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USD 15-60
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USD 80+
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Structure of 4530-20-5 * 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.
With dicyclohexyl-carbodiimide In dichloromethane at 15 - 20℃;
Step2: 2,5-Dioxopyrrolidine-1-yl 2-(fert-butoxycarbonylamino)acetate. /V-Boc-glycine (7.31 g, 41 .7 mmol) was dissolved in 100 mL of DCM and to the cooled (15°C) solution /V-hydroxysuccinimide (5.28 g, 45.9 mmol) was added. Λ/,Λ/'-dicyclohexylcarbodiimide (9.47 g, 45.9 mmol) was added to the formed suspension under vigorous stirring. After a few seconds, a cloudy white suspension formed, the mixture was allowed to reach room temperature and stirred for 1 h. It was subsequently filtrated over celite, washed with 50m L saturated sodium - - bicarbonate, dried over sodium sulfate and concentrated in vacuo to yield a crystalline powder. Yield: 7.02 g, 61 .8percent 1 H NMR (400 MHz, DMSO -cfe) : δ 1 .38 (s, 9H), 2.80 (s, 4H), 4.07 (d, J = 6 Hz, 2H), 7.43 (br s, 1 H). MS (ESI) m/z 567.2 [2M + Na]+.
61.8%
With dicyclohexyl-carbodiimide In dichloromethane at 15℃;
N-Boc-glycine (7.31 g, 41.7 mmol) was dissolved in 100 mL of DCM and to the cooled (15° C.) solution N-hydroxysuccinimide (5.28 g, 45.9 mmol) was added. N,N'-dicyclohexylcarbodiimide (9.47 g, 45.9 mmol) was added to the formed suspension under vigorous stirring. After a few seconds, a cloudy white suspension formed, the mixture was allowed to reach room temperature and stirred for 1 h. It was subsequently filtrated over celite, washed with 50 mL saturated sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo to yield a crystalline powder. Yield: 7.02 g, 61.8percent 1H NMR (400 MHz, DMSO-d6): δ 1.38 (s, 9H), 2.80 (s, 4H), 4.07 (d, J=6 Hz, 2H), 7.43 (br s, 1H). MS (ESI) m/z 567.2 [2M+Na]+.
Reference：
[1] Chemistry - A European Journal, 2016, vol. 22, # 52, p. 18865 - 18872
[2] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 15, p. 2443 - 2449
[3] Chemical communications (Cambridge, England), 2003, # 23, p. 2870 - 2871
[4] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 4, p. 402 - 407
[5] Helvetica Chimica Acta, 2004, vol. 87, # 5, p. 1077 - 1089
[6] Bioconjugate Chemistry, 2010, vol. 21, # 9, p. 1642 - 1655
[7] Patent: WO2013/107820, 2013, A1, . Location in patent: Page/Page column 42; 43
[8] Patent: US2014/357650, 2014, A1, . Location in patent: Paragraph 0265; 0268; 0269
[9] Journal of the Chemical Society, Dalton Transactions: Inorganic Chemistry (1972-1999), 1984, p. 2305 - 2308
[10] Journal of the American Chemical Society, 1993, vol. 115, # 10, p. 4228 - 4245
[11] Pharmaceutical Chemistry Journal, 1992, vol. 26, # 9-10, p. 753 - 756[12] Khimiko-Farmatsevticheskii Zhurnal, 1992, vol. 26, # 9-10, p. 72 - 74
[13] Journal of the American Chemical Society, 1996, vol. 118, # 29, p. 6975 - 6985
[14] Nucleosides and Nucleotides, 1998, vol. 17, # 9-11, p. 2135 - 2141
[15] Chemistry - A European Journal, 2001, vol. 7, # 19, p. 4280 - 4295
[16] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 12, p. 3220 - 3224
[17] Organic and Biomolecular Chemistry, 2015, vol. 13, # 13, p. 3950 - 3962
[18] Organic Process Research and Development, 2015, vol. 19, # 9, p. 1257 - 1262
[19] Journal of Molecular Biology, 2018, vol. 430, # 6, p. 842 - 852
7
[ 4530-20-5 ]
[ 3392-07-2 ]
Reference：
[1] Patent: WO2006/17352, 2006, A1, . Location in patent: Page/Page column 38
[2] Patent: US4782164, 1988, A,
Reference：
[1] J. Gen. Chem. USSR (Engl. Transl.), 1984, vol. 54, # 8, p. 1696 - 1698[2] Zhurnal Obshchei Khimii, 1984, vol. 54, # 8, p. 1904 - 1907
[3] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1984, vol. 33, p. 1067 - 1070[4] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1984, # 5, p. 1163 - 1165
11
[ 4530-20-5 ]
[ 107960-02-1 ]
[ 3392-07-2 ]
Reference：
[1] Journal of Organic Chemistry, 1987, vol. 52, # 12, p. 2364 - 2367
With sodium hydride In tetrahydrofuran at 0 - 20℃; for 26 h; Inert atmosphere
General procedure: (S)-2-(Tert-butoxycarbonyl(methyl)amino)-3-hydroxypropanoic acid(6a) Gummy substance (This compound was prepared byadding neat sodium hydride (10 equiv.) in portion wiseover a period of 2.0 h to a cooled (0 °C) solution of (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (1equiv.) and iodomethane (10 equiv.) in dry THF under astream of nitrogen. The reaction mixture was stirred at room temperature for 24 h under nitrogen atmosphere andthen diluted with ether (20 mL) and quenched with water(30 mL). The layers were separated and the aqueous layerwas extracted with ether (2 x9 15 mL), acidified to pH 3with a 20 percent aqueous solution of citric acid and extractedwith EtOAc (3 x 20 mL). The combined organic phasewas dried over Na2SO4 and evaporated to afford thecorresponding N-methylated product in 90 percent yield asGummy substance.)
91%
With sodium hydride In tetrahydrofuran at 0 - 20℃;
Sodium hydride (6.85 g, 171 mmol) was added to a mixture of (fer/-butoxycarbonyl)glycine (10 g, 57.1 mmol) and methyl iodide (75 g, 528 mmol) in THF (600 mL) at 0 °C. The mixture was slowly allowed to warm to rt overnight. Water (300 mL) was added and extracted into ethyl acetate (2 x 500 mL). The aqueous layer was acidified to pH 3 with 1 M Hci extracted with ethyl acetate (2 x 500 mL). The combined organic layer was extracted with saturated aqueous sodium chloride (500 mL), dried (MgSO^, filtration and concentrated to give the title compound as an oil (10 g, 91 percent).
91%
With sodium hydride In tetrahydrofuran at 0 - 20℃;
Sodium hydride (6.85 g, 171 mmol) was added to a mixture of (tert-butoxycarbonyl) glycine (10 g, 57.1 mmol) and methyl iodide (75 g, 528 mmol) in THF (600 mL) at 0 . The mixture was slowly allowed to warm to rt overnight. Water (300 mL) was added and extracted into ethyl acetate (2 x 500 mL). The aqueous layer was acidified to pH 3 with 1 M HCl extracted with ethyl acetate (2 x 500 mL). The combined organic layer was extracted with saturated aqueous sodium chloride (500 mL), dried (MgSO 4), filtration and concentrated to give the title compound as an oil (10 g, 91 percent).
Reference：
[1] Tetrahedron, 2002, vol. 58, # 9, p. 1719 - 1737
[2] Medicinal Chemistry Research, 2016, vol. 25, # 6, p. 1148 - 1162
[3] Tetrahedron Letters, 2005, vol. 46, # 25, p. 4377 - 4379
[4] Tetrahedron Letters, 2009, vol. 50, # 6, p. 611 - 613
[5] Patent: WO2017/100668, 2017, A1, . Location in patent: Page/Page column 155
[6] Patent: WO2018/103058, 2018, A1, . Location in patent: Page/Page column 155
[7] Journal of the American Chemical Society, 2009, vol. 131, # 50, p. 18072 - 18074
[8] Molecules, 2005, vol. 10, # 1, p. 259 - 264
15
[ 4530-20-5 ]
[ 64-17-5 ]
[ 14719-37-0 ]
Reference：
[1] Combinatorial Chemistry and High Throughput Screening, 2011, vol. 14, # 2, p. 132 - 137
[2] Tetrahedron, 1987, vol. 43, # 8, p. 1823 - 1826
[3] Journal of Organic Chemistry, 1995, vol. 60, # 10, p. 3112 - 3120
[4] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 14, p. 1511 - 1514
[5] The Journal of organic chemistry, 2002, vol. 67, # 24, p. 8291 - 8298
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
18
[ 4530-20-5 ]
[ 74-88-4 ]
[ 42492-57-9 ]
Reference：
[1] Chemistry - A European Journal, 2010, vol. 16, # 39, p. 11954 - 11962
[2] Journal of Natural Products, 2003, vol. 66, # 2, p. 183 - 199
19
[ 4530-20-5 ]
[ 6926-09-6 ]
Reference：
[1] Combinatorial Chemistry and High Throughput Screening, 2011, vol. 14, # 2, p. 132 - 137
[2] Tetrahedron Letters, 2016, vol. 57, # 9, p. 990 - 992
20
[ 83316-95-4 ]
[ 4530-20-5 ]
[ 6926-09-6 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1982, vol. 18, p. 1499 - 1502[2] Zhurnal Organicheskoi Khimii, 1982, vol. 18, # 8, p. 1716 - 1720
21
[ 4530-20-5 ]
[ 35150-09-5 ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 0.5 h; Inert atmosphere Stage #2: With 2,2,2-Trichloroethyl chloroformate In tetrahydrofuran for 0.5 h; Inert atmosphere Stage #3: With ammonium hydroxide In tetrahydrofuran at 20℃; for 16 h; Inert atmosphere
To a solution of Boc-Gly-OH (1.00 g, 5.70 mmol) in dry THF (16.0 mL) was added DIPEA (1.2 mL, 6.84 mmol) under N2 at 0 C. The reaction mixture was stirred at 0 C for 30 minutes before 2,2,2-trichloroethyl chloroformate (0.94 mL, 6.84 mmol) was added rapidly and continued stirring for 30 minutes. Then aqueous NH3 solution (2.0 mL) in THF (2.0 mL) was added. The resulting reaction mixture was allowed to reach room temperature and stirred for additionally 16 h. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between EtOAc (40 mL) and H2O (40 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL) and the combined organic layers were washed with saturated aqueous NaHCO3 solution (30 mL), water (30 mL), brine (30 mL); dried with MgSO4 and concentrated in vacuo. The crude was purified by column chromatography on silica gel to obtain glycineamide (798 mg, 80 percent) as colorless oil.
24%
With dmap; ammonium hydroxide; benzotriazol-1-ol In dichloromethane
(1) (Carbamoylmethyl)carbamic acid t-butyl ester To a solution of N-(t-butoxycarbonyl)glycine (3.01 g, 17.2 mmol) in anhydrous methylene chloride (150 ml) were added 1-hydroxybenzotriazole (4.63 g, 34.3 mmol), WSC (6.60 g, 34.4 mmol) and 4-dimethylaminopyridine (210 mg, 1.72 mmol) in an ice bath. The mixture was stirred at room temperature under an atmosphere of nitrogen overnight. After checking the completion of the reaction, 28percent aqueous ammonia solution was added thereto and resulting mixture was stirred for 15 minutes. After checking the completion of the reaction, the reaction mixture was partitioned between methylene chloride and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate: methanol (10: 1) as the eluant to afford (carbamoylmethyl)carbamic acid t-butyl ester (717.7 mg, yield 24percent) as a colorless and transparent syrup. 1H-NMR (400 MHz, CDCl3): δ(ppm) 6.202 (1H, br s), 5.763 (1H, br s), 5.267 (1H, br t, J-5.1 Hz), 3.820 (2H, d, J=5.1Hz), 1.456 (9H, s).
20%
With ammonium chloride; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 16 h;
To a stirring solution of 2S-M (10 g, 57.14 mmol) in CH2C12 (100 mL) were added HOBt (15.43 g, 114 mmol), EDCI.HC1 (21.8 g, 1 14 mmol) followed by NH4C1 (4.54 g, 85.71 mmol) and DIPEA (30.7 mL, 171 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h. After consumption of the starting material (by TLC), the reaction mixture was washed with water (2 x 100 mL). Organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to give crude; which was purified by silica gel column chromatography eluting with 2percent MeOH/CH2Cl2. After compound was triturated with ether (25 mL) and the precipitated solid was filtered to afford 2S-N (2 g, 20percent) as white solid. H-NMR: (500 MHz, DMSO-i/6): δ 7.52 (br s, 1H), 7.17 (br s, 1H), 3.46 (d, J = 6.5 Hz, 2H), 1.38 (s, 9H);
Reference：
[1] Journal of Medicinal Chemistry, 2018, vol. 61, # 3, p. 834 - 864
[2] Tetrahedron, 2018, vol. 74, # 15, p. 1951 - 1956
[3] Tetrahedron Letters, 2005, vol. 46, # 40, p. 6879 - 6882
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 15, p. 4994 - 4997
[5] Tetrahedron Letters, 2003, vol. 44, # 39, p. 7325 - 7328
[6] Phosphorus, Sulfur and Silicon and the Related Elements, 2007, vol. 182, # 3, p. 657 - 666
[7] Patent: EP1340757, 2003, A1,
[8] Patent: WO2014/120783, 2014, A1, . Location in patent: Paragraph 00132
[9] Monatshefte fuer Chemie, 1974, vol. 105, p. 1110 - 1135
[10] Synthesis, 1988, # 3, p. 259 - 261
[11] Journal of the American Chemical Society, 2002, vol. 124, # 38, p. 11272 - 11273
[12] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 3, p. 601 - 607
[13] Synthesis, 1989, # 1, p. 37 - 38
[14] Synthetic Communications, 2009, vol. 39, # 3, p. 395 - 406
[15] Journal of Organic Chemistry, 2009, vol. 74, # 15, p. 5260 - 5266
[16] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 22, p. 6828 - 6831,4
[17] Amino Acids, 2013, vol. 44, # 3, p. 977 - 982
[18] Journal of Chemical Research, 2016, vol. 40, # 2, p. 101 - 106
[19] Patent: CN103601742, 2016, B, . Location in patent: Paragraph 0117-0119
[20] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 4, p. 401 - 406
22
[ 4530-20-5 ]
[ 6148-64-7 ]
[ 67706-68-7 ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20 - 30℃; for 2 h; Stage #2: With magnesium chloride In tetrahydrofuran at 60℃; for 1 h;
(1) Carbonyldiimidazole (10.2 g, 63.1 mmol) was added to a suspension of 2-(tert-butoxycarbonylamino)acetic acid (10 g, 57.1 mmol) in THF (100 ml) and the mixture was stirred at room temperature for 2 hours. To the reaction solution were added magnesium chloride (5.4 g, 57.1 mmol) and potassium monoethylmalonate (9.7 g, 57.1 mmol) and the mixture was stirred at 60°C for 1 hour. The mixture was filtered to remove insoluble substances. The filtrate was diluted with ethyl acetate (200 ml), washed with 1N hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [developing solvent: hexane-ethyl acetate (2:1)] to obtain ethyl 4-(tert-butoxycarbonylamino)-3-oxobutanoate (11.9 g, 48.5 mmol, 85percent) as a colorless oil. 1H-NMR (CDCl3) δ: 1.29 (3H, t, J = 7.4 Hz), 1.45 (2H, s), 3.87 (2H, s), 3.96 (3H, s), 4.21 (2H, q, J = 7.2 Hz), 7.08 (1H, d, J = 8.7 Hz), 7.39 (9H, s), 3.49 (2H, s), 4.14 (2H, d, J = 5.8 Hz), 4.21 (2H, q, J = 7.4 Hz), 5.15-5.24 (1H, br).
75%
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 30℃; for 4 h; Stage #2: With triethylamine; magnesium chloride In tetrahydrofuran at 30℃; for 76 h;
To a solution of [(fert-butoxycarbonyl)amino]acetic acid (47 g, 268 mmol) in THF (470 mL) was added CDI (47.6 g, 294 mmol), and the resulting solution was allowed to stir at 30°C for 4 h. Treatment of potassium 3-ethoxy-3-oxopropanoate (54.6 g, 321 mmol) with magnesium chloride (35.7 g, 375 mmol) and TEA (40.6 g, 402 mmol) in THF (540 mL) at 30°C for 4 h generated the dianion as its magnesium chelate. To this solution was added the imidazolide solution, and a gummy precipitate began to form immediately. After stirring at 30°C for 72 h, the reaction was poured into ice-cold 1 M HCl aqueous solution (1000 mL) and extracted with EtOAc (800 mL χ 2). The combined organic layers was washed with saturated NaHC03 aqueous solution (800 mL) and brine (800 mL), was dried over Na2S04, filtered and concentrated to give crude product. Purification by column chromatography gave ethyl 4-[(tert- butoxycarbonyl)amino]-3-oxobutanoate (49 g, 75percent yield) as a red oil. 1H NMR (400 MHz, CDC13) δ 5.18 (br s, 1H), 4.20 (q, J = 7.2 Hz, 2H), 4.11-4.14 (m, 2H), 3.48 (s, 2H), 1.45 (s, 9H), 1.29 (t, J = 6.8 Hz, 3H).
Reference：
[1] Organic Letters, 2005, vol. 7, # 2, p. 215 - 218
[2] Patent: EP1650201, 2006, A1, . Location in patent: Page/Page column 23-24
[3] Patent: WO2016/118565, 2016, A1, . Location in patent: Paragraph 00399
[4] Journal of Medicinal Chemistry, 2008, vol. 51, # 3, p. 487 - 501
23
[ 4530-20-5 ]
[ 67706-68-7 ]
Reference：
[1] Journal of Organic Chemistry, 1987, vol. 52, # 20, p. 4531 - 4536
[2] Journal of Organic Chemistry, 2011, vol. 76, # 22, p. 9444 - 9451
[3] Patent: US2010/152206, 2010, A1,
24
[ 4530-20-5 ]
[ 35116-15-5 ]
[ 67706-68-7 ]
Reference：
[1] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1978, vol. 32, p. 187 - 192
25
[ 4530-20-5 ]
[ 45121-22-0 ]
Reference：
[1] Journal of the American Chemical Society, 1997, vol. 119, # 4, p. 656 - 673
26
[ 4530-20-5 ]
[ 75-03-6 ]
[ 149794-10-5 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: With sodium hydride In tetrahydrofuran at 0℃; for 1 h; Stage #2: at 0℃;
Following the general procedure of Grigg [Blaney, P.; Grigg, R.; Rankovic, Z.; Thornton- Pett, M.; Xu, J. Tetrahedron, 2002, 58, 1719-1737] a roundbottom flask was charged with sodium hydride (480mg 60percent dispersion in oil, 12.0 mmol, 4.0 equiv) and purged with nitrogen for 15 min. THF (6.OmL) was added to the flask, and the suspension was cooled to 0 0C using an ice water bath. A separate flask was charged with BOC-glycine a (525 mg, 3.0 mmol), dry THF (6.0 mL) and ethyl iodide (1.0 mL, 12 mmol, 4 equiv). This mixture was EPO <DP n="134"/>added dropwise to the NaH suspension in THF, with vigorous stirring at 0 0C. After 1 h of stirring, the reaction was warmed to room temperature and allowed to stir overnight. The reaction was again cooled to 0 0C, and methanol (4 mL) was added very slowly to quench the excess hydride. Deionized water was added to dilute the mixture, and methanol was removed under reduced pressure. Impurities were extracted into 90percent ethyl acetate-hexanes, the aqueous layer was then acidified by adding solid citric acid until the pH reached 2-3. The product was extracted into 90percent ethyl acetate-hexanes. This organic layer was dried (Na2SO4) and filtered. Removal of the solvents under reduced pressure afforded a quantitative yield of the product b.
100%
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: With citric acid In water
Following the general procedure of Grigg [Blaney, P.; Grigg, R.; Rankovic, Z.; Thornton-Pett, M.; Xu, J. Tetrahedron, 2002, 58, 1719-1737] a roundbottom flask was charged with sodium hydride (480mg 60percent dispersion in oil, 12.0 mmol, 4.0 equiv) and purged with nitrogen for 15 <n="72"/>min. THF (6.OmL) was added to the flask, and the suspension was cooled to 0 °C using an ice water bath. A separate flask was charged with BOC-glycine a (525 mg, 3.0 mmol), dry THF (6.0 mL) and ethyl iodide (1.0 mL, 12 mmol, 4 equiv). This mixture was added dropwise to the NaH suspension in THF, with vigorous stirring at 0 0C. After 1 h of stirring, the reaction was warmed to room temperature and allowed to stir overnight. The reaction was again cooled to 0 0C, and methanol (4 mL) was added very slowly to quench the excess hydride. Deionized water was added to dilute the mixture, and methanol was removed under reduced pressure. Impurities were extracted into 90percent ethyl acetate -hexanes, the aqueous layer was then acidified by adding solid citric acid until the pH reached 2-3. The product was extracted into 90percent ethyl acetate-hexanes. This organic layer was dried (Na2SO4) and filtered. Removal of the solvents under reduced pressure afforded a quantitative yield of the product b.
100%
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: With citric acid In water
Example 10 N-Boc-N-methyl-L-glycine; Following the general procedure of Grigg [Blaney, P.; Grigg, R.; Rankovic, Z.; Thornton-Pert, M.; Xu, J. Tetrahedron, 2002, 55, 1719-1737] a roundbottom flask was charged with sodium hydride (480mg 60percent dispersion in oil, 12.0 mmol, 4.0 equiv) and purged with nitrogen for 15 min. THF (6.OmL) was added to the flask, and the suspension was cooled to 0 0C using an ice water bath. A separate flask was charged with BOC-glycine a (525 mg, 3.0 mmol), dry THF (6.0 mL) and ethyl iodide (1.0 mL, 12 mmol, 4 equiv). This mixture was added dropwise to the NaH suspension in THF, with vigorous stirring at 0 °C. After 1 h of stirring, the reaction was warmed to room temperature and allowed to stir overnight. The reaction was again cooled to 0 0C, and methanol (4 mL) was added very slowly to quench the excess hydride. Deionized water was added to dilute the mixture, and methanol was removed under reduced pressure. Impurities were extracted into 90percent ethyl acetate-hexanes, the aqueous layer was then acidified by adding solid citric acid until the pH reached 2-3. The product was extracted into 90percent ethyl acetate-hexanes.This organic layer was dried (Na2SO4) and filtered. Removal of the solvents under reduced pressure afforded a quantitative yield of the product b.
100%
With sodium hydride In tetrahydrofuran at 0 - 20℃;
Example 29a b c Following the general procedure of Grigg [Blaney, P.; Grigg, R.; Rankovic, Z.; Thornton-Pett, M.; Xu, J. Tetrahedron, 2002, 58, 1719-1737] a roundbottom flask was charged with sodium hydride (480mg 60percent dispersion in oil, 12.0 mmol, 4.0 equiv) and purged with nitrogen for 15 min. THF (6.OmL) was added to the flask, and the suspension was cooled to 0 0C using an ice water bath. A separate flask was charged with BOC-glycine a (525 mg, 3.0 mmol), dry THF (6.0 mL) and ethyl iodide (1.0 mL, 12 mmol, 4 equiv). This mixture was added dropwise to the NaH suspension in THF, with vigorous stirring at 0 0C. After 1 h of stirring, the reaction was warmed to room temperature and allowed to stir overnight. The reaction was again cooled to 0 0C, and methanol (4 mL) was added very slowly to quench the excess hydride. Deionized water was added to dilute the mixture, and methanol was removed under reduced pressure. Impurities were extracted into 90percent ethyl acetate-hexanes, the aqueous layer was then acidified by adding solid citric acid until the pH reached 2-3. The product was extracted into 90percent ethyl acetate-hexanes. This organic layer was dried (Na2SO4) and filtered. Removal of the solvents under reduced pressure afforded a quantitative yield of the product b.
Reference：
[1] Patent: WO2006/69063, 2006, A1, . Location in patent: Page/Page column 132-133
[2] Patent: WO2007/106192, 2007, A2, . Location in patent: Page/Page column 70; 71
[3] Patent: WO2008/79735, 2008, A1, . Location in patent: Page/Page column 45
[4] Patent: WO2008/134679, 2008, A1, . Location in patent: Page/Page column 94
[5] Journal of the American Chemical Society, 1993, vol. 115, # 10, p. 4228 - 4245
[6] Patent: WO2010/21934, 2010, A2, . Location in patent: Page/Page column 44
[7] Patent: US2011/46066, 2011, A1,
27
[ 4530-20-5 ]
[ 75-03-6 ]
[ 149794-10-5 ]
Yield
Reaction Conditions
Operation in experiment
39.9%
Stage #1: With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.166667 h; Stage #2: at 60℃; for 10 h; Stage #3: With citric acid In water; ethyl acetate
General procedure: A suspension of NaH in mineral oil (40 mmol) was added to a stirred solution of Nα-Boc-Nα-alkylamino acid (10 mmol) in anhydrous THF (30 mL), and the mixture was stirred at 20 °C for 10 min. Then alkyl iodide (100 mmol) was added, and the mixture was stirred at 60 °C for 10 h, and maintained at rt overnight. The solvent was removed under vacuum, the residue partitioned in a mixture of ethyl acetate (100 mL) and water (25 mL), and acidified with citric acid to pH 3. The organic phase was separated, washed with saturated aqueous NaCl, containing 1percent of Na2S2O3, and dried over anhydrous MgSO4. After evaporation of ethyl acetate, the residue was loaded on Al2O3 (30 g), and eluted consecutively with heptane (to remove mineral oil), eluent A (for Boc-Xaa-OAlk), and finally, with eluent L (for Boc-Xaa-OH). The fractions were evaporated under vacuum. The traces of acetic acid from eluent L were removed by the azeotrope distillation with toluene under reduced pressure. The products were dried in a desiccator under the residual pressure of 0.13-0.26 kPa.
Stage #1: With triethylamine In dichloromethane at 20℃; for 12 h; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 12 h;
To a stirred solution of (tert-butoxycarbonyl)glycine (HN, 5.0 g, 28.57 mmol) and triethylamine (4.1 mL, 31.42 mmol) in DCM (80 mL) was added N,0-dimethylhydroxylamine (3.0 g, 31.42 mmol) followed by DCC (6.5 g, 31.42 mmol) in DCM (20 mL) and the reaction mixture was stirred at RT for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and washed with DCM. The filtrate was concentrated under reduced pressure to yield the crude compound which was purified by silica gel column chromatography using 10percent EtOAc/hexane to afford compound HO (6.0 g, 97.0percent) as an off-white solid. 1H NMR (400 MHz, CDC13): _ 5.27 (brs, 1H), 4.08 (brs, 2H), 3.72 (s, 3H), 3.21 (s, 3H), 1.46 (s, 9H).
91%
Stage #1: With 1,1'-carbonyldiimidazole In dichloromethane at 0℃; for 0.5 h; Stage #2: With triethylamine In dichloromethane at 20℃;
General procedure: This procedure has been carried out according to the following article: J. Am. Chem. Soc.,1999, 121 (13), pp 2974–2986.To a stirred solution of the corresponding Boc-protected amino acid (Boc-D-Ala-OH, Boc-LAla-OH or Boc-Gly-OH) (1.00 equiv) in anhydrous dichloromethane (0.3 M) at 0°C wasadded 1,1’-carbonyldiimidazole (1.40 equiv). After 30 min at 0°C, Et3N (1.40 equiv) and N,Odimethylhydroxylamine(1.40 equiv) were added. After 30 min, the reaction was stirred at r.tovernight. Et2O (for each 1.00 mmol of protected amino acid, add 6.70 mL of Et2O) wasadded and the organic layer was washed (x3) with a solution of HCl (1N) (for each 1.00mmol of protected amino acid, wash with 2.50 mL of HCl 1N), saturated solution of NaHCO3,brine and dried over MgSO4, filtered and concentrated to give the desired product ascolorless solid yield without further purification.
Reference：
[1] Patent: WO2018/165520, 2018, A1, . Location in patent: Page/Page column 226-227
[2] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 12, p. 2180 - 2183
[3] Journal of Organic Chemistry, 2006, vol. 71, # 17, p. 6678 - 6681
[4] Nucleosides, Nucleotides and Nucleic Acids, 2001, vol. 20, # 4-7, p. 1393 - 1397
[5] Arzneimittel-Forschung/Drug Research, 1989, vol. 39, # 4, p. 432 - 437
[6] Synthetic Communications, 1988, vol. 18, # 18, p. 2273 - 2280
[7] Tetrahedron Letters, 1999, vol. 40, # 45, p. 7925 - 7928
[8] Journal of Medicinal Chemistry, 2002, vol. 45, # 8, p. 1624 - 1632
[9] Journal of Medicinal Chemistry, 2007, vol. 50, # 23, p. 5790 - 5806
34
[ 4530-20-5 ]
[ 6638-79-5 ]
[ 121505-93-9 ]
Yield
Reaction Conditions
Operation in experiment
96%
With dmap; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide In dichloromethane; N,N-dimethyl-formamide at 0℃; for 24 h;
N-Boc-Gly-OH (10.5 g, 60.0 mmol), N, O-dimethylhydroxylamine hydrochloride (11.1 g, 120 mmol) and DIEA (31.2 g, 240 mmol) were dissolved in 1:1 1 CH2C12/DMF (500 mL) and cooled to 0 °C. 1-Hydroxy-1H- benzotriazole (HOBt, 11.0 g, 72.0 mmol), DCC (14.9 g, 72.0 mmol) and DMAP (ca. 100 mg) were added and the reaction was stirred for 24 h. The reaction was filtered to remove dicyclohexylurea and concentrated. The resulting slurry was diluted with 500 mL ethyl acetate and washed with NH4C1 (2 x 100 mL), NaHC03 (2 x 100 mL) and brine (100 mL). The organic layer was dried on MgS04 and concentrated. Chromatography on silica with 20percent EtOAc in hexane gave 12.6 g (96percent) of 4 as a colorless plate-like crystal. m.p. 101-102 °C. 1H NMR 8 5.25 (br, s, 1H), 4.07 (d, J=3.7, 2H), 3.70 (s, 3H), 3.19 (s, 3H), 1.44 (s, 9H).
94%
Stage #1: With dmap; triethylamine In dichloromethane at 0℃; for 1.5 h; Large scale Stage #2: at 0 - 24℃; for 25 h; Large scale
To a solution of Boc-Gly-OH (4250g, 24.26 mol), Ν,Ο-dimethylhydroxylamine- HCl(2839g, 29.10 mol) and DMAP(297g, 2.43 mol) in dichloromethane(36 L), is added triethylamine (5.54 L) at 0 °C over a period of 90 min followed by the addition of EDC hydrochloride (5674g, 29.60 mol). The mixture is stirred at 0 °C for lh then warmed to room temp for 24 h. The reaction mixture is cooled to 0 °C and quenched with 1.0M HC1 to pH 3 to 4, stirred at room temp for 20 min, then allowed to stand and separate. The organic phase is washed successively with 1.0M HC1 (15L), water (15.0 L) and brine (8.0 L), dried over Na2SC>4 and filtered. The filtrate is concentrated under reduced pressure to provide the title compound (4985 g; 94percent yield) as a white solid
90%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃;
Boc-glycine was coupled with N,O-dimethyl hydroxylamine hydrochloride, 1 equivalent, in DMF/CH2Cl2 (1:5) using HBTU reagent (1 eq.) and DIEA (2 eq.) at room temperature. The CH2Cl2 was evaporated in vacuo and the residue partitioned between diethyl ether and aq. NaHCO3. The aqueous layer was separated and the ether layer washed in turn with 1M HCl (.x.2), aq. NaHCO3, brine, and then dried over MgSO4. Filtration and removal of the solvent in vacuo left the product amide 69 as a viscous oil that slowly crystallised to a waxy solid and was further purified by chromatography on silica gel. Yield was >90percent. 1H NMR (300 MHz, CDCl3): δ 5.3, 1H, bs, NH; 4.09, 2H, bd, aH2; 3.72, 3H, s, OCH3; 3.20, 3H, s, NCH3; 1.46, 9H, s, Boc. 13C NMR (75 MHz, CDCl3): δ 79.6; 61.4; 41.7; 32.4; 28.3.
90%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; for 72.5 h;
Step 1: To a suspension of /V-(ie f-butoxycarbonyl)glycine (4.0 g, 23 mmol), Ν,Ο- dimethylhydroxylamine hydrochloride (3.0 g, 31 mmol) and /V,/V-dimethylpyridin-4-amine (300 mg, 2.5 mmol) in dry CH2CI2 (100 ml.) was added /V-(3-dimethylaminopropyl)-/V'- ethylcarbodiimide hydrochloride (5.2 g, 27 mmol) followed by triethylamine (5.4 mL, 39 mmol) at 0 °C. The mixture was stirred at that temperature 30 minutes and then at room temperature over 3 days. The suspension was washed with aqueous HCI (1 M, 2 x 40 mL) followed by a saturated aqueous solution of NaHC03 (2 x 40 mL). The organic layer was dried (Na2S04), filtered and concentrated in vacuo to yield fe/f-butyl {2-[methoxy(methyl)amino]-2-oxoethyl}carbamate as a white solid (4.5 g, yield 90percent). 1H-NMR (400 MHz, CDCI3): δ 1.45 (s, 9H), 3.20 (s, 3H), 3.71 (s, 3H), 4.08 (br s, 2H), 5.26 (br s, 2H).
82%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 15 h; Inert atmosphere
Preparation Example 15fe -Butyl 2-(methoxy(methyl)amino)-2-oxoethylcarbamate (45)To a mixture of N-Boc-glycine 44 (10.0 g, 57.1 mmol), Ν,Ο- dimethylhydroxylamine hydrochloride (6.68 g, 68.5 mmol), EDCI (13.1 g, 68.5 mmol), and HOBt (9.26 g, 68.5 mmol) in CH2C12 (200 mL) was added NMM (31.4 mL, 285 mmol). The resulting mixture was stirred at room temperature for 15 h. The reaction mixture was poured into 1.0 M HC1 solution, and extracted with EtOAc. The organic phase was washed with a saturated NaHC03 solution and brine, and then dried over anhydrous MgS04. After evaporation of solvent, the residue was triturated with hexanes (100 mL) to provide the Weinreb amide 45 (10.2 g, 82percent) as white solid.
80%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 16 h;
Example 54 - Synthesis of Compound 49 tert-butyl 2-(methoxy(methyl)amino)-2- oxoethylcarbamate (Boc-Gly Weinreb amide)49 tert-butyl 2-(methoxy(methyl)amino)- 2-oxoethylcarbamateTo a stirred mixture of Boc-Gly-OH (20 g, 114.1 mmol), DIPEA (19.8 ml_, 1 14.1 mmol) and BOP (50.5 g, 1 14.1 mmol) in DCM (20 ml.) was added a pre-mixed solution of N,O- dimethylhydroxylamine hydrochloride (11.2 g, 1 14.1 mmol) and DIPEA (19.8 ml_, 114.1 mmol) in DCM (20 ml.) at room temperature. The resulting mixture was stirred for 16 h then washed with 1 N HCI (3 x 120 ml_), H2O (3 x 120 ml_), saturated NaHCO3 aqueous solution (3 x 120 ml_) and brine (40 ml_), dried over MgSO4, filtered and concentrated under reduced pressure to give 49 as a white solid (20 g, 80percent), which was used in the next step without further purification. MS(ESI) 219 (M+1 ); HPLC fR 4.12 min.
80%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 16 h;
To a stirred mixture of Boc-Gly-OH (20 g, 114.1 mmol), DIPEA (19.8 mL, 1 14.1 mmol) and BOP (50.5 g, 1 14.1 mmol) in DCM (20 mL) was added a pre-mixed solution of N, O- dimethylhydroxylamine hydrochloride (11.2 g, 1 14.1 mmol) and DIPEA (19.8 mL, 114.1 mmol) in DCM (20 mL) at room temperature. The resulting mixture was stirred for 16 h then washed with 1 N HCI (3 x 120 mL), H2O (3 x 120 mL), saturated NaHCO3 aqueous solution (3 x 120 mL) and brine (40 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give 34 as a white solid (20 g, 80percent), which was used in the next step without further purification. MS(ESI) 219 (M+1 ); HPLC fR 4.12 min.
80%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 16 h;
To a stirred mixture of Boc-Gly-OH (20 g, 114.1 mmol), DIPEA (19.8 mL, 114.1 mmol) and BOP (50.5 g, 114.1 mmol) in DCM (20 mL) was added a pre-mixed solution of N,O-dimethylhydroxylamine hydrochloride (11.2 g, 114.1 mmol) and DIPEA (19.8 mL, 114.1 mmol) in DCM (20 mL) at room temperature. The resulting mixture was stirred for 16 h then washed with 1N HCl (3*120 mL), H2O (3*120 mL), saturated NaHCO3 aqueous solution (3*120 mL) and brine (40 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give 49 as a white solid (20 g, 80percent), which was used in the next step without further purification. MS (ESI) 219 (M+1); HPLC tR 4.12 min.
80%
Stage #1: With 4-methyl-morpholine; isobutyl chloroformate In dichloromethane at -25℃; for 0.5 h; Stage #2: at -25℃; for 5 h;
N-Boc-Gly-OH (20 mmol) was dissolved in CH2Cl2(100 mL) and cooled to 25 °C. NMM (44 mmol) and isobutyl chloroformate(22 mmol) were added. After stirring for 30 min, N,O-dimethylhydroxylaminehydrochloride (22 mmol) was added at 25 °C. After 5 h, the reaction mixturewas washed with 10percent KHSO4 (2 100 mL), sat. NaHCO3 (2 100 mL) and H2O(1 100 mL), dried over Na2SO4 and evaporated. The obtained yellowish solidwas purified by column chromatography using CH2Cl2/EtOAc (1+1) to give 1 asa white solid (80percent). mp 102–104 C (lit. 102–103 C);36 1H NMR (500 MHz,DMSO-d6) d 1.37 (s, 9H), 3.08 (s, 3H), 3.66 (s, 3H), 3.81 (d, 3J = 6.0 Hz, 2H), 6.79(t, 3J = 6.0 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) d 28.31, 32.23, 40.95, 61.21,78.05, 156.00, one carbon signal (CH2CO) is missing; LC-MS (ESI) (90percent H2O to100percent MeOH in 10 min, then 100percent MeOH for 10 min, DAD 200.0–400.0 nm): tr =8.16 min, 96percent purity, m/z= 219.2 ([M+H]+).
77%
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 0.5 h; Stage #2: at 20℃; for 12 h;
Example 33 (Compound 46) Step 1; N-tert-Butoxycarboxylglycine (10.0 g, 57.1 mmol) was dissolved in THF (100 mL). To the solution was added CDI (14.3 g, 59.0 mmol) at room temperature, and the mixture was stirred for 30 minutes. To the reaction mixture was added N,O-dimethylhydroxylamine hydrochloride (6.2 g, 64.0 mmol), and the mixture was further stirred at room temperature for 12 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give [(methoxymethylcarbamoyl)methyl]carbamic acid tert-butyl ester (9.55 g, yield: 77percent). APCI-MS m/z: 218 [M+H]+.
72%
Stage #1: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 0℃; for 1 h; Inert atmosphere Stage #2: With dmap; benzotriazol-1-ol In dichloromethane; N,N-dimethyl-formamide at 20 - 27℃; for 16 h;
Intermediate 83, [(teit-butoxycarbonyl)amino]acetic acid (5.00 g, 28.5 mmol), DIPEA (14.75 g, 104 mmol) and Intermediate 84, N-methoxymethanamine hydrochloride (5.60 g, 57.0 mmol)were dissolved in DCM (100 mL) and DMF (100 mL) and Intermediate 85, EDC hydrochloride (6.56 g, 34.0 mmol) was added. The reaction mixture was stirred under nitrogen at 0 °C for 1 h, then Intermediate 86, HOBt (4.63 g, 34.0 mmol) and DMAP (100 mg) were added portionwise and the resulting mixture was stirred for 16 h at room temperature. The reaction mixture was partitioned between H20 (250 mL) and DCM (100 mL), and the aqueous layer was furtherextracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na2SO4), filteredand the solvent was removed in vacuo. The residue was purified by column chromatography(Normal-Phase Silica, 0 to 3 percent methanol in DCM) to give tert-butyl {2-[methoxy(methyl)amino]-2-oxoethyl}carbamate (4.50 g, 72 percent) as a solid.LCMS (Method F): mlz 219 (M+H) (ES), at 1 .77 mi UV active.
71%
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;
2-(tert-Butoxycarbonylamino)acetic acid (800 mg, 4.57 mmol), N,O-dimethylhydroxylamine hydrochloride (535 mg, 5.48 mmol), EDCI (1.05 g, 5.48 mmol) and HOBt (740 mg, 5.48 mmol) were dissolved in DCM (25 mL), to which NMM (2.77 g, 27.42 mmol) was added at room temperature. The reaction mixture was stirred overnight. After the reaction was completed, DCM was evaporated in vacuo. The residue was dissolved in MeOH, filtered through a syringe filter, and then purified by reverse-phase preparative HPLC to provide the desired product (705 mg, 71percent) as a white solid1H NMR (400 MHz, CDCl3) δ 5.27 (br, 1H), 4.09 (d, J=4.6 Hz, 2H), 3.72 (s, 3H), 3.21 (s, 3H) 1.46 (s, 9H).MH+219.
6 g
Stage #1: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 0.25 h; Cooling with ice Stage #2: With triethylamine In dichloromethane at 20℃; for 2 h;
A mixture of Boc-glycine (8.75g, 50mmol, 1 equiv), EDCI (11.5g, 60mmol) and HOBt (7.43g, 55mmol) in DCM (100ml) was stirred in an ice bath for 15min to give a clear solution. Then N,O-Dimethylhydroxylamine hydrochloride (5.1g, 52.5mmol) and triethylamine (5.85ml, 55mmol) were added and the mixture was stirred for 2h at room temperature. Water (100ml) was added and the solution was stirred tempestuously. The precipitate so formed was filtered off and the filtrate was transferred into a separating funnel. The organic phase was separated and the aqueous phase was extracted with CH2Cl2 once again. The combined organic phase was washed with brine (X2), dried over MgSO4 and concentrated. The residue was recrystallized from PE-EA to give F1 (6.0g) as a crystal.
6.0 g
Stage #1: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 0.25 h; Stage #2: With triethylamine In dichloromethane at 20℃; for 2 h;
A mixture of l3oc-glycine (8.75 g, 50 mmol, 1 equiv), EDCI (11.5 g, 60 mmol) and HOSt (7.43 g, 55 mmol) in DCM (100 ml) was stirred in an ice bath for 15 mm to give a clear solution. Then N,O-Dimethylhydroxylamine hydrochloride (5.1 g, 52.5 mmol) and triethylamine (5.85 ml, 55 mmol) were added and the mixture was stirred for 2 h at room temperature. Water (100 ml) was added and the solution was stirred tempestuously. The precipitate so formed was filtered off and the filtrate was transferred into a separating funnel. The organic phase was separated and the aqueous phase was extracted with CH2C12 once again. The combined organic phase was washed with brine (X2), dried over MgSO4 and concentrated. The residue was recrystallized from PE-EA to give Fl (6.0 g) as a crystal.
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[3] Patent: WO2005/105138, 2005, A2, . Location in patent: Page/Page column 15-16
[4] Patent: WO2014/66151, 2014, A1, . Location in patent: Page/Page column 12
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[13] Patent: WO2010/96853, 2010, A1, . Location in patent: Page/Page column 96
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[ 4530-20-5 ]
[ 121505-93-9 ]
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[2] Journal of Organic Chemistry, 2011, vol. 76, # 15, p. 6209 - 6217
[3] Patent: US2013/53362, 2013, A1, . Location in patent: Paragraph 1013; 1014
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[ 4530-20-5 ]
[ 121505-93-9 ]
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[ 4530-20-5 ]
[ 75-65-0 ]
[ 111652-20-1 ]
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[2] Organic Syntheses, 2016, vol. 93, p. 37 - 49
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[ 4530-20-5 ]
[ 172876-96-9 ]
[ 85363-04-8 ]
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[ 4530-20-5 ]
[ 85363-04-8 ]
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[ 4530-20-5 ]
[ 96929-05-4 ]
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[ 4530-20-5 ]
[ 70-23-5 ]
[ 543-27-1 ]
[ 96929-05-4 ]
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With hydrogenchloride; NaH In tetrahydrofuran; water
a) tert-Butyl N-(2-hydroxy-2-oxoethyl)-N-(phenylmethyl)carbamate To a cold (-20°) suspension of 60percent NaH (120 g, 3.00 mol) in THF (700 mL) was added (30 min) a solution of Boc-glycine (175 g, 1.00 mol) in THF (300 mL). Thereafter, benzyl bromide was added to the mixture. After 15 min, the cooling bath was removed. The reaction mixture was stirred at room temperature for 1 h and then heated at reflux for 16 h. The reaction mixture was cooled to 0°. H2O (~50 mL) was added dropwise over a 30 min period. After another 30 min, H2O (600 mL) was added. The mixture was washed with hexane (3*500 mL). 1N Aqueous HCl (1.3 L) was added slowly to the aqueous layer, followed by the addition of 4N aqueous HCl (300 mL). The aqueous solution was extracted with EtOAc (1.5 L) and then CH2C12 (3*500 mL). The combined organic layers were serially washed with H2O and brine, dried (MgSO4, Na2SO4, charcoal), filtered through diatomaceous earth and concentrated under reduced pressure to give the title compound (241 g, 91percent yield) as a pale yellow solid: Mp 94-97°; 1H NMR (400 MHz, DMSO-d6) δ10.5 (broad s, 1H), 7.23-7.33 (m, 5H), 4.40 (s, 2H), 3.80, 3.72 (2s, 2H), 1.38, 1.35 (2s, 9H); MS (FAB) m/z 266 (MH)+; Anal. Calcd for C14H19NO4 (and accounting for water content, 0.58percent w/w as determined by Karl Fisher analysis): C, 63.01; H, 7.26; N, 5.25. Found: C, 62.79; H, 7.14; N, 5.13.
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[2] Patent: US6288091, 2001, B1,
44
[ 4530-20-5 ]
[ 7732-18-5 ]
[ 100-39-0 ]
[ 76315-01-0 ]
Yield
Reaction Conditions
Operation in experiment
0.58% w/w
With hydrogenchloride; NaH In tetrahydrofuran
a) tert-Butyl N-(2-hydroxy-2-oxoethyl)-N-(phenylmethyl)carbamate
To a cold (-20°) suspension of 60percent NaH (120 g, 3.00 mol) in THF (700 mL) was added (30 min) a solution of Boc-glycine (175 g, 1.00 mol) in THF (300 mL). Thereafter, benzyl bromide was added to the mixture. After 15 min, the cooling bath was removed. The reaction mixture was stirred at room temperature for 1 h and then heated at reflux for 16 h. The reaction mixture was cooled to 0°. H2 O (~50 mL) was added dropwise over a 30 min period. After another 30 min, H2 O (600 mL) was added. The mixture was washed with hexane (3*500 mL). 1N Aqueous HCl (1.3 L) was added slowly to the aqueous layer, followed by the addition of 4N aqueous HCl (300 mL). The aqueous solution was extracted with EtOAc (1.5 L) and then CH2 Cl2 (3*500 mL). The combined organic layers were serially washed with H2 O and brine, dried (MgSO4, Na2 SO4, charcoal), filtered through diatomaceous earth and concentrated under reduced pressure to give the title compound (241 g, 91percent yield) as a pale yellow solid: Mp 94-97°; 1 H NM (400 MHz, DMSO-d6) δ10.5 (broad s, 1H), 7.23-7.33 (m, 5H), 4.40 (s, 2H), 3.80, 3.72 (2s, 2H), 1.38, 1.35 (2s, 9H); MS (FAB) m/z 266 (MH)+; Anal. Calcd for C14 H19 NO4 (and accounting for water content, 0.58percent w/w as determined by Karl Fisher analysis): C, 63.01; H, 7.26; N, 5.25. Found: C, 62.79; H, 7.14; N, 5.13.
Reference：
[1] Patent: US6057451, 2000, A,
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[ 4530-20-5 ]
[ 28334-73-8 ]
Reference：
[1] Helvetica Chimica Acta, 1993, vol. 76, # 1, p. 563 - 595
[2] Tetrahedron Letters, 2012, vol. 53, # 45, p. 6148 - 6150,3
[3] Tetrahedron Letters, 2012, vol. 53, # 45, p. 6148 - 6150
[4] Supramolecular Chemistry, 2013, vol. 25, # 5, p. 269 - 275
[5] Patent: WO2016/65174, 2016, A1,
[6] Chemistry - An Asian Journal, 2018, vol. 13, # 4, p. 400 - 403
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Reference：
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With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 0 - 20℃; for 12h;Inert atmosphere;
General procedure: A mixture of L-valine p-TsOH salt 10a (100 mg, 0.30 mmol) and N-Boc valine (87.12 mg, 0.30 mmol) was taken in 2.5 mL of dry THF and cooled to 0 C under nitrogen atmosphere. After stirring, freshly distilled NMM (0.16 mL, 1.51 mmol) was added via syringe followed by HOBt (46.61 mg, 0.34mmol) and EDCI (65.18 mg, 0.34 mmol) in a single portion. The mixture was stirred overnight slowly warming to room temperature. After 12 hours, it was concentrated by a rotavapor and the residue was taken in EtOAc (20.0 mL), washed with saturated NaHCO3 solution followed by brine. The organic layer was dried over MgSO4, filtered, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography using hexane-EtOAc (8:2) to afford the title compound 11a
Following the general procedure of Grigg [Blaney, P.; Grigg, R.; Rankovic, Z.; Thornton- Pett, M.; Xu, J. Tetrahedron, 2002, 58, 1719-1737] a roundbottom flask was charged with sodium hydride (480mg 60% dispersion in oil, 12.0 mmol, 4.0 equiv) and purged with nitrogen for 15 min. THF (6.OmL) was added to the flask, and the suspension was cooled to 0 0C using an ice water bath. A separate flask was charged with BOC-glycine a (525 mg, 3.0 mmol), dry THF (6.0 mL) and ethyl iodide (1.0 mL, 12 mmol, 4 equiv). This mixture was EPO <DP n="134"/>added dropwise to the NaH suspension in THF, with vigorous stirring at 0 0C. After 1 h of stirring, the reaction was warmed to room temperature and allowed to stir overnight. The reaction was again cooled to 0 0C, and methanol (4 mL) was added very slowly to quench the excess hydride. Deionized water was added to dilute the mixture, and methanol was removed under reduced pressure. Impurities were extracted into 90% ethyl acetate-hexanes, the aqueous layer was then acidified by adding solid citric acid until the pH reached 2-3. The product was extracted into 90% ethyl acetate-hexanes. This organic layer was dried (Na2SO4) and filtered. Removal of the solvents under reduced pressure afforded a quantitative yield of the product b.
100%
Following the general procedure of Grigg [Blaney, P.; Grigg, R.; Rankovic, Z.; Thornton-Pett, M.; Xu, J. Tetrahedron, 2002, 58, 1719-1737] a roundbottom flask was charged with sodium hydride (480mg 60% dispersion in oil, 12.0 mmol, 4.0 equiv) and purged with nitrogen for 15 <n="72"/>min. THF (6.OmL) was added to the flask, and the suspension was cooled to 0 C using an ice water bath. A separate flask was charged with BOC-glycine a (525 mg, 3.0 mmol), dry THF (6.0 mL) and ethyl iodide (1.0 mL, 12 mmol, 4 equiv). This mixture was added dropwise to the NaH suspension in THF, with vigorous stirring at 0 0C. After 1 h of stirring, the reaction was warmed to room temperature and allowed to stir overnight. The reaction was again cooled to 0 0C, and methanol (4 mL) was added very slowly to quench the excess hydride. Deionized water was added to dilute the mixture, and methanol was removed under reduced pressure. Impurities were extracted into 90% ethyl acetate -hexanes, the aqueous layer was then acidified by adding solid citric acid until the pH reached 2-3. The product was extracted into 90% ethyl acetate-hexanes. This organic layer was dried (Na2SO4) and filtered. Removal of the solvents under reduced pressure afforded a quantitative yield of the product b.
100%
Example 10 N-Boc-N-methyl-L-glycine; Following the general procedure of Grigg [Blaney, P.; Grigg, R.; Rankovic, Z.; Thornton-Pert, M.; Xu, J. Tetrahedron, 2002, 55, 1719-1737] a roundbottom flask was charged with sodium hydride (480mg 60% dispersion in oil, 12.0 mmol, 4.0 equiv) and purged with nitrogen for 15 min. THF (6.OmL) was added to the flask, and the suspension was cooled to 0 0C using an ice water bath. A separate flask was charged with BOC-glycine a (525 mg, 3.0 mmol), dry THF (6.0 mL) and ethyl iodide (1.0 mL, 12 mmol, 4 equiv). This mixture was added dropwise to the NaH suspension in THF, with vigorous stirring at 0 C. After 1 h of stirring, the reaction was warmed to room temperature and allowed to stir overnight. The reaction was again cooled to 0 0C, and methanol (4 mL) was added very slowly to quench the excess hydride. Deionized water was added to dilute the mixture, and methanol was removed under reduced pressure. Impurities were extracted into 90% ethyl acetate-hexanes, the aqueous layer was then acidified by adding solid citric acid until the pH reached 2-3. The product was extracted into 90% ethyl acetate-hexanes.This organic layer was dried (Na2SO4) and filtered. Removal of the solvents under reduced pressure afforded a quantitative yield of the product b.
100%
With sodium hydride; In tetrahydrofuran; at 0 - 20℃;
Example 29a b c Following the general procedure of Grigg [Blaney, P.; Grigg, R.; Rankovic, Z.; Thornton-Pett, M.; Xu, J. Tetrahedron, 2002, 58, 1719-1737] a roundbottom flask was charged with sodium hydride (480mg 60% dispersion in oil, 12.0 mmol, 4.0 equiv) and purged with nitrogen for 15 min. THF (6.OmL) was added to the flask, and the suspension was cooled to 0 0C using an ice water bath. A separate flask was charged with BOC-glycine a (525 mg, 3.0 mmol), dry THF (6.0 mL) and ethyl iodide (1.0 mL, 12 mmol, 4 equiv). This mixture was added dropwise to the NaH suspension in THF, with vigorous stirring at 0 0C. After 1 h of stirring, the reaction was warmed to room temperature and allowed to stir overnight. The reaction was again cooled to 0 0C, and methanol (4 mL) was added very slowly to quench the excess hydride. Deionized water was added to dilute the mixture, and methanol was removed under reduced pressure. Impurities were extracted into 90% ethyl acetate-hexanes, the aqueous layer was then acidified by adding solid citric acid until the pH reached 2-3. The product was extracted into 90% ethyl acetate-hexanes. This organic layer was dried (Na2SO4) and filtered. Removal of the solvents under reduced pressure afforded a quantitative yield of the product b.
Following the general procedure of Grigg [Blaney, P.; Grigg, R.; Rankovic, Z.; Thornton-Pett, M.; Xu, J. Tetrahedron, 2002, 58, 1719-1737] a roundbottom flask was charged with sodium hydride (480mg 60% dispersion in oil, 12.0 mmol, 4.0 equiv) and purged with nitrogen for 15 min. THF (6.OmL) was added to the flask, and the suspension was cooled to 0 0C using an ice water bath. A separate flask was charged with BOC-glycine a (525 mg, 3.0 mmol), dry THF (6.0 mL) and ethyl iodide (1.0 mL, 12 mmol, 4 equiv). This mixture was added dropwise to the NaH suspension in THF, with vigorous stirring at 0 0C. After 1 h of stirring, the reaction was warmed to room temperature and allowed to stir overnight. The reaction was again cooled to 0 0C, and methanol (4 mL) was added very slowly to quench the excess hydride. Deionized water was added to dilute the mixture, and methanol was removed under reduced pressure. Impurities were extracted into 90% ethyl acetate-hexanes, the aqueous layer was then acidified by adding solid citric acid until the pH reached 2-3. The product was extracted into 90% ethyl acetate-hexanes. This organic layer was dried (Na2SO/t) and filtered. Removal of the solvents under reduced pressure afforded a quantitative yield of the product b.
With nitrogen; citric acid; In tetrahydrofuran; methanol; water;
Example 15 N-ethyl-Boc glycine Following the general procedure of Grigg [Blaney, P.; Grigg, R.; Rankovic, Z.; Thornton-Pett, M.; Xu, J. Tetrahedron, 2002, 58, 1719-1737] a roundbottom flask was charged with sodium hydride (480 mg 60% dispersion in oil, 12.0 mmol, 4.0 equiv) and purged with nitrogen for 15 min THF (6.0 mL) was added to the flask, and the suspension was cooled to 0 C. using an ice water bath. A separate flask was charged with BOC-glycine a (525 mg, 3.0 mmol), dry THF (6.0 mL) and ethyl iodide (1.0 mL, 12 mmol, 4 equiv). This mixture was added dropwise to the NaH suspension in THF, with vigorous stirring at 0 C. After 1 h of stirring, the reaction was warmed to room temperature and allowed to stir overnight. The reaction was again cooled to 0 C., and methanol (4 mL) was added very slowly to quench the excess hydride. Deionized water was added to dilute the mixture, and methanol was removed under reduced pressure. Impurities were extracted into 90% ethyl acetate-hexanes, the aqueous layer was then acidified by adding solid citric acid until the pH reached 2-3. The product was extracted into 90% ethyl acetate-hexanes. This organic layer was dried (Na2SO4) and filtered. Removal of the solvents under reduced pressure afforded a quantitative yield of the product N-ethyl-Boc-glycine b.
(S)-2-{(R)-2-[(S)-2-(2-{(S)-2-[(S)-2-Amino-3-(4-hydroxy-phenyl)-propionylamino]-3-mercapto-3-methyl-butyrylamino}-acetylamino)-3-(4-bromo-phenyl)-propionylamino]-3-mercapto-3-methyl-butyrylamino}-3-phenyl-propionic acid[ No CAS ]
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;
In a flask, 0.1 g Irinotecan (0.1704 mmoles), 0.059 g t-Boc-Glycine (0.3408 mmoles), and 0.021 g DMAP (0.1704 mmoles) were dissolved in 13 mL of anhydrous dichloromethane (DCM). To the solution was added 0.070 g DCC (0.3408 mmoles) dissolved in 2 mL of anhydrous DCM. The solution was stirred overnight at room temperature. The solid was removed through a coarse frit, and the solution was washed with 10 mL of 0.1N HCL in a separatory funnel. The organic phase was further washed with 10 mL of deionized H2O in a separatory funnel and then dried with Na2SO4. The solvent was removed using rotary evaporation and the product was further dried under vacuum. 1H NMR (DMSO): delta 0.919 (t, CH2CH3), 1.34 (s, C(CH3)3), 3.83 (m, CH2), 7.66 (d, aromatic H)
With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 3h;
EDC (0.031 mol) was added to a mixture of 3-nitro- benzenemethanamine, monohydrochloride (0.026 mol), N-[(l,l-dimethylethoxy)carbonyl]- glycine (0.031 mol) and triethylamine (0.065 mol) in DMF (q.s.) at room temperature and then the reaction mixture was reacted for 3 hours at room temperature. After an aqueous work- up with a 10 % citric acid solution, with water, with an aqueous NaHCO3 solution and with NaCl, the organic layer was dried and the solvent was evaporated, yielding 3.66 g (46 %) of intermediate 10.
(2S)-1-(glycylisoleucyl)pyrrolidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
171 mg (50%)
With N-ethyl-N,N-diisopropylamine; In dichloromethane; water; ethyl acetate; trifluoroacetic acid;
(b) (2S)-1-(Glycylisoleucyl)pyrrolidine-2-carbonitrile To a solution of Boc-glycine (0.21 g, 1.2 mmol) and PyBOP (0.62 g, 1.2 mmol) in dichloromethane (3 ml) was added DIPEA (522 mul, 3 mmol). To that solution was added the product of Example 5a (0.28 g, 0.9 mmol) followed by another portion of DIPEA (157 mul, 0.9 mmol). The reaction mixture was stirred overnight. The solvent was removed by rotary evaporation and the residue was taken up in ethyl acetate. The resulting solution was washed with 0.3M sodium bisulfate (2*), saturated sodium bicarbonate (2*), water and saturated sodium chloride. The organic phase was dried with anhydrous sodium sulfate and the solvent was removed by rotary evaporation. The residue was dissolved in a mixture of TFA (95%) and water (5%) and the mixture was stirred overnight. Most of TFA and water was removed under reduced pressure. The residue was subjected to purification by reverse-phase HPLC to give the trifluoroacetate salt of the final product as a white powder; yield 171 mg (50%).
With trifluoromethanesulfonic acid anhydride; N-ethyl-N,N-diisopropylamine; In dichloromethane; ethyl acetate;
a) Preparation of 2-(2-maleimidoethoxy)ethanol above (2.70 mmoles) was added 10 mL of methylene chloride, and the solution cooled to 0°. To the solution was added 1.11 g of 2,6-di-tertbutyl-4-methylpyridine (2.70 mmoles, 100 molpercent) followed by 0.45 mL of trifluoromethanesulfonic anhydride (2.70 mmoles, 100 molpercent). The heterogeneous mixture was stirred at 0° for 1 h. The solution was filtered, and to the filtrate was added a solution of 0.47 g of N-tBOC-glycine (2.70 mmoles, 100 molpercent) and 0.47 mL of diisopropylethylamine (2.70 mmoles, 100 molpercent) in 10 mL of CH2 Cl2. The mixture was stirred for 2 h at room temperature. Ethyl acetate (100 mL) was added and the solution extracted with water (1*50 mL) then dried over Na2S04. Filtration and removal of solvent gave an oil which was purified by flash chromatography on 100 mL of silica gel. The column was eluted with 400 mL of EtOAc/hexanes 1:1, giving 0.43 g of pure material (1.26 mmoles, 46percent). NMR (300 MHz, CDCl3) delta1.45 (s, 9H), 3.66 (m, 6H) 3.94(d, 2H), 4.26 (t, 2H), 5.14 (m, 1H), 6.74 (s, 2H).
1,1-dimethylethyl [(4-oxo-8-(trifluoromethyl)-4H-3,1-benzoxazin-2-yl)-methyl]-carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In 4-methyl-morpholine; methanol; dichloromethane; water;
STEP A: 1,1-dimethylethyl [(4-oxo-8-(trifluoromethyl)-4H-3,1-benzoxazin-2-yl)-methyl]-carbamate A mixture of 17.5 g of N-BOC glycine, 100 ml of methylene chloride and 13.7 ml of N-methyl-morpholine was cooled to -20° C. and a solution of 13 ml of isobutyl chloroformate in 50 ml of methylene chloride was added. After stirring for 30 minutes at -20° C., a solution of 10.25 g of <strong>[313-12-2]2-amino-3-trifluoromethyl benzoic acid</strong> [prepared by the process of J. Med. Chem., Vol. 16 (2) 101,6 (1973)] in 5.49 ml of N-methyl-morpholine and 120 ml of methylene chloride was added thereto and after stirring for 20 hours at ambient temperature, the mixuture was poured into 500 ml of water and 150 ml of 2N hydrochloric acid. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried and concentrated under reduced pressure to dryness. The residue was triturated with 50 ml of methanol and the mixture was frozen, separated, washed with methanol and dried under reduced pressure at 50° C. to obtain 11 g of 1,1-dimethylethyl [(4-oxo-8-(trifluoromethyl)-4H-3,1-benzoxazin-2-yl)-methyl]-carbamate melting at 176° C. Analysis: Calculated: percentC, 52.33; percentH, 4.39; percentN, 8.14; percentF, 16.55. Found: percentC, 52.5; percentH, 4.4; percentN, 7.9; percentF, 16.7.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; for 8h;
EXAMPLE 39 Preparation of tert-butyl 2-(isoquinolin-6-ylamino)-2-oxoethyl carbamate (F39) To N-Boc-glycine in DMF was added EDC, HOBT and <strong>[23687-26-5]6-aminoisoquinoline</strong>. This mixture was stirred for 8 hours. The reaction was washed with NaHCO3(sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, MeOH/CH2Cl2) gave tert-butyl 2-(isoquinolin-6-ylamino)-2-oxoethyl carbamate (E39).
[4-(4-Chloro-phenoxy)-phenylcarbamoyl]-methyl}-carbamic acid tert- butyl ester: To a cold solution (-15 0C) of feTt-butoxycarbonylamino-acetic acid (350 mg, 2.0 mmol) and 4-methylmorpholine (220 muL, 2.0 mmol) in anhydrous THF (10 mL), isobutyl chloroformate (261 muL, 2.0 mmol) in 1 mL of THF is added dropwise. After addition, the resulting solution is stirred for 15 min before adding 4-(4- chlorophenoxy) aniline (438 mg, 2.0 mmol) in one portion. The reaction mixture is allowed to warm to room temperature and stirred for 15 h. Quenched with water, the organic phase is separated and washed with water and dried over MgSO4. Concentration followed by purification with flash chromatography (silica gel, 0-20 percent ethyl acetate/hexanes) yields { [4-(4-chloro-phenoxy)-phenylcarbamoyl]-methyl}-carbamic acid tert-butyl ester as the desired product. 1H NMR (CDCl3) delta (ppm) 7.15 (b, IH), 7.47 (d, 2H), 7.27 (d, 2H), 6.96 (d, 2H), 6.90 (d, 2H), 5.25 (b, IH), 3.93 (d, 2H), 1.48 (s, 9H).
To a solution of N-Boc glycine (175 mg, 1.0 mmol) in anhydrousTHF (10 mL) is added 4- methyl morpholine (101 mg, 1.0 mmol) at 0 0C. After stirring at 0 0C for 5 min., isobutyl chloroformate (136.6 mg, 1.0 mmol) is added. After the addition, the mixture is allowed to warm up to room temperature and stirred for 15 min when 4-(4-chloro-phenoxy)-phenylamine (219.7 mg, 1.0 mmol) is added and stirred for 14 h. The reaction mixture is then poured into water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layer is washed with brine and dried (MgSO4). After removing the drying agent, the solution is concentrated and purified by flash column chromatography (silica gel, EtOAc/hexane) to provide the desired product [4-(4-Chloro- phenoxy)-phenylcarbamoyl]-methyl}-carbamic acid tert-butyl ester
Example 33: (lalpha,5alpha,6beta)-3-{6-[2-(4-Butoxycarbonyl-piperazin-l-yl)-2-oxo- ethylcarbamoyl]-2-phenyl-pyrimidin-4-yl}-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid:33.1 4-(2-tert-Butoxycarbonylamino-acetyl)-piperazine-l-carboxylic acid butyl ester:To a solution of Boc-Glycine (2351 mg) in DCM (150 mL) were added HOBT hydrate (2358 mg) and EDCI hydrochloride (3100 mg) and the mixture was stirred for 30 min at RT. Intermediate 1.4 (2500 mg) was then added and the reaction mixture was stirred at RT overnight. A IN NaHStheta4 aqueous solution was added to the mixture, the formed solid was filtered off and the 2 phases of the filtrate were separated. The org. phase was washed with sat. Na2CO3 solution, dried (MgSO^ and evaporated off to afford 4620 mg of the desired compound as white solid. LC-MS: tR = 0.92 min; [M+H]+: 344.27.
1. Weigh 175 mg Boc-glycine and 150 mg NMM into 20 mL THF.2. Add 100mg of isobutyl chloroformate under nitrogen atmosphere at 0 ° C and react at 0 ° C for 30min.3. To the above reaction solution was added 87.5mg CABT (purchased from Shanghai Ou Kun Chemical Co., Ltd.), the reaction was stirred at 0 ° C 2h, then stirred at room temperature for 12h.4. To the above reaction solution was added 100 mL of saturated NaHCO 3, extracted with 3 × 150 mL of ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate.5. After removing the organic phase by rotary evaporation under reduced pressure, the product was purified by column chromatography on silica gel. The final product Boc-glycine-CBT was eluted with dichloromethane: methanol (10: 1-5: 1).
With triethylamine; sodium iodide; In ethyl acetate; for 16h;Reflux;
Boc-Gly (4.88 g) and Et3N (triethylamine) (4.65 mL, 1.2 equivalent) are dissolved in 25 mL of ethyl acetate. Ethyl-1-chloroethyl carbonate (prepared according to Barcelo et al., Synthesis, 1986, 627) (4.68 g, 1.1 equivalent) and NaI (1.64 g, 0.4 equivalents) are added and the mixture is refluxed for 16 hrs. The precipitate is filtered and 15 mL of ethyl acetate and 20 mL of water are added to the filtrate. The organic phase is separated and the aqueous phase is extracted three times with ethyl acetate. The collected organic phases are washed with a 10percent citric acid solution, a 10percent NaHCO3 solution, a saturated NaCl solution, dried on Na2SO4, filtered and dry evaporated. An orangeoil of 7.8 g is obtained. Yield 95percent. Rf (cHexane/AcOEt : 8/2) 0.40.The oily product of step 1 is put into solution in 24 mL of CH2Cl2 and 21.3 mL of TFA. After stirring for 1 h at room temperature, the reaction mixture is dry evaporated. The obtained yellow oil is taken up in a ether /hexane mixture. The formed precipitate is washed three times with the ether /hexane mixture and then is dried. White solid 7.2 g (Yield 85percent)NMR (DMSOd6) delta (ppm): 1.2 (3H, q), 1.5 (3H, d), 3.90 (2H, dd), 4.10 (2H, q), 6.75 (1H, q), 8.37 (3H, s)
General procedure: A suspension of NaH in mineral oil (40 mmol) was added to a stirred solution of Nalpha-Boc-Nalpha-alkylamino acid (10 mmol) in anhydrous THF (30 mL), and the mixture was stirred at 20 C for 10 min. Then alkyl iodide (100 mmol) was added, and the mixture was stirred at 60 C for 10 h, and maintained at rt overnight. The solvent was removed under vacuum, the residue partitioned in a mixture of ethyl acetate (100 mL) and water (25 mL), and acidified with citric acid to pH 3. The organic phase was separated, washed with saturated aqueous NaCl, containing 1% of Na2S2O3, and dried over anhydrous MgSO4. After evaporation of ethyl acetate, the residue was loaded on Al2O3 (30 g), and eluted consecutively with heptane (to remove mineral oil), eluent A (for Boc-Xaa-OAlk), and finally, with eluent L (for Boc-Xaa-OH). The fractions were evaporated under vacuum. The traces of acetic acid from eluent L were removed by the azeotrope distillation with toluene under reduced pressure. The products were dried in a desiccator under the residual pressure of 0.13-0.26 kPa.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 168h;
To a solution of <strong>[67344-77-8]1-(3-bromophenyl)-N-methylmethanamine</strong> (6; 45.6 g, 228 mmol) in CH2Cl2 (700 mL) were added N-(tert-butoxycarbonyl)glycine (43.9 g, 251 mmol), WSCD*HCl (52.4 g, 274 mmol), and HOBt (37.1 g, 275 mmol). After being stirred at room temperature for 1 week, the mixture was diluted with water and the mixture was extracted with CHCl3. The organic layer was washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc = 7:1 to1:1) to give the product (49.1 g, 60percent) as an oil. 1H NMR (CDCl3): this compound exists as a pair of rotamers at room temperature. d 1.44 (minor rotamer, 9H, s), 1.46 (major rotamer, 9H, s), 2.90 (major rotamer, 3H, s), 2.98 (minor rotamer, 3H, s), 3.96?4.06 (2H, m), 4.44 (minor rotamer, 2H, s), 4.57 (major rotamer, 2H, s),5.54 (1H, br s), 7.06?7.25 (2H, m), 7.28?7.49 (2H, m); MS (ESI) m/z [M+H]+ 357, 359.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In 1,2-dichloro-ethane; at 20℃;
To a solution of <strong>[67344-77-8]1-(3-bromophenyl)-N-methylmethanamine</strong> (12.0 g) and N-(tert-butoxycarbonyl)glycine (11.5 g) in dichloroethane (80 ml) were added HOBt (9.7 g) and WSC hydrochloride (13.7 g), followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with CHCl3. The mixture was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain tert-butyl {2-[(3-bromobenzyl)amino]-2-oxoethyl}carbamate (21.3 g).
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In dichloromethane; at 20℃;
A mixture of 2-(tert-butoxycarbonylamino)acetic acid (200 mg, 1.14 mmol) and EEDQ (282 mg, 1.26 mmol) in DCM (5 mL) was stirred at room temperature for 15 min, then <strong>[42826-42-6]pivalohydrazide</strong> (145 mg, 1.26 mmol) was added and the mixture was continued stirring overnight. The reaction mixture was concentrated and purified by reverse phase chromatography to afford the title compound (100 mg, 32%) as a white solid. 1H NMR (400 MHz, CDC13) delta 8.98 (s, 1H), 8.28 (s, 1H), 5.24 (s, 1H), 3.92 (d, J= 5.8 Hz, 2H), 1.46 (s, 9H), 1.26 (s, 9H); LRMS (ES) calculated M + Na for C2iH25N504: 296.2; Found: 296.0.
N-tert-butyloxycarbonyl glycine irinotecan ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; diisopropyl-carbodiimide; In dichloromethane; at 4 - 20℃; for 3h;
IRI (61.9 mg, 0.1 mmol), Boc-Gly-OH (18 mg, 0.1 mmol), andDMAP (12 mg, 0.1 mmol) were dissolved in DCM (10 mL), cooledto 4 C, combined with DIPCDI (31 lL, 0.2 mmol) and stirred for3 h at room temperature. The reaction mixture was washed anddried as above. The residue was dissolved in 50percentTFA/DCM (1 mL)and solidified as above to give H2N-Gly-IRI TFA salt. To a solutionof this salt in dioxane (1 mL) EMCA (44 mg, 0.2 mmol) was added,followed by pyridine (17 lL, 0.1 mmol) and DIPCDI (16 lL,0.1 mmol). The mixture was stirred for a further 3 h at room temperatureand solidified with diethyl ether to give 5 (55 mg, 64percentyield).
4.02 g
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 4h;
BGC0222-SM1 (Irinotican, 3.50g,1.0eq) and DMF (52.5 mL) were added into a 250 mL round-bottomed flask. DMF wasremoved under reduced pressure at 60 oC. Then n-heptane (100 mL) was added and removed under reduced pressure for three times. DCM (105 mL), Boc-Gly-OH(1.08 g, 1.2 eq) and DMAP (63 mg, 0.1 eq) were added. DCC (1.59 g, 1.5 eq)dissolved in DCM (10 mL) was added into the reaction under 20 oC. The mixture was reactedfor 4 h until the reaction was completed (monitored by TLC). The mixture wasfiltered, IPA (120 mL) was added to the liquid, the solution was condensed toabout 30 mL and was poured into n-heptane (150 mL) to give white solid. Thesuspension was stirred for 1 h. The solid was filtered out and washed withn-heptane (30 mL*2) to give pale yellow solid BGC0222dwith 4.02 g. 1HNMR (400MHz, DMSO-d6): delta 0.93 (3H, t, J= 7.20 Hz), 1.04 (1H,d, J= 6.40 Hz), 1.25~1.31 (4H, m), 1.34~1.40 (9H, m), 1.76~1.85 (6H, m),2.11~2.19 (4H, m), 2.97~3.22 (6H, m), 3.38~3.41(2H, m), 3.79~3.85 (1H, m),3.92~3.98 (1H, m), 4.19~4.42 (2H, m), 5.29~5.40 (2H, m), 5.52 (2H, s), 7.21(1H, s), 7.43 (1H, H, t, J= 6.00 Hz), 7.69 (1H, dd, J= 2.40 Hz; 7.20 Hz), 8.00 (1H, d, J= 2.40 Hz), 8.13~8.17 (1 H, m);10.67 (1H, s); 13C NMR (100MHz, DMSO-d6)delta 169.99, 167.59, 157.01, 156.32,153.03, 152.07, 150.32, 146.84, 146.75, 145.70, 145.61, 131.35, 128.93, 127.48,126.39, 119.19, 115.46, 95.89, 78.94, 76.66, 66.72, 62.49, 50.02, 49.45, 43.45,43.06, 42.54, 31.72, 30.78, 28.64, 28.31, 26.21, 25.96, 25.87, 23.07, 22.69, 22.57,22.16, 14.42, 7.97. LC/MS (m/z): calcd for C40H49N5O9 743.35;found 744 [M+H]+.
6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one[ No CAS ]
[ 75-04-7 ]
[ 141699-57-2 ]
tert-butyl-(2-(3-(6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)pyrrolidin-1-yl)-2-oxoethyl)carbamate[ No CAS ]
tert-butyl-(2-(3-((6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)pyrido[2,3-d]pyrimidin-7-yl)oxy)pyrrolidin-1-yl)-2-oxoethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63 mg; 44 mg
step 1: 6-[2-Chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.19 g, 3.01 mmol), tert-butyl 3-methylsulfonyloxypyrrolidine-1-carboxylate (1.7 equiv., 5.11 mmol, 1360 mg) and cesium carbonate (2.5 equiv., 7.51 mmol, 2450 mg) were mixed in DMF (17.4 mL), and the reaction was stirred at 90 C. for 18 h. The mixture was diluted with EtOAc and 10% citric acid was added to adjust the pH to 9, and the layers were separated. The aqueous layer was extracted with EtOAc, and the organic layers were combined, washed with water and brine, dried (MgSO4), filtered, and finally concentrated in vacuo. The crude residue was purified by SiO2 chromatography eluting with DCM/EtOAc to afford 1307 mg (77% yield) off-white foam. LCMS and NMR analysis indicated a mixture of two regioisomers (i.e., tert-butyl 3-(6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)pyrrolidine-1-carboxylate and tert-butyl 3-((6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)oxy)pyrrolidine-1-carboxylate). The mixture was used in the next step without further purification. MS (ESI) m/z: 565 [M+1]+. step 2: The mixture from step 1 was dissolved in DCM (15 mL) and HOAc (1.05 equiv., 2.429 mmol, 0.1392 mL). MCPBA (1.05 equiv., 2.429 mmol, 544.3 mg) was added in one portion at 0 C., and the reaction was stirred at 0 C. for 1 h. The reaction mixture was evaporated, and the yellow gel was dissolved in a solution of ethylamine (2 mol/L) in THF (17.0 equiv., 39.32 mmol, 19.66 mL). The yellow solution was kept at 25 C. for 18 h. Na2SO3 (1 teaspoon) was added, and the suspension was stirred at 25 C. for 45 min. The mixture was diluted with EtOAc. After filtration and evaporation, the crude residue was purified by SiO2 chromatography eluting with DCM/EtOAc to afford a mixture of tert-butyl 3-(6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)pyrrolidine-1-carboxylate and tert-butyl 3-((6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)pyrido[2,3-d]pyrimidin-7-yl)oxy)pyrrolidine-1-carboxylate (1.00 g, 77% yield overall) as off-white solid. The mixture was used without in the next step without further purification. MS (ESI) m/z: 562 [M+1]+. step 3: The mixture obtained in step 2 (450 mg, 0.8006 mmol) was mixed with HCl (4 mol/L) in 1,4-dioxane (44.0 equiv., 35.23 mmol, 8.806 mL) and maintained at 25 C. for 4 h. The reaction mixture was diluted with EtOAc and NaHCO3 (s, aq) to pH 9 and the layers separated. The aqueous layer was extracted with EtOAc. The organic layers were combined, washed with water and brine, dried (MgSO4), filtered, and finally concentrated in vacuo. The product was obtained as a mixture of 6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)-8-(pyrrolidin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one and 6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-N-ethyl-7-(pyrrolidin-3-yloxy)pyrido[2,3-d]pyrimidin-2-amine (335 mg, 84% yield), which was used in the next step without further purification. MS (ESI) m/z: 462 [M+1]+. step 4: Boc-Gly-OH (4.0 equiv., 0.8745 mmol, 153.2 mg) and HATU (4.0 equiv., 0.8745 mmol, 339.3 mg) were mixed in 1,4-dioxane (1.0 mL) at 25 C. for 20 min. The white suspension was transferred into a solution of 6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-N-ethyl-7-pyrrolidin-3-yloxy-pyrido[2,3-d]pyrimidin-2-amine and 6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-2-(ethylamino)-8-pyrrolidin-3-yl-pyrido[2,3-d]pyrimidin-7-one (101 mg, 0.2186 mmol) in 1,4-dioxane (1.0 mL) and DIPEA (5.0 equiv., 1.093 mmol, 0.191 mL). The reaction was kept at 25 C. for 4 h. The crude was diluted with EtOAc and the pH was adjusted to 9 by addition of 10% citric acid. The layers were separated, and the aqueous layer was extracted by EtOAc. The organic layers were combined, washed with water and brine, dried (MgSO4), filtered, and finally concentrated in vacuo. The crude residue was purified by SiO2 chromatography eluting with DCM/EtOAc to give the two isomers: tert-butyl (2-(3-(6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)pyrrolidin-1-yl)-2-oxoethyl)carbamate: 63 mg, 46% yield, MS (ESI) m/z: 619 [M+1]+. tert-butyl (2-(3-((6-(2-chloro-4-(6-methylpyrazin-2-yl)phenyl)-2-(ethylamino)pyrido[2,3-d]pyrimidin-7-yl)oxy)pyrrolidin-1-yl)-2-oxoethyl)carbamate: 44 mg, 33% yield, MS (ESI) m/z: 619 [M+1]+.
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 1h;
Methyl 3-(2-aminoacetamido)-4-fluorobenzoate (I-58)HATU (8.2 mmol) was added to a mixture of N-Boc glycine (6.8 mmol), <strong>[369-26-6]methyl 3-amino-4-fluorobenzoate</strong> (6.2 mmol), diisopropylethylamine (3.6 mL, 20.5 mmol) and DMF (15 mL). The reaction was stirred at room temperature for 1 hr. LCMS indicated that the reaction was complete. The reaction was diluted with water and extracted with ethyl acetate. The organic extracts were dried over MgSC and concentrated. No further purification was necessary. The crude amide (I-57) (9.2 mmol) was dissolved in dichloromethane (15 mL) and treated with trifluoroacetic acid (8 mL). The reaction stirred at room temperature for 1 hr. LCMS indicated that the reaction was complete. The reaction was concentrated to dryness and the crude material was purified by preparative HPLC to give I-58.
To a 40 mL reaction vessel was added reagents in the following order: N-(tert- butoxycarbonyl)glycine (1.0 mmol), THF (4.0 mL), N-methyl morpholine (c.a. 0.2 mL, 2.0 mmol). This was stirred until complete dissolution. Next was added 2-chloro-4,6-dimethoxy-1,3,5- triazine (1.0 mmol) and this solution was stirred for 20 mins at 50 °C until a white precipitate fully formed. The precipitate was physically agitated to ensure all solids were well stirred. Next was added <strong>[369-26-6]methyl 3-amino-4-fluorobenzoate</strong> (1.3 mmol) and the reaction was stirred for 30 mins at 50 °C and then at room temperature for 2 hrs, then diluted with 5 mL of MeOH and then purified by being poured into water (rapidly stirred, 25 mL). A white solid was collected and treated with dichloromethane (5 mL) and TFA (5 mL), and heated to 34 °C for about 1 hr until removal of the Boc group was complete (by LCMS monitoring). The material was concentrated to dryness and subjected to reverse-phase chromatography (10 to 40 percent water/ACN) to give I-69. The desired fractions were then passed through polymer bound ion- exchange free base cartridges to removal any residual TFA (using product Stratospheres, SPE PL HC03 MP SPE 0.9 mmol nominal load x 2 units). Mobilizing eluent was MeOH (10 mL total flush volume).
Chemical synthesis of glycine dinitrobenzyl ester is performed essentially as described with minor modifications (Murakami, Ohta, Ashigai, & Suga, 2006). Briefly, 1.05 g of alpha-N-Boc-Glycine (6 mmol) and 1.08 g of <strong>[74367-78-5]3,5-dinitrobenzyl chloride</strong> (5 mmol) are dissolved in 1.4 mL triethylamine (10 mmol) and 1.0 mL dimethylformamide, and stirred for 16 h at 21C. Subsequently, 90 mL diethyl ether is added and the mixture is washed 3× with 30 mL 0.5 M HCl, 3× with 30 mL 4% NaHCO3, and once with 50 mL brine (saturated NaCl solution in water). The organic layer is extracted and mixed with anhydrous MgSO4 powder for drying and subsequently concentrated under reduced pressure using a rotary evaporator, before being incubated with 20 mL 4M HCl/ethyl acetate for 20 min at 21C. The mixture is concentrated, washed 3× with 30 mL of diethyl ether and dried. The residue is then dissolved in 1:3 (v/v) methanol-ethyl acetate and crystallized by slow addition of hexanes and mixing by manual shaking. The product is verified by mass spectrometry and NMR.
tert-butyl (2-oxo-2-((2-oxoindolin-5-yl)amino)ethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;
General procedure: To a solution of carboxylic acid 19 (300 mg, 1.13 mmol), in dry DMF (5 mL), under N2 atmosphere and cooled to 0 °C, were added TBTU (363 mg, 1.13 mmol) and DIPEA (6.18 mL, 39.55 mmol). After 30' a 0 °C, 5-amine-2-oxindole (168 mg, 1.13 mmol) was added and the temperature was kept at 0 °C for additional 30'. Later the mixture was slowly warmed to room temperature and left under stirring at rt overnight. Once TLC verified the disappearance of the precursor, the organic solvent was evaporated under vacuum and the crude product was purified by flash chromatography over silica gel, using 0-4percent MeOH as a gradient in CHCl3, to obtain pure 1 as a white solid (210 mg, 0.53 mmol, 47percent yield).
86%
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine;
N-Boc derivative 1a (2.64 mmol) was reacted through a condensation reaction with 5-amino-indol-2-one (391 mg, 2.64 mmol), in the presence of the condensing agent TBTU (848 mg, 2.64 mmol) and DIPEA (5.28 mmol, 0.92 ml_) as a base. The amide was obtained after purification of the crude product by column chromatography over silica gel using CHC /MeOH 92:8 as the eluent (693 mg, 2.27 mmol, 86percent yield).1 H-N MR (400 MHz, DMSO-de): delta 1 .39 (s, 9H, Boc); 3.46 (s, 2H, CH2 indole); 3.68 (d, 2H, J = 6.0 Hz, CH2 glycine); 6.73 (d, 1 H, J = 8.2 Hz, Ar); 7.00 (t, 1 H, J = 6.0 Hz, NH); 7.32 (dd, 1 H, J =2.0, 8.2 Hz, Ar); 7.49 (s, 1 H, Ar); 9.74 (br s, 1 H, NH); 10.27 (br s, 1 H, NH) ppm. Anal. Calcd for C15H19N3O4: C, 59.01 percent; H, 6.27percent; N 13.76percent; Found: C, 59.10percent; H, 6.19percent; N, 13.99percent.
General procedure: PPS1-4P2H1 was synthesized on NovaSyn TGR resin utilizingstandard Fmoc-peptide synthesis protocol and microwave-assistedpeptoid synthesis [38,39], as described in Scheme 1. The peptideportion with methionine and lysines was completed prior to peptoidsynthesis. Internal linker(s) were developed using orthogonallyprotected Lysine (ivDde-Lys(Fmoc)-OH). Peptoid residueswere coupled by using microwave assisted two step peptoidcoupling procedure. First reacting with bromoacetic acid and N,Ndiisopropylcarbodiimide(DIC), followed by respective amine substitution to couple a peptoid residue. Briefly the steps from thebeginning, 200mg of beads were loaded in 5mL reaction vessel andswelled in DMF for 30 min. Fmoc-Met-OH (92.9 mg, 5.0 eq), HOBt(5.0 eq), HBTU (5.0 eq) and DiPEA (10.0 eq) in 2 mL of anhydrousDMF was added to the beads and the reaction vessel was shakenovernight (Scheme 1, A). The solution was drained and beads wererinsed with DMF (10 x 2 mL). Fmoc was deprotected by treatingbeads with 20% piperidine/DMF twice, each for 10 min. Afterrinsing the beads, subsequent amino acids Fmoc-D-Lys-(Boc)-OH,Fmoc-Lys-(Boc)-OH, ivDde-Lys(Fmoc)-OH, ivDde-Lys-(Fmoc)-OH,Fmoc-Lys-(Boc)-OH, Fmoc-D-Lys-(Fmoc)-OH and Boc-Gly-OH werecoupled under similar reaction conditions, however duration of thereaction was 2.0 h (Scheme 1, B-H). Next, two ivDde protectinggroups were removed by treating beads with 5% Hydrazine/DMFsolution three times, each for 10 min (Scheme 1, I). At this point,two hydrophobic regions with four peptoid units in each weresynthesized using the two step microwave assisted peptoid synthesisprotocol as follows. First, 1 mL of Bromoacetic acid (2.0 M inanhydrous DMF) and N,N-diisopropylcarbodiimide (3.2 M inanhydrous DMF) were added to beads, gently shaken for 30 s andplaced in the microwave oven for 15 s with power set at 10%. Thebeads were again shaken for 30 s and placed in the microwave ovenfor another 15 s. Solution was drained and the beads were washedwith DMF (10 x 2 mL). Next, the beads were treated with 2.0 Msolution of the first primary amine, 4-Methoxybenzylamine (Npmba)dissolved in anhydrous DMF (2 mL) and subjected to thesame microwave procedure described above. The next three peptoidresidues of the hydrophobic region was completed byrepeating these two peptoid coupling steps using primary amines,(R)-(alpha)-Methylbenzylamine (Nmba), Piperonylamine (Npip) and(R)-(alpha)-Methylbenzylamine (Nmba). The synthesized compoundwas finally cleaved off from beads with the concomitant removal ofprotecting groups by treating the beads with 2 mL solution of 95%TFA, 2.5% water, and 2.5% Triisopropylsilane (TIS) for 2.0 h. Thecompound was purified using HPLC. Synthesis was confirmed byMALDI-TOF analysis and purity was confirmed by analytical HPLC.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
To a solution of <strong>[73335-64-5]1-(5-bromopyridin-3-yl)-N-methylmethanamine</strong>(10a; 1.37 g, 6.81 mmol) in CH2Cl2 (20 mL) wereadded N-(tert-butoxycarbonyl)glycine (1.37 g, 7.83 mmol), WSCD HCl (1.72 g, 8.95 mmol), and HOBt (1.20 g, 8.89 mmol). After being stirred at room temperature overnight, the mixture was dilutedwith saturated NaHCO3 aqueous solution and extracted with CHCl3. The organic layer was dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc = 4:1 to 1:2) to give the product (2.02 g,83%). 1H NMR (CDCl3): this compound exists as a pair of rotamersat room temperature. d 1.36 (minor rotamer, 9H, s), 1.39 (major rotamer, 9H, s), 2.79 (minor rotamer, 3H, s), 2.96 (major rotamer,3H, s), 3.79-3.88 (2H, m), 4.53 (major rotamer, 2H, s), 4.60 (minorrotamer, 2H, s), 6.76-6.85 (major rotamer, 1H, m), 6.85-6.91(minor rotamer, 1H, m), 7.86-7.91 (major rotamer, 1H, m), 7.93-7.97 (minor rotamer, 1H, m), 8.43-8.49 (1H, m), 8.61 (major rotamer,1H, d, J = 2.1 Hz), 8.66 (minor rotamer, 1H, d, J = 2.0 Hz); MS(FAB) m/z [M+H]+ 358.
tertbutyl 2-(6-amino-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-ylamino)-2-oxoethylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; at 20℃;
A mixture of 2-(tert-butoxycarbonylamino) acetic acid (1.75 g, 10 mmol), 5,6- diamino-1-methylpyrimidine-2,4(1H,3H)-dione (1.56 g, 10 mmol), DCC (8.25 g, 40 mmol) in DMF (40 mL) was stirred at rt overnight. The mixture was diluted with H20 (300 mL) and stirred for 30 mm, then filtered. The filtrate was concentrated in vacuo to give crude product which was purified by flash column chromatography (MeOHIDCM 10percent30percent) to give tertbutyl 2-(6-amino- 1 -methyl-2,4-dioxo- 1,2,3 ,4-tetrahydropyrimidin-5 -ylamino)-2- oxoethylcarbamate; ESI: m/z 314.2 (M+H)t This product (700 mg, 2.23 mmol) and NaOH (1 N aqueous, 9 mL, 9.00 mmol ) in EtOH (90 mL) was heated to 50 °C overnight. The solvent was concentrated in vacuo and the residue was diluted with H20 (100 mL). The pH was adjusted to 7.0 with iN HC1. The precipitate was collected by filtration and dried under vacuum.
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).
General procedure: Solid-phase peptide synthesis was carried out on Fmoc-cappedpolystyrene rink amide MBHA resin (100-200 mesh, 0.05-0.15 mmol scale). The following amino acidderivatives suitable for Fmoc SPPS were used: Fmoc-Cys(Trt)-OH, Fmoc-Gly-OH, Fmoc-Glu(tBu)-OH,Fmoc-Trp(Boc)-OH, Fmoc-Ala-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Pro-OH, Fmoc-Thr(tBu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Phe-OH, Fmoc-Val-OH, Fmoc-aPhe-OH, Fmoc-aVal-OH,Fmoc-aTyr(tBu)-OH, Fmoc-(N-Me)-Phe-OH, Fmoc-D-Ser(TBS)-OH, Fmoc-D-hSer(TBS)-OH, Boc-Gly-OH. Dry resin was washed with DMF 3x and allowed to swell in DMF for 2 h prior to use. Allreactions were carried out using gentle agitation. Fmoc deprotection steps were carried out by treating theresin with a solution of 20percent piperidine/DMF (15 min x 2). Coupling of Fmoc-protected amino acids aswell as (N2-Boc)-hydrazino acids was effected using 5 equiv. HATU (0.5 M in DMF), 10 equiv. DIEA(1.0 M in DMF), and 5 equiv. of the carboxylic acid in DMF at 50 oC (1 h). Coupling of residues Nterminalto the hydrazino acids was carried out with 30 equiv. collidine and 10 equiv. of pre-formed Fmocamino acid chlorides (or 10 equiv. of Fmoc amino acids with 3.3 equiv. triphosgene) in THF at rt (1 h x2).3 After each reaction the resin was washed with DMF 2x, DCM 1x, then DMF 1x. Peptides undergoingMitsunobu reactions were capped with Boc-Gly-OH, washed with DCM 3x, and treated with 5 equiv.TBAF in THF for 3 h at rt. After the reaction the resin was washed with DCM 3x and then treated with 5equiv. triphenylphosphine in THF followed by 5 equiv. of DIAD, then strirred overnight at rt. Peptideswere cleaved from the resin by incubating with gentle stirring in 2 mL of 95:5 TFA:H2O at rt for 2 h. Thecleavage mixture was filtered and the resin was rinsed with an additional 1 mL of cleavage solution. Thefiltrate was treated with 8 mL of cold Et2O to induce precipitation. The mixture was centrifuged and thesupernatant was removed. The remaining solid was washed 2 more times with Et2O and dried undervacuum. Cysteine-containing peptides were purified, lyophilized, dissolved in 10mM phosphate buffer(pH 8.9, 5percent v/v DMSO), stirred until analytical HPLC and MS showed complete conversion to the cyclicdisulfide (1-2 d), and then repurified. Peptides were analyzed and purified on C12 RP-HPLC columns(preparative: 4mu, 90A, 250 x 21.2 mm; analytical: 4mu, 90A, 150 x 4.6 mm) using linear gradients ofMeCN/H2O (with 0.1percent formic acid), then lyophilized to afford white powders. All peptides werecharacterized by LCMS (ESI), HRMS (ESI-TOF), and 1H NMR. Analytical HPLC samples for all purifiedpeptides were prepared as 1 mM in H2O containing 20 mM phosphate buffer at pH 7.0. Linear gradientsof MeCN in H2O (0.1percent formic acid) were run over 20 minutes and spectra are provided for lambda = 220 nm.
N-tert-butyloxycarbonyl glycine irinotecan ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
4.02 g
To a 250 mL round bottom flask was added 3.50 g of Compound 1 (1.0 eq), 52.5 mL of DMF, heated to 60 C to dissolve, 5-10 min, and the DMF was distilled off under reduced pressure. 300 mL of n-heptane was added and distilled under reduced pressure. Three times, after spin-drying, 105 ml of DCM, 1.08 g of Boc-Gly-OH (1.2 eq), 63 mg of DMAP (0.1 eq) were added, and a solution of 1.59 g of DCC (1.5 eq) dissolved in 10 ml of DCM was added dropwise and reacted at 20 C. for 4 hours. After monitoring the reaction is complete, filter, concentrate to the remaining 25% volume, add 120ml IPA, distill 75% of the solvent, add 150ml n-heptane, stir at room temperature for 1 hour, filter, wash with n-heptane twice, dry to light yellow solid 4.02 g of compound 2.
4.02 g
With dmap; dicyclohexyl-carbodiimide; In n-heptane; dichloromethane; at 20 - 60℃; for 4h;
To a 250 mL round bottom flask was added 3.50 g of compound 5 (1.0 eq), 52.5 ml of DMF, and heated to 60 C to dissolve. After 5-10 min, DMF was evaporated under reduced pressure, and 300 ml of n-heptane was added and distilled under reduced pressure, repeat three times, spin dry and add 105 ml DCM, 1.08 g Boc-Gly-OH (1.2 eq), 63 mg DMAP (0.1 eq).A solution of 1.59 g of DCC (1.5 eq) dissolved in 10 ml of DCM was added dropwise, and reacted at 20 C for 4 hours. After the TLC monitoring reaction was completed, filtration, concentration to the remaining 25% by volume, 120 ml of IPA was added, 75% of the solvent was distilled off, 150 ml of n-heptane was added, and the mixture was stirred at room temperature for 1 hour, filtered, washed twice with n-heptane, and dried to give a pale yellow solid (4.02 g)
With water; lithium hydroxide; In tetrahydrofuran; at 20℃; for 4h;
To a solution of 18.9 g N-Boc glycine ester (1 eq.) dissolved in THF (130 ml) was added aqueous solution of 5.85 g LiOH (1.5 eq.) and the resulting solution was stirred at room temperature for 4 hours. The reaction was monitored by TLC (60percent EtOAc/hexane; Rf: 0.3), SM is absent. Reaction mass was concentrated and crude mass was quenched with 5percent HCl (pH 3) and then extracted with EtOAc (4×80 ml), dried over sodium sulphate and concentrated under reduced pressure to get the compound. Quantity produced, 15 g; yield, 92percent; confirmed by Mass.
92%
With water; lithium hydroxide; In tetrahydrofuran; at 20℃; for 4h;
To a solution of 18.9 g N-Boc glycine ester (1 eq.) dissolved in THF (130 ml) was added aqueous solution of 5.85 g LiOH (1.5eq.) and the resulting solution was stirred at room temperature for 4 hours.The reaction was monitored by TLC (60percent EtOAc/hexane; Rf: 0.3), SM is absent.Reaction mass was concentrated and crude mass was quenched with 5percent HCl (pH 3) and then extracted with EtOAc (4×80 ml), dried over sodium sulphate and concentrated under reduced pressure to get the compound. Quantity produced, 15 g; yield, 92percent; confirmed by Mass.
With dmap; dicyclohexyl-carbodiimide; In n-heptane; dichloromethane; N,N-dimethyl-formamide; at 20℃; for 4h;
To a 250 mL round bottom flask was charged 3.50 g of Compound 6 (1.0 eq),52.5 ml of DMF was added and dissolved by heating at 60 ,After 5 to 10 minutes, the DMF was distilled off under reduced pressure,300 ml of n-heptane was added, and the mixture was distilled under reduced pressure.After repeating 3 times, after centrifugal dehydration,105 ml of DCM, 1.08 g of Boc-Gly-OH (1.2 eq) 63 mg of DMAP (0.1 eq) was added,1.59 g of DCC (1.5 eq) was added dropwise, dissolved in 10 ml of a solution of DCM, reacted at 20 DEG C for 4 hours,After the completion of the reaction, Filtered,The residue was concentrated to 25% volume and 120 ml of IPA was added, 75% of the solvent was distilled off, 150 ml of n-heptane was added, The mixture was stirred at room temperature for 1 hour, filtered, washed twice with n-heptane,And dried to obtain 4.02 g of a light yellow solid compound 7.
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