890707-28-5

Basic information

• Product Name: Bardoxolone
• Synonyms: 2-Amino-5-chloro-N,3-dimethylbenzamide;2-Amino-5-chloro-N,3-dimethylbenzamide 98%
• CAS NO: 890707-28-5
• Molecular Formula: C₉H₁₁ClN₂O
• Molecular Weight: 198.65
• EINECS: 1312995-182-4
• Mol File: 890707-28-5.mol
• Article Data: 27

Chemical Properties

• Melting Point: 130-132 °C
• Boiling Point: 308.8 °C at 760 mmHg
• Flash Point: 140.5 °C
• Appearance: /
• Density: 1.239
• Vapor Pressure: 0-0Pa at 20-25℃
• Storage Temp.: Keep in dark place,Sealed in dry,Room Temperature
• Solubility: Chloroform (Slightly), Ethyl Acetate (Slightly), Methanol (Slightly)
• PKA: 14.24±0.46(Predicted)
• CAS DataBase Reference: Bardoxolone(CAS DataBase Reference)
• NIST Chemistry Reference: Bardoxolone(890707-28-5)
• EPA Substance Registry System: Bardoxolone(890707-28-5)

Safety Data

• Hazardous Substances Data: 890707-28-5(Hazardous Substances Data)

Usage

Chemical Properties

Off-white powder

Uses

Bardoxolone is a synthetic oleanane triterpenoid that exerts multifunctional activities in the control of cellular growth and differentiation. Bardoxolone is capable of activating the transcription factor peroxisome proliferator activator receptor-γ (PPARγ), its apoptotic effects in malignant cells have been shown to occur independently of PPARγ. Bardoxolone was developed as an potential drug for the improvement of hyperglycemia, proteinuria, glomerulus structure, serum creatine, which may in turn be beneficial to treat diabetic kidney diseases, cancer and thromboembolic events.

Synthetic route

2-amino-3-methyl-5-chlorobenzoic acid methyl ester (79101-83-0) + methylamine (74-89-5) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
In methanol at 65 - 68℃; for 5h; Temperature;	98%
In methanol at 45℃; for 6h;	97.2%
In ethylene glycol; acetonitrile at 0 - 70℃; for 17.5 - 23h; Product distribution / selectivity;	84.8%

isopropyl 2-amino-5-chloro-3-methylbenzoate + methylamine (74-89-5) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
In isopropyl alcohol at 60℃; for 7h;	96.8%

2-amino-5-chloro-3-methylbenzoic acid ethyl ester + methylamine (74-89-5) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
In methanol at 50℃; for 6h;	95.4%

6-chloro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (120374-68-7) + methylamine (74-89-5) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
With acetic acid In ethyl acetate at 35 - 45℃; for 0.333333h;	95%
With acetic acid In ethyl acetate at 22 - 52℃; for 0.333333 - 2.75h; Product distribution / selectivity;	93%
With acetic acid In water; acetonitrile at 25 - 30℃; for 2.5h; Product distribution / selectivity;	87%

6-chloro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (120374-68-7) + methylamine hydrochloride (593-51-1) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
With potassium hydrogencarbonate In acetonitrile at 25 - 30℃; for 3h; Solvent; Reagent/catalyst; Temperature;	93.6%
Stage #1: methylamine hydrochloride With triethylamine In dichloromethane at 20℃; for 2h; Stage #2: 6-chloro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione With acetic acid In dichloromethane; ethyl acetate Reflux;
With potassium carbonate In ethanol at 25 - 80℃; for 5.5h; Reagent/catalyst; Temperature;

2-amino-5-chloro-3-methylbenzoic acid (20776-67-4) + methylamine (74-89-5) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
Stage #1: 2-amino-5-chloro-3-methylbenzoic acid With benzotriazol-1-ol; diisopropyl-carbodiimide In dichloromethane at 20℃; for 2h; Stage #2: methylamine In dichloromethane at 0℃; for 2h; Temperature;	92.6%
Stage #1: 2-amino-5-chloro-3-methylbenzoic acid With thionyl chloride for 3h; Reflux; Stage #2: methylamine In tetrahydrofuran; water at 20℃; Cooling with ice;	59.3%
Stage #1: 2-amino-5-chloro-3-methylbenzoic acid With thionyl chloride for 3h; Reflux; Stage #2: methylamine In tetrahydrofuran; water at 20℃; for 12h; Cooling with ice;	59.3%

6-chloro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (120374-68-7) + methylamine (74-89-5) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5) + 6-chloro-3,8-dimethyl-2,4(1H,3H)-quinazolinedione + 2-amino-5-chloro-3-methylbenzoic acid (20776-67-4)

Conditions	Yield
With water; acetic acid In ethyl acetate at 48 - 52℃; for 1h; Product distribution / selectivity;	A 87.3% B 3.4% C 1.7%

N-methyl-3-methyl-2-aminobenzamide (870997-57-2) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
With hydrogenchloride; dihydrogen peroxide; acetic acid at 5 - 20℃;	85%
Stage #1: N-methyl-3-methyl-2-aminobenzamide With hydrogenchloride In N,N-dimethyl-formamide at 10 - 30℃; Stage #2: With sodium sulfite In water; N,N-dimethyl-formamide at 30 - 35℃; for 3.25h; Stage #3: With sodium hydroxide; sodium sulfite In water; N,N-dimethyl-formamide at 10℃; for 0.25h; pH=2.2; Product distribution / selectivity;	72.7%
With N-chloro-succinimide In acetonitrile for 1h; Reflux;
With sulfuryl dichloride In dichloromethane at 0 - 30℃;
With thionyl chloride In acetonitrile at 40 - 50℃;

carbon monoxide (201230-82-2) + 2-bromo-4-chloro-6-methylphenylamine (146948-68-7) + methylamine (74-89-5) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
palladium diacetate; 1,4-di(diphenylphosphino)-butane In ethylene glycol at 25 - 110℃; under 2842.59 Torr; Inert atmosphere; Sealed tube;	70%

2-amino-5-chloro-3-methylbenzoyl chloride + methylamine (74-89-5) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
In dichloromethane
In dichloromethane

2-amino-5-chloro-3-methylbenzoic acid (20776-67-4) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: thionyl chloride / Reflux 2: dichloromethane View Scheme
Multi-step reaction with 2 steps 1: thionyl chloride / 3 h / Reflux 2: dichloromethane View Scheme
Multi-step reaction with 2 steps 1.1: 1,4-dioxane / 2 h / 50 °C 2.1: triethylamine / dichloromethane / 2 h / 20 °C 2.2: Reflux View Scheme

2-hydroxyethyl 2-amino-5-chloro-3-methylbenzoate (1391132-23-2) + 2-(dimethylamino)ethyl 2-amino-5-chloro-3-methylbenzoate (1391132-24-3) + methylamine (74-89-5) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
at 110℃; under 3876.26 Torr; for 6.06667h; Product distribution / selectivity; Sealed tube; Inert atmosphere;

3-methylantranilic acid (4389-45-1) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: N-chloro-succinimide / N,N-dimethyl-formamide / 0.67 h / 100 °C 2.1: thionyl chloride / 3 h / Reflux 2.2: 20 °C / Cooling with ice View Scheme
Multi-step reaction with 2 steps 1.1: N-chloro-succinimide / N,N-dimethyl-formamide / 0.67 h / 100 °C 2.1: thionyl chloride / 3 h / Reflux 2.2: 12 h / 20 °C / Cooling with ice View Scheme
Multi-step reaction with 2 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0.5 h / Cooling with ice 2: N-chloro-succinimide / acetonitrile / 1 h / Reflux View Scheme

o-toluidine (95-53-4) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: sodium sulfate / water / 40 °C 1.2: Reflux 2.1: sulfuric acid / 0.33 h / 80 °C 3.1: dihydrogen peroxide; sodium hydroxide / water / 0 - 50 °C 4.1: N-chloro-succinimide / N,N-dimethyl-formamide / 0.67 h / 100 °C 5.1: thionyl chloride / 3 h / Reflux 5.2: 20 °C / Cooling with ice View Scheme
Multi-step reaction with 5 steps 1.1: sodium sulfate / water / 40 °C 1.2: 0.17 h / Reflux 2.1: sulfuric acid / 60 - 80 °C 3.1: dihydrogen peroxide; sodium hydroxide / water / 0.5 h / 0 - 50 °C 3.2: pH 4 4.1: N-chloro-succinimide / N,N-dimethyl-formamide / 0.67 h / 100 °C 5.1: thionyl chloride / 3 h / Reflux 5.2: 12 h / 20 °C / Cooling with ice View Scheme
Multi-step reaction with 5 steps 1.1: sodium sulfate; hydrogenchloride; hydroxylamine hydrochloride / water / 0.17 h / Reflux 2.1: sulfuric acid / 0.83 h / 70 - 80 °C 3.1: dihydrogen peroxide; sodium hydroxide / water / 0.5 h / 0 - 50 °C 4.1: N-chloro-succinimide / N,N-dimethyl-formamide / 0.67 h / 100 °C 5.1: thionyl chloride / 3 h / Reflux 5.2: 12 h / 20 °C / Cooling with ice View Scheme

2-(hydroxyimino)-N-(2-methylphenyl)acetamide (1132-03-2) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sulfuric acid / 0.33 h / 80 °C 2.1: dihydrogen peroxide; sodium hydroxide / water / 0 - 50 °C 3.1: N-chloro-succinimide / N,N-dimethyl-formamide / 0.67 h / 100 °C 4.1: thionyl chloride / 3 h / Reflux 4.2: 20 °C / Cooling with ice View Scheme
Multi-step reaction with 4 steps 1.1: sulfuric acid / 60 - 80 °C 2.1: dihydrogen peroxide; sodium hydroxide / water / 0.5 h / 0 - 50 °C 2.2: pH 4 3.1: N-chloro-succinimide / N,N-dimethyl-formamide / 0.67 h / 100 °C 4.1: thionyl chloride / 3 h / Reflux 4.2: 12 h / 20 °C / Cooling with ice View Scheme
Multi-step reaction with 4 steps 1.1: sulfuric acid / 0.83 h / 70 - 80 °C 2.1: dihydrogen peroxide; sodium hydroxide / water / 0.5 h / 0 - 50 °C 3.1: N-chloro-succinimide / N,N-dimethyl-formamide / 0.67 h / 100 °C 4.1: thionyl chloride / 3 h / Reflux 4.2: 12 h / 20 °C / Cooling with ice View Scheme
Multi-step reaction with 3 steps 1.1: sulfuric acid / 1,2-dichloro-ethane / 12 h / 0 - 30 °C 2.1: acetic acid; dihydrogen peroxide / 0.25 h / 5 °C 2.2: 28.17 h / 5 - 20 °C 2.3: 3.75 h / 10 - 40 °C 3.1: acetic acid / ethyl acetate / 3.25 h / 0 - 25 °C / pH 9 - 10 View Scheme
Multi-step reaction with 3 steps 1.1: sulfuric acid / 1,2-dichloro-ethane / 12 h / 0 - 30 °C 2.1: acetic acid; dihydrogen peroxide / 0.25 h / 5 °C 2.2: 28.17 h / 5 - 20 °C 2.3: 3.75 h / 10 - 40 °C 3.1: potassium carbonate / ethanol / 5.5 h / 25 - 80 °C View Scheme

7-methyl-1H-indole-2,3-dione (1127-59-9) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: dihydrogen peroxide; sodium hydroxide / water / 0 - 50 °C 2.1: N-chloro-succinimide / N,N-dimethyl-formamide / 0.67 h / 100 °C 3.1: thionyl chloride / 3 h / Reflux 3.2: 20 °C / Cooling with ice View Scheme
Multi-step reaction with 3 steps 1.1: dihydrogen peroxide; sodium hydroxide / water / 0.5 h / 0 - 50 °C 1.2: pH 4 2.1: N-chloro-succinimide / N,N-dimethyl-formamide / 0.67 h / 100 °C 3.1: thionyl chloride / 3 h / Reflux 3.2: 12 h / 20 °C / Cooling with ice View Scheme
Multi-step reaction with 3 steps 1.1: dihydrogen peroxide; sodium hydroxide / water / 0.5 h / 0 - 50 °C 2.1: N-chloro-succinimide / N,N-dimethyl-formamide / 0.67 h / 100 °C 3.1: thionyl chloride / 3 h / Reflux 3.2: 12 h / 20 °C / Cooling with ice View Scheme
Multi-step reaction with 2 steps 1.1: acetic acid; dihydrogen peroxide / 0.25 h / 5 °C 1.2: 28.17 h / 5 - 20 °C 1.3: 3.75 h / 10 - 40 °C 2.1: acetic acid / ethyl acetate / 3.25 h / 0 - 25 °C / pH 9 - 10 View Scheme
Multi-step reaction with 3 steps 1: sulfuryl dichloride; acetic acid / 120 - 125 °C 2: sulfuric acid; acetic acid; dihydrogen peroxide / 60 - 65 °C 3: ethyl acetate / 20 °C View Scheme

benzoic acid (65-85-0) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: acetic acid; chlorine / 3 h / 30 - 40 °C / Inert atmosphere 2.1: 0.08 h 2.2: Grignard reagent / 1 h 3.1: sulfuric acid; nitric acid / 1 h / 0 - 40 °C 4.1: zinc; sodium hydroxide / 2 h / 70 °C 5.1: diisopropyl-carbodiimide; benzotriazol-1-ol / dichloromethane / 2 h / 20 °C 5.2: 2 h / 0 °C View Scheme

3,5-dichlorobenzoic acid (51-36-5) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 0.08 h 1.2: Grignard reagent / 1 h 2.1: sulfuric acid; nitric acid / 1 h / 0 - 40 °C 3.1: zinc; sodium hydroxide / 2 h / 70 °C 4.1: diisopropyl-carbodiimide; benzotriazol-1-ol / dichloromethane / 2 h / 20 °C 4.2: 2 h / 0 °C View Scheme

3-Chloro-5-Methylbenzoic Acid (56961-33-2) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sulfuric acid; nitric acid / 1 h / 0 - 40 °C 2.1: zinc; sodium hydroxide / 2 h / 70 °C 3.1: diisopropyl-carbodiimide; benzotriazol-1-ol / dichloromethane / 2 h / 20 °C 3.2: 2 h / 0 °C View Scheme

toluene (108-88-3) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: oxygen; cobalt(II) aceylacetonate; N-hydroxyphthalimide / dichloromethane / 1 h / 30 °C / 22502.3 Torr / Sealed tube 2.1: acetic acid; chlorine / 3 h / 30 - 40 °C / Inert atmosphere 3.1: 0.08 h 3.2: Grignard reagent / 1 h 4.1: sulfuric acid; nitric acid / 1 h / 0 - 40 °C 5.1: zinc; sodium hydroxide / 2 h / 70 °C 6.1: diisopropyl-carbodiimide; benzotriazol-1-ol / dichloromethane / 2 h / 20 °C 6.2: 2 h / 0 °C View Scheme

2-methyl-4,6-dichloroaniline (30273-00-8) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: copper bromide / N,N-dimethyl-formamide / 18 h / 90 - 95 °C 2: sodium hydroxide / 10 h / 70 - 75 °C 3: sulfuric acid / 16 h / Reflux 4: methanol / 5 h / 65 - 68 °C View Scheme

2-amino-5-chloro-3-methylbenzonitrile (939990-03-1) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide / 10 h / 70 - 75 °C 2: sulfuric acid / 16 h / Reflux 3: methanol / 5 h / 65 - 68 °C View Scheme

3-methyl-2-nitrobenzoic acid (5437-38-7) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: hydrogen / ethanol / 4 h / 50 °C / 1500.15 Torr 2: chlorine / 1,2-dichloro-ethane / 3 h / 50 °C 3: sulfuric acid / 6 h / 5 °C / Reflux 4: isopropyl alcohol / 7 h / 60 °C View Scheme
Multi-step reaction with 4 steps 1: hydrogen / ethanol / 4 h / 50 °C / 1500.15 Torr 2: chlorine / 1,2-dichloro-ethane / 3 h / 50 °C 3: sulfuric acid / 6 h / 5 °C / Reflux 4: methanol / 6 h / 50 °C View Scheme
Multi-step reaction with 4 steps 1: hydrogen / ethanol / 4 h / 50 °C / 1500.15 Torr 2: chlorine / 1,2-dichloro-ethane / 3 h / 50 °C 3: sulfuric acid / 8 h / 5 °C / Reflux 4: methanol / 6 h / 45 °C View Scheme
Multi-step reaction with 3 steps 1.1: thionyl chloride / toluene / 90 - 100 °C 1.2: 0 - 10 °C 2.1: palladium 10% on activated carbon; hydrogen / methanol 3.1: acetic acid; hydrogenchloride; dihydrogen peroxide / 5 - 20 °C View Scheme
Multi-step reaction with 4 steps 1: pyrographite; hydrazine hydrate; sodium hydroxide; iron(III) chloride hexahydrate / water / 70 °C 2: pyridine / acetonitrile / 4 h / 50 - 60 °C 3: acetic acid / water; acetonitrile / 1 h / Reflux 4: thionyl chloride / acetonitrile / 40 - 50 °C View Scheme

