* 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.
Reference:
[1] Australian Journal of Chemistry, 1987, vol. 40, # 1, p. 97 - 105
2
[ 556-50-3 ]
[ 24424-99-5 ]
[ 31972-52-8 ]
Yield
Reaction Conditions
Operation in experiment
96%
With guanidine hydrochloride In ethanol at 35 - 40℃; for 9 h;
General procedure: Amino acid or peptide (1 mmol) was added with stirring to a solution of guanidine hydrochloride (15 molpercent) and di-tert-butyl dicarbonate (2.5-3 mmol) in EtOH (1 mL), at 35-40°C. The reaction mixture was continued to stir until a clear solution was obtained. EtOH was evaporated under vacuum and the residue was successively washed with water (2 mL) and hexane or petroleum ether (2 mL) to afford almost pure N-Boc amino acids or N-Boc peptides. If necessary, the crude products could be recrystallized for further purification.
88%
With triethylamine In 1,4-dioxane; water at 23℃; for 16 h;
Et3N (3.16 mL, 22.71 mmol) and Boc2O (3.63 g, 16.65 mmol) wereadded to a suspension of diglycine (7; 2.00 g, 15.14 mmol) in a mixtureof dioxane (60 mL) and H2O (10 mL) at 0 °C. The mixture wasstirred at 23 °C for 16 h, diluted with H2O (250 mL), and acidifiedto pH 3 by addition of solid KHSO4. The mixture was extracted withEtOAc (5 × 50 mL), the combined organic phases were dried(Na2SO4), and all solvents were removed under reduced pressure;this gave 8 as a white solid, which was used without further purification.Yield: 3.10 g (13.35 mmol, 88percent).1H NMR (400 MHz, DMSO): δ = 12.55 (br s, 1 H), 8.03 (t, J = 5.5Hz, 1 H), 6.96 (t, J = 5.7 Hz, 1 H), 3.75 (d, J = 5.7 Hz, 2 H), 3.56 (d,J = 5.8 Hz, 2 H), 1.37 (s, 9 H).
88%
With triethylamine In 1,4-dioxane; water at 23℃; for 16 h;
Triethylamine (Et3N)(3.16 mL, 22.71 mmol) and Boc2O (3.63 g, 16.65 mmol)were added to a suspension of diglycine (2.00 g,15.14 mmol) in a mixture of dioxane (60 mL) and H2O(10 mL) at 0 C. The reaction mixture was maintained withstirring at 23 C for 16 h. Then, H2O (250 mL) was added,and the reaction mixture was acidified to pH 3 by the additionof solid KHSO4. The product was extracted with ethylacetate (5 × 50 mL), and residual water in the organicphases was removed with Na2SO4. Finally, all solventswere removed using a rotary evaporator to yield product6 as a white solid without purification. Yield: 3.10 g (88percent).1H NMR (300 MHz, DMSO‑d6) 12.6 (s, 1H), 8.0 (t, 1H,J = 5.8 Hz), 7.0 (t, 1H, J = 6.0 Hz), 3.8 (d, 2H,J = 5.8 Hz), 3.7 (d, 2H, J = 6.1 Hz), 1.4 (s, 9H). 13C NMR(125 MHz, DMSO‑d6) 174.6, 171.0, 156.2, 79.5, 44.6,42.6, 28.4. ESI-MS (m/z) calcd. For C9H16N2O5: 232.1;233.004 [M + H]+. Elemental analysis: calculated forC9H16N2O5: C 46.6, H 6.9, N 12.1. Found: C 46.5, H 7.3,N 12.1.
Reference:
[1] Tetrahedron Letters, 2011, vol. 52, # 12, p. 1260 - 1264
[2] European Journal of Inorganic Chemistry, 2016, vol. 2016, # 35, p. 5427 - 5434
[3] Synthesis (Germany), 2013, vol. 45, # 17, p. 2426 - 2430
[4] Bulletin of the Korean Chemical Society, 2018, vol. 39, # 8, p. 988 - 994
[5] Journal of Polymer Science, Part A: Polymer Chemistry, 2018, vol. 56, # 8, p. 914 - 921
[6] Organic and Biomolecular Chemistry, 2006, vol. 4, # 19, p. 3626 - 3638
[7] Chemical Communications, 2015, vol. 51, # 77, p. 14501 - 14504
[8] Journal of Medicinal Chemistry, 2016, vol. 59, # 7, p. 3331 - 3339
[9] Chemistry - A European Journal, 2007, vol. 13, # 8, p. 2358 - 2368
[10] Angewandte Chemie - International Edition, 2013, vol. 52, # 32, p. 8411 - 8415[11] Angew. Chem., 2013, vol. 125, # 32, p. 8569 - 8573
[12] Inorganica Chimica Acta, 2016, vol. 450, p. 211 - 215
[13] Analytical Biochemistry, 2016, vol. 512, p. 114 - 119
[14] Tetrahedron, 2017, vol. 73, # 22, p. 3173 - 3180
3
[ 31972-51-7 ]
[ 31972-52-8 ]
Reference:
[1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 20, p. 5512 - 5517
[2] Bulletin of the Chemical Society of Japan, 1983, vol. 56, # 6, p. 1678 - 1681
[3] Chemical and Pharmaceutical Bulletin, 1982, vol. 30, # 12, p. 4448 - 4456
[4] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1983, p. 803 - 808
[5] Journal of Medicinal Chemistry, 1980, vol. 23, # 10, p. 1113 - 1122
[6] Journal of the Chemical Society, Dalton Transactions: Inorganic Chemistry (1972-1999), 1985, p. 535 - 540
[7] Bulletin of the Chemical Society of Japan, 1986, vol. 59, p. 3553 - 3558
[8] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 23, p. 8365 - 8373
[9] Molecular Pharmaceutics, 2011, vol. 8, # 4, p. 1224 - 1232
[10] International Journal of Pharmaceutics, 2014, vol. 468, # 1-2, p. 133 - 141
4
[ 53487-98-2 ]
[ 31972-52-8 ]
Reference:
[1] Organic Letters, 2015, vol. 17, # 16, p. 4106 - 4109
[2] Chemistry - A European Journal, 2008, vol. 14, # 29, p. 8922 - 8927
[3] European Journal of Medicinal Chemistry, 1999, vol. 34, # 6, p. 525 - 529
[4] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2005, vol. 60, # 12, p. 1313 - 1320
[5] Polymer, 2012, vol. 53, # 8, p. 1694 - 1702
[6] Chemistry - An Asian Journal, 2018, vol. 13, # 4, p. 400 - 403
[7] Beilstein Journal of Organic Chemistry, 2018, vol. 14, p. 1112 - 1119
[8] Patent: US4169141, 1979, A,
5
[ 25438-03-3 ]
[ 31972-52-8 ]
Reference:
[1] Tetrahedron Letters, 1976, p. 2119 - 2120
[2] Patent: CN106749223, 2017, A, . Location in patent: Paragraph 0222; 0223; 0224
6
[ 4530-20-5 ]
[ 31972-52-8 ]
Reference:
[1] Bulletin of the Chemical Society of Japan, 1986, vol. 59, p. 3553 - 3558
[2] Bulletin of the Chemical Society of Japan, 1986, vol. 59, # 8, p. 2433 - 2438
[3] Journal of the Chemical Society, Dalton Transactions: Inorganic Chemistry (1972-1999), 1985, p. 535 - 540
[4] Journal of Medicinal Chemistry, 1980, vol. 23, # 10, p. 1113 - 1122
