Process for preparing aminotetrahydropyrans

Abstract

The present invention relates to a process for preparing 3-amino tetrahydropyrans and, more particularly, to an improved method for synthesizing a 2,3,5-substituted tetrahydropyran derivative, intermediate being used in the preparation of dipeptidyl peptidase-IV enzyme inhibitors (DPP-4 inhibitors).

Claims

1. A process for preparing a compound of formula (I): ##STR00046## wherein Ar is phenyl optionally substituted with one to five R substituents, each R is independently selected from halogen, (C.sub.1-C.sub.4)-alkyl, optionally substituted by halogen, or (C.sub.1-C.sub.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): ##STR00047## wherein each R.sub.1 and R.sub.2 is independently hydrogen or (C.sub.1-C.sub.4)-alkyl, or, wherein R.sub.1 and R.sub.2, when taken together, form a (C.sub.3-C.sub.7)-cycloalkyl group; with a compound of formula (III):
ArCHO(III) wherein Ar is as defined above; to give a compound of formula (IV): ##STR00048## wherein Ar, R.sub.1 and R.sub.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.sub.1 and R.sub.2 is a methyl group, or, wherein R.sub.1 and R.sub.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): ##STR00049## d) protecting the amino group to give a compound of formula (VI): ##STR00050## e) deprotecting the diol residue to give a compound of formula (VII): ##STR00051## f) regioselectively activating the primary hydroxy group to give a compound of formula (VIII): ##STR00052## wherein Z is an organo sulfonyl group; g) chemoselectively protecting a secondary hydroxy group to give a compound of formula (IX): ##STR00053## wherein Z is a hydroxy protecting group; h) performing a base-catalyzed cyclization to give a compound of formula (X): ##STR00054## 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): ##STR00055##

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): ##STR00056##

14. A compound of formula (IV): ##STR00057## wherein Ar is phenyl, optionally substituted with one to five substituents, each R is independently selected from halogen, (C.sub.1-C.sub.4)-alkyl, optionally substituted by halogen, or (C.sub.1-C.sub.4)-alkoxy, optionally substituted by halogen; and wherein each R.sub.1 and R.sub.2 is independently hydrogen or (C.sub.1-C.sub.4)-alkyl, or wherein R.sub.1 and R.sub.2, when taken together, form a (C.sub.3-C.sub.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): ##STR00058## wherein Ar is phenyl optionally substituted with one to five R substituents, each R is independently selected from halogen, (C.sub.1-C.sub.4)-alkyl, optionally substituted by halogen, or (C.sub.1-C.sub.4)-alkoxy, optionally substituted by halogen; wherein each R.sub.1 and R.sub.2 is independently hydrogen or (C.sub.1-C.sub.4)-alkyl, or, wherein R.sub.1 and R.sub.2, when taken together, form a (C.sub.3-C.sub.7)-cycloalkyl group; the process comprising: a) reacting, in the presence of a basic species or a catalyst, a compound of formula (II): ##STR00059## wherein R.sub.1 and R.sub.2 are as defined above; with a compound of formula (III):
ArCHO(III) wherein Ar is as defined above.

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

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

Description

EXAMPLE 1

Synthesis of (R)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde

(1) In a 100 mL single necked round bottom flask, equipped with a magnetic stirrer, 1,2:5,6-Di-O-cyclohexylidene-D-mannitol (5 g; 14,60 mmol) was dissolved in CH.sub.3CN/H.sub.2O (6:4, 25 ml).

(2) The mixture was cooled to 0 C. with an external ice bath and NaIO.sub.4 (6.246 g; 29.20 mmol) was added in portions over a period of 30 min. The resulting mixture was allowed to warm to room temperature and stirred for 2 hours.

(3) After the reaction time, a precipitate was filtered and washed with CH.sub.3CN/H.sub.2O. The solvent was removed under vacuum and title compound was obtained as a clear oil without any further purification (26 mmol; 89% yield).

EXAMPLE 2

Synthesis of (S)-2-(2-nitroethyl)-1,4-dioxaspiro[4.5]decane (II)

(4) Step (i): 2-nitro-1-((R)-1,4-dioxaspiro[4.5]decan-2-yl)ethanol

(5) In a 100 mL two necked round bottom flask, equipped with a mechanic stirrer, CH.sub.3NO.sub.2 (1.65 g; 27 mmol) was added to a solution of Example 1 compound (4.435 g; 26 mmol) in EtOH (12 ml).

(6) The mixture was cooled to 0 C. with an external ice bath and aq. 10% NaOH solution (2.6 ml; 1.04 g NaOH, 26 mmol) was added dropwise. The resulting mixture was stirred for 30 min, then allowed to warm to room temperature and stirred overnight. Subsequently, CH.sub.3COOH (1.56 g; 26 mmol) was added.

(7) The product was extracted with Et.sub.2O and the organic layer was washed two times with distilled water. The organic phase was then dried over Na.sub.2SO.sub.4 and the solvent removed under vacuum.

(8) The crude was purified by flash column chromatography on silica gel (eluent:

(9) Hexane/AcOEt=7/3) to yield a clear oil (19.5 mmol; 75% yield).

(10) TLC: Rf=0,37 (Hexane/AcOEt=7/3)

(11) Step (ii): (S)-2-(2-nitrovinyl)-1,4-dioxaspiro[4.5]decane

(12) In a 100 mL 2 necked round bottom flask, equipped with a magnetic stirrer and a nitrogen inlet tube, dry triethylamine (2.543 g; 25.18 mmol) was added to a solution of step (i) product (4.5 g; 19.46 mmol) in dry DCM (19 ml).

(13) The mixture was cooled to 0 C. with an external ice bath and MsCl (2.441 g; 21.31 mmol) was added dropwise.

(14) The resulting mixture was allowed to warm to room temperature and stirred under inert atmosphere for 2 hours. The reaction was quenched with sat. aq. Na.sub.2CO.sub.3.

(15) The organic phase was separated and aqueous phase extracted two times with DCM.

(16) The combined organic phases were washed with brine and dried over Na.sub.2SO.sub.4; the solvent removed under vacuum to afford the product in quantitative yield (19.37 mmol).

(17) TLC: Rf=0.55 (Hexane/AcOEt=9/1)

(18) .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.24 (s, 2H); 4.82 (dd, 1H); 4.29 (dd, 1H); 3.79 (dd, 1H); 1.75-1.65 (m, 8H); 1.48 (m, 2H).

(19) Step (iii): title compound (II)

(20) In a 25 mL two necked round bottom flask, fitted with a magnetic stirrer, a reflux condenser and a nitrogen inlet tube, N,N-diphenylthiourea (164 mg; 0.72 mmol) and Hantzsch ester (1.996 g; 7.88 mmol) were sequentially added to a solution of step (ii) product (1.535 g; 7.2 mmol) in dry DCM (7 ml).

(21) The solution was stirred at reflux under inert atmosphere for 24 h. The solvent was evaporated under controlled vacuum (200 mbar) and the crude was purified by flash column chromatography (eluent: CH.sub.2Cl.sub.2/MeOH=99/1).

(22) Title Compound was isolated as a brownish oil (5.54 mmol; 79% yield).

(23) TLC: Rf=0.54 (CH.sub.2Cl.sub.2)

(24) .sup.1H-NMR (300 MHz, CDCl.sub.3): 4.61 (dd, 2H); 4.21 (m, 1H); 4.13 (dd, 1H); 3.63 (dd, 1H); 2.34 (m, 1H); 2.17 (m, 1H); 1.65-1.55 (m, 8H); 1.40 (m, 2H).

EXAMPLE 2bis

Synthesis of (S)-2,2-dimethyl-4-(2-nitroethyl)-1,3-dioxolane

(25) Starting from 1,2:5,5-di-O-isopropiliden-D-mannitol and by following procedures described in Examples 1 and 2, the title compound (S)-2,2-dimethyl-4-(2-nitroethyl)-1,3-dioxolane was prepared in a 80-90% yield via intermediates (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde, 1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-nitroethanol and (S,E)-2,2-dimethyl-4-(2-nitrovinyl)-1,3-dioxolane.

EXAMPLE 3

Synthesis of 1-(2,5-difluorophenyl)-2-nitro-3-((S)-1,4-dioxaspiro[4.5]decan-2-yl)propan-1-ol (IV): diastereomeric mixture at C1, C2 with anti-diastereomer-(1R,2S) as major product

(26) In a 250 mL 2 necked round bottom flask, equipped with a magnetic stirrer and a nitrogen inlet tube, the chiral complex of Cu(II) was prepared in situ by addition of Cu(OTf).sub.2 (20 mg; 0.056 mmol) to a solution L-()-camphor-derived aminopyridine ligand (Ligand F) (16 mg; 0.067 mmol) in dry dioxane (4 mL).

(27) After 30 min, the mixture was cooled to 4 C. with an external ice water bath and triethylamine (11 mg, 0.11 mmol) was added.

(28) A solution of Example 2 compound [Compound (II)] (1.198 g; 5.56 mmol) in dry dioxane (1.5 mL), prepared under nitrogen atmosphere, was added; subsequently, 2,5-difluorobenzaldehyde Compound (III) (157 mg; 1.05 mmol) was added dropwise.

(29) The resulting mixture was allowed to warm to room temperature and stirred under inert atmosphere for 48 hours.

(30) The mixture was concentrated and then diluted in 3 mL of EtOAc. The organic layer was washed three times with 3 mL of distilled water. The organic phase was dried over Na.sub.2SO.sub.4 and the solvent was removed under vacuum.

(31) The crude was purified by flash column chromatography (eluent: CH.sub.2Cl.sub.2 200 mL, CH.sub.2Cl.sub.2/MeOH=99/1 400 mL, CH.sub.2Cl.sub.2/MeOH=98/2 400 mL).

(32) The following fractions were obtained:

(33) Starting material Compound (II) recovered as a clean product=635 mg

(34) Title compound (IV) (mix of all 4 diastereomers)=472 mg (conversion >95%)

(35) TLC: Rf=0.23 (CH.sub.2Cl.sub.2)

(36) The diastereoisomeric excess was determined by HPLC on chiral stationary phase (Chiralpack IB, flow 1 mL/min, pressure 39 bar, Hexane/2-Propanol=98/2).

