Carbon Dioxide → 1,1-Dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-hydroxybutanoate

温度

-70 °C

To a solution of (2S)-2-[(3-chloro-4-cyanophenyl)amino]-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoic acid (115.0 g, 0.35 mol) in THF (300 mL) at −65° C. in a dry-ice/acetone bath was added portionwise carbonyl diimidazole (68.9 g, 0.43 mol) at such a rate as to maintain or decrease temperature. After the addition was complete, the reaction was stirred for an additional 1 h. This solution was transferred to a jacketed addition funnel containing dry ice in the jacket to maintain a solution temperature of −70° C., then added to a mixture of NaBH4 (16.1 g, 0.43 mol), ice (600 mL), and THF (100 mL); the addition of the solution to the NaBH4 mixture was carried out at such a rate that the temperature did not exceed 0° C. over the course of the addition. The resultant reaction mixture was stirred for an additional 1 h at 0° C. The reaction mixture was allowed to warm to ambient temperature, whereupon EtOAc (400 mL) and H2O (400 mL) were added. The mixture was then acidified with 2 N HCl (approximately 800 mL) to pH 2.5. The organic layer was separated, and the aqueous phase was extracted twice with EtOAc (400 mL). The combined organics were washed with H2O (400 mL), aqueous NaHCO3 (400 mL), and brine (400 mL), dried over MgSO4, then filtered, before the solvents were removed in vacuo. The resultant solid was dissolved in CH2Cl2 (200 mL), then hexane (400 mL) was added to the solution to precipitate the product. The resultant slurry was filtered, and the collected solids were placed under vacuum in an oven at ambient temperature to yield the desired product, 109.8 g (99.8%). LC-MS (ES) m/e 311.5 (M+H)+.

1. temperatureto maintain
2. additionAfter the addition
3. customThis solution was transferred to a jacketed addition funnel
4. additiondid not exceed 0° C. over the course of the addition
5. customThe resultant reaction mixture
6. stirringwas stirred for an additional 1 h at 0° C
7. additionwere added
8. customThe organic layer was separated
9. extractionthe aqueous phase was extracted twice with EtOAc (400 mL)
10. washThe combined organics were washed with H2O (400 mL), aqueous NaHCO3 (400 mL), and brine (400 mL)
11. dry with materialdried over MgSO4
12. filtrationfiltered, before the solvents
13. customwere removed in vacuo
14. dissolutionThe resultant solid was dissolved in CH2Cl2 (200 mL)
15. additionhexane (400 mL) was added to the solution
16. customto precipitate the product
17. filtrationThe resultant slurry was filtered
18. customthe collected solids were placed under vacuum in an oven at ambient temperature

ORDレコード

ord-c5bcf3655a114209be819771ba659637

出典データセット

uspto-grants-2010_10

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US07816395B2