361441-97-6

Basic information

• Product Name: (S) - N- Boc- adamantylglycine
• Synonyms: (S) - N- Boc- adamantylglycine;(alphaS)-alpha-[[(tert-Butoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid;N-Boc-L-Adamantylglycine;(S)-Adamantylglycine;(2S)-2-(AdaMantan-1-yl)-2-((tert-butoxycarbonyl)aMino)acetic acid;(S)-Boc-adamantylglycine;N-Boc-AdGly;Saxagliptin impurity E
• CAS NO: 361441-97-6
• Molecular Formula: C₁₇H₂₇NO₄
• Molecular Weight: 309.4
• Mol File: 361441-97-6.mol
• Article Data: 6

Chemical Properties

• Melting Point: >300 °C (decomp)(Solv: ethyl acetate (141-78-6); ligroine (8032-32-4))
• Boiling Point: 460.324 °C at 760 mmHg
• Flash Point: 232.196 °C
• Appearance: /
• Density: 1.193
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Slightly), DMSO (Slightly)
• PKA: 4.21±0.10(Predicted)
• CAS DataBase Reference: (S) - N- Boc- adamantylglycine(CAS DataBase Reference)
• NIST Chemistry Reference: (S) - N- Boc- adamantylglycine(361441-97-6)
• EPA Substance Registry System: (S) - N- Boc- adamantylglycine(361441-97-6)

Safety Data

• Hazardous Substances Data: 361441-97-6(Hazardous Substances Data)

Usage

Uses

(S)-Boc-adamantylglycine is used to prepare saxagliptin (BMS-477118) as highly potent and long-acting and orally active dipeptidyl peptidase IV inhibitor for treatment of type 2 diabetes.

InChI:InChI=1S/C17H27NO4/c1-16(2,3)22-15(21)18-13(14(19)20)17-7-10-4-11(8-17)6-12(5-10)9-17/h10-13H,4-9H2,1-3H3,(H,18,21)(H,19,20)/t10?,11?,12?,13-,17?/m1/s1

Synthetic route

di-tert-butyl dicarbonate (24424-99-5) + (S)-(+)-(adamant-1-yl)aminoacetic acid hydrochloride (102502-64-7) → (alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6)

Conditions	Yield
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 20℃; for 19h;	92%
With triethylamine In methanol	80%
Stage #1: (S)-(+)-(adamant-1-yl)aminoacetic acid hydrochloride With sodium hydroxide In water at 0 - 5℃; for 0.25h; Stage #2: di-tert-butyl dicarbonate In tetrahydrofuran; water at 0 - 5℃;	80 g
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 19h; Inert atmosphere;	4.07 g

C17H27NO3 → (alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6)

Conditions	Yield
With sodium chlorite; potassium dihydrogenphosphate; 2-methyl-but-2-ene In tert-butyl alcohol at 0 - 10℃; for 19.5h;	82%

di-tert-butyl dicarbonate (24424-99-5) + (S)-(+)-β-amino-1-adamantaneacetic acid (95853-35-3) → (alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide for 19h;	4.07 g

(S)-2-(adamantan-1-yl)-2-(((R)-2-hydroxy-1-phenylethyl)amino)acetonitrile (361441-95-4) → (alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 78 percent / aq. HCl; AcOH / 18 h / 80 °C 2: H2; AcOH / Pd(OH)2/C / methanol / 18 h / 2585.74 Torr 3: 4.07 g / K2CO3 / dimethylformamide / 19 h View Scheme
Multi-step reaction with 3 steps 1: hydrogenchloride; water / acetic acid / 80 °C 2: hydrogen; palladium 10% on activated carbon / acetic acid 3: triethylamine / methanol View Scheme
Multi-step reaction with 3 steps 1.1: hydrogenchloride; acetic acid; water / 20 - 95 °C 2.1: acetic acid; hydrogen; 10% palladium hydroxide on charcoal / methanol / 20 °C 3.1: sodium hydroxide / water / 0.25 h / 0 - 5 °C 3.2: 0 - 5 °C View Scheme
Multi-step reaction with 3 steps 1: hydrogenchloride; water / acetic acid / 18 h / 80 °C 2: hydrogen; 20% palladium hydroxide-activated charcoal / methanol; acetic acid / 18 h / 2585.81 Torr 3: potassium carbonate / N,N-dimethyl-formamide / 19 h / 20 °C / Inert atmosphere View Scheme

