Note: Descriptions are shown in the official language in which they were submitted.
7~39
~(ethod of producing indan derivatives
This invention relates to a novel method of producing indan
derivatives of the general formula: ';
~. Rl
R ~ (I)
3 OOH
wherein Rl represents a hydrogen atom, an arylcarbonyl group or an
arylcarbonyl group substituted by alkyl ha~ing 1 to 4 carbon atoms,
alkoxy having 1 to 4 carbon atoms or halogen; R2 is a hydrogen atom
~ or a cycloalkyl group; and R3 is a hydrogen atom or a halogen atom.
i The indan derivatives of general formula ~I) have eminent
¦ 10 analgesic, antiinfla~matory and antipyretic properties and are of
value as, for example, analgesics, antiinflammatory agents, antipyretics
and other agents in huoan or animal use. For the production of these
compounds, there are known the processes disclosed in United States
Patent 3,923,866 and United States Patent 3,953,500, for instance.
Hovever, such known processes are not altogether satisfactory
in such aspects as production steps, yield purification procedure ` ',
and so forth.
The present invention seeks to provide a novel method for
producing the indan derivatives of the general formula (I~ which
has advantsges from the industrial point of view.
Tho present invention therefore relates to a method for
producing an indan derivative of general formula ~I), which comprises
tl~ reacting z compound of general formula:
Rl
R
<~
,,, '' ' '' i
c; ~ 107~
~ ,
wherein Rl, R2 and 23 have the meanings given above, with a sulfonylmethyl-
isonitrile compound of the general formula:
4SO2CH2NC
wherein R4 represents an alkyl group of 1 to 4 carbon atoms; an aryl
group which i; unsubstituted or substituted by alkyl of 1 to 4 carbon
atoms, or an aralkyl group or an aralkyl which is substituted by
alkyl of I to 4 carbon atoms; in the presence of a baso to produce
a methylideneindan compound of the general formula:
~3/ ~ ~IV~
/ NH-CH0
R4 SO2
! lo wherein Rl, R2, R3 and R4 have the meanings given above, and then
¦ (2) hydrolyzing the once-recovered methylideneindan compound. ,
Referring to thc above general formulas, the aryl moiety
¦ of said arylcarbonyl group Rl may for example be phenyl or naphthyl.
¦ This aryl group ~ se ~ay also be substituted, the substituents
¦ including straight-chain or branchcd lower alkyl groups having 1
j to 4 carbon atoms te.g. methyl, ethyl, n-propyl, isopropyl, n-butyl,
~, isobutyl, t-butyl, etc.), lower alkoxy groups having 1 to 4 carbon
atoms ~e.g. methoxy, eth^xy, n-propoxy, isopropoxy, n-butoxy,
isobutoxy, sec.-butoxy, etc.), or ha.ogen ~e.g. fluorine, chlorine,
bromine, etc.). One or more of such substituents, which may be
the same or different groups, may occur in optional positions on
v
7 D - 2 -
~ I
.. , ~_
. --. .. . .
I
;h ~ ~,076139
~. ,.
the aryl group. In the general formulas, the cycloalkyl group
R2 is one containing 5 to 7 carbon atoms ~e.g. cyclopentyl,
cyclohexyl, cycloheptyl, etc.) As examples of said halogen atom
represented by R3, there may be mentioned chlorine, bromine,
fluorine and iodine. As examples of aryl group represented by
R4, there may be mentioned phenyl and naphthyl. The aralkyl group
represented by R4 may for example be benzyl, phenethyl or the
like. The aryl and aralkyl groups may have substituents in optional
positions on the respective aromatic rings, said substituents boing
j 10 alkyl groups of 1 to 4 carbon atoms, namely methyl, ethyl, propyl or
butyl. The alkyl group, also alternatively designated by R4, is
an alkyl group containing 1 to 4 carbon atoms, thus being methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or t-butyl.
In the method according to the present invention, a
compound of gcneral formula tll) is first reacted with a sulfonyl-
methylisonitrile coopound tIII) in the presence of a base.
As examples of the base, there may be mentioned metol alkoxides
te.g. alkali metal alkoxide prepared from lower alcohols such as
methanol, ethanol, t-butanol, etc. and alkali metals such as
1 20 sodium, potassium and the liXe), alkali metal hydrides te.g. sodium
hydride, lithium hydride, etc.) and so on. When metal alkoxide is
used, it is normally nore expedient to use it as a solution in the
corresponding alco~ol.
