KR820000562B1 - Process for preparing 1,2-benzisoxa - zoloxyacetic acid derivatives - Google Patents

Abstract

1,2-Benzisoxazolyloxy acetic acids and derivatives of formula I[R = H, low alkyl, cycloalkyl; R1 = COOH, CHO, CN, 5-tetrazolyl; R2,R3,R4 = H, alkyl, halogen; R5,R6=H, low alkyl, A,A1=O or S were prepd. Thus 2.3 dichlorophenoxy acetic acid reacted with 2-fluorobenzoyl chloride to give 2.3 dichloro-4-(2-fluorobenzoyl)phenoxy acetic acid, which was converted to 2.3 dichloro-4-(2-fluorobenzohydroxymoyl)phenoxy acetic acid[II II was hydrolyzed to [7-chloro-3-(2-fluorophenyl -1,2-benzisoxazol-6-yl oxy acetic acid. The title compds. have diuretic, antihypertensive and uricosuric acitvity.

Description

Method for producing 1,2-benz isoxoxazoleoxyacetic acid derivative

The present invention relates to a method for preparing 1,2-benzisoxazole oxyacetic acid and related compounds of the following general formula (I), which are effective as diuretics, uric acid excretion agents, and antihypertensive agents.

In the above general formula

,

, 티에닐, 푸릴, 피릴, 피리딜 또는 피리딜 N-옥사이드이고

R¹은 탄소수가 1내지 8인 유리 또는 에스테르화된 카복실그룹,

,

또는

이며,R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, tricycloalkyl, cycloalkyl lower alkyl, cycloalkenyl lower alkyl, naphthyl,

,

, Thienyl, furyl, pyryl, pyridyl or pyridyl N-oxide

R ¹ is a free or esterified carboxyl group having 1 to 8 carbon atoms,

,

or

Is,

R ² , R ³ and R ⁴ are the same or different and each can be hydrogen, halogen or lower alkyl,

X is hydrogen, halogen, lower alkyl, lower alkylthio, lower alkoxy, hydroxy, trifluoromethyl, nitro, amino or acylamino,

R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are the same or different and can be hydrogen or lower alkyl,

A and A 'are the same or different and are 0 or S,

Z is chlorine, bromine or fluorine,

m and n are the same or different and are integers of 1,2 or 3, respectively.

Also included within the scope of the present invention are physiologically toxic salts.

Some compounds within the scope of the present invention have greater pharmaceutical activity than others. Among the latter compounds, compounds in which R ¹ is an esterified carboxyl group, CN, CN ₂ OH or CHO are preferably used as intermediates in the preparation of more active compounds.

As mentioned above, R can be an aliphatic or carboxyl group as well as a heterocycle group such as thienyl, furyl, pyryl or pyridyl.

Preferred compound groups are compounds in which R is an aromatic ring having an ortho substituent, in particular a halogen atom, preferably fluorine (where the attachment position can be anywhere in the ring). Also preferred are compound groups of the invention wherein R is a carboxyl group which may be esterified with lower alkoxy or benzyl groups. Further preferred compounds are those in which A and A 'are each oxygen.

As used herein, the following terms have the following meanings.

“Tienyl, furyl, pyryl or pyridyl” is an unsubstituted and substituted moiety wherein the substituent is halogen or lower alkyl.

"Lower" means 1 to 4 carbon atoms.

"Cycloalkyl" is a saturated carbocycle ring having 3 to 8 carbon atoms.

"Bicyclo and tricycloalkyl" are non- and tricarbocyclic cyclic systems having 7 to 10 carbon atoms.

"Cycloalkenyl" is an unsubstituted carbocycle ring having 5 to 8 carbon atoms.

The physiologically nontoxic salts of the present invention are salts with alkali or alkaline earth metal bases or nontoxic organic bases such as ethanolamine, dietanolamine or N-methylglucamine.

The compounds of the present invention may be prepared by the following reactions where R, R ¹ to R ⁸ , X, m and n are as described above and Y is chlorine or fluorine and the ambient temperature is 20 to 25 ° C unless otherwise indicated.

a ₁ ) The ethoxyalkanoic acid ester or nitrile of general formula (VI) is reacted with an acid halide of RCOZ under pretel-craft conditions to obtain a compound of general formula (VII).

