319460-85-0

Basic information

• Product Name: Axitinib
• Synonyms: Axitinib (usan);D03218;Axitinib(AG 013736);Axtinib;N-Methyl-2-({3-[(E)-2-(pyridin-2-yl)ethenyl]-1H-indazol-6-yl}sulfanyl)benzaMide;Inlyta;10mg;Axitinib (TINIBS)
• CAS NO: 319460-85-0
• Molecular Formula: C₂₂H₁₈N₄OS
• Molecular Weight: 386.47
• EINECS: 1308068-626-2
• Product Categories: Pharmaceuticals;Protein Kinase Inhibitors and Activators;Pfizer compounds;API;AG 013736;All Inhibitors;Inhibitors;Intermediates & Fine Chemicals
• Mol File: 319460-85-0.mol

Chemical Properties

• Melting Point: 213-215°C
• Boiling Point: 668.9 °C at 760 mmHg
• Flash Point: 358.3 °C
• Appearance: white to tan/
• Density: 1.4
• Vapor Pressure: 9.35E-18mmHg at 25°C
• Refractive Index: 1.728
• Storage Temp.: -20°C Freezer
• Solubility: DMSO: ≥8mg/mL
• PKA: 12.70±0.40(Predicted)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
• CAS DataBase Reference: Axitinib(CAS DataBase Reference)
• NIST Chemistry Reference: Axitinib(319460-85-0)
• EPA Substance Registry System: Axitinib(319460-85-0)

Safety Data

• Hazard Codes: Xn,N
• Statements: 22-50/53
• Safety Statements: 60-61
• RIDADR: UN 3077 9 / PGIII
• WGK Germany: 3
• Hazardous Substances Data: 319460-85-0(Hazardous Substances Data)

Usage

FDA approved axitinib use of treating advanced kidney cancer

January 27, 2012, the FDA approved axitinib for the treatment of advanced kidney cancer (renal cell carcinoma) which other drugs unanswer . Inlyta is manufactured and sold by Pfizer,and is a oral pill taken twice a day. Renal cell carcinoma is a type of tumor originating from the tubular endothelial cells. Axitinib can prevent certain protein called kinases playing a role in tumor growth and metastasis . Axitinib is a small molecule tyrosine kinase inhibitor, effective against multiple targets, including VEGF receptors 1, 2 and 3. Dr. Richard Pazdur, hematology and oncology drugs office director of FDA Drug Evaluation and Research Centre, said: "This is the seven kind of drugs allowed treating metastatic or advanced renal cell carcinoma since 2005 . Overall, during this time ,record level of drug development has dramatically changed the treatment of metastatic renal cell carcinoma paradigm, and offers a variety of treatment options for patients. " In recent years, the drug has been approved for the treatment of kidney cancer include sorafenib (2005), sunitinib (2006), temsirolimus(2007), everolimus (2009), bevacizumab(2009) and pazopanib(2009). The above information is edited by the lookchem of Tian Ye.

Originator

Pfizer (United States)

Biochem/physiol Actions

Axitinib (AG-013736) is an orally available, potent (picomolar) and selective tyrosine kinase inhibitor that blocks VEGF receptors 1, 2 and 3. The drug blocks VEGF-mediated endothelial cell survival, tube formation, and downstream signaling through endothelial nitric oxide synthase, Akt and extracellular signal-regulated kinase.

Clinical Use

Sold under the brand name Inlyta? by Pfizer, Inc., axitinib was approved by the FDA in January 2012 for the treatment of advanced renal cell carcinoma (RCC), specifically after the failure of other systemic treatments. Axitinib slows cancer cell proliferation by inhibition of the vascular endothelial growth factor (VEGF)/VEGF receptor tyrosine (RTK) signaling pathway. In particular, axitinib is a potent inhibitor of VEGF/RTK 1-3, which selectively slows angiogenesis, vascular permeability, and blood flow in solid tumors.

Synthesis

Numerous patents and papers have been disclosed on the synthesis of axitinib, a recently published manuscript details the development of the manufacturing route, and this route is depicted in the scheme. The synthesis began with Migita coupling of commercial iodide 17 with thiophenol 18. Interestingly, this transformation’s efficiency relied upon attention to the number of equivalents of base and an inert atmosphere in the reaction vessel, conditions which minimized catalyst poisoning during the reaction. Without isolation, indazole 19 was iodinated to afford diarylthioether 20 in 85-90% yield over the two steps. Protection of the indazole within 20 as its acetamide preceeded a Heck reaction with 2-vinylpyridine, and then subsequent removal of the indazole protection followed by a series of recrystallizations yielded axitinib (IV) in a combined 62% yield over the final 4 steps.

Drug interactions

Potentially hazardous interactions with other drugs Antipsychotics: avoid with clozapine (increased risk of agranulocytosis); avoid with pimozide. Concomitant use with strong CYP3A4/5 inhibitors: avoid; however, if concomitant use cannot be avoided then reduce the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability; if CYP3A4/5 inhibitor is discontinued, then increase the axitinib dose used prior to initiation of the strong inhibitor after 3-5 half-lives of the inhibitor (strong CYP3A4/5 inhibitors include ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, ritonavir, saquinavir, and voriconazole).

Metabolism

Axitinib is metabolised primarily in the liver by CYP3A4/5 and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Most of the drug is excreted via the faeces and urine as metabolites.

References

1) Hu-Lowe?et al.?(2008),?Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1,2,3; Cancer Res.,?14?7272 2) Ma and Waxman (2008),?Modulation of the antitumor activity of metronomic cyclophosphamide by the angiogenesis inhibitor axitinib; Mol. Cancer Ther.,?7?79 3) Pemovska?et al.?(2015),?Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation; Nature,?519?102 4) Rixe?et al.?(2007),?Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer; a phase II study; Lancet Oncol.,?8?975 5) Yuan?et al.?(2014),?Axitinib augments antitumor activity in renal cell carcinoma via STAT3-dependent reversal of myeloid-derived suppressor cell accumulation;?Biomed.Pharmacother.?68?751 6) Zhang?et al.?(2014),?Axitinib, a selective inhibitor of vascular endothelial growth factor receptor, exerts an anticancer effect in melanoma through promoting antitumor immunity;?Anticancer Drugs?25?204

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+

Synthetic route

(E)-N-methyl-2-{[3-(2-(pyridin-2-yl)ethenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl]thio}benzamide → axitinib (319460-85-0)

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 → axitinib (319460-85-0)

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 → axitinib (319460-85-0)

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 → axitinib (319460-85-0)

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

2-vinylpyridine (100-69-6) + 2-((3-iodo-1H-indazol-6-yl)thio)-N-methylbenzamide (885126-34-1) → axitinib (319460-85-0)

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;

bromobenzene (108-86-1) + tert-Butyl acrylate (1663-39-4) → axitinib (319460-85-0)

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

2-mercapto-N-methylbenzamide (20054-45-9) + (E)-6-bromo-3-(2-(pyridin-2-yl)vinyl)-1H-indazole → axitinib (319460-85-0)

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%

2-vinylpyridine (100-69-6) → axitinib (319460-85-0)

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

2-vinylpyridine (100-69-6) + N-1 Boc 2-(3-iodo-1H-indazol-6-ylsulfanyl)-N-methyl-benzamide → axitinib (319460-85-0)

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 → axitinib (319460-85-0)

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 → axitinib (319460-85-0)

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

6-Iodo-1H-indazole (261953-36-0) → axitinib (319460-85-0)

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

2-((1H-indazol-6-yl)thio)-N-methylbenzamide (944835-85-2) → axitinib (319460-85-0)

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

2-((3-iodo-1H-indazol-6-yl)thio)-N-methylbenzamide (885126-34-1) → axitinib (319460-85-0)

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

N-methyl-2-((1-acetyl-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide (1639137-80-6) → axitinib (319460-85-0)

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

2-mercapto-N-methylbenzamide (20054-45-9) → axitinib (319460-85-0)

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

(E)-6-nitro-3-[(2-pyridin-2-yl)vinyl]-1H-indazole → axitinib (319460-85-0)

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

(Ε)-6-nitro-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole (886230-75-7) → axitinib (319460-85-0)

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

(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

6-nitroindazole (7597-18-4) → axitinib (319460-85-0)

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

(Ε)-6-iodo-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole + 2-mercapto-N-methylbenzamide (20054-45-9) → axitinib (319460-85-0)

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

2,2'-dithiobenzoic acid (119-80-2) → axitinib (319460-85-0)

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

2,2'-dithiodibenzoic acid dichloride (19602-82-5) → axitinib (319460-85-0)

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

2,2'-dithiobis(N-methylbenzamide) (2527-58-4) → axitinib (319460-85-0)

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

3-iodo-6-nitro-1H-indazole (70315-70-7) → axitinib (319460-85-0)

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

1-acetyl-3-iodine-6-nitroindazole → axitinib (319460-85-0)

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

1,3-dibromobenzene (108-36-1) → axitinib (319460-85-0)

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

2,4-dibromoacetophenone (33243-33-3) → axitinib (319460-85-0)

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

(E)-1-(2,4-dibromophenyl)-3-(pyridin-2-yl)prop-2-en-1-one → axitinib (319460-85-0)

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

C21H16BrN3O2S → axitinib (319460-85-0)

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

axitinib (319460-85-0) + (2E)-but-2-enedioic acid (110-17-8) → C22H18N4OS*C4H4O4

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

axitinib (319460-85-0) + acetyl chloride (75-36-5) → N-methyl-2-((1-acetyl-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide (1639137-80-6)

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%

axitinib (319460-85-0) + 2-((tert-butyldimethylsilyl)oxy)ethyl (4-nitrophenyl) carbonate → C31H36N4O4SSi

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

2,3-dihydro-2H-furan (1191-99-7) + axitinib (319460-85-0) → N-methyl-2-((3-((E)-2-(2-pyridyl)vinyl)-1-(tetrahydrofuran-2-yl)-1H-indazol-6-yl)thio)benzamide

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

axitinib (319460-85-0) + 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	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%

axitinib (319460-85-0) + N-tert-butoxycarbonyl aspartic acid tert-butyl ester (34582-32-6) → N-methyl-2-((3-((E)-2-(2-pyridyl)vinyl)-1-(β-L-aspartyl)-1H-indazole-6-yl)thio)benzamide

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

axitinib (319460-85-0) + N-tert-butoxycarbonyl aspartic acid tert-butyl ester (34582-32-6) → C31H31N5O6S

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

axitinib (319460-85-0) + formaldehyd (50-00-0) → N-methyl-2-((3-((E)-2-(2-pyridyl)vinyl)-1-hydroxymethyl-1H-indazol-6-yl)thio)benzamide

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

axitinib (319460-85-0) + 4-Nitrophenyl chloroformate (7693-46-1) → C29H21N5O5S*(x)ClH

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

2-(2-(2-methoxyethoxy)ethoxy)ethyl (4-nitrophenyl) carbonate + axitinib (319460-85-0) → N-methyl-2-((3-((E)-2-(2-pyridyl)vinyl)-1-((3,6,9-trioxadecane-1-yl)oxycarbonyl)-1H-indazol-6-yl)thio)benzamide

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

axitinib (319460-85-0) + (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	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%

axitinib (319460-85-0) + di-tert-butyl dicarbonate (24424-99-5) → N-methyl-2-((1-(t-butoxycarbonyl)-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide

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

axitinib (319460-85-0) + t-butyl malonate (541-16-2) → N-methyl-2-((1-(t-butoxycarbonyl)-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide

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

axitinib (319460-85-0) → axitinib hydrobromic acid salt

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

axitinib (319460-85-0) + 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	Yield
With triethylamine In N,N-dimethyl-formamide at 20℃;	83.1%

axitinib (319460-85-0) → axitinib hydrochloric acid salt

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

axitinib (319460-85-0) + 1-dodecyl p-nitrophenyl carbonate (66398-02-5) → N-methyl-2-((1-dodecyloxycarbonyl-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide

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%

axitinib (319460-85-0) + di-tert-butyl dicarbonate (24424-99-5) → 6-((2-((t-butoxycarbonyl)(methyl)carbamoyl)phenyl)thio)-3-(2-(pyridin-2-yl)ethylenyl)-1H-indazol-1-carboxylic acid (E)-t-butyl ester

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

axitinib (319460-85-0) + methanesulfonic acid (75-75-2) → axitinib methanesulfonic acid salt

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

axitinib (319460-85-0) + pivaloyl chloride (3282-30-2) → N-methyl-2-((1-pivaloyl-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide

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

axitinib (319460-85-0) + 4-nitrophenyl (2,2,3,3-tetramethyl-4,7,10-trioxa-3-siladodecan-12-yl) carbonate → C35H44N4O6SSi

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

axitinib (319460-85-0) → N-methyl-2-((1-(2-(2-(tert-butyldimethylsilyloxy)ethoxy)ethoxycarbonyl)-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide

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

axitinib (319460-85-0) + (2-(2-methoxyethoxy)ethyl) (4-nitrophenyl) carbonate (105108-59-6) → N-methyl-2-((1-(1-oxo-2,5,8-trioxanayl)-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide

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

axitinib (319460-85-0) + 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	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%

axitinib (319460-85-0) + methyl (2-ethoxy)(4-nitrophenyl)carbonate (426264-10-0) → N-methyl-2-((3-((E)-2-(2-pyridyl)vinyl)-1-((2-methoxy-1-ethyl)oxycarbonyl)-1H-indazol-6-yl)thio)benzamide

