6-Bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole Chemical Properties

Boiling point:

353.4±22.0 °C(Predicted)

Density 

1.49

storage temp. 

Sealed in dry,Room Temperature

pka

3.48±0.10(Predicted)

Appearance

Off-white to yellow Solid

InChI

InChI=1S/C11H12BrFN2/c1-6(2)15-7(3)14-11-9(13)4-8(12)5-10(11)15/h4-6H,1-3H3

InChIKey

SJQZRZLUEGCXFN-UHFFFAOYSA-N

SMILES

C1(C)N(C(C)C)C2=CC(Br)=CC(F)=C2N=1

Safety Information

HS Code 

2933998090

6-Bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole Usage And Synthesis

Uses

6-Bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole is a pharmaceutical intermediate. It can be used in the preparation of Abemaciclib, a kinase inhibitor for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer who have experienced disease progression following endocrine therapy and prior chemotherapy.

Flammability and Explosibility

Not classified

Synthesis

The general procedure for the synthesis of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[D]imidazole using (E)-N-(4-bromo-2,6-difluorophenyl)-N'-isopropylacetamidine as starting material was as follows: potassium tert-butanolate (6.9 kg) was added batchwise to a (E)-N-(4-bromo-2,6-difluorophenyl)-N'-isopropylacetamidine (16.2 kg) N-methylformamide (76 kg) solution while controlling the reaction temperature below 30°C. The reaction mixture was heated to 70-75°C until the completion of the reaction was monitored by HPLC. The reaction solution was then cooled to 20-30°C and the reaction was quenched by addition of water (227 kg). Extraction was carried out with methyl tert-butyl ether (37 x 4 kg) and the combined organic phases were washed with brine (49 x 2 kg). The organic phase was concentrated to 25-30 L, n-hexane (64 kg) was added and the resulting slurry was filtered to give 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[D]imidazole (11 kg). Mass spectrum (ES+): m/z = 272 (M + H)+. For further purification, the crude product was dissolved in dichloromethane, filtered through silica gel and Celite pads, and finally recrystallized from a mixed solvent of methyl tert-butyl ether/hexane.

References

[1] Patent: US2010/160340, 2010, A1. Location in patent: Page/Page column 10
[2] Patent: WO2015/130540, 2015, A1. Location in patent: Page/Page column 22

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