Note: Descriptions are shown in the official language in which they were submitted.
5~5i
The present invention concerns a novel process for
preparing o-(2,6-dichloroanilino) phenylacetic acid haviny the
formula (I):
1~
Cl ~ Cl
~ (I)
~ o 1--CH2--cooH
,.1 ' ~ ,,
and salts thereof.
. .The eompound of formula (I) has been disclosed in a
series of patents sueh as Japanese patent publieatlon No.
23418/1967, and has been widely used as a non-steroidic analgesie
~ - and anti-inflammatory under the general name of "Declofenac".
: 10For pE~paration of this compound, various processes
:. have been proposed, inclusive of laetam ring cleavage diselosed
in the above Japanese publication No. 23418~1967, for example,
in Japanese patent publieations Nos. 27374/1969 and 11295~1970.
In summary, sueh proeesses use hydrolysis of the
. eompound having the general formula (B):
l ~ CH-Y
,', ' ~ , :
N-A (B) :;-~
12
,, .
wherein Rll is hydrogen atom, lower alkyl radieal or halogen atom
of atotnie nut~er up to 35, R12 is hydrogen atom, lower alkyl
. - 1 -
, ' " ' '; ' '' ,' ' ' ' ~' '~ " : : . ; :
.
,
6?56~
radical, halogen atom of atomic number up to 35 or trifluoro-
methyl radical, R13 is hydrogen atom, lower alkyl radical,
lower alkoxy radical or halogen atom of atomic number up to 35;
R11, R12 and R13 are not hydrogen at the same
time, R14 is hydrogen atom or halogen atom of atomic number up
to 35, R15 is hydrogen atom or lower alkyl radical, A is
hydrogen atom or acyl radical, especially lower alkanoyl,
Y ls cyano radical or -COOR16, and R16 is lower alkyl radical
or aralkyl radical, especially benzyl radical, or, if R16 is
benzyl, hydrogenolysis of the compound to obtain the compound
i having the general formula (C):
R
1~ R
-CH-COOH
.~ ~ .
NH (C)
R13 .~,Rll
~ .
12
In these processes starting materials for producing
material compound (B) to be hydrolyzed are the corresponding
N-phenylanthranilic acids. Many steps are required to obtain
material compound (B) from easily available materials. Some of
the steps are difficult to operate or inefficient, and hence,
such processes ar~ not economically advantageous.
One solution to such problems inherent in conventional
` 20 methods ls to develop a novel route to prepare the material
product (B) which does not go by way of N-phenylanthranilic
acids.
The objec-t o-f the present invention is to provide a
commercially ad~lantageous novel route of preparing o-(2,6-
dichloroanilino) phenylacetic acid and pharmaceutically accept-
-- 2 --
" .
' ,~;, . ': ,
~5~565
able salts thereof.
Applicant has succeeded in preparing a novel materialfor hydrolysis with a high yleld by utilizing Chapman Rearrange-
ment, and thus developed an economically advantageous novel
route to prepare the useful compound (I). Also, applicant has
found that the intermediate material can be readily and almost
quantitatively hydrolyzed to give the product compound (I).
The starting substance to prepare the intermediate
material can be synthesized from readily available materials
with a high yield. The chapman Rearrangement is performed
almost quantitatively. Thus, the present invention provides a
low-cost process for preparation of the end product.
The process according to the present invention comprises
the first step of changing the compound of the general formula
(II):
Cl/ I Cl
O
r --\ I (II)
( O ~ N=C-Z
,' CH2-Q
; . .
wherein Q is cyano or alkoxycarbonyl radical, and Z is sub- .
stituted or non-substituted phenyl radical, by chapman Rearrange-
ment to the compound of the general formula (III):
Cl ~ Cl (III)
(~;I-CO-Z
s~
wherein Q and Z are as defined above, and the second step of
hydrolyzing the thus obtained compound of the above general
formula (III).
The present process concerns not only the second
step but also the combination of the first and the second steps.
The present invention will now be described in
detail.
