* 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.
With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 13.33 h; Inert atmosphere
A cooled (0° C.) mixture of 2-bromoethylamine hydrobromide (12.000 g ; 58.56 mmol ; 1.0 eq.) in dioxane (60 ml) was treated with aq. 1M NaOH (117.2 ml ; 117.20 mmol ; 2.0 eq.), and dropwise (over 10 min.) with benzyl chloroformate (8.4 ml ; 58.8 mmol ; 1.0 eq.). The resulting mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 13 h. Et2O (300 ml) was added, and the colorless organic layer was further washed with water (75 ml), dried over anh. MgSO4, filtered, and finally concentrated to dryness under reduced pressure to afford (2-bromo-ethyl)-carbamic acid benzyl ester as a colorless oil which was further dried under HV (15.020 g ; 99percent). LC-MS: tR=0.95 min. ; [M+H]+: no ionisation.
99%
With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 13.3333 h; Inert atmosphere
B.3 /V-alkylation of imidazoles with Br(CH2^NHBoC or with (2-bromo-ethyl)-carbamic acid benzyl ester; Preparation of (2-bromo-ethyl)-carbamic acid benzyl ester; A cooled (00C) mixture of 2-bromoethylamine hydrobromide (12.000 g; 58.56 mmol; 1.0 eq.) in dioxane (60 ml) was treated with aq. 1 M NaOH (117.2 ml; 117.20 mmol; 2.0 eq.), <n="50"/>and dropwise (over 10 min.) with benzyl chloroformate (8.4 ml; 58.8 mmol; 1.0 eq.). The resulting mixture was further stirred at 00C, under nitrogen, for 10 min., and then at rt for 13h. Et2O (300 ml) was added, and the colorless organic layer was further washed with water (75 ml), dried over anh. MgSO4, filtered, and finally concentrated to dryness under reduced pressure to afford (2-bromo-ethyl)-carbamic acid benzyl ester as a colorless oil which was further dried under HV (15.020 g; 99percent). LC-MS: tR = 0.95 min.; [M+H]+: no ionisation.
95%
With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃;
Treat a 0 °C solution of 2-bromoethylamine hydrobromide (50 g, 0.246 mol) in dioxane (500 mL) with aqueous NaOH (1 M, 492 mL, 0.492 mol), add benzyl chloroformate (21.6 g, 0.127 mol) drop-wise, warm to RT and stir overnight. Pour the mixture into H20, extract with EtOAc (3X), wash the combined organics with brine, dry over Na2S04, concentrate to dryness and purify via silica gel chromatography (EtOAc/Petroleum ether) to afford the title compound (60 g, 95percent) as a white solid. 1H NMR (400 MHz, CDC13): δ 7.37-7.33 (m, 5 H), 5.12 (s, 2 H), 3.61 (t, J = 5.6 Hz, 2 H), 3.47 (t, J= 5.6 Hz, 2 H).
87%
With triethylamine In ethanol at 20℃; for 20 h;
General Synthesis Instructions for N-Z-2-bromoethylamine/N-Z-3-bromopropylamine: Add a solution of 1.5 equivalents of benzylchloroformiate in 50 ml Rotisol in drops to a solution of one equivalent of 2-bromoethylamine-hydrobromide or 3-bromopropylamine-hydrobromide and three equivalents of triethylamine in 150 ml Rotisol under refrigeration. Stir for 20 hours at room temperature, then concentrate the formulation to a small volume, take it up in 200 ml ethyl acetate, and extract twice against 200 ml 2 N hydrochloric acid each time. Remove the solvent and purify the residue via column chromatography on 100 g silica gel. Elute the apolar impurities with cyclohexane/diisopropyl ether (10:1), and elute the product with diisopropyl ether; N-Z-2-bromoethylamine (72): Quantities Used: 34.8 g (170 mmol) 2-bromoethylamine-hydrobromide, 72.0 ml (255 mmol) 50percent solution of benzylchloroformiate in toluene, 70.6 ml (510 mmol) triethylamine
64%
With N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 2 h;
To a solution of 2-bromoethylamine bromide (5 g, 24.4 mmole) in DMF (50 mL) was added diisopropylethylamine (8.5 mL, 48.8 mmole) and benzyl chloroformate (3.48 mL, 24.4 mmole). The mixture thus obtained was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel with ethyl acetate/hexanes (3/7) as eluent to give the desired compound 34 as an oil (4 g, 64percent). 1H NMR (CDCl3) No. 3.54 (bs, 2H), 3.61 (bs, 2H), 5.12 (s, 2H), 7.36 (m, 5H).
64%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2 h;
Synthesis of Compound 1: To a solution of 2-bromoethylamine bromide (5 g, 24.4 mmole) in DMF (50 mL) was added diisopropylethylamine (8.5 mL, 48.8 mmole) and benzyl chlroroformate (3.48 mL, 24.4 mmole). The mixture thus obtained was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel with ethyl acetate/hexanes (3/7) as gradient to give Compound 1 as an oil (4 g, 64percent). 1H NMR (CDCl3) δ 3.54 (bs, 2H), 3.61 (bs, 2H), 5.12 (s, 2H), 7.36 (m, 5H).
