DE2613838A1 - METHOD OF GENERATING THE SQUARE CLAMP ON O- (2,6-DICHLORANILINO) PHENYL SQUARE BRACKET TO ACETIC ACID AND SALT OF THE SAME - Google Patents

Description

18798

IKEDA MOHANDO CO., LTD. Nakaniikawa-gun, Tovama-ken (Japan)

Process for producing the [o- (2,6-dichloroanilino) -phenyLJ acetic acid and salts thereof

The invention relates to a method for producing the ro- (2,6-dichloroanilino) -phenyl_ [-acetic acid of the formula (I):

(D

CH ₀ -COOH

and of their salts.

The compound of formula (I) is in a number of publications previously described, for example in the Japanese Auslegeschrift 234-18 / 1967) and is under the designation "Diclofenac" on a large scale as a nonsteroidal.es used pain reliever and anti-inflammatory agent.

Various methods have been proposed for producing this connection, for example that in Japanese Auslegeschrift 23 ^ 18/1967 specified method in which a cleavage of the lactam ring takes place, as well as the method according to

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609841/1004

. 26-3838

Japanese published publications 2737V1969 and 11295/1970.

In the processes mentioned, the compound of the general formula (B) is hydrolyzed:

R ₁₅

CH-Y

(B)

In which R ₁ -, a hydrogen atom, a lower alkyl radical Ml or a halogen with an atomic number up to 35, R-J2 is a hydrogen atom, a lower alkali radical, a halogen atom with an atomic number up to 35 or a trifluoromethyl radical, R ₁ V a Hydrogen atom, a lower alkyl radical or a halogen atom with an atomic number up to 35? where R ₁₁ ? R ₁ O and R-, ^ are not all hydrogen, also R-, ^ a hydrogen atom or a halogen atom with an atomic number up to 35? Eic is a hydrogen atom or a lower alkyl radical, A is a hydrogen atom or an acyl radical, in particular a lower alkanoyl, Y is a cyano radical or -COOR ₁₆ and R _{16 is} a lower alkyl radical or aralkyl radical, in particular a benzyl radical, or it occurs when R ₁ / - a hydrogenolysis of the compound to form the compound of the general formula (C):

// \ _ GH-GOOH

( \
X = J

609841 / 100A

In this process, the corresponding starting materials for the production of the compound (B) to be hydrolyzed are used N-phenylanthranilic acids are used. To generate of the compound (B) from readily available substances, numerous steps are required, one of which some are difficult to carry out or with a low yield.

The problems associated with the usual procedures could dissolved v / ground if it were possible to produce the compound of formula (B) without using an N-phenylanthranilic acid.

The object of the invention is therefore to create a technically advantageous process for producing jjD- (2 _} 6-dichloroanilino) -phenylj-acetic acid and pharmaceutically acceptable salts thereof.

With the help of the Chapman rearrangement, the inventor has succeeded in developing a novel, hydrolyzable with high yield To produce substance and an economically advantageous process for producing the compound of the formula (I) develop. The inventor has also recognized that the intermediate product easily almost quantitatively to the Product of formula (I) can be hydrolyzed.

The starting material for the production of the intermediate product can be obtained from readily available substances with high yield are produced synthetically. The Chapman rearrangement is almost quantitative. The invention therefore provides a cheap method of producing the final product.

In the method according to the invention, the name "Diclofenac" is used as a non-steroidal pain-reliever

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known and anti-inflammatory agent | _o- (2,6-dichloroanilino) -phenylJ acetic acid by the hydrolysis of 2,6-dichlorophenyl-M- (p-cyanoiaethyl or alkoxycarbonylmethylphenyl) - (subst. or unsubst.) benzimidate generated. To produce the intermediate product, one can use the 2,6-dichlorophenyl-N- (o-cyanomethyl- or alkoxycarbonyl-methylphenyl) -benzimidate to the rearrangement according to Chapman, for example by 2,6-dichlorophenol with IT- (o-cyanomethyl- or alkoxycarbonylmethylphenyl) - (substituted or unsubstituted) benzimidoyl chloride is reacted.

