KR820000476B1 - Process for preparing 1,2-benzisoxazoloxyacetic acid derivatives - Google Patents

Abstract

Titla compds. (I; R = H, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, tricycloalkyl, cycloalkyl lower alkyl, cycloalkenyl lower alkyl, boxyl, -COZ, -CH2OH, -CHO, -CH; R2, R3, R4 = H, halogen, lower alkyl; R5, R6 = H, lower alkyl; A, A' = O, S; Z = Cl, Br, F; M, n = 1,2,3), useful as diuretic, were prepd. by reacting compd.(II) with compd.(III) followed by treatment. The treatment comprise hydrolysis, oxidn., N(R7)(R8) or NH2OH treatment, NHO3 treatment in glacial acetic acid, and dealkylation.

Description

Method for producing 1,2-benzisoxazoleoxyacetic acid derivative

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

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

이며, R², R³및 R⁴는 동일하거나 상이하고 각각은 수소, 할로겐 또는 저급알킬이 될 수 있고, X는 수소, 할로겐, 저급알킬, 저급알킬티오, 저급알콕시, 히드록시, 트리플루오로메틸, 니트로, 아미노 또는 아실아미노이며, R⁵, R⁶, R⁷, R⁸및 R⁹은 동일하거나 상이하고 수소 또는 저급알킬이 될수 있고; A 및 A'는 동일하거나 상이하고 0 또는 S이며; Z는 염소, 브롬 또는 불소이고; m 및 n은 동일하거나 상이하고 각기 1, 2 또는 3의 정수이다. 또한 본 발명의 범위내에는 생리적으로 무독한 염도 포함된다.Thienyl, furyl, pyryl, pyridyl or pyridyl N-oxide and 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, trifluoro Methyl, 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. 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. Of the latter compounds, compounds in which R ¹ is an esterified carboxyl group, CN, CH 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 those 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.

In the present specification, 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, diethanolamine or N-methylglucamine.

The compounds of the present invention may be prepared by one of several steps of 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 unless otherwise indicated. To 25 ° C.

a ₁ ) The phenol or alkoxybenzene of the following general formula (II) is reacted with an acid halide of RCOZ under Friedel-Craft conditions to obtain a compound of the following general formula (III).

Wherein R ¹⁰ is hydrogen or lower alkyl and R is as described above and Z is chlorine, bromine or fluorine.

In a preferred method, 1, 2-dichloroethane is used as solvent and aluminum chloride is used as Friedel Creft catalyst.

a ₂ ) The general formula RH compound is reacted with an acid halide of general formula (IV) under Friedel-Craft conditions to give a general formula (IIIa) compound.

, 티에닐, 피릴 또는 푸릴이고, Y, Z 및 R¹⁰은 A에서 정의한 바와 같다.Where R is

, Thienyl, pyryl or furyl, and Y, Z and R ¹⁰ are as defined for A.

In a preferred method, 1, 2-dichloroethane is used as solvent and aluminum chloride is used as Friedel-Craft catalyst.

a ₃ ) The compound of formula (IV) is reacted with a compound of formula R-MgZ or R-Li and then hydrolyzed to obtain a compound of formula (IIIa).

Wherein R ¹⁰ is lower alkyl and R is not hydrogen.

Preferred conditions are the use of tetrahydrofuran as solvent at −70 ° C. to ambient temperature.

a ₄ ) A compound of formula (IIIa) wherein R is hydrogen and R is lower alkyl is reacted according to the method of a ₃ ) to obtain a compound of formula (V).

Wherein R is not hydrogen.

a ₅ ) The compound prepared in step a ₄ ) is oxidized to obtain a compound of formula (IIIa) in which R is not hydrogen. One method uses chromium trioxide in glacial acetic acid.

a ₆ ) Dealkylation of the compound of general formula (III) or (IIIa) wherein R ¹⁰ is lower alkyl gives the corresponding compound (III) or (IIIa) wherein R ¹⁰ is hydrogen. One method uses aluminum chloride in benzene.

a ₇ ) The compounds of formula (III) or (IIIa) are treated with hydroxylamine hydrochloride in a solvent such as pyridine to give the corresponding compound of formula (VI).

a ₈ ) The compound of formula (VI) is cyclized by treatment with a base at ambient temperature to the reflux temperature of the reaction medium in the presence of a solvent to obtain the corresponding bicyclic compound of formula (VII).

Preferred cyclization is the use of sodium hydride base in the solvent of the dimethyl formamide-benzene mixture at reflux.

a ₉ ) The diphenol or dialkoxybenzene of the general formula (VIII) is reacted according to the step a ₁ ) to obtain the general formula (IX) compound.

a ₁₀ ) A compound of the general formula RH is reacted with an acid halide of the general formula (R) under Friedel-Craft conditions to give a compound of the general formula (XI).

, 티에닐, 피릴 또는 푸릴이고, Z, R², R³, R³및 R¹⁰은 전술한 바와 같다.Where R is

, Thienyl, pyryl or furyl, and Z, R ² , R ³ , R ³ and R ¹⁰ are as described above.

a ₁₁ ) The compound of formula (XII) is treated according to step a ₃ ) to afford the corresponding compound of formula (XI).

Wherein R ¹⁰ is lower alkyl.

a ₁₂ ) A compound of formula (XI) wherein R is hydrogen and R ¹⁰ is lower alkylyl is reacted according to step a ₃ ) to afford a compound of formula (XI).

Wherein R is not hydrogen.

a ₁₃₎ a step ₁₂₎ is oxidized to the compound R is obtained from the formula (XI) compounds other than hydrogen. One method is to use chromium trioxide in glacial acetic acid.

a ₁₄₎ R ¹⁰ is selectively alkylated ride in the general formula (XI) compound one lower alkyl by the R ¹⁰ is an equivalent to obtain the compound (V) or completely de-alkylation to the hydrogen ortho to the carbonyl group, the two R ¹⁰ All of them obtain a general formula (XI) compound which is hydrogen. The above process can be carried out in a solvent such as benzene, using 1 equivalent of aluminum chloride and the latter 2 equivalents.

a ₁₅ ) The general formula (XI) compound wherein at least the ortho position R ¹⁰ is hydrogen for at least the carbonyl group is treated according to step a ₇ ) to obtain the general formula (XIV) compound.

a ₁₆ ) Acetylating a compound of formula (XIV) yields a compound of formula (XV).

Wherein R ¹¹ is hydrogen, lower alkyl or acetyl.

The preferred method is to use acetic anhydride as reactant and solvent.

a ₁₇ ) The compound of formula (XV) is cyclized by treatment with a base in the presence of a solvent at ambient temperature to the reflux temperature of the reaction mixture to obtain a bicyclic compound of formula (VII).

a ₁₈₎ R ¹⁰ is de-alkylated to the formula (VII) compound one lower alkyl to obtain the corresponding compound of R ¹⁰ is hydrogen.

The preferred method is to treat with pyridine hydrochloride at 170-200 ° C.

화합물과 반응시켜 일반식(Ia) 화합물을 얻는다.a ₁₉ ) A compound of formula (VII), wherein R ¹⁰ is hydrogen, in the presence of a base and a solvent

Reaction with a compound yields a compound of formula (Ia).

Wherein R ¹ is a free or esterified carboxyl group, CN, CH ₂ OH or CH (OR ⁹ ) ₂ and R ⁹ is lower alkyl.

The preferred method is to use dimethylformamide as solvent and sodium hydrate as base.

b ₁ ) The compound of formula (IX) wherein R ¹⁰ is H is treated according to step a ¹⁹ ) to obtain a compound of formula (XX).

b ₂ ) The compound of formula (XX) is treated according to step a ₇ ) to obtain a compound of formula (XXI).

b ₃ ) The compound of formula (XXI) is treated according to step a ₁₆ ) to afford a compound of formula (XXII).

b ₄ ) The compound of general formula (XXII) is closed according to step a ₁₇ ) to obtain a compound (Ia) of the present invention.

c ₁₎ a step ₁₄₎ and R is a hydrogen treatment of the formula (XI) compound with a hydroxylamine-0-sulfonic acid in a solvent such as water, prepared by the obtained formula (VII) compound.

c ₂ ) The compound of formula (Ia) of the present invention is prepared by cyclizing a compound of formula (XX) wherein R is hydrogen.

d ₁ ) A compound of formula (VII) wherein R ¹⁰ is hydrogen and X is not hydroxy or amino is treated with a dialkylthiocarbamoyl halide in the presence of a base to give a compound of formula (XXIII).

Wherein 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.

d ₂ ) Thermally dissolving the compound of formula (XXIV) by melting and heating the compound of formula (XXIII).

d ₃ ) The compound of formula (XXIV) is hydrolyzed in a conventional manner to obtain a compound of formula (XXV).

One method is to use recovered sodium oxide as the hydrolysis agent.

d ₄ ) The compound of formula (XXV) is treated according to step a ₁₉ ) to obtain a compound of formula (lb).

e ₁ ) A compound of formula (XXVI) in which R ¹⁰ described in process a ₁₄ ) is lower alkyl and X is not amino or hydroxyl is treated according to processes d ₁ ), d ₂ ) and d ₃ ) XXVII) A compound is obtained.

e ₂ ) The compound of formula (XXVII) is treated according to steps a ₇ ), a ₁₆ ), a ₁₇ ) and a ₁₈ ) to obtain a compound of formula (XXVIII).

e ₃ ) The compound of formula (XXVIII) is treated according to step a ₁₉ ) to obtain a compound of formula (Ic).

f ₁ ) The compound of formula (XXVIII) is treated according to the processes d ₁ ), d ₂ ) and d ₃ ) to obtain a compound of formula (XXIX).

f ₂ ) The general formula (XXIX) compound is treated according to step a ₁₉ ) to obtain a general formula (Id) compound.

g) A compound of formula (la), (lb), (lc) or (Id) wherein R ¹ is a carboxylic ester or CN is converted to the corresponding compound where R ¹ is COOH.

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

h) The invention compounds of formula (la), (lb), (lc) or (Id) wherein R ¹ is CH (OR ⁹ ) ₂ are converted to the corresponding compounds wherein R ¹ is CHO. A suitable method is to hydrolyze with rare acid.

i) 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 h) wherein R ¹ is CHO; Convert to the corresponding compound where R ¹ is COOH.

A suitable method is to oxidize with potassium permanganate.

j) 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 .

, NH₂OH 또는

로 처리하여 R¹이

, CONHOH 또는

인 상응하는 화합물로 전환시킨다.1) Formula (I) compounds wherein R ¹ is COZ, with or without acid scavenger

, NH ₂ OH or

By treating R ¹ as

, CONHOH or

Is converted to the corresponding compound.

인 상응하는 화합물로 전환시킨다. 적합한 방법은 디메틸포름아미드중의 NH₃로 처리하는 것이다.a m) R ¹ is CN in the general formula (I) compounds R ¹ is

Is converted to the corresponding compound. A suitable method is to treat with NH ₃ in dimethylformamide.

, CONHOH,

또는 가수분해 공정에 의해 COOH 그룹으로 전환될 수 있는 기타의 비특정 그룹인 일반식(I)화합물을 산 또는 염기 가수분해하여 R¹이 COOH인 본 발명 화합물로 전환시킨다.n) R ¹ is COZ,

, CONHOH,

Or other non-specific group (I) compounds, which may be converted to COOH groups by a hydrolysis process, by acid or base hydrolysis to convert to compounds of the invention wherein R ¹ is COOH.

o) A compound of formula (I) wherein R ¹ is COOH is converted to a salt by treatment with a suitable organic or alkali / alkaline metal base in a suitable solvent.

이고, R¹⁰이 저급알킬이며 X가 히드록시 또는 아미노가 아닌 일반식(XXXI) 화합물을 강염기로 처리한 후 적합한 친전자체로 처리하여 R²가 할로겐 또는 저급알킬인 일반식(XXXII)화합물을 얻는다.p) R is

Where R ¹⁰ is lower alkyl and X is not hydroxy or amino, and is treated with a strong base followed by a suitable electrophile to obtain a compound of formula (XXXII) wherein R ² is halogen or lower alkyl. .

Preferred bases are n-butyllithium and preferred electrophiles are bromine, iodine, chlorine, N-halosuccinimide and alkyl halides.

q) The compound of formula (XXXIII) is treated with a halogen element in a solvent such as acetic acid to give a compound of formula (VII).

이고 X는 할로겐이고 R³및 R⁴또는 이들 모두가 할로겐이 될 수 있다.Wherein R ² is hydrogen or halogen and R ¹⁰ is hydrogen or lower alkyl and R is

And X is halogen and R ³ and R ⁴ or both may be halogen.

r) The compound of formula (Ie) is nitrated with nitric acid in glacial acetic acid to give the corresponding compound of formula (If).

Wherein m is 1 or 2 and X is not NO ₂ .

s) general formula) Ig) dealkylation of the compound to give the corresponding compound wherein x is hydroxy.

또는

이고 x는 알콕시이다.Where R is

or

And x is alkoxy.

This method is carefully treated with boron tribromide.

t) Reduction of the compound described as starting material of step s) except that x is nitro gives the corresponding compound wherein x is amino.

In this method, iron in ethanol aqueous hydrochloric acid solution is used.

u) Acylation of the starting compound of step s), wherein x is not amino, affords the corresponding compounds of the invention wherein x is acylamino. A suitable method is to acylate with anhydride.

인 상응하는 일반식(VII) 화합물을 얻는다.v) a compound of formula (VII) wherein R is pyridyl with an oxidant to

To yield the corresponding compound of formula (VII).

Suitable oxidizing agents are 3-chloro-perbenzoic acid.

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

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

For example, starting which can be used in steps a ₂ ), a ₄ ), a ₅ ), a ₁₂ ) and a ₁₃ ) to prepare the compounds of the invention in which the O-CH ₂ -R ¹ group is present at the 5-position The substance is 2-chloro-5-methoxybenzoic acid.

This material can be prepared from 2-chloro-5-nitroaniline, which can be easily purchased by known methods. Treatment with diazotization and CuCN, for example, yields 2-chloro-5-nitro benzonitrile and then reduced with iron in an aqueous ethanol hydrochloric acid solution to give 5-amino-2-chlorobenzonitrile; Diazotization reaction then yields 2-chloro-5-hydroxybenzonitrile; It is then methylated with dimethyl sulfate to give 2-chloro-5-methoxy-benzonitrile and then hydrolyzed to give 2-chloro-5-methoxy-benzoic acid.

