1-Benzyl-4-phenyl-pyrrolidine-3-carboxylic acid hydrochloride synthesis

Yield:885958-91-8 40%

Reaction Conditions:

Stage #1: 1-benzyl-4-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylic acidwith hydrogen;triethylamine;[(R)-2,2'-bis(diphenylphosphino)-6,6'-dimethylbiphenyl]ruthenium-diacetate in methanol at 80; under 30003 Torr; for 42 h;
Stage #2: with sodium hydroxide in methanol;2-methoxy-2-methylpropane;lithium hydroxide monohydrate;
Stage #3: with hydrogenchloride in lithium hydroxide monohydrate at 0; pH=6;Product distribution / selectivity;

Steps:

I.13; I.13.1 Preparation of the Racemate:

EXAMPLE 13 OF I (3R,4R)-1-Benzyl-4-phenyl-pyrrolidine-3-carboxylic acid and (3RS,4RS)-1-benzyl-4-phenyl-pyrrolidine-3-carboxylic acid Preparation of the Racemate: In a glove box (O₂ content<=2 ppm) a 6 ml autoclave equipped with a glass insert and a magnetic stirring bar was charged with 50 mg (0.18 mmol) of 1-benzyl-4-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid, 5.5 mg (0.0072 mmol) of Ru(OAc)₂((rac)-BIPHEMP), 17.9 mg (0.179 mmol, 1.0 eq.) of triethylamine and 1 ml of methanol. The racemic hydrogenation was run for 42 h at 80° C. under 40 bar of hydrogen. After cooling to room temperature the pressure was released from the autoclave. The reaction mixture was diluted with 30 ml of tert-butyl methyl ether and extracted with two portions of a 1 M aqueous sodium hydroxide solution. The layers were separated and the aqueous phase was poured on ice. The pH was adjusted to pH 6 using 2 M aqueous hydrochloric acid solution. After extraction with three portions of dichloromethane (3*50 ml) the combined organic layers were dried over sodium sulphate, filtered and concentrated in vacuo to give (3RS,4RS)-1-benzyl-4-phenyl-pyrrolidine-3-carboxylic acid in 40% yield (20 mg). MS m/e (%): 280 (M-H⁺, 100). ; The reactions in Table 13 were performed according to the procedure above. TABLE 13 Reaction Scale NEt₃ Yield Major e.e. No. (g) S/C Catalyst (equiv.) t (h) (%)enantiomer^a) (%)^a) 1 0.05 25Ru(OAc)₂((rac)- 1 42 40 racemate - BIPHEMP) 2 0.05 25Ru(OAc)₂((S)3,5- 1 68 23 (+) 97.7 Xyl,4-MeO- MeOBIPHEP) 3 0.05 25Ru(OAc)₂((S)- 1 68 25 (+) 92.7 BITIANP) ^a)Optical rotation and ee of (+)-(3R,4R)- or (-)-(3S,4S)-4-(phenyl)-pyrrolidine-1,3-di carboxylic acid-1-tert-butyl ester obtained after debenzylation and N-tert-butoxycarbonyl protection of the primary hydrogenation product (3R,4R)- or (3S,4S)-1-benzyl-4-phenyl-pyrrolidine-3-carboxylic acid.

References:

US2007/232653,2007,A1 Location in patent:Page/Page column 25; 26