JP2010208966A - Preparation method of 5-acyl-6-alkyl-2-oxo-1,2-dihydropyridine-3-carbonitriles - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for synthesizing a compound represented by formula (I), which is useful as a synthetic intermediate of a therapeutic agent for dementia, with high selectivity and in high yield. <P>SOLUTION: The method for preparing the compound represented by formula (I) (wherein R<SP>1</SP>is an optionally substituted aryl group or the like; and R<SP>2</SP>is a lower alkyl group) includes treating a mixture of a compound of formula (II) (wherein X is a lower alkylamino group or the like; and R<SP>1</SP>and R<SP>2</SP>are the same) and 2-cyanoacetamide, or a compound of formula (III), with a base in the presence of a metal cation capable of establishing a chelate structure with a carbonyl group. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a method for producing 5-acyl-6-alkyl-2-oxo-1,2-dihydropyridine-3-carbonitriles useful as intermediates for the production of a drug substance such as a dementia therapeutic drug.

  A 5-substituted-3-oxadiazol-1,6-naphthyridin-2 (1H) -one derivative expected as a therapeutic agent for dementia is disclosed in Patent Document 1. 5-Acyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile is one of the key intermediates of this derivative, and several production methods thereof are disclosed in Patent Document 1. Yes. Among them, the method shown in the following figure is 5- (3-methoxyphenyl) -3- (5-methyl-1,2,4-oxadiazol-3-yl) -1,6-naphthyridin-2 (1H) -one. It is promising as an industrial production method of (6).

  In the above process, the key intermediate 5- (3-methoxybenzoyl) -6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (4) is obtained by reacting compound (2) with 2-cyanoacetamide. It is obtained by ring-closing the reaction product. In this ring-closure reaction, the two carbonyl groups of compound (3) can both be reactive sites, so that key intermediate (4) and unnecessary geometric isomer (5) are formed in a ratio of about 1: 1. The yield of the product (4) was as low as 36%. Therefore, an improved production method for selectively synthesizing the key intermediate (4) has been desired.

しかし、当手法ではカルボニル基の保護および脱保護の工程が増加する上、収率も低い。 Attempts to selectively obtain the desired isomer from an asymmetric diketone have been disclosed by the method shown in the figure below (for example, see Non-Patent Document 1).

However, this method increases the number of steps for protecting and deprotecting the carbonyl group, and the yield is low.

International Publication No. 1999/03857 Pamphlet

J. Heterocyclic Chem., 1990, 27, P.511-518

  An object of the present invention is to provide a 5-acyl-6-alkyl- useful as a synthetic intermediate of a 5-substituted-3-oxadiazolyl-1,6-naphthyridin-2 (1H) -one derivative expected as a therapeutic agent for dementia. An object of the present invention is to provide a method capable of synthesizing 2-oxo-1,2-dihydropyridine-3-carbonitriles with high selectivity and high yield without increasing the number of steps from a known production method.

  As a result of intensive studies to solve the above problems, the present inventors have selected a structural isomer that is the target key intermediate by allowing a metal cation capable of building a chelate structure together with a carbonyl group to exist in the reaction system. The present invention was completed by finding out that it was possible to obtain the target. That is, according to the present invention, there is provided a method for selectively producing 5-acyl-6-alkyl-2-oxo-1,2-dihydropyridine-3-carbonitriles including the following embodiments.

（式中、Ｒ^１は置換されていてもよいアリール基または置換されていてもよいヘテロアリール基を意味し、Ｒ^２は低級アルキル基を意味する。）
で表される化合物の製造方法であって、 [Claim 1] The following formula (I)

(Wherein R ¹ represents an optionally substituted aryl group or an optionally substituted heteroaryl group, and R ² represents a lower alkyl group.)
A process for producing a compound represented by

（式中、Ｘは、ジ低級アルキルアミノ基、環状アミノ基、ヒドロキシル基、ハロゲン原子または低級アルコキシ基を意味し、Ｒ^１およびＲ^２は前掲と同じものを意味する。）
で表される化合物と２−シアノアセトアミドをカルボニル基と共にキレート構造を構築可能な金属カチオンの存在下で塩基を用いて処理する方法。 Following formula (II)

(In the formula, X represents a di-lower alkylamino group, a cyclic amino group, a hydroxyl group, a halogen atom or a lower alkoxy group, and R ¹ and R ² represent the same as described above.)
A compound represented by formula (2) and 2-cyanoacetamide with a carbonyl group in the presence of a metal cation capable of constructing a chelate structure using a base.

（式中、Ｒ^１およびＲ^２は前掲と同じものを意味する。）
で表される化合物を製造し、該化合物をカルボニル基と共にキレート構造を構築可能な金属カチオンの存在下で塩基を用いて処理する方法。 [Item 2] A process for producing a compound represented by formula (I) according to item 1,
The compound represented by formula (II) according to item 1 is reacted with 2-cyanoacetamide to produce the following formula (III):

(In the formula, R ¹ and R ² are the same as described above.)
The compound represented by these is processed using a base in the presence of a metal cation capable of building a chelate structure with a carbonyl group.

[Item 3] A method of treating with a base in the presence of a metal cation capable of constructing a chelate structure with a carbonyl group is a method of treating with a base in the presence of a Lewis acid having the metal cation as a counter cation. Item 3. The method according to Item 1 or Item 2.

[Item 4] The production method according to Item 3, wherein the Lewis acid having a metal cation capable of forming a chelate structure together with a carbonyl group as a counter cation is lithium chloride, lithium bromide or magnesium bromide.
CLAIM | ITEM 5 The manufacturing method of claim | item 3 whose Lewis acid which has a metal cation which can build a chelate structure with a carbonyl group as a counter cation is lithium chloride.
[Item 6] Item 1 or Item 2 wherein the treatment with a base in the presence of a metal cation capable of building a chelate structure with a carbonyl group is a treatment with a base having the metal cation as a counter cation. The manufacturing method as described in.
CLAIM | ITEM 7 The manufacturing method of claim | item 6 whose base which has a metal cation which can build a chelate structure with a carbonyl group as a counter cation is lithium carbonate, lithium tert-butoxide, or magnesium ethoxide.

[Item 8] The production method according to Item 6, wherein the base having a metal cation capable of constructing a chelate structure together with a carbonyl group as a counter cation is lithium tert-butoxide.

[Item 9] The production method according to any one of Items 1 to 8, wherein X is a di-lower alkylamino group.

  According to the present invention, by enabling a regioselective ring-closing reaction, a key intermediate of a compound useful as a therapeutic agent for dementia can be synthesized selectively and in high yield. And it is not necessary to discard a large amount of unnecessary structural isomers in the production process. Therefore, the present invention is useful as an efficient method for producing a compound useful as a therapeutic agent for dementia.

  Terms used in this specification will be described below. Unless otherwise indicated, the initial definition provided for a group or term herein applies to the group or term in this specification and the claims, either individually or as part of another group.

  The “lower alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms (C1-6 alkyl group), and specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, and a butyl group. , Isobutyl group, tert-butyl group, pentyl group, isopentyl group, hexyl group and the like.

  The “optionally substituted aryl group” includes a halogen atom, a C1-3 alkyl group, a trifluoromethyl group, a hydroxy group, a C1-3 alkoxyl group, a trifluoromethoxy group, a cyano group, an amino group, and a nitro group. It means a phenyl group or naphthyl group which may be substituted with 1 to 3 atoms or groups selected from the group, and specific examples include phenyl group, 4-chlorophenyl group, 4-methylphenyl group, 3-methoxyphenyl. Group, naphthyl group and the like.

  The “optionally substituted heteroaryl group” has 1 to 3 substituents selected from the group consisting of a halogen atom, a C1-C3 alkyl group, a hydroxy group, a C1-C3 alkoxy group, and an amino group. Means a 5- or 6-membered aromatic heterocycle containing 1 to 2 heteroatoms which are the same or different and are selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and the 5- to 6-membered aromatic Specific examples of the heterocyclic ring include a pyridyl group, a furyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, an isoxazolyl group, a pyridazinyl group, and a pyrimidinyl group.

  “Lower alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms, and specific examples include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec -Butoxy group, tert-butoxy group, pentyloxy group, hexyloxy group and the like.

