JPH01131180A - Production of furobenzisoxazole derivative - Google Patents

Abstract

PURPOSE:To industrially and advantageously obtain the title compound useful as a medicine, such as uric acid eccritic or diuretic agent, by reacting a novel benzisoxazole derivative with a sulfinium ylide in an inert solvent and, as desired, hydrolyzing the resultant reaction product. CONSTITUTION:A novel benzisoxazole derivative expressed by formula I [R1 is phenyl; R2 and R3 are H, halogen or alkyl; A is OH or N(R4)R5 (R4 and R5 are alkyl)] is reacted with a compound expressed by formula II (R6 is alkyl; R7 is alkyl; n is 0 or 1) in an inert solvent and the resultant reaction product, as desired, is hydrolyzed to afford the aimed furobenzisoxazole derivative expressed by formula III [e.g., 5-chloro-7,8-dihydro-3-phenylfuro[2,3-g]-1,2- benzisoxazole-7-carboxylic acid]. The compound expressed by formula III is also obtained by two methods other than that described above. Thereby the aimed compound can be produced in good yield in a short process.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel method for synthesizing a flobenzisoxazole derivative represented by the general formula (I), which is useful as a pharmaceutical agent such as a uric acid excretor or a diuretic, and a synthetic intermediate thereof (a synthetic intermediate thereof (general formula ■) Concerning.

CHt-λ (In the formula, R1 means a phenyl group substituted with a halogen atom/lower alkyl group, or unsubstituted, and R2 and R3 are the same or different and are a hydrogen atom, a halogen atom, or a lower alkyl group. and R5 means a lower alkyl group).

Flobenzisoxazole derivatives as shown in the general formula CI) are described, for example, in European Patent Publication No. 2058
It is described in Japanese Patent Application No. 72 and is known as a compound having a uric acid excretion effect or a diuretic effect. In addition, as its synthesis method, 6-hydroxy7-aryl-3-phenyl-1,
7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-methanol produced by treating 2,-benzoxazole with a peracid such as m-chloroperbenzoic acid A method of treating derivatives with chromium oxide is known. However, in this method,
The number of steps is long (processing operations are complicated), and not only is the yield unsatisfactory, but the peracid used has the risk of explosion, making it unsuitable for large-scale synthesis in factories.

Furthermore, the chromium oxide used is a carcinogenic substance, and there is also the problem of environmental pollution due to trace metals.

In view of the above circumstances, the present inventor has conducted extensive research into a synthetic method that is convenient for industrial production, and has found that it requires a short process and does not have the problems of peracid and chromium oxide mentioned above (and has a high yield). We have discovered a method for synthesizing a flobenzisoxazole derivative represented by the general formula (I) that is extremely satisfactory in terms of the following, and have led to the present invention. The manufacturing method is shown in ① to ② below.

■ General formula (III) f (In the formula, R1 means a phenyl group substituted with a halogen atom/lower alkyl group, or an unsubstituted phenyl group, and R2 and R3 are the same or different, a hydrogen atom, a halogen atom, The benzisoxazole derivative represented by atom or lower alkyl group means formalin or its derivative alkyl group. ) or by reacting formalin or a derivative thereof with an alkali hydroxide to form a compound represented by the general formula (II) in an inert solvent, where the general formula (fV) is a lower alkyl group or In the substituted lower alkyl group such as 2-hydroxyethyl group, R7 means a lower alkyl group, and n is an integer of 0 or 1. A method of reacting the compound shown in and then hydrolyzing it if desired.

In this production method, the formalin derivatives used in the step of obtaining the compound represented by the general formula (n) from the compound represented by the general formula (III) are those that generate formaldehyde during the reaction, such as formalin and paraformaldehyde. etc.' can be mentioned. General formula (n
) In order to obtain a compound represented by formula A in which A is an -OH group, the alkali hydroxide such as sodium hydroxide means the same as mentioned above. ) is the same as above) is reacted. Further, the reaction is preferably carried out in H2O, and the reaction temperature is 0 to 50°C, preferably room temperature.

