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CAS No. : | 5003-71-4 | MDL No. : | MFCD00012912 |
Formula : | C3H9Br2N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PQIYSSSTRHVOBW-UHFFFAOYSA-N |
M.W : | 218.92 | Pubchem ID : | 78701 |
Synonyms : |
|
Num. heavy atoms : | 6 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 36.04 |
TPSA : | 26.02 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.66 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 1.37 |
Log Po/w (WLOGP) : | -2.15 |
Log Po/w (MLOGP) : | 1.53 |
Log Po/w (SILICOS-IT) : | 0.55 |
Consensus Log Po/w : | 0.26 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.93 |
Solubility : | 2.58 mg/ml ; 0.0118 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.52 |
Solubility : | 6.62 mg/ml ; 0.0303 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.56 |
Solubility : | 6.06 mg/ml ; 0.0277 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.49 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.2% | at 20℃; for 3 h; | To a suspension of 3-bromopropylamine hydrobromide (50 g, 0.228 mol) in DCM (1000mL) were added (Boc)zO (52 g, 0.238 mol) and triethylamine (100 mL, 0.722 mol). Then thereaction was stirred at room temperature for another 3 hours. The solvent was removed in vacuo15 and the residue was washed with petroleum ether (500 mL). The mixture was filtered and thefiltrate was evaporated to give the title compound (54 g, 99.2 percent) as a colorless oil. 1H NMR(300 MHz, CDC13): 8 4.69 (brs, 1H), 3.43 (t, 2H, J = 6.6 Hz), 3.27- 3.23 (m, 2H), 2.10- 2.03 (m,2H), 1.27 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine In dichloromethane; ethyl acetate | Reference Example 4 Synthesis of Boc-aminopropyl bromide: In 20 ml of dichloromethane, 1.222 g (5.58 mmol) of 3-bromopropylamine hydrobromide was dissolved, 0.778 ml (5.58 mmol) of triethylamine was added thereto under ice-cooling, and 50 ml dichloromethane solution of 1.214 g (5.56 mmol) of Boc2O was further added dropwise thereto in 10 minutes, followed by stirring. After stirring at room temperature for 50 minutes, ethyl acetate was added thereto, followed by separation by washing with 5percent aqueous citric acid solution, water and saturated brine consecutively. After dehydration with sodium sulfate, the solvent was evaporated under reduced pressure to give 1.304 of the titled compound (98percent). The structure was identified by 1H-NMR. 1H-NMR (500 MHz,CDCl3) δ (ppm) = 1.44 (9H, s, Boc), 2.05 (2H, quant, -NHCH2CH2CH2Br), 3.28 (2H, q, -NHCH2CH2CH2Br), 3.44 (2H, t, -NHCH2CH2CH2Br), 4.64 (1H, s, NH) |
98% | With triethylamine In dichloromethane at 20℃; for 1 h; Cooling with ice | 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 Boc2O was further added dropwise thereto in 10 minutes, followed by stirring. After stirring at room temperature for 50 minutes, ethyl acetate was added thereto, followed by separation by washing with 5percent aqueous citric acid solution, water and saturated brine consecutively. After dehydration with sodium sulfate, the solvent was evaporated under reduced pressure to give 1.304 of the titled compound (98percent). The structure was identified by 1H-NMR. 1H-NMR (500 MHz,CDCl3) δ (ppm) = 1.44 (9H, s, Boc), 2.05 (2H, quant, - NHCH2CH2CH2Br), 3.28 (2H, q, -NHCH2CH2CH2Br), 3.44 (2H, t, -NHCH2CH2CH2Br), 4.64 (1H, s, NH) |
97% | With triethylamine In tetrahydrofuran at 0 - 20℃; | 3-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). |
95% | With triethylamine In dichloromethane at 20℃; for 14 h; | 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. |
94% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; | 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. |
93% | With potassium carbonate In 1,4-dioxane; water at 0 - 20℃; for 15 h; | 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). |