Other desired substituted alkoxy-ortho-halobenzoic acids, alkoxy (hydroxy) ortho-alkoxy- (hydroxy) benzoic acids, -aldehydes and -nitriles and various halo-alkoxy- (hydroxy)-and dialkoxy (hydroxy ) -Benzene can be prepared in a similar manner or by other conventional methods.

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. [See: C.M. Kagawa and M.J. Kalm, Arch. Intern Pharmacodyn. 137,241 (1962).

The drug is administered orally to six birds and the mean excretion 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 per day. 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 rats with essential hypertension by indirect tail hitting. [Reference: 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.

TABLE II

Antihypertensive action is sulfur 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.

The present invention is effective as a therapeutic agent for uric acid urination because it enhances uric acid excretion in mammals. Uric acid excretion is measured by oral administration of a test compound suspended or dissolved in a sufficient amount of distilled water in a group of six Wistar rats. Only the same amount of water is administered to the corresponding control group. Urine is collected for 5 hours and the amount of uric acid is measured with an Abbott Biochromatic Analyzer using a Uricosquant ^R reagent. Results for each group are expressed as mean mg of uric acid excreted per kg of rat. The treatment group compares statistical significance with the control group. Generally, it is considered that there is a uric acid excretion effect at 2.5 mg UA / kg or more. Representative data are shown in Table III.

TABLE III

Uric acid excretion is effective when a dose of 0.1 to 500 mg / kg of the compound of the present invention is administered 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 present compounds are as follows.

An effective amount of a compound of the present invention may be administered orally in a variety of ways, eg as capsules or tablets, parenterally in sterile solutions or suspensions and, in some cases, sterile solutions. The final product of the free acid is effective on its own but can be administered in the form of a pharmaceutically toxic salt in terms of stability, ease of crystallization and increased solubility.

The active compounds of the present invention can be administered orally with an inert diluent or edible carrier, or packed into gelatin capsules or compressed into tablets. For oral administration, the active compounds of the present invention are mixed with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, 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 preparations according to the invention are prepared so that oral unit dosage forms contain 1.0 to 300 mg of active compound.

Tablets, pills, capsules, troches, and the like may contain the following components. Binders such as microcrystalline cellulose, gum tragacanth or gelatin; Excipients such as starch or lactose; Disintegrants such as alginic acid, primogel, corn starch and the like; Lubricants such as magnesium stearate or sterotex; Lubricants such as colloidal silicon dioxide; Sweeteners such as sucrose or saccharin can be added or fragrances such as peppermint, methyl salicylate or orange fragrance.

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 present 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 the active compound in a parenteral dosage.

Solutions or suspensions may also contain the following compounds; Sterile diluents such as water for injection, saline, nonvolatile oil, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents; Antibacterial agents such as benzyl alcohol or methyl parabens; Antioxidants such as ascorbic acid or sodium hydrogen sulfate; Chelating agents such as ethylenediaminetetra acetic acid; Buffers such as acetate, citrate or phosphate and reagents for concentration adjustment such as sodium chloride or dextrose. Parenteral preparations may be filled in ampoules, disposable syringes or disposable vials made of glass or plastic.

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

Example 1

a. To 31.6 g of 2-fluorobenzoyl chloride solution in 100 ml of dichloro ethane is added 26.5 g of aluminum chloride over 30 minutes. Upon complete addition the mixture turns yellow and becomes black again. To the dark mixture is then added dropwise a solution of 32 g of 2,3-dichloroanisol in 50 ml of 1,2-dichloroethane. After complete addition the mixture is shaken for 2 hours and poured into 100 concentrated hydrochloric acid and 100 ml of crushed ice.

The organic phase in the mixture of two phases is evaporated under reduced pressure and the aqueous mixture is extracted with ether. The ether extract was washed with 10% potassium carbonate solution and water, dehydrated and the ether was evaporated to dryness. When an off-white solid remained, it was recrystallized from an ether-hexane mixture to give a 2'-fluoro-4- having a melting point of 74 ° to 77 ° C. Obtain methoxy-2,3-dichlorobenzophenone.

b. 38.5 g of 2'-fluoro-4-methoxy-2,3-dichloro benzophenone and 34.7 g of aluminum chloride in 250 ml of benzene were refluxed for 5 hours and a mixture of 100 ml of concentrated hydrochloric acid and 100 ml of ice was added. Pour into. The mixture of two phases is extracted with ethyl acetate and the combined extracts are dehydrated and concentrated to dryness to obtain a solid residue. The residue is treated with hexane and the resulting solid is recrystallized from an ether-hexane mixture to give 2,3-dichloro-4-hydroxy-2'-fluoro-benzophenone. Melting point: 128 ° to 131 ° C.

c. 31.8 g of 2,3-dichloro-4-hydroxy-2'-fluoro-benzophenone and 15.3 g of hydroxyamine hydrochloride in 150 ml of pyridine are refluxed for 64 hours. The pyridine is then evaporated under reduced pressure and 5% hydrochloric acid aqueous solution is added. The acidified solution is extracted with ethyl acetate and the combined extracts are dehydrated before being concentrated to dryness. The resulting solid material is recrystallized from an aqueous ethanol solution to obtain 2,3-dichloro-4-hydroxy-2'-fluorobenzophenone greedy. Melting point: 168 ° to 175 ° C.

d. 18.4 g of 2,3-dichloro-4-hydroxy-2'-fluoro benzophenone oxime and 3.6 g of sodium hydride in 120 ml of dimethylformamide and 120 ml of benzene for 3 hours Keep it on. The mixture is then brought to ambient temperature and 11.0 g of ethylbromo acetate in 30 ml of dimethylformamide is added dropwise.

After complete dropping, the mixture is shaken for 30 minutes and water is added to decompose the extra sodium hydride. The mixture is extracted with ethyl acetate and the combined extracts are dehydrated and evaporated to dryness to give a solid residue. The residue was recrystallized from 95% ethyl alcohol to give pure ethyl {[7-chloro-3- (2-fluorophenyl) -1,2-benzisoxazol-6-yl] oxy} with a melting point of 102 ° to 104 ° C. Acetate is obtained.

Example 2

10.0 g of ethyl {[7-chloro-3- (2-fluorophenyl-1,2-benzisooxazol-6-yl] oxy} acetate, a mixture of 100 ml of 10% sodium hydroxide and 350 ml of ethyl alcohol The mixture is refluxed for 3.5 hours, the ethyl alcohol is removed under reduced pressure and the residue is acidified with hydrochloric acid to produce a solid precipitate The precipitate is collected by filtration and dehydrated The dehydrated product is recrystallized from 95% ethyl alcohol to give a melting point of 190 The product {[7-chloro-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} acetic acid is obtained at ° C to 191 ° C.

Example 3

a. A mixture of 3.8 g of (2,3-dichloro-4-hydroxyphenyl) -2'-thienylmethanone and 2.0 g of hydroxylamine hydrochloride is refluxed in 20 ml of pyridine for 6 hours. Thereafter, pyridine is evaporated under reduced pressure. 5% hydrochloric acid is added to the residue and the mixture is acidified and extracted with ethyl acetate. The extract is washed with water, dehydrated and evaporated to dryness. The residue is recrystallized from a mixture of water and ethanol to give (2,3-dichloro-4-hydroxyphenyl) -2'-thienylmethanone oxime having a melting point of 179 to 183 ° C.

b. 0.62 g of sodium hydride was added to a mixture of 30 g of dimethylformamide and 3.0 g of (2,3-dichloro-4-hydroxy-phenyl) -2'-thienylmethanone oxime in 30 ml of toluene. do. The reaction mixture is then held at 100 ° C. for 2 hours at 115 ° C. for 2.5 hours. Cool the mixture and add dropwise 1.9 g of ethyl bromoacetate solution in 10 ml of dimethylformamide. After complete addition, the reaction mixture is shaken for 2.25 hours and water is added to decompose excess sodium hydride. The reaction mixture is extracted with ethyl acetate and the extract is washed with water, dehydrated and evaporated. The residue is recrystallized from ethanol to give ethyl {[7-chloro-3- (2-thienyl) -1,2-benzisoxazol-6-yl] oxy} acetate having a melting point of 142 to 143 ° C.

Example 4

a. A solution of 18.0 g 2,3-dichloro-4-hydroxy-benzophenone and 9.3 g hydroxylamine hydrochloride in 100 ml pyridine is refluxed for 2 hours. The pyridine is then evaporated under reduced pressure and the remaining solution is partitioned between 5% hydrochloric acid and ethyl acetate. The ethyl acetate extract is washed with water, dehydrated and evaporated to give 2,3-dichloro-4-hydroxy benzophenone oxime.

The above-mentioned 2,3-dichloro-4-hydroxybenzophenone is prepared using benzoyl chloride instead of 2-fluoro benzoyl hydrochloride by the method described in Examples 1 (a) and (b).

b. A solution of 2,3-dichloro-4-hydroxybenzophenone oxime and 2.6 g sodium hydride in 50 ml of dimethylformamide and 50 ml of toluene was heated to 118 ° C. and held for 50 minutes. Thereafter, the reaction is cooled and 7.9 g of ethyl bromo acetate in 50 ml of dimethylformamide is added dropwise. After complete dropping the reaction mixture is shaken for 40 minutes at ambient temperature. Water is added dropwise to the shake mixture to break up excess sodium hydride. Toluene was evaporated under reduced pressure and the resulting precipitate was collected by filtration and washed with ether to give ethyl [(7-chloro-3-phenyl-1,2-benzisoxazol-6-yl) oxy] having a melting point of 130 ° to 132 ° C. Acetate is obtained.

Example 5

To a solution of 8.3 g ethyl [7-chloro-3-phenyl-1,2-benzisooxazol-6-yl) oxy] acetate in 160 ml ethyl alcohol is added 6 ml 7N sodium hydroxide. Thereafter, the reaction mixture is refluxed for 45 minutes. The precipitate is collected by filtration and washed with ethyl alcohol and water. The precipitate is suspended in 200 ml of warm water and the mixture is acidified with concentrated hydrochloric acid. The acidified mixture is shaken for 1 hour and the gray precipitate is collected by filtration. The precipitate is recrystallized from ethyl acetate to give pure [(7-chloro-3-phenyl-1,2-benzisoxazol-6-yl) oxy] acetic acid having a melting point of 219 ° to 221 ° C.

Example 6

19.8 g of 3,2-dichloro-4-hydroxyphenyl-2'-furylmeth dissolve oxime in 200 ml of dimethylformamide and add 4.8 g of sodium hydride. After the hydrogen gas evolution is over, the reaction mixture is heated to 130 ° C.

The mixture is cooled to 5 ° C. and the cooling mixture is added to a 16.7 g solution in 20 ml of dimethylformamide. After shaking for 45 minutes, the reaction mixture is poured into water to give the crystalline product.

The product was collected by filtration, washed with ethyl alcohol and ether, recrystallized from ethyl alcohol-ethyl acetate mixture to ethyl [(7-chloro-3- (2-furyl) -1,2-benzisoxazol-6yl) oxy] acetate Get

Example 7

To a boiling suspension of 15.0 g of ethyl {[(7-chloro-3- (2-furyl) -1,2-benzisoxazol-6-yl)] oxy} acetate in 500 ml of boiling 95% ethyl alcohol 10 ml of 50% sodium hydroxide is added to precipitate the sodium salt.

300 ml of 95% ethyl alcohol is added and boiled for 30 minutes. The reaction mixture is cooled slowly and 100 ml of 5% hydrochloric acid solution is added. The product is separated with cooling and 250 ml of water is added to cool the diluted mixture with ice. The precipitate is collected by filtration and recrystallized with isopropyl alcohol to give {[7-chloro-3- (2-furyl) -1,2-benzisoxazol-6-yloxy} acetate having a melting point of 230 ° to 233 ° C.

Example 8

a. 28.3 g of (2,3-dichloro-4-hydroxyphenyl- (5'-methyl-2'-thienyl) methanone and 14.0 g of hydroxylamine hydrochloride are refluxed in 300 ml of pyridine for 16 hours. The solvent is then removed under reduced pressure and the residue is treated with 5% hydrochloric acid The treated residue is extracted with dichloroethane and ether mixture and dehydrated and the solvent is evaporated off.The product is treated with hexane to give the desired oxime, (2 , 3-dichloro-4-hydroxyphenyl)-(5'-methyl-2'-thienyl) methanone oxime is produced.

b. 5.3 g of sodium hydride is added to the oxime mixture in 200 ml of dimethylformamide. The reaction mixture is maintained at 120 ° C. for 1.5 hours and at 130 ° C. for 1 hour at 140 ° C. for 1 hour and then cooled to 35 ° C. To the cold mixture is added 13.3 g of ethyl bromoacetate in 20 ml of dimethylformamide and the mixture is shaken for 20 minutes. The reaction mixture is poured into saturated sodium chloride solution to obtain a crystalline product which is collected by filtration. The product was washed with methyl alcohol and ether and then recrystallized with isopropyl alcohol to yield ethyl {[7-chloro-3- (5-methyl-2-thienyl) -1,2-benzisoocta having a melting point of 149 ° to 150 ° C. Sazol-6-yl] oxy} acetate.

Example 9

(2,3-dichloro-4-hydroxyphenyl)-(5'-methyl-2 'instead of (2,3-dichloro-4-hydroxyphenyl)-(5'-methyl-3'-furyl) methanone -Thienyl) methanone and following the method described in Example 8 (a) followed by the method described in Example 8 (b) with ethyl {[7-chloro- with a melting point of 139 ° to 141 ° C. 3- (5-methyl-2-furyl) -1,2-benzisoxazol-6-yl] oxy} acetate is obtained.

Example 10

10 mL of 50 in 15.0 g of ethyl {[7-chloro-3- (5-methyl-2-furyl) -1,2-benzisoxazol-6-yl] oxy} acetate suspension in 100 mL of ethyl alcohol % Sodium hydroxide solution is added. The reaction mixture is refluxed with vigorous shaking for 1.5 hours and 100 ml of 5% hydrochloric acid is added. The resulting solution is cooled, diluted with water and the product precipitates out. The product was collected by filtration and recrystallized with methyl alcohol to obtain {[7-chloro-3- (5-methyl-2-furyl) -1,2-benzisoxazol-6-yl] oxy having a melting point of 217 ° to 219 ° C. } Get acetic acid.

Example 11

a. A mixture of 2,3-dichloro-4-hydroxy-4-methyl-benzo phenone and 12.5 g of hydroxylamine hydrochloride is refluxed in 200 ml of pyridine for 2 hours. The pyridine is then evaporated under reduced pressure and the residue is partitioned between ethyl acetate and 5% hydrochloric acid. The ethyl acetate extract is washed with water, dehydrated and concentrated to dryness to afford 2,3-dichloro-4-hydroxy-4'-methylbenzo phenone oxime.

b. The mixture of oxime and 5.2 g of sodium hydride is held in 300 ml of dimethylformamide at 87 ° C. for 3 hours. The mixture is cooled to ambient temperature and 16.0 g of ethyl bromo acetate in 50 ml of dimethylformamide is added dropwise. After complete dropping, the mixture was shaken for 30 minutes and poured into water to yield ethyl {[7-chloro-3- (4-tolyl) -1,2-benzisoxazol-6-yl] oxy} acetate with a melting point of 157 to 159 ° C. Get

Example 12

A mixture of 20 g ethyl {[7-chloro-3- (4-tolyl) -1,2-benzisooxazol-6-yl] oxy} acetate and 15 ml of 50% sodium hydroxide in 1 ml of 600 ml ethyl alcohol Reflux for time. The hot mixture is then diluted with 500 ml of water and acidified with concentrated hydrochloric acid. The acidified suspension was shaken for 30 minutes, filtered and the filter cake was recrystallized from dimethylformamide to obtain {[7-chloro-3- (4-tolyl) -1,2-1,2-benziso having a melting point of 257 to 260 ° C. Oxazol-6-yl] oxy} acetic acid.

Example 13

a. A mixture of 41 g of (2,3-dichloro-4-hydroxyphenyl) -4'-chlorobenzophenone and 18.9 g of hydroxylamine hydrochloride is refluxed in 300 ml of pyridine for 2 hours. The pyridine is then removed under reduced pressure and the residue is partitioned between ethyl acetate and 5% hydrochloric acid. Ethyl acetate is washed with water, dehydrated and concentrated to dryness to afford 3,3-dichloro-4-hydroxy-4'-chlorobenzophenone oxime.

b. A mixture of 41.5 g of oxime and 7.9 g of sodium hydride is maintained at 111 ° C. in 300 ml of dimethylformamide for 2 hours. The reaction mixture is then cooled to ambient temperature and then a mixture of 23 g of ethyl bromoacetate in 50 ml of dimethylformamide is added dropwise. After complete dropwise addition, the reaction mixture was shaken for 30 minutes and left for 16 hours. The mixture is poured into water to give a precipitate which is filtered to give ethyl {[7-chloro-3- (4-phenyl-1,2-benzisoxazol-6-yl] oxy} acetate having a melting point of 179 ° C.

Example 14

A mixture of 25 g of ethyl {7-chloro-3- (4-chlorophenyl) -1,2-benzisooxazol-6-yl] oxy} acetate and 20 ml of 50% sodium hydroxide at reflux in ethyl alcohol for 1 hour Let's do it. The hot mixture is diluted with 300 ml of water and acidified with concentrated hydrochloric acid. The acidified mixture was shaken for 30 minutes, filtered and the filter cake recrystallized from a dimethylformamide-ethyl acetate mixture to yield {[7-chloro-3- (4-chlorophenyl) -1,2- with a melting point of 254 ° C to 257 ° C. Benz isoxoxazol-6-yl] oxy} acetic acid.

In the above examples, although not specifically indicated, oxime precursors are prepared from suitable ketones in a similar manner as in Example 1.

Example 15

0.72 g of ethyl {[7-chloro-3- (2-thienyl) -1,2-benzisoxazol-6-yl] oxy} acetate in 10 ml of 40 ml ethyl alcohol and 10 ml aqueous sodium hydroxide solution The suspension of was refluxed for 1 hour. Then evaporated off in ethyl alcohol vacuum. The remaining suspension is acidified with concentrated hydrochloric acid and shaken at ambient temperature for 30 minutes. The resulting crude product was collected by filtration and recrystallized with ethyl alcohol to give a product having a melting point of 217 ° to 220 ° C. [[7-Chloro-3- (2-thienyl) -1,2-benzisoxazol-6-yl] Oxy} acetic acid is obtained.

Example 16

a. A reaction mixture of 32.8 g of 3-methyl-2-thiophencarboxylic acid chloride, 35.4 g of 2,3-dichloroanizol and 26.7 g of aluminum chloride is refluxed in 200 ml of carbon wed for 40 hours and poured into ice-hydrochloric acid. .

The crystalline product was collected by filtration, washed with hexane and recrystallized with a toluene-hexane mixture to give (2,3-dichloro-4-methoxy) (3-methyl-2-thienyl) methanone with a melting point of 136 to 138 ° C. Get

b. A mixture of 0.6 g of (2,3-dichloro-4-methoxy) (3-methyl-2-thienyl) methanone and NH ₂ OH HCl in pyridine is converted to the corresponding oxime. Oxime (mixture of isomers) (37.8 g) is then dissolved in 70 ml of dimethylformamide and the solution is added to a suspension of 3.3 g sodium hydride in 100 ml of dimethylformamide.

After the reaction is complete, pour into water. The pH of the aqueous mixture is adjusted to 6-7 with dilute hydrochloric acid. The resulting precipitate was collected by filtration, washed well with ether and recrystallized with a toluene-hexane mixture to give 7-chloro-3- (3-methyl-2-thienyl) -6-methoxy-1, having a melting point of 154 to 156 占 폚. Obtain 2-benzisoxazole.

c. A mixture of 13.3 g of 7-chloro-3- (3-methyl-2-thienyl) -6-methoxy-1,2-benzisoxazole and 25 g of B Br ₃ in CH ₂ Cl ₂ was refluxed for 18 hours. Pour into H ₂ O and extract with ether. The ether extract is dehydrated, evaporated and treated with hexane to give 7-chloro-6-hydroxy-3- (3-methyl-2-thienyl-1,2-benzisoxazole having a melting point of 197 to 198 ° C.

d. 10.3 g of 7-chloro-6-hydroxy-3- (3-methyl-2-thienyl) -1,2-benzisoxazole in 60 mL DMF was added to a NaH (1.1 g) suspension in 40 mL DMF. Add. Ethyl bromoacetate (6.7 g) is added and the reaction mixture is heated to 50 ° C. for 30 minutes. 100 mL H ₂ O and 25% water soluble NaOH are added and the reaction mixture is heated to 90 ° C. for 3 h. The reaction mixture is poured into H ₂ O and acidified with concentrated hydrochloric acid. The acidified mixture is extracted with ether, water, washed and dehydrated. Evaporate and recrystallize with ethyl acetate-hexane mixture to give {[7-chloro-3- (3-methyl-2-thienyl) -1,2-benz isoxazol-6-yl] oxy} acetic acid.

Example 17

A mixture of 10 mL of 50% NaOH with 15.0 g of ethyl {[7-chloro-3- (5-methyl-2-thienyl) -1,2-benzisoxazol-6-yl] oxy} acetate in Example 8b Was refluxed in 800 ml of ethanol for 30 minutes, 100 ml of 5% hydrochloric acid was added and the solution was homogenized. Once the product crystallizes, cool the solution and add water again. The product is filtered and recrystallized with isopropanol to give {[7-chloro-3- (5-methyl-2-thienyl) -1,2-benz isoxoxazol-6-yl] oxy} acetic acid.

Example 18

3-furoyl chloride (18.0 g) and 2,3-dichloro anisol (24.7 g) are dissolved in 125 ml CS ₂ and initially treated with AlCl ₃ (18.7 g) at 5 ° C. and then at room temperature. After 5 hours the reaction is complete with ice / HCl and extracted with CH ₂ Cl ₂ . Dehydration and evaporation yields a crystal product which is treated with hexane to give 4- (3-furoyl) -2,3-dichloroanisol having a melting point of 118 to 122 ° C.

16 ml of concentrated hydrochloric acid (0.186 mol) was added to 14.2 g of pyridine to prepare a dissolution tank of pyridine HCl, and the mixture was heated to 210 ° C. under nitrogen stream and H ₂ O was distilled off. Anisol (50 g) was added in part and heating continued for 1 hour, then the solution was poured on ice and extracted with ethyl acetate. Dehydration and evaporation yields 4- (3-fluyl) -2,3-dichlorophenol having a melting point of 138-142 ° C.

The phenol is mixed with hydroxylamine hydrochloride in pyridine and refluxed for 3 hours. Pyridine is evaporated and the resulting mixture is acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dehydrated and evaporated to dryness to obtain an oxime, which was dissolved in 100 mL and DMF and added to a NaH (70 g) suspension in 100 mL DMF. After warming at 120 ° C. for 2 hours, the reaction mass was cooled to 45 ° C. and ethylbromo acetate (24.0 g) in 20 mL DMF was added. The reaction / completed with brine and the resulting solid product are filtered off and washed with ethanol and ether to give crude phenoxy ester. The crude ester is refluxed in ethanol (500 ml) containing 10 ml of 50% in NaOH for 45 minutes, acidified and cooled to give crystalline acid. The acid is suspended in boiling methanol and recrystallized and DMF is added until dissolved. The addition of water immediately crystallised to give {[7-chloro-3- (3-furben) -1,2-ziisoxazol-6-yl] oxy} acetic acid having a melting point of 225 to 227 ° C.

Example 19

a. 18.5 g of AlCl ₃ is added to a solution of 24.6 g of 2,6-difluoro benzoyl chloride in 100 ml of 1,2-dichloro ethane for 30 minutes. 22.5 g 2,3-dichloroanisol solution in 100 mL 1,2-dichloro ethane are added.

The mixture is shaken for 1 hour and poured into 100 ml of hydrochloric acid and ice. The organic layer is separated and the aqueous layer is extracted with CHCl ₃ . The organic extract was washed with water, dehydrated (Na ₂ SO ₄ ) and evaporated to give an oil which was crystallized from hexane to give 2,3-dichloro-4-methoxy-2 ', 6'-difluorobenzophenone. Recrystallize with ether.

b. A mixture of 50.5 g of 2,3-dichloro-4-methoxy-2 ', 6'-difluorobenzophenone, 44.27 g of hydroxylamine HCl is refluxed for 48 h in 200 ml pyridine. Pyridine is evaporated under reduced pressure and the residue is partitioned between 5% HC1 and ethyl acetate. The extract is washed with water, dehydrated over Na ₂ SO ₄ and evaporated to give a mixture of isomers. Analytical samples of 2,3-dichloro-4-methoxy-2 ', 6'-difluorobenzophenone oxime are recrystallized from 95ethanol.

c. To a mixture of 5 g NaH in 200 ml DMF, 48 g 2,3-dichloro-4-methoxy-2 ', 6'-difluorobenzophenone oxime in 250 ml DMF was subjected to a temperature of about 40 ° C. under a nitrogen stream. Drop by After addition, the mixture is shaken for 30 minutes and poured into ice water. The crude product, a mixture of isomers, was filtered and chromatographed with CHCl ₃ as the extract on silica gel to give 7-chloro-3- (2,6-difluorophenyl) -6-methoxy- with a melting point of 175 to 179 ° C. 1,2-benzisoxazole is recrystallized from toluene.

d. A mixture of 10.8 g of 7-chloro-3- (2,6-difluorophenyl) -6-methoxy-1,2-benzisoxazole and 40.3 g of pyridine HCl was heated at 200 ° C. for 1 hour and shaken Pour into iced water. If 7-chloro-3- (2,6-difluorophenyl) -6-hydroxy-1,2-benzisoxazole product precipitates, it is filtered and dehydrated.

Reanalyze the sample with toluene.

e. A mixture of 1.18 g NaH and 9.2 g 7-chloro-3- (2,6-difluorophenyl) -6-hydroxy-1,2-benzisoxazole is shaken in 15 ml of DMF for 1 hour. . 6.06 g of ethylbromoacetate solution in 40 ml of DMF is added dropwise and shaken for 30 minutes. 10 mL of 50% NaOH is added and the reaction mixture is warmed at 80 ° C. for 1 h. Concentrated hydrochloric acid is added to the warmed solution until it is acidic.

Water was added to precipitate {[7-chloro-3- (2,6-difluorophenyl) -1,2-benzisooxazol-6-yl] oxy acetic acid, which was filtered and dehydrated and recrystallized from toluene-acetonitrile. To obtain a product having a melting point of 170 to 172 캜.

Example 20

a. A mixture of 20.36 g of fluorocinnamoyl chloride and 14.4 g of aluminum chloride in 100 ml of 1,2-dichloroethane was added dropwise to 17.7 g of 2,3-dichloro anisol in 1,2-dichloro ethane for 1 hour. Stir. The reaction is warmed to about 80 ° C. for one hour and poured into 100 ml of concentrated hydrochloric acid and ice. The aqueous layer is extracted with chloroform and the combined organic layers are washed with water, dehydrated with sodium sulfate and evaporated to give a solid residue. The residue is treated with hexane to give 4- (trans-α-fluorocinnamoyl) -2,3-dichloroanisol having a melting point of 137 to 138 ° C. Recrystallize the sample from toluene.

b. A mixture of 26.6 g of 4- (trans-α-fluorocinnamoyl) -2,3-dichloroanizol and 22.7 g of hydroxylamine hydrochloride is refluxed for 18 hours.

Pyridine is distilled in vacuo and the residue is treated with 5% hydrochloric acid. The product is filtered, dried and washed with ether-hexane to give a mixture of isomers. A sample of 4- (trans-fluorocinnamoyl) -2,3-dichloroanizol oxime having a melting point of 222 to 238 ° C is obtained by recrystallization with ethanol.

c. A mixture of 0.43 g sodium hydroxide and 60 g of 4-α-transfluorocinnamoyl) -2,3-dichloro anisoleoxime in 60 mL DMF is stirred for an hour and a half and poured into ice water. The resulting precipitate is filtered and dried to afford 7-chloro-3- (trans-beta-fluorostyryl) -6-methoxy-1,2-benzisoxazole. Recrystallization from toluene gives pure product.

d. A mixture of 1.4 g of 7-chloro-3- (trans-β-fluorostyryl) -6-methoxy-1,2-benzisooxazole and 5.6 g of pyridinehydrochloride was heated at 200 ° C. for 1 hour and poured into ice water. Pour with vigorous stirring.

