bicyclo[1.1.1]pentan-1-aMine

R)-2-(3-(N-(4-Chloro-3-fluorobenzyl)phenylsulfonamido)bicyclo[1.1.1]pentan-1-yl)-4, 4- dimethyl-4, 5-dihydro-1 H-imidazole-5-carboxylic acid hydrochloride (19, 500 mg, 0.92 mmol) was dissolved in MeCN, and DIEA (357.4 mg, 2.8 mmol, 3.0 equiv), bicyclo[1.1.1]pentan-3- amine hydrochloride (20, 165.3 mg, 1.4 mmol, 1.5 equiv), and COMU (473.7 mg, 1.1 mmol, 1.2 equiv) were added thereto. After stirring at room temperature for 2 h, the solvent was removed under reduced pressure and the residue was purified by preparative TLC (CHCh MeOH = 9:1 (v/v)) to give 21 as white solid (198.0 mg, 37%). MS: M/z Observed (m+H) 572. NMR: 1 H NMR (400 MHz, Methanol-d4) d 1.01 (s, 3H), 1.28 (s, 3H), 2.03 - 2.09 (m, 12H), 2.40 (s, 1 H), 3.77 (s, 1 H), 4.54 (s, 2H), 7.22 - 7.27 (m, 1 H), 7.31 (dd, J = 10.2, 2.0 Hz, 1 H), 7.46 (t, J = 7.9 Hz, 1 H), 7.58 - 7.65 (m, 2H), 7.66 - 7.73 (m, 1 H), 7.87 - 7.93 (m, 2H).To a solution of bicyclo[1.1.1]pentan-1 -amine hydrochloride (0.134 g, 1.1 eq.) in pyridine (20 mL) 3-fluoro-4-[5-(trifluoromethyl)-1 , 2, 4-oxadiazol-3-yl]benzoyl chloride (0.3 g, 1.0 eq.) was added slowly. The mixture was stirred for one hour at ambient temperature, concentrated to dryness and diluted with ethyl acetate and 5N aqueous solution of hydrochloric acid. The organic layer was separated, washed successively with brine and aqueous solution of sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated to dryness to afford the title compound as a white solid. Melting point: 191 C. 1H-NMR (MeOD, 400 MHz): d [ppm] = 2.2 (s, 6H), 2.5 (s, 1 H), 4.9 (m, 1 H), 6.0 (m, 1 H), 7.8 (m, 2H), 8.2 (m, 1 H).A mixture of 4-fluoro-2-(methylsulfonamido)benzoic acid (0.12 g, 0.52 mmol) and 1-Bicyclo[l.1. l]pentan-l -amine, HC1 (504 mg, 4.21 mmol) was suspended m methylene chloride (8 mL) under nitrogen. Triethylamine (1175 m, 8.43 mmol) was added and the reaction was cooled in an ice bath. 4-Nitrophenyl chloroformate (1019 mg, 5.06 mmol) was then added. LCMS shows a prominent peak with the desired mass for product. After 4 hours, the reaction was quenched with water and extracted with methylene chloride. The organic phase was washed with brine. Drying over magnesium sulfate, filtration and evaporation provided the crude 4-nitrophenyl bicycloj 1.1.1 Jpentan- l-ylcarbamate (1.02 g) as a colorless solid. This material was used in the subsequent step without purification. Diethyl 2-(aminomethylene)malonate (326 mg, 1.741 mmol) and 4- mtrophenyl bicyclo[l. l. l jjpentan-l-ylcarbamate (865 mg, 3.48 mmol) were dissolved in dioxane (1.5 mL). Diisopropyl ethylamine (608 m, 3.48 mmol) was added and the reaction vial was sealed and heated to 70 C overnight. The cooled reaction was diluted with ethyl acetate and wshed sequentially with water, 1 N hydrochloric acid, w'ater and brine. Drying over magnesium sulfate, filtration and evaporation provided the crude product. This material was applied to an 80 g Isco silica gel column and eluted with 0- 50% ethyl acetate in hexanes. Evaporation provided diethyl 2-((3-(bicyclo|T. l.l]pentan- l-yl)ureido)methylene)ma.onaie. Tins material was dissolved in ethanol (2 mL) under nitrogen. A solution of sodium ethoxide in ethanol (486 pi, 1.312 mmol) w'as added and the reaction stirred for ca. 1 hour. The reaction ws then quenched with 5% citric acid to generate a precipitate. The solid ws filtered, rinsed with wter and hexanes. Air drying gave ethyl 3-(bicyclo[l.1. l]pentan-l -yl)-2, 4-dioxo-l, 2, 3, 4-tetrahydropyrimidine-5- carboxylate (125 mg, 0.499 mmol). NMR (400 MHz, DMSO-de) 6 11 97 - 11.37 (m, 1H), 8.05 (s, 1H), 4.15 (q, J=7.1Hz, 2H), 2.35 (s, 6H), 1.23 (t, J=7.1Hz, 3H) (a peak - I l l - appears to be obscured by the DMSO); LCMS (M+H) = 251.2. HPLC RT 0.67 min (Waters Acquity SDS using the following method; Linear Gradient of 2% to 98% solvent B over 1.7 min; UV visualization at 220 nm; Column: BEH C18 2.1 min x 50 mm; 1.7 um particle (Heated to Temp. 50 C); Flow rate: 0.8 ml/min; Mobile phase A: 100% Water, 0.05% TFA; Mobile phase B: 100% Acetonitrile, 0.05% TFA).General procedure: N, N-Diisopropylethylamine (1.4-1.5 eq., or 2.4-3.0 eq. when the amine was used in hydrochloride form) and HATU (1.0-1.65 eq.) were added to a solution of the corresponding carboxylic acid (1 eq.) in DMF (0.08-0.12M), and the mixture was stirred at RT for 30 min. Subsequently, the appropriate amine (1.04-1.5 eq.) was added and the mixture was stirred at room temperature for a further 0.15-2 h. The reaction was then terminated by the addition of water and 1 M aqueous