Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2002-08-19
2004-05-04
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C558S441000
Reexamination Certificate
active
06730809
ABSTRACT:
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to novel processes and synthetic intermediates for the preparation of &agr;-difluoromethyl ornithine.
Eflornithine or &agr;-difluoromethylornithine (DFMO) has recently been approved in the United States in a topical cream for removing unwanted facial hair. Efficient, scaleable syntheses of DFMO are therefor useful to provide manufacturing
A preparation of DFMO have been described previously in U.S. Pat. No. 4,309,442 from ornithine. The relatively high cost of the starting material, ornithine, and the use of desirable reagents including flammable reagents, however, makes the route less attractive for commercial manufacture.
An alternative preparation of DFMO was described in Swiss patent CH 672 124 from starting materials including malonic acid esters and acrylonitrile. The process is burdened by the use of a Hoffman type reaction which is a potential run-away reaction.
From a manufacturing standpoint it would be advantageous to have a process for the synthesis of DFMO that utilizes readily available and inexpensive starting materials. Processes for DFMO that avoid potentially explosive reaction conditions are also highly desirable. In addition, processes for DFMO production that would avoid the use of halogenated solvents, which require costly waste disposal protocols and emissions monitoring are also preferable.
SUMMARY OF THE INVENTION
In one embodiment, the invention relates to processes for the preparation of DFMO, having the formula
The processes include the step of selectively reducing a nitrile moiety of a compound of the formula
wherein R
1
is linear or branched C
1
to C
4
alkyl and Z is (i) —NH
2
or (ii) a protected amino moiety selected from the group consisting of
wherein R
2
is hydrogen, linear or branched C
1
to C
4
alkyl or aryl, and
wherein R
4
is linear or branched C
1
to C
4
alkyl, alkoxy or aryl.
In another or the same step, the
moiety, if present, is hydrolyzed, producing as a result of the reduction step, or the reduction followed by hydrolysis steps, a compound of one of the following formulas
In another step the ester and amide (including the lactam) moieties of formulas 7, 9, or 10 are hydrolyzed to give the compound of formula 1.
In another aspect, the invention relates to intermediates useful in the preparation of DFMO. The intermediates include compounds of the formula
wherein R
5
is:
wherein R
2
is hydrogen, linear or branched C
1
to C
4
alkyl or aryl;
wherein R
4
is linear or branched C
1
to C
4
alkyl, alkoxy or aryl. Preferred intermediates include: ethyl 2-benzylideneamino-2-difluoromethyl-4-cyanobutanoate, ethyl 2-(diphenylmethylene)amino-2-difluoromethyl-4-cyanobutanoate, ethyl 2-amino-2-difluoromethyl-4-cyanobutanoate, or ethyl 2-acetylamino-2-difluoromethyl-4-cyanobutanoate, or salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, novel processes and intermediates for the preparation of difluoromethyl ornithine (DFMO or the compound of formula 1) are provided. The processes of the invention have been developed from readily available and inexpensive starting materials. Furthermore, the processes provide high yields of DFMO, simplify isolation and purification steps, and minimize the use of halogenated solvents.
In one embodiment of the invention an alkyl glycine ester of the formula 2 serves as a convenient starting material for a short synthesis of an alkyl 2-difluoromethyl-4-cyanobutanoate intermediate (compound of the formula 5) wherein R
1
is C
1
to C
4
linear or branched alkyl and R
2
is hydrogen, C
1
to C
4
linear or branched alkyl, or aryl. Compound of the formula 5 can then be converted by a number of processes to DFMO.