This reaction is preferably carried out in a solvent,
which may for example be an ether (e.g. dimethoxyethane, diethoxy- r
ethane, :etrahydrofuran, dioxane or the liXe~, nitrile (e.g. acetonitrile,
propionitrile or the like), alkyl halide Ce.g. methylene chloride,
~ ~ 1076139
`~. ethylene chloride, methylene bromide or the like2 and so on.
Thi5 reaction is usually carried out at a temperature
ranging from -70 to 10C, preferably at a temperature between
~ -S0~ and 0C and mcre preferably at a temperature betwcen
~ -20 and 0C, although the n,ost preferable temperature varies
with the type of solvent and of base employed and other conditions.
The aforesaid base is preferably used in a proportion of 1 to
1.5 moles per mole of compound (II), while said sulfonylmethylisonitrile
f
~:~
:~"'
.. - ,' ' I ' i
I 1
" ~ .
"'~''''' . I "
,' ~ ~i ~
, i ~.
, : '
.,-~,.,
... ,~,.......... ~ ,
.. ~ ''
- 10761~3$
. .
compound (III) is preferably employed in an equimolar
proportion relative to the base ~he resultant compound
(IV) can be easily separated and purified by conventional
separatory procedure~ such as extraction, recrystullization
and so forth. While compound (IV) is normally o~tained as
a mixture of two stereoisomers, it is generally a enable
to crystallization and, as such a mixture, can be easily
purified However, for the purpose of obtaining a compound
(I), the compound (IV) need not necessarily be purified
but the crude product once recovered may be direct]y sub-
Jected to the next reaction ~or example, the residue which
is obtained by the conce~tration of the reaction mixture
can be employed to the next reaction. ~ 1
Then, the compound of general formula (IV) is hydro- ,
lyzed. The catalyst for hydrolysis may be whichever of an
acid catalyst and a basic catalyst. As examples of the acid
catalyst, there may be mentioned mineral acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, phos-
phoric acid, etc., while said basic catalyst may for
example be selected from among alkali metal hydroxides such
as sodium h~droxide, potassium hydroxide and so forth.
While water alone may prove to be a useful solvent, the
reaction time may be considerably reduced by the concurrent
use of one of water-miscible ethers (e.g dioxane, tetra-
hydrofurar., dimethoxyethane, diethoxyethane, etc ), w&~er- ~ !
miscible alcohols (e.g. methanol, ethanol, t-butanol, etc.)
and water-miscible organic acids (e.g. acetic acid, propionic
acid, e~^ ) It is particularly advantageous, for commercial
. . ,
j, - i
1076139
purp)ses, to employ dioxane where the cAtalyst is a mineral
acid, or ethanol where an alkali metal hydroxide is used as
the catalyst. While the reaction temperature varies with
different catalysts that may be employed, the reaction is
generally conducted at a temperature ranging from 0C to
the boiling point of solvent used. It is particularly
advantageous, in commercial runs, to carry out the reaction
under reflux of the solvent employed.
~ he contemplated compound (I) thus ob'ained can be
eas;ly separated and purified by conventional separatory
I procedures such as extraction and recrystallization.
As a commercial production process, the method
, according to the present invention has a number of advant-
i ageous features, such as the reduced number of production
steps required, improved product yields and greatly facili-
tated reaction procedures.
Above anything else, the isolation and purification
¦ of intermediate compound (IV) and of end product compound
(I) are considei~ably facilitated. For example, column
chromatography and other complicated procedures may now
! be dispensed with.
¦ The following ~xsmples are further illustrative of
the present invention, it being, of course, to be under-
stood that the invention is by no means limited to such
specific embodiments. In the following examples, gram(s)
and milliliter(s) are simply abbreviated as "g." and 'lme.
' respectively.
. _
,
` ` ~ 1076139
l~;xample 1
To 300 m~. of dimethoxyethane was added 23.6 g of 4-
benzoyl-l-indanone together with 22,0 g. OI tosylmethyl-
isonitrile,
The mixture was cooled to -10C and stirred, To this
solutlon was added dropwise a solution of 22 g, of 28 /c
sotLium methoxide in methanol diluted with 100 m~ of dimethoxy-
ethane over a period of 1 hour, Following the dropwise addi-
tion, the mixture was stirred at -10C for 1 hour and, then,
a solution of 7 g, of scetic acid in 50 m~. of dimethoxy-
ethane was added dropwise. The reaction mixture was con-
centrated under reduced pressure and to the residue was
added water, The mixture was extracted with chloroform,
The extract was washed with water and dried over magnesium
sulfate. The solvent was then distilled off under reduced ' -
pressure, 'rO the residue was added 350 m~. OI benzene and,
after incubation, the mixture was allowed to cool. The
resultant crystals were collected by filtration. By the
above procedure was obtained 33.4 g, (?7.5 %) of 4-benzoyl-
l-~(N-formylamino)tosylmethylidene)indan, Recrystallization
i - from ethanol yielded crystals melting at 230-232~C.
