709031-43-6

Basic information

• Product Name: N-[(1S)-2-[(1S,3S,5S)-3-Cyano-2-azabicyclo[3.1.0]hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-2-oxoethyl]carbamic acid 1,1-dimethylethyl ester
• Synonyms: N-[(1S)-2-[(1S,3S,5S)-3-Cyano-2-azabicyclo[3.1.0]hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-2-oxoethyl]carbamic acid 1,1-dimethylethyl ester;Saxagliptin interMediate 4;CarbaMic acid, N-[(1S)-2-[(1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-2-oxoethyl]-,1,1-diMethylethyl ester;Boc-saxagliptin
• CAS NO: 709031-43-6
• Molecular Formula: C₂₃H₃₃N₃O₄
• Molecular Weight: 415.53
• EINECS: 1312995-182-4
• Mol File: 709031-43-6.mol
• Article Data: 15

Chemical Properties

• Boiling Point: 624.716 °C at 760 mmHg
• Flash Point: 331.617 °C
• Appearance: /
• Density: 1.29
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.594
• PKA: 11.45±0.46(Predicted)
• CAS DataBase Reference: N-[(1S)-2-[(1S,3S,5S)-3-Cyano-2-azabicyclo[3.1.0]hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-2-oxoethyl]carbamic acid 1,1-dimethylethyl ester(CAS DataBase Reference)
• NIST Chemistry Reference: N-[(1S)-2-[(1S,3S,5S)-3-Cyano-2-azabicyclo[3.1.0]hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-2-oxoethyl]carbamic acid 1,1-dimethylethyl ester(709031-43-6)
• EPA Substance Registry System: N-[(1S)-2-[(1S,3S,5S)-3-Cyano-2-azabicyclo[3.1.0]hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-2-oxoethyl]carbamic acid 1,1-dimethylethyl ester(709031-43-6)

Safety Data

• Hazardous Substances Data: 709031-43-6(Hazardous Substances Data)

Usage

Uses

Boc-Saxagliptin is a Saxagliptin (S143500) impurity, a potent and selective reversible inhibitor of dipeptidyl peptidase-4, which is being developed for the treatment of type 2 diabetes. It is absorbed rapidly after oral administration and has a pharmacokinetic profile compatible with once daily dosing.

InChI:InChI=1/C23H33N3O4/c1-21(2,3)30-20(28)25-18(19(27)26-16(11-24)5-15-6-17(15)26)22-7-13-4-14(8-22)10-23(29,9-13)12-22/h13-18,29H,4-10,12H2,1-3H3,(H,25,28)/t13?,14?,15-,16+,17+,18-,22?,23?/m1/s1

Synthetic route

(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile + Na(1+)*C17H26NO5(1-) → 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 (709031-43-6)

Conditions	Yield
Stage #1: Na(1+)*C17H26NO5(1-) With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In ethyl acetate; acetonitrile at 20℃; for 5h; Stage #2: (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile In ethyl acetate; acetonitrile at 20℃; for 2h; Reagent/catalyst;	97.9%

tert-butyl [(1S)-2-[(1S,3S,5S)-3-carbamoyl-2-azabicyclo[3.1.0]hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13'7]dec-1-yl)-2-oxoethyl]carbamate (361442-01-5) → 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 (709031-43-6)

Conditions	Yield
Stage #1: tert-butyl [(1S)-2-[(1S,3S,5S)-3-carbamoyl-2-azabicyclo[3.1.0]hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13'7]dec-1-yl)-2-oxoethyl]carbamate With pyridine; trifluoroacetic anhydride In tetrahydrofuran for 1h; Stage #2: With potassium hydroxide In methanol at 20℃; for 18h;	92%
Stage #1: tert-butyl [(1S)-2-[(1S,3S,5S)-3-carbamoyl-2-azabicyclo[3.1.0]hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13'7]dec-1-yl)-2-oxoethyl]carbamate With triethylamine In ethyl acetate at 5 - 25℃; for 0.666667h; Stage #2: With trifluoroacetic anhydride In ethyl acetate at 20℃; for 2h;	92.3%
Stage #1: tert-butyl [(1S)-2-[(1S,3S,5S)-3-carbamoyl-2-azabicyclo[3.1.0]hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13'7]dec-1-yl)-2-oxoethyl]carbamate With pyridine; trifluoroacetic anhydride In tetrahydrofuran at 0℃; for 1.5h; Stage #2: With potassium carbonate In tetrahydrofuran; methanol at 20 - 25℃; pH=> 10;	89%

(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile 4-methylbenzenesulfonate (929106-57-0) + (S)-N-boc-(3-hydroxyadamantan-1-yl)glycine succinimide ester → 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 (709031-43-6)

