DE1039061B - Process for the preparation of N-substituted 3-aminoisocamphane compounds, their salts, quaternary ammonium compounds and optically active isomers - Google Patents

Description

GERMAN

The invention relates to the preparation of new N-substituted derivatives of 3-aminoisocamphane.

The new compounds that can be prepared according to the invention have the general structural formula:

CH ₉

CH ₃

CH ₃
CH,

in which R is a lower alkyl group and R _{1 is} hydrogen or a lower alkyl group. They are valuable ganglia blocking agents.

According to one embodiment of the invention, 3- (N-methylamino) -isocamp'han can be obtained by Treated camphene with hydrogen cyanide in the presence of an acid and the 3- (N-formylamino) -isocamphane obtained is reduced.

The conversion of camphene to 3- (N-formylamino) -isocamphane is conveniently carried out by adding camphene with hydrogen cyanide and sulfuric acid or a sulfonic acid in glacial acetic acid at low temperatures under practically anhydrous conditions is brought into intimate contact. Although higher temperatures can also be used, it has been found that the highest yields of the desired formamido compound are obtained, when this reaction is carried out at temperatures below about 20 ° C. Generally will the reactants mixed at about 0 to 5 ° C and then the reaction mixture to about 20 ° C to the Heated to completion of the reaction.

The formamido compound can be prepared using hydrocyanic acid or a cyanide, which by reaction with the acid present yields the hydrocyanic acid in situ. The hydrocyanic acid should be present in amounts that are at least 1 mole per mole of camphene are equivalent. However, it has been found that it is preferred to employ at least 2 moles of hydrocyanic acid because the highest yields of the desired product are obtained with an excess will.

The sulfuric acid or sulfonic acid used to carry out the reaction should be practically anhydrous as it is desirable to carry out the reaction under practically anhydrous conditions. The acid should be present in an amount which is equivalent to at least 1 mole per mole of converted camphene be. In general, however, an excess of acid of, for example, 2 to 3 moles per mole Camphene used as the use of a

for the production of N-substituted

3-aminoisocamphane compounds,

their salts, quaternary

Ammonium compounds

and optically active isomers

Applicant:

Merck & Co., Inc.,
Rahway, NJ (V. St. A.)

Representative: E. Maemecke, Berlin-Lichterfelde West,

and Dr. W. Kühl, Hamburg 36, Esplanade 36 a,

Patent attorneys

Claimed priority:
V. St. v. America 6 June 1955

Karl Poster, Westfield, N.J.,

and Gustav Albert Stein, Plainfield, NJ (V. St. A.),
have been named as inventors

Excess acid leads to higher yields of the formamido compound. Except sulfuric acid can also use sulfonic acids, ζ. B. alkyl sulfonic acids, such as methanesulfonic acid or ethanesulfonic acid, aromatic Sulphonic acids, such as benzenesulphonic acids, toluenesulphonic acids or naphthalenesulphonic acids, are used will.

The camphene is expediently dissolved in glacial acetic acid, liquid hydrogen cyanide is added to the mixture, and the mixture is cooled the resulting solution to about 0 ° C and then adds a mixture of sulfuric acid in acetic acid, while maintaining the temperature of the reaction mixture between about 0-5 ° C. The received The reaction mixture is then allowed to warm to about 20 ° C; the reaction is then practically over.

The desired 3- (N-formylamino) -isocamphane is expediently separated off from the reaction mixture by adding cold water and extracting the formamido compound with a suitable solvent, such as chloroform. The product is recovered from the chloroform solution by adding a dilute aqueous alkaline solution such as sodium bicarbonate, the chloroform extract until the aqueous layer has a _pH value of

«09 638/435

3 4

about 7 to 8. The chloroform- the residue finally under reduced pressure

solution is then washed with water, which is then distilled.

To remove excess alkali, finally. In a similar way, other lower

dried and prepared under reduced pressure to dryness N-alkyl derivatives of 3-aminoisocamphane

evaporated. The residue will be 5 in petroleum ether. So if acetaldehyde instead of

dissolved, the solution cooled and the 3- (formylformaldehyde is used, the corresponding

amino) -isocamphan obtained in crystalline form. N-ethylamines and Ν, Ν-diethylamino compounds

The 3- (N-formylamino) -isocamphane can then be obtained.

