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Patented Dec. 17, 1946
~
2,412,749
UNITED" STATES PATENT OFFICE ‘ [
ma'rnop 0F ranmnmc mco'rmamnc
Edwin Frederic Pike and Robert s. Shane, De
troit, Mich., assign
y\ mesne
ents,
' to Gelatin Products Corporation, Detroit, Mich,
. a corporation of Michigan
No Drawing. Application Mai-ch 2, i942; '
'
.
Serial No. 433,050
1 Claim. (Cl. 260-2955)
The present invention‘ relates, to the iaethod' . ‘with it the water which is evolved in the reac
of preparing nicotinamide.
'
-
tion. It the withdrawn ammonia gas is passed
-
This invention has as an object the prepara
through a condenser it will be observed that
'. tio'n of nicotinamide by reacting nicotinic acid
with dry NH: and eliminating water. A tur
ther object is to produce nicotinamide by con
when the temperature of reactionv reaches
180-185° C. water is condensemirom the with
drawn ammonia gas and that the amount'of,
tacting these two speci?ed reactants under heat
water substantially increases when the tempera
conditions and a sweeping gas whereby the water
ture reaches 230° 0.. It is desired to keep the '
of reaction produced is removed immediately '
reaction time as short as possible and yet not to
from the zone of reaction. Our invention also 10 raise the temperature so high as to produce un
embraces the idea of employing dryaammonia
for the dehydration of ammonium nicotinate 2
where produced as an intermediate product in
the reaction or where treated ab initio.
Heretofore nicotinamide is reported in the
literature to have been made by‘ (1) reacting
nicotinyl chloride with ammonia and (2) react;
ing the esters of nicotinicacid with aqueous so-'
desirable
decomposition. A
temperature
of
around 23(3-235° C. has been found suitable.
While we do not wish to be bound by any
~theory of reaction, the mechanism of the re
action appears to be as follows: The NH: plays
a double role. First, the ammonium salt of
-nicotinic acid is formed, which salt is then de
' hydrated by excess dry gaseous NH: in its sec
ond'role to form nicotinamide. Heat is neces
lutions of ammonia or gaseous NHs, either at at
,mospheric pressure or at higher pressures'and 20 sary for the successful conduct of the reaction.
It is possible on the other hand that‘there is no
either at low temperatures or at moderately ‘ele
vated temperatures. However in method 1 it
i is necessary ?rst to prepare nicotinylpcl'iloride -
from nicotinic acid by the use of such‘ agents as
thionyl chloride, phosphorus trichloride or penta
chloride.
In
method
2
it is necessary
intermediate formation of the ammonium salt
and that the acid amide is formed in one stage.
The mechanism of the reactants involved may
25 be expressed as follows:
to
A. In two stages
initially synthesize the ester from nicotinic acid
or
a
derivative
of
this acid.
In
conse
quence thereof, by either of these methods the
cost of the product is increased very materially 30
coon + NH: _» Ocoonm
over what would be the cost it nicotinic acid
could be used directly with yields approximately
of the same order.
.
-
N
N
'
We have now found that it is possible to pro
duce nicotinamide in good yields by bringing a 35
stream of dry ammonia gas into contact with
nicotinic acid under the condition of elevated
reaction temperatures. As dry ammonia gas is
passed into nicotinic acid there first occurs a
spontaneous evolution of heat. It is believed 40
that ammonium nicotinate is an intermediate
product formed in the carrying out of the com
plete reaction herein set forth and that this
spontaneous evolution of heat is a consequence of
—COONHi - m0 ---. 04:01am
or
a
‘
B. In one stage
N
.
coon + NH; -+ Osman, + mo
its formation. Heat is applied to the reaction 45 The temperatures which we have employed in
mixture and incipient liquefaction occurs around
the synthesis of nicotinamide employing nicotinic
the point of introduction of the ammonia at
acid and dry NH; have varied from approxi
about 160° C. With the continuance of the
mately I75“ to approximately 300° C. at atmos
heating this liquefaction proceeds and as the
pheric pressure. Nicotinamide has been formed
temperature of reaction approaches 180-185" C. 50 in experimental runs in all the temperatures in-_
the entire mass becomes liquid. The dry am
termediate between these temperatures. The
monia gas is supplied in an amount in excess of
progress of the reaction and the resultant yields
that required to react with the provided quan
are not of course the same throughout this range.
tity of the nicotinicacid and such excess is
A preferred temperature is in- the neighborhood
withdrawn from the reaction mass and carries 55 of 235° C. at atmospheric pressure. We are not
9,412,749
4
limited to such preferred temperatures. We‘
know from our experiments that the reaction
does occur over the entire range of tempera
tures reported supra. . The-rate of reaction is, of
coursajboth a function,‘ of the temperature, and
the amount" of ammonia (NI-I3); 1At the lower
.
(boiling between 30° and 60° C. although other
fractions'can likewise be used) is added. The
nicotinamide precipitates out as a fine light yellow
or pale tan, powder. The melting point of this
material after .one recrystallization is 126° C.
‘A second recrystallization from the same solvent
gave material melting at 129° C. (uncorrected).
This material compares well in every respect
with the availablesamples now on the market.
10
The ‘following example will serve as illustra
end of the temperature ranges speci?ed, it takes
longer for the reaction to go to completion. At
the upper end of this range, the reaction pro
ceeds more rapidly.
Heat alone may be su?icient to cause the dehy- >. u tive of our invention:
dration of the ammonium nicotinate provided the
water liberated is withdrawn from the reaction
'
Example
zone. It is believed that the dehydration of am
400 grams of nicotinic acid were put into a
monium nicotinate to nicotinamlde may be in 15 ?ask and dry, ammonia gas in excess of the
equilibrium with the hydration of nicotinamide
to ammonium nicotinate. Hence, the removal
amount required to react with the provided quani
tityvof nicotinic- acid to form either ammonium
of the volatile constituent water from the reac
nicotinate or nicotinamlde was passed there
tion zone in a stream of an inert gas, whether
through. Heat was applied until the tempera
ammonia or some other inert gas, will cause the 20' ture reached 230—235° C. and the mass was main
‘progressive formation of nicotinamide at the
expense of ammonium nicotinate.
tained at such temperature until the reaction
was completed. Two to three hours were found
‘l Whereas ordinary atmospheric pressures are
su?icient to complete the, reaction. The reaction
product was allowed to cool while passing dry
employed ‘during'heating, the reaction can be
‘carried out under reduced pressure. When sub
25 ammonia gas therethrough.
The water of reac
atmospheric pressures are employed the tempera
tion was carried away by the excess of dry am
tures will be lower. Every temperature'between
monia gas being passed through the mass. After
175° and 300° C. will accordingly have a tem
the reaction was completed and the mass cooled
perature corresponding thereto at a pressure
extraction was accomplished in 700 cc. of warm
below 760 millimeters. ‘Also pressures above at 30 water with agitation. A small amount of bone
mospheric may‘ be employed provided water
black and celite was then-added, which is a
formed in'the reaction can be'removed.
standard method for decolorizing an organic solu
It is usually desirable to separate and purify
tion. The mass was then ?ltered and the nicotin
the nicotinamide'fromthe reaction mixture. By
amide crystallized from the ?ltrate after satura
one convenient procedure, when the reaction is 35 tion with ammonia at a lowered temperature.
concluded, the mixture containing thenicotin
The yield of nicotinamide ‘was 60% of the theo
amide is rapidly cooled in a stream of inert gas,
retical and the melting point was 12n8-129° C. more" particularly, dry ammonia gas to prevent
uncorrected‘.
deterioration from atmospheric oxygen and/or
There are various procedures by which the nico
moisture. Following this, the’ reaction mixture 40 tinic acid may be brought into intimate contact
is extracted with approximately four times its
with dry NHa. Our invention is .not limited to
own weight of acetone. The acetone solution is
any manipulative operation 'or method. .Further-,
decanted from the residue, if any, and to this
more there are various ways the impure nicotin
solution is added approximately 5% by- weight
amide initially produced may be ‘puri?ed, As
of calcium silicate. The mixture is now thor
many different embodiments of this invention
oughly stirred for a period of time to absorb
may be made without departing from the spirit
unreacted nicotinic acid on the calcium silicate.‘
and scope thereof, it is to be understood that
The slurry is then ?ltered‘at room temperature,
we do not limit ourselves to the speci?c embodi
following which the acetone solution is concen
ments thereof except as de?ned in the appended
trated to a point where nicotinamide crystallizes
claim. It is also to be understood that tempera- '
out. The slurry is ?ltered and the nicotinamlde
tures at‘ sub- or super-atmospheric pressures‘
is dried.
'
"
corresponding to the range 175-300° C. at atmos
By an alternative procedure which we have like
wise found satisfactory, the ‘reaction mixture after ‘
cooling'in a stream of NH: or other inert gas
such as nitrogen, one purpose of which is to ex
clude moisture containing air, is extracted with
water.- The nicotinamide may be recovered ex
pediently from this solution after saturation with '
NI-Is. The nicotinamlde may then be recrystal
lized. We prefer to do this from dioxane and
petroleum ether, although a large number of sol
vents, among which may be mentioned water,
_- alcohol, and ammonium hydroxide may be used.
“We donot intend‘ to limit the process to these
.speci?ed solvents.
~
-
~-:;._.When employing the dioxane and petroleum
ether, the following method with proportions set
outispreferred. ' The nicotinamlde is'taken up
in-‘twice. its. own weight of hot dioxane then 70
?ltered. I The solution is cooled and with constant
agitation, one part by weight of petroleum ether -
pheric pressures are to be accorded applicants as
within the true interpretation of the claim.
'
7 What we claim:
The process of preparing nicotinamlde com
prisingcontacting nicotinic acid with a stream of
dry ammonia gas at a temperature sumciently
high to liberate the-water of reaction, supplying
said ammonia gas during the reaction in an 1
amount in substantial excess over that required
to react with the nicotinic acid, continuously
sweeping such excess of gas through the reac
tion product, said gas excess carrying with it the
water of reaction as the same is formed, rapidly
cooling the reaction product in a stream of dry
ammonia gas, dissolving the reaction product-in
water, and saturating the aqueous solution with
ammonia to reprecipitate the nicotinamide.
ROBERT S. SHANE.
EDWIN FREDERIC PIKE.
_
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