Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2000-05-18
2002-04-30
Raymond, Richard L. (Department: 1614)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C549S030000
Reexamination Certificate
active
06380388
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to commercial processes for the production of antiviral 1,3-oxathiolane nucleoside analogues including, but not limited to, cis(−)-4-amino-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone (emtricitabine, (−)-FTC, 1) and cis(−)-4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone (lamivudine, 3TC, 2). In one embodiment, the present invention relates to novel crystalline intermediates useful in the preparation of antiviral 1,3-oxathiolane nucleoside analogues in enantiomerically enriched form, and to commercial processes for their preparation.
BACKGROUND OF THE INVENTION
Nucleoside analogues are well known therapeutic agents, often displaying antiviral activity against retroviruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and human T-lymphotropic virus (HTLV). Generally speaking, nucleoside analogues can exist in two distinct stereoisomeric forms, known as cis and trans diastereomers. However, it is usually only the cis diastereomers of nucleoside inhibitors which display significant biological activity. Each cis and trans diastereomer is further composed of two pairs of stereoisomers, known as enantiomers. For many nucleoside analogues, including (−)-FTC and 3TC, the antiviral activity is significantly more pronounced in one of two possible enantiomeric forms of the cis diastereomer. In the case of (−)-FTC and 3TC, the levorotatory, or (−), enantiomer is the major contributor to the desired antiviral activity, as is disclosed in the following: U.S. Pat. Nos. 5,486,520; 5,539,116;
J. Org. Chem.
1992, 57, 2217-2219;
J. Med. Chem.
1993, 36, 181-195. Consequently, commercial manufacturing methods which are capable of producing nucleoside analogues in enantiomerically enriched form are of primary importance for the continued chemical and pharmaceutical development of such 1,3-oxathiolane nucleoside analogues.
The prior art discloses several methods for the preparation of 1,3-oxathiolane nucleoside analogues by processes which do not address the issue of enantioselectivity and, consequently, provide 1,3-oxathiolane nucleoside analogues as mixtures of enantiomers. Examples of such methods for obtaining 1,3-oxathiolane nucleoside analogues as diastereomeric and/or enantiomeric mixtures may be found in U.S. Pat. No. 5,204,466 “Method and Compositions for the Synthesis of BCH-189 and Related Compounds”, U.S. Pat. No. 5,210,085 “Method for the Synthesis, Compositions, and Use of 2′-Deoxy-5-fluoro-3′-thiacytidine and Related Compounds”, U.S. Pat. No. 5,466,806 “Process for Preparing Substituted 1,3-Oxathiolanes with Antiviral Properties” and U.S. Pat. No. 5,763,606 “Stereoselective Synthesis of Nucleoside Analogues Using A Bicyclic Intermediate”. Such processes have obvious limitations for commercial production purposes since the degree of enantioselectivity imparted into the finished active compound is marginal or absent.
On the other hand, U.S. Pat. No. 5,728,575 (“Method of Resolution of 1,3-Oxathiolane Nucleoside Enantiomers”) describes the preparation of nucleoside analogues, including (−)-FTC, in enantiomerically enriched form using a process involving enzyme mediated hydrolysis of a racemic mixture of nucleoside analogue esters. Enzymes employed are selected from the group consisting of pig liver esterase (PLE), pig pancreatic lipase (PPL), and substillisin. Esters are selected from the group consisting of acetate, propionate, butyrate, and pentanoate. The enzyme preferentially catalyzes the hydrolysis of an ester group in one of the two enantiomers, allowing a subsequent separation of unhydrolyzed nucleoside analogue ester and hydrolyzed nucleoside analogue. The process can be depicted as follows:
While the degree of recognition displayed by the enzyme for hydrolysis of one enantiomer over the other is very high, the resolution of enantiomers occurs at a very late stage in the overall process to the nucleoside analogue. This is an undesirable situation from a commercial production and economic standpoint because the resolution of enantiomers of the 1,3-oxathiolane nucleoside analogue occurs in the penultimate step of the process therefore results in, at minimum, fifty percent loss of the batch material. Secondly, enzymatic hydrolysis occurs on the undesired enantiomer preferentially, which necessitates a subsequent hydrolysis step on the separated desired enantiomer to completely form the desired nucleoside analogue. The consequences of this additional step are increased manufacturing overhead costs and loss of material through non-stoichiometric conversion. Furthermore, the possibility of recovering the undesired enantiomer and recycling it into the process to form the desired enantiomer becomes highly improbable to complete in an economical manner due to the inherent challenge of simultaneously epimerizing the two stereocentres from one cis conformation to the second (desired) cis conformation. Finally, the introduction of impurities in the finished product, originating from the enzyme preparation itself, is a major concern since the enzymatic resolution occurs in the penultimate step of the process.
Published PCT application WO 00/09494 discloses processes for the preparation of 1,3-oxathiolane nucleoside analogues which, when used in conjunction with the prior art, may be used to produce enantiomerically enriched 1,3-oxathiolane nucleoside analogues, including (−)-FTC.
U.S. Pat. No. 5,663,320 “Processes for the Diastereoselective Separation of Nucleoside Analogue Synthetic Intermediates”, U.S. Pat. No 5,684,164 “Processes for Preparing Substituted 1,3-Oxathiolanes With Antiviral Properties”, U.S. Pat. No. 5,693,787 “Intermediates in the Synthesis of 1,3-Oxathiolanyl Cytosine Nucleoside Analogues”, U.S. Pat. No. 5,696,254 “Processes for the Diastereoselective Synthesis of Nucleoside Analogues” U.S. Pat. No. 5,744,596 “Nucleoside Analogues and Synthetic Intermediates”, and U.S. Pat. No. 5,756,706 “Processes for the Diastereoselective Synthesis of Nucleoside Analogues”, describe processes for the enantioselective preparation of nucleoside analogues, including 1,3-oxathiolane nucleoside analogues. For example, one such process involves the use of enantiomerically enriched intermediates of the form
where R is a chiral auxiliary, and L is a leaving group. Preferred chiral auxiliaries in this case are selected from (+) and (−)-menthol and (+) and (−)-norephedrine. Prior to the conversion of such intermediates into 1,3-oxathiolane nucleoside analogues, reduction of the substituted carbonyl group to a hydroxymethyl group is required. This may lead to undesired racemization of the 1,3-oxathiolane nucleoside analogue during chemical reduction thus resulting in economic and material loss, and necessitating further processing to arrive at material of pharmaceutically acceptable purity.
An improved method for the obtention of 1,3-oxathiolane nucleoside analogues is therefore required as there continues to exist an ongoing requirement to produce the therapeutically important antiviral agents, such as (−)-FTC and 3TC, using safe, efficient, and economical commercial processes avoiding the drawbacks of the prior art discussed above.
It is therefore an object of the invention to provide an improved process for obtaining 1,3-oxathiolane nucleoside analogues and intermediates useful in the obtention thereof which overcomes the disadvantages of the prior art.
Furthermore, it is an object of the invention to provide novel intermediates useful in the process for obtaining the 1,3-oxathiolane nucleoside analogues and intermediates useful in the obtention thereof. It is still a further object of the invention to provide novel intermediates useful in the manufacture of the 1,3-oxathiolane nucleoside analogues. It is still a further object of the invention to provide a process for the manufacture of the novel intermediates in enantiomerically enriched form.
Further and other
Horne Stephen E.
Murthy K. S. Keshava
Radatus Bruno K.
Reddy Gurijala V.
Senanayake Chandrawansha B. W.
Brantford Chemicals Inc.
Hughes Ivor M.
Hughes Neil H.
McKenzie Thomas
Raymond Richard L.
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