(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tert-butoxycarbonylamino-(3-hydroxy-adamantan-1-yl)-acetic acid (100 g; 0.307 mole) was added to dichloromethane (500 ml) with stirring. The methanesulfonic acid salt of (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide (64.8 g; 0.292 mole) was added, and the reaction mixture was stirred for 15 minutes at 25-35° C. In a separate flask, 1-hydroxybenzotriazole monohydrate (11.8 g; 0.077 mole) and triethylamine (34.2 g) were added to dichloromethane (500 ml) and stirred to form a solution. This solution was added to the reaction mixture gradually over 30 minutes at 25-30° C. The reaction mixture was then cooled to 5-15° C., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) (70.6 g) was added, and the mixture was stirred for 15 minutes at 5-15° C. Triethylamine (65.2 g) was added to the reaction mixture and stirred for 30 minutes. Temperature of the reaction mixture was raised to 25-35° C. and stirred continuously for 12 hours. Reaction completion was confirmed by HPLC. Water (500 ml) was added, the mixture was stirred, and the organic layer was separated. The organic layer was washed with dilute hydrochloric acid solution (500 ml, prepared by adding concentrated hydrochloric acid (60 ml) to water (440 ml)), and further washed with sodium bicarbonate solution (3 times), followed by washing with sodium chloride solution. Hydrogen chloride in isopropanol (14.2% w/w, 315.6 g) was added over 60 minutes, and the mixture was stirred for 4 hours. Completion of the reaction was confirmed by HPLC. The mixture was distilled under vacuum to remove dichloromethane. Toluene was added to the residue and distilled under vacuum. Acetonitrile (400 ml) was added to the residue followed by addition of triethylamine (79.2 g) over 15 minutes with stirring. The reaction mixture was cooled to 10-20° C., and trityl chloride (72.7 g) was added gradually, followed by stirring for 2 hours. Completion of the reaction was confirmed by HPLC. The mixture was distilled under vacuum to remove acetonitrile. Toluene was added to the residue and distilled under vacuum. Toluene (500 ml) followed by water (500 ml) were added to the residue, the mixture was heated at 45-55° C. and filtered and dried to obtain the product. (Yield=60.3%; HPLC purity=94%) the reaction mixture was stirred for 15 minutes at 25-35° C stirred to form a solution This solution was added to the reaction mixture gradually over 30 minutes at 25-30° C the mixture was stirred for 15 minutes at 5-15° C stirred for 30 minutes Temperature of the reaction mixture was raised to 25-35° C. stirred continuously for 12 hours Reaction completion the mixture was stirred the organic layer was separated The organic layer was washed with dilute hydrochloric acid solution (500 ml, prepared by adding concentrated hydrochloric acid (60 ml) to water (440 ml)) further washed with sodium bicarbonate solution (3 times) by washing with sodium chloride solution Hydrogen chloride in isopropanol (14.2% w/w, 315.6 g) was added over 60 minutes the mixture was stirred for 4 hours The mixture was distilled under vacuum to remove dichloromethane Toluene was added to the residue distilled under vacuum Acetonitrile (400 ml) was added to the residue followed by addition of triethylamine (79.2 g) over 15 minutes with stirring The reaction mixture was cooled to 10-20° C. trityl chloride (72.7 g) was added gradually by stirring for 2 hours The mixture was distilled under vacuum to remove acetonitrile Toluene was added to the residue distilled under vacuum were added to the residue the mixture was heated at 45-55° C. filtered dried to obtain the product

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A coupling reaction is then used to couple (αS)-α[[(1,1-dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid, (Formula VI) to (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide (Formula J) methanesulfonic acid salt or HCl salt in the presence of 1-hydroxybenzotriazole (HOBT) or other known coupling agent to produce 3-(aminocarbonyl)-(αS)-α-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-β-oxo-(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-2-ethanecarbamic acid, 1,1-dimethylethyl ester (Formula K). Formula K compound is subjected to dehydration by treating compound K with organic base such as pyridine or triethylamine, and trifluoroacetic anhydride or other dehydrating agent such as phosphorus oxychloride (POCl3) or cyanuric chloride, and then subjecting the reaction to hydrolysis by cooling to from about 25 to about 40° C. and treating with sodium hydroxide or other strong base such as KOH or LiOH to form Compound L. 3-cyano-(αS)-α-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-β-oxo-(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-2-ethanecarbamic acid, 1,1-dimethylethyl ester (Formula L), which is then deprotected to form the dipeptidyl peptidase IV inhibitor (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-1-oxoethyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile (Formula M). A coupling reaction

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (2S)-2-{[(Benzyloxy)carbonyl]amino}-2-(3-hydroxyadamantan-1-yl)acetic acid of Formula-XIV (20 gm), 1-ethyl-3-(3-dimethyl aminoporpyl)carbodiimide (13.8 gm), (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide of formula-III (14.8 gm) and 1-hydroxy benzotriazole (10.2 gm) were dissolved in N,N-dimethyl formamide (80 ml). The reaction mixture was cooled to about 20° C. Addition of N,N-diisopropylethylamine (15.8 gm) was then carried out for 15 min. The reaction mixture was stirred for 4 hrs and the solvent was distilled off. To the residue 2N HCl solution was added. Aqueous phase was extracted with ethyl acetate. Organic phase was washed with NaHCO3 solution, dried and evaporated to yield 23.3 gms (90%) of title product. MP: 105-106° C., H1NMR (300 MHz, CDCl3): 0.81 (dd, 1H), 0.96 (m, 1H), 1.46-1.82 (m, 12H), 1.93 (s, 1H), 2.2 (m, 3H), 2.45 (dd, 1H), 3.6 (m, 1H), 4.5-4.61 (dd, 1H), 4.76-4.86 (dd, 1H), 5.0 (s, 2H), 5.34 (d, 1H), 5.69 (s, 1H), 5.82-5.85 (dd, 1H), 6.83-6.89 (s, 1H), 7.31-7.35 (m, 5H). the solvent was distilled off To the residue 2N HCl solution was added Aqueous phase was extracted with ethyl acetate Organic phase was washed with NaHCO3 solution dried evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Path B: Coupling reaction of (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide or its salts of Formula-III with (2S)-2-{[(benzyloxy)carbonyl]amino}-2-(3-hydroxyadamantan-1-yl)acetic acid of formula-XIV to give benzyl N-[(1S)-2-[(1S,3S,5S)-3-carbamoyl-2-azabicyclo[3.1.0]hexan-2-yl]-1-(3-hydroxyadamantan-1-yl)-2-oxo-ethyl]carbamate of formula-XV, can be carried out in a suitable solvent, for example, tetrahydrofuran, N,N-dimethyl formamide, 1,4-dioxane or ethyl acetate using a coupling agent for example, 1,3-dicyclohexyl carbodiimide (DCC), 1-ethyl-3-(3′-dimethylaminoporpyl)carbodiimide (EDAC), 1-propane phosphonic acid cyclic anhydride or N-[(dimethyl amino)-1H-1,2,3-triazolo[4,5-b]pyridylmethylene]-N-methyl methanaminium hexafluoro phosphate N-oxide (HATU) and optionally a catalyst, for example, 1-hydroxybenzotriazole (HOBT) or 7-aza-1-hydroxy benzotriazole (HOAt) and optionally, with a base, for example, N,N-dimethylamino pyridine (DMAP), triethylamine, N,N-diisopropyl ethyl amine, or N-methyl morpholine.