(R)-N-((S)-(adamantan-1-yl)(carboxy)methyl)-2-hydroxy-1-phenylethan-1-ammonium chloride → (alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: H2; AcOH / Pd(OH)2/C / methanol / 18 h / 2585.74 Torr 2: 4.07 g / K2CO3 / dimethylformamide / 19 h View Scheme
Multi-step reaction with 2 steps 1: hydrogen; palladium 10% on activated carbon / acetic acid 2: triethylamine / methanol View Scheme
Multi-step reaction with 2 steps 1.1: acetic acid; hydrogen; 10% palladium hydroxide on charcoal / methanol / 20 °C 2.1: sodium hydroxide / water / 0.25 h / 0 - 5 °C 2.2: 0 - 5 °C View Scheme
Multi-step reaction with 2 steps 1: hydrogen; 20% palladium hydroxide-activated charcoal / methanol; acetic acid / 18 h / 2585.81 Torr 2: potassium carbonate / N,N-dimethyl-formamide / 19 h / 20 °C / Inert atmosphere View Scheme

1-adamantanemethanol (770-71-8) → (alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6)

Conditions	Yield
Multi-step reaction with 5 steps 1: 98 percent / oxalyl chloride; DMSO; Et3N / CH2Cl2 / 1 h / -78 °C 2: 65 percent / NaHSO3 / H2O; methanol / 16 h / Heating 3: 78 percent / aq. HCl; AcOH / 18 h / 80 °C 4: H2; AcOH / Pd(OH)2/C / methanol / 18 h / 2585.74 Torr 5: 4.07 g / K2CO3 / dimethylformamide / 19 h View Scheme
Multi-step reaction with 5 steps 1.1: potassium bromide; sodium hydrogencarbonate / dichloromethane / 0.25 h / 0 - 5 °C 1.2: 0 - 5 °C 2.1: sodium hydrogensulfite / methanol; water / 0 - 55 °C 3.1: hydrogenchloride; acetic acid; water / 20 - 95 °C 4.1: acetic acid; hydrogen; 10% palladium hydroxide on charcoal / methanol / 20 °C 5.1: sodium hydroxide / water / 0.25 h / 0 - 5 °C 5.2: 0 - 5 °C View Scheme
Multi-step reaction with 5 steps 1.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 1 h / -78 °C / Inert atmosphere 1.2: 0.5 h / -78 °C / Inert atmosphere 2.1: sodium hydrogensulfite / methanol; water / 18 h / 0 - 20 °C / Reflux 3.1: hydrogenchloride; water / acetic acid / 18 h / 80 °C 4.1: hydrogen; 20% palladium hydroxide-activated charcoal / methanol; acetic acid / 18 h / 2585.81 Torr 5.1: potassium carbonate / N,N-dimethyl-formamide / 19 h / 20 °C / Inert atmosphere View Scheme

1-Adamantanecarboxylic acid (828-51-3) → (alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6)

Conditions	Yield
Multi-step reaction with 7 steps 1: 100 percent / diethyl ether; hexane; methanol / 3 h / 20 °C 2: 96 percent / LiAlH4 / tetrahydrofuran / 1.5 h / 0 - 20 °C 3: 98 percent / oxalyl chloride; DMSO; Et3N / CH2Cl2 / 1 h / -78 °C 4: 65 percent / NaHSO3 / H2O; methanol / 16 h / Heating 5: 78 percent / aq. HCl; AcOH / 18 h / 80 °C 6: H2; AcOH / Pd(OH)2/C / methanol / 18 h / 2585.74 Torr 7: 4.07 g / K2CO3 / dimethylformamide / 19 h View Scheme
Multi-step reaction with 7 steps 1.1: thionyl chloride / 3 h / 20 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 2 h / 0 - 20 °C / Inert atmosphere 3.1: potassium bromide; sodium hydrogencarbonate / dichloromethane / 0.25 h / 0 - 5 °C 3.2: 0 - 5 °C 4.1: sodium hydrogensulfite / methanol; water / 0 - 55 °C 5.1: hydrogenchloride; acetic acid; water / 20 - 95 °C 6.1: acetic acid; hydrogen; 10% palladium hydroxide on charcoal / methanol / 20 °C 7.1: sodium hydroxide / water / 0.25 h / 0 - 5 °C 7.2: 0 - 5 °C View Scheme
Multi-step reaction with 7 steps 1.1: methanol; diethyl ether; hexane / 3 h / 20 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 1.5 h / 20 °C / Inert atmosphere 3.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 1 h / -78 °C / Inert atmosphere 3.2: 0.5 h / -78 °C / Inert atmosphere 4.1: sodium hydrogensulfite / methanol; water / 18 h / 0 - 20 °C / Reflux 5.1: hydrogenchloride; water / acetic acid / 18 h / 80 °C 6.1: hydrogen; 20% palladium hydroxide-activated charcoal / methanol; acetic acid / 18 h / 2585.81 Torr 7.1: potassium carbonate / N,N-dimethyl-formamide / 19 h / 20 °C / Inert atmosphere View Scheme

1-Adamantanecarbaldehyde (2094-74-8) → (alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: 65 percent / NaHSO3 / H2O; methanol / 16 h / Heating 2: 78 percent / aq. HCl; AcOH / 18 h / 80 °C 3: H2; AcOH / Pd(OH)2/C / methanol / 18 h / 2585.74 Torr 4: 4.07 g / K2CO3 / dimethylformamide / 19 h View Scheme
Multi-step reaction with 4 steps 1: sodium hydrogensulfite / 0 - 60 °C 2: hydrogenchloride; water / acetic acid / 80 °C 3: hydrogen; palladium 10% on activated carbon / acetic acid 4: triethylamine / methanol View Scheme
Multi-step reaction with 4 steps 1.1: sodium hydrogensulfite / methanol; water / 0 - 55 °C 2.1: hydrogenchloride; acetic acid; water / 20 - 95 °C 3.1: acetic acid; hydrogen; 10% palladium hydroxide on charcoal / methanol / 20 °C 4.1: sodium hydroxide / water / 0.25 h / 0 - 5 °C 4.2: 0 - 5 °C View Scheme
Multi-step reaction with 4 steps 1: sodium hydrogensulfite / methanol; water / 18 h / 0 - 20 °C / Reflux 2: hydrogenchloride; water / acetic acid / 18 h / 80 °C 3: hydrogen; 20% palladium hydroxide-activated charcoal / methanol; acetic acid / 18 h / 2585.81 Torr 4: potassium carbonate / N,N-dimethyl-formamide / 19 h / 20 °C / Inert atmosphere View Scheme

methyl adamantane-1-carboxylate (711-01-3) → (alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6)

Conditions	Yield
Multi-step reaction with 6 steps 1: 96 percent / LiAlH4 / tetrahydrofuran / 1.5 h / 0 - 20 °C 2: 98 percent / oxalyl chloride; DMSO; Et3N / CH2Cl2 / 1 h / -78 °C 3: 65 percent / NaHSO3 / H2O; methanol / 16 h / Heating 4: 78 percent / aq. HCl; AcOH / 18 h / 80 °C 5: H2; AcOH / Pd(OH)2/C / methanol / 18 h / 2585.74 Torr 6: 4.07 g / K2CO3 / dimethylformamide / 19 h View Scheme
Multi-step reaction with 6 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / 2 h / 0 - 20 °C / Inert atmosphere 2.1: potassium bromide; sodium hydrogencarbonate / dichloromethane / 0.25 h / 0 - 5 °C 2.2: 0 - 5 °C 3.1: sodium hydrogensulfite / methanol; water / 0 - 55 °C 4.1: hydrogenchloride; acetic acid; water / 20 - 95 °C 5.1: acetic acid; hydrogen; 10% palladium hydroxide on charcoal / methanol / 20 °C 6.1: sodium hydroxide / water / 0.25 h / 0 - 5 °C 6.2: 0 - 5 °C View Scheme
Multi-step reaction with 6 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / 1.5 h / 20 °C / Inert atmosphere 2.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 1 h / -78 °C / Inert atmosphere 2.2: 0.5 h / -78 °C / Inert atmosphere 3.1: sodium hydrogensulfite / methanol; water / 18 h / 0 - 20 °C / Reflux 4.1: hydrogenchloride; water / acetic acid / 18 h / 80 °C 5.1: hydrogen; 20% palladium hydroxide-activated charcoal / methanol; acetic acid / 18 h / 2585.81 Torr 6.1: potassium carbonate / N,N-dimethyl-formamide / 19 h / 20 °C / Inert atmosphere View Scheme

