Note: Descriptions are shown in the official language in which they were submitted.
~,03~i
13 This invention relates to a new process for the
.. . .
14 preparation of [1-oxo-(2-phenyl, halophenyl or thienyl~-2-
methyl-6,7-dichloro-5-indanyloxy]-acetic acid. Pharmaccutical
16 studies show that the above-mentioned products are effective
17 diuretic and saluretic agents which can be used in the
18 treatment of conditions associated with electrolyte and
19 fluid retention. The above-mentioned compounds are also
used in the treatment of hypertension. In addition, these
21 compounds are able to maintain the uric acid concentration
22 in the body at pretreatment levels and to even effect a
23 decrease in the uric acid concentration.
24 When administered in therapeutic dosages, in
conventional vehicles, the compounds effectively reduce
26 the amount of sodium and chloride ions in the body, lower
27 dangerous excesses of fluid levels to acceptable lcvcls
2~ and, in ~cneral, alleviate conditions usually associated
15682
' 1038396
1 with edema. In addition, the compounds overcome a major
2 problem associated with many of the presently available
3 diuretics and saluretics. For example, many of the
4 presently available diuretics and saluretics have a
tendency upon administration to induce hyperuricemia
6 which may precipitate uric acid or sodium urate, or both,
7 in the body which may cause from mild to severe cases of
8 gout. The instant compounds now provide an effective tool
9 to treat those patients, both human and animal, requiring
diuretic and saluretic treatment without incurring the
11 risk of inducing gout.
12 Thus, it is an object of the present invention
13 to provide a specific, highly efficient unified process
14 for the preparation of [1-oxo-(2-phenyl, halophenyl or
thienyl~2-methyl-6,7-dichloro-5-indanyloxy]-acetic acid
16 and its non-toxic pharmaceutically acceptable salt, ester
17 and amide derivatives. It is also an object of the present
18 invention to provide useful intermediates (II, above) which
19 are involved in the process of this invention. One advan-
tage of the instant process is that it allows one to use
21 relatively cheaper starting materials than previous processes.
22 The process of this invention can be shown
23 chemically by the following reaction sequence~
15682
Cl ` 1~83~
Cl_ ~ + CH2=C-COX
RO_ ~ (a)
or
I R Step A
CH3-CXCOX Lewis
(b) Acid
or
,R
CH2XC-COX
z (c)
II
Cl ~ R Step E
RO_ Z if Z is hydrogen
III \
\ - if Z is methyl
~<CH3 Ether Cleavage >~30 ~\CRH3
V VI
StepOD
~XCH2COR"
Cl O Cl CH3
Cl - ~ ~ CH3hydrolysis Cl_ ~ R'
C-CH2 - ~ R' ~if R" is not H O
VIII VII
15682
; 1038396
1 In the above reaction sequence
2 R = lower alkyl having up to 5 carbon atoms,
3 preferably methyl; H or CH2CO2R", wherein
4 R" is lower alkyl or hydrogen;
X = Cl, Br or I;
6 R = phenyl, methyl, halophenyl, preferably p-
7 chloro or p-fluorophenyl and thienyl,
8 preferably z-thienyl;
9 R' = phenyl, halophenyl, preferably p-chloro or
p-fluorophenyl and thienyl, preferably 2- thienyl;
11 R" = lower alkyl or H;
12 Z = H or methyl but is not methyl when R is
13 methyl, i.e. Z and R cannot be methyl at
14 the same time;
Y = phenyl, halophenyl, thienyl, diphenyliodo,
16 dihalophenyliodo, dithienyliodo.
17 More specifically, Step A of this invention
18 involves a reaction of 2,3-dichloroanisol or a related lower
19 alkyl ether or 2,3-dichlorophenoxyacetic acid or a related
lower alkyl ester and a suitable substituted or unsubstituted
21 acyl halide of the formulae shown in the reaction sequence.
22 These compounds are reacted under Friedel-Crafts reaction
23 conditions with an appropriate catalyst to produce an
24 intermediate 2-substituted indanone shown as Formula III.
If an a,a-disubstituted acyl halide is used in Formula II(c)
26 such as for example a-methyl-a-phenyl-~-bromopropionyl
27 chloride and R is CH2CO2H, then the desired indanone V is
28 formed directly. This reaction proceeds through a dehydro-
29 halogenation introducing a side chain followed by a ring
15682
1038396
1 closure to give intermediate Formula III. Typical substi-
2 tuted or unsaturated acyl halides are acrylyl chloride-,
3 a-halo isobutyryl chloride, or ~-halo isobutyryl chloride.
4 The Friedel-Crafts reaction conditions under which Step A
of the reaction is carried out are the use of a catalyst
6 such as Lewis acid particularly aluminum chloride or tin
7 chloride and use of a solvent particularly an inert organic
8 solvent which does not react appreciably with the reactants.
9 Typical of such inert solvents are methylene chloride,
tetrachloroethane, hexane, carbon disulfide or nitrobenzene.
11 Step A of the reaction is carried out at a temperature from
12 about 0 to the reflux temperature of the solvent, but
13 20-50 is preferred for a length of time sufficient to
14 substantially complete the reaction but generally from
about 4 to 6 hours at about 40C.
16 The a,c-disubstituted-~-halo propionyl halide of
17 Formula II(c) can be prepared by the general method of
18 Nicolaus, Mariani and Testa, "A New General Synthesis for
19 ~-Substituted Propionic Acid and its Derivatives", Bruno J.R.
Nicolaus, Luigi r~ariani and Emilio Testa (Lepetit Spa, Milan)
21 Chem. Abst. 55 27271d (1961).
22 Step B of the process involves alkyla~ing the
23 intermediate 2-methyl indanone, Formula III, if the ini'-ial
24 reactant Formula II was not an a,a-disubstituted propionyl
halide using an alkylating agent, YX wherein Y and X are
26 as defined above, particularly with diaryliodium halide or
27 methyl halide to yield an intermediate indanone, Formula V.
28 The alkylation reaction is carried out in the presence of
29 a suitable basic catalyst such as sodium tertiary butoxide,
15682
1038396
1 sodium hydride, sodamide, sodium methoxide or the like
2 in a suitable solvent such as any inert non-aqueous
3 organic solvent, particularly benzene or toluene. The
4 alkylation reaction is carried out for a time sufficient
to complete the reaction and preferably at a temperature
6 from about room temperature to a reflux temperature of the
7 particular solvent used. If in the compound Formula V
8 which is formed R' is phenyl, halophenyl or thienyl and
9 R is CH2CO2H, then the desired indanone is already formed.
It can be isolated from the reaction mixture by methods
11 known in the art such as by extracting the desired compound
12 from its reaction mixture with a solvent, boiling off said
13 solvent and then recrystallizing the desired indanone from
14 acetone or other suitable solvent.
If in the compound of Formula V R is lower alkyl,
16 this compound must further undergo an ether cleavage which
17 comprises treating the compound of Formula V with an ether
18 cleavage reagent and then treating the 5-hydroxy product
19 formed, Formula VI, with a haloacetic or ~seudohaloacetic
acid or ester thereof of the formula XCH2C-OR" wherein X is
21 Cl, Br, I, mesyl or tosyl and R" is hydrogen or lower alkyl.
22 Finally, if R" in the halo acetic acid ester is
23 lower alkyl, the product formed, Formula VII, must further
24 undergo a hydrolysis to form the desired indanone. If a
halo acetic acid is used as the reactant, then Formula VII
26 is the desired indanone.
27 Step C of the reaction scheme, namely, the ether
28 cleavage, is carried out with ether cleaving reagents, such
29 as aluminum chloride, pyridine hydrochloride, hydrogen bromide,
15682
1038396
1 sodium in liquid ammonia and the like. When aluminum
2 chloride is employed, the solvent may be heptane, carbon
3 disulfide, methylene chloride and the like and when pyridine
4 hydrochloride is employed, it is not necessary to employ a
solvent.
6 Generally, this ether cleavage is carried out
7 at temperatures from room temperature to reflux temperature
8 of any solvent used for any time sufficient to complete
9 substantial formation of the intermediate of Formula VI.
The reaction wherein the product of Formula VI
11 is reacted with a halo acetic acid or ester, the reaction
12 is generally conducted in the presence of a base, such as
13 alkali metal carbonate, hydroxide or alkoxide such as
14 potassium carbonate, sodium carbonate, potassium hydroxide,
sodium hydroxide, sodium ethoxide and the like. Any solvent
16 which is inert or substantially inert to the reactants and
17 in which the reagents are reasonably soluble may be employed.
