CA1289558C - Purification of 1-(alkylamino)-alkyl-2-keto-1,4- diazacycloalkanes - Google Patents
Purification of 1-(alkylamino)-alkyl-2-keto-1,4- diazacycloalkanesInfo
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- CA1289558C CA1289558C CA000521808A CA521808A CA1289558C CA 1289558 C CA1289558 C CA 1289558C CA 000521808 A CA000521808 A CA 000521808A CA 521808 A CA521808 A CA 521808A CA 1289558 C CA1289558 C CA 1289558C
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Abstract
ABSTRACT OF THE DISCLOSURE
A compound such as 1-(alkylamino)alkyl-2-keto-1,4-diazacycloalkanes having the formula are useful UV stabilizers and can be prepared by using an excess of base in forming the cyclized product which is then worked up forming a crude product without water or water immiscible solvent.
The crude product is purified by distillation without decomposition of the desired compound during distillation.
A compound such as 1-(alkylamino)alkyl-2-keto-1,4-diazacycloalkanes having the formula are useful UV stabilizers and can be prepared by using an excess of base in forming the cyclized product which is then worked up forming a crude product without water or water immiscible solvent.
The crude product is purified by distillation without decomposition of the desired compound during distillation.
Description
~8~
This invention relates to the preparation of l-(alkylamino)alkyl-2-keto-1,4-diazacycloalkanes.
The increasing use of polymers in p~ace of the more traditional types of structural materials (e.g., wood, metals, etc.) has necessitated the compounding of such polymers with a variety of stabilizers in order to enhance the ability of such polymers to withstand prolonged exposure to a variety of degradative forces. Degradation of such environmental sensitive polymers can be caused by exposure to light, heat and/or air. Such degradation is usually manifested by either a partial or total loss of structural integrity, changes in light transmission properties, changes in color, loss or reduction in flexibility and/or resiliency, or any combination of the above phenomenon. As will be appreciated, the stabilizers which are used in conjunction with the above polymeric materials, in addition to providing protection against such degradative changes, must also be compatible with the aesthetic properties of the polymeric article and be effective at low concentrations. The economics of the marketplace dictate that these stabilizers be relatively inexpensive and capable of preparation from readily available starting materials by simple and straightforward synthetic techniques.
The 2-keto-1,4-diazacycloalkanes have been found to be highly effective in the stabilization of polymeric materials against the photodegradative forces of ultraviolet light. The efficiency of such materials in the W stabilization of polymers is described in U.S. Patents 4,167,512 and 4,190,571.
One particular class of 2-keto-1,4-diazacycloalkanes ~, 1~8955~
is the class of l-(alkylamino)alkyl-2-keto-1,4-diazacycloalkanes.
It is known that such diazacycloalkanes can be prepared by non-catalytic base-induced ketoform 5 synthesis as described in U.S. Patent 4,466,915.
~he non-catalytic base-induced ketoform synthesis includes cyclization, work-up and purification. The cyclization involves a combination of an amine, a ketone or a benzaldehyde and a haloform such as chlor~form or bromoform and a base such as alkali metal hydroxide such as sodium hydroxide.
Work-up of the reaction product is done by working up the reactant by adding a solvent such as CHC13 and water as disclosed in Example 2 of U.S. Patent 4,466,915. The water layer is extracted with the solvent and combined with the original solvent layer wherein the combined solvent is washed with water.
The solvent layer is then dried over anhydrous magnesium sulfate to leave a yellow liquid which is purified by fractional distillation.
Using work-up as above involves an expensive step of using a water immiscible solvent such as CHC13 from which the crude reaction product has to be extracted. A solvent such as CHC13 is known to be toxic and it is desirable to avoid use of such a solvent. The solvent is used to avoid decomposition of the product during purification. It also has been found in the preparation of diazacycloalkanes, as the molecular weight of the diazacycloalkanes increase so does the boiling point of the diazacycloalkanes and there is a tendency of the reactant product of the cyclization to decompose during distillation unless certain precautions were followed.
~.' ~:89ro58 It is the object of the present invention to provide an improved process for the preparation of l-(alkylamino)alkyl-2-keto-1,4-diazacycloalkanes without decomposition during the purification.
SUMMARY OF THE INVENTION
A method of preparing l-(alkylamino)alkyl-2-keto-1,4-diazacycloalkane compound has been discovered wherein a cyclized product is prepared from a carbonyl-containing compound which is combined with a haloform, an amine and at least S.O moles of base to each mole of amine is added. Thereafter, the cyclized product is worked up without introducing water and without introducing a water immiscible solvent whereafter the crude product is purified to the desired l-(alkylamino)alkyl-2-keto-1,4-diazacycloalkane compound without decomposition of the compound occurring during the distillation.
