709031-78-7

Usage

References

Tahrani et al. (2009) Saxagliptin: a new DPP-4 inhibitor for the treatment of type 2 diabetes mellitus; Adv. Ther. 26 249 Augeri et al. (2005) Discovery and Preclinical Profile of Saxagliptin (BMS-477118): A Highly Potent, Long-Acting, Orally Active Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes; J. Med. Chem. 48 5025

Synthetic route

saxagliptin → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
With hydrogenchloride In water; ethyl acetate at 5 - 10℃;	99%
With chloro-trimethyl-silane In acetone for 1h;
Multi-step reaction with 2 steps 1: 20 - 30 °C 2: hydrogenchloride; water / acetone / 1.25 h View Scheme

(1S,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
With hydrogenchloride; water In methanol at 25℃; for 3h;	90%

C25H31N3O2 → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
Stage #1: C25H31N3O2 With palladium 10% on activated carbon In methanol at 25 - 30℃; for 2h; Stage #2: With hydrogenchloride In ethyl acetate at 25 - 30℃; for 4h;	80%
Stage #1: C25H31N3O2 With palladium 10% on activated carbon In methanol at 25 - 30℃; for 2h; Stage #2: With hydrogenchloride In water; ethyl acetate at 25 - 30℃; for 4h;	80%

C18H23N5O2 → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
Stage #1: C18H23N5O2 With ammonium chloride; zinc In methanol; water at 25 - 30℃; for 2h; Stage #2: With hydrogenchloride In water at 25 - 30℃; for 4h;	73%
Stage #1: C18H23N5O2 With ammonium chloride; zinc In methanol; water at 25 - 30℃; for 2h; Stage #2: With hydrogenchloride In water; ethyl acetate at 25 - 30℃; for 4h;	73%

saxagliptin monohydrochloride dihydrate → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
In ethanol at 45℃;

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;

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) → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 0.5 h / 0 °C 1.2: 0.58 h / 0 - 7 °C 2.1: hydrogenchloride / isopropyl alcohol; water / 2.08 h / 20 - 65 °C 3.1: 20 - 30 °C 4.1: hydrogenchloride; water / acetone / 1.25 h View Scheme
Multi-step reaction with 2 steps 1: triethylamine; trifluoroacetyl chloride / dichloromethane / 0 - 10 °C 2: hydrogenchloride / water; propan-1-ol / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: pyridine; trifluoroacetic anhydride / 0.5 h / Cooling with ice 1.2: 7.55 h / Cooling 2.1: dichloromethane / methanol / 20 °C / Inert atmosphere View Scheme

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

Conditions	Yield
With hydrogenchloride; water In acetone for 1.25h;
With ammonium chloride at 20℃; pH=4.53;

(S)-3-hydroxyadamantylglycine-L-cis-4,5-methanoprolinenitrile TFA salt (361442-05-9) → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
Stage #1: (S)-3-hydroxyadamantylglycine-L-cis-4,5-methanoprolinenitrile TFA salt With sodium hydroxide In water Stage #2: With hydrogenchloride In dichloromethane; water

benzyl N-[(1S)-2-[(1S,3S,5S)-3-carbamoyl-2-azabicyclo[3.1.0]hexan-2-yl]-1-(3-hydroxyadamantan-1-yl)-2-oxoethyl]carbamate → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: trifluoroacetic anhydride; 3-pyridinecarboxylic acid ethyl ester / ethyl acetate / 6 h / 0 - 5 °C 1.2: 2 h / 25 °C 2.1: 5%-palladium/activated carbon; hydrogen / acetonitrile / 4 h / 20 - 25 °C 3.1: hydrogenchloride / water; ethyl acetate / 5 - 10 °C View Scheme

benzyl N-[(1S)-2-[(1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl]-1-(3-hydroxyadamantan-1-yl)-2-oxoethyl]carbamate → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 5%-palladium/activated carbon; hydrogen / acetonitrile / 4 h / 20 - 25 °C 2: hydrogenchloride / water; ethyl acetate / 5 - 10 °C View Scheme

