Process for the preparation of (3R)-hydroxybutyl (3R)-hydroxybutyrate by enzymatic enantioselective reduction employing

1. A process for producing (3R)-hydroxybutyl (3R)-hydroxybutyrate of formula (I):

which process comprises submitting, to enantioselective reduction, a compound of the following formula (II), (Ill) or (IV):

2. A process according to claim 1 which further comprises producing the compound of formula (II) by treating 4-hydroxybutan-2-one of formula (V):

with diketene of formula (VI):

3. A process according to claim 1 which further comprises producing the compound of formula (II) by treating 4-hydroxybutan-2-one of formula (V):

with 2,2,6-trimethyl-4H-1,3-dioxin-4-one of formula (IX):

in the presence of a transesterification reagent.

4. A process according to claim 1 , which further comprises producing the compound of formula (II) by treating 4-hydroxybutan-2-one of formula (V):

with a compound of formula (X):

wherein R is halo or —OR 1 , wherein R 1 is selected from hydrogen, unsubstituted or substituted C 1-6 alkyl and —C(O)R 2 , wherein R 2 is unsubstituted or substituted C 1 - 6 alkyl or -alk-C(O)—R 3 , wherein alk is unsubstituted or substituted C 1-4 alkylene and R 3 is unsubstituted or substituted C 1-4 alkyl,

in the presence of an esterification reagent when R is —OR 1 and R 1 is hydrogen, or in the presence of a transesterification reagent when R is —OR 1 and R 1 is unsubstituted or substituted C 1-6 alkyl.

5. A process according to claim 1 which further comprises producing the compound of formula (III) by treating (R)-1,3-butanediol of formula (VII):

with diketene of formula (VI):

and isolating the compound of formula (III) from the resulting mixture of acylated products.

6. A process according to claim 1 which further comprises producing the compound of formula (III) by treating (R)-1,3-butanediol of formula (VII):

with 2,2,6-trimethyl-4H-1,3-dioxin-4-one of formula (IX):

in the presence of a transesterification reagent.

7. A process according to claim 1 which further comprises producing the compound of formula (III) by treating (R)-1,3-butanediol of formula (VII):

with a compound of formula (X):

wherein R is halo or —OR, wherein R 1 is selected from hydrogen, unsubstituted or substituted C 1-6 alkyl and —C(O)R 2 , wherein R 2 is unsubstituted or substituted C 1-6 alkyl or -alk-C(O)—R 3 , wherein alk is unsubstituted or substituted C 1-4 alkylene and R 3 is unsubstituted or substituted C 1-4 alkyl,

in the presence of an esterification reagent when R is —OR and R 1 is hydrogen, or in the presence of a transesterification reagent when R is —OR and R 1 is unsubstituted or substituted C 1-6 alkyl.

8. A process according to claim 1 which further comprises producing the compound of formula (IV) by treating 4-hydroxybutan-2-one of formula (V):

with (R)-4-methyloxetan-2-one of formula (VIII):

9. A process according to claim 1 wherein the enantioselective reduction is carried out using an enzyme.

10. A process according to claim 9 wherein the enzyme is a ketoreductase (KRED) or an alcohol dehydrogenase (ADH).

11. A process according to claim 9 wherein the enzyme is the alcohol dehydrogenase from Lactobacillus brevis (ADH-LB).

12. A process according to claim 9 wherein the step of submitting the compound of formula (II), (Ill) or (IV) to enantioselective reduction is carried out at a pH which is less than 7.0 but at least 4.0.

13. A process according to claim 9 wherein the step of submitting the compound of formula (II), (Ill) or (IV) to enantioselective reduction is carried out at a pH of from 5.0 to 6.0.

14. A process according to claim 1 wherein the enantioselective reduction is carried out using a chemical asymmetric reduction process.

15. A process for producing (3R)-hydroxybutyl (3R)-hydroxybutyrate of formula (I):

which process comprises:

(a) treating 4-hydroxbutan-2-one of formula (V):

with diketene of formula (VI):

to produce a compound of formula (II):

and

(b) submitting the compound of formula (II) to enantioselective reduction.

16. A process for producing (3-R) -hydroxybutyl (3-R)-hydroxybutyrate of formula (I):

which process comprises:

(a) treating (R)-1,3-butanediol of formula (VII):

with diketene of formula (VI):

and isolating a compound formula (III) from the resulting mixture of acylated products:

and

(b) submitting the compound of formula (III) to enantioselective reduction.

17. A process for producing (3-R-)hydroxybutyl (3J[yen])-hydroxybutyrate of formula (I):

which process comprises:

(a) treating 4-hydroxybutan-2-one of formula (V):

with (R)-4-methyloxetan-2-one of formula (VIII):

to produce a compound of formula (IV):

and

(b) submitting the compound of formula (IV) to enantioselective reduction.