886230-76-8

Basic information

• Product Name: (E)-3-[2-(Pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-amine
• Synonyms: (E)-3-[2-(Pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-amine;1H-Indazol-6-aMine,3-[(1E)-2-(2-pyridinyl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)-;6-amino-3-(E)-2-pyridin-2-yl-vinyl)-1- (tetrahydropyran-2-yl)-1H-indazole;(E)-3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-amine;3-[(E)-2-(2-Pyridinyl)vinyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-amine
• CAS NO: 886230-76-8
• Molecular Formula: C₁₉H₂₀N₄O
• Molecular Weight: 320.39
• Product Categories: Intermediate of Axitinib
• Mol File: 886230-76-8.mol
• Article Data: 8

Chemical Properties

• Boiling Point: 562.828 °C at 760 mmHg
• Flash Point: 294.188 °C
• Appearance: /
• Density: 1.29
• PKA: 4.31±0.10(Predicted)
• CAS DataBase Reference: (E)-3-[2-(Pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-amine(CAS DataBase Reference)
• NIST Chemistry Reference: (E)-3-[2-(Pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-amine(886230-76-8)
• EPA Substance Registry System: (E)-3-[2-(Pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-amine(886230-76-8)

Safety Data

• Hazardous Substances Data: 886230-76-8(Hazardous Substances Data)

Usage

Uses

Different sources of media describe the Uses of 886230-76-8 differently. You can refer to the following data:
1. (E)-3-[2-(Pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-amine is a heterocyclic derivative and can be used as a pharmaceutical intermediate.
2. Axitinib Pyran is a reagent used in synthesis of anti-angiogenic TKI-PET tracers.

Synthetic route

(Ε)-6-nitro-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-75-7) → (Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8)

Conditions	Yield
With sodiumsulfide nonahydrate In methanol at 65℃; for 3h; Temperature;	94.38%
With iron; ammonium chloride In ethanol; water at 50℃; for 2 - 8h;	91.8%
With iron; ammonium chloride In ethanol; water at 50℃; for 2 - 8h;	91.8%

6-nitroindazole (7597-18-4) → (Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium carbonate; iodine / N,N-dimethyl-formamide / 25 °C 2: methanesulfonic acid / dichloromethane; tetrahydrofuran / 5 h / 25 °C 3: N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 12 h / 100 °C 4: ammonium chloride; iron / ethanol; water / 2 h / 50 °C View Scheme
Multi-step reaction with 5 steps 1.1: potassium carbonate; iodine / N,N-dimethyl-formamide / 25 - 60 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 2.5 h / 60 °C 3.1: potassium carbonate; 1,10-Phenanthroline; copper(l) iodide / N,N-dimethyl-formamide / 8 h / 60 - 100 °C / Inert atmosphere 3.2: 60 °C 4.1: methanesulfonic acid / tetrahydrofuran / 6 h / Reflux 5.1: sodiumsulfide nonahydrate / water; methanol / 60 °C View Scheme
Multi-step reaction with 4 steps 1.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / acetonitrile / 2 h / 82 °C 2.1: sodium hydroxide; iodine / N,N-dimethyl-formamide / 14 h / 10 - 25 °C 2.2: 0.5 h / 20 °C 3.1: N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine; palladium dichloride / N,N-dimethyl-formamide / 12 h / 100 °C / Inert atmosphere 4.1: ammonium chloride; iron / water; ethanol / 2 h / 50 °C View Scheme
Multi-step reaction with 4 steps 1: iodine; potassium carbonate 2: methanesulfonic acid 3: N-ethyl-N,N-diisopropylamine; palladium diacetate; tris-(o-tolyl)phosphine 4: iron; ammonium chloride View Scheme
Multi-step reaction with 4 steps 1.1: trichlorophosphate / 5 h / 60 - 102 °C 2.1: methanesulfonic acid / dichloromethane / 6 h / 20 - 25 °C 3.1: sodium hydroxide / 1 h / 0 - 5 °C 3.2: 2 h / 20 °C 4.1: ammonium chloride; iron / ethanol; water / 6 h / 45 - 50 °C View Scheme

3-iodo-6-nitro-1H-indazole (70315-70-7) → (Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: methanesulfonic acid / dichloromethane; tetrahydrofuran / 5 h / 25 °C 2: N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 12 h / 100 °C 3: ammonium chloride; iron / ethanol; water / 2 h / 50 °C View Scheme
Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 2.5 h / 60 °C 2.1: potassium carbonate; 1,10-Phenanthroline; copper(l) iodide / N,N-dimethyl-formamide / 8 h / 60 - 100 °C / Inert atmosphere 2.2: 60 °C 3.1: methanesulfonic acid / tetrahydrofuran / 6 h / Reflux 4.1: sodiumsulfide nonahydrate / water; methanol / 60 °C View Scheme
Multi-step reaction with 3 steps 1: methanesulfonic acid 2: N-ethyl-N,N-diisopropylamine; palladium diacetate; tris-(o-tolyl)phosphine 3: iron; ammonium chloride View Scheme

3-iodo-6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (886230-74-6) → (Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 12 h / 100 °C 2: ammonium chloride; iron / ethanol; water / 2 h / 50 °C View Scheme
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine; palladium dichloride / N,N-dimethyl-formamide / 12 h / 100 °C / Inert atmosphere 2: ammonium chloride; iron / water; ethanol / 2 h / 50 °C View Scheme

(E)-6-nitro-3-[(2-pyridin-2-yl)vinyl]-1H-indazole → (Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: methanesulfonic acid / tetrahydrofuran / 6 h / Reflux 2: sodiumsulfide nonahydrate / water; methanol / 60 °C View Scheme

1-acetyl-3-iodine-6-nitroindazole → (Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium carbonate; 1,10-Phenanthroline; copper(l) iodide / N,N-dimethyl-formamide / 8 h / 60 - 100 °C / Inert atmosphere 1.2: 60 °C 2.1: methanesulfonic acid / tetrahydrofuran / 6 h / Reflux 3.1: sodiumsulfide nonahydrate / water; methanol / 60 °C View Scheme

6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (150187-67-0) → (Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydroxide; iodine / N,N-dimethyl-formamide / 14 h / 10 - 25 °C 1.2: 0.5 h / 20 °C 2.1: N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine; palladium dichloride / N,N-dimethyl-formamide / 12 h / 100 °C / Inert atmosphere 3.1: ammonium chloride; iron / water; ethanol / 2 h / 50 °C View Scheme

3,4-dihydro-2H-pyran (110-87-2) → (Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / acetonitrile / 2 h / 82 °C 2.1: sodium hydroxide; iodine / N,N-dimethyl-formamide / 14 h / 10 - 25 °C 2.2: 0.5 h / 20 °C 3.1: N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine; palladium dichloride / N,N-dimethyl-formamide / 12 h / 100 °C / Inert atmosphere 4.1: ammonium chloride; iron / water; ethanol / 2 h / 50 °C View Scheme

C19H18N4O3 → (Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8)

Conditions	Yield
With iron; ammonium chloride

2-methyl-5-nitroaniline (99-55-8) → (Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: sodium nitrite; acetic acid 2: iodine; potassium carbonate 3: methanesulfonic acid 4: N-ethyl-N,N-diisopropylamine; palladium diacetate; tris-(o-tolyl)phosphine 5: iron; ammonium chloride View Scheme

6-nitro-1H-indazole-3-carboxaldehyde (315203-37-3) → (Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: methanesulfonic acid / dichloromethane / 6 h / 20 - 25 °C 2.1: sodium hydroxide / 1 h / 0 - 5 °C 2.2: 2 h / 20 °C 3.1: ammonium chloride; iron / ethanol; water / 6 h / 45 - 50 °C View Scheme

C13H13N3O4 → (Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydroxide / 1 h / 0 - 5 °C 1.2: 2 h / 20 °C 2.1: ammonium chloride; iron / ethanol; water / 6 h / 45 - 50 °C View Scheme

C12H11BrFN3O + (Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8) → C31H30FN7O2

Conditions	Yield
With sodium t-butanolate; tris-(dibenzylideneacetone)dipalladium(0); johnphos In toluene at 102℃; for 18h;	88%

(Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8) → (Ε)-6-iodo-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole

Conditions	Yield
Stage #1: (Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole With sulfuric acid; acetic acid; sodium nitrite In water at -5 - 0℃; for 4h; Stage #2: With potassium iodide In water at 0℃; for 5.5h;	87%
Stage #1: (Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole With acetic acid; sodium nitrite In water at 0 - 5℃; for 1h; Stage #2: With iodine; potassium iodide In water at 0 - 5℃; for 3h;	81.2%
Stage #1: (Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole With hydrogenchloride; acetic acid; sodium nitrite In water at 0℃; Stage #2: With iodine; potassium iodide In dichloromethane; water at 0℃; for 2h;	65%
Stage #1: (Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole With acetic acid; sodium nitrite In water at 0℃; for 2h; Stage #2: With hydrogenchloride In water at 0℃; for 1.16667h; Stage #3: With iodine; potassium iodide In water at 0℃; for 2.08333h; Reagent/catalyst;	65.4%

(Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8) + Malonic acid monomethyl ester (16695-14-0) → methyl (E)-3-oxo-3-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)amino)propanoate

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 2h;	86%

(Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8) → C19H18N6O*ClH

Conditions	Yield
Stage #1: (Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole With sodium nitrite In water; acetic acid at 0℃; for 2.5h; Stage #2: With hydrogenchloride In water; acetic acid at 0℃; for 1.25h;

(Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8) → methyl 6-(2-(1-(tetrahydro-2H-pyran-2-yl)-3-((E)-2-(pyridin-2-yl)vinyl)-1H-indazol-6-ylthio)benzamido)hexanoate (1012060-43-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrogenchloride; sodium nitrite; acetic acid / water / 0 °C 1.2: 2 h / 0 °C 2.1: caesium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / dichloromethane; N,N-dimethyl-formamide / 80 °C View Scheme

(Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8) → methyl 6-(2-(3-((E)-2-(pyridin-2-yl)vinyl)-1H-indazol-6-ylthio)benzamido)hexanoate (1012060-44-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride; sodium nitrite; acetic acid / water / 0 °C 1.2: 2 h / 0 °C 2.1: caesium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / dichloromethane; N,N-dimethyl-formamide / 80 °C 3.1: toluene-4-sulfonic acid / water; methanol / 1 h / 60 °C View Scheme

(Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8) → N-(5-(hydroxycarbamoyl)pentyl)-2-(3-((E)-2-(pyridin-2-yl)vinyl)-1H-indazol-6-ylthio)benzamide (1012056-56-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: hydrogenchloride; sodium nitrite; acetic acid / water / 0 °C 1.2: 2 h / 0 °C 2.1: caesium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / dichloromethane; N,N-dimethyl-formamide / 80 °C 3.1: toluene-4-sulfonic acid / water; methanol / 1 h / 60 °C 4.1: hydroxylamine / methanol / 0.5 h / 20 °C 4.2: pH 6 - 7 View Scheme

(Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8) → (E)-methyl 5-(2-(3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-ylthio)phenoxy)pentanoate (1133966-04-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrogenchloride; sodium nitrite; acetic acid / water / 0 °C 1.2: 2 h / 0 °C 2.1: caesium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / dichloromethane; N,N-dimethyl-formamide / 16 h / 80 °C View Scheme

(Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8) → (E)-methyl 5-(2-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-ylthio)phenoxy)pentanoate (1133966-05-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride; sodium nitrite; acetic acid / water / 0 °C 1.2: 2 h / 0 °C 2.1: caesium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / dichloromethane; N,N-dimethyl-formamide / 16 h / 80 °C 3.1: toluene-4-sulfonic acid / ethanol; water; methanol / 65 °C View Scheme

(Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8) → (E)-2-(3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-ylthio)benzenamine (1133966-14-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrogenchloride; sodium nitrite; acetic acid / water / 0 °C 1.2: 2 h / 0 °C 2.1: sodium hydroxide / ISOPROPYLAMIDE / 155 °C / Inert atmosphere View Scheme

(Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8) → (E)-methyl 5-(2-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-ylthio)phenylamino)pentanoate (1133966-15-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride; sodium nitrite; acetic acid / water / 0 °C 1.2: 2 h / 0 °C 2.1: sodium hydroxide / ISOPROPYLAMIDE / 155 °C / Inert atmosphere 3.1: sodium hydroxide / N,N-dimethyl-formamide / 3 h / 140 °C View Scheme

(Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8) → (E)-ethyl 6-oxo-6-(2-(3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-ylthio)phenylamino)hexanoate (1133966-18-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride; sodium nitrite; acetic acid / water / 0 °C 1.2: 2 h / 0 °C 2.1: sodium hydroxide / ISOPROPYLAMIDE / 155 °C / Inert atmosphere 3.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 123 °C / Inert atmosphere View Scheme

(Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8) → (E)-ethyl 6-oxo-6-(2-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-ylthio)phenylamino)hexanoate (1133966-19-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: hydrogenchloride; sodium nitrite; acetic acid / water / 0 °C 1.2: 2 h / 0 °C 2.1: sodium hydroxide / ISOPROPYLAMIDE / 155 °C / Inert atmosphere 3.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 123 °C / Inert atmosphere 4.1: toluene-4-sulfonic acid / water; methanol / 64 °C View Scheme

(Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8) → (E)-2-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-ylthio)benzenamine (1133966-20-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride; sodium nitrite; acetic acid / water / 0 °C 1.2: 2 h / 0 °C 2.1: sodium hydroxide / ISOPROPYLAMIDE / 155 °C / Inert atmosphere 3.1: toluene-4-sulfonic acid / water; methanol / 2 h / Reflux 3.2: pH 10 View Scheme

(Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8) → (E)-methyl 7-oxo-7-(2-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-ylthio)phenylamino)heptanoate (1133966-21-8)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: hydrogenchloride; sodium nitrite; acetic acid / water / 0 °C 1.2: 2 h / 0 °C 2.1: sodium hydroxide / ISOPROPYLAMIDE / 155 °C / Inert atmosphere 3.1: toluene-4-sulfonic acid / water; methanol / 2 h / Reflux 3.2: pH 10 4.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 6 h / 123 °C / Inert atmosphere View Scheme

(Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8) → (E)-N-methyl-2-{[3-(2-(pyridin-2-yl)ethenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]thio}benzamide

Conditions	Yield
Multi-step reaction with 2 steps 1.1: acetic acid; sulfuric acid; sodium nitrite / water / 4 h / -5 - 0 °C 1.2: 5.5 h / 0 °C 2.1: potassium carbonate; copper(l) iodide; 2-vinylpyridine / N,N-dimethyl-formamide / 12 h / 100 °C View Scheme
Multi-step reaction with 2 steps 1.1: sodium nitrite; acetic acid / water / 2 h / 0 °C 1.2: 1.17 h / 0 °C 1.3: 2.08 h / 0 °C 2.1: bis[1,2-bis(diphenylphosphino)ferrocene]-palladium(0); caesium carbonate / N,N-dimethyl-formamide / 16 h / 80 °C / Inert atmosphere View Scheme

(Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8) → axitinib (319460-85-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: acetic acid; sulfuric acid; sodium nitrite / water / 4 h / -5 - 0 °C 1.2: 5.5 h / 0 °C 2.1: potassium carbonate; copper(l) iodide; 2-vinylpyridine / N,N-dimethyl-formamide / 12 h / 100 °C 3.1: water; hydrogenchloride; methanol / 6 h / 60 °C View Scheme
Multi-step reaction with 3 steps 1.1: sodium nitrite; acetic acid / water / 2 h / 0 °C 1.2: 1.17 h / 0 °C 1.3: 2.08 h / 0 °C 2.1: bis[1,2-bis(diphenylphosphino)ferrocene]-palladium(0); caesium carbonate / N,N-dimethyl-formamide / 16 h / 80 °C / Inert atmosphere 3.1: toluene-4-sulfonic acid / water; methanol / 4 h / 65 °C / Inert atmosphere View Scheme

(Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8) + 1,1-cyclopropanedicarboxylic acid monomethyl ester (113020-21-6) → methyl (E)-1-((3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)carbamoyl)cyclopropane-1-carboxylate

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 2h;

(Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8) + 4-chloro-3-(trifluoromethyl)phenyl isocyanate (327-78-6) → (E)-1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)urea

Conditions	Yield
Multi-step reaction with 2 steps 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 / dichloromethane / 8 h / 20 °C 2: trifluoroacetic acid / dichloromethane / 4 h / 20 °C View Scheme

(Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-76-8) + 4-chloro-3-(trifluoromethyl)phenyl isocyanate (327-78-6) → C27H23ClF3N5O2

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 dichloromethane at 20℃; for 8h;

Upstream product

• 315203-37-3 6-nitro-1H-indazole-3-carboxaldehyde 
• 99-55-8 2-methyl-5-nitroaniline 
• 110-87-2 3,4-dihydro-2H-pyran 
• 150187-67-0 6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 
• 886230-74-6 3-iodo-6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 
• 70315-70-7 3-iodo-6-nitro-1H-indazole 
• 7597-18-4 6-nitroindazole 
• 886230-75-7 (Ε)-6-nitro-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole 

Downstream Products

• 1012060-43-3 methyl 6-(2-(1-(tetrahydro-2H-pyran-2-yl)-3-((E)-2-(pyridin-2-yl)vinyl)-1H-indazol-6-ylthio)benzamido)hexanoate 
• 1012060-44-4 methyl 6-(2-(3-((E)-2-(pyridin-2-yl)vinyl)-1H-indazol-6-ylthio)benzamido)hexanoate 
• 1012056-56-2 N-(5-(hydroxycarbamoyl)pentyl)-2-(3-((E)-2-(pyridin-2-yl)vinyl)-1H-indazol-6-ylthio)benzamide 
• 1133966-04-7 (E)-methyl 5-(2-(3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-ylthio)phenoxy)pentanoate 
• 1133966-05-8 (E)-methyl 5-(2-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-ylthio)phenoxy)pentanoate 
• 1133966-14-9 (E)-2-(3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-ylthio)benzenamine 
• 1133966-15-0 (E)-methyl 5-(2-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-ylthio)phenylamino)pentanoate 
• 1133966-18-3 (E)-ethyl 6-oxo-6-(2-(3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-ylthio)phenylamino)hexanoate 
• 1133966-19-4 (E)-ethyl 6-oxo-6-(2-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-ylthio)phenylamino)hexanoate 
• 1133966-20-7 (E)-2-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-ylthio)benzenamine 
• 1133966-21-8 (E)-methyl 7-oxo-7-(2-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-ylthio)phenylamino)heptanoate 
• 885126-35-2 (E)-N-methyl-2-{[3-(2-(pyridin-2-yl)ethenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]thio}benzamide 
• 319460-85-0 axitinib 

Relevant articles and documents

Axitinib intermediate synthesis method

The invention relates to an axitinib intermediate synthesis method, and belongs to the field of chemical synthesis, wherein a target compound is obtained through a Vilsmeier reaction, pyranyl protection, a wittig reaction, a reduction reaction and an iodo reaction. According to the present invention, the palladium catalytic reaction is replaced with the wittig reaction, such that the use of the expensive palladium catalyst can be avoided, the post-treatment can be conveniently performed, and the production cost is saved.

A process for the preparation of intermediates axi for Nepal the preparation and application of axi for Nepal

The invention relates to a method for preparing an intermediate of axitinib and application of the intermediate in preparation of axitinib. The preparation method for the intermediate of axitinib 3-iodine-6-nitro-1-(teralin-2H-pyran-2-base)-1H-indazole comprises the following steps that 6-nitroindazole and 3,4-dihydro-2H-pyran react under the action of catalyst so as to protect perssad tetralin-2H-pyran-2-base at N-H site, and the key intermediate with high yield is obtained through iodination at site 3. The application of the intermediate in preparation of axitinib is as follows: Heck coupled reaction is carried out on the intermediate and 2-vinyl pyridine, then nitro reduction and diazo-reaction for iodination are sequentially carried out, finally, the axitinib is obtained after docking of 2-sulfydryl-N-methyl benzamide and deprotection. The related main initial raw materials are easy to purchase in markets, and the method has high yield and high molecule economic efficiency, is efficient and environment-friendly, and is suitable for industrial mass production.

Effective Laboratory-Scale Preparation of Axitinib by Two CuI-Catalyzed Coupling Reactions

The discovery and development of an efficient synthesis route to axinitib is reported. The first-generation route researched by Pfizer implemented two Pd-catalyzed coupling reactions as key steps. In this work, the development of Heck-type and C-S coupling reactions catalyzed by CuI is briefly described, using an economial and practical protocol. Aspects of this route, such as selecting optimal ligands, solvent, and other conditions, are discussed in detail. The scale-up experiment was carried out to provide more than 300 g of active pharmaceutical ingredients of axitinib in Form XLI with 99.9% purity in 39% yield. In short, we provide a new choice of synthesis route to axitinib, through two copper-catalyzed coupling reactions with good yield.