by reaction with an alkali aluminum hydride. The lower N-alkyl derivatives of to 3- (N-methylamino) -isocamphane can be reduced. io 3-Aminoisocamphane also obtained by 3-Amino-This reaction is expediently acylated in a suitable isocamphane with a lower aliphatic carbon-λγ-water-free, non-reactive solvent and the acylaminoisocamphane obtained, such as ethyl ether, with an alkali aluminum hydride, with, for example, lithium aluminum hydride reduced like lithium or sodium aluminum hydride. For example, 3- (N-ethylamino) isocam is listed. The alkali aluminum hydride is said to be prepared in a 15 phan by using 3-aminoisocamphane in an amount of about 2 moles of hydride per mole of formamido-1 molar equivalent of acetyl chloride in the presence of a compound. The reduction is converted to base and the 3- (N-acetylamino) obtained is expediently carried out in such a way that isocamphane with an alkali aluminum hydride according to, for. B. the lithium aluminum hydride in ethyl ether which dissolves in the reduction of the formylamino compound, a solution of 3- (N-formylamino) -isocamphane 20 described method is reduced. The monoin is added to anhydrous ether and the acetyl derivative obtained can also be refluxed for about 4 to 6 hours by reacting the solution. 3-Aminoisocamphane with glacial acetic acid or, preferably, at this point in time, the reduction of the form acetic anhydride in the presence of a small amount of amido compound is practically complete. The amount of sulfuric acid to be produced. In deformed methylamino compound is obtained, in this way the N-ethyl, N-propyl, water are added to the reaction mixture, the N-butyl, N-hexyl, N-octyl, N-isopropyl and the solution obtained is filtered and the filtrate is obtained on an N-isobutyl derivative of 3-aminoisocamphane, low volume is concentrated. The desired The lower N-alkyl derivatives of 3-Aminoiso-N-methyl compound is then easily obtained in the form of their camphane in lower 3- (N, N-dialkylamino) -hydrochloride by converting a solution of isocamphane with the monoalkyl derivative _{HCl saturated ether is added to the concentrate and acylated with a lower aliphatic acid and LiAlH 4 is} reduced, whereupon the hydrochloride of 3- (N-methyl- the acylated derivative obtained with, for example, amino) -isocamphane separates out in crystalline form. Thus 3- (N, N-diethyl, which can be separated off and dried. Amino) -isocamphane is produced by 3- (N-ethyl-

The formamido compound can by reacting 35 amino) isocamphan with acetic anhydride in Gegenmit a base converted into 3-aminoisocamphane was converted to a small amount of sulfuric acid will. For example, an aqueous and the N-acetyl derivative are heated with lithium aluminum-methanol solution the formamido compound is reduced with a hydride. Be in a similar fashion Alkali hydroxide, such as potassium or sodium hydroxide, other dialkyl derivatives, such as dipropyl, dibutyl, under reflux. The reaction product can be prepared from the 40 dihexyl, diisopropyl and diisobutyl compounds, The reaction mixture can be separated by the obtained. Following this procedure, in particular Solvent evaporated, the 3-Aminoisocamphan the dialkyl derivatives with various alkylsubstidurch Steam distillation removed from the tuenten, such as the methylethyl, ethylhexyl and methyl distillate obtained by extraction with an isopropyl derivative with water.

immiscible solvent and extracted from 45 The invention can be carried out by the reaction

the solvent extract can be reproduced by evaporation.
is won.

The N-methylaminoisocarnphane can then again be Example 1
by reaction of 3-aminoisocamphane with _{form->"/ ΛΤ} " ....,
aldehyde and hydrogen in the presence of a hydrogenation 50 ^a) 3- (N-formylammo) -isocamphane
In a three-necked flask equipped with a stirrer, the platinum group can be produced. Thus 3- (N-methylamino) -isocamphane is formed. Thermometer, dropping funnel and reflux condenser, if a mixture of the hydrochloride of 3-amino- was passed through the water from 5 to 10 ° C, isocamphane, water, formaldehyde and a small amount was provided, 31.7 g of dl-camphene and 58 ecm Amount of sodium acetate in the presence of palladium 55 added glacial acetic acid. The mixture was stirred until the charcoal reacted with hydrogen and all of the solid matter had dissolved, and the reaction continued until about 1 mole of water- then cooled to 10-12 ° C with stirring. Then substance per mole of 3-Aminoisocamphan is absorbed. 20 ecm of liquid hydrogen cyanide were added. When the reaction is continued until about while the mixture has continued to stir. When the 2 molar equivalents of hydrogen have been absorbed, the solution has now been cooled to 0 ° C. 3- (N, N-dimethylamino) -isocamphane was formed. The such a white crystal pulp. While the N-methyl derivatives produced in the reaction can easily be separated from the temperature by external cooling at 0 to 2 ° C, the reaction mixture was kept under reduced pressure with the addition of a solvent solution of 63.5 ecm of concentrated H ₂ SO ₄ in 58 ecm ice. The product obtained can then be started further purified by vinegar. After adding about 1 bis, by dissolving it in water, to the resulting 2 ecm sulfuric acid solution, the alkali reaction solution was added to make it alkaline to make it very liquid, and the main amount of the solid to make the alkaline solution with a substance with water was dissolved. In the course of the acid, the acid became immiscible solvents such as ether. added from 2 hours; meanwhile the extracted, the solvent solution evaporated and the 7 ° reaction mixture on a yellowish color. After this

