Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Reexamination Certificate
1999-12-20
2001-05-01
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
C558S410000
Reexamination Certificate
active
06225491
ABSTRACT:
SCOPE OF THE INVENTION
This invention relates to a method for converting benzaldehydes to the corresponding cyanohydroxymethylbenzene analogs and for subsequently reducing those compounds.
BACKGROUND OF THE INVENTION
The chemistry, isolation process and compounds of this invention are all useful in preparing certain end products which are useful pharmaceutical agents. More specifically this invention relates to intermediates and means for preparing and isolating intermediates which can be used to prepare certain known compounds having the following general structure
where R
1
and R
2
are exemplified by ether or thio-ether functionalities and R
3
is any one of a number of radicals of which a carboxylate is but one example. Compounds of these types can be found in the literature, more particularly in published patent applications such as, for example, PCT/US93/01990 published as WO93/19748, PCT/US93/02325 published as WO93/19750, PCT/US93/02516 published as WO93/19751, PCT/US93/01988 published as WO93/19747, PCT/US93/01991 published as WO93/19749 and PCT/US93/02230 published as WO93/19720. Of greatest interest are the acetonitriles disclosed in PCT/US93/01991. These compounds are all useful in treating a variety of disease states. In particular they are useful for treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor (TNF).
The compounds and processes of this invention are useful in making the afore mentioned pharmaceutical entities in so far as they have a —CN group on the cycloalkyl ring at the carbon forming a bond with the benzene ring carbon.
SUMMARY OF THE INVENTION
This invention relates to a process for converting a benzaldehyde to a cyanohydrin in an aqueous medium comprising first adding about 1 to 1.5 equivalents of an alkali metal bisulfite to a solution of the benzaldehyde, then adding an alkali metal cyanide to this mixture, and then adding a second charge of about 1.5 to 2.5 equivalents of the alkali metal bisulfite while maintaining the pH between about 6.5 to 7.5 and maintaining the temperature of the reaction mixture at between about 0 and 30° C.
GENERAL EMBODIMENTS
While the illustrations given herein are specific to isovanillin and the derivatives made therefrom, the chemistry disclosed herein can be used with other benzaldehydes.
The compound and chemistry of this invention can be used to make cyanohydrins. These cyanohydrins are intermediates in the path for making certain bicyclic compounds as noted above. The compounds made by the chemistry of this invention are intermediates in the processes outlined in the several PCT applications set out above, namely PCT/US93/01990 published as WO93/19748, PCT/US93/02325 published as WO93/19750, PCT/US93/02516 published as WO93/19751, PCT/US93/01988 published as WO93/19747, PCT/US93/01991 published as WO93/19749 and PCT/US93/02230 published as WO93/19720.
In general, this process comprises dissolving a benzaldehyde in an aqueous medium, preferably just water, then adding at least about an equivalent or more of an alkali metal bisulfite. Sodium is the preferred alkali metal cation. The temperature of the reaction mixture should be maintained at about room temperature during the addition of the bisulfite. Stirring or some form of mixing may be begun during the addition of the bisulfite, and is continued for about 15 minutes to upwards of an hour thereafter. A white solid may appear on additions of the bisulfite and during the period of mixing. The temperature of the mixture should be maintained at about room temperature during this period as well. After the aforesaid mixing period, the reaction mixture is cooled to between about 0 to 20° C. Once this is accomplished, an aqueous solution of alkali metal cyanide is added, preferably over a period of about 1 to 5 hours. At least about 1.5 and 2.5 equivalents of the cyanide salt are added. The preferred cation is potassium, though sodium or one of the other monovalent alkali metal ions could be used as well, provided it forms water soluble salts. During the addition of the cyanide, the temperature of the mixture is maintained at between about 0 and 20° C. by some cooling means. Stirring or some form of mixing is used to keep the mixture in motion during the addition of the cyanide. Once all of the cyanide has been added the pH of the mixture will have become basic. A pH of up to about 9 is not uncommon. Thereafter additional alkali metal bisulfite is added portion-wise or in one batch. In addition, the pH of the mixture is adjusted to between about pH 6.5 and 7.5; the additional bisulfite can effect this result or an acid can be added to the reaction vessel to bring the pH down into this range if the addition of the bisulfite is not sufficient to effect this change or it is desired to add a proton source to insure said pH range is attained. This pH range effectively shifts the equilibrium of the reaction to the cyanohydrin form. This pH range may also be optimal in-so-far as product stability is concerned. This second charge of bisulfite is preferably the same salt form as was initially added to the solution containing just the benzaldeyde. About 1.5 to 2.5 equivalents of the bisulfite should be added during the course of this second addition. Again the temperature of the reaction mixture is maintained at between about 0 and 30° C., though a range of 0 to 25° C. is more preferred. Once the second batch of bisulfite has been completely added, the reaction mixture is stirred long enough to effect completion of the reaction which is determined by some means such as a separatory means, e.g., thin layer chromatography or HPLC. The disappearance of the starting benzaldehyde or a repeating very small quantity of the substrate can be taken to mean the reaction has gone to completion or is at its final equilibrium.
The following examples are being provided to exemplify the invention. They are only examples and should not be read as limiting the invention in any manner. Reference is made to the claims for what is reserved to the inventor(s) hereunder.
REFERENCES:
patent: 6040471 (2000-03-01), Diederich
Kanagy James M.
Kingzig Charles M.
McKane Joseph K.
Murray Joseph
SmithKline Beecham Corporation
LandOfFree
Method for preparing certain acetonitriles 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 preparing certain acetonitriles, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for preparing certain acetonitriles will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2503523