Preparation and application of 1-(BOC-aminomethyl)cyclopropanol_Industrial additives

Background and overview^[1]

1-(BOC-Aminomethyl)cyclopropanol is an organic intermediate, which can be obtained from 1-(aminomethyl)cyclopropanol as raw material through (Boc)2O protection. There are reports in the literature that it can be used to prepare ALK inhibitors.

Preparation^[1]

Dissolve 1-(aminomethyl)cyclopropanol (250 mg, 2.87 mmol) in DCM (8 mL) containing dry DMF (2 mL). Boc₂O (626 mg, 2.87 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue (still containing DMF) was partitioned between brine (10 ml) and EtOAc (10 ml). The aqueous layer was extracted with EtOAc (2×10 ml), the combined organic layers were washed with brine (2×10 ml) and dried over Na₂SO₄ and concentrated in vacuo to yield 505 mg (94%) of light yellow oil that solidifies on standing. According to 1H-NMR, this appears to be a mixture of the expected product and 40% Boc₂O. The intermediate was dissolved in dry THF (2 mL) and this solution was added dropwise to 2.4 MLiAlH4 in THF (6 mL, 14.40 mmol) at room temperature. The mixture was stirred at 70°C overnight. The reaction mixture was cooled in an ice bath and saturated aqueous Na₂SO₄ solution (20 ml) was slowly added. The turbid mixture was filtered through celite, washed with EtOAc and the layers separated. The organic layer was washed with brine (2×20 mL) and dried over Na₂SO₄ and concentrated in vacuo to yield the title product as a yellow solid (150 mg).

Apply^[2]

1-(BOC-aminomethyl)cyclopropanol can be used to prepare compounds having the following structures for use as protein kinase modulators. This compound is an ALK inhibitor. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 80% to 85% of all lung cancer patients, and some of these patients are accompanied by genetic mutations. 2-5% of NSCLC cases have rearranged forms of anaplastic lymphoma kinase (ALK), a receptor-type protein tyrosine phosphokinase of the insulin receptor superfamily. ALK was initially discovered as an activated fusion oncogene in anaplastic large cell lymphoma. Subsequent studies have discovered ALK fusion forms in a variety of cancers, including systemic tissue dysplasia, inflammation Myofibroblast carcinoma, non-small cell lung cancer, etc. ALK’s mutations and abnormal activity in various cancers have made it a drug target for the treatment of ALK-positive cancers.

References

[1][Invented in China] CN201380056094.8 Fluoromethyl-substituted pyrrole carboxamide

[2][Invented in China] CN201811283367.3 Compounds used as protein kinase modulators and their applications