Reference：
[1] Journal of Medicinal Chemistry, 1981, vol. 24, # 4, p. 408 - 428
[2] Patent: US2011/105514, 2011, A1, . Location in patent: Page/Page column 21
[3] Patent: WO2009/156951, 2009, A2, . Location in patent: Page/Page column 47-48
[4] Chemical Communications, 2010, vol. 46, # 17, p. 2983 - 2985
[5] Journal of Organic Chemistry, 2000, vol. 65, # 26, p. 8979 - 8987
[6] Patent: WO2013/134298, 2013, A1, . Location in patent: Page/Page column 62
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[8] Inorganic Chemistry, 2017, vol. 56, # 11, p. 6429 - 6437
[9] European Journal of Organic Chemistry, 2005, # 3, p. 487 - 495
[10] Patent: WO2005/3105, 2005, A1, . Location in patent: Page 13; Fig. 6
[11] Patent: US2003/229037, 2003, A1, . Location in patent: Page/Page column 55, 21
[12] Chemical Communications, 2013, vol. 49, # 25, p. 2560 - 2562
[13] Organic Letters, 2008, vol. 10, # 5, p. 793 - 796
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[15] Patent: WO2005/112919, 2005, A2, . Location in patent: Page/Page column 160
[16] Patent: US2010/145036, 2010, A1, . Location in patent: Page/Page column 54; 56; 58; 61
[17] Journal of Organic Chemistry, 1997, vol. 62, # 20, p. 6754 - 6759
[18] Journal of Medicinal Chemistry, 2007, vol. 50, # 11, p. 2605 - 2608
[19] Patent: US6627651, 2003, B1,
[20] Patent: EP976722, 2000, A1,
[21] Patent: EP1182195, 2002, A1, . Location in patent: Example 99'
[22] Patent: US2010/152265, 2010, A1, . Location in patent: Page/Page column 53
[23] Patent: US2010/160256, 2010, A1, . Location in patent: Page/Page column 67
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[28] Patent: CN107673957, 2018, A, . Location in patent: Paragraph 0050-0052
[29] Patent: WO2008/103693, 2008, A2, . Location in patent: Page/Page column 75
2
[ 107-09-5 ]
[ 501-53-1 ]
[ 53844-02-3 ]
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 2, p. 568 - 571
[2] Journal of Organic Chemistry, 1950, vol. 15, p. 1067,1071
[3] Australian Journal of Chemistry, 1959, vol. 12, p. 296
[4] Patent: US4804684, 1989, A,
[5] Patent: US2006/3970, 2006, A1, . Location in patent: Page/Page column 10-11
3
[ 134307-72-5 ]
[ 53844-02-3 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2012, vol. 354, # 8, p. 1519 - 1528
[2] Chemistry - A European Journal, 1998, vol. 4, # 1, p. 137 - 151
[3] Patent: EP918790, 2004, B1, . Location in patent: Page 7; 11; 52
[4] Journal of Organic Chemistry, 2010, vol. 75, # 16, p. 5757 - 5759
(a) 2-Benzyloxycarbonylaminoethoxyamine hydrochloride A solution of 0.46 mol (78.5 g) of benzyloxycarbonyl chloride in 1 volume of acetone is added slowly to a solution of 0.45 mol (92.2 g) of 2-bromoethylamine in 1 liter of nomal sodium hydroxide solution. When the reaction has ended (about 48 hours), the acetone is evaporated off under reduced pressure and the residue is then acidified to between pH 1 and 2 and extracted with ether. Benzyloxycarbonylamino-2-bromoethane is obtained after evaporation.
With triethylamine; In N,N-dimethyl-formamide; at 0℃;
The synthesis of ZRBA4 is shown below in Scheme 8, and involves N-(2-chloroethyl)-N-methylethylenediamine which was synthesized as shown in Scheme 9
With sodium hydroxide; In 1,4-dioxane; water; at 0 - 20℃; for 13.33h;Inert atmosphere;
A cooled (0 C.) mixture of 2-bromoethylamine hydrobromide (12.000 g ; 58.56 mmol ; 1.0 eq.) in dioxane (60 ml) was treated with aq. 1M NaOH (117.2 ml ; 117.20 mmol ; 2.0 eq.), and dropwise (over 10 min.) with benzyl chloroformate (8.4 ml ; 58.8 mmol ; 1.0 eq.). The resulting mixture was further stirred at 0 C., under nitrogen, for 10 min., and then at rt for 13 h. Et2O (300 ml) was added, and the colorless organic layer was further washed with water (75 ml), dried over anh. MgSO4, filtered, and finally concentrated to dryness under reduced pressure to afford (2-bromo-ethyl)-carbamic acid benzyl ester as a colorless oil which was further dried under HV (15.020 g ; 99%). LC-MS: tR=0.95 min. ; [M+H]+: no ionisation.
99%
With sodium hydroxide; In 1,4-dioxane; water; at 0 - 20℃; for 13.3333h;Inert atmosphere;
B.3 /V-alkylation of imidazoles with Br(CH2^NHBoC or with (2-bromo-ethyl)-carbamic acid benzyl ester; Preparation of (2-bromo-ethyl)-carbamic acid benzyl ester; A cooled (00C) mixture of 2-bromoethylamine hydrobromide (12.000 g; 58.56 mmol; 1.0 eq.) in dioxane (60 ml) was treated with aq. 1 M NaOH (117.2 ml; 117.20 mmol; 2.0 eq.), <n="50"/>and dropwise (over 10 min.) with benzyl chloroformate (8.4 ml; 58.8 mmol; 1.0 eq.). The resulting mixture was further stirred at 00C, under nitrogen, for 10 min., and then at rt for 13h. Et2O (300 ml) was added, and the colorless organic layer was further washed with water (75 ml), dried over anh. MgSO4, filtered, and finally concentrated to dryness under reduced pressure to afford (2-bromo-ethyl)-carbamic acid benzyl ester as a colorless oil which was further dried under HV (15.020 g; 99%). LC-MS: tR = 0.95 min.; [M+H]+: no ionisation.
95%
With sodium hydroxide; In 1,4-dioxane; water; at 0 - 20℃;
Treat a 0 C solution of 2-bromoethylamine hydrobromide (50 g, 0.246 mol) in dioxane (500 mL) with aqueous NaOH (1 M, 492 mL, 0.492 mol), add benzyl chloroformate (21.6 g, 0.127 mol) drop-wise, warm to RT and stir overnight. Pour the mixture into H20, extract with EtOAc (3X), wash the combined organics with brine, dry over Na2S04, concentrate to dryness and purify via silica gel chromatography (EtOAc/Petroleum ether) to afford the title compound (60 g, 95%) as a white solid. 1H NMR (400 MHz, CDC13): delta 7.37-7.33 (m, 5 H), 5.12 (s, 2 H), 3.61 (t, J = 5.6 Hz, 2 H), 3.47 (t, J= 5.6 Hz, 2 H).
87%
With triethylamine; In ethanol; at 20℃; for 20h;
General Synthesis Instructions for N-Z-2-bromoethylamine/N-Z-3-bromopropylamine: Add a solution of 1.5 equivalents of benzylchloroformiate in 50 ml Rotisol in drops to a solution of one equivalent of 2-bromoethylamine-hydrobromide or 3-bromopropylamine-hydrobromide and three equivalents of triethylamine in 150 ml Rotisol under refrigeration. Stir for 20 hours at room temperature, then concentrate the formulation to a small volume, take it up in 200 ml ethyl acetate, and extract twice against 200 ml 2 N hydrochloric acid each time. Remove the solvent and purify the residue via column chromatography on 100 g silica gel. Elute the apolar impurities with cyclohexane/diisopropyl ether (10:1), and elute the product with diisopropyl ether; N-Z-2-bromoethylamine (72): Quantities Used: 34.8 g (170 mmol) 2-bromoethylamine-hydrobromide, 72.0 ml (255 mmol) 50% solution of benzylchloroformiate in toluene, 70.6 ml (510 mmol) triethylamine
64%
With N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 2h;
To a solution of 2-bromoethylamine bromide (5 g, 24.4 mmole) in DMF (50 mL) was added diisopropylethylamine (8.5 mL, 48.8 mmole) and benzyl chloroformate (3.48 mL, 24.4 mmole). The mixture thus obtained was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel with ethyl acetate/hexanes (3/7) as eluent to give the desired compound 34 as an oil (4 g, 64%). ¹H NMR (CDCl3) No. 3.54 (bs, 2H), 3.61 (bs, 2H), 5.12 (s, 2H), 7.36 (m, 5H).
64%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;
Synthesis of Compound 1: To a solution of 2-bromoethylamine bromide (5 g, 24.4 mmole) in DMF (50 mL) was added diisopropylethylamine (8.5 mL, 48.8 mmole) and benzyl chlroroformate (3.48 mL, 24.4 mmole). The mixture thus obtained was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel with ethyl acetate/hexanes (3/7) as gradient to give Compound 1 as an oil (4 g, 64%). 1H NMR (CDCl3) delta 3.54 (bs, 2H), 3.61 (bs, 2H), 5.12 (s, 2H), 7.36 (m, 5H).
With sodium chloride; potassium carbonate; In tetrahydrofuran; water;
Reference Example 99 Into a solution of 2-bromoethylamine hydrobromide (5.0 g) and potassium carbonate (5.06 g) in THF/water (20/5 ml) was added at 0 C. benzyl chloroformate (4.16 g), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to obtain benzyl 2-bromoethylcarbamate (7.32 g).
With triethylamine; In dichloromethane;
Step 1 Synthesis of benzyl-N-(2-bromoethyl)carbamate: 10 g (49 mmol) of 2-bromoethylamine hydrobromide and 15 ml of triethylamine were dissolved in dichloromethane. 7.8 ml (49 mmol) of benzyl chloroformate was added to the obtained solution under cooling with ice, and they were stirred at room temperature. The reaction mixture was treated with dichloromethane as the extractant in an ordinary manner to obtain a crude product, which was purified by the silica gel column chromatography to obtain the title compound. Yield: 10.6 g (41 mmol) (84 %) H-NMR (CDCl3) delta 3.45 (2H, t), 3.60 (2H, dt), 5.10 (2H, s), 5.20 (1H, brs), 7.30-7.38 (5H, m)
With sodium hydroxide; In 1,4-dioxane; water; at 0℃;
Reference Example 40Benzyl 2-bromoethylcarbamate To a 1,4-dioxane (50 mL) solution comprising benzylchloroformate (17.5729 g; manufactured by Wako Pure Chemical Industries, Ltd.), an aqueous solution of 2 -bromoethane amine hydrogen bromide salt-1,4-dioxane [104 mL; solution which was prepared by dissolving 2-bromoethane amine hydrogen bromide salt (21.3617 g; manufactured by Tokyo Chemical Industry, Co., Ltd.) in water (54 mL) and 1,4-dioxane (54 mL)] and an aqueous solution of 2 mol/L-sodium hydroxide (104 mL; manufactured by Kanto Chemical Co., Inc.) were added dropwise simultaneously, and stirred at 0 C. for 2 hours. The reaction solution was added with water and extraction was carried out twice with ethyl acetate. The organic layer was washed twice with saturated sodium hydride, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (?COLUMN-A?;n-hexane:ethyl acetate=94:6?73:27) to obtain the title compound (19.2014 g).1H-NMR (300 MHz, CDCl3); delta (ppm) 3.47 (2H, t, J=5.8), 3.60 (2H, t, J=5.8), 5.11 (2H, s), 7.27-7.40 (5H, m)LCMS: 258 [M+H]; retention time: 1.42 minutes:LCMS condition: C
With sodium hydroxide; In 1,4-dioxane; water; at 0℃;
Reference Example 66Benzyl 2-bromoethylcarbamate To a solution prepared by adding 1,4-dioxane (50 mL) to benzyl chloroformate (17.5729 g; manufactured by Wako Pure Chemical Industries, Ltd.), an aqueous solution of 2-bromoethanamine hydrobromide-1,4-dioxane [104 mL; solution prepared by dissolving 2-bromoethanamine hydrobromide (21.3617 g; manufactured by Tokyo Chemical Industry Co., Ltd.) in water (54 mL) and 1,4-dioxane (54 mL)]and a 2 mol/L aqueous solution of sodium hydroxide (104 mL; manufactured by Kanto Chemical Co., Inc.) were simultaneously added dropwise. The mixture was stirred for 2 hours at 0 C. Water was added to the reaction solution, and the mixture was extracted two times with ethyl acetate. The organic layer was washed with a saturated solution of sodium hydrogen carbonate, and was dried over magnesium sulfate. The organic layer was concentrated under reduced pressure. The resulting residue was purified by column chromatography (?COLUMN-A?; n-hexane:ethyl acetate=94:6?73:27), and thus the title compound (19.2014 g) was obtained.1H-NMR (300 MHz, CDCl3); delta(ppm) 3.47(2H, t, J=5.8), 3.60(2H, t, J=5.8), 5.11(2H, s), 7.27-7.40(5H, m)LCMS: 258 [M+H]; Retention time: 1.42 minutes; LCMS condition; C
With triethylamine; In chloroform; at 0 - 20℃;Cooling with ice;
To a solution of 2-bromoethylamine hydrobromide (120.0g) in chloroform (1400 ml) was added triethylamine (204 ml), and thereto was added dropwise benzyl chloroformate (100 ml) under ice-cooling slowly. The mixture was stirred at 0C for one hour, and warmed to room temperature, and further stirred overnight. To the reaction mixture was added water, and the mixture was extracted twice with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and dried under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate = 3/1) to give the title compound (110 g).
With triethylamine; In dichloromethane; at 20℃; for 8h;Cooling with ice;
In a three-necked flask, methylene chloride as a solvent, add 0.1mol at room temperature Bromoethylamine hydrobromide, 0.1 mol triethylamine and 150 mL Dichloromethane, Stirring and slowly dropping 0.1mol benzyl chloroformate under ice bath, the reaction at room temperature 8h, After the reaction was completed, the solvent was removed by rotary evaporation to give N-benzyloxycarbonyl-2-bromoethylamine; the molar ratio of N-benzyloxycarbonyl-2-bromoethylamine: imidazole: acetonitrile was 1: 1: Condensation reflux 8h, After completion of the reaction, the acetonitrile is removed by rotary evaporation to give 1- (N-benzyloxycarbonyl-aminoethyl) imidazole; 1- (N-benzyloxycarbonyl-aminoethyl) imidazole and equimolar 1,4-butane sulfonic acid The lactone was condensed and refluxed in acetonitrile (molar ratio of 1,4-butane sultone and acetonitrile 1:20) for 8h, And then with the molar reaction of trifluoromethanesulfonic acid condensation reflux 8h, The solvent was removed by rotary evaporation to give the product 1- (N-benzyloxycarbonyl-aminoethyl) -3- (4-sulfonic acid butyl) imidazolium trifluoromethanesulfonate; finally 1- (N-benzyloxycarbonyl- Aminoethyl) -3- (4-sulfonic acid butyl) imidazole trifluoromethanesulfonate and H2 under the action of Pd / C catalyst at room temperature for 10h, To obtain the target product 1-aminoethyl-3- (4-sulfonatobutyl) imidazolium triflate ([HO3S-bim-CH2CH2-NH2] CF3SO3), belonging to the novel acid Bifunctional ionic liquids. Its structure is as follows:
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;
Synthesis of Compound 1; To a solution of 2-bromoethylamine bromide (5 g, 24.4 mmole) in DMF (50 mL) was added diisopropylethylamine (8.5 mL, 48.8 mmole) and benzyl chlroroformate (3.48 mL, 24.4 mmole). The mixture thus obtained was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel with ethyl acetate/hexanes (3/7) as gradient to give Compound 1 as an oil (4 g, 64%). 1U NMR (CDCl3) delta 3.54 (bs, 2H), 3.61 (bs, 2H), 5.12 (s, 2H), 7.36 (m, 5H).
With sodium bromide; In DMF (N,N-dimethyl-formamide); at 80℃; for 2h;
To a mixture of methanesulfonate ester (1 mmol) and sodium bromide (0.515 g, 5 mmol, 5 eq.) was added dry DMF (10 ml) via syringe and the solution heated at 80C for two hours, and then allowed to cool to room temperature and the slurry filtered over Celite, and the DMF removed in vacuo. The bromide was then redissolved in diethylether (50 ml) and washed with water (3 x 30 ml) and brine (50 ml). The organic extract was dried over anhydrous Na2SO4, and the solvent removedin vacuo to give a colourless oil. The bromide was then purified by flash column chromatography (diethylether 20%/petrol 80% ? diethylether) to give pure bromide.
[2-(3-Hydroxy-propylamino)-ethyl]-carbamic acid benzyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74 - 88%
With potassium carbonate; sodium iodide; In DMF (N,N-dimethyl-formamide); at 20℃; for 24 - 72h;
To a stirred solution of bromide (1 mmol) and 4-amino-1-butanol (0.36 g, 4 mmol, 4 eq.) in anhydrous DMF (10 ml) under N2, was added anhydrous K2CO3 (0.276 g, 2 mmol, 2 eq.) and sodium iodide (15 mg, 0.1 mmol, 0.1 eq.). The reaction was stirred for 72 hours at room temperature, until reaction complete. The DMF was evaporated in vacuo and dried exhaustively under high vacuum. The resulting oily solid was redissolved in CH2Cl2 (100 ml) and washed with water (4 x 50 ml). The combined aqueous extracts were then washed with CH2Cl2 (40 ml) and the CH2Cl2 extracts dried over anhydrous Na2SO4. The CH2Cl2 was evaporated in vacuo to give a pale yellow oil.
tert-butyl 4-piperidinyl-carbamate formic acid salt[ No CAS ]
[ 53844-02-3 ]
benzyl 2-[4-(tert-butyloxycarbonylamino)piperidin-1-yl]ethylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium chloride; triethylamine; In water; acetonitrile;
A solution of benzyl 2-bromoethylcarbamate (7.23 g), tert-butyl 4-piperidinyl-carbamate formic acid salt (4.63 g) and triethylamine (8 ml) in acetonitrile (30 ml) was heated at reflux for 24 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to purification using column chromatography (ethyl acetate/hexane) to obtain benzyl 2-[4-(tert-butoxycarbonylamino)piperidin-1-yl]ethylcarbamate (5.5 g) as colorless crystals. 1H-NMR (200 MHz, CDCl3) delta1.22-1.43 (2H, m), 1.44 (9H, s), 1.84-1.97 (2H, m), 2.01-2.16 (2H, m), 2.39-2.49 (2H, m), 2.71-2.85 (2H, m), 3.23-3.35 (2H, m), 3.36-3.54 (1H, m), 4.29-4.54 (1H, m), 5.10 (2H, s), 5.18-5.32 (1H, m), 7.29-7.42 (5H, m).
With potassium carbonate; In acetonitrile;Heating / reflux;
General Synthesis Instructions for Protected Tricationic Head Groups: Dissolve three equivalents of the respective N,N'-dibenzyl-alpha,omega-diaminoalkane (21-25) and one equivalent of N-Z-2-bromoethylamine (72) or N-Z-3-bromopropylamine (73) in 60 ml acetonitrile. Stir with one equiavlent of potassium carbonate for approx. 4 hours with reflux. When no traces of N-Z-3-bromopropylamine or N-Z-2-bromoethylamine can be detected via thin-layer chromatography, add an additional equivalent of this adduct to the formulation and stir overnight with reflux. Remove the solvent, then purify residue on 100 g silica gel via column chromatography. Elute the apolar impurities with ethyl acetate/cyclohexane (2:1). Slowly switch to ethyl acetate and then ethyl acetate/methanol (6:1) to elute the product completely. Elute the unreacted N,N'-dibenzyl-alpha,omega-diaminoalkane with ethyl acetate/methanol 1:1; 1-Z-4,7-dibenzyl-1,4,7-triazaheptane (74) Quantities Used: 2.16 g (9.0 mmol) N,N'-dibenzyl-1,2-diaminoethane (21) 2.58 g (6.0 mmol) N-Z-2-bromoethylamine (72) 0.41 g (3.0 mmol) potassium carbonate
With triethylamine; In dichloromethane; at 0℃; for 1h;
2-BROMOETHYLAMINE hydrobromide (15 g, 73 MMOL) AND N- (BENZYLOXYCARBONYLOXY)- succinimide (15.5 g, 62 MMOL) are suspended in CH2CI2 (150 mL) at 0C. TEA (9 mL, 65 MMOL) is added slowly keeping the temperature at 0C. After 1h the mixture is washed with 0.5M aq. KHS04 (50 mL) and sat. aq. NaCl (50 mL), the organic phase is dried (NA2SO4), filtered and evaporated to provide the title compound
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 15h;Heating / reflux;
(2-Bromo-ethyl)-carbamic acid benzyl ester (1.10 g, 4.26 MMOL), 3, 3-diphenyl- pyrrolidine (Example A18, 836 mg, 3.75 MMOL) and DIPEA (1.0 mL 5.7 MMOL) are dissolved in THF (20 mL) and stirred for 15 h at reflux. The mixture is quenched with Na2CO3 (50 mL) and extracted with CH2CI2 (3 x 50 mL). The organic extracts are washed with sat. aq. NA2CO3 (30 mL), dried (NA2SO4), filtered and evaporated
With potassium carbonate; potassium iodide; In DMF (N,N-dimethyl-formamide); at 100℃;
To a solution of Compound 34 (3.34 g, 12.99 mmole) and valine tert-butyl ester (3.27 g, 15.59 mmole) in DMF (50 mL) was added potassium carbonate (5.39 g, 38.97 mmole) and potassium iodide (2.59 g, 15.59 mmole). The mixture thus obtained was stirred at 100C overnight. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel with ethyl acetate/hexanes (2/8) as eluent to give the desired compound 35 as an oil (3.12 g, 69%). ¹H NMR (CDCl3) No. 0.92 (m, 6H), 1.46 (s, 9H), 1.86 (m, 1H), 2.53 (m, 1H), 2.80 (m, 2H), 3.18 (m, 1H), 3.31 (m, 1H), 5.10 (s, 2H), 5.25 (bs, 1H), 7.36 (m, 5H) ; LC-MS (ESI) 296 (M+H-tbutyl+), 352 (M+H+).
69%
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 100℃;
Synthesis of Compound 2: To a solution of Compound 1 (3.34 g, 12.99 mmole) and valine tert-butyl ester (3.27 g, 15.59 mmole) in DMF (50 mL) was added potassium carbonate (5.39 g, 38.97 mmole) and potassium iodide (2.59 g, 15.59 mmole). The mixture thus obtained was stirred at 100 C. overnight. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel with ethyl acetate/hexanes (2/8) as gradient to give Compound 2 as an oil (3.12 g, 69%). 1H NMR (CDCl3) delta 0.92 (m, 6H), 1.46 (s, 9H), 1.86 (m, 1H), 2.53 (m, 1H), 2.80 (m, 2H), 3.18 (m, 1H), 3.31 (m, 1H), 5.10 (s, 2H), 5.25 (bs, 1H), 7.36 (m, 5H); LC-MS (ESI) 296 (M+H-tbutyl+), 352 (M+H+).
69%
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 100℃;
Synthesis of Compound 2; To a solution of Compound 1 (3.34 g, 12.99 mmole) and valine tert-butyl ester (3.27 g, 15.59 mmole) in DMF (50 mL) was added potassium carbonate (5.39 g, 38.97 mmole) and potassium iodide (2.59 g, 15.59 mmole). The mixture thus obtained was stirred at 100C overnight. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel with ethyl acetate/hexanes (2/8) as gradient to give Compound 2 as an oil (3.12 g, 69%). 1U NMR (CDCl3) delta 0.92 (m, 6H), 1.46 (s, 9H), 1.86 (m, IH), 2.53 (m, IH), 2.80 (m, 2H), 3.18 (m, IH), 3.31 (m, IH), 5.10 (s, 2H), 5.25 (bs, IH), 7.36 (m, 5H); LC-MS (ESI) 296 (M+H-rbutyl+), 352 (M+H+).
