341031-54-7

Basic information

• Product Name: Sunitinib Malate
• Synonyms: Malic acid Shu;N-[2-(Diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (2S)-2-hydroxybutanedioic acid (1:1) salt;SU 011248;SU112248;EZSolution Sunitinib Malate;Sunitinib Malate(SU 11248);Butanedioic acid, 2;N-(2-(Diethylamino)ethyl)-5-((Z)-(5-fluoro-1
• CAS NO: 341031-54-7
• Molecular Formula: C₄H₆O₅*C₂₂H₂₇FN₄O₂
• Molecular Weight: 532.566
• EINECS: 1308068-626-2
• Product Categories: Inhibitors;Oxetanes;APIs;Heterocycles;Intermediates & Fine Chemicals;Pfizer compounds;Pharmaceuticals;Tyrosine Kinase Inhibitors;SU-11248
• Mol File: 341031-54-7.mol

Chemical Properties

• Melting Point: 189-191°C
• Boiling Point: 572.1 °C at 760 mmHg
• Flash Point: 299.8 °C
• Appearance: /
• Density: 1.3600g/mLat 25°C(lit.)
• Storage Temp.: Store at +4°C
• Solubility: DMSO: >10mg/mL
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
• CAS DataBase Reference: Sunitinib Malate(CAS DataBase Reference)
• NIST Chemistry Reference: Sunitinib Malate(341031-54-7)
• EPA Substance Registry System: Sunitinib Malate(341031-54-7)

Safety Data

• Hazard Codes: T
• Statements: 61-2-48/25-36/37-22-53
• Safety Statements: 53-22-36/37-24/25
• WGK Germany: 2
• Hazardous Substances Data: 341031-54-7(Hazardous Substances Data)

Usage

Uses

1. Used in Anticancer Applications:
Sunitinib malate is used as an anti-cancer drug for the treatment of advanced renal cell carcinoma (RCC) and gastrointestinal stromal tumors (GIST). It works by inhibiting several receptor tyrosine kinases, including VEGFR2 (Flk-1), PDGFRβ, and c-Kit, which play a role in tumor growth and angiogenesis. This results in slowing tumor progression and inhibiting angiogenesis, making it particularly useful in highly vascularized cancers such as RCC and GIST.
2. Used in Drug Development:
Sunitinib malate is used as a multi-kinase inhibitor in the development of new antineoplastic drugs. Its ability to target several receptor tyrosine kinases makes it a promising candidate for the development of novel cancer therapies.
3. Used in Pharmaceutical Industry:
Sunitinib malate is used as a pharmaceutical compound in the production of cancer treatment medications. Its multi-targeted approach to inhibiting receptor tyrosine kinases has led to its widespread use in the development and formulation of cancer drugs.

Anticancer drug

Sunitinib malate is a kind of novel oral multi-targeted anticancer drugs and belongs to multi-targeted tyrosine kinase inhibitor with its trade name being “suntent”. It was successfully developed by Pfizer Company and has dual anti-tumor effect. Moreover, it is the only therapeutic drug which can go beyond the 2-year survival period of advanced kidney cancer and plays a central role in the field of carcinoma and gastrointestinal stromal tumor therapeutic areas. It entered into market in February 2006 in the United States. This drug was the first anti-cancer drug which was approved by the US FDA and can simultaneously treat two diseases. Sunitinib exerts its therapeutic role through preventing the tumor cells from getting the blood and nutrients needed for growth. Clinical trials have showed that the drug can delay the growth rate of gastrointestinal stromal tumors, and can shrink the size of renal cell tumors. Sunitinib malate is the first novel targeted drug being capable of selectively targets drugs for a variety of new tyrosine kinase receptors. It combine two kinds of anti-tumor mechanisms including both stopping the formation of anti-angiogenic which is responsible for supplying blood to tumor and direct attack of tumor cells. It represents the advent of a new round of targeted therapies, being able to attack the tumor directly without the toxicity of the conventional chemotherapy. The indications of Sunitinib malate are as follows: 1, Patients who failed in the treatment with matinib mesylate or of intolerant gastrointestinal stromal tumors (GIST). 2, inoperable advanced renal cell carcinoma (RCC). 3, advanced pancreatic endocrine tumors. The above information is edited by the lookchem of Dai Xiongfeng.

Biological Activity

Potent, ATP-competitive VEGFR, PDGFR β and KIT inhibitor (K i values are 2, 9, 17, 8 and 4 nM for VEGFR -1, -2, -3, PDGFR β and KIT respectively). Also inhibits cellular receptor phosphorylation of FLT3, RET and CSF-1R. Exhibits antiangiogenic and antitumor activity in multiple xenograft models.

Biochem/physiol Actions

Sunitinib has greater bioavailability and potency compared to other inhibitors. It prevents angiogenesis.

References

1) Deeks et al. (2006), Sunitinib; Drugs, 66 2255 2) Guo et al. (2006), Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors; Mol. Cancer. Ther., 5 1007 3) O’Farrell et al. (2003), SU11248 is a novel FLT3 yrosine kinase with potent activity in vitro and in vivo; Blood, 101 3597 4) Roskoski et al. (2007), Sunitinib: a EGF and PDGF receptor protein kinase and angiogenesis inhibitor; Biochem. Biophys. Res. Commun., 356 323

InChI:InChI=1/C23H30N4O2.C5H8O5/c1-6-27(7-2)11-10-24-23(29)21-15(4)20(25-16(21)5)13-18-17-12-14(3)8-9-19(17)26-22(18)28;6-3(5(9)10)1-2-4(7)8/h8-9,12-13,25H,6-7,10-11H2,1-5H3,(H,24,29)(H,26,28);3,6H,1-2H2,(H,7,8)(H,9,10)/b18-13-;/t;3-/m.0/s1

Synthetic route

(S)-Malic acid (97-67-6) + sunitinib (557795-19-4) → sunitinib malate (341031-54-7)

Conditions	Yield
In methanol; ethanol at 20℃; for 2h; Darkness;	100%
In ethanol for 2 - 4h; Product distribution / selectivity; Reflux; Industry scale;	93.6%
In ethanol for 2 - 4h; Product distribution / selectivity; Reflux;	93.6%

5-fluoroindol-2(3H)-one (56341-41-4) + (S)-Malic acid (97-67-6) + N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (356068-86-5) → sunitinib malate (341031-54-7)

Conditions	Yield
With pyrrolidine In ethanol at 78℃; for 3h;	80%
With pyrrolidine In ethanol at 78℃; for 3h;	80%
Stage #1: (S)-Malic acid; N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide In butan-1-ol at 48℃; Stage #2: 5-fluoroindol-2(3H)-one With pyrrolidine In butan-1-ol at 94℃; Product distribution / selectivity;	71.2%
Stage #1: 5-fluoroindol-2(3H)-one; N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide In ethanol at 8 - 10℃; Reflux; Stage #2: (S)-Malic acid In ethanol for 4 - 6h; Product distribution / selectivity; Reflux;	71%
Stage #1: (S)-Malic acid; N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide In tetrahydrofuran for 4 - 6h; Stage #2: 5-fluoroindol-2(3H)-one In tetrahydrofuran for 4 - 6h; Product distribution / selectivity; Reflux;

5-fluoroindol-2(3H)-one (56341-41-4) + 2-(N,N-diethylamino)ethyl ammonium di(L-malate) + N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (356068-86-5) → sunitinib malate (341031-54-7)

Conditions	Yield
In methanol; acetonitrile at 25 - 30℃; for 3h;	80%

5-fluoroindol-2(3H)-one (56341-41-4) + L-(-)-malic acid of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (1200435-83-1) → sunitinib malate (341031-54-7)

Conditions	Yield
With pyrrolidine In butan-1-ol at 20℃; Reflux;	75.1%

5-fluoroindol-2(3H)-one (56341-41-4) + L-malic acid ; ammonium-L malate (2689-91-0, 4601-92-7, 5972-71-4, 6283-27-8, 18841-14-0, 18841-15-1, 20261-05-6, 54944-40-0, 85273-27-4, 85273-28-5, 102607-29-4) + N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (356068-86-5) → sunitinib malate (341031-54-7)

Conditions	Yield
In methanol; acetonitrile at 25 - 30℃; for 3h;	75%

5-fluoroindol-2(3H)-one (56341-41-4) + di-(n-propyl ammonium) L-malate + N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (356068-86-5) → sunitinib malate (341031-54-7)

Conditions	Yield
In methanol; acetonitrile at 25 - 30℃; for 3h;	75%

5-fluoroindol-2(3H)-one (56341-41-4) + di-(diisopropyl ammonium) L-malate + N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (356068-86-5) → sunitinib malate (341031-54-7)

Conditions	Yield
In methanol; acetonitrile at 25 - 30℃; for 3h;	72.5%

5-fluoroindol-2(3H)-one (56341-41-4) + 2-(N,N-diethylamino)ethyl ammonium L-malate (1332307-07-9) + N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (356068-86-5) → sunitinib malate (341031-54-7)

Conditions	Yield
In methanol; acetonitrile at 25 - 30℃; for 3h;	72%

(S)-Malic acid (97-67-6) + 5-fluoro-1-(trimethylsilyl)-2-(trimethylsilyloxy)-1H-indole (1374685-40-1) + N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (356068-86-5) → sunitinib malate (341031-54-7)

Conditions	Yield
Stage #1: 5-fluoro-1-(trimethylsilyl)-2-(trimethylsilyloxy)-1H-indole; N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide; trimethylsilyl trifluoromethanesulfonate In acetonitrile for 13h; Reflux; Stage #2: (S)-Malic acid In methanol; acetonitrile at 20℃; for 22h;	70%
Stage #1: 5-fluoro-1-(trimethylsilyl)-2-(trimethylsilyloxy)-1H-indole; N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide With trimethylsilyl trifluoromethanesulfonate In acetonitrile for 13h; Reflux; Stage #2: (S)-Malic acid In methanol for 24h;
Stage #1: 5-fluoro-1-(trimethylsilyl)-2-(trimethylsilyloxy)-1H-indole; N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide With trimethylsilyl trifluoromethanesulfonate In acetonitrile for 9.5h; Reflux; Stage #2: (S)-Malic acid In methanol for 24h;

5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (253870-02-9) + 5-fluoroindol-2(3H)-one (56341-41-4) + (S)-Malic acid (97-67-6) + N,N-diethylethylenediamine (100-36-7) → sunitinib malate (341031-54-7)

Conditions	Yield
Stage #1: 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid; N,N-diethylethylenediamine With benzotriazol-1-ol; triethylamine; dicyclohexyl-carbodiimide In tetrahydrofuran for 20h; Stage #2: (S)-Malic acid In tetrahydrofuran for 4 - 6h; Reflux; Stage #3: 5-fluoroindol-2(3H)-one In tetrahydrofuran for 4 - 6h; Product distribution / selectivity; Reflux;	67%

2-(N,N-diethylamino)ethyl ammonium L-malate (1332307-07-9) + 5-fluoro-2-oxindole (1032268-12-4) + C14H24N3O5S(1-)*Na(1+) (1338703-87-9) → sunitinib malate (341031-54-7)

Conditions	Yield
In methanol; acetonitrile at 25 - 30℃; for 3h;	67%

5-fluoroindol-2(3H)-one (56341-41-4) + dipyrrolidine L-malate + N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (356068-86-5) → sunitinib malate (341031-54-7)

Conditions	Yield
In methanol; acetonitrile at 25 - 30℃; for 3h;	32%

5-fluoroindol-2(3H)-one (56341-41-4) + N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (356068-86-5) → sunitinib malate (341031-54-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: pyrrolidine / methanol / 5 - 7 h / Reflux 2: ethanol / 2 - 4 h / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane / acetonitrile / 7 h / Reflux 1.2: 3 h / 20 - 60 °C 2.1: methanol / 0.5 h / 20 °C / Inert atmosphere 2.2: 25 °C View Scheme

ethyl (5-formyl-2,4-dimethyl-1H-pyrrole)-3-carboxylate (2199-59-9) → sunitinib malate (341031-54-7)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: potassium hydroxide; water / methanol / 4 - 6 h / 60 - 70 °C 2.1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / tetrahydrofuran / 0.5 h 2.2: 16 h / 25 - 30 °C 3.1: pyrrolidine / methanol / 5 - 7 h / Reflux 4.1: ethanol / 2 - 4 h / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: potassium hydroxide; water / methanol / 4 - 6 h / 60 - 70 °C 2.1: triethylamine; dicyclohexyl-carbodiimide; benzotriazol-1-ol / tetrahydrofuran / 20 h 2.2: 4 - 6 h / Reflux 2.3: 4 - 6 h / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: potassium hydroxide; water / methanol / 4 - 6 h / 60 - 70 °C 2.1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / tetrahydrofuran / 0.5 h 2.2: 16 h / 25 - 30 °C 3.1: ethanol / 8 - 10 °C / Reflux 3.2: 4 - 6 h / Reflux View Scheme

