PROCESS FOR PRODUCING DIHYDRO-2H-PYRAN DERIVATIVES

20160251328

15/148716

May 06, 2016

Disclosed is a process for preparing dihydro-2H-pyran derivatives of formula I: [chemical expression included] wherein R1 and R2 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.

OKINAWA INSTITUTE OF SCIENCE AND TECHNOLOGY SCHOOL CORPORATION (Okinawa, JP)

1. A process for preparing dihydro-2H-pyran derivatives of formula I: [chemical expression included] wherein R1 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 R2 is alkyl or benzyl; which process comprises reacting aldehydes of the following formula: R1—CHO wherein R1 is as defined in the above; with pyruvates of the following formula: [chemical expression included] wherein R2 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.

4-5. (canceled)

6. A process for preparing cyclohexane derivatives of formula III: [chemical expression included] wherein R1 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 R2 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.

7. The process according to claim 6, wherein the base is (−)-cinchonidine, DMAP, or triethylamine.

8-9. (canceled)

10. A process for preparing dihydro-2H-pyran derivatives of formula V: [chemical expression included] wherein R1 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 R2 is alkyl or benzyl; and R3 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: R3—NH2 wherein R3 is as defined in the above.

11-15. (canceled)

07

edspap.20160251328