* 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.
The azide was combined with Pd/C (150 mg) in MeOH (7.0 ml_) and stirred 12 h under H2 (1 atm). The suspension was filtered over celite and the filtrate was concentrated to afford the amine (0.520 g, 2.7 mmol) in quantitative yields (Xie, H. Z.; Braha, O.; Gu, L. Q.; Cheley, S.; Bayley, H. Chem. Biol. 2005, 12, 109-120.)
90%
With palladium 10% on activated carbon; hydrogen In dichloromethane for 24 h;
To the alcohol 11-azido-3,6,9-trioxaundecan-1-ol, 2 (1.00 g, 4.56 mmol)dissolved in 0H2012 (8 mL), catalytic amount of 10percent Palladium on carbon(Pd/C) was added, and the reaction was stirred under H2 pressure (4 atm) during 24 hours. The solution was filtered through a short pad of celite and the solvent was evaporated. The amino derivative was isolated by flash column chromatography, eluting with a mixture CH2CI2/ MeOH (9:1), to give 4(790mg, 90percent) as a yellow-coloured syrup. 1H NMR (400 MHz): 6 3.70 (t, 2H, J =4.8 Hz, HOCH2CH2), 3.65—3.60 (m, 1OH, 5CH20), 3.56 (t, 2H, J = 4.8 Hz, OCH2CH2N), 3.50 (t, 2H, J = 4.8 Hz, CH2NH2), 2.83 (5, 2H, NH2), 2.27 (5, 1 H, OH) ppm. 130 NMR (100 MHz): 673.0 (NCH2C), 70.6, 70.3, 70.2, 69.9, 61.5 (COH), 41.5 (ON) ppm. HRMS calcd. for O8H2oNO4[M+H]: 194.1398; found194.1392.
86%
With water; triphenylphosphine In tetrahydrofuran at 20℃; for 4 h;
Example 3; This example describes the transformation of the azide product from example 2 to 2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethanol.; The azido product from example 2 (3.3 g, 15.1 mmol), triphenylphosphine (4.4 g, 16.8 mmol), and water (405 mg, 22.5 mmol) were mixed with 20-mL THF. After the solution was stirred for 4 hrs. at RT, the solvent was eliminated under reduced pressure and the residual product was purified on a silica-gel column that was eluted with CHCl3/CH3OH/Et3N (3:3:1). The desired compound was obtained as colorless oil (2.5 g, 86percent yield): Rf0.4 (CHCl3/CH3OH/Et3N, 3:3:1). Detection of the products on TLC plates was accomplished using a sulfuric acid solution (25.0 mL of conc. sulfuric acid, 12.6 g of ammonium molybdate, 0.57 g of cerium sulfate, and 225.0 mL of deionized water) and/or ninhydrin test solution (a mixture of solution i, ii, and iii: (i) 1 mL of 0.1 M aqueous potassium cyanide diluted to 50 mL with pyridine; (ii) 2.5 g of ninhydrin in 50 mL of ethanol; (iii) 40 g of phenol in 10 mL of ethanol). 1H-NMR (CDCl3) δ3.76-3.51 (m, 14H, CH2OCH2, HOCH2), 2.82 (t, J=4.9 Hz, 2H, CH2N).
79.6%
With water; triphenylphosphine In tetrahydrofuran at 20℃; for 5 h;
[0155] In the above reaction, at RT, compound 36 (278 mg), PPh3 (366 mg), and water (34 mg), were added to 5 mL THF, and stirred for four hours. Then the solvent was removed and the residue was purified by column (CHCl3/MeOH/Et3N 3:3:1). 195 mg of product 37 was obtained as light yellow oil, in a yield of 79.6percent.
8 g
With triphenylphosphine In tetrahydrofuran at 20℃; for 24 h; Cooling with ice
THF (50 mL) was added to N3-EG4-OH (9.2 g, 42.0 mmol). The resulting mixture was placed in an ice-water bath, and added dropwise with THF (75 mL) containing triphenylphosphine (13.21 g, 50.4 mmol, 1.2 eq). The reaction was carried out at room temperature for 24 hours. The resulting mixture was added with water (1965 uL, 109.2 mmol, 2.6 eq), and reacted at room temperature overnight. The resulting mixture was evaporated to remove the solvent, added with water (150 mL), washed with toluene (150 mL) and DCM (100 mL), and evaporated to remove the water phase to give 8 g product.
Reference：
[1] Helvetica Chimica Acta, 1991, vol. 74, # 8, p. 1697 - 1706
[2] Organic Letters, 2009, vol. 11, # 1, p. 193 - 196
[3] Angewandte Chemie - International Edition, 2015, vol. 54, # 35, p. 10327 - 10330[4] Angew. Chem., 2015, vol. 35, # 37, p. 10467 - 10471,5
[5] Chemistry - A European Journal, 2018, vol. 24, # 4, p. 813 - 817
[6] Patent: WO2009/132310, 2009, A1, . Location in patent: Page/Page column 66
[7] Journal of Organic Chemistry, 2001, vol. 66, # 13, p. 4494 - 4503
[8] Angewandte Chemie - International Edition, 2014, vol. 53, # 3, p. 810 - 814[9] Angew. Chem., 2014, vol. 126, # 3, p. 829 - 833,5
[10] Inorganica Chimica Acta, 2011, vol. 365, # 1, p. 38 - 48
[11] Angewandte Chemie - International Edition, 2012, vol. 51, # 9, p. 2151 - 2154
[12] Chemistry - A European Journal, 2012, vol. 18, # 21, p. 6548 - 6554
[13] Tetrahedron, 2007, vol. 63, # 25, p. 5539 - 5547
[14] Nucleosides, Nucleotides and Nucleic Acids, 2011, vol. 30, # 7-8, p. 490 - 502
[15] Chemical Communications, 2016, vol. 52, # 6, p. 1154 - 1157
[16] Patent: WO2017/50979, 2017, A1, . Location in patent: Page/Page column 43; 44
[17] Chemical Communications, 2008, # 24, p. 2809 - 2811
[18] Journal of the American Chemical Society, 2003, vol. 125, # 5, p. 1120 - 1121
[19] Patent: US7238792, 2007, B2, . Location in patent: Page/Page column 17
[20] Chemical Communications, 2009, # 27, p. 4121 - 4123
[21] Chemistry - A European Journal, 2011, vol. 17, # 6, p. 1828 - 1836
[22] Patent: WO2013/109859, 2013, A1, . Location in patent: Paragraph 0155
[23] Tetrahedron Letters, 1983, vol. 24, # 15, p. 1609 - 1610
[24] Journal of the American Chemical Society, 2001, vol. 123, # 31, p. 7560 - 7563
[25] Patent: EP1783137, 2007, A1, . Location in patent: Page/Page column 22
[26] Journal of the American Chemical Society, 2011, vol. 133, # 24, p. 9242 - 9245
[27] Journal of the American Chemical Society, 2011, vol. 133, # 32, p. 12382 - 12385
[28] European Journal of Organic Chemistry, 2013, # 35, p. 7952 - 7959
[29] Patent: WO2017/15693, 2017, A1, . Location in patent: Paragraph 0160
[30] Bioconjugate Chemistry, 2017, vol. 28, # 9, p. 2284 - 2292
[31] Patent: US2018/44280, 2018, A1, . Location in patent: Paragraph 0063; 0098; 0099
Reference：
[1] Journal of the American Chemical Society, 2003, vol. 125, # 5, p. 1120 - 1121
[2] Journal of the American Chemical Society, 2001, vol. 123, # 31, p. 7560 - 7563
[3] Journal of Organic Chemistry, 2001, vol. 66, # 13, p. 4494 - 4503
[4] Helvetica Chimica Acta, 1991, vol. 74, # 8, p. 1697 - 1706
[5] Inorganica Chimica Acta, 2011, vol. 365, # 1, p. 38 - 48
[6] Chemistry - A European Journal, 2011, vol. 17, # 6, p. 1828 - 1836
[7] Journal of the American Chemical Society, 2011, vol. 133, # 24, p. 9242 - 9245
[8] Nucleosides, Nucleotides and Nucleic Acids, 2011, vol. 30, # 7-8, p. 490 - 502
[9] Patent: US2012/4423, 2012, A1,
[10] Angewandte Chemie - International Edition, 2012, vol. 51, # 9, p. 2151 - 2154
[11] Chemistry - A European Journal, 2012, vol. 18, # 21, p. 6548 - 6554
[12] Chemistry - A European Journal, 2012, vol. 18, # 33, p. 10419 - 10426
[13] Organic and Biomolecular Chemistry, 2013, vol. 11, # 1, p. 27 - 30
[14] Patent: WO2013/109859, 2013, A1,
[15] European Journal of Organic Chemistry, 2013, # 35, p. 7952 - 7959
[16] Angewandte Chemie - International Edition, 2014, vol. 53, # 3, p. 810 - 814[17] Angew. Chem., 2014, vol. 126, # 3, p. 829 - 833,5
[18] Macromolecular Bioscience, 2015, vol. 15, # 1, p. 63 - 73
[19] Angewandte Chemie - International Edition, 2015, vol. 54, # 35, p. 10327 - 10330[20] Angew. Chem., 2015, vol. 35, # 37, p. 10467 - 10471,5
[21] Chemical Communications, 2016, vol. 52, # 6, p. 1154 - 1157
[22] Patent: WO2017/15693, 2017, A1,
[23] Patent: WO2017/50979, 2017, A1,
[24] Bioconjugate Chemistry, 2017, vol. 28, # 9, p. 2284 - 2292
[25] Patent: US2018/44280, 2018, A1,
4
[ 77544-60-6 ]
[ 86770-74-3 ]
Reference：
[1] Journal of the American Chemical Society, 2003, vol. 125, # 5, p. 1120 - 1121
[2] Journal of the American Chemical Society, 2001, vol. 123, # 31, p. 7560 - 7563
[3] Patent: US2012/4423, 2012, A1,
[4] Chemistry - A European Journal, 2012, vol. 18, # 33, p. 10419 - 10426
[5] Patent: WO2013/109859, 2013, A1,
[6] European Journal of Organic Chemistry, 2013, # 35, p. 7952 - 7959
[7] Angewandte Chemie - International Edition, 2014, vol. 53, # 3, p. 810 - 814[8] Angew. Chem., 2014, vol. 126, # 3, p. 829 - 833,5
[9] Macromolecular Bioscience, 2015, vol. 15, # 1, p. 63 - 73
[10] Angewandte Chemie - International Edition, 2015, vol. 54, # 35, p. 10327 - 10330[11] Angew. Chem., 2015, vol. 35, # 37, p. 10467 - 10471,5
[12] Chemical Communications, 2016, vol. 52, # 6, p. 1154 - 1157
[13] Patent: WO2017/15693, 2017, A1,
[14] Bioconjugate Chemistry, 2017, vol. 28, # 9, p. 2284 - 2292
5
[ 7732-18-5 ]
[ 86770-67-4 ]
[ 86770-74-3 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2013, vol. 11, # 1, p. 27 - 30
6
[ 86770-67-4 ]
[ 86770-74-3 ]
Reference：
[1] Patent: US4705886, 1987, A,
7
[ 106984-09-2 ]
[ 86770-74-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 2, p. 402 - 406
8
[ 65883-12-7 ]
[ 86770-74-3 ]
Reference：
[1] Journal of Organic Chemistry, 2001, vol. 66, # 13, p. 4494 - 4503
[2] Helvetica Chimica Acta, 1991, vol. 74, # 8, p. 1697 - 1706
[3] Chemistry - A European Journal, 2011, vol. 17, # 6, p. 1828 - 1836
[4] Nucleosides, Nucleotides and Nucleic Acids, 2011, vol. 30, # 7-8, p. 490 - 502
[5] Organic and Biomolecular Chemistry, 2013, vol. 11, # 1, p. 27 - 30
[6] Patent: US2018/44280, 2018, A1,
9
[ 86770-71-0 ]
[ 86770-74-3 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1984, # 9, p. 2672 - 2691
10
[ 86259-87-2 ]
[ 86770-74-3 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1984, # 9, p. 2672 - 2691
11
[ 105891-51-8 ]
[ 86770-74-3 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1984, # 9, p. 2672 - 2691
12
[ 125274-16-0 ]
[ 86770-74-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2018, vol. 61, # 9, p. 4020 - 4029
13
[ 146462-60-4 ]
[ 86770-74-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2018, vol. 61, # 9, p. 4020 - 4029
14
[ 868594-38-1 ]
[ 86770-74-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2018, vol. 61, # 9, p. 4020 - 4029
15
[ 24424-99-5 ]
[ 86770-74-3 ]
[ 106984-09-2 ]
Yield
Reaction Conditions
Operation in experiment
80%
at 20℃; for 2.16667 h;
EXAMPLE 5 Synthesis of 4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3- yl)isoindoline- 1 ,3-dione Step 1: Synthesis of S9 To a round-bottom flask, 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethanol (2.9 g, 15 mmol) was diluted in 10 mL of ethanol. Di-tert-butyl dicarbonate (3.6 g, 16.5 mmol) was dissolved in 10 mL of ethanol and the solution was dropwised within a period of 10 min. The resulting reaction mixture was stirred at room temperature for 2 h. After evaporation of the solvent, the residue was purified by column chromatography with DCM/ MeOH to obtain S9 as colorless oil (3.69 g, 80percent yield). 1H NMR (400 MHz, CDCI3) δ (ppm) 5.49 (s, 1H), 3.46-3.25 (m, 14H), 3.02 (s, 2H), 1.18 (s, 9H); ESI-MS calculated for Ci3H27NNa06 [M+Na]+ = 316.17, obtained: 316.18.
44%
With sodium hydroxide In tetrahydrofuran; water at 20℃; for 16 h;
Into a 100-mL round-bottom flask, was placed a solution of 2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethan-1-ol (3.0 g, 15.52 mmol, 1.00 equiv) in tetrahydrofuran/water (30/30 mL), di-tert-butyl dicarbonate (3.6 g, 16.49 mmol, 1.05 equiv), sodium hydroxide (2.5 g, 62.50 mmol, 4.00 equiv). The resulting solution was stirred for 16 h at room temperature. The resulting solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with brine (20 mL*1), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:1). This resulted in 2.0 g (44percent) of tert-butyl N-(2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl)carbamate as light yellow oil. LC-MS (ES+): m/z 294.05 [MH+], tR=0.93 min, (1.9 minute run).
15%
at 20℃; for 18 h;
To a stirred solution of 87 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethanol (100μL, 0.55mmol) in 88 dioxane (1mL) was added Boc2O (152μL, 0.66mmol). The mixture was stirred for 18hat rt and then evaporated under reduced pressure. The crude was taken up in DCM (6mL), washed with H2O (2×6mL) and brine (1×5mL), dried over MgSO4, filtered and evaporated under reduced pressure. The crude product was purified using flash silica column chromatography (99:1 DCM:MeOH) to yield the desired 89 tert-butyl N-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl)carbamate (24mg, 81.8μmol, 15percent), as a pale yellow oil (Rf 0.52, 9:1 DCM:MeOH). 1H NMR (400MHz, CDCl3) δ 3.75–3.67 (m, 4H, O-CH2), 3.66–3.57 (m, 8H, O-CH2CH2-O), 3.52 (t, J=5.2Hz, 2H, O-CH2), 3.29 (t, J=5.2Hz, 2H, NH-CH2), 1.43 (s, 9H, CH3 t Bu). 13C NMR (101MHz, CDCl3) δ 156.31, 79.19, 72.77, 70.72, 70.67, 70.55, 70.36, 70.20, 61.76, 40.67, 28.56. HRMS-ESI calculated for C13H27NNaO6 [M+Na]+ 316.1731, found m/z 316.1738. A solution of 91 bromine (7.3μL, 0.14mmol) in 67 DCM (0.2mL) at 0°C was added to a solution of 92 triphenylphosphine (37mg, 0.14mmol) and 93 Et3N (20μL, 0.14mmol) in anhydrous DCM (0.2mL) at 0°C. Following stirring at 0°C for 30min, a solution of 89 tert-butyl N-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl)carbamate (42mg, 0.14mmol) in DCM (0.2mL) was added dropwise. After stirring at 0°C for 2h, the mixture was evaporated under reduced pressure. The crude product was purified using flash silica column chromatography (5:1 hexane:EA) to yield the desired 94 tert-butyl N-(2-{2-[2-(2-bromoethoxy)ethoxy]ethoxy}ethyl)carbamate (13mg, 36.5μmol, 26percent) as a colourless oil. 1H NMR (400MHz, CDCl3) δ 5.03 (br s, 1H, NH), 3.81 (t, J=6.3Hz, 2H, O-CH2), 3.73–3.58 (m, 8H, O-CH2CH2-O), 3.54 (t, J=5.1Hz, 2H, O-CH2), 3.47 (tJ=6.3, 1.2Hz, 2H, CH2Br), 3.31 (q, J=5.6Hz, 2H, NH-CH2), 1.44 (s, 9H, CH3 t Bu). HRMS-ESI calculated for C13H26BrNNaO5 [M+Na]+ 378.0887, found m/z 378.0894. To a solution of 9e (13mg, 35.1μmol) in anhydrous DMF (0.7mL) was added NaH (60percent by mass dispersion in mineral oil) (5.5mg, 0.14mmol). After stirring for 30min, a solution of tert-butyl N-(2-{2-[2-(2-bromoethoxy)ethoxy]ethoxy}ethyl)carbamate (12.5mg, 35.1μmol) in anhydrous DMF (0.6mL) was added. The reaction mixture was stirred for 18h, then quenched with H2O (1.5mL), extracted with EA (4×2mL), washed with H2O (2×7mL), dried over MgSO4, filtered and evaporated under reduced pressure. The crude product was purified using flash silica column chromatography (99:1 DCM:MeOH) and semi-preparative RP-HPLC to yield the desired 17 (6.88mg, 10.7μmol, 31percent), as a white solid. 1H NMR (400MHz, DMSO-d6) δ 7.97 (s, 1H, ArH indole), 7.81–7.75 (m, 3H, ArH indole and MeOPh), 7.58 (d, J=9.0Hz, 1H, ArH indole), 7.12–7.05 (m, 2H, ArH MeOPh), 6.95 (dd, J=8.9, 2.5Hz, 1H, ArH indole), 6.74 (br s, 1H, NH), 4.21–4.07 (m, 4H, N1-CH2 & indole-O-CH2), 3.86 (s, 3H, O-CH3), 3.85–3.75 (m, 4H, O-CH2 & O-CH2 THP), 3.65–3.45 (m, 8H, O-CH2CH2-O), 3.37 (t, J=6.1Hz, 2H, O-CH2), 3.19 (td, J=11.7, 2.0Hz, 2H, O-CH2 THP), 3.05 (q, J=6.0Hz, 2H, NH-CH2), 2.13–2.02 (m, 1H, CH THP), 1.41–1.21 (m, 13H, O-CH2CH2 THP, CH3 t Bu). HRMS-ESI calculated for C35H48N2NaO9 [M+Na]+ 663.3252, found m/z 663.3247. Analytical RP-HPLC Rt=21.00min.
Reference：
[1] Helvetica Chimica Acta, 1991, vol. 74, # 8, p. 1697 - 1706
[2] Angewandte Chemie - International Edition, 2013, vol. 52, # 40, p. 10593 - 10597[3] Angew. Chem., 2013, vol. 125, # 40, p. 10787 - 10791
[4] Inorganica Chimica Acta, 2011, vol. 365, # 1, p. 38 - 48
[5] Patent: WO2017/176958, 2017, A1, . Location in patent: Paragraph 0859-0860
[6] Angewandte Chemie - International Edition, 2015, vol. 54, # 35, p. 10327 - 10330[7] Angew. Chem., 2015, vol. 35, # 37, p. 10467 - 10471,5
[8] Patent: US2017/8904, 2017, A1, . Location in patent: Paragraph 0376; 0383
[9] European Journal of Medicinal Chemistry, 2018, vol. 145, p. 770 - 789
[10] Patent: US4705886, 1987, A,
[11] Journal of the American Chemical Society, 2011, vol. 133, # 24, p. 9242 - 9245
[12] Patent: WO2015/38938, 2015, A1, . Location in patent: Paragraph 0466; 0468
[13] Patent: WO2016/149501, 2016, A2, . Location in patent: Paragraph 0314
EXAMPLE 5 Synthesis of 4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3- yl)isoindoline- 1 ,3-dione Step 1: Synthesis of S9 To a round-bottom flask, 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethanol (2.9 g, 15 mmol) was diluted in 10 mL of ethanol. Di-tert-butyl dicarbonate (3.6 g, 16.5 mmol) was dissolved in 10 mL of ethanol and the solution was dropwised within a period of 10 min. The resulting reaction mixture was stirred at room temperature for 2 h. After evaporation of the solvent, the residue was purified by column chromatography with DCM/ MeOH to obtain S9 as colorless oil (3.69 g, 80% yield). 1H NMR (400 MHz, CDCI3) delta (ppm) 5.49 (s, 1H), 3.46-3.25 (m, 14H), 3.02 (s, 2H), 1.18 (s, 9H); ESI-MS calculated for Ci3H27NNa06 [M+Na]+ = 316.17, obtained: 316.18.
79%
With potassium hydroxide; In 1,4-dioxane; at 10 - 20℃; for 16h;
To a stirred solution of 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethan-1-ol (1.0 g, 5.2 mmol, CAS86770-74-3) and KOH (0.32 g, 5.6 mmol) in 1,4 dioxane (4 mL) and water (8 mL) was added Boc-anhydride (1.24 g, 5.6 mmol) dropwise at 10 C. The resulting reaction mixture was allowed to warm to rt and stirred for 16 h. The reaction mixture was transferred into ice water and the resulting mixture was extracted using ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to afford crude product. The crude product was purified using silica gel column chromatography (8% MeOH-DCM) to give tert-butyl (2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate as a colorless oil (1.2 g, 79%). LC-MS (ESI+) m/z 293.13 (M+H)+.
44%
With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 16h;
Into a 100-mL round-bottom flask, was placed a solution of 2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethan-1-ol (3.0 g, 15.52 mmol, 1.00 equiv) in tetrahydrofuran/water (30/30 mL), di-tert-butyl dicarbonate (3.6 g, 16.49 mmol, 1.05 equiv), sodium hydroxide (2.5 g, 62.50 mmol, 4.00 equiv). The resulting solution was stirred for 16 h at room temperature. The resulting solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with brine (20 mL*1), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:1). This resulted in 2.0 g (44%) of tert-butyl N-(2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl)carbamate as light yellow oil. LC-MS (ES+): m/z 294.05 [MH+], tR=0.93 min, (1.9 minute run).
15%
In 1,4-dioxane; at 20℃; under 760.051 Torr; for 18h;
To a stirred solution of 87 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethanol (100muL, 0.55mmol) in 88 dioxane (1mL) was added Boc2O (152muL, 0.66mmol). The mixture was stirred for 18hat rt and then evaporated under reduced pressure. The crude was taken up in DCM (6mL), washed with H2O (2×6mL) and brine (1×5mL), dried over MgSO4, filtered and evaporated under reduced pressure. The crude product was purified using flash silica column chromatography (99:1 DCM:MeOH) to yield the desired 89 tert-butyl N-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl)carbamate (24mg, 81.8mumol, 15%), as a pale yellow oil (Rf 0.52, 9:1 DCM:MeOH). 1H NMR (400MHz, CDCl3) delta 3.75-3.67 (m, 4H, O-CH2), 3.66-3.57 (m, 8H, O-CH2CH2-O), 3.52 (t, J=5.2Hz, 2H, O-CH2), 3.29 (t, J=5.2Hz, 2H, NH-CH2), 1.43 (s, 9H, CH3 t Bu). 13C NMR (101MHz, CDCl3) delta 156.31, 79.19, 72.77, 70.72, 70.67, 70.55, 70.36, 70.20, 61.76, 40.67, 28.56. HRMS-ESI calculated for C13H27NNaO6 [M+Na]+ 316.1731, found m/z 316.1738. A solution of 91 bromine (7.3muL, 0.14mmol) in 67 DCM (0.2mL) at 0C was added to a solution of 92 triphenylphosphine (37mg, 0.14mmol) and 93 Et3N (20muL, 0.14mmol) in anhydrous DCM (0.2mL) at 0C. Following stirring at 0C for 30min, a solution of 89 tert-butyl N-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl)carbamate (42mg, 0.14mmol) in DCM (0.2mL) was added dropwise. After stirring at 0C for 2h, the mixture was evaporated under reduced pressure. The crude product was purified using flash silica column chromatography (5:1 hexane:EA) to yield the desired 94 tert-butyl N-(2-{2-[2-(2-bromoethoxy)ethoxy]ethoxy}ethyl)carbamate (13mg, 36.5mumol, 26%) as a colourless oil. 1H NMR (400MHz, CDCl3) delta 5.03 (br s, 1H, NH), 3.81 (t, J=6.3Hz, 2H, O-CH2), 3.73-3.58 (m, 8H, O-CH2CH2-O), 3.54 (t, J=5.1Hz, 2H, O-CH2), 3.47 (tJ=6.3, 1.2Hz, 2H, CH2Br), 3.31 (q, J=5.6Hz, 2H, NH-CH2), 1.44 (s, 9H, CH3 t Bu). HRMS-ESI calculated for C13H26BrNNaO5 [M+Na]+ 378.0887, found m/z 378.0894. To a solution of 9e (13mg, 35.1mumol) in anhydrous DMF (0.7mL) was added NaH (60% by mass dispersion in mineral oil) (5.5mg, 0.14mmol). After stirring for 30min, a solution of tert-butyl N-(2-{2-[2-(2-bromoethoxy)ethoxy]ethoxy}ethyl)carbamate (12.5mg, 35.1mumol) in anhydrous DMF (0.6mL) was added. The reaction mixture was stirred for 18h, then quenched with H2O (1.5mL), extracted with EA (4×2mL), washed with H2O (2×7mL), dried over MgSO4, filtered and evaporated under reduced pressure. The crude product was purified using flash silica column chromatography (99:1 DCM:MeOH) and semi-preparative RP-HPLC to yield the desired 17 (6.88mg, 10.7mumol, 31%), as a white solid. 1H NMR (400MHz, DMSO-d6) delta 7.97 (s, 1H, ArH indole), 7.81-7.75 (m, 3H, ArH indole and MeOPh), 7.58 (d, J=9.0Hz, 1H, ArH indole), 7.12-7.05 (m, 2H, ArH MeOPh), 6.95 (dd, J=8.9, 2.5Hz, 1H, ArH indole), 6.74 (br s, 1H, NH), 4.21-4.07 (m, 4H, N1-CH2 & indole-O-CH2), 3.86 (s, 3H, O-CH3), 3.85-3.75 (m, 4H, O-CH2 & O-CH2 THP), 3.65-3.45 (m, 8H, O-CH2CH2-O), 3.37 (t, J=6.1Hz, 2H, O-CH2), 3.19 (td, J=11.7, 2.0Hz, 2H, O-CH2 THP), 3.05 (q, J=6.0Hz, 2H, NH-CH2), 2.13-2.02 (m, 1H, CH THP), 1.41-1.21 (m, 13H, O-CH2CH2 THP, CH3 t Bu). HRMS-ESI calculated for C35H48N2NaO9 [M+Na]+ 663.3252, found m/z 663.3247. Analytical RP-HPLC Rt=21.00min.
With triethylamine; In tetrahydrofuran; methanol; chloroform;
D. Synthesis of 11-tert-Butyloxycarbonylamino-3,6,9-trioxaundecanol (Compound XXVII) To a suspension of Compound XXVI (12 g; 62.1 mmole) in 100 ml of dry tetrahydrofuran was added di-tert-butyl dicarbonate (15 g; 68.7 mmole). Much gas was generated. Triethylamine (10 ml; 7.26 g; 71.3 mmole) was added and the mixture stirred at room temperature. When gas evolution ceased, the solution was diluted with methanol and 20 g of silica gel was added. The solvents were removed under reduced pressure and the residue was fractionated on a column of silica gel using 8:1 chloroform:methanol as eluant. Fractions containing the product were pooled and concentrated to a syrup. Correct elemental analyses were obtained for carbon, hydrogen and nitrogen.
With sodium hydroxide; In water; acetonitrile; at 20℃; for 0.75h;
A solution of 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethanol (400 mg, 2.07 mmol, 0.33 mL) in 15 mL of acetonitrile/water (6:1) was treated with di-tert-butyl dicarbonate (603 mg, 2.77 mmol), followed by 2.8 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 the crude carbamate as a colorless oil.
With sodium hydroxide; In water; acetonitrile; at 20℃; for 0.75h;
A solution of 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethanol (400 mg, 2.07 mmol, 0.33 mL) in 15 mL of acetonitrile/water (6:1) was treated with di-tert-butyl dicarbonate (603 mg, 2.77 mmol), followed by 2.8 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 the crude carbamate as a colorless oil.
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 (7.0 ml_) and stirred 12 h under H2 (1 atm). The suspension was filtered over celite and the filtrate was concentrated to afford the amine (0.520 g, 2.7 mmol) in quantitative yields (Xie, H. Z.; Braha, O.; Gu, L. Q.; Cheley, S.; Bayley, H. Chem. Biol. 2005, 12, 109-120.)
100%
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 16h;
(70.0 g, 318 mmol) was stirred in MeOH at RT. The reaction was hydrogenated over 10% PD-C (7 g) for 16 h. The reaction was filtered through celite and concentrated in-vacuo to give 2-(2-(2-(2- aminoethoxy)ethoxy)ethoxy)ethan-1-ol (625) (61.4 g, 100%) which was used without further purification. Product confirmed by MS (ESI +ve).
100%
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 16h;
2-(2-(2-(2-Azidoethoxy)ethoxy)ethoxy)ethan-1-ol (13) (70.0 g, 318 mmol) was stirred in MeOH at RT. The reaction was hydrogenated over 10% PD-C (7 g) for 16 h. The reaction was filtered through celite and concentrated in-vacuo to give 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethan- 1-ol (25) (61.4 g, 100%) which was used without further purification. Product confirmed by MS (ESI +ve)
90%
With palladium 10% on activated carbon; hydrogen; In dichloromethane; under 3040.2 Torr; for 24h;
To the alcohol 11-azido-3,6,9-trioxaundecan-1-ol, 2 (1.00 g, 4.56 mmol)dissolved in 0H2012 (8 mL), catalytic amount of 10% Palladium on carbon(Pd/C) was added, and the reaction was stirred under H2 pressure (4 atm) during 24 hours. The solution was filtered through a short pad of celite and the solvent was evaporated. The amino derivative was isolated by flash column chromatography, eluting with a mixture CH2CI2/ MeOH (9:1), to give 4(790mg, 90%) as a yellow-coloured syrup. 1H NMR (400 MHz): 6 3.70 (t, 2H, J =4.8 Hz, HOCH2CH2), 3.65-3.60 (m, 1OH, 5CH20), 3.56 (t, 2H, J = 4.8 Hz, OCH2CH2N), 3.50 (t, 2H, J = 4.8 Hz, CH2NH2), 2.83 (5, 2H, NH2), 2.27 (5, 1 H, OH) ppm. 130 NMR (100 MHz): 673.0 (NCH2C), 70.6, 70.3, 70.2, 69.9, 61.5 (COH), 41.5 (ON) ppm. HRMS calcd. for O8H2oNO4[M+H]: 194.1398; found194.1392.
86%
With water; triphenylphosphine; In tetrahydrofuran; at 20℃; for 4h;
Example 3; This example describes the transformation of the azide product from example 2 to 2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethanol.; The azido product from example 2 (3.3 g, 15.1 mmol), triphenylphosphine (4.4 g, 16.8 mmol), and water (405 mg, 22.5 mmol) were mixed with 20-mL THF. After the solution was stirred for 4 hrs. at RT, the solvent was eliminated under reduced pressure and the residual product was purified on a silica-gel column that was eluted with CHCl3/CH3OH/Et3N (3:3:1). The desired compound was obtained as colorless oil (2.5 g, 86% yield): Rf0.4 (CHCl3/CH3OH/Et3N, 3:3:1). Detection of the products on TLC plates was accomplished using a sulfuric acid solution (25.0 mL of conc. sulfuric acid, 12.6 g of ammonium molybdate, 0.57 g of cerium sulfate, and 225.0 mL of deionized water) and/or ninhydrin test solution (a mixture of solution i, ii, and iii: (i) 1 mL of 0.1 M aqueous potassium cyanide diluted to 50 mL with pyridine; (ii) 2.5 g of ninhydrin in 50 mL of ethanol; (iii) 40 g of phenol in 10 mL of ethanol). 1H-NMR (CDCl3) delta3.76-3.51 (m, 14H, CH2OCH2, HOCH2), 2.82 (t, J=4.9 Hz, 2H, CH2N).
81%
With triphenylphosphine; In tetrahydrofuran; at 25℃; for 12h;
To a solution of G10-2 (2.2 g, 10.03 mmol, 1.00 equiv.) in tetrahydrofuran (20 mL) was added triphenylphosphine (2.88 g, 10.98 mmol, 1.10 equiv.). The resulting solution was stirred for 12 h at 25C. The resulting solution was diluted with 50 mL of water and washed with 3x50 mL of toluene. The aqueous was concentrated under vacuum. This resulted in 1.7 g (81%) of G10-3 as light yellow oil.
79.6%
With water; triphenylphosphine; In tetrahydrofuran; at 20℃; for 5h;
[0155] In the above reaction, at RT, compound 36 (278 mg), PPh3 (366 mg), and water (34 mg), were added to 5 mL THF, and stirred for four hours. Then the solvent was removed and the residue was purified by column (CHCl3/MeOH/Et3N 3:3:1). 195 mg of product 37 was obtained as light yellow oil, in a yield of 79.6%.
77%
With palladium 10% on activated carbon; hydrogen; In methanol;
General procedure: A methanol mixture of compound 10 (5 mmol) and 10% Pd/C (0.1 eq) was stirred overnight under H 2 atmosphere.The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain Compound 11.
Step 3. Synthesis of 11-amino-3,6,9-trioxaundecanol 3 g of 11-azide-3, 6, 9-trioxaundecanol obtained in the above step 2 was dissolved in 35 mL of tetrahydrofuran, and then 3.95 mg of triphenyl phosphine was added. After stirring at room temperature for 18 hours, 10 mL of water was added, and then the solution was further stirred overnight. The reaction solution was separated with toluene and water, and then the aqueous layer was lyophilized to obtain 2.4 g of the objective compound.
With palladium 10% on activated carbon; hydrogen; In methanol; for 6h;
Palladium on carbon (10%, 0.1 g) was added to a solution of 2-[2-[2-(2- azidoethoxy)ethoxy]ethoxy] ethanol (600 mg, 2.7 mmol) in methanol (20 ml). The flask was repeatedly evacuated and then filled with hydrogen gas three times, then the mixture was stirred under a hydrogen atmosphere for 6 h. The mixture was then filtered through a pad of celite, and the celite washed with methanol (2 x 50 ml). The filtrates were combined and the solvent removed under reduced pressure to give 2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy] ethanol (6) (495 mg, 95%) as a colourless oil which was used without further purification. 1H NMR (400 MHz, CDCI3) delta 2.77 (t, J = 5 Hz, 2H), 3.49-3.74 (m, 14H) - OH not observed; 13C NMR (100 MHz, CDCIs) delta 48.94, 61.41 , 70.01 , 70.17, 70.20, 70.41 , 70.51 , 72.91 ; ESI-MS (positive mode) m/z = 194 ([MH]+, 100 %); calculated for C8H19N04: 194.1
8 g
With triphenylphosphine; In tetrahydrofuran; at 20℃; for 24h;Cooling with ice;
THF (50 mL) was added to N3-EG4-OH (9.2 g, 42.0 mmol). The resulting mixture was placed in an ice-water bath, and added dropwise with THF (75 mL) containing triphenylphosphine (13.21 g, 50.4 mmol, 1.2 eq). The reaction was carried out at room temperature for 24 hours. The resulting mixture was added with water (1965 uL, 109.2 mmol, 2.6 eq), and reacted at room temperature overnight. The resulting mixture was evaporated to remove the solvent, added with water (150 mL), washed with toluene (150 mL) and DCM (100 mL), and evaporated to remove the water phase to give 8 g product.
