PROCEDURE FOR THE PREPARATION OF A GLYCINE DERIVATIVE

PROCEDE DE PREPARATION D'UN DERIVE DE LA GLYCINE

English Abstract

- 1 -
Abstract:
A procedure is described for the preparation of
.alpha.-(3,4,5-trimethoxybenzoylthio)-propionyl glycine by
reaction of .alpha.-halogenopropionyl glycine with salts of
3,4,5-trimethoxybenzoyl-thiobenzoic acid or, alternat-
ively, by acylation of the glycine with .alpha.-(3,4,5-tri-
methoxybenzoylthio)-propionic acid. The product is useful
for the treatment of bronchopathies, hepatopathies and
poisoning.

Claims

- 6-
Claims:
1. A process for the preparation of .alpha.-(3,4,5-trimethoxy-
benzoylthio)-propionyl glycine (I)
<IMG>
(I)
which comprises either (a) reacting a salt of 3,4,5-
trimethoxythiobenzoic acid having the formula
<IMG>
where Ar is the 3,4,5-trimethoxyphenyl residue and Me is
an alkaline metal or an equivalent thereof, with an .alpha.-
halogenopropionyl glycine having the formula:
<IMG>
where X is a halogen atom; or (b) reacting glycine with an
activated derivative of .alpha.-(3,4,5-trimethoxybenzoylthio)
propionic acid of the formula
<IMG>
where Ar is the 3,4,5-trimethoxyphenyl residue and Y is an
activating group.
2. The process of claim 1(a) wherein Me is potassium.
3. The process of claim 1(a) wherein Me is sodium.
4. The process of claim 1(a) wherein Me is magnesium.
5. The process of claim 2, 3 or 4 wherein X is bromine.
6. The process of claim 2, 3 or 4 wherein X is chlorine.
7. The process of claim 1(b) wherein Y is chlorine.
8. The process of claim 1(b) wherein Y is the <IMG>
residue.

Description

117~ 7
The subject of the present invention is a new
procedure for the preparation of a-(3,4,5-trimethoxy-
benzoylthio)-propionyl glycine (I).
CH3-CH-CO-NH-CH2-COOH
I ~ OCH3
CO ~ OCH3 (I)
OCH3
The above compound is known and has useful therapeutic
properties for the treatment of bronchopathies, hepato-
pathies and the consequences of poisoning. It was
previously obtained by acylation of a-mercaptopropionyl
glycine with 3,4,5-trimethoxybenzoyl chloride. This
lQ obviously involves the use of a-mercaptopropionyl 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
-halogenopropionyl glycine (III) in accordance with
diagram A below:
, j , ~
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1~ 7~377
DIAGRAM A
Ar-C ~ + CH3-CH-CO-NH-CH2-COOH ~ (I)
SMe x
. .
(II) (III)
where Ar is the 3,4,5-trimethoxyphenyl residue, while Me is
an alkaline metal, preferably sodium or potassium, or the
equivalent of an alkaline earth metal, preferably magne-
sium, and X is a halogen, preferably chlorine or bromine.
The reaction illustrated above is effected at temperat-
ures between 0 and 50C, preferably at ambient temperature;
its progress is easily followed by TLC (thin-layer chroma-
lQ tography). At ambient temperature the reaction is completein 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 ~-(3,4,5-trimethoxybenzoylthio)
propionic acid (IV), in accordance with diagram B below:
DIAGRAM B
CH3-CH-COY NH2 CH2 COOH ~ (I)
S +
CO-Ar
(IV) (V)
where Ar is as illustrated above, while 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 acyla-
tion of thiopropionic acid with 3,4,5-trimethoxybenzoyl
chloride. The reaction in accordance with diagram B is
preferably effected at temperatures below 20C, for times
between 4 and 20 hours; the product i8 separated by
filtration and subse~uent recrystallisation.
The examples which follow illustrate the procedures
according to the invention.
'', - .
.'; ,
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EXAMPLE 1
a) Potassium 3,4,5-trimethoxythiobenzoate
7.5 kg of KOH flakes are dissolved in 50 litres of meth-
anol; cooling externally to about 15C, 4.1 kg of H2S
are added, until alkalinity disappears. Still maintaining
the temperature at 15C, 15 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) -(3,4,5-trimethox~benzoylthio) propionyl glycine (I)
The solution obtained under a) is added to a solution of
13.6 kgs of ~-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 150
litres of concentrated HCl. The precipitate is centri-
fuged, washed with water, dried and recrystallised with
ethanol; this gives 18 kgs (80%) Of ~-t3,4,5-trimethoxY-
benzoylthio) propionyl glycine, m.p. 174-175C, whose
purity is confirmed by TLC.
EXAMPLE 2
The same procedure is followed as in Example 1 but using
the sodium salt of 3,4,5-trimethoxythiobenzoic acid. (I)
' is obtained with a yield of 66.5%.
EXAMPLE 3
; 30 Operating as in Example 1 but replacing the ~-bromoprop-
ionyl glycine with an equivalent quantity of the corres-
; ponding chlorine derivative, (I) is obtained with a yield
of 73%.
'
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-- 4 --
EXAMPLE 4
The procedure is the same as in Example 1 but using the
magnesium salt of 3,4,5-trimethoxythiobenzoic acid. The
yield of (I) is 46%.
EXAMPLE 5
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 15 and 20C, 767 ml of ~-thioprop-
ionic acid (commercial thiolactic acid, density 1.2);
then, at the same temperature and in portions, 2 kg of
3,4,5-trimethoxybenzoyl chloride. After overnight stir-
ring at ambient temperature this is acidified with HCl 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 calculated analysis.
b) ~-(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 over-
night, stirring, the excess SOC12 is evaporated. 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 20C. When the addition is finished, this is
left overnight, stirring, at ambient temperature, then an
ice-cold solution of HCl 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 172-174C (yield ~ 68%).
EXAMPLE 6
288 g (1 mole) of ~-(3,4,5-trimethoxybenzoylthio) prop-
ionic acid, obtained as in Example 5a), are dissolved in
.
:.

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5 litres of chloroform, to which are added, cooling to
10-15C, 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,
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. 173-175C.