(R)-1-Boc-3-(aminomethyl)pyrrolidine

A stirred suspension of scheme 34 compound 2-4 and 10 % Pd/C (5 g, 21 mmol) in MeOH (80 mL) was stirred under H2 (2 atm) at RT for 1.5 h. The reaction mixture was diluted with EA and filtered through a short column of celite .The celite column was rinsed with additional portions of EA and the combine organics fractions were dried over Na2S04 and concentrated in vacuo to afford scheme 34 2-5 (3.4 g, yield: 80.2 %) which was used in the next step immediately without further purification.[0161] To a stirred solution of the crude azide (29) (295 mg, 1 equiv.) in MeOH/CHCl3 (2 mL each) was added 10% Pd on carbon (30 mg, 10%). The solution was evacuated, placed under a H2 atmosphere (1 atm) and stirred at rt for 16 h. The suspension was then filtered through celite and washed with MeOH. The filtrate was concentrated under reduced pressure to afford the desired primary amine (30).A stirred suspension of i- 13b (105 mg, 0.464 mmol) and 10 wt.% palladium on carbon (49.0 mg, 0.046 mmol) in methanol (4.50 mL) was stirred under hydrogen (1 Atm.) at rt for 1 h. The reaction mixture was diluted with EtOAc and filtered through a short column of Celite . The Celite column was rinsed with additional portions of EtOAc, and the combined organic fractions were dried (sodium sulfate) and concentrated in vacuo to afford the title compound i-13c. mlz (ES) 201 (MH)+.Step C: Preparation of fers-butyl 3-faminomethyl)pyrrolidme-1-carboxylate (i-14c) A stirred suspension of 1:14b (105 mg, 0, 464 mmol) and 10 wt. % palladium on carbon (49.0 mg, 0.046 mmol) in methanol (4.50 mL) was stirred under hydrogen (1 Atm.) at rt for 1 h. The reaction mixture was diluted with EtOAc and filtered through a short column of Celite. The Celite column was rinsed with additional portions of EtOAc, and the combined organic fractions were dried (sodium sulfate) and concentrated in vacuo to afford the title compound B4c. mlz (ES) 201 (MH)+.A solution of tert-butyl3-(hydroxymethyl)pyrrolidine-1-carboxylate (1.687 g, 8.4 mmol) in acetone (30mL) was treated with triethylamine (2.3 mL, 16.8 mmol) and the mixture wascooled to 0 C, then treated dropwise with methanesulfonyl chloride (1.3 mL, 16.8 mmol). After 30 min the mixture was concentrated under vaccum and theresidue obtained partitioned between ethyl acetate and water. The aqueous phasewas extraced twice with ethyl acetate and combined extracts were washedsequentially with 10 % (w/ w) aqueous citric acid solution, saturated sodiumhydrogen carbonate solution, and brine, dried (sodium sulphate) andconcentrated under vacuum to afford tert-butyl3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (S3) which wasused directly in the next step. A solution of last crude compound in DMF (5 mL)was treated with a solution of sodium azide (0.819 g, 12.6 mmol) in water (4mL) and the reaction mixture was heated at 100 C for 30 min. The cooledmixture was concentrated under vacuum and the residue obtained was partitionedbetween ethyl acetate and water. The aqueous phase was extracted twice withethyl acetate and the combined extracts were washed with water and brine, dried(sodium sulphate) and concentrated under vacuum to afford tert-butyl3-(azidomethyl)pyrrolidine-1-carboxylate (S4) which was used directly inthe next step. A solution of the crude tert-butyl3-(azidomethyl)pyrrolidine-1-carboxylate in THF (10 mL) was treated with water(1 mL) then triphenylphosphine (0.860 g, 3.3 mmol) and the reaction mixture washeated to 55 C overnight. The cooled mixture was concentrated under vacuum toa solid residue. The solid was triturated with ether (20 mL) and filtered, rinsing with ether. The filtrate was concentrated under vacuum and the residuewas subjected to column chromatography on silica gel to afford compound 11g (0.689g, 40 %). 1H NMR (400 MHz, CDCl3) delta 3.51-3.40 (m, 2 H), 3.30 (s, 1 H), 2.99-2.98 (m, 1 H), 2.72 (t, 1 H, J = 7.2 Hz), 2.63-2.61(m, 1 H), 2.30-2.21 (m , 1 H), 1.98 (br, 1 H), 1.53 (br, 4 H), 1.45 (s, 9 H).[0162] Following general procedure 11, to a stirred solution of the amine (30) (109 mg, 1 equiv.) and Et3N (130 uL, 1.7 equiv.) in CH2Cl2 (7 mL) was added benzenesulfonyl chloride (97 uL, 1.4 equiv.). The resultant mixture was stirred at rt for 16 h. The mixture was then diluted with EtOAc and washed successively with 10% citric acid, H2O and brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (50% EtOAc in hexane) to afford the desired coupled product. The N-Boc group of the coupled product was then converted to the cyanamide (N-CN) following general procedure 3 (i.e. successive treatment with TFA and BrCN). The crude material was purified by flash chromatography (50% EtOAc in hexane) to afford the desired N-[(1-cyano-3-pyrrolidinyl)methyl]benzenesulfonamide (31).Methanesulfonyl chloride (222 mg, 150 L, 1.938 mmol) was added to a stirred solution of Compound (1) (312.53 mg, 0.84 mmol) was dissolved in 22.5 mL of tetrahydrofuran, and 1-t-butoxycarbonyl-3-(aminomethyl)pyrrolidine (336.47 mg, 1.68 mmol) was added.2.25 mL of a 2.5 M sodium hydroxide solution was added and the reaction was stirred for 30 minutes. After the completion of the reaction, 50 ml of a saturated aqueous solution of ammonium chloride was added to the mixture, and the mixture was evaporated to ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure to give crude product 7.1.(382 mg, yellow solid), the product was taken to the next step without purificationGeneral procedure: To a solution of 12e (2.0 g, 21 mmol) in toluene (50 mL) tertbutyl4-aminopiperidine-1-carboxylate (4.9 g, 6.25 mmol) andZn(OTf)2 (1.6 g, 4.5 mmol) were added. The resulting mixture washeated at reflux for 8 h and then cooled down to r. t. It was pouredinto 10% aqueous 23 (40 mL) and extracted with ethyl acetate(3 50 mL). The combined organic extracts were dried overanhydrous Na2SO4, filtered and concentrated in vacuo. The residuewas fractionated by column chromatography on silica gel using0/2.5% gradient of methanol in chloroform to give, on evaporationof the volatiles, orange oil. It was dissolved in 1, 4-dioxane(10 mL) and 4M HCl in 1, 4-dioxane (3 mL, 12.0 mmol) was added.The mixturewas stirred at r. t. and the brown crystalline precipitatewas collected by filtration. Yield 46%, m. p. 194-196 C (decomp.).A stock solution of lithium l-benzyl-2-(l, 5-dimethyl-6-oxo-l, 6-dihydropyridin-3-yl)-lH- imidazole-4-carboxylate (for an example preparation, see Intermediate 13, 395 mg, 1.20 mmol) and HATU (456 mg, 1.20 mmol) was prepared in DMF (6 mL), to which was added DIPEA (0.66 mL, 3.8 mmol). The solution was shaken and 0.5 mL was transferred to a vial containing rac-tert-butyl 3-(aminomethyl)pyrrolidine-l-carboxylate (0.12 mmol). The vial was capped and stood at RT for 2 h. The solvent was removed and the sample redissolved in DMSO (0.5 mL) and purified by MDAP (Method B). The solvent was removed under a stream of nitrogen and the sample dissolved in a solution of DCM (0.5 mL) and HCI in 1, 4- dioxane (4M, 0.5 mL). The solution was capped and stood at RT for 1 h, after which the solvent was removed to afford the title compound as the hydrochloride salt (19.4 mg, 0.04 mmol, 40%). LCMS (System A): tRET = 0.49 min; MH+ 406.To a stirred solution of tert-butyl 3-cyanopyrrolidine-1 -carboxylate(mixture of isomers, 3.1 g, 15.8 mmol) and TEA (1.3 mL, 9.4 mmol) inEtOH (90 mL) Raney nickel (2.04 g, 23.7 mmol) was added under nitrogen. The reaction mixture was stirred at room temperature for 16 h under 30 psi hydrogen pressure then was filtered through celite washing with ethanol (50 mL). The solution was concentrated underreduced pressure to afford the title compound (2.6 g, 82% yield, yellow liquid) as a mixture of isomers. LC-MS (ELSD) mlz: 201.2 (M+H). 1HNMR (CDCI3): 6 3.49-3.41 (m, 4H), 3.00-2.99 (m, 1H), 2.73 (m, 2H), 2.23-2.22 (m, 1 H), 2.00 (m, 1 H), 1 .46 (5, 9H).

Molecular Weight:200.28
XLogP3:0.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:200.152477885
Monoisotopic Mass:200.152477885
Topological Polar Surface Area:55.6
Heavy Atom Count:14
Complexity:211
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes