* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With sodium hydroxide In 1,4-dioxane; water at 20℃;
To the solution of Lysine HCl salt in 50 ml 1,4-dioxane/H2O (1:1), 1M NaOH is added until pH reaches 10-11. Then Boc anhydride in dioxane (6.0 g in 20 ml dioxane) is added by an addition funnel. The resulting solution is stirred at room temperature overnight. The mixture is concentrated in vacuo and acidified by 4M KHSO4 until pH=1-2. Extract by Ethyl acetate twice and dried in vacuo. Colorless liquid is obtained and yielding is 100percent
92%
With sodium hydroxide In 1,4-dioxane; water at 10 - 20℃; for 20 h;
Example 1 Boc-L-Lys(Boc)-OH A 2 L three-neck flask equipped with a mechanical stirrer was charged with a solution of L-lysine monohydrochloride (50.03 g, 274 mmol) in water (275 ml), 1,4-dioxane (275 ml) and 1 M sodium hydroxide solution (275 mmol, 275 ml) (resulting: pH 10.0). To this solution was added di-tert-butyl dicarbonate (179 g, 820 mmol) in one portion whilst stirring. The evolution of gas was noted, and the pH of the reaction mixture slowly decreased. A Metrohm Titrino 702 SM dosing unit was set up in "Set Endpoint Titration" mode in order to keep the pH of the reaction mixture constant at pH 7.30 by automatically dosing 1 M NaOH. Note: the reaction mixture apparently formed a buffered system at pH 7.05. LCMS (NQAD detection) indicated near-complete consumption of the lysine starting material after a reaction time of 20 h. The reaction mixture was concentrated by rotary evaporation to a total volume of ˜500 mL. Water (250 mL) was added (resulting pH: 8.8) and then EtOAc was added (250 mL). Solid KHSO4 (˜70 g) was added in portions until a pH of 2.3 was reached (Note: evolution of gas; the mixture formed a buffer at pH 2.3). The phases were separated, the aqueous layer was extracted with EtOAc (2*250 mL) and the combined organic phases were washed sequentially with 0.25 M KHSO4 (2*100 mL), water (50 mL) and brine (2*50 mL). Drying over Na2SO4 and concentration in vacuo yielded the title compound as a clear, colorless, sticky mass (98.18 g). LCMS: Purity (NQAD detection): 99percent, mass in agreement with molecular formula (neg. m/z=345 [M-1]-, 691 [2M-1]-). TLC (EtOAc/heptane=1/1 containing 2 vol percent AcOH, anisaldehyde staining): One major spot (Rf 0.28), no Boc2O present. A small impurity with a higher Rf was visible. Kaiser test: negative (no primary amines present). Isolated yield: 92percent
90%
With sodium hydrogencarbonate In tetrahydrofuran; water at 0 - 35℃; for 24 h;
Lysine hydrochloride (about 5 g, 27.3 mmoi) is dissolved in 50 ml ii2O and to it NaHCO3 (6.9 g, 82,1 mmol) is added and stirred. To this, Dibutyipyrocarbonat (Boc2O) (7.16 g, 65,5 mmoi) in 50 ml Tetrahydrofuran (Ti-IF) is added at a temperature of about 0°C. The solution is stned at room temperature (20°C to 35°C) and atmospheric pressure (1 atm) for aboutl2 hrs. After about 12 his, 7.16g, 65.5 mmoi of Boc2O is added again and stirred for about 12 hrs at room temperature (20°C to 35°C). At the end of the reaction, THF is removed under reduced pressure and the aqueous layer is washed with diethyl ether to remove organic impurities. Then the aqueous layer is acidified to pH 4-5 using citric acid solution. Then the aqueous layer is extracted with Dichloromethane (DCM). The organic layer is then washed with brine, dried over anhydrous Na2SO4. This DCM layer is removed under reduced jressure to obtain BOC-LYS (BOC)-OH with a yield of about 90percent, (‘H NMR: ö 5.6 (d, 1H), 4.9 (s, 1H), 4.15 (t, 1Ff), 3.09 (d, 2H), 1.8 (m, li-I), 1.67 (m, 1H), 1.54-1.32 22F{). [M+Na] obsd. == 369.2137 (calc. == 369.2002)
83%
With sodium hydrogencarbonate; sodium hydroxide In ethanol; water at 20℃; for 48 h; Cooling with ice
NaOH (0.8 g, 0.02 mol) was dissolved in7.5 mL of water and L-Lysine monohydrochloride (1.83 g, 0.01 mol) was added tothe solution, followed by addition of NaHCO3 (0.42 g, 0.005 mol). Asolution of di-tert-butyl-carbonate(4.55 g, 0.02 mol) in ethanol (10 mL) was added dropwise to the stirringsolution of the amino acid cooled with ice. After one hour, the reactionmixture was warmed up at room temperature and stirred for 2 days. Water (20 mL)was then added to dissolve the precipitate. Unreacted di-tert-butyl-carbonate was extracted three times with petroleumether. The aqueous layer was acidified with NaHSO4 1M up to pH 3 andthe product was extracted with EtOAc. The organic layer was washed twice withwater and dried over NaSO4. The solvent was removed under vacuum,yielding a transparent oil (2860 mg, 83percent yield). 1H NMR (400 MHz,DMSO-d6): δ 12.38 (bs, 1H, COOH), 6.98 (d, J=8.3 Hz, 1H, CH-NH-Boc), 6.74 (t, J=5.6 Hz, 1H, CH2-NH-Boc), 3.82 (m, 1H, CH-NH-Boc),2.88 (m, 2H, CH2-NH-Boc), 1.57 (m, 4H, CH2), 1.31-1.41(m, 20H, t-C4H9,CH2).
29.7 g
Stage #1: With sodium hydroxide In water at 15 - 60℃; for 12 h; Stage #2: With hydrogenchloride In water at 10 - 15℃;
Examplel Preparation of 2,6-bis-tertiarvbutoxycarbonylamino hexanoic acidTo a solution of L-lysine monohydrochloride (25g, 0.14mol) and sodium hydroxide (15g) in water (250 ml), ditertiary butyl dicarbonate (70.0 g, 0.32 mol) was added at 15-25°C. The temperature was slowly raised to 55-60 °C and the reaction mixture was stirred for 12 hours.. After completion of reaction, ( monitored by TLC), the reaction mixture was cooled to 10-15°C and pH was adjusted to 2.5-3.5 with 2N hydrochloric acid. The reaction mass' was then extracted with dichloromethane (2 x 125 ml) and combined organic layer was successively washed with water (150 ml) and brine (150 ml). Dichloromethane layer was distilled under vacuum at 30-40 °C to obtain 29.7g of title compound as a viscous oily mass having purity 96.5percent by HPLC.
