CA1111853A - 1,2-benzisoxazoloxyacetic acids and related compounds - Google Patents

1,2-benzisoxazoloxyacetic acids and related compounds

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Publication number
CA1111853A
CA1111853A CA316,532A CA316532A CA1111853A CA 1111853 A CA1111853 A CA 1111853A CA 316532 A CA316532 A CA 316532A CA 1111853 A CA1111853 A CA 1111853A
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chloro
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Gregory M. Shutske
Linda L. Setescak
Richard C. Allen
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Hoechst AG
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Hoechst AG
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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    • A61P7/10—Antioedematous agents; Diuretics
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
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    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
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    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom

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Abstract

Abstract of the disclosure:
Novel 1,2-benzisoxazoloxyacetic acids and relat-ed compounds, and methods for preparing same are described.
These compounds are useful as diuretic, uricosuric and antihypertensive agents.

Description

`53 This invention relates to novel 1,2-benzisoxazoloxy-acetic acids and related compounds which are useful as di-uretics, uricosurics, and antihypertensives, to methods of their preparation, and to pharmaceutical compositions con-taining such a compound as an active ingredient.
The compounds of this invention can be depicted by the general formula ~ -C-RI I

inwhich R is hydrogen, loweraLkyl, loweraLt;enyl, loweralkynyl, ~ycloall;yl, cyc1oa~enyl, bicycloa~yl, tricycloa~yl, cycloa~ylloweralkyl, cycloa~enyl-loweraL~cyl, naphthyl, ,~(CH2)~- ~ ,~ (X)~CH=C "hieny~, furyl, pyrryl, pyridyl or pyridyl N-oxidei Rl ia a free or esterified carboxyl group of fr~

1 to 8 carbon atoms,-COZ,-CON~ 8 ,-CH2OH,-CHO,-CH(OR )2,-CN, N
NH o -CONHC-NH2,-C-NHOH or^~:-OCH2CHCH2OH; R2, R3 and R4 are the same or different and each can be hy~lrogen, halo~en or lo~verall~yl: X i~ h)~drL)~el~, ~k halogen, loweralkyl, loweralkylthio, loweralkoxy, hydroxy, trirluoromethyl, nitro, amino or acylamino; R5, R , R7, R and R are the same or d~fferent and each can be hydrogen or loweralkyl; A and A' are the same or different and may be 0 or S; Z is chlorine, bromine or fluorine; and m and n are the same or different and each can be the integer 1, 2 or 3. Also included within the scope of the present in-vention are the physiologically acceptable salts of the above-depicted compounds which are capable Or forming same.
Some compounds within the scope Or this invention have greater pharmaceutical acti~ity than others. Some of the latter, such as those in which R is an esterified carboxyl group CN, CH20H or CH0 are nevertheless desirable as intermed~ates for the preparation of the more active compounds~ As indicated above, R may be a heterocyclic group such as thienyl, furyl, pyrryl or pyridyl, as well ~s an aliphatic or carbocyclic group. A preferred group of compounds are those in which R is an aromatic ring particularly a phenyl ring having an ortho substituent, 20 particularly a halogen atom, preferably fluoro with respect to the position of attachment to the overall ring structure.
A furthermore preferred group of compounds are those in which ~ is a carboxyl group wh~ch may be esterified by a lower alkoxy or benzyl group. Also preferred are compo-mds 25 in which A and A' each represent oxygen.
In the foregoing definitions and throughout this application the following terms have the following meanings.

"thienyl, furyl, pyrryl or pyridyll' means unsubstituted and substituted moieties wherein the substituents are halogen or loweralkyl;
"lower" means from 1 to 4 carbon atoms;
'Ic~cloalkyl'' means a saturated carbocyclic ring of from 3 to g carbon atoms;
"bicyclo- and tricycloalkyl," respectively, mean bi- and tricarbocyclic ring systems containing from 7 to 10 carbon atoms; and "cycloalkenyl" means an unsaturated carbocyclic ring Or from 5 to ~ carbon atoms.
The physiologically acceptable salts of this inven-tion include those formed with an alkali or alkaline earth metal base or with a non-toxic organic base such as ethanolamine, diethanolamine or N-methylglucamins.
The compounds of the present invention can be pre-pared by one of the following multi-step sequences of reactions in which unless otherwise indicated R, R through R~, X, m and n are as previously defined and Y is chlorine or fluorine and ambient temperature means about 20-25 C.
al) A phenol or alkoxybenzene of the formula ~3 l9 II

~=/ R

in which ~ is hydrogen or loweralkyl, is reacted under Friedel-Crafts conditions with an acid halide of the formula J~

~ 3 RCOZ
in which R is as defined earlier and ~ is chlorine, bromine or fluorine to provide a compound o* the formula /
R-C ~'~ ~O~ Rl I I I

A preferred method involves the use of 1,2-dichloroethane as a solvent and aluminum chloride as the Friedel-Crafts catalyst.
a2) A compound of the formula R-H

in which R is (x)'~ thienyl pyrryl or furyl is re-acted under Friedel-Crafts conditions with an acid halide Or the formula R2 z-c ~ oRlo IV

~R4 in which Y, Z and R10 are as defined in sequence A, above, to provide a compound of the formula ~_~ OR IIIa y 25 A prefer~d method involves use of 1l2-dichloroethane as a , ~ j , - ,...

11~1~3 solvent and aluminum chloride as the Friedel-Crafts catalyst.
a3) A compound of the formula NC ~ORl o IV
~ R4 in which R10 is loweralkyl is reacted with a compound of the formula R-MgZ or R-Li where R is not hydrogen followed by hydrolysis to afford a compound of Formula IIIa.
Preferred conditions include use of tetrahydrofuran as solvent at a temperature of -70 C to ambient.
a4) A compound of Formula IIIa in which R is hy-drogen and R10 is loweralkyl is reacted according to Method a3) to provide a compound of the formula R~oRlo V

y where R is not hydrogen.
a5) A compound as prepared in Method a~) is oxidized to provide a compound of Formula IIIa where~n R is not hydrogen. One such method involves use of chromium trioxide in glacial acetic acid.
a6) A compound of Formula III or IIIa in which R10 is loweralkyl, can be dealkylated by methods kncwn in the art to obtain the corresponding compound III or IIIa in which R is hydrogen. One such method involves treat-ing with aluminum chloride in benzene.
a7) A compound Or Formula III or IIIa is treated with hydroxylamine hydrochloride in a solvent such as pyridine to provide the corresponding compound of the f ormula 3 Nl I ~ORl VI
~4 a~) A compound of Formula VI is cyclized by treat-ment with a base in the presence of a solvent at a temp-erature Or from ambient to reflux of the reaction medium to provide the corresponding bicyclic compound of the formula R2 R3 : R ~ oR10 4!~o~ R4 A preferred method Or cyclizing utilizes the base sodium hydride in the solvent dimethylformamide-benzene mixture at reflux.
ag) A diphenol or2dialkoxybenzene of the formula ~ OR
S~ R4 VIII
p~l oo - 7a -wherein R , R3, R and R are as previously defined is reacted according to the procedure of Method al) ~o provide a compound of the formula R ~ OR410 IX

g ~ a10) A compound of the formula R-H in which R is (X)m , thienyl, pyrryl or furyl is reacted under Friedel-Crafts conditions with an acid halide of the formula R2 3 ~ OR

in which Z and R , R3, R4 and R are as pre~iously defined to provide a compound of the formula R
~_~OR
)~( 4 XI

all) A compound of the formula NC --~ OR10 XII

Rl >~ R4 in which R is loweralkyl is treated according to Method a3) to produce a corresponding compound of formula Xl.
al2) A compound of Formula Xl wherein R is hydrogen and R is loweralkyl is reacted according to Method a3) to provide a compound of the formula llli853 ~ OR
R ~ 4 RlOo R

in which R is not hydrogen.
al3) A compound as prepared in Method al2) is oxidized to pro~ide a compound of formula XI wherein R is not hydrogen.
One such method involves the use of chromium trioxide in glacial acetic acid.
al~) A compound of formula XI in which Rl~ is loweralkyl can be selectively dealkylated to provide the corresponding compound V in which R10 ortho to the carbonyl group is hydrogen or fully dealkylated to provide a compound 1~ as depicted in formula XI in which both R10 groups are hydrogen.
The former process can be effected by use of one equivalent o aluminum chloride, the latter by two equivalents, both processes occuring ~n such solvents as benzene.
al5) A compound of formula XI in which at least the R which is ortho to the carbonyl group is hydrogen is treated according to the procedure of Method g to provide a compound of the formula 3 R~oF~ XIV

HO

al6) A compound of formula XIV is acetylated to provide a compound of the formula R ~--~o~Rlo xv in which R is hydrogen, loweralkyl or acetyl.
A preferred method utilizes acetic anhydride as a reactant and solYent.

al7) A compound of formula XV is cycl~zed by treat-ment with a base in the presence of a solvent at a temp-erature of from ambient to reflux of the reaction mixture to provide the corresponding b~cyclic compound R~R4RlO VII

al~ ) A compound of formula VII in which R is loweralkyl can be dealkylated to afford the corresponding compound in which R is hydrogen. One preferred method is treatment with pyr1dine hydrochloride at 170-200C.
alg) A rompound of formula VII in which R is hydrogen is reacted with a compound of the formula Z-C~-R

~ R6
2~ wherein R is a free or esterified carboxyl group, CN~

CH20H or CH~oR9)2 and R9 is loweralk~l in the presence Or .. .~a a ba SQ and a solvent to provide a compound of the formula R2 R3 R5~1 S \~R4 Ia with Rl so defined.
A preferred method util~zes sodium hydride as the base and dimethylformamide as the solvent.
bl) A phenoxyalkanoic acid ester or nitrile of the formula ~ 3 ~/ \ ~ ¢ Rl ~ R4 R6 is treated according to the procedure of Method al) to provide a compound of the formula R-C ~ R XVII

y A preferred method ~s carried out with an aluminl~m chloride catalyst and carbon disulfide solYent.
b2) A com~ound of formula III or IIIa wherein R10 is hydrogen can be treated according to the procedure of 25 Method alg~ to provide a compound of the formula - 12 _ ~ I XVIII

in which R is a free or esterified carboxyl group, CN, CH20H or CH(oR9)2.
b3) A compound Or the formula XVIII or XIX can be treated according to the procedure of Method a7) to pro-vide a com~ound of the formula OH R2 R3 ~5 R-C ~ o_c_Rl XIX
~4 b~) A compound of Formula XIX ls cyclized according to the procedure of Method ag) to provide the corresponding compound of the invention of the formula Ia.
cl) A compound of formula IX in which R is H is treated according to the procedure of ~r~ethod al9) to pro-vide a compound of the formula R ~ O-CR6 R XX

R
HO

~ 3 c2) A compound of formula XX is treated according to the procedure of Method a7) to provide a compound of the formula HO R2 R3 R5 R ~R4-C6Rl XXI

HO

C3) A compound of formula 2XII is treated according to the procedure of Method al6) to provide a compound of the formula 3 CH3CO~ ~R l 5 R ~4 R XXII

HO

c~) h compound of the formula X~II is cyclized according to the procedure of Method a17) to provld~ a compound of the invention Ia.
dl) A compound of the formula Xl, as prepared in ~ethod al~), in which R is hydrogen is treatsd with hydroxylamine-o-sulfonic acid in a solvent such as water to produce a compound of the formula VII.
d2) A compound of formula XX in which R is hydrogen is treated according to th~ procedure of ~is~hod BB to produce a compound of the invention Ia.
el) A compound of formula VII in which R is L8~3 - 13a -hydrogen and X is other than hydroxy or amino is treated with a dialkylthiocarbamoyl halide in the presence of a base to produce a compound of the formula R~O-C-N/ XXIII

in which R and R are loweralkyl.
A preferred method involves the use of dimethylthio-carbamoyl chloride in dimethylformamide as a solvent and sodium hydr~de as the base.
e2) A compound of formula XXIII is thermally rear-ranged to a compound of the formula R2 R3 ~ lR7 R~ S-C-N XXIV

by heatin~ as a melt.
e3) A compo~nd of the formula XXIV is hydrolyzed by 20 a convenient method ~nown to the art to provide a compound of the formula ~2 R3 R_k~SH

` o R4 XXV

One such method utilizes dilu~e sodi~m hydroxide as the hydrolyzing agent.

e4) A comound of formLla XXV is treated according to the procedure of Meth~d a19) to pn~duce a compound of formLla R3 ~2 ~5 - C- R 1 I:b f1) A comçound of the formula
3 R4 ~SORl XXVI

as described in Mbthod al4) wherein R10 is loweralkyl an~ X may not be am mo or hydrDxyl, is treated successively aocording to the methods of e1), e2) a~d e3) to yield a ccnpcund of the fornLla R ~ RlO XXVII

HS R4.

f2) A compound of Fo ~ a XXVII is treated successively ac-oording to Methods ~ )~ a16), a17) and a18) Y of the formLla R2 R3 , ~ ~ H ~ ~~

- 25 f3) A co~pound of f~rm~la XXVIII is treated acoording b~
M~th~d al9) to yield a oom~ound of the formLla ~2 ~ R

Rlc-Rl Ic g1) A com~ound of formLla XXVIII is successively treated according to Methods e1), e2) and e3) to yield a compound of the formLla g2) A compound of f~rmLla XXIX is treated acoording to M~th~d a19) to yield a compound of the formula ~5_ l -R1 h) A conçound of the m vention of the form~la Ia, Ib, Ic or ~d in which R1 is a carboxylic acid ester or CN is r~adily converted to a corres-ponding o~m~cund in which R1 is CO~H.
Cne such suit~ble methDd is hydrolysis with a base such as s~dium hydr~xide.
i) A compound of the invention of the form~la Ia, Ib, Ic or Id m w~ich R is CH(OR )2 is r~;ly converted to a corresponding o~mpound in which R is CH~, One suit~ble method is hydrDl~sis with dilutR mineral acid.
_ j) A conpound of the formLla Ia in which X, R2, ~3 and R4 are n~t lower~lXyl in w~ich R1 is ~ OH or as prepared in Me~hod i) in which R1 i~ CHO is converted to a correspondiny com~und in which R1 is OCOH.
A suitabLe meth3d is oxidatlon with potassium permanganate.
1) A con~xn~d of the inv~ntion of the formLla ~2 3 R5 -Rl I

in which R1 is COOH is r~adi1y converted to a compound in which R1 is C03.
A suitakle method is treatment with SCZ2.
m) A compound of the formLLa R ~ A-l_R

m which R1 is COZ is readily converted bo the correspondUng co~pound in ich R1 is ~ RB, CONHOH, or OCNH~-NH2 via treabment respectively with N ~ 8~ NH20H or NH2C-NH2 in the presence or absence of an acid scavenger.
n) A compound of the invention of the formLla ~ R2 R3 R5 N~A' ~ A-l-Rl I

in which R1 is CN is readily oonverted b~ the corresponding oomp~und in which R1 is ~ . A sultakle method is the treatment with HN3 in di-methylformamide.
o) A compcund of the fornLla . R2 R3 ~5 -C RlI

inwhichR is COZ, CON~ 8 ~ CONffOH, CONHC-NH2 ,~N~ orany other 25 non-specifically defined group which is converti~le by a hydrolytic procedLIre to a COO~ group is converted to a compound of the invention in which Rl is C0033 via acid or basic hydrolysis.

p) A compound Or ~lle formula ~A -~-RI I

in which R is-COOH may b~~converte~ tp a salt via -treatmen~ in a suitable - - 801yént with a~ appropriate organic or aL~cali/alkaline earth base.
.
S q) A c~mpouDd of the formula ~OR ~

- D~ . .
~n which R is (X)~/ ~ Rl is lowerallcyl and X is not hydroxy or ami~o is treated with a strong base followed by a suitable electrophile to provide a compound of the formula R~Rlo ~I

~ which R is halogen or loweralkyl. A preferred base is n-butyllithium and preferred electrophiles include bromine, iodine, chlorine, N-halosuccinl-mides a~ aL~cylhalides.
r? A compound of ;h2formula ~R
- 15 ~=/ XX~II

in which R is hydrogen or halogen, RlOis hydrogen or iowerall;yl, R is and X is halogen is treated with elemental halogen in a solvent such as acetic ~cid to provide a compou~d of the formula ~ ~.3 R\--~OR 1~ VII
ll~o~R

wherein R3 an R4 or both may he :haloge~
, . - s) A compound of tl~ invention of the formula ~ COOR Ié

S in which m is 1 or 2 and X is not N02 is nitrated via treatment with nitric acid in glacial acetic acid to provide the corresponding compound of the formula ~ ~-C-COOH If t) A compound of the invention of the formula ;~A C Rl Ig ir. which R is ~, (X;rr~3_(CH2) - rm~CH=C- and X is al~oxy is deallcylated to provide a corresponding compound of the invention in which X is hydroxy, - 19 - ~ 3 A method is the careful treatment with boron tribromide.
u) A compound as described for the starting material of Method t), above, except that X is nitro and may be reduced by a convenient method known to the art to provide the corresponding compound in which X is amino. A method involves the use of iron filings in aqueous ethanolic hydrochloric acid.
v) A compound as described for the starting material of Method t), abové, except that X is amino and may be acylated by methods known to the art to prov~de the cor-responding compound of the in~ention in which X is acylamino.
A suitable method is acylation with an anhydride.
w) A compound of formula VII in which R is pyridyl is treated with an oxidizing agent to pro~ide a corresponding 15 compound of formula VII in which R ~s ~ ~ One such suitable oxidizing agent is 3-chloro-perbenzoic acid.
It can be appreciated that reaction times and exact reation conditions of any and all of the above reaction steps of the above-shown sequences of reactions are depen-20 dent upon particular reactants and solvents involved.
All starting materials shown aboYe are either knowncompounds or can easily be prepared by routine methods ~nown to the art from readily available materials.
For example, a starting ~aterial applicable in se-25 quence a2), a~l, a5), al21 and al3) to produce a compound _ 20 -of the invention wherein the 0-CH2-Rl group occupies the 5-position is 2-chloro-5-methoxybenzoic acid. Such a material can be prepared from the readily available 2-chloro-5-nitro-aniline via procedures readily known to one skilled in the art, e.g., diazotization and treatment with CuCN to afford 2-chloro-5-nitrobenzonitrile; followed by reduction with iron f~lings in aqueous ethanolic hydrochloric acid to 5-amino-2-chlorobenzonitrile; followed by diazotization to give 2-chloro-5-hydroxybenzonitrile; followed by methylation with dimethylsulfate to give 2-chloro-5-methoxybenzonitrile;
concluded with hydrolysis to 2-chloro-5-methoxybenzoic acid.
It is readily apparent that other required substituted alkoxy-ortho-halobenzoic acids, alkoxy(hydroxy)ortho-alkoxy-(hydroxy)benzoic acids, -aldehydes, and-nitriles, and various halo-alkoxy-(hydroxy)-, and dialkoxy(hydroxy)-benzenes can be readily obtained by similar sequences or other common reactions known to one skilled in the art.
The compounds of the invention are useful as diuret~c agents due to their ability to produce diuresis in mam~.als.
Diuretic activity is measured in mice by 3 method similar to that described by C.M. Kagawa snd M.J. Kalm, Arch. Intern, Pharmcodyn. 137, 2~1 (1952). Drugs are dosed orally to a group of 6 mice and the average volume or urine excreted is compared to ~divided by) the average volume excreted by a positive control group of 6 mice dosed orally with 1000 mg~kg of urea, a known diuretic agent. The resulting drug/

. `~

_ 20a ~ 3 urea ratios if greater than one are indicative of diuretic activity. The diuretic activity in this test of some of the compounds of this invention and of tienilic acid and ethacrynic acid, standard diuretics, is illustrated in Table I.

~ 21 ~ ~ 3 _t\ LE I

DOSE DRUG/UREA
COhIPOUND MC/~G P.O. RATIO
{ ~7-chloro-3-(2-fluorophenyl3~1, 2- ~ ~.2 benzisox~zol-6-yl]oxy}acetic acid _ 32 6.1 { ~7-chloro-3-(2-thienyl)- 1, 2- ~ ~ ~ ` ~ ----beDzisoxazol-6-yl]oxy}acetic acid 64 1, 2 { [7-chloro-3^phenyl-1,2-benzisoxazol-6-yl)oxy] }~cetic acid 64 2. 0 ~ ~ 7-chloro- 3-(2-furyl)- 1, 2-ben~isoxazol-6-yl]oxy}acetic ~cid 64 1.1 { [7-chloro-3-(4-tolyl)-1, 2- 4 1. 2 benzisoxazol-6-yl]oxy~acetic ~cid 64 2.0 { ~7-chloro-3-(4-chlorophenyl)-1, 2-benzisoxazol-6-yl]oxy}acetic acid 64 1.5 { ~7-chloro- 3-(5-methyl-2-furyl)- 1, 2-benzisoxazol-6-yl]oxy}acetic acid 64 2.û
{ ~7-chloro-3-(3-furyl)-1,2-be~zisoxazol-6-yl]oxy)acetic acid 64 2.0 { ~7-chloro-3-(2-chlorophenyl)-1, 2- 4 1. 3 benzisoxazol-6-yl]oxy}acetic acid 16 2.4 - 32 5.6 { ~7-chloro-3-(2-tolyl)-1, 2-beDzisoxazol-6-yl30xy}acetic acid 64~ 2. 3 [ (3-benzyl- 7- chloro- 1, 2 -benzisoxazol-6-yl)~acetic acid 64 1.2 { [ 7- chloro - 3 - ( 1- napthyl)- 1, 2 -benz -isoxazol-6-y~oxy ~acetic açid 64 1.1 { ~?-ch}oro- 3-(3-methyl-2-thienyl)- 1, 2-be~z,soxazol-6-yl]oxy}acetic acid 64 1. 4 { ~7-chloro-3-(2,6-difluorophenyl)-1,2- 4 3.1 benzisoxazol-6-yl]oxy}acetic acid 64 7.0 TAl3[E I
~5~
DOSE D~UG/U~A
~POUND ~,/KG P.o, R~l~o ~-(2-fluorophenyl)-i, 2-be~isoxa~ol- 4 1. 3 6-yl]oxy}~cetic acid 64 ~.6 { [3-(2-1uorophenyl)-7-methyl-1, 2- 8 2.1 benzisoxazol-6-yl]oxy} acetic acid 64 6. 4 [3-(2-fluorophenyl)- 7-iodo- 1, 2-benzisoxazol-6-yl]oxy}acetic acid 64 ~-{~7-bromo-3-(2-fluorophenyl)--1, 2- 4 1. 7 benzisoxazol-6-yl]oxy}acetic acid _ 64 6. 2 { [7-chloro-3-(trans-,~-fluorostyrl~- i, 2- ~ ~ ~
be~zisoxazol-6-yl]oxy}acetic acid 64 1. 0 { [5, 7-dichloro-3~(2-fluorophenyl)-1, 2-beDzisoxazol-6-yl]thio}acetic acid 64 3.1 Tie~ilic Acid 64 1. 8 16 }.2 E,thacrynic Acid 64 2. 5 Such utility is effected when a compound of the invention is administered to a patient requiring appropriate treatment at an oral, pare~teral or intrave~ous dose of from 0.1-500 mg/~;g of body weight per day.

