HU197313B - Process for producing 8-azaspiro <4.5> decane-7,9-dione-8-propine-/2/ - Google Patents

Abstract

The invention relates to a novel process for the preparation of piperazine derivatives of the formula I and pharmaceutically acceptable acid addition salts thereof, which comprises hydrogenating a compound of general formula II (wherein A is the group CC or CHCH) and, if desired, the thus obtained compound of formula I in a pharmaceutically suitable Saeureadditionssalz überfuehrt. The compound of formula I is a known anxioselective agent. The invention further relates to processes for the preparation of the intermediates used in the above process. {Process; manufacture; piperazine derivatives; pharmaceutically acceptable acid addition salts; anxioselective agent}

Description

The present invention relates to a new and improved process for the preparation of pharmaceutical intermediates. More particularly, the present invention relates to a process for the new preparation of 8-aza-spiro [4.5] decane-7,9-dione-8-propin (2).

The 8-aza-spiro [4.5] decane-7,9-dione-8-propin (2) is a valuable pharmaceutical intermediate that is primarily an anxioselectric 8-aza-spiro [4.5] decane-7. Can be used in the preparation of 9-dione derivatives.

According to a known process for the preparation of the compound of formula (I), Yao-Hua Wu et al., J.Med.Chem. 12, 876-881 (1969)] 8-oxaspiro [4.5] decane-7,9-dione and propargylamine in pyridine are refluxed for 15 hours, then the dilute reaction mixture is evaporated and the residue is purified by vacuum distillation. The compound of formula (I) is obtained in 76% yield.

The above process has several disadvantages, which are significant, especially when implemented on an industrial scale. The reaction time is very long (15 hours) and the reaction temperature used is high (above 115 ° C). The specific utilization of the reactor is unfavorable, and the treatment, regeneration and disposal of the pyridine used as a solvent poses problematic and serious environmental problems. A further disadvantage is that the propargyl aniline used in the reaction is a difficult to access, expensive, expensive material.

It is an object of the present invention to overcome the drawbacks of the known process and to provide a process which is advantageously feasible under industrial conditions for the preparation of 8-aza-spiro [4.5] decane-7,9-dione-8-propyne (2).

The present invention relates to a process for the preparation of 8-aza-spiro (4.5) decane-7,9-dione-8-propin (2) of formula (I) by reacting 8-aza-spiro [4.5] decane of formula (II) -7,9-dione is reacted with a propargyl halide of formula III (wherein Hal is bromine, chlorine or iodine) in an inert solvent medium in the presence of an acid binder. 7,9-Dione is commercially available, for example, its preparation is described in J. Chem.Soc. 1927, 602-604.

The present invention is based on the discovery that the process outlined above provides the compound of formula (I) in high yield, in good yields, avoiding the drawbacks of the known method, and in a simple manner on an industrial scale.

Preferred propargyl bromide may be used as the compound of formula (III) in the process of the present invention.

The reaction may be carried out in equimolar amounts of the compounds of the formulas II and III, but may also use a small excess of the propargyl halide of the formula III at 1020 mol%.

The process of the present invention may be carried out in an inert organic solvent. The reaction medium may be any solvent which does not react under the reaction conditions employed and does not adversely affect the desired course of the reaction. It has been found that ethers (e.g. tetrahydrofuran, dioxane, etc.), esters (e.g. ethyl acetate), nitriles (e.g. acetonitrile) or ketones (e.g. acetone or methyl ethyl ketone) or mixtures thereof are preferably used. .

The reaction is carried out in the presence of an acid acceptor. Alkali metal carbonates (particularly sodium carbonate or potassium carbonate) are preferably used for this purpose. However, other inorganic bases, e.g. alkaline earth metal carbonates (e.g., calcium carbonate), alkali metal hydrogencarbonates (e.g., sodium bicarbonate or potassium bicarbonate), alkali metal hydrides (e.g., sodium hydride) or alkali metal amides (e.g., sodium amide). In addition, tertiary organic bases may also serve as acid scavengers (e.g., trialkylamines, preferably triethylamine).

The reaction may be carried out over a wide temperature range. In general, it is possible to operate at a temperature of 45 to 110 ° C, preferably 55 to 110 ° C. The reaction temperature is primarily dependent on the solvent used.

The reaction proceeds very rapidly within a few hours.

The reaction mixture is processed very simply. After cooling the reaction mixture, insoluble materials (alkali metal carbonate, alkali metal halide) are removed by filtration or centrifugation and the filtrate is freed of solvent. The reaction yields a highly purified compound of formula (I) of high purity for further conversion which does not require further purification. An analytical sample of the product can be prepared by fractional vacuum distillation.

The compound of formula (I), as already mentioned, is a valuable pharmaceutical intermediate. This compound is e.g. can be converted to 8- {4- [4- (2-pyrimidinyl) -1-piperazinyl] butyl} -8-aza-spiro [4.5] decane-7,9-dione having the valuable anxioselective activity by treating with formaldehyde and 1- (2-Pyrimidinyl) piperazinyl is subjected to the Mannich reaction and the product is hydrogenated. The procedure is illustrated in Scheme A below.

The process of the present invention has the following advantages.

- the reaction does not require a long reaction time;

- no need for high temperatures above 100 ° C;

eliminating the difficulties of regeneration and destruction of the pyridine used in the previous process;

- the process is more environmentally friendly than the known method;

- the process is very feasible on an industrial scale, the specific utilization of the device is good; 5

- the yields achieved are very high;

- the compound of formula (I) is obtained in a very pure form and the resulting intermediate can be used without further purification to obtain the pharmaceutically effective final product.

The following examples further illustrate the process without limiting the invention to the examples.

Example 1

Preparation of 8-Aza-spiro [4.5] decane-7,9-dione-8-propine (2)

To a round bottomed flask with stirring, addition funnel and reflux condenser were 167.2 g (1.0 mol) of 8-azaspiro [4.5] decane-7,9-dione, 130.86 g (1.1 mol) of propargyl bromide, 2 g 25 (1.0 mol) of potassium carbonate and 250 ml of acetonitrile were weighed. The reaction mixture was heated to reflux for several hours, then cooled to room temperature, filtered, and the solvent removed. 178.6 g (87%) of the title compound are obtained. Mp .: 150 ° C / 53.31 Pa Colorless viscous oil.

Analysis: Calculated for C12H15NO2 (205.26): C, 70.22; H, 7.36; N, 6.82. 35 Found: C, 71.0; H, 7.42; N, 6.80.

Example 2 ⁴⁰

The procedure described in Example 1 was carried out with the change of 105.9 g (1.0 mol) of sodium carbonate instead of potassium carbonate. Yield: 162.2 g (79%), m.p. 150 ° C / 53.31 Pa. 45

Example 3

The procedure of Example 1 was carried out with the change of 50 mL of tetrahydrofuran instead of acetonitrile. Yield: 149.84 g (73%).

Mp .: 150 ° C / 53.31 Pa.

Example 4

The procedure described in Example 1 was carried out with the change of 240 mL of dioxane instead of acetonitrile 60. Yield: 170.4 g (83%). Mp .: 150 ° C / 53.32 Pa.

Example 5

The procedure of Example 1 was carried out with the change of using 320 ml of ethyl acetate instead of acetonitrile. Yield: 145.7 g (71%). Mp .: 150 ° C / 53.32 Pa.

Example 6

The procedure described in Example 1 was carried out with the change that 290 ml of acetone was used instead of acetonitrile. Yield: 153.95 g (75%). Mp .: 150 ° C / 53.32 Pa.

Example 7

The procedure of Example 1 was carried out with the change of using 250 ml of methyl ethyl ketone instead of acetonitrile. Yield: 178.6 g (87%). Mp .: 150 ° C / 53.32 Pa.

Claims (6)

PATENT CLAIMS A process for the preparation of 8-aza-spiro-f.5,5] decane-7,9-dione-8-propin (2) of the formula (I), characterized in that the 8-aza-spiro (II) of the formula (II) 4.5] decane-7,9-dione is reacted with a propargyl halide of formula III (wherein Hal is bromine, chlorine or iodine) in an inert solvent medium in the presence of an acid acceptor. 2. The process of claim 1 wherein the compound of formula III is propargyl bromide. The process according to claim 1 or 2, wherein the inert solvent is an ether, ester, nitrile or ketone. 4. A process according to claim 3 wherein the inorganic organic solvent is tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, acetone or methyl ethyl ketone or a mixture thereof. 5. Process according to any one of claims 1 to 3, characterized in that the acid acceptor is an alkali metal carbonate. 6. A process according to claim 5 wherein sodium carbonate or potassium carbonate is used.