DETAILED DESCRIPTION
miS invention relates to the purification of l-(alkylamino)alkyl-2-keto-1,4-diazacycloalkanes and derivatives thereof which find utility as W
stabilizers and as intermediates in the preparation of relatively high molecular weight stabilizers. The 25 1- (alkylamino)alkyl-2-keto-1,4-diazacycloalkanes may be represented by the general formula Il ~--R
(CH2 ) I n (CH2)m ~ (I) R5 ~ ~ R2 1~89558 wherein m repreSents an integer of 1 or 2, being the number of methylene groups forming a bridge of variable length; when m is 1, (I) represents a substituted l-(alkylamino)alkyl-2-piperazinone; n represents an integer in the range from 2 to about 10; Rl representS alkyl having from 1 to about 24 carbon atoms, cycloalkyl having from 5 to 12 carbon atoms, aralkyl having from 7 to about 20 carbon atoms, azaalkyl having from 1 to about 24 carbon ; R2, R3, R4 and R5 independently represent alkyl, haloalkyl, cyanoalkyl, cycloalkyl, hydroxy-cycloalkyl, aminoalkyl and alkenyl; R6 represents hydrogen, alkyl, hydroxyalkyl, oxy, hydroxy, haloalkyl, cyanoalkyl, aminoalkyl, alkenyl, aralkyl and carboalkoxy.
Preferably, R2, R3, R4 and Rs independently represent alkyl or haloalkyl having from 1 to about 12 carbon atoms, cyanoalkyl or aminoalkyl having from 2 to about 12 carbon atoms, 20 cycloalkyl or hydroxycycloalkyl having from 5 to about 14 carbon atoms, and alkenyl having from 7 to about 14 carbon atoms; R6 represents hydrogen, hydroxy, oxy, alkyl having from 1 to about 24 carbon atoms, hydroxyalkyl, haloalkyl, or aminoalkyl having from 1 to about 12 carbon atoms, cyanoalkyl having from 2 to about 12 carbon atoms and alkenyl or aralkyl having from 7 to about 14 carbon atoms.
The more preferred substituted l-(alkylamino)alkyl-2-keto-1,4-diazacycloalkanes are 30 those wherein R2, R3, R4, and R5 are selected from the group consisting of alkyl having from 1 to about 12 carbon atoms, and polymethylene having from 5 to 6 carbon atoms which are cyclizable; examples which include methyl, ethyl, propyl, n-butyl, 35 isobutyl, n-hexyl, 2-ethylheptyl, n-decyl, and where 9~8 the substituents are cyclizable, cyclopentyl, rnethylcyclopentyl, cyclohexyl, methylcyclonexyl, dimethyl cycloheptyl, piperidyl, 2,2,6,6-tetramethyl piperidyl, and the like.
Examples of most preferred substituted l-(alkylamino)alkyl-2-keto-l~4-diazacycloalkanes are:
1-[2-(2-butylamino)ethyl]-3,3,5,5-tetramethyl-2-piperaz inone;
1-[2-(isopropylamino)ethyl]-3,3,5,5-tetramethvl-2-piper azinone;
1-~2-(1,3-dimethylbutylamino)ethyl]-3,3,5,5-tetramethyl -2-piperazinone;
1-[2-(cyclohexylamino)ethyl]-3,3,5,5-tetramethyl-2-pipe razinone; and 1-[2-(cyclohexylamino)propyl]-3,3,5,5-tetramethyl-2-pip erazinone. The l-(alkylamino)alkyl-2-keto-1,4-diazacycloalkanes are generally prepared in a process which involves cyclization and purification. A reactant compound consisting of an amine nucleophilic agent, a haloform, a ketone and a base are mixed in the cyclization process. The amine which can be the primary or secondary amine is chosen to provide the desired substituents at preselected locations in the reactant compound, and to provide upon cyclization, the desired number of C atoms in the bridge (between N atoms) on one side of the ring, and also to provide the desired substituents on preselected C atoms of this bridge.
The presence of a haloform, such as chloroform or bromoform, takes part in the reaction as a necessary reagent, but may also have some function as a catalyst, though the precise mechanism or the manner in which the haloform affects the 5~8 reaction, is not understood. Since the haloform is reactant, it is essential that at least an equal molar amount (as the amine) be used if good yields of the reaction product are to be obtained. Lesser amounts of the haloform will yield product, but not in an amount desired.
For a l-(alkylamino)alkyl-2-keto-1,4-diazacycloalkane to be formed, useful carbonyl containing groups are those which cyclize forming a fixed 2-carbon bridge between the Nl and N4 atoms of the diaza ring.
Preferably, ketones are cycloalkanenones, dialkylketones and arylalkylketones are useful carbonyl containing groups. As described in U.S. Patent 4,466,915, aromatic monoaldehydes appear to be effective in the synthesis.
The amines, haloforms and carbonyl-containing compound and use thereof are described in U.S. Patent 4,466,915.
The preferred base for inducing the reaction according to the present invention is an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide. The alkali metal hydroxide is used in solid form, either in finely divided powder form, or commercial bead form. Preferably, at least 5.0 moles of base to mole of amine nucleophilic agent is used and more preferably between 5.0 and 6.0 moles of base is used. In theory, it has been determined that 4.0 moles of base would be sufficient in the cyclization, but it has been found that 25% to about 50% excess is required to practice the present invention.
Typically, in the cyclization portion of the synthesis, the reactants are mixed and the base is added last. In a more preferred embodiment, the carbonyl containin9 group and the halogen are combined into a mixture wherein the mixture is generally cooled to less than 0C by suitable means such as a circulatOry bath. Thereafter, cooled amine is added to the mixture while the temperature is maintained at between -5C and 10C and more preferably between 0C and 10C. After the amine was added, the base is added in an incremental basis. A
small amount of water can be added with the initial addition of the base to assist the reaction. The base is added to the system with stirring, and the heat is removed by cooling since the reaction is generally exothermic. Momentary increases of temperature up to 20C may occur at the early stage of the NaOH addition.
The reaction can proceed at the subatmospheric or superatmospheric pressures and pressure considerations are not critical to the practice of the invention except as to requirements of the system may dictate. Operation at atmospheric is most preferred because there appears to be no substantial advantage to be gained from operating at higher pressures.
The cyclized product is in the form of a slurry which requires a work-up which includes suction filtration to separate the solid and the liquid which contains the product. The cake is rinsed with acetone to insure all the organic materials are in the filtrate. No water or water immiscible solvent is introduced in the work up. A
trace of water layer (if any present) is removed from the filtrate whereafter the organic layer was stripped by an evaporator. The crude product is then purified by distillation.
1~89~S8 The decomposition of the product can be detected by regular means of a gas chromatograph (GC) and by visual observation wherein a vapor (smoke like) is noted in the distillation column during purification of the crude product.
It has been found that even if at least 5.2 molar ratio of base to amine is used in the cyclization portion of the synthesis, a decomposition of product in the purification step occurs if water is introduced to dissolve inorganic compounds during the work-up. The occurrence of this is shown in Example 1 below. Example 3 illustrates that decomposition during purification will occur if 4.9 molar ratio of base to amine is used even when the product is worked up and purified according to the present invention.
As a precaution against decomposition during distillation, it has further been found that an alkali metal hydroxide such as sodium hydroxide can be placed in the distillation pot.
The following examples are presented to illustrate this invention, and are intended in the illustrative and not limitative sense.
Example 1 Preparation of 1-[3-(cyclohexylamino)propyl]-3,3,5,5-tetramethyl-2-pip erazinone having the following structure:
N
(CH2)3 I
H3C ~ ~ CH3 ~3C l C~3 1~8~551~
In a 5-liter, 3-necked flask were placed 1833 millileters (24.9 moles) of acetone, and 230 milliliters (2.88 moles) of chloroform wherein the two ingredients were stirred and cooled to a temperature of about 6C wherein 562.4 grams (1.92 moles) of Nl-[3-(cyclohexylamino)propyl~-2-methyl-l~2-propanediam ine was added. ~hen the temperature of the pot reached 4C, 2.5 grams of sodium hydroxide (NaOH) and 2.5 grams of H20 were added; 6 minutes later 8 grams of ~aOH and 5.5 grams of H20 were added;
whereafter the rest of the NaOH was added in from 13 gram to 27 gram amounts over the next 4 hours. A
total of 399.4 grams (9.98 moles) of NaOH was added to the mixture. The molar ratio of base to amine was 5.2. The cyclized product reacted over the next 2 hours (after addition of the ~aOE~ was completed).
The range of the temperature of the reaction during this time was between about -5C and 10C. Work up of the cyclized product included addition of 1500 ml of H20. Two layers formed from which the organic layer was separated and then stripped using an evaporator whereafter a GC of the crude product was taken. The crude product was fractionally distilled. The first indication of decomposition was the presence of smoke in the distillation column. A
G.C. of the traction showed decomposition with the presence of low boils which were not found in the GC
of the original crude product.
Example 2 Preparation of 1-[3-(cyclohexylamino)propyl]-3,3,5,5-tetramethyl-2-pip erazinone as shown was prepared.
In a 2-liter, 3-necked flask were placed 668 35 milliliters (9.1 moles) of acetone and 133.6 grams 1~8955~
(1.12 moles) of chloroform. Then 165.8 grams (0.7 mole) of N~-[3-(cyclohexylamino)propyl]-2-methyl-ll2-propanediam ine was added. To this stirred and cooled mixture was added the base of sodium hydroxide beads starting with .5 gram NaOH beads, 1 gram H20, 2.5 grams NaOH
beads followed by 5 grams H20. Then the rest of the sodium hydroxide was added without any H20 while maintaining the pot temperature of between 1C
to 10C over a period of about 3 hours. In all toll, 146 grams (3.64 moles) of sodium hydroxide beads was added to the reaction. The molar ratio of base to amine was 5.2. The cyclized prod~ct slurry was filtered and the white filter cake was washed with 50n milliliters of acetone and then stripped. The crude product was fractionally distilled without decomposition and purity as measured by the G.C.'s was from 97 to 100~.
Exam~le 3 Preparation of 1-[3-(cyclohexylamino)propyl]-3,3,5,5-tetramethyl-2-pip erazinone as shown in Example 1 was prepared.
In one 5-liter, 3-necked flask were placed 2100 ml (28.6 moles) of acetone and 264 ml (3.3 25 moles) of chloroform. Then 690.8 grams (2.2 moles) of N'-[3-(cyclohexylamino)propyl]-2-methyl-1,2-propanediam ine was added. To this stirred and cooled mixture was added 440 grams (11 moles) of NaOH as was done in Examples 1 and 2. The molar ratio of base to amine was 5Ø
In a second 5-liter, 3-necked flask were placed 2100 ml of acetone, 264 ml of chloroform and 690.8 grams of N'-l3-(cyclohexylamino)propyl]-2-methyl-1,2-propanediam ~8~5sa ine. To this was added 422.4 grams (10.6 moles) of ~aOH as above. The molar ratio of base to amine was 4.8.
Both processes were worked up as in Example 2 whereafter the cyclized products were combined and vacuumed distillated. The molar ratio of the base to amine in the combined cyclized product was 4.9.
When G.C.'s of the tractions was taken, decomposition was found to occur even though water was not introduced to dissolve inorganic solids during the work-up.
This invention relates to the preparation of l-(alkylamino)alkyl-2-keto-1,4-diazacycloalkanes.
The increasing use of polymers in p~ace of the more traditional types of structural materials (e.g., wood, metals, etc.) has necessitated the compounding of such polymers with a variety of stabilizers in order to enhance the ability of such polymers to withstand prolonged exposure to a variety of degradative forces. Degradation of such environmental sensitive polymers can be caused by exposure to light, heat and/or air. Such degradation is usually manifested by either a partial or total loss of structural integrity, changes in light transmission properties, changes in color, loss or reduction in flexibility and/or resiliency, or any combination of the above phenomenon. As will be appreciated, the stabilizers which are used in conjunction with the above polymeric materials, in addition to providing protection against such degradative changes, must also be compatible with the aesthetic properties of the polymeric article and be effective at low concentrations. The economics of the marketplace dictate that these stabilizers be relatively inexpensive and capable of preparation from readily available starting materials by simple and straightforward synthetic techniques.
The 2-keto-1,4-diazacycloalkanes have been found to be highly effective in the stabilization of polymeric materials against the photodegradative forces of ultraviolet light. The efficiency of such materials in the W stabilization of polymers is described in U.S. Patents 4,167,512 and 4,190,571.
One particular class of 2-keto-1,4-diazacycloalkanes ~, 1~8955~
is the class of l-(alkylamino)alkyl-2-keto-1,4-diazacycloalkanes.
It is known that such diazacycloalkanes can be prepared by non-catalytic base-induced ketoform 5 synthesis as described in U.S. Patent 4,466,915.
~he non-catalytic base-induced ketoform synthesis includes cyclization, work-up and purification. The cyclization involves a combination of an amine, a ketone or a benzaldehyde and a haloform such as chlor~form or bromoform and a base such as alkali metal hydroxide such as sodium hydroxide.
Work-up of the reaction product is done by working up the reactant by adding a solvent such as CHC13 and water as disclosed in Example 2 of U.S. Patent 4,466,915. The water layer is extracted with the solvent and combined with the original solvent layer wherein the combined solvent is washed with water.
The solvent layer is then dried over anhydrous magnesium sulfate to leave a yellow liquid which is purified by fractional distillation.
Using work-up as above involves an expensive step of using a water immiscible solvent such as CHC13 from which the crude reaction product has to be extracted. A solvent such as CHC13 is known to be toxic and it is desirable to avoid use of such a solvent. The solvent is used to avoid decomposition of the product during purification. It also has been found in the preparation of diazacycloalkanes, as the molecular weight of the diazacycloalkanes increase so does the boiling point of the diazacycloalkanes and there is a tendency of the reactant product of the cyclization to decompose during distillation unless certain precautions were followed.
~.' ~:89ro58 It is the object of the present invention to provide an improved process for the preparation of l-(alkylamino)alkyl-2-keto-1,4-diazacycloalkanes without decomposition during the purification.
SUMMARY OF THE INVENTION
A method of preparing l-(alkylamino)alkyl-2-keto-1,4-diazacycloalkane compound has been discovered wherein a cyclized product is prepared from a carbonyl-containing compound which is combined with a haloform, an amine and at least S.O moles of base to each mole of amine is added. Thereafter, the cyclized product is worked up without introducing water and without introducing a water immiscible solvent whereafter the crude product is purified to the desired l-(alkylamino)alkyl-2-keto-1,4-diazacycloalkane compound without decomposition of the compound occurring during the distillation.
DETAILED DESCRIPTION
miS invention relates to the purification of l-(alkylamino)alkyl-2-keto-1,4-diazacycloalkanes and derivatives thereof which find utility as W
stabilizers and as intermediates in the preparation of relatively high molecular weight stabilizers. The 25 1- (alkylamino)alkyl-2-keto-1,4-diazacycloalkanes may be represented by the general formula Il ~--R
(CH2 ) I n (CH2)m ~ (I) R5 ~ ~ R2 1~89558 wherein m repreSents an integer of 1 or 2, being the number of methylene groups forming a bridge of variable length; when m is 1, (I) represents a substituted l-(alkylamino)alkyl-2-piperazinone; n represents an integer in the range from 2 to about 10; Rl representS alkyl having from 1 to about 24 carbon atoms, cycloalkyl having from 5 to 12 carbon atoms, aralkyl having from 7 to about 20 carbon atoms, azaalkyl having from 1 to about 24 carbon ; R2, R3, R4 and R5 independently represent alkyl, haloalkyl, cyanoalkyl, cycloalkyl, hydroxy-cycloalkyl, aminoalkyl and alkenyl; R6 represents hydrogen, alkyl, hydroxyalkyl, oxy, hydroxy, haloalkyl, cyanoalkyl, aminoalkyl, alkenyl, aralkyl and carboalkoxy.
Preferably, R2, R3, R4 and Rs independently represent alkyl or haloalkyl having from 1 to about 12 carbon atoms, cyanoalkyl or aminoalkyl having from 2 to about 12 carbon atoms, 20 cycloalkyl or hydroxycycloalkyl having from 5 to about 14 carbon atoms, and alkenyl having from 7 to about 14 carbon atoms; R6 represents hydrogen, hydroxy, oxy, alkyl having from 1 to about 24 carbon atoms, hydroxyalkyl, haloalkyl, or aminoalkyl having from 1 to about 12 carbon atoms, cyanoalkyl having from 2 to about 12 carbon atoms and alkenyl or aralkyl having from 7 to about 14 carbon atoms.
The more preferred substituted l-(alkylamino)alkyl-2-keto-1,4-diazacycloalkanes are 30 those wherein R2, R3, R4, and R5 are selected from the group consisting of alkyl having from 1 to about 12 carbon atoms, and polymethylene having from 5 to 6 carbon atoms which are cyclizable; examples which include methyl, ethyl, propyl, n-butyl, 35 isobutyl, n-hexyl, 2-ethylheptyl, n-decyl, and where 9~8 the substituents are cyclizable, cyclopentyl, rnethylcyclopentyl, cyclohexyl, methylcyclonexyl, dimethyl cycloheptyl, piperidyl, 2,2,6,6-tetramethyl piperidyl, and the like.
Examples of most preferred substituted l-(alkylamino)alkyl-2-keto-l~4-diazacycloalkanes are:
1-[2-(2-butylamino)ethyl]-3,3,5,5-tetramethyl-2-piperaz inone;
1-[2-(isopropylamino)ethyl]-3,3,5,5-tetramethvl-2-piper azinone;
1-~2-(1,3-dimethylbutylamino)ethyl]-3,3,5,5-tetramethyl -2-piperazinone;
1-[2-(cyclohexylamino)ethyl]-3,3,5,5-tetramethyl-2-pipe razinone; and 1-[2-(cyclohexylamino)propyl]-3,3,5,5-tetramethyl-2-pip erazinone. The l-(alkylamino)alkyl-2-keto-1,4-diazacycloalkanes are generally prepared in a process which involves cyclization and purification. A reactant compound consisting of an amine nucleophilic agent, a haloform, a ketone and a base are mixed in the cyclization process. The amine which can be the primary or secondary amine is chosen to provide the desired substituents at preselected locations in the reactant compound, and to provide upon cyclization, the desired number of C atoms in the bridge (between N atoms) on one side of the ring, and also to provide the desired substituents on preselected C atoms of this bridge.
The presence of a haloform, such as chloroform or bromoform, takes part in the reaction as a necessary reagent, but may also have some function as a catalyst, though the precise mechanism or the manner in which the haloform affects the 5~8 reaction, is not understood. Since the haloform is reactant, it is essential that at least an equal molar amount (as the amine) be used if good yields of the reaction product are to be obtained. Lesser amounts of the haloform will yield product, but not in an amount desired.
For a l-(alkylamino)alkyl-2-keto-1,4-diazacycloalkane to be formed, useful carbonyl containing groups are those which cyclize forming a fixed 2-carbon bridge between the Nl and N4 atoms of the diaza ring.
Preferably, ketones are cycloalkanenones, dialkylketones and arylalkylketones are useful carbonyl containing groups. As described in U.S. Patent 4,466,915, aromatic monoaldehydes appear to be effective in the synthesis.
The amines, haloforms and carbonyl-containing compound and use thereof are described in U.S. Patent 4,466,915.
The preferred base for inducing the reaction according to the present invention is an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide. The alkali metal hydroxide is used in solid form, either in finely divided powder form, or commercial bead form. Preferably, at least 5.0 moles of base to mole of amine nucleophilic agent is used and more preferably between 5.0 and 6.0 moles of base is used. In theory, it has been determined that 4.0 moles of base would be sufficient in the cyclization, but it has been found that 25% to about 50% excess is required to practice the present invention.
Typically, in the cyclization portion of the synthesis, the reactants are mixed and the base is added last. In a more preferred embodiment, the carbonyl containin9 group and the halogen are combined into a mixture wherein the mixture is generally cooled to less than 0C by suitable means such as a circulatOry bath. Thereafter, cooled amine is added to the mixture while the temperature is maintained at between -5C and 10C and more preferably between 0C and 10C. After the amine was added, the base is added in an incremental basis. A
small amount of water can be added with the initial addition of the base to assist the reaction. The base is added to the system with stirring, and the heat is removed by cooling since the reaction is generally exothermic. Momentary increases of temperature up to 20C may occur at the early stage of the NaOH addition.
The reaction can proceed at the subatmospheric or superatmospheric pressures and pressure considerations are not critical to the practice of the invention except as to requirements of the system may dictate. Operation at atmospheric is most preferred because there appears to be no substantial advantage to be gained from operating at higher pressures.
The cyclized product is in the form of a slurry which requires a work-up which includes suction filtration to separate the solid and the liquid which contains the product. The cake is rinsed with acetone to insure all the organic materials are in the filtrate. No water or water immiscible solvent is introduced in the work up. A
trace of water layer (if any present) is removed from the filtrate whereafter the organic layer was stripped by an evaporator. The crude product is then purified by distillation.
1~89~S8 The decomposition of the product can be detected by regular means of a gas chromatograph (GC) and by visual observation wherein a vapor (smoke like) is noted in the distillation column during purification of the crude product.
It has been found that even if at least 5.2 molar ratio of base to amine is used in the cyclization portion of the synthesis, a decomposition of product in the purification step occurs if water is introduced to dissolve inorganic compounds during the work-up. The occurrence of this is shown in Example 1 below. Example 3 illustrates that decomposition during purification will occur if 4.9 molar ratio of base to amine is used even when the product is worked up and purified according to the present invention.
As a precaution against decomposition during distillation, it has further been found that an alkali metal hydroxide such as sodium hydroxide can be placed in the distillation pot.
The following examples are presented to illustrate this invention, and are intended in the illustrative and not limitative sense.
Example 1 Preparation of 1-[3-(cyclohexylamino)propyl]-3,3,5,5-tetramethyl-2-pip erazinone having the following structure:
N
(CH2)3 I
H3C ~ ~ CH3 ~3C l C~3 1~8~551~
In a 5-liter, 3-necked flask were placed 1833 millileters (24.9 moles) of acetone, and 230 milliliters (2.88 moles) of chloroform wherein the two ingredients were stirred and cooled to a temperature of about 6C wherein 562.4 grams (1.92 moles) of Nl-[3-(cyclohexylamino)propyl~-2-methyl-l~2-propanediam ine was added. ~hen the temperature of the pot reached 4C, 2.5 grams of sodium hydroxide (NaOH) and 2.5 grams of H20 were added; 6 minutes later 8 grams of ~aOH and 5.5 grams of H20 were added;
whereafter the rest of the NaOH was added in from 13 gram to 27 gram amounts over the next 4 hours. A
total of 399.4 grams (9.98 moles) of NaOH was added to the mixture. The molar ratio of base to amine was 5.2. The cyclized product reacted over the next 2 hours (after addition of the ~aOE~ was completed).
The range of the temperature of the reaction during this time was between about -5C and 10C. Work up of the cyclized product included addition of 1500 ml of H20. Two layers formed from which the organic layer was separated and then stripped using an evaporator whereafter a GC of the crude product was taken. The crude product was fractionally distilled. The first indication of decomposition was the presence of smoke in the distillation column. A
G.C. of the traction showed decomposition with the presence of low boils which were not found in the GC
of the original crude product.
Example 2 Preparation of 1-[3-(cyclohexylamino)propyl]-3,3,5,5-tetramethyl-2-pip erazinone as shown was prepared.
In a 2-liter, 3-necked flask were placed 668 35 milliliters (9.1 moles) of acetone and 133.6 grams 1~8955~
(1.12 moles) of chloroform. Then 165.8 grams (0.7 mole) of N~-[3-(cyclohexylamino)propyl]-2-methyl-ll2-propanediam ine was added. To this stirred and cooled mixture was added the base of sodium hydroxide beads starting with .5 gram NaOH beads, 1 gram H20, 2.5 grams NaOH
beads followed by 5 grams H20. Then the rest of the sodium hydroxide was added without any H20 while maintaining the pot temperature of between 1C
to 10C over a period of about 3 hours. In all toll, 146 grams (3.64 moles) of sodium hydroxide beads was added to the reaction. The molar ratio of base to amine was 5.2. The cyclized prod~ct slurry was filtered and the white filter cake was washed with 50n milliliters of acetone and then stripped. The crude product was fractionally distilled without decomposition and purity as measured by the G.C.'s was from 97 to 100~.
Exam~le 3 Preparation of 1-[3-(cyclohexylamino)propyl]-3,3,5,5-tetramethyl-2-pip erazinone as shown in Example 1 was prepared.
In one 5-liter, 3-necked flask were placed 2100 ml (28.6 moles) of acetone and 264 ml (3.3 25 moles) of chloroform. Then 690.8 grams (2.2 moles) of N'-[3-(cyclohexylamino)propyl]-2-methyl-1,2-propanediam ine was added. To this stirred and cooled mixture was added 440 grams (11 moles) of NaOH as was done in Examples 1 and 2. The molar ratio of base to amine was 5Ø
In a second 5-liter, 3-necked flask were placed 2100 ml of acetone, 264 ml of chloroform and 690.8 grams of N'-l3-(cyclohexylamino)propyl]-2-methyl-1,2-propanediam ~8~5sa ine. To this was added 422.4 grams (10.6 moles) of ~aOH as above. The molar ratio of base to amine was 4.8.
Both processes were worked up as in Example 2 whereafter the cyclized products were combined and vacuumed distillated. The molar ratio of the base to amine in the combined cyclized product was 4.9.
When G.C.'s of the tractions was taken, decomposition was found to occur even though water was not introduced to dissolve inorganic solids during the work-up.
Claims (19)
1. A method for preparing 1-(alkylamino)-alkyl-2-ketone-1,4-diazacycloalkane compound com-prising:
a cyclization process forming a cyclized product wherein a carbonyl-containing compound selected from a group consisting of a ketone and benzaldehyde is combined with sufficient haloform whereafter an amine is added whereafter at least 5.0 moles of base to each mole of amine is added; work-up of said cyclized product to a crude product without introducing water and without introducing a water immiscible solvent whereafter the crude product is purified to said 1-(alkylamino)alkyl-2-keto-1,4-diazacycloalkane compound without decomposition of said compound occurring during the purification.
a cyclization process forming a cyclized product wherein a carbonyl-containing compound selected from a group consisting of a ketone and benzaldehyde is combined with sufficient haloform whereafter an amine is added whereafter at least 5.0 moles of base to each mole of amine is added; work-up of said cyclized product to a crude product without introducing water and without introducing a water immiscible solvent whereafter the crude product is purified to said 1-(alkylamino)alkyl-2-keto-1,4-diazacycloalkane compound without decomposition of said compound occurring during the purification.
2. A method of claim 1 wherein said 1-(alkyl-amino)alkyl-2-keto-1,4-diazacycloalkane has the formula wherein m represents an integer of 1 or 2;
n represents an integer in the range from 2 to about 10;
R1 represents alkyl of 1 to 24 carbon atoms, cycloalkyl having from 5 to 12 carbon atoms, aralkyl having from 7 to about 20 carbon atoms, azaalkyl having from 1 to about 24 carbon atoms;
R2, R3, R4 and R5 independently represent alkyl, haloalkyl, cyanoalkyl, cycloalkyl, hydroxy-cycloalkyl, aminoalkyl and alkenyl;
R6 represents hydrogen, alkyl, hydroxy-alkyl, hydroxy, oxy, haloalkyl, cyanoalkyl, amino-alkyl, alkenyl, aralkyl and carboalkoxy.
n represents an integer in the range from 2 to about 10;
R1 represents alkyl of 1 to 24 carbon atoms, cycloalkyl having from 5 to 12 carbon atoms, aralkyl having from 7 to about 20 carbon atoms, azaalkyl having from 1 to about 24 carbon atoms;
R2, R3, R4 and R5 independently represent alkyl, haloalkyl, cyanoalkyl, cycloalkyl, hydroxy-cycloalkyl, aminoalkyl and alkenyl;
R6 represents hydrogen, alkyl, hydroxy-alkyl, hydroxy, oxy, haloalkyl, cyanoalkyl, amino-alkyl, alkenyl, aralkyl and carboalkoxy.
3. A method according to claim 2 wherein R2, R3, R4 and R5 independently represent alkyl or haloalkyl having from 1 to about 12 carbon atoms, cyanoalkyl or aminoalkyl having from 2 to about 12 carbon atoms, cycloalkyl or hydroxycycloalkyl having from 5 to about 14 carbon atoms, and alkenyl having from 7 to about 14 carbon atoms;
R6 represents hydrogen, alkyl having from 1 to about 24 carbon atoms; hydroxyalkyl, haloalkyl, or aminoalkyl having from 1 to about 12 carbon atoms;
cyanoalkyl having from 2 to about 12 carbon atoms and alkenyl or aralkyl having from 7 to about 14 carbon atoms.
R6 represents hydrogen, alkyl having from 1 to about 24 carbon atoms; hydroxyalkyl, haloalkyl, or aminoalkyl having from 1 to about 12 carbon atoms;
cyanoalkyl having from 2 to about 12 carbon atoms and alkenyl or aralkyl having from 7 to about 14 carbon atoms.
4. A method of claim 1, 2 or 3 wherein said base is an alkali metal hydroxide.
5. A method of claim 4 wherein said alkali metal hydroxide is present in a molar ratio of base to amine in the range of about 5.0 to about 6.0 moles.
6. The method of claim 5 wherein said haloform is one of chloroform or bromoform.
7. A method of claim 6 wherein said cyclized product is formed at a temperature of between about -10°C to about 10°C.
8. A method of claim 1, 2, 3, 5, 6 or 7 wherein said crude product is purified in the presence of alkali metal hydroxide.
9. A method of claim 4 wherein said crude product is purified in the presence of alkali metal hydroxide.
10. In a process for preparing a polysubsti-tuted piperazinone reaction product from an N-substi-tuted-diamine comprising, reacting said diamine with a saturated acyclic or cyclic ketone present in an amount greater than the molar amount required to react with said diamine in the presence of an alkali metal hydroxide and sufficient haloform to produce said reaction product, and recovering said poly-substituted piperazinone, the improvement consisting essentially of (i) adding a large excess of solid alkali metal hydroxide, at least five moles for each mole of said diamine;
(ii) producing a substantially completely monoketonesoluble water-sensitive polysubstituted piperazin-2-one represented by the structure wherein n represents 2 or 3;
R1 represents C2-C24 alkyl, C5-C12 cycloalkyl or aralkyl of 7 to 20 carbon atoms; and R2, R3, R4 and R5 each represent C1-C12 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl or C5-C14 cycloalkyl;
(iii) separating an essentially anhydrous solution of said polysubstituted piperazinone in said ketone without contacting said solution with water; and (iv) distilling unwanted low-boiling byproducts and said ketone from said solution to purify said polysubstituted piperazinone without degrading it.
(ii) producing a substantially completely monoketonesoluble water-sensitive polysubstituted piperazin-2-one represented by the structure wherein n represents 2 or 3;
R1 represents C2-C24 alkyl, C5-C12 cycloalkyl or aralkyl of 7 to 20 carbon atoms; and R2, R3, R4 and R5 each represent C1-C12 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl or C5-C14 cycloalkyl;
(iii) separating an essentially anhydrous solution of said polysubstituted piperazinone in said ketone without contacting said solution with water; and (iv) distilling unwanted low-boiling byproducts and said ketone from said solution to purify said polysubstituted piperazinone without degrading it.
11. The process of claim 10 wherein said alkali metal hydroxide is selected from the group consisting of sodium hydroxide and potassium hydroxide present as a finely divided solid.
12. The process of claim 11 wherein said alkali metal hydroxide is present in the range from 5 to about 6 moles per mole of said diamine.
13. The process of claim 12 wherein said haloform is selected from the group consisting of chloroform and bromoform.
14. The process of claim 13 wherein said reacting is at a temperature in the range from about -10°C to about 10°C.
15. A method of preparing a 1-(alkylamino)-alkyl-3,3,5,5-tetraalkylpiperazinone compound com-prising:
a cyclization process forming a cyclized product wherein a ketone is combined with sufficient haloform whereafter an amine is added, thereafter at least 5.0 moles of a base is added; work-up of said cyclized product to a crude product without intro-ducing water or water immiscible solvent whereafter said crude product is purified to said 1-(alkyl-amino)alkyl-3,3,5,5-tetraalkylpiperazinone compound without decomposition of said compound occurring during purification.
a cyclization process forming a cyclized product wherein a ketone is combined with sufficient haloform whereafter an amine is added, thereafter at least 5.0 moles of a base is added; work-up of said cyclized product to a crude product without intro-ducing water or water immiscible solvent whereafter said crude product is purified to said 1-(alkyl-amino)alkyl-3,3,5,5-tetraalkylpiperazinone compound without decomposition of said compound occurring during purification.
16. A method of claim 15 wherein said base is an alkali metal hydroxide.
17. A method of claim 16 wherein said alkali metal hydroxide is present in a molar ratio of base to amine in the range of about 5.0 to about 6.0 mole of amine.
18. A method of claim 17 wherein said 1-(alkylamino)alkyl-3,3,5,5-tetraalkylpiperazinone is 1-[3-(cyclohexylamino)propyl]-3,3,5,5-tetramethyl-2-piperazinone.
19. A method of claim 15 wherein said crude product is purified in the presence of alkali metal hydroxide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US84855586A | 1986-04-07 | 1986-04-07 | |
| US848,555 | 1986-04-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1289558C true CA1289558C (en) | 1991-09-24 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000521808A Expired - Fee Related CA1289558C (en) | 1986-04-07 | 1986-10-30 | Purification of 1-(alkylamino)-alkyl-2-keto-1,4- diazacycloalkanes |
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| Country | Link |
|---|---|
| CA (1) | CA1289558C (en) |
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1986
- 1986-10-30 CA CA000521808A patent/CA1289558C/en not_active Expired - Fee Related
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