Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2000-06-23
2002-07-16
Padmanabhan, Sreeni (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S336000, C564S342000, C564S343000
Reexamination Certificate
active
06420606
ABSTRACT:
FIELD OF INVENTION
The present invention relates to methods for the production of alkoxy arylamine compounds.
BACKGROUND
Alkoxy arylamine compounds are of particular interest for use in the syntheses of numerous pharmaceutical drug candidates. For example, psychoactive drugs and other drugs used in the treatment of depression may be synthesized using alkoxy arylamine compounds.
Applicants believe that known methods for making alkoxy arylamine compounds exhibit certain drawbacks and inefficiencies. For example, U.S. Pat. No. 3,069,432, issued to Yale et al., discloses the synthesis of 2-(o-Bromobenzyloxy) aniline from o-nitrophenol and o-bromobenzyl bromide starting materials. The starting materials are first reacted in the presence of base to form a reaction product stream containing numerous components including an alkoxy nitroaryl compound. The Yale patent requires that the reaction product mixture be processed through filtering, washing and recrystallization in order to isolate the alkoxy nitroaryl compound for use in a subsequent reduction step in which the isolated alkoxy nitroaryl compound is reduced to an alkoxy arylamine compound using a large excess of iron powder in the presence of concentrated hydrochloric acid (“HCl”).
The present inventors have come to appreciate that prior art processes of the type used by Yale et al. are disadvantageous for several reasons. For example, one disadvantage is that the Yale process requires isolation of the alkoxy nitroaryl compound in order to conduct the acidic reduction of the subsequent step. Such isolation techniques tend to be time-consuming and costly, and they tend to have a negative impact on the overall efficiency of the synthesis procedure. Another disadvantage of the prior art processes is that the use of stoichiometric amounts of metal, such as iron, creates a relatively large amount of waste which is potentially harmful to the environment. Accordingly, such use tends to require a relatively large amount of time and expense to purify the desired product and to dispose properly of the waste.
Recognizing these and other drawbacks of the prior art, the present inventors have perceived a need for a new, efficient and more desirable method for producing a wide range of alkoxy arylamine compounds.
DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
The present invention is directed to methods of producing a wide range of alkoxy arylamine compounds, many of which find particular use in the syntheses of pharmaceutical drug candidates such as psychoactive drugs. As used herein, the term “alkoxy arylamine compound” refers generally to amines having the formula:
H
2
N—Ar—OR
wherein Ar is an unsubstituted or substituted aromatic group, and R is an unsubstituted or substituted alkyl, aralkyl or aryl group. The term “alkoxy arylamine compound” is also intended to encompass salts derived from amines of the formula noted above.
The present methods comprise generally, the steps of (a) alkylating a protected-amino arylalcohol to form a protected-amino arylether; and (b) deprotecting said protected-amino arylether to form an alkoxy arylamine compound. As used herein, the term “protected-amino arylalcohol” (“PAA”) refers generally to a compound of Formula I:
Z—N(H)—Ar—OH (I)
wherein Ar is an unsubstituted or substituted aromatic group which does not interfere with o-alkylation of the hydroxyl group and Z is an amine protecting group. Furthermore, as used herein, the term “protected-amino arylether” (“PAE”) refers generally to a compound of Formula II:
Z—N(H)—Ar—OR (II)
wherein R is an unsubstituted or substituted alkyl, aralkyl or aryl group.
In general, it is contemplated that the alkylation reaction of the present invention can be advantageously coupled with the deprotection reaction in a large number of circumstances and applications, and all such variations are within the scope of the present invention. In highly preferred embodiments, however, both the alkylation reaction and the deprotection reaction are solvent reactions. As used herein, the term “solvent reaction” refers to a reaction in which at least a portion of the reactants are solutes in a liquid phase solution. Furthermore, it is highly preferred that the deprotection reaction solution is compatible with the reaction solution used for the alkylation step. As used herein, the term “compatible solutions” refers to two or more reaction solutions which can be integrated, such as by mixing, without substantial degradation of the respective reactions occuring in each solution.
It will be appreciated that the use of compatible reaction solutions in accordance with the present invention has important advantages and desirable characteristics. In particular, the use of compatible reaction solutions contributes to the ability of the processes of the present invention to produce excellent yields and short overall reaction times without the need to isolate reaction products from solution between successive steps. As a result, it is possible that the alkylation step and the deprotection step can occur in the same reaction vessel. This not only provides a potentially important cost savings, it represents a potential improvement in the rate at which the desired compounds can be produced. In a batch-wise operation, the alkylation reaction can be allowed to continue to a high degree of completion, potentially even a substantial completion, at which point the reaction vessel is charged with the reactants and/or the reaction conditions in the vessel are changed so as to initiate the deprotection reaction. In view of the teaching herein, those skilled in the art can also readily appreciate that some degree of reaction overlap is thus possible to the extent consistent with other criteria for the production of the particular alkoxy arylamine compound that is desired.
The present methods can also be carried out with the same degree of flexibility in a continuous operating mode. For example, for embodiments in which the reaction vessel is a continuous tubular reactor (“CSTR”), the reactants necessary to initiate the alkylation reaction can be introduced into the vessel under conditions effective to initiate the alkylation reaction, which is allowed to continue for a sufficient residence time to achieve a high degree of reaction completion. The length along the tubular reactor at which the desired level of completion occurs can be readily determined, by calculation or by sampling, and the deprotection reactants can be introduced to the reactor at this location and/or the conditions in the reactor (such as reaction temperature) at this location can be altered (such as by heating or cooling) so as to initiate the deprotection reactions. It will be appreciated that the feed locations to a continuous stirred tank reactor, or any other type of continuous reactor, can be adjusted to initiate the deprotection reaction at the desired degree of completion of the alkylation reaction, as required for any particular application.
According to preferred embodiments, the alkylation reaction of step (a) comprises a solution reaction promoted by basic conditions and the deprotection reaction comprises a solution reaction promoted by basic conditions, that is, the alkylating and the deprotecting step each comprise reaction of the respective materials in the presence of basic reagents. Preferably, the alkylation solution and the deprotection solution are compatible solutions. As with the broad aspects of the present invention, the alkylation step and the deprotection step in such preferred embodiments can each be carried out in a batch mode, a continuous mode or a combination of batch and continuous modes.
Numerous other advantages are associated with the methods of the present invention. For example, by avoiding the use of metal-based compounds as essential elements in the reaction mechanism, the present invention is capable of avoiding the excessive clean-up and higher processing costs associated therewith. Furthermore, because alkoxy arylamine compounds can be synthesized according to the p
Aslam Mohammad
Cullen Margaret
MacManus Patrick
Padmanabhan Sreeni
Szuch Colleen D.
Witherspoon Sikarl A.
LandOfFree
Method for producing alkoxy arylamine compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for producing alkoxy arylamine compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for producing alkoxy arylamine compounds will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2898209