Synthesis of 2'-fluoro-6'-methylene-carbocyclic adenosine (fmca) and 2'-fluoro-6'-methylene-carbocyclic guanosine (fmcg)
AssigneeUniversity of Georgia Research Foundation, Ionc.
InventorsChung K. Chu, Varughese Alexander Mulamootttil, Ram C. Mishra, Uma Sharan Singh
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Abstract
The invention provides a new convergent approach for the synthesis of 2′-fluoro-6′- methylene-carbocyclic adenosine (FMCA) and 2′-fluoro-6′-methylene-carbocyclic guanosine (FMCG) from a readily available starting material in eight steps. An efficient and practical methodology for stereospecific preparation of a versatile carbocyclic key intermediate, (1S,3R,4R)-3-tert-butoxy-4-(tert-butoxymethyl)-2-fluoro-5-methylenecyclopentanol (compound 8 of scheme 1A or a) in only six (6) steps is also provided. Prodrugs of these compounds are also prepared.
Claims29
A process for synthesizing compound 8:
- from substituted pentanone derivative 1:
- comprising introducing a methylene group in a position α to the keto group of compound 1 by reacting compound 1 with a strong base in solvent at low temperature followed by the addition of Eschenmoser Salt and thereafter, iodomethane to provide compound 2A below:
- stereoselectively reducing the keto group of compound 2A using sodium borohydride in the presence of a Lewis acid (preferably, CeCl3) at reduced temperature to produce compound 2
- Or alternatively, forming compound 2 from compound by reacting compound 1 with paraformaldehyde in the presence of diisopropyl ammonium trifluoroacetate salt and diisopropylamine in solvent to produce compound 2A followed by stereoselectively reducing the keto group of compound 2A using sodium borohydride in the presence of a Lewis acid in solvent at reduced temperature to produce compound 2;
- Reacting compound 2 with AlMe3 in solvent produce compound 3
- Reacting compound 3 with tert-butyldiphenylsilyl chloride in weak base to produce compound 4;
- Fluorinating compound 4 with a fluorinating agent (preferably, diethylaminosulfur trifluoride DAST) to stereoselectively fluorinate the 2′ position to produce compound 7
- which is then deprotected to remove the silyl protecting group using tetrabutylammonium fluoride to provide compound 8,
- wherein the synthesis of compound 8 may be conducted in a single pot or in steps, with optimal separation and/or purification of any one or more steps to produce any one or more of compounds 2A, 2, 3, 4, 7 and 8.
A process to synthesizing compound 8:
- from substituted pentanone derivative 1:
- Comprising reacting compound 1 with paraformaldehyde in the presence of diisopropyl ammonium trifluoroacetate salt and diisopropylamine in solvent to produce compound 2A
- followed by stereoselectively reducing the keto group of compound 2A using sodium borohydride in the presence of a Lewis acid in solvent at reduced temperature to produce compound 2;
- Reacting compound 2 with AlMe3 in solvent to produce compound 3
- Reacting compound 3 with tert-butyldiphenylsilyl chloride in weak base to produce compound 4;
- Fluorinating compound 4 with diethylaminosulfur trifluoride (DAST) to stereoselectively fluorinate the 2′ position of compound 4 to produce compound 7
- which is then deprotected to remove the silyl protecting group to provide, compound 8
- wherein the synthesis of compound 8 may be conducted in a single pot or in steps, with optional separation and/or purification of any one or more steps to produce compounds 2A, 2, 3, 4, 7 and/or 8.
A process for preparing the compound 2′-Fluoro-6′-Methylene-Carbocyclic Adenosine (FMCA) compound 10 from compound 8
- Comprising condensing an amine protected 6-amino purine compound according to the chemical structure:
- where P represents one or two amine protecting groups (preferably two BOC groups) onto compound 8 in the presence of tiphenylphosphine and diisopropylazidocarboxylate (DIAD) in solvent to produce compound 8P
- where P represents one or two amine protecting groups (preferably, two BOC groups);
- and subjecting compound 8P to deprotection to produce compound 10 (FMCA)
- wherein the synthesis may be conducted in a single pot or in steps, with separation and/or purification to produce either of compounds 8P and compound 10.
A process for preparing the compound 2′-Fluoro-6′-Methylene-Carbocyclic Adenosine (FMCA) compound 10 from compound 8
- Comprising condensing a di-Boc protected 6-amino purine compound according to the chemical structure:
- onto compound 8 in the presence of triphenylphosphine and diisopropylazidocarboxylate (DIAD) in solvent to produce compound 9
- and subjecting compound 9 to deprotection to produce compound 10 (FMCA)
- wherein the synthesis may be conducted in a single pot or in steps, with separation and/or purification to produce compound 9 and/or compound 10.
A process for preparing the compound 2′-Fluoro-6′-Methylene-Carbocyclic Guanosine (FMCG) compound 11 from compound 8
- Comprising condensing an amine protected 6-amino purine compound according to the chemical structure:
- where P represents one or two amine protecting groups onto compound 8 in the presence of triphenylphosphine and diisopropylazidocarboxylate (DIAD) in solvent to produce compound 9P
- where P represents one or two amine protecting groups;
- and
- subjecting compound 9P to deprotection and conversion of the 6-chloro group to a keto group to produce compound 11 (FMCG)
- wherein the synthesis may be conducted in a single pot or in steps, with separation and/or purification to produce either of compounds 9P and/or compound 11.
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A method of producing a prodrug form of FMCA compound 10 or FMCG compound 11 comprising reacting compound 10 or compound 11 with a chlorophenylphosphoryl-L-alaninate reactant according to the chemical structure:
- where R is a C1-C20 alkyl group in the presence of weak base in solvent to produce the 5′-0-phosphoramidate prodrug forms of FMCA and FMCG:
- where R is C1-C20 alkyl group, or
- a pharmaceutically acceptable salt thereof.
Any one or more of compounds 2A, 2, 3, 4, 5, 6, 7, 8, 8P, 9, 9P, 9G, 10, 11, 12 or 12G 10P hereof or a salt thereof.
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A method of producing compound 2
- from substituted pentanone derivative 1:
- comprising introducing in a first step a methylene group in a position α to the keto group of compound 1 by reacting compound 1 with paraformaldehyde in the presence of diisopropyl ammonium trifluoroacetate salt and diisopropylamine in solvent, followed by reducing the compound obtained from the first step using a reducing agent in the presence of a Lewis acid at reduced temperature to produce compound 2
Dependencies are inferred from the claim text.