(S)-2,6-Bis-tert-butoxycarbonylaminohexanoicacid

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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 100percentLysine 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)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 NaHCOExamplel 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.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). 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).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).Commercially available L-lysine (0.146 g, 1.0 mmol) dissolved in H2O (5.0 mL) was mixed with NaHCOGeneral procedure: l-lysine, l-alanine, l-leucine, l-isoleucine, l-phenylalanine, l-threonine (5g, 1 equiv) was dissolved in Hl-lysine (5g, 1 equiv.) was dissolved in HTook 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 (BocSimilar 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.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).[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] Dissolve formula I-1 (2.322 g, 4.4 mmol) and HOBT (891 mg, 6.6 mmol) in DCM (50 mL) and react at -10 C for 10 min. Add EDCI (1.265 g, 6.6 mmol) to react for 30 min. Add I -3 (911 mg, 1.1 mmol). After 10 minutes of reaction, DIPEA (854 mg, 6.6 mmol) was added. After 20 minutes of reaction, the temperature was raised to room temperature and reacted overnight. The reaction was detected by TLC and washed with 10% hydrochloric acid solution (2 × 20mL), 5% NaHCO3 solution (2 × 20mL) and saturated brine (20mL), and the CH2Cl2 layer was dried over anhydrous Na2SO4. Compound I-4 was obtained as a white powder.Dissolve formula I-1 (1000 mg, 1.89 mmol) and HOBT (640 mg, 4.74 mmol) in DCM (50 mL), The reaction was carried out at -10 C for 10 min, and EDCI (908 mg, 4.74 mmol) was added to react for 30 min.N-hexylamine (109 mg, 0.945 mmol) was added, and after 10 minutes of reaction, DIPEA (734 mg, 5.67 mmol) was added.After 20 minutes of reaction, the temperature was raised to room temperature and reacted overnight. The reaction was detected by TLC and washed with 10% hydrochloric acid solution (2 × 20mL), 5% NaHCO3 solution (2 × 20mL) and saturated brine (20mL), and the CH2Cl2 layer was dried over anhydrous Na2SO4. Compound I-2 was obtained as a white powder.Dissolve formula I-1 (3.523 g, 6.7 mmol) and HOBT (1.121 g, 8.3 mmol) in DCM (50 mL) and react at -10 C for 10 min. Add EDCI (1.591 g, 8.3 mmol) to react for 30 min.I-5 (1.5 g, 0.83 mmol) was added, and after 10 minutes of reaction, DIPEA (1.074 mg, 8.3 mmol) was added. After 20 minutes of reaction, the temperature was raised to room temperature and reacted overnight. The reaction was detected by TLC and washed with 10% hydrochloric acid solution (3 × 20mL), 5% NaHCO3 solution (3 × 20mL) and saturated brine (2 × 20mL). The CH2Cl2 layer was dried over anhydrous Na2SO4 and distilled off under reduced pressure. The solvent gave Compound I-6 as a white powder.Weigh accurately 3.0g lysine, 11.13g Boc protected lysine, 9.87g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) and 3.83g of 1-hydroxybenzotriazole (HOBT) in a single-mouth bottle with a branch tube , Dichloromethane (DCM) was added under a nitrogen atmosphere to dissolve, and 21.33 mL of N, N-diisopropylethylamine (DIPEA) was added under an ice water bath.After 24 hours of reaction at room temperature, the reaction solution was washed, dried, and concentrated, and then purified and separated by column chromatography.De-tert-butoxycarbonyl (Boc) protection: accurately weigh 3.0g of the second-generation dendrimer in a single-necked bottle with a branch tube, count into DCM under nitrogen protection, and add 11.83mL of trifluoroacetic acid (TFA). The reaction was carried out at room temperature for 12 hours. After concentrating the obtained solution, ice-cold anhydrous ether was added and stirred overnight in the dark, and left standing. The supernatant was decanted and the remaining ether was spin-dried to obtain compound 1.(S)-

Molecular Weight:346.42
XLogP3:2.3
Hydrogen Bond Donor Count:3
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:11
Exact Mass:346.21038668
Monoisotopic Mass:346.21038668
Topological Polar Surface Area:114
Heavy Atom Count:24
Complexity:437
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes