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USD 15-60
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USD 80+
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Structure of 6338-55-2 * Storage: {[proInfo.prStorage]}
* 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 palladium on activated charcoal; hydrogen In methanol for 8 h; Inert atmosphere
2-(2-(2-azidoethoxy)ethoxy)ethanol (0.7 g, 3.99 mmol) was dissolved in MeOH (9 ml), then palladium on activated carbon (0.196 g) was added under stirring. The flask was submitted to 3 evacuation/H2 flushing cycles in order to establish the hydrogen atmosphere in the flask. The reaction was followed by TLC and showed completion after 8 h. The solution was filtered through celite to remove the Pd/C. The solution was concentrated under reduced pressure to give the title compound as an oil (0.6 g, quantitative yield)
100%
With hydrogen In methanol for 12 h;
The azide was combined with Pd/C (150 mg) in MeOH (8.0 ml_) and stirred 12 h under H2 (1 atm). The suspension was filtered over celite, and the filtrate was concentrated to afford the amine (0.590 g, 4.0 mmol) in quantitative yields (Sato, H.; Hayashi, E.; Yamada, N.; Yatagai, M.; Takahara, Y. Bioconjugate Chem. 2001 , 12, 701-710.).
99%
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 8 h;
Preparation of Compound 20f Pd/C (10 wt. percent, 1.0 g) was added to a solution of compound 2a (6.7 g, 38.2 mmol) in MeOH (38 mL). After stirring at room temperature for 8 hours under hydrogen, the reaction mixture was filtered through a celite pad and washed with MeOH (100 mL). Concentration provided compound 20f (5.6 g, 99 percent) as colorless oil, which was used without further purification. 1H- MR (400 MHz, CDC13) δ 3.95-3.25 (m, 12H), 2.90 (s, 2H).
99%
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 8 h;
Pd/C (10 wt. percent, 1.0 g) was added to a solution of compound 2a (6.7 g, 38.2 mmol) in MeOH (38 mL). After stirring at room temperature for 8 hours under hydrogen, the reaction mixture was filtered through a celite pad and washed with MeOH (100 mL). (0985) Concentration provided compound 20f (5.6 g, 99 percent) as colorless oil, which was used without further purification. 1H-NMR (400 MHz, CDC13) δ 3.95-3.25 (m, 12H), 2.90 (s, 2H).
93%
With triphenylphosphine In tetrahydrofuran; water at 45℃; for 12 h;
Triphenylphosphine (9.89 g, 37.70 mmol) was added to a solution of compound 2 (4.40 g, 25.10 mmol) in THF (20 mL) and water (10 mL), and the mixture was stirred for 12 h at 45 °C. The solvents were evaporated under reduced pressure at 40 °C, and the residue was dissolved with slightly acidic water with pH 5-6 by using 10percent KHSO4 aqueous solution. Water was removed under reduced pressure at 80 °C. Faintly yellow oil was obtained with a yield of 93percent (3.50 g). The product was used in the next step without further purification. 1H NMR (D2O): δ 2.69 (s, 2H, NH2), 3.20 (t, 2H, CH2), 3.63 (t, 2H, CH2), 3.71-3.72 (m, 6H, CH2), 3.75 (t, 2H, CH2), 5.43 (s, 1H, OH).
80%
With 5%-palladium/activated carbon; hydrogen In methanol at 24℃; for 1.5 h;
General procedure: Compound 6a (1.00 g, 5.27 mmol), and a catalytic amount of 5 percent Pd/C were dissolved in anhydrous methanol (30 mL) and the reaction mixture was stirred at 24 for 1.5 h under H2 atmosphere, then filtered on Celite®545. The filtrate was evaporated to dryness to afford pure compound 7a (0.62 g, 81percent).
1.03 g
With palladium on activated charcoal; hydrogen In methanol at 25℃; for 18 h;
The above synthesized azide 3 (1.27 g, 7.25 mmol) was dissolved in MeOH (15 mL). Pd/C (0.22 g, 0.03 mmol) was added, the flask was purged of argon and filled with hydrogen. The solution was stirred overnight at room temperature. The mixture was filtered through celite and the solvent was evaporated to yield the pure amino alcohol 4 (1.03 g, 95percent). 4: Light yellow oil; 1H NMR (400 MHz, CDCl3) δ 3.73-3.58 (m, 10H), 2.95 (bs, 2H), 2.82-2.79 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 72.9, 70.4, 70.3, 61.7, 49.2; HRMS Calcd for C6H16NO3 (M+H)+ 150.1125. Found 150.1125.
4.63 g
Stage #1: With triphenylphosphine In tetrahydrofuran at 20℃; for 48 h; Inert atmosphere Stage #2: With water In tetrahydrofuran at 20℃; for 48 h; Inert atmosphere
The synthesis was done according to literature under argon.[1] The crude educt 1 (6.00 g, 34.4mmol) was dissolved in THF (50 mL) and triphenylphosphine (11.7 g, 44.7 mmol) was added in two portions. After stirring for 48 h at room temperature, water (1.13 mL) was added and stirring was continued for another 48 h. The solvent was removed under reduced pressure and the residue is afterwards dried under high vacuum at 45 °C overnight. Water (119 mL) was added and the formed precipitate is removed by filtration. After washing the solid with water(200 mL), the solvent was evaporated under reduced pressure and the product was dried inhigh vacuum at 70 °C overnight.
6.2 g
With 5%-palladium/activated carbon; hydrogen In methanol at 20℃; for 12 h;
2-[2-(2-Chloroethoxy)ethoxy]ethanol (4,6.3 g, 37 mmol), NaI (1.8 g, 12 mmol), and NaN3 (3.9 g, 60 mmol) were dissolved in 30 mL of deionized water and then stirred at 60 °C for 16 h. The reaction mixture was filtered to remove insoluble matter. The filtered solution was extracted with 60 mL of EtOAc. The organic layer was dried over Na2SO4 and evaporated to yield the azide (6.5 g). The azide (6.5 g) was dissolved in MeOH containing 0.5 g of 5percent Pd–C and was stirred under a hydrogen atmosphere at room temperature for 12 h. The reaction mixture was filtered using Celite and was evaporated to yield the corresponding amine (6.2 g). The amine was dissolved in150 mL of CH3CN. This was followed by the addition of 30 mL of deionized water, 30 mL of 1 M NaOH, and (Boc)2O (8.1 g, 37 mmol) at room temperature for16 h. The reaction mixture was evaporated and the resultant residue was added to 100 mL of water and then extracted with an equal volume of EtOAc. The organic layer was dried over Na2SO4. After evaporation of the organic layer, the residue that was obtained was purified by silica gel column chromatography (200 g, MeOH-CHCl3 1/50) to yield 5 (6.2 g, 25 mmol) as acolorless oil. The yield from the three steps was 68percent. 1H NMR (270 MHz, CDCl3): 5.21 (1H, br. s), 3.68(2H, t, J = 7.1 Hz), 3.61–3.52 (6H, m), 3.50 (2H, t,J = 7.1 Hz), 3.24 (2H, t, J = 6.9 Hz), 2.88 (1H, br. s),1.37 (9H, s); 13C NMR (67.8 MHz, CDCl3): 155.9,79.1, 72.5, 72.4, 70.2, 70.1, 61.5, 40.3, 28.2; FD-MSm/z (rel.int.): 250 (100, [M + H]+), 249 (13.0, [M]+),57.0 (25.1), 31.0 (16.1); FD-HR-MS m/z: calcd. forC11H24NO5, 250.16545, found 250.16572.
23.5 g
With palladium on activated charcoal; hydrogen In methanol
To a 1L hydrogenation reactor were added 29g BP103a02, methanol 360 mL, palladium on carbon 5.0g, and stirred. Nitrogen was replaced, and hydrogen was introduced to react for 3-4h. After the completion of the reaction under the monitor of TLC, the reaction liquid was filtered, and the filtrate was concentrated to give 23.5g BP103a03 as an oil.
Reference：
[1] Helvetica Chimica Acta, 1991, vol. 74, # 8, p. 1697 - 1706
[2] Patent: US5144043, 1992, A,
[3] Organic Letters, 2009, vol. 11, # 1, p. 193 - 196
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 1151 - 1155
[5] Angewandte Chemie - International Edition, 2015, vol. 54, # 35, p. 10327 - 10330[6] Angew. Chem., 2015, vol. 35, # 37, p. 10467 - 10471,5
[7] Patent: WO2009/132310, 2009, A1, . Location in patent: Page/Page column 65-66
[8] Organic Preparations and Procedures International, 2001, vol. 33, # 5, p. 505 - 514
[9] European Journal of Organic Chemistry, 2011, # 9, p. 1641 - 1644
[10] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 586 - 590
[11] Patent: WO2017/89890, 2017, A1, . Location in patent: Page/Page column 102
[12] Patent: WO2017/89894, 2017, A1, . Location in patent: Page/Page column 113
[13] Langmuir, 2015, vol. 31, # 13, p. 3926 - 3933
[14] European Journal of Medicinal Chemistry, 2007, vol. 42, # 1, p. 37 - 53
[15] Inorganica Chimica Acta, 2011, vol. 365, # 1, p. 38 - 48
[16] Chinese Chemical Letters, 2017, vol. 28, # 4, p. 832 - 838
[17] Tetrahedron Letters, 1983, vol. 24, # 15, p. 1609 - 1610
[18] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 15, p. 3284 - 3288
[19] Tetrahedron Letters, 2000, vol. 41, # 22, p. 4287 - 4290
[20] Nucleosides, Nucleotides and Nucleic Acids, 2008, vol. 27, # 2, p. 157 - 172
[21] Patent: WO2009/29868, 2009, A1, . Location in patent: Page/Page column 25-26
[22] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 14, p. 4443 - 4450
[23] European Journal of Organic Chemistry, 2013, # 35, p. 7952 - 7959
[24] Beilstein Journal of Organic Chemistry, 2014, vol. 10, p. 1354 - 1364
[25] Chemistry - A European Journal, 2014, vol. 21, # 10, p. 3956 - 3967
[26] Bioscience, Biotechnology and Biochemistry, 2016, vol. 80, # 3, p. 432 - 439
[27] Bioconjugate Chemistry, 2017, vol. 28, # 9, p. 2284 - 2292
[28] Patent: EP3321279, 2018, A1, . Location in patent: Paragraph 0065
[29] Chinese Chemical Letters, 2018,
3
[ 1349193-22-1 ]
[ 6338-55-2 ]
Yield
Reaction Conditions
Operation in experiment
99%
With palladium 10% on activated carbon; hydrogen In ethanol at 70℃; Continuous-flow conditions
Using a 10percent Pd/C cartridge, a 0.05 M solution of 8-dibenzylamino-3,6-dioxaoctan-1-ol (1.00 g, 3.04 mmol) in absolute ethanol (60 mL) was cycled twice through an H-Cube.(R). continuous-flow reactor at a flow rate of 1 mL/min. The applied pressure was set to 70 bar and the temperature to 70 °C. At the end of the second run, the entire reaction mixture was collected and concentrated in vacuo to give the title compound9 (0.45 g, 99percent) as a colourless oil; νmax (film) 3365, 3312, 3302, 2873, 2854, 1599 cm-1; δH (200 MHz; D2O) 2.88 (2H, t, J 5.3, NH2CH2CH2O), 3.54-3.72 (10H, m, CH2O(CH2)2O(CH2)2OH); δC (50 MHz; D2O) 39.1, 60.0, 68.6, 69.2, 69.3, 71.4.