In the step of obtaining the compound represented by the general formula (I) from the compound represented by the general formula (II), the compound represented by the general formula (IV) is, for example, a compound represented by the general formula (0)n (R8)2=8 (formula sulfides such as (R6 and n have the same meanings as above) and general formula YCH2C0
OR? (In the formula, Y represents a halogen atom and R7 means the same thing as above.) It can be synthesized by reacting the compound represented by the formula, and then treated with a base, or it means the same thing as the general formula. ),
It can be synthesized by reacting a compound represented by the general formula Y@C00R7 (in which Y and R7 have the same meanings as above) and then treating with a base. The base used here is not particularly limited, but includes, for example, alkali carbonate and alkali hydride. Incidentally, since the compound represented by the general formula (rV) is usually unstable, it is generally reacted with the compound represented by the general formula (n) without being isolated from the reaction solution. As an inert solvent, it is inert to the reaction,
As long as the compound represented by the general formula (n) has excellent solubility, it can be used without any restriction, but preferably,
Examples include aprotic polar solvents such as dimethylformamide. The reaction temperature can be appropriately selected from 0 to 150''C. Hydrolysis can be easily carried out by a conventional method, for example, using an alkali hydroxide.

Compared to conventional manufacturing methods, this manufacturing method is industrially very advantageous, as it has a short process, extremely high yield, does not use peracid or chromium oxide, and is advantageous in terms of cost. I can say that.

Further, the compound represented by the general formula (II), which is an intermediate of this production method, is a new compound, and can be obtained, for example, from the compound represented by the general formula (III), as described above. This compound is a useful synthetic intermediate for the compound represented by general formula (I).

■ A compound represented by general formula (III) is added to X-CH2CH=CH2 (wherein X is
means halogen. ) to form the general formula (V) R.

(In the formula, RI ) (In the formula, R11R2 and R3 mean the same thing as above.) By producing an 0-allylphenol derivative represented by the formula, reacting it with a halogenohydrination agent, and then treating it with a base, the general formula (■) A method for producing a compound represented by the formula (in which R1, R2 and R3 have the same meanings as defined above) and oxidizing the compound with permanganate under a catalyst.

In this production method, the inert solvent used in the step of obtaining the compound represented by general formula (V) from the compound represented by general formula (III) is inert during the reaction and is Any compound represented by can be used without any particular restriction as long as it has excellent solubility, but dimethylformamide and the like are preferred. Further, the base is not particularly limited, and examples thereof include alkali hydroxide, alkali carbonate, etc., and the reaction temperature is 0 to 80°C.
, preferably proceeding between 50 and 60°C. The reaction time can be 1 to 5 hours.

The solvent used in the process of obtaining the compound represented by general formula (Vl) from the compound represented by general formula (V) may be any solvent as long as it is inert to high temperature conditions, such as dimethylaniline, diethylaniline, etc. etc. The reaction temperature is between 130°C and the boiling point of the solvent, preferably between 160 and 165°C. The reaction time can be 1 to 8 hours.

In the reaction to obtain compound (■) from compound (VI),
Examples of the halogenohydrination agent include halogenating agents such as N-promsuccinimide, N-bromoacetamide, N-chlorosuccinimide, calcium hypochloride, N-chlorourea, and chlorine, which are reacted in the presence of water. say. In addition, the base used next is:
Although there are no particular limitations, preferred examples include amines, alkali hydroxides, alkali carbonates, and the like.

In the oxidation reaction to obtain compound (I) from compound (■), potassium permanganate or the like is used as the oxidizing agent.

In addition, as a catalyst, for example, TDA-IC (CH3
0CH2CH20CH2CH2)3N], 18-cro
Acyclic and cyclic crown ethers such as wn-6 or phase transfer catalysts such as quaternary ammonium salts are used. The reaction temperature can be appropriately selected between 0 and 120°C.

In the process from compound (Vl) to compound (I), the reaction is preferably carried out in an inert solvent. Any suitable solvent may be used without any particular limitation, but polar solvents such as water, acetic acid, alcohols, and dimethyl sulfoxide are preferably used.

■ In the compound represented by the general formula (nI), the general formula (■)
CH2=CHC(OR4) 3 (■) (R4 in the formula
means a lower alkyl group. ) to produce a compound represented by general formula (IX) R1 (wherein R1s R2, R3 and R4 have the same meanings as above), and a halogenating agent is added to this compound. A method characterized in that it is allowed to act and then hydrolyzed.

In this production method, the step of reacting the compound represented by general formula (III) with the compound represented by general formula (■) and the step of reacting the compound represented by general formula (IX) with a halogenating agent are carried out using an inert solvent. It is preferable to take place inside the
The inert solvent to be used is one that is inert during the reaction and has excellent solubility of the raw material compound.
Although it can be used without particular limitation, hydrocarbons such as toluene and benzene, halogenated hydrocarbons, amines, dimethylformamide, etc. are preferably used. Further, the reaction for producing the compound represented by the general formula (IX) from the compound represented by the general formula (III) is preferably carried out in the presence of an acid, and as the acid, inorganic acids and organic acids can be used without limitation. However, particularly preferred acids include, for example, acetic acid, pivalic acid, and other carboxylic acids. - In the compound represented by the general formula (■), R4 in the formula is preferably a lower alkyl group having 1 to 5 carbon atoms, and specifically, for example, a methyl group or an ethyl group.

In the reaction in which a halogenating agent is reacted with the compound represented by the general formula (IX), chlorine, bromine, or a derivative thereof, such as sulfuryl chloride, N-chlorosuccinimide, etc., is used as the halogenating agent. At this time, it is preferable to use amines such as pyridine and triethylamine, and inorganic bases such as sodium carbonate, potassium carbonate, and sodium hydrogen carbonate in order to capture hydrogen halides and the like generated.

Through this reaction, a compound represented by the general formula (X) (in which RI N R2, R3 and R4 have the same meanings as above) is obtained, which is then subjected to a hydrolysis reaction. The general formula (
A compound represented by I) is obtained.

This hydrolysis reaction is easily carried out by a conventional method using, for example, an inorganic acid such as hydrochloric acid or sulfuric acid, or an alkali hydroxide.

The compound represented by the general formula (III), which is a synthetic intermediate for the flobenzisoxazole derivative represented by the general formula (I), can be produced, for example, by the method shown below.

(In the formula, R1, R2, and R3 are the same as those described above.) However, in this method, the chlorophenol derivative that is the raw material contains 2, 4, and 4. There is a risk of contamination with 5-trichlorophenol, so from an industrial perspective, the method shown by the following formula is particularly superior.'' (XIII) (XIV
) (Xv)C further)
(R) (in the formula, R11R2 and R3 are the same as above) is added to the compound represented by the general formula (XI) under a catalyst.
CQ is reacted to obtain a compound represented by the general formula (X II ). The catalysts used are AQCQ3, S
bCρ5, etc., and the reaction is carried out, for example, in an inert solvent such as toluene. Next, in a solvent such as pyridine, N
By reacting H2OH・HCl, general formula (XIII)
The compound shown is obtained. The reaction is carried out under reflux, and the reaction time can be 1 to 2 hours. Then, in an inert solvent such as dimethylformamide or dimethyl sulfoxide,
By reacting a dehydrating agent such as acetic anhydride or acetyl chloride with sodium acetate or potassium carbonate, the general formula (XI
V) and (X, V) are produced. General formula (XV) can be removed by subjecting this to acid hydrolysis using concentrated sulfuric acid or the like to make it alkaline. Then, by subjecting the general formula (X■) to a dealkylation reaction, a compound represented by the general formula (III) can be obtained. This dealkylation reaction is carried out in an inert solvent such as toluene or benzene in the presence of a Lewis acid such as aluminum chloride or boron trifluoride. The reaction also proceeds with pyridine hydrochloride and the like.

The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited thereto.

Example 1 a) 51 g (0.31 mol) of 2,5-dichlorophenol and 102.7 g (0.73 mol) of benzoyl chloride were dissolved in 500 mQ of 1,2-dichloroethane, and chlorinated with stirring under water cooling. Aluminum 102.4g (
After gradually adding 0.77 mol), the mixture was refluxed for 33 hours.

Add the reaction solution to cold ice water, add a small amount of concentrated hydrochloric acid, and extract with ether-ethyl acetate. After washing with water and drying and distilling off the solvent, 50 mQ of ethanol and 500 mQ of a 4N aqueous sodium hydroxide solution were added and stirred for 30 minutes. Refrigerate, neutralize with concentrated hydrochloric acid, add sodium hydrogen carbonate to pH 8-9
If you do so, crystals will precipitate. The crystals were collected by filtration, washed with water,
Recrystallization from toluene yields 50.8 g of 4-benzoyl-2,5-cyclophenol (yield θ1%).

b) 50.8g of phenol obtained in a) above (0°19
A mixture of 21.2 g (0.30 mol) of hydroxyamine hydrochloride and 7400 mQ of pyridine was refluxed for 2.5 hours, and then the solvent was distilled off. 500 mρ of dimethylformamide is added and dissolved in the resulting oil, and 69.4 g (1.24 mol) of powdered potassium hydroxide is added with stirring, followed by refluxing for 12 hours. Add cold water and acidify with hydrochloric acid to precipitate crystals. The crystals are collected by filtration, washed with water, and dried. The obtained crystals were treated with activated carbon and recrystallized from ethyl acetate-hexane to give 5-chloro-6-hydroxy-3
-Phenyl-1,2benzisoxazole 40.0g
(yield 85.5%).

C) 5.0 g of the benzoxazole compound obtained in b) above
(0.02 mol), formalin 0.2 mol and water 50
While stirring the mixture of mQ, an aqueous solution of 0.2 mol of dimethylamine<25 m of water, Q) is added dropwise at room temperature. After stirring for 1 hour, the solid was filtered and extracted with 5-chloro-7-dimethylaminomethyl-6-hydroxy-3-phenyl-1,
8.0 g of 2-benzisoxazole (yield 97%)
get. Melting point: 164-5°C.

d) A mixture of 0.01 mol of dimethyl sulfide and 0.01 mol of ethyl bromoacetate was left overnight. Dimethylformamide 10mρ, potassium carbonate 1.4g (0
, 01 mol) and stirred at room temperature for 30 minutes, 1.0 g (0,003 mol) of the compound obtained in step C) above was added. 5
After stirring at 5 to 65°C for 6 hours, 10 mΩ of a 20% aqueous sodium hydroxide solution was added, and the mixture was stirred at 70 to 80°C for 30 minutes.

After cooling and acidifying with hydrochloric acid, the precipitated crystals were collected by filtration, dried, and recrystallized with tetrahydrofuran-acetone to give colorless crystals of 5-chloro-7,8-dihydro-3-phenylfuro [2
,3-g] -1,2-benzisoxazole-7-
Carvone 48-50°C.

Example 2 The same reaction was carried out using thiodiglycol in place of the dimethyl sulfide used in Example 1d), and 5-
Chloro-7,8-dihydro-3-phenylfuro [2.
3-g] -1. 2-benzisoxazole-7-
Obtain carboxylic acid. (Yield 80%) Example 3 The compound (CH3
) Using 3SoL ethyl chlorocarbonate and sodium hydride, the same reaction was carried out to obtain 5-chloro-
7,8-dihydro-3-phenylfuro[2.3-g]-
1.2-benzoinoxazole-7-carboxylic acid is obtained.

(Yield 80%) Example 4 The same reaction was carried out using sodium hydride in place of the potassium carbonate used in Example 1d), and 5
-chloro-7,8-dihydro-3-phenylfuro [2.
3-g-1,2-benzisoxazole-7-carboxylic acid is obtained. (Yield 87%) Example 5 5-chloro-6-hydroxy-3-phenyl-1.2-
Dissolve 8.58 g of benzisoxazole in 95 mΩ of dimethylformamide, 7.2 g of potassium carbonate and 4 g of allyl bromide.

Add 52 mQ and stir at 50-60°C for 2.5 hours.

Thereafter, 400 mQ of water was added, stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration, washed with water, and dried. 96.5%) is obtained.

b) 6-allyloxy-5-chloro-3-phenyl-1
, 17.16 g of 2-benzisoxazole and 150 mΩ of dimethylaniline are stirred at 160-165° C. for 8 hours. After cooling the reaction solution, add 250mf of concentrated hydrochloric acid! , and extract with ether. Wash the ether layer with NaCΩ water,
After drying, ether is distilled off. When the obtained crystals were recrystallized from chloroform-n-hexane, 8.83 g (yield 51.5%) of 7-allyl-5-chloro-6-hydroxy-3-phenyl-1,2-benzisoxazole was obtained. can get. After concentrating the mother liquor to dryness, 80 mΩ of dimethylaniline was added, and the mixture was stirred at 160 to 165°C for 5.5 hours. After cooling the reaction solution, 100 mΩ of concentrated hydrochloric acid and water were added.
Stir for 40 to 50 minutes, and collect the precipitated crystals by filtration. When the crystals were washed with water and dried, 7.27 g of the desired 7-allyl-5-chloro-6-hydroxy-3-phenyl-1,2-benzisoxazole was obtained, and together with the previous crystals, 16.1 g ( A yield of 93.8%) is obtained.

Dissolve 5.5 g of N-bromosuccinimide in 095 mN of dry DMS in a water bath kept below 20°C.
g and 3.42 mQ of water. In a nitrogen gas atmosphere, 22
After stirring for an hour, slowly add 120 mρ of water and
Stir for 1 minute. After removing the supernatant liquid by decantation and thoroughly washing the viscous precipitate with water, 38 mρ of IN aqueous sodium hydroxide solution was added, and the mixture was stirred for 2.5 hours. After extraction with ether, the ether layer was washed with water, dried, and the ether was distilled off to obtain 4.9 g (yield: 85%) of -Rorome or Muni.

d) 5-chloro-7,8-dihydro-3-phenylfuro[2,3-g to 1,2-benzisoxazole-7-methanol 1.8 g to 1,2 dichlorothane 80
Dissolved in mp, 2.8 g of potassium permanganate and TDA
-1(CH3QCH2CH2,0CH2CH2)3
Nko 1. Add 9rr3Q and heat to reflux for 1.25 hours. After cooling, add 1.8 g of sodium sulfite and 80 mΩ of water.
and stir at room temperature for 30 minutes. 4N hydrochloric acid aqueous solution 20m
! 2 and ether are added, insoluble matter is filtered and removed, the ether layer is washed with 0.5N sodium hydroxide, and 4N hydrochloric acid aqueous solution and ether are added to the alkaline aqueous solution.

The ether extract was washed with NaCΩ water, dried, and then the ether was distilled off to obtain mg (43% yield) from a mixed solvent of tetrahydrofuran and acetone.

Melting point: 253-255°C Example 6 1.51 g of the compound obtained in Example 5-C) was heated to 1.2-
1.11 g of potassium permanganate and 18-Cr dissolved in 80 mρ of dichloroethane.

Add 185 mg of wn-6 and stir at room temperature to 40°C for 16 hours. Sodium sulfite 126mg 1 water 30mΩ
Add and stir at room temperature. Further, dilute hydrochloric acid and ethyl acetate were added, and after filtering and removing insoluble materials, the ethyl acetate was washed with a saturated aqueous sodium bicarbonate solution.
Add 4N hydrochloric acid aqueous solution and ethyl acetate to the alkali aqueous solution. The acetic acid ethyl ester extract was
After washing with water and drying, ethyl acetate is distilled off to obtain a mixed solvent of tetrahydrofuran and acetone (yield: 32%).

Melting point 253-5℃ Add 20mρ of water to 3.58g of potassium permanganate,
In ice water solution, AQiQuat336 (registered trademark, CH3
N [(CH2)7 CH3ko3Cρ, manufactured by Henkel)
is dissolved in 4 mρ of toluene, followed by a solution of 1.0 g of the compound obtained in Example 5-c) suspended in 6 mg of toluene, and then 20 mρ of toluene is added. After stirring at room temperature to 50°C for 23 hours, sulfite (I)
Add 4.8 g of Jium heptahydrate and the amount of water, and stir at room temperature for 30 minutes. After adding dilute hydrochloric acid and ether and filtering out insoluble matter, the organic layer is washed with IN aqueous sodium hydroxide solution, and 4N aqueous hydrochloric acid solution and ether are added to the alkaline aqueous solution.

The ether extract was washed with NaCΩ water, dried, and then the ether was distilled off.
). Melting point 252-5°C Example 8 15g was dissolved in 16mρ of dry dimethyl sulfoxide, and in a water bath kept below 10°C, 1.43g of N-bromosuccinimide and 0.72rrl of water were added. Add. After stirring for 24 hours in a water bath at about 22°C in a nitrogen gas atmosphere,
Add 30 mρ of 1,2-dichloroethane in a cup of ice water, then slowly add 20 mρ of water. After stirring for 1 hour, the organic layer was separated and washed with water, followed by adding 88 m of an IN aqueous sodium hydroxide solution and 5 m of 1,2-dichloroethane. After stirring at room temperature for 1.5 hours, the organic layer is separated, washed with water, dried and concentrated to about 20 m9 of solution. In the concentrate, 2.21 g of potassium permanganate and TDA-11,
Add 34rr3Q and heat to reflux for 45 minutes. After cooling, add 70 g of sulfite and 20 mQ of water, and stir at room temperature for 1 hour.

Add dilute hydrochloric acid aqueous solution and ethyl acetate to adjust the pH of the aqueous layer.
1 or less, the acetic acid ethyl ester layer was separated and N
a Cρ Wash with water. The acetic acid ethyl ester solution is washed with a saturated sodium bicarbonate aqueous solution, and a 4N hydrochloric acid aqueous solution and acetic acid ethyl ester are added to the alkaline aqueous solution. After washing the acetate ethyl ester extract with NaCΩ water and drying, the acetate ethyl ester was distilled off and recrystallized from a mixed solvent of tetrahydrofuran and acetone.
20 mg (yield 33%) is obtained.

Melting point 254-5°C.

Example 9 a) 5-'yrollo-6-hydroxy-3-phenyl-1
, 2-benzisoxazole-2,5 g triethyl orthoacrylate 3.5 g 1 A mixture of 2.0 g pivalic acid and 15 mΩ of toluene is heated under reflux for 2 hours. After cooling, diethyl ether was added, and the mixture was washed with 5% sodium hydroxide, an aqueous solution, and then water, and after drying, the solvent was distilled off. Recrystallization from a mixed solvent of dichloromethane and n-hexane yields 3.6 g of 5-chloro-7,7-jethoxy-3-phenylisoxazolo[5,4-f]chlorone.

Melting point: 119-120°C b) A mixture of 1°5 g of 5-chloro-7,7-ethoxy3-phenylisoxazolo[5,4-f] chlorine, 0.35 g of pyridine, and 20 rnQ of chloroborum was cooled with water and stirred. , to which 0.7 g of bromine and 5 m of chloroform were added. Add the mixture dropwise. After stirring at room temperature overnight, heat to reflux for 4 hours. After evaporating the solvent, 30 mΩ of diethyl ether and 50 mQ of 10% aqueous hydrochloric acid were added, stirred at room temperature for 2 hours, the ether layer was separated, dried, and the solvent was evaporated. The residue was subjected to M'El chromatography on silica gel using dichloromethane as a developing solvent to obtain 0.9 g of 5-chloro-7,8-dihydro-3-phenylfuro[2,3-gl-1,2-benzisoxazole-7]. - Obtain carboxylic acid ethyl ester.

c) Dissolve 0.9 g of 5-chloro-7,8-dihydro-3-phenylfuro[2,3-gl-1,2-benzisoxazole-7-carboxylic acid ethyl ester in 20 mg of ethanol with heating, % hydroxide)
Add 10 ohms of IJum aqueous solution and heat at 80 to 90℃ for 3
Stir for 0 minutes.

After cooling, acidify with hydrochloric acid and filter the precipitated crystals,
Recrystallization from a mixed solvent of tetrahydrofuran and azetone yields 0.8 g of 5-chloro-7,8-dihydro-3-
Phenylfuro[2°3-gl-1,2-benzisoxazole-7-carboxylic acid is obtained.

Melting point: 254-255°C.

Example 10 3.7 g of 5-chloro-7,7-jethoxy-3-phenylisoxazolo[5°4-f]chlorone obtained in Example 9-a), 0.87 g of pyridine, 50 g of chloroform
A mixture of m9 was stirred under water cooling, and a mixture of 1.5 g of sulfuryl chloride and 20 mΩ of chloroform was added dropwise thereto, followed by treatment in the same manner as in Example 9, resulting in 2.0 g of 5-chloro-7,8-dihydro-3. -Phenylfuro[2,3-
g]-1,2-benzisoxazole-7-carboxylic acid is obtained.

Melting point: 254-256°C.

Example 11 a) NaOH2,Og (0.05 mol) in H2O10
5-chloro-〇-hydroxy-3-phenyl-1,2-benzisoxazole f3 dissolved in 0mρ
．． Dissolve Og (0,0244 mol), add 10.8 g (0°125 mol) of 35% formalin, and stir at 70°C for 3 hours.

After cooling, the mixture was acidified with hydrochloric acid by adding water, and then extracted with diethyl ether-ethyl acetate.

After washing the organic layer with water and drying, the solvent was distilled off to give 5-chloro-
6-Hydroxy7-hydroxymethyl-3-phenyl-1,2-benzisoxazole 66g (odor rate 98%)
).

Melting point: 158-158°C.

