反应详情

温度

40 °C

BOC proline (CAS 15761-39-4) and 2-(R)-methyl-pyrrolidine hydrochloride (CAS 135324-85-5) are coupled in a manner substantially analogous to Procedure A in dichloromethane to give 2(S)-(2(R)-methyl-pyrrolidine-1-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester. The material is deprotected by stirring in dichloromethane at 5-10° C. while trifluoroacetic acid (10 eq,) is added and then stirred at room temperature for 18 hours. The reaction is concentrated and is dissolved in H2O. The pH is adjusted to 8-9 with K2CO3, and is extracted several times with CH2Cl2. The extracts are combined, dried (Na2SO4) and concentrated in vacuo to give (2(R)-methyl-pyrrolidin-1-yl)-pyrrolidin-2-yl-methanone. A 1 M lithium aluminum hydride/THF solution (3 eq.) is diluted with an equal volume of THF and stirred under N2 as a THF solution of (2(R)-methyl-pyrrolidin-1-yl)-pyrrolidin-2-yl-methanone is added dropwise, allowing the reaction to mildly exotherm. Reaction is stirred at 40° C. for 45 minutes, then at room temperature 18 hours. Reaction is cooled in an ice bath and is quenched with H2O (3 eq.), 4 N NaOH (3 eq.), and H2O (9 eq.) maintaining the reaction temperature less than 15° C. The reaction is stirred overnight, filtered, and the precipitate is washed three times with THF. The filtrate and washes are combined and concentrated to give 2-(R)-methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) m/e 169.3 (M+H)+ Intermediate is used as such or is purified by SCX chromatography or distillation.

1. additionis added dropwise
2. customthe reaction to mildly exotherm
3. customReaction
4. customat room temperature
5. custom18 hours
6. customReaction
7. temperatureis cooled in an ice bath
8. temperaturemaintaining the reaction temperature less than 15° C
9. stirringThe reaction is stirred overnight
10. filtrationfiltered
11. washthe precipitate is washed three times with THF
12. concentrationconcentrated