1611493-60-7

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• Synthesis

  

  Step 1: 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1-A, 3.15 g, 10.0 mmol) suspended in acetonitrile (36 mL) and acetic acid (4 mL) was treated with methanesulfonic acid (0.195 mL). The mixture was heated to 75 °C. After 7 hours, the crude mixture was cooled and stored at -10 °C for three days. The crude mixture was reheated to 75 °C for 2 hours, cooled, and used in the next step without purification.

  Step 2: Crude 1-(2,2-dihydroxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (16.8 mL from the crude mixture of Step 1, approximately 4 mmol) was mixed with (1S,3R)-3-aminocyclopentanol (0.809 g, 8 mmol), diluted with acetonitrile (16.8 mL), and treated with potassium carbonate (0.553 g, 4 mmol). The reaction mixture was heated to 85 °C, stirred for 15 min, cooled to ambient temperature, and stirred again for 16 h. HCl (50 mL, 0.2 Maq) was added, and the clear yellow solution was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to a yellow solid. The crude substance was precipitated from dichloromethane/hexane to give the desired intermediate 15-B as a light beige powder. Step 3: Compound 15-B (38 mg, 0.12 mmol) was dissolved in 1 mL of acetonitrile and treated with 2,4,6-trifluorobenzylmethylamine (34 mg, 0.21 mmol), HATU (50 mg, 0.13 mmol), and N,N-diisopropylethylamine (DIPEA) (23 mg, 0.18 mmol) and stirred at room temperature for 2 hours. Subsequent LCMS analysis showed that compound 15-B was completely consumed and intermediate 45-A was formed. The reaction mixture was then proceeded to the next step. Step 4: MgBr2 (55 mg, 0.30 mmol) was added to the crude reaction solution from the previous step. The reaction mixture was stirred at 50 °C for 1 hour, acidified with 10% HCl aqueous solution, partitioned between aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO4, filtered, concentrated, and purified by HPLC (ACN/H2O containing 0.1% TFA modifier) to obtain compound 45-Bictegravir.;

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