(2S)-2-{[(benzyloxy)carbonyl]amino}-2-(3-hydroxyadamantan-1-yl)acetic acid → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / ethyl acetate; acetonitrile / 8.25 h / 20 °C 2: 5%-palladium/activated carbon; hydrogen / acetonitrile / 4 h / 20 - 25 °C 3: hydrogenchloride / water; ethyl acetate / 5 - 10 °C View Scheme
Multi-step reaction with 4 steps 1.1: N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 4.25 h / 20 °C 2.1: trifluoroacetic anhydride; 3-pyridinecarboxylic acid ethyl ester / ethyl acetate / 6 h / 0 - 5 °C 2.2: 2 h / 25 °C 3.1: 5%-palladium/activated carbon; hydrogen / acetonitrile / 4 h / 20 - 25 °C 4.1: hydrogenchloride / water; ethyl acetate / 5 - 10 °C View Scheme

(1S)-α-amino-3-hydroxyadamantane-acetic acid hydrochloride (865999-64-0) → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium hydroxide / water / 4 h / 25 - 30 °C / pH 8.5 - 9.5 2: N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / ethyl acetate; acetonitrile / 8.25 h / 20 °C 3: 5%-palladium/activated carbon; hydrogen / acetonitrile / 4 h / 20 - 25 °C 4: hydrogenchloride / water; ethyl acetate / 5 - 10 °C View Scheme
Multi-step reaction with 5 steps 1.1: sodium hydroxide / water / 4 h / 25 - 30 °C / pH 8.5 - 9.5 2.1: N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 4.25 h / 20 °C 3.1: trifluoroacetic anhydride; 3-pyridinecarboxylic acid ethyl ester / ethyl acetate / 6 h / 0 - 5 °C 3.2: 2 h / 25 °C 4.1: 5%-palladium/activated carbon; hydrogen / acetonitrile / 4 h / 20 - 25 °C 5.1: hydrogenchloride / water; ethyl acetate / 5 - 10 °C View Scheme
Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 4 h / 15 - 35 °C 2.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / dichloromethane / 12 h / 5 - 35 °C 3.1: pyridine; trifluoroacetic anhydride / tetrahydrofuran / 3.5 h / 0 - 10 °C 3.2: 3.5 h / 25 °C / pH 10 - 11 4.1: water; hydrogenchloride / methanol / 3 h / 25 °C View Scheme

(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile 4-methylbenzenesulfonate (929106-57-0) → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / ethyl acetate; acetonitrile / 8.25 h / 20 °C 2: 5%-palladium/activated carbon; hydrogen / acetonitrile / 4 h / 20 - 25 °C 3: hydrogenchloride / water; ethyl acetate / 5 - 10 °C View Scheme

(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide → Saxagliptin hydrochloride (709031-78-7)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 4.25 h / 20 °C 2.1: trifluoroacetic anhydride; 3-pyridinecarboxylic acid ethyl ester / ethyl acetate / 6 h / 0 - 5 °C 2.2: 2 h / 25 °C 3.1: 5%-palladium/activated carbon; hydrogen / acetonitrile / 4 h / 20 - 25 °C 4.1: hydrogenchloride / water; ethyl acetate / 5 - 10 °C View Scheme

C12H17N3O3 → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: benzotriazol-1-ol / ethyl acetate; acetonitrile / 0.17 h / 25 - 30 °C / Inert atmosphere 1.2: 0.17 h / 25 - 30 °C 1.3: 0 - 30 °C / Inert atmosphere 2.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 2.2: 3 h / 25 - 45 °C 3.1: zinc; ammonium chloride / water; methanol / 2 h / 25 - 30 °C 3.2: 4 h / 25 - 30 °C View Scheme
Multi-step reaction with 4 steps 1.1: (S)-1-phenyl-ethylamine / acetone / 7 h / 25 - 65 °C 2.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / ethyl acetate; acetonitrile / 0.25 h / 20 °C 2.2: 4 h / 0 - 20 °C 3.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 3.2: 3 h / 25 - 45 °C 4.1: zinc; ammonium chloride / water; methanol / 2 h / 25 - 30 °C 4.2: 4 h / 25 - 30 °C View Scheme
Multi-step reaction with 4 steps 1.1: (S)-1-phenyl-ethylamine / acetone / 7 h / 25 - 65 °C 1.2: 2 h / 25 - 30 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / acetonitrile; ethyl acetate / 4 h / 0 - 20 °C 3.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 3.2: 3 h / 25 - 45 °C 4.1: zinc; ammonium chloride / water; methanol / 2 h / 25 - 30 °C 4.2: 4 h / 25 - 30 °C View Scheme

C12H17N3O3 → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / ethyl acetate; acetonitrile / 0.25 h / 20 °C 1.2: 4 h / 0 - 20 °C 2.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 2.2: 3 h / 25 - 45 °C 3.1: zinc; ammonium chloride / water; methanol / 2 h / 25 - 30 °C 3.2: 4 h / 25 - 30 °C View Scheme
Multi-step reaction with 3 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / acetonitrile; ethyl acetate / 4 h / 0 - 20 °C 2.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 2.2: 3 h / 25 - 45 °C 3.1: zinc; ammonium chloride / water; methanol / 2 h / 25 - 30 °C 3.2: 4 h / 25 - 30 °C View Scheme

C18H25N5O3 → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 1.2: 3 h / 25 - 45 °C 2.1: zinc; ammonium chloride / water; methanol / 2 h / 25 - 30 °C 2.2: 4 h / 25 - 30 °C View Scheme
Multi-step reaction with 2 steps 1.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 1.2: 3 h / 25 - 45 °C 2.1: zinc; ammonium chloride / water; methanol / 2 h / 25 - 30 °C 2.2: 4 h / 25 - 30 °C View Scheme

C19H25NO3 → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: (S)-1-phenyl-ethylamine / methanol / 7 h / 25 - 65 °C 2.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / ethyl acetate; acetonitrile / 0.25 h / 20 °C 2.2: 4 h / 0 - 20 °C 3.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 3.2: 3 h / 25 - 45 °C 4.1: palladium 10% on activated carbon / methanol / 2 h / 25 - 30 °C 4.2: 4 h / 25 - 30 °C View Scheme
Multi-step reaction with 4 steps 1.1: (S)-1-phenyl-ethylamine / methanol / 7 h / 25 - 65 °C 1.2: 1 h / 25 - 30 °C 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / acetonitrile; ethyl acetate / 4 h / 0 - 20 °C 3.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 3.2: 3 h / 25 - 45 °C 4.1: palladium 10% on activated carbon / methanol / 2 h / 25 - 30 °C 4.2: 4 h / 25 - 30 °C View Scheme

C19H25NO3 → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / ethyl acetate; acetonitrile / 0.25 h / 20 °C 1.2: 4 h / 0 - 20 °C 2.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 2.2: 3 h / 25 - 45 °C 3.1: palladium 10% on activated carbon / methanol / 2 h / 25 - 30 °C 3.2: 4 h / 25 - 30 °C View Scheme
Multi-step reaction with 3 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / acetonitrile; ethyl acetate / 4 h / 0 - 20 °C 2.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 2.2: 3 h / 25 - 45 °C 3.1: palladium 10% on activated carbon / methanol / 2 h / 25 - 30 °C 3.2: 4 h / 25 - 30 °C View Scheme

C25H33N3O3 → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 1.2: 3 h / 25 - 45 °C 2.1: palladium 10% on activated carbon / methanol / 2 h / 25 - 30 °C 2.2: 4 h / 25 - 30 °C View Scheme

