1,2-Pyrrolidinedicarboxylic acid, 1-(1,1-dimethylethyl) ester, (2S)- → HCID 67164292, compound

Participants

Reaction Steps

Equimolar amounts of (S) 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 D 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 h. The reaction is concentrated, dissolved in H2O, and the pH is adjusted to 8-9 with K2CO3. The mixture is extracted several times with CH2Cl2. The extracts are combined, dried (Na2SO4), filtered, 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 min, and then at room temperature 18 h. The mixture is cooled in an ice bath and quenched with H2O (3 eq.), 4 N NaOH (3 eq.), then H2O (9 eq.) while keeping the 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.

Provenance & Evidence