498-95-3

Basic information

• Product Name: Nipecotic acid
• Synonyms: (3R)-(-)-PIPERIDIN-3-YLCARBOXYLIC ACID;(+/-)-3-PIPERIDINE CARBOXYLIC ACID;3-PIPERIDINECARBOXYLIC ACID;L-NIPECOTIC ACID;DL-NIPECOTIC ACID;DL-3-PIPERIDINECARBOXYLIC ACID;(-)-D-NIPECOTIC ACID;D(-)-NIPECOTIC ACID
• CAS NO: 498-95-3
• Molecular Formula: C₆H₁₁NO₂
• Molecular Weight: 129.16
• EINECS: 207-873-9
• Product Categories: Nitrogen cyclic compounds;Amines and Anilines;Amino Acids and Derivatives;Piperidines, Piperidones, Piperazines;Piperidine;Organic acids;Heterocyclic Compounds;Miscellaneous;Unusual Amino Acids;Amino Acid Derivatives;GABA/Glycine receptor;Heterocycles;Miscellaneous Reagents
• Mol File: 498-95-3.mol
• Article Data: 22

Chemical Properties

• Melting Point: 261 °C (dec.)(lit.)
• Boiling Point: 239.22°C (rough estimate)
• Flash Point: 114.5 °C
• Appearance: off-white to pale yellow-beige powder
• Density: 1.1426 (rough estimate)
• Vapor Pressure: 0.0026mmHg at 25°C
• Refractive Index: 1.4587 (estimate)
• Storage Temp.: Store at 0-5°C
• Solubility: water: soluble50mg/mL, clear, colorless to faintly yellow
• PKA: pK1:3.35(+1);pK2:10.64(0) (25°C)
• Water Solubility: Soluble in water
• Merck: 14,6560
• BRN: 81096
• CAS DataBase Reference: Nipecotic acid(CAS DataBase Reference)
• NIST Chemistry Reference: Nipecotic acid(498-95-3)
• EPA Substance Registry System: Nipecotic acid(498-95-3)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-36-37/39
• WGK Germany: 3
• RTECS: TM6125380
• HazardClass: IRRITANT
• Hazardous Substances Data: 498-95-3(Hazardous Substances Data)

Usage

Chemical Properties

off-white to pale yellow-beige powder

Uses

(+/-)-Nipecotic Acid (cas# 498-95-3) is a compound useful in organic synthesis.

Definition

ChEBI: A piperidinemonocarboxylic acid that is piperidine in which one of the hydrogens at position 3 is substituted by a carboxylic acid group.

Synthesis Reference(s)

The Journal of Organic Chemistry, 28, p. 602, 1963 DOI: 10.1021/jo01037a531

General Description

R(?)-Nipecotic acid is a potential inhibitor of uptake of γ-aminobutyric acid (GABA) in rat brain slices. Lipophilic derivatives of nipecotic acid are used as drugs for the treatment of epilepsy.

InChI:InChI=1/C6H11NO2/c8-6(9)5-2-1-3-7-4-5/h5,7H,1-4H2,(H,8,9)

Synthetic route

methyl 3-pyridinecarboxylate (93-60-7) → nipecotic acid (498-95-3)

Conditions	Yield
With hydrogen In water at 120℃; under 11251.1 Torr; for 1h;	100%

nicotinic acid (59-67-6) → nipecotic acid (498-95-3)

Conditions	Yield
With platinum(IV) oxide; hydrogen In ethanol at 80℃; under 6205.94 Torr; for 0.666667h; Microwave irradiation;	98%
With ethanol; sodium
With hydrogenchloride; platinum Hydrogenation;

N-benzylnipecotic acid benzyl ester (141943-03-5) → 1-benzylpiperidine-3-carboxylic acid (141943-04-6) + nipecotic acid (498-95-3)

Conditions	Yield
With cyclohexa-1,4-diene; hydrogen; palladium on activated charcoal In ethanol for 0.166667h; Ambient temperature;	A 63% B 30%

potassium carbonate (584-08-7) + Ethyl nipecotate (71962-74-8) → nipecotic acid (498-95-3)

Conditions	Yield
With Ki In ethyl acetate; acetone	55%

nicotinic acid (59-67-6) → nipecotic acid (498-95-3) + 1,4,5,6-tetrahydronicotinate

Conditions	Yield
With (S)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldicyclohexylphosphine; hydrogen; di(norbornadiene)rhodium(I) tetrafluoroborate In methanol at 60℃; under 75006 Torr; for 20h; Product distribution; Further Variations:; Reagents;	A 8% B n/a

piperidine (110-89-4) + formic acid (64-18-6) → isonipecotic acid (498-94-2) + glycine (56-40-6) + pipecolic Acid (4043-87-2) + nipecotic acid (498-95-3)

Conditions	Yield
In water at 10 - 20℃; for 1h; contact glow discharge electrolysis (500-600 V, 45 mA);	A 4.3% B 0.1% C 0.8% D 2.9%

Pyridine-2,3-dicarboxylic acid (89-00-9) → nipecotic acid (498-95-3)

Conditions	Yield
With i-Amyl alcohol; sodium

3-methoxycarbonylpiperidine (50585-89-2) → dihydroarecoline (1690-72-8) + nipecotic acid (498-95-3)

Conditions	Yield
at 150℃; under 0.01 Torr;

Piperidine-3-carboxylic acid 4-nitro-phenyl ester (119228-39-6) → 4-nitro-phenol (100-02-7) + nipecotic acid (498-95-3)

Conditions	Yield
With water at 37℃; pH 7.4; other nipecotic acid phenyl esters; various solutions;

Piperidine-3-carboxylic acid 4-nitro-phenyl ester; hydrobromide → 4-nitro-phenol (100-02-7) + nipecotic acid (498-95-3)

Conditions	Yield
With Cu complex of polymer from 2,6-bis-aminomethylpyridine and 4,4'-bis-aminomethyldiphenylmethane; water In dimethyl sulfoxide at 25℃; Rate constant; var.reag.: Cu(2+) complex of 2,6-bis-benzylaminomethylpyridine; oligomers of 2,6-bis-aminomethylpyridine and 4,4'-bis-aminomethyldiphenylmethane;

1.2.5.6-tetrahydro-pyridine-carboxylic acid-(3) → nipecotic acid (498-95-3)

Conditions	Yield
With acetic acid; platinum Hydrogenation;
With hydrogenchloride; platinum Hydrogenation;

hydrogenchloride (7647-01-0) + guvacine (498-96-4) + platinum black → nipecotic acid (498-95-3)

Conditions	Yield
Hydrogenation;

guvacine (498-96-4) + acetic acid (64-19-7) + platinum black → nipecotic acid (498-95-3)

Conditions	Yield
Hydrogenation;

nicotinic acid (59-67-6) + ethanol (64-17-5) + sodium → nipecotic acid (498-95-3)

Pyridine-2,3-dicarboxylic acid (89-00-9) + i-Amyl alcohol (123-51-3) + sodium → nipecotic acid (498-95-3)

water (7732-18-5) + nicotinic acid hydrochloride (636-79-3) + platinum oxide → nipecotic acid (498-95-3)

Conditions	Yield
Hydration;

[(2-chloroethoxy)(3,4-chlorophenyl)(phenyl)]methane + Ethyl nipecotate (71962-74-8) → nipecotic acid (498-95-3)

Conditions	Yield
Ki; potassium carbonate In N,N-dimethylformamide (DMF); chloroform
Ki; potassium carbonate In N,N-dimethylformamide (DMF); chloroform

C15H36BrNO2Si3 → nipecotic acid (498-95-3)

Conditions	Yield
With water; triethylamine In tetrahydrofuran; pentane at -60 - 20℃; for 4h;

4-(4-bromobutylidene)-2,2,6,6-tetramethyl-3,5-dioxa-2,6-disilaheptane → nipecotic acid (498-95-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / pentane / 2 h / 20 °C / Inert atmosphere 2: triethylamine; water / tetrahydrofuran; pentane / 4 h / -60 - 20 °C View Scheme

5-bromopentanoic acid (2067-33-6) → nipecotic acid (498-95-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: lithium diisopropyl amide / tetrahydrofuran; hexane / 1 h / -78 - 20 °C / Inert atmosphere 2: trimethylsilyl trifluoromethanesulfonate / pentane / 2 h / 20 °C / Inert atmosphere 3: triethylamine; water / tetrahydrofuran; pentane / 4 h / -60 - 20 °C View Scheme

2-chloro-5-(5-ethyl-1,3-oxazol-2-yl)-6-methylnicotinonitrile (898229-16-8) + nipecotic acid (498-95-3) → 1-[3-cyano-5-(5-ethyl-1,3-oxazol-2-yl)-6-methylpyridin-2-yl]piperidine-4-carboxylic acid (898229-21-5)

Conditions	Yield
Stage #1: 2-chloro-5-(5-ethyl-1,3-oxazol-2-yl)-6-methylnicotinonitrile; nipecotic acid With triethylamine In ethanol at 120℃; for 0.333333h; Microwave irradiation; Stage #2: With hydrogenchloride In water	100%

ethanol (64-17-5) + nipecotic acid (498-95-3) → ethyl piperidine-3-carboxylate hydrochloride (4842-86-8)

Conditions	Yield
With thionyl chloride at 0℃; Reflux;	100%
With thionyl chloride at 0℃; for 24h; Reflux;	99%
With thionyl chloride In ethanol at -5℃; for 7h; Heating / reflux;	92%

3-amino-2-methylaminopyridine (5028-20-6) + nipecotic acid (498-95-3) → C12H16N4

Conditions	Yield
With polyphosphoric acid at 180℃; for 72h;	100%

2,3-Diaminopyridine (452-58-4) + nipecotic acid (498-95-3) → C11H14N4

Conditions	Yield
With polyphosphoric acid at 180℃; for 16h;	100%

methanol (67-56-1) + nipecotic acid (498-95-3) → methyl piperidine-3-carboxylate hydrochloride (89895-55-6)

Conditions	Yield
With thionyl chloride at 0 - 20℃; for 3h;	98%
With thionyl chloride	97%
With thionyl chloride

benzyl chloroformate (501-53-1) + nipecotic acid (498-95-3) → 1-benzyloxycarbonylpiperidine-3-carboxylic acid (78190-11-1)

Conditions	Yield
With sodium hydrogencarbonate In 1,4-dioxane	98%
With sodium hydroxide In water at 20℃;	89%
With sodium hydroxide	82%

di-tert-butyl dicarbonate (24424-99-5) + nipecotic acid (498-95-3) → N-(tert-butyloxycarbonyl)nipecotic acid (71381-75-4, 88495-54-9, 84358-12-3)

Conditions	Yield
	98%
With sodium hydroxide In tert-butyl alcohol at 0 - 20℃; for 12h;	97%
With triethylamine In methanol at 0 - 20℃; Inert atmosphere;	97%

methanol (67-56-1) + nipecotic acid (498-95-3) → 3-methoxycarbonylpiperidine (50585-89-2)

Conditions	Yield
With oxalyl dichloride at 0℃; for 1h;	98%
With sulfuric acid at 0 - 80℃;
With thionyl chloride at 0℃; for 1h; Inert atmosphere; Reflux;

4-fluoro-7-nitro-2,1,3-benzoxadiazole (29270-56-2) + nipecotic acid (498-95-3) → rac-1-(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)piperidine-3-carboxylic acid

Conditions	Yield
With sodium carbonate In water; acetonitrile at 0℃; for 0.116667h; Darkness;	98%

benzenesulfonyl chloride (98-09-9) + nipecotic acid (498-95-3) → 1-(phenylsulfonyl)piperidine-3-carboxylic acid (321970-54-1)

Conditions	Yield
Stage #1: nipecotic acid With sodium carbonate In water at 0℃; for 0.166667h; Stage #2: benzenesulfonyl chloride In water at 0 - 20℃; Stage #3: With hydrogenchloride In water at 0 - 5℃; for 0.25 - 0.5h; pH=3;	97.83%
With sodium carbonate In dichloromethane; water at 25℃; for 16h; Inert atmosphere;	91%

(E)-5,5-difluoro-7-(5-oxopentenyl)-1,3,10-trimethyl-5Hdipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-5-uide + nipecotic acid (498-95-3) → rac-(E)-7-{5-[3-(carboxy)piperidin-1-yl]pentenyl}-5,5-difluor-1,3,10-trimethyl-5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-5-uide

Conditions	Yield
Stage #1: (E)-5,5-difluoro-7-(5-oxopentenyl)-1,3,10-trimethyl-5Hdipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-5-uide; nipecotic acid With acetic acid In ethanol at 20℃; for 0.166667h; Inert atmosphere; Stage #2: With sodium cyanoborohydride In ethanol at 20℃; Inert atmosphere;	96%

formaldehyd (50-00-0) + 7-Hydroxy-3-(4-methoxy-phenyl)-chromen-4-on (485-72-3) + nipecotic acid (498-95-3) → 1-{[7-hydroxy-3-(4-methoxyphenyl)-4-oxo-4H-chromen-8-yl]methyl}piperidine-3-carboxylic acid (1400917-40-9)

Conditions	Yield
With dmap In ethanol Mannich Aminomethylation; Reflux; regioselective reaction;	95%

benzoyl chloride (98-88-4) + nipecotic acid (498-95-3) → (±)-1-benzoylpiperidine-3-carboxylic acid (13850-76-5)

Conditions	Yield
Stage #1: benzoyl chloride; nipecotic acid With potassium carbonate In tetrahydrofuran; water at 0 - 20℃; for 22h; Stage #2: With hydrogenchloride In water at 0℃; pH=1 - 2;	95%
With potassium carbonate In tetrahydrofuran; water at 0 - 20℃; for 22h;	95%
With potassium carbonate In tetrahydrofuran; water at 0 - 20℃; for 22h;	95%

Triethyl orthoacetate (78-39-7) + nipecotic acid (498-95-3) → 1-acetyl-piperidine-3-carboxylic acid ethyl ester (2637-75-4)

Conditions	Yield
In toluene at 110℃; for 24h;	94%

formaldehyd (50-00-0) + cladrin (24160-14-3) + nipecotic acid (498-95-3) → 1-{[7-hydroxy-3-(3,4-dimethoxyphenyl)-4-oxo-4H-chromen-8-yl]methyl}piperidine-3-carboxylic acid (1400917-43-2)

Conditions	Yield
With dmap In ethanol Mannich Aminomethylation; Reflux; regioselective reaction;	92%

Benzyl isothiocyanate (622-78-6) + nipecotic acid (498-95-3) → (±)-macahydantoins A

Conditions	Yield
Stage #1: nipecotic acid With pyridine for 0.166667h; Stage #2: Benzyl isothiocyanate With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride at 65℃; for 8h; Inert atmosphere;	92%
Stage #1: Benzyl isothiocyanate; nipecotic acid With pyridine at 20℃; for 2h; Stage #2: With dmap; triethylamine; HATU at 20℃; for 6h; Reagent/catalyst; Cooling with ice; Inert atmosphere;	1.172 g

formaldehyd (50-00-0) + 5-methylformononetin (128672-43-5) + nipecotic acid (498-95-3) → 1-{[7-hydroxy-3-(4-methoxyphenyl)-5-methyl-4-oxo-4H-chromen-8-yl]methyl}piperidine-3-carboxylic acid (1400917-38-5)

Conditions	Yield
With dmap In ethanol Mannich Aminomethylation; Reflux; regioselective reaction;	91%

Boc-Val-ONSu (3392-12-9) + nipecotic acid (498-95-3) → 1-((S)-2-tert-Butoxycarbonylamino-3-methyl-butyryl)-piperidine-3-carboxylic acid (208113-87-5)

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 120℃; for 2.5h;	90%

p-toluenesulfonyl chloride (98-59-9) + nipecotic acid (498-95-3) → 1-tosylpiperidine-3-carboxylic acid (5134-62-3)

Conditions	Yield
With sodium carbonate In water at 0 - 20℃; for 48h;	90%

pentafluorophenyl trifloroacetate (14533-84-7) + nipecotic acid (498-95-3) → 1-(2,2,2-Trifluoro-acetyl)-piperidine-3-carboxylic acid pentafluorophenyl ester

Conditions	Yield
With pyridine In N,N-dimethyl-formamide Ambient temperature;	89%

nipecotic acid (498-95-3) + n-hexadecanoyl chloride (112-67-4) → N-palmitoylpiperidine-3-carboxylic acid

Conditions	Yield
With potassium carbonate In water; acetone at 0 - 20℃;	86%

potassium phosphate + 4-bromo-1-iodo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene + nipecotic acid (498-95-3) → 1-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)piperidine-3-carboxylic acid

