Note: Descriptions are shown in the official language in which they were submitted.
15582Y
,
.~ ~
~L~63125 :
..
BACKGROUND OF T~IE INVENTION
.
This invention relates to a new class of compounds
which can generally be described as ~-oxo-2-aryl or thienyl- -
2-substituted (and 2-aryl-Z,3-disubstituted)-7-(and 6,7- ~ ;
disubstituted)-5-indanyloxy (or thioI7 alkanoic acids,
5-tetrazolyl analogues of such acids, and to the non-toxic
pharmacologically acceptable salt, ester and amide derivatives
thereof. These compounds will collectively be referred to
herein as " ~-oxo-2-aryl or thienyl-2-substituted-5-indanyloxy
(or thio ~ alkanoic acids" or more simply as "2-aryl or
thienyl substituted indanones" for convenience. Further,
this invention relates to a process for the preparation of
- 1 - :
"'
' 15582 :
.
3~ZS
1 such 2-aryl or thienyl substituted indanones, to pharmaceu- ~.
2 tical compositions comprising therapeuti.cally effective
3 amounts of such compounds and to methods, of treatment com
4 prising administering such compounds ancl compositions.
5 Pharmacological studies show that the instant
6 products are effective diuretic and saluretic agents which
7 can be used in the treatment of conditions associated with !~'"~ '
8 electrolyte and fluid retention. The instant products are
9 also useful in the treatment of hypertension. In addition,
10 these compounds are able to maintain the uric acid concen~
11 tration in the body at pretreatment levels or to even effect i
12 a decrease in the ur.ic acid concentration when administered .
13 in therapeutic dosages in conventional vehicles.
14 Many of the presently available diuretics and .~. ...
15 saluretics have a tendency upon administration to induce .;`~
16 hyperuricemia which may precipit.ate uric acid or sodium
17 urate or both in the body which may cause from mild to ;. ~-
18 severe cases of gout. The instant compounds of this
19 invention now provide an effective tool to treat those :.
patients requiring diuretic and saluretic treatment without ~ .~
21 incurring the risk of inducing gout~ In fact, when used in . ~ .
22 appropriate doses, the compounds of this invention function ;~
23 as uricosuric agents. : .
24 Thus, it is an object of the present invention to
provide 2-aryl or thienyl substituted indanones of the above
26 general description and to provide processes for the prepa- -
27 ration thereof. ::~
- ' .~' ,
:. - ~ - - . . , . :
~ 155~2 :
:~631~5 ~`
1 A further object of this invention is to provide
2 pharmaceutical compositions comprising therapeutically
3 effective amounts of such 2-aryl or thienyl substituted
4 indanones and to provide a method of treatment comprising
administering such compounds and composi.tions.
6 DETAIL~D DESCRIPTION OF THE INVENTION
7 The 2-aryl or thienyl substituted indanones of
8 the present invention have the following sturcture~
X2 0 ~,,
9 X ~ Rl and
10 HOCYA -.
I
11 X2 0 ~ '.,
~ R
N - ~ I ¦ R
12 ~ Y-A _ ~ / ~ Rl
II
3 X7
13 wherein ~ is ~ X ~ x8
14 wherein X is hydrogen, halogen such as chloro, bromo,
fluoro, or iodo, lower alkyl such as methyl, ethyl, n-propyl,
16 n-butyl, tertiary butyl, n-pentyl and the like; cycloalkyl
17 such as cyclopentyl or cyclohexyl; lower alkoxy such as
;
, ~ . :
~' lS582 I~ ~
~6~:~25 :~ ~
1 methoxy, nitro, hydroxy, amino, cyano, aminomethyl, sulfamoyl, ~ !
2 methanesulfonyl or chlorosulfonyl, acylamino such as acet-
3 amidol acylaminomethyl, suc~, as chloroacetylaminomethyl;
4 X7 is hydrogen~ loweralkyl such as methyl, halogen such as
chloro, bromo, ~luoro or iodo, or aminomethyl; and x8 is
6 hydrogen or lower alkyl such as methyl; and wherein A is
7 oxygen or sulfur; R is lower alkyl containing from 1 to 5
, .:, . .
8 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, : .
. .
9 n-butyl, isobutyl, tert-butyl, pentyl and the like; cyclo-
alkyl, for example, cycloalkyl containing from 3 to 6 carbon
11 atoms such as cyclopentyl, cyclohexyl and the like; cyclo-
12 alkyl lower alkyl such as cyclopropylmethyl, cyclopentyl-
13 methyl and the like, lower alkenyl containing ~rom 3 to 5 ~`
14 carbon atoms such as allyl, 1,2- or 3-butenyl, 1,2,3- or 4- ~ :
15 pentenyl and the like; phenyl lower alkyl wherein the lower ; ~:
16 alkyl moiety contains from 1 to 3 carbon atoms such as
17 benzyl, phenethyl, phenylpropyl and the like; phenyl lower
18 alkenyl such as cinnamyl and the like; aryl or substituted
,
19 aryl such as phenyl, halo-aryl, lower alkyl-aryl, or lower
alkoxyaryl or thienyl and the like; Rl is hydrogen; lower
21 alkyl, or aryl such as phenyl; and wherein R and R taken
22 together with the carbon atoms to which ~they are attached -
23 may ~orm a hydrocarbylene ring containing from 3 to 6 carbon
24 atoms; and wherein X is hydrogen, methyl or halo, such as
chloxo, bromo, ~luoxo and the like; x2 is methy~ trihalo~
26 methyl or halo such as chloro, bromo, fluoro and the like;
27 or Xl and x2 may be joined to form a hydrocarbylene chain
28 containing from 3 to 4 carbon atoms, for example, trimethyl-
29 ene, tetramethylene, 1,3-butadienylene and the like; and
,
- 4 _ ~ .
~ 155$2 I~
, .
~363~ZS ~
1 wherein Y is an alkylene or halo-alkylene radical having
2 from 1 to about 4 carbon atoms between the oxy (or thio)
3 and the carboxy group, for example, methylene, ethylene,
4 propylidene, isopropylidene, isobutylidene, fluoromethylene, :;.
and the like; and the non-toxic pharmaceutically acceptable
6 salt, amide~ anhydride and ester derivatives thereof.
7 The preferred compounds of this invention are
8 those compounds of Formulae I and II, above wherein ~ is
9 oxygen, Y is methylene and R, R, Rl, R , X ~ X2, X3, X7
and x8 are as defined above.
11 Particularly preferred compounds of this invention
12 are 1-oxo-2-aryl-2-substituted-6,7-disubstituted-5-indànyl-
13 oxyacetic acids, and the non-toxic pharmacologically
14 acceptable salts thereof, having the following structure:
~ f X4 ~ ~ ~ ;
Ia
17 wherein R2 is lower alkyl containing from 1 to 3 carbon atoms
18 such as methyl, ethyl, n-propyl or isopropyl, or cycloalkyl ..
19 containing 3 to 6 carbon atoms such as for example/ cyclo-
propyl, cyclopentyl or cyclohexyl; X4 and X5 are the same
21 or different radicals selected from methyl or chloro; and
22 x6 is hydrogen, methyl, chloro or fluoro and the non-toxic ~.
23 pharmaceutically acceptable salts thereof. ~; :
- 5 - :: :
.. . ~ . . . .
- :.
~ ~ ` 15582
~ 3125
1 The foregoing class of compouncls exhibits partic-
2 ularly good diuretic/saluretic activity. Such compounds
3 also either maintain the uric acid concentration of the
4 body at pretreatment levels or even cause a decrease in
uric acid concentration.
.. . .
;~6 Several methods may be employed to prepare the ~ ;
7 2-aryl or 2-thienyl substituted indanones of this invention.
8 One method comprises 2-alkylation of a [1-oxo-2-aryl or ;~
9 2-thienyl-5-indanyloxy (or thio)]alkanoic acid or ester of
structure III (infra) with an alkylating agent of the
11 formula RZ wherein Z is halo. This reaction is conducted ;
12 by first treating the [1-oxo-2-aryl or 2-thienyl-5-indanyl-
13 oxy (or thio)]alkanoic acid or ester with a suitable base
i14 for example an alkali metal hydride such as sodium hydride
and the like or an alkali metal alkoxide for example
16 potassium tertiary butoxide, sodium methoxide and the like,
17 or alkali metal amides such as sodium amide, lithium amide - ;
18 and the like. The resulting carbanion is then treated with
19 the alkylating agent, RZ. Any solvent which is inert or sub-
stantially inert to the reactants employed may be used.
21 Suitable solvents include for example, 1,2-dimethoxyethane,
22 tertiary butanol, benzene, dimethylformamide and the like.
23 The reaction may be conducted at a temperature in the range
24 of from about 0C to about 150C. In general, the reaction
is conducted at a temperature in the range of from about
26 0 - 50C. The following equation illustrates this process:
.
' ! '
.' ` ' ' '
.f~ t ~ 15582 IA
.,,. ~,
~ 3125 ~ ~
R30CYP_ ~R
\ Base
IIIRZ ~
:; ~
R30CYA ~ 1 ~ ~
when R3 = : :
lower alkyl, ":
Hydrolysis
when R ~
\ / t-butyl, pyrolysis
6 ~ R
7 HOCYA ~ Rl ^
8 wherein A, R, R, Rl~ Xl, X2, X3, X , X8, Z and Y are as
9 definèd above:and R3 is hydrogen or lower alkyl.
1^ A second method for preparing the [l-oxo-2-aryl-
11 2-substituted-5-indanyloxy(or thio)]alkanoic acids of this
12 invention comprises reacting a halo alkanoic acid or ester
13 thereof, O
14 R30CYZ
with a suitable 2-aryl or 2-thienyl-2-substituted-5-hydroxy- ~:
16 tor mercapto)-l-indanone (IV):
' ~
- 7 -
",
.. ,
r~ ~ 15582 IA
1~631Z5 ` ~
X2 o ' .
2 ~R \~ + R OCYZ
IV BASE 2
3 X O
4 :R30CYA~
.~:
when R3 =
lower alkyl,
6 EIydrolysis
\ I when R =
t-butyl, pyrolysis
8 HOCY~ R
9 wherein all substituents are as defined above.
In general, the reaction is conducted in the
11 presence of a base such as an alkali metal carbonate, hydrox-
12 ide or alkoxide such as potassium carbonate, sodium carbonate,
13 potassium hydroxide, sodium hydroxide, sodium methoxide and ` ~-
14 the like~ Any solvent which is inert or substantially inert
lS to the reactants and in which the reagents are reasonably
16 soluble may be employed. Acetone, ethanol and dimethylform-
17 amide for example have proven to be particularly advantageous
18 solvents. The reaction may be conducted at a temperature in
19 the range of from about 25C. to the reflux temperature of
the particular solvent employed. If the haloalkanoic acid
. . .
~ ..................... . .
~ 15582 IA ~
~L0~;312S
1 ester is employed, the ester obtained may be hydrolyzed to
2 the free acid by methods well-known to those skilled in the
3 art. When R3 is the tert-butyl group, the acid may be
4 obtained by acid catalyzed pyrolysis, sucll as by heating
the tert-butyl ester in the presence of a strong acid, for
6 example, in the presence of p-toluene-sulfonic acid, sulfu-
7 ric acid, gaseous hydrogen chloride, and the like. In
8 general, pyrolysis is effected by heating at a temperature ;
9 in the range from about 70-140C., preferably 80-100C.
Also, the pyrolysis may be conducted without a solvent or in
11 the prosence of a suitable non-aqueous medium in which the
12 reactants are reasonably soluble, for example, in the
13 presence of benzene, toluene, xylene and the like.
14 Two additional processes for preparing compounds
of Formula I are as illustrated by the following flow
16 diagram:
17 ~ NO2CN2CEl2Cl ~ R
HO~ Rl 2NCH2cH2 Rl
IVa / IVb
18
2 O ~ hydrolysis
0 ~ R decarboxylation ~R
R (H2C)2OEl \ R
I IVd ~;~
~ \ ' -:
hydrolysis
21 R"O2C\ xl ~ k R
2 (R"O2C)2CM ~ Rl
g IVc
~:: . . .
15582 IA `~ '
312S ~ ~
1 The ~irst process shown involves reacting a 5~
2 hydroxy (or mercapto) compound (IVa infra) with halonitro
3 ethane to form a 2-nitroethane intermediate (Formula IVb)
4 which intermediate upon hydrolysis yields the end product
5 (I). The preparation of the interr,ediat:e of Formula IVb ~:
6 is s~own in British Patent 1,325,528.
7 In the other process shown, the 5-hydroxy (or
8 mercapto) compound (IVa infra) is reacted with a malonic '. ~'
9 ester (whexein R" is loweralkyl, preferably ethyl) to form ~.
10 a malonic ester intermediate (IVc) which intermediate is ~:,
11 hydrolyzed to form another interr"ediate (Formula I'Vd)
12 which latter compound is then decarboxylated to form the
13 end product I.
14 Those 2-aryl or 2-thienyl substituted indanones
of this in~ention wherein the alkylene chain, Y, contains 2- '~
16 linear carbon atoms between the carboxy and oxy (or thio)
17 groups are prepared from the corresponding 5-hydroxy ~or : ,
18 mercapto) compounds (IV infra) by the reaction of the :'
19 latter with propiolactone or with an appropriately substituted '~
propiolactone in the presence of a base such as an aqueous
21 solution of sodium hydroxide, preferably while heating the
22 solution at reflux temperatures followed by the acification
23 of the carboxylate intermediate thus formed to the desired
24 acid. The following equation,illustrates th'e reaction: ,~
;~' " '
-- 10 --
- ~
~ 155 82 IA
~ 63~L25 :~ ~
x2
~\R 1 () 2 1 ( R ) 2
2 .: :
I V MOE~
X2 o ,~
MOCC ( R ) 2C ( R ) 2~ R
4 1 ~:
Acidi~ication :
HOCC(R ) 2C(R ) 2~ --~R
7 wherein all substituents are as defined above and M is a
~ ... .
8 cation derived ~rom an alkali mekal hydroxide or alkali :.:
9 metal carbonate such as sodium or potassium cation~ :
The 2-aryl or 2-thienyl-2-substituted-5-hydroxy-
11 (or mercapto)-l-indanones (IV, supra) which also exhibit .. : :~
12 diuretic, saluretic and uricosuric activity and which are
13 novel compounds themselves are prepared by treating the .
14 correspondingly substituted 2-aryl or 2-thienyl-2-substi~
15 tuted-5-lower alkoxy or aralkoxy (or lower alkyl or aralkyl -
16 thio)-l-indanone with an ether cleaving reagent such as
17 aluminum chloride, pyridine hydrochloride, sodium in liquid ;
18 ammonia, and the like. When aluminum chloride is emp].oyed .
- 11 -
, .
15582 I~ ;
. .
~ i3~Z~i ~
1 the solvent may be heptane, carbon disulfide~ methylene
2 chloride and the like. When pyridine hydrochloride is
3 employed, it is no~ necessary to employ ~ solvent. Those
4 2-aryl substituted indanones of th~ presen-t invention
5 wherein the aryl substituent, X3, is hyclroxy are conveniently ;~
6 prepared by treating the corresponding acid and tetrazole
7 (Formula I and II, supra) wherein the aryl substituent, X3,
8 is methoxy, with hydrogen bromide in acetic acid.
9 A preferred method for preparing the 5-hydroxy
or 5-mercapto compounds of Formula IV(supra) wherein the
11 aryl substituent, X3, is a lower alkoxy radical consists of
12 hydroyenolysis of the eorrespondiny 5-aralkoxy (or thio)
13 compound. The hydrogenolysis reaction is conveniently
14 conducted in a hydrogenation apparatus in a solvent such as
methanol, ethanol, acetic acid, and the like, in the presence
16 of a catalyst sueh as 5~ palladium on carbon or platinum on ~ ~`
17 earbon at a pressure of from about 1.0 to about ~0 atmos-
18 pheres.
19 2-Arylation or 2-thienyla~ion to obtain the
5-lower alkoxy or 5-aralkoxy (or lower alkyl thio or aralkyl
21 t~liO) compounds V (infra), whieh also exhibit diuretie,
22 saluretie, and uricosuric activity is effected by treating
23 the eorresponding 2-substituted eompound VI with a suitable ;~
24 reagent sueh as a diphenyl iodonium salt (when R is phenyl,
substitu~ed phenyl) or thienyl of the formula:
26 [R ]2I2 ; ;~
27 wherein R, X3 and Z are as defined above.
~ ~ 15582 L
., '~ ' .
