309956-78-3

Basic information

• Product Name: (R)-3-(Boc-Amino)piperidine
• Synonyms: CARBAMIC ACID, (3R)-3-PIPERIDINYL-, 1,1-DIMETHYLETHYL ESTER;(R)-TERT-BUTYL-PIPERIDINE-3-YICARBAMATE;(R)-PIPERIDIN-3-YL-CARBAMIC ACID TERT-BUTYL ESTER;(R)-3-AMINO-N-TBOC-PIPERIDINE;(R)-3-N-BOC-AMINO-PIPERIDINE;(R)-3-BOC-AMINOPIPERIDINE;(R)-(+)-3-TERT-BUTOXYCARBONYLAMINOPIPERIDINE;(R)-3-(TERT-BUTOXYCARBONYLAMINO)PIPERIDINE
• CAS NO: 309956-78-3
• Molecular Formula: C₁₀H₂₀N₂O₂
• Molecular Weight: 200.28
• EINECS: 1308068-626-2
• Product Categories: N-BOC;pharmacetical;Piperidine;Piperidine Series;Piperidines;Intermediates;(R)-3-(Boc-Amino)piperidine ada@tuskwei,com whatsapp;8618031153937
• Mol File: 309956-78-3.mol

Chemical Properties

• Melting Point: 121.0 to 125.0 °C
• Boiling Point: 304.8 °C at 760 mmHg
• Flash Point: 138.2 °C
• Appearance: /
• Density: 1.02 g/cm³
• Vapor Pressure: 0.000854mmHg at 25°C
• Refractive Index: 1.479
• Storage Temp.: Room temperature.
• Solubility: Soluble in methanol and ethanol.
• PKA: 12.37±0.20(Predicted)
• BRN: 10662518
• CAS DataBase Reference: (R)-3-(Boc-Amino)piperidine(CAS DataBase Reference)
• NIST Chemistry Reference: (R)-3-(Boc-Amino)piperidine(309956-78-3)
• EPA Substance Registry System: (R)-3-(Boc-Amino)piperidine(309956-78-3)

Safety Data

• Hazard Codes: Xi,N
• Statements: 37/38-41-50
• Safety Statements: 26-39-61-29-36
• RIDADR: 3077
• WGK Germany: 2
• HazardClass: 9
• PackingGroup: Ⅲ
• Hazardous Substances Data: 309956-78-3(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
(R)-3-(Boc-Amino)piperidine is used as an organic chemical synthesis intermediate for the preparation of dipeptidyl peptidase IV inhibitors derived from Alogliptin. It plays a significant role in the development of medications that help manage type 2 diabetes by inhibiting the DPP-4 enzyme, which in turn regulates blood glucose levels.
Additionally, as a Boc protected (R)-3-Aminopiperidine, it is utilized in the synthesis of various pharmaceutical agents, ensuring the stability and reactivity of the amino group during the chemical reactions, which is essential for the production of effective and safe medications.

Solubility in organics

Soluble in methanol and ethanol.

storage

Stable under recommended storage conditions. Incompatible with oxidizing agents.

InChI:InChI=1/C10H20N2O2/c1-10(2,3)14-9(13)12-8-5-4-6-11-7-8/h8,11H,4-7H2,1-3H3,(H,12,13)/t8-/m1/s1

Synthetic route

tert-butyl (R)-(+)-(N-benzylpiperidin-3-yl)carbamate (454713-13-4) → (R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3)

Conditions	Yield
With 5%-palladium/activated carbon; hydrogen In ethanol at 20 - 25℃; under 150015 Torr; for 20h;	97%
With palladium 10% on activated carbon; hydrogen In methanol at 45℃; under 1140.08 Torr; for 2h;	85%
With hydrogen; 10% palladium on activated carbon In metahnol at 20℃; for 24h;

(R)-3-(tert-butoxycarbonylamino)piperidine-1-carboxylic acid benzyl ester (485820-12-0) → (R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In methanol; water at 35 - 40℃; under 2250.23 - 3000.3 Torr; for 2h; Time; Autoclave; Inert atmosphere;	95.4%
With hydrogen; palladium 10% on activated carbon In ethanol at 20℃; under 760.051 Torr; for 168h;	92%
In ethanol

t-butyl (R)-piperidin-3-ylcarbamate R-mandelate (1189160-63-1) → (R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3)

Conditions	Yield
With sodium chloride; sodium hydroxide In water; butan-1-ol at 10 - 30℃;	79.7%

(R)-2-tert-butyloxycarbonylamino-1,5-pentanedimethanesulfonate → (R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3)

Conditions	Yield
With ammonium hydroxide In acetonitrile at 30℃; for 48h;	74%
Multi-step reaction with 2 steps 1: 2 h / 45 °C 2: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 45 °C / 1140.08 Torr View Scheme

D-Glutamic acid (6893-26-1) → (R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: thionyl chloride / 6 h / 30 °C 2.1: sodium tetrahydroborate; ethanol / 2 h / Cooling with ice; Reflux 3.1: triethylamine / dichloromethane / 0.5 h / 0 °C 3.2: 30 °C 4.1: ammonium hydroxide / acetonitrile / 48 h / 30 °C View Scheme
Multi-step reaction with 5 steps 1: water; N,N-dimethyl-formamide / 1 h / 20 - 30 °C 2: dimethylsulfide borane complex / tetrahydrofuran / 10 h / -5 - 50 °C 3: triethylamine / dichloromethane / 1 h / 0 - 20 °C 4: 2 h / 45 °C 5: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 45 °C / 1140.08 Torr View Scheme

1,5-dimethyl (2R)-2-[[(tert-butoxy)carbonyl]amino]pentanedioate → (R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium tetrahydroborate; ethanol / 2 h / Cooling with ice; Reflux 2.1: triethylamine / dichloromethane / 0.5 h / 0 °C 2.2: 30 °C 3.1: ammonium hydroxide / acetonitrile / 48 h / 30 °C View Scheme

di-tert-butyl dicarbonate (24424-99-5) → (R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: thionyl chloride / 6 h / 30 °C 2.1: sodium tetrahydroborate; ethanol / 2 h / Cooling with ice; Reflux 3.1: triethylamine / dichloromethane / 0.5 h / 0 °C 3.2: 30 °C 4.1: ammonium hydroxide / acetonitrile / 48 h / 30 °C View Scheme
Multi-step reaction with 5 steps 1: water; N,N-dimethyl-formamide / 1 h / 20 - 30 °C 2: dimethylsulfide borane complex / tetrahydrofuran / 10 h / -5 - 50 °C 3: triethylamine / dichloromethane / 1 h / 0 - 20 °C 4: 2 h / 45 °C 5: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 45 °C / 1140.08 Torr View Scheme

tert-butyl N-[(2R)-1,5-dihydroxypentan-2-yl]carbamate → (R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 0.5 h / 0 °C 1.2: 30 °C 2.1: ammonium hydroxide / acetonitrile / 48 h / 30 °C View Scheme
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 1 h / 0 - 20 °C 2: 2 h / 45 °C 3: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 45 °C / 1140.08 Torr View Scheme

N-[(1,1-dimethylethoxy)carbonyl]-D-glutamic acid (34404-28-9) → (R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: dimethylsulfide borane complex / tetrahydrofuran / 10 h / -5 - 50 °C 2: triethylamine / dichloromethane / 1 h / 0 - 20 °C 3: 2 h / 45 °C 4: hydrogen; palladium 10% on activated carbon / methanol / 2 h / 45 °C / 1140.08 Torr View Scheme

1-benzyloxycarbonylpiperidine-3-carboxylic acid (78190-11-1) → (R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3)

Conditions

Yield

Multi-step reaction with 6 steps 1: methanol / 40 - 50 °C 2: ethanol / 70 - 75 °C 3: methanesulfonyl chloride; ammonia; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / -10 - 25 °C 4: sodium hydroxide; sodium hypochlorite / water / 25 - 40 °C 5: sodium carbonate / methanol; water / 20 - 25 °C 6: palladium 10% on activated carbon; hydrogen / methanol; water / 2 h / 35 - 40 °C / 2250.23 - 3000.3 Torr / Autoclave; Inert atmosphere View Scheme

(R)-1-((benzyloxy)carbonyl)piperidine-3-carboxylic acid (160706-62-7) → (R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: methanesulfonyl chloride; ammonia; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / -10 - 25 °C 2: sodium hydroxide; sodium hypochlorite / water / 25 - 40 °C 3: sodium carbonate / methanol; water / 20 - 25 °C 4: palladium 10% on activated carbon; hydrogen / methanol; water / 2 h / 35 - 40 °C / 2250.23 - 3000.3 Torr / Autoclave; Inert atmosphere View Scheme

C14H18N2O3 → (R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide; sodium hypochlorite / water / 25 - 40 °C 2: sodium carbonate / methanol; water / 20 - 25 °C 3: palladium 10% on activated carbon; hydrogen / methanol; water / 2 h / 35 - 40 °C / 2250.23 - 3000.3 Torr / Autoclave; Inert atmosphere View Scheme

C8H11N*C14H17NO4 → (R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3)

Conditions

Yield

Multi-step reaction with 5 steps 1: ethanol / 70 - 75 °C 2: methanesulfonyl chloride; ammonia; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / -10 - 25 °C 3: sodium hydroxide; sodium hypochlorite / water / 25 - 40 °C 4: sodium carbonate / methanol; water / 20 - 25 °C 5: palladium 10% on activated carbon; hydrogen / methanol; water / 2 h / 35 - 40 °C / 2250.23 - 3000.3 Torr / Autoclave; Inert atmosphere View Scheme

(R)-1-benzylpiperidine-3-carboxylic azide → (R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: sulfuric acid / water / 1 h / 100 °C 2: sodium hydroxide / water / 2 h / 20 °C 3: 5%-palladium/activated carbon; hydrogen / ethanol / 20 h / 20 - 25 °C / 150015 Torr View Scheme

Ethyl nipecotate (71962-74-8) → (R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3)

Conditions

Yield

Multi-step reaction with 7 steps 1: isopropyl alcohol; water / 0.5 h / Reflux 2: sodium carbonate / N,N-dimethyl-formamide / 12 h / 60 °C 3: hydrazine hydrate / butan-1-ol / 8 h / Reflux 4: sulfuric acid; sodium nitrite / water / 1 h / 0 - 5 °C 5: sulfuric acid / water / 1 h / 100 °C 6: sodium hydroxide / water / 2 h / 20 °C 7: 5%-palladium/activated carbon; hydrogen / ethanol / 20 h / 20 - 25 °C / 150015 Torr View Scheme

(R)-piperidine-3-carboxylic acid ethyl ester*l-tartaric acid → (R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3)

Conditions	Yield
Multi-step reaction with 6 steps 1: sodium carbonate / N,N-dimethyl-formamide / 12 h / 60 °C 2: hydrazine hydrate / butan-1-ol / 8 h / Reflux 3: sulfuric acid; sodium nitrite / water / 1 h / 0 - 5 °C 4: sulfuric acid / water / 1 h / 100 °C 5: sodium hydroxide / water / 2 h / 20 °C 6: 5%-palladium/activated carbon; hydrogen / ethanol / 20 h / 20 - 25 °C / 150015 Torr View Scheme

(R)-1-benzylpiperidine-3-carboxylic acid ethyl ester (245529-50-4) → (R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3)

Conditions	Yield
Multi-step reaction with 5 steps 1: hydrazine hydrate / butan-1-ol / 8 h / Reflux 2: sulfuric acid; sodium nitrite / water / 1 h / 0 - 5 °C 3: sulfuric acid / water / 1 h / 100 °C 4: sodium hydroxide / water / 2 h / 20 °C 5: 5%-palladium/activated carbon; hydrogen / ethanol / 20 h / 20 - 25 °C / 150015 Torr View Scheme

(R)-1- benzylpiperidine-3-carboxylic acid hydrazide → (R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: sulfuric acid; sodium nitrite / water / 1 h / 0 - 5 °C 2: sulfuric acid / water / 1 h / 100 °C 3: sodium hydroxide / water / 2 h / 20 °C 4: 5%-palladium/activated carbon; hydrogen / ethanol / 20 h / 20 - 25 °C / 150015 Torr View Scheme

(3R)-1-benzyl-3-aminopiperidine (168466-84-0) → (R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide / water / 2 h / 20 °C 2: 5%-palladium/activated carbon; hydrogen / ethanol / 20 h / 20 - 25 °C / 150015 Torr View Scheme

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + 4-(methylamino)-3-nitrobenzoic acid (41263-74-5) → 1,1-dimethylethyl ((3R)-1-{[4-(methylamino)-3-nitrophenyl]carbonyl}-3-piperidinyl)carbamate (1549812-10-3)

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 20℃; for 16h;	100%
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 20℃; for 16h;	100%
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 20℃; for 16h;	100%

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + 3-methoxy-4-(methylamino)-5-nitrobenzoic acid (1549812-23-8) → (R)-(1-(3-methoxy-4-(methylamino)-5-nitrobenzoyl)piperidin-3-yl)carbamic acid tert-butyl ester (1549812-25-0)

Conditions	Yield
Stage #1: 3-methoxy-4-(methylamino)-5-nitrobenzoic acid 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 tetrahydrofuran; N,N-dimethyl-formamide for 0.666667h; Cooling with ice; Stage #2: (R)-piperidin-3-ylcarbamic acid tert-butyl ester In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 10h; Solvent; Temperature;	100%
Stage #1: 3-methoxy-4-(methylamino)-5-nitrobenzoic acid 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 for 0.5h; Stage #2: (R)-piperidin-3-ylcarbamic acid tert-butyl ester In N,N-dimethyl-formamide for 1.5h;	19.4 g
Stage #1: 3-methoxy-4-(methylamino)-5-nitrobenzoic acid 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 for 0.5h; Stage #2: (R)-piperidin-3-ylcarbamic acid tert-butyl ester In N,N-dimethyl-formamide for 1.5h;	19.4 g
Stage #1: 3-methoxy-4-(methylamino)-5-nitrobenzoic acid 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 for 0.5h; Stage #2: (R)-piperidin-3-ylcarbamic acid tert-butyl ester In N,N-dimethyl-formamide for 1.5h;	19.4 g

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + 3-bromo-5-fluoropyridine-2- carbonitrile (950670-18-5) → (R)-tert-butyl 1-(5-bromo-6-cyanopyridin-3-yl)piperidin-3-ylcarbamate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 100℃; for 1.5h;	100%

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + methyl 4-(6-carbamoyl-3-(methylthio)-1,2,4-triazin-5-ylamino)benzoate → (R)-methyl 4-(3-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-6-carbamoyl-1,2,4-triazin-5-ylamino)benzoate

Conditions	Yield
Stage #1: methyl 4-(6-carbamoyl-3-(methylthio)-1,2,4-triazin-5-ylamino)benzoate With 3-chloro-benzenecarboperoxoic acid In 1-methyl-pyrrolidin-2-one at 20℃; for 1h; Stage #2: (R)-piperidin-3-ylcarbamic acid tert-butyl ester With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 90℃; for 1.5h;	100%

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + 5-chloro-2-(4-cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)imidazole-4-carboxylic acid → tert-butyl N-[(3R)-1-[5-Chloro-2-(4-cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)imidazole-4-carbonyl]piperidin-3-yl]carbamate

Conditions	Yield
With 4-methyl-morpholine; 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 20℃; for 1h;	100%

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + 2-(4-Cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)imidazole-4-carboxylic acid → tert-butyl N-[(3R)-1-[2-(4-cyano-3-fluorophenyl)-1-(3-fluoro-4-1methoxyphenyl)imidazole-4-carbonyl]piperidin-3-yl]carbamate

Conditions	Yield
With 4-methyl-morpholine; 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 20℃; for 1h;	100%

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (3680-69-1) → (R)-tert-butyl (1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)carbamate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In butan-1-ol at 80℃; for 52h; Inert atmosphere; Sealed tube;	100%

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + 2-chloro-6,7-dimethoxyquinazolin-4-amine (23680-84-4) → tert-butyl (R)-(1-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-3-yl)carbamate

Conditions	Yield
In i-Amyl alcohol at 130℃; under 760.051 Torr; for 0.833333h; Microwave irradiation;	100%

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + 1-(but-2-ynyl)-6-chloro-3-(prop-2-ynyl)pyrimidine-2,4(1H,3H)-dione → tert-butyl (R)-(1-(3-(but-2-yn-1-yl)-2,6-dioxo-1-(prop-2-yn-1-yl)-1,2,3,6-tetrahydropyrimidin-4-yl)piperidin-3-yl)carbamate

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 65℃; for 5h;	99.8%
With potassium carbonate In N,N-dimethyl-formamide at 65℃; for 5h;	99%

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) → 3-(R)-aminopiperidine dihydrochloride

Conditions	Yield
With hydrogenchloride In tert-butyl methyl ether at 0 - 20℃; for 8h;	99%
With thionyl chloride In methanol at 30℃; for 10h;

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + C13H12ClN3O2 → C23H31N5O4

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 65℃; Temperature;	98.2%

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + (1aS,6aR)-3,5-dichloro-6,6a-di-hydro-1aH-1-oxa-cyclopropa[a]indene (1215279-81-4) → tert-butyl (R)-1-((1R,2R)-4,6-dichloro-2-hydroxy-2,3-dihydro-1H-inden-1-yl)piperidin-3-ylcarbamate (1571103-69-9)

Conditions	Yield
In acetonitrile at 80℃; regioselective reaction;	98%
In acetonitrile at 70℃; for 15h;	330 mg

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + 7-but-2-ynyl-8-iodo-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione → 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxycarbonylamino)-piperidin-1-yl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine

Conditions	Yield
With lithium hexamethyldisilazane In toluene at 60 - 65℃; Reagent/catalyst; Inert atmosphere;	97.8%
With lithium hexamethyldisilazane In toluene at 60 - 65℃; Reagent/catalyst; Inert atmosphere;	97.8%

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + 3,5-dichloro-pyrazine-2-carbonitrile (313339-92-3) → tert-butyl N-[(3R)-1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl]carbamate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1.5h;	97%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1.5h;	93%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1.5h;	2.5 g

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + 2,3-dichloro-5-trifluoromethylpyridine (69045-84-7) → (R)-tert-butyl (1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)carbamate

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 5h;	97%

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + C18H13BrFN5O3 → C28H32FN7O5

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 2h;	96.1%

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + benzyl chloroformate (501-53-1) → (R)-3-(tert-butoxycarbonylamino)piperidine-1-carboxylic acid benzyl ester (485820-12-0)

Conditions	Yield
With triethylamine In tetrahydrofuran at 0 - 5℃; for 24h;	96%
With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; for 4h; Saturated solution;
With triethylamine In tetrahydrofuran at 0 - 5℃; for 24h;

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9) → 2-[[6-[(3R)-3-tert-butoxycarbonylamino-1-piperidinyl]-3,4-dihydro-2,4-dioxo-3-methyl-1(2H)-pyrimidinyl]methyl]benzonitrile (1246610-74-1)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 6h; Product distribution / selectivity;	96%
With potassium carbonate at 80 - 90℃;	90%
With tetrabutylammomium bromide; potassium carbonate; sodium iodide In acetonitrile for 25h; Reflux;	89.3%

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + 6-amino-1-(2-cyanobenzyl)-3-methylpyrimidine-2,4(1H,3H)-dione (1246610-77-4) + (R)-piperidin-3-ylcarbamic acid tert-butyl ester hydrochloride (1217656-59-1) → 2-[[6-[(3R)-3-tert-butoxycarbonylamino-1-piperidinyl]-3,4-dihydro-2,4-dioxo-3-methyl-1(2H)-pyrimidinyl]methyl]benzonitrile (1246610-74-1)

Conditions	Yield
at 100℃; for 3h;	96%

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + Bromodiphenylmethane (776-74-9) → (R)-tert-butyl (1-benzhydrylpiperidin-3-yl)carbamate

Conditions	Yield
With triethylamine In dichloromethane at 60℃; for 14h;	96%

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + 2-bromo-1-(but-2-ynyl)-4-methyl-6-((4-methylquinazolin-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-5,7-(4H,6H)-dione (853029-57-9) → 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxycarbonylamino)-piperidin-1-yl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine

Conditions	Yield
With potassium carbonate In dimethyl sulfoxide; acetonitrile at 84 - 86℃; for 20h;	95.3%
With potassium carbonate In dimethyl sulfoxide; acetonitrile at 20 - 86℃; for 20h; Temperature;	95.3%
With potassium carbonate; potassium iodide In dimethyl sulfoxide at 80 - 85℃; Reagent/catalyst;	91%

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + 8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + 2-chloromethyl-4-methylquinazoline (109113-72-6) → 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxycarbonylamino)-piperidin-1-yl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine

Conditions	Yield
Stage #1: 8-bromo-7-(but-2-yn-1-yl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione; 2-chloromethyl-4-methylquinazoline With potassium carbonate In 1-methyl-pyrrolidin-2-one; acetonitrile at 50℃; for 6h; Stage #2: (R)-piperidin-3-ylcarbamic acid tert-butyl ester In 1-methyl-pyrrolidin-2-one; acetonitrile at 60℃; for 8h; Solvent; Temperature;	95.1%
With sodium carbonate at 55 - 60℃; for 6h; Concentration; Reagent/catalyst;	91.8%
Stage #1: (R)-piperidin-3-ylcarbamic acid tert-butyl ester; 8-bromo-7-(but-2-yn-1-yl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione With 1-methyl-pyrrolidin-2-one; potassium carbonate; potassium iodide for 10h; Stage #2: 2-chloromethyl-4-methylquinazoline for 12h; Time;	90%
Stage #1: 8-bromo-7-(but-2-yn-1-yl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione; 2-chloromethyl-4-methylquinazoline With potassium carbonate; potassium iodide In 1-methyl-pyrrolidin-2-one at 40 - 50℃; Stage #2: (R)-piperidin-3-ylcarbamic acid tert-butyl ester Reagent/catalyst; Solvent; Temperature;	86.7%
Stage #1: 8-bromo-7-(but-2-yn-1-yl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione; 2-chloromethyl-4-methylquinazoline With potassium carbonate; potassium iodide In 1-methyl-pyrrolidin-2-one at 40 - 50℃; Stage #2: (R)-piperidin-3-ylcarbamic acid tert-butyl ester In 1-methyl-pyrrolidin-2-one Reagent/catalyst; Solvent; Temperature;

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + N-ethoxycarbonyl-4-piperidone (29976-53-2) → C18H33N3O4 (1346006-05-0)

Conditions	Yield
With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane	95%

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + 7-but-2-ynyl-8-iodo-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione → Linagliptin

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 10h;	94.1%

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + 1-fluoro-2-nitro-4-trifluoromethyl-benzene (367-86-2) → (R)-tert-butyl 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ylcarbamate

Conditions	Yield
With sodium hydrogencarbonate In tetrahydrofuran at 70℃; for 14h;	94%

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + 8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) → 3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxycarbonylamino)piperidin-1-yl]xanthine (666816-91-7)

Conditions	Yield
With potassium carbonate In dimethyl sulfoxide at 114℃; for 6h;	94%
With potassium carbonate In dimethyl sulfoxide at 114℃; for 6h;	94%
With potassium carbonate In dimethyl sulfoxide at 114℃; for 6h;	94%

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (1188914-98-8) → tert-butyl (R)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidin-3-ylcarbamate (1188915-59-4)

Conditions	Yield
	94%
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃;	94%

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (1188914-98-8) → tert-butyl (S)-1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperidin-3-ylcarbamate (1188915-61-8)

Conditions	Yield
at 20℃;	94%

Upstream product

• 485820-12-0 (R)-3-(tert-butoxycarbonylamino)piperidine-1-carboxylic acid benzyl ester 
• 1189160-63-1 t-butyl (R)-piperidin-3-ylcarbamate R-mandelate 
• 6893-26-1 D-Glutamic acid 
• 861658-15-3 1,5-dimethyl (2R)-2-[[(tert-butoxy)carbonyl]amino]pentanedioate 
• 24424-99-5 di-tert-butyl dicarbonate 
• 397246-12-7 tert-butyl N-[(2R)-1,5-dihydroxypentan-2-yl]carbamate 
• 34404-28-9 N-[(1,1-dimethylethoxy)carbonyl]-D-glutamic acid 
• 78190-11-1 1-benzyloxycarbonylpiperidine-3-carboxylic acid 
• 160706-62-7 (R)-1-((benzyloxy)carbonyl)piperidine-3-carboxylic acid 
• 1050446-94-0 C₁₄H₁₈N₂O₃ 
• 16682-12-5 D-ornithine hydrochloride 
• 221874-51-7 (3R)-3-[(tert -butoxycarbonyl)amino]-2-piperidone 
• 88763-76-2 (R)-(+)-3-Amino-2-piperidinon 
• 168466-84-0 (3R)-1-benzyl-3-aminopiperidine 

Downstream Products

• 868609-89-6 [(R)-1-(4-bromo-phenyl)-piperidin-3-yl]-carbamic acid-tert-butylester 
• 853068-38-9 tert-butyl {(3R)-1-[3-(2-chloro-5-fluorobenzyl)-5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl]piperidin-3-yl}carbamate 
• 853068-43-6 tert-butyl {(3R)-1-[3-(2-chlorobenzyl)-5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl]piperidin-3-yl}carbamate 
• 910137-58-5 R-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-1-(4-fluoro-benzyl)-1H-benzimidazole-5-carbonic acid methyl ester 
• 910137-57-4 R-2-(3-tert-butoxycarbonylamino-piperidin-1-yl)-1-(4-fluoro-benzyl)-1H-benzimidazole-6-carbonic acid methyl ester 
• 946402-84-2 tert-butyl [(3R)-1-(3-phenylpropyl)-3-piperidinyl]carbamate 
• 1196507-77-3 (R)-tert-butyl 1-(3-benzamido-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate 
• 1196507-83-1 (R)-tert-butyl 1-(5-bromo-3-(3-methylbenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate 
• 1196508-39-0 (R)-tert-butyl 1-(5-bromo-3-(3-methoxybenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate 
• 1196508-54-9 (R)-tert-butyl 1-(5-bromo-3-(3-fluorobenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate 
• 1196508-97-0 (R)-tert-butyl 1-(5-bromo-3-(3-chloro-4-fluorobenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate 
• 1196508-99-2 (R)-tert-butyl 1-(5-bromo-3-(3-fluoro-4-methoxybenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate 
• 1196509-03-1 (R)-tert-butyl 1-(5-bromo-3-(1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate 
• 1246610-74-1 2-[[6-[(3R)-3-tert-butoxycarbonylamino-1-piperidinyl]-3,4-dihydro-2,4-dioxo-3-methyl-1(2H)-pyrimidinyl]methyl]benzonitrile 

Relevant articles and documents

Convenient synthesis of (R)-3-[(tert -Butoxycarbonyl)amino]piperidine and (R)-3-[(tert -Butoxycarbonyl)amino]azepane

(R)-3-[(tert -Butoxycarbonyl)amino]piperidine and (R)-3-[(tert -butoxycarbonyl)amino]azepane were prepared in two steps starting from d -ornithine and d -lysine, respectively. In the key step, N -Boc-protected 3-aminolactams were converted into imido esters by O-alkylation and then hydrogenated to amines, under mild conditions (5 bar H 2, room temperature) and without isolation, over a standard hydrogenation catalyst (5% Pt/C).

Synthesis method of chiral 3-aminopiperidine and derivatives of 3-aminopiperidine

The invention relates to a synthesis method of chiral 3-aminopiperidine and derivatives of 3-aminopiperidine. According to the synthesis method, R (or S)-piperidine-3-ethyl formate-L (or D)-tartrate is subjected to a hydrazinolysis reaction after being subjected to benzyl protection, and R or S-1-benzyl-3-aminopiperidine is obtained through azidation and Curtius rearrangement. R or S-1-benzyl-3-aminopiperidine is subjected to debenzylation, R or S-3-aminopiperidine can be obtained, R or S-1-benzyl-3-aminopiperidine is subjected to 3-t-butyloxycarboryl protection and debenzylation in sequence,R or S-(3-t-butyloxycarborylamino) piperidine can be obtained, and corresponding salts of R or S-3-aminopiperidine can be obtained through hydrolyzing deprotection of R or S-(3-t-butyloxycarborylamino) piperidine under the acidic condition. The synthesis method of chiral 3-aminopiperidine and the derivatives of 3-aminopiperidine is low in cost, facilitates industrialization and has high optical purity.

(R)- 3 - Boc - amino piperidine preparation method

The invention discloses a preparation method of (R)-3-Boc-aminopiperidine and relates to the technical field of preparation of piperidine heterocyclic compounds. The preparation method includes following steps: (1) with N-Cbz-3-piperidinecarboxylic acid as a raw material, performing chiral resolution with R-phenylethylamine to obtain a compound I; (2) performing an acid-amide condensation reaction to the compound I and ammonia gas to obtain a compound II; (3) performing a Hofmann degradation reaction to the compound II to obtain a compound III; (4) performing protection to the compound III with di-tert-butyl dicarbonate to obtain a compound IV; and (5) performing a hydrogenation and Cbz-removal reaction to the compound IV to prepare the (R)-3-Boc-aminopiperidine. The method is mild in reaction conditions, is safe and reliable, is excellent in process stability, is low in energy consumption, is high in yield, is green and environment-protective and is suitable for industrial production.

Amino-protected (R) - 3-amino-piperidine preparation method

The invention discloses a preparation method of amino protection (R)-3-amino piperidine, and the preparation method comprises the following steps: (1) in the presence of a first solvent or absence of a solvent, reacting a compound of formula V with benzylamine to obtain a compound of formula VI; (2) in the presence of a second solvent, performing catalytic hydrogenation of the compound of formula VI to remove benzyl to obtain the amino protection (R)-3-amino piperidine. According to the method, the defects of use of expensive metal catalysts and use of high-pressure hydrogenation and various splitting for synthesis of a chiral amino piperidine ring can be avoided, at the same time, the synthetic route is short, the process is simple, the yield is high, and the method is suitable for industrial mass production.

(R) - 3-amino-piperidine dihydrochloride preparation method

The invention discloses a method for preparing (R)-3-amino piperidine hydrochloride. D-glutamic acid is taken as a starting material, and the (R)-3-amino piperidine hydrochloride is obtained by reaction in the following five steps: (1) hydroxyl esterification and amido Boc protection; (2) ester reduction; (3) hydroxyl activation; (4) cyclization; (5) amino Boc removal protection. The preparation method disclosed by the invention is short in synthetic route and low in cost, and industrial production can be achieved.

MANUFACTURING METHOD FOR A PIPERIDINE-3-YLCARBAMATE COMPOUND AND OPTICAL RESOLUTION METHOD THEREFOR

Provided is a manufacturing method for a piperidin-3-ylcarbamate compound in which a pyridin-3-ylcarbamate compound and hydrogen are brought into contact in the presence of a palladium catalyst.

New substituted imidazo-pyridinones and imidazo-pyridazinones, the preparation thereof and their use as pharmaceutical compositions

The present invention relates to substituted imidazo-pyridinones and imidazo-pyridazinones of general formula wherein R1 to R4 are defined as in claim 1, the tautomers, the stereoisomers, the mixtures thereof and the salts thereof, which have valuable pharmacological properties, particularly an inhibitory effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV).

SUCCINATE SALTS OF HETEROCYCLIC DPP-IV INHIBITORS

The present invention relates to therapeutically active and selective hemisuccinate salts of inhibitors of the enzyme DPP-IV of formula (I), pharmaceutical compositions comprising the salts and the use of such salts for and the manufacture of medicaments for treating diseases that are associated with proteins that are subject to inactivation by DPP-IV, such as type 2 diabetes and obesity.

Heterocyclic substituted aminoazacycles useful as central nervous system agents

Heterocyclic substituted aminoazacyclic compounds of the formula (I):Z-R3, wherein Z is a defined aminoazacycle and R3 is a defined heterocycle moiety, pharmaceutical compositions of these compounds, and use of said compositions to control synaptic transmission in mammals.

HETEROCYCLIC COMPOUNDS THAT ARE INHIBITORS OF THE ENZYME DPP-IV

The present invention relates to therapeutically active and selective inhibitors of the enzyme DPP-IV of formula I, pharmaceutical compositions comprising the compounds and the use of such compounds for and the manufacture of medicaments for treating diseases that are associated with proteins that are subject to inactivation by DPP-IV, such as type 2 diabetes and obesity.