JPH0649671B2 - Anilines and their production method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention has the general formula [I] (In the formula, R is a fluorine atom, a cyclopropylamino group or an N-lower acylcyclopropylamino group, W is hydrogen,
The nitro group or amino group, X and Y each represent the same or different halogen atom.

Z is a fluorine atom or Wherein R ¹ and R ² are each hydrogen or a lower alkyl group, R ³ is hydrogen, a lower alkyl group, a lower acyl group, a lower alkoxycarbonyl group, a p-nitrobenzyl group or a p-aminobenzyl group, However, R and Z are not fluorine atoms at the same time. ) Relating to anilines.

Such anilines are novel compounds synthesized for the first time by the present inventors and are useful compounds as intermediates for pharmaceuticals. For example, from the compound of the present invention, a compound having excellent antibacterial activity, 1-cyclopropyl-6,8-difluoro-1,
4-Dihydro-7- (3-methyl, 4-methyl, 4-aminobenzyl or unsubstituted-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid can be prepared.

[Problems to be solved by the invention]

Such quinolonecarboxylic acids are also novel compounds synthesized for the first time by the present inventors, and as a production method thereof,
For example, the following method is shown.

The present invention relates to a method for producing such a quinolonecarboxylic acid, and relates to an intermediate for establishing a novel production method for the purpose of improving the yield and simplifying the operation, and the production method thereof.

[Means for solving problems]

The reaction between pentafluoronitrobenzene and amines is
For example, as shown by tetrahedron, 23 , 1347 (1967), simultaneous production of ortho and para isomers reduces the desired yield of anilines. Such properties are not limited to pentafluoronitrobenzene, but are common to nitrobenzenes having ortho and para positions substituted with fluorine atoms.

The present inventors have earnestly studied the method for producing aniline represented by the general formula [I] as a synthetic intermediate for quinolocarboxylic acid, and as a result, 2,3,4,5-tetrafluoronitrobenzene and amines have been obtained. It was found that the yield of the ortho isomer increased in the non-polar solvent in the reaction with, while the yield of the para isomer increased in the reaction in the polar solvent. Further, such characteristics are not limited to 2,3,4,5-tetrafluorobenzene, and are represented by the general formula [II] It has also been found that nitrobenzenes represented by the formula (X and Y are the same as above) are general.

A nonpolar solvent suitable for the compound represented by the general formula [II],
For example, in aromatic hydrocarbons such as benzene, toluene, xylene, etc., aliphatic hydrocarbons such as hexane, cyclohexane, petroleum ether, etc. or halogenated alkyls such as methylene chloride, chloroform, etc., at least equivalent amount or more, preferably 1 to 2 Equivalent amount of cyclopropylamine at -20 ° C
The solvent of the formula [III] is used by reacting at a boiling point of the solvent used, preferably in the temperature range of 0 ° C to room temperature. (In the formula, X and Y are the same as described above.) In this reaction,
It is also preferable to use an organic or inorganic base such as triethylamine, pyridine, potassium carbonate or magnesium oxide as a deoxidizing agent.

On the other hand, the compound represented by the general formula [II] is treated with a suitable polar solvent such as ethanol or dimethylsulfoxide (DMS).
O), dimethylformamide (DMF) tetrahydrofuran (THF), dioxane or a mixed solvent of these solvents and water, at least equivalent amount or more, preferably 1 to 2 equivalent amount of the general formula Z′H (in the formula, Z ′ Is Wherein R ¹ and R ² are each substituted with hydrogen or a lower alkyl group, R ³ is substituted with hydrogen, a lower alkyl group, a lower acyl group, a lower alkoxycarbonyl group, a p-nitrobenzyl group or an acyl group. May be p-aminobenzyl group. ) By reacting the amines represented by the formula (20) with the boiling point of the solvent from -20 ° C, preferably in the temperature range of 10 to 50 ° C, the compound of the general formula [V] (In the formula, X, Y and Z ′ are the same as the above.) In this reaction,
It is also preferable to use a suitable deoxidizing agent, but it can be replaced by using an excess of the amines Z'H used.

