Methyl (S)-3-(7-bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-1H-benzo(e)(1,4)diazepin-3-yl)propanoate
[CAS# 308242-23-1]

Identification

• Classification: Organic raw materials >> Carboxylic compounds and derivatives >> Carboxylic esters and their derivatives
• Name: Methyl (S)-3-(7-bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-1H-benzo(e)(1,4)diazepin-3-yl)propanoate
• Synonyms: methyl 3-[(3S)-7-bromo-2-oxo-5-pyridin-2-yl-1,3-dihydro-1,4-benzodiazepin-3-yl]propanoate
• Molecular Formula: C₁₈H₁₆BrN₃O₃
• Molecular Weight: 402.24
• CAS Registry Number: 308242-23-1
• EC Number: 889-719-6
• SMILES: COC(=O)CC[C@H]1C(=O)NC2=C(C=C(C=C2)Br)C(=N1)C3=CC=CC=N3

Properties

• Density: 1.5±0.1 g/cm³ Calc.^*
• Boiling point: 545.3±50.0 °C 760 mmHg (Calc.)^*
• Flash point: 283.6±30.1 °C (Calc.)^*
• Index of refraction: 1.661 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319-H335
• Safety Statements: P261-P305+P351+P338

Discovery and Applications

Methyl (S)-3-(7-bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propanoate is a key intermediate in the synthesis of benzodiazepine derivatives, including remimazolam. This compound is a substituted 1,4-benzodiazepin-2-one featuring a bromine atom at the 7-position, a pyridin-2-yl substituent at the 5-position, and a methyl propanoate side chain at the 3-position. The stereochemistry at the 3-position is defined as S, which is crucial for the biological activity of downstream pharmacologically active compounds.

The synthesis of this compound is documented in multiple patent publications, which describe methods for preparing the methyl ester with control over stereochemistry. Typical approaches involve constructing the benzodiazepine ring system followed by selective bromination and introduction of the pyridinyl group. The propanoate methyl ester can be installed either via alkylation of a carboxylic acid precursor or by esterification of the corresponding acid. Protection-deprotection strategies are often applied to ensure that the bromine and pyridinyl substituents are introduced without side reactions.

The main application of this compound is as an intermediate for the preparation of remimazolam, a fast-acting benzodiazepine sedative. Its chemical properties, such as the ester functionality, allow for further chemical modifications, including hydrolysis to the carboxylic acid or amide formation. The presence of the S-stereocenter ensures that the pharmacologically relevant enantiomer is produced in subsequent reactions. Controlling the stereochemistry is essential because the biological activity and metabolic stability of the final drug are strongly influenced by the configuration at this center.

The compound has been referenced in multiple patents describing both the preparation and the application in benzodiazepine derivatives. For example, WO-2021256679-A1 and KR-20210157146-A describe methods for preparing the compound with high stereochemical purity. Other patents, such as CN-116102558-A and EP-3658545-B1, detail its use as a key intermediate in producing biologically active benzodiazepines, highlighting its importance in pharmaceutical development. The compound’s ester group and aromatic substituents are strategically positioned to allow selective reactions that yield final drug candidates efficiently.

Due to its role as an intermediate, handling and storage require standard laboratory precautions. The compound should be stored in a cool, dry environment, away from light, to maintain stability of the ester and halogen substituents. It is compatible with common organic solvents used in pharmaceutical synthesis. Its stereochemical integrity must be preserved throughout the synthetic sequence to ensure that the final active pharmaceutical ingredient meets regulatory standards.

References

Method for preparing 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-4-yl]propionic acid methyl ester. WO-2021256679-A1. Priority date: 2020-06-19. Link

Preparation method of 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-4-yl]propionic acid methyl ester. KR-20210157146-A. Priority date: 2020-06-19. Link