Process for preparing aminotetrahydropyrans

1. A process for preparing a compound of formula (I):

wherein Ar is phenyl optionally substituted with one to five R substituents,

each R is independently selected from halogen, (C 1 -C 4 )-alkyl, optionally substituted by halogen, or (C 1 -C 4 )-alkoxy, optionally substituted by halogen;

and P is a primary amine protecting group;

the process comprising:

a) reacting, in the presence of a basic species or a catalyst, a compound of formula (II):

wherein each R 1 and R 2 is independently hydrogen or (C 1 -C 4 )-alkyl,

or, wherein R 1 and R 2 , when taken together, form a (C 3 -C 7 )-cycloalkyl group;

with a compound of formula (III):

Ar—CHO  (III)

wherein Ar is as defined above;

to give a compound of formula (IV):

wherein Ar, R 1 and R 2 are as defined above; and

b) converting a compound of formula (IV) into a compound of formula (I).

2. The process according to claim 1 , wherein said basic species is selected from the group consisting of alkaline hydroxides, alkaline alkoxides, carbonates and tertiary amines.

3. The process according to claim 1 , wherein said catalyst is an organometallic complex of Cu(II) or Cu(I) with a chiral ligand.

4. The process according to claim 3 , wherein said chiral ligand is N-[(1S,2S,4S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-2-Pyridinemethanamine (Ligand F) or 2,4-di-tert-butyl-6((E)-((R)-(6-methoxy-quinolin-4-yl)((2R,4S,8R)-8-vinyl-quinuclidin-2-yl)-methyl-imino)-methyl)-phenol (Ligand G).

5. The process according to claim 1 , wherein step a is carried out in an organic solvent selected from the group consisting of methanol, ethanol, acetonitrile, diethoxyethane, 2,2-dimethoxypropane, 1,2-dimethoxyethane, dioxane, THF and toluene.

6. The process according to claim 1 , wherein step a is carried out at a temperature ranging from −20° C. to 20° C.

7. The process according to claim 1 , wherein each of R 1 and R 2 is a methyl group, or, wherein R 1 and R 2 , when taken together, form a cyclohexyl group.

8. The process according to claim 1 , wherein Ar is 2,5-difluorophenyl.

9. The process according to claim 1 , further comprising:

c) chemoselectively reducing the compound of formula (IV) to give an amino-alcohol of formula (V):

d) protecting the amino group to give a compound of formula (VI):

e) deprotecting the diol residue to give a compound of formula (VII):

f) regioselectively activating the primary hydroxy group to give a compound of formula (VIII):

wherein Z is an organo sulfonyl group;

g) chemoselectively protecting a secondary hydroxy group to give a compound of formula (IX):

wherein Z′ is a hydroxy protecting group;

h) performing a base-catalyzed cyclization to give a compound of formula (X):

and

i) deprotecting the secondary hydroxy group to give a compound of formula I.

10. The process according to claim 9 , wherein Z is a tosyl group and Z′ is a tetrahydropyranyl group.

11. The process according to claim 1 , further comprising reacting a compound of formula (I) with an oxidizing agent in a presence of a solvent to convert the compound of formula (I) into a compound of formula Ibis (Ibis):

12. The process according to claim 11 , further comprising converting a compound of formula (Ibis) to omarigliptin.

13. The process according to claim 9 , further comprising reacting a compound of formula (I) with an oxidizing agent in a presence of a solvent to convert the compound of formula (I) into a compound of formula (Ibis):

14. A compound of formula (IV):

wherein Ar is phenyl, optionally substituted with one to five substituents,

each R is independently selected from halogen, (C 1 -C 4 )-alkyl, optionally substituted by halogen, or (C 1 -C 4 )-alkoxy, optionally substituted by halogen; and

wherein each R 1 and R 2 is independently hydrogen or (C 1 -C 4 )-alkyl,

or wherein R 1 and R 2 , when taken together, form a (C 3 -C 7 )-cycloalkyl group.

15. A compound having a formula:

1-(2,5-difluorophenyl)-2-nitro-3((S)-1,4-dioxaspiro[4.5]decan-2-yl)propan-1-ol (IV)

or

1-(2,4,5-trifluorophenyl)-2-nitro-3-((S)-1,4-dioxaspiro[4.5]decan-2-yl)propan-1-ol (IV).

16. A process for preparing a compound of formula (IV):

wherein Ar is phenyl optionally substituted with one to five R substituents, each R is independently selected from halogen, (C 1 -C 4 )-alkyl, optionally substituted by halogen, or (C 1 -C 4 )-alkoxy, optionally substituted by halogen; wherein each R 1 and R 2 is independently hydrogen or (C 1 -C 4 )-alkyl, or, wherein R 1 and R 2 , when taken together, form a (C 3 -C 7 )-cycloalkyl group; the process comprising:

a) reacting, in the presence of a basic species or a catalyst, a compound of formula (II):

wherein R 1 and R 2 are as defined above;

with a compound of formula (III):

Ar—CHO  (III)

wherein Ar is as defined above.

17. The process according to claim 16 , wherein each of R 1 and R 2 is a methyl group or, wherein R 1 and R 2 when taken together, form a cyclohexyl group.

18. The process according to claim 16 , wherein Ar is 2,5-difluorophenyl.