Reference：
[1] Patent: US2014/127138, 2014, A1, . Location in patent: Paragraph 0321; 0322
[2] Patent: US2016/376618, 2016, A1, . Location in patent: Paragraph 0206-0212
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 4, p. 1428 - 1436
[4] Patent: WO2014/97178, 2014, A1, . Location in patent: Page/Page column 49
[5] New Journal of Chemistry, 2018, vol. 42, # 5, p. 3192 - 3195
[6] Russian Journal of Applied Chemistry, 2005, vol. 78, # 6, p. 1003 - 1007
[7] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 21, p. 6891 - 6899
[8] Patent: WO2013/11526, 2013, A1, . Location in patent: Page/Page column 15-16
5
[ 56-87-1 ]
[ 24424-99-5 ]
[ 2483-46-7 ]
Yield
Reaction Conditions
Operation in experiment
92%
With sodium hydroxide In 1,4-dioxane; water at 20℃; for 12 h;
To a solution of l-lysine monohydrate (5.09 g, 31.0 mmol) in water/dioxane (1:1, 100 mL) were added di-tert-butyl dicarbonate (16.9 g, 78.0 mmol) and 1 N NaOH aq (35 mL). The reaction mixture was stirred at room temperature 12 h and then concentrated in vacuo until approximately 50 mL remained. The pH was adjusted to 1-2 by careful addition of an aqueous KHSO4 solution (150 g/L). The suspension was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure to afford the product (9.89 g, 28.5 mmol, 92percent) as an oil. 1H NMR (DMSO-d6, 200.1 MHz): δ = 12.40 (s, 1H, OH), 6.98 (d, J = 7.9 Hz, 1H), 6.76 (t, J = 5.4 Hz, 1H), 3.75-3.86 (m, 1H), 2.50-2.83 (m, 2H), 1.37 (s, 18H), 1.14-1.68 (m, 6H) ppm; 13C NMR (DMSO-d6, 50.3 MHz): δ = 173, 155.1, 77.4, 76.8, 52.9, 29.9, 28.6, 27.7, 22.4 ppm (one signal, probably around 40 ppm, is hidden by the solvent signal).
92%
With sodium hydroxide In 1,4-dioxane; water at 20℃; for 12 h;
To a solution of L-lysine monohydrate (5.09 g, 31.0 mmol) in water/dioxane (1:1, 100 mL) were added di-tert-butyl dicarbonate (16.9 g, 78.0 mmol) and 1 N NaOH aq. (35 mL). The reaction mixture was stirred at room temperature 12 h and then concentrated in vacuo until approximately 50 mL remained. The pH was adjusted to 1–2 by careful addition of an aqueous KHSO4 solution (150 g/L). The suspension was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure to afford the product (9.89 g, 28.5 mmol, 92percent) as an oil. 1H NMR (DMSO-d6, 200.1 MHz): δ = 12.40 (s, 1H, OH), 6.98 (d, J = 7.9 Hz, 1H), 6.76 (t, J = 5.4 Hz, 1H), 3.75–3.86 (m, 1H), 2.50–2.83 (m, 2H), 1.37 (s, 18H), 1.14–1.68 (m, 6H) ppm; 13C NMR (DMSO-d6, 50.3 MHz): δ = 173, 155.1, 77.4, 76.8, 52.9, 29.9, 28.6, 27.7, 22.4 ppm (one signal, probably around 40 ppm, is hidden by the solvent signal).
90%
Stage #1: With sodium carbonate In tetrahydrofuran; water for 0.25 h; Stage #2: at 0℃; Stage #3: With hydrogenchloride In tetrahydrofuran; water; ethyl acetate
Example 1; Synthesis of Lysine^-aminoethyl ester trihydrochloride ("trihydrochloride salt ") Di-Boc lysine (ref. 22117-48); L-lysine (450 grams, 2.46 mol) was charged to a 12 liter flask followed by water (3.6 liters) and THF (3.6 liters). Sodium carbonate (540 grams, 5.1 mol) was added and the mixture was stirred for 15 minutes. The mixture was then cooled to 0°C in an ice bath and to it was added di-/ert-butyl-dicarbonate (1 102 grams, 5.05 mol) in portions. The mixture was allowed to stir overnight. Ethyl acetate (1.5 liters) was added to the reaction mixture followed by 6N HC1 until the pH was <3 (caution: gas evolution.) The layers were allowed to separate and the aqueous layer was removed. The organic layer was dried over magnesium sulfate, then was concentrated under reduced pressure to give an oil. Mass recovery was approximately 770 grams (90percent yield).
90%
With sodium hydrogencarbonate In tetrahydrofuran; water at 0 - 20℃;
Commercially available L-lysine (0.146 g, 1.0 mmol) dissolved in H2O (5.0 mL) was mixed with NaHCO3 (0.252 g, 3.0 mmol). B0C2O (1 .048 g, 4.8 mmol) in 10.0 mL of THF was subsequently added to the mixture at 0 °C and stirred at room temperature overnight. At the end, THF was evaporated and the mixture was washed with diethyl ether. The aqueous layer was acidified to pH = 6 with citric acid, followed by CH2CI2 extraction. The organic layer was washed with water and brine, and dried over anhydrous Na2SO4. The mixture was then concentrated and purified by flash column chromatography (eluted with CH2Cl2/MeOH from 100:0 to 15:1 , v/v) to afford the desired compound as white solid (Yield: 90 percent).
64.3%
With sodium hydroxide In tetrahydrofuran; water at 0 - 20℃; for 24 h;
General procedure: l-lysine, l-alanine, l-leucine, l-isoleucine, l-phenylalanine, l-threonine (5g, 1 equiv) was dissolved in H2O (100mL), and to it NaOH (3 equiv) was added and stirred. To this, di-tert-butyl dicarbonate (Boc2O) (2.4 equiv) in 50mL of tetrahydrofuran (THF) was added at 0°C [39]. Then the reaction mixture was stirred at room temperature for 24h. At the end of the reaction, THF was removed under reduced pressure and the aqueous layer was washed with diethyl ether to remove organic impurities. Then the aqueous layer was acidified to pH 4–5 using 1M H2SO4 aqueous solution. The aqueous layer was then extracted with dichloromethane (DCM). The organic layer was then washed with brine and dried over anhydrous Na2SO4. The organic layer was removed under reduced pressure to obtain the compound.
64.3%
With sodium hydroxide In tetrahydrofuran; water at 0 - 20℃; for 24 h;
l-lysine (5g, 1 equiv.) was dissolved in H2O (100mL), and NaOH (3 equiv) was added to this solution and stirred. Di-tert-butyl dicarbonate (Boc2O) (2.4 equiv) in 50mL of tetrahydrofuran (THF) was added at 0°C [53]. Then the reaction mixture was stirred at room temperature for 24h. At the end of the reaction, THF was removed under reduced pressure and the aqueous layer was washed with diethyl ether to remove organic impurities. Then the aqueous layer was acidified to pH 4–5 using 1MH2SO4 aqueous solution. The aqueous layer was then extracted with dichloromethane (DCM). The organic layer was then washed with brine and dried over anhydrous Na2SO4. The organic layer was removed under reduced pressure to obtain the compound.