The product of 7-chloro-3- (trans-β-fluorostyryl) -6-hydroxy-1,2-benzisoxazole having a melting point of 226 to 229 ° C. is filtered and dried.

e. To 0.84 g of NaH in 100 ml of DMF, 6.77 g of 7-chloro-3- (trans-β-fluorostyryl) -6-hydroxy-1,2-benzisoxazole in 50 ml DMF was added dropwise under nitrogen atmosphere. The mixture is stirred for 1 hour, at which time 4.2 g of ethyl bromoacetate is added dropwise.

The reaction is stirred for 30 minutes, 15 ml of 50% sodium hydroxide is added and the reaction is heated to 80 ° C. for 1 hour. The reaction mixture is acidified with concentrated sulfuric acid and water is added to precipitate the product. The crude product was filtered, dried and recrystallized from 95% ethanol to 7-chloro-3- (trans-β-fluoro-styryl) -1,2-benzisoxazol-6-yl with a melting point of 200 to 203 ° C. Obtain oxy acetic acid.

Example 21

a. 40 g of AlCl was added over 30 minutes to a 52.23 g solvent of 2,4-difluoro benzoyl chloride in 200 ml of 1,2-dichloroethane. A solution of 48.3 g of 2,3-dichloroanizol in 100 ml of 1,2-dichloroethane is added dropwise. The gas slowly evaporates and the temperature rises to about 30 degrees Celsius. Pour the mixture into concentrated hydrochloric acid and ice. The organic layer was separated and the aqueous layer was extracted twice with chloroform. The combined organic layers are washed with water and dried by evaporation with sodium sulfate to give an oil. Treatment with hexane yields 2,3-dichloro-4-methoxy-2 ', 4'-difluorobenzophenone, which is recrystallized from ether.

b. To 67 g of 2,3-dichloro-4-methoxy-2 ', 4'-difluorobenzophenone in 300 ml of pyridine is added 58 g of hydroxylamine hydrochloride and the resulting mixture is refluxed for 18 hours. Pyridine is distilled under vacuum and the residue is partitioned between 5% hydrochloric acid and ethyl acetate. Ethyl acetate extracts were washed with water, dried over sodium sulfate and evaporated to afford 2,3-dichloro-4-methoxy-2 ', 6'-difluorobenzophenone oxyl as a mixture of isomers. Recrystallize the sample from 95% ethanol.

c. To a mixture of 5.7 g of NaH in 100 ml of DMF was added dropwise while maintaining 53 g of 2,3-dichloro-4-methoxy-2 ', 6'-difluorobenzophenone oxime dissolved in 250 ml of DMF. After stirring the mixture for an hour and a half, water is added to the product to precipitate the product. The crude product, a mixture of isomers, was chromatographed on silica gel using toluene-hexane as eluent to give 7-chloro-3- (2,4-difluorophenyl) -6-methoxy-1,2-benzisoxazole. Obtain a pure substance and recrystallize with toluene.

d. A solid mixture of 7.1 g of 7-chloro-3- (2,4-difluorophenyl) -6-methoxy-1,2-benzisooxazole and 27.8 g of pyridinehydrochloride was heated at 200 ° C. for an hour and the mixture Is poured into ice water with vigorous stirring to precipitate the product. The product is filtered and dried to afford 7-chloro-3- (2,4-difluorophenyl) -6-hydroxy-1,2-benzisoxazole, which is recrystallized from toluene. Melting point 186-190 캜.

e. A solution of 6.9 g of 7-chloro-3- (2,4-difluorophenyl) -6-hydroxy-1,2-benzisoxazole in 50 ml of DMF in a mixture of 0.86 g of NaH in 100 ml of DMF in the presence of nitrogen gas. Was added dropwise and 4.41 g of ethylbromoacetate in 25 ml of DMF was added. The mixture is stirred for 30 minutes, 50% sodium hydroxide is added and heated at 80 to 85 ° C. for 1 hour.

Concentrated hydrochloric acid is added until the mixture becomes acidic. Water is added to precipitate {[7-chloro-3- (2,4-difluorophenyl) -1,2-zenzioxoxazol-6-yl] oxy} acetic acid and recrystallize from the toluene-acetonitrile.

Example 22

a. Dimethyl sulfide (94.64 g) was added dropwise over 40 minutes to a cooling stirred solution of 2,5-dichlorophenol (122.25 g) and sodium hydroxide (31.5 g) dissolved in water (300 mL).

The mixture is stirred for 1 hour at room temperature, refluxed for another 2 hours and then cooled back to room temperature. The organic layer is separated and combined with the ether extract of the residual aqueous layer. The ether solution is dehydrated (saturated sodium chloride, sodium sulfate, calcium carbonate) and ether is removed to give 2,5-dichloroanisol. Distillation gives a colorless liquid (115 ° C. with vacuum aspirator).

A solution of O-fluorobenzoylchloride in carbon wetting (25 ml) was added to a suspension in carbon wetting (450 ml) (58.67 g) at room temperature and 70.8 g of 2,5-dichloroanizol in carbon wetting (25 ml) at room temperature. Add. The mixture is stirred at room temperature for 4 hours during which time a precipitate forms.

The mixture is refluxed for one hour, then cooled and 58 g AlCl ₃ is added. The resulting mixture is refluxed for 2 hours and stirred at room temperature for hours. The mixture is poured into ice / hydrochloric acid and extracted with methylene dichloride to give an oil. Treatment with hexane-ether gives a solid. Recrystallization with diisopropyl ether gives a solid which is partially dissolved at about 94 ° C. and then dissolved at about 120 ° C. After the solvent was removed from the filtrate, the remaining solid was treated with petroleum ether-ether to obtain 2,5-dichloro-4- (2-fluorobenzoyl) anizol and recrystallized from methanol.

b. A mixture of 2,5-dichloro-4- (2-fluorobenzoyl) anizol (3 g) and hydroxylamine hydrochloride (1.4 g) in pyridine (25 mL) was refluxed for several hours until the ketone body disappeared. Pyridine is removed under high vacuum and the residue is diluted with water and extracted with chloroform.

The chloroform solution is dried and the chloroform is removed to give a solid which is recrystallized with ether to give (Z) -2′-fluoro-2,5-dichloro-4-methoxybenzophenone oxime having a melting point of 188 ° C.

c. (Z) -2'-fluoro-2,5-dichloro-4-methoxybenzophenone oxime (3.14 g) solution in DMF (20 mL) was added dropwise to DMF (0.6 g) stirred suspension in (20 mL). . The mixture is stirred at rt for 18 h, poured into ice / water and extracted with chloroform. The chloroform solution is washed with unsaturated sodium chloride solution and dried over sodium sulfate-magnesium sulfate. Removal of chloroform gives a residue, which is treated with petroleum ether-ether to give a solid having a melting point of 165 to 166 ° C. The solvent is removed from the filtrate to give a solid which is treated with petroleum ether-ether to give 5-chloro-3- (2-fluorophenyl) -6-methoxy-1,2-benzisoxazole having a melting point of 165 to 166 ° C. .

α. A solution of 5-chloro-3- (2-fluorophenyl-6-methonesi-1,2-benzisoxazole (1 g) and boron tribromide (1.3 ml) in dichloroethane (30 ml) was refluxed for about 24 hours. The reaction mixture is poured into ice-water and extracted with dichloromethane to give solid 5-chloro-3- (2-fluorophenyl) -6-hydroxy-1,2-benzisoxazole having a melting point of 180 to 182 ° C. Get

e. 5-chloro-3- (2-fluorophenyl) -6-hydroxy-1,2-benzisoxazole (14.8 g) in DMF (40 mL) was dissolved in sodium hydride (3.0 g) in DMF (40 mL). To the suspension is added dropwise at room temperature and the mixture is stirred for 30 minutes at room temperature.

A solution of ethylbromoacetate (10.31 g) in DMF (40 mL) is added dropwise and the mixture is stirred at room temperature for 18 hours. 0.3 g of NaH suspended in DMF is added followed by 1 g of ethyl bromoacetate. The mixture is heated at 50 ° C. for 1 and a half hours. The ether extract is washed with water and saturated sodium chloride, dried over sodium sulfate and the solvent is removed to give a solid. Ethyl {[5-chloro-3- (2-fluorophenyl) -1,2-benzisoxazol-6-yl] oxy} acetate having a melting point of 114 to 115 ° C by treatment with petroleum ether-ether (1'1) Get

f. Ethyl {[5-chloro-3- (2-fluorophenyl) -1,2-benzisoxazol-6-yl] oxy} acetate (14 g), sodium hydroxide (8 g), ethanol (500 mL) and water ( 300 ml) of the mixture is refluxed for 5 hours, cooled in an ice bath and acidified with concentrated hydrochloric acid. The suspension is extracted with chloroform and the extract is dried with saturated sodium chloride to remove chloroform to give a solid having a melting point of 214 to 215 ° C. Recrystallization with a 3: 2 mixture of acetonitrile-toluene yields {[5-chloro-3- (2-fluorophenyl) 1,2-benzisoxazol-6-yl] oxy} acetic acid.

Example 23

a. To a solution of 57.6 g of 3,4-dichloro benzoyl chloride in 1,2-dichloroethane (150 mL) is added 36.7 g of AlCl ₃ over 30 minutes. To the resulting mixture is added dropwise 44.26 g of 2,3-dichloroanizol. Once the gas has evaporated the reaction mixture is heated to 60 ° C. for one hour. The mixture is then poured into 150 ml of concentrated hydrochloric acid and 150 ml of ice and extracted with chloroform and ethanol. The obtained organic layer was washed with 10% aqueous potassium carbonate solution and water, dried over sodium sulfate and evaporated to give 2-dichloro-4-methoxy-3 ', 4'-dichlorobenzophenone having a melting point of 113 to 140 ° C.

b. A mixture of 59 g of 2,3-dichloro-4-methoxy-3 ', 4'-dichlorobenzophenone and 40 g of AlCl in 400 ml of benzene was refluxed for 5 hours, then cooled to room temperature and maintained for 18 hours. The mixture is poured into 200 ml of concentrated hydrochloric acid and 200 ml of ice and stirred for 30 minutes at room temperature. Ethyl acetate is added to the mixture and the ethyl acetate / benzene layer is washed with water, dried over sodium sulfate and evaporated to give 2,3-dichloro-4-hydroxy-3 ', 4'-dichlorobenzophenone having a melting point of 179 ° to 180 ° C. .

c. 35.43 g of 2,3-dichloro-4-hydroxy-3 ', 4'-dichlorobenzophenone and 15.29 g of hydroxylamine in 300 ml of pyridine are refluxed for 2 hours. Pyridine is evaporated in vacuo. The residue is partitioned between ethyl acetate and 5% hydrochloric acid. The extract is washed with water, dried over sodium sulfate and evaporated to afford the corresponding oxyl.

6.0 g of NaH was added to a 35 g solution of oxime 35 mL in DMF and the mixture was heated to an internal temperature of 103 ° C. for 1 hour 45 minutes and then to an internal temperature of 100 ° C. for 3/4 hours. The reaction mixture is cooled to room temperature and a solution of 18.37 g of ethyl bromoacetate in 50 ml of DMF is added dropwise. The mixture is stirred for about 64 hours, poured into water and the resulting precipitate is filtered and washed with hexane. The crude product is recrystallized from ethanol to give ethyl {[7-chloro-3- (3,4-dichlorophenyl) -1,2-benzisoxazol-6-yl] oxy} acetate having a melting point of 123 to 125 ° C.

20 ml of 50% sodium hydroxide is added to a suspension of 19 g of ester in 400 ml of ethanol. When a precipitate is formed, the heterogeneous mixture is refluxed for 1 hour. 400 ml of water is added to the warmed mixture and concentrated hydrochloric acid is added to make the mixture acidic.

The suspension was stirred for 30 minutes and recrystallized from DMF-ethylacetate to produce {[7-chloro-3- (3,4-dichlorophenyl) -1,2-benzisoxazol-6-yl] oxy having a melting point of 222 to 224 ° C. } Acetic acid is obtained.

Example 24

a. The Frieden-Craft reaction of Example 23a was carried out on 36.7 g of AlCl _{3 and} 44.26 g of 2,3-dichloroanizol and 48.13 g of O-chlorobenzoyl chloride with a melting point of 117 to 120 ° C. for 2,3-dichloro-4-meth A white crystalline material of oxy-2'-chlorobenzophenone is obtained.

b. The process of Example 23b is repeated except that 68 g of 2,3-dichloro-4-methoxy-2'-chlorobenzophenone and 58.6 g of AlCl _{3 in} 500 ml of benzene are used. The obtained product is recrystallized from toluene to give 2,3-dichloro-4-hydroxy-2'-chlorobenzophenone having a melting point of 74 to 77 캜.

c. 25.02 g of hydroxylamine hydrochloride is added to a 2,3-dichloro-4-hydroxy-2'-chlorobenzophenone solution in 350 ml of pyridine. The mixture is refluxed for 2 hours. Pyridine is evaporated in vacuo and the residue is partitioned between ethyl acetate and 5% hydrochloric acid. The ethyl acetate extract is washed with water, dried over sodium sulfate and evaporated to give the corresponding oxime. 9.12 g of NaH is added to a 49 g solution of oxime in 300 ml DMF and the mixture is heated to an internal temperature of 80 to 84 ° C. for 1 hour. The reaction mixture was cooled to room temperature and 27.5 g of ethylbromo acetate was added to 50 ml of DMF. The mixture is stirred for 30 minutes and water is added to decompose excess NaH. The product is extracted with ethyl acetate. The ethyl acetate extract is washed with 10% sodium hydroxide and water, dehydrated over sodium sulfate and evaporated to give a mixture. The mixture is chromatographed on silica gel using chloroform as eluent to afford ethyl {[7-chloro-3- (2-chlorophenyl) -1,2-benzisoxazol-6-yl] oxy} acetate.

