DE2316839C2 - Process for the preparation of aminoadamantane derivatives - Google Patents

Description

H ₂ CI CH ₂

CH ₂

CH

where R ₁ and R _{2 are the} same or different and represent a hydrogen atom or a methyl radical, and R _{3 represents} a methyl radical or, together with -NR _2, the morpholine radical, and their salts of N- (I-adamantyl) -l-haloacetamine or . N-Methyl-N- (1-Adamantyl) -halogenacetamld and the alkali salt of an aminoethanol and optionally converting the free base obtained into their salts, preferably with a hydrogen hydrogen, according to Patent 1941218, characterized in that instead of the alkali salt of an aminoethanol initially only a monoalkali glycolate is used, then the hydroxyl group of the / J-hydroxyether obtained is exchanged for halogen with a conventional halogenating agent and the resulting N- (I -adamantyl) -2- (2-haloethoxy) acetamide reacts with the desired amine.

2. The method according to claim 1, characterized in that thionyl chloride is used as Halogenlerungsmlttel is used.

3. The method according to claims 1, characterized gekennzelchnnet that the reaction with the desired AmIn is carried out under increased pressure.

The invention relates to an improved process for the preparation of amnoadamantane compounds of the general Formula:

CH ₂ -

HC

CNC-CH ₂ -O-CH ₂ -CH ₂ -N

I Il

R ₁ O

R ₂

where R | and R _{2 are} identical or different and represent a hydrogen atom or a methyl radical and R _{3 represents} a methyl radical or, together with -NR _2, the morpholene radical, as well as their salts.

In the German Auslegeschrift 19 41 218 is a process for the production of the amlnoadamantane compounds referred to above described in the 1-Amlnoadamantan or 1-Methylamlnoadamantan with a Halogenacetylhalogenld reacted and the resulting N- (l-adamantyl) -halogenacetamld with an alkali salt of an aminoethanol in an inert solvent for Reaction is brought.

Although this known process is satisfactory in reactions with small molar amounts in each case, There are difficulties when this procedure is carried out in larger batches target. In the case of larger approaches, this is particularly the case the well-known implementation of N-d-AdamantyD-chloracetamide with sodium amlnoethanolate difficult since a quaternization of the nitrogen atom cannot be ruled out with certainty, which leads to inconsistent Reaction products leads.

The object of the invention is therefore a method for Preparation of amlnoadamantane compounds of the type mentioned above, with better yields in larger quantities Scale can be carried out from the corresponding N- (l-Adamantyl) -halogenacetamlden and the alkali salt of an aminoethanol and optionally converting the free base obtained into their salts, preferably with a hydrogen halide according to patent 1941218.

The solution to the problem is that instead of the alkali salt of an aminoethanol, first only a monoalkali glycolate is used, then the Hydroxyl group of the / J-hydroxyether obtained with a customary halogenating agent against halogen

exchanges and the resulting N- (l-adamantyl) -2- (2-halo3thoxy) acetamide reacts with the desired AmIn.

In a preferred embodiment, the halogenating agent is used Thionyl chloride used.

In some cases it has proven to be advantageous to carry out the reaction of N- <l-adamantyl) -2- (2-haloethoxy) -acetamlds with the desired amine at elevated pressure to reduce the reaction time. Instead of the N- (I-AdamantyI) -2- (2-haloethoxy) -acetamld Reacting with a primary or secondary amine can introduce the amine component an amine precursor can also be used from which the desired amine can easily be prepared. So can e.g. B. N- (1-Adamantyl) -2- (2-phthal! Mldoethoxy) -acetamine can be cleaved in very good yield with hydrazine to give the corresponding amine.

N-U-AdamantyO-halogenacetamld or N-methyl-N- (l-adamantyl) -hajogenacetamld are easy by reacting the corresponding 1-aminoadamantanes with a haloacetyl halide, preferably chloroacetyl chloride accessible. This reaction can be carried out without difficulties on a kg scale, with It is expedient to recover the halogen acid amlnoadamantane which is obtained as a by-product and to supply the released base to the reaction again. N- (1-adamantyl) chloroacetamide is obtained in yields of 90% and more, melting point 122 ° C .; N-methyl-N- (l-adamantyO-chloroacetamide is obtained in the same catfish in yields of 87% and more. Mp. 83 ° C.

Mono-alkali glycolate is made through at room temperature Introducing an alkali metal into an excess of glycol. The preferred alkali metal is sodium used. It has been shown that it is not necessary to isolate the glycolate in substance, but that Glykolathalttge Glykol can directly with the Adamantylhalogenacetamld be implemented without the risk of side reactions.

Halogen generators for replacing the hydroxide group on primary alcohols with halogen are the common to organic chemists. Halogenation with a mild halogenating agent is more useful carried out that does not attack the ether grouping; Phosphortrichlorld, among others, are suitable for this purpose, Phosphorus tribromide, thionyl chloride, phosphorusoxychloride.

In the context of the process according to the invention, thionyl chloride is preferably used as the halogenating agent, since a worldwide complete reaction takes place under mild conditions and the gaseous HCl or SO ₂ which is formed can easily be removed from the reaction mixture.

The above-mentioned amlnoadamantane compounds are used to obtain the halo-acid salts these in an inert solvent such as toluene, dissolved and dry hydrogen halide, such as HCl gas, introduced.

The following examples serve to illustrate the process according to the invention.

mantyD-chloroacetamide is added, and the mixture is stirred at 150 ° C. for 3 hours. Subsequently, ⁰ C 16 are in a vacuum at 120 to 140 distilled to 17 liters Äthylengiykol, the cooled residue with 5 liters of carbon tetrachloride and 15 liters of water are added and the mixture was intensively performed.

The phases are separated, the organic phase is freed from the solvent in vacuo and the residue brought to crystallization by slowly pouring into petroleum ether (boiling moose 50 to 75 ° C).

It is then centrifuged and the product is dried at 50 ° C. in a vacuum drying cabinet.

Yield: 85 to 90 «N- (1-adamantyl) -2- (2-hydroxyethoxy) acetamine hydrochloride (1) with a melting point of cyclohexane
M.p .: 71 ° C
Molecular weight: 253, 328

b) N- (l-Adamantyl) -2- {2-chloroethoxy) -acetamld (2)

2533 g of (1) are dissolved in a solvent mixture of 900 g of pyrene and 10 liters of 1,2-chloroethane. To this end, a solution of 800 ml of thionyl chloride in 2 liters of 1,2-chloroethane is added so quickly with cooling.

drops so that the temperature does not exceed 20 ° C. After the dropwise addition, the mixture is refluxed for 18 hours. Then it is washed 3 with 10 liters of water each time, the layers are separated, filtered and the solvent is completely distilled off. The residue is dissolved in 10 liters of petroleum ether (boiling pot 50 to 75 ° C) in the heat and slowly cooled while stirring. The precipitated crystal is abzentrlfuglert, washed with petroleum ether and dried at 5O ⁰ C in vacuo.

Yield: 85 to 90% of N- (1-adamantyl) -2- (2-chloroethoxy) acetamine (2) having a melting point

Petroleum ether (50 to 70)
M.p .: 66 ° C

Molecular weight: 271,
The halogenation

785

of N- (l-Adamantyl) -2- (2-hydroxyethoxy) -acetamld (1) can also be used with others Perform halogen detectors.

b ') N- (l-Adamantyl) -2- (2-chloroethoxy) -acetamld (2)

A mixture of 2533 g (1) and 225 g of pyridine is slowly added to 550 g of phosphorus trichloride with cooling to 0 ° C. When the addition is complete, the mixture is heated and stirred at 40 to 60 ° C. for 24 hours. The reaction mixture is taken up in CCl ₄ , washed with water and dilute Na ₂ CO ₃ solution and further worked up as indicated above.

example 1

N- (1-Adamantyl) -2- (2-dlmethylaminoethoxy) -acetamine hydrochloride

a) N- (I-Adamantyl) -2- (2-hydroxyethoxy) -acetamld (1)

230 g of sodium are dissolved in 3 liters of ethylene glycol, and the solution is made with another 15 liters of ethylene glycol diluted. 228O g of N- (I-Adab ") N- (1-adamantyl) -2- (2-bromoethoxy) -acetamine are then added

_{349 ml of freshly distilled PBr 3} are added dropwise to a solution of 2533 g (1) in 10 liters of carbon tetrachloride and 900 g of pyridine, stirred with exclusion of water and cooled to -10 ° C., at such a rate that the temperature

does not rise above 0 ° C.

After completion of the dropping, the cooling is removed, the mixture was warmed to room temperature with stirring and the mixture was then 48 hours left standing quietly. Then 3 χ with 10 liters of water

water washed and processed as indicated above welter.

Melting point: 73 ° C
Molecular weight: 316, 244

c) N- (1-adamantyl) -2- (2-dlmethylaminoethoxy) acetamide hydrochloride

15 (10 g of dimethylamine are dissolved in 10 liters of ethanol. 50 g of sodium iodide and 2717 g of (2) are added to this solution. The mixture is then heated to 60 to 70 ° C. under tubes for 24 hours, the pressure being approximately 0.4 atm increases. then, the ethanol is vacuum distilled off completely and the residue dissolved in 10 liters was added dilute hydrochloric acid. the hydrochloric acid solution is stirred with 100 g of activated carbon, i χ, each with 1.5 liters of petroleum ether and washed with solid sodium hydroxide to pH 9 The precipitated base is taken up in 30 liters of petroleum ether and, after drying over solid potassium hydroxide, precipitated as the hydrochloride by introducing hydrogen chloride.

Yield: 95% N- (1-AdamantyI) -2- (2-dlmethylamlnoethoxy) -acetamld-hydrochloride with a melting point from trichlorethylene
M.p .: 156 ^° C
Molecular weight: 316, 867

Starting from the N- (I-adamantyl) -chloracetamld used is the total yield from all three process steps about 68 to 73%, with careful processing of the mother liquors also increasing the yield possible are. Gas chromatographic and thin-layer chromatographic investigations prove that the end product is a uniform substance.

Example 2

N- (1-Adamantyl) -2- (2-morphoHnoathoxy) acetamide hydrochloride

c) 2717 g (2) are mixed with 4350 g of morpholine and 150 g of sodium iodide in 25 liters of toluene at normal pressure for 24 hours refluxed. Toluene and excess morpholine are then largely removed in vacuo removed and the residue taken up in 10 l of dilute hydrochloric acid. The hydrochloric acid solution is added in portions Treated with about 100 g of activated charcoal, 3 χ each with 1.5 1 petroleum ether washed and the aqueous phase brought to a pH between 9 and 10 with sodium hydroxide. « The deposited base is taken up in petroleum ether, the deposited base is taken up in petroleum ether, this solution dried over solid potassium hydroxide and then dried through Introduction of dry hydrogen chloride as hydrochloride precipitated. The precipitate is filtered off and Im Vacuum dried at 80 to 90 ° C.

Yield: 93% of N- (1-adamantyl) -2- (2-morpholnoethoxy) -acetamld-hydrochloride with a melting point from petroleum ether
Molecular weight: 358.907

As described in the examples, the desired bases precipitated as hydrochloride and isolated. But it is also possible to convert the bases into other salts, for example in the bromide, sas sulfate or in the phosphate.

In the above examples, N- (1-adamantyl) chloroacetamine with monosodium glycolate was used as the starting material implemented. The reaction mentioned and the subsequent subsequent reactions can also be carried out with N-methyl-N- (l-adamantyl) chloroacetamine be carried out as starting material, essentially the same yields of subsequent products were obtained ". It is also possible, instead of the N- (1-adamantyl) chloroacetamides mentioned, to use other N- (1-adaman; yl) haloacetamides to use.

Comparison (DE-As 19 43 218)

-Adamantyl) -2- (2-dlmethylam! Noethoxy) -acetamide-hydrochloride

23 g of Na are dissolved in 750 ml of dimethylamine ethanol. Subsequently, the excess alcohol completely distilled off and the resulting sodium salt carefully dried in vacuo. After drying The salt is dissolved in approx. 2000 ml of xylene while stirring. 228 g of N- <1-adamantyl) chloroacetamide are added to this solution added. The mixture obtained is then refluxed for 10 hours in a 3000 ml round bottom flask is boiled and, after cooling, the sodium chloride formed is filtered off. The xylene will Mostly completely distilled off in vacuo, the liquid residue in approx. 800 ml of carbon tetrachloride added and the hydrochloride precipitated by passing in dry hydrogen chloride.

For cleaning, the hydrochloride is dissolved in 1 l of acetone and excess hydrochloric acid with the solvent distilled off. This operation can be repeated until no more excess acid can be detected.

Then the concentrated acetone solution of the hydrochloride with a large excess added to petroleum ether and stirred for at least one hour, the N- (l-Adamanty!) - 2- (2-dimethylaminoethoxy) -acetam! d-hydroch! orld Accumulates in crystalline form. The product is filtered off and placed in a desiccator dried. Yield 90 g, which corresponds to 32% of the theoretical yield.

According to the chloride determination with mercury (II) nitrate, the product obtained is 93% Ig. Gas chromatographic or thin-layer chromatographic studies show that the substance is inconsistent. as The main impurity was identified with the quaternary salt isomers with the main product, which is also identified by Combination of N- (l-adamantyl) chloroacetamide and dimethylaminoethanol can be obtained in the cold.

The comparative experiment shows that the known process is only insufficiently satisfactory for larger batches Yields leads. All the more surprising are the good yields by the process according to the invention, based on the N- (l-adamantyl) chloroacetamine used, are between 68 and 73% across all three procedural stages. The expert had to assume that an additional process step would lead to a reduction in the overall yield.

Another advantage of the process is that the N- (l-adamantyl) -ha! Ogenacetamlde according to the invention only with easy to manufacture and easy to clean Substances are implemented.

The derivatives of 1-aminodamantane prepared according to the invention have excellent static properties.

Claims (1)

Claims: 1. Process for the preparation of aminoadamantane compounds of the general formula CH ₂ HC CH ₂ CH ₂
^N CH -NC-CH ₂ -O-CH ₂ -CH ₂ -N - (^ I II ^X R ₃ Ri O