  The “di-lower alkylamino group” means an amino group substituted by two identical or different alkyl groups having 1 to 4 carbon atoms, and specific examples include a dimethylamino group, a diethylamino group, a dipropylamino group, and diisopropyl. An amino group, a dibutylamino group, an ethylmethylamino group, etc. are mentioned.

  “Cyclic amino group” means a 5- to 7-membered cyclic amine containing at least one nitrogen atom and optionally containing an oxygen atom. Specific examples thereof include an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, Examples include a piperidinyl group, morpholinyl, thiamorpholinyl, piperazinyl, homopiperazinyl group and the like, preferably a pyrrolidinyl group and a piperidinyl group.

  “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

  Next, the manufacturing method of this invention is demonstrated below.

  5-Acyl-2-oxo-1,2-dihydropyridine-3-carbonitriles represented by the formula (I) have a chelate structure of a compound represented by the formula (II) and 2-cyanoacetamide together with a carbonyl group. It is produced by regioselective condensation ring closure by the following method in which it is treated with a base in the presence of a buildable metal cation.

Manufacturing method 1
The compound of the formula (I) is obtained by reacting the compound of the formula (II) with 2-cyanoacetamide in the presence of a Lewis acid having a metal cation capable of constructing a chelate structure together with a suitable base and a carbonyl group as a counter cation in a suitable solvent. Produced by reacting. The reaction includes a reaction in which the compound of formula (III) is generated from the reaction of the compound of formula (II) and 2-cyanoacetamide, and a reaction in which the compound of formula (III) is cyclized to generate a compound of formula (I). These reactions are usually allowed to proceed continuously.

  Specific examples of the solvent include methanol, ethyl acetate, tetrahydrofuran, acetone, acetonitrile, N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc., each alone or in combination of two or more. Can be used. N-methyl-2-pyrrolidone is preferred.

  Specific examples of the base include potassium carbonate, sodium carbonate, sodium hydrogen carbonate, triethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene, sodium methoxide, potassium tert-butoxide and the like. It is done. The amount of the base is usually 0.1 to 10 equivalents, preferably 0.5 to 2 equivalents, relative to the compound of formula (I).

  Specific examples of the Lewis acid having a metal cation capable of forming a chelate structure together with a carbonyl group as a counter cation include lithium chloride, lithium bromide, magnesium bromide and the like. The amount of Lewis acid is usually 0.1 to 10 equivalents, preferably 0.5 to 2 equivalents, relative to the compound of formula (II).

  The reaction temperature is generally −70 ° C. to 30 ° C., preferably −30 ° C. to 10 ° C.

Manufacturing method 2
A compound of formula (I) is produced by reacting a compound of formula (II) with 2-cyanoacetamide in a suitable solvent using a base having a metal cation capable of building a chelate structure together with a carbonyl group as a counter cation. Is done. The reaction also includes a reaction in which a compound of formula (III) is formed from the reaction of a compound of formula (II) and 2-cyanoacetamide, and a reaction in which the compound of formula (III) is cyclized to form a compound of formula (I). These reactions are usually allowed to proceed continuously.

  Specific examples of the solvent include methanol, ethyl acetate, tetrahydrofuran, acetone, acetonitrile, N, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, etc., each alone or in combination of two or more. Can be used. N-methyl-2-pyrrolidone is preferred.

  Specific examples of the base having a metal cation capable of forming a chelate structure together with a carbonyl group as a counter cation include lithium carbonate, lithium tert-butoxide, magnesium ethoxide and the like. The amount of the base is usually 0.1 to 10 equivalents, preferably 0.5 to 2 equivalents, relative to the compound of formula (I).

  The reaction temperature is generally −70 ° C. to 30 ° C., preferably −30 ° C. to 10 ° C.

  The compound of the formula (I) is prepared by continuously preparing the compound of the formula (II) from the reaction of the corresponding 1,3-diketone compound and N, N-dimethylformamide dimethyl acetal, without isolating it. It is manufactured also by implementing manufacturing method 1 or manufacturing method 2.

  The compound of the formula (II) can be produced by the method described in J. Heterocyclic Chem., 1990, 27, P.511 to 518, or a method analogous thereto, and can be isolated and purified or isolated. Can be used without purification.

  The compound of formula (III) obtained by condensing the compound of formula (II) and 2-cyanoacetamide in the presence of a base can be produced and isolated by a conventional method. When the compound of formula (II) is cyclized using a base in the presence of a metal cation capable of building a chelate structure with a carbonyl group, the compound of formula (I) is produced in high yield. The ring closure reaction of the compound of formula (II) is carried out in the same manner as in Production Method 1 and Production Method 2 described above.

  The compound of the formula (I) is a 5-substituted-3-oxadiazole-1,6-naphthyridin-2 (1H) -one derivative expected as a therapeutic agent for dementia by the method described in the example of Patent Document 1 Be guided to.

The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples. The compounds described in Examples, Reference Examples and Comparative Examples were identified and compared with the compounds prepared by the method described in Patent Document 1 by HPLC retention time and ¹ H-NMR of isolated crystals. The following compounds produced by the method described in Patent Document 1 were measured for instrument data such as ¹ H-NMR and elemental analysis to confirm the chemical structure. The chemical shift of ¹ H-NMR was reported using tetramethylsilane as an internal standard.

The purity of the compound was analyzed under the following conditions using HPLC.
Compound of Example 1 and Comparative Example 1 Mobile phase: 0.05% TFA aqueous solution / acetonitrile (70/30)
Column: SHISEIDO CAPCELL PAK C-18 SG120 S-5μm (4.6φx150 mm)
Temperature: 40 ° C
Flow rate: 1 mL / min
Wavelength: 254 nm

Compound of Example 2 and Comparative Example 2 Mobile phase: 0.05% aqueous TFA solution / acetonitrile (75/25)
Column: SHISEIDO CAPCELL PAK C-18 SG120 S-5μm (4.6φx150 mm)
Temperature: 40 ° C
Flow rate: 1 mL / min
Wavelength: 254 nm

Reference example 1 :
Production of 1- (3-methoxyphenyl) butane-1,3-dione:
To a toluene (4.2 L) suspension of sodium methoxide (314.8 g, 5.82 mol), add a solution of 3-methoxyacetophenone (350.0 g, 2.33 mol) in ethyl acetate (410.7 g, 4.66 mol) at 20-22 ° C. Added over a minute. The reaction mixture was stirred at 65-75 ° C. for 2 hours. After ice-cooling the reaction mixture, ice water (1.05 L) was added at 10 to 15 ° C., and 36% hydrochloric acid was added dropwise to adjust to pH 2. The organic layer was separated and washed with water (700 mL), followed by aqueous sodium chloride (130 g / 700 mL), and then the organic layer was dried over sodium sulfate and concentrated to obtain 439.8 g of the desired product. Yield 98.2%.

Comparative Example 1 :
Preparation of 5- (3-methoxybenzoyl) -6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile:
After stirring a mixture of 1- (3-methoxyphenyl) butane-1,3-dione (5.00 g, 26.0 mmol) and N, N-dimethylformamide dimethyl acetal (3.72 g, 31.2 mmol) at 80 ° C. for 2 hours, Ice-cooled.
The above reaction mixture was added dropwise to a solution of sodium methoxide (1.54 mL, 28.6 mmol) and 2-cyanoacetamide (2.4 g, 28.6 mmol) in N-methyl-2-pyrrolidone (50 mL) under ice cooling. After completion of the dropwise addition, the mixture was stirred for 2 hours under ice cooling. After adding water (50 mL) to the reaction mixture, acetic acid (5 mL) was added dropwise to make it acidic. Precipitated crystals were collected by filtration and washed successively with water, isopropanol, and isopropyl ether. The obtained crude crystals were added to N, N-dimethylformamide-methanol (21 mL / 21 mL) and stirred overnight at about 20 ° C., then the precipitated crystals were collected by filtration, washed with methanol and isopropyl ether in order. The target product (3.33 g) was obtained. Yield 48%, purity 98%.

Reference example 2 :
Production of 2-dimethylaminomethylene-1- (3-methoxyphenyl) butane-1,3-dione:
A mixture of 1- (3-methoxyphenyl) butane-1,3-dione (200.0 g, 1.04 mol) and N, N-dimethylformamide dimethyl acetal (148.8 g, 1.25 mol) was stirred at 70 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 260.1 g of the desired product. Yield 101%.

¹ H-NMR (400 MHz, CDCl3, 24 ° C.) δ: 7.74 (1 H, s), 7.45-7.30 (3 H, m), 7.10-7.05 (1 H, m) 3.86 (3 H, s), 3.80-2.30 (6 H, br), 2.01 (3 H, s). MS (ESI): 247 (M + H). Melting point: 64 ° C.

Example 1 :
Preparation of 5- (3-methoxybenzoyl) -6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile:
After stirring a mixture of lithium tert-butoxide (1.78 g, 22.2 mmol), 2-cyanoacetamide (1.87 g, 22.2 mmol) and N-methyl-2-pyrrolidone (25 mL) at 20-22 ° C. for 15 minutes, Cooled to 2 ° C. To the reaction mixture, a solution of the product of Reference Example 2 (5 g, 20.2 mmol) in N-methyl-2-pyrrolidone (20 mL) was added dropwise at 3 ° C. or less, and the mixture was stirred at the same temperature for 3 hours. After adding water (50 mL) to the reaction mixture, acetic acid (5 mL) was added dropwise to make it acidic. Precipitated crystals were collected by filtration, washed successively with water (15 mL) and 2-propanol (15 mL), and air-dried (60 ° C., 12 hours) to obtain 4.95 g of a crude product. N, N-dimethylformamide (15 mL) was added to the obtained crystals, and the mixture was stirred at 22 ° C. for 3 hours. The precipitated crystals were collected by filtration, washed with 2-propanol (15 mL), and air-dried (60 ° C., 12 hours) to obtain 4.08 g of the desired product. Yield 74.6%, purity 98.9%.

¹ H-NMR (400 MHz, DMSO, 23 ° C) δ: 13.03 (1 H, s), 8.10 (1 H, s), 7.46 (1 H, t, J = 7.6 Hz), 7.30-7.20 (3 H m) 3.81 (3 H, s), 2.39 (3 H, s). Analysis Calculated _{C 15 H 12 N 2 O 3} : C, 67.16; H, 4.51; N, 10.44. Found: 66.99; H, 4.50; N, 10.50. MS (APCI): 269 (M + H). Melting point: 266 ° C.

Reference Example 3 :
Production of 1- (3-thienyl) butane-1,3-dione:
To a suspension of potassium tert-butoxide (66.7 g, 594 mmol) in diisopropyl ether (600 mL), 3-acetylthiophene (50 g, 396 mmol) was added at about 20-25 ° C. and stirred for 10 minutes. Ethyl acetate (69.8 g, 792 mmol) was added dropwise to the reaction mixture at about 20 to 25 ° C., and the mixture was heated to reflux for 2 hours. The reaction mixture was ice-cooled and then extracted twice with water (300 mL). The aqueous layer was acidified with dropwise addition of concentrated hydrochloric acid / water (40 mL / 80 mL) with ice-cooling and stirring. Extracted twice with chloroform (300 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to obtain 71.9 g of the desired product. Yield 108%.

Comparative Example 2 :
Preparation of 6-methyl-2-oxo-5- (thiophene-3-carbonyl) -1,2-dihydropyridine-3-carbonitrile:
After stirring a mixture of 1- (3-thienyl) butane-1,3-dione (71.9 g, 427 mmol) and N, N-dimethylformamide dimethyl acetal (56 g, 470 mol) at 80 ° C. for 2 hours, ice Chilled.
The above reaction mixture was added dropwise at −20 ° C. to a solution of 2-cyanoacetamide (35.9 g, 427 mol) and potassium tert-butoxide (52.7 g, 470 mol) in N-methyl-2-pyrrolidone (720 mL). The mixture was stirred at the same temperature for 1.5 hours. After adding water (1440 mL) to the reaction mixture, acetic acid (60 g) was added dropwise to make it acidic. The precipitated crystals were collected by filtration and washed successively with water (500 mL) and isopropanol (200 mL). N, N-dimethylformamide / methanol (250 mL / 500 mL) was added to the obtained crystals and stirred at about 20 ° C. for 4 hours. The precipitated crystals were collected by filtration and washed with methanol to obtain 56.9 g of the desired product. It was. Yield 59%, purity 85%.

