Methods of producing oxazolidinone compounds

Details Methods of producing oxazolidinone compounds Methods of producing oxazolidinone compounds

2001-10-17

2004-12-21

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C544S369000, C546S271400, C548S229000, C548S255000, C548S262200, C548S311100, C548S565000, C548S952000, C549S426000, C549S060000, C549S483000

Reexamination Certificate

active

06833453

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a method of preparing pharmacologically active oxazolidinones and various intermediates used in the method. The oxazolidinone derivatives are useful as broad spectrum antimicrobial agents which are effective against a variety of human and veterinary pathogens.
BACKGROUND OF THE INVENTION
Compounds that contain the 5-acetamidomethyl-oxazolidinone moiety are well known to persons skilled in the art as pharmacologically useful antibacterial agents. For example, U.S. Pat. Nos. 5,164,510, 5,182,403, and 5,225,565 disclose antibacterial 5′-indolinyl-oxazolidinones, 3-(5′-indazolyl)-oxazolidinones, and 3-(fused-ring substituted)phenyl-oxazolidinones, respectively. Similarly, U.S. Pat. Nos. 5,231,188 and 5,247,090 disclose several tricyclic [6.5.5] and [6.6.5]-fused ring-oxazolidinones which are useful pharmaceutical agents. International Publication WO93/09103 discloses antibacterial mono- and di-halophenyl-oxazolidinones.
Persons skilled in the art use two primary methods to prepare the 5-acetamidomethyl-oxazolidinone moiety of these therapeutic agents. The first method involves condensation of an aromatic carbamate (Ar—HN—C(═O)—OR) or aromatic isocyanate (Ar—N═C═O) with a halopropanediol or another nitrogen-free three-carbon reagent to provide an intermediate oxazolidinone having a hydroxymethyl substituent at the C-5 position of the oxazolidinone. The hydroxyl group then is replaced by an acetamido group to give a pharmacologically active 5-acetamidomethyl-oxazolidinone.
Many variants of this two-step process have been developed, and examples are illustrated in U.S. Pat. Nos. 4,150,029, 4,250,318, 4,476,136, and 4,340,606, which disclose the synthesis of 5-hydroxymethyl-oxazolidinones from amines (Scheme A). The mixture of enantiomers produced by this process are
separated by fractional crystallization of their mandelic acid salts. The enantiomerically pure R-diol then is converted into the corresponding 5-(R)-hydroxymethyl-oxazolidinone by condensation with diethylcarbonate in the presence of sodium methoxide. The 5-(R)-hydroxymethyl-oxazolidinone then is aminated, and the resulting amine acylated in subsequent steps.
Likewise, U.S. Pat. No. 4,948,801,
J. Med. Chem.,
32, 1673 (1989), and
Tetrahedron,
45, 1323 (1989) disclose a method of producing oxazolidinones which comprises reacting an isocyanate (R—N═C═O) with (R)-glycidyl butyrate in the presence of a catalytic amount of a lithium bromide-tributylphosphine oxide complex at 135-145° C. to produce the corresponding 5-(R)-butyryloxymethyl-oxazolidinone. The butyrate ester then is hydrolyzed in a subsequent step to provide the corresponding 5-(R)-hydroxymethyl-oxazolidinone. The 5-(R)-hydroxymethyl-oxazolidinone then is aminated in a subsequent step.
Similarly, the following references disclose variations of the reaction of a carbamate with glycidyl butyrate:
Abstracts of Papers,
206th National Meeting of the American Chemical Society, Chicago, Ill., August, 1993; American Chemical Society: Washington, D.C., 1993; ORGN 089;
J. Med. Chem.,
39, 673 (1996);
J. Med. Chem.,
39, 680 (1996); International Publications WO93/09103, WO93/23384, WO95/07271, WO96/13502, and WO96/15130;
Abstracts of Papers,
35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Calif., September, 1995; American Society for Microbiology: Washington, D.C., 1995, Abstract No. F208;
Abstracts of Papers,
35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Calif., September, 1995; American Society for Microbiology: Washington, D.C., 1995, Abstract No. F207;
Abstracts of Papers,
35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Calif., September, 1995; American Society for Microbiology: Washington, D.C., 1995, Abstract No. F206;
Abstracts of Papers,
35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, Calif., September, 1995; and American Society for Microbiology: Washington, D.C., 1995, Abstract No. F227. The disclosed reactions use either n-butyllithium, lithium diusopropylamide, or lithium hexamethyldisilazide as the base to generate the nucleophilic anion or the carbamate over a temperature range of −78° C. to −40° C., followed by addition of the glycidyl butyrate at −78° C., and warming to 20-25° C. to produce the 5-(R)-hydroxymethyl-oxazolidinones wherein the ester is cleaved during the reaction.
As stated previously, the 5-(R)-hydroxymethyl-oxazolidinones then are aminated and acylated in subsequent steps. For example, International Publication WO95/07271 discloses the ammonolysis of 5-(R)-methylsulfonyloxymethyl-oxazolidinones. Likewise, U.S. Pat. No. 4,476,136 discloses a method of transforming 5-hydroxymethyl-oxazolidinones to the corresponding 5-(S)-aminomethyl-oxazolidinones (X) by treatment with methanesulfonyl chloride, followed by potassium phthalimide, then followed by hydrazine.
J. Med. Chem.,
32, 1673 (1989) and
Tetrahedron,
45, 1323 (1989) disclose a method of transforming 5-hydroxymethyl-oxazolidinones into the corresponding 5-(S)-acetamidomethyl-oxazolidinones by treating with methanesulfonyl chloride or tosyl chloride, followed by the stepwise addition of sodium azide, trimethylphosphite, or platinum dioxide/hydrogen, and acetic anhydride or acetyl chloride to give the desired 5-(S)-acetamidomethyl-oxazolidinone. Likewise, U.S. provisional application Serial No. 60/015,499 discloses a method of preparing 5-(S)-hydroxymethyl-oxazolidinone intermediates, as well as a process to convert these intermediates into 5-aminomethyl-oxazolidinone intermediates which can be acylated to produce pharmacologically active 5-(S)-acetamidomethyl-oxazolidinones. U.S. Pat. No.3,654,298 discloses the synthesis of 5-alkoxymethyl-3-aryl-oxazolidinones by sodium ethoxide induced cyclization of chlorocarbamates.
The second method (Scheme B) involves condensation of an aromatic carbamate (a) or isocyanate (b) with a protected nitrogen (NP)-containing three-carbon reagent to provide an oxazolidinone having the desired amine functionality at the 5-position (e). For example,
J. Med. Chem.,
33, 2569 (1990)
discloses the condensation of an isocyanate (b) with racemic glycidyl azide (c, NP═N
3
) to provide a racemic 5-azidomethyl-oxazolidinone (e). Two subsequent steps are required to convert the racemic azidomethyl-oxazolidinone into a racemic 5-acetamidomethyl-oxazolidinone (e, NP═NHAc), which has antibiotic activity.
International Publication WO99/24393 discloses the reaction of a benzylcarbamoyl amine with three carbon reagents containing amines (NP═NH
2
), acetamides (NP═NHAc), benzalimines (NP═N═C—Ph), or phthalimides. Likewise,
Tetrahedron Letters,
37, 7937-40 (1996) discloses a synthesis of acetamidomethyl-oxazolidinones involving the process of condensing a carbamate with 1.1 equivalents of n-butyl lithium (tetrahydrofuran (THF), −78° C.), followed by 2 equivalents of S-glycidylacetamide (a, NP=—NHAc), to give the corresponding 5-(S)-acetamidomethyl-oxazolidinone (e). The S-glycidylacetamide can be made by the procedure disclosed in Jacobsen et. al.,
Tet. Lett.
37, 7937 (1996).
The S-enantiomer of epoxide (c) (Scheme B, NP═NHCO
2
t-Bu) is well known in the literature, and has been used to prepare oxazolidinones as disclosed in International Publications WO 99/40094 and WO 99/3764, and German Patent application DE 19802239 A1, although by different routes than that shown in Scheme B. The (S)-epoxide (c) has been prepared by a hydrolytic kinetic resolution of the racemic epoxide as disclosed in WO 00/09463, and from R-glycidol as disclosed in WO 93/01174 and
J. Med. Chem.,
37, 3707 (1994). However, the (S)-epoxide has not been prepared in crystalline form.
The prior art is silent with respect to the use of carbamates (a) or isocyanates (b) in condensations with tert-butylcarbamoyl-, (BOC), or other carbamoyl-protected nitrogen-c

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