GB2096144A

GB2096144A - Preparation of alpha -(3,4,5- trimethoxybenzoylthio)-propionyl glycine

Info

Publication number: GB2096144A
Application number: GB8209992A
Authority: GB
Original assignee: Norton Healthcare Ltd
Current assignee: Norton Healthcare Ltd
Priority date: 1981-04-07
Filing date: 1982-04-05
Publication date: 1982-10-13
Also published as: FR2510565B1; IT1144700B; JPS57179155A; FI821046L; GB2096144B; FR2503152A1; FI821046A0; FR2503152B1; FR2510565A1; CA1171877A; IT8120976A0; DE3212766A1; JPS5941985B2

Abstract

A process for the preparation of alpha - (3,4,5-trimethoxybenzoylthio)- propionyl glycine of the formula <IMAGE> by reaction of alpha -halogeno-propionyl glycine with alkalimetal or alkaline earth metal salts of 3,4,5- trimethoxybenzoylthiobenzoic acid or alternatively, by acylation of the glycine with an activated derivative of alpha -(3,4,5-trimethoxybenzoylthio)- propionic acid.

Description

SPECIFICATION Preparation of a glycine derivative The present invention relates to a process for the preparation of a-(3,4,5-trimethoxybenzoylthio)propionyl glycine (I).

Compound (I), described in Italian Patent Application No. 25,883 A/80 of 11/11/1980, has useful therapeutic properties for the treatment of bronchopathies, hepatopathies and the consequences of poisoning.

According to the aforesaid patent application, said compound is obtained by acylation of amercaptopropionyl glycine with 3,4,5-trimethoxybenzoyl chloride. This obviously involves.the use of amercaptopropionyl glycine, which is expensive and has an unpleasant, persistent smell; moreover, the reaction yields are not very satisfactory.

It has now been found that compound (I) can be obtained with high yields and at considerably lower cost by reacting a salt of 3,4,5-trimethoxythiobenzoic acid (II) with an a-halogenopropionyl glycine (III) in accordance with reaction A below:

where Ar is the 3,4,5-trimethoxyphenyl residue, and Me is an alkaline metal, preferably sodium or potassium, or the equivalent of an alkaline earth metal, preferably magnesium, and X is a halogen, preferably chlorine or bromine.

The reaction iliustrated above is effected at temperatures between 0 and 500 C, preferably at ambient temperature; its progress is easily followed by TLC (thin-layer chromatography). At ambient temperature the reaction is complete in about 24 hours; by acidification (I) is obtained at a good state of purity.

Alternatively, it has been found that (I) can be obtained satisfactorily by acylation of glycine (V) with an activated derivative of a-(3,4,5-trimethoxybenzoylthio) propionic acid (IV), in accordance with reaction B below:

where Ar is as illustrated above, and Y is an activating group, such as Cl, -O-CO-O alkyl alkoxyl.

The intermediate product (IV) is in turn easily accessible, e.g. by acylation of thiopropionic acid with 3,4,5-trimethoxybenzoyl chloride. The reaction in accordance with B is preferably effected at temperatures below 200 C, for times between 4 and 20 hours; the product is separated by filtration and subsequent recrystallisation.

The examples which follow illustrate the process of the invention.

Example 1 a) Potassium 3,4,5-tri methoxythiobenzoate 7.5 kg of KOH flakes are dissolved in 50 litres of methanol; cooling externally to about 1 50C, 4.1 kg of H2S are added, until alkalinity disappears. Still maintaining the temperature at 1 50C, 1 5 kgs of 3,4,5-trimethoxybenzoyl chloride are added in portions and left overnight with the stirrer in operation.

Almost all the methanol is then removed at reduced pressure and the residue is taken up with a solution of 9 kgs of K2CO3 in 100 litres of water. The solution is filtered and used for the subsequent reaction.

b) a-(3,4,5-Trimethoxybenzoylthio)propionyl glycine (I) The solution obtained under a) is added to a solution of 1 3.6 kgs of a-bromopropionyl glycine and 9 kgs of K2CO3 in 50 litres of water and the whole is left for 24 hours with the stirrer in operation.

At this point the starting products are no longer identified by TLC. The solution is strained into a mixture of 200 litres of water and 1 50 litres of concentrated HCI. The precipitate is centrifuged, washed with water, dried and recrystallised with ethanol; this gives 1 8 kgs (80%) of a-(3,4,5- trimethoxybenzoylthio) propionyl glycine, m.p. 174-1 750C. whose purity is confirmed by TLC.

Example 2 The same process is followed as in Example 1 but using the sodium salt of 3,4,5trimethoxythiobenzoic acid. (I) is obtained with a yield of 66.5%.

Example 3 Operating as in Example 1 but replacing the a-bromopropionyl glycine with an equivalent quantity of the corresponding chlorine derivative, (I) is obtained with a yield of 73%.

Example 4 The process is the same as in Example 1 but using the magnesium salt of 3,4,5trimethoxythiobenzoic acid. The yield of (I) is 46%.

Example 5 a) a-(3,4,5-Trimethoxybenzoylthio)propionic acid To a solution of 3.3 kgs of K2CO3 in 9 litres of water are added, at between 1 5 and 200C, 767 ml of tz-thiopropionic acid (commercial thiolactic acid, density 1.2); then, at the same temperature and in portions, 2 kgs of 3,4,5-trimethoxybenzoyl chloride. After overnight stirring at ambient temperature this is acidified with HCI 1:1 and extracted with three portions of 15 litres of toluene. After washing with water and evaporation of the toluene solution, 2.6 kgs of an oily product are left, whose analytical data coincide with the caiculated analysis.

b) a-(3,4,5-Trimethoxybenzoylthio)propionyl glycine (I) The compound obtained in Example 5a) (2.6 kgs) is gradually added to 7 litres of thionyl chloride.

This is left overnight, with stirring, the excess SOCI2 is evaporated, and it is treated with 3 litres of benzene and re-evaporated under vacuum. The residue obtained (2.7 kgs) is gradually added to a solution of 730 g of glycine and 290 g of K2CO3 in 10 litres of water, ensuring that the temperature does not exceed 200 C. When the addition is finished, this is left overnight, with stirring, at ambient temperature, and then an ice-cold solution of HCI 1:1 is added to give pH 2. The precipitate is separated by filtration, washed thoroughly with water and recrystallised with methanol. This gives 2.03 kgs of product with a m.p. of 1 72-1 740C (yield - 68%).

Example 6 288 g (1 mole) of a-(3,4,5-trimethoxybenzoylthio) propionic acid, obtained as in Example 5a) are dissolved in 5 litres of chloroform, to which are added, cooling to 1 0-1 50C, 108 g (1 mole) of ethyl chlorocarbonate then 101 g (1 mole) of triethylamine. To the mixed anhydride solution so obtained are added 75 g (1 mole) of glycine, with swirling. After 36 hours' stirring at ambient temperature this is treated with 2 kgs of crushed ice and HCL 1:1 is added until the solution is acid (pH 1-2). The chloroform solution is separated, washed with water and evaporated to dryness. The residue is recrystallised with ethanol; (I) is obtained with a yield of 63%, m.p. 173-1 750C.

Claims

1. Process for the preparation of a-(3,4,5-trimethoxybenzoylthio)-propionyl glycine (I)

characterised in that a salt of 3,4,5-trimethoxythiobenzoic acid (II) is reacted with an a- halogenopropionyl glycine (III) in accordance with the reaction:

where Ar is the 3,4,5-trimethoxyphenyl residue, Me is an alkaline metal, or the equivalent of an alkaline earth metal, and X is a halogen atom.

2. Process in accordance with claim 1 , wherein Me is potassium.

3. A process in accordance with claim 1, wherein Me is sodium.

4. Process in accordance with claim 1, wherein Me is magnesium.

5. Process in accordance with any one of the preceding claims, wherein Xis bromine.

6. Process in accordance with any one of claims 1 to 4, wherein X is chlorine,

7. Process for the preparation of a-(3,4,5-trimethoxybenzoylthio)propionyl glycine (I) characterised in that glycine (V) is acylated with an activated derivative of a-(3,4,5trimethoxybenzoylthio)propionic acid (IV) in accordance with the reaction:

where Ar is the 3,4,5-trimethoxyphenyl residue, and while Y is an activating group.

8. Process in accordance with claim 7, wherein Y is chlorine.

9. Process in accordance with claim 7, wherein Y is the

residue.

10. Process for the preparation of a-(3,4,5-trimethoxybenzoylthio)propionyl glycine, substantially as set forth herein.

11. Process as claimed in claim 10, in accordance with any one of the Examples herein.

1 2. a-(3,4,5-Trimethoxybenzoylthio)-propionyl glycine prepared by the process of any one of the preceding claims.