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WO2016121777A1 - Procédé de production d'un composé pyrazine carboxamide, et intermédiaire de synthèse de ce dernier - Google Patents

Procédé de production d'un composé pyrazine carboxamide, et intermédiaire de synthèse de ce dernier Download PDF

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Publication number
WO2016121777A1
WO2016121777A1 PCT/JP2016/052229 JP2016052229W WO2016121777A1 WO 2016121777 A1 WO2016121777 A1 WO 2016121777A1 JP 2016052229 W JP2016052229 W JP 2016052229W WO 2016121777 A1 WO2016121777 A1 WO 2016121777A1
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Prior art keywords
compound
salt
formula
ethyl
methylpiperazin
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PCT/JP2016/052229
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English (en)
Japanese (ja)
Inventor
賢宏 秋葉
博昭 星井
逸郎 島田
孝輔 米ノ井
賢太郎 西川
泰浩 森永
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Astellas Pharma Inc
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Astellas Pharma Inc
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Priority to KR1020177020729A priority Critical patent/KR20170105021A/ko
Priority to JP2016572078A priority patent/JPWO2016121777A1/ja
Priority to CN201680007743.9A priority patent/CN107207468A/zh
Priority to CA2975072A priority patent/CA2975072A1/fr
Priority to MX2017009714A priority patent/MX2017009714A/es
Publication of WO2016121777A1 publication Critical patent/WO2016121777A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings

Definitions

  • 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.
  • Patent Document 1 We have already reported that compound (1) or a pharmaceutically acceptable salt thereof is useful as an active ingredient of a pharmaceutical composition for treating cancer (Patent Document 1).
  • compound (1) is described as Example 54
  • monomethanesulfonate (9) of compound (1) is described as Example 261.
  • compound (8) 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)”).
  • compound (8) 3,5-dichloro-6-ethylpyrazine-2-carboxamide
  • compound (8) tert-butyl (3R) -3-hydroxypyrrolidine-1-carboxylate
  • compound (10) is produced.
  • 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
  • compound ((7)) is produced by a known method
  • 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.
  • compound (3) 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.
  • compound (1) is a method for producing monomethanesulfonate (9) of compound (1) according to the method described in Example 254 of the same document.
  • 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%.
  • 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 is a method for which further improvement is desired in terms of industrial production.
  • 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.
  • 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.
  • Compound (2) or a salt thereof is compound (3).
  • the production method according to [1] which is produced by a production method characterized in that 3-chloropropanoyl chloride is allowed to act on a salt thereof and subjected to an acylation reaction.
  • Compound (3) or a salt thereof is compound (4).
  • the production method according to [4] which is produced by a production method characterized by subjecting a salt thereof to an aromatic nucleophilic substitution reaction at 80 ° C. to 90 ° C.
  • the compound disclosed in the present invention may be in a free form or form a salt.
  • 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.
  • 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.
  • 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. .
  • 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.
  • the compounds disclosed in the present invention may exist in tautomers. 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.
  • the compound represented by the formula (1) may be simply referred to as the compound (1), and other numbers may be similarly referred to.
  • methanesulfonic acid 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.
  • seed crystal refers to a seed crystal or a solid compound that serves as a seed for promoting crystallization.
  • the present invention can provide a method for producing 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.
  • Step 1 to Step 6 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.
  • 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).
  • the compound (8) and the compound (7) are used, and a mixture of these in the presence of a base, in a solvent inert to the reaction, under cooling to heating, in one embodiment, at 0 ° C.
  • the mixture is stirred at 80 ° C. to 90 ° C., usually for 1 hour to 2 days.
  • 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.
  • the compound (6) and the compound (5) are used, and a mixture of these in the presence of a base, in a solvent inert to the reaction, under cooling to heating, in one embodiment, at 0 ° C. to 100 ° C.
  • the mixture is usually stirred for 1 hour to 2 days.
  • 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.
  • tetrahydrofuran is used.
  • 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.
  • 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.
  • 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
  • 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) is 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).
  • 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.
  • 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.
  • 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.
  • this reaction is carried out, for example, by adding a methyl isobutyl ketone solution of 3-chloropropanoyl chloride to a predetermined solution of the compound (3) obtained without isolation in the third step, under cooling to heating.
  • it can be carried out by stirring at 0 ° C. to 40 ° C., usually for 30 minutes to 2 days.
  • 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.
  • 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).
  • DBU diazabicycloundecene
  • 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, in some embodiments, it can 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)
  • the compound (1) is added to a predetermined solution of methanesulfonic acid, or the predetermined solution of methanesulfonic acid is added to the predetermined solution of compound (1), and under cooling to heating, Stir at 0 ° C
  • 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.
  • aromatic hydrocarbons such as benzene, toluene, x
  • Acetone and in some embodiments, a mixed solution of acetone and water.
  • 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.
  • 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.
  • Example 1 shows the manufacturing method of a compound (1) shown by Reaction Scheme 2, and its monomethanesulfonate (9).
  • this invention is not limited to the method as described in the following Example.
  • 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.
  • naming software such as ACD / Name (registered trademark, Advanced Chemistry Development, Inc.) may be used for naming compounds.
  • concentration mol / L is expressed as M.
  • a 1M NaOH aqueous solution means a 1 mol mol / L NaOH aqueous solution.
  • 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.
  • this seed crystal can be manufactured by the method of obtaining a compound (6) by cooling to room temperature, filtering a solid, and wash
  • 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.
  • Step 3 Step 4 and Step 5 (continuous step) 5- ⁇ [(3R) -1-acryloylpyrrolidin-3-yl] oxy ⁇ -6-ethyl-3-( ⁇ 4- [4- (4 Synthesis of -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) pyrazin-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 to 59 ° C.
  • 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.
  • 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.
  • 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.
  • 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. Subsequently, water (746 L) was added dropwise, and the mixture was stirred at 44 ° C. to 45 ° C. for 1 hour. The mixture was cooled and stirred at 23 to 30 ° C. for 13 hours.
  • Step 6 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)) 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), dimethyl sulfoxide (209.9 kg) Dissolved at 53 ° C.
  • 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. Cooled and stirred at 22-30 ° C. for 1 hour.
  • 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.
  • Table 1 shows the yield of each step in Example 1 and the total yield.
  • Table 2 shows the yield of each step and the total yield in Example 2.
  • Table 3 shows the yield of each step and the total yield in Reference Example 1.
  • the production method of the present invention does not include a purification step by silica gel column chromatography. It is expected to be suitable for industrial production as a pharmaceutical product.
  • 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.
  • 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.
  • 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.
  • the crude product 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.
  • compound (9) can be obtained in a higher yield than Example 1.
  • Example 1 and Example 2 had a remarkably high overall yield compared to the known production method (Reference Example 1).
  • the compound (5) introduced in the first step of Reference Example 1 is introduced.
  • 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.
  • the production method of the present invention can be an industrially superior production method as compared with known production methods.
  • 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.

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Abstract

Le problème que cherche à résoudre l'invention est de fournir un nouveau procédé de production d'un composé pyrazine carboxamide utilisable comme matériau de base pour la production de produits pharmaceutiques, etc., ainsi qu'un intermédiaire de synthèse utilisé dans ledit procédé de production. La solution de l'invention s'appuie sur les recherches approfondies sur les méthodes de production industrielle de composés pyrazine carboxamide conduites par les inventeurs. Ces derniers ont montré qu'en utilisant un matériau préétabli et un intermédiaire de synthèse, il est possible de produire un composé pyrazine carboxamide à l'aide d'un procédé qui convient pour une production industrielle de produits pharmaceutiques, qui ne nécessite pas de purification par chromatographie sur colonne de gel de silice, et dont le rendement global est considérablement amélioré, aboutissant ainsi à la présente invention.
PCT/JP2016/052229 2015-01-28 2016-01-27 Procédé de production d'un composé pyrazine carboxamide, et intermédiaire de synthèse de ce dernier Ceased WO2016121777A1 (fr)

