Process for producing dihydro-2H-pyran derivatives
Disclosed is a process for preparing dihydro-2H-pyran derivatives of formula I: wherein R 1 and R 2 are defined herein. The process of the invention provides the compound of formula I in concise cascade reactions and in one pot. The compound of formulae I prepared by the process of the invention and its further transformed derivatives are useful for making pharmaceutical composition for the treatment of proliferative diseases.
1. A process for preparing dihydro-2H-pyran derivatives of formula I:
wherein
R 1 is alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl, which is optionally substituted with one or more substituent selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, nitro, cyano, halogen, hydroxyl, mono- or polyhalo alkyl, mono- or polyhalo alkoxy and phenyl; and
R 2 is alkyl or benzyl;
which process comprises reacting aldehydes of the following formula:
R 1 —CHO
wherein
R 1 is as defined in the above;
with pyruvates of the following formula:
wherein
R 2 is as defined in the above;
in the presence of catalytic amount of β-proline.
2. The process according to claim 1 , wherein the reaction is carried out in a solvent, preferably acetonitrile.
3. The process according to claim 1 , wherein the catalytic amount is about 5 mol % to about 50 mol %, preferably about 10 mol % to about 25 mol %, based on the aldehydes.
4. A process for preparing cyclohexane derivatives of formula III:
wherein R 1 is alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl, which is optionally substituted with one or more substituent selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, nitro, cyano, halogen, hydroxyl, mono- or polyhalo alkyl, mono- or polyhalo alkoxy and phenyl; and
R 2 is alkyl or benzyl;
which process comprises reacting the dihydro-2H-pyran derivatives of formula I according to claim 1 with nitromethane in the presence of a base.
5. The process according to claim 4 , wherein the base is (−)-cinchonidine, DMAP, or triethylamine.
6. A process for preparing dihydro-2H-pyran derivatives of formula V:
wherein
R 1 is alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl, which is optionally substituted with one or more substituent selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, nitro, cyano, halogen, hydroxyl, mono- or polyhalo alkyl, mono- or polyhalo alkoxy and phenyl; and
R 2 is alkyl or benzyl; and
R 3 is alkyl, cycloalkyl, aryl or heteroaryl, which is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, nitro, cyano, halogen, hydroxyl, mono- or polyhalo alkyl, mono- or polyhalo alkoxy and phenyl; which process comprises reacting the dihydro-2H-pyran derivatives of formula I according to claim 1 with amines of the following formula:
R 3 —NH 2
wherein R 3 is as defined in the above.