FI59989B - FOER REFRIGERATION FOR NAMINOALKYL SUBSTITUTES - Google Patents

Description

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Patent and Registration Office .... ........ ......

_. . . . (44) Date of issue and date of publication: Q,

Patent and registration documents Antekan utlagd och utl.tkrift «<i publicurad 31 * 07 * 8l (32) (33) (31) Requested atuoikaut —Bugird prloritut 09 * 11 * 72

Japan-Japan (JP) 112708/72 (71) Societe D'Etudes Scientifiques et Industrielles de 1'Ile-de-France, k6 boulevard de Latour-Maubourg, 75, Paris 7 ° »France-France (FR) (72) Akira Morimoto, 0saka-fu, Hisashi Takasugi, Osaka-shi, Japan-Japan JP) (7 ^) Oy Kolster Ab (5U) Process for the preparation of N-aminoalkyl-substituted benzamides -Förfarande för framställning av N-aminoalkyl-substituerade benzensider it is intended to provide a new process for the preparation of A-aminoalkyl-substituted benzamides (IV). Among these products (IV), N- (2-diethylaminoethyl) -2-methoxy - * + - amino-5-chlorobenzamide is currently labeled.

The invention relates to a process for the preparation of N-aminoalkyl-substituted benzamides of the formula / R3

C0NH-W-N

1 ^ f ΙΓ <™>

V

R 2 wherein R 1 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R 2 is an amino, acetamino, nitro or benzylamino group, and R 1 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, X is a hydrogen or halogen atom and 2,59989 W is An alkylene group having 1 to 3 carbon atoms.

The invention is characterized in that the amine of formula

E5 S

\ / C = N-W-N (I) / \

R6 RU

wherein R 1, R 2 and W are the same as above and R 1 and R 8 are an acyl group residue from which the carboxyl group at the end of the chain has been removed is reacted with an acylating agent to attach an acyl group of the formula CO-A "R 2 wherein R 1, R 8 and X have the same meaning as above, to give a benzamide of formula

CO-A,

- ® y (m)

x I

R 2 wherein R 1, R 8 and have the same meaning as above and A is a group of the formula ° n H, X 3 -N-W-N "

XR

^ 'R 5

Y-C

^ r6 ZQ.1 3 59989 ϊ © © / R3

N-W-Flt

c?

X

R 6 in the formulas R 1, R 2, R 2, R 8 and W have the same meaning as above and Y is an anionic group derived from an acylating agent, and that the obtained substituted compound is hydrolyzed.

The amines (i) used in the present invention are novel compounds and are prepared, for example, by the following methods:

{i) R

/ 3 R5 ^> co r6 V 1 \ \ k /

> C = N-W-N <I

(ii) R 1 -COOH or a reactive derivative thereof having a functional group p in the carboxyl group. H N-W-1 (3 i / 3 R5 ~ CONH-W-N <^ U imino halogenating group (eg phosphorus pentahalide) V / Ro

r5-c = n-w-n <^ J 1. B

halogen P o imino etherifying agent (e.g. alcohol) '5> c-h-w-h <"3 r6 h (in which case R1 is an alcohol residue).

^ 59989

In each formula, R 2, R 2, R 2 and K 2 have the same meaning as above.

Among the above symbols, R 1, R 2 and alkyl, ethyl, propyl and isopropyl can be mentioned as alkyl groups. Halogen X includes chlorine, bromine, iodine, fluorine, etc. As the alkylene group W, for example, ethylene and propylene can be mentioned.