90% | With triethylamine In dichloromethane at 0 - 20℃; | -Butyl (3-bromopropyI)carbamate. To a suspension of 3-bromopropylamine hydrobromide (10 g, 45.7 mmol) in CH2CI2 (100 mL) cooled in an ice bath was added triethylamine (15.9 mL, 113 mmol). Di-t-butyl-dicarbonate (10 g, 45.7 mmol) was added slowly in portions and the resulting mixture was stirred at 0 °C for 2 hrs and allowed to warm up to room temperature and stirred over-night. The reaction mixture was filtered, condensed and purified by flash chromatography to yield t-butyl (3- bromopropyl)carbamate (9.8 g, 90percent). 3/4 NMR (500 MHz, CDCl3/MeOH-rf,): δ 4.75 ( br s, 1H), 3.44 (t, = 6.6 Hz, 2H), 3.27 (m, 2H), 2.05 (m, 2H), 1.45 (s, 9H). |
87% | With triethylamine In dichloromethane at 20℃; for 12 h; | Di-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). 1H NMR (200 MHz, CDCl3) δ: 4.63 (s, 1H), 3.42 (t, J=6.5 Hz, 2H), 3.26 (td, J=6.5; 6.5 Hz, 2H), 2.03 (m, J=6.5 Hz, 2H), 1.43 (s, 9H). HMRS (ESI) calculated for C8H16NO2Br [M+H+], m/z 255.0703. found: 255.0695. |
87% | With triethylamine In dichloromethane at 20℃; for 12 h; | 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. 1H NMR (200 MHz, CDCl3) δ: 4.63 (s, 1H), 3.42 (t, J=6.5 Hz, 2H), 3.26 (td, J=6.5; 6.5 Hz, 2H), 2.03 (m, J=6.5 Hz, 2H), 1.43 (s, 9H); 13C NMR (125 MHz, CDCl3) δ: 156.09, 79.54, 39.96, 32.82, 30.90, 28.48. HRMS (ESI+) calculated for C8H16NO2Br [M+H]+, m/z 255.0703. found: 255.0695. Rf=0.59 (silica; cyclohexane-ethyl acetate 50:50). |
83% | With sodium hydroxide In dichloromethane; water at 20℃; for 3 - 16 h; | 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. 1NMRFAB-MS, m/z 238.0 (m+1), 240.0 (m+1). Analysis for CgHigBrNC^:Calcd: C, 40.35; H, 6.77; N, 5.88; Found: C, 40.12; H, 6.62; N, 6.06. |
83% | Stage #1: With trimethylamine In tetrahydrofuran for 0.5 h; Cooling with ice Stage #2: With 2-(N-methylamino)pyridine In tetrahydrofuran |
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)) |
80% | With sodium hydrogencarbonate; potassium bromide In chloroform; water for 5 h; Reflux | 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 NaHCO3 (24.4 mmole; 2.0 g) in 80 ml water, di-tert.-butyldicarbonate (24.4 mmole; 5.33 g) and KBr (48.8 mmole; 5.8 g) were added to a stirred suspension of 3-bromopropylammoniumbromide (24.4 mmole; 5.0 g) in 100 ml chloroform. The reaction was refluxed for 5 hours. After cooling to ambient temperature, the organic layer was separated, the aqueous layer extracted with chloroform and the combined organic layers dried with MgSO4, filtered, concentrated and purified by column chromatography. The title compound was obtained as a colorless oil (19.46 mmole; 80 percent).1H NMR (300 MHz, CDCl3) 4.73 (bs, 1H; NH); 3.41 (t; 3J = 6.5 Hz; 2H; CH2Br); 3.24 (m; 2H; CH2N); 2.02 (quint; 3J = 6.5 Hz; 2H; CH2CH2CH2); 1.41 (s; 9H; C(CH3)3). |
80% | With sodium hydrogencarbonate; potassium bromide In chloroform; water for 5 h; Reflux | Example 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 (24.4 mmole; 2.0 g) in 80 ml water, di-te/t-butyldicarbonate (24.4 mmole; 5.33 g) and KBr (48.8 mmole; 5.8 g) were added to a stirred suspension of 3-bromopropylammoniumbromide (24.4 mmole; 5.0 g) in 100 ml chloroform. The reaction was refluxed for 5 hours. After cooling to ambient temperature, the organic layer was separated, the aqueous layer extracted with chloroform and the combined organic layers dried with MgS04, filtered, concentrated and purified by column chromatography. The title compound was obtained as a colorless oil(19.46 mmole; 80 percent). 1 H NMR (300 MHz, CDCI3) 4.73 (bs, 1 H; NH); 3.41 (t; 3J = 6.5 Hz; 2H; CH2Br); 3.24 (m; 2H; CH2N); 2.02 (quint; 3J = 6.5 Hz; 2H; CH?CH?CH?); 1.41 (s; 9H; C(CH3)3). |
78.3% | With triethylamine In dichloromethane at 0℃; for 0.5 h; | 3-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. |