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KR1020177020729A KR20170105021A (ko) 2015-01-28 2016-01-27 피라진카르복사마이드 화합물의 제조 방법 및 그 합성 중간체
JP2016572078A JPWO2016121777A1 (ja) 2015-01-28 2016-01-27 ピラジンカルボキサミド化合物の製造方法及びその合成中間体
CN201680007743.9A CN107207468A (zh) 2015-01-28 2016-01-27 吡嗪甲酰胺化合物的制造方法及其合成中间体
CA2975072A CA2975072A1 (fr) 2015-01-28 2016-01-27 Procede de production d'un compose pyrazine carboxamide, et intermediaire de synthese de ce dernier
MX2017009714A MX2017009714A (es) 2015-01-28 2016-01-27 Metodos para producir compuesto de pirazin carboxamida e intermediario sintetico del mismo.

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018079570A1 (fr) * 2016-10-26 2018-05-03 アステラス製薬株式会社 Composition pharmaceutique stable
JP2023528859A (ja) * 2020-06-01 2023-07-06 ウィゲン・バイオメディシン・テクノロジー・（シャンハイ）・カンパニー・リミテッド 新規ピラジン化合物
US11945785B2 (en) 2021-12-30 2024-04-02 Biomea Fusion, Inc. Pyrazine compounds as inhibitors of FLT3
JP2025514336A (ja) * 2022-04-27 2025-05-02 杭州新元素▲薬▼▲業▼有限公司 尿酸を降下させるために使用できる化合物

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JPS5754177A (ja) * 1980-09-19 1982-03-31 Teikoku Hormone Mfg Co Ltd Chikanchiazoorujudotai
JPH08333333A (ja) * 1995-06-09 1996-12-17 Kanegafuchi Chem Ind Co Ltd １−［３−クロロ−（２ｓ）−メチルプロピオニル］−ピロリジン−（２ｓ）−カルボン酸の製造方法
WO2013108754A1 (fr) * 2012-01-17 2013-07-25 アステラス製薬株式会社 Composé pyrazine carboxamide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5754177A (ja) * 1980-09-19 1982-03-31 Teikoku Hormone Mfg Co Ltd Chikanchiazoorujudotai
JPH08333333A (ja) * 1995-06-09 1996-12-17 Kanegafuchi Chem Ind Co Ltd １−［３−クロロ−（２ｓ）−メチルプロピオニル］−ピロリジン−（２ｓ）−カルボン酸の製造方法
WO2013108754A1 (fr) * 2012-01-17 2013-07-25 アステラス製薬株式会社 Composé pyrazine carboxamide

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018079570A1 (fr) * 2016-10-26 2018-05-03 アステラス製薬株式会社 Composition pharmaceutique stable
JP2023528859A (ja) * 2020-06-01 2023-07-06 ウィゲン・バイオメディシン・テクノロジー・（シャンハイ）・カンパニー・リミテッド 新規ピラジン化合物
JP7777544B2 (ja) 2020-06-01 2025-11-28 ウィゲン・バイオメディシン・テクノロジー・（シャンハイ）・カンパニー・リミテッド 新規ピラジン化合物
US11945785B2 (en) 2021-12-30 2024-04-02 Biomea Fusion, Inc. Pyrazine compounds as inhibitors of FLT3
JP2025514336A (ja) * 2022-04-27 2025-05-02 杭州新元素▲薬▼▲業▼有限公司 尿酸を降下させるために使用できる化合物

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KR20170105021A (ko) 2017-09-18
MX2017009714A (es) 2017-11-17
JPWO2016121777A1 (ja) 2017-11-02
CN107207468A (zh) 2017-09-26

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