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(12) United States Patent (10) Patent No.: US 6,686,507 B2 Watson Et Al

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(12) United States Patent (10) Patent No.: US 6,686,507 B2 Watson Et Al 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, amine 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 aldehyde 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 ether 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 hydrolysis, 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 nitrogen-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 reductive amination 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 hydrogen 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 benzylamine 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.
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