332012-40-5

Basic information

• Product Name: Telatinib
• Synonyms: 2-Pyridinecarboxamide, 4-(((4-((4-chlorophenyl)amino)furo(2,3-D)pyridazin-7-yl)oxy)methyl)-N-methyl-;Bay 57-9352;Unii-18p7197Q7j;Telatinib(BAY 57-9352);4-[[[4-[(4-Chlorophenyl)amino]furo[2,3-d]pyridazin-7-yl]oxy]methyl]-N-methyl-2-pyridinecarboxamide;4-((4-(4-chlorophenylamino)furo[2,3-d]pyridazin-7-yloxy)methyl)-N-methylpicolinamide;4-[[[4-[(4-Chlorophenyl)amino]furo[2,3-d]pyridazin-7-yl]oxy]methyl]-N-methyl-2-pyridinecarboxamide Telatinib(BAY57-9352);Telatnib
• CAS NO: 332012-40-5
• Molecular Formula: C₂₀H₁₆ClN₅O₃
• Molecular Weight: 407.85292
• Product Categories: API;Inhibitors
• Mol File: 332012-40-5.mol
• Article Data: 4

Chemical Properties

• Boiling Point: 713.595 °C at 760 mmHg
• Flash Point: 385.368 °C
• Appearance: /
• Density: 1.417
• Solubility: insoluble in H2O; insoluble in EtOH; ≥20.5 mg/mL in DMSO
• PKA: 14.18±0.46(Predicted)
• CAS DataBase Reference: Telatinib(CAS DataBase Reference)
• NIST Chemistry Reference: Telatinib(332012-40-5)
• EPA Substance Registry System: Telatinib(332012-40-5)

Safety Data

• Hazardous Substances Data: 332012-40-5(Hazardous Substances Data)

Usage

Description

Telatinib is a multi-kinase inhibitor that inhibits VEGF receptor 2 (VEGFR2), VEGFR3, PDGFRα, and c-Kit (IC50s = 6, 4, 15, and 1 nM, respectively). It also binds to the transmembrane region of the ABCG2 efflux transporter and enhances intracellular accumulation of [3H]-mitoxantrone in ABCG2-overexpressing cells. Telatinib (15 mg/kg) decreases tumor growth rate and size in an H460/MX20 mouse xenograft model.

Uses

Different sources of media describe the Uses of 332012-40-5 differently. You can refer to the following data:
1. Telatinib (BAY 57-9352) is an orally available, potent multitargeted VEGFR-2, VEGFR-3, PDGFR-β and c-Kit tyrosine kinases inhibitor with an IC50 of 19 nM for the inhibition of VEGFR-2 autophosphorylation.
2. Telatinib small-molecule inhibitor of vascular endothelial growth factor receptors 2 and 3 (VEGFR-2/-3) and platelet-derived growth factor receptor β tyrosine kinases. Telatinib is used therapeuticall y in patients with advanced solid tumors.
3. Telatinib small-molecule inhibitor of vascular endothelial growth factor receptors 2 and 3 (VEGFR-2/-3) and platelet-derived growth factor receptor β tyrosine kinases. Telatinib is used therapeutically in patients with advanced solid tumors.

references

[1]. steeghs, n., et al., hypertension and rarefaction during treatment with telatinib, a small molecule angiogenesis inhibitor. clin cancer res, 2008. 14(11): p. 3470-6.[2]. strumberg, d., et al., phase i dose escalation study of telatinib (bay 57-9352) in patients with advanced solid tumours. br j cancer, 2008. 99(10): p. 1579-85.[3]. sodani, k., et al., telatinib reverses chemotherapeutic multidrug resistance mediated by abcg2 efflux transporter in vitro and in vivo. biochem pharmacol, 2014. 89(1): p. 52-61. [4]. eskens, f.a., et al., phase i dose escalation study of telatinib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 and 3, platelet-derived growth factor receptor beta, and c-kit, in patients with advanced or metastatic solid tumors. j clin oncol, 2009. 27(25): p. 4169-76.

