Manufacturable Process of a Novel EGFR Inhibitor (Larotinib) for the Treatment of ESCC

Abstract

The development of an efficient synthetic process for a clinical candidate Larotinib (4), which is an epidermal growth factor receptor (EGFR) inhibitor for the treatment of esophageal squamous cell carcinoma (ESCC), is reported for scale-up. The process used 3,4-dihydro-7-methoxy-4-oxoquinazolin-6-yl acetate (12) as the regulatory starting material and provided a stable and industrializable intermediate chloroquinazoline 11 under the process control. Further optimization of the process obviously improved the reaction yield and reduced the impurity level including alkyl halide potential genotoxic impurities (PGIs), at the same time avoiding the use of laborious and time-consuming column chromatography. More than 110 kg of Larotinib (4) in one batch can be finally produced stably for clinical research. Compared to our initial synthetic route in preclinical research, the overall yield of this optimized process increased significantly from 16.2 to 55.6%.

Continuous Flow Synthesis of a Key Intermediate Common to Gefitinib and Larotinib

“…Toluene demonstrated no appreciable benefit in the (COCl) 2 /DMF system (Table 2, entry 8), despite some published findings indicating that it may promote the chlorination reaction. 13 The reaction selectivity was significantly greater in DCE (Table 2, entry 3) than in acetonitrile or chloroform (Table 2, entries 7 and 10). Hence, optimal conditions using DCE and (COCl) 2 provided the highest yield of 60.7% (Table 2, entry 3).…”

“…It is interesting to note that even with agitation, the poorly soluble raw material will roll into a ball rather than a suspension when using EA as a solvent (Table , entry 6), drastically reducing the reaction contact area. Toluene demonstrated no appreciable benefit in the (COCl) 2 /DMF system (Table , entry 8), despite some published findings indicating that it may promote the chlorination reaction . The reaction selectivity was significantly greater in DCE (Table , entry 3) than in acetonitrile or chloroform (Table , entries 7 and 10).…”

“…For product 7 characterization, a 100 mL sample was filtered and vacuum-dried to obtain a white solid (96.1% yield, 98% purity). 1 H NMR (400 MHz, CD 3 ODd 4 ) δ 8.81 (s, 1H), 8.35 (s, 1H), 7.95 (dd, J 1 = 6.8, J 2 = 2.4 Hz, 1H), 7.66 (m, 1H), 7.37 (t, J = 8.8 Hz, 1H), 7.36 (s, 1H), 4.09 (s, 3H), 2.38 (s, 3H); 13 C NMR (100 MHz, CD 3 OD-d 4 ) δ 169.9, 161.0, 160.4, 159.0, 151.8, 143.2, 140.3, 134.7, 128.1, 126.1, 121.9, 119.0, 117.9, 108.4, 101.7, 57.7, 20. The reaction mixture of 7•HCl from step 2 was dissolved in MeOH (2.5 mL/g) and loaded into the ATR 3−1 with a plunger pump through a PTFE feed tube and a T-shaped inlet adaptor at a flow rate of 5 mL/min. At the same time, NaOH (0.8 g, 20 mmol, 2 equiv) dissolved in water (1.6 mL, 2.0 mL/g) was loaded into the ATR 3−1 at a flow rate of 20 μL/min via plunger pump through the T-shaped inlet adaptor, and the reaction was carried out at 30 °C with the rotational speed set to a constant 600 rpm.…”

“…The product was solubilized with MeOH and was analyzed by HPLC (85.1% yield, 98% purity). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.72 (s, 1H), 9.48 (s, 1H), 8.47 (s, 1H), 8.21 (dd, J 1 = 7.2, J 2 = 2.4 Hz, 1H), 7.83 (m, 1H), 7.78 (s, 1H), 7.40 (t, J = 8.8 Hz, 1H), 7.21(s, 1H), and 3.97 (s, 3H); 13 C NMR (100 MHz, DMSOd 6 ) δ 155.9, 154.0, 151.8, 146.8, 146.2, 137.2, 122.8, 121.7, 118.7, 116.6, 116.4, 109.6, 107.2, 105.3, and…”

“…1 H (400 MHz) and 13 C (100 MHz) NMR spectra were recorded at room temperature as solutions in DMSO-d 6 or CD 3 OD-d4. HPLC analysis was performed using a standard method on an Innoval ODS-2 column (250 mm × 4.6 mm, 5 μm), measuring at λ = 254 nm, using a mobile phase of ACN/ phosphate water = 60:40, at a flow rate of 1.0 mL/min, a column temperature of 30 °C, and using an injection volume of 3.0 μL.…”