To a solution of 5.86 g of ester in 200 ml of hot ethanol, 6 ml of 50% sodium hydroxide is added. When the precipitate forms, the suspension is refluxed for 1 hour. 200 ml of water is added to the mixture and concentrated hydrochloric acid is added to make the mixture acidic. The mixture is stirred at rt for 18 h. When the solid product precipitates, it is filtered and recrystallized with toluene to obtain {[7-chloro-3- (2-chlorophenyl) -1,2-benzisoxazol-6-yl] oxy} acetic acid having a melting point of 165 to 168 캜. Get

Example 25

a. The Friedel-Crafts reaction of Example 23a was repeated with 35.4 g of 2,3-dichloroanizol, 32.4 g of 0-toluoyl chloride and 28 g of AlCl _{3 in} 125 ml of 1,2-dichloroethane and then 2,3-dichloro-4- Obtain methoxy-2'-methylbenzophenone.

b. The method of Example 23b was repeated except using 34.6 g of 2,3-dichloro-4-methoxy-2'-methylbenzophenone, AlCl _{3 in} 300 ml of benzene. The obtained product is recrystallized from toluene to give 2,3-dichloro-4-hydroxy-2'-methylbenzophenone. Pyridine is evaporated in vacuo and the residue is partitioned between ethyl acetate and 5% hydrochloric acid. The ethyl acetate extract is washed with water and dehydrated with sodium sulfate to give the corresponding oxime. 2.43 g of NaH is added to a 12 g solution of oxime in 50 ml of DMF and 50 ml of toluene.

The mixture is heated to an internal temperature of 95-98 ° C. for 51/4 hours under a stream of nitrogen. Add 50 ml of DMF again and keep the internal temperature at 95 ℃ for 2 hours. The reaction mixture is cooled to 30 ° C. and 7.5 g ethylbromoacetate is added dropwise. The mixture is stirred for 1 hour after the addition is completed. Water is added and the product is extracted with ethyl acetate, dried over sodium sulfate and evaporated to afford ethyl {[7-chloro-3- (2-tolyl) -1,2-benzisoxazol-6-yl] oxy} acetate.

To a solution of 13.95 g of ester in 500 ml of hot ethanol is added 13 ml of 50% sodium hydroxide. Once a precipitate is formed, the suspension is refluxed for one and a half hours, 500 ml of water is added and concentrated sulfuric acid is added to acidify the mixture. After cooling, the solid product precipitated and was filtered and recrystallized with toluene to remove {[7-chloro-3- (2-tolyl) -1,2-benzisoxazol-6-yl] oxy} acetic acid having a melting point of 179 to 181 ° C. Get

Example 26

a. The Friedel-Craft reaction of Example 23a was repeated with 33.7 g of 2,3-dimethyl benzoyl chloride, 54 g of 2,3-dichloroanizol and 26.7 g of AlCl ₃ to repeat 2,3-dichloro-4-methoxy-2 ', 3 Prepare '-dimethylbenzophenone.

b. Example 23b The reaction is repeated using 2,3-dichloro-4-methoxy-2 ', 3'-dimethylbenzophenone in 300 ml of benzene. The obtained product is recrystallized with toluene to give 2,3-dichloro-4-hydroxy-2 ', 3'-dimethylbenzophenone.

c. A mixture of 31 g of 2,3-dichloro-4-hydroxy-2 ', 3'-dimethylbenzophenone and 30.5 g of hydroxylamine hydrochloride in 250 ml of pyridine is refluxed for about one week. Pyridine is evaporated in vacuo and the residue is partitioned between ethyl acetate and 5% hydrochloric acid. The ethyl acetate extracts are washed, dried over sodium sulphate and evaporated. Treatment with hexanes affords 2,3-dichloro-4-hydroxy-2 ', 3'-dimethylbenzophenone oxime.

d. To a 5 g solution of 2,3-dichloro-4-hydroxy-2 ', 3'-dimethylbenzophenone oxime in 70 ml of DMF was added 0.96 g of NaH. The internal temperature is maintained at 95-120 ° C. for 7 hours and then the mixture is heated to 130 ° C. for 1.5 hours. The reaction mixture is cooled and 2.94 g of ethylbromoacetate is added dropwise. The mixture is stirred for 1 hour and water is added dropwise. The product was filtered and recrystallized with 95% ethanol to give ethyl {[7-chloro-3- (2,3-dimethylphenyl) -1,2-benzisoxazol-6-yl] oxy} acetate having a melting point of 89 to 91 ° C. Get

e. A suspension of 2 g of ethyl {[7-chloro-3- (2,3-dimethylphenyl) -1,2-benzisooxazol-6-yl] oxy} acetate, 50 ml of ethanol and 5 ml of 50% sodium hydroxide was added for 1 hour. Reflux for a while. Sufficient hydrochloric acid is added to a 50 ml mixture of hot water to allow the reaction mixture to acidify. Cooling and adding water precipitates {[7-chloro-3- (2,3-dimethylphenyl) -1,2-benzisoxazol-6-yl] oxy} acetic acid with a melting point of 170 to 172 ° C.

Example 27

a. 29.3 g of 2-bromopyridine in 150 mL of dry THF is added to 75 mL of 2.6 M n-butyllithium cooled to -65 占 폚. 2,3-Dichloro-4-methoxybenzaldehyde (38.0 g) is added to 300 mL of THF and the reaction mixture is allowed to come to room temperature. It is poured into water and the crystalline product is filtered off, washed with ether and dehydrated to give α- (2,3-dichloro-4-methoxyphenyl) -2-pyridinmethanol having a melting point of 174 to 176 ° C.

b. α- (2,3-dichloro-4-methoxyphenyl) -2-pyripine methanol (31.86 g) is dissolved in 600 ml of acetic acid and 100 ml of water. Anhydrous chromium (11.0 g) is added for 5 minutes. After 3 hours the reaction mixture is poured into water and extracted with ether. The combined organic layers are washed well with 10% sodium hydrogen carbonate and brine and dried. The solvent is removed under reduced pressure to obtain a crystalline product of (2,3-dichloro-4-methoxyphenyl) (2-pyridyl) methanol having a melting point of 104 to 107 캜.

c. (2,3-dichloro-4-methoxyphenyl) (20pyridyl) methanol (32.0 g) is refluxed in 300 ml of ethanol containing 30 g of hydroxylamine for 4 hours. The reaction product is poured into water, made alkaline with NH ₄ OH and extracted with ethyl acetate. Dehydration and evaporation resulted in E- (2-pyridyl) (2,3-dichloro-4-methoxy-phenyl) methanone oxime and Z- (2-pyridyl) (2,3-dichloro-4-methoxy- A crude mixture of phenyl) methanone oxime is obtained.

The oxime mixture is taken up in 200 ml of DMF and added to a 3.1 g suspension of NaH in 150 ml DMF. After 15 minutes the reaction mixture is poured into water and the product is filtered off. Recrystallization with isopropanol removes unreacted E-oxime and affords 7-chloro-6-methoxy-3- (2-pyridyl) -1,2-benzisoxazole having a melting point of 164 to 166 ° C.

d. 7-Chloro-6-methoxy-3- (2-pyridyl) -1,2-benz isoxoxazole (24.4 g) is refluxed in 450 ml of 48% hydrobromide. Precipitated hydrobromide salt is filtered and neutralized with 10% sodium bicarbonate solution washed with ether. The free base is filtered and dried to give 7-chloro-6-hydroxy-3- (2-pyridyl) -1,2-benzisoxazole having a melting point of 209 to 211 ° C.

e. 7-Chloro-6-hydroxy-3- (2-pyridyl) -1,2-benzisooxazole (10.0 g) is dissolved in 80 ml of DMF and added to an ice-cold suspension of NaH (1.1 g) in 50 ml of DMF. . When the evaporation of hydrogen is complete, ethyl bromo acetate (7.5 g) in 20 ml of DMF is added. After 90 minutes, 200 ml of water and 10 ml of 50% sodium hydroxide are added and the reaction is heated to 65 ° C. for 45 minutes. The mixture was poured into water, acidified to pH 1-2, and the solid product was filtered and dried to produce {[7-chloro-3- (2-pyridyl) -1,2-benzisoxazol-6-yl having a melting point of 255 to 256 ° C. ] Oxy} acetic acid.

Example 28

a. Dissolve 7-chloro-6-hydroxy-3- (2-pyridyl) -1,2-benzisoxazole (9.9 g) in 600 ml of glacial acetic acid at 60 ° C. At this time, m-chloro-perbenzoic acid (85% of 8.3 g) is added. After heating at 60 ° C. for 14 h the reaction is poured into 2 L of water and the product is filtered off and washed with methanol and ether. The obtained product is recrystallized from DMF / water to give 7-chloro-6-hydroxy-3- (2-pyridyl) -1,2-benzisoxazole 1'-oxide having a melting point of 214 ° C in the form of hemihydrate.

b. Dissolve 7-chloro-6-hydroxy 3- (2-pyridyl) -1,2-benzisoxazole 1'-oxide (7.30 g) in 20 ml of DMF and add to NaH (1.33 g) suspension in 50 ml of DMF. do. After 15 minutes ethylbromo acetate (5.0 g) in 20 mL DMF is added and the reaction is heated at 50 ° C. for 10 hours. The reaction is cooled with water and acidified to filter the precipitate and dry well. The precipitate is again treated with 1.33 g of NaH and 5.0 g of ethyl bromoacetate in DMF. After 30 minutes, 200 ml of water and 10 ml of 50% sodium hydroxide are added and the reaction mixture is heated at 50 ° C. for 30 minutes. This is then acidified and a {[7-chloro-3- (2-pyridyl) -1,2-benzisoxazol-6-yl] oxy} acetic acid 1'-oxide having a melting point of 214 ° C (d).

Example 29

a. m-dimethoxybenzene (27.6 g) and 0-fluorobenzoylchloride (31.7 g) are dissolved in 200 mL of dichloroethane and AlCl ₃ (28.0 g) is added. After two hours, 56 g of AlCl ₃ was added again and the reaction was heated at 60 ° C. for 1.5 h. It is then poured into water and extracted with ethyl acetate. Dry and evaporate to give crystalline compound. Treatment with toluene yields 2,4-dihydroxy-2'-fluorobenzophenone having a melting point of 109-111 占 폚.

b. 2,4-dihydroxy-2'-fluorobenzophenone (25.0 g) is refluxed for 18 hours in 250 ml of pyridine containing 17.1 g of hydroxylamine hydrochloride. The reaction mixture is partitioned between ether and 5% hydrochloric acid and the organic layer is separated. Dry, evaporate and recrystallize with toluene to obtain pure isomers of 2,4-dihydroxy-2'-fluorobenzophenone [E-oxime] having a melting point of 170 to 172 ° C.

c. E-oxime 2,4-dihydro-2'-fluorobenzophenone oxime (18.6 g) is heated to 50 ° C. in 18.0 ml of acetic anhydride for 5 hours and warmed to 60 ° C. for 6 hours. An additional 3.0 ml of acetic anhydride is added and the reaction is left without shaking at room temperature for 73 hours. The crystalline product isolated from the reaction mixture is washed with cold ether to give E-4-acetoxy-2-hydroxy-2'-fluorobenzophenone 0-acetyloxime having a melting point of 132 to 134 ° C.

d. E-4-acetoxy-2-hydroxy-2'-fluorobenzophenone 0-acetyloxime (18.4 g) is taken up in 80 ml of DMF and added to NaH (3.3 g) cooling suspension in 100 ml of DMF. After 90 minutes the reaction mixture is poured into water and a small amount of insoluble precipitate is filtered off. The aqueous filtrate is acidified and extracted with ether to give 3- (2-fluorophenyl) -6-hydroxy-1,2-benzoisoxazole having a melting point of 206 to 210 ° C. after drying and evaporation.

e. 3- (2-fluorophenyl) -6-hydroxy-1,2-benzisoxazole (9.7 g) is dissolved in 80 ml of DMF and added to sodium hydride (1.4 g) cooling suspension in 50 ml of DMF. At the end of hydrogen evolution, ethyl bromoacetate (7.5 g) in 20 mL of DMF is added and the reaction mixture is brought to room temperature. After 2 hours, 20 ml of DMF and 10 ml of 50% NaOH are added and the reaction is heated at 50 ° C. After another 30 minutes the product is acidified and filtered. Recrystallization with toluene / CH ₃ CN gives {[3 (2-fluorophenyl) -1,2-benzisoxazol-6-yl] oxy} acetic acid having a melting point of 182 ° to 180 ° C.

Example 30

a. The Friedel-Craft reaction of Example 23a p is repeated with 31.55 g P-fluorobenzoyl chloride, 32 g dichloroanizol and 35.22 g AlCl ₃ in 1,2-dichloroethane. The crude product obtained is treated with warm hexane, cooled and filtered to give 2,3-dichloro-4-methoxy-4'-fluoro benzophenone.

b. A mixture of 39.5 g of 2,3-dichloro-4-methoxy-4'-fluorobenzophenone and 160 g of pyridine hydrochloride is heated at 200 ° C. for 1 hour. The reaction mixture is poured into iced water with stirring to form a precipitate. The precipitate is filtered and dried for about 18 hours to give 2,3-dichloro-4-hydroxy-4'-fluorobenzophenone.

c. 34.6 g of hydroxylamine HCl is added to a 2,3-dichloro-4-hydroxy-4'-fluorobenzophenone solution in 250 ml of pyridine. The mixture is refluxed for 4 hours. Pyridine is evaporated in vacuo. The residue is partitioned between 5% HCl and ethyl acetate. The ethyl acetate extract is washed with water, dried over Na ₂ SO ₄ and evaporated to give 2,3-dichloro-4-hydroxy-4'-fluorobenzophenone oxime having a melting point of 150 to 150 ° C. as a mixture of isomers.

d. To a mixture of 4.0 g of NaH in 50 ml of DMF is added dropwise a solution N ₂ of 20 g of 2,3-dichloro-4-hydroxy-4'-fluorobenzophenone oxime in 100 ml of DMF under pressure. The reaction mixture is heated to an internal temperature of 96 ° C. for 2 hours. The reaction mixture is cooled to 40 ° C., 12.3 g ethylbromoacetate is added dropwise and the mixture is stirred for 1 hour. 20 mL of 50 NaOH and 100 mL of water are added and the reaction is heated at 80-90 ° C. for 1 hour. Concentrated HCl is added until the reaction mixture is acidic, the mixture is stirred for 30 minutes and water is added. The solid product is collected by filtration and recrystallized to obtain a pure product of {[7-chloro-3- (4-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} acetic acid having a melting point of 233 to 237 ° C. .

