CA2476608A1 - The purification of 2-methoxy-5-trifluoromethoxybenzaldehyde - Google Patents
The purification of 2-methoxy-5-trifluoromethoxybenzaldehyde Download PDFInfo
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- CA2476608A1 CA2476608A1 CA002476608A CA2476608A CA2476608A1 CA 2476608 A1 CA2476608 A1 CA 2476608A1 CA 002476608 A CA002476608 A CA 002476608A CA 2476608 A CA2476608 A CA 2476608A CA 2476608 A1 CA2476608 A1 CA 2476608A1
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
- C07C251/24—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/85—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to a chemical modification
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Abstract
A process for the purification of 2-methoxy-5-trifluor-methoxy benzaldehyde oil in which the oil is converted to amine by reaction of a nitroaniline wit h the oil; the imine is isolated as a solid; and the solid imine is converted back to the 2-methodxy-5-trifluormethoxy benzaldehyde oil. The nitroaniline is selected from the group consisting of 3-nitroaniline, 3-methyl-2-nitroanilin e, 4-methyl-2-nitroaniline, 2 methyl-3-nitroaniline and 4-methdyl-3-nitroanilin e.
Description
Background of the Invention This invention relates to a new and useful process for the purification of 2-methoxy-5 trifluoro-methoxy benzaldehyde by conversion to a series of nitroanilines. In particular, it is concerned with a novel two step process for purifying the oil, 2-methoxy-5-trifluoro-methoxy benzaldehyde, wherein the oil is first converted to a nitroaniline. The nitroaniline is isolated as a solid imine and then simply converted back to the oil, 2-methoxy-5-trifluoro-methoxybenzaldehyde. The result is a drastic reduction in the impurities seen in the commercial source which is the usual starting ingredient for the preparation of substance P
receptor antagonists.
In accordance with the prior art United States Patent No. 5,294,744 issued March 15, 1994, there has already been described in a two-step reaction a process for preparing 5-substituted-2-methoxybenzaldehyde compounds wherein the substituent group is either isopropyl or trifluoromethoxy. The process involves (1 ) reacting a corresponding 4-substituted phenol compound with dimethyl carbonate in the presence of a tertiary-amine base to form the corresponding 4-substituted anisole compound. The second step (2) subjects the latter intermediate product obtained in the first step to aromatic C-formylation on the ring with hexamethylenetetramine in the presence of trifluoroacetic acid, followed by hydrolysis, to ultimately yield the desired aldehyde compound. The two aromatic aldehyde compounds so obtained, viz., 2-methoxy -5-trifluoromethoxybenzaldehyde and 2-methoxy- 5-isopropylbenzaldehyde, are known to be useful as intermediates that specifically lead to (2S, 3S)-cis-3-(2-methoxy-5-trifluoromethoxylbenzyl)amino-2-phenylpiperidine and (2S, 3S)-cis-2-(diphenylmethyl)-N-[(2-methoxy-5-isopropylphenyl)-methyl]-1-azabicyclo[2.2.2]octane-3-amine, respectively. The latter final products, in turn, are both known to be useful in the field of medicinal chemistry as substance P receptor antagonists.
In accordance with the prior art, there has already been described certain compounds which are known to be of value as substance P receptor antagonists. Included among these are such nitrogen-containing heterocyclic ring compounds as (2S, 3S)-cis-3-(2-methoxy-5-trifluoromethoxylbenzyl)amino-2-phenylpiperidine, which is described and claimed by J. A.
Lowe, III, et al., in United States Patent No. 5,773,450, issued June 30, 1998, and (2S, 3S) cis -2-(diphenylmethyl)-N-[(2-methoxy- 5-isopropylphenyl)-methyl]-1-azabicyclo[2.2.2]octane 3-amine, which is described and claimed by F. Ito, et al., in United States Patent No.
5,807,867, issued September 15, 1998. Both compounds are useful as non-steroidal anti inflammatory (N.S.A.I.) agents, being of specific value in the treatment of arthritis, asthma and inflammatory bowel disease.
In the past, these particular compounds have been prepared by various synthetic means but essentially by a method which involves the reductive amination of the appropriate aldehyde compound, i.e., by reacting either the oily compound 2-methoxy-5-isopropylbenzaldehyde or 2-methoxy-5-trifluoromethoxybenzaldehyde, as the case may be, with the corresponding heterocyclic 3-amino compound in the presence of a source of hydrogen or else it can be made by first condensing the aforesaid 3-amino compound with the aldehyde and then reducing the resulting imine intermediate to ultimately give the key benzylamine side chain. The starting aromatic aldehyde component in this particular reaction scheme had always been prepared in two steps starting from the corresponding known and readily available 4-substituted phenol compound. This, in turn, initially involved (1 ) first methylating the phenol compound with methyl iodide in an acetone solvent medium in the presence of solid potassium carbonate, followed by (2) direct formylation of the resulting 4-substituted methylated phenol (i.e., 4-substituted anisole compound) with a-dichloromethyl methyl ether in a methylene chloride solvent system in the presence of titanium tetrachloride as catalyst. However, this particular two-step method for the production of the aldehyde suffers from the drawback of being conducted in a non-homogenous reaction system in the first step, with all its attendant disadvantages, and in employing the somewhat hazardous titanium tetrachloride reagent as catalyst in the second step. In the latter connection, it should be noted that certain stringent safety requirements are normally called for when handling the latter agent, particularly when unit operations are conducted on a large scale.
Additionally, the use of various hazardous waste disposal techniques are also required for the removal of the titanium tetrachloride byproducts that are usually formed in the aforesaid aromatic formylation reaction.
In the past, F. Merger, et al. in the U.S. Pat. No. 4,129,949 indicate that they have prepared various methyl phenyl ethers, including both 4-methylanisole and 4-methoxyanisole, from the corresponding phenol compounds, using dimethyl carbonate in the presence of a tertiaryamine base as catalyst without the presence of a solvent. Although the Merger, et al.
patent also includes p-isopropylphenol in a long list of many other possible phenolic starting materials for the aforementioned reaction, there is no indication that 4-isopropylanisole was ever actually prepared in this particular manner. On the other hand, W. E.
