NO122178B - - Google Patents

Description

Process for the preparation of 4-aryl-4-acyloxy-azacycloalkanes.

The following invention relates to cyclic

connections, and more particularly concerns it

acyloxy-azacycloalkanes and a process for their production.

A cyano-azacycloalkane can be decyanated in one step by heating the cyclic cyano compound with an alkali metal amide, such as sodium, potassium or

lithium amide in the presence of an inert organic

aliphatic type solvent such

such as hexane or higher, or of the benzene type such as benzene, toluene or xylol.

The reaction will take place in the area of approx. 50 to 150° C. A preferred temperature range is in the range 90 to 110° C.

Another method for preparing decyanated azacycloalkanes involves hydrolyzing the corresponding cyano compound so that 4-amidoaza-cycloalkane is formed, after which the last compound is reacted with an alkali metal hydroxide which first forms a carbonic acid salt of the alkali metal, followed by decar- boxylation to the desired compound.

This step-by-step procedure is carried out

first at approx. 190° C for formation of amides

as the temperature is raised to approx. 250° C for

the last steps. If it is only desired

decyanated product without wanting to

secrete carbamides or the carbonic acid compounds, the reaction can only be carried out

by heating the cyano compound with the hydroxide and water between approx. 200 to 300°C.

The decyanated azacycloalkane can

is acyloxylated by heating the selected

azacycloheptane with a tetravalent lead salt

of a lower aliphatic acid in the presence of a

corresponding acid. The reaction temperature

held in the area approx. 100°C.

An acyloxy product can also be obtained by reacting 4-amido-azacycloalkane prepared as previously described with alkali metal hypobromite

(prepared by reacting an aqueous alkali metal hydroxide with bromine) to form the corresponding 4-amino-azacycloalkane. The latter is dissolved in an aqueous solution of acetic acid, and sodium nitrite is added. After the reaction, the product is made basic to

get the alcohol. The 4-hydroxy-azacycloalkane

can then be reacted with acetic acid or propionic anhydride to form an acyloxy product.

A further method for preparing the desired compounds comprises a series of known reactions, beginning with the preparation of N-(2-cyanoethyl)-N-(omega-cyanoalkane) methylamine. This product is then cyclized using lithium N-ethylanilide so that lithium derivatives of 4-iminoazacycloalkanes are formed, and the latter are then treated with a strong sulfuric acid to change the imine group into a carbonyl oxygen. The compound thus formed is reacted with phenyllithium, so that the same alcohol is formed as that produced above 4-amido, namely 4-phenyl-4-hydroxy-N-lower alkylazacycloalkane. As before, this compound is reacted with a fatty acid anhydride so that the corresponding 4-acyloxy compound is formed.

A preferred method for the production of acyloxy-azacycloalkanes because improved yields of the desired product are obtained will be described in the following, with the reaction steps first being shown:

In the above formulas, R means a lower alkyl, R, means a lower alkyl, alkenyl or aralkyl radical, R2, R3 and R5 each means hydrogen or lower alkyl, and R4 a lower alkyl, alkenyl, aryl or aralkyl radical.

X means a halogen such as chlorine, bromine or iodine or - OS020 - lower alkyl, while Z means an alkylene radical, n 2 or 3. (Z)n can mean an unbranched or branched chain of lower alkylene group, i.e. - CH2CH <, - or - CH2 - CHR -.

Ar meaning an aryl radical can represent either phenyl or phenyl radical having one to three substituents, such as lower alkyl, lower alkoxy, halogen, nitro, hydroxy, lower aliphatic aryl, lower acyloxy, amino and mono- and di-lower alkyl -amino radicals.

Reaction (1) is carried out with such acid-binding agents as K2CO;.,, Na2CO;! or CaCOH in high-boiling ether or alcohol such as di-n-butyl ether, di-isopropyl ether or n-butanol at a temperature in the range of approx. 80 to approx. 150° C. This reaction gives an omega, omega'-esterenitrile which is to be used in a self-condensing reaction, as azacycloalkane is formed.

Reaction (2) is a new cyclization step where the omega, omega'-esterenitrile is cyclized in the presence of an alkali catalyst dissolved in a carbon hydrogen catalyst such as, for example toluene, xylol, tetralin or decalin. Preferred catalysts are alkali metal alcoholates such as e.g. NaOCH3, NaOC2H5 or alkali metal hydrides such as NaH. The cyclization reaction is carried out at a temperature in the range of approx. 100 to approx. 150° C. The use of esternitrile instead of diester or dinitrile results in significantly improved yields of cyclized products.

The decyanation of azacycloalkanone according to reaction (3) is preferably carried out via an acid hydrolysis where e.g. HC1, HBr, HJ, H2S04 or H3P04 in water and while working at a temperature in the range of approx. 70 to approx. 140°C.

If desired, this decyanation process can also be carried out over an alkaline hydrolysis as explained earlier in the first process, operating under the conditions described above. The arylation and alcohol formation are carried out in reaction (4) by treating the decyanated azacycloalkanone with the desired aryl such as aryl alkali metal, e.g. aryllithium or arylsodium or instead of this, to use an arylmagnesium halide such as e.g. C(iH5MgBr. The arylating agent is dissolved in an ether-hydrocarbon mixture such as, for example, diethyl ether with benzol. The reaction is carried out at an initial temperature of about -35° to about + 10° C followed by a short heating period at about + 35 to + 80° C.

In reaction (5) to produce acyloxy-azacycloalkane, an acid anhydride is used, e.g. (C2H;-CO)20, or an acid halide, e.g. C2H5COCl together with an acid binding agent such as pyridine in ether or carbon hydrogen solvent such as benzene or a mixture of solvents. The reaction begins in a temperature range of approx. h-20 to -(-20° C and is followed by a short heating period in the range of approx. +35 to +80° C.

In the following example, a method for producing a typical compound according to the invention is shown in more detail.

Example:

. Synthesis of 4-phenyl-4-propionoxy-l,3-dimethylazacycloheptane from N-(2-carbo-methoxypropyl)-N-(3-cyanopropyl)

methylamine. (Compound I).

A mixture of 1.4 mol (187 g) of methyl 3-methyl-amino-2-methylpropionate, 1.4 mol (144 g) of 4-chlorobutyronitrile and 1.6 mol (221 g) of anhydrous potassium carbonate in 350 ml of di-n-butyl ether was heated to 110-115° with stirring for 15 hours. After cooling the mixture, the inorganic salts were filtered off, and the filtrate was extracted with aqueous hydrochloric acid. The acid extract was washed with ether, basified with a sodium hydroxide solution and extracted with ether. The ether extract was dried over anhydrous potassium carbonate, filtered and distilled.

The desired compound I was obtained as a colorless liquid, boiling point 100-105°

25

(0.25 mm), n D 1.4445.

Analysis, calculated for CHIH1SN00., : C, 60.60; H, 9.15; N, 14,15.

Found: C, 60.55; H, 9.09; N, 14.09.

1, 3- dimethylazacycloheptanone- 4.

(Compound III).

A mixture of 0.40 mol (79.3 g) of compound I and 0.42 mol (22.7 g) of sodium

methoxide in 1.5 liters of dry xylol was stirred under a nitrogen atmosphere as the temperature was gradually raised. A mixture of methanol and xylol was slowly distilled off. Within four hours, 250 ml of distillate had been collected. This was replaced with an equal volume of dry xylol, and the slow distillation was continued. The operation was repeated until the boiling point of pure xylol was reached. The total time required to collect 750 ml of distilled xylol was 12 hours. At this time, the sodium derivative of 5-cyano-1,3-dimethylazacycloheptanone-4 (compound II) was suspended in the xylol as an orange-coloured precipitate.

The cold mixture was extracted with 750 ml of 1.75 normal hydrochloric acid. The acid extract gave a strongly positive enol test with ferric chloride solution. An additional 250 ml of 12 normal hydrochloric acid was added, and the solution was heated to boiling with a reflux condenser for 24 hours. The evolution of carbon dioxide gas was violent at the beginning of the heating period, gradually decreased and was negligible after 24 hours. At this point the enol sample with ferric chloride was ne-Igative. The cold solution was made basic with 40% sodium hydroxide solution and extracted with ether. The ether extract was dried over anhydrous potassium carbonate, filtered and distilled.

1,3-Dimethylazacycloheptanone-4 (Compound III) was obtained as a pale yellow 29 liquid, bp 110° (35 mm), ri D 1.4656.

Analysis calculated for C8H15No : C,

68.10; H, 10.70; N. 9.93.

Found: C, 68.07; M, 10.45; N, 10.23.

4-phenyl-4-propionoxy-1,3-dimethyl-azacycloheptane (compound V).

A solution of phenyllithium was prepared under a nitrogen atmosphere from 0.667 g atom (4.6 g) of lithium and 0.332 mol (52.0 g) of bromobenzene in 50 mL of anhydrous ether. The solution was cooled to -20°C and 0.10 mol (12.7 g) of compound III in 100 ml of ether was added dropwise with stirring. The temperature was maintained at -20°C for y. ± hour after the addition was complete, the mixture was allowed to warm to room temperature and stand overnight under nitrogen. At this point, the tertiary alcohol 4-phenyl-4-hydroxy-1,3-dimethylazacycloheptane (compound IV) which can exist in two diastereoisomeric forms, was present as the lithium salt.

The mixture was cooled to 0°C and 0.35 mol (45 ml) of propionic anhydride in 100 ml of dry toluene containing 5 drops of 37 normal sulfuric acid was added dropwise with stirring. The temperature of the mixture was gradually raised, and approx. 75 ml of ether was distilled off while the same volume of toluene was added dropwise. A temperature of 70 to 80° C was then maintained for two hours.

The mixture was cooled to 0° C., and 200 ml of 1:3 48% hydrobromic acid-water solution was added dropwise with stirring. A three-phase system consisting of a toluene layer, an aqueous acid layer and the precipitated hydrobromide of compound V (which can exist in two diastereoisomeric forms) arose. After stirring for 15 minutes, the mixture was filtered and the precipitate washed with ether, then with cold water and partly with acetone. The crude and incompletely dried precipitate was dissolved in methanol-methyl-ethyl ketone solution and the solution concentrated to a small volume.

Hydrobramide, s.p. 201-202° C decomposition of compound V crystallized. It was filtered off and washed with methyl ethyl ketone. The recrystallization from methanol acetone raised the melting point to 207-207.5° C. The solubility of the hydrobromide in water at room temperature was 1-2 per cent.

Analysis calculated for Cl7H2(iBrNO.> : C,57 . 32; H, 7.36; N.3.93; Br, 22.41.

Found: C, 57.14; H, 7.48; N, 3.80; Br, 22.71.

Picratet, s.p. 162-163° C, of compound V was formed by adding aqueous lithium picrate to a solution of the hydrobromide in dilute acetic acid.

Analysis calculated for ColiH9SN4Ol|: C, 54.70; H, 5.59; N, 11.10.

Found: C, 54.46; H, 5.50; N, 11.04.

28 The base k.p. 126° C (0.3 mm) n D 1.5182,

was formed by treating an aqueous suspension of the hydrobromide with sodium hydroxide, extraction with ether, drying and vacuum distillation.

Analysis calculated for C17H95NO., : C, 74.15; H, 9.15; N, 5.09.

Found: C, 73.83; H, 9.34; N, 5.17.

The hydrochloride, s.p. 207° C. during decomposition, was formed by passing dry hydrogen chloride gas into a 1:2 methyl ethyl ketone-ether solution of the base.

Analysis calculated for C,7 H2(.ClNO., : C, 65.50; H, 8.41; N, 4.49; Cl, 11.37.

Found: C, 65.80; H, 8.63; N, 4.57; Cl, 11.1.

Another method for the preparation of the hydrochloride salt, which has general application for the preparation of other salts of the free azacycloalkane bases, is as follows: 0.1 mol of the base is dissolved in 10 ems of absolute ethanol, and 0.15 mol ethanolic hydrochloric acid is added dropwise while cooling. The excess of hydrochloric acid and ethanol is removed under reduced pressure at 35-45° C. The residue is taken up in 75 cm» of a 1 : 1 diisopropyl-ketone anhydrous ether mixture, po-des, then allowed to stand at -f- 5° C for 24 hours. The crystalline hydrochloride is filtered off and washed with ether and dried over concentrated H 2 SO 4 at 25° C. and 0.2 mm for 5 hours. The following salts can be prepared in the same way, using the corresponding acid and the same ratio of reactants and solvents: hydrobromide. hydroiodide, sulfate, acid sulfate, phosphate, maleate, malate, tartrate, citrate, succinate, acetate, propionate, acetylsalicylate, etc.

The free azacycloalkane bases can be used to produce quaternary ammonium compounds which have good wetting properties. To prepare such compounds, the free bases are reacted with halides of long-chain aliphatic compounds having from 8 to 18 carbon atoms such as lauryl bromide, the temperature for the reaction being in the range from approx. 50 to approx.

150° C. Another use of these alkylenimine compounds is their ability to combine with penicillin to form salts, this process being useful for the purification of penicillin and also for preparing therapeutically valuable penicillin salts . In addition, at least one series of azacycloalkanes, which are formed in particular from acetoxy- and propionoxy-azacycloalkanes, have been found to have valuable pharmacological properties, in particular an unexpectedly good analgesic effect. What has been said above applies equally to the free bases as to their acid addition salts.

The substituents in the aryl ring can be present during the arylation step by being part of the arylating agent or the selected substituent can be added after the arylation of the azacycloalkane ring. Where it is thus desired that the aryl radical comprises one or more hydroxy substituents in the ring, the reactions described above shall use corresponding alkoxy-substituted compounds as reaction participants. After the alkoxy-substituted aryl-cyano-azacycloalkanes have been formed, the alkoxy group can be converted into a hydroxy group by dissolving the nitrile in 48% hydrobromic acid, heating until development of alkyl bromide begins. The tempering process is held until the reaction is complete, after which excess acid is pumped off. The residue is then esterified by adding alcohol and sulfuric acid and heating to boiling with reflux cooling

overnight. The solution is then poured

on ice, and the sulfuric acid catalyst is removed by

to shake with excess barium carbonate.

The inorganic salts are filtered off, and the filtrate is concentrated to dryness. The product

can be recrystallized from alcohol.

The therapeutically useful compounds,

more particularly those that have an anagetic effect can be used either orally, in suppository form or parenterally. For oral use

the compound can be combined in a known manner

in the form of an elixir or other liquid form

with carriers such as suspending and taste- or odor-giving agents. They can therefore be used in dry form combined in the usual way

with binding agents, sugar or other carriers for tablets or capsules.

Claims (6)

1. Process for the production of 4-aryl-4-acyloxy-azacycloalkanes, characterized in that a 4-aryl-alkyl-substituted azacycloalkane with 7-8 members in the ring is reacted with an acylating agent capable of reacting with an active element in a radical in the 4-position of the ring, so that a 4-acyloxy-azacycloalkane with the formula is formed in which R, means a lower alkyl, alkenyl or aralkyl radical, R2, R3 and R5 means hydrogen or a lower alkyl, R4 means a lower alkyl, alkenyl, aryl or aralkyl radical, Ar means an aryl or aryl substituted radical, Z means an alkyl radical and n means the whole number 2 or 3. 2. Method according to claim 1, characterized in that the active element is hydrogen. 3. Method according to claim 1 or 2, characterized in that the radical in the 4-position containing the active element is the OH radical. 4. Process according to claim 1, 2 or 3, characterized in that the acylating agent is an acid anhydride, e.g. propionic anhydride. 5. Method according to one of the preceding claims, characterized in that the 4-aryl-alkyl-substituted azacycloalkane is 4-aryl-4-hydroxy-1,2-dimethylazacycloheptane. 6. Method according to any one of the preceding claims, characterized in that the 4-aryl-alkyl-substituted azacycloalkane is prepared by reacting an azacycloalkanone-4 with a Grignard reagent.