GB2182041A - Esters of diethylene glycol - Google Patents

Description

A L Y 1 1 GB2182041A 1

SPECIFICATION

Preparation of esters of diethylene glycol This invention relates to a process for the preparation of esters of diethylene glycol, particularly 5 monoesters. The invention also relates to esters prepared by the process.

Thus, according to one aspect the invention provides a process for the preparation of an ester of diethylene glycol wherein diethylene glycol is reacted with an acid of general formula 1 (CH 2) n CO 2 H R 3 NH - 1 2 I (wherein n is 0 or 1; R' is Cl, H or CH,; R2 is H, CF,, or CH,; and R3 is Cl or H) or a salt thereof.

The preparation of esters in accordance with the invention may be effected in a single step and it is not necessary to protect one of the hydroxyl groups of the diethylene glycol.

The process is conveniently effected with an excess of diethylene glycol compared to the quantity of acid of formula 1 or salt thereof. The reaction is advantageously effected in the presence of thionyl chloride, which is preferably present in a stoichiometric amount, or slight excess, compared to the quantity of acid of formula 1 or salt thereof.

As indicated above the process may be effected using a salt of the acid of formula 1, preferably an alkali metal salt such as, for example, a sodium or potassium salt.

The process according to the invention is conveniently effected at a temperature of from room temperature up to the temperature of a steam bath, the temperature generally being related to the time required to complete the reaction.

Examples of acids of formula 1 which may be employed in the process include:- 2-[(2,6-dichlorophenyi)amino]benzene acetic acid (i.e. n=1, RI=R3=Cl, and R2=1-1); 2-[(3-trifluoromethylphenyl)aminolbenzoic acid (i.e. n=O, RI=W=H, and R2=CIF3); 2-[(2,6-dichloro-3-methylphenyl)aminolbenzoic acid (i.e. n=O, Rl+R3=Cl, and R2=CH3); and 2-[(2,3-dimethylphenyi)aminolbenzoic acid (i.e. n=O, RI=R2=CH3, and R3=1- 1).

The esters prepared according to the invention are novel compounds and are included within the scope of the invention.

Examples of esters according to the invention include:2-[(2,6-dichlorophenyi)aminolbenzene acetic acid 2-(2-hydroxyethoxy) ethyl ester (Compound A); 2-[(3-trifluoromethylphenyi)aminolbenzoic acid 2-(2-hydroxyethoxy) ethyl ester; 2-[(2,6-dichloro-3methylphenyl)aminolbenzoic acid 2-(2-hydoxyethoxy)ethyl ester; and 2-[(2, 3-dimethylphenyl)aminolbenzoic acid 2-(2-hydroxyethoxy)-ethyl ester.

Compound A is a particularly preferred compound according to the invention. It has been found to exhibit pharmacological activity, particularly an anti- inflammatory activity. Thus, in a further aspect the invention provides pharmaceutical compositions comprising Compound A to gether with a pharmaceutical carrier or excipient.

In the process of the invention, the crude products from the reaction of diethylene glycol with 50 the acid of formula 1, optionally in the presence of thionyl chloride, may be isolated by adding water/diethyl ether as they are readily soluble in the organic solvent. They may be purified by passing through a column of silica gel, and then show only one spot in thin layer chromato graphy (60 F251 silica gel plates; mobile phase-chloroform; detection under a 254 nm light).

They also show only one peak in high pressure liquid chromatography. On the other hand 'H-NMR spectra are as expected for these compounds. All of them show the ester group band in their IR spectra.

The following non-limiting Examples serve to illustrate the invention:

Example 1-Preparation of 2-[(2,6-dichforophenyl)aminolbenzene acetic acid 2-(2-hydroxyethoxy)- 60 ethyl ester To a mixture of 180 mi of dry diethylene glycol and 4 m] thionyl chloride are added 15 g of sodium 2-[(2,6-dichlorophenyi)aminolbenzene acetate. After stirring at room temperature, 200 mi water and 250 mi diethyl ether are added, the aqueous layer is removed and the organic layer is successively washed with water, aqueous sodium hydroxide and water again. The ether solution 65 1 2 GB2182041A 2 is dried with anhydrous sodium sulfate and the solvent is removed by distillation. The oily residue is purified by passing through a chromatography column of silica gel and eluting with chloroform. On removal of the solvent, 16.5 9 (86%) of slightly yellow oil are obtained. v (ester)= 1720 cm-1.

Example 2-Preparation of 2-[(3-trifluoromethylphenyl)aminol-benzoic acid 2-(2-hydroxyethoxy)ethyl ester To 80 litres dry diethylene glycol, 3 litres thionyl chloride and 10 kg of 2-[(3-trifluoromethylphenyi)amino]benzoic acid are added. The mixture is heated on a steam bath for 6 hours. The resultant dark green solution is cooled and water/diethyl ether is added, the product being worked up in a similar way to that described in Example 1. After purification of the product, 7.8 kg (59%) of a light yellow oily product are obtained. v (ester)= 1683 cm-1.

Claims (14)

1. A process for the preparation of an ester of diethylene glycol wherein diethylene glycol is 15 reacted with an acid of general formula 1 (CH 2)J2 H R3 NH R1 R 2 1 (wherein n is 0 or 1; R' is Cl, H or CH3; R 2 is 1-1, CF, or CH3; and R 3 is Cl or 1-1) or a salt thereof.

2. A process according to claim 1 wherein the reaction is carried out in the presence of thionyl chloride.

3. A process according to either of claims 1 and 2 wherein the reaction is carried out at a temperature of from room temperature to steam bath temperature.

4. A process according to any one of the preceding claims wherein the salt of the acid of formula 1 is a sodium or potassium salt.

5. A process according to any one of the preceding claims wherein the acid of formula 1 is selected from 2-[(2,6-dichlorophenyi)aminolbenzene acetic acid, 2-[(3- trifluoromethylphenyl)amino]- benzoic acid, 2-[(2,6-dichloro-3-methylphenyl)aminol-benzoic acid, and 2[(2,3-dimethylphenyi)ami- 35 no]benzoic acid.

6. A process according to any one of the preceding claims, wherein the ester prepared is selected from 2-[(2,6-dichlorophenyi)amino]benzene acetic acid 2-(2- hydroxyethoxy)ethyl ester, 2 [(3-trifluoromethylphenyi)amino]benzoic acid 2-(2-hyd roxyethoxy) ethyl ester, 2-[(2,6-dichloro-3-me thylphenyi)amino]benzoic acid 2-(2-hydroxyethoxy)ethyl ester, and 2-[(2,3- dimethylphenyl)aminolbenzoic acid 2-(2-hydroxyethoxy)ethyl ester.

7. A process according to claim 1 substantially as herein described.

8. A process for the preparation of an ester of diethylene glycol substantially as herein described in either of the Examples.

9. An ester prepared by a process according to any one of the preceding claims.

10. An ester of diethylene glycol with an acid of formula 1 as defined in claim 1.

11. An ester selected from 2-[(2,6-dichlorophenyi)amino]benzene acetic acid 2-(2-hydroxy ethoxy)ethyl ester, 2-[(3-trifluoromethylphenyl)amino]benzoic acid 2-(2- hydoxyethoxy)ethyl ester, 2-[(2,6-dichloro-3-methylphenyi)-aminolbenzoic acid 2-(2-hyd roxyethoxy) ethyl ester, and 2-[(2,3- dimethylphenyi)aminolbenzoic acid 2-(2-hyd roxyethoxy) ethyl ester.

12. 2,6-Dichlorophenyi)aminolbenzene acetic acid 2-(2-hydroxyethoxy)ethyl ester.

13. A pharmaceutical composition comprising the ester according to claim 12 in association with a pharmaceutical carrier or excipient.

14. Each and every novel compound, process, composition and method substantially as herein disclosed.

Printed for Her Majesty's Stationery Office by Burgess & Son (Abingdon) Lid, Dd 899 1685, 1987. Published at The Patent Office, 25 Southampton Buildings, London, WC2A 1 AY, from which copies may be obtained.

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