6021-21-2

Basic information

• Product Name: N-(2-benzoyl-4-chlorophenyl)-2-chloro-N-methylacetamide
• Synonyms: 2-chloro-N-[4-chloro-2-(oxo-phenylmethyl)phenyl]-N-methylacetamide;N-(2-benzoyl-4-chlorophenyl)-2-chloro-N-methylacetamide;Einecs 227-875-3;5-Chloro-2-(2-chloro-N-methylacetamido)benzophenone;N-Methyl-2'-benzoyl-2,4'-dichloroacetanilide;2-N-MethylchloroacetilaMido-5-chlorobenzophenone;DiazepaM IMpurity B;2-chloro-N-(4-chloro-2-phenylcarbonyl-phenyl)-N-methyl-ethanamide
• CAS NO: 6021-21-2
• Molecular Formula: C₁₆H₁₃Cl₂NO₂
• Molecular Weight: 322.18592
• EINECS: 227-875-3
• Mol File: 6021-21-2.mol
• Article Data: 5

Chemical Properties

• Melting Point: 122-124℃
• Boiling Point: 509.3 °C at 760 mmHg
• Flash Point: 261.8 °C
• Appearance: /
• Density: 1.328
• Vapor Pressure: 1.72E-10mmHg at 25°C
• Refractive Index: 1.616
• Storage Temp.: -20°C Freezer, Under inert atmosphere
• Solubility: Chloroform (Slightly), DMSO (Slightly), Ethanol (Slightly, Sonicated), Methanol
• PKA: -2.06±0.50(Predicted)
• CAS DataBase Reference: N-(2-benzoyl-4-chlorophenyl)-2-chloro-N-methylacetamide(CAS DataBase Reference)
• NIST Chemistry Reference: N-(2-benzoyl-4-chlorophenyl)-2-chloro-N-methylacetamide(6021-21-2)
• EPA Substance Registry System: N-(2-benzoyl-4-chlorophenyl)-2-chloro-N-methylacetamide(6021-21-2)

Safety Data

• Hazardous Substances Data: 6021-21-2(Hazardous Substances Data)

Usage

Description

N-(2-Benzoyl-4-chlorophenyl)-2-chloro-N-methylacetamide, also known as Diazepam EP Impurity B, is a chemical compound derived from Diazepam, a well-known sedative and hypnotic drug. It is characterized by its benzoyl and chlorophenyl groups, which contribute to its pharmacological properties.

Uses

Used in Pharmaceutical Industry:
N-(2-Benzoyl-4-chlorophenyl)-2-chloro-N-methylacetamide is used as an impurity in the production of Temazepam (T017200), a pharmacologically active metabolite of Diazepam. It plays a role in the sedative and hypnotic effects of the drug, contributing to its use in treating anxiety, insomnia, and other related conditions.
As an impurity, it is essential to monitor and control the levels of Diazepam EP Impurity B in the final product to ensure the safety and efficacy of the medication. The presence of this impurity can affect the overall quality and performance of the drug, making it a critical component in the pharmaceutical manufacturing process.

InChI:InChI=1/C16H13Cl2NO2/c1-19(15(20)10-17)14-8-7-12(18)9-13(14)16(21)11-5-3-2-4-6-11/h2-9H,10H2,1H3

Synthetic route

chloroacetyl chloride (79-04-9) + 5-chloro-2-(methylamino)benzophenone (1022-13-5) → 2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2)

Conditions	Yield
In 2-methyltetrahydrofuran; dichloromethane at 90℃; under 5171.62 Torr; Temperature; Flow reactor;	99%
at 25℃; for 5h; Inert atmosphere;	94.5%
With sodium hydrogencarbonate In toluene at 40℃; for 2h;	92%
In toluene Solvent;
In acetonitrile Mechanism; Solvent;

2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → diazepam (439-14-5)

Conditions	Yield
With hexamethylenetetramine; ammonia; nitric acid In methanol; water; toluene	96.09%
With hexamethylenetetramine; urotropin hydrochloride In ethanol Heating;	90%
With hexamethylenetetramine; ammonia In methanol at 60℃; for 6h;	58.4%

pyridine (110-86-1) + 2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → 1-(6-Chloro-1-methyl-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl)-pyridinium; chloride (80356-39-4)

Conditions	Yield
	94%

2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → 6-chloro-3,4-epoxy-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenylquinoline (37393-81-0) + 6-chloro-1,2-dihydro-3-hydroxy-1-methyl-2-oxo-4-phenylquinoline (37393-79-6) + 3-amino-6-chloro-1,2-dihydro-1-methyl-2-oxo-4-phenylquinoline (5220-02-0) + 3,6-dichloro-1,2-dihydro-1-methyl-2-oxo-4-phenylquinoline + 6-Chloro-3-methyl-7b-phenyl-1,1a,3,7b-tetrahydro-1,3-diaza-cyclopropa[a]naphthalen-2-one + diazepam (439-14-5)

Conditions	Yield
With ammonia In ethanol at 80℃; for 2h; Mechanism; further reagent;	A n/a B n/a C n/a D n/a E n/a F 65%

2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → 6-chloro-1,2-dihydro-3-hydroxy-1-methyl-2-oxo-4-phenylquinoline (37393-79-6) + 3-amino-6-chloro-1,2-dihydro-1-methyl-2-oxo-4-phenylquinoline (5220-02-0) + 3,6-dichloro-1,2-dihydro-1-methyl-2-oxo-4-phenylquinoline + diazepam (439-14-5)

Conditions	Yield
With ammonia In ethanol at 80℃; for 2h; Further byproducts given;	A n/a B n/a C n/a D 65%

2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → 6-chloro-3,4-epoxy-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenylquinoline (37393-81-0) + 3,6-dichloro-1,2-dihydro-1-methyl-2-oxo-4-phenylquinoline

Conditions	Yield
With sodium hydrogencarbonate In ethanol at 60℃; for 48h;	A n/a B 5.3%

3-ethylamino propionitrile (21539-47-9) + 2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → N-(2-Benzoyl-4-chloro-phenyl)-2-[(2-cyano-ethyl)-ethyl-amino]-N-methyl-acetamide

Conditions	Yield
In 1,4-dioxane

3-(butylamino)propanenitrile (693-51-6) + 2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → N-(2-Benzoyl-4-chloro-phenyl)-2-[butyl-(2-cyano-ethyl)-amino]-N-methyl-acetamide (59049-46-6)

Conditions	Yield
In 1,4-dioxane

N-sec-butyl-β-alanine nitrile (21539-52-6) + 2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → N-(2-Benzoyl-4-chloro-phenyl)-2-[sec-butyl-(2-cyano-ethyl)-amino]-N-methyl-acetamide

Conditions	Yield
In 1,4-dioxane

2-aminoacetonitrile (540-61-4) + 2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → N-(2-Benzoyl-4-chloro-phenyl)-2-(cyanomethyl-amino)-N-methyl-acetamide (59049-39-7)

Conditions	Yield
In 1,4-dioxane

2-cyanoethylamine (151-18-8) + 2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → N-(2-Benzoyl-4-chloro-phenyl)-2-(2-cyano-ethylamino)-N-methyl-acetamide

Conditions	Yield
In 1,4-dioxane

N-(2-cyanoethyl)-N-methylamine (693-05-0) + 2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → N-(2-Benzoyl-4-chloro-phenyl)-2-[(2-cyano-ethyl)-methyl-amino]-N-methyl-acetamide (59049-40-0)

Conditions	Yield
In 1,4-dioxane

3-[(prop-2-en-1-yl)amino]propanenitrile (34508-81-1) + 2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → 2-[Allyl-(2-cyano-ethyl)-amino]-N-(2-benzoyl-4-chloro-phenyl)-N-methyl-acetamide

Conditions	Yield
In 1,4-dioxane

3-(pentylamino)propanenitrile (59676-91-4) + 2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → N-(2-Benzoyl-4-chloro-phenyl)-2-[(2-cyano-ethyl)-pentyl-amino]-N-methyl-acetamide

Conditions	Yield
In 1,4-dioxane

(+-)-3-amino-butyronitrile (16750-40-6) + 2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → N-(2-Benzoyl-4-chloro-phenyl)-2-(2-cyano-1-methyl-ethylamino)-N-methyl-acetamide

Conditions	Yield
In 1,4-dioxane

(RS)-2-methyl-3-aminopropionitrile (96-16-2) + 2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → N-(2-Benzoyl-4-chloro-phenyl)-2-(2-cyano-2-methyl-ethylamino)-N-methyl-acetamide

Conditions	Yield
In 1,4-dioxane

3-(methylamino)butanenitrile (67744-69-8) + 2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → N-(2-Benzoyl-4-chloro-phenyl)-2-[(2-cyano-1-methyl-ethyl)-methyl-amino]-N-methyl-acetamide (59049-42-2)

Conditions	Yield
In 1,4-dioxane

4-methylamino-butyronitrile (31058-09-0) + 2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → N-(2-Benzoyl-4-chloro-phenyl)-2-[(3-cyano-propyl)-methyl-amino]-N-methyl-acetamide

Conditions	Yield
In 1,4-dioxane

5-Aminopentanenitrile (6066-83-7) + 2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → N-(2-Benzoyl-4-chloro-phenyl)-2-[(3-cyano-propyl)-methyl-amino]-N-methyl-acetamide

3-butylamino-butyronitrile (54718-24-0) + 2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → N-(2-Benzoyl-4-chloro-phenyl)-2-[butyl-(2-cyano-1-methyl-ethyl)-amino]-N-methyl-acetamide

Conditions	Yield
In 1,4-dioxane

2-(Butylamino)-1-methylethyl Cyanide (63145-02-8) + 2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → N-(2-Benzoyl-4-chloro-phenyl)-2-[butyl-(2-cyano-2-methyl-ethyl)-amino]-N-methyl-acetamide

Conditions	Yield
In 1,4-dioxane

(R)-2-Methyl-3-methylamino-propionitrile (50840-30-7) + 2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → N-(2-Benzoyl-4-chloro-phenyl)-2-[(2-cyano-2-methyl-ethyl)-methyl-amino]-N-methyl-acetamide (50840-32-9)

Conditions	Yield
In 1,4-dioxane

glycine ethyl ester hydrochloride (5680-79-5) + 2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → ({[(2-Benzoyl-4-chloro-phenyl)-methyl-carbamoyl]-methyl}-amino)-acetic acid methyl ester (59049-68-2)

Conditions	Yield
With triethylamine In toluene

3-Allylamino-butyronitrile (76201-87-1) + 2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → 2-[Allyl-(2-cyano-1-methyl-ethyl)-amino]-N-(2-benzoyl-4-chloro-phenyl)-N-methyl-acetamide

Conditions	Yield
In 1,4-dioxane

2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → 3-amino-6-chloro-1,2,3,4-tetrahydro-4-hydroxy-1-methyl-2-oxo-4-phenylquinoline

Conditions	Yield
Multi-step reaction with 2 steps 1: NaHCO3 / ethanol / 48 h / 60 °C 2: NH3 / ethanol / 1 h / Heating View Scheme

2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → 3-pyridinio-6-chloro-1-methyl-4-phenyl-2-(1H)quinolone pseudo base chloride

Conditions	Yield
Multi-step reaction with 2 steps 1: 94 percent 2: 40percent sodium hydroxide / H2O View Scheme

2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → 3-amino-6-chloro-1,2-dihydro-1-methyl-2-oxo-4-phenylquinoline (5220-02-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 94 percent 2: 40percent sodium hydroxide / H2O 3: 38 percent / 220 °C / 0.5 Torr View Scheme

ethanolamine (141-43-5) + 2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → 10-chloro-7-methyl-11b-phenyl-2,3,7,11b-tetrahydro-benzo[f]oxazolo[3,2-d][1,4]diazepin-6-one (24111-44-2)

Conditions	Yield
With triethylamine In ethanol

2-(2-chloro-N-methyl-acetamido)-5-chlorobenzophenone (6021-21-2) → C19H19ClN2O4S

Conditions	Yield
Multi-step reaction with 5 steps 1.1: hexamethylenetetramine; ammonia / methanol / 6 h / 60 °C 2.1: lithium diisopropyl amide / tetrahydrofuran / 1 h / -78 °C 2.2: 3 h / -25 °C 3.1: ozone / dichloromethane / -78 °C 3.2: 0.08 h / -78 °C 3.3: 3 h / -78 - 25 °C 4.1: sodium tetrahydroborate / methanol / 1 h / 25 °C 5.1: triethylamine / dichloromethane / 1 h / 0 °C View Scheme

Upstream product

• 79-04-9 chloroacetyl chloride 
• 1022-13-5 5-chloro-2-(methylamino)benzophenone 

Downstream Products

• 59049-40-0 N-(2-Benzoyl-4-chloro-phenyl)-2-[(2-cyano-ethyl)-methyl-amino]-N-methyl-acetamide 
• 59049-42-2 N-(2-Benzoyl-4-chloro-phenyl)-2-[(2-cyano-1-methyl-ethyl)-methyl-amino]-N-methyl-acetamide 
• 50840-32-9 N-(2-Benzoyl-4-chloro-phenyl)-2-[(2-cyano-2-methyl-ethyl)-methyl-amino]-N-methyl-acetamide 
• 59049-68-2 ({[(2-Benzoyl-4-chloro-phenyl)-methyl-carbamoyl]-methyl}-amino)-acetic acid methyl ester 
• 24111-44-2 10-chloro-7-methyl-11b-phenyl-2,3,7,11b-tetrahydro-benzo[f]oxazolo[3,2-d][1,4]diazepin-6-one 
• 5220-02-0 3-amino-6-chloro-1,2-dihydro-1-methyl-2-oxo-4-phenylquinoline 
• 439-14-5 diazepam 
• 37393-79-6 6-chloro-1,2-dihydro-3-hydroxy-1-methyl-2-oxo-4-phenylquinoline 
• 37393-81-0 6-chloro-3,4-epoxy-1,2,3,4-tetrahydro-1-methyl-2-oxo-4-phenylquinoline 
• 80356-39-4 1-(6-Chloro-1-methyl-2-oxo-4-phenyl-1,2-dihydro-quinolin-3-yl)-pyridinium; chloride 
• 59049-39-7 N-(2-Benzoyl-4-chloro-phenyl)-2-(cyanomethyl-amino)-N-methyl-acetamide 

Relevant articles and documents

COMPOSITIONS AND METHODS FOR REDUCING TACTILE DYSFUNCTION, ANXIETY, AND SOCIAL IMPAIRMENT

The present invention provides novel peripherally-restricted benzodiazepines with reduced blood brain barrier permeability and methods of use thereof for reducing tactile dysfunction, social impairment, and anxiety in a subject diagnosed with Autism Spectrum Disorder, Rett syndrome, Phelan McDermid syndrome, or Fragile X syndrome.

Multistep Flow Synthesis of Diazepam Guided by Droplet-Accelerated Reaction Screening with Mechanistic Insights from Rapid Mass Spectrometry Analysis

Electrospray and Leidenfrost droplet accelerated reactions were used as a predictive tool for estimating the outcome of microfluidic synthesis as demonstrated by Wleklinski et al. Rapid analysis by electrospray-mass spectrometry (ESI-MS) also provided immediate feedback on reaction outcomes in flow reactions. Significant reaction acceleration was observed in electrospray relative to the corresponding bulk reaction. This rapid reaction screening and analysis method has allowed for the detection of previously unreported outcomes in the reaction between 5-chloro-2-(methylamino)benzophenone and haloacetyl chloride (halo = Cl or Br) in the continuous synthesis of diazepam. In our current study, a more detailed extension of the previous work, we report acceleration factors that are solvent dependent; additional byproducts that were observed on the microfluidic scale that were absent in the droplet reactions. Gaining insight from this combined droplet and microfluidic screening/rapid ESI-MS analysis approach, we have helped guide the synthesis of diazepam and showcased the potential of this method as a reaction optimization and discovery tool. Informed by these new insights, diazepam was synthesized in a high-yield two-step continuous flow process.

The Conversion of 2-(2-Chloroacetamido)benzophenones into 2,3-Dihydro-2-oxo-1,4-benzodiazepines. Part I. With Ammonia

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