NO783908L - 1,2-BENZISOXOZOLOXYDEACIC ACIDS AND RELATED COMPOSITIONS AND PROCEDURES FOR THEIR PREPARATION - Google Patents

Description

Process for the production of 1,2-benziSoxazoloxyacetic acids and.

derivatives.

The invention relates to 1,2-benzoxazoloxyacetic acids and derivatives which are effective as diuretics, uricosors and antihypertensives, methods for their preparation,

and pharmaceutical compositions containing such compounds as active substances.

The compounds produced according to the invention have the general formula

wherein R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, tricycloalkyl, cycloalkylloweralkyl, cycloalkenylloweralkyl, haftyl, thienyl, furyl, pyryl, pyridyl, or pyridyl-N-oxide; R"*" means a free or esterified carboxyl group with from 1 to 8 carbon atoms, -COZ, -CON^o , -CH9OH-, -CHO, -CHfOR9) -CN,

2 3 4-

R , R 1 and R 2 are the same or different and each represents hydrogen, halogen or lower alkyl; X represents hydrogen, halogen, lower alkyl, lower alkylthio, lower alkyloxy, hydroxy, trifluoromethyl, nitro, araino or acylamino; R 2 , R 2 , R 2 , R0g R^ are the same or different and each can represent hydrogen or lower alkyl; A and A'

are the same or different and can mean 0 or S; Z is chlorine,

bromine or fluorine; and m and n are the same or different and can each represent an integer 1, 2 or 3. Within the scope of the invention are also the physiologically tolerable salts of the above-mentioned compounds.

Some compounds within the scope of the invention have greater pharmaceutical activity than others. Some of the latter, such as those in which R"*" means an esterified carboxyl group CN, CE^OH

or CHO are intermediates for the production of the more active compounds. As indicated above, R can be a heterocyclic group such as thienyl, furyl, pyrryl or pyridyl, as well as an aliphatic or carboxyl group. A preferred compound group are those in which R means an aromatic ring, especially phenylrin, with an ortho-substituent, especially a halogen atom, preferably fluorine in relation to the position of the neighboring ring structure. A further preferred group of compounds are those in which R"*"

is a carboxyl group which may be esterified with a lower alkoxy or benzyl group. Also preferred are compounds in which A

and A' each represent' oxygen.

In the foregoing and the following, the following terms have certain meanings: "thienyl, furyl, pyrryl or pyridyl" means unsubstituted and substituted groups in which the substituents are halogen or lower alkyl;

"lower" means from 1 to 4 carbon atoms;

"cycloalkyl" means a saturated carbocyclic ring

from 3" to 8 carbon atoms;

"bicyclo- and tricycloalkyl", respectively, means

bi- and .tricarboxyl ring system containing from 7 "to 10 carbon atoms; and

"cycloalkenyl" means an unsaturated carbocyclic ring having from 5" to 8 carbon atoms.

The physiologically tolerable salts of the compounds according to the invention include those formed with an alkali or alkaline earth metal salt or with a non-toxic organic base such as ethanolamine, diethylamine or N-methylglucamine.

The compounds according to the invention can be prepared by means of one of the following multi-step methods, in which, unless otherwise indicated, R, R to R..':, X, m and n are as indicated above; Y is chlorine or fluorine and at room temperature means from 20-25°C.

a-^. A phenol or alkoxybenzene of formula

in which R"^ means hydrogen or lower alkyl, is reacted under Friedel-Crafts conditions with an acid halide of the formula

RCOZ

wherein R has the above meaning and Z means chlorine, bromine or fluorine for the preparation of compounds of formula

A preferred embodiment includes use

of 1,2-dichloroethane as a solvent and aluminum chloride as a Friedel-Crafts catalyst.

aQ. A compound of formula R-H

where R means

v.

, thienyl, pyrryl or furyl, are reacted. under Friedel-Crafts conditions with an acid halide of formula wherein Y, Z and R<10>have the above meaning in the sequence A, to form compounds of formula

A preferred embodiment includes the use of 1,2-dichloroethane as solvent and aluminum chloride as Friedel-Crafts catalyst.

aq. A compound with formula

in which R"^ means lower alkyl, is reacted with a compound with

formula R-MgZ or R-Li where R is not hydrogen followed by hydrolysis to form a compound of formula III a.

Preferred conditions include the use of tetrahydrofuran as solvent at a temperature of -70°C to room temperature.

aA. A compound of formula Illa, in which R means hydrogen and R means lower alkyl is converted according to the above-mentioned alternative a^) to a compound of formula

where R does not mean hydrogen.

a^. A compound prepared according to alternative a^) is oxidized to provide a compound of formula IIIa, in which R does not mean hydrogen. One such method involves the use of chromium trioxide in glacial acetic acid.

a^. A compound of formula III or IIIa, in which R means lower alkyl, can be dealkylated by methods known per se to obtain a corresponding compound III or IIIa, in which R~^ means hydrogen. One such method involves treatment with aluminum chloride in benzene.

sltj. A compound of formula III or IIIa is treated with hydroxylamine hydrochloride in a solvent such as pyridine to form the compound of formula

ag. A compound of formula VI is cyclized by treatment with a base in the presence of a solvent at a temperature from room temperature to the reflux temperature of the reaction mixture to form a corresponding bicyclic compound of formula

A preferred method for cyclization uses the base sodium hydride in solvent dimethylformamide-benzene mixture at reflux temperature.

a^. A diphenol or dialkoxybenzene of formula

2 3 Æ 10 in which R , RJ , IT" and R have the above-mentioned meaning are reacted according to the above-mentioned method a-^) to form a compound of formula a1Q. A compound of formula R-H in which R means

thienyl, pyrryl or furyl react under Friedel-

Craft's conditions with an acid halide of formula

9 QA] 0

wherein Z and R , RJ, R^" and R have the above meanings to form a compound of formula

a-Q. A compound of formula in which R"^ means lower alkyl is reacted according to alternative a^) to form a corresponding compound of formula XI. a-i 9 . A compound of formula XI, in which R means 10 hydrogen and R means lower alkyl is reacted according to alternative a^) to form a compound of formula wherein R is different from hydrogen a-j^« A compound prepared according to alternative a-^2 is oxidized to form a compound of formula XI wherein R is different from hydrogen This involves the use of chromium trioxide in glacial acetic acid. a-^- A compound of formula XI, in which R^~ ® means lower alkyl can be selectively dealkylated to form a compound corresponding to compound V, in which R"^ in the ortho position to the carbonyl group is hydrogen or fully dialkylated to form a compound as indicated by formula XI, in which both formulas R^^groups mean hydrogen. The above-mentioned method can be carried out with the help of one equivalent of aluminum chloride, the latter with two equivalents, both method alternatives are carried out in such solvents as benzene. a-^. A compound of formula XI, in which at least R"^ which is ortho to the carbonyl group' is hydrogen, is treated according to alternative g) to form a compound of formula a-^g. A compound of formula XIV is acylated to form a connection with formula

wherein R"^ means hydrogen, lower alkyl or acetyl.

A preferred method in which acetic anhydride is used as reaction component and solvent.

Shut up. A compound of formula XV is cyclized by treatment with a base in the presence of the solvent at a temperature from room temperature to the reflux temperature of the reaction mixture to form the corresponding bicyclic compound

a-^g. A compound of formula VII, in which R₂₂ is lower alkyl, can be dealkylated to provide the corresponding compound, in which R₂₂ ₂ is hydrogen. A preferred method is treatment with pyridine hydrochloride at 170-200°C.

a1Q. A compound of formula VII, where R<10>' means

^ 11 hydrogen reacts with a compound of formula Z-C-R, in which R

R?K

means a free or esterified carboxyl group, CN, CHoOH or CH(OR27)2 and Ry means lower alkyl in the presence of a base or solvent to form a compound of formula

wherein R has the above meaning.

Sodium hydride is preferably used as base and dimethylformamide as solvent.

b-^. A phenoxyalkanoic acid ester or nitrile of formula

is reacted according to the above-mentioned alternative a-^) to form a compound of formula

In a preferred embodiment, aluminum chloride is used as. catalyst and carbon disulphide as solvent.

b0. A compound of formula III or Illa, wherein

i0

R means hydrogen, is converted according to the above-mentioned alternative a-^q into a compound with formula

wherein R"*" means a free or esterified carboxyl group, CN, CH2OH or CH(OR<9>)2. b^• A compound of formula XVIII or XIX is treated according to the above-mentioned alternative a^ to form a compound of formula b^. Compounds of formula XIX are cyclized according to the above-mentioned alternative ag) to form corresponding compounds according to the invention with formula Ia. c-^. A compound of formula IX in which R^® means H is treated according to the above-mentioned alternative a-^q) to form compounds of formula Cg. A compound of formula XX is treated according to alternative a^) to form a compound of formula c^. A compound of formula XXII is treated according to alternative a-^g) to form a compound of formula c^. A compound of formula XXII is cyclized according to alternative a]_y) before forming a compound of formula Ia. d-^. A compound of formula XI, prepared according to alternative a-^)) in which R is hydrogen is treated with hydroxylamine-o-sulfonic acid in a solvent such as water to form a compound of formula 711. day A compound according to XX, in which R is hydrogen, is treated according to the above-mentioned method BB to form a compound of formula Ia. e-^. A compound of formula VII, wherein R^ is hydrogen and X is other than hydroxy or amino, is treated with dialkylthiocarbamoyl halide in the presence of a base to form a compound with formula

7 o

wherein R' and R are lower alkyl.

A preferred method comprises the use of dimethylthiocarbamoyl chloride in dimethylformamide as solvent and sodium hydride as base.

e.g. A compound of formula XXIII is thermally converted to a compound of formula

by heating as melt.

. A compound of formula XXIV is hydrolyzed by a method known per se to form a compound of formula

In this method, diluted sodium hydroxide can be used as a hydrolysing agent.

e^. A compound of formula XXV is treated according to the method according to alternative a-j_q) to form a compound of formula

f-^. A compound of formula as indicated in alternative a-^) > where R^ means lower alkyl and X is different from amino or hydroxyl, is treated successively according to alternatives e-^), e^) and e^) to form a compound of formula f2 - A compound of formula XXVII is treated successively according to alternatives a^) , a-^g) , a-^y) and a-^g) to form a compound of formula f^. A compound of formula XXVIII is treated according to alternatives a-^q) to give a compound of formula g-p A compound of formula XXVIII is treated successively according to alternatives e-^) , e^) and e^) to form compounds of formula g2'A compound of formula XXIX is treated according to alternative a-^q) to give a compound of formula

h. A compound produced according to the invention with formula Ia, Ib, Ic or Id, in which R"*" means a carboxylic acid ester or CN is converted into a corresponding compound, in which R<1> means COOH.

This can also be carried out by hydrolysis with a base such as sodium hydroxide.

i. A compound according to the invention with formula

1 / 9\

Ia, Ib, Ic or Id, wherein R means CR[ 0RJ) o is converted to a

1d-

corresponding compound in which R means CHO.

This can be done with hydrolysis using dilute mineral acid.

2 3

j. A compound of formula Ia, where X, R, R

and R^" is different from lower alkyl, wherein R"*" means CELOH or as indicated in alternative i), wherein R i means CHO is converted to a corresponding compound, wherein R"*" means COOH.

The oxidation can be carried out with potassium permanganate.

1. A compound according to the invention with formula I

in which R"*" means COOH, is directly transferred to a compound, in which R"*" means COZ, on treatment with SOZ^.

m. A compound with formula

wherein R"'" denotes COZ. transferred to the corresponding connection. wherein R^" means

— ____ _ — — _ . — — __ — _ j

CONHOH or CONHC-NH? at treatment trc-

MTI

/IL/ 1M11

respectively with N o, NH90H or NH„C-NH5 in the presence or absence

NH

of an acid scavenger.

n. A compound according to the invention with formula

in which R means CN, is converted to the corresponding compound in which R"*" means

This can take place during treatment

with HN^in dimethylformamide.

o. A compound with formula

wherein R1 means COZ,

or an unspecified group which can be transferred by hydrolysis to a COOH group is transferred to a compound according to the invention in which R"^~ means COOH by means of an acid or basic hydrolysis.

p. A compound with formula

in which R^ means COOH is converted to a salt by treatment in a suitable solvent with a corresponding organic or alkaline/ and alkaline earth base.

q. A compound with formula

wherein is lower alkyl and X is different from hydroxy or amino, is treated with a strong base followed by electrophilic treatment to form the compound of formula

p

wherein R means halogen or lower alkyl. A preferred base is n-butyllithium and preferred electrophiles include bromine, iodine, chlorine, N-halogensuccinimide and alkyl halides.

r. A compound with formula

in which R 2 means hydrogen or halogen, R 10 means hydrogen or lower alkyl, R means <C> and X means halogen, react with

x m

elemental halogen in a solvent such as acetic acid to form a compound of formula

wherein R 1 and R 2 can be halogen. s. A compound according to the invention of formula in which m means 1 or 2 and X is different from NCv, is nitrated by treatment with nitric acid in acetic acid to form a corresponding compound of formula t. A compound according to the invention of formula in which R means

and X means alkoxy is dealkylated to form one corresponding compound according to the invention in which X means hydroxy.

An alternative can be carried out with boron tribromide.

u. A compound as stated above for starting material with alternative t) except X means nitro is reduced by a method known per se to form the corresponding compound

wherein X means amino. One method involves the use of iron filings in aqueous ethanolic hydrochloric acid. v. A compound as indicated as the starting method for alternative t), except when X means amino, is acylated by a method known per se to form a corresponding compound according to the invention, in which X means acylamino. The acylation is preferably carried out with an anhydride. w. A compound of VII, wherein R is pyridyl is reacted with an oxidizing substance to form the corresponding compound of formula VII, wherein R is

, while

3-chloroperbenzoic acid is used as the preferred oxidizing agent.

It is clear that the reaction time and precise reaction conditions for the above method alternative are dependent on the particular reaction components and solvents used.

All starting materials mentioned above are either known compounds or can be easily prepared by known methods from readily available substances.

For example, an output method is applicable

in alternatives ag), a^), a^) , a-^) and a-^) to form a compound according to the invention in which the O-CHg-R^ group occupies the 5-position of a 2-chloro-5- methoxybenzoic acid. Such a compound can be prepared from the readily available 2-chloro-5-nitroaniline via methods known per se, e.g. diazothiazine and treatment with CuCN to form 2-chloro-5-nitrobenzonitrile; followed by reduction with iron filings in aqueous ethanolic hydrochloric acid to 5-amino-2-chlorobenzonitrile; followed by diazotization to form 2-chloro-5-hydroxybenzonitrile; followed by methylation with dimethyl sulfate to form 2-chloro-5-methoxy-benzonitrile; followed by hydrolysis to form 2-chloro-5-methoxybenzoic acid. It is clear that other necessary substituted alkoxy-ortho-halogenobenzoic acids, alkoxy(hydroxy)ortho-hydroxy-(hydroxy)benzoic acids, -aldehydes, and -nitriles, and various halo-alkoxy(hydroxy)-, and dihydroxy(hydroxy)-benzenes can be easily obtained by corresponding reactions or common known reactions.

As a compound according to the invention and usable as a diuretic. Diuretic activity is measured in mice by a method described by CM. Kagawa and M.J. 'Kalm, Arch. Intern, Pharmacodyn. 137, 241 (19&2). The compounds are dosed orally to

a group of 6 mice and the mean volume of urine excreted is compared to (divided by) the mean volume of urine excreted by a positive control group of 6 mice dosed orally with 1000 mg/kg urea, a known diuretic substance. The resulting compound/urea ratio is if greater than 1 indicative of diuretic activity. The diuretic activity in this test with some of the compounds according to the invention and a thienylic acid and ethacrylic acid, standard diuretics, is given in table 1.

Such an effect is exerted when compounds according to the invention are administered to a patient who requires average treatment at an oral, parenteral or intravenous dose of from 0.1-500 mg/kg of body weight per day, preferably 1.0-200 mg/kg of body weight per day.

The compounds produced according to the invention

are also useful as antihypertensive agents due to their ability to lower blood pressure. Antihypertensiveness is measured in its spontaneous hypertensive degree by the indirect tail docking method discussed by A. Schwartz, Ed., Methods in Pharmacology,

Vol. I, page 135>Appleton-Cenury-Crofts, New York, New York 1971- In this method, a group of 5 animals is treated orally with the compound for 3 days in relation to a control group of the same number. The drop in blood pressure is measured on the 3rd day after administration. The antihypertensive activity is expressed as mm increase in the main arterial blood pressure in the sample of some compounds according to the invention as indicated in Table II.

Such an effect is exerted when the compound according to the invention is administered to a patient who undergoes average treatment by oral, parenteral or intravenous dose from 0.1-500 mg/kg body weight per day. Preferably, the range is within the range of 1.0-200 mg/kg body weight per day.

The compounds prepared according to the invention are further useful as uricosuric substances due to their property of causing increased uric acid excretion in mammals. Uricosur activity is measured by a method where groups

of six Wistar rats are dosed orally with the test compound suspended or dissolved in a sufficiently distilled water so that the dose volume corresponds to 25 ml/kg. A corresponding control group is dosed with just water in the same amount. The urine is collected over five hours and the uric acid content is determined using an Abbott Biochromatic Analyzer which uses "Uricosquarit". The result for each group is expressed as average mg of uric acid excreted/kg rat. Treated groups are compared with control groups for statistical analysis. On average, values of 2.5 mg U.A./kg or higher are considered to indicate uricosur activity. Representative data are given in Table III.

Such an effect, in addition, when a compound produced according to the invention is administered to a patient who requires average treatment at an oral, parenteral or intravenous dose from 0.1-500 mg/kg body weight per day. Preferred range includes 1.0-200 mg/kg body weight per day.

The compounds produced according to the invention

can be used with advantage as diuretics and uricosuria. As is well known, many patients have an increase in the uric acid concentration in the blood during treatment with the most well-known and marked diuretics. Elevated uric acid levels are a very serious problem in patients with severe arthritis. In addition, elevated uric acid levels are considered a risk factor in cardiovascular diseases. Consequently, the properties of the compounds produced according to the invention to produce diuresis and increase uric acid excretion must be a very strong advantage.