Conditions	Yield
With triethylamine In tetrahydrofuran at 20℃; for 2h;	77%

(αS)-α-[[(1,1-dimethylethoxy)carbonyl]-amino]-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (361442-00-4) → 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 (709031-43-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 85 percent / EDAC; HOBT; TEA / dimethylformamide / 20 °C 2.1: pyridine; trifluoroacetic anhydride / tetrahydrofuran / 1 h 2.2: 92 percent / aq. KOH / methanol / 18 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; 4-methyl-morpholine / ethyl acetate; acetic acid butyl ester / 17.5 h / 0 °C / Inert atmosphere 2.1: trifluoroacetic anhydride; pyridine / tetrahydrofuran / 1.5 h / 0 °C 2.2: 20 - 25 °C / pH > 10 View Scheme
Multi-step reaction with 2 steps 1.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / ethyl acetate; acetonitrile / 3 h 2.1: trifluoroacetic anhydride; pyridine / tetrahydrofuran / 0.5 h / 0 °C 2.2: 18 h / 20 °C View Scheme

(S)-2-(adamantan-1-yl)-2-(((R)-2-hydroxy-1-phenylethyl)amino)acetonitrile (361441-95-4) → 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 (709031-43-6)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: 78 percent / aq. HCl; AcOH / 18 h / 80 °C 2.1: H2; AcOH / Pd(OH)2/C / methanol / 18 h / 2585.74 Torr 3.1: 4.07 g / K2CO3 / dimethylformamide / 19 h 4.1: 51 percent / KMnO4; aq. KOH / 1.5 h / 60 - 90 °C 5.1: 85 percent / EDAC; HOBT; TEA / dimethylformamide / 20 °C 6.1: pyridine; trifluoroacetic anhydride / tetrahydrofuran / 1 h 6.2: 92 percent / aq. KOH / methanol / 18 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1.1: hydrogenchloride; water / acetic acid / 80 °C 2.1: hydrogen; palladium 10% on activated carbon / acetic acid 3.1: triethylamine / methanol 4.1: potassium permanganate; potassium hydroxide / 90 °C 5.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / ethyl acetate; acetonitrile / 3 h 6.1: trifluoroacetic anhydride; pyridine / tetrahydrofuran / 0.5 h / 0 °C 6.2: 18 h / 20 °C View Scheme

(R)-N-((S)-(adamantan-1-yl)(carboxy)methyl)-2-hydroxy-1-phenylethan-1-ammonium chloride → 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 (709031-43-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: H2; AcOH / Pd(OH)2/C / methanol / 18 h / 2585.74 Torr 2.1: 4.07 g / K2CO3 / dimethylformamide / 19 h 3.1: 51 percent / KMnO4; aq. KOH / 1.5 h / 60 - 90 °C 4.1: 85 percent / EDAC; HOBT; TEA / dimethylformamide / 20 °C 5.1: pyridine; trifluoroacetic anhydride / tetrahydrofuran / 1 h 5.2: 92 percent / aq. KOH / methanol / 18 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: hydrogen; palladium 10% on activated carbon / acetic acid 2.1: triethylamine / methanol 3.1: potassium permanganate; potassium hydroxide / 90 °C 4.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / ethyl acetate; acetonitrile / 3 h 5.1: trifluoroacetic anhydride; pyridine / tetrahydrofuran / 0.5 h / 0 °C 5.2: 18 h / 20 °C View Scheme

1-adamantanemethanol (770-71-8) → 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 (709031-43-6)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: 98 percent / oxalyl chloride; DMSO; Et3N / CH2Cl2 / 1 h / -78 °C 2.1: 65 percent / NaHSO3 / H2O; methanol / 16 h / Heating 3.1: 78 percent / aq. HCl; AcOH / 18 h / 80 °C 4.1: H2; AcOH / Pd(OH)2/C / methanol / 18 h / 2585.74 Torr 5.1: 4.07 g / K2CO3 / dimethylformamide / 19 h 6.1: 51 percent / KMnO4; aq. KOH / 1.5 h / 60 - 90 °C 7.1: 85 percent / EDAC; HOBT; TEA / dimethylformamide / 20 °C 8.1: pyridine; trifluoroacetic anhydride / tetrahydrofuran / 1 h 8.2: 92 percent / aq. KOH / methanol / 18 h / 20 °C View Scheme

1-Adamantanecarboxylic acid (828-51-3) → 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 (709031-43-6)