Here, among the compounds represented by the general formula [V], Z '
For compounds wherein R ³ and R ⁵ are hydrogen groups, acid anhydride, acid halide or by the action of alkyl halocarbonate such, Z 'R ³ and R ⁵ is a lower acyl group or lower alkoxycarbonyl in the group It can be converted into a basic compound.

The thus obtained compounds represented by the general formulas [III] and [V] are further reacted with amines to convert the para-position or ortho-position fluorine atom into an amino group. Such reactions are accomplished by heating in a suitable solvent, but are readily accomplished by catalytically using potassium fluoride in an aprotic polar solvent such as DMSO or DMF.

Specifically, the compound represented by the general formula [III] is 1 to 50
Dissolved in DMSO, which is double the solution, preferably 2 to 10 times,
A compound represented by the general formula Z′H (Z ′ is the same as above) in the temperature range of room temperature to the boiling point of the solvent, preferably 30 to 100 ° C. in the presence of 10 equivalents, preferably 1 to 2 equivalents of potassium fluoride. Add from room temperature to boiling point of solvent, preferably 30-100
Stirring is continued in the temperature range of ° C to terminate the reaction, and then the compound of the general formula [IV] (In the formula, X, Y and Z ′ are the same as the above.)

The compound represented by the general formula [IV] can also be produced by reacting the compound represented by the general formula [V] with cyclopropylamine in the same manner as above.

Regarding the production of the compound represented by the general formula [IV] from the compound represented by the general formula [II], whether through the compound represented by the general formula [III] or the compound represented by the general formula [V] Is appropriately selected from the difference in reactivity of the nitrobenzenes represented by the general formula [II] with amines, that is, the amines represented by cyclopropylamine or Z'H, and the difficulty of purification of the reaction product. It

Next, N-acylanilines [VI] are produced from compound [V] by the action of acid anhydride or acid halide.
Preferable examples of the acid anhydride or acid halide include acetic anhydride and acetyl chloride.

(In the formula, R'represents lower alkyl, X, Y and Z '.
Is the same as above. ) In the present reaction, when an acid anhydride is used, it is 0 to 100 ° C., preferably room temperature to 6 ° C. in the absence or presence of a solvent.
It can be carried out in the temperature range of 0 ° C. It is also preferable to add a small amount of a proton catalyst such as sulfuric acid or phosphoric acid. When an acid halide is used, it can be reacted in a suitable solvent in the presence of a deoxidizing agent in the temperature range from 0 ° C. to the boiling point of the solvent used.

The compound [VI] is hydrogenated in a suitable solvent such as alcohols, acetic acid or the like or a mixed solvent thereof under a hydrogen stream in the presence of a suitable catalyst such as palladium carbon, Raney nickel or platinum at room temperature under normal pressure or pressure. The compound represented by the general formula [VII] can be converted by addition or with a reducing agent such as a metal or a metal salt.

(In the formula, X, Y, Z'and R'are the same as above) The compound [VII] can be converted to a deamino compound [VIII] by a nitrous acid or its ester via a diazonium salt.

(In the formula, X, Y, Z ′ and R ′ are the same as above.) As a preferable mode of carrying out the reaction, the compound [VII] is added to a suitable solvent containing at least an equimolar amount of alkyl nitrite, such as DMF or THF. , Acetonitrile or the like at 0 to 100 ° C, preferably room temperature to 80 ° C. The addition requires 5 to 60 minutes, and the compound [VII] may be diluted with an appropriate solvent and added dropwise.

Although the reaction is almost finished at the end of the addition, the reaction may be terminated by further maintaining it at room temperature to 80 ° C. for 5 to 60 minutes.

The compound [VIII] can be converted to the compound represented by the general formula [IX] by hydrolysis according to a conventional method.

(In the formula, X, Y and Z ′ are the same as above) [Examples] The present invention will be described below with reference to Examples.