Example 31

a. 2,6-dimethoxytoluene (20.0 g) and 0-fluorobenzoyl chloride (19.8 g) are dissolved in 250 ml of dichloroethane and cooled to 5 ° C. AlCl ₃ is added in part and when complete the reaction mixture is heated to room temperature for at least 30 minutes. Then reflux for 30 minutes. This is then poured into 5% HCl and left unchanged for 18 hours. Extract with ether, dry, concentrate and wash with hexane to obtain crystalline material of 2'fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone having a melting point of 118 to 120 ° C.

b. 2'fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone (30.0 g) is refluxed in 350 ml of pyridine containing 32.0 g of hydroxylamine hydrochloride. The solvent is removed in vacuo and the residue is partitioned between ether and 5% HCl. The ether is concentrated to dryness and the crude product is obtained and melt heated at 200 ° C. for 30 minutes under nitrogen atmosphere. The melt is cooled and the solid is well treated with hexane to give E-2'-fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone oxime having a melting point of 167-169 ° C.

c. E-2'-fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone oxime (20.0 g) is heated in a steam bath with 12 ml of acetic anhydride for 1 hour. Acetic anhydride is evaporated in vacuo and the product is partitioned between ether and H ₂ O, after which the ether is washed with 10% NaHCO ₃ . After evaporation, the crystalline material was treated with hexane to give 0-acetyl oxime for E-2'-fluoro-2-hydroxy-4-methoxy-3-methylbenzo having a melting point of 83 to 86 占 폚.

d. E-2'-fluoro-2-hydroxy-3-methylbenzophenone 0-acetyloxime (22.0 g) was dissolved in 100 mL of DMF and added to a 2.5 g suspension of NaH in 100 mL of DMF. The temperature is kept below 30 ℃ in an ice bath. After 40 minutes the reaction is poured into H ₂ O and extracted with ether. After washing well with H ₂ O, the ether was dried and evaporated to give crystalline product, which was then washed with cold hexane to give 3- (2-fluorophenyl) -6-methoxy-1,2- with a melting point of 105 to 108 ° C. Obtain benzisoxazoles.

e. 3- (2-fluorophenyl) -6-methoxy-7-methyl-1,2-benzisooxazole (16.1 g) is heated with 64 g of pyridine hydrochloride at 200 ° C. for 2 hours. The melt is poured into H ₂ O and extracted with ethyl acetate. After washing with 5% HCl, ethyl acetate was dried and evaporated to obtain 3- (2-fluorophenyl) -6-hydroxy-7-methyl-1,2-benzisoxazole having a melting point of 216 to 219 ° C.

f. Dissolve 3- (2-fluorophenyl) -6-hydroxy-7-methyl-1,2-benzisoxazole (10.6 g) in 90 mL of DMF, and use 8.0 g of ethyl bromoacetate and 6.7 g of K ₂ CO ₃ . Process. The reaction is heated at 60 ° C. for 2 hours and brought to ambient temperature. After 18 hours at ambient temperature water 200 and 50% NaOH (15 mL) are added and the solution is heated at 90 ° C. for 90 minutes. Drying and evaporation yields a crystalline material of {[3- (2-fluorophenyl) -7-methyl-1,2-benzisooxazol-6-yl] oxy} acetic acid having a melting point of 158 to 160 ° C.

Example 32

a. m-chloroanizol (28.5 g) and 0-fluoro benzoyl chloride (31.7 g) are dissolved in 200 mL of dichloroethane and treated with 26.7 g of AlCl ₃ at 10 ° C. Dry, evaporate and treat with hexane to give a material containing 2-chloro-2'-fluoro-4-methoxybenzophenone. Recrystallization with Et ₂ O / hexane affords ₂ -chloro-2'-fluoro-4-methoxybenzefenone having a melting point of 77 to 79 ° C.

b. 2-Chloro-2'-fluoro-4-methoxybenzophenone (15.5 g) is refluxed for 3 h in 150 ml of pyridine containing 10.0 g of hydroxylamine hydrochloride. Pyridine is removed in vacuo and the residue is partitioned between ether and 5% HC1. The organic layer is dried and evaporated to yield an isomeric mixture of oximes. The mixture is taken up in 50 ml of DMF and added to a 1.5 g suspension of NaH in 30 ml of DMF. After heating at 60 ° C. for 30 minutes, the reaction mixture is poured into H ₂ O and extracted with ether. Concentration under reduced pressure gives a solid. Recrystallization with ether gives 3- (2-fluorophenyl) -6-methoxy-1,2-benzisoxazole having a melting point of 101 to 103 캜.

c. 3- (2-fluorophenyl (-6-methoxy-1,2-benzisoxazole is dissolved in 400 ml of dry THF at -40 ° C and treated with 21 ml of 2.2 M n-butyllithium. After stirring for 1 hour I ₂ (11.7 g) in 90 mL of ether is added The reaction mixture is poured into Na ₂ S ₂ O ₃ and poured into H ₂ O. Dried and concentrated to 3- (2-fluorophenyl with a melting point of 135 to 138 ° C. ) -7-urido-6-methoxy-1,2-benzisoxazole is obtained.

d. 3- (2-fluorophenyl) -7-urido-6-methoxy-1,1-benzisoxazole (8.2 g) is refluxed for 18 h in 130 ml of CH ₂ Cl ₂ containing 6.6 ml of BBr ₃ . . The reaction mixture is poured into H ₂ O and extracted with ether. After drying and evaporation to good treatment with hexane, a crystalline product of 3- (2-fluorophenyl) -6-hydroxy-7-uredo-1,2-benzisoxazole having a melting point of 212 to 214 ° C is obtained.

e. 6.6 g of K ₂ CO ₃ and ethyl bromoacetate 7.1 at 60 ° C. were treated with 3- (2-fluorophenyl) -6-hydroxy-7-urido-1,2-benzisooxazole (7.80 g) in 80 mL of DMF. Treat with g. After one hour the temperature was raised to 90 ° C. and 80 ml of H ₂ O and 8 ml of 50% NaOH were added. After 30 minutes, the mixture was poured into H ₂ O, acidified, extracted with ether, dried, and evaporated to produce {[3- (2-fluorophenyl) -7-uredo-1,2-benzi having a melting point of 178 to 180 ° C. Oxazol-6-yl] oxy} acetic acid is obtained.

Example 33

a. 10 g of 3- (2-fluorophenyl) -6-methoxy-1,2-benzisoxazole of Example 32b is dissolved in 400 mL of anhydrous THF and treated with 21 mL of 2.2 M n-butyliridium at -40 ° C. Stir for 1 hour and add dropwise bromine (2.5 mL). The reaction mixture is poured into H ₂ O, extracted with ether and washed with solution. Drying and evaporation yields 7-bromo-3- (2-fluorophenyl) -6-methoxy-1,2-benzisoxazole having a melting point of 150 to 153 ° C. which is a material containing the desired bromination product.

b. 7-Bromo-3- (2-fluorophenyl) -6-methoxy-1,2-benzisoxazole (7.20 g) was refluxed in 130 ml of CH ₂ Cl ₂ containing 6.6 ml of BBr ₃ for 18 hours. do. The reaction mixture is poured into H ₂ O and extracted with ethyl acetate. Evaporation and treatment with hexanes yields the corresponding phenols having a melting point of 231 to 234 ° C. Phenol (6.30 g) in 80 ml of DMF was treated with 6.6 g of K ₂ CO ₃ and 7.9 g of ethyl bromoacetate at 60 ° C. After an hour, 80 ml of DMF and 8 ml of 50% NaOH are added and the temperature is raised to 90 ° C. After 45 minutes the reaction is acidified and extracted with ethyl acetate. Recrystallization with toluene / CH ₂ CN under evaporation yields {[7-bromo-3- (2-fluorophenyl) -1,2-benzisoxazol-6-yl] oxy} acetic acid with a melting point of 180 to 182 ° C. .

Example 34

a. 3.06 g of AlCl ₃ is added in portions to a mixture of ₄ g of 2-chloro resorcinol dimethyl ether and 3.7 g of 2,3-difluorobenzoyl chloride in 60 ml of 1,2-dichloroethane at 5 ° C. The mixture is allowed to warm to room temperature and refluxed for 30 minutes. The reaction mixture is poured into concentrated HCl-ice and left for about 72 hours. The aqueous layer was extracted with additional organic solvent, dried over Na ₂ SO ₄ and evaporated to 3-chloro-2-hydroxy-4-methoxy-2 ', 3'-difluorobenzo having a melting point of 161 to 132 °. Get phenol

b. To a solution of 24 g of 3-chloro-2-hydroxy-4-methoxy-2 ', 3'-difluorobenzophenone in 160 ml pyridine is added 22 g of hydroxyl amine. The mixture is refluxed for 2 hours and the pyridine is evaporated under vacuum. The residue is partitioned between ethyl acetate and HCl. The ethyl acetate extract is washed with water, dried over Na ₂ SO ₄ and evaporated to give a pale yellow solid consisting of two isomers. This solid is melted at 205 ° C. for about 13 minutes.

The residue is taken up in hot ethyl acetate and evaporated to dryness to afford E-3-chloro-2 ', 3'-difluoro-2-hydroxy-4-methoxy benzophenone oxime having a melting point of 198 to 199 ° C.

c. 1.5 g of E-3-chloro-2 ', 3'-difluoro-2-hydroxy-4-methoxy benzophenone oxime and 0.67 g of acetic anhydride are warmed at 60 ° C. for 30 minutes. The mixture is dissolved and solidified. The residue is partitioned between ethyl acetate and 10% NaHCO ₃ . Ethyl acetate extracts were washed, dried over Na ₂ SO ₄ and evaporated to E-3-chloro-2 ', 3'-difluoro-2-hydroxy-4-methoxybenzophenone with a melting point of 136 to 139 ° C. Acetyl oxime is obtained.

d. To a 1.4 g NaH mixture in 200 mL of DMF, a solution of 19 g of E-3-chloro-2 ', 3'-difluoro-2-hydroxy-4-methoxy benzophenyl 0-acetyloxime in 200 mL of DMF was added to a nitrogen atmosphere. Drop by The mixture is stirred for 30 minutes and warmed to 45 ° C. for 30 minutes. Water is added to precipitate the product, filtered and dried to give 7-chloro-3- (2,3-difluorophenyl) -6-methoxy-1,2-benzisoxazole having a melting point of 184 to 189 ° C.

e. The solid mixture of 12 g of 7-chloro-3- (2,3-difluorophenyl) -6-methoxy-1,2-benzisooxazole and 50 g of pyridine HCl is heated to 200 ° C. for 45 minutes. The mixture is placed in strongly stirred ice water to precipitate 7-chloro-6-hydroxy-3- (2,3-difluorophenyl) -1,2-benzisoxazole having a melting point of 250 to 254 ° C.

f. 6.36 g of K ₂ CO ₃ was added to a 12 g solution of 7-chloro-6-hydroxy-3- (2,3-difluorophenyl) 1,2-benzisoxazole in 120 ml of DMF, followed by Br CH ₂ CO ₂ C _Add 7.83 g of ₂ H ₅ . The reaction is warmed at 60 ° C. for 2 hours and left for 18 hours. 200 ml of water in the mixture. 15 ml of 50% NaOH is added.

The mixture is warmed to 90 ° C. for 90 minutes, poured into water and acidified.

The product was extracted with ethyl acetate, dried over Na ₂ SO ₄ and evaporated to produce {[7-chloro-3- (2,3-difluorophenyl) -1,2-benzisoxazole- having a melting point of 183 to 187 ° C. 6-yl] oxy} acetic acid.

Example 35

3.17 g of hydroxylamine HCl is added to a 10 g (0.033 mol) solution of 2'-fluoro-4-methoxy-2,3-dichlorobenzophenone of Example 1a in 100 ml of pyridine. The mixture is refluxed for 64 hours. Pyridine is evaporated and the residue is partitioned between 5% HCl and ethyl acetate. The ethyl acetate extract is washed with water, dried over Na ₂ SO ₄ and evaporated to give 2,3-dichloro-4-methoxy 2'-fluorobenzophenone having a melting point of 195-197 ° C.

b. To a solution of 8 g of 2,3-dichloro-4-methoxy-2'-fluorobenzophenone oxime in 50 ml of DMF was added 0.67 g of NaH under nitrogen atmosphere. The mixture was stirred for 1 hour and water was added to give 7-chloro-3- (2-fluorophenyl) -6-methoxy-1,2-benzisoxazole having a melting point of 155 to 158 ° C, filtered and dried.

c. A solid mixture of 2 g of 7-chloro-3- (2-fluorophenyl) -6-methoxy-1,2-benzisooxazole and 20 g of pyridine hydrochloride is heated at 190 to 210 ° C. for 1 hour. The hot reaction mixture is poured into strongly stirred ice water. The mixture is made slightly acidic. Filtration and drying affords 7-chloro-6-hydroxy-3- (2-fluorophenyl) -1,2-benzisoxazole. Melting Point 140 ~ 141 ℃

d. The process of Example 34f was carried out using 7-chloro-6-hydroxy-3- (2-fluorophenyl) -1,2-benzisoxazole, and ethyl {[7-chloro-3- (2-fluoro Lophenyl) -1,2-benzisooxazol-6-yl] oxy} acetate.

Example 36

a. 7-Chloro-6-hydroxy-3- (2-fluorophenyl) -1, 2-benzisoxazole of Example 35C in 30 ml of DMF was added dropwise with stirring to 1.1 g of NaH in 30 ml of DMF. After 1 hour, 2.6 ml of ethyl-2-bromopropionate is added and the solution is stirred for 1.5 hours. After pouring the solution on ice, ethyl-2-{[7-chloro-3- (2-fluorophenyl) -1,2-benzisoxazol-9-yl] oxy} propionate having a melting point of 79 ° C. precipitates. Filtered and dried.

b. 6.8 g of ethyl-2-{[7-chloro-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} propionate was dissolved in 35 ml of methanol and 25 ml of 15% NaOH. Add. The suspension is heated for 2 hours. The reaction mixture was poured into ice, acidified with HCl, precipitated with solid, filtered and dried in vacuo to yield 2-{[7-chloro-3- (2-fluorophenyl) -1,2-benzisoocta having a melting point of 159 to 161 ° C. Sazol-3-yl] oxy} propionic acid is obtained.

