WO2017183539A1

WO2017183539A1 - Method for producing bicyclic compound using meldrum's acid

Info

Publication number: WO2017183539A1
Application number: PCT/JP2017/015019
Authority: WO
Inventors: 和利鵜飼; 友和小倉; 中山　敬司
Original assignee: 第一三共株式会社
Priority date: 2016-04-18
Filing date: 2017-04-12
Publication date: 2017-10-26

Abstract

[Problem] To provide a compound that can be used on an industrial scale. [Solution] A compound represented by general formula (4) or a base adduct thereof. (In the formula, R³ and R⁴ independently represent a hydrogen atom or the like.)

Description

Method for producing bicyclic compound using Meldrum's acid

The present invention relates to a bicyclic γ-amino acid derivative or a pharmacologically acceptable salt thereof, particularly a compound having activity as an α ₂ δ ligand and a method for producing an intermediate thereof.

Compounds that show high affinity binding to the α ₂ δ subunit of voltage-gated calcium channels have been shown to be effective, for example, in the treatment of neuropathic pain (eg, Non-Patent Document 1 and Non-Patent Document 1). (See Patent Document 2).

So far, several types of α ₂ δ ligands are known as therapeutic agents for neuropathic pain, and examples of α ₂ δ ligands include gabapentin and pregabalin. Α ₂ δ ligands such as these compounds are useful for the treatment of epilepsy, neuropathic pain and the like (for example, Patent Document 1). Examples of other compounds are disclosed in Patent Document 2, Patent Document 3, Patent Document 4, and the like.
In addition, the applicant has previously reported Patent Documents 5-8 and the like as α ₂ δ ligands and production methods thereof.
Patent Documents 7 and 8 are known as methods for synthesizing a compound having the formula (1) having a bicyclic ketone structure that is an intermediate for producing an α ₂ δ ligand. From a compound having the formula (2) or the formula (3) via a compound having the formula (6) reacted with malonic acid, via a compound having the formula (7) obtained by decarboxylation, via a ketene derivative It has been reported that it is synthesized by the [2 + 2] reaction. (Patent Document 7 and Patent Document 8)

Patent Documents 5 and 6 report a method for producing a compound having the formula (1-6) as described in Scheme 1. That is, a compound having the formula (1-1) is reacted with a phosphonate to obtain a compound having the formula (1-2), and then reacted with nitromethane to obtain a compound having the formula (1-3). . Further, after reducing the nitro group of the compound having the formula (1-3), optical resolution is performed to obtain a compound having the formula (1-5), which is further hydrolyzed to have the formula (1-6) Have gained.

Meldrum's acid derivatives are known to decompose at ultra-high temperatures to produce ketene while generating acetone and carbon dioxide (eg, Non-Patent Document 3). Ketene is an important reactive species used in various reactions.
In addition, the flow-type manufacturing technology (flow synthesis) can shorten the reaction time and facilitate the reaction above the boiling point of the solvent, or it can quickly reach the target reaction temperature and immediately convert it to a stable temperature. It is said that it is suitable for reaction of a compound lacking stability of reactants and products (for example, Non-Patent Document 4).

US 2006/154929 US 2003/220397 US 2004/152779 US 2003/78300 US 2010/249229 US 2012/071685 US 2014/094624 US 2014/094623

The present invention provides a methodology for efficiently producing a compound having the formula (1).

(The compound having the formula (1) is a racemic mixture of the compound having the formula (1 ′) and the formula (1 ″), but is described as a compound having the above formula (1) for convenience.)
The present invention provides a compound having the formula (1), a compound having the general formula (4) produced from a compound having the formula (2) or the general formula (3), and further a compound having the general formula (4). The present invention relates to a method for efficiently producing and providing using a derived compound having the general formula (5) or (5 ′).

(Where
R ¹ and R ² each independently represent a C1-C6 alkyl group, or R ¹ and R ² together with the same nitrogen atom to which they are attached a 4-6 membered saturated heterocyclyl group. Show
R ⁵ and R ⁶ each independently represent a hydrogen atom, a C1-C6 alkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached represents a heterocyclic group,
R ⁷ represents a C1-C6 alkylcarbonyloxy group, a halogen atom, or a succinimide-N-oxy group,
X represents a halogen atom,
M represents a metal atom. )

As a result of intensive studies, the inventors solved the problem as described below, and provided a compound having the formula (1), the formula (2) or the general formula ( A compound having the general formula (4) is produced by reacting the compound having 3) with Meldrum's acid or a derivative thereof, and the compound having the general formula (4), and further having the general formula (4). Using a compound having the general formula (5) or (5 ′) derived from the compound, reacting at a high temperature with an appropriate base, or heating at a high temperature, the compound having the formula (1) Which has led to the success of the present invention.

In the condensation reaction between the compound having the formula (2) or the general formula (3) and meldrum acid or a derivative thereof, as a result of studying the compound to be used, the reaction time of the condensation reaction, the reaction conditions, etc., useless reagents are used. And succeeded in efficiently synthesizing a compound having the general formula (4).

(Each symbol in the formula is the same as above.)

The compound having the general formula (4) can be hydrolyzed to produce the compound having the formula (1) by adding an appropriate reaction reagent via the compound having the formula (6). On the other hand, the present inventors do not obtain a compound having the formula (1) through such a stepwise reaction, but directly add a suitable base to the compound having the general formula (4). We have succeeded in finding that a compound having the formula (1) can be obtained.

(Each symbol in the formula is the same as above.)

By adding an appropriate base to the compound having the general formula (4) to obtain the compound having the general formula (5) or (5 ′) as a crystal of the base adduct, a complicated purification method such as column chromatography We have developed a simple purification method that avoids the above and succeeded in obtaining a compound having the high purity formula (1).

(Each symbol in the formula is the same as above.)

It has been found that a compound having the general formula (5) or (5 ') gives a compound having the formula (1) only by heating.

Purification is carried out by adding an appropriate post-treatment to the compound having the general formula (4) obtained by mixing an appropriate amount of the reactants and performing flow synthesis (defined later) in stages. The present inventors have found a method by which a compound having the formula (1) can be efficiently produced by adding an appropriate base in an appropriate solvent to a compound having the general formula (4).
That is, the present invention includes the inventions described below.

[1]
A compound having the general formula (4) or a base adduct thereof.

(Wherein R ³ and R ⁴ each independently represent a hydrogen atom, a C1-C6 alkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, or R ³ and R ⁴ together with the same carbon atom to which they are attached represent a 3-6 membered cycloalkyl ring.)
[2]
The compound having the general formula (4) according to [1].
[3]
R ³ is a methyl group, an ethyl group, or a propyl group, and R ⁴ is a methyl group, an ethyl group, or a propyl group, or a compound having the general formula (4) according to [1] or a compound thereof Base adduct.
[Four]
The compound having the general formula (4) according to [1] or a base adduct thereof, wherein R ³ is a methyl group and R ⁴ is a methyl group.

[Five]
A method for producing a compound having the general formula (4) or a base adduct thereof according to [1], wherein the compound having the formula (2) and Meldrum's acid or a derivative thereof are used in the presence of a solvent and a base.

(Wherein R ³ and R ⁴ have the same meaning as described above.)
[6]
The production method according to [5], wherein R ³ is a methyl group, an ethyl group, or a propyl group, and R ⁴ is a methyl group, an ethyl group, or a propyl group.
[7]
The production method according to [5], wherein R ³ is a methyl group, and R ⁴ is a methyl group.
[8]
The solvent is N, N-dimethylacetamide or toluene, and the base is any one selected from the group consisting of morpholine, N-methylpiperazine, N-ethylpiperazine, piperidine, pyrrolidine, [5]-[7 ] The manufacturing method of any one of.
[9]
The production method according to any one of [5]-[8] by flow synthesis.

[Ten]
A process for producing a compound having the general formula (4) or a base adduct thereof according to [1] using a compound having the general formula (3) and Meldrum's acid or a derivative thereof in the presence of a solvent or a base.

(Wherein R ¹ and R ² represent a C1-C6 alkyl group, or R ¹ and R ² together with the same nitrogen atom to which they are bonded represent a 4-6 membered saturated heterocyclyl group. X represents a halogen atom, and R ³ and R ⁴ have the same meaning as described above.)
[11]
R ¹ is an ethyl group, a propyl group, an isopropyl group, or an isobutyl group, R ² is an ethyl group, a propyl group, an isopropyl group, or an isobutyl group, or R ¹ and R ² are It is bonded to the same nitrogen atom and is piperidine or morpholine, R ³ is a methyl group, an ethyl group, or a propyl group, and R ⁴ is a methyl group, an ethyl group, or a propyl group, [10] The production method according to [10].
[12]
The production method according to [10], wherein R ¹ is an isobutyl group, R ² is an isobutyl group, R ³ is a methyl group, and R ⁴ is a methyl group.
[13]
[10] The production method according to any one of [10] to [12], wherein the solvent is N, N-dimethylacetamide or acetonitrile.
[14]
The production method according to any one of [10] to [13], wherein the base is morpholine.
[15]
[10] The production method according to any one of [10] to [14], which is performed by flow synthesis.

[16]
A process for producing a compound having the formula (1) using the compound having the general formula (4) according to [1] or a base adduct thereof in the presence of a solvent and a base.

(Wherein R ³ and R ⁴ have the same meaning as described above.)
[17]
The production method according to [16], wherein R ³ is a methyl group, an ethyl group, or a propyl group, and R ⁴ is a methyl group, an ethyl group, or a propyl group.
[18]
The production method according to [16], wherein R ³ is a methyl group, and R ⁴ is a methyl group.
[19]
Solvents are N, N-dimethylacetamide (DMAc), N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), diglyme, sulfolane, xylene, propylene carbonate, benzonitrile, cyclohexanone, chlorobenzene, anisole, di- [16]-[18] The production method according to any one of [16] to [18], which is one or more selected from the group consisting of butyl ether, normal butyl acetate, methyl isobutyl ketone, and acetophenone.
[20]
Base consists of potassium acetate, pyridine, diazabicycloundecene (DBU), triethylamine, potassium fluoride, 1,2,4-triazole, imidazole, pyrazole, 1,2,3-benzotriazole, N-hydroxysuccinimide [16] The production method according to any one of [16] to [19], which is any one selected from the group.
[twenty one]
[16] The production method according to any one of [16] to [20] by flow synthesis.

[twenty two]
A compound having the formula (1) which undergoes a step of obtaining a compound having the general formula (6) or a salt thereof by hydrolysis using the compound having the general formula (4) or the base adduct thereof according to [1] Manufacturing method.

(Wherein R ³ and R ⁴ have the same meaning as described above.)
[twenty three]
[22] The production method according to [22].

[twenty four]
Using a compound having the general formula (4) described in [1] in the presence of a solvent or a base, a compound having the general formula (5) or (5 ′) is obtained, followed by heating to obtain the formula ( A method for producing a compound having 1).

(Wherein R ³ and R ⁴ are as defined above, and R ⁵ and R ⁶ are each independently a hydrogen atom, a C1-C6 alkyl group, an optionally substituted aryl group, or a substituted group. An aralkyl group which may be substituted, or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached represent a heterocyclic group,
R ⁷ represents a C1-C6 alkylcarbonyloxy group, a halogen atom, or a succinimide-N-oxy group, and M represents a metal atom. )
[twenty five]
R ³ is a methyl group, R ⁴ is a methyl group, and R ⁵ and R ⁶ are imidazolyl groups formed together with the nitrogen atoms to which they are bonded, or R ⁷ is an acetoxy group or a fluorine atom. The production method according to [24], wherein M is potassium or sodium.
[26]
The production method according to [24] or [25], wherein the solvent is N, N-dimethylacetamide.
[27]
A method for producing a compound having the formula (1) according to any one of [24]-[26], wherein the base is imidazole.
[28]
The production method according to any one of [24]-[27] by flow synthesis.

[29]
A method for producing a compound having the formula (1) by heating using a compound having the general formula (5) or (5 ′).

(Wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and M have the same meaning as described above.)
[30]
Using the compound having the general formula (4) described in [1] or a base adduct thereof, a compound having the formula (1) is produced in the presence of a solvent and a base, and the compound having the formula (1) is prepared. A method for producing a compound having the formula (1-6) or a salt thereof by using the compound having the formula (1-6).

(Wherein R ³ and R ⁴ have the same meaning as described above.)

According to the present invention, an important intermediate for producing a compound known to have an α2δ ligand action can be synthesized efficiently and with high quality, which has a great industrial advantage.

(Description of each substituent, etc.)