The compounds according to the invention comprise: [/7-chloro-3-(1-buten-2-yl)-1,2-benzisoxazol-6-yl7oxy-acetic acid; N -chloro-3-ethyl-1,2-benzisoxazol-6-yl)oxy/acetic acid; (T7-Chloro-3-cyclopropyl-1>2-benzisoxazol-6-yl)oxy7-acetic acid; (1"7-Chloro-3-cyclohexyl-1,2-benzisoxazol-6-yl)oxy_7-acetic acid; 'acetic acid; [/3~ (1-adamantyl)-7-chloro-1,2-benzisoxazol-6-yl7oxy}-acetic acid; ^/7-chloro-3-(1-cyclohexen-1-yl)-1, 2-benzisoxazol-6-yl7:>-'ox£}-acetic acid;

((7-Chloro-3-cyclopropylmethyl-1,2-benzisoxazol-6-yl)-oxy-7-acetic acid;

(7-Chloro-3-cyclopentylmethyl-1,2-benzisoxazol-6-yl)oxyacetic acid; |</7>-Chloro-3-(2-c<y>chloro<p>entene-1-meth<y>l)-1,2-benzisoxazol-6-yl7ox<y>| acetic acid;

/J"7-chloro-3-propargyl-1,2-benzisoxazol-6-yl)oxy/acetic acid; ^/7-chloro-3-(4-methoxypentyl)-1,2-benzisoxazol-6-yl7oxy \ - acetic acid;

β-chloro-3-(3-trifluoromethylphenyl)-1β-benzisoxazol-yl/oxyβ-acetic acid;

7-chloro-3-(4-nitrophenyl)-1,2-benzisoxazol-6-yl7oxy}

acetic acid;

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

N/7-Chloro-3-(4-acetamidophenyl)-1,2-bis oxazol-6-yl7oxy-acetic acid;

{/ N ,5-Dichloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl-(oxy)-acetic acid;

4,7-dichloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl7oxy}-acetic acid;

^("4-Methyl-3-phenyl-1>2-benzisoxazol-6-yl)oxyT"acetic acid; ((5-methyl-3-phenyl-1,2-benzisoxazol-6-yl)oxy_7 acetic acid; 17-Chloro-3-(2-pyrryl)-1,2-benzisoxazol-6-yl7oxy}acetic acid (3-phenyl-1,2-benzisoxazol-4-yl)oxyacetic acid; (3-phenyl-1,2-benzisoxazol-5-yl)oxy-acetic acid;

((3-phenyl-1,2-benzisoxazol-7-yl)oxy7acetic acid;

benzyl 7-chloro-3-(2-fluorophenyl)-1,2-benzis oxazol-6-yl oxy_/acetate; n-propyl(_3-(2-thienyl)-1,2-benzisoxazol-6-yl7-oxy-acetate; t-butyl/T3-phenyl-1,2-benzisoxazol-7-yl)oxy-7-acetate;

β-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl7oxy}-acetyl chloride; N/7-Bromo-3-(2-fluoro-4-hydroxyphenyl)-1,2-benzisoxazol-6-yl7-oxy}acetic acid; N,7-Chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yloxyethyl amide N,N-dietyl-1,7-chloro-3-(2 -fluorophenyl)-1,2-benzisoxazol-6-yl/-oxy-acetamide;

2-{/7-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl7oxy}-ethanol; 1,1-diethoxy-2-([7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl7oxy)ethane;

{[7-Chloro-3-(2-fluorophenyl)-1,2-benzis oxazol-6-yl]oxyj-ac et aldehyde; 1/ j-chromo-J-(2-fluorophenyl)-1,2-benzisoxazol-6-yl7oxy}-acetonitrile; N-Hydroxy-[N]-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl-oxy}acetamide; N-amidino-{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl7oxy}-acetamide; 5-([7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl7oxymethyl}-tetrazole;

N -bromo-5-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl/oxy}-acetic acid;

{Z7-bromo-5-methyl-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl7oxy>-acetic acid;

glyceryl (7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl)oxy>-acetate

β-chloro-3-(2-fluorophenyl)-1,2-benzisothiazol-6-yl7thio)-acetic acid; [ Jj-bromo-3-(2-fluoroenyl)-1,2-benzisothiazol-6-yl7"thio}-acetic acid ; ^/7-rmethyl-3-(2 , 5-difluoroenyl)-1,2 -benzis oxazol-6-yl/oxyacetic acid;

β-Z7-bromo-3-(2,3-difluorophenyl)-1,2-benzisoxazol-6-yl7oxy}-acetic acid;

$ Jj-bromo-3-(2,5-difluoroenyl)-1,2-benzis oxazol-6-yl/oxyj- - acetic acid;

β-chloro-3-(2-fluorophenyl)-1,2-benzisothiazol-6-yl-7oxy)-acetic acid; -Z7-bromo-3-(2-fluorophenyl)-1,2-benzisotiazol-6-yl7oxy}-acetic acid;

β-Chloro-3-β-4-(methylthio)phenyl-1,2-benzisoxazol-6-yl-7-oxy-acetic acid;

[^/ j-fluoro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl7oxy)-acetic acid;

and, N -chloro-3-(3-fluoro-2-thienyl)-1,2-benzisoxazol-6-yl/oxy}-acetic acid.

Effective amounts of the compounds produced according to the invention can be administered to a patient using different methods, for example orally as capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solvents. The end products in the form of free acids, when effective in and of themselves, can be formulated and administered in the form of their pharmaceutically acceptable acid addition salts due to stability, ease of crystallization, increase in solubility and the like.

The active compounds according to the invention can be administered orally, for example by means of an inert diluent or by means of a digestible carrier, or can be enclosed in gelatin capsules or can be pressed into tablets.

For oral therapeutic administration, the active compounds according to the invention can be incorporated with aids and used in the form of tablets, dragees, capsules, elixirs, suspensions, syrups, biscuits, chewing gum and the like. These preparations must contain at least 0.5% of the active substance, but the content can be varied depending on the particular form and is usually between /[% to approx. ^ 0% of unit weight. The amount of active substance in such compounds is such that suitable doses are obtained. Preferred preparations according to the invention are thus prepared

that an oral dosage unit contains between 1.0-300 milligrams of active substance.

Tablets, pills, capsules, dragees and the like may also contain the following substances: ■■ binders such as micro-crystalline cellulose, gum tragacanth or gelatin; and auxiliary substances such as starch or lactose, explosives such as alginic acid, "Primogel", corn starch and the like; lubricant such as magnesium stearate or "Sterotex"; lubricant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate, or orange flavor. When the dosage unit is a capsule, it may contain, in addition to the above substances, a liquid carrier such as fatty oil. Other dosage units may contain other different materials that modify the physical form of the dosage unit, e.g. as coating. Thus, tablets or pills can be coated with sugar, shellac, or other entric coating substances.

A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, colors and flavourings. Materials used for the production of these different compositions must be pharmaceutical pure and non-toxic in the quantities used.

For parenteral therapeutic administration can

the active compounds according to the invention are incorporated into a solution or suspension. These preparations must contain at least 0.1% active compound, but can be varied to between 0.5 and approx. 30% by weight of this. The amount of active compound in such compositions is such that a suitable dose is obtained.

Preferred compositions of preparations according to the invention are prepared so that a parenteral dose unit contains between 0.5 and 100 mg of active substance.

The solutions or suspensions may also include the following substances: sterile diluent such as water for injection, saline solution, solid oils, polyethylene glycols, glycerol, glycerine, propylene glycol or other synthetic solvents; antibacterial substances such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulphite; gelatinizing agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for adjusting tosmotic pressures such as sodium chloride or dextrose. The parenteral preparations may be available in ampoules, disposable syringes or caps made of glass or plastic.

The invention shall be explained in more detail with help

of the following examples.

Example 1

a. To a solution of 31 > 6 g of 2-fluorobenzoyl chloride in 100 ml of dichloroethane, slowly add 26.5 g of aluminum chloride over the course of 30 minutes. After completion of the addition, the mixture turns yellow and then darkens. A solution of 32 g of 2,3-dichloroanisole in 50 ml of 1,2-dichloroethane is then added dropwise to this dark mixture. After completion of the addition, the mixture is stirred for 2 hours and then poured over a mixture of 100 ml of concentrated hydrochloric acid and 100 ml of crushed ice.

The organic phase of the two-phase mixture is evaporated under vacuum and the aqueous mixture is extracted with ether. The combined ether extracts are washed successively with a 10% potassium carbonate solution, water and dried and the ether is evaporated to dryness and the white solid residue is recrystallized from an ether-hexane mixture to give 2'-fluoro-4-methoxy-2,3-dichlorobenzophenone of m.p. 74° to.77°C

b. A mixture of 38.5 g of 2f<->fluoro-4-methoxy-2,3-dichlorobenzophenone and 34>7g of aluminum chloride in 250 ml of benzene is refluxed for 5 hours, then poured onto a mixture of 100 ml of concentrated hydrochloric acid and 100 ml of ice.

The two-phase mixture is extracted with ethyl acetate and the combined extracts are evaporated to dryness. The residue is triturated with hexane and the solid is recrystallized from an ether-hexane mixture to give 2,3-dichloro-4-hydroxy-2'-fluoro-benzophenone with a melting point of 128 to 131°C. c. A solution of 31.8 g of 2,3-dichloro-4-hydroxy-2f<->fluoro-benzophenone and 15.3 g of hydroxylamine hydrochloride in 150 ml of pyridine is refluxed for 64 hours. The pyridine is then evaporated under vacuum and a 5% aqueous hydrochloric acid solution is added. The acidic solution is extracted with ethyl acetate and the combined extracts are dried before they are evaporated to dryness. The resulting solid is recrystallized from an aqueous ethanolic solution to give 2,3-dichloro-4-hydroxy-2T<->fluorobenzophenoxime, mp 168 to 175°C d. A solution of 18.4 g of 2,3-dichloro- 4-hydroxy-2'-fluorobenzophenoxime and 3>6 g of sodium hydride in 120 ml of dimethylformamide and 120 ml of benzene are kept at a temperature of 80-85°C for 3 hours. The reaction mixture is then cooled to room temperature, after which 11.0 g of ethyl bromoacetate in 20 ml of dimethylformamide are added dropwise. After the addition is complete, the mixture is stirred for 30 minutes and then water is added to decompose excess sodium hydride. The mixture is extracted with ethyl acetate and the combined extracts are dried and evaporated to dryness leaving a solid residue. The residue is recrystallized several times from 95% ethyl alcohol

and gives the pure product ethyl β/7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl7oxy}acetate with a melting point of 102 to 104°C.

analysis:

Calculated for C^H-^CIFNO^: 58.38^0; 3.75% H; 4.01N.

Found: 58.11%C; 3.62% H; 3.86%N.

Example 2

A mixture of 10.0 g of ethyl ('/7-chloro-3-(2-fluoro-phenyl-1,2-benzisoxazol-6-yl7oxy)acetate, 100 ml of 10% sodium hydroxide and 350 ml of ethyl alcohol is refluxed for 3 .5 hours. The ethyl alcohol is then evaporated under vacuum and the residue is acidified with a 5% hydrochloric acid solution which gives a solid precipitate. The precipitate is collected on the filter and dried. The dried product is recrystallized from 95% ethyl alcohol to give the product ^/7-chloro-3- (2-fluorophenyl)-1,2-benzisoxazol-6-yl-7-oxyacetic acid with a melting point of 190 to 191°C.

Example 3

a. To a mixture of 12.5 g of aluminum chloride and 45 ml of carbon disulphide, add dropwise 7>1 g of 2-fluorobenzoyl chloride

while maintaining the temperature below 0°C. This temperature is maintained for 1.5 hours. While maintaining this temperature, slowly add 5 g of 2,3-dichlorophenoxyacetic acid. After the addition is complete, the reaction mixture is maintained at this temperature for 30 minutes and is then heated to room temperature, after which it is refluxed for 28 hours. Carbon disulfide is decanted from the refluxed solution

and leaves a dark orange residue which is poured onto a mixture of 500 ml ice/water and 100 ml concentrated hydrochloric acid. The resulting pale red precipitate is filtered off, washed with 300 ml of hot water (50°C) and dried in a vacuum. The dried product is recrystallized twice from aqueous ethyl alcohol to give

2,3-dichloro-4-(2-fluorobenzoyl)phenoxyacetic acid with melting point 153 to 156°C.

b. A mixture of 1.0 g of 2,3-dichloro-4-(2-fluoro-benzophenoxyacetic acid and 1 g of hydroxylamine hydrochloride in 10 ml of pyridine is refluxed for 2 hours. The solvent is then evaporated in vacuo and the residue is stirred for 16 hours with 5 % hydrochloric acid. The product is filtered off and the combined solid is recrystallized from aqueous ethyl alcohol to give 2,3-dichloro-4-(2-fluorobenzohydroxymoyl)phenoxyacetic acid with a melting point of 91 to 36°G. c. A mixture of 0.3 g of 2, 3-dichloro-4-(2-fluorobenzo-hydroxymoyl)phenoxyacetic acid and 0.05 g of sodium hydride in 5 ml of benzene and 5 ml of dimethylformamide are refluxed for 3 hours. After cooling, 5% hydrochloric acid is added to the mixture, whereby the benzene is separated. The benzene is evaporated in vacuum and the resulting precipitate is collected by filtration and recrystallized from aqueous ethyl alcohol to give the product ^ Jj-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl7oxy)'acetic acid mp 188-189°C.

Analysis:

Calculated for C-^HqClFNO^: 56.00%C; 2.83% H; 4.36%N

Found: 55.94%C; 2.86%Mr 4.32%N.

Example• 4

a. A mixture of 3.8 g of (2,3-dichloro-4-hydroxyphenyl)-2'-thienylmethanone and 2.0 g of hydroxylamine hydrochloride in 20 ml of pyridine is refluxed for 6 hours. The pyridine is then evaporated in vacuo. 5% hydrochloric acid is added to the residue and the acidified mixture is extracted with ethyl acetate. The extract is washed successively with water, dried and evaporated to dryness. The residue is recrystallized from an ethanol/water mixture to give (2,3-dichloro-4-hydroxyphenyl)-2T<->thienylmethanone oxime with a melting point of 179 to 183°C.

b. 0.62 g of sodium hydride is added to a mixture of 3.0 g of (2,3-dichloro-4-hydroxy-phenyl)-2<1->thienylmethanone oxime in 30 ml of dimethylformamide and 30 ml of toluene. The reaction mixture is then held at 100°C for two hours and then at 115°C for 2.5 hours. The mixture is cooled for dropwise addition of a solution

of 1.9 g of ethyl bromoacetate in 10 ml of dimethylformamide. After the addition is finished, the reaction mixture is stirred for 2.25 hours and then water is added to decompose any excess sodium hydride. The reaction mixture is extracted with ethyl acetate and the extract is successively washed with water, dried and evaporated. The residue is recrystallized from ethanol and gives ethyl β-7-chloro-3-(2-thienyl)-1,2-benzisoxazol-6-yl7oxy}acetate with a melting point of 142 to 143°C.

Analysis:

Calculated for C^H-^CINO^S : 53>33%C, 3.58%H, 4.15%N

Found: 53.28%C, 3.58%H, 4.17%N

Example 5

a. A solution of 18.0 g of 2,3-dichloro-4-hydroxy-benzophenone and 9>3 g of hydroxylamine hydrochloride in 100 ml of pyridine is refluxed for 2 hours. The pyridine is then evaporated under vacuum and the remaining liquid is distributed between 5% hydrochloric acid and ethyl acetate. The ethyl acetate extract is washed with water, dried and evaporated to give 2,3-dichloro-4-hydroxy-benzophenone oxime.

2,3-dichloro-4-hydroxybenzophenone is prepared

in accordance with the procedure described in example 1 (a) and (b) with benzoyl chloride instead of 2-fluorobenzoyl chloride.

b. A solution of 2,3-dichloro-4-hydroxybenzophenone oxime and 2.6 g of sodium hydride in 50 ml of dimethylformamide and .

50 ml of toluene is heated to 118°C and kept at this temperature for 50 minutes. The reaction mixture is then cooled before 7>9 g of ethyl bromoacetate in 50 ml of dimethylformamide are added dropwise. After the addition is complete, the reaction mixture is stirred at room temperature for 40 minutes. To the well-stirred mixture, water is added dropwise to decompose any excess sodium hydride. The toluene is evaporated under vacuum and the resulting precipitate is collected by filtration and then purified with ether to give the product ethyl (["7-chloro-3-phenyl-1,2-benzisoxazol-6-yl)oxy]acetate of melting point 130 to 132°C Analysis: Calculated for C^H^CINO^: 6l, 54%C , 4.25$H, 4.22%N Found: 6l.34#C, 4.15$H, 4.17% N

Example 6

6 ml of 7N sodium hydroxide is added to a solution of 8.3 g of ethyl (7-chloro-3-phenyl-1,2-benzisoxazol-6-yl)oxy-7-acetate, example 5, in 160 ml of ethyl alcohol. The mixture is then refluxed for 45 minutes. The precipitate is collected by filtration and washed successively with ethyl alcohol and ether. The precipitate is suspended in 200 ml of hot water and the mixture is acidified with concentrated hydrochloric acid. The acidified mixture is stirred for one hour and the gray precipitate is filtered off. The precipitate is recrystallized from ethyl acetate to give the pure product ((7-chloro-3-phenyl-1,2-benzisoxazol-6-yl)oxy_7acetic acid, mp 219. to 221°C

Analysis:

Calculated for C^H-^CINO^: 59.32%C, 3.32%H, 4.6l%N Found: 59.33%C, 3>38%H, 4.57%N

Example 7

19>8 g of 3>2-dichloro-4-hydroxyphenyl-2'-furylmethanone oxime are dissolved in 200 ml of dimethylformamide, then 4.8 g of sodium hydride are added. After the evolution of hydrogen gas has ended, the reaction mixture is heated to 130°C. The mixture

is cooled to 5 u and to the cooled mixture is added a solution of 16.7 g of bromoacetate in 20 ml of dimethylformamide.

After stirring for 45 minutes, the reaction mixture is poured into water

to form a crystalline product. The product is filtered off,

washed successively with ethyl alcohol and ether and finally recrystallized from an ethyl alcohol-ethyl acetate mixture to give the product ethyl (7-chloro-3-(2-furyl)-1,2-benzisoxazol-6-yl)oxyj-acetate with a melting point of 151 to 152°C.

Analysis:

Calculated for C^H-^ClNCy 56.00%C, 3.76%H, 4.35%N

Found: 55.91%C, 3.83%H, 4.32%N.

Example 8

To a boiling suspension of 15>0 g of ethyl (C7-chloro-3-(2-furyl)-1,2-benzisoxazol-6-yl)oxy_7acetate, Example 7 >

10 ml of a 5% sodium hydroxide solution is added to 5°0 ml of boiling 95% ethyl alcohol, which causes the sodium salt to precipitate almost immediately. A further 300 ml of 95% ethyl alcohol is added and the boiling is maintained for 30 minutes. reaction mix-

none is cooled slowly, after which a 100 ml is added

5% hydrochloric acid solution. The product begins to separate

upon cooling, 250 ml of water is added and the diluted mixture is precipitated with ice. The precipitate is filtered off and recrystallized from isopropyl alcohol to give 1/7-chloro-3-(2-furyl)-1,2-benzisoxazol-6-yl7oxy}acetic acid, mp 230 to 233°C.

Analysis:

Calculated for C-^HgClNO^: 53.17%C, 2.74%H, 4.77'%N

Found: 52.83%C, 2.83%H, 4.74%N

Example 9

a. A mixture of 28.3 g of (2,3-dichloro-4-hydroxyphenyl (5f<->methyl-2^-thienylmethanone and 14)0 g of hydroxylamine hydrochloride in 300 ml of pyridine is refluxed for 16 hours. The solvent is then removed under vacuum and the residue is treated with 5% hydrochloric acid. The treated residue is extracted in series

followed by a mixture of dichloroethane and ether and dried and the solvent removed by evaporation. The product is triturated with hexane to form the desired oxime, (2,3-dichloro-4-hydroxyphenyl)-(5l<->methyl-2*-thienyl)methanone oxime.

b. To a mixture of the above-mentioned oxime in 200 ml of dimethylformamide, add 5>3g of sodium hydride. The reaction mixture is maintained in sequence at 120°C for 1.5 hours, 130°C for 1 hour and 140°C for 1 hour and is then cooled to 35°C. To the cooled mixture is added 18.3 g of ethyl bromoacetate in 20 ml of dimethylformamide and the mixture stir for 20 minutes. The reaction mixture is poured into a saturated sodium chloride solution to

give a crystalline product which is filtered off. The product is washed successively with methyl alcohol and ether and then recrystallized from isopropyl alcohol to give ethyl β-chloro-3-(5-methyl-2-thienyl)-1,2-benzisoxazol-6-yl7oxyacetate, m.p. 149 to 150 °C.

Analysis:

Calculated for C^H^CINO^S: 54.62%C, 4.04%H, 3.98%N Found: 54.60%C, 3.97%H, 3.98%N

Example 10

Use of (2,3-dichloro-4-hydroxyphenyl)-(5'-methyl-3'-furyl)methanone instead of (2,3-dichloro-4-hydroxyphenyl)-(5,-methyl-2|- thienyl)methanone in the method described in example 9(a) and with the following method" described in example 9{b)

gives ethyl β-chloro-3-(5-methyl-2-furyl)-1,2-benzisoxazol-6-yl/-oxy/acetate, m.p. 139 to 141°C

Analysis:

Calculated for C^H-^CINO^: 57.23%C, 4.20%H, 4.17#N Found: 57.28%C, 4.18%H, 3.93%N

Example 11

To a suspension of 15.0 g of ethyl 7-chloro-3-(5-methyl-2-furyl)-1,2-benzisoxazol-6-yl-7oxyacetate, example 10, in 800 ml of ethyl alcohol is added 10 ml of 50% sodium hydroxide solution. The reaction mixture is refluxed with vigorous stirring for 1.5 hours and 100 ml of 5% hydrochloric acid is added. The resulting solution is then cooled and diluted with water as the product begins to crystallize. The product is filtered off and recrystallized from methyl alcohol to give £/7-chloro-3-(5-methyl-2-furyl)-1,2-benzisoxazol-6-yl7oxy3-acetic acid, melting point 217-219°C

Analysis

Calculated for C-^H^CINO: 54.65%C, 3.28%H, 4.55%N

Found: 54.74%C, 3.40%H, 4.49%N

Example 12

a. A mixture of 2,3-dichloro-4-hydroxy-4'-methyl-benzophenone and 12.5 g of hydroxylamine hydrochloride in 200 ml of pyridine is refluxed for 2 hours. The pyridine is then evaporated under vacuum and the residue is distributed between ethyl acetate and 5% hydrochloric acid. The ethyl acetate extract is then sequentially washed with water, dried and evaporated to dryness leaving 2,3-dichloro-4-hydroxy-4'-methylbenzophenone oxime.

b. A mixture of the above-mentioned oxime and 5>2 g of sodium hydride in 300 ml of dimethylformamide is kept at 87°C for 3' hours. The mixture is cooled to ambient temperature, after which 16.0 g of ethyl bromoacetate in 50 ml of dimethylformamide are added dropwise. After the addition is complete, the mixture is stirred for 30 minutes and poured into water to form a precipitate which is ethyl 3/7-chloro-3-(4-tolyl)-1,2-benzis oxazol-6-yl7oxy} acetate,

with melting point 157-159°C.

Example 13

A mixture of 20 g of ethyl β-chloro-3-(4-tolyl)-1,2-benzisoxazol-6-yl-7-oxyacetate, example 12, and 15 ml of 50% sodium hydroxide in 600 ml of ethyl alcohol is refluxed for 1 hour. The hot mixture is then diluted with 500 ml of water

and acidified with concentrated hydrochloric acid. The acidified suspension is successively stirred for 30 minutes and filtered and the filter cake recrystallized from dimethylformamide to give the product β-chloro-3-(4-tolyl)-1,2-benzisozol-6-yl7oxyacetic acid with a melting point of 257 to 260°C.

Analysis:

Calculated for C^H-^CINO^: 60.48%, 3.7&%H, 4>41%N

Found: 60.39%C, 3.>77%H, 4.38%N.

Example 14

a. A mixture of 41 g of (2,3-dichloro-4-hydroxyphenyl) 4T<->chlorobenzophenone and 18.9 g of hydroxylamine hydrochloride in 300 ml. pyridine is refluxed for 2 hours. Pyridine is then removed under vacuum and the residue is distributed between ethyl acetate and 5%

hydrochloric acid. The ethyl acetate portion is successively washed with water, dried and concentrated to dryness leaving 2,3-dichloro^4-hydroxy-4f<->chlorobenzophenoxime.

b. A mixture of 41>5 g of the above-mentioned oxime and 7.9 g of sodium hydride in 300 ml of dimethylformamide is maintained at a temperature of 111° C. for 2 hours. The reaction mixture is then cooled to room temperature, after which 23 g of ethyl bromoacetate in 50 ml of dimethylformamide are added dropwise. After the addition is complete, the reaction mixture is stirred for 30 minutes and allowed to stand for 16 hours. The mixture is poured into water to give a precipitate which is filtered off and which is ethyl 7~chloro-3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl7oxy}acetate, melting point 179°C.

Example 15

A mixture of 25 g of ethyl chloro-3-[4-chlorophenyl)-1,2-benzisoxazol-6-yl7oxy} acetate, example 14, and 20 ml of 50% sodium hydroxide in 400 ml of ethyl alcohol is refluxed for 1 hour. The hot mixture is diluted with 300 ml of water and then acidified with concentrated hydrochloric acid. The acidic mixture is stirred for 30 minutes and then filtered and the filter cake recrystallized from a dimethylformamide-ethyl acetate mixture to give the product β/7-chloro-3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl/oxy}acetic acid with a melting point of 254 to 257°C-Analysis: Calculated for C-^HgClgNO^: 53.28%C, 2.68%H, 4.14%N Found: 53.01%C, 2.39%H, 4.03%N.

The above examples, when not specifically indicated, are oxime products prepared from the corresponding ketone consistent with example 1c.

Example 16

A suspension of 0.72 g of ethyl 2-chloro-3-(2-thienyl-1,2-benzispxazol-6-yl7oxy)acetate, Example 4" and 10 ml of concentrated aqueous sodium hydroxide in 40 ml of ethyl alcohol is refluxed for 1 hour. Then ethyl alcohol is removed by evaporation in vacuo. The remaining suspension is acidified with concentrated hydrochloric acid and then stirred at room temperature for 30 minutes. The resulting crude product is filtered off and then recrystallized from ethyl alcohol to give the product -chloro-3-(2-thienyl)-1 ,2-benzisoxazol-6-yl7oxy} acetic acid with a melting point of 217-220°C.

Analysis:

Calculated for C-^HgClNO^S: 50.41#C, 2.60%H, 4.52%N.

Found: 50.13#C, 2.47%H, 4.48%N.

Example 17

a. A reaction mixture of 32.8 g of 3-methyl-2-thiophene-carboxylic acid chloride and 35.4 g of 2,3-dichloroanisole and 26.7 g of aluminum chloride in 200 ml of carbon disulphide is refluxed for 40 hours and then poured into glacial hydrochloric acid. The resulting crystalline product is collected by filtration and is then sequentially washed with hexane and recrystallized from a toluene-hexane mixture to give the product (2,3-dichloro-4-methoxy)(3-methyl-2-thienyl)methanone of m.p. 136 - 138°C.

Analysis:

Calculated for C13H10C1202S: 51.84^0, 3.35%H, 10.65%S

Found: 51.81%C, 3>35%H, 10.85#S.

b. A mixture of 0.6 g of (2,3-dichloro-4-methoxy)'(3-methyl-2-thienylJmethanone and NHgOH.HCl in pyridine is transferred to the corresponding oxime. Then the oxime (mixture of isomers) ( 37>8g) dissolved in 70 ml of dimethylformamide and the solution added to a suspension of 3)3 g of sodium hydride in 100 ml of dimethylformamide. After the reaction has finished, it is poured into water.

The pH of the aqueous mixture is adjusted to 6-7 with dilute hydrochloric acid. The precipitate formed is collected by filtration and successively washed well with ether and recrystallized from a toluene-hexane mixture to give the product 7-chloro-3-(3-methyl-2-thienyl)-6-methoxy-1,2-benzisoxazole of m.p. 154-156 C. Analysis: Calculated for C13H10C1N02S: 55.8l%C, 3>60%H, 5>01#N, 11.46#S Found: 55.90%C, 3.54%H, 4, 98%N, 11.22%S.

c. A mixture of 13.3 g of 7-chloro-3-(3-methyl-2thienyl)-6-methoxy-1,2-benzisoxazole and 25 g of BBr^i CHgClg- is refluxed for approx. l8 hours and then poured into 'H 2 O and extracted with ether. The ether extract is dried and evaporated and then triturated with hexane to give 7-chloro-6-hydroxy-3-(3-methyl-2-

thienyl)-1,2-benzisoxolol, melting point 197-198°C.

Analysis:

Calculated for C-^HgClNOgS: 54.24%C, 3.03%H, 5.27%N

Found: 54.22%C, 3.05%H, 5.08%N. d. A mixture of 10.3 g of 7-chloro-6-hydroxy-3-(3-methyl-2-thienyl)-1,2-benzisoxazole in 60 ml of DMF is added to a suspension of NaH (1,1g) in 40 ml of DMF. Ethyl bromoacetate (6.7g) is added and the reaction mixture is heated to 50°C for 30 minutes. 100 ml of HgO and 25% aqueous NaOH are added and the reaction mixture is heated to 90°C for 3 hours. The reaction mixture is then poured into HgO and acidified with concentrated hydrochloric acid. The acidified mixture is extracted with ether, water, washed and dried. Evaporation and recrystallization from an ethyl acetate-hexane mixture gives 1/7-chloro-3-(3-methyl-2-thienyl)-1,2-benzisoxazol-6-yl7oxy}acetic acid.

Analysis:

Calculated for C^H^CINO^S: 51.93#C, 3.11#H; 4.33%N,

Found: 51.93%C, 3.05%H; 4.28%N.'

Example 18

A mixture of 15>0 g of ethyl N/7-chloro-3-(5-methyl;-2-thlen<y>1)-1,2-benzisoxazol-6-yl7ox<y>J-acetate from Example 9b and 10 ml. 50% NaOH in 800 ml of ethanol is refluxed for 30 minutes and then 10 ml of 5% HC1 is added, the solution becoming homogeneous. A product begins to crystallize when the solution is cooled and additional water is added. The product is filtered off

and is recrystallized from isopropanol and gives β/7-chloro-3-(5-methyl-2-thienyl)-1,2-behzisoxazol-6-yl7oxy}acetic acid, with a melting point of 235-238°c.

Analysis:

Calculated for C^H^CINO^S: 51.93%C, . 3.11%H, 4.33%N, 9.91%S. Found: 51.69%C, 3.14%H, 4.20%N, 10.02%S

Example 19

3-furoyl chloride. (18.0 g) and 2,3-dichloroanisole

(24.7 g) is dissolved in 125 ml of CS2 and treated with AlCl^ (18.7g), first at 5°C°g then at room temperature. After 5 hours*, the reaction is terminated with ice/HCl and extracted with CH^Cl^. Drying and evaporation gives a crystalline product

which is triturated with hexane to give 4-(3-fluoroyl)-2,3-dichloroanisole, mp 118-122°C.

A molten bath of pyridine HCl is prepared by

adding 16 ml of concentrated HCl (0.186 mol) to 14.2 g of pyridine and heating the mixture to 210°C under nitrogen and distilling off HgO. Anisole (5.0 g) is added portionwise and heating is continued for 1 hour and the solution is poured over ice and extracted with ethyl acetate. Drying and evaporation gives 4-(3-furoyl)-2,3-dichlorophenol, melting point 138-142°C.

The phenol is combined with hydroxylamine hydrochloride

in pyridine and refluxed for three hours. Pyridine is evaporated and the remaining mixture is acidified with hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried and evaporated to dryness to give an oxime which is dissolved in 100 ml DMF and added to a suspension of NaH (7.0g) in 100 ml DMF. After heating for two hours at 120°C, the reaction mixture is cooled to 45°C and ethyl bromoacetate (24.0 g) in 20 ml of DMF is added. The reaction is stopped by cooling and a resulting solid product is filtered off and washed with ethanol and then ether to give crude phenoxy ester. Hydrolysis of crude ester for 45 minutes in refluxing ethanol (500 ml) containing 10 ml of 50% NaOH gives a crystalline acid after acidification and cooling. The acid is recrystallized by suspending in boiling methanol and adding DMF until dissolution occurs. Then water is added and crystallization begins immediately and gives 3/7-chloro-3-(3-furyl)-1,2-benzisoxazol-6-yl7oxy}acetic acid, melting point 225-227°C.

Analysis:

Calculated for C13HgCIN05: 53.17%C, 2.74%H, 4>77%N

Found: 53.36C, 2.85%H, 4.71%N.

Example 20

a. To a solution of 24.6 g of 2,6-difluorobenzoyl chloride in 100 ml of 1,2-dichloroethane, 18.5 g of AlCl is added in portions over the course of 30 minutes. A solution of 22.5 g of 2,3-dichloroanisole in 100 ml of 1,2-dichloroethane is added. The mixture is stirred for one hour and poured over 100 ml of concentrated HCl and ice. The organic layer is separated and the aqueous layer is extracted with CHCl^. The organic extract is washed with water, dried (NagSO4) and evaporated to give an oil which crystallizes from hexane to give

solid 2,3-dichloro-4-methoxy-2<1>,6',difluorobenzophenone which on recrystallization from ether has a melting point of 94t96°C. Analysis:

Calculated for C-^HgClgFgOg: 53.02%C, 2.54%H, 11.98%F

Found: 53.21%C, 2.50%H, 12.08%F

b. A mixture of 50.5 g of 2,3-dichloro-4-methoxy-2',6'-difluorobenzophenone, 44>27 g of hydroxylamine HCl in 200 ml of pyridine is refluxed for 48 hours. Pyridine is evaporated in vacuo and the residue is distributed between 5% HCl and ethyl acetate. The extract is washed with water, dried over Na 2 SO 4 and evaporated to give a mixture of isomers. An analytical sample of 2,3-dichloro-4-nietoxy-26f<->difluorobenzophenone oxime, melting point 173-189°C is recrystallized from 95% ethanol.

Analysis:

Calculated for C-^HgClgFgNOg: 50.62$C, 2.73%H, 4.22%N.

Found: 50.84%C, 2.68%H, 4.14%N. c. To a mixture of 5 g of NaH in 200 ml of DMF, add dropwise 48 g of 2,3-dichloro-4-nietoxy-2',6T-difluorobenzophenone oxime in 250 ml of DMF in a nitrogen atmosphere while maintaining the temperature at approximately 40°C After addition, the mixture is stirred for 30 minutes and poured into ice water. A crude product, which is a mixture of isomers, is filtered off and chromatographed on silica gel with CHCl 2 as eluent to give 7-chloro-3-(2,6-difluorophenyl)-6-methoxy-1,2-benzisoxazole which is recrystallized from toluene for analysis, melting point 175-179°C.

Analysis:

Calculated for C^HgCIFgNOg: 56.87%C,' 2.73%H, 4.74%N

Found: 56.99%C, 2.64%H, 4.64%N. 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 is heated at 200°C for 1 hour and then poured in vigorously stirred ice water.

A product of 7-chloro-3-(2,6-difluorophenyl)-6-hydroxy-1,2-benzisoxazole is precipitated, which is filtered and dried. An analytical sample is recrystallized from toluene, melting point 216-220°C.

Analysis:

Calculated for C13HgClF2N02: 55.43%C, 2.15%H, 4.97%N.

Found: 55.59%C, 2.29%H, 4.96%N.

e- A mixture of 1.18 g of NaH and 9.2 g of 7-chloro-3-(2,6-difluorophenyl)-6-hydroxy-1,2-benzisoxazole in 15 ml of DMF is stirred for 1 hour. A solution of 6.06 g of ethyl bromoacetate in 40 ml of DMF is added dropwise and stirred for half an hour. 10 ml of 50% NaOH are added and the reaction mixture is heated to 80°C for 11 hours. Concentrated HC1 is added to the hot solution until it is acidic. Water is added and [/7-chloro-3-(2,6-difluorophenyl)-1,2-benzisoxazol-6-yl7oxy}acetic acid is precipitated which is filtered off, dried and recrystallized from toluene-acetonitrile to give a product with melting point 170-172°C.

Analysis:

Calculated for C^HgOiF,^: 53.04%C, 2.37%H, 4.12%N.

Found: 53.17%C, 2.38%H, 4.18%N.

Example 21

a. A mixture of 20.36 g α-fluorocinnamoyl chloride and 14.4 g AlCl^ in 100 ml 1,2-dichloroethane is stirred for 1 hour followed by the dropwise addition of 17.7 g 2,3-dichloroanisole in 100 ml 1,2 -dichloroethane. The reaction mixture is heated to about 80°C for 1 hour and poured over 100 ml of concentrated HCl

and ice cream. The aqueous layer is extracted with CHCl^ and the combined organic layers are washed with water, dried over Na 2 SO^ and evaporated to a solid residue. The residue is triturated with hexane to give 4-(trans-α-fluorocinnamoyl)-2,3-dichloroanisole. A sample is recrystallized from toluene, melting point 137-138°C.

Analysis:

Calculated for C16H11C12F02: 59.-10#C, '3.41%H, 5.84%F. Found: 59.38%C, 3.46%H, 5.86%F.

b. A mixture of 26.6 g of 4-(trans-α-fluorocinnamoyl)-2,3-dichloroanisole and 22.7 g of hydroxylamine HCl is refluxed for 18 hours. Pyridine is evaporated in vacuo and the residue is triturated with 5% HCl. A product is filtered off, dried and purified with ether-hexane which gives a mixture of isomers. A sample of 4-(trans-α-fluorocinnamoyl)-2,3-dichloroanisole oxime is recrystallized from ethanol, melting point 222-238°C.

Analysis:

Calculated for Cl6H12Cl2FN02: 56.49%C, 3>56%H, 4.12%N.

Found: 46.47%C, 3.51#H, 4.02%N. c. A mixture of 0.43 g of NaH and 4 g of 4-trans-cc-fluorocinnamoyl)-2,3-dichloroanisole oxime in 60 ml of DMF is stirred for half an hour and poured onto ice water. The precipitate formed is filtered off and dried to give 7-chloro-3-(trans-1-fluorostyryl)-6-methoxy-1,2-benzisoxazole. Recrystallization from toluene gives a pure product, melting point 155-161°C.

Analysis:

Calculated for C^H-j^ClFNC^: 63.27% C, 3.65% H, 4.61% N. Found: 63.18%C, 3.42%H, 4.65%N.

d. A mixture of 1.4 g of 7-chloro-3-(trans-(3-fluorostyryl)-6-methoxy-1,2-benzisoxazole and 5>6 g of pyridine HCl is treated at 200°C for 1 hour and poured then in well-stirred ice water A product 7~chloro-3-( trans-(3-fluorostyryl )-6-hydroxy-1,2-benzisoxazole is precipitated and filtered and dried, melting point 226-229°C

Analysis:

Calculated for C-^H^ClFNOg: 62.19% C, 3.13% H, 4.84% N. Found: 62.43%C, 3.17%H, 4.92%N.

e. To a mixture of 0.84 g of NaH in 100 ml of DMF, add dropwise 6.77 g of 7-chloro-3-(trans-(3-fluorostyryl)-6-hydroxy-1,2-benzisoxazole in 50 ml of DMF in a ^-atmosphere. The mixture is stirred for 1 hour and then 4.2 g of ethyl bromoacetate is added dropwise. The reaction mixture is stirred for half an hour and 15 ml of 50% NaOH is added and the reaction mixture is heated for 1 hour

at ..'80°C. The react ion mixture is made acidic with concentrated HC1 and a product is precipitated by the addition of water. The crude product is filtered, dried and recrystallized from 95% ethanol to give /7-chloro-3-(trans-p-fluorostyryl)-1,2-benzisoxazol-6-yl7oxy-acetic acid, melting point 200-203°C.

Analysis:•

Calculated for C-^H^CIFNO^: 58.72% C, 3.10% E, 4>0% N. Found: 59>03%C, 3.29%H, 4.01%N.

Example 22

a. To a solution of 52.23 g of 2,4-difluorobenzoyl chloride in 200 ml of 1,2-dichloroethane is added 40 g of AlCl^ over a 30-minute period. A solution of 48.3 g of 2,3-dichloroanisole in 100 ml of 1,2-dichloroethane is added dropwise. It's a slow one

gas evolution and the temperature increases to about 30°C The reaction mixture is heated to 43°C°g and the gas continues to evolve for about 30 minutes. The mixture is poured over concentrated HCl and ice. The organic layer is separated and the aqueous layer is extracted twice with CHCl 2 . The combined organic layers are washed with water, dried (Na 2 SO 4 ) and evaporated to give an oil. Trituration with hexane gives 2,3-dichloro-4-methoxy-2<*>,4f<->difluoro-benzophenone which is recrystallized from ether, melting point 139-141°C Analysis: Calculated for C^HgCl^Og: 53, 02%C, 2.54%H, 11.98%N. Found: 53.09%C, 2.43%H, 11.84%N.

b. 58 g of hydroxylamine HCl are added to 67 g of 2,3-dichloro-4-methoxy-2<T>,4'-difluoro-benzophenone in 300 ml of pyridine and the resulting mixture is refluxed for 18 hours. Pyridine is evaporated in vacuo and the residue is distributed 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<T>,6<*->difluoro-benzophenone oxime as a mixture of isomers. A sample is recrystallized from 95% ethanol, melting point 180-186°C.

Analysis:

Calculated for C-^HgClgFgNOg: 50.62%C, 2.73%H, 4.22%N.

Found: 50.63%C, 2.80%H, 4.55%N.

c. To a mixture of 5.7 g NaH in 100 ml DMF,

a solution of 53 g of 2,3/dichloro-4-methoxy-2<1>,6'-difluorobenzophenone oxime in 250 ml of DMF is added dropwise while maintaining a temperature of approximately 30°C. After the mixture has been stirred one by one half an hour, a product is precipitated by the addition of water. The crude product which is a mixture of isomers is chromatographed on silica gel with toluene-hexane as eluent to form a pure product 7-chloro-3-(2,4-difluorophenyl)-6-methoxy-1,2-benzisoxazole which is "recrystallized from toluene, melting point 189-191°C.

Analysis:

Calculated for C-^HgClFgNOg: 56.87%C, 2.73%H, 4>74%N

Found: 56.94%C, 2.77%H, 4.66%N.

d. A solid mixture of 7.1 g of 7-chloro-3-(2,4-difluorophenyl)-6-methoxy-1,2-benzisoxazole. and 27.8 g of pyridine HCl are heated at 200°C for one hour._and the mixture is poured into vigorously stirred ice water to precipitate a product. The product is filtered and dried to give 7-chloro-3-(2,4-difluorophenyl)-6-hydroxy-1',2-benzisoxazole which is recrystallized from toluene, melting point 186-190°C.

analysis:

Calculated for C-^HgClFgNOg: '55.43%C, 2.15%H, 4.97%N.

Found: 55.68%C, 2.16%H, 4.92%N.

e. To a mixture of 0.86 g of NaH in 100 ml of DMF, under Ng, add dropwise a solution of 6.9 g of 7-chloro-3-(2,4-difluoro-phenyl)-6-hydroxy-1, 2-benzisoxazole in 50 ml of DMF followed by the addition of 4) 41 g of ethyl bromoacetate in 25 ml of DMF. The mixture is stirred for half an hour and 15 ml of 50% NaOH is added and the mixture is heated for one hour at 80-85°C. Concentrated hydrochloric acid is then added until the mixture is acidic. f/7-chloro-3-(2,4-difluorophenyl)-1,2-benzisoxazol-6-yl7oxy}-acetic acid is precipitated by the addition of water and recrystallized from toluene acetonitrile, melting point 200-203°C.

Analysis:

Calculated for C-^HgClFgNO^: 53.04%C, 2.37%H, 4.12%N.

Found: 53.24%C, 2.55%H, 4.39%N.

Example 23.

a. Dimethyl sulphate (94>64 g) is added dropwise over 40 minutes to a cooled, stirred solution of 2,5-dichlorophenol (122.25 g) and sodium hydroxide (31.5 g) 1 water (300 ml) The mixture is stirred at room temperature for 1 hour, then

at reflux temperature for 2 hours, then cooled to room temperature. The organic layer is separated and combined with ether extracts of the remaining aqueous layer. The ether solution is dried (saturated NaCl, NagSO₂, KgCO₂) and the ether is removed to give 2,5-dichloroanisole. Distillation gives a colorless liquid (115°C at aspirator vacuum).

A solution of o-fluorobenzoyl chloride (69)76 g)

in carbon disulfide (25 ml) is added at room temperature to a suspension of aluminum chloride (58.67 g) in carbon disulfide (450 ml) followed by the addition at room temperature of 70.8 l g of 2,5-dichloroanisole in carbon disulfide (25 ml). The mixture is stirred for 4 hours at room temperature, during which a precipitate forms. The mixture is then refluxed for one hour,

and cooled, and 5^.0 g of AlCl^ are added. The resulting mixture is refluxed for 2 hours and stirred at room temperature for 18 hours. The mixture is poured over ice/HCl and extracted with methylene dichloride to give an oil. Trituration with hexane-

ether gives a solid. Recrystallization from diisopropyl ether gives a solid which partially melted at approx. 94°C then at approx. 120°C. The remaining solid after removal of. solvent from the filtrate is treated with ether-petroleum ether to give 2,5-dichloro-4-(2-fluorobenzoyl)anisole and recrystallization from methanol gives mp 100-103°C.

Analysis:

Meant for. C 1 Z|HgCl 2 F0 2 : 56.21%C, 3.04%H.

Found: 56.26%C, 3.00%H.

b. A mixture of 2,5-dichloro-4-(2-fluorobenzoyl)-

anisole (3g) and hydroxylamine hydrochloride (1.4g) in pyridine (25ml) are refluxed for several hours until no ketone remains. Pyridine is removed under high vacuum and the residue is diluted with water, then extracted with chloroform. The chloroform solution is dried and the chloroform is removed to give a solid which is recrystallized from ether to give (z)-2%fluoro-2,5-dichloro-4-methoxybenzophenoxime, mp 188°C.

Analysis:

Calculated for C^H-^Cl<g>FNO<g>: 53.52%C, 3.21%H, 4.46%N

Found: 53.44%C, 3.22%H, 4.36%N..-

e. A solution of (z)-2,-fluoro-2,5-dichloro-4-methoxy-benzophenone oxime (3.14 g) 1 DMF (20 ml) is added dropwise to a stirred suspension of sodium hydride (0.6 g ) in DMF (20 mL). The mixture is stirred for 18 hours at room temperature, poured

then in ice/water and extracted with chloroform. The chloroform solution is washed with water, saturated sodium chloride and dried over Na 2 SO 2 -MgSO 4 . Removal of chloroform gives a residue which, on treatment with ether-petroleum ether, gives a solid with melting point l65-l66<?>C. Removal of solvent from the filtrate gives a solid which, on treatment with ether-petroleum ether, gives 5-chloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole, melting point 165-166°C.

Analysis:

Calculated for C-^HgClFNOg : 60.55% C, 3.27% H, 5>04% N, 12.77% Cl. Found: 60.71%C, 3.14%H, 4.99%N, 12.75%C1.

d. A solution of 5-chloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole (1g) and boron tribromide (1.3 ml)

in dichloroethane (30 ml) reflux for approx. 24 hours. The reaction mixture is poured onto ice-water and extracted with dichloromethane to give a solid 3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole, mp 180-182°C

Analysis:

Calculated for C-^H^FClNOg: 59.22%C, 2.68%H, 5.31#N

■Found: 58, SO% C, 2.68%H, 5.17%N.

e. A solution of 5-chloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole (14.8 g) in DMF (40 ml) is added dropwise at room temperature to a suspension of sodium hydride (3, 0 g) in DMF (40 Ml) and* the mixture is stirred at room temperature for half an hour. A solution of ethyl bromoacetate (10.31 g) in DMF (40 ml) is then added dropwise and the mixture is stirred for 18 hours at room temperature. A further 0.3 g of NaH suspended in DMF is added, followed by 1 g of ethyl bromoacetate!',' The mixture is heated to 50°C for 1.5 hours, cooled and poured over ice/water and extracted with ether. The ether extracts are washed with water, saturated sodium chloride, dried over sodium sulfate and the solvent removed to give a solid. Trituration with ether-petroleum ether (1:1) gives ethyl 5-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl_7oxy-acetate, melting point 114-H5°C'

Analysis:

Calculated for C-^H^CIFNO^: 58.37%C, 3.75%H, 4.00%N Found: 58.15%C, 3.66%H, 3.93%N f. A mixture of ethyl { /5-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl7oxy}acetate (14 g) sodium hydroxide (8 g), ethanol (500 ml) and water (300 ml) are refluxed for 5 hours, cooled in an ice bath and acidified with concentrated hydrochloric acid. The suspension is extracted with chloroform, the extract is dried with saturated sodium chloride and the chloroform is removed to give a solid, mp 214-215°C Recrystallization from 3.2 mixture acetonitrile-toluene gives \ J^ >- chloro- 3-(2-f enyl)-1,2-benzisoxazol-6-yl7oxy}acetic acid. Analysis: Calculated for C^H^CIFNO^: 56.00%C, 2.82%H, 4>35%N Found: 55»79%C, 2.69%H, 4>27%N.

Example 24

a. To a solution of 57.6 g of 3,4-dichlorobenzoyl chloride in 1,2-dichloroethane (150 ml) add 36.7 g of AlCl₂ in portions over the course of 30 minutes. 44.26 g of 2,3-dichloroanisole in 1,2-dichloroethane (150 ml) are added dropwise to the resulting mixture. There is a gas evolution and the reaction mixture is heated to

60°C for one hour. The mixture is then poured over 150 ml of concentrated HCl and 150 ml of ice and then extracted with CHCl 2 and then ethanol. The resulting organic layer is washed with 10% aqueous KgCO^, then water, dried over (NagSO^) and evaporated to give 2-dichloro-4-methoxy-3',4<1->dichlorobenzophenone, mp 113-140°C .

b. A mixture of 53 g of 2,3-dichloro-4-methoxy-3<*>,4'-dichlorobenzophenone and 40 g of AlCl^ in 400 ml of benzene is refluxed for five hours and then cooled to room temperature and maintained there^i- about. 18 hours. The mixture' is poured over 200 ml of concentrated HCl and 200 ml of ice and is then stirred at room temperature for half an hour. Ethyl acetate is added to the mixture and the ethyl acetate/benzene layer is washed with water, dried over Na2SO4

and then evaporated to give 2,3-dichloro-4-hydroxy-4,4'-dichlorobenzophenone, mp 179-180°C.

c. A mixture of 35.43 g of 2,3-dichloro-4-hydroxy-3',4'-di-chloro-benzophenone and. 15.29 g of hydroxylamine HCl in 3°° ml of pyridine are refluxed for 2 volumes. Pyridine is evaporated in a vacuum. The residue is distributed between ethyl acetate and 05% HCl. The extract is washed with water, dried over NaSO^ and evaporated to give the corresponding oxime."

To a solution of 35 g oxime in 300 ml DMF, 6.0 g NaH is added and the mixture is heated to an internal temperature of 103°C for 1 hour 45 minutes followed by

100°C internal temperature for 3/4 hour. The reaction mixture is cooled to room temperature and a solution of 18.37 g of ethyl bromoacetate in 5 ml of DMF is added dropwise. The mixture is stirred for approx. 64 hours, poured over water and the precipitate that forms is filtered off and cleaned with hexane. A crude product is recrystallized from ethanol to give ethyl β/7-chloro-3-(3,4-dichloro-phenyl)-1,2-benzisoxazol-6-yl7-oxyacetate, mp 123-125°C

20 ml of 50% NaOH are added to a suspension of 19 g of the ester in 400 ml of ethanol. A precipitate forms and the heterogeneous mixture is refluxed for 1 hour. To the hot mixture is added 4°0 ml of water followed by concentrated HCl

until the mixture is sour. The suspension is stirred for half an hour, filtered and recrystallized from DMF-ethyl acetate to give {/7-chloro-3-(3,4-dichlorophenyl)-1,2-benzisoxazol-6-yl7oxy)acetic acid, mp 222-224°C .

Analysis:

Calculated for C-^HgC^NO^: 48.35% C, 2.16% H, 3.76% N.

Found: 58.40%C, 2.03%H, 3.93%N.

Example 25

a. The Friedel-Crafts product from example 24a is repeated with 48.13 g of o-chlorobenzoyl chloride which is combined with 36.7 g of AlCl^

and 44>26 g of 2,3-dichloroanisole to give a white crystalline product, namely 2,3-dichloro-4-methoxy-2,'-chlorobenzophenone, mp 117-120°C.

b. The procedure according to example 24b is repeated with the exception that 68 g of 2,3-dichloro-4-methoxy-2'-chlorobenzophenone is combined with 58.6 g of AlCl₂ in 500 ml of benzene. The resulting product is recrystallized from toluene to give 2,3-dichloro-4-hydroxy-2'-chlorobenzophenone,

c. Add 25.02 g of hydroxylamine HCl to a solution of 53 g of 2,3-dichloro-4-hydroxy-2'-chlorobenzophenone. The mixture is refluxed for 2 hours. Pyridine is evaporated in vacuo, the residue is distributed between ethyl acetate and 5% HCl. The ethyl acetate extract is washed with water, dried over Na^SO^ and evaporated to give the corresponding oxime. To a swelling of 49 g of the oxime in 300 ml of DMF, 9.12 g of NaH are added and the mixture is heated to an internal temperature of 80-84°C for 1 hour. The reaction mixture is cooled to room temperature and a solution of 27.5 g of ethyl bromoacetate in 50 ml of DMF is added dropwise. The mixture is stirred for half an hour and water is added to decompose excess NaH. The product is extracted with ethyl acetate. The ethyl acetate extract is washed with 10% NaOH and water, dried over Na2SO4 and evaporated to give a mixture. Chromatography of the mixture on silica gel with CHCl^ as eluent gives ^/7-chloro-3-(2-chlorophenyl)-1,2-

benzisoxazol-G-yl/oxvjacetate.

To a solution of 5>86 g of the ester in 200 ml of hot ethanol, add 6 ml of $0% NaOH. A precipitate forms and the suspension is refluxed for one hour. Two hundred milliliters of water are added to the mixture and sufficiently concentrated HC1 to make the mixture acidic. The mixture is stirred for 18 hours at room temperature. A solid precipitates out and is filtered and recrystallized from toluene to give ^</>y<->chloro-3-(2-chlorophenyl)-1,2-benzisoxazol-6-yl7oxyJ acetic acid, mp 165-168°C. Analysis: Calculated for C^H<g>ClgNO^: 53.28%C, 2.68%H, 4.14#N. Found: 53.50%C, 2.67%H, 3.95%N.

Example 26

a. The Friedel-Craft method according to example 24a

repeated with 35.4 g of 2,3-dichloroanisole, 32.4 g of o-toluoyl chloride and 28 g of AlCl^ which are combined in 125 ml of 1,2-dichloroethane to give a product, namely 2,3-dichloro-4-methoxy -2'-methylbenzophenone.

b. The procedure according to example 24b is repeated except that 38 g of 2,3-dichloro-4-methoxy-2.,-methylbenzophenone is combined with 34.6 g of AlCl₂ in 300 ml of benzene. The resulting product is recrystallized from toluene to give 2,3-dichloro-4-hydroxy-2N<->methylbenzophenone. c. 13.9 g of hydroxylamine HCl are added to a solution of 28 g of 2,3-dichloro-4-hydroxy-2T<->methylbenzophenone in 250 ml of pyridine and the mixture is refluxed for 48 hours. Pyridine is evaporated in vacuo and the residue is distributed between ethyl acetate and 5% HCl. The ethyl acetate extract is washed with water, dried over Na2SO4 and evaporated to give the corresponding oxime. 2.43 g of NaH are added to a solution of 12 g of oxime in 50 ml of DMF and 50 ml of toluene. The mixture is heated under Ng to an internal temperature of 95-98°C for 5 l/4 hours. A further 50 ml of DMF is added and the internal temperature is maintained at 95°C for a further two hours. The reaction mixture is cooled to 30°C and 7.5 g of ethyl bromoacetate are added dropwise. After complete addition, the mixture is stirred for 1 hour. Water is added and the product is extracted with ethyl acetate, dried over Na 2 SO 4 and evaporated to give ethyl /j-chloro-3-(2-tolyl)-1,2-benzisoxazol-6-yl7oxy acetate.

To a solution of 13.95 g of the ester

in 500 ml of hot ethanol, add 13 ml of 50% NaOH. A precipitate forms and the suspension is refluxed for 1 l/2 hours. 500 ml of water is added followed by the addition of concentrated HCl until the mixture is acidic. A solid precipitates out on cooling and the product is filtered off and recrystallized from toluene to give {(7-chloro-3-(2-tolyl)-1,2-benzisoxazol-6-yl7oxy)-acetic acid, mp 179-181°C.

Analysis:

Calculated for C^H-^CINO^: 60.48%C, 3.8l%H, 4.41%N

Found: 60.76%C, 3.91%H, 4.26%N.

Example 27

a. The Friedel-Craft procedure of Example 24a is repeated with 33 >7 g of 2,3-dimethylbenzoyl chloride, 54 g of 2,3-dichloroanisole and 26.7 g of AlCl₂ to form 2,3-dichloro-4-methoxy-2 ',+'-Dimethylbenzophenone.

b. The procedure according to example 24b is repeated with 39 g of 2,3-dichloro-4-methoxy-2N,3'-dimethylbenzophenone in 300 ml of benzene.

The resulting product is recrystallized from 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 pyridine is refluxed for approx. 1 week. Pyridine is evaporated in vacuo and the residue is distributed between ethyl acetate and 5% HCl. The ethyl acetate extract is washed, dried over Na2SO4 and evaporated. Trituration with hexane gives 2,3-dichloro-4-hydroxy-2',3'-dimethylbenzophenone oxime. d. To a solution of 5 g of 2,3-dichloro-4-hydroxy-2',3'-dimethylbenzophenone oxime in 70 ml of DMF, add 0.96 g of NaH.

The internal temperature is kept between 95-120°C for 7 hours, then the mixture is heated to 130°C for 1.5 hours. The reaction mixture is cooled and 2.94 g of ethyl bromoacetate are added dropwise. The mixture is stirred for an hour and water is added dropwise. The product formed is filtered and recrystallized from 95% ethanol to give

ethyl 1/7-chloro-3-(2,3-dimethylphenyl)-1,2-benzisoxazol-6-yl-7-oxo-acetate, melting point 89-91°C-

Analysis:

Calculated for C10H18ClN0^: 63.42% C, 5.04% H, 3.89% N. ' Found: 63.25%C, 5.02%H, 3.79%N. e. A suspension of 2 g of ethyl β-chloro-3-(2,3-dimethyl-phenyl)-1,2-benzoxazol-6-yl β-acetate, 50 ml of ethanol and 5 ml of 50%. NaOH is refluxed for 1 hour. To the hot mixture is added 50 ml of water sufficiently concentrated HC1 to make the reaction mixture acidic. On cooling and addition of water {(7-chloro-3-(2,3-dimethylphenyl)-1,2-benzisoxazol-6-yl7oxy3-acetic acid precipitates, melting point 170-172°C.

Analysis:

Calculated for C^H-^CINO^: 6l.54%C, 4.25%H, 4.22%N,

Found: 6l.65%C, 4.38%H, 4.01%N.

Example 28

a. 29.3 g of 2-bromopyridine in 150 ml of dry THF is added to 75 ml of 2.6 M n-butyl lithium which has been cooled to -65°C. Then 2,3-dichloro-4-methoxybenzaldehyde (38.0 g) in 300 ml of THF is added and the reaction mixture comes to room temperature. It is cured in H 2 O and the crystalline product is filtered off, washed with ether and dried to give α-(2,3-dichloro-4-methoxyphenyl)-2-pyridinemethanol, mp 174-176°C.

b.. a-(2,3-dichloro-4-methoxyphenyl)-2pyridinemethanol (31.86 g) is dissolved in 600 ml of acetic acid and 100 ml of HgO. Chromic anhydride (11.0 g) is added portionwise over the course of five minutes. After three hours, the reaction mixture is poured into H 2 O 2 and extracted with ether. The combined organic phase is washed well with 10% NaHCO 3 , then brine and dried. Removal of the solvent under reduced pressure gives a crystalline product, namely (2,3-dichloro-4-methoxyphenyl)(2-pyridyl)methanone, mp 104-107°C.

Analysis:

Calculated for C-^HgClgNOg: 55.34%C, 3.21%H, 4.97%N. Found: 55.29%C, 3.26%H, 4.93%N.

c. (2,3-dichloro-4-methoxyphenyl)(2-pyridyl)methanone (32.0 g) is refluxed for 4 hours in 300 ml of ethanol containing 30 g of hydroxylamine hydrochloride. The reaction mixture is poured into HgO which has been made basic with NH^OH and extracted with ethyl acetate. Drying and evaporation give eh ra" oxime mixture of E-(2-pyridyl)

(2,3-dichloro-4-methoxy-phenyl)methanone oxime and Z-(2-pyridyl)

(2,3-dichloro-4-methoxyphenyl)methanone oxime.

The oxime mixture is dissolved in 200 ml of DMF and added to a suspension of 3.1 g of NaH in 150 ml of DMF. After 15 minutes, the reaction mixture is poured into HgO and the product is filtered off.

A recrystallization from isopropanol removes unreacted E-oxime

and gives 7-chloro-6-methoxy-3-(2-pyridyl)-1,2-benzisoxazole, melting point 164°, 166°C.

Analysis:

Calculated for C-^HgClNgOg: 59.89%C, 3.48%H, 10.74%N, Found: 59.53%C, 3.37%H, 10.63%N. d. 7-Chloro-6-methoxy-3-(2-pyridyl)-1,2-benzisoxazole (24.4 g) is refluxed for 1.5 hours in 450 ml of 48% HBr. The precipitated hydrobromide salt is filtered off, washed with ether and neutralized with 10^NaHCO^ solution. The free base is filtered off and dried to give 7-chloro-6-hydroxy-3-(2-pyridyl)-1,2-benzisoxazole, melting point 209-21°C.

Analysis:

Calculated for C^H^ClN<g>O<g>: 58.43%C, 2.85%H, 11.36#N. Found: 58.16%C, 2.8l$H, 11.42$N. ■. e. 7-chloro-6-hydroxy-3-(2r-pyridyl)-1,2-benzisoxazole (10.0 g) is dissolved in 80 ml DMF and added to an ice-cold suspension of NaH (1.1 g) in 50 ml DMF. After completion of hydrogen evolution, ethyl bromoacetate (7.5 g) is added in 20 ml of DMF. - After a further 90 minutes, 200 ml of HgO and 10 ml of 50% NaOH are added and the reaction mixture is heated to 65°C for 45 minutes. The mixture is poured into H2O, acidified to pH 1-2, and a solid product is filtered off and dried to give ^Jj-chloro-3-(2-pyridyl)-1,2-benzisoxazol-6-yl7oxyJ-acetic acid, m.p. 255-256°C. Analysis: Calculated for C^HgClNgO^: 55.18%C, 2.4&%H, 9.20%N, Found: 55>35%C, 2.88%H, 9.45%N.

Example 29

. a. 7-Chloro-6-hydroxy-3-(2-pyridyl)-1,2-benzisbxazole, example 28, (9.9 g) is heated in 600 ml of glacial acetic acid at 60 C. Then m-chloroperbenzoic acid (8 .3 g 85%). After heating at 60°C for a total of 14 hours, the reaction mixture is poured into 2 liters of HgO and the product is filtered off

and washed with methanol, then ether. In this way, the

comes 7-chloro-6-hydroxy-3-(2-pyridyl)-1,2-benzisoxazole 1'-

oxide in the form of a hemihydrate after recrystallization from DMF/H2O, melting point 214°C.

Analysis:

Calculated for C-^H^CIN^. 0.5H 2 O: 53.05%C, 2.97%H, 10.31%N Found: 53.14%C, 2.82%H, 10.47#N.

b. 7-chloro-6-hydroxy-3-(2-pyridyl)-1,2-benzisoxazole 1'-oxide (7.30 g) is dissolved in 200 ml DMF and added to a suspension of NaH (1.33 g) in 50 ml DMF. After 15 minutes, ethyl bromoacetate (5.0 g) in 20 ml of DMF is added and the reaction is heated at 50°C for 10 hours. The reaction mixture is quenched,

with HgO, acidify and the precipitate is filtered off and dried well. The precipitate is treated again with 1.33 g of NaH and 50 g of ethyl bromoacetate in DMF. After 30 minutes, 200 ml of HgO and 10 ml of 50% NaOH are added and the reaction mixture is heated at 50°C for 130 minutes. It is acidified and [/j-chloro-3-(2-pyridyl)-1,2-benzisoxazol-6-yl7oxy^racetic acid 1'-oxide is produced, melting point 214°C during decomposition. Analysis:

Calculated for C^H<g>ClN<g>O^: 52.43%C, 2.83%H, 8.74%N.

Found: 52.35%C, 2-.79%H, 8.93%N.

Example 30

a. m-dimethoxybenzene (27.6 g) and o-fluorobenzoyl chloride (31.7 g) are dissolved in 200 ml of dichloroethane and A1C1« (28.0 g) is added portionwise. After 2 hours, a further 56 g of A1C1„ are added

rO

and the reaction mixture is heated at 60 C for 1.5 hours. It is then poured into HgO and extracted with ethyl acetate. Drying and evaporation gives a crystalline compound. Trituration with toluene gives 2,4-dihydroxy-2'-fluorobenzophenone. melting point 109-111°C.

Analysis:

Calculated for Zy^^ Oy 67.24%C, 3.91#H, 8.18%F Found: 66.85%C, 3.75%H, 8.35%F.

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 then partitioned between ether and 5% HCl and the organic layer is separated. Drying

and evaporation gives, after recrystallization from toluene, a pure isomer of 2,4-dihydroxy-2'-fluorobenzophenone/E-oxime/, melting point 170-172°C.

Analysis:

Calculated for C-^H-^FNO^: 63.16%C, 4.08%H, 5.67%N,

Found: 63.56%C, 4.28%H, 5.56%N.

c. The E-oxime 2,4-dihydro-2|-fluorobenzophenoxime (1816 g) is heated at ^ 0°C in 18.0 ml of acetic anhydride for 5 hours, then at 60°C for 6 hours. A further 3.0 ml of acetic anhydride is added and the reaction mixture is allowed to stand at room temperature for approx. 73 hours. The crystalline product which separates from the reaction mixture is washed with cold ether to give a pure product of E-4-acetoxy-2-hydroxy-2T<->fluorobenzophenone O-acetyloxime, mp 132-134°C

'Analysis:

Calculated for C-^H^FNO^: 6l.63#C,. 4.26%H, 4.23%N.

Found: 6l.80%C, 4.08%H, 4.0$N.

d. E-4-acetoxy-2-hydroxy-2'-fluorobenzophenone O-acetyl oxime (18.4 g) is dissolved in 80 ml DMF and added to an ice-cold suspension of NaH (3.3 g) in 100 ml DMF . After 90 minutes, the reaction mixture is poured onto HgO and some undissolved precipitate is filtered off. Acidification of the aqueous filtrate and extraction with ether gives, after drying and evaporation, 3-(2-fluorophenyl)-•6-hydroxy-1,2-benzisoxazole, melting point 206-210°C.

Calculated for C-^HgFNOg: 68.12%C, 3.52%H, 6.11%N.

Found: 68.43%C, 3.59%H, 6.14%N.

e. 3-(2-Fluorophenyl)-6-hydroxy-1,2-benzisoxazole (9>7g) is dissolved in 80 ml of DMF and added to an ice-cooled suspension of NaH (1.4 g) in ^0 ml of DMF. When hydrogen evolution stops, ethyl bromoacetate (7>5g) 1 20 ml DMF is added and the reaction mixture is cooled to room temperature. After 2 hours, 200 ml of HgO and 10 ml of 50% NaOH are added and the reaction is heated to 5°°c• After a further JO minutes, a product is collected after acidification and filtration. Recrystallization from toluene/CH 2 CN gives 2-(2-fluoro-phenyl)-1,2-benzisoxazol-6-yl-7-oxy-acetic acid, melting point 182-184°C.

Analysis:-

Calculated for C-^H^FNO^62.72%C, 3.51#H, 4.88%N.

Found: 62.56%C, 3.61%H, 5.06%N.

Example 31

a. Friedel-Crafts' method according to example 24a is repeated with 31>55 g of p-fluorobenzoyl chloride, 32 g of 2,3-dichloroanisole and 35.22 g of AlCl3 combined in 1,2-dichloroethane and reacted. The resulting crude product is triturated with hot hexane, cooled and filtered to give 2,3-dichloro-4-methoxy-4'-fluorobenzophenone.

b. A mixture of 39.5 g of 2,3-dichloro-4-methoxy-4f<->fluorobenzophenone and 160 g of pyridine hydrochloride is heated to 200°C for 1 hour. The reaction mixture is poured into ice water while stirring and a precipitate forms. The precipitate is filtered off and dried for approx. l8 hours to give 2,3-dichloro-4-hydroxy-4T<->fluorobenzo-

phenon.

c. To a solution of 35 g of 2,3-dichloro-4-hydroxy-

4f fluorobenzophenone in 250 ml of pyridine is added 34)6 g of hydroxylamine HCl. The mixture is refluxed for 4 hours. The pyridine is evaporated in vacuo. The residue is distributed 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 as a mixture of isomers, mp 150-156°C.

Analysis:

Calculated for C-^HgClgFNOg : 52.02% C, 2.69% H, 4.67% N.

Found: 52.19%C, 2.74%H, 4.69%N.

d. A solution of 20 g of 2,3-dichloro-4-hydroxy-4'-fluoro-benzophenone oxime in 100 ml of DMF in a Ng atmosphere is added dropwise to a mixture of 4.0 g of NaH in 50 ml of DMF. The reaction mixture is heated to an internal temperature of 96°C for 2 hours. The reaction mixture is cooled to 40°C and 12.3 g of ethyl bromoacetate are added dropwise and the mixture is stirred for one hour. 20.ml ^ 0%

NaOH and 100 ml of water are added and the reaction mixture is heated

at 80-90°C for 1 hour. Concentrated HCl is added until the reaction mixture is acidic and the mixture is stirred for 1/2 hour and water is added. A solid product is collected by filtration and recrystallization to give a pure product of m.p. 233-237°C.

Analysis:

Calculated for C-^H^CIFNO^: 56.00%C, 2.83%H, 4.36/øN.

Found: 55>76%C, 2.90%H, 4.29%N.

Example 32 -.

a. Dissolve 2,6-dimethoxytoluene (20.0g) and o-fluorobenzoyl chloride (19.8 g) in 250 ml of dichloroethane and cool to 5°C. AlCl3 is added in portions and after the addition is complete, the reaction mixture is heated to room temperature over the course of 30 minutes, and refluxed for 30 minutes. It is then poured into 5% HC1 and allowed to stand for 18 hours. Extraction with ether, followed by drying and concentration gives a crystalline material which is washed with hexane to give 2f<->fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone, mp 118-120°C.

Analysis:

Calculated for C-^H-^FO^: 69.22%C, 5.04%H, 7.30%F

Found: 69.23%C, 5.01%H, 6.98%F

b. 2'-Fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone (30.0 g) is refluxed for 18 hours in 350 ml of pyridine containing 32.0 g of hydroxylamine hydrochloride. The solvent is removed in vacuo and the residue is distributed between ether and 5% HCl. Drying and concentration of the ether gives a crude product which is heated and melted at 200°C for 30 minutes in a nitrogen atmosphere. The mixture is cooled and the solid mass triturated well with hexane to

gives E-2'-fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone oxime, melting point 167-169°C

Analysis:

Calculated for C^H-^FNO^: 65.44%C, 5.13%H, 5.09%N". Found: • 65-.49%C, 5.26%H, 4.83% N. c. E-2|-Fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone oxime (20.0 g) is heated on a steam bath for 1 hour with 12 ml of acetic anhydride. The acetic anhydride is evaporated in vacuo and the product is partitioned between ether and H<g>O, then the ether is washed with 10% NaHCO^ Evaporation and trituration of the crystalline product with hexane gives E-2'-fluoro-2-hydroxy-4methoxy-3methylbenzophenone O-acetyl oxime, melting point 83-86°C .

Analysis:

Calculated for C-^H^FNO^: 64.34%C, 5.08%H, 4>42%N, Found: 64.30%C, 5.08%H, 4.26%N. d. E-2 T-fluoro-2-hydroxy-4-methoxy-3methylbenzophenone O-acetyl oxime (22.0 g) is dissolved in 100 ml DMF and added to a suspension of 2.5 g NaH in 100 ml DMF. An ice bath is used to keep the reaction temperature below J0°C. After 40 minutes, the reaction mixture is poured into H<g>O and extracted with ether.

After washing well with HgO, the ether is dried and evaporated to

give a crystalline product which is washed with cold hexane to give 3-(2-fluorophenyl)-6-methoxy-7-methyl-1,2-benzisoxazole, mp 105-108°C.

Analysis:

.Calculated for C-^H-^FNOg: 70.03%C, 4.70%H, 5.45%N.

Found: 69.96%C, 4.76%H, 3.36%N,

e. 3-(2-fluorophenyl)-6-methoxy-7-methyl-1,2-benzisoxazole (16.1 g) is heated at 200°C for two hours with 64 g of pyridine hydrochloride. The mixture is poured into H<g>O and extracted with ethyl acetate. After washing with 5% HCl, ethyl acetate is dried and evaporated to

give 3-(2-fluorophenyl)-6-hydroxy-7-methyl-1,2-benzisoxazole, mp 216-219°C.

Analysis:

Calculated for C-^H^FNO<g>: 69.13%C, 4.14#H, 5.76%N Found: 68.91%C, 4.03%H, 5.82%N

f. 3-(2-fluorophenyl)-6-hydroxy-7-methyl-1,2-benzisoxazole (10.6 g) is dissolved in 90 ml DMF and treated with 8.0 g ethyl bromoacetate and 6.7 g KgCO^. The reaction mixture is heated at 60°C for 2 hours and then cooled to ambient temperature. After 18 hours at ambient temperature, water (200 ml) is added

and 50% NaOH (15MI) and the solution is heated at 90°C for 90 minutes. The mixture is poured into H<g>O and acidified and then extracted with ether. Drying and evaporation gives crystalline product of {(3-(2-fluorophenyl)-7-methyl-1,2-benzisoxazol-6-yl7oxy}-acetic acid, melting point 158-160°C.

Analysis:

Calculated for C^ K^ FNO^ : 63.78%C, 4>02%H, 4.65%N.

Found: 63.89%C, 4.06%H, 4.58%N.

Example 33

a. m-chloroanlsol (28.5 g) and o-fluorobenzoyl chloride (31.7 g) are dissolved in 200 ml of dichloroethane and treated at 10°C

with 26.7 g of AlCl^. After 45 minutes, the reaction mixture is poured over ice and extracted with ether. Drying and evaporation, followed by trituration with hexane gives the substance containing 2-chloro-2'-fluoro-4-methoxybenzophenone. Recrystallization from EtgO/hexane gives 2-chloro-2'-fluoro-4-methoxybenzophenone, melt-

point 77-79°c.

Analysis:

Calculated for C-^H^ClFOg: 63 , 53%C , 3.8l%H, 7 , 1Q% F

Found: 63.77%C, 3>75%H, 7.25%F.

b. 2-Chloro-2.,-fluoro-4-methoxybenzophenone (15.5 g) is refluxed for 3 hours in 150 ml of pyridine containing 10.0 g of hydroxylamine hydrochloride. The pyridine is removed in vacuo and the residue is distributed between ether and 5% HC1. Drying and evaporation of the organic phase gives an isomeric mixture of oximes. The mixture is dissolved in 50 ml of DMF and added to a suspension of 1.5 g of NaH

in 30 ml 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 from ether gives 3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole, melting

point 101-103°C.

Analysis:

Calculated for C^H^FNOg: 69.13%C, 4.14%H, 5>76%N.

Found: 69.08%C, 4.29%H, 5.65%N.

c. 10 g of 3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole are 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, 1^ (11.7 g) is added

in 90 ml of ether. The reaction mixture is poured into NagSgO^, then HgO. Drying and concentration gives 3-(2-fluorophenyl)-7-iodo-6-methoxy-1,2-benzisoxazole, melting point 135-138°C. Analysis: Calculated for: C^H<g>FINO<g>: 45.55%C, 2.46%H, 3.80%N, 34.38^1. Found: 44.94%C, 2.43$*, 3>70%N, 34.09%I

d. 3-(2-fluorophenyl)-7-iodo-6-methoxy-1,2-benzisoxa-

sol (8.2 g) is refluxed for 18 hours in 130 ml of CHgClg containing 6.6 ml of BBr^. The reaction mixture is poured into HgO and extracted into ether.

Drying and evaporation gives a crystalline product which is triturated well with hexane to give 3-(2-fluorophenyl)-6-hydroxy-7-iodo-1,2-benzisoxazole, mp 212-214°C Assay: Calculated for C-^ FINE: 43.97%C, 1.99%H, 3.95%N, 35.74%I<->Found: 44.19%C, 2.00%H, 3.86%N, 35, 12%I.

e. 3-(2-Fluorophenyl)-6-hydroxy-7-iodo-1,2-benzisoxazole (7.80 g) in 80 ml DMF is treated at 60°C with 6.6 g KgCO^ and 7.9 g ethyl bromoacetate. After one hour the temperature is increased to 90°C and 80 ml of HgO and 8 ml of 50% NaOH are added. After a further 30 minutes the mixture is poured into HgO and acidified and extracted

then in ether, dried and evaporated to give {_/ 3~ (2-fluorophenyl)-7-iodo-1,2-benzisoxazol-6-yl7oxy}acetic acid, mp 178-180°C.

Analysis:

Calculated for C-^H^FINO^: 43.61%C, 2.20%H, 3.39%N.

Found: 43.25%, 2.12%H, 3.28%N.

Example 34

a. 10 g of 3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole from example 33 b are dissolved in 400 ml dry THF and treated at

-40<W>C with 21 ml of 2.2 M n-butyllithium. After stirring for one hour, bromine (2.5 ml) is added dropwise. The reaction mixture is poured into HgO, extracted with ether and washed with NagSO^O^ solution. Drying and evaporation gives a material containing the desired brominated product, 'J-bromo-J-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole, mp 150-153°C

Analysis:

Calculated for C-^HgBrFNOg: 52.19% C, 2.82% H, 4.35% N, 24.81% Br. Found: 51.97%C, 2.83%H, 4.28%N, 25.17%Br.

b. 7-Bromo-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole (7.20 g) is refluxed for 18 hours in 130 ml CH 2 Cl 2 containing 6.6 ml BBr 2 . The reaction mixture is poured into HgO and extracted with ethyl acetate. Evaporation and trituration with hexane gives the corresponding phenol, melting point 231-234°C.

The phenol (6.30 g) in 80 ml of DMF is treated at 60°C

with 6.6 g of KgCO and 7.9 g of ethyl bromoacetate. After one hour, 80 ml of H20 and 8 ml of 50% NaOH are added and the temperature is increased to 90°G.

After a further 45 minutes, the reaction mixture is acidified and extracted with ethyl acetate. Evaporation and recrystallization from toluene/CHgCN gives {(/7''-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl/oxy}acetic acid, melting point 180-182°C

Analysis:

Calculated for C-^H^BrFNO^: 49.20%C, 2.48%H, 3.83%N,

Found: 49.19%C, 2.47%H, 3.88%N.

Example 35

a. To a mixture of 4 g of 2-chlororesorcinol dimethyl ether and 3>7 g of 2,3-difluorobenzoyl chloride in 60 ml of 1,2-dichloroethane, add portionwise at 5°C > 3.0 g of AlCl^. The mixture is heated to room temperature and then boiled for 30 minutes. The reaction mixture is poured into concentrated HCl ice and allowed to stand

about. 72 hours. The aqueous layer is extracted with additional organic solvents, dried over Na^SO^ and evaporated to give 3-chloro-2-hydroxy-4-methoxy-2<f>,3'-difluorobenzophenone, mp 161-162°C

Analysis:

Calculated for C-^HgClFgO^: 56.30%C, 3.04%H, 12.72%F.

Found: 56.26%C, 3.06%H, 12.56%F.

b. To a solution of 24 g of 3_chloro-2-hydroxy-4-methoxy-2<1>,3<T_>difluorobenzophenone in 160 ml of pyridine, add 22 g of hydroxylamine HCl. The mixture is refluxed for 2 hours and pyridine is evaporated in vacuo. The residue is distributed between ethyl acetate and 5% HCl. The ethyl acetate extract is washed with water, dried over Na2SO4 and evaporated to give a yellow solid consisting of

of two isomers. The solid substance is melted at 205°C for approx. 13 minutes. The residue is dissolved in hot ethyl acetate and then evaporated to dryness to give E-3-chloro-2<\>,3<1->difluoro-2-hydroxy-4-methoxy-benzophenone oxime, mp 198-199°C-

Analysis:

Calculated for C-^H^ClFgNO^ : 53 , 60%C , 3.21%H, 4.47%N,

Found: 53.95%C, 3.29%H, 4.42%N.

c. A mixture of 1.5 g of E-3-chloro-2T,3*-difluoro-2-hydroxy-4-methoxybenzophenoxime and 0.67 g of acetic anhydride is heated at 60°C for 30 minutes. The mixture dissolves and then solidifies. The residue is distributed between ethyl acetate and 10%

NaHCO3. The ethyl acetate extract is washed, dried over Na2SO4 and evaporated to give E-3-chloro-2<1>,3'-difluoro-2-hydroxy-4-methoxy-benzophenone O-acetyloxime, mp 136-139°C.

Analysis:

Calculated for C-LgH^ClFgNO^: 54.02%C, 3.40%H, 3.94%N. Found: 53.89%C, 3.48%H, 3.97%N. d. A solution of 19 g E-3-chloro-2',3'-difluoro-2-hydroxy-4-methoxybenzophenone O-acetyl oxime in 200 ml DMF is added dropwise to a mixture of 1.4 g NaH in 200 ml DMF in a N^ atmosphere. The mixture is stirred for 1/2 hour and then heated at 45°C for 1/2 hour. Water is added and a product is precipitated which is filtered and dried to give 7-chloro-3-(2,3-difluorophenyl)-6-methoxy-1,2-benzisoxazole, melting point 184-189°C.

Analysis:

Calculated for C-^HgClFgNOg: 56.87^0, 2.73%H, 4.74%N. Found: 56.95%C, 2.84%H, 4.77$N.

e. A solid mixture of 12.4 g of 7-chloro-3-(2,3-difluoro-phenyl)-6-methoxy-1,2-benzisoxazole and 50 g of pyridine HCl is heated to 200°C for 45 minutes. The mixture is poured into well-stirred ice water and 7-chloro-6-hydroxy-3-(2,3-difluorophenyl)-1,2-'

benzisoxazole, melting point 250-154°C

• Analysis:

Calculated for C-^HgClFgNOg: 55.43%C, 2.15%H, 4>97%N

Found: 55.60%C, 2.25%H, 4.91%N.

f. To a solution of 12 g of 7-chloro-6-hydroxy-3-(2,3-difluorophenyl)-1,2-benzisoxazole in 120 ml of DMF, add 6.36 g of KgCO^ followed by 7.83 g of BrCHgCOgCgH ^. The reaction mixture is heated at 60°C for two hours and then allowed to stand for 18 hours. To the mixture, add 200 ml of water and 15 ml of 5°% NaOH. The mixture is heated at 90°C for 90 minutes, poured into water and fermented. The product is extracted with ethyl acetate which is dried over Na2SO4 and evaporated to give { /J-chloro-3-(2,3-difluorophenyl)-1,2-benzisoxazol-6-yl7oxy)acetic acid, melting point 183-187°C

Analysis:

Calculated for C-^HgClFgNO^: 53.04%C, 2.37$*,. 4.12%N Found: 53.20%C, 2.49%H, 3.88%N.

Example 36

a. To a solution of 10 g (0.033 ml) of 2T<->fluoro-4-methoxy-2,3-dichlorobenzophenone according to example la in 100 ml of pyridine. add 3>17 g of hydroxylamine HC1. The mixture is refluxed for approx. 64 hours. The pyridine is evaporated and the residue is distributed between 5% HCl and ethyl acetate. The ethyl acetate extract is washed with water, dried over Na2SO4 and evaporated to give 2,3-dichloro-4-methoxy-2'-fluorobenzophenone, mp 195-197°c«

Analysis:

Calculated for C-^H^ClgFNOg : 53.52%C, 3.21%H, 4.46%N,

Found: 53.55%C, 3.10%H, 4.42%N.

b. To a solution of 8 g of 2,3-dichloro-4-methoxy-2'-fluorobenzophenoxime in 50 ml of DMF, add 0.67 g of NaH under an N atmosphere. The mixture is stirred for 1 hour and water is added to precipitate 7-chloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole which is filtered and dried, melting point 155-158°C..

Analysis:

Calculated for C-^HgClFNOg: 60.55%C, 3.26%H, 5.05%N.

Found: 60.63%C, 3.15$H, 5.01$N. c. A solid mixture of 2 g of 7-chloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole and 20 g of pyridine hydrochloride is heated for 1 hour at 190 - 210°C. The hot reaction mixture is poured into well-stirred ice water. The mixture is made slightly acidic. 7-chloro-6-hydroxy-3-(2-fluorophenyl)-1,2-benzisoxazole is collected by filtration and dried, melting point 140-141°C.

Analysis:

Calculated for C-^H^ClFNOg: 59.22% C, 2.68% H, 5.31% N.

Found: 59.16%C, 2.65%H, 5.23%N.

d. The procedure according to example 35f can be carried out with 7-chloro-6-hydroxy-3-(2-fluorophenyl)-1,2-benzisoxazole to give yl jijj-chloro-3-(2-fluorophenyl)-1 ,2-b enzis oxaz ol-6-yl7oxy}ac et at, the product according to example

Example 37

a. Dissolve 2-chlororesorcinol dimethyl ether (22.0 g) and o-fluorobenzoyl chloride (20.2 g) in 250 ml of dichloroethane, cool in an ice bath and treat with A1C1^ (18.6 g). 15 minutes after complete addition, the reaction mixture is heated to reflux

for 30 minutes. It is poured into HgO and extracted with ethyl acetate. Evaporation and trituration with hexane gives 3~chloro-2'-fluoro-2-hydroxy-4-methoxybenzophenone, melting point 132-133°C

Analysis:

Calculated for C^H-^CIFO^: 59.90%C, 3.59%H, 12.63%C1.

Found: 59.77%C, 3.59%H, 12.51%C1.

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

Analysis:

Calculated for C-^H^CIFNO^: 56.86%C, 3.75%H, 4.79%N.

Found: 56.67%C, 3.68%H, 4.66%N. c. E-3-chloro-2f<->fluoro-2-hydroxy-4-methoxybenzophenone oxime (18.1 g) is heated at 60°C for 30 minutes with 9 ml of acetic anhydride. The reaction mixture is partitioned between ether and 10% NaHCO^ and washed with 10% NaHCO^ until the wash water remains basic. Drying, evaporation and trituration with hexane gives E-3-chloro-2'-fluoro-2-hydroxy-4-methoxy-benzophenone O-acetyl oxime, melting point 125-128°C.

Analysis:

Calculated for C^H-^CIFNO^: 56.90%C, 3.88%H, 4.15#N.

Found: 56.79%C, 3.85%H, 4.20%N.

d. The procedure of Example 35^ can be repeated to form 7-chloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole. Then the method according to example 36c and d can be used

to give ethyl β-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl-7-oxyacetate.

Example 38

a. 5.0 g of 7-chloro-6-hydroxy-3-(2-fluorophenyl)-1,2-benzisoxazole according to example 36 c in 30 ml of DMF is 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. The solution is then poured onto ice and precipitated

ethyl-2- )_ r 7-chloro-3-(2-fluorophenyl)-1,2-benzisoxaaol-6-yl7oxy} propionate which is filtered off and dried, melting point 79°C

Analysis:

Calculated for C^H^CIFNO^: 59.50%C, 4.13%H, 3.85%N, 9.60%C1 Found: 59.48%C, 4.09%H, 4.00% N, 9.58% Cl.

b. 6.8 g of ethyl 2-([7-chloro-3-(2-fluorophenyl)-1,2-b-enisoxazol-6-yl7oxy)'propionate. is dissolved in 35 ml of methanol and 25 ml of a 15% NaOH solution is added. The suspension is heated for two hours. The reaction mixture is poured onto ice, acidified with HCl and a solid precipitates which is filtered and dried in vacuo to give 2,-|^7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-3 - yl7oxy}-propionic acid, melting point 159-161°C

Analysis:

Calculated for C1gH11ClFN04_: 57.2%C, 3.28%H, 4.18%N, 10.55%C1 Found: 56.8%C, 3.24%H, 4.17%N, 10.51 %C1.

Example 39

a. To a mixture of 21 g of 2,5-difluorobenzoyl chloride and 20.4 g of 2-chlororesorcinol dimethyl ether in 250 ml of 1,2-dichloroethane, add 15)7 g of AlCl in portions at 5-10°C. The mixture up-

warm to room temperature and then reflux 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 Na2SO4 and evaporated to give 3-chloro-2<1>,5'-difluoro-2-hydroxy-4-methoxybenzophenone, mp 178-180°C.

Analysis:

Calculated for C^H^CIF^: 56.30%C, 3>04%H, 12.72%N.

Found: 56.16%C, 3.01#H, 12.75%N.

b. A mixture of 28 g of 3-chloro-2<T>,5<T->difluoro-2hydroxy-4-methoxybenzophenone and 26 g of hydroxylamine HCl in 250 ml of pyridine is refluxed for three hours. The pyridine is evaporated and the residue is distributed 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 as a mixture of isomers. The solid product is heated at 200-210°C for about 30-45 minutes, recrystallized from toluene to give E-3-chloro-2<f>,5'-difluoro-2-hydroxy-4-methoxy-benzophenone oxime, melting point 209-210°C.

Analysis:

Calculated for C14H10CIF2N03: 53.60%C, 3.29%H, 4.47%N. Found: 53.61%C, 3.22%H, 4.43%n.

c- A mixture of 19 g of E-3-chloro-2<f>,5»-difluoro-2-hydroxy-4-methoxybenzophenone oxime is heated with 9 ml of acetic anhydride at 60°C for 30 minutes. On cooling, the mixture becomes

solid. The residue is partitioned between ethyl acetate and 10% NaHCO The ethyl acetate extract is washed with water, dried over NapSO^ and evaporated to give E-3-chloro-2',5'-difluoro-2-hydroxy-4-methoxy-benzophenone O-acetyl oxime, m.p. 130-131°C.

Analysis:

Calculated for Cl5Hl2ClF2N04: 54.02%C,3.40%H,3.94%N. Found: 53.76%c, 3.37%H, 3.89%N.. d. To a suspension of NaH/200 ral DMF in a N2 atmosphere is added dropwise 19.5 g of E-3-chloro-2., 5'-difluoro-2-hydroxy-4-methoxybenzophenone O-acetyl oxime in 50 mL DMF. The mixture is stirred for 30 minutes and water is added to precipitate 7-chloro-3-(2,5-difluorophenyl)-6-methoxy-1,2-benzisoxazole, melting point 198-199°C.

Analysis: Calculated for C14HgClF2N02: 56.87%C, 2.73%H, 4.74%N. Found: 56.74%C, 2.70%H, 4.70%N.

