709031-38-9

Basic information

• Product Name: 1H-Pyrrole-1-carboxylic acid, 2-(aMinocarbonyl)-2,3-dihydro-, 1,1-diMethylethyl ester, (2S)-
• Synonyms: 1H-Pyrrole-1-carboxylic acid, 2-(aMinocarbonyl)-2,3-dihydro-, 1,1-diMethylethyl ester, (2S)-;(S)-Boc-2-carbaMoyl-2,3-dihydro-1H-pyrrole;(2S)-2-(Aminocarbonyl)-2,3-dihydro-1H-pyrrole-1-carboxylic acid 1,1-dimethylethyl ester;(S)-tert-butyl 2-carbaMoyl-2,3-dihydropyrrole-1-carboxylate;(S)-tert-Butyl 2-carbamoyl-2,3-dihydro-1H-pyrrole-1-carboxylate;Saxagliptin impurity I;Saxaint-T;tert-butyl (S)-2-carbamoyl-2,3-dihydro-1H-pyrrole-1-carboxylate
• CAS NO: 709031-38-9
• Molecular Formula: C₁₀H₁₆N₂O₃
• Molecular Weight: 212.24564
• EINECS: 1312995-182-4
• Mol File: 709031-38-9.mol
• Article Data: 9

Chemical Properties

• Boiling Point: 386.461 °C at 760 mmHg
• Flash Point: 187.525 °C
• Appearance: /
• Density: 1.188 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.523
• Storage Temp.: 2-8°C
• PKA: 15.57±0.20(Predicted)
• CAS DataBase Reference: 1H-Pyrrole-1-carboxylic acid, 2-(aMinocarbonyl)-2,3-dihydro-, 1,1-diMethylethyl ester, (2S)-(CAS DataBase Reference)
• NIST Chemistry Reference: 1H-Pyrrole-1-carboxylic acid, 2-(aMinocarbonyl)-2,3-dihydro-, 1,1-diMethylethyl ester, (2S)-(709031-38-9)
• EPA Substance Registry System: 1H-Pyrrole-1-carboxylic acid, 2-(aMinocarbonyl)-2,3-dihydro-, 1,1-diMethylethyl ester, (2S)-(709031-38-9)

Safety Data

• Hazardous Substances Data: 709031-38-9(Hazardous Substances Data)

Usage

Description

1H-Pyrrole-1-carboxylic acid, 2-(aMinocarbonyl)-2,3-dihydro-, 1,1-diMethylethyl ester, (2S)is a complex organic compound with a unique molecular structure. It is characterized by a pyrrole ring, an aminocarbonyl group, and a 1,1-dimethylethyl ester group. 1H-Pyrrole-1-carboxylic acid, 2-(aMinocarbonyl)-2,3-dihydro-, 1,1-diMethylethyl ester, (2S)is a chiral molecule, with the (2S)configuration indicating the stereochemistry at the chiral center.

Uses

Used in Pharmaceutical Industry:
1H-Pyrrole-1-carboxylic acid, 2-(aMinocarbonyl)-2,3-dihydro-, 1,1-diMethylethyl ester, (2S)is used as an impurity in the development of Saxagliptin (S143500), a potent and selective reversible inhibitor of dipeptidyl peptidase-4. 1H-Pyrrole-1-carboxylic acid, 2-(aMinocarbonyl)-2,3-dihydro-, 1,1-diMethylethyl ester, (2S)is being developed for the treatment of type 2 diabetes, as it rapidly absorbs after oral administration and has a pharmacokinetic profile compatible with once daily dosing.
Used in Drug Development:
1H-Pyrrole-1-carboxylic acid, 2-(aMinocarbonyl)-2,3-dihydro-, 1,1-diMethylethyl ester, (2S)serves as a crucial intermediate in the synthesis of various pharmaceuticals, particularly those targeting type 2 diabetes. Its unique structure and properties make it a valuable building block for the development of new drugs with improved efficacy and safety profiles.
Used in Research and Development:
1H-Pyrrole-1-carboxylic acid, 2-(aMinocarbonyl)-2,3-dihydro-, 1,1-diMethylethyl ester, (2S)is also utilized in research and development for the study of its chemical properties, reactivity, and potential applications in various fields, including medicinal chemistry, materials science, and chemical engineering.