63%
With sodium hydroxide In tetrahydrofuran; water at 20℃; for 24 h; Cooling with ice
Took L- lysine (5g, 34.2mmol) and sodium hydroxide (4.1g, 102.61mmol) was added in 250mL single-port flask, 100mL of water was added, under ice-cooling with stirring, to a light brown clear yellow system; di-tert butyl ester (Boc2O) (17.92g, 82.09mmol) was dissolved in 50mL of tetrahydrofuran was then added dropwise (1d / s) to the reaction system; After the addition was complete, the system was transferred into a reaction was continued at room temperature for 24 hours.The reaction time after the reaction is stopped, the system was removed by rotary evaporation under reduced pressure of tetrahydrofuran, and the system is washed with ether (50ml × 2) removing the organic impurities in the system; then with 1M sulfuric acid solution to adjust the system pH 4 and then extracted with dichloromethane (50mL × 3) and the combined organic phase was washed with saturated sodium chloride (50mL × 1), and finally dried over anhydrous sodium sulfate, suction filtered, concentrated, and dried in vacuo to give a yellow foamy solid 7.5g, 63percent yield.
45%
With potassium hydroxide In water at 50℃;
Similar to the method of Ke et al. (42), L-lysine (4.4 g, 30mmol) and KOH (2.3 g, 39 mmol) were dissolved in water (100ml) and THF (12.5 ml). Di-tert-butyl dicarbonate (14.4 g, 66 mmol) was added in portions, and the mixture was stirred for14 h at 50 °C. A 1 M solution of HCl was added dropwise to adjust the pH to 5.5, followed by extraction with EtOAc (3 100 ml). The combined extracts were dried with MgSO4 and concentrated in vacuo. Column chromatography on silica gel with hexane/EtOAc (2:1) yielded N,N-di-(tert-butyloxycarbonyl)-L-lysine (4.6 g, 13.3 mmol, 45percent) as a colorless solid.
34.2 g
Stage #1: With sodium carbonate In tetrahydrofuran; water for 0.25 h; Stage #2: at 0 - 20℃;
To a solution of L-lysine (20 g, 109.5 mmol) in 160 mL of water and 160 mL of tetrahydrofuran was added sodium carbonate (24 g, 226.4 mmol). After stirring for 15 minute, the reaction mixture was cooled down to 0 °C and di-tert-butyl-dicarbonate (48.93 g, 224.4 mmol) was slowly added. After stirring overnight at room temperature, the reaction mixture was diluted with ethyl acetate (66.7 mL) and 6N hydrochloric acid solution (56.7mL) was added to adjust pH to 3 or lower. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to provide the desired product (34.2 g, 98.8 mmol).
Reference：
[1] Organic and biomolecular chemistry, 2003, vol. 1, # 14, p. 2612 - 2620
[2] Chemistry - A European Journal, 2004, vol. 10, # 23, p. 5901 - 5910
[3] Journal of Materials Chemistry, 2012, vol. 22, # 19, p. 10035 - 10041
[4] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 6, p. 1241 - 1250
[5] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 20, p. 4606 - 4609
[6] Patent: WO2012/106588, 2012, A2, . Location in patent: Page/Page column 17-18
[7] Journal of Medicinal Chemistry, 2017, vol. 60, # 9, p. 3684 - 3702
[8] Patent: WO2018/187867, 2018, A1, . Location in patent: Page/Page column 24
[9] Helvetica Chimica Acta, 2000, vol. 83, # 2, p. 322 - 327
[10] Organic and Biomolecular Chemistry, 2013, vol. 11, # 21, p. 3461 - 3468
[11] Journal of the American Chemical Society, 2000, vol. 122, # 33, p. 7927 - 7935
[12] Tetrahedron, 2003, vol. 59, # 31, p. 5837 - 5848
[13] Angewandte Chemie - International Edition, 2014, vol. 53, # 4, p. 1113 - 1117[14] Angew. Chem., 2013, vol. 126, # 04, p. 1131 - 1135,5
[15] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 1489 - 1509
[16] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 925 - 945
[17] Patent: CN105566149, 2016, A, . Location in patent: Paragraph 0043; 0044; 0045
[18] Chemical Communications, 2015, vol. 51, # 31, p. 6832 - 6835
[19] Journal of Biological Chemistry, 2013, vol. 288, # 34, p. 24717 - 24730
[20] Molecular Crystals and Liquid Crystals (1969-1991), 1989, vol. 170, p. 195 - 214
[21] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 23, p. 9984 - 9990
[22] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2012, vol. 67, # 7, p. 731 - 746
[23] Macromolecules, 2015, vol. 48, # 6, p. 1688 - 1702
[24] Journal of Medicinal Chemistry, 2016, vol. 59, # 23, p. 10520 - 10529
[25] Patent: WO2017/14332, 2017, A1, . Location in patent: Paragraph 74; 75
[26] Patent: CN106995384, 2017, A, . Location in patent: Paragraph 0065; 0066
[27] Patent: CN107382893, 2017, A, . Location in patent: Paragraph 0035-0036
6
[ 24424-99-5 ]
[ 13734-28-6 ]
[ 2483-46-7 ]
Yield
Reaction Conditions
Operation in experiment
93%
With triethylamine In 1,4-dioxane; water for 18 h; Cooling with ice
[0043] Nα-(tert-butoxycarbonyl)-L-lysine (1) (985 mg, 4 mmol) was dissolved in anhydrous 1,4-dioxane (3 mL) and water (3 mL). After adding triethylamine (615 μL, 4.4 mmol), to the solution was added di-tert-butyl dicarbonate (960 mg, 4.4 mmol) dropwise under ice-cooling, and then the mixture was stirred for 18 hours. Completion of the reaction was confirmed by TLC (ethyl acetate:n-hexane=5:1), and the reaction solution was poured into a 0.5 N aqueous solution of hydrochloric acid (80 mL). The mixture was extracted with ethyl acetate (3×40 mL) and the organic layer was washed with saturated saline (80 mL) and dried over anhydrous magnesium sulfate. After evaporation under a reduced pressure, the obtained material was purified by flash column chromatography (ethyl acetate:n-hexane=1:1 to 2:1) to give intermediate 2 (1.29 g, 93percent) as a white solid. [0044] 1H-NMR (300 MHz, CDCl3) δ: 5.21 (br s, 1H), 4.62 (br s, 1H), 4.28 (br s, 1H), 3.14 (d, 2H, J=6.0 Hz), 1.88 (br s, 1H), 1.76 (br s, 1H), 1.45-1.23 (m, 22H), 0.92-0.88 (m, 1H).
To a solution of L-<strong>[13515-95-2]lysine methyl ester dihydrochloride</strong> (1 g, 4.3 mmol) prepared in step 1 in ethyl acetate (20 mL) was slowly added triethylamine (0.9 g, 8.9 mmol). After stirring for 10 minutes at room temperature, di-boc lysine (2.6 g, 7.4 mmol) prepared in step 1 and N-hydroxysuccinimide (0.9 g, 7.4 nimwere added. To the reaction mixture dicyclohexylcarbodimide (1.5 g, 7.4 mmol) was added at 0 °C. After stirring overnight, the reaction mixture was cooled down to 0 °C, filtered to remove precipitate. The organic layer was washed with saturated sodium bicarbonate solution, 12percent sodium bisulfate solution, saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol/triethylamine = 95/5/0.1) to provide the desired product (2.3 g, 2.8 mmol).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 48.5h;Cooling with ice;
Weigh 4.0 g of H-Lys-OMe · 2HCl, 14.8 g of Boc-Lys (Boc) -OH, 5.1 g of HOBT and 13.2 g of EDC · HCl in a 100 mL round bottom flask with a tube. Add 30 mL double distilled DCM, stirred to dissolve, add 28.3 mL DIEA reaction in ice bath for 0.5 h, Then reacted at room temperature for 48 h. Water pump to remove the solvent, The chloroform was dissolved, washed successively with 1 M HCl, saturated NaHCO3 and NaCl, After drying over anhydrous MgSO4 overnight, filtration, solvent removal, After silica gel column chromatography (eluent DCM / EA = 1: 1) of 200-300 mesh, a white powder MeO-Lys (G2) -Boc4 (Compound 1)
{5-<i>tert</i>-butoxycarbonylamino-5-[(4-oxo-2,3,4,5,6,11-hexahydro-1<i>H</i>-5,11-diaza-benzo[<i>a</i>]trinden-8-ylmethyl)-carbamoyl]-pentyl}-carbamic acid <i>tert</i>-butyl ester[ No CAS ]
{5-[3,4-bis-(2,3,5,6-tetrafluoro-pyridin-4-ylethynyl)-phenylcarbamoyl]-5-<i>tert</i>-butoxycarbonylamino-pentyl}-carbamic acid <i>tert</i>-butyl ester[ No CAS ]
(5-{2-[3,4-bis-(2,3,5,6-tetrafluoro-pyridin-4-ylethynyl)-benzoylamino]-ethylcarbamoyl}-5-<i>tert</i>-butoxycarbonylamino-pentyl)-carbamic acid <i>tert</i>-butyl ester[ No CAS ]
N4-(di-N-tert-butoxycarbonyl-lysyl)-5'-O-palmitoyl-deoxycytidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dicyclohexyl-carbodiimide; In ISOPROPYLAMIDE; at 0 - 4℃; for 90h;
14 grams of 5'-O-palmitoyl-deoxycytidine is dissolved in 100 ml dimethylacetamide, 1 molar equivalent of di-tert-butoxycarbonyl-lysine is added, and the mixture is cooled in an ice bath. 1.2 molar equivalents (7.4 g) of dicyclohexylcarbodiimide are added and the mixture is stirred at 4 C. for 90 hours. The precipitate (dicyclohexylurea) is removed by filtration. 100 ml of water is added to the filtrate, followed by 1 liter of ethyl acetate. N4-(di-N-tert-butoxycarbonyl-lysyl)-5'-O-palmitoyl-deoxycytidine is separated from unreacted reagents by chromatography over silica gel. The t-butoxycarbonyl protecting groups are removed by the standard methods of treatment with an acid, such as trifluoroacetic acid.
Triamides of glycine and beta-alanine (207a and 207b, respectively) were formed using the same reaction conditions (Scheme 12). Triamides with alpha-branched amino acids could also be formed. For example, under the conditions described, a triamide with bis-BOC-lysine side chains was formed (compound 207c). The C24 esters of 207a-c were hydrolyzed with LiOH in THF and methanol to give alcohols 208a-c. Deprotection using HCl in dioxane (208a-c) gave triamides 209a-c in good yield.
With dmap; diisopropyl-carbodiimide; In dichloromethane; at 20℃; for 18h;
NH2 NJ , Y) LY0 OH OH 1) LyseBoc) OH. DMAP H2N, < OO0Hz DIC, DCM, rt z O I w w v w v w t O 4HCI HO 2) 4M HCI In 1, 4-dioxan HAN HPLC: Column: Waters Symmetry C18 3.5 micron 4.6 mm x 150 mm; Temperature: 25C ; Mobile phase: (A = 0.025 % TFA in H20 ; B = 0. 025% TFA in MeCN), 95% A/5% B (start); linear gradient to 100% B over 12 min, hold for 4 min; linear gradient to 95% B/5% A over 2 min; linear gradient to 95% A/5% B over 4 min; Flow rate: 2.5 ML/MIN ; Detector wavelength: 474 NM. To a mixture of astaxanthin 2E (11.5 g, 19.3 mmol) and BocLys (Boc) OH (20.0 g, 57.7 mmol) in methylene chloride (500 mL) were added 4-dimethylaminopyridine (DMAP) (10.6 g, 86.6 mmol) and 1,3- diisopropylcarbodiimide ("DIC") (13.4 g, 86.7 mmol). The round-bottomed flask was covered with aluminum foil and the mixture was stirred at ambient temperature under nitrogen overnight. After 16 hours, the reaction was incomplete by HPLC and TLC. An additional 1.5 equivalents of DMAP and DIC were added to the reaction and after 2 hours, the reaction was complete by HPLC. The mixture was then concentrated to 100 mL and a white solid (1,3-diisopropylurea) was filtered off. The filtrate was flash chromatographed through silica gel (10% to 50% Heptane/EtOAc) to give the desired product as a dark red solid (XXI) (28.2 g, >100% YIELD). H NMR (DMSO-D6) 8 7.24 (2 H, t, J=6.3 Hz), 6.78 (2 H, d, 5.0 Hz), 6.57-6. 27 (14 H, m), 5.50-5. 41 (2 H, m), 3.99-3. 97 (2 H, d, 6.0 Hz), 2.90 (4 H, m), 2.03 (4 H, m), 2.00 (6 H, s), 1.97 (6 H, s), 1.82 (6 H, s), 1.70-1. 55 (4 H, m), 1.39-1. 33 (36 H, m), 1.24-1. 13 (8 H, m), 1.01-0. 99 (6 H, m), 0.86-0. 83 (6 H, m). HPLC : 21.3 min (24.6% AUC) ); 22.0 min (48.1% (AUC) ); 22.8 min (20.6% (AUC) ). TLC (1: 1 Heptane/EtOAc: RF 0. 41; Rf 0. 5; RF 0. 56). LC/MS analysis was performed on a Agilent 1100 LC/MSD VL ESI system by flow injection in positive mode; Mobile Phase: A=0.025% TFA in H2O ; B=0.025% TFA in MeCN, 10% A/90% B (start); Starting pressure: 10 bar; PDA Detector 470 NM. +ESI, m/z=1276.1 (M+NA.
With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In DMF (N,N-dimethyl-formamide); for 3h;
Step d) Synthesis and salification of derivative (IA) BOC-LYS (BOC) -OH (418 MG, 1.2 MMOLES) AND 1-HYDROXY-LH-BENZOTRIAZOLE (HOBT, 193 mg, 1.4 mmoles) are dissolved in a small round-bottom flask in 5 ml of dry DMF under stirring at room temperature. 5'N, N'-dicyclohexylcarbodiimide (DCC, 270 mg, 1.3 mmoles) is added and after further 15'the solution becomes opalescent, which indicates activation of the amino acid. The octaamino- octapropoxy derivative (Va) (130 mg, 0. 1 mmoles) is added drop by drop, dissolved in 2 ml of dry DMF. The reaction is left under stirring for 3 h, then filtered and evaporated to dryness under reduced pressure. The reaction mixture is then subjected to column chromatography on silica gel at atmosphere pressure using a CH2CL2/ETOH gradient, starting from 96: 4 to 92: 8.302 mg of acylated intermediate derivative is obtained (yield 78%) which, by treatment with trifluoracetic acid for 1 h, yields the corresponding salt. The compound was characterized by means of MS, IH and 13C NMR SPECTROSCOPY. H-NMR spectrum signals are hereinafter reported: (400 MHZ, DMF d6, 297 K) 8 0.78 (t, J= 7.2 Hz, CH3, 24 H), 1.59 (m, 2xCH2,32 H), 1.79 (m, CH2, 16 H), 2.02 (m, CH2, 16 H), 3.03 (t, J= 6.5 Hz, OCH2, 16 H), 3.53 (M, CH2NH3+, 16 H), 3.98 (bs, ArCH2Ar, 16 H), 4.23 (bt, J= 6.2 Hz, CH, 8 H), 7.45 (S, ArH, 16 H), 8.42 (bs, NH3+, 24H), 8.78 (bs, NH3+, 24H), 10.61 (s, NH, 8H).
With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide; In dichloromethane; at -10 - 20℃;
The diamine 100 mg (0.176 mmol), HOBt 2 eq (0.353 mmol, 54 mg), BOC2Lys 2.4 eq (0.423 mmol, 135 mg) and DIPEA 2 eq (0.353 mmol, 62 ml) was dissolved in CH2Cl2 (20 ml). The mixture was cooled at -10 C. and DCC 2.4 eq (0.423 mmol, 87 mg) was added. The mixture was stirred at -10 C. and allowed to reach room temperature very slowly and set aside overnight. The DCU was removed by filtration, and solvent was evaporated off. The crude was redissolved in AcOEt (30 ml), was washed successively 4% NaHCO3 (2×15 ml), 4% citric acid (2×15 ml), water (20 ml) and finally brine (20 ml). Organic phase was dried over anhydrous sodium sulfate and was evaporated to dryness. The residue was chromatographied on silica gel and was eluated with hexane/AcOEt 1/1 (rf=0.01) to AcOEt/MeOH 9/1 (rf=0.6) yield 152 mg (71%) as oil. 1H-NMR (CDCl3): 7.05 sbroad(1H); 6.69 sbroad (1H); 5.6-4.7 m (6H); 4.9-4.1 m (4H); 3.7-3.0 m (16H); 2.2-2.0 m (6H); 2.0-1.0 m (88H); 0.88 t (3J=6.8 Hz, 6H (-CH3)2).
Step 1: 1 g of Boc-Lys(Boc)-OH.DCHA was dissolved in 10 ml of ethyl acetate in a 50 ml round-bottomed flask, followed by addition of 1.2 equivalents of aqueous 2M sulfuric acid solution (i.e. 2.2 ml). Two clear phases were obtained. The organic phase was set aside. 5 ml of cold distilled water were added to the aqueous phase and the resulting mixture was then extracted with 2*5 ml of ethyl acetate. The organic phases were combined and washed with 2*10 ml of distilled water and then dried over magnesium sulfate and the solvent was evaporated off on a rotary evaporator (bath temperature below 40 C.). The colorless oil was dried under vacuum to give 0.47 g of Boc-Lys(Boc)-OH.
20
O-benzotriazol-1-yl-N,N,N,',N'-bis(tetramethylene)uronium hexafluorophosphate[ No CAS ]
[ 2483-46-7 ]
4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride[ No CAS ]
(S)-{4-[4,4-Bis-(4-fluoro-phenyl)-butylcarbamoyl]-4-tert-butoxycarbonylamino-butyl}-carbamic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
814 mg (81%)
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;
EXAMPLE 67 Preparation of (S)-{4-[4,4-Bis-(4-fluoro-phenyl)-butylcarbamoyl]-4-tert-butoxycarbonylamino-butyl}-carbamic acid tert-butyl ester A solution of 581 mg (1.68 mmol) BOC-Lys(Boc)-OH (Bachem Inc., Torrance, Calif.), 0.88 mL (5 mmol) N,N-diisopropylethylamine, and 636 mg (1.68 mmol) O-benzotriazol-1-yl-N,N,N,',N'-bis(tetramethylene)uronium hexafluorophosphate in 4 mL dry DMF was stirred at 3 for 35 minutes, at which time 500 mg (1.68 mmol) 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride was added, and the reaction stirred an additional 30 minutes at which time it was diluted with 20 mL diethyl ether, and washed with 20 mL saturated aqueous sodiumbicarbonate solution and twice with 20 mL brine, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue thus obtained was further purified by silica gel chromatography using 1:1 ethyl acetate:hexanes as eluant, to give 814 mg (81%) of titled compound; mp 54-59 C. APCI-MS m/z 590.4(MH+).
NH<SUB>2</SUB>-Lys(Boc)-2-chloro-trityl resin[ No CAS ]
[ 2483-46-7 ]
[ 68858-20-8 ]
[ 76-05-1 ]
[ 794590-41-3 ]
Yield
Reaction Conditions
Operation in experiment
64%
With pyridine; In methanol; dichloromethane; for 0.5h;
Example 7 H-Lys-Val-Lys-NH-Cetyl *3TFA The protective peptide is built on 13.5 g (10.8 mmol) of H-Lys(Boc)-2-chlorotrityl resin using Fmoc-Val-OH and Boc-Lys(Boc)-OH. The resin is treated for 3*10 min with 80 ml of TFA 1% in methylene chloride and the solution is neutralized with pyridine:methanol solution and purified by prep. HPLC. Yield: Boc-Lys(Boc)-Val-Lys(Boc)-OH 4.66 g (6.915 mmol, 64%)
PEG2-amine (compound 20, 1.25 mmol) is azeotroped and toluene is removed in vacuo to dryness. The azeotroped PEG2-amine is dissolved in 200 niL of DCM and Boc-Lys-Boc (compound 2, 2.638 g, 5 mmol) and DMAP (610 mg, 5mmol) are added and the reaction mixture is cooled to 0 0C for 15 minutes before the addition of EDC (958 mg, 5 mmol). The reaction mixture is allowed to warm to room temperature with stirring overnight. The solvent is removed in vacuo to dryness and the residue is recrystallized form IPA to give the product:
PEG-diamine(compound 1, Mw. 20 kDa, 25 g, 1.25 mmol) was azeotroped and toluene was removed in vacuo to dryness. Dissolved in 200 mL of DCM and Boc-Lys-Boc (compound 2, 2.638 g, 5 mmol) and DMAP (610 mg, 5mmol) were added and the reaction mixture was cooled to 0 0C for 15 minutes before the addition of EDC (958 mg, 5 mmol). The reaction mixture was allowed to warm to room temperature with stirring overnight. The solvent was removed in vacuo to dryness and the residue was recrystallized form 2-Propanol to give 14 g of the product: 13C NMR delta 171.30, 78.3, 53.44, 39.08, 38.27, 31.59, 28.72, 27.63, 27.52, 21.71.
N-(3-aminopropyl)methacrylamide hydrochloride[ No CAS ]
C23H42N4O6[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 4; Synthesis of P-2; Compound 10 - To a cooled (0 0C) solution of 7V,7V-di-boc-lysine(dicyclohexylammonium) salt (4.2 g, 8.0 mmol) in dichloromethane (200 mL), was added /V-(3~dimethylaminopropyl)-N'-ethylcarbodiirnide hydrochloride (1.8 g, 9.6 mmol), 1- hydroxy-benzotriazole hydrate (1.3 g, 9.6 mmol). and triethylamine (1.3 mL, 9.6 mmol). After stirring for 30 min. at 0 0C, 7V-(3-aminopropyl)methacrylamide hydrochloride (1.7 g, 9.6 mmol) and triethylamine (1.3 mL, 9.6 mmol) were added. The reaction was stirred for 8 h., then washed with saturated NaHCO3 (3 x 75 mL). The DCM layer was dried with MgSO4, reduced in volume in vacuo, and purified by flash column chromatography (2% - 20% methanol in DCM) to give compound 6. TLC: Rf = 0.71 (10% MeOH/DCM). The approp?ate fractions were pooled and concentrated to about 5 mL (not taken to dryness to avoid polymerization), then 1.25 M methanohc HCl (30 mL) was added and the reaction was stirred for 48 h., and concentrated in vacuo to give 10 as a white foam (2.1 g, 78%). H NMR (D2O, 500 MHz) delta 1.44 (p, J = 8.3 Hz, 2H), 3.71 (p, J = 7.8 Hz, 2H), 1.78 (p, J= 6.9 Hz, 2H), 1.90 (m, 2H), 1.92 (s, 3H), 3.00 (t, J = 7.7 Hz, 2H), 3.29 (m, 4H), 3.95 (t, J = 6.7 Hz, IH), 5.44 (s, IH), 5.67 (s, IH).
BOC protected lysine (6.25 g, 0.018 mole) was dissolved in about 40 mL of tetrahydrofuran under a nitrogen atmosphere. The solution was cooled to about 0 C. using an ice-water bath and carbonyl diimidazole (2.93 g, 0.018 mole) was added to the cooled solution. The reaction mixture was then allowed to stir for about 5 min. at about 5 C. and then for about 30 min. at room temperature. To the resulting solution was then added by dropwise addition a solution of hexadecanol (4.38 g, 0.018 mole) in about 10 mL of tetrahydrofuran. The resulting solution was then warmed to about 45 C. and allowed to stir for about 12 h. After stirring, the solvent was evaporated under reduced pressure; the resulting residue dissolved in ethyl acetate; the ethyl acetate washed with 0.1 N hydrochloric acid (3 times), saturated aqueous sodium hydrogen carbonate (3 times), and brine (3 times); and the organic phase dried (Na2SO4). The ethyl acetate was then removed under reduced pressure to provide crude BOC protected lysine hexadecanoate that was purified using silica gel column chromatography eluted with 0 to 20 percent ethyl acetate in hexane. The solvent was then evaporated under reduced pressure to provide purified BOC protected lysine hexadecanoate. Trifluoroacetic acid (20 mL) was added to the purified BOC protected lysine hexadecanoate and the resulting reaction mixture stirred for about 5 h. Excess trifluoroacetic acid was removed under reduced pressure. The resulting residue was then dissolved in methanol and passed through a Dowex 550A(OH) resin (50 g) (commercially available from Dow Chemical Company of Midland Mich.) and the solvent removed under reduced pressure to provide lysine hexadecanoate that was dried under vacuum to provide dried lysine hexadecanoate (3.6 g).
Lysine hexadecanoate: BOC protected lysine (6.25 g, 0.018 mole) was dissolved in about 40 mL of tetrahydrofuran under a nitrogen atmosphere. The solution was cooled to about 0 C. using an ice-water bath and carbonyl diimidazole (2.93 g, 0.018 mole) was added to the cooled solution. The reaction mixture was then allowed to stir for about 5 min. at about 5 C. and then for about 30 min. at room temperature. To the resulting solution was then added by dropwise addition a solution of hexadecanol (4.38 g, 0.018 mole) in about 10 mL of tetrahydrofuran. The resulting solution was then warmed to about 45 C. and allowed to stir for about 12 h. After stirring, the solvent was evaporated under reduced pressure; the resulting residue dissolved in ethyl acetate; the ethyl acetate washed with 0.1 N hydrochloric acid (3 times), saturated aqueous sodium hydrogen carbonate (3 times), and brine (3 times); and the organic phase dried (Na2SO4). The ethyl acetate was then removed under reduced pressure to provide crude BOC protected lysine hexadecanoate that was purified using silica gel column chromatography eluted with 0 to 20 percent ethyl acetate in hexane. The solvent was then evaporated under reduced pressure to provide purified BOC protected lysine hexadecanoate. Trifluoroacetic acid (20 mL) was added to the purified BOC protected lysine hexadecanoate and the resulting reaction mixture stirred for about 5 h. Excess trifluoroacetic acid was removed under reduced pressure. The resulting residue was then dissolved in methanol and passed through a Dowex 550A(OH) resin (50 g) (commercially available from Dow Chemical Company of Midland Mich.) and the solvent removed under reduced pressure to provide lysine hexadecanoate that was dried under vacuum to provide dried lysine hexadecanoate (3.6 g).
With benzotriazol-1-ol; diisopropyl-carbodiimide; In tetrahydrofuran; at 20℃;Inert atmosphere;
General procedure: To a solution of Boc-amino acid (1.2 mmol) in dry THF (10 mL) were added HOBt (162 mg, 1.2 mmol), DIC (152 mg, 1.2 mmol), and 2,7-diamino-10-(3,5-dimethoxybenzyl)-9,10-dihydro-acridone 4 (187 mg, 0.5 mmol). The reaction suspension was stirred under nitrogen overnight at room temperature. The volatile parts were removed under reduced pressure and compound 5 was obtained by column chromatography. Compound 5 was suspended and stirred in hydrochloride 1,4-dioxane solution (15 mL), The suspension was stirred at room temperature until TLC indicated completion of reaction. Yellow solids were obtained after filtration
With potassium hydroxide; In ethanol; at 25 - 30℃; for 3h;
Add 1.0 g of lysine to a 50 ml round bottom flask,7.5 g of di-tert-butyl dicarbonate (BOC anhydride),1.1 g of potassium hydroxide and not less than 20 g of ethanol,The reaction was stirred at 25-30 C for 3 hours on a magnetic stirrer.Ethyl alcohol is removed on a rotary evaporator,Add 20g of ethyl acetate,Wash 20g in water three times,The upper organic layer is dried over sodium sulfate.Then, the crystallization was stirred at 1-10 C for 15 hours.filter,Drying gave 1.54 g of a white solid.Is di-tert-butoxycarbonyl lysine,Its molar yield was 65.0% (based on lysine).
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
{5-tert-Butoxycarbonylamino-5-[(l -hydroxy- 1 ,3-dihydro-benzo [c] [1,2] oxaborol-3- ylmethyl)-carbamoyl]-pentyl}-carbamic acid tert-butyl esterNHBoc Boc[0571] DIPEA (0.96 mL, 5.5 mmol), HATU (1.05 g, 2.76 mmol) and Al (0.50 g, 2.5 mmol) were added sequentially to a solution of 2,6-bis-tert-butoxycarbonylamino- hexanoic acid (0.79 g, 2.3 mmol) in DMF (10 mL) at rt. The bath was removed and the solution was stirred at rt O/N. The mixture was concentrated in vacuo and the residue was taken up in EtOAc, washed with H2O (3 x 30 mL), dried (Na2SO4), and <n="180"/>concentrated in vacuo. The residue was purified by flash chromatography (2% MeOH in EtOAc) to give the title compound: yield 0.67 g (55%).[0572] 1H NMR (400 MHz, DMSO-J6) delta (ppm): 9.24 (d, J= 7.8 Hz, IH), 7.95 (q, J= 6.8 Hz, IH), 7.71 (t, J= 6.5 Hz, IH), 7.50-7.28 (m, 3H), 6.89-6.60 (m, 2H), 5.23- 5.06 (m, IH), 3.94-3.73 (m, 2H), 3.60-3.47 (m, IH), 3.47-3.37 (m, IH), 2.85 (dd, J = 15.4, 5.7 Hz, 3H), 1.37 (s, 18H).
Step 2: [0150] 194 mg of ester derivative from step 1, 282 mg of HBTU, and 0.132 ml of DIEA were dissolved in 4.0 ml of dry DMF under argon. The resulting mixture was stirred for 1 hour at RT. A suspension of 316 mg of <strong>[2483-46-7]2,6-bis((tert-butoxycarbonyl)amino)hexanoic acid</strong> in 1.0 ml of dry DMF was added, and the resulting reaction mixture was stirred at 50 C. overnight. The reaction mixture was combined with 5.0 ml of ice cold water and extracted with ethyl acetate. The organic layer was dried and concentrated to obtain a crude residue. This residue was purified by chromatography to obtain the desired product. Yield of the product was 30%.
Step 1: [0119] 84.0 mg (0.17 mmol) of <strong>[2483-46-7]2,6-bis((tert-butoxycarbonyl)amino)hexanoic acid</strong>, 120.0 mg (0.31 mmol) of HBTU (O-Benzotriazole-N,N,N?,N?-tetramethyl-uronium-hexafluoro-phosphate), and 75.0 mul (0.30 mmol) of DIEA (N,N-Diisopropylethylamine) were dissolved in anhydrous 3.0 ml DMF (dimethyl formamide). The reaction was stirred for 1 hour at room temperature under inert gas (argon). After 1 hour 95.0 mg of celecoxib (0.25 mmol) was added to the reaction under argon and the resulting reaction were stirred for 15 hours at room temperature. At the end of the reaction, the solvent was evaporated and the product was purified by flash column chromatography. Yield of the product was 50%.
Compound 120 (14.01 g, 40 mmol) and HBTU (14.06 g, 37 mmol) were dissolved in anhydrous10 DMF (80 mL). Triethylamine (11.2 mL, 80.35 mmol) was added and stirred for 5 min. The reaction mixturewas cooled in an ice bath and a solution of compound 121 (1 0 g, mmol) in anhydrous DMF (20 mL) wasadded. Additional triethylamine ( 4.5 mL, 32.28 mmol) was added and the reaction mixture was stirred for18 h under an argon atmosphere. The reaction was monitored by TLC (ethyl acetate:hexane; 1:1; Rf = 0.4 7).The solvent was removed under reduced pressure. The residue was taken up in EtOAc (300 mL) and washed15 with 1M NaHS04 ( 3 x 150 mL), aqueous saturated NaHC03 solution (3 x 150 mL) and brine (2 x 100 mL).Organic layer was dried with Na2S04. Drying agent was removed by filtration and organic layer wasconcentrated by rotary evaporation. Crude mixture was purified by silica gel column chromatography and eluted by using 35- 50% EtOAc in hexane to yield a compound 122 (15.50 g, 78.13%). The structure wasconfirmed by LCMS and 1H NMR analysis. Mass m/z 589.3 [M + H(
78.13%
Compound 120 (14.01 g, 40 mmol) and HBTU (14.06 g, 37 mmol) were dissolved in anhydrous DMF (80 mL). Triethylamine (11.2 mL, 80.35 mmol) was added and stirred for 5 min. The reaction mixture was cooled in an ice bath and a solution of compound 121 (10 g, mmol) in anhydrous DMF (20 mL) was added. Additional triethylamine (4.5 mL, 32.28 mmol) was added and the reaction mixture was stirred for 18 h under an argon atmosphere. The reaction was monitored by TLC (ethyl acetate:hexane; 1:1; Rf = 0.47). The solvent was removed under reduced pressure. The residue was taken up in EtOAc (300 mL) and washed with 1M NaHSO4 ( 3 x 150 mL), aqueous saturated NaHCO3 solution (3 x 150 mL) and brine (2 x 100 mL). Organic layer was dried with Na2SO4. Drying agent was removed by filtration and organic layer was concentrated by rotary evaporation. Crude mixture was purified by silica gel column chromatography and eluted by using 35- 50% EtOAc in hexane to yield a compound 122 (15.50 g, 78.13%). The structure was confirmed by LCMS and 1H NMR analysis. Mass m/z 589.3 [M + H]+.