1~631~5
1 This reaction is conducted by :Eirst treating the
2 2-substituted compound VI with a suitable base, for example
3 an alkali metal hydride such as sodium hydride and the
4 like, an alkali metal akoxide, for examp:Le sodium methoxide,
potassium tertiary butoxide and the like, or an alkali
6 metal amide such as sodium amide, lithium amide and the like.
7 The resulting carbaniQn is then treated with the arylating
8 agent. Any solvent which is inert or substantially inert
9 to the reactants employed may be used; suitable solvents
include, for example, 1,2-dimethoxyethane, tertiary butanol,
11 benzene, dimethylformamide and the like. The reaction may
12 be conducted at a temperature in the range of from about
13 25-150C. The following equation illustrates this process:
1~ x2
Xl, ~ R `'.';' :. '
R4A ~J _ LR1 ~ [R] 2I Z
16 VI ~ :
. ~Base
l7 R4A- 1~ R
18
V '~'
19 wherein all substituents are as defined above and R4 is
lower alkyl or aralkyl~ The t-lower alkoxy or 5-aralkoxy
21 (or lower alkyl thio or aralkyl thio) reactants (VI, supra)
22 employed in this particular procedure may be obtained by
- 13 -
.- .: -
` 15582 IA
,..~
1~;3125 -:
1 well-known etherification methods of the corresponding
2 5-hydroxy (or mercapto) indanones, which are known com-
3 pounds and are described in U.S. Patents 3,668,241 and ~-
4 3,704,314.
5 A second method ~or preparing the ethers of ~ ~:
6 formula V (supra) comprises 2-alkylation of the corresponding
7 2-aryl or 2-thie~yl compound VII (infra) with a suitable
8 alkylating agent of the formula, RZ, wherein R and Z are ~.
9 as defined above. This reaction is conducted by ~irst
treating the 2-aryl or 2-thienyl compound (VII) with a suit-
11 able base, for example, an alkali metal hydride such as
: 12 sodium hydride and the like, an alkali metal alkoxide, for
13 example, sodium methoxide, pokassium tertiary butoxide ancl
14 the like, or an alkali metal amide sudhas sodium amide,
15 lithium amide and the like. The resulting carbanion is `.
16 then treated with the alkylating agent, RZ. Any solvent
17 which is inert or substantially inert to the reactants
18 employed may be used. Suitable solvents include or example
19 1,2-dimethoxyethane, tertiary butanol, benzene, dimethyl- ::.
formamide and the like. The reaction may be conducted at
21 a temperature in the range of about 0 to 150C. The follow-
22 ing equation illustrates this process.
23xl ~ R + RZ `
R4A J ~ Rl 1 BASE
24
VII x2 O
R4 ~ R
26 wherein all substituent~ are as described above.
- 14 -
` 15582 I~.
, -
~3;1 25 ;
1 One method for preparing the indanone inter-
2 mediate (VIa, infra) useful in the preparation o~ the
3 2-aryl substituted indanones of this invention comprises
4 the cyclialkylation of a 4-lower alkoxy (or lower alkyl
S thio) substituted E2-alkylidenealkanoyl (or 2-alkylidene- ;
6 aralkanoyl)]benzene (VIII) by treatment with a Lewis acid
7 such as concentrated sulfuric acid~ polyphosphoric acid,
8 boron trifluoride and the like. The reaction may be con- ~:
:,
9 ducted at a temperature in tha range of from abou-t 0~ to
10 about 60C. The following e~uation illustrates this ~:
11 process: :
12 xl ~ _ ~-C-R5 xl ~ R5
4 1 11 It 1 CYClialk~lation
R A ~ R R A
VIII VIa ~ ~
. ,~: . -
14 wherein R5 is the substituted phenyl group of formula I .`
or is R, as previously defined, and all other substituents
16 have been defined.
17 ~The 4-lower alkoxy ~and lower alkyl thio)-substi-
18 tuted ~(2-alkylidenealkanoyl) (or 2 alkylidene)]aralka-
19 noyl)]benzenes (VIII, supra) employed may be prepared by
several methods. One method, limited to the preparation of
21 the nuclear lower alkoxy (and lower alkyl thio)-4-(2-methyl~
22 enealkanoyl) (and 2-methylenearalkanoyl)benzenes (VIIa,
23 infra~ comprises treating a nuclear lower alkoxy-(or lower ~ ?
24 alkyl thio)-4-alkanoylbenzene (or 4 aralkanoylbenzene) (IX)
with dimethylamine hydrochloride and paraformaldehyde follow-
26 ed by treatment of the Mannich intermediate (IXa), thus
,
~ 15582 IA
"~ .
31;~5
1 obtained, wi-th aqueous sodium bicarbonate or anhydrous
2 dimethylformamide, either with or without heat, to afford
3 the desired compound, (VIIIa). The following equation
4 illustrates this process:
Xl ~ -CH2R5 ~ C-CHR
R4O ~ HN(CI-I3)2 HCl R O ~ N~HCl
7 Paraformaldehyde / \
IX ¦ IXa C~3 CH3
8 x2 O
Xl~-C-RS
9 R4O ~ 1 2
VIIa
wherein all substituents are as defined above.
11 A second method for preparing the 4-lower alkoxy~
12 tand lower alkyl thio)substituted (2-alkylidenealkanoyl)-
13 benzenes wherein Rl is methyl, comprises treating a 4-lower
14 alkoxy (o~ lower alkyl th:io) substitutecl 2-bromo-2-methyl-
propionylbenzene (X, infra) with a dehydrobrominating agent
16 such as lithium bromide, lithium chloride and the like.
17 Suitable solvents for this reaction include dimethylform-
18 amide and the like. This rea~tion is conventiently conducted
19 at a temperature in the range of from about 50 to about 120C
The following equation illustrates this reaction:
- 16 -
15582 IA ~
~;3125 ~:
2 x2
1 X ~ ~ r-~ C-~-CH3 ~ -~CCEI3
R O ~ ~ ~ 1 LiBr ~ R40._~ CHR
X VIIIb
3 :~
4 wherein all substituents are as defined above. ~::
5 A third method for preparing the 4-lower alkoxy ~ :
6 ~and lower alkyl thio) E2-alkylidenealkanoyl (or 2-alkyl-
7 idenaralkanoyl)]benzenes (VIIc) comprises treating a 4-
8 lower alkoxy (or lower alkyl thio) substituted allcanoyl or
9 aralkanoylbenzene (IXa) with a methylene inserting reagent
10 such as a bis-dimethylaminomethane in the presence o~ an :~ .
ll alkanoia acid anhydride such as acetic anhydride. The ~ :
12 reaction is conducted at a temperature of from about 25 . :~
13 to about 50Co Any solvent which is inert or substantially ~:
14 inert to the reactants employed may be used, but in general .
the methylene inserting reagent, such as bis-dimethylamino~
16 methane, serves as the solvent medium. The following ~ .
17 e~uation illustrates this process~
~ CC82-RS ~ C-C-R5
19 R4A _t,J R4A_~J 2 ` ' -~
~, .~,, ~. - , ,
2 0 IXb [(CEI3)2N] 2 CH 2 VI I I C
21 wherein all sub6tituents are as defined above.
- 17 - ;
: . . . , .. . :, . .. . . . .
r-~ ~~ 15582
~631~:5
1 The [4~10wer alkoxy (and lower alkyl thio)-
2 substituted]alkanoyl and aralkanoylbenzenes (XXb) are
3 either known compounds or may be prepared by the reaction
4 of an alkanoyl halide or aralkanoyl halide with a nuclear
S lower alkoxy (or lower alkyl thio) substituted benzene (XI),
6 in the presence of a Friedel-Crafts catalyst such as ~`
7 aluminum chloride and the like. The reaction sol~ent and
8 the temperature at which the reaction i8 conducted are not
9 critical aspects of this reaction inasmuch as any solvent
10 which is inert to the acyl halide and nuclear lower alkoxy
11 (or lower alkyl thio) substituted benzene may be employed -
12 with good results. In this regard, it has been found that
13 methylene chloride and carbon disulfide are particularly
14 suitable solvents. The following equation illustrates this
15 process:
R4A~ + R5CEI CZ Cl~t X ~C C~12R
17 :. .,
XI IXb
18 Those compounds of the instant invention wherein
19 R and Rl are joined to form a cyclopropyl ring (XIII, infra)
are prepared by treating a tl-oxo-2-indene-5-yloxy)-alkanoic
21 acid (XII) with an alkali metal base such as sodium hydride
22 and the like followed by treatment with a methylating agent~
23 for example, trimethylsulfoxonium iodide and the like. The
24 (1-oxo-2-indene-5 yloxy)alkanoic acids employed a~e described
in U.S. Patent 3,668,241. The following equation illustrates
26 this process:
~ 18 -
. ..
, . , ,
, .
1 5582Y
3~ZS
X o
o X ~ R '~ .
XII
: \~ X2 o
H O C `~ A~
XI I I
wherein all substituents are as defined above.
The nuclear lower alkoxy precursors of those com-
pounds of the instant invention wherein R and Rl are joined to
form a cyclohexyl ring are prepared according to the following `
procedure:
4 ~ + ~ Crafts > 4 ~ C
~ Halogenation
~_ ~11~
R4A R4A -: .
Dehydrohalogenation ~
" . '' '~-' '
~ Cyclialkylation
R4A ~
- 19 - ~ .
.. . .
r~ 15582 I~
31Z~ ~:
1 wherein the substituents are as defined above.
2 Those compounds of Formula I wherein R is aryl
3 and -the X3 substituents are cyano, chlorosul~onyl, sulfamoyl,
4 nitro, amino or aminomethyl are generally prepared from the
compounds of Formula I or an intermediate thereto such as
6 a compound of formula IV wherein R is unsubstituted aryl
7 or thienyl or from a compound of Formula ~V or I when R is
8 substituted aryl wherein the substituents can be converted
9 to the desired substituent by methods well known in the art.
10 For example, when R is unsubstituted aryl the compounds of ~
11 Formula I can be reacted with chlorosulfonic acid to yield -
12 a compound wherein X3 is chlorosulfonyl and the latter com-
13 pound reacted with ammonia to yield a compound of Formula I
14 wherein ~ is sulfamoyl. Other conversions a.re shown
specifically in the examples, such as for example in
16 Examples 21, 22 and 31. ~ ~.
17 Also included within the scope of this invention
18 are the ester and amide derivatives of the instant products
19 which are prepared by conventional methods well known to
those skilled in the art. Thus, for example, the ester
21 derivatives may be prepared by the reaction o~ the [l-oxo-
22 2~aryl or 2-thienyl-2-substituted-5-indanyloxy (or thio)]-
23 alkanoic acid o~ this invention with an alcohol, for example, ~
24 with a lower alkanol. The amide derivatives may be prepared ~.
by converting a [1-oxo-2-aryl or 2-thienyl-2-substituted-
26 5-indanyloxy tor thio)]alkanoic acid to i~ corresponding .~.
27 acid chloride by treatment with thionyl chloride followed
28 by treating said acid chloride with ammonia, an appropriate
29 mono-lower alkyl amine, di-lower alkyl amine or a hetero
~ 20 -
15582 IA
`,
1C~6312~ ~
1 amine, such as piperldine, morpholine and the like~ to
2 produce the corresponding amide compound. These and other
3 equivalent methods for the preparation of the ester and ;.~:
4 amide derivatives of the instant products will be apparent
to one having ordinary skill in the art and to the extent
6 that said derivatives are both non-toxic and pharmacologic- '
7 ally acceptable;said derivativesare the functional equiva- ` ~.;
8 lent of the corresponding [1-oxo-2-aryl or 2-thienyl-2-sub- ~:
9 stituted-5-indanyloxy (or thio)]alkanoic acids. ~: .
10 In addition to the salts, esters and amides .
11 being functionally equivalent to the caxboxylic products,
: . . .
12 those compounds wherein the carboxyl group is replaced ~ `
13 by a S-tetrazolyl radical are also functionally equivalent .
14 to the carboxylic acids. These tetrazole analogs are
15 prepared as depicted in the following equation: ' ;:. :
16 Xl ~ x~
HA ~ ZCH2CN/Base NCCH A ~ Rl
IV / XIV . .
/ hydrolysis
18 ~ ~ NaN3/NH4Cl
2 O ~2
19 xl ~ I ~ R H ~ ~ o ~;
~ ~ CH2A ¦ I ~ R :
20 HOCCH2A R N - N ~ 1
I
21 Formula I wherein
22 Y is methylene
- 21 -
, . . . .
. .
~ 15582
1C~63125
1 wherein all substituents are as defined above. ~ ;
2 The 5-hydroxy (or thio)-l-indanone (IV above) is
3 treated with a halo~cetonitrile such as chloroacetonitrile,
4 bromoacetonitrile or iodoacetonitrile in the presence of a
5 base such as potassium carbonate and the like in a suitable
6 solvent such as acetone, dimethylformamide, dimethoxyethane
7 and the like at a temperature in the range of from 25 to
8 100C. to afford the corresponding nitrile (XIV) ~hich,
9 upon treatment with sodium azide and ammonium chlori.de in
dimethyl~ormamide at a temperatuxe in the range oE .~rom
11 25 to 100C., af~ords the 5-~1-oxo-2-aryl or 2-thienyl-
12 2-substituted-5-indanyloxy (or thio)methyl]tet~azole.
13 A still further proGess for preparing compounds
14 of Formula I (the end product) wherein Y is methylene
involves a hydrolysis of the nitrile compound shown in
16 Formula XIV above. This is a typi.cal hydrolysis of a nitrile
17 reaction and is well known to persons skilled in the art.
~8 Many of the instant compounds herein disclosed
19 contain an asymmetric carbon atom in the 2-position of the
indanyl ring. When this situation exists, the optical
21 antipodes may be separated by methods described below.
22 This inYention embraces, therefore, not only the racemic .
23 ~1-oxo-2-aryl or 2-thienyl-2-substituted-5-indanyloxy-
2~ (or thio)]alkanoic acids but also their opitcally active
25 antipodes. .-
26 Separation of the optical isomers of the racemic
27 acids may be accomplished by forming a salt of the racemic
28 mixture with an op-tically active base such as (-~) or (-)
29 amphetimine, (-)-cinchonidine, dehydroabietylamine, (-~) or
(-)-~-methylbenzylamine, (+) or (-)-~-(l-naphthyl)ethylamine,
- 22 -
~ ~ 15582
;~;
3~63~LZ~ ::
:
1 brucine or strychnine and the like in a suitable solvent
2 such as methanol, ethanol, 2 propanol, benzene, acetonitrile,
3 nitromethane, acetone and the like. There is thus formed
4 in the solution two diastereomeric salts one of which is
usually more soluble in the ~lvent than the other. Repetitive
6 recrystallization of the crystalline salt generally aEfords
7 a pure diastereomer. The optically pure 2-aryl or 2-thienyl i
8 indane acid is obtained by acidification of the salt with a
9 mineral acid, extraction into ether, evaporation of the
solvent and recrystallization of the optically pure antipode. -
11 The other optically pure antipode may generally
12 be obtained by using a different base to form the diastereo-
13 meric salt. It is of advantage to isolate the partial}y
14 resolved acid from the filtrates of the purification of the
one diastereomeric salt and to further purify this substance
16 through the use of another optically active base.
17 The examples which follow illustrate the 2-aryl
18 and 2-thienyl indane products of the invention and the metho~
19 by which they are prepared. However, the examples are illus~
trative only and it will be apparent to those having ordinary
21 skill in the art that all of the products embraced by Formula
22 I, supra, may also be prepared in an analogous manner by sub-
23 stituting the appropriate staxting materials for those set
24 forth in the examples.
~,
- 23 - ~
15582 IA ~
,
~ 3~5 ::
1 EXAMPLE 1
2 Preparation of (l-Oxo-2-methyl-2-phenyl-6,7-dichloro-
3 5-indanvloxy)acetic acid
4 ~ 2,3-Dichloro-5-phenyl,cetylanisole
To a stirred mixture of 2,3-dichloroanisole t62 ~,
6 0.35 mole), phenylacetyl chloride (54 g., 0.35 mole) and
7 carbon disulfide (250 ml.) is added portionwise aluminum
8 chloride (47 g., 0.35 mole) with cooling at 0-5C. The
9 reaction mixture is left at 25C. for 17 hours, the carbon
disulfide removed, and the residue treated with ice-water
11 and concentrated hydrochloric acid (50 ml.) to give 68.8 g.
12 of 2,3-dichloro-5-phenylacetylanisole which melts at 126-
13 129C. on crystallization from benzene:cyclohexane, 2:1.
14 Elemental analysis for C15~I12C1202:
Calc.: C, 61.04; ~, 4.10;
16 Found: C, 61.46; H, 4.11.
17 Step B: 2,3-Dichloro-4-(2-phenylacryloyl)- ~
18 anisole ~ -
19 Acetic anhydride (100 ml.) is added dropwise to
a suspension of 2,3-dichloro-4-phenylacetylanisole (29.5 g.,
21 0.01 mole) in bis(dimethylamino)methane tl ml.) ~mder
22 nitrogen with cooling to maintain the reaction mixture
23 temperature below 60C. The reaction mixture is stirred at
24 25C. for 2 hours, and poured into ice water (1500 ml.) to
precipitate 7.4 g, o~ 2,3-dichloro-4-(2-phenylacryloyl)-
26 anisole which melts at 87-89C.
27 Elemental analysis for C16H12C1202:
229 Calc.: C, 62.56; H, 3.94;
Found: C, 62.67; H, 4.04.
, 2 4 -
,
.
15582 IA
'
'~"
1Ste~ C: 2-Phenyl-5-methoxy-6,7-dichloro-
2l-indanone
32,3-Dichloro-4-(2~henylacryloyl)anisole (7.4 g.,
4 0.024 mole) is added portionwise to cold, concentrated
sulfuric acid (150 ml.) with stirring. The reaction mixture
6 is stirred in an ice bath for 2 hours, ~hen added dropwise
.
7 to ice-water to precipitate 3.91 g. o~ 2-phenyl-5-methoxy-
8 6,7-dichloro-1-indanone which melts at 193-195C. upon
9 crystallization from benzene:cyclohexane, 1:2. ``~
10Elemental analysis for C16H12C12O
11Calc~: C, 62.56; H, 3.94; ;
Found: C, 62.84; H, 4.00. `~
13Step D: 2-Phenyl-5-hydroxy-6,7-dichloro-
14l-indanone _ _
15A stirred mixture of 2-phenyl-5-methoxy~6,7-
16dichloro-l-indanone (3.91 g., 0.0127 mole) and pyridine ~- ~
17hydrochloride (40 g.) is heated at 190C. ~or one hour, ~ ~;
18 then poured into water (600 ml.). The 2-phenyl 5-hydroxy-
19 6,7-dichloro-1-indanone which separates (2.48 g.) melts at
250-252C. after recrystallization from ethanol:water, 2:1.
21Elemental analysis for C15HloC12O2:
223Calc.: C, 61.46; H, 3.44;
Found: C, 60.94; H, 3.66.
24Step E: (l-Oxo-2-phenyl 6,7-dichloro-5-indanyl-
25oXY)aCetiC acid
262-Phenyl-5-hydroxy-6,7-dichloro-1-indanone (5.86 g,~
27 0.023 mole), iodoacetic acid ~4,28 g., 0.023 mole), potassium
28 carbonate (3.04 g., 0.022 mole) and acetone (250 ml.) are
29 heated at reflux for 48 hours. The reaction mixture is coo~d ~ ;
to 25C., concentrated in vacuo to give a solid product which
- 25 -
15582 IA
,
1C~63~Z5
1 is dissolved in water and acidified witll 6N hydrochloric
2 acid to precipitate 6.8 g. of a mixture of (1-oxo-2-phenyl-
3 6,7-dichloro-5-indanyloxy)acetic acid and 2-phenyl-5-hydroxy-
4 6~7-dichloro-1-indanone. The phenol is removed by crystal-
lization with ni-tromethane. Concentrating the filtrate to
6 dryness in vacuo and triturating with toluene gives 470 mg.
7 of (1-oxo-2-phenyl-6,7-dichloro-5-indanyloxy~acetic acid
8 which melts at 181-185C.
9Elemental analysis for C17H12C12O
10Calc.: C, 58.14; H, 3.45; Cl, 20.19;
11Found: C, 58.17; ~I, 3.54; Cl, 19.9~.
12Step F: (l-oxo-2-phenyl-2-methyl-6,7-d:Lchloro-
135-indan~loxy~acetic acid _
14A s~irred solution of (l-oxo-2-phenyl-6,7-di-
15chloro-5-indanyloxy)acetic acid (0.351 gm., 0.001 mole) in -
16 dimethylformamide (7 ml.) is cooled in an ice bath then
17 trea~ed with sodium hydride (0.084 g. of a 57% oil dis-
18 persion,.002 moles) and stirred for two hours. Methyl
19 iodide (1 ml.) is added and the reaction mixture is stirred
at 25C. for tvc hours, poured into ice water, and acLdified
'.
~:
- 26 -
; ~ , ~ ~ , . . .
15582 I
~63~1LZ~ :
1 with dilute aqueous hydrochloric acid affording (l-oxo-
2 2-phenyl-2-methyl-6,7-dichloro-5-indanylo:xy)acetic acid
3 which melts at 168-169C. : :
4 EX~MPLE 2 .
Where in ~xample 1, Step A, there is substi-
6 tuted for the 2,3-dichloroanisole an equivalent amount
7 of 2-chloro-3-methylanisole, 2,3-dimethylanisole, 3-
8 methylanisole, or 2-methyl-3-chloroanisole, respectively, .-
9 and Steps B through F are employed as described there
is obtained~
11 (1-oxo-2-phenyl 2,7-dimethyl-6-chloro-5-
12 indanyloxy)acetic acid .
13 (1-oxo-2-phenyl-2,6,7-trimethyl-5-
14 indanyloxy)acetic acid
(1-oxo-2-phenyl-2,7-dimethyl-5-
16 indanyloxy)acetic acid
17 (1-oxo-2-phenyl-2,6-dimethyl-7-chloro-5- ~.-
18 indanyloxy)acetic acid
lg EXAMPLE 3
Where in Example 1, there is substituted for the .
21 phenylacetyl chloride of Step A an equivalent amount of
22 p-methylphenylacetyl chloride, m-methylphenylacetyl chloride,
23 o-chlorophe~ylacetyl chloride, p-fluorophenylacetyl chloride,
24 and Steps B through F are employed as therein described there
25 is obtained respectively: ~-
-27-
''I .
. . . ~ . .
: :
,~ ~ 155~2 l
,, ,
1~i3~;~S ~:
1 [1-oxo-2-methyl-2-(4-methylphenyl)-
2 6,7-dichloro-5-indanyloxy]acetic acid
3 [1-oxo-2~methyl-2-~3-methylphenyl)-
4 6,7-dichloro-5-indanyloxy]acetic acid
[l~oxo-2-(2-chlorophenyl)-2-methyl-
6 6,7-dichloro-5-indanyloxy]acetic acid ;
7 El-oxo-2-(4-fluorophenyl~-2-methyl-
8 6,7-dichloro-5-indanyloxy]acetic acid ;~
- ~ .
'~'';
g B'~AMPLE 4
Where in Example 1, the 2-alkylating agent,
11 methyl iodide, of Step ~ is replaced by an equivalent
12 amount of ethyliodide, al~ylbromide, benzylbromide, and
13 cinnamylbromide, respectively, there is obtained, respec-
14 tively:
(1-oxo-2-ethyl-2-phenyl-6t7-dichloro-5-
16 indanyloxy)acetic acid
17 (1-oxo-2-allyl-2-phenyl-6,7-dichloro-5-
18 indanyloxy)acetic acid
19 (1-oxo-2-benzyl-2-phenyl-6,7-dichloro-5-
indanyloxy)acetic acid
21 (1-oxo-2-cinnamyl-2-phenyl-6,7-dichloro-5-
22 indanyloxy)acetic acid
~.
23 EXAMPLE 5
24 (1-Oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic
acid
. _ . . _ _ .
26 _ep A: 2',3',-Dichlo,o-4'-methoxyisobutyro- "~
27 phenone
28 A stirred mixture of 2,3-dichloroanisole (I) (100
. :
i~ :
_28_
15582 IA ~ -
,~ . ' ! '
~3125 ~ ~:
l g., 0.565 mole) and isobutyryl chloride (II) (66 g., 0.62 ;~
2 mole) in methylene chloride (400 mlO) is cooled to 5C. and
3 treated with aluminum chloride (83 g., 0.62 mole) during a
4 one-hour period. The reaction mixture is allowed to warm
to 25C. and after 24 hours is poured into ice water (400 ml.)
6 and hydrochloric acid (30 ml.). The organic phase is wash~
7 with 5% sodium hydroxide, water, dried over magnesium sulfate
8 and distilled at reduced pressure affording 68 g. of 2', 3'~
9 dichloro-4'-methoxyisobutyrophenone (III) which distills at
120-130C./O.S mm.
ll Elemental analysis for CllH12Cl~O :
2 Calc.: C, 53.46; H, 4.89;
Found: C, 54.25; H, 5.07.
14 Step B: 2-Bromo-2',3'-dichloro-4'-methoxyiso-
butyro~enone --
. . . ~
16 A stirred solution of 2',3'-dichloro-4'-methoxy~
17 isobutyrophenone (45 g., 0.183 mole) in acetic acid (150 ml.) ~`
18 is treated during one-half hour with bromine (30 g., 0.187 ;;
l9 mole). The reaction mixture is stirred lO minutes, then
poured into ice water (600 ml.~ containing sodium bisulfite
21 ~2 g.). The 2-bromo-2',3'-dichloro-4'-methoxyisobutyro-
22 phenone (IV) which separates (48 g.) melts al 72-73C.
23 after recrystallization from hexane.
24 Elemental analysis for CllHllBrC1202:
24 Calc.: C, 40.52; H, 3.40; ~
25 Found: C, 40.68; ~, 3.38~ -
- 29 - -
15582 IA ~ ~
1063125 ~
1 Step C: 2-Methylene-2' r 3'-dichloro-4'-methoxy-
2 propiophenone
3 A solution of 2-bromo-2',3'-dichloro-4'-methoxy- ~ ;
4 isobutyrophenone (32 g., 0.1 mole) and anhydrous lithium
bromide (17.4 g., 0.2 mole3 in DMF (200 ml.) is stirred at
6 95C. in an inert atmosphere for three hours and poured into
7 ice water (500 ml.). The 2-methylene-2',3'-dichloro-4'-
8 methoxypropiophenone (V) which separates melts at 59C.
9 after recrystallization from petroleum ether.
Elemental analysis for CllHloC1203:
11 Calc.: C, 53.90; H, 4.11;
12 Found: C, 53.72; H, 4.11.
13 Step D: 2-Methyl-5-methoxy-6,7-dichlorc)-1-indanone
14 A solution o~ 2-methylene-2',3'-dichloro-4'-
methoxypropiophenone (40 g., 0.163 mole) in concentrated
16 sulfuric acid (75 ml.) is allowed to stand at 25C. for
17 24 hours and then is slowly poured into vigorously stirred ;
18 ice water (500 ml.). The 2-methyl-5 methoxy-6,7-dichloro-
19 l-indanone which separates (40 g.) melts at 129C. `~
20 after recrystallization from methylcyclohexane. ~;
21 Elemental analysis ~or CllHloC1202: ~;
22 Calc.: C, 53.90; H, 4.11;
23 Found: C, 53.84; H, 4.00.
24 Step E: 2-Methyl-2-phenyl-5-methoxy-6,7-diChloro-
~~~ l-indanone
., ,,, , , , _ . , _ _ _ . ~ . : .
26 Potassium tert-butoxide (8.42 g., 0O075 mole)
27 dissolved in ~ert-butanol (300 ml.) is added to a refluxing
~ `` ,~ .
- 30 -
: .: . . . . .
,: ' : .:. . .
,,: : - , : : . . .
~ 15582~
.
1~63~Z5
1 solution of 2-methyl-5-methoxy-6,7-dichloro-l~indanone
2 (12.26 g., O.OS mole), refluxing is continued for 2 hrs.,
3 then a suspension of diphenyliodonium chloride ~19.0 g.,
4 0~06 mole) in tert-butanol (1 1.) is added and refluxing
i~ continued for 2 hrs. The reaction mixture is cooled to
6 25C., 300 ml. water added, and the mixture concentrated to
7 dryness in vacuo to give 4.97 g. of 2-methyl-2-phenyl-S-
8 methoxy-6,7-dichloro-1-indanone which melts at 161-163C.
9 after crystallization from benzene: cyclohexane, 1:2.
Elemental analysis or C17H14C12O~:
11 Calc.: C, 63.57; H, 4.39;
12 Found: C, 63.24; H, 4.68.
13 ~p_~: 2-Methyl-2-phenyl-S-hydroxy-6,7-dichloro-
1~ l-indanone
A stirred mixture of 2-methyl-2-phenyl-5-methoxy-
16 6,7-dichloro-1-indanone ~4.94 g., 0.015 mole) and pyridine
17 hydrochloride ~50 g.) 1s heated at 175C. for one hour, then
18 poured into water ~500 ml.). The 2-methyl-2-phenyl-5-
19 hydroxy-6,7-dichloro--1-indanone which separat~ (2.05 g.)
melts at 194-196C. a~ter recrystallization from ethanol:
21 water, 2:1.
22 Elemental analysis Eor C16H C12O2:
23 Calc.: C, 62.56; H, 3.94;
24 Found: C, 62.60; H, 4.11.
Step G: (l-Oxo-2-methyl-2-phenyl-6,7-dichloro-
26 5-in_anyloxy)acetic acid
27 A 3~irred mlxture oE 2-methyl-2-phenyl-S-hydroxy-
28 6,7-di~hloro-1-indanone ~2.05 g., 0.0067 mole), potassium
-31
i'~ ''f~
155~2 ~
~3~ZS ~ `
,
1 carbonate (1.85 g., 0.0134 mole) and ethyl bromoacetate
2 (2.23 g., 0.0134 mole) in dimethylformamicle (30 ml.) is
3 warmed at 55-60C. for 3 hours, then ~reated with potassium
4 hydroxide (0.97 g., 0.0147 mole) dissolved in a minimum
amount of water in methanol (30 ml.) and heated on a steam
6 bath for 2 1/2 hours. The reaction mixture is poured into
7 water (500 ml.), acidified with 6 N hydrochloric acid and the
8 precipitate collected after trituration with ether-petroleum
g ether and dried to give 1.31 g. of (1-oxo-2 methyl-2-phenyl- ~-
6,7 dichloro-5-indanyloxy)acetic acid which melts at 168
11 169C. on crystallization from acetic acid:water, 1:1.
12 Elemental analysis Eor Cl~H14C12O~:
13 Calc.: C, 59.20; H, 3.86;
14 Found: C, 58.94; H, 4.20.
- ,i~, .
EXAMPLE 6
16 Where in Example 5, there is substituted for `~
17 the 2,3-dichloroanisole of Step ~ an equivalent amount
18 of 2-chloro-3 methylanisole, 2,3-dimethylanisole and 2- ~ ;
19 methyl-3-chloroanisole, respectively, the following com-
pounds of this invention are obtained, respectively:
21 (1-oxo-2,7-dimethyl-2-phenyl-6-chloro-5- `
22 indanyloxy)acetic acid
23 (1-oxo-2,6,7-trimethyl-2-phenyl-5- ~ ~-
24 indanyloxy)acetic acid
(1-oxo-2,6-dimethyl-2-phenyl-7-chloro-5-
26 indanyloxy)acetic acid
-~2-
~J' ~ ` ~
15S~2 ~
. - .
~L~63~S
:~
1 EXAMPLE 7
2 Preparation of [l-Oxo-2-(~-chlorophenyl)-2-methyl-6t7
3 dichloro-5-indanyloxy]acetic acid hemihy~drate
4 Step A: 2-(4-chlorophenyl)-2-methyl-5-methoxy- ~-
6,7-dichloro-1-indanone
6 Potassium tert-butoxide (2.81 g., 0.025 mole~
7 dissolved in tert-butanol (150 ml.) is added to a refluxing
8 solution of 2-methyl-5-methoxy-6,7-dichloxo-1-indanone (4.90
9 g., 0.02 mole) in tert-butanol (100 ml.)-benzene (200 ml.),
refluxing is continued for 3 hours, then 4,4'-dichloro-
11 diphenyliodonium chloride (11.55 g., 0.03 mole) is added
12 and refluxing is continued for 2 hours. The reaction mixture
13 is cooled to 25C., 100 ml. water added, and the m:ixture
14 concentrated to dryness in vacuo to give 4.30 y. of 2-
(4-chlorophenyl)-2-methyl-5-methoxy-6,7-dichloro-1-indanone
16 which melts at 176-178qC. after crystallization from cyclo-
17 hexane:benzene, 5~
18 Step B: 2-( ~ Chlorophenyl)-2-methyl-5-hydroxy-
19 6,7-dichloro-1-indanone
A stirred mixture of 2-(4-chlorophenyl)-2-methyl-
21 5-methoxy-6,7-dichloro-1-indanone (4.15 g., 0.012 mole) and
2~ pyridine hydrochloride (40 g.) is heated at 180C. for one
23 hour, then poured into water (500 ml.). The 2-(4-chloro-
24 phenyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone which
separates (3.11 g.) melts at 211-213C. after crystalliza-
26 ~iG~ from ethanol:water, 1:1. ~
27 Elemental analysis for C16HllC13O2: ~-
28 Calc.: C, 56.25; H, 3.25;
29 Found: C, 55.53; H, 3.23.
~,~
-33-
. .