Smith in the Journal of Organic Chemistry, Vol. 37, No. 24, p. 3972 (1972) reports on its direct C-formylation of several aromatic compounds, including 2,6-dimethylanisole, via a method which involves the use of hexamethylenetetramine in trifluoroacetic acid in a modified Duff reaction, but there is no indication in the aforesaid paper by Smith that such a reaction could ever be successfully carried out using other non-acidic derivatives of anisole as substrate. In particular, there is no indication that the reaction of Smith could be applied to parasubstituted derivatives of anisole.
RUG 14 2003 fl~.'32~FR PFIZER PRTENT DEPT.212 857 3753 TO 5164320391011498 P.06 REPLACEMENT SHEET
particular, there is no indication that the reaction of Smith could be applied tv parasubstituted derivatives of anisvle.
Chemical Abstracts, 99(15), 1983, nv. 122032 teaches that benzaldehydes may be purified via their imines. The imines may be then hydrolyzed with hydrochloric acid to form the benzaldehydes.
8ummary of th~ion A process for the purification of 2-methoxy 5-tritluoro-methoxy benzaldehyde oil comprising converting the oil to an to amine ray reacting of a nitroanline with the oil; isolating the imine as a solid; and converting back the solid imine to the 2-methoxy-5-trifluoromethvxy 14 benzaldehyde oil. The vitro-aniline is selected from the group crrnsisting of 3-nitroaniline. 3-methyl-2-nitrvaniline, ~-methyl-2-nitroaniline, 2-methyl-3-nitroaniline and 4-methyl-3-nitroaniline. The iminess are selected from the group consisting of (Z-Methoxyr 5-trifluoramethoxybenzylidener(3-nitrvphenyl)arnine;
(2-Methoxy-5-trifiuoromefhoxybenzylidene)-(4~methyl-2-nitrophenyl)amine;
(2-Methoxy-5-trifluvrvmethoxybenzyfidener(3- methyl-Z-nitropherryl)amine;
(2-Methoxy-5-trifluvramethoxybenzyfidene)-(2-methyl-3-niavphenyl)amine:
(2-Methvxy 5-trifluoromethoxybenzylidene~(4- methyl-8-nitrophenyl)amine;
(2 Methoxy-5-trifluoromethoxybenzylidene)-(4-nitrvphenyl)emine;
(2-Methoxy 5-irifluvrQmethvxybenzylidene~.(3,5-dinitrophenyl)amine:
(2-Methoxy 5-trifluoromethoxybenzylidene)-(1,6-diniirophenyl)amine;
(~-Methoxy 5-triHuoromethvxybenzyiidene~(2,Mdirlitrophenyl)amine;
(2,-Mettroxy~-tfifluorvmethoxybenzylidene)-(5-methyl-a-nitrophenyl)amine; and (2-Methvxy-5-trifluoromethoxybenzyfidene)-(8-methyl-2-nitrophenyl)amine.
The temperature range in which to precipitate the imine is about 30 to about 40°C.
The solvent used to recrystallize the imine is selected from the group consisting of ethanol, methanol and ethanvUhexane. The solvent used to recrystallze the 2-methoxy 5-trifluoromethoxy benzaldehyde is a mixture of hexane and hydrochloric acid.
Detailed Description of The Invention In accordance wifh the process of this invention, a purified solid from the oil, 2 methoxy 5-trifluaromethoxybenzaldehyde, was attemptaed by a protection reaction with its aldehyde functional group. Two ways were first investigated: ~dtrer making the acetal or the imine. The acetal reactions were not successful. However, the'second attempt using a nitroaniline compound gave a solid imine which was easily deprotected and gave a good yield. More importantly, the processes had highly decreased the level of impurity of 2 methoxy 5-frifluoromethoxybenzaldehyde, now again in the oil farm.
~AME''NDFp-S~=1EE~T
EmPf .zeit:14/03/2003 17:4 ~'=- -- °'-r"r'Irur'rv.r r~ .:933 P.006 Scheme 1 OCF3 OCF3 ~ ~ OCF3 -NOz Hexane / HC1 1M
+ I -NOz ~N
OCHa ~ NHz OCHa OCH3 Scheme 2: substrate descriptions:
X1 X2 X3 ~ XS
1 - - - NOa -- - CH3 NO~ -8 NO~ _ _ - ~ ~ NOZ
9 - - NO~ - NOZ
- CH3 - - NO~
11 CH3 - - - NOz The idea behind the purification of the aldehyde was to make a solid from the oil and to filtered out the impurities. At first, the focus was on the possibility of making the acetal but that was without success. Next investigative reactions of imine formation were tried with some amines using nitroaniline analogues. This gave a solid very quickly and easily.
10 The imine formation implies equilibrium and most nitro compounds do not have good solubility in such solvent. But the high stability of the conjugated structure proposed by the imine drove the equilibrium to the formation of the imine. The difference of solubility between the original nitroaniline analogues and the imine helped to complete the reaction with a very good yield.
Having discerned that the main problem was to search for a good mixture of solvent that ensures a precipitation of the imine, it was possible to manage the solubility by controlling the temperature and the solvent composition. It was also possible to obtain a list of conditions to enhance imine formation. Adjusting the temperature gave better control of the reaction.
The best conditions were achieved with the 3-nitroaniline analogue. The solution was heated to 55°C where it became homogeneous and then, the solution was slowly cooled to 31-34°C where precipitation started. For 1 hour, the solution was stirred between 34-37°C to get a better crystallization. The solution was slowly cooled down to 0 °C, filtered and washed with cold hexane.
Because the solid imine is stabilized by its conjugated structure, it is possible to recrystallized it at high temperature without decomposing it. Analysis on the 3-nitroaniline imine complex showed that the recrystallization processes give only one isomer. By keeping the solid in solution, NMR shows its transformation to other isomers with time. This suggests that the imine is in equilibrium between its geometric isomers.
The deprotection reaction implies that there is a biphasic system in which the imine is stirred for a certain time. The acid aqueous layer stabilizes the amine and the benzaldehyde showed a great solubility in hexane. Depending on the nitroaniline analogue, it can take between 1 hour and 15 hours to form the imine.
It appears that the formation of the imine via the ntiroaniline works best because of its easy reaction conditions and its defined recrystallization conditions.
However, further investigation into the other amine analogues resulted in better conditions for most of the other amine analogues.
Accordingly to these results, the deprotection of benzaldehyde derivatives can be done by any nitroaniline analogues as long as solubility conditions are fixed.
receptor antagonists.
In accordance with the prior art United States Patent No. 5,294,744 issued March 15, 1994, there has already been described in a two-step reaction a process for preparing 5-substituted-2-methoxybenzaldehyde compounds wherein the substituent group is either isopropyl or trifluoromethoxy. The process involves (1 ) reacting a corresponding 4-substituted phenol compound with dimethyl carbonate in the presence of a tertiary-amine base to form the corresponding 4-substituted anisole compound. The second step (2) subjects the latter intermediate product obtained in the first step to aromatic C-formylation on the ring with hexamethylenetetramine in the presence of trifluoroacetic acid, followed by hydrolysis, to ultimately yield the desired aldehyde compound. The two aromatic aldehyde compounds so obtained, viz., 2-methoxy -5-trifluoromethoxybenzaldehyde and 2-methoxy- 5-isopropylbenzaldehyde, are known to be useful as intermediates that specifically lead to (2S, 3S)-cis-3-(2-methoxy-5-trifluoromethoxylbenzyl)amino-2-phenylpiperidine and (2S, 3S)-cis-2-(diphenylmethyl)-N-[(2-methoxy-5-isopropylphenyl)-methyl]-1-azabicyclo[2.2.2]octane-3-amine, respectively. The latter final products, in turn, are both known to be useful in the field of medicinal chemistry as substance P receptor antagonists.
In accordance with the prior art, there has already been described certain compounds which are known to be of value as substance P receptor antagonists. Included among these are such nitrogen-containing heterocyclic ring compounds as (2S, 3S)-cis-3-(2-methoxy-5-trifluoromethoxylbenzyl)amino-2-phenylpiperidine, which is described and claimed by J. A.
Lowe, III, et al., in United States Patent No. 5,773,450, issued June 30, 1998, and (2S, 3S) cis -2-(diphenylmethyl)-N-[(2-methoxy- 5-isopropylphenyl)-methyl]-1-azabicyclo[2.2.2]octane 3-amine, which is described and claimed by F. Ito, et al., in United States Patent No.
5,807,867, issued September 15, 1998. Both compounds are useful as non-steroidal anti inflammatory (N.S.A.I.) agents, being of specific value in the treatment of arthritis, asthma and inflammatory bowel disease.
In the past, these particular compounds have been prepared by various synthetic means but essentially by a method which involves the reductive amination of the appropriate aldehyde compound, i.e., by reacting either the oily compound 2-methoxy-5-isopropylbenzaldehyde or 2-methoxy-5-trifluoromethoxybenzaldehyde, as the case may be, with the corresponding heterocyclic 3-amino compound in the presence of a source of hydrogen or else it can be made by first condensing the aforesaid 3-amino compound with the aldehyde and then reducing the resulting imine intermediate to ultimately give the key benzylamine side chain. The starting aromatic aldehyde component in this particular reaction scheme had always been prepared in two steps starting from the corresponding known and readily available 4-substituted phenol compound. This, in turn, initially involved (1 ) first methylating the phenol compound with methyl iodide in an acetone solvent medium in the presence of solid potassium carbonate, followed by (2) direct formylation of the resulting 4-substituted methylated phenol (i.e., 4-substituted anisole compound) with a-dichloromethyl methyl ether in a methylene chloride solvent system in the presence of titanium tetrachloride as catalyst. However, this particular two-step method for the production of the aldehyde suffers from the drawback of being conducted in a non-homogenous reaction system in the first step, with all its attendant disadvantages, and in employing the somewhat hazardous titanium tetrachloride reagent as catalyst in the second step. In the latter connection, it should be noted that certain stringent safety requirements are normally called for when handling the latter agent, particularly when unit operations are conducted on a large scale.
Additionally, the use of various hazardous waste disposal techniques are also required for the removal of the titanium tetrachloride byproducts that are usually formed in the aforesaid aromatic formylation reaction.
In the past, F. Merger, et al. in the U.S. Pat. No. 4,129,949 indicate that they have prepared various methyl phenyl ethers, including both 4-methylanisole and 4-methoxyanisole, from the corresponding phenol compounds, using dimethyl carbonate in the presence of a tertiaryamine base as catalyst without the presence of a solvent. Although the Merger, et al.
patent also includes p-isopropylphenol in a long list of many other possible phenolic starting materials for the aforementioned reaction, there is no indication that 4-isopropylanisole was ever actually prepared in this particular manner. On the other hand, W. E.
Smith in the Journal of Organic Chemistry, Vol. 37, No. 24, p. 3972 (1972) reports on its direct C-formylation of several aromatic compounds, including 2,6-dimethylanisole, via a method which involves the use of hexamethylenetetramine in trifluoroacetic acid in a modified Duff reaction, but there is no indication in the aforesaid paper by Smith that such a reaction could ever be successfully carried out using other non-acidic derivatives of anisole as substrate. In particular, there is no indication that the reaction of Smith could be applied to parasubstituted derivatives of anisole.
RUG 14 2003 fl~.'32~FR PFIZER PRTENT DEPT.212 857 3753 TO 5164320391011498 P.06 REPLACEMENT SHEET
particular, there is no indication that the reaction of Smith could be applied tv parasubstituted derivatives of anisvle.
Chemical Abstracts, 99(15), 1983, nv. 122032 teaches that benzaldehydes may be purified via their imines. The imines may be then hydrolyzed with hydrochloric acid to form the benzaldehydes.
8ummary of th~ion A process for the purification of 2-methoxy 5-tritluoro-methoxy benzaldehyde oil comprising converting the oil to an to amine ray reacting of a nitroanline with the oil; isolating the imine as a solid; and converting back the solid imine to the 2-methoxy-5-trifluoromethvxy 14 benzaldehyde oil. The vitro-aniline is selected from the group crrnsisting of 3-nitroaniline. 3-methyl-2-nitrvaniline, ~-methyl-2-nitroaniline, 2-methyl-3-nitroaniline and 4-methyl-3-nitroaniline. The iminess are selected from the group consisting of (Z-Methoxyr 5-trifluoramethoxybenzylidener(3-nitrvphenyl)arnine;
(2-Methoxy-5-trifiuoromefhoxybenzylidene)-(4~methyl-2-nitrophenyl)amine;
(2-Methoxy-5-trifluvrvmethoxybenzyfidener(3- methyl-Z-nitropherryl)amine;
(2-Methoxy-5-trifluvramethoxybenzyfidene)-(2-methyl-3-niavphenyl)amine:
(2-Methvxy 5-trifluoromethoxybenzylidene~(4- methyl-8-nitrophenyl)amine;
(2 Methoxy-5-trifluoromethoxybenzylidene)-(4-nitrvphenyl)emine;
(2-Methoxy 5-irifluvrQmethvxybenzylidene~.(3,5-dinitrophenyl)amine:
(2-Methoxy 5-trifluoromethoxybenzylidene)-(1,6-diniirophenyl)amine;
(~-Methoxy 5-triHuoromethvxybenzyiidene~(2,Mdirlitrophenyl)amine;
(2,-Mettroxy~-tfifluorvmethoxybenzylidene)-(5-methyl-a-nitrophenyl)amine; and (2-Methvxy-5-trifluoromethoxybenzyfidene)-(8-methyl-2-nitrophenyl)amine.
The temperature range in which to precipitate the imine is about 30 to about 40°C.
The solvent used to recrystallize the imine is selected from the group consisting of ethanol, methanol and ethanvUhexane. The solvent used to recrystallze the 2-methoxy 5-trifluoromethoxy benzaldehyde is a mixture of hexane and hydrochloric acid.
Detailed Description of The Invention In accordance wifh the process of this invention, a purified solid from the oil, 2 methoxy 5-trifluaromethoxybenzaldehyde, was attemptaed by a protection reaction with its aldehyde functional group. Two ways were first investigated: ~dtrer making the acetal or the imine. The acetal reactions were not successful. However, the'second attempt using a nitroaniline compound gave a solid imine which was easily deprotected and gave a good yield. More importantly, the processes had highly decreased the level of impurity of 2 methoxy 5-frifluoromethoxybenzaldehyde, now again in the oil farm.
~AME''NDFp-S~=1EE~T
EmPf .zeit:14/03/2003 17:4 ~'=- -- °'-r"r'Irur'rv.r r~ .:933 P.006 Scheme 1 OCF3 OCF3 ~ ~ OCF3 -NOz Hexane / HC1 1M
+ I -NOz ~N
OCHa ~ NHz OCHa OCH3 Scheme 2: substrate descriptions:
X1 X2 X3 ~ XS
1 - - - NOa -- - CH3 NO~ -8 NO~ _ _ - ~ ~ NOZ
9 - - NO~ - NOZ
- CH3 - - NO~
11 CH3 - - - NOz The idea behind the purification of the aldehyde was to make a solid from the oil and to filtered out the impurities. At first, the focus was on the possibility of making the acetal but that was without success. Next investigative reactions of imine formation were tried with some amines using nitroaniline analogues. This gave a solid very quickly and easily.
10 The imine formation implies equilibrium and most nitro compounds do not have good solubility in such solvent. But the high stability of the conjugated structure proposed by the imine drove the equilibrium to the formation of the imine. The difference of solubility between the original nitroaniline analogues and the imine helped to complete the reaction with a very good yield.
Having discerned that the main problem was to search for a good mixture of solvent that ensures a precipitation of the imine, it was possible to manage the solubility by controlling the temperature and the solvent composition. It was also possible to obtain a list of conditions to enhance imine formation. Adjusting the temperature gave better control of the reaction.
The best conditions were achieved with the 3-nitroaniline analogue. The solution was heated to 55°C where it became homogeneous and then, the solution was slowly cooled to 31-34°C where precipitation started. For 1 hour, the solution was stirred between 34-37°C to get a better crystallization. The solution was slowly cooled down to 0 °C, filtered and washed with cold hexane.
Because the solid imine is stabilized by its conjugated structure, it is possible to recrystallized it at high temperature without decomposing it. Analysis on the 3-nitroaniline imine complex showed that the recrystallization processes give only one isomer. By keeping the solid in solution, NMR shows its transformation to other isomers with time. This suggests that the imine is in equilibrium between its geometric isomers.
The deprotection reaction implies that there is a biphasic system in which the imine is stirred for a certain time. The acid aqueous layer stabilizes the amine and the benzaldehyde showed a great solubility in hexane. Depending on the nitroaniline analogue, it can take between 1 hour and 15 hours to form the imine.
It appears that the formation of the imine via the ntiroaniline works best because of its easy reaction conditions and its defined recrystallization conditions.
However, further investigation into the other amine analogues resulted in better conditions for most of the other amine analogues.
Accordingly to these results, the deprotection of benzaldehyde derivatives can be done by any nitroaniline analogues as long as solubility conditions are fixed.
Table 1: Purity analysis by High Performance Liquid Chromatography of 2-Methoxy-5-trifluoromethoxybenzylidene from corresponding imine Corresp. ImineLot# H38680-127RelativeRelativeRelativeRelative Substrate Area% RetentionRetentionRetentionRetention [FROM SCHEME Time Time Time Time 2 0.74 ABOVE 0.36 0.59 0.69 2.4 - 0.1 0.2 0.5 1.5 - - - -1 0.4 0.06 - - 0.1 1 0.6 - - 0.07 0.08 1 - - - - 0.3 1* - - - - 0.2 2 - - - 0.1 -3 _ _ _ _ _ 4 0.5 - - 0.08 -0.2 - - 0.08 0.5 All were made trom the normal lot.
All compounds show a important decrease of impurity. Moreover, compounds (2-5 Methoxy-5-trifluoromethoxybenzylidene)-(3-nitrophenyl)amine and 2-Methoxy-5-trifluoromethoxybenzylidene)-(4-mehtyl-2-nitrophenyl)amine in which corresponding imine were made from 3-methyl-3-nitroaniline and 4-methyl-2-nitroaniline respectively and 2-Methoxy-5-trifluoromethoxybenzylidene)-(3-nitrophenyl)amine which was made from 3-nitroaniline present a complete elimination of the regio-isomer.
Table 2. Source of starting material Product ~ Company Lot Number 3-nitroaniline Aldrich 05720TG
3-methyl-2-nitroanilineAldrich 04406LV
4-methyl-2-nitroanilineEastman Organic ChemistryNot specified 2-methyl-3-nitroanilineAldrich 0211AJ
4-methyl-3-nitroanilineAldrich 080877 Table 3:
Elemental Analysis # IUPAC name MassTheoretical Obtained Offset Values Values C H N C H N C H N
1 (2-Methoxy-5- 340 52.953.268.2352.953.068.20-0.40-6.44+1.46 trifluoromethoxybenzyli dene)-(3-nitrophenyl)amine 2 (2-MethoXy-5- 354 54.243.707.9154.233.348.34-2.27+15.41+5.44 trifluoromethoxybenzyli dene)-(4-mehtyl-2-nitrophenyl)amine 3 (2-MethoXy-5- 354 54.243.707.9153.363.357.82-1.62-9.46-1.14 trifluoromethoxybenzyli .
dene)-(3-mehtyl-2-nitrophenyl)amine 4 (2-MethOXy-5- 354 54.243.707.9153.903.397.85-0.65-7.67+1.58 trifluoromethoxybenzyli dene)-(2-methyl-3-nitrophenyl)amine (2-MethOXy-5- 354 54.243.707.9154.223.367.88-0.04-9.19-0.38 trifluoromethoxybenzyli dene)-(4-mehtyl-3-nitrophenyl)amine Example I
Formation of (2-Mefhoxy 5-trifluoromefhoxybenzylidene)-(3-nitrophenyl)amine:
5 In a flask containing 3-nitroaniline (6.27 g, 45.4 mmol) was added hexane (140 ml) and ethanol (10 ml) and stirred vigorously to make the heterogeneous solution.
It was heated to 55°C and then 2-methoxy-5-trifluoromethoxybenzaldehyde (10g, 45.4 mmol) was added.
The solution then became orange clear. It was then stirred for 15 minutes and slowly cooled down to room temperature. The solid appeared at 31°C. The solid was filtered and washed with cold hexane to give a yellow powder (13.63g, 88.2%).
The solid (3g) was recrystallized in hexane (120 ml) and EtOH (2 ml). At 55°C the solution went clear and was cooled down to 32°C at which time big particles appeared. The temperature was maintained at 32-37°C for 1 hour at which a wadding like solid appeared _8-and replaced the big particles. The solution was cooled down to 0°C.
The solid was filtered and washed with cold hexane to a white solid (2.66g, 88.6%) named above.
Example II
Formation of 2-methoxy 5-trifluoromethoxybenzaldehyde:
In a flask containing 2-Methoxy-5-trifluoromethoxybenzylidene)-(3-nitrophenyl)amine (0.4g, 1.18 mmol), added hexane (20 ml) and HCI (20 ml). It was stirred vigorously for less than 2 hours. The layers were separated and the organic one was washed with HCI 5 M. 2-Methoxy-5-trifluoromethoxybenzylidene gave a really light yellow oil (0.210g, 81%).
Overall yield: 63.3%.
Table 3: Modification of the general procedure according to each substrate:
SubstrateProtection conditionsRecrystallizationDeprotection conditions Solvent: EtOH (5 Overnight stirring vol) 2 Reaction temp: RT None (increase HCI conc.
to 0 C ?) 33.5 % 75.3 Solvent: EtOH (1 vol) Overnight stirring Hexane (10 vol) 3 None (increase HCI conc.
?) Reaction temp: 60 C
26.9 Solvent: EtOH (5 vol) Hexane (10 vol) 1 hour stirring 4 None Reaction temp: 60 86.0 C
66.2 Solvent: EtOH (2.5 vol) Hexane (10 vol) - 3 hours stirring I 5 None Reaction temp: 60 64.5 C
74.3 _g_ Table 4: All reaction conditions tried and corresponding yield.
Substrate Condition (for 1 g of CP-130,209)Result ~
Solvent : MeOH (10 vol) 67 Room temperature Yellow solid Solvent : EtOH (10 vol) 50.8 Room temperature Light yellow solid Solvent : MeOH (10 vol) 9.22 Temperature : 55 C Light yellow solid Solvent : 25 % EtOH / Hexane 81 (15 vol) Temperature : 60 C Light yellow solid Solvent : 6.6 % EtOH / Hexane88.2 (15 vol) Temperature : 55 C Light Yellow solid Solvent : MeOH (10 vol) 53 mg. Seemed to be the Temperature : 60 C good product.
Solvent : EtOH (5 vol) 33.5 Temperature : 60 C Fluffy yellow solid Solvent : 60 % EtOH / hexane (5 vol) Stayed soluble Temperature : 55 C
Solvent : MeOH (8 vol) Stayed soluble Room temperature Solvent : MeOH (3 vol) 0.256 g Room temperature yellow solid Solvent : EtOH (1 vol) 75.7 Room temperature yellow, impure Solvent : EtOH (3 vol) 51.7%
Room temperature yellow impure Solvent : 10 % EtOH /hexane (5 vol) No reaction Temperature : 60 C
Solvent : 40 % EtOH l Hexane (10 vol) Stayed soluble Temperature : 56 C
Solvent : EtOH (2 vol) Stayed soluble Room temperature Solvent : EtOH (2 vol) 78.8 Temperature : 0 C Light yellow solid Solvent : 10 % EtOH / hexane 74.3 (10 vol) Temperature : 60 C Very light yellow Substrate Condition (for 1 g of CP-130,209)Result Solvent : 40 % EtOH / hexane (10 vol) Stayed clear Temperature : 60 C
Solvent : EtOH (3 vol) 63.2 Room temperature Beige powder Solvent : EtOH (4 vol) 66.2 Room temperature White-beige powder Solvent : 6.6 % EtOH / Hexane (15 vol) Temperature : 60 C
Insoluble Solvent : MeOH (10 vol) Room temperature Stayed soluble Solvent : 20 % EtOH / Hexane (15 vol) Insoluble Temperature : 58 C
Solvent : 33 % EtOH / Hexane (15 vol) Stayed soluble Temperature : 60 C
Solvent : MeOH (2 vol) Stayed soluble Temperature : 60 C
Solvent : EtOH (3 vol) No reaction Temperature : 60 C
Solvent : 6.6 % EtOH / Hexane (15 vol) Insoluble Temperature : 57 C
Solvent : EtOH (15 vol) Stayed soluble Temperature: 50 C
Solvent : MeOH (5 vol) Stayed soluble Temperature: 50 C
Solvent : MeOH (2 vol) Stayed soluble Temperature : 60 C
Solvent : 6.6 % EtOH / hexane (15 vol) Insoluble Temperature : 54 C
Solvent : 6.6 % EtOH / hexane (15 vol) Insoluble Temperature : 58 C
Solvent : 20 % EtOH / EtOAc (10 vol) Insoluble Temperature : 58 C
Solvent : MeOH (10 vol) Insoluble Temperature : 60 C
Solvent : EtOH (3 vol) Insoluble Temperature : 60 C
Solvent : MeOH (10 vol) ~ Temperature : 60 C Stayed soluble Substrate Condition (for 1 g of CP-130,209)Result Solvent : MeOH (4 vol) 0.83 g.
Room temperature Orange yellow solid.
Solvent : 40 % EtOH / hexane (10 vol) Stayed soluble Temperature : 62 C
Solvent : MeOH (10 vol) Stayed soluble Temperature : 60 C
Solvent : MeOH (3 vol) Stayed soluble Temperature : 60 C
All compounds show a important decrease of impurity. Moreover, compounds (2-5 Methoxy-5-trifluoromethoxybenzylidene)-(3-nitrophenyl)amine and 2-Methoxy-5-trifluoromethoxybenzylidene)-(4-mehtyl-2-nitrophenyl)amine in which corresponding imine were made from 3-methyl-3-nitroaniline and 4-methyl-2-nitroaniline respectively and 2-Methoxy-5-trifluoromethoxybenzylidene)-(3-nitrophenyl)amine which was made from 3-nitroaniline present a complete elimination of the regio-isomer.
Table 2. Source of starting material Product ~ Company Lot Number 3-nitroaniline Aldrich 05720TG
3-methyl-2-nitroanilineAldrich 04406LV
4-methyl-2-nitroanilineEastman Organic ChemistryNot specified 2-methyl-3-nitroanilineAldrich 0211AJ
4-methyl-3-nitroanilineAldrich 080877 Table 3:
Elemental Analysis # IUPAC name MassTheoretical Obtained Offset Values Values C H N C H N C H N
1 (2-Methoxy-5- 340 52.953.268.2352.953.068.20-0.40-6.44+1.46 trifluoromethoxybenzyli dene)-(3-nitrophenyl)amine 2 (2-MethoXy-5- 354 54.243.707.9154.233.348.34-2.27+15.41+5.44 trifluoromethoxybenzyli dene)-(4-mehtyl-2-nitrophenyl)amine 3 (2-MethoXy-5- 354 54.243.707.9153.363.357.82-1.62-9.46-1.14 trifluoromethoxybenzyli .
dene)-(3-mehtyl-2-nitrophenyl)amine 4 (2-MethOXy-5- 354 54.243.707.9153.903.397.85-0.65-7.67+1.58 trifluoromethoxybenzyli dene)-(2-methyl-3-nitrophenyl)amine (2-MethOXy-5- 354 54.243.707.9154.223.367.88-0.04-9.19-0.38 trifluoromethoxybenzyli dene)-(4-mehtyl-3-nitrophenyl)amine Example I
Formation of (2-Mefhoxy 5-trifluoromefhoxybenzylidene)-(3-nitrophenyl)amine:
5 In a flask containing 3-nitroaniline (6.27 g, 45.4 mmol) was added hexane (140 ml) and ethanol (10 ml) and stirred vigorously to make the heterogeneous solution.
It was heated to 55°C and then 2-methoxy-5-trifluoromethoxybenzaldehyde (10g, 45.4 mmol) was added.
The solution then became orange clear. It was then stirred for 15 minutes and slowly cooled down to room temperature. The solid appeared at 31°C. The solid was filtered and washed with cold hexane to give a yellow powder (13.63g, 88.2%).
The solid (3g) was recrystallized in hexane (120 ml) and EtOH (2 ml). At 55°C the solution went clear and was cooled down to 32°C at which time big particles appeared. The temperature was maintained at 32-37°C for 1 hour at which a wadding like solid appeared _8-and replaced the big particles. The solution was cooled down to 0°C.
The solid was filtered and washed with cold hexane to a white solid (2.66g, 88.6%) named above.
Example II
Formation of 2-methoxy 5-trifluoromethoxybenzaldehyde:
In a flask containing 2-Methoxy-5-trifluoromethoxybenzylidene)-(3-nitrophenyl)amine (0.4g, 1.18 mmol), added hexane (20 ml) and HCI (20 ml). It was stirred vigorously for less than 2 hours. The layers were separated and the organic one was washed with HCI 5 M. 2-Methoxy-5-trifluoromethoxybenzylidene gave a really light yellow oil (0.210g, 81%).
Overall yield: 63.3%.
Table 3: Modification of the general procedure according to each substrate:
SubstrateProtection conditionsRecrystallizationDeprotection conditions Solvent: EtOH (5 Overnight stirring vol) 2 Reaction temp: RT None (increase HCI conc.
to 0 C ?) 33.5 % 75.3 Solvent: EtOH (1 vol) Overnight stirring Hexane (10 vol) 3 None (increase HCI conc.
?) Reaction temp: 60 C
26.9 Solvent: EtOH (5 vol) Hexane (10 vol) 1 hour stirring 4 None Reaction temp: 60 86.0 C
66.2 Solvent: EtOH (2.5 vol) Hexane (10 vol) - 3 hours stirring I 5 None Reaction temp: 60 64.5 C
74.3 _g_ Table 4: All reaction conditions tried and corresponding yield.
Substrate Condition (for 1 g of CP-130,209)Result ~
Solvent : MeOH (10 vol) 67 Room temperature Yellow solid Solvent : EtOH (10 vol) 50.8 Room temperature Light yellow solid Solvent : MeOH (10 vol) 9.22 Temperature : 55 C Light yellow solid Solvent : 25 % EtOH / Hexane 81 (15 vol) Temperature : 60 C Light yellow solid Solvent : 6.6 % EtOH / Hexane88.2 (15 vol) Temperature : 55 C Light Yellow solid Solvent : MeOH (10 vol) 53 mg. Seemed to be the Temperature : 60 C good product.
Solvent : EtOH (5 vol) 33.5 Temperature : 60 C Fluffy yellow solid Solvent : 60 % EtOH / hexane (5 vol) Stayed soluble Temperature : 55 C
Solvent : MeOH (8 vol) Stayed soluble Room temperature Solvent : MeOH (3 vol) 0.256 g Room temperature yellow solid Solvent : EtOH (1 vol) 75.7 Room temperature yellow, impure Solvent : EtOH (3 vol) 51.7%
Room temperature yellow impure Solvent : 10 % EtOH /hexane (5 vol) No reaction Temperature : 60 C
Solvent : 40 % EtOH l Hexane (10 vol) Stayed soluble Temperature : 56 C
Solvent : EtOH (2 vol) Stayed soluble Room temperature Solvent : EtOH (2 vol) 78.8 Temperature : 0 C Light yellow solid Solvent : 10 % EtOH / hexane 74.3 (10 vol) Temperature : 60 C Very light yellow Substrate Condition (for 1 g of CP-130,209)Result Solvent : 40 % EtOH / hexane (10 vol) Stayed clear Temperature : 60 C
Solvent : EtOH (3 vol) 63.2 Room temperature Beige powder Solvent : EtOH (4 vol) 66.2 Room temperature White-beige powder Solvent : 6.6 % EtOH / Hexane (15 vol) Temperature : 60 C
Insoluble Solvent : MeOH (10 vol) Room temperature Stayed soluble Solvent : 20 % EtOH / Hexane (15 vol) Insoluble Temperature : 58 C
Solvent : 33 % EtOH / Hexane (15 vol) Stayed soluble Temperature : 60 C
Solvent : MeOH (2 vol) Stayed soluble Temperature : 60 C
Solvent : EtOH (3 vol) No reaction Temperature : 60 C
Solvent : 6.6 % EtOH / Hexane (15 vol) Insoluble Temperature : 57 C
Solvent : EtOH (15 vol) Stayed soluble Temperature: 50 C
Solvent : MeOH (5 vol) Stayed soluble Temperature: 50 C
Solvent : MeOH (2 vol) Stayed soluble Temperature : 60 C
Solvent : 6.6 % EtOH / hexane (15 vol) Insoluble Temperature : 54 C
Solvent : 6.6 % EtOH / hexane (15 vol) Insoluble Temperature : 58 C
Solvent : 20 % EtOH / EtOAc (10 vol) Insoluble Temperature : 58 C
Solvent : MeOH (10 vol) Insoluble Temperature : 60 C
Solvent : EtOH (3 vol) Insoluble Temperature : 60 C
Solvent : MeOH (10 vol) ~ Temperature : 60 C Stayed soluble Substrate Condition (for 1 g of CP-130,209)Result Solvent : MeOH (4 vol) 0.83 g.
Room temperature Orange yellow solid.
Solvent : 40 % EtOH / hexane (10 vol) Stayed soluble Temperature : 62 C
Solvent : MeOH (10 vol) Stayed soluble Temperature : 60 C
Solvent : MeOH (3 vol) Stayed soluble Temperature : 60 C
Claims (6)
1. A process for the purification of 2-methoxy 5-trifluoro-methoxy benzaldehyde oil comprising (a) converting said oil to an imine by reaction of a nitroaniline with said oil, (b) isolating said imine as a solid and;
(c) converting back said solid imine is to said 2-methoxy 5-trifluoro-methoxy benzaldehyde oil.
(c) converting back said solid imine is to said 2-methoxy 5-trifluoro-methoxy benzaldehyde oil.
2. The process according to claim 1 wherein the nitroaniline is selected from the group consisting of 3 nitroaniline, 3-methyl-2 nitroaniline, 4-methyl-2-nitroaniline. 2 methyl-3-nitroaniline and 4-methyl-3-nitroaniline.
3. The process according to claim 1 wherein the amines are selected from the group consisting of (2-Methoxy-5-trfluoromethoxybenzylidene)-(3-nitrophenyl)amine;
(2-Methoxy 5-trifluoromethoxybenzylidene)-(4-methyl-2-nitrophenyl)amine;
(2-Methoxy-5-trifluoromethoxybenzylidene}-(3-methyl-2-nitrophenyl)amine;
(2-Methoxy-5-trifluoromethoxybenzylidene)-(2-methyl-3-nitrophenyl)amine;
(2-Methoxy-5-trifluoromethoxybenzylidene)-(4- methyl-3-nitrophenyl)amine;
(2-Methoxy 5-trifluoromethoxybenzylidene)-(4-nitrophenyl)amine;
(2-Methoxy-5-trifluoromethoxybenzylidene)-(3,5-dinitrophenyl)amine;
(2-Methoxy-5-trifluoromethoxybenzylidene)-(1,6-dinitrophenyl)amine;
(2-Methoxy 5-trifluoromethoxybenzylidene)-(2,4-dinitrophenyl)amine;
(2-Methoxy-5-trifluoromethoxybenzylidene)-(5-methyl-2-nitrophenyl)amine; and (2-Methoxy-5-trifluoromethoxybenzylidene)-(6-methyl-2-nitrophenyl)amine.
(2-Methoxy 5-trifluoromethoxybenzylidene)-(4-methyl-2-nitrophenyl)amine;
(2-Methoxy-5-trifluoromethoxybenzylidene}-(3-methyl-2-nitrophenyl)amine;
(2-Methoxy-5-trifluoromethoxybenzylidene)-(2-methyl-3-nitrophenyl)amine;
(2-Methoxy-5-trifluoromethoxybenzylidene)-(4- methyl-3-nitrophenyl)amine;
(2-Methoxy 5-trifluoromethoxybenzylidene)-(4-nitrophenyl)amine;
(2-Methoxy-5-trifluoromethoxybenzylidene)-(3,5-dinitrophenyl)amine;
(2-Methoxy-5-trifluoromethoxybenzylidene)-(1,6-dinitrophenyl)amine;
(2-Methoxy 5-trifluoromethoxybenzylidene)-(2,4-dinitrophenyl)amine;
(2-Methoxy-5-trifluoromethoxybenzylidene)-(5-methyl-2-nitrophenyl)amine; and (2-Methoxy-5-trifluoromethoxybenzylidene)-(6-methyl-2-nitrophenyl)amine.
4. The process according to claim 1, wherein the temperature range to precipitate the amine is about 30 to about 40°C.
5. The process according to claim 1 wherein the solvent used to recrystallize the amine is selected from the group consisting of ethanol, methanol and ethanol/hexane.
6. The process according to claim 1 wherein the solvent used to recrystallize the 2-methoxy 5-trifluoromethoxy benzaldehyde is a mixture of hexane and hydrochloric acid.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US36193102P | 2002-03-06 | 2002-03-06 | |
| US60/361,931 | 2002-03-06 | ||
| PCT/IB2003/000783 WO2003074462A1 (en) | 2002-03-06 | 2003-02-24 | The purification of 2-methoxy-5-trifluoromethoxybenzaldehyde |
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| Publication Number | Publication Date |
|---|---|
| CA2476608A1 true CA2476608A1 (en) | 2003-09-12 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002476608A Abandoned CA2476608A1 (en) | 2002-03-06 | 2003-02-24 | The purification of 2-methoxy-5-trifluoromethoxybenzaldehyde |
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| Country | Link |
|---|---|
| US (1) | US6686507B2 (en) |
| EP (1) | EP1483227A1 (en) |
| JP (1) | JP2005519106A (en) |
| AR (1) | AR038722A1 (en) |
| AU (1) | AU2003248597A1 (en) |
| BR (1) | BR0308187A (en) |
| CA (1) | CA2476608A1 (en) |
| MX (1) | MXPA04008556A (en) |
| TW (1) | TW200306968A (en) |
| WO (1) | WO2003074462A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US7122700B2 (en) * | 2004-07-30 | 2006-10-17 | Xerox Corporation | Arylamine processes |
| JP5869577B2 (en) * | 2010-09-16 | 2016-02-24 | ビーエーエスエフ ソシエタス・ヨーロピアＢａｓｆ Ｓｅ | Process for producing 2-methyl-3- (4-tert-butylphenyl) propanal with high para isomer purity |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH256510A (en) * | 1946-10-01 | 1948-08-31 | Sific Aktiengesellschaft | A process for the extraction and purification of α-diketones from complex mixtures containing other ketones. |
| US4192949A (en) | 1977-06-28 | 1980-03-11 | Basf Aktiengesellschaft | Preparation of aralkyl phenyl ethers and alkyl phenyl ethers |
| UA27776C2 (en) | 1991-05-31 | 2000-10-16 | Пфайзер Інк. | Quinuclidine derivatives, pharmaceutically acceptable saults thereof which are substance p receptor antagonists in mammals, pharmaceutical composition possessing antagonist activity on substance p in mammals |
| KR0154882B1 (en) | 1991-06-20 | 1998-11-16 | 알렌 제이. 스피겔 | Fluoroalkoxybenzylamino derivatives of nitrogen containing heterocycles |
| US5294744A (en) | 1993-04-20 | 1994-03-15 | Pfizer Inc. | Formylation process for aromatic aldehydes |
-
2002
- 2002-12-09 US US10/314,598 patent/US6686507B2/en not_active Expired - Fee Related
-
2003
- 2003-02-24 AU AU2003248597A patent/AU2003248597A1/en not_active Abandoned
- 2003-02-24 JP JP2003572934A patent/JP2005519106A/en active Pending
- 2003-02-24 WO PCT/IB2003/000783 patent/WO2003074462A1/en not_active Application Discontinuation
- 2003-02-24 CA CA002476608A patent/CA2476608A1/en not_active Abandoned
- 2003-02-24 MX MXPA04008556A patent/MXPA04008556A/en not_active Application Discontinuation
- 2003-02-24 BR BR0308187-7A patent/BR0308187A/en not_active Application Discontinuation
- 2003-02-24 EP EP03743467A patent/EP1483227A1/en not_active Withdrawn
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| MXPA04008556A (en) | 2004-12-06 |
| BR0308187A (en) | 2004-12-21 |
| US6686507B2 (en) | 2004-02-03 |
| WO2003074462A1 (en) | 2003-09-12 |
| TW200306968A (en) | 2003-12-01 |
| US20030176741A1 (en) | 2003-09-18 |
| EP1483227A1 (en) | 2004-12-08 |
| JP2005519106A (en) | 2005-06-30 |
| AR038722A1 (en) | 2005-01-26 |
| AU2003248597A1 (en) | 2003-09-16 |
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