Note: Descriptions are shown in the official language in which they were submitted.
Back~round of the Invention
Field of the Invention
This invention relates to a process for the preparat~on
of N-(substituted) morpholine compounds such as N-methyl morpholine,
and more particularly, pertains to an improved liquid phase
catalyzed process for selectively preparing N-(substituted)
morpholine compounds.
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~L~9Z114
Prior Art
N-(substituted) morpholine compounds such as
N-alkyl morpholine or N-aryl morpholine are well-kn~wn as
polyurethane catalysts. N-alkyl morpholines are generally
prepared by reaction of an alkanol with morpholine. Morpholine
in turn is prepared by various methods, such as for example,
reaction of diethylene glycol and ammonia over nickel catalyst
at high temperatures and pressures. The disadvantage of such
a multi-step process for the preparation of N-(substituted)
morpholine compounds is readily apparent.
Another known method for preparation of N-(substituted)
morpholine involves the cyclic dehydration of a corresponding
N-(substitu~ed) diethanolamine with stoichiometric amounts of
concentrated acid such as hydrochloric, suifuric and the like.
The salt-free product is obtained by subsequent neutralization
and salt recovery. It ha~ been disclosed ~hat N-sryl substituted
morpholine may be prepared by the cyclic dehydration of an N-aryl
substituted diethanolamine in the presence of a stoichiometric
amount of phosphorous pentoxide. See, for example, R.E. Rindsfusz
u. V. L. Harnack, Am. Soc. 42, 1725 (1920).
The above processes involve caustic neutralization with
attendant problems. In addition, the particular N-(substituted)
diethanolamine must be obtained as a reactant. Another method
disclosed for production of N-alkyl substituted morpholine involves
the vapor phase cyclic dehydration of a corresponding N-alkyl
diethanolamine at 375C to 400C in the presence of silica-
A~-2771-2
alumina, For example, see I. Ishiguro, E. Kitamura u.
M. Matsumura, J. Pharm. Soc. Japan 74, 1162 (1954), C. A.
49, 14767g (1955). This method suffers from the attendant
problem of vapor phase synthesis with low yields and extensive
by-product formation.
Unexpectedly it has been found that N-(substituted)
morpholine compounds, including the N-(substituted) C-(alkyl
substituted) morpholines, can be selectively produced directly
from the readily available and easily obtainable corresponding
oxydialkanol and a primary amine without the attendant
deficiencies of previously known processes. Additionally,
the compo~mds effective in catalyzing the synthesis of the
instant invention are readily available and need only be
present in catalytically effective amounts. Thus, there is
no need for a subsequent neutralization and salt recovery
step in practicing the instan~ process. Additionally, the
reaction is carried out substantially in liquid phase,
alleviating the problem of vapor phase synthesis.
.
One outstanding feature of the instant invention
resides in the simpl~city and availability of the reactants.
The co-reactant, a pr~mary amine, is easily obtainable or
may be synthesized by well-kn~wn methods.
Summary of the Invention
In accordance with the broad aspects of the instant
invention, N-(substituted) morpholine compounds of the
formula:
3l~gfg~
R 11
/~n~\
N-R'
~ ~/
R H
wherein each R is, independently, hydrogen or a lower alkyl radical or a sub-
stituted lower alkyl radical and R' contains from 1 to 20 carbon atoms and is
an alkyl radical, a s~bstituted alkyl radical, an aryl radical, a substituted
aryl radical, a cyclic radical, a substituted cyclic radical, a heterocyclic
radical or a substituted heterocyclic radical are produced by a process which
includes contacting an oxydialkanol compound with a primary amine in the pres-
ence of from about 0.1 to about 10.0 mole percent based upon the amount of
said oxydialkanol present of a phosphorus-containing substance selected from
the group consisting of acidic metal phosphates, phosphoric acids and their
anhydrides, or phosphorous acids and their anhydrides, Cl-C8 alkyl or C6-C20
aryl phosphate esters, Cl-C8 alkyl or C6-C20 aryl phosphite esters, Cl-C20
alkyl or Cl-C20 aryl alkyl-substituted phosphorous acids and phosphoric acids,
alkali metal monosalts of phosphoric acid, the thioanalogs of the foregoing,
and mixtures thereof at a temperature of from about 220C to about 350C under
pressure sufficient to maintain the mixture essentially in liquid phase; and,
recovering from the resultant reaction mixture said N-(substituted) morpholine
compound.
By varying the oxydialkanol utilized,lone can achieve, for example,
C-(alkyl substituted) N-(substituted) morpholine. The primary amine may be a
substituted or unsubstituted aryl amine or a substituted or unsubstituted
alkyl amine.
Description of the Preferred Embodiments
In accordance with this invention, a process for producing an N-
(substituted) morpholine compound is provided. In brief, the preferred pro-
cess comprises the steps of reacting an oxydialkanol compound and preferably
oxydiethanol with a primary alkyl amine in the presence of a catalytically
effective amount of a phosphorous-conta.ining substance at a temperature of
from about 240DC to about 325C under pressure sufficient to maintain the
mixture essentially in liquid phase.
- 4a -
AL-2771-2
The N-(substituted) morpholine compounds that can
be produced in accordance with the instant inven~ion can be
depicted by the formula
R H
S ~
O ,~ ~,
\~/
R H
wherein each R is independently hydrogen or a lower alkyl radical
and R' is an alkyl radical which may itself be substituted, an
aryl radical or a substituted aryl radical. Examples of these
compounds are N-methyl morpholine, N-phenyl morpholine, N~(amino-
ethyl)morpholine, N-(2-N'N' dime~hylaminoethyl)morphbline,
N-methyl-2,6-di-ethyl morpholine and the like. The above list is
given only as an example of the class of compounds that can be
formed and not as an exhaustive list of the N-(substituted)
morpholines that can be prepared in accordance with the inven~ion.
It will be realized by those skilled in the art that
both R and R' may contain substituted moieties which are non-
deleterious to the reaction, such as for example oxy, thio or
tertiary amino moieties.
The oxydlalkanol compound that can be used has
the general formula
H R R H
I I 1` I
OH - C - C - O - C - C - OH
R R R R
whereirl each R is independently a lower alkyl radical or
hydrogen. The preferred oxydialkanol compound is of the above
formula wherein each R is independently hydrogen.
AL-2771-2
The primary amine that can be utilized has the
formula
R'NH2
wherein R' is an alkyl radical, a substituted alkyl radical,
an aryl radical, or a substitu~ed aryl radical. In addition,
~ .
the alk7~radical may be cyclic or heterocyclic. Examples uf
primary amines are methylamine, ethylamine, aniline, 2,6-di-
methylaniline, the naphthylamines, N-(2-aminoethyl)morpholine,
N-(2-aminoethyl)piperazine, C-(aminoalkyl)morpholines and the
like.
Addltionally, R' may contain substituted moieties
whlch are nondeleterious to the reactlon such as oxy, thio
or tertiary amino moieties. The only requirement of the above
compounds is that they contain a single nitrogen moiety having
two labile hydrogen~ and that the constituents or moieties
linked with the nitrogen are not or do not contain constituents
deleterious to the reaction. For example, primary amines
containing a second primary amine group or a hydroxy group will
often substantlally increase the by-products and side reactions.
~0 Suitable phosphorus-containing substances which can
be employed lnclude, for example9 acidic metal phosphates,
phosphoric acid compounds and their anhydrides, phosphorous
acid compounds and anhydrides, alkyl or aryl phosphate esters,
alkyl or aryl phosphite esters, alkyl or aryl substituted
AL~2771-2
phosphorous and phosphoric acids, alkali metal monosalts o
phosphoric acid, the thioanalogs of the foregoing~ and mixtures
of any of the above.
More particularly, suitable acidic metal phospha-tes
include boron phosphate, ferric phosphate, aluminum phosphate,
etc.
Suitable phosphoric acid compounds include aqueous
or anhydrous phosphoric acids such as orthophosphoric acid,
pyrophosphoric acid~ metaphosphoric acid, and condensed phos-
phoric acids such as polyphosphoric acids. Accordingly, an
example of a suitable phosphorous acid is orthophosphorous acid.
In addition, any commercially available mono-, di-,
or tri-alkyl or aryl phosphate or phosphite ester can be
employed as the catalyst in the inventive process. Additionally,
bis(phosphates) and secondary phosphate esters such as those
disclosed ln U.S. 3,869~526 and U,S, 39869~527, respectively, can
be used. Preferably, the lower alXyl esters are employed such as
those having from 1 to about 8 carbon atoms per alkyl group. Pre-
ferred aryl esters contain from about 6 to about 20 carbon atoms
and may include a phenyl group or alkyl-substituted phenyl group.
