Process for producing aminoalkyltetrahydropyran derivatives

Abstract

The purpose of the present invention is to provide a method for producing, at a high yield, an aminoalkyl tetrahydropyran derivative for use in the treatment and / or prevention of pain. The present invention is a production method in which a compound represented by formula (2) or a salt thereof is reacted with a base, to be converted to an alkyl tetrahydropyran derivative represented by formula (1) or a pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] The present invention relates to a method for producing an aminoalkyltetrahydropyran derivative, a salt thereof, or a hydrate thereof, which is used for the treatment and / or prevention of pain.

Background Art

[0002] As a method for producing an aminoalkyltetrahydropyran derivative used for the treatment and / or prevention of pain, 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyran-5-carboxylic acid methyl is converted to methyl 4-(3-methoxyphenyl)-3,6-dihydro-2H-pyran-5-carboxylate by a coupling reaction with arylboronic acid, the olefin is reduced by a hydrogenation reaction, then isomerization from the cis form to the trans form is carried out in the presence of a base, further conversion to an alcohol derivative by reduction of the ester, substitution to a dimethylamino group via sulfonylation, and then demethylation to induce the derivative is known (Patent Document 1).

[0003]

Chemical Formula

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] However, the method described in Patent Document 1 is not suitable for industrial-scale production because it is carried out under low-temperature conditions of -78°C for the demethylation reaction of methoxyphenol and the yield is extremely low. Therefore, it is not suitable for providing aminoalkyltetrahydropyran derivatives on an industrial scale. In addition, since the substitution efficiency from the sulfonyl group to the dimethylamino group is also poor, it is difficult to say that it is 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 not suitable for industrial-scale production such as the reaction at -78°C. A second object of the present invention is to provide a method for producing aminoalkyltetrahydropyran in a high yield. The present invention only needs to achieve one of the first object and the second object, and it is preferable to achieve both.

Means for Solving the Problems

[0006] As a result of intensive studies, the present inventors have found a method for producing an aminoalkyltetrahydropyran derivative that can be synthesized in a 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 completed the present invention. That is, the present invention is as follows.

[0007] [1] The following general formula (1);

Chemical formula

[10] The production method according to any one of [1] to [9], characterized in that the aminoalkyltetrahydropyran derivative (1) is an active ingredient used for the treatment and / or prevention of pain. [Advantages of the Invention]

[0008] 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 reactions at -78°C. According to the present invention, an aminoalkyltetrahydropyran derivative can be produced in a high yield. [Modes for Carrying Out the Invention]

[0009] Hereinafter, the production method of the aminoalkyltetrahydropyran derivative according to the present invention will be described in detail.

[0010] The aminoalkyltetrahydropyran derivative (1) which is the product of the present invention has the following formula (1a); [Chemical formula] (In the formula, *1 and *2' represent asymmetric carbons, the main product is the trans enantiomer or a mixture thereof, and R 1 , R 2 , R 3 , R 4 , R 5 is the same as described above. Hereinafter, it may be referred to as compound (1a).) or the following formula (1b);

Chemical formula

[0011] Here, R 1represents 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, a tert-butyl group, and the like. Examples of the substituent of the substituted alkyl group include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, a nitro group, a nitroso group, a cyano group, a hydroxyamino group, an alkylamino group having 1 to 12 carbon atoms, a dialkylamino group having 1 to 12 carbon atoms, an aralkylamino group having 7 to 12 carbon atoms, a dialkylamino group having 7 to 12 carbon atoms, an alkylsulfonylamino group having 1 to 12 carbon atoms, a sulfonic acid group, a sulfonamide group, an azide group, a trifluoromethyl group, a carboxy group, an acyl group having 1 to 12 carbon atoms, an aroyl group having 7 to 12 carbon atoms, a hydroxy group, an alkyloxy group having 1 to 12 carbon atoms, an acyloxy group having 1 to 12 carbon atoms, an aroyloxy group having 7 to 12 carbon atoms, a silyloxy group having 1 to 12 carbon atoms, an alkylcarbonyloxy group having 1 to 12 carbon atoms, or an alkylthio group having 1 to 12 carbon atoms, and the number of substituents is 1 to 5. R 1 is preferably a hydrogen atom or an unsubstituted alkyl group, more preferably a hydrogen atom or a methyl group.

[0012] Here, R 2 , R 3 each independently represents 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 the above R 1 . Also, examples of the substituents that the alkyl group may have and the number thereof are the same as those in the case of the above R 1 . R 2 , R 3 is preferably a hydrogen atom or an unsubstituted alkyl group, more preferably a hydrogen atom or a methyl group. R 2 and R 3 are preferably the same.

[0013] Here, R 4 , R 5 each independently represents a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms. R4 、R 5 Examples of the alkyl group represented by are the same as those exemplified in the description of the above R 1 . Also, examples and the number of substituents that the alkyl group may have are the same as those in the case of R 1 . R 4 、R 5 is preferably an unsubstituted alkyl group, more preferably a methyl group.

[0014] Further, the amine compound (2) which is a precursor in the present invention is represented by the following formula (2a);

Chemical formula

Chemical formula

[0015] Here, Q represents a sulfonyl group, and a group in which -C(=O)- of an acyl group is replaced by -S(=O)2- is preferred. 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 methanesulfonyl group, ethanesulfonyl group, trifluoromethanesulfonyl group; benzenesulfonyl groups, p-toluenesulfonyl group, o-chlorobenzenesulfonyl group, m-chlorobenzenesulfonyl group, p-chlorobenzenesulfonyl group, o-nitrobenzenesulfonyl group, m-nitrobenzenesulfonyl group, p-nitrobenzenesulfonyl group, etc., which may have an alkyl group having 1 to 4 carbon atoms, a halogen atom, etc. bonded to the benzene ring; (+)-10-camphorsulfonyl group and the like. The sulfonyl group is preferably a methanesulfonyl group or a p-toluenesulfonyl group, and more preferably a methanesulfonyl group.

[0016] By using the amine compound (2) or a salt thereof as a precursor and hydrolyzing the sulfonyl group using a base, a demethylation reaction under low-temperature conditions that is not suitable for industrial-scale production such as a reaction at -78 °C can be avoided, and the aminoalkyltetrahydropyran derivative (1) or a pharmaceutically acceptable salt thereof can be produced in a high yield.

