130641-38-2

Basic information

• Product Name: Bindarit
• Synonyms: Bindarit;Propanoic acid, 2-Methyl-2-[[1-(phenylMethyl)-1H-indazol-3-yl]Methoxy]-;2-[(1-Benzyl-1H-indazol-3-yl)methoxy]-2-methylpropionic acid;AF 2838;2-((1-Benzyl-1H-indazol-3-yl)Methoxy)-2-Methylpropanoic acid
• CAS NO: 130641-38-2
• Molecular Formula: C₁₉H₂₀N₂O₃
• Molecular Weight: 324.378
• Product Categories: Aromatics;Heterocycles;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 130641-38-2.mol
• Article Data: 4

Chemical Properties

• Boiling Point: 542.869 °C at 760 mmHg
• Flash Point: 282.117 °C
• Appearance: /
• Density: 1.18±0.1 g/cm3 (20 ºC 760 Torr)
• Vapor Pressure: 1.28E-12mmHg at 25°C
• Refractive Index: 1.594
• Storage Temp.: 2-8°C
• PKA: 3.59±0.10(Predicted)
• CAS DataBase Reference: Bindarit(CAS DataBase Reference)
• NIST Chemistry Reference: Bindarit(130641-38-2)
• EPA Substance Registry System: Bindarit(130641-38-2)

Safety Data

• Hazardous Substances Data: 130641-38-2(Hazardous Substances Data)

Usage

Description

Bindarit is an inhibitor of monocyte chemoattractant protein (MCP) production that is selective for MCP-1/CCL2, MPC-3/CCL7, and MCP-2/CCL8 over other chemokines. It inhibits LPS- or C. albicans-induced production of MCP-1/CCL2 in isolated human monocytes (IC50s = 172 and 403 μM, respectively). Bindarit downregulates NF-κB signaling and prevents p65 and p65/p50-mediated MCP-1/CCL2 promoter activation in RAW264.7 cells. It delays the onset of proteinuria and prolongs survival in a mouse model of experimental lupus nephritis when administered at a dose of 50 mg/kg. It prevents LPS-induced increases in MCP-1/CCL2 expression in mouse brain and spinal cord when administered at a dose of 200 mg/kg and reduces the incidence and severity of experimental autoimmune encephalomyelitis (EAE) in mice. Bindarit is also a noncompetitive inhibitor of monocarboxylate transporter 4 (MCT4; Ki = 30.2 μM for the human transporter) that is selective for MCT4 over MCT1.

Uses

Different sources of media describe the Uses of 130641-38-2 differently. You can refer to the following data:
1. Bindarit shows anti-inflammatory activity due to a selective inhibition of a subfamily of inflammatory chemokines. Bindarit is a also protein antidenaturant agent. Bindarit modulates the NFkB pathway and has been shown to reduce secondary phase of adjuvant arthritis in rats.
2. Bindarit exhibits selective inhibition against monocyte chemotactic proteins MCP-1/CCL2, MCP-3/CCL7 and MCP-2/CCL8.

InChI:InChI=1/C19H20N2O3/c1-19(2,18(22)23)24-13-16-15-10-6-7-11-17(15)21(20-16)12-14-8-4-3-5-9-14/h3-11H,12-13H2,1-2H3,(H,22,23)

Synthetic route

1-benzyl-3-chloromethyl-1H-indazole + ethyl 2-hydroxy-2,2-dimethylethanoate (80-55-7) → 2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2)

Conditions	Yield
Stage #1: ethyl 2-hydroxy-2,2-dimethylethanoate With sodium hexamethyldisilazane In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 5℃; for 1.5h; Inert atmosphere; Stage #2: 1-benzyl-3-chloromethyl-1H-indazole With tetra-(n-butyl)ammonium iodide In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 25℃; for 10h; Inert atmosphere;	88.7%

benzyl bromide (100-39-0) → 2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: potassium tert-butylate / toluene / 0.5 h / 20 °C / Inert atmosphere 1.2: 4.5 h / 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 7 h / -10 °C / Inert atmosphere 2.2: 0 °C 3.1: hydrogenchloride / toluene; water / 2 h / 90 °C 4.1: sodium hydride / N,N-dimethyl-formamide; toluene / 1.5 h / Inert atmosphere 4.2: 10 h / 90 °C 5.1: sodium hydroxide / 3 h / Reflux View Scheme
Multi-step reaction with 5 steps 1.1: potassium tert-butylate / toluene / 0.5 h / 20 °C / Inert atmosphere 1.2: 4.5 h / 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 7 h / -10 °C / Inert atmosphere 2.2: 2 h / 0 °C 3.1: hydrogenchloride / toluene; water / 2 h / 90 °C 4.1: sodium hydride / toluene; mineral oil / 1.5 h / Inert atmosphere 4.2: 10 h / 90 °C 5.1: sodium hydroxide / 3 h / Reflux View Scheme

3-bromo-1H-indazole (40598-94-5) → 2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: potassium tert-butylate / toluene / 0.5 h / 20 °C / Inert atmosphere 1.2: 4.5 h / 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 7 h / -10 °C / Inert atmosphere 2.2: 0 °C 3.1: hydrogenchloride / toluene; water / 2 h / 90 °C 4.1: sodium hydride / N,N-dimethyl-formamide; toluene / 1.5 h / Inert atmosphere 4.2: 10 h / 90 °C 5.1: sodium hydroxide / 3 h / Reflux View Scheme
Multi-step reaction with 5 steps 1.1: potassium tert-butylate / toluene / 0.5 h / 20 °C / Inert atmosphere 1.2: 4.5 h / 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 7 h / -10 °C / Inert atmosphere 2.2: 2 h / 0 °C 3.1: hydrogenchloride / toluene; water / 2 h / 90 °C 4.1: sodium hydride / toluene; mineral oil / 1.5 h / Inert atmosphere 4.2: 10 h / 90 °C 5.1: sodium hydroxide / 3 h / Reflux View Scheme

(1-Benzyl-1H-indazol-3-yl)-methanol (131427-21-9) → 2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride / toluene; water / 2 h / 90 °C 2.1: sodium hydride / N,N-dimethyl-formamide; toluene / 1.5 h / Inert atmosphere 2.2: 10 h / 90 °C 3.1: sodium hydroxide / 3 h / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: hydrogenchloride / toluene; water / 2 h / 90 °C 2.1: sodium hydride / toluene; mineral oil / 1.5 h / Inert atmosphere 2.2: 10 h / 90 °C 3.1: sodium hydroxide / 3 h / Reflux View Scheme

1-benzyl-3-chloromethyl-1H-indazole → 2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide; toluene / 1.5 h / Inert atmosphere 1.2: 10 h / 90 °C 2.1: sodium hydroxide / 3 h / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydride / toluene; mineral oil / 1.5 h / Inert atmosphere 1.2: 10 h / 90 °C 2.1: sodium hydroxide / 3 h / Reflux View Scheme

N-benzyl-3-iodo-1H-indazole (205643-28-3) → 2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: isopropylmagnesium chloride / 2-methyltetrahydrofuran / 2 h / -10 °C / Inert atmosphere 1.2: 2 h / 0 °C 2.1: hydrogenchloride / toluene; water / 2 h / 90 °C 3.1: sodium hydride / N,N-dimethyl-formamide; toluene / 1.5 h / Inert atmosphere 3.2: 10 h / 90 °C 4.1: sodium hydroxide / 3 h / Reflux View Scheme
Multi-step reaction with 5 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 2 h / -10 °C / Inert atmosphere 1.2: 0 °C 2.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 0.25 h / 20 °C / Inert atmosphere 3.1: hydrogenchloride / toluene; water / 2 h / 90 °C 4.1: sodium hydride / N,N-dimethyl-formamide; toluene / 1.5 h / Inert atmosphere 4.2: 10 h / 90 °C 5.1: sodium hydroxide / 3 h / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: isopropylmagnesium chloride / 2-methyltetrahydrofuran / 2 h / -10 °C / Inert atmosphere 1.2: 2 h / 0 °C 2.1: hydrogenchloride / toluene; water / 2 h / 90 °C 3.1: sodium hydride / toluene; mineral oil / 1.5 h / Inert atmosphere 3.2: 10 h / 90 °C 4.1: sodium hydroxide / 3 h / Reflux View Scheme
Multi-step reaction with 5 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 2 h / -10 °C / Inert atmosphere 1.2: 0 °C 2.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 0.25 h / 20 °C / Inert atmosphere 3.1: hydrogenchloride / toluene; water / 2 h / 90 °C 4.1: sodium hydride / toluene; mineral oil / 1.5 h / Inert atmosphere 4.2: 10 h / 90 °C 5.1: sodium hydroxide / 3 h / Reflux View Scheme

1-benzyl-1H-indazole-3-carbaldehyde (1186509-61-4) → 2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 0.25 h / 20 °C / Inert atmosphere 2.1: hydrogenchloride / toluene; water / 2 h / 90 °C 3.1: sodium hydride / N,N-dimethyl-formamide; toluene / 1.5 h / Inert atmosphere 3.2: 10 h / 90 °C 4.1: sodium hydroxide / 3 h / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 0.25 h / 20 °C / Inert atmosphere 2.1: hydrogenchloride / toluene; water / 2 h / 90 °C 3.1: sodium hydride / toluene; mineral oil / 1.5 h / Inert atmosphere 3.2: 10 h / 90 °C 4.1: sodium hydroxide / 3 h / Reflux View Scheme

C21H24N2O3 → 2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2)

Conditions	Yield
Stage #1: C21H24N2O3 With sodium hydroxide for 3h; Reflux; Stage #2: With hydrogenchloride In water
Stage #1: C21H24N2O3 With sodium hydroxide for 3h; Reflux; Stage #2: With hydrogenchloride In water

1-benzyl-3-bromoindazole (29985-03-3) → 2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 7 h / -10 °C / Inert atmosphere 1.2: 0 °C 2.1: hydrogenchloride / toluene; water / 2 h / 90 °C 3.1: sodium hydride / N,N-dimethyl-formamide; toluene / 1.5 h / Inert atmosphere 3.2: 10 h / 90 °C 4.1: sodium hydroxide / 3 h / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 7 h / -10 °C / Inert atmosphere 1.2: 2 h / 0 °C 2.1: hydrogenchloride / toluene; water / 2 h / 90 °C 3.1: sodium hydride / toluene; mineral oil / 1.5 h / Inert atmosphere 3.2: 10 h / 90 °C 4.1: sodium hydroxide / 3 h / Reflux View Scheme

morpholine (110-91-8) + 2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2) → 1-benzyl-3-[(1,1-dimethyl-2-morpholin-4-yl-2-oxyethoxy)methyl]-1H-indazole (1186580-36-8)

Conditions	Yield
Stage #1: 2-((1-benzylindazol-3-yl)methoxy)-2-methyl propionic acid With sodium methylate In methanol at 20℃; for 0.166667h; Stage #2: morpholine With thionyl chloride In toluene at 20℃;

2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2) → 2-[(1-benzyl-1H-indazol-3-yl)methoxy]-2-methylpropan-1-ol (1186507-73-2)

Conditions	Yield
Stage #1: 2-((1-benzylindazol-3-yl)methoxy)-2-methyl propionic acid With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether at 20℃; Stage #2: With water; sodium hydroxide In tetrahydrofuran; diethyl ether

2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2) → 2-[(1-benzyl-5-chloro-1H-indazol-3-yl)methoxy]-2-methylpropanoic acid (1186507-48-1)

Conditions	Yield
With chlorine; acetic acid at 20℃;

2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2) → 2-[(1-benzyl-5-bromo-1H-indazol-3-yl)methoxy]-2-methylpropanoic acid (1186507-66-3)

Conditions	Yield
With bromine; acetic acid at 10 - 20℃;

2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2) → 1-benzyl-3-[(1,1-dimethyl-2-morpholin-4-ylethoxy)methyl]-1H-indazole. (1186610-50-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium methylate / methanol / 0.17 h / 20 °C 1.2: 20 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran; diethyl ether / 20 °C / Reflux View Scheme

2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2) → 1-benzyl-3-[(1,1-dimethyl-2-morpholin-4-ylethoxy)methyl]-1H-indazole maleate

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium methylate / methanol / 0.17 h / 20 °C 1.2: 20 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran; diethyl ether / 20 °C / Reflux 3.1: ethanol / 20 °C View Scheme

Upstream product

• 131427-22-0 1-benzyl-3-chloromethyl-1H-indazole 
• 80-55-7 ethyl 2-hydroxy-2,2-dimethylethanoate 
• 29985-03-3 1-benzyl-3-bromoindazole 
• 1186509-61-4 1-benzyl-1H-indazole-3-carbaldehyde 
• 205643-28-3 N-benzyl-3-iodo-1H-indazole 
• 131427-21-9 (1-Benzyl-1H-indazol-3-yl)-methanol 
• 40598-94-5 3-bromo-1H-indazole 
• 100-39-0 benzyl bromide 

Downstream Products

• 1186610-50-3 1-benzyl-3-[(1,1-dimethyl-2-morpholin-4-ylethoxy)methyl]-1H-indazole. 
• 1186507-66-3 2-[(1-benzyl-5-bromo-1H-indazol-3-yl)methoxy]-2-methylpropanoic acid 
• 1186507-48-1 2-[(1-benzyl-5-chloro-1H-indazol-3-yl)methoxy]-2-methylpropanoic acid 
• 1186507-73-2 2-[(1-benzyl-1H-indazol-3-yl)methoxy]-2-methylpropan-1-ol 
• 1186580-36-8 1-benzyl-3-[(1,1-dimethyl-2-morpholin-4-yl-2-oxyethoxy)methyl]-1H-indazole 

Relevant articles and documents

PROCESSES OF MAKING 2-((1-BENZYL-1H-INDAZOL-3-YL)METHOXY)-2-METHYLPROPANOIC ACID AND ITS DERIVATIVES

The invention in this disclosure is related to the processes of making Bindarit or derivatives thereof. Specifically, the present invention provides, in part, new processes for making 2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid and its derivatives. By way of non-limiting example, synthesis and purification processes of 2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid are provided by the invention in this disclosure.

PROCESS FOR THE PREPARATION OF 1-BENZYL-3-HYDROXYMETHYL- 1H- INDAZOLE AND ITS DERIVATIVES AND REQUIRED MAGNESIUM INTERMEDIATES

The present invention relates to the process for the conversion of 1-benzyl-3-hydroxymethyl-1H-indazole according to formula (II), to the 1-benzyl-3-hydroxymethyl-1H-indazole according to formula (I).