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

Analysis: Calculated for C^HgClFgNOg: 55.43%C, 2.15%H, 4.97%N. Found: 55>26%C, 2.02%H, 4>93%N-

f. To a solution of 9.3 g of 7-chloro-3-(2,5-difluorophenyl)-6-hydroxy-1,2-benzisoxazole in 100 ml of DMF

4.97 g of K^CO^ and 6.07 g of ethyl bromoacetate are added dropwise. The mixture is heated for 2 hours at 60°C. Add 200 ml of water and 15 ml of 50% NaOH to the mixture. The mixture is stirred at 9°C for 90 minutes and then poured into water and acidified. The product is extracted with ethyl acetate, dried over Na2SO4 and evaporated to give

β-Chloro-3-(2,5-difluorophenyl)-1,2-benziso-sazol-6-yl-7-oxyacetic acid.

Analysis:

Calculated for C-^HgClFgNO^: 53.04%C, 2.37%H, 4.12#N. Found: 53.37%C, 2.39%H, 4.01#N.

Example 40»

a. Dissolve 2-chlororesorcinol dimethyl ether (3->4g) in 20 ml of CH2Cl2 and add TiCl^ (4.3 ml). Dichloromethyl methyl ether (2.3 g) is added to the solution • After 30 minutes, the reaction mixture is poured into HgO and extracted with ether. Drying and evaporation gives 3_chloro-2,4-dimethoxybenzaldehyde, melting point 107-108°C.

Analysis:

Calculated for C^HgClO^: 53.88%C, 4.52%H, 17.68#C1. Found: 53.93%C, 4.52%H, 17.42%C1.

b. 3-chloro-2',4-dimethoxybenzaldehyde (2.75 g) is refluxed for 30 minutes in 20 ml of dichloroethane containing 1.8 g of AlCl₂. The reaction mixture is then poured into HgO and extracted with CHgClg.

Evaporation and recrystallization from isopropanol gives 3-chloro-2-hydroxy-4-methoxybenzaldehyde, melting point 125°C Analysis: Calculated for CgH^ClO^: 51.49#C, 3.78%H, 19.00%C1. Found: 51.33%C, 3.78%H, 18.65%Cl. c. 3-Chloro-2-hydroxy-4-methoxybenzaldehyde (1.48 g) is suspended in 15 ml H 2 O and hydroxylamine-O-sulfonic acid (1.08 g) is added along with 0.1 g NagSO 2 . After three hours, a further 15 ml of H 2 O are added. After a total of four hours, the reaction mixture is treated with Q% NaHCO 3 solution and then extracted with ether. Evaporation and trituration with hexane gives a solid product. Recrystallization from toluene/hexane gives 7-chloro-6-methoxy-1,2-benzisoxazole, melting point 115-118°C. Analysis: Calculated for CgHgClNOg 52.33%C, 3.29%H, 7.63%N. Found: 52.35%C, 3.30%H, . 7.71^N. d. The procedure according to example 35e and f can be used with 7-chloro-6-methoxy-1,2-benzisoxazole to give 7-chloro-1,2-benzisoxazol-6-yl7oxy}acetic acid.

Example 41

a. To a solution of 1.7 g of 2-chlororesorcinol dimethyl ether and 2.08 g of o-trifluoromethylbenzoyl chloride in 50 ral of 1,2-dichloroethane is gradually added at 5-7°C 1.6 g of ferric chloride. The mixture is brought to room temperature and allowed to stand for 18 hours. ^The reaction mixture is refluxed for 30 minutes and poured into 5%

HC1 and ice. The aqueous phase is extracted with additional organic solvent. The combined organic extracts are washed with water, dried over NagSO4 and evaporated to give 3-chloro-2-hydroxy-4-methoxy-2*-trifluoromethylbenzophenone, mp 101-102°C

Analysis:

Calculated for C^ft^ClF^: 54.48%C, 3.05%H, 17.24%F. Found.: 54.16%C, . 2.91% H, 17.1 6% F.

b. The procedure of the preceding examples (such as Example 35) can be used with 3-chloro-2-hydroxy-4-methoxy-2'-trifluoromethylbenzophenone to give the corresponding oxime, cyclization of the oxime and formation of the acid to give {/ 7-Chloro-3-(2-trifluoromethylphenyl)-1,2-benzisoxazol-6-yl/oxyacetic acid.

Example 42

a. 10 g of 7-chloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole according to example 36b is dissolved in glacial acetic acid (800 ml) while stirring and chlorine gas is fed through slowly for 1/2 hour to give a solution containing a small amount of suspended starting material. The reaction mixture is stirred for 18 hours at room temperature and then the reaction mixture is poured onto ice water with stirring to form 5,7-dichloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole, melting point 121°C.

Analysis:

Calculated for C-^HgClgFNOg: 53>87%C, 2.59%H, 4>49%N. Found: 53.54%C, 2.59%H, 4.51%N.

b. 10 g of 5,7-dichloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole are combined with 100 g of pyridine hydrochloride and heated at 200°C for 1/2 hour. The hot melt is quickly poured into stirred ice water and a formed precipitate is filtered off and dried for 48 hours in a vacuum (64°C). The solid is recrystallized from toluene and gives 5>7-dichloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole, melting point 194-196°C.

Analysis:

Calculated for C-^HgClgFNOg: 52.44%C, 2.01%H, 4.70%N, 23.53%C1 Found: 52.07%C, 2.08%H. 4.96% N, 23.92% Cl.

c. 1.4 g NaH is suspended in 50 ml 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 is added dropwise. The solution is heated to 45°C for one hour. Ethyl bromoacetate (4.0g) in 20 ml of DMF is added dropwise and the reaction is stirred at 40°C for 2 hours. The solution is poured into 1 liter of water, stirred and extracted

with ethyl acetate. The organic extract is washed with saturated NaCl solution and the solvent is removed in vacuo to give ethyl[/5,7-dichloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl7oxy} acetate, m.p. 105-106°C.

Analysis:

Calculated for C^H-^Cl<g>FNO<g>:53>26%C, 3.13#H, 3>65%N, 18.39%Cl. Found: 52.91%C, 3.00%H, 3.41%N, 18.09%CL.

d. 14.0 g of ethyl β-5,7-dichloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl7oxy}acetate is heated in 75% ethanol/HgO (700 ml) while stirring until dissolved. 20 ml of a 50% solution of NaOH is added and a precipitate forms. Upon further heating and stirring, the precipitate dissolves and is stirred for 2 ½ hours. The ethanol is then evaporated in a vacuum and the residue is made acidic

with 10% HCl. The precipitate is filtered and dried in vacuo to give 5>7-dichloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl7oxy} acetic acid, melting point 160-170°C.

Analysis:

Calculated for C^HgClgFNO^: 50.59%C, 2.2.6%H, 3.93%N.

Found: 50.53%C, 2.3%H, 3.88%N.

Example 43

a. To a suspension of NaH (1.0 g) of a 5% dispersion in mineral oil of 50 ml DMF is added a solution of 5.0 g of 7-chloro-3-(2-fluorophenyl)-6-hydroxy-1 ,2-benzisoxazole according to example 36c in 50 ml DMF. The solution is stirred for 1 hour at room temperature, then cooled to 5°0°S, 3.5 g of N,N-dimethylthiocarbamoyl chloride are added all at once. The reaction is gradually brought to 60°C and stirred for 2.5 hours. The solution is then poured into water and extracted with methylene chloride until the extracts are colourless. The combined organic extracts are washed with 10% KgCO 3 , then with saturated NaCl. The solvent is removed in vacuo to give 7-chloro-6-(O-N,N-dimethylthiocarbamyl)-3-(2-fluorophenyl)-1,2-benzisoxazole, mp 153-154°C

Analysis:

Calculated for C-^H^ClFNgOgS: 54.8%C, 3.4%H, 7.9%N, ■ 9.1%S. Found: 54.4%C, 3.4%H, 7.9%N, 9.1%S.

b. 4.5 g of 7-chloro-6-(O-N,N-dimethylthiocarbamyl)-3-(2-fluorophenyl)-1,2-benzisoxazole is heated under nitrogen at 205°C for 45 minutes. A mixed cooled solid is recrystallized from ethyl acetate to give colorless prisms of 7-chloro-6-(S-N,N-dimethylthiocarbamyl)-3-(2-fluorophenyl)-1,2-benzisoxazole, mp 140-142°C.

Analysis:

Calculated for C^H-^ClFNgOpS: 54.77%C, 3.44%H, 7.98%N, 3 , H% S. Found: 54.87%C, 3.56%H', 7, 86%N, 9.28%S.

c. Dissolve 2.0 g of 7-chloro-6-(S-N,N-dimethylthiocarbamyl)-3-(2-fluorophenyl)-1,2-benzisoxazole in methanol and add 25 ml of 15% aqueous NaOH. The solution is refluxed for three hours. The reaction mixture is poured into a large amount of water, acidified with

HCl to form 7-chloro-3-(2-fluorophenyl)-6-mercapto-1,2-benzisoxazole, mp 125-129°C

Analysis:

Calculated for C-^H^CIFNOS: 55.81%C, 2.50H, 5.01%N, 11.46%S. Found: 55>94%C, 2.58%H, 5.09%N, 11.52%S. d. 3.2 g of 7-chloro-3-(2-fluorophenyl)-6-mercapto-1,2-' benzisoxazole, 3.1 g of KgCO^ and 3.67 g of ethyl bromoacetate are added to 60 ml of DMF and heated for 2 hours at 50°C with stirring.

The solution is poured into 700 ml H 2 O and extracted with ethyl acetate.

The combined organic extracts are dried over KgCO 4 , and the solvent is removed in vacuo to give 1/j-chloro-J-(2-fluorophenyl)-1,2-benzisoxazol-6-yl7thio)-acetate.

Analysis:

Calculated for C^H^CIFNO^S: 55.89%C, 3.56%H, 3.83%N, 8.76%S. Found: 55.92%C, 3.70%H, 3.80%N, Q^ lfoS.

e. Dissolve 1.7 g of ethyl (7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl)thioacetate in 50 ml of ethanol while stirring and heating. A 50% solution of NaOH is added (3 ml) with 25 ml of water and a precipitate forms. After one hour, ethanol is removed and the residue is made acidic with HC1. The precipitate is filtered and dried to give 5>7-dichloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl7-thioacetic acid, mp 165°C

Analysis:

Calculated for C-^HgClFNO^S: 53.41%C, 2.67%H, 4>15%N, 9.49%S. Found: 53.39%C, 2.68%H, 4.19%N, 9.44%S.

Example 44

a. To a solution of o-fluorobenzoyl chloride (47)6 g)

in 100 ml of dichloromethane, AlCl^ (40.0 g) is added portionwise over the course of 30 minutes. To the resulting dark solution is added dropwise a solution of l-chloro-3,5-dimethoxybenzene (52.0 g)

in 120 ml of dichloromethane, over 15 minutes. After stirring at room temperature for 4 hours, the mixture is poured into 1 liter of ice-diluted HCl solution and then stirred for 30 minutes.

The organic layer is collected, evaporated to an oil, which dissolves

in ether, washed with water, dilute NaOH solution, water, then dried (saturated NaCl, anhydrous MgSO^). After filtering,

the solvent is evaporated to a substance obtained, which is purified on silica gel, eluted with dichloromethane to give 2-chloro-4,6-dimethoxy-2'-fluorobenzophenone, melting point 88-92°C.

Analysis:

Calculated for C15H12C1F03: 6l.13#C, 4>H#H, 12.03%C1, 6.45$\ Found: 60.95%C, 4.06%H, 11.85%C1, 6.38 %F.

b. To a solution of 2-chloro-4,6-dimethoxy-2f<->fluorobenzophenone (33 g) in 150 ml of dichloroethane, add AlCl^ (15 g) in portions over the course of 15 minutes. After stirring under .-

reflux (90°C) for 3 hours, cool the mixture, pour into 1 liter of ice-diluted HCl solution, stir for 30 minutes and then extract with ether. The ether/dichloroethane solution is washed with water, then dried (saturated NaCl, anhydrous MgSO 4 ) and filtered.

After filtration, the solvent is evaporated

to give 2-chloro-2'-fluoro-6-hydroxy-4-methoxybenzophenone, mp 85-90°C.

Analysis:

Calculated for C-^H^CIFC^: 59.90%C, 3.59$*, 6.77$" • Found: 59.78%C, 3.53%H, . 7.00%F. c 2-chloro-2<*->fluoro-6-hydroxy-4-methoxybenzophenone (28.5 g) and hydroxylamine hydrochloride (14 g) are added to 125 ml of pyridine. After stirring at reflux (120°C) for 3 hours, the mixture is cooled, the pyridine is evaporated to a yellow semi-solid, the solid is dissolved in ether, washed with water,

then dried (saturated NaCl, anhydrous MgSO^). After filtration, the solvent is evaporated to form an oil, which solidifies to Z-2-chloro-2 1-fluoro-6-hydroxy-4-methoxybenzophenone oxime, mp 130-140°C, by trituration with petroleum ether.

Analysis:

Calculated for C-^H-^CIFNO^: 56.86%C, 3.75%H, 4.74$J. Found: 56.74%C,. 3.70#H, 4>74%N. d. Z-2-chloro-2'-fluoro-6-hydroxy-4-methoxybenzo-phenonoxime is reacted with acetic anhydride as indicated in Example 30 c to form E-2-chloro-2'-fluoro-6-hydroxy-4 -methoxybenzophenone O-acetyl oxime.

e.. To a suspension of NaH (2.4 g) in 20 ml DMF, a solution of E-2-chloro-2f<->fluoro-6-hydroxy-4-methoxy-benzophenone O-acetyl oxime (15 g ) in 50 ml DMF. After stirring at ambient temperature, the mixture is poured into 1 liter of ice water, stirred for 30 minutes and the precipitate collected. The precipitate is washed with water then dried to give 4~chloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole, mp 113-H5°C«

Analysis:

Calculated for C-^H-^ClFNOg: 60.55%C, 3.27$*, 5.05$*

Found: 60.52%C, 3.33$*, 4.96$J.

f. By using 4-chloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole as indicated in the preceding examples, such as example 20 d and e, 4-chloro-3-(2 -fluorophenyl)-1,2-benzisoxazol-6-yl7oxy}acetic acid, melting point 172-174°C.

Example 45

a. To a mixture of 3.9 g of AlCl^ and 4.67 g of 2,3-dichloroanisole in 10 ml of 1,2-dichloroethane at -10°C, 5 g of o-methoxybenzoyl chloride is added dropwise. The mixture is stirred in 2 l/ 2 hr and eventually warmed to 5°C. The reaction mixture was poured onto conc. HCl and ice. The mixture was stirred 1/2/ hr to cleave the complex. The aqueous layer was extracted with additional organic solvent. The combined organic layers were washed to neutrality, dried over Na2SO4 ^and evaporated to give an oil which solidifies on trituration with hexane.The crude product is recrystallized from 95% ethanol to give 2,3-dichloro-2',4-dimethoxybenzophenone, mp 94-96°C

'Analysis:

Calculated for C-^H-^ClgO^ : 58.00%C, 3.89%H,

Found: 57.84%C, 3.81%H.

b. A solid mixture of 13 g of 2,3-dichloro-2T,4-dimethoxy-benzophenone and 52 g of pyridine HCl is heated at 200°C for 1 hour.

The hot mixture is then poured into well-stirred ice water. The product is extracted with ethyl acetate. The extract is dried over Na2SO4 and evaporated to give 2,3-dichloro-2*,4-dihydroxybenzophenone, mp 197-201°C.

Analysis:

Calculated for C^H^Cl<g>O^: 55.15%C, 2.80%H.

Found: 55.26%C, 2.86%H.

c. To a suspension of 2.87 g of NaH in 150 ml of DMF, add 30.76 g of 2,3-dichloro-24-dihydroxybenzophenone in 100 ml of DMF followed by the addition of 18.37 g of ethyl bromoacetate. The mixture is stirred for approximately 1/2 hour, poured into ice and acid and extracted with CHCl^. The CHCl^extract is dried over NaSO^ and evaporated to give ethyl 2,3-dichloro-4-(2-hydroxybenzoyl)phenoxyacetate, mp 109-110°C.

Analysis:

Calculated for C-^H^Cl^: 55>30%C, 3.82%H.

Found:- 55.15%C, 3.81%H.

d. Using ethyl 2,3-dichloro-4-(2-hydroxybenzoyl)-phenoxyacetate and the procedure according to the preceding examples, the corresponding oxime can be formed and cyclized and the ester hydrolyzed to give /7-chloro-3- 2-hydroxyphenyl)-1,2-benzisoxazol-6-yl7oxyacetic acid.

Example 46

a. To a stirred solution of phenacetyl chloride (25 g) in 15 ml of carbon disulfide, AlCl (22 g) is added portionwise over a period of 30 minutes, followed by a solution of 2,3-dichloroanisole (28 g) in 50 ml carbon disulfide.

After stirring at reflux (50°C for 3 hours, the mixture is cooled, then AlCl^ (22 g) is added and the mixture is stirred under reflux for 2 hours'. The mixture is cooled, poured into a solution of cold 15% HC1, stirred for 30 minutes and is then 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-phenacetylphenol, mp 173-180°C. Analysis:

Calculated for C14H10C12O2: 59.81%C, 3.59%H.

Found: 60.15%C, 3.65%H.

b. 2,3-dichloro-4-phenacetylphenol is reacted with hydroxylamine hydrochloride in pyridine as mentioned in previous examples to give 2,3-dichloro-4-phenylacetylphenol oxime. c. To a suspension of NaH (2.54 g) in 10 ml dry DMF is added a solution of 2,3-dichloro-4-phenacetylphenol oxime (6.3 g) in 25 ml dry DMF.

After stirring for 2 hours at 80°C, the mixture is cooled, then a solution of ethyl bromoacetate (4.2 g) in 10 ml of dry DMF is added and stirred at room temperature for 30 minutes and then at 60°C for 30 minutes.

After cooling, the mixture is poured into 500 ml of water, stirred for 30 minutes, then extracted with ethyl acetate.

The organic layer is washed with water, then dried (sat

NaCl, anhydrous MgSO^). After filtration, the solvent is evaporated to an oil from which 1-(3-benzyl-7-chloro-1,2-benzisoxazol-6-yl)oxyacetate is obtained, melting point 120-122°C.

Analysis:

Calculated for C-LgH-^ClNO^: 62.52%C, 4.66%H, 4.05%N.