Compound 15 (3.7 g, 17.36 mmol) was dissolved in 30 mL of aqueous ammonia and stirred at 70 ° C for 24 h.After the reaction was completed, the solvent was spun off and 15 mL of water was added. The mixture was washed with dichloromethane (3 * 20 mL) and dried over anhydrous sodium sulfate. After the organic solvent was removed, 2.4 g of compound 16 was obtained with a yield of 93percent
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 11, p. 3280 - 3283
[2] Tetrahedron, 1982, vol. 38, # 22, p. 3359 - 3362
[3] Chemical Communications, 2010, vol. 46, # 20, p. 3508 - 3510
[4] Journal of the American Chemical Society, 2011, vol. 133, # 39, p. 15280 - 15283
[5] Journal of the American Chemical Society, 2011, vol. 133, # 32, p. 12382 - 12385
[6] Journal of Medicinal Chemistry, 2017, vol. 60, # 8, p. 3498 - 3510
6
[ 5197-62-6 ]
[ 6338-55-2 ]
Reference：
[1] Journal of Polymer Science, Part A: Polymer Chemistry, 2011, vol. 49, # 14, p. 3184 - 3192
[2] European Journal of Medicinal Chemistry, 2007, vol. 42, # 1, p. 37 - 53
[3] Organic Preparations and Procedures International, 2001, vol. 33, # 5, p. 505 - 514
[4] Tetrahedron, 1982, vol. 38, # 22, p. 3359 - 3362
[5] Journal of the American Chemical Society, 2011, vol. 133, # 32, p. 12382 - 12385
[6] Journal of the American Chemical Society, 2011, vol. 133, # 39, p. 15280 - 15283
[7] Beilstein Journal of Organic Chemistry, 2014, vol. 10, p. 1354 - 1364
[8] Langmuir, 2015, vol. 31, # 13, p. 3926 - 3933
[9] Bioscience, Biotechnology and Biochemistry, 2016, vol. 80, # 3, p. 432 - 439
[10] Patent: WO2017/89890, 2017, A1,
[11] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 15, p. 3284 - 3288
[12] Patent: WO2017/89894, 2017, A1,
7
[ 112-27-6 ]
[ 6338-55-2 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1984, # 9, p. 2672 - 2691
[2] Helvetica Chimica Acta, 1991, vol. 74, # 8, p. 1697 - 1706
[3] Inorganica Chimica Acta, 2011, vol. 365, # 1, p. 38 - 48
[4] European Journal of Organic Chemistry, 2011, # 9, p. 1641 - 1644
[5] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 1151 - 1155
[6] European Journal of Organic Chemistry, 2013, # 35, p. 7952 - 7959
[7] Angewandte Chemie - International Edition, 2015, vol. 54, # 35, p. 10327 - 10330[8] Angew. Chem., 2015, vol. 35, # 37, p. 10467 - 10471,5
[9] Patent: EP3127900, 2017, A1,
[10] Chinese Chemical Letters, 2017, vol. 28, # 4, p. 832 - 838
[11] Journal of Medicinal Chemistry, 2017, vol. 60, # 8, p. 3498 - 3510
[12] Bioconjugate Chemistry, 2017, vol. 28, # 9, p. 2284 - 2292
[13] Patent: CN104725453, 2017, B,
[14] Patent: EP3321279, 2018, A1,
[15] Chinese Chemical Letters, 2018,
8
[ 86770-70-9 ]
[ 6338-55-2 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1984, # 9, p. 2672 - 2691
9
[ 77544-68-4 ]
[ 6338-55-2 ]
Reference：
[1] Inorganica Chimica Acta, 2011, vol. 365, # 1, p. 38 - 48
[2] European Journal of Organic Chemistry, 2011, # 9, p. 1641 - 1644
[3] European Journal of Organic Chemistry, 2013, # 35, p. 7952 - 7959
[4] Angewandte Chemie - International Edition, 2015, vol. 54, # 35, p. 10327 - 10330[5] Angew. Chem., 2015, vol. 35, # 37, p. 10467 - 10471,5
[6] Chinese Chemical Letters, 2017, vol. 28, # 4, p. 832 - 838
[7] Bioconjugate Chemistry, 2017, vol. 28, # 9, p. 2284 - 2292
[8] Patent: EP3321279, 2018, A1,
[9] Chinese Chemical Letters, 2018,
10
[ 139115-89-2 ]
[ 6338-55-2 ]
Reference：
[1] Helvetica Chimica Acta, 1991, vol. 74, # 8, p. 1697 - 1706
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 1151 - 1155
Reference：
[1] Bulletin de la Societe Chimique de France, 1951, p. 340
17
[ 6338-55-2 ]
[ 24424-99-5 ]
[ 139115-92-7 ]
Yield
Reaction Conditions
Operation in experiment
90%
With triethylamine In methanol for 18 h; Reflux
Di-tert-butyl dicarbonate (1.75 g, 8.04 mmol) was added to a solution of amino alcohol 4 (600 mg, 4.02 mmol) in a 9:1 (v/v) mixture of methanol/triethylamine (68 mL). The reaction was left stirring under reflux and upon completion, the solvent was removed under reduced pressure and the residue extracted with DCM/water. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to yield 5 (902 mg, 90percent). 5: Yellow oil; 1H NMR (400 MHz, CDCl3) δ 3.77-371 (m, 2H), 3.66-3.55 (m, 8H), 3.49-3.31 (m, 2H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 156.2, 79.9, 73.0, 70.6, 70.5, 70.0, 61.9, 40.5, 28.6; HRMS Calcd for C11H24NO5 (M+H)+ 250.1654. Found 150.1649.
84%
With triethylamine In methanol for 3 h; Reflux
Di-tert-butyl dicarbonate (1.43 g, 6.57 mmol) was added to a stirred solution of 9 (0.48 g, 3.19 mmol) in 10percent (v/v) TEA/MeOH (20 mL) at rt. The reaction mixture was heated at reflux for 3 h and then allowed to cool to rt. The solvent was removed in vacuo and the residual oil was purified by column chromatography (EtOAc/MeOH, 95:5) to yield the intermediate, 8-tert-butoxycarbonylamino-3,6-dioxaoctan-1-ol (0.67 g, 84percent), as a colourless oil; Rf 0.40 (EtOAc/MeOH, 95:5); νmax (film) 3356, 2976, 1694, 1526 cm-1; δH (200 MHz; CDCl3) 1.38 (9H, s, C(CH3)3), 2.98 (1H, br s, OH), 3.25 (2H, br dt, NHCH2CH2O), 3.49 (2H, t, J 5.3, NHCH2CH2O), 3.54-3.61 (6H, m, O(CH2)2OCH2), 3.68 (2H, br dt, CH2CH2OH), 5.27 (1H, br s, NH); δC (50 MHz; CDCl3) 28.7, 39.9, 61.3, 69.9, 70.5, 70.6, 72.3, 79.5, 156.3; m/z (CI) 250 ([M+H]+, 15percent), 150 (100); HRMS (ESI) m/z: [M+H]+, found 250.1649. C11H24NO5 requires 250.1649.
66%
With triethylamine In acetonitrile at 0 - 20℃; Inert atmosphere
2-(2-(2-aminoethoxy)ethoxy)ethanol (0.6 g, 4.062 mmol) was dissolved in acetonitrile (25 ml). The solution was cooled to 0°C and Et3N (1.13 ml, 8.12 mmol, 2 eq.) was added followed by Boc2O (0.268 g, 1.23 mmol). The reaction was followed by TLC and stirred overnight at room temperature. Water (15 ml) was added and the solution was extracted with EtOAc (3x30 ml), brine was used to help separating the two layers (5 ml) and also (30 ml) for washing. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 96:4) to give the title compound as a yellow oil (0.670 g, 66 percent yield)
50%
With sodium hydroxide In methanol; water
Compound 16 (2.6 g, 17.4 mmol) was dissolved in a mixture of 10 mL of methanol and 5 mL of water,0.695g sodium hydroxide was dissolved in 10mL of water was added to the above solution,Then a solution of (Boc) 2O (4.167 g, 19.1 mmol) in methanol (5 mL) was added and stirred overnight.After the reaction was completed, the solvent was removed by spin-drying, 15 mL of water was added and extracted with dichloromethane (3 * 20 mL). After drying over anhydrous sodium sulfate, the organic solvent was removed and the residue was eluted with 1: 1 EtOAc / Column chromatography gave 2.15 g of compound 17 in 50percent yield.
34%
With sodium hydroxide In water; acetonitrile at 20℃; for 0.75 h;
A solution of 2-(2-(2-aminoethoxy)ethoxy)ethanol (100 mg, 0.67 1 mmol, 89 jiL) in 4.8 mL of acetonitrile/water (6:1) was treated with di-tert-butyl dicarbonate (151 mg, 0.691 mmol), followed by 0.5 mL of 1 N NaOH (aq). After stirring at RT for 45 mm, the organic solvent was removed in vacuo, the residue was dissolved in saturated NH4C1 (aq), and the desired carbamate was extracted with EtOAc. Removal of EtOAc provided 57 mg (34percent yield) of tert-butyl 2-(2-(2-hydroxyethoxy)ethoxy)ethylcarbamate as a colorless oil.
34%
With sodium hydroxide In water; acetonitrile at 20℃; for 0.75 h;
A solution of 2-(2-(2-aminoethoxy)ethoxy)ethanol (100 mg, 0.67 1 mmol, 89 tL) in 4.8 mL of acetonitrile/water (6:1) was treated with di-tert-butyl dicarbonate (151 mg, 0.69 1 mmol), followed by 0.5 mL of 1 N NaOH (aq). After stirring at RT for 45 mm, the organic solvent was removed in vacuo, the residue was dissolved in saturated NH4C1 (aq), and the desired carbamate was extracted with EtOAc. Removal of EtOAc provided 57 mg (34percent yield) of tert-butyl 2-(2-(2-hydroxyethoxy)ethoxy)ethylcarbamate as a colorless oil.
6.2 g
With sodium hydroxide In water; acetonitrile at 20℃; for 16 h;
2-[2-(2-Chloroethoxy)ethoxy]ethanol (4,6.3 g, 37 mmol), NaI (1.8 g, 12 mmol), and NaN3 (3.9 g, 60 mmol) were dissolved in 30 mL of deionized water and then stirred at 60 °C for 16 h. The reaction mixture was filtered to remove insoluble matter. The filtered solution was extracted with 60 mL of EtOAc. The organic layer was dried over Na2SO4 and evaporated to yield the azide (6.5 g). The azide (6.5 g) was dissolved in MeOH containing 0.5 g of 5percent Pd–C and was stirred under a hydrogen atmosphere at room temperature for 12 h. The reaction mixture was filtered using Celite and was evaporated to yield the corresponding amine (6.2 g). The amine was dissolved in150 mL of CH3CN. This was followed by the addition of 30 mL of deionized water, 30 mL of 1 M NaOH, and (Boc)2O (8.1 g, 37 mmol) at room temperature for16 h. The reaction mixture was evaporated and the resultant residue was added to 100 mL of water and then extracted with an equal volume of EtOAc. The organic layer was dried over Na2SO4. After evaporation of the organic layer, the residue that was obtained was purified by silica gel column chromatography (200 g, MeOH-CHCl3 1/50) to yield 5 (6.2 g, 25 mmol) as acolorless oil. The yield from the three steps was 68percent. 1H NMR (270 MHz, CDCl3): 5.21 (1H, br. s), 3.68(2H, t, J = 7.1 Hz), 3.61–3.52 (6H, m), 3.50 (2H, t,J = 7.1 Hz), 3.24 (2H, t, J = 6.9 Hz), 2.88 (1H, br. s),1.37 (9H, s); 13C NMR (67.8 MHz, CDCl3): 155.9,79.1, 72.5, 72.4, 70.2, 70.1, 61.5, 40.3, 28.2; FD-MSm/z (rel.int.): 250 (100, [M + H]+), 249 (13.0, [M]+),57.0 (25.1), 31.0 (16.1); FD-HR-MS m/z: calcd. forC11H24NO5, 250.16545, found 250.16572.
34.8 g
With triethylamine In methanol for 1 h; Reflux
To a 1 L three-necked flask were added 23.5 g compound BP103a03 (1. 0eq), 68.6g (Boc)2O (2.0 eq), a mixed solution of methanol:triethylamine (9:1) 500ml, stirred and warmed to reflux, and reacted for 1h. After the completion of the reaction under the monitor of TLC, methanol triethylamine was evaporated off, and dissolved with water. Dichloromethane was extracted for 3 times. The organic layers were combined and washed once with water, dried over anhydrous sodium sulfate. The solvents were evaporated off, and dried to give 34.8g BP103a04 as a solid.
Reference：
[1] Helvetica Chimica Acta, 1991, vol. 74, # 8, p. 1697 - 1706
[2] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 14, p. 4443 - 4450
[3] Tetrahedron, 2011, vol. 67, # 49, p. 9588 - 9594
[4] Journal of Medicinal Chemistry, 2009, vol. 52, # 22, p. 7029 - 7043
[5] Inorganica Chimica Acta, 2011, vol. 365, # 1, p. 38 - 48
[6] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 1151 - 1155
[7] Patent: CN104725453, 2017, B, . Location in patent: Paragraph 0073; 0076
[8] Patent: WO2015/38938, 2015, A1, . Location in patent: Paragraph 0461; 0462
[9] Patent: WO2016/149501, 2016, A2, . Location in patent: Page/Page column 0308
[10] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 3, p. 1084 - 1090
[11] European Journal of Organic Chemistry, 2011, # 9, p. 1641 - 1644
[12] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 586 - 590
[13] European Journal of Organic Chemistry, 2013, # 35, p. 7952 - 7959
[14] Bioscience, Biotechnology and Biochemistry, 2016, vol. 80, # 3, p. 432 - 439
[15] Patent: EP3321279, 2018, A1, . Location in patent: Paragraph 0065
2-[2-(2-Amino-ethoxy)-ethoxy]-ethanol (7) was prepared according to a literature method.5c To a stirred solution of 7 (0.6 g, 4.0 mmol) in 10 mL EtOH was added a solution of di-tert-butyl dicarbonate (0.88 g, 4 mmol) in 10 mL EtOH dropwise at 0 C under N2. The mixture was vigorously stirred and allowed to warm up to room temperature slowly overnight (16 h). The solvents were evaporated off under vacuum to give 8 as a colorless oil (0.933 g, 94%). This material was used for the next step reaction without further purification. NMR (400 MHz, CDCh): d 5.11 (s, 1H), 3.76 (m, 2H), 3.70-3.60 (m, 6H), 3.57 (t, J= 5.2 Hz, 2H), 3.33 (br q, J= 5.0 Hz, 2H), 2.45 (br s, 1H), 1.45 (m, 9H).
90%
With triethylamine; In methanol; for 18h;Reflux;
Di-tert-butyl dicarbonate (1.75 g, 8.04 mmol) was added to a solution of amino alcohol 4 (600 mg, 4.02 mmol) in a 9:1 (v/v) mixture of methanol/triethylamine (68 mL). The reaction was left stirring under reflux and upon completion, the solvent was removed under reduced pressure and the residue extracted with DCM/water. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to yield 5 (902 mg, 90%). 5: Yellow oil; 1H NMR (400 MHz, CDCl3) delta 3.77-371 (m, 2H), 3.66-3.55 (m, 8H), 3.49-3.31 (m, 2H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) delta 156.2, 79.9, 73.0, 70.6, 70.5, 70.0, 61.9, 40.5, 28.6; HRMS Calcd for C11H24NO5 (M+H)+ 250.1654. Found 150.1649.
85%
With potassium hydroxide; In 1,4-dioxane; water; at 20 - 25℃; for 18.5h;
Intermediate 91a: tert-Butyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate Di-tert-butyl dicarbonate (3.22 g, 14.75 mmol) in dioxane (10 mL) was added dropwise to <strong>[6338-55-2]2-(2-(2-aminoethoxy)ethoxy)ethan-1-ol</strong> (2.00 g, 13.41 mmol) and potassium hydroxide (0.83 g, 14.75 mmol) in water (20 mL) at 20 C. over a period of 30 minutes. The resulting mixture was stirred at RT for 18 hours. The reaction mixture was diluted with water (10 mL), and extracted with DCM (2*50 mL). The combined organics were washed with saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford the title compound (2.83 g, 85%) as a colourless oil; 1H NMR (400 MHz, CDCl3, 30 C.) 1.45 (9H, s), 2.65 (1H, s), 3.24-3.42 (2H, m), 3.56 (2H, t), 3.59-3.7 (6H, m), 3.72-3.78 (2H, m), 5.16 (1H, s); m/z: ES+ [M+H]+250.2.
84%
With triethylamine; In methanol; for 3h;Reflux;
Di-tert-butyl dicarbonate (1.43 g, 6.57 mmol) was added to a stirred solution of 9 (0.48 g, 3.19 mmol) in 10% (v/v) TEA/MeOH (20 mL) at rt. The reaction mixture was heated at reflux for 3 h and then allowed to cool to rt. The solvent was removed in vacuo and the residual oil was purified by column chromatography (EtOAc/MeOH, 95:5) to yield the intermediate, 8-tert-butoxycarbonylamino-3,6-dioxaoctan-1-ol (0.67 g, 84%), as a colourless oil; Rf 0.40 (EtOAc/MeOH, 95:5); numax (film) 3356, 2976, 1694, 1526 cm-1; deltaH (200 MHz; CDCl3) 1.38 (9H, s, C(CH3)3), 2.98 (1H, br s, OH), 3.25 (2H, br dt, NHCH2CH2O), 3.49 (2H, t, J 5.3, NHCH2CH2O), 3.54-3.61 (6H, m, O(CH2)2OCH2), 3.68 (2H, br dt, CH2CH2OH), 5.27 (1H, br s, NH); deltaC (50 MHz; CDCl3) 28.7, 39.9, 61.3, 69.9, 70.5, 70.6, 72.3, 79.5, 156.3; m/z (CI) 250 ([M+H]+, 15%), 150 (100); HRMS (ESI) m/z: [M+H]+, found 250.1649. C11H24NO5 requires 250.1649.
72%
With triethylamine; In dichloromethane; at 20℃; for 2h;
A solution of <strong>[6338-55-2]2-(2-(2-aminoethoxy)ethoxy)ethan-1-ol</strong> (1.5 g, 10.1 mmol), triethylamine (3.3 mL, 15.1 mmol), and Boc-anhydride (3.3 g, 15.1 mmol) in DCM (10 mL) was stirred at rt for 2 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using DCM (3×25 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (3% MeOH-DCM) to give tert-butyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate as a colorless oil (1.8 g, 72%). LC-MS (ESI+) m/z 267.35 (M+H)+.
66%
With triethylamine; In acetonitrile; at 0 - 20℃;Inert atmosphere;
<strong>[6338-55-2]2-(2-(2-aminoethoxy)ethoxy)ethanol</strong> (0.6 g, 4.062 mmol) was dissolved in acetonitrile (25 ml). The solution was cooled to 0C and Et3N (1.13 ml, 8.12 mmol, 2 eq.) was added followed by Boc2O (0.268 g, 1.23 mmol). The reaction was followed by TLC and stirred overnight at room temperature. Water (15 ml) was added and the solution was extracted with EtOAc (3x30 ml), brine was used to help separating the two layers (5 ml) and also (30 ml) for washing. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 96:4) to give the title compound as a yellow oil (0.670 g, 66 % yield)
50%
With sodium hydroxide; In methanol; water;
Compound 16 (2.6 g, 17.4 mmol) was dissolved in a mixture of 10 mL of methanol and 5 mL of water,0.695g sodium hydroxide was dissolved in 10mL of water was added to the above solution,Then a solution of (Boc) 2O (4.167 g, 19.1 mmol) in methanol (5 mL) was added and stirred overnight.After the reaction was completed, the solvent was removed by spin-drying, 15 mL of water was added and extracted with dichloromethane (3 * 20 mL). After drying over anhydrous sodium sulfate, the organic solvent was removed and the residue was eluted with 1: 1 EtOAc / Column chromatography gave 2.15 g of compound 17 in 50% yield.
34%
With sodium hydroxide; In water; acetonitrile; at 20℃; for 0.75h;
A solution of <strong>[6338-55-2]2-(2-(2-aminoethoxy)ethoxy)ethanol</strong> (100 mg, 0.67 1 mmol, 89 jiL) in 4.8 mL of acetonitrile/water (6:1) was treated with di-tert-butyl dicarbonate (151 mg, 0.691 mmol), followed by 0.5 mL of 1 N NaOH (aq). After stirring at RT for 45 mm, the organic solvent was removed in vacuo, the residue was dissolved in saturated NH4C1 (aq), and the desired carbamate was extracted with EtOAc. Removal of EtOAc provided 57 mg (34% yield) of tert-butyl 2-(2-(2-hydroxyethoxy)ethoxy)ethylcarbamate as a colorless oil.
34%
With sodium hydroxide; In water; acetonitrile; at 20℃; for 0.75h;
A solution of <strong>[6338-55-2]2-(2-(2-aminoethoxy)ethoxy)ethanol</strong> (100 mg, 0.67 1 mmol, 89 tL) in 4.8 mL of acetonitrile/water (6:1) was treated with di-tert-butyl dicarbonate (151 mg, 0.69 1 mmol), followed by 0.5 mL of 1 N NaOH (aq). After stirring at RT for 45 mm, the organic solvent was removed in vacuo, the residue was dissolved in saturated NH4C1 (aq), and the desired carbamate was extracted with EtOAc. Removal of EtOAc provided 57 mg (34% yield) of tert-butyl 2-(2-(2-hydroxyethoxy)ethoxy)ethylcarbamate as a colorless oil.
6.2 g
With sodium hydroxide; In water; acetonitrile; at 20℃; for 16h;
2-[2-(2-Chloroethoxy)ethoxy]ethanol (4,6.3 g, 37 mmol), NaI (1.8 g, 12 mmol), and NaN3 (3.9 g, 60 mmol) were dissolved in 30 mL of deionized water and then stirred at 60 C for 16 h. The reaction mixture was filtered to remove insoluble matter. The filtered solution was extracted with 60 mL of EtOAc. The organic layer was dried over Na2SO4 and evaporated to yield the azide (6.5 g). The azide (6.5 g) was dissolved in MeOH containing 0.5 g of 5% Pd-C and was stirred under a hydrogen atmosphere at room temperature for 12 h. The reaction mixture was filtered using Celite and was evaporated to yield the corresponding amine (6.2 g). The amine was dissolved in150 mL of CH3CN. This was followed by the addition of 30 mL of deionized water, 30 mL of 1 M NaOH, and (Boc)2O (8.1 g, 37 mmol) at room temperature for16 h. The reaction mixture was evaporated and the resultant residue was added to 100 mL of water and then extracted with an equal volume of EtOAc. The organic layer was dried over Na2SO4. After evaporation of the organic layer, the residue that was obtained was purified by silica gel column chromatography (200 g, MeOH-CHCl3 1/50) to yield 5 (6.2 g, 25 mmol) as acolorless oil. The yield from the three steps was 68%. 1H NMR (270 MHz, CDCl3): 5.21 (1H, br. s), 3.68(2H, t, J = 7.1 Hz), 3.61-3.52 (6H, m), 3.50 (2H, t,J = 7.1 Hz), 3.24 (2H, t, J = 6.9 Hz), 2.88 (1H, br. s),1.37 (9H, s); 13C NMR (67.8 MHz, CDCl3): 155.9,79.1, 72.5, 72.4, 70.2, 70.1, 61.5, 40.3, 28.2; FD-MSm/z (rel.int.): 250 (100, [M + H]+), 249 (13.0, [M]+),57.0 (25.1), 31.0 (16.1); FD-HR-MS m/z: calcd. forC11H24NO5, 250.16545, found 250.16572.
34.8 g
With triethylamine; In methanol; for 1h;Reflux;
To a 1 L three-necked flask were added 23.5 g compound BP103a03 (1. 0eq), 68.6g (Boc)2O (2.0 eq), a mixed solution of methanol:triethylamine (9:1) 500ml, stirred and warmed to reflux, and reacted for 1h. After the completion of the reaction under the monitor of TLC, methanol triethylamine was evaporated off, and dissolved with water. Dichloromethane was extracted for 3 times. The organic layers were combined and washed once with water, dried over anhydrous sodium sulfate. The solvents were evaporated off, and dried to give 34.8g BP103a04 as a solid.
34.8 g
With triethylamine; In methanol;
A mixed solution of 23.5 g of the compound BP103a03 (1.0 eq), 68.6 g of (Boc) 2O (2.0 eq) and 500 ml of methanol: triethylamine (9: 1) was added to a 1 L three-necked flask, After the completion of the reaction, methanol triethylamine was distilled off, water was added to dissolve, and the mixture was extracted three times with dichloromethane. The organic layer was combined and washed once with water , Dried over anhydrous sodium sulfate, the solvent was distilled off,34.8 g of solid BP103a04 was obtained.
With triethylamine; In dichloromethane; at 20℃; for 2h;
To a stirred solution of <strong>[6338-55-2]2-(2-(2-aminoethoxy)ethoxy)ethan-l-ol</strong> (1.0 g, 6.72 mmol) in DCM (25 mL) was added (Boc)20 (1.92 g, 13.5 mmol), TEA (1.36 g, 13.5 mmol) at r.t. The reaction mixture was stirred at r.t. for 2 h. TLC (10% MeOH / 90% DCM, silica gel plate) showed complete consumption of the starting material after this time. The mixture was concentrated in vacuo to give tert-butyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate (1.7 g, crude) as a yellow oil, the crude product was used directly with further purification.
34.8 g
With triethylamine; In methanol; for 1h;Reflux;
To a 1 L three-necked flask, 23.5 g of a compound BP103a03 (1.0 eq), 68.6 g (Boc)2O (2.0 eq), and a mixture of methanol and triethylamine (9:1) (500 ml) were added, and the mixture was stirred and refluxed for 1 h. After completion of the reaction was monitored by TLC, methanol was evaporated triethylamine, dissolved in water and extracted three times with dichloromethane, and the combined organic layers were washed with water once, dried over anhydrous sodium sulfate, the solvent was distilled off, and dried to give a solid BP103a04 of 34.8g
f) Preparation of 8-amino-3,6-dioxaoctanol. A mixture of 8-azido-3,6-dioxaoctanol (3.0 g, 17 mmoles) and 10% Pd/C (0.3 g) in methanol (30 mL) was hydrogenated at 45 psig for 1 hour. The catalyst was removed by filtration through celite and the solvent was removed to provide the amine (2.6 g, 100%). NMR (CDCl3) delta2.62 (s, 2H, NH2), 2.79 (m, 2H), 3.53 (m, 10H).
100%
With palladium on activated charcoal; hydrogen; In methanol; for 8h;Inert atmosphere;
2-(2-(2-azidoethoxy)ethoxy)ethanol (0.7 g, 3.99 mmol) was dissolved in MeOH (9 ml), then palladium on activated carbon (0.196 g) was added under stirring. The flask was submitted to 3 evacuation/H2 flushing cycles in order to establish the hydrogen atmosphere in the flask. The reaction was followed by TLC and showed completion after 8 h. The solution was filtered through celite to remove the Pd/C. The solution was concentrated under reduced pressure to give the title compound as an oil (0.6 g, quantitative yield)
100%
With hydrogen;palladium on activated charcoal; In methanol; under 760.051 Torr; for 12h;
The azide was combined with Pd/C (150 mg) in MeOH (8.0 ml_) and stirred 12 h under H2 (1 atm). The suspension was filtered over celite, and the filtrate was concentrated to afford the amine (0.590 g, 4.0 mmol) in quantitative yields (Sato, H.; Hayashi, E.; Yamada, N.; Yatagai, M.; Takahara, Y. Bioconjugate Chem. 2001 , 12, 701-710.).
99%
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 8h;
Preparation of Compound 20f Pd/C (10 wt. %, 1.0 g) was added to a solution of compound 2a (6.7 g, 38.2 mmol) in MeOH (38 mL). After stirring at room temperature for 8 hours under hydrogen, the reaction mixture was filtered through a celite pad and washed with MeOH (100 mL). Concentration provided compound 20f (5.6 g, 99 %) as colorless oil, which was used without further purification. 1H- MR (400 MHz, CDC13) delta 3.95-3.25 (m, 12H), 2.90 (s, 2H).
99%
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 8h;
Pd/C (10 wt. %, 1.0 g) was added to a solution of compound 2a (6.7 g, 38.2 mmol) in MeOH (38 mL). After stirring at room temperature for 8 hours under hydrogen, the reaction mixture was filtered through a celite pad and washed with MeOH (100 mL). (0985) Concentration provided compound 20f (5.6 g, 99 %) as colorless oil, which was used without further purification. 1H-NMR (400 MHz, CDC13) delta 3.95-3.25 (m, 12H), 2.90 (s, 2H).
93%
With triphenylphosphine; In tetrahydrofuran; water; at 45℃; for 12h;
Triphenylphosphine (9.89 g, 37.70 mmol) was added to a solution of compound 2 (4.40 g, 25.10 mmol) in THF (20 mL) and water (10 mL), and the mixture was stirred for 12 h at 45 C. The solvents were evaporated under reduced pressure at 40 C, and the residue was dissolved with slightly acidic water with pH 5-6 by using 10% KHSO4 aqueous solution. Water was removed under reduced pressure at 80 C. Faintly yellow oil was obtained with a yield of 93% (3.50 g). The product was used in the next step without further purification. 1H NMR (D2O): delta 2.69 (s, 2H, NH2), 3.20 (t, 2H, CH2), 3.63 (t, 2H, CH2), 3.71-3.72 (m, 6H, CH2), 3.75 (t, 2H, CH2), 5.43 (s, 1H, OH).
80%
With 5%-palladium/activated carbon; hydrogen; In methanol; at 24℃; for 1.5h;
General procedure: Compound 6a (1.00 g, 5.27 mmol), and a catalytic amount of 5 % Pd/C were dissolved in anhydrous methanol (30 mL) and the reaction mixture was stirred at 24 for 1.5 h under H2 atmosphere, then filtered on Celite545. The filtrate was evaporated to dryness to afford pure compound 7a (0.62 g, 81%).
The synthesis of amidite 2 is outlined in FIG 4. First, commercially available 2- (2-(2-chloroethoxy)ethoxy)ethanol, was converted, via the azide, to 2-(2-(2- aminoethoxy)ethoxy)ethanol, in a one pot synthesis in 88% yield. Briefly, a mixture of 2-(2-(2-chloroethoxy)ethoxy)ethanol (50.0 g, 0.297 mol) and sodium azide (19.28 g, 0.297 mol) in 450 ml N,N-dimethylformamide was stirred overnight at 90 0C. The <n="27"/>mixture was cooled, diluted with 500 ml tetrahydrofuran, and, after stirring for 1 hour, was filtered. The solid salts were washed with tetrahydrofuran. The combined filtrate and washings, which contain the azide were stirred and treated with triphenylphosphine (83.76 g, 0.319 mol), added in two portions, and stirring protected from the atmosphere for 48 hours. Water (8.1 ml) was added, and stirring was continued for another 48 hours. The mixture was evaporated on a membrane pump vacuum, and then on an oil pump vacuum, at a bath temperature of 45 0C. The residue was stirred with 850 ml of water and filtered. The solid was washed with water, and the combined filtrate and washings were concentrated on a membrane pump vacuum at a bath temperature of 700C. The resulting yellowish oil was distilled under vacuum (0.2 mm Hg) to give 2-(2-(2- aminoethoxy)ethoxy)ethanol as a colorless oil: 39.3 g, 88% yield. 1H NMR (CDCl3): delta 3.54-3.72 (m, 8H, CH2-O), 3.51 (t, 2eta, CH3-OH), 2.82 (t, 2H, CH2-NH2), 2.30 (bs, 3H, NH2+0H); 13C NMR (Me2SO-d6): delta 73.82, 73.24, 70.63, 70.49, 61.06, 42.14; ESI+ MS: [M+H]+ 150.3, calculated for C5H16NO3 150.2.
1.03 g
With palladium on activated charcoal; hydrogen; In methanol; at 25℃; for 18h;
The above synthesized azide 3 (1.27 g, 7.25 mmol) was dissolved in MeOH (15 mL). Pd/C (0.22 g, 0.03 mmol) was added, the flask was purged of argon and filled with hydrogen. The solution was stirred overnight at room temperature. The mixture was filtered through celite and the solvent was evaporated to yield the pure amino alcohol 4 (1.03 g, 95%). 4: Light yellow oil; 1H NMR (400 MHz, CDCl3) delta 3.73-3.58 (m, 10H), 2.95 (bs, 2H), 2.82-2.79 (m, 2H); 13C NMR (100 MHz, CDCl3) delta 72.9, 70.4, 70.3, 61.7, 49.2; HRMS Calcd for C6H16NO3 (M+H)+ 150.1125. Found 150.1125.
4.63 g
The synthesis was done according to literature under argon.[1] The crude educt 1 (6.00 g, 34.4mmol) was dissolved in THF (50 mL) and triphenylphosphine (11.7 g, 44.7 mmol) was added in two portions. After stirring for 48 h at room temperature, water (1.13 mL) was added and stirring was continued for another 48 h. The solvent was removed under reduced pressure and the residue is afterwards dried under high vacuum at 45 C overnight. Water (119 mL) was added and the formed precipitate is removed by filtration. After washing the solid with water(200 mL), the solvent was evaporated under reduced pressure and the product was dried inhigh vacuum at 70 C overnight.
6.2 g
With 5%-palladium/activated carbon; hydrogen; In methanol; at 20℃; for 12h;
2-[2-(2-Chloroethoxy)ethoxy]ethanol (4,6.3 g, 37 mmol), NaI (1.8 g, 12 mmol), and NaN3 (3.9 g, 60 mmol) were dissolved in 30 mL of deionized water and then stirred at 60 C for 16 h. The reaction mixture was filtered to remove insoluble matter. The filtered solution was extracted with 60 mL of EtOAc. The organic layer was dried over Na2SO4 and evaporated to yield the azide (6.5 g). The azide (6.5 g) was dissolved in MeOH containing 0.5 g of 5% Pd-C and was stirred under a hydrogen atmosphere at room temperature for 12 h. The reaction mixture was filtered using Celite and was evaporated to yield the corresponding amine (6.2 g). The amine was dissolved in150 mL of CH3CN. This was followed by the addition of 30 mL of deionized water, 30 mL of 1 M NaOH, and (Boc)2O (8.1 g, 37 mmol) at room temperature for16 h. The reaction mixture was evaporated and the resultant residue was added to 100 mL of water and then extracted with an equal volume of EtOAc. The organic layer was dried over Na2SO4. After evaporation of the organic layer, the residue that was obtained was purified by silica gel column chromatography (200 g, MeOH-CHCl3 1/50) to yield 5 (6.2 g, 25 mmol) as acolorless oil. The yield from the three steps was 68%. 1H NMR (270 MHz, CDCl3): 5.21 (1H, br. s), 3.68(2H, t, J = 7.1 Hz), 3.61-3.52 (6H, m), 3.50 (2H, t,J = 7.1 Hz), 3.24 (2H, t, J = 6.9 Hz), 2.88 (1H, br. s),1.37 (9H, s); 13C NMR (67.8 MHz, CDCl3): 155.9,79.1, 72.5, 72.4, 70.2, 70.1, 61.5, 40.3, 28.2; FD-MSm/z (rel.int.): 250 (100, [M + H]+), 249 (13.0, [M]+),57.0 (25.1), 31.0 (16.1); FD-HR-MS m/z: calcd. forC11H24NO5, 250.16545, found 250.16572.
23.5 g
With palladium on activated charcoal; hydrogen; In methanol;
To a 1L hydrogenation reactor were added 29g BP103a02, methanol 360 mL, palladium on carbon 5.0g, and stirred. Nitrogen was replaced, and hydrogen was introduced to react for 3-4h. After the completion of the reaction under the monitor of TLC, the reaction liquid was filtered, and the filtrate was concentrated to give 23.5g BP103a03 as an oil.
With palladium on activated charcoal; hydrogen; In methanol; ethyl acetate; at 20℃;
General procedure: S3 (1.44 g, 3.86 mmol) was dissolved in EA/MT (20 mL/10 mL) in N2, then Pd/C (20 mg) was added into the mixture. After the replacement of H2 this mixture was stirring overnight at room temperature in ordinary pressure. When this reaction completed, evaporated the solvent under N2 and obtained S4 (1.96 g, 90%).
23.5 g
With palladium on activated charcoal; hydrogen;
In a 1 L hydrogenation reactor, 29 g of Compound 3, 360 mL of methanol,5.0 g of palladium carbon was added, stirred, purged with nitrogen,Hydrogen gas was introduced and reacted for 3 to 4 h, followed by monitoring by TLC,After completion of the reaction, the reaction solution was filtered,The filtrate was concentrated to obtain 23.5 g of oily substance of BP103a03.
23.5 g
With palladium on activated charcoal; hydrogen; In methanol;
To a 1 L hydrogenation reactor, 29 g of BP103a02, 360 mL of methanol, and 5.0 g of palladium on carbon were added, stirred, replaced with nitrogen, and reacted with hydrogen for 3-4 h. After the TLC monitoring reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated to give 23.5 g of an oil of BP103a03
3.53 g
With palladium 10% on activated carbon; hydrogen; In methanol; under 760.051 Torr;
A solution of 2-(2-(2-chloroethoxy)ethoxy)ethan-l-ol (12.5 g, (0402) 74.1 mmol) and sodium azide (7.25 g, 1 1 1 .5 mmol) in DMF (125 raL) was allowed to stir at 100C overnight. The mixture was filtered and evaporated to give 2-(2-(2-azidoethoxy)ethoxy)ethan-l-ol . A solution of the crude material and 0% Pd/C (1.12 g) in methanol (100 mL) was hydrogenated (1 atm) overnight. The mixture was filtered, evaporated and purified via flash chromatography (0-20% MeOH/DCM) to give the amine (3.53 g, 32% over 2 steps) IH-NMR (400 MHz, CDC13): delta 3 ,75-3 ,71 (dd, 2H), 3.69-3.64 (m, 2H), 3.64-3.61 (m, 2H), 3.59-3.53 (m, 2H), 3.48-3.45 (m, 21 1), 2.88 (t, ./ 5.1 Hz, 2HY
A solution of the amino alcohol (620) (313.6 g, 2.1mol) in THF (3.5 L) was treated, portion- wise, with N-(Benzyloxycarbonyloxy)succinimide (621) (550 g, 2.21mol). Once the reaction was complete (18 h) the THF was removed under reduced pressure and the residue dissolved in CH2Cl2 (2.5 L), then washed with an equal volume of HCl (1 M), NaHCO3 (Sat. Aq.), H2O and brine. The organic extract was dried (MgSO4), filtered and concentrated. The crude material (600g) was subjected to chromatography (4kg silica; 1-12% CH3OH-CH2Cl2) to yield HO- Trig-NHZ (622) (468g, 78%) as a clear-yellow viscous oil.
78%
In tetrahydrofuran; for 18h;
A solution of the amino alcohol (20) (313.6 g, 2.1mol) in THF (3.5 L) was treated, portion-wise, with N-(Benzyloxycarbonyloxy)succinimide (21) (550 g, 2.21mol). Once the reaction was complete (18 h) the THF was removed under reduced pressure and the residue dissolved in CH2Cl2 (2.5 L), then washed with an equal volume of HCl (1 M), NaHCO3 (Sat. Aq.), H2O and brine. The organic extract was dried (MgSO4), filtered and concentrated. The crude material (600g) was subjected to chromatography (4kg silica; 1-12% CH3OH-CH2Cl2) to yield HO-Trig- NHZ (22) (468g, 78%) as a clear-yellow viscous oil
2-methyl-acrylic acid 2-hydroxy-3-[3-({2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethyl}-{2-[2-hydroxy-3-(2-methyl-acryloyloxy)-propoxycarbonyl]-ethyl}-amino)-propionyloxy]-propyl ester[ No CAS ]
General procedure: The desired aminoalcohol (17 mmol, 2-(2-aminoethoxy)ethanol or 2-[2-(2-aminoethoxy)ethoxy]ethanol) was dissolved in CH3OH (10 mL) and TEA (5.45 mL, 39.2 mmol) was added. To this solution, stirred at room temperature, was added dropwise a solution of benzyloxycarbonyl chloride (ZCl, 3.2 g, 18.77 mmol) in CH3OH (5 mL). After the addition was complete the reaction mixture was stirred at room temperature for 20 h, protected from moisture with a CaCl2 drying tube. The solvent was then evaporated and the crude was dissolved in CH2Cl2 (150 mL) and washed first with a 5% aqueous solution of KHSO4 (2 × 50 mL) and then with water (2 × 50 mL). The evaporation of the dried solvent (Na2SO4) afforded the product as a clear oil pure enough to be used in the following steps.
75%
With sodium hydrogencarbonate; In water; acetonitrile; at 20℃; for 12h;
To a solution of 2-[2-(2-aminoethoxy)ethoxy]ethanol (3.50 g, 23.5 mmol, CAS6338-55-2) in CH3CN (30 mL) and H2O (30 mL) was added CbzCl (4.80 g, 28.1 mmol) and NaHCO3 (5.91 g, 70.4 mmol). The reaction mixture was stirred at rt for 12 hours. On completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (petroleum ether:ethyl acetate=5:1 to 1:1) to give the title compound (5.00 g, 75% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) delta 7.38-7.29 (m, 5H), 5.47 (s, 1H), 5.11 (s, 2H), 3.71 (s, 2H), 3.65-3.56 (m, 8H), 3.43-3.37 (m, 2H).
68%
With sodium hydrogencarbonate; In water; acetonitrile; at 0 - 20℃; for 2h;Inert atmosphere;
General procedure: The amino-alcohol 14 (1 equiv) was dissolved in water (2.5 mL / mmol) containing NaHCO3 (3 equiv). Benzyl chloroformate (1.2 equiv) dissolved in acetonitrile (2.5 mL / mmol) was added dropwise at 0 C. The mixture was stirred 1 h at 0 C and 1 h at room temperature. Addition of 0.1 N HCl (to reach pH 4), extraction with EtOAc (3x), drying over MgSO4 and concentration gave crude 15, that was purified by column-chromatography on silica gel (EtOAc / DCM (1:1)).
60%
With triethylamine; In dichloromethane; at 20℃;
The synthesis was done according to literature under argon.[ 2 ] A solution of 2 (3.00 g,20.1 mmol) in water (44 mL) was cooled to 0 C. In five portions, NaHCO3 (1.71 g,20.3 mmol) and Z-chloride (3.55 mL, 26.1 mmol) in toluene (2.3 mL) were added and thesolution was stirred overnight at room temperature. After separation of the layers, the aqueouslayer was extracted with EtOAc (3 50 mL) and the organic phase was washed with brine(1 50 mL). Drying with MgSO4, filtering and evaporating the solvent under reduced pressure gave the crude product, which was purified by silica gel column chromatography using EtOAc as eluent.
53%
With triethylamine; In tetrahydrofuran; at 0℃; for 1.5h;Inert atmosphere;
Preparation of Compound 20g Benzyl chloroformate (6 mL, 42.2 mmol) were slowly added to a solution of compound 20f (5.6 g, 38.2 mmol) and triethylamine (8 mL, 57.6 mmol) in THF (200 mL) at 0 C for 30 minutes under N2. After stirring for 1 hour at 0 C, the reaction mixture was concentrated and the crude product was purified by column chromatography, which produced the compound 20g (5.7 g, 53 %). 1H- MR (400 MHz, CDC13) delta 7.45-7.20 (m, 5H), 5.61 (br s, 1H), 5.07 (s, 2H), 3.85-3.20 (m, 12H).
53%
With triethylamine; In tetrahydrofuran; at 0℃; for 1.5h;Inert atmosphere;
Benzyl chloroformate (6 mL, 42.2 mmol) were slowly added to a solution of compound 20f (5.6 g, 38.2 mmol) and triethylamine (8 mL, 57.6 mmol) in THF (200 mL) at 0 C for 30 minutes under N2. After stirring for 1 hour at 0 C, the reaction mixture was concentrated and the crude product was purified by column chromatography, which produced the compound 20g (5.7 g, 53 %). 1H-NMR (400 MHz, CDC13) delta 7.45-7.20 (m, 5H), 5.61 (br s, 1H), 5.07 (s, 2H), 3.85-3.20 (m, 12H).
45%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere;
To a solution of <strong>[6338-55-2]2-(2-(2-aminoethoxy)ethoxy)ethan-l-ol</strong> (3.53 g, (0405) 23.7 mmol) and diisopropylethylamine (8.2 mL, 47.3 mmol) in dichloromethane (75 mL) at 0C was added benzyl chloroformate (5 mL, 35.5). The solution was allowed warm to room temperature and stirred for 2 hours. The mixture was evaporated and purified by flash chromatography (20-100% EtOAc/hexanes) to give the benzyl carbamate (3 g, 45%). IH-NMR (400 MHz; CDC13): delta 7.37- 7.31 (m, 5H), 5.37 (s, 1H), 5. 14-5.09 (s, 2H), 3.72-3.71 (m, 2H), 3 ,64-3 ,59 (m, 3.40 (q, J = 5.2 Hz,
With potassium carbonate; In methanol; for 14h;Heating / reflux;
A mixture of 1.03 g (5 mmol) of 5 and 1.49 g (10 mmol) of <strong>[6338-55-2]2-[2-(2-amino-ethoxy)-ethoxy]-ethanol</strong> was dissolved in methanol and then 0.7 g (5 mmol) of potassium carbonate was added. The reaction mixture was refluxed for 14 h. After workup the residue was purified by column chromatography (EtOH to EtOH:H2O=2:1) to give, 800 mg of an oily product (15, 65% yield) along with 200 mg of recovered starting material. 1H NMR (DMSO-d6, deltappm): 2.70-2.95(m, 4H, -CH2-NH-CH2-), 3.55-3.73(m, 10H, 5×-OCH2), 4.13(m, 1H, OCH), 4.42(dd, 1H, imidazole-CHa-, J=13.8 Hz, 8.7 Hz), 4.68(dd, 1H, imidazole-CHb-, J=13.8 Hz, 3.3 Hz), 7.18(s, 1H, -CH), 7.57(s, 1H, -CH). 13C NMR (DMSO-d6, deltappm): 49.57, 53.03, 54.44, 61.93, 68.41, 69.04, 69.93, 71.21, 73.67, 128.45,129.57, 146.45.
