Liquid phase process for the synthesis of annulated pyridines over molecular sieve catalysts

The present invention relates to an improved liquid phase process for the synthesis of annulated pyridines (fused pyridines) over molecular sieve catalysts. In particular, the present invention provides a process for producing 1,2,3,4,5,6,7,8-octahydroacridine and octahydrophenanthridine by reacting cyclohexanone and formaldehyde with ammonia in liquid phase over molecular sieve catalysts with high yields and selectivity. The present invention provides a non-corrosive, eco-friendly process, where the life time of the catalyst is longer, it can be recycled and reused for many times, less wastage of compounds (e.g. high atom selectivity) and high selectivity of the products.

Annulated pyridines like 9-amino-5,6,7,8tetrahydroacridine (tacrine) are drug or drug intermediates for various diseases like Alzheimer's disease, which is the most common cause of dementia in old people. Many methods of producing pyridine bases are known, for example reacting an aliphatic aldehyde and/or ketone with ammonia in gaseous phase using a solid acid catalyst such as amorphous aluminosilicate and the like (Japanese Patent Application Kokai (Laid-open) No.63176/76, Japanese Patent Publication No.3 41546/71 and 32790/69). Crystalline aluminosilicate, called zeolite is used as the catalyst for producing pyridine bases from an aliphatic aldehyde and ketone (or formaldehyde) and ammonia (U.S. Pat. No. 4,220,783, Japanese Patent Application Kokai (Laid-open) No.38362/85, Indian Patent Nos. IN-185390, IN-185654). According to these processes one ring pyridine compounds are produced but fused ring heterocyclics have not yet been reported over zeolite molecular sieve catalysts. Increasing applications of these annelated pyridines demand an eco-friendly, economical and free handling process. The present invention provides an eco-friendly and economical process for synthesis of a variety of these compounds.

The synthesis of octahydroacridine and octahydrophenanthridine was carried out using homogenous catalyst like ammonium acetate and ammonium hydroxide but the yield were lower than 54% and usual disadvantages of homogenous catalysis were observed (J. Org. Chem. 42 (No. 16), p 2742 (1977). The synthesis of octahydrophenanthridine was also carried out using p-tolune sulfonic acid and POCl 3 as homogenous catalyst(s) from 2(1-cyclohexenyl)-cyclohexanone and RCONH 2 (U.S. Pat. No. 4,006,236 (1977). The reaction time is longer, 10-24 hrs and the catalyst can not be reused and silica-alumina, chronia or magnesia catalyst(s) at comparatively high reaction temperature 180-425° C. in vapour phase with low selectivity for a particular product. Our process using molecular sieve is eco-friendly, catalyst is reusable, separation is easy and selective.

The main objective of the present invention is to provide process for the synthesis of octahydroacridine, octahydrophenanthridine and their derivatives, by using (modified or unmodified) zeolite or molecular sieve catalyst, which is an eco-friendly heterogeneous catalytic method.

Another objective of the invention is to improve yield and selectivity of the product.

The present invention provides an improved process for the synthesis of annulated pyridines over a molecular sieve catalyst, the process comprising reacting a cyclic ketone having 5-8 carbons and an aliphatic aldehyde of the formula R 1 CHO wherein R 1 is hydrogen or an alkyl group having 1 to 4 carbon atoms, with ammonia in an organic solvent in presence of a zeolite-type molecular sieve or heterogeneous catalyst, separating the catalyst to obtain the desired product.

In one embodiment of the invention, the cyclic ketone is cyclohexanone.

In another embodiment of the invention, the aliphatic aldehyde is selected from the group consisting of formaldehyde, acetaldehyde, propionaldehyde, and butyraldehyde.

In another embodiment of the invention, the molar ratio of cyclic ketone:aliphatic aldehyde-ammonia is in the range of 1:10.5 to 5.0.

In another embodiment of the invention, the reaction is carried out in liquid phase with a molar ratio of ammonia to cyclic ketone in the range of 0.5 to 5.0 and at a temperature in the range of 100° C. to 250° C., for a period of 4-8 hrs.

In another embodiment of the invention, the reaction is carried out in an autoclave.

In another embodiment of the invention, the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetonitrile and acetone, preferably methanol.

In another embodiment of the invention, the catalyst is selected from the group consisting of H-beta (Hβ), HY, HZSM-5 having a Si/Al ratio in the range of 40-300, H-mordenite, montmorillonite and SiO 2 —Al 2 O 3 zeolite and molecular sieve H—AlMCM-41.

In another embodiment of the invention, the ratio of Si to Al in the zeolite catalyst is in the range of 2.5-300.

In another embodiment of the invention, the catalyst is reusable.

In another embodiment of the invention, the annulated prydine obtained comprises 1,2,3,4,7,8,9,10-otahydrophenanthridine, 1,2,3,4,5,6,7,8-octahydroacridine, 6-methyl octabydrophenanthridine, 6-ethyloctahydrophananthridine and 6-propyloctahydrophenanthridine.

The present invention provides a process for the preparation of octahydroacridine of the formula number 1 to 9 below from cyclic ketones and aliphatic aldehyde with ammonia over molecular sieves. These annelated pyridines, like 9-amino-5,6,7,8-tetrahydroacridine (tacrine), are drug molecules or drug intermediates for various diseases like Alzheimer's disease, which is the most common cause of dementia in old people.

Salient Features of the Process

(a) The present invention provides a process that comprises of environmentally clean and economical technology and enables reusability of the catalyst; (b) The process provides an eco-friendly method with high selectivity towards the product. (c) The method provides a selective heterogeneous catalyst with longer life. (d) This method provides a route, wherein the kind and composition of annulated pyridines can be varied by varying the starting materials, (e) It also provides an efficient, economical method for synthesizing octahydroacridine and octahydrophenanthridine from cyclohexatone and formaldehyde with ammonia over various molecular sieve catalysts.

The present invention relates to a process for producing annulated pyridines by reacting a cyclic ketone and an aliphatic aldehyde with ammonia in liquid phase in the presence of a commercial or synthesized catalyst.

The aliphatic cyclic ketone used in the present invention includes cyclohexanone, cyclopentanone, cycloheptanone and cyclooctanone. The aliphatic aldehyde includes formaldehyde, acetaldehyde propionaldehyde, butyraldehyde and formamide. The combination of different cyclic ketones and aliphatic aldehydes as starting materials determines the main compounds of the annulated pyridine to be produced. Typical examples are given in the Table 1.

The reaction of the present invention may be conducted in a batch-mode in an autoclave,

The reaction in batch-mode were carried out in Parr autoclave(600 mL) in the reaction temperature range of 100-250° C. under constant stirring (30-60 revolutions per min). The typical molar ratio of cyclohexanone:formaldehyde:NH 3 was 1:1:3 and 222 mL methanol was used as solvent. The autoclave time was 6 h.

A combination of cyclic ketone, aliphatic aldehyde and ammonia (or nitrogen source), for production of octahydroacridine and octahydrophenanthridine, was taken in the molar ratio of 1:1:0.5-5. The reaction can be effected without trouble or without much coking if the (liquid) starting materials contains water, methanol or the like solvent, Formaldehyde can be used in the form of formalin. The amount of coke deposited was less so higher yields of the products were obtained; in comparison with other commercial processes. The coke can be removed by heating the catalyst at 450° C. to 550° C.; for about 4-10 h.

The present invention is described below with reference to the following illustrative and non-limiting examples.