Note: Descriptions are shown in the official language in which they were submitted.
10609~)3
This invention relal;es to novel indanylpropionic acid
derivatives, which are useful pharmaceutically by virtue of
exhibiting anti-inflammatory, analgesic and antipyretic
activities, and to the ir preparation
The invention provides compounds having the formula:
~ CH3
(wherein R represents an ethyl group or an isopropyl group)
and pharmaceutically acceptable salts thereof.
The compounds of formula (I) and their pharmaceutically
acceptable salts can exist in the form of optical isomers. The
individual isomers, as well as mixtures thereof, are included
within the scope of the invention.
In accordance with the invention, the compounds of
formula (I) and their pharmaceutically acceptable salts are
prepared by hydrolysing an indan derivative of formula:
R ~ I H - Y (II)
(wherein R has the meaning previously given; and Y represents
an alkoxycarbonyl group ha~ing from 1 to 4 carbon atoms in
the alkoxy moiety, a cyano group or a carbamoyl group ) to
obtain a compound of said formula (I) and, if appropriate,
q~
~ ~ . . "
~:. ' ' ' " - ~ ~
,
~6~9~3
salifying said compound of formula (I) to obtain a pharmaceutically
acceptable salt thereof.
The hydrolysis is suitably performed by treating the
indan derivative of formula (II) with a mineral acid, or with
an alkali or alkaline earth metal base. It is generally convenient
to use an aqueous solution of the acid or base, optionally in
the presence of a water-miscible organic solvent, The mineral
acid may be, for example, hydrochloric, hydrobromic, sulphuric
or phosphoric acid, and is preferably hydrochloric or hydrobromic
acid. The base may be a hydroxide, carbonate or bicarbonate of
an alkali or alkaline earth metal, and is preferably a hydroxide
of an alkali metal, for example potassium hydroxide or sodium
hydroxide. If the reaction is carried out in the presence of a
water-miscible organic solvent, this may suitably be a
carboxylic acid (e. g. acetic or propionic acid), an alcohol,
(e. g. methanol, ethanol, isopropanol or n-propanol), a glycol
(e, g. ethylene glycol or diethylene glycol), a dialkylformamide
(e. g. dimethylformamide)9 or a dialkylacetamide (e. g, dimethyl-
acetamide). It is preferred to use an aqueous mixture of such
an organic solvent.
The hydrolysis reaction is preferably carried out with
heating to a temperature of from 70 to 150C. The reaction
period will vary, depending mainly on the reaction temperature
2,
~0609103
and the nature of the starting material, but it is generally in
the range of from 3 to 18 hours.
After completion of the reaction, the desired product
can be re covered from the reaction mixture by conventional
techniques. For example, if a mineral acid is employed for
the hydrolysis, the reaction mixture can be poured into ice -
water and extracted with an appropriate organic solvent (e. g.
ether), the extract shaken with a dilute aqueous alkaline
solution, the aqueous layer acidified and re-extracted with an
lû appropriate organic solvent, the resulting extract washed and
dried, and the solvent distilled off to give the desired product.
On the other hand, if an alkali or alkaline earth metal base is
employed for the hydrolysis, the product can be recovered by
distilling off the solvent from the reaction mixture, diluting the
residue with water, shaking the resulting aqueous solution with
a water-immiscible organic solvent (e. g. ether), acidiying it
and extracting it with an appropriate organic solvent (e. g.
ether), washing the extract with water and drying it, and then
distilling off the solvent from the extract to give the desired
product. If necessary, the product thus obtained can be purified
by conventional methods, such as recrystallisation, distillation
under reduced pressure, or column chromatography.
The indanylpropionic acid derivative of formula (I) thus
. . , : , ' , ~ : ' '
' ~ : . ' . ,
106()903
obtained can, if appropriate, be converted into a pharmaceutically
acceptable salt thereof by neutralisation in the conventional manner,
Such pharmaceutically acceptable salts include alkali or alkaline
earth metal salts such as the sodium, potassium, calcium and
aluminium salts, the ammonium salt, and organic amine salts
such as the triethylamine, dicyclohexylamine, procaine, dibenzyl-
amine, piperidine and N-ethylpiperidine salts.
The starting materials of formula (II), used in the process
of the invention, are themselves new compounds and can be
prepared by the process summarised in the followmg reaction
scheme: - .
l060sa3
1st step ~ {~CH2
(III) (IV)
2nd step ~CH2CN 3rd step
(~)
/~ 4th step ~5H-COOR
R ~d
(lIa) (IIb) .
\th step
\~ ','.
R ~3 CH-CONH2
( IIc)
: ,: .
1060903
In the reaction scheme, R has the meaning already defined,
and R represents an alkyl group having from 1 to 4 carbon atoms.
In the first step of the reaction scheme, the compound (III)
is heated with formaldehyde in aqueous hydrochloric acid solution
at 50 - 100 C, to give the compound (IV). In the second step, the
compound (IV) is refluxed with an alkali metal cyanide (e. g.
potassium cyanide or sodium cyanide) in an appropriate organic
solvent, to give the compound (V). In the third step, the compound
(V) is refluxed with a methyl halide (e. g. methy~. iodide), in the
presence of an alkali metal compound such as sodium amide,
sodium hydride or n-butyl lithium, in an appropriate organic
solvent, giving the compound (IIa), which is one of the starting
materials of formula (II) used in the process of the invention.
If desired, the compound (IIa) can be converted into the compound
(IIb), another of the starting materials of formula (II), by
refluxing it with an alkanol having from 1 to 4 carbon atoms,
in the presence of an acid catalyst (e. g. concentrated sulphuric
acid or concentrated hydrochloric acid), Alternatively, the
compound (IIa) can be converted into the compound (IIc), which
is the third type of the starting materials of formula (II), by
reacting it with a mineral acid (e. g. concentrated sulphuric
acid or concentrated hydrochloric acid), at a reaction temperature
in the range of from room temperature to 9 0C.
1060903
~t the end of any of the reaction steps in the preparation
of the compounds of formula (II), the desired product can be
isolated from the reaction mixture by conventional techniques
and, if necessary, purified by one of the usual methods, such
as column chromatography or thin-layer chromatography.
The two compounds of formula (III), used as starting
materials in the preparation of the compounds of formula (II),
are already known. The compound of forrmlla (III) wherein R
is an ethyl group can be prepared by the process described by
T. Wagner-lauregg et al. in Chem. Ber. 74, 1522 (1~41); and
the compound of formula (III) wherein R is an isopropyl group
can be prepared by the process described by Pl. A. Plattner et
al, in Helv. ~him. Acta, 30, 689 (1947)
When a mixture of optical isomers is obtained in any of
the processes described hereinabove, if desired it can be resolved -
by conventional techniques at a convenient point in the synthesis.
So far as we are aware, no indanylpropionic acid
derivatives have previously been described in the scientific
literature. We have discovered that the indanylpropionic acid
derivatives of the present invention have potent anti-inflammatory,
analgesic and antipyretic activities, in association with extremely
low toxicities. By virtue of these properties, the compounds of
the invention are useful as pharmaceuticals; and, accordingly, the
- invention also provides a pharmaceutical composition, comprising
1060903
a compound of said formula (I) or pharmaceutically acceptable
salt thereof, together with a pha~maceutical carrier or diluent.
The compounds of formula (I) and their pharmaceutically
acceptable salts can be administered orally or parenterally,
by conventional methods. Accordingly, the pharmaceutical
composition of the invention can be formulated for oral or
parenteral administration, using solid or liquid pharmaceutical
carriers and diluents, and optionally also appropriate
pharmaceutical adjuvants, for example as tablets, capsules,
injectable liquids and suspensions. The optimum dosage can
vary, depending on the age, body weight and clinical condition
of the patient, but the total daily dosage for adults would generally
be in the range of from 50 mg to 2000 mg of the compound of the
invention, conveniently administered in divided doses three or
four times a day.
The pharmacological properties of the compounds of the
invention are illustrated by the following tests, in which acetyl-
salicylic aoid was used for comparative purposes.
I. Anti-inflammatory activity
( 1 ) Carrageenin -Oedema Test in Rats
The test compounds shown in Table 1 were administered
orally, in aqueous gum tragacanth suspension, to male rats of the
Wistar strain having a body weight of 120 - 150 g which had fasted
overnight. After 30 minutes, inflammation was induced by the
- 8.
; . '' , ... .::
1060'~03
method of Winter et al., Proc. Soc:. Exp. Biol. ~ed. 111 544(1962), by
injecting subcutaneously 0. 05 ml of a 1% carrageenin suspension
into the plantar tissue of the hind paw. Paw oedema was
measured volumetrically, immediately before and also 3 hours
after the carrageenin injection, and the response (R) was
calculated by the following equatiorl:-
~ = (~-Vo) / ~o
where Vo and V represent the paw volumes 0 and 3 hours after
the carrageenin injection, respectively.
(2) Adjuvant-induced Arthritis Test in Rats (Therapeutic
Effect on Established Arthritis).
7 ~ 8 Week old female rats of the Lewis or Sprague Dawley
strain were injected intradermally in the hind paw with 0. 5 mg of
heat-killed Mycobacterium butyricum in 0. 05 ml of liquid
paraffin. Eighteen days after this adjuvant injection, the animals
with well-established arthritis were selected and then treated for
7 consecutive days with the test compounds shown in Table 1,
administered twice a day orally. The response to this therapy
was assessed by measuring the thickness of the injected foot with
a micrometer at the beginning (day 18) and at the end (day 25) of
the therapy period.
II Analgesic Activity on Inflammatory Pain
(1) Yeast-Induced Pain Test in Rats (Randall-Selitto's Method)
Male rats of the Wistar slrain, with a body weight of 70 -
9.
: . . . ..
106a\903
80 g, were injected in the plantar surface of the hind paw with
0.1 ml of a 5% suspension of dried yeast, to produce inflammation
therein. The pain reaction threshold when pressure was applied
to the paw was then measured, using the apparatus described by
S Randall and Selitto in Archs int. Pharmacodyn. Ther. 111~
409 (1957), and those animals were selected which satisfied the
following conditions :-
(a) the threshold in the inflamed paw was less than
50 mm Hg; and
(b) the difference in thresholds between the non-inflamed
and inflamed paws was more than 50 mm Hg.
The test compounds shown in Table 1 were administered orally
to these selected animals, 4 hours after the injection of the dried
yeast suspension. The pain reaction threshold was determined
as before, and the percentage increase in pain threshold (% IPT)
of each animal was calculated from the equation:
% IPT=(Pd-Pi/Po-Pi) x 100
where Poand Pi represent the thresholds before medication in
the non-inflamed and inflamed paws, respectively, and Pd
, _ ,
represents the threshold in the inflamed paw after medication.
The value of Pd was measured 1 and 3 hours after the administration
of the test compounds, and a mean value for the % IPT was calculated
from these two measurements.
10.
; ~060~03
(2) Thermal Pain Test in Rats
The method described by Y. Ii~uka and K. Tanaka in
Folia Pharmacol. Japan, 70, 697 (1974) was used for this
test. 5 to 7 Week old male rats of the Wistar strain received
a standard heat injury on their hind paw, by dipping it for 5
secondsin water at 57 C. More than 1 hour later, a pain
reaction could readily be evoked by further application of heat
(5 seconds at 40 C) - that is to sayJ immediately after this
treatment the animal raised its injured paw, presumably to
avoi~ further pain which might be caused by contact with the
wire netting of its cage. The "pain reaction time" was taken
as the total time during which this paw-raising behaviour
occurred over a period of 30 seconds. The test compounds
shown in Table 1 were administered orally to the rats 2 hours
after the first application of heat, and the response to the drugs
was assessed by calculating the mean value of the pain reaction
times measured 1 and 2 hours after drug administration.
III. Antipyretic Activity
.
TTG-induced Fever Test in Guinea~pigs
: .
Antipyretic activity was determin~ d by a modification
of the method described by Kobayashi and Takagi in Jap. J.
Pharmacol. 18, 80 (1968). Fever was induced in female
guinea-pigs of the Hartley strain with a body weight of about
300 g, whlch had fasted overnight, by injecting them with 10 jug/ml/kg
.
,
, . . .
~060'103
of TTG (a polysaccharide elaborated by Pseudomonds luorescens,
produced by Fujisawa Pharmaceutical Co., Ltd., Japan). One
hour after the injection, those test animals were selected which
had a rectal temperature in the range of from 0. 8C to 1. 2 C
above normal. The test compounds shown in Table 1 were
administered orally to these selected animals 1. 5 hours after
the TTG injection, and the response to the drugs was assessed by
calculating the mean value of the rectal temperatures measured 1
and 2 hours after drug administration.
Statistical Analysis
The results obtained in the pharmacological tests were
analysed. In order to obtain the regression line of H (percentage
inhibition of response) over D (dose of the test drug), the H for
each animal was calculated from the ratio of the response to the
mean response in a non-medicated group. The regression line
and ID50 (inhibition dose 50%) were obtained by the method of
least squares. Confidence limits for the ID values were calculated
by means of Fieller's Equation.
However, in the adjuvant-arthritis test, the ratio (RR)
of responses after/before medication was first calculated, the
response being assessed by measuring the thickness of the injected
foot. The value of EI for each animal was then calculated from the
ratio of RR to RRc, where RRc represents the mean value of RR
1 2.
1060~03
for a non-medicated group.
In the test by the Randall-Selitto method, the value of
H for each animal was obtained directly from the percentage
increase in the pain threshold, after adjusting it by the
corresponding mean value for a non-medicated group.
ute Toxicit~
The acute toxicity of the two compounds OI the invention
shown in Table 1 was determined by administering a single oral
dose to male ICR mice 5 weeks old. The lethal effect was . .
expressed as X/n, in which ~ is the number of animals which
were dead one week after administration and n was the total number. .
of animals used in the test.
The data thus obtained rom the pharmacological tests
are shown in Table 1. The ranges of values shown in parantheses
for ID50 (inhibition dose 50%) are those corresponding to statistical
confidence limits of 95%. In the case of the adjuvant-arthritis
test, the values given are for ID30 (inhibition dose 30%).
' ' ' '
.
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~ ~ ., h ~ ' ~--~ ~i ~1
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~ h ~ O-- di 1:- ~
.~ ~ ~3 ~1` t~ ~
~ ~ ol
i~ ~ ¦ O~ N ~ N
!~ ¦ I ~ ~ ~
o ~ ol O O oo
~, ~¢~ ~ ~ ~:; l ..
o .~ ~ ~
a = 'o ~: O o ~
_ E~, c~ C~ d ¢~d
1060'~03
The invention is illustrated l~y the following Examples 1
to 7, while the subsequent Preparations 1 to 5 illustrate the
synthesis of the starting materials of formula (II) and intermediates
therefor.
Example 1
2-(2-Ethylindan-5-yl)propionic acid
5 g of ethyl 2-(2-ethylindan-5-yl)propionate were dissolved
in a mixture of 50 ml of 10% aqueous potassium hydroxide solution
and 80 ml of ethanol, and the resulting solution was refluxed for
4 hours over a water bath. After completion of the reaction, the
reaction mix~ure was poured ir.to ice-water, and the resulting
solution was shaken with ether to remove unreacted starting
material. The aqueous layer was separated off, acidified to
pH 4 - 5 with dilute hydrochloric acid, 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,
leaving 3. 2 g of a pale yellow oil. This oil was distilled under
reduced pressure, giving the desired product as a colourless oil
boiling at 165 - 166C/1. 5 mmHg.
Elemental analysis:
Calculated for C14H18 2 ' %; ' %-
Found: C, 76. 93%; H, 8. 53%.
10609()3
Example 2
Piperidine 2-(2-ethylinda_-yl)propionate
200 mg of piperidine were added to a solution of 360 rng
of 2-(2-ethylindan-5-yl)propionic acid in 2 ml of benzene,
The solvent and excess piper;dine were distilled off under
reduced pressure, and the residue was cooled, leaving 300 mg
of a colourless powder. This powder was recrystallised from a
mixture of chloroform and petroleum ether, giving the desired
product as colourless prisms melting at 95 - 96C with
decomposition.
Elemental analysis (%):
Calculated for ClgH2902N: C, 75. 20; H, 9. 63; N, 4. 62
Found: C, 74, 72; H, 9. 69; N, 4, 82
Example 3
Sodium 2-(2-ethylindan-5-yl)propionate
2. 2 g of sodium hydroxide and 12. 2 g of 2-(2-ethylindan-
5-yl)propionic acid were dissolved in a mixture of 9 ml of water
and 21 ml of ethanol, the solvent was distilled off, and ether was
added to the residue. The precipitate obtained was collected on a
filter and washed with ether, giving 12. 9 g of a white powder.
This powder was recrystallised from a mixture of ethanol and
ether, giving the desired product as white needles melting at
178 - 181C,
16.
?
~060903
Elemental analysis(%)
Calculated for C14H1~702Na C, 69- 98; H~7 13
Found: C, 7 0. 22; H, 7 . 27
:Example 4
2-(2-Isopropylindan-5-yl)propionic acid
2. 6 g of ethyl 2-~2-isopropylindan-5-yl)propionate were
dissolved in a mixture of 20 ml of 10% aqueous potassium hydroxide
solution and 80 ml of ethanol, and the resulting solution was
refluxed for 3 hours ov~r a water bath. After completion of the
reaction, the organic solvent was distilled off from the reaction
mixture, and water was added to the residue. The aqueous layer
was separated off and shaken with ether, to remsve unreacted
starting material, acidified to pH 4 - 5 with dilute hydrochloric
acid, and extracted with ether. The extract was washed with
water and dried over anhydrous sodium sulphate. The solvent
was distilled off from the extract, leaving 2.1 g of colourless
crystals. These crystals were recrystallised from a mixture of
benzene and n-hexane, giving the desired product as colourless
prisms melting at 90 - 91. 5 C.
Elemental analysis(%)
Calculated fo 15 20 2
l~ound: C, 77 . 59; H, 8. 65
106~903
Example S
2-(2-Isopropylindan-5-yl)propionic acid
1. 05 g of 2-(2-isopropylindan-5-yl)propionitrile were
dissolved in a mixture of 15 ml of concentrated hydrochloric
acid and lS ml of dioxane, and -the resulting solution was
refluxed for 6 hours over an oil bath. After completion of
the reaction, the reaction mixture was poured into ice-water,
and the resulting 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, leaving
0. 81 g of colourless crystals. These crystals were recrystallised
from n-hexane, to give the desired product as colourless prisms
melting at 90 - 91. 5C.
,
This product was shown to be identical with the one obtained
in Example 4, by means of a mixed melting point determination
and their infrared spectra.
Example 6
2-(2-Isopropylindan-5-yl)propionic acid
15 ml of concentrated hydrochloric acid were added to
2. 3 g of 2-(2-isopropylindan-5-yl)propionic acid amide and the
resulting mixture was refluxed for 1. 5 hours. After completion
of the reaction, the reaction mixture was worked up in the same
way as in Example 5, giving 2.1 g of the desired product as
colourless prisms melting at 90 - 91. 5C.
18.
.:
10t~0903
This product was shown to be identical with the one obtained
in Example 4 by means of a mixed melting point determination and
their infrared spectra.
Example 7
Aluminium bis[ 2 ~2 -isopropylindan- 5 -yl)propionate~
2. 32 g of 2-(2-isopropylindan-S-yl)propionic acid and
1. 02 g of aluminium isopropoxide were added to 30 ml of toluene.
The resulting mixture was refluxed for 3 hours, then 10 ml of
water and 2Q ml of isopropanol were added to it, and the mixture
was refluxed for a further 1 5 hours. After completion of the
reaction, the solvent was distilled off from the reaction mixture,
and 30 ml of ethanol were added to the residue. The precipitate
obtained was collected on a filter, giving 2. 2 g of the desired
product as a white powder.
Elemental Analysis(%)
Calculated for C30H3905Al H20: C, 68. 68; H, 7. 87
Found: C, 68. 92; H, 7. 60
Preparation 1
2-Ethyl-S-~-cyanoethylindan (IIa)
(1) 2-Ethyl-5-chloromethylindan (IV)
100 ml. of concentrated hydrochloric acid were added with
ætirring to a mixture of 60 g of 2-ethylindan, 30 g of paraformaldehyde,
68 ml of acetic acid and 45 ml of phosphoric acid. The resulting
19.
10609Q3
mixture was heated with stirring for 5 hours at 90 - 95 C, After
completion of the reaction, the reaction mixture was poured into
ice-water, and the resulting mixture was extracted with ether.
The ether extract was washed with water and dried over anhydrous
sodium sulphate, Tbe solvent was distilled off from the extract,
leaving a pale yellow oil. This oil was subjected to vacuum
distillation, giving 46 g of the desired product as a colourless oil
boiling at 108 C/2mmHg.
Elemental analysis(%):
Calculated for C12H15Cl: C, 74. 03; H, 7. 77; Cl, 18- 21
Found: C, 73. 59; H, 7. 90; Cl, 17, 67
2) 2-Ethyl-5-cyanomethylindan (V)
30 g of 2-ethyl-5-chloromethylindan and 15 g of potassium
cyanide were dissolved in a mixture of 20 ml of water and 80 ml
of ethanol, and the resulting solution was refluxed for 5 hours
over a water bath. After completion of the reaction, the ethanol
was distilled off under reduced pressure, leaving a colourless oil.
This oil was subjected to vacuum distillation, giving 18. 7 g of the
desired product as a colourless oil boiling at 130C/3mmHg.
Elemental analysis~%):
Calculated for C13H15N: C, 84. 28; H, 8. 16; N, 7. 56
Found: C, 84. 46; H, 8, 42; N, 7. 34
20,
106(~903
(3) 2-(2-Ethylindan-5-yl)propionitrile (IIa)
0, 8 g of sodium amide and 3, 7 g of 2-ethyl-5-
cyanomethylindan in 20 rnl of anhydrous benzene were added to
10 ml of anhydrous ben~ene. The resulting mixture was refluxed
for 3 hours, then 4, 3 g of methyl iodide were added to it, and
the mixture was heated with stirring for 5 hours at about 70 C
in a pressure vessel. After completion of the reaction, water
was added to the reaction mixture. The benzene layer was
separated off, washed with water, and dried over anhydrous sodium
I0 sulphate. The solvent was distilled off, giving 1. 6 g of the desired product as a colourless oil.
Preparation 2
Ethyl 2-(2-ethylindan-5-yl)propionate (IIb)
4. 4 ml of concentrated sulphuric acid were added to a
solution of 4. Og of 2-(2-ethylindan-5-yl)propionitrile in 8 ml
of absolute ethanol, and the resulting mixture was refluxed
for 12 hours over a water bath. After completion of the reaction,
the reaction mixture was poured into ice-water, and the resulting
mixture was extracted with ether. The ether extract was washed
first with water and then with 101/o aque ous sodium carbonate
solution, and dried over anhydrous sodium sulphate. The solvent
was distilled off from the extract, leaving an oil. This oil was
subjected to vacuum distillation, giving 3. 4 g of the desired product
as a colourless oil boiling at 120 - 122 C/2mmHg,
21,
.
1060'903
Elemental analysis ~%):
Calculated for C16H22O2
Found: C, 78.22; H, 9.08
Preparation 3
.
2-(2-Isopropylindan-5-yl)propionitrile (IIa)
(1) 2-Isopropyl-5-chloromethylindan (IV)
A mixture of 100 ml of concentrated hydrochloric acid, 70
g of 2-isopropylindan, 30 g of paraformaldehyde, 70 ml of acetic
acid and 50 ml of phosphoric acid was heated with stirring for 5
hours at 90 - 95C. The reaction mixture was then worked up in
the same way as in Preparation 1(1), giving 53 g of the desired
product as a colourless oil.
(2) 2-Isopropyl-5-cyanomethylindan (V)
32 g of 2-isopropyl-5-chloromethylindan and 15 g of potassium
cyanide were dissolved in a mixture of 20 ml of water and 80 ml
of ethanol, and the resulting solution was refluxed for 5 hours
over a water bath. The reaction mixture was then worked up in the
same way as in Preparation 1(2), giving 22 g of the desired pro-
duct as a colourless oil.
(3) 2-(2-Isopropylindan-5-yl)propionitrile (IIa)
1.0 g of a 50% suspension of sodium hydride in liquid para-
ffinand 4.0 g of 2-isopropyl-5-cyanomethylindan in 20 ml of
anhydrous benzene were added to 10 ml of anhydrous benzene. The
resulting mixture was refluxed for 3 hours, then 4.3 g of
- 22 -
- ' `
10610903
methyl lodide were added to it, and the resulting mixture was
heated with stirring for 5 hours at about 70C in a pressure
vessel. The reaction mixture was then worked up in the same
way as in Preparation 1(3), giving a pale yellow oil. This oil
was subjected to vacuum distillation, giving 2,1 g of the desired
product as a colourless oil boiling at 142 - 145C/0, 5 mmHg.
Elemental analysis(%)
Calculated for C15H19N: C, 84 45; H, 8 98; N, 6- 57
Found: C, 84 88; H, 9. 01; N, 6. 29
' 10 Preparation 4
Ethyl 2-(2-isoyropylindan-5-yl)propionate (Ilb)
`~ 4. 4 ml of concentrated sulphuric acid were added to a
solution of 4, 3 g of 2-(2-isopropylindan-5-yl)propionitrile in
8 ml of absolute ethanol, and the resulting mixture was refluxed
for 12 hours over a water bath. The mixture was then worked up
in the same way as in Preparation 2, giving a colourless oil.
This oil was subjected to vacuum distillation, giving 3. 5 g of
the desired product as a colourless oil boiling at 160 - 163C/2mmHg
( bath tempe rature ).
Elemental analysis(%)
ated for C17H242 C~ 78- 42; H~ 9~ 29
. Found: C, 78, 54; H, 9. 33
~: 23.
D
. ' ' ' : ,
1060903
Preparation 5
2-(2-Isopropylindan-5-yl)propionic acid amide (IIc)
25 ml of concentrated hydrochloric acid were added to
3. 2 g of 2-(2-isopropropylindan-5-yl)propionitrile, and the
resulting rmixture was warmed to about 30C with stirring for
1, 5 hours. After completion of the reaction, the reaction mixture
. ~ was poured into ice-water. The precipitate produced was collected
: ~ on a filter, washed with water and recrystallised from a mixture of
: ethyl acetate and n-hexane, giving 3. 0 g of the desired product
as colourless plates with a melting point of 112-114C.
Elemental analysis(%):
.:,
Calculated for C15H210N: C, 77, 88; H, 9. 15; N, 6- 05
Found: C, 78, 06; H, 8. 99; N, 6. 35
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