* 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.
Reference：
[1] Journal of Chemical Research, Miniprint, 1996, # 8, p. 2143 - 2161
2
[ 2508-29-4 ]
[ 24424-99-5 ]
[ 75178-90-4 ]
Yield
Reaction Conditions
Operation in experiment
98%
With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃;
N-t-Boc-5 -amino- 1-pentanol. To a 1.0 L one-neck round-bottom flask containing a solution of 5 -amino- 1-pentanol (15.0 g, 145.4 mmol) in water (140 mL) and saturated aqueous NaHCC>3 (1.4 mL), a solution of di-tert-butyl dicarbonate (33.3 g, 152.7 mmol) in THF (280 mL) was added. The mixture was then stirred at room temperature overnight with the flask open to the atmosphere. The reaction mixture was diluted with saturated aqueous NaHCC>3 (90 mL) and extracted with EtOAc (400 mL). The organic layer was separated, dried over Na2S04, filtered, and the solvent was evaporated providing 28.9 g (98percent) of the final product as clear colorless oil. 'll NMR analysis showed the product was clean of impurities, and no further purification was attempted. Alternatively, N-t-Boc-5- amino- 1-pentanol can be obtained from TCI America of Portland, OR.
98%
at 0 - 20℃; for 4 h;
Step 1: Synthesis of tert-butyl 5-hydroxypentylcarbamate (AU)[0558] To a stirred solution of 5-aminopentan-l-ol (AT, 3.1 g, 30.05 mmol) in dichloromethane (30 mL) was added di-tert-butyl dicarbonate (6.56 g, 30.06 mmol) at 0 °C. The resulting mixture was then stirred at rt for 4h. The solvent was removed under reduced pressure to give a crude residue which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v= 1: 2)) to give AU (yield: 98percent) as a colorless oil. LC-MS (ES+): m/z 204.00 [MH+], tR=1.29 min (2.6 minute run).
98%
With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃;
N-t-Boc-5-amino-l-pentanol. To a 1.0 L one-neck round-bottom flask containing a solution of 5-amino-l -pentanol (15.0 g, 145.4 mmol) in water (140 mL) and saturated aqueous NaHC03 (1.4 mL), a solution of di-tert-butyl dicarbonate (33.3 g, 152.7 mmol) in THF (280 mL) was added. The mixture was then stirred at room temperature overnight with the flask open to the atmosphere. The reaction mixture was diluted with saturated aqueous NaHC03 (90 mL) and extracted with EtOAc (400 mL). The organic layer was separated, dried over Na2S04, filtered, and the solvent was evaporated providing 28.9 g (98percent) of the final product as clear colorless oil. NMR analysis showed the product was clean of impurities, and no further purification was attempted. Alternatively, N-t-Boc-5-amino-l-pentanol can be obtained from TCI America of Portland, OR.
98%
at 0 - 20℃; for 4 h;
To a stirred solution of 5-aminopentan-1-ol (AT, 3.1 g, 30.05 mmol) in dichloromethane (30 mL) was added di-tert-butyl dicarbonate (6.56 g, 30.06 mmol) at 0° C. The resulting mixture was then stirred at rt for 4 h. The solvent was removed under reduced pressure to give a crude residue which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v=1:2)) to give AU (yield: 98percent) as a colorless oil. LC-MS (ES+): m/z 204.00 [MH+], tR=1.29 min (2.6 minute run).
98%
at 0 - 20℃; for 4 h;
Step 1: Synthesis of tert-butyl 5-hydroxypentylcarbamate (AU) To a stirred solution of 5-aminopentan-1-ol (AT, 3.1 g, 30.05 mmol) in dichloromethane (30 mL) was added di-tert-butyl dicarbonate (6.56 g, 30.06 mmol) at 0° C. The resulting mixture was then stirred at room temperature for 4 hours. The solvent was removed under reduced pressure to give a crude residue which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v=1:2)) to give AU (yield: 98percent) as a colorless oil. LC-MS (ES+): m/z 204.00 [MH+], tR=1.29 min (2.6 minute run).
95%
With sodium hydroxide In 1,4-dioxane; water at 20℃; for 12 h;
General procedure: To a solution of 2a (or 2b–e, 20 mmol) in a mixture of dioxane (15 mL) and H2O (7 mL), wasadded 5N NaOH (4.8 mL) and a solution of Boc2O (5.0 g, 23 mmol) in dioxane at 0 °C. After stirred atrt overnight, the reaction mixture was concentrated in vacuo. The residue was extracted from 10percentcitric acid with AcOEt, and dried over anhydrous Na2SO4. Evaporation of the solvents gave the pureproduct 3a–e. 3a was obtained as a colorless oil (2.67 g, 83percent).
93.1%
at 20℃; Cooling with ice
To a solution of 41 (20 g, 194 mmol) in DCM (0.2 L) was added (Boc)20 dropwise (42.3 g, 194 mmol) under an ice bath. The reaction was stirred at RT over night. Then the mixture solution was extracted with DCM and washed with water. The combined organic layers were washed with saturated NaCl, dried over Na2S04, and filtered. The solvent was removed in vacuum to give 42 as an oil (37 g, yield 93.1 percent). XH NMR (300 MHz, CDC13) δ: 3.5(m, 2H), 3.2 (m, 2H), 1.6-1.5(m, 4H), 1.4-1.3(m, 1 1H).
83%
With dmap; triethylamine In chloroform at 20℃; for 3 h;
5-Amino-1-pentanol (30, 2 g, 19 mmol), Boc2O (4.5 g, 20 mmol), Et3N (2.1 g, 21 mmol), DMAP (0.23 g, 1.9 mmol) and CHCl3 (20 mL) were placed in a 100 mL reaction flask. The reaction mixture was allowed to stir for 3 h at rt. After the volatile materials were removed under reduced pressure, the resulting reside was purified by flash column chromatography (CHCl3) to yield 31. To a flame-dried 100 mL round-bottom flask containing a magnetic stirring bar were charged 31 (30 mmol), Et3N (30 mmol), DMAP (3 mmol), and CHCl3 (30 mL). The solution was cooled to 0 °C, and TsCl (30 mmol) dissolved in CHCl3 was added to the solution over 10 min. The reaction mixture was stirred at rt for 3 h. After all the volatile materials were removed under reduced pressure, the crude residue was purified by flash column chromatography (CHCl3) to get 32. 31: 83percent; 1H NMR (300 MHz, CDCl3): δ 3.63 (2H, m, CH2N), 3.11 (2H, m, CH2OH), 1.61–1.39 (15H, m, 3×CH2, –C(CH3)3).
74%
With potassium carbonate In methanol; water at 20℃; for 2 h;
A mixture of 5-amino-1-pentanol (3.0 g, 29.1 mmol), t-Boc anhydride (6.1 g, 34.9 mmol), and K2CO3 (4 g) in 50/50 water/methanol (25 mL) was stirred at ambient temperature for 2 h. The reaction mixture was quenched with water (25 mL) and extracted with EtOAc (2x25 mL). Combined extracts were washed with water and brine, dried (MgSO4), and filtered. Solvent removal gave the product as a viscous colourless oil (4.4 g, 74percent). 1H NMR (CDCl3): δ ppm 1.3–1.63 (m, 15H), 3.07–3.18 (m, 2H), 3.65 (t, J = 6.44 Hz, 2H), 4.55 (br s, 1H). 13C NMR (CDCl3): δ ppm 22.89, 28.38, 29.80, 32.20, 40.39, 62.53. 79.07, 156.08. HRMS (ESI+) m/z calcd for [M+H]+ C10H22NO3 204.15997, found 204.16070.
Reference：
[1] Synthesis, 1990, p. 366 - 368
[2] Journal of Medicinal Chemistry, 2018, vol. 61, # 17, p. 7892 - 7901
[3] Tetrahedron Letters, 1992, vol. 33, # 20, p. 2833 - 2836
[4] Carbohydrate Research, 1999, vol. 322, # 3-4, p. 201 - 208
[5] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 3, p. 1376 - 1392
[6] Patent: WO2016/27262, 2016, A1, . Location in patent: Page/Page column 68
[7] Patent: WO2015/17519, 2015, A1, . Location in patent: Paragraph 000222
[8] Patent: WO2016/118666, 2016, A1, . Location in patent: Paragraph 0556; 0557; 0558
[9] Patent: WO2016/118697, 2016, A1, . Location in patent: Paragraph 270
[10] Patent: US2018/72711, 2018, A1, . Location in patent: Paragraph 0377; 0378
[11] Patent: US2018/99940, 2018, A1, . Location in patent: Paragraph 0791-0792
[12] Journal of Medicinal Chemistry, 2007, vol. 50, # 21, p. 5217 - 5226
[13] Bioconjugate Chemistry, 2018,
[14] Patent: US5679708, 1997, A,
[15] Angewandte Chemie - International Edition, 2012, vol. 51, # 32, p. 8110 - 8113
[16] Tetrahedron, 1998, vol. 54, # 28, p. 7955 - 7976
[17] Journal of the American Chemical Society, 2003, vol. 125, # 51, p. 15935 - 15940
[18] Molecules, 2013, vol. 18, # 11, p. 13957 - 13978
[19] Angewandte Chemie - International Edition, 2005, vol. 44, # 15, p. 2275 - 2279
[20] Patent: WO2013/116682, 2013, A1, . Location in patent: Paragraph 00223
[21] Journal of Organic Chemistry, 1983, vol. 48, p. 24
[22] Analytical Chemistry, 1998, vol. 70, # 8, p. [d]1629-1638
[23] Organic and Biomolecular Chemistry, 2011, vol. 9, # 11, p. 4108 - 4115
[24] Beilstein Journal of Organic Chemistry, 2013, vol. 9, p. 15 - 25
[25] Journal of Materials Chemistry B, 2014, vol. 2, # 10, p. 1344 - 1353
[26] Journal of Medicinal Chemistry, 2014, vol. 57, # 11, p. 4924 - 4939
[27] European Journal of Medicinal Chemistry, 2014, vol. 82, p. 16 - 35
[28] Chemistry - A European Journal, 2016, vol. 22, # 9, p. 3009 - 3018
[29] Journal of Medicinal Chemistry, 2014, vol. 57, # 22, p. 9673 - 9686
[30] Chemistry - A European Journal, 2013, vol. 19, # 5, p. 1762 - 1768
[31] Journal of the American Chemical Society, 2013, vol. 135, # 17, p. 6396 - 6398
[32] Advanced Synthesis and Catalysis, 2014, vol. 356, # 10, p. 2321 - 2329
[33] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 14, p. 4351 - 4357
[34] Organic Letters, 2015, vol. 17, # 24, p. 6054 - 6057
[35] Journal of Medicinal Chemistry, 2015, vol. 58, # 13, p. 5287 - 5307
[36] Tetrahedron Letters, 1996, vol. 37, # 19, p. 3379 - 3382
[37] Journal of the American Chemical Society, 1999, vol. 121, # 4, p. 866 - 867
[38] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 11, p. 1253 - 1256
[39] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 21, p. 4828 - 4832
[40] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 23, p. 7671 - 7680
[41] Journal of the American Chemical Society, 2002, vol. 124, # 29, p. 8584 - 8592
[42] Tetrahedron Letters, 2004, vol. 45, # 38, p. 7081 - 7085
[43] Patent: US6884868, 2005, B1,
[44] Chemistry Letters, 2011, vol. 40, # 9, p. 959 - 961
[45] Organic Letters, 2014, vol. 16, # 16, p. 4070 - 4073
[46] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 2, p. 283 - 287
[47] Tetrahedron, 2017, vol. 73, # 27-28, p. 3866 - 3877
[48] Journal of Medicinal Chemistry, 2017, vol. 60, # 16, p. 7067 - 7083
[49] ChemMedChem, 2018, vol. 13, # 18, p. 1957 - 1971
3
[ 85908-96-9 ]
[ 75178-90-4 ]
Reference：
[1] Angewandte Chemie - International Edition, 2009, vol. 48, # 7, p. 1324 - 1327
[2] Chemistry - An Asian Journal, 2018, vol. 13, # 17, p. 2559 - 2565
4
[ 2508-29-4 ]
[ 34619-03-9 ]
[ 75178-90-4 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 20℃; Cooling with ice
To a stirred solution of 5-aminopentan-1-ol (13-1, 947.1 mg, 9.2 mmol) in CH2Cl2 (36 mL) was added Boc2O solution (4.2 mL, (18.3 mmol) in 10 mL of CH2Cl2) on ice. After being stirred at room temperature for 30 min, the reaction mixture was diluted with CHCl3, washed with aqueous saturated NaHCO3, and concentrated in vacuo. The residue was subjected to flash column chromatography (SiO2, n-hexane/EtOAc = 4:1, and then CHCl3/MeOH = 10:1) to obtain 13-2 (1.97 g, quant). 1H NMR (500 MHz, CDCl3) δ 4.58 (broad s, 1H), 3.63 (borad t, J = 6.0 Hz, 2H), 3.11 (broad q, J = 7.0 Hz, 2H), 1.60-1.55 (m, 2H), 1.53-1.47 (m, 2H), 1.43 (s, 9H), 1.40-1.35 (m, 2H); HRMS (ESI, positive) m/z 226.1388 [M+Na]+ (calcd for C10H21NO3 226.1414).
100%
at 20℃; for 2 h; Inert atmosphere
5-Aminopentan-1-ol (5.0 g, 48.47 mmol)and di-tert-butyl dicarbonate (12.69g, 58.16 mmol) were dissolved in anhydrous DCM (25 mL) and stirred undernitrogen for 2 h. Water (15 mL) was added and the product was extracted in DCM(3 x 20 mL). The combined organic extracts were sequentially washed with aq NaHCO3and brine, dried over MgSO4, filtered, and concentrated to give theproduct as colorless oil (9.85 g, 100percent). 1H NMR (CDCl3) d 3.62 (m, 2H), 3.11 (m, 2H), 1.62-1.31 (m, 15H).13C NMR (75 MHz, CDCl3) d 155.9, 79.5, 62.8,41.8, 31.9, 29.9, 28.4, 22.7. IR: 3341, 2934, 1687, 1527, 1169 cm-1. MS m/z (ESI) 204.20 (M+ +1).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 6, p. 1608 - 1611
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 9, p. 2808 - 2811
5
[ 2508-29-4 ]
[ 75178-90-4 ]
Yield
Reaction Conditions
Operation in experiment
95%
With triethylamine In tetrahydrofuran; dichloromethane; chloroform
EXAMPLE 31 5-(N-t-Boc)-amino-1-pentanol A solution of (t-Boc)2O (21.8 g, 100 mmol) in anhydrous THF (100 mL) was added to a solution of 5-aminopentan-1-ol (10.3 g, 100 mmol) and Et3N (30.3 g, 300 mmol) in anhydrous THF (20 mL) at 0° C. The resulting solution was stirred at rt overnight. The solvent was evaporated, and the residue was dissolved in CHCl3. The solution was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography on a silica gel column using CH2Cl2 and then 20:1 CH2Cl2-MeOH as eluents to give 19.3 g (95percent) of the title compound as a pale yellow oil. 1H NMR (CDCl3) δ 1.50-1.80 (m, 6H), 2.57-2.85 (m, 8H), 3.85 (s, 4H), 3.94 (s, 2H), 3.95 (s, 2H), 7.08 (d, 2H, J=7.4 Hz), 7.57 (d, 2H, J=7.5 Hz). 13C NMR (CDCl3) δ 26.04, 26.76, 26.98, 47.51, 47.76, 47.96, 48.08, 49.27, 53.84, 54.06, 120.48, 120.69, 136.73, 157.86, 158.15, 158.84. HRMS (FAB) m/z 369.2758 (M+H)+(C21H33N6 requires 369.2767).
Reference：
[1] Chemical and pharmaceutical bulletin, 1983, vol. 31, # 9, p. 3360 - 3362
[2] Journal of Medicinal Chemistry, 1994, vol. 37, # 16, p. 2537 - 2551
8
[ 75178-90-4 ]
[ 83948-54-3 ]
Yield
Reaction Conditions
Operation in experiment
81%
With carbon tetrabromide; triphenylphosphine In tetrahydrofuran at 0 - 20℃;
tert-butyl N-(5-bromopentyl)carbamate[00376] A solution of 5-bromopentan-l-ol (3.00 g, 14.8 mmol) in THF (41 mL) was cooled to 0 °C and CBr4 (7.34 g, 22.1 mmol) and PPh3 (5.96 g, 22.7 mmol) were added. After stirring for 1 h at 0 °C, additional CBr4 (2.55 g, 7.68 mmol) and PPh3 (2.17 g, 8.27 mmol) were added. The mixture was then stirred for 14 h at rt, diluted with 30percent EtOAc/hexane, filtered, and washed with 30percent EtOAc/hexane. The combined filtrates were concentrated in vacuo and the residue was purified by column chromatograph (Si02, CHCl3/hexane, 20 to 100percent) to afford the target product (3.2 g, 81percent).
Reference：
[1] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 5, p. 510 - 515
[2] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 11, p. 1156 - 1161
[3] Journal of Medicinal Chemistry, 2018, vol. 61, # 17, p. 7892 - 7901
[4] Patent: WO2012/177782, 2012, A1, . Location in patent: Page/Page column 87
[5] Journal of Organic Chemistry, 1983, vol. 48, p. 24
[6] Journal of the American Chemical Society, 2013, vol. 135, # 17, p. 6396 - 6398
[7] ChemMedChem, 2014, vol. 9, # 3, p. 542 - 548
[8] Carbohydrate Research, 1999, vol. 322, # 3-4, p. 201 - 208
[9] Journal of Medicinal Chemistry, 1994, vol. 37, # 16, p. 2537 - 2551
[10] Bioconjugate Chemistry, 2013, vol. 24, # 12, p. 2088 - 2103
[11] Organic Letters, 2014, vol. 16, # 16, p. 4070 - 4073
With triethylamine; In water; acetone; at 0 - 20℃; for 4h;
Step 1.1 Add 6-amino-1-hexanol (100.0 g, 0.97 mol) to a 2000 ml three-necked flask.Then add acetone (600 mL) and water (600 mL);Slowly add Boc2O (211.4 g, 0.97 mol) at 0 CAnd triethylamine (107.7 g,1.06 mol). After stirring at room temperature for 4 hours, the solvent was distilled off by a rotary evaporator.Add 1500 mL of ethyl acetate and separate the organic phase.Wash with water (1000 mL) and saturated brine (1000 mL),Dry over anhydrous sodium sulfate. The filtrate is dried,Obtained a colorless oil, compound 1(1-Boc amino-5-pentanol, 197.1 g, yield 100%),Used directly in the next reaction;
98%
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 20℃;
N-t-Boc-5 -amino- 1-pentanol. To a 1.0 L one-neck round-bottom flask containing a solution of 5 -amino- 1-pentanol (15.0 g, 145.4 mmol) in water (140 mL) and saturated aqueous NaHCC>3 (1.4 mL), a solution of di-tert-butyl dicarbonate (33.3 g, 152.7 mmol) in THF (280 mL) was added. The mixture was then stirred at room temperature overnight with the flask open to the atmosphere. The reaction mixture was diluted with saturated aqueous NaHCC>3 (90 mL) and extracted with EtOAc (400 mL). The organic layer was separated, dried over Na2S04, filtered, and the solvent was evaporated providing 28.9 g (98%) of the final product as clear colorless oil. 'll NMR analysis showed the product was clean of impurities, and no further purification was attempted. Alternatively, N-t-Boc-5- amino- 1-pentanol can be obtained from TCI America of Portland, OR.
