DK152730B - Method for production of 8-{4-[4-(2-pyrimidinyl)-1- piperazinyl]-butyl}-8-azaspiro(4,5)-decane-7,9-dione - Google Patents

Description

The present invention relates to a particular process for the preparation of 8- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -8-azaspiro (4,5) -decane-7,9-dione of formula

and the process of the invention is peculiar to said compound

wherein M represents an alkali metal, e.g., sodium, is reacted with a compound of the general formula

wherein X is a halogen atom, e.g., chlorine and R is an alkyl or aryl group, e.g., methyl or p-tolyl, to form a compound of the general formula

wherein X has the meaning given above, which is then reacted in a manner known per se with a compound of the formula

The compound of formula I, also known by the trivial name buspirone, is a known drug-active compound. U.S. Patent No. 3,717,634 discloses a process for its preparation wherein 8-oxaspiro (4,5) -decane-7,9-dione is reacted with 4-amino-1-butanol to 8- (4-hydroxybutyl) -8-azaspiro (4,5) -decane-7,9-dione converted to 8- (4-chloro-butyl) -8-azaspiro (4,5) -decane-7,9-dione (IV) which is finally reacted with 1- (2-pyrimidinyl) -piperazine (V).

However, the method of producing the intermediate IV included in this known process is not satisfactory for industrial production as the yield is quite low (about 40%) and after the two steps of the method, the products should also be purified by distillation in high vacuum. . Further, 4-amino-1-butanol used as one of the starting materials is extremely difficult to prepare and expensive.

U.S. Patent No. 3,717,634 also discloses a method by which a compound of formula II is reacted with 1- (4-chlorobutyl) -4- (2-pyrimidinyl) -piperazine. However, this is not the case in practice, for 1- (4-chlorobutyl) -4- (2-pyrimidinyl) -piperazine is not a stable compound, but is spontaneously cyclized to a quaternary ammonium compound.

It has now been found that the compound of formula IV can be made remarkably simpler and in very good yield if an 8-alkali metal-8-azaspiro (4,5) -decane-7,9-dione (II) is reacted with a 4-halogen -1-butylalkyl (or aryl) sulfonate (III). Advantageously, as alkali metal, sodium and as halogen chlorine are used.

Among the sulfonates in particular, the methanesulfonate and t-tolylsulfonate are discussed. The reaction is advantageously carried out in a polar aprotic solvent such as Ν, Ν-dimethylformamide or Ν, Ν-dimethylacetamide, at 50-150 ° C and most advantageously at ca. 80 ° C.

It is known to prepare compounds of formula III from R-sulfonic acid chloride and 4-halogen-1-butanol by carrying out the reaction in pyridine (Can. J. Chem. 34 ^ (1956) 757). However, it is more advantageous to use an inert organic solvent and at least an equimolar amount of a tertiary amine. In particular, methylene chloride and triethylamine are discussed.

For example, the compound of formula II can be prepared by reacting 3,3-tetramethylene glutaric acid with urea to give the corresponding imide, which is then reacted with an alkali metal alkoxide to form compound II.

The example serves to further elucidate the process of the invention, wherein A illustrates the process reaction of the compound of formula II with the compound of formula III, and B illustrates the process of reaction of the compound of formula IV with the compound of formula V.

Example A

8- (4-chlorobutyl) -8-azaspiro (4,5) -dekan-7,9-dione

A mixture containing 120 g (0.63 mole) of 8-sodium-8-azaspiro (4,5) -decane-7,9-dione and 165 g (0.63 mole) of 4-chlorobutyl p-toluenesulfonate (or 118 (4-chlorobutylmethanesulfonate) in 700 ml of Ν, Ν-dimethylformamide (or Ν, Ν-dimethylacetamide) is heated under stirring for 2 hours to 80 ° C. The mixture is cooled to 20 ° C and filtered. The solvent is removed under reduced pressure. To the liquid residue is added 1000 ml of methylene chloride and the resulting solution is washed twice with 500 ml of 0.5 N NaOH solution and twice with 500 ml of water. The solvent is removed under reduced pressure to give 140-148 g (85-90%) of the title product as an oily liquid.

1 H NMR (CDCl 3): 61.6 (12H, m), 2.5 (4h, s), 3.5 (2H, t), 3.75 (2H, t).

Example B

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

A mixture containing 50.0 g (0.19 mole) of 8- (4-chloro-butyl) -8-azaspiro (4,5) -decane-7,9-dione, 31.8 g (0.19 mole) 1- (2-Pyrimidinyl) -piperazine and 41 g of sodium carbonate in 300 ml of Ν, Ν-dimethylformamide are refluxed for 18 hours. The solution is filtered and the solvent removed under reduced pressure. The oily residue is crystallized from 2-propanol to give 58.3 g (85%) of the title product as colorless crystals, m.p. 109-110 ° C. 1 H NMR (CDCl 3): 61.5 (12H, m), 2.45 (6h, t), 2.55 (4H, s), 3.75 (6H, m), 6.4 (1H) , t), 8.25 (2H, d).

Claims (2)

A process for the preparation of 8- {4- [4- (2-pyrimidinyl) -1-piperazinyl] -butyl} -8-azaspiro (4,5) -decane-7,9-dione of the formula characterized by a compound of the formula wherein M is an alkali metal atom preferably sodium is reacted with a compound of the formula wherein X is a halogen atom, preferably chlorine, and R is an alkyl or aryl group, preferably methyl or p-tolyl, to form a compound of the formula then reacted in a known manner with a compound of the formula Process according to claim 1, characterized in that the reaction between compound II and compound III is carried out in a polar aprotic solvent, preferably Ν, Ν-dimethylformamide or Ν, Ν-dimethylacetamide, at 50-150 ° C and advantageously at ca. 80 ° C.