Molecular sieve abstract
The present invention relates to a process for producing annulated
pyridines by reacting cyclic ketone, aldehyde and ammonia in presence
of molecular sieve type catalysts in an environmentally friendly,
economical and highly selective heterogeneous method.
Molecular sieve claims
1. A 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.sup.1CHO
wherein R.sup.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.
2. A process as claimed in claim 1 wherein the cyclic ketone is
selected from the group consisting of cyclohexanone, cyclopentanone,
cycloheptanone and cyclooctanonie.
3. A process as claimed in claim 1 wherein the aliphatic aldehyde
is selected from the group consisting of formaldehyde, acetaldehyde
propionaldehyde, butyraldehyde and formamide.
4. A process as claimed in claim 1 wherein the cyclic ketone is
cyclohexanione.
5. A process as claimed in claim 1 wherein the molar ratio of cyclic
ketone:aliphatic aldehyde:ammonia is in the rage of 1:1:0.5 to 5.0.
6. A process as claimed in claim 1 wherein 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.degree. C. to 250.degree. C., for a period of 4-8 hrs.
7. A process as claimed in claim 1 wherein the reaction is carried
out in an autoclave.
8. A process as claimed in claim 1 wherein the organic solvent
is selected from the group consisting of methanol, ethanol, isopropanol,
acetonitrile and acetone.
9. A process as claimed in claim 1 wherein the solvent is methanol.
10. A process as claimed in claim 1 wherein the catalyst is selected
from the group consisting of H-beta (H.beta.), HY, HZSM-5 having
a Si/Al ratio in the range of 40-300 H-mordenite, montmorillonite
and SiO.sub.2--Al.sub.2O.sub.3 zeolite and molecular sieve H-AlMCM-41.
11. A process as claimed in claim 1 wherein ratio of Si to Al in
the zeolite catalyst is in the range of 2.5-300.
12. A process as claimed in claim 1 wherein the catalyst is reusable.
13. A process as claimed in claim 1 wherein the annulated prydine
obtained comprises 12347/8910-octahydrophenanthridine, 12345678-octahydroacridine,
6-methyl octahydrophenanthridine, 6-ethyloctabydrophananthridine
and 6-propyloctahydrophenanthridine.
Molecular sieve description
FIELD OF THE INVENTION
[0001] 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 12345678-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.
BACKGROUND OF THE INVENTION
[0002] Annulated pyridines like 9-amino-5678tetrahydroacridine
(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. 4220783 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.
[0003] 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.sub.3
as homogenous catalyst(s) from 2(1-cyclohexenyl)-cyclohexanone and
RCONH.sub.2 (U.S. Pat. No. 4006236 (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.degree. 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.
OBJECTS OF THE INVENTION
[0004] 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.
[0005] Another objective of the invention is to improve yield and
selectivity of the product.
SUMMARY OF THE INVENTION
[0006] 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.sup.1CHO wherein R.sup.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.
[0007] In one embodiment of the invention, the cyclic ketone is
cyclohexanone.
[0008] In another embodiment of the invention, the aliphatic aldehyde
is selected from the group consisting of formaldehyde, acetaldehyde,
propionaldehyde, and butyraldehyde.
[0009] 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.
[0010] 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.degree. C. to 250.degree. C., for a period of 4-8 hrs.
[0011] In another embodiment of the invention, the reaction is
carried out in an autoclave.
[0012] In another embodiment of the invention, the organic solvent
is selected from the group consisting of methanol, ethanol, isopropanol,
acetonitrile and acetone, preferably methanol.
[0013] In another embodiment of the invention, the catalyst is
selected from the group consisting of H-beta (H.beta.), HY, HZSM-5
having a Si/Al ratio in the range of 40-300 H-mordenite, montmorillonite
and SiO.sub.2--Al.sub.2O.sub.3 zeolite and molecular sieve H--AlMCM-41.
[0014] In another embodiment of the invention, the ratio of Si
to Al in the zeolite catalyst is in the range of 2.5-300.
[0015] In another embodiment of the invention, the catalyst is
reusable.
[0016] In another embodiment of the invention, the annulated prydine
obtained comprises 123478910-otahydrophenanthridine, 12345678-octahydroacridine,
6-methyl octabydrophenanthridine, 6-ethyloctahydrophananthridine
and 6-propyloctahydrophenanthridine.
DETAILED DESCRIPTION OF THE INVENTION
[0017] 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-5678-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 [0018]
(a) The present invention provides a process that comprises of environmentally
clean and economical technology and enables reusability of the catalyst;
[0019] (b) The process provides an eco-friendly method with high
selectivity towards the product. [0020] (c) The method provides
a selective heterogeneous catalyst with longer life. [0021] (d)
This method provides a route, wherein the kind and composition of
annulated pyridines can be varied by varying the starting materials,
[0022] (e) It also provides an efficient, economical method for
synthesizing octahydroacridine and octahydrophenanthridine from
cyclohexatone and formaldehyde with ammonia over various molecular
sieve catalysts.
[0023] 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.
[0024] 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. TABLE-US-00001 TABLE 1 Aldehyde
Ketone Main products formed Formaldehyde Cyclohexanone Octahydroacridine,
Octahydrophenanthridine Acetaldehyde Cyclohexanone 6-methyloctahydrophenanthridine
Propionaldehyde Cyclohexanone 6-ethyloctahydrophenanthridine Butyraldehyde
Cyclohexanone 6-propyloctahydrophenanthridine Valaraldehyde Cyclohexanone
6-butyloctahydrophenanthridine Formaldehyde Cyclopentanone Bis-bicyclopentylpyridine
Formaldehyde Cycloheptanone Bis-bicycloheptylpyridine
[0025] The reaction of the present invention may be conducted in
a batch-mode in an autoclave,
[0026] The reaction in batch-mode were carried out in Parr autoclave(600
mL) in the reaction temperature range of 100-250.degree. C. under
constant stirring (30-60 revolutions per min). The typical molar
ratio of cyclohexanone:formaldehyde:NH.sub.3 was 1:1:3 and 222 mL
methanol was used as solvent. The autoclave time was 6 h.
[0027] 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.degree. C. to 550.degree. C.; for about 4-10
h.
[0028] The present invention is described below with reference
to the following illustrative and non-limiting examples.
EXAMPLE 1
[0029] The reaction of cyclohexanone, formaldehyde and ammonia
was carried out in an autoclave (600 ml) in presence of methanol
as a solvent. H.beta. (H-beta) was used as catalyst. The reaction
was carried out in the temperature range of 100.degree. C. to 215.degree.
C. for 6 h. The amount of catalyst was 2 g. The molar ratio of cyclohexanone:formaldehyde:ammonia
was 1:1:3 The liquid: catalyst ratio was 104.8 by weight. In a
typical experiment the reaction. (autoclavation) temperature was
150.degree. C. The selectivities of octahydrophenainthridine were
50.2 60.5 44.8 and 32.2 percent at 53.0 83.0 97.7 and 98.7 percent
conversions of cyclohexanone at 100.degree.(4), 150.degree.(14),
170.degree.(20) and 215.degree. C.(49 atm) reaction temperature
respectively. The selectivities of octahydroacridine were 7.7 21.7
39.4 and 42.2 percent respectively. With the increase of the autoclavation
temperature the autogeneous pressure increased. With increase of
autoclavation temperature the conversion and selectivities for octahydroacridine
increased while the selectivities for octahydrophenanthridine decreased.
The other products were cyclohexamine and cyclohexanoneoxime. Under
similar to the supercritical conditions and with the increase of
reaction temperature, there is substantial increase of reactive
collisions, miscibility is increased, the mass transfer and heat
transfer effects are enhanced resulting into increased yield of
preferably of octahydroacridine using active zeolite catalyst.
EXAMPLE 2
[0030] The reaction was carried out as explained in Example 1
with HZSM-S catalyst. The autoclavation temperature was 150.degree.
C. The selectivities of octahydrophenanthridine and octahydroacridine
were 54.6 and 28.8 percent at 80.3 percent conversion of cyclohexanone,
over HZSM-5 (SiO.sub.2/Al.sub.2O.sub.3=40).
EXAMPLE 3
[0031] Reaction was carried out as described in Example 1 with
HY zeolite as a catalyst, The selectivities for octahydrophenanthridine
and octahydroacridine were 62.3% and 31.2% at 57.2% conversion of
cyclohexanone over HY zeolite. Autoclavation temperature was 150.degree.
C.
EXAMPLE 4
[0032] The reaction was carried out as described in Example 1
with H-mordenite as a catalyst. The selectivities of octahydrophenanthridine
and octahydroacridine were 70.8% 19.8% at 89.1% conversion of cyclohexanone
over H-mordenite zeolite. The autoclavation temperature was 150.degree.
C.
EXAMPLE 5
[0033] The reaction of cyclohexanone, formaldehyde and ammonia
was carried out as described in Example 1 with EMCM-41 (SiO.sub.2/Al.sub.3O.sub.3=30)
as a catalyst. The selectivities of octahydrophenanthridine and
octahydroacridine were 64.6% and 24.1% at 91.6% conversion of cyclohexanone
over HMCM-41 mesoporons molecular sieve catalyst. The autoclavation
temperature was 150.degree. C.
EXAMPLE 6
[0034] The reaction of cyclohexanone, formaldehyde and ammonia
was carried out as described in Example 1 with HZSM-5 (SiO.sub.2/Al.sub.2O.sub.3=40-280)
as a catalyst. The selectivities of octahydrophenanthridine were
40.4%, 48.7% and 54.6% at 71.3%, 81.0% and 80.3% conversions of
cyclohexanone over HZSM-5 (SiO.sub.2/Al.sub.2O.sub.3=280) HZSM-5
(150) and HZSM-5 (40) zeolites respectively. The selectivities of
octahydroacridine were 10.6%, 18.4% and 28.8% respectively. The
autoclavation temperature was 150.degree. C.
EXAMPLE 7
[0035] The reactions of cyclohexanone, formaldehyde and ammonia
were carried out as described in example 1 with H-beta (1-4 gm)
as a catalyst. The selectivities of octahydropheaanthridine were
38.4 60.6 and 73.6 percent at 75.6 83.0 and 94.4 percent conversions
of cyclohexaaone over H-beta(1 gm), H-beta(2 gm) and H-beta(4 gm)
zeolites respectively. The selectivities of octahydroacridine were
12.6 21.7 and 19.7 percent respectively. The autoclavation temperature
was 150.degree. C.
EXAMPLE 8
[0036] The reactions of cyclohexanone, formaldehyde and ammonia
were carried out as described in example 1 with H-beta (2 gm) as
a catalyst. The effect of solvent has been studied. The amount of
solvent was 222 ml. The selectivities of octahydrophenanthridine
were 60.6 44.1 37.7 20.4 and 8.4 percent at 83.0 84.4 77.7
76.4 and 83.6 percent conversions of cyclohexanone for methanol
(p=14 atm), ethanol (p=11 atm), acetonitrile (p=10 atm) and acetone
(p=13 atm) as a solvent respectively. The corresponding selectivities
for octahydroacridine were 21.7 38.3 40.1 12.9 and 2.2 percent
respectively. The molar ratio of cyclohexanone:formaldehyde:ammonia
was 1:1:3.
EXAMPLE 9
[0037] The reaction of cyclohexanione, formaldehyde and ammonia
was carried out as described in example 1 with H-beta (2 gm) as
a catalyst, the reaction was carried out at 228.degree. C. autoclavation
(reaction) temperature and pressure was 64 atm. The reaction conditions
are similar to the supercritical conditions for 6 hr using methanol
(220 ml) as a solvent. The selectivities for octahydrophenanthridine
and octahydroacridine were 23.9 and 40.6 percent at 98.4 percent
conversion of cyclohexanone.
EXAMPLE 10
[0038] The reactions of cyclohexanone, aliphatic aldehyde and ammonia
were carried out as described in example 1 with H-beta (2 gm) as
a catalyst. The reaction was carried out at 150.degree. C. using
methanol (220 ml) as a solvent and the molar ratio of cyclohexanone:aliphatic
aldehyde:ammonia was 1:1:3. The selectivities for 6-methyloctahydrophenanthridine,
6-ethyloctahydrophenanthridine, 6-propyloctahydrophananthridine
and 6-butyloctahydrophenanthridine were 80.9 45.4 63.2 and 27.7
percent at 97.0 90.0 96.4 and 93.5 percent conversions of cyclohexanone
respectively.
EXAMPLE 11
[0039] The reactions of cyclohexanone, acetaldehyde and ammonia
were carried out as described in example 1 using methanol (220 ml)
as a solvent; by varying the various zeolites as catalysts. The
reactions were carried out at 150.degree. C. and the molar ratio
of cyclohexanone:acetaldehyde:ammonia was 1:1:3. The selectivities
for 6-methylphenanthridine were 80.9 39.5 54.3 32.2 56.9 79.8
47.1 48.4 percent at 97.0 84.9 94.9 87.3 96.7 95.8 87.7 and
90.3 percent conversions of cyclohexanone for H-beta, HZSM-5 (SiO.sub.2/Al.sub.2O.sub.3=280),
HZSM-5(40), HY, H-mordenite, HMCM-41(SiO.sub.2/Al.sub.2O.sub.3=30),
Montmorillonite (K-10) and SiO.sub.2--Al.sub.2O.sub.3 (amorphous)
catalysts respectively.
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