~ 15582 I~
31ZS ~ ~
1 Step C~ Oxo-2-~4-chlorophenyl)~2-methyl-
2 6,7-dichloro-5-indanyLcxy)acetic acid
3 hemihydrate _ _
4A stirred mixture of 2-(4-chlorophenyl)-2-methyl-
5-hyd~oxy-6,7-dichloro-1-indanone (2.95 g., 0.00863 mole),
6 potassium carbonate (2.26 g., 0.0163 mole) and ethylbromo-
7 acetate (2.72 g., 0.0163 mole) in dimethylformamiae (50 ml.~
8 is warmed at 55-60C. for two hours, then treated with water
9 (50 ml.)-10N sodium hydroxide solution (2.5 ml., 0.025 mole)
and heated at 80C. for one hour. The reaction mixture is
11 added slowly to water t500 ml.)-12N hydrochloric acid tlO ml.) -~
12 to precipitate 1.37 y. of [1-oxo-2-(4-chlorophenyl)-2-
13 mekhyl-6,7-dichloro-5-indanyloxy)acetic acid hemihydrate ;
14 which melts at 141-142C. after cry~tallization ~rom acetic
acid: water, 1:1.
16Elemental analysis for C18H13C13O4 1/2H2O~
17Calc.: C, 52.90; H, 3.45; Cl, 26.03;
18Found: C, 52.47; H, 3.45; Cl, 26.11.
19EXAMPLE 8
Prepaxation of [l-Oxo-2-(4-methoxyphenyl)-2-methyl-6,7-di
21 chloro-5-indanyloxy]acetic acid
22Step A: 2-Methyl-5-hydroxy-6,7-dichloro-
23l-indanone _ _ _ _
24A stirred mixture of 2-methyl-5-methoxy-6,7-di-
chloro-l-indanone (30.0 g., 0.123 mole) and pyridine hydro-
26 chloride (270 g.) is heated at 180C. for one hour, then
27 poured into water (1500 ml.). The 2-methyl-5-hydroxy-
286,7-dichloro-1-indanone which separates (27.6 g.) melts `
29 at 224-230C. and is used without further purification.
,
- 3~ - ~
15582
~631~5 ~
:, '
1 Step B~ 2-Methyl-5-benzyloxy-6,7-dichloro-
2 l-indanone
3 A stirred mixture o~ 2-methyl-5-hydroxy-6,7-di-
4 chloro-1-indanone (27.6 g., 0.12 mole), potassium carbonate
(24.9 g., 0.18 mole) and benzyl bromide t21.4 ml., 0.18 mole)
6 in dimethylformamide (100 ml.) is warmed at 55-60C. for
7 2 hrs., then poured into water (1 1.) to precipitate 35.5 g.
8 of 2-methyl-5-benzyloxy-5,7-dichloro-1-indanone which melts
9 at 153-155C. after crystallization from benzene:hexane, 3:2.
Elemental analysis for C17H14Cl O :
11 Calc.: C, 63.57; Hr 4-39;
12 Found: C, 64.28; ~I, 4.61.
13 Step C: 2-(4-Methoxyphenyl)-2-methyl-5-benzyloxy-
14 6,7~dichloro-1-indanone
Potassium tert-butoxide (8.42 g., 0.075 mole)
16 dissolved in tert-butanol (450 ml.) is added to a refluxing
17 solution of 2-methyl-5-benzyloxy-6,7~dichloro-1-indanone
18 (16.1 g., 0.05 mole) in tert -butanol (150 ml.)-benzene
,
19 (600 ml.), refluxing is continued for 2.5 hrs., then 4,4'-
dimethoxydiphenyliodonium chloride (37.66 g., 0.10 mole)
21 is added and refluxing is continued for 3 hrs. The reaction
22 mixture is cooled to 25C., 500 ml. water added, and the
23 mixture concentrated ln vacuo to give a brown oil which on
24 ethex extraction, drying over anhydrous magnesium sulfate,
removal of the ether and chromatographing of the residue on
26 silica gel with chloroform gives 3.44 g. of 2-(4-methoxy- ~;
27 phenyl)-2-methyl-5-benzyloxy-6,7-dichloro-1-indanone which
28 melts at 115-119C. and is used without further purification.
- 35 -
",
! 15582 IA
1~631;~S ~:
1 Step D: 2-(4-Methoxyphenyl)-2-methyl-5-hydroxy-
2 6,1-dichloro-1-indanone
3 2-(4-Methoxyphenyl)-2-methyl-5-benzyloxy-6,7-di-
4 chloro-l-indanone (3.44 g., 0.008 mole) is catalytically
5 hydrogenated in absolute ethanol (300 ml.) over 5% palladium `~
6 on carbon (500 mg.) in a Parr apparatus at 25C. for 4 hrs. ~ ;
-: .
7 The reaction mixture is filtered and concentrated in vacuo ~ -
8 to give 2.6 g. of 2-(4-methoxyphenyl)-2-methyl-5-hYdrOxy-
9 6,7-dichloro-1-indanone which melts at 149-156C. and is .
used without further purification.
11 Step E: [l-Oxo-2-t4-methoxyphenyl)-2-methyl-
12 6,7-dichloro-5-indanyloxy]acetic acid
~: :
13 A stirred mixture of 2-(4-methoxyphenyl)-2-methyl
14 5-hydroxy-6,7-dichloro-1-indanone (2.6 g., 0.0077 mole),
15 potassium carbonate (2.14 g., 0.0154 mole) and ethyl bromo- ~
16 acetate (2.58 g., 0.0154 mole) in dimethylformamide (60 ml.) ;;
17 is warmed at 55-60C. for 2.5 hrs., then treated with water
18 (60 ml.),-lON sodium hydroxide solution (3 ml., 0.03 mole) ;~
19 and heated at 100C. for one hour. The reaction mixture is
20 added slowly to crushed ice-water (600 ml.)-12N hydrochloric ;
21 acid ~20 ml.) to precipitate 1.69 g. of [1-oxo-2-(4-methoxy-
22 phenyl~-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid which
23 melts at 173-175~C. after crystallization from nitromethane.
24 Elemental analysis for ClgH16C12O~
Calc.: C, 57.74; H, 4.08;
26 Found: C, 57.35; H, 4.31.
;'
~ .
- 36 -
~ , ~ : : .
15582 IA ~
~L~631;Z 5 ~ :
1 EXAMPLE 9
2 Preparation o~ Oxo-2-(4-hydroxyphenyl)-2-methyl-6,7-di-
3 chloro-5-indanYloxY]acetic acid
4 A stirred mixture of ~l-oxo~2-(4 methoxyphenyl)-
2-methyl-6,7-dichloro-5-indanyloxy]acetic acid (1.80 g.,
6 0.0046 mole~, Example 8, Step E, 48% hydrobromic acid
7 (50 ml.) and acetic acid (50 ml.) is hea~ed at reflux ~or
8 one hour, then poured into crushed ice-water (800 ml.) to
9 precipitate 900 mg. of ~1-oxo-2-(4-hydroxyphenyl)-2-methyl-
6,7-dichloro-5-indanyloxy]-acetic acid which melts at
11 220-222C. after crystallization from acetic acid: water, 1:1,
12 and nitromethane.
13Elemental analysis for C18II14C12O5-1/3CH3NO2
14Calc.: C, 54.84; H, 3.77; N, 1.16;
15Found: C, 54.38; H, 3.93; N, 0.94.
16EXAMPLE 10
17Ethyl (l-Oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)- -
18 acetate
19To a solution of (l-oxo-2-methyl-2-phenyl-6,7-
dichloro-5-indanyloxy)acetic acid (1.0 g.), obtained from
21 Example 5, in ethanol (10 ml.) is aclded borontri~luoride
22 etherate (1.0 ml.). The reaction mixture is refluxed
23 ~or 1/2 hour, treated with water and cooled to afford the
24 ethyl (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)-
acetate.
:-
- 37 -
~ ~ 15582 IA
~1~63~25
1 EXAMPLE 11
:`
2 N-Ethyl-(l-oxo-2-methyl-2-phenyl-6r7-dichloro-5-indanyloxy
3 acetamide
.. . - - -- ~
4 A solution of (l~oxo-2-methyl-2-phenyl-6,7~
dichloro-5-indanyloxy)acetic acid (1.0 g.) obtained from
6 Example 5 and thionyl chloride (0.5 ml.) in benzene (20 ml.)
7 is refluxed for one hour. The solvent is distilled at
8 reduced pressure and the residue is treated with benzene
9 (10 ml.) and ethyl amine (1 ml.). After two hours at 25C.
11~ the reaction mixture is poured into water and extracted
11 with ether; the ether extract is washed first with diluted
12 hydrochloric acid then with a~ueous sodium bicarbonate. The
13 ether solution is dried over magnesium ~ulfate evaporated at
14 ~educed pressure to afford the desired N-ethyl-(l-oxo-2-
methyl-2-phenyl-6l7-dichloro-5-indanyloxy)acetamide.
16
17 EXAMPLE 12
18 Preparation of [l-Oxo-2-(4-fluorophenyl)--2-methyl-6,7-di- i~
19 chloro-5-indanYloxY]acetic acid
Step A. 2-(4-Fluorophenyl)-2-methyl-5-methoxy-
21 6,7-dichloro-1-indanone
... ..... _ _ .............. _._~
22 Potassium t_ -butoxide (3.38 g., 0.03 mole)
23 dissolved in tert-butanol tlSo ml.) is added to a refluxing
24 solution of 2-methyl-5-methoxy-~,7-dichloro-1-indanone ~ ~;
(4.90 g., 0.02 mole) in tert-butanol (50 ml.)-benzene (200 m~
26 refluxing is continued for 3 hours, then 4,4'-difluorodi-
27 phenyliodonium chloride (10.58 g., 0.03 mole) is added and
28 refluxing is continued for 2-1/2 hours. The reaction mixture
29 is cooled to 25C.~ 100 ml. water added, and the mixture
concentrated to dryness in vacuo to give 1.24 g. of 2-(4-
31 fluorophenyl)-2-methyl-5-methoxy-6,7-dichloro-1-indanone
32 which melts at 163-170C. on treatment with ether-hexane
33 and is used without further purification.
.
- 38
. .
: . . . . . .
.... .
15582 IA
1~63~Z5 ;
1 Step B: 2-(4~Fluorophenyl)-2-methyl-5-hydr
6 7-dichloro~l-indanone
2 -~
3 A stirred mixture of 2-(4-fluorophenyl)-2-methyl
4 5-methoxy-6,7-dichloro-1-indanone (1.2 g., 0.00354 mole) and
pyridine hydrochloride (12 g.) is hea~ed at 180C. for one
6 hour, then poured into water (500 ml.). The 2-(4-1uoro-
7 phenyl)-2-methyl-5-hydroxy-6,7~dichloro-1-indanone melts
8 at 193-200C. and is used without further purification~
9 Step C: [l-Oxo-2-(4-fluorophenyl)-2-methyl~
6~?7-dichloro-5-indanyloxy]acetic acid
11 A stirred mixture of 2-(4-fluorophenyl)-2-methyl-
12 5-hydroxy-6,7-dichloro-1-indanone (1.04 g., 0.0032 mole),
13 potassilm carbonat.e (0.885 g., 0.0064 mole) and ethyl bromo-
14 acetate (1.07 g., 0.0064 mole) in dimethylformamide (30 ml.)
is warmed at 55-60C. for 3 hours, then treated with water
16 (30 ml.)-lON sodium hydroxide solution (I m~., 0.01 mole)
17 and heated at 80C. for one hour. The reaction mixture is
18 added slowly to water (500 ml.) -12N hydrochloric acid
19 (10 ml.) to precipitate 450 mg. of 11-oxo-2-(4-fluorophenyl)-
2-methyl-6,7-dichloro-5-indanyloxy]acetic acid which melts
21 at 150-156C. after crystallization from ethyl acetate:hexane,
22 1:3. `
23 Elemental analysis for C18H13C12FO4:
24 Calc.: C, 56.42; H, 3.42; Cl, 18.50;
Found: C, 56.30; EI, 3.65; Cl, 18.57. ;
26 EXAMP E 13
27 Preparation of (l-Oxo-2l2-diphenyl-6,7-dichloro-5- -
28 indanylo~)acetic acid
29 Step A: 2,2-Diphenyl-5--methoxy-6,7-dichloro-
30 l-indanone -
31 Potassium tert-butoxide (7.0 g., 0.0624 mole)
32 dissolved in tert-butanol (500 ml.) is added to a mixture
'
- 39 -
.: :.: : , , -
,. . .. . : ..
15532 IA
~L~6~ S
1 of 2-phenyl-5-methoxy-6,7-dichloro-1-indanone (9.59 g.,
2 0.0312 mole), diphenyliodoni~ chloride (39.6 g., 0.125 mole),
3 tert-butanol (1500 ml.) and benzene (500 ml.) at 70 C. during
4 one hour, then stirred at 70C. for 2 hours. The reaction
mixture is concentrated ln vacuo to 1/4 o~ its volume,
6 unreacted iodonium salt filtered o~, and the remaining
7 liquid concentrated to dryness to give 5.71 g. of 2,2-di-
8 phenyl-5-methoxy-6,7-dichloro-1-indanone which melts at
9 172-174C~ after crystallization from cyclohexane.
Elemental analysis ~or C22H16C12O2: ;
11 Calc.: C, 68.94; H, 4.21;
12 E'ound: C, 68.99; Hl 4.34.
13 Step B: 2,2-Diphenyl-5-hydroxy-6,7-dichloro-
14 l-indanone
,
A stirred mix~ure of 2,2-diphenyl-5-methoxy-
16 6,7-dichloro-1-indanone (5.5 g., Q.014 mole) and pyridine
17 hydrochloride (55 g.) is heated at 175C. for one half hour,
18 then poured into water (500 ml.). The 2,2-diphenyl-5-hydroxy-
19 6,7-dichloro-1-indanone which separates (4.94 g.) melts at
207-213C.
21 Elemental analysis for C21H14C12O2:
22 Calc.: C~ 68.31; ~I, 3.82;
23 Found: C, 67.86; H, 3.88. !
24 Step_C: (l-Oxo-2,2-diphenyl-6,7-dichloro-
5-indanyloxy)acetic acid
~ . - . - ,
26 A stirred mixture of 2,2~diphenyl-5-hydroxy-
27 6,7-dichloro-1-indanone (4.9 g., 0~0133 mole), potassium ~ -
28 carbonate 13.68 g., 0.0266 mole) and ethyl bromoacetate
29 (4.45 g., 0.0266 mole) in dimethylformamide (150 ml.) is -~
warmed at 55-60C. for 3.5 hours, then trea~ed with water
- 40 -
. , ', . ' ' , .~'` ' ' ' '
! lA
~L~63~;2 5
1 (150 ml.)-lON sodium hydroxide solution ~7.5 ml., 0.075 mole)
2 and heated at 90C. for 1.5 hrs. The reaction mixture is
3 added slowly to water (1 1.)-12N hydrochloric acid (30 ml~)
4 to precipitate 3.60 g. of (1-oxo-2,2-diphenyl-6,7-dichloro-
5-indanyloxy)acetic acid which melts at 251-252C. after
6 crystallization from first acetic acid, then nitromethane.
7 Elemental analysis for C23H16C1204:
8 Calc.: C, 64.65; H, 3.77; Cl, 16.59;
9 Found: C, 64.69; ~I, 3.94; Cl, 16.73.
EXAMPLE 14
11 Preparation of (l-Oxo-2,3-diphenyl-2-methyl-6,7-dichloro-
12 5-indcLnyloxy)acetic acid ~~
13 Step A: 2',3'-Dichloro-4'-methoxypropiophen _
14 A stirred mixture of 2,3-dichloroanisole (177.0 g.,
1.0 mole) and propionyl chloride (101.8 g., 1.1 mole) in
16 methylene chloride (600 ml.) is cooled to 5C. and treated
17 with aluminum chloride (146.7 g., 1.1 mole) during a 1-1/2
18 hour period. The reaction is allowed to warm to 25C. and
19 after 16 hours is poured into ice-water (2 1.) and concent-
rated hydrochloric acid (200 ml.j. The organic phase is
21 washed with 10~ sodium hydroxide solution and saturatecL salt
22 solution, and dried over magnesium sulfate. Afterevapor~ion
23 of the solvent, the product is crystallized from hexane to
24 give 124.5 g. (53%) of 2',3'-dichloro-4'-methoxypropiophe~e ;
which melts at 51-54C.