m-Toluic acid (99-04-7) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: nitric acid / -10 - -5 °C 2.1: thionyl chloride / toluene / 90 - 100 °C 2.2: 0 - 10 °C 3.1: palladium 10% on activated carbon; hydrogen / methanol 4.1: acetic acid; hydrogenchloride; dihydrogen peroxide / 5 - 20 °C View Scheme

N,3-dimethyl-2-nitrobenzamide (600126-70-3) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: palladium 10% on activated carbon; hydrogen / methanol 2: acetic acid; hydrogenchloride; dihydrogen peroxide / 5 - 20 °C View Scheme

6-methylisatoic anhydride (66176-17-8) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: acetic acid / water; acetonitrile / 1 h / Reflux 2: thionyl chloride / acetonitrile / 40 - 50 °C View Scheme

5-chloro-7-methyl-1H-indole-2,3-dione (14389-06-1) → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: sulfuric acid; acetic acid; dihydrogen peroxide / 60 - 65 °C 2: ethyl acetate / 20 °C View Scheme

(E)-2-(hydroxyimino)-N-(o-tolyl)acetamide → 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: sulfuric acid / 60 - 65 °C 2: sulfuryl dichloride; acetic acid; dihydrogen peroxide / 60 - 125 °C 3: ethyl acetate / 20 °C View Scheme
Multi-step reaction with 4 steps 1: sulfuric acid / 60 - 65 °C 2: sulfuryl dichloride; acetic acid / 120 - 125 °C 3: sulfuric acid; acetic acid; dihydrogen peroxide / 60 - 65 °C 4: ethyl acetate / 20 °C View Scheme

3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (500011-86-9) + 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5) → rynaxypyr (500008-45-7)

Conditions	Yield
With 3-Methylpyridine; methanesulfonyl chloride In propiononitrile at -5 - 20℃; for 4h; Product distribution / selectivity;	97%
With 3-Methylpyridine; methanesulfonyl chloride In acetone at -5 - 5℃; for 3h; Product distribution / selectivity;	96.4%
With pyridine; methanesulfonyl chloride In acetonitrile at -5 - 20℃; for 4h; Product distribution / selectivity;	96.8%

2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5) + C9H6Br2ClN3O2 → C18H15Br2Cl2N5O2

Conditions	Yield
With pyridine; methanesulfonyl chloride In acetonitrile at -5℃; for 2.16h;	95.6%

2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5) + acetone (67-64-1) → 6-chloro-2,2,3,8-tetramethyl-2,3-dihydroquinazolin-4(1H)-one (1488427-93-5)

Conditions	Yield
With toluene-4-sulfonic acid for 1h; Reflux;	95%

furfural (98-01-1) + 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5) → 6-chloro-2-(furan-2-yl)-3,8-dimethyl-2,3-dihydroquinazolin-4(1H)-one (1542270-67-6)

Conditions	Yield
With β-cyclodextrine-SO3H In water at 50℃; for 0.416667h; Green chemistry;	94%

2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5) + 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxaldehyde (1072138-63-6) → C18H14BrCl2N5O (1351217-99-6)

Conditions	Yield
With toluene-4-sulfonic acid In toluene for 1h; Reflux;	92%

2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5) + 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride (943982-60-3) → rynaxypyr (500008-45-7)

Conditions	Yield
Stage #1: 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine With 3-Methylpyridine In acetonitrile at 25 - 35℃; Stage #2: 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride In acetonitrile at 25 - 35℃; Solvent; Temperature;	91.1%
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 12h; Cooling with ice;	89.3%
Stage #1: 2-amino-3-methyl-5-chlorobenzoyl-N-methylamine; 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl chloride In acetonitrile at 20℃; for 1.16667h; Reflux; Stage #2: With sodium hydrogencarbonate In acetonitrile Product distribution / selectivity;

2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5) + cyclohexanone (108-94-1) → 6'-chloro-3',8'-dimethyl-1'H-spiro[cyclohexane-1,2'-quinazolin]-4'(3'H)-one (1542270-66-5)

Conditions	Yield
With β-cyclodextrine-SO3H In water at 50℃; for 0.416667h; Green chemistry;	90%

2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5) + 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carbonyl chloride → rynaxypyr (500008-45-7)

Conditions	Yield
In acetonitrile at 20℃; for 3.16667h; Reflux;	84%

2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5) + dicyanozinc (557-21-1) → 2-amino-3-methyl-5-cyanobenzoyl-N-methylamine

Conditions	Yield
With zinc; bis(tri-tert-butylphosphine)palladium(0) In 1,4-dioxane for 11h; Product distribution / selectivity; Heating / reflux;	83%

2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5) + potassium cyanide (151-50-8) → 2-amino-3-methyl-5-cyanobenzoyl-N-methylamine

Conditions	Yield
chloro(1-naphthyl)bis(triphenylphosphine)nickel(II); chloro(2-naphthalenyl)bis(triphenylphosphine)nickel In ethanol; xylene at 45℃; Product distribution / selectivity;	82.5%
With zinc; bis(tri-tert-butylphosphine)palladium(0); 18-crown-6 ether In 1,4-dioxane for 24h; Product distribution / selectivity; Heating / reflux;	65%

2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5) + C9H6ClN3O (1450664-91-1) → 6-chloro-2-(3-chloro-1-(pyridin-2-yl)-1H-pyrazol-5-yl)-3-cyclopropyl-8-methyl-2,3-dihydroquinazolin-4(1H)-one (1450664-92-2)

Conditions	Yield
With toluene-4-sulfonic acid In toluene for 1h; Reflux;	82%

2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5) + 1-(3,5-dichloropyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride → C19H13Cl3F3N5O2 (1104384-03-3)

Conditions	Yield
With triethylamine In dichloromethane at 20℃; for 3h;	81%

2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5) + 1-(3,5-dichloropyridin-2-yl)-3-(prop-2-ynyloxy)-1H-pyrazole-5-carbonyl chloride (1104384-31-7) → C21H16Cl3N5O3 (1104384-07-7)

Conditions	Yield
With triethylamine In dichloromethane at 20℃; for 3h;	81%

2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5) + C8H3Cl3N4O → N-(2-(methylcarbamoyl)-4-chloro-6-methylphenyl)-3-chloro-1-(6-chloropyrazin-2-yl)-1H-pyrazole-5-carboxamide

Conditions	Yield
With triethylamine In acetonitrile	76%

2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5) + 1-(6-chloropyrazin-2-yl)-3-bromo-1H-pyrazole-5-carbonyl chloride → N-(2-(methylcarbamoyl)-4-chloro-6-methylphenyl)-3-bromo-1-(6-chloropyrazin-2-yl)-1H-pyrazole-5-carboxamide

Conditions	Yield
With triethylamine In acetonitrile	75%

2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5) + C12H7Cl2F2N3O2 → N5-(4-chloro-2-methyl-6-(methylcarbamoyl)phenyl)-1-(2-chloro-4,5-difluorophenyl)-N3-methyl-1H-pyrazole-3,5-dicarboxamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 12h;	75%

2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5) + C12H7Cl2F3N2O2 → N-(4-chloro-2-methyl-6-(methylcarbamoyl)phenyl)-1-(2-chloro-5-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃;	73.5%

2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5) + chloroacetyl chloride (79-04-9) → 5-chloro-2-(2-chloroacetamido)-N,3-dimethylbenzamide (1374598-54-5)

Conditions	Yield
With triethylamine In dichloromethane at 20℃; for 3.6h;	73%

2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5) + C10H3BrCl2F2N2O → 3-bromo-N-(4-chloro-2-methyl-6-(methylcarbamoyl)phenyl)-1-(2-chloro-4,5-difluorophenyl)-1H-pyrazole-5-carboxamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 12h;	73%

2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5) + 1-(pyrazin-2-yl)-3-bromo-1H-pyrazole-5-formyl chloride → N-(2-(methylcarbamoyl)-4-chloro-6-methylphenyl)-3-bromo-1-(pyrazin-2-yl)-1H-pyrazole-5-carboxamide

Conditions	Yield
With triethylamine In acetonitrile	72%

2-amino-3-methyl-5-chlorobenzoyl-N-methylamine (890707-28-5) + C9H6Cl2N4O2 → N-(2-(methylcarbamoyl)-4-chloro-6-methylphenyl)-3-methoxyl-1-(6-chloropyrazin-2-yl)-1H-pyrazole-5-carboxamide

Conditions	Yield
With triethylamine In acetonitrile	71%

Upstream product

• 120374-68-7 6-chloro-8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione 
• 74-89-5 methylamine 
• 79101-83-0 2-amino-3-methyl-5-chlorobenzoic acid methyl ester 
• 65-85-0 benzoic acid 
• 51-36-5 3,5-dichlorobenzoic acid 
• 56961-33-2 3-Chloro-5-Methylbenzoic Acid 
• 108-88-3 toluene 
• 99-04-7 m-Toluic acid 
• 600126-70-3 N-3-dimethyl-2-nitrobenzamide 
• 95-69-2 4-chloro-2-methylbenzeneamine 
• 88-72-2 1-methyl-2-nitrobenzene 
• 201230-82-2 carbon monoxide 
• 30273-00-8 2-methyl-4,6-dichloroaniline 
• 14389-06-1 5-chloro-7-methyl-1H-indole-2,3-dione 

Downstream Products

• 890707-29-6 2-amino-3-methyl-5-cyanobenzoyl-N-methylamine 
• 500007-35-2 C₁₉H₁₄Cl₂N₆O₂ 
• 1527508-09-3 N-(4-chloro-2-methyl-6-(methylcarbamoyl)phenyl)-1-(2-chloro-6-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide 
• 1374598-54-5 5-chloro-2-(2-chloroacetamido)-N,3-dimethylbenzamide 
• 1257069-77-4 C₂₁H₁₉Cl₂N₅O₄ 
• 1257069-74-1 C₂₃H₂₄Cl₂N₆O₃ 
• 1257069-71-8 C₂₅H₂₆Cl₂N₆O₃ 
• 1257069-68-3 C₂₅H₂₀Cl₂N₆O₃ 
• 1257069-65-0 C₂₃H₂₄Cl₂N₆O₃ 
• 1257069-63-8 C₂₂H₂₂Cl₂N₆O₃ 
• 1257069-61-6 C₂₆H₂₂Cl₂N₆O₃ 
• 1257069-49-0 C₂₀H₁₈Cl₂N₆O₃ 
• 1257069-48-9 C₂₅H₂₅Cl₂N₅O₄ 
• 1257069-46-7 C₂₆H₂₁Cl₂N₅O₄ 

Relevant articles and documents

A PROCESS FOR THE SYNTHESIS OF ANTHRANILIC ACID/AMIDE COMPOUNDS AND INTERMEDIATES THEREOF

The present invention disclosed a process for the synthesis of compound of formula (Z) or a salt thereof, wherein, R, R1, R2, R3 and R10 are as defined in the detailed description. The process further comprises the synthesis of an anthranilic diamide compound of formula (I).

Synthetic method of chlorantraniliprole pesticide intermediate 2 - amino -5 - chlorine - N and 3 -dimethylbenzamide

The invention relates to a synthetic method of a chlorantraniliprole pesticide intermediate 2 - amino -5 - chlorine - N and 3 -dimethylbenzamide. Chloro, formylation gave 2 - amino -5 - chloro - N, 3 - dimethyl. The method has the advantages of simple reaction, low cost and high yield, and is a method suitable for industrial production.

PROCESS FOR THE PREPARATION OF CHLORANTRANILIPROLE

The present invention relates to two novel, efficient and one-pot methods for synthesizing chlorantraniliprole. In the first scheme, Chlorantraniliprole is prepared by a novel telescopic process starting from 3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid a key raw material-A (Key RM-A). In the second scheme, starting from Key RM-A, the process steps use of a novel variant of anthranilic acid (Methyl 2-amino-5-chloro-3-methylbenzoate), to get Chlorantraniliprole. Furthermore, the present invention also relates to the synthesis of key starting material for the synthesizing chlorantraniliprole in-situ. All the in-situ steps of the disclosed synthesis methods obtain good yield, without using any expensive reagent or base or harsh reaction conditions, which makes the process simple, environment friendly and more cost effective. With this process the production cost of chlorantraniliprole and its intermediates is substantially reduced; fewer by-products are formed during its synthesis and since it's a one-pot reaction, isolation and purification are easy to achieve.