(37) Diastereomeric ratio: 45/10/14/31

(38) Compound (IV), major diastereomer: anti-diastereomer-(1R,2S)

(39) .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.26 (m, 1H); 7.04 (m, 2H); 5.71 (bs, 1H); 5.05 (ddd, 1H); 4.21 (dd, 1H); 3.60 (dd, 1H); 3.55 (m, 1h); 2.35 (m, 1H); 1.76 (m, 1H); 1.65-1.55 (m, 8H); 1.40 (m, 2H).

EXAMPLE 3bis

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

(40) By following procedures described in Example 3, nitro aldol reaction of a compound of formula II, Example 2 compound, with a compound of formula III, 2,5-difluorobenzaldehyde, to give title compound of formula IV was performed in the presence of ligand F exploring different experimental conditions, stoichiometry, solvents, temperature, copper salts, etc., resulting in a 55-75% yield; data are reported in Table 1 below:

(41) TABLE-US-00001 TABLE 1 Entry Solvent Temperature Catalyst Time Diastereoisomers 1 Dioxane 0 Cu(OTf).sub.2 24 h 35/10/30/23 5% in mol 2 EtOH RT Cu(OTf).sub.2 24 h 33/10/37/19 5% in mol 3 Dioxane 24 h C.; Cu(OTf).sub.2 48 h 47/8/20/25 24 h RT 5% in mol 4 Dioxane RT Cu(OTf).sub.2 60 h 55/9/11/25 5% in mol 5 Dioxane RT Cu(OTf).sub.2 24 h 40/10/25/25 5% in mol 6 EtOH RT Cu(AcO).sub.2H.sub.2O 24 h 27/10/39/24 5% in mol 7 EtOH RT Cu(AcO).sub.2H.sub.2O 6 h 36/12/33/19 5% in mol 8 Dioxane RT Cu(OTf).sub.2 24 h 31/11/36/21 10% in mol 9 Dioxane 5 Cu(OTf).sub.2 24 h 32/11/36/21 5% in mol

(42) Entry 9 was repeated by using Cu(OAc).sub.2 (0.05 eq.) in the presence of ligand B (0.06 eq) as catalyst to give a compound of formula IV in 80% yield (diastereoisomers rate 28:15:7:50). The diastereomeric ratio was determined in the nitro aldol of general formula IV by HPLC on chiral stationary phase.

EXAMPLE 3ter

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

(43) By following procedures described in Example 3, nitro aldol reaction of a compound of formula II, Example 2 compound, with 2,4,5-trifluorobenzaldeyde of formula III to give title compound of formula IV was performed in the presence of copper diacetate Cu(OAc).sub.2 (0.05 eq.) with a chiral ligand (0.06 eq); results obtained by exploring different ligands, solvents and temperatures (reaction time 24h) are reported in Table 2 below:

(44) TABLE-US-00002 TABLE 2 temp (1S,2R):(1R,2R): yield entry ligand ( C.) solvent (1R,2S):(1S,2S) (%) 1 A rt dioxane:THF (85:15) 13:32:24:31.sup.+ 85 2 A +5 dioxane:THF (85:15) 14:35:5:46 84.sup.+ 3 B +5 Dioxane:THF (85:15) 27:13:10:59 83 4 B 10 THF 5:39:3:52 20 5** B +5 dioxane 17:18:25:40.sup.+ >99 6 C +5 dioxane:THF (85:15) 27:25:21:27 10.sup.+ 7 C 10 THF 31:21:22:26 16 8 D +5 dioxane 34:15:12:39 80.sup.+ 9 E +5 dioxane 7:9:60:24 60.sup.+

EXAMPLE 3quater

Synthesis of 1-(2,5-difluorophenyl)-2-nitro-3-((S)-1,4-dioxaspiro[4.5]decan-2-yl)propan-1-ol (IV): diastereomeric mixture at C1, C2 with anti-diastereomer-(1R,2S) as major product

(45) In a 250 mL 2 necked round bottom flask, equipped with a magnetic stirrer and a nitrogen inlet tube, a solution of quinidine derivative ligand G (60 mg; 0.099 mmol) in dry THF (3 mL) was added to Cu(OTf).sub.2 (36 mg; 0.099 mmol). After 1 hour, a solution of Example 2 compound [Compound (II)] (2.133 g; 9.86 mmol) in dry THF (1.0 mL), prepared under nitrogen atmosphere, was added; subsequently, 2,5-difluorobenzaldehyde Compound (III) (280 mg; 1.97 mmol) was added dropwise. The mixture was cooled to 20 C. with an external ice water bath and triethylamine (11 mg, 0.99 mmol) was added. The resulting mixture was stirred at 20 C. under inert atmosphere for 24 hours. The reaction was quenched with 250 microL of HCl solution (10% in water) and stirred for 5 minutes; then, diluted in 10 mL of EtOAc and 10 ml of water. The organic phase was separated and the aqueous phase extracted three times with EtOAc. The combined organic phases was dried over Na.sub.2SO.sub.4 and the solvent was removed under vacuum to give 2.5 g of crude. The crude was purified by flash column chromatography (eluent: CH.sub.2Cl.sub.2/MeOH=99/1).

(46) The following fractions were obtained:

(47) Starting material Compound (II) recovered as a clean product=1.750 g

(48) Title compound (IV) (mix of all 4 diastereomers)=694 mg (conversion 98%)

(49) TLC: Rf=0.23 (CH.sub.2Cl.sub.2)

(50) The diastereoisomeric excess was determined by HPLC on chiral stationary phase (Chiralpack IB , flow 1 mL/min, pressure 39 bar, Hexane/2-Propanol=98/2).

(51) Diastereomeric ratio: 55/23/12/10

(52) Compound (IV), major diastereomer: anti-diastereomer-(1R,2S)

(53) .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.26 (m, 1H); 7.04 (m, 2H); 5.71 (bs, 1H); 5.05 (ddd, 1H); 4,21 (dd, 1H); 3.60 (dd, 1H); 3.55 (m, 1h); 2.35 (m, 1H); 1.76 (m, 1H); 1.65-1.55 (m, 8H); 1.40 (m, 2H).

(54) To note that purification of major isomer (as amino alcohol after hydrogenation) resulted to be easier because of the low content (10) of minor isomer.

EXAMPLE 4

Synthesis of 2-amino-1-(2,5-difluorophenyl)-3-((S)-1,4-dioxaspiro[4.5]decan-2-yl)propan-1-ol (V), anti-diastereomer isolated as major product: (1R,2S)-2-amino-1-(2,5-difluorophenyl)-3-((S)-1,4-dioxaspiro[4.5]decan-2-yl)propan-1-ol

(55) A reactor, equipped with a magnetic stirrer, was charged with Example 3 compound [Compound (IV) mix of all 4 diastereomers] (458 mg, 1.28 mmol), 5% Pd/C (50% solution in water; 273 mg 6.8 mg Pd, 0.064 mmol) in MeOH (6 ml). The reactor was introduced in an autoclave and it was subjected to H.sub.2 pressure (25 atm). The mixture was stirred at room temperature overnight. The catalyst was removed by filtration and the solvent was removed under vacuum to give crude product Compound (V) as a mix of all 4 diastereomers. The diastereoisomers were separated by flash column chromatography (eluent: CH.sub.2Cl.sub.2/MeOH=95/5+0.5% TFA); two out of the four possible diastereoisomers were obtained:

(56) Compound (V) syn-diastereomer: 40 mg, and

(57) Compound (V) anti-diastereomer-(1R,2S): 97 mg.

(58) TLC: Rf=0.38 and 0.39 (CH.sub.2Cl.sub.2/MeOH=1/1)

(59) Compound (V), anti-diastereomer-(1R,2S)

(60) .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.24 (m, 1H); 6.96 (m, 2H); 4.97 (d, 1H); 4.24 (m, 1H); 4.00 (dd, 1H); 3.48 (dd, 1H); 3.36 (m, 1H); 2.66 (bs, 2H); 1.65-1.50 (m, 10H); 1.37 (m, 2H).

EXAMPLE 4bis

Synthesis of 2-amino-1-(2,4,5 -trifluorophenyl)-3-((S)-1,4-dioxaspiro[4.5]decan-2-yl)propan-1-ol (V)

(61) Starting from a compound of formula IV obtained in Example 3ter, by following procedures described in Examples 4, the title compound 2-amino-1-(2,4,5-trifluorophenyl)-3-((S)-1,4-dioxaspiro[4.5]decan-2-yl)propan-1-ol (V) was prepared in a 90% yield.

EXAMPLE 5

Synthesis of benzyl (1R,2S)-1-(2,5 -difluorophenyl)-1-hydroxy-3-((S)-1,4-dioxaspiro[4.5]decan-2-yl)propan-2-ylcarbamate (VI): P=Cbz

(62) In a 5 mL 2 necked round bottom flask, equipped with a magnetic stirrer and a nitrogen inlet tube, dry triethylamine (60.6 mg; 0.60 mmol) was added to a solution of Example 4 compound [Compound (V) anti-diastereomer-(1R,2S)] (97 mg; 0.30 mmol) in dry THF (1 ml). The mixture was cooled to 0 C. with an external ice bath and benzyl chloroformate (75 mg; 0.44 mmol) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred under inert atmosphere for 18 hours. EtOAc and H.sub.2O were added; the organic phase was separated and the aqueous phase extracted two times with EtOAc. The combined organic phases were washed with brine end then was dried over Na.sub.2SO.sub.4. The solvent was removed under controlled vacuum to obtain 130 mg of crude product which was purified by flash column chromatography on silica gel (eluent: Hexane/AcOEt=8/2). Title compound was isolated as a clear oil (0.18 mmol; 60% yield).

(63) TLC: Rf=0,21 (Hexane/AcOEt=8/2)

(64) .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.40-7.26 (m, 5H); 7.24 (m, 1H); 6.96 (m, 2H); 5.41 (bd, 1H); 5.20 (bs, 1H); 5.15 (s, 2H); 4.24 (dd, 1H); 4.19 (m, 1H); 4.01 (dd, 1H); 3.52 (dd, 1H); 1.76 (m, 1H); 1.68-1.48 (m, 9H); 1.35 (m, 2H).

EXAMPLE 6

Synthesis of N-((1R,2S)-1-(2,5-difluorophenyl)-1-hydroxy-3-((S)-1,4-dioxaspiro[4.5]decan-2-yl)propan-2-yl)acetamide (VI): P=Acetyl

(65) In a 25 mL 2 necked round bottom flask, equipped with a magnetic stirrer and a nitrogen inlet tube, dry triethylamine (297 mg; 2.94 mmol) was added to a solution of Compound (V) [anti-diastereomer-(1R,25)] (162 mg; 0.49 mmol) in dry THF (5 ml). The mixture was cooled to 0 C. with an external ice bath and acetyl chloride (154 mg; 1.97 mmol) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred under inert atmosphere for 18 hours. EtOAc and H.sub.2O were added; the organic phase was separated the aqueous phase was extracted two times with EtOAc. The combined organic phases were washed with brine and dried over Na.sub.2SO.sub.4; the solvent was removed under vacuum to obtain 200 mg of crude product which was purified by flash column chromatography on silica gel (eluent: Hexane/EtOAc=7/3). Title compound was isolated as a clear oil (0.34 mmol; 70% yield).

(66) TLC: Rf=0.16 (Hexane/AcOEt=7/3)

(67) .sup.1H-NMR (300 MHz, CDCl.sub.3):

(68) 7.30 (m, 1H); 6.96 (m, 2H); 5.20 (d, 1H); 4.30-4.10 (m, 2H); 4.02(dd, 1H); 3.52 (ddd, 1H); 2 (s, 3H); 1.72 (m, 1H), 1.65-1.50 (m, 9H); 1.37 (m, 2H).

EXAMPLE 7

Synthesis of N-((1R,2S,4S)-1-(2,5 -difluorophenyl)-1,4,5 -trihydroxypentan-2-yl)acetamide (VII): P=Acetyl

(69) In a 10 mL one necked round bottom flask, equipped with a magnetic stirrer, Example 6 compound (91 mg; 0.25 mmol) was dissolved in THF (1 ml). The mixture was cooled to 0 C. with an external ice bath and aq. HCl (2.7 M; 1 ml) was added dropwise.

(70) The resulting mixture was allowed to warm to room temperature and stirred for 8 hours. The reaction was then quenched with NaHCO.sub.3 aqueous solution; the organic phase was separated the aqueous phase was extracted three times with EtOAc. The combined organic phases were dried over Na.sub.2SO.sub.4and concentrated under vacuum to obtain 73 mg of crude.

(71) The product was purified by flash column chromatography on silica gel (eluent: CH.sub.2Cl.sub.2/MeOH=95/5).

(72) Title compound was isolated as a clear oil (0.16 mmol; 64% yield).

(73) TLC: Rf=0.13 (CH.sub.2Cl.sub.2/MeOH=95/5)

(74) .sup.1H-NMR (300 MHz, CDCl.sub.3):

(75) 7.27 (m, 1H); 7.04 (m, 2H); 5.06 (d, 1H); 4.38 (m, 1H); 3.62(m, 1H); 3.44 (dd, 1H); 3.36 (m, 2H); 1.91 (s, 3H); 1.62 (ddd, 2H).

EXAMPLE 8

Synthesis of (2S,4S,5R)-4-acetamido-5 -(2,5 -difluorophenyl)-2,5-dihydroxypentyl 4-methylbenzenesulfonate (VIII): P=Acetyl

(76) In a vial, equipped with a magnetic stirrer, Example 7 compound (47 mg; 0.16 mmol) and Bu.sub.2SnO (2 mg; 0.008 mmol) were suspended in CH.sub.2Cl.sub.2 (1 ml) and TEA (18 mg; 18 mmol) were added. The mixture was cooled to 0 C. with an external ice bath and p-toluensulfonyl chloride (TsCl) (34 mg; 0.18 mmol) was added in small portions.

(77) The resulting mixture was allowed to warm to room temperature and was stirred for 18 hours. The catalyst was then removed by filtration the solvent was evaporated under vacuum to obtain 75 mg of crude product.

(78) The product was purified by flash column chromatography on silica gel (eluent: CH.sub.2Cl.sub.2/MeOH=99/1). Title compound was isolated as a clear oil (0.07 mmol; 43% yield).

(79) TLC: Rf=0.28 (CH.sub.2Cl.sub.2/MeOH=98/2)

(80) .sup.1H-NMR (300 MHz, CDCl.sub.3):

(81) 7.76 (d, 2H); 7.35 (d, 2H); 7.20 (m, 1H); 6.98 (m, 2H); 6.37 (d, 2H); 5.18 (d, 1H); 4.34 (m, 1H); 3.92-3.80 (m, 3H); 2.46 (s, 3H); 2.06 (s, 3H); 1.65 (ddd, 1H); 1.31 (ddd, 1H).

EXAMPLE 9

Synthesis of N-((2R,3 S,5 S)-2-(2,5-difluorophenyl)-5-hydroxytetrahydro-2H-pyran-3-yl)acetamide (I): P=Acetyl in mixture with N-((2R,3S,5S)-2-(2,5-difluorophenyl)-5-(tetrahydro-2H-pyran-2-yloxy)tetrahydro-2H-pyran-3-yl)acetamide (X): with P=Acetyl, Z=THP

(82) In a vial, equipped with a magnetic stirrer, a solution of Example 8 compound (20 mg; 0.045 mmol), 3,4-dihydropyran (15 mg; 0.18 mmol) and p-TsOH.H.sub.2O (2 mg; 0.011 mmol) in dry CH.sub.2Cl.sub.2 (0.5 ml) was prepared under N.sub.2 atmosphere. The mixture was stirred over 4 hours at room temperature and then the solvent was removed under vacuum. The crude product was directly used in the next step.

(83) In a 10 mL 2 necked round bottom flask, equipped with a magnetic stirrer and a nitrogen inlet tube, NaH (50% in mineral oil, 15 mg; 0.31 mmol) was washed by pentane three time. Dry THF (1 mL) was added, then the mixture was cooled to 0 C. with an external ice bath and a solution of the previously obtained crude compound in THF (1 mL) was added dropwise. The resulting mixture was allowed to warm up to room temperature and stirred for 48 hours. After that a 1 M HCl solution (2 mL) was added and the mixture was stirred for 18 hours. The reaction was diluted with EtOAc, the organic phase was separated and the aqueous phase was extracted two times with EtOAc. The combined organic phases were dried over Na.sub.2SO.sub.4 and the solvent was removed under vacuum to obtain 10 mg of crude.

(84) The crude mixture was passed through a plug of silica gel (eluent: CH.sub.2Cl.sub.2/MeOH=98/2) obtaining an isolated fraction of pure product.

(85) LC-MS analysis of the isolated fraction showed the following peaks:

(86) Mass (ESI+) m/z=272 [M+H].sup.+ corresponding to the desired product Compound (I); P=Ac

(87) Mass (ESI+) m/z=356 [M+H].sup.+ corresponding to the cyclised product still protected at the hydroxyl group Compound (X); P=Ac, P=THP

EXAMPLE 10

Synthesis of benzyl (1R,2S,4S)-1-(2,5-difluorophenyl)-1,4,5-trihydroxy-pentan-2-yl-carbamate (VII): P=Cbz

(88) In a 10 mL one necked round bottom flask, equipped with a magnetic stirrer, Example 5 compound (97 mg; 0.26 mmol) was dissolved in THF (1 ml). The mixture was cooled to 0 C. with an external ice bath and diluted HCl (2.7 M; 1 ml) was added dropwise.

(89) The resulting mixture was allowed to warm to room temperature and stirred for 8 hours. The reaction was then quenched with NaHCO3 aqueous solution. The organic phase was separated and the aqueous phase extracted three times with EtOAc. The combined organic phases were dried over Na2SO4 and the solvent was removed under vacuum to obtain 100 mg of crude.

(90) The product was purified by flash column chromatography on silica gel (eluent: CH2Cl2/MeOH=95/5). Title compound was isolated as a clear oil (0.20 mmol; 77% yield).

(91) TLC: Rf=0.20 (CH2Cl2/MeOH=95/5)

(92) 1H-NMR (300 MHz, CDCl3):

(93) 7.40-7.26 (m, 5H); 7.23 (m, 1H); 6.98 (m, 2H); 5.35 (bd, 1H); 5.13 (bs, 3H); 5.15 (s, 2H); 4.13 (m, 1H); 3.77 (m, 1H); 3.63 (ddd, 1H); 3.48 (ddd, 1H); 1.86 (m, 1H); 1.5 (m, 1H).

EXAMPLE 11

Synthesis of (2S,4S,5R)-4-(benzyloxycarbonylamino)-5-(2.5-difluorophenyl)-2,5-dihydroxy-pentyl 4-methylbenzenesulfonate (VIII): P=Cbz

(94) In a vial, equipped with a magnetic stirrer, Example 10 compound (70 mg; 0.18 mmol) and Bu2SnO (1 mg; 0.004 mmol) were suspended in CH2Cl2 (1 ml) and TEA (18 mg; 0.18 mmol) was added.

(95) The mixture was cooled to 0 C. with an external ice bath and TsCl (34 mg; 0.18 mmol) was added in small portions.

(96) The resulting mixture was allowed to warm to room temperature and stirred for 18 hours.

(97) The catalyst was then removed by filtration and the solvent was removed under vacuum to obtain 118 mg of crude.

(98) The product was purified by flash column chromatography on silica gel (eluent:

(99) CH2Cl2/MeOH=95/5). Title compound was isolated as a clear oil (0.09 mmol; 50% yield).

(100) Rf=0.84 (CH2Cl2/MeOH=95/5)

(101) 1H-NMR (300 MHz, CDCl3):

(102) 7.80 (dd, 2H); 7.40-7.21 (m, 7H); 6.96 (m, 2H); 5.41 (bd, 0.4H); 5.30 (bd, 0.6H); 5.18 (bs, 0.4H); 5.11 (s, 0.8H); 5.08 (bs, 0.60); 5.00 (s, 1.2H); 4.16 (m, 1H); 3.93 (m, 1H); 3.65 (m, 1H); 3.21 (bs, 0.6H); 3.07 (bs, 0.4); 2.45 (s, 3H); 1.86-1.54 (m, 2H).

