Process for the synthesis of an annulated pyridine base

Details Process for the synthesis of an annulated pyridine base Process for the synthesis of an annulated pyridine base

2001-03-27

2002-12-17

Dentz, Bernard (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S079000, C546S093000

Reexamination Certificate

active

06495690

ABSTRACT:

FIELD OF INVENTION
The present invention relates to an improved process for the synthesis of an annulated pyridine base. More particularly, the present invention relates to a process for the synthesis of an annulated pyridine base over a molecular seive. The present invention particularly relates to a process for producing 1,2,3,4,5,6,7,8,-octahydroacridine by reacting cyclohexanone and formaldehyde with ammonia in gaseous phase over a molecular seive with high yields and selectivity. This 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, no-wastage of compounds (i.e. high atom selectivity) and high selectivity of the products.
BACKGROUND OF THE INVENTION
Annulated pyridines such as 9-amino-5,6,7,8 tetrahydroacridine (Tacrine) are drug intermediates for treatment of various diseases such as Alzheimer's disease, which is the most common cause of dementia in elderly people. Several methods of producing pyridine bases are known in the art such as 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. 63,176/76, Japanese Patent Publication Nos. 41,546/71, and 32,790/69). It is also known that crystalline aluminosilicate (zeolite) is used as the catalyst for producing pyridine bases from an aliphatic aldehyde and/or ketone and ammonia (U.S. Pat. No. 4,220,783 and Japanese patent application Kokai (Laid-Open) No. 38,362/85). These processes however, disclose preparation of only one ring pyridine compounds. The fused ring system has not yet been explored over any of these catalysts.
Increasing applications of these annulated pyridines demands an eco-friendly, economical and free handling process. The present invention provides an eco-friendly and economical process for the synthesis of a variety of these compounds.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide a process for the synthesis of octahydro acridine by using a specific zeolite catalyst, which is an eco-friendly heterogeneous catalytic method.
Another object of the present invention is to improve the yield and selectivity of the product.
SUMMARY OF THE INVENTION
The present invention relates to develop a process for the preparation of octahydro acridine of the formula #1 to 9# from cyclic ketones and aliphatic aldehyde with ammonia over molecular sieves. Annulated pyridines like 9-amino-5,6,7,8 tetrahydroacridine (Tacrine) are drug molecules for treatment of various diseases like Alzheimer's disease, which is the most common cause of dementia in elderly people.
Accordingly the present invention relates to a process for the synthesis of an annulated pyridine base said process comprising reacting a cyclic ketone containing 5 to 8 carbon atoms and an aliphatic aldehyde of the formula R
1
CHO wherein R
1
is hydrogen or alkyl having 1 to 3 carbon atoms with ammonia in a gaseous phase, the mole ratio of ammonia to cyclic ketone being in the range of 0.5 to 5.0, the reaction temperature being in the range of 350° C. to 450° C., in the presence of a mesoporous sieve catalyst.
In one embodiment of the invention, the the annulated pyridine base is selected from compounds of the formula
In another embodiment of the invention cyclohexanone is used as cyclic ketone and formaldehyde is used as the aliphatic aldehyde to obtain 1,2,3,4,5,6,7,8-octahydro acridine.
In another embodiment of the invention the molar ratio of cyclohexanone: formaldehyde: ammonia is 1:1:0.5-5.
In another embodiment of the invention methanol is added to the starting materials in an amount of up to 0.5 mole per mole of cyclohexanone.
In another embodiment of the invention the temperature of the reaction is in the range of 300 to 400° C.
In another embodiment of the invention acetaldehyde is used as the aliphatic aldehyde to obtain 9-methyl octahydro acridine.
In another embodiment of the invention propionaldehyde is used as the aliphatic aldehyde to obtain 9-ethyl octahydro acridine.
In another embodiment of the invention butyraldehyde is used as the aliphatic aldehyde to obtain 9-propyl octahydro acridine.
In another embodiment of the invention cyclopentanone is used as the cyclic ketone to obtain bis cyclo pentyl pyridine.
In another embodiment of the invention cycloheptanone is used as the cyclic ketone to obtain bis cycloheptyl pyridine.
In another embodiment of the invention cyclooctanone is used as the cyclic ketone to obtain bis cyclooctyl pyridine.
In another embodiment of the invention the proportion of Si to the Al in the zeolite is in the range of 2.5 to 25.
In another embodiment of the invention the catalyst is selected from the group consisting of Al-MCM41, ZSM-5, HY and H-BEA.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for producing annulated pyridines by reacting cyclic ketones and an aliphatic aldehyde with ammonia in gaseous phase in the presence of a catalyst, wherein the catalyst was obtained by commercial or synthesized.
The aliphatic cyclic ketones used in the present invention includes, cyclohexanone, cyclo pentanone, cycloheptanone and cyclooctanone and aliphtic aldehydes such as formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde and formaldehyde. The combination of different cyclic ketones and aliphatic aldehydes as the starting materials determines the main compounds of the annulated pyridine to be produced. The typical examples are shown in the following Table 1.
TABLE 1
Aldehyde
ketone
Main products formed
Formaldehyde
cyclo hexanone
Octahydro acridine
Acetaldehyde
cyclo hexanone
9-Methyl octahydroacridine
Propionaldehyde
cyclo hexanone
9-Ethyl octahydroacridine
Formaldehyde
cyclo pentanone
Bis bi cyclopentyl pyridine
Formaldehyde
cyclo heptanone
Bis bi cycloheptyl pyridine
The reaction of the present invention may be conducted in a mode of fixed bed, fluidised bed or moving bed.
The molar ratio of ammonia to the aliphatic cyclic ketone is 0.5 to 5 mol/mol. The weight hourly space velocity (WHSV) used is 0.25 to 1.00 Hr.sup.−1. The reaction temperature is preferably 350° C. to 450° C. Although, the pressure of the reaction gases can be used in the range from below the atmospheric pressure to several atmospheric pressures, usually the pressure in the range used is atmospheric pressure.
The particularly preferable combination of a cyclic ketone and aliphatic aldehyde and ammonia for production of octahydro acridine in the molar ratio of 1:1:0.5-5.
The reaction can be effected without any trouble if the gaseous starting materials may contain water, methanol or the like. However, when acetaldehyde and formaldehyde are used as the starting materials, the amount of methanol is preferably up to 0.5 mole per mole of the acetaldehyde. Formaldehyde can be fed in a form of formalin. Further, as the aliphatic aldehyde or ketone, a dimer, a trimer, the other oligomers or polymers capable of generating a monomer of aliphatic aldehyde or ketone in an evaporator or a reactor can also be used.
Although deposition of carbon on the catalyst is detected during the reaction, the amount of the carbon deposited on the catalyst is smaller as the result of which higher yields of pyridine bases was obtained in composition with in conventional processes.
Regeneration of the catalyst is easily effected by any conventional method such as burning out the carbon deposited on the catalyst by passing air through the catalyst layer at a temperature of 450° C. to 550° C.


REFERENCES:
patent: 4220783 (1980-09-01), Chang et al.
patent: 4675410 (1987-06-01), Feitler et al.
patent: 1550726 (1979-08-01), None
patent: 9003366 (1990-04-01), None
patent: 9700861 (1997-01-01), None

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