Example 37

a. To a mixture of 21 g of 2,5-difluorobenzoyl chloride and 20.4 g of 2-chlororesorcinoldimethyl ether in 250 ml of 1,2-dichloroethane was added 15.7 g of AlCl ₃ at 5-10 ° C. in portions. The mixture is allowed to warm to room temperature and refluxed for 30 minutes. The mixture is poured into concentrated HCl and ice and stirred for about 1 hour. The product is extracted with ethyl acetate, dried over Na ₂ SO ₄ and evaporated to afford 3-chloro-2 ', 5'-difluoro-2-hydroxy-4-methoxybenzophenone having a melting point of 178 to 180 ° C.

b. A mixture of 28 g of 3-chloro-2'-5'-difluoro-2-hydroxy-4-methoxybenzophenone and 26 g of hydroxylamine HCl in 250 ml pyridine is refluxed for 3 hours. Pyridine is evaporated and the residue is partitioned between ethyl acetate and 5% HCl. The ethyl acetate extract is washed with water, dried over Na ₂ SO ₄ and evaporated to give a solid product that is a mixture of isomers. The solid is heated at 200 to 21 ° C. for about 30 to 45 minutes and recrystallized from toluene to give E-3-chloro-2 ′, 5′-difluoro-2-hydroxy-4-methoxy having a melting point of 209 to 210 ° C. Obtain benzophenol oxime.

c. 19 g of E-3-chloro-2 ', 5'-difluoro-2-hydroxy-4-methoxybenzophenone oxime is warmed at 60 ° C for 30 minutes. Upon cooling the mixture solidifies. The residue is partitioned between ethyl acetate and 10% NaHCO ₃ . Ethyl acetate extract was washed with water, dried over Na ₂ SO ₄ and evaporated to a melting point of 130 to 131 ° C. E-3-chloro-2 ', 5'-difluoro-2-hydroxy-4-methoxybenzophenone 0 Get acetyl oxime

d. To a 200 ml suspension of NaH / DMF under N ₂ atm is added dropwise E-3-chloro-2 ', 5'-difluoro-2-hydroxy-4-methoxybenzophenone 0-acetyloxime in 50 ml. The mixture is stirred for 30 minutes and water is added to give 7-chloro-3- (2,5-difluorophenyl) -6-methoxy-1,2-benzoisoxazole having a melting point of 198 to 199 ° C.

e. A mixture of 10 g of 7-chloro-3- (2,5-difluorophenyl) -6-methoxy-1,2-benzisooxazole and 40 g of pyridine HCl is heated at 200 ° C. for 45 minutes. The high thermal mixture is poured into strongly stirred ice water to precipitate the product. The product is filtered and dried to give 7-chloro-3- (2,5-difluorophenyl) -6-hydroxy-1,2-benzisoxazole having a melting point of 256 to 257 ° C.

f. 4.97 g of DMF and 200 ml of ethyl bromoacetate are added dropwise to a solution of 9.3 g of 7-chloro-3- (2,5-difluorophenyl) -6-hydroxy-1,2-benzisoxazole in 100 ml of DMF. . 15 ml of water 50% NaOH of this mixture is added. The mixture is stirred at 90 ° C. for 90 minutes, poured into water and acidified. The product is extracted with ethyl acetate, dried over and evaporated to afford {[7-chloro-3- (2,5-difluorophenyl) -1,2-benzisoxazol-6-yl) oxy]} acetic acid.

Example 38

a. Dissolve 2-chlororesorcinoldimethyl ether (3.4 g) in 20 ml and add TiCl ₄ (4.3 ml). Dichloromethyl ether (2.3 g) is added to this solution. After 30 minutes the reaction mixture is poured into H ₂ O and extracted with ether. Dry and evaporate to afford 3-chloro-2,4-dimethoxybenzaldehyde having a melting point of 10 < 7 >

b. 3-Chloro-2,4-dimethoxybenzaldehyde (2.75 g) was refluxed in 20 ml of dichloroethane containing 1.8 g of AlCl ₃ for 30 minutes. The reaction mixture is poured into H ₂ O and extracted with CH ₂ Cl ₂ . Evaporate and recrystallize with isopropanol to give 3-chloro-2-hydroxy-4-methoxybenzaldehyde having a melting point of 125 ° C.

c. 3-Chloro-2-hydroxy-4-methoxybenzaldehyde (1.48 g) is suspended in 15 mL of H ₂ O, hydroxylamine 0-sulfonyl acid (1.08 g) is added and 0.1 g Na ₂ SO ₄ is added. After 3 h additional 15 ml of H ₂ O are added. After a total of 4 hours the reaction mixture is treated with 8% NaHCO ₃ and extracted with ether. Evaporate and treat with hexane to give a solid product. Recrystallization from toluene / hexane yields 7-chloro-6-methoxy-1,2-benzisoxazole having a melting point of 115 to 11 ° C.

d. The method of Examples 34e and f was carried out with 7-chloro-6-methoxy-1,2-benzisoxazole to obtain {[7-chloro-1,2-benzisoxazol-6-yl] oxy} acetic acid. .

Example 39

a. 1.6 g of ferric chloride is slowly added to a solution of 1.7 g of 2-chlororesorcinol dimethyl ether and 2.08 g of 0-trifluoromethylbenzoyl chloride in 50 ml of 1,2-dichloroethane at 5 to 7 ° C. The mixture is raised to room temperature and left for 18 hours. The reaction mixture is refluxed for 30 minutes and poured into ice with 5% HCl. The aqueous layer is extracted with additional organic solvent. The combined organic extracts are washed with water, dried over Na ₂ SO ₄ and evaporated to afford 3-chloro-2-hydroxy-4-methoxy-2'-trifluoromethyl benzophenone having a melting point of 101 to 102 ° C.

b. The method described in the previous example (such as example 34) was carried out with 3-chloro-2-hydroxy-4-methoxy-2'-trifluoro methylenezophenone to give the corresponding oxime and cyclized oxime And {[7-chloro-3- (2-trifluoromethylphenyl) -1,2-benzisooxazol-6-yl] oxy} acetic acid is obtained as an acid.

Example 40

a. 10 g of 7-chloro-3- (2-fluorophenyl) -6-methoxy-1,2-benzisoxazole of Example 35b was dissolved in glacial acetic acid (800 ml) with stirring, and chlorine gas was slowly injected for 30 minutes. A solution containing a small amount of suspended starting material is obtained. The reaction mixture was stirred at room temperature for 18 hours, and then the reaction mixture was poured into ice water with stirring to give 5,7-dichloro-3- (2-fluorophenyl) -6-methoxy-1,2-benzisoocta having a melting point of 121 ° C. Soazole is precipitated.

b. 10 g of 5,7-dichloro-3- (2-fluorophenyl) -6-methoxy-1,2-benzisoxazole are mixed with 100 g pyridine hydrochloride and heated at 200 ° C. for 0.5 h. The hot melt is quickly poured into iced water with stirring and the resulting precipitate is filtered and dried in vacuo (64 ° C.) for 48 hours. The solid is recrystallized from toluene to give 5,7-dichloro-3- (2-fluoro-phenyl-6-hydroxy-1,2-benzisoxazole having a melting point of 194 to 196 ° C.

c. 1.4 g of NaH is suspended in 50 ml of DMF with stirring. A solution of 7.2 g of 5,7-dichloro-3- (2-fluorophenyl) -6-hydroxy-1,2-benzisoxazole in 50 ml of DMF was added dropwise. The solution is heated to 45 ° C. for 1 hour. Ethylbromoacetate (4.0 g) in 20 mL DMF was added dropwise and the reaction stirred at 40 ° C. for 2 hours.

The solution is poured into 1 l of water, stirred and extracted with ethyl acetate. The organic extract was washed with saturated NaCl solution and the solvent was removed in vacuo to yield ethyl {[5,7-dichloro-3- (2-fluorophenyl) -1,2-benzisoxazole-6- having a melting point of 105 to 106 캜. General] oxy} acetate is obtained.

d. 75% ethanol / water (700 mL) with ethyl {[5,7-dichloro-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} acetate stirring until solution Heat in.

20 ml of 50% solution is added to form a precipitate.

Continue heating and stirring to precipitate the solution which is stirred for 2.5 hours. Ethanol is evaporated in vacuo and the residue is acidified with 10% HCl. The precipitated solid was filtered and dried in vacuo to afford {[5,7-dichloro-3- (2-fluorophenyl) -1,2-benzisoxazol-6-yl] oxy} acetic acid with a melting point of 160 to 170 ° C. Get

Example 41

a. To a 50% DMF-dispersed NaH (1.0 g) suspension in 50 ml DMF, Example 35 ° C. 7-chloro-3- (2-fluorophenyl) -6-hydroxy-1,2-benzisoxazole in 50 ml DMF Add 5.0 g. The solution is stirred at room temperature for 1 hour, cooled to 5 ° C. and immediately 3.5 g of N, N-dimethylthio carbamoyl chloride are added all.

The reaction is slowly warmed up to 60 ° C. and stirred for 2.5 hours. The solution is poured into water and extracted with methylene chloride until the extract is colorless. The combined organic extracts are washed with 10% K ₂ CO ₃ and saturated NaCl. The solvent is removed in vacuo to give 7-chloro-6- (0-N, N-dimethylthiwacarbamyl) -3- (2-fluorophenyl) -1,2-benzisoxazole having a melting point of 153 to 154 ° C. .

b. 7-Chloro-6- (0-N, N-dimethylcarbamoyl) -3- (2-fluorophenyl) -1,2-benzisoxazole is heated under nitrogen at 205 ° C. for 45 minutes. The resulting cooled solid was recrystallized from ethyl acetate to give a prism colorless, 7-chloro-6- (S, N, N-dimethylcarbamyl) -3- (2-flophenyl) -1,2 with a melting point of 140 to 142 ° C. -Get benzisoxazole.

c. 2.0 g of 7-chloro-6- (SN, N-dimethylthiocarbamyl) -3- (2-fluorophenyl) -1,2-benzisoxazole- was dissolved in methanol and 25 ml of 15% water-soluble NaOH was added. do. The solution is refluxed for 3 hours. The reaction mixture is poured into a large amount of water and acidified with HCl to give 7-chloro-3- (2-fluorophenyl) -6-mercapto-1,2-benzisoxazole having a melting point of 125 to 129 ° C.

d. 3.2 g of 7-chloro-3- (2-fluorophenyl) -6-mercapto-1,2-benzisooxazole, 3.1 g K ₂ CO ₃ and 3.67 g ethylbromo acetate were added to 60 ml of DMF and stirred Warm at 50 ° C. for 2 hours. The solution is poured into 700 mL H ₂ O and extracted with ethyl acetate.

The combined organic extracts were dried over K ₂ CO ₃ and the solvent was removed in vacuo to afford ethyl {[7-chloro-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] thio} acetate. Get

e. Dissolve ethyl {[7-chloro-3- (2-fluorophenyl-1,2-benzisoxazol-6-yl] thio} acetate in 50 ml of ethanol while stirring and warming. Add 1 mL of water to give a solid precipitate, after 1 h ethanol is removed and the residue is acidified with HCl The precipitate is filtered and dried to produce {[5,7-dichloro-3- (2-fluoro) with a melting point of 165 ° C. Phenyl) -1,2-benzisooxazol-6-yl] -thio} acetic acid.

Example 42

a. To a solution of 0-fluorobenzoyl chloride (47.6 g) in 100 mL dichloromethane is partially added AlCl ₃ (40.0 g) over about 30 minutes. To the resulting dark solution was added dropwise a solution of 1-chloro-3,5-dimethoxybenzene (52.0 g) in 120 ml dichloromethane over 15 minutes. After stirring for 4 hours at room temperature, the mixture is poured into 1 L of ice-lime HCl solution and stirred for 30 minutes. The organic layers are combined, the oil is evaporated, dissolved in ether, washed with water, diluted with NaOH solution and water and dried over saturated NaCl or anhydrous MgSO ₄ . After filtration, the solvent is evaporated to give a solid which is purified by silica gel and eluted with dichloromethane to give 2-chloro-4,6-dimethoxy-2'-fluorobenzophenone having a melting point of 88 to 92 캜.

b. To a solution of 2-chloro-4,6-dimethoxy-2'-fluorobenzophenone (33 g) in 150 mL of 150 mL dichloroethane was partially added AlCl ₃ (15 g) over 15 minutes. After stirring under reflux at 90 ° C. for 3 hours, the mixture is cooled, poured into 1 L of ice-dichloric acid solution, stirred for 30 minutes and extracted with ether. The ether / dichloroethane solution is washed with water, dried (saturated NaCl, anhydrous HgSO ₄ ) and filtered.

After filtration the solvent is evaporated to afford 2-chloro-2'-fluoro-6-hydroxy-4-methoxybenzophenone having a melting point of 85 to 90 ° C.

c. To 125 ml of pyridine is added 2-chloro-2'-fluoro-6-hydroxy-4-methoxybenzophenone (28.5 g) and hydroxylamine hydrochloride (14 g). After reflux stirring at 120 ° C. for 3 hours, the mixture is cooled and pyridine is evaporated to yield a yellow semisolid. The solid is dissolved in ether, washed with water and dried (saturated NaCl, anhydrous MgSO ₄ ).

After filtration the solvent is evaporated and treated with petroleum ether to give Z-2-chloro-2'-fluoro-6-hydroxy-4-methoxybenzophenone oxime having a solidified melting point of 130 to 140 ° C.

d. When Z-2-chloro-2'-fluoro-6-hydroxy-4-methoxybenzophenone oxime is reacted with acetic anhydride as described in Example 29 ° C, E-2-chloro-2'-fluoro -6-hydroxy-4-methoxybenzophenone 0-acetyloxime is obtained.

e. To the NaH suspension in 20 mL DMF is added E-2-chloro-2'-fluoro-6-hydroxy-4-methoxybenzophenone-0-acetyloxime in mL. After stirring for 2 hours at room temperature, the mixture is poured into 1 l of ice water, stirred for 30 minutes and the precipitate collected. The precipitate is washed with water and dried to give 4-chloro-3- (2-fluorophenyl) -6-methoxy-1,2-benzisoxazole having a melting point of 113 to 115 ° C.

f. Melting point 172 to 174 ° C. using 4-chloro-3- (2-fluorophenyl) -6-methoxy-1,2-benzisoxazole in the process described in the foregoing examples such as Examples 19d and e. {[4-chloro-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} acetic acid is obtained.

