JP2008169160A - Piperidine compound and method for producing its intermediate - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for efficiently and inexpensively producing a compound (II) (particularly its optically active substance) or its salt in an industrial scale and to provide a useful intermediate used for the method. <P>SOLUTION: The method for producing the compound (II) or its salt comprises cyclizing a compound (I) or its salt in the presence of a cyclic secondary amine which may have a substituent (wherein Ar is an aromatic group which may have a substituent). <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a method for producing a piperidine compound useful as an intermediate for pharmaceutical synthesis and a compound useful as the intermediate.

  The piperidine compound represented by the following general formula (II) is useful as, for example, a synthetic intermediate of an NK-1 antagonist.

  As a method for synthesizing the piperidine compound, Patent Document 1 describes a method using an expensive metal 4-methoxypyridine as a starting material and using an organic metal, but this method requires multiple steps. Patent Document 2 also describes a method using 4-aminobutan-2-one ethylene acetal as a starting material in addition to the method described in Patent Document 1, but this method is not limited to 4-aminobutane. The number of steps is required for the synthesis of 2-one ethylene acetal itself. These methods are racemic synthesis methods. However, in order to obtain an optically active form, it is necessary to separate the racemic form by optical resolution or the like. As a method for directly synthesizing an optically active substance, it is considered possible to synthesize according to the method described in Non-Patent Document 1, but there are problems such as the need to use an equivalent amount of an asymmetric auxiliary group.

JP 2005-154380 A JP 2005-524636 A “Journal of American Chemical Society”, 1994, vol. 116, p. 4719

  An object of the present invention is to provide a method for producing a compound represented by the general formula (II) (particularly an optically active substance thereof) or a salt thereof efficiently and inexpensively on an industrial scale, and a useful novel intermediate used in the method Is to provide.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors, as will be described later, a compound represented by the general formula (I) (preferably a compound represented by the general formula (IV)) Or a salt thereof may be a cyclic secondary amine optionally having a substituent (preferably an optically active substance thereof, more preferably a substituent having an acidic proton, and further having a substituent. It has been found that by reacting in the presence of a good optically active cyclic secondary amine), the compound represented by the general formula (II) (preferably its optically active substance) or a salt thereof can be easily obtained. The invention has been completed.

That is, the present invention is as follows.
[1] General formula (I):

(In the formula, Ar represents an aromatic group which may have a substituent)
A compound represented by the general formula (II), wherein the compound (hereinafter also referred to as compound (I)) or a salt thereof is cyclized in the presence of an optionally substituted cyclic secondary amine. ):

(Wherein Ar has the same meaning as above)
Or a salt thereof (hereinafter also referred to as compound (II)).

[2] The compound represented by the general formula (I) is represented by the general formula (IV):

(Wherein A ¹ , A ² , A ³ , A ⁴ and A ⁵ each independently represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 4 carbon atoms)
The production method of the above-mentioned [1], which is a compound represented by the following (hereinafter also referred to as compound (IV)).

[3] The production method of the above-mentioned [2], wherein A ¹ is methyl, A ² , A ⁴ and A ⁵ are hydrogen atoms, and A ³ is a fluorine atom.
[4] The production method of the above-mentioned [1], wherein the cyclic secondary amine which may have a substituent is optically active.
[5] The above-mentioned [1], wherein the cyclic secondary amine which may have a substituent is a cyclic secondary amine which has a substituent having an acidic proton and may further have a substituent. Manufacturing method.

[6] The cyclic secondary amine which may have a substituent is represented by the formula (III):

(Wherein, X ¹ and X ² each independently represent a hydrogen atom, a hydroxyl group or a protected hydroxyl group)
The production method of the above-mentioned [1], which is a compound represented by the following (hereinafter also referred to as compound (III)).

[7] The cyclic secondary amine which may have a substituent is represented by the formula (IIIa):

(Wherein, X ¹ and X ² each independently represent a hydrogen atom, a hydroxyl group or a protected hydroxyl group)
The production method of the above-mentioned [1], which is a compound represented by the formula (hereinafter also referred to as compound (IIIa)).

[8] Ar—CHO (wherein Ar represents an aromatic group which may have a substituent) is reacted with 4-aminobutan-2-one or a salt thereof, I):

(Wherein Ar has the same meaning as above)
Or a salt thereof.

[9] Ar—CHO (wherein Ar represents an aromatic group which may have a substituent) is reacted with 4-aminobutan-2-one or a salt thereof to form a compound represented by the general formula (I):

(Wherein Ar has the same meaning as above)
A compound represented by general formula (I) or a salt thereof; and a compound represented by general formula (I) or a salt thereof cyclized in the presence of an optionally substituted cyclic secondary amine, Formula (II):

(Wherein Ar has the same meaning as above)
A step of obtaining a compound represented by the formula:
A process for producing a compound represented by the general formula (II) or a salt thereof.

[10] Ar—CHO (wherein Ar represents an aromatic group which may have a substituent) is reacted with 4-aminobutan-2-one or a salt thereof to form a compound represented by the general formula (I):

(Wherein Ar has the same meaning as above)
A compound represented by formula (I) or a salt thereof; and a compound represented by formula (I) or a salt thereof represented by formula (IIIa):

(Wherein, X ¹ and X ² each independently represent a hydrogen atom, a hydroxyl group or a protected hydroxyl group)
Is cyclized in the presence of a compound represented by the general formula (IIa):

(Wherein Ar has the same meaning as above)
A step of obtaining a compound represented by formula (hereinafter also referred to as compound (IIa)) or a salt thereof;
A process for producing a compound represented by the general formula (IIa) or a salt thereof.

[11] The compound represented by the general formula (I) is represented by the general formula (IV):

(Wherein A ¹ , A ² , A ³ , A ⁴ and A ⁵ each independently represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 4 carbon atoms)
The manufacturing method in any one of said [8]-[10] which is a compound represented by these.
[12] The production method of the above-mentioned [11], wherein A ¹ is methyl, A ² , A ⁴ and A ⁵ are hydrogen atoms, and A ³ is a fluorine atom.

[13] General formula (I):

(In the formula, Ar represents an aromatic group which may have a substituent)
Or a salt thereof.

[14] General formula (IV):

(Wherein A ¹ , A ² , A ³ , A ⁴ and A ⁵ each independently represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 4 carbon atoms)
Or a salt thereof.
[15] The compound according to [14] above, wherein A ¹ is methyl, A ² , A ⁴ and A ⁵ are hydrogen atoms, and A ³ is a fluorine atom.

  According to the present invention, compound (II) or a salt thereof can be produced efficiently and inexpensively on an industrial scale. In addition, when an optically active substance is used as a cyclic secondary amine which may have a substituent, an optically active substance of compound (II) or a salt thereof can be easily produced without using a method such as optical resolution. Can do.

Hereinafter, the present invention will be described in detail.
The “aromatic group” in the “optionally substituted aromatic group” represented by Ar is an aromatic hydrocarbon group such as phenyl, naphthyl, anthracenyl; pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, Aromatic heterocyclic groups such as isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, pyrrolyl, furyl, thienyl, indolyl, benzofuranyl, benzothiophenyl and the like can be mentioned, and phenyl is preferable. Examples of the substituent that the “aromatic group” may have include a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, and an alkanoyloxy group having 1 to 8 carbon atoms. Can be mentioned.

  Here, as a halogen atom, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom are mentioned, Preferably it is a fluorine atom.

  Examples of the alkyl group having 1 to 8 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Preferably, it is a C1-C4 alkyl group, More preferably, it is methyl.

  Examples of the alkoxy group having 1 to 8 carbon atoms include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy , N-octyloxy and the like, preferably an alkoxy group having 1 to 4 carbon atoms, and more preferably methoxy.

  Examples of the alkanoyloxy group having 1 to 8 carbon atoms include acetyloxy and pivaloyloxy, preferably an alkanoyloxy group having 1 to 4 carbon atoms, and more preferably acetyloxy.

  The substituent is preferably a halogen atom or an alkyl group having 1 to 4 carbon atoms, and particularly preferably a fluorine atom or methyl.

  Ar is preferably a phenyl group which may be substituted with a halogen atom, an alkyl group having 1 to 4 carbon atoms or the like, and more preferably a phenyl group which may be substituted with a fluorine atom, methyl or the like. .

Examples of the “halogen atom” represented by A ¹ , A ² , A ³ , A ⁴ or A ⁵ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Among these, a fluorine atom is preferable.

Examples of the “alkyl group having 1 to 4 carbon atoms” represented by A ¹ , A ² , A ³ , A ⁴ or A ⁵ include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and and tert-butyl. Of these, methyl is preferable.

A ¹ , A ² , A ³ , A ⁴ and A ⁵ are preferably each independently a hydrogen atom, a fluorine atom or methyl, more preferably A ¹ is methyl, and A ² , A ⁴ And A ⁵ is a hydrogen atom and A ³ is a fluorine atom, or A ¹ , A ² , A ⁴ and A ⁵ are hydrogen atoms and A ³ is a fluorine atom, A ¹ is methyl, A ² , A ⁴ and A ⁵ are hydrogen atoms, and A ³ is a fluorine atom.

Examples of the hydroxyl protecting group in the “protected hydroxyl group” represented by X ¹ and X ² include benzyl, 1-phenylethyl, 1-phenylpropyl, 1-phenylbutyl, 2-methyl-1-phenylpropylene. Aralkyl ethers such as 1-phenylpentyl, 2-methyl-1-phenylbutyl, 3-methyl-1-phenylbutyl, diphenylmethyl, 1,1-diphenylethyl, triphenylmethyl, naphthylmethyl, 1-naphthylethyl System protecting group: methyl, tert-butyl, 1-ethoxyethyl, 3,4,5,6-tetrahydro-2H-pyran-2-yl, 1-methoxy-1-methylethyl, methoxymethyl, 2-methoxyethoxymethyl (Substituted) alkyl ether protecting groups such as trimethylsilyl, triethylsilane Silyl ether-based protecting groups such as ruthenium, tripropylsilyl, triisopropylsilyl, tributylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl; acetyl, propanoyl, butanoyl, isobutanoyl, pivaloyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, Nonanoyl, decanoyl, undecanoyl, dodecanoyl, benzoyl, 4-nitrobenzoyl, 4-methoxybenzoyl, 4-methylbenzoyl, 4-tert-butylbenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-tri Fluoromethyl, 3-nitrobenzoyl, 3-methoxybenzoyl, 3-methylbenzoyl, 3-tert-butylbenzoyl, 3-fluorobenzoyl, 3-c Lorobenzoyl, 3-bromobenzoyl, 2-nitrobenzoyl, 2-methoxybenzoyl, 2-methylbenzoyl, 2-tert-butylbenzoyl, 2-fluorobenzoyl, 2-chlorobenzoyl, 2-bromobenzoyl, 3,5-dinitro Benzoyl, 3,5-dimethoxybenzoyl, 3,5-dimethylbenzoyl, 3,5-di-tert-butylbenzoyl, 3,5-difluorobenzoyl, 3,5-dichlorobenzoyl, 3,5-dibromobenzoyl, 2, 4-dinitrobenzoyl, 2,4-dimethoxybenzoyl, 3,5-bis (trifluoromethyl), 2,4-dimethylbenzoyl, 2,4-di-tert-butylbenzoyl, 2,4-difluorobenzoyl, 2, 4-dichlorobenzoyl, 2,4-dibromobenzoyl, , 5-dinitrobenzoyl, 2,5-dimethoxybenzoyl, 2,5-dimethylbenzoyl, 2,5-di-tert-butylbenzoyl, 2,5-difluorobenzoyl, 2,5-dichlorobenzoyl, 2,5-dibromo And ester protecting groups such as benzoyl, 3,4,5-trifluorobenzoyl, 4-phenylbenzoyl, 2-phenylbenzoyl, 4-methoxycarbonylbenzoyl, 3-methoxycarbonylbenzoyl, 2-methoxycarbonylbenzoyl, etc. Of these, benzoyl, tert-butyldimethylsilyl and the like are preferable, and tert-butyldimethylsilyl is more preferable.

  The “cyclic secondary amine” of the “cyclic secondary amine optionally having substituent (s)” is not particularly limited as long as it is a cyclic compound having NH as a ring constituent atom. In addition to the above, a 3- to 8-membered saturated cyclic compound (eg, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, which may further have 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom) Among them, pyrrolidine and piperidine are preferable.

  The “cyclic secondary amine” may have a substituent. Examples of the substituent include a phenyl group and a substituted alkyl group (the alkyl group is preferably an alkyl group having 1 to 6 carbon atoms, and examples of the substituent include a dialkylamino group (such as a dimethylamino group). ), Acetylamino group, pyrrolidinyl group, piperidinyl group, morpholinyl group, halogen atom, etc.), hydroxyl group, protected hydroxyl group, carboxyl group, alkylsulfonylamino group, perfluoroalkylsulfonylamino group, alkylaminocarbonyl An amino group, an alkylaminothiocarbonylamino group, a tetrazoyl group, etc. are mentioned. The number of the substituents is not particularly limited, but is preferably 1 to 3, and in the case of 2 or more, the substituents may be the same or different.

The “cyclic secondary amine optionally having a substituent” is preferably a phenyl group, a substituted alkyl group, a hydroxyl group, a protected hydroxyl group, a carboxyl group, an alkylsulfonylamino group, a perfluoroalkylsulfonyl group. Pyrrolidine or piperidine optionally substituted with a substituent selected from an amino group, an alkylaminocarbonylamino group, an alkylaminothiocarbonylamino group and a tetrazoyl group, more preferably a carboxyl group, an alkylsulfonylamino group, a par It has a substituent having an acidic proton such as a fluoroalkylsulfonylamino group, an alkylaminocarbonylamino group, an alkylaminothiocarbonylamino group, or a tetrazoyl group, and may further have the above-mentioned substituent, pyrrolidine or piperi More preferably, an acidic proton such as a carboxyl group, an alkylsulfonylamino group, a perfluoroalkylsulfonylamino group, an alkylaminocarbonylamino group, an alkylaminothiocarbonylamino group, or a tetrazoyl group is attached to a carbon atom adjacent to NH. It is pyrrolidine or piperidine, which may further have the above substituent, and more preferably a carboxyl group, an alkylsulfonylamino group, a perfluoroalkylsulfonylamino group on a carbon atom adjacent to NH. A pyrrolidine having a substituent having an acidic proton such as an alkylaminocarbonylamino group, an alkylaminothiocarbonylamino group, or a tetrazoyl group, and further having the above-mentioned substituent, and still more preferably a compound ( I I), that is, having a carboxyl group on the carbon atom adjacent to NH, and a good pyrrolidine which may have a hydroxyl group and / or a protected hydroxyl group, particularly preferably, the X ¹ and X ² Compound (III), which is both a hydrogen atom (ie, proline), or Compound (III) wherein X ¹ is tert-butyldimethylsilyloxy and X ² is a hydrogen atom, most preferably Proline.

  Compound (I), (II) or (IV) may be in the form of a salt. Examples of the salt include inorganic acid addition salts (for example, hydrochloric acid addition salt, hydrobromic acid addition salt, nitric acid addition salt, sulfuric acid addition salt, phosphoric acid addition salt, etc.), organic acid addition salts (for example, formic acid addition salt, Acetic acid addition salt, oxalic acid addition salt, malonic acid addition salt, citric acid addition salt, fumaric acid addition salt, lactic acid addition salt, malic acid addition salt, succinic acid addition salt, tartaric acid addition salt, trifluoroacetic acid addition salt, etc.) And acid addition salts thereof.

  In the present invention, compound (I) or a salt thereof is cyclized in the presence of a cyclic secondary amine which may have a substituent which is a catalyst (hereinafter also simply referred to as a cyclic secondary amine), to give compound ( II) or a salt thereof is produced. The cyclization reaction is preferably performed in a solvent.

  The order of addition of compound (I), cyclic secondary amine and solvent is not particularly limited. For example, (1) First, compound (I) or a salt thereof is dispersed or dissolved in a solvent, and then cyclic secondary amine is added. (2) First, a method in which a cyclic secondary amine is dispersed or dissolved in a solvent, and then compound (I) or a salt thereof is added. (3) A cyclic secondary amine and a compound (I) or a salt thereof are added. Examples thereof include a method of adding a solvent.

  The amount of the cyclic secondary amine to be used is generally 0.005 mol to 1 mol, preferably 0.05 mol to 0.5 mol, per 1 mol of compound (I) or a salt thereof. When the amount used is less than this range, the reaction rate is not sufficiently obtained, and when it is more than this range, the effect corresponding to the amount used tends to be not obtained.

  The solvent is not particularly limited as long as it does not inhibit the reaction. For example, aliphatic hydrocarbon solvent, aromatic solvent, ether solvent, alcohol solvent, ester solvent, water, chlorinated hydrocarbon solvent, aprotic polarity A solvent, a mixed solvent thereof or the like can be preferably used, but an aprotic polar solvent is particularly preferable. Examples of the aliphatic hydrocarbon solvent include n-pentane, n-hexane, isohexane, n-heptane, isoheptane, n-octane, isooctane, n-nonane, isononane, n-decane, isodecane, n-undecane, n-dodecane, Cyclopentane, cyclohexane, methylcyclohexane, tert-butylcyclohexane, petroleum ether, etc .; aromatic solvents include benzene, toluene, ethylbenzene, isopropylbenzene, tert-butylbenzene, xylene, mesitylene, monochlorobenzene, monofluorobenzene , Α, α, α-trifluoromethylbenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,2,3-trichlorobenzene, 1,2,4-trichlorobenzene, etc .; ether solvents age Is tetrahydrofuran (THF), methyltetrahydrofuran, diethyl ether, di-n-propyl ether, diisopropyl ether, di-n-butyl ether, di-n-pentyl ether, di-n-hexyl ether, di-n-heptyl ether, di-n-octyl ether , Methyl tert-butyl ether (MTBE), cyclopentyl methyl ether, 1,2-dimethoxymethane, diethylene glycol dimethyl ether, anisole, diphenyl ether and the like; alcohol solvents include methanol, ethanol, n-propanol, isopropyl alcohol, n-butyl Alcohol, isobutyl alcohol, tert-butyl alcohol, 1-pentanol, 2-pentanol, isopentyl alcohol, 1-hexanol 2-hexanol, isohexyl alcohol, 1-heptanol, 2-heptanol, 3-heptanol, isopeptyl alcohol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol mono n-propyl ether, ethylene glycol monoisopropyl ether, Ethylene glycol mono n-butyl ether, ethylene glycol mono isobutyl ether, ethylene glycol mono tert-butyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol mono n-propyl ether, diethylene glycol monoisopropyl ether, diethylene glycol mono n-butyl ether, diethylene glycol monoisobutyl Examples of the ester solvent include ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butyl acetate, amyl acetate, isoamyl acetate, and the like. Chlorinated carbonization Examples of the hydrogen solvent include dichloromethane, chloroform, 1,2-dichloroethane; examples of the aprotic polar solvent include dimethyl sulfoxide, sulfolane, N, N-dimethylformamide (DMF), 1,3-dimethyl-2- Imidazolidinone (DMI), N, N-dimethylacetamide, N, N-dimethylpropionamide, N, N-dimethylpropyleneurea (DMPU), N-methylpyrrolidone, γ-butyrolactone, dimethyl carbonate, diethyl carbonate, ethylene carbonate Bonate, propylene carbonate, acetonitrile, propionitrile, benzonitrile and the like can be mentioned. Among them, N, N-dimethylformamide, acetonitrile, benzonitrile, dimethyl sulfoxide and the like are preferable, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, Benzonitrile is particularly preferred.

  The amount of the solvent to be used is generally 1 L-100 L, preferably 3 L-30 L, per 1 kg of compound (I) or a salt thereof. When the amount of the solvent is less than this range, the stirrability tends to deteriorate, and when it exceeds this range, the reaction time tends to be longer.

  The reaction temperature is generally −30 ° C. to 80 ° C., preferably −10 ° C. to 40 ° C., more preferably −5 ° C. to 30 ° C. The reaction time is usually 1 to 48 hours although it depends on the reaction temperature, the amount of reagent used, and the like.

  The reaction pressure is usually normal pressure, but in order to increase the reaction rate, for example, a pressure of about 0.1 to 5 Mpa may be applied.

  Isolation of compound (II) can be performed by subjecting the reaction solution to a post-treatment by a conventional method (for example, neutralization, extraction, washing with water, distillation, crystallization, etc.). In addition, the compound (II) can be purified by recrystallization, extraction purification, distillation, adsorption treatment of activated carbon, silica, alumina and the like, and chromatography methods such as silica gel column chromatography. Compound (II) may be converted to a desired acid addition salt using, for example, an appropriate acid (for example, hydrochloric acid).

  In order to obtain an optically active compound (II) or a salt thereof, the cyclic secondary amine is preferably an optically active material. The optically active substance is preferably an optically active substance of compound (III), particularly compound (IIIa), among which L-proline and 4- (tert-butyldimethylsilyloxy) -L-proline are preferable, and L -Proline is particularly preferred.

  Here, when compound (IIIa) is used as the optically active compound of compound (III), compound (IIa) or a salt thereof is obtained, and conversely, compound (IIIb):

(Wherein, X ¹ and X ² have the same meaning as above)
And a compound represented by general formula (IIb):

(Wherein Ar has the same meaning as above)
(Hereinafter also referred to as compound (IIb)) or a salt thereof.

Compound (I) or a salt thereof used as a raw material is preferably compound (IV) or a salt thereof, more preferably, A ¹ is methyl, and A ² , A ⁴ and A ⁵ are hydrogen atoms. Compound (IV) wherein A ³ is a fluorine atom or a salt thereof, or Compound (IV) wherein A ¹ , A ² , A ⁴ and A ⁵ are a hydrogen atom and A ³ is a fluorine atom, or a salt thereof Particularly preferred is compound (IV) or a salt thereof, wherein A ¹ is methyl, A ² , A ⁴ and A ⁵ are hydrogen atoms, and A ³ is a fluorine atom.

  Further, Compound (I) (including Compound (IV)) or a salt thereof is a novel compound. For example, Ar-CHO (wherein Ar has the same meaning as described above) is converted into Tetrahedron Letters 45, 8505 (2004). ) Can be produced by reacting with 4-aminobutan-2-one or a salt thereof (for example, hydrochloride) produced by the method described in the above. The reaction is preferably performed in a solvent.

  The order of addition of Ar—CHO, 4-aminobutan-2-one or a salt thereof and a solvent is not particularly limited. For example, (1) Ar-CHO is first dispersed or dissolved in a solvent, and then 4-aminobutane- A method of adding 2-one or a salt thereof, (2) a method of first dispersing or dissolving 4-aminobutan-2-one or a salt thereof in a solvent, and then adding Ar-CHO, and (3) adding Ar-CHO to Examples include a method of adding 4-aminobutan-2-one or a salt thereof and a solvent.

  The usage-amount of 4-aminobutan-2-one or its salt is 1 mol-4 mol normally with respect to 1 mol of Ar-CHO, Preferably it is 1.2 mol-2.4 mol. When the amount used is less than this range, the reaction rate is not sufficiently obtained, and when it is more than this range, the effect corresponding to the amount used tends to be not obtained.

  The solvent is not particularly limited as long as it does not inhibit the reaction. For example, an ether solvent, an aqueous solvent, or a mixed solvent thereof can be suitably used, and an ether solvent is particularly preferable. As ether solvents, tetrahydrofuran (THF), methyltetrahydrofuran, diethyl ether, di-n-propyl ether, diisopropyl ether, di-n-butyl ether, di-n-pentyl ether, di-n-hexyl ether, di-n-heptyl ether, di-n -Octyl ether, methyl tert-butyl ether (MTBE), cyclopentyl methyl ether, 1,2-dimethoxymethane, diethylene glycol dimethyl ether, anisole, diphenyl ether and the like; water solvents include water, saline, aqueous sodium sulfate, magnesium sulfate An aqueous solution, an aqueous magnesium chloride solution, an aqueous ammonium chloride solution, an aqueous ammonium sulfate solution and the like can be mentioned. Of these, saline, a mixed solvent of MTBE and saline are particularly preferable.

  The usage-amount of a solvent is 1L-200L normally with respect to 1 kg of Ar-CHO, Preferably it is 10L-100L. When the amount of the solvent is less than this range, the stirrability tends to deteriorate, and when it exceeds this range, the reaction time tends to be longer.

  The reaction temperature is generally −20 ° C. to 80 ° C., preferably −10 ° C. to 40 ° C., more preferably 5 ° C. to 35 ° C. The reaction time is usually 0.5 to 12 hours, although it depends on the reaction temperature and the amount of reagent used.

  Isolation of compound (I) can be performed by subjecting the reaction solution to a post-treatment by a conventional method (for example, neutralization, extraction, washing with water, distillation, crystallization, etc.). In addition, the compound (I) can be purified by recrystallization, extraction purification, distillation, adsorption treatment of activated carbon, silica, alumina, etc., or chromatography methods such as silica gel column chromatography, but no particular purification is applied. As it is, for example, the extracted solution can be used as it is, or the residue after the solvent is distilled off can be used in the next step. Compound (I) may be converted to a desired acid addition salt using, for example, an appropriate acid (for example, hydrochloric acid).

  Hereinafter, the present invention will be described more specifically with reference to examples. The present invention is not limited by these.

Example 1 Synthesis of 4- (4-fluorobenzylideneamino) butan-2-one
To 4-aminobutan-2-one hydrochloride (1.24 g, 10 mmol) synthesized according to the method of Tetrahedron Letters 45, 8505 (2004), saturated saline (10 ml), MTBE (45 ml) and 4-fluorobenzaldehyde (0. 62 g, 5.0 mmol) was sequentially added at room temperature, and a 1.0 M aqueous sodium hydroxide solution was added to the solution to adjust the pH to about 10-12, followed by stirring at room temperature for 8 hours. After separating the organic layer of the reaction solution, the aqueous layer is extracted twice with MTBE (50 ml), the organic layers are combined, washed with saturated brine (50 ml), dried over anhydrous potassium carbonate, and concentrated under reduced pressure at around room temperature. Gave the title compound (0.74 g, 77%).
¹ H-NMR (CDCl ₃ , 400MHz) δppm: 8.29 (s, 1H), 7.69 (dd, J = 5Hz, 8Hz, 2H), 7.08 (t, J = 8Hz, 2H), 3.84 (t, J = 7Hz , 2H), 2.83 (t, J = 7Hz, 2H), 2.2 (s, 3H).

Example 2 Synthesis of 4- (4-fluoro-2-methylbenzylideneamino) butan-2-one
4-aminobutan-2-one hydrochloride (18.5 g, 150 mmol) synthesized according to the method of Tetrahedron Letters 45, 8505 (2004) was added to saturated saline (300 ml) and 4-fluoro-2-methylbenzaldehyde (10.4 g). , 75 mmol) were added sequentially at room temperature, and a 1.0 M aqueous sodium hydroxide solution was added to the solution to adjust the pH to about 12, followed by stirring at room temperature for 1 hour. MTBE (200 ml) was added to the reaction solution and stirred, and the organic layer was separated, the aqueous layer was extracted twice with MTBE (200 ml), the organic layers were combined, washed with saturated brine (200 ml), and then anhydrous potassium carbonate. And dried under reduced pressure near room temperature to give the title compound (14.1 g, 91%).
¹ H-NMR (CDCl ₃ , 400MHz) δppm: 8.57 (s, 1H), 7.80 (t, J = 6Hz, 1H), 6.85-6.92 (m, 2H), 3.85 (t, J = 7Hz, 2H), 2.84 (t, J = 7Hz, 2H), 2.48 (s, 3H), 2.19 (s, 3H).

Example 3 Synthesis of (R) -2- (4-fluorophenyl) piperidin-4-one 4- (4-Fluorobenzylideneamino) butan-2-one (96.6 mg, 0.5 mmol) was added to acetonitrile (3 8 g) and L-proline (11.5 mg, 0.1 mmol) were added, and the mixture was stirred at 25 ° C. for 28 hours. Saturated aqueous ammonium chloride solution (5 ml) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (30 ml). The organic layers were combined and extracted three times with 10% hydrochloric acid (30 ml). The extracted aqueous layer was washed twice with ethyl acetate (25 ml), neutralized with 1.0 M aqueous sodium hydroxide solution to pH 7-8, and extracted three times with ethyl acetate (30 ml). The extracted organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (50 mg, 52%). The optical purity of the obtained compound was 64% ee.
¹ H-NMR (CDCl ₃ , 400MHz) δppm: 7.35 (dd, J = 6Hz, 8Hz, 2H), 7.04 (t, 8Hz, 2H), 3.91 (dd, J = 4Hz, 10Hz, 1H), 3.47 (ddd , J = 2Hz, 7Hz, 12Hz, 1H), 3.02 (dt, J = 3Hz, 12Hz, 1H), 2.40-2.62 (m, 4H).

Example 4 Synthesis of (R) -2- (4-fluoro-2-methylphenyl) piperidin-4-one 4- (4-Fluoro-2-methylbenzylideneamino) butan-2-one (103.7 mg, 0 0.5 mmol) was added acetonitrile (5.0 g) and L-proline (11.5 mg, 0.1 mmol), and the mixture was stirred at 25 ° C. for 44 hours. Saturated aqueous ammonium chloride solution (5 ml) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (30 ml). The organic layers were combined and extracted three times with 10% hydrochloric acid (30 ml). The extracted aqueous layer was washed twice with ethyl acetate (25 ml), neutralized with 1.0 M aqueous sodium hydroxide solution to pH 7-8, and extracted three times with ethyl acetate (30 ml). The extracted organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (80 mg, 77%). The optical purity of the obtained compound was 55% ee.
¹ H-NMR (CDCl ₃ , 400MHz) δppm: 7.52 (dd, J = 6Hz, 9Hz, 1H), 6.91 (dt, J = 2Hz, 9Hz, 1H), 6.85 (dd, J = 2Hz, 9Hz, 1H) , 4.10 (dd, J = 4Hz, 10Hz, 1H), 3.49 (ddd, J = 2Hz, 7Hz, 12Hz, 1H), 3.03 (dt, J = 3Hz, 12Hz, 1H), 2.41-2.63 (m, 4H) , 2.33 (s, 3H).

Example 5 Synthesis of (R) -2- (4-fluorophenyl) piperidin-4-one The reaction was performed in the same manner as in Example 3 except that DMF was used instead of acetonitrile as the reaction solvent and the reaction time was 20 hours. The title compound was obtained. The yield was 41% and the optical purity was 47% ee.

Example 6 Synthesis of (R) -2- (4-fluorophenyl) piperidin-4-one 4- (tert-butyldimethylsilyloxy) -L-proline was used in place of L-proline as a catalyst, and the reaction was reduced to 0. The title compound was obtained in the same manner as in Example 3 except for 24 hours at ° C. The yield was 52% and the optical purity was 61% ee.

Example 7 Synthesis of (R) -2- (4-fluoro-2-methylphenyl) piperidin-4-one Example except that benzonitrile was used instead of acetonitrile as a reaction solvent and the reaction time was 4 days. The title compound was obtained in the same manner as in 4. The yield was 68% and the optical purity was 56% ee.

Using Example 8 (R) -2- (4-fluoro-2-methylphenyl) in place of L- proline as a synthesis catalyst for piperidin-4-one 4-(tert-butyldimethylsilyloxy) -L- proline The title compound was obtained in the same manner as in Example 3 except that the reaction was performed at 0 ° C. for 38 hours. The yield was 96% and the optical purity was 50% ee.

LC condition Daicel Chiral Cell OD-H 4.6mm x25cm
Isopropanol / hexane = 1/9 (Vol)
0.6ml / min,
UV220nm

  According to the present invention, compound (II) can be produced efficiently and inexpensively on an industrial scale without using expensive reagents. Moreover, when an optically active substance is used as the cyclic secondary amine, an optically active substance of compound (II) can be produced without using a technique such as optical resolution.

Claims (15)

Formula (I):

(In the formula, Ar represents an aromatic group which may have a substituent)
Or a salt thereof is cyclized in the presence of an optionally substituted cyclic secondary amine, represented by the general formula (II):

(Wherein Ar has the same meaning as above)
Or a salt thereof. The compound represented by the general formula (I) is represented by the general formula (IV):

(Wherein A ¹ , A ² , A ³ , A ⁴ and A ⁵ each independently represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 4 carbon atoms)
The manufacturing method of Claim 1 which is a compound represented by these. The production method according to claim ² , wherein A ¹ is methyl, A ² , A ⁴ and A ⁵ are hydrogen atoms, and A ³ is a fluorine atom.   The production method according to claim 1, wherein the cyclic secondary amine which may have a substituent is optically active.   The production method according to claim 1, wherein the cyclic secondary amine which may have a substituent is a cyclic secondary amine which has a substituent having an acidic proton and may further have a substituent. The cyclic secondary amine which may have a substituent is represented by the formula (III):

(Wherein, X ¹ and X ² each independently represent a hydrogen atom, a hydroxyl group or a protected hydroxyl group)
The manufacturing method of Claim 1 which is a compound represented by these. The cyclic secondary amine which may have a substituent is represented by the formula (IIIa):

(Wherein, X ¹ and X ² each independently represent a hydrogen atom, a hydroxyl group or a protected hydroxyl group)
The manufacturing method of Claim 1 which is a compound represented by these. General formula (I), wherein Ar—CHO (wherein Ar represents an aromatic group which may have a substituent) is reacted with 4-aminobutan-2-one or a salt thereof:

(Wherein Ar has the same meaning as above)
Or a salt thereof. Ar-CHO (wherein Ar represents an aromatic group which may have a substituent) is reacted with 4-aminobutan-2-one or a salt thereof to form a compound represented by the general formula (I):

(Wherein Ar has the same meaning as above)
A compound represented by general formula (I) or a salt thereof; and a compound represented by general formula (I) or a salt thereof cyclized in the presence of an optionally substituted cyclic secondary amine, Formula (II):

(Wherein Ar has the same meaning as above)
A step of obtaining a compound represented by the formula:
A process for producing a compound represented by the general formula (II) or a salt thereof. Ar-CHO (wherein Ar represents an aromatic group which may have a substituent) is reacted with 4-aminobutan-2-one or a salt thereof to form a compound represented by the general formula (I):

(Wherein Ar has the same meaning as above)
A compound represented by formula (I) or a salt thereof; and a compound represented by formula (I) or a salt thereof represented by formula (IIIa):

(Wherein, X ¹ and X ² each independently represent a hydrogen atom, a hydroxyl group or a protected hydroxyl group)
Is cyclized in the presence of a compound represented by the general formula (IIa):

(Wherein Ar has the same meaning as above)
A step of obtaining a compound represented by the formula:
A process for producing a compound represented by the general formula (IIa) or a salt thereof. The compound represented by the general formula (I) is represented by the general formula (IV):

(Wherein A ¹ , A ² , A ³ , A ⁴ and A ⁵ each independently represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 4 carbon atoms)
The manufacturing method in any one of Claims 8-10 which is a compound represented by these. A ¹ is ^methyl, A 2, ^{A 4} and ^{A 5} are hydrogen atoms, and ^{A 3} is a fluorine atom, a manufacturing method of claim 11, wherein. Formula (I):

(In the formula, Ar represents an aromatic group which may have a substituent)
Or a salt thereof. Formula (IV):

(Wherein A ¹ , A ² , A ³ , A ⁴ and A ⁵ each independently represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 4 carbon atoms)
Or a salt thereof. The compound according to claim 14, wherein A ¹ is methyl, A ² , A ⁴ and A ⁵ are hydrogen atoms, and A ³ is a fluorine atom.