Substituents R ³ and R ^{4 for} compounds having general formula (4):
R ³ and R ⁴ each independently represent a hydrogen atom, a C1-C6 alkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, or R ³ and R ⁴ Together with the same carbon atom to which they are attached represent a 3-6 membered cycloalkyl ring.
"C1-C6 alkyl group" refers to a straight or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -Butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methyl Pentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2 , 3-dimethylbutyl group, 2-ethylbutyl group and the like.
R ³ and R ⁴ are preferably a methyl group, an ethyl group, or a propyl group, and more preferably a methyl group.
The “optionally substituted aryl group” means a C1-C6 alkyl group such as a methyl group or an ethyl group, a phenyl group which may be substituted with 1 to 3 groups such as a cyano group, a nitro group or a halogen atom, methyl Group, C1-C6 alkyl group such as ethyl group, cyano group, nitro group, naphthyl group optionally substituted by 1-3 halogen atoms, etc., preferably phenyl group.
The “optionally substituted aralkyl group” means a C1-C6 alkyl group such as a methyl group or an ethyl group, a benzyl group or a methyl group which may be substituted with a cyano group, a nitro group or a halogen atom. Group, a C1-C6 alkyl group such as an ethyl group, a cyano group, a nitro group, a naphthylmethyl group optionally substituted by 1-3 halogen atoms, and the like, and a benzyl group is preferred.
"3-6 membered cycloalkyl ring together with the same carbon atom to which they are attached" is cyclopropane, cyclobutane, cyclopentane, cyclohexane, each ring being a C1-C6 alkyl group, cyano 1-3 may be substituted with a group, a nitro group, a halogen atom or the like.
“Salt” refers to a salt of a compound having an acidic group or basic group, which can be formed into an ion pair by reacting with a base or acid.
The “basic salt” is preferably an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as magnesium salt or calcium salt; N-methylmorpholine salt, triethylamine salt, Organic base salts such as tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt or glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid Amino acid salts such as salt and aspartate.

As the “acid salt”, preferably, hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate, Inorganic acid salts such as phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate, aryl sulfones such as benzene sulfonate and p-toluene sulfonate Acid salt, acetate salt, malate salt, fumarate salt, succinate salt, citrate salt, ascorbate salt, tartrate salt, succinate salt, maleate salt, etc .; and glycine salt, lysine salt , Amino acid salts such as arginine salt, ornithine salt, glutamate, aspartate.

The compound of the present invention or a pharmacologically acceptable salt thereof may absorb moisture, adhere to adsorbed water, or become a hydrate when left in the air or by recrystallization. The present invention also includes such various hydrates, solvates and polymorphic compounds.

The “base adduct” is referred to as a base adduct because, when the compound has a Lewis acidic group, a Lewis basic compound is appropriately reacted to form the added compound. Examples of Lewis basic compounds include potassium acetate, pyridine, diazabicycloundecene (DBU), triethylamine, potassium fluoride, 1,2,4-triazole, imidazole, pyrazole, 1,2,3-benzotriazole, Examples thereof include N-hydroxysuccinimide. These Lewis basic compounds can form base adducts with compounds such as, for example, α, β-unsaturated dicarbonyl compounds. Tertiary amines also have Lewis basicity, and when they are added, they form quaternary ammoniums, but generate enol-type base adducts with intramolecular ion pairs in which anions are raised on oxygen atoms. Conceivable.

Substituents R ¹ , R ² and X for compounds having general formula (3):
R ¹ and R ² represent a C1-C6 alkyl group, or R ¹ and R ² together with the same nitrogen atom to which they are attached represent a 4-6 membered saturated heterocyclyl group,
X represents a halogen atom.

The “C1-C6 alkyl group” has the same meaning as described above, and R ¹ and R ² are preferably an ethyl group, a propyl group, an isopropyl group, or an isobutyl group, and more preferably an isobutyl group. It is.
“A 4-6 membered saturated heterocyclyl group together with the same nitrogen atom to which they are attached” is a 4-6 membered saturated cyclic group containing at least a carbon atom and one nitrogen atom. A saturated cyclic group which may contain one or more nitrogen atoms, oxygen atoms or sulfur atoms, and has a bond on the nitrogen atom. In the compound having the general formula (3), the nitrogen atom having a bond is present as an iminium ion.
As the substituent, the saturated cyclic group containing at least a carbon atom and one nitrogen atom is an iminium ion such as an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, and each group is a C1-C6 alkyl group, a cyano group. 1-3 may be substituted with a group, a nitro group, a halogen atom or the like. Preferred is an iminium ion of a piperidinyl group.
As this substituent, a saturated cyclic group containing at least a carbon atom and one nitrogen atom, and a saturated cyclic group containing one or more nitrogen atoms, oxygen atoms or sulfur atoms include morpholinyl group, piperazinyl An iminium ion such as a group, and each group may be substituted with 1-3 of C1-C6 alkyl group, cyano group, nitro group, halogen atom and the like. Preferably, it is an iminium ion of a morpholinyl group.

The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

Substituents R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and M for compounds having general formula (5) or (5 ′):
R ³ and R ⁴ each independently represent a hydrogen atom, a C1-C6 alkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, or R ³ and R ⁴ Together with the same carbon atom to which they are attached represents a 3-6 membered cycloalkyl ring,
R ⁵ and R ⁶ each independently represent a hydrogen atom, a C1-C6 alkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached represents a heterocyclic group,
R ⁷ represents a C1-C6 alkylcarbonyloxy group, a halogen atom, or a succinimide-N-oxy group,
M represents a metal atom.

The “C1-C6 alkyl group” has the same meaning as described above, but the “C1-C6 alkyl group” suitable as R ³ and R ⁴ is a methyl group.
The “optionally substituted aryl group” has the same meaning as described above.
The “optionally substituted aralkyl group” has the same meaning as described above.
“3-6 membered cycloalkyl ring together with the same carbon atom to which they are attached” is as defined above.
“Heterocyclic group together with the nitrogen atom to which they are attached” means a saturated or unsaturated cyclic group in which one or more of the atoms forming the ring are a nitrogen atom and other hetero groups It includes a cyclic group containing an atom, and a plurality of cyclic groups are condensed.
Specifically, there are groups as shown below.
Aziridinyl group, 1H or 2H azilinyl group, azetidinyl group, pyrrolidinyl group, pyrrolyl group, imidazolyl group, pyrazoyl group, oxazoyl group, thiazoyl group, imidazolinyl group, piperidinyl group, morpholinyl group, piperazinyl group, pyridyl group, tetrahydropyridyl group, pyrazinyl Group, pyrimidinyl group, thiazinyl group, triazoyl group, indoyl group, isoindoyl group, benzoimidazoloyl group, benzotriazoyl group, quinolyl group, isoquinolyl group, quinoxalyl group, tetrahydroisoquinolyl group, decahydroisoquinolyl group, dia Zabicycloundecenyl group, dioxopyrrolidinyl group, preferably imidazolyl group, pyrazoyl group, pyridyl group, triazoyl group, benzoimidazoloyl group, benzotriazoyl group, diazabicyclounde Group, a dioxopyrrolidinyl group.