98%
In dichloromethane; at 0 - 20℃; for 4h;
Step 1: Synthesis of tert-butyl 5-hydroxypentylcarbamate (AU)[0558] To a stirred solution of 5-aminopentan-l-ol (AT, 3.1 g, 30.05 mmol) in dichloromethane (30 mL) was added di-tert-butyl dicarbonate (6.56 g, 30.06 mmol) at 0 C. The resulting mixture was then stirred at rt for 4h. The solvent was removed under reduced pressure to give a crude residue which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v= 1: 2)) to give AU (yield: 98%) as a colorless oil. LC-MS (ES+): m/z 204.00 [MH+], tR=1.29 min (2.6 minute run).
98%
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 20℃;
N-t-Boc-5-amino-l-pentanol. To a 1.0 L one-neck round-bottom flask containing a solution of 5-amino-l -pentanol (15.0 g, 145.4 mmol) in water (140 mL) and saturated aqueous NaHC03 (1.4 mL), a solution of di-tert-butyl dicarbonate (33.3 g, 152.7 mmol) in THF (280 mL) was added. The mixture was then stirred at room temperature overnight with the flask open to the atmosphere. The reaction mixture was diluted with saturated aqueous NaHC03 (90 mL) and extracted with EtOAc (400 mL). The organic layer was separated, dried over Na2S04, filtered, and the solvent was evaporated providing 28.9 g (98%) of the final product as clear colorless oil. NMR analysis showed the product was clean of impurities, and no further purification was attempted. Alternatively, N-t-Boc-5-amino-l-pentanol can be obtained from TCI America of Portland, OR.
98%
In dichloromethane; at 0 - 20℃; for 4h;
To a stirred solution of 5-aminopentan-1-ol (AT, 3.1 g, 30.05 mmol) in dichloromethane (30 mL) was added di-tert-butyl dicarbonate (6.56 g, 30.06 mmol) at 0 C. The resulting mixture was then stirred at rt for 4 h. The solvent was removed under reduced pressure to give a crude residue which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v=1:2)) to give AU (yield: 98%) as a colorless oil. LC-MS (ES+): m/z 204.00 [MH+], tR=1.29 min (2.6 minute run).
98%
In dichloromethane; at 0 - 20℃; for 4h;
Step 1: Synthesis of tert-butyl 5-hydroxypentylcarbamate (AU) To a stirred solution of 5-aminopentan-1-ol (AT, 3.1 g, 30.05 mmol) in dichloromethane (30 mL) was added di-tert-butyl dicarbonate (6.56 g, 30.06 mmol) at 0 C. The resulting mixture was then stirred at room temperature for 4 hours. The solvent was removed under reduced pressure to give a crude residue which was purified by flash silica gel chromatography (eluent: ethyl acetate/petroleum ether (v:v=1:2)) to give AU (yield: 98%) as a colorless oil. LC-MS (ES+): m/z 204.00 [MH+], tR=1.29 min (2.6 minute run).
97.3%
With triethylamine; In dichloromethane; at 20℃;
Weigh 2.09 g of compound 82 and 5.6 mL of triethylamine in 50 mL of dichloromethane, cool to 0 C, and slowly add 4.43 g of di-tert-butyl dicarbonate dropwise. After the dropwise addition, react overnight at room temperature. Use the reaction solution with It was washed with 1N HCl (100 mL × 3), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 4 g of compound 83 with a yield of 97.3%
96%
In methanol;
Working Example 17 N-[N-[(2S,3S)-3-trans-ethoxycarbonyloxirane-2-carbonyl]-L-phenylalanyl]-1-amino-5-methoxypentane 5-Amino-1-pentanol (5.44 ml. manufactured by Tokyo Kasei Kogyo Co., Ltd.) was dissolved in methanol (110 ml). To the solution was added, under ice-cooling, di-tert-butyl dicarbonate (11.5 ml, manufactured by Wako Pure Chemical Industries, Ltd.), and the mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated, which was subjected to a silica gel column chromatography (500 ml). Elution was conducted with a hexane eluent supplemented with ethyl acetate sequentially. The fraction eluted with 40% to 100% (v/v) ethyl acetate was concentrated to give N-Boc-5-amino-1-pentanol (9.71 g) as a colorless oily product (yield 96%).
95%
With sodium hydroxide; In 1,4-dioxane; water; at 20℃; for 12h;
General procedure: To a solution of 2a (or 2b-e, 20 mmol) in a mixture of dioxane (15 mL) and H2O (7 mL), wasadded 5N NaOH (4.8 mL) and a solution of Boc2O (5.0 g, 23 mmol) in dioxane at 0 C. After stirred atrt overnight, the reaction mixture was concentrated in vacuo. The residue was extracted from 10%citric acid with AcOEt, and dried over anhydrous Na2SO4. Evaporation of the solvents gave the pureproduct 3a-e. 3a was obtained as a colorless oil (2.67 g, 83%).
95%
With iodine; In methanol; at 25℃; for 12h;
To a solution of 5-aminopentan-1-ol (21.3 g, 206 mmol) in MeOH (200 mL) was added I2 (2.63 g, 10.3 mmol) and tert-butoxycarbonyl tert-butyl carbonate (54.2 g, 248 mmol). The mixture was stirred at 25 C. for 12 hours. On completion, the mixture was concentrated to give a residue. The residue was purified by silica gel chromatograph to give the title compound (40.0 g, 95% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) delta 4.60 (s, 1H), 3.69-3.59 (m, 2H), 3.12 (d, J=5.6 Hz, 2H), 1.9-1.7 (m, 1H), 1.61-1.36 (m, 15H).
93.1%
In dichloromethane; at 20℃;Cooling with ice;
To a solution of 41 (20 g, 194 mmol) in DCM (0.2 L) was added (Boc)20 dropwise (42.3 g, 194 mmol) under an ice bath. The reaction was stirred at RT over night. Then the mixture solution was extracted with DCM and washed with water. The combined organic layers were washed with saturated NaCl, dried over Na2S04, and filtered. The solvent was removed in vacuum to give 42 as an oil (37 g, yield 93.1 %). XH NMR (300 MHz, CDC13) delta: 3.5(m, 2H), 3.2 (m, 2H), 1.6-1.5(m, 4H), 1.4-1.3(m, 1 1H).
92%
With triethylamine; In 1,4-dioxane; at 20℃; for 5h;
5-amino-1-pentanol (A, 1.15 g, 11.0 mmol) was dissolved in dioxane (20 mL) and di-tert-butyldicarbonate (3.2 g, 14.7 mmol) and trimethylamine (9.2 mL, 66.0 mmol) were added in portions. The mixture was stirred at room temperature for 5 h until TLC (hexane:EtOAc 1:1) showed complete consumption of the starting material. The solvent was evaporated and the residue purified by silica gel column chromatography by elution with hexane:EtOAc (6:4) ? (4:6). 2.07 g (92% yield) of tert-butyl (5-hydroxypentyl)carbamate B was obtained. 1H RMN (200 MHz, CDCl3): delta 3.45 (t, 2H, J = 6.2 Hz, CH2OH), 2.95 (t, 2H, J = 6.4 Hz, CH2NHBoc), 1.46-1.6 (m, 15H, 3 × CH2 + (CH3)3C); 13C RMN (50.3 MHz, CDCl3): delta 156.2 (C=O), 78.9 (C(CH3)3), 62.0 (CH2OH), 40.5 (CH2NH), 32.0, 29.6 (2 × CH2), 28.3 (C(CH3)3), 22.9 (CH2).
83%
With dmap; triethylamine; In chloroform; at 20℃; for 3h;
5-Amino-1-pentanol (30, 2 g, 19 mmol), Boc2O (4.5 g, 20 mmol), Et3N (2.1 g, 21 mmol), DMAP (0.23 g, 1.9 mmol) and CHCl3 (20 mL) were placed in a 100 mL reaction flask. The reaction mixture was allowed to stir for 3 h at rt. After the volatile materials were removed under reduced pressure, the resulting reside was purified by flash column chromatography (CHCl3) to yield 31. To a flame-dried 100 mL round-bottom flask containing a magnetic stirring bar were charged 31 (30 mmol), Et3N (30 mmol), DMAP (3 mmol), and CHCl3 (30 mL). The solution was cooled to 0 C, and TsCl (30 mmol) dissolved in CHCl3 was added to the solution over 10 min. The reaction mixture was stirred at rt for 3 h. After all the volatile materials were removed under reduced pressure, the crude residue was purified by flash column chromatography (CHCl3) to get 32. 31: 83%; 1H NMR (300 MHz, CDCl3): delta 3.63 (2H, m, CH2N), 3.11 (2H, m, CH2OH), 1.61-1.39 (15H, m, 3×CH2, -C(CH3)3).
81%
In dichloromethane; at 0 - 20℃; for 1h;
To a stirred solution of 5-aminopentan-1-ol (10.0 g, 96.9 mmol) in DCM (75 mL) was added Boc-anhydride (25.4 g, 116.3 mmol) dropwise at 0 C. The resulting reaction mixture was allowed to warm to room temperature and stirred at rt for 1 h. The reaction mixture was transferred into ice water and the resulting mixture was extracted using DCM (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give tert-butyl (5-hydroxypentyl)carbamate as colorless oil (16 g, 81%). 1H NMR (400 MHz, DMSO) delta 4.56 (bs, 1H), 3.69-3.64 (m, 2H), 3.17-3.12 (m, 2H), 1.64-1.62 (m, 2H), 1.54-1.53 (m, 6H), 1.51-1.49 (m, 1H), 1.46 (s, 9H), 1.43-1.37 (m, 2H).
81%
In dichloromethane; at 0 - 20℃; for 1h;
To a stirred solution of 5-aminopentan-1-ol (10.0 g, 96.9 mmol) in DCM (75 mL) was added Boc-anhydride (25.4 g, 116.3 mmol) dropwise at 0 C. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using DCM (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give tert-butyl (5-hydroxypentyl)carbamate as colorless oil (16 g, 81%). 1H NMR (400 MHz, DMSO) delta 4.56 (bs, 1H), 3.69-3.64 (m, 2H), 3.17-3.12 (m, 2H), 1.64-1.62 (m, 2H), 1.54-1.53 (m, 6H), 1.51-1.49 (m, 1H), 1.46 (s, 9H), 1.43-1.37 (m, 2H).
74%
With potassium carbonate; In methanol; water; at 20℃; for 2h;
A mixture of 5-amino-1-pentanol (3.0 g, 29.1 mmol), t-Boc anhydride (6.1 g, 34.9 mmol), and K2CO3 (4 g) in 50/50 water/methanol (25 mL) was stirred at ambient temperature for 2 h. The reaction mixture was quenched with water (25 mL) and extracted with EtOAc (2x25 mL). Combined extracts were washed with water and brine, dried (MgSO4), and filtered. Solvent removal gave the product as a viscous colourless oil (4.4 g, 74%). 1H NMR (CDCl3): delta ppm 1.3-1.63 (m, 15H), 3.07-3.18 (m, 2H), 3.65 (t, J = 6.44 Hz, 2H), 4.55 (br s, 1H). 13C NMR (CDCl3): delta ppm 22.89, 28.38, 29.80, 32.20, 40.39, 62.53. 79.07, 156.08. HRMS (ESI+) m/z calcd for [M+H]+ C10H22NO3 204.15997, found 204.16070.
With triethylamine; In water; acetone;
PREPARATION 277 To an ice-cooled solution of 5-aminopentan-1-ol (5.0 g) in water (40 ml) and acetone (40 ml) was added triethylamine (8.78 g) and di-tert-butyl dicarbonate (13.75 g), then the solution was stirred at 30 C. for 3 hours. The solvent was evaporated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give a crude yellow oil (12.7 g). The crude oil was purified by silica gel chromatography (50:1-4:1 dichloromethane-methanol) to give 5-hydroxypentylcarbamic acid tert-butyl ester (8.68 g), as a pale yellow oil. IR (KBr): 3344.0, 2975.6, 2935.1, 2665.7, 1706.7, 1695.1, 1529.3, 1280.5, 1249.6, 1178.3, 1168.7 cm-1. NMR (DMSO-d6, delta): 1.1-1.6 (15H, m), 2.88 (2H, dd, J=6.5 and 12.6 Hz), 3.2-3.5 (2H, m), 4.33 (1H, t, J=5.1 Hz), 6.75 (1H, m).
1.3 g
With triethylamine; In dichloromethane; at 20℃; for 1h;
To a solution of 5-amino-1-pentanol (0.525 g, 5.1 mmol) and triethylamine (0.779 mL, 5.6 mmol) in dichloromethane (1 6 mL) was added a solution of di-tert-butyl dicarbonate (1 .1 g, 5.1 mmol) in dichloromethane (5 mL). The mixture was stirred at room temperature for 1 h and then washed with 0.5 M HCI (1 ml) three times. The organic phase was dried over MgSO4. The solid was filtered off and the solvent was evaporated under vacuum to obtain a white solid (1 .3 g). The product was analysed by NMR (CDC ) and the structure was in concordance.
In dichloromethane; at 20℃; for 2h;
General procedure: (a) A solution of 5-hydroxylpentylamine (or 10-hydroxyldecylamine) (1.0 mmol) and (Boc)2O (1.2 mmol) in dry DCM(10 mL) was stirred at room temperature for 2 h before the reaction mixture was partitioned in ddH2O (20 mL) and DCM (20 mL), the DCM layer was isolated and the ddH2O layer was extracted with DCM for three times. The combined organics were then sequentially washed with saturated aqueous NaHCO3 solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure on arotary evaporator. (b) To the obtained colorless oily residue was added CBr4 (1.2 mmol) and dry DCM (10 mL), and the resulting solution was stirred at 0 C while to which a solution of PPh3 (1.2 mmol) in dry DCM (5 mL) was added. After the addition was complete, the reaction mixture was stirred at room temperature overnight before being concentrated under reduced pressure on a rotary evaporator. To the residue was then added hexanes (30 mL) while stirring, the resulting precipitate was filtered off and the filtrate was concentrated under reduced pressure again, the resulting white crystalline precipitate was filtered off again and the filtrate was then concentrated under reduced pressure. (c) To the residue (a white solid) was added 50% (v/v) TFA/DCM (6 mL) and the resulting solution was stirred at room temperature for 8 h before being concentrated. The resulting residue was then dissolved in cold diethyl ether (6 mL), and to the stirred solution was added hydrobromic acid (?40%) (~1.0 mmol). The resulting white precipitate was collected via filtration and washed with cold diethyl ether, affording the crude material that predominantly contained 5-bromopentylamine hydrobromide (or 10-bromodecylamine hydrobromide). 5-bromopentylamine hydrobromide: 1H NMR (400 MHz, CD3OD) delta3.50 (t, J = 8.0 Hz, 2H), 2.96 (t, J = 8.0 Hz, 2H), 1.97-1.89 (m, 2H),1.75-1.67 (m, 2H), 1.61-1.53 (m, 2H); ESI-MS calcd for C5H13BrN ([M+H]+) 166.02; found: 166.03. 10-bromodecylamine hydrobromide: 1HNMR (400 MHz, CD3OD) delta 3.46 (t, J=8.0 Hz, 2H), 2.93 (t, J=8.0 Hz,2H), 1.89-1.82 (m, 2H), 1.71-1.64 (m, 2H), 1.49-1.37 (m, 12H); ESIMScalcd for C10H23BrN ([M+H]+) 236.10; found: 236.23. The twocrude preparations were then used directly for the synthesis depicted in Scheme 2.
2517.7 mg
In dichloromethane; at 0 - 20℃; for 8h;
5-Amino-1-pentanol (1024.4 mg, 9.9297 mmol) was dissolvedin CH2Cl2 (15 mL). To the solution was added Boc2O (2300 muL) dropwise at 0 C. The whole was stirred at roomtemperature for 8 h. H2O (10 mL) was added. The organiclayer was separated, washed with brine (5 mL), dried overNa2SO4, evaporated, and vacuum-dried to yield compound 7 asa yellow oil (2517.7 mg), which was used without furtherpurification.
With carbon tetrabromide; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;
tert-butyl N-(5-bromopentyl)carbamate[00376] A solution of 5-bromopentan-l-ol (3.00 g, 14.8 mmol) in THF (41 mL) was cooled to 0 C and CBr4 (7.34 g, 22.1 mmol) and PPh3 (5.96 g, 22.7 mmol) were added. After stirring for 1 h at 0 C, additional CBr4 (2.55 g, 7.68 mmol) and PPh3 (2.17 g, 8.27 mmol) were added. The mixture was then stirred for 14 h at rt, diluted with 30% EtOAc/hexane, filtered, and washed with 30% EtOAc/hexane. The combined filtrates were concentrated in vacuo and the residue was purified by column chromatograph (Si02, CHCl3/hexane, 20 to 100%) to afford the target product (3.2 g, 81%).
terf-Butyl 5-hydroxypentylcarbamate (2g, 9.8 mmol) was dissolved in anhydrous dichloromethane (20 mL) and cooled to O0C. Triethylamine (2.46 ml_, 17.7 mmol) was added dropwise followed by slow addition of methanesulfonyl chloride (1.13 mL, 14.7 mmol). The mixture was stirred at room temperature overnight and quenched with saturated sodium bicarbonate solution. The reaction mixture was extracted with dichloromethane and the combined organic layers washed with water and brine. The organic extract was dried(MgSO4) filtered, and concentrated to afford 211 as a yellow solid in quantitative yield. LRMS(ESI): (calc) 281.1 ; (found), 304.1 (M+Na)+
97%
With triethylamine; In dichloromethane; at -10℃; for 3h;
To a stirred mixture of tert-butyl 5-hydroxypentylcarbamate (2)(9.8 g, 48.2 mmol) and triethyl amine (13.44 mL, 96.0 mmol) in DCM (85 mL) at-10 oC was added methanesulfonyl chloride (4.5 mL, 57.9 mmol) in adropwise fashion and the resulting solution was stirred at the same temperaturefor 3h. The reaction was quenched with the addition of water (5 mL). Theorganic phase was washed with water, brine, dried over MgSO4,filtered and evaporated under reduced pressure to afford the title compound asyellow oil (13.16g, 97%). The product was directly taken to next step withoutany further purification. 1H NMR(CDCl3) d 4.22 (t, 2H, J = 6.42 Hz), 3.09 (m, 2H), 1.82 (m, 4H), 1.56-1.40(m, 11H). 13C NMR (75 MHz, CDCl3) d 155.8, 79.3, 70.0,41.8, 37.9, 29.8, 28.3, 22.5. IR: 2981, 1707, 1516, 1354, 1171 cm-1. MS m/z (ESI) 304.26 (M +Na+).
86.9%
With triethylamine; In dichloromethane; for 1.33333h;Cooling with ice;
To a solution of 42 (10 g, 49.2 mmol) in DCM (100 mL) and Et3N (9.9 g, 98.5 mmol) was added methanesulfonyl chloride (6.7 g, 59.1 mmol) in portions over 20 minutes under an ice bath. The reaction was stirred for 1 hour. The mixture was extracted with DCM. The combined organic layers were washed with saturated NaCl, dried over a2S04, and filtered. The filtrate was concentrated to give 43 (12 g, yield: 86.9 %). XH NMR (300 MHz, CDC13) delta: 4.0 (m, 2H), 3.1-3.0 (m, 3H), 3.2-3.1 (m, 2H),1.6-1.5 (m, 4H), 1.4-1.3 (m, 11H).
81%
With triethylamine; In diethyl ether; benzene; at 8 - 20℃; for 7h;
MsCl (2.07 g, 18.1 mmol) in 7 mL ofdry C6H6 was added during 20 min under stirring to thecooled (8C) solution of 5NBocaminopentanol1(3.86 g, 19 mmol) and Et3N (2.53 g, 25 mmol) in40 mL of C6H6/Et2O (2 : 1). The mixture was stirredfor 1 h at 8C and 6 h at 20C. The precipitate was filtered, and filtrates were washed successively with 1 NaHCO3 (3 × 10 mL), H2O (10 mL), 10% citric acid(2 × 10 mL), H2O (5 mL), and 5 NaCl (15 mL) anddried over MgSO4/NaHCO3. The solvent was evaporated in vacuum, the residue was triturated with hexane, the precipitate was filtered and dried in air,recrystallized from an Et2Ohexane mixture. Compound (X) was obtained in a yield of 4.32 g (81%).
80%
With triethylamine; In dichloromethane; at -10℃; for 5h;
General procedure: To a stirred solution of tert-butyl 5-hydroxypentyl-carbamate(500 mg, 2.46 mmol) and TEA (498 mg, 4.92 mmol) in 5mL DCMat -10 C was added MsCl (338 mg, 2.95 mmol) dropwise and thesolution was stirred at the same temperature for 5 h. The reactionwas then quenched with water. The organic layer was washed withwater, brine, dried over MgSO4, filtered and evaporated underreduced pressure to give the desired product as yellow oil (552 mg,80%, Rf 0.5 (EtOAc)) The mesylatewas used in the next step withoutany further purification. Under N2 atmosphere 5-(tert-butoxycarbonylamino)pentyl methanesulfonate (350 mg, 1.2 mmol) wasdissolved in 5mL THF followed by the addition of LiBr (313 mg,3.6 mmol) to the solution. The reaction mixture was stirred for 16 hunder reflux, then THF was removed under vacuum. The mixturewas diluted with 10 mL water and it was extracted with DCM(3 x 10 mL). The combined organic phase was washed with water(3 x 10 mL) and brine (3 x 10 mL), dried over MgSO4 and evaporatedin vacuo. The product was purified by column chromatographyon silica gel 60 (n-hexane-EtOAc 9:1) to give whitecrystalline product (230 mg, 72%).
With triethylamine; In dichloromethane; at 0 - 20℃; for 5.5h;
General procedure: To a solution of N-Boc protected alcohol (60 mmol) and TEA (60 mmol) in dry DCM (100 mL) kept in an ice bath (0 C) was slowly added methane sulfonyl chloride (60 mmol)) and reaction mixture was stirred for 30 min at 0 C. The ice bath was removed and reaction mixture was further allowed to stir at room temperature for 5 h (Completion of the reaction was monitored by TLC). Then water (50 mL) was added with stirring, the resulting solution was transferred to a reparatory funnel, organic layer was separated and aqueous layer was extracted with DCM (2 × 75 mL). The combined organic layers were washed with brine (50 mL) dried over anhydrous sodium sulfate and concentrated on rotary evaporator. See individual experiments for more details.
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 4.5h;
5-((tert-butoxycarbonyl)amino)pentyl 4-methylbenzenesulfonate (13-3).
To a stirred solution of 13-2 (1.97 g, 9.7 mmol) in CH2Cl2 (32 mL) on ice was added TsCl (2.78 g, 14.6 mmol), Et3N (4.0 mL, 28.9 mmol) and DMAP (117.4 mg, 0.96 mmol). After being stirred for 4.5 h, the reaction mixture was diluted with CHCl3, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was subjected to flash column chromatography (SiO2, n-hexane/EtOAc = 1:0, 8:1, and then 4:1) to obtain 13-3 (3.14 g, 91%). 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 4.51 (broad s, 1H), 4.00 (t, J = 6.5 Hz, 2H), 3.06-3.02 (broad q, J = 6.5 Hz, 2H), 2.44 (s, 3H), 1.67-1.61 (m, 2H), 1.42-1.38 (m, 11H), 1.35-1.29 (m, 2H); HRMS (ESI, positive) m/z 380.1497 [M+Na]+ (calcd for C17H27NO5S 380.1502).
91%
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 25℃; for 12h; Inert atmosphere;
1001.1-1001.2.1 Step 1: 5-(teri-Butoxycarbonylamino)pentyl 4-methylbenzenesulfonate
Under nitrogen, to a stirring solution of fert-butyl 5-hydroxypentylcarbamate (4.00 g, 19.7 mmol), DMAP (0.24 g, 1.99 mmol) and Et3N (5.51 mL, 39.5 mmol) in DCM (70 mL) was added TsCl (5.68 g, 29.8 mmol) portionwise at 0°C. The resulting solution was stirred at 25°C for 12 hours. The reaction mixture was diluted with water. The organic layers were separated, and the aqueous phase was extracted with DCM. The combined organic layers were dried over Na2SC>4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient: 0-30% ethyl acetate/petroleum ether) to yield 6.4 g (91%) of the title compound as a colorless oil. LCMS (ESI): RT (min) = 1.38. [M+H]+ = 358, method A.
91%
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 25℃; for 12h; Inert atmosphere;
1001.1.2; 1001.2.2; 1001.3.2; 1001.4.2 Step 2: 5-(teri-Butoxycarbonylamino)pentyl 4-methylbenzenesulfonate
Under nitrogen, to a stirred solution of fert-butyl 5-hydroxypent lcarbamate (4.00 g, 19.7 mmol), DMAP (0.24 g, 1.99 mmol) and Et3N (5.51 mL, 39.5 mmol) in DCM (70 mL) was added TsCl (5.68 g, 29.8 mmol) portionwise at 0 °C. The resulting solution was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water. The organic layers were separated, and the aqueous was extracted with DCM. The combined organic layers were dried over Na2SC>4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient: 0-30% ethyl acetate/petroleum ether) to yield 6.4 g (91%) of the title compound as a colorless oil. LCMS (ESI): RT (min) = 1.38. [M+H]+ = 358, method A
80%
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃;
77.6%
In lithium hydroxide monohydrate; triethylamine
P.9.1 1)
1) Synthesis of 5-t-butoxycarbonylamino-1-p-toluenesulfonyloxypentane (22) 5-t-Butoxycarbonylamino-1-pentanol [3.048 g (15.0 mmol.)] was dissolved in triethylamine (40 ml), to which was added, under ice-cooling, p-toluenesulfonyl chloride [3.146 g (16.5 mmol.)], and the mixture was stirred at room temperature for 19 hours. After completion of the reaction, water was added to the reaction mixture. The whole mixture was subjected to extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, then the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by column chromatography (silica gel: 170 g; eluent: n-hexane/ethyl acetate = 2/1) to obtain the desired product (22) [4.162 g (77.6%, colorless solid substance).
76%
With triethylamine In dichloromethane
75%
With 4-dimethylaminopyridine; triethylamine In chloroform at 0 - 20℃; for 3.16667h;
4.2.41. Synthesis of tert-butyl 5-hydroxypentylcarbamate (31) and the corresponding O-tosylate 32
5-Amino-1-pentanol (30, 2 g, 19 mmol), Boc2O (4.5 g, 20 mmol), Et3N (2.1 g, 21 mmol), DMAP (0.23 g, 1.9 mmol) and CHCl3 (20 mL) were placed in a 100 mL reaction flask. The reaction mixture was allowed to stir for 3 h at rt. After the volatile materials were removed under reduced pressure, the resulting reside was purified by flash column chromatography (CHCl3) to yield 31. To a flame-dried 100 mL round-bottom flask containing a magnetic stirring bar were charged 31 (30 mmol), Et3N (30 mmol), DMAP (3 mmol), and CHCl3 (30 mL). The solution was cooled to 0 °C, and TsCl (30 mmol) dissolved in CHCl3 was added to the solution over 10 min. The reaction mixture was stirred at rt for 3 h. After all the volatile materials were removed under reduced pressure, the crude residue was purified by flash column chromatography (CHCl3) to get 32. 31: 83%; 1H NMR (300 MHz, CDCl3): δ 3.63 (2H, m, CH2N), 3.11 (2H, m, CH2OH), 1.61-1.39 (15H, m, 3×CH2, -C(CH3)3). 32: 75 %; 1H NMR (300 MHz, CDCl3): δ 7.75 (2H, d, J=8.5Hz, Ts), 7.32 (2H, d, J=8.5Hz, Ts), 3.98 (2H, t, J=6.0Hz, CH2OTs), 3.02 (2H, m, CH2N), 1.63 (2H, m, CH2CH2CH2), 2.45 (3H, s, Ar-CH3), 1.40 (11H, m, CH2CH2CH2, -C(CH3)3), 1.30 (2H, s, CH2CH2CH2); 13C NMR (75 MHz, CDCl3): δ 155.9, 144.6, 133.1, 129.8, 127.8, 70.3, 40.2, 29.4, 28.4, 28.3, 22.6, 21.6, 14.1.
71%
With triethylamine In dichloromethane at 0 - 20℃; for 1h;
46%
With sodium hydroxide In tetrahydrofuran at 20℃;
46%
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 20℃; for 3h;
37%
With potassium carbonate; triethylamine In dichloromethane at 20℃; for 72h;
5.3. 5-((tert-Butoxycarbonyl)amino)pentyl 4-methylbenzenesulfonate (2)
A mixture of tert-butyl (5-hydroxypentyl)carbamate (1.5 g,7.4mmol), p-toluenesulfonyl chloride (1.5 g, 7.9 mmol), triethylamine (100 μL, 0.72 mmol), and potassium carbonate (2 g, 14.5 mmol) in dichloromethane (10 mL) was stirred at ambient temperature for3 days. Water (100mL) was added and the mixture extracted with ethyl acetate (2x50 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and solvent removed to leave a light brown oil (2.41 g). Flash chromatography (hexane/EtOAc, 30:70) gave a colourless oil from heart fractions which crystallised upon trituration with pentane to give the product as a white solid (0.97 g, 37%). A further 1.2 g (45%) was isolated from other fractions. Mp 47-48 °C. 1H NMR (CDCl3): δ ppm 1.30-1.38 (m, 2H), 1.40-1.48 (m, 11H), 1.61-1.71 (m,2H), 2.45 (s, 3H) 3.06 (q, J = 6.56 Hz, 2H), 4.02 (t, J = 6.33 Hz, 2H), 4.50 (br s, 1H), 7.35 (m, J = 7.99 Hz, 2H), 7.79 (m, 2H). 13C NMR (CDCl3): δ ppm 21.85, 22.88, 28.62, 29.65, 40.44, 70.55, 79.36, 128.10, 130.05, 133.35, 144.94, 156.14. HRMS (ESI+) m/z calcd for [M+H]+ C17H28NO5S 358.1683, found 358.1679.
In lithium hydroxide monohydrate; triethylamine
P.9.1 (1)
(1) Synthesis of 5-t-butoxycarbonylamino-1-p-toluenesulfonyloxypentane(22) 5-t-Butoxycarbonylamino-1-pentanol[3.048 g(15.0 mmol.)] was dissolved in triethylamine(40 ml), to which was added, under ice-cooling, p-toluenesulfonyl chloride[3.146 g(16.5 mmol.)], and the mixture was stirred at room temperature for 19 hours. After completion of the reaction, water was added to the reaction mixture. The whole mixture was subjected to extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, then the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by column chromatography(silica gel:170 g;eluent:n-hexane/ethyl acetate=2/1) to obtain the desired product(22)[4.162 g(77.6%, colorless solid substance). TLC[Silica Gel;n-hexane/AcOEt(2/1)]:Rf=0.38. NMR(90 MHz,CDCl3) δ: 1.24 to 1.80(6H,m,CH2 x3), 1.41(9H,s,CH3 x3), 2.43(3H,s,Ar-CH,), 3.04(2H,q,CH2 NHCO), 4.01(2H,t,CH2 OTs), 4.18(1H,br.NH), 7.33,7.78(each 2H,d,aromatic protons). IR(film)cm-1: 3370, 2970, 2920, 2850, 1700, 1595, 1510, 1390, 1360, 1270, 1250, 1190, 1170, 1097, 946, 815.
Stage #1: N-(tert-butyloxycarbonyl)-5-aminopentanol With 4-dimethylaminopyridine; triethylamine In dichloromethane for 0.333333h;
Stage #2: p-methylbenzene sulfonyl chloride In dichloromethane at 0 - 20℃; for 16h;
172.1 Preparation of 5-(tert-butoxycarbonylamino)pentyl 4-methylbenzenesulfonate
To a solution of tert-butyl N-(5-hydroxypentyl)carbamate (2.0 g, 9.84 mmol) in DCM (50 mL) was added Et3N (2.76 mL, 19.68 mmol) and catalytic amount of DMAP. The mixture was stirred for 20 minutes, and then to the mixture 4-methylbenzenesulfonyl chloride (1.88 g, 9.84 mmol) was added portionwise at 0° C. The mixture was warmed to room temperature and stirred for 16 hours. The mixture was washed with 1 M hydrochloric acid, followed by saturated aqueous NaHCO3 solution. The organic layer was dried over anhydrous Na2SO4 and concentrated to give 5-(tert-butoxycarbonylamino)pentyl 4-methylbenzenesulfonate which was directly used for the next step without further purification.
Stage #1: N-(tert-butyloxycarbonyl)-5-aminopentanol With 4-dimethylaminopyridine; triethylamine In dichloromethane for 0.333333h;
Stage #2: p-methylbenzene sulfonyl chloride In dichloromethane at 0 - 20℃; for 16h;
172.1 Step 1: Preparation of 5-(/£ /-butoxycarbonylamino)pentyl 4-methylbenzenesulfonate
Step 1: Preparation of 5-(/£ /-butoxycarbonylamino)pentyl 4-methylbenzenesulfonate To a solution of /tvv-butyl N- ( 5 - h yd ro x y p e n t y ) c a rba mate (2.0 g.9.84 mmol) in DCM (50 ml.) was added Eh (2.76 mL, 19.68 mmol) and catalytic amount of DMAP. The mixture was stirred for 20 minutes, and then to the mixture 4-met hyibenzenesu 1 fo ny 1 chloride (1.88 g, 9.84 mmol) was added portionwise at 0 °C. The mixture was warmed to room temperature and stirred for 16 hours. The mixture was washed with 1 M hydrochloric acid, followed by saturated aqueous NaHCO; solution. The organic layer was dried over anhydrous Na.>SO.i and concentrated to give 5-(tert-butoxycarbonylamino)pentyl 4-methylbenzenesulfonate which was directly used for the next step without further purification.
4.2 g
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 20℃;
56.1 Step 1: Preparation of 5-(tert-butoxycarbonylamino)pentyl 4-methylbenzenesulfonate
Step 1: Preparation of 5-(tert-butoxycarbonylamino)pentyl 4-methylbenzenesulfonate To a mixture of tert-butyl N-(5-hydroxypentyl)carbamate (4.52 g, 22.26 mmol) and triethylamine (3.72 mL, 26.7 mmol) in DCM (200 mL) at rt was added p-toluenesulfonyl chloride (5.09 g, 26.7 mmol) and DMAP (0.272 g, 2.226 mmol). After being stirred overnight, the reaction mixture was concentrated in vacuo and the residue was purified by flash column to give 5-(tert-butoxycarbonylamino)pentyl 4-methylbenzenesulfonate (4.2 g).
With triethylamine In dichloromethane Inert atmosphere;
With triethylamine In dichloromethane at -10 - 0℃;
2.43 g
With 4-dimethylaminopyridine; triethylamine In dichloromethane for 0.5h; Inert atmosphere;
2.3 g
With N-ethyl-N,N-diisopropylamine at 20℃; for 16h;
4 tert-butyl 5-hydroxypentylcarbamate
A mixture of tert-butyl 5-hydroxypentylcarbamate (4.50 g, 22.17 mmol), TsCI (6.34 g, 33.25 mmol) and DIPEA (8.60 mg, 66.51 mmol) in DCM (65 mL) was stirred at rt for 16 hours. The mixture was concentrated in vacuo and the residue was diluted with DCM (200 mL), washed with brine (200 mL x2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, PE:EA=10:1-1:10) to yield the title compound as a yellow oil (2.3 g, 30%). LCMS (m/z): 258 [M + H-100]+, 380 [M + Na]+.
2.3 g
With N-ethyl-N,N-diisopropylamine at 20℃; for 16h;
4 tert-butyl 5-hydroxypentylcarbamate
A mixture of tert-butyl 5-hydroxypentylcarbamate (4.50 g, 22.17 mmol), TsCI (6.34 g, 33.25 mmol) and DIPEA (8.60 mg, 66.51 mmol) in DCM (65 mL) was stirred at rt for 16 hours. The mixture was concentrated in vacuo and the residue was diluted with DCM (200 mL), washed with brine (200 mL x2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, PE:EA=10:1-1:10) to yield the title compound as a yellow oil (2.3 g, 30%). LCMS (m/z): 258 [M + H-100]+, 380 [M + Na]+.
With hydrogenchloride; sodium hydroxide In tetrahydrofuran; water
81 5-(t-Boc)amino-1-pentanyl tosylate
EXAMPLE 81 5-(t-Boc)amino-1-pentanyl tosylate A solution of tosyl chloride (28.6 g, 0.15 mol) in 200 mL of THF was added dropwise into a mixture of NaOH (24.0 g, 0.6 mol) and 5-(t-Boc)amino-1-pentanol (prepared by treating 5-amino-1-pentanol with Di-t-butyldicarbonate as per the procedure of Example 22(b)) (20.3 g, 0.1 mol) in 200 mL of H2O and 300 mL of THF at 0° C. The resulting solution was stirred at rt overnight. The reaction solution was poured onto 100 g of ice and 80 mL of HCl (37%) and extracted with CHCl3. The combined organic phase was washed with 5% NaHCO3 solution and brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on a silica gel column using CH2Cl2 as an eluent to give 15.6 g (46%) of the title compound as an pale yellow oil. 1H NMR (CDCl3) δ 1.21-1.45 (m, 4H), 1.42 (s, 9H), 1.57-1.70 (m, 2H), 2.44 (s, 3H), 3.00-3.10 (q, 2H, J=6.3 Hz), 4.00 (t, 2H, J=6.4 Hz), 4.50 (m, 1H), 7.33 (d, 2H, J=8.2 Hz), 7.77 (d, 2H, J=8.2 Hz). 13C NMR (CDCl3) δ 21.5, 22.6, 28.4, 29.3, 40.1, 70.4, 78.8, 127.8, 129.8, 133.1, 144.7, 156.0. HRMS (FAB) m/z 358.1688 (M+1)+(C17H28NO4S requires 358.1688). Anal. Calcd for C17H27NO4S: C, 57.11; H, 7.62; N, 3.92. Found: C, 56.98; H, 7.59; N, 4.08.
With methanesulfonyl chloride; triethylamine; In DCM;
Methane sulfonyl chloride (1 eq) was added to a stirring solution of N-Boc propan-1 -ol, N-Boc butan-1-ol or N-Boc pentan-1-ol (1 eq) and EtJM (3 eq) in DCM. Upon completion the reaction was quenched with NaHCO3 solution. The DCM layer was dried over magnesium sulfate and concentrated in vacuo to produce a crude residue which was used crude or purified by flash column chromatography.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at -20 - 20℃; for 2h;Inert atmosphere;
Example 24: Methyl 2-(5-(tert-butoxycarbonylamino)pentyloxy)-4-fluorobenzoate (I- 25} The reaction was carried out under N2 atmosphere. Triphenyl phosphine (0.52 mol) was added to a solution of <strong>[392-04-1]methyl 4-fluoro-2-hydroxybenzoate</strong> (0.47 mol), tert-butyl 5-hydroxypentylcarbamate (0.47 mol) and diisopropyl azodicarboxylate (DIAD;0.94 mol) in THF (1 1) drop wise at -20C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 h. The resulting mixture was used directly in the next step without further purification.
tert-butyl (5-hydroxypentyl)carbamate (13-2).
To a stirred solution of 5-aminopentan-1-ol (13-1, 947.1 mg, 9.2 mmol) in CH2Cl2 (36 mL) was added Boc2O solution (4.2 mL, (18.3 mmol) in 10 mL of CH2Cl2) on ice. After being stirred at room temperature for 30 min, the reaction mixture was diluted with CHCl3, washed with aqueous saturated NaHCO3, and concentrated in vacuo. The residue was subjected to flash column chromatography (SiO2, n-hexane/EtOAc = 4:1, and then CHCl3/MeOH = 10:1) to obtain 13-2 (1.97 g, quant). 1H NMR (500 MHz, CDCl3) δ 4.58 (broad s, 1H), 3.63 (borad t, J = 6.0 Hz, 2H), 3.11 (broad q, J = 7.0 Hz, 2H), 1.60-1.55 (m, 2H), 1.53-1.47 (m, 2H), 1.43 (s, 9H), 1.40-1.35 (m, 2H); HRMS (ESI, positive) m/z 226.1388 [M+Na]+ (calcd for C10H21NO3 226.1414).
100%
In dichloromethane at 20℃; for 2h; Inert atmosphere;
tert-Butyl 5-hydroxypentylcarbamate (2)
5-Aminopentan-1-ol (5.0 g, 48.47 mmol)and di-tert-butyl dicarbonate (12.69g, 58.16 mmol) were dissolved in anhydrous DCM (25 mL) and stirred undernitrogen for 2 h. Water (15 mL) was added and the product was extracted in DCM(3 x 20 mL). The combined organic extracts were sequentially washed with aq NaHCO3and brine, dried over MgSO4, filtered, and concentrated to give theproduct as colorless oil (9.85 g, 100%). 1H NMR (CDCl3) d 3.62 (m, 2H), 3.11 (m, 2H), 1.62-1.31 (m, 15H).13C NMR (75 MHz, CDCl3) d 155.9, 79.5, 62.8,41.8, 31.9, 29.9, 28.4, 22.7. IR: 3341, 2934, 1687, 1527, 1169 cm-1. MS m/z (ESI) 204.20 (M+ +1).
Stage #1: N-(tert-butyloxycarbonyl)-5-aminopentanol; acetic acid (3aR,5R,6R,7R,7aR)-6-acetoxy-5-acetoxymethyl-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-7-yl ester at 20℃; for 0.5h; Molecular sieve; Inert atmosphere;
Stage #2: With trimethylsilyl trifluoromethanesulfonate at 20℃; Inert atmosphere;
Stage #3: acetic anhydride Further stages;
2.1
Compound 2. Compound 2 was prepared by a procedure adopted from the literature (Westerlind, U. et al. Glycoconj. J. 2004, 21, 227-241). To a 500-mL one-neck round-bottom flask was added 2-acetamido-l,3,4,6-tetra-0-acetyl-2-deoxy-D- galactopyranose 1 (12.8 g, 32.8 mmol) followed by anhydrous CH2CI2 (150 mL) and trimethylsilyl trifluoromethanesulfonate (14.3 mL, 79.2 mmol). This mixture was stirred at reflux overnight (ca. 18 h) under a flow of argon gas. The reaction mixture was cooled to 0° C and treated with triethylamine (6.4 mL, 45.9 mmol) for 30 min before being warmed to room temperature, then washed with saturated aqueous NaHCC>3 (100 mL). The organic layer was separated and dried over Na2S04, filtered and evaporated providing crude oxazoline intermediate. To the crude oxazoline product was added anhydrous CH2CI2 (200 mL), N-t-Boc-5-amino-l-pentanol (10.0 g, 49.2 mmol) and 3 A molecular sieves (18.0 g, dried at 150°C for >24h). This mixture was stirred at room temperature for 30 min under a blanket of argon gas. Trimethylsilyl trifluoromethanesulfonate (2.97 mL, 16.4 mmol) was added to the reaction mixture, and the solution was stirred at room temperature overnight . The solution was cooled to 0°C and treated with triethylamine (3.2 mL, 23.07 mmol) for 30 min before being warmed to room temperature. After the reaction reached room temperature the mixture was filtered, and the mother liquor was evaporated providing the crude product as brown oil which was dissolved in anhydrous pyridine (100 mL) and treated with acetic anhydride (36 mL, 38.2 mmol). This mixture was stirred under an argon atmosphere at room temperature overnight , then evaporated under vacuum yielding a brown liquid, which was dissolved in CH2CI2 (200 mL). The solution was vigorously stirred with a saturated aqueous NaHCC>3 solution (100 mL) and solid NaHCC>3 in an open flask at room temperature to quench remaining Ac20and the organic layer was separated. The aqueous layer was extracted with CH2CI2 (1 x 200 mL) and all organic layers were combined. The organic layers were washed with saturated aqueous NaHCC>3 solution (1 x 100 mL), separated, dried over Na2S04, filtered and evaporated providing the crude product as a brown oil which was then dissolved in CH2CI2 (15 mL) and purified using column chromatography (S1O2, column size 7.5 cm ID x 16.0 cm length, EtOAc: Hexanes 1 :3 v/v for 500 mL, EtOAc : Hexanes 4: 1 v/v for 500 mL, 100% EtOAc for 1.0 L, 10 % MeOH in EtOAc v/v for 3.0 L). Product-containing fractions were pooled and evaporated under vacuum to a white solid which was further purified by trituration with ether to yield the desired product as a white solid (5 g, 29%). ESI MS [M+H]+ m/z 533.4.
With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; for 10h; Inert atmosphere;
1.4.2 Synthesis of Compound 4
A flame dried 100 mL round bottom flask was charged with diol 2 (1.32 g, 5.84 mmol), 5-N-tert-butoxycarbonylamino-1-pentanol (2.37 g, 11.7 mmol), Ph3P (3.06 g, 11.7 mmol), and THF (15 mL). The resulting solution was cooled to 0° C. under Argon, and DEAD (2.16 mL) was added to the solution dropwise to give a dard red solution. The mixture was then warmed to room temperature and stirred until no starting material remained (ca. 10 h). THF was removed and the residue was purified by column chromatography (DCM/hexane/ether=4:4:1) to give pure product.
Stage #1: 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranose With trimethylsilyl trifluoromethanesulfonate In dichloromethane for 18h; Inert atmosphere; Reflux;
Stage #2: With triethylamine In dichloromethane at 0 - 20℃; for 0.5h;
Stage #3: N-(tert-butyloxycarbonyl)-5-aminopentanol; trifluoroacetic acid Further stages;
4
[271] Compound 2. Compound 2 was prepared by a procedure adopted from the literature (Westerlind, U. et al. Glycoconj. J. 2004, 21, 227-241). To a 500-mL one -neck round-bottom flask was added 2-acetamido-l,3,4,6-tetra-0-acetyl-2-deoxy-D-galactopyranose 1 (12.8 g, 32.8 mmol) followed by anhydrous CH2CI2 (150 mL) and trimethylsilyl trifluoromethanesulfonate (14.3 mL, 79.2 mmol). This mixture was stirred at reflux overnight (ca. 18 h) under a flow of argon gas. The reaction mixture was cooled to 0 °C and treated with triethylamine (6.4 mL, 45.9 mmol) for 30 min before being warmed to room temperature, then washed with saturated aqueous NaHC03 (100 mL). The organic layer was separated and dried over Na2S04, filtered and evaporated providing crude oxazoline intermediate. To the crude oxazoline product was added anhydrous CH2CI2 (200 mL), N-t-Boc-5- amino-l -pentanol (10.0 g, 49.2 mmol) and 3 A molecular sieves (18.0 g, dried at 150 °C for >24h). This mixture was stirred at room temperature for 30 min under a blanket of argon gas. Trimethylsilyl trifluoromethanesulfonate (2.97 mL, 16.4 mmol) was added to the reaction mixture, and the solution was stirred at room temperature overnight. The solution was cooled to 0 °C and treated with triethylamine (3.2 mL, 23.07 mmol) for 30 min before being warmed to room temperature. After the reaction reached room temperature the mixture was filtered, and the mother liquor was evaporated providing the crude product as brown oil which was dissolved in anhydrous pyridine (100 mL) and treated with acetic anhydride (36 mL, 38.2 mmol). This mixture was stirred under an argon atmosphere at room temperature overnight , then evaporated under vacuum yielding a brown liquid, which was dissolved in CH2CI2 (200 mL). The solution was vigorously stirred with a saturated aqueous NaHC03 solution (100 mL) and solid NaHC03 in an open flask at room temperature to quench remaining Ac2Oand the organic layer was separated. The aqueous layer was extracted with CH2CI2 (1 x 200 mL) and all organic layers were combined. The organic layers were washed with saturated aqueous NaHC03 solution (1 x 100 mL), separated, dried over Na2S04, filtered and evaporated providing the crude product as a brown oil which was then dissolved in CH2CI2 (15 mL) and purified using column chromatography (S1O2, column size 7.5 cm ID x 16.0 cm length, EtOAc: Hexanes 1 :3 v/v for 500 mL, EtOAc : Hexanes 4: 1 v/v for 500 mL, 100% EtOAc for 1.0 L, 10 % MeOH in EtOAc v/v for 3.0 L). Product-containing fractions were pooled and evaporated under vacuum to a white solid which was further purified by trituration with ether to yield the desired product as a white solid (5 g, 29%). ESI MS [M+H]+ m/z 533.4 Compound 3. To a 100 mL round bottom flask was added Compound 2 (3.14 g, 5.9 mmol) followed by trifluoro acetic acid (10 mL, TFA). The mixture was stirred until all of the carbohydrate was completely dissolved, then the TFA was evaporated under vacuum to yield light yellow oil. To the oily residue was added diethyl ether (10 mL), the mixture was sonicated for 2-5 min, and the supernatant was decanted. The trituration process was repeated (3 x 10 mL Et20), and the crude product was dried under vacuum to yield a white foam (3.2 g), which was used as described below.
Stage #1: 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-β-D-galactopyranose With trimethylsilyl trifluoromethanesulfonate In dichloromethane for 18h; Inert atmosphere; Reflux;
Stage #2: With triethylamine In dichloromethane at 0 - 20℃; for 0.5h;
Stage #3: N-(tert-butyloxycarbonyl)-5-aminopentanol Further stages;
4
[271] Compound 2. Compound 2 was prepared by a procedure adopted from the literature (Westerlind, U. et al. Glycoconj. J. 2004, 21, 227-241). To a 500-mL one -neck round-bottom flask was added 2-acetamido-l,3,4,6-tetra-0-acetyl-2-deoxy-D-galactopyranose 1 (12.8 g, 32.8 mmol) followed by anhydrous CH2CI2 (150 mL) and trimethylsilyl trifluoromethanesulfonate (14.3 mL, 79.2 mmol). This mixture was stirred at reflux overnight (ca. 18 h) under a flow of argon gas. The reaction mixture was cooled to 0 °C and treated with triethylamine (6.4 mL, 45.9 mmol) for 30 min before being warmed to room temperature, then washed with saturated aqueous NaHC03 (100 mL). The organic layer was separated and dried over Na2S04, filtered and evaporated providing crude oxazoline intermediate. To the crude oxazoline product was added anhydrous CH2CI2 (200 mL), N-t-Boc-5- amino-l -pentanol (10.0 g, 49.2 mmol) and 3 A molecular sieves (18.0 g, dried at 150 °C for >24h). This mixture was stirred at room temperature for 30 min under a blanket of argon gas. Trimethylsilyl trifluoromethanesulfonate (2.97 mL, 16.4 mmol) was added to the reaction mixture, and the solution was stirred at room temperature overnight. The solution was cooled to 0 °C and treated with triethylamine (3.2 mL, 23.07 mmol) for 30 min before being warmed to room temperature. After the reaction reached room temperature the mixture was filtered, and the mother liquor was evaporated providing the crude product as brown oil which was dissolved in anhydrous pyridine (100 mL) and treated with acetic anhydride (36 mL, 38.2 mmol). This mixture was stirred under an argon atmosphere at room temperature overnight , then evaporated under vacuum yielding a brown liquid, which was dissolved in CH2CI2 (200 mL). The solution was vigorously stirred with a saturated aqueous NaHC03 solution (100 mL) and solid NaHC03 in an open flask at room temperature to quench remaining Ac2Oand the organic layer was separated. The aqueous layer was extracted with CH2CI2 (1 x 200 mL) and all organic layers were combined. The organic layers were washed with saturated aqueous NaHC03 solution (1 x 100 mL), separated, dried over Na2S04, filtered and evaporated providing the crude product as a brown oil which was then dissolved in CH2CI2 (15 mL) and purified using column chromatography (S1O2, column size 7.5 cm ID x 16.0 cm length, EtOAc: Hexanes 1 :3 v/v for 500 mL, EtOAc : Hexanes 4: 1 v/v for 500 mL, 100% EtOAc for 1.0 L, 10 % MeOH in EtOAc v/v for 3.0 L). Product-containing fractions were pooled and evaporated under vacuum to a white solid which was further purified by trituration with ether to yield the desired product as a white solid (5 g, 29%). ESI MS [M+H]+ m/z 533.4
Stage #1: maleiimide; N-(tert-butyloxycarbonyl)-5-aminopentanol With triphenylphosphine In tetrahydrofuran at 20℃; for 0.166667h;
Stage #2: With di-isopropyl azodicarboxylate In tetrahydrofuran at 20℃; for 16h;
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 3h; Inert atmosphere; Cooling with ice;
1.3; 2.3; 3.3
(3) 800mg of compound indicated in formula (IV), 406mg of (5-hydroxypentyl) carbamic acid tert-butyl ester and 735mg triphenylphosphate (PPh3Dissolved in 15mL tetrahydrofuran (THF) and protected with nitrogen, ice water bath, 566mg of diisopropyl azodicarboxylate (DIAD) was added dropwise to the above solution, and then raised to room temperature for 3h after the reaction, 1mL of water quenching reaction was added to obtain reaction liquid III, the reaction solution III was distilled under reduced pressure to remove the solvent, and then purified by silica gel column chromatography (eluent ethyl acetate / n-hexane, volume ratio of 1:1) to obtain 667mg of white solids, the compound shown in formula (V);
With pyridine; 4-dimethylaminopyridine at 20℃; for 3h;
Intermediate 37: 5-((tert-butoxycarbonyl)amino)pentyl-4-methylbenzenesulfonate
(5-hydroxypentyl)aminocarboxylate tert-butyl ester(500 mg, 2.463 mmol),A mixture of p-toluenesulfonyl chloride (706 mg, 3.695 mmol) and 4-dimethylaminopyridine (154 mg, 1.232 mmol) in pyridine (5 mL) was stirred at room temperature for 3 hours.The resulting reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL),The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure,400 mg of the target crude product was obtained as a pale yellow oil. The crude product was used directly in the next step.
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