hydrochloric acid. The precipitate was filtered off, taken up in DCM, dried over magnesium sulfate and filtered, and the solvent was removed under reduced pressure. Alternatively, the acidification was followed by extraction with ethyl acetate, drying of the combined organic phases over magnesium sulfate or sodium sulfate, filtration and removal of the solvent under reduced pressure. The crude product was then purified either by normal phase chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures) or by preparative RP-HPLC (water/acetonitrile gradient). Alternatively, the reaction mixture was diluted with a little acetonitrile, water and formic acid and the crude solution obtained was purified by RP-HPLC (water/acetonitrile gradient). Further alternatives for work-up, if carried out, are described with the respective experiment.To a suspension of 4-[[2-(5-tert-butyl-2-hydroxy-phenyl)acetyl]amino]pyridine-2-carboxylic acid (step 3) (25 mg, 0.08 mmol) in DMF (0.5 mL) was added bicyclo[1.1.1]pentan-3-amine h drochloride 11 m 0.09 mmol DIPEA 0.05 mL, 0.3 mmol) and HATU (43 mg, 0.11 urs, the mixture was partitioned between us portion extracted with EtOAc (2 x 20 d with water (20 mL), brine (20 mL), dried de residue was purified by C18 reverse- N in water with 0.1% formic acid to afford the titled compound as a white powder.1H NMR (500 MHz, DMSO-d6) delta 10.70 (s, 1H), 9.28 (s, 1H), 9.07 (s, 1H), 8.44 (d, J = 5.5 Hz, 1H), 8.16 (d, J = 2.1 Hz, 1H), 7.84 (dd, J = 5.5, 2.2 Hz, 1H), 7.16 (d, J = 2.5 Hz, 1H), 7.08 (dd, J = 8.4, 2.5 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 3.65 (s, 2H), 2.44 (s, 1H), 2.09 (s, 6H), 1.23 (s, 9H). LC-MS (Method A): Rt 3.71 mins; MS m/z 394 = [M+H]+Synthesis of 3-(bicyclo[1.1.1]pentan-1-yl)-1, 5, 3-dioxazepane 25 M Sodium hydroxide (4 mL) was added to a 1:1 mixture of A microwave vial was charged with ethyl 2-(3-bromo-4-methylphenyl)-3, 3, 3- trifluoro-2-hydroxypropanoate (53 mg, 0.16 mmol) (single enantiomer from Example 82, Step 3) and bicyclo[l. l. l]pentan-l-amine hydrochloride (93 mg, 0.78 mmol). The vial was placed under nitrogen, and then tetrahydrofuran (1.3 mL) and triethylamine (0.22 mL, 1.6 mmol) were added. The vial was placed in 0 C bath, and trimethylaluminum (0.39 mL, 0.78 mmol, 2 M in toluene) was added dropwise. The reaction mixture was warmed to rt. The vial was sealed, and the reaction mixture was heated at 80 C. After heating for 15 min, the reaction mixture was cooled slightly and vented to relieve pressure. The reaction mixture was then heated for 2.5 h at 80 C. Heating was discontinued, and the reaction mixture sat at rt for 2 d. The reaction mixture was added slowly into 1 N HC1 (5.5 mL) that was cooled to 0 C, resulting in gas evolution. The aqueous mixture was warmed to rt and extracted with ethyl acetate (3 x 4 mL). The combined organics were washed with sat. NaHC03 (8 mL) and brine (8 mL). The organic layer was then dried over MgSC , filtered, and concentrated. Purification via silica gel chromatography (1-4% MeOH/CH2Cl2) afforded the title compound as a white solid (50 mg, 84%). LCMS for Ci5Hi6BrF3N02 (M+H)+: calculated m/z = 378.0, 380.0; found 378.0, 380.0.[0302] To a solution of 1-80-6 (40 mg, 0.060 mmol, trifluoroacetic acid salt) in pyridine (0.5 mL) was added bicyclo[l. l. l]pentan-l-amine hydrochloride (21 mg, 0.18 mmol). The mixture was cooled to 0 C. HOBt (8 mg, 0.6 mmol, ) was added and the mixture was stirred at 0 C for 10 minutes. EDCI (34 mg, 0.18 mmol) was added to this mixture at 0 C. The reaction mixture was stirred at 0 C for 20 minutes and then stirred at 25 C for another 1.5 hours under a nitrogen atmosphere. The mixture was diluted with water (5 mL) then concentrated under reduced pressure. The residue was diluted with water (20 mL) and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. T he residue was purified by preparative reverse phase HPLC using a water/acetonitrile gradient with 0.1% trifluoroacetic acid additive. The isolated material was adjusted to pH = 7 with a saturated aqueous sodium bicarbonate solution. The mixture was concentrated under reduced pressure to remove volatile organics, then extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum to provide 1-80 (15 mg) as a white solid. LCMS of 1-80: RT = 2.420 min, m/z 628.3 [M+H]+.

Molecular Weight:119.59
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:1
Exact Mass:119.0501770
Monoisotopic Mass:119.0501770
Topological Polar Surface Area:26
Heavy Atom Count:7
Complexity:70.9
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes