Note: Descriptions are shown in the official language in which they were submitted.
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CO~ll~uOu~ PROC~.~S~ FOR THE HY~ROLYSIS OF
CY~NOPY~IDI~nES UnD3ER SUBSTA~rTIALLY ~iDI ~ ATIC CO ~ ITIONS
I~BACKGROU~D
This invention relates to a continuous process for
the hydrolysis o~ cyanopyridines, and in particular to
such a process conducted under substantially adiabatic
ls conditions. The hydrolysis conditions can be
controlled to produce amides, carboxylic acids or their
mixtures as major products.
Several products resulting from the hydrolyses of
cyanopyridines are well-known products of commerce.
For example, pyridine substituted amides and carboxylic
acids are important vitamins, precursors to medicines
and chemical intermediates. In the area of amides, the
best known example includes niacinamide (also known as
nicotinamide and 3-pyridine carboxamide) and in the
area of carboxylic acids, the best know example
includes niacin (also known as nicotinic acid and 3-
pyridine carboxylic acid). Niacinamide and niacin,
both commonly referred to as vitamin B3, are members of
the B-vitamin complex and precursors of coenzymes I and
II, and are important supplements to the diet of hl~m~n.~
and ~n;m~l S. Pellegra related deaths in the United
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States caused by vitamin B3 deficiency dropped from
7,3~8 in 1929, to 70 in 1956, primarily as a result of
increased availability of vitamin B3. Higher growth
rates occur in animals having diets supplemented with
vitamin B3 and in the case of rllm;n~nts, higher milk
production also occurs. In 1985, the U.S. market for
niacinamide and niacin was estimated at 6,700 metric
tons. See Kirk-Othmer, Encyclopedia of Chemical
Technology, Third Edition, Vol. 24, pages 59-93 for a
general discussion of the B3 Vitamins. Isonicotinic
acid, a precursor to isonicotinic acid hydrazide
(isoniazid) and related drugs used in the ~reatment of
tuberculosis can be prepared by the hydrol~sis of 4-
cyanopyridine.
As to preparative methods for these compounds,
cyanopyridines have frequently been hydrolyzed in batch
and continuous processes with catalytic to
stoichiometric excesses of a base. A majority of the
methods reported have been batch processes. For
example, 4-cyanopyridine in the presence of sodium
hydroxide at a molar ratio of 1:(0.03-0.075) and at
120~-170~C is reported to give isonicotinamide. See
U.S.S.R. SU 1,553,531 (1990); CA:113:78174f (1990).
Similarly, 2-cyanopyridine is reported to react with
sodium hydroxide at a molar ratio of 1:(0.03-0.20) and
at temperatures ranging from 100~-130~C to give 2-
picolinamide. See U.S.S.R. SU 1,553,530 (1990);
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,
--3--
CA:113:78173e (l9go). With a molar ratio of 4-
cyanopyridine:sodium hydroxide of 1:(1.5-1 75) and a
~ hydrolysis temperature of 50~-80~C, the reported
hydrolysis product was isonicotinic acid. See U.S.S.R.
SU 1,288,183; C~:106:176187n ~1987). The hydrolysis of
3-cyanopyridine with excess ammonia at 107~-lO9~C for 12
hours was reported to give mixtures of nicotinamide and
niacin. See J. Am Chem. Soc. 65, at pages 2256-7
(1943). In still another variation, the hydrolysis of
lo 3-cyanopyridine has been reported with a polymeric
base, Dowex lX4 (in the hydroxide form~, to yield
nicotinamide. See Dutch Patent Application No.
7706612-A; CA:90:186814e. U.S. Patent No. 4,314,064
describes the continuous hydrolysis of 3-cyanopyridine
with 0.3 to 3.0 moles of an alkali metal hydroxide for
each 100 moles of cyanopyridine at pressures of between
3 to 20 bars and with heating or cooling to maintain
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. .
Company Ltd., describes the conversion of 2-, 3-, and
4-cyanopyridine into their corresponding amides using
cultured broths of an Agrobacterium bacteria. Japanese
Patent No. 9300770000, assigned to Nitto Chemical Ind.
Co. Ltd., describes the hydration of aromatic nitriles,
including 3- and 4-cyanopyridine, using the action of
Corynebacterium or Nocardia bacterium to give the
corresponding aromatic amides with high selectivities.
In view of this background there r~; n~ a need
and demand for a continuous process for the hydrolysis
of cyanopyridines which provides for increased
production rates while also providing high yields and
product selectivity. Additionally, the continuous
process should be capable of being operated employing
starting materials which are readily available, and in
simple equipment requiring mi n i m~l controls. The
present invention addresses these needs.
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... .
P
A feature of the present invention i8 the
discovery that the continuous hydrolysis of
cyanopyridines can be carried out in the presence o~ a
base and under substantially adiabatic conditions to
provide a vigorous reaction which surprisingly leads to
increased production rates with high yields and
lo selectivities. Thus one preferred embodiment of the
invention provides a continuous process ~or hydrolyzing
a cyanopyridine (for example 2-, 3-, or 4-
cyanopyridine) by combining two or more feed streams to
form a reaction mixture containing the cyanopyridine,
water, and a base (~or example, ammonia, an alkali
metal hydroxide or an alkali metal carbonate) and
reacting the reaction mixture under substantially
adiabatic conditions. Processes of the invention can
be carried out in a variety of continuous systems
including for example a simple flow tube, require no
temperature control other than an initiation
temperature and can be substantially completed in less
than a minute. For a given cyanopyridine, the required
initiation temperature is a function of the
cyanopyridine's reactivity toward hydrolysis and its
~ concentration in addition to the base utilized and the
ratio of that base to the cyanopyridine. The ratio of
base to cyanopyridine also affects whether the major
product is an amide or a carboxylic acid. Preferred
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.
hydrolyses of 2-cyanopyridine, 3-cyanopyridine and 4-
cyanopyridine can be controlled to produce
picolinamide, picolinic acid, nicotinamide, niacin,
isonicotinamide or isonicotinic acid at surprisingly
S high production rates, with unexpected selectivities
and surprisingly short reaction times.
Another preferred embodiment of the present
invention provides a process which includes the steps
of combining a first stream containing a cyanopyridine
with a second stream containing water and a base, where
at least one of the streams is heated to a temperature
of about 20~ to about 300~C, and passing the streams
after they are combined through a reaction zone, to
cause the hydrolysis to proceed under substantially
adiabatic conditions. The first stream can include
only a cyanopyridine as a melt or can additionally
include water and/or another non-interfering solvent.
Although several reactor designs including a series of
cascade reactors, loop reactors, or flow tubes can
provide a suitable reaction zone a flow tube reactor is
preferred. Preferred hydrolysis reactions include the
hydrolysis of 3-cyanopyridine with alkali metal
hydroxides such as sodium or potassium hydroxide to
give nicotinamide or niacin in high yields and
conversions with a min;mllm of impurities.
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DESCRIPTION
~ For the purposes of promoting an understanding of
the principles of the invention, reference will now be
made to certain of its embodlments and specific
language will be used to describe the same. It will
nevertheless be understood that no limitation of the
scope o~ the invention is thereby intended, such
alterations, further modifications and applications of
the principles of the invention as described herein
being contemplated as would normally occur to one
skilled in the art to which the invention relates.
As indicated above, the present invention provides
unique processes for the continuous hydrolyses of
cyanopyridines in the presence of a base under
substantially adiabatic conditions, which surprisingly
lead to increased production rates with high yields and
selectivities. In this regard, the term
"substantially adiabatic conditions" is meant to
include conditions wherein substantially all of the
heat generated by the hydrolysis reaction is retained
within the reaction mixture during the period of
reacting. That is, substantially no effort is made to
cool the combined reactants within the reaction zone
during the period of reacting. As a result, heat from
the hydrolysis reaction is usually generated faster
than it can be dissipated to surrounding regions and
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. ..
the temperature of the reaction mixture within the
reaction zone reaches substantially that temperature
caused by the uncontrolled exotherm of the hydrolysis
reaction. Typically, the temperature of the reaction
s mixture increases by at least about 20 ~C. "Reaction
zone" is meant to include a region within a continuous
reactor where a cyanopyridine combined with a base
undergoes a rapid exothermic reaction producing the
hydrolysis product. Applicant's preferred process can
be carried out in a variety of continuous systems, only
requires control o~ the flow rates and initiation
temperature and is completed within less than about
thirty seconds after initiation has occurred.
The continuous hydrolysis of cyanopyridines
according to embodiments of the preferred process
produces primarily amides, carboxylic acids or their
mixtures. 2,- 3-, and 4-Cyanopyridines are hydrolyzed
with the applicants' preferred process to give
picolinamide, picolinic acid, nicotinamide, niacin,
isonicotinamide and isonicotinic acid. In addition, a
wide variety of substituted and unsubstituted
cyanopyridines are also suitable for use in the
invention. Representative substituents include groups
such as alkyl having up to about 9 carbon atoms, aryl,
cyano, amino, alkylamino, hydroxy, and halo (e.g. -Cl
and -Br) etc. ~uitable substituents may remain
unchanged as a result o~ the hydrolysis reaction or may
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_ g _
.. . .
be transformed during hydrolysis into a new
substituent. The preferred cyanopyridines for use in
the hydrolysis process include non-substituted
cyanopyridines ~2-cyanopyridine, 3-cyanopyridine, and
4-cyanopyridine) and substituted cyanopyridines with up
to four additional groups which do not detrimentally
interfere with the hydrolysis reaction and are either
commercially available or can be obtained by methods
known to the art and literature. More preferred
cyanopyridines are non-substituted 2-cyanopyridine, 3-
cyanopyridine, and 4-cyanopyridine, for example as can
be obtained from Reilly Industries, Inc., of
Indianapolis, Indiana and the Cambrex Corporation, East
Rutherford, New Jersey. Although not necessary for the
present invention, it is preferred that the
cyanopyridines used be of high purity, for example
about 9~ to about 99.9~ or more pure.
A variety of bases are known to facilitate
hydrolysis reactions and the particular base employed
is not critical to the broad aspects of the invention.
Suitable bases for use in the invention generally
include those bases compatible with the aqueous
hydrolysis system which accelerate the hydrolysis of
cyanopyridines. Preferred bases for use in the
invention are ammonia, alkali metal hydroxides such as
sodium or potassium hydroxide and alkali metal
carbonates such as sodium or potassium carbonate.
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Although not required, the bases are commonly used in
solution, more preferably in water. Preferred aqueous
solutions of base have contained from about 5 to about
50~ by weight base.
s
Processes of the invention can be conducted with
varying amounts of water relative to cyanopyridine so
as to control the reaction product, to improve the
products flow through the reactor, and to effect the
1o magnitude of the temperature increase caused by the
uncontrolled exothermic hydrolysis reaction. The
preferred amount of water for control of reaction
product depends on the number of cyano groups on the
cyanopyridine undergoing hydrolysis and whether amide
or carboxylic acid groups are desired. For hydration,
each cyano group reacts with one (l) molecule of water
to give an amide group and two (2) molecules of water
to give a carboxylic acid group. As a result, the
preferred number of moles of water per mole of
2~ cyanopyridine utilized for product control can be
determined for each cyanopyridine by adding (a) the
number of cyano groups being hydrolyzed to amide groups
multiplied by one (l), and (b) the ~umber of cyano
groups being hydrolyzed to carboxylic acid groups
multiplied by two (2). For preferred processes, at
least a slight excess of water is typically used. It
can be added separately, with the cyanopyridine, with
the base or some combination thereor. Typically, water
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4 iS added with both the cyanopyridine and the base for
~eed to processes of the invention. Preferred
cyanopyridine solutions have been from about 20~ to
about 85~ by weight cyanopyridine in water, with more
5 preferred cyanopyridine solutions containing from about
35~ to about 70~ by weight cyanopyridine, for amide and
for carboxylic acid formation.
In preferred processes, a cyanopyridine, at least
lo one base, and su~icient water are combined in a
continuous manner to give a reaction mixture at an
initial temperature sufficient to initiate and maintain
hydrolysis without additional heating and sufficient to
cause the rapid hydrolysis of the cyanopyridine. This
15 initial temperature is referred to herein as the
initiation temperature. To initiate hydrolysis when
heating is necessary, at least one reactant stream can
be preheated to a temperature sufficient to cause the
reaction mixture to reach the initiation temperature
20 and begin hydrolysis immediately upon combining the
reactant streams. The amount of heating necessary is a
function of the quantities and heat capacities of the
various streams being combined as well as the
concentrations of the reactants. For aqueous
25 cyanopyridine solutions ranging between about 20~ to
about 85~ by weight cyanopyridine, initiation
temperatures between about 20~ to about 300~C have
proven sufficient. For amide formation, initiation
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temperatures of about 60~ to about 140~C have been most
preferred while for carboxylic acid formation,
initiation temperatures of about 60~ to about 200 ~C
have been most preferred. In advantageous processes,
the hydrolysis is rapid and exothermic, causing a rapid
increase in the temperature of the combined reactant
streams within the reaction zone. For example, in more
advantageous processes, the hydrolysis reaction has
caused the temperature of the reaction mixture to
lo increase by at least about 20~C and the reaction is
completed within less than about 30 seconds and
typically in less than about 5 seconds.
The choice of base and its amount relative to the
cyanopyridine can be controlled to cause the product to
contain primarily a preferred amide or a preferred
carboxylic acid. With stronger bases such as sodium
and potassium hydroxide smaller quantities of base are
adequate, while with weaker bases such as ammonia,
larger quantities of base are required. Control of
these parameters to achieve the desired products or
product mixtures will be well within the purview o~ one
skilled in the art given the teachings herein. Because
bases can be either monobasic or dibasic and
cyanopyridines can have more than one cyano group, the
relative amounts of these reactants can be effectively
understood in terms of equivalents. The number of
equivalents of base can be determined by multiplying
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the number of moles of a base (determined in the usual
manner) by the number of protons a mole of that base
will react with. The number of equivalents of
cyanopyridine can be determined by multiplying the
number of moles of a cyanopyridine (determined in the
usual manner) by the number of cyano groups present.
The ratio o~ base to cyanopyridine will be a ratio of
the number of equivalents of base per equivalents of
cyanopyridine. In the preferred process, the ratio of
base to cyanopyridine can vary depending on the
hydrolysis product desired, the strength of the base
utilized and the amount of water present. Generally,
amide formation is favored when the ratio of
equivalents of base to e~uivalents of cyanopyridine is
about (O.Ol to 50):lO0 and acid formation is favored
when the ratio of equivalents of base to equivalents of
cyanopyridine is about (50 to 200):lO0.
Although the present continuous hydrolysis can be
carried out in a variety of customary continuous
processing apparatuses such as cascades of reaction
vessels, loop reactors or flow tubes, a flow tube
reactor is preferred. For the preferred process, at
least two reactant streams together containing
cyanopyridine, water, and base are fed into a reactor,
with sufficient heat applied to at least one of the
reactant streams to cause the combined streams to reach
an initiation temperature. Although not re~uired, the
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. , ,
reactant streams can pass through a mixing region
immediately prior to entering the reactor or as an
initial stage of the reactor. The mixing region can
include a static mixer, a region containing packing
s materials or other mechanical forms known in the art.
The reactor can also be equipped to operate at ambient
pressure or at a prescribed pressure above atmospheric
pressure. Because of the uncontrolled exothermic
nature of the hydrolysis, reactors designed to operate
lo above atmospheric pressure have generally been equipped
with a pressure relieve valve vented to a catch pot and
set below the pressure limit of the reactor. After
hydrolysis, the reaction products exit the reactor and
can pass into a receiver for future processing or can
pass directly into a recovery system.
For the preferred continuous processes high
production rates, selectivities, and yields are
typically obtained. For instance, for nicotinamide
formation by hydrolysis of 3-cyanopyridine, production
rates ranging from between about 200 to several
thousand kg per hour per liter of reactor volume can be
obtained, with the applicant's work in systems to date
readily achieving about 200 to about 1000 kg per hour
2s per liter and more often about 400 to about 900 kg per
hour per liter. Similar production rates can be and
have been obtained for the hydrolysis of 3-
cyanopyridine to niacin. The yields of amides and
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-15-
carboxylic acids utilizing the preferred continuous
process have typically ranged between about 95~ to
- about 99.5~ with usually between about 0 to about 0.2~
o~ unreacted nitrile remaining. By-products, either
S amide or carboxylic acid, have typically ranged between
about 1 to about 5~.
Products from the continuous hydrolysis can be
i~olated by conventional methods. These methods
include known batch or continuous crystallization
methods, batch or continuous evaporative procedures, or
combinations thereof. Niacinamide suitable for feed
grade applications can be obtained by continuously
dehydrating or drying the hydrolysis mixture utilizing
a falling film evaporator and cooling belt technology,
for example as described in U.S. Patent No. 4,314,064.
Carboxylic acid products can be recovered by first
reacting the basic salt with an acid and isolating the
free carboxylic acid by conventional methods such as
crystallization. The hydrolysis products obtained by
the process of the present invention are useful as
vitamins (i.e. niacinamide and niacin), as chemical
intermediates in the manufacture , for example, of
products used in the agricultural and pharmaceutical
industries.
For the purposes of promoting a further
understanding of the present invention and its
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.
pre~erred features and embodiments, the following
examples are being provided. It will be understood,
however, that these examples are illustrative, and not
limiting, in nature.
Examples 1-10 were carried out in a 1 liter
autoclave to simulate the first stage of a cascade of
reaction vessels. Examples 11-14 were carried out in a
flow tube reactor. Hydrolysis reactions to give
pyridine substituted carboxylic acids have given
similar results in both reactors. However, better
selectivity for amide formation has been obtained in
the flow tube reactor. For all examples the
compositions of solutions are given in weight percents.
EXAMPLES 1-10
~ xamples 1-10 set ~orth in Table 1 were conducted
using the following procedure. An aqueous solution of
the indicated cyanopyridine (abbreviated "CNrl) was
heated in a stirred stainless steel autoclave equipped
with a heating mantle to an initiation temperature,
heating was discontinued and an aqueous solution o~ the
indicated base was quickly injected (typically in less
than 5 seconds). When the temperature of the reaction
mixture began to drop, the maximum temperature was
noted, the heating mantle dropped and the autoclave was
cooled rapidly in cold water. The reaction mixture was
~ analyzed by HPLC to determine the amounts of the
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, .
corresponding amide, carboxylic acid and cyanopyridine.
As examples 1-10 demonstrate, the cyanopyridine
concentrations, choice of base, amount o~ base, and the
initiation temperature can be controlled in the
hydrolysis of cyanopyridines under substantially
adiabatic conditions to produce pyridine substituted
amides and carboxylic acids. The choice o~ conditions
produces high yields o~ the pyridine substituted amide
or carboxylic acid.
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. oo ~ ~ _ ~ V
~ Z ~ '~ X ~ ~ ~ ~ ~' ~ ~' ~
oo O ~~ '~ ~ ~ ~ ~ ~ o o~ o
~Z ~ ~ ~ 'e o o 8 ~~ -- ~
~~~~ ~~ cr~ ~
Z ~ ~ o ~ o ~ 8o o o
V ~ t- ~ ~ ~o O ~ ~ ~ o ~~
Z ~ ~ V V o
~ 00 ~ OV
z a~ Ov v o~ O '~
~ 8 8 ~ 8 ~ 8 5
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--19--
. _
, EXAMPLES 11-14
r The continuous hydrolysis of 3-cyanopyridine was
carried out in an insulated flow tube reactor having a
length of 5.5 feet and an inner diameter of 1.049
inches and no means for cooling. At one end, the
reactor was connected in series to a static mixer, a
heater, and a pump for introducing the 3-cyanopyridine
solution. Between the static mixer and the pump, was
10 an inlet pipe ~or introducing an aqueous solution of
sodium hydroxide. Thermocouples were placed: (a~
between the heater and the static mixer, (b) at the
entry of the reactor and (c) near the exit of the
reactor. At its exit, the reactor was connected to a
15 receiver equipped with a water condenser. Between the
reactor and the receiver were placed (a) nearer the
reactor, a pressure relief valve and (b) nearer the
receiver a back pressure regulator set at approximately
200 psi or alternatively, a ball valve restricted to
20 create the desired pressure.
For Example 11, an aqueous solution containing 60~
by weight of 3-cyanopyridine was fed through the heater
at a uniform rate of 142 gallons/hour, increasing its
25 temperature to 115 ~C. A 7~ aqueous solution of sodium
hydroxide wa~ metered into the 3-cyanopyridine stream
at a uniform rate of 5 gallons/hour and the combined
streams fed into the reactor through the static mixer.
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. .
The combined reactants entered the flow tube reactor at
a temperature of 116 ~C, reached a temperature of 156.9
~C within about 4 seconds and immediately exited the
reactor and passed into the holding vessel. The ratio
of sodium hydroxide to cyanopyridine was 1.1:100. A
sample of the hydrolysis product was analyzed and ~ound
to contain on a water free basis: a) 96.04
nicotinamide; b) 0.23~ 3-cyanopyridine; and c) 3.73~
sodium nicotinate. Table 2 summarizes the results
from Examples 11-14 carried out in a flow tube reactor
utilizing the method described above. Other
substituted cyanopyridines, including 2-cyanopyridine
and 4-cyanopyridine, can be hydrolyzed in the flow tube
reactors to give amides, carboxylic acids, or mixtures.
s For the hydrolysis of 2-cyanopyridine or its
derivatives to give the carboxylic acid, m~xtmllm
temperatures above about 135~C should be avoided to
prevent decarboxylation of the initially formed
carboxylic acid.
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TABLE2
Example No. 11 12 13 14
3 -Cyanopyridine
- concentration 60% 60% ~ 60% 60%
- flow-rate, galAlr 142 161 140 145.6
Sodium Hy~Lu~ide
- cu,lc~ ion 7% 6.6% 6.6% 8.1%
- flow-rate, gal/hr 5 2,2 10.8 6.64
Tniti:ltion T~ .. d ~v,~C 115 120 115 110
~,.x;.. ,.. T~ e, ~C 156.9 190 195.8 ~200
NaOH:C~ c 1.1:1000.4: 100 2.3:1001.7:100
Product
- ni~o~in~ , % 96.04 93.17 96.04 96.99
- cyanopyridine, &:; 0.23 5.66 0.00 0.00
- sodium llicul~.. t~" % 3.73 1.16 3.96 3.01
While the invention has been illustrated and
S described in detail in the foregoing description, the
same is to be considered as illustrative and not
restrictive in character, it being understood that only
the preferred embodiment has been shown and described
and that all changes and modifications that come within
the spirit of the invention are desired to be
protected.
All publications cited herein are indicative of
the level of s~ill in the art and are hereby
incorporated by reference as if each had been
individually incorporated by reference and fully set
~ forth.
