Synthesis, Optimization, and Large-Scale Preparation of the Low-Dose Central Nervous System-Penetrant BACE1 Inhibitor LY3202626 via a [3 + 2] Nitrone Cycloaddition

Abstract

Herein we report a summary of the synthetic development of LY3202626 from the initial discovery route to a final route that was scaled to make 150 kg. Key developments include the use of a [3 + 2] cyclization to set the cis ring junction of the formed isoxazoline, a one-pot thiazine formation, and three different ways to install the aniline: (1) Cu-catalyzed azide coupling and reduction, (2) nitration and reduction, and (3) Buchwald coupling with acetamide.

Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor

“…Compounds 20−22 were prepared in one step from diamine 19 and the corresponding acid chloride as described in Scheme 3. 28 Amides 20−22 displayed potency at least 25-fold greater than that of LY2886721 with high LEAN values, indicating that the addition of heavy atoms efficiently translated to higher BACE1 potency (Table 4). The X-ray structure of compound 22 (Figure 5) showed that the methoxypyrazine group filled the S3 pocket of the BACE enzyme.…”

“…Nevertheless, we elected to explore compounds 20 – 22 and make data-driven decisions regarding their strengths and weaknesses. Compounds 20 – 22 were prepared in one step from diamine 19 and the corresponding acid chloride as described in Scheme …”

“…After 1–2 min, 5-difluoropyridine-2-carboxylic acid (110 mg, 782 μmol) was added in a single portion to prepare the acid chloride. A separate solution of (4aR,7aS)-7a-(5-amino-2-fluorophenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo­[3,4- d ]­[1,3]­thiazin-2-amine (150 mg, 372 μmol) in ethanol (1.9 mL) and water (1.9 mL) was heated to 50 °C . To this solution while at 50 °C was added dropwise the acid chloride solution.…”

“…A separate solution of (4aR,7aS)-7a-(5amino-2-fluorophenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7tetrahydropyrrolo [3,4-d][1,3]thiazin-2-amine (150 mg, 372 μmol) in ethanol (1.9 mL) and water (1.9 mL) was heated to 50 °C. 28 To this solution while at 50 °C was added dropwise the acid chloride solution. The reaction was stirred at 50 °C for 1 h and then cooled to room temperature.…”

Synthesis of BACE1 Inhibitors E2609/E2071 via Oxime–Olefin Cycloaddition Following a Process Risk Mitigation Strategy

“…The resulting first-generation route outlined in Scheme consists of 19 synthetic stages and proceeds in 4.8% overall yield. Process highlights of the route include multiple crystalline intermediates in the late stages, a diastereoselective [3 + 2] cycloaddition (dr 13:1) to establish the relative stereochemistry of all three stereogenic centers (Stage 5), and a classical diastereomeric salt resolution utilizing dibenzoyl- d -tartaric acid ( d -DBTA) to isolate the desired enantiomer whose configuration was confirmed by X-ray (Stage 7). Pyrazinoic acid 16 was prepared from acid 18 in 4 steps employing deoxofluorination as the key step.…”