[5] Chemical and Pharmaceutical Bulletin, 1982, vol. 30, # 12, p. 4448 - 4456
[6] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1983, p. 803 - 808
[7] Collection of Czechoslovak Chemical Communications, 1988, vol. 53, # 11B, p. 2787 - 2790
[8] Collection of Czechoslovak Chemical Communications, 1990, vol. 55, # 9, p. 2357 - 2359
[9] Tetrahedron Letters, 1976, p. 2119 - 2120
[10] Molecular Pharmaceutics, 2011, vol. 8, # 4, p. 1224 - 1232
[11] Polymer, 2012, vol. 53, # 8, p. 1694 - 1702
[12] Science China Chemistry, 2013, vol. 56, # 2, p. 159 - 168
[13] International Journal of Pharmaceutics, 2014, vol. 468, # 1-2, p. 133 - 141
[14] Organic Letters, 2015, vol. 17, # 16, p. 4106 - 4109
[15] Chemical Biology and Drug Design, 2016, vol. 88, # 6, p. 884 - 888
[16] Patent: CN106749223, 2017, A,
[17] Chemistry - An Asian Journal, 2018, vol. 13, # 4, p. 400 - 403
[18] Beilstein Journal of Organic Chemistry, 2018, vol. 14, p. 1112 - 1119
7
[ 3655-05-8 ]
[ 56-40-6 ]
[ 31972-52-8 ]
Reference:
[1] Organic Process Research and Development, 2015, vol. 19, # 9, p. 1257 - 1262
8
[ 236424-82-1 ]
[ 31972-52-8 ]
Reference:
[1] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 5, p. 749 - 762
9
[ 24424-99-5 ]
[ 31972-52-8 ]
Reference:
[1] Science China Chemistry, 2013, vol. 56, # 2, p. 159 - 168
[2] Organic Process Research and Development, 2015, vol. 19, # 9, p. 1257 - 1262
[3] Chemical Biology and Drug Design, 2016, vol. 88, # 6, p. 884 - 888
[4] Chemistry - An Asian Journal, 2018, vol. 13, # 4, p. 400 - 403
10
[ 123872-97-9 ]
[ 31972-52-8 ]
Reference:
[1] Collection of Czechoslovak Chemical Communications, 1988, vol. 53, # 11B, p. 2787 - 2790
11
[ 131326-18-6 ]
[ 31972-52-8 ]
Reference:
[1] Collection of Czechoslovak Chemical Communications, 1990, vol. 55, # 9, p. 2357 - 2359
12
[ 103339-87-3 ]
[ 31972-52-8 ]
Reference:
[1] Bulletin of the Chemical Society of Japan, 1986, vol. 59, # 8, p. 2433 - 2438
13
[ 83316-95-4 ]
[ 31972-52-8 ]
Reference:
[1] Bulletin of the Chemical Society of Japan, 1986, vol. 59, # 8, p. 2433 - 2438
14
[ 56-40-6 ]
[ 18185-77-8 ]
[ 31972-52-8 ]
Reference:
[1] Science China Chemistry, 2013, vol. 56, # 2, p. 159 - 168
15
[ 556-50-3 ]
[ 57022-34-1 ]
[ 31972-52-8 ]
Reference:
[1] Bulletin de l'Academie Polonaise des Sciences, Serie des Sciences Chimiques, 1964, vol. 12, p. 21 - 24
16
[ 66866-43-1 ]
[ 56-40-6 ]
[ 31972-52-8 ]
Reference:
[1] Chemical Biology and Drug Design, 2016, vol. 88, # 6, p. 884 - 888
17
[ 6066-82-6 ]
[ 31972-52-8 ]
[ 29248-48-4 ]
Yield
Reaction Conditions
Operation in experiment
65.4 mg
Stage #1: With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In dichloromethane at 20℃; for 0.333333 h; Stage #2: for 48 h;
To a solution of Gly-Gly (1.00 g, 7.57 mmol) in dioxane:water (30:5 mL) at room temperature was added triethylamine (1.15 g,11.4 mmol) and di-tert-butyl-dicarbonate (1.84 g, 8.33 mmol) consecutively. The mixture was stirred at room temperature overnight, then diluted with water, acidified to approximately pH 2via the addition of solid KHSO4, extracted with EtOAc, dried(Na2SO4), and concentrated in vacuo to afford (tert-butoxycarbonyl)glycylglycine [8] as a white solid. To a solution of crude (tertbutoxycarbonyl)glycylglycine (0.106 g, 0.451 mmol) in anhydrous dichloromethane (5.00 mL) was added triethylamine (45.6 mg,0.451 mmol) and propylphosphonic anhydride solution (T3P®) [9] (0.344 g, 0.541 mmol) at room temperature. The mixture was stirred for 20 min, followed by the addition of N-hydroxy succinimide (51.9 mg, 0.451 mmol). The reaction was stirred for 48 h and upon completion, the organic layer was washed with brine (3),dried (Na2SO4), and concentrated in vacuo to afford the product as a white solid. The crude solid was triturated from diethyl ether toafford 65.4 mg (44percent) of the product as a white solid: 1H NMR(400 MHz, CDCl3) d 6.76 (brs, 1 H), 5.15 (brs, 1 H), 4.43 (d, 2 H,J 5.7 Hz), 3.87 (d, 2 H, J 5.3 Hz), 2.85 (s, 4 H), 1.45 (s, 9 H); ESIMSm/z 330 [MH]. Direct infusion ESI-MS on a high resolution accurate mass measurements (Exactive Plus, Thermo Fisher Scientific) in the negative ion mode yielded an elemental composition of the expected product within 5 ppm (see Fig. 1).
Reference:
[1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 22, p. 5973 - 5982
[2] Journal of Pharmaceutical Sciences, 1984, vol. 73, # 2, p. 275 - 277
[3] Analytical Biochemistry, 2016, vol. 512, p. 114 - 119
With diisopropyl-carbodiimide; In dichloromethane; at 0 - 20℃;
N,N'-Diisopropylcarbodiimide (770 muIota_,, 5.0 mmol) was added to a solution of Boc-GlyGly-OH (Bachem America, Torrance, CA; 920 mg, 4.0 mmol) and N-hydroxysuccinimide (NHS, 575 mg, 5.0 mmol) in dichloromethane (50 mL) at 0C. The solution was stirred at room temperature overnight. Precipitated urea was filtered out, and the filtrate was evaporated to remove dichloromethane under vacuum. Boc-GlyGly-NHS was isolated by recrystallization in 2- propanol with a 63% yield verified with proton nuclear magnetic resonance spectroscopy (FIGS. 6-8) recorded in CDCb using a 300 MHz, Bruker Avance. The solution of Boc- GlyGly-NHS (16 mg, 48 muiotaetaomicron) in chloroform (40 mL) was added to a solution of Cyanine3 amine (25 mg, 40 mupiiotaomicron) and trimethylamine (7 mu,, 50 muetaiotaomicron) in DMSO (100 mu.,) and stirred at room temperature overnight. The mixture was washed with 0.5 N HC1 aq. (50 mL x 2), saturated NaHCCb (50 mL x 2), and saturated NaCl (50 mL x 2), then dried with MgS04. After MgS04 removal by filtration, Boc-GlyGly-Cy3 was isolated by evaporating chloroform under vacuum with an 89% yield verified by NMR. The mixture of Boc-GlyGly-Cy3 (30 mg, 35.6 mutauetaomicron) in 4 M hydrochloric acid (HC1), 1 ,4- dioxane (80 mu), and 1 ,4-dioxane (920 mu) was stirred at room temperature for 4 hours. GlyGlyCy3 was obtained by evaporation of dioxane under vacuum, with a 98% yield verified with NMR.
