JP7709969B2 - Method for producing aminoalkyltetrahydropyran derivatives - Google Patents

Description

The present invention relates to a method for producing an aminoalkyltetrahydropyran derivative, its salt, or a hydrate thereof, which is used for the treatment and/or prevention of pain.

A known method for producing aminoalkyltetrahydropyran derivatives used in the treatment and/or prevention of pain is to convert them to methyl 4-(3-methoxyphenyl)-3,6-dihydro-2H-pyran-5-carboxylate by a coupling reaction with methyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyran-5-carboxylate and an arylboronic acid, reduce the olefin by a hydrogenation reaction, and then isomerize the cis form to a trans form in the presence of a base. The ester is then reduced to convert the derivative to an alcohol derivative, which is then substituted with a dimethylamino group via sulfonylation, and then demethylated to derive the derivative (Patent Document 1).

International Publication No. 2019/156074

However, the method described in Patent Document 1 is not suitable for providing an aminoalkyltetrahydropyran derivative on an industrial scale because the demethylation reaction of methoxyphenol is carried out at a low temperature of −78° C., which is not suitable for industrial-scale production, and the yield is extremely low. In addition, the efficiency of the substitution of a sulfonyl group with a dimethylamino group is low, so that the method cannot be said to be an efficient production method.
A first object of the present invention is to provide a method for producing an aminoalkyltetrahydropyran derivative without using production conditions that are unsuitable for industrial-scale production, such as a reaction at -78°C.
A second object of the present invention is to provide a process for producing aminoalkyltetrahydropyrans in high yield.
It is sufficient for the present invention to achieve either the first object or the second object, and it is preferable for the present invention to achieve both of the first object and the second object.

As a result of intensive investigations, the present inventors have found a method for producing an aminoalkyltetrahydropyran derivative that can be synthesized in high yield without requiring low temperature conditions such as −78° C. by reacting an amine compound having a sulfonylated phenol skeleton with a base, and have thus completed the present invention.
That is, the present invention is as follows.

[1] The following general formula (1);
(wherein R ¹ to R ³ each independently represent a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, R ⁴ to R ⁵ each independently represent a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, and *1 and *2 represent asymmetric carbons), or a pharma- ceutically acceptable salt thereof, comprising the steps of:
(wherein R ¹ to R ⁵ , *1 and *2 are as defined above; Q represents a sulfonyl group), or a salt thereof, is reacted with a base to convert it into an aminoalkyltetrahydropyran derivative represented by formula (1) or a pharma- ceutically acceptable salt thereof.
[2] The process according to [1], wherein the amine compound (2) or a salt thereof is reacted with a base in an aqueous solvent.
[3] The production method according to [1] or [2], wherein R ¹ is a hydrogen atom.
[4] The production method according to any one of [1] to [3], wherein R ² and R ³ are hydrogen atoms.
[5] The production method according to any one of [1] to [4], wherein R ⁴ and R ⁵ are methyl groups.
[6] The production method according to any one of [1] to [5], wherein Q is a methanesulfonyl group or a p-toluenesulfonyl group.
[7] The following general formula (3);
(wherein R ¹ to R ³ , *1 and *2 are as defined above) is disulfonylated to give a phenol derivative (3) (hereinafter, sometimes referred to as compound (3)), represented by the following general formula (4):
(wherein R ¹ to R ³ , *1, *2, and Q are as defined above), followed by reacting the disulfonyl compound (4) with a secondary amine to produce the amine compound (2) or a salt thereof.
[8] The phenol derivative (3) is represented by the following general formula (5);
The method according to [ ^{7 ]} , characterized in that it comprises a step of producing the compound from an alcohol derivative (5) represented by the formula (5) (hereinafter, sometimes referred to as compound (5)):
[9] The aminoalkyltetrahydropyran derivative (1) is represented by the following formula (6a):
The process according to any one of [1] to [8], which is 3-[(3R,4R)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol, 3-[(3S,4S)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol, or a mixture of the two enantiomers thereof.
[10] The method according to any one of [1] to [9], wherein the aminoalkyltetrahydropyran derivative (1) is an active ingredient used for the treatment and/or prevention of pain.

According to the present invention, an aminoalkyltetrahydropyran derivative can be produced without using production conditions that are not suitable for industrial-scale production, such as a reaction at -78°C.
According to the present invention, an aminoalkyltetrahydropyran derivative can be produced in high yield.

The method for producing the aminoalkyltetrahydropyran derivative according to the present invention is described in detail below.

The product of the present invention, the aminoalkyltetrahydropyran derivative (1), is represented by the following formula (1a):
(In the formula, *1 and *2' represent asymmetric carbons, the main product is a trans enantiomer or a mixture thereof, and R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are the same as above. Hereinafter, this compound may be referred to as compound (1a).)
Or the following formula (1b):
(wherein *1 and *2" represent asymmetric carbons, the main product is a cis enantiomer or a mixture thereof, and ^R1 , ^R2 , ^R3 , ^R4 , and ^R5 are the same as above. Hereinafter, this may be referred to as compound (1b)).
The aminoalkyltetrahydropyran derivative (1) is preferably a trans enantiomer or a mixture thereof.
The trans and cis are determined based on the relationship between the phenyl group bonded to the carbon of *1 and the exocyclic methylene group bonded to the carbon of *2 (the methylene group of the aminomethyl group in the examples of compounds (1a) and (1b)). The "mixture thereof" means, for example, a mixture of enantiomers, and may be either an equal mixture (racemic mixture) or an unequal mixture of enantiomers.

Here, ^R1 represents a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms. Examples of the unsubstituted alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. Examples of the substituent of the substituted alkyl group include halogen atoms such as fluorine atom, chlorine atom, bromine atom, and iodine atom, nitro group, nitroso group, cyano group, hydroxyamino group, alkylamino group having 1 to 12 carbon atoms, dialkylamino group having 1 to 12 carbon atoms, aralkylamino group having 7 to 12 carbon atoms, diaralkylamino group having 7 to 12 carbon atoms, alkylsulfonylamino group having 1 to 12 carbon atoms, sulfonic acid group, sulfonamide group, azide group, trifluoromethyl group, carboxy group, acyl group having 1 to 12 carbon atoms, aroyl group having 7 to 12 carbon atoms, hydroxy group, alkyloxy group having 1 to 12 carbon atoms, acyloxy group having 1 to 12 carbon atoms, aroyloxy group having 7 to 12 carbon atoms, silyloxy group having 1 to 12 carbon atoms, alkylcarbonyloxy group having 1 to 12 carbon atoms, and alkylthio group having 1 to 12 carbon atoms. The number of the substituents is 1 to 5.
R ¹ is preferably a hydrogen atom or an unsubstituted alkyl group, and more preferably a hydrogen atom or a methyl group.

Here, R ² and R ³ independently represent a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms. Specific examples of these groups are the same as those exemplified in the description of R ^1. In addition, examples and the number of substituents that the alkyl group may have are also the same as those in the case of R ¹ .
R ² and R ³ are preferably a hydrogen atom or an unsubstituted alkyl group, more preferably a hydrogen atom or a methyl group. It is preferable that R ² and R ³ are the same.

Here, R ⁴ and R ⁵ independently represent a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms. Specific examples of the alkyl group represented by R ⁴ and R ⁵ are the same as those exemplified in the description of R ¹ above. In addition, examples and the number of substituents that the alkyl group may have are also the same as those in the case of R ^{1. R 4} and R ⁵ are preferably an unsubstituted alkyl group, and more preferably a methyl group.

