CA1050565A - Process for preparing o-(2,6-dichloroanilino) phenylacetic acid and salts thereof - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

O-(2,6-dichloroanilino) phenylacetic acid, known as a non-steroidic analgesic and anti-inflammatory under the general name of "Diclofenac" is prepared by hydrolyzing N-(sub-stituted or unsubstituted)-benzoyl-N-(o-cyanomethyl or alkoxy-carbonylmethylphenyl)-2,6-dichlorophenylamine. The inter-mediate material may be prepared by Chapman Rearrangement of 2,6-dichlorophenyl-N-(o-cyanomethyl or alkoxycarbonylmethyl-phenyl)benzimidate, which may be made by reacting 2,6-di-chlorophenol with N-(o-cyanomethyl or alkoxycarbonylmethyl-phenyl)-(substituted or non-substituted) benzimidoyl chloride.

Description

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) :;-~

,, .

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 ~ .

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-" .
' ,~;, . ': , ~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 ( (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 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 ~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 . . . .
' ~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.

(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.

(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%).

(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), .. :

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%).

(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.

(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.

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.

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Claims (36)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparation of o-(2,6-dichloroanilino) phenylacetic acid of the formula (I):

(I) and pharmaceutically acceptable acid addition salts thereof, which comprises hydrolysing a compound of the general formula (III):

(III) wherein Q is a cyano group or an alkoxycarbonyl group, and Z
is a substituted or non-substituted phenyl group of the general formula (VIII):

wherein R1, R2 and R3, which may be the same or different, are selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy; and, if desired, converting the hydrolysis product to a pharmaceutically acceptable acid addition salt thereof.

2. A process according to claim 1, wherein the hydrolysis is carried out under an alkaline hydrolysis condition.

3. A process according to claim 1, wherein Q is a cyano group.

4. A process according to claim 1, wherein Q is an alkoxy carbonyl group.

5. A process according to claim 4, wherein Q is an ethoxycarbonyl group.

6. A process according to claim 1, wherein R1, R2 and R3 are hydrogen.

7. A process according to claim 1, wherein at least one of R1 and R2 is selected from chlorine and bromine.

8. A process according to claim 1, wherein at least one of R1 and R2 is a methyl group.

9, A process according to claim 1, wherein R1 is a t-butoxy group.

10. A process according to claim 1, wherein at least one of R1, R2 and R3 is a methoxy group.

11. A process according to claim 1, wherein the hydrolysis is carried out in a solvent.

12. A process according to claim 1, wherein the hydrolysis is performed stepwise, and the process further comprises isolation of an intermediate compound of the general formula (VII):

(VII) wherein Z is as defined above.

13. A process according to claim 1, 3 or 4, wherein said hydrolysis is carried out under alkaline conditions in a solvent as reaction medium at an elevated temperature for a period of time of 5 minutes to 48 hours.

14. A process for preparation of o-(2,6-dichloroanilino)-phenylacetic acid of the formula (I):

(I) and pharmaceutically acceptable acid addition salts thereof, which comprises rearranging a compound of the general formula (II):

(II) wherein Q is a cyano group or an alkoxycarbonyl group, and Z
is a substituted or non-substituted phenyl group of the general formula (VIII):

wherein R1, R2 and R3, which may be the same or different, are selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy, by a Chapman Rearrangement to a compound of the general formula (III):

(III) wherein Q and Z are as defined above; then hydrolysing the obtained compound (III), to obtain the compound (I), and, if desired, converting the hydrolysis product to a pharma-ceutically acceptable acid addition salt thereof.

15. A process according to claim 14, wherein the hydrolysis is carried out under an alkaline hydrolysis condition.

16. A process according to claim 14, wherein Q is a cyano group.

17. A process according to claim 14, wherein Q is an alkoxycarbonyl group.

18. A process according to claim 17, wherein Q is an ethoxycarbonyl group.

19. A process according to claim 14, wherein R1, R2 and R3 are hydrogen.

20. A process according to claim 14, wherein at least one of R1 and R2 is selected from chlorine and bromine.

21. A process according to claim 14, wherein at least one of R1 and R2 is a methyl group.

22. A process according to claim 14, wherein R1 is a t-butoxy group.

23. A process according to claim 14, wherein at least one of R1, R2 and R3 is a methoxy group.

24. A process according to claim 3, wherein R1 is chlorine, and R2 and R3 are hydrogen.

25. A process according to claim 3, wherein R1 is methyl and R2 and R3 are hydrogen.

26. A process according to claim 3, wherein R1 is methoxy and R2 and R3 are hydrogen.

27. A process according to claim 5, wherein R1 is chlorine and R2 and R3 are hydrogen.

28. A process according to claim 5, wherein R1 is methyl and R2 and R3 are hydrogen.

29. A process according to claim 5, wherein R1 is methoxy and R2 and R3 are hydrogen.

30. A process according to claim 16, wherein R1 is chlorine and R2 and R3 are hydrogen.

31. A process according to claim 16, wherein R1 is methyl and R2 and R3 are hydrogen.

32. A process according to claim 16, wherein R1 is methoxy and R2 and R3 are hydrogen.

33. A process according to claim 18, wherein R1 is chlorine and R2 and R3 are hydrogen.

34. A process according to claim 18, wherein R1 is methyl and R2 and R3 are hydrogen.

35. A process according to claim 18, wherein R1 is methoxy and R2 and R3 are hydrogen.

36. A process according to claim 14, 16 or 17, wherein said rearranging is carried out in an inert atmosphere at a temperature from about 200° to 350°C. for a period of time of about 5 minutes to 10 hours; and said hydrolyzing is carried out under alkaline conditions in a solvent as reaction medium, at an elevated temperature for a period of time of 5 minutes to 48 hours.