65.4 mg
To a solution of Gly-Gly (1.00 g, 7.57 mmol) in dioxane:water (30:5 mL) at room temperature was added triethylamine (1.15 g,11.4 mmol) and di-tert-butyl-dicarbonate (1.84 g, 8.33 mmol) consecutively. The mixture was stirred at room temperature overnight, then diluted with water, acidified to approximately pH 2via the addition of solid KHSO4, extracted with EtOAc, dried(Na2SO4), and concentrated in vacuo to afford (tert-butoxycarbonyl)glycylglycine [8] as a white solid. To a solution of crude (tertbutoxycarbonyl)glycylglycine (0.106 g, 0.451 mmol) in anhydrous dichloromethane (5.00 mL) was added triethylamine (45.6 mg,0.451 mmol) and propylphosphonic anhydride solution (T3P) [9] (0.344 g, 0.541 mmol) at room temperature. The mixture was stirred for 20 min, followed by the addition of N-hydroxy succinimide (51.9 mg, 0.451 mmol). The reaction was stirred for 48 h and upon completion, the organic layer was washed with brine (3),dried (Na2SO4), and concentrated in vacuo to afford the product as a white solid. The crude solid was triturated from diethyl ether toafford 65.4 mg (44%) of the product as a white solid: 1H NMR(400 MHz, CDCl3) d 6.76 (brs, 1 H), 5.15 (brs, 1 H), 4.43 (d, 2 H,J 5.7 Hz), 3.87 (d, 2 H, J 5.3 Hz), 2.85 (s, 4 H), 1.45 (s, 9 H); ESIMSm/z 330 [MH]. Direct infusion ESI-MS on a high resolution accurate mass measurements (Exactive Plus, Thermo Fisher Scientific) in the negative ion mode yielded an elemental composition of the expected product within 5 ppm (see Fig. 1).
With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 25℃; for 13h;
38
Example 38. N-Boc-glycylglycyl-L-phenylalanine Methyl Ester (S74)To N-Boc-glycylglycine (696 mg, 3.00 mmol, 1.00 equiv) in THF (10.0 niL) at 00C was added EDCI (1.15 g, 6.00 mmol, 2.00 equiv), HOBt ( 810 mg, 6.00 mmol, 2.00 equiv), n,n-diisopropylethyl amine (1.56 mL, 9.00 mmol, 3.00 equiv) and A-(Dimethylamino)pyridine (36 mg, 0.030 mmol, 0.10 equiv) and L-phenylalanine methyl ester (647 mg, 3.00 mmol, 1. 00 equiv). The reaction mixture was stirred for 1 hr at 00C and stirred for 12 h at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and dried (Na2SO4). The filtrate is concentrated in vacuo and the residue is purified by chromatography on silica gel eluting with DCM/MeOH 10:1 (v/v) to afford 1.10 g of the title compound as a colorless oil (93% yield).R/= 0.50 (DCM/MeOH 10:1 (v/v)). NMR Spectroscopy: 1U NMR (500 MHz, CDCl3, 23 0C, δ): 7.29-7.21 (m, 2H), 7.13-7.11 (m, 2H), 7.02 (d, /= 8.0 Hz, IH), 5.46 (br s, IH), 4.82 (dd, / = 14.0 Hz, 6.5 Hz, IH), 3.94 (dd, / = 16.5 Hz, 5.5 Hz, IH), 3.88 (dd, /= 16.5 Hz, 6.0 Hz, IH), 3.80 (d, / = 5.0 Hz, 2H), 3.69 (s, 3H), 3.13 (dd, / = 14.0 Hz, 6.0 Hz, IH), 3.04 (dd, /= 14.0 Hz, 7.0 Hz, IH), 1.45 (s, 9H). 13C NMR (125 MHz, CDCl3, 23 0C, δ): 171.79, 170.07, 168.53, 156.07, 135.78, 129.15, 128.49, 127.05, 80.16, 53.36, 52.30, 44.01, 42.75, 37.71, 28.24.
With guanidine hydrochloride In ethanol at 35 - 40℃; for 9h;
2.4. General procedure for N-tert-butoxycarbonylation of aminoacids and peptides (Table 2, entries 1-12):
General procedure: Amino acid or peptide (1 mmol) was added with stirring to a solution of guanidine hydrochloride (15 mol%) and di-tert-butyl dicarbonate (2.5-3 mmol) in EtOH (1 mL), at 35-40°C. The reaction mixture was continued to stir until a clear solution was obtained. EtOH was evaporated under vacuum and the residue was successively washed with water (2 mL) and hexane or petroleum ether (2 mL) to afford almost pure N-Boc amino acids or N-Boc peptides. If necessary, the crude products could be recrystallized for further purification.
95%
With triethylamine In methanol for 4h; Reflux;
88%
With triethylamine In 1,4-dioxane; water at 23℃; for 16h;
2-[2-(tert-Butoxycarbonylamino)acetamido]acetic Acid (8)
Et3N (3.16 mL, 22.71 mmol) and Boc2O (3.63 g, 16.65 mmol) wereadded to a suspension of diglycine (7; 2.00 g, 15.14 mmol) in a mixtureof dioxane (60 mL) and H2O (10 mL) at 0 °C. The mixture wasstirred at 23 °C for 16 h, diluted with H2O (250 mL), and acidifiedto pH 3 by addition of solid KHSO4. The mixture was extracted withEtOAc (5 × 50 mL), the combined organic phases were dried(Na2SO4), and all solvents were removed under reduced pressure;this gave 8 as a white solid, which was used without further purification.Yield: 3.10 g (13.35 mmol, 88%).1H NMR (400 MHz, DMSO): δ = 12.55 (br s, 1 H), 8.03 (t, J = 5.5Hz, 1 H), 6.96 (t, J = 5.7 Hz, 1 H), 3.75 (d, J = 5.7 Hz, 2 H), 3.56 (d,J = 5.8 Hz, 2 H), 1.37 (s, 9 H).
88%
With triethylamine In 1,4-dioxane; water at 23℃; for 16h;
Synthesis of Compound 6.
Triethylamine (Et3N)(3.16 mL, 22.71 mmol) and Boc2O (3.63 g, 16.65 mmol)were added to a suspension of diglycine (2.00 g,15.14 mmol) in a mixture of dioxane (60 mL) and H2O(10 mL) at 0 C. The reaction mixture was maintained withstirring at 23 C for 16 h. Then, H2O (250 mL) was added,and the reaction mixture was acidified to pH 3 by the additionof solid KHSO4. The product was extracted with ethylacetate (5 × 50 mL), and residual water in the organicphases was removed with Na2SO4. Finally, all solventswere removed using a rotary evaporator to yield product6 as a white solid without purification. Yield: 3.10 g (88%).1H NMR (300 MHz, DMSO-d6) 12.6 (s, 1H), 8.0 (t, 1H,J = 5.8 Hz), 7.0 (t, 1H, J = 6.0 Hz), 3.8 (d, 2H,J = 5.8 Hz), 3.7 (d, 2H, J = 6.1 Hz), 1.4 (s, 9H). 13C NMR(125 MHz, DMSO-d6) 174.6, 171.0, 156.2, 79.5, 44.6,42.6, 28.4. ESI-MS (m/z) calcd. For C9H16N2O5: 232.1;233.004 [M + H]+. Elemental analysis: calculated forC9H16N2O5: C 46.6, H 6.9, N 12.1. Found: C 46.5, H 7.3,N 12.1.
85%
With sodium hydroxide In 1,4-dioxane; water at 20℃; for 12h;
69%
With sodium hydroxide In 1,4-dioxane at 5 - 20℃;
66.7%
With triethylamine In 1,4-dioxane; water at 20℃; for 16h;
Compound 5b:
Glycylglycine (6.61 g, 50 mmol) was dissolved in 35 mL of deionized water and 35 mL of 1,4-dioxane, Et3N (11 mL) and di-tert-butyl dicarbonate (12.5 mL, 55 mmol) were dropwise added, and the mixture was stirred at room temperature for 16 h. Then, deionized water (30 mL) and ethyl acetate (120 mL) were added, the liquid phase was removed and washed with ethyl acetate (120 mL) twice, then it was acidified with citric acid solids to pH 2.5. The aqueous phase was extracted with ethyl acetate (100 mL) thrice, the organic phase was dried over Na2SO4 and concentrated to get white solid powder with the yield of 3 66.7%.