CH,

5 ^ - ^ γ 1 039 061 -CHO LiAlH ₄ 6th ^ CH ₃ -> ■! CH ₃ "NH-CH ^ CH ₂ HCN ^ '^ i
CH ₂ CH ₃ CH ₂ CH ₃ acid alcohol NH-
CH ₃ ^^ \ / - "CH ₃ CH ₃ a) alkali
b) CH ₃ ^^ H ₃ / Pd CH ₃ Acylating _c CH ₃ CH ₃ NH-
CH ₃ -Acyl NH ₂
CH ₃ CH ₃ CH ₃ CHO I.
[IR ₂

H,

LiAlH ₄

f)

2R ₃ CHO
H ₂ Pd

d)

CH. i

NH-CH ₂ -R _{2 acylate}

CH ₂

CH ₃

CH ₃
CH ₃

-CH ₂ -R ₂

~ Acyl

LiAlH ₄
H)

R ₃ = H, low molecular weight alkyl radical.

CH ₉

CH ₃
CH ₃

CH ₂ Rg

all acid was added, the yellow-orange reaction mixture remained at for an additional hour Stirred from 0 to 2 ° C. The cold bath was removed and the reaction temperature was allowed to rise in 2 hours 22 ° C rise. The viscous reaction mixture was 15 to 30 minutes in vacuo at a pressure of Stirred 25 to 35 mm Hg to remove most of the excess hydrogen cyanide.

After the main amount had been removed, the reaction was terminated by slowly adding 500 ecm of cold water. The reaction temperature was kept at 18 to 20 ° C. by external cooling. The milky solution obtained was extracted twice with 100 ecm each and once with 50 ecm chloroform. Particular care must be taken here, since both the aqueous and the organic extracts contain hydrogen cyanide. The chloroform layer was washed twice with 100 cc of water and then contacted with a 10% sodium bicarbonate solution to a _pH value 7-8, and finally with portions of 150 cc of water until the aqueous layer was free of cyanide.

After the final water wash, the chloroform layer became over 20 g of anhydrous sodium sulfate dried, filtered and placed on a water bath in vacuo at a pressure of 25 to 35 mm Hg evaporated to dryness. When practically no more chloroform distilled over, the yellow became viscous Residue with 100 ecm n-heptane (“Skellysolve C”) at a pressure of 25 to 35 mm Hg at 100 ° C pulled out to remove the remaining chloroform. The residue was dissolved in 140 ecm of n-heptane dissolved at 100 ° C. After all of the residue went into solution, the mixture became slow cooled with stirring to allow slow crystallization. After 5 hours it was the temperature dropped to 20-25 ° C and a copious white precipitate had settled. The mixture was cooled to 5 ° C. with stirring for 8 to 10 hours, filtered and washed with cold n-heptane (3 x 10 ecm) and finally with 3 x 15 ecm of petroleum ether washed. The resulting dl-3- (N-FormyI-amino) -isocamphane melted at 160 to 163 ° C.

b) 3-aminoisocamphane

dl-3- (N-formylamino) isocamphane (21.75 g) was added in a mixture containing 70 g of sodium hydroxide, 70 ecm Water and 210 ecm of methanol contained, dissolved and

the resulting solution was refluxed for about 16 hours. After most of the methanol had been removed (in vacuo at about 50 ° C.), the alkaline liquid was distilled with steam until no more oil passed over. The distillate was saturated with sodium chloride and the amine extracted with ether. After drying with anhydrous Na ₂ SO ₄ and removal of the ether, the oily residue crystallized; the dl-3-aminoisocamphane was obtained as a waxy solid which ^{melted at 172 to 174 °} C. and softened ^{at 171 ° C.}

After subliming the product under reduced pressure, the dl-3-aminoisocamphane melted at 173 to 175 ° C.

The amine is slightly soluble in water, the _pH value of the solution is about 10.5. For further identification it was converted into the hydrochloride, which was obtained in quantitative yield and in crystalline form by neutralizing the base with HCl and concentrating the solution.

for

C ₁₀ H ₁₉ N-HCl

(Molecular weight

analysis
189.73):

Calculated C 63.30, H 10.63, N 7.38, Cl 18.69%; found C 63.59, H 10.79, N 7.06, Cl 18.83%.

The hydrochloride is completely soluble in water; it does not melt below 300 ° C.

The phosphate was obtained in a similar manner.

Analysis for C ₁₀ H ₁₉ NH ₃ PO ₄ (molecular weight 404.53):

Calculated .. C 47.80, H 8.83, N 5.58, P 12.30%;

Found ... C 47.84, H 8.69, N 6.70, P 11.94%.

The phosphate is a white crystalline salt, soluble in water but insoluble in ethanol. It melts at 281 to 283 ° C with foaming.

To a solution of 4.68 g (0.021 mol) dl-3- (N, N-dimethylamino) -isocarnphane hydrochloride in 100 ecm of water were 8.4 ecm of 2.5 N NaOH with ice cooling was added and the free amine was extracted from the mixture with 4 x 50 ecm benzene. After this Wash the combined benzene extracts with a small amount of water (25 ecm) and dry over anhydrous magnesium sulfate, the solvent was removed in vacuo. The free amine was in 10 ecm of absolute ethanol dissolved; 3 ecm of methyl iodide and 3 ecm of a 1% freshly prepared solution of sodium ethylate in ethanol were added. The mixture was on the water bath for about 18 hours heated to reflux; the white crystalline precipitate was filtered off, with ethanol (4 x 1 ecm) and then washed with ether. After air drying, the crude solid product was treated with chloroform (10 x 10 ecm) rubbed. By evaporating the chloroform extract, the quaternary ammonium salt, the trimethylammonium iodide of dl-3-Aminoisocamphans, which at 181 to 182 ° C melted with decomposition.

This product crystallized from water in thick needles.

c), d) 3- (N, N-dimethylamino) isocamphane

A mixture of 20 g (0.105 mol) of the hydrochloride of dl-3-aminoisocamphane, 150 ecm of water, 34 ecm of 40% aqueous formaldehyde solution, 1.0 g of sodium acetate (anhydrous) and 2.0 g of catalyst (5% palladium on charcoal ) was hydrogenated at room temperature and a pressure of 18 kg for about 18 hours. After this time 1 mole of hydrogen had been absorbed and the reaction had slowed down considerably. Then 2 g of palladium catalyst were added to the reaction mixture and the hydrogenation was continued at room temperature and 2.72 atm for a further 24 hours until another mole of hydrogen had been absorbed. After the catalyst had been filtered off, the clear, colorless filtrate was concentrated in vacuo at about 40 to 50 ° C. and the oil that remained was extracted several times with water and ethanol in order to remove excess formaldehyde. The partially crystalline residue was dissolved in 100 ecm of water and the solution was made alkaline with 45 ecm 2, Sn-NaOH while cooling with ice. The amine was then extracted with 1 x 100 ecm and 3 x 50 ecm ether, the combined ether extracts washed with 1 x 100 ecm water, then dried over anhydrous magnesium sulfate. After the solvent had been removed, the pale yellow oily residue was fractionally distilled in vacuo. Yield 16.2 g of dl-3- (N, N-dimethylamino) -isocamphane, b.p. ₂ = 65 to 66 ° C, n * i = 1.4898.

The base was converted into the hydrochloride by dissolving the amine in 160 ecm of anhydrous ether and precipitated with HCl ethereal solution using Congo red as an indicator. To filtering and washing with ether were 16.4 g of hydrochloride, which is at 166 to 169 ° C under Decomposition melted, preserved.

Analysis for C ₁₂ H ₂₄ ClN (molecular weight 217.8): Calculated
found

C 66.18, H 11.11, N 6.43, Cl 16.28%: C 66.17, H 10.81, N 6.54, Cl 16.1%.

By crystallizing the hydrochloride from boiling methyl isobutyl ketone (1 g of substance 17 ecm) a crystalline product was obtained, which melted at 171 to 172 ° C with decomposition. After a second crystallization, the Melting point 173 to 174 ° C (with decomposition).

e) 3-acetamidoisocamphane

120 ecm of acetic anhydride were gradually added to 30 g of dl-3-aminoisocamphane (mp 174 ° C.) under external conditions Cooling added. After about 1 ecm of concentrated sulfuric acid has been added with thorough stirring a clear solution was obtained which remained at room temperature for about 15 hours. That The reaction mixture was then slowly added to 600 ecm of water with cooling and vigorous stirring. The white amorphous precipitate formed gradually became crystalline upon stirring. He was Aspirated, washed well with water and air dried. The dl-3-acetamidoisocamphane melted at 132 to 134 ° C.

By crystallization from hot n-heptane (boiling point 95 to 100 ° C, 18 cem / g), the F. rose to 133 bis 135.5 ° C.

Analysis for C ₁₂ H ₂₁ NO (molecular weight 195.3):

Calculated. "... C 73.77, H 10.83, N 7.18%;

found C 73.48, H 10.58, N 7.18%.

f) 3- (N-ethylamino) isocamphane

A solution of 4.0 g of once crystallized dl-3-acetamidoisocamphane in 90 ecm of anhydrous Ether was stirred in the course of 25 minutes to a solution of 1.75 g (0.046 mol) Lithium aluminum hydride added in 100 ecm absolute ether. After refluxing for 3 hours the mixture was cooled slightly, and under vigorous

9 10

Stirring, 8.3 ecm of water were very carefully washed to water and poured over calcium chloride. The white, granular precipitate was dried. After filtration, the solution was filtered and washed with ether. The ether extracts are removed in a vacuum on the water bath. It was washed with 2 x 50 ecm of water, then a solid, somewhat sticky residue of anhydrous sodium sulfate was dried over. After receiving 5 231.2 g. After removal of the last traces of ether concentrating the extract to a small chloroform by repeated trituration with petroleum volume ethereal HCl under cooling to ether, the cake was finally with about 500 cc of a _pH value of about 3 was added. The petroleum ether formed (boiling point 30 to 60 ° C) under reflux white precipitate was filtered off with suction, heated with ether until a thick crystal slurry was obtained, washed to free HCl and then in the air i ° After one day of cooling, the white crystalline dried. The dl-3 - (N-ethylamino) -isocamphane mass sucked off, first with petroleum ether (2 · 125 ecm), hydrochloride melted at 248 ° C. By crystalline then with n-heptane (2 · 125 ecm) and again with Sation from boiling isopropanol (225 cm) was washed petroleum ether (2 x 125 ecm). After air-pure dl-3- (N-ethylamino) -isocamphane hydrochloride drying at room temperature to a constant level, the weight at 268 to 261 ° C with decomposition was 180.6 g of dl-3- (N-formylamino) - melted. isocamphans, which melted at 160 to 165 ° C. _Λ,, .. ^ _TT TT ^ ₁ , „,,,. _1a ,, - ο. The combined Petroläther- and n-heptane-washing analysis for C ₁₂ H ₂₄ HCl (molecular weight 217.78): _liquids * _ere mono- _under reduced pressure

Calculated C 66.18, H 11.11, N 6.43, Cl 16.28%; concentrated and the remaining oil found in a possible C 66.04, H 11.16, N 6.16, Cl 16.12%. _ao small amount of hot petroleum ether (about 75 ecm) if the N-ethyl compound obtained is dissolved with vinegar. The solution was placed in a cooling acid anhydride in the presence of a small amount for two days. The deposited dl-3- (N-formyl-sulfuric acid according to the information under e) be-amino) -isocamphane was then filtered off and, if the acylated derivative was obtained. Petroleum ether and n-heptane washed as above. The acylated ethyl derivative was then written with lithium. A further 12.6 g of a proaluminum hydride were reduced by the method described in the previous example with a melting point of 158 to 164 ° C. You get.

then held the 3- (N, N-diethylaminoHsocarnphane. The dl-3- (N-Formylamino) -isocamphan (193 g)

was in 1.91 n-heptane with heating on the

Example 2 3 ° water bath dissolved. After clarifying the solution

the clear filtrate was removed by filtration at room

a) 3- (N-Formylamino) -isocamphan left to stand at temperature until crystallization in a three-necked round-bottomed flask (5 l) with a stirrer had ended. The crystalline product was filtered off with suction, the dropping funnel and thermometer were fitted, were washed with a little cold n-heptane and glacial acetic acid was added to the 325 ecm. Air was then dried in portions. The dl-3- (N-formylamino) -iso-wise, with stirring, a total of 133 g of nacamphan melted at 169 to 174 ° C.
trium cyanide (granules, 2.6 mol) added while

the temperature was kept at 15 ° C. To the i) 3- (N-methylamino) -isocamphane

thick white slurry was added dropwise

a previously prepared cold mixture of 325 ecm of ice 40 to 4.23 l of anhydrous ether in a three-necked vinegar and 360 ecm of concentrated sulfuric acid is added to the flask (121), which is set with a stirrer, reflux condenser. After adding a few ecm at 15 ° C. and adding a dropping funnel, the thick slurry quickly became 78 g, and (2.05 mol) lithium aluminum hydride was added. The rest of the glacial acetic acid-sulfuric acid mixture was gently mixture was added under stirring at 0 to 2 ⁰ C. For the addition, ins- 45 were heated until all the hydride had dissolved, which required a total of about 2 hours. After the hours required.

Addition, stirring was continued for 15 minutes. A solution of 168 g (0.92 mol) dl-3- (N-formyl-

Amino) -isocamphane was then added dropwise over the course of one hour, as described in Example 2, a) Solution of 178 g (1.3 mol) of dl-camphene in hen is prepared, in 181 l of anhydrous 50 ecm of glacial acetic acid was added while the tempe- 50 ether was then over the course of about 1 hour temperature was maintained at about 0 ° C (± 3 ° C). added with stirring. Then the mixture became

The stirring was continued for 2 hours at 0 ^° C .; heated under reflux for about 6 hours, whereupon the reaction mixture turned slightly, slightly cooled, and yellowish-pink with stirring with 347 ecm of water. The cold bath was removed and added, evolving hydrogen. Temperature could rise to 15-20 ° C in about 2-55. Stirring was continued until the precipitate rose for 3 hours. The ice bath was then converted back into a powder that had been sucked off; while maintaining the temperature at about 20 ° C and washing with ether (about 2 liters total), the mixture was gradually diluted with 3 liters of water with vigorous stirring. After the concentrate containing 60 amino) -isocamphane had been concentrated once to 1.6 liters and the dl-3- (N-methylene was stirred well for 1 or 2 hours at room temperature), the oily product was washed twice with about 350 ecm of water and then dried over 500 ecm each and once with 200 ecm chloroform anhydrous sodium sulfate. The dry extracted, and the combined extracts were wet ether concentrate was then washed twice with 500 ecm of water in an ice bath. The chilled; While stirring, a cold, saturated chloroform extract was then neutralized by slowly adding 65 ethereal hydrogen chloride solution, stirring it with 500 ecm of water and gradually adding solid sodium bicarbonate until the mixture reacted acidic against Congo red, until the solution was about 440 ecm more anhydrous with HCl- gas in aqueous phase a _pH value of about 7 had, 0 ° C saturated ether WO were required. After approximately 88 g of NaHCO _{3 were} required. After the precipitation was complete, the white separation was the chloroform layer with 2 x 500ccm 70 crystalline dl-3- (N-methylamino) -isocamphanhydro-

chloride filtered off and washed with anhydrous ether (about 11) until the wash liquid was neutral.

dl - 3 - (N - methylamine ») - isocamphane hydrochloride was air dried at room temperature. 156.5 g of a product were obtained which, in 249 ° C melted with decomposition.

The dl-3- (N-methylamino) isocamphane hydrochloride (156.5 g) was dissolved in 1.5 liters of boiling isopropanol and then allowed to stand at room temperature for about 2 days to crystallize. After filtration the product was washed with a little cold isopropanol (2 × 70 ecm) and washed at room temperature air dried. 104 g of a product were obtained which melted at 249 ° C. with decomposition.

To a cold solution of 25.0 g of dl-3- (N-methylamino) -isocamphane hydrochloride 50 ecm of 2.5 N sodium hydroxide were added to 200 ecm of water. the free base was extracted with 2 x 100 ecm portions of ether. The ether solution was over sodium sulfate dried and obtained 21.0 g of free amine.

A solution of the amine obtained (21.0 g) in 210 ecm acetone was mixed with a solution of 26.5 g of d-camphorsulfonic acid in 200 ecm acetone. The first crop of crystals was filtered off after standing for 2 hours at room temperature. The obtained d-3- (N-methylamino) -isocamphan-d-camphorsulphonate melted at 213 to 214 ° C and had a rotation [α] ²⁵ = + 31.2 ° (c = 2Vo in absolute ethanol). Recrystallization did not increase the specific rotation or the melting point of the salt.

The d-3- (N-methylamino) -isocamphane hydrochloride was prepared by treating the d-camphorsulphonic acid salt with one equivalent of 2.5 N sodium hydroxide, extracting the free base with ether and treating the dried ethereal solution with a solution of hydrogen chloride in ether . After recrystallizing twice from isopropanol, the d-3- (N-methylamino) -isocamphane hydrochloride had a rotation [a] ²⁵ = +20.6 (c = 1.57 in chloroform) and melted at 262 to 264 ° C. with decomposition.

The l-3- (N-methylamino) -isocamphan-d-camphorsulphonate could be obtained from the mother liquors, from which the d-form was separated, by evaporating these solutions under reduced pressure. By converting the salt into the free base and treating the free base with a solution of hydrogen chloride in ether, the 1-3- (N-methyl ami no) -isocamphan hydrochloride was obtained, which could be further purified by recrystallization from isopropanol. A product with [a] ^2J about -20 ° was then obtained.

Example 3
e) 3- (N-butyrylamino) isocamphane

Normal butyryl chloride (16 ecm) became 8.0 g of dl-3-aminoisocamphane in small portions with ice cooling and then 80 ecm 2O% sodium hydroxide solution was gradually added. The mixture was stirred vigorously until the reaction stopped and then at 150 ecm Water diluted. After the reaction mixture had been extracted with 3 × 80 ecm benzene, the combined were Extracts with 2.5 N NaOH (75 ecm), water (2-100 ecm), 2.5N HCl (75 ecm) and again with Washed 3 x 100 ecm of water. After drying the extract and removing the solvent became dl-3- (N-butyrylamino) -isocamphan (melting point 75 to 76.5 ° C).

Analysis for C ₁₄ H ₂₅ NO (molecular weight 223.35):

. Calculated C 75.28, H 11.28, N 6.27%;

found C 75.49, H 11.01, N 6.33%.

f) 3- (N-n-butylamino) isocamphane

ίο To a solution of 2.62 g (0.069 mol) LiAlH ₄ in 150 ecm absolute ether, 7.0 g (0.031 mol) dl-3- (N-butyrylamino) -isocamphane, dissolved in 60 ecm dry ether, were added with stirring, added. After gentle refluxing overnight, the mixture was treated with 13 ml of water and the powdery metal hydroxide mixture formed was filtered off and washed with ether. After washing the ether extract with water (3 x 50 ecm), it was _{dried over anhydrous Mg SO 4} and concentrated to a volume of about 30 ecm. The hydrochloride was then treated with an ethereal H Cl solution (about 8 cc, 3 _H p -value =) precipitated, filtered off and the reaction product washed with ether until it was acid free. After crystallization from 400 ecm of methyl isobutyl ketone, pure dl-3- (Nn-butylamino) -isocamphane hydrochloride, melting at 212.5 to 213.5 ° C., was obtained.

Analysis for C ₁₄ H ₂₁ N-HCl (molecular weight 245.83):

Calculated C 68.40, H 11.48, N 5.70, Cl 14.43%;

found C 68.75, H 11.72, N 5.96, Cl 14.1%.

g) N-ethyl-N-acetyl ^ -amino-dl-isocamphane

N-ethyl-2-amino-dl-isocamphane (19.0 g) became made from the hydrochloride in the usual way and with 76 ecm acetic anhydride and 0.4 ecm concentrated sulfuric acid by heating on a steam bath for 4 hours. To rapid cooling in 600 ecm of water. Filtering and washing were 17.49 g (yield = 75%) N-ethyl-N-acetyl-2-amino-dl-isocamphan obtained. F. = 83.5 to 85 ° C.

Analysis for C ₁₄ H ₂₅ NO (molecular weight 223.35):

Calculated C 75.28, H 11.28, N 6.27%;

found C 75.52, H 11.15, N 6.26%.

h) N, N- (diethyl) -3-amino-dl-isocamphane

N-Ethyl-N-acetyl-2-amino-dl-isocamphane (18.38 g, 0.08 mol) was reduced with LiAlH ₄ (33.4 g, 0.88 mol) in 1000 ecm of absolute ether for 68 hours. The hydrochloride was obtained in an amount of 20.26 g (yield = 100%). F. = 120 to 125 ° C after sintering.

The product was dissolved in boiling benzene (1500 ecm); the solution was concentrated to about 1000 ecm and left to cool to room temperature. 13.00 g were obtained Standing in the drying oven formed a stable hydrate.

Analysis for C ₁₄ H ₀₇ N-HCl-H ₂ O (molecular weight 263.85):

, Calculated H ₂ O 6.8%;

found H ₂ O 9.3% (KF).

Analysis for C ₁₄ H ₂₇ N · H Cl (molecular weight 245.83):

Calculated C 68.41, H 11.48, N 5.66, Cl 14.45%; found C 68.16, H 11.20, N 4.88%.

The anhydrous substance melted at 145 to 147 ° C; the hydrate melted very fuzzy.

Example 4

5 e) 3- (N-3,3-dimethylbutyrylamino) isocamphane

To 6.0 g of dl-3-aminoisocamphane cooled in ice water, a total of 12.0 ecm of tertiary butylacetyl chloride was added in proportions of 3 ecm over the course of about 10 minutes with stirring. A total of 60 ecm of 20% strength NaOH was then gradually added to the thick slurry with thorough stirring. After shaking for 2 to 3 hours, the reaction mixture was diluted with 200 ecm of water and extracted with 3 × 60 ecm of benzene. The benzene extracts were washed with 2.5N NaOH (50 ecm), water (2 x 80 ecm), 2.5 N HCl (50 ecm) and finally with 4 x 70 ecm water. After drying over magnesium sulfate and removal of solvent the crystalline obtained at 106 to 108 ⁰ C melting dl-3- (N-3,3-Dimethyl-butyrylamino) -isocamphan.

Crystallization from hot n-heptane (boiling point 95 to 100 ° C) turned into a pure one at 107 to 108.5 ° C obtained melting product.

