SU571187A3 - Method of obtaining derivatives of 2-aminomethyl-4,6-digahaloidophenol derivatives - Google Patents

Description

(54)

METHOD OF OBTAINING 2-AMINOMETHYL-4,6 DIGALOIDOPHENOL DERIVATIVES

This invention relates to a process for the preparation of new compounds, derivatives of 2-amino-methyl-4, 6-dihalo-phenol, which can be used in pharmaceuticals.

In organic synthesis, the reaction of phenol hydroxymethylation with formaldehyde is well known, followed by the reaction product interaction with amines.

However, in the literature there is no information on the preparation of compounds derived from 2-aminomethyl-4, 6-dihalophenol, which possess valuable properties. Most of the chlorohydrates of these compounds dissolve very easily in water as well as in chloroform, i.e. these compounds have hydrophobic and hydrophilic properties.

A method for the preparation of 2-aminomethyl-4,6-dihalophenol derivatives of the general formula is proposed. / B, CHj-N

to,

OK.

R2 is alkyl, cycloalkyl, aryl, arylalkyl group or RI and Rj, when combined with nitrogen atoms, form a saturated heterocyclic ring, in which oxygen, nitrogen or sulfur atoms can also be found;

RE is hydrogen, alkyl, alkoxyalkyl, carboxyalkyl, carbamylalkyl, arylalkyl, acyl, sulfonyl group or alkali metal anion,

or their salts with acids or bases, which consists in the fact that 2, 4 - dihalodophenol general formula

h: - / VoH

X

where X is as defined, is reacted with formaldehyde and amine of the general formula

/ R,

t

n

inert solvent and the best compound of the general formula - ,,.

.

.

X

either converted to salt, or reacted with a compound of general formula YR3

where RS has the above values; Y is a halogen atom, followed by the separation of the target products in a known manner.

The following reactions take place in a good yield in an inert solvent, for example, in hexamethylphosphoric triamide, under the conditions, under these conditions, the formation reaction is practically not occurring. Quaternary base group -

Example 1. To cool to 10 ° C, a mixture of 300 ml of a 35% formaldehyde solution and 2 liters of dioxane, with overmixing, added dropwise 453 g of M-methylcyclohexylamine. Then, 1008 g of 2,4-dibromophenol is added, the mixture is added and heated at reflux for 3 hours, then evaporated in vacuo to a syrupy consistency of the reaction mass. Pa: Brown brown with methanol and after seeding into the cooled solution, crystalline N- (2-hydroxy-3, 5-dibromobenzyl) -N-methylvodohexylamine is obtained, which is washed on the filter with methanol, the freezing point is 65-67 ° C. The hydrochloride of this compound was also added to an alcoholic solution of HCI. The hydrochloride melts at 182-186 ° C after recrystallization from ethanol.

PRI mme R 2. 100 g of the base obtained according to Example 1 is dissolved in 150 ml of dimethylformamide and added portionwise to 6.08 t of lithium amide while stirring, while the temperature of the mixture rises to 40 ° C. From a transparent a colorless powder, which is the phenol t lithium phenol N - (2 -oxy - 3, 5 - dibromobenzyl) - N - methylcyclohexylamine with a temperature of 130 ° C, is precipitated out soon.

Example 3. To a solution of 200 g of base prepared according to Example 1 in 600 ml of acetone, 150 ml of a 29% solution of sodium methylate are added dropwise with stirring. The solution is then mixed under vacuum and the residue is stirred with ether, and phenol Na (phenol is taken up base) crystallizes out with a pour point of 200-203 ° C.

EXAMPLE 4 A solution of 8.6 g of acetyl chloride in 20 ml of chloroform was added dropwise to a stirred solution of 37.7 g of chloroform obtained according to the example of base. The temperature of the mixture is increased to 40 ° C. Then the mixture is heated to reflux for 30 minutes, the cooled solution is washed with water, dried over NajSO4, and evaporated in

vacuum. The residue is dissolved in a small amount of methanol. In the interaction of this solution with an alcoholic solution of HCI and ether, N - (2 - acetoxy - 3, 5 dibromobenzyl) - N - methylshichlohexylamine hydrochloride precipitates, which, after recrystallization from ethanol, has a m.p. 183-192 ° C.

Example 5: 7.66 g of phenol and Li, obtained in Example 2, were dissolved in 300 ml of dimethylformamide. A solution of 3.43 g of ethyl iodide in 10 ml of dimethylformamide is added dropwise to the solution while stirring. After 2 h, the reaction mixture is heated to 50 ° C and kept at this temperature for 1 h. Then the solvent is distilled off in vacuum, the residue is dissolved in chloroform, the solution

washed with water and the dried solution is rinsed. The residue is treated with an alcohol solution

HCi and get crystalline hydrochloride N (2 - ztoxy - 3, 5 - dibromobenzkl) - N - methyl cyclohexylamine, which after recrystallization from alcohol has so pl. 205 C.

Example 6. To a solution of 80 g of tert-butylamine in 350 ml of dioxine cooled to 15 ° C, a mixture is added dropwise with stirring

95 ml of 35% formaldehyde solution and 100 ml of dioxane. The mixture is left overnight, after which a solution of 252 g of 2, 4-dibromophenol in 250 ml of dioxane is added while stirring, and the main part of the product

reaction precipitates out. At the end of the addition, the mixture is cooled for 1 hour, the precipitate is sucked off, washed on the filter with alcohol and dried. Dioxane mother liquor and alcohol wash water concentrate. Remaining reaction

in the form of hydrochloride, they are planted out of dioxane concentrate while heating the mixture with an alcoholic solution of HCI, the free base is prepared by the action of NaHCOa in Hj 0 / CHCf medium, on this hydrochloride.

Total yield 268 g (79.5% of theory).

After recrystallization from ethyl acetate, N - (2 - hydroxy - 3, 5 - dibromobenzyl) - treT butylamine is obtained in the form of colorless random needles; m.p. 173-175 ° C.

Example 7. To a suspension of 6.74 g obtained by

Example 6 of a base in 10 ml of hexamethylphosphoric acid triamide (THMP) with stirring was added dropwise 4 ml of a 29% sodium methoxide solution. The solution is heated to 40 ° C and for

A solution of 3 - boron chloride in 5 ml of THMP is added dropwise in 3 hours. The mixture is stirred at 40 ° Cj for another 3 hours, then the cooled mixture is transferred and 2 (10 ml of saturated water {{NaCl solution, cooled, with ice, is extracted several times with ether. The combined ether extracts are washed with 0.1N NaOH and water, they are dried over N32804, the mixture is mixed with activated carbon and filtered. After the alcoholic fHCI is added from the filtrate, N - (2 - Lsi: zyloxy 3, 5 - dibromobenzyl) - ipci nv p1 drops out of the filtrate ..

which after recrystallization from alcohol has. 204-208 ° C

Yield 7.9 g (85.4% of theory). Other 2-aminomethyl-4, 6-dihalo-phenol derivatives are also prepared by the proposed method.

or their salts with basic acids, about tl and h and y and i and cj with the fact that 2, 4 - dihalophenol common formul

Claims (1)

Formula of the invention The method of obtaining the derivatives of 2-a shnometil4, 6 - dihalophenol of the general formula -1G | Gv, -1 ( R, OR, X where X is one. halo atoms, ca; RI is hydrogen or LOW alkyl; Rj is alkyl, cycloalkyl, aryl, arylalkyl fugt or Rj and Rj., When bonded to a nitrogen atom, form a saturated heterocyclic ring, which can also contain oxygen, nitrogen or sulfur atoms, RS is hydrogen, alkyl, alkoxyalkyl, carboxyalkyl, carbamylalkyl, arylalkyl, acyl, sulfonyl ipynna or alkali metal anion. where X has the above meaning, is reacted with formaldehyde and amines of the general formula / RI HN R. where RI and Rj are as defined above, in an inert solvent and the resulting compound is either reacted with ijjopNr / nbi YR3, where Rj has the indicated values, Y is a halogen atom, or is isolated in a known manner as ocHOBamiH or a salt. Priority featured: 02.01.73 where Bz is a. alkyl, alkoxyalkyl, carboxyalkyl, carbam} chalkyl, arylalkyl, acyl or sulfoyl group. 08/24/73 where Out is hydrogen or an alkali metal anion.