Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-19
2001-09-11
Kifle, Bruck (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06288239
ABSTRACT:
CROSS-REFERENCE TO RELATED APPLICATION
None
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
None
BACKGROUND OF THE INVENTION
(1) Field of the Invention
The present invention relates to a one-step route to 5-trityloxymethyl-oxazolidinone from 3-hydroxy-4-trityloxy butyramide. In particular, the present invention relates to the preparation of chiral forms of the 5-trityloxymethyl-2-oxazolidinone.
(2) Description of Related Art
Optically pure oxazolidinones can be obtained by carbonylation of vicinal amino alcohols with reagents such as phosgene, ethyl chloroformate and carbonyl imidazole. The preparation of optically-pure 5-trityloxymethyl-oxazolidinone would normally require the preparation of the corresponding optically-pure 5-hydroxymethyl-oxazolidinone followed by a tritylation step to produce 5-trityloxymethyl oxazolidinone.
Oxazolidinones have emerged as a very important class of compounds in drug development especially in the areas of antimicrobials (Diekema, D. J., et al., Drugs 59 7-16 (2000)) and behavioral disorders (Brenner, R., et al., Clin. Therapeut. 22 4 411-419 (2000)). They are especially active against some of the most resistant human pathogens including vancomycin-resistant enterococci, methicillin-resistant
Staphylococcus aureus
, cephalosporin-resistant
Streptococcus pneumoniae
and several organisms that display penicillin resistance (Diekema, D. J., et al., Drugs 59 7-16 (2000)). Linezolid (4) was recently recommended for approval for the treatment of infections from antibiotic resistant bacterial strains especially those that are resistant to vancomycin.
Optically active 3,4-dihydroxybutanoic acids and their &ggr;-lactones are important sources of chirality. They can be obtained in commercial quantities from carbohydrates such as starch, lactose, maltodextrins, cellulose and arabinose by oxidative degradation (Hollingsworth, R. I. Biotechnology Annual Review 2 281-291 (1996); Hollingsworth, R. I., J. Org. Chem. 64 7633-7634 (1999)). See also U.S. Pat. Nos. 5,292,939, 5,808,107, 5,319,110 and 5,374,773 to Hollingsworth. Chiral amino propane diols can be made by Hoffman degradation of the isopropylidene acetals of optically active 3,4-dihydroxybutyric acid amides (Wang, G., et al., J. Org. Chem. 64 1036-1038 (1999)).
SUMMARY OF THE INVENTION
The present invention relates to A process for the preparation of 5-trityloxymethyl-oxazolidinone which comprises:
(a) reacting with stirring a 4-trityl ether of 3,4-dihydroxybutyramide with an alkali or alkaline earth hypohalite in water in the presence of an alkali alkaline earth metal hydroxide and an organic solvent in a reaction mixture to produce the 5-trityloxymethyl-oxazolidine;
(b) separating the 5-trityloxymethyl-oxazolidinone from the reaction mixture in the organic solvent; and
(c) removing the organic solvent to produce the 5-trityloxymethyl-oxazolidinone.
The present invention also relates to the novel 5-trityloxymethyl-oxazolidinone 1 produced by the process. Preferably the compounds are chiral.
OBJECTS
It is thus an object of the present invention to provide a one step process enabling the production of novel 5-trityloxymethyl-oxazolidinone from a trityl ether of an amide. Further, it is an object of the present invention to provide for the preparation of chiral products. Further still, it is an object of the present invention to provide a process which is relatively simple and economical by comparison to the prior art and produces the product in high yield and purity. These and other objects will become increasingly apparent by reference to the following description.
DESCRIPTION OF PREFERRED EMBODIMENTS
The reaction involved in the present process is as follows in Scheme 1
where Tr is a trityl (triphenylmethyl) group. The bracketed compound (3) is a hypothesized isocyanate intermediate which is unstable and forms the ring structure of the 5-trityloxymethyl-2-oxazolidinone (1) from the starting 3-hydroxy-4-trityloxybutyramide 2. The preferred product is the chiral (S)-5-trityloxymethyl-oxazolidinone.
In Scheme 1, the alkali metal hydroxide can be lithium, sodium or potassium hydroxide. The alkaline earth metal hydroxide can be calcium hydroxide, or magnesium hydroxide. Preferably there is an excess of 2 to 6 moles of OH
−
over the moles of the 4-trityl ether of the amide.
The hypohalite(OCl
−
or OBr
−
) can also be an alkali metal or alkaline earth metal hypohalite as discussed above for the base. Usually the alkaline earth metal is the same for both OH
−
and OCl
−
or OBr
−
; however they can be different.
Most preferably the reaction in step (a) is conducted with an organic solvent which form a 2-phase system with water under the reaction conditions. Besides tetrahydrofuran other solvents are dioxane, propanol and ether. The yields are better with the organic solvent, probably since the product 1 separates into the organic solvent as it is formed. The reaction is conducted at a temperature between about 10° and 80° C. and at atmospheric pressures. The reaction is complete in 6 to 8 hours at 55°-60° C.
The product 1 is purified by removing the miscible organic solvent by evaporation or other means and recrystallizing from a second organic solvent. Dichloromethane is preferred; however other solvents are chloroform, hexanes, alcohol or mixtures of these.
The 4-trityl ether of 3,4-dihydroxybutyramide in step (a) is prepared by reacting excess trityl chloride (preferably in a molar ratio 1.1 to 1.5 to 1 based upon the amide). Other halides such as Br, F or I could be used. The amine base is preferably pyridine although other amines such as triethylamine can be used to react with the HCl or other acid produced in the reaction. The organic solvent is preferably a mixture of dimethyl formamide and tetrahydrofuran with the exclusion of water. The solvent is removed preferably by vacuum and then the ether is washed with hexane to remove excess trityl chloride. The temperature is between about 5° and 40° C. and the pressures are atmospheric. The reaction is complete in 24 to 48 hours. This trityl ether is then used to form the oxazolidinone.
Thus this invention provides a trityl protected, optically pure 5-hydroxymethyl-oxazolidinone such as (S)-5-trityloxymethyl-2-oxazolidinone (1) in a simple high-yield process from optically active 3-hydroxy-&ggr;-butyrolactone using the 4-O-trityl ether of chiral 3,4-dihydroxybutyramide as the starting material.
Because an isocyanate that is hydrolyzed with water is an intermediate species in the Hoffman rearrangement, in principle a vicinal hydroxyl group can act as a nucleophile resulting in cyclization to form an oxazolidinone system. In the present invention, a separate carbonylation reaction using phosgene, ethyl chloroformate or some similar reagent would be avoided. This is illustrated in Scheme 1 for the 4-trityl ether of (S)-3,4-dihydroxybutyric acid amide (2) via the isocyanate 3.
The overall process involves essentially only two steps, only one of which involves the formation of the oxazolidinone 1. The first step is the preparation of the trityl ether from the dihydroxybutyamide 2, a known compound. This amide is obtained in quantitative yield by treating the 3-hydroxy-&ggr;-butyrolactone with aqueous ammonia at room temperature. The second step is the rearrangement of the trityl ether (2) under conditions where the intermediate isocyanate (3) is protected from water, allowing the neighboring hydroxyl group to participate, whilst protecting the final product from base hydrolysis. Hoffman rearrangement using a 2-phase solvent system, in this case tetrahydrofuran/water, gave the protected hydroxymethyl oxazolidine 1 directly in >90% isolated yield and in >99% optical purity. This represents a very significant economy in the synthesis of an important, optically-pure, protected 5-(hydroxymethyl)-2-oxazolidinone in essentially 4 steps from starch, maltose, lactose or similar 4-linked carbohydrate source. The trityl group can be selectively removed allowing the hydroxymethyl function to be transformed i
Hollingsworth Rawle I.
Wang Guijun
Board of Trustees operating Michigan State University
Kifle Bruck
McLeod Ian C.
Uppu Rao
LandOfFree
5-trityloxymethyl-oxazolidinones and process for the... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 5-trityloxymethyl-oxazolidinones and process for the..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 5-trityloxymethyl-oxazolidinones and process for the... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2444832