26 Step B: 2,3-Dichloro-4-(2-benzylidenemethyl~n~e
27 To a mixture of 2',3'-dichloro-4'-methoxypropio-
28 phenone (124.5 g.t 0.53 mole) and benzaldehyde (54.4 ml.,
29 0.53 mole) dissolved in ethanol (1 1.) is added dropwise 20%
sodium hydroxi~e solution (117.0 ml., 0.59 mole). The prod~
-41 -
. .
v~ ` 15582 I1
~ i3~ S : `
1 begins to precipitate after three quarters of the base has
2 been added~ After two hours at 25C. thle solid product is
3 collected by suction filtration to give 163.2 g. (95%) of
4 2,3-dichloro-4-(2-benzylidenemethyl)anisole which melts
at 137.5-139C. after crystallization from ethanol.
6Elemental analysis for C17H14C12O2:
7Calc.: C, 63.57; ~, 4.39;
8Found: C, 63.69; H, 4.49
9Step C: 2-Methyl~3-phenyl-5-methoxy-6,7-di-
chloro-1-indanone
112,3-Dichloro-4~(2-benzylidenemethyl)anisole
12 (100 g., 0.32 mole) and tri~luoroacetic acid (400 ml.) are
13 heated at gentle reflux for 67 hours. The trifluoroacetic
14 acid is removed, the oily residue triturated with ether to
give 80.0 g. of 2-methyl-3-phenyl-5-methoxy-6,7-dichloro-
16 l-indanone which on crystallization from benzene melts at ;~
17 155-157C.
18Elemental analysis for C17H14C12O2:
19Calc.: C, 63.57; ~, 4.39;
20Found: C, 63.17; H, 4.59. ;~
21Step D: 2,3-Diphenyl-2-methyl-5-methoxy-6,7-di- ~;
22 chloro-l-indanone -~
. . _
23Sodium methoxide (2.4 g., 0.045 mole) is added
24 portionwise to a stirred mixture of 2-methyl-3-phenyl- - ``
25 5-methoxy-6,7-dichloro-1-indanone (6.44 g., 0.02 mole), -~ -
26 diphenyliodonium chloride t31.6 g., 0.1 mole), dry dimethyl- ;
27 ~ormamide (200 ml.) and benzene (200 ml.) at 70C. under
28 nitrogen, and heating at 70C. is continued for 2 hours.
29 The reaction mixture is poured into water (1.5 1.), the -
benzene layer separated, dried over anhydrous magnesium
- 42 -
. ,~ . . . ;, .
. . . . ~ .
15582 IA
1~63:;~25
1 sulfate then concentrated in vacuo to yive 2.48 g. o~
2 2,3-diphenyl-2-methyl-5-methoxy-6 r 7-dichloro-1-indanone
3 after trituration with hexane. This m~aterial which melts
4 at 197-207C. is used without further pw~ification.
Step E: 2,3-Diphenyl-2-methyl--5-hydroxy-
6 --~ 6~7-dichloro-1-indanone
7 A stirred mixture of 2,3-diphenyl-2-methyl-
8 5-methoxy-6,7-dichloro-1-indanone (2.48 g.r 0.0065 mole)
9 and pyridine hydrochloride (25 g.) is heated at 175C. for
one hour, then poured into water (500 ml.). The 2,3-di-
11 phenyl-2-methyl-5-hydroxy-6,7-dichloro-1-indanone which
12 separates (2.24 g.) melts at 238-244C. and is usecl without
13 further purification.
14 Step F~ Oxo 2,3-diphenyl-2-methyl-6,7-di-
chloro-5-indanYloxY)acetic acid
16 A stirred mixture of 2,3-diphenyl-2-methyl-5-
17 hydroxy-6,7-dichloro-1-indanone (2.24 g., 0.00585 mole),
18 po~assi~m carbonate (1.62 g., 0.0117 mole) and ethyl bromo-
19 acetate (1.96 g., 0.0117 mole) in dimethylformamide (100 ml.)
is warmed at 55-6GC. for 3 hours, then treated with water
21 (100 ml.)-lON sodium hydroxide solution (5 ml., 0.05 mole)
22 and heated at 90C. for 1.5 hours. The reaction mixture is
23 added slowly to water (1 1.) -12N hydrochloric acid (10 ml.)
24 to precipitate 1.14 g. of (1-oxo-2,3-diphenyl-2-methyl-
6,7-dichloro-5-indanyloxy)acetic acid which melts at
26 203-205C. after crystallization from nitromethane.
27 Elemental analysis for C24H18C1204: ~;
28 Calc.: C, 65~32; H, 4.11;
29 Found: C, 65.30; Ht 4.19.
- 43 -
. .
:' , , .
15582 IA
3125
1 EX~PLE 15
2 Preparation of (l-Oxo~2-ethyl-2-phenyl-6,7-dichloro-5-
3 indanyloxy)acetic acid
4 Step A: 2-Ethyl~2-phenyl-5-methoxy-6,7-di-
chloro-l-indanone
6 Sodium methoxide (1.24 g., 0.023 mole) is added
; 7 portionwise to a stirred mixture o~ 2-phenyl-5-methoxy-
8 6,7-dichloro-1-indanone ~4.61 g., 0.015 mole), iodoethane
9 (15.5 ml., 0.15 mole), benzene ~60 ml.) and dimethylform-
amide (60 ml.) under nitrogen in an ice-water bath. The
; 11 reaction mixture is left to come to ambient temperature ~`
12 over one hour, then poured into water (1 1.), the benzene ,~
13 layer separated, dried over anhydrous magnesium sulfate and
14 concentrated in vacuo to give 3.23 y. o~ 2-ethyl-2-phenyl-
5-methoxy-6,7-dichloro-1-indanone which melts a-t 139-141C.
16 on crystallization from benzene:hexane, 1~
17Elemental analysis for C18H16C12O2:
18Calc.: C, 64.49 H, 4.81;
19E'ound: C, 64.73; H, 4.99.
20Step B: 2-Ethyl-2~phenyl-5-hydroxy-6,7-dichloro-
21 l--indanone _
22A stirred mixture of 2-ethyl-2-phenyl-5-methoxy- ~`
23 6,7-dichloro-1-indanone (3.01 c~., 0.009 mole) and pyridine
24 hydrochloride (35 g.) is heated at 175C for one half hour,
then poured into water (350 ml.). The 2-ethyl-2-phenyl~
26 5-hydroxy-6,7-dichloro-1-indanone which separates ~2.64 g.)
27 melts at 177-179C.
28Elemental analysis for C17H14C12O2:
29CA1C.: C, 63.57; H, 4.3g;
30Found~ C, 63.73; H, 4.81.
. .
... . . . .
~ ~ ~ 15582 IA
,
11Cl 6~31~:5 ~ ~
1 Step C~ Oxo-2-ethyl-2-phenyl-6,7-dichloro-
2 5-indanyloxy)acetic acid
3A stirred mixture of 2-ethyl-2~-phenyl-5-hydroxy-
4 6,7-dichloro-1-indanone (2.6 g., 0.008 mole)~ potassium
carbonate (2.24 g., 0.016 mole) and ethyl bromoacetate
6 (2.71 g., 0.016 mole) in dimethylformamicle (40 ml~) is
7 warmed at 55-60C. for 2.5 hours, then treated with water
8 (40 ml.)-lON sodium hydroxide solution (3 ml., 0.03 mole)
9 and heated at 100C. for one hour. The reaction mixture
is added slowly to water (600 ml.) -12N hydrochloric acid
11 (10 ml.) to give a gummy r~sidue which on ether extraction,
12 drying and concentrating ln vacuo gives 2.16 g. of (l-oxo-
13 2-ethyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid
14 which melts at 187-189C.
15Elemental analysis for ClgH16C12O4:
16Calc.: C, 60.18; H, 4.25;
17Found: C, 59.~6; H, 4.24.
18 EXAMPLE 16 -~
19 Preparation of (l-Oxo-2-cyclopentyl-2-phenyl-6,7~dichloro-
5-indanyloxy)acetic acid
... . _ _ . . . .
21 Ste~_A: 2-Cyclopentyl-2-phenyl-5-methoxy-6,7-
22 dichloro-l-indanone
23 Sodi~ methoxide (1.63 g., 0.03 mole) is added
24 portionwise to a stirred mixture of 2-phenyl-5-methoxy-
6r7-dichloro-1-indanone (4,61 g., 0.015 mole), cyclopentyl
26 bromide (16 ml., 0.15 mole), benzene (60 ml.) and dimethyl `~
27 formamide (60 ml.) under nitrogen at 25C. The reaction
28 mixture is stirred at 25C. for 16 hours, then poured into
29 water (1 1.), the benzene layer separated, dried over -
: `
- 45 -
15582 IA
10~i3125 ;~
1 anhydrous magnesium sulfate and concentrated in vacuo
2 leaving a red-brown oily residue which is chromatographed
3 with chloroform on silica gel to gi~e 1.42 g. of 2-cyclo-
4 pentyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone which
melts at 105-108C.
6 -Elemental analysis for C21H20C12O2:
7 Calc.: C, 67.21; ~, 5.37;
8 Found: C, 66.88; ~I, 5.53.
9 Step B: 2-Cyclopentyl-2-phenyl-5-hydroxy `~
6,7-dichloro-1-indanone
.... . - .
11A stirred mixture o~ 2-cyclopentyl-2-phenyl-~
12 5-methoxy-6,7-dichloro-1-indanone (1.40 g., 0.0037 mole)
13 and pyridine hydrochloride (14 g.) is heated at 175C. for
14 one half hour, then poured into water (400 ml.~. The ;
2-cyclopentyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone
16 which separates (1.1 g.) melts at 161-170C. on crystalli-
17 zation from butyl chloride; chloroform, 5:1. ;`
18Elemental analysis for C ~ Cl O : ~;
20 18 2 2 ;;:
19Calc.: C, 66.49; H, 5.02;
20Found: C, 65.52; H, 5.03. ;
21Step C: (l-Oxo-2-cyclopentyl-2-phenyl-
226,7-dichloro-5-indanyloxy?acetic acid
23A stirred mixture of 2-cyclopentyl-2-phenyl-5- ~;-
24 hydroxy-6,7-dichloro-1-indanone (1.10 g~, 0.003 mole),
25potassium carbonate (0.85 g., 0.006 mole) and ethyl bromo- -
26 acetate (1.02 g., 0.006 mole) in dimethylformamide (20 ml.)
27 is warmed at 55-60C. for 3 hours, then treated with water
28 ~20 ml.)-lON sodium hydroxide solution (1.2 ml., 0.012 mole)
29 and heated at 100C. for one hour. The reaction mixture is ;~
added slowly to water ~300 ml.)-12N hydrochloric acid (5 ml.)
:
- 46 - -
~ 15582 IA
31~25
1 to precipitate 680 mg. of (1-oxo-2-cyclopentyl-2-phenyl-
2 6,7-dichloro-5-indanyloxy)acetic acid which mel~s at
3 184-186C. after crystallization from nitromethane.
4Elemental analysis for C22H20C12O4:
5Calc.: C, 63.02; H~ 4.81;
6Found: C, 62.59; H, 4.86. ~ -
7EXAMPIE 17
8 Preparation of [l-Oxo-2-methyl-2-(4-nitrophenyl)-6,7-di- -
9 chloro-5-indanyloxv]acetic acid
Step_A: 2-Methyl-2-(4-nitrophenyl)-5-methoxy-
11 6,7-dichloro-1-indanone
12 Amyl nitrate (40 ml.) is added in 10 ml. incre~
13 ments at two hour intervals to 2-mekhyl-2-phenyl-5-methoxy-
14 6,7-dichloro-1-indanone (9.36 g., 0.03 mole) in polyphos-
phoric acid (150 g.) at 50-60C. with stirring. The total
16 heating period is 8 hours. The reaction mixture is treated ;~
17 with crushed ice-water to precipitate 4O82 g. of 2-methyl-2-
18 (4-nitrophenyl)-5-methoxy-6,7-dichloro-i-indanone which
19 melts at 179-180C. after crystallization from butyl chlori~e
20Elemental analysis for C17H13C12NO~:
21Calc.: C, 55.76; H, 3.58; N, 3.82;
22Found: C, 55.83; H, 3.66; N, 3.85. ~
23Step B: 2-Methyl-2-(4-ni~rophenyl)-5-hydroxy- ~ -
246,7-dichloro-1-indanone
25A stirred mixture of 2-methyl-2-(4-nitrophenyl- ~
265-meth~xy-6,7-dichloro-1-indanone (4.82 g., 0.013 mole) and ~ -
27 pyridine hydrochloride (50 g.) is heated at 175C. for one-
28 hal~ hour, then poured into crushed ice-water (1 1.). The
29 2-methyl-2-(4-nitrophenyl)-5-hydroxy-6,7-dichloro-1-indanone ~ -
- ~7 -
.
15582 IA
~ ~3125 ~ ~ -
1 which separates (4.42 gO) melts at 268-270C. after
2 crystallization from ethanol.
3 Elemental analysis for C16HllC12NO4: -
~ .
4 Calc.: C, 54.57; H, 3.15; N, 3.98;
Found: C, 54.18; ~I, 3.27, N, 4.66.
6 Step C: [l-Oxo-2-methyl~2-(4-nitrophenyl)-6,7-
7 dichloro-5 _ danyloxy]acetic acid
8 A stirred mixture of 2-methyl-2-(4-nitrophenyl-
9 5-hydroxy-6,7-dichloro-1-indanone (4.4 g., 0.0126 mole), ;~
potassium carbonate (3.49 g., O.0252 mole) and ethyl bromo- `~
11 acetate (4.21 g., 0.0252 mole) in dimekhylformamide (150 ml.)
12 is warmed at 55-60C. for 3hours, then treated with water
13 (150 ml.)-lON sodium hydroxide solution (7.5 ml.~ 0.075 mole)
14 and heated a~ 100C. or l.S hours. The reaction mixture is
added slowly to water (1 1.)~12N hydrochloric acid (15 ml.)
16 to precipitate 2.44 g. of [1-oxo-2-methy~-2-(4~nitrophenyl~
17 6,7-dichloro-5-indanyloxy]acetic acid which melts at 202- -~
18 205C. after crystallization from nitromethane.
lg Elemental analysis for C18H13C12NO6:
Calc.o C, 52.70; H, 3.19; N, 3.41;
21 Found: C, 52.72; H, 3.16; N, 3.30.
22 EXAMPLE 18 ~
.. .
23 Preparation of [l-Oxo-2-(4-aminophenyl)-2-methyl-6,7-dichloro-
24 5 indanyloxY]acetic acid
[1-Oxo-2-methyl-2-(4-nitrophenyl)-6,7-dichloro-
26 5-indanyloxy}acetic acid (6.11 g., 0.015 mole) in absolute
27 ethanol (250 ml.)-36N sulfuric acid (2 ml.) is catalytically
28 hydrogenated over 5% palladium on carbon (500 mg.) in a Parr -~
29 apparatus. After one hour, the reaction mixture is filtered~
- 48 -
..
:
15582 IA ~
~63~'~5
1 then concentrated in vacuo to a 50 ml. volume. Water
. - - - . . .
2 (200 ml.) is added to precipitate the et;hyl ester which is
3 hydrolyzed by refluxing in ethanol ~200 ml.)~ 10N soaium
4 hydroxide solution (4.5 ml., 0.045 mole) and water (100 ml.)
for 1.5 hours. The reaction mixture is cooled, concentrated ~ -
6 to 1/3 its volume, filtered, then neutralized with 6N hydro-
;7 chloric acid to precipitate 1.09 g. of [1-oxo-2-(4-amino- ;
8 phenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid
9 which melts at 235-236C. dec.
10Elemental analysis for C18H15C12NO4:
11Calc.: C, 56.86; H~ 3.98; N, 3.68;
12Found: C, 56.46; H, 4.04; N, 3.62.
13EXAMPLE 19
14 Preparation of 5-(1-Oxo-2-methyl-2-phenyl-6,7-dichloro-5-
indanyloxymethyl)tetrazole
_ _ ............ ..... .
16Step A: ~l-Oxo-2-methyl-2-phenyl-6,7-dichloro-5-
17indanyloxy)acetonitrile _
182-MethyI-2-phenyl-5-hydroxy-6,7-dichloro-1-
19 indanone (4.61 g., 0.015 mole), chloroacetonitrile (1.13 g.,
200.015 mole), potassium carbonate (2,08 g., 0.015 mole), ;
21 potassium iodide (0.25 g., 0.0015 mole) and acetone (75 ml.)
22 are heated at reflux ~or 23 hours. The reaction mixture is
23 cooled to 25C. and concentrated to dryness ln vacuo to
24 give an oily residue which on trituration with water gives
5.12 g. of (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyl-
26 oxy)acetonitrile which melts at 163-165C. on crystallization
27 from cyclohexane:benzene, 5~
28Elemental analysis for C18H13C12NO2
29Calc.: C, 62.45; ~, 3.78; N, 4.05;
30Found: C, 63.06; H, 4.03; N, 4.03.
- 49 -
: .
?~a;~
15582 I
~L~63~ZS `:~ ~
1 Step B: 5-(1-Oxo-2-methyl-2-phenyl-6,7-dichloro-
2 5-indanylox~methyl)tetxazole _
3 (1-Oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyl- ~-~
4 oxy)acetonitrile (4.87 g., 0.014 mole), sodium az~de (1.09 g.,
0~0168 mole), ammonium chloride (0.90 g., 0.0168 mole) and
,~ ,. .
6 dimethylformamide (30 ml.) are heated at 80C. for 2-1/2 hrs.
7 The reaction mixture is poured into water (500 ml.), the
8 solution filtered and acidified wi th 6N hydrochloric acid to
.. ..... ..
9 precipitate 2.60 g. of 5-(1-oxo-2-methyl-2-phenyl-6,7-di-
chloro-5-indanyloxymethyl)tetrazole which melts at 227-229C.
11 after crystallization from ethanol.
12 Elemental analysis for C18H14C12N4O2:
13 Calc.: C, 55.54; M, 3.63; N, 14.39;
14 Found: C, 55.29; H, 3.90; N, 14.40,
EXAMPLE 20 -
16 Preparation of [l-Oxo-2-(4-bromophenyl)-2-methyl-6,7-dichloro-
17 5-indan~loxy]acetic acid _
18 Step A: 2,3-Dichloro-4-(4=bromophenyl)acety~nisole
19 To a stirred mixture of 2,3-dichloroanisole (73.5 g.,
0~414 mole), 4-bromophenylacetyl chloride ~105 g., 0.456 mole)
21 and carbon disulfide (300 ml.) is added portionwise aluminum
22 chloride (60.9 g., 0.456 mole) with cooling at 0-5C. The
23 reaction mixture is left at 25C. for 17 hours, then flushed
24 with nitrogen, and the solid residue treated with crushed
ice and 12N hydrochloric aGid (80 ml.) to give 147.7 g. of
26 2,3-dichloro-4-(4-bromophenyl~acetylanisole which melts at
27 163-164.5C. after crystallization from benzene:hexane, 1:1.
28 Elemental analysis for C15HllBrC12O2
29 Calc~: C, 48.16; H, 2.96;
30 Found: C, 48.38; H, 3.10.
- 50 -
.. : . , ,, . :
. .
15582 IA~
~31;2 5
1Step B 2',3l-Dichloro-4'-methoxy-2-(4-bromo-
2~henyl)acrylophenone
3To a suspension of 2,3-dichloro-4-(4-bromophenyl)-
4 acetyl anisole (142.5 g., 0.38 mole) in bis-dimethylamino-
methane (325 ml.) under nitrogen is added dropwise acetic
6 anhydride (325 ml.) with cooling to maintain the reaction
7 mixture temperature below 40C. The reaction mixture is
8 stirred at 25C. for one hour, then poured into crushed
9 ice-wat~r (4 1.) to precipitate 143 g. of 2',3'-aichloro-
4'-methoxy-2-(4-bromophenyl)acrylophenone which melts at
11110-116C. after crystallization from benzene:hexane, 1:5. ~;
12Elemental analysis for C16HllBr~12O2:
13Calc.: C~ 49.78; H, 2.87;
14Found: C, 49.73; H, 2.88.
15Step C: 2-(4-Bromophenyl)-5-methoxy-6,7-dichloro-
16l-indanone
; ~ :
172~,3'-Dichloro-4'-methoxy-2-(4-bromophenyl3acrylo-
18 phenone (143 g., 0.37 mole) dissolved in dichloromethane
19 (2 1.) is drizzled into cold 36N sulfuric acid (1 1.)-di-
chloromethane (1 1.) in an ice bath over 4 hours. After
21 stirring for an additional half hour, the reaction mixture is
22 slowly added to crushed ice, the dichloromethane layer
23 separated, washed with saturated salt solution, concentrated
24 in vacuo to give 134.8 g. of 2-(4-bromophenyl)-5-methoxy-
6,7-dichloro-1-indanone which melts at 202-203C. after tri-
26 turation with water followed by cxystallization rom benzene:
27 hexane, 1
28 Elemental analysis for C16HllBrC12O2:
29 Calc.: C, 49.78; H, 2,87;
Found: C, 50,46; H, 3.07.
- 51 -
- , . ~ . .
15582 IA
~ i31~5
, ,
1Step D: 2-(4-Bromophenyl)-2-methyl-5-methoxy-
26,7-dichloro-1-indanone
3Sodium methoxide (28.4 g., 0.522 mole) is added
4 to a stirred mixture of 2-(4-bromopheny1)-5-methoxy-6,7-
dichloro-l-indanone (134.6 g., 0.348 moLe), iodomethane
6 (217 ml., 3.48 mole), dry benzene (1700 ml.) and dry dimethyl~
7 formamide (1700 ml.) under nitrogen in an ice-water bathO `;~
8 The reaction mixture is left to come to ambient temperature
9 over 2 hours, then poured into water (8 1.) to precipitate
92.2 g. of 2-(4-bromophenyl) 2-methyl-5-methoxy-6,7~dichloro-
11 l-indanone, m.p. 200-203C., which is not soluble in the
12 benzene present.
13Elemental analysis for C17H13BrC12O2
14Calc.: C, 51.03; H, 3.28;
15Found: C, 50.71; H, 3.24.
165tep E: 2-(4-Bromophenyl)-2-methyl-5-hydroxy-
176,7-dichloro-1-indanone
.
18A stirred mixture of 2~(4-bromophenyl)-2-methyl-
19 5-methoxy-6,7-dichloro-1-indanone (5.0 g., 0.0125 mole) and
20pyridine hydrochloride (50 y.) is heated a-t 185C. for one ~`~
21 hour, then poured into crushed ice-water (500 ml.). rrhe
22 2-(4-bromophenyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone
23 which separates (~.68 g.) melts at 221-223C. after
24 crystallization from ethanol.
25Elemental analysis for C16HllBrC12O2:
26Calc.: C, 49,78; H, 2~87;
27Found: C, 49.18; H, 2.87.
- 52 -
.. , . ~
~ ~ 15582 Ii
3~.~5
1Step F: [l-Oxo-2-(4-bromophenyl)-2-methyl-
26,7-dichloro-5~indanyloxy3acetic acid `-
3A stirred mixture of 2-(4-bromophenyl)-2-methyl- ~-
4 5-hydroxy-6,7-dichloro-1-indanone (4.48 g., 0.0116 mole),
potassium carbonate (3.88 g., 0.0232 mole) and ethyl bromo~
6aceta~e (3.21 g., 0.0232 mole) in dimethylformamide (100 ml.~ ~ ;
7 is warmed at 55-60C. for 3 houxs, then treated with water
8 (100 ml.)-lON sodium hydroxide solution (5 ml~, 0.05 mole~
9 and heated at 100C. for 2 hours. The reaction mixture is ~ ~
10 added slowly to crushed ice-water (1500 ml.)-12N hydro- ;
11 chloric acid (50 ml.) to precipitate 3.24 g. of [1-oxo-2-
12 (4-bromophenyl)-2-methyl-6,7-dichloro-5-indanyloxy~acetic
13 acid which melts at 171-172C. after crystallization from
14 nitromethane fGllowed by acetic acid: water, 3:2.
15Elemental analysis for C18H13BrC12O4:
16Calc- C, 48.68; H, 2.95; ;~
17Found: C, 48.64; H, 2.93.
18EXAMPLE 21 ~ -
19Preparation of [l-Oxo-2-(4-cyanophenyl)-2-methyl-6,7-di- ;~
chloro-5-indanYloxy}acetic acid
21Step A: 2-(4-Cyanophenyl)-2-methyl-5-methoxy-
~26 7-dichloro-1-indanone
232-(4-Bromophenyl)-2-methyl-5-methoxy-6,7-dichloro-
24l-indanone (8.00 g., 0.02 mole), cuprous cyanide (3.94 g., ;~
0.04 mole) and dimethylformamide (100 ml. ) are heated at
26 reflux for 8 hours, added to warm sodium cyanide solution
27 (3 g. in 400 ml. water), extracted with benzene, the benzene
28 solution dried over anhydrous magnesium sul~ate, then
29 concentrated in vacuo to give an oily residue. Chromato-
graphing with chloroform on silica gel gives 1.13 g. of
- 53 -
.. , ., , ,., ~. .
,~ J~` 11582 IA
;
~i3:~25
1 2-(4-cyanophenyl)-2-methyl-5-methoxy-6,7-dichloro-1
2 indanone melting at 161-163C. a~ter crystallization from
3 benzene:hexane, 2
4 Elemental analysis for C18H13cl2No2;
Calc.: C, 62.45; H, 3.78; N, 4.05;
6 Found: C, 61.37; H, 3~68; N, 3.73.
7 Step B: 2-(4-Cyanophenyl)-2-methyl-5-hydroxy-
8 6,7-dichloro-1-indanone ~ -
9 A stirred mixture of 2-(4-cyanophenyl)-2-methyl-
5-methoxy-6,7-dichloro-1-indanone (2.08 g., 0.006 mole) and
11 pyridine hydrochloride (20 g.) is hea-ted at 185C. for
12 2 hours, then poured into ice-water (300 ml.). The 2-(4-
13 cyanophenyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone
14 which separates (1.89 g.) melts at 189-196C. and is used
without further purification.
16 Ste~ C~ Oxo-2-(4-cyanophenyl)-2-methyl~
17 6,7-dichloro-5-indan~loxv]acetic acid
.. ._.................. . ~:
18 A stirred mixture of 2-(4-cyanophenyl)-2-methyl~
19 5-hydroxy-6,7-dichloro-1-indanone (1.8 g., 0.0054 mole),
pokassium carbonate (1.5 g., 0.0109 mole) and ethyl bromo-
21 acetate (1.8 g., 0.0109 mole) in dimethylformamide (60 ml.)
22 is warmed at 55 60C. for 3 hours, then treated with water
23 (60 ml.)-lON sodium hydroxide solution (3 ml., 0.03 mole)
24 and heated at 100C. for 1.5 hours~ The reaction mixture
is added slowly to ice-water (300 ml.)-12N hydrochloric
26 acid (5 ml.) to precipitate 160 mg. of [1-oxo-2-(4-cyano-
27 phenyl)~2-methyl-6,7-dichloro-5-indanyloxy]acetic acid .
28 which melts atl84-5C. after crystallization from acetic ~-~
29 acid: water, 1~
Elemental analysis for C19H13C12N04 H2 ~ ;
31 Calc.: C, 55.90: ~I, 3.70; N, 3.43;
32 Found: C, 55.77; H, 3.53; N, 4.00.
32
- 54 -
~ 15582 IA
~31~5 ~::
1 EX~MPLE 22
2 Preparation of [l-Oxo-2-methyl-2-(4-sulfamoylphenyl)-6,7-
3 dichloro-5-indanyloxy]acetic acid _ _
4 Step A: [l-Oxo-2-(4-chlorosulfonylphenyl)-2-methyl-
6,7-dichloro-5-indanyloxy}acetic acid
6 (1-Oxo-2-methyl-2-phenyl-6,7-dichloxo-5-indanyloxy)-
7 acetic acid (0.50 g., 0.0014 mole) ~ added portionwise with
8 stirring to chlorosulfonic acid (5 ml.) in an ice-water bath.
9 The reaction mixture is stirred at 0C. for 2 hours, left to
come to ambient temperature for 2 hours, then slowly added to
11 crushed ice to precipitate 0.51 g. of ~1-oxo-2-(4-chloro- ` -
12 sulfonylphenyl)-2-methyl-6,7-Aichloro-S-indanyloxy]acetic acid
13 ~hich melts at 209-210C. after crystallization from acetic
14 acid:water, 3:2.
15Elemental analysis for C18H13C13O4S:
16Calc.: C, 46.62; ~I, 2.83; Cl, 22.94;
17Found: C, 46.67; II, 2.79; Cl, 22.59.
18Step B: [1 Oxo-2-methyl-2-(4-sulfamoylphenyl)- -
196,7-dichloxo-5 indanyloxy]acetic acld
20[1-Oxo-2-(4-chlorosulfonylphenyl)-2-methyl-6,7-di-
21 chloro-5-indanylxoy]acetic acid (2.0 g., 0.0043 mole) is
22 added portionwise to liquid ammonia with stirring. The
23 ammonia is left to evaporate (3 hours). The residue is
24 dissolved in water (400 ml.), filtered, and acidified with
25 12N hydrochloric acid to precipitate 78~ mg~ of ~1-oxo-2- ~ ;
26 methyl-2-(4-sul~amoylphenylj-6,7-dichloro-5~indanyloxy]~
27 acetic acid which melts at 258-260C. after crystallization
. . ,
28 from acetic acid.
29Elemental analysis for C18H15C12NO6S-1/4 CH3CO2H:
30Calc.: C~ 48.38; H, 3.51; N, 3.05;
31Found: C, 48.15; H, 3.52; N, 2.86. ;~ ~
~ ~.
- 55 -
~ ~ 15582 IA ;
i3125
1 EXAMPLE 23
2 Process for preparing (l-Oxo-2-met}lyl-2-phenyl-6,7-di-
3 chloro=5-indanylox~acetic acid (See British Pat. 1,328,528)
, . ~, - :
4 A mixture of l-(l-oxo~2-methyl-2-phenyl-6,7-di-
chloro-5-indanyloxy)-2-nitroethane (3 g~) and 6N hydro-
6 chloric acid (100 ml.) is refluxed for 16 hours, cooled and
7 extracted with ether. The ether layer is washed with wa~er ~ `
8 and extracted with dilute aqueous sodium bicarbonate which
9 upon acidification affords 2.~ g. of (1-oxo-2-methyl-2- ~ -
phenyl-6,7-dichloro-5-indanyloxy)acetic acid whi~h melts
11 at 168-169C.
'`'' '' '
12 EXAMPLE 24
13 Process ~or preparing (l-oxo-2-methyl-2-phenyl-6,7-dichloro-
14 5-indanyloxy)acetic acid _
To a suspension of sodium hydride (0.24 g., 0.01
16 mole) in 1,2-dime~hoxyethane (10 ml.) is added a solution of -~
17 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone (3.07 g.,
18 0.01 mole) in 1,2-dimethoxyethane (10 ml.) over a 15 minute
19 period. When the evolution of hydrogen ceases diethyl-2-
20 bromomalonate (2.39 g., 0.01 mole) is added and the mixture ~-
21 is refluxed ~or 1 hour. The solvent is distilled at reduced
22 pressure. The residual diethyl-2-(1-oxo-2-methyl-2-phenyl-
23 6,7-dichloro-5-indanyloxy)malonate is dissolved in ethanol
24 (50 ml.) then water (50 ml.) and sodium bicarbonate (2.5 g.)
are added and the mixture is re~luxed for four hours, cooled,
26 acidified, extracted with ether, washed with water, and dried
27 over magnesium sulfate.
28 The ether is evaporated at reduced pressure to
29 give crude 2-(1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyl-
oxy)-malonic acid which is heated at 150C. until evolution
- 56 -
.- - , . . .
~ ~ 15582 IA
3~;~5
1 of carbon dio~ide ceases affording (1-oxo-2-methyl-2-
2 phenyl-6,7-dichloro-5-indanyloxy~acetic acid which melts
3 at 168-169C. after recrystallization from nitromethane.
.
4 EXAMP E 25
Process for preparing (l-oxo-~-methyl-2-phenyl-6,7-dichloro-
6 5-indanYloxy)acetic acid
.
7 A mixture of (l-oxo-2-methyl-2-phenyl-6,7-dichloro-
8 5-indanyloxy)acetonitrile (3.0 g.), Example 19, Step A,
9 acetic acid (20 ml.), water (5 ml.) and concentrated sulfuric
acid (5 ml.) is refluxed for 2 hours then poured into ice-
11 water (100 ml.) affording 2.5 g. of (1-oxo-2-methyl~2-phenyl-
12 6,7-dichloro-5-indanyloxy)acetic acid which melts at 168-16
13 after recrystallization Erom acetic acid.
