Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-01-09
2002-12-17
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06495700
ABSTRACT:
BACKGROUND OF THE INVENTION
Phenserine and phenserine analogs are known acetylcholinesterase inhibitors making them useful in the treatment of Alzheimer's diseases and as anti-inflammatory agents. Please note U.S. Pat. Nos. 5,306,825 and 5,734,062. Phenserine has been produced by the conversion of physostigmine salt such as physostigmine salicylate to eseroline which is then reacted in a organic solvent in the presence of a base catalyst at a basic pH with an isocyanate such as phenyl isocyanate to produce phenserine and it's analogs. This process has suffered from many disadvantages due to the fact that it involved numerous processing steps in producing the phenserine or its analogs from the physostigmine salt. This resulted in poor yields of phenserine with a relatively low purity.
In the first step of this reaction, the physostigmine salt is converted to the physostigmine free base and this free base is then hydrolyzed to eseroline by treatment with a base in an organic solvent. The eseroline base produced by this method, such as disclosed in U.S. Pat. No. 5,498,726, requires extensive work-up involving numerous steps to separate it from the reaction mixture so that it can be later converted to phenserine. In another method, the eseroline base was also prepared by reacting the physostigmine with a metal alkoxide in an alcohol such as disclosed in U.S. Pat. No. 5,306,825, or by hydrolysis of physostigmine in a water miscible organic solvent with aqueous sodium hydroxide or potassium hydroxide solution, such as disclosed in U.S. Pat. No. 4,978,673, European Patent 0298,202 or via its eseroline fumarate salt (
Heterocycles
1987, 26:5 pages 1271-1275). In these processes it is necessary to neutralize the crude reaction mixture with mineral acids or organic acids such as disclosed in U.S. Pat. Nos. 4,978,673 and 5,498,726. It is also necessary to prevent oxidation of the eseroline base in the solution by either applying a vacuum to the reaction mixture or by carrying out the reaction under an inert atmosphere such as disclosed in U.S. Pat. Nos. 5,306,825 and 5,498,726. These processes require isolation of the eseroline base from the reaction mixture in which it was formed leading to significant degradation unless strict precautions are taken to exclude air. Therefore, it has been long desired to provide an easy method for converting physostigmine salt to eseroline so that the eseroline can be converted to phenserine.
In the next step of this reaction, eseroline is reacted with an isocyanate to produce phenserine or a derivative thereof. This reaction is generally carried out in the presence of water immiscible organic solvents such as ethyl ether, diisopropyl ether, benzene, toluene or petroleum ether in the presence of traces of an alkaline substance such as an alkali metal hydroxide. Please note U.S. Pat. Nos. 4,978,673, 5,306,828 and 5,498,726. Other U.S. patents, such as U.S. Pat. Nos. 5,705,657 and 5,726,323 describe the use of quaternary phosphonium salts and quaternary ammonium salts with a metal cyanate or bicyclic amidine catalyst for the formation of phenserine. This process has been flawed with difficulties especially with regard to the isolation and purification of phenserine or its derivatives.
SUMMARY OF THE INVENTION
In accordance with this invention, phenserine and phenserine analogs of the formula
wherein R is a lower alkyl and R
1
is lower alkyl, phenyl, phenyl lower alkyl, cycloalkyl, or cycloalkyl lower alkyl;
are prepared from physostigmine compounds of the formula
wherein R is as above;
or a salt thereof, via an eseroline compound of the formula:
wherein R is as above;
by reacting the compound of formula II with an isocyanate of the formula:
R
1
—N═C═O V
wherein R
1
is as above;
via a unique selection of reaction conditions, solvents and processing conditions which allow the phenserine compounds of Formula III to be produced in an economic manner in high yields and in a highly purified form. This is accomplished without the necessity of utilizing a large number of processing steps. Therefore, the use of this process makes it ideally suited for large scale production of phenserine and its analogs in a highly efficient and economic manner.
DETAILED DESCRIPTION OF THE INVENTION
The process of this invention is carried according to the following reaction scheme
wherein R and R
1
are a lower alkyl and phenyl, phenyl lower alkyl or cycloalkyl, lower alkyl.
In accordance with the process of this invention the physostigmine compound of Formula I or it's salt is reacted to form the eseroline compound of Formula II by hydrolyzing the physostigmine compound of Formula I with an alkali metal hydroxide, in an aqueous reaction medium. The eseroline compound of Formula II is then isolated in pure form, from the aqueous reaction medium.
The purified eseroline is then treated with a strong organic base in an anhydrous reaction medium containing a water miscible organic solvent. The treated eseroline compound is then reacted, without isolating it from the said reaction medium, with an isocyanate of the formula V. This reaction is carried out by mixing said isocyanate compound of formula V with said eseroline compound in said reaction medium to form said phenserine compound of formula III. Thereafter the reaction is quenched by addition of water, allowing phenserine compound of formula III to be easily isolated in pure form. In this addition, the water can be added to the reaction mixture or the reaction mixture can be added to water. Generally it is preferred to add the reaction mixture to water.
This process can be utilized to make any of the enantiomers of Formula III, i.e., the (+) or (−) enantiomer, as well as, the racemate thereof. Depending upon the particular enantiomer of Formula I used a starting material, the compound of Formula II and III will be produced having the same stereoconfiguration at the quarternary chiral center of the compound of Formula I. On the other, the compound of Formula I can be used as a racemate to produce the compound of Formula II and III as racemates.
In the first step of the reaction of this invention, step (a), the physostigmine compound or salt thereof of Formula I is converted to the eseroline compound of Formula II. This reaction is a hydrolysis reaction carried out in the presence of an alkali metal hydroxide. Physostigmine is a compound which undergoes significant deterioration and therefore is used in the form of an acid addition salt. In accordance with the prior procedures when the physostigmine salt of Formula I is hydrolyzed to the eseroline compound of Formula II, the physostigmine salt is first converted to a free base and thereafter hydrolyzed.
In accordance with this invention the physostigmine salt of Formula I is hydrolyzed in one step without the need for conversion to its free base. This is accomplished by carrying out the hydrolysis with an alkali metal hydroxide in an aqueous medium. In carrying out this reaction any alkali metal hydroxide can be utilized. If desired, the aqueous solution may contain the compound of Formula I or, more preferably, contain this compound in the form of its salt. If desired, this aqueous solution can also contain a water immiscible organic solvent. Any conventional water immiscible organic solvent which is inert in this hydrolysis reaction can be utilized. Among the preferred solvents are included lower alkyl ethers such as ethyl ether, t-butylmethyl ether and diisopropyl ether. In carrying out this reaction temperature and pressure are not critical. This reaction of step (a) can be carried out at room temperature. However, generally temperatures from about 20°-50° C. are utilized in carrying out this reaction. In carrying out step a) it is important that no water miscible organic solvents be used in the hydrolysis. In this way the hydrolysis reaction and recovery of the compound of Formula II is carried out in absence of any water miscible organic solvents. By this procedure, there is a direct conversion of the acid addition salt of
Anderson Rebecca
Axonyx, Inc.
Gibbons Del Deo Dolan Griffinger & Vecchione
McKane Joseph K.
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