The “C1-C6 alkylcarbonyloxy group” is a group in which a carbonyloxy group is bonded to a C1-C6 alkyl group, and preferably an acetoxy group.
The “halogen atom” has the same meaning as described above. Preferable is a fluorine atom.
The “metal atom” is an alkali metal such as sodium, potassium or lithium; an alkaline earth metal such as magnesium or calcium, and preferably an alkali metal.

The “meldrum acid derivative” means that malonic acid and R ³ and R ⁴ derived from various ketones are each independently a hydrogen atom, a C1-C6 alkyl group, an optionally substituted aryl group, or , An optionally substituted aralkyl group, or a compound in which R ³ and R ⁴ together with the same carbon atom to which they are attached form a 3-6 membered cycloalkyl ring.

“Flow synthesis” is a method in which a reaction is performed by passing through a tube reactor or the like in which necessary raw materials, reagents and the like are adjusted in temperature as a solution.

(Description of each manufacturing process, etc.)
Below, each manufacturing process is demonstrated in detail. In addition, by performing each process by flow synthesis | combination by this invention, reaction can be performed with a small amount of solvent, a small amount of reagents, and a short reaction time with a high yield.

(1)
Method for producing a compound having the general formula (4) by a condensation reaction between a compound having the formula (2) and Meldrum's acid or a derivative thereof

(Each symbol in the formula is the same as above.)
Meldrum acid or a derivative thereof, and a base are added to a solution of the compound having the formula (2), and then the reaction is performed by heating.
Solvents that can be used: Commonly used solvents may be used, but N, N-dimethylacetamide (DMAc), toluene and the like are preferable.
Bases that can be used: bases that are usually used may be used, but morpholine, N-ethylpiperazine, pyrrolidine and the like are preferable.
The reaction temperature is usually 20-100 ° C. The reaction time is usually 10 minutes to 1 hour.

Hereinafter, the flow synthesis of the compound having the general formula (4) will be described.

Each symbol in the formula is the same as described above, and other symbols used in the scheme have the following significance.

: Pump (for feeding liquid)

: Joint part (T-shape, part where solution is mixed)

: Column reactor (reacts packed with individual catalyst and reactant)

: Back pressure valve (pressure valve to make it higher than the boiling point of the solvent)

: Tube reactor (A tube with a thin system or a metal tube wrapped around it. The actual reaction is carried out in this.)

: Batch pot (pot for receiving solution)

Step A1
Step A1 is a step in which a reaction is performed in a column reactor to produce acetal from alcohol and aldehyde.
In this step, the equivalent amount of reagent is theoretically equivalent to 1 equivalent, but in many ordinary reactions, no improvement in yield is observed. On the other hand, in the case of flow synthesis, the equivalents of all reagents can be obtained in a sufficiently high yield with one equivalent or a small excess. For example, the compound having the general formula (4) can be obtained in a sufficiently high yield by using one equivalent or a small excess of each reagent relative to normal butyraldehyde.
Solvents that can be used in the reaction are more efficient for flow synthesis when the solvents are unified. In such a case, ether solvents such as tetrahydrofuran and 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, etc. Alcohol solvents such as toluene, hydrocarbon solvents such as toluene, nitrile solvents such as acetonitrile, aliphatic ester solvents such as ethyl acetate, or amide solvents such as N, N-dimethylacetamide and N, N-dimethylformamide In particular, polar solvents such as acetonitrile and N, N-dimethylacetamide are suitable. In Step A1, the reaction can be carried out smoothly without using a solvent.
The reaction temperature is preferably in the range of −30 ° C. to 50 ° C., more preferably in the range of −10 ° C. to 20 ° C.
The reaction time is usually 5-30 minutes.

Step A2
Step A2 is a step for producing the compound having the formula (2) by reacting the acetal produced in Step A1 with an acid and an acid anhydride in a tube reactor.
In this step, about 0.3 equivalents of acid and about 2 equivalents of acid anhydride may be used.
The solvent that can be used for the reaction is the same solvent as Step A1.
In Step A2, for example, a solvent such as N, N-dimethylacetamide (DMAc) can be added and the reaction can be performed at a concentration of about 2 mol / L.
The reaction temperature is preferably in the range of 120 ° C to 300 ° C, more preferably in the range of 180 ° C to 250 ° C.
The reaction time is usually 10-40 minutes.
In a tube reactor, a pressure of about 5 bar is appropriate as a back pressure.

Step A3
Step A3 is a step of producing a compound having the general formula (4) by reacting the compound having the formula (2) produced in Step A2 with Meldrum's acid or a derivative thereof in a tube reactor.
Also in this step, about 1 equivalent of Meldrum's acid or its derivative may be used.
The solvent that can be used for the reaction is the same solvent as Step A1.
In Step A3, for example, a solvent such as N, N-dimethylacetamide (DMAc) can be added and the reaction can be performed at a concentration of about 2 mol / L.
The reaction temperature is preferably in the range of 50 ° C to 100 ° C, more preferably 60 ° C to 80 ° C.
The reaction time is usually 10-30 minutes.

(2)
Method for producing a compound having the general formula (4) by a condensation reaction between the compound having the general formula (3) and Meldrum's acid or a derivative thereof

(Each symbol in the formula is the same as above.)
Meldrum acid or a derivative thereof, and a base are added to a solution of the compound having the general formula (3), and then the reaction is performed by heating.
Solvents that can be used include ether solvents such as tetrahydrofuran and 1,2-dimethoxyethane, alcohol solvents such as methanol, ethanol, and 2-propanol, hydrocarbon solvents such as toluene, nitrile solvents such as acetonitrile, and acetic acid. Aliphatic ester solvents such as ethyl or amide solvents such as N, N-dimethylacetamide and N, N-dimethylformamide are suitable, and polar solvents such as acetonitrile and N, N-dimethylacetamide are particularly suitable. It is.
The base that can be used is usually the base used, but is preferably morpholine.
The reaction temperature is usually preferably 20-40 ° C.
The reaction time is usually preferably about 30 minutes.

The symbols used in the scheme have the same significance as above.