The compound of formula 3 can be obtained from the glycine ester of the formula H
2
NCH
2
CO
2
R
1
, (formula 2) wherein R
1
is C
1
to C
4
alkyl. Preferably the alkyl group is methyl, ethyl, or t-butyl. Glycine ethyl ester, for example, is readily available from a number of commercial vendors as its hydrochloride salt. The compound of the formula 3 can be formed by treatment of the glycine ester of the formula 1 with an aryl aldehyde or ketone of the formula PhC(O)R
2
, wherein R
2
is hydrogen, C
1
to C
4
alkyl or aryl (Scheme 1). A dehydrating agent such as magnesium sulfate or sodium sulfate can optionally be used to remove the water generated in the reaction. If the glycine ester of the formula 2 is provided as an acid addition salt, a tertiary amine base, e.g., triethylamine (TEA), tributylamine (TBA) or N,N-diisopropylethylamine, can be included in the reaction mixture to generate the neutral form of the ester.
While conventional methods for the preparation of Schiff's base derivatives of glycine alkyl ester utilize halogenated reaction solvents such as dichloromethane, applicants have found that the reaction for the preparation of aldimine type intermediates (R
2
=H), can be advantageously carried out in acetonitrile at temperatures of about 10 to 35° C., preferably at about 20 to 25° C. The use of acetonitrile as a reaction solvent simplifies reaction work-up procedures and processing. The magnesium sulfate and tertiary amine base-acid addition salt (if used) can be simply removed by, for example, filtration, and the filtrate used directly in the next synthetic step, where acetonitrile also serves as the reaction solvent.
These reaction conditions can provide high yields and conversions, preferably >98% for both yield and conversion, of compound of the formula 3.
In embodiments of the process where the amino group is protected as a ketone imine (i.e., R
2
=C
1
to C
4
alkyl or aryl) the condensation reaction can also be accomplished using an aprotic solvent, e.g., xylene or toluene (preferably toluene), and catalytic amount of a Lewis acid, e.g., boron trifluoride etherate, triphenyl boron, zinc chloride, aluminum chloride, and the like. The condensation reaction can include the use of a Dean Stark trap and/or the use of other such dehydrating techniques known to those of ordinary skill to hasten the reaction rate by removing the formed water effectively.
The alkyl 4-cyanobutanoate of the formula 4 is, in one embodiment, obtained from the compound of the formula 3 by a Michael reaction. For example, compound of the formula 3 is treated with acrylonitrile, a base such as potassium carbonate and a phase transfer catalyst (PTC), such as triethylbenzylammonium chloride, tetrabutylammonium chloride, tetraethylammonium chloride, or trimethylbenzylammonium chloride at temperatures of from about 10 to about 45° C., preferably from about 20 to 35° C. Methods for the phase transfer catalyzed Michael addition of &agr;-amino acids wherein the &agr;-amino groups are protected as benzaldimines can be found in Yaozhong et al.,
Tetrahedron
1988, 44, 5343-5353.
The compound of formula 4 is then alkylated using a strong base and a halodifluoromethane alkylating reagent to form the compound of formula 5. Suitable strong bases include those that are effective in deprotonating the compound of formula 4 at the position &agr; to the carboxylate. Examples of strong bases include alkali metal alkoxides of the formula MOR
3
wherein M is Na, Li or K and R
3
is C
1
to C
4
linear or branched alkyl; alkali metal hydrides, or alkali metal amide (e.g., sodium amide, sodium bistrimethylsilylamides). Preferably the alkoxide base is either a sodium or potassium alkoxide, more preferably a sodium alkoxide, such as sodium ethoxide or sodium t-butoxide. Preferably, a slight molar excess of base is used in the reaction such as from about 1.6 to 2.0 equivalents.
The alkylation reaction is carried out, for example, by deprotonation at a temperature of from about −35 to about 25° C. Once the &agr;-anion has been generated, the alkylating reagent is introduced and the temperature of the reaction can be, for example, from about −5 to about 20° C. (for R
2
=aryl). Useful halodifluoromethane alkylating reagents include difluoroiodomethane, chlorodifluo
Chadwick Scott T.
Costello Carrie A.
Price Benjamin A.
Vemishetti Purushotham
Zhao Shannon X.
Killos Paul J.
Knobbe Martens Olson & Bear LLP
Women First Healthcare, Inc.
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