41526-21-0

Basic information

• Product Name: N-[4-Bromo-2-(2-pyridylcarbonyl)phenyl]-2-chloroacetamide
• Synonyms: N-[4-Bromo-2-(2-pyridylcarbonyl)phenyl]-2-chloroacetamide;2-(2-Chloroacetylamido)-5-bromobenzoyl)pyridine;2-(2-Chloroacetamido-5-Bromobenzoyl)Pyridine;N-(4-Bromo-2-picolinoylphenyl)-2-chloroacetamide
• CAS NO: 41526-21-0
• Molecular Formula: C₁₄H₁₀BrClN₂O₂
• Molecular Weight: 353.6
• EINECS: 255-427-7
• Product Categories: (intermediate of bromazepam)
• Mol File: 41526-21-0.mol
• Article Data: 2

Chemical Properties

• Melting Point: 131-132 °C(Solv: ethanol (64-17-5))
• Boiling Point: 574.3 °C at 760 mmHg
• Flash Point: 301.1 °C
• Appearance: /
• Density: 1.596 g/cm³
• Vapor Pressure: 3.41E-13mmHg at 25°C
• Refractive Index: 1.651
• Storage Temp.: Sealed in dry,Store in freezer, under -20°C
• Solubility: Chloroform (Slightly), Ethyl Acetate (Slightly)
• PKA: 11.28±0.70(Predicted)
• CAS DataBase Reference: N-[4-Bromo-2-(2-pyridylcarbonyl)phenyl]-2-chloroacetamide(CAS DataBase Reference)
• NIST Chemistry Reference: N-[4-Bromo-2-(2-pyridylcarbonyl)phenyl]-2-chloroacetamide(41526-21-0)
• EPA Substance Registry System: N-[4-Bromo-2-(2-pyridylcarbonyl)phenyl]-2-chloroacetamide(41526-21-0)

Safety Data

• Hazardous Substances Data: 41526-21-0(Hazardous Substances Data)

Usage

Uses

N-(4-Bromo-2-picolinoylphenyl)-2-chloroacetamide is a derivative of 2-(2-Amino-5-bromobenzoyl)pyridine (A601785); an intermediate in the preparation of Bromazepam (B678500).

InChI:InChI=1/C14H10BrClN2O2/c15-9-4-5-11(18-13(19)8-16)10(7-9)14(20)12-3-1-2-6-17-12/h1-7H,8H2,(H,18,19)

Synthetic route

2-amino-5-bromobenzoyl pyridine (1563-56-0) + chloroacetyl chloride (79-04-9) → N-(4-bromo-2-picolinoylphenyl)-2-chloroacetamide (41526-21-0)

Conditions	Yield
With sodium hydrogencarbonate In dichloromethane Inert atmosphere;	98.5%
With pyridine In dichloromethane at 20℃; for 0.5h;	94%

hexamethylenetetramine (100-97-0) + N-(4-bromo-2-picolinoylphenyl)-2-chloroacetamide (41526-21-0) → N,N'-methylenebis<3-(2'-o-pyridoyl-4-bromo)phenyl>-4-imidazolidinone (76895-76-6) + 4-oxo-3-(4-bromo-2-(2-pyridylcarbonyl)phenyl)imidazolidine (76895-81-3) + bromazepam (1812-30-2)

Conditions	Yield
With urotropin hydrochloride In methanol; water Heating;	A n/a B n/a C 80%
With hydrogenchloride In methanol; water for 7h; Heating;

N-(4-bromo-2-picolinoylphenyl)-2-chloroacetamide (41526-21-0) → N,N'-methylenebis<3-(2'-o-pyridoyl-4-bromo)phenyl>-4-imidazolidinone (76895-76-6) + 4-oxo-3-(4-bromo-2-(2-pyridylcarbonyl)phenyl)imidazolidine (76895-81-3) + bromazepam (1812-30-2)

