361440-67-7

Basic information

• Product Name: (1S,3S,5S)-3-(Aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester
• Synonyms: (1S,3S,5S)-3-(Aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester;(1S,3S,5S)-3-(AMinocarbonyl)-2-azabicylo[3.1.0]hexane-2-carboxylic acid tert-butyl ester;(1S,3S,5S)-3-(AMinocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid;(1S,3S,5S)-tert-butyl 3-carbaMoyl-2-azabicyclo[3.1.0]hexane-2-carboxylate;N-Boc-L-cis-4,5-MethanoprolineaMide;(1S,3S,5S)-3-(AMinocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl este;2-Azabicyclo[3.1.0]hexane-2-carboxylic acid, 3-(aminocarbonyl)-, 1,1-dimethylethyl ester, (1S,3S,5S)-;Saxagliptin INT 2
• CAS NO: 361440-67-7
• Molecular Formula: C₁₁H₁₈N₂O₃
• Molecular Weight: 226.274
• EINECS: 1308068-626-2
• Mol File: 361440-67-7.mol
• Article Data: 10

Chemical Properties

• Boiling Point: 388.9 °C at 760 mmHg
• Flash Point: 189.024 °C
• Appearance: /
• Density: 1.228
• Refractive Index: 1.538
• Storage Temp.: 2-8°C
• PKA: 16.00±0.20(Predicted)
• CAS DataBase Reference: (1S,3S,5S)-3-(Aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester(CAS DataBase Reference)
• NIST Chemistry Reference: (1S,3S,5S)-3-(Aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester(361440-67-7)
• EPA Substance Registry System: (1S,3S,5S)-3-(Aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester(361440-67-7)

Safety Data

• Hazardous Substances Data: 361440-67-7(Hazardous Substances Data)

Usage

Uses

N-Boc-L-cis-4,5-Methanoprolineamide is an intermediate used to prepare methanoprolinenitrile-contg. dipeptide mimetics as DPP-IV inhibitors and as antidiabetic agents.

InChI:InChI=1/C11H18N2O3/c1-11(2,3)16-10(15)13-7-4-6(7)5-8(13)9(12)14/h6-8H,4-5H2,1-3H3,(H2,12,14)/t6-,7-,8-/m0/s1

Synthetic route

(5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9) + tetramethylammonium trifluoromethanesulphonate (25628-09-5) → [1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7)

Conditions	Yield
With n-butyllithium; C40H54NiP2 In tetrahydrofuran; hexane at 0 - 20℃; for 16h; Reagent/catalyst; Solvent; Inert atmosphere;	93%

(1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (197142-36-2) → [1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7)

Conditions	Yield
Stage #1: (1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -15℃; for 0.5h; Stage #2: With ammonia In tetrahydrofuran; 1,4-dioxane at -30 - 20℃;	84%
Stage #1: (1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -15℃; for 0.583333h; Stage #2: With ammonia In tetrahydrofuran; 1,4-dioxane at -30 - 20℃;	84%
Stage #1: (1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid With C17H28N2O5; isobutyl chloroformate In tetrahydrofuran at -15℃; for 0.583333h; Inert atmosphere; Stage #2: With ammonia In tetrahydrofuran; 1,4-dioxane at -30 - 20℃; Inert atmosphere;	84%
Stage #1: (1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid With methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -20℃; for 0.5h; Inert atmosphere; Stage #2: With ammonia In tetrahydrofuran at -5 - 20℃; for 3h;	9.84 g

(5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9) + diiodomethane (75-11-6) → [1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7)

