tert-Butyl 3-bromopropylcarbamate

White low melting solid

Reference Example 4 In 20 ml of 6 dichloromethane, 1.222 g (5.58 mmol) of 3-bromopropylamine hydrobromide was dissolved, 0.778 ml (5.58 mmol) of 126 triethylamine was added thereto under ice-cooling, and 50 ml dichloromethane solution of 1.214 g (5.56 mmol) of Boc3-Bromopropylamine hydrobromide (100 g, [457] mmol) was suspended in 1.6 L of anhydrous THF. This mixture was cooled to [0°C] in an ice/water bath and stirred vigorously while 190 mL of triethylamine was added. To this mixture was added dropwise tert-butoxycarbonyl anhydride (112.6 g, 516 mmol) in 200 mL THF. The ice bath was allowed to warm to ambient temperature and the mixture was stirred overnight at which time TLC indicated the reaction was complete. The mixture was then filtered and the filtrate was concentrated under vacuum. The residual oil was diluted with 1500 mL hexane and stored at-20°C for 3 days. The mixture was then decanted and the residual solid was dried under vacuum to give [101] g (94percent yield) of the title intermediate as a crystalline white solid. [APOS;H NMR (DMSO-D6, ] 300 MHz): [8] 1.35-1. 39 (s, 9H), 1.91-1. 95 [(M, ] 2H), 2.99-3. 04 (t, 2H), 3.43-3. 52 (t, 2H), 6.95-6. 99 (t, 1H).3-bromopropylamine hydrobromide 4 (5.00 g, 22.8 mmol) was dissolved in dry 100 ml dichloromethane and Boc 2 O (5.48 g, 25.1 mmol) and triethylamine (3.5 mL, 25.1 mmol) were added thereto. The reaction mixture was stirred at room temperature for 14 hours. Thereafter, 100 ml of dichloromethane was added, followed by washing with 1 M hydrochloric acid aqueous solution, water and brine in this order. The organic phase was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 5.17 g of Compound 5 as a colorless oil. Yield 95percent.To a mixture of 3-bromopropan-1 -amine hydrobromide (98.5 g, 45 mmol, 1 .0 eq) and Boc20 (93.3 g, 42.8 mmol, 0.95 eq) in DCM (500 ml) was added dropwise DIPEA (64.0 g, 49.5 mmol). The resulting mixture was stirred at room temperature overnight. Then, the reaction mixture was washed with water, 1 N HCI and brine, dried over Na2S04 and filtered. The solvent was evaporated to give the expected compound (95.8 g, 94percent yield) as a white solid.To a suspension of NaH (60 percent in mineral oil) (1 1.1 g, 278 mmol, 1 .3 eq) in DMF (150 ml) was added dropwise a solution of 2-(1 H-indol-3-yl)acetamide (37.2 g, 214 mmol, 1 .0 eq) in DMF (150 ml) at 0°C under N2 and the reaction mixture was stirred for 30 min. Then a solution of the previous compound (55.9 g, 235 mmol, 1.1 eq) in DMF (100 ml) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 30 min and at room temperature for 10 hrs. The reaction mixture was diluted in water (500 ml) and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2S04 and filtered. The solvent was evaporated under vacuum. The crude product was purified by column chromatography over silica gel eluted with MeOH/DCM (0/100 to 3/97) to give the intermediate 3 (52.8 g, 75percent yield) as a solid.A solution of 3-bromopropylamine hydrobromide (1.0 g, 4.6 mmol) in a 2:1 dioxane/H2O (45 mL) was cooled to 0° C. and treated with K2CO3 (6.22 g, 45 mmol) and di-tert-butyl dicarbonate (1.5 g, 6.9 mmol). The reaction was stirred for 15 h while warming to room temperature. The dioxane was removed in vacuo and the remaining aqueous mixture was acidified with 5 N HCl and extracted with ethyl acetate (5*25 mL). The combined organic layers were dried with MgSO4 and yielded 3-bromo-N-(tert-butoxycarbonyl)propylamine as a colorless oil (0.93 g, 93percent). 1H-NMR (CDCl3/TMS, ppm): 1.41 (s 9H, CH3), 2.02 (quintet, J=6.4 Hz, 2H, CH2), 3.23 (m, 2H, NCH2), 3.41 (t, J=6.6 Hz, CH2Br), 4.8 (broad, 1H, NH); 13C-NMR (CDCl3, ppm): 28.3 (CH3), 30.7, 32.6, 38.9 (CH2), 79.3 (quaternary C), 155.9 (CO); MS (CI, m/z): 239, 241 (M+H+ Calc. for C8H16BrNO2 237.03644).