3167-50-8

Basic information

• Product Name: 2-Aminopyrimidine-5-carboxylic acid
• Synonyms: 2-Amino-5-carboxypyrimidine, 2-Amino-5-carboxy-1,3-diazine;5-Pyrimidinecarboxylic acid, 2-amino-;ASISCHEM C63548;2-AMINOPYRIMIDINE-5-CARBOXYLIC ACID;2-Aminopyrimidine-5-carboxylicacid95%;5-Pyrimidinecarboxylic acid, 2-amino- (7CI,8CI,9CI);2-Aminopyrimidine-5-carboxylic acid ,97%;2-AMino-5-pyriMidinecarboxylic acid
• CAS NO: 3167-50-8
• Molecular Formula: C₅H₅N₃O₂
• Molecular Weight: 139.11
• Product Categories: Heterocycle-Pyrimidine series;AMINOACID;PYRIMIDINE;pharmacetical;Carboxylic Acids;Pyrazines, Pyrimidines & Pyridazines;API intermediates;Carboxylic Acids;Pyrazines, Pyrimidines & Pyridazines
• Mol File: 3167-50-8.mol
• Article Data: 8

Chemical Properties

• Melting Point: >300 °C
• Boiling Point: 474.584 °C at 760 mmHg
• Flash Point: 240.82 °C
• Appearance: /
• Density: 1.534 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.663
• Storage Temp.: 2-8°C(protect from light)
• PKA: 4.19±0.10(Predicted)
• CAS DataBase Reference: 2-Aminopyrimidine-5-carboxylic acid(CAS DataBase Reference)
• NIST Chemistry Reference: 2-Aminopyrimidine-5-carboxylic acid(3167-50-8)
• EPA Substance Registry System: 2-Aminopyrimidine-5-carboxylic acid(3167-50-8)

Safety Data

• Hazard Codes: Xi,Xn
• Statements: 20/21/22-36/37/38
• Safety Statements: 36/37-24/25-22
• Hazardous Substances Data: 3167-50-8(Hazardous Substances Data)

Usage

InChI:InChI=1/C5H5N3O2/c6-5-7-1-3(2-8-5)4(9)10/h1-2H,(H,9,10)(H2,6,7,8)

Synthetic route

2-amino-pyrimidine-5-carboxylic acid methyl ester (308348-93-8) → 2-amino-pyrimidine-5-carboxylic acid (3167-50-8)

Conditions	Yield
Stage #1: 2-amino-pyrimidine-5-carboxylic acid methyl ester With methanol; lithium hydroxide; water at 60℃; Stage #2: With hydrogenchloride; water In methanol pH=4;	90%
Stage #1: 2-amino-pyrimidine-5-carboxylic acid methyl ester With water; lithium hydroxide In methanol at 60℃; Stage #2: With hydrogenchloride In water pH=4;	90%
Stage #1: 2-amino-pyrimidine-5-carboxylic acid methyl ester With water; lithium hydroxide In methanol at 60℃; Stage #2: With hydrogenchloride In water pH=4;	90%
With lithium hydroxide In methanol; water at 60℃;	90%
With water; lithium hydroxide In tetrahydrofuran; methanol at 20℃; for 3h;

methyl 3,3-dimethoxypropionate (7424-91-1) + Methyl formate (107-31-3) + guanidine hydrochloride salt → 2-amino-pyrimidine-5-carboxylic acid (3167-50-8)

Conditions	Yield
Stage #1: methyl 3,3-dimethoxypropionate With sodium methylate In 1,4-dioxane; methanol Reflux; Large scale; Stage #2: Methyl formate In 1,4-dioxane; methanol at 20℃; Large scale; Stage #3: guanidine hydrochloride salt Large scale; Further stages;	65%

methyl 3,3-dimethoxypropionate (7424-91-1) + Methyl formate (107-31-3) + guanidine hydrochloride (50-01-1) → 2-amino-pyrimidine-5-carboxylic acid (3167-50-8)

Conditions	Yield
Stage #1: methyl 3,3-dimethoxypropionate With sodium methylate In 1,4-dioxane; methanol Reflux; Large scale; Stage #2: Methyl formate Large scale; Stage #3: guanidine hydrochloride Large scale; Further stages;	65%

