Preparation method of (R)-(-)-1-amino-2-propanol_Industrial additives

Background and overview^[1]

(R)-(-)-1-amino-2-propanol, as an important synthetic intermediate, is widely used in the preparation of medicines and pesticides. The chiral compound (R)-1-amino-2-propanol Alcohol is an important intermediate in the synthesis of nucleoside drugs (such as the anti-AIDS drug tenofovir). Tenofovir is a nucleotide reverse transcriptase inhibitor developed by Gilead Sciences in the United States. It is a prodrug of tenofovir. It was first launched in the United States in 2001 and is mainly used clinically to treat human immunodeficiency virus (HIV) infection. It can be used in combination with other antiretroviral drugs, and it also has good anti-hepatitis B virus (HBV) activity and is effective against combined HIV/HBV infection and lamivudine-resistant strains.

Preparation^[1-2]

Report 1,

(1) Dissolve sodium tert-butoxide (300g, 3.12mol) in tetrahydrofuran (2L), slowly add trifluoroacetamide (294g, 2.6mol) under ice bath, stir for 30 minutes; then add under ice bath (R)-propylene oxide (166g, 2.96mol), naturally warmed to room temperature, continued to stir for 10h, and then stirred for 2h at 35°C; after the reaction, a total of 1.3L of 2N (equivalent concentration) hydrochloric acid was added dropwise to the system. Neutralize, then add 1.3 L of water, let stand to separate layers, extract the aqueous phase with methylene chloride, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a total of 423 g of intermediate product I, with a yield of 95%.

1H-NMR (CDCl3, MHz) of intermediate product I: δ1.07 (d, 3H), 3.36 (m, 2H), 3.99 (m, 1H), 7.11 (brs, 1H).

(2) Dissolve the intermediate product I (420g, 2.45mol) obtained in step (1) in methanol (2L), add 350mL water and potassium carbonate (744g, 5.4mol), stir at room temperature for 6h, filter and concentrate To dryness, the obtained product was dissolved in dichloromethane, filtered to remove insoluble matter, dried over anhydrous sodium sulfate, concentrated, and distilled under reduced pressure to obtain the target product (R)-(-)-1-amino-2-propanol. 171g, yield 93%. 1H-NMR (CDCl3, MHz): δ1.17(d,3H), 2.45(dd,1H), 2.66(dd,1H), 3.54-3.67(m,1H), 3.76(brs,3H).

Report 2,

Add 290g acetone and 1g glacial acetic acid into the three-necked flask at room temperature, add 35g ammonia gas and stir for 4 hours. Add 58g (R)-(+)-1,2-epoxypropane dropwise into the reaction flask. After completion, heat to reflux, react for 2 hours, lower the temperature and reduce pressure to distill excess acetone, and directly add 800g of dilute hydrochloric acid (the concentration of the dilute hydrochloric acid is 5wt%) to the crude product for hydrolysis, stir at room temperature for 30 minutes, and add sodium hydroxide aqueous solution (the concentration of the sodium hydroxide aqueous solution is 10wt) %) to adjust pH=10, distill the filtrate under reduced pressure, and obtain 56 g of product through rectification, with a yield of 74.66%. After detection by gas chromatography, the content of (R)-(-)-1-amino-2-propanol is >99wt%.

References

[1] [China invention, China invention authorization] CN202010535582.9 Preparation method of chiral 1-amino-2-propanol

[2] [Chinese invention, Chinese invention authorization] CN201610128208.0 A preparation method of R-1-amino-2-propanol