Process for the Preparation of (R)-4,4-Dialkoxy-Pyran-3-Ols Such as (R)-4,4-Dimethoxy-Pyran-3-Ol
The present invention is concerned with novel processes for the preparation of (R)-4,4-dimethoxy-pyran-3-ol. This compound is useful as an intermediate in the synthesis of compounds which possess pharmacological activity including CCR2 antagonists.
1 . A process for the preparation of (R)-4,4-dialkoxy-pyran-3-ol of the formula:
which comprises: reacting 4,4-dialkoxy-pyran-3-one of the formula:
where R1 is independently C1-4alkyl, and where R2 is independently C 1 -4alkyl, with a ketone reductase in the presence of nicotinamide adenine dinucleotide phosphate and a cofactor recycling system; to give a (R)-4,4-dialkoxy-pyran-3-ol of the formula:
2 . A process for the preparation of (R)-4,4-dimethoxy-pyran-3-ol of the formula:
which comprises: reacting 4,4-dimethoxy-pyran-3-one of the formula:
with a ketone reductase in the presence of nicotinamide adenine dinucleotide phosphate and a cofactor recycling system; to give (R)-4,4-dimethoxy-pyran-3-ol of the formula:
3 . The process of claim 2 wherein said ketone reductase is selected from KRED101, KRED102, KRED105, KRED107 and KRED 108.
4 . The process of claim 2 wherein the ketone reductase is KRED 101.
5 . The process of claim 2 wherein the ketone reductase is present at a concentration of about 0.095 to 0.105 g/L.
6 . The process of claim 2 wherein the ketone reductase is present at an activity of about 900 U to 1000 U.
7 . The process of claim 2 wherein the substrate 4,4-dimethoxy-pyran-3-one is present at a concentration of about 95 to 105 g/L.
8 . The process of claim 2 wherein the cofactor recycling system comprises glucose and a glucose dehydrogenase.
9 . The process of claim 8 wherein the cofactor recycling system further comprises nicotinamide adenine dinucleotide phosphate.
10 . The process of claim 9 wherein the nicotinamide adenine dinucleotide phosphate is present at a concentration of about 0.12 g/L.
11 . The process of claim 8 wherein glucose is present at a concentration of about 120 to 140 g/L.
12 . The process of claim 8 wherein the glucose dehydrogenase is present at a concentration of about 0.28 to 0.33 g/L.
13 . The process of claim 2 wherein the reaction mixture comprises a phosphate buffer.
14 . The process of claim 2 wherein the reaction mixture further comprises a solvent selected from methanol, ethanol, IPA, acetonitrile and DMSO.
15 . The process of claim 2 comprising the further step of extracting the reaction mixture with a solvent selected from toluene, alcohol, acetonitrile, methyl ethyl ketone, ethyl acetate, isopropyl acetate, and THF.
16 . The process of claim 15 wherein the reaction mixture is extracted with acetonitrile at a temperature of about 20° C. to 30° C.
17 . The process of claim 15 wherein the reaction is extracted with acetonitrile, and wherein the organic layer is dried with toluene.
18 . The process of claim 15 comprising the further step of concentrating the solvent by vacuum distillation.