78.13%
Compound 120 (14.01 g, 40 mmol) and HBTU (14.06 g, 37 mmol) were dissolved in anhydrous DMF (80 mL). Triethylamine (11.2 mL, 80.35 mmol) was added and stirred for 5 min. The reaction mixture was cooled in an ice bath and a solution of compound 121 (10 g, mmol) in anhydrous DMF (20 mL) was added. Additional triethylamine (4.5 mL, 32.28 mmol) was added and the reaction mixture was stirred for 18 h under an argon atmosphere. The reaction was monitored by TLC (ethyl acetate:hexane; 1:1; Rf = 0.47). The solvent was removed under reduced pressure. The residue was taken up in EtOAc (300 mL) and washed with 1M NaHSO4 ( 3 x 150 mL), aqueous saturated NaHCO3 solution (3 x 150 mL) and brine (2 x 100 mL). Organic layer was dried with Na2SO4. Drying agent was removed by filtration and organic layer was concentrated by rotary evaporation. Crude mixture was purified by silica gel column chromatography and eluted by using 35- 50% EtOAc in hexane to yield a compound 122 (15.50 g, 78.13%). The structure was confirmed by LCMS and 1H NMR analysis. Mass m/z 589.3 [M + H]+.
78.13%
Compound 120 (14.01 g, 40 mmol) and HBTU (14.06 g, 37 mmol) were dissolved in anhydrous DMF (80 mL). Triethylamine (11.2 mL, 80.35 mmol) was added and stirred for 5 mm. The reaction mixture was cooled in an ice bath and a solution of compound 121 (10 g, mmol) in anhydrous DMF (20 mL) was added. Additional triethylamine (4.5 mL, 32.28 mmol) was added and the reaction mixture was stirred for 18h under an argon atmosphere. The reaction was monitored by TLC (ethyl acetate:hexane; 1:1; Rf = 0.47). The solvent was removed under reduced pressure. The residue was taken up in EtOAc (300 mL) and washed with 1M NaHSO4 ( 3 x 150 mL), aqueous saturated NaHCO3 solution (3 x 150 mL) and brine (2 x 100 mL). Organic layer was dried with Na2SO4. Drying agent was removed by filtration and organic layer was concentrated by rotary evaporation. Crude mixture was purified by silica gel column chromatography andeluted by using 35 - 50% EtOAc in hexane to yield a compound 122 (15.50 g, 78.13%). The structure was confirmed by LCMS and ?H NMR analysis. Mass m/z 589.3 [M + H].
Tert-butyloxycarbonyl (Hoc)-protected lysine (Chem Impex Int?l Inc., Wood Dale, Ill.) was chlorinated using thionyl chloride in benzene. The resulting compound was reacted with DOTAAm4 followed by deprotection of Hoc-protecting groups using HC1 to yield compound Id.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;
General procedure: Step 2: Oleylamine (1.2 equiv.) was added to the anhydrous dichloromethane solution of the product obtained in last step (1 equiv.), HOBt (1.2 equiv.), EDCI (1.2 equiv.) and DIEA (2 equiv.) in ice-salt-bath at 0C. The mixture was stirred at 0C for 1h and then at room temperature overnight. The reaction solution was washed with saturated aqueous NaHCO3 solution (2×50mL) and brine (50mL). The organic solvent was dried over Na2SO4, filtered, and concentrated to afford an oil solid, which was further purified by column chromatography on silica gel (EA/PE=1/2, v/v) to yield pure compound 1 (85%) or 2 (66%).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;
General procedure: Step 2: Oleylamine (1.2 equiv.) was added to the anhydrous dichloromethane solution of the product obtained in last step (1 equiv.), HOBt (1.2 equiv.), EDCI (1.2 equiv.) and DIEA (2 equiv.) in ice-salt-bath at 0C. The mixture was stirred at 0C for 1h and then at room temperature overnight. The reaction solution was washed with saturated aqueous NaHCO3 solution (2×50mL) and brine (50mL). The organic solvent was dried over Na2SO4, filtered, and concentrated to afford an oil solid, which was further purified by column chromatography on silica gel (EA/PE=1/2, v/v) to yield pure compound 1 (85%) or 2 (66%).
General procedure: NMM (2 equiv.) was added to a solution of Boc-Lys(Boc)-OH (1 equiv.) in anhydrous DCM at 0C, followed by dropwise addition of IBCF (1.5 equiv.). The mixture was stirred for 30min, then benzocaine or compound 6 (1.5 equiv.) was added, and the resulting mixture was stirred at 0C for 1h and then at room temperature for 12h. The precipitate was filtered off and the filtrate was washed with H2O (2×40mL), brine (40mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA/DCM=1/2, v/v) to yield pure compound 10 (37%) or 11 (25%).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;
General procedure: Step 2: Oleylamine (1.2 equiv.) was added to the anhydrous dichloromethane solution of the product obtained in last step (1 equiv.), HOBt (1.2 equiv.), EDCI (1.2 equiv.) and DIEA (2 equiv.) in ice-salt-bath at 0C. The mixture was stirred at 0C for 1h and then at room temperature overnight. The reaction solution was washed with saturated aqueous NaHCO3 solution (2×50mL) and brine (50mL). The organic solvent was dried over Na2SO4, filtered, and concentrated to afford an oil solid, which was further purified by column chromatography on silica gel (EA/PE=1/2, v/v) to yield pure compound 1 (85%) or 2 (66%).
General procedure: NMM (2 equiv.) was added to a solution of Boc-Lys(Boc)-OH (1 equiv.) in anhydrous DCM at 0C, followed by dropwise addition of IBCF (1.5 equiv.). The mixture was stirred for 30min, then benzocaine or compound 6 (1.5 equiv.) was added, and the resulting mixture was stirred at 0C for 1h and then at room temperature for 12h. The precipitate was filtered off and the filtrate was washed with H2O (2×40mL), brine (40mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA/DCM=1/2, v/v) to yield pure compound 10 (37%) or 11 (25%).
General procedure: The relevant Boc-AA1-OH (1.1 equiv), TBTU (1.1 equiv) and DIEA (2.0 equiv) were dissolved in CH2Cl2 anhydrous at room temperature and the mixture stirred for 30 min prior to addition of bromothiazole 5 (1.0 equiv). The mixture was stirred and allowed to proceed at room temperature for further 23h, with periodic monitoring by TLC. The solvent was then reduced at 3mL and the residue was submitted to column chromatography on silica using DCM/Acetone 10:1 (v/v).
With 1-hydroxy-pyrrolidine-2,5-dione; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃;
The solution of Bis-Boc-Lysine, TPPamine hydrochloride, Et3N, and NHS in DMF, EDC was added at room temperature (RT). After being stirred overnight at it, AcOEt was added and mixture was washed with 0.1% H2504 in Brine, NaHCO3, and Brine, and dried over Mg504. The residue was purified with colunm chromatography (CHC13:MeOR, 10:0 to 8:2). 512 mg was obtained (36% Yield). Single peak on HPLC and NMR confirmed the product.
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