L-boroPro-pn + (alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → C31H49BN2O5

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0 - 20℃;	93%

(alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) + (2S,4S,5S)-4,5-methano-L-proline carboxylamide trifluoroacetate → [(S)-1-Adamantan-1-yl-2-((1S,3S,5S)-3-carbamoyl-2-aza-bicyclo[3.1.0]hex-2-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (862784-24-5)

Conditions	Yield
With TEA; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃;	90%

(S)-1-(((R)-1-amino-5-(benzyloxy)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-aminium 2,2,2-trifluoroacetate (66025-93-2) + (alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → tert-butyloxycarbonyl (S)-2-adamant-1-ylglycyl-L-alanyl-D-isoglutamine benzyl ester

Conditions

Yield

Stage #1: (alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 0.5h; Stage #2: (S)-1-(((R)-1-amino-5-(benzyloxy)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-aminium 2,2,2-trifluoroacetate With triethylamine In 1,4-dioxane; dichloromethane at 0 - 20℃; for 49h;

82%

(alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → (αS)-α-[[(1,1-dimethylethoxy)carbonyl]-amino]-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (361442-00-4) + (S)-2-((tert-butoxycarbonyl)amino)-2-(3,5-dihydroxyadamantan-1-yl)acetic acid (681282-72-4)

Conditions	Yield
With potassium hydroxide; potassium permanganate at 60 - 90℃; for 1.5h;	A 51% B 17%
With potassium hydroxide; potassium permanganate In water at 60 - 90℃; for 1.5h;	A 51% B 17%

(alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → (αS)-α-[[(1,1-dimethylethoxy)carbonyl]-amino]-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (361442-00-4)

Conditions	Yield
With potassium permanganate; water; potassium hydroxide at 60 - 90℃; for 1.5h;	51%
With potassium permanganate; potassium hydroxide at 90℃;	49%
With potassium permanganate; tetrabutylammomium bromide; potassium hydroxide In water at 20 - 25℃;	18.6 g

C20-O-trityl-prostratin-ol (1262389-74-1) + (alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → C56H67NO8

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 14h;	24.8%

(alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) + (S)-2-Amino-N4,N4-dimethyl-N1-(3,3,3-trifluoro-2-hydroxy-1-methyl-propyl)-succinamide; hydrochloride → {(S)-Adamantan-1-yl-[(S)-2-dimethylcarbamoyl-1-(3,3,3-trifluoro-2-hydroxy-1-methyl-propylcarbamoyl)-ethylcarbamoyl]-methyl}-carbamic acid tert-butyl ester

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane for 2.5h;

L-Alanine methyl ester (10065-72-2) + (alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → (S)-2-((S)-2-Adamantan-1-yl-2-tert-butoxycarbonylamino-acetylamino)-propionic acid methyl ester (882034-92-6)

Conditions	Yield
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane

N-(cyanomethyl)ethylamine (24426-40-2) + (alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → [adamantan-1-yl-(cyanomethyl-ethyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester

Conditions	Yield
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane

N-propene-2 aminoacetonitrile (54243-43-5) + (alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → [adamantan-1-yl-(allyl-cyanomethyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester

Conditions	Yield
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane

propylamino acetonitrile (16728-81-7) + (alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → [adamantan-1-yl-(cyanomethyl-propyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester

Conditions	Yield
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane

2-amino-2-methylpropionic acid methyl ester (13257-67-5) + (alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → 2-(2-adamantan-1-yl-2-tert-butoxycarbonylamino-acetylamino)-2-methyl-propionic acid methyl ester (882034-93-7)

Conditions	Yield
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane

benzylaminoacetonitrile (3010-05-7) + (alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → [adamantan-1-yl-(benzyl-cyanomethyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester

Conditions	Yield
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane

(cyclopropylamino)acetonitrile (30858-68-5) + (alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → [adamantan-1-yl-(cyanomethyl-cyclopropyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester

Conditions	Yield
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane

2-aminoacetonitrile (540-61-4) + (alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → [adamantan-1-yl-(cyanomethyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester

Conditions	Yield
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane

(methylamino)acetonitrile (5616-32-0) + (alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → [adamantan-1-yl-(cyanomethyl-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester

Conditions	Yield
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane

(alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → 2-adamantan-1-yl-2-amino-N-cyanomethyl-acetamide

Conditions	Yield
Multi-step reaction with 2 steps 1: EDAC; HOAt; Et3N / CH2Cl2 2: TFA / CH2Cl2 View Scheme

(alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → 2-adamantan-1-yl-2-amino-N-cyanomethyl-N-methyl-acetamide

Conditions	Yield
Multi-step reaction with 2 steps 1: EDAC; HOAt; Et3N / CH2Cl2 2: TFA / CH2Cl2 View Scheme

(alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → (S)-2-Adamantan-1-yl-2-amino-N-((S)-cyano-methyl-methyl)-acetamide

Conditions	Yield
Multi-step reaction with 5 steps 1: EDAC; HOAt; Et3N / CH2Cl2 2: aq. NaOH / methanol / 50 °C 3: NMO; i-BuOCOCl; NH3 / -15 °C 4: TFAA / CH2Cl2 5: TFA / CH2Cl2 View Scheme

(alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → 2-adamantan-1-yl-2-amino-N-(cyano-dimethyl-methyl)-acetamide

Conditions	Yield
Multi-step reaction with 5 steps 1: EDAC; HOAt; Et3N / CH2Cl2 2: aq. NaOH / methanol / 50 °C 3: NMO; i-BuOCOCl; NH3 / -15 °C 4: TFAA / CH2Cl2 5: TFA / CH2Cl2 View Scheme

(alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → 2-adamantan-1-yl-2-amino-N-cyanomethyl-N-ethyl-acetamide

Conditions	Yield
Multi-step reaction with 2 steps 1: EDAC; HOAt; Et3N / CH2Cl2 2: TFA / CH2Cl2 View Scheme

(alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → 2-adamantan-1-yl-2-amino-N-cyanomethyl-N-cyclopropyl-acetamide

Conditions	Yield
Multi-step reaction with 2 steps 1: EDAC; HOAt; Et3N / CH2Cl2 2: TFA / CH2Cl2 View Scheme

(alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → 2-adamantan-1-yl-2-amino-N-cyanomethyl-N-propyl-acetamide

Conditions	Yield
Multi-step reaction with 2 steps 1: EDAC; HOAt; Et3N / CH2Cl2 2: TFA / CH2Cl2 View Scheme

(alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → 2-adamantan-1-yl-N-allyl-2-amino-N-cyanomethyl-acetamide

Conditions	Yield
Multi-step reaction with 2 steps 1: EDAC; HOAt; Et3N / CH2Cl2 2: TFA / CH2Cl2 View Scheme

(alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → 2-adamantan-1-yl-2-amino-N-benzyl-N-cyanomethyl-acetamide

Conditions	Yield
Multi-step reaction with 2 steps 1: EDAC; HOAt; Et3N / CH2Cl2 2: TFA / CH2Cl2 View Scheme

(alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → {adamantan-1-yl-[(cyano-dimethyl-methyl)-carbamoyl]-methyl}-carbamic acid tert-butyl ester

Conditions	Yield
Multi-step reaction with 4 steps 1: EDAC; HOAt; Et3N / CH2Cl2 2: aq. NaOH / methanol / 50 °C 3: NMO; i-BuOCOCl; NH3 / -15 °C 4: TFAA / CH2Cl2 View Scheme

(alpha S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]tricyclo[3.3.1.13,7]decane-1-acetic acid (361441-97-6) → {(S)-Adamantan-1-yl-[((S)-cyano-methyl-methyl)-carbamoyl]-methyl}-carbamic acid tert-butyl ester

Conditions	Yield
Multi-step reaction with 4 steps 1: EDAC; HOAt; Et3N / CH2Cl2 2: aq. NaOH / methanol / 50 °C 3: NMO; i-BuOCOCl; NH3 / -15 °C 4: TFAA / CH2Cl2 View Scheme

Upstream product

• 24424-99-5 di-tert-butyl dicarbonate 
• 95853-35-3 (S)-(+)-β-amino-1-adamantaneacetic acid 
• 361441-95-4 (S)-2-(adamantan-1-yl)-2-(((R)-2-hydroxy-1-phenylethyl)amino)acetonitrile 
• 770-71-8 1-adamantanemethanol 
• 828-51-3 1-Adamantanecarboxylic acid 
• 2094-74-8 1-Adamantanecarbaldehyde 
• 711-01-3 methyl adamantane-1-carboxylate 
• 102502-64-7 (S)-(+)-(adamant-1-yl)aminoacetic acid hydrochloride 

Downstream Products

• 102502-64-7 (S)-(+)-(adamant-1-yl)aminoacetic acid hydrochloride 
• 361442-00-4 (αS)-α-[[(1,1-dimethylethoxy)carbonyl]-amino]-3-hydroxytricyclo[3.3.1.1^3,7]decane-1-acetic acid 
• 681282-72-4 (S)-2-((tert-butoxycarbonyl)amino)-2-(3,5-dihydroxyadamantan-1-yl)acetic 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 
• 709031-43-6 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 
• 1564266-00-7 (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile 
• 1564265-93-5 (2S,4S,5R)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile 
• 1564265-94-6 (S)-3-hydroxyadamantylglycine-D-cis-4,5-methanoprolinenitrile 
• 1564265-93-5 saxagliptin 

Relevant articles and documents

Protected amino hydroxy adamantane carboxylic acid and process for its preparation

Dipeptidyl peptidase IV (DP 4) inhibiting compounds are provided. The provided compounds can be used for treating diabetes and related diseases, especially Type II diabetes, and other diseases as set out herein, employing such DP 4 inhibitor or a combination of such DP 4 inhibitor and one or more of another antidiabetic agent such as metformin, glyburide, troglitazone, pioglitazone, rosiglitazone and/or insulin and/or one or more of a hypolipidemic agent and/or anti-obesity agent and/or other therapeutic agent.

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

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

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

Efforts to further elucidate structure-activity relationships (SAR) within our previously disclosed series of β-quaternary amino acid linked L-cis-4,5-methanoprolinenitrile dipeptidyl peptidase IV (DPP-IV) inhibitors led to the investigation of vinyl substitution at the β-position of α-cycloalkyl-substituted glycines. Despite poor systemic exposure, vinyl-substituted compounds showed extended duration of action in acute rat ex vivo plasma DPP-IV inhibition models. Oxygenated putative metabolites were prepared and were shown to exhibit the potency and extended duration of action of their precursors in efficacy models measuring glucose clearance in Zuckerfa/fa rats. Extension of this approach to adamantylglycine- derived inhibitors led to the discovery of highly potent inhibitors, including hydroxyadamantyl compound BMS-477118 (saxagliptin), a highly efficacious, stable, and long-acting DPP-IV inhibitor, which is currently undergoing clinical trials for treatment of type 2 diabetes.