Conditions	Yield
Stage #1: (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester; diiodomethane With diethylzinc In water; ethyl acetate; toluene at -10 - 0℃; for 105h; Inert atmosphere; Stage #2: With trifluoroacetic acid In water; ethyl acetate; toluene at -10 - 16℃; for 1.66667h; Reagent/catalyst; Inert atmosphere;	70%
Stage #1: diiodomethane With copper(I) bromide; zinc In tert-butyl methyl ether at 20℃; for 0.5h; Simmons-Smith Cyclopropanation; Inert atmosphere; Stage #2: (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester In tert-butyl methyl ether at 20℃; for 4.5h; Simmons-Smith Cyclopropanation; Inert atmosphere;	68%
Stage #1: diiodomethane With diethylzinc In 1,2-dimethoxyethane; dichloromethane; toluene at -30 - -25℃; for 0.75h; Simmons-Smith Reaction; Stage #2: (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester In 1,2-dimethoxyethane; dichloromethane; toluene at 22 - 24℃; Stage #3: With sodium hydrogencarbonate In 1,2-dimethoxyethane; dichloromethane; water; toluene at 15℃; for 1h;	55%
With diethylzinc In 1,2-dimethoxyethane; dichloromethane at -30 - 20℃; Simmons-Smith Cyclopropanation; stereoselective reaction;	45%
Stage #1: diiodomethane With diethylzinc In 1,2-dimethoxyethane; dichloromethane; toluene at -30 - -20℃; for 0.75h; Large scale; Stage #2: (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester In 1,2-dimethoxyethane; dichloromethane; toluene at -25 - 24℃; Large scale;

di-tert-butyl dicarbonate (24424-99-5) → [1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7)

Conditions	Yield
Multi-step reaction with 6 steps 1: dmap 2: lithium triethylborohydride / toluene / -70 - -60 °C 3: dmap; trifluoroacetic anhydride; N-ethyl-N,N-diisopropylamine 4: water; lithium hydroxide / ethanol 5: ammonia; N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride / tetrahydrofuran 6: diethylzinc / 1,2-dimethoxyethane; dichloromethane / -30 - 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: dmap / dichloromethane / 6 h / 20 °C 2.1: lithium triethylborohydride / tetrahydrofuran; toluene / 3 h / -78 °C 2.2: -78 °C 2.3: 2 h / -78 - 20 °C 3.1: diethylzinc / 1,2-dichloro-ethane / 19 h / -15 °C 4.1: lithium hydroxide; water / methanol / 20 h / 20 - 50 °C 5.1: C17H28N2O5; isobutyl chloroformate / tetrahydrofuran / 0.58 h / -15 °C / Inert atmosphere 5.2: -30 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 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 View Scheme

5-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (194594-23-5) → [1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: dmap; trifluoroacetic anhydride; N-ethyl-N,N-diisopropylamine 2: water; lithium hydroxide / ethanol 3: ammonia; N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride / tetrahydrofuran 4: diethylzinc / 1,2-dimethoxyethane; dichloromethane / -30 - 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; trifluoroacetic anhydride / toluene / 3 h / 15 - 80 °C 2.1: copper(I) bromide; trifluoroacetic acid; zinc / tetrahydrofuran / 18 h / 25 - 50 °C / Inert atmosphere 3.1: lithium hydroxide / ethanol; water / 6 h / 35 °C 4.1: N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride / tetrahydrofuran / 0.5 h / -20 °C / Inert atmosphere 4.2: 3 h / -5 - 20 °C View Scheme

(S)-ethyl N-tert-butoxycarbonylpyroglutamate (144978-35-8, 144978-12-1) → [1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7)

Conditions	Yield
Multi-step reaction with 5 steps 1: lithium triethylborohydride / toluene / -70 - -60 °C 2: dmap; trifluoroacetic anhydride; N-ethyl-N,N-diisopropylamine 3: water; lithium hydroxide / ethanol 4: ammonia; N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride / tetrahydrofuran 5: diethylzinc / 1,2-dimethoxyethane; dichloromethane / -30 - 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: lithium triethylborohydride / tetrahydrofuran; toluene / 3 h / -78 °C 1.2: -78 °C 1.3: 2 h / -78 - 20 °C 2.1: diethylzinc / 1,2-dichloro-ethane / 19 h / -15 °C 3.1: lithium hydroxide; water / methanol / 20 h / 20 - 50 °C 4.1: C17H28N2O5; isobutyl chloroformate / tetrahydrofuran / 0.58 h / -15 °C / Inert atmosphere 4.2: -30 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 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 View Scheme

ethyl (S)-pyroglutamate (7149-65-7) → [1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7)

