NO115783B - - Google Patents

Description

Substituted azacycloalkanes and derivatives thereof.

The present invention relates to cyclic compounds, and more particularly to azacycloalkanes and a process for their production.

The preparation of the compounds includes

ter as a first step alkylation of a 2-aryl-4-dialkylamino-butyronitrile with a polymethylene sulfonic acid ester or halide having from 3 to 8 methylene groups, this reaction being carried out in the presence of a reagent capable of replacing active hydrogen. After the alkylation reaction, the product obtained is cyclized,

an inert solvent with a high boiling point is used. The cyclic compound prepared here can then be hydrolysed and then esterified to give a carb-alkoxy compound, or the cyanazacycloalkane reacted either with an alkyl Grignard or alkyl lithium and then hydrolysed to form an acyl-azacycloalkane, or decyanated and the resulting azacycloalkane is acyloxylated.

The following reactions illustrate the main steps in the process:

In the above steps, reaction (2) probably first forms an azacycloalkane alkanohalogenide, which decomposes as the temperature is increased so that azacycloalkane is formed.

Where it is desirable to have a lower alkyl group in the 2- or 3-position in azacycloal-Icanet, the compounds can be prepared in accordance with the following reaction steps:

In the above formula, R means an aryl radical, especially a substituted or unsubstituted phenyl or benzhydryl radical. Preferred substituents in a ring, which can be in any position and can be from one to three, are lower alkyl, lower alkoxy, halogen, nitro, hydroxy, aliphatic acyl and acyloxy, amino and mono and di-lower alkyl substituted amino radicals.

The radicals R, and R2, which can either be the same or different from each other, mean lower alkyl and preferably alkyl with from 1 to 4 carbon atoms. The radicals R 3 and R 1 can be either methyl or ethyl groups. With respect to the dihalide-alkane reagents, the term "halo" is intended to mean chlorine, bromine, or iodine. It should be noted that both halogen groups can be the same, i.e. both mean e.g. bromine, or they can be different, i.e. one can e.g. mean bromine and the other e.g. chlorine. The radical R4 means either hydrogen, - COO. lower alkyl, - CO . lower alkyl, - CONH2, - COOH or - O - CO . lower alkyl with an alkyl group preferably having no more than three carbon atoms.

The designation n is intended to mean a whole number, from 1-6.

For reaction (1), the starting compounds are reacted in the presence of a reagent capable of replacing active hydrogen, preferably an alkali metal amide such as sodium, potassium or lithium amide, although phenyl-sodium, phenyl-lithium can also be used or butyl lithium. The reaction is carried out in the presence of a solvent which can either be ethyl ether or an aromatic hydrocarbon, such as benzene, toluene or xylol. To obtain the best results, substantially anhydrous conditions should be used and, although not necessary, an inert atmosphere, such as nitrogen gas, is desirable for the reaction. The reaction proceeds easily at ordinary temperatures and, although room temperature or a temperature from approx. 10° to 35° C, you can operate in a larger area from approx.

— 10° C to approx. 50°.

After the alkylation reaction, the azacycloalkanes are produced by a cyclization reaction which is carried out by heating the alkylated product in the range from approx. 200—approx. 250° C. If desired, an inert organic solvent can be used, such solvents being selected with a boiling point range within the specified temperature range, under reflux cooling. Tetralin, nitrobenzene, and especially the higher alcohols have been found to be effective.

The alcohols, such as n-decyl alcohol, trimethyl-nonyl alcohol and 5-ethyl-2-nonyl alcohol are particularly suitable as solvents during reflux cooling.

When the cyclic aminonitriles have been prepared, these can either be hydrolysed to an acid and then esterified, or they can be changed to an acyl group by alkyl lithium or an alkyl Grignard followed by hydrolysis. To form acid esters, the aminonitrile is hydrolyzed under either acidic or alkaline conditions. For acid hydrolysis, any strong acid can be used, such as syrupy phosphoric acid, concentrated hydrobromic acid, etc., although 80-95 percent sulfuric acid is preferred. Alkaline hydrolysis is also useful and, as an example, potassium hydroxide in an alkylene glycol will give the desired product. The hydrolysis reaction can be carried out at a temperature of approx. 100— 150° C with a more preferred range of approx. 110-120° C.

The produced cyclic acid or salt, obtained as a product of the hydrolysis step, is then esterified using a substantially anhydrous lower aliphatic alcohol, preferably one having no more than three carbon atoms and, more preferably, ethyl alcohol is used. The final cyclic ester can be prepared by concentrating the esterification reaction mixture, neutralizing with an aqueous alkaline solution and extracting the free base with a selective solvent and finally distilling off the solvent.

To form acyl-azacycloalkanes, the nitrile is dissolved in absolute ether and this solution is added to R4. MgBr or Rr, . Li i' absolute ether. R 4 is the same radical as indicated above. An immediate reaction occurs. The addition reaction is completed by heating on a steam bath and, if necessary, by replacing the ether with toluene. The reaction mixture is poured onto ice in the presence of hydrogen chloride which is heated slightly to hydrolyze the imino compound formed as an intermediate. The acylase-cycloalkane product is then in the aqueous layer and is obtained by separating the two Hag, and making the aqueous layer alkaline and extracting with ether. The ether extract is then distilled to obtain the desired product.

In the preparation of azacycloalkanes which have a lower alkyl group in the 2- or 3-position in the ring, one can start from 1- or 2-.alkyl-2-haloethane and carry out the steps as shown in reactions (4) to (8).

The starting compound, whether it is 1- or 2-alkyl-2-halogenethane, is reacted with the nitrile R - CH 2 CN essentially in the manner described for reaction (1). A mixture of two aminonitriles is formed. A further alkylation step, which is identified as reaction (5) but by using a halogenated alkyl compound as reactant, is carried out in a similar manner to reaction (1). This gives an alkylated mixture which is then subjected to cyclization.

The cyclization of the alkylated product shown in reaction (6) provides a useful cyclic compound as a precipitate and a liquid fraction which can later be readily processed to form another cyclic compound. It has been found that when a mixture containing 1-alkyl-1-tertiary-amino-haloalkyl-cyanide is heated in the presence of a highly polar organic compound having a relatively high dielectric constant or dipole moment, a cyclization of the aminohaloalkane takes place which results in the formation of a cyclic quaternary ammonium compound which is precipitated from the reaction. The temperature for the reaction can vary from approx. 70°—approx. 120° C, a preferred temperature being close to 100° C.

The preferred method for carrying out cyclization reaction (6) comprises dissolving the aminonitriles in the polar solvent so that a solution of approx. 0.1-5.0 mol per litres, and then the mixture is heated until no more salt is precipitated. If desired, one can use, in addition to the polar solvent, any solvent which will make the reaction product less soluble in it. Thus hydrocarbon solvents such as heptane, benzene, toluene, xylol etc. have been found to be suitable for mixing with a polar solvent. While the preferred dilution in the solvent is about 1.0 mol per liter or in the range indicated above, satisfactory results can be obtained with a dilution as strong as 0.01 mole or thereabouts. While it has been suggested that the proper concentration of the alkylation product in the solvent or solvents can only be prepared and heated, the reaction can also be carried out by heating the solvent and adding the alkylation product in small amounts. It has been found that in high concentrations, such as approx. 5.0 mol or greater, the reaction yields are excellent, but the quality of the product is poor, while at low concentrations, such as 0.001 mol or lower, the quality of the product becomes good, but the yields are so low as to make the process uneconomical .

The polar solvent chosen has been found to be an important factor

in the cyclization process as illustrated by reaction (6). It was discovered that strongly polar solvents gave very satisfactory results, as such solvents have a dipole moment under standard conditions (20° C) of approx. 2.5 to approx. 4.5 de-bye units or something less. The dielectric constant should have a value (epsilon) above 10 and preferably of approx. 15-40 measured under standard conditions. The solvent chosen should also have a boiling point above 70° C. Examples of strongly polar solvents include nitrobenzene, ortho-nitrotoluene, benzonitrile, 2-nitropropane and solvents of a similar nature.

The method for cyclization of 2-alkyl haloalkane cyanides comprises the use of an inert solvent with a high boiling point and that these nitrile compounds are reacted under reflux cooling conditions in the range from approx. 150° to approx. 300° C. Higher alcohols, such as undecanol, are preferably used, although mineral oils such as heavy naphtha or kerosene are also effective. At approx. 150° C. it is assumed that the corresponding quaternary ammonium compound is formed, and as heating progresses, alkyl halide is released, which suggests the formation of azacycloheptane.

To prepare the azacycloalkanes from

the quaternary salt, the latter is cleaved to remove the alkyl halide. This cleavage reaction is carried out by heating the quaternary salt in the range of approx. 200 to approx. 250° C. If desired, an inert organic solvent can be used, such a solvent being selected with a boiling point range within the reaction temperature range indicated and under reflux cooling conditions. The higher alcohols have been found to be particularly effective, although mineral oils such as heavy naphtha or kerosene can also be used. The mentioned alcohols are partial solvents

clay for the quaternary salt as well as for the reaction product.

When the cyclic reaction product remains in solution in the solvent, it can be removed by a solvent extraction process. For this step, the reaction mixture is extracted with a concentrated mineral acid in aqueous solution which is separated and washed. The washed extract is now made alkaline and is then extracted with solvents, using ether or another solvent in which the free base is soluble. The latter can then be isolated by distilling off the solvent.

After the preparation of the cyclic aminonitrile, the latter can then be treated as indicated above to introduce a -COO. lower alkyl or - CO . lower alkyl in the 4-position instead of the cyano radical.

The following procedures are used if

it is desirable to introduce a - CONH2 or COOH radical instead of the cyano group, or if one wishes to remove the last substituent.

To prepare a 4-aryl-azacycloheptane, a 4-azyl-4-cyano-azacycloheptane is heated with an alkali metal amide such as a sodium, potassium or lithium amide in the presence of an inert organic solvent

of the aliphatic type such as hexane or

higher, or of the benzol type, such as benzol, toluene or xylol. The reaction will take place in the area of approx. 50° to approx. 150° C. A preferred temperature range for the operation is in the vicinity of 90° to 110° C.

Another method for the preparation of 4-aryl-azacycloheptanes comprises hydrolyzing the corresponding cyano-form bond to form 4-amido-azacycloheptane, after which this is reacted with an Al-I potassium metal hydroxide which first forms the carboxylic acid salt of the alkali metal followed by decarboxylation to the desired connection. This step-by-step procedure is first carried out at approx. 190°C to form the amide, with the temperature increased near ca. 250° C for the final step. If only the final product is sought, and intermediate products are not desired, the reaction can be carried out by simply heating the cyano compound with the hydroxide and water between approx. 200° to 300° C.

The amide in relatively pure form can be prepared by reacting the 4-cyano base with a higher alcohol and base, such as KOH at a temperature in the vicinity of 160° C. Such alcohols as heptanol or octanol are suitable for the reaction. Naturally, lower alcohols such as methyl alcohol can be used if operating under pressure.

To produce carboxylic acid compounds, the above-mentioned method can be followed, but operating at a temperature above 160° C, namely in the vicinity of 200° C.

The synthesis of the 4-acyloxy compounds is carried out by heating the selected 4-aryl-1-lower-alkyl-azacycloalkane with a tetravalent lead salt of a lower aliphatic acid in the presence of the corresponding acid at a temperature of approx. 100° C. A preferred salt and acid is lead tetraacetate and acetic acid.

The following examples illustrate in more detail methods for producing typical compounds according to the invention.

Example 1:

Preparation of 4-carbethoxy-4-phenyl-1-methyl-azacyclooctane and salts thereof.

A solution of 0.75 mol (141 g) of 2-phenyl-4-dimethylaminobutyronitrile in 300 ml of ether was added dropwise to 0.90 mol (35.1 g) of sodium amide suspended in 700 ml of ether. The operations were carried out at 30° C. under a nitrogen atmosphere with stirring. The mixture was refluxed for two hours, then cooled to -30°C. A solution of 0.89 mol (153 g) of tetramethylene chlorobromide in 300 ml of ether was added dropwise at -25° to -20°C. On completion of the addition, the temperature was gradually raised to room temperature, and the mixture stood overnight. The precipitated inorganic salts were filtered off and the ether distilled from the filtrate under vacuum. The liquid residue contained 1-dimethylamino-3-cyano-3-phenyl-7-chloroheptane.

1 liter of trimethylnonanol was added to the residue, and the resulting solution was added dropwise to 1 liter of stirred trimethylnonanol which was boiled with a reflux condenser (boiling point 225° C) during 1.5 hours. The solution was stirred and boiled with a reflux condenser for an additional two hours and then cooled under a nitrogen atmosphere. Dilute hydrogen chloride was used to extract the amine. The acid extract was washed with ether, then basified with sodium hydroxide solution and extracted with ether. The ether extract was dried, filtered and evaporated to give a red viscous syrupy residue. The product obtained was 3-cyano-3-phenyl-1-methyl-azacyclooctane which was distilled off

- from a large mass of resinous material at 140—160° C (0.3—0.4 mm). Repeated distillation gave a yellow liquid, b.p

27 27

130—134° C (0.3 mm) nD 1.5270, d 4 1.010

Analytical calculated for C15H20N2<:> C, 78.90;

H, 8.82; N, 12.75; MD 69.54.

Found: C, 79.06; H, 9.32; N, 12.57; MD 69.48. The picrate, melting point 158-159° C, was formed in acetone-methanol.

Analytical calculated for C2lH,,3H5O7 : C,

55.18; H, 5.07; N, 15.32.

Found: C, 55.33; H, 4.89; N, 15,13.

A mixture of 0.04 mol (9.1 g) of the cyanocyclic base, 10.6 g of 98% sulfuric acid and 2.6 g of water was heated to 115-130° C. for three hours. The mixture was cooled slightly, and 75 ml abs. ethanol was added and the mixture refluxed overnight. The alcohol was distilled off at atmospheric pressure, the cooled residue entirely in an ice-cold saturated aqueous sodium carbonate solution, then extracted with ether. The ether extract was dried, filtered and distilled to give the compound 4-carbethoxy-4-phenyl-1-methyl-azacyclooctane,

boiling point 130—133° C (0.3 mm), n 261.5215,

d 2^ 1.042.

Analytical calculated for C17H250.,N:C, 74.18;

H, 9.15; N, 5.08; MD 80.70.'

Found: C, 74.07; H, 9.06; H, 5.64; MD 80.68. The methiodide, m.p. 165-167° C. during decomposition was formed in a mixture of acetone and ether.

Analytical calculated for ClgH2S0., NJ : C,

51.82; H, 6.76; N, 3.36; J,' 30.5. Found: C, 51.92; H, 6.86; N, 3.09; J, 30.5.

Example 2:

Preparation of 4-carbethoxy-4-phenyl-l- methyl-azacycloheptane.

Reaction (1) was carried out in a manner in ;

similar to what is indicated in example 1, 1 first paragraph, but in that trimethylene bromide was used as the halide reagent and in that the molar ratios were kept essentially the same. The product obtained was 1-dimethyl-amino-3-cyano-3-phenyl-6-bromohexane. This product was then cyclized as indicated in the above example to give 4-cyano-1-methyl-4-phenyl-azacycloheptane, bp 132—

136/0.35 mm, picrate, melting point 174— 175° C.

A solution of 8.4 g (0.04 mol) of the 4-cyano compound in 10.6 g of concentrated sulfuric acid and 2.6 g of water was kept at 110-120° (bath temperature) for three hours. Then, while repeatedly adding abs. ethanol, 95 per cent aqueous ethanol was slowly distilled off over the course of 16 hours. The reaction mixture was concentrated to 50 cm 3 , cooled, poured into 200 ems of a cold saturated aqueous solution of sodium carbonate and extracted with ether. The ether extract, after drying and filtration, gave by distillation the desired 4-carbethoxy compound, boiling point 122— 124°/0.3 mm nD26° = 1.5210; d2«° = 1.038,

Mn (calculated) = 76.1, MD (observed»

= 76.9.

Analytical: Calculated for CHiH230.,N : C,

73.51; H, 8.86; N, 5.36.

Found: C, 73.66; H, .8.89; N, 5.67.

Picrate, Melting point 169—170°/acetone-methanol.

Analytical: Calculated for CooH.^O,,!^ : C,

53.90; H, 5.35; N, 11.43.""

Found: C, 54.18; H, 5.39; N, 11.41. Hydrochloride, melting point 139—141°/diisopropyl ketone ether.

Analytical: Calculated for CHi H040„NC1 : C,

64.55; H, 8.12; N, 4.71; Cl, 11.91? Found: N, 4.94; Cl, 12.4; C, 64.15; H, 8.41.

Example 3:

Preparation of '4-carbethoxy-1,2-dimethyl-4-phenyl-azacycloheptane and salts thereof. A solution of 1.43 mol (167.6 g) of phenylacetonitrile in 250 ml of toluene was added with 1.29 mol (50.3 g) of sodium amide at such a rate that a temperature of 35-40° was maintained. The addition was carried out under a nitrogen atmosphere with stirring. After an additional two hours at 35-40°, the mixture was cooled to 5°. A dry toluene solution of 1-dimethylamino-2-chloropropane, prepared on the same day from 1.23 mol (193 g) of the hydrochloride and 1.37 mol (54.6 g) sodium hydroxide in 500 ml of water and 250 ml of toluene, was then added dropwise at 5-10°. This temperature was maintained for an additional hour and then allowed to rise to room temperature and stand overnight. The mixture was washed with water, extracted with 6n-hydrochloric acid, the acid extract washed with ether, basified and extracted with ether. The ether extract was dried, filtered and distilled. A mixture of the isomers of butyronitriles boiled at 95-98° (0.2 mm), 28 n D 1.5028. A stirred solution of 0.85 mol (172.8 g) of a mixture containing 4-dimethylamino-3- and 4-methyl-2-phenyl-n-butyronitrile in 1.2 L toluene under a nitrogen atmosphere was portionwise added 1.09 mol (42.6 g) of sodium amide. The rate of addition was controlled so that a temperature of 35-40° was maintained. This temperature was maintained for an additional two hours. The red solution was cooled to -30° in a dry ice-acetone bath and 0.898 mol (141.3 g) of trimethylene chloride bromide in 250 ml of toluene was added at such a rate as to maintain a temperature between -25° and -15°. This temperature was maintained for an additional 1/2 hour, and then the stirred mixture was allowed to warm to room temperature and stand overnight. The mixture was filtered and the toluene distilled off from the filtrate at 30-35° (35 mm). The liquid residue contained a mixture of 1-dimethylamino-1- and 2-methyl-3-cyano-3-phenyl-6-chloro-hexane.

The liquid residue from the previous step was diluted to 850 ml with nitrobenzene, and the resulting solution was heated to 100° for 17 hours to precipitate the quaternary salt. The cooled mixture was filtered and the precipitate washed several times with acetone to give substantially pure 2-methyl-quaternary salt with melting point 251-215.5° during decomposition. Recrystallization from ethanol gave fine white crystals of 4-cyano-1,2-dimethyl-4-phenyl-azacycloheptane methochloride m.p. 259° during decomposition. The filtrate was kept for the preparation of 3-methylazacycloalcan.

Analytical calculated for CH;H.,.,CIN., : C,

69.00; H, 8.32; N, 10.05; cT,' 12.70.

Found: C, 68.46; H, 8.73, N, 10.29; Cl, 12,14.

The filtrate from the quaternary salt contained 2-methyl-chloro-hexane unchanged.

0.378 mol (105.7 g) of 2-methyl quaternary was suspended in 378 ml of undecanol (boiling point 225°). The mixture was heated to reflux temperature with stirring, after which the solid was dissolved with evolution of methyl chloride gas. The stirring and boiling with reflux cooling was continued until the evolution of gas was negligible. The solution was cooled under nitrogen and extracted with 6n-hydrochloric acid. • The acid extract was washed with ether, made basic, extracted with ether, the ether extract dried, filtered and the solvent removed.

Distillation of the liquid residue gave 4-cyano-1,2-dimethyl-4-phenyl-azacyclo-27 heptane, b.p. 123-126° (0.2 mm), nD

97

1.5341, d 4 1.019.

Analytical calculated for C,rH2(lN2 : C, 78.90;

H, 8.83; N, 12.27; M„ 69.54.

Found: C, 78.50; H, 8.87; N, M„ 69.40.

Picrate, melting point 199—202° below

decomposition was prepared in methanol.

A mixture of 64.0 g (0.28 mol) of the 1,2-dimethyl-cyano base, 84.0 g of 98% sulfuric acid and 19.8 ml of water was heated at 115-120° for 3 hours. After some cooling, 375 ml abs were added. ethanol and the mixture was refluxed for 24 hours. The alcohol was distilled off at 760 mm, then the cooled residue was poured into ice-cold saturated sodium carbonate solution and extracted with ether. The ether extract was dried, filtered and the solvent removed.

Vacuum distillation of the liquid residue gave 4-carbethoxy-1,2-dimethyl-4-phenyl-azacycloheptane, boiling point 122-124°

(0.25 mm), n^<6> 1.5207, d^<6> 1.035.

Analytical calculated for C17H2rjN02 : C,

74.15; H, 9.15; N, 5.09; Mn 80.68. Found: C, 74.69; H, 9.31; N, 5.92, M„ 80.92.

The picrate, melting point 177-178°, was prepared in methanol-ether.

Analytical calculated for C,)oHMSN4Ol, : C,

54.70; H, 5.59, N,' 11.10."

Found: C, 54.68; H, 5.72; N, 11.63.

The hydrochloride, melting point 145—146.5°,

was prepared by passing an equivalent weight of dry hydrogen chloride gas into a solution of 1 g of base in 2 ml of n-butyl acetate and 1 ml of ether. Crystals were precipitated after the solution had been kept at 5° C. for 24 hours. Analytical calculated for C17H2(iClNO., : C, 65.50; H, 8.41; N, 4.49; Cl, 11.37.

Found: C, 65.30; H, 8.44; N, 4.36; Cl, 11.36.

The acid sulphate, melting point 110—114°,

was prepared by adding 0.12 mol of sulfuric acid to a solution of 0.10 mol of base in 50 ml of methyl isobutyl ketone and 50 ml of ether at 5° C. The salt that precipitated was recrystallized from methyl isobutyl ketone.

Analytical calculated for C,7H.>7NO,;S: C, 54.68; H, 7.29; N, 3.75; S, 8.58.

Found: C, 54.64; H, 7.21; N, 4.04; S, 8.50.

Sometimes one only wants solutions of the salts when the isolation of a solid product is undesirable. Solutions of the organic acid addition salts were prepared by adding the base to an equivalent amount of the desired acid in water or water-alcohol mixtures.

Example 4: 4-carbo-isopropoxy-1,2-dimethyl-4-phenylazacycloheptane and salts thereof.

32.0 g (0.14 mol) of 4-phenyl-4-cyano-1,2-dimethyl-azacycloheptane was added to a cooled mixture of 42.0 g of 98% sulfuric acid and 9.9 ml of water. The mixture was heated in an oil bath for 3 hours at 110-120° C (most at 120° C).

After cooling to 80-90° C, this product was mixed with 187 ems of isopropyl alcohol and refluxed for 24 hours. At the end of the boiling period, most of the alcohol was distilled off, and 187 ems of isopropyl alcohol was added, and this was also distilled off. It was ensured that not all the alcohol was distilled off, as a very small amount remained, so that the remaining liquid would not be overheated.

The remaining liquid was cooled and poured into an excess of a saturated sodium carbonate solution. The product was extracted three times with ether, all the ether extracts were dried over anhydrous potassium carbonate, filtered and the ether removed at 250 mm.

Final purification by vacuum distillation gave the final product as a colorless liquid, boiling point = 118—120° C/0.25

mm nD = 1.5160, d 4 = 0.999, MD (calculated) = 87.03.

The picrate, melting point = 193-194° C during decomposition, was prepared in methanol-ether.

Example 5:

Preparation of 4-carbethoxy-1,3-dimethyl-4-phenylazacycloheptane and salts thereof.

The filtrate from the preparation of the cyclic quaternary salt, obtained as described in Example 3, was extracted with 6n-hydrochloric acid. The acid extract was washed with ether, basified with 4n sodium hydroxide solution and then extracted with ether. The ether extract was dried over anhydrous potassium carbonate, filtered, and the ether was distilled off. The liquid residue contained 2-methylchlorohexane. It was diluted to 1.16 L with undecanol. This solution was added dropwise to 580 ml of stirred undecanol (boiling point 225°), which was kept under reflux cooling. Methyl chloride was developed. The stirring and boiling under reflux was continued until gas evolution was negligible. The solution was cooled under nitrogen and then extracted with 6n-hydrochloric acid. The acid extract was washed with ether, basified with 4n sodium hydroxide solution and then extracted with ether. The ether extract was dried over anhydrous potassium carbonate, filtered and the ether distilled off. Vacuum distillation of the liquid residue gave substantially pure 4-cyano-1,3-dimethyl-4-phenyl-azacycloheptane, boiling point 117-120° (0.25

mm), nD 1.5330, d ° 1.016.

Analytical calculated for Cir,H20N2:C, 78.90;

H, 8.83; N, 12.27; MD 69.54.

Found: C, 78.41; H, 8.89; N, 11.65; MD

69.80.

A mixture of 29.7 g (0.13 mol) of a 1,3-dimethyl-cyanobase, 39.0 g of 98% sulfuric acid and 9 ml of water was heated at 115-120° for three hours. After some cooling, 175 ml of absolute ethanol was added and the mixture was refluxed for 24 hours. The excess of alcohol was distilled off at 760 ml, the cold residue completely in an ice-cold saturated solution of sodium carbonate and the mixture extracted with ether. The ether extract was dried over anhydrous potassium carbonate, filtered, the ether removed and the liquid residue vacuum distilled to give 3-methyl-ethyl ester, b.p. 119-121° (0.25 mm), n ^' 1.5202, d ^

1.045.

Analytical calculated for e17HQ5N02 : C,

74.15; H, 9.15; N, 5.09, Mp" 80.68. Found: C, 74.26; H, 9.01; N, 5.63; MD 80.40.

The picrate, melting point 160-162°, was prepared in isopropanol. Analytical calculated for C2SH08N40,, : C, 54.70; H, 5.59; N, 11.10. Found: "c, 54^66; H, 5.51; N, 11.37.

The hydrochloride, m.p. 197-199° during decomposition, was prepared in methyl isobutyl ketone and recrystallized from acetone. Analytical calculated for Cl7H2(iClNOo : C,

65.50; H, 8.41; N, 4.49; Cl, 11.37.

Found: C, 65.28; H, 8.60; N, 4.60; Cl, 11.87.

The 3-methyl ethyl ester could be further purified using its hydrochloride, which was relatively insoluble in cold methyl isobutyl ketone compared to the analogous 2-methyl compound, which was readily soluble in the same solvent.

Example 6:

Preparation of 1-methyl-4-phenyl-azacycloheptane and salts thereof.

A mixture of 0.05 mol (10.7 g) 4-cyano-1-methyl-4-phenylazacycloheptane and 0.11 mol (4.3 g) sodium amide in 100 ml toluene was refluxed while stirring for 6 hours. The cooled mixture was washed with water, then the toluene layer was extracted with acid, the acidic extract washed with ether, treated with sodium hydroxide and the reaction product extracted with ether. The ether extract was dried, filtered and distilled. The product, 1-methyl-4-phenyl-azacycloheptane was collected at 88-90° (0.25 mm); n £> 1.5288.

Analytical calculated for CnH„N : C, 82.47;

H, 10.12; N, 7.40.

Found: C, 82.20; H, 10.41; N, 7.51.

The picrate, melting point 149-150° C, was prepared in methanol.

Analytical calculated for CiyH22N407 : C,

54.55; H, 5.30; N, 13.38.

Found: C, 54.52; H, 5.03; N, 13.20.

0.1 mole (3.6 g) of hydrogen chloride gas was introduced into 50 ml of a cold 1:1 ether-acetone solution containing 0.1 mole (18.9 g) of the base. The precipitated hydrochloride was filtered off and washed with ether. It could be further purified by recrystallization from methyl ethyl ketone so that it gave a fine if solid, melting point 78-79° C.

0.1 mole (14.2 gm) of methyl iodide was slowly added to a cold acetone solution containing 0.1 mole (18.9 g) of the base. The mixture was kept at 25° for three hours, then the precipitated white solid was filtered from and washed with acetone, m.p. 146-147° C. of 1-methyl-4-phenyl-azacycloheptanemethodide.

0.1 mole (17.0 g) of isopropyl iodide was added to an ether solution containing 0.1 mole (18.9 g) of the base, and the mixture was allowed to stand at room temperature for 2 days. The precipitated yellowish solid was filtered off and washed with ether; melting point 166-169° C for 1-methyl-4-phenyl-azacycloheptane-isopropiodide.

It is clear that other salts as well as the quaternary ammonium compounds can be prepared by following the methods indicated above. In addition to the aforementioned salts, the corresponding salts can thus be prepared by reacting the free base with hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid or other inorganic acids, as well as the lower aliphatic acids such as acetic acid, propionic acid, lactic acid etc. for other quaternary salts, different alkyl halides of lower and higher type can be used, such as lauryl bromide or chloride, where it is desirable to have an alkyl group with a long chain in the base moiety.

Example 7:

In the same way as indicated in example 6, starting from 0.05 mol (11.4 g) 4-cyano-1,2-dimethyl-4-phenylazacycloheptane, the free base 1,2-dimethyl- 4-phenyl-azacycloheptane, boiling point 106-108°

C (0.2 mm), n ^ 1.5255.

Analytical calcd for C 2 H 2 N : C, 82.65;

N, 10.40; N, 6.88.

Found: C, 82.25; H, 10.35; N, 6.66.

The picrate, melting point 128-130° C, was prepared in methanol-ether.

Analytical calculated for C20H24N4O7 : C,

55.60; H, 5.59; N, 12.95.

Found: C, 55.35; H, 5.58; N, 12.70.

Example 8:

By following the procedure stated in example 6 and starting from 0.05 mol (11.4 g) of 4-cyano-1,2-dimethyl-4-phenylazacycloheptane, the product obtained is 1,3-dimethyl-4 -f enylazacycloheptane with a boiling point of 98—100° C (0.25 mm),

n ^ 1.5251.

Analytical calculated for C14H91N: C, 82.65;

H, 10.40; N, 6.88.

Found: C, 82.06; H, 10.35; N, 6.60.

The methiodide, melting point 184-190°C, was prepared in acetone. Analytical calculated for <C>15H24NJ: C, 52.20; H, 7.00; N, 4.06;

J. 36.75.

Found: C, 51.86; H, ^.14; N, 3.72; J, 36.4.

Example 9:

A mixture of 0.03 mol (6.4 g) of 4-cyano-1-methyl-4-phenylazacycloheptane, 0.12 mol (6.8 g) of potassium hydroxide, and 0.06 mol (1.1 g) of water was heated in an air bath at 200-300° C under partial vacuum (approx. 200 mm) for 45 minutes. The crude product was distilled directly from the mixture at 15-20 mm. On recrystallization, 1-methyl-4-phenyl-azacycloheptane was obtained, bp 92 24 -94° C (0.3 mm), nD 1.5301. The picrate, with a melting point of 148-149° C, was prepared in methanol and recrystallized from aqueous acetic acid. No depression of the melting point was observed when mixing with the picrate of the product obtained according to Example 6.

Example 10:

Preparation of 4-carbamyl-4-phenyl-1- me ty 1 - azacycloheptane.

A mixture of 0.030 mol (6.4 g) 4-cyano-4-phenyl-1-methyl-azacycloheptane

was dissolved in 75 ml of heptanol-2 containing 0.035 mol (2.0 g) of potassium hydroxide. The solution was heated to boiling under reflux (157-160° C) with stirring for 2 hours. The cold mixture was extracted with acid, the acid extract was washed with ether, reacted with sodium hydroxide and the ether extracted. The ether extract was dried, filtered and concentrated. A liquid residue was obtained which

began to crystallize after standing overnight. Extraction with n-hexane accelerated the crystallization. The white crystals were filtered off and washed with n-hexane so that it gave 4-carbamyl-4-phenyl-1-methylazacycloheptane monohydrate with a melting point of 95-96°C.

Analytical calculated for C14H20N9O. H 10 : C, 67.15; H, 8.86; N, 11.20.

Found: C, 67.11; H, 8.87; N, 10.76.

Example 11:

Preparation of 4-carboxy-4-phenyl-1- methylazacycloheptane.

0.03 mol cyanobase is dissolved in 0.06 mol KOH for approx. 100 ml of methanol. The material is heated to around 200° C under pressure. The mixture is cooled and reacted with 0.03 mol of concentrated sulfuric acid. Potassium sulphate is precipitated, and this is filtered off. 0.015 mol of sulfuric acid is added to the filtrate, and the solution is concentrated to a small volume. It is then diluted with acetone, and the sulfate salt of 4-carboxy-4-phenyl-1-methyl-azacycloheptane crystallizes out, melting point 250-251° C (during decomposition). Analytical calculated for C, 4H, C)N09 .1 /2H2S4

: C, 59.52; H, 7.14; N, 4.96; S, 5.68.

Found: C, 59.27; H, 7.30; N, 5.00; S, 5.30.

The compounds described above are useful for the preparation of other cyclic compounds which have special functional groups in the 4-position next to the aryl group. The compounds prepared as described in examples 6-9 will thus, when brought to react with lead tetra-acetate or higher aliphatic acid salt at approx. 100° C in the presence of acetic acid or higher corresponding carboxylic acids result in the addition of an acyloxy radical in the 4-position of the ring.

Example 12: 4-acetoxy-4-phenyl-1-methylazacyclo heptane and salts thereof.

0.30 mol of 4-phenyl-1-methylazacycloheptane is dissolved in 300 ml of acetic acid. The temperature in the solution is raised to 80° C. Under mechanical stirring, 0.33 mol of lead tetraacetate is added in portions so that a temperature of 80-85° C is maintained. Carbon dioxide and an aliphatic carbon-hydrogen gas are evolved. The temperature is maintained for an extra half hour, then the acetic acid is removed under reduced pressure. The cooled residue is treated with sufficient ice-cold sodium sulfate solution to precipitate

all lead as PbS04. The filtrate is made alkaline with ice-cold sodium carbonate solution, then extracted repeatedly with chloroform. The combined chloroform extracts are dried over anhydrous potassium carbonate, filtered, and the solvent distilled off. When the residue is distilled under reduced pressure, a portion of unreacted starting material is obtained as a result, boiling point 95-100° C (0.3 mm). This is followed by a fraction with a higher boiling point, boiling point 147-152° C (0.3 mm),

n ^ 1.5279, containing the product.

The picrate, melting point 183-183.5° C, during decomposition, is prepared in methanol-ether and recrystallized from acetone-methanol.

Analytical calculated for C.)1H.)4N4Oy : C,

52.95; H, 5.08.

Found: C, 53.18; H, 5.36.

The methiodide, melting point 218-219° C during decomposition, is prepared in a mixture of acetone and ether.

Analytical calculated for CUiHo4JNO(, : C,

49.37; H, 6.21; N, 3.60; J, 32.6".

Found: C, 49.38; H, 6.54; N, 3.38; J, 32.6.

Example 13: 4-acetoxy-4-phenyl-1,2-dimethyl- azacycloheptane.

Starting from 1,2-dimethyl-4-phenylazacycloheptane, the acetoxy group is introduced in an analogous manner to that described above. Fractional distillation of the residue gives, as previously mentioned, pre-reacted starting material, boiling point 95-100° C (0.3 mm). This is followed by a higher-boiling fraction, boiling point 138—

148° C (0.3 mm), nD 1.5296, containing the product.

The methiodide, melting point 60-65° C during decomposition, is prepared in ether and is very hygroscopic.

Example 14. 4-Propionoxy-4-phenyl-1,3-dimethylazacycloheptane.

0.30 mol of 4-phenyl-1,3-dimethylazacycloheptane is dissolved in 300 ml of propionic acid. By

80-85° C, 0.33 mol of lead tetrapropionate is added in portions while stirring. Half an hour after complete addition, the propionic acid is removed under vacuum. The cooled residue is treated with sufficient ice-cold aqueous Na 2 SO 4 solution to precipitate all lead as PbSO 4 . The filtrate is made alkaline with ice-cold aqueous Na2COa, and then extracted with CHC13. The chloroform extract is dried, filtered and concentrated. Vacuum distillation of the residue gives, after a course of unreacted starting amine, the product as a high-boiling liquid.

Example 15: 4-acetoxy-4-phenyl-1,3-dimethyl- azacycloheptane. Starting from 1,3-dimethyl-4-phenylazacycloheptane, the acetoxy group is introduced in an analogous manner as described above. Fractional distillation of the residue yields a portion of unreacted starting material with a boiling point of 95-100° C (0.3 mm). This is followed by a high-boiling fraction, bp 142-152°C 27 5 (0.3 mm), nD ' 1.5242, containing the product.

The metiodide, melting point 95-97° C, was prepared in ether.

Analytical calculated for C17H9(iJNO, : C, 50.61; H, 6.50; N, 3.47. Found: C, 50.82; H, 6.85; N, 3.50. '

In the same way, using lead tetra-isobutyrate with isobutyric acid, or higher lead salts with corresponding acids, other acyloxy compounds can be prepared.

Compounds of the 4-acyl type having the formula were prepared

in the manner described above, the table giving typical compounds of this class and characteristic data.

The azacycloalkanes have many uses

shares. An important application is when

the formation of aliphatic quaternary compounds

species with long chains that can be prepared in a known manner by allowing the cycloalkanes to react

gers with long-chain aliphatic halides having from 8 to 18 carbon atoms,

such as lauryl bromide, as the reaction temperature is in the range from approx.

50—150° C. Another use of these alkyl-enimine compounds is in their ability to combine with penicillin so that it

ner salts of these, as this progress

method is useful in the purification of penicillin and even in the preparation of therapeutically valuable penicillin salts. In addition, it has been found that at least one series of azacycloalka-

ners that are formed, especially azacyclohepta-

ner, have valuable pharmacological effects

ger and it is noted an unexpectedly good an-

algesic effect. The above-mentioned usability applies equally to the free bases and their acid addition salts.

Where it is desirable that the aryl radicals comprise one or more hydroxy substituents

ter in the ring, in the reactions described above, corresponding alkoxy-substituted compounds must be used as reaction

funds. After the alkoxy-substituted aryl-cyano-azacycloalkane has been formed, one can convert the alkoxy group into the hydroxy

group by dissolving the nitrile in 48 per cent hydrochloric acid and heating until evolution of alkyl bromide begins. The temperature is maintained until the reaction is complete, after which the excess acid is removed. Re-

the side is then esterified by adding alcohol and sulfuric acid and heating to boiling with a reflux condenser overnight. The solution is then poured onto ice, and the sulfuric acid catalyst is removed by shaking off excess barium carbonate. The inorganic

low salts are filtered off, and the filtrate is concentrated to dryness. The product can be recrystallized from alcohol.

As an example for the production of a

salt of cyano-carbalkoxy- or acyl-free base, the process for the preparation of the hydrochloride acid addition salt of 4-phenyl-4-carbethoxy-N-methyl-azacyclo-hep-

tan is followed.

0.1 mol of the base is dissolved in 10. cm?> abs.

ethanol, and 0.15 mol ethanolic hydrochloric acid added

tea drop by drop while cooling. Excess hydrochloric acid and ethanol are removed under reduced pressure at 35-45°. The remainder is taken up in 75

cm.3 of a 1 : 1 diisopropyl-ketone-anhydrous ether mixture, inoculated and then allowed to

stand at -f 5° for 24 hours. The crystalline hydrochloride is filtered off, washed with ether and dried over concentrated H2SO4 at 25° and

0.2 mm for 5 hours. The following salts can be prepared in the same way, using

then the corresponding acid and the same for-

keep reagents and solvents

agents: hydrobromide, hydroiodide, sulfate,

acid sulfate, phosphate, maleate, malate, tartrate,

citrate, succinate, acetate, propionate, acetyl-

salicylate, etc.

All of these azacycloalkanes are asym-

risks, and the product obtained is a racial

misc mixture of optically active substances.

If desired, these dl connections can be

solved in dextro- and laevo-form by combi-

treating the free base with an optically active organic carboxylic acid in a suitable solvent and selectively isolating d- or 1-stereoisomers;

The therapeutically useful compounds,

more especially those that have an analgesic effect

ning, can be used either orally, in suppository form or parenterally. For oral use, the compounds can be combined on

known way in the form of an elixir or other liquid form with inert carrier substances,

such as suspending and taste and smell

substances. They can also be used in dry form, combined in the usual way with binders

clay, sugar and other carriers for tablets

single capsule form.

Claims (8)

1. Procedure for the production of azacycloalkane nitriles with possible after- following replacement of the cyano group with hydrogen or -COO. lower alkyl, - CO . lower alkyl, - CONH2, - COOH or -O-CO . lower alkyl, with alkyl groups which preferably have no more than three carbon atoms, characterized in that a 1-dialkylamino-3-cyano-3-aryl-omega-haloalkane with from 6 to 11 carbon atoms, which may have a methyl substituent in 1- or the 2-position, is heated in an organic solvent to a temperature no more than approx. 250° C, whereby an azacycloalkane nitrile is formed, the term "aryl" in the first-mentioned compound meaning a phenyl or substituted phenyl radical. 2. Method according to claim 1, characterized in that the haloalkane compound is caused to react in an alcoholic solvent with a relatively high boiling point. 3. Method according to claim 1, characterized in that a strong polar solvent is used and that the reaction is carried out at a temperature of no more than approx. 120° C when starting from 1- or 2-methyl-haloalkane of the type described. 4. Method according to claim 1, characterized in that 1-dimethyl-amino-3-cyano-3-aryl-omega-halohexane which, if desired, has methyl in the 1- or 2-position is heated so that a 4-aryl-4 -cyano-N-methyl-azacycloheptane compound. 5. Method according to claims 1 and 4, characterized in that the cyano group is hydrolysed and esterified so that it gives the corresponding 4-carb-lower alkoxy compound. 6. Method according to claim 1 and 4, characterized in that a 4-aryl-4-cyano-N-methyl-azacycloheptane compound is brought to react with an organo-metallic compound and then hydrolyzed so that it gives the corresponding 4-carb -lower alkyl compound. 7. Method according to claims 1 and 4, characterized in that the 4-cyano compound is heated with a strong alkaline agent to a temperature that is no more than approx. 250° C, whereby, depending on the temperature range, an azacycloheptane is formed which in the 4-position has only an aryl radical, or in this position has an amide or carboxylic acid radical as well as an aryl radical. 8. Method according to claim 1, 4 and 7, characterized in that the 4-aryl-N-methylazacycloheptane compound is heated with or without methyl groups in the 2- or 3-position in the presence of a tetravalent lead salt of a lower aliphatic carboxylic acid together with the corresponding lower aliphatic carboxylic acid so that the corresponding 4-acyloxy compound is formed.