Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2000-11-10
2002-02-19
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S188000
Reexamination Certificate
active
06348625
ABSTRACT:
CROSS-REFERENCE TO RELATED APPLICATIONS
Not Applicable
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not Applicable
REFERENCE TO A MICROFICHE APPENDIX
Not Applicable
BACKGROUND OF THE INVENTION
This invention relates to a method for the novel preparation of some N-substituted-1-adamantanecarboxamides and some 1-adamantaneacetamides by treating 1-adamantanecarboxylic acid or 1-adamantaneacetic acid with N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine, followed by the addition of aqueous ammonia or amines.
The amide linkage is present in peptides and proteins. Moreover, the amide functional group is present in many medicinal compounds. Thus, reactions that lead to the formation of the amide linkage and/or the amide functional group are useful in pharmaceutical research as well as the development of drugs.
N-Substituted-1-adamantanecarboxamides are useful as potential antiviral agents as well as intermediates in the synthesis of antiviral agents. Therefore, this invention has potential commercial application as a convenient and rapid method for the preparation of adamantanecarboxamides, other carboxamides, more complex compounds containing the amide functional group, and compounds containing the amide linkage.
Traditionally, carboxamides in general, and adamantanecarboxamides in particular (Novakov, et al.,
Khim
-
Farm. Zh
., 1987, 21(4), 454-8; Danilenko, et. al.,
Khim
.-
Farm. Zh
., 1976, 10(5), 49-52) have been prepared from the corresponding acids via the acid chlorides. In general,this method is long and tedious.
According to most methods, preparation of acid chlorides requires refluxing the acids in excess thionyl chloride from thirty minutes to as long as several hours, followed by distillation to remove unreacted thionyl chloride. According to one method 1,3-adamantane(bis)acetic acid was refluxed in excess thionyl chloride for twenty-four hours to prepare the corresponding acid chloride (Aigami, et. al.,
J. Med. Chem
., 1975, 18(7), 713-21). Another method for the preparation of some adamantanecarboxamides involved refluxing the corresponding acid in thionyl chloride and benzene for eight hours, followed by distillation to remove the benzene and excess thionyl chloride (Krasutskii, et al.,
Khim
.-
Farm. Zh
., 1985, 19(7), 825-29). Still another method involved refluxing the adamantanecarboxylic acids in thionyl chloride containing a catalytic amount of N,N-dimethylformide (Fridman, et. al.,
Khim
.-
Farm. Zh
., 1974, 8(7), 6-8). Also, adamantanecarboxamides have been prepared by heating the corresponding acids with phosphorus pentachloride in carbon tetrachloride for one hour (Danilenko, et. al.,
Khim
.-
Farm. Zh
., 1976, 10(6), 37-41). Usually, after the acid chloride has been isolated from excess co-reactant, solvent, and/or by products, it is dissolved in a solvent such as anhydrous tetrahydrofuran or anhydrous dioxane, aqueous ammonia or the amine is added, and the mixture is allowed to stand for about twelve hours.
There are several disadvantages to using the methods described above. These methods require: 1) reflux and distillation apparatus; 2) traps for the hydrogen chloride and sulfur dioxide evolved in the thionyl chloride reaction; 3) heating apparatus; and 4) isolation of the acid chloride. Thus, unlike the method described in this invention, the above methods are long and tedious.
Additionally, adamantanecarboxamides have been prepared in our laboratories using DATE [1-(N,N-diethylamino)-1,1,2-trifluoro-2-chloroethane] (Anderson, et. al.,
Synthetic Comm
., 1988, 18(16 & 17), 1967-1974; Anderson, et. al.,
The Chemist
, January/February 2000, 7-10). The reagent DATE was prepared from diethylamine and chlorotrifluoroethylene, according to a modified procedure of Yarovenko and Raksha (Yarovenko and Raksha,
J. Gen. Chem. USSR
, 1959,29,2125-28). Chlorotrifluoroethylene gas was bubbled slowly into diethylamine contained in a gas drying tube cooled by an ice water bath. This was continued for at least twelve hours, and the product was collected by vacuum distillation. There are several disadvantages to using this reagent. First, the procedure for preparation of the reagent required about twenty four hours. Second, the reagent is not very stable at room temperature and decomposes within a few days even when stored in the refrigerator. Third, preparation of the reagent requires somewhat sophisticated equipment. The reagent used in this invention is commercially available from Lancaster Synthesis in Windham, N.H. Further, the reagent is stable over a long period of time. Thus, unlike the method described in this invention, the procedure using DATE is long and tedious.
BRIEF SUMMARY OF THE INVENTION
The invention described herein provides a method for preparing adamantanecarboxamides and adamantaneacetamides in high yields (80-100%) by treating the 1-adamantanecarboxylic acid or 1-adamantaneacetic acid with N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine, followed by addition of aqueous ammonia or the appropriate amine. The procedure is convenient and rapid, requiring no more than one or two hours. Several reactions can be carried out simultaneously.
DETAILED DESCRIPTION OF THE INVENTION
The carboxamides are prepared by a procedure that is carried out in a wide mouth polyethylene bottle on a magnetic stirrer at ambient temperature. Isolation of the amide is completed by filtering and washing with water, followed by a small amount of ethyl ether. The entire reaction, including isolation of the product, can be completed within one or two hours. The method works equally as well for the preparation of 3-substituted-1-adamantanecarboxamides and 3-substituted-1-adamantaneacetamides. In the case of 3-hydroxy-1-adamantanecarboxylic acid and 3-hydroxy-1-adamantaneacetic acid, the hydroxy group must be protected otherwise it is converted to a fluoro group. Thus, 3-hydroxy-1-adamantanecarboxylic acid yields 3-fluoro-1-adamantanecarboxamide.
The procedure consists of adding the 1-adamantanecarboxylic acid to N,N-diethyl-1,1,2,3,3,3-hexafluoropropylamine contained in a wide mouth polyethylene bottle during which time the acid fluoride forms immediately through an exothermic reaction. The rate of addition of the acid may be adjusted to control the temperature and prevent the evolution of hydrogen fluoride or the reaction bottle may be cooled in an ice water bath briefly. The intermediate acid fluoride is not isolated. After the reaction mixture cools to room temperature by allowing it to stand at room temperature or by cooling it in an ice water bath, cold aqueous ammonia or the desired amine is added and the amide precipitates immediately. An excess of an inexpensive amine is added to convert the hydrogen fluoride to the amine salt. For more expensive amines, aqueous base is added to convert the hydrogen fluoride to the salt prior to the addition of the amine. The amide is collected by filtration and washed copiously with water followed by a minimum amount of ethyl ether. For large scale preparations the oily amide by product, N,N-diethyl-2,3,3,3-tetrafluoropropionamide, can be collected from the filtrate by separation from the water phase using a separatory funnel. Similarly, for large scale preparations, the hydrogen fluoride salt of ammonia or the amine can be recovered by evaporation of the water. Several reactions can be carried out simultaneously.
REFERENCES:
patent: 5382673 (1995-01-01), Clark et al.
patent: 9732835 (1997-09-01), None
Novakov et al, Khim. Farm. Zhu, No. 4, pp 454-458, 1985.*
Danilenko et al, Khim. Farm. Zhu., No. 5, pp 49-52, 1974.*
Aigami et al, J. Med. Chem., vol. 18, No. 7, pp 712-721, 1975.*
Krasutski i et al, Khim. Farm. Zhu., vol. 19, No. 7, pp 825-829, 1985.*
Fridman et al, Khim. Farm. Zhu, vol. 8, No. 7, pp 396-398., 1974.*
Danilenko et al, Khim. Farm. Zhu, vol. 10. No. 6, pp 37-41, 1976.*
Stetter et al, Chem. Ber., vol. 93, pp 226-230, 1960.*
Anderson et al, Synth. Commun., vol. 18, pp 1967-1974, 1988.*
Anderson et al, The Chemist, pp 7-10, Jan./Feb. 2000.*
Yarovenko et al, J. Gen. Chem. USSR., vol. 29, pp 2125-212
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