Preparation of 3-hydroxy-3,6-dimethylhexahydrobenzofuran-2-one and derivatives thereof

• US 10,399,954 B2
• Filed: 09/12/2016
• Issued: 09/03/2019
• Est. Priority Date: 09/11/2015
• Status: Active Grant

• Current Assignee: P2 Science, Inc.
• Original Assignee: P2 Science, Inc.
• Inventors: Foley, Patrick, Yang, Yonghua, Salam, Tania
• Primary Examiner(s): Rozof, Timothy R
• Application Number:
  US15/759,135
• Publication Number:
  US 20190002424A1
• Time in Patent Office: 1,086 Days
• CPC Class Codes: A23L 27/2052 having oxygen or sulfur as the only hetero atoms
• CPC Class Codes: A23L 27/88 Taste or flavour enhancing agents
• CPC Class Codes: A23V 2002/00 Food compositions, function of food ingredients or processes for food or foodstuffs
• CPC Class Codes: A61K 8/4973 with oxygen as the only hetero atom
• CPC Class Codes: A61Q 13/00 Formulations or additives for perfume preparations essential oils or perfumes per se C11B9/00
• CPC Class Codes: C07C 2601/16 the ring being unsaturated
• CPC Class Codes: C07C 45/66 by dehydration
• CPC Class Codes: C07C 49/543 to a six-membered ring
• CPC Class Codes: C07D 307/83 Oxygen atoms

Abstract

The present invention relates to the synthesis of intermediate compounds which can be used in the synthesis of mint lactone and related compounds, including 3,6-dimethylhexahydrobenzofuran-2-ones, isomers, and other derivatives.

Claims

1. A method of producing an α

-hydroxylactone, comprising the steps of;

(a) forming a cyanohydrin intermediate from a hydroxy-ketone, wherein the hydroxy-ketone is 1-(2-hydroxy-4-methyl-cyclohexyl)ethanone, via cyanohydrin formation, wherein said cyanohydrin intermediate comprises a nitrile; and

(b) hydrolyzing and lactonizing said nitrile of said cyanohydrin intermediate in the presence of an aqueous acid to generate an α

-hydroxylactone, wherein said α

-hydroxylactone is 3-hydroxy-3,6-dimethylhexahydrobenzofuran-2-one.

2. The method of claim 1, wherein said hydroxy-ketone is the compound of formula (VI),

3. The method of claim 1, wherein said cyanohydrin formation is performed using an aqueous mixture of a cyanide salt in the presence of ammonium chloride.

4. The method of claim 3, wherein said cyanide salt comprises sodium cyanide or potassium cyanide.

5. The method of claim 1, wherein the method further comprises the step of forming the hydroxy-ketone by treating isopulegol with O₃ to cleave the double bond, followed by quenching with a suitable quenching agent to generate the 1-(2-hydroxy-4-methyl-cyclohexyl)ethanone.

6. The method of claim 1, wherein the step of hydrolyzing said cyanohydrin intermediate is performed using a strong aqueous acid, wherein said aqueous acid comprises concentrated hydrochloric acid.

7. The method of claim 2, further comprising deoxygenating said α

-hydroxylactone compound of formula (IV) to yield a compound of formula (VII), a compound of formula (VIII) or a mixture thereof,

8. The method of claim 7, wherein said α

-hydroxylactone compound is deoxygenated via (a) chlorination, followed by (b) reduction with zinc in presence of an acid.

9. The method of claim 2, further comprising eliminating the hydroxyl group of said α

-hydroxylactone of formula (IV) to yield mint lactone, the compound of formula (V),

15. The method of claim 3, wherein a phase transfer catalyst is used to facilitate reaction with a nonaqueous phase during said cyanohydrin formation.

16. The method of claim 4, wherein a phase transfer catalyst is used to facilitate reaction with a nonaqueous phase during said cyanohydrin formation.

17. The method of claim 5, wherein the suitable quenching agent is sodium bisulfite.

18. The method of claim 7, wherein said deoxygenation is performed by reacting the compound of formula (IV) with a halogenating agent followed by reduction.

19. The method of claim 8, wherein the chlorination of step (a) is performed with thionyl chloride or phosphorus trichloride.

20. The method of claim 8, wherein the acid of the reduction of step (b) is acetic acid.

10. A method of producing mint lactone, the compound of formula (V),

11. The method of claim 10, further comprising hydrogenating the compound of formula (V) in the presence of a base to obtain a mixture comprising one or more compounds of the following formulas (VII) through (X):

12. The method of claim 11, wherein said base is introduced to said compound in advance of hydrogenation to promote ring-opening and isomerization.

13. The method of claim 10, wherein the step of eliminating the hydroxyl group is performed by (a) halogenating said α

-hydroxylactone, and eliminating the halogen, or (b) using a strong acid at an elevated temperature.

14. The method of claim 10, wherein the step of eliminating the hydroxyl group is performed using a strong acid at an elevated temperature, and wherein said strong acid is a phosphoric acid.