DE1183911A - Process for the preparation of new Halogenacetylammo methylbenzolderivaten - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Boarding school Class: C 07 c

German KL: 12 q- 32/21

Number: 1183 911

File number: St 12615 IVb / 12q

Filing date: May 29, 1957

Opening day: December 23, 1964

The invention relates to a process for the preparation of new, pharmacologically active haloacetylaminomethylbenzene derivatives of the general formula I.

Ac

NH ₂ C

• N

Ac

The two aminomethyl substituents are in the m- or p-position to one another. Z is a low molecular weight alkyl radical with 1 to 8 carbon atoms, a hydroxyalkyl radical of the formula

- Y - OH, an alkoxyalkyl radical of the formula

- Y - O - R or an acyloxyalkyl radical of Formula —Y - O - Ac ', where Y is an alkylene bridge with 2 to 6 carbon atoms, the two free valence bonds of which are on different carbon atoms are, R is an alkyl radical with 1 to 8 carbon atoms, Ac 'is an acyl radical with 1 to 8 carbon atoms, Ac is a mono- or dihaloacetyl radical, and Q means a hydrogen or halogen atom.

These compounds are pharmacologically active. They have comparable known compounds superior amebicidal properties to.

The xylylene radical of the compounds is represented by the following formula:

Method of making new
Haloacetylaminomethylbenzene derivatives

Applicant:

Sterling Drug Inc., New York, N.Y. (V. St. A.)

Representative:

Dr. F. Zumstein,

Dipl.-Chem. Dr. rer. nat. E. Assmann

and Dipl.-Chem. Dr. R. Koenigsberger,

Patent Attorneys, Munich 2, Bräuhausstr. 4th

Named as inventor:

Dr. Alexander Robert Surrey,

Albany, N. Y. (V. St. A.)

Claimed priority:

V. St. ν. America dated May 29, 1956 (587 937)

Settlement of a diamine of the formula

-H ₂ C

CH ₂ -

II

It is well known in the art in the form of the xylylene dihalide derivatives and simple xylylene diamine derivatives. As will be shown below, these known xylylene derivatives can be used as Intermediates used in the preparation of the compounds to be prepared according to the invention will.

The N, N '- bis - haloacetyl - N, N' - substituted 1,4- (or 1,3) - bis - aminomethylbenzene derivatives, at where Z is an alkyl radical, stands for - Y - OH or - Y - O - R, are prepared by

with 2 equivalents of a mono- or dihaloacetylating agent. If Z is - Y - O - R or alkyl, as indicated above, then a haloacetyl halide is used as such, preferably below room temperature, optionally with ice-cooling, the halogen atom vicinal to the carbonyl function is preferably chlorine. If Z has the meaning given above —Y — OH, then one uses as a halogen acetylating agent, low molecular weight alkyl esters of a halogen acetic acid and facilitates the Reaction by heating the reactants on a steam bath to approximately 50 to 100 ° C.

409 759/393

The reaction already takes place at room temperature, but proceeds without the application of heat slower.

If Z stands for —Y - O - Ac ', the Compounds according to the invention by reacting bis-aminomethylbenzene derivatives in which Z is for - Y - OH stands with an acylating agent of the group Ac "- halogen, (Ac") 20 or formic acid produced, where Z and Y have the meanings given above and where Ac " with the exception of formyl is a carboxylic acid residue having 2 to 8 carbon atoms. When a haloalkylacetyl radical is to be introduced, the halogen radical which is in the position adjacent to the Carbonyl group, preferably chlorine, but bromine, iodine or fluoroalkylacyl radicals can also be to be introduced. When an acid halide is used as the acylating agent, the The reaction is preferably carried out below room temperature, if necessary with ice cooling. If an acid anhydride is used, the reaction can take place at room temperature or higher Temperature, preferably on a steam bath.