Step B1
Step B1 is a step in which enamine is produced from amine and aldehyde by performing reaction in a column reactor.
The equivalent amount of the reagent used in synthesizing the compound having the general formula (4) is theoretically equivalent to 1 equivalent, but in many usual reactions, no improvement in yield is observed. On the other hand, in the case of flow synthesis, the equivalents of all reagents can be obtained in a sufficiently high yield with one equivalent or a small excess. For example, the compound having the general formula (4) can be obtained in a sufficiently high yield by using one equivalent or a small excess of each reagent relative to normal butyraldehyde.
Solvents that can be used in the reaction are more efficient for flow synthesis when the solvents are unified. In such a case, ether solvents such as tetrahydrofuran and 1,2-dimethoxyethane, methanol, ethanol, 2-propanol, etc. Alcohol solvents such as toluene, hydrocarbon solvents such as toluene, nitrile solvents such as acetonitrile, aliphatic ester solvents such as ethyl acetate, or amide solvents such as N, N-dimethylacetamide and N, N-dimethylformamide In particular, polar solvents such as acetonitrile and N, N-dimethylacetamide are suitable. In Step B1, the reaction can be carried out smoothly without using a solvent.
The reaction temperature is preferably in the range of −30 ° C. to 50 ° C., and more preferably near room temperature.
The reaction time is usually 5-30 minutes.
In the column reactor, a pressure of about 40 psi is appropriate as the back pressure.

Step B2
Step B2 is a step in which the enamine produced in Step B1 is reacted with allyl halide in a tube reactor to produce a compound having the general formula (3).
Also in this step, about 1 equivalent of allyl halide may be used.
The solvent that can be used for the reaction is the same solvent as Step B1.
In Step B2, for example, a solvent such as acetonitrile (MeCN) or N, N-dimethylacetamide (DMAc) can be added and the reaction can be performed at a concentration of about 2 mol / L.
The reaction temperature is preferably in the range of 60 ° C to 180 ° C, more preferably in the range of 100 ° C to 150 ° C.
The reaction time is usually 30-40 minutes.
In a tube reactor, a pressure of about 100 psi is appropriate as a back pressure.

Step B3
Step B3 is a step of producing a compound having the general formula (4) by reacting the compound having the general formula (3) generated in Step B2 with Meldrum's acid or a derivative thereof in a tube reactor.
Also in this step, about 1 equivalent of Meldrum's acid or its derivative may be used.
The solvent that can be used for the reaction is the same solvent as Step B1.
In Step B3, for example, a solvent such as N, N-dimethylacetamide (DMAc) can be added and the reaction can be performed at a concentration of about 0.5 mol / L.
The reaction temperature is preferably in the range of 50 ° C to 100 ° C, more preferably 60 ° C to 80 ° C.
The reaction time is usually 10-15 minutes.

(3)
Method for producing a compound having the formula (1) by adding a base to a compound having the general formula (4)

(Each symbol in the formula is the same as above.)
A compound having the formula (1) is obtained by adding a base to a solution of the compound having the general formula (4) and then heating.
Solvents that can be used are N, N-dimethylacetamide (DMAc), N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), diglyme, sulfolane, xylene, propylene carbonate, benzonitrile, cyclohexanone, chlorobenzene, Anisole, dibutyl ether, normal butyl acetate, methyl isobutyl ketone and acetophenone are preferred, and N, N-dimethylacetamide (DMAc) is preferred.
Bases that can be used are preferably potassium acetate, pyridine, diazabicycloundecene (DBU), triethylamine, potassium fluoride, 1,2,4-triazole, imidazole, pyrazole, 1,2,3-benzotriazole N-hydroxysuccinimide, more preferably imidazole.
The reaction temperature is usually preferably 120-220 ° C, more preferably 120 ° C.
The reaction time is usually preferably 10 minutes to 48 hours, more preferably 15 hours.

In this step, the reaction time can be shortened by using microwaves and heating.
The microwave that can be used is usually preferably 5-150 W, and more preferably 150 W.

(Four)
Method for producing a compound having the formula (1) after hydrolyzing (and partially decarboxylating) the compound having the general formula (4) to obtain a compound having the formula (6)

(Each symbol in the formula is the same as above.)
Step4-1
Step of hydrolyzing (and partially decarboxylating) a compound having the general formula (4) to form a compound having the formula (6) In this step, N, N-dimethyl is used as a solvent in the presence of water. Perform using acetamide (DMAc) or toluene.
In this step, the reaction temperature is usually 160-180 ° C., and the reaction time is 5-10 minutes.
Step4-2
A step of heating a compound having formula (6) (including a partially decarboxylated compound) to form a compound having formula (1). In this step, in the presence of acetic anhydride and triethylamine,
Solvents that can be used: N, N-dimethylacetamide (DMAc), toluene Reaction temperature: 120-180 ° C
Reaction time: 30 minutes-12 hours

(Five)
A method for producing a compound having the formula (1) after once obtaining a compound having the general formula (5) or (5 ′) by adding a base to the compound having the general formula (4)

(Each symbol in the formula is the same as above.)
Step 5-1: Step of obtaining a compound having the general formula (5) or (5 ′) Bases that can be used:
When the base used is an amine, primary amines, secondary amines, tertiary amines and the like are considered. Particularly suitable are amines such as benzylamine for primary amines, morpholine, pyrrolidine, piperidine, imidazole, etc. for secondary amines, and diazabicycloundecene (DBU) for tertiary amines and 1 , 4-diazabicyclo [2.2.2] octane (DABCO) and the like.
When the base used is an organic acid base, an alkali metal or alkaline earth metal salt of a C2-C6 alkyl carboxylic acid is preferable, and examples thereof include sodium acetate and potassium acetate.
When the base used is an inorganic base, it may be a base having an alkali metal or an alkaline earth metal, an alkali metal salt of a carboxylic acid, an alkaline earth metal salt, an alkali metal salt of an alcohol or an alkaline earth metal Salt is good.
The equivalent of the base to be used varies depending on the kind of the base to be used, but usually the equivalent of the base to be added is preferably in the range of 0.5 to 3 equivalents, particularly preferably in the range of 0.9 to 1.5 equivalents. The equivalent amount of the reagent used in the synthesis of the compound having the general formula (4) is theoretically equivalent to 1 equivalent, but in many reactions, no improvement in yield is observed.
Solvents that can be used include ether solvents such as tetrahydrofuran and 1,2-dimethoxyethane, alcohol solvents such as methanol, ethanol, and 2-propanol, hydrocarbon solvents such as toluene, nitrile solvents such as acetonitrile, and acetic acid. Aliphatic ester solvents such as ethyl or amide solvents such as N, N-dimethylacetamide and N, N-dimethylformamide are suitable, and polar solvents such as acetonitrile and N, N-dimethylacetamide are particularly good. .
The reaction temperature can be any temperature as long as it is within the boiling point of the solvent, and is preferably carried out at around room temperature.
The reaction time is usually preferably 5 minutes to 2 hours.

