US006686,507B2 (12) United States Patent (10) Patent No.: US 6,686,507 B2 Watson et al. (45) Date of Patent: Feb. 3, 2004

(54) PURIFICATION OF 2-METHOXY-5- 5,294,744 A 3/1994 Godek et al...... 568/442 TRFLUOROMETHOXYBENZALDEHYDE 5,773,450 A 6/1998 Lowe et al...... 514/329 5,807,867 A 9/1998 Ito et al...... 514/305 (75) Inventors: Timothy J. N. Watson, Waterford, CT (US); Patrice Arpin, Sorel-Tracy (CA); OTHER PUBLICATIONS Michael G. Vetelino, North Stonington, CT (US) W. E. Smith, Journal of Organic Chemistry, vol. 37, No. 24, (73) Assignee: Pfizer Inc, New York, NY (US) p. 3972 (1972). (*) Notice: Subject to any disclaimer,- the term of this Chemical Abstracts, 99(15), 1983, No. 122032. patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. Primary Examiner James O. Wilson Assistant Examiner Sikarl A. Witherspoon (21) Appl. No.: 10/314,598 (74) Attorney, Agent, or Firm-Peter C. Richardson; Paul (22) Filed: Dec. 9, 2002 H. Ginsburg; Jolene W. Appleman (65) Prior Publication Data (57) ABSTRACT US 2003/0176741 A1 Sep. 18, 2003 A process for the purification of 2-methoxy-5-trifluoro Related U.S. Application Dat methoxybenzaldehyde oil in which the oil is converted to (60) Provisionalelated application U.S. ApplicationNo. 60/361.931, Uata filed on Mar. 6, by reaction of a nitroaniline- with the oil;1. the imine- - is- 2002. isolated as a Solid; and the Solid imine is converted back to (51) Int. Cl...... C07C 45/90 the 2-methoxy-5-trifluoromethoxy benzaldehyde oil. The (52) U.S. Cl...... 568,438 nitroaniline is selected from the group consisting of (58) Field of Search ...... 568/438 3-nitroaniline, 3-methyl-2-nitroaniline, 4-methyl-2- (56) Ref Cited nitroaniline, 2 methyl-3-nitroaniline and 4-methyl-3- CS nitroaniline. U.S. PATENT DOCUMENTS 4,192,949 A 3/1980 Merger et al...... 560/67 6 Claims, No Drawings US 6,686,507 B2 1 2 PURIFICATION OF 2-METHOXY-5- Side chain. The Starting aromatic component in this TRIFLUOROMETHOXYBENZALDEHYDE 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, BACKGROUND OF THE INVENTION initially involved (1) first methylating the phenol compound This invention relates to a new and useful proceSS for the with methyl iodide in an acetone Solvent medium in the purification of 2-methoxy-5-trifluoro-methoxy benzalde presence of Solid potassium carbonate, followed by (2) hyde by conversion to a Series of nitroanilines. In particular, direct formylation of the resulting 4-substituted methylated it is concerned with a novel two Step process for purifying phenol (i.e., 4-Substituted anisole compound) with the oil, 2-methoxy-5-trifluoro-methoxybenzaldehyde, C.-dichloromethyl methyl in a methylene chloride wherein the oil is first converted to a nitroaniline. The Solvent System in the presence of titanium tetrachloride as nitroaniline is isolated as a Solid imine and then simply catalyst. However, this particular two-step method for the converted back to the oil, 2-methoxy-5-trifluoro-methoxy production of the aldehyde suffers from the drawback of benzaldehyde. The result is a drastic reduction in the impu being conducted in a non-homogenous reaction System in 15 the first Step, with all its attendant disadvantages, and in rities Seen in the commercial Source which is the usual employing the Somewhat hazardous titanium tetrachloride Starting ingredient for the preparation of Substance Precep reagent as catalyst in the Second step. In the latter tor antagonists. connection, it should be noted that certain Stringent Safety In accordance with the prior art U.S. Pat. No. 5,294,744 requirements are normally called for when handling the issued Mar. 15, 1994, there has already been described in a latter agent, particularly when unit operations are conducted two-step reaction a proceSS for preparing 5-Substituted-2- on a large Scale. Additionally, the use of various hazardous methoxybenzaldehyde compounds wherein the Substituent waste disposal techniques are also required for the removal group is either isopropyl or trifluoromethoxy. The proceSS of the titanium tetrachloride byproducts that are usually involves (1) reacting a corresponding 4-Substituted phenol formed in the aforesaid aromatic formylation reaction. compound with dimethyl carbonate in the presence of a 25 tertiary-amine base to form the corresponding 4-Substituted In the past, F. Merger, et al. in the U.S. Pat. No. 4,129,949 anisole compound. The Second step (2) Subjects the latter indicate that they have prepared various methyl phenyl intermediate product obtained in the first Step to aromatic e the rS, including both 4-methyla niSole and C-formylation on the ring with hexamethylenetetramine in 4-methoxyanisole, from the corresponding phenol the presence of trifluoroacetic acid, followed by , compounds, using dimethyl carbonate in the presence of a to ultimately yield the desired aldehyde compound. The two tertiaryamine base as catalyst without the presence of a aromatic aldehyde compounds So obtained, viz., 2-methoxy Solvent. Although the Merger, et al. patent also includes 5-trifluoromethoxybenzaldehyde and 2-methoxy-5- p-isopropylphenol in a long list of many other possible isopropylbenzaldehyde, are known to be useful as interme phenolic starting materials for the aforementioned reaction, diates that specifically lead to (2S,3S)-cis-3-(2-methoxy-5- there is no indication that 4-isopropylanisole was ever trifluoromethoxylbenzyl)amino-2-phenylpiperidine and (2S, 35 actually prepared in this particular manner. On the other 3S)-cis-2-(diphenylmethyl)-N-(2-methoxy-5- hand, W. E. Smith in the Journal of Organic Chemistry, Vol. 37, No. 24, p. 3972 (1972) reports on its direct isopropylphenyl)-methyl-1-azabicyclo2.2.2]octane-3- C-formylation of Several aromatic compounds, including amine, respectively. The latter final products, in turn, are 2,6-dimethylanisole, via a method which involves the use of both known to be useful in the field of medicinal chemistry 40 hexamethylenetetramine in trifluoroacetic acid in a modified as Substance P receptor antagonists. Duff reaction, but there is no indication in the aforesaid In accordance with the prior art, there has already been paper by Smith that Such a reaction could ever be Success described certain compounds which are known to be of fully carried out using other non-acidic derivatives of ani value as Substance P receptor antagonists. Included among Sole as Substrate. In particular, there is no indication that the these are Such -containing heterocyclic ring com 45 pounds as (2S, 3S)-cis-3-(2-methoxy-5- reaction of Smith could be applied to parasubstituted deriva trifluoromethoxylbenzyl)amino-2-phenylpiperidine, which tives of anisole. is described and claimed by J. A. Lowe, III, et al., in U.S. SUMMARY OF THE INVENTION Pat. No. 5,773,450, issued Jun. 30, 1998, and (2S,3S)-cis A process for the purification of 2-methoxy-5-trifluoro 2-(diphenylmethyl)-N-(2-methoxy-5-isopropylphenyl)- 50 methyl-1-azabicyclo2.2.2]octane-3-amine, which is methoxybenzaldehyde oil comprising converting the oil to an to amine by reacting of a nitroaniline with the oil; described and claimed by F. Ito, et al., in U.S. Pat. No. isolating the imine as a Solid; and converting back the Solid 5,807,867, issued Sep. 15, 1998. Both compounds are useful imine to the 2-methoxy-5-trifluoromethoxy benzaldehyde as non-steroidal anti-inflammatory (N.S.A.I.) agents, being oil. The nitro-aniline is Selected from the group consisting of of Specific value in the treatment of arthritis, asthma and 55 3-nitroaniline, 3-methyl-2-nitroaniline, 4-methyl-2- inflammatory bowel disease. nitroaniline, 2-methyl-3-nitroaniline and 4-methyl-3- In the past, these particular compounds have been pre nitroaniline. The imineSS are Selected from the group con pared by various Synthetic means but essentially by a Sisting of method which involves the of the (2-Methoxy-5-trifluoromethoxybenzylidene)-(3- appropriate aldehyde compound, i.e., by reacting either the 60 oily compound 2-methoxy-5-isopropylbenzaldehyde or nitrophenyl)amine; 2-methoxy-5-trifluoromethoxybenzaldehyde, as the case (2-Methoxy-5-trifluoromethoxybenzylidene)-(4-mehtyl may be, with the corresponding heterocyclic 3-amino com 2-nitrophenyl)amine; pound in the presence of a Source of or else it can (2-Methoxy-5-trifluoromethoxybenzylidene)-(3-mehtyl be made by first condensing the aforesaid 3-amino com 65 2-nitrophenyl)amine; pound with the aldehyde and then reducing the resulting (2-Methoxy-5-trifluoromethoxybenzylidene)-(2-methyl imine intermediate to ultimately give the key 3-nitrophenyl)amine; US 6,686,507 B2 3 4 (2-Methoxy-5-trifluoromethoxybenzylidene)-(4-mehtyl 3-nitrophenyl)amine; SCHEME 2 (2-Methoxy-5-trifluoromethoxybenzylidene)-(4- Substrate descriptions: nitrophenyl)amine; X3 (2-Methoxy-5-trifluoromethoxybenzylidene)-(3,5- X2 X4 dinitrophenyl)amine; OCF (2-Methoxy-5-trifluoromethoxybenzylidene)-(1,6- dinitrophenyl)amine; Xs (2-Methoxy-5-trifluoromethoxybenzylidene)-(2,4- X1 dinitrophenyl)amine; 2N (2-Methoxy-5-trifluoromethoxybenzylidene)-(5-methyl OCH3 2-nitrophenyl)amine; and 15 (2-Methoxy-5-trifluoromethoxybenzylidene)-(6-methyl X X- X X Xs 2-nitrophenyl)amine. 1 - NO, 2 - CH NO, The temperature range in which to precipitate the imine is 3 - CH NO, 4 - NO, CH about 30 to about 40°C. The solvent used to recrystallize the 5 - CH, NO, imine is Selected from the group consisting of ethanol, 6 - NO, methanol and ethanol/hexane. The Solvent used to recryS 7 - NO, NO, 8 NO, NO, tallze the 2-methoxy-5-trifluoromethoxybenzaldehyde is a 9 - NO, NO, mixture of hexane and hydrochloric acid. 25 10 - CH NO, 11 CH NO, 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 DETAILED DESCRIPTION OF THE but that was without Success. Next investigative reactions of INVENTION imine formation were tried with Some using nitroa niline analogues. This gave a Solid very quickly and easily. The imine formation implies equilibrium and most nitro compounds do not have good Solubility in Such Solvent. But 35 the high Stability of the conjugated Structure proposed by the In accordance with the process of this invention, a purified imine drove the equilibrium to the formation of the imine. Solid from the oil, 2-methoxy-5- The difference of solubility between the original nitroaniline trifluoromethoxybenzaldehyde, was attempted by a protec analogues and the imine helped to complete the reaction tion reaction with its aldehyde . Two ways with a very good yield. Having discerned that the main problem was to Search for were first investigated: either making the acetal or the imine. 