CZ86394A3 - Process for preparing 1-r1-3-r2-tricyclo(3,3,1,1,3,7)decyl-5-amine - Google Patents

Abstract

A description of the method of producing 1-R1-3-R2-tricyclo (3,3,1,1,<3,7>)decyl-5-amine of the general formula I, where R1 and R2 are hydrogen atoms or methyl groups, by the solvolysis of 1-R1-3-R2- tricyclo (3,3,1,1, <3,7>) decyl-5-acetamide by the action of the hydroxide of an alkaline metal in an anhydrous medium of methanol at temperatures of 110-140 degrees C in non-pressure equipment. The reaction is characterized by a small discard, small demands for production equipment, high selectivity and high conversion into 1-R1-3-R2-tricyclo(3,3,1,1<3,7>)decyl-5-amine. Tricyclo(3,3,1,1<3,7>)decyl-5-amine of formula II in the form of hydrochloride or sulphate in a drug form is used for treating Parkinsons disease and for treating and prophylaxis of virus diseases of type A. 1,3-dimethyl-tricyclo(3,3,1,1,<3,7>)decyl-5-amine of formula III hydrochloride is used as a myotonolytic agent for treating diseases of the central nervous system.

Description

A method for producing L-R-3-R 2 tricykIo (3,3, l, l ^{3 '7)} decyl-5-amine

Technical field

3.7

The present invention relates to a process for the preparation of 1-R 1 -3-R 2 -tricyclo (3,3,1,1 ') decyl-5-amine (1-R 1 -R 3 -R 2 -adamantyl-5-amine) of formula T.

r ₂ (I) / where R 1, R 1 are hydrogen atoms (1-aminoadamantane, formula II):

. 0Η3Λ0 3, \ W I qvafl __

AND

IX | msoa 1 c 0 V f, G

(Π), or methyl groups (1,3-dimethy-5-aminoadamantane, formula ΙΠ)

CH,

nh ₂ ch ₃ (III).

of formula II in the form of the hydrochloride or sulfate is used in the dosage form for treatment

S-s.

Parkinson's disease and for the treatment and prophylaxis of type A viral diseases. The compound of formula HI in the form of the hydrochloride is used as a myotonolytic and for the treatment of diseases of the central nervous system.

2. Background Art

W7 · adamantane, 1-haloadamantane or II directly prepared by Koch reaction (1961)], by reaction with aluminum chloride a) Τα é Described are methods of preparation II from N- (1-adamantyl) acetamide. Adamantane can be used with hydrogen cyanide [Haaf W .: Angew.Chem. 73,144 _x trichloride [P. Kovacic, Roskos PO J.Am.Chem.Soc.91,6457 (1969)] or nitration fauctsMjg) _{and (j Amantani} nitric acid in acetic acid and subsequent reduction to (Π) [Co EIDuPont ., J. Org. Chem. 26,2207 (1971)] Due to the toxicity or hazard of the reagents and the relatively low yields, these procedures are of theoretical importance only.

The compound of formula Π can be further prepared by melting 1-bromo adamantane with thiourea [Nagoya T., Shimizu Y .: Japan Kokai 72-25162 (1972)], with thiocyanate [Nagoya T., Shimizu Y .: Japan Kokai 72-25163 (1972) )], with urea [Burkhard J., Landa S .: Sb.VŠCHT Praha, Fuel Technology 1973, D 29,91] or with formamide [Nováček A., Hedrlin I .: ČSSR Patent 126 397 (1968), Poliš J .: USSR Patent 408,546 (1970)]. Hydrolysis of the intermediates with hydrochloric acid affords the compound of formula (Π) as the hydrochloride.

In a similar manner, a compound of formula HI is prepared by melting 1,3-dimethyl-5-chloro-adamantane with urea at 220 ° C (Austrian patent 329532, Merz + Co.1973).

The disadvantage of most of these processes, which require high temperatures (150 ° C and above), is the severe sublimation of 1-haloadamantane, which causes major technological difficulties in larger batches. Another disadvantage is the low selectivity of the reaction, where besides the N-substituted intermediates, O-substituted intermediates are also formed. This leads to losses in the yield of the desired product, which are greatly increased by the necessary recrystallization of the crude product.

Pressure aminolysis of 1-bromadamantane liquid with ammonia is also described [Neth. Appl. 74-02316 (1974)]. This reaction requires large excess ammonia in addition to the pressure equipment in order to increase the selectivity of the reaction to the primary amine. The consequent need to regenerate large amounts of liquid ammonia limits the use of this production method to laboratory scale only.

J _and K ₀ relatively preferred is an alkaline solvolysis Preparation II Z''W Nl-adamantyl. N1-adamantylacetamide is a relatively stable, crystalline intermediate and its alkaline solvolysis proceeds with great selectivity. However, reaction temperatures above 130 ° C are required to achieve good conversion. The preparation of Π by solvolysis of N1-adamantylacetamide with sodium hydroxide in diethylene glycol or its analogues at 140 ° C is described [Stetter H., Mayer I, Schwarz M .: Chem.Ber.93, 226 (1960)]. A great disadvantage of this otherwise simple process is the difficult recovery of the high-boiling solvent, which makes it practically impossible to utilize the reaction in larger batches for environmental reasons.

An attempt to solve this disadvantage was to carry out the hydrolysis of N-1-adamantylacetamide 50 with an aqueous solution of sodium hydroxide in methanol, which can be easily regenerated. However, this process requires a reaction temperature of 170 ° C and a working overpressure of 1.5 MPa (GB1 092 808 (1967)). After the reaction, methanol can be easily recovered, but this process requires special high-pressure equipment and high temperatures for hydrolysis, which cannot be achieved by heating with commercially available 0.4 MPa steam.

SUMMARY OF THE INVENTION

In verifying the preparation of 1-aminoadamantane by alkaline hydrolysis of N-1-adamantylacetamide

A 50% aqueous solution of sodium hydroxide in methanol according to the known method has been found that water has a very negative effect on the

-3 ~ / y

F ίΰί / άζ /? / ~ Sjy Z fvr ~> i / Á- <7, x / X

Due to the effect of water, high temperatures above 160 ° C and correspondingly large operating pressures are required for the desired conversion. Hydrolysis of N-1-adamantylacetamide with 50% aqueous sodium hydroxide by PTC catalysis at 130 ° C gave only 0.2% of 1-aminoadamantane after 21 hours in the absence of alcohol. These findings show that the dominant role of solvolysis is played by oxide and not hydroxyl ions. Alkoxide ions are formed in an anhydrous environment by the reaction of an alcohol with an alkali metal hydroxide. Based on these findings, an original yet simple process for the preparation of 1-aminoadamantane from N-1-adamantylacetamide has been developed, eliminating the disadvantages of the above processes, i.e. either work with difficult to recover solvents or work at high pressures and temperatures.

The disadvantages of the processes described above by alkali solvolysis are eliminated by the process according to the invention, the common feature of which is solvolysis of N-1-adamantylacetamide and a new feature is solvolysis in an anhydrous medium (methanol, ethanol, isopropanol).

Solvolysis of 1 part by weight I is carried out with 0.5-1.5 parts by weight of alkali metal hydroxide in an environment of 0.5-3.0 parts by weight of anhydrous methanol, ethanol or isopropanol at a temperature of 110-140 ° C for 10-30 h. The reaction is simple and is characterized by small wastes, high selectivity and high conversion, which is greater than 99% after 15 hours of reaction. This very simple method of hydrolysis allows the use of readily recoverable methanol as a solvent while simultaneously carrying out the reaction at 110-140 ° C in a commercially available iron or stainless steel apparatus without the use of expensive high pressure equipment. Using the above relative proportions of reagents, the vapor pressure of methanol is reduced to such an extent that it allows the desired reaction temperatures to be achieved without the need for a high-pressure device. Instead of potassium hydroxide, sodium hydroxide may also be used, but it is less preferred than potassium hydroxide, especially in terms of solubility and foaming of the reaction mixture. Instead of methanol, ethanol, isopropanol or butanol may also be used, but these are less preferred than methanol due to the worse solvating effects on the reaction components and the more difficult solvent recovery, mainly due to the formation of azeotropes with undesirable water. The reaction can also be carried out at temperatures below 110 ° C, but the reaction rate rapidly decreases. After completion of the reaction, the mixture is cooled, diluted with water, the alcohol is distilled off and the crude 1-aminoadamantane is extracted with a suitable inert solvent, for example toluene. Subsequent treatment of Π or IH into the reindeer form with an inorganic or organic acid is carried out in a manner known per se. The waste aqueous potassium hydroxide solution is, for example, treated after neutralization with sulfuric acid and refining to potassium sulfate.

The preparation method I according to the invention is further explained in the following examples. DETAILED DESCRIPTION OF THE INVENTION

Example 1:

g of N-1-adamantylacetamide, 40 g of potassium hydroxide and 24 g of methanol were stirred and refluxed for 15 hours. The reaction temperature gradually decreased from 138 ° C to 128 ° C. Analysis of the resulting sample by gas chromatography showed a relative content of 1-aminoadamantane of 99% and a content of N-1-adamantylacetamide of less than 1%. The reaction mixture was then cooled to 120 ° C, water (50 ml) was added dropwise and methanol distilled (28 ml of crude methanol was obtained). Toluene (40 ml) was added to the remaining reaction mixture at 90 ° C, stirred for 15 minutes and then stripped. The lower aqueous caustic phase was carefully separated and the toluene solution of 1-aminoadamantane was extracted at 50 ° C with a solution of 22 ml of 36% hydrochloric acid in 120 ml of water. The aqueous phase was separated, refined with 2 g of activated carbon and, after filtration, precipitated with a solution of 6 ml of 93% sulfuric acid in 50 ml of water. After filtration and stirring in

-4-ethanol gave 36.7 g of 1-aminoadamantane sulfate (88.5% of theory) with a purity greater than 99%.

Example 2

N-1-adamantylacetamide was hydrolyzed with the feedstock feedstocks of Example 1 except that 80 g of a 50% aqueous solution was used instead of 40 g of potassium hydroxide and the reaction was carried out in an autoclave. After 24 hours of reaction at 125 ° C, only 23% 1-aminoadamantane and 77% starting material were found in the mixture.

Example 3

2.0 g of N-1-adamantylacetamide, 1.3 g of sodium hydroxide and 5.0 ml of n-butanol were stirred in a 110-115 ° C bath for 30 hours. The resulting gel-like mixture was cooled to 90 ° C, 2.0 mL of n-butanol and 3.0 mL of water were added, and the mixture was stirred at that temperature to form two liquid phases. The upper organic phase was separated and the aqueous lye phase was repeatedly extracted with 5.0 ml of n-butanol. The combined organic phases were precipitated with a solution of 1.0 mL of 47.5% sulfuric acid in 10.0 mL of water. The suspension was stirred for 1 hour, filtered, washed 5 times with 10.0 ml water and 3 times with 10.0 ml acetone. The product was dried, weighed and analyzed. 1.81 g of 1-aminoadamantane sulfate (88.4% of theory) were obtained with a purity greater than 98.0%.

Example 4

1.0 g of 1,3-dimethyl-5-acetamidoadamantane, 1.0 g of potassium hydroxide and 0.6 g of methanol were vigorously stirred and refluxed for 21 hours. The reaction temperature gradually decreased from 136 ° C to 125 ° C. Analysis of the resulting mixture showed a relative content of 1,3-dimethy 1-5-aminoadamantane of 99.5%. and a starting material content of less than 0.5%. After diluting the mixture with water and distilling off the methanol, the product was extracted with 10 ml of toluene and after separation and drying of the organic phase with anhydrous sodium sulfate, the product was precipitated in the form of the hydrochloride by addition of 0.5 g of 36% hydrochloric acid. The resulting product was filtered, washed with 5.0 ml of acetone, dried, weighed and analyzed. 0.8 gl was obtained, 3-dimethyl-5-aminoadamantane hydrochloride (82% of theory) with a purity higher _(than 99%.

Claims (2)

Claims # · 1. A process for preparing 1-R - 3 R ₂ ..tricyklo (3,3, I, L ^{3 '7)} decyl-5-amine of formula I _NH2 w run KDE Ri, R ₂ are hydrogen atoms or methyl groups, an anhydrous medium, L-R-3-R ₂ tricyclo (3,3, l, l ^{3 '7)} 5-decyl acetamide, characterized by solvolysis of 1 part by weight of L-R-3-R ₂ .tricyklo (3,3, l, l ^{3 '7)} 5-decyl-acetamide performed by action of 0.5 to 1.5 parts by weight of alkali metal hydroxide in an anhydrous medium methanol, ethanol or isopropanol at 110-140 ° C for 10-30 h. 2. The process according to claim 1, characterized in that, after the reaction mixture was diluted with water and stripped to an aliphatic alcohol and 1-R -3-R ₂ tricyclo (3,3, l, l ^{3 '7)} decyl-5- the amine is extracted with an inert solvent such as toluene for further processing to form a salt with an inorganic or organic acid.