2-tert-butyl 4-ethyl 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate (86770-31-2) → sunitinib malate (341031-54-7)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: hydrogenchloride / isopropyl alcohol / 25 - 50 °C 2.1: trichlorophosphate / 2 - 3 h / 0 - 50 °C 2.2: 25 - 30 °C / pH 12 - 13 3.1: potassium hydroxide; water / methanol / 4 - 6 h / 60 - 70 °C 4.1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / tetrahydrofuran / 0.5 h 4.2: 16 h / 25 - 30 °C 5.1: pyrrolidine / methanol / 5 - 7 h / Reflux 6.1: ethanol / 2 - 4 h / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: hydrogenchloride / isopropyl alcohol / 25 - 50 °C 2.1: trichlorophosphate / 2 - 3 h / 0 - 50 °C 2.2: 25 - 30 °C / pH 12 - 13 3.1: potassium hydroxide; water / methanol / 4 - 6 h / 60 - 70 °C 4.1: triethylamine; dicyclohexyl-carbodiimide; benzotriazol-1-ol / tetrahydrofuran / 20 h 4.2: 4 - 6 h / Reflux 4.3: 4 - 6 h / Reflux View Scheme
Multi-step reaction with 5 steps 1.1: hydrogenchloride / isopropyl alcohol / 25 - 50 °C 2.1: trichlorophosphate / 2 - 3 h / 0 - 50 °C 2.2: 25 - 30 °C / pH 12 - 13 3.1: potassium hydroxide; water / methanol / 4 - 6 h / 60 - 70 °C 4.1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / tetrahydrofuran / 0.5 h 4.2: 16 h / 25 - 30 °C 5.1: ethanol / 8 - 10 °C / Reflux 5.2: 4 - 6 h / Reflux View Scheme

5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (253870-02-9) → sunitinib malate (341031-54-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / tetrahydrofuran / 0.5 h 1.2: 16 h / 25 - 30 °C 2.1: pyrrolidine / methanol / 5 - 7 h / Reflux 3.1: ethanol / 2 - 4 h / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / tetrahydrofuran / 0.5 h 1.2: 16 h / 25 - 30 °C 2.1: ethanol / 8 - 10 °C / Reflux 2.2: 4 - 6 h / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: 1,1,1,3,3,3-hexamethyl-disilazane / ammonium sulfate / 5 h / Reflux 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h 2.2: 25 °C 3.1: N,N-dimethyl-formamide / 25 °C 4.1: methanol / 8 h / 25 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1.1: ammonium sulfate; 1,1,1,3,3,3-hexamethyl-disilazane / 5 h / Reflux 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.25 h / 25 °C 2.2: 1 h / 40 °C 3.1: acetonitrile; N,N-dimethyl-formamide / 1 h / 25 °C 4.1: methanol / 0.5 h / 20 °C / Inert atmosphere 4.2: 25 °C View Scheme
Multi-step reaction with 3 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / acetonitrile / 2 h / 35 °C / Large scale 1.2: 2 h / 35 °C / Large scale 2.1: triethylamine / 2 h / 60 °C / Large scale 3.1: methanol / 1 h / 40 °C / Large scale View Scheme

5-fluoro-1H-indole-2,3-dione (443-69-6) → sunitinib malate (341031-54-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrazine / 5.5 h / 100 - 130 °C 2: pyrrolidine / methanol / 5 - 7 h / Reflux 3: ethanol / 2 - 4 h / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: hydrazine / 5.5 h / 100 - 130 °C 2.1: ethanol / 8 - 10 °C / Reflux 2.2: 4 - 6 h / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: hydrazine / 5.5 h / 100 - 130 °C 2.1: triethylamine; dicyclohexyl-carbodiimide; benzotriazol-1-ol / tetrahydrofuran / 20 h 2.2: 4 - 6 h / Reflux 2.3: 4 - 6 h / Reflux View Scheme

2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (2199-51-1) → sunitinib malate (341031-54-7)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: trichlorophosphate / 2 - 3 h / 0 - 50 °C 1.2: 25 - 30 °C / pH 12 - 13 2.1: potassium hydroxide; water / methanol / 4 - 6 h / 60 - 70 °C 3.1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / tetrahydrofuran / 0.5 h 3.2: 16 h / 25 - 30 °C 4.1: pyrrolidine / methanol / 5 - 7 h / Reflux 5.1: ethanol / 2 - 4 h / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: trichlorophosphate / 2 - 3 h / 0 - 50 °C 1.2: 25 - 30 °C / pH 12 - 13 2.1: potassium hydroxide; water / methanol / 4 - 6 h / 60 - 70 °C 3.1: triethylamine; dicyclohexyl-carbodiimide; benzotriazol-1-ol / tetrahydrofuran / 20 h 3.2: 4 - 6 h / Reflux 3.3: 4 - 6 h / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: trichlorophosphate / 2 - 3 h / 0 - 50 °C 1.2: 25 - 30 °C / pH 12 - 13 2.1: potassium hydroxide; water / methanol / 4 - 6 h / 60 - 70 °C 3.1: dicyclohexyl-carbodiimide; benzotriazol-1-ol / tetrahydrofuran / 0.5 h 3.2: 16 h / 25 - 30 °C 4.1: ethanol / 8 - 10 °C / Reflux 4.2: 4 - 6 h / Reflux View Scheme

N,N-diethylethylenediamine (100-36-7) → sunitinib malate (341031-54-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: methanol / 1 h / 25 - 30 °C 2: acetonitrile; methanol / 3 h / 25 - 30 °C View Scheme
Multi-step reaction with 2 steps 1: methanol / 1 h / 25 - 30 °C 2: acetonitrile; methanol / 3 h / 25 - 30 °C View Scheme
Multi-step reaction with 2 steps 1.1: p-toluenesulfonyl chloride / N,N-dimethyl-formamide / 0.25 h / 15 - 19 °C 1.2: 15 - 19 °C 1.3: 0.67 h / 13 - 16 °C 2.1: methanol / 25 - 30 °C View Scheme
Multi-step reaction with 6 steps 1.1: dichloromethane / 0.5 h / 0 - 20 °C 2.1: zinc / methanol; acetic acid / 65 - 70 °C 3.1: sulfuric acid / water; methanol / 3.5 h / 60 - 65 °C 4.1: oxalyl dichloride / dichloromethane / 2.5 h / 0 - 10 °C / Inert atmosphere 4.2: 30 °C 5.1: potassium hydroxide / N,N-dimethyl-formamide / 3.5 h / 20 °C / Darkness; Inert atmosphere 6.1: methanol; ethanol / 2 h / 20 °C / Darkness View Scheme
Multi-step reaction with 3 steps 1.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / acetonitrile / 2 h / 35 °C / Large scale 1.2: 2 h / 35 °C / Large scale 2.1: triethylamine / 2 h / 60 °C / Large scale 3.1: methanol / 1 h / 40 °C / Large scale View Scheme

N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (356068-86-5) → sunitinib malate (341031-54-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydrogensulfite / ethanol; water / 10 - 20 °C 2: acetonitrile; methanol / 3 h / 25 - 30 °C View Scheme
Multi-step reaction with 2 steps 1.1: 1,1,1,3,3,3-hexamethyl-disilazane / ammonium sulfate / 5 h / Reflux 1.2: 29.3 h / Reflux 2.1: methanol / 8 h / 25 °C / Inert atmosphere View Scheme

5-fluoroindol-2(3H)-one (56341-41-4) → sunitinib malate (341031-54-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 1,1,1,3,3,3-hexamethyl-disilazane / ammonium sulfate / 5 h / Reflux 1.2: 29.3 h / Reflux 2.1: methanol / 8 h / 25 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: ammonium sulfate / Inert atmosphere; Reflux 2.1: trimethylsilyl trifluoromethanesulfonate / acetonitrile / 13 h / Reflux 2.2: 22 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: ammonium sulfate / Inert atmosphere; Reflux 2: trimethylsilyl trifluoromethanesulfonate / N,N-dimethyl-formamide; acetonitrile / Reflux 3: methanol / 8 h / 25 °C / Inert atmosphere View Scheme

5-((Z)-(5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (356068-93-4) → sunitinib malate (341031-54-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h 1.2: 25 °C 2.1: N,N-dimethyl-formamide / 25 °C 3.1: methanol / 8 h / 25 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.25 h / 25 °C 1.2: 1 h / 40 °C 2.1: acetonitrile; N,N-dimethyl-formamide / 1 h / 25 °C 3.1: methanol / 0.5 h / 20 °C / Inert atmosphere 3.2: 25 °C View Scheme
Multi-step reaction with 2 steps 1.1: p-toluenesulfonyl chloride / N,N-dimethyl-formamide / 0.25 h / 15 - 19 °C 1.2: 15 - 19 °C 1.3: 0.67 h / 13 - 16 °C 2.1: methanol / 25 - 30 °C View Scheme

(Z)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl 5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxylate (452105-55-4) → sunitinib malate (341031-54-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 25 °C 2: methanol / 8 h / 25 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: acetonitrile; N,N-dimethyl-formamide / 1 h / 25 °C 2.1: methanol / 0.5 h / 20 °C / Inert atmosphere 2.2: 25 °C View Scheme

N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, hydrochloride → sunitinib malate (341031-54-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide / water / 90 °C / pH 8 - 9 2: methanol / 8 h / 25 °C / Inert atmosphere View Scheme

sunitinib mesylate → sunitinib malate (341031-54-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide / water / 80 °C / pH 8 - 9 2: methanol / 8 h / 25 °C / Inert atmosphere View Scheme

5-fluoro-1-(trimethylsilyl)-2-(trimethylsilyloxy)-1H-indole (1374685-40-1) → sunitinib malate (341031-54-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: trimethylsilyl trifluoromethanesulfonate / N,N-dimethyl-formamide; acetonitrile / Reflux 2: methanol / 8 h / 25 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1.1: 1,1,1,3,3,3-hexamethyl-disilazane / trifluorormethanesulfonic acid / acetonitrile / 48 h / 20 - 65 °C 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.17 h 2.2: 25 °C 3.1: N,N-dimethyl-formamide / 25 °C 4.1: methanol / 8 h / 25 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: trimethylsilyl trifluoromethanesulfonate / acetonitrile; N,N-dimethyl-formamide / Reflux 2.1: methanol / 0.5 h / 20 °C / Inert atmosphere 2.2: 25 °C View Scheme

sunitinib hydrochloride (1327155-72-5) → sunitinib malate (341031-54-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: water / 90 °C 2.1: methanol / 0.5 h / 20 °C / Inert atmosphere 2.2: 25 °C View Scheme

sunitinib methanesulfonic acid (1275588-72-1) → sunitinib malate (341031-54-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: water / 80 °C 2.1: methanol / 0.5 h / 20 °C / Inert atmosphere 2.2: 25 °C View Scheme

N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (590424-05-8) → sunitinib malate (341031-54-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: oxalyl dichloride / dichloromethane / 2.5 h / 0 - 10 °C / Inert atmosphere 1.2: 30 °C 2.1: potassium hydroxide / N,N-dimethyl-formamide / 3.5 h / 20 °C / Darkness; Inert atmosphere 3.1: methanol; ethanol / 2 h / 20 °C / Darkness View Scheme

sunitinib malate (341031-54-7) → (Z)-N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-yliden)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide L-malate

Conditions	Yield
In ethanol Product distribution / selectivity; Reflux;

Upstream product

• 56341-41-4 5-fluoroindol-2(3H)-one 
• 97-67-6 (S)-Malic acid 
• 356068-86-5 N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide 
• 1200435-83-1 L-(-)-malic acid of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide 
• 253870-02-9 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid 
• 100-36-7 N,N-diethylethylenediamine 
• 2199-59-9 ethyl (5-formyl-2,4-dimethyl-1H-pyrrole)-3-carboxylate 
• 86770-31-2 2-tert-butyl 4-ethyl 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate 
• 443-69-6 5-fluoro-1H-indole-2,3-dione 
• 2199-51-1 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 
• 2689-91-0 L-malic acid ; ammonium-L malate 
• 1332307-07-9 2-(N,N-diethylamino)ethyl ammonium L-malate 
• 1327155-72-5 sunitinib hydrochloride 
• 1275588-72-1 sunitinib methanesulfonic acid 

Downstream Products

• 557795-19-4 sunitinib 

Relevant articles and documents

A high-purity malic acid lin's preparation method

The invention relates to a high-purity malic acid lin's preparation method, the method comprises the following steps: (1) the formula II compound as a starting material, the use of 1 - ethyl - (3 - dimethyl amino propyl) carbonylamino-carbodiimide hydrochloride with 1 - hydroxy benzotriazole as the condensing agent, under certain temperature and N, N diethylethylenediamine reaction to obtain compound III; (2) in the step (1) the reaction solution, between the step (1) the resulting reactant with 5 - fluoro indole - 2 - one reaction at certain temperature, to obtain compound IV; (3) in the step (2) of the reaction solution, so that the step (1) the resulting reactant with L - malic acid reaction at certain temperature, to obtain compound I; providing at least to a certain extent one of the solve the above technical problems or at least provide a useful commercial choice. The reaction route is operating time is short, simple operation, reaction system is stable, higher product yield, purity of the product is relatively high, it is suitable for industrial production.

