Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
1060904
This invention relates to the synthesis of compouncls
having valuabl.e pharmaceutical properties.
This application is a divisional application of copendi
application No. 246,057 filecl Feb. 18r 1976.
The copending application provides oxoindanylpropionic
acids having the formula
o
R ~ C~I-COOII (I)
wherein R represents an ethyl group or an isopropyl group.
: ~s described in our Canadian Patent Application I~o.
219,910wehave previously discovered substituted idanylpropionic
acids of formula
R ~ CI~-COOH ~VI)
(wherein R has the meaning previously given) and pharmaceutically
~- acceptable salts thereof which exhibit anti-inflammatory, analgesic
and antipyretic activities; and we have also described therein the
`.~
~` 30
,' ~ ~
-- 1 --
;
- 1061)904
~reparatiOn of these compound by hydrolysis of the corresponding
acid amide, nitrile or alkyl esters. ~e have now further discovered
that these substituted indanylpropionic acids of formula (VI) can
advantageously be prepared by the reduction of the oxoindanylpro-
pionic acids offormula (I) of the copending application 246,037.
According to the present invention therefore there is
provided a process for preparing a compound of formula
H-COOH
R ~ CH3 (VI)
. .
wherein R represents
an ethyl group or an isopropyl group or a pharmaceutically accep- :
table salt thereof, which comprises reacting a compound having the
` formula
O
~ ~ fH-COOH
~ CH3 (I)
wherein R represents an ethly group or an isopropyl group
with a reducing agent capable of reducing the carbonyl group to a
methylene group without reducing the carboxyl group, and when
~: required salifying the reaction product to obtain a pharmaceutically
~: acceptable salt thereof.
The oxoindanylpropionic acids of formula (I) can be
prepared by reacting a dicarboxylic acid of formula
~ CH-COOH
.- HOOC-CH-CH2 ~ CH3 (II)
R
- 2 -
:'
f
~j
10~90~
(wherein R has the meaning previously given) with a condensing
agent. A conventional condensing agent can be used in the reaction,
for example a mineral acid such as polyphosphoric, sulphuric or
hydrofluoric acid, a mixture of phosphorus pentoxide and methane-
sulphonic acid, or a Lewis acid such as aluminium chloride or boron
trifluoride etherate. The reaction is usually performed with
heating to a temperature of from 50C to 120C. The reaction period
varies with the reaction ternperature, but is generally from 1 to 5
hours. In most cases, the condensing agent can also serve as
reaction solvent and a separate solvent is not necessary, but when
the
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. 20
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.
1060904
condensing agent is a Lewis acid it is preferred to employ a solvent
of the type normally used in Friedel-Crafts reactions, for example
carbon disulphide or ligroin.
After completion of the reaction, the desired product
of formula (I) can be recovered from the reaction mixture by con-
ventional means: for example, the reaction mixture is poured into
ice-water, the resulting mixture is extracted with a suitable
organic solventS such as ether, the extract is washed with water
and dried, and the solvent is distilled off from the extract to
give the desired product. If required, the product can be purified
by the usual methods, such as vacuum distillation or column chroma-
tography; or alternatively, it can be salified with an organic
amine, for instance piperidine, morpholine, triethylamine, dicyclo-
hexylamine or dibenzylamine, and purified by recrystallization of
` the salt.
The starting materials of formula (II) are also new
; compounds and can be prepared by the process shown in the following
; reaction scheme: -
.:
.; '
.~.
"~.
,, .
.~ ' ' .
, - 3 -
' 10609(~'~
~ ICOOR2 1 ~CH-COOR
XCHzl~ C~3~C00~2 1 3
CCOR2
(III)(IV) (V)
,
~CH-COOH
-HOOC-CH-CH2--~ ~ 3
( II)
. . ,
.:
wherein R has the meaning previously given, each of R and R
represents an alkyl group having from 1 to 4 carbon atoms, and
X represents a chlorine or bromine atom.
The substituted benzyl halide (III), which is the starting
material in the process shown in the reaction scheme, can be
prepared by the method described by J. M. Maillard et al., in
Chimie Therapeutique, vol. 8, 487 (1973). This is then reacted
;~ 10 with the malonic ester (IV) in the presence of an alkali metal base,
~ in an inert organic solvent, to obtain the tricarboxylic acid ester (V).
; Suitable examples of the alkali metal base for use in this
reaction are alkoxides such as sodium methoxide, sodium ethoxide
,
and potassium t-b;lltoxide, amides such as sodium amide and potassium
',' 15 amide, and hydrides such as sodium hydride and potassium hydride.
The reaction solvent is preferably an alcohol such as methanol,
(4)
;:
,, .
. , ~ : ~ ' ':
.:
1060so~a
ethanol or t-butanol, a diaL'cylamide of an alkanoic acid such as
dimethylformamide or dimethylacetamide, dimethylsulphoxide, an
ether such as tetrahydrofuran, dioxane or 1, 2-dimethoxyethane,
or an aromatic hydrocarbon such as benzene, toluene or xylene.
The reaction is preferably performed at a temperature of 0-50 C
and for a period of 1-5 hours. The product (V) can be isolated
from the reaction mixture by conventional means: for example,
the mixture is poured into ice-water and acidified e. g. with
hydrochloric acid, the resulting mixture is extracted with a suitable
.
organic solvent, and the extract is washed with water, dried and
evaporated to dryness,
The tricarboxylic acid ester (V) is hydrolyzed and then
decarboxylated to give the dicarboxylic acid (II). The hydrolysis
can be effected by treating compound (V) with an aqueous acid
; ~ (e. g. hydrochloric, hydrobromic or sulphuric acid) or base
(e. g. sodium hydroxide or potassium hydroxide). The reaction is
preferably performed in water or in an aqueous organic solvent,
` for instance aqueous methanol, ethanol, n. propanol, ethylene
5: glycol, diethylene glycol, dimethylformamide or dimethylacetamide.
The reaction temperature is usually from room temperature to 110 C
and the reaction time from 1 to 12 hours, The product can be
recovered by conventional means. The product can be decarboxylated
by heating it to 100-200 C, optionally in the presence of a solvent,
`
(S)
.
~ ' '
106()904
for instance a dialkylamide of an alkanoic acid such as dimethyl-
formamide or dimethylacetamide, or an aromatic hydrocarbon such
as toluene, xylene or cymene. If a solvent is not employed, the
decarboxylation is preferably performed under reduced pressure
or under an atmosphere of a gas inert to the reaction, such as
nitrogen, in order to suppress side-reactions. The reaction
period varies with the temperature and the nature of the starting
material, but is generally from 15 minutes to 3 hours, The product
of formula (II) can be isolated from the reaction mixture by
conventional means, for example by distilling off the solvent, if
one is used, and purifying the residue by recrystallization or
column chromatography.
; The reduction of the oxoindanylpropionic acids (I) to
~ '~
the pharmaceutically active indanylpropionic acids (VI) can be
effected by means of reducing agents conventionally used for
converting a keto group to a methylene group without reducing a
carboxyl group which is also present in the molecule, For example,
the reduction can be performed by means of zinc amalgam and
hydrochloric acid (Clemmensen reduction), by catalytic hydro-
genation in the presence of a metal catalyst such as palladium on
, ~ carbon, palladium oxide, platinum oxide or platinum black, by
, means of hydrazine and a base such as sodium hydroxide or sodium
ethoxide (Wolff-Kishner reduction), or by means of an alkyl
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1060904
mercaptan such as 1, 2-ethanedithiol and a desulphurization catalyst
such as Raney nickel (Dithioacetal reduction). It is preierred to
use zinc amalgam and hydrochloric acid or catalytic hydrogenation.
When performing the reduction by hydrogenation in the presence of
a catalyst such as palladium on carbon, it is preferred to add an
acid, such as sulphuric, perchloric, trifluoroacetic or p-toluene-
sulphonic acid, in the conventional manner. The choice of reaction
solvent is not particularly critical, provided that it does not
participate in the reaction, but it is preferred to use water, an
organic solvent such as an alcohol (e. g. methanol, ethanol or
n-propanol), an ether ~e. g. tetrahydrofuran, dioxane OD~ 1, 2-
dimethoxyethane), a glycol (e. g. ethylene glycol, diethy~ene glyeol
j ~ or triethylene glycol) or an acid such as acetic or prop~onie acid,
or a mixture of such an organic solvent with water. The reaetion
temperature is also not partieularly critical and may g~nerally be
from room temperature to about 200 C - thus, catalyti~ hydrogenation
may conveniently be performed at room temperature ar~d at atmos-
' pheric pressure, or under a pressure 2-3 times atmospheric, while
the other types of reduction are preferably effected with heating to
70-~00 C. The reaction time varies with the temperature and the
type of reducing agent employed, but is generally from l to 24 hours.
After completion of the reduction, the desired produet
of formula (VI) can be recovered from the reaction mixture by
,
~: '
~ .
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` :106090~
conventional techniques: for instance, the reaction mixture is
filtered to remove insolubles, the filtrate is extracted with a
suitable organic solvent, the organic extract is washed with water
and dried, and the solvent is distilled off from the extract to give
the desired product. If required, the product thus obtained can be
purified by conventional means such as recrystallization, vacuum
distillation or column chromatography.
- The indanylpropionic acids of formula (VI) thus obtained
can be saiified in the conventional manner, to yield pharmaceutically
acceptable salts such as those with aL~ali or alkaline earth metals
(e, g. the sodium, potassium, calcium and aluminium salts), the
ammonium salt, and salts with organic bases (e. g. the triethylamine,
dicyclohexylamine, dibenzylamine, piperidine and N-ethylpiperidine
; salts).
Due to the presence of asymmetric carbon atoms, the
compounds of formulae (I) and (VI) exhibit optical isomerism; When
mixtures of optical isomers are obtained, these can be resolved by
the conventional techniques, to isolate the individual optical isomers.
As used in this Specification, the formulae (I) and (VI) are intended
to include the individual optical isomers, as well as mixtures thereof.
,,
The pharmacological properties of the compounds of
.
' (8)
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~.
,.. . ~ .,.
106V904
formula (VI) and suitable formulations for their administration are
described in our CQ.~2adian Patent Application No. 219910.
The process of the present invention for preparing the
pharmaceutically active compounds of formula (VI) is commercially
more advantageous than the earlier process referred to hereinabove,
: ~ . since in the earlier process the yields of intermediates are relatively
lower and their isolation is relatively difficult by comparison with
the present process.
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106090~
The invention is illustrated by the following Examples.
E ~ample 1
2-(2-Isopropylindan-5-yl)propionic acid (VI)
(1) Ethyl 2 -l4 -(2, 2 -diethoxycarbonyl-3 -methyl-
butyl)-phenyl]propionate (V)
70 g of diethyl isopropylmalonate were added dropwise to a mixture
of 8, 5 g of a 50% suspension of sodium hydride in mineral oil and
' 180 ml of dimethylformamide, at a temperature below 30 C; then
40 g of ethyl 2-(4-chloromethylphenyl)propionate were added
dropwise to the resulting solution at 20-30C, and the mixture was
stirred for 2 hours at 40 C. The reaction mixture was then poured
into 50Q ml of ice-water, acidified with hydrochloric acid and
extracted with ether. The extract was dried over anhydrous sodium
,
sulphate and evaporated to dryness. The residue was distilled under
reduced pressure, giving 41 g of the desired product as a colourless
oil boiling at 159-160 C/0. 005 mmHg,
Analysis:
Calculated for C22H32O6 (%): C, 67- 32; H~ 8- 22
:.
- Found (%): C, 67. 82; H, 8. 47
,......................................................................... .
(2) 2-[4-(2-Carboxy-3-methylbutyl)phenyl]-
propionic acid lII)
40. 8 g of ethyl 2-[4-(2, 2-diethoxycarbonyl-3-methylbutyl)phenyl]-
:: :
,,, (10)
-
1060904
propionate were added dropwise to a mixture of 80 g of potassium
hydroxide and 80 ml of water at 105C, and the mixture was refluxed
for 7 hours. After cooling, the ml~ture was washed wit}l ether,
acidified with concentrated hydrochloric acid, and extracted with
ether. The extract was washed successively with water and aqueous
sodium chloride solution, dried over anhydrous sodium sulphate and
evaporated to dryness. The residue was heated for 1 hour at 180-
200 C under a pressure of 15 mmHg, giving 26 g of the desired
product as a pale yellow semi-solid,
. . .
(3) 2-(2-Isopropyl-l-oxoindan-6-yl)propionic
acid (I)
26 g of 2-[4-(2-carboxy-3-methylbutyl)phenyl]propionic acid were
added to 120 ml of concentrated sulphuric acid. The mixture was
heated for 3 hours at 100 C, then poured into ice-water and extracted
with ether. The extract was washed with water, dried over anhydrous
sodium sulphate and evaporated to dryness. Vacuum distillation of
the residue gave 15.7 g of the desired product as a colourless oil
boiling at 184 C/0. 002 mmHg.
~ .
Analysis:
Calculated for C15H18O3 (%): C, 73- 14; H~ 7- 37
.,
; Found (%): C, 73. 08; H, 7. 51
The corresponding morpholine salt had a melting point of 130-132 C.
'"
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..
, ,
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.
1060904
(4) 2-(2-Isopropylindan-5-yl)propionic acid (VI)
(a) A mixture of 15 g of 2-(2-isopropyl-1-oxoindan-6-yl)propionic
acid, 40 g of zinc amalgam, 50 ml of concentrated hydrochloric acid,
200 ml of dioxane and 30 ml of water was heated under reflux for 15
hours. After completion of the reaction, the reaction mixture was
extracted with ether. The ether extract was washed with water and
dried over anhydrous sodium sulphate. The solvent was distilled
off from the extract and the residue was recrystallized from
n-hexane, giving 9. 5 g of the desired product as colourless crystals
.,
with a melting point of 90-91_'5 C.
Analysis:
:
Calculated for C15H20O2 (%): C, 77- 55; H~ 8- 68
Found (%): C, 77. 62; H, 8. 73
... .
Aluminium bis~2-(2-isopropylindan-5-yl)propionate]
2. 32 g of 2-(2-isopropylindan-5-yl)propionic acid and 1. 02 g of
aluminium isopropoxide were added to 30 ml of toluene. The
mixture was heated under reflux for 3 hours, then 10 ml of water
and 20 ml of isopropanol were added to it, and the resulting mixture
was heated under reflux for another 12 hours, After completion of
the reaction, the solvent was distilled off under reduced pressure
and 30 ml of ethanol were added to the residue. The precipitate
which formed was recovered by filtration, giving 2. 2 g of the desired
product as white crystals.
(12)
, . .
.
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106090~
Analysis:
Calculated for C30H3gosAl~ H2O (%)
C, 68.68; H, 7. 87
Found (%): C, 68, 93; H, 7. 50
- 5 (b) A mixture of 1 g of 2-(2-isopropyl-1-oxoindan-6-yl)propionic
acid, 0, 2 g of lO~ palladi~m pr. carbon, 0.1 ml of concentrated
sulphuric acid and 20 ml of ethanol was subjected to catalytic
hydrogenation at room temperature and under atmospheric pressure,
After the theoretical amount of hydrogen had been absorbed,
insolubles were filtered off and washed with ethanol. The washings
were combined with the filtrate and the solvent was distilled off.
The residue was taken up in 20 ml of water and extracted with ether.
The ether extract was washed with water and dried over anhydrous
sodium sulphate. The solvent was distilled off from the extract and
the residue was recrystallized from n-hexane, giving 0. 7 g of the
...
desired product as colourless crystals with a melting point of
;i
90-91. S C. No depression of melting point was observed in a
mixed melting point determination using a sample of these crystals
,; together with a sample of the product of Example 1 (4)~a), and the
two products also had completely identical infra-red spectra,
. .
Example 2
2-(2-Ethylindan-5-yl)propionic acid (VI)
s
(13)
:
l060so4
(1) 3~thyl 2-14-(2, 2-diethoxycarbonyl-
butyl)phenyl~propionate (V)
11. 3 g of diethyl ethylmalonate were added dropwise to a mixture
of 3. 0 g of a 50~o suspension of sodium hydride in mineral oil
and 50 ml of dimethylformamide, at a temperature below 50 C,
then 11. 3 g of ethyl 2-(4-chloromethylphenyl)propionate were
added dropwise to the resulting solution at 20-30 C, and the
mixture was stirred for 2 hours at 70 C. The reaction mixture
was then worked up as in Example 1 (1), giving 14, 4 g of the
desired product as a pale yellow oil boiling at 140-146C/0. 02 mmHg.
::
Analysis:
Calculated for C21H30O6 (%): C, 66- 64; H, 7- 99
- Found (%): C, 66. 61; H, 7. 63
(2) 2-[4-(2-Carboxybutyl)phenyl]propionic acid (II) ~ -
14 g of ethyl 2-[4-(2, 2-diethoxycarbonylbutyl)phenyl]propionate were
added to a mixture of 14 g of potassium hydroxide, 100 ml of water
and 10 ml of ethanol, and the resulting mixture was refluxed for
6 hours. The reaction mixture was then worked up as in Example 1
(2), giving 11.1 g of a pale yellow oil. This oil was heated for
3 hours at 160-170 C and subjected to vacuum distillation, giving
7, 2 g of the desired product as a colourless oil boiling at 230 C/
:
- ~ 0. 05 mmHg,
: , :
~ ( 14 )
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1060904
Analysis:
Calculated for C14H18O4 (%): C, 67-18; H~ 7- 25
Found (%) C, 67. 03; H, 7. 37
(3) 2-(2-Ethyl-l-oxoindan-6-yl)propionic acid (I)
7 g of 2-[4-(2-carboxybutyl)phenyl]propionic acid were added to
35 ml of concentrated sulphuric acid and the mixture was heated
for 1 hour at 100 C. The reaction mixture was then worked up as
in Example 1 (3), giving 4,1 g of the desired product as a colourless
oil boiling at 197-200 C/0. 15 mmHg.
Analysis-
~! Calculated for C14H16O3 (%~: C, 72- 39; H, 6~ 94
.~,
` Found (%): C, 72. 32; H, 7,10
The corresponding piperidine salt had a melting point of 85-86 C.
(4) 2-(2-Ethylindan-5-yl)propionic acid (VI)
lS A mixture of 10. 5 g of 2-(2-ethyl-1-oxoindan-6-yl)propionic acid,
.:
20 g of zinc amalgam, 30 ml of concentrated hydrochloric acid,
150 ml of dioxane and 20 ml of water was heated under reflux for
15 hours. After completion of the reaction, the reaction mixture
was extracted with ether. The ether extract was washed with water
and dried over anhydrous sodium sulphate. The solvent was distilled
off from the extract and the residue was subjected to vacuum
distillation, giving 8. 2 g of the desired product as a colourless oil
(15)
' -
-
106~)904
with a boiling point of 165-166 C/l. 5 mmHg.
Analysis:
Calculated for C14H1802 (%): C, 77. 03; H, 8. 31
Found (%): C, 76, 95; H, 8. 35
2-(2-Ethylindan-5-yl)propionic acid piperidine salt
360 mg of 2-(2-ethylindan-5-yl)propionic acid were dissolved in
2 ml of benzene, and 200 mg of piperidine were added to the solution.
The solvent was distilled off under reduced pressure, and the residue
was cooled, giving 300 mg of a white powder. This powder was
recrystallized from a mixture of chloroform and petroleum ether,
giving the desired product as colourless prisms with a melting
point of 95-96C (with decomposition),
Analysis:
Calculated for C19H2gO2N (%):
C, 75. 2~; H, 9.63; N, 4.62
:
Found (%): C, 74. 70; H, 9. 89; N, 4. 83
Sodium 2-(2-ethylindan-5-yl)proplonate
- A solution of 2. 2 g of sodium- hydroxide in 9 ml of water and 21 ml
of ethanol was added to 12, 2 g of 2-(2-ethylindan-5-yl)propionic
acid. After dissolution was complete, the solvent was distilled off
under reduced pressure and ether was added to the residue. The
precipitate which separated out was recovered by filtration and washed
(16)
'' '
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'
1060904
with ether, giving 12. 9 g of a white powder. This powder was
recrystallized from a mixture of ethanol and ether, ~iving the
desired product as white needles with a melting point of 178-181 C.
Analysis:
Calculated for C14H1702Na (%): C, 69. 98; H, 7.13
Found (%): C, 70. 33; H, 7. 29
,.
r
(17)
. ' .
