CH677924A5 - - Google Patents

Description

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description

The invention relates to a new and improved process for the preparation of piperazine derivatives, intermediates which can be used in this process and a process for the production thereof.

The invention relates to a new and improved process for the preparation of 8- {4- [4- (2-pyrimidinyI) 1-piperazinyl] butyl} -8-aza-spiro [4,5] decane-7,9-dione of formula I, this compound is a known valuable anxioselective active ingredient (British Patent No. 1,332,194).

Several processes are known for the preparation of the compound of formula I.

According to British Patent No. 1,332,194, the compound of the formula I is prepared in such a way that the 8-oxa-spiro [4,5] decan-7,9-dione is prepared with 1- [4-aminobutyl] -4- [2'-pyrimidinyl] piperazine. This reaction is carried out in pyridine at the boiling point of the reaction mixture. The desired compound of formula I is obtained in the form of a crude product with moderate yields. The crude product is purified in the form of the free base either by crystallization or by fractional vacuum distillation. The disadvantage of the first cleaning method above is the high losses. The fractional distillation is carried out at high temperature (240-265 ° C) under low pressure (13.3 Pa) and represents a heavy thermal load and leads to damage to the product.

Another method described in British Patent No. 1,332,194 is 8- [4-chloro-butyll-8-aza-spiro [4,5,] decan-7,9-dione with N- [2-pyrimidinyl ] -piperazine in the presence of sodium carbonate in n-butanol at the boiling point of the reaction mixture for 3 days. The very long reaction time precludes the economical application of this method in operation. Another disadvantage is that cleaning the product is very complicated and expensive. Yet another disadvantage of the process is that the 1-bromo-4-chloro used in the preparation of 8- [4-chloro-butyl] -8-aza-spiro [4,5] decane-7,9-dione -butane is very difficult to access.

According to a further method described in British Patent No. 1,332,194, 8-oxa-spiro [4,5] decane-7,9-dione is first converted into 8-aza-spiro [4,5] decane-7, 9-dione manufactured. By reacting N- [2-pyrimidinyl] -piperazine and 1-bromo-4-chloro-butane, 1- [4-chloro-butyl] -4- [2-pyrimidinylj-piperazine is prepared, which is carried out in the above manner is reacted with 8-aza-spiro [4,5] decan-7,9-dione. This synthetic route contains several stages that are difficult to carry out chemically. The desired end product of the formula I can only be obtained in a form suitable for pharmaceutical use after several purification steps. Another disadvantage is the difficult accessibility of the t-bromo-4-chlorobutane used as the starting material.

The 1- [4-aminobutyl] -4- [2-pyrimidinyl] piperazine can be prepared by treating 1- [2-pyrimidinyl] piperazine with 3-chloropropionitrile in n-butanol as the medium at the boiling point the reaction mixture heated for an extended period of time (about 16 hours). The intermediate product obtained must be purified by crystallization (yield 70%). The Nitrii obtained as an intermediate is catalytically hydrogenated with a yield of about 70% (British Patent No. 1,332,194).

According to Hungarian Patent No. 187 999, the compound of formula I is prepared as follows: the 1- [4-chloro-butyl] -4- [2-pyrimidinyl] -piperazine is first turned into the spiro-quaternary ammonium piperazine derivative of the Formula IX formed, which is reacted with 8-aza-spiro [4,5] decane-7,9-dione in the presence of a strong base. This process has serious disadvantages. The yield is low, the synthesis consists of many stages and the purification of the product is difficult.

According to Swiss Patent No. 647 518, the 8-aza-spîro [4,51decan-7,9-dione is first reacted with 1,4-dibromo-butane, whereupon the 4-bromo-butyl derivative obtained is treated with piperazine and the product obtained is finally reacted with 2-chloro-pyrimidine. The aim of this process is to produce the compound designated 14C isotope and the process is unsuitable for implementation in operation.

According to Spanish Patent No. 536 286, the potassium salt of 8-aza-spiro [4,5] -decan-7,9-dione is reacted with 4-chloro-butyraldehide, whereupon the product obtained is reductively treated with N- [2 -Pyrimidinyl] -piperazine is treated. This procedure is only of theoretical importance and plays no role in the product tone in the company.

The aim of the present invention is to remedy the above disadvantages of the known processes and to create a new process for the preparation of the compound of the formula I, which is also inexpensive, simple and economical to carry out in operation, uses readily available starting materials and the compound of the formula I. with good yields and in a pure state.

The invention relates to a new and improved process for the preparation of 8- {4- [4- (2-pyrimidinyl) -1-piperazinyi] butyl} -8-aza-spiro [4,5] decane-7,9- dions of the formula I and pharmaceutically suitable acid addition sets thereof, which is characterized in that a compound of the general formula II (in which A denotes the group -CsC- or -CH = CH-) is hydrogenated and, if desired, the compound of the formula thus obtained I transferred to a pharmaceutically acceptable acid addition salt.

In one embodiment of the process according to the invention, the compound of the formula IIA is hydrogenated. The hydrogenation can be carried out in the presence of a metal catalyst with hydrogen

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will. Palladium or Raney nickel can be used as the catalyst. The procedure can be particularly advantageous by carrying out the hydrogenation in the presence of a palladium catalyst applied to carbon. The hydrogenation of the compound of formula IIA can be carried out in an inert organic solvent. Low aliphatic alcohols (e.g. methanol or ethanol) are primarily considered as the reaction medium.

The hydrogenation can preferably be carried out under atmospheric pressure, at room temperature.

The compound of formula I obtained can be isolated in a very simple manner from the reaction mixture in a known manner. The procedure can be such that the catalyst is filtered and the filtrate is evaporated. The catalyst can be returned to the hydrogenation process without further treatment.

The desired compound of formula I is obtained in a very pure state and is suitable for pharmaceutical purposes without further purification.

According to a further embodiment of the process according to the invention, the compound of the formula IIB is hydrogenated. The reduction can be carried out in the presence of a metal catalyst (advantageously palladium) by catalytic hydrogenation. The reaction can be carried out in an inert organic solvent as a medium. Lower aliphatic alcohols (e.g. methanol or ethanol) are primarily suitable for this purpose. The hydrogenation of the compound of formula IIB is advantageously carried out at room temperature under atmospheric pressure.

The compound of formula II thus obtained can be converted into an acid addition salt in a customary manner by reaction with the corresponding acid in an inert solvent. Pharmaceutically acceptable inorganic acids (e.g. hydrochloric acid, hydrogen bromide, sulfuric acid, nitric acid) or organic acids (e.g. maleic acid, fumaric acid, lactic acid, malic acid, tartaric acid, succinic acid, etc.) are suitable for salt formation.

The compounds of general formula II used as starting materials are new.

The invention further relates to new compounds of the general formula II (in which A denotes the group —CsC— or —CH = CH-) and acid addition salts thereof.

The general formula II includes the following compounds: 8- {4- [4- (2-pyrimidinyl) -1-piperazinyl] but-2-ynyl} -8-aza-spiro [4,5] decane-7,9 -dione of the formula IIA and 8- {4- [4- (2-pyrimidinyl) -1-piperazinyl] but-2-enyl} -8-aza-spiro [4,5] decan-7,9-dione der Formula IIB.

The compounds of the general formula II are valuable intermediates which can be used in the preparation of the compounds of the formula I and have valuable pharmacological properties themselves.

They are used for the production of pharmaceutical preparations which contain as active ingredient a compound of the general formula II or a pharmaceutically suitable acid addition salt thereof and suitable inert solid or liquid carriers.

The compounds of general formula II, wherein A is the group -C = C- or -CH = CH- and acid addition salts thereof, can be prepared by a) preparing the compound of formula IIA using the propyne derivative of formula III with the amine the formula IV is subject to a Mannich condensation, or b) for the preparation of the compound of the formula IIA the propyne derivative of the formula III is reacted with an alkylmagnesium halide of the general formula V (in which R denotes an alkyl group containing 1-4 carbon atoms and Hlg chlorine , Is iodine or bromine); the compound of general formula VI obtained (in which Hlg has the above meaning) is reacted with at least a molar equivalent amount of trioxymethylene or formaldehyde; the substituted amino alcohol of formula VII obtained is converted into a reactive ester of general formula VIII (in which X represents a reactive ester group) and the resulting compound of general formula VIII is reacted with an amine of formula IV, or c) to prepare the compound of formula IIB subjecting the compound of formula IIA to partial hydrogenation and, if desired, converting a compound of general formula II obtained into an acid addition salt or releasing it from a salt.

According to process variant a), the compound of the formula IIA is prepared by subjecting the propyne derivative of the formula III to a Mannich condensation with an amine of the formula IV. Mannich condensation is carried out in a manner known per se / Calvin A. Bühler, Donald E. Pearson: Survey of Organic Syntheses (USA 1970) Vol. 1 page 465 /. The procedure can advantageously be such that the formaldehyde is used in the form of paraformaidehyde. The reaction can preferably be carried out in an inert organic solvent. Ether (e.g. diethyl ether, dioxane, tetrahydrofuran) are primarily suitable as the reaction medium. The desired compound of Formet IIA can be isolated from the reaction mixture in a known manner (e.g. by extraction with a suitable solvent).

In the first stage of process variant b), the propyne derivative of the formula III is reacted with an alkyl-magnesium halide of the general formula V. R represents a straight-chain or branched alkyl group containing 1-4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, isobutyl

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etc.). As Grignard compound of the general formula V, methyl magnesium iodide, methyl magnesium bromide, methyl magnesium chloride, ethyl magnesium iodide, ethyl magnesium bromide or ethyl magnesium chloride can preferably be used. Implementation of the compounds of the formulas. III and V can advantageously be realized in anhydrous ether as a medium.

The compound of general formula VI obtained in this way is reacted - preferably without isolation - with at least a molar equivalent amount of trioxymethylene or formaldehyde. The formaldehyde can preferably be added in the form of gaseous formaldehyde. The trioxymethylene or formaldehyde is preferably used in an amount of 1-1.1 moles (preferably 1-1.05 moles) - based on 1 mole of the compound of the general formula VI. The compound of formula Vii obtained can be obtained by concentrating the ethereal solution.

The compound of formula VII thus obtained is converted in a manner known per se into a reactive ester of the general formula VIII. X is preferably halogen (e.g. chlorine, bromine or iodine), alkylsulfonyloxy (e.g. methanesulfonyloxy) or arylsulfonyloxy (e.g. phenylsulfonyloxy, p-bromophenylsulfonytoxy or p-toluenesulfonyloxy). According to a particularly advantageous embodiment of this process step, the compound of formula VII is reacted with p-toluenesulfonyl chloride. The reaction can be carried out at room temperature or with gentle warming.

The compound of general formula VIII thus obtained can be reacted with the amine of formula IV in a manner known per se, after or advantageously without isolation. This reaction is advantageously carried out in an inert organic solvent. Aromatic hydrocarbons (e.g. benzene, toluene or xylene) are primarily suitable as the reaction medium. The reaction can preferably be carried out with heating and it is particularly advantageous to work at the boiling point of the reaction mixture.

The compound of formula IIA thus obtained can be isolated from the reaction mixture by known methods (e.g. concentration).

According to process variant c), the compound of formula IIA is converted into the compound of formula IIB by partial hydrogenation. The partial hydrogenation is carried out catalytically, advantageously in the presence of a poisoned metal catalyst. According to a particularly advantageous embodiment of this process variant, a palladium catalyst poisoned with quinoin, calcium carbonate or lead acetate is used [Org. Synt. Coli. Vol. 3, 629 (1955)}. The partial hydrogenation according to the invention can preferably be carried out under atmospheric pressure, at room temperature. The reaction can preferably be carried out in an inert organic solvent. Lower aliphatic alcohols (e.g. methanol or ethanol) are particularly suitable for this purpose. The compound of formula IIB formed can be isolated by known methods (e.g. by filtering the catalyst and concentrating the filtrate).

The compound of general formula II obtained can be converted into acid addition salts by known methods. Pharmaceutically acceptable inorganic or organic acids (e.g. hydrochloric acid, hydrogen bromide, sulfuric acid, nitric acid or maleic acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, etc.) are advantageously suitable for salt formation. The salt formation can generally be carried out by reacting the base of the general formula II in an inert solvent with a molar equivalent amount of the corresponding acid.

The compound of general formula II can be released from the acid addition salts in a known manner (e.g. by treatment with a base).

The 8-aza-spiro [4,51decan-7,9-dione-8-prop-2-in the formula III used as the starting material is a known compound.

The invention further relates to a process for the preparation of the 8-aza-spiro [4,5] decan-7,9-dione-8-prop-2-ins of the formula III, characterized in that the 8-aza reacting spiro [4,5] -decan-7,9-dione of the formula X in an inert solvent, in the presence of an acid binder, with a propargyl hafogenide of the general formula XI (in which shark means bromine, chlorine or iodine).

According to a known process, the 8-aza-spiro [4,5] decane-7,9-dione-8-prop-2-in the formula III is prepared in such a way that the 8-oxa-spiro [4,5] decane -7,9-dione and propargylamine in pyridine are boiled for 15 hours, after which the thin reaction mixture is concentrated and the residue is purified by distillation under reduced pressure [Yao-Hua Wu and co-workers: J. Med. Chem. 12, 876 -881 (1969)]. The desired compound of formula III is obtained in a yield of 76%.

The above known method has several disadvantages, which are particularly serious in operation. The reaction time is very long (15 hours), the reaction temperature is high (over 115 ° C). The specific utilization of the reactor volume is unfavorable, the handling, treatment, regeneration and destruction of the pyridine used as solvent is problematic and environmentally unfriendly. Another disadvantage is that the propargylamine used as the starting material is expensive and difficult to access.

Another object of the invention is to eliminate the above disadvantages of the known method and to create a method for producing the compound of formula III which can also be carried out at low cost.

The invention is based on the knowledge that the desired compound of the formula III by reacting the 8-aza-spiro [4,5] decane-7,9-dione of the formula X with a propargyl halide of the general

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neri Formula XI can be produced under simple conditions in a way that is easy to implement even in operation.

Propargyl bromide can preferably be used as the starting material of the general formula XI.

The starting materials of the general formula X and XI can preferably be used in equimolar amounts, but the propargyl halide of the general formula XI can also be used in a slight excess of about 10-20 mol%.

The reaction can be carried out in an inert organic solvent. Any organic solvent which does not react with the reaction components under the conditions used and does not adversely affect the course of the reaction is suitable as the reaction medium. Ether (e.g. tetrahydrofuran, dioxane), esters (e.g. ethyl acetate), nitriles (e.g. acetonitrile) or ketones (e.g. acetone or methyl ethyl ketone) or a mixture thereof can preferably be used as the reaction medium.

The reaction is carried out in the presence of an acid binder. Alkali carbonates (e.g. sodium carbonate or potassium carbonate) are primarily suitable for this purpose. Other inorganic bases can also be used, e.g. Alkaline earth carbonates (e.g. calcium carbonate), alkali bicarbonates (e.g. sodium bicarbonate, potassium bicarbonate), alkali hydrides (e.g. sodium hydride) or alkali amides (e.g. sodium amide etc.). Tertiary amines can also play the role of acid binders (e.g. trialkylamines such as triethylamine).

The reaction can be carried out over a wide temperature range. You can generally work at 45-110 ° C - preferably between 55 ° C and 100 ° C. The reaction temperature mainly depends on the solvent used.

The implementation takes place very quickly and the reaction time is only a few hours. The reaction mixture can be worked up in a very simple manner. The reaction mixture can be cooled, the insoluble substances (alkali carbonate, alkali metal halide) removed by filtration or centrifugation and the filtrate concentrated. The desired compound of formula III is obtained in such a purity that further purification is unnecessary. A sample of analytical purity can be obtained by fractional distillation under reduced pressure.

The advantages of the production process according to the invention for the compounds of the formula (I) can be summarized as follows:

- no long reaction time is necessary;

- The use of a reaction temperature exceeding 100 ° C is not necessary;

- the disadvantages associated with the regeneration and destruction of pyridine are eliminated;

- The process is rather environmentally friendly than the known method;

- The method is inexpensive and economically feasible even in operation;

- The specific use of the devices is favorable;

- high yield;

- high degree of purity;

-Use of easily accessible raw materials;

- The intermediate product obtained can be processed without further purification.

Further details of the method according to the invention can be found in the examples below, without restricting the scope of protection to these examples.

Preparation of the compound of formula I.

example 1

8- {4- [4- (2-Pyrimidinyl) -1-piperazinyl] butyl} -8-aza-spiro [4,5] decane-7,9-dione

A solution of 38.15 g (0.1 mol) of 8- {4- [4- (2-pyrimidinyl) -1-piperazinyl] but-2-ynyl} -8-aza-spiro- [4,5] Decan-7,9-dione and 150 ml of ethanol are added to 1 g of a palladium / bone carbon catalyst, whereupon the mixture is hydrogenated at room temperature under atmospheric pressure with vigorous stirring until the hydrogen uptake comes to a standstill (2 equivalents of hydrogen, approx 5 I). The catalyst is removed by filtration and can be used for further hydrogenation without any treatment. The solvent is removed under reduced pressure. 36.85 g of the compound set in the title are obtained, yield 95.6%, melting point: 91-99 ° C. (the melting point given in the literature is 90-98 ° C.).

Analysis: on formula C21H31N5O2 (385.52)

calculated: C% = 65.43, H% = 8.11, N% = 18.17;

found: C% = 65.01, H% = 8.00, N% = 18.15.

The hydrochloride is formed from the above base with an equivalent amount of hydrochloric acid-containing ethanol. The salt melts at 200-202 ° C (the melting point given in the literature is 201.5-202.5 ° C),

Analysis: for the formula C21H32N5O2 • HCl (421.98)

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calculated: C% = 59.77, H% = 7.65, N% = 4.30, Cl "% = 8.40;

found: G% = 59.51, H% = 7.50, N% = 4.26, Cl "% = 8.37.

Preparation of the compound of formula IIA

Example 2

8- {4- [4- (2-Pyridinyl) -1-piperazinyl] -but-2-ynyl} -8-aza-spiro [4,5] decan-7, g-dione in a equipped with stirrer and reflux condenser 250 ml round bottom flasks become 20.5 g (0.1 mol) 8-aza-spiro [4.5] decane-7,9-dione-8-prop-2-yne, 25 ml dioxane, 17.2 g (0.105 Weighed out mol) 1- (2-pyrimidinyl) piperazine, 3.6 g paraformaldehyde and 0.2 g copper (II) acetate. The reaction mixture is heated to boiling for 3 hours, then cooled to room temperature, poured into water and extracted three times with 50 ml of benzene each. The combined benzene solutions are clarified with activated carbon and concentrated on a hot water bath. 33.95 g of the compound mentioned in the title are obtained. Yield 89%, m.p .: 78-80 ° C (petroleum ether).

Analysis for the formula C21H27N5O2 (381.49)

calculated: C% a 66.12, H% = 7.13, N% = 18.36;

found: C% = 66.02, H% = 7.22, N% = 18.30.

Example 3

8- {4-t4- (2-pyridinyl) -1-piperazinyl] but-2-ynyl} -8-aza-spiro [4,5] decane-7,9-dione

"From 15.6 g (0.11 mol) of methyl iodide and 2.68 g (0.11 g-atom) of magnesium in 170 ml of anhydrous ether, a Grignard blend is made, which with vigorous stirring is a solution of 20.5 g (0.1 mol) 8-aza-spiro [4,5] decane-7,9-dione-8-prop-2-in and 50 ml of anhydrous ether is added dropwise. The reaction mixture is heated to boiling until the methane gas evolution stops, after which 3 g (0.1 mol) of trioxymethylene (or 0.1 mol of anhydrous gaseous formaldehyde) is added or introduced. The reaction mixture is heated to boiling for a further 4 hours and then poured into a solution of 10 g of ammonium chloride and 35 ml of ice-cold water. The ethereal solution is separated, dried over anhydrous magnesium sulfate and concentrated.

The oily residue (22.8 g, 96%) is mixed without purification with a suspension of 4.9 g (0.1 mol) of sodium amide and 70 ml of anhydrous benzene, after which 19 g (0 , 1 mol) of p-toluenesulfonyl chloride are added. After the addition is complete, the reaction mixture is stirred at room temperature for a few hours and washed successively with 40 ml of water, 40 ml of a saturated sodium bicarbonate solution and 40 ml of water, and dried over anhydrous magnesium sulfate. 17.2 g (0.105 mol) of 1- (2-pyrimidinyl) piperazine are added to the benzene solution, and the reaction mixture is heated to boiling. The mixture is washed with an aqueous sodium bicarbonate solution and water, and the benzene solution is concentrated under reduced pressure. The separated crystals are filtered. 23.65 g of the compound mentioned in the title are obtained in the form of white crystals. Yield 62%, m.p .: 78-79 ° G. Analysis: based on the formula C2tH27N502 (381.49)

calculated: C% = 66.12, H% = 7.13, N% = 18.36;

found: G% = 65.85, H% = 7.02, N% = 18.10.

Preparation of the compound of formula IIB

Example 4

8- {4- [4- (2-Pyrimidinyl) -1-piperazinyl] but-2-enyl} -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-spirol4,5,] decane are placed in a hydrogenation apparatus Weighed -7.9-dione, 150 ml of ethanol, 1 g of a palladium / bone charcoal catalyst and 1 ml of "Chinoiin S" deactivator. The mixture is hydrogenated at room temperature until the theoretical amount of hydrogen (1 molar equivalent) is taken up. The catalyst is filtered and the filtrate is concentrated. 37.2 g of the compound mentioned in the title are obtained. Yield 97%. Analysis: on the formula C21H29N5O2 (383.5)

calculated: C% = 65.77, H% = 7.62, N% = 18.26;

found: C% = 65.18, H% = 27.47, N% = 18.15.

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Preparation of the compound of formula III Example 5

8-aza-spiro [4,5] decane-7,9-dione-8-prop-2-in

In a round-bottom flask equipped with a stirrer, dropping funnel and reflux condenser, 167.2 g (100 mol) of 8-aza-spiro [4.5] decan-7,9-dione, 130.86 g (1.1 mol) of propargibromide, 138 are , 2g (1.0 mol) of potassium carbonate and 250 ml of acetonitrile. The reaction mixture is heated to reflux with stirring for a few hours, then cooled to room temperature, filtered and the filtrate is evaporated. 178.6 g of the compound mentioned in the title are obtained, yield 87%. The boiling point of the colorless viscous oil obtained is 150 ° C / 53.31 Pa.

Analysis: on the formula C12H15NO2 (205.26)

calculated: C% = 70.22, H% = 7.36, N% = 6.82;

found: C% = 71.10, H% = 7.42, N% = 6.80.

Example 6

The procedure is as in Example 5, with the difference that the potassium carbonate is replaced by 105.9 g (1.0 mol) of sodium carbonate. 162.2 g of the compound mentioned in Example 5 are obtained. Yield 79%, boiling point: 150 ° C / 53.31 Pa.

Example 7

The procedure is as in Example 5, with the difference that the acetonitrile is replaced by 250 ml of tetrahydrofuran. 149.84 g of the compound mentioned in Example 5 are obtained. Yield 73%, boiling point 150 ° G / 53.31 Pa.

Example 8

The procedure is as in Example 5, with the difference that the acetonitrile is replaced by 240 ml of dioxane. 170.4 g of the compound mentioned in Example 5 are obtained. Yield 83%, boiling point: 150 ° C / 53.32 Pa.

Example 9

The procedure is as in Example 5, with the difference that the acetonitrile is replaced by 320 ml of ethyl acetate. 145.7 g of the compound mentioned in Example 5 are obtained. Yield 71%, boiling point: 150 ° C / 53.32 Pa.

Example 10

The procedure is as in Example 5, with the difference that the acetonitrile is replaced by 290 ml of acetone. 153.95 g of the compound mentioned in Example 5 are obtained. Yield 75%, boiling point: 150 ° C / 53.32 Pa.

Example 11

The procedure is as in Example 5, with the difference that the starting material is replaced by 250 ml of methyl ethyl ketone. 178.6 g of the compound mentioned in Example 5 are obtained. Yield 87%, boiling point: 150 ° C / 53.32 Pa.

Claims (10)

Claims 1. Process for the preparation of the 8- {4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl} -8-aza-spiro [4,5] de-can-7,9-dione of the formula I. 7 5 10th 15 20th 25th 30th 35 40 45 50 55 60 CH 677 924 A5 n - (ch2) 4 "n (i) and pharmaceutically suitable acid addition salts thereof, characterized in that a compound of formula II 0 in which A denotes the group -C = C- or -CH = CH-, hydrogenates and, if desired, converts the compound of the formula I thus obtained into a pharmaceutically suitable acid addition salt. 2. The method according to claim 1, characterized in that the compound of formula IIA 3. The method according to claim 2, characterized in that one uses a palladium or Raney nickel catalyst. 4. The method according to claim 3, characterized in that one carries out the hydrogenation at atmospheric pressure and at room temperature. 5. The method according to claim 4, characterized in that one carries out the hydrogenation in an inert organic solvent, preferably in a lower aliphatic alcohol - in particular methanol or ethanol. 6. The method according to claim 1, characterized in that the compound of formula HB n-ch2-ch = ch - ch2- n ö (IIB) hydrogenated in the presence of a metal catalyst. 7, Method according to claim 6, characterized in that one uses a palladium catalyst. 8, Compounds of formula II, wherein A is the group -CsC- or -CH = CH-, and acid addition salts thereof, as a means for performing the method according to claim 1. 9, application of the method according to claim 1 to compounds of formula IIA 8th 5 10. Application of the method according to claim 1 to compounds of formula IIA 0 which are obtained by using the 8-aza-spiro [4,5] decan-7,9-dione of the formula X (IIA) 9 5 10th 15 20th 25th 30th 35 40 45 50 55 60 CH 677 924 A5 .0 NH (X) 0 in an inert solvent, in the presence of an acid binder with a propargyl halide of the formula XI Hal-CH2-C = CH (XI), where shark means bromine, chlorine or iodine, to 8-aza-spiro [4,5] decane-7,9-dione-8-prop-2-ins of the formula III wherein shark means bromine, chlorine or iodine, the latter with an alkyl magnesium halide of the formula V R-Mg-Hlg (V), wherein R is an alkyl group containing 1 to 4 carbon atoms and Hlg is chlorine, iodine or bromine, the resulting compound of formula VI wherein Hlg has the above meaning, reacted with at least a molar equivalent amount of trioxymethylene or formaldehyde; the substituted amino alcohol of the formula VII obtained 0 n-ch2-c = ch s p N-CH2-C = C-Mg - Hlg * 0 (VI), 0 n-ch2-c = c - ch2-oh ^ 0 (VII) into a reactive ester of formula VIII 10th 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 CH 677 924 A5 | i - ch2- c = c - ch2-x (VIII) transferred, wherein X represents a reactive ester group, and the compound of formula VIII obtained with an amine of formula IV 11 CH 677 924 A5 - N N (I) n- ch2-a- ch2- n n b ( H ) • c-ch2-n N-CH2-CH = CH-CH2-N N CH 677 924 A5 ( in ) HN N ■ {IV) R - Mg - Hlg (V) N - CH2 ~ C = C - Mg - Hlg 0 (VI) CH677 924 A5 -ch2-c sc- ch2-0h 0 (vii) ch2- c = c - ch2-x (vili) 0 nh '0 (x) ok (XI) 10th 15 20th 25th 30th 35 40 45 50 55 60 65 CH 677 924 A5 n- ch2- c s c-ch2-n n (IIA) which are obtained by using the 8-aza-spiro [4,5] decan-7,9-dione of the formula X (X) in an inert solvent, in the presence of an acid binder with a propargyl halide of the formula XI Hal-CH2-C = CH (XI), where shark means bromine, chlorine or iodine, to 8-aza-spiro [4,5Jdecan-7,9-dione-8-prop-2-ins of the formula III - ch2- c = ch (HD / wherein shark means bromine, chlorine or iodine, the latter with an amine of formula IV HN N (IV) and formaldehyde.