40 a good mixture of Solvent that ensures a precipitation of the The acetal reactions were not Successful. However, the imine, it was possible to manage the Solubility by controlling Second attempt using a nitroaniline compound gave a Solid the temperature and the Solvent composition. It was also imine which was easily deprotected and gave a good yield. possible to obtain a list of conditions to enhance imine More importantly, the processes had highly-decreased the formation. Adjusting the temperature gave better control of level of impurity of 2-methoxy-5- 45 the reaction. The best conditions were achieved with the 3-nitroaniline trifluoromethoxybenzaldehyde, now again in the oil form. analogue. The solution was heated to 55° C. where it became homogeneous and then, the Solution was slowly cooled to Scheme 1 31-34 C. where precipitation started. For 1 hour, the solution was stirred between 34–37 C. to get a better OCF 50 crystallization. The solution was slowly cooled down to 0 C., filtered and washed with cold hexane. N Because the Solid imine is Stabilized by its conjugated Structure, it is possible to recrystallized it at high tempera -- --NO -- ture without decomposing it. Analysis on the 3-nitroaniline 2 imine complex showed that the recrystallization processes 55 give only one isomer. By keeping the solid in solution, NMR OCH O NH2 shows its transformation to other isomers with time. This Suggests that the imine is in equilibrium between its geo OCF N OCF metric isomers. --NO. The deprotection reaction implies that there is a biphasic 2 Hexane/HCl 1M 60 system in which the imine is stirred for a certain time. The -- acid aqueous layer Stabilizes the amine and the benzalde 2 N hyde showed a great Solubility in hexane. Depending on the nitroaniline analogue, it can take between 1 hour and 15 OCH OCH O hours to form the imine. 65 It appears that the formation of the imine via the nitroa niline works best because of its easy reaction conditions and its defined recrystallization conditions. However, further US 6,686,507 B2 S 6 investigation into the other amine analogues resulted in better conditions for most of the other amine analogues. Accordingly to these results, the deprotection of benzal dehyde derivatives can be done by any nitroaniline ana logues 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. Imine Relative Relative Relative Substrate Retention Retention Retention Relative FROM SCHEME 2 H3868O-127 Time Time Time Retention ABOVE Lot # Area 26 O.36 0.59 O.69 Time 0.74 2.4 O1 O.2 0.5 1.5 1. 0.4 O.O6 O1 1. O6 O.O7 O.08 1. O.3 1: O.2 2 O1 3 4 0.5 O.08 5 O.2 O.08 0.5

All were made from the normal lot.

All compounds Show a important decrease of impurity. More over, compounds (2-Methoxy-5- TABLE 2 trifluoromethoxybenzylidene)-(3-nitrophenyl)amine and Source of starting material 2-Methoxy-5-trifluoromethoxybenzylidene)-(4-methyl-2- nitrophenyl)amine in which corresponding- imine- - were made Product Company Lot Number from 3-methyl-3-nitroaniline and 4-methyl-2-nitroaniline 3-nitroaniline Aldrich O572OTG 3-methyl-2-nitroaniline Aldrich O44O6LV respective ly and 2-Methox y - 5- 35 4-methyl-2-nitroaniline Eastman Organic Chemistry Not specified trifluoromethoxybenzylidene)-(3-nitrophenyl)amine which 2-methyl-3-nitroaniline Aldrich O211A was made from 3-nitroaniline- present a complete elimina 4-methyl-3-nitroaniline Aldrich O8O877 tion of the regio-isomer.

TABLE 3 Elemental Analysis Theoretical Values Obtained Values Offset %

# IUPAC name Mass C H N C H N C H N 1 (2-Methoxy-5- 340 52.95 3.26 8.23 52.95 3.06 8.20 -0.40 -6.44 +1.46 rifluoromethoxybenzyl idene)-(3- nitrophenyl)amine 2 (2-Methoxy-5- 354 54.24 3.70 7.91 54.23 3.34 8.34 -2.27 +15.41 +5.44 rifluoromethoxybenzyl idene)-(4-mehtyl-2- nitrophenyl)amine 3 (2-Methoxy-5- 354 54.24 3.70 7.91 53.36 3.35 7.82 -1.62 -9.46 -1.14 rifluoromethoxybenzyl idene)-(3-mehtyl-2- nitrophenyl)amine 4 (2-Methoxy-5- 354 54.24 3.7O 7.91 53.90 3.39 7.85 -0.65 - 7.67 - 1.58 rifluoromethoxybenzyl idene)-(2-methyl-3- nitrophenyl)amine 5 (2-Methoxy-5- 354 54.24 3.7O 7.91 54.22 3.36 7.88 -0.04 -9.19 -0.38 rifluoromethoxybenzyl idene)-(4-mehtyl-3- nitrophenyl)amine US 6,686,507 B2 7 8 EXAMPLE I Formation of (2-Methoxy-5- TABLE 4-continued trifluoromethoxybenzylidene)-(3-nitrophenyl)amine: All reaction conditions tried and corresponding yield. In a flask containing 3-nitroaniline (6.27 g., 45.4 mmol) 5 was added hexane (140 ml) and ethanol (10 ml) and stirred Substrateubstrate Condition (for 1 ggo of CP-130,209)) ResultCS Vigorously to make the heterogeneous Solution. It was Temperature: 60°C. Light yellow solid heated to 55 C. and the n 2-methoxy-5- Solvent; 6.6% E.OH/Hexane (15 vol) 88.2% trfluoromeif th oxybenzaldehvde y (10 9: 45.4 mmol) WS 2 Temperature:Solvent: MeOH 55°C. (10 vol) 53Light mg. Yellow Seemed solid to be added. The Solution then became orange clear. It was then 10 Temperature: 60° C. the good product. stirred for 15 minutes and slowly cooled down to room Solvent: EtOH (5 vol) 33.5% temperature. The solid appeared at 31° C. The solid was Temperature: 60° C. Fluffy yellow solid filteredCCC. dC. WSCChed W1with CO ld heXane tIO give a yellow11 Temperature:Solvent: 60% 55°EtOH/hexane C. (5 vol) Stayed soluble powder (13.63 9: 88.2%). 3 Solvent: MeOH (8 vol) Stayed soluble The solid (3 g) was recrystallized in hexane (120 ml) and 15 SC, "NEG". vol) 0.256 g EtOH (2 ml). At 55° C. the solution went clear and was Room temperature yellow solid cooled down to 32 C. at which time big particles appeared. Solvent: EtOH (1 vol) 75.7% The temperature was maintained at 32-37 C. for 1 hour at Room temperature tly Impure which a wadding like Solid appeared and replacedd the big 20 Solvent:Room temperature EtOH (3 vol) yellow1.7% impure particles. The solution was cooled down to 0 C. The solid Solvent: 10% EtOH/hexane (5 vol) No reaction was filtered and washed with cold hexane to a white Solid Temperature: 60° C. (2.66 9: 88.6%) named above. 4 Solvent: 40% EtOH/Hexane (10 vol) Stayed soluble Temperature: 56° C. Solvent: EtOH (2 vol) Stayed soluble EXAMPLE II Room temperature 25 Solvent: EtOH (2 vol) 78.8% Formation of 2-methoxy-5 Temperature: O C. Light yellow solid trifluoromethoxybenzaldehyde: Solvent: 10% EtOH/hexane (10 vol) 74.3% Temperature: 60° C. Very light yellow In flask containing 2-Methoxy-5- 5 Solvent: 40% EtOH/hexane (10 vol) Stayed clear trifluoromethoxybenzylidene)-(3-nitrophenyl)amine (0.4 g, Temperature: 60° C. 1.18 mmol), added hexane (20 ml) and HCl (20 ml). It was 30 Solvent: EtOH (3 vol) 63.2% d stirred vigorously for less than 2 hours. The layers were SC, Evo ) Bis powder separated and the organic one was washed with HCl 5 M. Room temperature White-beige powder 2-Methoxy-5-trifluoromethoxybenzylidene gave a really 6 Solvent: 6.6% EtOH/Hexane (15 vol). Insoluble light yellow oil (0.210 g, 81%). Overall yield: 63.3%. Temperature: 60° C. 35 Solvent: MeOH (10 vol) Stayed soluble Room temperature TABLE 3 Solvent: 20% EtOH/Hexane (15 vol). Insoluble Temperature: 58 C. Modification of the general procedure according to each substrate Solvent: 33% EtOH/Hexane (15 vol) Stayed soluble Temperature: 60° C. Sub- Recrystal- Deprotection 40 Solvent: MeOH (2 vol) Stayed soluble strate Protection conditions lization conditions Temperature: 60° C. Solvent: EtOH (3 vol) No reaction 2 Solvent: EtOH (5 vol) None Overnight stirring Temperature: 60° C. Reaction temp: RT to O. C. (increase HCI conc.?) 7 Solvent: 6.6% EtOH/Hexane (15 vol). Insoluble 33.5% 75.3% Temperature: 57 C. 3 Solvent: EtOH (1 vol) None Overnight stirring Solvent: EtOH (15 vol) Stayed soluble Hexane (10 vol) (increase HCI conc.?) 45 Temperature: 50 C. Reaction temp: 60° C. Solvent: MeOH (5 vol) Stayed soluble 26.9% Temperature: 50 C. 4 Solvent: EtOH (5 vol) None 1 hour stirring Solvent: MeOH (2 vol) Stayed soluble Hexane (10 vol) 86.0% Temperature: 60° C. Reaction temp: 60° C. 8 Solvent: 6.6% EtOH/hexane (15 vol). Insoluble 66.2% 50 Temperature: 54 C. 5 Solvent: EtOH (2.5 vol) None -3 hours stirring 9 Solvent: 6.6% EtOH/hexane (15 vol). Insoluble Hexane (10 vol) 64.5% Temperature: 58 C. Reaction temp: 60° C. Solvent: 20% EtOH/EtOAc (10 vol). Insoluble 74.3% Temperature: 58 C. Solvent: MeOH (10 vol) Insoluble 55 Temperature: 60° C. Solvent: EtOH (3 vol) Insoluble TABLE 4 Temperature: 60° C. 1O Solvent: MeOH (10 vol) Stayed soluble All reaction conditions tried and corresponding yield. Temperature: 60° C. Solvent: MeOH (4 vol) 0.83 g. Substrate Condition (for 1 g of CP-130,209) Result 60 Room temperature Orange yellow solid. 1. Solvent: MeOH (10 vol) 67% Solvent: 40% EOH hexane (10 vol) Stayed soluble Room temperature Yellow solid Temperature: 62 C. Solvent: EtOH (10 vol) 50.8% 11 Solvent: MeOH (10 vol) Stayed soluble Room temperature Light yellow solid Temperature: 60° C. Solvent: MeOH (10 vol) 9.22% Solvent: MeOH (3 vol) Stayed soluble Temperature: 55° C. Light yellow solid 65 Temperature: 60° C. Solvent: 25% EtOH/Hexane (15 vol) 81% US 6,686,507 B2 9 10 What is claimed is: (2-Methoxy-5-trifluoromethoxybenzylidene)-(4- 1. A process for the purification of 2-methoxy-5-trifluoro nitrophenyl)amine; methoxybenzaldehyde comprising (2-Methoxy-5-trifluoromethoxybenzylidene)-(3,5- (a) converting Said oil to an imine by reaction of a dinitrophenyl)amine; nitroaniline with Said oil, 5 (2-Methoxy-5-trifluoromethoxybenzylidene)-(1,6- (b) isolating said imine as a Solid and; dinitrophenyl)amine; (c) converting back said Solid imine is to said 2-methoxy 5-trifluoro-methoxybenzaldehyde oil. (2-Methoxy-5-trifluoromethoxybenzylidene)-(2,4- 2. The proceSS according to claim 1 wherein the nitroa dinitrophenyl)amine; niline is Selected from the group consisting of 3 nitroaniline, (2-Methoxy-5-trifluoromethoxybenzylidene)-(5-methyl 3-methyl-2-nitroaniline, 4-methyl-2-nitroaniline, 2 methyl 2-nitrophenyl)amine; and 3-nitroaniline and 4-methyl-3-nitroaniline. (2-Methoxy-5-trifluoromethoxybenzylidene)-(6-methyl 3. The proceSS according to claim 1 wherein the imines are Selected from the group consisting of 2-nitrophenyl)amine. 15 4. The process according to claim 1 wherein the tempera (2-Methoxy-5-trifluoromethoxybenzylidene)-(3- ture range to precipitate the imine is about 30 to about 40 nitrophenyl)amine; C. (2-Methoxy-5-trifluoromethoxybenzylidene)-(4-mehtyl 5. The process according to claim 1 wherein the solvent 2-nitrophenyl)amine; used to recrystallize the imine is Selected from the group (2-Methoxy-5-trifluoromethoxybenzylidene)-(3-mehtyl consisting of ethanol, methanol and ethanol/hexane. 2-nitrophenyl)amine; 6. The process according to claim 1 wherein the Solvent (2-Methoxy-5-trifluoromethoxybenzylidene)-(2-methyl used to recrystallize the 2-methoxy-5-trifluoromethoxyben 3-nitrophenyl)amine; Zaldehyde is a mixture of hexane and hydrochloric acid. (2-Methoxy-5-trifluoromethoxybenzylidene)-(4-mehtyl 3-nitrophenyl)amine; k k k k k