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Structure of 5437-45-6 * 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.
General procedure: A mixture of the silica gel-adsorbed acid 2 (0.033 g), 2-bromoacetic acid (3a) (0.137 g, 0.988 mmol), and phenylmethanol (4a) (0.108 g, 1.000 mmol) under argon was stirred at 80 °C for 24 h. After the reaction mixture was cooled to room temperature, the addition of diethyl ether (5 mL × 5) and decantation resulted in complete separation of the organic layer and the silica gel-adsorbed acid 2. After the solvent was removed under reduced pressure, the product was purified by column chromatography on silica gel with hexane/EtOAc (v/v = 10/1) to give benzyl 2-bromoacetate (5aa) (0.189 g, 83percent). The silica gel-adsorbed acid 2 was dried under vacuum at room temperature, and recovered as a white powder (0.033 g, 99percent).
Reference：
[1] Journal of Molecular Catalysis A: Chemical, 2013, vol. 367, p. 116 - 120
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Yield
Reaction Conditions
Operation in experiment
100%
With toluene-4-sulfonic acid In benzene at 120℃; for 24 h;
[First Step]: Bromoacetic acid (20.8 g, 150 mmol), benzyl alcohol (16.2 g, 150 mmol), p-toluenesulfonic acid (258 mg, 1.5 mmol) and benzene (300 mL) were added to a two-necked flask equipped with a Dean-Stark trap, and were subjected to dehydration condensation at 120°C for 24 hours, and then the solvent was distilled off under reduced pressure with an evaporator. Then, the residue was purified by silica gel flash column chromatography (hexane/ethyl acetate=10/1, 5/1), and thus bromoacetic acid benzyl ester (34.3 g, 150 mmol) was obtained quantitatively as a yellow oily product. Rf 0.71 (hexane/ethyl acetate=4/1); 1H NMR (500 MHz, ppm, CDCl3, J=Hz) δ 3.81 (s, 2H), 5.14 (s, 2H), 7.31 (s, 5H); 13C NMR (125 MHz, ppm, CDCl3) δ 25.74, 67.79, 128.27, 128.48, 128.54, 134.88, 166.91; IR (neat, cm-1) 2959, 1751, 1458, 1412, 1377, 1167, 972, 750, 698
100%
at 120℃; for 24 h;
Bromoacetic acid (20.8 g, 150 mmol), benzyl alcohol (16.2 g, 150 mmol), p-toluenesulfonic acid (258 mg, 1.5 mmol) and benzene (300 mL) were added to a two-necked flask equipped with a Dean-Stark trap, and were subjected to dehydration condensation at 120°C for 24 hours, and then the solvent was distilled off under reduced pressure with an evaporator. Then, the residue was purified by silica gel flash column chromatography (hexane/ethyl acetate=10/1, 5/1), and thus bromoacetic acid benzyl ester (34.3 g, 150 mmol) was obtained quantitatively as a yellow oily product. Rf 0.71 (hexane/ethyl acetate=4/1); 1H NMR (500 MHz, ppm, CDCl3, J=Hz) δ 3.81 (s, 2H), 5.14 (s, 2H), 7.31 (s, 5H); 13C NMR (125 MHz, ppm, CDCl3) δ 25.74, 67.79, 128.27, 128.48, 128.54, 134.88, 166.91; IR (neat, cm-1) 2959, 1751, 1458, 1412, 1377, 1167, 972, 750, 698
100%
With toluene-4-sulfonic acid In benzene at 120℃; for 24 h; Dean-Stark trap
[First Step] In a two-necked flask equipped with a Dean-Stark trap, bromoacetic acid (20.8 g, 150 mmol), benzyl alcohol (16.2 g, 150 mmol), paratoluenesulfonic acid (258 mg, 1.5 mmol) and benzene (300 mL) were charged, followed by dehydration condensation at 120°C for 24 hours. The solvent was distilled off under reduced pressure using an evaporator, and then purified by silica gel flash column chromatography (hexane/ethyl acetate = 10/1, 5/1) to quantitatively obtain bromoacetic acid benzyl ester (34.3 g, 150 mmol) as a yellow oily product. Rf 0.71 (hexane/ethyl acetate = 4/1); 1H MR (500 MHz, ppm, CDCl3) δ3.81 (s, 2H), 5.14 (s, 2H), 7.31 (s, 5H); 13C NMR (125 MHz, ppm, CDCl3) δ25.74, 67.79, 128.27, 128.48, 128.54, 134.88, 166.91; IR (neat, cm-1) 2959, 1751, 1458, 1412, 1377, 1167, 972, 750, 698.
83%
at 80℃; for 24 h; Inert atmosphere
General procedure: A mixture of the silica gel-adsorbed acid 2 (0.033 g), 2-bromoacetic acid (3a) (0.137 g, 0.988 mmol), and phenylmethanol (4a) (0.108 g, 1.000 mmol) under argon was stirred at 80 °C for 24 h. After the reaction mixture was cooled to room temperature, the addition of diethyl ether (5 mL × 5) and decantation resulted in complete separation of the organic layer and the silica gel-adsorbed acid 2. After the solvent was removed under reduced pressure, the product was purified by column chromatography on silica gel with hexane/EtOAc (v/v = 10/1) to give benzyl 2-bromoacetate (5aa) (0.189 g, 83percent). The silica gel-adsorbed acid 2 was dried under vacuum at room temperature, and recovered as a white powder (0.033 g, 99percent).
Reference：
[1] Tetrahedron, 2008, vol. 64, # 8, p. 1823 - 1828
[2] Journal of Materials Chemistry, 2010, vol. 20, # 41, p. 9226 - 9230
[3] Patent: EP2345651, 2011, A1, . Location in patent: Page/Page column 11
[4] Patent: EP2345638, 2011, A1, . Location in patent: Page/Page column 11
[5] Patent: EP2460795, 2012, A1, . Location in patent: Page/Page column 9
[6] Angewandte Chemie - International Edition, 2018, vol. 57, # 11, p. 2958 - 2962[7] Angew. Chem., 2018, vol. 130, # 11, p. 3008 - 3013,6
[8] Journal of Molecular Catalysis A: Chemical, 2013, vol. 367, p. 116 - 120
[9] Journal of Medicinal Chemistry, 2012, vol. 55, # 14, p. 6541 - 6553
[10] Tetrahedron Letters, 1996, vol. 37, # 37, p. 6653 - 6656
[11] Journal of the Chemical Society, 1910, vol. 97, p. 426
[12] Monatshefte fuer Chemie, 1913, vol. 34, p. 1874
[13] Journal of Agricultural and Food Chemistry, 1958, vol. 6, p. 843
[14] J. Gen. Chem. USSR (Engl. Transl.), 1967, vol. 37, # 9, p. 1880 - 1885[15] Zhurnal Obshchei Khimii, 1967, vol. 37, # 9, p. 1980 - 1987
[16] The Journal of organic chemistry, 1976, vol. 41, # 4, p. 699 - 700
[17] Patent: EP2495246, 2012, A1, . Location in patent: Page/Page column 12-13
[18] Medicinal Chemistry Research, 2014, vol. 23, # 1, p. 503 - 517
[19] Organic Letters, 2017, vol. 19, # 13, p. 3524 - 3527
[20] Patent: JP2017/210426, 2017, A, . Location in patent: Paragraph 0053; 0054
4
[ 598-21-0 ]
[ 100-51-6 ]
[ 5437-45-6 ]
Reference：
[1] Organic Syntheses, 2012, vol. 89, p. 501 - 509
[2] Synthesis, 2003, # 17, p. 2647 - 2654
[3] Organic Letters, 2007, vol. 9, # 16, p. 3195 - 3197
[4] Angewandte Chemie - International Edition, 2010, vol. 49, # 52, p. 10181 - 10185
[5] Organic Letters, 2016, vol. 18, # 10, p. 2443 - 2446
[6] Chemistry - A European Journal, 2016, vol. 22, # 38, p. 13599 - 13612
[7] Journal of Organic Chemistry, 2017, vol. 82, # 1, p. 502 - 511
[8] Organic Letters, 2017, vol. 19, # 9, p. 2282 - 2285
[9] Asian Journal of Chemistry, 2017, vol. 29, # 10, p. 2171 - 2176
[10] Medicinal Chemistry Research, 2018, vol. 27, # 2, p. 458 - 469
[11] Advanced Synthesis and Catalysis, 2018, vol. 360, # 7, p. 1510 - 1516
[12] Chemical Communications, 2018, vol. 54, # 28, p. 3516 - 3519
[13] Organic Letters, 2018, vol. 20, # 9, p. 2663 - 2666
[14] Organic and Biomolecular Chemistry, 2018, vol. 16, # 25, p. 4683 - 4687
[15] Journal of Heterocyclic Chemistry, 2018, vol. 55, # 7, p. 1720 - 1728
[16] Chinese Journal of Chemistry, 2018, vol. 36, # 9, p. 857 - 865
[17] Synthesis (Germany), 2018, vol. 50, # 16, p. 3187 - 3196
[18] Journal of the American Chemical Society, 2018, vol. 140, # 50, p. 17773 - 17781
5
[ 96-32-2 ]
[ 100-51-6 ]
[ 5437-45-6 ]
Reference：
[1] Chemical Communications, 2009, # 41, p. 6249 - 6251
6
[ 79-08-3 ]
[ 100-51-6 ]
[ 5437-45-6 ]
Reference：
[1] Patent: US4596791, 1986, A,
7
[ 108-95-2 ]
[ 5437-45-6 ]
Reference：
[1] Patent: US2003/8882, 2003, A1,
8
[ 78385-35-0 ]
[ 78385-37-2 ]
[ 5437-45-6 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1982, p. 1435 - 1440
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Reference：
[1] Journal of the Chemical Society, 1956, p. 1521,1523
10
[ 13837-45-1 ]
[ 78385-35-0 ]
[ 78385-37-2 ]
[ 5437-45-6 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1982, p. 1435 - 1440
[00209] (.S)-Benzyl 2-(3-((teri-Butoxycarbonyl)amino)-2-oxopiperidin-l-yl)acetate (134). A solution of 0.36 g of 133 (1.68 mmol) in 5 mL of anhydrous THF was added to a suspension of 134 mg (3.36 mmol) of sodium hydride (60% dispersion in mineral oil) in 10 mL of anhydrous THF. The reaction was stirred at room temperature for 15 min, and 280 (403 mg, 1.76 mmol) of benzyl bromoacetate was added. After 5 h stirring at room temperature, 30 mL of EtOAc was added, followed by 20 mL of water. The organic phase was washed with 20 mL of brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to afford an oily residue. The residue was purified by chromatography on a silica gel column (10 chi 2 cm). Elution with 3: 1 hexanes-EtOAc afforded 134 as colorless oil: yield 353 mg (58%); Silica gel TLC ? 0.52 (3: 1 hexanes- EtOAc); 'H NMR (CDC13) delta 1.35 (s, 9H), 1.47-1.63 (m, 1H), 1.75-1.85 (m, 2H), 2.26- 2.38 (m, 1H), 3.17-3.34 (m, 2H), 4.01 (m AB system, 2H), 3.93-4.07 (m, 1H), 4.99-5.11 (m, 2H), 5.43 (br s, 1H) and 7.16-7.31 (m, 5H); 1 C NMR (CDC13) delta 20.8, 27.8, 28.3, 48.7, 48.9, 51.6, 66.8, 79.3, 128.2, 128.3, 128.5, 135.3, 155.8, 168.6 and 170.3.
5 -Methyl-2-hexenoic acid benzyl ester 5 a; Triethyl phosphite (leq) and benzyl bromoacetate 3a (leq) were heated at 800C with concurrent removal of ethyl bromide for 1 hour. After the distillation was complete, the heating was stopped and isovaleraldehyde 4 (1.25eq) was added to the cooled residue. A 50% aq. solution of potassium carbonate (2.5eq) in water was added. The solution became turbid after 15 minutes. It was stirred for 3-4 hours at 25-300C and monitored by HPLC. Water was added and extracted thrice with ethyl acetate. The combined organic layers were washed with water and dried over <n="19"/>sodium sulfate. Concentration under reduced pressure at 45-500C gave 5-methyl-2- hexenoic acid benzyl ester 5a in 95-99% yield as a colourless to pale yellow oil.1H NMR (CDCl3, delta): 0.92 (d, 6H, J=6.65Hz), 1.32 (m, IH), 2.09 (m, 2H), 5.17 (s, 2H), 5.86 (d, IH, J = 15.6Hz), 7.00 (dt, IH, J=7.5,7.8Hz), 7.35 (m, 5H).13C NMR (CDCl3, delta): 23.07, 28.48, 42.21, 66.68, 122.65, 128.81, 129.21, 128.85,136.87, 149.63, 167.06.IR (cm1, neat): 1722, 1654, 1460.
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;
4-Benzyloxy-2-hydroxybenzaldehyde (1 g, 4.39 mmol) was dissolved in distilled dimethylformamide (DMF, 8 mL), the solution was added with benzyl bromoacetate (1.1 g, 4.82 mmol) and cesium carbonate (1.57 g, 4.83 mmol), and the mixture was stirred overnight at room temperature under an argon atmosphere. The reaction solution was added with water (150 mL), and the mixture was extracted three times with ethyl acetate (100 mL). The extracted organic layer was washed five times with water (50 mL) and once with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained solid was purified by column chromatography (carrier: silica gel 60 N, solvent: dichloromethane), and recrystallized from hexane to obtain the objective compound, Compound 1, as white solid at a yield of 93%.1H NMR (300 MHz, CDCl3): delta 4.73 (s, 2H), 5.03 (s, 2H), 5.23 (s, 2H), 6.35 (d, J=2.0 Hz, 1H), 6.66 (dd, J=2.0, 8.8 Hz, 1H), 7.33-7.40 (m, 10H), 7.94 (d, J=8.8 Hz, 1H), 10.38 (s, 1H). 13C NMR (75 MHz, CDCl3): delta 65.4, 67.1, 70.3, 99.6, 107.6, 119.4, 127.5, 128.3, 128.4, 128.6, 128.7, 130.7, 134.8, 135.6, 161.6, 164.9, 167.8, 188.0. MS (ESI+): 399 [M+Na]+.Anal. Calcd for C23H20O5: N, 0; C, 73.39; H, 5.36. Found: N, 0; C, 73.18; H, 5.62. Mp: 84.4-85.7 C.
With potassium carbonate; In acetonitrile; at 75℃;Inert atmosphere;
General procedure: General Method for Linker Addition to t-Butyl-DO3A (2a, 2c, 2d) [0115] Under N2, t-butyl-DO3A (0.939 g, 1.827 mmol, 1 eq), the benzyl protected bromo-acid (4a or 4c or 4d) (2.740 mmol, 1.5 eq), and K2CO3 (0.756 g, 5.48 mmol, 3 eq) were added to 50 mL dry ACN. This was allowed to reflux at 75 C. overnight. The K2CO3 was filtered away and the ACN removed by evaporation. The reaction was diluted with DCM and washed three times with water, and three times with brine. The product was purified by silica gel chromatography with a gradient from 7% to 12% MeOH in DCM. RRN 51 t-butyl-DO3A-benzyl acetate (2a) [0116] (95% yield) M/Z calculated: 662.43, observed: 663.99 [M+H]+ [0117] 1H NMR (500 MHz, CDCl3) 1.46 (m, 27H), 2-4 (broad peaks, 24H), 5.07 (s, 2H), 7.32 (m, 5H) [0118] 13C NMR (125 MHz, CDCl3) 28.02, 48.67, 50.04, 52.74, 55.49, 55.96, 56.61, 81.87, 81.99, 82.23, 126.50, 126.67, 126.75, 134.01, 169.87, 172.79, 174.79
90%
With potassium carbonate; In acetonitrile; at 20 - 75℃; for 16h;Inert atmosphere;
Example 2-Synthesis of Tri-tert-butyl 2,2',2'-(10-(2-(benzyloxy)-2-oxoethyl)-1,4,7,10 tetraazacyclododecane-1,4,7- triyl)triacetate The procedure of was followed. More specifically, to a suspension of Tri-tert-butyl 2,2',2'-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (5.10 g, 10 mmol) in acetonitrile, K2CO3 powder (4.14 g, 30 mmol, 3 eq.) and subsequently benzyl bromoacetate (3.43 g, 15 mmol) were added in acetonitrile 75 mL at 75 C. Reaction was stirred at room temperature for 16 hrs. Reaction process was monitored by TLC. The precipitated solids were removed by filtration and the filtrate was concentrated to give the crude product, which was purified by silica gel column chromatography using CH2Cl2/MeOH (100:0 to 90:10) to give a colorless solid of Tri-tert-butyl 2,2',2'-(10-(2-(benzyloxy)-2-oxoethyl)-1,4,7,10 tetraazacyclododecane-1,4,7- triyl)triacetate (5.97 g, 90 %). Rf : 0.8 (CHCl3/MeOH 90:10). Mp: 195 C (recrystallized from toluene to give yellow crystals). 1H NMR (300 MHz, CDCl3) delta 7.33 (m, 5H, H5', H6' and H7'), 5.11 (s, 2H, H3'), 3.78 (s, 2H, H1'), 3.43 (br, 6H, H8 and H13), 3.32-3.14 (m, 4H, H6), 3.04-2.88 (m, 12H, H2, H3, H5), 1.46 (s, 18H, H12), 1.45 (s, 9H, H17). 13C NMR (75MHz, CDCl3) delta 174.3 (C9 and C14), 172.9 (C2'), 144.7 (C4'), 129.8 (C6'), 128.7 (C7'), 127.3 (C5'), 81.7 (C11), 81.5 (C17), 75.3 (C3'), 58.3, 57.1, 53.8 (C8, C13, C1'), 52.6, 52.3, 50.5 (C2, C3, C4, C5), 27.5 (C17), 27.4 (C12). MALDI (m/z) for [M+H]+ calculated 662.8 found 663.4. MS (ESI+): m/z 663.4 [M+H]+, 685.3 [M+Na]+.
90%
With potassium carbonate; In acetonitrile; at 20 - 75℃; for 16h;
The procedure of Strauch, R. C, et al., J. Am. Chem. Soc. 2011 , 133, 16346-49 was followed. More specifically, to a suspension of Tri-tert-butyl 2,2',2"-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (5.10 g, 10 mmol) in acetonitrile, K2CO3 powder (4.14 g, 30 mmol, 3 eq.) and subsequently benzyl bromoacetate (3.43 g, 15 mmol) were added in acetonitrile 75 mL at 75 C. Reaction was stirred at room temperature for 16 hrs. Reaction process was monitored by TLC. The precipitated solids were removed by filtration and the filtrate was concentrated to give the crude product, which was purified by silica gel column chromatography using CH2Cl2/MeOH (100:0 to 90:10) to give a colorless solid of Tri-tert-butyl 2,2',2"-(10-(2-(benzyloxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (5.97 g, 90 %). Rf : 0.8 (CHCl3/MeOH 90:10). Mp: 195 C (recrystallized from toluene to give yellow crystals). 1H NMR (300 MHz, CDCl3) delta 7.33 (m, 5H, H5', H6' and H7'), 5.1 1 (s, 2H, H3'), 3.78 (s, 2H, H1'), 3.43 (br, 6H, H8 and H13), 3.32-3.14 (m, 4H, H6), 3.04-2.88 (m, 12H, H2, H3, H5), 1 .46 (s, 18H, H12), 1 .45 (s, 9H, H17). 13C NMR (75MHz, CDCl3) delta 174.3 (C9 and C14), 172.9 (C2'), 144.7 (C4'), 129.8 (C6'), 128.7 (C7'), 127.3 (C5'), 81 .7 (C11), 81 .5 (C17), 75.3 (C3'), 58.3, 57.1, 53.8 (C8, C13, C1'), 52.6, 52.3, 50.5 (C2, C3, C4, C5), 27.5 (C17), 27.4 (C12). MALDI (m/z) for [M+H]+ calculated 662.8 found 663.4. MS (ESI+): m/z 663.4 [M+H]+, 685.3 [M+Na]+.
52%
With potassium carbonate; In acetonitrile; at 85℃; for 48h;
The compound (2) (1 g, 1.9 mmol) and potassium carbonate (0.54 g, 3.8 mmol) were co-dissolved in anhydrous acetonitrile (50 ml). A solution of benzyl bromoacetate (0.46 g, 1.9 mmol) in dry acetonitrile (10 mL) was added. he mixture was heated under reflux at 85 C for 48 hours, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure and separated and purified by column liquid chromatography (SiO2, CHCl3/ CH3OH = 10 / 0.5) To give the compound (3) (0.66 g, 52%) as a brown oil.Having a structure of Formula 4:
With triethanolamine; In ethyl acetate; N,N-dimethyl-formamide;
Part A. Preparation of Phenylmethyl 2-(1,4,7,10-Tetraaza-4,7,10-tris(((tert-butyl)oxycarbonyl)methyl)cyclododecyl)-acetate A solution of <strong>[122555-91-3]tert-butyl (1,4,7,10-tetraaza-4,7-bis(((tert-butyl)oxycarbonyl)methyl)cyclododecyl)acetate</strong> (0.922 g, 1.79 mmol), TEA (1.8 mL) and benzyl bromoacetate (0.86 mL, 5.37 mmol) in anhydrous DMF (24 mL) was stirred at ambient temperatures under a nitrogen atmosphere for 24 h. The DMF was removed under vacuum and the resulting oil was dissolved in EtOAc (300 mL). This solution was washed consecutively with water (2*50 mL) and saturated NaCl (50 mL), dried (MgSO4), and concentrated to give the title compound as an amorphous solid (1.26 g). MS: m/e 663.5 [M+H].
With triethanolamine; In ethyl acetate; N,N-dimethyl-formamide;
Part A. Preparation of Phenylmethyl 2-(1,4,7,10-Tetraaza-4,7,10-tris(((tert-butyl)oxycarbonyl)methyl)cyclododecyl)acetate A solution of <strong>[122555-91-3]tert-butyl (1,4,7,10-tetraaza-4,7-bis(((tert-butyl)oxycarbonyl)methyl)cyclododecyl)acetate</strong> (0.922 g, 1.79 mmol), TEA (1.8 mL) and benzyl bromoacetate (0.86 mL, 5.37 mmol) in anhydrous DMF (24 mL) was stirred at ambient temperatures under a nitrogen atmosphere for 24 h. The DMF was removed under vacuum and the resulting oil was dissolved in EtOAc (300 mL). This solution was washed consecutively with water (2*50 mL) and saturated NaCl (50 mL), dried (MgSO4), and concentrated to give the title compound as an amorphous solid (1.26 g). MS: m/e 663.5 [M+H].
With sodium carbonate; In acetonitrile;
g 1-(Benzyloxycarbonylmethyl)-4,7,10-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (as sodium bromide complex) 20 g (38.87 mmol) of 1,4,7-tris(tert-butoxy-carbonylmethyl)-1,4,7,10-tetraazacyclododecane (D03A-tris-tert-butyl ester, produced according to EP 0 299 795, Example 22a, is dissolved in 100 ml of acetonitrile. Then, 11.45 g (50 mmol) of bromoacetic acid benzyl ester and 10.6 g (100 mmol) of sodium carbonate are added and stirred for 12 hours at 60 C. The salts are filtered out, the filtrate is evaporated to dryness in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: methylene chloride/methanol=20:1). Yield: 21.72 g (73% of theory) of a colorless amorphous powder
With potassium carbonate; In acetonitrile; at 60℃;
To a mixture of DO3A(tBu)3 (2.03 g, 3.92 mmol) and K2CO3 (0.75 g, 7.84 mmol) in CH3CN (120 mL) was added benzyl bromoacetate (0.65 g, 15.7 mmol) and the resulting mixture was stirred overnight at 60 C. After filtration, the filtrate was evaporated to afford DO3A(tBu)3(Bn)1 as a white gummy residue, which is used for the next step without further purification. Yield: >99%. 1H NMR (CDCl3, 270 MHz): d 1.46-1.50 (br, 27H), 2.60-3.55 (br, 24H), 5.18 (s, 2H), 7.35 (m, 5H).
2.58 g
With potassium carbonate; In acetonitrile; at 25℃; for 3h;Inert atmosphere;
To a stirred solution of compound 3 (48) (2.00 g, 3.9 mmol, dissolved for 10min) and K2CO3 (2.15 g, 15.6 mmol) in ACN (40 mL) and Benzyl-2-bromoacetate (0.80 mL, 5.1 mmol) was added dropwise in the suspension under Ar conditions at 0 C and the reaction mixture was stirred for 3 h at 25 C. The reaction was monitored by TLC (CH2Cl2:MeOH/4:1 ) and LC-MS. The suspension was filtered and the filtrate was concentrated to yield a white foaming solid (2.58 g). ESI-MS: C3sH59N4O8+ m/z = 663.5 [M+H+]+. The crude material (2.58 g, 3.9 mmol) was dissolved in TFA (10 mL) at 0 C under Ar atmosphere and stirred at 25 C for 26 h and the conversion was monitored by LC-MS. The reaction mixture was coevaporated with toluene (3x10 ml_) to yield a green sticky solid (4.19 g). The crude material was dissolved in a HCI solution (0.1 M in H2O, 75ml_) and lyophilized to yield a yellow colored solid (3.1 1 g). A part of the crude material 5 (1 .00 g) was diluted in ACN/H2O (1/1 ), filtered and purified by reversed phase column chromatography (column: Macherey-Nagel, C18, 250x40 mm, eluent: ACN/H2O/O.I % HCOOH) to yield a white solid (250 mg, 40%). 1H NMR (500 MHz, De-DMSO). delta 7.38- 7.30 (m, 5H, Ar-H), 5.1 1 (s, 2H, OCH2), 3.65 (bs, 2H, CH2COOBn), 3.49 (2xbs, 6H, CH2COOH), 2.96 (bs, 8H), 2.82 ppm (bs, 4H). 13C NMR (125 MHz, De-DMSO). delta 170.9, 10 170.3, 163.3, 136.0, 128.5, 128.1 , 128.0, 65.4, 55.3, 55.0, 54.0, 51 .4, 50.4, 49.8, 49.3 ppm. ESI-MS: C^sHssNUOs" m/z = 495.24485 [M+H+]+, Ae = 0.2 ppm
With potassium carbonate; In acetone; for 48h;Heating / reflux;
[00424] (2-Methyl-1H-indol-4-yloxy)-acetic acid benzyl ester (2): A mixture of 4- hydroxy-2-methylindole (3.0 g, 0.02 mole), bromo-acetic acid benzyl ester (4.6 g, 0.02 mole), potassium carbonate (2.8 g, 0.02 mole) in acetone was refluxed for 48 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (10:1 Hex:EtOAc) to afford intermediate (2). Yield: 3.5 g, 58 %.
58%
With potassium carbonate; In acetone; for 48h;Heating / reflux;
A mixture of <strong>[35320-67-3]4-hydroxy-2-methylindole</strong> (3.0 g, 0.02 mole), bromo-acetic acid benzyl ester (4.6 g, 0.02 mole), potassium carbonate (2.8 g, 0.02 mole) in acetone was refluxed for 48 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (10:1 Hex:EtOAc) to afford intermediate (2). Yield: 3.5 g, 58%.
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 1h;
Reference example19 2-methyl-1H-indol-4-yloxyphenylmethyl acetic acid benzyl ester Under argon gas, potassium carbonate (2.14g) and bromoacetic acid benzyl (1.08ml) were added to N, N-dimethyl formamide (10ml) solution containing <strong>[35320-67-3]4-hydroxy-2-methyl-1H-indole</strong> (612mg), which was stirred at 60C for 1hour.. water was added to the reactive mixture, which was extracted by ethyl acetate.. The organic layer was sequentially washed with water and saturated brine, and then dried by anhydrous sodium sulfate.. The residue obtained by removal of the solvent was recrystallized by ethylacetate-hexane to give a title compound (1.3g) having the following physical properties. TLC:Rf 0.45 (hexane: ethyl acetate=7:3); NMR(CDCl3):delta 7.87 (brs, 1H), 7.40-7.30 (m, 5H), 7.01-6.94 (m, 2H), 6.44-6.36 (m, 2H), 5.25 (s, 2H), 4.80 (s, 2H), 2.43 (s, 3H).
With hydrogenchloride; ammonium hydroxide; sodium hydroxide; triethylamine; In tetrahydrofuran; methanol; dichloromethane; water;
Reference Example 39 2-(4-Methyl-piperazin-1-yl)-acetic acid A mixture of 1-methylpiperazine (10.7 g), benzylbromoacetate (24 g), triethylamine (28 ml) and dichloromethane (100 ml) was stirred at ambient temperature for 4 hours. The reaction was concentrated to dryness, taken up in tetrahydrofuran (100 ml), filtered, and the filtrate evaporated to dryness. The residue was taken up in methanol (100 ml), treated with aqueous sodium hydroxide solution (100 ml, 1M) and stirred at reflux for 24 hours. The reaction was concentrated to dryness, diluted with water (100 ml) and then acidified to pH6.0 by addition of concentrated hydrochloric acid. The mixture was evaporated.. A portion of the resulting brown oil (2.0 g) was taken up in water (100 ml), treated with Dowex 50WX8 resin (80 g) and stirred at ambient temperature for 10 minutes. The mixture was filtered and the resin washed with water until the washings were neutral. The resin was then stirred with 2.0M aqueous ammonia (3*100 ml) for 5 minutes and filtered. The combined ammonia washings were concentrated to leave the title compound as a white waxy solid (0.8 g).
benzyl (1-phenyl-1,2,3,4-tetrahydro-β-carbolin-2-yl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium chloride; sodium hydrogencarbonate; triethylamine; In dichloromethane; water;
EXAMPLE 71 Benzyl (1-phenyl-1,2,3,4-tetrahydro-beta-carbolin-2-yl)acetate 147 mg (1.45 mmol) of triethylamine and 277 mg (1.21 mmol) of benzyl bromoacetate were added successively to a solution of 300 mg (1.21 mmol) of 1-phenyl-1,2,3,4-tetrahydro-beta-carboline, as obtained in Example 70, in 10 ml of methylene chloride, with ice-cooling, and the resulting mixture was stirred at room temperature for 3 hours. After this time, 277 mg of benzyl bromoacetate and 183 mg of triethylamine were added to the reaction mixture, and the resulting mixture was allowed to stand for 2 days. At the end of this time, first a saturated aqueous solution of sodium hydrogencarbonate and then water were added successively to the reaction mixture, which was then extracted with ethyl acetate. The resulting extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the ethyl acetate was removed by evaporation under reduced pressure to give 0.61 g of a crude mixture. The resulting residue was subjected to column chromatography using 13 g of silica gel with a 9:1 by volume mixture of hexane and ethyl acetate as the eluent, to yield 0.49 g of the title compound as yellow crystals in quantitative yield. The product was subsequently recrystallized from ethyl acetate to yield 0.37 g of the title compound as yellow crystals, melting at 130.8-132.0 C. Nuclear Magnetic Resonance Spectrum (CDCl3, 270 MHz), delta ppm: 2.80-3.30 (4H, multiplet); 3.36 (1H, doublet, J=16 Hz); 3.50 (1H, doublet, J=16 Hz); 5.07 (1H, singlet); 5.12 (1H, doublet, J=16 Hz); 5.18 (1H, doublet, J=16 Hz); 7.05-7.57 (15H, multiplet).
With sodium iodide; In N,N-dimethyl-formamide; acetonitrile;
EXAMPLE 7 N-[3,5-bis(Decyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester A mixture of 20.0 g (0.0493 mol) of 3,5-bis(decyloxy)benzenamine, 23.6 ml (0.148 mol) of benzyl bromoacetate, 26.4 (0.123 mol) of <strong>[20734-58-1]1,8-bis(dimethylamino)naphthalene</strong> and 2.1 g of sodium iodide in 300 ml acetonitrile and 65 ml of DMF was stirred at reflux for 48 hours. The reaction mixture was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with 0.5N HCl, with saturated NaHCO3, dried and concentrated under reduced pressure to an oil. Purification by HPLC using 10% ethyl acetate-hexane gave 15.7 g (45% yield, mp 55-57) of N-[3,5-bis(decyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester. Anal. Calcd for C44 H63 NO6: C, 75.28; H, 9.04; N, 2.00. Found: C, 75.49; H, 9.14; N, 2.10.
5-[3-amino-5-(octadecyloxy)phenoxy]pentanoic acid methyl ester[ No CAS ]
ethyl acetate n-hexane[ No CAS ]
[ 20734-58-1 ]
[ 5437-45-6 ]
N-[3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With sodium iodide; In ethyl acetate; N,N-dimethyl-formamide; acetonitrile;
EXAMPLE 63 N-[3-(Octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester A mixture of 6.77 g (13.8 mmol) of 5-[3-amino-5-(octadecyloxy)phenoxy]pentanoic acid methyl ester, 6.6 ml (41.3 mmol) of benzyl bromoacetate, 7.4 g (34.4 mmol) of <strong>[20734-58-1]1,8-bis(dimethylamino)naphthalene</strong> and 0.6 g (3.9 mmol) of sodium iodide in 150 ml of acetonitrile and 50 ml of DMF was stirred at reflux under an argon atmosphere for 48 hours. The reaction mixture was concentrated at reduced pressure to remove the solvents and ethyl acetate was added to the residue. The extract was washed with 0.5N HCl, with NaHCO3 solution, dried and concentrated at reduced pressure to an oil. Purification by HPLC using 20% ethyl acetate-hexane gave 6.55 g (60% yield, mp 48-50) of N-[3-(octadecyloxy)-5-[(5-methoxy-5-oxopentyl)oxy]phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester. Anal. Calcd for C48 H69 NO8: C, 73.16; H, 8.83; N, 1.78. C, 73.02; H, 8.91; N, 1.75.
3-amino-5-(octadecyloxy)benzoic acid methyl ester[ No CAS ]
ethyl acetate n-hexane[ No CAS ]
[ 20734-58-1 ]
[ 5437-45-6 ]
N-[3-(methoxycarbonyl)-5-(octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With sodium iodide; In ethyl acetate; N,N-dimethyl-formamide;
EXAMPLE 68 N-[3-(Methoxycarbonyl)-5-(octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester A mixture of 3.25 g (7.74 mmol) of 3-amino-5-(octadecyloxy)benzoic acid methyl ester, 3.7 ml (23 mmol) of benzyl bromoacetate, 4.2 g (19.4 mmol) of <strong>[20734-58-1]1,8-bis(dimethylamino)naphthalene</strong> and 0.3 g (2.2 mmol) of sodium iodide in 65 ml of acetronitrile and 20 ml of DMF was stirred and heated at reflux under argon for 48 hours. The reaction mixture was concentrated at reduced pressure and ethyl acetate was added to the residue. The extract was washed with 0.05N HCl, with saturated NaHCO3 solution, dried and concentrated at reduced pressure to a solid which was purified by HPLC using 15% ethyl acetate-hexane to give 2.6 g (48% yield, mp 62-63) of N-[3-(methoxycarbonyl)-5-(octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester. Ana. Calcd for C44 H61 NO7: C, 73.81; H, 8.59; N, 1.96. Found: C, 73.46; H, 8.69; N, 2.01.
With sodium iodide; In ethyl acetate; N,N-dimethyl-formamide; acetonitrile;
EXAMPLE 74 N-[(3-Carbamoyl)-5-(octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester A mixture of 3.0 g (7.4 mmol) of 3-amino-5-(octadecyloxy)benzamide, 3.6 ml (22 mmol) of benzyl bromoacetate, 4.0 g (18.5 mmol) of <strong>[20734-58-1]1,8-bis(dimethylamino)naphthalene</strong> and 0.3 g (2.1 mmol) of sodium iodide in 60 ml of acetonitrile and 20 ml of DMF was stirred and heated at reflux under argon for 48 hours. The solvents were removed at reduced pressure and the residue was dissolved in ethyl acetate. The extract was washed with 0.05N HCl, with NaHCO3 solution, dried and concentrated at reduced pressure to a solid. Purification by HPLC using 20% ethyl acetate-toluene gave 2.24 g (43% yield, mp 112-114) of N-[(3-carbamoyl)-5-(octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester. Anal. Calcd for C43 H60 N2 O6: C, 73.68; H, 8.63; N, 4.00. Found: C, 73.69; H, 8.64; N, 3.90.
N-[2-oxo-2-(phenylmethoxy)ethyl]-N-[3,4-bis(tetradecyloxy)phenyl]glycine phenylmethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With sodium iodide; In water; N,N-dimethyl-formamide; acetonitrile;
EXAMPLE 118 N-[2-oxo-2-(phenylmethoxy)ethyl]-N-[3,4-bis(tetradecyloxy)phenyl]glycine phenylmethyl ester A mixture of 2.8 g (5.4 mmol) of 3,4-bis(tetradecyloxy)benzenamine, 8.6 ml (54 mmol) of benzyl bromoacetate, 2.9 g (13.5 mmol) of <strong>[20734-58-1]1,8-bis(dimethylamino)naphthalene</strong> and 0.3 g of sodium iodide in 60 ml of acetonitrile and 10 ml of DMF was stirred under argon for 48 hours. The solvents were removed at reduced pressure and the residue was treated with water and extracted with ethyl acetate. The dried extract was concentrated and purified by HPLC using 10% ethyl acetate-hexane to give 3.2 g (73% yield, mp 52-52) of N-[2-oxo-2-(phenylmethoxy)ethyl]-N-[3,4-bis(tetradecyloxy)phenyl]glycine phenylmethyl ester. The structure was confirmed by nmr and mass spectra.
N-(Carboxymethyl)-N-[3-di-decylaminocarbonyl)phenyl]glycine[ No CAS ]
N-[3-(di-decylaminocarbonyl)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With sodium iodide; In water; N,N-dimethyl-formamide; acetonitrile;
EXAMPLE 174 N-(Carboxymethyl)-N-[3-di-decylaminocarbonyl)phenyl]glycine A mixture of 1.0 g (2.4 mmol) of 3-(di-decylaminocarbonyl)benzenamine, 3.8 mL (24 mmol) of benzylbromoacetate, 1.3 g (6 mmol) of <strong>[20734-58-1]1,8-bis(dimethylamino)naphthalene</strong> and 0.36 g (2.4 mmol) of sodium iodide in 20 mL of anhydrous acetonitrile and 5 mL of DMF was stirred under argon at reflux for 40 hours. The solvents were removed at reduced pressure, water was added and the product was extracted with ethyl acetate. The dried extract was concentrated at reduced pressure and the residue was purified by HPLC using 20% ethyl acetate-hexane to give 1.2 g (70% yield) of N-[3-(di-decylaminocarbonyl)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester as an oil.
EXAMPLE 97 N-[3-(Acetylamino)-5-(octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine phenylmethyl ester A mixture of 1.1 g (2.63 mmol) of 3-(acetylamino)-5-(octadecyloxy)benzenamine, 4.2 ml (26 mmol) of benzyl bromoacetate, 1.4 g (6.6 mmol) of <strong>[20734-58-1]1,8-bis(dimethylamino)naphthalene</strong> and 0.4 g (2.63 mmol) of sodium iodide in 40 ml of acetronitrile and 5 ml of DMF was stirred at reflux for 48 hours. The solvents were removed at reduced pressure and the residue was purified by HPLC using 35% ethyl acetate-hexane to give 0.3 g (16% yield, mp 89-90) of N-[3-(acetylamino)-5-(octadecyloxy)phenyl]-N-[2-oxo-2-(phenylmethoxy)ethyl]glycine benzyl ester. The structure was confirmed by nmr and mass spectra.
With tetrabutylammomium bromide; In N-methyl-acetamide;
3-Amino-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one was also prepared as follows: a solution of <strong>[86499-35-6]3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one</strong> (5.0 g, 0.028 mol), in dimethylformamide (100 ml) was added under a nitrogen atmosphere to a stirred suspension of sodium hydride [prepared from the 60% mineral oil dispersion (1.2 g) by washing with petroleum ether (3*150 ml)] in dimethylformamide (400 ml) to which tetrabutylammonium bromide (10.0 g, 0.031 mol) had been added. The reaction mixture was maintained at 50 for 15 minutes, then a solution of benzyl bromoacetate (7.2 g, 0.031 mol) in dimethylformamide (25 ml) was added.
With tetrabutylammomium bromide; In N-methyl-acetamide;
3-Amino-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepine-2-one was also prepared as follows: a solution of <strong>[86499-35-6]3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one</strong> (5.0 g, 0.028 mol), in dimethylformamide (100 ml) was added under a nitrogen atmosphere to a stirred suspension of sodium hydride [prepared from the 60% mineral oil dispersion (1.2 g) by washing with petroleum ether (3*150 ml)] in dimethylformamide (400 ml) to which tetrabutylammonium bromide (10.0 g, 0.031 mol) had been added. The reaction mixture was maintained at 50 for 15 minutes, then a solution of benzyl bromoacetate (7.2 g, 0.031 mol) in dimethylformamide (25 ml) was added.
1-benzyloxycarbonylmethyl-3-benzyloxycarbonylmethylamino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one[ No CAS ]
[ 86499-35-6 ]
[ 5437-45-6 ]
1-Carboxymethyl-3-carboxymethylamino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one[ No CAS ]
[ 86499-51-6 ]
Yield
Reaction Conditions
Operation in experiment
With tetrabutylammomium bromide;Pd-C; In N-methyl-acetamide; ethanol; dichloromethane; water; toluene;
EXAMPLE 11 1-Carboxymethyl-3-carboxymethylamino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one A solution of 1-benzyloxycarbonylmethyl-3-benzyloxycarbonylmethylamino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (4.8 g; 0.01 mol) in ethanol (550 ml) was hydrogenated at room temperature and atmospheric pressure using 5% Pd-C (0.85 g) as catalyst until uptake of hydrogen ceased. Water (300 ml) was added, the catalyst filtered off, and the solvent removed under reduced pressure. The residue was triturated with ether to give the title diacid, m.p. 232-236. The starting material was prepared as follows: A solution of <strong>[86499-35-6]3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one</strong> (5.0 g, 0.028 mol) in dimethylformamide (100 ml) was added under a nitrogen atmosphere to a stirred suspension of sodium hydride [prepared from the 60% mineral oil dispersion (1.2 g) by washing with petroleum ether (3*150)] in dimethylformamide (400 ml) to which tetrabutylammonium bromide (10.9 g, 0.031 mol) had been added. The reaction mixture was maintained at 50 for 15 minuites, then a solution of benzyl bromoacetate (7.2 g, 0.031 mol) in dimethylformamide (25 ml) was added. The reaction mixture was stirred for an additional 18 hours at 50, then cooled to room temperature, and the dimethylformamide removed under high vacuum. The residue was stirred with toluene/dichloromethane (1:1, 500 ml) to precipitate inorganic salts. After filtration, the solution was evaporated under reduced pressure, and the residue chromatographed on silica gel (200 g). Elution with 0-15% ethyl acetate in toluene gave 1-benzyloxycarbonylmethyl-3-benzyloxycarbonylmethylamino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one as the first fraction. Further elution gave 3-benzyloxycarbonylamino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 124-127 C. and 3-amino-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (see example 1).
With tetrabutylammomium bromide;Pd-C; In N-methyl-acetamide; ethanol; dichloromethane; water; toluene;
EXAMPLE 11 1-Carboxymethyl-3-carboxymethylamino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one. A solution of 1-benzyloxycarbonylmethyl-3-benzyloxycarbonylmethylamino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (4.8 g; 0.01 mol) in ethanol (550 ml) was hydrogenated at room temperature and atmospheric pressure using 5% Pd-C (0.85 g) as catalyst until uptake of hydrogen ceased. Water (300 ml) was added, the catalyst filtered off, and the solvent removed under reduced pressure. The residue was triturated with ether to give the title diacid, m.p. 232-236. The starting material was prepared as follows: A solution of <strong>[86499-35-6]3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one</strong> (5.0 g, 0.028 mol) in dimethylformamide (100 ml) was added under a nitrogen atmosphere to a stirred suspension of sodium hydride [prepared from the 60% mineral oil dispersion (1.2 g) by washing with petroleum ether (3*150)] in dimethylformamide (400 ml) to which tetrabutylammonium bromide (10.9 g, 0.031 mol) had been added. The reaction mixture was maintained at 50 for 15 minutes, then a solution of benzyl bromoacetate (7.2 g, 0.031 mol) in dimethylformamide (25 ml) was added. The reaction mixture was stirred for an additional 18 hours at 50, then cooled to room temperature, and the dimethylformamide removed under high vacuum. The residue was stirred with toluene/dichloromethane (1:1, 500 ml) to precipitate inorganic salts. After filtration, the solution was evaporated under reduced pressure, and the residue chromatographed on silica gel (200 g). Elution with 0-15% ethyl acetate in toluene gave 1-benzyloxycarbonylmethyl-3-benzyloxycarbonylmethylamino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one as the first fraction. Further elution gave 3-benzyloxycarbonylamino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 124-127 C. and 3-amino-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (see example 1).
With tetrabutylammomium bromide;Pd-C; In N-methyl-acetamide; ethanol; dichloromethane; water; toluene;
EXAMPLE 11 1-Carboxymethyl-3-carboxymethylamino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one A solution of 1-benzyloxycarbonylmethyl-3-benzyloxycarbonylmethylamino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (4.8 g; 0.01 mol) in ethanol (550 ml) was hydrogenated at room temperature and atmospheric pressure using 5% Pd-C (0.85 g) as catalyst until uptake of hydrogen ceased. Water (300 ml) was added, the catalyst filtered off, and the solvent removed under reduced pressure. The residue was triturated with ether to give the title diacid, m.p. 232-236. The starting material was prepared as follows: A solution of <strong>[86499-35-6]3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one</strong> (5.0 g, 0.028 mol) in dimethylformamide (100 ml) was added under a nitrogen atmosphere to a stirred suspension of sodium hydride [prepared from the 60% mineral oil dispersion (1.2 g) by washing with petroleum ether (3*105)] in dimethylformamide (400 ml) to which tetrabutylammonium bromide (10.9 g, 0.031 mol) had been added. The reaction mixture was maintained at 50 for 15 minuites, then a solution of benzyl bromoacetate (7.2 g, 0.031 mol) in dimethylformamide (25 ml) was added. The reaction mixture was stirred for an additional 18 hours at 50, then cooled to room temperature, and the dimethylformamide removed under high vacuum. The residue was stirred with toluene/dichloromethane (1:1, 500 ml) to precipitate inorganic salts. After filtration, the solution was evaporated under reduced pressure, and the residue chromatographed on silica gel (200 g). Elution with 0-15% ethyl acetate in toluene gave 1-benzyloxycarbonylmethyl-3-benzyloxycarbonylmethylamino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one as the first fraction. Further elution gave 3-benzyloxycarbonylamino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 124-127 C. and 3-amino-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (see example 1).
[3-(S)-Amino-2-oxo-cyclopentyl]-acetic acid benzyl ester hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; ethyl acetate;
A. [3-(S)-Amino-2-oxo-cyclopentyl]-acetic acid benzyl ester hydrochloride Sodium hydride (0.13 g, 3.3 mmol, 60% by weight) is added to a solution of [2-oxopyrrolidin-3-(S)-yl]-carbamic acid tert-butyl ester (0.6 g, 3 mmol) in THF (30 mL) at 0 C. The mixture is stirred for 30 minutes then benzyl 2-bromo-acetate (0.76 g, 3.3 mmol) is added. The resulting solution is warmed to room temperature and stirred for 1.5 hours. The reaction mixture is quenched with saturated ammonium chloride solution then diluted with methylene chloride. The organic layer is separated, washed with brine, dried over MgSO4, filtered and concentrated. The residue is purified by flash chromatography (0-3% MeOH/CH-2Cl2) and the material isolated is treated in ethyl acetate with HCl gas (as described in EXAMPLE 1, Part I) to give the title compound (0.55 g, 1.9 mmol) as a pale yellow solid. 1H NMR (CD3OD, 300 MHz) delta7.32 (m, 5H), 5.17 (s, 2H), 4.15 (d, 2H), 4.08 (m, 1H), 3.54 (m, 2H), 2.54 (m, 1H), 2.03 (m, 1H). EI MS, [M-]+=248.
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;
1) [N-(3-Benzyloxycarbonylaminopropyl)]aminoacetic acid benzyl ester N-Benzyloxycarbonyl-1,3-diaminopropane hydrochloride (4.64 g) was suspended in N,N-dimethylformamide (80 mL), and, at room temperature, triethylamine (3.72 mL) and bromoacetic acid benzy ester (4.5 g) were added to the suspension, followed by stirring for 18 hours. The reaction mixture was cooled to 0C, and water, 1M aqueous hydrochloric acid, and diethyl ether were added for partitioning the mixture. Saturated aqueous sodium hydrogencarbonate was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The resultant aqueous layer was further extracted with ethyl acetate, and the organic layers were combined, followed by washing with saturated brine and drying over sodium sulfate anhydrate. After a filtration step, the solvent was evaporated under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform - methanol), to thereby give [N-(3-benzyloxycarbonylaminopropyl)]aminoacetic acid benzyl ester as an oily product (4.72 g, 67%). 1H-NMR(400MHz,CDCl3)delta:1.62-1.74(2H,m), 2.69(2H,t,J=6.6Hz), 3.29(2H,q like,J=6.6Hz), 3.44(2H,s), 5.09(2H,s), 5.16(2H,s), 7.25-7.42(10H,m). ESI-MSm/z:357(M+H)+.
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60 - 65℃;
Molecule A can be prepared by slowly, i.e. within 3 hours, adding a solution of di-tert-butyl dicarbonate (7.9 g, 36 mmol) in CHCl3 (100 mL, passed through Al2O3) to a solution of cyclen (2.2 g, 13 mmol) and triethylamine (5.5 mL, 39 mmol) in CHCl3 (120 mL) at room temperature. The reaction mixture is stirred for 24 hours at room temperature, and the organic solvent is removed under reduced pressure. The remaining residue is purified by silica gel column chromatography (hexanes/AcOEt) to provide molecule A as a colourless, amorphous solid (4.4 g, 72%)[ E. Kimura, J. Am. Chem. Soc., 1997, 199, 3068-3076].The tri-BOC protected molecule A (15.2 g) is then dissolved in 20 mL of acetonitrile, after which 19 mL of diisopropylethylamine and 7.9 g of benzylbromoacetate in 10 mL acetonitrile are added. The solution is heated up to 60-65 C. and stirred overnight under an argon atmosphere. The mixture is then concentrated by evaporation of the solvent and dissolved in dichloromethane. The solution is washed with 1 M NaOH. The organic layer is dried with Na2SO4 and thereafter reduced by evaporation and co-evaporation with toluene. The pure product, molecule B, is isolated by silica column chromatography using hexane/ethyl acetate(1/1) as eluent. The yield is about 90%.Molecule B (6.22 g) is dissolved in 60 mL dichloromethane and 60 mL trifluoracetic acid (TFA). The solution is stirred under a nitrogen atmosphere. After 3 hours the solvents are evaporated and another portion of TFA (40 mL) is added. After 2 hours of further stirring the TFA is evaporated and the remaining mixture is co-evaporated twice with toluene, leaving the crude TFA-salt of molecule C as an oil, of which then 10 g is used in a following step without further purification. The oil is dissolved and stirred in 45 mL DMF and 31 mL diisopropylethylamine. Then, 4.7 g bromo acetamide is added and the mixture is stirred for two days at 50 C., during which time a precipitate is developed. The mixture is brought in 600 mL ether, is stirred and the brown precipitate is isolated by filtration and washing with ether. The solid is then washed four times with portions of 25 mL of 25% NH3 solutions in water and finally with 30 mL of water. Drying under vacuum at 40 C. results in a white solid product of molecule D (yield=85%).Molecule D (1.7 g) is then hydrogenated at 70 psi overpressure in 100 mL water using Pd/C (10%) as catalyst. The mixture is filtered over celite, the celite is washed with some water and the filtrate is freeze dried and then dried over P2O5 in vacuum to afford 1.1 gram of a fine white hygroscopic powder of molecule E.For the coupling of molecule E to the carrier, in the example given to a PPI dendrimer, the amide coupling agent HBTU (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) is used. The coupling of the paramagnetic complex to the dendrimer is illustrated in FIG. 5. For convenience, the dendrimers are denoted as circles. The dendrimers used are commercially available poly(propylene imine) (PPI) dendrimers (from Aldrich under the name DAB-Am-X or from SyMO-Chem) with a diaminobutane (DAB) derived core. The most used name for those dendrimers is DAB-Am-X, wherein X refers to the number of surface amino groups. In this synthesis, DAB-Am-4 and DAB-Am-16 have been used in order to respectively obtain a DOTAM-G1 complex and a DOTAM-G3 complex. The formation of DOTAM-G1 and DOTAM-G3 is similar, only the value for the number n of end groups is different, i.e. for DOTAM-G1 n=4 and for DOTAM-G3 n=16.For the coupling of molecule E to the G1 PPI dendrimer, 0.39 mL diisopropylethylamine is added to a mixture of 312 mg HBTU in 3 mL dry DMF. Molecule E (300 mg) is added, the mixture is stirred until a clear solution is acquired. This may take about 5 to 10 minutes. Subsequently, 60 mg DAB-Am-4 in 3 mL DMF is added. The mixture is stirred overnight under an inert atmosphere, after which it is dropped into 150 mL of ether. The sticky precipitate is taken up in a small amount of methanol and precipitated into ether giving a white solid, that is again precipitated from methanol into ether. Finally, the solid is dissolved in methanol and eluted over an anion exchange column (Dowex OH-). Evaporation of the solvent gave about 200 mg of product, which in the further synthesis will be called molecule II.For the coupling of molecule E to the G3 PPI dendrimer, 0.25 mL diisopropylethylamine is added to a mixture of 164 mg HBTU in 1 mL dry DMF. Molecule E (172 mg) is added and the mixture is stirred until a clear solution is acquired. This may take about 5 to 10 minutes. The third generation PPI-dendrimer DAB-Am-16 (41 mg) in 1 mL dry DMF is then added and the solution is stirred overnight under an inert atmosphere of nitrogen. The mixture is poured into 40 mL of stirred ether giving a precipitate; the ether is replaced by another portion of ether (washing step), and the precipitate is dried. Finally, the precipitate is dissolved in water an...
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;
A mixture of 1,2, 3-triazole (2.07 g, 30 mmol), benzyl bromoacetate (6.9 g, 30 mmol), and diisopropylethylamine (5,1 ML, 30 mmol) in 40 mL CH2C12 was stirred overnight at room temperature. This mixture was then diluted with ether until no further precipitate formed. The solid was filtered and washed with ether. The filtrate was concentrated and the residue was purified on silica gel using 10% hexane in CH2C12 to give the title compound's isomer, benzyl 2- (2- (1, 2,3-triazolyl) acetate as amorphous solid. Further elution with a solvent mixture containing equal amounts of ether and CH2C12GAVE the title compound as amorphous solid. 1H NMR (400 MHz, CDC13) : 8 2. 251 (s, 2H0, 7.267-7. 390 (m, 5H), 7.723 (s, 1H), 7.785 (s, LH).
With potassium carbonate; In acetonitrile; at 20 - 45℃;
4-tert-Butyl 1-methyl L-aspartate hydrochloride (19.6 g, 81.8 mmol) was suspended in acetonitrile (150 ml), potassium carbonate (27.6 g, 200 mmol) and benzyl bromoacetate (24.3 g, 106 mmol) were added with stirring at room temperature, and the resulting mixture was stirred overnight at 45C. The mixture was left standing to cool to room temperature and then insoluble matter was removed by filtration. The filtrate was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane = 4:1 ? 2:1) to give the title compound (25.4 g, 89%) as a yellow oil. 1H-NMR (CDCl3) delta: 1.43 (9H, s), 2.33 (1H, brs), 2.60-2.72 (2H, m), 3.49 (1H, d, J=17.3 Hz), 3.57 (1H, d, J=17.6 Hz), 3.63 (1H, t, J=7.0 Hz), 3.71 (3H, d, J=3.4 Hz), 5.15 (2H, s), 7.32-7.36 (5H, m).
To a solution of <strong>[16251-45-9](4S,5R)-(-)-4-methyl-5-phenyl-2-oxazolidinone</strong> (400 mg, 2.26 mmol) in DMF (5 mL) at 0 C. was added NaH (60% in mineral oil, 108 mg, 2.71 mmol), and the reaction mixture was stirred for 5 min. Benzyl-2-bromoacetate (680 muL, 4.29 mmol) was slowly added to the reaction mixture, while stirring. After 17 h, the reaction mixture was diluted with ethyl acetate (100 mL), and washed with 0.5 N HCl (100 mL), saturated aqueous NaHCO3 (100 mL), then brine (100 mL). Dried (Na2SO4) and concentrated to yield the crude product, which was purified by silica gel column chromatography (30% EtOAc in hexanes) to yield (4S,5R)-(-)-(4-methyl-2-oxo-5-phenyloxazolidin-3-yl)acetic acid benzylester (731 mg, 99%).
To a solution of (4S)-phenyl-2-oxazolidinone (400 mg, 2.45 mmol) in DMF (5 mL) at 0 C. was added NaH (60% in mineral oil, 117 mg, 2.94 mmol), and the reaction mixture was stirred for 5 min. Benzyl-2-bromoacetate (737 muL, 4.65 mmol) was added and the reaction mixture was stirred at 23 C. for 17 h. The reaction mixture was partitioned between 1.0 N HCl (100 mL) and ethyl acetate (200 mL). The organic layer was washed with saturated aqueous NaHCO3 (100 mL), brine (100 mL), dried over Na2SO4, and concentrated in vacuo to yield a brown oil that was purified by silica gel column chromatography (0-50% EtOAc in hexanes) to yield (2-oxo-[4S]-phenyloxazolidin-3-yl) acetic acid benzyl ester (635 mg, 83%).
To a solution of (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone (400 mg, 2.26 mmol) in DM (5 mL) at 0 C. was added NaH (60% in mineral oil, 108 mg, 2.71 mmol) and the reaction mixture was stirred for 5 min. Benzyl-2-bromoacetate (680 muL, 4.29 mmol) was slowly added to the reaction mixture, while stirring. After 17 h, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with 0.5 N HCl (100 mL), saturated aqueous NaHCO3 (100 mL), then brine (100 mL). The reaction mixture was dried (Na2SO4) and concentrated to yield the crude product, which was purified by silica gel column chromatography (30% EtOAc in hexanes) to yield (4R,5S)-(+)-(4-methyl-2-oxo-5-phenyloxazolidin-3-yl)acetic acid benzyl ester (640 mg, 87%).
Example 4.; Preparation 2-Ally-3 -(carbomethoxy)benzyloxybenzaldehyde; Reaction Scheme: Experimental:Preparation of 2-Allyl-3-benzyloxybenzaldehyde (3)Table 7.Experimental ProcedureTo a solution of <strong>[79950-42-8]2-allyl-3-hydroxybenzaldehyde</strong> (1) (1.00 g, 0.006 mol) in acetone (20 mL) was added powdered potassium carbonate (3.30 g) and benzyl bromoacetate (2) (1.53 g, 0.006 mol). The reaction mixture was stirred at 40 °C (oil bath temperature) for 5 h. The reaction mixture was checked by tic (Note 1). The reaction was complete. The mixture was filtered, and the filtrate was concentrated in vacuo to get crude viscous liquid. The crude product was purified by silica gel column chromatography using a mixture of ethyl acetate and hexanes (4- 10percent) to get colorless viscous liquid (1.73 g, 88.7percent). 1H NMR (CDC13, 300 Hz) 3.89 (m, 2H), 4.74 (s, 2H), 4.95 - 5.00 (m, 2H), 5.22 (s, 2H), 5.97-6.06 (m, 1H), 6.97 (m, 1H), 7.29-7.34 9m, 6H), 7.54 (m, 1H). Note 1 : Completion of the reaction was monitored by thin layer chromatography (TLC) thin layer silica gel plate; eluent: 10percent ethyl acetate in hexanes.
In neat (no solvent); at 80℃; for 6h;Inert atmosphere;
General procedure: A mixture of the silica gel-adsorbed acid 2 (0.033 g), 2-bromoacetic acid (3a) (0.137 g, 0.988 mmol), and phenylmethanol (4a) (0.108 g, 1.000 mmol) under argon was stirred at 80 C for 24 h. After the reaction mixture was cooled to room temperature, the addition of diethyl ether (5 mL × 5) and decantation resulted in complete separation of the organic layer and the silica gel-adsorbed acid 2. After the solvent was removed under reduced pressure, the product was purified by column chromatography on silica gel with hexane/EtOAc (v/v = 10/1) to give benzyl 2-bromoacetate (5aa) (0.189 g, 83%). The silica gel-adsorbed acid 2 was dried under vacuum at room temperature, and recovered as a white powder (0.033 g, 99%).
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 2h;
A solution of 5-nitroisoindoline-1,3-dione (1.00 g, 5.20 mmol), benzyl 2-bromoacetate (1.225 ml, 7.81 mmol) and K2CO3 (1.079 g, 7.81 mmol) in DMF (10 ml) was heated at 90 C. for 2 hours. The insoluble inorganic salts were filtered off, and the filtrate was diluted with ethyl acetate and washed with 1N HCl and with brine. The organic layer was dried over Na2SO4 and the solvent was removed under vacuum. The residue was purified by crystallization from MeOH to afford benzyl 2-(5-nitro-1,3-dioxoisoindolin-2-yl)acetate (1.39 g, 4.08 mmol, 78% yield, MS/ESI+ not detectable [MH]+).
78%
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 2h;
step 1 : Preparation of benzyl 2-(5-nitro-1 ,3-dioxoisoindolin-2-yl)acetate(218):A solution of 5-nitroisoindoline-1 ,3-dione (1 .00 g, 5.20 mmol), benzyl 2-bromoacetate (1 .225 ml, 7.81 mmol) and K2C03(1 .079 g, 7.81 mmol) in DMF (10 ml) was heated at 90C for 2 hours. The insoluble inorganic salts were filtered off and the filtrate was diluted with ethyl acetate and washed with 1 N HCI and with brine. The organic layer was dried over Na2S04 and the solvent was removed under vacuum. The residue was purified by crystallization from MeOH to afford benzyl 2-(5-nitro-1 ,3-dioxoisoindolin-2-yl)acetate (1 .39 g, 4.08 mmol, 78% yield, MS/EST not detectable [MH] +). Step 2: Preparation of benzyl 2-(5-amino-1 ,3-dioxoisoindolin-2-yl)acetate
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 4h;
To a suspension (39 mL) of <strong>[138007-24-6]ter<strong>[138007-24-6]t-butyl piperidine-4-carboxylate</strong></strong> (2.6 g) in acetonitrile was added diisopropylethylamine (4.4 mL), subsequently, benzyl bromoacetate (2.0 mL) was added at room temperature in portions, and the mixture was stirred for 4 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. This was washed with an aqueous saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:3?0:1) to obtain the title compound (3.4 g) having the following physical property values.; TLC: Rf 0.66 (hexane:ethyl acetate=2:1); 1H-NMR (CDCl3): delta 1.44 (s, 9H) 1.68-1.92 (m, 4H) 2.10-2.35 (m, 3H) 2.83-2.96 (m, 2H) 3.26 (s, 2H) 5.16 (s, 2H) 7.25-7.41 (m, 5H).
Step 209.2: To a solution of 1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxylic acid tert- butyl ester (279mg) in MeCN (10ml) was added Cs2CO3 (407mg) followed by benzyl bromoacetate (0.2ml). The resulting white suspension was stirred at RT for 48h, diluted with EA and washed with water and brine. The aq. phases were extracted with EA. The combined org. layers were dried (MgS04), filtered off and evaporated to dryness. The residue was purified by CC (Biotage, SNAP 25g cartridge, DCM/MeOH 97/3 for 10CV) to afford 371 mg of oil. The oil was purified by preparative chiral HPLC (I) to afford the two regioisomers, both as mixture of benzyl and ethyl ester that formed during the evaporation of the fractions after HPLC purification: Step 209.3: The Boc protecting group of 1-benzyloxycarbonylmethyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester was cleaved using a method analogous to that of Example 16 step 16.4 to give (4,5,6,7-tetrahydro-imidazo[4,5-c]pyridin-1-yl)-acetic acid benzyl ester. Step 209.4: To a solution of (4,5,6,7-tetrahydro-imidazo[4,5-c]pyridin-1-yl)-acetic acid benzyl ester (176mg) in MeOH was added formaldehyde (36.5% in water, 0.052ml_) followed by NaBH3CN (29mg) and AcOH (0.5ml_). The reaction mixture was stirred at RT overnight. DCM was added and the mixture was washed with sat. NaHCO3. The aq. layer was extracted with DCM, the combined org. layers were dried (MgS04), filtered off and evaporated to dryness. The residue was purified by CC (Biotage, SNAP 10g cartridge, solvent A: DCM; solvent B: DCM/MeOH 8/2; gradient in %B: 25 for 3CV, 25 to 50 over 2CV, 50 for 5CV, 50 to 100 over 3CV, 100 for 2CV) to afford (5-methyl-4,5,6,7-tetrahydro-imidazo[4,5-c]pyridin-1-yl)-acetic acid benzyl ester (39mg, yellow oil). (5-Methyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-2-yl)-acetic acid benzyl ester (1 1 1 mg, colourless oil). LC-MS (B): tR = 0.54min; [M+H]+: 286.16. 1H-NMR (CDCl3): 7.40-7.33 (m, 5H); 7.18 (s, 1 H); 5.21 (s, 2H); 4.89 (s, 2H); 3.50 (s, 2H); 2.86 (t, 2H, 6.0Hz); 2.76 (t, 2H, 5.5Hz); 2.49 (s, 3H). Roesy signal seen between CH2 at 4.89ppm and CH at 7.18ppm. (5-Methyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1 -yl)-acetic acid benzyl ester (45mg, pale yellow solid). LC-MS (B): tR = 0.54min; [M+H]+: 286.16. 1H-NMR (CDCl3): 7.40-7.33 (m, 6H); 5.21 (s, 2H); 4.85 (s, 2H); 3.47 (s, 2H); 2.75 (t, 2H, 6.0Hz); 2.67 (t, 2H, 5.5Hz); 2.49 (s, 3H). Roesy signal seen between CH2 at 4.85ppm and CH2 at 2.67ppm. Step 215.2: The final compound was prepared using a method analogous to that of Example 14 step 14.2, (5-methyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-2-yl)-acetic acid benzyl ester replacing intermediate 14.1 and using MeOH instead of MeOH/AcOH. LC-MS (B): tR = 0.17min; [M+H]+: 196.29.
With caesium carbonate; In acetonitrile; at 20℃; for 1h;
Step 212.1 : To a solution of <strong>[7170-01-6]<strong>[7170-01-6]3-methyl-1H-1,2,4-triazol</strong>e</strong> (1 g) in MeCN (40ml) was added Cs2CO3 (3.72g) followed by benzyl bromoacetate (1.89ml_). The reaction mixture was stirred at RT for 1 h and evaporated to dryness. The residue was taken up in EA and washed with water, sat. NH4Cl and brine. The aq. layers were extracted with EA, the combined org. layers were dried (MgSO4), filtered off and evaporated in vacuo. The residue was purified by CC (Biotage, SNAP 100g cartridge, solvent A: DCM; solvent B: DCM/MeOH 8/2; gradient in %B: 15 for 12CV, 15 to 25 over 2CV, 25 for 3CV) to afford 2.23g of oil. The oil was purified by preparative chiral HPLC (II) to afford the two regioisomers, both as mixture of benzyl and ethyl ester that formed during the evaporation of the fractions after HPLC purification. The second eluting compound also contains the methyl ester analog due to the addition of MeOH to the fractions before evaporation. First eluting compound: (5-Methyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester (1.07g, brown oil, contains 16% of the ethyl ester analog). LC-MS (B): tR = 0.68min; [M+H]+: 232.16. 1H-NMR (CDCl3): 7.83 (s, 1 H); 7.40-7.33 (m, 5H); 5.23 (s, 2H); 4.93 (s, 2H); 2.43 (s, 3H). Roesy signal seen between CH2 at 4.93 ppm and CH3 at 2.43 ppm. Second eluting compound: (3-Methyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester (1.15g, yellow oil, contains 30% of the ethyl ester and 20% of the methyl ester analogs). LC-MS (B): tR = 0.67min; [M+H]+: 232.16. 1H-NMR (CDCl3): 8.05 (s, 1 H); 7.40-7.30 (m, 5H); 5.23 (s, 0.95H, CH2 of benzyl ester); 4.93-4.88 (3s, 2H); 4.27 (q, 0.58H, CH2 of ethyl ester); 3.81 (s, 0.65 H, CH3 of methyl ester); 2.42 (s, 3H). Roesy signal seen between CH at 8.05ppm and CH2 at 4.93-4.88ppm.
With caesium carbonate; In acetonitrile; at 20℃; for 1h;
Step 212.1: To a solution of <strong>[7170-01-6]<strong>[7170-01-6]3-methyl-1H-1,2,4-triazol</strong>e</strong> (1 g) in MeCN (40 mL) was added Cs2CO3 (3.72 g) followed by benzyl bromoacetate (1.89 mL). The reaction mixture was stirred at RT for 1 h and evaporated to dryness. The residue was taken up in EA and washed with water, sat. NH4Cl and brine. The aq. layers were extracted with EA, the combined org. layers were dried (MgSO4), filtered off and evaporated in vacuo. The residue was purified by CC (Biotage, SNAP 100 g cartridge, solvent A: DCM; solvent B: DCM/MeOH 8/2; gradient in % B: 15 for 12CV, 15 to 25 over 2CV, 25 for 3CV) to afford 2.23 g of oil. The oil was purified by preparative chiral HPLC (II) to afford the two regioisomers, both as mixture of benzyl and ethyl ester that formed during the evaporation of the fractions after HPLC purification. The second eluting compound also contains the methyl ester analog due to the addition of MeOH to the fractions before evaporation. [0921] First eluting compound: (5-Methyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester (1.07 g, brown oil, contains 16% of the ethyl ester analog). LC-MS (B): tR=0.68 min; [M+H]+: 232.16. 1H-NMR (CDCl3): 7.83 (s, 1H); 7.40-7.33 (m, 5H); 5.23 (s, 2H); 4.93 (s, 2H); 2.43 (s, 3H). Roesy signal seen between CH2 at 4.93 ppm and CH3 at 2.43 ppm. [0922] Second eluting compound: (3-Methyl-[1,2,4]triazol-1-yl)-acetic acid benzyl ester (1.15 g, yellow oil, contains 30% of the ethyl ester and 20% of the methyl ester analogs). LC-MS (B): tR=0.67 min; [M+H]+: 232.16. 1H-NMR (CDCl3): 8.05 (s, 1H); 7.40-7.30 (m, 5H); 5.23 (s, 0.95H, CH2 of benzyl ester); 4.93-4.88 (3s, 2H); 4.27 (q, 0.58H, CH2 of ethyl ester); 3.81 (s, 0.65H, CH3 of methyl ester); 2.42 (s, 3H). Roesy signal seen between CH at 8.05 ppm and CH2 at 4.93-4.88 ppm.
dibenzyl-N,N'-(nonane1,9-diyl)diglycinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31%
With triethylamine; In dichloromethane; at 0 - 20℃;
General procedure: a) Synthesis of dibenzyl esters of diglycines by direct N,N'-dialkylation of diamines by benzyl bromoacetate: To an ice-cooledsolution of diamine (0.043 mol, 1 mol equiv) and TEA (8.70 g, 11.9 mL, 0.086 mol, 2 mol equiv) in DCM (250 mL), solution of BBA (17.9 g,13.5 mL, 0.086 mol, 2 mol equiv) in DCM (100 mL), was added dropwise, during 4 h. After additional stirring for 24 h, mixture was washedwith H2O (3 x100 mL) and then with brine (2 x100 mL), and dried over anh. Na2SO4. The solvent was removed in vacuo and the remainingmaterial was purified on a SiO2 column by dry-flash chromatography using below mentioned solvents as eluents.
dibenzyl-N,N'-(dodecane-1,12-diyl)diglycinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20%
With triethylamine; In dichloromethane; at 0 - 20℃;
General procedure: a) Synthesis of dibenzyl esters of diglycines by direct N,N'-dialkylation of diamines by benzyl bromoacetate: To an ice-cooledsolution of diamine (0.043 mol, 1 mol equiv) and TEA (8.70 g, 11.9 mL, 0.086 mol, 2 mol equiv) in DCM (250 mL), solution of BBA (17.9 g,13.5 mL, 0.086 mol, 2 mol equiv) in DCM (100 mL), was added dropwise, during 4 h. After additional stirring for 24 h, mixture was washedwith H2O (3 x100 mL) and then with brine (2 x100 mL), and dried over anh. Na2SO4. The solvent was removed in vacuo and the remainingmaterial was purified on a SiO2 column by dry-flash chromatography using below mentioned solvents as eluents.