Example 43

a. AlCl ₃ (22 g) was added in portions to a stirred solution of phenacetylchloric acid in 150 mL of carbon dioxide over 30 minutes, followed by a 2,3-dichloroanisol solution in 50 mL of carbon dioxide. After stirring for 3 hours at reflux (50 ° C.), the mixture is cooled and AlCl ₃ (22 g) is added and the mixture is stirred at reflux for 2 hours. The mixture is cooled, poured into cold 15% HCl solution, stirred for 30 minutes and extracted with ethyl acetate / ethyl ether. The organic extract is washed with water and dried (saturated NaCl, anhydrous MgSO ₄ ). After filtration, the solvent is evaporated to give 2,3-dichloro-4-phenacetyl having a melting point of 173 to 180 ° C.

b. 2,3-dichloro-4-phenacetylphenol is reacted with hydroxylamine hydrochloride in pyridine in the manner generally described in the above examples to give 2,3-dichloro-4-phenacetylphenol oxime.

c. To a NaH (2.54 g) suspension in 10 mL of anhydrous DMF is added a 2,3-dichloro-4-phenacetylphenol oxime (6.3 g) solution in 25 mL anhydrous DMF. After stirring at 80 ° C. for 2 hours, the mixture is cooled and a solution of ethyl bromoacetate (4.2 g) in 10 ml anhydrous DMF is added and stirred at room temperature for 30 minutes and at 60 ° C. for 30 minutes. After cooling, the mixture is poured into 500 ml of water, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer is washed with water and dried (saturated NaCl, anhydrous MgSO ₄ ).

After filtration the solvent is evaporated to give an oil from which ethyl {[3-benzyl-7-chloro-1,2-benz isoxoxazol-6-yl] oxy} acetate having a melting point of 120 to 122 ° C.

d. Ethyl {[3-benzyl-7-chloro-1,2-benzisoxazol-6-yl] oxy} acetate (25.0 g) was added to 650 mL of anhydrous ethanol followed by 50% NaOH solution (30 mL). The mixture was stirred at reflux (80 ° C) for 1 hour, 500 ml of water was added, the pH was adjusted to 1 with concentrated hydrochloric acid, and diluted again with 1 L of water. The precipitate obtained is collected, washed with water and dissolved in dichloromethane. The dichloromethane solution is washed with water and dried. (Saturated NaCl, anhydrous MgSO ₄ ).

After filtration, the solvent is evaporated to yield {[3-benzyl-7-chloro-1,2-benzisoxazol-6-yl) -oxy]} acetic acid having a melting point of 147 to 153 ° C.

Example 44

a. The Friedel-Craft reaction of Example 43 was repeated with 2,3-dichloroanizol, -1-naphthylchloride and AlCl ₃ (2,3-dichloro-4-hydroxyphenyl) (1-naphthyl) methanone Get

b. 9.87 g of hydroxylamine hydrochloride is added to a 22.48 g solution of (2,3-dichloro-4-hydroxy-phenyl)-(1-naphthyl) methanone in 150 ml of pyridine. The mixture is refluxed for about 64 hours. Additional hydroxylamine HCl (9.87 g) is added and the reaction mixture is refluxed for 18 hours. Pyridine is evaporated in vacuo and the residue is partitioned between 5% HCl and ethyl acetate. The ethyl acetate extract is washed with water, dried over NaSO ₄ and evaporated to give a semisolid product. This product is dissolved in about 100 ml of ethyl acetate and passed through a charcoal column. The filtrate was evaporated and treated with hexane-ether to have a melting point of 145 to 160 ° C. (2,3-dichloro-4-hydroxyphenyl the filtrate was evaporated and treated with hexane-ether to have a melting point of 145 to 160 ° C. (2,3 -Dichloro-4-hydroxyphenyl- (1-naphthyl) methanone oxime is obtained.

c. To a 3 g solution of (2,3-dichloro-4-hydroxyphenyl)-(1-naphthyl) methanone oxime in 25 ml of DMF was added 0.54 g of NaH under N ₂ . The mixture is heated for 1 h 20 min until an internal temperature of 100 ° C.

The mixture was stirred for 18 hours, water was added and the product was washed with ethyl acetate extract with water, dried over Na ₂ SO ₄ and evaporated to ethyl {[7-chloro-3- (1-naphthyl) with a melting point of 75 to 85 ° C. -1,2-benz isoxoxazol-6-yl] oxy} -acetate.

d. 1.85 g of ethyl {[7-chloro-3- (1-naphthyl) -1,2-benzisoxazol-6-yl] oxy} acetate, 100 ml of ethanol and 2 ml of 50% NaOH were refluxed for 1 hour. do. 100 ml of water is added to the hot mixture followed by sufficient concentrated HCl to allow the mixture to acidify.

The reaction mixture is stirred and cooled to form a precipitate. Ethanol was evaporated in vacuo and {[7-chloro-3- (1-naphthyl) -1,2-benzisoxazol-6-yl] oxy} acetic acid having a melting point of 172 to 174 ° C. was filtered off and dried in vacuo. Let's do it.

Example 45

a. The Friedel-Crafts reaction described in the above examples was repeated with 2,3-dichloroanizol, 3-fluorobenzoyl chloride and AlCl ₃ , yielding 2,3-dichloro-4-hydroxy-3'-fluorobenzope Get the paddy.

b. 1.58 g of hydroxyl amine chloride is added to a 5 g solution of 2,3-dichloro-4-hydroxy-3'-fluoro-benzophenone in 50 ml of pyridine. The mixture is refluxed for 18 hours. Pyridine is evaporated in vacuo and the residue is partitioned between 5% HCl and ethyl acetate. Ethyl acetate is washed with water, dried over Na ₂ SO ₄ and evaporated to afford 2,3-dichloro-4-hydroxy-3-fluoro benzophenone oxime having a melting point of 178 to 185 ° C. as a mixture of isomers.

c. To a 3 g solution of 2,3-dichloro-4-hydroxy-3'-fluorobenzophenone oxime in 20 ml of DMF was added 0.25 g of NaH under N ₂ atmosphere. The mixture is stirred for 18 hours. The mixture is heated to 100 ° C. for 1 hour. The reaction mixture is poured into ice water to give 7-chloro-3- (3-fluorophenyl) -6-methoxy-1,2-benzisoxazole having a melting point of 149 to 150 ° C.

d. A solid mixture of 14.47 g of 7-chloro-3- (3-fluorophenyl) -6-methoxy-1,2-benzisooxazole and 58 g of pyridine is heated at 190 to 200 ° C. for 1 hour. The hot mixture is poured into ice-water with vigorous stirring and filtered to collect 7-chloro-6-hydroxy-3- (3-fluorophenyl) -1,2-benzisoxazole and washed well with H ₂ O.

e. A 10.2 g solution of 7-chloro-6-hydroxy-3- (3-fluorophenyl) -1,2-benzisoxazole is added to a 1.3 g mixture of NaH in 25 ml of DMF. A solution of 6.68 g of ethylbromo acetate in 25 ml of DMF is added and the mixture is stirred for 2 hours 30 minutes. 10 ml 50% NaOH, 175 ml H ₂ O and 30 ml DMF are added to the reaction mixture and then heated at 80-85 ° C. for 1 hour. The mixture was acidified with concentrated hydrochloric acid, water was added and filtered to afford {[7-chloro-3- (3-fluorophenyl) -1,2-benzisoxazol-6-yl] oxy} acetic acid having a melting point of 205 to 209 ° C. Get

Example 46

a. Chlorine gas was added to a solution of 1.0 g of 4-chloro-3- (0-fluorophenyl (-6-methoxy-1,2-benzisoxazole) in Example 42e in 50 ml glacial acetic acid (the solution was added for 5 minutes. Purify).

After stirring at room temperature for 1 hour, the mixture is poured into 500 ml water, stirred for 15 minutes and the precipitate obtained is extracted with ether / ethyl acetate. The organic layer was washed with water, dried (saturated NaCl, anhydrous MgSO ₄ ), the solvent was evaporated after filtration and 3- (0-fluorophenyl-6-methoxy-4,5,7-trichloro- with a melting point of 120 to 140 ° C. Obtain 1,2-benzisoxazole.

b. The process of Examples 19d and e was carried out with 3- (0-fluorophenyl) -6-methoxy-4,5,7-trichloro-1,2-benzisoxazole, where {[4,5,7- Trichloro-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} acetic acid is obtained.

Example 47

10 g of 7-chloro-6-hydroxy-3- (2-fluorophenyl-1,2-benzisoxazole of Example 32C is dissolved in 70 mL of DMF and 7.86 g of K ₂ CO _{3 is} added with stirring.

3.6 ml of chloroacetonitrile are added and the mixture is stirred at room temperature for 0.5 hours and then raised to 55 ° C. for 2 hours. Stirring at room temperature is continued for 15 hours, 1.5 ml of chloroacetonitrile are added and the reaction is stirred at 50 ° C. for 6 hours. This is obtained by pouring a large amount of ice / water and filtering the precipitated {[7-chloro-3- (2-fluorophenyl) -1,2benzisoxazol-6-yl] oxy} -acetonitrile.

Example 48

7-Chloro-6-hydroxy-3- (2-fluorophenyl) -1,2-benzisoxazole in 75 ml of DMF is added to a 3.0 g suspension in 75 ml of DMF.

After 1 hour at room temperature 16.7 ml of ethyl 2-bromoisobutylate is added. After 72 h at 50 ° C. the mixture is taken / poured into HCl and extracted with CH ₂ Cl ₂ and the organic layer is washed with 5% K ₂ CO ₃ followed by saturated NaCl. It is dried over MgSO ₄ , filtered and evaporated to a brown oil. The oil was distilled off under reduced pressure to remove unreacted ethyl 2-bromoisobutylate and the residue was treated with ether / petroleum ether, filtered and the mother liquor was evaporated to yield and distill the oil (200 ° C., 1 mm). ) Ethyl-2-{[7-chloro-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} -2-methylpropionate.

Example 49

a. To a mixture of 46 g of 4-chloro-2-fluorobenzoyl chloride and 38.9 g of dichloroanizol in 150 ml of 1,2-dichloroethane was slowly added 32 g of AlCl. The mixture is warmed to 40 ° C. with vigorous gasification. Pour the mixture into concentrated HCl and ice. The organic layer is separated and the aqueous layer is extracted with additional organic solvent. The combined organic extracts are washed with water, dried over Na ₂ SO ₄ and evaporated. The crude product is treated with hexane to give 2,3-dichloro-4-methoxy-4-chloro-2'-fluoro-benzophenone.

Re-crystallize the sample from EtOH. Melting Point 115 ~ 16 ℃

b. 2,3-dichloro-4-methoxy-4'-chloro-2'-fluorobenzophenone was replaced with 2,3-dichloro-4-methoxy-4'-chloro-2'- in the same manner as in Example 20b. Convert to fluorobenzophenone oxime.

c. To a mixture of 2.24 g of NaH in 100 ml of DMF is added dropwise 2,3-dichloro-4-methoxy-4'-chloro-2'-fluorobenzophenone oxime in 100 ml of DMF. After dropping, the mixture is stirred for 1 hour and the reaction mixture is poured into ice water. The precipitated product was filtered and dried to give a mixture of isomers and chromatographed on silica gel using 50% hexane and 50% toluene as eluent to give 7-chloro-3- (4-chloro-2-fluorine having a melting point of 193 to 194 ° C. Rophenyl) -6-methoxy-1,2-benzisoxazole is obtained.

d. A solid mixture of 5.4 g of 7-chloro-3- (4-chloro-2-fluorophenyl) -6-methoxy-1,2-benzisooxazole and 22.4 g of pyridine HCl is heated at 200 ° C. for 2 hours. The reaction mixture is poured into iced water with vigorous stirring to give the demethylated product.

To a solution of 3.9 g of demethylated product in 40 mL was added 1.9 g of K ₂ CO ₃ and 2.3 g of ethylbromoacetate. The reaction is warmed to 60 ° C. for 2 hours and left for 18 hours. 100 ml of water and 10 ml of 50% NaOH are added to the reaction mixture. The mixture was heated at 90 ° C. for 90 minutes and the reaction mixture was poured into water, acidified, extracted with ethyl acetate, dried and evaporated to produce {[7-chloro-3- (4-chloro-2-fluoro) having a melting point of 226 to 227 ° C. Lophenyl) -1,2-benzisoxazol-6-yl] oxy} acetic acid.

Example 50

Ethyl-2- [7-chloro-3- in Example 1d in 200 ml of ether containing sufficient amount of tetrahydrofuran to be solution in a suspension of 9 g of little aluminum hydride (90%) in 100 ml anhydrous ether. A 10 g solution of (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} acetate is added. The reaction mixture is stirred at room temperature for 2 hours and refluxed for 1 hour. And it is a _{0.9㎖ H 2 O, 0.9㎖ 15%} NaOH ( and 2.7㎖ H ₂ O to the reaction mixture in the stirred suspension was filtered and the filtrate was concentrated melting point 112 ℃ 2 -. {[7- Chloro-3 (2-fluorophenyl) -1,2-benzisoxazol-6-yl] oxy} ethanol is obtained.

Example 51

4.9 g of ethyl-{[7-chloro-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} -2-methylpropionate of Example 51 in 35 ml of methanol It is dissolved and 30 ml of 15% NaOH solution is added thereto. The suspension is refluxed for 4 hours, poured into ice water and acidified to form an oily precipitate. This precipitate is extracted with ether and the ether extract is washed with 10% NaHCO ₃ .

The basic extract was acidified with concentrated HCl and cooled, followed by 2-{[7-chloro-3- (2-fluorophenyl) -1,2-benzisoxazol-6-yl] oxy} -2- Obtain methyl propionic acid.

Example 52

3.35 g NaN ₃ and 2.25 g AlCl ₃ are stirred in 50 mL THF at reflux for 0.5 h. A 5 g solution of {[7-chloro-3- (2-fluorophenyl) -1,2-benzisooxazol-6-yl] oxy} acetonitrile in Example 47 in 50 mL THF was added and the reaction mixture was added for about 120 hours. Stir while refluxing. Water is added to the reaction mixture and the solvent is removed. The residue is treated with ash HCl and extracted with CHCl ₃ . Extracting the chloroform solution with 15% NaOH forms a precipitate which is filtered off, dissolved in hot water and acidified to 7-chloro-3- (2-fluorophenyl) -6-{[5-tetra with a melting point of 198 to 200 ° C. Zolylmethyl] oxy} -1,2-benzisoxazole is obtained.

Claims (1)

Reacting a compound of formula (a) with a compound of formula (b), followed by hydrolysis, oxidation,

or

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

In the above 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,

or

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, trifluoro Methyl, 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 O 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.