Step 5-2: Step of obtaining a compound having the formula (1) The solvents that can be used are the same as those that can be used in Step C1.
The reaction temperature is in the range of 100 ° C. to 300 ° C., and particularly preferably in the range of 120 ° C. to 250 ° C.
The reaction time is usually preferably 10 minutes to 48 hours.

In the following, by the batch method and flow synthesis, the compound having the general formula (4) is passed through the compound having the general formula (5) or (5 ′), followed by heating to obtain the formula (1). A method for obtaining a compound having the above will be described.

(Each symbol in the formula is the same as above.)

Step C1
Step C1 is a step of treating a compound having the general formula (4) with a base to produce a compound having the general formula (5) which is a base adduct.
As a base for producing a base adduct from a compound having the general formula (4), that is, as a base for obtaining a compound having the general formula (5), a primary amine having a normal alkyl or aralkyl group, An aromatic primary amine, a secondary amine having an alkyl group, an araalkyl group, or the like, or an aromatic secondary amine, further a tertiary amine having an alkyl group or an aralkyl group, or an aromatic tertiary amine is preferable. Here, the base adduct refers to a reaction adduct of a Michael addition acceptor with a nucleophilic Lewis base.
When the base used is an amine, an amine such as benzylamine is preferable for a primary amine, and morpholine, pyrrolidine, piperidine, imidazole, or the like is preferable for a secondary amine.
When the base used is an organic acid base, an alkali metal salt or alkaline earth metal salt of a C2-C6 alkylcarboxylic acid is preferable, and examples thereof include sodium acetate and potassium acetate.
When the base used is an inorganic base, it may be a Lewis base capable of Michael addition, and may be a base having an alkali metal or an alkaline earth metal, such as potassium fluoride.
The equivalent of the base to be used varies depending on the kind of the base to be used, but usually the equivalent of the base to be added is preferably in the range of 0.5 to 3 equivalents, particularly preferably in the range of 0.9 to 1.5 equivalents. The equivalent amount of the reagent used in synthesizing the compound having the general formula (5) is theoretically equivalent to 1 equivalent, but in many reactions, no improvement in yield is observed.
On the other hand, in the case of flow synthesis, the compound having the general formula (5) can be obtained in a sufficiently high yield with the equivalent amount of all reagents being one equivalent or a small excess.
Solvents that can be used include ethers such as tetrahydrofuran and 1,2-dimethoxyethane, alcohols such as methanol, ethanol and 2-propanol, hydrocarbons such as toluene, nitriles such as acetonitrile, and acetic acid. Aliphatic ester solvents such as ethyl or amide solvents such as N, N-dimethylacetamide and N, N-dimethylformamide are suitable, and polar solvents such as acetonitrile and N, N-dimethylacetamide are particularly good. .
The reaction temperature can be any temperature as long as it is within the boiling point of the solvent, and is preferably carried out at around room temperature.
The reaction time is usually about 5 minutes to 2 hours.

Step C2
Step C2 is a step of heating the compound having the general formula (5) to generate the compound having the formula (1).
Solvents that can be used are the same as those that can be used in Step C1.
The reaction temperature is in the range of 100 ° C. to 300 ° C., and particularly preferably in the range of 120 ° C. to 250 ° C.

When a compound having the formula (1) is obtained only by heating the compound having the general formula (4), the bases to be added to the compound having the general formula (4) include imidazole and sodium acetate among the above-mentioned bases. Or potassium acetate is good.
When the compound having the formula (1) is obtained only by heating the compound having the general formula (4), the solvent includes ethers such as tetrahydrofuran, 1,2-dimethoxyethane, diglyme, methanol, ethanol, 2- Alcohol solvents such as propanol, hydrocarbon solvents such as toluene, nitrile solvents such as acetonitrile, aliphatic ester solvents such as ethyl acetate, or amides such as N, N-dimethylacetamide and N, N-dimethylformamide Suitable solvents are, for example, polar solvents such as acetonitrile and N, N-dimethylacetamide, and ether solvents such as diglyme.

When obtaining the compound having the formula (1) only by heating the compound having the general formula (4), the reaction temperature is in the range of 100 ° C. to 300 ° C., and particularly in the range of 120 ° C. to 250 ° C.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the scope of the present invention is not limited thereto.

The abbreviations used in the examples have the following significance.
DMAc: N, N-dimethylacetamide MeCN: Acetonitrile MW: Microwave MP-TsOH: Macroporous polystyrene sulfonic acid

: Sample loop (Inject sample solution and push out with pump)

: FT-IR (Measurement equipment, implemented inline)

(Production Example 1)
(1,1-bis (allyloxy) butane)
Acetal method (flow synthesis)

Prepare a mixture of butyraldehyde (75.1 g, 1.04 mol) and allyl alcohol (121.0 g, 2.08 mol), fill with a mixture of MS3A (48.0 g) and MP-TsOH (24.0 g), and cool to 0 C The mixture was passed through a jacketed column reactor (22 mm id, 30 cm) at a flow rate of 2.4 ml / min. The solution obtained by continuous operation for 30 minutes contained 56.68 g of the title compound (GC quantitative value, yield 95%).

(Production Example 2)
2-ethylpent-4-enal (2)
Compound (2) (flow synthesis)

1,1-bis (allyloxy) butane (20 g, 117.5 mmol), Ac ₂ O (24.0 g, 235.0 mmol) and Maleic acid (4.1 g, 35.2 mmol) were added to DMAc (60 mL). The mixed and completely dissolved solution was passed through a tube reactor (10 mL) heated to 220 ° C. at a flow rate of 1.00 mL / min. The solution obtained by continuous operation for 1.5 hours contained 10.5 g of the title compound (GC quantitative value, yield 89%).

(Example 1)
5- (2-Ethylpent-4-en-1-ylidene) -2,2-dimethyl-1,3-dioxane-4,6-dione (4 ')
(Example 1-1)
Compound (2) to Compound (4 ') (batch reaction)

2-ethylpent-4-enal (0.89 g, 7.94 mmol) is dissolved in DMAc (5.0mL), Meldrum's acid 1.4 (1.42g, 9.85 mmol), morpholine 8 (8μL, μ0.09 mmol) are added, and stirred at 25 、 C did. The completely dissolved solution was stirred at 60 ° C. for 2 hours. The resulting solution contained the title compound in an NMR quantitative value of 1.5 g (yield 80%).