High-purity L-sunitinib malate preparation method

The present invention discloses a high-purity L-sunitinib malate preparation method, which comprises the following reaction route defined in the specification, wherein the step a comprises that a B5 compound and 5-fluoroindol-2-one are subjected to an Aldol condensation reaction to obtain a sunitinib free base (B6 compound), the step b comprises that the B6 compound and L-malic acid are subjected to a salt forming reaction to obtain the L-sunitinib malate, and the step a and the step b are performed in a dark place. According to the present invention, the HPLC purity of the prepared L-sunitinib malate can achieve more than 99.8%, the single impurity content can be controlled at less than 0.1%, and the quality difficulty of the application of the L-sunitinib malate in the preparation is effectively solved.

PROCESS FOR THE PERPARATION OF SUNITINIB AND ITS ACID ADDITION SALTS THEREOF

The present invention relates to an improved process for the preparation of Sunitinb. The process involves the activation of 5-((Z)-(5-fluoro-2-oxoindolin-3-ylidene) methyl)-2,4-dimethyl-1H-pyrrole-3carboxylic acid to corresponding suitable carboxylic acid activating group. The present invention also relates to novel acid addition salts of Sunitinb and preparation thereof.

PROCESSES FOR THE PREPARATION OF 3-(PYRROL-2-YL)METHYLENE)-2-PYRROLONES USING 2-SILYLOXY-PYRROLES

The present invention provides for synthetic processes for the making of substituted 3-((pyrrol-2-yl)methylene)-2-pyrrolones, including sunitinib. The present invention also provides for a process of crystallizing substantially pure sunitinib L-malate.

PROCESS FOR THE DIRECT PREPARATION OF MALIC ACID SALT OF SUNITINIB

The present invention relates to a process for the direct preparation of malic acid salt of sunitinib.

PROCESS FOR PREPARATION OF HIGH PURITY N- [2- (DIETHYLAMINE) ETHYL] - 5 - FORMYL - 2, 4 - DIMETHYL - 1H - PYRROLE - 3 - CARBOXYAMIDE

The present invention relates to preparation of high purity N-[2- (diethylamine)ethyl]-5-formyl-2,4-dimethyl- 1 H-pyrrole-3-carboxyamide, comprising purification to obtain the product including less than 0.07% of desethyl derivative, N- [2-(ethylamine)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxyamide. N-[2- (diethylamine)ethyl]-5-formyl-2,4-dimethyl- 1 H-pyrrole-3-carboxyamide containing less than 0.07% of desethyl derivative is the valuable intermediate in the process for preparation of active pharmaceutical ingredient sunitinib.

PROCESSES FOR THE PREPARATION OF 3-(PYRROL-2-YL)METHYLENE)-2-PYRROLONES USING 2-SILYLOXY-PYRROLES

The present invention provides for synthetic processes for the making of substituted 3-(Pyrrol-2-yl)methylene)-2-pyrrolones, including sunitinib. The present invention also provides for a process of crystallizing substantially pure sunitinib L-malate.

CRYSTALLINE FORMS OF L-MALIC ACID SALT OF SUNITINIB

The present invention relates to crystalline forms of L-malic acid salt of sunitinib and its preparation. The crystalline forms of the present invention are designated as Form V and Form VI of L-malic acid salt of sunitinib. Formula (I).

PROCESS FOR THE PREPARATION OF HIGH PURITY SUNITINIB AND ITS PHARMACEUTICALLY ACCEPTABLE SALT

The present invention relates to an improved process for the preparation of N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide—Sunitinib base of formula (I) and its pharmaceutically acceptable malate salt of formula (I(a)).

NOVEL PROCESS

The present invention relates to novel processes for the preparation of sunitinib and salts thereof, in particular sunitinib (2S)-2-hydroxybutanedioate. The invention further relates to novel intermediates, their use in the preparation of sunitinib or salts thereof and to processes for the preparation of said intermediates. The invention also relates to compositions comprising sunitinib or its pharmaceutically acceptable salts.