WO1992022522A1

WO1992022522A1 - A process for the preparation of n-(2,6-dichlorophenyl)-n-phenyl-n-(chloroacetyl)-amine

Info

Publication number: WO1992022522A1
Application number: PCT/EP1992/001240
Authority: WO
Inventors: Stefano Maiorana; Guido Galliani; Giorgio Chiodini
Original assignee: Laboratorio Chimico Internazionale S.P.A.
Priority date: 1991-06-11
Filing date: 1992-06-04
Publication date: 1992-12-23
Also published as: ITMI911604A1; IT1248032B; ITMI911604A0; AU1925392A; ZA924236B

Abstract

N-(2,6-dichlorophenyl)-N-phenyl-N-(chloroacetyl)-amine of formula (I) (intermediate for the synthesis of Diclofenac) is prepared by means of rearrangement of N-(2,6-dichlorophenoxyacetyl)-aniline to give N-(2,6-dichlorophenyl)-aniline which, in its turn, is transformed into the final product by reaction with chloroacetyl chloride.

Description

A PROCESS FOR THE PREPARATION OF N- ( 2 , 6-DICHLORO- PHENYL ) -N-PHENYL-N- ( CHLOROACETYL ) -AMINE

The present invention relates to an improved process for the preparation of N-(2,6-dichlorophenyl)- N-phenyl-N-(chloroacetyl)-amine, of formula (I):

Compound I is of great practical importance since it is an essential intermediate for the synthesis of [2-(2,6-dichloroanilino)phenyl]-acetic acid, known under the common name Diclofenac, which is widely used as an antiphlogistic and antirheumatic agent.

A number of different processes for the prepara¬ tion of Diclofenac are known, for example those described in US-Pat 3558690, US-Pat 3652762, US-Pat 377470. An essential intermediate for the most convenient among those processes is N-(2,6- dichlorophenyl)-N-ρhenylaniline (II) which is transformed into Diclofenac by means of various steps, the first of which consists in the acylation to N-(2,6- dichlorophenyl)-N-phenyl-N-(chloroacetyl)-am ne.

According to the usual synthesis scheme, bromobenzene is condensed with 2,6-dichloroaniline in the presence of copper at high temperature, to obtain N-(2,6-dichlorophenyl)-aniline (II) which is subse- quently transformed into N-(2,6-dichlorophenyl)-N- phenyl-N-(chloroacetyl)-amine. The drawback of this process resides in the low yields of the condensation of bromobenzene and 2,6-dichloroaniline as well as in that a chlorine-bromine halogen interchange occurs at some degree, due to the presence of copper, therefore the final product is polluted by brominated impurities which are almost impossible to remove and are very harmful in consideration of the pharmaceutical use of the final product.

Now it has surprisingly been found that inter¬ mediate I for the synthesis of Diclofenac can be prepared in remarkably good yields with a very simple process, which gives the final in a very high purity. Scheme I shows the steps of the process of the present invention.

Scheme I

(X) (XI) wherein X is a chlorine atom or a ^-C₄ alkoxy group.

N-chloracetylaniline (V) , obtained by chloroacety- lation of aniline, is condensed with 2,6-dichlorophenol

(VI) to give N-(2,6-dichlorophenoxyacetyl)-aniline

(VII) which, in an alkali medium, undergoes rearrange¬ ment to N-(2, 6-dichlorophenyl)-N-aniline (II), which can be transformed into the final product by reaction with chloroacetyl chloride.

Alternatively, N-(2,6-dichlorophenoxyacetyl)- aniline (VII) can be prepared according to scheme II, from an alkyl 2,6-dichlorophenoxyacetate (VIII), which can in its turn be obtained from 2,6-dichlorophenol (VI) and an alkyl chloroacetate (IX), the subsequent steps remaining the same as those of scheme I:

Scheme II

(VI) (IX) (VIII)

aniline

(VII⁾

The rearrangement reaction giving diarylamine (II) from arylaminocarbonylmet oxyaryl (VII) can be carried out in solvents of various nature, such as water, lower alcohols, glycols, ethylene glycol monomethyl ether or dimethylether, tetrahydrofuran, dioxane, arenes (benzene, toluene, xilenes), chlorohydrocarbons (trichloroethylene, di- or tetrachloroethane) , pyridine; or in aprotic polar solvents, such as dimethyIformamide, dimethylsulfoxide and the like, and the mixtures thereof. The base promoting the rear- rangement can be of various nature, also depending on the selected solvent: an alkali or alkaline-earth hydroxide or carbonate, such as NaOH, KOH, Ca(OH)₂, Na₂-CO,, ^{K C0} ₃' ^etc«; ^{a c}ι~^C4 alkali metal alkoxide, for example sodium or potassium methoxide, ethoxide or t.butoxide; a tertiary amine, such as triethylamine, N- methylmorpholine and the like; a quaternary ammonium hydroxide, for example tetramethyl-, tetraethyl- or te- trabutyl ammonium, trimethylbenzyl ammonium hydroxide and the like. Also particularly strong bases, such as NaH, KH, NaNH₂ o K H₂, proved to be suitable; the addition of crown ethers can moreover increase the reaction rate. The amount of the added base can be stoichiometric or catalytic; mixtures of strong and less strong bases can also be used, for example NaOH/Na₂C0₃ or KOH/K₂C0₃.

A substantial advantage of the invention resides in that all the above mentioned steps can be carried out in a single reactor, practically without isolating any one of products (V), (VII) and (II). As a consequence, even though the above scheme apparently involves many steps, the technical execution thereof is, on the contrary, very simple.

In practice, the process of the invention is carried out by placing into a suitable reactor aniline (III), respectively 2,6-dichlorophenol (VI) together with an appropriate solvent, suitably a halogenated hydrocarbon such as dichloromethane, chloroform, trichloroethylene or tetrachloroethylene, or in an aromatic hydrocarbon, such as toluene, then adding reagent (IV) (or (IX)) (for example methyl chloroacetate or chloroacetyl chloride). Intermediate (V) (respectively (VIII)) forms within a short time at the reflux temperature of the reaction mixture. Then the reaction mixture is added with dichlorophenol (VI) (respectively aniline (III)). The condensation, when yielding (VII), is suitably effected in the presence of a hydrochloric acid binding agent, advantageously an alkali or alkaline-earth hydroxide or carbonate, such as sodium, potassium or calcium hydroxide or carbonate. At this time the base, for example KOH, is added, and rearrangement is achieved (II) by heating at temperatures of 20-150°C, for example the mixture's reflux temperature, for some hours. Acylation of a ine (II) with chloroacetyl chloride (IV) can be effected conventionally, at a mild temperature; however, such a reaction proved to proceed . in almost quantitative yields when adding to the reaction mixture, besides chloracetyl chloride, also an equimolar amount of a tertiary base, suitably triethylamine (TEA). An analogue TEA addition is preferably effected also in chloroacetylation of aniline (III) or in the reaction of (VI) with (IX). In both cases the reaction is carried out at temperatures of 10°-90^CC, preferably at 25-50°C.

Preferred solvents are perchloroethylene (- tetra- chloroeth lene) and toluene.

The resulting final product (I) is thus obtained easily, in total yields from 70 to 80% based on the starting aniline (II).

The following examples illustrate the process of the present invention. EXAMPLE 1

150 1 of toluene and 8 kg of aniline (0.086 kmole) are placed into a 250 1 reactor fitted with condenser, stirrer and feeding and fume removal devices.

The mixture is stirred and 11.36 kg of chloroa- cetyl chloride (0.1 kmole), and an equimolar amount of TEA (10.1 kg) are slowly added. The reaction mixture is stirred for about 6 hours at 30°C. At this time the reaction for the formation of (V) is completed; 50 1 of water are added, the mixture is shortly stirred, then it is left to decant and the TEA.HCl aqueous solution is discarded. About 21.5 kg of K₂CO. (0.155 kmole) and 16.3 kg (0.1 kmole) of 2,6-dichlorophenol (VI) are added in the same reactor. The mixture is refluxed for about 30 hours checking pH to maintain it alkaline. When all intermediate (V) is transformed into (VII) (the reaction is checked by TLC), about 7 kg of KOH are added and reflux is continued for 7 more hours to transform all (VII) into (II). After that, about 100 1 of water are added, the mixture is decanted, the aqueous phase is discarded and the organic phase is washed with water to neutral pH.

The organic phase is separated, heated to about 60^βC and added dropwise with 15.4 kg of chloroacetyl chloride (0.13 kmole) and an equimolar amount of TEA. The mixture is stirred for about 12 hours at 30 - 50°C. When the reaction is over, about 1/3 of solvent is di- stilled off, the mixture is cooled to about 40°C, 70 1 of water and 30% NaOH are added to pH 6-7. The mixture is cooled to 5°-10°C and stirred for about 1 hour, then it is filtered and washed with toluene on the filter. After drying, 23 kg of N-(2,6-dichlorophenyl)-N-phenyl- N-(chloroacetyl)-amine (I) are added, m.p. 140.5°C.

Yield 80%.

EXAMPLE 2 a) 150 1 of toluene and 16.3 kg (0.1 kmole) of 2,6- dichlorophenol (VI) are placed into a reactor similar to that of example 1; then 5.94 kg (0.11 kmole) of sodium methoxide are added in portions, under stirring, at 25-30^βC, then 11.93 kg (0.11 kmole) of methyl chloroacetate dissolved in 15 1 of toluene are dropped therein. Temperature is kept at 30-50^CC for about three hours, then the mixture is cooled to 20°C. b) 30 litres of water are added to the mixture, which is strongly stirred, then it is left to decant and the aqueous layer containing sodium chloride is discarded. c) The toluene solution is added with 9.3 kg (0.1 kmole) of aniline and it is gradually heated to reflux, distilling all the methanol, formed following the anilide (VII) formation, with some litres of toluene and a small amount of water. Then 7 kg of KOH are added and the procedure of example 1 is repeated, to obtain the final product (I) in very good purity, in a 82% yield. EXAMPLE 3

The procedure of Example 2 is repeated, but with the following changes: the reaction is carried out in dimethylformamide instead of toluene, washing with water according to step b) is avoided, and potassium hydroxide is replaced by an equivalent amount of sodium hydroxide for the rearrangement.

The final product is obtained in a 84% yield.

Claims

1. A process for the preparation of N-(2,6-dichlo- rophenyl)-aniline (II), characterized in that (2,6-di- chlorophenoxyacetyl)-aniline (VII) is subjected to a rearrangement in an alkali medium, according to the scheme below:

(VII)

2. A process according to claim 1, characterized in that the base is selected from the group consisting of alkali and alkaline-earth metal hydroxides, carbonates,

C^-C^ alkoxides, hydrides and amides, tertiary amines and quaternary ammonium hydroxides.

3. A process according to claims 1 and 2, characteri¬ zed in that the base amount is stoichiometric or catalytic.

4. A process according to claims 1-3, characterized in that (2,6-dichlorophenoxyacetyl)-aniline (VII) is prepared by reacting chloracetylaniline (V) with 2,6- dichlorophenol (VI).

5. A process according to claims 1-3, characterized in that (2,6-dichlorophenoxyacetyl)-aniline (VII) is prepared from a C₁-C₄ alkyl 2, 6-dichlorophenoxyacetate (VII) and aniline (III).

6. A process for the preparation of N-(2,6-dichlo- rophenyl)-N-phenyl-N-chloroacetylamine (I), characteri¬ zed in that: a) aniline (III) is subjected to chloroacetylation, to obtain N-chloracetylaniline (V) which is reacted with 2,6-dichlorophenol (VI) to give (2,6- dichlorophenoxyacetyl)-aniline (VII); or a') 2,6-dichlorophenol (VI) is transformed into a

^Cl~^c4 ^alk ! 2,6-dichlorophenoxyacetate (VIII), by reaction with a

alkyl chloroacetate (IX), then (VIII) is reacted with aniline (III) to give (2,6-dichlorophenoxyacetyl)-aniline (VII) ; b) (VII) is subjected to a rearrangement in the presence of bases, to give N-(2,6-dichlorophenyl)- aniline (II) ; c) (II) is chloroacetylated according to the scheme below:

(I) (II) wherein X is chlorine or C,-C. alkoxy, whereas R is C,- C₄ alkyl, steps a (or a¹), b and c being carried out without isolation of the intermediates, in the same reactor and in the same solvent.

7. A process according to claim 6, characterized in that the solvent is selected from the group consisting of water; lower alcohols; glycols; ethers; arenes; chlorohydrocarbons ; pyridine; aprotic polar solvents and mixtures thereof.

8. A process according to claims 6-7, characterized in that steps a) and c) are effected in the presence of an acid-binding agent.

9. A process according to claim 8, characterized in that the acid-binding agent is selected from tertiary bases and alkali or alkaline-earth hydroxides or carbonates.

10. As a novel intermediate, N-(2,6-dichlorophe- noxy ) acet y 1-ani line .