HU198477B - Process for producing pyrimidinyl piperazine derivatives - 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 provides new and improved pharmacologically active known 8 (4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl} -8-aza-1-spiro [4.5] decane-7,9-dione). process.

It is known that 8- {4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl} butyl-8-azaspiro [4.5] decane-7,9-dione of formula (I) has valuable anxioselective properties. has (l 332 194) no. British Patent Specification). Several processes are known in the literature for the preparation of the compound of formula (I).

No. 1,332,194. U. S. Patent No. 4,193,129 discloses the preparation of a compound of formula (I) by reacting 8-oxaspiro [4.5] decane-7,9-dione with 1- (4-aminobutyl) -4 (2'-pyrimidinyl) piperazine. They reacted. The reaction is carried out in pyridine at the boiling point of the reaction mixture. The desired compound of formula (I) is obtained in crude form in 55% yield. The crude product is purified by crystallization or fractional vacuum distillation in the base form. The disadvantage of the first purification method is the high loss, while the fractional vacuum distillation, due to the high temperature used (240-265 ° C) and low pressure (13.3 Pa), places the product under severe thermal stress, which can lead to material damage.

No. 1,332,194. According to another method described in British Patent Application, 8- (4-chlorobutyl) -8-azaspiro [4.5] decane-7,9-dione and N- (2-pyrimidinyl) piperazine in the presence of sodium carbonate in n-butanol at reflux for 3 days overreact. The very long reaction time calls into question the economical application of the process under industrial conditions. A further disadvantage is that the cleaning of the product can only be accomplished by complicated and demanding operations. It is a further disadvantage that the 1-bromo-4-chlorobutane used in the preparation of 8- (4-chlorobutyl) -8-azaspiro [4.5] decane-7,9-dione is a hardly accessible and only poorly prepared compound.

No. 1,332,194. According to a further process described in British Patent Application, 8-azaspiro [4.5] decane-7,9-dione is first prepared from 8-azaspiro [4.5] decane-7,9-dione. Reaction of N- (2-pyrimidinyl) piperazine with 1-bromo-4-chlorobutane gives 1- (4-chlorobutyl) -4- (2-pyrimidinyl) piperazine and this compound is prepared by 8-aza-spiro [4.5] with decane-7,9-dione as described above. The process yields the final product of formula (I) through several chemically difficult and delicate steps which are suitable for therapeutic purposes only after multiple purifications. A further disadvantage of the process is the complicated and cumbersome preparation of l-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 at reflux for a longer period. (reaction time 16 hours). The resulting intermediate is subjected to crystallization purification (70% yield). Intermediate nitrile is catalytically hydrogenated under pressure in about 70% yield (British Patent No. 1,332,194).

No. 187,999. A further process for the preparation of a compound of formula (I) is described in Hungarian Patent No. 5,600,900. Accordingly, 1- (4-chlorobutyl) -4- (2-pyrimidinyl) piperazine is first converted to the spiroquatemerammonium piperazine derivative of formula (IX), which in the presence of a strong base, 8-aza-spiro [4.5] decane With -7,9-dione. The process has many disadvantages. Thus, the yield is poor, the synthesis involves extra steps and the product is very difficult to purify.

No. 647,518. In the Swiss patent process, 8-aza-spiro [4.5] decane-7,9-dione is first reacted with 1,4-dibromobutane and then the resulting 4-bromobutyl derivative is reacted with piperazine to give 2-chloro with pyrimidine. The purpose of the process is to produce the compound labeled with the ' ⁴ C isotope and is of no industrial significance.

No. 536,286. According to a Spanish patent, the potassium salt of 8-azaspiro [4.5] decane-7,9-dione is reacted with 4-chlorobutyraldehyde and the resulting product is reacted with N- (2-pyrimidinyl) piperazine under reductive conditions. The procedure is of theoretical interest only and has no industrial significance.

It is an object of the present invention to overcome the above drawbacks of the known methods by the preparation of the desired compound of formula (I) in commercially feasible manner, using readily available starting materials, in good yield and in high purity.

The present invention relates to a process for preparing 8- (4- (4- (4 (2-pipimidinyl) -1-piperazinyl) butyl) -8-aza-spiro [4.5] decane-7,9-dione of the formula (I): hydrogenating a compound of formula (II) wherein A is -C5C- or -CH = CH-.

In one embodiment of the process of the present invention, the compound of formula (ΠΑ) is hydrogenated. The hydrogenation can be carried out in the presence of a metal catalyst with hydrogen gas. Palladium or Raney nickel is preferably used as the catalyst. In a particularly preferred embodiment of the process, the hydrogenation is carried out in the presence of palladium on charcoal. The hydrogenation of the compound of formula (IIA) may be carried out in an inert organic solvent medium. Preferably, the reaction medium is lower aliphatic alcohols, especially methanol or ethanol.

The hydrogenation is preferably carried out at atmospheric pressure at room temperature.

The compound of formula (I) precipitated from the reaction mixture can be isolated in a known manner and very simply. Alternatively, the catalyst is filtered off and the filtrate is de-solvented. The catalyst can be used for further reduction operations without further treatment.

The resulting compound of formula (I) is of high purity and can be used for therapeutic purposes without particular purification.

In another embodiment of the process of the present invention, the compound of formula (IIB) is reduced. The reaction is carried out by catalytic hydrogenation in the presence of a metal catalyst (preferably palladium). The reaction may be carried out in an inert organic solvent medium. Preferred reaction media are lower aliphatic alcohols, especially methanol or ethanol. The hydrogenation of the compound of formula (IIB) is preferably carried out at atmospheric pressure and at room temperature.

The compound of formula (I) thus obtained is reacted in a known manner with the appropriate acid in an inert solvent

HU 198477 can be converted into an acid addition salt. Pharmaceutically acceptable inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, etc.) or organic acids (e.g. maleic acid, fumaric acid, lactic acid, tartaric acid, succinic acid, etc.) may be used.

The compounds of formula (Π) used as starting materials are new and their preparation is described and claimed in Hungarian Patent Application No. T / 45,991.

The compound of formula IIA can be prepared by:

a) subjecting the propin derivative (III) to Mannich condensation with the amine (IV); obsession

b) reacting the propine derivative of formula (III) with an alkylmagnesium halide of formula (V) wherein R is C 1 -C 4 alkyl and H 2 is chlorine, bromine or iodine to give the compound of formula VI ( wherein Hg is as defined above) with at least a molar equivalent of trioxymethylene or formaldehyde, converting the resulting amino alcohol of formula VH into a reactive ester, and then obtaining the compound of formula VIH (wherein X is a reactive acid residue) with a piperazine derivative.

The compound of formula IIB can be prepared by partial hydrogenation of the compound of formula IIA in the presence of a poisoned catalyst.

Details of the preparation of the starting materials are given in the examples.

The advantage of our process is that it is easy to implement under industrial conditions, it is easily accessible, it is possible to use low-cost starting materials and it provides a high purity product in good yield.

Further details of our process are set forth in the following examples, without limiting the invention to the examples (the data of p.p. and f.p. in the example are uncorrected).

Example 1

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

38.15 g (0.1 mol) of 8- {4- [4- (2-pyrimidinyl) -1-piperazinyl] but-2-yn-yl} -8-aza-spiro [4.5] decane-7, To a solution of 9-dione in 150 ml of ethanol was added 1 g of palladium-on-charcoal (Selkat 2; Fine Chemicals Cooperative, Budapest) and hydrogenated under vigorous shaking at atmospheric pressure and room temperature (2 equivalents of hydrogen, ca. 5.0 liters). ). The catalyst is removed by filtration and can be used directly without further treatment for further hydrogenation. The reaction mixture was evaporated in vacuo. 36.85 g (95.6%) of the title compound are obtained. Mp: 91-99 ° C (Literature: 90-98 'C).

Analysis for C21 H31 N5 O2 (385.52):

Found: C, 65.43; H, 8.11; N, 18.17; Found: C, 65.01; Η% = 8.00; N, 18.15.

From the above base, hydrochloric acid containing an equivalent amount of hydrochloric acid is formed into ethanol salt. The hydrochloride melts at 200-202 'C (literal melting point

201.5-202.5 'C).

Analysis based on C21H32CLN5O2.HCL (421.98):

Found: C, 59.77; H, 7.65;

N, 4.3P; Cl- = 8.40;

Found: C, 59.51; H, 7.50; N, 4.26. Cl-% = 8.37.

Example 2

Preparation of starting material of formula IIA A) Preparation of 8-aza-spiro [4.5] decane-7,9-dione-8-propyne (2) 167.2 g (1.0) in a round-bottomed flask with stirring, addition funnel and reflux condenser. 8-aza-spiro [4.5] decane-7,9-dione, 130.86 g (1.1 mmol) propargyl bromide, 140 g (1 mol) potassium carbonate and 250 ml acetonitrile are added. The reaction mixture was refluxed for several hours, then cooled to room temperature, filtered and the solvent removed. 179.5 g (87%) of the title compound are obtained. MP: 150 'C / 5.31 Pa.

Analysis: Calculated for C12H15NO2 (205.26): C, 70.22; H, 7.36;

N, 6.82.

Found: C, 71.0; H, 7.42; N, 6.80.

Bi) Preparation of 8- {4- (4- (2-pyrimidinyl) -1-piperazinyl) but-2inyl} -8-azaspiro [4.5] decane-7,9-dione.

In a 250 ml round-bottomed flask equipped with a stirrer and reflux condenser, 20.5 g (0.1 mol) of 8-aza-spiro [4.5] decane-7,9-dione-8-propin (2), 25 ml of dioxane,

1- (2-Pyrimidinyl) piperazine (17.2 g, 0.105 mol), paraformaldehyde (3.6 g) and copper (II) acetate (0.2 g) 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 hot water bath. Yield: 33.95 g (89%). M.p. 78-80 ° C from petroleum ether).

Analysis: Calculated for C21H27N5O2 (381.49):

Calculated: C, 66.12; H, 7.13;

N, 18.36.

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

B2) Preparation of 8- [4- (4- (2-pyrimidinyl) -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) of magnesium in 170 ml of anhydrous ether, 20.5 g (0.1 mol) of a Grignard compound are added dropwise with vigorous stirring. A solution of 8-azaspiro [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 evaporated.

The oily residue (22.8 g, 96%) was treated without further purification with a slurry of sodium amide (3.9 g, 0.1 mol) in anhydrous benzene (70 ml), and then, at the end of the evolution of ammonia gas, moles) of p-toluenesulfonyl chloride are added. After the addition was complete, the reaction mixture was stirred at room temperature for several hours and then treated successively with 40 ml of sodium hydroxide solution.

After washing with saturated solution of bicarbonate and 40 ml of water again, it was dried over anhydrous magnesium sulfate. To the benzene solution was added 17.2 g (0.105 mol) of 1- (2-pyrimidinyl) piperazine and heated at reflux for a few hours. The reaction mixture was washed with aqueous sodium bicarbonate solution and then water, and the benzene solution was removed in vacuo. The residue is taken up in petroleum ether and the crystals are filtered off. 23.65 g (62%) of the title compound are obtained in the form of white crystals, 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

The starting material of formula IIB is prepared as follows:

Preparation of 8-4- [4- (2-pyrimidinyl) -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-2in-yl] -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 a quinoline S activity reducing agent. It is then hydrogenated at room temperature up to the theoretical amount of hydrogen (1 molar equivalent). The catalyst was filtered off and the solution was evaporated. Yield: 37.2 g (97%).

Analysis for C21 H29 N5 O2 (383.5): Calculated: C, 65.77; H, 7.62;

N, 18.26;

Found: C, 65.18; H, 7.47; N, 18.15. The above base melts at 79-80 'C (from petroleum ether). Salt formation: From the above base, an equivalent amount of fumaric acid in anhydrous ethyl alcohol is formed into a hot hydrogen fumarate salt.

Data for 2- (E) -butenidoate (111):

M.p .: 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.

U.V .: Xmax 1: 242nm (Σ = 23205)

Λmax 2: 300 nm (Σ = 2110)

Example 4

8- {4- (4- (2-Pyrimidinyl-1-piperazinyl) butyl) -8-azaspiro [4.5] decane-7,9-dione

38.35 g (0.1 mol) of 8- {4- (4- (2-pyrimidinyl-1-piperazinyl) buten-2-yl) -8-aza-spiro [4.5] decane-7, is charged to the hydrogenation apparatus. 9-dione, 150 ml of anhydrous dioxane and 1 g of palladium on charcoal. It is then hydrogenated at room temperature while shaking the apparatus (shaker) until the theoretical amount of hydrogen (1 molar equivalent) is taken up. The catalyst was filtered off and the solvent removed. 37 g of the title compound are obtained, m.p. 93-99 ° C.

Analysis for C21H31N5O2 (385.52); Found: C, 65.43; H, 8.11;

N, 18.17;

Found: C, 65.14; H, 8.05; N, 18.20.

Claims (10)

PATENT CLAIMS: A process for the preparation of 8- {4 - [- (2-pyrimidinyl) -1-piperazinyl] butyl) -8-aza-spiro [4.5] decane-7,9-dione of the formula (I): The compound of formula (() (wherein A is -CÜC- or CH = CH-) is hydrogenated. 2. The process of claim 1, wherein the compound of formula (HA) is hydrogenated. 3. A process according to claim 1 wherein the compound of formula (ΠΒ) is hydrogenated. Process according to claim 1 or 2, characterized in that the hydrogenation of the compound of formula (ΠΑ) is carried out in the presence of a metal catalyst. 5. A process according to claim 4 wherein the catalyst is palladium or Raney nickel. The process of claim 5, wherein the hydrogenation is carried out at atmospheric pressure and at room temperature. The process of claim 6, wherein the hydrogenation is carried out in an inert organic solvent medium. 8. The process according to claim 7, wherein the inorganic organic solvent used is a lower aliphatic alcohol, preferably methanol or ethanol. Process according to claim 1 or 3, characterized in that the hydrogenation of the compound of formula (ΠΒ) is carried out in the presence of a metal catalyst. The process according to claim 9, wherein the metal catalyst is palladium.