Conditions	Yield
Multi-step reaction with 6 steps 1: dmap 2: lithium triethylborohydride / toluene / -70 - -60 °C 3: dmap; trifluoroacetic anhydride; N-ethyl-N,N-diisopropylamine 4: water; lithium hydroxide / ethanol 5: ammonia; N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride / tetrahydrofuran 6: diethylzinc / 1,2-dimethoxyethane; dichloromethane / -30 - 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: dmap / dichloromethane / 6 h / 20 °C 2.1: lithium triethylborohydride / tetrahydrofuran; toluene / 3 h / -78 °C 2.2: -78 °C 2.3: 2 h / -78 - 20 °C 3.1: diethylzinc / 1,2-dichloro-ethane / 19 h / -15 °C 4.1: lithium hydroxide; water / methanol / 20 h / 20 - 50 °C 5.1: C17H28N2O5; isobutyl chloroformate / tetrahydrofuran / 0.58 h / -15 °C / Inert atmosphere 5.2: -30 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 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 View Scheme

(5S)-4,5-dihydro-1H-pyrrol-1,5-dicarboxylic acid [1-(1,1-dimethylethyl)] 5-ethyl ester (178172-26-4) → [1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: water; lithium hydroxide / ethanol 2: ammonia; N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride / tetrahydrofuran 3: diethylzinc / 1,2-dimethoxyethane; dichloromethane / -30 - 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: isopropyl alcohol / 3 h / 50 °C / Inert atmosphere 2.1: ethyl acetate / 0.25 h / 8 °C / Inert atmosphere 2.2: 2 h / 8 - 12 °C / Inert atmosphere 3.1: ammonium hydroxide / 0.5 h / 0 - 20 °C 4.1: diethylzinc / ethyl acetate; water; toluene / 105 h / -10 - 0 °C / Inert atmosphere 4.2: 1.67 h / -10 - 16 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1.1: sodium hydroxide 2.1: sodium hydroxide / water 3.1: ammonium hydroxide / Inert atmosphere 4.1: diethylzinc / ethyl acetate; water; toluene / 105 h / -10 - 0 °C / Inert atmosphere 4.2: 1.67 h / -10 - 16 °C / Inert atmosphere View Scheme

(S)-1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid diisopropylethylamine salt (709031-37-8) → [1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: ammonia; N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride / tetrahydrofuran 2: diethylzinc / 1,2-dimethoxyethane; dichloromethane / -30 - 20 °C View Scheme

4,5-duhydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl) dicyclohexylamine salt (709031-41-4) → [1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydroxide / water 2.1: ammonium hydroxide / Inert atmosphere 3.1: diethylzinc / ethyl acetate; water; toluene / 105 h / -10 - 0 °C / Inert atmosphere 3.2: 1.67 h / -10 - 16 °C / Inert atmosphere View Scheme

C15H20N4O6*C12H23N → [1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: ammonium hydroxide / Inert atmosphere 2.1: diethylzinc / ethyl acetate; water; toluene / 105 h / -10 - 0 °C / Inert atmosphere 2.2: 1.67 h / -10 - 16 °C / Inert atmosphere View Scheme

lithium (2S)-1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole-2-carboxylate → [1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: ethyl acetate / 0.25 h / 8 °C / Inert atmosphere 1.2: 2 h / 8 - 12 °C / Inert atmosphere 2.1: ammonium hydroxide / 0.5 h / 0 - 20 °C 3.1: diethylzinc / ethyl acetate; water; toluene / 105 h / -10 - 0 °C / Inert atmosphere 3.2: 1.67 h / -10 - 16 °C / Inert atmosphere View Scheme

(S)-1-tert-butoxycarbonyl-5-methoxycarbonyl-pyrrolidin-2-one (108963-96-8) → [1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: lithium triethylborohydride / tetrahydrofuran / 5 - 10 °C 1.2: 3 h / 120 °C 2.1: lithium hydroxide monohydrate / methanol; water / -5 - 30 °C 3.1: 4-methyl-morpholine; methanesulfonyl chloride; ammonia / -15 - -8 °C 4.1: zinc; copper(I) bromide / tert-butyl methyl ether / 0.5 h / 20 °C / Inert atmosphere 4.2: 4.5 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1.1: lithium triethylborohydride / toluene; tetrahydrofuran / 3 h / -70 - -60 °C / Inert atmosphere 1.2: 3.33 h / -60 - 20 °C 2.1: water; lithium hydroxide / methanol / 2 h / 0 - 20 °C 3.1: methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 3 h / -20 - 0 °C 3.2: 0 - 20 °C 4.1: n-butyllithium; C40H54NiP2 / tetrahydrofuran; hexane / 16 h / 0 - 20 °C / Inert atmosphere View Scheme

L-Pyroglutamic acid (98-79-3) → [1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: thionyl chloride / -5 - 30 °C 2.1: triethylamine / toluene / -5 - 0 °C 2.2: -5 - 30 °C 3.1: lithium triethylborohydride / tetrahydrofuran / 5 - 10 °C 3.2: 3 h / 120 °C 4.1: lithium hydroxide monohydrate / methanol; water / -5 - 30 °C 5.1: 4-methyl-morpholine; methanesulfonyl chloride; ammonia / -15 - -8 °C 6.1: zinc; copper(I) bromide / tert-butyl methyl ether / 0.5 h / 20 °C / Inert atmosphere 6.2: 4.5 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 6 steps 1.1: thionyl chloride / 5 h / -5 - 0 °C / Large scale 2.1: dmap / toluene / 3 h / 25 °C / Large scale 3.1: lithium triethylborohydride / toluene; tetrahydrofuran / 0.5 h / -45 °C / Large scale 3.2: 3 h / 25 °C / Large scale 4.1: lithium hydroxide monohydrate / water; ethanol / 2 h / 25 °C / Large scale 5.1: methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 2 h / -25 - -20 °C / Large scale 5.2: 3 h / 0 - 20 °C / Large scale 6.1: diethylzinc / dichloromethane; toluene; 1,2-dimethoxyethane / 0.75 h / -30 - -20 °C / Large scale 6.2: -25 - 24 °C / Large scale View Scheme

methyl (S)-pyroglutamate (4931-66-2) → [1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: triethylamine / toluene / -5 - 0 °C 1.2: -5 - 30 °C 2.1: lithium triethylborohydride / tetrahydrofuran / 5 - 10 °C 2.2: 3 h / 120 °C 3.1: lithium hydroxide monohydrate / methanol; water / -5 - 30 °C 4.1: 4-methyl-morpholine; methanesulfonyl chloride; ammonia / -15 - -8 °C 5.1: zinc; copper(I) bromide / tert-butyl methyl ether / 0.5 h / 20 °C / Inert atmosphere 5.2: 4.5 h / 20 °C / Inert atmosphere View Scheme

(S)-1-tert-butyl 2-methyl 2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (83548-46-3) → [1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: lithium hydroxide monohydrate / methanol; water / -5 - 30 °C 2.1: 4-methyl-morpholine; methanesulfonyl chloride; ammonia / -15 - -8 °C 3.1: zinc; copper(I) bromide / tert-butyl methyl ether / 0.5 h / 20 °C / Inert atmosphere 3.2: 4.5 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: water; lithium hydroxide / methanol / 2 h / 0 - 20 °C 2.1: methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 3 h / -20 - 0 °C 2.2: 0 - 20 °C 3.1: n-butyllithium; C40H54NiP2 / tetrahydrofuran; hexane / 16 h / 0 - 20 °C / Inert atmosphere View Scheme

(1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-formic acid ethyl ester (214193-11-0) → [1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: lithium hydroxide; water / methanol / 20 h / 20 - 50 °C 2.1: C17H28N2O5; isobutyl chloroformate / tetrahydrofuran / 0.58 h / -15 °C / Inert atmosphere 2.2: -30 - 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: lithium hydroxide / ethanol; water / 6 h / 35 °C 2.1: N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride / tetrahydrofuran / 0.5 h / -20 °C / Inert atmosphere 2.2: 3 h / -5 - 20 °C View Scheme

tert-butyl (2S)-(1-tert-butoxycarbonyl)-5-hydroxypyrrolidine-2-carboxylate (228579-90-6) → [1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; trifluoroacetic anhydride / toluene / 3 h / 15 - 80 °C 2.1: copper(I) bromide; trifluoroacetic acid; zinc / tetrahydrofuran / 18 h / 25 - 50 °C / Inert atmosphere 3.1: lithium hydroxide / ethanol; water / 3 h / 85 °C 4.1: N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride / tetrahydrofuran / 0.5 h / -20 °C / Inert atmosphere 4.2: 3 h / -5 - 20 °C View Scheme

(S)-di-tert-butyl 2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (501096-37-3) → [1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: copper(I) bromide; trifluoroacetic acid; zinc / tetrahydrofuran / 18 h / 25 - 50 °C / Inert atmosphere 2.1: lithium hydroxide / ethanol; water / 3 h / 85 °C 3.1: N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride / tetrahydrofuran / 0.5 h / -20 °C / Inert atmosphere 3.2: 3 h / -5 - 20 °C View Scheme

(5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9) + 1,2-dibromomethane (74-95-3) → [1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7)

Conditions	Yield
With copper(I) bromide; zinc In tetrahydrofuran at 25 - 40℃; for 28h; Inert atmosphere;	0.5 g

trifluoroacetic acid (76-05-1) + [1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7) → (2S,4S,5S)-4,5-methano-L-proline carboxylamide trifluoroacetate

Conditions	Yield
In dichloromethane at 0℃; for 18h;	100%
In dichloromethane at 0℃; for 18h;	100%

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

Conditions	Yield
With hydrogenchloride In tetrahydrofuran; ethyl acetate at 20℃; for 18h;	100%
With hydrogenchloride In tetrahydrofuran; water; ethyl acetate at 20℃; for 18h;	100%

[1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7) → (2S,4S,5S)-4,5-methano-L-proline carboxylamide trifluoroacetate

Conditions	Yield
With trifluoroacetic acid In dichloromethane at 0℃; for 12h;	100%

[1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7) → (1S,3S,5S)-tert-butyl 3-cyano-2-azabicyclo[3.1.0]hexane-2-carboxylate (361442-57-1)

Conditions	Yield
With pyridine; trifluoroacetic anhydride at -20 - 20℃; for 9h;	100%
With trifluoroacetic anhydride In pyridine at 20℃; for 4h;	93.6%
With pyridine; trifluoroacetic anhydride at -20 - 20℃; for 9h;	80%

methanesulfonic acid (75-75-2) + [1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7) → (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide methane sulphonic acid (709031-45-8)

Conditions	Yield
In isopropyl alcohol at 60 - 70℃; for 5h;	96.7%
In isopropyl alcohol at 55 - 65℃; for 3.5h; Large scale reaction;	94%
In isopropyl alcohol at 60℃;	80%

di-tert-butyl dicarbonate (24424-99-5) + [1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7) → C21H34N2O7 (1313751-21-1)

Conditions	Yield
With dmap In acetonitrile at 20℃; for 5h;	65%

[1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7) → (1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (197142-36-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: dmap / acetonitrile / 5 h / 20 °C 2.1: sodium hydroxide / tetrahydrofuran / 16 h / 20 °C 2.2: pH 3 View Scheme

[1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7) → C37H43N5O7 (1313751-22-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: dmap / acetonitrile / 5 h / 20 °C 2.1: sodium hydroxide / tetrahydrofuran / 16 h / 20 °C 2.2: pH 3 3.1: N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline / dichloromethane / 16 h / 20 °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) → 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-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7) → (R)-N-Boc-3-hydroxyadamantylglycine-L-cis-4,5-methanoprolinenitrile (1564266-92-7)

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

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

Conditions	Yield
Multi-step reaction with 4 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 4.1: hydrogenchloride / isopropyl alcohol; water / 1.5 h / 65 °C View Scheme
Multi-step reaction with 5 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 5.1: water; dichloromethane View Scheme

[1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7) → (R)-3-hydroxyadamantylglycine-L-cis-4,5-methanoprolinenitrile

Conditions	Yield
Multi-step reaction with 4 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 4.1: hydrogenchloride / isopropyl alcohol; water / 1.5 h / 65 °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) → 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)

Conditions	Yield
Multi-step reaction with 2 steps 1: isopropyl alcohol / 60 °C 2: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / ethyl acetate; acetonitrile / 3 h View Scheme
Multi-step reaction with 2 steps 1: dichloromethane / 18 h / 0 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; triethylamine / N,N-dimethyl-formamide / 0 - 20 °C View Scheme
Multi-step reaction with 2 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 View Scheme

[1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7) → (R)-N-Boc-3-hydroxyadamantylglycine-L-cis-4,5-methanoprolinamide (1528611-63-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: isopropyl alcohol / 60 °C 2: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / ethyl acetate; acetonitrile / 3 h View Scheme

[1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7) → (1S,3S,5S)-2-[(2S)-2-triphenylmethylamino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide

Conditions	Yield
Multi-step reaction with 2 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 View Scheme
Multi-step reaction with 2 steps 1: isopropyl alcohol / 5 h / 60 - 70 °C 2: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / dichloromethane / 12 h / 5 - 35 °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) → (1S,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile

Conditions	Yield
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 3 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 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-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester (361440-67-7) → (1S,3S,5S)-2-(2-(((2r,3aR,5S,6aS)-5-hy droxy-2-methyloctahydropentalen-2-yl )amino)acetyl)-2-azabicyclo[3.1.0]hex ane-3-carbonitrile

Conditions	Yield
Multi-step reaction with 4 steps 1.1: trifluoroacetic anhydride / pyridine / 4 h / 20 °C 2.1: acetonitrile / 48 h / 20 °C 3.1: triethylamine / 4 h / 0 - 5 °C 3.2: 2 h / 0 °C 4.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 20 °C View Scheme

Upstream product

• 709031-41-4 4,5-duhydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl) dicyclohexylamine salt 
• 709031-38-9 (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester 
• 25628-09-5 tetramethylammonium trifluoromethanesulphonate 
• 74-95-3 1,1-dibromomethane 
• 501096-37-3 (S)-di-tert-butyl 2,3-dihydro-1H-pyrrole-1,2-dicarboxylate 
• 228579-90-6 tert-butyl (2S)-(1-tert-butoxycarbonyl)-5-hydroxypyrrolidine-2-carboxylate 
• 214193-11-0 (1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-formic acid ethyl ester 
• 83548-46-3 (S)-1-tert-butyl 2-methyl 2,3-dihydro-1H-pyrrole-1,2-dicarboxylate 
• 4931-66-2 methyl (S)-pyroglutamate 
• 98-79-3 L-Pyroglutamic acid 
• 108963-96-8 (S)-1-tert-butoxycarbonyl-5-methoxycarbonyl-pyrrolidin-2-one 
• 709031-37-8 (S)-1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid diisopropylethylamine salt 
• 178172-26-4 (5S)-4,5-dihydro-1H-pyrrol-1,5-dicarboxylic acid [1-(1,1-dimethylethyl)] 5-ethyl ester 
• 7149-65-7 ethyl (S)-pyroglutamate 

Downstream Products

• 197142-36-2 (1S,3S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid 
• 709031-43-6 3-cyano-(αS)-α-(3-hydroxytricyclo[3.3.1.1^3,7]dec-1-yl)-β-oxo-(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-2-ethanecarbamic acid 1,1-dimethylethyl ester 
• 1564265-93-5 saxagliptin 
• 1564265-93-5 (R)-3-hydroxyadamantylglycine-L-cis-4,5-methanoprolinenitrile 
• 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 
• 866083-42-3 (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile 
• 929106-57-0 (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carbonitrile 4-methylbenzenesulfonate 
• 709031-78-7 Saxagliptin hydrochloride 
• 709031-45-8 (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide methane sulphonic acid 
• 361440-69-9 (2S,4S,5S)-4,5-methano-L-proline carboxylamide trifluoroacetate 

Relevant articles and documents

Method for preparing saxagliptin intermediates

The invention discloses a method for preparing saxagliptin intermediate compounds. The method includes steps of carrying out reaction on compounds I and dibromomethane in ether organic solvents in the presence of acid under the catalytic effects of cuprous catalysts and zinc powder to obtain the saxagliptin intermediate compounds. The method has the advantages of low cost, little environmental pollution, simplicity and convenience in operation and applicability to industrialization.

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.

An cost-effective and safe process of L-cis-4,5-methanoproline amide, the key synthetic intermediate of saxagliptin, via an improved Simmons-Smith reaction

L-cis-4,5-Methanoproline amide, a key intermediate of saxagliptin, was synthesized by an improved Simmons-Smith reaction. The zinc carbenoid was formed through Zn/CuBr and CH2I2, under the optimized condition, the title compound was gained with 68% yield and excellent diastereomeric selectivity (40:1 d.r.). The absence of the flammable and expensive ZnEt2 makes this procedure very attractive in large scale production.