Preparation of 3-hydroxy-3,6-dimethylhexahydrobenzofuran-2-one and derivatives thereof
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.
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),
and wherein said α-hydroxylactone is the compound of formula IV,
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 O 3 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),
10. A method of producing mint lactone, the compound of formula (V),
comprising the steps of:
(a) forming a cyanohydrin intermediate from a hydroxy-ketone, wherein the hydroxy-ketone is the compound of formula (VI),
via cyanohydrin formation, wherein said cyanohydrin intermediate comprises a nitrile;
(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 the compound of formula IV,
and
(c) eliminating the hydroxyl group of said α-hydroxylactone of formula (IV) to yield 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.
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.