14
EXAMPLE 26
16 (1,2-Dichloro-5a~5,6~7,8,8a-hexahydro-8a-phenyl-9-oxofluoren-
17 3-yloxy)acetic acid
. .
18 Step A: Cyclohexyl (2,3-dichloro-4-methoxy-
19 phen~l) ketone
A stirred mixture of 2,3-dichloroanisole (88.5 g.,
21 0.5 mole) and cyclohexanecarbonyl chloride (81 g., 0.55 mole)
22 in methylene chloride (400 ml.) is cooled to 5C. and treat~
23 with aluminum chloride (74 gv, 0.55 mole) during a 1/2 hour
24 period. The reaction is allowed to warm to 25C. and after
16 hours is poured in~o ice-water (1 1.) and hydrochloric
26 acid (200 ml.). The organic phase is washed with 10% sodium
27 hydroxide and saturated salt solution, and dried over
28 magnesium sulfate. After evaporation of the solvent, the
29 product is crystallized from hexane to give 42.3 gO of
cyclohexyl (2,3-dichloro-4-methoxyphenyl) ketone which meltS
31 at 97-98C.
- 57 -
~.^ . . .
~ ~ 15582 IA
,
~L~i631;~5
1Elemental analysis for C14H16C12O
2Calc.: C, 58.55; H, 5.62;
3Found: C, 58.92; H, 5.64.
4Step B: l-Bromocyclohexyl(2,3-dichloro~4-
5methoxyphenyl) ketone
~, ~
6Bromine (22.4 g., 0.14 mole) in acetic acid (50mL)
7 is added dropwise to a stirred solution of cyclohexyl-(2,3-
8 dichloro-4-methoxyphenyl) ketone (40 g.~ 0.14 mole) and 30%
9 hydrobromic acid (0.5 ml.) in acetic acid (400 ml.) during a ~-
one and one half hour period at 25C. The mixture is pouxed
11 into water (1.5 l.j and sodium bisulfite (10 g.). The product
12 which precipitates is crys~allized from cyclohexane to give
13 47.3 g. of 1-bromocyclohexyl(2,3-dichloro-4-methoxyphenyl)
14 ketone which melts at 94-95C.
15Elemental analysis for C14H15BrC12O2: ~-
16Calc.: C, 45.93; Hr 4.13; `
17Found: C, 45.77; H, 4.11.
18Step C: l-Cyclohexenyl(2,3-dichloro-4-methoxy-
19phenvl) ketone
20l-Bromocyclohexyl (2,3-dichloro-4-methoxyphenyl)
21 ketone (47.3 g., 0.13 mole), lithium chloride (16.5 g.,
220.39 mole) and dimethylformamide (200 ml.) are heated at ;
23 90C. for two hours, then poured into water (1 1.) to give
24 36.5 g. of l-cyclohexenyl (2,3-dichloro-4-methoxyphenyl)
ketone which melts at 125-129C. after drying at 60C.
26 under vacuum for 16 hours. ~ ;
27Elemental analysis for C14H14C12O2:
28 Calc.: C, 58.96; H, 4.95;
29 Found: C, 58.87; EI, 5.10.
~ .
:' '
58 -
,
:'' ' ' ` ', ' ' : ', ', . . , ~,
~ 15582 IA
~3~
1 Step D: la~l~2~3~4~4a-~Iexahydro-6-methoxy-7~8
2 dichlorofluoren-9-one
3 A stirred mixture of l-cyclohlexenyl (2,3-dichloro-
4 4-methoxyphenyl) ketone t34 g., 0.12 mole) and polyphosphoric
acid (340 g.) is heated at 90C. for 17 hours in a resin pot.
6 Crushed ice (1 kg.~ is added to precipitate the product
7 which on crystallization from benzene:cyclohexane, 1:1,
8 gives 18.4 g. of la,l,2,3,4,4a-hexahydro-6-methoxy-7~8-
9 dichlorofluoren-9-one which melts at 169-171C.
Elemental analysis for C14H14C12O2:
11 Calc.: C, 58.96; H, 4.95;
12 Found: C, 59.35; H, 5.43.
13 Step E: la-phenyl-la~l/2,3,4,4a-hexahydro-67
14 methoxy-7,8-dichlorofluor~n-9-one
Potassium tert-bu-toxide (1.69 g., 0.015 mole) in
16 tert-butanol (40 ml.) is added to a refluxing solution of
17 la,l,2,3,4,4a-hexahydro-6-methoxy-7,8-dichloro-fluoren-9-
18 one (2.85 g., 0.01 mole) in dry benzene (50 ml.) tert-;~
19 butanol (10 ml.) under nitrogen and refluxing is continued
for 0.5 hours. The reaction mixture is cooled to 25C.,
21 diphenyliodonium chloride (4.75 g., 0.015 mole) is added
22 and refluxing is continued ~or 2 hours. The reaction
23 mixture is cooled to 25C., 50 ml. water added, and the
24 mixture concentrated to dryness in vacuo to give 3.0 g. of
25 la-phenyl-la,1,2,3,4,4a-hexahydro-6-methoxy-7,8-dichloro- -
26 fluoren-9-one which melts at 136-142C. and is used with-
27 out further purification.
~ 59 -
~ 15582 IA
3125
1 Step F: la-Phenyl-l a,1,2,3/4~4~-hexahydro-6-
2-~-~~ hydroxy-7,8-dichlorofluoren-9-one
- :
3A stirred mixture of la-phenyl-la,1,2,3,4,4a-
4 hexahydro-6-methoxy-7,8-dichlorofluoren-9-one (3.0 g.,
0.0083 mole) and pyridine hydrochloride (30 g.) is heated
6 at 180C. for 2 hours, then poured into water (800 ml.).
7The la-phenyl-la~,2,3,4,4a-hexahydro-6-hydroxy-7,8- ;
8 dichlorofluoren-9-one which separates (1.71 g.) melts at
9 213-215C. after crystallization from absolute ethanol.
10Elemental analysis for ClgH16C1202:
11Calc.: C, 65.72; H, 4.64;
12Found: C, 66.27; H, 4.78.
13Step G: (1,2-Dichloro-5a,5,6,7,8,8a-hexahydro-
148a-phenyl-9-oxo-fluoren-3-yloxy)acetic
acid
,
16A stirred mixture of la-phenyl-la-1,2,3,4,4a- ;
17 hexahydro-6-hydroxy-7,8-dichlorofluoren-9-one (1.7 g.~
18 0.0049 mole), potassium carbonate (1.36 g., 0.0098 mole)
19 and ethyl bromoacetate (1.64 g., 0.0098 mole) in dimethyl-
form~mide ~50 ml.) is warmed at 55-60C. for 3 hours,
21 then treated with water (50 ml.)-lON sodium hydroxide
22 solution (2.5 ml., 0.025 mole) and heated at 80C. for '!'~
23 1.5 hours. The reaction mixture is added slowly to water
24 (500 ml.)-12N hydrochloric acid (10 ml.) to precipitate
1.51 g. of (1,2-dichloro-5a,5,6,7,8,8a-hexahydro-8a-phenyl-
26 9-oxo-fluoren-3-yloxy)acetic acid which melts at 194-196C. -
27 after crystallization from acetic acid: water, 1
28Elemental analysis for C21H18C1204
29 Calc.: C, 62.24; H, 4.48;
Found- C, 62.27; H, 4.56.
'.',`~:'" '' ''
'
- 60 - ~ -
:. . . .. . . .
~ 15582 IA
~................................................................ .
~3~25 ; ~
1 EXAM LE 27
2 Preparation of (l-oxo-2-methyl-2-phenyl-6,7-dichloro-
3 5-indanYloxv)acetic acid
.~ ,.
4Step A: Tert-butyl (l-oxo-2-methyl 2-phenyl-
56,7-dichloro-5-indanylox~)acetate
6A mixture of 2-methyl-2-phenyl-5-hydroxy-6,7-
7 dichloro-1-indanone (9.2 g., 0.03 mole), potassium carbonate
8 (8029 g., 0.06 mole) and tert-butyl bromoacetate (6.44 g~
9 0.033 mole) in dimethylformamide (30 ml.) is stirred at
25C. for two hours. The reaction mixture is poured into
11 cold water (150 ml.) and the tert-butyl (1-oxo-2-methyl-
12 2-phenyl-6,7-dichloro-5-indanyloxy)acetate which separates
13 is filtered, rinsed with water and dried~
14 Step B: (1-Oxo-2-methyl-2-phenyl-6,7-dichloro-
5-indan~loxy)acetic acid
16 A solution of tert-butyl (l-oxo-2-methyl-2-phenyl-
17 6,7-dichloro-5-indanyloxy)acetate (1.0 g., 0.00237 mole) in
18 benzene (25 ml.) is treated with methanesulfonic acid
19 ~2 drops) and refluxed for 1/2 hour. The reaction mixture
is treated with cyclohexane (20 ml.) and cooled affording
21 (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic
22 acid which is filtered and dried.
23 EXAMPLE ?8 ~
24 Preparation of [l-Oxo-2-methyl-2-(2-thienyl)-6,7-dichloro- `
5-indanvloxv]acetic acid
26 Step A: 2,2'-Dithienyl iodonium chloride
27 To acetic anhydride (70 ml.) at -20C. there is
28 added dropwise with stirring fuming nitric acid (27 ml.),
29 then iodine (25 g., 0.1 mole) and trifluoroacetic acid
(47 ml., 0.61 mole). The mixture is left to warm to ambient
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. ~ . .
. .
~ ~ 155S2 IA
1~3~25 ~ ~
1 temperature while the iodine dissolves over 3 hours. The
2 sol~ent is removed by distillation in vacuo, the pot temper
3 ature never exceeding 50C. The residue is dissolved in
4 acetic anhydride (150 ml.), the solution cooled to -10C. ;
and a mixture of thiophene (63 ml., 0.08 mole), acetic
6 anhydride (350 ml.) and trifluoroacetic acid (50 ml.) is ~
7 added dropwise in one hour. After cooling at 5C. for ;
8 17 hours, the mixture is distilled in vacuo, the pot temper- -
9 ature never exceeding 50C. Water (500 ml.) is added to the
residue, the solution filtered and ammonium chloride (21.36 ~, -
11 0.4 mole) in water (100 ml.) added to precipitate 26.6 g. of
12 2,2'-dithienyl iodonium chloride which melt~ at 235-236C.
13 after crystallization from methanol.
14 Elemental analysis for C8H6ClIS2:
Calc.: C, 29.24; ~, 1.84;
16 Found: C, 28.90; H, lr92.
17 Step B: 2-Methyl-2-(2-thienyl)-5-methoxy-6,7-
18 dichloro-l-indanone
19 Potassium tert-butoxide (5.06 g., 0.045 mole)
20 dissolved in tert-butanol tl ml.) is added to a refluxing ii ;
21 solution of 2-methyl-5-methoxy-6,7-dichloro-1-indanone
22 prepared by the method described in Example 5, Steps A to D,
23 (7.35 g., 0.03 mole) in tert-butanol (150 ml.)-benzene
24 (150 ml.)~ refluxing is con~inued for 3 hours under nitrogen,
then the mixture is cooled slightly and solid dithienyl-
26 iodonium chloride (16 r5 g~, 0.05 mole) is added in one portio~
27 ~eating at reflux is continued for 2 hours. The reaction
28 mixture is cooled to 25C., 100 ml. water added, and the
29 mixture concentrated to dryness in vacuo to give 3.85 g. of
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; - . , - . . . .. . . .
,~ f~ 15582 IA ~
1 2-methyl-2-~2-thienyl)-5-methoxy-6~7-dichloro-1-indanone
2 which melts at 145-146.5C. after trituration with ether
3 and crystallization from benzene:hexane, 1:4.
4Elemental analysis for C15H12lC1202S:
5Calc.: C, 55.06; H, 3.70;
6Found: C, 55.24; H, 3.77.
7Step C: 2-Methyl-2-(2-thienyl)-5~hydroxy-6,7-
8 dichloro-l-indanone
9A stirred mixture of 2-methyl-2-~2-thienyl)-
5-methoxy-6,7-dichloro-1-indanone (3.65 g., 0.0112 mole)
11 and pyridine hydrochloride (36 g.) is heated at 175C.
12 for one-half hour, then poured into crushed ice-water
13 (500 ml.). The 2-methyl-2-(2-thienyl)-5-hyclroxy-6,7-
14 dichloro-l-indanone which Reparates (3.37 g.) melts at
224-226C. after crystallization from ethanol: water, 2:1.
16Elemental analysis for C14HloC1202S:
17Calc.: C, 53.69; H, 3.22;
18Found: C, 53.27; El, 3.36. ~ -
19Step D: ~l-Oxo-2-methyl-2-(2-thienyl)-6,7-
20dichloro~5-indany-oxy]acetic acid ~ ;
21~ stirred mixture of 2-methyl-2-(2-thienyl-5-
22 hydroxy-6,7-dichloro-1-indanone (3.13 g., 0.01 mole), potas-
23 sium carbonate (2.77 g.~ 0.02 mole) and ethyl bromoacetate
24 (3.34 g., 0.02 mole) in dimethylformamide (40 ml.) is warmed
at 55-60C. for 2 hours, then treated with water (40 ml.)
26 -lON soaium hydroxide solution (4 ml., 0~04 mole) and heated ;~
27 at 100C. for one hour. The reaction mixture is added slowly
28 to crushed ice-water (700 ml.)-12N hydrochloric acid (10 ml.)
29 to precipitate 1.78 g. of [1-oxo-2-methyl-2-(2-thienyl)-
6,7-dichloro-5-indanyloxy]acetic acid which melts at 161-
31 162Cr after crystallization from nitromethane.
~ 63 ~
~ ~ 15582 IA
~631;Z~
1 Elemental analysis ~or C16H12C12O4S: ~?
2 Calc.: ~, 51.78; H, 3.24; Cl, 19.10;
3 Found: C, 51.66; H~ 3.34; Cl, 19.21.
EXAMPLE 29
.
5Where in Example 5, Step A, there is substituted
6 ~or the 2,3-dichloroanisole an equivalent amount o~ 2-
7 chloro-3-methylanisole, 2,3-dimethylanisole, 3-methyl~
8 anisole, or 2-methyl-3-chloroanisole, respectively, and
9 Steps B ~hrough D in Example 5 and Steps ~ through D in ~;
Example 28 are employed as described, there is obtained~
11[1-oxo-2-(2-thienyl)-2,7-dimethyl-6-chloro~
125-indanyloxy]acekic acid;
13[1-oxo-2-(2-thienyl)-2,6,7-trimethyl-5-
14indanyloxy]acetic acid;
15[1-oxo-2-(2-thienyl)-2,7-dimethyl-5
16indanyloxy]acetic acid;
17[1-oxo-2-(2-thienyl)-2,6-dimethyl-7-chloro-
185-indanyloxy]acetic acid.
19 EXAMPLE 30
.: . . ,
20Where in Example 28, Step A, there is substituted
21 for the thiophene an equivalent amount o~ 2-methylthiophene,
22 2-bromothiophene, 2-chlorothiophene, or 2,5-dimethylthio~
23 phene, respectively, and Steps ~ through D are employed as -~
24 described, there is obtained~
25[1-oxo-2-methyl-2-(5-methyl-2-thienyl)-6,7-
26dichloro-5-indanyloxy]acetic acid; ~-~
27[1-oxo-2-methyl-2-(5-bromo-2-thienyl)-6,7
28dichloro-5-indanyloxy]acetic acid;
29[1-oxo-2-methyl-2-(5-chloro-2-thienyl)-6,7- ~;
30dichloro-5-indanyloxy]acetic acid; -~`
31[1-oxo-2-methyl-2-(2,5-dimethyl-3-thienyl)-
326,7-dichloro-5-indanyloxy]acetic ac:id.
~.
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~ ~ 15582 I~
i3~25 ~:
1 EXAMPLE 31 ~;
2 Preparation of ~l-Oxo-2-(4-aminomethylphenyl)-2-methyl-
3 6,7-dichloro-5-indanyloxy]aceti~ acid
. _ _
4 Step A: ~l-Oxo-2-[4-(2-chloroacetamidomethyl)-
phenyl~-2-methyl-6,7-dichloro-5-indanyl-
6 ~
7 Well-pulverized N-hydroxymethyl-2-chloroacet~mide ~ ;
8 (3.37 g., 0.0274 mole) is added portionwise -to (1-oxo-2-
9 methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid
10 (10.0 g., 0.0274 mole) in 36N sulfuric acid (100 ml.) and ~
11 acetic acid (100 ml.) with stirring at 40-50C. over one- ` ;
12 half hour. Additional N-hydroxymethyl-2-chloroacetamide
13 (1.68 g., 0.014 mole) is added over a four hour period until
14 no starting material remains. A~ter stirring at 25C. for
16 hours the reaction mixture is added to crushed ice-water
16 (2 1.) to precipitate ll.9g. of ~1-oxo-2-[4-(2-chloroacet~
17 amidomethyl)phenyl]-2-methyl-6,7-dichloro-5-indanyloxy~-
18 acetic acid which melts at 138-141C. and is used in the
19 next step ~ithout purification.