Conditions	Yield
With hexamethylenetetramine; urotropin hydrochloride In methanol; water Heating; Yields of byproduct given;	A n/a B n/a C 80%
With hydrogenchloride; hexamethylenetetramine In methanol; water for 7h; Heating;	A n/a B n/a C 79%

N-(4-bromo-2-picolinoylphenyl)-2-chloroacetamide (41526-21-0) → bromazepam (1812-30-2)

Conditions	Yield
With hexamethylenetetramine; ammonium acetate In isopropyl alcohol for 4h; Inert atmosphere; Reflux;	75%

N-(4-bromo-2-picolinoylphenyl)-2-chloroacetamide (41526-21-0) → 2-acetamido-7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepine

Conditions	Yield
Multi-step reaction with 3 steps 1: 2N HCl / methanol; H2O / 7 h / Heating 2: NH4Cl / methanol; H2O / 17 h / Heating 3: pyridine / 24 h / 20 °C View Scheme

N-(4-bromo-2-picolinoylphenyl)-2-chloroacetamide (41526-21-0) → 2-amino-7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepine hydrochloride

Conditions	Yield
Multi-step reaction with 2 steps 1: 2N HCl / methanol; H2O / 7 h / Heating 2: NH4Cl / methanol; H2O / 17 h / Heating View Scheme

methanol (67-56-1) + N-(4-bromo-2-picolinoylphenyl)-2-chloroacetamide (41526-21-0) → C15H13BrN2O3

Conditions	Yield
Stage #1: N-(4-bromo-2-picolinoylphenyl)-2-chloroacetamide With hexamethylenetetramine; ammonium acetate In isopropyl alcohol for 4h; Inert atmosphere; Reflux; Stage #2: methanol Inert atmosphere;

ethanol (64-17-5) + N-(4-bromo-2-picolinoylphenyl)-2-chloroacetamide (41526-21-0) → C16H15BrN2O3

Conditions	Yield
Stage #1: N-(4-bromo-2-picolinoylphenyl)-2-chloroacetamide With hexamethylenetetramine; ammonium acetate In isopropyl alcohol for 4h; Inert atmosphere; Reflux; Stage #2: ethanol Inert atmosphere;

N-(4-bromo-2-picolinoylphenyl)-2-chloroacetamide (41526-21-0) → ethyl 6-(pyridin-2-yl)-8-((triisopropylsilyl)ethynyl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate

Conditions

Yield

Multi-step reaction with 4 steps 1.1: hexamethylenetetramine; ammonium acetate / isopropyl alcohol / 4 h / Inert atmosphere; Reflux 2.1: potassium tert-butylate / tetrahydrofuran / 1.5 h / -20 - -15 °C / Inert atmosphere 2.2: 2.25 h / -20 - -15 °C / Inert atmosphere 3.1: potassium tert-butylate / tetrahydrofuran / 12 h / -20 - -15 °C / Inert atmosphere 4.1: palladium diacetate; tris-(o-tolyl)phosphine; triethylamine / acetonitrile / 4 h / 75 °C / Inert atmosphere View Scheme

N-(4-bromo-2-picolinoylphenyl)-2-chloroacetamide (41526-21-0) → HZ-166 (612527-56-7)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: hexamethylenetetramine; ammonium acetate / isopropyl alcohol / 4 h / Inert atmosphere; Reflux 2.1: potassium tert-butylate / tetrahydrofuran / 1.5 h / -20 - -15 °C / Inert atmosphere 2.2: 2.25 h / -20 - -15 °C / Inert atmosphere 3.1: potassium tert-butylate / tetrahydrofuran / 12 h / -20 - -15 °C / Inert atmosphere 4.1: palladium diacetate; tris-(o-tolyl)phosphine; triethylamine / acetonitrile / 4 h / 75 °C / Inert atmosphere 5.1: tetrabutyl ammonium fluoride / tetrahydrofuran; water / -20 - 20 °C / Inert atmosphere; Cooling with ice View Scheme

N-(4-bromo-2-picolinoylphenyl)-2-chloroacetamide (41526-21-0) → ethyl 6-(pyridin-2-yl)-8-[(trimethylsilyl)ethynyl]-4H-benzo[f]imidazo[1,5a][1,4]diazepine-3-carboxylate (612527-54-5)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: hexamethylenetetramine; ammonium acetate / isopropyl alcohol / 4 h / Inert atmosphere; Reflux 2.1: potassium tert-butylate / tetrahydrofuran / 1.5 h / -20 - -15 °C / Inert atmosphere 2.2: 2.25 h / -20 - -15 °C / Inert atmosphere 3.1: potassium tert-butylate / tetrahydrofuran / 12 h / -20 - -15 °C / Inert atmosphere 4.1: palladium diacetate; tris-(o-tolyl)phosphine; triethylamine / acetonitrile / 6 h / Inert atmosphere; Reflux View Scheme

N-(4-bromo-2-picolinoylphenyl)-2-chloroacetamide (41526-21-0) → C18H19BrN3O4P

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hexamethylenetetramine; ammonium acetate / isopropyl alcohol / 4 h / Inert atmosphere; Reflux 2.1: potassium tert-butylate / tetrahydrofuran / 1.5 h / -20 - -15 °C / Inert atmosphere 2.2: 2.25 h / -20 - -15 °C / Inert atmosphere View Scheme

N-(4-bromo-2-picolinoylphenyl)-2-chloroacetamide (41526-21-0) → ethyl 8-bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate (69585-94-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hexamethylenetetramine; ammonium acetate / isopropyl alcohol / 4 h / Inert atmosphere; Reflux 2.1: potassium tert-butylate / tetrahydrofuran / 1.5 h / -20 - -15 °C / Inert atmosphere 2.2: 2.25 h / -20 - -15 °C / Inert atmosphere 3.1: potassium tert-butylate / tetrahydrofuran / 12 h / -20 - -15 °C / Inert atmosphere View Scheme

Upstream product

• 1563-56-0 2-amino-5-bromobenzoyl pyridine 
• 79-04-9 chloroacetyl chloride 

Downstream Products

• 76895-76-6 N,N'-methylenebis<3-(2'-o-pyridoyl-4-bromo)phenyl>-4-imidazolidinone 
• 76895-81-3 4-oxo-3-(4-bromo-2-(2-pyridylcarbonyl)phenyl)imidazolidine 
• 1812-30-2 bromazepam 

Relevant articles and documents

Imidazodiazepine anticonvulsant, KRM-II-81, produces novel, non-diazepam-like antiseizure effects

The need for improved medications for the treatment of epilepsy and chronic pain is essential. Epileptic patients typically take multiple antiseizure drugs without complete seizure freedom, and chronic pain is not fully managed with current medications. A positive allosteric modulator (PAM) of α2/3-containing GABAA receptors (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81 (8) is a lead compound in a series of imidazodiazepines. We previously reported that KRM-II-81 produces broad-based anticonvulsant and antinociceptive efficacy in rodent models and provides a wider margin over motoric side effects than that of other GABAA receptor PAMs. The present series of experiments was designed to fill key missing gaps in prior preclinical studies assessing whether KRM-II-81 could be further differentiated from nonselective GABAA receptor PAMs using the anticonvulsant diazepam (DZP) as a comparator. In multiple chemical seizure provocation models in mice, KRM-II-81 was either equally or more efficacious than DZP. Most strikingly, KRM-II-81 but not DZP blocked the development of seizure sensitivity to the chemoconvulsants cocaine and pentylenetetrazol in seizure kindling models. These and predecessor data have placed KRM-II-81 into consideration for clinical development requiring the manufacture of kilogram amounts of good manufacturing practice material. We describe here a novel synthetic route amenable to kilogram quantity production. The new biological and chemical data provide key steps forward in the development of KRM-II-81 (8) as an improved treatment option for patients suffering from epilepsy.