(adamant-1-yl)-acetic acid (4942-47-6) → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: thionyl chloride / 1.5 h / 20 °C / Inert atmosphere 1.2: 3 h / 25 - 75 °C 2.1: sulfuric acid; nitric acid / water / 0 - 10 °C 3.1: tetrabutylammomium bromide; sodium azide / water; toluene / 25 - 80 °C 4.1: benzotriazol-1-ol / ethyl acetate; acetonitrile / 0.17 h / 25 - 30 °C / Inert atmosphere 4.2: 0.17 h / 25 - 30 °C 4.3: 0 - 30 °C / Inert atmosphere 5.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 5.2: 3 h / 25 - 45 °C 6.1: zinc; ammonium chloride / water; methanol / 2 h / 25 - 30 °C 6.2: 4 h / 25 - 30 °C View Scheme
Multi-step reaction with 7 steps 1.1: thionyl chloride / 1.5 h / 20 °C / Inert atmosphere 1.2: 3 h / 25 - 75 °C 2.1: sulfuric acid; nitric acid / water / 0 - 10 °C 3.1: tetrabutylammomium bromide; sodium azide / water; toluene / 25 - 80 °C 4.1: (S)-1-phenyl-ethylamine / acetone / 7 h / 25 - 65 °C 5.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / ethyl acetate; acetonitrile / 0.25 h / 20 °C 5.2: 4 h / 0 - 20 °C 6.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 6.2: 3 h / 25 - 45 °C 7.1: zinc; ammonium chloride / water; methanol / 2 h / 25 - 30 °C 7.2: 4 h / 25 - 30 °C View Scheme
Multi-step reaction with 7 steps 1.1: thionyl chloride / 1.5 h / 20 °C / Inert atmosphere 1.2: 3 h / 25 - 75 °C 2.1: sulfuric acid; nitric acid / water / 0 - 10 °C 3.1: 3 h / 110 °C 4.1: (S)-1-phenyl-ethylamine / methanol / 7 h / 25 - 65 °C 5.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / ethyl acetate; acetonitrile / 0.25 h / 20 °C 5.2: 4 h / 0 - 20 °C 6.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 6.2: 3 h / 25 - 45 °C 7.1: palladium 10% on activated carbon / methanol / 2 h / 25 - 30 °C 7.2: 4 h / 25 - 30 °C View Scheme
Multi-step reaction with 7 steps 1.1: thionyl chloride / 1.5 h / 20 °C / Inert atmosphere 1.2: 3 h / 25 - 75 °C 1.3: 3 h / 0 - 75 °C 2.1: sulfuric acid; nitric acid / 0 - 10 °C 2.2: 2 h / 0 - 10 °C 3.1: 3 h / 110 °C 4.1: (S)-1-phenyl-ethylamine / methanol / 7 h / 25 - 65 °C 4.2: 1 h / 25 - 30 °C 5.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / acetonitrile; ethyl acetate / 4 h / 0 - 20 °C 6.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 6.2: 3 h / 25 - 45 °C 7.1: palladium 10% on activated carbon / methanol / 2 h / 25 - 30 °C 7.2: 4 h / 25 - 30 °C View Scheme
Multi-step reaction with 7 steps 1.1: thionyl chloride / 1.5 h / 20 °C / Inert atmosphere 1.2: 3 h / 25 - 75 °C 1.3: 3 h / 0 - 75 °C 2.1: sulfuric acid; nitric acid / 0 - 10 °C 2.2: 2 h / 0 - 10 °C 3.1: tetrabutylammomium bromide; sodium azide / toluene; water / 25 - 80 °C 4.1: (S)-1-phenyl-ethylamine / acetone / 7 h / 25 - 65 °C 4.2: 2 h / 25 - 30 °C 5.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / acetonitrile; ethyl acetate / 4 h / 0 - 20 °C 6.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 6.2: 3 h / 25 - 45 °C 7.1: zinc; ammonium chloride / water; methanol / 2 h / 25 - 30 °C 7.2: 4 h / 25 - 30 °C View Scheme