Conditions	Yield
Multi-step reaction with 10 steps 1.1: 100 percent / diethyl ether; hexane; methanol / 3 h / 20 °C 2.1: 96 percent / LiAlH4 / tetrahydrofuran / 1.5 h / 0 - 20 °C 3.1: 98 percent / oxalyl chloride; DMSO; Et3N / CH2Cl2 / 1 h / -78 °C 4.1: 65 percent / NaHSO3 / H2O; methanol / 16 h / Heating 5.1: 78 percent / aq. HCl; AcOH / 18 h / 80 °C 6.1: H2; AcOH / Pd(OH)2/C / methanol / 18 h / 2585.74 Torr 7.1: 4.07 g / K2CO3 / dimethylformamide / 19 h 8.1: 51 percent / KMnO4; aq. KOH / 1.5 h / 60 - 90 °C 9.1: 85 percent / EDAC; HOBT; TEA / dimethylformamide / 20 °C 10.1: pyridine; trifluoroacetic anhydride / tetrahydrofuran / 1 h 10.2: 92 percent / aq. KOH / methanol / 18 h / 20 °C View Scheme
Multi-step reaction with 10 steps 1.1: sulfuric acid; nitric acid; water / -5 - 1 °C 2.1: sodium tetrahydroborate / tetrahydrofuran / 2.5 h / 0 - 31 °C 2.2: 14.5 h / 0 - 30 °C 2.3: 1 h / 0 - 10 °C 3.1: potassium bromide; sodium hydrogencarbonate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hypochlorite / dichloromethane; water / 0 - 5 °C 4.1: sodium hydrogensulfite / water / 0.17 h / 0 - 2 °C 5.1: water / 0.17 h / 0 - 2 °C 5.2: 14.5 h / -4 - 80 °C 6.1: hydrogenchloride; water / 1 h / 24 - 80 °C 6.2: 12 h / 80 - 82 °C 7.1: acetic acid; palladium(II) hydroxide; hydrogen / methanol / 5 h / 48 - 52 °C / 2625.26 - 3000.3 Torr 8.1: potassium carbonate; water / tetrahydrofuran / 0.17 h / 3 - 10 °C 8.2: 2.08 h / 3 - 26 °C 8.3: 12 h / 40 °C 9.1: benzotriazol-1-ol / dichloromethane / 0.08 h / -5 - 0 °C 9.2: 15.5 h / -7 - 10 °C 10.1: pyridine; trifluoroacetic anhydride / tetrahydrofuran / 6.33 h / -3 - 15 °C 10.2: 7 - 15 °C / pH 10 - 10.5 View Scheme

1-Adamantanecarbaldehyde (2094-74-8) → 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 (709031-43-6)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: 65 percent / NaHSO3 / H2O; methanol / 16 h / Heating 2.1: 78 percent / aq. HCl; AcOH / 18 h / 80 °C 3.1: H2; AcOH / Pd(OH)2/C / methanol / 18 h / 2585.74 Torr 4.1: 4.07 g / K2CO3 / dimethylformamide / 19 h 5.1: 51 percent / KMnO4; aq. KOH / 1.5 h / 60 - 90 °C 6.1: 85 percent / EDAC; HOBT; TEA / dimethylformamide / 20 °C 7.1: pyridine; trifluoroacetic anhydride / tetrahydrofuran / 1 h 7.2: 92 percent / aq. KOH / methanol / 18 h / 20 °C View Scheme
Multi-step reaction with 7 steps 1.1: sodium hydrogensulfite / 0 - 60 °C 2.1: hydrogenchloride; water / acetic acid / 80 °C 3.1: hydrogen; palladium 10% on activated carbon / acetic acid 4.1: triethylamine / methanol 5.1: potassium permanganate; potassium hydroxide / 90 °C 6.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / ethyl acetate; acetonitrile / 3 h 7.1: trifluoroacetic anhydride; pyridine / tetrahydrofuran / 0.5 h / 0 °C 7.2: 18 h / 20 °C View Scheme

methyl adamantane-1-carboxylate (711-01-3) → 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 (709031-43-6)

Conditions

Yield

Multi-step reaction with 9 steps 1.1: 96 percent / LiAlH4 / tetrahydrofuran / 1.5 h / 0 - 20 °C 2.1: 98 percent / oxalyl chloride; DMSO; Et3N / CH2Cl2 / 1 h / -78 °C 3.1: 65 percent / NaHSO3 / H2O; methanol / 16 h / Heating 4.1: 78 percent / aq. HCl; AcOH / 18 h / 80 °C 5.1: H2; AcOH / Pd(OH)2/C / methanol / 18 h / 2585.74 Torr 6.1: 4.07 g / K2CO3 / dimethylformamide / 19 h 7.1: 51 percent / KMnO4; aq. KOH / 1.5 h / 60 - 90 °C 8.1: 85 percent / EDAC; HOBT; TEA / dimethylformamide / 20 °C 9.1: pyridine; trifluoroacetic anhydride / tetrahydrofuran / 1 h 9.2: 92 percent / aq. KOH / methanol / 18 h / 20 °C View Scheme

(S)-(+)-β-amino-1-adamantaneacetic acid (95853-35-3) → 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 (709031-43-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 4.07 g / K2CO3 / dimethylformamide / 19 h 2.1: 51 percent / KMnO4; aq. KOH / 1.5 h / 60 - 90 °C 3.1: 85 percent / EDAC; HOBT; TEA / dimethylformamide / 20 °C 4.1: pyridine; trifluoroacetic anhydride / tetrahydrofuran / 1 h 4.2: 92 percent / aq. KOH / methanol / 18 h / 20 °C View Scheme

(alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → 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 (709031-43-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 51 percent / KMnO4; aq. KOH / 1.5 h / 60 - 90 °C 2.1: 85 percent / EDAC; HOBT; TEA / dimethylformamide / 20 °C 3.1: pyridine; trifluoroacetic anhydride / tetrahydrofuran / 1 h 3.2: 92 percent / aq. KOH / methanol / 18 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium permanganate; potassium hydroxide / 90 °C 2.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / ethyl acetate; acetonitrile / 3 h 3.1: trifluoroacetic anhydride; pyridine / tetrahydrofuran / 0.5 h / 0 °C 3.2: 18 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20.5 h / 0 - 20 °C / Inert atmosphere 2: pyridine; potassium bromate; rhodium(III) chloride hydrate / water; acetonitrile / 60 °C View Scheme

N-tert-butoxycarbonyl-3-hydroxy-1-adamantaneglycine → 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 (709031-43-6)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: ethyl acetate / 17.42 h / 20 - 70 °C / Resolution of racemate 2.1: hydrogenchloride / ethyl acetate; water / pH 3 3.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; 4-methyl-morpholine / ethyl acetate; acetic acid butyl ester / 17.5 h / 0 °C / Inert atmosphere 4.1: trifluoroacetic anhydride; pyridine / tetrahydrofuran / 1.5 h / 0 °C 4.2: 20 - 25 °C / pH > 10 View Scheme

(αS)-α-[(1,1-dimethylethoxy)carbonyl]amino-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid → 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 (709031-43-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride / ethyl acetate; water / pH 3 2.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; 4-methyl-morpholine / ethyl acetate; acetic acid butyl ester / 17.5 h / 0 °C / Inert atmosphere 3.1: trifluoroacetic anhydride; pyridine / tetrahydrofuran / 1.5 h / 0 °C 3.2: 20 - 25 °C / pH > 10 View Scheme

(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride → 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 (709031-43-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; 4-methyl-morpholine / ethyl acetate; acetic acid butyl ester / 17.5 h / 0 °C / Inert atmosphere 2.1: trifluoroacetic anhydride; pyridine / tetrahydrofuran / 1.5 h / 0 °C 2.2: 20 - 25 °C / pH > 10 View Scheme
Multi-step reaction with 2 steps 1.1: methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / Cooling with acetone-dry ice 1.2: 20 °C 2.1: pyridine; trifluoroacetic anhydride / 0.5 h / Cooling with ice 2.2: 7.55 h / Cooling View Scheme

N-tert-butoxycarbonyl-2-(3-hydroxy-1-adamantyl)-D-glycine (1334321-39-9) → 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 (709031-43-6)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine; isobutyl chloroformate / tetrahydrofuran / 1.5 h / -8 °C 1.2: 18 h / -8 - 25 °C 2.1: ethyl acetate / 17.42 h / 20 - 70 °C / Resolution of racemate 3.1: hydrogenchloride / ethyl acetate; water / pH 3 4.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; 4-methyl-morpholine / ethyl acetate; acetic acid butyl ester / 17.5 h / 0 °C / Inert atmosphere 5.1: trifluoroacetic anhydride; pyridine / tetrahydrofuran / 1.5 h / 0 °C 5.2: 20 - 25 °C / pH > 10 View Scheme

(S)-(+)-(adamant-1-yl)aminoacetic acid hydrochloride (102502-64-7) → 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 (709031-43-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: triethylamine / methanol 2.1: potassium permanganate; potassium hydroxide / 90 °C 3.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / ethyl acetate; acetonitrile / 3 h 4.1: trifluoroacetic anhydride; pyridine / tetrahydrofuran / 0.5 h / 0 °C 4.2: 18 h / 20 °C View Scheme

5-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (194594-23-5) → 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 (709031-43-6)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: dmap; trifluoroacetic anhydride; N-ethyl-N,N-diisopropylamine 2.1: water; lithium hydroxide / ethanol 3.1: ammonia; N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride / tetrahydrofuran 4.1: diethylzinc / 1,2-dimethoxyethane; dichloromethane / -30 - 20 °C 5.1: isopropyl alcohol / 60 °C 6.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / ethyl acetate; acetonitrile / 3 h 7.1: trifluoroacetic anhydride; pyridine / tetrahydrofuran / 0.5 h / 0 °C 7.2: 18 h / 20 °C View Scheme

(S)-ethyl N-tert-butoxycarbonylpyroglutamate (144978-35-8, 144978-12-1) → 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 (709031-43-6)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: lithium triethylborohydride / toluene / -70 - -60 °C 2.1: dmap; trifluoroacetic anhydride; N-ethyl-N,N-diisopropylamine 3.1: water; lithium hydroxide / ethanol 4.1: ammonia; N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride / tetrahydrofuran 5.1: diethylzinc / 1,2-dimethoxyethane; dichloromethane / -30 - 20 °C 6.1: isopropyl alcohol / 60 °C 7.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / ethyl acetate; acetonitrile / 3 h 8.1: trifluoroacetic anhydride; pyridine / tetrahydrofuran / 0.5 h / 0 °C 8.2: 18 h / 20 °C View Scheme
Multi-step reaction with 7 steps 1.1: lithium triethylborohydride / toluene; tetrahydrofuran / 0.5 h / -45 °C / Large scale 1.2: 3 h / 25 °C / Large scale 2.1: lithium hydroxide monohydrate / water; ethanol / 2 h / 25 °C / Large scale 3.1: methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / -25 - -20 °C / Large scale 3.2: 3 h / 0 - 20 °C / Large scale 4.1: diethylzinc / dichloromethane; toluene; 1,2-dimethoxyethane / 0.75 h / -30 - -20 °C / Large scale 4.2: -25 - 24 °C / Large scale 5.1: hydrogenchloride / water; tetrahydrofuran; ethyl acetate / 18 h / 20 °C 6.1: methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / Cooling with acetone-dry ice 6.2: 20 °C 7.1: pyridine; trifluoroacetic anhydride / 0.5 h / Cooling with ice 7.2: 7.55 h / Cooling View Scheme

ethyl (S)-pyroglutamate (7149-65-7) → 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 (709031-43-6)

Conditions	Yield
Multi-step reaction with 9 steps 1.1: dmap 2.1: lithium triethylborohydride / toluene / -70 - -60 °C 3.1: dmap; trifluoroacetic anhydride; N-ethyl-N,N-diisopropylamine 4.1: water; lithium hydroxide / ethanol 5.1: ammonia; N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride / tetrahydrofuran 6.1: diethylzinc / 1,2-dimethoxyethane; dichloromethane / -30 - 20 °C 7.1: isopropyl alcohol / 60 °C 8.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / ethyl acetate; acetonitrile / 3 h 9.1: trifluoroacetic anhydride; pyridine / tetrahydrofuran / 0.5 h / 0 °C 9.2: 18 h / 20 °C View Scheme
Multi-step reaction with 8 steps 1.1: dmap / toluene / 3 h / 25 °C / Large scale 2.1: lithium triethylborohydride / toluene; tetrahydrofuran / 0.5 h / -45 °C / Large scale 2.2: 3 h / 25 °C / Large scale 3.1: lithium hydroxide monohydrate / water; ethanol / 2 h / 25 °C / Large scale 4.1: methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / -25 - -20 °C / Large scale 4.2: 3 h / 0 - 20 °C / Large scale 5.1: diethylzinc / dichloromethane; toluene; 1,2-dimethoxyethane / 0.75 h / -30 - -20 °C / Large scale 5.2: -25 - 24 °C / Large scale 6.1: hydrogenchloride / water; tetrahydrofuran; ethyl acetate / 18 h / 20 °C 7.1: methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / Cooling with acetone-dry ice 7.2: 20 °C 8.1: pyridine; trifluoroacetic anhydride / 0.5 h / Cooling with ice 8.2: 7.55 h / Cooling View Scheme

(5S)-4,5-dihydro-1H-pyrrol-1,5-dicarboxylic acid [1-(1,1-dimethylethyl)] 5-ethyl ester (178172-26-4) → 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 (709031-43-6)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: water; lithium hydroxide / ethanol 2.1: ammonia; N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride / tetrahydrofuran 3.1: diethylzinc / 1,2-dimethoxyethane; dichloromethane / -30 - 20 °C 4.1: isopropyl alcohol / 60 °C 5.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / ethyl acetate; acetonitrile / 3 h 6.1: trifluoroacetic anhydride; pyridine / tetrahydrofuran / 0.5 h / 0 °C 6.2: 18 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1.1: lithium hydroxide monohydrate / water; ethanol / 2 h / 25 °C / Large scale 2.1: methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / -25 - -20 °C / Large scale 2.2: 3 h / 0 - 20 °C / Large scale 3.1: diethylzinc / dichloromethane; toluene; 1,2-dimethoxyethane / 0.75 h / -30 - -20 °C / Large scale 3.2: -25 - 24 °C / Large scale 4.1: hydrogenchloride / water; tetrahydrofuran; ethyl acetate / 18 h / 20 °C 5.1: methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / Cooling with acetone-dry ice 5.2: 20 °C 6.1: pyridine; trifluoroacetic anhydride / 0.5 h / Cooling with ice 6.2: 7.55 h / Cooling View Scheme