Preferred ran~s include 1. 0-2()0 mg/kg of l~ody weight per day.
i Compounds of the inveQiOn are also useful as antihyperteQ~,ive agents due to their abili~ to depress blood pressurei~ mammals. Antihyper-tensive activ.ty is measure in the sponca~eous hypertens~ve rat by Ihe indirec{
~ail cu~ method described by A. Schwart~, Ed., Mechods in Pharmacol:~gy, .

Vol, I, page 135, Appleton-Century-Crofts, New Yorl;, Ne-v York 1971. In this procedure a group of 5 arlimals are treated orally with the drug f~r 3 days in relation to a control group of the same number. The drop in blood pressure is measured on the third day following administration. The anti-hypertensive activity expressed as mm decrease in mean arterial blood ~- pressure in this test of some of the compounds of this invention i~ illustrated in Table II.
TAI~J L II
BLOOD PRES.SURE
DECREAS~
COlvlPOUND MG/I;G P.O. mm/llG
{~7-chloro-3-phenyl-1, Z-benzisoxazol-6-yl]oxy}acetic acid50 15 .. . . .
t [7-c~loro-3-(2-furyl)-1, 2- ~~~^~_ `~ ~-~- ~ - - - ~--benzisoxazol-6-yl]oxy)acetic acid 50 22 ~ [7-chloro-3-(4-tolyl)-1, 2-be~zisoxazol-6-yl]oxy}acetic acid 50 ~ 16 { [7-chloro- 3-(4-chlorophenyl)- 1, 2-beDzisoxazol-6-yl]oxy~acetic acid 50 16 { [7-chloro-3-~5-methyl-2~thienyl)-1, 2- 5û 53 keDzisox~zol-6-ylJoxy}acetic acid 10 35 [(3-benzyl-7-chloro-1, 2-benzisoxazol-6-yl)oxy~acetic acid 50 27 [ 7- chloro- 3- ( 1- napthyl)- 1, 2 -benzis oxazol-6-yl30xy}acetic acid 50 39 { ~7-chloro-3-~2, 3-dimethylphenyl)-1, 2-benzisoxazol-6-yl]oxy} acetic acid 50 21 ~7- chloro- 3- (4-fluorophenyl)- 1, 2 -benzisoxazol-6-yl~oxy}acetic acid 50 19 t ~7-chloro- 3- (2 -pyridyl~- 1, 2-benzisoxazol-6-yl~oxy}acetic acid oxide 50 21 ~3-(2-fluorophenyl)-7-methyl-1,2-benziscxa-zol-6-ylJoxy}acetic acid 5û 28 [ 7- chloro- 3- (trans 7~ - nuorosty~yl)- 1, 2-be~zisoxazol~6-yl]oxy~cetic acid 50 27 - 2~ _ ~

Such utility is effected with a compound of the invention is administered to a patient requiring appropriate treatment at an oral, parenteral or intravenous dose of from 0.1-500 mg/kg of body weight per day. Preferred ranges include 1.0-200 mg/kg of body weight per day.
The compolLnds of the invention are further useful as uricosuric agents due to their ability to cause increased uric acid excretion in mammals. Uricosuric activity is measured in a procedure whereby groups of six Wistar rats are dosed orally with the test compound suspended or dissolved in sufficient distilled water such that the volume dosed is equiYalent to 25 ml/kg. A corresponding control group is dosed with water only at this level. Urine is collected for five hours and uric acid content determined on an Abbott Biochromatic Analyzer using Uricosquant reagent. The results for each group are expressed as average mg of uric acid excreted/kg of rat. Treated groups are compared with control groups for statistical significance.
In general, values Or 2.5 mg U.h./kg or greater are considered to indicate uricosuric activity. ~epresentative data is given in Table III.

TABLE lll COMPOUND DOSE MG/KG MG U.A. /KG.
{ [7-chloro-3-(2-thienyl)-1,2-benzisoxazol-6-yl~oxy}ace~io aoid 256 3 5 7-chloro- 3-phenyl- 1, 2-benzisoxa-zol-6-ylpxy]acetic acid 128 2. 6 { ~7-chloro-3-(2-furyl)-1,2-benzisoza- -zol-6-yl]oxy)acetic acid 128 2.5 { ~7-chloro-3-(5-methyl-2-thienyl)-1, 2-be~zisoxazol-6-ylJoxy~acetic acid lZ8 3 4 { [ 7-chloro- 3- (3-furyl)- 1, 2-benzisoxazol-6-yl]oxy } acetic acid, 128 2.7 [7-chloro-3-(2-fluorophenyl)-1, 2- 64 3. 3 benzisox~7Ol-6-yl]oxy}acetic acid 128 4-256 5. 7 512 13. 5 {~7-chloro-3-(4-fluorophenyl)- 1, 2-beDzisoxazol-6-yl]oxy}acetic acid 32 3. 0 -{ ~7-chloro-3-(2, 6-difluorophe~l)-1, 2~
be~zlsoxazol-6-yl]oxy}acetic acid 64 2.5 { [ 7-chloro-3- (2, 4-difluorophenyl)- 1, 2-benzisoxazol-6-yl]oxy}aoetic acid 64 4 { [3-(2-fluorophenyl)-1,2-beDzisoxazol-6-yl]oxy}acetic acid 128 2.5 { [5, 7-dichloro-3-(2-fluorophenyl)-1, 2-beDzisoxazol-6-yljthio} acetic acid 128 3. 8 Tienilic Acid 64 2. 9 Ethacrynic Acid inactive Such utility is effected when a compound of the invention is adminis~ered to a patient re~uiring approrpriate treatment at an oral, pare~teral or intravenous dose of from 0.1-500 mg/kg of body weight per day.
Preferred ranges include 1. 0-200 mg/kg of L)ody weigllt per day 8S~

It is noteworthy that a significant advantage of these compounds is their dual ability as diuretics and uricosurics.
As is known, many patients experience an increa~e in uric acid concentration of the blood during treatment with most of the currently marketed diuretics. Elevated uric acid levels are a serious problem in patients with gouty arthritis.
Additionally, eleYated uric acid levels are increasingly being considered a risk factor in cardiovascular disease.
Accordingly, this concomitant ability to produce diuresis and increase uric acid excretion represents a major advantage of the com~ounds disclosed herein.
Ccmpounds of the invention include:
~ [7-chloro-3- (1-buten-2-yl)-1,2-benzisoxazol-6-yl]-oxy} acetic acid;
[(7-chloro-3-ethyl-1,2-benzisoxazol-6-yl)oxy]acetic acid;
[(7-chloro-3-cyclopropyl-1,2-benzisoxazol-6-yl)oxy]-acetic acid;
[(7-chloro-3-cyclohexyl-1,2-benzioscxazol-6-yl)oxy]-acetic acid;
~[7-chloro-3-(2-norbornyl)-1,2-benz soxazol-6-yl3Oxy~-ace~ic acid;
~L3-(l-adamantyl)-7-chloro-1,2-bQnzisoxazol-6-yl30xy~ -ace~ic acid;
~[7-chloro-3-(1-cyclohexen-1-yl)-1,2-b~nzisoxazol-6-yl]
oxy3acetic acid;
~(7-chloro-3-cycloprGpylmPthyl-1~2-b~z~scxazol-~-yl)-oxy]acetic acid;

5~

[(7-chloro-3-cyclopentylmethyl-1,~-benzisoxazol-6-yl)ox~r acetic acid;
~ [7-chlors-3-(2-cyclopenten-}-methyl)~1,2-benzisoxazol-6-yl3o~J~acetic acidj ~(7-chloro-3-propargyl-1, 2-benzisox~701-6-yl)oxy]acetic acid;
{ [7-c~loro-3-(4-methoxyphenyl)-1,2-benzisoxazol-6-yl]oxy}-acetic acid;
{ [7-chloro-3-(4-hydroxy-2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid;
~7-chloro-3- (3-trifluorome~:hylphl?ny1j-1 ,2-benzisoxazol-yl ~ o~:y3acetic acid;
{~7-chloro-3-(4-~iLrophc;ly~ ,?.~ ziso:c:izo~.-6-y~ 1oxy}-ace tic acid;
~7-chlor4-3-(4-aminophenyl)-1,2-benzisoxazol-6-yl]oxy~-. - ace-tic acid; ~
.(,[7-chloro-3- (4-~cetamidophenyl) -1 ,2-benziso:c~zol -6-yl )_ oxy3 ~ce tic acid;

{~4, 5-dichloro-3-(2-fluorophenyl)-1, 2-ben~isoxazol-6-yl~oxy ~-- acetic acid, {L(4, 7-dichloro-3-(2-fluorophenyl)-1, 2-bel~zisoxazol-6-yl~oxy}-ac:etic acid;

s~

~(4-methyl-3-phenyl-1,2-benzisoxazol-6-yl)oxy]~cetic aeid [ (5-methyl-3-phenyl-1,2-benziso;~2zc1-6-yl)oxy~cetic acid {[7-chloro-3- (~-pyrryl~ -benziso,Y~zol-6-yl~ oxy}.~cet~ c ac id;

[(3-phenyl-1,2-benzisoxa ol-4-yl)o:cy)~c~tic 2cid;
~(3-phen~1-1,2-benzisoxazol-5-~l)o.~y]~cetic acid;
[~3-phenyl-1,2-ben7isoxazol-7-yl)o:cylacetic 2cid;
benzyl ~7-chloro-3-(2-fluoro?hcnyl)-1,2~ben iso~.~7ol-6-yl oxy acet~te;
1~ n-propyl~3-(2~thienyl)-1,2-benziosxl7,ol~-6-yl30xy3ace~ate t-butyl[(3-phcnyl-1,2-benziso:cazol-7-yl~o~ c~ c~

{~7-cllloro-3-(2-fluor~pllenyl)-1,2-~ctlzi~ux~zol-6-yl30~y}-acetyl chloride;
{[7-bromo-3-(2-fluoro-4-hydroxyphenyl3-1,2-benzisoxazol-6-yl30xy}aceci~ acid;
S {[7 chloro-3-(2-fruorophenyl)-~,2-ben~isoxazol-&-yl~oxy}-acetamide;
-~ N, N-diethyl-~17-chloro-3-(2-fluorophenyl)-1, 2-benzisoxa~ol-6-yl~oxy ~acetarrlide;

5~

2- {[7-bromo-3-(2-fluorophenyl)-l, 7-benzisoxazol-6-yl]oxy} -ethanol;
1, 1-diethoxy-2-{[7-chloro-3-(2-fluorophenyl)-l, 2-benzisoxazol-6-yl~ox3i~ ethane;
{[7-chloro-3-(2-fluorophenyl)-1, 2-benzisoxazol-6-yl~oxy~-acetaldehyde;
{[7-bromo-3-(2-fluorophenyl)-l, 2-ben~isoxazol-6-yl]oxy }-acetonitrile;
~a-hydroxy-{[7-chloro-3-(2-fluorophenyl)~1, 2-benzisox2zol-5-yl]oxy ~acetamide;
N-amidino-{[7-chloro-3-(2-fluorophenyl)-l, 2-benzisoxazol-6-yl~oxy ~acetamide;
5- {[ 7-chloro 3- (2- fluorophenyl)- 1, ~-benzisoxazol- 6-yl]oxy-methyl~tetrazole;
{[7-bromo-5-chloro-3-(2-fluorophenyl)-1, 2-berLziso;cazol-6-yl]oxy}acetic acid, {~7-bromo-5-mechyl-3-~2-fluorophenyl)-i, 2-~enzisoxazol-6-yl~oxy~acetic acid;

,~lyceryl~ 7- chloro- 3- ~2 - fhlorophe1.y l)- 1, 2 -benzi~ox2zol- 6-yl~oxy~ace~ate;
~ ~7-chloro-3-(2-fluorophenyl~-l, 2-!)eQzisothi~zol-6-yl~thiol-acetic acid;

~[7-bromo-3-(2-fluorophenyl)-1, 2-benzisothiazol-6-yl~thio3-. ., _, . , . . ~. . .
acetic acid;
~[7-bromo-3-(2, 6-difluorophenyl~-1, 2-benzisoxazol-6-yl30xy~-acetic acid;
~[7-methyl-3-(2, 5-difluorophenyl)-1, 2-ber~isoxazol-6-yl]oxy3-- ~ acetic acid;
~[7-bromo-3-(2, 3-difluorophenyl)-l, 2-benzisoxazol-6-yl]oxy3-acetic acid;
~7-bromo-3-(2, 5-difluorophenyl)-1, 2-berlzisoxazol-6-yl~oxy}-acetic acid.
~ ~ 7-chloro-3-~2-fluorophenyl)-1, 2-benzisothiazol-6-yl30xy~^
acetic acid;
~[7-bromo 3-(2-fluorophepyl)-1, 2-benzisothiazol-6-yl]oxy3-acctic acid;
~7-chloro^3-~4-(3ncthylthio)phenyl]-1, 2-benzisoxazol-6-yl]-- oxy~acetic acid;
~i7-fluoro-3-(2-fluorop~enyl)-1, 2-benzisoxazol-6-yl]oxy~-acetic acid; and ~[7-c~loro-3-(3-fluoro-2-thienyl)-1, 2-benzisoxazol-6-yl3oxy~}
? cetic acid.

~ 5 Effective quantities of the compounds of the invention may be administered to a patient by any one of various methods, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solu-tions. The free acid final products, while effective them-selves, may be formulated and administered in the form of the~r pharmaceutically acceptable salts for purposes of stability, convenience of crystallization, ,ncreased solu-bility and the like.
The active compounds of the present invention may beorally administered, for examplet with an inert diluent or with an edible carrier, or they may be enclosed in gelatin capsules~ or they may be compressed into tablets. For the lS purpose of oral therapeut~c administration, the active compounds of th~ invention may be incorporated with exci-~ients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum and the like. These preparations should contain at least G. 5% of ~ctive co~.pound, but may be varied depending upon the particular form and ma~ conveniently be ~etween ~ to absut 70~ of the weight of the unit. The amo~.t of active compound in such compositions is such that a suitable docage will be obtained. Preferred co~.positions and ~re~arations according to the present inYention are prepared so that an oral dosage unit forn ccntains ~etween 1.0-3CC~ m~ rams of active c ompolmd .

The tablets, pills, capsules, troches and the like may also contain the following ingredients: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; and excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, corn starch and the like;
a lubricant such as magnesium stearate or Sterotex; a gli-dant 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 flavoring. I~hen the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings.
Thus, tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these Yarious com-positions should be pharmaceutically pure and non-toxic in the amounts used.
For the purposes of parenteral therapeutic administra-tion, the active compounds of the invention may be incorporated into a solution or suspension. These pr~parations should contain at least 0.1% of active compound~ but may be ~aried to be between 0. 5 and about 30% of the weight thereof.

The amount of active compound in such compositions is such that a suitable dosage will be obtained. Preferred composi-tions and preparations according to the present in~ention are prepared so that a parenteral dosage unit contains be-5 tween 0.5 to 100 milligrams of active compound.
The solutions or suspensions may also include thefollowing components: a sterile diluent such as water for in~ection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents;
antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agen~s such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment Or tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringe~ or miltiple dose vials made of glass or plastic.
The present invention is further illustrated by the following examples of representati~e compo~1nds and pro-cedures.
Example 1 a. To a solution of 31.6 g of 2_fluorobenzoyl chloridein 100 ml of dichloroethane there is added incrementally 26.5 g of aluminum chloride over a 30 minute period. Upon completion of the addition the mixture turns yellow and then darkens. Thereafter to this darkened mixture there is added dropwise a solution of 32 g of 2,3-dichloroanisole in 50 ml 1~

of 1,2-dichloroethane. After the addition is complete the mixture is stirred for 2 hours before being poured over a mixture of 100 ml of concentrated hydrochloric acid and 100 ml Or crushed ice.
~he organic phase of the two-phase mixture is eva-porated under vacuum and the aqueous mixture is extracted with ether. The combined ether extracts successively are washed with a lO~o potassium carbonate solution, washed with water and dried and the ether is evaporated to dryness leaving an off-white solid which is recrystallized from an ether-hexane mixture to yield the product 2'-fluoro-~-methoxy-2,3-dichlorobenzo~henone having a melting point of 7~ to 77C.
b. To a mixture of 3g.5 g of 2'-fluoro-~-methoxy-2,3-dichlorobenzophenone and 3~.7 g of aluminum chloride in 250 ml of benzene is refluxed for 5 hours, then poured over a mixtura of 100 ml of concentrated hydrochloric acid and 100 ml o~ ice. The two-phase mixture is extracted with ethyl acetate and the combined extracts are dried and concentrated to dryness leaving a solid residue. The residue is tri-turated with hexane and the resulting solid is recrystallized from an ether-hexane mixture ~o yield the product 2,3-dichloro-4-hydroxy-2'-fluoro-benzophenone having a melting point of 12g to 131C.
c. A solution Or 31.g g of 2,3-dichloro-~-hydroxy-2'-fluoro-benzophenone and 15.3 g of hydroxylamine hydro-.'.,I'Y~

chloride in 150 ml of pyridine is refluxed for 64 hours.
Thereafter, the pyridine is evaporated under vacuum and a 5% aqueous hy~hloric acid solution is added. The acidi-fied solution is extracted with ethyl acetate and the com-bined extracts are dried before being concentrated to dry-ness. The resulting solid is recrystallized from an aqueous ethanol solut~on to yield the product 2,3-dichloro-4-hydroxy-2'-fluorobenzophenone oxime with a melting point of 16g to 175C.
d. A solution of 1~.4 g of 2,3-dichloro-4-hydroxy-2'-fluorobenzophenone oxime and 3.6 g of sodium hydride in 120 ml of dimethylformamide and 120 ml of benzene is main-tained at a temperature of from ~O-g5 C. for 3 hours. There-after, the mixture is permitted to reach ambient temperature after which a solution of 11.0 g of ethyl bromoacetate in 20 ml of dimethylformamide is added dropwise. After the addition is complete, the mixture is stirred for 30 minutes and then water is added to decompose any excess sodium hydride. The mixture is extracted with ethyl acetate and the combined extracts are dr~ed and evaporated to dryness leaving a solid residue. The residue is recrystallized several times from 95~ ethyl alcohol to yield the pure pro-duct ethyl ~[7-chloro-3-(2-fluorophenyl)-1,2-~enzisoxazol-6-yl]oxy~ acetate having a melting point of 102 to 10~ C~
Analysis:
Calculated for C17H~3ClF~0~: 5g.3g~oC; 3.75~H; ~.OlN.

36 J,~85~

Found: 5~.11%C; 3 . 62%H; 3 . ~6~oN .
Example 2 A mixture Or 10.0 g of~[7-chloro-3-(2-fluorophenyl 1,2-benzisoxazol-6-yl]oxy3 acetate, 100 ml of 10% sodium hydroxide, and 350 ml of ethyl a~cohol is refluxed for 3.5 hours. Thereafter the ethyl alcohol is removed under vacuum and the residue is acidified with a 5% hydrochloric acid solution effecting a solid precipitate. The precipitate is collected by filtration and dried. The dried product is recrystallized from 95% ethyl alcohol to yield the product 7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl oxy acetic acid having a melting point of 190 to 191C.
Example 3 a. To a mixture of 12.5 g of aluminum chloride and ~5 ml of carbon disulfide there is added dropwise 7.1 g of 2-fluorobenzoyl chloride while maintaining the temperature below 0C. This low temperature is maintained for 1.5 hours.
While maintaining this same low t~mperature, 5 g of 2,3-dichlorophenoxyacetic acid is added incrementally. After addition is complete, the reaction mixture is maintained at this low temperature for 30 minutes and then permitted to reach ambient temperature after which it is refluxed for 2 hours. The carbon disulfide is decanted from the refluxed solution leaving a dark orange residue which is poured onto a mixture of 500 ml of ice/water and 100 ml of concentrated hydrochloric acid. The resulting pink precipitate is collected ~0 37 ~ 53 by filtration, rinsed with 300 ml of warm water (50C.) and dried in ~acuum oven. The dried product is recrystallized twice from aqueous ethyl alcohol to form the product 2,3_ dichloro-~-(2-fluorobenzoyl)phenoxyacetic acid having a S melting point of 153 to 156 C.
b. A mixture of 1.0 g of 2,3-dichloro-4-(2-fluoro-benzoyphenoxyacetic acid and 1 g of hydroxylamine hydro-chloride in 10 ml of pyridine is refluxed for 2 hours.
Thereafter, the soivent is evaporated in vacuo and the residue ~s stirred for 16 hours with 5% hydrochloric acid.
The product is filtered off and the collect solid is recry-stallized from aqueous ethyl alcohol to gi~e the product 2,3-dichloro-4-(2-fluorobenzohydroximoyl)phenoxyacetic acid ha~ing a melt~ng point of 91 to 96 C.
lS c. A mixture of 0.3 g of 2,3-dichloro-~-(2-fluoro-benzohydroximoyl)phenoxyac~tic acid and 0.05 g of sodium hydride in 5 ml of benzene and 5 ml of dimethylformamide is refluxed for 3 hours. To the mixtur , after it has been permitted to cQol there is add~d 5% hydrochloric ac~d causin~
the benzene to separate. The bsnzene is e~apora~ed in vacuo and the resulting precipitate is collected by filtration and recrystallized from aqueous ethyl alcohol ~o yield the pro-duct ~L7-chloro-3-(2-fluorophenyl)-1,2 benzisoxazol-6-yl] oxy~-~cetic acid having a melting point of lgg to 1~9 C.
2S hnaly5i5:
~alculated for C15H9ClFN0~: 56.oo%c; 2.g3%H; ~.36qoN

~ , - 3~ -Found: 55.94%C; 2.g6qolH; ~.32~oN
Example 4 a. A mixture of 3.g g of (2 ~ 3-dichloro-~-hydroxy-phenyl)2'-thienylmethanone and 2.0 g of hydroxylamine hydro-chloride in 20 ml Or pyridine is refluxed for 6 hours.
Thereafter, the pyridine is evaporated in vacuo. To the residue there is added 5% hydrochloric acid and the acidified mixture is extracted with ethyl acetate. The extract, ~e-quentially, is washed with water, dried and evaporated to dryness. The residue is rccrystallized from an ethanol and water mixture to yield the produce (2,3-dichloro-4-hydroxy-phenyl)-2'-thienylmethanone oxime having a melting point of 179 to 1~3 C.
b. To a mixture of 3.0 g of (2,3-dichloro-4-hydroxy-phenyl)-2'-thienylmethanone oxime in 30 ml of dimethylformamide and 30 ml of toluene is added 0.62 g of sodium hydride.
Thereafter, the reaction mixture is maintained at 100C. for 2 hours and then at 115C. for 2.5 hours. The mixture is permitted to cool prior to adding thereto dropwise a solution of 1.9 g of ethyl bromoacetate in 10 ml of dimethylformamide.
After- addition is complete, 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 ethylacetate and the extract is, sequentially, washed with water, dried and evaporated. The residue is recrystal-lized from ethanol to yield the product ethyl~-chloro-3-(2-thienyl~-1,2-benzisoxazol-6-yl]oxy~acetate having a ., 5~3 melting point of 142 to 1~3 C.
Analysis:
Calculated for C15H12ClN04S: 53.33%C; 3-5~oH; 4-15%N
Found: 53. 2g1oC; 3 5~%H; 4 17%~
Example 5 a. A solution of 1~.0 g of 2,3-dichloro-4-hydroxy-benzophenone and 9.3 g of hydroxylamine hydrochlor~de in 100 ml of pyridine is refluxed ~or 2 hours. Thereafter, the pyr~dine is evaporated under vacuum and the residual liquid is partitioned between 5% hydrochloric acid and ethyl acetate.
The ethylacetate extract is washed with water, dried, and e~aporated to give 2,3-dichloro-~_hydroxy-benzophenone oxime.
Said 2,3-dichloro-4-hydroxybenzophenone is prepared in a manner consistent with the procedure described in Example l(a) and (b) with benzoyl chloride replacing 2-fluorobenzoyl chloride.
b. A solution of 2,3-dichloro-~-hydroxybenzophenone oxime and 2.6 g of sod1um hydride in 5O ml of dimethylformam-ide and 50 ml of toluene is heated to 11~C. and maintained at this temperature for 50 minutes. Therea~ter, the reaction is permitted to cool prior to the dropwise addition of 7.9 g of ethyl bromoacetate in 50 ml of dimethylformamide.
After the addition is ccmplete the reaction mixkure is stirred at ambien~ temperature for ~O minutes. To the well stirred mixture water is added dropwise to decompose any excess sodium hydride~ The toluene is evaporated under vacuum and the re-. ~

sulting precipitate is collected by filtration and then rinsed with ether to yield the product ethyll(7-chloro-3-phenyl-1,2-benzisoxazol-6-yl)oxy] acetate hav~ng a melting point of 130 to 132 C.
Analysis:
Calculated for C17H14~1N04: 61.54%C; 4.25%H; 4.22%N
Found: 61.34~C; 4.15%H; 4.17%N
Example 6 To a solution o~ g.3 g of ethy~(7-chloro-3-phenyl-1,2-benzisoxazol-6-yl)oxy]acetate, Example 5, in 160 ml of ethyl alcohol is added 6 ml of 7N sodium hydroxide. There--after, the react~on m~xture is refluxed for 45 minutes. The precipitate is collected by filtration and then successively rinsed with ethyl alcohol and ether. The precipitate is suspended in 200 ml of hot water and this mixture is acidified with concentrated hydrochloric acid. The acidified mixture is stirred for 1 hour and the gray precipitate is collected by filtration. The precipitate is recrystallized from ethyl acetate to yield the pure product [(7-chloro-3-phenyl-1,2-benzisoxazol-6-yl)oxy] acetic acid having a melting point o~ 219 to 221 C.
Analysis:
Calculated for C15HloClN04: 59.32%C; 3.32%H; 4.61%N
Found: 59.33%C; 3. 3~oH; 4 . 57~o~

~1 -Example 7 19.~ g of 3,2-dichloro-4-hydroxyphenyl-2'-furyl-methanone oxime is dissolved i~ 200 ml of dimethylformamide, then 4.~ g of sodium hydride is added thereto. After hydrogen gas evolution ceases the reaction mixture is heated at 130C.
The mixture is cooled to 5C. and to the cooled mixture is added a solution of 16.7 g of bromoacetate in 20 ml o~ dimethyl-rormamide. After stirring for ~5 minutes the reaction mixture is then poured into water to produce a crystalline product.
The product is collected by filtration, successi~ely washed with ethyl alcohol and ether and finally recrystallized from an ethyl alcohol-ethyl acetate mixture to yield the product ethyl[t7-chloro-3-~2-furyl)-1,2-benzisoxazol-6-yl~Oxy]acetate having a melting point of 151 to 152C.
Analysis:
Calculated for C15H12ClNOs: 56.00qoC; 3.7~oH; ~.35%N
Found: 5 5 . 91%C; 3.~3%H; 4~ 32~oN
Example g To a boiling suspension of 15.0 g of ethyl[(7-chloro-3-t2-furyl)-1,2-benzisoxazol-6-yl)oxy]aceta~e, Example 7, in 500 ml of boiling 95~ ethyl alcohol there is added 10 ml of a 50~ sodium hydroxide solution causing the sodium salt to precipitate out almost immediately. An additional 300 ml of 95% ethyl alcohol is added and boiling ls maintained for 30 zs minutes. The reaction mixture is permitted to cool slightly, after which 100 ml of a 5~0 hydrochloric acid solution is added thereto. The product begins to separate with cooling, 250 ml of water is added and the d~luted mixture is chilled with ice. The precipitate is collected by filtration and recrystallized from isopropyl alcohol to yield the produc~
~[7-chloro-3-(2-furyl)-1,2_benzisoxazol-6-yl]oxy~ acetic acid having a melting point of 230 to 233C.
Analysis:
Calculated for C13H~ClN05: 53.17%C; 2.74%H; 4.77~oN
Found: 52.g3%C; 2.~3%H; 4.74~N
Example 9 a. A mixture of 2g.3 g of (2,3-dichloro_~_hydroxy-~yl)-(5'-methyl-2~-thienyl)methanone and 14.0 g of hydroxy-lamine hydrochloride in 300 ml of pyridine is refluxed for 16 hours. Thereafter, the solvent is removed under vacuum and the residue is treated with 5% hydrochloric acid. The treated residue is successively extracted with a mixture of dichloro-ethane and ether and dried and the solvent remo~ed by eva-poration. The product is tr~turated with hexane to produce the desired oxime, (2,3-dichloro-~-hydroxyphenyl)-(5'-methyl-20 2~-thienyl)methanone oxime.
b. To a mixture of the above oxime in 200 ml of dimethylformamide there is added 5.3 ~ Or sodium hydride.
The reaction mixture is maintained, successively, at 120C.
for 1. 5 hours, 130 C. for 1 hour, and 1~0C. for 1 hour, 25 then cooled to 35 C. To this cooled mixtvure 1~.~ g of the ethyl bromoacetate in 20 ml of dimethylformamide there is t~
.

~ 5 added and the mixture is st~rred for 20 minutes. The reaction m~xture is poured into a saturated sodium chloride solution to yield a crystalline product which is collected by fil-tration. The product is washed successively with methyl alcohol and ether and then recrystallized from isopropyl alcohol to give the product ethyl~[7-chloro-3-t5-methyl-2-thienyl)-1,2-benzisoxazol-6-yl]oxy~ acetate ha~ing a melting point of 149 to 150C.
Analysis:
Calculated for C16H14ClN04S: 54.62~oC; 4.0~%H; 3.9~1oN
Found: 54.60~oC; 3 . 97~H; 3 . 9~qoN
Example 10 The substitut~on of (2,3-dichloro-4-hydroxyphenyl)-(5'-methyl-3'-furyl)methanone for (2,3-dichloro-4-hydroxy-phenyl)-(5'-methyl-2'-thienyl)methanone ~n the procedure described in Example 9(a3 and, thereafter following the procedure described in Example 9(b) provides ethyl~[7-chloro-3-(5-methyl-2-furyl)-1,2-benzisoxazol-6-yl~ oxy3 acetate, ha~ing a melting point of 139 to 141C.
Analysis:
Calculated for C16Hl~ClN05: 57.23%C; 4.20%H; 4.17%N
Found: 57.2~%C; 4.1~%H; 3. 93~oN
Exam~le 11 .
To a suspension of 15.0 g of ethyl [7-chloro-3-(5-methyl-2-furyl~-1,2-benzisoxazol-6-yl~oxy acetate, Example 10, in ~00 ml of ethyl alcohol there is added 10 ml of a 50~o ,~"
. . .
- 4~ -sodium hydroxide solution. The reaction mixture is refluxed with ~igorous stirring for 1.5 hours and 100 ml of 5% hydro-chloric ac~d is added thereto. The resulting solution is sequentially chilled and diluted with water as the product begins to crystallize. The product is collected by filtration and recrystall~zed from methyl alcohol to yield~[7-chloro-3-(5-methyl-2-furyl)-1,2-benzisoxazol-6-yl]oxy~acetic acid, mp 217-219C.
Analysis Calculated for C14HloClN0 5~.65%C; 3.2~oH; ~.55%N
Found:54.7~%C; 3. ~O~oH; 4.49%N
Exam~le 12 a. A mixture of 2,3-dichloro-4-hydroxy-~'-methyl_ benzophenone and 12.5 g of hydroxylamine hydrochloride in 200 ml of pyridine is refluxed for 2 hours. Thereafter the pyri~
dine is evaporated off under vacuum and the residue is partitioned between ethyl acetate and 5% hydrochloric ac~d.
The ethyl acetate extract is, ~uccessively, washed with water, dried and concentrated to dryness lea~ing 2,3-dichloro-~-hydroxy-4'-methylbenzophenone oxime.
b. A mixture of the above oxime and 5.2 g of sodium hydride in 300 ml of dimethylformamide is maintained at ~7C.
for 3 hours. This mixtu~e is permitted to cool to ambient temperature, after which 16.0 g of ethyl bromoacetate in 50 ml of dimethylformamide is added thereto dropwise. After addition is complete the mixture is stirred for 30 minutes . ~

~ 3 - ~5 -and poured into water to produce a precipitate which is ethyl ~[7-chloro-3-(4-tolyl)-1,2-benzisoxazol-6-ylloxy~acetate, mp 157-159 C.
Example 1~
A mixture o~ 20 g of ethylf[7-chloro-3-(~-tolyl)-l, 2-benzisoxazol-6~yl]oxy ~acetate, Example 12, and 15 ml of 50% sod~um hydroxide in 600 ml of ethyl alcohol is refluxed for 1 hour. Thereafter, the hot mixture is 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 is recrystallized - from dimethylformamide to yield the product ~7-chloro-3-(4-. tolyl)-1,2-benzisoxazo1-6-y1]oxy~acetic acid having a melting point of 257 to 260 C.
lS Analys~s:
Calculated for C17Hl~Cl~0~: 60.~oC; 3.7~H, 4.41%N
Found:60.3g%C; 3.77%H; ~.3 Example 14 a. A mixture Or ~1 g of 12,3-d~chloro-~-hydroxy-phenyl3-~'-chlorobenzophenone and lg.9 g of hydroxylamine hydrochloride in 300 ml of pyridine is refluxed for 2 hours.
Thereafter, the pyridine is removed under vacuum and the residue is partitioned between ethyl acetate and 5% hydrochloric acid. The ethyl acetate portion is, successively, washed with water, dried and cGncentrated to dryness lea~ing 2,3-dichloro-~-h.ydroxy-~'-chlorobenzophenone ~xime.

:

_ 46 -b. A mixture of the 41.5 g of the above oxime and 7.9 g of sodium hydr~de in 300 ml of dimethylformamide is maintained at a temperature of 111C. for 2 hours. There-after, the reaction mixture is permitted to cool to ambient S temperature after which a mixture of 23 g of ethyl bromo-acetate in 50 ml of dimethylformamide is added thereto drop-wise. After addit~on is complete the reaction mixture is stirred for 30 minutes and permitted to stand for 16 hours.
The mixture is poured into water to yield a precipitate, collected by filtration, of ethyl~[7-chloro-3-(4-chloro-phenyl)-1,2-benzisoxazol-6-yl]oxy~ acetate, m.p. 179 C.
Example 15 A mixture of 25 g of ethyl~[7-chloro-3-(4-chloro-phenyl)-1,2-benzisoxazol-6~1 ]oxy~acetate~ Example 1~, and 20 ml of 50~0 sodium hydroxide in 400 ml of ethyl alcohol i~
refluxed for 1 hour~ Th~ hot mixture is diluted with 300 ml of water and then ac~dified with concentrated hydrochloric acid. The acidified mixture is st~rred for 30 minutes and then filtered and the filter cake ~s recrystallized from a dimethylformamide-ethylacetate mixture to yield the product ~[7-chloro-3-(4-chlorophenyl)-1,2-benzisoxazol-6-y~ oxy7 _ acetic acid having a melting point of 254 to 257 C.
Analysis:
Calculated for C15HgC12N04: 53.2g%C; 2.6g%H; 4.14%N
Found: 53.01%C; 2.39%H; ~.03~oN
In the above examples, where not spec~fically shown, the oxime precursor is prepared from tne appropriate ketone in a fashion similar to Example lc.
Example 16 A suspension of 0.72 g of ethyl {[7-chloro-~-(2-thienyl)-1,2-benzisoxazol-6-yl]oxy~acetate, Example ~, and 10 ml of concentrated a~ueous sodium hydroxide in ~0 ml of ethyl alcohol is refluxed for 1 hour. Thereafter, the ethyl alcohol is remo~ed by e~aporation in vacuo. The residual suspension is acidified with concentrated hydrochloric acid and then stirred at ambient temperature for 30 minutes. The resulting crude product is collected by filtration and then recrystal-lized from ethyl alcohol to provide the product, mp 217-220C, of~[7-chloro-3-(2-thienyl)-1,2-benzisoxazol-6_y~ oxy3 a~etic acid.
Analysis:
Calculated for C13HgClN04S: 50.41%C; 2.6C~oH; 4.52%N.
Found: 5C.13%C; 2. ~7%H; ~ oN .

a. A reaction mixture of 32.~ g of 3-methyl-2-thiophene carboxylic acid chloride and 35.~ g of 2,3-dichloro-anisole and 2~.7 g of aluminum chloride in 200 ml of carbondisulfide is refluxed for 40 hours before being poured into ice-hydrochloric acid. The resulting crystalline product is collected by filtration and then sequentially washed with hexane and recrystallized from a toluene-~exane mixture to provide the product, mp 136-13g C, of (2,3-dichloro-~-methoxy)(3-methyl;2-thienyl)methanone-8~3 ~g Analysis:Calculated for C13HloC1202S: 51.~4%C; 3.35%H; 10.65qoS.
Found: 51.~1%C; 3.35%H; 10.~5%S.
b. A mixture of o.6 g of (2,3-dichloro-~-methoxy) (3-methyl-2-thienyl)methanone and NH20H-HCl in pyridine is converted to its corresponding oxîme. Thereafter, the oxime-(mixture of isomers)(37.~g) is dissolved ~n 70 ml o~ d~methyl-formamide and the solution added to a suspension of 3.3 g of sodium hydride ~n 100 ml of dimethylformamide. After the reaction is completed it is poured into water. The pH of the aqueous mixture is ad~usted to 6-7 with dilute hydrochloric acid. The resulting precipitate is collected by filtration and then sequentially washed well with ether and recrystal-lized from a toluene-hexane mixture to provide the product, mp 154-156Cj 7-chloro-3-(3-methyl-2-th~enyl~-6-methoxy-1, 2-benzisoxazole.
Analysis:
Calculated for C13HloClN02S: 55.~1%C; 3 . 60~o~; 5.C1%N; 11.46%S.
Found: 55.90~7C; 3.5~%H; 4.9~90N; 11.22%S.
c. A mixture of 13.3 g of 7-chloro-3-(3-methyl-2 thienylJ-6-methoxy-1,2-benzisoxazole and 25 g of BBr3 ~n CH2C12 is refluxed about lg hours and then poured into H20 and extracted with ether. The ether extract is dried and e~aporated and then triturated with hexane to yield 7-chloro-25 6-hydroxy-3-(3-methyl-2-thienyl)-1,2-benzisoxalole, mp 197-19~C.

Analysis:
Calculated for C12H~ClN02S; 54.2~%C; 3.03%H; 5.2710N.
Found: 54. 22~oC; 3.05%H; 5.0g%N.
d. A mixture of 10.3 g of 7-chloro-6-hydroxy-3-(3-methyl-2-thienyl)-1,2-benzisoxazole in 60 ml DMF is added to a suspension of NaH (1.1 g) in 40 ml DMF. ~thyl bromo- -acetate (6.7 g) is added thereto and the reaction mixture is heated to 50 C for 30 minutes. 100 ml H20 and 25% aqueous NaOH is added and the reac~ion mixture is heated to 90C for three hours. The reaction mixture is then poured into H20 and acidified with concentrated hydrochloric acid. The acid-ified mixture is extracted with ether, water, washed and dried. Evaporation and recrystallization form an ethyl acetate-hexane mixture which gi~es fi,'-chloro-3-(3-methyl-2-thienyl)-1,2-benzi soxa zol-6-yl]oxy7~ic acid.
Analysis:
Calculated ror Cl~HloClN04S: 51.93%C; 3.11%H; ~.33%N.
Found: 51.93%C; 3.05%H; ~.2~%N.

A mixture of 15.0 g of ethyl~[7-chloro-3-(5-methyl-2-thienyl)-1,2-benzisoxazole-6-yl]oxy3acetate of Example 9b and 10 ml of 50% NaOH in gOO ml of ethanol is refluxed for 30 minutes and then 100 ml of 5% HCl is added, ma~ing the solu-tion homogeneous. A product begins to crystallize as the solution cools and additional water is added. The product is filtered off and recrystallized from isopropanol giving ~[7-chloro-3-(5-methyl-2-thienyl)-1,2-benzisoxazol-6-yl ~oxy3 -acetic acid, mp 235-23~ C.
Analysis:
Calculated for Cl~HloC1~04S: 51.93%C; 3.11%H; 4.33%N; 9.91%S.
Found: 51.6g%C; 3.1~%H; 4.20~oN; 10.02%S.
Example 19 3-Furoyl chloride (lg.0 g) and 2,3-dichloro anisole (2~.7 g) are dissol~ed in 125 ml of CS2 and treated with AlC13 (1~.7 g), first at 5 C and then at room temperature.
After five hours the reaction is quenched with ~ce/HCl and extracted with CH2C12. Drying and evaporat~on gives a cry-stalline product that is triturated with hexane to yield ~-(3-furoyl~_2,3-dichloroanisole, mp llg-122C.
A molten bath of pyridine HCl is prepared by adding 16 ml of concentrated HCl (o.1~6 mole) to 1~.2 g of pyridine and heating the mixture to 210C under nitrogen and allowing the H20 to distill out. The anisole (5.0 g) is added in portions and hsating is continued for one hour and the solution poured over ice and extracted with ethyl acetate. Drying and evapora-tion gi~es ~-(3-furoyl)-2,3-dichlorophenol, mp 13g-1~2GC.
The phenol is combined with hydroxylamine hydrochloride in pyridine and refluxed for three hours. The pyridine is evaporated off and the resultant mixture is acidified with hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate extract is water washed, dried and evaporated to dryness to yield an oxime which is dissol~ed in 100 ml of ~7 ~$~
_ 51 -DMF and added to a suspension of NaH l7.0 g) in 100 ml of DMF. After warming for two hours at 120C, the reaction is cooled to 45C and ethyl bromoacetate (24.0 g) in 20 ml of DMF is added. The reaction is quenched with brine and a resultant solid product filtered and washed with ethanol and then ether to give a crude phenoxy ester. Hydrolysis of the crude ester for 45 m~nutes in refluxing ethanol (500 ml) containing 10 ml of 50qO NaOH gives a crystalline acid after acidifying and chilling. The acid is recrystallized by sus-pending it in boiling methanol and adding D~ until dissol-ution occurs. Water is then added and crystallization begins immediately to yield ~[7-ch'oro-3-(3-furyl)-1,2-benzis~xazol-6-yl]oxy7acetic acid, mp 225_227 C.
Analysis:
Calculated for C13HgClN05: 53.17%C; 2.74%H; 4.77qoN.
Found: 53.3~qoC; 2 R5%H; 4.71%N.
Example 20 a. To a solution of ~4.6 g of 2,6-difluoro benzoyl-chloride in 100 ml of 1,2-dichloroethane, 1~.5 g of AlC13 is added in portions over a 30 minute per~od. A solution of 22.5 g of 2,3-dichloroan~sole in 100 ml of 1~2-dichloroethane is added theret~. The mixture ~s stirred for one hour and poured over 100 ml concentrated HCl and ice. The organic layer is separated and the aqueous layer extracted with CHC13. The organic extract is washed with water, dried (~a2S04) and evaporated to give an oil ~hich crystallizes s~

from hexane to yield solid 2,3-dichloro-~-methoxy-2',6'-difluorobenzophenone which upon recrystallization from ether has an mp 94-96C.
Analysis:
Calculated for C14H~C12F202: 53.02%C; 2.54%H; 11.9g%Fo Found: 53.21%C; 2.50qoH; 12.0~%F.
b. A mixture of 50.5 g of 2,3-dichloro-4-methoxy-2',6'-difluorobenzophenone, ~.27 g of hydroxylamine HCl in 200 ml of pyridine is refluxed for ~g hours. The pyridine is eva-porated in vacuo and the residue pQrtitioned betw~en 5%
HCl and ethyl acetate. The extract is washed with water, dried over Na2S04 and evaporated to give a mixture of isomers.
An analytical sample of 2,3-dichloro-~-methoxy-2',6'-difluoro-benzophenone oxime, mp 173-lg9C is recrystallized from 95%
ethanol.
Analysis:
Calculated for C14HgC12F2N02: ~0.62%C; 2-73%~; ~-22%N-Found: 50.~%C; 2.6~; 4.14%N.
c. To a mixture of 5 g of NaH ~n 200 ml of DMF, 4g g of 2,3-dichloro-~-methoxy-2~,6'-difluorobenzophe~one oxime in 250 ml of DMF is added dropwise in an atmosphere of N2 while the temperature is maintained at approximately 40 C.
After the addition, the mixture is stirred 30 minutes and poured into ice water. A crude product, ~hich is a mixture of isomers, is filtered off and chromato~raphed on silica gel 35;~

with CHC13 as eluant to yield 7-chloro-3-(2,6-difluorophenyl)-6-methoxy-1,2-benzisoxazole which is recrystallized from toluene for analysis, mp 175-179C.
Analysis:
Calculated for C14H~ClF2N02: 56.~7%C; 2.73%H; 4.7~%N.
Found: 56.99%C; 2.64%H; 4.61~%N.
d. A mixture of 10.~ g of 7-chloro-3-(2,6-difluoro-phenyl)-6-methoxy-1,2-benzisoxazole and 1~0.3 g of pyridine HCl is heated at 200C for 1 hour snd then poured into ~rigor-ously stirred ~ce water. A product of 7-chloro-3-(2,6-difluorophenyl)-6-hydroxy-1,2-benzisoxazole precipitates and is filtered and dried. An analytical sample is recrystallized from toluene, mp 216-220 C.
Analysis:
Calculated for C13H6ClF2N02: 5~.43%C; 2.15%H; 4.97~oN.
Found: 55.59%C; 2.29%H; 4.96%N.
e. A mixture of l.lg g of ~aH and 9.2 g of 7-chloro-3-(2,6-difluorophenyl)-6-hydroxy-1,2-benzisoxazole in 15 ml of DMF is stirred 1 hour. A solution of 6.o6 g of ethyl 20 bromoacetate in 1~0 ml of DMF is added thereto dropwise and stirred for one half hour. Ton milliliters of 50% NaOH
is added and the reaction mixture is warmed to ~0C for 1 hour. Concentrated ~Cl is added to the warm solution until acidic. Water is added and ~[7-chloro-3-(2,6-difluorophenyl)-25 1,2-benzisoxaæol-6-yl3Oxy3acetic acid precipitates which is filtered, drled and recrystallized from toluene-acetonitrile to give a product having a melting point of 170-17? C.
Analysis:
Calculated for C15H~ClF2N04: 53.04%C; 2.37%H; 4.12%N.
Found: 53.17%C; 2.3~%H; 4.1~%N.
Example 21 a. A mixture of 20.36 g Or ~fluorocinnamoyl chlor$de and 14.4 g Or AlC13 in 100 ml of 1,2-dichloroethane is stirred 1 hour followed ~y the dropwise sddition of 17.7 g of 2,3-dichloroanisole in 100 ml of 1,2-dichloroethane. The reaction mixture is warmed to approximately ~0C for 1 hour and poured over 100 ml Or concentrated HCl and ice. The aqueous layer is extracted with CHC13 and the combined organic layer washed with water, dried over Na2S0~ and evaporated to a solid residue. The residue is triturated with hexane to give ~-(trans--fluoroc~nnamoyl)-2,3-dichloroanisole. A sample is recrystallized from toluene, mp 137-13~ C.
Analysis Calculated for C16HllC12F02: 59.10%C; 3.41%H; 5.~%F.
Found: 59.3~%C; 3.~6%H; 5. ~qoF .
b. A mixture of 26.6 g of 4-(trans-a-fluorocinnamoyl)-2,3-dichloroanisole and 22.7 g of hydroxylamine HCl is refluxed 1~ hours. The pyridine ~s evaporated in ~acuo and the residue triturated with 5% HCl. A product is filtered off, dried and rinsed with ether-hexane g~ving a mixture of isomers. A
25 sample of ~-~trans-~-fluorocinnamoyl)_2,3-dichloroanisole oxime is recrystallized from ethanol, mp 222-23~C.

i~

s~

Analysis:
Calculated forC16H12C12P~02 56.49%C; 3-56%H; 4-12%N-Found: 56.47~oC; 3.51%H; 4.02S~N.
c. A mixture of G.43 g of NaH and 4 g of 4_(trans-a-
5 fluorocinnamoyl)-2,3-dichloroanisole oxime in 60 ml of DMF
is stirred for one half hour and poured into ice water. A
precipitate which formed is filtered and dried gi~ring 7-chloro-3-(trans-B-fluorostyryl)-6-methoxy-1,2-benzisoxazole.
Recrystallization ~rom toluene gires a pure product, mp 155-161C.
Analysis:
Calculatedfor C16HllClFN02: 63.27%C; 3.65~H; 4.61%N
Found: 63. l~oC; 3 . 42%H; 4.65%N.
d.A mixture Or 1.~ g of 7-chloro-3-(trans-~-fluoro-15 styryl3-6-methoxy-1,2-benzisoxazole and 5.6 g of pyridine Ht~l is heated at 200C for 1 hour and then poured into vig-orously stirring ice water. A product of 7-chloro-3-(trans-g-fluorostyryl)-6-hydroxy-1,2-benzisoxazole precipitates and is filtered and dried, mp 226_229 C.
20 Analysis:
Calculated for C15HgClFN02: 62.19~oC; 3.135~H; 4.g~%N.
Found: 62.1,3%C; 3.17%H; ~.92%N.
e.To a mixture of O.g4 g of Na~l in 100 ml of DMF,
6.77 g oî 7-chloro-3-~trans- g-fluorostyryl3-6-hydroxy_lJ2-25 benzisoxazole in 50 ml of DMF is added dropwise in an atmos-phere of N2. The mixture is stirred 1 hour and then 1~.2 g of - 56~

ethyl bromoacetate is added dropwise thereto. The reaction mixture is stirred for one half hour and fifteen milliliters of 50~0 NaOH is added and the reaction mixture warmed to ~0C
for 1 hour. The reaction mixture is made acid~c with con-centrated HCl and a product precipitates by the addition of water. The crude product is f~ltered, dried and recrystal-lized from 95% ethanol giving ~7-chloro-3-(trans-~-fluorostyryl~-1,2-benzisoxazol-6-yl]oxy acetic acid, mp 200-203C.
Analysis:
Calculatedfor C17HllClFN04: 5~.72%C; 3.1B%H; 1~.03%N.
Found:59.03%C; 3.29%H; I~.Olq~oN.
~22 a. To a solution of 52.23 g of 2,4-difluorobenzoyl-chloxide ir 200 ml of 1,2-dichloroethane, 40 g of AlC13 15 is added over a 30 minute period. A solution Or 4~.3 g of 2,3-dichloroanisole in 1()0 ml 1,2-dichloroethane is added dropwise. There is a slow evolution of gas and the temperature rises to approximately 30C. The reaction mixture is warmed to 1,3 C and the gas continues to evolve for ap~roximately 30 20 minutes~ The mixture is poured over concentrated HCl and ice. The organic layer is separated and the a~ueous layer is extracted two times with CHC13. The combined organic layers are washed with water, dried (Na2SO~) and evaporated ~o g~ve an oil. Trituration with hexane yields 2,3-dichloro-25 ~-methoxy-2',1~'-difluorobenzophenone which is recrystallized from ether, mp 139-11~1 C.

Analysis:
Calculated for Cl~H~C12F202: 53.02%C; 2.54%H; 11.9~oN.
~ound: 53.09~oC; 2.~3%H; 11.~4qoN.
b. To 67 g of 2,3-dichloro-~-methoxy-2',4'-difluoro-benzophenone in 300 ml of pyridine is added ~g g of hydroxy-lamine HCl and the resultant mixture is refluxed for 1~
hours. The pyridine is evaporated in vacuo and the residue ~s partitioned between 5% HCl and ethyl 3cetate. The ethyl-acetate extract is washed with water, dried over Na2S04 and evaporated to give 2,3_dichloro-~-methoxy_2',6-'-difluoro-benzophenone oxime as a mixture of isomers. A sample is recrystallized from 95% ethanolS mp 1~0-1~6C.
Analysis:
Calculated for Cl~HgC12F2N02: 50.62%C; 2.73%Hj ~.22%N.
Found: 50.63%C; 2.gO~H; ~.55~oN.
c. To a mixture of 5.7 g of NaH in 100 ml of DMF, a solution of 53 g of 2,3-dichloro-~-methoxy-2',6'-difluoro-benzophenone oxime in 250 ml of D~F is added dropwise main-taining the temperature at approximately 30C. After the mixture is stirred for one and one half hours, a product is precipitated by the addition of water. The c.ude product, wh~ch is a mixture of isomers, is chromatographed on silica gel wlth toluene-hexane as eluant to obtain a pure produc~
of 7-chloro-3-(2,4-difluorophenyl)-6-methoxy-1,2-benzisoxa-zole which is recrystallized from toluene, mp 1~9-191 5.
Analys-s:

- 5g -Calculated for C14HgClF2N02: 56.~7%C; 2.73%H; 4.74~gN.
Found: 56.94%C; 2.77%H; 4.66~gN.
d. A solid m~xture of 7.1 g of 7-chloro-3-(2,4-difluoro-phenyl)-6-methoxy-1,2-benzisoxazole and 27.g g of pyridine HCl is heated at 200 C for one hour and the mixture poured into ~gorously stirred ice water to precipitate a product.
The product is filtered and dried giving 7-chloro-3-~2,4-difluorophenyl)-6-hydroxy-1,2-benzisoxazole which is recry-stallized from toluene, mp lB6-190 C.
Analysis:
Calculated for C13H6ClF2N02: 55.43%C; 2.15%H; 4.97~oN.
Found: 55. 6g~oC; 2.16~H; ~.92%N.~
e. To a mixture of o.~6 g of NaH in 100 ml of DMF, under N2, a solution of 6.9 g of 7-chloro-3-(2,4-difluoro-phenyl)-6-hydroxy-1,2-benæisoxazole in 50 ml of DMF is added dropwise followed by the addit~on of 4.~1 g of ethyl bromo-acetate in 25 ml of DMF. The mixture is stirred for one half hour and fifteen milliliters of 50~0 NaOH is added and the mixture warmed for 1 hour at ~O-g5 C. Concentrated HCl is then added until the mixture is acidic. ~[7-chloro-3-(2,4-difluorophenyl)-1,2-benzisoxazol-6-yl~oxy ~acetic acid is precipitated by the addition of water and recrystallized from toluene-acetonitrile, mp 200~203 C.
Analysis:
Calculated for ClsH~ClF2N04: 53.04~pC; 2.37%H; 4.12~N.
Found: 53.24%C; 2.55%H; ~.39~gN.

a. Dimethylsulfate (94.6~ g) is added dropwise o~er a 40 minute period to a cooled stirred solution of 2,5-dichloro-phenol (122.25 g) and sodium hydroxide (31.5 g) in water (300 ml). This mixture is stirred at room temperature for one hour, then at reflux for 2 hours, then cooled to room temperature. The organ~c layer is separated and combined with ether extracts of the remaining aqueous layer. The ether solut~on is dried (saturated NaCl, Na2S04, K2C03) and the ether removed to give 2~5-dichloroanisole. Distil-lation gives a colorless liquid (115C at aspirator vacuum).
A solution of o-fluorobenzoyl chloride (69.76) in carbon disulfide (25 ml) is added at room temperature to a suspension of aluminum chloride (5~.67 g) in carbon disulfide (450 ml) followed by the addition at room temperature of 70.~1 g of 295_dlchloroanisole in carbon disulfide (25 ml). The mixture is stirred ~ hours at room temperature, during which time a precipitate forms. The mixture is then refluxed for one hour, cooled, and 5~ g of AlC13 is added. The resultant mixture is then refluxed for 2 hours and stirred at room temperature for lg hours. The mixture is poured over ice/
HCl and extracted with methylene dichloride to given an oil.
Trituration with hexane-ether gives a solid. Recrystallization from diisopropyl ether gives a solid, melting partially at about 9~C then at a~out 120C. The solid remaining after removal of the solvent from the filtrate is treated with ether-petroleum ~ther to gi~e 2,5-dichloro-~-(2-fluorobenzoyl) anisole and recrystallization from methanol gives mp 100-103C.
Analysis:
Calculated for C14H9C12F02: 56.21%C; 3.0~%H-Found: 56.26~oC; 3 . OOqoH .
b. A mixture of 2,5-dichloro-4-(2-fluorobenzoyl) anisole (3 g) and hydroxylamine hydrochloride ~ g) in pyridine (25 ml) is refluxed for several hours until no ketone remains. The pyridine is removed under high vacuum and the residue diluted with water, then extracted with chloroform.
The chloroform solution is dried and the chloroform removed to give a solid which is r~crystallized from ether to afford (z)-2'-fluoro-2,5-dichloro-4-methoxybenzophenone oxime, mp lggoc.
Analysis:
~alculated for Cl~HlCCl~FN02: 53.52~o5; 3.21~H; ~.~6%N.
Found: 53~4~%C; 3.22%~; ~.3~oN .
c. A solution o~ (z)-2'-fluoro-2,5-dichloro-4-2Q methoxybenzophenone oxime (3.1~ gl in DMF (20 ml) is added dropwise to a stirred suspension of sodium hydride (o.6 g) in DMF (20 ml). The mixture is sti.red lg hours at room temperature, then poured into ice/~3~er and extracted with chloroform. Tne chlsrGform solution is w~shed with water, saturated sodium chloride and dried over ~a2SO~-MgSO~. Re-moval of the chloroform giv~s a residue that on treatment with ether-petroleum ether gives a solid, mp 165-166C.
Remo~al of the solvent from the filtrate yields a solid that on treatment w~th ether-petroleum ether gives 5-chloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole, mp 165-166C.
Analysis:
Calculated for C14H9ClFN02: 60.55%C; 3.27%H; 5.04%N; 12.77%Cl.
Found: 60.71%C; 3.1~%H; 4. 99~oN; 12.75%Cl.
d. A solution of 5-chloro-3-t2-fluorophenyl)-6-methoxy-1,2-benzisoxazole (l g) and boron tribromide (1.3 ml) in dichloroethane (30 ml) is refluxed for about 24 hours.
The reaction mixture is poured onto ice-water and extracted with dichloromethane to give a solid of 5-chloro-3-(2-fluoro-phenyl)-6-hydroxy-1,2-benzisoxazole, mp 1~0-lg2C.
Analysis:
Calculated for C13H7FClN02: 59.22%C; 2.6g%H; 5.31%N.
Found: 5~.90%C; 2.6~,H; 5.17%N.
- e. A solution of 5-chloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole (1~.~ g) in DMF (~0 ml) is added dro~wise at room temperature to a suspension of sodium hydride (3.0 g) in DMF (~0 ml) and the mixture is stirred at room temperature for one half hour. A solution of ethyl bromo-acetate (10.31 g) in D~F ~0 ml) is then added dro~wise and the mixture stirred 1~ hours at room temperature. An addi-tional 0.3 g of NaH suspended in DMF is added, followed by 1 g of ethyl bromoacetate. The mixture is war~.ed to 50C
for 1 and one half hours, cooled and poured over ice/water - 62 _ and extracted with ether. The ether extracts are washed with water, saturated sodium chloride, dried over sodium sulfate and the solvent is removed to give a solid. Trituration with ether-petroleum ether (1:1) gives ethyl ~[5-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy~ acetate, mp 11~-115 C. -Analysis:
Calculated for C17H13ClFN04: 5g.37%C; 3.75%B; 4.00qoN.
Found: 5g.15%C; 3.66qoH; 3.93%N.
f. A mixture of ethyl f [5-chloro-3-(2-fluo~ophenyl)-1,2-benzisoxazol-6-yl ] oxy3 acetate 114 g) sodium hydroxide (~ g), ethanol (500 ml) and water (300 ml) is refluxed for five hours, cooled in an ice bath and acidified with con-centrated llydrochloric ac~d. The suspension is extracted with chloroform, the extract dried with saturated sodium chloride and the chloroform removed to give a solid, mp 214-215C. Recrystallization from a 3:2 mixture of acetonitrile-toluene gives~ [5-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl] oxy3 acetic acid.
Analysis:
Calculated for C15H9ClFN04: 56.00%C; 2.~2~H; 4.35~N-~ound: 5 5 7~oC; 2.69%H; ~.27~.
Exam~le 24 a. To a solution of 57.6 g of 3,~-dichlorobenzoyl-chloride in 1,2-dichloroethane (150 ml) is added 36.7 g of AlC13 in portions over a 30 minute period. To the resultant s~

mixture is added dropwise 4~.26 g of 2,3_dichloroanisole in 1,2-dichloroethane (150 ml). There is an eYolution of gas and the reaction mixture ~s heated to 60 C for one hour. The mixture is then ~oured over 150 ml of concentrated HCl and 150 ml of ice and then extracted with CHC13 and then ethanol.
The resultant organic layer is washed with lO~o aqueous K2C03, then water, dried over (Na2S04) and evaporated to yield 2 d~chloro-4-methoxy-3',4'-dichlorobenzophenone, mp 113-140C.
b. A mixture of 53 g of 2,3-dichloro-4-methoxy-3', 4'-dichlorobenzophenone and 40 g AlC13 in ~00 ml of benzene is refluxed for five hours and then cooled to room temperature and maintained there for about 1~ ho~urs. The mixture is then poured over 200 ml of concentrated HCl and 200 ml of ise and then stirred at room temperature for one half hour. Ethyl-acetate is added to the mixture and the ethyl acetate/benzene layer is washed with water, dried over Na2S0~ and then eva-porated to yield 2,3-dichloro-~-hydroxy-3',4'-dichloroben~o-~henone, m~ 179-1~0 C.
c. A mixture of 35.~3 g of 2,3-dichloro-4-hydroxy-3', 4'-di-chlorobenzo~henone, and 15.29 g of hydroxyla~ine HCl in 300 ml Or pyridine is refluxed for 2 hours. The pyridine is evaDorated in vacuo. ~he residue partitionQd between ethyl acetate and 5% HC1. The extract is washed with water, dried over Na2SO~ and evaporated to give the corresl~onding oxime.
To a solu~on of 35 g of the oxime in 300 ml of D~F, 6~

6.o g of NaH is added and the mixture heated to an internal temperature of 103 C for one hour 45 minutes followed by 100C
~nternal temperature for three fourths of an hour. The re-action mixture is cooled to room temperature and a solution of 1~.37 g of ethyl bromoacetate in 50 ml of DMF is added dropwise. The mixture is stirred for about 6~ hours, poured over water and the precipitate which forms is filtered off and rinsed with hexane. A crude product is recrystallized from ethanol to gi~e ethyl ~ ~-chloro-3-(3,4-dichlorophenyl)-1,2-benz~soxazol-6-yl~oxy3acetate, mp 123-125 C.
To a suspension of 19 g of the ester in 400 ml of ethanol, 20 ml of 50~ NaOH is added. A precipitate forms and the heterogeneous mixture is refluxed for 1 hour. To the hot mixture ~00 ml of water is added followed by con-centrated HCl until the mixture is acidic. The suspensionis stirred one half hour, filtered and recrystallized fro~
D~IF-ethylacetate to give~[7-chloro-3-(3,~-dichlorophenyl)-1,2-benzisoxazol-6-yl] oxy~ acetic acid, mp 222-224C.
Analysis:
Calculated for C15H~C13N04: 4g.35%C; 2.16%H; 3.76q7N.
Found: 5~.~C%C; 2.C3~H; 3.93%N.
2xam~1e 25 a. The Friedel-Crafts procedure of Example 2~ a is repeated with 4g.13 g of o-chlorobenzoyl chloride being combined with 36.7 g AlC13 and ~.26 g of 2,3-dichloroanisole to yield 3 white crystalline product of 2,3-dichloro-4-methoxy-8~3 ~ 64a -2'-chlorobenzophenone, mp 117-120C.
b. The procedure of Example 2~ b is repeated except that 6g g of 2,3-dichloro-4-methoxy-2' chlorobenzophenon~ is combined with 5g.6 g of AlC13 in 5GO ml of benzene. The resultant product is recrystallized from toluene to yield 2,3-dichloro-4-hydroxy-2'-chlorobenzophenone, mp 74-77 C.
c. To a solution of 53 g of 2,3-dichloro-~-hydroxy-2'-chlorobenzophenone in 350 ml of pyridine, 25.02 g of hydroxy-lamine HCl is added. The mixture is refluxed 2 hours. The ~yr~dine is evaporated in vacuo, the residue partitioned between ethyl acetate and 5% HCl. The ethyl acetate extract is washed with water, dried o~er Na2SO~ and evaporated to give the corresponding oxime. To a solution of 49 g of the oxime in 300 ml of DMF, 9.12 g of Na~ is added and the mixture heated to an internal ~emperature of gO-g~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 addsd dropwise. The mixture is stirred one half hour and water added to decompose excess NaH. The product is extracted with ethyl acetate. The ethyl acetate extract is washed w~th lO~o NaOH and water, dried o~er Na2SO~ and eYaporated to give a mixture. Chromatography of the mixture on silica gel with CHCl as eluant yields ethyl ~[7-chloro-3-(2-chlorophenyl)-1,2-benzisoxazole-6-yl] oxy ~acetate.
To a solution of 5.~6 g of th~ ester in 2CO ml of hot ethanol, 6 ml of 50~0 NaOH is added. A pre~ipitate forms and iX

s~
- 64b -the suspension is refluxed for one hour. Two hundred milli-liters of water are added to the mixture and enough concen-trated HCl to make the mixture acidic. The mixture is stirred 1~ hours at room temperature. A solid product precipitates S out and is filtered and recrystallized from toluene giving ~[7-chloro-3-(2-chlorophenyl)-1,2-benzisoxazol-6-yl] oxy~
acetic acid, mp 165-16gC.
Analysis:
Calculated for C15HgC12N04: 53.2~gC; 2.6~oH; 4.14%N.
Found: 53. 50~oC; 2.67%H; 3.95~oN.
Example 26 a The Friedel-Crafts procedure of Example 24 a is repeated with 35.~ g of 2,3_dichloroanisole, 32.4 g of o_ toluoyl chloride and 2~ g of AlC13 being combined in 125 ml of 1,2-dichloroethane to yield a product of 2,3-dichloro-4-methoxy-2'-methylbenzophenone.
b. The procedure of Example 2~ b i9 repeated except that 3g g of 2,3-dichloro-4-methoxy-2'-methylbenzophenone is combined with 34.6 g of AlC13 in 300 ml of benzene. The resultant product is recrystallized from toluene to yield 2,3-dichloro-4-hydroxy-2'-methylbenzophenone.
c. To a solution of 28 g of 2,3-dichloro-~-hydroxy-2'_ methylbenzophenone in 250 ml of pyridine, 13.9 g of hydroxy-lamine HCl is added and the mixture is refluxed 4~ hours.
The ~yridine is evaporated in vacuo and the residue is parti-tioned between ethyl acetate and 5% HCl~ The ethylacetate _ 64c -extract is washed with water, dried over Na2SO4 and e~aporated to give the corresponding oxime. To a solution of 12 g of the oxime in 50 ml of DMF and 50 ml of t~luene, 2.43 g of NaH is added. The mixture is heated under N2 to an internal temperature of 95-9g C for 5 and one quarter hours. An additional 5O ml of DMF is added and the internal temperature held at 95 C for another two hours. The reaction mixture is cooled to 3O C and 7.5 g of ethyl bromoacetate is added drop-wi~e. After addition is complete the mixture is stirred one hour. Water is added and the product extracted ethylacetate, dried o~er Na2SO~ and evaporated to giYe ethyl ~7-chloro-3---(2-tolyl)-1,2-benzisoxazol-6-yl ox~acetate.
To a solution of 13.95 g of the ester in 5OC ml of hot ethanol, 13 ml of 5O~O NaOH is added. A precipitate forms and the suspension is refluxed one and one half hours. Five hundred milliliters of water is added followed by the addi-tion of concentrated HCl until the mixture is ac~dic. A
solid product precipitates on cooling and the product is filtered off and recrystallized from toluene giving~ 7-chloro-3-(2-tolyl)-1,2-~enzisoxazol-6-yl oxy3acetic acid, mp 179-1 glC .
Analysis:
Calculated for C16H12Cl~O~: 60.4~1oC; 3.~ ; 4.41~N.
Found: 50.76~5; 3.91%H; 4 .26~gN.
_xam~le 27 a. The riedel-Crafts procedure of Example 24 a is 5~
- 64d -repeated with 33.7 g of 2,3-dimethylbenzoyl chloride, 5~ g of 2,3-dichloroanisole and 26.7 AlC13 being reacted to form 2,3-dichloro-4 methoxy-2',3'-dimethylbenzophenone.
b. The procedure of Example 2~ b is repeated with 39 g of 2,3-dichloro-~-methoxy-2',3'-dimethylbenzophenone in 300 ml of benzene. The resultant product is recrystallized from toluene to yield 2,3_dichloro-~-hydroxy-2',3'-dimethyl-benzophenone.
c. A mixture of 31 g of 2,3-dichloro-~-hydroxy-2', 3'-dimethylbenzophenone and 30.5 g of hydroxylamine hydro-chloride in 250 ml of pyrid~ne is refluxed for about on~ week.
The pyridine is evaporated in vacuo and the residue is parti-tioned between ethyl acetate and 5% HCl. The ethylacetate extract is washed, dried over Na2S04 and evaporated. Tri-tura~ion with hexane gives 2,3-dichloro-~-hydroxy-2',3'_ dimethylbenzophenone oxime.
d. To a solution of 5 g of 2,3-dichloro-~-hydroxy-2', 3'-dimethylbenzophenone oxime in 70 ml of D~F, 0.95 g of NaH
is added. The internal temperature is held between 95-120C
for seven hours, then the mixture is heated at 130C for 1.5 hours. The reaction mixture is cooled and 2.9~ g of ethyl bromoacetate is added dro~wise. The mixture is stirred one hour and water is added dropwise. The product which forms is filtered off and recrystallized from 95% ethanol to yield ethyl-~7-chloro-3-(2,3-dimethylphenyl)-1,2-benzisoxazol-6-yl]oxy~acetate, mp g9-91C.

5~
- 64e -Analysis:
Calculated for C19Hl~ClNO~: 63.~2%C; 5.C~H; 3.~9%N.
Found: 63.2 5~oC; 5.02%H; 3. 7g~oN .
e. A suspension of 2 g of ethyl ~[7-chloro-3-(2,3-dimethylphenyl)-1,2-benzisoxazol-6-yl]oxy~acetate, 50 ml of ethanol and 5 ml of 5C~ NaOR is refluxed 1 hour. To the hot mixture 50 ml of water is added enough concentrated HCl to make the reaction mixture acidic. Upon cooling and adding water, ~[7-chloro-3-(2,3-dimethylphenyl)-1,2-benzisoxazol-6-yl]oxy3acetic acid is precipitated, mp 170-172C.
- Analysis:
Calculated for C17H14ClNO4: . ~; %H; %N
Found~ 61~ 65~cc; 4. 38~oH; 4. Ol~N.

E:x.~ plc 2~
;.
a . 29 . 3 g of 2-bromopyridine in 150 ml of dry TH~ i~ a~ded to 75 ml of 2. 6 M n-butyllithium that was chilled to -65 (:,'. 2,3-~ichlorn -4-methoxyben~aldehyde (38. 0 g) is then added in 300 ml Or THF and the reaction mixture allowed to come to room tem.perature. It is poured into H20 and the crystalline product filtered off, washed with ether and dried to ~ive ~-(2,3-dichloro-4-methoxyphenyl)-2-pyridinemethanol, mp 174-~76C.
b. o4 (2, 3-dichloro- 4-methoxypl-enyl)-2-pyridinemethanol (31. 36 g) is dissolved in 600 ml of acetic acid and 100 ml of H2O. Chromic anhydride (11. 0 ~) is added portionwise over five minutes. After three hours the reaction mixture is poured into H20 and extracted with ether. The com-bined or~anic phase s washed well with 10% NaHCO3, then brine7and dried.
Removal of the solYeht under reduced pressure gives a crystalline product of (2, 3-dichloro-4-methoxyphenyl)(2-pyridyl)methanone, mp 104-107 C.
A~aiysis:
Calculated for C13H9512N02: 55. 34%C; 3. 21~H; 4. 975~!.
Found: 55. 29%C; 3. 26C,7GH; 4. 93!,rGN.

c. (2,3-dichlorD-4-~Lhoxyphenyl?(2-pyridyl)methanone (32.0 g) is re-fluxed for four hours in 300 ml of ethanol containing 30 g of hydr~xylamine - hydrochloride. The reaction mixture is p~ured into H20, made ~asic with NH40H and extracted with ethyl acetate. Drying and evaporation gi~res a crude oxime mixture of E-(2-pyridyl)(2r3~dichlor~-4-methoxy-phen~l)meth3nDne oxime and Z-(2-pyridyl)(2,3-dichlor~-4-meth~xyphenyl)methanone oxi~e.
The oxime mixture is dissolved in 200 ml of DMF and added to a suspe~sio~ of 3.1 g NaH ih 150 ml of DMF. After 15 minutes the reaction mixture is poured into H2O and the product filtered off One recrystalliza-- , tion from isopropanol removes unreacted E-oxime, giving 7-chloro-6-methoxy - 3-(2-pyridyl)- 1, 2-benzisoxazole, mp 164-166C .
A~lysl5:
CalculatedforC13H9ClN202: 59.89~YoC; 3 48~,r~; 10.75%N.
Found: 59. 53~,C; 3. 37%H; 10. 635~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% ~3r. The precipitated hydrobromide salt is filtered off, washed with ether and neutralized with 109'o 1~aHC03 solution. The free base is filtered off and dried, giving 7-- chloro-6-hydroxy- 3- (2-pyridyl)- 1, 2-benzisoxazole, mp 209 -211 C.
ADalysis:
Calculatet for C12H7ClN2O2: S8. 43%C; 2- 85~oH; 11- ~65~N~

- Fou~d: 58.16%C; 2. 81%H; 11. 42C~
=--- e. 7-chloro-6-hydroxy-3-(2-pyridyl)-1, 2-benzisoxazole -(10. 0 g) is dissolved in 8û ml of D~VIF ant added to an ice cold sl:spension of NaH (1.1 g~ in 50 ml of ~MP. When hydrogen evolution ceases, ethyl bromo-aceta~e (7. 5 g) in 20 ml of DMF is added. Af~er an ~dditional 9û minutes, 200 ml of H20 and 10 ml of 5C% NaOH are added and the reaction warmed at 65 C for 45 minutes. The mixture is poured into H20, acidified to pH 1-2, and a solid product filtered and dried to give ~[7-chloro-3-(2-pyridyl)-1,2-benzisoxazole-6-yl]oxy3acetic acid, mp 255-256 C.
Analysis:
Calculated for C14HgClN20~ 55.1g~oC; 2.4~%H; 9.20%N.
Found: 5 5 . 3 5~oC; 2. ~gqoH; 9 . ~5%N .
Exam~le 29 a. 7-chloro-6-hydroxy-3-(2-pyridyl)-1,2-benzisoxazole, Example 2g d (9.9 g) is dissolved in 600 ml of glacial acetic acid at 60 C. m-chloro-perbenzoic acid (g.3 g of ~5%) is then added portionwise. After warming at 6GC for a total of 1~ hours the reaction mixture is poured into 2 1 of H20 and the product filtered off and washed with methanol, then ether. Obtained in this manner is 7-chloro-6-hydroxy-3-(2-pyridyl)-1,2-bPnzisoxazole l'-oxide in the form of a hemi-hydrate after recrys'allization from DI~F/~20, m~ 214C.
Analysis:
Calculated for C12~7ClN203-0-5H20: 53.05%C; 2.~7~; 10.31~N.
Found: - 53 .1~C; 2 . ~2~H; 10. 47~oN .
b. 7-chloro-6-hydr~xy-3-(2-pyridyl)-1,2-be~zisoxazole l'-oxide ~7.30 ~) is d-ssolved in 200 ml of-D~lF and added to a suspension of NaH (1.33 ~) in 50 ml of D~F. After 15 minutes ethyl ~romoacet~te ~5.0 g) in 20 m7 of 3~F is added and the re3ction is warmed at 50C for 10 hours. The reactio~ mixture ., ~

~ ~S ~ !
- 6~ -is quenched with H20, acidified and the precipitate filtered off and dried well. The precipitat~ is treated again with 1.33 g of NaH and 5.0 g of ethyl bromoacetate in DMF. After 3C minutes 200 ml of H20 and 10 ml of 50% NaOH are added and the reaction mixture is warmed at 50 C for 30 minutes. It is then acidified and ~[7-chloro-3-(2-pyridyl)-1,2-benziso~a-sol-6-yl]oxy~acetic acid l'-oxide is obtained, mp 21~C(d). '' Analysis: ' Calculated for C14H9ClN205: 52.~3%C; 2-~3%H; ~-74%N-Found: 52.35%C; 2. 791oH; ~ . 93~N. , Exampl~_~O , a. m-dimethoxybenzene (27.6 g) and ,c,-fluorobenzoyl chloride (31.7 g) are dissolved in 200 ml ~f dichlorosthane and AlC13 (2~.0 g) is addod portionwise. After t~o hours an , additiona~ 56 g of AlC13 is added and the reaction mixture warmed at 60 C for 1.5 hours. It is then poured into H20 and extracted with ethylacetate. Drying and evaporation gives a cr~Jstalline com~,ound. Trituration with toluene gives 2,4- 1, dihydroxy-2'-fluorobenzophenone, mp 109-111C.
Analysis:
~alculated for C13H9F03: 67.2~C; 3.91~H, ~ %F.
Found: 66.~5%C; 3.75~sH; ~-35%F- --b. 2,l~-dih~droxy-2'-fluorobenzophenono (25.0 g) is ,' refluxod I-~ hours in ?50 ml of pyridine containing 17.1 g of ', 25 hydroxylamine hydrochloride. The reaction mixture is then '-' partitionod between ether and 5~ HCl and the organic layer is f ~, - 69 _ separated. Drying and evaporation gives, after crystallization from toluene, one ~ure isomer of 2,4-dihydroxy-2'-fluorobenzo-phenone [E-oxime], mp 17C-172 C.
Analysis:
S Calculated for C13HloFN03: 63.16~C; ~.0~%H; 5.67%N.
Found: - 63. 56%C; ~ . 2~oH; 5. 561oN .
c. The E-oxime 2,4-dihydro-2'-fluorobenzophenone oxime (1~.6 g) is warmed at 50 C in 1~.0 ml of acetic anhydride for 5 hours then at 60 C for 6 hours. An additional 3.0 ml of acetic anhydride is added and the reaction is allowsd to remain undisturbed at room temperature for about 73 hours.
The crystalline product which separates from the reaction mixture is washed with cold ether to give a Dure product of E-~-acetoxy-2-hydroxy-2'-fluorobenzophenone 0-acetyl oxime, mp 132-13~C.
Analysis:
C~lculated for C17~ 5: 61-63%C; ~-26~H; ~-23~oN-Found: 61.~C~C; I~,C~H; ~.07~N.
d. E-~-acetoxy-2-hydroxy-2'-fluorobenzophenone 0-acetyloxime (1~.~ g) is dissolved in ~0 ml of DMF and added to an ice-cold sus?ension of Na~ (3.3 g) in 100 ml of D~F.
After 90 minutes the reaction mixture is po~red into u2o and a little ins~luble precipitate is flltered off. Acidi-fication of th.e aque~us filtrate and extraction with ether giv~s, arter drying and evaporation, 3-l2-fluoropheny~)-6-hydroxy-1,2-benzisoxazole, mp 2C6_21CC.

~ 5 Calculated for C13HgFN02: 6~ .12%C; 3 . ~2~H; 6. llqoN .
Found: 6~.~3%C; 3. 59qoH; 6. l~oN .
e. 3 - ( 2 -fluorophenyl)-6-hydroxy-1, 2 -benzisoxazole (9.7 g) is dissolved in ~0 ml of DMF and added to an ice-cooled suspension of NaH (1.~ g) in 50 ml of DMF. when hydrogen evolution stops, ethyl bromoacetate (7.5 g) in 20 ml of DMF
is added and the reaction mixture is allowed to come to room temperature. After two hours 200 ml of H20 and 10 ml of 50qO
NaOH are added and the reaction warmed at 50 C. After an additional 30 minutes a product is collected after acidi-fication and filtering. Recrystallization from toluene/
CH3CN gives ~[3_(2-fluorophenyl)_1,2-benzisoxazol-6-yl]oxy3 -acetic acid, mp lg2-lg4C.
An~lysis:
Calculated for C15HloFNO~: 62.72%C; 3.51~oH; ~.gg~oN.
Found: 62.56~C; 3.61%H; 5.o6%N.
xam~le 31 a The Friedel-Crafts procedure of Example 24 a is repeated with 31. 55 g of p-fluorobenzoyl chloride, 32 g of 2,3-dichlor~anisole and 35.22 g of AlCl combined in 1,2-dichloroethane and reacted. The resultant crude product is triturated with warm hexane, cooled and filtered to yield 2,3-dichloro-4-methoxy-~'-fluorobenzophenone.
b. A mixture of 35.~ g of 2,3-dichloro-~-methoxy-~'-fluorobenzoph~none and 160 g of pyridine hydrochloride is heated at ~00 C for one hour. The reactio~ mixture is p~ured , ~

~ 5 into ice water with stirring and a precipitate forms. The precipltate is filtered and dried for about 1~ hours to yield 2,3-dichloro-4-hydroxy-~'-fluorobenzophenone.
c. To a solution of 35 g of 2,3-dichloro-~-hydroxy-~'-fluorobenzophenone in 250 ml pyridine, 34.6 g of hydroxy-lamine HCl is added. The mixture is refluxed for ~ hours.
The pyridine is evaporated in vacuo. The residue ls parti-tioned between 5% HCl and ethyl acetate. The ethyl acetate extract is washed with water, dried over Na2S04 and e~aporated to give 2,3-dichloro-~-hydroxy-~'-fluorobenzophenone oxime as a mixture of isomers, mp 150-156C.
Analysis:
Calculated for C13H~C12FN02 52.02%C; 2.69~H; ~.67%N.
Found 52.19%C; ~.7~%~; 4.6g%N.
d To a mixture of 4.0 g NaH in 50 ml DMF, a solution of 20 g of 2,3-dichloro-4-hydroxy-4'-fluorober.zophenone oxime in 100 ~.1 of DMF is added dropwise in an atmosphere of N2.
The reaction mixture is heated to an internal temperature of 96C for 2 hours. The reaction mixture is cooled to ~o?C
and 12.3 g of ethyl bro~oacetate is added dropwise and the mixture is stirred for one hour. T~enty ~.illiliters of 5G~
NaO~ and lOC ml of water is added and the re3cticn is heated at ~0-90 C for on~ hour. Concentrated HCl is added until ~he reaction mixture is acidic and the mixture is stirred for one half hour and water added. A solid product is collectcd by filtration and recr~s~allized to gire a ~ure ~roduct of S~3 - 72 _
7-chloro-3-(~-fluorophenyl~-1,2-benzisoxazol-6-yl~oxy7acetic acid, mp 233-237 C.
Analysis:
Calculated for C15H9ClFN0~: 56.00%C; 2.~3%H; 4.36%N.
Found: 55.76%C; 2.90~oH; 4.29~oN.
Example 32 a. 2,6-dimethoxytoluene (20.0 g) and o-fluorobenzoyl chloride (19.~ g) are dissolved in 250 ml Or dichloroethane and chilled to 5C. AlCl~ is added por~ionwise and when the addition is complete the reaction mixture is allowed to warm to room temperature over 30 minutes, then refluxed 30 minutes.
It is then poured into 5% HCl and allowed to stand undis-turbed 1~ hours. Extraction with ether, followed by drying and concentration, gives crystalline material that is washed with hexane to gi~e 2'-fluoro-2-hydroxy-~-methoxy-3-methyl-benzophenoneJ mp llg-120C.
Analysis:
Calculated for C15H13F03: 69.22%C; 5.C~%~; 7.30%~.
Found: 69.23~C; 5.Cl~H; 6.9g%F.
b. 2~-fluoro_2_hydrox~_~-methoxy-3-methylbenzophenone (30.0 g) is refluxed lg hours in 350 ml of pyridine containing 32.0 g of hydroxylamine hydrochloride. The solvent is removed in vacuo and the residue is distributed betl,~een ether and 5%
~Cl. Drying 3nd concentration of the ether gives a crude product that is heated as a melt at 2CO~C for 30 minut~s in a nitrogen atmosphere. m~ he melt is allo-led to cool and the solid mass is triturated well with hexan to give E-2'-fluoro-2_hydroxy_4_methoxy-3_methylbenzophenone oxime, mp 167-Analysis: Calculated for C15Hl~FN03: 65.44%C; 5.13%H; 5.09%N.
Found: 65.~9~C; 5.26%H; ~ %N.
c. E-2'-fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone oxime (20.0 g) is warmed on a steam bath for one hour with 12 ml of acetic anhydride. The acetic anhydride is evaporated in vacuo and the product is distributed between ether and H20, then the ether is washed with 10~ NaHC03. Evaporation and tr~turation of the crystalline product with hexane gi~es E-2'-fluoro-2-hydroxy-~-methoxy-3-methylbenzophenone 0-acetyl oxime, mp ~3-~6 G.
Analysis: Calculated for C12H16FN04: 6~.34%C; 5.0g%H; ~.42%N.
Found: 6~.30%C; 5.0~%H; ~.26%N.
d. E-2'-fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone 0-acetyl o~ime (22.0 g) is dissolved in 100 ml of D~lF and added to a suspension of 2.5 g NaH in 100 ml D~F. An ice bath is appli~d to keep the reaction temperature <30C. After ~0 minutes the reaction is poured into H20 and extracted ~lith ether. After washing well with H20~ the et,her is dried and evaporated to gi~e a crystalline product that is washed with cold hexane t~ give 3-(2-fluoropher.yl)-6-~ethoxy-?-meth 2-benzisoxazole, mp ~05-10~C.
Analysis:
Calculated f~r C15~12F~C2 70-03~C; ~ 7~; 5 ~5~
Found: 69.9~?C; ~.7~U; 3.3f~N.

- 7~ -e. 3-(2-fluorophenyl)-6-methoxy_7-methyl-1,2-benzisoxa-zole ~16.1 g) is heat~d at 200C for two h~urs with 6~ g of pyridine hydrochloride. The melt is poured into H20 and ex-tracted with ethyl acetate. After washing with 5~0 ~Cl the ethyl acetate is dried and evaporated to give 3-~2-fluoro-phenyl)-6-hydr~xy-7-methyl-1,2-benzisoxazole, mp 216-219C.
Analysis:
Calculated for Cl~HloFN02: 69.13%C; 4.1~%H; 5.7~N.
Found: 6g.91%C; ~.03%H; 5.~2%N.
f. 3-(2-fluorophenyl)-6-hydroxy-7-methyl-1,2-ben-zisoxazole (10.6 g~ is dissol~ed in 90 ml of D~$F and treated with ~.0 g of ethyl bromoacetate and 6.7 g of K2C03. The reaction is warmed at 6C C for 2 hours then allowed to re'urn to amb-ent. After 1~ hours at ambient, water (200 ml) and 50~0 NaCH (15 ml) are added a-,d the soluti~n haated at 90 C
for 9C minutes. The mi~ure is p~ured int3 H20 a~d acidified and then it is extracted i~to ether. ~r~Jing and e-rap3ra~ion gives crystalline ~r~duct ~f~[3-(2-fluo~~henyl)-7-me~h.yl-1, 2-benzisoxazo~ yl]oxy3acetic acid, mp 15~-16C C.
Analysis Calculate~ for C16~12FNO~: 63-7~7~; ~ 02~ 6~N-Foun~: 63.~9~ 7.~ .5 _xaml~le 33 a. ~-chl~raanisola (?g.5 g) a~,~ o-fluor_~er.z3jl chl~ride ~31.7 g) are ~iss~l~ed i~ ~C0 ~1 o~ dichl~oe'~3ne and ~re3tad at 10 C with 26~7 g of AlC13. After ~5 minutes t~ reacti~n ~ S 3 - 75 ~

mixture is poured over ice and extracted with ether.
Drying and eva~oration, followed by trituration with hexane gives material that contains 2-chloro-2'-fluoro-~-methoxy-benzophenone. Recrystallization from Et20/hexane gives 2_ch1oro-2'_fluoro_4_methoxybenzophenone, mp 77-79 C.
Analysis:
Calculated for Cl~HloClF02: 63.53%c; 3.gl%H; 7-1~9oF-Found: 63.77%C; 3.75~H; 7.25%F-b. 2-chloro-2'-fluoro-~-methoxybenzophenone ( 15. 5 g) is refluxed for thre~ hours in 150 ml of pyridine containing 10.0 g of hydroxylamine hydrochloride. The pyridine is removed in ~acuo and the residue is distributed between ether and 5% HCl. Drying and evaporation of the organic phase gives an isomeric mixture of oximes. The mixture is dissolved in 50 ml of D~.F and is added to a suspension of 1.5 g NaH in 30 ml f DMF. After warming at 60 C for 30 minutes the reaction mixture is poured into H20 and extracted with ether. roncentration under reduced pressure gives a solid. Recr~s~ allization from eth~r gives 3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole, mp 101-103 C.
Analysis:
Calculated for C,~'~.lCFN02: 69.13%C; ~ ; 5.76~oN.
Found: 69.0gq,c; ~.29~H; 5.65~N.
c. 10 g of 3-(2-fluoropheny')-6-methoxy_1,2_ benzisoxazole 3re dissolved in ~00 ml of dr~J THF at -~C~C
and treated with 21 ml of 2.2 M n-butyllithiu.-;. After ~ 5 stirring for one hour, I2 (11.7 g) in 90 ml of ether is added. The reaction mixture is poured into Na2~203, then H 0. Drying and concentration gi~es 3-(2-fluorophenyl)-7-iodo-6-methoxy-1,2-benzisoxazole, mp 135-13~C.
Analysis:
Calculated for: C14H9FlN02: ~5.55%C; 2.~6%H; 3.~0~N; 3~.3~oI.
Found: 44.9~%C; 2.43%H; 3.70%N; 3~.09%I.
d. 3-(2-fluorophenyl)-7-iodo-6-methoxy-1)2-ben-zisoxazole (~.2 g) is refluxed 1~ hours in 130 ml of CH2C12 containing 6.6 ml of BBr3. The reaction mixture is poured into H20 and extracted into ether. Drying and evaporation gives a crystalline product that is triturated well with hexane to yield 3-(2-fluorophenyl)-6-hydroxy_7-iodo-1, 2_benzisoxazole, mp 212-214 C.
Analysis:
Calculated for C13H7FlN02: 43.97%C; 1-99%H; 3-95%N; 35-74%I-Found: ~.l9~C; 2.0G~H; 3.g6~N; 35.12%I.
e. 3-(2-fluorophenyl)_5-hydroxy-7_iodo_1,2_ benzisoxazole (7.~0 g~ in ~0 ml of DMF is treated at 60C
with 6.6 g of K2CG3 and 7.9 g of ethyl brom~acet3te.
After one hour the temperature is increasQd to 9G C
and ~0 ml of H20 and ~ ml of 50% NaOH are added. After an additional 30 minutes mixture is poured into H O and acidi-fied and then extracted into ether, dried and evaporated to yield ~{3_(2_fl~oro~henyl~_7_iodo_1,2_ben~isox3zol-6_ yl~ oxy~acetic acid, m~ 17g-lgC C.

Analysis:
Calculated for C15H9FlN04: 43.61%C; 2.20~1oH; 3.39~oN.
Found: 43.25%C; 2.12%H; 3.2~%N.
Example 3l~
a.10 g of 3-(2-fluorophenyl)_6-methoxy-1,2_ benzisoxazole of Example 33 b are dissolYed in 400 ml of dry THF and treated at -1~0C with 21 ml of 2.2 M n-butyl-lithium. After stirring for one hour, bromine (2.5 ml) is added dropwise. The reaction mixture is poured into H20, 10 extracted into ether and wash~d with Na2S203 solution.
Drying and e~a~orating gives a material that contains the desired brominated product, 7-bromo-3-(2-fluorophenyl)-6-m thoxy-1,2-benzisoxazole, mp 1~0-153Q~.
Analysis:
Calculatedfor C14H9BrFN02: 52.191oC; 2.~2~H; 1,.35%N; 214.~1%Br.
Found: 51.97%C; 2.~3%H; 4.2~gN; 25.17%Br.
b.7-bromo-3-(2-fluorophenyl)-6-methoxy-1,2-ben-zisoxazo'e17.20 g) is refluxed for 18 ho~rs in 130 ml o~
CH2C12 containing 6.6 ml of ~Br3. The reaction mixture is 20 poured int~ H 0 and extracted into ethyl acetate. Evapora-tion and trituration with hexane gives the corresponding rph~nol, mo 231-23l, C.
The phenol (6.30 g) in ~C ml of DMF is treated at 60C with 6.6 g of K2C03 and ?.9 g of ethyl bro~.aa~etate.
25 After one hour, ~Oml of H20 and g ml of 5C~ NaCH are added and the tem~erature is raised to 90 C. After an additional ~.
. ~

5~
- 77a -1~5 minutes the reaction is acidified and extracted into ethylacetate. E~raporation and recrystallization from toluene/CH2CN gives ~[7-bromo-3-(2-fiuorophenyl)-1,2_ benzisoxazol-6-yl]oxy3acetic acid, mp lgO-lg2C.
Analysis:
Calculatedfor C15H9BrPN04: 49.20%C; 2.4~%H; 3-~3%N-Found:~9.19~oC; 2.1,7%H; 3. ~9oN .
Example 35 a.To a mixture Or 4 g of 2-chloroesorcinol dimethyl ether and 3.7 g of 2,3-difluorobenzoyl chloride in 60 snl of 1,2-dichloroethane at 5C, 3.06 g of AlC13 is added in portions. The mixture is allowed to warm to room tempera-ture and then refluxed for 30 minutes. The reaction mixture is poured into concentrated HCl-ice and is permitted to stand ~bout 72 hours. The aqueous layer is extracted with additional organic solvent, dried over Na2S0~ and evaporated to give 3-chloro-2-hydroxy-4-methoxy-2',3'-difluorobenzo~henone, mp 161-162 C.
Analysis:
Calculated for Cl~,H9ClF203: 56.30%C; 3.0~%H; 12.72q~3F.
Found: 56.26 %C; 3.06%H; 12.56~3F.
b. To a solution of 2L, g of 3-chloro-2-hydroxy~
methoxy-2',3'-difluoroben~ophenone in 160 ml pyridine, 22 g of hydroxylamine HCl is added. The mixt ~re is refluxed for 2 hours and the pyridine evaporated in racuo. The residue is partitioned between ethyl acetate and 5% ~Cl.

- 77b -The ethyl acetate extract is washed with water, dried over Na2~04 and evaporated to give a pale yellow solid which consists of two isomers. The solid is melted at 205C
for approximately 13 minutes. The residue is dissolved in hot ethylacetate and then evaporated to dryness giving E-3-chloro-2~,3'-difluoro-2-hydroxy-4-methoxybenzophenone oxime, mp 19B_199 C.
Analysis: -Calculated for C14HloClF2N03: 53.60~oC; 3.21%H; 4.47%N.
Found: 53-95%C; 3.29~oH; 4.42%N.
c. A mixture of 1.5 g of E-3-chloro-2',3'-difluoro-2_hydroxy-4-methoxybenzophenone oxime and 0.67 g of acetic anhydride are warmed at 60 C for 30 minutes. The mixture is dissolved and then solidified. The residue is parti-tioned between ethyl acetate and 10% NaH503. The ethyl acetate extract is washed, dried over Na2S0~ and evaporated to give E-3-chloro-2',3'-difluoro-2-hydroxy-~-methoxy-benzophanone 0-acetyl oxime, mp 136-139C.
Analysis:
Calculated for C16~12ClF2N04: 54.02%C; 3.~0~H; 3-94~N-Found: 53-~9~oC; 3-4g%H; 3-97%~-d. To a mixture of 1. 4 g of NaH in 200 ml of DMI:, a ~;oluti~n - of 19 g of E-3-chloro-2', 3'-difluoro-2-hydroxy-4-methoxybenzophenone O--, acetyl oxime in 200 ml of DMF is added dropwise in an atmosphere of N?.
The mixture is stirred for o~e half hour and then warmed at 45 C for one 5 half hour. Water is added and a product precipitates and is filtered and dried giving 7-chloro-3-(2, 3-dinuorophenyl)-6-methoxy- 1, 2-benzisoxazole, mp 184-189C.
Analysis:
Calculated for C14H8ClF2~2 56- 8 %
_ , 10 Found: 56.95~oC; 2.84%~; 4.77%N.
e. A solid mixture of 12. 4 g of 7-chloro-3-(2, 3-difluoro-phenyl3-6-methoxy-1, 2-benzisoxazole and 50 g of pyridine HCl is heated to 200C for 4~ minutes. The mixture is poured into vigorously stirriLl ice vater and 7-chloro-6-hydroxy-3-(2, 3-difluorophenyl)-1, 2-benzisoxazole precipitates, mp 250-254C.
Analysis:
Calculatedfor C13H6ClF2N02: 55.43%C; 2.15%H; 4- %N
Found: SS. 60~3'oC: 2. 25','0H; 4. 91%N.
f. To a solution of 12 g of 7-chloro-6-hydroxy-3-(2, 3-di-fluorophenyl)-l, 2-benzisoxazole in 120 ml of DMF, 6. 36 g of K2C03 ~-~ added followed by 7. 83 g of BrCH2C02C2H5. The reaction is warmed at 60C
for two hours and ~hen allowed to stand for 18 hours. To the mucture 200 ml - - - of water and lS ml o~f 50% NaOH are added. The mixture is warmed at 90 C
~or 90 minutes, poured into water and acidified. The product is extracted into ethylacetate~vhich is dried orer Na2S04 and evaporated to give ~7-_ . _ - chloro-3-(2, 3-difluorophenyl)-1, 2-benzisoxazol 6-yl]oxy3acetic acid, mp 183-187C.
.

_ 79 _ Analysis:
Calculated for C15H8ClF2No4: s3 04%C; 2. 37(Do~; 4 12(T~
Found: 53. 20%C; 2. 49~H; 3 889~N
Exarnple 36 a. To a solution of 10 g (0. 033 m) of 2'-fluoro-~-methoxy-2, 3-dichlorobenzophenone of Example 1 a in 100 ml of pyridine, 3.17 g of hydroxy~mine HCl is added. The mixture is refluxed for about 64 hours.
The pyridine is evaporated and the residue partitioned between 5% HCl and ethyla~etate. The ethylacetate extract is washed with water, dried over Na2S04 and evaporated to gi~e 2, 3-dichloro-4-methoxy-2'-fluorobenzo-~henone, mp 195-197 C.
Analysis:
- Calculated for C14HloC12FN02: 53.52~C; 3.21%H; 4.46~N.
Found: 53. 55%C; 3. lO~H; 4. 42~N.
b. To a solution of 8 g of 2, 3-dichloro-4-methoxy-2'-fluoro-benzophenone oxime in 5~ ml of DMF, 0. 67 g of NaH is added under a N2 atmosphere. The mixtule is stirred for one hour and water is added tO pre-cipi~ate 7-chloro-3-(2-fluorophenyl)-6-mcthoxy-1, 2-berzisoxazole which is filtered and dried, mp 155-158 C.
20 Analysis:
Calculated for C14HgClFN02 60. 55%C; 3. 26%H; 5. 05%N.
Found: 60. 63%C; 3.15%H; S. 01%N.
c. A solid mixtllre of 2 g of 7-chloro-3-(2-fluorophenyl)-6- -methoxy-1, 2-benzisoxazole and 20 g of pyridine hydrochloride is hea~ed at 190-210 C for one hour. The hot reactlon mixture is poured in~o vigorously stirred ice water. The m~cture is made slightly acidic. 7-chloro-6-hydroxy-3- 52 -fluorophenyl)- 1, 2 -benziso:c~zole is col lected L~y ~i ILration a nd d ried, mp lgo-l4loc - ~o -Analysis:
Calculated for C13H7ClFN02: 59.22%C; 2.6~H; 5-31~N-Four.d: 59.1 ~C; 2.65~H;. 5.23%N.
d. The procedure of Example 35 f may be employed with 7-chloro-6-hydroxy-3-(2-fluorophsnyl)-1,2-benzisoxa-zole to yield ethyl ~[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy3acetate, the product of Example.
Example 37 a- 2-chlororesorcinol dimethyl ether t22.C g) and o-fluoro-benzoyl chloride (20.2 g~ are dissolved in 250 ml of dichloroethane, chilled in an ice bath and treated with AlC13 (lg.6 g~. Fifteen minutes after the 3ddition is complete, the reaction is heated to reflux for 30 minutes. It is poured into H 0 and extracted with ethyl acetate. Evapor~tion and trituration with hexane gives 3-chloro-2'-fluoro-2-hyd-oxy-~-methoxybenzophenone, mp 132-133C.
Analysis Calculated for Cl~HloClF03: 59.90%C; 3.59~H; 12.63~Cl.
~ound: 59.77~C; 3.59~,H; 12.51~,Cl.
b. 3-chloro-2'-fluoro-2-hydrox~ et'..oxybenzophen~ne (2~,6 g) is refluxed for 1~ hours in 3C0 ~1 of pyridine containing 12.2 g of hydroxyl3mine hydrochloride. The reaction mixture is concentrated under reduced ~ressure and is d~stributed bet~een ether and 5q~ HCl. The or~anic - phase is dried and eva~orated and the resulting cr~stalline product fused at 205 C for 45 minutes. The ~roduct is ~ ~ 3 - ~Oa -coolQd and recrystallized from toluene to give ~-3-chloro-2'- luoro-2-hydroxy-~-methoxybenzophenone oxime, mp lg~-1~6 C.
Analysis:
Calculated ~or Cl~HllCl~N03- 56.g6~oC; 3.75~,H; ~.79~^N.
Found: 56.67~C; 3.6~H; ~.66~N.

c . E - 3- chloro- 2 ' - fluoro - 2 -hyd ro~;y - 4- methoxybenzophenonc oxime (18.1 g) is warmed at 60C for 30 minutes v~ith 9 ml of acctic ~Lnhyclridc.
The reactioZZ mixture is distributed benveen ether Znd 10% ~taHCO3 ~nd was1~ed with 10% NaHCO3 until the washes remained basic. Drying, ev~poration 5 and trituraCion with hexane gives E-3-chloro-2'-fluoro-2-hydroxy-4-methoxy-o - benzophenone O-acetyl oxime, mp 125-128 C.
Analysis: - -Calculated for C16H13ClFNO4: 56. 90%C; 3. 88%H; 4.15~N.
Found: 56. 79%C; 3. 85%H; 4. 20%N.
d. nZe procedure of Example 35 d may be repeated to yield 7-chloro-3-(2-fluoropheryl)-6-methoxy-1, 2-benzisoxazole. Thereafter the procedures of Example 36 c and d may be employed to yield ethylf[7-- chloro-3-(2-fluorophenyl)-1, 2-benzisoxazol-6-yl]oxy3acetate, ~xample 38 lS a. 5. 0 g of 7-chloro-6-hydroxy-3-(2-fluorophenyl)- 1, 2-benz-isoxazole of Example 36 c in 30 ml of DMF is added dropwise with stirring to 1.1 g Na}l in 30 ml DMF. After one hour, 2. 6 ml of ethyl-2-bromopro-prionate is added and the solution is stirred 1. 5 hours. The solution is then poured o~to ice and ethyl-2-~[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxa-20 zole-6-yl]ox~1propionate precipitates which is filtered and dried, mp 79 C.
Analysis:
CalcuLated for C18H15ClFNO4: 59. 50%C; 4.13%H; 3. 8~%N; 9. 60%Cl.

Fou~Zd: , 59. 48~oC; 4. 09%H; 4. boæN; 9. 58~oGl. -b. 6. 8 g of ethyl-2-~{7-chloro-3-(2-fluorophenyl)-1, 2-25 benzisoxazole-6-yl]oxyJpropionate is dissolved in 35 ml of methanol an-l 2~
m~ of a 15% NaOH solutioZZ is added. The suspension is heated for two hours.

The rcaction mixture is poured onto ice, acidified with ~ICl ~nd a solid prc-cipit~tes which is filtered and dried in vacuo to give 2-fi[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-3-yl]oxy3propionic acid, m? 159-161 C.
~; Analysis:

16 11 4 . 5'0C; 3.28~H; 4.18/oN; 10.55"'oCl.
Pound:56.83'oC; 3.24~H; 4.179~N; 10.51%Cl.
Example 39 a. To a mixture of 21 g of 2, 5-dinuorobenzoyl chloride and 20. 4 g of 2-chlororesorcinol dimethyl ether in 250 ml of 1, 2-dlchloroethane at 5-10C
15. 7 g of AlC13 is added in portions. The mixture is allo~ed to warm to room temperature and is then refluxed for 30 minutes. The mixture is poured into concentrated HCl and ice and stirred for approximately one hour. The product is extracted with ethyl acetate, driéd over Na2S04 and evaporated to give 3-chloro-2', 5'-difluoro-2-hydroxy-4-methoxybenzo-phenone, mp 178-180 C.
Analysis: -14 9 2 3 ~0; 3.04~1; 12. 725~N.
Found:56.16%C; 3. 01%H; 12. 7~%N.
-- b. A mixture of 28 g of 3-chloro-2 ', 5 '-difluoro~Z-12ydroxy-20 4-methoxybenzophenone and 26 g of hydroxylamine ~Cl in 250 ml pyridine is refluxed for three hours. Pyridine is evaporated and the residue partltioned - ben~een ethyl acetate and 5% HCl. The ethyl acetate extract is washed with -~~ water, dried over Na,2SO4 and evaporated to give a solid product as a mixture of isomers. The solid is heated at 200-210 C for approximately 30-45 - 25 minutes and recrystall~zed from toluene giving E-3-chloro-2',5'-dlfluoro-2-hydroxy-4-methoxybenzophenone oxime, mp 209-210C.

Analys is:

CalCUIated fr C14H10ClF2N3 53-60%C; 3-29'~H; 4 47'~
Found: 53. 61~C; 3. 22%H; 4. 43/~oN.
c. A mixture of 17 g oi E~ s:llioro-2', ~ fluorG-2-hydroxy-5 4-methoxy benzophe~one oxim is warmed with 9 ml of acetic anhydride at 60C for 30 minutes. On cooling the mixture solidifies. The residue is partitioned between ethyl acetate and 10% NaHC03. The ethylacetate extract is w shed with water, dried over Na2SO4and evaporated to give E-3-chloro-2 ', 5 ' -difluoro-2 -hydroxy- 4- methoxybenzophenone Q-acetyl oxime, mp 130-Analysis:

16 12 2 4 %; %H; . 9 ~.
Found:- 53. 76%C; 3. 37%H; 3. 89%N.
d. To a suspension of NaH/200 ml of DMF in an atmosphere of N2, 19. 5 g of E;-3-chloro-2', 5'-diauoro-2-hydroxy-4-methoxybenzophenone ~a~etyl oxime in 50 rnl of r~MP is added dropwise. The mixture is stirred 30 minutes and water is added to precipitate 7-chlors~-3-(2, 5-difluorophenyl)-6-methoxy-1,2-benzisoxazole, mp 198-199 C.
-- Analysis:
Calculated for C14~8ClF2N02: 56. 87%C; 2.73%H; 4. 74%N.
Found:56. 74%C; 2. 70%~; 4. 70%N.
e. A mixture of 10 g of 7-chloro-3-(2, S-difluoropherlyl~-6-methoxy-l~ 2-beILzisoxazole and 40 g of pyridine HCl is heated at 200C for 45 minutes. The hot mixcure is poured into vlgorously stirred ice wa~ér and ~- 25 a product precipitates out. The product is filtered and dried ~ivi~g 7-chloro^
3-(2, S-d inuorophenyl)- 6-hydroxy- 1, 2-benzisoxazole, mp 256-257 C.

- 84 - 1~ 53 A nalys is:
Calcul~te~l lor C13~6CI~2 2 Foun~ 55. 26%C; 2. I)2'~oH; 4. 939 f. To a solutlcn of 9. 3 g of 7-chloro-3-(2, 5-difIuoropheny})-6-hydroxy-1, 2-benzisoxazole ii~ lOD ml of DMF~4. 97 g of K2C03 and 6. 07 g of ethyl bromoacetate is added dropwise. The mixture is heated for two .. ..
hours at 60C. To the mixnlre 200 ml of water and lS ml of 50% NaOH are .. ..
added. The mixture is stirred at 90C for 90 mi~utes and thén poured into water and acidified. The product is extracted with ethylacetate, dried over - '10 Na2S04 and evaporated to give ~[7-chloro-3-(2, 5-difluorophenyl)-1, 2-bem-isoxazol-6-yl]oxy~acetic acid.
. - Analysis:
Calculated for C~5H8ClF2N04: 53.04%C; 2.37%H; 4.12C/oN.
Fou~d: 53. 37%C; 2. 39%H; 4. OlC~70N~
Example 40 - a. 2-chlororesorcinol dimethyl ether (3. 4 g) is dissolved in 20 ml of CH2C12 and TiC14 (4. 3 ml) is added. To this solution is added di-chloromethyl methyl ether (2. 3 g). After 30 minuces the reaction mixture - is poured into H~O and extracted with ether. Drying and evaporation gi~res 3-c~loro-2,4-dimethoxybenzaldehyde, mp 107-lOB C.
Analysis:
Calculated for C9HgC103 53. 88%C; 4.52~H; 17.68%Cl Found: , 53, 93%C; 4 52%H; 17 42%Cl b 3-chloro-2, 4-diméthoxyben~aldehyde (2. 75 g) is reflw;ed for 30 minutes in 20 ml of dichloroethane containing l. 3 g oi AIC13. The reaction mixture is then poured into H20 and extracted wil:h CH 2 C12.

' - 85 - 't ~85~
Evaporation and recrystallizat~on Irom isopr~ nol ~ivcs 3-cllloro-2-hydroxy-4-methoxybenzaldehyde, mp 125 C.
Analysis:
Calculated for C8H7C103: 51. 49%C; 3. 78/~oH; 19. OO~Cl.
Fou~d: 51. 33%C; 3. 78%H; 18. 65%Cl.
c. 3-chloro-2-hydro:;y-4-methoxybenzaldehyde (1. 48 g~ is -~. suspended in 15 ml of H20 and 2yd~Jlanine-0-sulfonic acid (1. 08 g) is added, along with 0.1 g of Na2S04. After three hours an additional 15 ml of-H20 is added. A*er a total of four hours the reaction mixture is treated - ~ 10 wi~h 8% t~laHC03 solution and then extracted into ether. Furaporation and trituration with hexane gives a solid product. Recryscallization from toluene~hexane gives 7-chloro-6-methoxy-1, 2-benzisoxazole, mp 115-118 C.
ADalysis:
{:alculated for C8H6CIN02: 52. 33%C; 3. 29%H; 7, 63~N.
Found: 52.35%C; 3.30~oH; 7.71~N.
d. The procedure of Example 3~ e and f may be employed with 7-chloro-6-methoxy-1, 2-benzisoxazole to yield ~[7-chloro-1, 2-benzisoxa-zol- 6-yl]oxy~ acetic acid .
- Example 41 _ ~. To a solution of 1. 7 g of 2-chlororesorcinol dirnethyl ether and 2.0B, of o-trUluoromethyl benzoyl chloride in 50 ml of 1, 2-dichloroethane at 5-7 - 1. 6 g of ferric chloride is added gradually. The mixture is brought to room temperature and allowed to stand ~8 hours. The reaction mixture is re-fluxed 30 minutes and poured into 5% HCl a~d ice. The aqueous phase is -- 25, extracted with additiof~l:organic solv~nt. The combined organic extracts are washed with water,- dried oYer Na2504 and evaporated to give ~chloro-2-hydroxy-4-methoxy-2'-tr~fluoromechylbenzop~lenone, mp 101-102C.

~6 Analysis: -Calculated for C15HloClF30 3: 54. 485~,C; 3. Oa~vlI; 17. 24~
Found: 54.165'oC; 2.91,~oH; 17.16~F.
b. The procedures described in the fore~oing examples 5 (such as Example 35) may b.e employed with 3-chloro-2-hydroxy-4-methoxy-2'-trifluoromethylbenzophenone to obtain the corresponding oxime, cyclizing tbe oxime and forming the acid to yield ~[7-chloro-3-(2-trifluoro-me~ylphenyl)-1, 2-benzisoxazol-6-yl~oxy3acetic acid.
. Example 42 - ' 10 a. 10 g of 7-chloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole of Example 36 b is dissolved in glacial acetic acid (S00 ml) with stirring and chlorine gas is bubbled through at a slow rate for one half hour to give a solution containing a small amount of suspended starting material. The reaction mixture is stirred for 18 hours at room 15 .temperature and then the reaction mixture is poured onto ice water with stirring to ~ ipitate 5, 7-dichloro- 3-(2-fluorophenyl)-6-methoxy- 1, 2-benz- .
isoxazole, mp 121C.
Analysis:
- CalculatedforC14H8C12FNO2: 53.87%C; 2.59%H; 4.49%N.
- - 20 ~ound: 53.54%C; 2.599~; 4.~1%N.
. b. 10 g of 5, 7-dichloro-3-(2-fluorophenyl~-6-methoxy-1, 2-- benzisoxazole is combined with 100 g pyridine hydrochloride and heated at -~~ 200 C for 0. i hours~ The bot melt is quiclcly poured into stirred ice water and a resultant precipitate is filtered and dried for 4~ hours in vacuo (64 C).
-- 25 The solid is recrystalrized from toIuesie affording 5, 7-dichloro-3-(2-fluoro-phenyl) 6-hydroxy- 1, 2-benzisoxazole, mp 194-196C.

- 87 ~ 3 ~ 5 Analysis:

Calculated fcr C13H6C12FNO2: 52. 44%C; 2.01~; 4. 70%N; 23. 53%Cl.

Found: 52. 07%C; 2. 08%H; 4. 96,WoN; 23. 92%Cl.

c. 1. 4 g NaH is suspended in 50 ml DMF vith stirring.

S A solution of 7. 2 g of 5, 7-dichloro-3-(2-fluorophenyl~-6-hydroxy-1, 2-benzisox~zole in 50 ml DMF is added dropwise. The solution is heated-to s. 45 C for one hour. Ethyl bromoacetate (4. 0 g) in 20 ml DMF is added drop-.
wise and the ~eaction is stirred at 40 C for two hours. The solution Is poured into 1 1 of water, stirred and extracted with ethylacetate. rhe organic ex-10 tracts are washed with saturzted NaCl solution and the solvent removed irlvacuo ai~ording ethyl~5, 7-dichloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy3acetate, mp 105-106 C. >
Analysis:
Calcu~ted for C17H12C12FNO2: 53. 26%C; 3. 13%H; 3. 65~oN~; 18. 39%Cl.
Found: 52. 91%C; 3. 00%H; 3. 41%N; 18. 09%Cl.
d. 14. 0 g of ethylj[5, 7-dichloro-3-(2-fluorophenyl)-1, 2-benzisoxazole-6-yl~oxy3acetate is heated in 75% ethanol/~20 (700 ml) with stirring until a solution results. 20 ml of a 50% solution of NaOH is added and a precipitate forms. With additional heating and stirring the 20 precipitate goes into solution and is allowed ~o stir for 2. 5 hours. The ethanol is then evaporated in ~acuo and the residue is made acidic with 10%
~Cl. The precipitated solid is filrered and dried in ~acuo to afford ~[5, 7--- dichloro-3-~2-fluoropherlyl~-1, 2-benzisoxazole-6-yl]oxy~acetic acid, mp ~
160-170 C.

25 Analysis:
Calculated for C~5~38C12FNO~: 50. 59%C; 2.26~; 3.93~N.
Found: 50. 53%C; 2. 32~,~,; 3. 88~7VN.

~3 g~

_arr.~le ~3 a. To a suspension of NaH (1.0 g) of a 5C~c dispersion ir. min~ral oil 5C ml DM~ is add~d a solution cf 5.0 g of 7-chloro-3-(2-fluorophenyl)-5-hydroxy-1,2-benzisoxazole of Exampte 36 c in 5C ml DMF. The solution is stirred one hour at r30m temperature, then cooled to 5~C and 3.5 g of N,~-dimethylthiocarbam~lJl chloride is add~d all at once.
The reaction is brou~ht gradually to 6~ C and stirr~d for 2.5 hours. The solution i~ th~n poured into water and extracted with methylene cTr.loride until th~ extracts ar2 colorless. The combined organic extracts are wash~d with lC~ K2C03, then with saturat~d ~TaCl. Th~ s~'Y~n~ is re-m~ved in ~acuo yieldir.g 7-c~.lor~-6-(C-~',I!-dim~thylt~.io-c~rbamyl)-3-(2-flu~tro~he~yl)-1,2-b~nzis~x~z~le, ~.p 153-~5~C.An~lysis:
Calcul3te~ f~r C16~12~1F~J2C2~ 5~ ' Found: 5l,.~-C; 3.~; 7.9~ ; 9.1q,S.
b. ~.5 g ~f 7-chlor~-6-(0-~T,~-dimethylthiocarbarr.yl)-3_(2-fluoro~.enyl)-1~2_benzisoxazole i5 heated under nitro~en a~, 205 C for ~5 minut~-. A resultanl cool~d solid is recr~J~t311ized frs~. et~y' ace,at~ af~rdir.~ c~l~rless ~~lsms ~ ?-^~ r~ J,~ l.r~ hyl~ c~Y~3m~1)-3-(~-fluoro~h~.yl)-',2-b~nzi_ox3zol~ 1I.C-l~i2 C.

.. ~

S~
~9 Analysis:
Calculated for C16H12ClFN202S 5~-77%C; 3-44%H; 7-9~%N; 9-14~S-Found: 5~.~7%C; 3.56%H; 7.g6%N; ~.2g%S.
c. 2.0 g of 7-chloro-6_(S-N,N-dimethylthiocarbamyl)-3_(2-fluorophenyl)~1,2-benzisoxazole is dissolved in methanol and 25 ml of 15% aqueous NaOH is added. The solution is refluxed for three hours. The reaction mixture is poured into a large quantity of water, acidified with HCl to precipitate 7-chloro-3-(2-fluoroph~nyl)-6-mercapto-1,2-benzisoxazole, mp 125-129 C.
Analysis:
Calculated for C13H7ClFNOS: 55.~1%C; 2.50%H; 5.01~N; 11.46%S.
Found: 55.9~%C; 2.5~H; 5.09~7N; 11.52~S.
d. 3.2 g of 7-chloro-3-(2-fluorophenyl)-6-mercapto-1,2-benzisoxazole, 3.1 g K2C03, and 3.67 g of ethyl bromo-acetate are added to 60 ml DMF and warmed for two hours at 50C with stirring. The solution is poured into 700 ml H20 and extracted with ethyl acetate. Thc co~,bined organic extracts are dried over K2CC3, and the solvent is removed in vacuo to afford ethyl ~[7-ch~oro-3-(~-fluorophenyl)-1,2-benzisoxazole-6-yl]thio7-acetate.
Analysis:
Calculated for C17~13ClFN03~: 55.~9~C; 3.56~,H; 3-~3%N; ~-75~,S-~ound: 55.92~C; 3.7C;~,H; 3.3C~,N; g.91~.
e. 1.7 g of ethyl ~[7-chloro-3-(2-fluorophenyl)-1, 2-benæisoxazole-6-yl~thl~7acetate is dissolved in 50 ml of e~h~nol with stirring and .~arming. A 5~, solution o~ NaOH

is added (3 ml) with 25 ml water and a precipitate of a solid ~s obtained. After one hour, the etha~l is removed and the residue is mada acidic with HCl. The pr~cipitate is filtQ-ed and dried affording ~[5,7-dichlor3-3-(2-~luorophenyl)-1,2-benzisoxazole-6-yl]-thio3acetic acid, mp 165 C.
Analysis:
Calculated for C H ClFNO S: 53.~1%C; 2.67%H; ~.15~N; 9.~9~S.
Found:53 . 39~oC; 2.5~H; ~.19~oN; 9 . 4~S .
Exa~ple 44 a. To a s31uti~n of o-~lu~-3benzoyl chl~ride (47.6 g) in 100 ml dichlor~methane is added AlC13 (~C.O g) p3rti~n-wise, in about thirty minutes. T~ this resulta~t dark sol-uti~n is 3dded dr~ise a s~lution o~ 1-chloro-3,5-dimethoxy-benzene (52.0 g) in 120 ml dichlor~methane, in fifteen minutes. After stirring at a~.bient temperature f~r four h~urs, the mixture is p^ured in ~ ~ne lit~r iced-dilute .YCl soluti~n ~.d then s~irred f~- 30 minutes. The 3r~anic layer is c~llected, evap3-ated t~ an oil, ~,lhich is diss~ ed ir.t~
ether, washed with ~later, dilute NaOH s31uti^n., ~atQ-, then dried (saturated ~aCl, anhydr~us ~SO~. Aft~r filterin~, the sol~ent is e-rapo-ated t3 a s~id, ,Jhi~h ~s purified ~y silica gQl, eluted ~ith dich'~r~metha~Q t~ yiel~ 2-chl3r~ ,5-di~.eth~xy-2'-fluorobenzo~h~none, m? ~_92 C.
Ar.alysis:
2515 ,2C_. ~3: 51,13~r; ~ '!; 12 ~;3~1; 6 L ~
F~und: ~r).95~C; L~cfc~7; 11.~5~,Cl; 6,3~ F.

~, b. T~ a soluti~n ~f 2-chloro_~,6-dimethoxy-2'-fluorobenzophen~ne (33 g) in 150 ml dich'~r~ethane is add~d, porti~nwise in fifteen minutes, AlCl (15 g). After stirring at reflux (90 C) for three h~urs, the mixture is cooled, poured into one liter ice-dilute HCl solution, stirred for 30 minutes then extracted into ether. The ether/dichloro-ethane solution is washed with water, then dried (saturated NaCl, anhydrous 2~gaO~) and fi'tered.
After filtering, the solvents are evaporated to yield 2-chloro-2'_fluoro_6-hydroxy_4_methoxybenz~henone, mp ~5-9~ C.
Analysis:
Calculated for Cl~HlCClF03: 59.9C~C; 3.5~ ; 6.77~F.
FotL~d: 59.7g~,C; 3.53~H; 7.CC-~F.
c. T~ 125 ml ~ridine s added ~-chlor3-2'-fluor~-6-hydr~xy-~-~.eth~xybe~z~p~,enone (2~.5 g) and hydro~J'~mine hydroch'oride (1~ ~). After stirring at reflux (12C C) fo~
threQ ho~rs, the mixture is c~led, the ~yri~ine eva~orat~d to a ye'low se~i-solid. Th.e solid is dissolv~d in ether, washed with ~r~ater, then dried (saturated ~JaCl, anhydrous ~'gSO~). After flltering, 'he aol-~en~ s ~v3?0r3~ved to an oil, which s^lidifies to Z-~-chlor~ flu ro-S-hydroxy-~-methoxyben~ot?hQnonQ oxime, m~ 13C-lLr~ v~or. trituration ~J~th ~etroleum ether.
Ar.alys s:
Ca_cu_~v~ ~ 5~ 51..C3 55~ C; 3-75 I; 4-74 ~-Fo-nd: 55.74~^C; 3.7C~:; L.74~

. ,i ~1~3 d. The Z-2-chloro-2'-fluoro-6-hydroxy-4-methoxyben2O-phenone oxime may be reacted with acetic anhydride as de-scribed in Example 30 c to form E-2-chloro-2'-fluoro-6-hydroxy-4-methoxybenzophenone 0-acetyl oxime.
e. T~ a suspension of NaH (2.4 g) in 20 ml DMF, is added a solution of E-2-chloro-2'-fluoro-6-hydroxy-~-methoxybeniophenone 0-acetyl oxime ~15 g) in 50 ml DMF.
After stirring at ambient temperature for two hours, the mixture is poured into one 1 ice-water, stirred for 30 minutes and a precipitate is collected. The precipitate is washed with water then dried to yield 4-chloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole, mp 113-115 C.
Analysis:
Calculated for C14HlgClFN02: 60.55~tC; 3.27%H; 5.05~oN.
Found: 60.52~tC; 3.33%H;. 4.96N.
f. Using ~-chl~ro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole with th~ procedures dèscribed in the fore-going examples, such as Exam?le 20 d and e, ~[4-chloro-3-(2-fluorophenyl)-1,2-benzlsoxazol-6-yl]oxy~acetic acid, mp 172-174 C is obtained.
Ex~m~l~ 45 a. To a mixture of 3.9 g of AlC13 and 4.57 g Or 2,3-dichloroanisole in 70 ml of ~t2-dichloroethane at -10 C, 5 g of o-methoxybenzoyl chloride is added dropwise. he mixture is stirred for 2.5 hours and is gradually Jarmed to 5 C. The reaction mixture is poured into c~ncentrated ~Cl - .

and ice. The mixture is stirred one half hour to decompose the compl~x. The aqueous layer is extracted with additional organic solvent. The com~ined organic layers are washed until neutral, dried over Na2~0~ and evaporated to ~iYe an oil which solidifies on trituration with hexane. The crude ~roduct is recrystallized from 95% ethanol givin~ 2,3-dichloro-2~ dimethoxybenz~phenone, mp 94-96C.
Analysis:
Calcu~ated for C15H12C1203 5 0~
Found: 57.~%C; 3.gl%H;
b. A solid mixture of 13 g of 2,3-dichloro-2~
dimethoxybenzophenone and 52 g of pyridine HCl is heated at 200 C for one hour. Th~ hot mixture is then poured into ~igorously stirred ice water. The product is extracted with ethyl acetate. The extract is dried over Na2S0~ and eva-porated to give 2,3-dichloro-2',~-dihydroxybenzophenone, mp 197-~01C.
Analysis-Calculated for C13~3C1203: 5~.15~C; 2.gO~.
Yound: 5~.2~%C; 2.~6~,.~
c. To a ~uspension of 2.~7 g of NaH in 150 ml DMF, 30.76 g of 2,3-dichlor3-2',~-dihydroxybenzo~henone in 100 ml of D~F is added followed by the addition of 1~.37 g of ethyl bro~oacetate. The ~.ixture is sti.red a~roxi~ately ore and one half hours, ~oured into ice and acid and ~xtracted with CHC13. The CHCl extract is dried over ~a2S0 ~la 94 ~185;3 and evaporated to give ethyl 2,3-dichloro-4-(2-hydroxy-benzoyl)phenoxy acetate, mp 109-110 C.
Analysis:
Calculated for C17Nl~C1205: 55.30~ ; 3 Found: 55.15%C; 3.~1%H.
d. Employing ethyl 2,3-dichloro-4-(2-hydroxybenzoyl) phenoxy acetate and the procedures of the foregoing examples, the corresponding oxime may be formed and cyclized and the ester hydrolyzed to y~eld r~7-chloro-3-2-hydroxyphenyl)-1, 2_benzisoxazol-6-yl~oxy~acetic acid.
Exam~l~ 46 a. To a stirring solution Or phenacetyl chloride -! (25 g) ~n 1~0 ml carbon disulfide, is added AlCl (22 g) portionwise over a period of thirty minutes, followed by a solution of 2,3-dichloroanisole (2B g) in 5C ml carbon disul~ide.
After stirring at reflux (50 C) for three hours, the mixture i~ cooled, then AlC13 (22 g) i9 added and the mix-ture is stirred at reflux for two hours. The mixture i9 cooled, poured into a solution of cold 15~ HCl, stirred for 30 minutes then extracted with ethyl acetate/ethyl ether.
The organic extract is washed with water then dried (sat-urated NaC~, anhydrous ~g~04) After filtering, the s~lvents are ev3porated to giYe 2,3-dichloro-4-phenacetylphenol, mp 173-1~0 C.
Analysis:

