Reaction sequence for the synthesis of nootkatone, dihydronootkatone, and tetrahydronootkatone

Patent metadata

Field	Value
Publication number	US-10435344-B2
Application number	US-201615781914-A
Country	US
Kind code	B2
Filing date	Dec 8, 2016
Priority date	Dec 10, 2015
Publication date	Oct 8, 2019
Grant date	Oct 8, 2019

Abstract

An inexpensive, stereoselective synthesis for nootkatone, tetrahydronootkatone, and their derivatives is disclosed utilizing ozonolysis. The starting materials used in the synthesis are inexpensive and the reactions are commercially feasible and amenable to scaling up. The principal starting material, (−)-β-Pinene, is on the GRAS list (generally recognized as safe).

First claim

What is claimed is:

1. A method of synthesizing nootkatone comprising the steps of:
ozonolysis of Compound 6

to produce crude Compound 7

without purification;
converting crude Compound 7 to produce Compound 8

and
converting compound 8 to nootkatone.

2. The process of claim 1 , wherein the ozonolysis step comprises
oxidizing Compound 6 with ozone/O 2 in MeOH; and
adding (CH 3 ) 2 S to produce Compound 7.

3. The process of claim 1 , wherein the ozonolysis step comprises
oxidizing Compound 6 with ozone/O 2 in CH 2 Cl 2 ; and
adding AcOH and zinc to produce Compound 7.

4. The process of claim 1 , further comprising the steps of:
ozonolysis of β-pinene (Compound 1)

to produce crude nopinone (Compound 2)

without purification; and
converting crude nopinone to Compound 6

through intermediate steps.

5. The process of claim 4 , wherein the ozonolysis of β-pinene comprises
oxidizing β-pinene with ozone/O 2 in MeOH; and
adding (CH 3 ) 2 S to produce Compound 2.

6. The process of claim 4 , wherein the ozonolysis of β-pinene comprises
oxidizing β-pinene with ozone/O 2 in CH 2 Cl 2 ; and
adding AcOH and zinc to produce Compound 2.

7. A process of making a nootkatone derivative comprising the steps of:
ozonolysis of Compound 6

to produce crude Compound 7

without purification;
converting crude Compound 7 to produce Compound 8

and
converting compound 8 to nootkatone.

8. The process of claim 7 , wherein the ozonolysis step comprises
oxidizing Compound 6 with ozone/O 2 in MeOH; and
adding (CH 3 ) 2 S to produce Compound 7.

9. The process of claim 7 , wherein the ozonolysis step comprises
oxidizing Compound 6 with ozone/O 2 in CH 2 Cl 2 ; and
adding AcOH and zinc to produce Compound 7.

10. The process of claim 7 , further comprising the steps of:
ozonolysis of β-pinene (Compound 1)

to produce crude nopinone (Compound 2)

without purification; and
converting crude nopinone to Compound 6

through intermediate steps.

11. The process of claim 10 , wherein the ozonolysis step comprises
oxidizing β-pinene with ozone/O 2 in MeOH; and
adding (CH 3 ) 2 S to produce Compound 2.

12. The process of claim 1 , wherein the ozonolysis of Compound 6 comprises
oxidizing β-pinene with ozone/O 2 in CH 2 Cl 2 ; and
adding AcOH and zinc to produce Compound 2.

13. The process of claim 7 , wherein the nootkatone derivative is selected from the group consisting of isonootkatone, tetrahydronootkatone, 11,12-dihydronootkatone, 1,10-dihydronootkatone, nootkatol, and dihydronootkatone.

14. The process of claim 13 , wherein the nootkatone derivative is selected from the group consisting of isonootkatone, dihydronootkatone, and tetrahydronootkatone.

15. The process of claim 4 , wherein converting crude nopinone to Compound 6 comprises the steps of:
converting the crude nopinone to

converting

converting

converting

to Compound 6.

16. The process of claim 15 ,
wherein the crude nopinone is reacted with acetaldehyde and a base to produce

wherein

is reacted with methallyl chloride and a metal to produce

wherein

is subjected to Oxy-Cope rearrangement to produce

wherein

is reacted with a methyl halide and a base to produce Compound 6.

17. The process of claim 7 , wherein converting crude nopinone to Compound 6 comprises the steps of:
converting the crude nopinone to

converting

converting

converting

to Compound 6.

18. The process of claim 17 ,
wherein the crude nopinone is reacted with acetaldehyde and a base to produce

wherein

is reacted with methallyl chloride and a metal to produce

wherein

is subjected to Oxy-Cope rearrangement to produce

wherein

is reacted with a methyl halide and a base to produce Compound 6.

Assignees

• Laine Roger
• Univ Louisiana State

Inventors

• Laine Roger

Classifications

• C07C45/66

  by dehydration · CPC title

• C07C45/68

  by increase in the number of carbon atoms · CPC title

• C07C2602/28

  Hydrogenated naphthalenes · CPC title

• C07C45/512

  the singly bound functional group being a free hydroxyl group · CPC title

• A61K31/122

  having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin · CPC title