CA1063125A - (1-oxo-2-aryl or thienyl-2-substituted-5-indanyloxy (or thio)) alkanoic acids and derivatives thereof and processes for preparing same - Google Patents
(1-oxo-2-aryl or thienyl-2-substituted-5-indanyloxy (or thio)) alkanoic acids and derivatives thereof and processes for preparing sameInfo
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- CA1063125A CA1063125A CA210,670A CA210670A CA1063125A CA 1063125 A CA1063125 A CA 1063125A CA 210670 A CA210670 A CA 210670A CA 1063125 A CA1063125 A CA 1063125A
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- methyl
- lower alkyl
- dichloro
- hydrogen
- oxo
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
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- C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
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- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
ABSTRACT OF THE DISCLOSURE
(1-Oxo-2-aryl or thienyl-2-substituted-5-indanyloxy (or thio)] alkanoic acid, derivatives thereof, their salts, esters and amides are disclosed. The products display a dual pharmaceutical utility in that they exhibit diuretic, saluretic and uricosuric activity. Also disclosed are processes for the preparation of such [1-oxo-2-aryl or thienyl-2-substituted-5-indanyloxy (or thio)] alkanoic acids, pharmaceutical compositions comprising therapeutically effective amounts of such compounds and methods of treat-ment comprising administering such compounds and composi-tions.
(1-Oxo-2-aryl or thienyl-2-substituted-5-indanyloxy (or thio)] alkanoic acid, derivatives thereof, their salts, esters and amides are disclosed. The products display a dual pharmaceutical utility in that they exhibit diuretic, saluretic and uricosuric activity. Also disclosed are processes for the preparation of such [1-oxo-2-aryl or thienyl-2-substituted-5-indanyloxy (or thio)] alkanoic acids, pharmaceutical compositions comprising therapeutically effective amounts of such compounds and methods of treat-ment comprising administering such compounds and composi-tions.
Description
, .~ ~
~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- -
~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 :
.
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
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
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
with a suitable 2-aryl or 2-thienyl-2-substituted-5-hydroxy- ~:
16 tor mercapto)-l-indanone (IV):
' ~
", .. , r~ ~ 15582 IA
1~631Z5 ` ~
X2 o ' .
2 ~R \~ + R OCYZ
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 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: ,~
;~' " ' - ~
~ 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 .
, .
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
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 .- .: -` 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
VII x2 O
R4 ~ R
26 wherein all substituent~ are as described above.
` 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:
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 -. ..
, . , , , .
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 -`, 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 :
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
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
with a suitable 2-aryl or 2-thienyl-2-substituted-5-hydroxy- ~:
16 tor mercapto)-l-indanone (IV):
' ~
", .. , r~ ~ 15582 IA
1~631Z5 ` ~
X2 o ' .
2 ~R \~ + R OCYZ
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 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: ,~
;~' " ' - ~
~ 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 .
, .
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
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 .- .: -` 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
VII x2 O
R4 ~ R
26 wherein all substituent~ are as described above.
` 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:
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 -. ..
, . , , , .
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 -`, 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 , . . . .
. .
~ 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 .
. .
~ 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, ~ ~ 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
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 ::
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 -, .
' '~"
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
~, - 23 - ~
15582 IA ~
, ~ 3~5 ::
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 -, .
' '~"
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 -, 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 '.
~:
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 -; ~ , ~ ~ , . . .
~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: ~-
~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 ~.
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
. . . ~ . .
: :
,~ ~ 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 ~.
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~ -
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 ~ `` ,~ .
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
,: ' : .:. . .
,,: : - , : : . . .
~ 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~, .
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
:~
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.
~,~
. .
~ 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.
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~ - ~
~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.
", ! 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.
;' ~ .
~ , ~ : : .
15582 IA ~
~L~631;Z 5 ~ :
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.
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.
:-~ ~ 15582 IA
~1~63~25 :`
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.
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
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~, .
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
:~
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.
~,~
. .
~ 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.
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~ - ~
~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.
", ! 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.
;' ~ .
~ , ~ : : .
15582 IA ~
~L~631;Z 5 ~ :
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.
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.
:-~ ~ 15582 IA
~1~63~25 :`
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.
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.
.
. .
: . . . . . .
.... .
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. ;
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 ' .: :.: : , , -,. . .. . : ..
~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 . , ', . ' ' , .~'` ' ' ' ' ! 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.
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~
. .
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 . ,~ . . . ;, .
. . . . ~ .
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.
. .
:' , , .
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 -: `
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.) :
~ 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. ~ -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 -.
~ ~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~
..
:
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.
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.
: .
?~a;~
~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, 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.
.. : . , ,, . :
. .
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.
- , . ~ . .
~ 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.
.. , . ~
~ ~ 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 .. , ., , ,., ~. .
,~ 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.
~ 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. ;~ ~
~ ~.
~ ~ 15582 IA ;
i3125 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.
'`'' '' ' 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 .- - , . . .
~ ~ 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.
.
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.
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.
~.^ . . .
~ ~ 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.
~ .
:' ' , :'' ' ' ` ', ' ' : ', ', . . , ~, ~ 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
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 ; ~
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 ~ . . .
. ~ . .
. .
~ ~ 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 ; - . , - . . . .. . . .
,~ 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.
.
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.
.: . . , 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.
~.
~ ~ 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.
~ ~ 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.
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
.
. .
: . . . . . .
.... .
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. ;
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 ' .: :.: : , , -,. . .. . : ..
~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 . , ', . ' ' , .~'` ' ' ' ' ! 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.
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~
. .
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 . ,~ . . . ;, .
. . . . ~ .
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.
. .
:' , , .
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 -: `
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.) :
~ 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. ~ -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 -.
~ ~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~
..
:
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.
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.
: .
?~a;~
~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, 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.
.. : . , ,, . :
. .
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.
- , . ~ . .
~ 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.
.. , . ~
~ ~ 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 .. , ., , ,., ~. .
,~ 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.
~ 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. ;~ ~
~ ~.
~ ~ 15582 IA ;
i3125 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.
'`'' '' ' 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 .- - , . . .
~ ~ 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.
.
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.
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.
~.^ . . .
~ ~ 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.
~ .
:' ' , :'' ' ' ` ', ' ' : ', ', . . , ~, ~ 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
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
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~3~25 ; ~
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 ~ . . .
. ~ . .
. .
~ ~ 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 ; - . , - . . . .. . . .
,~ 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.
.
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.
.: . . , 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.
~.
~ ~ 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.
~ ~ 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.
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) ,, . -~ ~ 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.
,: . .. . : . : ;
~ 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:
~, 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.
, ,~
~ ~ 15532 IA
~i3~ 5 ~
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~
, ...
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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. ~-: - :
:,~ ,, 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 ;~
A. j_ ,' ., , , ' ' ,: , . . .
15582 ~.
,. ',, ~;
~L~633L25 : :
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. `
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38 [a]25 = ~88. (C, 2, acetone) ,, . -~ ~ 15582 IA
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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.
,: . .. . : . : ;
~ 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:
~, 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.
, ,~
~ ~ 15532 IA
~i3~ 5 ~
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~
, ...
. ,~
. : .
-~ , : . . , ' ' ~ ~ 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. ~-: - :
:,~ ,, 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 ;~
A. j_ ,' ., , , ' ' ,: , . . .
15582 ~.
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~L~633L25 : :
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. `
. ' ' ', ' ~
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,
Claims (12)
1 . A process for preparing a compound of the formula:
wherein R0 is or ;
A is oxygen or sulphur;
R is lower alkyl, lower alkenyl, phenyl lower alkyl, thienyl, phenyl lower alkenyl, phenyl, cycloalkyl or cycloalkyl lower alkyl;
R1 is hydrogen, lower alkyl or aryl; or R1 and R may be joined together to form a cycloalkylene;
Y is alkylene or haloalkylene containing from 1 to about 4 carbon atoms;
X3 is hydrogen, nitro, lower alkyl, lower alkoxy, cycloalkyl, halo, amino, cyano, sulfamoyl, or methanesulfonyl;
X7 is hydrogen, lower alkyl or halogen;
X8 is hydrogen or lower alkyl;
X1 is hydrogen, halo or methyl;
X2 is halo, methyl or trihalomethyl; or X1 and X2 may be joined together to form a hydrocarbylene chain containing from 3 to about 4 carbon atoms;
which comprises:
A. treating a compound of the formula:
wherein A, R0, R, R1, X1, X2, X3, X7 and X8 are as defined above with a reagent of the formula: ZY-?-OR3, wherein Y
is as defined above, Z is halo and R3 is hydrogen or lower alkyl, in the presence of a base and hydrolyzing the resulting ester when R3 is a lower alkyl other than t-butyl or pyrolyzing the resulting ester when R3 is t-butyl; or B. alkylating a compound of the formula:
where X1, X2, R0, R1, R3 and A are as defined previously, with an alkylating agent of the formula: RZ wherein Z is halo and R is as defined above, and hydrolyzing the result-ing ester when R3 is a lower alkyl other than t-butyl or pyrolyzing the resulting ester when R3 is t-butyl.
wherein R0 is or ;
A is oxygen or sulphur;
R is lower alkyl, lower alkenyl, phenyl lower alkyl, thienyl, phenyl lower alkenyl, phenyl, cycloalkyl or cycloalkyl lower alkyl;
R1 is hydrogen, lower alkyl or aryl; or R1 and R may be joined together to form a cycloalkylene;
Y is alkylene or haloalkylene containing from 1 to about 4 carbon atoms;
X3 is hydrogen, nitro, lower alkyl, lower alkoxy, cycloalkyl, halo, amino, cyano, sulfamoyl, or methanesulfonyl;
X7 is hydrogen, lower alkyl or halogen;
X8 is hydrogen or lower alkyl;
X1 is hydrogen, halo or methyl;
X2 is halo, methyl or trihalomethyl; or X1 and X2 may be joined together to form a hydrocarbylene chain containing from 3 to about 4 carbon atoms;
which comprises:
A. treating a compound of the formula:
wherein A, R0, R, R1, X1, X2, X3, X7 and X8 are as defined above with a reagent of the formula: ZY-?-OR3, wherein Y
is as defined above, Z is halo and R3 is hydrogen or lower alkyl, in the presence of a base and hydrolyzing the resulting ester when R3 is a lower alkyl other than t-butyl or pyrolyzing the resulting ester when R3 is t-butyl; or B. alkylating a compound of the formula:
where X1, X2, R0, R1, R3 and A are as defined previously, with an alkylating agent of the formula: RZ wherein Z is halo and R is as defined above, and hydrolyzing the result-ing ester when R3 is a lower alkyl other than t-butyl or pyrolyzing the resulting ester when R3 is t-butyl.
2. A process for preparing a compound of the formula:
wherein R0 is or ;
R is lower alkyl;
X1 and X2 are selected from the group consisting of chloro and methyl;
X3 is hydrogen, nitro, lower alkyl, lower alkoxy, cycloalkyl, halo, amino, cyano, sulfamoyl, methanesulfonyl;
X7 is hydrogen, lower alkyl or halogen;
X8 is hydrogen or lower alkyl;
which comprises treating a compound of the formula:
wherein R0, R, X1, X2, X3, X7 and X8 are as above with a reagent of the formula: , wherein Z is halo and R3 is hydrogen or lower alkyl in the presence of a base and when R3 is lower alkyl, hydrolyzing the resulting ester.
wherein R0 is or ;
R is lower alkyl;
X1 and X2 are selected from the group consisting of chloro and methyl;
X3 is hydrogen, nitro, lower alkyl, lower alkoxy, cycloalkyl, halo, amino, cyano, sulfamoyl, methanesulfonyl;
X7 is hydrogen, lower alkyl or halogen;
X8 is hydrogen or lower alkyl;
which comprises treating a compound of the formula:
wherein R0, R, X1, X2, X3, X7 and X8 are as above with a reagent of the formula: , wherein Z is halo and R3 is hydrogen or lower alkyl in the presence of a base and when R3 is lower alkyl, hydrolyzing the resulting ester.
3. A process for preparing a compound of the formula:
wherein R0 is or ;
R is lower alkyl;
X1 and X2 are selected from the group consisting of chloro and methyl;
X3 is hydrogen, nitro, lower alkyl, lower alkoxy, cycloalkyl, halo, amino, cyano, sulfamoyl or methanesulfonyl;
X7 is hydrogen, lower alkyl or halogen;
X8 is hydrogen or lower alkyl;
which comprises treating a compound of the formula:
wherein R0, R, X1, X2, X3, X7 and X8 are as above with a reagent of the formula: , wherein Z is halo and R3 is t-butyl in the presence of a base and pyrolyzing the t-butyl ester to form the desired product.
wherein R0 is or ;
R is lower alkyl;
X1 and X2 are selected from the group consisting of chloro and methyl;
X3 is hydrogen, nitro, lower alkyl, lower alkoxy, cycloalkyl, halo, amino, cyano, sulfamoyl or methanesulfonyl;
X7 is hydrogen, lower alkyl or halogen;
X8 is hydrogen or lower alkyl;
which comprises treating a compound of the formula:
wherein R0, R, X1, X2, X3, X7 and X8 are as above with a reagent of the formula: , wherein Z is halo and R3 is t-butyl in the presence of a base and pyrolyzing the t-butyl ester to form the desired product.
4. A process of Claim 2, wherein R0 is or ;
X3 is hydrogen, methyl, chloro or fluoro;
X7 and X8 are hydrogen;
R is lower alkyl; and X1 and X2 are selected from the group consisting of methyl and chloro.
X3 is hydrogen, methyl, chloro or fluoro;
X7 and X8 are hydrogen;
R is lower alkyl; and X1 and X2 are selected from the group consisting of methyl and chloro.
5. The process of Claim 4, wherein R0 is ;
X3 is hydrogen;
X1 and X2 are chloro;
R is methyl;
R3 is ethyl;
Z is bromo;
and the base is potassium carbonate for preparing (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid.
X3 is hydrogen;
X1 and X2 are chloro;
R is methyl;
R3 is ethyl;
Z is bromo;
and the base is potassium carbonate for preparing (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid.
6. The process of Claim 3, wherein R0 X3 is hydrogen;
X1 and X2 are chloro;
R is methyl;
R3 is t-butyl;
Z is bromo;
and the base is potassium carbonate for preparing [1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy]acetic acid.
X1 and X2 are chloro;
R is methyl;
R3 is t-butyl;
Z is bromo;
and the base is potassium carbonate for preparing [1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy]acetic acid.
7. A compound of the formula:
wherein R0 is or ;
A is oxygen or sulphur;
R is lower alkyl, lower alkenyl, phenyl lower alkyl, thienyl, phenyl lower alkenyl, phenyl, cycloalkyl or cycloalkyl lower alkyl;
R1 is hydrogen, lower alkyl or aryl; or R1 and R may be joined together to Form a cycloalkylene;
Y is alkylene or haloalkylene containing from 1 to about 4 carbon atoms;
X3 is hydrogen, nitro, lower alkyl, lower alkoxy, cycloalkyl, halo, amino, cyano, sulfamoyl, or methanesulfonyl;
X7 is hydrogen, lower alkyl or halogen;
X8 is hydrogen or lower alkyl;
X1 is hydrogen, halo or methyl;
X2 is halo, methyl or trihalomethyl; or X1 and X2 may be joined together to form a hydrocarbylene chain containing from 3 to about 4 carbon atoms, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.
wherein R0 is or ;
A is oxygen or sulphur;
R is lower alkyl, lower alkenyl, phenyl lower alkyl, thienyl, phenyl lower alkenyl, phenyl, cycloalkyl or cycloalkyl lower alkyl;
R1 is hydrogen, lower alkyl or aryl; or R1 and R may be joined together to Form a cycloalkylene;
Y is alkylene or haloalkylene containing from 1 to about 4 carbon atoms;
X3 is hydrogen, nitro, lower alkyl, lower alkoxy, cycloalkyl, halo, amino, cyano, sulfamoyl, or methanesulfonyl;
X7 is hydrogen, lower alkyl or halogen;
X8 is hydrogen or lower alkyl;
X1 is hydrogen, halo or methyl;
X2 is halo, methyl or trihalomethyl; or X1 and X2 may be joined together to form a hydrocarbylene chain containing from 3 to about 4 carbon atoms, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.
8. A compound of the formula:
wherein R0 is or ;
R is lower alkyl;
X1 and X2 are selected from the group consisting of chloro and methyl;
X3 is hydrogen, nitro, lower alkyl, lower alkoxy, cycloalkyl, halo, amino, cyano, sulfamoyl, methanesulfonyl;
X7 is hydrogen, lower alkyl or halogen;
X8 is hydrogen or lower alkyl, when prepared by the process defined in Claim 2 or by an obvious chemical equivalent.
wherein R0 is or ;
R is lower alkyl;
X1 and X2 are selected from the group consisting of chloro and methyl;
X3 is hydrogen, nitro, lower alkyl, lower alkoxy, cycloalkyl, halo, amino, cyano, sulfamoyl, methanesulfonyl;
X7 is hydrogen, lower alkyl or halogen;
X8 is hydrogen or lower alkyl, when prepared by the process defined in Claim 2 or by an obvious chemical equivalent.
9. A compound of the formula:
wherein R0 is or ;
R is lower alkyl;
X1 and X2 are selected from the group consisting of chloro and methyl;
X3 is hydrogen, nitro, lower alkyl, lower alkoxy, cycloalkyl, halo, amino, cyano, sulfamoyl or methanesulfonyl;
X7 is hydrogen, lower alkyl or halogen;
X8 is hydrogen or lower alkyl, when prepared by the process defined in Claim 3 or by an obvious chemical equivalent.
wherein R0 is or ;
R is lower alkyl;
X1 and X2 are selected from the group consisting of chloro and methyl;
X3 is hydrogen, nitro, lower alkyl, lower alkoxy, cycloalkyl, halo, amino, cyano, sulfamoyl or methanesulfonyl;
X7 is hydrogen, lower alkyl or halogen;
X8 is hydrogen or lower alkyl, when prepared by the process defined in Claim 3 or by an obvious chemical equivalent.
10. The compound of Claim 8, wherein R0 is or ;
X3 is hydrogen, methyl, chloro or fluoro;
X7 and X8 are hydrogen;
R is lower alkyl; and X1 and X2 are selected from the group consisting of methyl and chloro, when prepared by the process defined in Claim 4 or by an obvious chemical equivalent.
X3 is hydrogen, methyl, chloro or fluoro;
X7 and X8 are hydrogen;
R is lower alkyl; and X1 and X2 are selected from the group consisting of methyl and chloro, when prepared by the process defined in Claim 4 or by an obvious chemical equivalent.
11. The compound of Claim 8 , wherein R0 is ;
X3 is hydrogen;
X1 and X2 are chloro;
R is methyl;
R3 is ethyl;
Z is bromo, when prepared by the process defined in Claim 5 or by an obvious chemical equivalent.
X3 is hydrogen;
X1 and X2 are chloro;
R is methyl;
R3 is ethyl;
Z is bromo, when prepared by the process defined in Claim 5 or by an obvious chemical equivalent.
12. The compound of Claim 9, wherein R0 is ;
X3 is hydrogen;
X1 and X2 are chloro;
R is methyl;
R3 is t-butyl;
Z is bromo, when prepared by the process defined in Claim 6 or by an obvious chemical equivalent.
X3 is hydrogen;
X1 and X2 are chloro;
R is methyl;
R3 is t-butyl;
Z is bromo, when prepared by the process defined in Claim 6 or by an obvious chemical equivalent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US40573673A | 1973-10-11 | 1973-10-11 | |
| US49265174A | 1974-07-30 | 1974-07-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1063125A true CA1063125A (en) | 1979-09-25 |
Family
ID=27019215
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA210,670A Expired CA1063125A (en) | 1973-10-11 | 1974-10-03 | (1-oxo-2-aryl or thienyl-2-substituted-5-indanyloxy (or thio)) alkanoic acids and derivatives thereof and processes for preparing same |
Country Status (27)
| Country | Link |
|---|---|
| JP (1) | JPS5939415B2 (en) |
| KR (1) | KR870000034B1 (en) |
| AR (4) | AR213065A1 (en) |
| AT (1) | AT342036B (en) |
| BG (1) | BG28255A3 (en) |
| CA (1) | CA1063125A (en) |
| CH (2) | CH613933A5 (en) |
| CS (1) | CS190439B2 (en) |
| CY (1) | CY1074A (en) |
| DD (1) | DD118075A5 (en) |
| DE (2) | DE2448454C2 (en) |
| EG (1) | EG11741A (en) |
| ES (2) | ES430900A1 (en) |
| FR (1) | FR2247218B1 (en) |
| GB (2) | GB1474460A (en) |
| HK (1) | HK47680A (en) |
| HU (1) | HU169587B (en) |
| IE (1) | IE39927B1 (en) |
| IL (1) | IL45779A (en) |
| KE (1) | KE3068A (en) |
| LU (1) | LU71078A1 (en) |
| MY (1) | MY8100163A (en) |
| NL (2) | NL187854C (en) |
| PH (2) | PH22225A (en) |
| RO (2) | RO64568A (en) |
| SU (1) | SU738509A3 (en) |
| YU (1) | YU39727B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE51535B1 (en) * | 1980-09-02 | 1987-01-07 | Merck & Co Inc | Pharmaceutical compositions containing 4-((6,7-dihalogen-2,3-dihydro-1-oxo-1h-inden-5-yl)-oxy)butanoic acid compounds |
| US5489712A (en) * | 1994-11-04 | 1996-02-06 | Hoechst Celanese Corporation | Process for preparing cyclic ketones |
| CN109748785A (en) * | 2019-01-14 | 2019-05-14 | 山东大学 | Two aromatic hydrocarbon substituted propenone class compounds of one kind and preparation method and application |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3704314A (en) * | 1968-11-25 | 1972-11-28 | Merck & Co Inc | (1-oxo-2-alkylideneindanyloxy) and (1-oxo - 2 - alkylideneindanylthio) alkanoic acids |
| US3668241A (en) * | 1968-11-25 | 1972-06-06 | Merck & Co Inc | Substituted 1-oxoinden-5-yloxy alkanoic acids |
-
1974
- 1974-09-27 NL NLAANVRAGE7412829,A patent/NL187854C/en not_active IP Right Cessation
- 1974-10-02 DD DD181462A patent/DD118075A5/xx unknown
- 1974-10-03 CA CA210,670A patent/CA1063125A/en not_active Expired
- 1974-10-03 IE IE2046/74A patent/IE39927B1/en unknown
- 1974-10-04 IL IL45779A patent/IL45779A/en unknown
- 1974-10-04 PH PH16378A patent/PH22225A/en unknown
- 1974-10-07 GB GB2684976A patent/GB1474460A/en not_active Expired
- 1974-10-07 GB GB4337274A patent/GB1474459A/en not_active Expired
- 1974-10-07 CY CY1074A patent/CY1074A/en unknown
- 1974-10-08 AT AT807874A patent/AT342036B/en not_active IP Right Cessation
- 1974-10-08 FR FR7433813A patent/FR2247218B1/fr not_active Expired
- 1974-10-08 KR KR7403765A patent/KR870000034B1/en active
- 1974-10-09 RO RO7480173A patent/RO64568A/en unknown
- 1974-10-09 HU HUME1782A patent/HU169587B/hu not_active IP Right Cessation
- 1974-10-09 RO RO7487617A patent/RO71480A/en unknown
- 1974-10-09 AR AR255982A patent/AR213065A1/en active
- 1974-10-09 LU LU71078A patent/LU71078A1/xx unknown
- 1974-10-10 CH CH356578A patent/CH613933A5/en not_active IP Right Cessation
- 1974-10-10 SU SU742075603A patent/SU738509A3/en active
- 1974-10-10 DE DE2448454A patent/DE2448454C2/en not_active Expired
- 1974-10-10 ES ES430900A patent/ES430900A1/en not_active Expired
- 1974-10-10 CH CH1365874A patent/CH610290A5/en not_active IP Right Cessation
- 1974-10-10 YU YU2727/74A patent/YU39727B/en unknown
- 1974-10-10 CS CS746931A patent/CS190439B2/en unknown
- 1974-10-10 BG BG7427912A patent/BG28255A3/en unknown
- 1974-10-10 DE DE2463215A patent/DE2463215C2/en not_active Expired
- 1974-10-11 JP JP49116987A patent/JPS5939415B2/en not_active Expired
- 1974-10-12 EG EG459/74A patent/EG11741A/en active
-
1976
- 1976-02-04 AR AR262139A patent/AR213620A1/en active
- 1976-02-04 AR AR262138A patent/AR213170A1/en active
- 1976-07-16 ES ES449917A patent/ES449917A1/en not_active Expired
- 1976-07-22 PH PH18722A patent/PH22017A/en unknown
-
1977
- 1977-02-10 AR AR266508A patent/AR213840A1/en active
-
1980
- 1980-07-25 KE KE3068A patent/KE3068A/en unknown
- 1980-08-28 HK HK476/80A patent/HK47680A/en unknown
-
1981
- 1981-12-30 MY MY163/81A patent/MY8100163A/en unknown
-
1991
- 1991-03-05 NL NL9100396A patent/NL9100396A/en not_active Application Discontinuation
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