As the residue of the acyl group R 1 and R 8 from which the carbonyl group at the end of the chain has been removed, there can be mentioned, for example, a hydrogen atom, straight-chain, branched and cyclic, saturated and unsaturated aliphatic hydrocarbon groups containing oxygen or sulfur at the carbon chain or at the molecular end; aromatic aliphatic hydrocarbon residues, aromatic oksialifaattiset hydrocarbon residues, aromatic tioalifaattiset hydrocarbon residues, heterocyclic group-substituted aliphatic hydrocarbon residues, heterocyclic-set oksialifaattiset hydrocarbon residues and heterosykiiset tioalifaattiset residues containing aliphatic hydrocarbon radicals described above bonded directly or through an oxygen or sulfur atom, aromatic hydrocarbon ice-nöksiin or heterocyclic groups; aromatic hydrocarbon residues and heterocyclic groups. Examples of the above aliphatic hydrocarbon residues include methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohexyl , allyl, 1-propenyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclohexylethyl, cyclohexenylmethyl, cyclohexadienylmethyl, methoxymethyl, cyclohexyloxymethyl and methyl Examples of the above-mentioned aromatic hydrocarbon residues include phenyl, naphthyl, tolyl, xylyl, mesityl and cumenyl groups. Examples of the above heterocyclic groups include saturated and unsaturated, monocyclic and polycyclic compounds containing at least one heteroatom in their ring, such as furan, thiophene, pyrrole, pyrazole, imidazole, triazole, thiazole, isothiazole, isothiazole, isothiazole, thiatriazole, oxetriazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, benzthiophene, benzofuran, indone, indazole, benzimidazole, benzothiazole, quinazine, quinoxazole, purine, quinoline, isoquinoline, phthalazine, phthalazine . These aliphatic hydrocarbon residues, aromatic hydrocarbon residues and heterocyclic groups may optionally contain at least one substituent which is a hydrogen atom or hydroxyl, mercapto, carboxyl, alkyl, alkoxy, alkylthio, nitro, cyano, alkanoyl, aral -, arylcarbonyl, alkanoloxy, aralkanoyloxy or arylcarbonyloxy group. The hydroxyl, sulfonyl and mercapto groups present as substituents can be protected with ordinary protecting groups.

5 59989

It is preferred that the acylating agent to introduce the acyl group of formula II be used in the form of a reactive derivative of the corresponding carboxylic acid in which the carboxyl group is replaced by a functional group such as acid anhydride, active amide and active ester groups. As such a derivative, mention may be made, for example, of acid chlorides, acid azides, acid anhydrides, e.g. mixed anhydrides of dialkyl-phosphoric acid, mixed anhydrides of phenylphosphoric acid, mixed anhydrides of diphenyl-phosphoric acid-phosphoric anhydride, di-benzyl-phosphoric acid, mixed anhydrides anhydrides, mixed sulfurous acid anhydrides, mixed anhydrides of thiosulfuric acid, mixed anhydrides of sulfuric acid, mixed anhydrides alkylcarbonic, aliphatic carboxylic acid mixed anhydride (aliphatic carboxylic acid may be mentioned e.g. pivalic acid, valeric acid, isovaleric acid, 2-ethylbutyric acid and trichloro-acetic acid), aromatic carboxylic acid mixed anhydride (ar As the organic carboxylic acid, mention may be made, for example, of benzoic acid) and symmetrical acid anhydrides, acid amides of imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole and the like. and esters such as cyanomethyl esters, methoxymethyl esters, vinyl esters, propargyl esters, p-nitrophenyl esters, , pyranyl esters, pyridyl esters, piperidyl esters, 8-quinolyl thioesters, and esters with Ν, Ν-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridine, N-hydroxysuccinimide and N-hydroxyphthalimide. These are appropriately selected depending on the organic carboxylic acid used.

The reaction is usually carried out in a solvent, and the solvent may be any solvent which does not adversely affect the reaction, such as benzene, dichloromethane, chloroform, tetrahydrofuran, etc.

In the present invention, the temperature is not particularly critical, and the reaction temperature is appropriately selected depending on the amine (i) used and the acylating agent used. The substituted benzamides (lii) thus formed, which are new compounds, can be used in the next step after isolation and purification, but in many cases the liquid reaction mixture is used as such in the next step.

The substituted benzamide (III) is then hydrolyzed to the desired product (IV). The hydrolysis proceeds sufficiently if the liquid reaction mixture containing the product (Ui) obtained in the previous step is poured into water, but the hydrolysis can be carried out with an alkali metal or alkaline earth metal hydroxide or bicarbonate, e.g. sodium hydroxide, potassium hydroxide, magnesium hydroxide, etc. base. , pyridine and picoline or in the presence of an acid such as acetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc. The hydrolysis can also be performed by alcoholysis using an alcohol solvent.

In this reaction there is an acetamino group, this group is also sometimes hydrolyzed to give the desired product (IV) in which the group has been converted into an amino group.

This feature is, of course, also within the scope of this invention.

The reaction temperature in this hydrolysis reaction is not particularly critical and the reaction proceeds sufficiently at ambient room temperatures.

In the case where X of the reaction product (IV) is hydrogen, it can be converted, if desired, to a compound in which X is a chlorine atom by reaction with a chlorinating agent. As the chlorinating agent, for example, chlorine, isocyanuric acid chloride and N-chlorocyric acid amides or imides such as N-chloroacetamide and N-chlorosuccinimide can be mentioned. The chlorination reaction is usually carried out in a solvent, and any solvent which has no adverse effects on this reaction can be used, such as lower alcohols * such as dioxane and acetic acid. Although the temperature in this chlorination reaction is not particularly critical, in many cases the reaction is carried out under cooling or heating.

In the case where the Rg of the product is a nitro or benzylamino group, this can be converted to an amino group, for example, by hydrolysis.

The present invention will now be described with reference to Examples.

Example 1 Preparation of starting N- (N- (2-diethylaminoethyl) amino) -pentan-2-one: 12 g of 2, U-pentanedione were dissolved in 10 ml of anhydrous ethanol and 13.9 g of 2- (diethylaminoethyl) amine. dissolved in 1 ml of anhydrous ethanol was added to said solution. The mixture was stirred at room temperature for 4 hours, and the solvent was distilled off under reduced pressure. The residue was distilled under reduced pressure to give 17 g of U- (N- (2-diethylaminoethyl) imino) -pentan-2-one, which boiled at 11-115 ° C under k mm Hg.

Preparation of N- (diethylaminoethyl) -2-methoxy-U-acetamido-5-chlorobenzamide: 2.97 g of U- (N- (2-diethylaminoethyl) imino) pentan-2-one prepared as described above was dissolved in 20 ml. dried chloroform and the solution was added dropwise with stirring to a solution of 2.62 g of 2-methoxy-U-acetamido-5-chlorobenzoic acid chloride in 10 ml of dried formaldehyde at room temperature under water vapor protection conditions and the mixture was stirred at room temperature for 5 hours. The resulting liquid reaction mixture was extracted with 10%. 11a with hydrochloric acid and the extract was washed with ethyl ether. The pH was adjusted to 9 with potassium carbonate and the liquid was extracted with chloroform. The extract was washed with water and dried over magnesium sulfate. The solvent was then removed by distillation to give 3.2 g of N- (2-di-7,59989 ethylaminoethyl) -2-methoxy-acetamido-5-chlorobenzamide.

The product thus obtained was recrystallized from ethyl ether to obtain crystals having a melting point of 99.5-101 ° C.

By repeating the procedures of the above example, using N- (2-diethylaminoethyl) iminomethylbenzene (b.p. 97-101 ° C, 0.3) instead of b- (N- (2-diethylaminoethyl) imino) pentan-2-one mm Hg), 2- (N- (2-diethylaminoethyl) imino) methylphenol (b.p. 11 + -16 ° C, 0.2 r Hg) and ethyl 2- (N- (2-diethylaminoethyl) iminopropionate (b.p. 137-139 ° C, 8 mm Hg), N- (2-diethylaminoethyl) -2-methoxy-1 + -acetamido-5-chlorobenzamide was similarly obtained.

By similar procedures, the following compounds were prepared: N- (2-diethylaminoethyl) -2-methoxy-U-amino-5-chlorobenzamide (m.p. lk5-1 (6 ° C), N- (2-diethylaminoethyl) -2-methoxy-b -Nitro-5-chlorobenzamide (m.p. 70-72 ° 0), N- (2-diethylaminoethyl) -2-methoxy-1-aminobenzamide (yellow in the form of a sticky paste), N- (2-aminoethyl) -2-methoxy -1 + -amino-5-chlorobenzamide (m.p. 150-153 ° C) and N- (2-diethylaminoethyl) -2-methoxy-1-benzylaminobenzamide (m.p. 106-108 ° C).

The N- (2-diethyl) -2-methoxy-U-acetamido-5-chlorobenzamide, N- (2-diethylaminoethyl) -2-methoxy-t-nitro-6-chlorobenzamide and N- (2-diethylaminoethyl) 2-Methoxy-yl-benzylamino-5-chlorobenzamide was converted to N- (2-diethylaminoethyl) -2-methoxy-t-amino-5-chlorobenzamide having a melting point of 1-5-11-11 + 6 ° C, e.g. by hydrolysis under heating with sodium hydroxide in aqueous solution, by reduction in ethanol using a Raney nickel catalyst, or by reduction in ethanol using a palladium-carbon catalyst, respectively.

1.0 g of N- (2-diethylaminoethyl) -2-methoxy-t-aminobenzamide prepared by the same procedures was dissolved in 26 ml of acetic acid, and 10 ml of acetic acid containing 0.35 g of chlorine was added dropwise over 20 minutes while maintaining the solution. temperature at 15-20 ° C with stirring. The resulting mixture was allowed to stand overnight without stirring. After the reaction, acetic acid was distilled off from the reaction mixture, and the residue was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was removed by distillation. Recrystallization of the residue from benzene gave N- (2-diethylaminoethyl) -2-methoxy-1 * -amino-5-chlorobenzamide, melting at 1 ° C + 11 ° C + 2 ° C.

Claims (1)

A process for the preparation of N-aminoalkyl-substituted benzamides of the formula / H 3 CONH-WN "" RU * |) - a (iv) x I R 2 wherein R 1 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R 8 is an amino group , an acetamino, nitro or benzylamino group, R 1 and R 2 represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, X is a hydrogen or halogen atom and W is an alkylene group having 1 to 3 carbon atoms, characterized in that the amine, of the formula H5 * 3 ^ C = NWN (I) r6 rU wherein R1 and W are as defined above and R1 and R8 are a residue of the acyl group from which the terminal carboxyl group has been removed are reacted with an acylating agent to attach the acyl group of the formula C0- ^ ®1 (II) R2 wherein Rj, Rg and X have the same meaning as above, to give a benzamide of the formula 9 59989 CO-A f ^ S) - ® 1 \ (III) x ^ Y R2 wherein R 1 and X are as defined above and A is a group of the formula -NW- N 1 3 and that the resulting sutured product is hydrolyzed. 59989 10 For the preparation of N-aminoalkylsubstituted benzamides Raed formeIn Ro ^ 3 C0NH-WN sy> —cr R2 color R1 is a hydrogen atom or an alkyl group having 1-3 cholatomers, R8 is an amino-, acetamino-, nitro- or benzylamino group , and R 1 is a substituent or an alkyl group having 1-3 cholaters, X is a substituent or a halogen atom and W is an alkenyl group having 1 to 3 cholatomers, the amine is a form of R «- R- 5 \ / 3 ^ C = NWN (I) color R ^, R ^ och W is an angylated group and R ^ och Rg is an acyl group, the carboxyl group of which is further reacted with an acyl group having an acyl group of the form CO - A "R2 color R2 and X have an angular character of the benzylic acid form of CO-A - OR1 (lii) r2