Found: 62.35%C, 4.74%H, 3.83%N.

d. Add ethyl (3-benzyl-7-chloro-1,2-benzisoxazol-6-yl)oxy}acetate (25.0g) to 650 ml of absolute ethanol followed by 50% NaOH solution (30 ml). After stirring at reflux

(80 °C) for 1 hour, 500 ml of water is added, the pH is adjusted to 1

with concentrated HC1, then dilute further with 1 liter of water. The precipitate formed is collected, washed with water, then dissolved in dichloromethane. Dichloromethane<p>plosnin<g>en. washed with water, and then dried (saturated NaCl, anhydrous MgSO^).

After filtration, the solvent is evaporated

to give (3-benzyl-7-chloro-1,2-benzisoxazol-6-yl)oxy}acetic acid, mp 147-153°C.

Analysis:

Calculated for C-LgH-^ClNO^: 60.48% C, 3.81% H, 4.41% N, 11.16% Cl. Found: 60.36%C, 3.96%H, 4.33%N, 10.91%C1.

Example 47

a. The Friedel-Craft procedure of Example 46 is repeated with 2,3-dichloroanisole, 1-naphthyl chloride and AlCl^ to

give (2,3-dichloro-4-hydroxyphenyl)(1-naphthyl)methanone.

b. Add 9.87 g of hydroxylamine hydrochloride to a solution of 22.48 g of (2,3-dichloro-4-hydroxy-phenyl)-(1-naphthyl)methanone in 150 ml of pyridine. The mixture is refluxed for approx. 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 distributed between 5% HCl and ethyl acetate. The ethyl acetate extract is washed with water, dried over Na 2 SO 4 and. is evaporated to give a semi-solid product. This product dissolves

in about 100 ml of ethyl acetate and passed through a column of activated charcoal. The filtrate is evaporated to give a solid which on trituration with hexane-ether gives (2,3-dichloro-4-hydroxyphenyl)-(1-naphthyl)methanone oxime, mp 145-160°C.

Analysis:

Calculated for C-^H-^ClgNOg: 6l.46#C, 3.34%H, 4.22%N.

Found: 6l.53%C, 3.45%H, 4.14%N.

c. To a solution of 3 g of (2,3-dichloro-4-hydroxyphenyl)-(1-naphthyl)methanone oxime in 25 ml of DMF, add 0.54 g of NaH under Ng. The mixture is heated to an internal temperature of 100°C for 1 hour and 20 minutes. The reaction mixture is then cooled to room temperature and 1.65 g of ethyl bromoacetate is added dropwise. The mixture is stirred for 18 hours, water is added and the product is extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried over Na 2 SO 4 and evaporated to give ethyl 7-chloro-3-(1-naphthyl)-1,2-benzisoxazol-6-yl7oxy-acetate, m.p. 75-85°C

Analysis:

Calculated for C^H^CINO^: 66.06% C, 4.22% H, 3.67% N. Found: 65.81%C, 4.24%H, 3.53%N. d. A suspension of 1.85 g of ethyl β-7-chloro-3-(1-naphthyl)-1,2-benzisoxazol-6-yl7oxy}acetate, 100 ml of ethanol and 2 ml of 50% NaOH is refluxed for one hour. To the hot mixture is added 100 ml of water followed by enough concentrated HCl to make the mixture acidic. The reaction mixture is stirred and the precipitate is formed by cooling. Ethanol is evaporated in vacuum °g£ZT-chloro-3-(1-naphthyl)-1,2-benzisoxazol-6-yl7oxy}acetic acid is filtered off and dried in vacuum, melting point 172-174°C« Analysis: Calculated for C-^ H-^CINO^: 64.50%C, 3.42%H, 3.96%N, ' Found: 64.51%C, 3.38%H, 3.97%N.

Example 48

a. The Friedel-Craft reaction mentioned in the previous example is repeated with 2,3-dichloroanisole, J-fluorobenzoyl chloride and AlCl 2 to give 2,3-dichloro-4-hydroxy-3T<->fluorobenzophenone.

b. 1.58 g of hydroxylamine hydrochloride is added to a solution of 5 g of 2,3-dichloro-4-hydroxy-3'-fluorobenzophenone in 50 ml of pyridine. The mixture is refluxed for 18 hours. Pyridine is evaporated in vacuo and the residue is distributed between 5% HCl and ethyl acetate. The ethyl acetate is washed with water, dried over Na 2 SO 4 and evaporated to give 2,3-dichloro-4-hydroxy-3'-fluorobenzophenone oxime as a mixture of isomers, mp 178-185°C. Analysis: Calculated for C-^H-LQClgFNOg: 53 > 52%C , J, 21% K, 4.46%N.

Found: 53.66%C, J, H% E, 4.39%N.

c. To a solution of 3 g of 2,3-dichloro-4-hydroxy-3'-fluorobenzophenoxime in 20 ml of DMF, add 0.25 g of NaH in a Ng 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, mp 149-150°C. Analysis:

Calculated for C-^H^ClFNOg: 60.55%C, 3.2.6%H, 5.05%N.

Found: 60.54%C, 3.00%H, 4.91%N. d. A solid mixture of 14.47 g of 7-chloro-3-(3-fluorophenyl)-6-methoxy-1,2-benzisoxazole and 58 g of pyridine hydrochloride is heated at 190 - 200°C for 1 hour. The hot mixture is poured into well-stirred ice-water and 7-chloro-6-hydroxy-3-(3-fluorophenyl)-, 1,2-benzisoxazole is collected by filtration and washed well with HgO, melting point 215-217°C.

Analysis:

Calculated for C-^H^ClFNOg: 59.22% C, 2.68% H, 5.31% N.

Found: 59.15%C, 2.66%H, ■ 5.16%N.

e. A solution of 10.2 g of 7-chloro-6-hydroxy-3-(3-fluorophenyl)-1,2-benzisoxazole is added to a mixture of 1.3 g of NaH in 25 ml of DMF. A solution of 6.68 g of ethyl bromoacetate in 25 ml of DMF is added and the mixture is stirred for 2 1/2 hours. 10 ml of 50% NaOH, 175 ml of HgO and 30 ml of DMF are added to the reaction mixture, which is then heated at 80-85°C for 1 hour. The mixture is made acidic with concentrated HC1, water is added and. £/7~Chloro-3-(3-fluorophenyl)-1,2-benzisoxazol-6-yl7oxy)acetic acid is collected by filtration, mp 205-209°C.

Analysis:

Calculated for C-^H^CIFNO^: 56.00%C, 2.83%H, 4.36%N.. Found: 55.96%C, 2.8l%H, 4.21#N.

Example 49

a. Chlorine gas is added to a solution of 1.0 g of 4-chloro-3-(o-fluorophenyl)-6-methoxy-1,2-benzisoxazole, according to example 44e> in 50 ml of glacial acetic acid (the solution is bubbled for 5 minutes). After stirring at room temperature for 1 hour, the mixture is poured

in 500 ml of water, stirred for 15 minutes and the precipitate formed is extracted with ether/ethyl acetate. The organic layer is washed with water, then dried (saturated NaCl, anhydrous MgSO^) and after

filtration, the solvent is evaporated to give 3-(o-fluorophenyl)-6-methoxy-4,5,7-trichloro-1,2-benzisoxazole, melting point 120-140°C.

Analysis:

Calculated for C-^H^Cl^FNOg : 48.51%C, 2.04%H

Found: 48.15°C, 2.27% H.

b. The procedure according to example 20 d and e can be used with 3-(o-fluorophenyl)-6-methoxy-4,5,7-trichloro-1,2-benzisoxazole to give [/4,5,7-trichloro- 3-(2-Fluorophenyl)-1,2-benzisoxazol-6-yl7oxyacetic acid.

Example 50

10 g of 7-chloro-6-hydroxy-3-(2-fluorophenyl)-1,2-benx-isoxazole according to example 36c are dissolved in 70 ml of DMF and 7.86 g of KgCO3 are added while stirring. 3.6 ml of chloroacetonitrile are added and the mixture is stirred for 1/2 hour at room temperature, then the temperature is raised to 55°C for 2 hours. Stirring is continued for 15 hours at room temperature and 1.5 ml of chloroacetonitrile is added and the reaction mixture is stirred for 6 hours at 5°°C. It is poured into a large volume of ice/HgO and £/7-chloro-3-(2-fluorophenyl) -1,2-benzisoxazol-6-yl7oxy}-acetonitrile which precipitates together by filtration, melting point 147°C• Analysis: Calculated for C-^HgCIFNgOg: 59.51%C, 2.66%H, 9.25%N . Found: 59.38%C, 2.67%H, 9.36%N.

Example 51

15 g of 7-chloro-6-hydroxy-3-(2-fluorophenir)-1,2-benzisoxazole in 75 ml of DMF are added to a suspension of 3.0 g

NaH in 75 mL DMF. After 1 hour at room temperature, 16.7 ml of ethyl 2-bromoisobutyrate is added. After 72 hours at 50°C, the reaction mixture is poured into ice/HCl and extracted with CH 2 Cl 2 and the organic phase is washed with 5% K 2 CO 2 followed by washing with saturated NaCl. It is dried over MgSO^, filtered and evaporated to a brown oil. The oil is distilled off under reduced pressure to remove unreacted ethyl-2-bromoisobutyrate and the residue is triturated with ether/petroleum ether, filtered and the mother liquor is evaporated to oil which is distilled (200°C, 0.1mm) giving ethyl-2-£/7-chloro -3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl7oxy}-2-methylpropionate.

Analysis:

Calculated for C^H-^CIFNO^: 60.6%C, 4.53%H, 3.70#N,-Found: 60.0%C, 4.72%H, 3.60%N.

Example 52

a. To a mixture of 46 g of 4-chloro-2-fluorobenzoyl chloride and 38.9 g of 2,3-dichloroanisole in 150 ml of 1,2-dichloroethane, gradually add 32 g of AlCl^. The mixture is heated to 40°C under strong gas evolution. The mixture is poured 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 Na2SO4 and evaporated. The crude product is triturated with hexane and

gives 2,3-dichloro-4-methoxy-4,-chloro-2'-fluorobenzophenone.

An analytical sample is recrystallized from EtOH, melting point 115-116°C.

Analysis:

Calculated for C^HgCl^FOg : 50.41%C, 2.42%H, 5.80%F. Found: 50.11%C, 2.36%H, 6.17%F. b. Corresponding to example 21B, 2,3-dichloro-4-methoxy-4,-chloro-2'-fluorobenzophenone is transferred to 2,3-dichloro-4-methoxy-4,-chloro-2'-fluorobenzophenone oxime. c. To a mixture of 2.24 g of NaH in 100 ml of DMF, 21.75 g of 2,3-dichloro-4-methoxy-4,-chloro-2-fluorobenzophenoxime in 100 ml of DMF are added dropwise. After addition, the mixture is stirred for 1 hour and the reaction mixture is poured into ice water.

A product that precipitates is filtered off and drying gives a mixture of isomers which is chromatographed on silica gel with $ 0% hexane and ^ 0% toluene as eluent to give 7~chloro-3-(4-chloro-2-fluorophenyl)-6 -methoxy-1,2-benzisoxazole, melting point 193-194°C.

Analysis:

Calculated for C-^HgClgFNOg: 53.87% C, 2.58% H, 4.49% N. Found: 54.01%C, 2.56%H, 4.44%N. d. A solid mixture of 5.4 g of 7-chloro-3-(4-chloro-2-fluoro-phenyl)-6-methoxy-1,2-benzisoxazole and 22.4 g of pyridine HCl is heated at 200°C in 2 hours. The reaction mixture is then poured into well-stirred ice water and a demethylated product is formed.

To a solution of 3>9 g of the demethylated product in 40 ml of DMF, 1.9 g of KgCO 2 and 2.3 g of ethyl bromoacetate are added. The reaction mixture is heated to 60°C for 2 hours and set aside

for l8 hours. 100 ml of water and 10 ml of 50% NaOH are added to the reaction mixture. The mixture is heated at 90°C for 90 minutes and the reaction mixture is poured into water, acidified and extracted with ethyl acetate, dried and evaporated to give [/7-chloro-3-(4-chloro-2-fluorophenyl)-1,2-benzisoxazole -6-yl7oxy^acetic acid, melting point 226-227°C.

Analysis:

Calculated for C-^HgClgFNO^: 50.59%C, 2.26%H, 3.93%N.

Found: '50.39%C, 2.24%H, 4.06%N.

Example 53

To a suspension of 0.9 g of lithium aluminum hydride (98%) in 100 ml of anhydrous ether is added a solution of 10 g of ethyl-2-y/j-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6 -yl7oxy3-acetate according to example 1d in 200 ml of ether containing sufficient tetrahydrofuran to cause dissolution. The reaction mixture is stirred for two hours at room temperature and one hour under reflux. 0.9 ml of H^O, 0.9 ml of 15% NaOH and 2.7 ml of H^O are added to the reaction mixture. The stirred suspension is filtered and the filtrate is concentrated to give 2-[/7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl7oxy)-ethanol, mp 112°C.

Analysis :

Calculated for C-^H-^CIFNO^: 58.63^0, 3.58%H, 4.56%N.

Found: 58.48^0, 3.62%H, 4.49%N.

Example 54

4.5 g of ethyl 2-(γ/J-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl7oxyJ-2-methylpropionate, according to example 51) are dissolved in 35 ml of methanol and 30 ml of 15% NaOH are added.The suspension is heated under reflux for 4 hours and then poured into ice-water and acidified to form an oily precipitate.

This precipitate is extracted with ether and the ether extracts are washed with 10% NaHCO 3 . The basic extracts are acidified with concentrated HCl and cooling here gives 2-^-/7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl7oxy)-2-methylpropionic acid, melting point 108°C.

Analysis:

Calculated for C-^H-^CIFNO^: 58.45%C, 3.72%H, 4.01%N. Found: 58.39%C, 3.75%H, 3.96%N.

Example 55

3.35 g of NaN₂ and 2.25 g of AlCl₂ are stirred in 50 ml of THF under reflux for 1/2 hour. A solution of 5 g [/7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl7oxy}acetonitrile, according to example 50, in 50 ml of THF is added and the reaction mixture is stirred under reflux for approx. 120 hours. Water is added to the reaction mixture and the solvent is removed. The residue is treated with dilute HCl and extracted with CHCl^. Extraction of the chloroform solution with 15% NaOH forms a precipitate which is filtered, washed in hot water and acidified to give 7-chloro-3-(2-fluorophenyl)-6-[/5-tetrazolylmethyl/oxy}-1,2 -benzisoxazole, melting point 198-200°C.

Analysis:

Calculated for C-^HgClFN^Og: 52.17% C, 2.60% H, 20.28% N. Found: 52.02%C, 2.69%H, 20.37%N.

Claims (8)

1. Compound, characterized in that it has a formula wherein R means hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl cycloalkenyl, bicycloalkyl, tricycloalkyl, cycloalkyl lower alkyl, cycloalkenyl lower alkyl, naphthyl thienyl, furyl, pyrryl, pyridyl or pyridyl N-oxide, R"4)ether is a free or esterified carboxyl group with from 1 to 8 carbon atoms, -COZ, -COW <R> o, -CH.OH, -CHO, -CH(OR^) <2> , R , R^ and R^" are the same or different and mean hydrogen, halogen, or lower alkyl, X means hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, hydroxy, trifluoromethyl, r g 7 8 9 nitro, amino or acylamino; R^, R , R', R and R J are equal or different and can mean hydrogen or lower alkyl; A and Af are the same or different and mean 0 or S; Z means chlorine, bromine or fluorine; and m and n are the same or different and may each be whole numbers 1, 2 or 3; as well as physiologically tolerable salt thereof. 2. Connection according to claim 1, characterized by formula 3. Compound according to claim 1, characterized by the fact that A and A' both mean oxygen. 4. Process for the preparation of compound of formula I in which R, R1,.R2, R <3> , R^, r <5> , r°, A and A• have the meaning specified in claim 1, characterized by either) that a compound of formula in which R, R , RJ, R , A and A' have the meaning specified in claim 1, is reacted with a compound of formula 15 6 where R , R? and R has the meaning stated in claim 1 and Z means chlorine, bromine or fluorine in the presence of a base and et solvent, orb) a compound of formula or a compound of formula wherein R, R"*", R <2> , R-^, R^ and R^ have the meaning stated in claim 1 is cyclized by treatment with a base in the presence of a solvent at a temperature from room temperature to the reflux temperature of the reaction medium, orc ) a connection with formula in which R<1> , R <2> , R^, R^, R 50 g R^ has the meaning stated in claim 1 and R means hydrogen is reacted with hydroxylamine-o-sulfonic acid, or d) possible conversion of a compound of formula I, in which R"^ means a carboxylic acid ester or CN by hydrolysis to a corresponding compound, in which R"*" means COOH, or e) optional conversion of compounds of formula I, in which R1 means CH(OR1)9 by hydrolysis to a corresponding compound in which R means -CHO, or f) possible conversion of a compound of formula I, in which A and A' each means oxygen, X, R , RJ and R^" does not mean lower alkyl and R1 means CH9 OH or CHO by oxidation to a corresponding compound, in which R means COOH, or g) possible conversion of a compound of formula I in which R"1" means COOH to a corresponding compound in which R^" means COZ, h) any transfer of a connection with formula I, wherein R 1 is COZ. when treated with NHgOH or to a corresponding compound in which R"^ means CONHOH or or i) possible conversion of a compound of formula I, in which R1 means CN by treatment with HNQ in dimethyl-1 j formamide to the corresponding compound, wherein R means j) any transfer of a connection with formula I, wherein R<1> means COZ, , CONHOH, via acid or basic'hydrolysis to the corresponding compound in which R <1> means COOH, or k) possible conversion of a compound of formula I, in which R"*" means COOH to the corresponding salt via treatment with a suitable organic or alkali/alkaline earth base, or l) possible transfer of compound with formula 1, where R means where m means 1 or 2 and X does not betvr NO^ by treatment with saloeteric acid in glacial acetic acid to a— corresponding compound in which R means and m) any transfer of compound of formula 1, in which R means and X is alkoxy by dealkylation to a corresponding compound wherein X is hydroxy. 5- Method according to claim 4" characterized in that a compound of formula I is prepared in which A and A <1> each means oxygen. 6. Pharmaceutical composition useful for producing diuresis comprising a pharmaceutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier therefor. 7. Pharmaceutical composition for increasing uric acid excretion comprising a pharmaceutical effective amount of a compound according to claim 1 and a pharmaceutical tolerable carrier therefor. 8. Pharmaceutical composition for lowering blood pressure comprising a pharmaceutical effective amount of a compound according to claim 1 and a pharmaceutical tolerable carrier therefor.