EXAMPLE 12

Synthesis of benzyl (1R,2S)-1-(2,5-difluorophenyl)-1-hydroxy-3-((S)-oxiran-2-yl)propan-2-ylcarbamate (XI): P=Cbz

(103) In a 25 mL 2 necked round bottom flask, equipped with a magnetic stirrer and a nitrogen inlet tube, NaH (50% in mineral oil; 6 mg; 0.129 mmol) was washed by pentane three times. Dry THF (1 mL) was added, then the mixture was cooled to 0 C. with an external ice bath and solution of Example 11 compound (46 mg; 0.086 mmol) in THF (1 mL) was added dropwise.

(104) The resulting mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction was then quenched with NH4Cl aqueous s.s.; the organic phase was separated the aqueous phase was extracted two times with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated under vacuum to obtain 36 mg of crude.

(105) The product was purified by flash column chromatography on silica gel (eluent: Hexane/EtOAc=7:3). Title compound was isolated as a clear oil (0.026 mmol; 31% yield) and 22 mg of Example 11 compound was recovered.

(106) Rf=0.17 (Hexane/EtOAc=6:4)

(107) 1H-NMR (300 MHz, DMSO, 330K):

(108) 7.35-7.09 (m, 8H); 4.95 (d, 2H); 4.90 (m, 1H); 3.92(m, 1H); 2.89 (m, 1H); 2.65 (m, 1H); 2.47 (m, 1H); 1.70 (m, 2H).

EXAMPLE 13

Synthesis of (1R,2S)-2-acetamido-1-(2,5-difluorophenyl)-3-((S)-1,4-dioxaspiro[4.5]decan-2-yl)propyl acetate (VIbis): P=Acetyl; W=Acetyl

(109) In a 5 mL one necked round bottom flask, equipped with a magnetic stirrer and under nitrogen atmosfere, a mixture 1:1 pyridine/Ac2O (0.5 ml) was added to Compound (V) [anti-diastereomer-(1R,2S)] (120 mg; 0.37 mmol) cooling at 0 C.

(110) The resulting mixture was allowed to warm to room temperature and stirred under inert atmosphere for 18 hours. EtOAc and H2O were added; the organic phase was separated the aqueous phase was extracted two times with EtOAc. The combined organic phaseswere washed with brine and dried over Na2SO4; the solvent was removed under vacuum to obtain 157 mg of crude. The product was purified by flash column chromatography on silica gel (eluent: Hexane/EtOAc=7/3). Title compound was isolated as a clear oil (0.29 mmol; 77% yield).

(111) TLC: Rf=0.18 (Hexane/AcOEt=1/1)

(112) .sup.1H-NMR (300 MHz, CDCl.sub.3):

(113) 7.08 (m, 1H); 6.99 (m, 2H); 6.17 (d, 1H); 6.10 (d, 1H); 4.63 (m, 1H); 4.28 (m, 2H); 4.05(dd, 1H); 3.51 (dd, 1H); 2.15 (s, 3H);1.87 (s, 3H); 1.85-1.80 (m, 2H), 1.65-1.50 (m, 8H); 1.44-1.40 (m, 2H).

EXAMPLE 14

Synthesis of (1R,2S,4S)-2-acetamido-1-(2,5-difluorophenyl)-4,5-dihydroxypentyl acetate (VIIbis): P=Acetyl; W=Acetyl

(114) In a 10 mL one necked round bottom flask, equipped with a magnetic stirrer, compound VIbis (140 mg; 0.34 mmol) was added and it was dissolved in THF (1 ml). The mixture was cooled to 0 C. with an external ice bath and HCl solution (1 ml; 2.7 M) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred for 8 hours. The reaction was then quenched with NaHCO.sub.3 aqueous solution; the organic phase was separated the aqueous phasewas extracted three times with EtOAc. The combined organic phases were dried over Na.sub.2SO.sub.4 and concentrated under vacuum to obtain 144 mg of crude.

(115) The product was purified by flash column chromatography on silica gel (eluent: CH.sub.2Cl.sub.2/MeOH=95/5). Title compound was isolated as a clear oil (0.24 mmol; 71% yield).

(116) TLC: Rf=0.32 (CH.sub.2Cl.sub.2/MeOH=9/1)

(117) .sup.1H-NMR (300 MHz, CDCl.sub.3):

(118) 7.03 (m, 3H); 6.20 (d, 1H); 6.06 (d, 1H); 4.55 (m, 1H); 3.65 (m, 1H); 3.49 (m, 2H); 2.18 (s, 3H); 1.91 (s, 3H); 1.63 (m, 1H); 1.40 (m, 1H).

EXAMPLE 15

Synthesis of (1R,2S,4S)-2-acetamido-1-(2,5-difluorophenyl)-4-hydroxy-5-(tosyloxy)pentyl acetate (VIIIbis): P=Acetyl; W=Acetyl

(119) In a vial, equipped with a magnetic stirrer,compound VIIbis (78 mg; 0.24 mmol) and Bu.sub.2SnO (3 mg; 0.012 mmol) were suspended in CH.sub.2Cl.sub.2 (1 ml) and TEA (24 mg; 0.24 mmol) were added. The mixture was cooled to 0 C. with an external ice bath and TSCl (45 mg; 0.24 mmol) was added in small portions.

(120) The resulting mixture was allowed to warm to room temperature and was stirred for 18 hours. The catalyst wasthen removed by filtration the solvent was evaporated under vacuum to obtain 108 mg of product (0.22 mmol; 92% yield), that was used in the next step without further purification.

(121) TLC: Rf=0.22 (CH.sub.2Cl.sub.2/MeOH=98/2)

(122) .sup.1H-NMR (300 MHz, CDCl.sub.3):

(123) 7.78 (d, 2H); 7.42 (d, 2H); 6.99 (m, 3H); 6.37 (d, 2H);5.18 (d, 1H); 4.34 (m, 1H); 3.92-3.80 (m, 3H); 2.46 (s, 3H); 2.06 (s, 3H); 1.65 (ddd, 1H); 1.31 (ddd, 1H).

EXAMPLE 16

Synthesis of (1R,2S,4S)-2-acetamido-1-(2,5 -difluorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)-5-(tosyloxy)pentyl acetate (IXbis): P=Acetyl; Z=THP W=Acetyl

(124) In a 5 mL, one necked-round bottom flask, equipped with a magnetic stirrer,a solution of compound VIIIbis (108 mg; 0.22 mmol), 3,4-dihydropyran (112 mg; 1.36 mmol) and p-TsOH (4.2 mg; 0.022 mmol) in dry CH.sub.2Cl.sub.2 (2 ml) was prepared under N.sub.2 atmosfere. The mixture was stirred for 5 hours at room temperature and then the solvent was removed under vacuum. The crude reaction mixture was purified by flash column chromatography on silica gel (eluent: CH.sub.2Cl.sub.2/MeOH=99/1).

(125) Two fractions (ratio 50/50) were obtained and analysed by .sup.1H-NMR; they were supposed to be two diasteroisomers formed by protective group and therefore riunited (IXbisA)

(126) When 20 equivalents of DHP and 5 hours only as reaction time were used only one major product was obtained (65% yield, r.d. ratio 87/13) (IXbisB).

EXAMPLE 17

Synthesis of N-((2R,3S,5S)-2-(2,5 -difluorophenyl)-5-hydroxytetrahydro-2H-pyran-3-yl)acetamide (I): P=Acetyl

(127) Compound IXbis (119 mg; 0.21 mmol) was placed into a round bottom flask and was dissolved in MeOH (1 mL) and K2CO3 s.s. was added (1 mL). The mixture was stirred 18 h at rt. After concentration and extraction with AcOEt the crude was used in the following step without further purifiction.

(128) In a 10 mL, 2 necked-round bottom flask, equipped with a magnetic stirrer and a nitrogen inlet tube, NaH (25 mg; 0.63 mmol) was washed with pentane three times. Dry THF (0.5 mL) was added, then the mixture was cooled to 0 C. with an external ice bath and a solution of the crude previously obtained in THF (0.5 mL) was added dropwise.

(129) The resulting mixture was allowed to warm up to room temperature and stirred for 24 hours. The reaction was quenched with H.sub.2O and diluted with EtOAc; the phases were separated and the aqueous phase was extracted three times with EtOAc. The combined organic phases were dried over Na.sub.2SO.sub.4and concentrated under vacuum to obtain 21 mg of crude, that was used in the next step without further purification.

(130) In a 5 mL, one necked-round bottom flask, equipped with a magnetic stirrer, a solution of the crude previously obtained in THF was prepared and then a 1 M HCl solution (1 mL) was added. The mixture was stirred for 18 hours at room temperature. The reaction was diluted with EtOAc, the organic phase was separated and the aqueous phase was extracted three times with EtOAc. The combined organic phases were dried over Na.sub.2SO.sub.4 and the solvent was removed under vacuum to obtain 15 mg of crude.

(131) The product was purified by flash column chromatography on silica gel (eluent: CH.sub.2Cl.sub.2/MeOH=98/2). Title compound was isolated as a clear oil. The product was fully characterized by NMR and Mass spectroscopy.

(132) Starting from IXbisA a 50/50 mixture of 2 diastereoisomers was obtained in 43% yield.

(133) Starting from IXbisB only 1 diastereoisomer was obtained in 53% yield.

(134) Desired product: Compound (I) single diastereomer (trans-diastereomer) obtained from IXbisB; P=Ac

(135) Mass (ESI+) m/z=294 [M+Na].sup.+

(136) .sup.1H-NMR (300 MHz, CDCl.sub.3):

(137) 7.30 (m, 1H); 6.95 (m, 2H); 5.30 (bd, 1H); 4.46 (d, 1H); 4.38-4.31 (m, 1H); 4.07 (d, 2H); 3.70 (d, 1H); 2.39.2.33 (m, 2H); 1.81 (s, 3H).

(138) It is thus evident to a person skilled in the art how the process according to the invention, besides having very high yields, makes it possible to simply and efficiently obtain a key synthon in the preparation of pharmaceutical active ingredients, in particular omarigliptin, bearing the correct steric configuration at all three of the chiral centers present in the molecular structure.