JPS6327349B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides 3-acyl-octahydro-2,5-methanobenzo[ g] quinoline-3-carboxylic acid lower alkyl esters. U.S. Patent No. 3932422 specifies 1, 2,
3,4,5,6-hexahydro-11(eq)-(2-
Certain 3-acyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g ] Quinolines are described. However, even under the most favorable reaction conditions, conventional methods produce significant amounts of 2-substituted-1,2,3,4,
4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinolines are produced, so the yield of the main products, the 2,6-methano-3-benzazosines, is quite low. Compounds produced according to the present invention have the formula: It is indicated by. These compounds are 1-R ₁ -3-R ₅ CO
−4aα−R ₃ 5α−R ₄ −6−R ₂ ″−7−R ₂ −8−
R ₂ ′−9−R ₂ −1, 2, 3, 4, 4a, 5, 10,
10a-Octahydro-2,5-methanobenzo[g]quinoline-3-carboxylic acid lower alkyl esters, also having the formula: 3-R ₁ -6(eq)-R ₄ -7-R ₂ ″-8-
R ₂ −9−R ₂ ′−10−R ₂ −11(ax)−R ₃ −11(eq)
-CH ₂ CH ₂ COR ₅ It is useful in the production of -2,6-methano-3-benzazocines. In the above formula, R ₁ is a lower alkyl group,
represents a cycloalkyl lower alkyl group or a phenyl lower alkyl group; R ₂ represents a hydrogen atom or a lower alkoxy group; R ₂ ′, R ₂ ″ and R ₂ each represent a hydrogen atom; R ₃ represents a hydrogen atom or a lower alkyl group; R ₄ represents a lower alkyl group, R ₅ represents a lower alkyl group, a lower alkylthio lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy group, a cycloalkyl group, a cycloalkyl lower alkyl group, a 2-furyl group , 2-furyl-(CH ₂ ) ₂ group or a lower alkyl-substituted phenyl group, and Alk is a lower alkyl group. In this specification, the term "lower alkyl group",
"Lower alkoxy group" means methyl group, ethyl group,
A straight line having about 1 to 7 carbon atoms, as exemplified by propyl, isopropyl, butyl, non-adjacent t-butyl, methoxy, ethoxy, propoxy, isopropoxy or t-butoxy. Refers to a chain or branched saturated acyclic group. As used herein, the term "cycloalkyl group"
is, for example, a cyclopropyl group, a cyclobutyl group,
It means a saturated carbocyclic group having 3 to 7 ring carbon atoms, as exemplified by a cyclopentyl group, a cyclohexyl group, a 2-methylcyclobutyl group, a 4-ethylcyclohexyl group, and the like. The above-mentioned US Pat. No. 3,932,422 discloses that 1-R ₁ -3-R' ₅ CO-4aα-
R ₃ −5α−R ₄ −6−R″ ₂ −7−R ₂ −8−R′ ₂ −9−
R ₂ -1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline in an inert organic solvent with formic acid or benzyl di-lower alkylammonium formate or tri-lower formate A method for preparing a compound of the formula is described, which consists of heating with an alkylammonium. The product of formula a is produced by opening the starting material of formula a by cleavage of the bond indicated by letter (b). However, in this method, the cleavage of the bond represented by (a) and the subsequent recyclization of the R' ₅ CO carbonyl group to the nitrogen atom result in a significant amount of 1-R ₁ -2 represented by the formula
−R′ ₅ −4aα−R ₃ −5α−R ₄ −6−R″ ₂ −7−R ₂ −
8-R' ₂ -1, 2, 3, 4, 4a, 5, 10, 10a-
Octahydro-3,5-ethenobenzo[g]quinolines are also formed, thus reducing the yield of the main product of formula a. These two transformations are represented by the following reaction scheme. (In the formula, R ₁ , R ₂ , R ₂ ′, R ₂ ″, R ₃ and R ₄ have the meanings as described above, and R ₅ ′ is a hydrogen atom, a lower alkyl group, a phenyl group, or a phenyl lower alkyl group. On the other hand, using the novel compounds of formula of the present invention, the compounds of formula By heating with ammonium or tri-lower alkylammonium formate at a temperature usually in the range of 120-150°C, it can be produced in high yield without the formation of by-products of the formula. Ring opening between the 2-ring carbon atom and the 3-ring carbon atom of the compound, hydrolysis and decarboxylation of the 3-carbo lower alkoxy group: COOAlk occur simultaneously.Suitable solvents include toluene, xylene, and mesitylene. The preferred solvent is formic acid in mesitylene.A second advantage of using the β-ketoester of the invention of formula rather than the compound of formula a is that when using the former it can be Whereas reaction times of up to 6 days may be required, when using β-ketoesters of the formula, a few minutes to several hours are usually sufficient, and in most cases, at 145°C, the solvent is The reaction is complete in 4 to 6 hours using formic acid in mesitylene as a solvent, and in 9 to 13 minutes using trimethylammonium formate. In all cases, the course of the reaction is as follows: It is routine to track the reaction by placing it on a chromatographic plate and noting the disappearance of the zone due to the starting materials over the course of the reaction time. 1−R ₁ −3−R ₅ ″CO−4aα denoted by b
−R ₃ −5α−R ₄ −6−R ₂ ″−7−R ₂ −8−R ₂ ′−9
−R ₂ −1, 2, 3, 4, 4a′, 5, 10, 10a−
Octahydro-2,5-methanobenzo[g]quinoline is reacted with an alkali metal amide, such as sodaamide or lithium diisopropylamide, and the alkali metal salt formed is converted into a suitable acyl halide according to the following reaction scheme: R ₅ - It is produced by reacting with CO-X (lower alkyl haloformate when R ₅ is a lower alkoxy group). [In the formula, R ₁ , R ₂ , R ₂ ′, R ₂ ″, R ₂ , R ₃ , R ₄ and
Alk has the above meaning, and R ₅ ″ and R ₅ have the same meaning as R ₅ , provided that when R ₅ ″ is a lower alkoxy group, R ₅ must represent a lower alkoxy group, and a halogen atom, and M-N=B is an alkali metal (M) amide (N=B)] The above reaction is preferably carried out at a temperature of about -10 to -70°C. A suitable solvent is tetrahydrofuran,
Diethyl ether or dioxane. The starting material represented by formula b and its method of preparation are disclosed in US Pat. No. 3,932,422. As shown above, the 3-acyl group (-COR ₅ ″) of the compound represented by formula b, the β-
The 3-acyl group (R ₅ CO-) of the ketoester and the 3-
The configuration of the carbo-lower alkoxy group (-COOAlk) is not known with absolute certainty.
However, as far as the structure of the 2,6 methano-3-benzazocines (prepared from the β-keto esters of the formula) is concerned, the question of configuration at the 3-position of the compound of the formula is not unresolved. . This is because the asymmetry in the third place is
This is because the compound represented by the formula is destroyed when it is converted to the compound represented by the formula. Compounds of formula with both possible configurations at position 3 can be used to prepare compounds of formula. The compounds of the invention can exist in the form of stereochemical isomers, ie optical and geometric isomers. In the nomenclature used for compounds of formula, the configuration is relative to the hydroaromatic ring and the symbol "β" refers to the cis configuration relative to the 2,5-methano bridge of the compound of formula It shows that. Conversely, the symbol "α" indicates a trans configuration with respect to the group. The structure of the compound of the present invention was established by the synthesis method, elemental analysis values, IR spectrum, and NMR spectrum. Reaction progress and product homogeneity were routinely confirmed by thin layer chromatography. A description of how the invention is carried out, and the best mode believed, is provided below to enable any person skilled in the art to carry out the invention. Melting points are uncorrected unless otherwise noted. A 3-R ₅ CO-octahydro- represented by the formula
2,5-methanobenzo[g]quinoline-3-carboxylic acid lower alkyl ester 1 By acylation of the corresponding 3-carboxylic acid lower alkyl ester Example 1 A 2.4Nn-butyllithium (50 ml; 0.12 mol)
To the hexane solution was added a solution of redistilled diisopropylamine (13.1 g; 0.13 mol) in dry tetrahydrofuran (110 ml) over about 30 minutes while maintaining the temperature at 0°C. Then, it was cooled to -60°C and 7-methoxy-1,4aα,5α-trimethyl-1,2,3,4,4a,5,10,10a-
Ethyl octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate (34.3g; 0.1
mol) in tetrahydrofuran (110 ml) was added over 2 hours. It was then treated with a solution of redistilled hexanoyl chloride (18.8 g; 0.13 mol) in tetrahydrofuran (100 ml) over a period of about 30 minutes while cooling at -60°C. The resulting clear reaction mixture was poured into 500 ml of aqueous sodium bicarbonate solution and extracted twice with 100 ml each of ether, the combined ether extracts were washed with brine, then dried over sodium sulfate and evaporated to dryness to give 44 g of an oil. I got something. This oil solidified upon standing. Recrystallize the residue from hexane to obtain 27.5g (63%)
3-(1-oxohexyl)-7-methoxy-
1,4aα,5α-trimethyl-1,2,3,4,
Ethyl 4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate, mp 117-120°C, was obtained. The following compound represented by the formula was produced by a method similar to that described above. B 7-methoxy-1,4aα,5α-trimethyl-
3-(4-methyl-1-oxopentyl)-1,
2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-
Ethyl carboxylate (22.8 g, 43%; after recrystallization from pentane, mp 97-100°C) 40.5 g (0.12 mol) of 7-methoxy-1,
4aα,5α-trimethyl-1,2,3,4,4a,
Ethyl 5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate is reacted with 0.13 moles of lithium diisopropylamide and the resulting salt is reacted with 17.5 g (0.13 moles) of 4-methylpentachloride. C7-methoxy-1,5α-dimethyl-3-(1
-oxopentyl)-1,2,3,4,4a,
Ethyl 5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate (5.2 g, 27%; after recrystallization from pentane mp87~
92℃) 15.0 g (0.046 mol) of 7-methoxy-1,
5α-dimethyl-1,2,3,4,4a,5,10,
0.047 ethyl 10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate
mol of lithium diisopropylamide and the resulting salt was prepared by reacting with 5.7 g (0.046 mol) of pentanoyl chloride. Table 1 was prepared using a method similar to that described in Example 1 above.
The following compounds of the formula listed in were prepared. The melting point and the solvent used for crystallization are “mp
(°C)/solvent” column.

【table】

【table】

[Table] 2 Corresponding 3-carboxylic acid ester or 3-
Case by carboxylation of R ₅ ″CO ketone Example 2 A Lithium diisopropylamide (0.055 mol)
A solution in tetrahydrofuran (60ml) was prepared from butyllithium and diisopropylamine using the method described in Example 1 above. The solution thus prepared was cooled to -75°C, and while maintaining the temperature at -75°C, 7-methoxy-1,
4aα,5α-trimethyl-1,2,3,4,4a,
Ethyl 5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate (17.1 g; 0.05 mol) was added for about 30 minutes.
Ethyl chloroformate (5.4 g; 0.05 mol) was then dissolved in tetrahydrofuran (80 mol) at -75°C for 1 hour.
ml) solution. Stir for 1 hour, then pour into 400 ml of aqueous sodium bicarbonate solution,
Working up in the same manner as described in Example 1 yielded 9.7 g of crude material, which was recrystallized from pentane.
6.3g (30%) of 7-methoxy-1,4aα,5α
-trimethyl-1,2,3,4,4a,5,10,
Diethyl 10a-octahydro-2,5-methanobenzo[g]quinoline-3,3-dicarboxylate, mp 89-91°C, was obtained. In a manner similar to that described above, a suitable 3-R ₅ ″CO-1,2,3,4,
The following compound of formula was prepared using 4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline and ethyl chloroformate in the presence of diisopropylamide.

【table】

【table】

[Formula] Example 3 Comparison of the method from the compound of the present invention and the conventional method in the production of the compound of the formula JP-A-50-160275 (US Pat.
The superior overall yields obtained with the compounds of the invention for the preparation of 3-benzazocines of the formula compared to the conventional process disclosed in US Pat. 7-methoxy-1,4aα,5α-trimethyl- represented by formula b
1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-
7-Methoxy-1,4aα,5α-trimethyl-3-(1-oxoethyl)-1,2,3, of the present invention, which is an intermediate represented by the formula from ethyl carboxylate.
4,4a,5,10,10a-octahydro-2,5-
7-methoxy-, which is an intermediate of formula c (R ₅ ″ is CH ₃ ), by a method via ethyl methanobenzo[g]quinoline-3-carboxylate.
1,4aα,5α-trimethyl-1,2,3,4,
4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylic acid and 7-
Methoxy-1,4aα,5α-trimethyl-3-(1
-oxoethyl)-1,2,3,4,4a,5,
8-Methoxy-3,6(eq),11(ax)-trimethyl-1, by conventional method via 10,10a-octahydro-2,5-methanobenzo[g]quinoline,
2,3,4,5,6-hexahydro-11(eq)-
This is demonstrated by the following description, which compares the yields of each stage and the overall yield obtained in the production of (3-oxobutyl)-2,6-methano-3-benzazosine. A Method from Compounds of the Invention (Step 1A) Lithium diisopropylamide (0.127 mol) using the method described in Example 1
A solution of was prepared in tetrahydrofuran (150ml). The solution thus prepared was cooled to -70°C, and 7-methoxy-1,4aα,5α-trimethyl-1,2,3,
4,4a,5,10,10a-octahydro-2,5
-methanobenzo[g]quinoline-3-carboxylate (40.4 g, 0.118 mol) in tetrahydrofuran (200 ml). After the addition was complete, the mixture was stirred for an additional 30 minutes and then treated with a solution of acetyl chloride (9.9 g, 0.127 mol) in tetrahydrofuran (150 ml) over a period of 1 hour with stirring, maintaining the temperature at -70°C. The reaction mixture was then worked up as described in Example 1 and the crude product was recrystallized from hexane to give 18.2
g (40%) of 7-methoxy-1,4aα,5α-trimethyl-3-(1-oxoethyl)-1,2,
3,4,4a,5,10,10a-octahydro-
Ethyl 2,5-methanobenzo[g]quinoline-3-carboxylate, mp 120-123°C, was obtained. (Step 2A) The above product (1.23 g, 0.0032 mol) in mesitylene (22 ml)/97% formic acid (81.8
ml) The solution was heated at reflux for 19 hours, then the solvent was removed in vacuo and the residue was treated with aqueous sodium bicarbonate and ether. The ether extract was dried over anhydrous magnesium sulfate, then treated with ethereal hydrogen chloride solution and recrystallized from acetone.
The product was isolated in free base form and yielded 0.36 g (36
%) of 8-methoxy-3,6(eq),11(ax)-
Trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,
6-methano-3-benzazosine, mp67-69
°C, was obtained (total yield from the initial starting material was 14
%). B Conventional method (Step 1B) 10.0 g (0.029 mol) of 7-methoxy-1,4aα,5α-trimethyl-1,2,
3,4,4a,5,10,10a-octahydro-
Ethyl 2,5-methanobenzo[g]quinoline-3-carboxylate was dissolved in ethanol (100 ml)/water (50 ml) containing 2 g (0.05 mol) of sodium hydroxide, heated under reflux for about 16 hours, and then concentrated. This made the capacity small. The residue was diluted with about 20 ml of water, and the pH was adjusted to about 6.5-7.0 with dilute hydrochloric acid.
Dilute the product mixture with 200 ml of ethanol,
The solution was dried under vacuum. After drying the residue by repeated concentration from boiling benzene/toluene, the product was crystallized from acetonitrile.
7.9 g (>100%) of 7-methoxy-1,4aα,
5α-trimethyl-1,2,3,4,4a,5,
10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylic acid, mp118
~121°C was obtained. (Step 2B) Above product (3.15g, 0.010mol)
A solution of anhydrous tetrahydrofuran (50 ml) was treated dropwise with stirring under a nitrogen atmosphere with 20 ml (0.020 mol) of a 1.7 mol solution of methyllithium.
The resulting mixture was stirred for approximately 30 minutes and then poured into a solution of 10 g of ammonium subsalt in water (100 ml). Extract twice with ether, dry the ether extract with magnesium sulfate, and dry.
1.4 g of brown oil was obtained which was extracted with boiling pentane to give 0.5 g (16%) of 7-methoxy-1,
4aα,5α-trimethyl-3-(1-oxoethyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline was obtained. The aqueous solution remaining after extraction of the crude product with ether is saturated with solid sodium hydroxide, the oil that separates is dissolved in water and made strongly acidic, the solid that separates is collected, dried and converted to the hydrochloride. g (0.0062 mol) of the hydrochloride salt of the starting carboxylic acid (mp 295-297°C) was obtained. Therefore,
The corrected reaction yield, based on recovered starting material, is 42%. (Step 3B) 1.0g (0.0032
7-methoxy-1,4aα,5α-trimethyl-3-(1-oxoethyl)-1,2,3,
4,4a,5,10,10a-octahydro-2,5
-22 ml of methanobenzo[g]quinoline solution
of mesitylene and 1.8 ml of formic acid for a total of 67 hours, and the reaction progress was monitored from time to time by thin layer chromatography. The reaction mixture was worked up as described in Step 2A to yield 60 mg (6%).
8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-
Methano-3-benzazosine, mp62-65℃,
I got it. The overall yield from the original starting material was 2.5% based on the recovered starting material of Step 2.

Claims (1)

[Claims] 1 Formula: [In the formula, R ₁ represents a lower alkyl group, a cycloalkyl lower alkyl group, or a phenyl lower alkyl group; R ₂ represents a hydrogen atom or a lower alkoxy group, and R ₂ ′, R ₂ ″ and R ₂ each represent a hydrogen atom , R ₃ represents a hydrogen atom or a lower alkyl group, R ₄ represents a lower alkyl group, R ₅ represents a lower alkyl group, a lower alkylthio lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy group, a cycloalkyl group , a cycloalkyl lower alkyl group, a 2-furyl group, a 2-furyl-(CH ₂ ) ₂ group, or a lower alkyl-substituted phenyl group, and Alk is a lower alkyl group.] 2 R ₁ is lower The compound according to claim 1, which is an alkyl group or a cycloalkyl lower alkyl group; R ₂ is a lower alkoxy group. 3 7-Methoxy-1,4aα,5α-trimethyl-
3-(1-oxohexyl)-1,2,3,4,
4a,5,10,10a-octahydro-2,5-methanobenzo[g]ethyl quinoline-3-carboxylate; 7-methoxy-1,4aα,5α-trimethyl-
3-(4-methyl-1-oxopentyl)-1,
2,3,4,4a,5,10,10a-octahydro-
Ethyl 2,5-methanobenzo[g]quinoline-3-carboxylate; 7-methoxy-1,4aα,5α-trimethyl-3-(1-oxobutyl)-1,2,
3,4,4a,5,10,10a-octahydro-2,
Ethyl 5-methanobenzo[g]quinoline-3-carboxylate; 7-methoxy-1,5α-dimethyl-
3-(1-oxopentyl)-1,2,3,4,
4a,5,10,10a-octahydro-2,5-methanobenzo[g]ethyl quinoline-3-carboxylate; 7-methoxy-1,4aα,5α-trimethyl-
3-(3-methyl-1-oxobutyl)-1,2,
3,4,4a,5,10,10a-octahydro-2,
Ethyl 5-methanobenzo[g]quinoline-3-carboxylate; 7-methoxy-1,4aα,5α-trimethyl-3-(1-oxopropyl)-1,2,3,
4,4a,5,10,10a-octahydro-2,5-
Ethyl methanobenzo[g]quinoline-3-carboxylate; 7-methoxy-1,5α-dimethyl-3-
(1-oxoethyl)-1,2,3,4,4a,5,
10,10a-octahydro-2,5-methanobenzo[g]ethyl quinoline-3-carboxylate; 1-cyclopropylmethyl-7-methoxy-4aα,5α-
Dimethyl-3-(1-oxopentyl)-1,2,
3,4,4a,5,10,10a-octahydro-2,
Ethyl 5-methanobenzo[g]quinoline-3-carboxylate; 7-methoxy-1,4aα,5α-trimethyl-3-(1-oxoethyl)-1,2,3,
4,4a,5,10,10a-octahydro-2,5-
Ethyl methanobenzo[g]quinoline-3-carboxylate; 7-methoxy-1,5α-dimethyl-3-
(1-oxohexyl)-1,2,3,4,4a,
5,10,10a-octahydro-2,5-methanobenzo[g]ethyl quinoline-3-carboxylate; 7
-Methoxy-1,4aα,5α-trimethyl-3-
(1-oxoheptyl)-1,2,3,4,4a,
5,10,10a-octahydro-2,5-methanobenzo[g]ethyl quinoline-3-carboxylate; 7
-Methoxy-1,5α-dimethyl-3-(4-methyl-1-oxopentyl)-1,2,3,4,
4a,5,10,10a-octahydro-2,5-methanobenzo[g]ethyl quinoline-3-carboxylate; 7-methoxy-1,4aα,5α-trimethyl-
3-(1-oxopentyl)-1,2,3,4,
4a,5,10,10a-octahydro-2,5-methanobenzo[g]ethyl quinoline-3-carboxylate; 7-methoxy-1,4aα,5α-trimethyl-
3-[(4-methylthio)-1-oxobutyl]-
1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-
Ethyl carboxylate; 7-methoxy-1,4aα,5α
-Trimethyl-3-(1-oxo-3-phenylpropyl)-1,2,3,4,4a,5,10,10a
-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylic acid ethyl; 7-methoxy-
1,4aα,5α-trimethyl-1,2,3,4,
4a,5,10,10a-octahydro-2,5-methanobenzo[g]diethyl quinoline-3,3-dicarboxylate; 7-methoxy-1,4aα,5α-trimethyl-3-(2-furoyl)-1, 2, 3, 4,
4a,5,10,10a-octahydro-2,5-methanobenzo[g]ethyl quinoline-3-carboxylate; 7-methoxy-1,4aα,5α-trimethyl-
3-[3-(2-furyl)-1-oxopropyl]-
1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-
Ethyl carboxylate; or 7-methoxy-1,
4aα,5α-trimethyl-3-(1-oxo-3-
cyclopentylpropyl)-1,2,3,4,
The compound according to claim 2, which is ethyl 4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate. 4 formula: [In the formula, R ₁ represents a lower alkyl group, a cycloalkyl lower alkyl group, or a phenyl lower alkyl group; R ₂ represents a hydrogen atom or a lower alkoxy group, and R ₂ ′, R ₂ ″ and R ₂ each represent a hydrogen atom , R ₃ represents a hydrogen atom or a lower alkyl group, R ₄ represents a lower alkyl group, R ₅ represents a lower alkyl group, a lower alkylthio lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy group, a cycloalkyl group , a cycloalkyl lower alkyl group, a 2-furyl group, a 2-furyl-(CH ₂ ) ₂ group, or a lower alkyl-substituted phenyl group, and Alk is a lower alkyl group.] In the method for producing a compound represented by the formula Ib: (wherein R ₁ , R ₂ , R ₂ ′, R ₂ ″, R ₂ , R ₃ and R ₄ are as defined above, and R ₅ ″ has the same meaning as R ₅ ) is reacted with an alkali metal amide and the alkali metal salt formed has the formula: R ₅
-CO-X (in the formula, R ₅ has the same meaning as R ₅ ,
However, when R ₅ ″ is not a lower alkoxy group, it must represent a lower alkoxy group, and X is a halogen atom.