55%
With sodium hydroxide In 1,4-dioxane; water at 20℃; for 20h;
42%
With sodium hydroxide In 1,4-dioxane; water at 20℃; for 1h; Cooling with ice;
With sodium hydroxide In 1,4-dioxane at 23℃; for 1h;
With sodium hydroxide In tetrahydrofuran; water at 0 - 23℃;
With triethylamine In tetrahydrofuran; water for 12h;
With triethylamine In 1,4-dioxane; water at 20℃;
2.1. 2,5-diOxopyrrolidin-1-yl-(tert-butoxycarbonyl)glycylglycinate synthesis
To a solution of Gly-Gly (1.00 g, 7.57 mmol) in dioxane:water (30:5 mL) at room temperature was added triethylamine (1.15 g,11.4 mmol) and di-tert-butyl-dicarbonate (1.84 g, 8.33 mmol) consecutively. The mixture was stirred at room temperature overnight, then diluted with water, acidified to approximately pH 2via the addition of solid KHSO4, extracted with EtOAc, dried(Na2SO4), and concentrated in vacuo to afford (tert-butoxycarbonyl)glycylglycine [8] as a white solid.
With triethylamine In 1,4-dioxane; water at 20℃; for 24h;
4.2.6. Synthesis of compound 8
1, 4-dioxane (35 mL) and Et3N (79 mmol) were added to a solution of glycylglycine (6.61 g, 50 mmol) in deionized water (35 mL), followed by adding Boc2O (12.5 mL, 55 mmol). The solution was stirred for 24 h at room temperature, and then a solution of deionized water (30 mL) and EtOAc (120 mL) were added. The aqueous phase was washed with EtOAc (120 mL) again, then it was acidified with citric acid solids to pH 2.5. The aqueous phase was extracted with EtOAc (100 mL) thrice. The organic phase was dried over anhydrous sodium sulfate, and evaporated under vacuum to obtain compound 8b.
1-palmitoyl-2-(Boc-Gly-Gly)-sn-glycero-3-phosphocholine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94.4%
With dmap; dicyclohexyl-carbodiimide; In chloroform; at 25℃; for 4h;Sonication;
To a suspension of 1-palmitoyl-2-hydroxy-sn-glycero-3-phos-phocholine (0.5002 g, 1 mmol) in 25 mL of CHCl3 was addedBOC-gly-gly (0.7012 g, 3 mmol), followed by DCC (0.6189 g,3 mmol), DMAP (0.3665 g, 3 mmol) and 1 g of glass beads. Thereaction was sonicated for 4 h at 25 C. The mixture was thenfiltered to remove DCC-urea and glass beads, the solvent collectedwas evaporated under reduced pressure to one third of its volumeand loaded on a silica gel column, eluted with a stepwise gradientof CHCl3/MeOH (5:1 and 5:2) to remove DMAP and theimpurities, followed by CHCl3/MeOH/H2O (65:25:4). The fractionscorresponding to the product were combined, evaporated,re-dissolved in benzene and freeze-dried to give a white solid 7(0.6702 g, 0.94 mmol, 94.4%). IR (Nujol): 3300 br m, 1744 vs, 1709 s,1686 vs, 1248 m cm1. 1H NMR (CDCl3, 200 MHz) d 0.87 (br t, 3H),1.24 (br s, 24H), 1.41 (s, 9H), 1.56 (m, 2H), 2.29 (t, 2H, J = 7 Hz), 3.31(br s, 9H), 3.37-3.83 (m, 4H), 4.01 (m, 4H), 4.22-4.26 (m, 4H), 4.57(m, 1H), 5.22 (m, 1H), 5.73 (m, 1H). 13C NMR (CDCl3, 50 MHz)d 14.09, 22.66, 24.78, 27.93, 28.38, 29.16, 29.33, 29.52, 29.68, 31.89,33.93, 41.17, 43.65, 54.18, 59.47, 62.22, 63.93, 66.01, 71.84, 79.49,156.23, 169.80, 170.51, 173.56. Rf (CHCl3/MeOH/H2O 65:25:4) 0.44.Anal. Cald for C33H64N3O11P2.5H2O: C, 52.50; H, 9.21; N, 5.57;found: C, 52.57; H, 8.88; N, 5.58. HRMS MH+ C33H64N3O11PH Cald:710.4351, found: 710.4320. [a]D25 +6.03 (c 0.96, CHCl3/MeOH 4:1).
Stage #1: N-(9-fluorenylmethoxycarbonyl)sarcosine In dichloromethane Inert atmosphere;
Stage #2: With piperidine In methanol; dichloromethane; N,N-dimethyl-formamide for 0.35h; Inert atmosphere;
Stage #3: Boc-Gly-Gly-OH; 2-[2-{({(9H-fluoren-9-yl)methoxy}carbonyl)amino}acetamido]acetic acid Further stages;
Synthesis of H-GGGGS-OH(5)
Compound 5 was synthesized by solid phase from Boc-GG-OH, Fmoc-GG-OH and Fmoc-Sar-OH similarly as for product 1 accept coupling to deprotected sarcosine.Thus, 2-chlorotritylchloride resin (1.12 mmol/gr) was placed in a reactor and suspended in DCM under nitrogen atmosphere. Then a mixture of Fmoc-Sar-OH (2, 2 eq.) and DIPA (8eq.) in DCM was added. The resin loading reaction was allowed to proceed for4-5 hr and then the resin was capped by an addition of a few drops of methanol. The Fmoc protecting group was removed with 20% piperidine/DMF (3 x 7 min). Then, Fmoc-GG-OH (1.0 eq.) was dissolved in dichloroethane (0.20 M), triphosgene (0.4eq.) was added followed by careful addition of collidine (3 eq.) to the vigorously stirred mixture. After 2 mins, preactivated mixture was poured toreaction vessel and coupling was procced for 2h at rt. In the next step, Fmoc was removed by above mentioned procedure, and Boc-GG-OH (3 eq), was coupled to the peptidyl resin by PyBop (3 eq) as mentioned for 1. The cleavage and isolation as for 1 yielded finally the desired 5. Purification was conducted on semi-preparative HPLC (CH3CN/0.1% TFA in H2O) leading to pure product 5 at 84% yield.
Stage #1: Boc-Gly-Gly-OH With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In ethyl acetate
Stage #2: 3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)aniline In ethyl acetate at 20℃; for 24h;
Compound 5c.
Compound 5b (2.320 g, 10 mmol) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (3.211 g, 10 mmol) were dissolved in 40 mL of ethyl acetate, triethylamine (2.8 mL, 20 mmol) was added. After the color of the solution turns yellow, compound 5a (2.46 g, 12 mmol) was added with stirred at room temperature for 24 h. Then the mixture was filtered, and the solid was reprecipitated in dichloromethane/ethanol to get white solid powder with the yield of 56%.
Stage #1: Boc-Gly-Gly-OH With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In ethyl acetate at 20℃; for 0.166667h;
Stage #2: 3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)aniline In ethyl acetate at 20℃; for 24h;
4.2.6. Synthesis of compound 8
TBTU (3.211 g, 10 mmol) was added to a mixture of compound 8b (2.320 g, 10 mmol) and triethylamine (2.8 mL, 20 mmol) in 40 mL ethyl acetate, then stirred at room temperature for 10 min. Afterward compound 8a (2.46 g, 12 mmol) was added to the solution and stirred at room temperature for 24 h. Then the mixture was filtered, and the solid was reprecipitated in CH2Cl2/ethanol 10:1 (v/v) to obtain compound 8c.