4-Methylmorpholine → tert-butyl 2-({[(1S)-3-hydroxy-1-phenylpropyl]amino}carbonyl)-1,3-thiazolidine-3-carboxylate

温度

-25 °C

Commercial 3-(tert-butoxycarbonyl)-1,3-thiazolidine-2-carboxylic acid (III) (1 g, 4.29 mmol) was dissolved in dry THF (50 ml). A mechanical stirrer was placed in the flask and the solution stirred vigorously. The solution was cooled down to −25° C. and N-methyl morpholine (1.084 g, 10.72 mmol) was added in dry THF (5 ml). A solution of isobutyl-chloroformate (0.615 g, 4.5 mmol) in dry THF (10 ml) was then added dropwise over a period of 10 minutes with continued vigorous stirring, the reaction's exotherm being maintained at the optimal temperature of −25° C. by the use of a dry-acetone bath. After the complete addition of the chloroformate, the reaction mixture was stirred at −25° C. for 30 min after which time an amine (IV)/(IV*), e.g., (3S)-3-amino-3-phenyl-1-propanol (0.778 g, 5.14 mmol) was added drop-wise over a period of 10 min. The reaction mixture was allowed to gradually warm to room temperature and stirred overnight. The solvent was removed and the residue re-dissolved in ethyl acetate (150 ml). The organic layer was washed subsequently with a saturated solution of ammonium chloride (100 ml), saturated bicarbonate (100 ml) and brine (100 ml). Organics then dried with magnesium sulfate and concentrated in vacuo. The product (V), e.g., tert-butyl 2-({[(1S)-3-hydroxy-1-phenyl-propyl]amino}carbonyl)-1,3-thiazolidine-3-carboxylate, was finally obtained as a white foam (1.5 g, 95%). The antipodal intermediate, tert-butyl 2-({[(1S)-3-hydroxy-1-phenyl-propyl]amino}carbonyl)-1,3-thiazolidine-3-carboxylate, as well as the racemic inter-mediate, tert-butyl 2-({[3-hydroxy-1-phenylpropyl]amino}carbonyl)-1,3-thiazolidine-3-carboxylate were made according to the same protocol, starting from commercial (3R)-3-amino-3-phenylpropan-1-ol or 3-amino-3-phenylpropan-1-ol, respectively.

1. customA mechanical stirrer was placed in the flask
2. temperaturethe reaction's exotherm being maintained at the optimal temperature of −25° C. by the use of
3. customa dry-acetone bath
4. additionAfter the complete addition of the chloroformate
5. additionwas added drop-wise over a period of 10 min
6. temperatureto gradually warm to room temperature
7. stirringstirred overnight
8. customThe solvent was removed
9. dissolutionthe residue re-dissolved in ethyl acetate (150 ml)
10. washThe organic layer was washed subsequently with a saturated solution of ammonium chloride (100 ml), saturated bicarbonate (100 ml) and brine (100 ml)
11. dry with materialOrganics then dried with magnesium sulfate
12. concentrationconcentrated in vacuo

ORDレコード

ord-cdebee24e1e64ad78b2c56758ce9f5fc

出典データセット

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08415480B2