DE1470357A1 - Process for the preparation of new acylated piperidine (4) amines - Google Patents

Description

Process for the preparation of new acylated piperidine- (4) -amines The invention relates to processes for the preparation of new acylated piperidine- (4) -amines of the formula and also of their acid addition salts and mono- or bisquaternary ammonium compounds.

In the above formula, Ri denotes hydrogen or a lower alkyl radical, R2 hydrogen, a straight-chain or branched alkylreate with 1-18 carbon atoms, an aryl or aralkyl radical, both in the aromatic core lower * 1 or alkoxy groups or substituted by halogen atoms, R3 is a straight or branched alkyl radical with 1-18 carbon atoms or a straight-chain or branched alkenylate with 2-18 carbon atoms, where R2 and R3 together must contain at least 6 carbon atoms, R4 and R5 'die be the same or different, lower alkyl create or together with the nitrogen atom one optionally interrupted by a further hetero atom and / or by Alkyl or aryl radicals substituted heterocyclic ring, and A a divalent one aliphatic hydrocarbon radical with 2-4 carbon atoms.

According to the invention, the new compounds are obtained by reacting a piperidine (4) amine of the formula in which R, 1, R2, R4, R5 and A have the meanings given, with a reactive derivative of a carboxylic acid of the formula R3-III, in which R, which has meanings already started, is obtained by customary methods. All reactive derivatives of the acid mentioned can be esters, activated anhydrides, which can be obtained, for example, by reacting the acid with a chloroformic acid ester, or imidazolido, but the acid halides are preferred. The reaction with an acid halide is expediently carried out at room temperature either in an organic solvent such as benzene, tetrahydrofuran or chloroform, possibly in the presence of an acid-binding agent, or according to Schotten-Baumann in an aqueous solution in the presence of an inorganic base. In the reaction in an organic solvent, all acid-binding agents can be inorganic or tertiary organic bases, for example pyridine, and the latter can then also serve as solvents at the same time.

The reaction with an ester, an activated anhydride or aines Imidazolide is also conveniently carried out at room temperature, preferably in one organic solvents such as 3ensol, tetrahydrofuran, dioxane and the like.

If compounds are obtained in which R2 is hydrogen, then If desired, these can be subsequently converted into compounds by customary methods in which R2 has one of the other meanings given with the exception of one Owns aryl creatine. Post-alkylation or aralkylation is expediently carried out by means of an alkyl or aralkyl halide in the presence of one basic catalyst, for example in the presence of an alkali metal, an alkali amide or alkali hydride.

If desired, the bases obtained can subsequently be customarily used Mathodes with an inorganic or organic acid, for example with hydrochloric acid, Sulfuric acid, phosphoric acid, tartaric acid, succinic acid, citric acid, maleic acid or adipic acid, in its acid addition salt or by reaction with a compound of the formula R6Y, in which R6 is an alkyl or aralkyl radical and Y is a halogen atom or denotes the recipe for an alkylsohulphuric acid or an aromatic sulfonic acid, be converted into their mono- or blue-quarternary ammonium compounds.

The 4-aminopiperidimes of the formula II used as starting materials are likewise new, they can be, for example, according to de @ @ by P. Brooks and co-workers. in J. Chem. Soc. 1957, p. 3165 described process obtained by reducing the corresponding oxines by means of sodium in ethanol or by means of catalytic hydrogenation. using this process, for example, the following starting materials of the formula II were produced: RK booty Ri RnmiHg ° C% R " (CH) gNCHCHg-HH0, 0152-354 (C 5) 2JCH2CH2 HR 0.3 82-3 59 (CH3) 2XCB2CH2CH2 HH 0.2 99-100 68 ta6H) 2NCIi2CPICH2-H ii 0.02 9 -5 40 2 ECH2CE2 HH 0, 2 96-97 72 / "CHgCHg-HH0, 0595-643 r ~~, / \ '!' V O wCH2cR2-R H 0.02 115-7 49 tfl3) 2N0g2CK2H2 H C6HSCH2 0.02 136-9 60 . ~~ Z ~, The compounds have valuable therapeutic properties, in particular they have an analgesic, spasmolytic, antihypertensive and antimicrobial effect;

The following examples serve to explain the invention in more detail: Example 1.

Dde munch of 2.8 g of 1- (dimethylaminopropyl) -piperidine- (4) - amine and 3, 7 g of myristic acid chloride in 10 ml of absolute benzene are mixed and the mixture is refluxed for 2 hours or left at room temperature overnight. After cooling, 50 ml of Wasner and 5 ml of 2N hydrochloric acid are added.

The aqueous phase is separated off and extracted once with ether and then geotellt with 2N sodium hydroxide solution. The failed product is in Ether absorbed and the solution dried over sodium sulfate, distilling off Baoh the solvent remains a fecter residue, which recrystallizes aue Petrolither will. 3.6 g of N-myristoyl-1- (3-dimethylaminopropyl) piperidine anion are obtained of m.p. = 88-89 ° C.

2 g of N- (n-butyl) -1- (3-dimethylaminopropyl) -piperidine- (4) -amine become gelat in 20 ml of absolute benzene, 0.9 g of anhydrous soda and 2.05 g of myristic acid chloride added and the mixture g with occasional shaking for 24 hours at room temperature atehon left. Then it is diluted with a further 20 ml of absolute * benzene, heated to boiling and filtered hot. That The filtrate is concentrated and the RUcketand summed up with dihydrochloride. After recrystallization from Easigeeter / Iaopropanol 2.4 g of N-myristoyl-N- (n-butyl) -1- (3-dimethylamino-propyl) -piperidine- (4) -amine-dihydrochloride are obtained of m.p. = 248-250 ° C.

Example 3.

2.3 g of N-tetradscyl-1- (3-dimethylaminopropyl) -piperidine- (4) -amine become Gelat in 10 ml trookenom chloroform and with 2 ml Trockenom pyridine and 0.5 g acetyl chloride offset. it is left to stand overnight at room temperature and the precipitated product is then filtered off Pyridine hydrochloride. The filtrate is concentrated and the RUckotand sum dihydrochloride processed After recrystallization of eue ethyl acetate / isopropanol, 0.9 g is obtained N-acetyl-N-tetra-acyl-1- (3-dimethylaminopropyl) -piperidine- (4) -amine-dihydrochloride of m.p. = 237-239 ° C (decomposition).

Following the procedure of Examples 1-3, the following compounds of the formula I were produced: R ' $ < R ..,. ...... ~. r. (CH3) 2-CH2Cfi2-H H CH3 Ci2 5 89-90 (CH3) 2N-CH2CH2 HH CH3 (CH2) 7 94-5 / (CH3) 2N-CH2CH2-Fi H GH2 = CH- (CH2) 78-80 (aR3) 2N-Ch CB2 HH CH3 (CH2) 12 902 . (Cg3) 2N-Cg2ag2-X H CE3tCE2) 16 96- () 2X- [z2CH2Ch BH CE3 (CH2) 5 58-60 (Ce} 2J CH2CF HH aH3 (CX2) t 93-4 (cl.) 2ffiF XX ° | - (g) 8 76-8 (ON.) N-OHgCHCH- HHCH- (OH) 87-9 (OR3) 2X ~ 0hCh * XH Cb () 16 90-: (a2XS) 2xOg2CH2 HH CH (CN) 5 50-1 2H52gCH2CH2 H i CH3 (CH2) 51-2 (C285) 2NCH2cHS HH CN CH (CH2) 8 67-8 I. i (C) NCHCH HHCH (CH) 80-1 (C2H5) 2NCHSCY2 8 H CH3 (CH2) 12 83-5 (C) NCHCH HHCH (CH) 62-3 (C6H5) 2NCH2OH2cH2 HX CH3 (CH2) 5, i R. R4xJ-AZ 3 tp. ° O rif'- (o6a5) h, CE29 E fl 49 (C6H5) 2NcH2CH2CH2 HH CH (CE2) 16 65-7 CH2CH2 HH GH2 = CH-CB) 8 96-8 CPH2CH2 9 H CE3 (CH2} 12 106-8 (/ fCHCHg HH CH = CH (CH) Q 110-2 CH2CH2 HI CR3 (aHZ) 10 120-1 9 CF CE2 HH oR (ohm) 12 116-8 LJ 9 CH2eR2 g H CH3 (CEz) 12 118-9 (aR3) 2XCH2CH2CF X C4Hg CF zCH (CF) 8 2S0-2 (HC1) (CHg) 2NC * CH2CH2 H c6R5c X2 CH2s [R (CH2) 253-4 ~. ~~~ ~ ~ ~ 1 Caal) ~ Example 4.

A solution of 1.2 g of N-myristoyl-1- (3-dimethylaminopropyl) piperidine (4) amine in 59 ml of absolute ethyl acetate is heated to 60 ° C. with 5 g of methyl iodide for 2 hours. The resulting Nioderechlag is suctioned off and recrystallized from absolute ethanol. 1.2 g of N-myristoyl-1- (3-trimethylammoniumpropyl) -1-methyl-piperidinium- (4) -amine-diiodide with a melting point of 243-246 ° C. are obtained. The following compounds of the formula are obtained according to the same method 4th, NAR 3 YP. * 0 J (CH) 2XCH2CH2 CH2-CR- (eg2) 8 146-150 (eR3) 2XCE2CH2 CH3 (CH2) 12 179-182 (CH3) 21NCH2CR2CH2 CH2 = Ca (C2) 8 208-210 (CE3) 2XCR2aM7CH2 CE3 (CH2) 10 235-237

Claims (1)

Claim Process for the preparation of new N-Aoyl-piperidin- (4) -amines of the formula in which Ri is hydrogen or a lower alkyl radical, R2 is hydrogen, a straight-chain or branched alkyl root with 1-18 carbon atoms, an aryl or aralkyl radical, both of which can be substituted in the aromatic nucleus by lower alkyl or alkoxy groups or by halogen atoms,., 113 a straight-chain or branched alkyl radical with 1-18 carbon atoms or oinen straight-chain or branched alkenyl radical with 2.18 carbon atoms, where R2 and R3 together must contain at least 6 carbon atoms, R4 and R5, which can be the same or different, lower alkyl radicals or together with the Nitrogen atom denotes a heterocyclic ring optionally interrupted by a further heteroatom and substituted by alkyl or aryl groups, and A denotes a divalent aliphatic hydrocarbon group with 2-4 carbon atoms, as well as their acid addition salts and mono- or bisquaternary ammonium compounds, characterized in that a piperi Din- (4) -amine of the formula in which R1, R2, R4, R5, and A have the meanings given, with a reactive derivative of a carboxylic acid of the formula R3-COOH III, in which R3 has the meanings mentioned above, preferably with an acid halide, optionally in the presence of an acid-binding agent is reacted, and if a compound is obtained in which R2 is hydrogen, this is optionally subsequently converted into its prebond by customary methods, in which R2 has one of the other meanings given except that of an arylate, and / or then the base obtained, if appropriate is converted by customary methods into its acid addition salt with zoner inorganic or organic acid or optionally with a compound of the formula RGY 0 in which X6 is an alkyl or aralkyl radical and Y is a Halogenatoa odor don beet of an alkylsulfuric acid or an aromatic: sulfonic acid, in a mono - or bisquaternary A @@ onium compound transferred wi