CS274423B2 - Method of 8-(4-(4-(2-pyrimidinyl)-1-piperazinyl) butyl)-8-aza-spiro (4,5)-decane-7,9-dione preparation - Google Patents

Description

The invention relates to a process for the preparation of the therapeutically active known 8- {4- [4- (2-pyrimidinyl) 1-piperazinyl] + butyl] -8-aza-1-spiro (4,5j + decane-7,9-dione of formula I)

i- / CH _2/4 -n

and pharmaceutically acceptable acid addition salts thereof.

The -7,9-dione of formula I has valuable anxioselective properties (GB Patent No. 1,332,194). Several methods are known in the art for the preparation of a compound of formula (I).

According to GB Patent No. 1,332,194 the compound of formula I is prepared by the reaction of 8-oxa-spiro [4,

pyridine at the boiling point of the reaction mixture. The desired compound of formula I is obtained in crude form in moderate yield. The crude product is purified as the free base by crystallization or traction distillation in vacuo. A disadvantage of the above-mentioned first purification method is the considerable losses, while the fractionated distillation under vacuum is carried out at high temperature (240-265 ° C) at low pressure (13.3 Pa), which requires considerable heat load and leads to product decomposition.

According to another method disclosed in this patent, 8- (4-chlorobutyl) -8-aza-spiro- [4,5] decane-7,9-dione is reacted for three days at the boiling point of the reaction mixture with N- (2-pyrimidinyl). + + piperazine in the presence of sodium carbonate in n-butanol. The process is unsuitable for industrial scale production due to the extremely long reaction time. Another disadvantage is that the product can only be purified using complex and lengthy methods. A further disadvantage is that 1-bromo-4-chlorobutane used as the starting material in the preparation of 8- (4-chlorobutyl) -8-aza-spiro [4,5} decane-7,9-dione is a very difficultly available compound , which can only be prepared using complex methods.

According to yet another method disclosed in this patent, 8-oxa-spiro [4,5- decane-7,9-dione is first converted to 8-aza-spiro- [4,5] decane-7,9-dione. 1- (4-Chlorobutyl) -4- (2-pyrimidinyl) piperazine prepared from N- (2-pyrimidinyl) piperazine and 1-bromo-4-chlorobutane is reacted with 8-aza-spiro [4,5] decane- 7,9-dione. The process involves several steps which are very sensitive and can only be carried out with considerable difficulty. The compound of formula (I) obtained is suitable for pharmaceutical use only after multiple purification. A further disadvantage lies in the difficult availability of the 1-bromo-4-chlorobutane used as starting material.

1- (4-Aminobutyl) -4- (2-pyrimidinyl) piperazine can be prepared by reacting 1- (2-pyrimidinyl) piperazine with 3-chloropropionitrile in n-butanol as the medium at the boiling point of the reaction mixture for an extended period of time (reaction). time is 16 hours). The intermediate obtained must be subjected to crystallization purification (yield 70%). The nitrile intermediate is catalytically hydrogenated under pressure in a yield of 70% (GB Patent No. 1,332,194).

Hungarian Patent No. 187,999 discloses another method wherein compounds of Formula I are prepared from 1- (4-chlorobutyl) -4- (2-pyrimidinyl) -piperazine via a spiroquaternary ammonium piperazine derivative of Formula I

which is reacted with 8-aza-spiro [4,5-decane-7,9-dione in the presence of a strong base. The method is accompanied by numerous drawbacks. The yield is low, the synthesis is multistage and the contaminated product obtained can only be difficult to purify.

According to Swiss Patent No. 647,518, 8-aza-spiro [4.5] decane-7,9-dione is first reacted with 1,4-dibromobutane, the 4-bromobutyl derivative thus obtained is reacted with piperazine and then allowed to react. the product thus obtained is reacted with 2-chloropyrimidine. The subject of this patent is the preparation of a compound labeled with a CC isotope, therefore it is of theoretical importance only.

According to Spanish patent No. 536 286, the potassium salt of 8-aza-spiro [4,5] decane-7,9-dione is reacted with 4-chlorobutyraldehyde, and the product obtained is then reacted with N- / 2-pyrimidinyl under reducing conditions. / piperazine. The method is not suitable for industrial scale production.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a process which overcomes the drawbacks of the above known methods and allows suitable preparation of the compound of formula I also on an industrial scale using readily available starting materials in good yield and high purity.

The present invention provides a process for the preparation of an 8-aza-spiro [4,5] + decane-7,2-dione of the formula:

8- [4- [4- (2-Pyrimidinyl) -1-piperazinyl] + butyl] and its pharmaceutically acceptable addition salts, a compound of formula II

wherein A is -C-C- or -CH = CH-, hydrogenates in an inert organic solvent in the presence of a metal catalyst, optionally converting the compound of formula I so obtained into a pharmaceutically acceptable acid addition salt.

According to a preferred embodiment of the invention, the compound of formula IIA is hydrogenated

in the presence of a metal catalyst with hydrogen. As a catalyst, palladium or Raney nickel can be advantageously used. Preferably, the hydrogenation is carried out in the presence of a palladium catalyst applied to the activated carbon carrier. The hydrogenation is carried out in an inert organic solvent. As reaction medium preferably aliphatic alcohols having 1 to 4 carbon atoms, in particular methanol or ethanol, may be used. The hydrogenation can be carried out preferably at atmospheric pressure at room temperature.

The compound of formula I can be isolated from the reaction mixture by known methods. One method is to remove the catalyst by filtration and evaporating the filtrate. The catalyst can be recycled directly to the hydrogenation without further treatment.

The obtained compound of formula I is of high purity and is suitable for pharmaceutical use without any special purification.

According to another preferred embodiment of the invention, the compound of formula IIB is hydrogenated

and catalytic hydrogenation. Preferably, palladium may be used as the metal catalyst. The reaction is carried out in an inert organic solvent. As reaction medium preferably aliphatic alcohols having 1 to 4 carbon atoms, in particular methanol or ethanol, can be used. The hydrogenation can preferably be carried out at atmospheric pressure at room temperature.

The compound of formula I obtained can be converted to an acid addition salt by known methods. Any pharmaceutically acceptable inorganic acid such as hydrochloric, hydrobromic, sulfuric, nitric and the like, or an organic acid such as maleic, fumaric, lactic, malic, tartaric, succinic, etc. may be used.

The starting materials of the formula II are novel compounds.

Also within the scope of the invention are compounds of formula II wherein A is -C -CC- or -CH = CH-.

These are the following new compounds:

8- [4- [4- (2-pyrimidinyl) -1-piperazinyl] -2-butynyl} -8-aza-spiro [4,5] decane-7,9-dione of formula IIA;

8- [4- [4- (2-Pirimidinyl) 1-piperazinyl] -2-butenyl [8-aza-spiro-C4,5] decane-7,9-dione of formula IIB.

The compounds of formula (II) are, on the one hand, useful intermediates useful in the preparation of the therapeutically active known compound of formula (I), while on the other hand they have valuable pharmaceutical properties.

The pharmaceutical compositions comprise as active ingredient a compound of formula II, wherein A is as defined above, or a pharmaceutically acceptable acid addition salt thereof, in admixture with a suitable inert carrier.

The pharmaceutical compositions can be prepared by known methods used in the pharmaceutical industry and contain conventional pharmaceutical carriers and excipients.

A process for the preparation of compounds of formula II wherein A is -C-C- or -CH = CH- and their acid addition salts is

a) for the preparation of a compound of formula IIA, in subjecting a propyne derivative of formula III

/ 111 /

Mannich condensation with an amine of formula IV

/ 'V or

b) for the preparation of a compound of formula IIA, in the reaction of a propyne derivative of formula III with an alkylmagnesium halide of formula V

R-Mg-H1 (V), wherein R is C 1 -C 4 alkyl and H 1 is chloro, iodo or bromo, in the reaction of the compound of formula (VI) thus obtained

(71) wherein H 1 is as defined above, with at least one molar equivalent of trioxymethylene or formaldehyde, in the conversion of the substituted amino alcohol of formula VII

wherein X denotes a reactive ester group, C 8 with a piperazine derivative of the formula in the reaction of the compound of formula (IV) thus obtained, or

c) for preparing a compound of formula IIB, subjecting the compound of formula IIA to partial hydrogenation, and optionally converting the compound of formula II thus obtained into an acid addition salt or liberating a base from the acid addition salt.

According to method a), a compound of formula IIA is prepared by subjecting a propyne derivative of formula III to a Mannich condensation with an amine of formula IV. The Mannich condensation is carried out in a known manner (Calvin A. Buehler, Donald E. Pearson: Survey of Organic Syntheses (USA, 1970), Vol. 1, p. 465). Preferably, the formaldehyde is used in the form of paraformaldehyde. The reaction may be carried out in an inert organic solvent, or an ether (e.g. diethyl ether, dioxane or tetrahydrofuran) may be used as the reaction medium.The compound of formula IIA may be isolated from the reaction mixture in a manner known per se (e.g. organic solvent).

In the first step of method b), the propyne derivative of formula III is reacted with an alkylmagnesium halide of formula V. R represents a straight or branched alkyl group having 1 to 4 carbon atoms (for example methyl, ethyl, n-propyl, isobutyl, etc.). As the compound of formula (V), methylmagnesium iodide, methylmagnesium bromide, methylmagnesium chloride, ethylmagnesium iodide, ethylmagnesium chloride or ethylmagnesium bromide may be advantageously used. The reaction of the compounds of formula III and V can advantageously be carried out in an anhydrous ether medium with heating.

The compound of formula (VI) obtained is preferably reacted without isolation with at least a molar equivalent amount of trioxymethylene or paraformaldehyde. It is preferred to use gaseous formaldehyde. Trioxymethylene or formaldehyde is preferably used in an amount of 1 to 1.1 mol, in particular 1.0 to 1.05 mol, based on 1 mol of the compound of the general formula (VI). The reaction may be carried out preferably under heating. The compound of formula (VII) may be isolated by evaporation of the ether solution.

The resulting compound of formula VII is converted to the ester of formula VIII by a known method. X is preferably halogen (e.g. chlorine, bromine or iodine), alkylsulfonyloxy (e.g. methanesulfonyloxy) or arylsulfonyloxy (e.g. phenylsulfonyloxy, p-bromophenyl sulfonyloxy, p-toluenesulfonyloxy, etc.). Preferably, the compound of formula VII is reacted with p-toluenesulfonyl chloride. The reaction may be carried out at room temperature or with gentle heating.

The lacto-obtained compound of formula VIII is reacted without or after isolation, preferably directly without isolation, with a piperazine derivative of formula IV. The reaction may be carried out in a manner known per se. The reaction may preferably be carried out in an inert organic solvent. As the reaction medium, for example, aromatic hydrocarbons (for example benzene, toluene, xylene, etc.) can be used. The reaction can be advantageously carried out under heating, in particular at the boiling point of the reaction mixture.

The compound of formula (IIA) thus obtained can be isolated in a known manner (for example by evaporation of the reaction mixture).

According to method c), a compound of formula IIB is prepared by subjecting a compound of formula IIA to partial hydrogenation. The reduction is carried out by catalytic hydrogenation, preferably in the presence of a poisoned metal catalyst. Preferably, the palladium catalyst is poisoned with quinoline, calcium carbonate or lead acetate. Particularly preferred is the use of a quinoline poisoned catalyst (Org. Synt. Coli., 3, 629 (1955)). Partial hydrogenation can advantageously be carried out at room temperature and at atmospheric pressure. A lower aliphatic alcohol (e.g. methanol or ethanol) can be advantageously used as the reaction medium The compound of formula (IIB) thus obtained can be isolated by known methods (for example from catalyst filtration and evaporation of the filtrate).

The compound of formula (II) can be converted to the acid addition salt by known methods. Pharmaceutically acceptable inorganic or organic acids (for example hydrochloric, hydrobromic, sulfuric, nitric, or maleic, fumaric, lactic, malic, tartaric, succinic, etc.) may be preferably used for salt formation. The salt formation can advantageously be carried out by reacting the free base of formula II with a molar equivalent amount of the appropriate acid in an inert organic solvent.

The compound of formula (II) may be liberated from the acid addition salt by a known method by treatment with a suitable base.

8-Aza-spiro [4,5] decane-7,9-dione-8- (2-propyne) - formula III used as starting material in the above processes is a known compound.

The process for the preparation of 8-aza-spiro [4,5] decane-7,9-dione-8- (2-propyne) of the formula III consists of the reaction of 8-aza-spiro [4,5] decane-7,9-dione of formula X

with a propargyl halide of formula XI

Hal - CH ₂ - C = CH (XI), wherein Hal represents bromine, chlorine or iodine, in an inert solvent in the presence of an acid binding agent.

It is known that 8-aza-spiro [4,5-decane-7,9-dione-8- (2-propyne) of formula III can be prepared by heating a mixture of 8-oxa-spiro- [4,5] -decane- 7,9-dione and propargylamine in pyridine to boiling for 15 hours, evaporation of the diluted reaction mixture and purification of the residue by vacuum distillation [Yao-Gua Wu et al., J, Med. Chem. 12, 876-881 (1969)]. The compound of formula III is obtained in 76% yield.

The above process has various drawbacks which are particularly serious in industrial scale production. The reaction time is very long (15 hours) and the temperature used is high (above 115 ° C). The specific utilization of the reactor volume is unfavorable. The treatment, recovery and elimination of pyridine used as solvent is problematic and involves a serious risk of environmental contamination. A further disadvantage is that the propargylamine used as the starting material is difficult to access and expensive.

Eliminating the above drawbacks of the known methods and providing an economical process for the preparation of the compound of formula III, which can also be used on an industrial scale, is based on the finding that by reaction of 8-aza-spiro [4,5-decane-7,9-dione of formula X with the propargyl halide of the formula XI gives the compound of the formula III in good yield and high purity in an easy and simple manner.

Ί

CS 274423 Β2

Propargyl bromide can preferably be used as the compound of formula XI.

The starting material of formula (X) and (XI) may be used in equivolar amounts, but the propargyl halide of formula (XI) may also be applied in small, i.e. 10 to 20 mol%. surplus.

The reaction may be carried out in any suitable inert organic solvent. Any organic solvent that does not interfere with the reactants and does not adversely affect the reaction may be used as the reaction medium. It is preferred to use an ether (e.g. tetrahydrofuran, dioxane, etc.), an ester (e.g. ethyl acetate), a nitrile (e.g. acetonitrile) or a ketone (e.g. acetone or methyl ethyl ketone) or mixtures thereof as the reaction medium.

The reaction is carried out in the presence of an acid binding agent. For this purpose, an alkali metal carbonate (especially sodium or potassium carbonate) may be advantageously used, but other inorganic bases may also be used, for example an alkaline earth metal carbonate (eg calcium carbonate), an alkali metal bicarbonate (eg sodium or potassium bicarbonate), a hydride alkali metal (e.g., sodium amide, etc.). In addition, organic bases (e.g., trialkylamines such as triethylamine) can also be used as an acid binding agent.

The reaction temperature can be varied within a wide range. In general, the reaction is carried out at a temperature in the range of 45 to 110 ° C, preferably 55 to 100 ° C. The reaction temperature depends on the solvent used.

The reaction proceeds very quickly, the reaction time being several hours.

The reaction mixture can be worked up in a very simple manner. The reaction mixture was cooled, insoluble materials (alkali metal carbonate, alkali metal halide) were removed by filtration or centrifugation and the filtrate was evaporated. Thus, the compound of formula III is obtained in high purity, and can be used for further reactions directly without further purification. A sample of the analytical purity of the product was obtained by fractional distillation under vacuum.

The advantages of the above method of the invention may be summarized as follows:

- a long reaction time is not required;

the reaction may be carried out at a temperature not exceeding 100 ° C;

- pyridine is not used, therefore the difficulties that accompany solvent recovery and elimination are eliminated;

the method is more environmentally friendly;

the method is applicable on an industrial scale;

- the specific use of the device is favorable;

- the yield is very high;

the desired compound of formula III is obtained in high purity and can be used for the next reaction directly without further purification.

The process will be explained in more detail in the following examples without limiting the scope of the invention.

Β

He did

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

To a solution of 38.15 g (0.1 mol) of B- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butin-2-yl-8-aza-spirop 4,5] decane-7,9- of dione in 150 ml of ethanol, 1 g of palladium on charcoal catalyst is added, then the mixture is hydrogenated at atmospheric pressure at room temperature with vigorous stirring until hydrogen consumption ceases (2 equivalents of hydrogen, about 5 L). The catalyst is removed by filtration and can be used directly in the next hydrogenation step. The filtrate was evaporated in vacuo. 36.65 g of the desired compound are obtained, yield 95.6%.

Mp: 91-99 ° C (prior art melting point 90-98 ° C).

Analysis for C ₂ 11N5O2 (385.52) calculated: 65.43% C, 8.11% H, 18.17% N;

Found: C, 65.01; H, 8.00; N, 18.15.

The above base is converted to the hydrochloride by reaction with an equimolar amount of hydrogen chloride in ethanol. The hydrochloride melts at 200 to 202 ° C (melting point in the prior art is 201.5 to 202.5 ° C).

For CΗΗHΗ 4,3 (421.98) calculated: 59.77% C, 7.65% H, 4.3X N, 8.40% Cl ';

Found: C 59.51, H 7.50, N 4.26, Cl 8.37.

Example 2

Preparation of 8- [4- (4- (2-pyrimidinyl) -1-piperazinyl) butyl] -8-aza-spiro [4.5] decane-7,9-dione

Weigh 38.59 g (0.1 mol) of 8- {4-C4- (2-pyrimidinyl) -1-piperazinyl] buten-2-yl; -8-aza-spirof4,5] decane-7,9-dione, 150 ml of anhydrous dioxane and 1 g of palladium on carbon. The mixture was then hydrogenated at room temperature with shaking until the theoretical amount of hydrogen (1 mol equivalent) was taken up. The catalyst was filtered off and the solvent was evaporated. In this way, 37 g of the desired compound are obtained, m.p. 93 ° C.

Analysis for ^C 21 ^H 31 ^N 5 ^O 2 (85.52) calculated: 65.43% C, 8.11 XH, 18.17 XN;

found: 65.14 X C, 8.05 X H, 18.20 X N.

Claims (7)

SUBJECT OF THE INVENTION 1. A process for the preparation of 8- (4- [4- (2-pyrimidinyl) -1-piperazinyl) -butyl] -8-pyraziro [4,5] decane-7,9-dione of formula I and its pharmaceutically acceptable acid addition salts, characterized in that the compound of formula II is n-ch ₂ -a-ch ₂ -n NO> ^{/ Π ό} wherein A represents -CC- or -CH = CH-, is hydrogenated in an inert organic rozpozštědle the presence of a metal catalyst, if necessary, the obtained compound of formula I into a pharmaceutically acceptable acid addition salt. 2. The process of claim 1, wherein the compound of formula IIA (HA) is hydrogenated. 3. The method according to claim 1, characterized in that a compound of formula IIB O \ j -CH ₂ -CH = CH-CH ₂ -N ^ \? - (/ 113 /. ''O 4. A process according to claim 2 wherein the catalyst is palladium or Raney nickel. 5. The process of claim 3 wherein the catalyst is palladium. 6. A process according to any one of claims 1 to 3, wherein the hydrogenation is carried out at atmospheric pressure and room temperature. 7. Process according to claim 1, wherein the inert organic solvent is an aliphatic alcohol having 1 to 4 carbon atoms, preferably methanol or ethanol.