A kind of preparation method of cobicistat intermediate and its intermediate and application
A technology for intermediates and uses, applied in the field of pharmaceutical chemical synthesis, can solve the problems of increased by-products, unsuitable for industrial production, and reduced reaction yields, and achieves the effects of improving yields, being beneficial to environmental maintenance, and reducing side reactions.
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Embodiment 1
[0064] Embodiment 1. Synthesis of compound 8a
[0065]
[0066] Add compound 9a (20g, 1.0eq.), compound 10 (34.4g, 1.1eq.) into dichloromethane (240ml), stir at room temperature under nitrogen protection to obtain a clear solution. Diisopropylethylamine (17.3 g, 1.2 eq.) was added dropwise to the mixture. After the addition was complete, the reaction was kept at temperature until the raw material 9a was consumed. The reaction solution was washed successively with 1N hydrochloric acid (80ml), saturated sodium bicarbonate (80ml) and saturated brine (80ml), and dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to remove the organic solvent under reduced pressure, and the crude solid obtained was slurried with tert-butyl methyl ether (MTBE) (70ml) for half an hour, and then filtered. The obtained precipitate was dried to obtain compound 8a (32.3 g, yield 90%).
Embodiment 2
[0067] Embodiment 2. Synthesis of compound 8b
[0068]
[0069] Compound 9a (20g, 1.0eq.), Boc-anhydride (26.8g, 1.1eq.) was added into dichloromethane (240ml), stirred at room temperature under nitrogen protection to obtain a clear solution. Diisopropylethylamine (5.4 g, 1.2 eq.) was added dropwise to the mixture, and the dropwise addition was completed, and the reaction was maintained until the raw material 9a was consumed. The reaction solution was washed successively with 1N hydrochloric acid (80ml), saturated sodium bicarbonate (80ml) and saturated brine (80ml), and dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to remove the organic solvent under reduced pressure, and the crude solid obtained was slurried with tert-butyl methyl ether (MTBE) (70ml) for half an hour, and then filtered. The obtained precipitate was dried to obtain compound 8b (30.1 g, yield 96%).
Embodiment 3
[0070] Embodiment 3. Synthesis of compound 7a
[0071]
[0072] Compound 8a (32g, 1.0eq.) and lithium chloride (8.5g, 2.0eq.) were added into methanol (500ml), stirred and dissolved under nitrogen protection until clear. The mixture was cooled to below 5°C in an ice-water bath, sodium borohydride (7.5 g, 2.0 eq.) was added to the reaction solution in batches, and the reaction solution was kept at room temperature for reaction after addition. The reaction was monitored by TLC until the starting material disappeared. The reaction solution was placed in an ice-water bath to cool down to below 5°C, 15ml of water was added dropwise to the mixture, and then 2N hydrochloric acid was added dropwise until the pH was 2-3. Most of the solvent was evaporated, the residue was adjusted to pH 9 with 2mol / L NaOH solution, the aqueous layer was washed with dichloromethane (30ml x 3), the combined organic layers were washed with water (30ml) and saturated brine (30ml), anhydrous sulfuric ac...
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