2-(1-adamantyl)-2-bromoacetic acid (59768-70-6) → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: sulfuric acid; nitric acid / water / 0 - 10 °C 2.1: tetrabutylammomium bromide; sodium azide / water; toluene / 25 - 80 °C 3.1: benzotriazol-1-ol / ethyl acetate; acetonitrile / 0.17 h / 25 - 30 °C / Inert atmosphere 3.2: 0.17 h / 25 - 30 °C 3.3: 0 - 30 °C / Inert atmosphere 4.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 4.2: 3 h / 25 - 45 °C 5.1: zinc; ammonium chloride / water; methanol / 2 h / 25 - 30 °C 5.2: 4 h / 25 - 30 °C View Scheme
Multi-step reaction with 6 steps 1.1: sulfuric acid; nitric acid / water / 0 - 10 °C 2.1: tetrabutylammomium bromide; sodium azide / water; toluene / 25 - 80 °C 3.1: (S)-1-phenyl-ethylamine / acetone / 7 h / 25 - 65 °C 4.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / ethyl acetate; acetonitrile / 0.25 h / 20 °C 4.2: 4 h / 0 - 20 °C 5.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 5.2: 3 h / 25 - 45 °C 6.1: zinc; ammonium chloride / water; methanol / 2 h / 25 - 30 °C 6.2: 4 h / 25 - 30 °C View Scheme
Multi-step reaction with 6 steps 1.1: sulfuric acid; nitric acid / water / 0 - 10 °C 2.1: 3 h / 110 °C 3.1: (S)-1-phenyl-ethylamine / methanol / 7 h / 25 - 65 °C 4.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / ethyl acetate; acetonitrile / 0.25 h / 20 °C 4.2: 4 h / 0 - 20 °C 5.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 5.2: 3 h / 25 - 45 °C 6.1: palladium 10% on activated carbon / methanol / 2 h / 25 - 30 °C 6.2: 4 h / 25 - 30 °C View Scheme
Multi-step reaction with 6 steps 1.1: sulfuric acid; nitric acid / 0 - 10 °C 1.2: 2 h / 0 - 10 °C 2.1: 3 h / 110 °C 3.1: (S)-1-phenyl-ethylamine / methanol / 7 h / 25 - 65 °C 3.2: 1 h / 25 - 30 °C 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / acetonitrile; ethyl acetate / 4 h / 0 - 20 °C 5.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 5.2: 3 h / 25 - 45 °C 6.1: palladium 10% on activated carbon / methanol / 2 h / 25 - 30 °C 6.2: 4 h / 25 - 30 °C View Scheme
Multi-step reaction with 6 steps 1.1: sulfuric acid; nitric acid / 0 - 10 °C 1.2: 2 h / 0 - 10 °C 2.1: tetrabutylammomium bromide; sodium azide / toluene; water / 25 - 80 °C 3.1: (S)-1-phenyl-ethylamine / acetone / 7 h / 25 - 65 °C 3.2: 2 h / 25 - 30 °C 4.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / acetonitrile; ethyl acetate / 4 h / 0 - 20 °C 5.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 5.2: 3 h / 25 - 45 °C 6.1: zinc; ammonium chloride / water; methanol / 2 h / 25 - 30 °C 6.2: 4 h / 25 - 30 °C View Scheme

α-bromo-3-hydroxy-1-adamantyl acetic acid → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: tetrabutylammomium bromide; sodium azide / water; toluene / 25 - 80 °C 2.1: benzotriazol-1-ol / ethyl acetate; acetonitrile / 0.17 h / 25 - 30 °C / Inert atmosphere 2.2: 0.17 h / 25 - 30 °C 2.3: 0 - 30 °C / Inert atmosphere 3.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 3.2: 3 h / 25 - 45 °C 4.1: zinc; ammonium chloride / water; methanol / 2 h / 25 - 30 °C 4.2: 4 h / 25 - 30 °C View Scheme
Multi-step reaction with 5 steps 1.1: tetrabutylammomium bromide; sodium azide / water; toluene / 25 - 80 °C 2.1: (S)-1-phenyl-ethylamine / acetone / 7 h / 25 - 65 °C 3.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / ethyl acetate; acetonitrile / 0.25 h / 20 °C 3.2: 4 h / 0 - 20 °C 4.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 4.2: 3 h / 25 - 45 °C 5.1: zinc; ammonium chloride / water; methanol / 2 h / 25 - 30 °C 5.2: 4 h / 25 - 30 °C View Scheme
Multi-step reaction with 5 steps 1.1: 3 h / 110 °C 2.1: (S)-1-phenyl-ethylamine / methanol / 7 h / 25 - 65 °C 3.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / ethyl acetate; acetonitrile / 0.25 h / 20 °C 3.2: 4 h / 0 - 20 °C 4.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 4.2: 3 h / 25 - 45 °C 5.1: palladium 10% on activated carbon / methanol / 2 h / 25 - 30 °C 5.2: 4 h / 25 - 30 °C View Scheme
Multi-step reaction with 5 steps 1.1: tetrabutylammomium bromide; sodium azide / toluene; water / 25 - 80 °C 2.1: (S)-1-phenyl-ethylamine / acetone / 7 h / 25 - 65 °C 2.2: 2 h / 25 - 30 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / acetonitrile; ethyl acetate / 4 h / 0 - 20 °C 4.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 4.2: 3 h / 25 - 45 °C 5.1: zinc; ammonium chloride / water; methanol / 2 h / 25 - 30 °C 5.2: 4 h / 25 - 30 °C View Scheme
Multi-step reaction with 5 steps 1.1: 3 h / 110 °C 2.1: (S)-1-phenyl-ethylamine / methanol / 7 h / 25 - 65 °C 2.2: 1 h / 25 - 30 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine / acetonitrile; ethyl acetate / 4 h / 0 - 20 °C 4.1: pyridine; trifluoroacetic anhydride / ethyl acetate / 0 - 5 °C 4.2: 3 h / 25 - 45 °C 5.1: palladium 10% on activated carbon / methanol / 2 h / 25 - 30 °C 5.2: 4 h / 25 - 30 °C View Scheme

(αS)-α-[[(1,1-dimethylethoxy)carbonyl]-amino]-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (361442-00-4) → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: hydrogenchloride / isopropyl alcohol; dichloromethane / 8 h / 10 - 35 °C 2.1: triethylamine / dichloromethane / 4 h / 15 - 35 °C 3.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / dichloromethane / 12 h / 5 - 35 °C 4.1: pyridine; trifluoroacetic anhydride / tetrahydrofuran / 3.5 h / 0 - 10 °C 4.2: 3.5 h / 25 °C / pH 10 - 11 5.1: water; hydrogenchloride / methanol / 3 h / 25 °C View Scheme
Multi-step reaction with 3 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 3.1: dichloromethane / methanol / 20 °C / Inert atmosphere View Scheme

(1S)-1-[triphenylmethylamino]-3-hydroxyadamantane-1-acetic acid → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / dichloromethane / 12 h / 5 - 35 °C 2.1: pyridine; trifluoroacetic anhydride / tetrahydrofuran / 3.5 h / 0 - 10 °C 2.2: 3.5 h / 25 °C / pH 10 - 11 3.1: water; hydrogenchloride / methanol / 3 h / 25 °C View Scheme

