1-BENZYLPYRROLIDIN-3-YL-METHANOL

Synthesis of (l-benzvl-pyrrolidin-3-vlmethvl)-methyl-amineStep a: Synthesis of l-(benzyl-pyrrolidin-3-yI)-methanolA solution of the compound l-benzyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (1.0 eq.) (commercially available) in toluene was cooled to 0°C under inert atmosphere. To the mixture was added solution of borane (3.75 eq.) in dimethyl sulphideand refluxed the mixture for 16 hours at 100°-110°C. The resulting reaction mixture was cooled to room temperature and subsequently to -5° to -10°C followed by the addition of sodium bicarbonate solution dropwise. The mixture was slowly brought to room temperature and subsequently refluxed the reaction mixture for 2 hours. The mixture was cooled and organic layer was separated. Aqueous layer was extracted with toluene. The combined toluene layers were washed with water and brine solution. The organic solvent was evaporated under reduced pressure to furnish the title compound. Yield: 99.14percent.Compound b was prepared by a similar procedure to Wu's (J. Org. Chem. 1961, 1519.) except using THF to dissolve methyl l-benzyl-5-oxo-3pyrrolidinecarboxylate: [0388] A solution of methyl 1-benzyl-5-oxo-3pyrrolidinecarboxylate (a) (8.00 g, 34.30 mmol) in 10 mL of anhydrous THF was slowly added to a slurry of powdered lithium aluminum hydride (1.82 g, 48.01 mmol) in 30 mL of absolute ether. The addition was made over a period of 0.5 hour with efficient stirring so as to maintain a moderate reflux rate. When the addition was complete, refluxing and stirring was continued for 2 hours, after which the reaction mixture was left at room temperature. The mixture was quenched with 3 mL of water, and stirred for 2 hours. The white precipitate was filtered and washed with 2.x.30 mL of ether. The solid was extracted with Soxhlet type apparatus in EtOH for 8 hours. Th EtOH was removed. The residue was washed with Et2O (3.x.20 mL). The Et2O solutions were combined, dried over MgSO4, and concentrated. The residue was distilled under vacuum. The fraction at 137-145° C./1 mmHg was collected to give compound b (4.0 g) as a colorless oil.The solution of lithium aluminumhydride (1N solution in THF, 22 mL) was added dropwise to the solution of the colorless oil from step 1 in anhydrous THF (30 mL) at 0° C. A. The organic phase was washed with water, dried over sodium sulfate and concentrated to yield 11.65 g of N-benzyl-3-hydroxymethylpyrrolidine. (MS) The alcohol (0.06 moles, 11.5 g) in 75 ml 2 N sulfuric acid was added dropwise to a stirred solution of chromium dioxide (0.15 moles, 15.0 g) in 100 ml 2 N sulfuric acid. The solution was stirred at room temperature for 16 hours. The solution was treated with barium hydroxide hydrate (0.317 mmoles, 100 g) in 250 ml hot water. The solid was filtered and washed with water. The aqueous solution was extracted with ether. Carbon dioxide was bubbled through the solution until the pH was 7.0.General procedure: A mixture of methyl 5, 6-dimethoxy-1-oxo-2, 3-dihydro-1H-indene-2-carboxylate 64 (0.53 g, 2.12 mmol, 1.1 eq.), the appropriate alcohol (1.88 mmol, 1.0 eq.) and amberlyst-15 (0.054 g, 10%wt of ketoester) in toluene (25 ml) was refluxed using a set-up with a distillation condenser to remove methanol. After completion ofthe reaction (as monitored by TLC), the catalyst was filtered off and the filtrate concentrated in vacuo. The residue was then acidified with 3 M aqueous hydrochloric acid (30 ml) and diluted with ethylacetate (30 ml). The aqueous layer was separated and the organiclayer washed with an additional 3M aqueous hydrochloric acid (2 xml). The aqueous layers were then combined and basified with solid potassium carbonate after which they were diluted with dichloromethane (30 ml). The organic layer was then separated andthe aqueous layer extracted with dichloromethane (2 x 25 ml). The organic layers were then combined, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to afford the product. The products were used without any further purification.To a stirred solution of methyl-1-benzyl-5-oxo-3-pyrrolidinecarboxylate 32 (3.00 g, 12.86 mmol, 1.0 eq.) in toluene (50 ml), was added Red-Al (20.06 g, 19.30 ml, 64.50 mmol, 65 wt % intoluene) at 15-20 C. The contents were stirred for 2-3 h at rt. The reaction was quenched by the slow addition of 10% aqueous sodium hydroxide (1 ml) and then diluted with water (40 ml). The contents were stirred for 30 min, and the toluene layer was separated, washed with a saturated solution of sodium chloride (30 ml). The organic layer was separated, dried (Na2SO4), filtered and evaporated in vacuo to yield (1-benzylpyrrolidin-3-yl)methanol 33 as a clear oil (1.41 g, 57%) which was used without any further purification. Rf 0.19 (10% methanol:dichloromethane); numax (neat)/cm-13341, 2792, 1450, 1050, 697; 1H NMR (300 MHz, CDCl3); delta 7.34e7.19(m, 5H, ArH's), 3.68-3.57 (m, 4H, -OH, CH2aOH & CH2Ph), 3.49 (dd, 1H, J 5.2 &10.1, CH2bOH), 2.77 (dt, 1H, J 4.5 & 8.8 Hz, CHCH2aN), 2.64-2.49 (m, 2H, CH2CH2N), 2.44-2.27 (m, 2H, CHCH2bN &CHCH2OH), 2.05-1.90 (m, 1H, CH2aCH2N), 1.73-1.59 (m, 1H, CH2bCH2N); 13C NMR (75 MHz, CDCl3); delta 138.44, 128.91, 128.43, 127.23, 67.20, 60.23, 58.04, 53.78, 38.93, 27.03; HRMS m/z (ESI)192.1422 ([M + H]+ requires 192.1383).

Molecular Weight:191.27
XLogP3:1.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:3
Exact Mass:191.131014166
Monoisotopic Mass:191.131014166
Topological Polar Surface Area:23.5
Heavy Atom Count:14
Complexity:166
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes