HU206320B - Process for producing 8-aza-spiro/4,5/decane-7,9-dione - Google Patents

Abstract

aza-spiro-(4,5)-decane-7,9-dione a pharmaceutical intermediate, of glu formula (1) is prepd from 3,3-tetra: methylene-glutane-acid (11) and acetic acetic-anhydride. 8-oxa-spiro-(4,5) decane-7,9-dione is not isolated from the reaction mix, while acetic-acid forming during reaction is removed, the reaction mix is treated with ammonium-acetate. High yield, high purity prods are obtd in this one-step reaction

Description

The present invention relates to a novel process for the preparation of a spiro chemical compound of formula (I).

The compound of formula (I) may be used as an intermediate in the preparation of pharmaceutical compounds such as Buspiron. 5

Several methods are known for preparing the compound of formula (I).

According to one method [Kon, G.A.R., Thorpe, J.F .:

J. Chem. Soc. 115, 686-704 (1919)] 20% potassium hydroxide 8-azaspiro [4,5] decane-6,10-dicarbonitrile-7,9-dione 10 boiling in aqueous solution of 3,3-tetramethylene-2,4-dicarboxylglutaramide, which is very important (observing the 45 minute exact reaction time) which, after isolation and dewatering, is decarboxylated at 160 ° C in 56% yield. . With a shorter reaction time, the reaction does not take place and with longer reaction time, tar formation occurs.

According to another method [Sircan, S.S.G .: J. Chem.

Soc., 1927, 602-604], is converted from the 3,3-tetramethylene glutaric acid of formula (II) into a diammonium salt which, after isolation and drying, is converted to about 68% yield by heating at 220-230 ° C. desired compound.

Zeid, MG: Pharmazie 35, 669-71 (1980) describes a general procedure for the preparation of nitrogen-substituted derivatives of compounds of formula (I). According to 25 (II) 3,3-tetramethylene glutaric acid is reacted with (III) is 8-oxa-spiro [4.5] decane-7,9-dione as an amine of formula R-NH ₂ in a solvent of formula and the resulting The N-substituted -3,3-tetramethylene glutaramide acid, after preparation, is cyclized by heating at 180-200 ° C.

Methods are also known [Thole, B. and Thorpe, J.

99: 446 (1911) J. Chem. Soc., According to which 3-tetramethylene glutaric acid (II) is converted to 8-oxaspiro [4,5] decane-7 (III). 9-dione is then melted at 35-190 ° C with 35 urea and ammonium carbonate as the source of ammonia. The communication does not mention the production of the process and the quality of the product obtained.

In summary, the prior art processes for the preparation of 40 compounds of formula I have several drawbacks. In the synthesis starting from the 3,3-tetramethylene glutaric acid of formula (II), either the 8-oxaspiro [4,5] decane-7,9-dione of formula (III) or the diammonium salt of formula (II) or the 3 3-Tetramethylene glutaramide produces 45 acids which are cyclized at high temperature in a melt.

The compounds of formula (I) are also prepared in a multi-step synthesis starting from the dinitrile derivative of formula (IV). The disadvantages of the known processes are that they require several steps and the yield is medium. In many cases, the product obtained is of poor purity and becomes suitable for pharmaceutical use only by the addition of further purification operations.

It is an object of the present invention to overcome the drawbacks of the known processes by producing a compound of formula (I) in a single step, in good yield, in a purity suitable for pharmaceutical downstream use, under industrial conditions. 60

The present invention relates to a process for the preparation of 8-aza-spiro [4,5] decane-7,9-dione of formula (I) from 3,3-tetramethylene glutaric acid of formula (II) by reacting 3-tetramethylene glutaric anhydride, and the reaction of 8-oxa-spiro generated (ΙΠ) without isolating the formula decane-7,9-dione [4,5] in addition to the re- action generated by _this removal of acetic acid with ammonium acetate react.

The present invention is based on the discovery that when 8-oxaspiro [4,5] decane-7,9-dione (III) formed by the ring closure of compound (II) with acetic anhydride is reacted with ammonium acetate to form removal of acetic acid eliminates the need to isolate the compound of formula III. The desired compound of formula (I) is obtained in one step in excellent yield in very pure condition.

The process can also be carried out by preparing the ammonium acetate in situ from the acetic acid formed in the reaction and reacting it with the compound of formula III in the reaction mixture. The formation of ammonium acetate is preferably carried out with an aqueous solution of ammonium hydroxide.

The reaction of the compound of formula (II) with acetic anhydride is preferably carried out at a temperature of about 130 ° C.

The acetic anhydride may be used in an equimolar amount or in a small excess (1-1.10 mmol) with the compound of formula (Π). The reaction is complete within a few hours.

Ammonium acetate was then added to the reaction mixture while distilling acetic anhydride from acetic anhydride and the temperature was raised to 180-190 ° C.

The amount of ammonium acetate per mole of compound (II) added is about 10%. 2 moles may be used. The reaction was continued until the removal of acetic acid was complete.

Alternatively, after the reaction of the compound of formula (II) with acetic anhydride, ammonium hydroxide is added to the reaction mixture. The ammonium acetate formed in situ then reacts and the water and acetic acid are removed by continuous heating.

The advantage of our procedure is that

- can be done in one step;

- is produced in excellent yield;

- provides a high purity product;

- easy to implement under industrial conditions.

Further details of the process are set forth in the following Examples, without limiting the invention to the Examples. ₄

Example 1

100 cm ³ (1.06 mole) of acetic anhydride was weighed into a round-bottomed flask equipped with a thermometer

186.2 g (1.0 mole) of 3,3-tetramethylene glutaric acid. The reaction mixture was heated to 130 ° C with stirring and maintained at this temperature for several hours. Subsequently, the. 154.2 g (2.0 mol) of ammonium acetate were added to the reaction mixture by distillation of the acetic acid formed during the reaction, and the reaction was continued

Finally, the temperature of the mixture should be 180-190 ° C. Continue heating until acetic acid is removed from the system. The residue consists of 160 g (96%) of 8-azaspiro [4,5] decane-7,9-dione. 152 DEG C. (from methyl alcohol; same as in literature).

Example 2 With a stirring flask, a thermometer was charged with 110 cm ³ (1.17 mol) acetic anhydride, 186.2 g * (1.0 mol) 3,3-tetramethylene glutaric acid, and the reaction mixture was heated to 130 ° C. and maintained at this temperature for several hours. 200 cm ^{3 of} aqueous ammonium hydroxide solution (fs: 0.928) are then added dropwise to the reaction mixture. Water and acetic acid are removed from the system by continuous heating (reaction temperature 180-190 ° C at the end of the distillation).

The residue consists of 165.05 g (98%) of 8-aza-spiro [4,5] decane-7,9-dione. Mp 152 ° C (reference 152 ° C; from methanol).

Content (based on N): 98.7%.

Claims (7)

PATENT CLAIMS A process for the preparation of 8-aza-spiro [4,5] decane-7,9dione of formula (I) from 3,3-tetramethylene glutaric acid of formula (II), characterized in that the 3,3-tetramethylene of formula (II) is glutaric acid is reacted with acetic anhydride and the reaction mixture is treated with ammonium acetate without isolation of the resulting 8-oxaspiro [4,5] -decane-7,9-dione of formula (III). Process according to claim 1, characterized in that the ammonium acetate is prepared from acetic acid formed during the reaction. 10 3. A process according to claim 2 wherein aqueous ammonium hydroxide is used to form the ammonium acetate. The process of claim 1, wherein the reaction of the compound of formula (11) with acetic anhydride is conducted at a temperature in the region of 130 ° C. 5. or any of claims 4 to 4. A process wherein the amount of acetic anhydride is 1.00 to 1.10 moles per mole of compound (II). 20 The process according to claim 1, wherein the reaction with ammonium acetate is carried out at 180190 ° C. A process according to claim 1 or 6, characterized in that 2 moles of ammonium acetate are used per mole of the compound of formula (Π). .