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

Temperature

-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 record

ord-cdebee24e1e64ad78b2c56758ce9f5fc

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08415480B2