With triethylamine; In dimethyl sulfoxide; at 150℃; for 4h;Product distribution / selectivity;
Example 4 This example describes two methods for the preparation of bis-N,N'-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)perylenetetracarboxylic diimide. Method A: 2-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]ethanol (2.6 g, 13.5 mmol), perylenetetracarboxylic dianhydride (2.2 g, 5.6 mmol), and triethylamine (25 mL, 180 mmol) were mixed with 50 mL of dry DMSO (4A activated MS, 3 days) in a 250-mL flask under argon. After the reaction mixture was stirred for 4 h at 150 C., the reaction solution was cooled to 80 C. and transferred to a 1000-mL flask. A mixture of 600 mL 10% aqueous HCl and 300 mL methanol was added to the reaction solution, then the solution was stirred for additional 2 hours at 60 C. After the mixture was cooled to RT overnight, the precipitate was collected using paper filter. The resulting collection was washed with 400 mL water, and the water layer was re-extracted with 50 mL chloroform. The filtrate could be extracted with chloroform to gain more products, but these products were contaminated and needed column purification. The combined organic layer was concentrated to give the crude title product; further purification was carried out on a silica-gel column eluted with CH2Cl2/CH3OH (5:1). Detection of the products on TLC plates was accomplished using UV light or sulfuiric acid solution (5% conc. sulfuric acid in EtOH). The title compound was obtained as dark-red solid (3.6 g, 86% yield): Rf0.4 (CH2Cl2/CH3OH, 10:1). 1H-NMR (60-70 mg/0.5 ml; CDCl3/CD3OD/100/5) delta7.96 (d, 4H, J=8.1 Hz, aromatic ring), 7.61 (d, 4H, J=8.1 Hz, aromatic ring), 4.32 (t, 4H, J=5.7 Hz, CH2N), 3.65-3.29 (m, 28H, CH2OCH2, HOCH2); 13C-NMR (60-70 mg/0.5 ml; CDCl3/CD3OD/100/5) delta162.7, 133.1, 130.4, 128.1, 124.7, 122.5, 122.4, 72.9, 70.79, 70.76, 70.4, 70.2, 68.0, 61.6, 39.5. 1H-NMR (DMSO-d6) delta7.13 (bd, 4H, aromatic ring), 6.92 (bd, 4H, aromatic ring), 4.59 (t, 4H, J=5.7 Hz, CH2N), 3.65-3.29 (m, 28H, CH2OCH2, HOCH2); 13C-NMR (DMSO-d6) delta161.2, 131.4, 128.8, 125.9, 122.6, 120.2, 72.3, 69.8, 69.7, 69.6, 66.5, 60.2, 45.67. MS (MALDI): m/z 765.82 [M+Na]+. Anal. Calcd. for C40H42N2O12 (742.77): C, 64.68; H, 5.70; N, 3.77. Found: C, 64.24; H, 5.52; N, 3.83.
(9H-fluoren-9-yl)methyl (2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With triethylamine; In dichloromethane; at 20℃; for 0.166667h;
Step A: (9H-fluoren-9-yl)methyl (2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate (11- 1) To a stirred solution of 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethanol (1.00 g, 5.17 mmol) in DCM (15 mL) was added 9-fluorenylmethyl chloroformate (1.34 g, 5.17 mmol) and triethylamine ( 1.08 mL, 7.76 mmol). The resulting solution was stirred at room temperature for 10 minutes. The reaction was concentrated onto silica gel and flash column separation using a 0-10% isopropanol/ dichloromethane gradient gave 11-1 as an oil (1.43 g, 66%) LRMS (ES) (M+H)+ : observed = 416.1, calculated = 415.4.
With triethanolamine; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran;
Part A Preparation of 11-Benzyloxycarbonylamino-3,6,9-trioxaundecanol A solution of <strong>[86770-74-3]11-amino-3,6,9-trioxaundecanol</strong> (6.56 g, 0.034 mol) and TEA (5.2 mL, 0.037 mol) in DCM (200 mL) was treated with benzyl chloroformate (5.1 mL, 0.036 mol) in one portion. After 18 h the solution was concentrated to a viscous oil and triturated with ether (3*100 mL). The combined triturants were concentrated to give an amber oil (9.4 g). Flash chromatoraphy on silica gel (6% MeOH/EtOAc) gave the title compound as a colorless viscous oil (7.0 g, 63%). 1H NMR (CDCl3): 7.36-7.25 (m, 5H), 6.04 (bs, 1H), 5.08 (s, 2H), 3.72-3.48 (m, 14H), 3.41-3.31 (m, 2H).
63%
With triethanolamine; In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran;
Part A Preparation of 11-Benzyloxycarbonylamino-3,6,9-trioxaundecanol A solution of <strong>[86770-74-3]11-amino-3,6,9-trioxaundecanol</strong> (6.56 g, 0.034 mol) and TEA (5.2 mL, 0.037 mol) in DCM (200 mL) was treated with benzyl chloroformate (5.1 mL, 0.036 mol) in one portion. After 18 h the solution was concentrated to a viscous oil and triturated with ether (3 x 100 mL). The combined triturants were concentrated to give an amber oil (9.4 g). Flash chromatoraphy on silica gel (6% MeOH/EtOAc) gave the title compound as a colorless viscous oil (7.0 g, 63%). 1H NMR (CDCl3): 7.36-7.25 (m, 5H), 6.04 (bs, 1H), 5.08 (s, 2H), 3.72-3.48 (m, 14H), 3.41-3.31 (m, 2H).
55%
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)).
22.7%
With sodium carbonate; In tetrahydrofuran; water; at 5 - 20℃; for 16h;
(61.4 g, 318 mmol) was stirred in H2O (500 ml) with Na2CO3 (50.51 g, 476 mmol) at 5C. Benzyl chloroformate (626) (65.0 g, 381 mmol) in THF (480 ml) was added dropwise and the reaction stirred for 16 h allowing to warm to RT. THF was removed in-vacuo and the aqueous layer extracted with EtOAc (× 3). The combined organics were dried (Na2SO4), concentrated in-vacuo and the residue purified by automated flash chromatography (5% MeOH/DCM) to give benzyl (2-(2-(2-(2- hydroxyethoxy)ethoxy)ethoxy) ethyl)carbamate (627) (23.6 g, 22.7%). Product confirmed by MS (ESI +ve).
22.7%
With sodium carbonate; In tetrahydrofuran; water; at 5 - 20℃; for 16h;
2-(2-(2-(2-Aminoethoxy)ethoxy)ethoxy)ethan-1-ol (25) (61.4 g, 318 mmol) was stirred in H2O (500 ml) with Na2CO3 (50.51 g, 476 mmol) at 5C. Benzyl chloroformate (26) (65.0 g, 381 mmol) in THF (480 ml) was added dropwise and the reaction stirred for 16 h allowing to warm to RT. THF was removed in-vacuo and the aqueous layer extracted with EtOAc (× 3). The combined organics were dried (Na2SO4), concentrated in-vacuo and the residue purified by automated flash chromatography (5% MeOH/DCM) to give benzyl (2-(2-(2-(2- hydroxyethoxy)ethoxy)ethoxy) ethyl)carbamate (27) (23.6 g, 22.7%). Product confirmed by MS (ESI +ve).
L-α-dioleoylphosphatidyl(11-amino-3,6,9-trioxa)undecanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium acetate; calcium chloride;phospholipase D; In dichloromethane; water; at 30℃;pH 6.5;Enzymatic reaction;
Step 4. Synthesis of L-alpha-dioleoylphosphatidyl(11-amino-3,6,9-trioxa)undecanol 25 mL of dichloromethane, 3.5 mL of a buffer solution [sodium acetate (100 mM) - calcium chloride (50 mM) buffer solution (pH 6.5)] and 500 Unit of phospholipase D were added to 1 g of L-alpha-dioleoylphosphatidylcholine and 1.5 g of 11-amino-3, 6, 9-trioxaundecanol obtained in the above step 3, and then the solution was stirred overnight at 30 C. After concentrating the dichloromethane layer, the residue was purified with silica gel column chromatography to obtain 1.12 g of the objective compound.
v. 17-hydroxy-3,9,12,15-tetraoxa-6-aza-5-oxo-heptadecanoic acid (6) The amine 5 was mixed with dichloromethane and some DMF as co-solvent. 1.5 mole eqv. diglycolic anhydride wad added and the mixture heated to 40C. for a couple of hours. After cooling to room temperature and stirring over weekend the reaction mixture was evaporated under reduced pressure. The residue was mixed with water and pH adjusted to pH between 11-12 with 1N NaOH(aq) for hydrolysis of the ester. The solution was allowed to stir over night and was thereafter acidified with HCl to pH 1-2 and evaporated under reduced pressure. LC-MS of the residue showed a major peak with the expected masses M+H+ 310.15 and M+Na+ 332.13
100 mg of compound 4 was dissolved in methanol and hydrazine monohydrate added. The mixture was heated to 50 0C for 3 hours, cooled to room temperature and stirred at room temperature over night.MS confirmed desired product (M+H+ 194.1).