The preferred method is to use an aluminum chloride catalyst and a carbon wed solvent.

의 화합물과 염기 및 용매존재하에 반응시켜 일반식(ⅩⅧ)의 화합물을 얻는다.a ₂ ) A compound of formula (III) or (IIIa) wherein R ¹⁰ is hydrogen;

The compound of Formula 1 is reacted in the presence of a base and a solvent to obtain a compound of the general formula (VII).

In the above food

R is a free or esterified carboxyl group,

CN, CH ₂ OH or CH (OR ⁹ ) ₂ .

a ₃ ) The compound of formula (VII) is treated with hydroxylamine hydrochloride in a solvent to obtain a compound of formula (VII).

a ₄ ) The compound of formula (VII) is subjected to ring closure by treatment with a base at ambient temperature to reflux of the reaction medium in the presence of a solvent to obtain the corresponding compound of formula (Ia).

b ₁ ) A compound of formula III is obtained by treating a compound of formula IV wherein R ¹⁰ is hydrogen and X is not hydroxy or amino with dialkylthiocarbamoyl halide in the presence of a base.

In the above food

R ⁷ and R ⁸ are lower alkyl.

The preferred method is to use dimethylthiocarbamoyl chloride in dimethylformamide as solvent and sodium hydride as base.

b ₂ ) The compound of general formula (XIII) is melt-heated and thermally displaced by the compound of general formula (XIV).

b ₃ ) The compound of formula (XIV) is hydrolyzed in a conventional manner to obtain a compound of formula (XV).

One method is to use a rare sodium hydroxide as a hydrolysis agent.

화합물과 반응시켜 일반식(Ⅰb) 화합물을 얻는다.b ₄ ) Formula (VV) compound in the presence of a base and a solvent

Reaction with a compound affords the compound of formula (lb).

c ₁ ) A compound of formula (XVI) wherein R ¹⁰ is lower alkyl and X is not amino or hydroxyl is treated according to the processes b ₁ ), b ₂ ) and b ₃ ) to obtain a compound of formula (VII).

c ₂ ) The compound of formula (III) is treated with hydroxylamine hydrochloride in a solvent such as pyridine, acetylated, treated with base in the presence of solvent at ambient temperature to reflux of the reaction mixture, or dealkylated. (Iii) A compound is obtained.

화합물과 반응시켜 일반식(Ⅰ_c) 화합물을 얻는다.c ₃ ) General formula (VIII) compound in the presence of a base and a solvent

Reaction with a compound yields a compound of general formula (I _c ).

d ₁ ) The general formula (VII) compound is treated according to the steps b ₁ ), b ₂ ) and b ₃ ) to obtain a general formula (VII) compound.

화합물과 반응시켜 일반식(Ⅰd) 화합물을 얻는다.d ₂ ) General formula (VIII) compound in the presence of a base and a solvent

The compound is reacted with a compound to give a compound of general formula (Id).

e) The compound of general formula (Ia), (Ib), (Ic) or (Id) in which R ¹ is carboxylic ester or CN is converted to the corresponding compound in which R ¹ is COOH.

A suitable method is to hydrolyze with a base such as sodium hydroxide.

f) The compounds of the invention of general formula (la), (lb), (lc) or (ld) in which R ¹ is CH (OR ⁹ ) ₂ are converted to the corresponding compounds in which R ¹ is CHO.

A suitable method is to hydrolyze with succinic acid.

g) a compound of formula (Ia) wherein X, R ² , R ³ and R ⁴ are not lower alkyl and R ¹ is CH ₂ OH or a compound of formula (Ia) prepared by step (f) in which R ¹ is CHO; Is converted to the corresponding compound wherein R ¹ is COOH.

A suitable method is to oxidize with potassium permanganate.

h) A compound of formula (I) wherein R ¹ is COOH is converted to a compound wherein R ¹ is COZ.

A suitable method is to treat with SOZ ₂ .

로 처리하여 R¹이

, CONHOH 또는

인 상응하는 화합물로 전환시킨다.i) a compound of formula (I) wherein R 'is COZ, with or without or

By treating R ¹ as

, CONHOH or

Is converted to the corresponding compound.

The reaction time and exact reaction conditions of the reaction step depend on the specific reactants and solvents used.

All starting materials are known compounds or can be readily prepared from readily available materials.

The compound of the present invention is effective as a diuretic because it causes diuretic action in mammals. Diuretic activity is measured in mice in a manner similar to that described in the following text. [Reference: C.M. Kagawa and M.J. Kalm, Arch, Intern. Pharmcodyn. 137, 241 (1962).

The drug is orally administered to six birds and the average excretory urine volume is compared with the average volume excreted in the six control rats orally administered 1000 mg / kg of the known diuretic urea.

As a result, a drug / urea ratio greater than 1 indicates that there is a diuretic effect.

The diuretic test results of the compound of the present invention and the standard diuretics thienic acid and ethacrynic acid are shown in Table 1.

TABLE 1

Diuretic effect is obtained when a compound of the present invention is administered to a patient by oral, parenteral or intravenous doses of 0.1 to 500 mg / kg daily. Preferred dosage ranges are 1.0 to 200 mg / kg.

The compound of the present invention is also effective as an antihypertensive agent because it has a blood pressure lowering effect in mammals. Antihypertensive action is measured in mice with comminuted hypertension by indirect tail hitting. See A. Schwartz, Ed., Methods in Phamacology, Voll, page 135, Appleton-Century-Crofts, New York, New York 1971. In this method, five groups were orally administered drug for 3 days and compared with the same number of control groups. Blood pressure drop is measured on day 3 after administration.

The antihypertensive action (expressed in mm reduction in mean arterial blood pressure) in some compound tests of the present invention is shown in Table II below.

TABLE 2

Antihypertensive action is effective when the compound of the present invention is administered orally, parenterally or intravenously at 0.1 to 500 mg / kg per day. Preferred dosage ranges are 1.0 to 200 mg / kg per day.

) 시약을 사용하여 애보트 바이오크로마틱 분석기(Abbott Bio-chromatic Analyzer)로 측정한다.The compounds of the present invention are effective as agents for treating uric aciduria because they enhance uric acid excretion in mammals. Uric acid excretion is measured by oral administration of a test compound suspended or dissolved in sufficient distilled water in a group of six Wistar rats. Only the same amount of water is administered to the corresponding control group. Urine was collected for 5 hours and the amount of uric acid was collected in Uricosquant.

The reagent is measured using an Abbott Bio-chromatic Analyzer.

Results for each group are expressed as the average mg of uric acid excreted per kg of rat. The treatment group compares statistical significance with the control group. In general, it is considered that urine acid excretion is more than 2.5 mg U.A / kg. Representative data is shown in Table 3.

TABLE 3

Uric acid excretion is effective when a daily dose of 0.1 to 500 mg / kg of the compound of the present invention is administered to a patient orally, parenterally or intravenously. Preferred dosage ranges are 1.0 to 200 mg / kg.

The present invention has the unique advantage that the compound has both diuretic and uric acid excretion. As is known, many patients experience increased uric acid levels in the blood while being treated with conventional diuretics. Elevated uric acid levels are a serious problem for patients with gouty arthritis. In addition, elevated uric acid levels are emerging as a risk factor in cardiovascular disease. Therefore, the simultaneous action of causing diuretic action and increasing uric acid excretion is an important advantage of the compounds described herein.

The compound of the present invention is as follows.

{[7-chloro-3- (1-buten-2-yl) -1,2-benzisooxazol-6-yl] oxy} acetic acid;

{[(7-chloro-3-ethyl-1,2-benzisoxazol-6-yl) 3 oxy} acetic acid;

{[7-chloro-3-cyclopropyl-1,2-benzisooxazol-6-yl) oxy} acetic acid;

{[7-chloro-3-cyclohexyl-1,2-benzisooxazol-6-yl) oxy} acetic acid;

{[7-chloro-3- (2-norbornyl) -1,2-benzisooxazol-6-yl] oxy} acetic acid;

{[3- (1-adamantyl) -7-chloro-1, 2-benzisoxazol-6-yl] oxy} acet;

{[7-chloro-3- (1-cyclohexen-1-yl) -1,2-benzisooxazol-6-yl] oxy} acetic acid;

{[7-chloro-3-cyclopropylmethyl-1,2-benzisooxazol-6-yl) oxy} acetic acid;

{[7-chloro-3-cyclopentylmethyl-1,2-benzisooxazol-6-yl) oxy} acetic acid;

{[7-chloro-3- (2-cyclopentene-1-methyl) -1,2-benzisooxazol-6-yl) oxy} acetic acid;

{[7-chloro-3-propargyl-1,2-benzisooxazol-6-yl) oxy} acetic acid;

{[7-chloro-3- (4-methoxyphenyl) -1,2-benzisooxazol-6-yl) oxy} acetic acid;

{[7-chloro-3- (4-hydroxy-2-fluorophenyl) -1,2-benzisooxazol-6-yl) oxy} acetic acid;

{[7-chloro-3- (3-trifluoromethylphenyl) -1,2-benzisoxazol-yl] oxy} acetic acid;

{[7-chloro-3- (4-nitrophenyl) -1,2-benzisooxazol-6-yl] oxy} acetic acid;

{[7-chloro-3- (4-aminophenyl) -1,2-benzisoxazol-6-yl] oxy} acetic acid;

{[7-chloro-3- (4-acetamidophenyl) -1,2-benzisooxazol-6-yl] oxy} acetic acid;

{[4,5-dichloro-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} acetic acid;

{[4,7-dichloro-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} acetic acid;

{[4-methyl-3-phenyl-1,2-benzisooxazol-6-yl) oxy} acetic acid;

{[5-methyl-3-phenyl-1,2-benzisoxazol-6-yl] oxy} acetic acid;

{[7-chloro-3- (2-pyridyl) -1,2-benzisooxazol-6-yl] oxy} acetic acid;

{[3-phenyl-1,2-benzisoxazol-4-yl] oxy} acetic acid;

{[3-phenyl-1,2-benzisoxazol-5-yl] oxy} acetic acid;

{[3-phenyl-1,2-benzisoxazol-7-yl] oxy} acetic acid;

{Benzyl- [7-chloro-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} acetate;

n-propyl-{[3- (2-thienyl) -1,2-benzisoxazol-6-yl] oxy} acetate;

t-butyl-[(3-phenyl-1,2 (benzisoxazol-7-yl] oxy} acetate;

{[7-chloro-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} acetylchloride;

{[7-bromo-3- (2-fluoro-4-hydroxyphenyl) -1,2-benzisooxazol-6-yl] oxy} acetic acid;

{[7-chloro-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} acetamide;

N, N-diethyl-{[7-chloro-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} acetamide;

{2- [7-bromo-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} ethanol;

{1,1-diethoxy-2- [7-chloro-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} ethane;

{[7-chloro-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} acetaldehyde;

{[7-bromo-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} acetonitrile;

N-hydroxy-{[7-chloro-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} acetamide;

N-amino-{[7-chloro-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} acetamide;

5-{[7-chloro-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} methyltetrazole;

{[7-bromo-5-chloro-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} acetic acid;

{[7-bromo-5-methyl-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} acetic acid;

Glyceryl-{[7-chloro-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} acetate;

{[7-chloro-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] thio} acetic acid;

{[7-bromo-3- (2-fluorophenyl) -1,2-benzisooctathia-6-yl) thio} acetic acid;

{[7-bromo-3- (2,6-difluorophenyl) -1,2-benzisooxazol-6-yl] oxy} acetic acid;

{[7-methyl-3- (2,5-difluorofluoro) -1,2-benzisooxazol-6-yl] oxy} acetic acid;

{[7-bromo-3- (2,3-difluorophenyl) -1,2-benzisooxazol-5-yl] oxy} acetic acid;

{[7-bromo-3- (2,5-difluorophenyl) -1,2-benzisooxazol-6-yl] oxy} acetic acid;

{[7-chloro-3- (2-fluorophenyl) -1,2-benzisothiazol-6-yl] oxy} acetic acid;

{[7-bromo-3- (2-fluorophenyl) -1,2-benzisothiazol-6-yl] oxy} acetic acid;

{[7-chloro-3- [4- (methylthio) phenyl-1,2-benzisooxazol-6-yl] oxy} acetic acid;

{[7-fluoro-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} acetic acid and

{[7-chloro-3- (3-fluoro-2-thienyl) -1,2-benzisoxazol-6-yl) oxy} acetic acid.

An effective amount of a compound of the present invention may be administered orally in various ways, for example, as a capsule or tablet, or parenterally, in some cases, as a sterile solution or suspension, in some cases as a sterile solution. The final product of the free acid is effective on its own but can be formulated and administered in the form of a pharmaceutically unfavorable salt in terms of stability, ease of crystallization and increased solubility.

The active compounds of the present invention can be administered orally with inert diluents or edible carriers, or packed into gelatin capsules or compressed into tablets. For oral administration, the active compound of the present invention is mixed with excipients and used in formulations such as excising, troche, capsule, elixir, suspension, syrup, oblato, chewing gum and the like. Such formulations contain at least 0.5% of active compound, but are dependent on the particular formulation and conveniently have a unit weight of 4% to 70%. The amount of active compound in such a composition depends on the suitable dose.

Preferred compositions and formulations according to the present invention are those wherein the oral unit dosage form contains from 1.0 to 300 mg of active compound.

Tablets, pills, capsules, troches, and the like may contain the following components. Microcrystalline cellulose, gumtragacanth or gelatin with each silver binder; Starch or lactose and each excipient; Alginic acid, primogel, corn starch and the like; Magnesium stearate or sterotex and each suspending agent; Sugars such as colloidal silicon dioxide or saccharin and angles can be added as sweeteners or peppermint, methyl salicylate or orange fragrances and angles can be added.

When the unit dosage form is a capsule, it may contain not only said substance but also a liquid carrier such as fatty oil. Other unit dosage forms may contain various materials that change the physical form of the dosage unit, such as a coating material. Thus tablets or pills can be coated with sugars, shellac or other enteric coatings. Syrups may contain sucrose and certain preservatives, dyes and colorants and fragrances as sweeteners as well as active compounds.

The materials used to prepare these various compositions should be pharmaceutically pure and nontoxic at normal doses. For parenteral administration for therapeutic purposes, the active compounds of the invention are prepared as solutions or suspensions. These formulations contain at least 0.1% of active compound but can vary from 0.5 to 30% by weight. The amount of active compound in these compositions depends on the suitable dose.

Preferred compositions and preparations according to the invention are those which contain from 0.5 to 100 mg of active compound in parenteral dosages.

Solutions or suspensions may also contain the following compounds; Water for injection, saline, non-volatile oil, polyethylene glycol, glycerin, propyllin glycol or other synthetic solvents and each is a sterile diluent; Antibacterial agents such as benzyl alcohol or methyl parabens; Sulfate agents such as ascorbic acid or sodium hydrogen sulfate; Chelating agents such as ethylindiaminetetraacetic acid; Buffers such as acetate, citrate or phosphate and reagents for concentration adjustment such as sodium chloride or dextrose may be filled in ampoules, disposable syringes or multiple vials made of glass or plastic.

The invention is further illustrated in the following examples using representative compounds and methods.

Example 1

a. 7.1 g of 2-fluorobenzoyl chloride is added dropwise to a mixture of 12.5 g of aluminum chloride and 45 ml of carbon weaned carbon while maintaining the temperature below 0 ° C. The low temperature is maintained for 1.5 hours. 5 g of 2,3-nichloro-phenoxyacetic acid is added while maintaining the same low temperature. After complete addition, the reaction mixture is held at this low temperature for 30 minutes, then brought to ambient temperature and refluxed for 28 hours.

The carbon wetting is decanted from the reflux solution to obtain a dark orange residue which is poured into a mixture of 500 ml of ice water and 100 ml of concentrated hydrochloric acid. The resulting pink precipitate is collected by filtration, washed with 300 ml of warm water (50 ° C.) and dehydrated under reduced pressure. The dehydrated product is recrystallized twice with water soluble ethyl alcohol to give 2,3-dichloro-4- (2-fluorobenzoyl) phenoxyacetic acid having a melting point of 153 ° -156 ° C.

b. A mixture of 1.0 g of 2,3-dichloro-4- (2-fluoro benzoylphenoxyacetic acid and 1 g of dihydroxylamine hydrochloride is refluxed in 10 ml of pyridine for 2 hours, after which the solvent is evaporated in vacuo and residual The water is shaken with 5% hydrochloric acid for 16 hours The product is filtered and the solid collected is recrystallized with water-soluble alcohol to give 2,3-dichloro-4- (2-fluorozenzohydroxy) having a melting point of 91 ° to 96 ° C. Imoyl) phenoxyacetic acid.

c. A mixture of 0.3 g of 2,3-dichloro-4- (2-fluorobenzohydroxymoyl) phenoxyacetic acid and 0.05 g of sodium hydride is refluxed in 5 ml of benzene and 5 ml of dimethyl formamide for 3 hours. After cooling, 5% hydrochloric acid is added to the mixture to separate the benzene. Benzene was evaporated in vacuo and the resulting precipitate was collected by filtration and recrystallized with water-soluble ethyl alcohol to yield {[7-chloro-3- (2-fluorophenyl) -1,2-benzisoxazol-6-yl] oxy} acetic acid. Get Melting Point 188 ° to 189 ° C

Elemental Analysis: C ₁₅ H ₉ ClFNO ₄

Calculated Value: C 56.00% H 2.8% N 4.36%

Found: C 55.94 H 2.86 N 4.32

Example 2

a. 2-Chlorosolzyl dimethyl ether (22.0 g) and 0-fluorobenzoyl chloride (20.2 g) are dissolved in 250 ml of dichloroethane, cooled in an ice bath and treated with AlCl ₂ (18.6 g). The addition is complete at 15 minutes and the reaction is heated to reflux for 30 minutes. It is poured into H ₂ O and extracted with ethyl acetate. Evaporate and treat with hexane to afford 3-chloro-2'-fluoro-2-hydroxy-4-methoxybenzophenone having a melting point of 132-133 占 폚.

Elemental Analysis: C ₁₄ H ₁₀ ClFO ₃

Calculated Value: C 59.90% H 3.50% N 12.63%

Found: C 59.77 H 3.59 N 12.51

b. 3-Chloro-2'-fluoro-2-hydroxy-4-methoxybenzophenone (24.6 g) is refluxed for 18 h in 300 ml of pyridine containing 12.2 g of hydroxylamine hydrochloride. The reaction mixture is concentrated under reduced pressure and partitioned between 5% with ether. The organic layer is dried, evaporated and the resulting crystalline product is dissolved at 205 ° C. for 45 minutes. The product is cooled and recrystallized from toluene to give E-3-chloro-2'-fluoro-2-hydroxy-4-methoxybenzophenone oxime having a melting point of 184 to 186 ° C.

Elemental Analysis: C ₁₄ H ₁₁ ClFNO ₃

Calculated Value: C 56.86% H 3.75% N 4.79%

Found: C 56.67 H 3.68 N 4.67

c. E-3-chloro-2'-fluoro-2-hydroxy-4-methoxy benzophenone oxime (18.1 g) is warmed with 60 ml of acetic anhydride at 60 ° C. for 30 minutes. The reaction mixture was partitioned in ether and 10% NaHCO ₃ and washing with water until a basic wash with 10% NaHCO _3. Dry, evaporate and treat with hexane to give E-3-chloro-2'-fluoro-2-hydroxy-4-methoxy-benzophenone 0-acetyloxime having a melting point of 125 to 128 ° C.