The Ν, Ν'-disubstituted as starting materials 1,4- (or 1,3) -bis- (aminomethyl) -benzenes of the formula III, where Z is - Y - OH, - Y - O - R or R and Q has the meaning given above, can be prepared by various methods will. The preferred method is the conversion of terephthalaldehyde, isophthalaldehyde or their ring-substituted analogs with at least 2 equivalents of an amine of the formula Z - NH2 called. The resulting bis-anil of the formula

35

Z-N = HC

CH = N - Z IV

is then catalytically reduced with hydrogen without isolation, so that the N, N'-disubstituted 1,4 (or 1,3) bis (aminomethyl) benzene derivative is obtained as an intermediate product. The formation of the Bisanils is preferably by heating an amine Z - carried out with NH2 terephthalaldehyde or isophthalaldehyde at about 50 to 150 ⁰ C, usually on a steam bath, and preferably with removal of the water formed. The catalytic hydrogenation of the Anils is carried out under a hydrogen pressure of preferably I to 3 atmospheres in a wide range of temperatures, but preferably at 25 to 6O ⁰ C. The reaction is carried out by starting at room temperature and gradually increasing the temperature until hydrogen uptake begins. Higher temperatures can be used if desired. The hydrogenation catalysts used are those customarily used for the reduction of anilene to secondary amines, for example palladium animal charcoal, Raney nickel and platinum oxide. Starting materials of the formula III, in which Z is —- Y-OH ₅ -YOR or R and Q has the meaning given above, can also be obtained by reacting the corresponding xylene dihalides, preferably the dichlorides or dibromides, with 2 equivalents of a primary amine Formula Z - NH2 can be produced. On the other hand, these starting materials according to formula III can also be prepared step by step by first reacting a xylylene dihalide with excess ammonia and then reacting the bis (aminomethyl) benzene obtained with 2 equivalents of a halide of the formula Z - (halogen), the halogen being preferred Is chlorine or bromine.

From J. Am. Chem. Soc. 76: 2214-2216 (1954); Vol. 77 (1955), p. 3798, and Vol. 77 (1955), S. 5406, it is already known to produce amebicidally active compounds which differ from the compounds according to the invention Compounds produced differ in that they only have one substituted aminomethyl radical have on the benzene ring. However, the amebicidal activity of these compounds is only a fraction of that according to the invention produced benzene derivatives.

N-CH ₂

N '

^ R

R. Z Q Amebicide
effectiveness
ED50 ± SE »
(mg / kg / day) CH2CH2OH CHCl ₂ H 6.5 ± 0.8 CH ₂ CH ₂ OCHO CHCl ₂ H 10.5 ± 0.9 CH2CH2OC2H5 CHCl ₂ H 1.14 ± 0.10 CH ₃ CHCl ₂ H 4.3 ± 1.2 C ₂ H ₅ CHCl ₂ H 1.90 ± 0.26 C2H5 CH ₂ Cl H 3.8 ± 0.5 iC ₃ H ₇ CH ₂ Cl H 2.55 ± 0.38 C2H5 CHCl ₂ Cl 0.47 ± 0.14

^a ED50 ± SE is the lowest oral dose (mg / kg / day ± standard error) required to rid 50% of hamsters from the amebicidal infection (Endamoeba criceti) (calculated according to Miller and Tainter [Proc. Soc . Exper. Biol. Med., Vol. 57, p. 261 (1944)]).

In contrast to their extraordinarily high effectiveness, the compounds have a very high low toxicity. For example, each of the compounds has N, N'-bis- (dichloroacetyl) -N, N'-bis- (2-oxyethyl) -1, 4-bis- (aminomethyl) -benzene and N, N'-bis (dichloroacetyl) -N, N'-diethyl-1,4-bis (aminomethyl) benzene an acute oral ALD 50 value (in mice) greater than 12,000 mg / kg.

Table II

^ C-Z O

Z Q Amebicide R. effectiveness
AED ₅₀ " CHCl ₂ H (mg / kg / day) CH ₂ CH ₂ OH ineffective at CHCl ₂ H 100 CH ₂ CH ₂ OCHO ineffective at CHCl ₂ H 100 CH ₂ CH ₂ OCOCH ₃ CHCl ₂ H > 50 ^b CH ₂ CH ₂ OC ₂ H ₅ CHCl ₂ H 43.6 CH ₃ CHCl ₂ 2-Cl 36.2 iC ₃ H ₇ CH ₂ Cl H 31.6 iC ₃ H ₇ > 100 ^c

^a AEDjjo is the approximately effective dose (mg / kg / day) required to free 50% of hamsters from the amebicidal infection (calculated according to W right [J. Am. Pharm. Assoc, Vol. 30, p. 177 to 180 (1941)]).

^b At 50 mg / kg / day, one in three hamsters was freed from the amebicidal infection.

^e At 100 mg / kg / day, one in three hamsters was freed from the amebicidal infection.

Manufacture of the raw materials
A. Bis (hydroxyalkylaminomethyl) benzenes

B. Bis- (alkylaminomethyl) benzenes hydrogenation of Anils in 80% yield 1,4-bis- (dimethylaminomethyl) benzene as the dihydrochloride, melting at above 260 ⁰ C.

C. Bis (alkoxyalkylaminomethyl) benzenes

The preparation of these intermediate products is illustrated by the following illustration of 1,4-bis (2-ethoxyethylaminomethyl) benzene: 6.7 g of terephthalaldehyde were used in small amounts

ίο added to 8.9 g of 2-ethoxyethylamine with swirling and cooling in an ice bath. The mixture was allowed to stand at room temperature for 2 hours. Approximately 25 ml of ethanol was then added and the bis-anil was hydrogenated at 45 ° C and 18.144 kg hydrogen pressure (40 pounds) using 250 mg palladium chloride and 2.0 g animal charcoal. After the theoretical amount of hydrogen had been consumed, the catalyst was removed by filtration and the alcohol in vacuo by distillation, giving 1,4-bis (2-ethoxyethylaminomethyl) benzene, which was obtained after treatment with ethanolic hydrochloric acid and ether 6.5 g of the crystalline dihydrochloride resulted, melting point above 250 ^° C. A sample was recrystallized from ethanol for analysis.

The preparation of these intermediate compounds is carried out by the preparation of 1,4'-bis (2-hydroxyäthylaminomethyfj-benzene explained:

A mixture of 30 g of terephthalaldehyde and 27.3 g of ethanolamine was heated in vacuo on a steam bath for 1 hour. The solid bis-anil obtained was practically completely dissolved in 300 ml of ethanol and catalytically reduced with hydrogen in the presence of palladium and animal charcoal at 50.degree. After removing the catalyst by filtration, the solvent was distilled off. The solid residue was recrystallized from ethanol and gave 20 g of the product with a melting point of 127 to 129 ^° C.

40

The preparation of these intermediate products is described below by the preparation of 1,4-bis (ethylaminomethyl) benzene described.

5.0 g (0.037 mol) of terephthalaldehyde were added to 12 ml of a 70% strength aqueous ethylamine solution and allowed to stand for ^x / a hour. 10 ml of 95 percent ethanol, 250 mg of PdCl ₂ and 2 g of animal charcoal were added to the mixture of bis-anil. The hydrogenation was carried out at 35 to 40 ° C in a Parr apparatus, with 83% of the theoretical amount of hydrogen being absorbed. After filtering off the catalyst, the alcohol and the excess ethylamine were evaporated off under reduced pressure. To give l, 4-bis (äthylaminomethyl) benzene, which was treated with ethanolic hydrochloric acid and ether to give 6.0 gl, 4-bis (äthylaminomethyl) -benzoldihydrochlorid as a white, crystalline product, melting above 300 ⁰ C received.

In an analogous manner there were obtained from 7.0 g of terephthalaldehyde and 12 g of isopropyl amine by hydrogenation of the Anils 7 gl, 4-bis (diisopropylaminomethyl) -benzene dihydrochloride, melting at above 260 ⁰ C.

Were in the same way 13.4 g of terephthalaldehyde and 30 ml with a 60% aqueous solution of Reacted methylamine, it was obtained after

D. 2-chloro-1,4-bis (ethylaminomethyl) benzene dihydrochloride

A mixture of 14 g of chloro-p-xylene (2-chloro-1,4-dimethylbenzene), 30 g (19 ecm) sulfuryl chloride and 150 mg benzoyl peroxide was on a steam bath Refluxed for 1 hour. The reaction mixture was then concentrated in vacuo and gave 2-chloro-1,4-bis (chloromethyl) benzene, this was then mixed with 140 g of a 70% aqueous solution of ethylamine and the obtained mixture stirred overnight at room temperature. The reaction mixture was then im Concentrated vacuum and gave a crystallized product, which from absolute ethanol with a Yield of 7 g of 2-chloro-1,4-bis (ethylaminomethyl) benzene dihydrochloride, M.p. = 300 ° C.

No protection is claimed for the manufacture of these starting materials.

The following examples serve to illustrate the invention.

example 1

HN'-Bis-idichloracetyO-N.N'-bis-P-oxyethyl) -1,4-bis- (aminomethyl) -benzene

A mixture of 5 gl, 4-bis (2-oxyäthylaminomethyl) benzene and 7.1 g of methyl dichloroacetate was heated for 4 hours at 6O ⁰ C. The solid product was stirred into 40 ml of 1η hydrochloric acid, collected and washed with water. The yield was 8 g. After three recrystallizations from isopropanol, the product melted at 162.9 to 164.8 ° C. (corrected).

Example 2

N, N'-bis (chloroacetyl> N, N'-diethyl-1,4-bis (aminomethyl) benzene

A mixture of 7.0 g of 1,4-bis (ethylaminomethyl) benzene dihydrochloride, dissolved in 15 ml of water, 45 ml of a 10% aqueous sodium hydroxide

solution and 50 ml of ethylene dichloride was stirred while cooling in an ice bath. To the cold one Mixture was added dropwise over half an hour 6.6 g of monochloroacetyl chloride, in 10 ml of ethylene dichloride dissolved, added. The organic layer was separated, first with 5% aqueous sodium hydroxide solution, then washed with 10% aqueous hydrochloric acid. The solution was filtered and the solvent evaporated. The obtained oil was poured into water, cooled and gave N ^ '- bis-dichloroacetyty-N.N'-diethyl-1,4-bis- (aminomethyl) -benzene as a white, crystalline product. After a single recrystallization from isopropanol- η-hexane, 6.0 g (corresponding to 66% of theory) of the purified product were obtained, m.p. = 100.4 bis 103.2 ° C (corrected).

In the above example, the intermediate is 1,4-bis (ethylaminomethyl) benzene dihydrochloride first converted into the free base by sodium hydroxide, which then with the monochloroacetyl chloride reacted. On the other hand, this reaction can also be carried out using the bis-amine as free base and a correspondingly smaller amount of sodium hydroxide are carried out.

Other N, N'-bis (haloacetyl) -N, N'-bis (alkyl) -l, 4- (or 1,3) -bis- (aminomethyl) -benzenes are prepared using the corresponding reactants, for example N, N'- bis (dibromoacetyl) - N, N'- diethyl - 1,4 - bis (aminomethyl) benzene, F. = 134.8 to 136.4 ° C (corrected).

Example 3

N, N'-bis- (dichloroacetyl) -N, N'-bis- (2-ethoxyethyl) -1,4-bis- (aminomethyl) benzene

A mixture of 6.0 g of 1,4-bis (2-ethoxyethylaminomethyl) benzene dihydrochloride, dissolved in 15 ml of water, 30 ml of 10% sodium hydroxide solution, 45 ml of ethylene dichloride was stirred in a bottle, who stood in an ice bath. To the cold mixture was added dropwise in the course of half an hour 5.5 g of dichloroacetyl chloride dissolved in 25 ml of ethylene dichloride. The stirring was continued for another 10 minutes. The organic layer was then separated, first with 5% aqueous sodium hydroxide solution and then washed with 5% aqueous hydrochloric acid and finally with water. The Evaporation in vacuo gave a solid mass, which was recrystallized from ethanol and 4.5 g of N, N'-bis (dichloroacetyl) - N, N '- bis - (2 - ethoxyethyl) -1,4 - bis (aminomethyl) benzene as a crystalline product of m.p. = 137.6 to 143.9 ° C (corrected).

According to the procedure described in Example 2, this compound can also be used of the bis-amine in the form of its free base and a correspondingly smaller amount of sodium hydroxide can be obtained.

Example 4

N, N'-bis (dichloroacetyl) -N, N'-bis (2-formyloxyethyl) -1,4-bis (aminomethyl) benzene

A mixture of 3.6 g of the N, N'- bis (dichloroacetyl) - N, N'- bis - (2 - oxyethyl) -1, 4-bis (aminomethyl) benzene obtained according to Example 3 and 10 ml of formic acid was on a steam bath for 3 hours

heated. The obtained oil was poured into water and extracted with chloroform. The chloroform solution was filtered and the filtrate concentrated in vacuo to give an oily product which was first triturated with ethyl acetate, then η-hexane was added and the trituration was continued, whereupon, after recrystallization from ethyl acetate, N, N'-bis- ( dichloroacetyl) -N, N'-bis- (2-formyloxyäthyl) -1,4-bis (aminomethyl) benzene corrected as a crystalline product, mp = 133.5 to 137.1 ⁰ C () received.

Example 5

N, N'-bis (dichloroacetyl) -N, N'-bis (2-acetoxyethyl> 1,4-bis (aminomethyl) benzene

A mixture of 2.5 g of the N, N'-bis (dichloroacetyl) -N, N'-bis (2-oxyethyl) -1,4-bis (aminomethy!) Benzene obtained according to Example 3, 1.5g acetic anhydride and 0.45g pyridine was added for 12 hours left to stand at room temperature. About 10 ml of water was then added to the reaction mixture and the solid components are filtered off and recrystallized from ethyl acetate, whereupon 2.3 g of N, N'-bis- (dichloroacetyl) -N, N'-bis- (2-acetoxyethyl) - 1,4 - bis - (aminomethyl) - benzene as a white, crystalline product of m.p. = 152.2 to 154.4 ° C (corrected) was obtained.

The same product can be obtained by reacting N, N'-bis- (dichloroacetyl) -N, N'-bis- (2-oxyethyl) - 1,4 - bis (aminomethyl) - benzene with acetyl chloride instead of acetic anhydride.

Example 6

N ^ '- bis-imonochloracetyO-N ^' - diisopropyl-1,4-bis- (aminomethyl) -benzene

This compound was made according to the procedure described in Example 2 using of 7.0 g of 1,4-bis (isopropylaminomethyl) benzene dihydrochloride and 6.5 g of monochloroacetyl chloride. 4.2 g of the product were obtained therefrom F. = 126.1 to 128.2 ° C (corrected).

Example 7

N ^ '- Bis-dichloroacetylV ^ N'-dimethyl-1,4-bis- (aminomethyl) -benzene

This compound was prepared according to the procedure described in Example 2 using of 4.5 g of 1,4'-bis (methylaminomethyl) benzene dihydrochloride and 6.1 g of dichloroacetyl chloride. This gave 3.7 g of the white, crystalline product with a melting point of 105.2 to 107.7 ° C. (corrected).

Example 8

RN'-bis-idichloroacetylJ-RN'-diethyl-1,4-bis (aminomethyl) benzene

This compound was prepared according to the procedure described in Example 2 from 7 g of 1,4'-bis (ethylaminomethyl-benzene dihydrochloride and 8.8 g of dichloroacetyl chloride. 7 g of the product with a melting point of 98.0 to 102 were obtained , 2 ⁰ C (corrected).

Example 9

N ^ '- bis-idichloracetyO- ^ N'-diisopropyl-1,4-bis- (aminomethyl) -benzene

This compound was prepared according to the procedure described in Example 2 using 3.0 g of 4'-bis (isopropylaminomethyl) benzene dihydrochloride and 4.5 g of dichloroacetyl chloride. From this was obtained 1.8 g of the product, mp = 175.9 to 180.1 ⁰ C (uncorrected).

The new Ν, Ν'-disubstituted N, N'-bis (haloacetylaminomethyl) benzenes are used for medicinal purposes generally administered orally in solid form with the aid of a suitable carrier.

Example 10

2-chloro-N, N'-bis- (dichloroacetyl) -N, N'-diethyll, 4-bis- (aminomethyl) -benzene ·

This compound was prepared as described in Example 2 using 6 g 2-chloro-1 ^ -bis-iäthylaminomethyO-benzene dihydrochloride, 3.5 g sodium hydroxide, 75 ecm water, approximately 100 ecm ethylene dichloride and 6.5 g dichloroacetyl chloride in about 10 ecm of ethylene dichloride. In this way, 7.5 g of 2-chloro-N, N'-bis (dichloroacetyl) -N, N'-diethyl-1,4-bis (aminomethyl) benzene, F. = 90.2 to 92.6 ° C (corrected), obtained after recrystallization from isopropyl alcohol.

Example 11

2-chloro-N, N'-bis- (dibromoacetyl) -N, N'-diethyl-1,4-bis- (aminomethyl) -benzene

This compound was prepared according to the method described in Example 2 using 6.0 g of 2-chloro-1,4-bis (ethylaminomethyl) benzene dihydrochloride, 4.0 g of sodium hydroxide, 50 ecm of water, 50 ecm of ethylene dichloride and 9.5 g of dibromoacetyl bromide in 50 ecm of ethylene dichloride. This gave 3.3 g of 2-chloro-N, N'-bis (dibromoacetyl) -N ₅ N '- diethyl - 1,4 - bis - (aminomethyl) - benzene, m.p. = 115.2 to 122.4 ° C (corrected), obtained after recrystallization from ethanol, ethanol-ether and isopropyl alcohol.

Claims (1)

Claim: Process for the preparation of new haloacetylaminomethylbenzene derivatives the general formula 35 40 Ac NH ₂ C in which the two aminomethyl substituents are in the m- or p-position to one another, Z is a low molecular weight alkyl radical with 1 to 8 carbon atoms, a hydroxyalkyl radical of the formula - Y - OH _{5 is} an alkoxyalkyl radical of the formula - Y - O - R or an acyloxyalkyl radical of the formula —Y - O - Ac ', where Y is an alkylene radical with 2 to 6 carbon atoms, the two free valences of which are on different carbon atoms, R is an alkyl radical with 1 to 8 carbon atoms, Ac 'is an acyl radical having 1 to 8 carbon atoms and Ac is a mono- or dihaloacetyl radical, and Q is a hydrogen or halogen atom, characterized in that, in a manner known per se, corresponding amines are used instead of Ac in the above formula Carry hydrogen atom, where Z is an alkyl, —Υ — Ο — H or —Υ — Ο — R radical with the above meanings, reacts with 2 equivalents of a mono- or dihaloacetyl halide, diamines of the above formula in which Z has the above Meaning - Y has OH and in which there is a hydrogen in place of Ac, is reacted with 2 equivalents of a low molecular weight mono- or dihaloacetic acid alkyl ester and the reaction product, if appropriate, by means of formic acid or an acylating agent s Ac "- halogen or (Ac") 2O, where Ac "represents a carboxylic acid radical with 2 to 8 carbon atoms, also acylated in the - Z-OH group. ^y 409 759/393 12.64 © Bundesdruckerei Berlin