(S)-1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid diisopropylethylamine salt (709031-37-8) → 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 (709031-43-6)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: ammonia; N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride / tetrahydrofuran 2.1: diethylzinc / 1,2-dimethoxyethane; dichloromethane / -30 - 20 °C 3.1: isopropyl alcohol / 60 °C 4.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / ethyl acetate; acetonitrile / 3 h 5.1: trifluoroacetic anhydride; pyridine / tetrahydrofuran / 0.5 h / 0 °C 5.2: 18 h / 20 °C View Scheme

(5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9) → 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 (709031-43-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: diethylzinc / 1,2-dimethoxyethane; dichloromethane / -30 - 20 °C 2.1: isopropyl alcohol / 60 °C 3.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / ethyl acetate; acetonitrile / 3 h 4.1: trifluoroacetic anhydride; pyridine / tetrahydrofuran / 0.5 h / 0 °C 4.2: 18 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: diethylzinc / dichloromethane; toluene; 1,2-dimethoxyethane / 0.75 h / -30 - -20 °C / Large scale 1.2: -25 - 24 °C / Large scale 2.1: hydrogenchloride / water; tetrahydrofuran; ethyl acetate / 18 h / 20 °C 3.1: methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / Cooling with acetone-dry ice 3.2: 20 °C 4.1: pyridine; trifluoroacetic anhydride / 0.5 h / Cooling with ice 4.2: 7.55 h / Cooling View Scheme

[1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7) → 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 (709031-43-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: isopropyl alcohol / 60 °C 2.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / ethyl acetate; acetonitrile / 3 h 3.1: trifluoroacetic anhydride; pyridine / tetrahydrofuran / 0.5 h / 0 °C 3.2: 18 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: hydrogenchloride / water; tetrahydrofuran; ethyl acetate / 18 h / 20 °C 2.1: methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / Cooling with acetone-dry ice 2.2: 20 °C 3.1: pyridine; trifluoroacetic anhydride / 0.5 h / Cooling with ice 3.2: 7.55 h / Cooling View Scheme

(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide methane sulphonic acid (709031-45-8) → 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 (709031-43-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / ethyl acetate; acetonitrile / 3 h 2.1: trifluoroacetic anhydride; pyridine / tetrahydrofuran / 0.5 h / 0 °C 2.2: 18 h / 20 °C View Scheme

C25H32F3N3O5 (1194836-75-3) → 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 (709031-43-6)

Conditions	Yield
With potassium carbonate In methanol; water at 40 - 45℃; for 3h;	100 g

[(S)-1-Adamantan-1-yl-2-((1S,3S,5S)-3-cyano-2-aza-bicyclo[3.1.0]hex-2-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (862590-98-5) → 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 (709031-43-6)

Conditions	Yield
With pyridine; potassium bromate; rhodium(III) chloride hydrate In water; acetonitrile at 60℃; Solvent;

3-hydroxytricyclo[3.3.1.13'7]decane-1-carbaldehyde → 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 (709031-43-6)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: sodium hydrogensulfite / water / 0.17 h / 0 - 2 °C 2.1: water / 0.17 h / 0 - 2 °C 2.2: 14.5 h / -4 - 80 °C 3.1: hydrogenchloride; water / 1 h / 24 - 80 °C 3.2: 12 h / 80 - 82 °C 4.1: acetic acid; palladium(II) hydroxide; hydrogen / methanol / 5 h / 48 - 52 °C / 2625.26 - 3000.3 Torr 5.1: potassium carbonate; water / tetrahydrofuran / 0.17 h / 3 - 10 °C 5.2: 2.08 h / 3 - 26 °C 5.3: 12 h / 40 °C 6.1: benzotriazol-1-ol / dichloromethane / 0.08 h / -5 - 0 °C 6.2: 15.5 h / -7 - 10 °C 7.1: pyridine; trifluoroacetic anhydride / tetrahydrofuran / 6.33 h / -3 - 15 °C 7.2: 7 - 15 °C / pH 10 - 10.5 View Scheme

C11H17O5S(1-)*Na(1+) → 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 (709031-43-6)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: water / 0.17 h / 0 - 2 °C 1.2: 14.5 h / -4 - 80 °C 2.1: hydrogenchloride; water / 1 h / 24 - 80 °C 2.2: 12 h / 80 - 82 °C 3.1: acetic acid; palladium(II) hydroxide; hydrogen / methanol / 5 h / 48 - 52 °C / 2625.26 - 3000.3 Torr 4.1: potassium carbonate; water / tetrahydrofuran / 0.17 h / 3 - 10 °C 4.2: 2.08 h / 3 - 26 °C 4.3: 12 h / 40 °C 5.1: benzotriazol-1-ol / dichloromethane / 0.08 h / -5 - 0 °C 5.2: 15.5 h / -7 - 10 °C 6.1: pyridine; trifluoroacetic anhydride / tetrahydrofuran / 6.33 h / -3 - 15 °C 6.2: 7 - 15 °C / pH 10 - 10.5 View Scheme

(2S)-[((1S)-2-hydroxy-1-phenylethyl)amino]-(3-hydroxytricyclo[3.3.1.13'7]dec-1-yl)ethanenitrile → 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 (709031-43-6)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: hydrogenchloride; water / 1 h / 24 - 80 °C 1.2: 12 h / 80 - 82 °C 2.1: acetic acid; palladium(II) hydroxide; hydrogen / methanol / 5 h / 48 - 52 °C / 2625.26 - 3000.3 Torr 3.1: potassium carbonate; water / tetrahydrofuran / 0.17 h / 3 - 10 °C 3.2: 2.08 h / 3 - 26 °C 3.3: 12 h / 40 °C 4.1: benzotriazol-1-ol / dichloromethane / 0.08 h / -5 - 0 °C 4.2: 15.5 h / -7 - 10 °C 5.1: pyridine; trifluoroacetic anhydride / tetrahydrofuran / 6.33 h / -3 - 15 °C 5.2: 7 - 15 °C / pH 10 - 10.5 View Scheme

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 (709031-43-6) → saxagliptin

Conditions	Yield
With hydrogenchloride In water; isopropyl alcohol at 60 - 65℃; for 2.08333h; Temperature;	98.4%
Stage #1: 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 With hydrogenchloride In water; isopropyl alcohol at 20 - 65℃; for 2.08333h; Stage #2: With sodium hydroxide In dichloromethane; water; isopropyl alcohol Product distribution / selectivity;	86%
With hydrogenchloride In water; isopropyl alcohol at 60℃; for 2h;	78%

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 (709031-43-6) + trifluoroacetic acid (76-05-1) → (S)-3-hydroxyadamantylglycine-L-cis-4,5-methanoprolinenitrile TFA salt (361442-05-9)

Conditions	Yield
In dichloromethane at 20℃; for 2.5h;	95%
In dichloromethane at 20℃; for 2.5h;	90%
In dichloromethane at -5 - 2℃;	17.05 g

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 (709031-43-6) → (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloric acid salt

Conditions	Yield
With hydrogenchloride In water; isopropyl alcohol at 60 - 65℃; for 3h;	89%

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 (709031-43-6) → saxagliptin monohydrate (945667-22-1)

Conditions	Yield
Stage #1: 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 With hydrogenchloride In methanol; dichloromethane; water for 18h; Stage #2: With sodium hydroxide; water In methanol; dichloromethane for 0.333333h; pH=9.0 - 10.5; Product distribution / selectivity;	81%
Stage #1: 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 With hydrogenchloride In water; ethyl acetate at 23℃; for 4h; Stage #2: With water; potassium carbonate In ethyl acetate at 16 - 20℃; for 2h; Product distribution / selectivity;	77%
Stage #1: 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 With hydrogenchloride In water; isopropyl alcohol at 65℃; for 1.5h; Stage #2: With sodium hydroxide; water; potassium carbonate In dichloromethane; isopropyl alcohol pH=~ 9; Product distribution / selectivity;

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 (709031-43-6) + nicotinic acid (59-67-6) → [(1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile] nicotinate monohydrate

Conditions	Yield
Stage #1: 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 With hydrogenchloride; water at 30 - 65℃; Stage #2: nicotinic acid In dichloromethane at 20 - 30℃; Solvent;	80%

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 (709031-43-6) + sodium benzoate (532-32-1) → (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 benzoate

Conditions	Yield
Stage #1: 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 With hydrogenchloride In water; ethyl acetate at 20℃; Stage #2: sodium benzoate In water; isopropyl alcohol	79%

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 (709031-43-6) + salicylic acid (69-72-7) → [(1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile] salicylate

Conditions	Yield
Stage #1: 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 With hydrogenchloride In water; isopropyl alcohol at 30 - 65℃; Stage #2: salicylic acid In dichloromethane at 20 - 30℃;	77%