74% | With triethylamine In dichloromethane at 0 - 20℃; for 8 h; Inert atmosphere | To a stirred solution of 3-bromopropan-l -amine hydrobromide (AQ; 1.0 g, 4.56 mmol) in CH2C12 (10 mL) was added Et3N (1.65 mL, 11.42 mmol) followed by Boc-anhydride (1.095 g, 5.02 mmol) at 0 °C under inert atmosphere. The resulting reaction mixture was stirred for 8 h at RT. After complete consumption of the starting material (by TLC), the reaction mixture was extracted with CH2C12 (2x30 mL). The combined organic extracts were washed with water, brine, dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude. The crude material was purified by silica gel column chromatography eluting with 20percent EtOAc/hexane as eluent to afford AR (0.8 g, 3.35 mmol, 74percent) as a pale-brown liquid. JH NMR (400 MHz, CDC13): δ 4.63 (bs, NH), 3.44 (t, J = 6.4 Hz, 2H), 3.28 (t, J = 6.4 Hz, 2H), 2.08-2.01 (m, 2H), 1.44 (s, 9H). |
62.6% | With pyridine; sodium hydroxide In tetrahydrofuran; water at 20℃; for 6 h; | In 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 (Boc2O, 4.8 g, 0.022 mol) dissolved in 20 mL tetrahydrofuran was added dropwise and the mixture was kept stirring for 6 h under room temperature. After that, the reaction mixture was poured into distilled water and extracted with EtOAC, dried with MgSO4 anhydride and concentrated under reduced pressure, and the crude product was purified by flash column chromatography (eluent: EtOAC/hexane = 1/4, v/v) to obtain 3-Bromo-1-propamine-NHBOC (9) as a yellowish oil (3.1 g, 62.6percent yield) . 1H NMR (CDCl3, 300 Hz) δ 4.31(1H, -CHCON-), 3.34(2H, -CH2-), 3.11(2H, -CH2-), 1.99(2H, -CH2-), 1.27 (9H, Boc). |
3.4 g | Stage #1: With dmap; triethylamine In dichloromethane at 20℃; for 0.5 h; Stage #2: With hydrogenchloride In dichloromethane; water |
A CH2Cl2 solution (5 mL) containing 4-dimethyl aminopyridine (0.34 g, 0.0028 mol) and triethylamine (1.39 g, 0.0138 mol) was slowly added to a solution of 3-bromopropylamine hydrobromide (3 g, 0.0138 mol) and di-tert-butyl pyrocarbonate (3.15 g, 0.0145 mol) in CH2Cl2 (10mL). After turning transparent, the mixture was continuously stirred at room temperature for 30 min. Water (10 mL) was added and the product was extracted with CH2Cl2, washed with 0.5 M HCl (2×5 mL), dried (Na2SO4), and then evaporated to yield tert-butyl 3-bromopropylcarbamate (as a colorless oil, 3.4 g). o-Methoxyphenyl piperazine (5.30 g, 0.0276 mol) and NaI (1.0 g) were added to a solution of tert-butyl 3-bromopropylcarbamate in CH2Cl2 (20 mL), and the mixture was continuously stirred at room temperature for 5 h. The reaction mixture was washed with water, and the combined organic layer was dried (Na2SO4) and evaporated under a reduced pressure. The crude was purified using silica gel chromatography with ethyl acetate and petroleum ether as eluents to produce intermediate 13 (4.1 g, yield 85percent). Excessive TFA was added to a solution of 13 (4.1 g) in CH2Cl2 (20 mL), and the mixture was stirred at room temperature overnight. Saturated Na2CO3 aq.was added and extracted with CH2Cl2. The combined organic layer was dried (Na2SO4) and then evaporated under a reduced pressure to obtain 14 (2.5 g, yield 86percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate In 1,4-dioxane; water | 3-(2,5,7,8-Tetramethyl-(2R-(4R,8,12-trimethyltridecyl)chroman-6-yloxy)propyl-1-ammonium Chloride (19) 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). |
93% | With K2CO3 In 1,4-dioxane; water | 3-(2,5,7,8-Tetramethyl-(2R-(4R,8,12-trimethyltridecyl)chroman-6-yloxy)propyl-1-ammonium Chloride (19) 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, 93 percent). 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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate In 1,4-dioxane; water | 3-(2,5,7,8-tetramethyl-(2R-(4R,8, 12-trimethyltridecyl) chroman-6-yl oxy)propyl-1-ammonium chloride (1 9) 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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With triethylamine In 1,4-dioxane | Step 1: N-tert-butoxycarbonyl-3-bromopropylamine. To a 0° C. solution of 3-bromopropylamine hydrobromide (10.0 g, 45.7 mmol) in 1:1 aqueous dioxane was added triethylamine (12.8 mL, 91.8 mmol), di-tert-butyldicarbonate (20.2 g, 92.6 mmol), and saturated aqueous NaHCO3 (3 mL). The cold bath was removed and the reaction mixture was stirred for 3.5 hours. The reaction mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with 10percent aqueous citric acid and brine, dried over Na2 SO4, filtered, and concentrated in vacuo. Chromatography on silica gel (10:1, then 6:1, then 3:1 hexane, ethyl acetate) gave N-tert-butoxycarbonyl-3-bromopropylamine (21.1 g, 79percent) as a clear yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: With sodium hydroxide In waterInert atmosphere Stage #2: Inert atmosphere |
1.11 3-(BenzyIoxycarbonylamino)propyl bromide, 12.Br NHCbz12 3-Bromopropylamine hydrobromide (5.0 g, 22.8 mmol) was dissolved in an aqueous NaOH solution (15 wtpercent, 80 ml) and cooled to 0°C under nitrogen before benzyl chloroformate was added dropwise. The reaction was left to stir overnight then ethyl acetate (100 ml) was added and the phases were separated. The organic phase was further washed with a HC1 solution (2 M, 100 ml), a NaOH solution (2 M, 100 ml), brine (100 ml), dried over Na2S04, and evaporated to yield 12 as a clear oil (6.22 g, 22.8 mmol, 100percent). Rf = 0.31 (8:2 Hexane Ethyl acetate); NMR (300 MHz, CDC13) δ = 7.40-7.33 (m, 5H, ArCH), 5.1 1 (s, 2Η, CH2Ph), 4.94 (bs, 1Η, NHCbz), 3.45 (t, 3J(H,H) = 6.4 Hz, 2H, CH2Br), 3.36 (q, 3J(H,H) = 6.4 Hz, 2H, CH2NHCbz), 2.08 (q, 3J(H,H) = 6.4 Hz, 2H, CH2Q3/4CH2); 13C NMR (75 MHz, CDC13) 6 = 156.4 (CO), 136.4 (ArCCH2), 128.5 (ArCH), 128.2 (ArCH), 127.0 (ArCH), 66.8 (CH2Ph), 39.4 (CH2NHCbz), 32.4 (CH2CH2CH2), 30.6 (CH2Br); HRMS (ESI+): m/z calculated for CnH, BrN02Na [M + Naf : 294.0106, found 294.0099. |
98% | With sodium hydroxide In dichloromethane at 0 - 20℃; Inert atmosphere | Preparation Example 15 : 3-(4-(3-chlorophenyl)piperazin-l- yl)propan-l-amine dihydrochloride; Step 1 : Benzyl 3-bromopropylcarbamate; Benzylchloroformate (8.6 ml, 60 mmol) was added to a stirred mixture of 3-bromopropylamine hydrobromide (6.6 g, 30 mmol) in methylene chloride (100 ml) and 3N sodium hydroxide solution (100 ml) at 0 0C. After stirring two phase reaction mixture at room temperature for overnight, organic layer was separated and washed with water twice (30 ml x 2). After drying with MgSO4, the volatile solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc:Hx = 1 :4) to obtain desire compound (8.6 g, 98percent) as colorless oil.1H NMR (400 MHz, CDCl3) δ 7.40-7.30 (m, 5H), 5.10 (s, 2H), 3.72 (brs, 2H), 2.25-2.18 (m, 2H), 1.98 (br, 2H), 1.81-1.78 (m, 3H).MH+ 272 |
72% | With triethylamine In dichloromethane at 20℃; | To an ice cooled suspension of 3-bromopropylamine bromhydrate (0.9 g, 4.11 MMOL) and triethylamine (1.3 mL, 9.05 MMOL) in dry DICHLOROMETHANE was slowly added a solution of benzyl CHLOROFORMIATE (0.6 mL, 4.11 MMOL) in dry dichloromethane (1 mL). The reaction mixture was stirred at room temperature overnight. Then it was washed with saturated aqueous NaCI (2 x 15 mL), dryed (anhidrous NA2SO4), filtered and evaporated to dryness. The residue was purified by CCTLC on the chromatotron using hexane, ethyl acetate (4: 1), to give 0.8 g (72 percent) of (1) as a white foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine In dichloromethane at 0 - 20℃; | TEA ( 6.91 g, 68.5 mmol) was added dropwise to an ice-cooled mixture of 3- bromopropylamine.hydrobromide (10.Og, 45.6 mmol) and N-(Benzyloxycarbonyloxy)- succinimide (11.22g, 47.9 mmol) in DCM (200 mL). The stirred mixture was allowed to warm to room temperature overnight, then washed with water (3x), brine, dried (MgSO4), filtered and concentrated, providing 11.43 g (92percent) of N-(Benzyloxycarbonyl)- 3-bromopropylamine, as a pale yellow oil . |
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