(Example 1-2)
Compound (2) to Compound (4 ') (Flow synthesis)

To the DMAc solution obtained by the above method in which 2-ethylpent-4-enal (5.05 g, 45.0) mmol) was dissolved, Meldrum's (7.14 g, 49.5 mmol), morpholine (3.92 g, 45.0 mmol) were added, The mixture was stirred and dissolved at 0 ° C. The mixed and completely dissolved solution was passed through a tube reactor (10 mL) heated to 70 ° C at a flow rate of 0.33 mL / min. The solution obtained by continuous operation for 3 hours contained 8.90 g of the title compound (UPLC (registered trademark) quantitative value, yield 95%).

(Example 2)
5- (2-Ethylpent-4-en-1-ylidene) -2,2-dimethyl-1,3-dioxane-4,6-dione (4 ')
Enamine method (continuous 3 process flow)

The flow device was installed as described above. Feed A with diisobutylamine, Feed B with butyraldehyde, Feed C with DMAc solution of allyl bromide (24.20 g, 200 mmol) (100 mL, 2.0 M in total), Feed D with Meldrum acid (14.41 g, 100 mmol), morpholine (875 μL, 10.0 mmol) of DMAc solution (total 200 mL, 0.5 M against Meldrum's acid) was prepared. Feed A at 106 μL / min, Feed B at 55 μL / min, Feed C at 305 μL / min, Feed D at 1.20 mL / min, and a column packed with MS4A (30.00 g) as shown in the figure A reactor (15 mm id, 30 cm), a tube reactor heated to 120 ° C. (16 mL), and a tube reactor heated to 60 ° C. (10 mL × 2) were passed through. The solution obtained by continuous operation for 5 hours contained 26.79 g of the title compound (UPLC® quantitative value, yield 62%).
¹ H NMR (CDCl ₃ ) (500 MHz): δ = 0.92 (3H, t, J = 7.5 Hz), 1.42-1.53 (1H, m), 1.62-1.72 (1H, m), 1.74 (s, 6H) , 2.12-2.21 (1H, m), 2.33-2.42 (1H, m), 3.69-3.78 (1H, m), 4.97-5.06 (2H, m), 5.66-5.77 (1H, m), 7.63 (1H, d, J = 11.0 Hz).
¹³ C NMR (CDCl ₃ ) (125 MHz): δ = 11.8, 27.3, 27.59, 27.60, 38.5, 41.1, 104.8, 117.2, 118.8, 135.1, 159.9, 161.9, 171.7.

(Example 3)
3-ethylbicyclo [3.2.0] hept-3-en-6-one (1)
(Example 3-1)
Compound (4 ') to Compound (1) (batch reaction)

Compound (4 ') (200 mg, 0.839 mmol, content 86.1%) and imidazole (57.2 mg, 0.840 mmol) were added to DMAc (1.0 mL) at room temperature, followed by stirring at 120 ° C for 15 hours. After cooling to room temperature, it was diluted with MeCN and 1M hydrochloric acid, and the title compound was quantified with UPLC (registered trademark) (yield = 49.10 mg, yield = 56.6%).

(Example 3-2)
Compound (4 ') to Compound (1) (microwave reactor)

Compound (4 ') (100 mg, 0.420 mmol, 86.1% content) and imidazole (28.6 mg, 0.420 mmol) were added to DMAc (1.0 mL) at room temperature under a nitrogen atmosphere. Subsequently, the mixture was stirred for 10 minutes at 160 ° C. (Max 150 W) in a microwave reactor (CEM, Discover (registered trademark)), and then cooled to room temperature. The obtained reaction solution was diluted with MeCN and 1M hydrochloric acid, and the title compound was quantified with UPLC (registered trademark) (yield = 38.74 mg, yield = 81.2%).

(Example 3-3)
Compound (4 ') to Compound (1) (flow synthesis)

Compound (4 ′) (200 mg, 0.839 mmol, content 86.1%)) and imidazole (57.2 mg, 0.840 mmol) were added to DMAc (1.0 mL), and the mixture was stirred at room temperature. 1.0 mL (equivalent to 166.6 mg, 0.699 mmol) of the obtained solution (1.2 mL) was introduced into the sample loop (1.0 mL), and passed through a 10 ml tube reactor heated to 200 ° C. at 500 μL / min (residence time). 20 min). Subsequently, the reaction solution was diluted with MeCN and 1M hydrochloric acid, and the title compound (1) was quantified with UPLC (registered trademark) (yield = 58.23 mg, yield = 71.0%).

(Example 4)
5- [2-ethyl-1- (1H-imidazol-1-yl) pent-4-en-1-yl] -2,2-dimethyl-1,3-dioxane-4,6-dione (5 ')
Compound (4 ') → Compound (5'')

To the DMAc solution obtained in Example 1-2 in which the compound (4 ′) was dissolved, toluene (5 mL), water (5 mL), 5% (w / w) sodium bicarbonate water (2 mL) were added, Liquid separation was performed. The aqueous layer was re-extracted with toluene (2 mL). The obtained organic layers were matched, and liquid separation washing was repeated twice with 5% (w / w) sodium bicarbonate water (2 mL).
Thereafter, the mixture was washed with 0.5N hydrochloric acid (2 mL) and separated with water (2 mL). The obtained organic layer was substituted with MeCN, and imidazole (303 mg, 4.45 mmol) was added at room temperature under a nitrogen atmosphere. After stirring at room temperature for 30 minutes, the mixture was stirred at room temperature for 2 hours. The crystals were filtered, washed with MeCN (3 mL), and vacuum dried at 40 ° C. to obtain the title compound (1.18 g, yield 91.5%).

Compound (5 '):
¹ H NMR (CD ₂ Cl ₂ , 500 MHz): δ = 0.92 (3H, t, J = 7.0 Hz), 1.42-1.53 (1H, m), 1.59-1.60 (1H, m), 1.62-1.70 (1H , m), 1.72 (s, 6H), 2.14-2.20 (1H, m), 2.35-2.40 (1H, m), 3.64-3.71 (1H, m), 4.88-5.16 (3H, m), 5.69-5.82 (1H, m), 7.10 (1H, m), 7.58 (1H, d, J = 11.5 Hz), 7.73 (1H, s).