In the first step of the process according to the invention, the compound of the general formula (II):

(II) i

N = G-Z

CH ₂ -Q

in which Q is the cyano or alkoxycarbonyl radical and Z is a Substituted or unsubstituted phenyl radical means subjected to the Chapman rearrangement, the Compound of general formula (III) is obtained:

(III)

in which Q and Z have the meanings given above. In the second step of the procedure, this connection is made of the general formula (III) hydrolyzate.

The invention consists not only in the second process

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step, but also in the combination of the first and the second process step.

The subject of the present invention will be described in detail below.

It is known that after Chapman which can obtain H-arylanthranyl acid (see for example "Journal of the Chemical Society", 1937 »p. 1954-) · So far, however, no attempt has been made to the N- (aroyl) -N- (o-cyanomethyl-phenyl) -arylamine, which as Serve precursors for the [_o- (arylamino) phenyl J acetic acid can, despite the substitution on the aryl nuclei, with the help of the Chapman rearrangement. In the production the Γο- (subst. anilino) -phenyl-acetic acid by the rearrangement According to Chapman, two different working methods can be used. For example, you can connect to the Generate formula (I) according to the first working method according to the following scheme:

—Τ *

(V)

N = rC-

CH,

in (in) I

in which Q and Z have the meanings given above.

A rearrangement of the 2,6-dichlorophenol takes place

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(IV) 2,6-DiChIOrPt obtained
benzimidates (II) to the compound (III).

phenyl) -

The other way of working corresponds to the following reaction

, Cl Cl

tion scheme: /

C-Z +

(Ha)

(III)

The obtained from the 2,6-dichloroaniline (VI), subst. Phenyl M- (2,6-dichlorophenyl) benzimidate (Ha) the compound (III) rearranged.

In the context of the invention, the first-mentioned mode of operation applied because the synthesis of the starting substance and the rearrangement according to Chapman are easy to carry out.

In the present process, o- (substituted or unsubstituted benzamide) phenylacetonitrile is used as the starting substance or the o- (substituted or unsubstituted benzamide) phenylacetic acid ester used. The starting compound is processed into the corresponding imdoyl chloride (V), which then with the sodium salt of 2,6-dichlorophenol (IV) to the corresponding new compound 2,6-dichlorophenyl-N- (subst. or unsubstituted phenyl) benzimidate (II) condensed will. This represents the starting material for the first step of the inventive method (see the following

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pending examples 1-24- for the production of starting materials). In the first process step, the Chapman rearrangement is preferably carried out at a temperature of about 200 ° to 350 ° C. Complete implementation of the "reaction takes about 5 minutes" to 20 hours. Both the reaction temperature and the reaction time can be determined experimentally The process step leads to a higher yield if it is carried out under an inert atmosphere, for example a nitrogen atmosphere. The yield can easily exceed 30% , and an approximately quantitative reaction can also be achieved. The reaction can be carried out without a solvent ( Reaction medium) and is preferably carried out without a solvent, because otherwise it would have to be separated again. However, a solvent can also be used if this is advantageous for controlling the reaction. Suitable solvents are, for example, nitrobenzene, diphenyl ether, triacetyn and benzophenone .

The substituent Z of the starting compound (II) used in the context of the invention is as indicated above became a substituted or unsubstituted phenyl radical. Any substituent can be present on the benzene nucleus be present, which has no influence on the desired reaction.

A comparison with an electron accepting group such as chlorine, and an electron donating group, such as the methyl and methoxy group shows results obtained, that the electron donating group has the advantage that the complete implementation of the reaction takes less time requires. It has also been shown that positional isomerism one and the same substituent, for example the use of an o-, m- or p-methyl group to which

-8th-

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yield achieved in this process step is not a pronounced one Has influence.

The second step of the process according to the invention, which causes hydrolysis, is described below.

The compound (III) can be acidic or alkaline Hydrolyze conditions. When hydrolyzed with an alkali, the product (I) becomes higher in yield and obtained a higher purity. When the substance (III) is to be converted directly into the compound (I), used it is advisable to use an alkali, such as sodium hydroxide or potassium hydroxide, in excess.

The hydrolysis can be carried out in stages by using reaction conditions, such as the temperature and the reaction time, and appropriately choose the solvent and the amount of alkali (see Example 5). In this case, one is obtained stepwise or partial hydrolysis, because the substituent Q is more easily hydrolyzable than the substituted or unsubstituted one Benzoyl group GO-Z. You can then get a partially hydrolyzed Separate the product that is the next fcaid specified Formula VII has when in formula III Q has the meaning COOH.

The invention includes methods with multi-stage and with single-stage hydrolysis.

In all cases one uses in this process step preferably a solvent (reaction medium). Suitable solvents are, for example, water (in excess about the theoretical amount), alcohols such as methanol, ethanol, propanol, butanols, amyl alcohol, ethylene glycol, Polyäthylenglyko1, Propyleneglykol, also acetone and Methyl ethyl ketone and mixtures thereof.

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The reaction temperature preferably corresponds to the boiling point of the solvent used, i.e. the reflux temperature, however, other temperatures can also be used. The reaction time can be in the range from about 5 minutes to 48 hours can be selected.

The method according to the invention is described below using exemplary embodiments which also include the production of the starting materials. Examples 1 to 24 for the production of the starting materials (a) Production of IT- (o-cyanomethylphenyl) -p-methoxy-benzimidoyl chloride:

10.0 g of o-aminophenylacetonitrile and 15.5 S

p-anisoyl chloride were condensed to 15.0 g of 2- (p-methoxybenzamide) phenylacetonitrile (m.p. 154-156 ⁰ C). The yield was 74.4%.

The condensation product was treated with phosphorus pentachloride or thionyl chloride in the usual manner. 16.1 g of the aforementioned compound were obtained in the form of a crude, pale yellow oil. The yield was 100%.

(b) Generation of the 2,6-dichlorophenyl-N- (o-cyanomethylphenyl) -p-methoxybenzimidate.

1.5 g of sodium metal were in 20 ml of anhydrous ^ ethanol solved. The solution was added in a nitrogen atmosphere 9.2 g of 2,6-dichlorophenol were added with cooling, whereby the sodium salt was formed.

The solution obtained in this way became 40 ml of a Wasaer-free essential solution added, the 15.1 g of the l> T- (o-Cyanome thy! phenyl) - initially present as an oil

10 -

609841/1004

- ίο -

p-methoxybenzimidoyl chloride. The mixture 'was then stirred for 2 hours at room temperature.

The reaction mixture was poured into ice water and the oil formed was extracted with 50 ml of ethyl acetate. The organic Layer was washed with water and concentrated by drying on anhydrous sodium sulfate. The remaining Crystals were recrystallized from alcohol, leaving an 18.5 g of a colorless crystal powder with a melting point of 88-89 ° G were obtained.

Similar to the above, various similar ones were made Starting materials of the formula (II) generated, where

Z -

The results are summarized in Table 1.

In Examples 2-19 and 20-24 for the generation of starting materials, the corresponding acid chloride was used instead of the p-anisoyl chloride mentioned above under (a) ZGOGl is used, where Z has the meaning explained above. In Examples 13 to 24, instead of of the o-aminoacetonitrile of O-aminophenylacetic acid ethyl- ester used.

The yields given in Table 1 are the total yields, the 2- (p-methoxybenzamide) phenylacetonitrile or the corresponding 2- (substituted or unsubst. Benzamide) -phenylacetonitrile or the corresponding 2- (substituted or unsubstituted benzamide) -phenylacetic acid ethyl ester are related.

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609841 / 1G (H.

example 1

A mixture of 5 g of the 2,6-dichlorophenyl-N- (o-cyanomethylphenyl) -p-chlorobenzimidate produced according to Example 8 for the production of starting materials and 25 g of diphenyl ether was subjected to rearrangement reaction for 1 hour in a nitrogen atmosphere refluxed with stirring.

Most of the diphenyl ether used as the solvent was distilled off under a reduced pressure of 5 torr. By recrystallizing the residue from ethanol, 4-7 g of IT-p-chlorobenzoyl-N- (o-cyanomethylphenyl) -2,6-dichlorophenylamine were obtained in the form of a colorless powder with a melting point of 14-7-14-9 ⁰ O . The yield was 94.0 %.

(2) 1.0 g of the rearrangement product thus obtained, 3 x 0 g of potassium hydroxide and 30 ml of n-butanol were added mixed and refluxed for hydrolysis for 2 h in a nitrogen atmosphere with stirring.

Most of it became under a vacuum of 5 Torr the solvent is distilled off. The residue was dissolved in 100 ml of water. The aqueous solution was with 50 ml Ether extracted and the ethereal layer separated. The aqueous layer was cooled below 5 C and with Normal hydrochloric acid acidified. The precipitated crystals were washed twice with ether and the combined ethereal solutions washed with water and with anhydrous Dried sodium sulfate. After distilling off The deposited crystals from benzene were uinkrystallisiert by ether under a reduced pressure, whereby 0.33 g colorless Crystals with a melting point of 156-158 ° C were obtained. The yield was 51%

From the results of the mixture melting point determination,

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"60 9841 / 100A

the comparison of the IR spectra and the elemental analysis it emerges that this product is the same substance as o- (2,6-dichloroanilino) acetic acid, which after the proposed in Japanese Patent Publication 234-18 / 1967 Procedure had been generated.

(1) A mixture of 6 g of the 2,6-dichlorophenyl-IT-Co-cyanomethylphenyl-m-methylbenzimidate produced according to Example 4- for the production of starting materials and 30 g of diphenyl ether was used for the rearrangement for 1 hour 30 minutes in a nitrogen atmosphere refluxed with stirring. In the compound described in Example 1 (1) were manner g Nm-toluoyl-N- (o-cyanomethylphenyl) -2,6-dichlorophenylamine obtained in the form of a colorless powder having a melting point of 173-174- ⁰ C 5}. 2 The yield was 86.5%.

(2) 10 g of the rearrangement product obtained, 3> 0 g of potassium hydroxide and 30 ml of n-butanol were mixed and refluxed for hydrolysis for 2 h in a nitrogen atmosphere with stirring. In the compound described in Example 1 (2) manner there was obtained 0.4 g of a colorless powder, which was identical with the compound obtained in Example 1 (2) substance having a melting point of 156-158 ⁰ C. The yield was 64.5%.

Example 3

(1) A mixture of 6.0 g of the 2,6-dichlorophenyl-N- (o-cyanomethy! Phenyl) -benzimidate produced according to Example 2 for the production of starting materials and 30 g of diphenyl ether for the rearrangement was 1 hour 20 minutes in a nitrogen atmosphere refluxed with stirring. In the manner indicated in Example 1 (1) 5? 3 g of N-benzoyl-N-

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609841/1004

of a colorless powder having a melting point of 171-172 ⁰ G (o-cyanomethylphenyl) -2,6-dichlorophenylamine in shape. The yield was 88.3%.

(2) 1.0 g of the rearrangement product thus obtained, 3.0 g of potassium hydroxide and 30 ml of n-butanol were mixed and refluxed for hydrolysis for 2 hours in a nitrogen atmosphere with stirring. In the compound described in Example 1 (2) manner there was obtained 0.4 g of a colorless powder substance obtained with the according to Example 1 (2) was identical to a melting point of 156-158 ⁰ G. The yield was 52.0%.

Example 4

(1) In the same manner as in Example 1 (1), a mixture of 5 g of that used in Example 9 was used for the production 2,6-dichlorophenyl-N- (ocyanomethylphenyl) -p-bromobenzimidate produced from raw materials and 25 g of diphenyl ether processed. There were 4.3 N-p-bromobenzoyl-N- (o-cyanomethylphenyl) -2,6-dichlorophenylamine obtained in the form of a colorless powder with a melting point of 161-162 ° G. The yield was 86.0%.

(2) In the manner indicated in Example 1 (2), a mixture of 1.0 g of the resulting rearrangement product, 3.0 g of potassium hydroxide and 30 ml of n-butanol processed. Ss 0.3 g of a colorless powder was obtained which had a melting point of the substance obtained in Example 1 (2) from I56-I58 C was identical. The yield was 51%

Example 5

(1) A mixture of 2.0 g of that according to Example 13 for the production of raw materials produced 2,6-dichlorophenyl-N- (o-ethoxycarbonylmethylphenyl) benzimidate and of 10.0 g of diphenyl ether for the rearrangement was 1 hour 40 minutes in one

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609841 / 100Λ

Nitrogen atmosphere refluxed with stirring. In the procedure given in Example 1 (1), 1.8 g of ΕΓ-benzoyl-N- (ο-ethoxycarbonylmethy! Phenyl) -2,6-dichlorophenylamine in the form of colorless Eüstallen with a melting point of ⁰ ° C. were obtained. The yield was 90%.

(2) 4.0 g of the rearrangement product thus obtained, 8.0 g of sodium hydroxide and 1 ml of η-amyl alcohol were mixed with 8 ml of water and refluxed with stirring in a nitrogen atmosphere for 5 hours to carry out hydrolysis. In the manner indicated in Example 1 (2), 2.77 g of a colorless powder which was identical to the substance obtained in Example 1 (2) and having a melting point of 156-158 ° C. were obtained. The yield was 65 ₅ 2 / ο.

(2A) A mixture of 16.0 g of the resulting rearrangement product, 16 g of a 50/6 strength sodium hydroxide solution and 32 ml of ethanol was refluxed for hydrolysis for 30 minutes in a nitrogen atmosphere with stirring. Ethanol was distilled off under reduced pressure. The residue was dissolved in 100 ml of water and the solution was acidified with formal hydrochloric acid. The crystals which precipitated out were filtered off, washed with water, dried and recrystallized from ethanol. There were 13.8 g $ T-benzoyl-IT (o-carboxymethylphenyl) -2,6-dichlorophenylamine a colorless powder with a melting point of 181-182 ⁰ G in shape. In this substance, the group Q in the formula (III) was hydrolyzed and the benzoyl group remained unchanged. The yield was 92%

(2B) 1.0 g of the partially hydrolyzed product obtained according to (2A), 4 ml of n-amyl alcohol, 2 ml of water and 2 g of sodium hydroxide were used for further hydrolysis for 5 h in a nitrogen atmosphere refluxed with stirring.

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609841/1004

In the example given in Example 1 (2), a obtained colorless powder with the substance obtained in Example 1 (2) with a melting point of 156-158 ° C was identical.

Example 6

(1) A mixture of 6.0 g of 2,6-dichlorophenyl-N- (o-cyanomethy! Phenyl) -p ~ tert-butyl-benzimidate and 30 ml of diphenyl ether was used for the rearrangement for 1 h 10 min in a Refluxed under a nitrogen atmosphere with stirring.

In the manner indicated in Example 1 (1) were 4-.9 g N-p-tert-butyl-benzoyl-N- (o-cyanomethylphenyl) -2,6-dichlorophenylamine in the form of colorless E & stalls with a melting point obtained from 189-190 ° C. The yield was 81.7%.

(2) 1.0 g of the rearrangement product obtained,

10 ml of a 30% potassium hydroxide solution and 15 ml of ethanol were allowed to hydrolyze for 48 hours in a nitrogen atmosphere refluxed with stirring.

In the compound described in Example 1 (2), it has been 0.4-1 g of a colorless powder obtained which was identical to that obtained in Example 1 (2) substance having a melting point of 156-158 ⁰ C. The yield was 60.7%

Examples 7-25.

In the manner indicated in Examples 1 to 6, other substances were processed. Information about the The rearrangement products obtained in Examples 1 to 25 are shown in Table 2. Except for example 25 Starting materials used, according to the above be. written examples for the production of raw materials had been generated.

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60 9841/1004

With regard to the results of the elemental analysis given in Table 2, it should be mentioned that the chemical Formulas and calculated values are not given because they appear from Table 1, which contains the examples for the production of raw materials.

All hydrolysis products produced according to Examples 7 to 25 had C. The results of the mixed melting point determination and the comparison of the IR spectra gave a melting point of 156-158 ⁰ that the products with the [o- (2,6-dichloroanilino) -phenyl_j - acetic acid produced by the method of the above-mentioned Japanese Patent Application .234-18 / 1967.

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609841/1004

Examples for - 17 - ' the H generation , 26 13838 formula Table 1 H C ₂₂ H ₁₆ N ₂ O ₂ Gl ₂ Substituent H C ₂₁ H ₁₄ N ₂ OCl ₂ R ₂ H Q of raw materials C ₂₂ H ₁₆ N ₂ OGl ₂ Part A 4-CH ₃ O H H CN It H H H GN Enamel It at 2-GH ₃ H H CN Point
⁰ C C ₂₁ H ₁₃ N ₂ OGl ₃ game 3-CH ₃ H H CN 88-89 It 1 4-GH ₃ H H CN 152-153 ■ It 2 2-Eq H H CN 115-116 C ₂₁ H ₁₃ N ₂ Od ₂ Br 3 3-ci H H CN 109-110 C ₂₅ H ₂₂ N ₂ OGl ₂ 4th 4-Cl H H CN 98-99 C ₂₁ H ₁₂ N ₂ OGl ₄ 5 4-Br H H CN 130-131 C ₂₃ H ₁₈ N ₂ OCl ₂ 6th Zl + η tt ) H H CN 113-114 C ₂₃ H ₁₉ NO ₃ Cl ₂ 7th 2-Cl 4-Cl H GN 120-121 C ₂₄ H ₂₁ NO ₃ Cl ₂ 8th 3-CH ₃ 5-CH ₃ H CN 114-115 ti 9 H H H CO ₂ G ₂ H ₅ 161-162 It 10 2-CH ₃ H H U 142-143 C ₂₃ H ₁₈ NO ₃ Gl ₃ 11 3-CH ₃ H H It II6-II7 dd 12th 4-CH ₃ H H dd 137-138 G ₂₃ H ₁₈ NO ₃ Cl ₂ Br 13th 3-Cl H H tr 137-138 C ₂₄ H ₂₁ NO ₄ Cl ₂ 14th 4-G1 H H Il 80-81 Π TT T \ TO Π Λ
^υ 27 27 ^iNU 3 2 15th 4-Br H H Il 95-97 C ₂₃ H ₁₇ NO ₃ Cl ₄ 16 4-CH ₃ O H 5-CH ₃ It 88-89 C ₂₅ H ₂₃ NO ₃ Cl ₂ 17th 4-tG ₄ Hc ) H 9841 dd 101-102 C ₂₆ H ₂₅ NO ₃ Cl ₂ 18th 2-Cl 4-Cl ti 108-110 19th 3-CH ₃ 5-CH ₃ dd 94-96 20th 3-CH ₃ O 4-GH ₃ O O " 105-106 21 60 / 1004
- 18 - I74-I75 22nd 95-97 23 120-121 24

Examples for C. H Ή - 18th - 2613838 Found σ H Ή te % 64.25 3.92 6.81 Table 1 64.13 3.68 6.87 79.8 Ana 66.16 3.70 7.35 66.36 3.42 7.16 74.9 Calculated 65.85 4.08 7.09 the production of raw materials 66.98 3.84 7.28 75.0 part B 66.85 4.08 7.09 66.76 3.89 7.08 69.2 66.85 4.18 7.09 1 y s e 66.58 3.91 7.02 73.4 Dp-! _ 60.68 3.15 6.74 60.58 2.95 6.66 70.5 iJCi J--
game 60.68 3.15 6.74 60.44 2.91 6.78 67.5 60.68 3.15 6.74 60.79 2.86 • 6.72 59.8 1 54.81 2.85 6.09 54.96 2.61 6.08 80.3 2 68.66 5.07 6.40 68.95 5.08 6.29 70.5 3 56.03 2.69 6.22 56.11 2.41 6.18 72.3 4th 67, ^ - 9 4.43 6.84 67.51 4.16 6.80 90.0 VJl 64.50 4.47 3.27 . 64.56 4.18 3.52 89.5 6th 65.17 4.79 3.17 65.12 4.86 3.10 64.8 7th 65.17 4.79 3.17 65.12 4.90 2.99 77.3 8th 65.17 4.79 3.17 64.87 4.58 3.13 67.0 9 59.70 3.92 3.03 59.51 3.77 2.89 62.7 10 59.70 3.92 3.03 59.36 3.59 3.23 82.5 11 54.46 3.58 3.76 54.19 3.37 2.56 81.6 12th 63.02 4.63 3.06 63.20 4.36 3.26 76.2 13th 66.94 5.62 2.89 67.13 5.87 2.90 62.4 14th 55.56 3.45 2.82 55.79 3.42 2.80 66.4 15th 65.80 5.08 3.07 65.68 4.78 3.10 77.1 16 60.24 4.86 2.70 60.40 4.67 2.86 72.1 17th 18th 19th 20th 21 22nd 23 24

- 19 609841/10 04

generation - 19th - Substituent H Q Tabel 2 R ₂ H
H CN Starting
material H H CN
CN Part A according to
example 5-CH ₃
H H
H CN 8th of rearrangement products (III) H H GO ₂ C ₂ H ₅
GN example 4th
2 H
H H GN 9 H H CN 1 13th
10 % H H CN 2
3 3 4-eq H H CN 4th 5 3-GH ₃
H H H CN 5
6th 6th 4-Br H H CN 7th 7th H 4-eq C. CN 8th 1 2-GH ₃ 5-CH ₃ H CO ₂ H ₅ 9 . 11 4-GH ₃ H H It 10 12th 2-Eq H H ti 11 14th 3-Cl H H If 12th 15th 4-GH ₃ O H H It 13th 16 2-Cl H H
H If 14th 17th 3-GH ₃ H H ti
It 15th 18th 2-GH ₃ H
H H ti 16 19th 3-CH ₃ 4-eq 5-CH ₃ O. It 17th 20th
21 4-GH ₃ 5-CH ₃ H Il 18th 22nd 3-G1 4-CH ₃ O It 19th 23 4-eq H 20th
21 24 4-Br 22nd 4 Gh ₃ O ' 23 2-Eq 24 3-CH ₃ 25th 3-OH ₃ 2-G1

- 20 -

, 609841/1

Generation of - 20 - C. a 1 j , 2613838 N Table 2 60.44 6.51 Enamel 66.68 7.10 Point 66.36 H Cm) 7.19 part B ⁰ C 55.04 3.43 5.89 147-149 Rearrangement products 64.24 3.84 3.41 At- 173-174 68.85 3.44 s e 6.47 game 171-172 A η 66.84 3.07 7.00 161-162 66.62 4.18 7.03 1 143-144 60.82 5.03 6.67 2 189-190 60.84 3.84 6.76 3 I72-I73 64th, 47th 3.84 6.72 4th I74-I75 56.12 2.88 6.16 5 201-202 67.40 2.88 3.41 6th 164-165 65.25 3.64 3.40 7th 166-167 65.30 2.42 3.35 8th I5I-I52 65.25 4.18 3.43 9 221-222 60.00 4.55 3.26 10 127-128 59.97 4.50 3.27 11 124-125 54.21 4.56 2.97 12th 135-137 63.12 3.63 3.31 13th I5O-I5I 67.11 3.69 3.15 14th 138-140 55.70 - 3.38 3.04 15th 136-137 66.02 4.36 3.36 16 137-138 60.02 5.48 2.80 17th 190-191 59.53 3.15 3.17 18th 140-141 4.90 19th 178-180 4.66 20th 141-142 3.62 21 125-126 22nd 23 24 25th

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Claims (1)

- 21 claims; CH ₂ -COOH and pharmaceutically acceptable acid addition salts this acid, characterized in that a compound of the general formula (III): (III) in which Q is a cyano group or an alkoxycarbonyl group and Z is a substituted or unsubstituted phenyl group of the general formula (VIII): mean, in which H ₁ , R ₂ ^{and R} 3 mean hydrogen, halogen, lower alkyl and lower alkoxy groups, hydrolyzed and the hydrolysis product is optionally converted into the desired salti 2. The method according to claim 1, characterized in that - 22 - 609841/1004 the hydrolysis is carried out under alkaline conditions. 3. The method according to claim 1, characterized in that in the general formula (III) Q is a cyano group "means. 4-, The method according to claim 1, characterized in that in the general formula (III), Q represents an alkoxycarbonyl group ". 5. The method according to claim 4-, characterized in that in the general formula (III) Q is an ethoxycarbonyl group means. 6. The method according to claim 1, characterized in that in the general formula (VIII) R-, Rp and R ^ hydrogen mean. 7. The method according to claim 1, characterized in that in the compound of the general formula (VIII) at least one of the substituents R- and Rp is chlorine or bromine is. 8. The method according to claim 1, characterized in that in the compound deu general formula (VIII) at least one of the substituents R-, and Rp a methyl group is. 9. The method according to claim 1, characterized in that in the general formula (VIII) R-. a tert-butoxy group means. 10. The method according to claim 1, characterized in that - 23 - 609841/1004 in the compound of the general formula (VIII) at least one of the substituents R-. , Rp and R ^ is a methoxy group. 11. The method according to claim 1, characterized in that that the hydrolysis is carried out in a reaction medium. 12. The method according to claim 1, characterized in that that the hydrolysis is carried out in stages and as an intermediate a compound of general Formula (VII): N-CO-Z (VII) CH ₂ -COOH is separated, in which Z has the meaning given above. 13 · Process for the production of o- (2,6-dichloroanilino) -phenyl-acetic acid of the formula (I): (D CH2-COOH . 1 and of pharmaceutically acceptable acidic addition salts of this acid, characterized in that one Compound of the general formula (II): "609841 / 100A (II) - N = CZ CH ₂ -Q in which Q is a cyano group or alkoxycarbonyl group and Z is a substituted or unsubstituted phenyl group of the general formula (VIII): R-. means in which R ₁ , R ₂ and R, hydrogen 3! halogen, a lower alkyl group or a lower alkoxy group, is subjected to the Chapman rearrangement, a compound of the general formula (III): N-CO-Z (III) CH _p -Q is obtained, in which Q and Z have the meanings given above, whereupon the compound of formula (III) hydrolyzed and the hydrolysis product in! the desired salt is converted. Process according to Claim 13, characterized in that the hydrolysis is carried out under alkaline conditions will. 15. The method according to claim 13, characterized in that in the general formula (III) Q is a cyano group. - 25 609841/1004 16. The method according to claim 1, characterized in, that in the general formula (III) Q is an alkoxycarbonyl group means. 17. The method according to claim 16, characterized in that in the general formula (III) Q is an ethoxycarbonyl group means. 18. The method according to claim 13 »characterized in that in the general formula (VIII) R-, R ₂ and R ^ are hydrogen. 19 · The method according to claim 13, characterized in that that in the compound of the general formula (VIII) at least one of the substituents R 1 and R p is chlorine or bromine. 20. The method according to claim 13, characterized in that in the compound of the general formula (VIII) at least one of the substituents R-, and Rp a Is methyl group. 21. The method according to claim 13, characterized in that in the general formula (VIII) R-, a tert. Means butoxy group. 22. The method according to claim 13, characterized in that at least one of the substituents R-,, R ₀ and R, is a methoxy group. 23 · The method according to claim 13, characterized in, that the Chapman rearrangement is carried out in a reaction medium « - 26 - 609841/1004 Process according to claim 3 or 5, characterized in that R ₁ signifies chlorine and R ₂ and R ^ signify hydrogen. 25 · The method according to claim 3 or 5, characterized in that that R-, denotes a methyl group and R ~ and R, Mean hydrogen. 26. The method according to claim 3 or 5, characterized in that R-. represents a methoxy group and R _p and R _{3 represent} hydrogen. 27. The method according to claim 15 or 17, characterized in that R _{n is} chlorine and R ₀ and R _{2 are} water ⁷ I d. ο mean substance. 28. The method according to claim I5 or 17, characterized in that that R-. represents a methyl group and R2 and R ^ Mean hydrogen. 29 · The method according to claim 15 or 17, characterized in that R- denotes a methoxy group and . Rp and R ^ mean hydrogen. 609841/1004