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 (709031-43-6) → C18H25N3O2*1.33ClH*1.67H2O

Conditions	Yield
With hydrogenchloride In water; ethyl acetate at 20 - 25℃; for 3h;

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 (709031-43-6) → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / isopropyl alcohol; water / 2.08 h / 20 - 65 °C 2: 20 - 30 °C 3: hydrogenchloride; water / acetone / 1.25 h View Scheme
With hydrogenchloride In propan-1-ol; water Product distribution / selectivity; Reflux;
With hydrogenchloride; water In isopropyl alcohol at 20 - 65℃; for 1h;	50 g
With dichloromethane In methanol at 20℃; Inert atmosphere;

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 (709031-43-6) → (1S,3S,5S)-2-[(2S)-2-propan-2-ylideneamino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]-hexane-3-carbonitrile (1346445-79-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride / isopropyl alcohol; water / 2.08 h / 20 - 65 °C 2: 20 - 30 °C View Scheme

Upstream product

• 866083-42-3 (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile 
• 361442-00-4 (αS)-α-[[(1,1-dimethylethoxy)carbonyl]-amino]-3-hydroxytricyclo[3.3.1.1^3,7]decane-1-acetic acid 
• 929106-57-0 (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile 4-methylbenzenesulfonate 
• 361442-57-1 (1S,3S,5S)-tert-butyl-3-cyano-2-azabicyclo[3.1.0]hexane-2-carboxylate 
• 700376-57-4 (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide 
• 30074-09-0 α-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid 
• 709031-35-6 dichloro-(3-hydroxy-adamantan-1-yl)-acetic acid methyl ester 
• 709031-29-8 (αS)-α-amino-3-hydroxytricyclo[3.3.1.1^3,7]decane-1-acetic acid 
• 128665-98-5 α-hydroxytricyclo[3.3.1.1^3,7]decane-1-acetic acid methyl ester 
• 709031-28-7 3-hydroxy-α-oxotricyclo [3.3.1.1^3,7]decane-1-acetic acid 
• 98-79-3 L-Pyroglutamic acid 
• 90104-21-5 1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid 
• 709031-34-5 dichloro-(tricyclo[3.3.1.1^3,7]decan-1-yl)acetic acid methyl ester 

Downstream Products

• 1564265-93-5 saxagliptin 
• 945667-22-1 saxagliptin monohydrate 
• 1370409-28-1 C₁₈H₂₅N₃O₂*1.33ClH*1.67H₂O 
• 709031-78-7 Saxagliptin hydrochloride 

Relevant articles and documents

Method for preparing saxagliptin

The invention discloses a method for preparing saxagliptin, and belongs to the technical field of drug synthesis. The method comprises the following steps: (a) converting amide on a compound shown ina formula I into cyano and removing Boc groups to obtain a compound shown in a formula II; (b) condensing the compound shown in the formula II and a compound shown in a formula III to obtain a compound shown in a formula IV; and (c) removing Boc groups on the compound shown in the formula IV to obtain a compound shown in a formula V. According to the method, different raw materials and reaction reagents are selected, and a process route is changed, so that four procedures of salifying, condensing, cyanating and de-protecting are shortened into three procedures of cyanating, condensing and de-protecting; meanwhile, cyanating and condensation reaction are realized at the room temperature, the requirements on reaction conditions are reduced, and industrial production can be realized.

Preparation method of medication saxagliptin for treating diabetes

The invention provides a preparation method of saxagliptin with a shorter synthetic route. (S)-3-amino-3-cyano-propionic ether protected by diethyl acetylenedicarboxylate and an amino group is used asa starting material in the presence of an organic phosphine ligand and a palladium catalyst, and is subjected to cyclization, decarboxylation and cyclopropanation to obtain an intermediate product (1S, 3S, 5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile p-toluenesulfonate, and then the intermediate product is reacted with carboxyl-activated (S)-N-t-butyloxycarboryl-(3-hydroxyadamantane-1-yl)glycineto increase the reaction rate and obtain a saxagliptin product with a high yield and high purity, the reaction route is greatly shortened, the yield in each step is high, the reaction time is short, the production cost is reduced, and industrial production is facilitated.

Method for synthesizing Saxagliptin and intermediate

A method for synthesizing Saxagliptin and its intermediate is disclosed. According to the method, propylphosphonic anhydride is used in a peptide coupling reaction and a dehydration reaction of formamide, thus reducing side reaction of racemization and decreasing toxicity of aftertreatment; and ethylene glycol diethyl ether is preferably used as a solvent in the dehydration reaction of formamide, thus increasing reaction temperature of propylphosphonic anhydride dehydration and shortening reaction time so as to reduce side reaction of racemization.