N-Boc-cis-4-Hydroxy-L-proline

White powder

The reducing agent (4.0 to 5.0 e.q.) was added to the solvent, Cold to a certain temperature, Add the substrate in batches to exotherm, HPLC monitoring reaction, Reaction is completed, The reaction solution was added to water, Cooling to 0 ~ 5C, With dilute hydrochloric acid pH 2 ~ 3, EA extraction(5X * 3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the crude product. The crude productThe product was crystallized from a mixed solvent of ethyl acetate and alkane.Commercially available (Aldrich) compound 6 (525 mg, 4 mmol) was dissolved in water (10 mL) and THF (5 L). NaOH (aq) was added to give pH 9-10. Boc anhydride (959 mg, 4.4 mmol) was dissolved in THF (2 mL) and added to the reaction dropwise. The reaction was maintained at a pH 9-10 with NaOH (aq). Upon completion, the reaction was acidified to pH of 3 with dilute HC1 (aq) and extracted with EtOAc (2x). The organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a Boc-protected proline (compound 6a) as a solid. This solid was washed with hexanes (3x) and dried under high vacuum to give the intermediate (882 mg, 95percent) which was then dissolved in anhydrous DMF (5 mL).HOBt (641 mg, 4.18 mmol) and EDAC (874 mg, 4.56 mmol) were added and stirred for 15 minutes. Compound 2 (1.87 g, 4.2 mmol) and TEA (1.1 ml, 7.6 mmol) were added and the reaction was stirred for 4 hours. The reaction material was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate solution (3x) and saturated aqueous sodium chloride solution. The organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The material was purified with CombiFlash (0-10percent MeOH in DCM) to give compound 7 (345mg, 15percent). Mass Spectrum (m/e): (M+H)To a solution of (2S, 4S)-4-hydroxypyrrolidine-2-carboxylic acid (3.9 g, 29.7 mmol) in THF (26.7 mL) and water(13.3 mL) was added di-tert-butyl dicarbonate (7.14 g, 32.7 mmol) and sodium hydroxide (2.0 N, 22.9 mL, 45.8 mmol)and the mixture stirred at room temperature overnight. The mixture then had 10percent citric acid (50 mL) added followed byEtOAc and extraction with water and brine. The organic extract was dried, filtered and concentrated to afford 5.31 g(77percent) of the title compound. MS (ESI) m/z 232 (M+H)+.Example 127A Synthesis of Compound 74 N-Boc-cis-4-hydroxyproline methyl ester (73) (1.3 g, 5.3 mmol) was dissolved in ethanol (20 mL). To the solution was added 2 N NaOH aqueous solution (5.3 mL, 10.6 mmol). The reaction was completed after 4 h, and was acidified with 10percent citric acid. Ethanol was evaporated, and the final product recovered by extraction with ethylacetatetwater. The organic layer was dried over sodium sulfate, filtered, and concentrated to yield N-Boc-cis-4-hydroxyproline (74) (960 mg, 78percent)A mixture of 1 -tert-butyl 2-methyl (2S, 4S)-4-hydroxypyrrolidine- 1 , 2-dicarboxylate (5 g, 20.39 mmol, 1.00 equiv), methanol (100 mL), water (20 mL), and sodium hydroxide (2.85 g, 71.26 mmol, 3.50 equiv) was stirred for 12 h at 20°C. The resulting solution was concentrated and dissolved in water. The pH value of the solution was adjusted to 3-4 with 5percent of HC1, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in the title compound (2.4 g, 51percent) as a white solid.

Molecular Weight:231.25
XLogP3:0.3
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:3
Exact Mass:231.11067264
Monoisotopic Mass:231.11067264
Topological Polar Surface Area:87.1
Heavy Atom Count:16
Complexity:296
Undefined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes