CA1092114A - Method of producing an n-(substituted) morpholine compound - Google Patents

Abstract

METHOD OF PRODUCING AN N-(SUBSTITUTED) MORPHOLINE COMPOUND
(D#75,011-2-F) Abstract of the Disclosure An improved process for selectively producing an N-(substituted)morpholine compound is disclosed wherein an oxydialkanol compound is contacted with a primary amine in the presence of a catalytically effective amount of a phosphorus-containing substance at a temperature of from about 220°C to about 350°C under a pressure sufficient to maintain the mixture essentially in liquid phase, said N-(substituted) morpholine compound produced having the formula:

Description

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.

~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~

/~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 -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.

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.

~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 ~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 ~ ~ 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 ~ ~ 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 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 ~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.

Claims (10)

THE EMBODIMENTS OP THE INVENTION IN WnIICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEPINED AS FOLLOWS:

1. A process for selectively producing an N-(substituted) morpholine compound of the formula wherein each R is, independently, hydrogen or a lower alkyl radical, and R' contains from 1 to 20 carbon atoms and is an alkyl radical, a substituted al-kyl radical, an aryl radical, a substituted aryl radical, a cyclic radical, a substituted cyclic radical, a heterocyclic radical or a substituted hetero-cyclic radical comprising the steps of: contacting an oxydialkanol of the for-mula wherein each R, independently, is hydrogen or a lower alkyl radical with a primary amine in the presence of from about 0.1 to about 10.0 mole percent based upon the amount of said oxydialkanol present of a phosphorous-containing substance selected from the group consisting of acidic metal phosphates, phos-phoric acids and their anhydrides, or phosphorous acids and their anhydrides, C1-C8 alkyl or C6-C20 aryl phosphate esters, C1-C8 alkyl or C6-C20 aryl phos-phite esters, C1-C alkyl or C1-C20 aryl alkyl-substituted phosphorous acids and phosphoric acids, alkali metal monosalts of phosphoric acid, the thioana-logs of the foregoing, and mixtures thereof at a temperature of from about 220°C to about 350°C under pressure sufficient to maintain the mixture es-sentially in liquid phase; and, recovering from the resultant reaction mix-ture said N-(substituted) morpholine compound.

2. The process in accordance with claim 1 wherein said contacting is accomplished at a temperature of from about 240°C to about 325°C.

3. The process in accordance with claim 1 wherein said contacting is accomplished at a pressure ranging from about 0 psig to about 4,000 psig.

4. The process of claim 3 wherein said pressure range is from about at atmospheric to about 2,000 psig.

5. The process in accordance with claim 1 wherein the mole ratio of said oxydialkanol reactant to said primary amine reactant ranges from about 0.5:1 to 20:1.

6. The process in accordance with claim 5 wherein said mole ratio is 1.1 to 10:1.

7. The process in accordance with claim 1 wherein said phosphorus-containing substance is phosphorous acid.

8. The process in accordance with claim 1 wherein said oxydialkanol is oxydiethanol and wherein said primary amine is methylamine.

9. The process in accordance with claim 1 wherein said primary amine is an alkylenediamine.

10. The process in accordance with claim 9 wherein said alkylenediamine is ethylenediamine.