InChI:InChI=1/C10H16N2O3/c1-10(2,3)15-9(14)12-6-4-5-7(12)8(11)13/h4,6-7H,5H2,1-3H3,(H2,11,13)/t7-/m0/s1

Synthetic route

(5S)-4,5-dihydro-1H-pyrrol-1,5-dicarboxylic acid [1-(1,1-dimethylethyl)] 5-ethyl ester (178172-26-4) → (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9)

Conditions	Yield
With sodium isopropylate; formamide In diethyl ether at 20℃; for 2.16667h; Solvent; Temperature; Cooling with ice;	93%
With Candida antarctica lipase B; ammonium carbamate; Ascarite; calcium chloride at 50℃; for 72h; Product distribution; Kinetics; Further Variations:; Reagents; Temperatures;	81%
Multi-step reaction with 2 steps 1: water; lithium hydroxide / ethanol 2: ammonia; N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride / tetrahydrofuran View Scheme

N-BOC dehydroproline DIPEA → (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9)

Conditions	Yield
Stage #1: N-BOC dehydroproline DIPEA With methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -25 - -20℃; for 2h; Stage #2: With ammonia In tetrahydrofuran at 0 - 20℃; for 3h;	90%

(S)-1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid diisopropylethylamine salt (709031-37-8) → (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9)

Conditions	Yield
Stage #1: (S)-1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid diisopropylethylamine salt With methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -20 - 0℃; for 3h; Stage #2: With ammonium carbonate In tetrahydrofuran at 0 - 20℃;	90%
With ammonia; methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran	1.5 g

1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid (90104-21-5) → (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9)

Conditions	Yield
Stage #1: 1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid With methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -25 - -20℃; for 2h; Large scale; Stage #2: With ammonia In tetrahydrofuran at 0 - 20℃; for 3h; Large scale;	90%
With 4-methyl-morpholine; ammonia; methanesulfonyl chloride at -15 - -8℃;	359.7 g

4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid 1-(1,1-dimethylethyl) sodium salt + 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (3945-69-5) → (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9) + 4, 6-DIMEO-1, 3,5-triazene ether (DMT-ether)

Conditions	Yield
With sodium hydroxide; sodium dihydrogenphosphate; ammonium chloride at 20℃; for 4h; pH=6.20; Conversion of starting material;	A 87% B 12%

(5S)-4,5-dihydro-1H-pyrrol-1,5-dicarboxylic acid [1-(1,1-dimethylethyl)] 5-ethyl ester (178172-26-4) → (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9) + (R)-tert-butyl 2-carbamoyl-2,3-dihydro-1H-pyrrole-1-carboxylate

Conditions	Yield
With sodium methylate; formamide In methanol at 20℃; for 4.5h;

di-tert-butyl dicarbonate (24424-99-5) → (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9)

Conditions	Yield
Multi-step reaction with 5 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 View Scheme
Multi-step reaction with 4 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 View Scheme

5-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (194594-23-5) → (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme

(S)-ethyl N-tert-butoxycarbonylpyroglutamate (144978-35-8, 144978-12-1) → (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme
Multi-step reaction with 3 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 View Scheme

ethyl (S)-pyroglutamate (7149-65-7) → (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9)

Conditions	Yield
Multi-step reaction with 5 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 View Scheme
Multi-step reaction with 4 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 View Scheme

4,5-duhydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl) dicyclohexylamine salt (709031-41-4) → (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide / water 2: ammonium hydroxide / Inert atmosphere View Scheme

C15H20N4O6*C12H23N → (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9)

Conditions	Yield
With ammonium hydroxide Inert atmosphere;

lithium (2S)-1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole-2-carboxylate → (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme

C13H17N3O3 → (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9)

Conditions	Yield
With ammonium hydroxide at 0 - 20℃; for 0.5h;	1.75 g

(S)-1-tert-butoxycarbonyl-5-methoxycarbonyl-pyrrolidin-2-one (108963-96-8) → (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 3 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 View Scheme

L-Pyroglutamic acid (98-79-3) → (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9)

Conditions	Yield
Multi-step reaction with 5 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 View Scheme
Multi-step reaction with 5 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 View Scheme

methyl (S)-pyroglutamate (4931-66-2) → (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme

(S)-1-tert-butyl 2-methyl 2,3-dihydro-1H-pyrrole-1,2-dicarboxylate (83548-46-3) → (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: lithium hydroxide monohydrate / methanol; water / -5 - 30 °C 2: 4-methyl-morpholine; methanesulfonyl chloride; ammonia / -15 - -8 °C View Scheme
Multi-step reaction with 2 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 View Scheme

(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%

(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;

(5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9) → [1S-(<α, 3<β, 5<α)-3-aminocarbonyl]-2-azabicyclo [3.1.0] hexane-2-carboxylic acid 1,1-dimethylethyl ester

Conditions	Yield
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℃;	55%

(5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9) + (13)C(2)H2I2 (1217038-24-8) → (1S,3S,5S)-tert-butyl 3-carbamoyl-6-[13CD2]-2-azabicyclo[3.1.0]hexane-2-carboxylate (1572922-54-3)

Conditions	Yield
Stage #1: (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester With diethylzinc In dichloromethane; toluene at 0℃; for 0.5h; Inert atmosphere; Stage #2: (13)C(2)H2I2 In dichloromethane; toluene at 0 - 20℃; for 17h; Simmons-Smith Cyclopropanation; Inert atmosphere;	40%

(5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9) + <14C>methylene iodide (58401-84-6) → (1S,3S,5S)-tert-butyl 3-carbamoyl-6-[14C]-2-azabicyclo[3.1.0]hexane-2-carboxylate

Conditions	Yield
With water; diethylzinc In dichloromethane; toluene; pentane at -10 - 20℃; for 21h; Simmons-Smith Cyclopropanation; Inert atmosphere;	10.2%

(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

(5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9) → (R)-N-Boc-3-hydroxyadamantylglycine-L-cis-4,5-methanoprolinenitrile (1564266-92-7)

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

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

Conditions	Yield
Multi-step reaction with 5 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 5.1: hydrogenchloride / isopropyl alcohol; water / 1.5 h / 65 °C View Scheme
Multi-step reaction with 6 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 6.1: water; dichloromethane View Scheme

(5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9) → (R)-3-hydroxyadamantylglycine-L-cis-4,5-methanoprolinenitrile

Conditions

Yield

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

(5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9) → (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide methane sulphonic acid (709031-45-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: diethylzinc / 1,2-dimethoxyethane; dichloromethane / -30 - 20 °C 2: isopropyl alcohol / 60 °C View Scheme

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

Conditions	Yield
Multi-step reaction with 3 steps 1: diethylzinc / 1,2-dimethoxyethane; dichloromethane / -30 - 20 °C 2: isopropyl alcohol / 60 °C 3: 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 3 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 View Scheme

(5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9) → (R)-N-Boc-3-hydroxyadamantylglycine-L-cis-4,5-methanoprolinamide (1528611-63-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: diethylzinc / 1,2-dimethoxyethane; dichloromethane / -30 - 20 °C 2: isopropyl alcohol / 60 °C 3: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine / ethyl acetate; acetonitrile / 3 h View Scheme

(5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9) → tert-butyl((S)-2-((1S,3S,5S)-3-(6-[13CD2])-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-1-(3,5-dihydroxyadamantan-1-yl)-2-oxoethyl)carbamate (1572922-58-7)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: diethylzinc / dichloromethane; toluene / 0.5 h / 0 °C / Inert atmosphere 1.2: 17 h / 0 - 20 °C / Inert atmosphere 2.1: 1,3,5-trichloro-2,4,6-triazine / N,N-dimethyl-formamide / 1.2 h / 0 °C 3.1: hydrogenchloride / 1,4-dioxane / 1.2 h / 47 °C / Inert atmosphere 4.1: 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 View Scheme

(5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9) → C17(13)CH23(2)H2N3O3*ClH (1572922-53-2)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: diethylzinc / dichloromethane; toluene / 0.5 h / 0 °C / Inert atmosphere 1.2: 17 h / 0 - 20 °C / Inert atmosphere 2.1: 1,3,5-trichloro-2,4,6-triazine / N,N-dimethyl-formamide / 1.2 h / 0 °C 3.1: hydrogenchloride / 1,4-dioxane / 1.2 h / 47 °C / Inert atmosphere 4.1: 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 5.1: hydrogenchloride / water; isopropyl alcohol View Scheme

(5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9) → C22(14)CH33N3O4

Conditions

Yield

Multi-step reaction with 4 steps 1: diethylzinc; water / dichloromethane; pentane; toluene / 21 h / -10 - 20 °C / Inert atmosphere 2: 1,3,5-trichloro-2,4,6-triazine / N,N-dimethyl-formamide / 1.2 h / 0 °C 3: hydrogenchloride / 1,4-dioxane / 1.2 h / 47 °C / Inert atmosphere 4: 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 View Scheme

(5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9) → (1S,3S,5S)-tert-butyl 3-cyano-6-[14C]-2-azabicyclo[3.1.0]hexane-2-carboxylate

Conditions	Yield
Multi-step reaction with 2 steps 1: diethylzinc; water / dichloromethane; pentane; toluene / 21 h / -10 - 20 °C / Inert atmosphere 2: 1,3,5-trichloro-2,4,6-triazine / N,N-dimethyl-formamide / 1.2 h / 0 °C View Scheme

(5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9) → (1S,3S,5S)-6-[14C]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride

Conditions	Yield
Multi-step reaction with 3 steps 1: diethylzinc; water / dichloromethane; pentane; toluene / 21 h / -10 - 20 °C / Inert atmosphere 2: 1,3,5-trichloro-2,4,6-triazine / N,N-dimethyl-formamide / 1.2 h / 0 °C 3: hydrogenchloride / 1,4-dioxane / 1.2 h / 47 °C / Inert atmosphere View Scheme

(5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9) → 6-[14C]-saxagliptin

Conditions

Yield

Multi-step reaction with 5 steps 1.1: diethylzinc; water / dichloromethane; pentane; toluene / 21 h / -10 - 20 °C / Inert atmosphere 2.1: 1,3,5-trichloro-2,4,6-triazine / N,N-dimethyl-formamide / 1.2 h / 0 °C 3.1: hydrogenchloride / 1,4-dioxane / 1.2 h / 47 °C / Inert atmosphere 4.1: 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 5.1: hydrogenchloride / water; isopropyl alcohol 5.2: 10 - 20 °C View Scheme

(5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9) → (1S,3S,5S)-tert-butyl 3-cyano-6-[13CD2]-2-azabicyclo[3.1.0]hexane-2-carboxylate (1572922-55-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: diethylzinc / dichloromethane; toluene / 0.5 h / 0 °C / Inert atmosphere 1.2: 17 h / 0 - 20 °C / Inert atmosphere 2.1: 1,3,5-trichloro-2,4,6-triazine / N,N-dimethyl-formamide / 1.2 h / 0 °C View Scheme

(5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid 1-(1,1-dimethylethyl) ester (709031-38-9) → (1S,3S,5S)-6-[13CD2]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride (1572922-56-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: diethylzinc / dichloromethane; toluene / 0.5 h / 0 °C / Inert atmosphere 1.2: 17 h / 0 - 20 °C / Inert atmosphere 2.1: 1,3,5-trichloro-2,4,6-triazine / N,N-dimethyl-formamide / 1.2 h / 0 °C 3.1: hydrogenchloride / 1,4-dioxane / 1.2 h / 47 °C / Inert atmosphere View Scheme

Upstream product

• 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 
• 90104-21-5 1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid 
• 709031-41-4 4,5-duhydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl) dicyclohexylamine salt 
• 709031-37-8 (S)-1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrole-2-carboxylic acid diisopropylethylamine salt 
• 7149-65-7 ethyl (S)-pyroglutamate 
• 144978-35-8 (S)-ethyl N-tert-butoxycarbonylpyroglutamate 
• 194594-23-5 5-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester 
• 24424-99-5 di-tert-butyl dicarbonate 
• 178172-26-4 (5S)-4,5-dihydro-1H-pyrrol-1,5-dicarboxylic acid [1-(1,1-dimethylethyl)] 5-ethyl ester 
• 3945-69-5 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride 

Downstream Products

• 361440-67-7 [1S-(1α,3β,5α)]-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid 1,1-dimethylethyl ester 
• 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 
• 709031-45-8 (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide methane sulphonic acid 
• 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 
• 709031-78-7 Saxagliptin hydrochloride 

Relevant articles and documents

Biocatalytic ammonolysis of (5S)-4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)-5-ethyl ester: Preparation of an intermediate to the dipeptidyl peptidase IV inhibitor Saxagliptin

An efficient biocatalytic method has been developed for the conversion of (5S)-4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)-5-ethyl ester (1) into the corresponding amide (5S)-5-aminocarbonyl-4,5-dihydro-1H- pyrrole-1-carboxylic acid, 1-(1,1-dimethylethyl)ester (2), which is a critical intermediate in the synthesis of the dipeptidyl peptidase IV (DPP4) inhibitor Saxagliptin (3). (Chemical presented) Candida antartica lipase B mediates ammonolysis of the ester with ammonium carbamate as ammonia donor to yield up to 71% of the amide. The inclusion of Ascarite and calcium chloride as adsorbents for carbon dioxide and ethanol byproducts, respectively, increases the yield to 98%, thereby offering an efficient and practical alternative to chemical routes which yield 57-64%.

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.