Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-02-04
2002-03-05
Owens, Amelia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C568S338000
Reexamination Certificate
active
06353122
ABSTRACT:
BACKGROUND OF THE INVENTION
Cyclobutyl carbocyclic nucleosides have recently been found to have potent biological activity. Among these is the antiviral agent of the Formula I
which is active against herpes simplex virus type I and 2, varicella zoster virus, human cytomegalovirus, vaccina virus, murine leukemia virus and human immunodeficiency virus.
A number of successful syntheses of the antiviral agent of Formula I have been described using the protected trans-2,3-bis (hydroxymethyl)-cyclobutanones of Formula II as a key intermediate
wherein R is a protecting group. Norbeck, D. W., et al., in European Patent Application 366,059 published May 2, 1990, describe the preparation of purinyl and pyrimidinyl antiviral agents including the compound of Formula I by several synthetic routes using the intermediate of Formula II. Bisacchi, G. S., et al., in U.S. Pat. No. 5,064,961, issued Nov. 12, 1991, also disclose a process for the preparation of the antiviral compound of Formula I using a key intermediate of Formula II.
The most useful method for the preparation of this key intermediate is from a protected-(trans)-1,2-hydroxymethylcyclopropane of Formula IlIl
wherein R is a protecting group which through a series of standard transformations is prepared from Feist's acid. The conversion of a compound of Formula IlIl by epoxidation with m-chloroperoxybenzoic acid (m-CPBA) to the intermediate epoxide and subsequent ring expansion to a cyclobutanone of Formula II by treatment with catalytic lithium iodide was described by Hsiao, C.-N., et al.,
Tetrahedron Lett
., 31, 6609 (1990) and Godfrey, Jr., J. D., et al., U.S. Pat. No. 5,237,096 (1993).
Organic peroxyacids, in general, have been successfully used for the epoxidation of methylenecyclopropanes to their respective oxaspiropentanes, generally followed by isomerization to cyclobutanone. Conia, J. M., et al.,
Chem. Comm
., 1579 (1971) prepared cyclobutanone in high yield by epoxidation of methylenecyclopropane with p-nitroperbenzoic acid in methylene chloride followed by rearrangement with catalytic Lil. Crandall, J. K., et al., in
J. Org. Chem
., 43, 3533 (1978) also described the epoxidation and rearrangement of substituted methylenecyclopropanes using m-CPBA, a more commonly used reagent. These authors also noted that the presence of substituent ester groups on the cyclopropane ring significantly deactivated the double bond toward epoxidation with p-nitroperbenzoic acid.
Although the prior art method works reasonably well on a small scale, a number of problems were encountered on a larger scale in the m-CPBA epoxidation of the compound of Formula III. In order to achieve a reasonable reaction rate, the reaction is run fairly concentrated in methylene chloride. The by-product m-chlorobenzoic acid (m-CBA) precipitates out and must be removed by filtration. In addition, under prolonged reaction time, opening of the epoxide by m-CBA acid to give significant amounts of the benzoate ester was observed and the amount of the benzoate side product was difficult to control. Furthermore, the epoxidation did not go to completion with the preferred benzoyl protecting group, even after prolonged reaction for over 24 hours. The workup was also quite tedious, as excess m-CPBA needs to be quenched and the resulting m-CBA removed prior to proceeding with the rearrangement step. Thus, there is a need for a method which does not produce by-products, avoids long reaction times, is economical and easy to handle and which would be suitable for larger scale production.
SUMMARY OF THE INVENTION
The present invention provides an improved method for converting methylenecyclopropanes to cyclobutanones via an intermediate cyclopropyl epoxide using a mixture of cyclohexanone and potassium peroxymonosulfate. The method is simple, inexpensive, and amenable to large scale preparation of the cyclobutanones of Formula II
wherein R is a hydroxy-protecting group.
REFERENCES:
patent: 5064961 (1991-11-01), Bisacchi et al.
patent: 5237096 (1993-08-01), Godfrey et al.
patent: 5773614 (1998-06-01), Godfrey et al.
J.K. Crandall and W.W. Conover, “Peracid Oxidation of Methylenecyclopropanes”,J. Org. Chem., 43 (18), pp.3533-3535 (1978).
C.-N. Hsiao and S.M. Hannick, “Efficient Synthesis of Protected (2S,3S)-2,3-BIS (Hydroxymethyl)Cyclobutanone, Key Intermediates for the Synthesis of Chiral Carbocyclic Analogues of Oxetanocin”,Tet. Letters, 31 (46), pp.6609-6612 (1990).
J.R. Salaün and J.M. Conia,Chem. Comm., pp. 1579-1580 (1971).
Brodfuehrer Paul R.
Sattleberg, Sr. Thomas R.
Algieri Aldo A.
Bristol--Myers Squibb Company
Owens Amelia
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