HU198204B - Process for production of derivatives of piperasine - Google Patents

Abstract

(A) 8-(4-(4-(2-pyrimidinyl) -1-piperazinyl)-2-butenyl or -butynyl)-8-aza-spiro (4,5)decane-7,9-diones of formula (I) and their acid-addn. salts are new, where A=CH=CH or C=C. - (B) prodn. of 8-(4-(4-(2-pyrimidinyl) -1-piperazinyl)butyl)-8-aza-sp iro (4,5) decane-7,9-dione of formula (II) or its acid addn. salts is effected by hydrogenating (I) and opt. converting the prod. to a salt.

Description

The present invention relates to the preparation of new piperazine derivatives.

More particularly, the present invention relates to a process for the preparation of new piperazine derivatives of the formula I and their acid addition salts which comprises:

A is -C = C- or -CH = CH-)

The compounds of formula (I) are valuable pharmaceutical intermediates which may be used primarily in the preparation of piperazine derivatives having anxioselective activity.

According to the process of the present invention, the compounds of the formula I and their acid addition salts can be prepared by:

a) in the preparation of a compound of formula Ia, which is a narrower group of compounds of formula I, subjecting the propin derivative of formula II to Mannich condensation with the amine of formula III; obsession

b) in the preparation of a compound of formula I, which is a narrower group of compounds of formula I, by reacting the propine derivative of formula II with an alkyl magnesium halide of formula IV wherein R is C 1-4 alkyl; and Hyg is chlorine, iodine or bromine), the resulting compound of formula V (wherein Hg is as defined above) is conjugated with at least a molar equivalent of trioxymethylene or formaldehyde to give the substituted anino alcohol (VII). converting the compound of formula (VII) to the piperazine derivative of formula (III); and, if desired, preparing the compound of formula (IB), which is a narrower group of compounds of formula (I), by partially hydrogenating the compound of formula (IA) and optionally converting or liberating the resulting compound of formula (I) into an acid addition salt.

According to process (a) of the present invention, the compound of formula (IA) is prepared by subjecting the propin derivative of formula (II) to Mannich condensation with the piperazine derivative of formula (III). Mannich condensation can be carried out in a manner known per se. [Calvin A. Buehler; Donald E. Pearson: Survey of Organic Syntheses. (USA, 1970) Vol. 1, p. 465] It is preferable to provide the reaction with formaldehyde in the form of paraformaldehyde. The reaction is preferably carried out under heating, preferably at the reflux temperature of the reaction mixture. The reaction is preferably carried out in an inert organic solvent. The reaction media are preferably ethers (e.g. diethyl ether, dioxide or tetrahydrofuran). The desired compound (IA) can be recovered from the reaction mixture in a known manner (e.g., by extraction with a suitable organic solvent).

In the first step of process b) of the present invention, the propin derivative of formula II is reacted with an alkyl magnesium halide of general formula IV. R represents a linear or branched C 1 -C 4 alkyl group (e.g., methyl, ethyl, n-propyl, isobutyl, etc.). Preferably the compound of formula (IV) is methyl iodide, methyl bromide, methyl chloride, ethyl iodide, ethyl chloride or ethyl bromide. The reaction of the compounds of formula (II) and (IV) is preferably carried out under heating in anhydrous ethereal medium.

The compound of formula (V) thus obtained is reacted, preferably without isolation, with at least a molar equivalent of thyroxymethylene or formaldehyde. Formaldehyde gas is preferably used. The trioxymethylene or formaldehyde may be used in an amount of from 1 to 1.1, preferably from 1.0 to 1.05 molar equivalent. Preferably, the reaction is carried out while heating. The resulting compound (VI) can be recovered by evaporation of the ethereal solution.

The compound of formula (VI) thus obtained is then converted in a known manner into the reactive ester of formula (VII). Preferably X is a halogen atom (e.g., chlorine, bromine or iodine), an alkylsulfonyloxy group (e.g., methanesulfonyloxy group) or an arylsulfonyloxy group (e.g., phenylsulfonyloxy). , p-bromophenylsulfonyloxy or p-tosyloxy). In a preferred embodiment, the compound of formula (VI) is reacted with p-toluenesulfonyl chloride. The reaction can be carried out at room temperature or under slight heating.

The resulting compound (VII), after isolation or preferably without isolation, is reacted with the piperazine derivative (III) in a known manner. The reaction is preferably carried out in an inert organic solvent. The reaction medium is preferably aromatic hydrocarbons (e.g. benzene, toluene or xylene). The reaction is preferably carried out under heating, particularly preferably at the reflux temperature of the reaction mixture.

The resulting compound of formula (IA) may be isolated by known methods (e.g., by evaporation of the reaction mixture).

According to the process of the present invention, the compound of formula IA is optionally converted to the compound of formula IB by partial hydrogenation. The partial hydrogenation may be carried out catalytically, preferably in the presence of a poisoned metal catalyst. In a particularly preferred embodiment of the process, a palladium catalyst poisoned with quinoline, calcium carbonate or lead acetic acid can be used. Particularly preferred is quinoline

HU 198204 Β Toxic catalyst [Org. Synth. Coll. Vol. 3, 629 (1955)]. The partial hydrogenation of the present invention is preferably carried out at room temperature and atmospheric pressure. Preferably, the reaction is carried out in an inert organic solvent medium. Aliphatic alcohols such as methanol or ethanol are particularly preferably used as the reaction medium in low carbon atoms. The resulting compound of formula (IB) may be isolated by conventional means, e.g. filtering the catalyst and evaporating the filtrate.

The resulting compound of formula (I) can be converted into the acid addition salt in a known manner. Pharmaceutically acceptable inorganic or organic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or maleic acid, fumaric acid, lactic acid, malic acid, tartaric acid, succinic acid, etc.) are preferably used for the salt formation. The salt formation is preferably carried out by reacting the base of formula (I) with a molar equivalent of the appropriate acid in an inert organic solvent medium.

From an acid addition salt, the compound of formula (I) may be liberated by treatment with an appropriate base in a known manner.

The novel compounds of formula (I), as mentioned above, are valuable pharmaceutical intermediates. The compounds of formula (I) by the catalytic hydrogenation of 8 - {4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl] -8-aza-spiro (4,5), a highly valuable anxioselective agent of formula (VIII) to decane-7,9-dione (Buspiron). The advantage of this process is that it makes Buspiron available in a clean condition in good yields and in good industrial conditions.

The propin derivative of formula (II) used as starting material in the process of the present invention is a novel compound prepared by the reaction of 8-azaspiro (4,5) decane-7,9-dione with propargyl bronide. This process is described in our patent application T / 45 992. Further details of our process are set forth in the following examples; without limiting the invention to the examples.

Example 1

For the preparation of 8- {4- [4- (2-pyrimidinyl) -1-piperazinyl] but-2-ynyl} -8-azaspiro (4 ₎ 5) decane-7,9-dione

In a 250 ml round-bottomed flask with stirrer and reflux, 20.5 (0.1 mol)

8-aza-spiro (4,5) decane-7,9-dioxon-8-propin (2), 25 m ^{3 of} dioxane, 17.2 (0.105 mole) of 1- (2-pyrimidinyl) piperazine, , 6 g of paraformaldehyde and 0.2 g of copper (II) acetate were weighed. The reaction mixture was refluxed for 3 hours, cooled to room temperature, poured into water and extracted with benzene (3 x 50 mL). The combined benzene solutions were clarified with activated carbon and de-solvented on a boiling water bath. Yield: 33.95 g (89%), m.p. 78-80 ° C (from petroleum ether).

Analysis for C21H27N5O2 (381.49):

Calculated: C, 66.12; % H, 7.13; % N, 18.36;

Found: C, 66.02; % H, 7.22; % N, 18.30.

Example 2

Preparation of 8- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -but-2-ynyl} -8-aza-spiro (4,5) decane-7,9-dione

Methyl iodide (15.6 g, 0.11 mol) and magnesium (2.68 g, 0.11 g) in magnesium ether (170 ml) were prepared by dropwise addition of 20.5 g (0.1 mol) in anhydrous ether under vigorous stirring. A solution of 8-aza-spiro (4,5) decane-7,9-dione-8-propin (2) in 50 ml of anhydrous ether. The reaction mixture was heated to reflux until methane gas evolution ceased and then 3 g (0.1 mol) of trioxymethylene (or 0.1 mol of anhydrous formaldehyde gas) was added. The reaction mixture was refluxed for an additional 4 hours and then poured into a solution of 10 g of ammonium chloride in 35 ml of ice-water. The ethereal solution was separated, dried over anhydrous magnesium sulfate and concentrated.

The oily residue (22.8 g, 96%) was treated without further purification with a slurry of 3.9 g (0.1 mol, sodium amide in 70 ml of anhydrous benzene), and 19 g (0.1 mol) of ammonia gas ceased at room temperature. After completion of the addition, the reaction mixture was stirred for 3 hours at room temperature, washed successively with water (40 ml), saturated sodium bicarbonate solution (40 ml) and water (40 ml) anhydrous. After drying over sulfate, 1- (2-pyrimidinyl) piperazine (17.2 g, 0.105 mol) was added to the benzene solution and the mixture was heated at reflux for two hours, washed with aqueous sodium bicarbonate and water, and the benzene solution was washed with water. The residue was taken up in petroleum ether and the crystals were filtered to give 23.65 g of the title compound as white crystals. 62%, m.p. 78-79 ° C.

Analysis: Calculated for C21H27N5O2 (381.49): C, 66.12; % H, 7.13; % N, 18.36;

Found: C, 65.85; % H, 7.02; % N, 18.10.

Example 3

Preparation of 8- {4- [4- (2-pyridinidinyl) -1-piperazinyl] buten-2-yl} -8-aza-spiro (4,5) decane-7,9-dione

38.15 g (0.1 mol) of 8- {4- [4- (2-pyrimidinyl) -1-piperazinyl) but-2-ynyl) -8-aza-spiro (4,5) decane were charged into the hydrogenation apparatus. -7,9-dione, 150 ml of ethanol, 1 g of palladium on charcoal and 1 ml of quinoline S 'activity reducing agent. Then, at room temperature, the theoretical amount of hydrogen (1 mol

HU 198204 Β

equivalent). The catalyst was filtered off and the solution was evaporated. Yield: 37.2 g (97%).

Analysis: Calculated for C 21 H 29 N 5 O 2 (383.5): C, 65.77; % H, 7.62; % N, 18.26;

Found: C, 65.18; % H, 7.47; % N, 18.15.

The base melts at 78-80 ° C (from petroleum ether) Salt formation: The base is dissolved in hot ethyl alcohol and an equivalent amount of fumaric acid is added. Upon cooling, the hydrogen fumarate salt crystallizes. 190-192 ° C.

Analysis: Calculated for C 25 H 33 N 5 O 6 (499.55): C, 60.10; % H, 6.66; % N, 14.02;

Found: C, 60.03; % H, 6.44; % N, 14.00.

UV: Xaax ¹ : 242 nm (C = 23,205)

Xeax ² : 300 nm (E ⁼ 2110)

Claims (18)

PATENT CLAIMS A process for the preparation of a compound of formula I and acid addition salts thereof A is -C = C- or -CH = CH-) characterized in that a) in the preparation of a compound of formula I, which is a narrower group of compounds of formula I, by subjecting the propin derivative of formula II to Mannich condensation with an amine of formula III; obsession b) in the preparation of a compound of formula I, which is a narrower group of compounds of formula I, by reacting the propine derivative of formula II with an alkyl magnesium halide of formula IV wherein U is a C 1 -C 4 alkyl group; and Hyg is chlorine, iodine, or bromine), reacting the resulting compound of formula V (wherein Hg is as defined above) with at least a molar equivalent of trioxymethylene or formaldehyde to form a substituted aminoalkobol of formula (VI). converting the compound of formula (VII) to the piperazine derivative of formula (III); and then optionally hydrogenating the compound of formula (IA) obtained by a) or b) to form a narrower compound of formula (I) and then optionally converting the compound of formula (I) to an acid addition salt. or release from its salt. Process (a) according to claim 1, characterized in that the Mannich condensation is carried out using paraformaldehyde. Process according to claim 2, characterized in that the reaction is carried out under heating, preferably at the boiling point of the reaction mixture. Method a) according to claim 1 or steps 2-3. Process according to any one of claims 1 to 4, characterized in that the reaction is carried out in an inert solvent. The process according to claim 4, wherein the inert solvent is an ether, preferably dioxane. Process b) according to claim 1, characterized in that the alkyl magnesium balogenide of the formula IV is methyl magnesium iodide, methyl magnesium bromide, methyl magnesium chloride, ethyl magnesium iodide. , ethyl magnesium chloride or ethyl magnesium iodide. 7. A process according to claim 6, wherein the reaction of the compound of formula (II) and the compound of formula (IV) is carried out under heating in an ethereal medium. Process b) according to claim 1, characterized in that the compound of formula V is used. with heating with trioxymethylene or formaldehyde gas. The process according to claim 8, wherein the trioxyoxyethylene or formaldehyde is used in an amount of 1-1.1 molar equivalent, preferably 1.0-1.05 molar equivalent. Process b) according to claim 1, wherein the compound of formula VI is converted to an ester of formula VII wherein X is halogen, alkylsulfonyloxy or arylsulfonyloxy. 11. A process according to claim 10 wherein X is selected from the group consisting of X, chlorine, bromine, iodine, methanesulfonyloxy, phenylsulfonyloxy, p-bromophenylsulfonyl, and the like. to an ester of formula VII containing an oxy or tosyloxy group. Process according to claim 10 or 11, characterized in that the compound of formula (VI) is reacted with p-toluenesulfonyl chloride. Process (b) according to claim 1, characterized in that the reaction of the compound (VII) with the piperazine derivative (II) is carried out under heating in an inert organic solvent. Process according to claim 13, characterized in that the reaction is carried out in an aromatic hydrocarbon, preferably benzene, toluene or xylene. 15. A process according to claim 1, wherein the compound of formula IA is hydrogenated with hydrogen in the presence of a poisoned catalyst to a compound of formula IB. A process according to claim 15 wherein the palladium catalyst is poisoned with quinoline, calcium carbonate or lead acetate. HU 198204 Β Process according to claim 15 or 16, characterized in that the partial hydrogenation is carried out at room temperature and atmospheric pressure. 18. 15-17. Process according to any one of claims 1 to 3, characterized in that the partial hydrogenation is carried out in a lower aliphatic alcoholic medium, preferably in methanol. 5 or in ethanol.