It has been known that N aryl anthranyl acid is
obtained by chapman Rearrangement. (See, for example, "Journal
;~ 10 of the Chemical Society" pO 1954 1937)~ However, no one has
attempted to date to prepare N-(aroyl)-N(o-cyanomethylphenyl)-
aryl-amine which can be a precursor of o-(arylamino) phenyl-
acetic acid by Chapman Rearrangement regardless of substitution
on the aryl nuclei. There are two ways to prepare [o-(substitut-
ed anilino) phenylacetic] acid by Chapman Rearrangement. Taking
the case of preparing compound (I), one way i6 illustrated in
the reaction scheme below:
:' Cl
C ~ Cl (
OEI CH2-Q
(IV) (V)
; - . '
C ~ Cl
I C Cl
C-Z ~ c~C~O_z
Q
-- (II) (III)
.' i , . . .
., , , . ., .
,,
~5~6~
wherein Q and Z are as defined above.
This way entails rearrangement of 2,6-dichloro
phenyl N-(substituted phenyl) benzimidate (II), which is
obtained from 2,6-dichlorophenol (IV), to compound (III).
The other way is as follows:
Cl Cl
N = c--z t ~
Cl
(VI)
Cl ~ ~ Q Cl ~ Cl
(~ z ~ ~lcoz
Cl CH2-Q
(IIa) ~III) -
In this way substituted phenyl ~-(2,6-dichlorophenyl)
benzimidate (IIa), which is obtained from 2j6-dichloroaniline
(VI), is rearranged to compound (III).
Applicant has adopted the former way taking into
account the ease of synthesizing the starting material and
realizing Chapman Rearrangement.
The present process starts from o-(substituted or
non-substituted benzamide) phenylacetonitril or o-(substituted
or non-substituted benzamide) phenylacetic acid ester. The
startiny compound is changed to the corresponding imidoylchloride
~V), and then the imidoyl chloride is condensed with sodium salt
of 2,6-dichlorophenol (IV) to give corresponding novel compound
2,6-dich1orophenyl N-(substituted or non-substituted phenyl)
benzimidate (II), which is the material for the first step of
the invention. (See Examples of preparing starting materials 1
- 5 -
., ; . . ~ . . - :
; , , , , , . :
, , , . . . ~
5~5
through 24 shown below.~ The Chapman Rearrangement in the first
step is carried out at a -temperature pre~erably from about 200
to 350C. The reaction completes wlthin from about 5 minutes to
10 hours. soth the reaction temperature and period can be
experimentally decided. If the step is practiced under inert
atmosphere such as nitrogen atmosphere, a higher yield will be
achieved. The yield readily exceeds 90%, and moreover, an
approximately quantitative reaction is possible. The reaction
takes place without solvent (medium), and it is preferable to
10 use no solvent from the view of eliminating the separation step
thereof. However, solvent may be used if it is useful for
controlling the reaction. ~cceptable solvents are, for example,
nitrobenzene, diphenylether, triacetyne and benzophenoneO
The substituent Z on the s-tarting compound (II) used
in the present invention stands for, as noted above, substituted
or non-substituted phenyl radical, and the substituent, if any,
on the benzene nucleus may be any substituent as far as it has
,1
no effect on the desired reaction.
Comparing the results obtained in the cases of
20 electron attractive group such as chlorine and electron donative
group such as methyl and methoxy, the latter case is advantageous
because the reaction completes generally in a shorter period.
Position isomerism of the same substituent, such as o-, m- and
' p- methyl group are found to have no pronounced influence on
- the yield of this step.
The second step of the invention, the hydrolysis, is
now described.
The hydrolysis of compound (III) may be performed
under either ~cidic or alkaline condition. Hydrolysis with
alkali gives higher yield and purity of product (I). If direct
conversion of the material (III) to the compound (I) is intended,
it is convenient to use excess amount-of alkali such as sodium
- 6 -
~S~ii65
hydroxide or potassium hydroxide.
The hydrolysis can be carried out stepwise by con-
trolling reaction conditions such as temperature, period, and
selectlng sol~ent and amount of alkali, (See Example 5.). The
stepwise (or partial) hydrolysis takes place because substituent
Q is more easily hydrolyzed than substituted or non-substituted
benzoyl group shown as CO-Z. Thus, it is possible to isolate a
partially hydrolyzed product (VII shown below: in III, Q =
COOH).
The present invention includes both processes where
the hydrolysis is effected stepwise and processes where it is
effected at once.
In any event, it is preferable to use a solvent
(reaction medium) in this step. Acceptable solvents are, for
example, water (in an amount excess to the theoretical amount)
alcohols such as methanol, ethanol, propanol, butanols, amyl
alcohol, ethylene glycol, polyethylene glycol, propylene glycol;
; acetone, methylethyl ketone, and the mixtures thereof.
Reaction temperature is preferably the boiling point
of the solvent used, i.e. the reflux temperature, although
other temperatures may be used. Reaction period may be chosen
within the range from about 5 minutes to 48 hours.
The present process will be illustrated with examples
which include preparation of starting materials.
Examples of Pre~aration of Materials 1 throuqh 24
(a) Preparation of N-(o-cyanomethyl phenyl)-p- -
methoxybenzimidoylchloride:
O-Aminophenylacetonitril (10.0 g) and p-anisoyl
chloride (15.5 g) were condensed to give 2-(p-methoybenzamide)
phenylacetonitril ~m.p. 154 to 6C~ (15.0 g, yield 74.4%).
The condensation product was then treated, according
to the conventional manner, with phosphor pentachloride or
-- 7 --
. . . .
'
~5~i6~
thionylchloride. The above compound was obtained in a crude
pale yellow oil (16.1 g, 100%).
(b) Preparation of 2,6-dichlorophenyl N-(o-cyano-
methylphenyl)-p-methoxy benzimidate.
Metallic sodium (l.S g) was dissolved in anhydrous
~; methanol (20 ml). To the solution 2,~-dichlorophenol (9.2 g)
was added under cooling and in nitrogen atmosphere to ~orm
sodium salt.
Then, an anhydrous ether solution (40 ml) con-taining
~-(o-cyanomethylphenyl)-p-methoxybenzimidoyl chloride (16.1 g
as oil) was added to the resulting solution under cooling below
5C for over 30 minutes, and the mixture was stirred for 2 hours
at a room temperature.
The reaction mixture was poured into ice water, and
the resulting oil was extracted with 50 ml of ethyl acetate.
Organic layer was washed with water and dried on anhydrous sodium
sulphate for concentration. The residual crystals were recrystal-
ized from alcohol to give a colorless powdery crystal ~m.p. 88
to 89C~ (18.5 g).
In a similar manner to the above procedures, there
were prepared various similar starting materials which are
represented by the formula (II) wherein
: .
Z ~
R3 ~
'~:
The results are given collectively in Table 1.
In the Examples of Preparation of Materials 2 through
19 and 20 through 24, the corresponding acid chloride ZCOCI
(Z stands for the above specific groups) was used in place
of p-anisoyl chloride mentioned in above (a). Also, in the
~ ~5~
Examples 13 through 24, o-aminophenylace-tic acid ethyl ester was
used in place of o-amlnoace-tonitril.
The yields shown in Table 1 are the overall yields
based on 2-(p-methoxybenzamide) phenylacetonitril, or the
corresponding 2-(substituted or non-substi-tuted benzamide)
phenylace-tonitril or 2-(substituted or non-substituted benzamide)
phenylacetic acid ethyl ester.
EXAMPLE 1
(1) A mixture of 2,6-dichlorophenyl N-(o-cyanomethyl
phenyl)-p-chlorobenzimidate (5 g) prepared in Example 8 of
Preparation of Material and diphenyl ether (25 g) was refluxed
in nitrogen atmosphere under stirring over 1 hour for the rear-
rangement reaction.
- The major part of the solvent, diphenylether, was
distilled out under the reduced pressure of 5 mm Hg, and the
residue was recrystallized from ethanol to give N-p~chlorobenzoyl-
N-(o-cyanomethylphenyl)-2,6-dichloro phenylamine, colorless
powder ~m.p. 147 to 90C~ (4~7 g, 94.0%).
(2) The rearrangement product -thus obtained (1.0 g),
potassium hydroxide (3.0 g) and n-butanol (30 ml) were mixed and
stirred under reflux in nitrogen atmosphere over 2 hours to
hydrolyze.
Major part of the solvent was distilled out under a
reduced pressure of 5 mm Hg. The residue was dissolved in
100 ml of water, the water solution was extracted with 50 ml
of ether, and the ether layer was separated. The water layer
was cooled to below 5C and acidified with lN-hydrochloride acid.
Precipitated crystals were extracted twice with ether, and the
combined ether layer was washed with water and dried with
anhydrous sodium sulphate. The crystals which deposit upon
distilling out ether under a reduced pressure were recrystallized
from benzene to give colorless crystals ~m.p. 156-8C~ (0.33 g,
_ g _
.. . . . . . ..
.. , . , . , , , ~ .
,
~)5~565
51%).
It was confirmed that the product is the same substance
as o-(2,6-dichloroanilino) acetic acid obtained by the process
proposed in Japanese Patent Publication 23418/1967 according to
the results of mixed melting point examination, comparison of
IR spectra and elemen-tal analysis.
EXAMPLE 2
(1) The mixture of 2,6-dichlorophenyl N-(o-cyano-
methylphenyl)-m-methylbenzimidate (6 g) prepared in Example 4 of
Preparation of Materials and diphenyl ether (30 g) was refluxed
in nitrogen atmosphere under stirring over 1 hour and 30 minutes
to cause the rearrangement. Through the same procedures as those
of Example 1 (1), colorless powder of N-m-toluoyl-N-(o-cyano-
methylphenyl~-2,6-dichlorophenylamine rm.p. 173 to 4C~,
(5.2 g, 86.5%) was obtained.
(2) The rearrangement product thus ob-tained (1.0 g),
,
potassium hydroxide (3.0 g) and n-butanol (30 ml) were mixed
and stirred in nitrogen atmosphere under a reflux condition over
!-' 2 hours to cause hydrolysis. Also through the same procedures
.
as those of Example 1 (2), there was obtained colorless powder
which was the same substance as obtained in Example 1 (2)
~m.p. 156 to 80C~ (0.4 g, 64.5%).
EXAMPLE 3
(1) The mixture of 2,6-dichlorophenyl N-(o-cyano-
methylphenyl)-benzimidate (6.0 g) prepared in Example 2 of
Preparation of Materials and diphenyl ether (30 g) was refluxed
ln nitrogen atmosphere under stirring over 1 hour and 20 minutes
~, to cause the rearrangement. Through the same procedures as those
~` of Example 1 (1), colorless powder of N-benzoyl-N-(o-cyanomethyl-
phenyl)-2,6-dichlorophenylamine ~m.p. 171 to 2C~ (5.3 g, 88.3%)
was obtained,
(2) The rearrangement product -thus obtained (1.0 g),
.. :
-- 10 --
potassium hydroxide (3.0 g) and n-butanol (30 ml) were mixed
and stirred in nitrogen atmosphere under a reflux condition over
2hours to cause hydrolysis. Also through the same procedures
as those o-f Example 1 (2), there was obtained colorless powder
which was the same substance as obtained in Example 1 (2)
.p. 156 to 8C~ (0.4 g, 52.0%).
EXAMPLE 4
(1) The same procedures as those of Example l (1)
were repeated on the mixture of 2,6-dichlorophenyl N-(o-
cyanomethylphenyl~-p-bromobenzimidate (5 g) prepared in Example 9
of Preparation of Materials and diphenylether (25 g). Colorless
powder of N-p-bromobenzoyl-N-(0-cyanomethylphenyl)-2,6-dichloro-
phenylamine ~m.p. 161 to 20C~ (4O3 g, 86.0%) was obtained.
(2) The same procedures as those o-f Example 1 (2)
were repeated on~the mixture of the rearrangement product (1.0 g)
thus obtained, potassium hydroxide (3~0 g) and n-butanol (30 ml),
and colorless powder whi~h was -the same substance as obtained in
Example 1 (2) tm.p. 156 to 8C~. (0.3 g, 51.7%) was obtained.
E ~ LE 5
(1) The mixture of 2,6-dichlorophenyl N-(o-ethoxy-
carbonylmethylphenyl) benzimidate (2~0 g) prepared in Example 13
: ~ of Preparation of Materials and diphenylether (10.0 g) was re-
fluxed in nitrogen atmosphere under stirring over 1 hour and .
40 minutes to cause the rearrangement. Through the same pro-
cedures as those of Example 1 (1), colorless crystals of N-
:~ benzoyl-N-(0-ethoxycarbonylmethyl phenyl)-2,6-dichlorophenylamine
~m.p. 143 to 4C~ (1.8 g, 90%) were obtained.
(2) The rearrangement product thus obtained (4.0 g),
.. , sodium hydroxide (8.0 g) and n-amyl alcohol (16 ml) were mixed
with water (8 ml) and stirred in nitrogen atmosphere under reflux
condition for 5 hours for hydrolysis~ The same procedures as
those of Example 1 (2) gave colorless powder of the same substance
'
-- 11 -- :
~5~56~
a,s obtained in Example 1 (2) Cm.p. 156 to 8C~ (2.77 g, 65.2%).
(2A) The rearrangement product -thus obtained (16.0 y),
50% sodium hydroxide solution (16 g) and ethanol (32 ml) were
stirred in ni-trogen atmosphere under reflux for 30 minutes to
cause hydrolysis. Ethanol was distilled out under a reduced
pressure. The residue was dissolved in water (100 cc) and the
solution was acidified with lN-hydrochloric acid to precipitate
crystals. The crystals were filtered, washed with water, dried
and recrystallized from ethanol. Thus, there was obtained color-
less powder of N-benzoyl-N-(o-carboxymethylphenyl)-2,6- dichloro-
phenylamine, which is the substance in which group Q of the
formula (III) was hydrolyzed and the benzoyl group remained
unchanged Cm.p. 181 to 2C~ (13.8 g, 92%),
(2B) The partially hydrolyzed product obtained in (2A)
(1.0 g), n-amyl alcohol (4 ml), water (2 ml) and sodium hydroxide
. ( 2 g) were stirred in nitrogen atmosphere under reflux for 5
hours to cause further hydrolysis.
Through the same procedures as those of Example 1 (2),
there was obtained colorless powder which was the same substance
as obtained in Example 1 (2) m.p. 156 to 8C.
EXAMPLE 6
(1) The mixture of 2,6-dichlorophenyl N-(o-cyanO-
methyl phenyl)-p-(tert)-butyl benzimidate (6.0 g) and diphenyl
ether (30 ml) was refluxed in nitrogen atmosphere under stirring
1 hour and lO minutes to cause rearrangement. As the result of
the same procedures as those of Example 1 (1), colorless crystals
of N-p-(t)-butylbenzoyl-N-(o-cyanomethylphenyl)-2,6-dichloro-
phenylamine ~m.p. 189 to 90C~ (4.9 g, 81.7%) were obtained.
(2) The rearrangement product thus obtained (1.0 g),
30% potassium hydroxide solution (10 ml) and ethanol (15 ml)
were stirred in nitrogen atmosphere under reflux for 48 hours
to cause hydrolysis.
- 12 -
As the result of the same procedures as Example 1 (2),
colorless powder which was the same substance obtained in
Example 1 (2) ~m.p. 156 to 8C~ (0.41 g, 60.7%) was obtained.
EXAMPLES 7 T~mOUGH 25
.. .. .
Materials other than the materials used in the above
Examples were treated by the same procedures as Examples 1 to 6.
The results on the rearrangement products are collectively given
in Table 2 together with the results of Examples 1 to 6. The
Examples except for Example 25 used the materials prepared in the
above described Examples of Preparation of Materials.
As to the elemental analysis in the Table, chemical
formulas and calculations are not shown because they ayree with
those of the materials and can be seen from the corresponding
Examples of Preparation of Materials enumerated in Table 1. `
All the hydrolysis products of Examples 7 through 25
showed melting point of 156 to 8C. It was confirmed upon
the results of mixed melting point examination and the comparison
of IR spectra that the products are the same substance as
o-(2,6~dichloroanilino? phenylacet:ic acid obtained by the method
disclosed in the above mentioned Japanese Patent Publication
234 8/1967.
'`
, , :
- 13 -
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