DE1092932B - Process for the preparation of amoebicidally active N-dichloroacet-oxy-anilide esters - Google Patents

Description

GERMAN

The invention relates to a method for producing therapeutically valuable acetanilide compounds, namely amoebicidal N-dichloroacet-oxy-anilide ester of the general formula

CLCHCON - ο

> —O —C —R '

(I)

Cl ₂ CHCON-

R O

where R is a lower alkyl group and R 'is an alkyl, alkenyl, phenyl or mono- or polysubstituted group Means alkyl group.

It is already known that N-acylated m-oxyaniline compounds have amoebicidal effects. From this, however, it could not be concluded that either the compounds prepared according to the invention have such effects.

Compounds of the aforementioned general formula I are prepared in such a way that a phenol of general formula

_N

- <· V-OH

wherein R has the meaning given above, with a carboxylic acid of the general formula R'COOH or with an acid anhydride of the general formula (R'C O) ₂ O or with an acid halide of the general formula R'C OX, where X is a halogen atom and R 'each has the meanings given above, is esterified in a manner known per se, optionally in the presence of an acid-binding agent.

Finally, it is also possible to obtain compounds of the general formula I by reacting compounds the general formula

.

-OM

(III)

Cl ₂ CHCON-

with an acid halide of the general formula R'COX, where R, R 'and X are as defined above and M is an alkali metal. The amoebicidal activity of the compounds according to the invention has been demonstrated in animals in the following manner. The technique is essentially that described by Jones (Annals of Tropical Medicine and Parasitology, 1946, 40, p. 130), in which newly weaned rats are inoculated intracaecally with trophozoites of Entamoeba histolytica. Starting on the day after vaccination, each animal from a group of rats is given five daily doses of the drug to be tested by means of a gastric tube; the animals are sacrificed 1 day after administration of the last dose. The cecum of every rat is examined both microscopically as a process of manufacture
amoebicidally active N-dichloroacetoxy-anilide ester

Applicant:

Boots Pure Drug Company Limited,
Nottingham (Great Britain)

Representative: Dr. M. Eule, patent attorney,
Munich 13, Kurfürstenplatz 2

Claimed priority:
Great Britain 3 November 1955

Peter Oxley, Gerald Woolfe,
Norman William Bristow, James Millers,

George Alfred Harrison Williams
and Eric Charles Wilmshurst, Nottingham

(Great Britain),
have been named as inventors

also examined macroscopically, and in each rat the degree of infection after one becomes arbitrary selected scale. The average degree of infection is then calculated for each group, below referred to as A. D. I. One sees a connection as amoebic if the A. D. I. of the treated Group is less than half the A.DI of the untreated control group. With highly potent drugs the rats are completely freed from the amoeba, and the A.DI is then equal to zero. In the following The table shows the results obtained in the above test with the compounds according to the invention. Details are given about the daily dose of the test compound and its effectiveness specified. The "effectiveness" is defined here as the number that you get when you use the Control group obtained A.DI. divided by the A.D.I. of the treated group (each number being the Represents the result of an experiment). A number obtained in this way which is greater than 1 means that the test compound shows amoebicidal activity. The larger this number, the higher the effectiveness. In the case of a complete expulsion of the amoeba by the test compound, one can therefore assess the "effectiveness" call it infinitely large.

009 648/405

1. 4- (Dichloroacet-N-methylamido) -phenyl-crotonate

2. 4- (Dichloroacet-N-methylamido) -phenyl-propionate ... I

3. Dichloroacet-4-dichloroacetoxy-N-methylanilide

4. dichloroacet ^ -acetoxy-N-methylanilide j

5. 4-chloroacetoxy-N-dichloroacet-N-methylanilide <

6. 4-α-Chlorpropionyloxy-N-dichloroacet-N-methylanilide I.

7. 4-N-Butyryloxy-N-dichloroacet-N-methylanilide <

8. 4-Benzoyloxy-N-dichloroacet-N-methylanilide <

200

100

50

25th

100
50
25th

200

200
100

200
50

200
50

200
50

200
50

6.4
5.3
5.0
4.5

3.8; 1.9
3.8; 1.9
2.2

5.0

2.0; 1.9; 2.7
2.4

infinite
4.2

10.0
5.2

infinite
1.9

infinite
infinite

Compounds of the general formula II and processes for their preparation are in the older U.S. Patent 1,046,063.

The following examples serve to illustrate the present invention.

example 1

In the preparation of 4- (dichloroacet-N-methylamido) -phenyl-crotonate, 11 g of crotonyl chloride are added dropwise with stirring to a mixture of 23.4 g of dichloroacet-4-oxy-N-methylanilide, 24.2 g of dimethylaniline and 30 cm ³ petroleum ether (boiling range 60 to 8O ⁰ C) was added. The resulting mixture is stirred and kept at about 50 ^° C. for 5 hours. After this time the mixture is allowed to cool, whereupon 60 cm ^{3 of} benzene and 55 cm ^{3 of} 2N hydrochloric acid are added. The precipitate obtained in this way, unchanged dichloroacet-4-oxy-N-methylanilide, is filtered off. After the filtrate has been left to stand, the organic layer is separated off and ^{washed successively with 100 cm 3 of} water and 100 cm ^{3 of} saturated sodium carbonate solution and then dried over anhydrous magnesium sulfate. The solvent is distilled off and the solid body thus obtained is recrystallized from aqueous alcohol. In this way 4- (dichloroacet-N-methylamido) -phenyl-crotonate is obtained in the form of a crystalline solid body with a melting point of 103 to 104 ° C. (The analysis gave 4.5% N; C ₁₃ H ₁₃ O ₃ NCl ₂ requires 4.6 N.)

55

Example 2

In the preparation of 4- (dichloroacet-N-methylamido) -phenyl-propionate, 19.4 g of propionyl chloride are added dropwise with stirring to a mixture of 46.8 g of dichloroacetHl-oxy-N-methylanilide, 17.4 g of pyridine and 100 cm ³ petroleum ether (boiling range 60 to 8O ⁰ C) was added. The resulting mixture is stirred and kept at a temperature of 30 to 40 ^° C. for 3 hours. After this time, the mixture is allowed to cool, whereupon 120 cm ^{3 of} benzene and 120 cm ^{3 of} 2N hydrochloric acid are added. The organic layer is separated and ^{washed successively with 100 cm 3 of} water and 100 cm ^{3 of} saturated sodium carbonate solution. After drying over anhydrous sodium sulfate, the solvent is distilled off and the solid body thus obtained is recrystallized twice from alcohol. Obtained in this manner 4- (Dichloroacet-N-methylamido) phenyl-propionate as a crystalline solid substance having a melting point from 81 to 81.5 ⁰ C. (The analysis showed 5.1% N; C ₁₂ H ₁₃ O ₃ NcI ₂ requires 4.8% N.)

Example 3

In the preparation of dichloroacet-4-dichloroacet-oxy-N-methylanilide, 5.6 g of dichloroacetyl chloride are added with stirring to a suspension of 10 g of the sodium derivative of dichloroacet-4-oxy-N-methylanilide in 50 cm ^{3 of} toluene. The mixture thus obtained is heated on the steam bath with stirring for 30 minutes. After the mixture has been allowed to cool, it is ^{washed with 100 cm 3 of} water and then with 100 cm ^{3 of} 2N sodium hydroxide solution and then dried over anhydrous sodium sulfate. The solvent is distilled off and the solid body thus obtained is recrystallized from alcohol. In this way, dichloroacet-4-dichloroacetoxy-N-methylanilide is obtained in the form of a crystalline solid body with a melting point of 95.5 to 96.5 ° C. (The analysis gave 4.2% N; C ₁₁ H ₉ O ₃ NCl ₄ requires 4.1% N.)

The sodium salt of dichloroacet-4-oxy-N-methylanilide used in the above reaction is prepared in the following manner: 27.3 g of a 28.68% strength (percent by weight) solution of sodium methoxide in methanol become 36 g of dichloroacet-4-oxy -N-methylanide added in 250 cm ^{3 of} methanol. The solution thus obtained is evaporated to dryness under reduced pressure. In this way, the desired sodium salt is obtained, which can be ground to a cream-colored powder.

Example 4

In the production of dichloroacet-4-acetoxy-N-methylanilide, 6.25 cm ^{3 of} acetic anhydride, a mixture of 11.7 g of dichloroacet-4-oxy-N-methylanilide, 30 cm ^{3 of} water, 15 cm ^{3 of} a 5N sodium hydroxide solution and 50 g ice added. The resulting mixture is shaken vigorously, a light brown resin separating out and solidifying. The crude product is filtered off and out

recrystallized aqueous alcohol. Dichloroacet ^ -acetoxy-N-methylanilide is obtained in this way in the form of a crystalline solid body with a melting point of 89.5 ° C. (Analysis found 47.75% C, 4.2% H; C ₁₁ H ₁₁ 0 ₃ N Cl ₂ requires 47.9% C and 4.0% N.)

Example 5

In the production of 4-benzoyloxy-N-dichloroacet-N-methylanilide, a mixture of 11.7 g of dichloroacet-4-oxy-N-methylanilide, 100 cm ^{3 of} water, 12 cm ^{3 of} 6N sodium hydroxide solution, 8 g of benzoyl chloride and 50 mg sodium sulfite stirred vigorously at room temperature until the reaction is complete. The resulting solid is filtered off and recrystallized twice from alcohol. In this way, 4-benzoyloxy-N-dichloroacet-N-methylanilide is obtained in the form of a crystalline solid body with a melting point of 114 to 177 ° C. (The analysis gave 4.5% N; C ₁₆ H ₁₃ O ₃ NCl ₂ requires 4.1% N.)

Example 6 _ao

In the preparation of 4-chloroacetoxy-N-dichloroacet-N-methylanilide, 17 g of chloroacetyl chloride are slowly stirred into a suspension of 23.4 g of dichloroacet-4-oxy-N-methylanilide in 300 cm ^{3 of} ether and 12.5 cm ³ Added pyridine. The mixture thus obtained is stirred for 1 hour at room temperature before the addition of 100 cm ^{3 of water.} The ether layer is separated and ^{washed with two portions of 100 cm 3 of} water. During the second wash, the product crystallizes out in the ether layer; it is filtered off and recrystallized from alcohol. Obtained in this manner 4-chloroacetoxy-N-dichloracet-N-methylanilide in the form of a crystalline solid substance having a melting point of 113 ⁰ C. (The analysis showed 4.8% N; C ₁₁ H ₁₀ O ₃ NCl ₃ requires 4 , 5% N.)

In exactly the same way, if α-chloropropionyl chloride is used instead of chloroacetyl chloride, 4-α-chloropropionyloxy-N-dichloroacet-N-methylanilide is obtained in the form of a crystalline solid with a melting point of 69 to 71 ° C 4.6% N; C ₁₂ H ₁₂ O ₃ NCl ₃ requires 4.3% N.)

Example 7

In the manufacture of 4-n-butyryloxy-N-dichloroacet-N-methylanilide 23.7 g of butyric anhydride are long

sam added to a solution of 23.4 g of dichloroacet-4-oxy-N-methylanilide in 100 cm ^{3 of} pyridine. The solution obtained in this way is kept at a temperature of 20 ^° C. for 3 days and then poured into a large excess of water. The oil which separates out slowly crystallizes out; the crystals are filtered off and recrystallized from 70% alcohol. In this way, 4-n-butyryloxy-N-dichloroacet-N-methylanilide is obtained in the form of a crystalline solid body with a melting point of 42 to 43 ° C. (The analysis showed 4.6% N; C ₁₃ H ₁₆ O ₃ NCl ₂ requires 4.6% N.)

Claims (2)

Patent claims: 1. Process for the preparation of amoebicidally active N-dichloroacet-oxy-anilide esters of the general formula CLCHCON O - C - R ' where R is a lower alkyl group and R 'is an alkyl, alkenyl, phenyl or a mono- or polychlorosubstituted alkyl group, characterized in that a phenol of the general formula CLCHCON OH (II) wherein R has the above meaning with a carboxylic acid of the general formula R'CO OH or with an acid anhydride of the general formula (R'CO) ₂ O or an acid halide of the general formula R'C OX, where X is a halogen atom and R 'each has the abovementioned meanings, is esterified in a manner known per se - optionally in the presence of an acid-binding agent. 2. The method according to claim 1, characterized in that the phenol in the form of a salt, especially in the form of an alkali metal salt. 1 009 648/405 11.60