-Butyl (3-bromopropyI)carbamate. To a suspension of 3-bromopropylamine hydrobromide (10 g, 45.7 mmol) in CHDi-tert-butyl dicarbonate (3.71 g, 16 9 mmol) and triethylamine (10 mL). were added to a solution of 3-bromopropylamine hydrobromide 3 (3.72 g, 16.9 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at room temperature for 12 hours. The reaction progress was monitored by TLC. After this period, the reaction was complete. The solvent was removed under reduced pressure. Saturated sodium chloride solution (100 mL) was added to this residue and the mixture was extracted with diethyl ether (2×50 mL). The organic phases were combined, washed with saturated sodium chloride solution (3×50 mL) and dried over sodium sulfate. After filtration, the solvent was removed under reduced pressure to give compound 4 in the form of a slightly brown solid. The compound was sufficiently pure to be used in the rest of the synthesis without further purification (3.50 g, 87percent). di-tert-Butyl dicarbonate (3.71 g, 16.9 mmol) and triethylamine (10 mL) were added to a solution of 3-bromopropylamine hydrobromide 7b (3.72 g, 16.9 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After this time, reaction was complete. The solvent was removed under reduced pressure. A saturated solution of sodium chloride (100 mL) was added to this residue and the mixture was extracted with diethyl ether (2×50 mL). The organic phases were combined, washed with a saturated solution of sodium chloride (3×50 mL) and dried over sodium sulfate. After filtration, the solvent was removed under reduced pressure to give compound 8 in the form of a slightly brown solid. The compound was sufficiently pure to be used in the rest of the synthesis without additional purification (3.50 g, 87percent). M.p.: 32-33° C. To a solution of 3-bromopropylamine hydrobromide (100 g, 457 mmol) in water (250 mL) was added a solution of di-tert-butyl dicarbonate (49.84 g, 228 mmol) in dichloromethane (600 mL). The resulting biphasic mixture was stirred vigorously, then a solution of sodium hydroxide (36.56 g, 914 mmol) in water (250 mL) was added and the mixture was stirred at room temperature for 3 to 16 hours. The organic layer was washed sequentially with water, 0.2 N HCl until the pH reached 1, then again with water until the pH reached 6 to 7. The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 45.18 grams (83percent) of l-tert-butoxycarbonylamino-3-bromopropane as a pale orange oil. In a solution of 3-bromopropan-1 -amine hydrobromide (1.00 g, 0.46 mmol) in THE (40m1) trimethylamine (imI, 0.58 mmol) is added and the resulting reaction mixture isstirred for half an hour, then catalytic amount of 2-methylaminopyridine is added into the reaction mixture. Einally, in ice cold condition 1.23 ml of Boc anhydride is also added into it, in a dropwise manner and the reaction mixture is stirred for overnight. Now slowly, the reaction mixture is quenched with ammonium chloride and extracted with ethyl acetate. The combined organic phase is washed with brine and finally dried over anhydrousNa2504. The crude product is further purified by flash chromatography by using 60-1 20mesh silica gel and ethyl acetate/hexane as mobile phase. The product tert-butyl (3-bromopropyl)carbamate is obtained as a yellowish solid upon cooling at 4 00 (Yield: 0.9 g(83percent))Example A: 2-Amino-N-(3-(3-(2, 5-dioxo-4-(3, 4, 5-trimethoxyphenyl)-2, 5-dihydro-1H-pyrrol-3-yl)-1H-indol-1-yl)propyl)-4-methylpentanamideTert.-butyl-3-bromopropylcarbamate A modified procedure of Wescott et al. (J. Org. Chem. 2003, 68(26): 10058-10066) was used to prepare the title compound. A solution of NaHCOExample A: 2-Amino-N-(3-(3-(2, 5-dioxo-4-(3, 4, 5-trimethoxyphenyl)-2, 5-dihydro-1 H- pyrrol-3-yl)-1 H-indol-1 -yl)propyl)-4-methylpentanamide rerf.-butyl-3-bromopropylcarbamate A modified procedure of Wescott et al. (J. Org. Chem. 2003, 68(26): 10058-10066) was used to prepare the title compound. A solution of NaHC03-Bromopropylamine hydrobromide (105.10 g, 0.480 mol) was placed in a 2 L four-necked flask, and 978.88 g of dichloromethane and 115.8 g of di-tert-butyl dicarbonate (115.13 g, 0.528 mol) And the mixture was stirred at 0 ° C. (ice bath). Then, triethylamine (92.58 g, 0.915 mol) was added to the dropping funnel and added dropwise to the slurry solution in the four-necked flask over 30 minutes. After the start of the dropwise addition, the reaction solution vigorously foamed and a white solid precipitated. After completion of the dropwise addition, the mixture was stirred for 2 hours. After completion of the reaction, 500 ml of pure water was added to the reaction solution and extracted. The obtained organic layer was washed twice with pure water and dried with anhydrous magnesium sulfate. After removing the desiccant, the solvent was distilled off to obtain a colorless transparent oil. 500 ml of hexane was added to this oily substance and crystallization was carried out at -78 ° C. to obtain a white solid. The solid was collected by suction filtration and dried under reduced pressure. It was confirmed by 1 H-NMR measurement that the obtained white solid was tert-butyl 3-bromopropyl carbamate. The yield was 89.55 g and the yield was 78.3percent.To a stirred solution of 3-bromopropan-l -amine hydrobromide (AQ; 1.0 g, 4.56 mmol) in CHIn a 100 mL flask with 3-Bromo-1-propamine hydrobromide salt (11, 4.4 g, 0.02 mol) and pyridine (10 mL) dissolved in 100 mL tetrahydrofuran/20percentNaOH (w/w) aqueous solution (v/v = 1/1) mixed solution, then di-tert-butyl dicarbonate (BocA CHTo a solution of tert-butyl 3-hydroxypropylcarbamate (5 g, 28.57 mmol) indichloromethane (200 mL) was added triphenylphosphine (1 1.52 g, 42.85 mmol) followed by carbon tetrabromide (14.22 g, 42.85 mmol) at 0 °C. The reaction mixture was stirred at rt for 18 h while monitoring by TLC. The solvent was removed under reduced pressure and the residue was purified by column chromatography (60- 120 mesh silica gel) using 5-10percent ethyl acetate in pet-ether to give tert-butyl 3 -bromopropylcarbamate (4.5 g, 66.46percent) as a light-brown liquid. 1H NMR (400 MHz, CDC1Triphenylphosphine (1.553 g, 5.9 mmol) was dissolved in 30 mL of dichloromethane and cooled to 0° C. Triethylamine (0.830 mL, 5.9 mmol) was added via syringe. To a mixture of 3-bromopropan-l -amine (10.95 g, 50 mmol) and TEA (15.4 mL, 110 mmol) in DCM (100 ml) at 0 °C was added (Boc)The NaOH solution (1 N, 132 ml) is slowly added to the 3 - bromo - propylamine hydrobromide 9 (13.40 g, 60 mmol) of di-T-butyl ester and ((Boc)2 O, 13.1 g, 60 mmol) in THF (200 ml) stirring in the mixture, the reaction mixture stirring at room temperature 3 h. After removing the THF, the residue redissolved in diethyl ether (60 ml) in, for HCl (1 N), saturated NaHCO3 And NaCl washing, by Na2 SO4 Drying. The mixture is filtered and concentrated, to obtain compound 10 of light yellow oily matter (13.42 g, 94percent).3-bromopropylamine hydrobromide 1(4.000 g, 18.3 mmol) and di-tert-butyl dicarbonate (7.987 g, 36.6 mmol) were dissolved in anhydrous DCM (100 mL) under nitrogen gas flow. To the stirred solution was added DiPEA (3.50 mL, 20.2 mmol). After 12 hours the solvent was removed and the residue dissolved in ethanol (10 mL) to which imidazole(18.7 mmol) was added and stirred for 30 minutes. The mixture was diluted with chloroform (100 mL) and washed with 1percent HCI solution (3 x 50 mL). The organic phase was dried with sodium sulphate and evaporated to yield 2 (4.389 g, 95percent). 1H NMR (500 MHz, CDCI3): O 3.44 (t, J = 6.5 Hz, 2H), 3.27 (t, J = 6.5 Hz, 2H), 2.05 (p, J = 6.5 Hz, 2H), 1.44 (5, 9H).3-(2, 5, 7, 8-Tetramethyl-(2R-(4R, 8, 12-trimethyltridecyl)chroman-6-yloxy)propyl-1-ammonium Chloride (19) 3-(2, 5, 7, 8-Tetramethyl-(2R-(4R, 8, 12-trimethyltridecyl)chroman-6-yloxy)propyl-1-ammonium Chloride (19) 3-(2, 5, 7, 8-tetramethyl-(2R-(4R, 8, 12-trimethyltridecyl) chroman-6-yl oxy)propyl-1-ammonium chloride (1 9) Step 1:

Molecular Weight:238.12
XLogP3:2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:5
Exact Mass:237.03644
Monoisotopic Mass:237.03644
Topological Polar Surface Area:38.3
Heavy Atom Count:12
Complexity:143
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes