Axitinib supplier | CasNO.319460-85-0

Name
Axitinib
EINECS 638-771-6
CAS No. 319460-85-0
Article Data20
CAS DataBase
Density 1.35 g/cm³
Solubility
Melting Point 213-215 °C
Formula C₂₂H₁₈N₄OS
Boiling Point 668.9 °C at 760 mmHg
Molecular Weight 386.477
Flash Point 358.3 °C
Transport Information
Appearance Off-white solid
Safety 60-61
Risk Codes 22-50/53
Molecular Structure
Hazard Symbols Xn,N
Synonyms AG013736;Benzamide,N-methyl-2-[[3-[(1E)-2-(2-pyridinyl)ethenyl]-1H-indazol-6-yl]thio]-;
PSA 95.97000
LogP 5.03000

Synthetic route

: (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

Conditions

Conditions	Yield
With toluene-4-sulfonic acid In neat (no solvent) for 0.75h; Milling;	99%
With toluene-4-sulfonic acid In methanol; water at 64℃; for 1 - 5h; Product distribution / selectivity;	98%
With toluene-4-sulfonic acid In methanol; water at 65℃; for 4h; Reagent/catalyst; Inert atmosphere;	95.4%

: C22H18N4OS*C4H4O4

: 319460-85-0
axitinib

Conditions

Conditions	Yield
With 1,2-diaminopropan In 1-methyl-pyrrolidin-2-one at 40 - 70℃; for 1h;	95%

: 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]indazole ethylacetate solvate

: 319460-85-0
axitinib

Conditions

Conditions	Yield
In methanol; acetic acid at 60℃;	92%
Stage #1: 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]indazole ethylacetate solvate With toluene-4-sulfonic acid In ethanol at 82℃; for 14h; Stage #2: With sodium hydrogencarbonate In ethanol; water at 20℃; for 2h;

: 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]indazole p-toluene sulfonic acid salt

: 319460-85-0
axitinib

Conditions

Conditions	Yield
In NaHCO3; ethyl acetate at 65℃;	92%

: 100-69-6
2-vinylpyridine

: 885126-34-1
2-((3-iodo-1H-indazol-6-yl)thio)-N-methylbenzamide

: 319460-85-0
axitinib

Conditions

Conditions	Yield
Stage #1: 2-((3-iodo-1H-indazol-6-yl)thio)-N-methylbenzamide With palladium diacetate; acetic anhydride; N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1-methyl-pyrrolidin-2-one at 25 - 50℃; Inert atmosphere; Stage #2: 2-vinylpyridine In 1-methyl-pyrrolidin-2-one at 50 - 95℃; for 12h;	70.68%
With tris-(o-tolyl)phosphine; lithium bromide; palladium diacetate In 2,4-dichlorophenoxyacetic acid dimethylamine at 110℃; for 25h; Product distribution / selectivity; Heck Reaction;
With N,N,N',N'-tetramethyl-1,8-diaminonaphthalene; tris-(o-tolyl)phosphine; lithium bromide; palladium diacetate In DMA at 110℃; for 25h; Product distribution / selectivity; Inert atmosphere;

: 108-86-1
bromobenzene

: 1663-39-4
tert-Butyl acrylate

: 319460-85-0
axitinib

Conditions

Conditions	Yield
With triethylamine In neat (no solvent) at 100℃; for 24h; Heck Reaction; Green chemistry;	70%

: 20054-45-9
2-mercapto-N-methylbenzamide

: (E)-6-bromo-3-(2-(pyridin-2-yl)vinyl)-1H-indazole

: 319460-85-0
axitinib

Conditions

Conditions	Yield
With palladium diacetate; N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene In 1,4-dioxane for 48h; Inert atmosphere; Reflux;	54%

: 100-69-6
2-vinylpyridine

: 319460-85-0
axitinib

Conditions

Conditions	Yield
Multi-step reaction with 3 steps 1: palladium diacetate; triethylamine; triphenylphosphine; tetrabutylammomium bromide; sodium bromide / neat (no solvent) / 1.5 h / Milling 2: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / neat (no solvent) / 0.83 h / Milling 3: toluene-4-sulfonic acid / neat (no solvent) / 0.75 h / Milling View Scheme

Yield

Multi-step reaction with 3 steps
1: palladium diacetate; triethylamine; triphenylphosphine; tetrabutylammomium bromide; sodium bromide / neat (no solvent) / 1.5 h / Milling
2: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / neat (no solvent) / 0.83 h / Milling
3: toluene-4-sulfonic acid / neat (no solvent) / 0.75 h / Milling
View Scheme

: 100-69-6
2-vinylpyridine

: N-1 Boc 2-(3-iodo-1H-indazol-6-ylsulfanyl)-N-methyl-benzamide

: 319460-85-0
axitinib

Conditions

Conditions	Yield
Stage #1: 2-vinylpyridine; N-1 Boc 2-(3-iodo-1H-indazol-6-ylsulfanyl)-N-methyl-benzamide for 2h; Heck Reaction; Stage #2: With tris-(o-tolyl)phosphine; palladium diacetate In N,N-dimethyl-formamide at 100℃; Stage #3: With trifluoroacetic acid Product distribution / selectivity;

1,2-bis(diphenylphosphino)ethane; 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridine-2-yl)ethenyl]indazole; mixture of: 1,2-bis(diphenylphosphino)ethane; 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridine-2-yl)ethenyl]indazole; mixture of

: 319460-85-0
axitinib

Conditions

Conditions	Yield
In tetrahydrofuran at 20 - 65℃; for 18h; Purification / work up;

: N-methyl-2-((1-(t-butoxycarbonyl)-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide

: 319460-85-0
axitinib

Conditions

Conditions	Yield
With trifluoroacetic acid In N,N-dimethyl-formamide

: 261953-36-0
6-Iodo-1H-indazole

: 319460-85-0
axitinib

Conditions

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium hydrogencarbonate; tris-(dibenzylideneacetone)dipalladium(0) / 1-methyl-pyrrolidin-2-one / 0.5 h / 25 °C / Inert atmosphere; Large scale 1.2: 3 h / 25 - 50 °C / Inert atmosphere; Large scale 2.1: iodine; potassium hydroxide / 1-methyl-pyrrolidin-2-one; water / 5.5 h / 25 °C / Inert atmosphere; Large scale 3.1: N-ethyl-N,N-diisopropylamine; palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / 1-methyl-pyrrolidin-2-one / 50 °C / Inert atmosphere; Large scale 4.1: 1-methyl-pyrrolidin-2-one / 50 - 90 °C / Inert atmosphere; Large scale 5.1: 1,2-diaminopropan / water; tetrahydrofuran / 12.5 h / 50 °C / Inert atmosphere; Large scale View Scheme

Yield

Multi-step reaction with 5 steps
1.1: 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium hydrogencarbonate; tris-(dibenzylideneacetone)dipalladium(0) / 1-methyl-pyrrolidin-2-one / 0.5 h / 25 °C / Inert atmosphere; Large scale
1.2: 3 h / 25 - 50 °C / Inert atmosphere; Large scale
2.1: iodine; potassium hydroxide / 1-methyl-pyrrolidin-2-one; water / 5.5 h / 25 °C / Inert atmosphere; Large scale
3.1: N-ethyl-N,N-diisopropylamine; palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / 1-methyl-pyrrolidin-2-one / 50 °C / Inert atmosphere; Large scale
4.1: 1-methyl-pyrrolidin-2-one / 50 - 90 °C / Inert atmosphere; Large scale
5.1: 1,2-diaminopropan / water; tetrahydrofuran / 12.5 h / 50 °C / Inert atmosphere; Large scale
View Scheme

: 944835-85-2
2-((1H-indazol-6-yl)thio)-N-methylbenzamide

: 319460-85-0
axitinib

Conditions

Conditions	Yield
Multi-step reaction with 4 steps 1: iodine; potassium hydroxide / 1-methyl-pyrrolidin-2-one; water / 5.5 h / 25 °C / Inert atmosphere; Large scale 2: N-ethyl-N,N-diisopropylamine; palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / 1-methyl-pyrrolidin-2-one / 50 °C / Inert atmosphere; Large scale 3: 1-methyl-pyrrolidin-2-one / 50 - 90 °C / Inert atmosphere; Large scale 4: 1,2-diaminopropan / water; tetrahydrofuran / 12.5 h / 50 °C / Inert atmosphere; Large scale View Scheme

Yield

Multi-step reaction with 4 steps
1: iodine; potassium hydroxide / 1-methyl-pyrrolidin-2-one; water / 5.5 h / 25 °C / Inert atmosphere; Large scale
2: N-ethyl-N,N-diisopropylamine; palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / 1-methyl-pyrrolidin-2-one / 50 °C / Inert atmosphere; Large scale
3: 1-methyl-pyrrolidin-2-one / 50 - 90 °C / Inert atmosphere; Large scale
4: 1,2-diaminopropan / water; tetrahydrofuran / 12.5 h / 50 °C / Inert atmosphere; Large scale
View Scheme

: 885126-34-1
2-((3-iodo-1H-indazol-6-yl)thio)-N-methylbenzamide

: 319460-85-0
axitinib

Conditions

Conditions	Yield
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / 1-methyl-pyrrolidin-2-one / 50 °C / Inert atmosphere; Large scale 2: 1-methyl-pyrrolidin-2-one / 50 - 90 °C / Inert atmosphere; Large scale 3: 1,2-diaminopropan / water; tetrahydrofuran / 12.5 h / 50 °C / Inert atmosphere; Large scale View Scheme

Yield

Multi-step reaction with 3 steps
1: N-ethyl-N,N-diisopropylamine; palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / 1-methyl-pyrrolidin-2-one / 50 °C / Inert atmosphere; Large scale
2: 1-methyl-pyrrolidin-2-one / 50 - 90 °C / Inert atmosphere; Large scale
3: 1,2-diaminopropan / water; tetrahydrofuran / 12.5 h / 50 °C / Inert atmosphere; Large scale
View Scheme

: 1639137-80-6
N-methyl-2-((1-acetyl-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide

: 319460-85-0
axitinib

Conditions

Conditions	Yield
With 1,2-diaminopropan In tetrahydrofuran; water at 50℃; for 12.5h; Inert atmosphere; Large scale;	28.0 kg

: 20054-45-9
2-mercapto-N-methylbenzamide

: 319460-85-0
axitinib

Conditions

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium hydrogencarbonate; tris-(dibenzylideneacetone)dipalladium(0) / 1-methyl-pyrrolidin-2-one / 0.5 h / 25 °C / Inert atmosphere; Large scale 1.2: 3 h / 25 - 50 °C / Inert atmosphere; Large scale 2.1: iodine; potassium hydroxide / 1-methyl-pyrrolidin-2-one; water / 5.5 h / 25 °C / Inert atmosphere; Large scale 3.1: N-ethyl-N,N-diisopropylamine; palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / 1-methyl-pyrrolidin-2-one / 50 °C / Inert atmosphere; Large scale 4.1: 1-methyl-pyrrolidin-2-one / 50 - 90 °C / Inert atmosphere; Large scale 5.1: 1,2-diaminopropan / water; tetrahydrofuran / 12.5 h / 50 °C / Inert atmosphere; Large scale View Scheme

Yield

: (E)-6-nitro-3-[(2-pyridin-2-yl)vinyl]-1H-indazole

: 319460-85-0
axitinib

Conditions

Conditions	Yield
Multi-step reaction with 5 steps 1.1: methanesulfonic acid / tetrahydrofuran / 6 h / Reflux 2.1: sodiumsulfide nonahydrate / water; methanol / 60 °C 3.1: acetic acid; sulfuric acid; sodium nitrite / water / 4 h / -5 - 0 °C 3.2: 5.5 h / 0 °C 4.1: potassium carbonate; copper(l) iodide; 2-vinylpyridine / N,N-dimethyl-formamide / 12 h / 100 °C 5.1: water; hydrogenchloride; methanol / 6 h / 60 °C View Scheme

Yield

Multi-step reaction with 5 steps
1.1: methanesulfonic acid / tetrahydrofuran / 6 h / Reflux
2.1: sodiumsulfide nonahydrate / water; methanol / 60 °C
3.1: acetic acid; sulfuric acid; sodium nitrite / water / 4 h / -5 - 0 °C
3.2: 5.5 h / 0 °C
4.1: potassium carbonate; copper(l) iodide; 2-vinylpyridine / N,N-dimethyl-formamide / 12 h / 100 °C
5.1: water; hydrogenchloride; methanol / 6 h / 60 °C
View Scheme

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

: 319460-85-0
axitinib

Conditions

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodiumsulfide nonahydrate / water; methanol / 60 °C 2.1: acetic acid; sulfuric acid; sodium nitrite / water / 4 h / -5 - 0 °C 2.2: 5.5 h / 0 °C 3.1: potassium carbonate; copper(l) iodide; 2-vinylpyridine / N,N-dimethyl-formamide / 12 h / 100 °C 4.1: water; hydrogenchloride; methanol / 6 h / 60 °C View Scheme
Multi-step reaction with 4 steps 1.1: ammonium chloride; iron / water; ethanol / 2 h / 50 °C 2.1: sodium nitrite; acetic acid / water / 2 h / 0 °C 2.2: 1.17 h / 0 °C 2.3: 2.08 h / 0 °C 3.1: bis[1,2-bis(diphenylphosphino)ferrocene]-palladium(0); caesium carbonate / N,N-dimethyl-formamide / 16 h / 80 °C / Inert atmosphere 4.1: toluene-4-sulfonic acid / water; methanol / 4 h / 65 °C / Inert atmosphere View Scheme

Yield

Multi-step reaction with 4 steps
1.1: sodiumsulfide nonahydrate / water; methanol / 60 °C
2.1: acetic acid; sulfuric acid; sodium nitrite / water / 4 h / -5 - 0 °C
2.2: 5.5 h / 0 °C
3.1: potassium carbonate; copper(l) iodide; 2-vinylpyridine / N,N-dimethyl-formamide / 12 h / 100 °C
4.1: water; hydrogenchloride; methanol / 6 h / 60 °C
View Scheme

Multi-step reaction with 4 steps
1.1: ammonium chloride; iron / water; ethanol / 2 h / 50 °C
2.1: sodium nitrite; acetic acid / water / 2 h / 0 °C
2.2: 1.17 h / 0 °C
2.3: 2.08 h / 0 °C
3.1: bis[1,2-bis(diphenylphosphino)ferrocene]-palladium(0); caesium carbonate / N,N-dimethyl-formamide / 16 h / 80 °C / Inert atmosphere
4.1: toluene-4-sulfonic acid / water; methanol / 4 h / 65 °C / Inert atmosphere
View Scheme

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

: 319460-85-0
axitinib

Conditions

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

: 7597-18-4
6-nitroindazole

: 319460-85-0
axitinib

Conditions

Conditions	Yield
Multi-step reaction with 8 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 6.1: acetic acid; sulfuric acid; sodium nitrite / water / 4 h / -5 - 0 °C 6.2: 5.5 h / 0 °C 7.1: potassium carbonate; copper(l) iodide; 2-vinylpyridine / N,N-dimethyl-formamide / 12 h / 100 °C 8.1: water; hydrogenchloride; methanol / 6 h / 60 °C View Scheme
Multi-step reaction with 7 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 5.1: sodium nitrite; acetic acid / water / 2 h / 0 °C 5.2: 1.17 h / 0 °C 5.3: 2.08 h / 0 °C 6.1: bis[1,2-bis(diphenylphosphino)ferrocene]-palladium(0); caesium carbonate / N,N-dimethyl-formamide / 16 h / 80 °C / Inert atmosphere 7.1: toluene-4-sulfonic acid / water; methanol / 4 h / 65 °C / Inert atmosphere View Scheme

Yield

Multi-step reaction with 8 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
6.1: acetic acid; sulfuric acid; sodium nitrite / water / 4 h / -5 - 0 °C
6.2: 5.5 h / 0 °C
7.1: potassium carbonate; copper(l) iodide; 2-vinylpyridine / N,N-dimethyl-formamide / 12 h / 100 °C
8.1: water; hydrogenchloride; methanol / 6 h / 60 °C
View Scheme

Multi-step reaction with 7 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
5.1: sodium nitrite; acetic acid / water / 2 h / 0 °C
5.2: 1.17 h / 0 °C
5.3: 2.08 h / 0 °C
6.1: bis[1,2-bis(diphenylphosphino)ferrocene]-palladium(0); caesium carbonate / N,N-dimethyl-formamide / 16 h / 80 °C / Inert atmosphere
7.1: toluene-4-sulfonic acid / water; methanol / 4 h / 65 °C / Inert atmosphere
View Scheme

: (Ε)-6-iodo-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole

: 20054-45-9
2-mercapto-N-methylbenzamide

: 319460-85-0
axitinib

Conditions

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate; copper(l) iodide; 2-vinylpyridine / N,N-dimethyl-formamide / 12 h / 100 °C 2: water; hydrogenchloride; methanol / 6 h / 60 °C View Scheme

: 119-80-2
2,2'-dithiobenzoic acid

: 319460-85-0
axitinib

Conditions

Conditions	Yield
Multi-step reaction with 5 steps 1: thionyl chloride / N,N-dimethyl-formamide / 4 h / Reflux 2: tetrahydrofuran / 11 h / 0 - 20 °C / pH 9 - 10 3: sodium tetrahydroborate / tetrahydrofuran / 0 - 30 °C 4: potassium carbonate; copper(l) iodide; 2-vinylpyridine / N,N-dimethyl-formamide / 12 h / 100 °C 5: water; hydrogenchloride; methanol / 6 h / 60 °C View Scheme

: 19602-82-5
2,2'-dithiodibenzoic acid dichloride

: 319460-85-0
axitinib

Conditions

Conditions	Yield
Multi-step reaction with 4 steps 1: tetrahydrofuran / 11 h / 0 - 20 °C / pH 9 - 10 2: sodium tetrahydroborate / tetrahydrofuran / 0 - 30 °C 3: potassium carbonate; copper(l) iodide; 2-vinylpyridine / N,N-dimethyl-formamide / 12 h / 100 °C 4: water; hydrogenchloride; methanol / 6 h / 60 °C View Scheme

: 2527-58-4
2,2'-dithiobis(N-methylbenzamide)

: 319460-85-0
axitinib

Conditions

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium tetrahydroborate / tetrahydrofuran / 0 - 30 °C 2: potassium carbonate; copper(l) iodide; 2-vinylpyridine / N,N-dimethyl-formamide / 12 h / 100 °C 3: water; hydrogenchloride; methanol / 6 h / 60 °C View Scheme

: 70315-70-7
3-iodo-6-nitro-1H-indazole

: 319460-85-0
axitinib

Conditions

Conditions	Yield
Multi-step reaction with 7 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 5.1: acetic acid; sulfuric acid; sodium nitrite / water / 4 h / -5 - 0 °C 5.2: 5.5 h / 0 °C 6.1: potassium carbonate; copper(l) iodide; 2-vinylpyridine / N,N-dimethyl-formamide / 12 h / 100 °C 7.1: water; hydrogenchloride; methanol / 6 h / 60 °C View Scheme

Yield

Multi-step reaction with 7 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
5.1: acetic acid; sulfuric acid; sodium nitrite / water / 4 h / -5 - 0 °C
5.2: 5.5 h / 0 °C
6.1: potassium carbonate; copper(l) iodide; 2-vinylpyridine / N,N-dimethyl-formamide / 12 h / 100 °C
7.1: water; hydrogenchloride; methanol / 6 h / 60 °C
View Scheme

: 1-acetyl-3-iodine-6-nitroindazole

: 319460-85-0
axitinib

Conditions

Conditions	Yield
Multi-step reaction with 6 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 4.1: acetic acid; sulfuric acid; sodium nitrite / water / 4 h / -5 - 0 °C 4.2: 5.5 h / 0 °C 5.1: potassium carbonate; copper(l) iodide; 2-vinylpyridine / N,N-dimethyl-formamide / 12 h / 100 °C 6.1: water; hydrogenchloride; methanol / 6 h / 60 °C View Scheme

Yield

Multi-step reaction with 6 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
4.1: acetic acid; sulfuric acid; sodium nitrite / water / 4 h / -5 - 0 °C
4.2: 5.5 h / 0 °C
5.1: potassium carbonate; copper(l) iodide; 2-vinylpyridine / N,N-dimethyl-formamide / 12 h / 100 °C
6.1: water; hydrogenchloride; methanol / 6 h / 60 °C
View Scheme

: 108-36-1
1,3-dibromobenzene

: 319460-85-0
axitinib

Conditions

Conditions	Yield
Multi-step reaction with 6 steps 1: aluminum (III) chloride / 1 h / 100 °C / Inert atmosphere 2: potassium hydroxide / methanol; water / 1.5 h / 20 °C 3: hydrogenchloride / methanol; water / 12 h / 50 °C 4: copper(I) oxide / i-Amyl alcohol / 5 h / Inert atmosphere; Reflux 5: tetrabutyl ammonium fluoride / tetrahydrofuran / 12 h / 50 °C 6: N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; palladium diacetate / 1,4-dioxane / 48 h / Inert atmosphere; Reflux View Scheme

Yield

Multi-step reaction with 6 steps
1: aluminum (III) chloride / 1 h / 100 °C / Inert atmosphere
2: potassium hydroxide / methanol; water / 1.5 h / 20 °C
3: hydrogenchloride / methanol; water / 12 h / 50 °C
4: copper(I) oxide / i-Amyl alcohol / 5 h / Inert atmosphere; Reflux
5: tetrabutyl ammonium fluoride / tetrahydrofuran / 12 h / 50 °C
6: N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; palladium diacetate / 1,4-dioxane / 48 h / Inert atmosphere; Reflux
View Scheme

: 33243-33-3
2,4-dibromoacetophenone

: 319460-85-0
axitinib

Conditions

Conditions	Yield
Multi-step reaction with 5 steps 1: potassium hydroxide / methanol; water / 1.5 h / 20 °C 2: hydrogenchloride / methanol; water / 12 h / 50 °C 3: copper(I) oxide / i-Amyl alcohol / 5 h / Inert atmosphere; Reflux 4: tetrabutyl ammonium fluoride / tetrahydrofuran / 12 h / 50 °C 5: N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; palladium diacetate / 1,4-dioxane / 48 h / Inert atmosphere; Reflux View Scheme

Yield

Multi-step reaction with 5 steps
1: potassium hydroxide / methanol; water / 1.5 h / 20 °C
2: hydrogenchloride / methanol; water / 12 h / 50 °C
3: copper(I) oxide / i-Amyl alcohol / 5 h / Inert atmosphere; Reflux
4: tetrabutyl ammonium fluoride / tetrahydrofuran / 12 h / 50 °C
5: N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; palladium diacetate / 1,4-dioxane / 48 h / Inert atmosphere; Reflux
View Scheme

: (E)-1-(2,4-dibromophenyl)-3-(pyridin-2-yl)prop-2-en-1-one

: 319460-85-0
axitinib

Conditions

Conditions	Yield
Multi-step reaction with 4 steps 1: hydrogenchloride / methanol; water / 12 h / 50 °C 2: copper(I) oxide / i-Amyl alcohol / 5 h / Inert atmosphere; Reflux 3: tetrabutyl ammonium fluoride / tetrahydrofuran / 12 h / 50 °C 4: N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; palladium diacetate / 1,4-dioxane / 48 h / Inert atmosphere; Reflux View Scheme

Yield

Multi-step reaction with 4 steps
1: hydrogenchloride / methanol; water / 12 h / 50 °C
2: copper(I) oxide / i-Amyl alcohol / 5 h / Inert atmosphere; Reflux
3: tetrabutyl ammonium fluoride / tetrahydrofuran / 12 h / 50 °C
4: N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; palladium diacetate / 1,4-dioxane / 48 h / Inert atmosphere; Reflux
View Scheme

: C21H16BrN3O2S

: 319460-85-0
axitinib

Conditions

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrabutyl ammonium fluoride / tetrahydrofuran / 12 h / 50 °C 2: N-ethyl-N,N-diisopropylamine; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; palladium diacetate / 1,4-dioxane / 48 h / Inert atmosphere; Reflux View Scheme

: 319460-85-0
axitinib

: 110-17-8
(2E)-but-2-enedioic acid

: C22H18N4OS*C4H4O4

Conditions

Conditions	Yield
With palladium In 1-methyl-pyrrolidin-2-one; ethanol at 65 - 75℃; for 1h; Solvent;	99.9%

: 319460-85-0
axitinib

: 75-36-5
acetyl chloride

: 1639137-80-6
N-methyl-2-((1-acetyl-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide

Conditions

Conditions	Yield
In dichloromethane at 20℃; for 16h; Cooling with ice;	99%
With triethylamine In dichloromethane at 20℃; for 16h; Cooling with ice; Inert atmosphere;	99%

: 319460-85-0
axitinib

: 2-((tert-butyldimethylsilyl)oxy)ethyl (4-nitrophenyl) carbonate

: C31H36N4O4SSi

Conditions

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 20℃; for 16h;	98%

: 1191-99-7
2,3-dihydro-2H-furan

: 319460-85-0
axitinib

: N-methyl-2-((3-((E)-2-(2-pyridyl)vinyl)-1-(tetrahydrofuran-2-yl)-1H-indazol-6-yl)thio)benzamide

Conditions

Conditions	Yield
With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 80℃; for 2h;	96%

: 319460-85-0
axitinib

: p-nitrophenyl 13,13,14,14-tetramethyl-3,6,9,12-tetraoxa-13-silapentadec-1-yl carbonate

: N-methyl-2-((1-(13-hydroxy-1-oxo-2,5,8,11-tetraoxatridec-1-yl)-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide hydrochloride

Conditions

Conditions	Yield
Stage #1: axitinib; p-nitrophenyl 13,13,14,14-tetramethyl-3,6,9,12-tetraoxa-13-silapentadec-1-yl carbonate With triethylamine In N,N-dimethyl-formamide at 20℃; Stage #2: With hydrogenchloride; ethanol at 20℃; for 2h;	95.3%

: 319460-85-0
axitinib

: 34582-32-6
N-tert-butoxycarbonyl aspartic acid tert-butyl ester

: N-methyl-2-((3-((E)-2-(2-pyridyl)vinyl)-1-(β-L-aspartyl)-1H-indazole-6-yl)thio)benzamide

Conditions

Conditions	Yield
With diphenylphosphoranyl azide; triethylamine In N,N-dimethyl-formamide at 20℃; for 4h;	93.6%

: 319460-85-0
axitinib

: 34582-32-6
N-tert-butoxycarbonyl aspartic acid tert-butyl ester

: C31H31N5O6S

Conditions

Conditions	Yield
With diphenyl phosphoryl azide; triethylamine In N,N-dimethyl-formamide at 20℃; for 4h;	93.6%

: 319460-85-0
axitinib

: 50-00-0
formaldehyd

: N-methyl-2-((3-((E)-2-(2-pyridyl)vinyl)-1-hydroxymethyl-1H-indazol-6-yl)thio)benzamide

Conditions

Conditions	Yield
With triethylamine In water; N,N-dimethyl-formamide at 0℃; for 3h;	93%

: 319460-85-0
axitinib

: 7693-46-1
4-Nitrophenyl chloroformate

: C29H21N5O5S*(x)ClH

Conditions

Conditions	Yield
In tetrahydrofuran at 80℃; for 7h;	92%

: 2-(2-(2-methoxyethoxy)ethoxy)ethyl (4-nitrophenyl) carbonate

: 319460-85-0
axitinib

: N-methyl-2-((3-((E)-2-(2-pyridyl)vinyl)-1-((3,6,9-trioxadecane-1-yl)oxycarbonyl)-1H-indazol-6-yl)thio)benzamide

Conditions

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 20℃;	89%
With triethylamine In N,N-dimethyl-formamide at 20℃;	89%

: 319460-85-0
axitinib

: (2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)ethyl)(4-nitrophenyl) carbonate

: N-methyl-2-((1-(2-(2-hydroxyethoxy)ethoxycarbonyl)-3-(( 1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide hydrochloride

Conditions

Conditions	Yield
Stage #1: axitinib; (2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)ethyl)(4-nitrophenyl) carbonate With triethylamine In N,N-dimethyl-formamide at 20℃; Stage #2: With hydrogenchloride; ethanol at 20℃; for 2h;	87.8%

: 319460-85-0
axitinib

: 24424-99-5
di-tert-butyl dicarbonate

: N-methyl-2-((1-(t-butoxycarbonyl)-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide

Conditions

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 20℃;	87%
With triethylamine In N,N-dimethyl-formamide at 20℃;	77%
With triethylamine In N,N-dimethyl-formamide for 1h;	4.1 g
With triethylamine In N,N-dimethyl-formamide for 1h;	4.1 g
With triethylamine In N,N-dimethyl-formamide for 1h;	4.1 g

: 319460-85-0
axitinib

: 541-16-2
t-butyl malonate

: N-methyl-2-((1-(t-butoxycarbonyl)-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide

Conditions

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 20℃;	87%

: 319460-85-0
axitinib

: axitinib hydrobromic acid salt

Conditions

Conditions	Yield
With hydrogen bromide In isopropyl alcohol at 20 - 50℃;	84%

: 319460-85-0
axitinib

: p-nitrophenyl 13,13,14,14-tetramethyl-3,6,9,12-tetraoxa-13-silapentadec-1-yl carbonate

: N-methyl-2-((1-(13,13,14,14-tetramethyl-3,6,9,12-tetraoxa-13-silapentadec-1-yl)-3-(( 1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide

Conditions

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 20℃;	83.1%

: 319460-85-0
axitinib

: axitinib hydrochloric acid salt

Conditions

Conditions	Yield
With hydrogenchloride In isopropyl alcohol at 20 - 50℃;	83%

: 319460-85-0
axitinib

: 66398-02-5
1-dodecyl p-nitrophenyl carbonate

: N-methyl-2-((1-dodecyloxycarbonyl-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide

Conditions

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 20℃; for 3h;	82.3%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 3h;	82.3%

: 319460-85-0
axitinib

: 24424-99-5
di-tert-butyl dicarbonate

: 6-((2-((t-butoxycarbonyl)(methyl)carbamoyl)phenyl)thio)-3-(2-(pyridin-2-yl)ethylenyl)-1H-indazol-1-carboxylic acid (E)-t-butyl ester

Conditions

Conditions	Yield
With dmap In dichloromethane at 25℃; for 16h;	81.9%

: 319460-85-0
axitinib

: 75-75-2
methanesulfonic acid

: axitinib methanesulfonic acid salt

Conditions

Conditions	Yield
In isopropyl alcohol at 20 - 50℃;	81%

: 319460-85-0
axitinib

: 3282-30-2
pivaloyl chloride

: N-methyl-2-((1-pivaloyl-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide

Conditions

Conditions	Yield
With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere;	81%
With triethylamine In dichloromethane at 20℃; Inert atmosphere; Cooling with ice;	81%

: 319460-85-0
axitinib

: 4-nitrophenyl (2,2,3,3-tetramethyl-4,7,10-trioxa-3-siladodecan-12-yl) carbonate

: C35H44N4O6SSi

Conditions

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide	81%

: 319460-85-0
axitinib

: N-methyl-2-((1-(2-(2-(tert-butyldimethylsilyloxy)ethoxy)ethoxycarbonyl)-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide

Conditions

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 20℃;	81%

: 319460-85-0
axitinib

: 105108-59-6
(2-(2-methoxyethoxy)ethyl) (4-nitrophenyl) carbonate

: N-methyl-2-((1-(1-oxo-2,5,8-trioxanayl)-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide

Conditions

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 20℃; for 3h;	80.6%

: 319460-85-0
axitinib

: 4-nitrophenyl (2,2,3,3-tetramethyl-4,7,10-trioxa-3-siladodecan-12-yl) carbonate

: N-methyl-2-((1-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxycarbonyl)-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide hydrochloride

Conditions

Conditions	Yield
Stage #1: axitinib; 4-nitrophenyl (2,2,3,3-tetramethyl-4,7,10-trioxa-3-siladodecan-12-yl) carbonate With triethylamine In N,N-dimethyl-formamide at 20℃; Stage #2: With hydrogenchloride; ethanol at 20℃; for 2h;	79.8%

: 319460-85-0
axitinib

: 426264-10-0
methyl (2-ethoxy)(4-nitrophenyl)carbonate

: N-methyl-2-((3-((E)-2-(2-pyridyl)vinyl)-1-((2-methoxy-1-ethyl)oxycarbonyl)-1H-indazol-6-yl)thio)benzamide

Conditions

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 20℃; for 3h;	79.8%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 3h;	79.8%

: 319460-85-0
axitinib

: 67036-14-0
4-nitrophenyl n-pentyl carbonate

: N-methyl-2-((3-((E)-2-(2-pyridyl)vinyl)-1-pentyloxycarbonyl-1H-indazol-6-yl)sulfanyl)benzamide

Conditions

Conditions	Yield
With triethylamine at 20℃; for 3h;	77%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 3h;	77%

Axitinib Specification

1. Introduction of Axitinib
Axitinib is one kind of white crystalline powder or off-white solid. The IUPAC name of Axitinib is N-methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfanyl]benzamide. The product's categories are All Inhibitors; Inhibitors; Intermediates & Fine Chemicals; Pharmaceuticals; Protein Kinase Inhibitors and Activators. It is a small molecule tyrosine kinase inhibitor under development by Pfizer. Axitinib can soluble in DMSO at 33 mg/mL; soluble in ethanol at 1.7 mg/mL with warming; very poorly soluble in water; maximum solubility in plain water is estimated to be about 10-50 µM; buffers, serum, or other additives may increase or decrease the aqueous solubility.

2. Properties of Axitinib
Physical properties about Axitinib are:
(1)ACD/LogP: 4.15; (2)# of Rule of 5 Violations: 0; (3)ACD/LogD (pH 5.5): 4.14; (4)ACD/LogD (pH 7.4): 4.15; (5)ACD/BCF (pH 5.5): 830.65; (6)ACD/BCF (pH 7.4): 834.47; (7)ACD/KOC (pH 5.5): 4273.12; (8)ACD/KOC (pH 7.4): 4292.77; (9)#H bond acceptors: 5; (10)#H bond donors: 2; (11)#Freely Rotating Bonds: 5; (12)Polar Surface Area: 76.32 Å²; (13)Index of Refraction: 1.728; (14)Molar Refractivity: 113.45 cm³; (15)Molar Volume: 284.8 cm³; (16)Polarizability: 44.97×10^-24 cm³; (17)Surface Tension: 75.2 dyne/cm; (18)Density: 1.35 g/cm³; (19)Flash Point: 358.3 °C; (20)Enthalpy of Vaporization: 98.31 kJ/mol; (21)Boiling Point: 668.9 °C at 760 mmHg; (22)Vapour Pressure: 9.35E-18 mmHg at 25°C.

3. Structure Descriptors of Axitinib
(1)SMILES:O=C(NC)c4ccccc4Sc1ccc2c(c1)nnc2\C=C\c3ncccc3
(2)InChI:InChI=1/C22H18N4OS/c1-23-22(27)18-7-2-3-8-21(18)28-16-10-11-17-19(25-26-20(17)14-16)12-9-15-6-4-5-13-24-15/h2-14H,1H3,(H,23,27)(H,25,26)/b12-9+
(3)InChIKey:RITAVMQDGBJQJZ-FMIVXFBMBT
(4)Std. InChI:InChI=1S/C22H18N4OS/c1-23-22(27)18-7-2-3-8-21(18)28-16-10-11-17-19(25-26-20(17)14-16)12-9-15-6-4-5-13-24-15/h2-14H,1H3,(H,23,27)(H,25,26)/b12-9+
(5)Std. InChIKey:RITAVMQDGBJQJZ-FMIVXFBMSA-N

4. Uses of Axitinib
Axitinib (AG-013736) is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors 1 (VEGFR-1), 2 (VEGFR-2), and 3 (VEGFR-3), platelet derived growth factor receptor (PDGFR), and cKIT (CD117). Axitinib inhibits many targets which is including VEGFR-1, VEGFR-2, VEGFR-3, platelet derived growth factor receptor (PDGFR), and cKIT (CD117). It also can inhibit growth of breast cancer in xenograft models and has been successful in trials with renal cell carcinoma (RCC) and several other tumor types. A Phase II clinical trial showed good response in combination chemotherapy with gemcitabine for advanced pancreatic cancer.

Product Name

Axitinib

Synthetic route

Axitinib Specification

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