2-aminopyrimidine-5-carboxylic acid ethyl ester (57401-76-0) → 2-amino-pyrimidine-5-carboxylic acid (3167-50-8)

Conditions	Yield
With potassium hydroxide In methanol for 5h; Heating;	60%

ethyl 2-chloropyrimidine-5-carboxylate (89793-12-4) → 2-amino-pyrimidine-5-carboxylic acid (3167-50-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: NH3 View Scheme

ethyl 2-(ethylthio)pyrimidine-5-carboxylate (151323-66-9) → 2-amino-pyrimidine-5-carboxylic acid (3167-50-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: H2O; chlorine 2: NH3 View Scheme

4-chloro-2-ethylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (2223-96-3) → 2-amino-pyrimidine-5-carboxylic acid (3167-50-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: aqueous ethanol; zinc-powder 2: H2O; chlorine 3: NH3 View Scheme

2-amino-pyrimidine-5-carboxylic acid (3167-50-8) → 2-amino-1,4,5,6-tetrahydropyrimidine-5-carboxylic acid hydrochloride

Conditions	Yield
With hydrogenchloride; platinum(IV) oxide; hydrogen In water for 48h;	96%
With hydrogenchloride; hydrogen; palladium on activated charcoal under 1499.7 Torr; for 4h; Ambient temperature;	95%

2-amino-pyrimidine-5-carboxylic acid (3167-50-8) + 7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (1032570-74-3) → 2-amino-N-{7-methoxy-8-[3-(4 morpholinyl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}-5- pyrimidinecarboxamide (1032568-63-0)

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 17h; Large scale;	96%
With dmap; C9H19N3*ClH In ethanol; N,N-dimethyl-formamide at 20℃; for 15h;	96%
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	40%
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	40%

2-amino-pyrimidine-5-carboxylic acid (3167-50-8) + N-(4-methyl-3-(piperidin-4-yloxy)phenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzoamide trihydrochloride → N-(3-((1-(2-aminopyrimidine-5-carbonyl)piperidin-4-yl)oxy)-4-methylphenyl)-4-((4-methy lpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide

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℃; for 2h;	79%

2-amino-pyrimidine-5-carboxylic acid (3167-50-8) → 2-aminopyrimidine (109-12-6)

Conditions	Yield
for 3h; Heating;	74%

2-amino-pyrimidine-5-carboxylic acid (3167-50-8) + rel-N-[8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxy-2-methylpropyl}oxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]amine → rel-2-amino-N-{8-({(2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-hydroxy-2-methylpropyl}oxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide

Conditions	Yield
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 24h;	68%

2-amino-pyrimidine-5-carboxylic acid (3167-50-8) + 4-[[3-[[5-(trifluoromethyl)-2-pyridyl]oxy]phenyl]methylene]-cyclohexanamine (1428929-08-1, 1428954-51-1) → 2-amino-N-[4-[[3-[[5-(trifluoromethyl)-2-pyridyl]oxy]phenyl] methylene]cyclohexyl]pyrimidine-5-carboxamide (1428926-93-5, 1428947-75-4, 1428949-41-0)

Conditions	Yield
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 18h;	62%

2-amino-pyrimidine-5-carboxylic acid (3167-50-8) + 2-amino-7-(3-morpholin-4-ylpropoxy)-8-methoxyquinazolin-4(3H)-one → N-[7-(3-morpholin-4-ylpropoxy)-8-methoxyquinazoline-4(3H)-one-2-yl]-2-amino-5-pyrimidinecarboxamide

Conditions	Yield
With DBN; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate In acetonitrile at 20℃; for 12h;	61.1%

2-amino-pyrimidine-5-carboxylic acid (3167-50-8) + 2-methyltryptamine (2731-06-8) → 2-amino-N-(2-(2-methyl-1H-indol-3-yl)ethyl)pyrimidine-5-carboxamide

Conditions	Yield
Stage #1: 2-amino-pyrimidine-5-carboxylic acid With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 2-methyltryptamine In N,N-dimethyl-formamide at 20℃; for 24h;	59%

2-amino-pyrimidine-5-carboxylic acid (3167-50-8) + 1-t-Butoxycarbonylpiperazine (57260-71-6) → tert-butyl 4-[(2-aminopyrimidin-5-yl)carbonyl]piperazine-1-carboxylate

Conditions	Yield
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 12h;	56.6%

2-amino-pyrimidine-5-carboxylic acid (3167-50-8) + 3,4,9,10-tetrahydro-2H-[1,4]coumaine[2,3-h]imidazo[1,2-c]quinazolin-7-amine → C18H17N7O3

Conditions	Yield
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	54%

2-amino-pyrimidine-5-carboxylic acid (3167-50-8) + 3-amino-6-(benzyloxy)-5-methoxy-2-methylisoquinolin-1-(2H)-one → 2-amino-N-(6-(benzyloxy)-2-methyl-5-methoxy-1-oxo-1,2-dihydroisoquinoline-3-yl)pyrimidine-5-carboxamide

Conditions	Yield
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 48h;	40%

2-amino-pyrimidine-5-carboxylic acid (3167-50-8) + 3-amino-4-methyl-N-(4-((4-methylpiperazin-1-yl) methyl)-3-(trifluoromethyl)phenyl)benzamide (1202649-62-4) → 2-amino-N-(2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)pyrimidine-5-carboxamide (1581701-25-8)

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 12h;	38%

2-amino-pyrimidine-5-carboxylic acid (3167-50-8) + C18H22N2O → 2-amino-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)pyrimidine-5-carboxamide

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℃;	35%

2-amino-pyrimidine-5-carboxylic acid (3167-50-8) → 2-Amino-1,4,5,6-tetrahydro-pyrimidine-5-carbonyl chloride; hydrochloride

Conditions	Yield
Multi-step reaction with 2 steps 1: 95 percent / H2, aq. HCl / 10percent Pd/C / 4 h / 1499.7 Torr / Ambient temperature 2: 0.53 g / oxalyl chloride / benzene / 2.5 h / Heating View Scheme

2-amino-pyrimidine-5-carboxylic acid (3167-50-8) → 2-amino-5-(methoxycarbonyl)-1,4,5,6-tetrahydropyrimidine hydrochloride

Conditions	Yield
Multi-step reaction with 2 steps 1: 95 percent / H2, aq. HCl / 10percent Pd/C / 4 h / 1499.7 Torr / Ambient temperature 2: 81.2 percent / SOCl2 / Heating View Scheme

2-amino-pyrimidine-5-carboxylic acid (3167-50-8) → 2-amino-5-(ethoxycarbonyl)-1,4,5,6-tetrahydropyrimidine hydrochloride

Conditions	Yield
Multi-step reaction with 2 steps 1: 95 percent / H2, aq. HCl / 10percent Pd/C / 4 h / 1499.7 Torr / Ambient temperature 2: 82.1 percent / SOCl2 / Heating View Scheme

2-amino-pyrimidine-5-carboxylic acid (3167-50-8) → 2-amino-5-(isopropyloxycarbonyl)-1,4,5,6-tetrahydropyrimidine hydrochloride

Conditions	Yield
Multi-step reaction with 2 steps 1: 95 percent / H2, aq. HCl / 10percent Pd/C / 4 h / 1499.7 Torr / Ambient temperature 2: 34.2 percent / SOCl2 / Heating View Scheme

2-amino-pyrimidine-5-carboxylic acid (3167-50-8) → 2-amino-5-(propyloxycarbonyl)-1,4,5,6-tetrahydropyrimidine hydrochloride

Conditions	Yield
Multi-step reaction with 2 steps 1: 95 percent / H2, aq. HCl / 10percent Pd/C / 4 h / 1499.7 Torr / Ambient temperature 2: 75.2 percent / SOCl2 / Heating View Scheme

2-amino-pyrimidine-5-carboxylic acid (3167-50-8) → 2-amino-5-(propargyloxycarbonyl)-1,4,5,6-tetrahydropyrimidine hydrochloride

Conditions	Yield
Multi-step reaction with 3 steps 1: 95 percent / H2, aq. HCl / 10percent Pd/C / 4 h / 1499.7 Torr / Ambient temperature 2: 0.53 g / oxalyl chloride / benzene / 2.5 h / Heating 3: 53.2 percent / Ambient temperature View Scheme

2-amino-pyrimidine-5-carboxylic acid (3167-50-8) → 5-(trifluoromethyl)pyrimidin-2-amine (69034-08-8)

Conditions	Yield
With HF; SF4

2-amino-pyrimidine-5-carboxylic acid (3167-50-8) + 3-methyl-N-(3-methylbutyl)-1-butanamine (544-00-3) → C15H26N4O (1187663-51-9)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 50℃;

2-amino-pyrimidine-5-carboxylic acid (3167-50-8) + 4-phenoxy benzaldehyde (67-36-7) → C18H13N3O3

Conditions	Yield
With scandium tris(trifluoromethanesulfonate) In methanol; dichloromethane at 20℃; for 1h;

Upstream product

• 7424-91-1 methyl 3,3-dimethoxypropionate 
• 107-31-3 Methyl formate 
• 50-01-1 guanidine hydrochloride 
• 151323-66-9 ethyl 2-(ethylthio)pyrimidine-5-carboxylate 
• 57401-76-0 2-aminopyrimidine-5-carboxylic acid ethyl ester 
• 308348-93-8 2-amino-pyrimidine-5-carboxylic acid methyl ester 
• 2223-96-3 4-chloro-2-ethylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester 
• 89793-12-4 ethyl 2-chloropyrimidine-5-carboxylate 

Downstream Products

• 1032568-63-0 copanlisib 
• 1428926-93-5 2-amino-N-[4-[[3-[[5-(trifluoromethyl)-2-pyridyl]oxy]phenyl] methylene]cyclohexyl]pyrimidine-5-carboxamide 
• 1581701-25-8 2-amino-N-(2-methyl-5-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)phenyl)pyrimidine-5-carboxamide 
• 69034-08-8 5-(trifluoromethyl)pyrimidin-2-amine 
• 109-12-6 2-aminopyrimidine 

Relevant articles and documents

SYNTHESIS OF COPANLISIB AND ITS DIHYDROCHLORIDE SALT

The present invention relates to a novel method of preparing copanlisib, copanlisib dihydrochloride, or hydrates of copanlisib dihydrochloride, to novel intermediate compounds, and to the use of said novel intermediate compounds for the preparation of said copanlisib, copanlisib dihydrochloride, or hydrates of copanlisib dihydrochloride. The present invention also relates to copanlisib dihydrochloride hydrates as compounds.

Discovery and SAR of Novel 2,3-Dihydroimidazo[1,2-c]quinazoline PI3K Inhibitors: Identification of Copanlisib (BAY 80-6946)

The phosphoinositide 3-kinase (PI3K) pathway is aberrantly activated in many disease states, including tumor cells, either by growth factor receptor tyrosine kinases or by the genetic mutation and amplification of key pathway components. A variety of PI3K isoforms play differential roles in cancers. As such, the development of PI3K inhibitors from novel compound classes should lead to differential pharmacological and pharmacokinetic profiles and allow exploration in various indications, combinations, and dosing regimens. A screening effort aimed at the identification of PI3Kγ inhibitors for the treatment of inflammatory diseases led to the discovery of the novel 2,3-dihydroimidazo[1,2-c]quinazoline class of PI3K inhibitors. A subsequent lead optimization program targeting cancer therapy focused on inhibition of PI3Kα and PI3Kβ. Herein, initial structure–activity relationship findings for this class and the optimization that led to the identification of copanlisib (BAY 80-6946) as a clinical candidate for the treatment of solid and hematological tumors are described.

ARYLAMINOALCOHOL-SUBSTITUTED 2,3-DIHYDROIMIDAZO[1,2-C]QUINOLINES

The present invention relates to substituted phenoxypyridine compounds of general foumula (I); in which R1, R2 and R3 are as defined in the claims, to methods of preparing said compounds, to intermediates for the preparation of said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and /or angiogenesis disorder, as a sole agent or in combination with other active ingredients.