MC895A1 - Process for preparing N- (diethylaminoethyl) 2-methoxy 4-amino-5-chlorobenzamide - Google Patents

Description

PATENT FOR INVENTION

Process for preparing N-(diethylaminoethyl)-2-methoxy-4-

amino-5-chlorobenzamide

FRATMANN S.A.

The present invention relates to a process for preparing N-(diethylaminoethyl)-2-methoxy-4-amino-5-chlorobenzamide by chlorination of an N-substituted and O-alkylated p-aminosalicylic acid ester and by its subsequent transformation using diethyl-amino ethy lamin e.

The process is generally carried out in such a way that, starting with p-aminosalicylic acid, whose carboxyl group is esterified and hydroxyl group is alkylated, the amino group at position 4 is blocked by acetylation using acetic anhydride to carry out the subsequent steps. This acetyl group is then removed again after the introduction of the other substituents.

However, it has been observed that the yield, during the preparation of benzamide, described above, by the usual process, could be substantially improved if, during the blocking of the amino group in position 4, it was not acetylated, but substituted in another way.

The process according to the invention is characterized essentially in that after esterification and O-alkylation of p-amino-salicylic acid, the amino group in position 4 is, before chlorination, substituted by a radical of para-toluene sulfamido acid, which is again eliminated after transformation by means of diethyl-amino ethylamine.

According to a preferred method of preparation of the invention, methyl 2-methoxy-4-aminobenzoate can be transformed by means of para-toluene sulfochloride, while the removal of this radical from paratoluene sulfamido acid can be achieved simply by heating n-(diethylaminoethyl)-2-methoxy-4-(paratoluene sulfamido) 5-chlorobenzamide in concentrated sulfuric acid.

The reactions take place according to the following pattern:

cooh cooch oh

+ so4(ch3)2

3

och

3

t 2

nh,

2

coach

+ ci:so2-// \V ch3

nh_

COACH

(II)

GDOCH

+ Cl,

ch,

COACH

(III)

coo ch„

C2H5

3 -fH2N_CH2-CH2-l|r_

sor(£\cl'.

C„ H_ 2 5 Cl

0.25

CONH- CH - N

2 I

C H OCH3 2 5

.CH,

(IV)

NH-SO // V

conh - ch _ - ch -n ù z j

' • ' C,Hc och3 , 2 5

+ h2so4

conh- ch2- ch2

OCH,

nh-

so

Cl

CoHc | 2 5

N

SH5

(V)

nh„

4.

The invention will be illustrated by means of the following example: methyl 2-methoxy-4-aminobenzoate (I)

In a 2-litre flask equipped with a stirrer, a thermometer and a bromine ampoule, 35 g (0.229 mol) of para-5 amino salicylic acid and 700 ml of acetone are introduced.

When the solution is obtained, 33 g 6 (0.6 mol) of potash is introduced in six portions over 2 hours 30 minutes: the stirring must be extremely vigorous.

Next, 51 ml (0.54 mol) of methyl sulfate 10 is added dropwise and the mixture is left to stir for 3 hours at room temperature. The acetone is then distilled under vacuum by gently heating it in a water bath.

Add 700 ml of water. Wring out, wash with water, and dry in an oven at 50°C. 36 g (87% yield) of (I) is obtained with a melting point of 158°C.

2-methoxy-4-(paratoluene sulfamide)methyl(II) benzoate

15 In a 1-liter flask equipped with a stirrer, a thermometer, and a distillation column, 36 g (0.198 mol) of (I), 42 g (0.26 mol) of para-toluene sulfochloride, 400 ml of toluene, and 2 g of triethanolamine are introduced. 20 ml is distilled extremely slowly for 4 hours, with the temperature in the bulk being 115°C.

We cool it and let it crystallize overnight.

The mixture is filtered and washed several times with 200 ml of a 20% hydrochloric acid solution, then with water until the wash water reaches a neutral pH. It is then dried in an oven at 50°C. 54 g (81.3% yield) of (II) with a melting point of 143°C is obtained.

2-methoxy-4-(paratoluene sulfamido)5-methyl chlorobenzoate_ (III)

In a 250 mL round-bottom flask equipped with a stirrer and a bromine funnel, 24.5 g (0.0732 mol) of (II) and 50 mL of acetic acid are introduced. Over the resulting suspension, a solution of 5.2 g (0.0732 mol) of chlorine in 137 mL of acetic acid is added dropwise over half an hour at room temperature.

Let it shake for 3 hours and then rest overnight.

The mixture is poured into 1.5 liters of water, filtered, washed with water and alcohol, and dried at 50°C. 24.5 g (90% yield) of (III) is obtained with a melting point of 177°C.

N-(diethylaminoethyl)2-methoxy-4-(paratoluene sulfamido)5-chlorobenzamide (IV)

In a 250 ml flask equipped with a stirrer and a condenser, 145 ml of toluene, 21.5 g (0.0583 mol) of (III) and 20.7 g (0.0583 mol x 3) of diethylaminoethylamine are introduced and then heated for 2 hours 30 minutes under reflux.

The mixture is cooled, filtered, the precipitate is washed with toluene, and dried in an oven at 50 °C. 26 g (yield of 98.5%) of (IV) is obtained with a melting point of 144 °C.

N-(diethylaminoethyl)2-methox:y-4-amino-5-chlorobenzamide (V)

In a round-bottom flask, 10 g of (IV) and 15 mL of 96% sulfuric acid are placed. The mixture is heated in a water bath at 60-70°C for 1 hour. It is then cooled, poured onto crushed ice, and adjusted to pH 10 with 35 mL of 40% sodium hydroxide solution. The resulting precipitate is filtered, washed with water, dried in an oven, and recrystallized in isopropanol.

After recrystallization, 5 g (yield of 76%) of (V) is obtained with a melting point of 145-146°C.

N-(diethylaminoethyl) 2-methoxy-4-amino-5-chlor r ob enzamide, known by the common name metoclopramide, is a major drug used in gastrointestinal disorders as a digestive behavior modifier.

Claims (1)

. s. i?. 7. SUMMARY The invention relates to a process for preparing N-(diethylamino-ethyl)-2-methoxy-4-amino-5-chlorobenzamide by chlorination of an N-substituted and O-alkylated P-aminosalicylic acid ester and by its subsequent transformation using diethylaminoethylamine, characterized Raise by the following points considered separately or in combination: After esterification and O-alkylation of p-aminosalicyli- acid, the amino group at position 4 is, before chlorination, substituted by a radical of paratoluene sulfamido acid, which is again eliminated after transformation by means of diethylaminoethylamine. •Methyl(I) 2-methoxy-4-aminobenzoate is reacted with paratoluene sulfo chloride. " . The elimination of the radical of paratoluene sulfamido acid is obtained • : • by heating N-(diethylaminoethyl)-2-methoxy-4-(paratoluene 15 sulfamido)-5-chlorobenzamide (IV) in concentrated sulfuric acid. by Power of Attorney