JP2013010734A - Method for producing n-substituted lactam compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new method for producing an N-substituted lactam compound with high yield without requiring special equipment.SOLUTION: This method for producing the N-substituted lactam compound (3) includes a step of reacting a lactone compound (1) with an amine compound (2) represented by HN-Rin the presence of water. In the formulae, Rrepresents an optionally substituted methylene group; Rrepresents an optionally substituted divalent alicyclic hydrocarbon group or an optionally substituted divalent heterocyclic group; Rrepresents an optionally substituted methylene group; m represents 1 or 2; and n represents 0, 1, 2 or 3.

Description

  The present invention relates to a method for producing an N-substituted lactam compound.

  Formula (3)

[Wherein R ¹ has an aralkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, and a substituent. May represent an aromatic hydrocarbon group which may have a substituent or a heterocyclic group which may have ^a substituent, R ^a represents a methylene group which may have a substituent, and R ^b has a substituent. Represents a divalent alicyclic hydrocarbon group which may be substituted or a divalent heterocyclic group which may have a substituent, R ^c represents a methylene group which may have a substituent, m is 1 Or 2 and n represents 0, 1, 2 or 3. ]
The N-substituted lactam compounds represented by are useful as chemical raw materials, intermediates for the production of medical and agricultural chemicals, and the like.

  As a method for producing an N-substituted lactam compound, for example, Non-Patent Document 1 discloses that N-benzyl-pyrrolidine-2 is reacted with γ-butyrolactone and benzylamine in the absence of a solvent by heating to 220 ° C. A method for obtaining ON is described. Non-Patent Document 2 discloses that γ-butyrolactone and benzylamine are heated to 220 ° C. in a microwave in the presence of 1-n-butyl-3-methylindazolium tetrafluoroborate in 1,4-dioxane. A method is described in which N-benzyl-pyrrolidin-2-one is obtained by reaction by heating.

Tetrahedron, Vol.60 (2004) p.4567-4578 J. Org. Chem., Vol. 73 (2008) p.8627-8630

  In the method described in Non-Patent Document 1, the yield of the N-substituted lactam compound is not always satisfactory, and the method described in Non-Patent Document 2 requires special reaction equipment that generates microwaves.

  Therefore, there has been a demand for a new method and the like that can produce an N-substituted lactam compound with an excellent yield without requiring special equipment.

As a result of intensive studies, the present inventors have reached the present invention.
That is, the present invention is as follows.

  [1] Formula (1)

[Wherein, R ^a represents a methylene group which may have ^a substituent, and R ^b has a divalent alicyclic hydrocarbon group or a substituent which may have a substituent. Represents a divalent heterocyclic group, R ^c represents a methylene group which may have a substituent, m represents 1 or 2, and n represents 0, 1, 2 or 3. ]
A lactone compound (hereinafter sometimes referred to as lactone compound (1)),
Equation _{(2): H 2 N-} R 1
[Wherein R ¹ has an aralkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, and a substituent. Represents an aromatic hydrocarbon group or a heterocyclic group which may have a substituent. ]
A compound represented by formula (3), which comprises a step of reacting in water with an amine compound represented by formula (hereinafter, sometimes referred to as amine compound (2)).

[Wherein R ¹ , R ^a , R ^b , R ^c , m and n are as defined above. ]
A method for producing an N-substituted lactam compound represented by the formula (hereinafter sometimes referred to as N-substituted lactam compound (3)).

[2] The production method according to [1], wherein the step is a step of reacting the lactone compound represented by the formula (1) and the amine compound represented by the formula (2) under heating.
[3] The production method according to [1] or [2], wherein the step is performed under a pressurized condition.
[4] The production method according to any one of [1] to [3], wherein the amount of water used in the step is in the range of 4 to 210 mol with respect to 1 mol of the lactone compound represented by the formula (1). .
[5] The production method according to any one of [1] to [4], wherein the lactone compound represented by the formula (1) is a γ-lactone compound, a δ-lactone compound, or an ε-lactone compound.
[6] The production method according to any one of [1] to [5], wherein R ¹ is a benzyl group which may have a substituent or an allyl group which may have a substituent.

  ADVANTAGE OF THE INVENTION According to this invention, the new method etc. which can manufacture a N-substituted lactam compound with the outstanding yield can be provided, without requiring special equipment.

Hereinafter, the present invention will be described in detail.
Examples of the “divalent alicyclic hydrocarbon group” include a cycloalkanediyl group, a cycloalkenediyl group, a cycloalkynediyl group, and the like.

  The “divalent heterocyclic group” is a monocyclic or bicyclic aromatic or non-aromatic divalent heterocyclic ring containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Groups and the like. Specifically, for example, pyrrole diyl group, thiophene diyl group, frangiyl group, pyrazole diyl group, imidazole diyl group, oxazole diyl group, isoxazole diyl group, oxadiazole diyl group, triazole diyl group, thiadiazole diyl group, 5-membered aromatic heterocyclic group such as isothiazolediyl group; 6-membered aromatic heterocyclic ring such as pyridinediyl group, pyridazinediyl group, pyrimidinediyl group, pyrazinediyl group; pyrrolidinediyl group, pyrrolindiyl group, imidazolinediyl group, pyra 5-membered non-aromatic heterocyclic group such as zolidinediyl group, pyrazolinediyl group, oxazolidinediyl group, thiazolidinediyl group; pyrandiyl group, piperidinediyl group, tetrahydropyridinediyl group, dihydropyridinediyl group, piperazinediyl group, morpholine 6-membered non-aromatic heterocyclic group such as N-diyl group, thiomorpholine diyl group; indole diyl group, isoindole diyl group, benzothiophene diyl group, isobenzothiophene diyl group, benzofuranyl group, isobenzofuranyl group, indazolediyl group , Benzimidazoldiyl group, imidazopyridinediyl group, benzothiazolediyl group, quinolinediyl group, isoquinolinediyl group, and other bicyclic aromatic heterocyclic groups; indolinediyl group, isoindolinediyl group, thiochromandiyl group, chromandiyl group, etc. And a bicyclic non-aromatic heterocyclic group.

Examples of the “cycloalkanediyl group” include a C _{3 to} C ₁₀ cycloalkanediyl group, specifically a cyclopropanediyl group (cyclopropane-1,1-diyl group, cyclopropane-1,2-diyl group). ), Cyclobutanediyl group (cyclobutane-1,1-diyl group, cyclobutane-1,2-diyl group, etc.), cyclopentanediyl group (cyclopentane-1,1-diyl group, cyclopentane-1,2-diyl group) Etc.), cyclohexanediyl group (cyclohexane-1,1-diyl group, cyclohexane-1,2-diyl group, etc.), cycloheptanediyl group (cycloheptane-1,1-diyl group, cycloheptane-1,2-diyl) Group), cyclooctanediyl group (cyclooctane-1,1-diyl group, cyclooctane-1,2-diyl group, etc.), Nonanediyl group (cyclononane-1,1-diyl group, cyclononane-1,2-diyl group, etc.), cyclodecanediyl group (cyclodecane-1,1-diyl group, cyclodecane-1,2-diyl group, etc.) It is done.

Examples of the “cycloalkenediyl group” include a C _{4 to} C ₁₀ cycloalkenediyl group, specifically, a cyclobutenediyl group (a 2-cyclobutene-1,1-diyl group, 1-cyclobutene-1, 2-diyl group, 2-cyclobutene-1,2-diyl group, etc.), cyclopentenediyl group (2-cyclopentene-1,1-diyl group, 1-cyclopentene-1,2-diyl group, etc.), cyclohexenediyl group ( 2-cyclohexene-1,1-diyl group, 1-cyclohexene-1,2-diyl group, etc.), cycloheptene diyl group (2-cycloheptene-1,1-diyl group, 1-cycloheptene-1) , 2-diyl group, etc.), cyclooctene diyl group (2-cyclooctene-1,1-diyl group, 1-cyclooctene-1,2-diyl group, etc.), cyclononene di Group (2-cyclononene-1,1-diyl group, 1-cyclononene-1,2-diyl group, etc.), cyclodecenediyl group (2-cyclodecene-1,1-diyl group, 1-cyclodecene-1,2) -Diyl group and the like).

The "cyclo alkyne diyl group", for example, include C ₈ -C ₁₀ cycloalkyl alkyne diyl group include cyclooctene Chin-diyl (2-cyclooctyne-1,1-diyl group, 3-Shikurohepuchin -1 , 2-diyl group, etc.), cyclononine diyl group (2-cyclononine-1,1-diyl group, 3-cyclononine-1,2-diyl group, etc.), cyclodecyne diyl group (2-cyclodecyne-1, 1-diyl group, 3-cyclodecyne-1,2-diyl group, etc.).

  Examples of the “aralkyl group” include an aralkyl group having 7 to 12 carbon atoms, and specific examples include a benzyl group, a phenylethyl group, and naphthylmethyl. As a substituent which an aralkyl group has, a halogen atom, an alkoxy group, a nitro group, a cyano group, an alkyl group, an aryl group etc. are mentioned, for example, One or more can be substituted.

  Examples of the “alkenyl group” include linear or branched alkenyl groups having 2 to 10 carbon atoms, specifically vinyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl groups. , Nonenyl group, decenyl group and the like. As a substituent which an alkenyl group has, a halogen atom, an alkoxy group, a nitro group, a cyano group, an aryl group etc. are mentioned, for example, One or more can be substituted.

  Examples of the “alkynyl group” include linear or branched alkynyl groups having 2 to 10 carbon atoms, specifically ethynyl group, propargyl group, butynyl group, pentynyl group, hexynyl group, heptynyl group, octynyl group. , Noninyl group, decynyl group and the like. As a substituent which an alkynyl group has, a halogen atom, an alkoxy group, a nitro group, a cyano group, an aryl group etc. are mentioned, for example, One or more can be substituted.

  Examples of the “aromatic hydrocarbon group” include aryl groups having 6 to 10 carbon atoms, and specifically include phenyl group, naphthyl group and the like. As a substituent which an aromatic hydrocarbon group has, a halogen atom, an alkoxy group, a nitro group, a cyano group, an alkyl group etc. are mentioned, for example, One or more can be substituted.

  The “heterocyclic group” is, for example, a monocyclic or bicyclic aromatic or non-aromatic heterocyclic group containing 1 to 3 heteroatoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom. A cyclic group etc. are mentioned. Specifically, for example, 5-membered fragrance such as pyrrolyl group, thienyl group, furyl group, pyrazolyl group, imidazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, oxadiazolyl group, triazolyl group, tetrazolyl group, thiadiazolyl group, etc. Heterocyclic group: 6-membered aromatic heterocycle such as pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group; pyrrolidinyl group, pyrrolinyl group, imidazolidinyl group, imidazolinyl group, pyrazolidinyl group, pyrazolinyl group, oxazolidinyl group, thiazolidinyl group, isothiazolyl 5-membered non-aromatic heterocyclic group such as a group; 6-membered non-aromatic heterocyclic group such as pyranyl group, piperidyl group, tetrahydropyridyl group, dihydropyridyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group; Bicyclic aromatic heterocycles such as enedryl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, isobenzofuranyl, indazolyl, benzimidazolyl, imidazolpyridyl, benzothiazolyl, quinolyl, and isoquinolyl Groups; bicyclic non-aromatic heterocyclic groups such as indolinyl group, isoindolinyl group, thiochromanyl group, chromanyl group and the like.

  Substitution of methylene group, divalent alicyclic hydrocarbon group, divalent heterocyclic group, cycloalkanediyl group, cycloalkenediyl group, cycloalkynediyl group, aralkyl group, aromatic hydrocarbon group, heterocyclic group Examples of the group include a halogen atom, an alkoxy group, a cycloalkoxy group, a nitro group, a cyano group, an alkyl group, a cycloalkyl group, and an aryl group (the general aryl group may have an alkyl group, a halogen atom, and nitro). Etc., and one or more substituents can be substituted.

  Examples of the substituent of the alkenyl group and alkynyl group include a halogen atom, an alkoxy group, a nitro group, a cyano group, and an aryl group (the general aryl group may have an alkyl group, a halogen atom, and nitro). One or more can be substituted.

  Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

Examples of the “alkoxy group” include linear or branched C _{1 to} C ₁₀ alkoxy groups, and specifically include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a sec-butoxy group, Examples thereof include a tert-butoxy group, a pentyloxy group, a hexyloxy group, a heptyloxy group, an octyloxy group, a nonyloxy group, and a decyloxy group.

Examples of the “cycloalkoxy group” include a C _{4 to} C ₁₀ cycloalkoxy group, and specifically include a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, a cyclooctyloxy group, a cyclo Nonyloxy group, cyclodecyloxy group, etc. are mentioned.

Examples of the “alkyl group” include a linear or branched C _{1 to} C ₁₀ alkyl group, and specifically include a methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, tert -A butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, etc. are mentioned. Preferably, a methyl group, an ethyl group, an isopropyl group, a sec-butyl group, a tert-butyl group, etc. are mentioned.

Examples of the “cycloalkyl group” include a C _{4 to} C ₁₀ cycloalkyl group, and specifically include a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, a cyclodecyl group, and the like. Can be mentioned.

Examples of the “aryl group” include C ₆ -C ₁₀ aryl groups, and specific examples include a phenyl group and a naphthyl group.

R ¹ is preferably an aralkyl group which may have a substituent or an alkenyl group which may have a substituent, more preferably a benzyl group or a substituent which may have a substituent. An allyl group which may have a group.

R ^a is preferably a methylene group.
m is preferably 1.

R ^b is preferably a divalent cycloalkanediyl group which may have a substituent or a monocyclic divalent heterocyclic group which may have a substituent, and more preferably, It is a divalent cycloalkanediyl group that may have a substituent, and particularly preferably a divalent C _{3 to} C ₆ cycloalkanediyl group that may have a substituent.

R ^c is preferably a methylene group.
n is preferably 0 or 1, more preferably 0.

  Examples of the lactone compound (1) include a γ-lactone compound, a δ-lactone compound, and an ε-lactone compound, and preferably a γ-lactone compound. Examples of the lactone compound (1) include compounds represented by the following formulas (1-1) to (1-12). When the lactone compound (1) has an asymmetric carbon, the lactone compound (1) may be an optically active substance.

The particularly preferred lactone compound (1) is, as already explained, R ^a is a methylene group, R ^b is a divalent cycloalkanediyl group which may have a substituent, m is 1 and n is 0. Lactone compound (1). In particular, the lactone compound (1) represented by the following formula (1 ′) is preferable.

(Wherein, R ^d represents an alkanediyl group having 1 to 4 carbon atoms which may have a substituent.)
Among the specific examples of the lactone compound (1), the lactone compound (1) represented by the formula (1 ′) is represented by the formulas (1-1) to (1-6) and (1-9). ) Are applicable.

  Examples of the amine compound (2) include allylamine, aniline, chloroaniline, dichloroaniline, trichloroaniline, fluoroaniline, methoxyaniline, dimethoxyaniline, nitroaniline, dinitroaniline, aminofuran, aminopyrrole, aminothiophene, aminopyran, amino Pyridine, benzylamine, chlorobenzylamine, dichlorobenzylamine, trichlorobenzylamine, fluorobenzylamine, methoxybenzylamine, dimethoxybenzylamine, nitrobenzylamine, dinitrobenzylamine, chlorobenzylamine, dichlorobenzylamine, trichlorobenzylamine, fluoro Benzylamine, methylbenzylamine, ethylbenzylamine, methoxybenzylamine, dimethoxybenzene Jiruamin, aminomethyl benzonitrile, phenylethylamine, include naphthyl methylamine etc., preferably, allylamine, benzylamine, methoxybenzylamine, and the like.

  Examples of the N-substituted lactam compound (3) include compounds represented by the following formulas (3-1) to (3-48). When the N-substituted lactam compound (3) has an asymmetric carbon, the N-substituted lactam compound (3) may be an optically active substance.

  The N-substituted lactam compound (3) is produced by a step of reacting the lactone compound (1) and the amine compound (2) in water. Hereinafter, the reaction between the lactone compound (1) and the amine compound (2) may be referred to as this reaction.

  The lactone compound (1) is a commercially available compound or can be easily prepared from a commercially available compound. For example, it can prepare according to patent document WO2007 / 122745. The lactone compound (1) may be prepared by a method other than the above.

  The amount of the amine compound (2) used is 0.8 to 10 mol, preferably 1 to 6 mol, more preferably 1.1 to 4 mol, and still more preferably, per 1 mol of the lactone compound (1). The range of 1.7-3 mol is mentioned.

  The amount of water used in this reaction is preferably in the range of 3 to 500 mol, more preferably in the range of 4 to 210 mol, per 1 mol of the lactone compound (1).

  In this reaction, the reaction can be performed using only water as a solvent, but the reaction can also be performed using a mixed solvent of water and an organic solvent. Examples of the organic solvent include aliphatic hydrocarbons (hexane, heptane, cyclohexane, etc.), aromatic hydrocarbons (benzene, toluene, xylene, ethylbenzene, chlorobenzene, dichlorobenzene, etc.), halogenated hydrocarbons (dichloromethane, dichloroethane, Chloroform, chlorobutane, etc.), ether (tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether, methyl tert-butyl ether, diethyl ether, etc.), alcohol (methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-methyl- 2-propanol etc.), nitriles (acetonitrile, propionitrile etc.) etc., or a mixture of two or more of these. Preferred organic solvents include methanol, ethanol and the like. The amount of the organic solvent used is, for example, in the range of 0 to 100 parts by weight, preferably in the range of 0.1 to 20 parts by weight, more preferably in the range of 0.1 to 2 parts by weight with respect to the lactone compound (1). It is done.

  In this reaction, it is also preferable to add an additive. Examples of such additives include inorganic acids (hydrogen chloride, hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, etc.), organic acids (formic acid, acetic acid, citric acid, oxalic acid, methanesulfone). Acid, toluenesulfonic acid, trifluoromethanesulfonic acid and the like), acidic ion exchange resin, γ-alumina, N-hydroxybenzotriazole, tetrabutylammonium bromide and the like. Preferred additives include toluene sulfonic acid, γ-alumina and the like.

  As reaction temperature, the range of 100-300 degreeC is preferable, Preferably it is the range of 130-200 degreeC, More preferably, the range of 160-200 degreeC is mentioned.

  This reaction is also preferably performed under pressurized conditions. The pressure in the case of performing under pressure conditions is, for example, in the range of 0.1 to 5 MPa, preferably in the range of 0.5 to 2 MPa.

  By subjecting the reaction mixture obtained by this reaction to post-treatment, the N-substituted lactam compound (3) can be isolated. For example, after mixing the reaction mixture and water, if necessary, the mixture is further mixed with water and an organic solvent that can be separated to separate the liquid, so that excess amine compound (2), additive, and these are hydrolyzed. The decomposed component can be distributed to the aqueous layer, while the N-substituted lactam compound (3) can be distributed to the organic layer. After mixing the reaction mixture and water at the time of the post-treatment, the acid layer is acidified by adding an acid, or the aqueous layer at the time of the liquid separation operation is acidified by mixing an acidic aqueous solution with the reaction mixture. An amount of the amine compound (2) can be efficiently distributed to the aqueous layer. A preferable range of the pH of the aqueous layer is, for example, in the range of 1 to 7, and more preferably in the range of 4 to 6.

  Examples of organic solvents that can be separated from water include aliphatic hydrocarbons (hexane, heptane, cyclohexane, etc.), aromatic hydrocarbons (benzene, toluene, xylene, ethylbenzene, chlorobenzene, dichlorobenzene, etc.), and halogenated hydrocarbons. (Dichloromethane, dichloroethane, chloroform, chlorobutane, etc.), ether (methyl tert-butyl ether, etc.), ketone (methyl isobutyl ketone, etc.), ester (ethyl acetate, butyl acetate, etc.), etc., or a mixture of two or more of these .

  The organic layer obtained by liquid separation may be further subjected to water washing, inorganic salt water washing, basic water washing, acid water washing, or the like. Water washing, inorganic salt washing, basic water washing, acidic water washing, etc. may be repeated.

  The solution containing the N-substituted lactam compound (3) thus obtained may be used as it is as a chemical raw material, a pharmaceutical intermediate for producing agricultural chemicals, or the like, or by N-substituted lactam compound (3) by solvent concentration or the like. And the isolated N-substituted lactam compound (3) may be used as a chemical raw material, an intermediate for the production of medical and agrochemicals, and the like. The N-substituted lactam compound (3) may be further purified by methods such as column chromatography and recrystallization.

Hereinafter, the present invention will be described in more detail with reference to examples.
Example 1
Synthesis of (1R, 5S) -3-benzyl-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-one (Compound A) In a 200 mL autoclave, (1R, 5S) -6,6- 19.3 g of a toluene solution containing 15.0 g (118.6 mmol) of dimethyl-3-oxabicyclo [3.1.0] hexane-2-one (compound B), 25.7 g (239.7 mmol) of benzylamine and water 64.8 g (3.6 mol) was charged and mixed, and then heated to 180 ° C. under a pressure of 0.9 MPa. After stirring at the same temperature for 10 hours and cooling to 35 ° C., 12.2 g (117.1 mmol) of 1N hydrochloric acid was added dropwise to the reaction mixture to adjust the pH to 4. The reaction mixture was extracted twice with 45 g of methyl tert-butyl ether. As a result of quantifying the reaction mass, it contained 24.1 g (111.8 mmol, yield 94.3%) of Compound A. The obtained organic layers were mixed, washed once with 45 g of water, the organic layer was concentrated under reduced pressure conditions, and the solvent was distilled off. 64 g of heptane was added to the concentrated solution, and the temperature was raised to 65 ° C., then 1.5 g of activated carbon was added, and the mixture was stirred at the same temperature for 0.5 hour. The mixture was filtered, and the filtration residue was washed with 45 g of heptane. The obtained filtrate and washing solution were mixed and concentrated under reduced pressure conditions to distill off the solvent. 60 g of heptane was added to the resulting concentrated liquid, the temperature was raised to 47 ° C., and (1R, 5S) -3-benzyl-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-one was added. 0.02 g was added and stirred for 1 hour. Then, it cooled to 5 degreeC and filtered the precipitated crystal | crystallization. The obtained crystals were further washed with 38 g of heptane at 5 ° C. and then dried under reduced pressure to obtain 21.57 g of white crystals containing 21.52 g (99.9 mmol, yield 84.3%) of Compound A ^*) .
¹ H-NMR (CDCl ₃ ) δ: 7.34 to 7.24 (5H, m), 4.50 (1H, d, J = 14 Hz), 4.15 (1H, d, J = 15 Hz), 3 .37 (1H, dd, J = 7 Hz, 11 Hz), 2.99 (1H, d, J = 11 Hz), 1.85 (1H, d, J = 7 Hz), 1.58 (1H, dd, J = 7Hz, 7Hz), 1.09 (3H, s), 0.94 (3H, s)
*) Quantitative analysis was performed under the following conditions using HPLC.
[HPLC conditions]
Column: CAPCELLPAC C18 MGIII, 4.6 mmφ × 100 mm, 3 μm (manufactured by Shiseido)
Flow rate: 1.35 ml / min
Detection wavelength: UV 220nm
Mobile phase: Liquid A (0.1% phosphoric acid) / liquid B (acetonitrile)
Gradient condition:
Time (minutes) 0 45
A liquid 95 30
B liquid 5 70
Column temperature: 35 ° C

Example 2
Synthesis of Compound A A 200 mL autoclave was charged with 9.82 g of a toluene solution containing 7.58 g (60.1 mmol) of Compound B, 12.87 g (120 mmol) of benzylamine and 32.5 g (1.80 mol) of water, and mixed. It heated to 170 degreeC on 0.7 MPa of pressure conditions. The mixture was stirred at the same temperature for 15 hours to obtain a reaction mixture containing 12.3 g (57.3 mmol, yield 95.6%) of Compound A ^*) .
*) The reaction mixture was quantified under the same HPLC conditions as in Example 1.

Example 3
Synthesis of Compound A A 1000 mL autoclave was charged with 64.77 g of a toluene solution containing 50.0 g (396.3 mmol) of Compound B, 84.9 g (792.7 mmol) of benzylamine and 214 g (11.9 mol) of water, and mixed. The mixture was heated to 195 ° C. under a pressure of 1.6 MPa. The mixture was stirred at the same temperature for 10 hours to obtain a reaction mixture containing 81.56 g (378.9 mmol, yield 95.6%) of Compound A ^*) .
*) The reaction mixture was quantified under the same HPLC conditions as in Example 1.

Examples 4 to 10, Comparative Example 1
Synthesis of Compound A The reaction was carried out in the same manner as in Example 2 except that the amount of water described in Example 2 was replaced with the amount described in Table 1 and the amount of water was changed. The results are shown in Table 1.

Example 11
Synthesis of Compound A A 200 mL autoclave was charged with 14.71 g of a toluene solution containing 11.36 g (90.1 mmol) of Compound B, 19.3 g (180 mmol) of benzylamine, 16.2 g (899 mmol) of water and 22.7 g of methanol and mixed. Then, it was heated to 160 ° C. under a pressure condition of 1.0 MPa. The mixture was stirred at the same temperature for 21 hours to obtain a reaction mixture containing 17.5 g (81.3 mmol, yield 90.3%) of Compound A ^*) .
*) The reaction mixture was quantified under the same HPLC conditions as in Example 1.

Example 12
Synthesis of Compound A A 200 mL autoclave was charged with 9.81 g of a toluene solution containing 7.57 g (60.0 mmol) of Compound B, 12.85 g (120 mmol) of benzylamine, 10.84 g (600 mmol) of water, and 15.1 g of methanol and mixed. Then, it was heated to 170 ° C. under a pressure condition of 1.2 MPa. The mixture was stirred at the same temperature for 15 hours to obtain a reaction mixture containing 12.1 g (56.2 mmol, yield 93.5%) of Compound A ^*) .
*) The reaction mixture was quantified under the same HPLC conditions as in Example 1.

Example 13
Synthesis of Compound A A 200 mL autoclave was charged with 5.05 g (39.6 mmol, content 99.0%) of Compound B, 8.49 g (79.3 mmol) of benzylamine, 17.96 g (997 mmol) of water, and 10.03 g of methanol. After mixing, the mixture was heated to 165 ° C. under a pressure of 0.9 MPa. The mixture was stirred at the same temperature for 12 hours to obtain a reaction mixture containing 8.39 g (39.0 mmol, yield 98.5%) of Compound A.
Thereafter, 3.99 g of 35% hydrochloric acid was added to adjust the pH to 5, followed by extraction twice with 15 g of toluene. The obtained organic layers were combined, concentrated under reduced pressure conditions to distill off the solvent, and then 23 g of heptane was introduced. After cooling to 10 ° C., the precipitated crystals were filtered, washed with 14 g of heptane, and dried. 7.05 g (32.7 mmol, 82.5% yield) of crystals of compound A were obtained ^*) .
*) The reaction mixture was quantified under the same HPLC conditions as in Example 1.

Example 14
Synthesis of Compound A A 200 mL autoclave was charged with 14.69 g of a toluene solution containing 11.34 g (90.0 mmol) of Compound B, 16.39 g (153 mmol) of benzylamine, 16.2 g (900 mmol) of water, and 22.78 g of methanol and mixed. Then, it was heated to 170 ° C. under a pressure condition of 1.2 MPa. The mixture was stirred at the same temperature for 15 hours to obtain a reaction mixture containing 17.96 g (83.4 mmol, yield 92.8%) of Compound B ^*) .
*) The reaction mixture was quantified under the same HPLC conditions as in Example 1.

Example 15
Synthesis of Compound A A 200 mL autoclave was charged with 9.80 g of a toluene solution containing 7.57 g (60.0 mmol) of Compound B, 32.1 g (300 mmol) of benzylamine, and 10.8 g (600 mol) of water. It heated to 170 degreeC under the pressure conditions of 6 MPa. The mixture was stirred at the same temperature for 15 hours to obtain a reaction mixture containing 11.8 g (54.9 mmol, yield 91.5%) of Compound A ^*) .
*) The reaction mixture was quantified under the same HPLC conditions as in Example 1.

Example 16
Synthesis of Compound A 14.69 g of toluene solution containing 11.34 g (89.9 mmol) of Compound B in a 200 ml autoclave, 19.26 g (179.8 mmol) of benzylamine, 16.25 g (899 mmol) of water, 22.71 g of methanol and p -Toluenesulfonic acid monohydrate 3.51 g (18.0 mmol) was charged and mixed, and then heated to 170 ° C under a pressure of 1.2 MPa. The mixture was stirred at the same temperature for 15 hours, and the resulting reaction mixture was quantified ^*) . The yield of compound A based on compound B was 95.4%.
*) The HPLC conditions are the same as the HPLC conditions of Example 1.

Example 17
Synthesis of Compound A 4.90 g of a toluene solution containing 3.78 g (30.0 mmol) of Compound B in a 100 ml autoclave, 3.54 g (33.0 mmol) of benzylamine, 5.5 g (305 mmol) of water, and 0.38 g of γ-alumina (3.00 mmol) was charged, mixed and heated to 170 ° C. in an autoclave. The mixture was stirred at the same temperature for 15 hours, water was added to the resulting reaction mixture, and the mixture was stirred and separated to determine the organic layer and the aqueous layer ^*) . The yield of compound A based on compound B was 89.9%.
*) The HPLC conditions are the same as the HPLC conditions of Example 1.

Example 18
Synthesis of (1R, 5S) -3-allyl-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-one In a 100 ml autoclave, 5.0 g (39.6 mmol) of Compound B and allylamine After charging and mixing 53 g (79.3 mmol) and 21.4 g (1.19 mol) of water, the mixture was heated to 175 ° C. under pressure. The mixture was stirred at the same temperature for 15 hours, and the resulting reaction mixture was quantified ^*) . The yield based on compound B was 100%.
¹ H-NMR (CDCl ₃ ) δ: 5.75-5.65 (1H, m), 5.22-5.16 (2H, m), 3.84 (1H, dd, J = 7 Hz, 15 Hz) , 3.72 (1H, dd = 7Hz, 15Hz), 3.48 (1H, dd, J = 7Hz, 11Hz), 3.08 (1H, d, J = 11Hz), 1.81 (1H, d, J = 7 Hz), 1.61 (1H, dd, J = 6 Hz, 6 Hz), 1.11 (3H, s), 1.01 (3H, s)
*) The HPLC conditions are the same as the HPLC conditions of Example 1.

Example 19
Synthesis of (1R, 5S) -6,6-dimethyl-3-[(1S) -1-phenylethyl] -3-azabicyclo [3.1.0] hexane-2-one Compound B 5.00 g in a 100 ml autoclave (39.6 mmol), 9.61 g (79.3 mmol) of (S)-(−)-1-phenylethylamine and 21.4 g (1.2 mol) of water were charged and mixed, and then under a pressure condition, 175 ° C. Heated. The mixture was stirred at the same temperature for 37.5 hours, and the resulting reaction mixture was quantified ^*) . The yield of (1R, 5S) -6,6-dimethyl-3-[(1S) -1-phenylethyl] -3-azabicyclo [3.1.0] hexan-2-one with respect to compound B was 91%. Met.
¹ H-NMR (CDCl ₃ ) δ: 7.35-7.23 (5H, m), 5.39 (1H, q, J = 8 Hz), 3.45 (1H, dd, J = 7 Hz, 11 Hz) , 2.78 (1H, d, J = 10 Hz), 1.82 (1H, s), 1.78 (1H, dd, J = 2 Hz, 7 Hz), 1.52 (3H, d, J = 7 Hz) , 1.01 (3H, s), 0.64 (3H, s)
*) The HPLC conditions are the same as the HPLC conditions of Example 1.

Example 20
Synthesis of (1R, 5S) -3-[(4-methoxyphenyl) methyl] -6,6-dimethyl-3-azabicyclo [3.1.0] hexan-2-one In a 100 ml autoclave, 8.00 g of compound B ( 63.42 mmol), 17.4 g (126.8 mmol) of 4-methoxybenzylamine and 11.43 g (0.63 mol) of water were mixed and heated to 175 ° C. under pressure. The mixture was stirred at the same temperature for 47.5 hours, and the resulting reaction mixture was quantified ^*) . The yield of (1R, 5S) -3-[(4-methoxyphenyl) methyl] -6,6-dimethyl-3-azabicyclo [3.1.0] hexan-2-one with respect to compound B was 94%. there were.
¹ H-NMR (CDCl ₃ ) δ: 7.19-7.16 (2H, m), 6.89-6.83 (2H, m), 4.39 (1H, d, J = 15 Hz), 4 .13 (1H, d, J = 14 Hz), 3.80 (3H, s), 3.35 (1H, dd, J = 7 Hz, 11 Hz), 2.98 (1H, d, J = 11 Hz), 1 .83-1.81 (1H, m), 1.55 (1H, dd, J = 6 Hz, 6 Hz), 1.08 (3H, s), 0.92 (3H, s)
*) The HPLC conditions are the same as the HPLC conditions of Example 1.

  The present invention provides a new method for producing the N-substituted lactam compound of the formula (1) in an excellent yield without requiring special equipment.

Claims (6)

Formula (1)

[Wherein, R ^a represents a methylene group which may have ^a substituent, and R ^b has a divalent alicyclic hydrocarbon group or a substituent which may have a substituent. Represents a divalent heterocyclic group, R ^c represents a methylene group which may have a substituent, m represents 1 or 2, and n represents 0, 1, 2 or 3. ]
A lactone compound represented by
Equation _{(2): H 2 N-} R 1
[Wherein R ¹ has an aralkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, and a substituent. Represents an aromatic hydrocarbon group or a heterocyclic group which may have a substituent. ]
Having the step of reacting with an amine compound represented by formula (3)

[Wherein R ¹ , R ^a , R ^b , R ^c , m and n are as defined above. ]
The manufacturing method of the N-substituted lactam compound shown by these.   The method according to claim 1, wherein the step is a step of reacting the lactone compound represented by the formula (1) and the amine compound represented by the formula (2) under heating.   The manufacturing method of Claim 1 or 2 with which the said process is performed on pressurization conditions.   The production method according to any one of claims 1 to 3, wherein the amount of water used in the step is in the range of 3 to 500 mol with respect to 1 mol of the lactone compound represented by the formula (1).   The production method according to claim 1, wherein the lactone compound represented by the formula (1) is a γ-lactone compound, a δ-lactone compound, or an ε-lactone compound. The production method according to any one of claims 1 to 5, wherein R ¹ is a benzyl group which may have a substituent or an allyl group which may have a substituent.