Conditions	Yield
With ammonia	86%

N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1396776-39-8) + nipecotic acid (498-95-3) → N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1-(piperidine-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1396771-96-2)

Conditions	Yield
Stage #1: N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide; nipecotic acid With triethylamine In dimethyl sulfoxide at 20℃; for 0.25h; Stage #2: With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate In dimethyl sulfoxide	85%

formic acid (64-18-6) + nipecotic acid (498-95-3) → N-formylpiperidine-3-carboxylic acid

Conditions	Yield
Stage #1: formic acid With acetic anhydride for 1h; Heating; Stage #2: nipecotic acid at 25℃; for 16h;	85%

nipecotic acid (498-95-3) + methyl iodide (74-88-4) → 3-carboxy-1,1-dimethyl-piperidinium; chloride (62581-21-9)

Conditions	Yield
With sodium hydroxide In methanol for 12h; Heating;	84%

2-(tert-Butoxycarbonyloxyimino)-2-phenylacetonitrile (58632-95-4) + nipecotic acid (498-95-3) → N-(tert-butyloxycarbonyl)nipecotic acid (71381-75-4, 88495-54-9, 84358-12-3)

Conditions	Yield
With triethylamine In water; acetone	81%
With sodium hydrogencarbonate In 1,4-dioxane Acylation;
With triethylamine In water; acetone for 12h;

2'-chlorobiphenyl-3-sulfonyl chloride (933674-72-7) + nipecotic acid (498-95-3) → C18H18ClNO4S (1394241-89-4)

Conditions	Yield
In N,N-dimethyl-formamide; acetone at 0 - 20℃; Inert atmosphere;	79%

methanesulfonic acid 2-methoxy-6-pentadecyl-benzyl ester (1361955-58-9) + nipecotic acid (498-95-3) → 1-(2-methoxy-6-pentadecylbenzyl)piperidine-3-carboxylic acid (1363400-62-7)

Conditions	Yield
With triethylamine In acetonitrile at 85℃;	76%

Upstream product

• 59-67-6 nicotinic acid 
• 7732-18-5 water 
• 636-79-3 nicotinic acid hydrochloride 
• 584-08-7 potassium carbonate 
• 71962-74-8 Ethyl nipecotate 
• 93-60-7 methyl 3-pyridinecarboxylate 
• 4138-26-5 nipecotamide 
• 88466-74-4 (3S)-1-phenylmethoxycarbonylpiperidine-3-carboxylic acid 
• 2067-33-6 5-bromopentanoic acid 
• 89-00-9 Pyridine-2,3-dicarboxylic acid 
• 123-51-3 i-Amyl alcohol 
• 64-17-5 ethanol 
• 498-96-4 guvacine 
• 64-19-7 acetic acid 

Downstream Products

• 71962-74-8 Ethyl nipecotate 
• 89895-55-6 methyl piperidine-3-carboxylate hydrochloride 
• 71381-75-4 N-(tert-butyloxycarbonyl)nipecotic acid 
• 78190-11-1 1-benzyloxycarbonylpiperidine-3-carboxylic acid 
• 219519-90-1 1-(benzyloxycarbonylamino(benzyloxycarbonylimino)methyl)piperidine-3-carboxylic acid 
• 498-95-3 (R)-nipecotic acid 
• 80851-96-3 1-piperidin-3-yl-ethanone 
• 193693-68-4 (S)-1-{[(9H-fluoren-9-yl)methoxy]carbonyl}piperidine-3-carboxylic acid 
• 193693-67-3 (R)-1-{[(9H-fluoren-9-yl)methoxy]carbonyl}piperidine-3-carboxylic acid 
• 676259-95-3 piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-(2,6-diisopropyl-phenyl) ester 
• 219519-90-1 1-(benzyloxycarbonylamino(benzyloxycarbonylimino)methyl)piperidine-3-carboxylic acid 
• 19999-64-5 1-methyl-3-piperidinecarboxylic acid hydrochloride 
• 885068-59-7 1-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-piperidine-3-carboxylic acid 
• 321970-54-1 1-(phenylsulfonyl)piperidine-3-carboxylic acid 

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