Elemental analysis, for C25H2104NS
Calcd. C, 69.58; H, 4.91; N, 3.25
Found C, 69.42; H, 4.92; N, 3.24
Examole 2
To 300 m~, of dimethox"-cthane was added 25.5 g. of
~? 4-(4-methylbenzoyl)-1-indanvne together with 22.4 g, of
r' tosylmethylisonitrile, The mixt~re was cooled to -10C 1'
. -- 7 --
- 1~761~9
~.
and stirred. To this solution was added dropwise a solution
of 22,4 g. of 28 % sodium methoxide in methnnol diluted
with 100 m~. of dimethoxyethane over a period of 1 hour,
Following the dropwise addition, the mixture was stirred
at -10C for 30 minutes and, then, a solution of 7,2 g. of
acetic acid in 10 m~, of dimethoxyethane was added dropwise.
The reaction mixture was concentrated under reduced pressure
and to the residue was added water. The mixture was extracted
with chloroform, The extract was washed with wster and dried
over magnesium sulfate, The solvent was distilled off under
reduced pressure. To the residue was added 500 m~. of
~ benzene and, after incubation, the mixture was allowed to
! cool. The resultant crystals were then collected by filtra-
tion. By the above procedure was obtained 33,8 g. (74.4 %)
of l-((N-formylamino)tosylmethylidene~-4-(4-methylbenzoyl)indan.
i Recrystallization from ethanol yielded crystals melting at
t 200-204C.
~, Elemental analysis, for C26H2304NS
~ Cal^d, C, 70.10; H, 5,20; N, 3,14
~ Found C, 70,15; H, 5.09; N, 3,14
t xample 3
To 30 m~. of dimethoxyethane was added 2,5 g, of 4-
(4-methylbenzoyl)-1-indartone ~cgether with 2.2 g, of tosyl-
methylisonitrile. The mixture was cooled to -10C and
stirred, To this solution wa.s added dropwise a solution
of sodium ethoxide (prepared from 250 mg, of sQdium metal
and 3 m~, of dry ethanol) diluted with 10 m~, of dimethoxy-
ethane over a period of 30 minutes, Following the dropwise
., _
~; r 1076139
addition, the mixtur~ was stirred at - 5C for 1 hour and,
then, a solution of 0.7 g, of acetic acid in 5 m~, of dimethoxy-
ethane was added dropwise, The reaction mixture was concent- ;
rated under reduced pressure and to the residue was added
water, The mixture was extracted with chloroform, The
extract was washed with water and dried over magnesium
` sulfate, The solvent was then distilled off under reduced
; pressure, To the residue was added 50 m~, of benzene and,
after incubation, the mixture waa allowed to cool, The
resultant crystals were collected by filtration. By the
above procedure was obtained 3,37 g. (75.7 %) of 1~
formylamino)tosylmethylidene)-4-(4-methylbenzoyl)indan,
In spectral data, this product was found to be identical
Witil the crystals obtained in Example 2.
Example 4
To 15 m~. of dry tetrahydrofuran was added 1,25 g. of
, 4-(4-methylbenzoyl)-1-indanone together with 1,1 g, of
i tosylmethylisonitrile. The mixture was cooled to -10C and
¦ stirred. To this solution was added dropwise a solution of
1.1 g, of 28 '~ sodium methoxide in methanol diluted with
~ 5 m~, of dry tetrahydrofuran over a period of 20 minutes.
j Following the dropwise addition, the mixture was stirred
at -10C for 1 hour ar.d, then, a solution of 0,35 g, of
acetic acid in 5 m~. of tetrahydrofuran was added dropwise,
~he reaction mixture was concentrated under reduced pressure
~ and to the residue was added water. The mixture was extracted
¦ with chloroform, The extract was washed with water and
3 dried over magnesium sulfate, The solvent was then distilled
'':
)
~ .
076139
off under reduced pressure. To the residue was added 25 m~.
of benzene and, after incubation, the mixture was allowed
to cool. The resultant crystals were collected by filtra- -
tion. 9y the above procedure was obtained 1.4 g. (64 /0) of
l-((N-for~ylamino)tosylmethylidene)-4-(4-methylbenzoyl)-
indan. In spectral data, this produc' was found to be
identical with the crystals obtained in ~xample 2.
Example 5
~o 20 ml. of dimethoxye~hane was added 1.8 g. of 4-
(4-chlorobenzoyl)-1-indanone together with 1.5 g of tosyl-
methylisonitrile. The mixture was cooled to -10C and
stirred To this solution was added dropwise a solution of
1.5 g. of 28 % sodium methoxide in ~ethanol diluted with !
5 mf. of dimethoxyethane over a period of 15 minutes,
j Following the dropwise addition, the mixture was stirred
, at -10C for 1 nour and, then, a solution of 0.5 g. of
¦ acetic acid in 5 m~. of dimethoxyethane was added dropwise.
S The reaction mixture was concentrated under reduced pressure
and to the residue was added water. The mixture was extracted
with chloroform. The extract was washed with water and dried
over magnesium sulfate, ~he solvent was then distilled off
under reduced pressure. ~o the residue was added 20 m~.
of benzene and, after incubation, the mixture was allowed
to cool The resultant crystals were collected by filtra-
tion.
~y the above procedure was obtained 2.45 g. (79.0 %)
o of 4-(4-chlorobenzoyl)-l-((N-formylamino)tosylmethylidene)-
- ~ indan. Recrystallization from ethanol yielded crystals
. y
-- 10 --
,
7 613~9
melting at 185-188C.
Elemental analysis, for C25H2004NSC~
Calcd, C, 64,44; H, 4,33; N, 3.01; Cf, 7.61 ,'
- Found C, 64.58; H, 4,39; N, 2.99; ce, 7.55
Ex~mDle 6
To 15 m~. of dimethoxyethane was added 1.25 g, of 6-
chloro-5-cyclohexyl-1-indanone together with 1,1 g. of
tosylmethylisonitrile. The mixture was cooled to -10C
and stirred, To this solution was added dropwise a solution
of 1,1 g, of 28 % sodium methoxide in methanol diluted ~rith
) 5 me~ of dimethoxyethane over a period of 15 minutes,
I After the dropwise addition h~d been completed, the mixture
was stirred at -10C for 1 hour and, then, a solution of
0.35 g. of acetic acid in 5 mf. of dimethoxyethane was
added dropwise. The reaction mixture was concentrated under
~ reduced pressure and to the residue was added water. The
¦ mixture was extracted with chloroform. The extract was
washed with water and dried over magnesium sulfate. The
solvent was then distilled off under reduced pressure. ~ke
residue was dissolved in 100 me. of ether under heating and
filtered. The filtrate was allowed to cool, ana, ~e
resultant crystals were collected by filtration. By the
abovo procedure wa:; obtained 1.3 g. (71 ~o) of 6-chloro-5-
cyclohexyl-l-~(N-formylamino)tosylmethylidene)indan,
melting point: 195-199CC.
Elemental analysis, for C24H2603NSCe
Calcd, C, 64,92; H, 5.90; N, 3,16
E r c, 64.94; H, 6.07; N, 3,15
- 1 1 - I
-~
1o76139
; i By a procedure similar to that described above, the
following compound was synthesized. 5-Cyclohexyl-l-((N-
- formylamino)tosylmethylidene)indan, melting point: 135-138C.
; Elemental analysis, for C24H270~NS
Calcd C, 70.38; H, 6.65; N, ~.42
Found C, 7G.05; H, 6.94; N, 3.39
; Example 7
To 40 m~. of acetonitrile was added 2.36 g. of 4-
benzoyl-l-indanone together with 2.3 g. of tosylmethyl-
isonitrile. ~he mixture was cooled to -15C and stirred.
To this solution was added dropwise a solution of 2.2 g. of
28 % so~ium ~ethoxide in meth:nol over a period of 8 minutes
~. !
!' ' Following the dropwise addition, the mixture was stirred
at -12 to -lO~C for 2 hours. After 0.7 g. of acetic acid
¦ - was added to the mixture, the solvent was distilled off
under reduced pressure. To the residue was added water.
I The mixture was extracted with chloroform. ~he extract
¦ was washed with water and dried over ma~nesium sulfate.
- ¦ The solvent was then distilled off under reduced pressure.
~ To the residue was added 15 m~. of benzene and1 after
., ~
¦ incubation the mixture was allowed to cool. ~he resultant
crystals were then collected by filtration.
By the above procedure was obtained 2.4 g. (56 %) of
4 benzoyl-l-~(N-formylemi.lo)tosylmethylidene)indan. In
.
spectral data, this product was fo~nd to be iden.ical
with tbe crystals obtained in ~xample~
.
- ~ Example 8
To 32 4 g. of 1-((N-formylamino)tosylmeth~Jlidene1-4-
- 12 - _
1076139
(4-methylbenzoyl)indan was added 350 m~ of dioxane together
with 350 m~. of concentrated hydrochloric acid and the
- mixture was refluxed in an oil bath at 110C for 4 hours.
The reaction mixture was concentrated under reduced pressure
and tG the residue was added water. ~he mixture was extracted
with ether. ~he extract was washed with water and extracted
twice with 200 m~. portions of a 5 % aqueous solution of
potassi~ carbonate. ~he extracts were combined and washed
with ether.
~ he extract was acidified with hydrochloric ac d and
the p:ecipitate obtained was extracted with benzelle. The
benzene layer was washed with water ard aqueous sodium
chloride, dried over anhydrous sodium sulfate and, after
additiGn of activated carbon, filtered. ~he filtrate was
concentrated under reduced pressure and the residue was
recrystallized from a mixture of 50 me. of benzene and
150 m~ of cyclohexane.
; ~y the above procedure was obtained 15.6 g. (76.5 %)
of 4-(4-methylbenzoyl)-1-indancarboxylic acid. Recr~stalli-
zation from 4Q % aqueous ethanol yielded crystals melting
at 133-135C.
Elemental analysis~ for C18H1603
Calcd C, 77.12; ~, 5.75
Found C, 77.18; H, 5.4~
Similarly, the following compounds were synthesizcd.
4--v~zoyl-1-indancarboxylic acid
melting point: 101.5-103C; yield 75 ,~
j 4-(4-C~lorobenzoyl)-l-indancarboxylic acid
_ melting poirt: 137.5-139.5~C; yield 78 %
- 13 -
r~
1076~3g
6-Chloro-5-cyclohexyl-1-indancarboxylic acid
meltir~ point: 151-152C; yield 75 ,'
xample 9
To 2,4 g. of 4-benzoyl-1-((N-foImylamino)tosylmethyl-
idene~indan was added 15 me. of acetic acid to~ether with
15 m~. of concentrated hydrccil~oric acid and the mixture was
refluxed for 3 hours. The solvent was distilled off under
reduced pressure and to the residue was ~dded water. The
mlxture was extracted with benzene. The extract was washed
with water and then extracted three times with 15 ml.
portions of a 5 k aqueous solutio~ of potassium carbonate.
The extracts were combined and decolored with activated
carbon. The extract was acidified with hydrochloric acid
and ex~racted three times with benzene. The benzene layer
was washed with water and dried over magnesium sulfate.
~he solvent was distilled off under reduced pressure and
the residue was recrystallized from a mixture of 2~5 ml.
of benzene and 7.5 me. of cyclohexane. By the ahove
procedure was obtained 1.1 g. (7:; %) of 4-benzoyl-1-indan-
carboxylic acid as crystals melting at 101-103C.
Example 1~
To 60 me. of dimethoxyethane was added 5.G g. of 4-
(4-methylbenzoyl)- -indanone toge'uher with 4.4 g, of tosyl-
methylisonitrile. The ~ixture was cooled to -10C ar.d
stirred, ~o this solution was added dropwise a
solution of 4.4 g. of 28 ,~ ~odiu~ methoxide in methanol
diluted with 20 me. of dimethoxyethane over a period of
- 14 _
1C~76139
30 minutes. ~ollowing the dropwise addition, the mixture
was stirred at -10C for 1 hour. The solvent was distil1ed
off under reduced pressure and 100 m~. of dioxane and 100 mr.
of concentrated hydrochloric acid were added to the residue.
The mixture was refluxed for 4 hours, and the reaction
mixture was concentrated under reduced pressure To the
residue was added water. The mixture was extracted with
benzene The extract was washed with water and then extracted
with 5 /~ aqueous solution of po-tassium carbonate. The extract
was washed with benzene and acidified with hydrochloric acid
ar.d the precipitate obtained was extracted with benzene.
The benzene layer was washed with water and aqueous solution
of sodium chloride, dried over sodium sulfate and, after
ado~tion of activated carbon, filtered. The ~iltrate was
r eoncentrated ~nd the residue was recrystallized from a 40 %
acueous ethanol By the sbove procedura was obtained 2.82 g
(50 ,S) of 4-(4-~ethylbenzoyl~ dancarboxylic acid. In
speetral data, this product was found to be identical with
the crystals obtained in Example ~.
~ By a similar procedure to the above, 1.2 g. (50 %)
; ~ of 5-cyclohexyl~ dancarboxylic acid was obtained from
`~ 2.1 g. of 5-eyclohexyl-1-indanone and 2.2 g.-of tosyl-
~ met~ylisonitrile. Melti~g point: 140-144C.
.~ I
,, i
,
,, I
~ 15 -
,