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%

axitinib (319460-85-0) + 4-nitrophenyl n-pentyl carbonate (67036-14-0) → N-methyl-2-((3-((E)-2-(2-pyridyl)vinyl)-1-pentyloxycarbonyl-1H-indazol-6-yl)sulfanyl)benzamide

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

Upstream product

• 100-69-6 2-vinylpyridine 
• 885126-34-1 2-((3-iodo-1H-indazol-6-yl)thio)-N-methylbenzamide 
• 885126-37-4 N-1 Boc 2-(3-iodo-1H-indazol-6-ylsulfanyl)-N-methyl-benzamide 
• 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 
• 261953-36-0 6-Iodo-1H-indazole 
• 944835-85-2 2-{(1H-indazol-6-yl)thio}-N-methylbenzamide 
• 1639137-80-6 N-methyl-2-((1-acetyl-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide 
• 20054-45-9 N-methyl-2-sulfanylbenzamide 
• 886230-75-7 (Ε)-6-nitro-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole 
• 886230-76-8 (Ε)-6-amino-3-[2-(pyridin-2-yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)indazole 
• 7597-18-4 6-nitroindazole 
• 119-80-2 2,2'-dithiobenzoic acid 
• 19602-82-5 2,2'-dithiodibenzoic acid dichloride 
• 2527-58-4 2,2'-dithiobis(N-methylbenzamide) 

Downstream Products

• 1347304-18-0 Axitinib sulfoxide 

Relevant articles and documents

Axitinib: A Photoswitchable Approved Tyrosine Kinase Inhibitor

The goal of photopharmacology is to develop photoswitchable enzyme modulators as tunable (pro-)drugs that can be spatially and temporally controlled by light. In this context, the tyrosine kinase inhibitor axitinib, which contains a photosensitive stilbene-like moiety that allows for E/Z isomerization, is of interest. Axitinib is an approved drug that targets the vascular endothelial growth factor receptor 2 (VEGFR2) and is licensed for second-line therapy of renal cell carcinoma. The photoinduced E/Z isomerization of axitinib has been investigated to explore if its inhibitory effect can be turned “on” and “off”, as triggered by light. Under controlled light conditions, (Z)-axitinib is 43 times less active than that of the E isomer in an VEGFR2 assay. Furthermore, it was proven that kinase activity in human umbilical vein cells (HUVECs) was decreased by (E)-axitinib, but only weakly affected by (Z)-axitinib. By irradiating (Z)-axitinib in vitro with UV light (λ=385 nm), it is possible to switch it almost quantitatively into the E isomer and to completely restore the biological activity of (E)-axitinib. However, switching the biological activity off from (E)- to (Z)-axitinib was not possible in aqueous solution due to a competing irreversible [2+2]-photocycloaddition, which yielded a biologically inactive axitinib dimer.

Photoswitchable azo‐ and diazocine‐functionalized derivatives of the vegfr‐2 inhibitor axitinib

In this study, we aimed at the application of the concept of photopharmacology to the approved vascular endothelial growth factor receptor (VEGFR)‐2 kinase inhibitor axitinib. In a previous study, we found out that the photoisomerization of axitinib’s stilbene‐like double bond is unidirectional in aqueous solution due to a competing irreversible [2+2]‐cycloaddition. Therefore, we next set out to azologize axitinib by means of incorporating azobenzenes as well as diazocine moieties as photoresponsive elements. Conceptually, diazocines (bridged azobenzenes) show favorable photoswitching properties compared to standard azobenzenes because the thermodynamically stable Z‐isomer usually is bioinactive, and back isomerization from the bioactive E‐isomer occurs thermally. Here, we report on the development of different sulfur– diazocines and carbon–diazocines attached to the axitinib pharmacophore that allow switching the VEGFR‐2 activity reversibly. For the best sulfur–diazocine, we could verify in a VEGFR‐2 kinase assay that the Z‐isomer is biologically inactive (IC50 >> 10,000 nM), while significant VEGFR‐2 inhibition can be observed after irradiation with blue light (405 nm), resulting in an IC50 value of 214 nM. In summary, we could successfully develop reversibly photoswitchable kinase inhibitors that exhibit more than 40‐fold differences in biological activities upon irradiation. Moreover, we demonstrate the potential advantage of diazocine photoswitches over standard azobenzenes.

