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Патент USA US2058547

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Patented Oct. 27, 1936
‘ 2,058,547
UNITED STATES PATENT OFFICE * “
PROCESS FOR- CATALYTIO SYNTHESIS OF
,HETEROCYCLIC AMINES AND PRODUCTS
PRODUCED THEREBY
,
Homer Adkins, Madison, Wis, and Howard L
Crarner, Cuyahoga Falls, Ohio
No Drawing. Application June 2'7, 1932,
.
Serial No. 619,524
‘ _ 23 Claims.
(01. 260-43)
This invention relates to the catalytic alkyla
tion of the heterocyclic amines.v More particu
, larly, it relates to the liquid phase alkylation, in
the presence of a contact catalyst, of the nitro
5 gen-heterocyclic amines, among them piperidine,
place of-piperidine as a starting material, pyri
dine plus hydrogen maybe used.
7
Although the invention is not limited thereto, .
a reduced nickel catalyst prepared according to
the process outlined more fully in the patent 5
application of Homer Adkins-Serial No. 616,093,
?led June 8, 1932, has been found to be highly
alpha and beta pipecoline, pyrrolidine, indoline,
‘etc. Among other advantages characterizing the
e?icient in this type of reaction. - The catalyst
process of the invention are its simplicityhhigh ,of
that application is preferably prepared by
degree of e?iciency, and excellent yields of prac
grinding acid-washed kieselguhr having associate 10
10 tically pure products.
‘ Heretofore, it has been possible to prepare .ed therewith, in approximately equal amount,
amines by reacting alcohol and ammonia in the a nickel salt dissolved in water, preferably nickel
nitrate. After being ground to a cream-like con- _
vapor phase over an oxide catalyst, but such re
actions have required hours for their comple ‘sistency, a basic carbonate in water solution,
‘15 tion, have given but low yields ‘and have resulted preferably sodium bicarbonate, is added thereto. 15
in products seriously contaminated by undesired The resulting precipitated nickel carbonate is
by-products; By the present invention, these
disadvantages are eliminated and a simple, sat
isfactory process provided employing the liquid,
20 rather than vapor, phase for bringing about the
reaction.
.
-
'
The invention involves, among other things,
the discovery that by reacting at a temperature
'between about 175° and about 250° 0., in the liq
25 uid phase and in the presence of a reduced nickel
catalyst, a hydroxy compound and a nitrogen
heterocyclic compound containing. replaceable
hydrogen attached to the nuclear nitrogen atom,
water is eliminated between the hydroxy com
30 pound and the heterocyclic compound and a ter
'tiary heterocyclic compound is formed. Although
the reactions may be carried out efficiently at
any temperature between about 175“ and about
250° C., it has been found that working at a tem
35 perature of around 200° C. is even more e?lcient.
As a rule, little or no alkylation takes place below
4O
100° C. Although not strictly necessary-in the
practice of the invention, it will generally be
found preferable to carry out the reactionunder
superatmospheric condltionsof pressure and with
then reduced to elementary nickel 'by heating
in the presence of hydrogen, methanol, ethanol,
or other reducing gas for about an hour at a
temperature of 425-475” C.
20 ,
\ Forthe purposes of the present invention, the
catalyst need not be prepared .by the method
outlined above. For example, one may use nickel
prepared by (l) the reduction of any nickel
salt, either supported or unsupported, by hydro- 25
gen or other reducing agents; (2) the treatment
of a nickel alloy such as nickel-aluminum or
nickel-silicate with aqueous alkalis; (3) the re
duction of nickel salts in admixture with salts of
other metalsyof group VIII or I of the periodic 30
table acting as co-catalysts; or (4) the reduc
tion of nickel salts mixed with promoters such
as oxides of the metals of groups II, III, IV, V
and VI of the periodic table. Still other meth
ods of preparing a reduced nickel catalyst pos- 35
sessing catalytic activity for use in the present
invention are (1) the mechanical subdivision of
massive nickel; (2) the anodic oxidation of nickel
surfaces followed' by reduction; (3) the colloidal
dispersiomof metallic nickel and (4) the precipi- 40
tation by more electropositive metals such as alu
agitation of the materials such as is obtained in minum and zinc. Other contact catalysts may,
a shaking autoclave. Usually pressures in the _ of course, be used with excellent results, exam
neighborhood of 100 atmospheres will be found
ples being‘those-of copper and cobalt prepared
highly efficient.
in a similar manner.
It has been found that ratios
45 of amine to alcohol of the order of 1 :2 give higher
_
yields than equimolar ratios even though ‘only
Any nitrogen heterocyclic compound contain
ing replaceable‘ hydrogen attached to the nuclear
molar ratios react.
nitrogen atom or any of the unsaturated parent
-
.
In place of the nitrogen heterocyclic compound
50 containing replaceable hydrogen attached to the
hetero nitrogen atom, unsaturated parent ring
compounds maybe used with excellent results
' when the reaction is carried out in the presence
ring compounds which, when treated with hydro
gen, produce such a nitrogen heterocyclic com- 60
pound containing replaceable hydrogen attached
to the nitrogen atom, may be used in the inven
tion. Examples of heterocyclic.compoundscon
of hydrogen under pressure. Thus in case a ter~ ' taining replaceable hydrogen attached to‘ they
55 tiary piperidine compound is to be prepared,_ in
45
hetero nitrogen atom are piperidine, alpha and 55
2
2,058,547
beta pipecoline, alpha ethyl piperidine and other
alkyl piperidines, alpha benzyl piperidine, 2-phe
Example 5
nyl ethyl piperidine, 4-phenyl ethyl piperidine,
0.45‘mb1. of piperidine and .5 mol. of butanol
pyrrolidine, alpha methyl pyrrolidine, alpha were reacted under a pressure of ‘approximately
piperidyl pyrrolidine, pyrazoline, pyrazolidine, v100 atmospheres of the hydrogen for 31/2 hours
in the presence of 3 grams of a reduced nickel $1
catalyst similar to that used in Example 1 at ‘
indoline, tetra hydro carbazole, hexahydro car
bazole and dihydro glyoxaline .
azole, alpha. phenyl piperidine, dipiperidyls, lupe
200 degrees C. A yield of 35% N-n-butyl piperi
dine, boiling point 167-172 degrees C., was ob
hydro quinoline, tetra, hydro quinaldine, decahy
tained. The comparatively low yield was due
to the smaller amount of alcohol employed. It 10
Still others are dihydro mu methyl benzimin
'10 tidines, copellidines, tetra hydro quinoline, deca
dro quinaldine and ms. dihydro acridine. The
parent ring compounds, well-known to chemists,
are not speci?cally disclosed since their‘hydro
has been noticed that,_in general, ratios of about '
genated forms have been given above.
Example 6
Piperidine and cyclohexanol in the ratio of 1
mol. to 2 mols., respectively, were reacted at 200"
1:2 of amine to alcohol, respectively, give higher
yields.
Any hydroxy compound, aliphatic, alicyclic,
aryl, aralkyl, heterocyclic or heteroalkyl, may be
employed. Examples are methanol, ethanol, pro
.
'
degrees C. under a pressure of approximately 100
panol. butanol, alpha and beta naphthol, deca' atmospheres of hydrogen for about 470 minutes '
hydro naphtholstetra hydro naphthols, methyl in
the presence of 4 grams of the reduced nickel 20
cyclohexanol, ethyl cyclohexanol, cyclo hexanol. catalyst
used, in Example -1. The product, N
benzyl alcohol. phenyl ethyl alcohol, furfuryl al-' cyclo hexyl piperidine, boiling point 98 to 100 de
cohol, the cresols, tetra hydro furfuryl alcohol, grees C. at 100 mm. pressure, was obtained in a
hydroxy pyridine and hydroxy piperidine. In yield
of 76%.
-,
25 generalfthe substantially neutral organic com- '
pounds containing an OH radical attached to
carbon are applicable for the practice of the in
vention.
'
i
By this invention, a new process for preparing
tertiary heterocyclic amines is thus provided
wherein reactions may be carried .out-e?iciently
‘
at low temperatures in comparison with the prior
As illustrative of the invention, but not limi-' art processes. The reactions proceed practically
ftative thereof,- the following examples are given: to completion with almost no undesirable side
30
reactions. Further, by the use of reduced nickel,
Example 1
’ Approximately 0.5 mol. of piperidine was react- ‘
a catalyst is provided which does not deteriorate '
as rapidly as the prior art catalysts. Still fur- ‘
ed with ,1 mol. of ethanol under a pressure of
ther, by working in the liquid phase the use of
approximately 100 atmospheres of nitrogen in
more compact, e?icient and simpli?ed
_
apparatus -
the presence of about 2 grams of a reduced
is permitted and likewise a greater ease and ac
curacy in the manipulation of the starting ma
terials and of the ?nal products is attained.‘
Although only the preferred forms of the in
vention have been described in detail, it will be‘ 40
apparent to those skilled in the art that it is
not so limited but that‘various minor modi?ca
tions may be made therein, without departing
from the spirit of the invention or from the
scope of the appended claims. It is intended
that the patent shall cover, by suitable expres
nickel-catalyst prepared by the process‘ outlined
in application Serial No. 616,093, ?led June 8..
40 1932, for 31/2 hours at a temperature of 200 de
grees C. The product, N-ethyl piperidine, boil
ing point 125-129 degrees C., was obtained in
a yield of about 80% by fractional distillation.
Example 2
Alpha methyl piperidine and ethanol were re
acted in a shaking ‘autoclave in proportions of
.5 mol. to 1 mol., respectively, for about 7 hours
in the presence of 3 grams of the nickel catalyst
referred to. in Example v1, at a temperature of
about 200 degrees C. and under a pressure of
approximately 100 atmospheres of hydrogen.
N-ethyl alpha methyl piperidine, boiling point
sion in the appended claims, whatever features
of patentable novelty reside in the invention.
What is claimed is:
'
1. A process of preparing tertiary heterocyclic
amines which comprises reacting at a tempera
ture between approximately 175° C. and approxi
145-147 degrees 0., was obtained in a yield of
mately 250° C., under superatmospheric pressure,
about 84%.
in the liquid phase and in the presence of a cata
Example 3
0.5 mol. of alpha methyl piperidine and about
1 mol. of butanol-l were reacted under a pressure
of approximately 100 atmospheres of nitrogen
60 in the presence of 3 gramsot the reduced nickel
lyst selected from the group consisting of copper,
cobalt and nickel, a substantially neutral organic
hydroxy compound in which the hydroxy radical
is directly attached to a carbon atom and a heter
ocyclic compound containing only nitrogen as
the heterocyclic atom, a replaceable hydrogen
‘ catalyst'employed in Examples 1 and 2 for 31/2 atom being attached to the hetero nitrogen atom.
hours at a temperature of about 200 degrees C. »
2. A process of preparing tertiary heterocyclic
N-n-butyl alpha‘ methyl piperidine, boiling point amines which comprises reacting under super
185-190 degrees C., 'was obtained in a yield of atmospheric pressure, at a temperature between
65 about 78%.
'
approximately 175° and approximately 250° C., in
‘ Example 4
Piperidine and ethanol in‘ proportions of about
the liquid phase and ‘in the presence of a nickel
catalyst, an aliphatic alcohol and a heterocyclic
60
65
compound containing only nitrogen as the hetero
.5 mol. to 1 mol., respectively, were reactedunder ' ‘cyclic
atom, a replaceable hydrogen atom being
a. pressure-of approximately 100-atmospheres of
hydrogen in the presence of 2 grams of the nickel
catalyst used in Example 1 for 31/2 hours at 200
degrees C.
N-ethyl piperidine, boiling point
1 125-129 degrees C., was obtained in a yield of
75
about 78%.
attached to a nuclear nitrogen atom.
3. A process of preparing tertiary heterocyclic 70
amines which comprises reacting under superat
mospheric pressure, at a temperature between
approximately 175° and approximately 250° C., in
the liquid phase and in the presence of a nickel
3
2,058,547
catalyst, a hydrogenated hydroxy compound of
presence of a reduced nickel catalyst prepared by
the benzene and naphthalene series and a hetero - levigating a foraminous carrier having associated
- cyclic compound containing only nitrogen as the therewith a soluble nickel salt, adding to the
heterocyclic atom, a replaceable hydrogen atom levigate a basic carbonate and reducing'the re
sulting precipitatednickel carbonate.
being attached to a nuclear nitrogen atom.
4. A process of preparing N-cyclohexyl piperi
, 13. A process of preparing heterocyclic amines
dine which comprises reacting at a temperature
which comprises reacting in the liquid phase and
under superatmospheric pressure, an aliphatic al
cohol containing not more than seven carbon
atoms and a piperidyl compound containing re
placeable hydrogen attached to the hetero nitro
between approximately 175° and approximately
250° C., in the liquid'phase and in the presence
10 of a reduced nickel catalyst, cyclohexanol and
piperidine.
-'
'
- 5. A process of preparing tertiary heterocyclic - gen atom at a temperature between approximate
amines which comprises reacting under superat
mospheric pressure, at a temperature between ap
proximately 175° and approximately 250°C., in the
liquid phase and in the presence of a nickel cata
lyst, an aliphatic alcohol and an azine compound"
containing only nitrogen as the hetcrocyclic atom,
a replaceable hydrogen atom being attached to a
20 nuclear nitrogen atom.
'
ly 175° and approximately 250° C. in the‘presence
of a reduced nickel catalyst prepared by levigating
a foraminous carrier having associated therewith
a soluble nickel salt, adding to the levigate a basic
carbonate and reducing the resulting precipi
tated nickel carbonate.
7
14. A process of preparing heterocyclic amines
which comprises reacting in the liquid phase and ‘
6. A process of preparing ‘tertiary heterocyclic ' under superatmosphericpressure, an aliphatic al
cohol containing not more than seven carbon
amines which, comprises reacting under super
> atmospheric pressure, at a temperature between
atoms and‘ a piperidyl compound containing re
approximately v175° and approximately 250° C., in
placeable hydrogen attached to, the hetero nitro
v25 the liquid phase and in the presence of a nickel . .ly
gen175°
atom
and
at'approximately
a temperature 250°
between
C. inapproximate-_
the presence
catalyst, an aliphatic alcohol and a piperidyl com
of
a
reduced
nickel.catalyst
prepared
by
levigating
pound containing replaceable hydrogen attached
a mixture of approximately equal quantities of
acid washed kieselguhr and nickel nitrate dis-_
30 amines which comprises reacting under superat
solved in water, adding to the levigate an aqueous 0
mospheric- pressure, at a temperature between solution of sodium bicarbonate and treating the
approximately 175° and approximately 250° C., in resulting precipitated nickel carbonate with a
the .liquid phase and in the presence oi a reduced stream of hydrogen for‘at least 60 minutes at. a .
temperature of 425-475" C.
nickel catalyst, an alicyclic- alcohol and a pip
15. A process of preparing tertiary heterocyclic 35
_ eridyl compound containing replaceable hydrogen
amines
which comprises reacting at a tempera
attached to the nuclear. nitrogen atom. 8. A process, of preparing tertiary heterocyclic ture between approximately 175° C. and approxi
mately 250° C., in the liquid phase and in the
amines which comprises reacting at a tempera
presence of a metal catalyst selected from the
ture between approximately 175° and approxi
group consisting of copper, cobalt and nickel, a 40
mately 250° C., in the liquid phase and in the pres
heterocyclic
compound containing nitrogen as the
ence of a reduced nickel catalyst, “an aliphatic
alcohol containing not more than seven carbon heterocyclic atom, a replaceablehydrogen atom
atoms and a heterocyclic compound containing being attached to a nuclear nitrogen atom, and a
compound of the formula R-OH, wherein R is
only nitrogen as the heterocyclic atom, a replace
45
able hydrogen atom being attached to a nuclear a radical selected from the group consisting oi.’
‘ . to the nuclear nitrogen atom.
, 7. A process of preparing tertiary heterocyclic
9. A process of preparing tertiary heterocyclic
amines which comprises reacting at a tempera
ture between approximately 175° and approxi
mately 250° C., in the liquid phase and in the‘
the aliphatic radicals including the phenalkyls,
the aryl radicals of the naphthalene and alkyl
benzene series, the hydrogenated aryl radicals of
the ‘benzene and naphthalene series, and the fur
furyl and hydrogenated furfuryl radicals.
presence of a nickel catalyst, an aliphatic alcohol
containing not more than seven carbon atoms and
which comprises reacting in the liquid phase,
nitrogen atom»
50.
-
a piperidyl compound containing replaceable hy
drogen attached to the nuclear nitrogen atom.
55
16. A process of preparing heterocyclic amines
under superatmospheric pressure, at a tempera
ture between approximately 175° C. and approxi
10. A process oi preparing tertiary piperidines . mately 250° C., and in‘ the presence of a nickel
which comprises reacting at a temperature be
tween approximately 175° and approximately 250°
catalyst, a heterocyclic compound containing only
nitrogen as the hetreocyclic atom, a replaceable
hydrogen atom being attached to a heteronitro
.gen atom, and a compound of the formula
C., in the liquid phase and in the presence of a
nickel catalyst, a saturated aliphatic alcohol and
_ RF-OH, wherein R is a radical selected from the 60
60 a piperidyl compound containing replaceable hy
group consisting of the aliphatic radicals includ
drogen attached to the nuclear nitrogenatom. _
11. A process of preparing tertiary heterocyclic ing the phenalkyls, the aryl radicals of the naph
thalene and alkyl benzene series, the hydro
amines which comprises reacting at a tempera
genated aryl, radicals of the benzene and naph
ture between approximately 175° and approxi
thalene
series and the iuriuryl and hydrogenated 65
mately
250°
C.,
in
the
liquid
phase
and
in
the
pres'
65
ence of a reduced nickel catalyst, an aliphatic
alcohol containing not more than seven carbon
furfuryl radicals.
-
-
17. The process which comprises reacting at a
temperature between approximately 175° C. and
atoms and piperidine.
'
"
12. A process of preparing heterocylic amines’ approximately 250° C., in the liquid phase and in
which
comprises reacting in the liquid phase, an the presence of a catalyst selected from the group
70
alcohol and a heterocycli'c compound containing consisting of copper, cobalt and nickel, an alcohol
and a compound 01' the formula R'=NH, wherein
only nitrogen as the heterocyclic atom, a replace
R’
acycloaliphatic chain having not more than
able hydrogen atom being attached to a hetero ?veisnor
less than four carbon atoms and with N
nitrogen atom, at a temperature between approxi
75
forms a heterocyclic group.
mately
175°
and
approximately
250°
'C.
in
the
75
.
4
2,058,547
18. The process which comprises reacting at a
temperature between approximately 175° C. and
approximately 250° C., in the liquid phase and in
the presence of a catalyst selected from the group
consisting of copper, cobalt‘ and nlckeL'a com
20. N-n-butyl alpha methyl piperidine. 1
21. A process of preparing tertiary heterocyclic
amines which comprises reacting at a tempera
ture between approximately 175° C. and approxi
mately 250° C., 'in the liquid phase and in the
pound of the formula R"=NH, wherein R’ is a _ presence of a catalyst selected from the group
consisting of copper, cobalt and nickel, an alcohol
nor less than four carbon atoms and with N forms and a hetrocyclic compound containing only ni4
a heterocyclic group, with a compound of the for
trogen as the heterocyclic atom, a replaceable hy
10 mula R-OH, wherein R is a radical selected from drogen atom being attached to a nuclear nitrogen 10
the group consisting of the aliphatic radicals in
atom.
'
.
cycloaliphatic chain having ‘not more than ?ve
cluding the phenalkyls, the aryl radicals of the.
naphthalene and alkyl benzene series, the hydro
genated aryl radicals of the benzene and napha
15 lene series, and the furfuryl and hydrogenated
iuriuryl radicals.
-
.
19. A process of preparing tertiary heterocyclic ~
amines which comprises reacting at a tempera
ture between approximately 175°v C. and approxi
20 mately 250° C., in the liquid phase and in the ‘
presence of a catalyst selected from the group
consisting of copper; cobalt and nickel, a hetero
cyclic compound containing only nitrogen as the
22. A process of preparing tertiary heterocyclic
amines which comprises reacting at a tempera
ture between approximately 175° and approxi-‘
mately 250° C., in the liquid phase and in the 15
presence of a nickel catalyst, an alcohol and a
heterocyclic compound containing only nitrogen
as the heterocyclic atom, a replaceable hydrogen
atom being attached to a nuclear nitrogen atom.
23. A process of preparing tertiary heterocyclic 20
amines which comprises condensing water from
H attached to the heteronitrogen atom 01’ a het
erocyclic group and OH attached to a carbon
' heterocyclic atom, a replaceable hydrogen atom 25 being attached to a nuclear nitrogen atom, with atom of a substantially neutral organic hydroxy 25
compound, said condensation reaction being car
a compound of the formula R-OH, wherein R is ried out at a temperature between approximately
a radicalselected from the group consisting of . 175° C. and approximately 250° C., in the liquid
so
‘_
the aliphatic radicals including the phenalkyls, phase and in the presence of _a catalyst selected
the aryl radicals of the naphthalene and alkyl ‘from
group consisting of copper, cobalt and
benzene series, the hydrogenated aryl radicals of nickelthe
30
catalysts.
the benzene and naphthalene series, and the fur
HOMER
ADKINS.
furyl and hydrogenated furfuryl radicals.
HOWARD I. CRAMER.
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