Elemental Analysis: C ₁₆ H ₁₃ ClFNO ₄

Calculated Value: C 56.90% H 3.88% N 4.15%

Found: C 56.79 H 3.85 N 4.20

d. Example 34d is repeated to obtain 7-chloro-3- (2-fluorophenyl) -6-methoxy-1,2-benzisoxazole. Example 35 The process of 35 ° C. yields ethyl {[7-chloro-3- (2-fluorophenyl) -1,2-benzisoxazol-6-yl] oxy} acetate.

Example 3

a. 5 g of methoxybenzoyl chloride is added dropwise to a mixture of 3.9 g of AlCl ₃ and 4.67 g of 2,3-dichloroanizol in 70 ml of 1,2-dichloroethane at −10 ° C. The mixture is stirred for 2.5 hours and slowly warmed up to 5 ° C.

The reaction mixture is poured into concentrated hydrochloric acid and ice. The mixture is stirred for 1 and a half hours to break up the complex. The aqueous layer is extracted with additional organic solvent. The combined organic layers are washed until neutral, dried over Na ₂ SO ₄ , evaporated to give an oil and solidified by treatment with hexane. The crude product is recrystallized from 95% ethanol to give 2,3-dichloro-2 ', 4'-dimethoxybenzophenone having a melting point of 94 to 96 占 폚.

Elemental Analysis: C ₁₅ H ₁₂ Cl ₂ O ₃

Calculation: C 58.00% H 3.89%

Found: C 57.84 H 3.81

b. The solid mixture of 13 g of 2,3-dichloro-2 ', 4-dimethoxybenzophenone and 52 g of pyridine HCl is heated to 200 ° C. for 1 hour. The product is extracted with ethyl acetate.

The extract is dried over Na ₂ SO ₄ and evaporated to afford 2,3-dichloro-2 ', 4-dihydroxy benzophenone having a melting point of 197 to 201 ° C.

Elemental Analysis: C ₁₃ H ₃ Cl ₂ O ₃

Calculated Value: C 55.15% H 2.80%

Found: C 55.26 H 2.86

c. To a 2.87 g suspension of NaH in 150 ml of DMF, 30.76 g of 2,3-dichloro-2 ', 4-dihydroxy benzophenone in 100 ml of DMF are added followed by ethyl bromoacetate. The mixture is stirred for about an hour and a half, poured into ice and acid and extracted with CHCl ₃ . The CHCl ₃ extract is dried over Na ₂ SO ₄ and evaporated to give ethyl 2,3-dichloro-4- (2-hydroxybenzoyl) phenoxyacetate having a melting point of 109 to 110 ° C.

Elemental Analysis: C ₁₇ H ₁₄ Cl ₂ O ₅

Calculated Value: C 55.30% H 3.82%

Found: C 55.15 H 3.81

d. The corresponding oximes were prepared and cyclized using the ethyl 2,3-dichloro-4- (2-hydroxybenzoyl) phenoxy acetate in the above-described example and hydrolyzed to the ester {[7-chloro-3-2- Hydroxyphenyl) -1,2-benzisooxazol-6-yl) oxy} acetic acid.

Claims (1)

The compound of formula (3) is then cyclized with a base upon treatment, followed by hydrolysis, oxidation,

, NH ₂ OH or

A process for preparing a compound of formula (I) characterized by treatment, HN ₃ treatment in dimethyl formamide, acid or basic hydrolysis, organic or alkaline / alkaline metal base treatment, nitric acid treatment or dealkylation in glacial acetic acid.

In the general formula, R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, tricycloalkyl, cycloalkyl lower alkyl, cycloalkenyl lower alkyl, naphthyl,

Thienyl, furyl, pyryl, pyridyl or pyridyl N-oxide, R ¹ is a free or esterified carboxyl group having 1 to 8 carbon atoms,

R ² , R ³ and R ⁴ are the same or different and each can be hydrogen, halogen or lower alkyl, X is hydrogen, halogen, lower alkyl, lower alkylthio, lower alkoxy, hydroxy, trifluoromethyl, Nitro, amino or acylamino, and R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are the same or different and can be hydrogen or lower alkyl; A and A 'are the same or different and are 0 or S; Z is chlorine, bromine or fluorine; m and n are the same or different and are integers of 1,2 or 3, respectively; B is OH or

And D is OH, chlorine or fluorine.