18 Ethanol, dimethylformamide, benzene and toluene, for example,
19 have proved to be particularly advantageous solvents. The
reaction may be conducted at a temperature in the range of
21 from about 25C. to the reflux temperature of the particular
22 solvent employed. The reaction with the haloacetic acid or
23 ester is generally complete in about 10 to 60 minutes. If
24 the haloacetic acid ester is employed, the ester obtained
may be hydrolyzed to the free acid by methods well known
26 to those skilled in the art.
27 The invention herein can be illustrated by the
28 following examples:
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1038396
1 EXAMPLE 1
. .
2 2-Methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone
3 Step A: 2-Methyl-5-methoxy-6,7-dichloro-
l-indanone
4 2,3-Dichloroanisole (177 g., 1.0 mole), anhydrous
aluminum chloride (280 g., 2.10 mole) and 545 ml. of carbon
6 disulfide are mixed under a nitrogen atmosphere. The
7 mixture is stirred at 25-30 while adding 110 ml. of ~-bromo-
8 2-methylpropionyl bromide (209 g., 0.91 mole) over 1-1/2
9 hours. The reaction mixture is aged at 25-30 for one
hour, then at 43-45 for 4 hours. After finally stirring
11 overnight at 25 the batch is quenched, carefully, into a
12 mixture of 2.72 liters of ice and water. The temperature
13 increases to 28 during the quench and the batch is aged
14 for 10 minutes. The layers are separated and the aqueous
phase is extracted with 2 x 550 ml. of toluene. The combined
16 organic phase is washed with 275 ml. of 10% sodium
17 bicarbonate solution, dried over magnesium sulfate, and
18 concentrated ln vacuo to dryness to yield 207 g. (93~) of
19 2-methyl-5-methoxy-6,7-dichloro-1-indanone.
Step B: 2-Methyl-2-phenyl-5-methoxy-
21 6,7-dichloro-1-indanone
22 2-Methyl-5-methoxy-6,7-dichloro-1-indanone
23 (245 g., 1.0 mole), 2.19 liters of t-butanol (sieve-dried)
24 and 1.74 liters of benzene (azeotropically dried) are mixed
under a nitrogen atmosphere and heated to 50. A solution
26 of potassium t-butoxide (190 g., 1.7 moles) in 1.74 liters
27 of t-butanol (sieve-dried) is added all at once. The batch
28 is heated to reflux (78) and refluxed for 30 minutes. Cooled
29 to 30 and bromobenzene (372.5 g., 2.5 moles) added
over 15 minutes (initial temperature rise). The mixture is
15682
1038~96
1 heated to reflux (71), refluxed for 10 minutes and cooled
2 again to 30. Water (903 ml.) is added,gradually, at 30-40
3 and the batch is concentrated in vacuo to a volume of 887 ml.
4 The solids are collected by filtration. The filter cake is
washed with 3 x 350 ml. of water and dried in vacuo at 45
6 giving a crude yield of 200 g. 60% of 2-methyl-2-phenyl-5-
7 methoxy-6,7-dichloro-1-indanone.
8 The crude material is recrystallized from 1.37
9 liters of boiling ethanol, cooled to 0-5 and filtered.
The solids are washed with cold ethanol and dried ln vacuo
11 at 45 to yield 100 g. 50% of 2-methyl-2-phenyl-5-methoxy-
12 6,7-dichloro-1-indanone.
13 Following the procedure above but using p-chloro-
14 bromo benzene or 2-thienyl bromide in place of bromobenzene
in Step B, there is prepared an equivalent amount of 2-methyl-
16 2-p-chloro-5-methoxy-6,7-dichloro-1-indanone and 2-methyl-
17 2-(2-thienyl)-5-methoxy-6,7-dichloro-1-indanone.
18 EXAMPLE 2
19 2-Methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone
2,3-Dichloroanisole (177 g., 1.0 mole), anhydrous
21 aluminum chloride (280 g., 2.10 mole) and 545 ml. of carbon
22 disulfide are mixed under a nitrogen atmosphere. The
23 mixture is stirred at 25-30 while adding 261.5 gm. (1 mole)
24 of a-methyl-a-phenyl-~-bromo propionyl chloride over 1-1/2
hours. The reaction mixture is aged at 25-30 for one hour,
26 then at 43-45 for 4 hours. After finally stirring overnight
27 at 25 the batch is quenched, carefully, into a mixture of
28 2.73 liters of ice and water. The temperature increases to
29 28 during the quench and the batch is aged for 10 minutes.
15682
1038396
1 The layers are separated and the aqueous phase is extracted
2 with 2 x 550 ml. of toluene. The combined organic phase is
3 washed with 275 ml. of 10% sodium bicarbonate solution, dried
4 over magnesium sulfate, and concentrated in vacuo to dryness
to yield 207 g. (93%) of 2-methyl-2-phenyl-5-methoxy-6,7-
6 dichloro-l-indanone.
7 Following the procedure above but using a-methyl-
8 p-chlorophenyl or 2-thienyl-~-bromo propionyl chloride in
9 place of ~-methyl-~-phenyl-~-bromo propionyl chloride, there
is produced an equivalent amount of 2-methyl-2-p-chloro-
11 phenyl-5-methoxy-6,7-dichloro-1-indanone and 2-methyl-2-
12 (2-thienyl)-5-methoxy-6,7-dichloro-1-indanone respectively.
13 EXAMPLE 3
14 2-Methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone
Step A: 2-Methyl-5-methoxy-6,7-dichloro-
16 1-indanone
17 This compound is prepared by a procedure identical
18 to Example 1 except ~-chloro-2-methyl propionyl chloride is
19 substituted for the dibromo analog.
Step B: 2-Methyl-2-phenyl-5-methoxy-
21 6,7-dichloro-1-indanone
22 This compound is prepared by a procedure identical
23 to Example 1.
24 EXAMPLE 4
2-Methyl-S-methoxy-6,7-dichloro-1-indanone
_
26 Step A: 2-Methyl-5-methoxy-6,7-dichloro-
27 l-indanone
28 This compound is prepared by a procedure ldentical
29 to Example 1 except ~-chloro-2-methylpropionyl chloride is
substituted for ~-bromo-2-methylpropionyl bromide.
-- 10 --
15682
~038396
1Step B: 2-Methyl-5-methoxy-6,7-dichloro-
2l-indanone
3This compound is prepared by a procedure
4 identical to Example 1.
5EXAMPLE 5
62-Methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone
7Step A: 2-Methyl-5-methoxy-6,7-dichloro-
8l-indanone
9This compound is prepared by a procedure identical
to Example 1.
11 Step B: 2-Methyl-2-phenyl-5-methoxy-
126,7-dichloro-1-indanone
13 This compound is prepared by a procedure identical
14 to Example 1 except that chlorobenzene is substituted for
bromobenzene as alkylating agent.
16EXAMPLE 6
172-Methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone
18Step A: 2-Methyl-5-methoxy-6,7-dichloro-
19l-indanone
20This compound is prepared by a procedure identical
21 to Example 1, Step A.
22 Step B: 2-Methyl-2-phenyl-5-methoxy
23 6,7-dichloro-1-indanone
24 This compound is prepared by a procedure identical
to Example 1, Step B, except that 317 grams of diphenyl
26 iodonium chloride are substituted for 372.5 grams of
27 bromobenzene.
28EXAMPLE 7
292-Methyl-2-p-chlorophenyl-5-methoxy-6,7-dichloro-1-indanone
30Step A: 2-Methyl-5-methoxy-6,7-dichloro-
31l-indanone
32This compound is prepared by a procedure identical
33 to Example 1, Step A.
15682
1038396
1 Step B: 2-Methyl-2-p-chlorophenyl-5-
2 methoxy-6,7-dichloro-1-indanone
3 This compound is prepared by a procedure identical
4 to Example 1, Step B,except that 387 grams of di-p-chloro-
phenyl iodonium chloride are used in place of 372.5 grams
6 of bromobenzene.
7 EXAMPLE 8
8 2-Methyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone
9 Step A: 2-Phenyl-5-methoxy-6,7-dichloro-
l-indanone
11 This compound is prepared by a procedure identical
12 to Example 1 except that 266 g., 0.91 mole, of a-bromo-2-
13 phenylpropionyl bromide is substituted for a-bromo-2-methyl-
14 propionyl bromide. ~he crude yield is 285 g. (93%) of
2-phenyl-5-methoxy-6,7-dichloro-1-indanone. After
16 recrystallization from benzene-cyclohexane 2:1, the m.p.
17 is 193-195C.
18 Step B: 2-Methyl-2-phenyl-5-methoxy-6,7-
19 dichloro-l-indanone
2-Phenyl-S-methoxy-6,7-dichloro-1-indanone
21 (50.84 g.~ was dissolved in dry dimethylformamide (700 ml.)
22 and dry benzene (700 ml.) in a 3 liter flask equipped with
23 a nitrogen inlet tube, air condenser, and hopper for sodium
24 methoxide. Iodomethane (103 ml.) was added to the solution
under nitrogen while cooling in an ice-water bath, and
26 sodium methoxide (13.5 g.) was added portionwise from the
27 hopper through the Gooch tubing over 3/4 hour. During the
28 addition, the reaction mixture turned bright red, then the
29 color slowly disappeared and a solid precipitate formed.
After stirring for 1/2 hour in an ice-water bath, the reaction
- 12 -
.
15682
103~i
1 mixture was added to water (~4 liters) and extracted with
2 benzene. Upon drying the benzene solution over molecular
3 sieves and concentrating to dryness, a pale yellow solid
4 product formed; yield: 45.6 g., m.p. 161-165C. (86%).
A sample recrystallized from benzene-cyclohexane (1:2)
6 melts at 164-165C.
7 EXAMPLE 9
8 (1-Oxo-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)-
9 acetic acid
Step A: (l-Oxo-2-methyl-6,7-dichloro-5-
11 indanyloxy)-acetic acid
12 This compound is prepared by a procedure identical
13 to Example 1 except that 2,3-dichlorophenoxyacetic acid is
14 substituted for 2,3-dichloroanisole.
Step B: (l-Oxo-2-phenyl-2-methyl-6,7-
16 dichloro-5-indanyloxy)-acetic acid
17 This compound is prepared by a procedure identical
18 to Example 1 except that (1-oxo-2-methyl-6,7-dichloro-5-
19 indanyloxy)-acetic acid is substituted for 2-methyl-5-
methoxy-6,7-dichloro-1-indanone.
21 EXAMPLE 10
22 (1-Oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)-
23 acetic acid
24 Step A: (l-Oxo-2-methyl-6,7-dichloro-5-
indanyloxy)-acetic acid
26 This compound is prepared by a procedure identical
27 to Example 3 except that 2,3-dichlorophenoxyacetic acid is
28 substituted for 2,3-dichloroanisole.
29 Step B: (l-Oxo-2-phenyl-2-methyl-6,7-
dichloro-5-indanyloxy)-acetic acid
31 This compound is prepared by a procedure identical
32 to Example 3 except that (1-oxo-2-methyl-6,7-dichloro-5-
33 indanyloxy)-acetic acid is substituted for 2-methyl-5-
34 methoxy-6,7-dichloro-1-indanone.
- 13 -
15682
1038396
1 BXAMPLE 11
2 (1-Oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)-
3 acetic acid
4 Step A~ Oxo-2-methyl-6,7-dichloro-5-
indanyloxy)-acetic acid
6 This compound is prepared by a procedure identical
7 to Example 4 except that 2,3-dichlorophenoxyacetic acid is
8 substituted for 2,3-dichloroanisole.
9 Step B: (l-Oxo-2-phenyl-2-methyl-6,7-
dichloro-5-indanyloxy)-acetic acid
11 This compound is prepared by a procedure identical
12 to Example 4 except that tl-oxo-2-methyl-6,7-dichloro-5-
13 indanyloxy)-acetic acid is substituted for 2-methyl-5-
14 methoxy-6,7-dichloro-1-indanone.
EXAMPLE 12
16 (1-Oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)-
17 acetic acid
18 Step A: (l-Oxo-2-methyl-6,7-dichloro-5-
19 indanyloxy)-acetic acid _
This compound is prepared by a procedure identical
21 to Example 5 except that 2,3-dichlorophenoxyacetic acid
22 is substituted for 2,3-dichloroanisole.
23 Step B: (l-Oxo-2-phenyl-2-methyl-6,7-
24 . dichloro-5-indanyloxy)-acetic acid
This compound is prepared by a procedure identical
26 to Example 5 except that (1-oxo-2-methyl-6,7-dichloro-
27 5-indanyloxy)-acetic acid is substituted for 2-methyl-
28 5-methoxy-6,7-dichloro-1-indanone.
29 EXAMæLE 13
(1-Oxo-2-phenyl-2-methyl-6,7-dichloro-5-indanyloxy)-acetic acid
-
31 This compound is prepared by a procedure identical
32 to Example 2 except that 2,3-dichlorophenoxyacetic acid is
33 substituted for 2,3-dichloroanisole.
