846-49-1

Usage

Chemical Properties

White Crystalline Solid

Originator

Tavor,Wyeth,Italy,1972

Uses

An anxiolytic, and anticonvulsant. Controlled substance (depressant)

Manufacturing Process

The starting material was 2-amino-2',5-dichlorobenzophenone which was reacted with hydroxylamine and then with chloroacetyl chloride. The intermediate thus obtained is reacted with methylamine and then with acetic anhydride. To a slightly warm suspension of 3-acetoxy-7-chloro-5-(o-chlorophenyl)-1,3- dihydro-2H-1,4-benzodiazepin-2-one thus obtained was added 4N sodium hydroxide solution with stirring. All the solid dissolved and soon a thick white solid precipitated out. The solid was filtered, washed well with water and recrystallized from ethanol. The product was isolated as a solvate with 1 mol of ethanol. When heated it loses the ethanol of solvation and melts at 166°C to 168°C.

Brand name

Ativan (Baxter Healthcare); Ativan (Biovail); Loraz (Quantum Pharmics).

Therapeutic Function

Tranquilizer

General Description

Lorazepam, 7-chloro-5-(2-chlorophenyl)-3-dihydro-3-hydroxy-2H-1,4-benzodiazepine-2-one(Ativan), is the 2'-chloro derivative of oxazepam. In keepingwith overall SARs, the 2'-chloro substituent increases activity.As with oxazepam, metabolism is relatively rapid anduncomplicated because of the 3-hydroxyl group in the compound.Thus, it also has short half-life (2–6 hours) and similarpharmacological activity.

InChI:InChI=1/C15H10Cl2N2O2/c16-8-5-6-12-10(7-8)13(19-15(21)14(20)18-12)9-3-1-2-4-11(9)17/h1-7,15,21H,(H,18,20)

Upstream product

• 848-75-9 lormetazepam 
• 2848-96-6 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2-oxo-2H-1,4-benzodiazepin-3-yl acetate 
• 14405-03-9 2-chloroacetamido-2’,5-dichlorobenzophenone 
• 2958-36-3 (2-amino-5-chloro-phenyl)-(2-chloro-phenyl)-methanone 
• 125534-53-4 lorazepam acetone solvate 
• 2955-37-5 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one-4-oxide 
• 89722-85-0 Trifluoro-acetic acid 7-chloro-5-(2-chloro-phenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl ester 

Downstream Products

• 134051-36-8 Benzoic acid 7-chloro-5-(2-chloro-phenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl ester 
• 18878-24-5 3-O-ethyllorazepam 
• 130753-96-7 2-Methyl-3-nitro-benzoic acid 7-chloro-5-(2-chloro-phenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl ester 
• 130753-89-8 7-chloro-5-(2-chlorophenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl 2-(6-methoxynaphthalen-2-yl)propanoate 
• 82841-78-9 lorazepam-α-chloro-propionate 
• 71107-65-8 lorazepam-β-phenyl-propionate 
• 71107-66-9 lorazepam-α-methyl-β-phenyl-propionate 
• 2958-36-3 (2-amino-5-chloro-phenyl)-(2-chloro-phenyl)-methanone 
• 60628-61-7 7-chloro-5-(2-chloro-phenyl)-3-fluoro-1,3-dihydro-benzo[e][1,4]diazepin-2-one 
• 93955-15-8 6-chloro (2'-chloro-4-phenyl) quinazoline 2 carboxaldehyde 
• 54699-91-1 7-chloro-5-(2-chlorophenyl)-2,3-dioxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine 
• 60628-58-2 3-Fluoro-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one 
• 130754-08-4 (S)-2-(6-Methoxy-naphthalen-2-yl)-propionic acid (R)-7-chloro-5-(2-chloro-phenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl ester 
• 130753-89-8 (S)-2-(6-Methoxy-naphthalen-2-yl)-propionic acid (S)-7-chloro-5-(2-chloro-phenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl ester 

Relevant academic research and scientific papers

New crystal form of lorazepam, preparation method and pharmaceutical applications thereof

The invention relates to a new crystal form for preparing lorazepam, a preparation method and pharmaceutical applications thereof, wherein specifically the lorazepam crystal has diffraction peaks at about 12.17 DEG, about 14.15 DEG, about 15.27 DEG, about 16.84 DEG, about 17.91 DEG and about 20.81 DEG in a powder X-ray diffraction pattern represented by a 2[theta] angle by using Cu-Kalpha radiation, for example, the crystal has diffraction peaks at about 7.93 DEG, about 9.04 DEG, about 12.17 DEG, about 14.15 DEG, about 15.27 DEG, about 16.84 DEG, about 17.91 DEG, about 20.81 DEG, about 21.44 DEG and about 26.38 DEG. The invention further provides a preparation method of the new crystal of larazepam, and pharmaceutical applications of the new crystal form. According to the invention, the prepared new crystal form for preparing lorazepam shows excellent properties defined in the specification.

Light-stabilized pharmaceutical composition, and preparation method and pharmaceutical application thereof

The invention relates to a light-stabilized pharmaceutical composition, and a preparation method and pharmaceutical application thereof. Specifically, the pharmaceutical composition comprises a lorazepam crystal and pharmaceutical adjuvants. The lorazepam crystal is radiated by Cu-K alpha. In a powder X-ray diffraction pattern expressed by an angle of 2 theta, there are diffraction peaks at approximately 12.17 degrees, approximately 14.15 degrees, approximately 15.27 degrees, approximately 16.84 degrees, approximately 17.91 degrees and approximately 20.81 degrees. For example, the crystal hasdiffraction peaks at approximately 7.93 degrees, approximately 9.04 degrees, approximately 12.17 degrees, approximately 14.15 degrees, approximately 15.27 degrees, approximately 16.84 degrees, approximately 17.91 degrees, approximately 20.81 degrees, approximately 21.44 degrees and approximately 26.38 degrees. A new crystal form and the pharmaceutical composition, which are used for preparing lorazepam and prepared by the method, exhibit excellent properties as described in the description of the invention.

Method for preparing lorazepam

The invention relates to a method for preparing lorazepam. The method comprises the following steps: subjecting a ketone substrate as shown in a formula I, glacial acetic acid, potassium acetate, potassium persulfate and iodine to a reaction under heating and stirring conditions to obtain an acetoxy substrate as shown in a formula II; dropwise adding a sodium hydroxide solution into a mixture of ethanol and the acetoxy substance as shown in the formula II, carrying out stirring to realize a complete reaction, performing filtering to obtain a filter cake, and reacting the filter cake with ethylacetate and a citric acid solution to obtain a crude lorazepam product; and crystallizing the crude lorazepam product by using ethanol and ethyl acetate in sequence. The invention further relates tothe pharmaceutical application of larazepam prepared by using the method. The larazepam is particularly used for treating or preventing anxiety, epilepsy, convulsion, sedation and hypnosis. The methoddisclosed by the invention has excellent technical effects as described in the specification.

Efficient synthesis of 3-hydroxy-1,4-benzodiazepines oxazepam and lorazepam by new acetoxylation reaction of 3-position of 1,4-benzodiazepine ring

Simple, efficient, and scalable syntheses of 3-hydroxy-1,4-benzodiazepines, oxazepam (1), and lorazepam (2) were developed. The syntheses are based on the new acetoxylation reaction of the 3-position of the 1,4-benzodiazepine ring. The reaction involves iodine (20-50 mol %)-catalyzed acetoxylation in the presence of potassium acetate (2 equiv) and potassium peroxydisulfate (1-2 equiv) as a stoichiontetric oxidant affording the corresponding 3-acetoxy-1,4- benzodiazepines in good-to-high yields. The latter were converted by selective saponification to 3-hydroxy-1,4-benzodiazepines of very high purity (>99.8%) in an overall yield of 83% (oxazepam) and 64% (lorazepam).

A METHOD OF PURIFICATION OF LORAZEPAM

A new method of purification of Lorazepam is disclosed that consists in removing products of synthesis, decomposition products, water or other solvent that forms a solvate with Lorazepam, by crystallization or stirring in an organic solvent of the ether, ester or ketone type. Lorazepam prepared via this method can be utilized in the pharmaceutical industry for the manufacture of pharmaceuticals.

Process for preparing pure crystalline lorazepam

The present invention provides a process for preparing crystalline lorazepam substantially free of bound solvent from a lorazepam alcohol solvate or hydrate by suspending the lorazepam solvate in an organic medium selected from ethyl acetate, cyclohexane, dichloromethane, toluene and mixtures thereof. This process is useful in producing the anti-anxiety and sedative agent lorazepam in increased yields. A process for converting lorazepam lower alcohol solvates to lorazepam hydrate is also disclosed.

Process for preparing pure crystalline lorazepam

The present invention provides a process for preparing crystalline lorazepam substantially free of bound solvent from a lorazepam alcohol solvate or hydrate by suspending the lorazepam solvate in an organic medium selected from ethyl acetate, cyclohexane, dichloromethane, toluene and mixtures thereof. This process is useful in producing the anti-anxiety and sedative agent lorazepam in increased yields. A process for converting lorazepam lower alcohol solvates to lorazepam hydrate is also disclosed.

3-FLUOROBENZODIAZEPINES

Benzodiazepines that bear a fluorine substituent in the metabolically active C-3 position were prepared by the reaction of diethylaminosulfur trifluoride (DAST) with the corresponding 3-hydroxybenzodiazepines.These products are surprisingly stable to hydrolysis and possess potent antianxiety and muscle-relaxing properties.

Lorazepam and oxazepam esters. Hydrophobicity, hydrolysis rates and brain appearance

Six prodrug-type esters of oxazepam and lorazepam, which are potent benzodiazepine tranquillizers, were synthesized in 2-14C-labelled form. Pharmacokinetics of the compounds administered i.p. to mice were compared with respect to the effect of the acyl groups on the brain appearance of the esters and the parent drugs. Brain accumulation of the compounds administered was characterized by the areas under the brain-to-blood concentration ratio-time functions (AUQ). The rates of brain penetration were characterized by the slope of the correlation between i.v. dose and 1-min brain levels. These slopes as well as AUQ values depended upon hydrophobicity (R[M]) according to an optimum function. The lag times of the brain appearance of the parent drugs showed a minimum at about the same R[M] at which AUQ values were maximal. The rates of brain appearance of the parent compounds correlated with the hepatic microsomal hydrolysis rate of their esters.

Screening, detection and biotransformation of lormetazepam, a new hypnotic agent from the 1,4-benzodiazepine series

The paper describes a screening procedure for 7-chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-2,3-dihydro-1H-1,4-benzodiaze pin-2-one (lormetazepam, Noctamid) and other important analytical data (TLC, GLC, UV-, IR- and mass spectra) of this new benzodiazepine derivative. Screening results after a single p.o. dose of 1 mg lormetazepam (Noctamid-1) are also reported.