Example 1 Synthesis of N-cyclopropyl-2,3,4-trifluoro-6-nitroaniline 8.82 g of cyclopropylamine and 15.63 triethylamine in 100 m of anhydrous toluene solution of 20.0 g of 2,3,4,5-tetrafluoronitrobenzene. 5 to 1 g of anhydrous toluene solution
The solution was added dropwise at 0 ° C for 50 minutes. After stirring at the same temperature for 1.5 hours, 100 m of benzene and 150 m of ice water were added to the reaction solution to separate the layers. The organic layer was washed 3 times with 1% hydrochloric acid, further washed with water and dried over anhydrous sodium sulfate. After concentrating the extract, the residue was purified by a silica gel column (methylene chloride-n-hexane) to obtain 18.79 g (yield 78.9%) of the desired product as an orange oil.

Example 2 Synthesis of 2,4-dichloro-N-cyclopropyl-3-fluoro-6-nitroaniline To a solution of 3,4-dichloro-2,5-difluoronitrobenzene (2.5 g) in anhydrous toluene, 0.94 g of cyclopropylamine and Triethylamine 1.67g anhydrous toluene 3m 5-10
It was added dropwise at 20 ° C for 20 minutes. After stirring at the same temperature for 2 hours, ice water (100 m) was added to the reaction solution and the mixture was extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous Glauber's salt and concentrated, and the resulting residue was purified by a silica gel column to give the desired product as an orange oil 2.5.
g (yield 86.0%) was obtained.

Example 3 Synthesis of 2,4-dichloro-N-cyclopropyl-3- (4-ethoxycarbonyl-1-piperazinyl) -6-nitroaniline 2,4-dichloro-N-cyclopropyl-3-fluoro-6- Nitroaniline 1.50g and potassium fluoride 0.4g anhydrous DM
1.1 g of 1-ethoxycarbonylpiperazine was added all at once with stirring at room temperature while adding 10 m of SO. Reaction liquid at 35 ℃
After stirring for 1 hour at 60 to 85 ° C for 2 hours and further at 100 ° C for 4.5 hours, the reaction solution was poured into 100 m of ice water and extracted with benzene. The extract is washed with water, dried over anhydrous Glauber's salt and concentrated,
The obtained residue was purified by a silica gel column and recrystallized from ethanol-water to obtain 1.71 g (yield 74.9%) of the desired product as orange needle crystals. Melting point 80-82 ° C Elemental analysis value (%): Calculated value as C ₁₆ H ₂₀ Cl ₂ N ₄ O ₄ C: 47.66 H: 5.00 N: 13.89 Measured value C: 47.67 H: 5.04 N: 13.97 Example 4 4- (4-Ethoxycarbonyl-1-piperazinyl) -2,3,5-trifluoronitrobenzene synthesis a) 2,3,4,5-tetrafluoronitrobenzene 50g Ethanol 250m while stirring and stirring 1-ethoxycarbonyl 40.55 g piperazine and 38. triethylamine.
91 g of ethanol 100m solution was added dropwise at 25 to 35 ° C for 1 hour. After stirring for 1.5 hours at room temperature, the mixture was cooled in an ice bath and the precipitated crystals were collected by filtration and washed with ethanol to obtain 65.95 g (yield 77.2%) of the desired product as yellow prism crystals. Melting point 106-107 ° C Elemental analysis value (%): Calculated value as C ₁₃ H ₁₄ F ₃ N ₃ O ₄ C: 46.85 H: 4.23 N: 12.61 Actual value C: 46.96 H: 4.29 N: 12.62 b) 2,3 While adding 39,74 g of 4,4,5-tetrafluoronitrobenzene to a mixed solution of 180 m of ethanol and 20 m of water and stirring in an ice bath, 33.84 g of 1-ethoxycarbonylpiperazine and 42.6 m of triethylamine in a 60 m solution of ethanol at 18 to 20 ° C. Dropwise over 75 minutes. The reaction solution
After stirring at 20 to 25 ° C for 3.5 hours, the mixture was allowed to stand at 5 ° C overnight, the precipitated crystals were collected by filtration and washed with water-ethanol to obtain 59.72 g (yield 87.8%) of the desired product as yellow prism crystals.

Melting point 106-107.5 ° C Example 5 Synthesis of 4- (4-ethoxycarbonyl-3-methylene-1-piperazinyl) -2,3,5-trifluoronitrobenzene 2,3,4,5-tetrafluoronitrobenzene 9.75 g DMS
2-Methylpiperazine in O-water (60m-20m) solution
5.0 g and triethylamine 7.5 g were melt | dissolved in THF20m, and it dripped at 15-20 degreeC 20 minutes. After stirring at the same temperature for 15 minutes, the reaction solution was cooled in a salt-ice bath, and 10.85 g of ethyl chlorocarbonate was added dropwise at 5 to 8 ° C for 5 minutes. After stirring for 30 minutes at room temperature, the reaction mixture was poured into ice water and the precipitate was collected by filtration to obtain 80m of ethanol.
Dissolved in. After standing overnight at room temperature, the precipitate was filtered off, the filtrate was cooled to 5 ° C. and allowed to stand, and the precipitated crystal was collected by filtration to obtain 13.93 g (yield 80.2%) of the desired product as a yellow prism crystal.

Melting point 76-77 ° C. Elemental analysis: Calculated value as C ₁₄ H ₁₆ F ₃ N ₃ O ₄ C: 48.42 H: 4.64 N: 12.10 Measured value C: 48.41 H: 4.52 N: 12.10 Example 6 2,3,5- Synthesis of trifluoro-4- (4-methyl-1-piperazinyl) nitrobenzene To a solution of 10.0 g of 2,3,4,5-tetrafluoronitrobenzene in ethanol (100 m), 5.14 g of methylpiperazine and 7.78 g of triethylamine in 50 m of ethanol. After that, it was added dropwise at 20 ° C. for 40 minutes. After stirring at the same temperature for 1 hour, the reaction solution was poured into 500 m of ice water, the precipitate was collected by filtration and recrystallized from n-hexane to obtain 9.97 g of the desired product as a brown prism crystal (yield 70.7).
%) Was obtained. Melting point 82-84 ° C Elemental analysis value (%): Calculated value as C ₁₁ H ₁₂ F ₃ N ₃ O ₂ C: 48.00 H: 4.40 N: 15.27 Actual value C: 48.01 H: 4.40 N: 15.20 Example 7 N- Synthesis of cyclopropyl-3- (4-ethoxycarbonyl-1-piperazinyl) -2,4-difluoro-6-nitroaniline a) 4- (4-ethoxycarbonyl-1-piperazinyl) -2,3,5
-Trifluoronitrobenzene (65.0 g) and potassium fluoride (17.0 g) were added to anhydrous DMSO (195 m) and cyclopropylamine (13.4 g) was added at once while stirring at room temperature.
The red reaction solution, which exothermed to 50 ° C., was further stirred at 45 ° C. for 1 hour, poured into 1200 m of ice water, the precipitate was collected by filtration, and recrystallized from ethanol-water to obtain the desired product of orange prism crystals 72.02.
g (yield 99.7%) was obtained.

Melting point 88-89 ° C Elemental analysis value (%): Calculated value as C ₁₆ H ₂₀ F ₂ N ₄ O ₄ C: 51.89 H: 5.44 N: 15.13 Measured value C: 51.98 H: 5.49 N: 15.16 b) 4- ( 4-ethoxycarbonyl-1-piperazinyl) 2,3,5-
Toluene 20 g of trifluoronitrobenzene 1.0 g, cyclopropylamine 0.21 g and triethylamine 0.45 g
m, 70-80 ℃ for 3 hours, 90-100 ℃ for 2 hours
Stir for hours. After cooling, the reaction solution was washed with water and dried over anhydrous sodium sulfate. After concentration, the residue was recrystallized from n-hexane to obtain 0.84 g (yield 75.6%) of the desired product as orange prism crystals.

Melting point 82.5 to 84 ° C Example 8 Synthesis of N-cyclopropyl-3- (4-ethoxycarbonyl-3-methyl-1-piperazinyl) -2,4-difluoro-6-nitroaniline 4- (4-ethoxycarbonyl- 3-methyl-1-piperazinyl)-
2.75 g of 2,3,5-trifluoronitrobenzene and 3.10 g of potassium fluoride were added to 40 m of anhydrous DMSO and 2.84 g of cyclopurpyramine was added at once while stirring at room temperature. The reaction solution, which exothermed to 45 ° C, was further stirred at 45 ° C for 2 hours, poured into 300 m of ice water, the precipitate was collected by filtration, and recrystallized from ethanol to obtain 16.96 g of the desired product as orange prism crystals (yield 97.4%). Got

Melting point 99-100.5 ° C. Elemental analysis: Calculated as C ₁₇ H ₂₂ F ₂ N ₄ O ₄ C: 53.12 H: 5.77 N: 14.58 Measured value C: 53.19 H: 5.72 N: 14.63 Example 9 N-cyclopropyl-2 Synthesis of 2,4-difluoro-3- (4-methyl-1-piperazinyl) -6-nitroaniline 2,3,5-trifluoro-4- (4-methyl-1-piperazinyl) nitrobenzene 9.50 g and potassium fluoride 3 g anhydrous DM
While adding to 29 m of SO 2 and stirring at room temperature, 2.96 g of cyclopropylamine was added at once. The reaction solution which exothermed to 52 ° C. was further stirred at 45 ° C. for 1 hour, poured into 220 m of ice water and adjusted to pH 9-10 with 1N aqueous sodium hydroxide solution to precipitate crystals. The crystals were collected by filtration and recrystallized from water-ethanol to obtain 10.12 g of the desired product as orange prism crystals (yield 9
3.9%).

Mp from 77.5 to 76 ° C. Elemental _{analysis: C 14 H 18 F 2 N} 4 O 2 Calculated C: 53.84 H: 5.81 N: 17.94 Found C: 53.81 H: 5.77 N: 18.03 Example 10 N-cyclopropyl -N -[3- (4-ethoxycarbonyl-
1-Piperazinyl) -2,4-difluoro-6-nitrophenyl]
Synthesis of Acetamide 70.82 g of N-cyclopropyl 3- (4-ethoxycarbonyl-1-piperazinyl) -2,4-difluoro-6-nitroaniline was added to 70 m of acetic anhydride, and about 1 m of concentrated sulfuric acid was slowly added dropwise while stirring. An exotherm results in a brown solution. 2 at room temperature
After stirring for an hour, the reaction solution was poured into ice water 1 (), potassium carbonate powder was added to decompose excess acetic anhydride, and the precipitate was collected by filtration,
The target product of yellow prism crystals after recrystallization from water-ethanol
78.18 g (yield 99.1%) was obtained. Mp 108-110 ° C. Elemental analysis (%): Calculated as _{C 18 H 22 F 2 N 4} O 5 C: 52.42 H: 5.38 N: 13.59 Found C: 52.56 H: 5.37 N: 13.69 Example 11 N- Synthesis of cyclopropyl-N- [2,4-difluoro-3- (4-methyl-1-piperazinyl) -6-nitrophenyl] acetamide N-cyclopropyl-2,4-difluoro-3- (4-methyl-1) -Piperazinyl) -6-nitroaniline 9.80 g acetic anhydride 19.6 m
When about 2 m of concentrated sulfuric acid was slowly added to the mixture with stirring, the mixture generated heat and became a brown solution. After cooling, the reaction solution was poured into ice water, adjusted to pH 9-10 with 40% sodium hydroxide aqueous solution and extracted with chloroform. The organic layer was washed successively with a dilute aqueous sodium hydroxide solution and water, dried over anhydrous sodium sulfate and concentrated to obtain 12.43 g (quantitative) of the target product as a brown oil.

Example 12 Synthesis of N- [6-amino-3- (4-ethoxycarbonyl-1-piperazinyl) -2,4-difluorophenyl] -N-cyclopropylacetamide N-cyclopropyl-N- [3- (4-ethoxycarbonyl-
1-Piperazinyl) -2,4-difluoro-6-nitrophenyl]
78.0 g of acetamide and 10.4 g of 10% palladium carbon were added to 800 m of ethanol, and hydrogenation was carried out at room temperature for 4 hours in a hydrogen stream at atmospheric pressure. After filtering the reaction mixture,
The mixture was concentrated to m, cooled at 5 ° C., and the precipitated crystals were collected by filtration to obtain 67.37 g (yield 93.1%) of the target product as pale yellow prism crystals.
Mp 157.5 to 158.5 ° C. Elemental analysis (%): Calculated as _{C 18 H 24 F 2 N 4} O 3 C: 56.53 H: 6.33 N: 14.65 Found C: 56.64 H: 6.45 N: 14.55 Example 13 N- Cyclopropyl-N- [3- (4-ethoxycarbonyl-
Synthesis of 1-piperazinyl) -2,4-difluorophenyl] acetamide N- [6-amino-3- (4-ethoxycarbonyl-1-piperazinyl) -2,4-difluorophenyl] -N-cyclopropylacetamide Dissolve 1.0g in anhydrous DMF 6m, and add to t-butyl nitrite 0.4g anhydrous DMF 5m solution 55-65 ℃ 10
Dropped in minutes. After stirring at 65 ° C for 10 minutes, the reaction solution was poured into ice water and extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The obtained residue was separated and purified by a silica gel column to give 0.64 g of the desired product as a pale yellow oil (yield 6
6.7%) was obtained.

Example 14 N-cyclopropyl-N- [3- (4-ethoxycarbonyl-
Synthesis of 1-piperazinyl) -2,4-difluoroaniline N- [6-amino-3- (4-ethoxycarbonyl-1-piperazinyl) -2,4-difluorophenyl] -N-cyclopropylacetamide 62.0 g Is dissolved in 300 m of anhydrous DMF, and 55 to 60 is added to a solution of 25.1 g of t-butyl nitrite in 150 m of anhydrous DMF.
The solution was added dropwise at 1 ° C for 1 hour. After stirring for another 30 minutes, the reaction solution was poured into 1 () in ice water and extracted three times with 500 m of benzene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, 63.03 g of a dark red oily matter was obtained.

50.0 g of the dark red oil obtained above was added with a 20% aqueous sulfuric acid solution 70
0 m was added and the mixture was stirred at 40 ° C. for 9 hours. The reaction solution is ice water 300
Pour into the m and add potassium carbonate powder to neutralize and add benzene.
It was extracted 3 times at 500 m. Wash the organic layer with saturated saline,
The extract was dried over anhydrous sodium sulfate and concentrated, and the residue was isolated and purified by a silica gel column (ethyl acetate-n-hexane, 1: 3) to obtain 16.89 g of the desired product as a yellow oil.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display location C07D 241/04 8615-4C 295/20 A

Claims (9)

[Claims] 1. A general formula [I] (In the formula, R is a fluorine atom, a cyclopropylamino group or an N-lower acylcyclopropylamino group, W is hydrogen,
The nitro group or amino group, X and Y each represent the same or different halogen atom. Z is a fluorine atom, or Indicates. Here, R ¹ and R ² may each be substituted with hydrogen or a lower alkyl group, and R ³ may be substituted with hydrogen, a lower alkyl group, a lower acyl group, a lower alkoxycarbonyl group, a p-nitrobenzyl group or an acyl group. p-Aminobenzyl group, provided that R and Z are not fluorine atoms at the same time. ) Anilines represented by. 2. General formula [II] (Wherein X and Y each represent the same or different halogen atom) cyclopropylamine is allowed to act on the compound represented by the general formula [III] (In the formula, X and Y are the same as the above.). 3. A general formula [III] (In the formula, X and Y each represent the same or different halogen atom.) The compound represented by the general formula Z′H (wherein Z ′ is Wherein R ¹ and R ² are each substituted with hydrogen or a lower alkyl group, R ³ is substituted with hydrogen, a lower alkyl group, a lower acyl group, a lower alkoxycarbonyl group, a p-nitrobenzyl group or an acyl group. Optionally a p-aminobenzyl group. ) A general formula [IV] characterized by reacting amines represented by (Wherein X, Y and Z ′ are the same as defined above). 4. General formula [II] (In the formula, X and Y each represent the same or different halogen atom.) A compound represented by the general formula Z′H (wherein Z ′ is Wherein R ¹ and R ² are each substituted with hydrogen or a lower alkyl group, R ³ is substituted with hydrogen, a lower alkyl group, a lower acyl group, a lower alkoxycarbonyl group, a p-nitrobenzyl group or an acyl group. Optionally a p-aminobenzyl group. ) A general formula [V] characterized by reacting amines represented by (Wherein X, Y and Z ′ are the same as defined above). 5. A general formula [V] (In the formula, X and Y are the same or different halogen atoms Z ' Indicates. Here, R ¹ and R ² may each be substituted with hydrogen or a lower alkyl group, and R ³ may be substituted with hydrogen, a lower alkyl group, a lower acyl group, a lower alkoxycarbonyl group, a p-nitrobenzyl group or an acyl group. It is a p-aminobenzyl group. ) A compound of the general formula [IV] characterized by reacting a compound represented by (Wherein X, Y and Z'are the same as defined above). 6. A general formula [IV] (In the formula, X and Y are the same or different halogen atoms Z ' Indicates. Here, R ¹ and R ² may each be substituted with hydrogen or a lower alkyl group, and R ³ may be substituted with hydrogen, a lower alkyl group, a lower acyl group, a lower alkoxycarbonyl group, a p-nitrobenzyl group or an acyl group. It is a p-aminobenzyl group. ) An acid anhydride or an acid halide is allowed to act on the compound represented by the formula [VI] (Wherein R'represents a lower alkyl group and X, Y and Z'are the same as defined above). 7. A general formula [VI] (In the formula, R ′ is a lower alkyl group, X and Y are the same or different halogen atoms, and Z ′ is Indicates. Here, R ¹ and R ² may each be substituted with hydrogen or a lower alkyl group, and R ³ may be substituted with hydrogen, a lower alkyl group, a lower acyl group, a lower alkoxycarbonyl group, a p-nitrobenzyl group or an acyl group. It is a p-aminobenzyl group. ) The compound represented by the general formula [VII] characterized by reducing the compound (Wherein R ′, X, Y and Z ′ are the same as defined above) 8. A general formula [VII] (In the formula, R ′ is a lower alkyl group, X and Y are the same or different halogen atoms, and Z ′ is Indicates. Here, R ¹ and R ² may each be substituted with hydrogen or a lower alkyl group, and R ³ may be substituted with hydrogen, a lower alkyl group, a lower acyl group, a lower alkoxycarbonyl group, a p-nitrobenzyl group or an acyl group. It is a p-aminobenzyl group. ) A compound represented by the general formula [VIII] characterized by treating with a nitrous acid or a derivative thereof. (Wherein R ′, X, Y and Z ′ are the same as defined above) 9. A general formula [VIII] (In the formula, R ′ is a lower alkyl group, X and Y are the same or different halogen atoms, and Z ′ is Indicates. Here, R ¹ and R ² may each be substituted with hydrogen or a lower alkyl group, and R ³ may be substituted with hydrogen, a lower alkyl group, a lower acyl group, a lower alkoxycarbonyl group, a p-nitrobenzyl group or an acyl group. It is a p-aminobenzyl group. ) A compound of the general formula [IX] characterized by hydrolyzing a compound represented by (Wherein X, Y and Z'are the same as defined above).