Organic compounds -- part of the class 532-570 series – Organic compounds – Pteroyl per se or having -c- – wherein x is chalcogen – bonded...
Reexamination Certificate
2001-06-18
2003-07-29
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Pteroyl per se or having -c-, wherein x is chalcogen, bonded...
C544S265000, C544S266000, C544S272000, C544S276000, C544S277000, C544S298000, C544S301000, C544S302000, C544S311000, C544S312000, C544S313000, C544S314000, C544S316000, C544S317000, C544S318000, C544S319000, C544S320000, C544S322000, C544S323000, C544S327000, C544S332000, C544S334000, C544S335000
Reexamination Certificate
active
06600044
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to commercial processes for the production of antiviral cis-1,3-oxathiolane and 1,3-dioxolane nucleoside analogues, some of which include, but are not limited to cis-(−)-4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone (1, Lamivudine, 3TC, BCH-189) and its 5-fluoro analogue, cis-(−)-4-amino-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone (2, Emtricitabine, (−)-FTC)). In particular, the present invention relates to a new and efficient process for converting the undesired trans-1,3-oxathiolane and 1,3-dioxolane nucleoside isomers to the desired cis-1,3-oxathiolane and 1,3-dioxolane nucleoside isomers by a method of anomerization/transglycosylation, and a highly efficient method of separating the anomeric mixture of 1,3-oxathiolane nucleoside analogues to their single anomers.
2,5-Disubstituted 1,3-oxathiolanes with pyrimidines or purine bases possess potent activities against the replication of the human immunodeficiency viruses (HIV) and hepatitis B virus (HBV). 3TC (1) has been approved as an antiviral for the treatment of HIV and HBV infection and its 5-fluoro analogue, (−)-FTC (2) is currently in advanced clinical trials for the same infections and shown promise as selective agent.
Generally speaking, there are two chiral centers in most of 1,3-oxathiolane and 1,3-dioxolane nucleosides and these nucleosides can exist in two distinct stereoisomeric forms, known as cis (&bgr;) and trans (&agr;) diastereomers. Each cis- or trans-diastereomer is further composed of a pair of stereoisomers, known as enantiomers, and one of which displays high activity against viral infection. For many nucleoside analogues, including 3TC and FTC, the antiviral activity is significantly more pronounced in one of two possible enantiomeric forms of cis-diastereomer. In the case of 3TC and FTC, the levorotatory, or (−), enantiomer is the major contributor to the desired antiviral activity, as is disclosed in the following: U.S. Pat. No. 5,047,407; PCT WO 91/17159; U.S. Pat. No. 5,486,520; U.S. Pat. No. 5,539,116
; J. Org. Chem
. 1992, 57, 2217-2219
; J. Med. Chem
. 1993, 36, 181-195. Therefore, it would be very advantageous if these antiviral nucleoside analogues, especially 3TC and (−)-FTC, could be produced industrially in a straight forward and in a highly diastereoselective and enatioselective manner. Processes which would allow efficient preparation of pharmacologically desirable diastereomerically enriched cis-isomer, or, separation of cis/trans mixtures to provide diastereomerically enriched cis-isomer, or, efficient conversion into diastereomerically enriched cis-isomer from a mixture of trans-diastereomer and cis-diastereomer, are highly desirable.
Generally speaking there are two main strategies that have been used in the prior art for obtaining the desired enantiomer from the coupling of an oxathiolane derivative and a base. In the first strategy, the oxathiolane derivative is racemic and it is coupled to a base using various known coupling procedures giving only the racemic cis-isomer or a mixture of isomers (cis/trans) which is separated using known diastereomeric techniques to give the desired racemic cis-isomer. The racemic cis-isomer is resolved using enzymatic or chiral chromatography techniques (see for example EP 517145, PCT WO 00/09494). In the second strategy, single enantiomer or enantiomerically enriched 1,3-oxathiolane derivatives are coupled to a base to give a mixture of cis/trans-diastereomers, which can be separated using known diastereomeric techniques (see for example PCT W095/29174, PCT WO 00/09494).
The first strategy is not attractive because the resolution is performed at the end of the process and guarantees that 50% of the product would be the unwanted enantiomer which could not be easily converted to the desired enantiomer since two chiral centers would have to be inverted.
An advantage of the second strategy is that the resolution at the C-2 position of 1,3-oxathiolane derivatives occurs early in the process. Although an anomeric mixture may result where up to 50% of the product could be the unwanted trans-isomer, the possibility of converting the trans-isomer to the cis-isomer via anomerization/trans-glycosilation stands a much better chance of success than what would be needed in the first strategy since only one chiral center needs to be inverted. The second strategy could give a theoretical yield of 100% after the coupling step.
Nucleoside anomerization employing protic acids or Lewis acids has been applied to a wide variety of nucleosides and includes for example: 2M HCl, see F. Seela and H. D. Winkler, in “2-Amino-7-&bgr;-D-arabinofuranosyl-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine: a facile preparation and anomerization of a 7-deazapurine nucleoside” (
Carbohydrate Research
, 1983, 118, 29-53); 1M HBr, see J. Cadet,
Tetrahedron Lett
., 1974, 867-870; NaI/HOAc, see J. Matulic-Adamic, et. al., in “Stereochemical features of the anomerizations in the 5,6-dihydrothymine nucleoside series” (
J. Chem. Soc. Perkin Trans
. 1, 1988, 2681-2686); 2N HClO
4
, see J. Cadet and R. Teoule, in “Nucleic acid hydrolysis. I. Isomerization and anomerization of pyrimidic deoxyribonucleosides in an acidic medium” (
J. Am. Chem. Soc
., 1974, 96, 6517-6519); Ac
2
O/H
2
SO
4
, see R. T. Walker et. al., in “A mild procedure for the anomerization of 2′-deoxynucleosides” (
Tetrahedron Lett
., 1993, 34, 6779-6782) and R. T. Walker et. al., in “Anomerisation process” (PCT WO 94/05686); Lewis acids, see D. Thacker and T. L. V. Ulbricht, in “General Lewis acid catalysis of glycoside anomerization and O→N-glycosyl rearrangement” (
Chem. Commun
. 1967, 122-123); AcOH, see L. N. Beigelman et. al., in “Epimerization during the acetolysis of 3-O-acetyl-5-O-benzoyl-1,2-O-isopropylidene-3-C-methyl-&agr;-D-ribofuranose. Synthesis of 3′-C-methylnucleosides with the &bgr;-D-ribo-and &agr;-D-arabino configurations” (
Carbohydr. Res
. 1988, 181, 77-88). This type of anomerization involves acid catalyzed sugar ring opening, forming a carbon cation at the anomeric carbon and cyclization to form the anomeric mixture of the nucleosides. This method is not suitable for 1,3-oxathiolane nucleoside analogues since the C-2 position of 1,3-oxathiolane ring could be epimerized under the reaction condition, which has been confirmed by Charron, et al. in “Recycling of an undesired trans-[1,3]-oxathiolane nucleoside analogue by epimerization” (82
nd
Canadian Institute for Chemistry Conference, Organic Chemistry Abstract #530, May 30-Jun. 2, 1999, Toronto, Canada).
Base mediated anomerization has also been reported such as in, for example, 1:1 4N aqueous NaOH/Methanol; see V. W. Armstrong, et. al., in “The base catalysed anomerisation of &bgr;-5-formyluridine; crystal and molecular structure of &agr;-formyluridine” (
Nucleic Acid Res
., 1976, 3, 1791-1810); 2N aqueous NaOH, T. Ueda, et. al., in “Synthesis of 5-alkyl-and 5-acyl-uridines via 6-mercaptouridine (nucleosides and nucleotides. XVII)” (
Heterocycles
, 1977, 8, 427-432); anhydrous LiOH or KOH/MeOH, T. C. Britton et al., in “Process for anomerizing nucleosides” (EP 587364). This method may not be suitable for 1,3-oxathiolane systems since the 2-hydroxymethyl branch could also be epimerized. This comes about because the methine (C-2 position of 1,3-oxathiolane ring) proton on the oxo,thio acetal system is acidic, can be abstracted and thereby can lead to epimerization.
Nucleoside trans-glycosylation has been accomplished by the treatment of protected nucleoside with a base in the presence of a Lewis acid. The method has been applied for preparing anomeric mixture of the nucleosides, for example, H. Vorbruggen et. al. in “Nucleoside Synthesis, XXII. Nucleoside Synthesis with Trimethylsilyl Triflate and Perchlorate as Catalysts” (
Chem. Ber
. 1981, 114 , 1234-1255) disclosed that a silylated &agr;-pyrimidinedione ribofuranosyl nucleoside was treated with TMS-triflate
Murthy K. S. Keshava
Reddy Gurijala V.
Senanayake Chandrawansha B. W.
Wang Zhi-xian
Brantford Chemicals Inc.
Ivor M. Hughes, Barrister & Solicitor, Patent & Trademark Agents
McKenzie Thomas
Raymond Richard L.
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