for industrial production as a pharmaceutical with improved overall yield.

That is, the present invention relates to a novel production method of the following compound (1) or a salt thereof and a useful synthetic intermediate in the production method.
[1]
Compound (2)

又はその塩に塩基を作用させて脱塩化水素反応に付すことを特徴とする化合物（１）

Or a compound (1) characterized by subjecting a salt to a base and subjecting the salt to a dehydrochlorination reaction

又はその塩の製造方法。
［２］
化合物（２）又はその塩が、化合物（３）

Or the manufacturing method of the salt.
[2]
Compound (2) or a salt thereof is compound (3).

又はその塩に３−クロロプロパノイルクロリドを作用させてアシル化反応に付すことを特徴とする製造方法により製造されたものである、［１］に記載の製造方法。
［３］
化合物（３）又はその塩が、化合物（４）

Or the manufacturing method as described in [1] which is manufactured by the manufacturing method characterized by making 3-chloropropanoyl chloride act on the salt, and attaching | subjecting to an acylation reaction.
[3]
Compound (3) or a salt thereof is compound (4).

又はその塩を脱保護反応に付すことを特徴とする製造方法により製造されたものである、［２］に記載の製造方法。
［４］
化合物（４）又はその塩が、化合物（６）

Or the manufacturing method as described in [2] which is manufactured by the manufacturing method characterized by attaching | subjecting the salt to deprotection reaction.
[4]
Compound (4) or a salt thereof is compound (6).

又はその塩に化合物（５）

Or a compound thereof (5)

を作用させて芳香族求核置換反応に付すことを特徴とする製造方法により製造されたものである、[３]に記載の製造方法。
［５］
化合物（６）又はその塩が、化合物（８）

The production method according to [3], which is produced by a production method characterized by subjecting to an aromatic nucleophilic substitution reaction.
[5]
Compound (6) or a salt thereof is compound (8).

又はその塩に2-ブタノール中、塩基存在下、化合物（７）

Or a salt thereof in 2-butanol in the presence of a base (7)

又はその塩を作用させて、80℃〜90℃にて芳香族求核置換反応に付すことを特徴とする製造方法により製造されたものである、[４]に記載の製造方法。
［６］
[１]〜[５]のいずれかに記載の方法で製造された化合物（１）又はその塩に、メタンスルホン酸を作用させてモノメタンスルホン酸塩を形成することを特徴とする化合物（９）

Alternatively, the production method according to [4], which is produced by a production method characterized in that an aromatic nucleophilic substitution reaction is performed at 80 ° C. to 90 ° C. by acting a salt thereof.
[6]
A compound (9) characterized in that methanesulfonic acid is allowed to act on the compound (1) produced by the method according to any one of [1] to [5] or a salt thereof to form a monomethanesulfonate. )

の製造方法。
［７］
化合物（２）

Manufacturing method.
[7]
Compound (2)

又はその塩。

Or a salt thereof.

Moreover, this invention relates to the manufacturing method of the following compounds (4) or its salt.
[8]
Compound (6)

又はその塩に化合物（５）

Or a compound thereof (5)

又はその塩を作用させて化合物（４）

Or a compound thereof (4)

又はその塩を製造する方法。
［９］
化合物（８）

Or the method of manufacturing the salt.
[9]
Compound (8)

又はその塩に2-ブタノール中、塩基存在下、化合物（７）

Or a salt thereof in 2-butanol in the presence of a base (7)

又はその塩を作用させて、80℃〜90℃にて反応させ、化合物（６）又はその塩を製造した後、さらに化合物（５）又はその塩を作用させて化合物（４）又はその塩を製造する方法。
［１０］
[１]に記載の製造方法であって、式（１）の化合物の粗製体を含む溶液を活性炭で処理することにより、該粗製体に含まれる不純物の一部を除去する工程を含む製造方法。
［１１］
[６]に記載の製造方法であって、反応溶媒としてアセトンとジメチルスルホキシドの混合溶媒を用いることを特徴とする製造方法。

Alternatively, after reacting at 80 ° C. to 90 ° C. by reacting with a salt thereof to produce compound (6) or a salt thereof, compound (4) or a salt thereof is further reacted with compound (5) or a salt thereof. How to manufacture.
[10]
The production method according to [1], comprising a step of removing a part of impurities contained in the crude product by treating the solution containing the crude product of the compound of formula (1) with activated carbon. .
[11]
[6] The production method according to [6], wherein a mixed solvent of acetone and dimethyl sulfoxide is used as a reaction solvent.

  In addition, the compound disclosed in the present invention may be in a free form or form a salt. Specific examples of such a salt include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, Inorganic acids such as nitric acid and phosphoric acid, 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 And acid addition salts with organic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid and glutamic acid.

  In addition, the compounds disclosed in the present invention may be free isomers, various hydrates or solvates of the salts thereof, and polymorphic substances. The present invention includes those substances, and those substances. The manufacturing method using is also included. Furthermore, 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 production methods using these compounds. .

  In addition, the compound disclosed in the present invention may be a free form or a salt, or may be various hydrates or solvates thereof, and these crystals, Alternatively, it may be amorphous.

  Furthermore, the compounds disclosed in the present invention may exist in tautomeric forms. In the present specification, only one form of these isomers may be described. However, the present invention includes other isomers and production methods using other isomers, and separation of isomers. And a production method using the separated isomers, 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 similarly referred to.

In the present specification, “by allowing methanesulfonic acid to act on compound (1) or a salt thereof” means that methanesulfonic acid is allowed to act on compound (1) or a salt thereof, or compound (1) or a salt thereof. After neutralizing the salt, methanesulfonic acid may be allowed to act.

In the present specification, the “seed crystal” refers to a seed crystal or a solid compound that serves as a seed for promoting crystallization.

  INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a production method of compound (1) and its monomethanesulfonate (9), which is suitable for industrial production as a pharmaceutical product, and a synthetic intermediate useful in the production method.

  Hereinafter, the present invention will be described in detail.

  The production method (Step 1 to Step 6) of the compound (1) of the present invention and its monomethanesulfonate (9) is shown in Reaction Scheme 2, and will be described in detail below for each step.

(Reaction Scheme 2)

Step 1 This step consists of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (8) and 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] aniline (7 ) To the aromatic nucleophilic substitution reaction, and 5-chloro-6-ethyl-3- {4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] anilino} pyrazine This is a process for producing -2-carboxamide (6). In this reaction, the compound (8) and the compound (7) are used, and these mixtures are cooled to heated in a solvent inert to the reaction in the presence of a base, and in some embodiments, at 0 ° C. to 100 ° C. In some embodiments, the mixture is stirred at 80 ° C. to 90 ° C. for usually 1 hour to 2 days. Examples of the solvent used here are not particularly limited, but ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, alcohols such as methanol, ethanol, 2-propanol and 2-butanol, N, N-dimethyl Examples include formamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, acetonitrile, and mixtures thereof, and some embodiments include 2-butanol. Examples of the base include, but are not limited to, organic bases such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, and a certain embodiment includes N, N-diisopropylethylamine.

Second Step This step is for 5-chloro-6-ethyl-3- {4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] anilino} pyrazine-2-carboxamide (6). , Tert-butyl (3R) -3-hydroxypyrrolidine-1-carboxylate (5) was allowed to act on the aromatic nucleophilic substitution reaction, and tert-butyl (3R) -3-{[5-carbamoyl-3 -Ethyl-6-({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazin-2-yl] oxy} pyrrolidine-1-carboxylate (4) It is a manufacturing process. In this reaction, the compound (6) and the compound (5) are used, and these mixtures are cooled to heated in a solvent inert to the reaction in the presence of a base, and in some embodiments, at 0 ° C. to 100 ° C. The mixture is usually stirred for 1 hour to 2 days. Examples of the solvent used here are not particularly limited, but ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, N, N-dimethylformamide, N-methyl-2-pyrrolidone, 1,3-dimethyl- Examples include 2-imidazolidinone, dimethyl sulfoxide, acetonitrile, and a mixture thereof. In one embodiment, tetrahydrofuran is used. Examples of the base include, but are not limited to, organic bases such as lithium diisopropylamide and potassium tert-butoxide, or inorganic bases such as sodium hydride, and certain embodiments include potassium tert-butoxide.

Third Step This step is for tert-butyl (3R) -3-{[5-carbamoyl-3-ethyl-6-({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] Phenyl} amino) pyrazin-2-yl] oxy} pyrrolidine-1-carboxylate (4) is cooled to heated in a solvent inert to the reaction under acidic conditions such as concentrated hydrochloric acid and trifluoroacetic acid. In one embodiment, the mixture is stirred at 0 ° C. to 100 ° C., usually for 1 hour to 2 days, subjected to a deprotection reaction, and 6-ethyl-3- {4- [4- (4-methylpiperazin-1-yl) This is a step of producing 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. As an aspect, hydrous ethanol or hydrous 2-propanol is mentioned, and as an aspect, hydrous ethanol is mentioned.
In this step, without isolating the compound (3), a predetermined solvent (but not limited to, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether and tetrahydrofuran, dichloromethane, 1 , Halogenated hydrocarbons such as 2-dichloroethane and chloroform, ketones such as 2-butanone and methyl isobutyl ketone, esters such as ethyl acetate and isopropyl acetate, and mixtures thereof with alcohols such as 2-propanol In some embodiments, liquid separation operation may be performed using methyl isobutyl ketone or a mixed solution of methyl isobutyl ketone and 2-propanol, and the organic layer may be used as it is to proceed to the next step.

Step 4 This step consists of 6-ethyl-3- {4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] anilino} -5-[(3R) -pyrrolidin-3-yloxy ] Pyrazin-2-carboxamide (3) was allowed to react with 3-chloropropanoyl chloride and subjected to an acylation reaction to give 5-{[(3R) -1- (3-chloropropanoyl) pyrrolidin-3-yl ] Oxy} -6-ethyl-3- {4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] anilino} pyrazine-2-carboxamide (2). In this reaction, 3-chloropropanoyl chloride is stirred in a solvent inert to the reaction under cooling to heating, in one embodiment at -10 ° C to 0 ° C, usually for 30 minutes to 2 days. Examples of the solvent used here are not particularly limited, but ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, N, N-dimethylformamide, N-methyl-2-pyrrolidone, 1,3-dimethyl- Examples include 2-imidazolidinone, acetonitrile, and mixtures thereof, and in some embodiments, a mixture of tetrahydrofuran and N, N-dimethylformamide. In addition, the isolation of compound (2) is not performed in this step, and the next step can be directly performed using the solution of this reaction.
In addition, this reaction is carried out, for example, by cooling a solution of 3-chloropropanoyl chloride in methyl isobutyl ketone to a predetermined solution of compound (3) obtained without isolation in the third step, under cooling to heating. As an aspect, it can also carry out by stirring at 0 degreeC-40 degreeC normally for 30 minutes-2 days. Examples of the predetermined solution include methyl isobutyl ketone, a mixed solution of methyl isobutyl ketone and 2-propanol described in the third step, water, and a mixture thereof. Further, a liquid separation operation can be performed without isolating the compound (2), and the aqueous layer can be used as it is to proceed to the next step.

Step 5 This step consists of 5-{[(3R) -1- (3-chloropropanoyl) pyrrolidin-3-yl] oxy} -6-ethyl-3- {4- [4- (4-methylpiperazine -1-yl) piperidin-1-yl] anilino} pyrazine-2-carboxamide (2) was subjected to dehydrochlorination under basic conditions such as aqueous sodium hydroxide and diazabicycloundecene (DBU). , 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] Phenyl} amino) pyrazine-2-carboxamide (1) is produced. In this reaction, for example, an equivalent amount or an excess amount of DBU is added to a mixture of the compound (2) obtained without isolation in the fourth step and tetrahydrofuran and N, N-dimethylformamide, and the mixture is cooled to Under heating, in one embodiment, the mixture is usually stirred at 0 ° C. to 40 ° C. for 10 minutes to 2 days.
In this reaction, for example, an equal or excessive amount of an aqueous sodium hydroxide solution is added to the aqueous solution of compound (2) obtained as a water layer by performing a liquid separation operation without performing an isolation operation in the fourth step, Under cooling to heating, as an embodiment, it can also be carried out by stirring at 0 ° C. to 40 ° C., usually for 10 minutes to 2 days.

Step 6 This step consists of 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- [4- (4-methylpiperazin-1-yl)] Piperidin-1-yl] phenyl} amino) pyrazine-2-carboxamide (1) is reacted with methanesulfonic acid to give 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl -3-({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazine-2-carboxamide monomethanesulfonate (9) In this reaction, 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 compound (1), and under cooling to heating, Stir at 0 to 100 ° C., usually for 1 hour to 2 days. Solvents used in a given solution of methanesulfonic acid include aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, dichloromethane, 1,2-dichloroethane, chloroform Halogenated hydrocarbons such as, 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, Examples include N-dimethylformamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, acetonitrile, water, and mixtures thereof. Acetone, and in some embodiments, a mixed solution of acetone and water. And the like. 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, methanol, ethanol, Alcohols such as 2-propanol and 2-butanol, ketones such as acetone, 2-butanone and methyl isobutyl ketone, esters such as ethyl acetate and isopropyl acetate, N, N-dimethylformamide, N-methyl-2-pyrrolidone 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, acetonitrile and a mixture thereof. As an embodiment, acetone, acetonitrile or a mixed solvent of acetone and dimethyl sulfoxide can be mentioned, and as an embodiment, acetone can be used. And dimethyl sulfoxide If solvents.

  In each step in Reaction Scheme 2, it may be advantageous to use a seed crystal to facilitate the reaction.

Each compound in Reaction Scheme 2 is a free compound, a salt thereof (eg, a pharmaceutically acceptable salt thereof), a hydrate or solvate, or a hydrate or solvate of the salt, Isolated as a form material and purified. The pharmaceutically acceptable salt of each compound in Reaction Scheme 2 can also be produced by subjecting it to a conventional salt formation reaction.
Isolation and purification are carried out by applying ordinary chemical operations such as extraction, fractional crystallization, and various fractional chromatography.

Hereinafter, based on Example 1 or 2, the manufacturing method of a compound (1) and its monomethanesulfonate (9) is demonstrated in detail. In addition, both Example 1 and Example 2 show the manufacturing method of the compound (1) shown by Reaction Scheme 2, and its monomethanesulfonate (9). In addition, this invention is not limited to the method as described in the following Example. In addition, the seed crystals of the compounds used in the examples are the methods described in the examples, the methods described in International Publication Nos. 2013/108754 and 2010/128659, or the like. It can be manufactured by a method. The seed crystals of the compound used in Example 2 can also be produced by the method described in Example 1 or a method analogous thereto. A known production method of compound (1) shown in Reaction Scheme 1 is shown as Reference Example 1.
In the present specification, the following abbreviations may be used.
D1: peak δ value in 1H-NMR in deuterated chloroform (ppm), D2: peak δ value in 1H-NMR in dimethyl sulfoxide-d6 (ppm), ESI +: mass measured using ESI as ionization method M / z value in analysis ([M + H] + unless otherwise noted), s: single line (spectrum), d: double line (spectrum), t: triple line (spectrum), q: quadruple line (Spectrum), m: multiple line (spectrum). In the structural formula, CH ₃ SO ₃ H indicates monomethanesulfonate, and H ₂ NOC- indicates an aminocarbonyl group.

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

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

Example 1

Step 1 Synthesis of 5-chloro-6-ethyl-3- {4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] anilino} pyrazine-2-carboxamide (compound (6))
3,5-dichloro-6-ethylpyrazine-2-carboxamide (13.0 kg), 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] aniline (17.8 kg), N, N- A solution of diisopropylethylamine (15.3 kg) in 2-butanol (105.0 kg) was stirred at 80 to 85 ° C. for 1 hour. After adding seed crystals (2.6 g) of 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 collected by filtration and washed with 2-butanol. Dry under reduced pressure and use 5-chloro-6-ethyl-3- {4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] anilino} pyrazine-2-carboxamide (21.7 kg) as a solid I got it. In addition, this seed crystal can be manufactured by the method of obtaining a compound (6) by cooling to room temperature, filtering a solid, and wash | cleaning with 2-butanol on the same reaction conditions performed without adding a seed crystal.
ESI +: 458.3, 460.3
D1: 1.27 (3H, t, J = 7.6Hz), 1.62-1.78 (2H, m), 1.90-1.98 (2H, m), 2.28-2.74 (11H, m), 2.30 (3H, s), 2.84 ( 2H, q, J = 7.5Hz), 3.68-3.74 (2H, m), 5.54-5.61 (1H, s), 6.93 (2H, d, J = 9.2Hz), 7.51 (2H, d, J = 9.2Hz ), 7.67-7.73 (1H, s), 10.56 (1H, s)

Second step tert-butyl (3R) -3-{[5-carbamoyl-3-ethyl-6-({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino ) Synthesis of pyrazin-2-yl] oxy} pyrrolidine-1-carboxylate (compound (4))
Tert-butyl (3R) -3-hydroxypyrrolidine-1-carboxylate (17.3 kg) and potassium tert-butoxide (10.4 kg) were added to tetrahydrofuran (188.5 kg), and the mixture was stirred and dissolved at 24 ° C. Add 5-chloro-6-ethyl-3- {4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] anilino} pyrazine-2-carboxamide (21.2 kg), 55 ° C-60 The reaction was carried out at ° C for 16 hours. After cooling to 24 ° C., water (212 L) was added dropwise, and seed crystals (4.2 g) of compound (4) were added. Water (212 L) was added dropwise, and the mixture was stirred at 24 ° C. to 26 ° C. for 21 hours. The solid was collected by filtration, washed with a mixed solvent of tetrahydrofuran and water, dried under reduced pressure, and tert-butyl (3R) -3-{[5-carbamoyl-3-ethyl-6-({4- [4- (4 -Methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazin-2-yl] oxy} pyrrolidine-1-carboxylate (25.6 kg) was obtained as a solid. This seed crystal was cooled to room temperature under the same reaction conditions that were carried out without adding the seed crystal, and after adding water dropwise and stirring under ice cooling, the solid was collected by filtration and washed with a mixed solvent of tetrahydrofuran and water. The compound (4) can be produced by a method.
ESI +: 609.4
D1: 1.20 (3H, t, J = 7.4Hz), 1.47 (9H, s), 1.60-1.78 (4H, m), 1.90-1.99 (2H, m), 2.08-2.22 (2H, m), 2.30 ( 3H, s), 2.30-2.74 (11H, m), 3.41-3.72 (6H, m), 5.27-5.37 (1H, s), 5.46-5.55 (1H, s), 6.91 (2H, d, J = 9.2 Hz), 7.39-7.50 (2H, m), 7.56-7.65 (1H, s), 10.51-10.62 (1H, m)

Step 3, Step 4 and Step 5 (continuous step) 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- [4- (4 -Methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazine-2-carboxamide (compound (1))
tert-butyl (3R) -3-{[5-carbamoyl-3-ethyl-6-({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazine- 2-yl] oxy} pyrrolidine-1-carboxylate (25.1 kg), 2-propanol (104.8 kg), water (107 L) and concentrated hydrochloric acid (27.4 kg) were stirred at 55 ° C. to 59 ° C. for 3 hours. Methyl isobutyl ketone (106.9 kg) and 2-propanol (41.9 kg) were added, and a solution of sodium hydroxide (21.1 kg) and sodium chloride (13.4 kg) in water (134 L) was added dropwise at 21 to 26 ° C. Separation of the organic layer, 6-ethyl-3- {4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] anilino} -5-[(3R) -pyrrolidine-3 -Iloxy] pyrazine-2-carboxamide (compound (3)) was obtained as a mixed solution of methyl isobutyl ketone and 2-propanol (third step).
The resulting 6-ethyl-3- {4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] anilino} -5-[(3R) -pyrrolidin-3-yloxy] pyrazine-2 -Add water (134L) to methyl isobutyl ketone and 2-propanol mixed solution of carboxamide and stir at 25-28 ° C, drop 3-methylpropanoyl chloride (11.1kg) in methyl isobutyl ketone (42.8kg). did. After stirring for 30 minutes at 25 ° C. to 28 ° C., 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 and 5-{[(3R) -1- (3-chloropropanoyl) pyrrolidin-3-yl] oxy} -6-ethyl-3- {4- [4- (4-methylpiperazine -1-yl) piperidin-1-yl] anilino} pyrazine-2-carboxamide (compound (2)) was obtained as an aqueous hydrogen chloride solution (step 4).
5-{[(3R) -1- (3-chloropropanoyl) pyrrolidin-3-yl] oxy} -6-ethyl-3- {4- [4- (4-methylpiperazin-1-yl) obtained ) Piperidin-1-yl] anilino} pyrazine-2-carboxamide in 2-chloropropanol (209.6 kg) was added to an aqueous solution of hydrogen chloride, and water was added with sodium hydroxide (7.0 kg) at an internal temperature of 23 ° C. to 25 ° C. with stirring. (80 L) The solution was added dropwise. After reacting at 25 ° C. for 10 minutes, water (187 L) and seed crystals (13.4 g) of compound (1) were added at 26 ° C. After stirring at 24 ° C to 27 ° C for 2 hours, the mixture was 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, dried under reduced pressure, and 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({ 4- [4- (4-Methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazine-2-carboxamide (20.4 kg) was obtained as a solid (5th step). This seed crystal was obtained by performing a liquid separation operation in the last step without adding a liquid separation operation before adding 3-chloropropanoyl chloride under a series of similar reaction conditions performed without adding the seed crystal. Water was added to the organic layer under ice-cooling and stirred, and then the solid was collected by filtration and washed with a mixed solvent of 2-propanol and water to obtain compound (1).
Further, 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 of the compound (3) and the compound (2) is purified by silica gel column chromatography. I confirmed that there was. The physicochemical data of the compounds (3), (2) and (1) are described below.
6-ethyl-3- {4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] anilino} -5-[(3R) -pyrrolidin-3-yloxy] pyrazine-2-carboxamide ( Silica gel column chromatography purified product) (compound (3))
ESI +: 509.2
D1: 1.21 (3H, t, J = 7.6Hz), 1.57-1.75 (2H, m), 1.90-2.03 (3H, m), 2.07-2.22 (1H, m), 2.30 (3H, s), 2.30- 2.74 (13H, m), 2.90-3.00 (1H, m), 3.08-3.22 (3H, m), 3.66-3.74 (2H, m), 5.21-5.29 (1H, s), 5.40-5.48 (1H, s ), 6.92 (2H, d, J = 7.2Hz), 7.48 (2H, d, J = 7.2Hz), 7.51-7.58 (1H, s), 10.58 (1H, s)

5-{[(3R) -1- (3-chloropropanoyl) pyrrolidin-3-yl] oxy} -6-ethyl-3- {4- [4- (4-methylpiperazin-1-yl) piperidine- 1-yl] anilino} pyrazine-2-carboxamide (silica gel column chromatography purified product) (compound (2))
ESI +: 599.1
D2: 1.16 (3H, t, J = 7.4Hz), 1.43-1.55 (2H, m), 1.79-1.87 (2H, m), 2.11-2.40 (5H, m), 2.13 (3H, s), 2.40- 2.86 (12H, m), 3.31-3.44 (1H, m), 3.54-3.88 (7H, m), 5.45-5.55 (1H, m), 6.90-6.98 (2H, m), 7.39-7.47 (2H, m ), 7.53-7.62 (1H, s), 7.81-7.90 (1H, s), 10.94-11.02 (1H, m)

5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl } Amino) pyrazine-2-carboxamide (compound (1))
ESI +: 563.5
D1: 1.15-1.29 (3H, m), 1.56-1.75 (2H, m), 1.90-2.00 (2H, m), 2.10-2.74 (15H, m), 2.29 (3H, s), 3.63-3.96 (6H , m), 5.25-5.34 (1H, s), 5.51-5.60 (1H, s), 5.69-5.77 (1H, m), 6.31-6.52 (2H, m), 6.87-6.96 (2H, m), 7.39 -7.47 (2H, m), 7.53-7.62 (1H, s), 10.53-10.60 (1H, m)

Step 6 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- [4- (4-methylpiperazin-1-yl) piperidine-1- [Il] phenyl} amino) pyrazine-2-carboxamide Synthesis of monomethanesulfonate (compound (9)) To a mixture of acetone (62.6 kg), purified water (20 L), methanesulfonic acid (3.05 kg), 5- {[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino ) Pyrazine-2-carboxamide (19.87 kg) was added and dissolved at 46 ° C. After filtering the solution, a mixed solvent of acetone (12.5 kg) and purified water (4 L) was added, and further acetone (140.9 kg) was added dropwise at 45 ° C. to 48 ° C. After stirring at 42 ° C. to 45 ° C. for 1 hour, a seed crystal (4.0 g) of compound (9) was added and stirred at 44 ° C. to 47 ° C. for 8 hours. Acetone (140.9 kg) was added dropwise at 46 ° C to 47 ° C, followed by stirring at 20 ° C to 30 ° C for 32 hours. The solid was collected by filtration, 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- (4-methylpiperazin-1-yl) piperidine-1 -Il] phenyl} amino) pyrazine-2-carboxamide monomethanesulfonate (18.37 kg) was obtained as a solid.
ESI +: 563.5
D2: 1.12 (3H, t, J = 7.6Hz), 1.35-1.46 (2H, m), 1.70-1.89 (2H, m), 2.09-3.06 (18H, m), 2.26 (3H, s), 3.25- 3.48 (1H, m), 3.54-3.93 (5H, m), 5.43-5.52 (1H, m), 5.59-5.68 (1H, m), 6.08-6.14 (1H, m), 6.46-6.65 (1H, m ), 6.86-6.98 (2H, m), 7.36-7.48 (2H, m), 7.50-7.60 (1H, m), 7.79-7.86 (1H, s), 8.90-9.30 (1H, m), 10.90-11.02 (1H, m)

Example 2

Step 1 Synthesis of 5-chloro-6-ethyl-3- {4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] anilino} pyrazine-2-carboxamide (compound (6))
3,5-dichloro-6-ethylpyrazine-2-carboxamide (34.0 kg), 4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] aniline (44.5 kg), N, N- Diisopropylethylamine (39.9 kg) and 2-butanol (274.7 kg) were stirred at 83 ° C. to 86 ° C. for 1 hour. After adding seed crystals (7 g) of 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 dimethyl sulfoxide (486.2 kg) was added, 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 collected by filtration and washed with dimethyl sulfoxide and 2-butanol. Dry under reduced pressure and use 5-chloro-6-ethyl-3- {4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] anilino} pyrazine-2-carboxamide (55.7 kg) as a solid I got it.

Second step tert-butyl (3R) -3-{[5-carbamoyl-3-ethyl-6-({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino ) Synthesis of pyrazin-2-yl] oxy} pyrrolidine-1-carboxylate (compound (4))
To tert-butyl (3R) -3-hydroxypyrrolidine-1-carboxylate (67.8 kg) and tetrahydrofuran (491.6 kg) was added potassium tert-butoxide (40.2 kg), and the mixture was stirred at 24 ° C. to 25 ° C. for 30 minutes. . Subsequently, 5-chloro-6-ethyl-3- {4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] anilino} pyrazine-2-carboxamide (55.3 kg), tetrahydrofuran (196.6 kg) was added and reacted at 55-62 ° C for 17 hours. After cooling to 26 ° C., water (277 L) was added dropwise, seed crystals (111 g) of compound (4) were 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 collected by filtration, washed with a mixed solvent of tetrahydrofuran and water, dried under reduced pressure, and crude tert-butyl (3R) -3-{[5-carbamoyl-3-ethyl-6-({4- [4- ( 4-Methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazin-2-yl] oxy} pyrrolidine-1-carboxylate (65.1 kg) was obtained as a solid.
Crude tert-butyl (3R) -3-{[5-carbamoyl-3-ethyl-6-({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} obtained 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. It cooled and stirred at 0 degreeC-5 degreeC for 14 hours. The solid was collected by filtration, washed with 2-butanol cooled to 3.5 ° C., dried under reduced pressure, and tert-butyl (3R) -3-{[5-carbamoyl-3-ethyl-6-({4- [4- (4-Methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazin-2-yl] oxy} pyrrolidine-1-carboxylate (63.2 kg) was obtained.

Third Step 6-Ethyl-3- {4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] anilino} -5-[(3R) -pyrrolidin-3-yloxy] pyrazine-2 -Synthesis of carboxamide (compound (3))
tert-butyl (3R) -3-{[5-carbamoyl-3-ethyl-6-({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazine- 2-yl] oxy} pyrrolidine-1-carboxylate (59.8 kg), ethanol (283.1 kg), 35% -37% hydrochloric acid (61.4 kg), and water (239 L) were stirred at 55 ° C. to 61 ° C. for 5 hours. After cooling to 49 ° C., a solution of sodium hydroxide (23.6 kg) in water (239 L) was added. The pH was adjusted to 11 with 1M aqueous sodium hydroxide solution, seed crystals (120 g) of compound (3) were added, and the mixture was stirred at 44 ° C. to 45 ° C. for 4 hours. Subsequently, water (837 L) was added dropwise, cooled to 30 ° C., a solution of sodium hydroxide (2.0 kg) in water (60 L) was added, and the mixture was stirred at 23 ° C. to 29 ° C. for 3 hours. The solid was collected by filtration, washed with water, and then dried under reduced pressure. 6-ethyl-3- {4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] anilino} -5-[( 3R) -Pyrrolidin-3-yloxy] pyrazine-2-carboxamide (49.0 kg) was obtained.

4th and 5th steps (continuous process) 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- [4- (4-methylpiperazine-1) Synthesis of -yl) piperidin-1-yl] phenyl} amino) pyrazine-2-carboxamide (compound (1))
6-ethyl-3- {4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] anilino} -5-[(3R) -pyrrolidin-3-yloxy] pyrazine-2-carboxamide ( 48.4 kg), N, N-dimethylformamide (457.4 kg), tetrahydrofuran (215.1 kg) were cooled to −8 ° C., and a solution of 3-chloropropanoyl chloride (15.7 kg) in tetrahydrofuran (107.6 kg) was added dropwise. Stir at -8 ° C. for 3 hours, then 5-{[(3R) -1- (3-chloropropanoyl) pyrrolidin-3-yl] oxy} -6-ethyl-3- {4- [4- (4- Obtained as a solution of methylpiperazin-1-yl) piperidin-1-yl] anilino} pyrazine-2-carboxamide (compound (2)) in N, N-dimethylformamide and tetrahydrofuran (step 4).
5-{[(3R) -1- (3-chloropropanoyl) pyrrolidin-3-yl] oxy} -6-ethyl-3- {4- [4- (4-methylpiperazin-1-yl) obtained Tetrahydrofuran (107.6 kg) and DBU (49.3 kg) were added to a solution of piperidin-1-yl] anilino} pyrazine-2-carboxamide in N, N-dimethylformamide and tetrahydrofuran, and the mixture was stirred at 5 to 11 ° C. for 18 hours. . 35% -37% hydrochloric acid (5.7 kg) and water (145 L) were added, and the mixture was heated to 20 ° C. and seed crystal (97 g) of compound (2) was added, followed by stirring at 20 ° C. to 23 ° C. for 16 hours. . Subsequently, water (920 L) was added and stirred at 22 ° C. to 24 ° C. for 1 hour, and then a solution of potassium hydrogen carbonate (32.2 kg) in water (145 L) was added and stirred at 5 ° C. to 7 ° C. for 9 hours. The solid was collected by filtration, washed with a mixed solvent of acetone and water, and then dried under reduced pressure to give crude 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({ 4- [4- (4-Methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazine-2-carboxamide (50.0 kg) was obtained.
Crude 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- [4- (4-methylpiperazin-1-yl) piperidine-1 -Iyl] phenyl} amino) pyrazine-2-carboxamide (49.7 kg), acetone (58.7 kg), tetrahydrofuran (331.4 kg) were dissolved at 47 ° C. 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. Activated carbon was removed by filtration, and acetone (58.7 kg), tetrahydrofuran (22.1 kg), water (149 L) and seed crystals (99 g) of compound (1) were added to the filtrate, and the mixture was stirred at 45 ° C. to 48 ° C. for 1 hour. Then, water (746L) was dripped and it stirred at 44 to 45 degreeC for 1 hour. It cooled and stirred at 23-30 degreeC for 13 hours. The solid was collected by filtration, washed with a mixed solvent of acetone and water, and then dried under reduced pressure to give 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4 -[4- (4-Methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazine-2-carboxamide (47.7 kg) was obtained (fifth step).
In the fourth step, compound (2) is used in the next step without isolation, but it is confirmed to be the target compound by the retention time of high performance liquid chromatography (HPLC). ("Retention time = 21 minutes; retention time of compound (2) obtained in Example 1 = 21 minutes", "HPLC measurement conditions; detector (ultraviolet absorptiometer, measurement wavelength 210 nm), column (YMC-Triart C18 , Inner diameter 4.6mm, length 150mm, particle size 3μm, made by YMC, column temperature (40 ℃), flow rate (1.2mL / min), mobile phase A (45mmol / L perchloric acid aqueous solution), mobile phase B (acetonitrile ), Mobile phase feeding conditions (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%, 37 ~ 39 minutes: Mobile phase A 10% Mobile phase B 90%, 39-40 minutes: Mobile phase A 10 → 85% Mobile phase B 90 → 15%, 40 ~ 45 minutes: Mobile phase A 85% Mobile phase B 15% ) ")

Step 6 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- [4- (4-methylpiperazin-1-yl) piperidine-1- Synthesis of [Il] phenyl} amino) pyrazine-2-carboxamide monomethanesulfonate (compound (9))
5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl } Amino) pyrazine-2-carboxamide (42.4 kg), acetone (968.9 kg) and dimethyl sulfoxide (209.9 kg) were dissolved at 53 ° C. After the solution was filtered, acetone (66.8 kg) and a solution of methanesulfonic acid (7.02 kg) in acetone (66.8 kg) were added dropwise for 20%, and then seed crystals (42 g) of compound (9) were added. Subsequently, the remaining acetone solution of methanesulfonic acid was added dropwise, acetone (33.4 kg) was added, and the mixture was stirred at 55 ° C. for 30 minutes. It cooled and stirred at 22-30 degreeC for 1 hour. The solid was collected by filtration, washed with acetone, and then dried under reduced pressure to give 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- [4- ( 4-Methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazine-2-carboxamide monomethanesulfonate (47.4 kg) was obtained.

Reference example 1

Step 1 Synthesis of tert-butyl (3R) -3-[(5-carbamoyl-6-chloro-3-ethylpyrazin-2-yl) oxy] pyrrolidine-1-carboxylate (compound (10))
To a mixture of tert-butyl (3R) -3-hydroxypyrrolidine-1-carboxylate (2600 mg) and N, N-dimethylformamide (60 mL) was added 55% oily sodium hydride (540 mg) under ice cooling, and 1 Stir for half an hour. Under ice-cooling, 3,5-dichloro-6-ethylpyrazine-2-carboxamide (3000 mg) was added to the reaction solution, 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 resulting 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-1-carboxylate (855 mg ) Was obtained as a solid.

Second step tert-butyl (3R) -3-{[5-carbamoyl-3-ethyl-6-({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino ) Synthesis of pyrazin-2-yl] oxy} pyrrolidine-1-carboxylate (compound (4))
tert-Butyl (3R) -3-[(5-carbamoyl-6-chloro-3-ethylpyrazin-2-yl) oxy] pyrrolidine-1-carboxylate (90 mg), 4- [4- (4-methylpiperazine -1-yl) piperidin-1-yl] aniline (210 mg), N, N-diisopropylethylamine (140 μL), N-methylpyrrolidone (500 μL) were mixed at 150 ° C. using a microwave reactor (Viotage). For 2 hours. The reaction mixture was allowed to cool, water and diisopropyl ether were added, the insoluble material was collected by filtration, and tert-butyl (3R) -3-{[5-carbamoyl-3-ethyl-6-({4- [4- ( 4-Methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazin-2-yl] oxy} pyrrolidine-1-carboxylate (101 mg) was obtained as a solid.

Third Step 6-Ethyl-3- {4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] anilino} -5-[(3R) -pyrrolidin-3-yloxy] pyrazine-2 -Synthesis of carboxamide (compound (3))
tert-butyl (3R) -3-{[5-carbamoyl-3-ethyl-6-({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazine- To a solution of 2-yl] oxy} pyrrolidine-1-carboxylate (330 mg) in dichloromethane (5 mL) was added trifluoroacetic acid (4 mL) at 0 ° C. and stirred for 2 hours. The solvent was distilled off, and chloroform and a saturated aqueous sodium hydrogen carbonate solution were added to the residue to carry out a liquid separation operation. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol / 28% aqueous ammonia) to give 6-ethyl-3- {4- [4- (4-Methylpiperazin-1-yl) piperidin-1-yl] anilino} -5-[(3R) -pyrrolidin-3-yloxy] pyrazine-2-carboxamide (174 mg) was obtained.

Fourth Step 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- [4- (4-methylpiperazin-1-yl) piperidine-1- Synthesis of [Il] phenyl} amino) pyrazine-2-carboxamide (compound (1))
6-ethyl-3- {4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] anilino} -5-[(3R) -pyrrolidin-3-yloxy] pyrazine-2-carboxamide ( 174 mg) in chloroform (20 mL) was added N, N-diisopropylethylamine (390 μL) and acryloyl chloride (130 μL) under ice cooling, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution 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% aqueous ammonia) to give 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy}. -6-Ethyl-3-({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazine-2-carboxamide (159 mg) was obtained.

Step 5 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- [4- (4-methylpiperazin-1-yl) piperidine-1- Yl] phenyl} amino) pyrazine-2-carboxamide Synthesis of monomethanesulfonate (compound (9)) Acetonitrile (3 mL) and 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6 -Ethyl-3-({4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazine-2-carboxamide (100 mg) was heated to 50 ° C. 2M aqueous methanesulfonic acid solution (80 μL) was added. The mixture was stirred at 50 ° C. for 30 minutes and then stirred at room temperature for 20 hours. The precipitated solid was collected by filtration, dried under reduced pressure at 50 ° C. for 6 hours, and 5-{[(3R) -1-acryloylpyrrolidin-3-yl] oxy} -6-ethyl-3-({4- [4- (4-Methylpiperazin-1-yl) piperidin-1-yl] phenyl} amino) pyrazine-2-carboxamide monomethanesulfonate (97 mg) was obtained as a solid.

  The effects of the present invention are shown below.

  Table 1 shows the yield of each step and the total yield in Example 1.

  Table 2 shows the yield of each step in Example 2 and the total yield.

  In addition, Table 3 shows the yield of each step and the total yield in Reference Example 1.

  Unlike the known production method (Reference Example 1 in Reaction Scheme 1), the production method of the present invention (Example 1 and Example 2 in Reaction Scheme 2) does not include a purification step by silica gel column chromatography. It is expected to be suitable for industrial production as a pharmaceutical product. In particular, in Reference Example 1, compound (11) in which another molecular compound (3) is Michael-added to the target compound (1) by using acryloyl chloride as an acylating agent in the fourth step is formed as a by-product. (11) had to be removed by silica gel column chromatography. In the present invention, by-product formation was avoided by using 3-chloropropanoyl chloride instead of acryloyl chloride, and silica gel column chromatography was used. Purification by was unnecessary. Therefore, it is expected that the production method is not only troublesome by using silica gel column chromatography but also excellent in cost.

  In addition, in the production method of the present invention (Example 2), the compound (3) which has been used in a continuous reaction so far is changed by changing the reaction solvent from 2-propanol used in Example 1 to ethanol in the third step. Can be easily isolated. Further, in the fifth step, in the course of the purification operation of compound (1), the crude product is once dissolved in acetone and tetrahydrofuran, added with activated carbon, stirred, and filtered to remove impurities of unknown structure. It became possible to remove. Further, by using acetone and dimethyl sulfoxide instead of acetone and water as the solvent in the sixth step, compound (9) can be obtained in a higher yield than Example 1.

  In addition, it was confirmed that the production method (Example 1 and Example 2) of the present invention had a remarkably high overall yield compared to the known production method (Reference Example 1). In particular, the compound (5) introduced in the first step of Reference Example 1 is introduced. In the present invention, the compound (7) is introduced into the compound (8) to form the compound (6), and then the compound (5) is introduced. It was confirmed that it was possible to obtain a high yield.

  From the above, it is expected that the production method of the present invention can be an industrially superior production method as compared with known production methods. In particular, it is expected that a high total yield can be achieved by the production method of the present invention.

  The present invention provides a method for producing compound (1) and its monomethanesulfonate salt, which is suitable for industrial production as a pharmaceutical product, with high yield and low cost, and a synthetic intermediate useful in the production method. Can be done.

Claims (9)

Formula (2)

The compound of formula (1) or a salt thereof is subjected to dehydrochlorination reaction by reacting with a base (1)

Or a salt thereof. The compound of formula (2) or a salt thereof is represented by formula (3)

The manufacturing method of Claim 1 which is manufactured by the manufacturing method characterized by making 3-chloropropanoyl chloride act on the compound of this, or its salt, and attaching | subjecting to acylation reaction. The compound of formula (3) or a salt thereof is represented by formula (4)

The manufacturing method of Claim 2 which is manufactured by the manufacturing method characterized by attaching | subjecting the compound of this, or its salt to deprotection reaction. The compound of the formula (4) or a salt thereof is represented by the formula (6)

Or a salt thereof of formula (5)

The manufacturing method of Claim 3 which is manufactured by the manufacturing method characterized by making the compound or its salt act, and attaching | subjecting to an aromatic nucleophilic substitution reaction. The compound of formula (6) or a salt thereof is represented by formula (8)

Or a salt thereof in 2-butanol in the presence of a base, formula (7)

The manufacturing method of Claim 4 which is manufactured by the manufacturing method characterized by making the compound or its salt act, and subjecting to aromatic nucleophilic substitution reaction at 80 to 90 degreeC. A compound of formula (1) produced by the method according to any one of claims 1 to 5 or a salt thereof, wherein methanesulfonic acid is allowed to act to form a monomethanesulfonate salt (9) ) A method for producing a compound.

Formula (2)

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