With potassium carbonate; In acetonitrile; at -15 - 20℃;
2-Amino-N,N-dimethylacetamide (51.1 mg, 0.500 mmol) was dissolved in acetonitrile (4 mL), and potassium carbonate (104 mg, 0.750 mmol) was added thereto, followed by cooling to ?10° C. to ?15° C. Then, benzyl 2-bromoacetate (0.086 mL, 0.550 mmol) diluted with acetonitrile (1 mL) was added dropwise, and the temperature was gradually raised to room temperature, followed by stirring overnight
With potassium carbonate; In acetonitrile; at -15 - 20℃;
L-Alanineamide hydrochloride (62.3 mg, 0.500 mmol) was dissolved in acetonitrile (3 mL), and potassium carbonate (173 mg, 1.25 mmol) was added thereto, followed by cooling to -10 C. to -15 C. Then, benzyl 2-bromoacetate (0.086 mL, 0.550 mmol) diluted with acetonitrile (1 mL) was added dropwise. The temperature was allowed to rise to room temperature, followed by stirring overnight. After insoluble matters were separated by filtration, the filtrate was concentrated under reduced pressure
With potassium carbonate; In acetonitrile; at 0℃; for 5h;
Step 1 Synthesis of Benzyl 2-(2-Acetamidoethylamino)acetate (0346) N-(2-Aminoethyl)acetamide (102 mg, 1.00 mmol) was diluted with acetonitrile (4 mL), and potassium carbonate (207 mg, 1.50 mmol) was added thereto, followed by cooling to 0 C. Then, benzyl 2-bromoacetate (0.172 mL, 1.50 mmol) diluted with acetonitrile (1 mL) was added dropwise, followed by stirring for 5 hours. After insoluble matters were separated by filtration, the filtrate was concentrated under reduced pressure to obtain a crude product of Step 1. (0347) Yield: 265 mg (0348) MS (ESI) m/z 251 [M+H]+
With potassium carbonate; In acetonitrile; at 60℃;
[00599] Intermediate 62a: benzyl 2-(4-methylpyrazol-1-yI)acetate[00600] Benzyl bromoacetate (0.l7mL, 1.lmmol) was added to a flask containing fomepizole (0.O7mL, 0.91 mmol) and potassium carbonate (379mg, 2.74mmol) in MeCN (3mL). Thereaction mixture was heated to 60 C and left to stir overnight. The reaction was then cooled to room temperature and quenched by the addition of water (2OmL) and extracted with EtOAc (3 x2OmL). The combined organic layers were dried over Na2504, filtered and concentrated in vacuo.The residue was purified by column chromatography using an eluent of 0-10% EtOAc in heptane togive benzyl 2-(4-methylpyrazol-1-yl)acetate (205mg, 0.89mmol, 97% yield) as a white solid.1H NMR (CDCI3,400MHz) O/ppm: 7.40- 7.33 (6H, m), 7.24 (1H, 5), 5.20 (2H, 5), 4.89 (2H, 5), 2.09(3H, 5).MS Method 2: RT: 1.61 mm, mlz 231.2 [M+H]
benzyl 2-[4-(trifluoromethyl)imidazol-1-yl]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With potassium carbonate; In acetonitrile; at 60℃;
[00611] Intermediate 64a: benzyl 2-[4-(trifluoromethyl)imidazol-1 -yI]acetate[00612] Benzyl bromoacetate (0.l4mL, 0.88mmol) was added to a flask containing potassiumcarbonate (305mg, 2.2mmol) and <strong>[33468-69-8]4-(trifluoromethyl)-1H-imidazole</strong> (1 00mg, 0.73mmol) in MeCN(3mL). The reaction mixture was heated to 60 C and left to stir overnight. The reaction was then quenched by the addition of water (2OmL) and extracted with EtOAc(3x2OmL). The combined organic layers were dried over Na2504, filtered and reduced in vacuo to afford the product benzyl 2- [4-(trifluoromethyl)imidazol-1-yl]acetate (1 94mg, 0.68mmol, 93% yield) as a yellow oil.1H NMR (CDCI3,400MHZ) O/ppm: 7.55 (1H, 5), 7.41 -7.30 (6H, m), 5.23 (2H, 5), 4.75 (2H, 5).
benzyl 2-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With potassium carbonate; In acetonitrile; at 60℃;
[00638] Intermediate 67a: benzyl 2-[2-methyl-4-(trifluoromethyl)imidazol-1 -yI]acetate[00639] Benzyl 2-bromoacetate (0.l3mL, 0.8Ommol) was added to a stirring solution of <strong>[33468-67-6]2-methyl-4-(trifluoromethyl)-1H-imidazole</strong> (1 00mg, 0.67mmol) and potassium carbonate (276mg,2.OOmmol) in MeCN (3mL). The reaction mixture was heated to 60 C and left to stir overnight. The reaction was then quenched by addition of water (2OmL) and extracted with EtOAc (3 x 2OmL). The combined organic layers were dried over Na2504, filtered and concentrated in vacuo to give benzyl 2-[2-methyl-4-(trifluoromethyl)imidazol-1 -yl]acetate (200mg, 0.67mmol, 100% yield) as a yellow oilwhich was used in the next step without further purification.MS Method 2: RT: 1.78 mm, mlz 299.1 [M+H]
benzyl 2-(3-isopropylpyrazol-1-yl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
[00754] Intermediate 80a: benzyl 2-(3-isopropylpyrazol-1 -yI)acetate[00755] 5-lsopropyl-1H-pyrazole (1 00mg, 0.91 mmol) and potassium carbonate (376mg, 2.72mmol) was left to stir in MeCN (3mL) for 30 mins before the addition of benzyl bromoacetate (0.21 mL, 1 .36mmol). The resultant mixture was heated to 60 C and left to stir at temperature overnight. The reaction was then quenched by addition of water (2OmL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give benzyl 2-(3-isopropylpyrazol-1-yl)acetate (200mg, 0.77mmol, 85%) which was used inthe next step without further purification.1H NMR (CDCI3,400MHZ) O/ppm: 7.41-7.33 (6H, m), 6.18 (1H, d, J= 2.3Hz), 5.21 (2H, 5), 4.96 (2H, 5), 3.04 (1H, sept, J= 7.0Hz), 1.31 (3H, 5), 1.29 (3H, 5).MS Method 2: RT: 1.87 mi mlz 259.0 [M+H]
benzyl 2-(3-cyclopropylpyrazol-1-yl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
[00759] Intermediate 81a: benzyl 2-(3-cyclopropylpyrazol-1-yI)acetate[00760] A suspension of 3-cyclopropyl-1 H-pyrazole (100mg, 0.g2mmol) and potassium carbonate (383mg, 2.77mmol) in MeCN (3mL) was left to stir at room temperature for 30 minutes before the addition of benzyl bromoacetate (0.21 mL, 1 .3gmmol) and sodium iodide (139mg, 0.g2mmol). The resulting mixture was heated to 60 C and left to stir overnight. The reaction was quenched by theaddition of water (2OmL) and extracted with EtOAc (3 x 2OmL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography using an eluent of 0-20% EtOAc in heptane to give benzyl 2-(3-cyclopropylpyrazol- 1-yl)acetate (204mg, 0.8Ommol, 86% yield) as a colourless oil.1H NMR (CDCI3,400MHZ) O/ppm: 7.42-7.32 (6H, m), 5.98 (1H, d, J= 2.3Hz), 5.21 (2H, 5), 4.89 (2H,5), 1.64 (1H, tt, J= 8.3Hz, 5.0Hz), 0.97-0.88 (2H, m), 0.77-0.72 (2H, m). MS Method 2: RT: 1.88 mi mlz 257.0 [M+H]
(S)-benzyl 2-(3-((tert-butoxycarbonyl)amino)-2-oxopyrrolidin-1-yl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
[00203] (.S)-Benzyl 2-(3-((feri-Butoxycarbonyl)amino)-2-oxopyrrolidin-l-yl)acetate (127). A solution of 290 mg (1.45 mmol) of 126 in 5 mL of anhydrous THF was added to a suspension of 116 mg (2.90 mmol) of sodium hydride (60% dispersion in mineral oil) in 10 mL of anhydrous THF. The reaction was stirred at room temperature for 15 min, and 241 (348 mg, 1.52 mmol) of benzyl bromoacetate was added. After 5 h stirring at room temperature, 30 mL of EtOAc was added, followed by 20 mL of water. The organic phase was washed with 20 mL of brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to afford an oily residue. The residue was purified by chromatography on a silica gel column (10 chi 2 cm). Elution with 3: 1 hexanes-EtOAc afforded 127 as a colorless oil: yield 301 mg (60%); silica gel TLC i? 0.38 (3: 1 hexanes- EtOAc); NMR (CDC13) delta 1.39 (s, 9H), 1.80-1.96 (m, 1H), 2.50-2.62 (m, 1H), 3.29 (dd, 1H, J= 9.2 and 8.4 Hz), 3.40 (td, 1H, J= 9.6 and 6.7 Hz), 3.98 (d, 1H, J= 17.7 Hz), 4.15 (d, 2H, J= 17.7 Hz), 5.10 (s, 2H), 5.24 (s, 1H) and 7.21-7.41 (m, 5H); 1 C NMR (CDC13) delta 28.0, 28.3, 44.5, 44.6, 51.9, 67.1, 80.0, 128.3, 128.5, 128.6, 135.1, 155.7, 168.1 and 173.0.
dibenzyl 2,2'-(2-oxo-1H-imidazole-1,3(2H)-diyl)diacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
240 mg
With caesium carbonate; In acetone; at 65℃; for 6h;Sealed tube;
Step 1. A mixture of lH-imidazol-2(3H)-one (100 mg, 1.19 mmol), cesium carbonate (853 mg, 2.62 mmol) and benzyl 2-bromoacetate (0.40 mL, 2.50 mmol) in acetone (10 mL) was sealed and heated in an oil bath at 65 °C for 6 h. The reaction mixture was filtered and concentrated in vacuo. The residual solid was purified by FCC (80 g silica gel, eluted with gradient 30percent~100percent EtOAc-hexanes) to afford dibenzyl 2,2'-(2-oxo-lH-imidazole- l,3(2H)-diyl)diacetate (240 mg) as a colorless oil. LC-MS retention time = 1.16 min; m/z = 381.3 [M+H]+. (Column: Waters Aquity BEH C18 2.1 X 50 mm 1.7^m-particles; Solvent A = 100percent Water/ 0.05percent TFA; Solvent B = 100percent Acetonitrile/0.05percent TFA; Flow Rate = 0.8 mL/min. Start percent B = 2; Final percent B = 98; Gradient Time = 1.5 minutes; Wavelength = 220 nm). NMR (400 MHZ, CDCh) delta ppm 7.46 - 7.32 (m, 10H), 6.33 (s, 2H), 5.22 (s, 4H), 4.48 (s, 4H).
(S)-benzyl 2-((tetrahydrofuran-3-yl)amino)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56.1%
To a stirred solution of <strong>[204512-95-8](S)-3-aminotetrahydrofuran hydrochloride</strong> (16.0g, 130mmol) in anhydrous THF (250mL) at 0C was added dropwise Et3N (41.5mL, 298mmol) within 20min and stirred another 20min, then a solution of benzyl 2-bromoacetate (29.6g, 130mmol) was added slowly at 0C followed by NaI (1.90g, 13.0mmol). The reaction mixture was stirred at 0C for 30min and then allowed to warm to room temperature and stirred overnight. The solvent was removed under diminished pressure and the residue was treated with water (200mL) and extracted with three 150mL portions of ethyl acetate. The combined organic extracts were dried over Na2SO4 and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (30×6cm). Elution with 3:1 hexanes-ethyl acetate gave 3a as a yellow oil: yield 17.1g (56.1%). 1H NMR (400MHz, CDCl3) delta 7.39-7.30 (m, 5H), 5.16 (s, 2H), 3.91 (dd, J=15.6, 7.6Hz, 1H), 3.80-3.74 (m, 2H), 3.57 (dd, J=9.2, 3.6Hz, 1H), 3.44 (d, J=1.2Hz, 2H), 3.41-3.36 (m, 1H), 2.08-2.00 (m, 1H), 1.76-1.68 (m, 2H); LC-MS (ESI) [M+H]+ m/z 236.2.
ethyl 1-[2-(benzyloxy)-2-oxoethyl]-1H-tetrazole-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With potassium carbonate; In N,N-dimethyl-formamide; at 25 - 30℃;
To a 3 necked flask equipped with overhead stirrer was added a solution of ethyl lH-tetrazole-5- carboxylate (20 g, 140.8 mmol) in dimethylformamide (200 ml) at 25-30C under stirring. To this potassium carbonate (21.38 g, 154.9 mmol) was added under continuous stirring, and effervescence was observed. Benzyl bromoacetate (29 g, 126.7 mmol) was added to it drop wise using addition funnel at 25-30C. The progress of reaction was monitored by thin layer chromatography using mixture of chloroform and methanol (9: 1) as solvent system. After complete consumption of starting material the reaction mixture was filtered through celite bed to remove insoluble inorganic material and then added to water (2000 ml) under stirring. The aqueous reaction mixture was extracted with ethyl acetate (3x500 ml). The organic extracts were combined and washed with brine (1x500 ml), dried over anhydrous sodium sulfate. The volatiles were removed under reduced pressure to yield 32 g of ethyl l-[2-(benzyloxy)-2-oxoethyl]-lH-tetrazole-5-carboxylate in 78% yield
ethyl 1-[2-(benzyloxy)-2-oxoethyl]-1H-imidazole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
To a solution ethyl lH-imidazole-2-carboxylate (6 g, 42.8 mmol , prepared as per the procedure depicted in Synthetic communication, 44(7), 968-975, 2014) in DMF (30 ml) at 25-30 °C followed by potassium carbonate (7.1 g, 51.3 mmol) under stirring. After 15 minutes of stirring benzyl bromoacetate (9.8 g, 42.8 mmol) was added drop-wise at same temperature. The progress of reaction was monitored by TLC (methanol: DCM, 1:9). After complete consumption of starting material the reaction mixture was filtered through celite bed to remove insoluble inorganic and poured on to water (150 ml). The aqueous reaction mixture was extracted with dichloro methane (3x 60 ml). The organic extracts were combined and washed with brine (60 ml), dried over anhydrous sodium sulphate. The volatiles were removed under reduced pressure to yield 12 g of yielded ethyl l-[2-(benzyloxy)-2-oxoethyl]-lH-imidazole-2-carboxylate in 97percent yield.
To a solution of 1,4,7,10-tetraazacyclododecane free base 1(714 mg, 4.067 mmol) in chloroform (35 mL), N-(tert-Butoxycarbonyloxy)succinimide (8.134 mmol) was added. The reaction mixture was stirred at room temperature for 28 h. Solvent was removed by rotary evaporation and 30 mL of NaOH 3 M was added to the remaining residue. The aqueous phase was extracted with chloroform (3.3 mL). The extracts were combined and dried (over K2CO3). The solvent was removed by rotary evaporation and the residue was dried in vacuum for several hours. 513 mg of the unpurified compound from the preceding reaction (1.3761 mmol)was solubilized in acetonitrile. 0.67 mL (2.87 mmol) of benzyl bromoacetate and 0.474 g (3.412 mmol) K2CO3 were added to this solution at room temperature, after which the mixture was heated under reflux for 8 h. The solids were discarded by filtration over Celite and the solvent was removed under vacuum. Chromatographic purification (alumina, 98/2 DCM/MeOH) yielded 2 as aslowly solidifying colourless oil (736 mg, 87% over all for two steps). 1H NMR (500 MHz, CDCl3) d (ppm): 7.31 (m, 10H), 5.11 (s,4H), 3.54 (s, 4H), 3.49 (m, 8H), 2.86 (m, 8H), 1.41 (s, br 18H). 13C(500 MHz, CDCl3) d (ppm): 171.48, 157.11, 136.02, 79.33, 66.04,55.04, 54.51, 46.68, 28.46. ESI-MS (C36H52N4O8); m/z = 668 [M+H]+.
(S)-dibenzyl 2-((2-(benzyloxy)-2-oxoethyl)amino)succinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
587 mg
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 35℃;
A) (S)-Dibenzyl 2-((2-(benzyloxy)-2-oxoethyl)amino)succinate Benzyl 2-bromoacetate (0.377 mL) was added to a mixture of <strong>[6327-59-9](S)-dibenzyl 2-aminosuccinate hydrochloride</strong> (555.7 mg), N,N-diisopropylethylamine (0.832 mL), and acetonitrile (10 mL) at 0 C., followed by stirring at room temperature overnight. N,N-Diisopropylethylamine (0.832 mL) was added to the reaction mixture at room temperature, followed by stirring at the same temperature for 72 hours. Water and ethyl acetate were added to the reaction mixture at 0 C., followed by extraction with ethyl acetate. The organic layer was washed with a saturated saline solution and was then dried over anhydrous sodium sulfate, and the solvent was distilled under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (587 mg). MS: [M+H]+ 462.1.
With caesium carbonate; In acetonitrile; at 20℃; for 1h;
To a solution of 3-methyl-1 H-1 ,2,4-triazole (1 g) in MeCN (40mL) was added Cs2C03 (3.72g) followed by benzyl bromoacetate (1 .89mL) and the mixture was stirred for 1 h at RT. The reaction mixture was diluted with EA and washed with water (2x) and brine. The aq. layers were extracted with EA (2x) and the combined org. layers were dried over MgS04, filtered off and evaporated to dryness. The residue was purified by CC (Biotage, SNAP 100g cartridge, solvent A: DCM; solvent B: DCM/MeOH 8:2; gradient in %B: 85/15 for 12CV, 85/15 to 75/25 for 2CV, 75/25 for 3CV) to afford 2.3g as yellowish oil (52:48 mixture of regioisomers). The mixture of regioisomers was purified by preparative chiral HPLC (I). Second eluting fraction: (3-methyl-[1 ,2,4]triazol-1-yl)-acetic acid benzyl ester. LC-MS (A): tR = 0.67min; [M+H]+: 232.16. 1 H-NMR (CDCI3): 8.05 (s, 1 H); 7.40-7.30 (m, 5H); 5.23 (s, 0.95H, CH2); 4.93-4.88 (3s, 2H); 2.42 (s, 3H). Roesy signal seen between CH (triazole) at 8.05ppm and CH2 at 4.93-4.88ppm.
(S)-benzyl 2-[(1-(4-methoxyphenyl)ethyl)amino]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With triethylamine; In dichloromethane; at 20℃;
To a solution of <strong>[6298-96-0](S)-1-(4-methoxyphenyl)ethylamine</strong> (1.95 mL, 12.0 mmol) and triethylamine (5 mL, 36.1 mmol) in dichloromethane was added benzyl bromacetate (1.95 mL, 13.2 mmol). The reaction was stirred at room temperature overnight, quenched with water and extracted with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give (S)-2-[(1). Benzyl (4-methoxyphenyl)ethyl)amino]acetate (2.2 g, 62% yield
benzyl 2-((2-fluorophenyl)(methyl)amino)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73.2%
With potassium carbonate; In water; at 70℃; for 14h;
Benzyl 2-bromoacetate (0.50 niL, 3.2 mmol), <strong>[1978-38-7]2-fluoro-N-methylaniline</strong> (0.399 g, 3.19 mmol), and potassium carbonate (2.202 g, 15.93 mmol) were dissolved in water (9.11 mL) and heated to 70 C for 14h. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed with brine, dried with sodium sulfate and concentrated under reduced pressure. The residue was purified on ISCO 0-100?/o EtOAc in hexanes on a 40 g column to yield Example 006A (0.750 g, 2.33 mmol, 73.2 % yield). Compound 006A was used without further purification. LC/MS (Method A) RT = 1.14 min, MS (ESI) m/z: 274.1 (M+H)+.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 24h;
Methyl <strong>[6702-50-7]3-hydroxy-4-methoxybenzoate</strong> (21) (0.956 g, 5.19 mmol) was dissolved in dimethylformamide (10 mL). K2CO3 (potassium carbonate) (1.44 g, 10.4 mmol), and methyl bromoacetate (1.45 mL, 5.71 mmol) was added, and the reaction mixture was stirred at room temperature for 24 h. The residue was filtered and concentrated, re-dissolved in ethyl acetate and washed with 1M NaOH (sodium hydroxide), brine and dried with MgSC (magnesium sulfate). Purification by silica gel chromatography (hexane:ethyl acetate 3: 1) gave compound 22 (1.61 g, 4.88 mmol, 94%). MS (ESI) : m/z calcd for Ci8Hi805 [M+H] + 331.11; found 331.57.
2,9,10-trimethoxy-3-benzyloxyformylmethylenoxyprotoberberine chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
With potassium carbonate; In N,N-dimethyl-formamide;
General procedure: To a stirred solution of JTH (100 mg, 0.29 mmol) in anhydrous CH3CN or DMF, K2CO3 (122 mg,0.88 mmol) was added and heated to 70 °C. Then R1Br or benzyl chloroformate (2?4 eq) was added andstirred for 5?6 h. The mixture was cooled to precipitate completely, filtrated and washed by CH2Cl2 toafford compounds 5a?g.
benzyl2-(5-methoxy-2-oxobenzo[d]thiazol-3(2H)-yl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
General procedure: A mixture of appropriate amine 74a-i (1 equiv), 78 K2CO3 (1.05 equiv), and a catalytic amount of NaI in 79 acetone was stirred at room temperature. Benzyl, ethyl, or 80 methyl bromoacetate 75, 76, 77 (1.1 equiv) was added dropwise to the mixture, which was then refluxed for 2h (Scheme 2, see also Supplementary data).
benzyl 2-(1,2,3,4-tetrahydro-1-oxonaphthalen-6-yloxy)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
Potassium carbonate (17.120 g, 125.11 mmols) was added to a solution of hydroxy tetralone 3 (6.76 g, 41.70 mmols) in anhydrous acetone (200 mL) placed under nitrogen, and the mixture was left under stirring for 1 hour at room temperature. Ethyl bromoacetate (7 mL) was then added, and the reaction was left under stirring overnight at 57C, then filtered to eliminate inorganic salts, and finally, the filtrate was evaporated at low pressure. The resulting residue was then taken up with AcOEt (200 mL) and washed with a saturated solution of NaHCO3 (2 x 100 mL) and brine (2 x 100 mL). The organic phase was then dried and evaporated to give a brown oil. Finally, the crude product was purified by flash chromatography on silica gel (-hexane/ AcOEt 5:1) to give the pure compound 4 as a yellow oil (6.67g, 61% yield). The preparation is similar to that of the synthesis of ethyl 2-(l,2,3,4-tetrahydro-l- oxonaphthalen-7-yloxy) acetate (4). In this case, benzyl bromoacetate is used as reagent instead of ethyl bromoacetate. As in the case of 4, 4' also presents as a transparent oil. (93% yield). 1H NMR (CDCl3) : delta 2.14 (m, 2H), 2.63 (t, J=5.6 Hz, 2H), 2.90 (t, J=6.4 Hz, 2H), 4.72 (s, 2H), 5.25 (s, 2H), 6.65-8.12 (m, 8H).
With caesium carbonate; triethylamine; potassium iodide; In acetone; at 20℃; for 24h;
<strong>[35354-74-6]Honokiol</strong> (0.5g, 1.88mmol)Was dissolved in acetone, and then Cs2CO3 (0.88 mmol),TEA (0.5 mL, 3.76 mmol),Benzyl-2-bromoacetate (1.88 mmol)And KI (3.76 mmol) were added and reacted at room temperature for 24 hours.After the reaction was completed, the mixture was concentrated under reduced pressure to remove the solvent, and the reaction mixture was washed with water and DCM. The organic layer was dried over anhydrous MgSO 4, filtered and concentrated under reduced pressure. The obtained residue was subjected to silica column chromatography (DCM: Ether: HEX = 6: 2: 22 v: v: v, Rf = 0.7).To give compound 4(White liquid, 100 mg, 9% yield).
benzyl 2-(4-benzyl-3-oxopiperazin-1-yl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
Triethylamine (20.0 mL, 142.3 mmol, 2.5 equiv) was added at room temperature to a suspension of l-benzylpiperazin-2-one hydrochloride (13 g, 56.9 mmol, 1 equiv) in THF (300 mL). After stirring at room temperature for 30 minutes, benzyl bromoacetate (10.8 mL, 68.3 mmol, 1.2 equiv) was added to the reaction, which was then stirred an additional 4 hours at room temperature. The mixture was partitioned between water (0.5 L) and ethyl acetate (0.2 L). The aqueous layer was extracted with ethyl acetate (2 x 0.2 L). The combined organic layers were washed with saturated brine (0.5 L), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on an Interchim system (RediSep 220 g column), eluting with a gradient of 0 to 100% ethyl acetate in heptanes, to give Benzyl 2-(4-benzyl-3-oxopiperazin-l-yl)acetate as a beige oil (17.8 g, 93% yield).
Starting with 4?-hydroxy-2,4-dimethoxybenzophenone (CAS Number 41351- 30-8). (0318) (0319) [00183] To a solution of 4?-hydroxy-2,4-dimethoxybenzophenone 14 g, 0.054 mol) in acetone (60 mL) at room temperature benzyl-bromoacetate was added (13.5 g, 0.059 mol). The mixture was stirred at rt for 16 h.
To a slurry of <strong>[910209-21-1]sodium cyclopropanesulfinate</strong> (5.79 g, 45.2 mmol) in DMF (30 mL) was added benzyl 2-bromoacetate (5.97 mL, 37.7 mmol). The resulting mixture was stirred overnight at RT, after which it was diluted with H2O and Et2O. The aqueous layer was extracted with Et2O. The combined Et2O layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to afford I-2B (9.37 g, 36.8 mmol, 98% yield) as a light yellow oil. 1H NMR (400 MHz, CDCl3) delta ppm 1.02-1.09 (m, 2H) 1.24-1.31 (m, 2H) 2.67-2.76 (m, 1H) 4.03-4.09 (m, 2H) 5.26 (s, 2H) 7.34-7.44 (m, 5H).
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