Elemental analysis value C+4 H(.CρNO3(molecular weight 275
．． 69) NMRCCDCQ3+DMSO-d6) δ: 5°05
(2H, s), 7.25-7.57 (3H% m)
, 7.84 (IH% s) , 7.57-7.95
(2H,m), 9.50 (IHlbS) b) 5-chloro-6-hydroxy-7-hydroxymethyl-3-phenyl-1,2 obtained in Example 1l-a) above
-Benzisoxazole 0゜91g (0,0033
mol), 2 CO3 1° 4g (0.01 mol), ethoxycarbonylmethylsulfonium bromide 2.3g
(0,01 mol) and dimethylformamide 10 m
The mixture of ρ is stirred at room temperature for 6 hours. After washing the organic layer with water and drying, the solvent was distilled off to obtain 5-chloro-7°8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acid ethyl ester. Add 15 mR of 2N-NaOH and heat. After cooling, add 2N-HCl2 to make it acidic with hydrochloric acid, and extract with diethyl ether-ethyl acetate. The organic layer is washed with water, dried, and the solvent is removed. The residue obtained by distillation was crystallized with acetone, filtered and dried to give 5-chloro-7,8-dihydro-3-phenylfuro [2,3-g
0.84 g (yield: 81%) of 2-1,2-benzisoxazole-7-carboxylic acid is obtained.

Example 12 S (CH2CH20H) 21.4 g (0,0115
mole) and BrCH2COOC2H51゜7g (0
, 0102 mol) is stirred overnight. There 5-
Chloro-6-hydroxy-7-hydroxymethyl-3-
Phenyl-1,2-benzisoxazole 0.91g
(0,0033 mol), K2 CO31,4g (0
, 01 mol) and 10 mΩ of dimethylformamide were added, and the mixture was stirred at room temperature for 6 hours. Add water and extract with diethyl ether-ethyl acetate. After washing the organic layer with water and drying, the solvent was distilled off, and 15 mρ of 2N-NaOH was added to the resulting residue and heated. After cooling, the mixture was acidified with hydrochloric acid by adding 2N-HCρ, and then extracted with diethyl ether-ethyl acetate. After washing the organic layer with water and drying, the solvent was distilled off and the resulting residue was crystallized with acetone. The crystals were filtered and dried to give 5-chloro-7.
,8-dihydro-3-phenylfuro[2,3-g]-1
, 2-benzisoxazole-7-carvone (yield 51%).

Example 13 Resorcin φ dimethyl ether 100g (0.

724 mol) of SO2CQ2e1m while stirring under water cooling.
ρ (0,759 mol) was added dropwise over 2.5 hours, followed by stirring at room temperature for 2.5 hours. Toluene 300m there
ρ, benzoyl chloride 105.9g (0,75
3 mol) was added, and while stirring under water cooling, kQCQa 10
2.3 g (0,767 mol) was added over 1 hour, then stirred at room temperature for 2 hours, and then refluxed for 40 minutes. Gradually pour into a refrigerator and ice water, add conc HCQ400mfi, and extract with Ac0Et. After washing the organic layer with water, the solvent is distilled off to obtain crude crystalline 2-benzoyl-4-chloro-5-methoxyphenol. This crystal is pyridine 500mΩ
Dissolved in NH2OH4IHCI2201.2g (2
, 90 mol) and refluxed for 1.5 hours. The solvent was distilled off in a refrigerator, acidified with hydrochloric acid, and then extracted with AcOEt. After washing the organic layer with water and drying, the crystals obtained by distilling off the solvent were dissolved in 600 mQ of dimethylformamide, and 20 mQ of acetic anhydride was added.
7mQ (2°18 mol), sodium acetate 180.7g
(2°20 mol) and refluxed for 3 hours. Cold machine, 0
The mixture was gradually poured into 2N-NaOH10R, and the precipitated crystals were collected by filtration, washed with water, and dried. Add this crystal to 1000ml of acetic acid.
Ω to dissolve it, 50 mρ (0,938 mol) of concentrated sulfuric acid, 800 rrl of H2O! and reflux for 4 hours. The mixture was gradually poured into 3N-NaOH 8Ω cooled in a cold machine and water with stirring, the precipitated crystals were collected by filtration, washed with water and dried, and the obtained crystals were dissolved in CH2CΩ21ρ, 20g of activated carbon was added, and after refluxing for 30 minutes, After removing the activated carbon by suction filtration and distilling off the solvent, recrystallization with C2H50H3Ω yields 5-
84.8 g of chloro-6-medoxy-3-phenyl-1,2-benzisoxazole (yield: 3
5%).