Analysis for C ₁₆ H ₂₉ NO (molecular weight 251.40):

Calculated C 76.44, H 11.63, N 5.57%;

found C 76.13, H 11.48, N 5.59%.

f) 3- (N-3,3-dimethylbutylamino) -i socamphan

To a mixture of 6.1 g (0.16 mol) of lithium aluminum hydride in 350 ecm of absolute ether, 6.77 g (0.027 mol) of dl -3 - (N-3,3-dimethylbutyrylamino) - isocamphane dissolved in 80 ecm of ether were added . After refluxing for about 19 hours, the reaction mixture was decomposed by the gradual addition of 30 ecm of water and the inorganic salts were nitrated and washed with ether. The ether filtrate was washed with water (3 x 100 ecm) and dried over magnesium sulfate. After concentration to a small volume, the hydrochloride was precipitated by adding a cold, saturated ethereal hydrogen chloride solution (about 10 ecm) ⁴ S until it became acidic against Congo paper. The precipitated dl-3- (N-3,3-dimethylbutylamino) -isocamphane hydrochloride was nitrated and washed with ether. After crystallization from hot methyl isobutyl ketone, the product melted at 233-234 ° C. with decomposition.

Analysis for C ₁₆ H ₃₁ N-HCl (molecular weight 273.89):

Calculated C 70.16, H 11.78, N 5.12%; «

found C 70.25, H 11.86, N 5.31%.

Both the N-alkyl derivatives of 3-aminoisocamphane and their acid addition salts as well as the quaternary ammonium salts of the tertiary amines are useful new chemical compounds with valuable pharmacological properties. So 3- (N-methylamino) -isocamphane has been found to be a valuable ganglia-blocking agent that the transmission of nerve impulses by both the sympathetic and the parasympathetic Inhibits ganglia of the autonomic nervous system. This compound has been found to be about twice as effective and one has a much longer duration of action than hexamethylene bis (trimethylammonium) bromide. Investigations were carried out on an anesthetized dog after bilateral vagotomy, whereby first, the irritation of the peripheral end of the incised vagus; second, the occlusion of the A. carotid and third, nicotine injection response was observed.

The N-alkyl derivatives of 3-Aminoisocamphan can be used in amounts of 10 to 50 mg per day as a Ganglia blocking agent can be administered both orally and by injection.

For oral administration, the new compounds can be in suitable form such as tablets or capsules containing suitable excipients and conventional bases and by known methods be administered.

In addition to the hydrochloride, other salts of 3- (N-methylamino) -isocamphane can also be used other quaternary ammonium salts of the tertiary aminoisocamphane compounds, such as the chlorine or Bromomethylate or the Methosulfate can be used. Examples of the applicable quaternary Ammonium salts are the iodine methylate of 3- (N, N-dimethylamino) -isocamphane, the chloromethylate of 3- (N, N ~ diethylamino) -isocainphane and methosulphate of 3- (N, N-diisopropylamino) isocamphan.

Claims (4)

PATENT CLAIMS: 1. Process for the preparation of N-substituted 3-Aminoisocamphanverbindungen the general formula CH, CH ₃ CH ₃
CH, in which R is a lower alkyl group and R _{1 is} hydrogen or a lower alkyl group whose salts, quaternary ammonium compounds and optically active isomers, characterized in that camphene is brought into intimate contact with hydrogen cyanide in the presence of an acid, the 3- (N- Formylamino) isocamphane reduced with alkali aluminum hydrides, the 3- (N-methylamino) isocamphane obtained, if desired, aeylated in the usual manner and the 3- (N-methyl-N-acylamino) isocamphane obtained is reduced with an alkali aluminum hydride or the 3- ( N-formylamino) isocamphane hydrolyzed in a known manner with an alcoholic alkali metal hydroxide solution and 1 mol of the 3-aminoisocamphane obtained is treated in a known manner with 1 or 2 mol of a low molecular weight aliphatic aldehyde and hydrogen in the presence of a platinum group catalyst or first aeylated in a known manner and then the 3-N-acylaminoisocamphan obtained with an alkali aluminum hydride red uziert and the N-substituted 3-aminoisocamphanes obtained converted in the usual way into salts or quaternary ammonium compounds or broken down into optically active isomers. 2. The method according to claim 1, characterized in that dl-camphene is used as the starting material used. 15 16 3. The method according to claim 1, characterized in 5. The method according to claim 1, characterized in that the reduction of the 3- (N-acyl is characterized, that one is low molecular weight aliphatic and N-alkyl-N-acylamino) - isocamphane used with tables aldehyde formaldehyde.
Lithium aluminum hydride performs. 6. The method according to claim 1, characterized 4. The method according to claim 1, characterized in that the acylation of 3-Aminoiso is characterized that the acid is sulfuric acid or camphane with acetic anhydride in the presence Sulphonic acids used in glacial acetic acid. carried out by sulfuric acid. © 809 638/433 9.58