[0017] Also, the amine compound (2) or a salt thereof can be produced by aminating a disulfonyl compound (4) obtained by disulfonylating a phenol derivative (3) (for example, by amination by reaction with a secondary amine).

[0018] The phenol derivative (3) has the following formula (3a):

Chemical formula

[0019] Further, the disulfonyl compound (4) is the following formula (4a); [Chemical formula] (In the formula, *1 and *2′, R 1 , R 2 , R 3 , Q are the same as described above. Hereinafter, it may be referred to as compound (4a). Compound (4a) is a trans enantiomer or a mixture thereof.) or the following formula (4b); [Chemical formula] (In the formula, *1 and *2′′, R 1 , R 2 , R 3 , Q are the same as described above. Hereinafter, it may be referred to as compound (4b). Compound (4b) is preferably a cis enantiomer or a mixture thereof.) The distinction between trans and cis and the meaning of "mixture thereof" are the same as those of compound (1a) and compound (1b). Preferably, the disulfonyl compound is a trans enantiomer or a mixture thereof (compound (4a)).

[0020] The amine compound can be produced in good yield by aminating the disulfonyl compound (4) obtained from the phenol derivative (3) in the present invention.

[0021] Furthermore, the phenol derivative (3) can be produced, for example, by demethylating an alcohol derivative (5).

[0022] The alcohol derivative (5) is represented by the following formula (5a);

Chemical formula

Chemical formula

[0023] More preferably, the alcohol derivative (6) is the following formula (6a);

Chemical formula

[0024] In the demethylation reaction of the alcohol compound (5) in the present invention, low-temperature conditions that are not suitable for production on an industrial scale, such as the reaction at -78 °C, are not required, and the phenol derivative can be produced in a high yield.

[0025] Next, a method for producing the aminoalkyltetrahydropyran derivative and the like will be described.

[0026] Step 1: Process for producing an aminoalkyltetrahydropyran derivative (1) or a pharmaceutically acceptable salt thereof from an amine compound (2) or a salt thereof [Chemical formula] (In the formula, *1 and *2, R 1 , R 2 , R 3 , R 4 , R 5 , and Q are the same as described above.) This step is a step of producing compound (1) by reacting a base with compound (2) or a salt thereof in a solvent.

[0027] As the reaction solvent for this process, there are no particular restrictions as long as it does not affect the reaction. For example, water; alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, tert-butanol, ethylene glycol, etc.; aromatic hydrocarbon solvents such as benzene, toluene, etc.; aliphatic hydrocarbon solvents such as pentane, hexane, heptane, methylcyclohexane, etc.; halogen solvents such as carbon tetrachloride, chloroform, methylene chloride, 1,2-dichloroethane, chlorobenzene, etc.; ester solvents such as ethyl acetate, isopropyl acetate, tert-butyl acetate, etc.; sulfoxide solvents such as dimethyl sulfoxide, etc.; amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.; urea solvents such as dimethylpropyleneurea, etc.; phosphonic acid triamide solvents such as hexamethylphosphoric triamide, etc.; ketone solvents such as acetone, methyl ethyl ketone, etc.; nitrile solvents such as acetonitrile, propionitrile, etc. can be used. Preferably, they are water, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, and more preferably water. These can be used alone or in combination of two or more. When using two or more in combination, the mixing ratio is not particularly limited. When using two or more in combination, it is preferably a mixed solvent of water and a solvent other than water.

[0028] Regarding the amount of solvent used, if it is too much, it is not preferable in terms of cost and post-treatment. Therefore, the upper limit is preferably 50 times the weight or less, more preferably 20 times the weight or less, based on the compound (2) or its salt. The lower limit is preferably 0.1 times the weight or more, more preferably 0.5 times the weight or more, based on the compound (2) or its salt. Within such a range, the cost is not too high and the post-treatment is also simple.

[0029] As the base used for the hydrolysis in this process, there are tertiary amines such as triethylamine, tri-n-butylamine, N-methylmorpholine, N-methylpiperidine, diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, 1,4-diazabicyclo[2,2,2]octane; metal hydroxides such as lithium hydroxide, sodium hydroxide, barium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide; metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate; metal hydrogencarbonates such as lithium hydrogencarbonate, sodium hydrogencarbonate, potassium hydrogencarbonate; metal alkoxides such as lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; metal hydrides such as sodium hydride. Preferably, they are metal hydroxides and metal alkoxides, more preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide, still more preferably sodium hydroxide or potassium hydroxide, and particularly preferably sodium hydroxide.

[0030] The amount of the base used is preferably 0.1 to 50 times the molar amount relative to the compound (2) or its salt, and more preferably 1 to 20 times the molar amount.

[0031] The reaction temperature in this process, while shortening the reaction time, for the purpose of suppressing side reactions, is preferably -40 to 150 °C, more preferably -20 to 100 °C, and still more preferably 40 to 100 °C.

[0032] There is no particular limitation on the reaction time in this process, and it can be set as appropriate. Preferably, it is 0.001 to 72 hours, and more preferably 0.1 to 48 hours.

[0033] In this process, the mixing order and mixing method of the compound (2) or its salt, the base, and the reaction solvent are not particularly limited.

[0034] As a post-reaction treatment, general treatments for obtaining the target product from the reaction solution may be performed. For example, water may be added to the reaction solution after the reaction as necessary to obtain a basic aqueous solution containing the target product, and a general organic solvent such as methylene chloride, diethyl ether, toluene, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, etc. may be used to perform a washing operation to recover the target product on the aqueous layer side.

[0035] As a method for obtaining the target product from the basic aqueous solution containing the target product (such as a reaction mixture containing water, an aqueous layer recovered by washing with the organic solvent, etc.), a general 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 product, and an acid is added. By adding the acid, the basic aqueous solution containing the target product becomes a basic, neutral, or acidic aqueous solution, and the target product is extracted to the extraction solvent side to obtain an extract.

[0036] Examples of the acid include bisulfates such as sodium bisulfate and potassium bisulfate; 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. Since hydrogen chloride is difficult to handle as a gas, 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.

[0037] 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.

