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

HRID 552578Notes

Reaction equation

HRID 552578 reaction equation
[C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1>ClCCl>[C:4]([O:3][C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:19]1[CH2:20][CH2:21][CH2:22][C@H:18]1[CH3:17])=[O:12])=[O:2])([CH3:5])([CH3:6])[CH3:7]

Participants

4

Reactant 2

HCID 850831,2-Pyrrolidinedicarboxylic acid, 1-(1,1-dimethylethyl) ester, (2S)-HCID 11147704(2R)-(-)-2-Methylpyrrolidine hydrochloride

Product 1

HCID 67164292HCID 67164292, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

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.

Sources & evidence

ORD record
ord-9086720f906f4a55af0136d29e6bb310
Source dataset
uspto-grants-2011_05
Patent number
US07951826B2

Reaction notes

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