CA1070305A - Method of producing morpholine compound - Google Patents
Method of producing morpholine compoundInfo
- Publication number
- CA1070305A CA1070305A CA252,910A CA252910A CA1070305A CA 1070305 A CA1070305 A CA 1070305A CA 252910 A CA252910 A CA 252910A CA 1070305 A CA1070305 A CA 1070305A
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- Prior art keywords
- morpholine
- aryl
- alkyl
- substituted
- compound
- Prior art date
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/023—Preparation; Separation; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/033—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
Abstract
METHOD OF PRODUCING MORPHOLINE COMPOUND
(D#75,009-3-F) Abstract of the Disclosure An improved process for producing a morpholine compound is disclosed which comprises the steps of contacting an aminoalkoxyalkanol compound with a catalytically effective amount of a phosphorus-containing substance at a temperature of from about 250°C to about 350°C under a pressure sufficient to maintain the mixture essentially in liquid phase, said amino-alkoxyalkanol compound having the formula:
wherein each R, independently, is hydrogen or a lower alkyl radical, and R' is hydrogen, an alkyl radical, a substituted alkyl radical, an aryl radical, or a substituted aryl radical;
and. recovering said morpholine compound.
(D#75,009-3-F) Abstract of the Disclosure An improved process for producing a morpholine compound is disclosed which comprises the steps of contacting an aminoalkoxyalkanol compound with a catalytically effective amount of a phosphorus-containing substance at a temperature of from about 250°C to about 350°C under a pressure sufficient to maintain the mixture essentially in liquid phase, said amino-alkoxyalkanol compound having the formula:
wherein each R, independently, is hydrogen or a lower alkyl radical, and R' is hydrogen, an alkyl radical, a substituted alkyl radical, an aryl radical, or a substituted aryl radical;
and. recovering said morpholine compound.
Description
Background of the Invention Field of the Invention _ This invention relates to a process for the preparation of a morpholine compound such as morpholine, N-(su~stituted) morpholine compounds and C-(substituted) morpholine compounds, and morë particularly pertains to an improved liquid phase process for selectively preparing morpholine compounds.
Prior Art N-(substituted) morpholine compounds such as N-alkyl morpholine or N-aryl morpholine are well-known as , . ~ : . . , - -- - :- , . ............ .. :: . :
, ~ : .. ; ,.... ., , : : .: .. . . . . .
-"`` 10~(~3~
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-(substituted) diethanolamine with stoichiometric amounts of concentrated acid such as hydrochloric, sulfuric and the like with a subsequent neutralization and salt recovery step. It has been disclosed that N-aryl substituted morpholine may be prepared by the cyclization dehydration of an N-aryl substituted diethanolamine in the presence of a stoichiometric amount of phosphorus pentoxide, See, for example, R. E. Rindsfusz u.
V. L. Harnackj 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-alumina. For example, see I. Ishiguro, E. Kitamura u. M. Matsumura, J. Pharm. Soc. Japan `` 10'~0305 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.
In U. S. Patent No. 3,151,112, the basic process for the preparation of morpholine is disclosed. Such process has been operated through the years on a commercial basis.
However, this procedure does have one drawback in that the metal hydrogenation catalyst employed,tends to lose activity after some period of time when utilized in this diethylene-glycol-ammonia reacting process. Additionally, morpholine produced by such methods usually contains 1 to 2% impurities such as ethylene glycol monomethyl ether which are difficult to physically remove from the morpholine product. Such impurities are undesirable when the morpholine is used as an emulsifying agent or as a chain stopper in the emulsion polymerization of synthetic rubbers.
Recently it has been disclosed that morpholine can be produced by the'gas phase reaction of diethylene glycol with ammonia over a nickel catalyst at 200C to 250C. See for example Dobrovol-skii, S. V. et al Zh. Vses. Khim. Obshchest, 1969, 14(5), 589-90. Additionally, it is disclosed that
Prior Art N-(substituted) morpholine compounds such as N-alkyl morpholine or N-aryl morpholine are well-known as , . ~ : . . , - -- - :- , . ............ .. :: . :
, ~ : .. ; ,.... ., , : : .: .. . . . . .