The amine compound (2) which is a precursor in the present invention is represented by the following formula (2a):
(In the formula, *1 and *2', R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Q are the same as above. Hereinafter, this compound may be referred to as compound (2a). Compound (2a) is a trans enantiomer or a mixture thereof.)
Or the following formula (2b):
(wherein *1 and *2'', R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Q are the same as above. Hereinafter, this may be referred to as compound (2b). Compound (2b) is a cis enantiomer or a mixture thereof.) is preferred.
The distinction between trans and cis and the meaning of "a mixture thereof" are the same as for compound (1a) and compound (1b).
The amine compound (2) is more preferably a trans enantiomer or a mixture thereof (compound (2a)).

Here, Q represents a sulfonyl group, and a group in which -C(=O)- of an acyl group is replaced with -S(=O) ₂ - is preferable. Examples of the sulfonyl group include alkanesulfonyl groups having 1 to 4 carbon atoms, which may have a halogen atom bonded to the alkane moiety, such as a methanesulfonyl group, an ethanesulfonyl group, or a trifluoromethanesulfonyl group; benzenesulfonyl groups having an alkyl group having 1 to 4 carbon atoms, a halogen atom, or the like, which may be bonded to the benzene ring, such as a benzenesulfonyl group, a p-toluenesulfonyl group, an o-chlorobenzenesulfonyl group, an m-chlorobenzenesulfonyl group, a p-chlorobenzenesulfonyl group, an o-nitrobenzenesulfonyl group, an m-nitrobenzenesulfonyl group, or a p-nitrobenzenesulfonyl group; and a (+)-10-camphorsulfonyl group. The sulfonyl group is preferably a methanesulfonyl group or a p-toluenesulfonyl group, and more preferably a methanesulfonyl group.

By using the amine compound (2) or a salt thereof as a precursor and hydrolyzing the sulfonyl group using a base, it is possible to avoid the demethylation reaction under low-temperature conditions that are not suitable for industrial-scale production, such as a reaction at -78°C, and to produce the aminoalkyltetrahydropyran derivative (1) or a pharma- ceutically acceptable salt thereof in high yield.

The amine compound (2) or a salt thereof can be produced by aminating the disulfonyl compound (4) obtained by disulfonylation of a phenol derivative (3) (e.g., by aminating by reaction with a secondary amine).

The phenol derivative (3) is represented by the following formula (3a):
(In the formula, *1 and *2', R ¹ , R ² and R ³ are the same as above. Hereinafter, this may be referred to as compound (3a). Compound (3a) is a trans enantiomer or a mixture thereof.)
Or the following formula (3b):
(wherein *1 and *2″, R ¹ , R ² and R ³ are the same as above. Hereinafter, this may be referred to as compound (3b). Compound (3b) is a cis enantiomer or a mixture thereof).
The distinction between trans and cis and the meaning of "a mixture thereof" are the same as for compound (1a) and compound (1b).
The phenol derivative is more preferably a trans enantiomer or a mixture thereof (compound (3a)).

The disulfonyl compound (4) is represented by the following formula (4a):
(In the formula, *1 and *2', R ¹ , R ² , R ³ and Q are the same as above. Hereinafter, the compound may be referred to as compound (4a). Compound (4a) is a trans enantiomer or a mixture thereof.)
Or the following formula (4b):
(wherein *1 and *2'', R ¹ , R ² , R ³ and Q are the same as above. Hereinafter, this may be referred to as compound (4b). Compound (4b) is a cis enantiomer or a mixture thereof.) is preferred.
The distinction between trans and cis and the meaning of "a mixture thereof" are the same as for compound (1a) and compound (1b).
The disulfonyl compound is preferably a trans enantiomer or a mixture thereof (compound (4a)).

In the present invention, the amine compound can be produced in good yield by aminating the disulfonyl compound (4) obtained from the phenol derivative (3).

Furthermore, the phenol derivative (3) can be produced, for example, by demethylating the alcohol derivative (5).

The alcohol derivative (5) is represented by the following formula (5a):
(In the formula, *1 and *2', R ¹ , R ² and R ³ are the same as above. Hereinafter, this may be referred to as compound (5a). Compound (5a) is a trans enantiomer or a mixture thereof.)
Or the following formula (5b):
(wherein *1 and *2″, R ¹ , R ² and R ³ are the same as above. Hereinafter, this may be referred to as compound (5b). Compound (5b) is a cis enantiomer or a mixture thereof.) is preferred.
The distinction between trans and cis and the meaning of "a mixture thereof" are the same as for compound (1a) and compound (1b).
The alcohol derivative (5) is preferably a trans enantiomer or a mixture thereof (compound (5a)).

The alcohol derivative (6) is more preferably represented by the following formula (6a):
The compound is 3-[(3R,4R)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol, 3-[(3S,4S)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol, or a mixture of the two enantiomers thereof.

In the present invention, the demethylation reaction from the alcohol compound (5) does not require low-temperature conditions that are unsuitable for industrial-scale production, such as a reaction at −78° C., and can produce the phenol derivative in high yield.

Next, the production method of the above aminoalkyltetrahydropyran derivatives will be described.

Step 1: A step of producing an aminoalkyltetrahydropyran derivative (1) or a pharma- ceutically acceptable salt thereof from an amine compound (2) or a salt thereof.
(In the formula, *1 and *2, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Q are the same as above.)
This step is a step of producing compound (1) by reacting compound (2) or a salt thereof with a base in a solvent.

The reaction solvent in this step is not particularly limited as long as it does not affect the reaction, and examples of the reaction solvent include water; alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, tert-butanol, and ethylene glycol; aromatic hydrocarbon solvents such as benzene and toluene; aliphatic hydrocarbon solvents such as pentane, hexane, heptane, and methylcyclohexane; halogen-based solvents such as carbon tetrachloride, chloroform, methylene chloride, 1,2-dichloroethane, and chlorobenzene; ester solvents such as ethyl acetate, isopropyl acetate, and tert-butyl acetate; sulfoxide solvents such as dimethyl sulfoxide; amide solvents such as N,N-dimethylformamide and N,N-dimethylacetamide; urea solvents such as dimethylpropyleneurea; phosphonic acid triamide solvents such as hexamethylphosphonic acid triamide; ketone solvents such as acetone and methyl ethyl ketone; and nitrile solvents such as acetonitrile and propionitrile. Water, tert-butanol, tetrahydrofuran, and 2-methyltetrahydrofuran are preferred, and water is even more preferred. These may be used alone or in combination of two or more. When two or more types are used in combination, the mixing ratio is not particularly limited. When two or more types are used in combination, a mixed solvent of water and a solvent other than water is preferable.

The amount of the solvent used is preferably 50 times by weight or less, more preferably 20 times by weight or less, relative to the compound (2) or a salt thereof, since too much is undesirable in terms of cost and post-treatment. The lower limit is preferably 0.1 times by weight or more, more preferably 0.5 times by weight or more, relative to the compound (2) or a salt thereof. If the amount is within this range, the cost is not too high and post-treatment is easy.

Examples of bases used for hydrolysis in this step include tertiary amines such as triethylamine, tri-n-butylamine, N-methylmorpholine, N-methylpiperidine, diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, and 1,4-diazabicyclo[2,2,2]octane; metal hydroxides such as lithium hydroxide, sodium hydroxide, barium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, and calcium hydroxide; metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; metal alkoxides such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, and potassium tert-butoxide; and metal hydrides such as sodium hydride. Preferred are metal hydroxides and metal alkoxides, more preferred are lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, magnesium hydroxide and calcium hydroxide, further preferred are sodium hydroxide and potassium hydroxide, and particularly preferred is sodium hydroxide.

The amount of the base used is preferably 0.1 to 50 times the molar amount of compound (2) or a salt thereof, and more preferably 1 to 20 times the molar amount.

The reaction temperature in this process is preferably -40 to 150°C, more preferably -20 to 100°C, and even more preferably 40 to 100°C, in order to shorten the reaction time while suppressing side reactions.

There is no particular restriction on the reaction time of this step and it may be set appropriately, but it is preferably 0.001 to 72 hours, and more preferably 0.1 to 48 hours.

In this process, the order and method of mixing the compound (2) or a salt thereof, the base, and the reaction solvent are not particularly limited.

As a treatment after the reaction is completed, a general treatment for obtaining the target substance from the reaction solution may be performed. For example, water may be added to the reaction solution after the reaction is completed as necessary to obtain a basic aqueous solution containing the target substance, and a washing operation may be performed to recover the target substance in the aqueous layer using a general organic solvent such as methylene chloride, diethyl ether, toluene, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, etc.

As a method for obtaining a target substance from a basic aqueous solution containing the target substance (such as a reaction mixture containing water or the aqueous layer recovered by washing with the organic solvent), a common extraction solvent, such as methylene chloride, diethyl ether, toluene, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, etc., is added to the basic aqueous solution containing the target substance, and an acid is also added. By adding an acid, the basic aqueous solution containing the target substance becomes a basic, neutral, or acidic aqueous solution, and the target substance is extracted into the extraction solvent, thereby obtaining an extract.

The acid may be, for example, hydrogen sulfates such as sodium hydrogen sulfate and potassium hydrogen sulfate; dihydrogen phosphates such as sodium dihydrogen phosphate and potassium dihydrogen phosphate; inorganic acids such as hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, nitric acid, phosphoric acid, and boric acid; carboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, pivalic acid, chloroacetic acid, trichloroacetic acid, trifluoroacetic acid, oxalic acid, L-tartaric acid, D-tartaric acid, and mandelic acid; methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or camphorsulfonic acid, and more preferably potassium dihydrogen phosphate and hydrogen chloride. Hydrogen chloride is a gas and difficult to handle, so hydrochloric acid may be used instead. These may be used alone or in combination of two or more. When using two or more, the mixing ratio is not particularly limited.

The basic, neutral, or acidic aqueous solution preferably has a pH of 5 to 11, more preferably a pH of 6 to 9.5 or less, and particularly preferably a pH of 6.5 to 10.

The organic layer may be recovered by an extraction process in which the acid and an extraction solvent (organic solvent) are added, and the target substance may be re-extracted by adding the extraction solvent to the aqueous layer from which the acid has been removed. The aqueous layer from which the acid has been removed may be basic, neutral, or acidic. However, when the aqueous layer is acidic (particularly an acidic aqueous solution having a pH of 5 or less) (i.e., an acidic aqueous solution containing the target substance), it is preferable to add not only the general extraction solvent (methylene chloride, diethyl ether, toluene, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, etc.) but also a base (for example, a base similar to the base used in hydrolysis, preferably an alkali metal hydroxide such as sodium hydroxide) to the acidic aqueous solution containing the target substance, as a method of obtaining the target substance from the acidic aqueous solution. By adding a base to the acidic aqueous solution, the pH can be adjusted to the preferred range (more preferably, a basic aqueous solution can be obtained), and a liquid (extracted liquid) in which the target substance is dissolved in the extraction solvent (organic solvent) can be obtained by layer separation.

The resulting extract (organic layer) is subjected to reduced pressure heating or other procedures to distill off the extraction solvent, yielding the target product. The target product thus obtained is of sufficient purity to be used in subsequent processes, but may be further purified by common purification techniques such as crystallization, column chromatography, and activated carbon treatment to increase its purity.

The solvent (hereinafter referred to as the crystallization solvent) used for crystallization of the compound (1) or a pharma- ceutically acceptable salt thereof (hereinafter referred to as the compound (1) or a salt thereof) is not particularly limited, and examples thereof include alcohol-based solvents, ether-based solvents, aliphatic hydrocarbon-based solvents, aromatic hydrocarbon-based solvents, ketone-based solvents, ester-based solvents, and nitrile-based solvents. Specific examples of these include the solvents exemplified as the reaction solvent. Preferred are alcohol-based solvents and nitrile-based solvents, more preferably ethanol, isopropanol, and acetonitrile, and particularly preferably acetonitrile. These may be used alone or in combination of two or more kinds. When two or more kinds are used in combination, the mixing ratio is not particularly limited.

The amount of the crystallization solvent used is preferably 50 times or less by weight, more preferably 20 times or less by weight, relative to the compound (1) or a salt thereof, since too much is undesirable in terms of cost and post-treatment. The lower limit is preferably 0.1 times or more by weight, more preferably 0.5 times or more by weight, relative to the compound (1) or a salt thereof. If the amount is within this range, the cost is not too high and post-treatment is easy.

The method for crystallization is not particularly limited, but examples thereof include the following methods, which may be appropriately selected depending on the combination of organic solvents.
(a) A method in which the compound (1) or a salt thereof is dissolved in an organic solvent and then cooled to cause crystallization.
(b) A method in which the compound (1) or a salt thereof is dissolved in an organic solvent, and then a good solvent is added or the solution is concentrated and replaced with a poor solvent to cause crystallization.
(c) A method in which the compound (1) or a salt thereof is mixed in an organic solvent and reslurried.

Methods (a), (b), and (c) may be combined as appropriate to perform crystallization. Seed crystals may also be added during crystallization.

The temperature at which the crystallization methods (a) to (c) are carried out is not particularly limited, but may be appropriately selected depending on the type of solvent used, and may be set according to the target amount of precipitation and quality of crystals, preferably below the temperature at which compound (1) or a salt thereof dissolves in the solvent or mixed solvent used.

The compound (1) or a salt thereof precipitated by the above crystallization methods (a) to (c) can be separated and obtained by methods such as vacuum filtration, pressure filtration, or centrifugation. In addition, if the mother liquor remains in the obtained crystals and the purity of the crystals decreases, the quality can be improved by further washing with an organic solvent, if necessary.

The preferred method for drying the crystals is reduced pressure (vacuum drying) at temperatures below approximately 60°C to avoid thermal decomposition or melting.

Step 2: A step of converting the phenol derivative (3) into a disulfonyl compound (4), followed by producing the compound (2) or a salt thereof.
(In the formula, *1 and *2, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Q are the same as above.)

Disulfonylation Step This step is a step in which a phenol derivative represented by the formula (3) is treated with a sulfonylating agent in the presence of a base in a solvent to produce a disulfonyl compound represented by the formula (4).

The reaction solvent in this step is not particularly limited as long as it does not affect the reaction, and examples thereof include aromatic hydrocarbon solvents, halogenated solvents, ether solvents, etc. Specific examples of these include the solvents exemplified as reaction solvents in step 1. Aromatic hydrocarbon solvents and halogenated solvents are preferred, and toluene or methylene chloride is particularly preferred. These may be used alone or in combination of two or more types. When two or more types are used in combination, the mixing ratio is not particularly limited.

The amount of the solvent used is preferably 50 times or less by weight relative to the compound (3), more preferably 20 times or less by weight, since too much is undesirable in terms of cost and post-treatment. The lower limit is preferably 0.1 times or more by weight relative to the compound (3), more preferably 0.5 times or more by weight. Within such a range, the cost is not too high and post-treatment is easy.

Examples of bases used in the disulfonylation in this step include tertiary amines, metal hydroxides, metal hydrogen carbonates, metal alkoxides, metal hydrides, etc. Specific examples of these include the bases exemplified as bases used in the hydrolysis in step 1. Preferred are tertiary amines, more preferred are triethylamine, tri-n-butylamine, N-methylmorpholine, N-methylpiperidine, and diisopropylethylamine, and particularly preferred is triethylamine.

The amount of the base used is preferably 0.1 to 50 times the molar amount of compound (3), and more preferably 1 to 20 times the molar amount of compound (3).

Examples of the sulfonylating agent used in this step include halides (chlorides, bromides, etc.) of the sulfonyl group represented by Q, and acid anhydrides. Preferred are methanesulfonyl chloride, methanesulfonyl fluoride, methanesulfonyl bromide, methanesulfonic anhydride, ethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, o-chlorobenzenesulfonyl chloride, m-chlorobenzenesulfonyl chloride, p-chlorobenzenesulfonyl chloride, o-nitrobenzenesulfonyl chloride, m-nitrobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, trifluoromethanesulfonyl anhydride, (+)-10-camphorsulfonyl chloride, etc. More preferred are methanesulfonyl chloride or p-toluenesulfonyl chloride, and even more preferred is methanesulfonyl chloride.

The amount of the sulfonylating agent used is preferably 0.1 to 50 times the molar amount of compound (3), and more preferably 2 to 10 times the molar amount.

The reaction temperature for the disulfonylation in this process is preferably -40 to 80°C, more preferably -20 to 50°C, in order to shorten the reaction time while suppressing side reactions.

There is no particular restriction on the reaction time for disulfonylation in this process and it may be set appropriately, but it is preferably 0.001 to 24 hours, and more preferably 0.1 to 12 hours.

In the disulfonylation process of this step, the mixing order and method of compound (3), base, sulfonylating agent, and reaction solvent are not particularly limited.

Treatment after the reaction can be carried out in the usual manner to obtain the product from the reaction solution. For example, water can be added to the reaction solution after the reaction is completed to wash it, or, if necessary, an acidic solution such as an aqueous hydrochloric acid solution, an aqueous sulfuric acid solution, or an aqueous ammonium chloride solution can be added to wash it. Extraction can also be carried out using a common extraction solvent, such as toluene, methylene chloride, diethyl ether, ethyl acetate, hexane, tetrahydrofuran, or 2-methyltetrahydrofuran. The reaction solvent and extraction solvent can be distilled off from the resulting extract by reducing pressure, heating, or other operations to obtain the target product.

The target product obtained in this manner has sufficient purity for use in subsequent steps, but the purity may be further increased by common purification techniques such as fractional distillation, column chromatography, activated carbon treatment, and crystallization in order to further increase the yield of the subsequent steps or the purity of the compound obtained in the subsequent steps.

Amination Step This step is a step in which a secondary amine is allowed to act on the compound (4) in a solvent to produce the compound (2) or a salt thereof.

There are no particular limitations on the reaction solvent as long as it does not affect the reaction, and examples include water, amide solvents, and ether solvents. Specific examples of these include the solvents exemplified as reaction solvents in step 1. Preferred are water, tetrahydrofuran, and N,N-dimethylformamide, and more preferably water. These may be used alone or in combination of two or more types. When two or more types are used in combination, the mixing ratio is not particularly limited.

The amount of the solvent used is preferably 50 times or less by weight relative to the compound (4), and more preferably 20 times or less by weight, since too much is undesirable in terms of cost and post-treatment. The lower limit is preferably 0.1 times or more by weight relative to the compound (4), and more preferably 0.5 times or more by weight. Within such a range, the cost is not too high and post-treatment is easy.

The secondary amine used in the amination in this step includes NHR ⁴ R ⁵ (wherein R ⁴ and R ⁵ are the same as above), for example, dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, pyrrolidine, piperidine, and morpholine, and preferably dimethylamine. Since dimethylamine is a gas and difficult to handle, dimethylamine hydrochloride or an aqueous dimethylamine solution may be used instead. An aqueous dimethylamine solution is particularly preferred.

The amount of the secondary amine used is preferably 0.1 to 100 times the molar amount of compound (4), more preferably 1 to 50 times the molar amount, and particularly preferably 20 times the molar amount.

The reaction temperature in this process is preferably -40 to 150°C, more preferably -20 to 120°C, and even more preferably 40 to 100°C, in order to shorten the reaction time while suppressing side reactions.

There is no particular restriction on the reaction time of this step and it may be set appropriately, but it is preferably 0.001 to 72 hours, and more preferably 0.1 to 48 hours.

In this process, the mixing order and mixing method of the compound (4), secondary amine, and reaction solvent are not particularly limited.

After the reaction is complete, the reaction solution may be subjected to a general extraction process using a general extraction solvent such as methylene chloride, diethyl ether, toluene, ethyl acetate, tetrahydrofuran, or 2-methyltetrahydrofuran.

The extract (organic layer) containing the target substance thus obtained may be acidified by adding water and an acid to the extract to obtain an acidic aqueous solution (aqueous layer) containing the target substance, in order to further increase the yield in the subsequent step or the purity of the compound obtained in the subsequent step. By transferring the target substance to the aqueous layer, organic impurities can be reduced.

Examples of acids to be added to the extract containing the target compound (2) include hydrogen sulfates such as sodium hydrogen sulfate and potassium hydrogen sulfate; dihydrogen phosphates such as sodium dihydrogen phosphate and potassium dihydrogen phosphate; inorganic acids such as hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, nitric acid, phosphoric acid, and boric acid; carboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, pivalic acid, chloroacetic acid, trichloroacetic acid, trifluoroacetic acid, oxalic acid, L-tartaric acid, D-tartaric acid, and mandelic acid; methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid, and more preferably potassium hydrogen sulfate and hydrogen chloride. Hydrogen chloride is difficult to handle as a gas, so hydrochloric acid may be used instead. These may be used alone or in combination of two or more. When two or more are used in combination, the mixing ratio is not particularly limited.

The acidic aqueous solution preferably has a pH of 7 or less, more preferably a pH of 6 or less, and particularly preferably a pH of 5 or less.

Next, as a method for obtaining the target substance from the acidic aqueous solution containing the target substance in the organic layer, a common extraction solvent, such as methylene chloride, diethyl ether, toluene, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, etc., is added to the acidic aqueous solution containing the target substance, and a base is added to make it a basic aqueous solution, thereby obtaining an extract (organic layer).

Examples of the base to be added to the acidic aqueous solution containing the target substance include tertiary amines, metal hydroxides, metal hydrogen carbonates, metal alkoxides, etc. Specific examples of these include the bases exemplified as the base to be used for hydrolysis in step 1. Metal hydroxides are preferred, and sodium hydroxide is more preferred. Note that solid sodium hydroxide is deliquescent and difficult to handle, so an aqueous sodium hydroxide solution may be used instead.

The basic aqueous solution preferably has a pH of 7 or higher, more preferably a pH of 8 or higher, and particularly preferably a pH of 9 or higher.

The target product is obtained by distilling off the extraction solvent from the obtained extract by heating under reduced pressure or the like. Alternatively, the target product may not be obtained in the organic layer, but a salt of compound (2) may be obtained by removing water from the acidic aqueous solution containing the target product. The target product thus obtained (compound (2) or a salt thereof) has a sufficient purity for use in the subsequent steps, but may be further purified by common purification techniques such as crystallization, column chromatography, and activated carbon treatment in order to increase the purity.

The solvent used for the crystallization of the compound (2) is not particularly limited, and examples thereof include alcohol-based solvents, ether-based solvents, aliphatic hydrocarbon-based solvents, aromatic hydrocarbon-based solvents, ketone-based solvents, ester-based solvents, and nitrile-based solvents. Specific examples of these include the solvents exemplified as reaction solvents in step 1. Preferred are alcohol-based solvents and aliphatic hydrocarbon-based solvents, and more preferred is ethanol. These may be used alone or in combination of two or more types. When two or more types are used in combination, the mixing ratio is not particularly limited.

The amount of the solvent used is preferably 50 times or less by weight relative to the compound (2), and more preferably 20 times or less by weight, since too much is undesirable in terms of cost and post-treatment. The lower limit is preferably 0.1 times or more by weight relative to the compound (2), and more preferably 0.5 times or more by weight. Within such a range, the cost is not too high and post-treatment is easy.

The crystallization method can be the same as the crystallization method for compound (1) described above.

The drying method for the crystals can be carried out in the same manner as the drying method for compound (1) described above.

Step 3: A step of producing the compound (3) from the alcohol derivative (5)
(In the formula, *1 and *2, R ¹ , R ² , and R ³ are the same as above.)
This step is a step of producing the compound (3) by reacting an acid and a scavenger with the alcohol derivative (5) represented by the formula (5) in a solvent.

There are no particular limitations on the reaction solvent as long as it does not affect the reaction, and aromatic hydrocarbon solvents, aliphatic hydrocarbon solvents, halogenated solvents, ester solvents, sulfoxide solvents, amide solvents, urea solvents, phosphonic acid triamide solvents, ketone solvents, nitrile solvents, etc. can be used. Specific examples of these include the solvents exemplified as reaction solvents in step 1. Aromatic hydrocarbon solvents and halogenated solvents are preferred, and toluene or methylene chloride is particularly preferred. These may be used alone or in combination of two or more types. When two or more types are used in combination, the mixing ratio is not particularly limited.

The amount of the solvent used is preferably 50 times or less by weight relative to the compound (5), more preferably 20 times or less by weight, since too much is undesirable in terms of cost and post-treatment. The lower limit is preferably 0.1 times or more by weight relative to the compound (5), more preferably 0.5 times or more by weight. Within such a range, the cost is not too high and post-treatment is easy.

The acid used in this step includes Lewis acids such as boron halides, such as boron trifluoride, boron trichloride, and boron tribromide, and aluminum halides, such as aluminum chloride (III) and aluminum bromide (III), and solvates thereof, with aluminum chloride (III) being preferred. For boron trifluoride, boron trifluoride diethyl ether complex may be used.

The amount of the acid used is preferably 0.01 to 20 times the molar amount of compound (5), and more preferably 0.1 to 10 times the molar amount.

Examples of scavengers used in this process include thiols such as methanethiol, ethanethiol, butanethiol, octanethiol, dodecanethiol, and thioglycolic acid; and thioethers such as dimethyl sulfide, diethyl sulfide, tetrahydrothiophene, and thioanisole. Thiols are preferred, and thiols having approximately 6 to 15 carbon atoms, such as 1-dodecanethiol, are even more preferred.

The amount of the capture agent used is preferably 0.01 to 20 times the molar amount of compound (5), and more preferably 0.1 to 10 times the molar amount.

This process can be carried out at an extremely low temperature of -78°C, but has the advantage that such extremely low temperatures are not required. The reaction temperature in this process is preferably -40 to 200°C, more preferably -20 to 150°C, and particularly preferably -10 to 50°C, in order to shorten the reaction time while suppressing side reactions.

There is no particular restriction on the reaction time of this step and it may be set appropriately, but it is preferably 0.001 to 72 hours, and more preferably 0.1 to 48 hours.

In the reaction of this process, the mixing order and mixing method of the compound (5), acid, scavenger, and reaction solvent are not particularly limited.

As a treatment after the reaction is completed, a general treatment for obtaining the target substance from the reaction solution may be carried out. For example, water may be added to the reaction solution after the reaction is completed, and an extraction operation may be carried out using a general extraction solvent such as methylene chloride, diethyl ether, toluene, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, etc. If necessary, an inorganic salt such as sodium chloride may be added to improve the extraction efficiency of the target substance. The inorganic salt may be a solid, or an aqueous solution of an inorganic salt with no particular concentration restriction may be used.

The extract thus obtained containing the target substance may be made basic by adding water and a base or an aqueous solution of a base to the extract in order to further increase the yield in the subsequent step or the purity of the compound obtained in the subsequent step, thereby obtaining a basic aqueous solution containing the target substance.

Examples of bases to be added to the extract include tertiary amines, metal hydroxides, metal bicarbonates, metal alkoxides, etc. Specific examples of these include the bases exemplified as the base used for hydrolysis in step 1. Metal hydroxides are preferred, and sodium hydroxide is more preferred. Note that solid sodium hydroxide is deliquescent and difficult to handle, so an aqueous solution of sodium hydroxide may be used instead.

The basic aqueous solution preferably has a pH of 7 or higher, more preferably a pH of 8 or higher, and particularly preferably a pH of 9 or higher.

Next, as a method for obtaining the target substance from a basic aqueous solution containing the target substance, a common extraction solvent, such as methylene chloride, diethyl ether, toluene, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, etc., is added to the basic aqueous solution containing the target substance, and an acid is added to make it an acidic aqueous solution, thereby obtaining an extract.

Examples of the acid include inorganic acids such as hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, nitric acid, phosphoric acid, and boric acid; carboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, pivalic acid, chloroacetic acid, trichloroacetic acid, trifluoroacetic acid, oxalic acid, L-tartaric acid, D-tartaric acid, and mandelic acid; and more preferably, hydrogen chloride. Note that hydrogen chloride is a gas and difficult to handle, so hydrochloric acid may be used instead.

The acidic aqueous solution preferably has a pH of 7 or less, more preferably a pH of 6 or less, and particularly preferably a pH of 5 or less.

The resulting extract may be washed by adding water or an aqueous solution such as an aqueous sodium chloride solution. The reaction solvent and extraction solvent are distilled off from the resulting extract by procedures such as heating under reduced pressure to obtain the target product. The target product thus obtained is of sufficient purity for use in subsequent processes, but may be further purified by common purification techniques such as crystallization, column chromatography, and activated carbon treatment to increase the purity.

The solvent used for crystallization of the compound (3) is not particularly limited, and examples thereof include ether-based solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, cyclopentyl methyl ether, and diethyl ether; alcohol-based solvents, aliphatic hydrocarbon-based solvents, aromatic hydrocarbon-based solvents, ketone-based solvents, ester-based solvents, and nitrile-based solvents. Specific examples of these include the solvents exemplified as reaction solvents in step 1. Preferred are alcohol-based solvents and nitrile-based solvents, and more preferred is acetonitrile. These may be used alone or in combination of two or more types. When two or more types are used in combination, the mixing ratio is not particularly limited.

The amount of the solvent used is preferably 50 times or less by weight relative to the compound (3), more preferably 20 times or less by weight, since too much is undesirable in terms of cost and post-treatment. The lower limit is preferably 0.1 times or more by weight relative to the compound (2), more preferably 0.5 times or more by weight. Within such a range, the cost is not too high and post-treatment is easy.

The crystallization method can be the same as the crystallization method for compound (1) described above.

The drying method for the crystals can be carried out in the same manner as the drying method for compound (1) described above.

This application claims the benefit of priority based on Japanese Patent Application No. 2020-106516, filed on June 19, 2020. The entire contents of the specification of Japanese Patent Application No. 2020-106516, filed on June 19, 2020, are incorporated by reference into this application.

The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to the following examples, and it is of course possible to carry out the invention with appropriate modifications within the scope of the above and below-mentioned aims, all of which are included in the technical scope of the present invention. In the following, unless otherwise specified, "%" means "mass %" and "area %" means area percentage.

In the following examples, the HPLC analysis conditions used are as follows:

Analysis conditions 1
Measuring equipment: Agilent 1220 Infinity
Column: YMC Meteoric Core C18 (150 x 4.6 mm)
Flow rate: 1.5ml/min
Detection wavelength: 210 nm
Injection volume: 10μl
Column temperature: 40°C
Mobile phase A: 0.1% phosphoric acid aqueous solution Mobile phase B: acetonitrile Gradient conditions (mobile phase B concentration, time): 15% (0 min) → 80% (8 to 15 min) → 15% (15.1 to 20 min)

Analysis conditions 2
Measuring equipment: Agilent 1220 Infinity
Column: YMC Meteoric Core C18 (150 x 4.6 mm)
Flow rate: 1.5ml/min
Detection wavelength: 210 nm
Injection volume: 10μl
Column temperature: 40°C
Mobile phase A: 10 mM sodium lauryl sulfate aqueous solution (pH 2)
Mobile phase B: acetonitrile Gradient conditions (mobile phase B concentration, time): 30% (0 min) → 70% (8 to 15 min) → 30% (15.1 to 20 min)

In the following examples, the mass spectrometry measurement conditions used are as follows:

Measurement equipment: Waters ACQUITY UPLC H-Class
Column: BEH (50 x 2.1 mm, 1.7 μm)
Flow rate: 0.74ml/min
Detection wavelength: 190-400 nm
Injection volume: 10μl
Column temperature: 40°C
Mobile phase A: 0.1% formic acid/ _H2O
Mobile phase B: 0.1% formic acid / acetonitrile Gradient conditions (mobile phase B concentration, time): 10% (0 min) → 90% (4.5 min) → 10% (4.5-5.0 min)
Mass spectrometry: ESI (Electron Spray Ionization)

In the following examples, nuclear magnetic resonance spectra (hereinafter referred to as ¹ H NMR) were measured using tetramethylsilane as a standard substance and expressed as δ values (ppm). Deuterated chloroform (hereinafter referred to as CDCl ₃ ) was used as the measurement solvent.

The symbols used in the Examples section have the following meanings.
DIPEA: N,N-diisopropylethylamine (TfO) ₂ O: trifluoromethanesulfonic anhydride NaOMe: sodium methoxide THF: tetrahydrofuran LiAlH ₄ : lithium aluminum hydride

(Reference Example) Preparation of a mixture (7a) of [(3R,4R)-4-(3-methoxyphenyl)tetrahydropyran-3-yl]-methanol and [(3S,4S)-4-(3-methoxyphenyl)tetrahydropyran-3-yl]-methanol

Preparation of methyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyran-5-carboxylate (8)

Methyl 4-oxotetrahydropyran-3-carboxylate (40.0 g, 252.9 mmol) was dissolved in dichloromethane (400 g), DIPEA (65.4 g, 505.8 mmol) was added, and the mixture was cooled to 0° C. (TfO) ₂ O (78.5 g, 278.2 mmol) was added dropwise, and the mixture was stirred at 0° C. for 10 minutes. After confirming the completion of the reaction under analysis condition 1, the reaction mixture was washed twice with a 5% aqueous sodium hydrogen carbonate solution (200 g) and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain compound (8) as an oil (124.8 g, pure amount 73.4 g, 252.9 mmol, yield 100%).
^1H NMR (500MHz, _CDCl3 ): δ4.45-4.46 (t, 2H, J=2.5Hz), 3.88-3.91 (t, 2H, J=5.5Hz), 3.82 (s, 3H), 2.52-2.56 (m, 2H).

Preparation of methyl 4-(3-methoxyphenyl)-3,6-dihydro-2H-pyran-5-carboxylate (9)

Methyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyran-5-carboxylate (8) (124.8 g, pure amount 73.4 g, 252.9 mmol) was dissolved in 1,4-dioxane (400 g), and 3-methoxyphenylboronic acid (40.4 g, 265.5 mmol) and potassium carbonate (52.4 g, 379.4 mmol) were added and suspended. After nitrogen replacement, [1,1'-bis(diphenylphosphinoferrocene)]dichloropalladium(II) (1.9 g, 2.5 mmol) was added, heated to 110°C, and stirred overnight under reflux. After confirming the completion of the reaction under analysis condition 1, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water (300 g) and ethyl acetate (100 g) were added to the concentrate and mixed, and the layers were separated to recover the organic layer (organic layer A). The aqueous layer after layer separation was washed twice with ethyl acetate (200 g), and the resulting washing liquid (organic layer) was mixed with the organic layer (organic layer A) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain compound (9) as an oily compound (57.3 g, pure content 56.0 g, 225.6 mmol, yield 89.2%).
^1H NMR (500MHz, _CDCl3 ): δ7.25-7.28 (t, 1H, J = 7.8Hz), 6.83-6.86 (dd, 1H, J = 2.5Hz, 8.5Hz), 6.74-6.75 (m, 1H), 6.70 (m, 1H), 4.44-4.46 (t, 2H, J=2.8Hz), 3.88-3.91 (t, 2H, J=5.8Hz), 3.80 (s, 3H), 3.51 (s, 3H), 2.49-2.52 (m, 2H).

Preparation of mixture of methyl (3R,4R)-4-(3-methoxyphenyl)tetrahydropyran-3-carboxylate and methyl (3S,4S)-4-(3-methoxyphenyl)tetrahydropyran-3-carboxylate (10b)

Methyl 4-(3-methoxyphenyl)-3,6-dihydro-2H-pyran-5-carboxylate (9) (108.3 g, pure content 105.7 g, 425.9 mmol) was dissolved in ethyl acetate (161.5 g) and ethanol (713.0 g). After adding and mixing 10% palladium carbon (32.5 g) wet with about 50% water under a nitrogen atmosphere, the atmosphere was replaced with hydrogen and the mixture was stirred at room temperature for 2.5 hours. After confirming the completion of the reaction under analysis condition 1, the reaction mixture was filtered through Celite, and the filter cake was washed with ethyl acetate (200 ml), and the washing liquid and the filtrate were combined. The mixture of the washing liquid and the filtrate was concentrated under reduced pressure to obtain compound (10b) as an oily compound (106.0 g, pure content 90.6 g, 362.0 mmol, yield 85.0%).
^1H NMR (500MHz, _CDCl3 ): δ7.22-7.25 (t, 1H, J = 8.0Hz), 6.86-6.88 (d, 1H, J = 8.5Hz), 6.83 (m, 1H), 6 75-6.78 (dd, 1H, J=2.5Hz, 8.0Hz), 4.28-4.31 (dd, 1H, J=1.0Hz, 12.0Hz), 4. 18-4.22 (m, 1H), 3.80 (s, 3H), 3.74-3.79 (m, 1H), 3.55-3.60 (m, 1H), 3.53 (s , 3H), 3.05-3.08 (m, 1H), 2.92 (s, 1H), 2.70-2.79 (m, 1H), 1.72-1.75 (m, 1H).

Preparation of mixture of methyl (3S,4R)-4-(3-methoxyphenyl)tetrahydropyran-5-carboxylate and methyl (3R,4S)-4-(3-methoxyphenyl)tetrahydropyran-5-carboxylate (10a)

Methanol (525.1 g) was added to a mixture (10b) (104.9 g, pure content 89.7 g, 358.2 mmol) of (3R,4R)-4-(3-methoxyphenyl)tetrahydropyran-3-methyl carboxylate and (3S,4S)-4-(3-methoxyphenyl)tetrahydropyran-3-methyl carboxylate, and the mixture was dissolved. A 28% NaOMe/methanol solution (82.6 g, pure content 23.1 g, 428.4 mmol) was added, and the mixture was stirred at 70° C. for 1 hour. After confirming the completion of the reaction under analysis condition 1, the reaction mixture was cooled to room temperature and added to a 10% aqueous ammonium chloride solution (419.4 g). After concentrating under reduced pressure, ethyl acetate (419.4 g) was added and mixed, and the layers were separated to obtain an organic layer (organic layer A). The aqueous layer after layer separation was washed with ethyl acetate (419.4 g). The obtained washing liquid (organic layer) was mixed with the organic layer (organic layer A). The mixture was washed with a 10% aqueous sodium chloride solution (104.9 g) to remove the aqueous layer, and the organic layer was then concentrated under reduced pressure to obtain compound (10a) as an oily compound (104.5 g, pure content 90.7 g, 362.1 mmol, yield 101.2%).
^1H NMR (500MHz, _CDCl3 ): δ7.20-7.24 (m, 1H), 6.80-6.81 (d, 1H, J = 8.0Hz), 6.75-6.77 (m, 2H), 4.16-4.19 (dd, 1H, J = 4.5Hz, 11.5Hz), 4.06-4.09 (dd, 1H, J=4.0Hz, 11.5Hz), 3.80 (s, 3H), 3.52-3.58 (m, 2H), 3.48 (s, 3H), 3.01-3.06 (m, 1H), 2.90-2.95 (m, 1H), 1.77-1.90 (m, 2H).

Preparation of a mixture of [(3R,4R)-4-(3-methoxyphenyl)tetrahydropyran-3-yl]-methanol and [(3S,4S)-4-(3-methoxyphenyl)tetrahydropyran-3-yl]-methanol (7a)

A mixture (10a) (87.5 g, pure content 76.0 g, 303.8 mmol) of methyl (3S,4R)-4-(3-methoxyphenyl)tetrahydropyran-5-carboxylate and methyl (3R,4S)-4-(3-methoxyphenyl)tetrahydropyran-5-carboxylate was dissolved in THF (612.5 g) and cooled to −5° C., and LiAlH ₄ (8.6 g, 227.2 mmol) was added in portions. The mixture was stirred at −5° C. for 1 hour, and the completion of the reaction was confirmed under analysis condition 1, after which a 10% aqueous ammonium chloride solution (612.5 g) was added dropwise. Dichloromethane (612.5 g) was added, and the reaction mixture was filtered through Celite, and the filtrate was separated into layers to recover an organic layer (organic layer A). The aqueous layer after layer separation was washed twice with dichloromethane (612.5 g). The obtained washing liquid (organic layer) was mixed with the organic layer (organic layer A). The mixed liquid was washed with water (175.0 g) to remove the aqueous layer, and the organic layer was concentrated under reduced pressure. Toluene (262.5 g) was added and the mixture was concentrated again under reduced pressure to obtain compound (7a) as an oily compound (73.5 g, pure content 63.9 g, 287.4 mmol, yield 94.6%).
^1H NMR (500MHz, _CDCl3 ): δ7.23-7.26 (m, 1H), 6.81-6.83 (d, 1H, J=7.0Hz), 6.76-6.78 (m, 2H), 4.20-4.2 3 (dd, 1H, J = 4.0Hz, 11.0Hz), 4.04-4.07 (dd, 1H, J = 4.0Hz, 11.5Hz), 3.81 (s, 3H), 3 ．． 47-3.52 (m, 1H), 3.42-3.45 (m, 1H), 3.35-3.39 (t, 1H, J = 11.0Hz), 3.26-3.31 (m, 1H), 2.54-2.60 (m, 1H), 2.01-2.06 (m, 1H), 1.85-1.91 (m, 1H), 1.72-1.75 (m, 1H).

(Example 1) Preparation of a mixture of 3-[(3R,4R)-3-(hydroxymethyl)tetrahydropyran-4-yl]phenol and 3-[(3S,4S)-3-(hydroxymethyl)tetrahydropyran-4-yl]phenol (11a)

Dichloromethane (541.1 g) was added to a mixture (7a) (36.0 g, pure content 31.3 g, 140.7 mmol) of [(3R,4R)-4-(3-methoxyphenyl)tetrahydropyran-3-yl]-methanol and [(3S,4S)-4-(3-methoxyphenyl)tetrahydropyran-3-yl]-methanol, and the mixture was dissolved in dodecanethiol (71.2 g, 351.7 mmol) and cooled to 0° C. Aluminum chloride (III) (46.9 g, 351.7 mmol) was added in portions and stirred at room temperature for 20 hours. After confirming the completion of the reaction under analysis condition 1, water (312.7 g) was added to the reaction mixture, the mixture was stirred, and the layers were separated to recover the organic layer (organic layer A). Dichloromethane (180.0 g) and sodium chloride (80.0 g) were added to the aqueous layer obtained by the layer separation, and the organic layer obtained by layer separation was mixed with the organic layer (organic layer A), concentrated under reduced pressure, and the solvent was replaced with toluene (180.0 g), and then THF (50.0 g) was added and mixed. Water (93.8 g) was added, and the pH was adjusted to 13 using a 30% aqueous sodium hydroxide solution. Concentrated hydrochloric acid was added dropwise to the aqueous layer obtained by removing the organic layer, and the pH was adjusted to 7. Ethyl acetate (180.0 g) was added and mixed, and the pH was adjusted to 1 with concentrated hydrochloric acid, and the organic layer (organic layer B) was recovered by layer separation. After layer separation, the aqueous layer was washed with ethyl acetate (180.0 g), and the obtained washing liquid (organic layer) was mixed with the organic layer (organic layer B). The mixed liquid was then washed with 20% saline (31.3 g) to remove the aqueous layer. The organic layer was then concentrated under reduced pressure to obtain compound (11a) as a solid (25.2 g, pure content 23.1 g, 110.7 mmol, yield 78.7%).
^1H NMR (500MHz, _CDCl3 ): δ7.16-7.19 (t, 1H, J = 7.8Hz), 6.70-6.76 (m, 3H), 6.16 (s, 1H), 4.26-4.30 (dd, 1H, J =4.5Hz, 12.0Hz), 4.10-4.11 (dd, 1H, J = 4.0Hz, 11.5Hz), 3.51-3.55 (m, 1H), 3.44-3.47 (dd, 1H, J=3.5Hz, 11.0Hz), 3.35-3.40 (t, 1H, J=11.3Hz), 3.24-3.28 (dd, 1H, J=7.5Hz, 11.0Hz), 2.50-2.55 (m, 1H), 2.10-2.11 (m, 1H), 1.85-1.90 (m, 1H), 1.75-1.78 (m, 1H).

Example 2: Preparation of a mixture of 3-[(3R,4R)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol and 3-[(3S,4S)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol (6a)

(Example 2-1) Preparation of a mixture (12a) of [[(3R,4R)-4-(3-methylsulfonyloxyphenyl)tetrahydropyran-3-yl]methyl] methanesulfonate and [[(3S,4S)-4-(3-methylsulfonyloxyphenyl)tetrahydropyran-3-yl]methyl] methanesulfonate

A mixture of 3-[(3R,4R)-3-(hydroxymethyl)tetrahydropyran-4-yl]phenol and 3-[(3S,4S)-3-(hydroxymethyl)tetrahydropyran-4-yl]phenol (11a) (21.4 g, 102.5 mmol) was dissolved in dichloromethane (680.0 g), triethylamine (31.1 g, 307.6 mmol) was added, and the mixture was cooled to 0°C. Methanesulfonyl chloride (35.2 g, 307.6 mmol) was added dropwise, and the mixture was stirred at 0°C for 10 minutes, after which the completion of the reaction was confirmed under analysis condition 1. The reaction mixture was washed twice with a 10% aqueous ammonium chloride solution (310.0 g) to remove the aqueous layer, and the organic layer was washed twice with water (310.0 g) to remove the aqueous layer, and the obtained organic layer was concentrated under reduced pressure to obtain compound (12a) as an oil (43.4 g).

(Example 2-2) Preparation of a mixture (13a) of [3-[(3R,4R)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenyl] methanesulfonate and [3-[(3S,4S)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenyl] methanesulfonate

A 50% aqueous dimethylamine solution (74.0 g, pure content 37.0 g, 820.1 mmol) was added to a mixture (12a) (43.4 g) of methanesulfonate [[(3R,4R)-4-(3-methylsulfonyloxyphenyl)tetrahydropyran-3-yl]methyl] and methanesulfonate [[(3S,4S)-4-(3-methylsulfonyloxyphenyl)tetrahydropyran-3-yl]methyl], and the mixture was stirred at 80° C. overnight. After confirming the completion of the reaction under analysis condition 2, the reaction mixture was cooled to 20° C. and extracted twice with 2-methyltetrahydrofuran (164.5 g). The organic layers obtained by the two extractions were mixed, and a 5% aqueous potassium hydrogen sulfate solution (85.5 g) was added to the mixture, and the mixture was adjusted to pH 2 with concentrated hydrochloric acid, followed by layer separation to obtain an aqueous layer (aqueous layer A). Water (42.7 g) was added to the organic layer obtained by layer separation to wash it. The obtained washing liquid (aqueous layer) was mixed with the above-mentioned aqueous layer (aqueous layer A). The mixed liquid was adjusted to pH 11 by adding a 30% aqueous sodium hydroxide solution, and extracted with 2-methyltetrahydrofuran (85.5 g). The extract was concentrated under reduced pressure to obtain a 2-methyltetrahydrofuran solution (55.8 g) of compound (13a).
^1H NMR (500MHz, _CDCl3 ): δ7.37-7.40 (t, 1H, J = 7.8Hz), 7.14-7.18 (m, 3H), 4.40 (m, 1H), 4.05-4.08 (dd, 1H, J = 3.5Hz, 11.0Hz), 3.46-3.5 1 (m, 1H), 3.17-3.21 (m, 4H), 2.42-2.44 (m, 1H), 2.15 (m, 7H), 1.81-1.89 (m, 2H), 1.74-1.77 (m, 1H), 1.61 (m, 1H).

(Example 2-3) Preparation of a mixture of 3-[(3R,4R)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol and 3-[(3S,4S)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol (6a)

Water (50.0 g) was added to a 2-methyltetrahydrofuran solution (55.8 g) of a mixture (13a) of methanesulfonic acid [3-[(3R,4R)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenyl] and mixed, and 30% sodium hydroxide (41.0 g, pure content 12.3 g, 307.6 mmol) was added and stirred at 80° C. for 22.5 hours. After confirming the completion of the reaction under analysis condition 2, the reaction mixture was cooled to 20° C., and water (85.4 g) and dichloromethane (85.4 g) were added for washing and layer separation, and the target product was recovered in the aqueous layer. The obtained aqueous layer was washed with dichloromethane (85.4 g), and then the layers were separated and the target product was recovered in the aqueous layer again. Dichloromethane (85.4 g) was added to the aqueous layer after layer separation, and the pH was adjusted to 8 using potassium dihydrogen phosphate. The aqueous layer (aqueous layer A) was separated and removed, and the target substance was extracted into the organic layer side (organic layer A). Dichloromethane (85.4 g) was then added to the aqueous layer A to re-extract the target substance into the organic layer side (organic layer B). The obtained organic layer A and organic layer B were mixed, filtered (pore size 1 μm), and the filtrate was concentrated under reduced pressure. Acetonitrile (82.9 g) was added to the concentrate, stirred at 65 ° C. for 2 hours, cooled to 0 ° C., and the solid and mother liquor were separated by filter filtration, and the solid was washed with cold acetonitrile. The obtained wet crystals were dried under reduced pressure at 40 ° C. to obtain compound (6a) (19.0 g, 80.6 mmol, yield 78.6%, chemical purity 100 area%).
^1H NMR (500MHz, _CDCl3 ): δ7.16-7.19 (t, 1H, J = 8.3Hz), 6.73-6.75 (d, 1H, J = 8.0Hz), 6.68-6.69 ( m, 2H), 4.32-4.35 (dd, 1H, J = 11.5Hz, 2.5Hz), 4.04-4.07 (dd, 1H, J = 11.0H z, 4.5Hz), 3.46-3.51 (t, 1H, J=12.0Hz), 3.15-3.20 (t, 1H, J=10.8Hz), 2. 30-2.35 (m, 1H), 2.01-2.08 (m, 8H), 1.82-1.90 (m, 2H), 1.71-1.74 (m, 1H). MS (ESI) m/z: 236.4 (M+H) ⁺ .

The aminoalkyltetrahydropyran derivative (1) produced by the present invention can be used as an active ingredient for the treatment and/or prevention of pain.

Claims (10)

The following general formula (1):

(wherein R ¹ to R ³ each independently represent a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, R ⁴ to R ⁵ each independently represent a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, and *1 and *2 represent asymmetric carbons), or a method for producing a pharma- ceutical acceptable salt thereof, comprising the steps of:

(wherein R ¹ to R ⁵ , *1 and *2 are as defined above; Q represents a methanesulfonyl group, an ethanesulfonyl group, a trifluoromethanesulfonyl group, a benzenesulfonyl group, a p-toluenesulfonyl group, an o-chlorobenzenesulfonyl group, a m-chlorobenzenesulfonyl group, a p-chlorobenzenesulfonyl group, an o-nitrobenzenesulfonyl group, a m-nitrobenzenesulfonyl group, a p-nitrobenzenesulfonyl group or a (+)-10-camphorsulfonyl group ) is reacted with a base to convert the compound into an aminoalkyltetrahydropyran derivative represented by formula (1) or a pharma- ceutical acceptable salt thereof. The method according to claim 1, characterized in that the amine compound (2) or a salt thereof is reacted with a base in an aqueous solvent. The method according to claim 1 or 2, wherein R ¹ is a hydrogen atom. The method according to any one of claims 1 to 3, wherein R ² and R ³ are hydrogen atoms. The method according to any one of claims 1 to 4, wherein R ⁴ and R ⁵ are methyl groups. The method according to any one of claims 1 to 5, wherein Q is a methanesulfonyl group or a p-toluenesulfonyl group. The following general formula (3):

(wherein R ¹ to R ³ , *1 and *2 are the same as above) is disulfonylated to give a phenol derivative (3) represented by the following general formula (4):

(wherein R ¹ to R ³ , *1, *2 and Q are as defined above), followed by reacting the disulfonyl compound (4) with a secondary amine to produce the amine compound (2) or a salt thereof. The phenol derivative (3) is represented by the following general formula (5):

8. The process according to claim 7, comprising a step of producing the compound from an alcohol derivative (5) represented by the formula (wherein R ¹ to R ³ , *1 and *2 are as defined above). The aminoalkyltetrahydropyran derivative (1) is represented by the following formula (6a):

The process according to any one of claims 1 to 8, wherein the phenol is 3-[(3R,4R)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol represented by the formula (I), 3-[(3S,4S)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol represented by the formula (I), or a mixture of the two enantiomers thereof. The method according to any one of claims 1 to 9, characterized in that the aminoalkyltetrahydropyran derivative (1) is an active ingredient used for the treatment and/or prevention of pain.