Water → (R)-2-methyl-1-((S)-pyrrolidin-2-ylmethyl)pyrrolidine

Temperature

40 °C

BOC proline (CAS 15761-394) 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. Reaction is concentrated, is dissolved in H2O, 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. The reaction mixture is stirred at 40° C. for 45 minutes, then at room temperature 18 hours. The mixture is cooled in an ice bath and is quenched with H2O (3 eq.), 4 N NaOH (3 eq.), then H2O (9 eq.) while keeping reaction temperature less than 15° C. The mixture 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+) 169.3 (M+H)+ The title compound is used as such or is purified by SCX chromatography or distillation.

1. additionis added dropwise
2. customthe reaction
3. customat room temperature
4. custom18 hours
5. temperatureThe mixture is cooled in an ice bath
6. customreaction temperature less than 15° C
7. stirringThe mixture is stirred overnight
8. filtrationfiltered
9. washthe precipitate is washed three times with THF
10. concentrationconcentrated

ORD record

ord-9c1b247f9b9342689956c27725d3768d

Source dataset

uspto-grants-2010_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07696234B2