Example 2 :
Preparation of 6-methyl-2-oxo-5- (thiophene-3-carbonyl) -1,2-dihydropyridine-3-carbonitrile:
A mixture of 1- (3-thienyl) butane-1,3-dione (7.0 g, 41.61 mmol) and N, N-dimethylformamide dimethyl acetal (5.45 g, 45.77 mmol) was stirred at 80 ° C. for 1 hour.
Under ice-cooling, lithium chloride (2.12 g, 49.93 mmol) was added to a solution of potassium tert-butoxide (5.60 g, 49.93 mmol) in N-methyl-2-pyrrolidone (70 mL), and the mixture was stirred for 10 minutes. 2-Cyanoacetamide (4.20 g, 49.93 mmol) was added, and then the reaction mixture was added dropwise with stirring under ice cooling (5 ° C.), followed by stirring for 30 minutes. Water (140 mL) was poured into the reaction mixture, and the mixture was acidified with acetic acid (6 mL). The precipitated crystals were collected by filtration, washed with water, and then washed with isopropanol (50 ml). Methanol (80 ml) was added to the crude crystals, and the mixture was stirred at about 20 ° C. for 1 hour. The precipitated crystals were collected by filtration, washed with methanol (30 ml) and dried to obtain 6.54 g of the desired product. Yield 68%, purity 96.6%.

¹ H-NMR: (400 MHz, DMSO, 23 ° C.) δ: 12.99 (1 H, s), 8.27 (1 H, dd, J = 1.4, 2.8 Hz), 8.25 (1 H, s), 7.69 (1 H, dd, J = 2.8, 5.2 Hz), 7.47 (1 H, dd, J = 1.4, 5.2 Hz), 2.38 (3 H, s). MS (ESI): 245 (M + H), 262 (M + NH 4). Melting point: 273 ° C (decomposition).

According to the production method of the present invention, 5-acyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile represented by the formula (I) can be synthesized with high selectivity. There is no need to discard a large amount of unnecessary isomers. Therefore, the present invention is extremely useful as an efficient method for producing a 5-substituted-3-oxadiazol-1,6-naphthyridin-2 (1H) -one derivative expected as a therapeutic agent for dementia.

Claims (9)

Formula (I) below

(Wherein R ¹ represents an optionally substituted aryl group or an optionally substituted heteroaryl group, and R ² represents a lower alkyl group.)
A process for producing a compound represented by
Following formula (II)

(In the formula, X represents a di-lower alkylamino group, a cyclic amino group, a hydroxyl group, a halogen atom or a lower alkoxy group, and R ¹ and R ² represent the same as described above.)
A compound represented by formula (2) and 2-cyanoacetamide with a carbonyl group in the presence of a metal cation capable of constructing a chelate structure using a base. A method for producing a compound represented by formula (I) according to claim 1,
A compound represented by the formula (II) according to claim 1 and 2-cyanoacetamide are reacted to form the following formula (III):

(Wherein R ¹ represents an optionally substituted aryl group or an optionally substituted heteroaryl group, and R ² represents a lower alkyl group.)
The compound represented by these is processed using a base in the presence of a metal cation capable of building a chelate structure with a carbonyl group.   The method of treating with a base in the presence of a metal cation capable of constructing a chelate structure together with a carbonyl group is a method of treating with a base in the presence of a Lewis acid having the metal cation as a counter cation. Or the manufacturing method of Claim 2.   The production method according to claim 3, wherein the Lewis acid having a metal cation capable of forming a chelate structure together with a carbonyl group as a counter cation is lithium chloride, lithium bromide or magnesium bromide.   The production method according to claim 3, wherein the Lewis acid having a metal cation capable of forming a chelate structure together with a carbonyl group as a counter cation is lithium chloride.   The method of treating with a base in the presence of a metal cation capable of constructing a chelate structure together with a carbonyl group is a method of treating with a base having the metal cation as a counter cation. Manufacturing method.   The production method according to claim 6, wherein the base having a metal cation capable of constructing a chelate structure together with a carbonyl group as a counter cation is lithium carbonate, lithium tert-butoxide, or magnesium ethoxide.   The production method according to claim 6, wherein the base having a metal cation capable of constructing a chelate structure together with a carbonyl group as a counter cation is lithium tert-butoxide. X is a di-lower alkylamino group, The manufacturing method as described in any one of Claims 1-8.