. ~

- 95 ~ 53 14 10 2 2 59 ~ ; 3 59,~
Found: 60.15%C; 3.65~,H.
b. 2,3-dichloro-Ls-~henacetylphenol is reactsd with hydroxylamine hydrochloride in pyridine as generally des-cribed in the foregoing examples to yield 2,3-dichloro-~-phenacetylphenol oxime.
c. To a suspension of NaH (2.54 g) in 10 ml of dry DMF is added a solution of 2,3-dichloro-Ls-phenacet phenol oxime (6.3 g) in 25 ml dry DMF.
After stirring at ~0C for two hours, the mixture is cooled, then a s~lution of ethyl bromoacetate (1$.2 g) in 10 ml dry DMF is added and stirred at ambient temperature for 30 minutes and then at 60 C for 30 minutes.
After cooling, the mixture is p~ured into 500 ml of water, stirred for 30 minutes, then extr3ctsd with ethyl-acetate. The organic layer is washed with water then dried (saturated NaCl, anhydrous ~SCI). After filtering, the solvent is evap~rated to an oil from which ethyl ~[3-benzyl-7-chloro-1,2-benzisoxazol-5-yl]oxy~acQtate was ~btained, m~
120-122C.
Analysis:
Calcul3ted f~r Cl~H16ClN01: 62.52~C; ~.66~;H; Is.C-5~N.
Found: 62.35~C; 1$- 7!,~,~; 3 . g3%~ .
d. To 65C ml absolute ethan~ s ~dded ethyl ~(3-- 25 benzyl-7-c~loro-1,2-benzisoxaz~1-6-yl) ~xy3acetate (25.0 g) f~llowed by 5C~ NaCH s~lutio~ (3C rr.l). After stirring at _ 96 ~

reflux (~0C) for one hour, 500 ml of water is added, the pH ad~usted to 1 with c~ncentrated HCl, then further diluted with 1 liter water. The resultant precipitate is collected, washed with water, then dissolved in dichloromethane. The dichloromethane solution is washed with water, then dried (saturated NaCl, anhydrous MgS04).
After filtering, the solv~nt is evaporated to ~(3-benzyl-7-chloro-1,2-benzisoxazol-6-yl)oxy~ acetic acid, mp 1~7-153C.
Analysis-Calculated for C16H12ClNO~: 60.~%C; 3.~1~H; ~.~1%N; 11.16qoCl.
Found: 60.36~C; 3 .96q~H; 4.33%N; 10 . 91%C 1.
Exam~le ~7 a. The Friedel-Crafts procedure of Example ~6 is repeated with 2,3-dichloroanisole, l-naphthyl chloride and AlC13 to yield (2,3-dichlor~-~-hydroxyphenyl)(l-naphthyl) methanone.
b. To a solution of 22 4~ g of (2,3-dichloro-~-hydroxyphenyl)-(l-naphthyl)methanone in 150 ml of pyridine, 9.g7 g of hydroxylamine-hydrochloride are addsd. The mixture is refluxed for about 6~ hours. Additional hydroxylamine-HCl (9.~7 g) is added and reaction mixture refluxed for 1~
hours. The pyridine is evaporated in vacuo and the residue is partitioned betwe~n 5~ HCl and ethyl acetate. The eth~Jl acetate extract is washed with water, dried over ~32S0~ and evaporated to give a semi-solid ~roduc~. Thls p-oduct is 97 ~ 53 dissol~ed in approximately 100 ml of ethyl acetate and ~assed through a column of charcoal. The filtra~e is eva-porated to gi~re a solid which upon trituration with hexane-ether yielded (2,3-dichloro-4-hydroxyphenyl)-(1-naphthyl) methanone oxime, mp 145-160 C.
Analysis:
Calculated for C17HllC12N02: 61.46%C; 3 3 %
Found: 61.53%C; 3.1,5%H; 4.14%N.
c. To a solution of 3 g of (2,3-dichloro-4-hydroxy-phenyl)-(l-naphthyl)methanone oxime in 25 ml of D2~r1F, 0.51 g of NaH is added under ~2. Ths mixture is heated to an internal temperature of lOCC for one hour and 20 minutes.
The reaction ;nixture is cooled to room temperature and 1.65 g of ethyl bromoacetate is added dropwise. The mixture 15 is stirred for lB hours, water is added and the product is extracted w~th ethyl acetate. The ethyl acetate extract is washed with water, dried over Na2SO~ and e~r~porated to give ethyl ~ chloro-3-(1-naphthyl)-1,2-benzi soxa zo l- 6-yl] oxy3 acetate, mp 75-B5C.
20 Analysis:
Calculated for C21H16ClNO~: 66.0~"5; 4.22a~sH; 3-76~N-Found: 65.B1~C; 1,.214~H; 3.53q~
d. A sus~ension of l.g5 g of ethyl- ~[7-chloro-3-(l-naphthyl)-1,2-benzisoxazol-6-yl]oxy3acet~te, lCO zr.l of ethanol and 2 ml ~f 50~? I~aOJ is refluYed f~r one hour. To the hot mixture, 100 ml of water ~ s added f~llo~,7ed by en~uFh :'~.7i - 9~ 8~ ~

concentrated HCl to make the mixture acidic. Th~ reaction mixture is stirred and a precipitate forms on cooling.
Ethanol is evaporated in vacuo and ~[7-chlOro-3~ naphthyl) 1,2-benzisoxazol-6-yl]oxy~acetic acid is filtered off and dried in vacuum, mp 172-174C.
Analysis:
Calculated for C19H12ClNO~: 64.50%C; 3.42~H; 3.96%N.
Found: 64.51~C; 3.3~^H; 3-97%N-~xam~le 4~
a. The Friedel-Crafts reaction described in the foregoing examples is repeated with 2,3-dichloroanisole, 3-fluorobenzoyl chloride and AlC13 to yield, 2,3-dichloro-4-hydroxy-3'-fluorobenzophenon~.
b. To a solution of 5 g of 2,3-dichloro-~-hydroxy-3'-fluorob~nzophenone in 50 ml of pyridine, 1D 5~ g ~f hydroxy-lamine hydrochloride i5 added. The mixture is refluxed for 1~ hours. The pyridine is evap3rated in vacuo and the residue is partitioned between 5~ HCl and ~thylacetate.
The ethylacetate is washed with water, dried over Na2S04 and eva~orated to give 2,3-dichloro-~-hydroxy_3'_fluoro_ benzophenone oxime as a mixture of isomers, mp 17~ 5C.
Analysis:
Calculated for Cl~HloC12FN02: 53.52%C; 3.~1%H; ~.46~N.
Found- 53.55~5; 3. l~T~ . 39~I,.
c. To a solution ~ 3 g o~ 2,3-dichlo~o-4-hydrox-~-3'~fluorobenzophenone oxime in 25 ml ~f ~ , C~25 g of ~JaH

~ 99 ~ ~ 3 is add~d in an atmosphere of N . The mixture is stirred for 1~ hours. The mixture is heated to 100 C for one hour.
The reaction r~ixture is poured into ice water to yield 7-chloro-3-(3-fluorophenyl)-6-methoxy-1,2-benzisoxazole, mp 1L,9-150C.
Analysis:
Calculated for C14HgClFN02 60.55%C; 3.26q~H; 5.C5%N.
Found: 60.54~C; 3.005~H; l,. 91~DoN .
d. A solid mixture of 1~.47 g of 7-chloro-3-(3-fluoroph~nyl)-6-m~th~xy-1,2-benzisoxazole and 5~ ~g of py-ridine hydrochlo-ide is heated at 190-2CO C f~r one hour.
The hot mixture is poured into vigorously stirred ice water and 7-ch~oro-5-hydroxy-3-(3-fluorop~.Qnyl)-1,2-benzisoxazole is collected by filtration and washed well ~ith ~2' mr~
215-217 C.
Analysis:
Calculated for C13U7ClF~2 59.~2~C; 2-6~A4; 5-31~N-Found: 59.15~C; 2.S~qH; 5.15~.
e. A s~lution of 10.2 g of 7 chlo-~-5-hy(3r~xy-3-(3-fluorophenyl)-1,2-b~nzisoxazole is added to a m~xture of 1.3 g o~ NaH in 25 ml of D~F. A solution of v~.5~ 0 Or ethyl bromoacetate in 25 rnl of DI~F is added and ~he mixture is stirr~d f~r two and one ~i~lf hours. lC rnl ~f ~0% NaO~', 175 ~Al Of u~o and 3C ml of D.~.F are addDd to ~he reaction mix~ ure which is then h~at~d at ~G-v~5 r for one hol~r. The mixture is ~ade acidic l~it~l concentra+ ~d U5-, ,;a~er s add~d arld ~7-chloro-3-(3-1luo~o~henyl)-1,2-benziaoxazo'-6-yl]ox~y3-r - 100 - ~ 3 acetic acid is collected by filtration, mp 205-209 C.
Analysis:
Calculated for C15HgClFNO~ 56.00~oC 3 2.~3%H; ~.36~oN.
Found: 55.96%C; 2.~ H; It.21%N.
Exam~le ~9 a. To a solution of 1.0 g of 4-chloro-3-(o-fluoro-phenyl)-6-methoxy-1,2-benzisoxazole, of Example ~ e, in 50 ml gl~cial acetic acid is added chlorine gas (the solution is purged for five minutes). After stirring at ambient temperature for one hour, the mixture is poured into 500 ml water, stirred for fifteen minutes and a resultant precipitate is extracted into ether/et~yl acetate. The organic layer is washed with water, then dri~d (saturated NaCl, anh~Jdrous ~gS0~) and after fîltering the solvents are evaporated to yield 3-(o-fluorophenyl)-6-methoxy-~,5,7-trichloro-1,2-benzisoxazole, mp 12C-l~0 C.
Analysis:
Calculated for Cl~H7C13FN02: ~-51%C; 2-0~%H-Found~ 5~C; 2.27~H.
b. The procedures of xamples 2~ d and e may be employed with 3-(o-fluorophenyl)-5-~;eth3xy-~,5,7-trichloro-1,2-benzisoxazole to yiel~ ~[~,5,7-t-ichloro-3-(2-fluoro-phenyl)-1,2-benzisoxazol-5-yl]oxy~acetic acid.
.xam~le 50 10 ~ of 7-chloro-6-hydroxy-3-(~-f'u3raphenyl)-1,2-benæisoxaz31e of ~xample 36 c is dissa ved in ?C ~.1 D~V~F and !~a 7.g6 g K2C03 is added with stirring. 3.5 ml of chloroacetoni-trile is added and the mixture is stirred 0.5 hours at room te~.perature, then raised to 55 C for 2 hours. Stirring is continued 15 hours at room temperature and 1.5 ml of chloroacetonitrile is added and the reaction stirred 6 hours at 50 C. It is poured into a large volume of ice/H 0 and ~[7-chloro-3-(2-fluorophenyl~-1,2-benzisoxazole-6-yl]oxy~-acetonitrile which is ~recipitated is collected by filtration, mp 1~7C.
Analysis Calculated for C15H~ClFN202: 59.51%C; 2.56~H; 9.25%N.
Fou~d: 59.3~%C; 2.67~,H; 9.36%N.
Exam~le 51 15 g ~f 7-chlor~-6-hydroxy-3-(2-fluor3?henyl)-1,2-benzisoxazole in 75 ml DM~ is added to 3 susoensio~ of 3.0 g NaX in 75 ml D~IF. After one hour at roo~ tem~erature, 16.7 ml of ethyl-2-bromoisobutyrate is added. After 72 hours at 5C~ C the reaction mixture is poured into ice/H51 and extrac~ed with CH2C12 and the organic ~hase is washed with 5~ K2C03, followed by ~ashing ~rith saturated !~aCl. It is dried over ~0~, filtered and is evaporated to a broT~n oil.
The ~il is di~tilled at reduced pressure to remove unreacted ethyl-?-bromoisobutyrate and the residu~ is t.lturated with ether/petro'eum ether, filtered and the m~thQr liqu~r is ~vanorated to an oil which is distil'ed ~CC C, .1 ~) affording ethyl-2- ~[7-chloro-3-(2-fluoro ~h enyl)-1,2-benzi-- 102 _ soxazole-6-yl]oxy3-2-methyl propionate.
Analysis:
Calculated for C19H17ClFN04: 60.6qoC; ~.53%H; 3.70~aN.
Found: 60.o10c; ~.72%H; 3.6017N.
Example 52 a. To a mixture of ~6 g of l,-chloro-2-fluorobenzoyl chloride and 3~.9 g of 2,3-dichloroanisole in 150 ml of 1,2-dichloroethane, 32 g of AlCl is added gradually. The mixture is warmed to ~0 C with a vi~orous evolution of gas. 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 com~ined organic ex-tracts are washed w~th water, dried oYer Na2S0~ a~d evaporated.
The crude product is triturated with hexane to give 2,3-dichloro-~-methoxy-~'-chloro-2'-fluorobenzophenone. An analytical sample is recrystallized from ~tOU, m~ 115-116 C.
Analysis:
Calculated for Cl~HgC13F02: 5C.~1%C; 2.42~H; 5.gC%~.
Found: 50. ll~oC; 2.36~H; 6.17%F.
b. In a manner similar to that of ~xam~le 21 b, 2,3-dichloro-~-methoxy-~'-chloro-2'-fluorobenzophenone is con-verted into 2,3_dichloro_~_methoxy_~'_chloro_2'_fluoro_ benzo~henone oxime.
c. To a mixture of 2.2~ g of Na~ in lCC ml D~F, 21.75 g of 2,3-dichloro-~-m~thoxy-~'-chloro_2'-fluorobenzophenone oxime in 100 ml of D~,F is added drop~ise. After addition ~' ....

- lC3 _ ~ 5 ~

the mixture is stirred one hour and the reaction mixture poured into ice water. A product which precipitates is filter?d ~nd dried giving a mixture of isomers which is chro~.atographed on silica gel with 50% hexane and 5C%
t~luene is eluant to yield 7-chloro-3-(~-chloro-2-fluoro-phenyl)-6-methoxy-1,2-benzisoxazole, mp 193-19~ C.
Analysis:
Calculated for C14H~C12FN02: 53.~7%C; 2.5~%H; ~.~9~oN.
Found: 5~.01%C; 2.5~%H; ~ 7N.
d. A solid mixture of 5.4 g of 7-chloro-3-(~-chloro-2_fluorophenyl)-6-methoxy-1,2-ben~isoxazole and 22.~ g of ~yridine HCl is heated at 200 C for two hours. The reaction mixture is then pour~d into vigorously stirring ice water and a demethylated product is obtained.
To a solution of 3.9 g of the demethylated product in ~0 ml of D~F, 1~9 g of K2C03 and 2.3 g of ethyl bromo ace-tate are added. The reaction is warmed to 6CC for two hours and permitted to stand lg hours. To the re3ction mixture 100 ml of water and lC ml Or 50~ NaOH are added.
The mixture is heated at 90 C for 90 minutes ar.d the reaction mixture is ?oured into water, acidified and extracted with ethyl acetate, dried and evaporated to yield ~[7-chloro-3-(~-chloro-2-fluorophenyl)-1,2-benzisox3zol-6-yl]oxy3 ace~ic acid, mp ?26-227 C.
Analysis-Calcul~ted for C15HgC12FN0~ 5~.59~C; ? 2~ ; 3.S3~.
Fo~nd: 50.39~; ?.2~ .C6~

lo~ -_ample 53 T~ a suspension of .9 g lithium aluminum hydride (9~) in lCO ~1 anhydr~us ether is added a solution of lO g ethyl-2- ~[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl ]oxy~ acetate of Example 1 d in 2CO ml ether containing sufficient tetrahydrofuran to effect solution. The reaction mixture is stirred for two hours at room temperature and one hour at reflux. To the reaction mixture is added O.9 ml H2O, O.9 ml 15~ NaOH and 2.7 ml H 0. The stirred suspension is filtered and the filtrate is concentrated to afford 2_~ [7-chloro-3-(2-fluorophenyl)-1,2-b~nzisoxazole-5-yl]oxy~
ethanol, mp 112 C.
Analysis:
Calculated for C15~11ClFN03: 5~.63%C; 3-5~H; 4-56%N-F~und: 5~ C; 3.62~H; ~.~9~,N.
~xamrle 5~
~.5 g ~f ethyl-2- ~7-chl~r3-3-(2-fluarophenyl)-1,2-benzisoxazole-6-yl]~xy~ -2-methylpr~pi~r.ate, ~r ~xa;nple 51, is dissolved in 35 ml ~e+han~l and 3C .~.1 of a 15~, ~aCH
solution is added tharet~. The suspension is heated at reflux f~r ~ h~urs and then poured into ice-water, and acidified, pr3ducin~ an oily ~reci~itate. This precip tate is extracted with ether and the ether extracts ara washed with iO~ Na~C03. The basic exfracts are aci~i~ied with cencentrated H~l ar.d chilling +hereo~ af~rds 2-~ ~-chl~r3-3_(2 lu~r~pher,y'~-1,2-benzisoxaz~le-6-y' ~axy3 -2-methyl _ 105 -propionic acid, mp lOg C.
Analysis:
Calculated for C17~13ClFN4 5~-45%C; 3-72%H; 4-~1~7N-Found: 5~.3g~oC; 3.75%H; 3.9Ç~gN.
Example 55 3.35 g NaN3 and 2.25 g of AlC13 are stirred in 50 ml THF at reflux for 0.5 hour. A solution of 5 g ~[7-chloro-3-(2-fluoro~henyl)-1,2-benzisoxazole-6-yl]oxy~acetonitrile, of Example 5~, in 50 ml THF is added and the reaction mixture is stirred at reflux for about 120 hours. To the reaction miXtUrg i3 added water and the solvent is removed. The residue is treated with di ute HCl and extracted with CHC13.
Upon attempted extraction of the chlor~form solution with 15~7 NaOH a precipitate forms which is filtered, dissolved in -hot water and acidified to afford 7-chloro-3-(2-fluorophenyl)-6- ~ [5-tetrazolylmethyl]oxy~-1,2-~enzisoxazole, mp 19~-20CC.
Analysis:
Calculated for C15HgClFNsO2: 52.17%C; 2.6C~7H; 20.2g~N.
Found: 52.02~C; 2.69~,H; 20.37~7N.

Claims (6)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the formula I

I
wherein R is hydrogen, loweralkyl, loweralkenyl, loweralkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, tricycloalkyl, cyclo-alkylloweralkyl, cycloalkenylloweralkyl, naphthyl, , , thienyl, furyl, pyrryl, pyridyl or pyridyl N-oxide; R1 is a free or esterified carboxyl group of from 1 to 8 carbon atoms, -COZ, , -CH2OH, -CHO, , -CN, , , , or ; R2 R3 and R4 are the same or different and each can be hydrogen, halogen, or loweralkyl; X is hydrogen, halogen, loweralkyl, loweralkoxy, loweralkylthio, hydroxy, trifluoromethyl, nitro, amino or acylamino; R5, R6, R7, R8 and R9 are the same or different and can be hydrogen or loweralkyl; A and A' are the same or different and can be 0 or S; Z is chlorine, bromine or fluorine; and m and n are the same or different and each can be the integer 1, 2 or 3; or a physiologically acceptable salt thereof, in which a) a compound of the formula wherein R, R2, R3, R4, A and A' are as defined above is reacted with a compound of the formula wherein R1, R5 and R6 are as defined above and Z is chlorine, bromine or fluorine in the presence of a base and a solvent, or b) a compound of the formula or a compound of the formula wherein R, R1, R2, R3, R4 and R5 are as defined above and Y is chlorine, or fluorine is cyclized by treatment with a base in the presence of a solvent at a temperature of from ambient to reflux of the reaction medium, or c) a compound of the formula wherein R1, R2, R3, R4, R5 and R6 are as defined above and R
is hydrogen is reacted with hydroxylamine-o-sulfonic acid, or d) a compound of the formula I in which R1 is a carboxylic acid ester or CN is converted by hydrolysis to a corresponding compound in which R1 is COOH, or e) a compound of the formula I in which R1 is CH(OR9)2 is converted by hydrolysis to a corresponding compound in which R1 is -CHO, or f) a compound of the formula I in which A and A' each represent oxygen, X, R2, R3 and R4 are not loweralkyl and R1 is CH2OH or CHO is converted by oxidation to a corresponding compound in which R1 is COOH, or g) a compound of the formula I in which R1 is COOH is converted to a corresponding compound in which R1 is COZ, or h) a compound of the formula I in which R1 is COZ is converted by treatment with , NH2OH or to the corresponding compound in which R1 is , CONHOH or , or i) a compound of the formula I in which R1 is CN is converted by treatment with HN3 in dimethylformamide to the corresponding compound in which R1 is , or j) a compound of the formula I in which R1 is COZ, , CONHOH, , is converted via acid or basic hydrolysis to the corresponding compound in which R1 is COOH, or k) a compound of the formula I in which R1 is COOH is converted to the corresponding salt via treatment with an appropriate organic or alkali/alkaline earth base, or 1) a compound of the formula I in which R is wherein m is 1 or 2 and X is not NO2 is converted via treatment with nitric acid in glacial acetic acid to a corresponding compound in which R is , or m) a compound of the formula I in which R is , or and X is alkoxy is converted by dealkylating to a corresponding compound in which X is hydroxy, or n) a compound of the formula I wherein X is nitro is reduced to provide the corresponding compound wherein X is amino, or o) a compound of the formula I wherein X is amino is acylated to provide a corresponding compound where X is acylamino.
2. A compound of the formula I as defined in claim 1, whenever obtained according to a process as claimed in claim 1 or by an obvious chemical equivalent thereof.
3. A process as claimed in claim 1 wherein the compound has the formula I' I' wherein R, A', R2, R3, R4, R5, R6 and R' are as defined in claim 1.
4. A compound of the formula I' as defined in claim 3, whenever obtained according to a process as claimed in claim 3 or by an obvious chemical equivalent thereof.
5. A process as claimed in claim 1 wherein A and A' each represent oxygen.
6. A compound of the formula I as defined in claim 1, wherein A and A' each represent oxygen, whenever obtained according to a process as claimed in claim 5 or by an obvious chemical equivalent thereof.
CA316,532A 1977-11-21 1978-11-20 1,2-benzisoxazoloxyacetic acids and related compounds Expired CA1111853A (en)

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US4337261A (en) * 1980-07-28 1982-06-29 Hoechst-Roussel Pharmaceuticals Inc. (1,2-Benzisoxazol)phenoxyacetic acids as diuretics
US4427691A (en) * 1981-02-25 1984-01-24 Hoechst-Roussel Pharmaceuticals Inc. 1,2-Benzisoxazoloxyethylamines and intermediates for the preparation thereof
US4452804A (en) * 1981-02-25 1984-06-05 Hoechst-Roussel Pharmaceuticals Inc. 1,2-Benzisoxazoloxyethylamines and intermediates for the preparation thereof
US4644064A (en) * 1981-02-25 1987-02-17 Hoechst-Roussel Pharmaceuticals Inc. 1,2-benzisoxazoloxyethylamines and intermediates for the preparation thereof
US4504669A (en) * 1981-02-25 1985-03-12 Hoechst-Roussel Pharmaceuticals Inc. 1,2-Benzisoxazoloxyethylamines and intermediates for the preparation thereof
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US4458076A (en) * 1983-05-31 1984-07-03 Hoechst-Roussel Pharmaceuticals 3-(4-Piperidinyl)-1,2-benzisothiazoles
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