[1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7) → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: isopropyl alcohol / 5 h / 60 - 70 °C 2.1: dichloromethane / 0.25 h / 25 - 35 °C 2.2: 13.25 h / 5 - 35 °C 3.1: pyridine; trifluoroacetic anhydride / tetrahydrofuran / 3.5 h / 0 - 10 °C 3.2: 3.5 h / 25 °C / pH 10 - 11 4.1: water; hydrogenchloride / methanol / 3 h / 25 °C View Scheme
Multi-step reaction with 4 steps 1.1: isopropyl alcohol / 5 h / 60 - 70 °C 2.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / dichloromethane / 12 h / 5 - 35 °C 3.1: pyridine; trifluoroacetic anhydride / tetrahydrofuran / 3.5 h / 0 - 10 °C 3.2: 3.5 h / 25 °C / pH 10 - 11 4.1: water; hydrogenchloride / methanol / 3 h / 25 °C View Scheme
Multi-step reaction with 4 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 4.1: dichloromethane / methanol / 20 °C / Inert atmosphere View Scheme

(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide methane sulphonic acid (709031-45-8) → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / dichloromethane / 12 h / 5 - 35 °C 2.1: pyridine; trifluoroacetic anhydride / tetrahydrofuran / 3.5 h / 0 - 10 °C 2.2: 3.5 h / 25 °C / pH 10 - 11 3.1: water; hydrogenchloride / methanol / 3 h / 25 °C View Scheme
Multi-step reaction with 3 steps 1.1: dichloromethane / 0.25 h / 25 - 35 °C 1.2: 13.25 h / 5 - 35 °C 2.1: pyridine; trifluoroacetic anhydride / tetrahydrofuran / 3.5 h / 0 - 10 °C 2.2: 3.5 h / 25 °C / pH 10 - 11 3.1: water; hydrogenchloride / methanol / 3 h / 25 °C View Scheme

(5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9) → Saxagliptin hydrochloride (709031-78-7)

Conditions

Yield

Multi-step reaction with 5 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 5.1: dichloromethane / methanol / 20 °C / Inert atmosphere View Scheme

(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride → Saxagliptin hydrochloride (709031-78-7)

Conditions	Yield
Multi-step reaction with 3 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 3.1: dichloromethane / methanol / 20 °C / Inert atmosphere View Scheme

malonic acid (141-82-2) + Saxagliptin hydrochloride (709031-78-7) → saxagliptin hydrochloride-malonic acid cocrystal (3:2)

Conditions	Yield
In methanol at 20 - 25℃; for 0.75h;	100%

saxagliptin + Saxagliptin hydrochloride (709031-78-7) → saxagliptin hydrochloride-saxagliptin cocrystal (1:1)

Conditions	Yield
In isopropyl alcohol for 0.75h; Solvent;	100%

Saxagliptin hydrochloride (709031-78-7) + urea (57-13-6) → saxagliptin hydrochloride-urea cocrystal (1:3)

Conditions	Yield
In ethyl acetate at 65℃;	93%

glycolic Acid (79-14-1) + Saxagliptin hydrochloride (709031-78-7) → saxagliptin hydrochloride-glycolic acid cocrystal (1:1)

Conditions	Yield
In 5,5-dimethyl-1,3-cyclohexadiene at 20 - 25℃;	83%

Saxagliptin hydrochloride (709031-78-7) → saxagliptin

Conditions	Yield
In dichloromethane; water	81%
With sodium carbonate In dichloromethane; water at 25 - 30℃; for 0.5h; pH=9 - 10;	74%
With sodium carbonate In dichloromethane; water at 25 - 30℃; for 0.5h; pH=9 - 10;	74%