[0038] An organic layer may be recovered by an extraction treatment in which the acid and an extraction solvent (organic solvent) are added, and the extraction solvent may be added again to the once-removed aqueous layer to re-extract the target substance. The once-removed aqueous layer may be basic, neutral, or acidic, but when it is acidic (especially acidic with a pH of 5 or less) (i.e., an acidic aqueous solution containing the target substance), as a method for obtaining the target substance from the acidic aqueous solution, not only the general extraction solvent (the methylene chloride, diethyl ether, toluene, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, etc.) but also a base (for example, the same base as the above-mentioned base used for hydrolysis. Preferably an alkali metal hydroxide such as sodium hydroxide) is preferably added. By adding a base to the acidic aqueous solution, the pH can be adjusted to the preferred range (more preferably, it can be made into a basic aqueous solution), and by performing liquid separation, a liquid (extract) in which the target substance is dissolved in the extraction solvent (organic solvent) can be obtained.

[0039] The obtained extract (organic layer) is subjected to an operation such as heating under reduced pressure to distill off the extraction solvent, and the target substance can be obtained. The target substance thus obtained has a sufficient purity for use in subsequent processes, but for the purpose of increasing the purity, the purity may be further increased by general purification methods such as crystallization, column chromatography, and activated carbon treatment.

[0040] The solvent used for crystallization of the compound (1) or a pharmaceutically acceptable salt thereof (hereinafter referred to as the compound (1) or its salt) (hereinafter referred to as the crystallization solvent) is not particularly limited, and examples include alcohol solvents, ether solvents, aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents, ketone solvents, ester solvents, and nitrile solvents. Specific examples thereof include the solvents exemplified as the reaction solvent. Preferably, they are alcohol solvents and nitrile solvents, more preferably ethanol, isopropanol, and acetonitrile, and particularly preferably acetonitrile. 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.

[0041] As the amount of the crystallization solvent used, if it is too much, it is not preferable in terms of cost and post-treatment. Therefore, it is preferably 50 times by weight or less, more preferably 20 times by weight or less, based on the compound (1) or a salt thereof. As the lower limit, it is preferably 0.1 times by weight or more, more preferably 0.5 times by weight or more, based on the compound (1) or a salt thereof. If it is within such a range, the cost is not too high and the post-treatment is also simple.

[0042] The method for performing crystallization is not particularly limited. For example, the following methods can be mentioned and can be appropriately selected according to 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 for crystallization. (b) A method in which the compound (1) or a salt thereof is dissolved in an organic solvent and then crystallization is carried out by adding a poor solvent or concentrating and replacing with a poor solvent. (c) A method in which the compound (1) or a salt thereof is mixed in an organic solvent and triturated.

[0043] The methods (a), (b), or (c) may be appropriately combined for crystallization. Also, a seed crystal may be added during crystallization.

[0044] The implementation temperature in the crystallization methods (a) to (c) above is not particularly limited and may be appropriately selected according to the type of solvent used. Preferably, it is set below the temperature at which the compound (1) or a salt thereof dissolves in the solvent or mixed solvent used, according to the target precipitation amount and the quality of the crystal.

[0045] The compound (1) or a salt thereof precipitated by the crystallization methods (a) to (c) above can be separated and obtained by methods such as vacuum filtration, pressure filtration, or centrifugation. Also, when 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 as necessary.

[0046] As the method for drying the crystals, it is preferable to perform vacuum drying (under reduced pressure) at about 60 °C or lower while avoiding thermal decomposition and melting.

[0047] Step 2: Process for converting a phenol derivative (3) into a disulfonyl compound (4), and subsequently producing the compound (2) or a salt thereof

Chem.

[0048] Disulfonylation step This step is a step of producing a disulfonyl compound represented by the formula (4) by treating a phenol derivative represented by the formula (3) with a sulfonylating agent in the presence of a base in a solvent.

[0049] The reaction solvent in this step is not particularly limited as long as it does not affect the reaction. Examples thereof include aromatic hydrocarbon solvents, halogen solvents, ether solvents and the like. Specific examples thereof include the solvents exemplified as the reaction solvent in Step 1. Preferably, they are aromatic hydrocarbon solvents or halogen solvents, and particularly preferably toluene or methylene chloride. 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.

[0050] The amount of the solvent used is preferably 50 times by weight or less, more preferably 20 times by weight or less, based on the compound (3), because too much is not preferable 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, based on the compound (3). Within such a range, the cost is not too high and the post-treatment is simple.

[0051] Examples of the base used for the disulfonylation in this process include tertiary amines, metal hydroxides, metal hydrogen carbonates, metal alkoxides, metal hydrides and the like. Specific examples thereof include the bases exemplified as the base used for hydrolysis in Step 1. Tertiary amines are preferred, triethylamine, tri-n-butylamine, N-methylmorpholine, N-methylpiperidine, diisopropylethylamine are more preferred, and triethylamine is particularly preferred.

[0052] The amount of the base used is preferably 0.1 to 50 times the molar amount relative to the compound (3), and more preferably 1 to 20 times the molar amount.

[0053] Examples of the sulfonylating agent in this process include halides (chlorides, bromides, etc.) of the sulfonyl group represented by Q, acid anhydrides and the like. Preferably, 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, trifluoromethanesulfonic anhydride, (+)-10-camphorsulfonyl chloride and the like. More preferably, methanesulfonyl chloride or p-toluenesulfonyl chloride, and even more preferably methanesulfonyl chloride.

[0054] The amount of the sulfonylating agent used is preferably 0.1 to 50 times the molar amount relative to the compound (3), and more preferably 2 to 10 times the molar amount.

[0055] The reaction temperature for the disulfonylation in this process is preferably -40 to 80°C, and more preferably -20 to 50°C, for the purpose of shortening the reaction time while suppressing side reactions.

[0056] There is no particular limitation on the reaction time of the disulfonylation in this process, and it may be set as appropriate. Preferably, it is 0.001 to 24 hours, more preferably 0.1 to 12 hours.

[0057] In the disulfonylation of this process, the mixing order and mixing method of the compound (3), base, sulfonylating agent, and reaction solvent are not particularly limited.

[0058] As the treatment after the reaction is completed, general treatment for obtaining the product from the reaction solution may be performed. For example, water is added to the reaction solution after the reaction is completed for washing, or if necessary, an acid aqueous solution such as hydrochloric acid aqueous solution, sulfuric acid aqueous solution, ammonium chloride aqueous solution, etc. is added for washing. Further, extraction may be performed using a general extraction solvent, such as toluene, methylene chloride, diethyl ether, ethyl acetate, hexane, tetrahydrofuran, 2-methyltetrahydrofuran, etc. The target product can be obtained by distilling off the reaction solvent and extraction solvent from the obtained extract by operations such as reduced pressure and heating.

[0059] The target product obtained in this way has sufficient purity for use in subsequent processes. However, for the purpose of further increasing the yield of subsequent processes or the purity of the compound obtained in subsequent processes, the purity may be further increased by general purification methods such as fractional distillation, column chromatography, activated carbon treatment, crystallization, etc.

[0060] Amination step This process is a process for producing the compound (2) or a salt thereof by allowing a secondary amine to act on the compound (4) in a solvent.

[0061] The reaction solvent is not particularly limited as long as it does not affect the reaction. For example, water, amide solvents, ether solvents, etc. can be mentioned. Specific examples thereof include the solvents exemplified as the reaction solvent in Step 1. Preferably, they are water, tetrahydrofuran, N,N-dimethylformamide, and more preferably water. 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.

[0062] As the amount of the solvent used, if it is too large, it is not preferable in terms of cost and post-treatment. Therefore, it is preferably 50 times by weight or less, more preferably 20 times by weight or less, based on the compound (4). As the lower limit, it is preferably 0.1 times by weight or more, more preferably 0.5 times by weight or more, based on the compound (4). Within such a range, the cost is not too high and the post-treatment is also simple.

[0063] As the secondary amine used for the amination in this step, NHR 4 R 5 (In the formula, R 4 and R 5 are the same as above), and examples thereof include dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, pyrrolidine, piperidine, and morpholine. Dimethylamine is preferred. Since dimethylamine is difficult to handle as a gas, dimethylamine hydrochloride or an aqueous solution of dimethylamine may be used instead. An aqueous solution of dimethylamine is particularly preferred.

[0064] The amount of the secondary amine used is preferably 0.1 to 100 times the molar amount, more preferably 1 to 50 times the molar amount, and particularly preferably 20 times the molar amount, based on the compound (4).

[0065] The reaction temperature in this step is preferably -40 to 150 °C, more preferably -20 to 120 °C, and even more preferably 40 to 100 °C, for the purpose of shortening the reaction time while suppressing side reactions.

[0066] There is no particular limitation on the reaction time in this step, and it may be appropriately set. Preferably, it is 0.001 to 72 hours, more preferably 0.1 to 48 hours.

[0067] In this step, the mixing order and mixing method of the compound (4), the secondary amine, and the reaction solvent are not particularly limited.

[0068] As a treatment after the reaction is completed, nothing may be particularly done, and it may proceed to the subsequent process, or general treatment for obtaining the target substance from the reaction solution may be performed. For example, an extraction operation may be performed on the reaction solution after the reaction is completed using a general extraction solvent such as methylene chloride, diethyl ether, toluene, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, etc.

[0069] The extract (organic layer) containing the target substance thus obtained may be made acidic by adding water and an acid to the extract for the purpose of further increasing the yield of the subsequent process or the purity of the compound obtained in the subsequent process, and may be obtained as an acidic aqueous solution (aqueous layer) containing the target substance. By transferring the target substance to the aqueous layer side, organic impurities can be reduced.

[0070] Examples of the acid added to the extract containing the compound (2) which is the target substance include acid hydrogensulfates such as sodium hydrogensulfate and potassium hydrogensulfate; 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 hydrogensulfate and hydrogen chloride. Since hydrogen chloride is difficult to handle as a gas, 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.

[0071] 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.

[0072] Next, as a method for obtaining the target substance on the organic layer side from the acidic aqueous solution containing the target substance, a general 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).

[0073] Examples of the base added to the acidic aqueous solution containing the target substance include tertiary amines, metal hydroxides, metal hydrogen carbonates, metal alkoxides, etc. Specific examples thereof include the bases exemplified as the base used for hydrolysis in Step 1. A metal hydroxide is preferred, and sodium hydroxide is more preferred. Since solid sodium hydroxide is solid and deliquescent and difficult to handle, an aqueous solution of sodium hydroxide may be used instead.

[0074] The basic aqueous solution preferably has a pH of 7 or more, more preferably a pH of 8 or more, and particularly preferably a pH of 9 or more.

[0075] The obtained extract is subjected to an operation such as heating under reduced pressure to distill off the extraction solvent, and the target substance can be obtained. Alternatively, without obtaining the target substance on the organic layer side, water may be removed from the acidic aqueous solution containing the target substance to obtain a salt of Compound (2). The target substance (Compound (2) or its salt) thus obtained has a sufficient purity for use in subsequent steps, but for the purpose of increasing the purity, the purity may be further increased by general purification methods such as crystallization, column chromatography, activated carbon treatment, etc.

[0076] The solvent used for the crystallization of Compound (2) is not particularly limited, and examples include alcohol solvents, ether solvents, aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents, ketone solvents, ester solvents, and nitrile solvents. Specific examples thereof include the solvents exemplified as the reaction solvent in Step 1. Alcohol solvents and aliphatic hydrocarbon solvents are preferred, and ethanol is more preferred. 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.

[0077] As the amount of the solvent used, if it is too much, it is not preferable in terms of cost and post-treatment. Therefore, it is preferably 50 times by weight or less, more preferably 20 times by weight or less, based on the compound (2). As the lower limit, it is preferably 0.1 times by weight or more, more preferably 0.5 times by weight or more, based on the compound (2). Within such a range, the cost is not too high and the post-treatment is also simple.

[0078] As a method for performing crystallization, it can be carried out in the same manner as the crystallization method of the compound (1).

[0079] The method for drying the crystals can be carried out in the same manner as the drying method of the compound (1).

[0080] Step 3: Process for producing the compound (3) from an alcohol derivative (5)

Chemical formula

[0081] As the reaction solvent, there is no particular limitation as long as it does not affect the reaction. Aromatic hydrocarbon solvents, aliphatic hydrocarbon solvents, halogen solvents, ester solvents, sulfoxide solvents, amide solvents, urea solvents, phosphonic acid triamide solvents, ketone solvents, nitrile solvents, etc. can be used. Specific examples thereof include the solvents exemplified as the reaction solvent in Step 1. Preferably, aromatic hydrocarbon solvents and halogen solvents are used, and particularly preferably toluene or methylene chloride. These can 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.

[0082] As the amount of the solvent used, if it is too much, it is not preferable in terms of cost and post-treatment. Therefore, it is preferably 50 times by weight or less, more preferably 20 times by weight or less, relative to the compound (5). As the lower limit, it is preferably 0.1 times by weight or more, more preferably 0.5 times by weight or more, relative to the compound (5). If it is within such a range, the cost is not too high and the post-treatment is also simple.

[0083] Examples of the acid used in this step include boron halides such as boron trifluoride, boron trichloride, and boron tribromide, aluminum halides such as aluminum(III) chloride and aluminum(III) bromide, and other Lewis acids and their solvates. Preferably, it is aluminum(III) chloride. For boron trifluoride, boron trifluoride diethyl ether complex may be used.

[0084] The amount of the acid used is preferably 0.01 to 20 times the molar amount, more preferably 0.1 to 10 times the molar amount, relative to the compound (5).

[0085] Examples of the scavenger used in this step include thiols such as methanethiol, ethanethiol, butanethiol, octanethiol, dodecanethiol, and thioglycolic acid; thioethers such as dimethyl sulfide, diethyl sulfide, tetrahydrothiophene, and thioanisole. Preferably, they are thiols, and more preferably thiols having about 6 to 15 carbon atoms such as 1-dodecanethiol.

[0086] The amount of the scavenger used is preferably 0.01 to 20 times the molar amount, more preferably 0.1 to 10 times the molar amount, relative to the compound (5).

[0087] This step can be carried out at an extremely low temperature of -78°C, but it has the advantage that such an extremely low temperature is not required. The reaction temperature of this step is preferably -40 to 200°C, more preferably -20 to 150°C, and particularly preferably -10 to 50°C, for the purpose of shortening the reaction time while suppressing side reactions.

[0088] There is no particular limitation on the reaction time of this step, and it may be set as appropriate. Preferably, it is 0.001 to 72 hours, and more preferably 0.1 to 48 hours.

[0089] In the reaction of this step, the mixing order and mixing method of the compound (5), acid, scavenger, and reaction solvent are not particularly limited.

[0090] As the treatment after the reaction is completed, general treatment for obtaining the target product from the reaction solution may be performed. For example, after the reaction is completed, water may be added to the reaction solution, and extraction operation may be performed using a general extraction solvent such as methylene chloride, diethyl ether, toluene, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, etc. Further, inorganic salts such as sodium chloride may be added for the purpose of improving the extraction efficiency of the target product if necessary. The inorganic salt may be solid, and an aqueous solution of an inorganic salt whose concentration is not particularly limited may also be used.

[0091] The extract containing the target product thus obtained may be made basic by adding water and a base or an aqueous solution of a base to the extract for the purpose of further increasing the yield of the subsequent step or the purity of the compound obtained in the subsequent step, and obtained as a basic aqueous solution containing the target product.

[0092] Examples of the base to be added to the extract include tertiary amines, metal hydroxides, metal hydrogen carbonates, metal alkoxides, etc. Specific examples thereof include the bases exemplified as the base used for hydrolysis in Step 1. Preferably, it is a metal hydroxide, and more preferably sodium hydroxide. Since solid sodium hydroxide is solid and hygroscopic and difficult to handle, an aqueous solution of sodium hydroxide may be used instead.

[0093] The basic aqueous solution preferably has a pH of 7 or more, more preferably a pH of 8 or more, and particularly preferably a pH of 9 or more.

[0094] Next, as a method for obtaining the target substance from a basic aqueous solution containing the target substance, a general 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 to obtain an extract.

[0095] 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; methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or camphorsulfonic acid, and more preferably hydrogen chloride. Since hydrogen chloride is difficult to handle as a gas, hydrochloric acid may be used instead.

[0096] 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.

[0097] The obtained extract may be washed by adding water or an aqueous solution such as an aqueous sodium chloride solution. By performing operations such as heating under reduced pressure on the obtained extract, the reaction solvent and the extraction solvent are distilled off to obtain the target substance. The target substance thus obtained has a sufficient purity for use in subsequent processes, but for the purpose of increasing the purity, the purity may be further increased by general purification methods such as crystallization, column chromatography, and activated carbon treatment.

[0098] The solvent used for crystallization of the compound (3) is not particularly limited, and examples include ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, cyclopentyl methyl ether, and diethyl ether; alcohol solvents, aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents, ketone solvents, ester solvents, and nitrile solvents. Specific examples thereof include the solvents exemplified as the reaction solvent in Step 1. Alcohol solvents and nitrile solvents are preferred, and acetonitrile is more preferred. 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.

[0099] If the amount of the solvent used is too large, it is not preferable in terms of cost and post-treatment. Therefore, it is preferably 50 times by weight or less, more preferably 20 times by weight or less, based on the compound (3). The lower limit is preferably 0.1 times by weight or more, more preferably 0.5 times by weight or more, based on the compound (2). Within such a range, the cost is not too high and the post-treatment is also simple.

[0100] The crystallization can be carried out in the same manner as the crystallization method of the compound (1).

[0101] The drying method of the crystals can also be carried out in the same manner as the drying method of the compound (1).

[0102] 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 herein by reference.

Examples

[0103] Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited by the following examples, and it is of course possible to appropriately modify and implement it within the scope that conforms to the gist of the foregoing and following descriptions, and all of them are included in the technical scope of the present invention. In the following, unless otherwise specified, “%” means “mass %” and “area %” means area percentage.

[0104] In the following examples, the HPLC analysis conditions used are as follows.

[0105] Analysis condition 1 Measuring instrument: Agilent 1220 Infinity Column: YMC Meteoric Core C18 (150×4.6 mm) Flow rate: 1.5 ml / min Detection wavelength: 210 nm Injection volume: 10 μl Column temperature: 40 °C Mobile phase A: 0.1% aqueous phosphoric acid solution Mobile phase B: Acetonitrile Gradient conditions (mobile phase B concentration, time): 15% (0 min) → 80% (8 - 15 min) → 15% (15.1 - 20 min)

[0106] Analysis condition 2 Measuring instrument: Agilent 1220 Infinity Column: YMC Meteoric Core C18 (150×4.6 mm) Flow rate: 1.5 ml / min Detection wavelength: 210 nm Injection volume: 10 μl Column temperature: 40 °C Mobile phase A: 10 mM aqueous sodium lauryl sulfate solution (pH 2) Mobile phase B: Acetonitrile Gradient conditions (mobile phase B concentration, time): 30% (0 min) → 70% (8 - 15 min) → 30% (15.1 - 20 min)

[0107] In the following examples, the mass spectrometry measurement conditions used are as follows.

[0108] Measuring instrument: Waters ACQUITY UPLC H-Class Column: BEH (50×2.1 mm, 1.7 μm) Flow rate: 0.74 ml / min Detection wavelength: 190 - 400 nm Injection volume: 10 μl 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 method: ESI (Electron Spray Ionization)

[0109] In the following examples, the nuclear magnetic resonance spectrum (hereinafter 1 referred to as 1H NMR) was expressed in δ values (ppm) using tetramethylsilane as the reference substance. Also, deuterated chloroform (hereinafter referred to as CDCl3) was used as the measurement solvent.

[0110] The meanings of the symbols used in the examples section are as follows. DIPEA: N,N-diisopropylethylamine (TfO)2O: Trifluoromethanesulfonic anhydride NaOMe: Sodium methoxide THF: Tetrahydrofuran LiAlH4: Lithium aluminum hydride

[0111] (Reference Example) Production of a mixture (7a) of [(3R,4R)-4-(3-methoxyphenyl)tetrahydropyran-3-yl]-methanol and [(3S,4S)-4-(3-methoxyphenyl)tetrahydropyran-3-yl]-methanol

[0112]

Chemical formula

[0113] Production of methyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyran-5-carboxylate (8)

[0114]

Chem.

[0115] Methyl 4 - oxotetrahydropyran - 3 - carboxylate (40.0 g, 252.9 mmol) was dissolved in dichloromethane (400 g). After adding DIPEA (65.4 g, 505.8 mmol), the solution was cooled to 0 °C. (TfO)2O (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 Analytical 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 content 73.4 g, 252.9 mmol, yield 100%). 1 1H NMR (500 MHz, CDCl3): δ 4.45 - 4.46 (t, 2H, J = 2.5 Hz), 3.88 - 3.91 (t, 2H, J = 5.5 Hz), 3.82 (s, 3H), 2.52 - 2.56 (m, 2H).

[0116] Production of methyl 4-(3-methoxyphenyl)-3,6-dihydro-2H-pyran-5-carboxylate (9)

[0117]

Chem.

[0118] Methyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyran-5-carboxylate (8) (124.8 g, pure content 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 substitution, [1,1'-bis(diphenylphosphinophenylene)]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 Analytical 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 then 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 obtained washing solution (organic layer) was mixed with the organic layer (organic layer A) and then 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%). 1 1H NMR (500 MHz, CDCl3): δ 7.25 - 7.28 (t, 1H, J = 7.8 Hz), 6.83 - 6.86 (dd, 1H, J = 2.5 Hz, 8.5 Hz), 6.74 - 6.75 (m, 1H), 6.70 (m, 1H), 4.44 - 4.46 (t, 2H, J = 2.8 Hz), 3.88 - 3.91 (t, 2H, J = 5.8 Hz), 3.80 (s, 3H), 3.51 (s, 3H), 2.49 - 2.52 (m, 2H).

[0119] Production of a mixture (10b) of methyl (3R,4R)-4-(3-methoxyphenyl)tetrahydropyran-3-carboxylate and methyl (3S,4S)-4-(3-methoxyphenyl)tetrahydropyran-3-carboxylate

[0120]

Chem.

[0121] 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 by adding ethyl acetate (161.5 g) and ethanol (713.0 g). Under a nitrogen atmosphere, 10% palladium on carbon (32.5 g) of approximately 50% water-wetted product was added and mixed, then 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 Analytical Condition 1, the reaction mixture was filtered through Celite, and the filter cake was washed with ethyl acetate (200 ml). The washing solution and the filtrate were combined. The combined solution of the washing solution 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%). 1 1H NMR (500 MHz, CDCl3): δ 7.22 - 7.25 (t, 1H, J = 8.0 Hz), 6.86 - 6.88 (d, 1H, J = 8.5 Hz), 6.83 (m, 1H), 6.75 - 6.78 (dd, 1H, J = 2.5 Hz, 8.0 Hz), 4.28 - 4.31 (dd, 1H, J = 1.0 Hz, 12.0 Hz), 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).

[0122] Production of a mixture (10a) of methyl (3S,4R)-4-(3-methoxyphenyl)tetrahydropyran-5-carboxylate and methyl (3R,4S)-4-(3-methoxyphenyl)tetrahydropyran-5-carboxylate

[0123]

Chemical Structure

[0124] A mixture of methyl (3R,4R)-4-(3-methoxyphenyl)tetrahydropyran-3-carboxylate and methyl (3S,4S)-4-(3-methoxyphenyl)tetrahydropyran-3-carboxylate (10b) (104.9 g, pure content 89.7 g, 358.2 mmol) was dissolved by adding methanol (525.1 g). After adding a 28% NaOMe / methanol solution (82.6 g, pure content 23.1 g, 428.4 mmol), the mixture was stirred at 70 °C for 1 hour. After confirming the completion of the reaction under Analytical Condition 1, the reaction mixture was cooled to room temperature and added to a 10% aqueous ammonium chloride solution (419.4 g). After concentration 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 solution (organic layer) was mixed with the said 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 then the organic layer was 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%). 1 1H NMR (500 MHz, CDCl3): δ 7.20 - 7.24 (m, 1H), 6.80 - 6.81 (d, 1H, J = 8.0 Hz), 6.75 - 6.77 (m, 2H), 4.16 - 4.19 (dd, 1H, J = 4.5 Hz, 11.5 Hz), 4.06 - 4.09 (dd, 1H, J = 4.0 Hz, 11.5 Hz), 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).

[0125] [(3R,4R)-4-(3-methoxyphenyl)tetrahydropyran-3-yl]-methanol and [(3S,4S)-4-(3-methoxyphenyl)tetrahydropyran-3-yl]-methanol mixture (7a) production

[0126]

Chemical Structure

[0127] A mixture of methyl (3S,4R)-4-(3-methoxyphenyl)tetrahydropyran-5-carboxylate and methyl (3R,4S)-4-(3-methoxyphenyl)tetrahydropyran-5-carboxylate (10a) (87.5 g, pure content 76.0 g, 303.8 mmol) was dissolved by adding THF (612.5 g). After cooling to -5°C, LiAlH4 (8.6 g, 227.2 mmol) was added portionwise. The mixture was stirred at -5°C for 1 hour. After confirming the completion of the reaction under Analytical Condition 1, 10% aqueous ammonium chloride solution (612.5 g) was added dropwise. After adding dichloromethane (612.5 g), the reaction mixture was filtered through celite, and the filtrate was separated into layers to recover the organic layer (organic layer A). The aqueous layer after layer separation was washed twice with dichloromethane (612.5 g). The obtained washing solution (organic layer) was mixed with the above-mentioned organic layer (organic layer A). The mixture was washed with water (175.0 g) to remove the aqueous layer, and then 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%). 1 1H NMR (500 MHz, CDCl3): δ 7.23 - 7.26 (m, 1H), 6.81 - 6.83 (d, 1H, J = 7.0 Hz), 6.76 - 6.78 (m, 2H), 4.20 - 4.23 (dd, 1H, J = 4.0 Hz, 11.0 Hz), 4.04 - 4.07 (dd, 1H, J = 4.0 Hz, 11.5 Hz), 3.81 (s, 3H), 3.47 - 3.52 (m, 1H), 3.42 - 3.45 (m, 1H), 3.35 - 3.39 (t, 1H, J = 11.0 Hz), 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).

[0128] (Example 1) Production of a mixture (11a) of 3-[(3R,4R)-3-(hydroxymethyl)tetrahydropyran-4-yl]phenol and 3-[(3S,4S)-3-(hydroxymethyl)tetrahydropyran-4-yl]phenol

[0129]

Chemical Structure

[0130] A mixture of [(3R,4R)-4-(3-methoxyphenyl)tetrahydropyran-3-yl]-methanol and [(3S,4S)-4-(3-methoxyphenyl)tetrahydropyran-3-yl]-methanol (7a) (36.0 g, pure content 31.3 g, 140.7 mmol) was dissolved by adding dichloromethane (541.1 g), and dodecanethiol (71.2 g, 351.7 mmol) was added and cooled to 0 °C. Aluminum(III) chloride (46.9 g, 351.7 mmol) was added portionwise, and the mixture was stirred at room temperature for 20 hours. After confirming the completion of the reaction under Analytical Condition 1, water (312.7 g) was added to the reaction mixture and 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, mixed, and the organic layer obtained by layer separation was mixed with the organic layer (organic layer A), concentrated under reduced pressure, 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 30% aqueous sodium hydroxide solution. Concentrated hydrochloric acid was added dropwise to the aqueous layer obtained by removing the organic layer. After adjusting the pH to 7, ethyl acetate (180.0 g) was added and mixed, and the pH was adjusted to 1 with concentrated hydrochloric acid. The layers were separated to recover the organic layer (organic layer B). The aqueous layer after layer separation was washed with ethyl acetate (180.0 g), and the obtained washing solution (organic layer) was mixed with the organic layer (organic layer B). The mixture was washed with 20% brine (31.3 g) to remove the aqueous layer, and then the organic layer was 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%). 11H NMR (500 MHz, CDCl3): δ 7.16 - 7.19 (t, 1H, J = 7.8 Hz), 6.70 - 6.76 (m, 3H), 6.16 (s, 1H), 4.26 - 4.30 (dd, 1H, J = 4.5 Hz, 12.0 Hz), 4.10 - 4.11 (dd, 1H, J = 4.0 Hz, 11.5 Hz), 3.51 - 3.55 (m, 1H), 3.44 - 3.47 (dd, 1H, J = 3.5 Hz, 11.0 Hz), 3.35 - 3.40 (t, 1H, J = 11.3 Hz), 3.24 - 3.28 (dd, 1H, J = 7.5 Hz, 11.0 Hz), 2.50 - 2.55 (m, 1H), 2.10 - 2.11 (m, 1H), 1.85 - 1.90 (m, 1H), 1.75 - 1.78 (m, 1H).

[0131] (Example 2) Production of a mixture of 3-[(3R,4R)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol and 3-[(3S,4S)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol (6a)

[0132]

Chem.

[0133] (Example 2-1) Production of a mixture (12a) of methanesulfonic acid [[(3R,4R)-4-(3-methylsulfonyloxyphenyl)tetrahydropyran-3-yl]methyl] and methanesulfonic acid [[(3S,4S)-4-(3-methylsulfonyloxyphenyl)tetrahydropyran-3-yl]methyl]

[0134]

Chem.

[0135] A mixture (11a) (21.4 g, 102.5 mmol) of 3 - [(3R,4R) - 3 - (hydroxymethyl)tetrahydropyran - 4 - yl]phenol and 3 - [(3S,4S) - 3 - (hydroxymethyl)tetrahydropyran - 4 - yl]phenol was dissolved in dichloromethane (680.0 g), and triethylamine (31.1 g, 307.6 mmol) was added and cooled to 0 °C. Methanesulfonyl chloride (35.2 g, 307.6 mmol) was added dropwise, and after stirring at 0 °C for 10 minutes, the completion of the reaction was confirmed under Analytical Condition 1. The reaction mixture was washed twice with a 10% aqueous ammonium chloride solution (310.0 g) to remove the aqueous layer, then 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).

[0136] (Example 2-2) Production of a mixture (13a) of methanesulfonic acid [3-[(3R,4R)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenyl] and methanesulfonic acid [3-[(3S,4S)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenyl]

[0137]

Chem.

[0138] A mixture (12a) (43.4 g) of methanesulfonic acid [[(3R,4R)-4-(3-methylsulfonyloxyphenyl)tetrahydropyran-3-yl]methyl] and methanesulfonic acid [[(3S,4S)-4-(3-methylsulfonyloxyphenyl)tetrahydropyran-3-yl]methyl] was added with 50% aqueous dimethylamine solution (74.0 g, pure content 37.0 g, 820.1 mmol), and stirred at 80 °C overnight. After confirming the completion of the reaction under Analytical Condition 2, the reaction mixture was cooled to 20 °C and extracted twice with 2-methyltetrahydrofuran (164.5 g). The organic layers obtained from the two extractions were mixed, 5% aqueous potassium hydrogen sulfate solution (85.5 g) was added to the mixture, then adjusted to pH 2 with concentrated hydrochloric acid, and layer separation was performed to obtain an aqueous layer (aqueous layer A). Water (42.7 g) was added to the organic layer obtained by layer separation for washing. The obtained washing solution (aqueous layer) was mixed with the said aqueous layer (aqueous layer A). 30% aqueous sodium hydroxide solution was added to the mixture to adjust the pH to 11, and extraction was performed 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). 1 H NMR (500 MHz, CDCl3): δ 7.37 - 7.40 (t, 1H, J = 7.8 Hz), 7.14 - 7.18 (m, 3H), 4.40 (m, 1H), 4.05 - 4.08 (dd, 1H, J = 3.5 Hz, 11.0 Hz), 3.46 - 3.51 (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).

[0139] (Example 2-3) Production of a mixture (6a) of 3-[(3R,4R)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol and 3-[(3S,4S)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol

[0140] [Chemical]

[0141] 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 methanesulfonic acid [3-[(3S,4S)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenyl], water (50.0 g) was added and mixed, and 30% sodium hydroxide (41.0 g, pure content 12.3 g, 307.6 mmol) was added, followed by stirring at 80 °C for 22.5 hours. After confirming the completion of the reaction under Analytical Condition 2, the reaction mixture was cooled to 20 °C, water (85.4 g) and dichloromethane (85.4 g) were added for washing and layer separation, and the target product was recovered on the aqueous layer side. The obtained aqueous layer was washed with dichloromethane (85.4 g), followed by layer separation, and the target product was recovered again on the aqueous layer side. Dichloromethane (85.4 g) was added to the aqueous layer after layer separation, adjusted to pH 8 using potassium dihydrogen phosphate, and the aqueous layer (aqueous layer A) was separated and removed to extract the target product into the organic layer side (organic layer A). Next, dichloromethane (85.4 g) was added to the aqueous layer A to re-extract the target product into the organic layer side (organic layer B). After mixing the obtained organic layer A and organic layer B, filtration (pore size 1 μm) was carried out, 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 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%). 11H NMR (500 MHz, CDCl3): δ 7.16 - 7.19 (t, 1H, J = 8.3 Hz), 6.73 - 6.75 (d, 1H, J = 8.0 Hz), 6.68 - 6.69 (m, 2H), 4.32 - 4.35 (dd, 1H, J = 11.5 Hz, 2.5 Hz), 4.04 - 4.07 (dd, 1H, J = 11.0 Hz, 4.5 Hz), 3.46 - 3.51 (t, 1H, J = 12.0 Hz), 3.15 - 3.20 (t, 1H, J = 10.8 Hz), 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) + .

Industrial Applicability

[0142] The aminoalkyltetrahydropyran derivative (1) produced by the present invention can be used as an active ingredient for use in the treatment and / or prevention of pain.

Claims

1. The following general formula (1); 【Chemical 1】 (wherein R １ ~R ３ each independently represents a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, and R ４ ~R ５ each independently represents a substituted or unsubstituted alkyl group having 1 to 12 carbon atoms, and *1 and *2 represent asymmetric carbons.), a method for producing an aminoalkyltetrahydropyran derivative (1) represented by the following general formula (2); or a pharmaceutically acceptable salt thereof: 【Chemical 2】 (wherein, R １ to R ５ , *1, and *2 are the same 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, an m-chlorobenzenesulfonyl group, a p-chlorobenzenesulfonyl group, an o-nitrobenzenesulfonyl group, an m-nitrobenzenesulfonyl group, a p-nitrobenzenesulfonyl group, or a (+)-10-camphorsulfonyl group.), or a salt thereof and a base are reacted to convert them into the aminoalkyltetrahydropyran derivative represented by the formula (1), or a pharmaceutically acceptable salt thereof.

2. The production method according to claim 1, characterized in that the amine compound (2) or a salt thereof and a base are reacted in an aqueous solvent.

3. Said R １ The production method according to claim 1 or 2, wherein R is a hydrogen atom.

4. Said R ２ and R ３ The production method according to any one of claims 1 to 3, wherein is a hydrogen atom.

5. Said R ４ and R ５ The production method according to any one of claims 1 to 4, wherein is a methyl group.

6. The production method according to any one of claims 1 to 5, wherein Q is a methanesulfonyl group or a p-toluenesulfonyl group.

7. The following general formula (3); [Chemical Formula 3] (In the formula, R １ to R ３ , *1, and *2 are the same as described above.) By disulfonylating the phenol derivative (3) represented by the following general formula (4); 【Chemical Formula 4】 (wherein R １ ~R ３ , *1, *2, and Q are the same as described above.) and converting it into a disulfonyl compound (4), and subsequently reacting the disulfonyl compound (4) with a secondary amine to produce the amine compound (2) or a salt thereof. The production method according to any one of claims 1 to 6, which comprises a step of

8. The phenol derivative (3) is the following general formula (5); 【Chemical Formula 5】 (wherein R １ ~R ３ , *1, and *2 are the same as defined above). The production method according to claim 7, which comprises a step of producing from the alcohol derivative (5) represented by the formula.

9. The aminoalkyltetrahydropyran derivative (1) is the following formula (6a); 【Chemical Formula 6】 3-[(3R,4R)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol, 3-[(3S,4S)-3-(dimethylaminomethyl)tetrahydropyran-4-yl]phenol, or a mixture of two enantiomers thereof, and the production method according to any one of claims 1 to 8.

10. The production 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.

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