(Example 5)
3-ethylbicyclo [3.2.0] hept-3-en-6-one (1)
Compound (5 '') → Compound (1)

Compound (5 ″) (5.0 g, 16.3 mmol) was added to DMAc (100 mL), and dissolved by stirring at room temperature. The resulting solution (103.4 mL 97.5 g) was passed through a 10 ml tube reactor heated to 200 ° C. at 500 μL / min (retention time 20 minutes). Subsequently, the reaction solution was diluted with MeCN, and the title compound was quantified with UPLC (registered trademark) (yield = 1.63 g, yield = 73.7%).

Claims

A compound having the general formula (4) or a base adduct thereof.

(Wherein R 3 and R 4 each independently represent a hydrogen atom, a C1-C6 alkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, or R 3 and R 4 together with the same carbon atom to which they are attached represent a 3-6 membered cycloalkyl ring.)
A compound having the general formula (4) according to claim 1.
R 3 is a methyl group, an ethyl group, or a propyl group, and R 4 is a methyl group, an ethyl group, or a propyl group, or a compound having the general formula (4) according to claim 1, Base adduct.
2. The compound having the general formula (4) or a base adduct thereof according to claim 1, wherein R 3 is a methyl group and R 4 is a methyl group.
2. The process for producing a compound having the general formula (4) or a base adduct thereof according to claim 1, wherein the compound having the formula (2) and Meldrum's acid or a derivative thereof are used in the presence of a solvent and a base.

(Wherein R 3 and R 4 have the same meaning as described above.)
6. The production method according to claim 5, wherein R 3 is a methyl group, an ethyl group, or a propyl group, and R 4 is a methyl group, an ethyl group, or a propyl group.
6. The production method according to claim 5, wherein R 3 is a methyl group and R 4 is a methyl group.
The solvent is N, N-dimethylacetamide or toluene, and the base is any one selected from the group consisting of morpholine, N-methylpiperazine, N-ethylpiperazine, piperidine, pyrrolidine. The production method according to any one of the above.
The manufacturing method according to any one of claims 5 to 8, which is performed by flow synthesis.
2. The process for producing a compound having the general formula (4) or a base adduct thereof according to claim 1, wherein the compound having the general formula (3) and Meldrum's acid or a derivative thereof are used in the presence of a solvent and a base.

(Wherein R 1 and R 2 represent a C1-C6 alkyl group, or R 1 and R 2 together with the same nitrogen atom to which they are bonded represent a 4-6 membered saturated heterocyclyl group. X represents a halogen atom, and R 3 and R 4 have the same meaning as described above.)
R 1 is an ethyl group, a propyl group, an isopropyl group, or an isobutyl group, R 2 is an ethyl group, a propyl group, an isopropyl group, or an isobutyl group, or R 1 and R 2 are Bonded to the same nitrogen atom, piperidine or morpholine, R 3 is a methyl group, an ethyl group, or a propyl group, and R 4 is a methyl group, an ethyl group, or a propyl group, Item 11. The production method according to Item 10.
11. The production method according to claim 10, wherein R 1 is an isobutyl group, R 2 is an isobutyl group, R 3 is a methyl group, and R 4 is a methyl group.
The production method according to any one of claims 10 to 12, wherein the solvent is N, N-dimethylacetamide or acetonitrile.
The production method according to any one of claims 10 to 13, wherein the base is morpholine.
The manufacturing method according to any one of claims 10 to 14, which is performed by flow synthesis.
A process for producing a compound having the formula (1) using the compound having the general formula (4) according to claim 1 or a base adduct thereof in the presence of a solvent and a base.

(Wherein R 3 and R 4 have the same meaning as described above.)
17. The production method according to claim 16, wherein R 3 is a methyl group, an ethyl group, or a propyl group, and R 4 is a methyl group, an ethyl group, or a propyl group.
17. The production method according to claim 16, wherein R 3 is a methyl group and R 4 is a methyl group.
Solvent is N, N-dimethylacetamide (DMAc), N, N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), diglyme, sulfolane, xylene, propylene carbonate, benzonitrile, cyclohexanone, chlorobenzene, anisole, di- The production method according to any one of claims 16 to 18, wherein the production method is one or more selected from the group consisting of butyl ether, normal butyl acetate, methyl isobutyl ketone, and acetophenone.
Base consists of potassium acetate, pyridine, diazabicycloundecene (DBU), triethylamine, potassium fluoride, 1,2,4-triazole, imidazole, pyrazole, 1,2,3-benzotriazole, N-hydroxysuccinimide The production method according to any one of claims 16 to 19, which is any one selected from the group.
The manufacturing method according to any one of claims 16 to 20, which is performed by flow synthesis.
A compound having the formula (1) which undergoes a step of obtaining a compound having the general formula (6) or a salt thereof by hydrolysis using the compound having the general formula (4) according to claim 1 or a base adduct thereof. Manufacturing method.

(Wherein R 3 and R 4 have the same meaning as described above.)
23. The manufacturing method according to claim 22, which is performed by flow synthesis.
Using the compound having the general formula (4) according to claim 1 in the presence of a solvent or a base, the compound having the general formula (5) or (5 ′) is obtained, and then heated to obtain the formula ( A method for producing a compound having 1).

(Wherein R 3 and R 4 are as defined above, and R 5 and R 6 each independently represent a hydrogen atom, a C1-C6 alkyl group, an optionally substituted aryl group, or Represents an optionally substituted aralkyl group, or R 5 and R 6 together with the nitrogen atom to which they are bonded represent a heterocyclic group, R 7 represents a C1-C6 alkylcarbonyloxy group, halogen An atom or a succinimide-N-oxy group, and M represents a metal atom.)
R 3 is a methyl group, R 4 is a methyl group, and R 5 and R 6 are imidazolyl groups formed together with the nitrogen atom to which they are bonded, or R 7 is an acetoxy group or a fluorine atom. 25. The production method according to claim 24, wherein M is potassium or sodium.
26. The production method according to claim 24 or 25, wherein the solvent is N, N-dimethylacetamide.
27. The method for producing a compound having the formula (1) according to any one of claims 24-26, wherein the base is imidazole.
28. The production method according to any one of claims 24-27, which is performed by flow synthesis.
A method for producing a compound having the formula (1) by heating using a compound having the general formula (5) or (5 ′).

(Wherein R 3 , R 4 , R 5 , R 6 , R 7 and M have the same meaning as described above.)
A compound having the formula (1) is produced using the compound having the general formula (4) according to claim 1 or a base adduct thereof in the presence of a solvent and a base, and the compound having the formula (1) A method for producing a compound having the formula (1-6) or a salt thereof by using the compound having the formula (1-6).

(Wherein R 3 and R 4 have the same meaning as described above.)