Upstream product

• 1370409-28-1 saxagliptin monohydrochloride dihydrate 
• 865999-64-0 (2S)-2-amino-2-(3-hydroxyadamantan-1-yl)acetic acid hydrochloride 
• 929106-57-0 (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile 4-methylbenzenesulfonate 
• 700376-57-4 (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide 
• 709031-38-9 (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester 
• 709031-39-0 (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride 
• 768-90-1 1-Adamantyl bromide 
• 709031-34-5 dichloro-(tricyclo[3.3.1.1^3,7]decan-1-yl)acetic acid methyl ester 
• 90104-21-5 1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid 
• 98-79-3 L-Pyroglutamic acid 
• 709031-28-7 3-hydroxy-α-oxotricyclo [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 
• 709031-29-8 (αS)-α-amino-3-hydroxytricyclo[3.3.1.1^3,7]decane-1-acetic acid 
• 709031-35-6 dichloro-(3-hydroxy-adamantan-1-yl)-acetic acid methyl ester 

Downstream Products

• 1564265-93-5 saxagliptin 

Relevant academic research and scientific papers

A sand geleg sandbank salt and its preparation method

The invention relates to a saxagliptin salt and a preparation method thereof. The saxagliptin salt has a structure represented by the formula II. Saxagliptin p-toluene sulfonate with a stable crystal form can be obtained through the salt-forming reactions between saxagliptin free alkali and p-toluene sulfonic acid under different solution systems. Stability researches show that saxagliptin p-toluene sulfonate has a better thermal stability than that of saxagliptin monohydrate and saxagliptin hydrochloride. Moreover, the preparation method of the saxagliptin salt is simple and is suitable for industrial production.

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.

A PROCESS FOR PREPARATION OF SAXAGLIPTIN AND ITS HYDROCHLORIDE SALT

Described is an improved and industrially feasible process for the preparation of Saxagliptin or its hydrochloride salt. Also described are the novel intermediates and their use in the preparation of Saxagliptin or its hydrochloride salt.

PROCESS FOR PREPARATION OF (IS, 3S, 5S)-2-[(2S)-2-AMIN0-2-(3-HYDROXY-l-ADAMANTYL) ACETYL]-2-AZABICYCLO [3.1.0] HEXANE-3-CARBONITRILE

Provided are novel processes for the preparation of Saxagliptin and novel intermediates employed in the process for preparing Saxagliptin.

SAXAGLIPTIN HYDROCHLORIDE SOLID DISPERSION

The present invention provides a novel amorphous solid dispersion of saxagliptin hydrochloride in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.

PROCESS FOR THE PREPARATION OF (1S, 3S, 5S)-2-[2(S)-2-AMINO-2-(3-HYDROXY-1-ADAMANTAN-1-YL ACETYL]-2-AZABICYCLO [3.1.0] HEXANE-3-CARBONITRILE

The present invention relates to an improved process for the preparation of (1S,3S,5S)-242(S)-2-amino-2-(3-hydroxy-1-adamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile and its intermediates.

PROCESS FOR PREPARATION OF (1S, 3S, 5S)-2-[(2S)-2-AMINO-2-(3-HYDROXY-1-ADAMANTYL) ACETYL]-2-AZABICYCLO [3.1.0] HEXANE-3-CARBONITRILE

Provided are novel processes for the preparation of Saxagliptin and novel intermediates employed in the process for preparing Saxagliptin.

POLYMORPHS OF SAXAGLIPTIN HYDROCHLORIDE AND PROCESSES FOR PREPARING THEM

The invention provides polymorphs of Saxagliptin hydrochloride, processes for preparing polymorphs of Saxagliptin hydrochloride, and pharmaceutical compositions of polymorphs of Saxagliptin hydrochloride.

SAXAGLIPTIN INTERMEDIATES, SAXAGLIPTIN POLYMORPHS, AND PROCESSES FOR PREPARATION THEREOF

The invention provides Saxagliptin Schiff bases, polymorphs of Saxagliptin and (1S,3S,5S)-2-[(2S)-2-propan-2-ylideneamino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, processes for preparing Saxagliptin hydrates, and pharmaceutical compositions thereof.

CRYSTAL FORMS OF SAXAGLIPTIN

The present invention relates to novel polymorphic forms of Saxagliptin Hydrochloride. The present invention also relates to methods of making polymorphic forms of Saxagliptin Hydrochloride.