- 14 -
15682
S038396
1 Following the above procedure but using a-methyl
2 a-p-chlorophenyl or 2-thienyl-~-bromo propionyl chloride in
3 place of a-methyl-a-phenyl-~-bromo propionyl chloride there
4 is produced an equivalent amount of [1-oxo-2-methyl-2 (p-
chlorophenyl or 2-thienyl)-2-methyl-6,7-dichloro-5-
6 indanyloxy]acetic acid.
7 EXAMPLE 14
8 2-Methyl-5-methoxy-6,7-dichloro-1-indano_e
9 Step A: 2-Methyl-5-methoxy-6,7-dichloro-
l-indanone
11 This compound is prepared by a procedure identical
12 to Example 1 except methacrylic acid acid chloride is
13 substituted for a-bromo-2-methylpropionyl bromide.
14 EXAMPLE 15
Preparation of (l-Oxo-2-phenyl-2-methyl-6,7-dichloro-
16 5-indanvloxy)-acetic acid
17Step A: 2-Phenyl-2-methyl-5-hydroxy-6,7-
18dichloro-l-indanone
-
192-Phenyl-2-methyl-5-methoxy-6,7-dichloro-1-
20indanone (3.5 g., 0.0109 mole) is added to dry hexane
21(180 ml.) and aluminum chloride (4.36 g., 0.0327 mole)
22 is added. The mixture is refluxed for one hour and the
23 hexane is decanted from the gummy residue which then is
24 added to ice water (200 ml.) containing 12N hydrochloric
acid (15 ml.). The solid that separates is crystallized
26 from benzene to obtain 2.84 g. of 2-phenyl-2-methyl-5-
27 hydroxy-6,7-dichloro l-indanone.
28Step B: (l-Oxo-2-phenyl-2-methyl-6,7-
29dichloro-5-indanyloxy)-acetic acid
302-Phenyl-2-methyl-5-hydroxy-6,7-dichloro-1-
31indanone (2.84 g., 0.00926 mole) is added to dimethyl-
32 formamide (DMF) (40 ml.). Potassium carbonate (3.21 g.,
15682
10383g6 ,
1 0.0232 mole) and ethyl bromoacetate (3.34 g., 0.0232 mole)
2 are added. The mixture is stirred at 55-60C. for 2-1/2
3 hours, then 40 ml. of 10% sodium hydroxide are added and
4 the mixture is stirred at 80-85C. for 1-1/2 hours. The
mixture is then added to 500 ml. of 2% hydrochloric acid.
6 The solid that separates is taken up in ether. The ether
7 extract is washed with water, dried over magnesium sulfate
8 and evaporated, leaving a gummy solid that is crystallized
9 from acetic acid to obtain 183 mg. of (1-oxo-2-phenyl-2-
methyl-6,7-dichloro-5-indanyloxy)-acetic acid.
11 Following the procedure above but using 2-p-
12 chlorophenyl or 2-(2-thienyl)-2-methyl-5-methoxy-6,7-
13 dichloro-l-indanone in place of 2-phenyl-2-methyl-5-methoxy-
14 6,7-dichloro-1-indanone, there is produced an equivalent
amount of[l-oxo-2-(p-chlorophenyl or 2-thienyl)-2-methyl-
16 6,7-dichloro-5-indanyloxy]acetic acid, respectively.
17 EXAMPLE 16
18 [1-Oxo-2-(p-chlorophenyl or 2-thienyl)-2-methyl-6,7-
19 dichloro-5-indan loxv]-acetic acid
y
Step A: (l-Oxo-2-methyl-6,7-dichloro-5-
21 indanyloxy)-acetic acid
22 This material is prepared in a manner identical
23 to Example 1, Step A, except that 2,3-dichlorophenoxyacetic
24 acid is substituted for 2,3-dichloroanisole.
Step B: [l-Oxo-2-(p-chlorophenyl or 2-thienyl)-
26 2-methyl-6,7-dichloro-5-indanyloxy]-
27 acetic acid
28 This product is prepared by a procedure identical
29 to Example 1, Step B, except that (l-oxo-2-methyl-6,7-
dichloro-5-indanyloxy)-acetic acid is substituted for
31 2-methyl-5-methoxy-6,7-dichloro-1-indanone.
32 Any departurefrom the above description which cOnforms
33 to the present invention is intended to be included within
34 the scope of the claims.
- 16 -