Obtained 5-chloro-6-medoxy-3-phenyl-1
, 25 g (0,096 mol) of 2-benzisoxazole was dissolved in 250 mρ of toluene, and while stirring under water cooling, 328.3 g (0°213 mol) of AρCΩ was gradually added, and the mixture was stirred at 80±5°C for 3.5 hours. do. Cold machine, H(,
Pour slowly into Q solution and extract with ethyl acetate. After washing the organic layer with water and drying, the solvent was distilled off and recrystallized from ethyl acetate-n-hexane to give 5-chloro-6-hydroxy-3-
Phenyl-1,2-benzisoxazole 22.4g
(Yield 95%).

Claims (1)

[Claims] 1. General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (which are the same or different and mean a hydrogen atom, a halogen atom, or a lower alkyl group), a)
General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 means a phenyl group substituted with a halogen atom/lower alkyl group, or unsubstituted, and R_2 and R_3 are the same or different, It means a hydrogen atom, a halogen atom, or a lower alkyl group, and A represents an OH group or ▲There are numerical formulas, chemical formulas, tables, etc.▼, and R_4
and R_5 means a lower alkyl group. ) The benzisoxazole derivative represented by the general formula ▲mathematical formula, chemical formula, table, etc. in an inert solvent has R_7 (in the formula, R_6 is a lower alkyl group or a substituted lower alkyl group such as 2-hydroxyethyl group, R_7 means a lower alkyl group, n is 0 or 1.) A production method characterized by reacting the compound represented by the following and then optionally hydrolyzing it, b) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 means a phenyl group substituted with a halogen atom, a lower alkyl group, or an unsubstituted phenyl group, and R_2 and R_3 are the same or different and represent a hydrogen atom, a halogen atom, or a lower alkyl group. The o-allylphenol derivative represented by (meaning the same thing as)) and oxidizing it with permanganate in the presence of a catalyst, or c) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 means a phenyl group substituted with a halogen atom/lower alkyl group, or unsubstituted, and R_2 and R_3 are the same or different and mean a hydrogen atom, a halogen atom, or a lower alkyl group. ), the general formula CH_2=CHC(OR_4)_3 (in the formula R_
4 means lower alkyl. ) to produce a compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. , followed by the action of a halogenating agent and further hydrolysis. 2. General formulas ▲ Numerical formulas, chemical formulas, tables, etc. ▼
2 and R_3 are the same or different and mean a hydrogen atom, a halogen atom, or a lower alkyl group, A represents an OH group or a group - ▲There are numerical formulas, chemical formulas, tables, etc.▼, and R_4 and R_5 are lower alkyl groups. means. ) is a benzisoxazole derivative represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R_4 in the formula
and R_5 means a lower alkyl group. ) or by reacting formalin or a derivative thereof with an alkali hydroxide. 3. General formulas ▲ Numerical formulas, chemical formulas, tables, etc. ▼
2 and R_3 are the same or different and mean a hydrogen atom, a halogen atom, or a lower alkyl group. ) is a general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1, R_2 and R_3 mean the same as above.) -CH_2-CH=CH_2
(In the formula, X means a halogen atom.) by reacting,
By obtaining a compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. 1. A method for producing a frobenzisoxazole derivative according to claim 1, which comprises obtaining a fluorobenzisoxazole derivative according to claim 1. 4. General formulas ▲ Numerical formulas, chemical formulas, tables, etc. means a hydrogen atom, a halogen atom, or a lower alkyl group, A represents a -OH group or a group ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and R_4 and R_5 mean a lower alkyl group). Isoxazole derivatives. 5. General formulas ▲ Numerical formulas, chemical formulas, tables, etc. ▼
2 and R_3 are the same or different and mean a hydrogen atom, a halogen atom, or a lower alkyl group. ) is reacted with formalin or a derivative thereof with the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (in the formula, R_4 and R_5 mean a lower alkyl group), or There are general formulas, mathematical formulas, chemical formulas, tables, etc. that are characterized by reacting formalin or its derivatives with alkali hydroxide. (In the formula, R_1, R_2 and R_3 mean the same as above, and A is -OH A method for producing a benzisoxazole derivative represented by a group or a group ▲ where there are mathematical formulas, chemical formulas, tables, etc. ▼, and R_4 and R_5 mean the same as above. 2) General formulas ▲ Numerical formulas, chemical formulas, tables, etc. , means a halogen atom, a lower alkyl group, and A is an -OH group, or a benzisoxazole derivative represented by ▲ where R_4 and R_5 mean a lower alkyl group.