With palladium 10% on activated carbon; hydrogen; In ethanol; at 70℃; under 52505.3 Torr;Continuous-flow conditions;
Using a 10% Pd/C cartridge, a 0.05 M solution of 8-dibenzylamino-3,6-dioxaoctan-1-ol (1.00 g, 3.04 mmol) in absolute ethanol (60 mL) was cycled twice through an H-Cube continuous-flow reactor at a flow rate of 1 mL/min. The applied pressure was set to 70 bar and the temperature to 70 C. At the end of the second run, the entire reaction mixture was collected and concentrated in vacuo to give the title compound9 (0.45 g, 99%) as a colourless oil; numax (film) 3365, 3312, 3302, 2873, 2854, 1599 cm-1; deltaH (200 MHz; D2O) 2.88 (2H, t, J 5.3, NH2CH2CH2O), 3.54-3.72 (10H, m, CH2O(CH2)2O(CH2)2OH); deltaC (50 MHz; D2O) 39.1, 60.0, 68.6, 69.2, 69.3, 71.4.
3'-[(2S)-2-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[4-(1H-tetrazol-5-yl)phenyl]amino}propyl]-6-methylbiphenyl-3-carboxylic acid[ No CAS ]
tert-butyl [(trans-4-[(2S)3-[5'-({2-[2-(2-hydroxyethoxy)ethoxy]ethyl}carbamoyl)-2'-methylbiphenyl-3-yl]-1-oxo-1-[4-(1H-tetrazol-5-yl)phenyl]amino}propan-2-yl]carbamoyl}cyclohexyl)methyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;
Example 57A tert-Butyl [(trans-4-[(2S)3-[5'-({2-[2-(2-hydroxyethoxy)ethoxy]ethyl}carbamoyl)-2'-methylbiphenyl-3-yl]-1-oxo-1-[4-(1H-tetrazol-5-yl)phenyl]amino}propan-2-yl]carbamoyl}cyclohexyl)methyl]carbamate 3'-[(2S)-2-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[4-(1H-tetrazol-5-yl)phenyl]amino}propyl]-6-methylbiphenyl-3-carboxylic acid (100 mg, 0.15 mmol) and 2-[2-(2-aminoethoxy)ethoxy]ethanol (26 mg, 0.17 mmol) were dissolved in tetrahydrofuran (4 ml), N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (67 mg, 0.17 mmol) and N,N-diisopropylethylamine (23 mg, 0.17 mmol) were added and the mixture was stirred at RT overnight. Subsequently, the mixture was concentrated and the residue was purified chromatographically by HPLC (Method 10). This gave 56 mg (47% of theory) of the title compound. LC-MS (Method 4): Rt=1.12 min; MS (ESIpos): m/z=813.6 [M+H]+.
3'-[(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[4-(1H-tetrazol-5-yl)phenyl]amino}propyl]-2-methylbiphenyl-4-carboxylic acid[ No CAS ]
tert-butyl [(trans-4-[(2S)-3-[4'-({2-[2-(2-hydroxyethoxy)ethoxy]ethyl}carbamnoyl)-2'-methylbiphenyl-3-yl]-1-oxo-1-[4-(1H-tetrazol-5-yl)phenyl]amino}propan-2-yl]carbamoyl}-cyclohexyl)methyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;
Example 61A tert-Butyl [(trans-4-[(2S)-3-[4'-({2-[2-(2-hydroxyethoxy)ethoxy]ethyl}carbamnoyl)-2'-methylbiphenyl-3-yl]-1-oxo-1-[4-(1H-tetrazol-5-yl)phenyl]amino}propan-2-yl]carbamoyl}-cyclohexyl)methyl]carbamate 3'-[(2S)-2-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[4-(1H-tetrazol-5-yl)phenyl]amino}propyl]-2-methylbiphenyl-4-carboxylic acid (100 mg, 0.15 mmol) and 2-[2-(2-aminoethoxy)ethoxy]ethanol (26 mg, 0.17 mmol) were dissolved in tetrahydrofuran (4 ml), N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (67 mg, 0.17 mmol) and N,N-diisopropylethylamine (23 mg, 0.17 mmol) were added and the mixture was stirred at RT overnight. Subsequently, the mixture was concentrated and the residue was purified chromatographically by HPLC (Method 10). This gave 55 mg (46% of theory) of the title compound. LC-MS (Method 4): Rt=1.10 min; MS (ESIpos): m/z=813.6 [M+H]+.
5'-[(2S)-2-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[4-(1H-tetrazol-5-yl)phenyl]amino}propyl]-2'-methylbiphenyl-3-carboxylic acid[ No CAS ]
tert-butyl [(trans-4-[(2S)-3-[3'-({2-[2-(2-hydroxyethoxy)ethoxy]ethyl}carbamoyl)-6-methylbiphenyl-3-yl]-1-oxo-1-[4-(1H-tetrazol-5-yl)phenyl]amino}propan-2-yl]carbamoyl}-cyclohexyl)methyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;
Example 64A tert-Butyl [(trans-4-[(2S)-3-[3'-({2-[2-(2-hydroxyethoxy)ethoxy]ethyl}carbamoyl)-6-methylbiphenyl-3-yl]-1-oxo-1-[4-(1H-tetrazol-5-yl)phenyl]amino}propan-2-yl]carbamoyl}-cyclohexyl)methyl]carbamate 5'-[(2S)-2-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]amino}-3-oxo-3-[4-(1H-tetrazol-5-yl)phenyl]amino}propyl]-2'-methylbiphenyl-3-carboxylic acid (100 mg, 0.15 mmol) and 2-[2-(2-aminoethoxy)ethoxy]ethanol (26 mg, 0.18 mmol) were dissolved in tetrahydrofuran (4 ml), N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (67 mg, 0.18 mmol) and N,N-diisopropylethylamine (23 mg, 0.18 mmol) were added and the mixture was stirred at RT overnight. Subsequently, the mixture was concentrated and the residue was purified chromatographically by HPLC (Method 10). This gave 48 mg (41% of theory) of the title compound. LC-MS (Method 4): Rt=1.12 min; MS (ESIpos): m/z=813.6 [M+H]+.
With triethylamine; In acetonitrile; at 22℃; for 16h;
To a solution of SL_0496 (40 mg, 59 mumol) in MeCN (15 mL) was added <strong>[6338-55-2]2-(2-(2-aminoethoxy)ethoxy)ethan-1-ol</strong> (8.8 mg, 59 mumol) followed by NEt3 (25 muL, 177 mumol). The resulting yellow solution was left at 22 C. for 16 hours, at which point TLC analysis indicated complete consumption of starting material. Solvent was removed in vacuo, and crude residue was purified by silica gel chromatography (0?30% MeOH/DCM) to provide 37 mg (91% yield) of SL_0501 as a clear oil. 11-INMR (300 MHz, DMSO-d6) delta 7.22-7.15 (m, 3H), 5.65-5.61 (m, 2H), 4.60-4.50 (m, 5H), 3.62 (t, J=6.6 Hz, 2H), 3.55 (dd, J=4.0, 5.5 Hz, 2H), 3.52-3.45 (m, 14H), 3.43-3.36 (m, 10 H), 3.15-3.07 (m, 6H), 1.70 (p, J=6.5 Hz, 2H), 1.48 (p, J=6.8 Hz, 2H), 1.42-1.25 (m, 4H). MS (ESI+) calc'd for C29H55ClN3O13+ [M+H]+ 688.34, found 688.3.
With triethylamine; In acetonitrile; at 22℃; for 22h;
To a solution of SL_0212 (512 mg, 1.52 mmol) in MeCN (20 mL) was added <strong>[6338-55-2]2-(2-(2-aminoethoxy)ethoxy)ethan-1-ol</strong> (226 mg, 1.52 mmol) followed by NEt3 (424 muL, 3.04 mmol). The resulting yellow solution was left at 22 C. for 22 hours, at which point TLC analysis indicated complete consumption of starting material. Solvent was removed in vacuo, and crude residue was purified by silica gel chromatography (0?10% MeOH/DCM) to provide 376 mg (71% yield) of SL_0485 as a clear oil. 1H NMR (300 MHz, DMSO-d6) delta 7.17 (t, J=5.7 Hz, 1H), 5.79 (m, 2H), 4.56 (m, 2H), 4.45 (d, J=4.2 Hz, 2H), 4.13 (dd, J=13.0, 3.9 Hz, 1H), 3.92 (dd, J=13.0, 4.3 Hz, 1H), 3.72 (td, J=9.5, 7.9, 3.4 Hz, 1H), 3.52-3.49 (m, 4H), 3.49-3.44 (m, 2H), 3.43-3.37 (m, 5H), 3.12 (q, J=5.9 Hz, 2H), 1.75-1.57 (m, 2H), 1.55-1.1 (m, 2H).
With triethylamine; In acetonitrile; at 22℃; for 16h;
To a solution of SL_0498 (120 mg, 177 mumol) in MeCN (15 mL) was added <strong>[6338-55-2]2-(2-(2-aminoethoxy)ethoxy)ethan-1-ol</strong> (26 mg, 177 mumol) followed by NEt3 (74 muL, 531 mumol). The resulting yellow solution was left at 22 C. for 16 hours, at which point TLC analysis indicated complete consumption of starting material. Solvent was removed in vacuo, and crude residue was purified by silica gel chromatography (0?10% MeOH/DCM) to provide 106 mg (87% yield) of SL_0503 as a clear oil. 1H NMR (300 MHz, DMSO-d6) delta 7.22-7.12 (m, 3H), 5.79 (m, 2H), 4.55 (t, J=5.5, 1H), 4.47-4.43 (m, 4H), 4.04 (t, J=4.8 Hz, 2H), 3.62 (t, J=6.6 Hz, 2H), 3.55 (t, J=4.8 Hz, 2H), 3.52-3.45 (m, 14H), 3.44-3.36 (m, 10H), 3.16-3.06 (m, 6H), 1.70 (p, J=6.7 Hz, 2H), 1.49 (p, J=6.9 Hz, 2H), 1.42-1.25 (m, 4H). MS (ESI+) calc'd for C29H55ClN3O13+ [M+H]+ 688.34, found 688.3
With triethylamine; In acetonitrile; at 22℃; for 24h;
To a solution of SL_0160 (269 mg, 732 mumol) in MeCN (10 mL) was added <strong>[6338-55-2]2-(2-(2-aminoethoxy)ethoxy)ethan-1-ol</strong> (109 mg, 732 mumol) followed by NEt3 (200 muL, 145 mumol). The resulting yellow solution was left at 22 C. for 24 hours, at which point TLC analysis indicated complete consumption of starting material. Solvent was removed in vacuo, and crude residue was purified by silica gel chromatography (0?100% EtOAc/hexanes) to provide 220 mg (80% yield) of SL_0483 as a clear oil. 1H NMR (300 MHz, DMSO-d6) delta 7.15 (t, J=5.4 Hz, 1H), 5.62 (dt, J=11.4, 5.7 Hz, 1H), 5.49 (dt, J=11.4, 6.5 Hz, 1H), 4.57-4.51 (m, 3H), 4.24 (d, J=5.7 Hz, 2H) 3.51-3.46 (m, 6H), 3.42-3.37 (m, 4H), 3.11 (q, J=5.9 Hz, 2H), 0.87 (s, 9H), 0.05 (s, 6H). MS (ESI+) calc'd for C17H35NaNO6Si+ [M+H]+ 400.21, found 400.2.
2-(2,2,3,3-tetramethyl-4,7,10-trioxa-3-siladodecan-12-yl)isoindoline-1,3-dione[ No CAS ]
[ 6338-55-2 ]
Yield
Reaction Conditions
Operation in experiment
77%
Hydrazine monohydrate (322.6 mL, 9.2 mmol) was added to a solution of 2-(2,2,3,3-tetramethyl-4,7,10-trioxa-3-siladodecan-12-yl)isoindoline-1,3-dione (822 mg, 2.09 mmol) in ethanol (120 mL), and stirred under heat reflux overnight.After cooling to room temperature, concentrated hydrochloric acid (2 mL) was added and stirred under heat refluxfor 2 hours. This solution was cooled to room temperature, then the insolubles were filtered off, and the filtrate wasconcentrated under a reduced pressure. Water was added to the residue, which was washed with ethyl acetate. Theaqueous layer was adjusted to pH = 9 with a 3N sodium hydroxide aqueous solution and washed with dichloromethane/methanol (v/v) = 10/1. The solvent in the aqueous layer was distilled away under a reduced pressure, and thendichloromethane was added to the residue. The insolubles were filtered off, and then the solvent was distilled awayunder a reduced pressure to obtain the title compound (239.1 mg, 77%) as a pale yellow oily matter.1H NMR (400 MHz, CDCl3) delta 3.73 (2H, t, J = 4.4 Hz), 3.69-3.64 (6H, m), 3.59 (2H, t, J = 4.4 Hz), 3.03 (2H, br t, J = 4.4 Hz)
1-(4-ethynylphenyl)-3-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
4-Ethynylaniline (170.4 mg, 1.5 mmol) was added to a solution of 4-nitrophenyl chloroformate (289.3 mg, 1.4mmol) in tetrahydrofuran (6.8 mL), stirred at room temperature for 3 hours, and then the solvent was distilled away undera reduced pressure. To a solution of the resulting crude product in dichloromethane (4 mL), a solution of 2-[2-(2-aminoethoxy)ethoxy]ethanol (239 mg, 1.6 mmol) in dichloromethane (4 mL) and triethylamine (303 mL, 2.2 mmol) wereadded, stirred at room temperature overnight, and then the solvent was distilled away under a reduced pressure. Theresidue was purified by silica gel column chromatography (ethyl acetate/methanol (v/v) = 100/0 ? 90/10) to obtain thetitle compound (325.4 mg, 77%) as a pale yellow oily matter.1H NMR (400 MHz, CDCl3) delta 8.30 (1H, br s), 7.32 (4H, m), 6.22 (1H, br t, J = 4.4 Hz), 4.37 (1H, br s), 3.72 (2H, br t, J= 4.4 Hz), 3.55-3.53 (6H, m), 3.49 (2H, t, J = 4.4 Hz), 3.36-3.34 (2H, m), 3.05 (1H, s)
2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02’6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetic acid trifluoroacetic acid salt[ No CAS ]
2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0[2,6]]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 3h;
Into a 25-mL round-bottom flask, was placed a solution of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0[2,6]]trideca- 2(6),4,7,10,12-pentaen-9-yl]acetic acid (TFA salt) [prepared as previously described by Filippakopoulos, P. et al. in Nature 2010, 468, 1067-1073 and by Zengerle, M. et al. in ACS Chemical Biology 2015, 10, 1770-1777] (150.0 mg, 0.37 mmol, 1.00 equiv) in N,N- dimethylformamide (5 mL). This was followed by the addition of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (171.0 mg, 0.45 mmol, 1.20 equiv) at 0C . N,N-diisopropylethylamine 0.2 ml was added into at 0 C . To this was added 2-[2-(2-aminoethoxy)ethoxy]ethan-1-ol (168.0 mg, 1.13 mmol, 3.00 equiv) at 0 C . The resulting solution was stirred for 2 h at room temperature. The resulting solution was stirred for 1 h at 10C . The reaction was then quenched by the addition of water (20 mL). The resulting solution was extracted with ethyl acetate (2,0 mL x 3) and the organic layers combined. The resulting mixture was washed with brine (20 mL x 1). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dicnloromethane/methanol (10: 1). This resulted in 140.0 mg (70%) of 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.0[2,6]]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]acetamide as yellow oil.
methyl 4-([2-[2-(2-hydroxyethoxy)ethoxy]ethyl]amino)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 130℃; for 12h;
Into a 25-mL round-bottom flask, was placed methyl 4-fluorobenzoate (500.0 mg, 3.24 mmol, 1.00 equiv), NMP (10 mL), potassium carbonate (894.24 mg, 6.47 mmol, 2.00 equiv), 2-[2-(2-aminoethoxy)ethoxy]ethan-1-ol (580.0 mg, 3.89 mmol, 1.20 equiv). The resulting solution was stirred 12 h at 130C in an oil bath. The resulting solution was extracted with ethyl acetate (50 mL x 3) and the organic layers combined. The resulting mixture was washed with brine (50 mL x 3). The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (9/1). This resulted in 300.0 mg (33%) of methyl 4-([2-[2-(2-hydroxyethoxy)ethoxy]ethyl]amino)benzoate as light yellow oil. LC-MS (ES+): m/z 284,05[MH+]
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 10h;Inert atmosphere;
A mixture of compound 3 (1.26 g, 8.45 mmol) and DIEA (2.70 g, 20.89 mmol) in dry DMF (5 mL) was added to a solution ofcompound 4 (2.90 g, 7.06 mmol) in dry DMF (20 mL) at 0 C. The mixture was stirred at 0 C for 30 min then stirred for 10 h at room temperature under nitrogen atmosphere. DMF was then removed under reduced pressure at 80 C, and the crude product was dissolved with DCM then the organic phase washed with brine solution and dried over MgSO4. Purification with column chromatography on silica gel with DCM/MeOH (15:1, v/v) as eluent affords the product as white powder with a yield of 94% (2.50 g). 1H NMR (DMSO-d6): delta 1.27-1.51 (m, 6H, CH2), 2.05 (t, 2H, CH2), 2.55 (d, 1H, CH2), 2.79-2.83 (m,1H, CH2), 3.08 (t, 1H, CH), 3.09 (t, 2H, CH2), 3.15-3.51 (m,10H, CH2), 4.10 (d, 1H, CH), 4.28 (d,1H, CH), 4.60 (t, 1H, OH), 6.35 (s, 1H, NH), 6.41 (s, 1H, NH), 7.84 (s,1H, NH).
General procedure: Amine (1.00 equiv) and4dimethylaminopyridine (0.1 50 equiv) were added to a solution of urea intermediate 16 (1 equiv) in dichloromethane (0.2 M). The reaction flask was sealed with a Teflon wrapped glass stopper and heated to 40 C. lpon consumption of the starting: materials as determined by thin layer chromatography. the reaction mixture was cooled to 23 ?41 and concentrated under reduced pressure. ?i?he crude residue was purified by flash column chromatography on silica gel to afford substituted ureas 13a-13c.
To a stirring mixture of 2-[2-(2-aminoethoxy)moholine (21.0 mE, 191 nmol) in dioxane (100 mE) wasethoxy]ethanol (51 08A, 25.0 g, 167 mmol) and N-methyladded dropwise a solution of Fmoc-OSu (62.2 g, 184 mmol)in dioxane (50 mE). Afier stirring overnight, the reactionwas concentrated in vacuo to afford a light yellow oil. Thecrude was re-dissolved in EtOAc and washed with sat.NaHCO3 (aq.) and brine. The organic layer was removed invacuo to afford an oil, which was purified by 5i02 ciromai-Prtography to provide the FmocNH-PEG2-OH (S108, 55 g,88% yield). ESI+mlz calcd 371.4, found 372.2 [M+H].
88%
With 4-methyl-morpholine; In 1,4-dioxane;
To a stirring mixture of 2-[2-(2-aminoethoxy)ethoxy]ethanol (S108A, 25.0 g, 167 mmol) and N-methyl morpholine (21.0 mL, 191 mmol) in dioxane (100 mL) was added dropwise a solution of Fmoc-OSu (62.2 g, 184 mmol) in dioxane (50 mL). After stirring overnight, the reaction was concentrated in vacuo to afford a light yellow oil. The crude was re-dissolved in EtOAc and washed with sat. NaHCO3 (aq.) and brine. The organic layer was removed in vacuo to afford an oil, which was purified by SiO2 chromatography to provide the FmocNH-PEG2-OH (S108, 55 g, 88% yield). ESI+ m/z calcd 371.4, found 372.2 [M+H]+.
Compound 15 (3.7 g, 17.36 mmol) was dissolved in 30 mL of aqueous ammonia and stirred at 70 C for 24 h.After the reaction was completed, the solvent was spun off and 15 mL of water was added. The mixture was washed with dichloromethane (3 * 20 mL) and dried over anhydrous sodium sulfate. After the organic solvent was removed, 2.4 g of compound 16 was obtained with a yield of 93%
2-[2-(2-[[4-(benzyloxy)benzene]sulfonamido]ethoxy)ethoxy]ethan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With triethylamine; In dichloromethane;
To a 250-mL round-bottom flask was added 2-[2-(2- aminoethoxy )ethoxy ] ethan- 1 -ol (5.3 g, 35.53 mmol, 2 equiv), CH2CI2 (50 mL), triemylamine (5.37 g, 53.07 mmol, 3 equiv), and INT-L3 (R1 = H, 5 g, 17.7 mmol, 1 equiv). The resulting solution was stirred overnight. The reaction was then quenched by the addition of 50 mL of water and extracted with 3 x 50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum The residue was applied onto a silica gel column with CftCh/methanol (0-55%) providing 6.4 g (92%) of 2-[2-(2-[[4-(benzyloxy)benzene]sulfonamido]ethoxy)emoxy]ethan-l-ol (I T-T1) as a white solid.
S48 (0.45 g, 3.00 mmol), DIPEA (1.6 mL, 9.00 mmol) were added, dissolving in DMF (20 mL) at -12 C for 30 min in N2. Then S5 (in DMF, 5 mL, 0.71 g, 1.00 mmol) was dropped into this mixture, stirring overnight. After this reaction the solvent was removed, the mixture was dissolved in deionized water (25 mL), then the aqueous was washed by DCM (25 mL) three times. This aqueous dialyzed in deionized water 5 times and freeze-dried to get S49 (1.21 g, 67%).
N-(2-formylquinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide[ No CAS ]
N-(2-(((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)amino)methyl)quinolin-8-yl)-4-(trifluoromethyl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine; In 1,2-dichloro-ethane; at 20℃; for 18h;
General procedure: A solution of compound (ZDR019) (3.0 g, 7.88 mmol), dimethylamine hydrochloride (1.92 g, 23.6 mmol), sodium triacetoxyborohydride (3.32 g, 15.7 mmol) and N,N- diisopropylethylamine (4.8 ml_, 27.5 mmol) in 1,2-dichloroethane (150 mL) was stirred at room temperature for 18 h. The reaction was quenched through the addition of water (100 mL) and the pH adjusted to pH 6-7 using aqueous phosphate buffer solution (0.5 M, pH 7) . The mixture was then diluted with dichloromethane (100 mL) and the separated aqueous layer further extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with aqueous phosphate buffer solution (0.5 M, pH 7) (100 mL), dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. Purification by flash chromatography (dichloromethane/methanol, 20: 1 10: 1 7: 1) afforded compound (ZDR022) as a white solid (2.40 g, 5.86 mmol, 74%).
2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione[ No CAS ]
2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 115℃; for 20h;
To a solution of 2-[2-(2-aminoethoxy)ethoxy]ethanol (1.80 g, 12.0 mmol, CAS6338-55-2) and 2-(2,6-dioxo-3-piperidyl)-4-fluoroisoindoline-1,3-dione (4.00 g, 14.4 mmol, Intermediate R) in dioxane (35.0 mL) was added DIPEA (9.36 g, 72.3 mmol). The reaction mixture was stirred at 115 C. for 20 hrs. On completion, the mixture was concentrated in vacuo to remove the solvent. The residue was purified by silica gel chromatography (PE:EA=1:1) to give the title compound (2.90 g, 59% yield) as yellow solid. 1H NMR (400 MHz, CDCl3) delta 8.28 (s, 1H), 7.50 (dd, J=7.2, 8.4 Hz, 1H), 7.11 (d, J=7.2 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.57 (t, J=5.2 Hz, 1H), 4.96-4.85 (m, 1H), 3.77-3.67 (m, 8H), 3.64-3.59 (m, 2H), 3.48 (q, J=5.2 Hz, 2H), 2.92-2.70 (m, 3H), 2.62 (s, 1H), 2.17-2.08 (m, 1H).
55%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃;
General procedure: Compound 38/56 (1.0 equiv.), amine (1.2equiv.), and DIPEA (2.0 equiv.) in DMF were stirred at 90 C overnight. The reaction was cooled to room temperature and poured into water. The resulting mixture was extracted with ethylacetate and the organic layer was washed with water 1, brine 1,dried over anhydrous Na2SO4, filtered, and evaporated to drynessunder vacuum. The residue crude product was purified by column chromatography to afford the desired compound.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃;
2-(2,6- Dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (1.0 equiv.), compound 13a/13b/13c (1.5 equiv.) and DIPEA (3.0 equiv.) in 2 mL DMF were stirred at 90 C overnight. Water was added to the reaction mixture and it was extracted with EtOAc. The organic phase was washed with water x1, brine x1, dried over Na2SO4, filtered and evaporated to dryness. The resulting mixture was purified by column chromatography using DCM and MeOH as eluents to afford 14a-c. (0329) [0151] 2-(2,6-Dioxopiperidin-3-yl)-4-((2-(2-(2- hydroxyethoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione (14a): 1H NMR (400 MHz, CDCl3) delta 8.19 (br s, 1H), 7.55-7.44 (m, 1H), 7.10 (d, J = 7.1 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 6.57 (t, J = 5.2 Hz, 1H), 4.91 (dd, J = 12.0, 5.4 Hz, 1H), 3.85-3.65 (m, 8H), 3.64-3.59 (m, 2H), 3.51-3.43 (m, 2H), 2.92-2.68 (m, 3H), 2.57 (br s, 1H), 2.18-2.07 (m, 1H) ppm.
2.90 g
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 115℃; for 20h;
To a solution of 2-[2-(2-aminoethoxy)ethoxy]ethanol (1.80 g, 12.0 mmol) and 2-(2,6- dioxo-3- piperidyl)-4-fluoroisoindoline-1,3-dione (4.00 g, 14.4 mmol, from IRW-003) in dioxane (35 mL) was added DIEA (9.36 g, 72.3 mmol). The reaction mixture was stirred at 115C for 20 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (2.90 g, 59% yield) as a yellow solid. 1H NMR (400MHz, CDCl3) d 8.22 (s, 1H), 7.42 (dd, J = 7.6, 8.4 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.50 (t, J = 5.6 Hz, 1H), 4.85 (dd, J = 5.6, 11.6 Hz, 1H), 3.69 - 3.64 (m, 4H), 3.62 (s, 4H), 3.57 - 3.51 (m, 2H), 3.41 (q, J = 5.6 Hz, 2H), 2.84 - 2.64 (m, 3H), 2.10 - 2.00 (m, 1H), 1.65 (s, 1H)
See FIG. 22 for the synthesis of DBCO-PEG-OH (compound [IV]). To a solution of 2- (2- (2-aminoethoxy) ethoxy) ethan-1-ol (compound [I], 0.267 g, 1.789 mmol) in 2 ml anhydrous DCM at RT was added DBCO- (Compound [II], 0.24 g, 0.596 mmol) in DMF (5 mL) was slowly added.After the addition is complete,The reaction solution was stirred for 2 hours at RT. HPLC showed complete disappearance of the succinimide. The reaction was maintained in the dark at -20 C in the freezer.The next morning,The reaction solution was warmed below RT and diluted with 3 ml DCM.Silica gel (5 g) was added and the slurry was evaporated to dryness on a rotary evaporator.Loading the remaining powder onto the ISCO loading cartridge,Purification by column chromatography (12 g silica gel column, 5-20% methanol / DCM)0.2 g of DBCO-PEG-OH (compound [IV]) was obtained. Yield: 77%
((N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)aminoethoxy)ethoxy)ethanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
A solutionof 2-[2-(2-aminoethoxy)ethoxy]ethanol (0.41 g, 2.75 mmol, 1.1 eq.) and Et3N (660 L, 4.75mmol, 1.9 eq.) in methanol (15 mL) was stirred at 30C for 1 h. NBD-Cl (0.5 g, 2.50 mmol, 1eq.) was added and the reaction was stirred in the dark for 16 h at 30C. Insoluble material wasremoved by filtration, and the filtrate was dried. The resulting solid was dissolved in H2O (5mL) and purified on a sephadex LH-20 column, eluting with H2O to give the product as anorange solid (0.33 g, 1.05 mmol, 42% yield).LRMS (ESI-): m/z calculated 311.10 ([M-H]-), found 311.18 ([M-H]-), (ESI+): m/z calculated335.27 ([M+Na]+), found 335.09 ([M+Na]+); HRMS (ESI+): m/z calculated 335.09621([M+Na]+) for C12H16N4O6Na, found 335.09650 ([M+Na]+).
A solution of 5-[(3aS, 4S, 6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4- yl]pentanoic acid (1.00 g, 4.09 mmol) in DMA (10.0 mL) was treated with HATU (2.02 g, 5.32 mmol) for 10 min at 0 C under nitrogen atmosphere followed by the addition of TEA (1.71 mL, 16.9 mmol) and 2-[2-(2-aminoethoxy)ethoxy]ethan-1-ol (672 mg, 4.50 mmol) at 0 C. The resulting mixture was stirred for 2 h at room temperature and was concentrated under reduced pressure. The residue was re-dissolved in DCM (50.0 mL) and washed with brine (50.0 mL). The aqueous phase was concentrated under reduced pressure and the residue was purified by reversed phase flash chromatography with the following conditions: Column: WelFlash TM C18-I, 20-40 um, 330 g; Eluent A: water (plus 10 mmol/L FA); Eluent B: ACN; Gradient: 1% - 20% B in 20 min; Flow rate: 80 mL/min; Detector: UV 220/254 nm; desired fractions were collected at 10% B and concentrated under reduced pressure to afford 5-[(3aS, 4S, 6aR)-2-oxo-hexahydro-1H- thieno[3,4-d]imidazol-4-yl]-N-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]pentanamide (1.17g, 76%) as a white solid. 1H NMR (400 MHz, DMSO-d6) d 7.91 (t, J = 5.6 Hz, 1H), 6.43 (s, 1H), 6.39 (s, 1H), 4.66 (s, 1H), 4.31 (m, 1H), 4.13 (m, 1H), 3.48 (d, J = 5.1 Hz, 2H), 3.42 (s, 1H), 3.41 (s, 3H), 3.39 (s, 3H), 3.18 (q, J = 5.9 Hz, 2H), 3.15-3.05 (m, 1H), 2.85-2.80 (m, 1H), 2.58 (d, J = 12.4 Hz, 1H), 2.07 (t, J = 7.4 Hz, 2H), 1.65-1.60 (m, 1H), 1.52-1.43 (m, 3H), 1.38-1.22 (m, 2H). LC/MS (ESI, m/z): [(M + 1)]+ = 376.30
With hydrogenchloride; In 1,4-dioxane; dichloromethane; at 25℃; for 0.333333h;
To a solution of <strong>[139115-92-7]tert-butyl N-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate</strong> (3.00 g, 12.0 mmol) in DCM (30 mL) was added HCl/dioxane (4 M, 15 mL). The reaction mixture was stirred at 25C for 20 minutes. On completion, the residue was concentrated in vacuo to give the compound (1.80 g, 100% yield) as yellow oil. The crude product was used to the next step directly without further purification.
2-(2-(2-((3,4-bis(benzyloxy)benzyl)amino)ethoxy)ethoxy)ethan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13 g
Stage #1: 3,4-dibenzyloxybenzaldehyde; 2-(2-(2-aminoethoxy)ethoxy)ethan-1-ol In methanol at 65℃; for 6h;
Stage #2: With sodium tetrahydroborate In methanol at 50℃;
10.1 Step 1) Preparation of 2-(2-(2-((3,4-bis(benzyloxy)benzyl)amino)ethoxy)ethoxy)ethan-1-ol (AL-5)
3,4-Bis(benzyloxy)benzaldehyde (1101, 25 g, 78.6 mmol) was dissolved in methanol (MeOH, 250 mL), andthen 2-(2-(2-aminoethoxy)ethoxy)ethanol (L-3, 11.7 g, 78.6 mmol) was added thereto. The mixture was stirred at 65°Cfor about 6 hours. After cooling to room temperature, sodium borohydride (NaBH4, 3 g, 78.6 mmol) was further addedand then stirred at 50°C overnight. Water was added to the reaction solution to complete the reaction, and the compound was extracted with ethyl acetate (EtOAc, 50 mL x 3). The extracted compound was washed with brine, and the remainingwater was removed with sodium sulfate. After filtering, the solution was concentrated and the concentrated solution waspurified by column chromatography using silica gel (methylene chloride/methanol = 20: 1). Thereby, 2-(2-(2-((3,4-bis(benzyloxy)benzyl)amino)ethoxy)ethoxy)ethan-1-ol (AL-5, 13 g) was obtained as a yellow liquid. 1H NMR (DMSO-d6, 400MHz) δ (ppm) 7.46-7.30 (m, 10H), 7.06 (d, J=1.6Hz, 1H), 6.97 (d, J=8Hz, 1H), 6.82 (d, J=1.2Hz, 1H), 5.10 (d, J=4Hz,4H), 3.61 (s, 2H), 3.50-3.39 (m, 11H), 2.58 (t, J=6Hz, 2H) ESI-MS Calcd m/z for C27H33N5O5 [M+H]+ 452.10 Found 451.56
Stage #1: menthoxyacetic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.166667h;
Stage #2: 2-(2-(2-aminoethoxy)ethoxy)ethanol In N,N-dimethyl-formamide at 20℃;
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