-"`` 10~(~3~
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-(substituted) diethanolamine with stoichiometric amounts of concentrated acid such as hydrochloric, sulfuric and the like with a subsequent neutralization and salt recovery step. It has been disclosed that N-aryl substituted morpholine may be prepared by the cyclization dehydration of an N-aryl substituted diethanolamine in the presence of a stoichiometric amount of phosphorus pentoxide, See, for example, R. E. Rindsfusz u.
V. L. Harnackj 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-alumina. For example, see I. Ishiguro, E. Kitamura u. M. Matsumura, J. Pharm. Soc. Japan `` 10'~0305 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.
In U. S. Patent No. 3,151,112, the basic process for the preparation of morpholine is disclosed. Such process has been operated through the years on a commercial basis.
However, this procedure does have one drawback in that the metal hydrogenation catalyst employed,tends to lose activity after some period of time when utilized in this diethylene-glycol-ammonia reacting process. Additionally, morpholine produced by such methods usually contains 1 to 2% impurities such as ethylene glycol monomethyl ether which are difficult to physically remove from the morpholine product. Such impurities are undesirable when the morpholine is used as an emulsifying agent or as a chain stopper in the emulsion polymerization of synthetic rubbers.
Recently it has been disclosed that morpholine can be produced by the'gas phase reaction of diethylene glycol with ammonia over a nickel catalyst at 200C to 250C. See for example Dobrovol-skii, S. V. et al Zh. Vses. Khim. Obshchest, 1969, 14(5), 589-90. Additionally, it is disclosed that
2-amino-2'-hydroxydiethyl ether which is an intermediate of that reaction may be used as a starting product under the same reaction conditions to yield morpholine.
Unexpectedly it has been found that morpholine compounds and more specifically morpholine itself can be 10~'()305 selectively produced directly from an aminoethoxyethanol compound in substantially liquid phase without the attendant deficiency of previously known processes. Surprisingly, under the rigorous reaction conditions, i.e. temperatures in the range of from about 250C to 350C, the process is very selective to the desired morpholine product without encountering the decomposition of the reactant and the attendant production of unwanted side products Additionally, it has been found that the morpholine-containing reaction product is substan-tially free of ethleneglycol monomethyl ether.
Further, the compounds effective in catalyzing the synthe~is 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 instant process.
Additionally, the reaction is carried out substantially in liquid phase, alleviating the problem of vapor phase synthesis.
Summary of the Invention In accordance with the broad aspects of the instant invention, morpholine compounds of the formula:
R H
~N-R' ~ H
wherein R is hydrogen or a lower alkyl radical and R' is hydrogen, an alkyl radical, a substituted alkyl radical, an aryl radical, or a substituted aryl radical are produced by a ~070305 - process which includes contacting an aminoalkoxyalkanol compound with a catalytically effective amount of a phosphorus-containing substance at a temperature of from about 250C to about 350C under pressure sufficient to maintain the mixture essentially in liquid phase; and, recovering from the resultant reaction mixture said morpholine compound.
In accordance with one embodiment, an N-(substituted) morpholine is produced by use of the corresponding N-(substituted) aminoethoxy ethanol as a starting reagent. In accordance with another embodiment, a C-(substituted) morpholine is produced by use of the corresponding C-(substituted) aminoethoxy ethanol as a starting reagent, According to the preferred embodiment, morpholine which i5 ~ubstantially free of ethyleneglycol monomethyl ether 15 i9 produced by contacting 2-amino-2'-hydroxydiethyl ether with a catalytically effective amount of a phosphorus-containing substance and preferably phosphorous acid at a temperature of from about 275C to about 325C under a pressure of from about 50 p8ig to about 1,000 psig. The morpholine is then recovered from the reaction product.
Description of the Preferred Embodiments In accordance with a greatly preferred embodiment, an autoclave is charged with a solution of phosphorous acid (H3PO3)and 2-amino-2'-hydroxydiethyl ether, sealed and heated under a nitrogen atmosphere to a temperature of 275C to 325C. The ~emperature is maintained for about 2,0 hours, , , , . ~
After cooling to room temperature the autoclave is vented and the reaction mixture recovered. Morpholine produced is recovered from the collected reaction mixture by standard distillation techniques.
Generally, N-(substituted) morpholine compouhd C-(substituted) morpholine compounds, and N-(substituted) C-(substituted) morpholine compounds can be prepared in a similar manner to the process described hereinabove for producing morpholine. In brief, the proce s involves the cyclic dehydration of an aminoethoxyethanol in the presence of a catalytically effective amount of a phosphorus-containing substance. The pressure is sufficient to maintain the mixture essentially in liquid phase. By utilizing N-(substituted) and/or C-(substituted) aminoethoxyethanol , compounds, the corresponding morpholine compound can be directly synthesized.
The morpholine compounds tha~ can be produced in accordance with the instant invention can be generally depicted by the formula:
R H
` ~ N-R' R X
~; wherein each R, independently, is hydrogen or a lower alkyl radical and R' is hydrogen, an alkyl radical which may itself be substi-tuted, an aryl radical or a substituted aryl radical. Examples of these compounds are morpholine, N-methyl morpholine, N phenyl morpholine, N-(2-N'N'-dimethylaminoethyl)morpholine, 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 morpholine compounds that can be prepared in accordance with the invention.
It will be realized by those skilled in the art that - both R and R' may contain substituted moieties which are non-dele~erious to the reaction, such as for example oxy, thio or tertiary amino moieties.
One outstanding advantage of the instant process resides in the flexibili~y one can obtain in product formation.
Since the process embodies a direct cyclic-dehydration of a single reactant, selectivity to the desired product is enhanced.
Thus one only need obtain the corresponding aminoalkoxyalkanol , ..... .
compound to produce the desired morpholine compound.
Generally, the compounds useful as ~tarting reagents can be generally described as aminoalkoxyalkanol compounds and more particularly as aminoethoxyethanol compounds. The amino ; ,:.
~ moiety need only contain a single labile hydrogen and be free .;. .
of substituent groups which are deleterious to the reaction.
Interfering or competing groups may be utilized as amino ~ubstituents with the expected sacrifice in yield.
The aminoalkoxyalkanol compounds that can be used are generally depicted by the formula:
H R R H R' OH - C - C - O - C - C - NH
R R R R
' "
107030~;
wherein each R, independently, is hydrogen or a lower alkyl radical and R' is hydrogen, an alkyl radical, a substituted alkyl radical, an aryl radical or a substituted aryl radical.
In addition, the all.~yl radical may be cyclic or heterocyclic.
- 5 Examples of suitable aminoalkoxyalkanol amines are N-methyl-aminoethoxyethanol, N-ethylaminoethoxyethanol, N-phenylamino-ethoxyethanol, N-napthylaminoethoxyethanol, N-morpholinoamino-ethoxyethanol, N-(N'-methylpiperazinoethyl) aminoethoxyethanol and the like. The C-(substituted) aminoethoxyethanol compounds may also be used, e.g. those C-(substituted) compounds corres-ponding to the above compounds.
Suitable phosphorus-containing substances which can be employed include, for example, acidic metal phosphates, phosphoric scid compounds and their anhydrides, phosphorous acid compounds and anhydrides, alkyl or aryl phosphate esters, alkyl or aryl phosphite esters, alkyl or aryl substituted phosphorous and phosphoric acids, alkali metal monosalts of pho~phoric acid, the thioanalogs of the foregoing, and mixtures of any of the above.
More particularly, suitable acidic metal phosphates . .
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.
- . . ., ,. .. - - -- - - - - -. -- . .. ~ .. .. - - . .. -. : .
~ 070305 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 in U. S. 3,869,526 and U. S. 3,869,527, respectively~
can be used. Preferably, the lower alkyl esters are employed such as those having from l to about 8 carbon atoms per alkyl .^
group. Preferred aryl esters contain from about 6 to about 20 carbon atoms and may lnclude a phenyl group or alkyl-substituted phenyl group.
Further, suita~le alkyl or aryl substituted phosphorous 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 acid3 include alkyl or aryl groups and have from l to about 20 carbon atoms in each aryl or alkyl group.
`~ Specific examples of alkyl and aryl substituted phosphorous and phosphoric acids that may be used in accordance : with the invention are phenylphosphinic acid, ethylphosphonic acid, phenylphosphonic acid, naphthaphosphonic acid, and methyl~
phosphinic acld. Examples of the alkyl and aryl substituted phosphorous and phosphoric acid esters are methylphenyl phosphonate, dimethylphenyl phosphonate, methylphenyl phosphinate, ethyl naphthaphosphinate, and propylmethyl phosphonate.
The above-mentioned phosphorus-containlng substances are not intended to be exhaustive of those that can be employed 10~0305 as a catalyst in the inventive process. Those materials set forth are merely intended to be representative of the types of substances that we have found to be particularly effective Yet, of the substances and the types of compounds mentioned, we particularly prefer to employ those that are known to be most reac~ive such as orthophosphoric acids, 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, more often 0.5 to S.0 mole ~ percent based on aminoglycol 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 , i8 not employed in an amount higher than about 5.0 mole percent, based upon the aminoethoxyethanol reactant present, inasmuch as phosphorylation reactions can occur if higher amounts are used which adversely affect the yield of desirable products The particular amount employed 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 conditions employed.
The specific phosphorus-containing substance employed as a catalyst can be employed alone, in combination with other phosphoru~-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 utilized.
Other catalysts ~hat may be used with the phosphorus-containing substance include alpha- and gamma-aluminas, silica, carborundum, 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 aminoglycol employed.
The reactants and the catalyst, all described hereinabove, are admixed in any desired manner so as to provide intimate admixture of reactants and intimate contact ; thereof with the catalyst. The admixture is then heated to a temperature of from above about 250C to about 350C, preferably about 275C to about 325C, under a pressure sufficient to maintain the reaction mass in liquid phase which normally ranges from about 1 to about 1,500 psig, depending upon reactants employed. More often the pressure range is 50 to 1,000 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;
however, some decomposition will begin to occur when greatly extended contact times are utilized. Generally the complete conversion can 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 abou~
1/2 to about 5 hours.
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 spa~e velocities of reactants of from about 0.1 to about 4, and preferably from about 0.5 to 2 grams reactants per milliliter of total reactor volume per hour.
The desired morpholine compound can be readily ; 10 recovered from the reaction product mass in substantially pure form by conventional procedures, such as distillation, wlthout difficulty. For example, the reaction product mass ` may be directly distilled, or initially flltered to remove . formed solids which usually are amine salt complexes of the
Unexpectedly it has been found that morpholine compounds and more specifically morpholine itself can be 10~'()305 selectively produced directly from an aminoethoxyethanol compound in substantially liquid phase without the attendant deficiency of previously known processes. Surprisingly, under the rigorous reaction conditions, i.e. temperatures in the range of from about 250C to 350C, the process is very selective to the desired morpholine product without encountering the decomposition of the reactant and the attendant production of unwanted side products Additionally, it has been found that the morpholine-containing reaction product is substan-tially free of ethleneglycol monomethyl ether.
Further, the compounds effective in catalyzing the synthe~is 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 instant process.
Additionally, the reaction is carried out substantially in liquid phase, alleviating the problem of vapor phase synthesis.
Summary of the Invention In accordance with the broad aspects of the instant invention, morpholine compounds of the formula:
R H
~N-R' ~ H
wherein R is hydrogen or a lower alkyl radical and R' is hydrogen, an alkyl radical, a substituted alkyl radical, an aryl radical, or a substituted aryl radical are produced by a ~070305 - process which includes contacting an aminoalkoxyalkanol compound with a catalytically effective amount of a phosphorus-containing substance at a temperature of from about 250C to about 350C under pressure sufficient to maintain the mixture essentially in liquid phase; and, recovering from the resultant reaction mixture said morpholine compound.
In accordance with one embodiment, an N-(substituted) morpholine is produced by use of the corresponding N-(substituted) aminoethoxy ethanol as a starting reagent. In accordance with another embodiment, a C-(substituted) morpholine is produced by use of the corresponding C-(substituted) aminoethoxy ethanol as a starting reagent, According to the preferred embodiment, morpholine which i5 ~ubstantially free of ethyleneglycol monomethyl ether 15 i9 produced by contacting 2-amino-2'-hydroxydiethyl ether with a catalytically effective amount of a phosphorus-containing substance and preferably phosphorous acid at a temperature of from about 275C to about 325C under a pressure of from about 50 p8ig to about 1,000 psig. The morpholine is then recovered from the reaction product.
Description of the Preferred Embodiments In accordance with a greatly preferred embodiment, an autoclave is charged with a solution of phosphorous acid (H3PO3)and 2-amino-2'-hydroxydiethyl ether, sealed and heated under a nitrogen atmosphere to a temperature of 275C to 325C. The ~emperature is maintained for about 2,0 hours, , , , . ~
After cooling to room temperature the autoclave is vented and the reaction mixture recovered. Morpholine produced is recovered from the collected reaction mixture by standard distillation techniques.
Generally, N-(substituted) morpholine compouhd C-(substituted) morpholine compounds, and N-(substituted) C-(substituted) morpholine compounds can be prepared in a similar manner to the process described hereinabove for producing morpholine. In brief, the proce s involves the cyclic dehydration of an aminoethoxyethanol in the presence of a catalytically effective amount of a phosphorus-containing substance. The pressure is sufficient to maintain the mixture essentially in liquid phase. By utilizing N-(substituted) and/or C-(substituted) aminoethoxyethanol , compounds, the corresponding morpholine compound can be directly synthesized.
The morpholine compounds tha~ can be produced in accordance with the instant invention can be generally depicted by the formula:
R H
` ~ N-R' R X
~; wherein each R, independently, is hydrogen or a lower alkyl radical and R' is hydrogen, an alkyl radical which may itself be substi-tuted, an aryl radical or a substituted aryl radical. Examples of these compounds are morpholine, N-methyl morpholine, N phenyl morpholine, N-(2-N'N'-dimethylaminoethyl)morpholine, 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 morpholine compounds that can be prepared in accordance with the invention.
It will be realized by those skilled in the art that - both R and R' may contain substituted moieties which are non-dele~erious to the reaction, such as for example oxy, thio or tertiary amino moieties.
One outstanding advantage of the instant process resides in the flexibili~y one can obtain in product formation.
Since the process embodies a direct cyclic-dehydration of a single reactant, selectivity to the desired product is enhanced.
Thus one only need obtain the corresponding aminoalkoxyalkanol , ..... .
compound to produce the desired morpholine compound.
Generally, the compounds useful as ~tarting reagents can be generally described as aminoalkoxyalkanol compounds and more particularly as aminoethoxyethanol compounds. The amino ; ,:.
~ moiety need only contain a single labile hydrogen and be free .;. .
of substituent groups which are deleterious to the reaction.
Interfering or competing groups may be utilized as amino ~ubstituents with the expected sacrifice in yield.
The aminoalkoxyalkanol compounds that can be used are generally depicted by the formula:
H R R H R' OH - C - C - O - C - C - NH
R R R R
' "
107030~;
wherein each R, independently, is hydrogen or a lower alkyl radical and R' is hydrogen, an alkyl radical, a substituted alkyl radical, an aryl radical or a substituted aryl radical.
In addition, the all.~yl radical may be cyclic or heterocyclic.
- 5 Examples of suitable aminoalkoxyalkanol amines are N-methyl-aminoethoxyethanol, N-ethylaminoethoxyethanol, N-phenylamino-ethoxyethanol, N-napthylaminoethoxyethanol, N-morpholinoamino-ethoxyethanol, N-(N'-methylpiperazinoethyl) aminoethoxyethanol and the like. The C-(substituted) aminoethoxyethanol compounds may also be used, e.g. those C-(substituted) compounds corres-ponding to the above compounds.
Suitable phosphorus-containing substances which can be employed include, for example, acidic metal phosphates, phosphoric scid compounds and their anhydrides, phosphorous acid compounds and anhydrides, alkyl or aryl phosphate esters, alkyl or aryl phosphite esters, alkyl or aryl substituted phosphorous and phosphoric acids, alkali metal monosalts of pho~phoric acid, the thioanalogs of the foregoing, and mixtures of any of the above.
More particularly, suitable acidic metal phosphates . .
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.
- . . ., ,. .. - - -- - - - - -. -- . .. ~ .. .. - - . .. -. : .
~ 070305 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 in U. S. 3,869,526 and U. S. 3,869,527, respectively~
can be used. Preferably, the lower alkyl esters are employed such as those having from l to about 8 carbon atoms per alkyl .^
group. Preferred aryl esters contain from about 6 to about 20 carbon atoms and may lnclude a phenyl group or alkyl-substituted phenyl group.
Further, suita~le alkyl or aryl substituted phosphorous 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 acid3 include alkyl or aryl groups and have from l to about 20 carbon atoms in each aryl or alkyl group.
`~ Specific examples of alkyl and aryl substituted phosphorous and phosphoric acids that may be used in accordance : with the invention are phenylphosphinic acid, ethylphosphonic acid, phenylphosphonic acid, naphthaphosphonic acid, and methyl~
phosphinic acld. Examples of the alkyl and aryl substituted phosphorous and phosphoric acid esters are methylphenyl phosphonate, dimethylphenyl phosphonate, methylphenyl phosphinate, ethyl naphthaphosphinate, and propylmethyl phosphonate.
The above-mentioned phosphorus-containlng substances are not intended to be exhaustive of those that can be employed 10~0305 as a catalyst in the inventive process. Those materials set forth are merely intended to be representative of the types of substances that we have found to be particularly effective Yet, of the substances and the types of compounds mentioned, we particularly prefer to employ those that are known to be most reac~ive such as orthophosphoric acids, 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, more often 0.5 to S.0 mole ~ percent based on aminoglycol 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 , i8 not employed in an amount higher than about 5.0 mole percent, based upon the aminoethoxyethanol reactant present, inasmuch as phosphorylation reactions can occur if higher amounts are used which adversely affect the yield of desirable products The particular amount employed 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 conditions employed.
The specific phosphorus-containing substance employed as a catalyst can be employed alone, in combination with other phosphoru~-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 utilized.
Other catalysts ~hat may be used with the phosphorus-containing substance include alpha- and gamma-aluminas, silica, carborundum, 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 aminoglycol employed.
The reactants and the catalyst, all described hereinabove, are admixed in any desired manner so as to provide intimate admixture of reactants and intimate contact ; thereof with the catalyst. The admixture is then heated to a temperature of from above about 250C to about 350C, preferably about 275C to about 325C, under a pressure sufficient to maintain the reaction mass in liquid phase which normally ranges from about 1 to about 1,500 psig, depending upon reactants employed. More often the pressure range is 50 to 1,000 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;
however, some decomposition will begin to occur when greatly extended contact times are utilized. Generally the complete conversion can 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 abou~
1/2 to about 5 hours.
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 spa~e velocities of reactants of from about 0.1 to about 4, and preferably from about 0.5 to 2 grams reactants per milliliter of total reactor volume per hour.
The desired morpholine compound can be readily ; 10 recovered from the reaction product mass in substantially pure form by conventional procedures, such as distillation, wlthout difficulty. For example, the reaction product mass ` may be directly distilled, or initially flltered to remove . formed solids which usually are amine salt complexes of the
3 15 phosphorus-containing substance, and then distilled. The desired morpholine compound can then be separately collected overhead in salt-free form. Such distillation recovery procedures are well-known in the art and, therefore, will not be more particularly discussed herein.
The following example illustrates the nature of the inventive process but is not intended to be limitative thereof.
;~ Example l.j In this example morpholine was produced directly from a primary aminoalkoxyalkanol compound. To a dry nitrogen purged l-liter stainless steel autoclave equipped with a stirring means was charged a solution consisting of 420.6 g (4.0 moles) 2-(2-aminoethoxy)ethanol and 16.0 g (0.058 moles) aqueous 30% phosphorous acid. The autoclave contents were padded with nitrogen and heated to a temperature of about 300 for 2 hours under a pressure of 325-850 psig. Upon cooling, the crude reaction product was recovered and analyzed by Karl Fischer titration sh~wing 14.8 wt. % water. Upon GLC
A % analysis the recovered crude product showed the foll~w-ing: % 2-(2-aminoethoxy)ethanol conversion, 74.7; %
selectivity to morpholine, 74.5; % selectivity to dimorpholino-ethane, 3.9, % selectivity to hydroxyethoxyethyl morpholine, 1.7; and selectivity to aminoethoxyethyl morpholine 13.5.
While th~ invention has been explained in relation to its preferred embodiment, it is to be understood that various modifications thereof will become apparent to those ~ 15 skilled in the art upon reading the specification and is `~ intended to cover such modifications as fall within the `` scope of the appended claims.
'~
,:, ,
The following example illustrates the nature of the inventive process but is not intended to be limitative thereof.
;~ Example l.j In this example morpholine was produced directly from a primary aminoalkoxyalkanol compound. To a dry nitrogen purged l-liter stainless steel autoclave equipped with a stirring means was charged a solution consisting of 420.6 g (4.0 moles) 2-(2-aminoethoxy)ethanol and 16.0 g (0.058 moles) aqueous 30% phosphorous acid. The autoclave contents were padded with nitrogen and heated to a temperature of about 300 for 2 hours under a pressure of 325-850 psig. Upon cooling, the crude reaction product was recovered and analyzed by Karl Fischer titration sh~wing 14.8 wt. % water. Upon GLC
A % analysis the recovered crude product showed the foll~w-ing: % 2-(2-aminoethoxy)ethanol conversion, 74.7; %
selectivity to morpholine, 74.5; % selectivity to dimorpholino-ethane, 3.9, % selectivity to hydroxyethoxyethyl morpholine, 1.7; and selectivity to aminoethoxyethyl morpholine 13.5.
While th~ invention has been explained in relation to its preferred embodiment, it is to be understood that various modifications thereof will become apparent to those ~ 15 skilled in the art upon reading the specification and is `~ intended to cover such modifications as fall within the `` scope of the appended claims.
'~
,:, ,
Claims (7)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing a morpholine compound of the formula wherein R is hydrogen or a lower alkyl radical and R' is hydrogen, an alkyl radical, a substituted alkyl radical, an aryl radical or a substituted aryl radical comprising the steps of: contacting an aminoalkoxyalkanol compound with a catalytically effective amount of a phosphorus-containing substance selected from the group consisting of acidic metal phosphates, phosphoric acids and their anhydrides, phosphorous acids and their anhydrides, alkyl or aryl phosphate esters, alkyl or aryl phosphite esters, alkyl or aryl substi-tuted phosphorous acids and phosphoric acids, alkali metal monosalts of phos-phoric acid, the thioanalogs of the foregoing, and mixtures thereof at a tem-perature of from about 250°C to about 350°C under a pressure sufficient to maintain the mixture essentially in liquid phase, said aminoalkoxyalkanol compound having the formula:
wherein each R, independently, is selected from the group consisting of hydro-gen and lower alkyl radicals, and wherein R' is selected from a group consist-ing of hydrogen, alkyl radicals, substituted alkyl radicals, aryl radicals and substituted aryl radicals; and, recovering said morpholine compound from the resulting reaction mixture.
wherein each R, independently, is selected from the group consisting of hydro-gen and lower alkyl radicals, and wherein R' is selected from a group consist-ing of hydrogen, alkyl radicals, substituted alkyl radicals, aryl radicals and substituted aryl radicals; and, recovering said morpholine compound from the resulting reaction mixture.
2. The process in accordance with claim 1 wherein said contacting is accomplished at a temperature of from about 275°C to about 325°C.
3. The process in accordance with claim 1 wherein said contacting is accomplished at a pressure ranging from about 1 psig to about 1,500 psig.
4. The process of claim 3 wherein said pressure range is from about 50 to about 1,000 psig.
5. The process in accordance with claim 1 wherein said phosphorus-containing substance is phosphorous acid.
6. The process in accordance with claim 1 wherein said phosphorus-containing substance is present in an amount of from about 0.1 to about 10.0 mole percent based upon the amount of said aminoalkoxyalkanol present.
7. The process in accordance with claim 1 wherein said aminoalkoxy-alkanol is 2-amino-2'-hydroxydiethyl ether.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US58302275A | 1975-06-02 | 1975-06-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1070305A true CA1070305A (en) | 1980-01-22 |
Family
ID=24331364
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA252,910A Expired CA1070305A (en) | 1975-06-02 | 1976-05-20 | Method of producing morpholine compound |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JPS51141882A (en) |
| AU (1) | AU504669B2 (en) |
| BE (1) | BE842468A (en) |
| CA (1) | CA1070305A (en) |
| DE (1) | DE2624072A1 (en) |
| FR (1) | FR2313373A1 (en) |
| GB (1) | GB1492359A (en) |
| IT (1) | IT1063218B (en) |
| NL (1) | NL7605638A (en) |
| ZA (1) | ZA763137B (en) |
-
1976
- 1976-05-05 GB GB18423/76A patent/GB1492359A/en not_active Expired
- 1976-05-19 JP JP51056756A patent/JPS51141882A/en active Pending
- 1976-05-20 CA CA252,910A patent/CA1070305A/en not_active Expired
- 1976-05-24 FR FR7615662A patent/FR2313373A1/en active Granted
- 1976-05-26 ZA ZA763137A patent/ZA763137B/en unknown
- 1976-05-26 NL NL7605638A patent/NL7605638A/en not_active Application Discontinuation
- 1976-05-28 DE DE19762624072 patent/DE2624072A1/en not_active Withdrawn
- 1976-05-31 AU AU14438/76A patent/AU504669B2/en not_active Expired
- 1976-06-01 BE BE167544A patent/BE842468A/en unknown
- 1976-06-01 IT IT23855/76A patent/IT1063218B/en active
Also Published As
| Publication number | Publication date |
|---|---|
| AU504669B2 (en) | 1979-10-25 |
| IT1063218B (en) | 1985-02-11 |
| FR2313373A1 (en) | 1976-12-31 |
| DE2624072A1 (en) | 1976-12-23 |
| BE842468A (en) | 1976-12-01 |
| JPS51141882A (en) | 1976-12-07 |
| NL7605638A (en) | 1976-12-06 |
| ZA763137B (en) | 1977-05-25 |
| AU1443876A (en) | 1977-12-08 |
| GB1492359A (en) | 1977-11-16 |
| FR2313373B1 (en) | 1980-01-11 |
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