With hydrazine hydrate; In methanol; at 20 - 50℃;
iv. 11-amino-3,6,9-trioxa-hydroxy-undecane 100 mg of compound 4 was dissolved in methanol and hydrazine monohydrate added. The mixture was heated to 50C. for 3 hours, cooled to room temperature and stirred at room temperature over night. MS confirmed desired product (M+H+ 194.1).
4-[(2R,3S,4R,5S)-4-(4-chloro-2-fluorophenyl)-3-(3-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carbonyl]amino}-3-methoxybenzoic acid carboxymethyl ester[ No CAS ]
[ 86770-74-3 ]
4-[(2R,3S,4R,5S)-4-(4-chloro-2-fluorophenyl)-3-(3-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carbonyl]amino}-3-methoxybenzoic acid (2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethylcarbamoyl)methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%
In a 20 mL round-bottomed flask, 2-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)-acetic acid (Example 69, 150 mg, 152 muL, 222 mumol), HATU (84.6 mg, 222 mumol) and Hunig's base (86.2 mg, 117 muL, 667 mumol) were combined with dry tetrahydrofuran (2 mL) to give an off-white suspension at room temperature. It was stirred for 30 min and the solution became clear. 2-(2-(2-(2-Aminoethoxy)ethoxy)ethoxy)ethanol (43.0 mg, 222 mumol) was added. After stirring at room temperature overnight, the reaction mixture was concentrated. The residue was reconstituted with ethyl acetate. It was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was absorbed on small amount of silica gel and loaded on a 24 g pre-packed silica gel column. Eluting the column with 0-10% methanol in ethyl acetate over 20 min gave 4-[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid (2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethylcarbamoyl)methyl ester as an off-white solid (20 mg, 10% yield). LCMS (ES+) m/z calcd. for C41H48Cl2F2N4O9[(M+H)+]: 849. found: 849
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;
Example 28 Synthesis of Compound 122 To the solution of intermediate carbonate 1B obtained in Example 11 (5.04 mumol, 5 mg) in DCM (7.77 mmol, 0.5 mL) was added <strong>[86770-74-3]2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethan-1-ol</strong> (0.050 mmol, 9.75 mg) and Hunig's base (0.050 mmol, 8.81 muL). The reaction mixture was stirred overnight at rt and the volatiles were removed. The crude material was purified by RP-column chromatography to afford Compound 122 (3.1 mg, 58.8%) as a white solid. Observed ESI HRMS: m/z 1045.6173 [M+H]+. The 1H NMR spectrum of Compound 122 is shown in FIG. 44.
To a solution of 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethanol (256 mg, 1.32 mmol) in DCM (30 mL) were added BCN-OSu (351 mg, 1.20 mmol) and Et3N (502 muIota_, 364 mg, 3.60 mmol). The resulting solution was stirred for 30 min and washed with a saturated aqueous solution of NH4CI. After separation, the aqueous phase was extracted with DCM (30 mL). The combined organic phases were dried (Na2S04) and concentrated. The residue was purified with column chromatography (MeOH in DCM 0? 10%). The product was obtained as a colourless oil (397 mg, 1.07 mmol, 90%). H NMR (400 MHz, CDCI3) delta (ppm) 5.93 (bs, 1 H), 4.14 (d, J = 8.1 Hz, 2H), 3.77-3.69 (m, 4H), 3.68-3.59 (m, 8H), 3.58-3.52 (m, 2H), 3.42-3.32 (m, 2H), 2.34-2.16 (m, 6H), 1.66-1.51 (m, 2H), 1 .36 (quintet, J = 8.7 Hz, 1 H), 1.00-0.85 (m, 2H).
67%
With triethylamine; for 1.33333h;
To a solution of 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethanol (0.50 g, 2.6 mmol) was added BCN-OSu (29-1 , 0.69 g, 2.3 mmol) and Et3N (0.97 ml_, 0.70 g, 7.0 mmol). The resulting mixture was mixture was stirred for 80 min and saturated aqueous NH4CI (60 ml_) was added. After separation, the aqueous phase was extracted with DCM (60 ml_). The combined organic layers were dried (Na2SC>4) and concentrated. The residue was purified with silica gel chromatography (DCM 10% MeOH in DCM), which yielded 578 mg (1.56 mmol, 67%) of the desired product. 1 H NMR (400 MHz, CDCIs) d (ppm) 5.98-5.85 (bs, 1 H), 4.14 (d, J = 8.0 Hz, 2H), 3.78-3.59 (m, 12H), 3.58-3.52 (m, 2H), 3.42-3.32 (m, 2H), 3.19-3.06 (bs, 1 H), 2.35-2.16 (m, 6H), 1 .70-1.50 (m, 2H), 1.36 (quintet, J = 8.6 Hz, 1 H), 0.99-0.87 (m, 2H).
With triethylamine; In acetonitrile; for 1h;
To 300 mg of BCN-NHS (1.03 mmol) 10 ml of acetonitrile were added followed by addition of 1.0 ml triethylamine. To reaction solution first 0.3 ml of OHPEG 4-NH2 was added and reaction was stirred for half hour before it was tested byTLC reaction was not complete. Then additional 0.2 ml of OH-PEG4-NH2 were added to total 0.5 ml of OH-PEG4-NH2 (2.83 mmol) and reaction was stirred for half hour till completion as was observed by TLC (TLC mobile phase: 90% Chloroform, 10% Methanol; Staining PMA). Reaction solution was evaporated under reduced pressure to dryness by rotovapor followed by purification by silica column. The reactionsolution was eluted with 5% MeOH: 95% dichloromethane. The pure fractions were evaporated to dryness by rotovapor. The obtained product - 200 mg (53%) was tested by TLC. According to TLC the purity was about 90% therefore the product was used as is the next step/steps.
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; at 20℃; for 5h;
To a solution of 1-7 and HATU (147 mg) in DMF (1 mL) was added dropwise DIEA (135 muL) and tetraethylene glycol monoamine (45 muL). After stirring at room temperature for 5 h, the reaction was quenched by 10% aqueous citric acid, and the reaction mixture was extracted with EtOAc. The organic phase was washed with 1N HCl, brine, and saturated NaHC03. After drying over MgSO4 and filtration, solvent was removed with a rotary evaporator, and the mixture was purified by silica gel chromatography (DCM: MeOH=30: 1) to afford 1-27 in 70% yield. Q-TOF LC/MS m/z 609.3797 [M+H]+ (calcd. 608.37 for C32H52N2O9 [M]+); 1HNMR (400 MHz, CDCl3) delta -0.45 (1H, m), 0.685 (1H, m), 0.825 (6H, m), 1.13 (9H, s), 1.27-1.64 (6H, m), 1.94 (1H, m), 2.05 (1H, m), 2.64 (2H, m), 3.38-3.91 (16H, m), 4.07 (1H, t, J=8 and 12 Hz ), 4.25 (1H, m), 4.99 (1H, m), 6.35-7.06 (4H, aromatic H); 13C NMR (100 MHz, CDC13) delta 21.45, 24.12, 25.92, 28.20, 30.00, 31.10, 38.40, 39.51, 40.65, 49.28, 50.18, 52.77, 61.65, 69.98, 70.22, 70.60, 70.90, 72.60, 73.92, 80.30, 120.40, 123.35, 129.95, 132.23, 132.46, 159.12, 171.62, 173.23, 174.34.
2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione[ No CAS ]
[ 86770-74-3 ]
2-(2,6-dioxopiperidin-3-yl)-4-((2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃;
To a solution of <strong>[86770-74-3]2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethan-1-ol</strong> (244 mg, 1.64 mmol) in DMF (5 mL) was added DIEA (0.28 mL, 2.18 mmol). After stirring at 80 C for overnight, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (DCM : MeOH = 100 : 0 to 80 : 20) to afford 2-37 (284 mg, 58 %) as a dark green liquid.
40%
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 triethylamine; In N,N-dimethyl-formamide; at 90℃;
General procedure: Compound 17 (2 mmol) was dissolved in DMF (10 mL), and compound 11 (3 mmol) and triethylamine (202 mg, 2 mmol) were added. The mixture was stirred at 90C overnight.Concentrated to remove DMF, the residue was redissolved in ethyl acetate and washed with saturated brine.The organic layer was concentrated and purified by column chromatography (DCM/MeOH=100:1) to obtain compound 18.Then, in the presence of DIPEA, compound 18 was treated with an excess of tosyl chloride in dichloromethane.After stirring overnight at room temperature, the mixture was washed with 1M HCl, saturated sodium bicarbonate and saturated brine, respectively.The solvent was concentrated to obtain compound 19.
1-((2,4-dinitrophenyl)amino)-13-oxo-3,6,9-trioxa-12-azahexadecan-16-oic acid[ No CAS ]
[ 86770-74-3 ]
N1-(2-(2-(2-(2-((2,4-dinitrophenyl)amino)ethoxy)ethoxy)ethoxy)ethyl)-N4-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)succinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33.7%
The a solution of l-((2,4-dinitrophenyl)amino)-13-oxo-3,6,9-trioxa-12-azahexadecan-16-oic acid (980 mg, 2.138 mmol) in N,N-dimethylformamide (DMF) (20.00 mL), was added HATU (1.301 g, 3.42 mmol) followed by DIPEA (2.383 mL, 13.68 mmol), and the resulting mixture was stirred at rt for 5 min before 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethanol (454 mg, 2.352 mmol) was added and the mixture was stirred for 16 h. After this period, water (0.5 mL) was added and the mixture was concentrated in vacuo (30 C, 0-1 mbar vacuum). The evaporation residue was taken up in DCM and washed consecutively with aq. NaH2P04, water, and sat. aq. NaHCC . The organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The evaporation residue was subjected to normal phase purification on a Biotage Ultra SNAP 100 g Si02 column (2-15% MeOH/DCM) to afford Nl -(2-(2-(2-(2-((2,4-dinitrophenyl)amino)ethoxy)ethoxy)ethoxy)ethyl)-N4-(2-(2-(2-(2- hydroxyethoxy)ethoxy)ethoxy)ethyl)succinamide (456 mg, 0.720 mmol, 33.7 % yield) as a viscous bright yellow oil.1H NMR (400 MHz, CHLOROFORM-i/)? ppm 9.09 (d, .7=2.69 Hz, 1 H), 8.79 (br. s., 1 H), 8.24 (dd, .7=9.54, 2.20 Hz, 1 H), 7.24 (br. t, .7=4.80, 4.80 Hz, 1 H), 6.98 (d, .7=9.54 Hz, 1 H), 6.59 (br. t, .7=5.00, 5.00 Hz, 1 H), 3.83 (t, .7=5.26 Hz, 2 H), 3.48 - 3.75 (m, 26 H), 3.35 - 3.44 (m, 4 H), 2.50 (t, .7=2.57 Hz, 4 H). LCMS (2 min TFA): Rt = 0.75 min, [M+H]+= 634.1
A 10 mE Pressure tube was charged with0-Methoxy PLY a (0.459 g, 2.187 mmol) with 5 mE DCM. To it, tetra peg amine alcohol b (0.507 g, 2.625 mmol) was added and heated at 80 C. for 18 irs. Afier completion of reaction, compound was washed with water and extracted with CHC13. Final product d was purified by column chromatography (Silica 60-120 mesh, Ethyl acetate:Hexane:80:20 and then Methanol: CHC13: 10:90). Yield was 63%.ESIMS mlz=372.0175 [M+1] for [C2,H24N05]+.?H NMR (500 MHz, CDC13-d6) oe: 12.20 (s, 1H), 8.20 (d, J=10 Hz, 1H), 8.06 (d, J=5 Hz, 1H), 8.01 (t, J=5 Hz, 10Hz, 2H), 7.49 (t, J=5 Hz, 10Hz, 2H), 6.85 (d, J=10 Hz, 1H), 4.56 (m, 1H), 3.76 (m, 4H), 3.36-3.62 (m, 11H)
5-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)pentanoic acid[ No CAS ]
[ 86770-74-3 ]
C27H46N2O14[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
With benzotriazol-1-ol; diisopropyl-carbodiimide; In tetrahydrofuran; at 0 - 25℃; for 16h;
To a solution of G10-3 (10 g, 22.35 mmol, 1.00 equiv.) in tetrahydrofuran (100 mL) was added 1-hydroxybenzotriazole (3 g, 22.20 mmol, 1.00 equiv.), N, N-diisopropylcarbodiimide (5.62 g, 44.53 mmol, 2.00 equiv.). This was followed by the addition of 2-[2-[2-(2- aminoethoxy)ethoxy]ethoxy]ethan-l-ol (5.6 g, 28.98 mmol, 1.30 equiv.) with stirring at 0C. The resulting solution was stirred for 16 h at 25C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column. The crude product was purified by Flash. This resulted in 8 g (58%) of G10-4 as light yellow oil. MS m/z [M+H]+ (ESI): 623., 1H NMR (DMSO, 400Hz, ppm): delta 7.82 (d, J= 4.4 Hz, 2H), 5.22 (s, 1H), 4.98 (dd, J= 11.2 Hz, 3.6 Hz, 1H), 4.58 (t, J= 5.2 Hz, 1H), 4.49 (d, J= 8.4 Hz, 1H), 4.01 (s, 3H), 3.83-3.91 (m, 1H), 3.67- 3.73 (m, 1H), 3.48-3.51 (m, 10H), 3.37-3.42 (m, 5H), 3.19-3.20 (m, 2H), 2.11 (s, 3H), 2.08-2.10 (m, 2H), 2.08 (s, 3H), 1.89 (s, 3H), 1.77 (s, 3H), 1.40-1.60 (m, 4H).
To a solution of 4-mercapto-4-methylpentanoic acid (163 mg, 1.10 mmol) in MeCN (2.0 mL) were added sequentially acetic anhydride (1 14 pL, 1.21 mmol, 1.10 equiv.), Et3N (307 pL, 2.20 mmol, 2.00 equiv.) and DMAP (1.34 mg, 1 1.0 pnnol). The mixture was stirred for 32 minutes, followed by the addition 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethanol (319 mg, 1.65 mmol, 1.50 equiv.). The resulting reaction mixture was stirred for 18 hours at rt and then cone in vacuo. The residue was purified by silica chromatography (1 10% MeOH in DCM). The desired product was obtained as a yellow oil (342 mg, 1.05 mmol, 96%). 1 H NMR (400 MHz, CDC ) d (ppm) 7.22 (bs, 1 H), 3.79-3.71 (m, 4H), 3.71-3.59 (m, 8H), 3.57-3.51 (m, 2H), 3.50-3.41 (m, 2H), 2.43-2.34 (m, 2H), 1.98-1.89 (m, 2H), 1.65 (bs, 1 H), 1.40 (s, 6H). LCMS (ESI+) calculated for CMHSONOSS* (M+H+) 324.18, found 324.36.
4-fluoro-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione[ No CAS ]
[ 86770-74-3 ]
4-((2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)amino)-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34%
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.
benzyl (S)-(14-acetamido-1-hydroxy-13-oxo-3,6,9-trioxa-12-azaoctadecan-18-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere;
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