Synthetic route

4-(hydroxymethyl)-N-methylpyridine-2-carboxamide (332013-43-1) + 4-chloroanilino-7-chlorofuro[2,3-d]pyridazine (332013-40-8) → Telatinib (332012-40-5)

Conditions	Yield
With potassium hydroxide; 18-crown-6 ether In toluene at 83 - 87℃; Product distribution / selectivity;	46%
With potassium hydroxide; 18-crown-6 ether In toluene at 20 - 85℃;	46%

4-(hydroxymethyl)-N-methylpyridine-2-carboxamide (332013-43-1) + 4-chloro-7-[N-(4-chlorophenyl)amino]-[2,3-d]furopyridazine (332013-41-9) → Telatinib (332012-40-5)

Conditions	Yield
With potassium hydroxide; 18-crown-6 ether In toluene at 20 - 87℃; Product distribution / selectivity;	46%
Stage #1: 4-(hydroxymethyl)-N-methylpyridine-2-carboxamide; 4-chloro-7-[N-(4-chlorophenyl)amino]-[2,3-d]furopyridazine; 18-crown-6 ether In toluene at 20℃; for 0.166667h; Stage #2: With potassium hydroxide In toluene at 80℃; for 24h; Product distribution / selectivity;

4-chloroanilino-7-chlorofuro[2,3-d]pyridazine (332013-40-8) + 2-methylaminocarbonyl-4-pyridylcarbinol hydrochloride (1182334-19-5) → Telatinib (332012-40-5)

Conditions	Yield
With potassium tert-butylate In tetrahydrofuran; toluene at 95℃; for 24h; Temperature; Time; Autoclave;	37.7%

N-Methylformamide (123-39-7) + N-(4-chlorophenyl)-7-(4-pyridinylmethoxy)-furo[2,3-d]pyridazin-4-amine → Telatinib (332012-40-5) + 4-(4-chlorophenylamino)-2-methylaminocarbonyl-7-(2-methylaminocarbonyl-4-pyridylmethoxy)-furo[2,3-d]pyridazine (332012-41-6)

Conditions	Yield
With sulfuric acid; hydroxylamine-O-sulfonic acid; iron(II) sulfate In water at 20℃; for 1.83333h; Product distribution / selectivity;	A 15.2% B n/a
Stage #1: N-Methylformamide; N-(4-chlorophenyl)-7-(4-pyridinylmethoxy)-furo[2,3-d]pyridazin-4-amine With sulfuric acid; iron(II) sulfate; hydroxylamine-O-sulfonic acid In water at 20℃; for 1.83333h; Stage #2: With sodium citrate In water at 0℃; for 0.166667h; Product distribution / selectivity;	A 15.2% B n/a
With sulfuric acid; iron(II) sulfate; hydroxylamine-O-sulfonic acid In water at 20℃; for 1.66667h;	A 15.2% B n/a

ethyl 2-methylaminocarbonyl-4-picolinate (332013-42-0) → Telatinib (332012-40-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium tetrahydroborate / isopropyl alcohol; methanol / 8 h / 25 °C / Large scale 1.2: 1 h / 0 °C / Large scale 2.1: potassium tert-butylate / toluene; tetrahydrofuran / 24 h / 95 °C / Autoclave View Scheme
Multi-step reaction with 2 steps 1.1: sodium tetrahydroborate / ethanol / 18 h / 20 °C 1.3: pH 9 2.1: potassium hydroxide; 18-crown-6 ether / toluene / 83 - 87 °C View Scheme
Multi-step reaction with 2 steps 1: sodium tetrahydroborate / ethanol / 18 h / 20 °C 2: potassium hydroxide; 18-crown-6 ether / toluene / 20 - 85 °C View Scheme

4,7-dichlorofuro[2,3-d]pyridazine (13177-70-3) → Telatinib (332012-40-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: ethanol / 4 h / Heating / reflux 2: potassium hydroxide; 18-crown-6 ether / toluene / 83 - 87 °C View Scheme
Multi-step reaction with 2 steps 1: ethanol / 4 h / Heating / reflux 2: potassium hydroxide; 18-crown-6 ether / toluene / 20 - 85 °C View Scheme