The thus obtained compound (200 mg), 2-bromoethylcarbamic acid benzyl ester (480 mg; synthesised according to the process described in JP-A-9-249623) and potassium carbonate (343 mg) were suspended in DMF (2 mL), and the mixture was stirred at 80 C. for 3 hours. The reaction mixture was cooled and then poured into water (50 mL). The reaction mixture was extracted with ethyl acetate (50 mL) twice. The organic layer was dried over anhydrous sodium sulfate (5 g) and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (99:1 chloroform/methanol) to yield the title compound (214 mg) as a colorless crystal. 1H-NMR (DMSO-d6): delta (ppm) 10.42 (1H, s), 7.49 (1H, t, J=5.3), 7.36-7.28 (5H, m), 7.20 (1H, d, J=8.4), 6.74 (1H, d, J=1.8), 6.58 (1H, dd, J=2.1, 8.7), 5.04 (2H, s), 3.95 (2H, t, J=5.7), 3.38 (2H, quartet, J=5.7), 2.25 (3H, s), 2.10 (3H, d, J=0.6); TLC (99:1 chloroform/methanol): Rf=0.34; LC-MS: elution time 4.6 minutes; m/z=337 (M-H)-.
(Step A) Synthesis of 6-[2-(N-Benzyloxycarbonyl)aminoethoxy]-2,3-dimethylbenzofuran 6-Hydroxy-2,3-dimethylbenzofuran (324 mg; synthesised according to the process described in J. Heterocyclic Chem., vol. 36, p. 509 (1999)), <strong>[53844-02-3]N-benzyloxycarbonyl-2-bromoethylamine</strong> (516 mg; synthesised according to the process described in WO 97/25311) and potassium carbonate (691 mg) were reacted according to the procedure of the step B of Example 13 to yield the title compound (398 mg). 1H-NMR (CDCl3): delta (ppm) 2.10 (3H, s), 2.33 (3H, s), 3.59 (2H, quartet, J=5.2), 4.03 (2H, t, J=4.9), 5.10 (2H, s), 5.29 (1H, brs), 6.78 (1H, dd, J=2.2, 8.2), 6.88 (1H, d, J=2.2), 7.23 (1H, d, J=8.2), 7.24-7.36 (5H, m).
With hydrogen bromide; In N,N-dimethyl acetamide; potassium carbonate; acetic acid; ethyl acetate;
(Step A) Synthesis of 6-(2-Aminoethoxy)-2,3-diphenyl-1H-indole 6-Hydroxy-2,3-diphenyl-1H-indole (2.50 g; synthesised according to the process described in J. Chem. Soc., p. 5097 (1957)) was dissolved in N,N-dimethylacetamide (20 mL), to which <strong>[53844-02-3]N-benzyloxycarbonyl-2-bromoethylamine</strong> (2.93 g; synthesised according to the process described in WO 97/25311) and potassium carbonate (2.42 g) were added. After stirring at 70 C. for 14.5 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried. The solvent was distilled off under reduced pressure. The residue was purified twice by silica gel column chromatography (9:1-1:1 hexane/ethyl acetate) to yield a compound (900 mg) as a brown amorphous solid. This was dissolved in a solution of 30% hydrobromic acid in acetic acid (10 mL), followed by stirring at room temperature for 1 hour. Ether (100 mL) was added to the reaction mixture and the generated precipitate was filtered. The compound obtained by filtration was dissolved in ethyl acetate. The thus obtained solution was washed with a saturated aqueous sodium bicarbonate solution and saturated brine and then dried. The solvent was distilled off under reduced pressure to yield the title compound (630 mg). 1H-NMR (DMSO-d6): delta (ppm) 1.99 (2H, brs), 2.92 (2H, t, J=5.8), 3.96 (2H, t, J=5.8), 6.72 (1H, dd, J=2.2, 8.5), 6.92 (1H, d, J=2.2), 7.24-7.43 (11H, m), 11.36 (1H, brs).
(Step A) Synthesis of 6-[2-(N-benzyloxycarbonyl)aminoethoxy]-2,3-dimethylbenzothiophene 6-Hydroxy-2,3-dimethylbenzothiophene (356 mg; synthesised according to the process described in Phosphorus, Sulfur and Silicon, vol. 153-154, p. 397 (1999)), <strong>[53844-02-3]N-benzyloxycarbonyl-2-bromoethylamine</strong> (516 mg; synthesised according to the process described in WO 97/25311) and potassium carbonate (691 mg) were reacted according to the procedure of the step B of Example 13 to yield the title compound (356 mg). 1H-NMR (CDCl3): delta (ppm) 2.25 (3H, s), 2.43 (3H, s), 3.62 (2H, quartet, J=5.2), 4.07 (2H, t, J=4.9), 5.11 (2H, s), 5.26 (1H, brs), 6.93 (1H, dd, J=2.2, 8.5), 7.20 (1H, d, J=2.2), 7.28-7.38 (5H, m), 7.44 (1H, d, J=8.5).
3-(2-benzyloxycarbonylaminoethoxy)dibenzothiophene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N-methyl-acetamide; water; ethyl acetate;
A. Synthesis of 3-(2-benzyloxycarbonylaminoethoxy)dibenzothiophene (Intermediate 38) To a solution of 370.6 mg of 3-hydroxydibenzothiophene [prepared by the method reported by H. Kudo in J. Heterocycl. Chem., 22 (1), 215-218 (1985)] and 768 mg of potassium carbonate in 4 ml of dimethylformamide, 720 mg of Intermediate 0 were added and the mixture was heated at 60 C. for 30 hours. Thereto were added ethyl acetate and water to effect extraction, whereupon the organic layer was dried and the solvent was distilled off under a reduced pressure to thereby obtain 637 mg of the above-identified compound after purification by a column chromatography (mathanol/chloroform of 1/100). Rf=0.17 (ethyl acetate/n-hexane of 1/5).
A. Synthesis of 2-benzyloxycarbonylamino-1-bromoethane (Intermediate 0) To a solution of 25 g of 2-bromoethylamine hydrochloride (supplied from Tokyo Chemical Industry Co.,Ltd.) and 34 ml of triethylamine in 450 ml of methylene chloride, 19 ml of benzyloxycarbonyl chloride were added dropwise over a period of 20 minutes under cooling by ice water with agitation, whereupon the agitation was continued for further 19 hours. The reaction mixture was then rinsed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution successively, whereupon the organic layer was dried and the solvent was evaporated off under a reduced pressure. The residue was cooled with ice water and the crystals were filtered off and washed with hexane. whereby 29.4 g of the above-identified compound were obtained. Rf=0.58 (chloroform).
This product is reacted with N-hydroxyphthalimide following the procedure of Example 1-a to give N-2-benzyloxycarbonylaminoethoxyphthalimide in the form of white crystals melting at 95 C. with a yield of 73%.
S-[2-(benzyloxycarbonylamino)ethyl]-L-homocysteine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; ammonium chloride; In ammonia; water;
EXAMPLE 5 N-[S-(2-Aminoethyl)-N-(1-Carboxy-3-phenylpropyl)-L-homocysteinyl]-L-proline A solution of L-homocystine (5.0 g., 0.0186 mole) in 150 ml of liquid ammonia was treated with sodium metal (1.68 g., 0.0730 mole) until a blue color persisted, and a trace of ammonium chloride was added to dispel the blue color. The solution was cooled to -65 C. until it just began to solidify, and the slurry was treated with benzyloxycarbonyl-2-bromoethylamine (10.0 g., 0.0388 mole) over 2 minutes. The resulting pink slurry was allowed to warm to room temperature overnight to evaporate the ammonia. The remaining white solid was dissolved in 100 ml of water which was filtered and neutralized to pH 7 with 6N hydrochloric acid to precipitate S-[2-(benzyloxycarbonylamino)ethyl]-L-homocysteine; a white solid; nmr (10% NaOD in D2 O): delta1.85 (m, 2H, S--CH2 --CH2 --CH), 2.51 (t, 2H, S--CH2 --CH2 --CH), 2.68 (t, 2H, aminoethyl--S--CH2 --), 3.33 (t, 2H,--NCH2 --), 5.12 (S, 2H, benzyl), 7.41 (S, 5H, aromatic); ms(trimethylsilyl): 369 (M-15), 206 (loss of --CH2 CH2 NHCO2 Bz).
The starting material can be prepared as follows: 15.0 G. of 5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester are reacted with 25.8 g. of 2-[(benzyloxycarbonyl)amino]ethyl bromide in a manner analogous to that described in Example 14. Thereafter, there is obtained an oily crude product, which is chromatographed on 250 g. of silica gel with methylene chloride/ethyl acetate (4:1) as the eluant. From the uniform fractions there is obtained 2-{2-[(benzyloxycarbonyl)amino]ethyl}-5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester; melting point 102-104 C. Recrystallization from ethanol increases the melting point to 104-105 C.
3-[2-(benzyloxycarbonylamino)ethoxy]benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium iodide; tetra-(n-butyl)ammonium iodide; calcium carbonate; In N-methyl-acetamide; ethyl acetate;
Step 2 Synthesis of 3-(2-aminoethoxy)benzonitrile hydrobromide: 8 g of benzyl-N-(2-bromoethyl)carbamate, 3.7 g of 3-hydroxybenzonitrile, 4.3 g of calcium carbonate, 5.1 g of potassium iodide and 1.1 g of tetrabutylammonium iodide were stirred in dimethylformamide at 60C. After the treatment with ethyl acetate as the extractant in an ordinary manner, the product was purified by the silica gel column chromatography to obtain 3-[2-(benzyloxycarbonylamino)ethoxy]benzonitrile.
Step 1 Synthesis of benzyl-N-(2-bromoethyl)carbamate: 10 g (49 mmol) of 2-bromoethylamine bromate and 15 ml of triethylamine were dissolved in dichloromethane. 7.8 ml (49 mmol) of benzyl chloroformate was added to the solution under cooling with ice, and they were stirred at room temperature. After the treatment with dichloromethane as the extractant in an ordinary manner, the crude product was obtained. The crude product was purified by the silica gel column chromatography to obtain the title compound. Yield: 10.6 g (41 mmol) (84 %) H-NMR (CDCl3) delta 3.45 (2H, t), 3.60 (2H, dt), 5.10 (2H, s), 5.20 (1H, brs), 7.30-7.38 (5H, m)
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