Further, suitable alkyl or aryl substitu~ed phos-
phorous and phosphoric acids which may be employed as a catalyst
include alkyl phosphonic acids, aryl phosphonic acids, alkyl
phosphinic acids and aryl phosphinic acids. Preferably, such
acids include alkyl or aryl groups and have from 1 to about 20
carbon atoms in each aryl or alkyl group.
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~9 ~
Specific examples of alkyl and aryl substltuted phos-
phorous and phosphoric acids that may be used in accordance with
the invention are phenylphosphinic acid, ethylphosphonic acid,
phenylphosphonic acid, naphthaphosphonic acid, and methyl-
phosphinic acid. Examples of the alkyl and aryl substituted
phosphorous and phosphoric acid esters are methylphenyl phos-
phonate, dimethylphenyl phosphonate, methylphenyl phosphinate,
ethyl naphthaphosphinate, and propylmethyl phosphonate.
The above-mentioned phosphorus-containing substances
are not intended to be exhaustive of those that can be employed
as a catalyst in the inventive process. Those materials set
forth are merely intended to be representative of the types of
substances that we ha~e found to be particularly effective.
Yet, of the substances and the types of compound~ mentioned9
we particularly prefer to employ those that are known to be
most reactive such as orthophosphoric acid, polyphosphoric
acids, boron phosphate, aluminum phosphate, ferric phosphate,
and orthophosphorous acid. Of these, most preferred is
orthophosphorous acid.
The phosphorus-containing substance is employed in
only a catalytically effective amount, normally from about
0.1 to about 10.0 mole percent, most often 0.5 to 5.0 mole
percent based on oxydialkanol material employed as a reactant.
Most often the amount of catalyst used is 1.0 to 3.0 mole
percent Preferably, the phosphorus-containing substance is
not employed in an amount higher than about 10.0 mole percent,
based upon the oxydialkanol reactant present, inasmuch
AL-2771~2
~09Xrl~llL4
as phosphorylation reactions can occur if higher amounts
are used which adversely affect the yield of desirable
products. The particular amount emplo~ed for a given
reaction can vary widely, however, depending upon the
reactivity of the catalyst material, reactivity of
reactants, types of reactants employed and particular
processing condi~ions employed.
The specific phosphorus~containing substance
employed as a catalyst can be employed alone, in combination
with other phosphorus-containing substances or can be used
in combination with other acid materials. For example, it
has been found that phosphoric acid-impregnated silicas or
admixtures of orthophosphorous acid and silica-alumina can
be utillzed. Other materials that may be used with the
phosphoru~-containi~g substance include alpha- and gamma-
aluminas, silLca, carborundum9 etc. When an additional
catalyst is used it is present in an amount of 0~1 to 10.0
weight percentage additional catalyst based upon glycol
employed.
The reactants and the catalyst, all de~cribed
hereinabove, are admixed in any desired manner so as to
provide intimatP admixture of reactants and intimate contact
thereof with the catalyst. The admixture is then heated to
a temperature of from above about ~20C to about 350C,
preferably about 240C to about 325C, under a pressure
sufficient to malntain the reaction mass in liquid phase which
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~0 9 ~
normally ranges from about 0 to about 4,000 psig, depending
upon reactants employed. More often the pressure range ls
atmospheric to 2,000 psig. The reaction is allowed to proceed
at the temperature employed until the desired amount of
conversion is obtained.
Time of reaction has not been found to be critical
and complete conversion can usually be determined by the
cessation of formation of water of reaction. It is also not
critical to control the amount of water of reaction present
during the reaction, such as by removal thereof as it is formed.
Usually, we prefer to carry out the reaction at the above-
described temperatures for about 1/2 to about 5 hours.
Normally9 the oxydialkanol compound and the primary
amlne are reacted at molar ratios of from about 0.5:1 to about
20:1, and preferably about 1:1 to about 10:1, moles oxydialkanol
per mole of primary amine compound.
The process of the invention can be carried out
batchwise or continuously employing well-known batch and
continuous processing techniques and conventional processing
apparatus. Where the process is carried out continuously, we
prefer to employ space velocities of reactants of from about
0.1 to about 4, and preferably from about 0.5 to 2, grams
total reactants per milliliter of total reactor volume per
hour.
The desired N-(substituted) morpholine compound
can be readily recovered from the reaction product mass in
substantially pure form by conventional procedures, such as
AL-2771-2
~ ~ 2~ ~ ~
distillation, without difficulty. For example, the reaction
product mass may be directly distilled, or initially filtered
to remove formed solids which usually are amine salt complexes
of ~he phosphorus-con~aining substance, and then dis-
tilled. The desir2d N-(substituted) morpholine compound
can then be separately collected overhead in sal~-free form.
Such d-lstillation recovery procedures are well-known in the
art and, therefore, will not be more particularly discussed
herein.
The following examples illustrate ~he nature of the
inventive process but are not intended to be limitative thereof.
Example 1
In this example, an N-(substituted) morpholine was
prepared in accordance with the instant invention. Into a
clean, dry, 3-neck, round-bottorn flask equipped with a
nitrogen inlet, a thermometer, a mechanical stirrer, and
a 30-centimeter Vigreux column, the column being further
equipped with a Dean Stark trap, a water condenser and a
second thermometer, was charged with 106 g of diethylene glycol
(1.0 mole), 185.5 g n-dodecylamine (1.0 mole) and 11.4 g of
_,
85% phosphoric acid (0.1 mole). The mixture was then heated
under a nitrogen atmosphere at atmospheric pressures to a
~emperature of about 140C whereupon a clear solution was
observed. The reaction ~ixture was further heated to a
temperature of 230C. The temperature of the reaction
mixture gradually increased to about 260C over a period
11
AL-2771-2
~ ~ 2
of about 22 hours. During this period, a liquid wa~
collected in the Dean Stark trap as a dual phase condensed
distillate The upper phase was returned periodically to
the reaction flask.
At the end of the 22-hour period, the reaction
mixture was cooled and filtered yielding 81 g of a
solid residue and 144 g filtrate. The filtrate was then
distilled by conventional means into three fractions, as
shown in Table I below:
Table I
N-n-
(dodecyl) meq/g
Pot. Temp., morpholine, Total
Fraction Wt.? gc!mm GLC A % /0 N Amine
1 13to 130/0.1 85.3 - -
2 85130-140/0.1 97.6 5.42(1)3.89(2)
Residue 43 - 29.9 - -
(l)Theoretical value based upon complete conversion of
reactants to desired product is 5.50.
(2)Theoretical value based upon complete conversion of
reactants to the desired product is 3.92.
Example II
A clean, dry, 1400 ml. rocking autoclave was
charged with a mixture of 424.5 g (4.0 moles~ of oxy-
diethanol (diethylene glycol) and 120.2 g (2.0 moles) of
ethylenediamine. To the charged solution was added 29.6 g
(O.108 moles) aqueous 30% phosphorous acid. The autoclave
12
AL-2771~-2
~ 9 ~
was sealed and the reaction mixture heated under a nitrogen
atmosphere ~o a temperature of abou~ 300C. The autoclave
contents were held at this temperature for 2.0 hours at
450-925 psig. Upon cooling to room temperature, the
autoclave was vented and the reaction product recovered.
The recovered product was shown to contain 9.0% water by
Karl Fischer titration. Upon GLC A % analysis the recovered
reaction product analyzed as follows: % oxydiethanol con-
version, 41.3; % ethylenediamine conversion, 92.1; %
selectivity 2-aminoethyl morpholine7 59.2; selectivity to
dimorpholinoethane, 5.7.
The example illustrates that an N-amino alkylated
amine compound can be produced in a~cordance with the
invention.
ExamRle III
In this example aniline was used as the amine
compound. A one liter, clean, dry, stainless steel lined
autoclave was charged with 187 g (2.0 moles) aniline, 212 g
(2.0 moles) oxydiethanol, and 5.7 g (0.05 moles) of 85%
phosphorous acid. The autoclave was sealed and the mixture
heated under nitrogen for 2 hourR at about 280C. During
this time the pressure reached a maximum of 292 psig. Upon
cooling,the crude reacti~n product was distilled into three
fractions. A first fraction weighed 290 g and was obtained
at a pot temperature of 206 C/ atm. A second frac~ion
AL-2771-2
~Q g Z~ ~ ~
weighed 208 g and was obtained at a pot temperature of
205C/16 mm Hg. The residue weighed 114 g. Each fraction
was then subjected to GLC analysis which showed the foll~wing
values in Area %: % conversion aniline, 78.9; % conversion
oxydiethanol, 80.7; % selectivity to phenylmorpholine, 65.7.
While the invention has been explained in relation
to its preferred embodiment, it is to be understood that
various modifications thereof will become apparent to those
skiiled in the art upon reading the specification and is
intended to cover such modifications as fall within the scope
of the appended claims.
14