PROCESS FOR PREPARING AXITINIB, PROCESS FOR PURIFYING THE INTERMEDIATE 2-((3-IODO-1H-INDAZOL-6-YL)THIO)-N-METHYLBENZAMIDE, PROCESS FOR PURIFYING AXITINIB VIA THE AXITINIB HCL SALT, SOLID FORM OF THE AXITINIB HCL SALT

1) A process for preparing Axitinib ( N-methyl-2-({3-[(E)-2-pyridin-2- ylethenyl]-lH-indazol-6-yl}sulfanyl)benzamide; compound of formula (l)) 2) A process for purifying the intermediate 2-((3-iodo-lH-indazol-6- yl)thio)-N-methylbenzamide (compound of formula (lla)) 3) A process for purifying Axitinib using the Axitinib HCI salt (compound of formula (VIII)) as an intermediate 4) A solid form of the Axitinib HCI salt (form J) characterized by an XRPD pattern

CONTROLLED-RELEASE TYROSINE KINASE INHIBITOR COMPOUNDS WITH LOCALIZED PK PROPERTIES

The present invention relates to a water-insoluble controlled-release tyrosine kinase inhibitor ( TKI ) compound for use in the treatment of a cell-proliferation disorder, wherein said water-insoluble controlled-release TKI compound releases one or more TKI drug, wherein the water-insoluble controlled-release TKI compound is administered by intra-tissue administration and wherein the total amount of TKI moieties and TKI drug molecules remaining locally in such tissue 3 days after said intra-tissue administration is at least 25% of the amount of TKI moieties or TKI drug molecules administered by said intra-tissue administration; and to related aspects.

Method for preparing axitinib and intermediates thereof

The invention discloses a method for preparing axitinib and intermediates thereof. A chemical name of the axitinib is N-methyl-2-[(3-(1E-2-(pyridine-2-yl)ethylene)-1H-indazole-6-yl)sulfur]benzamide, and a chemical formula of the axitinib is C22H18N4OS. The preparation process disclosed by the invention is simple in process, readily available in raw materials, economic, environmentally friendly, high in product yield and product purity, contributes to realizing industrialization, reduces the production cost and is suitable for mass production. The provided novel intermediates and the preparation method thereof have significance on the economic technology of the axitinib.

Bromide-assisted chemoselective Heck reaction of 3-bromoindazoles under high-speed ball-milling conditions: Synthesis of axitinib

A mechanically-activated chemoselective Heck coupling for the synthesis of 3-vinylindazoles has been developed with the aid of catalytic amounts of TBAB and NaBr as both dehalogenation restrainer and grinding auxiliary. After tuning of the chemical conditions and mechanical parameters, a series of non-activated 3-bromoindazoles and a broad scope of olefins worked well to give the corresponding coupling products in good to excellent yields. A further application of this protocol was performed in a two-step mechanochemical Heck/Migita cross coupling, which provided a highly efficient route for the synthesis of axitinib.

Preparation method of drug Axitinib for resisting kidney cancer

The invention discloses a preparation method of the drug Axitinib for resisting the kidney cancer. The chemical name of the drug Axitinib for resisting the kidney cancer is N-methyl-2-[(3-(1E-2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)sulphur]benzamide, and the chemical formula of the Axitinib is C22H18N4OS. The preparation technology is simple in process, the raw materials are easy to obtain, the preparation method is economical, environmentally friendly, easy to industrialize, capable of promoting economic and technology development of raw materials of the drug Axitinib for resisting the kidneycancer and reducing the production cost, and suitable for large-scale production.

Axitinib fumarate, crystal form thereof and preparation methods for Axitinib fumarate and crystal form thereof

The invention relates to the technical field of medical chemistry and particularly relates to Axitinib fumarate, a crystal form thereof and preparation methods for the Axitinib fumarate and the crystal form thereof. The prepared Axitinib fumarate and the crystal form thereof are high in Axitinib fumarate yield and high in purity. In addition, the Axitinib fumarate provided by the invention can further be used for preparing Axitinib after the Axitinib fumarate is dissociated. According to the preparation method for the Axitinib fumarate, disclosed by the invention, the Axitinib fumarate is prepared through subjecting the Axitinib and fumaric acid to a salt forming reaction. The Axitinib may be a direct crude product prepared by disclosures in the existing documents, or may also be pure Axitinib which is obtained through carrying out certain-aftertreatment impurity removal. Even if crude Axitinib and fumaric acid are subjected to salt forming, the Axitinib fumarate with high purity can be prepared through the salt forming reaction.

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.

Processes for the Preparation of Axitinib

Processes for the preparation of Axitinib in good yield (generally greater than 80%) are provided that avoid the use of a palladium-catalyzed coupling reaction.