Step B: Ethyl[l-oxo-2-~4-aminomethylphenyl)-2-
21 methyl-6,7-dichloro-5-indanyloxy]acetate
22 hydrochloride
.,.. ~
23 ~1-Oxo-2-[4-(2-chloroacetamidomethyl)phenyl~-2-
24 methyl-6,7-dichloro-5-indanyloxy~acetic acid (2.0 g., 0.004
25 mole), absolute ethanol (20 ml.) and 12N hydrochloric acid ~ -;
26 (q ml.) are combined and heated at reflux for 3 hours. On
27 cooling to 5C. 1.14 g. of ethyl~l-oxo-2-(4-aminomethyl- `~
28 phenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetate hydro- `~
29 chloride precipitates and melts at 211-213C. after crystal-
lization from ethanol.
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~ ~ 155~2 IA
.
.
1~6;3~25
1Elemental Analysis for C21H21C12NO4-Hcl:
2Calc.: C, 54.98; H, 4.83; N, 3.05;
3Found: C, 54.39; II, 4.72; N, 2.76.
4 Step C: [l-Oxo-2-(4-aminomethylphenyl)-2-me-thyl-
S 6,7-dichloro-5-indan~yloxy]acetic acid
6 sodium salt
7 Ethyl [l-oxo-Z-(4-aminomethylphenyl)-2-methyl~
8 6,7-dichloro-5-indanyloxy]acetate hydrochloride (1.57 g.,
9 0.0034 mole), sodium bicarbonate (1.15 g., 0.0136 mole),
10 absolute ethanol (50 ml.) and water (50 ml.) are combined ~;
11 and heated at reflux for 1.5 hours leaving a solution which
12 is filtered, then neutralized with lN hydrochloric acid ~;~
13 (10.26 ml., 0.01026 mole) to precipitate 900 mg. of ;
14 [1-oxo-2-(4-aminomethylphenyl)-2-methyl-6,7-dichloro-5-
indanyloxy]acetic acid sodium salt which melts at 270-271C.
16 after drying.
17 Elemental Analysis for clgH17C12NO4Na:
18 Calc.: C, 54.83; H, 3~87; N, 3~37;
19 Found: C, 55.07; H, 4.27; N, 3.20.
EXAMPLE 32
21 Resolution of the Optical Isomers of (l-Oxo-2-methyl-
22 ~ -5-indanylox~aeetic acid
23 Step A: (~)-isomer
24 A ~ixture of raeemie (l-oxo-2-methyl-2-phenyl-
6,7-dichloro-5-indanyloxy)aeetie aeid (26 g., 0.071 mole)
26 and L~ a-methylbenzylamine (8.6 g., 0.071 mole) is `
27 dissolved in hot aeetonitrile (250 ml.) and aged at 25C.
28 for 18 hours.
29 The acetonitrile is decanted from the resultant
salt (13.2 g.) which is thrice recrystalli~ed from a minimum
31 volume of 2-propanol affording 1.9 g. o salt of the pure
32 (~) enantiomar whieh is converted to the acid by treatment
33 of the salt with dilute hydrochloric acid and ether. The
34 ether phase is washed with water, dried over magnesium
sulfate and the ether distilled at reduced pressure. The
36 (~)-isomer melts at 163C. a~ter crystallization from
37 toluene.
38 [a]25 = ~88. (C, 2, acetone)
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,,
. -
~ ~ 15582 IA
:~
1 Step B: ~-)-isomer
2 By following substantially the procedure described
3 in Step A using as the reactants partially resolved (l-oxo- ~;
4 2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid
(15.5 g., 0.042 mole; (obtained ~rom the acetonitrile mother
6 liquor of Step A) and D-(+)-a-methylbenzylamine ~5.15 g.,
7 0.042 mole, in acetonitrile (150 ml.) and thrice recrystal-
8 lizing the resultant salt from a minimum volume of 2-propan~,
9 there is obtained 2.2 g. of the salt of the pure (-)-enan-
tiomer.
11 The (-)-isomer melts at 164C a~ter crystallization
12 from toluene. `
13 ~a]2s = -88 (C, 2, acetone)
14 The novel compounds of this invention are diuretic ~-
and salure~ic agents. In addition, these compounds are also
16 able to maintain the uxic acid concentration in the blood at
17 pretreatment levels or even cause a decrease in uric acid
18 concentration.
19 The compounds of this invention can be administer-
ed in a wide variety of therapeutic dosages in conventional
21 vehicles as, for example, by oral administration in the form ~-
22 of a tablet or by intravenous injection. Also, the daily
23 dosage of the products may be varied over a wide range as,
24 for example, in the form of scored tablets containing 2.5,
1, 5, 10, 25, 50, 100, 150, 200, 250 and 500 milligrams of
26 the active ingredient for the symptomatic adjustment of the
27 dosage to the patient to be treated. These dosages are well
28 below the toxic or lethal dose of the products.
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,: . .. . : . : ;
~ 15582 IA
~i3:1Z~
1 A suitable unit dosaye form of the products of
2 this invention can be administered by mixing 50 milligrams
3 of a tl-oxo-2-aryl or 2-thienyl-2-substituted-5-indanyloxy
4 (or thio)]alkanoic acid (I) of this invlention or a suitable
; 5 salt, ester, amide derivative, 5-tetrazolyl analog thereof,
6 with 149 mg. of lactose and 1 mg. of magnesium stearate
7 and placing the mixture into a No. 1 gelatin capsule. Simi- i;
8 larly, by employing more of the active ingredient ancl less ~;
9 lactose, other dosage forms can be put up in No. 1 gelatin
; 10 capsules. Should it be necessary compressed tablets, pills, `~
11 or other desired unit dosages can be prepared to incorporate
12 the compounds of this invention by conventional methods, and, ;~
13 if desired, can be made up as elixirs or as injectable
14 solutions by methods well known to pharmacists. An efec-
tive amoun'~ of the drug is ordinarily supplied at a dosage
16 level of from about 0.025 mg. to about 20 mg./kg. of body `- 1
¦ 17 weight. Preferably the range is from about 0.06 mg. to ~ ~;
I8 7 mg./kg. of body weight.
19 It is also within the scope of this invention to
20 combine two or more of the compounds of this invention in -
21 a unit dosage form or to combine one or more of the compounds
22 of this invention with other known diuretics and saluretics ~`!'~ ,
1 23 or with other desired therapeutic and/or nutritive agents ~ ;
24 in dosage unit form. For example, the compounds of this
25 invention can be combined with anti-hypertensive compounds, ;~
26 and particularly with an iagent such as methyl-dopa or
27 reserpine. Also a combination or mixture of different
- 68 - `
~ 582 IA
~63~25
1 indanones of Formula I with each other can be advantageous
2 particularly where one compound has greater cliuretic
3 activity and the other has greater uricosuric activity.
4 The following example is includecl to illustrate
the preparation of a representative dosage form:
~,
6 EXAMPLE 33
7 Preparation of dry-filled capsules containing 10 mg. of
8 active ingredient per capsule ~`
9 Per Capsule
(1-Oxo-2-methyl-2-phenyl-6,7-
11 dichloro-5-indanyloxy)acetic acid10 mg.
12 ~actose 189 mg.
13 Magnesium stearate 1 mg.
14 Capsule (Size Mo. 1) 200 mg.
The ~l-oxo-2-methyl-2-phenyl-6,7-dichloro-5-
16 indanyloxy)acetic acid is reduced to a No. 60 powder and ~ -
17 then lactose and magnesium stearate are passed through a
18 No. 60 bolting cloth onto the powder and the combined
19 ingredients admixed for 10 minutes and then filled into a
No. 1 dry gelatin capsule.
21 Similar dry-filled capsules can be prepared by
22 replacing the active ingredient of the above example by
23 a molar equivalent amount of any of the other novel com-
24 pounds of this invention.
- 69 -
, ,~
~ ~ 15532 IA
~i3~ 5 ~
1 EXAMPLE 34
2 Parenteral Solution of Sodium ~1-oxo-2-methyl-2-phenyl-
3 6,7-dichloro-5-1ndanyloxy)acetate _ _
4 (1-Oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy]-
5 acetic acid (1 gm.) is treated with sodium bicarbonate~`~
6 (0.25 gm.) in water (10 ml.) and the mixture stirred and ;~
7 heated to effect solution. The solution is diluted with
8 water to a volume of 50 ml. and sterilized by autoclaving
9 at 120C. for one hour.
10 EXAMPLE 35 ~;
11 Dry-filled capsules containing 10 mg. of active ingredient
12 and 0~125 mg._of reserpine per capsule
13 Per ca~slle
14 (1-Oxo-2-methyl-2-phenyl-6,7-
15 dichloro-5-indanyloxy~acetic acid . . . 10 mg. ;
16 Reserpine . . . . . . . . . . . . . . . . 0.125 mg.
. . .
17 ~actose . . . . . . . . . . . . . . . . 188.875 mg.
18 Magnesium stearate . . . . . . . . . . . 1 mg. ;
19 Capsule (size No. 1) 200 mg.
The (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-
21 indanyloxy)acetic acid and reserpine are united and reduced
22 to a No. 60 powder and then lactose and magnesium stearate
23 are passed through a No. 60 bolting cloth onto the powder
24 and the combined ingredients are admixed for ten minutes
25 and then filled into a No. 1 dry gelatin capsule. ~
26 Similar dry-filled capsules can be prepared by ;
27 replacing the indanyloxyacetic acid ingredient of the
28 above example by any of the compounds of this invention.
~ ~ 15582 IA
, .
1~631ZS : ~
1 EXAMPI~ 36
2 Dry-filled capsules containing 10 mg. o:E active inyredient ~ ;~
3 and 250 mg. of levo-3-(3,4-dihydroxy~enyl) 2-methylalanine
4 Per Capsule
(1-Oxo-2-methyl-2-phenyl-6,7-
6 dichloro-5-indanyloxy)acetic acid . . . . 10 mg.
7 Levo-3-(3,4-dihydroxyphenyl)-2-
8 methylalanine . . . . . . . . . . . . . . 265 mg~
9 Lactose . . . . . . . . . . . . . . . . . . 124 mg.
Magnesium stearate . . . . . . . . . . ~ . 1 mg.
11 Capsule (size No. O) 400 mg.
12 The (l-oxo-2-methyl-2-phenyl-6,7-dichloro-5-
13 indanyloxy)acetic acid and levo-3-(3,4-dihydroxyphenyl)-2-
14 alanine are united and reduced to a No. 60 powder and then
lactose and magnesium stearate are passed through a No. 60
16 bolting cloth onto the powder and the combined ingredients
17 admixed for ten minutes and then filled into a No. O dry `
118 gelatin capsule.
. . .:
19 It will be apparent from the foregoing description
that the 1-oxo-2,2-disubstituted-5-indanyloxyalkanoic acid
21 products (I) of this invention constitute a valuable class
~.
22 of aompounds which have not been prepared heretofore. One
23 skilled in the art will also appreciate that the processes
24 disclosed in the above examples are merely illustrative and ~
25 are capable of a wide variation and modification without ~ ;
26 departing from the spirit of this invention~
,
...
. ,~
- 71 -
. : .
-~ , : . . , ' '
~ ~ 15582 I~ ~
106312~ ~
1 EX~MPI.E 37
2 Dry-filled capsules containing 50 mg. of ac~ive ingredient -~
3 per capsule `
4 Per Capsule
,; :
(1-Oxo-2-methyl-2-(2-thienyl)~
6 6,7-dichloro-5-indanyloxy)- ~ -;
7 acetic acid ~ . . . . . . . , . . . 50 mg.
8 Lactose . . . . . . . . . . . . 149 mg. i ~;
9 Magnesium Stearate . . . . . . . . . . 1 mg.
Capsule (Size No. 1)200 mg.
11 The (l-oxo-2-methyl-2-(2-thienyl)-6,7-dichloro~
. . .: , . -
12 5-indanyloxy)acetic acid is reduced to a No. 60 powder and
13 then lactose and magnesium stearate are passed through a
14 No. 60 bolting cloth onto the powder and the combined
15 ingredients admixed for 10 minutes and then filled into a ;
16 No. 1 dry gelatin capsule.
li Similar dry-filled capsules can be prepared by ;
, , ~
; 18 replacing the active ingredient of the above example by
19 a molar equivalent amount of any of the other novel com-
20 pounds of this invention. ~-
: - :
:,~ ,,
21 EXAMPLE 38
22 Parenteral Solution of sodium(1-oxo-2-methyl-2-(2-thienyl)-
23 6,7-diehloro-5-indanyloxy)acetate
~.
24 (1-Oxo-2-methyl-2-thienyl-6,7-dichloro-5-indan~
25 yloxy)acetie acid (1 gm.) is treated with sodium bicarbon- ~ ~-
26 ate (0.25 gm~) in water (10 ml.) and the mixture stirred ~ ~ -
27 and heated to effect solution. The solution is diluted with
28 water to a volume of 50 ml. and sterilized by autoe:Laving
29 at 120C. for one hourO ;~
- 72 -
A. j_ ,' ., , , ' ' ,: , . . .
15582 ~.
,. ',, ~;
~L~633L25 : :
1 EXAMPLE 39
2 Dry-filled capsules containing 25 mg. oE active ingredient ~
3 and Q.125 mg. of reserpine per capsule 7 ; ''
4 Per Capsule
(1-Oxo-2-methyl-2-(2--thienyl)~
6 6,7-dichloro-5-indanyloxy)-
~ 7 acetic acid . . . . . . . . . ~ . 25 mg.
- 8 Reserpine . .... . . . . . . . . . 0.125 mg.
9 Lactose . . . . . . . . . . . .173.875 mg.
Magnesium stearate . . . . . . . . 1 mg.
11 Capsule (size Wo. 1) 200 mg.
12 The (l-oxo-2-methyl-2-(2-thienyl)-6,7-dichloro- -
13 5-indanyloxy)acetic acid and reserpine are united and reduced
14 to a No. 60 powder and then lactose and magnesium stearate
are passed through a No. 60 bolting cloth onto the powder
16 and the combined ingredients are admixed for ten minutes
17 and then filled into a No. 1 dry gelatin capsule.
18 Similar dry-filled capsules can be prepared by
19 replacing khe indanyloxyacetis acid ingredient of the
above example by any of the compounds of this invention.
" :
21 EX~PLE 40
22 Dry-filled capsules containing 10 mg. of active ingredient
23 and 250 mg. of levo-3-(3,4-dihydroxyphenyl)-2-meth~lalanine
24 Per Capsule
tl-Oxo-2-methyl 2-(2-thienyl)-
26 6,7-dichloro-5-indanyloxy)- -;~
27 acetic acid . . . . . . . . . .10 mg. ~'
28 Levo-3-(3,4-dihydroxyphenyl)-2-
29 methylalanine . . . . . . . . . 250 mg.
Lactose . . . . . . . . . . . . . 139 mg.
31 Magnesium stearate . . . . . . . 1 mg.
32 Capsule (Size No. O) 400 mg~
- 73 - ;
... ~ , . . .. . .
~ 15582 IA
'~..' ' '
~3~Z5 ~ `
. :
1 The (l-oxo-2-methyl~-(2-thienyl)-6,7 dichloro-
2 5-indanyloxy)acetic acid and levo-3-(3,4-dihydroxyphenyl)-2-
3 alanine are united and reduced to a No. 60 powder and then
''f 4 lactose and magnesium stearate are passed through a No. 60
bolting cloth onto the powder and the combined ingredients
6 admixed for ten minutes and then filled into a No. 0 dry
7 gelatin capsule.
8 It will be apparent from the foregoing description -
9 that the [1-oxo-2,2-disubstituted-5-indanyloxy]alkanoic acid
products (I) of this invention constitute a valuable class
11 of compounds which have not been prepared heretofore. One
12 skilled in the art will also appreciate that the processes
13 disclosed in the above examples are merely illustrative and
14 are capable of a wide variation and modification without
i 15 departing from the spirit of this invention. `
. ' ' ', ' ~
.`;
.' ~
::
'
'
: :`
- 74 -
,
