709031-43-6

Usage

Uses

1. Used in Pharmaceutical Industry:
Boc-Saxagliptin is used as an impurity in the development and manufacturing of Saxagliptin, a drug for the treatment of type 2 diabetes. Its presence in the final product is crucial for ensuring the safety, efficacy, and quality of the medication.
2. Used in Research and Development:
Boc-Saxagliptin serves as a valuable compound for researchers studying the structure-activity relationship of DPP-4 inhibitors. It can be used to investigate the effects of structural modifications on the potency, selectivity, and pharmacokinetic properties of Saxagliptin and related compounds.
3. Used in Quality Control and Regulatory Compliance:
Boc-Saxagliptin is utilized in the quality control processes of Saxagliptin manufacturing. It helps to ensure that the final drug product meets the required standards for purity, potency, and safety as stipulated by regulatory authorities.
4. Used in Drug Synthesis and Optimization:
Boc-Saxagliptin can be employed as a starting material or intermediate in the synthesis of novel DPP-4 inhibitors with potentially improved properties, such as enhanced potency, selectivity, or pharmacokinetic profiles. This can lead to the development of more effective treatments for type 2 diabetes.

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

• 361442-01-5 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 
• 361442-00-4 (αS)-α-[[(1,1-dimethylethoxy)carbonyl]-amino]-3-hydroxytricyclo[3.3.1.1^3,7]decane-1-acetic acid 
• 361441-95-4 (S)-2-(adamantan-1-yl)-2-(((R)-2-hydroxy-1-phenylethyl)amino)acetonitrile 
• 770-71-8 1-adamantanemethanol 
• 828-51-3 1-Adamantanecarboxylic acid 
• 2094-74-8 1-Adamantanecarbaldehyde 
• 711-01-3 methyl adamantane-1-carboxylate 
• 95853-35-3 (S)-(+)-β-amino-1-adamantaneacetic acid 
• 361441-97-6 (alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.1^3,7]decane-1-acetic acid 
• 709031-39-0 (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride 
• 1334321-39-9 N-tert-butoxycarbonyl-2-(3-hydroxy-1-adamantyl)-D-glycine 
• 102502-64-7 (S)-(+)-(adamant-1-yl)aminoacetic acid hydrochloride 
• 194594-23-5 5-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester 
• 144978-35-8 (S)-ethyl N-tert-butoxycarbonylpyroglutamate 

Downstream Products

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

Relevant academic research and scientific papers

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 saxagliptin

The invention discloses a preparation method of saxagliptin. The preparation method comprises the following steps: reacting (S)-N-tert-butyloxycarbonyl-(3-hydroxyadamantan-1-yl)glycine with (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride under the catalysis of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate/N,N-diisopropylethylamine to obtain (1S)-2-(1S,3S,5S)-3-carbamoyl-2-azabicyclo[3,1,0]hex-2-yl]-1-(3-hydroxyadamantan-1-yl)-2-oxoethyl tert-butyl carbamate, and removing protecting groups under acidic adjustment so as to obtain (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]decan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-nitrile. The method has the advantages of safety, easiness in operation, usage cheap and easily available raw materials, mild and easily controllable reaction conditions, simple post-reaction treatment, high yield and the like.

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.

Novel intermediates for preparing saxagliptin, preparing methods thereof and preparing methods of saxagliptin using the same

The present invention relates to a novel intermediate used in the production of saxagliptin, a production method thereof, and a method for producing saxagliptin using the same. According to the present invention, the use of the novel intermediate which is represented by chemical formula 1 enables the production of high purity saxagliptin or a pharmaceutically acceptable salt thereof in high yield through a simple and economical way.COPYRIGHT KIPO 2017

PROCESS FOR PREPARING DIPEPTIDYL PEPTIDASE IV INHIBITORS AND INTERMEDIATES THEREFOR

A process for preparing an amine of the structure which comprises a. treating an aqueous solution of a keto acid of the structure with ammonium formate, nicotinamide adenine dinucleotide, dithiothreitol and partially purified phenylalanine dehydrogenase and/or formate dehydrogenase enzyme (PDH/FDH); and b. adjusting pH of the reaction mixture with sodium hydroxide to form the desired amine which is substantially free of undesirable excess ammonium ions.

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.

A hypoglycemic compound, preparation method thereof, pharmaceutical composition containing the same and its use

The invention provides a blood sugar reducing compound, a preparation method of the blood sugar reducing compound, a medicine composition including the blood sugar reducing compound and an application of the medicine composition. The compound is a compound shown in a general formula (I) or a pharmaceutically acceptable salt, a solvate, a polymorphism body, an enantiomer or a racemic mixture thereof, the general formula is described in the specification, wherein R1, R2, R3 and R4 are independently H, optionally substituted alkyl, optionally substituted naphthenic base, optionally substituted alkoxy, optionally substituted aryl, optionally substituted aralkyl, or optionally substituted naphthenic base formed by R1 and R2, or optionally substituted heterocyclic radical formed by R2 and R3, or optionally substituted heterocyclic radical formed by R3 and R4. The compound is actively transported by a PepT1 transporter to be absorbed by the gastrointestinal tract, and decomposed in the intestinal tract and the liver to slowly generate saxagliptin, thus the blood concentration of the saxagliptin is increased, and the retention time of the saxagliptin in blood is prolonged. The blood sugar reducing treatment effect is favorably increased and the side reaction is favorably reduced due to stable blood concentration.

PROCESS FOR THE PREPARATION OF SAXAGLIPTIN AND ITS INTERMEDIATES

The present invention provides intermediates of saxagliptin and processes for their preparation. The present invention also provides a process for the preparation of saxagliptin or salts or hydrates thereof by using the intermediates.

Synthesis and biological evaluation of all eight stereoisomers of DPP-IV inhibitor saxagliptin

All eight stereoisomers of saxagliptin have been synthesized and evaluated for their inhibitory activity against DPP-IV. It was unambiguously confirmed that the configuration of saxagliptin was critical to potent inhibition of DPP-IV. Docking study was performed to elucidate the configuration-activity relationship of saxagliptin stereoisomers. Tyr662 and Tyr470 have been suggested as the key residues of DPP-IV interacting with the inhibitors. This work provides valuable information for further inhibitor design against DPP-IV.

PROCESS FOR THE PREPARATION OF INTERMEDIATES OF SYNTHESIS OF SAXAGLIPTIN AND NOVEL COMPOUNDS

The object of the present invention is the preparation of saxagliptin and novel intermediate compounds.