4,7-dichlorofuro[2,3-d]pyridazine (13177-70-3) → Telatinib (332012-40-5) + 4-(4-chlorophenylamino)-2-methylaminocarbonyl-7-(2-methylaminocarbonyl-4-pyridylmethoxy)-furo[2,3-d]pyridazine (332012-41-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: ethanol / 4 h / Heating / reflux 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 24 h / 125 °C 3.1: sulfuric acid; iron(II) sulfate; hydroxylamine-O-sulfonic acid / water / 1.83 h / 20 °C 3.2: 0.17 h / 0 °C View Scheme
Multi-step reaction with 3 steps 1: ethanol / 4 h / Heating / reflux 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / 24 h / 125 °C 3: sulfuric acid; iron(II) sulfate; hydroxylamine-O-sulfonic acid / water / 1.67 h / 20 °C View Scheme

isonicotinic acid ethylester (1570-45-2) → Telatinib (332012-40-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sulfuric acid; dihydrogen peroxide; iron(II) sulfate / water / 0.5 h / 6 - 22 °C 1.2: pH ~ 5 2.1: sodium tetrahydroborate / ethanol / 18 h / 20 °C 2.3: pH 9 3.1: potassium hydroxide; 18-crown-6 ether / toluene / 83 - 87 °C View Scheme
Multi-step reaction with 3 steps 1: sulfuric acid; dihydrogen peroxide; iron(II) sulfate / water / 0.5 h / 6 - 22 °C 2: sodium tetrahydroborate / ethanol / 18 h / 20 °C 3: potassium hydroxide; 18-crown-6 ether / toluene / 20 - 85 °C View Scheme

furan-2,3-dicarboxylic acid (4282-24-0) → Telatinib (332012-40-5)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: chloro-trimethyl-silane / 15.5 h / 20 °C 2.1: ethanol; water; hydrazine / 5.5 h / Heating / reflux 2.2: 4 h / Heating / reflux 3.1: pyridine; trichlorophosphate / 4 h / Heating / reflux 4.1: ethanol / 4 h / Heating / reflux 5.1: potassium hydroxide; 18-crown-6 ether / toluene / 83 - 87 °C View Scheme
Multi-step reaction with 5 steps 1: chloro-trimethyl-silane / 15.5 h / 20 °C 2: hydrazine / ethanol / 5.5 h / Heating / reflux 3: pyridine; trichlorophosphate / 4 h / Heating / reflux 4: ethanol / 4 h / Heating / reflux 5: potassium hydroxide; 18-crown-6 ether / toluene / 20 - 85 °C View Scheme

furan-2,3-dicarboxylic acid (4282-24-0) → Telatinib (332012-40-5) + 4-(4-chlorophenylamino)-2-methylaminocarbonyl-7-(2-methylaminocarbonyl-4-pyridylmethoxy)-furo[2,3-d]pyridazine (332012-41-6)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: chloro-trimethyl-silane / 15.5 h / 20 °C 2.1: ethanol; water; hydrazine / 5.5 h / Heating / reflux 2.2: 4 h / Heating / reflux 3.1: pyridine; trichlorophosphate / 4 h / Heating / reflux 4.1: ethanol / 4 h / Heating / reflux 5.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 24 h / 125 °C 6.1: sulfuric acid; iron(II) sulfate; hydroxylamine-O-sulfonic acid / water / 1.83 h / 20 °C 6.2: 0.17 h / 0 °C View Scheme
Multi-step reaction with 6 steps 1: chloro-trimethyl-silane / 15.5 h / 20 °C 2: hydrazine / ethanol / 5.5 h / Heating / reflux 3: pyridine; trichlorophosphate / 4 h / Heating / reflux 4: ethanol / 4 h / Heating / reflux 5: 1,8-diazabicyclo[5.4.0]undec-7-ene / 24 h / 125 °C 6: sulfuric acid; iron(II) sulfate; hydroxylamine-O-sulfonic acid / water / 1.67 h / 20 °C View Scheme

4-chloroanilino-7-chlorofuro[2,3-d]pyridazine (332013-40-8) → Telatinib (332012-40-5) + 4-(4-chlorophenylamino)-2-methylaminocarbonyl-7-(2-methylaminocarbonyl-4-pyridylmethoxy)-furo[2,3-d]pyridazine (332012-41-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 24 h / 125 °C 2.1: sulfuric acid; iron(II) sulfate; hydroxylamine-O-sulfonic acid / water / 1.83 h / 20 °C 2.2: 0.17 h / 0 °C View Scheme
Multi-step reaction with 2 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 24 h / 125 °C 2: sulfuric acid; iron(II) sulfate; hydroxylamine-O-sulfonic acid / water / 1.67 h / 20 °C View Scheme

methyl 3-methoxycarbonylfuran-2-carboxylate (52900-79-5) → Telatinib (332012-40-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: ethanol; water; hydrazine / 5.5 h / Heating / reflux 1.2: 4 h / Heating / reflux 2.1: pyridine; trichlorophosphate / 4 h / Heating / reflux 3.1: ethanol / 4 h / Heating / reflux 4.1: potassium hydroxide; 18-crown-6 ether / toluene / 83 - 87 °C View Scheme
Multi-step reaction with 4 steps 1: hydrazine / ethanol / 5.5 h / Heating / reflux 2: pyridine; trichlorophosphate / 4 h / Heating / reflux 3: ethanol / 4 h / Heating / reflux 4: potassium hydroxide; 18-crown-6 ether / toluene / 20 - 85 °C View Scheme

methyl 3-methoxycarbonylfuran-2-carboxylate (52900-79-5) → Telatinib (332012-40-5) + 4-(4-chlorophenylamino)-2-methylaminocarbonyl-7-(2-methylaminocarbonyl-4-pyridylmethoxy)-furo[2,3-d]pyridazine (332012-41-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: ethanol; water; hydrazine / 5.5 h / Heating / reflux 1.2: 4 h / Heating / reflux 2.1: pyridine; trichlorophosphate / 4 h / Heating / reflux 3.1: ethanol / 4 h / Heating / reflux 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 24 h / 125 °C 5.1: sulfuric acid; iron(II) sulfate; hydroxylamine-O-sulfonic acid / water / 1.83 h / 20 °C 5.2: 0.17 h / 0 °C View Scheme
Multi-step reaction with 5 steps 1: hydrazine / ethanol / 5.5 h / Heating / reflux 2: pyridine; trichlorophosphate / 4 h / Heating / reflux 3: ethanol / 4 h / Heating / reflux 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / 24 h / 125 °C 5: sulfuric acid; iron(II) sulfate; hydroxylamine-O-sulfonic acid / water / 1.67 h / 20 °C View Scheme

5,6-dihydrofuro[2,3-d]pyridazine-4,7-dione (13177-71-4) → Telatinib (332012-40-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: pyridine; trichlorophosphate / 4 h / Heating / reflux 2: ethanol / 4 h / Heating / reflux 3: potassium hydroxide; 18-crown-6 ether / toluene / 83 - 87 °C View Scheme
Multi-step reaction with 3 steps 1: pyridine; trichlorophosphate / 4 h / Heating / reflux 2: ethanol / 4 h / Heating / reflux 3: potassium hydroxide; 18-crown-6 ether / toluene / 20 - 85 °C View Scheme

5,6-dihydrofuro[2,3-d]pyridazine-4,7-dione (13177-71-4) → Telatinib (332012-40-5) + 4-(4-chlorophenylamino)-2-methylaminocarbonyl-7-(2-methylaminocarbonyl-4-pyridylmethoxy)-furo[2,3-d]pyridazine (332012-41-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: pyridine; trichlorophosphate / 4 h / Heating / reflux 2.1: ethanol / 4 h / Heating / reflux 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 24 h / 125 °C 4.1: sulfuric acid; iron(II) sulfate; hydroxylamine-O-sulfonic acid / water / 1.83 h / 20 °C 4.2: 0.17 h / 0 °C View Scheme
Multi-step reaction with 4 steps 1: pyridine; trichlorophosphate / 4 h / Heating / reflux 2: ethanol / 4 h / Heating / reflux 3: 1,8-diazabicyclo[5.4.0]undec-7-ene / 24 h / 125 °C 4: sulfuric acid; iron(II) sulfate; hydroxylamine-O-sulfonic acid / water / 1.67 h / 20 °C View Scheme

3-Furoic acid (488-93-7) → Telatinib (332012-40-5)

Conditions	Yield
Multi-step reaction with 6 steps 1: n-butyllithium / tetrahydrofuran; hexanes / 2.5 h / -78 - -10 °C 2: chloro-trimethyl-silane / 15.5 h / 20 °C 3: hydrazine / ethanol / 5.5 h / Heating / reflux 4: pyridine; trichlorophosphate / 4 h / Heating / reflux 5: ethanol / 4 h / Heating / reflux 6: potassium hydroxide; 18-crown-6 ether / toluene / 20 - 85 °C View Scheme

3-Furoic acid (488-93-7) → Telatinib (332012-40-5) + 4-(4-chlorophenylamino)-2-methylaminocarbonyl-7-(2-methylaminocarbonyl-4-pyridylmethoxy)-furo[2,3-d]pyridazine (332012-41-6)

Conditions

Yield

Multi-step reaction with 7 steps 1: n-butyllithium / tetrahydrofuran; hexanes / 2.5 h / -78 - -10 °C 2: chloro-trimethyl-silane / 15.5 h / 20 °C 3: hydrazine / ethanol / 5.5 h / Heating / reflux 4: pyridine; trichlorophosphate / 4 h / Heating / reflux 5: ethanol / 4 h / Heating / reflux 6: 1,8-diazabicyclo[5.4.0]undec-7-ene / 24 h / 125 °C 7: sulfuric acid; iron(II) sulfate; hydroxylamine-O-sulfonic acid / water / 1.67 h / 20 °C View Scheme

Telatinib (332012-40-5) + methanesulfonic acid (75-75-2) → 4-[({4-[(4-chlorophenyl)amino]furan[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide methanesulfonate (332013-26-0)

Conditions	Yield
In methanol for 0.25h; Autoclave; Reflux; Large scale;	77.4%

Telatinib (332012-40-5) + toluene-4-sulfonic acid (104-15-4) → 4-[({4-[(4-chlorophenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide 4-methylbenzenesulfonate (332013-24-8)

Conditions	Yield
In methanol; diethyl ether for 0.166667h;
Stage #1: Telatinib; toluene-4-sulfonic acid In methanol for 0.0833333h; Stage #2: In methanol; diethyl ether at 0℃; for 0.833333h;
In methanol; diethyl ether at 0℃; for 0.916667h;

Upstream product

• 123-39-7 N-Methylformamide 
• 488-93-7 3-Furoic acid 
• 13177-71-4 5,6-dihydrofuro[2,3-d]pyridazine-4,7-dione 
• 52900-79-5 methyl 3-methoxycarbonylfuran-2-carboxylate 
• 332013-40-8 4-chloroanilino-7-chlorofuro[2,3-d]pyridazine 
• 4282-24-0 furan-2,3-dicarboxylic acid 
• 1570-45-2 isonicotinic acid ethylester 
• 13177-70-3 4,7-dichlorofuro[2,3-d]pyridazine 
• 332013-42-0 ethyl 2-methylaminocarbonyl-4-picolinate 
• 1182334-19-5 2-methylaminocarbonyl-4-pyridylcarbinol hydrochloride 
• 332013-43-1 4-(hydroxymethyl)-N-methylpyridine-2-carboxamide 
• 332013-41-9 4-chloro-7-[N-(4-chlorophenyl)amino]-[2,3-d]furopyridazine 

Downstream Products

• 332013-26-0 4-[({4-[(4-chlorophenyl)amino]furan[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide methanesulfonate 
• 332013-24-8 4-[({4-[(4-chlorophenyl)amino]furo[2,3-d]pyridazin-7-yl}oxy)methyl]-N-methyl-2-pyridinecarboxamide 4-methylbenzenesulfonate 

Relevant articles and documents

Industrial production method tela for Nepal of methanesulfonic acid

The invention provides an industrial production method of telatinib mesylate. According to the method, 2-methylamino carbonyl-4-picolinic acid ethyl ester is used as a raw material, sodium borohydride is used as a reducing agent, or sodium borohydride and Lewis acid are selected for catalytic reduction, 2-methylamino carbonyl-4-pyridinemethanol is obtained after reduction in an organic solvent, an intermediate 2-methylamino carbonyl-4-pyridinemethanol hydrochloride monohydrate is obtained through salt formation, the 2-methylamino carbonyl-4-pyridinemethanol hydrochloride monohydrate and 4-chloro-anilino-7-chlorofuro[2,3-d]pyridazine have a condensation reaction under the action of potassium tert-butoxide to form telatinib free alkali, the telatinib free alkali reacts with methane sulfonic acid to form salt finally, and the telatinib mesylate is obtained through cooling and crystallization. The process operation is simple and safe, reaction conditions are mild, the obtained product is high in purity and meets the quality requirement, and the method is suitable for large-scale industrial production.

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