* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Organic Chemistry, 1987, vol. 52, # 9, p. 1710 - 1713
2
[ 456-22-4 ]
[ 459-46-1 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 1, p. 413 - 421
3
[ 456-22-4 ]
[ 25569-77-1 ]
Yield
Reaction Conditions
Operation in experiment
95%
With potassium carbonate; p-toluenesulfonyl chloride In acetonitrile at 20℃; for 2.5 h;
General procedure: TsCl (0.5 mmol, 0.10 g) was added to the mixture of carboxylic acid (1 mmol) and K2CO3 (1.5 mmol, 0.20 g) in dry CH3CN (5 mL), the reaction mixture was stirred at roomtemperature for the appropriate time (20-180 min, Table 2) until the TsCl was no longer detectable by TLC. After the completion of the reaction, CH2Cl2 or Et2O (2×10 mL) was added to the reaction mixture, stirred, filtered, and the organic layer was dried over CaCl2. The evaporation of the solvent afforded a highly pure product.
Reference：
[1] Letters in Organic Chemistry, 2017, vol. 14, # 6, p. 431 - 439
[2] Bulletin of the Chemical Society of Ethiopia, 2011, vol. 25, # 2, p. 255 - 262
[3] Journal of Organic Chemistry, 1970, vol. 35, p. 3233 - 3237
[4] Journal of the American Chemical Society, 2005, vol. 127, # 44, p. 15521 - 15527
[5] Journal of Medicinal Chemistry, 2007, vol. 50, # 9, p. 2249 - 2253
[6] Journal of Organic Chemistry, 2015, vol. 80, # 5, p. 2874 - 2878
4
[ 456-22-4 ]
[ 403-43-0 ]
[ 25569-77-1 ]
Reference：
[1] New Journal of Chemistry, 2017, vol. 41, # 3, p. 931 - 939
5
[ 456-22-4 ]
[ 456-03-1 ]
Reference：
[1] Chemistry - An Asian Journal, 2015, vol. 10, # 6, p. 1286 - 1290
Reference：
[1] Journal of the American Chemical Society, 2008, vol. 130, # 43, p. 14082 - 14083
10
[ 456-22-4 ]
[ 74-88-4 ]
[ 403-15-6 ]
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 4, p. 1501 - 1504
[2] Journal of Organic Chemistry, 2005, vol. 70, # 4, p. 1501 - 1504
11
[ 456-22-4 ]
[ 598-30-1 ]
[ 74-88-4 ]
[ 403-15-6 ]
[ 321-21-1 ]
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 4, p. 1501 - 1504
[2] Journal of Organic Chemistry, 2005, vol. 70, # 4, p. 1501 - 1504
12
[ 456-22-4 ]
[ 74-88-4 ]
[ 403-15-6 ]
[ 321-21-1 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1995, # 10, p. 1265 - 1272
13
[ 456-22-4 ]
[ 594-19-4 ]
[ 74-88-4 ]
[ 403-15-6 ]
[ 321-21-1 ]
[ 64436-59-5 ]
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 4, p. 1501 - 1504
14
[ 456-22-4 ]
[ 456-06-4 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 396 - 406
[2] Journal of Chemical Research - Part S, 2003, # 12, p. 768 - 769
[3] Heterocyclic Communications, 2002, vol. 8, # 6, p. 601 - 606
[4] Journal of Labelled Compounds and Radiopharmaceuticals, 2006, vol. 49, # 2, p. 125 - 137
[5] Journal of Chemical Research, 2010, vol. 34, # 12, p. 680 - 683
[6] Journal of Chemical Research, 2011, vol. 35, # 4, p. 234 - 237
[7] Monatshefte fur Chemie, 2010, vol. 141, # 4, p. 479 - 484
[8] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2011, vol. 79, # 5, p. 1837 - 1842
[9] Journal of Chemical Research, 2011, vol. 35, # 6, p. 364 - 367
[10] Journal of Molecular Structure, 2011, vol. 1003, # 1-3, p. 52 - 61
[11] Journal of Molecular Structure, 2012, vol. 1011, p. 121 - 127
[12] Journal of Agricultural and Food Chemistry, 2012, vol. 60, # 4, p. 1036 - 1041
[13] Letters in Drug Design and Discovery, 2012, vol. 9, # 3, p. 276 - 281
[14] Medicinal Chemistry, 2012, vol. 8, # 6, p. 1190 - 1197,8
[15] Medicinal Chemistry, 2012, vol. 8, # 6, p. 1190 - 1197
[16] Medicinal Chemistry Research, 2012, vol. 21, # 11, p. 3646 - 3655
[17] Medicinal Chemistry Research, 2013, vol. 22, # 3, p. 1305 - 1312
[18] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 8, p. 2286 - 2297
[19] Medicinal Chemistry Research, 2013, vol. 22, # 11, p. 5344 - 5348
[20] Chemical Biology and Drug Design, 2013, vol. 82, # 5, p. 546 - 556
[21] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 1, p. 192 - 194
[22] Journal of the Brazilian Chemical Society, 2014, vol. 25, # 1, p. 104 - 111
[23] Journal of Chemical Research, 2014, vol. 38, # 5, p. 300 - 303
[24] Medicinal Chemistry Research, 2014, vol. 23, # 4, p. 1661 - 1671
[25] Synthetic Communications, 2014, vol. 44, # 18, p. 2724 - 2737
[26] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 22, p. 5154 - 5156
[27] Journal of the Chemical Society of Pakistan, 2014, vol. 36, # 5, p. 852 - 857
[28] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 15, p. 3052 - 3056
[29] Chemical Communications, 2015, vol. 51, # 76, p. 14365 - 14368
[30] Journal of Heterocyclic Chemistry, 2015, vol. 52, # 5, p. 1296 - 1301
[31] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 6014 - 6024
[32] Comptes Rendus Chimie, 2015, vol. 18, # 12, p. 1320 - 1327
[33] Phosphorus, Sulfur and Silicon and the Related Elements, 2016, vol. 191, # 6, p. 904 - 907
[34] RSC Advances, 2015, vol. 5, # 118, p. 97089 - 97101
[35] Asian Journal of Chemistry, 2015, vol. 27, # 10, p. 3605 - 3608
[36] Asian Journal of Chemistry, 2016, vol. 28, # 3, p. 639 - 643
[37] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2015, vol. 70, # 8, p. 609 - 616
[38] Bioorganic Chemistry, 2016, vol. 65, p. 126 - 136
[39] Medicinal Chemistry Research, 2016, vol. 25, # 4, p. 627 - 643
[40] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 21, p. 5611 - 5617
[41] Journal of the Brazilian Chemical Society, 2016, vol. 27, # 11, p. 1998 - 2010
[42] Letters in Drug Design and Discovery, 2016, vol. 13, # 9, p. 968 - 981
[43] Journal of the Chemical Society of Pakistan, 2016, vol. 38, # 5, p. 864 - 881
[44] Chinese Journal of Chemistry, 2016, vol. 34, # 12, p. 1236 - 1244
[45] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 2, p. 1423 - 1429
[46] Chemical Biology and Drug Design, 2017, vol. 90, # 2, p. 236 - 243
[47] Patent: CN104672162, 2017, B,
[48] Biomedicine and Pharmacotherapy, 2017, vol. 94, p. 499 - 513
[49] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 20, p. 5652 - 5661
[50] Oriental Journal of Chemistry, 2017, vol. 33, # 6, p. 2930 - 2936
[51] Pharmaceutical Chemistry Journal, 2018, vol. 51, # 10, p. 907 - 917
[52] RSC Advances, 2018, vol. 8, # 12, p. 6306 - 6314
[53] Journal of Chemistry, 2017, vol. 2017,
[54] Patent: CN108218848, 2018, A,
15
[ 456-22-4 ]
[ 455-86-7 ]
Reference：
[1] Journal of the Chemical Society, Chemical Communications, 1995, # 1, p. 17 - 18
16
[ 456-22-4 ]
[ 1201-31-6 ]
[ 455-86-7 ]
[ 446-17-3 ]
[ 61079-72-9 ]
[ 121602-93-5 ]
[ 1583-58-0 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 7, p. 605 - 609
17
[ 403-33-8 ]
[ 75-05-8 ]
[ 456-22-4 ]
[ 4640-67-9 ]
Yield
Reaction Conditions
Operation in experiment
64%
With sodium hydride In tert-butyl methyl ether; water at 90℃;
Methyl 4-fluorobenzoate (50 g)Was added to a suspension of sodium hydride in methyl-tert-butyl ether (MTBE)(2 eq.) At 90 ° C.4-fluorobenzoylacetonitrile was obtained in about 64percent yield.4-fluorobenzoic acid with a purity of 81percent, 17.5percent4-methoxybenzoylacetonitrile was about 3percent
Reference：
[1] Patent: JP2018/43989, 2018, A, . Location in patent: Paragraph 0129
To a cold solution of 4-fluorobenzoic acid (50.0 g, 0.36 mol, 1.0 equiv) in concentrated H2SO4 (180 ml) was added portionwise potassium nitrate (39.7 g, 0.39 mol, 1.1 equiv). The reaction mixture was stirred overnight at rt and then poured on crushed ice (800 g) with constant stirring. The resulting mixture was kept overnight at rt, filtered and washed thoroughly with water, and finally dried by making an azeotrope with toluene to yield 59.5 g (90percent) of the title compound as a light yellow solid. 1H NMR (400 MHz, DMSO): δ 7.69-7.74 (m, 1H), 8.29-8.32 (m, 1H), 8.56 (d, J=7.2 Hz, 1H), 13.75 (br s, 1H).
75%
at 20℃; for 10 h;
To a solution of 4-fluoro-benzoic acid (5.0 g, 36 mmol) in conc. H2SO4 (36 mL) at 0 °C was added HNO3 (5.6 mL). After the stirring at room temperature for 10 h, the mixture was poured into H2O (200 mL). The precipitate was collected by filtration, washed with water and dried to give 4-fluoro-3-nitrobenzoic acid (5.0 g, 75 percent) as a white solid. 1H NMR (CDCl3, 500 MHz) δ: 7.44 (1H, dd, J = 10.5, 9.0 Hz), 8.39 (1H, m), 8.83 (1H, dd, J = 7.0, 2.0 Hz).
Reference：
[1] Patent: US2008/249101, 2008, A1, . Location in patent: Page/Page column 20
[2] Journal of Medicinal Chemistry, 2003, vol. 46, # 10, p. 1905 - 1917
[3] Tetrahedron Letters, 2017, vol. 58, # 43, p. 4145 - 4148
[4] Journal of Organic Chemistry, 2014, vol. 79, # 11, p. 5134 - 5144
[5] Bulletin de la Classe des Sciences, Academie Royale de Belgique, 1921, vol. <5> 7, p. 536[6] Chem. Zentralbl., 1922, vol. 93, # I, p. 22
[7] Recueil des Travaux Chimiques des Pays-Bas, 1914, vol. 33, p. 336
[8] Patent: WO2012/93101, 2012, A1, . Location in patent: Page/Page column 240-241
[9] Chemistry - A European Journal, 2015, vol. 21, # 20, p. 7571 - 7581
20
[ 456-22-4 ]
[ 7697-37-2 ]
[ 453-71-4 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1914, vol. 33, p. 336
21
[ 456-22-4 ]
[ 7697-37-2 ]
[ 453-71-4 ]
[ 350-46-9 ]
Reference：
[1] Bulletin de la Classe des Sciences, Academie Royale de Belgique, 1921, vol. <5> 7, p. 536[2] Chem. Zentralbl., 1922, vol. 93, # I, p. 22
22
[ 456-22-4 ]
[ 2267-40-5 ]
Yield
Reaction Conditions
Operation in experiment
75%
at 150℃; for 24 h;
3-Chlorosulfonyl-4-fluoro-benzoic Acid Chlorosulphonic acid (100 ml, 1.5 mol) was gradually added to 4-fluorobenzoic acid (43 g, 0.307 mol) with stirring. The clear dark yellow mixture was heated to 150° C. for 24 hours. The yellow solution was cooled back to room temperature and poured onto ice with vigorous stirring. The white precipitate was filtered and pressed dry. The solid was dried overnight in a desiccator under vacuum and over activated silica (54.65 g, 75percent). Mp: 116-117° C.; m/z (LC-MS, ESP), RT=4.03min, (M--1)=237-239 (ratio 1:3).
51%
at 160℃;
Example 2: 2-fluoro-5-(4-methoxy-benzoyl)-benzenesulfonamide; 3-Chlorosulfonyl-4-fluoro benzoic acid <n="45"/>52419A 4-Fluoro- benzoic acid (8 g, 57 mmol) is added carefully to chlorosulfonic acid (58 g, 498 mmol) then sodium chloride (10 g, 169 mmol) is added in small portions. After complete addition, the reaction is heated at 160 0C for 5 h. The reaction mixture is cooled down and poured into ice-water. A white solid precipitate is collected and redissolved in ethyl acetate. The organic layer is washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and the solvent is removed in vacuo. The residue is triturated with hexane to give 7 g (51percent yield) of the title compound as a white solid. 1H NMR (CDCb): δ 8.78 (m, 1 H), 8.52 (m, 1 H), 7.5 (t, 1 H). MS (m/z): 308 (M-1).
Reference：
[1] Patent: US2004/2492, 2004, A1, . Location in patent: Page/Page column 48-49
[2] Patent: WO2009/118292, 2009, A1, . Location in patent: Page/Page column 42-43
[3] Journal of Medicinal Chemistry, 1997, vol. 40, # 13, p. 2017 - 2034
[4] Bioorganic and medicinal chemistry, 2002, vol. 10, # 3, p. 639 - 656
[5] Journal of Medicinal Chemistry, 2005, vol. 48, # 5, p. 1596 - 1609
[6] Patent: WO2010/31813, 2010, A1, . Location in patent: Page/Page column 54
[7] Patent: WO2016/168619, 2016, A1, . Location in patent: Paragraph 00214
[8] Angewandte Chemie - International Edition, 2017, vol. 56, # 1, p. 248 - 253[9] Angew. Chem., 2017, vol. 129, # 1, p. 254 - 259,6
[10] ChemMedChem, 2018, vol. 13, # 12, p. 1165 - 1171
23
[ 7790-94-5 ]
[ 456-22-4 ]
[ 2267-40-5 ]
Reference：
[1] Archiv der Pharmazie, 2015, vol. 348, # 6, p. 399 - 407
24
[ 456-22-4 ]
[ 345-29-9 ]
Reference：
[1] Journal of the American Chemical Society, 2009, vol. 131, # 41, p. 14654 - 14655
25
[ 456-22-4 ]
[ 6148-64-7 ]
[ 1999-00-4 ]
Yield
Reaction Conditions
Operation in experiment
24.8 kg
Stage #1: With magnesium chloride In tetrahydrofuran at 25 - 65℃; for 18 h; Inert atmosphere Stage #2: at 25 - 30℃; for 12 h; Inert atmosphere
To a 500 L stainless steel reactor, ethyl malonate potassium salt (31.6 kg, 185.56 mol) and THF (80.0 L) were added with stirring under an atmosphere of nitrogen. Magnesium chloride (16.6 kg, 185.56 mol) was added in portions while maintaining the temperature at 28 – 35 °C. The reaction temperature was raised to 60 – 65 °C and maintained at 60 – 65 °C for 6 h. Next, the reaction temperature was brought back to 25 – 30 °C and the resulting reaction mixture was stirred at 25 – 30 °C for 12 h (RM-1). In another 250 L stainless steel reactor, CDI (27.8 kg, 174.14 mol) and THF (40.0 L) were added with stirring under an atmosphere of nitrogen. Next, a solution of 4-fluorobenzoic acid (20.0 kg, 142.74 mol) in THF (40.0 L) was added at 25 – 30 °C. The resulting clear solution was stirred at 25 – 30 °C for 3 h (RM-2) (Note: RM-2 preparation was started after 9 h stirring of RM-1). Subsequently, RM-2 was added slowly to RM-1 at 25 – 30 °C over a period of 2 h. The resulting slurry was further stirred at 25 – 30 °C for 12 h under an atmosphere of nitrogen, when there was not more than 2.0percent of 2-1 remaining in the reaction mixture, as determined by HPLC analysis. The reaction mixture was cooled to 15 – 20 °C and the pH was adjusted to 6.0 – 6.5 using 4.0 N aq. HCl. The resulting mixture was extracted with ethyl acetate (90.0 L x 3). The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated at 40 – 45 °C under vacuum (500 – 600 mm Hg) to give 2-2 (24.8 kg, 82percent yield) as a red oil, which was contaminated with trace amounts of 2-1, DCM, and EtOAc, and used for the next step without further purification. HPLC purity: 96.4percent; LC-MS (ESI): m/z 209 [M-H]-; 1H NMR (400 MHz, CDCl3): δ 7.99 – 7.96 (m, 2H), 7.16 – 7.12 (m, 2H), 4.23 (q, J = 7.1 Hz, 2H), 3.96 (s, 2H), 1.26 (t, J = 7.1 Hz, 3H).
Reference：
[1] RSC Advances, 2018, vol. 8, # 27, p. 15009 - 15020
[2] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 5, p. 963 - 968
With dmap In <i>tert</i>-butyl alcohol at 0 - 20℃; for 4 h;
Tert-butyl 4-fluorobenzoate. To the solution of 4-fluorobenzoic acid (10 g, 0.07 mol) in tert-Butanol (200 ml) was added 4-di methylaminopyridine (4.36 g, 35.7 mmol), then Pyrocarbonic acid di-tert-butyl ester (31.1 g, 0.14 mol) was added at °C, the solution was stirred for 4h at room temperature, then water (200 ml) was added and extracted with dichloromethane, evaporated the solvent purified by column chromatography (silica gel, Petroleum ether / ethyl acetate = 20: 1) to give tert-butyl 4-fluorobenzoate (10.2 g, 74percent) H- NMR (300 MHz, CD3OD) 1H-NMR (300 MHz, CD3OD) δ 7.98(m, 2H), 7.15 (m, 2H), 1.59 (s, 9H)
74%
With dmap In <i>tert</i>-butyl alcohol at 0 - 20℃; for 4 h;
To the solution of 4-fluorobenzoic acid (10 g, 0.07 mol) in tert-Butanol (200 ml) was added 4-di methylaminopyridine (4.36 g, 35.7 mmol), then Pyrocarbonic acid di-tert-butyl ester (31.1 g, 0.14 mol) was added at 0° C., the solution was stirred for 4 h at room temperature, then water (200 ml) was added and extracted with dichloromethane, evaporated the solvent purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=20:1) to give tert-butyl 4-fluorobenzoate (10.2 g, 74percent) H-NMR (300 MHz, CD3OD) 1H-NMR (300 MHz, CD3OD) δ 7.98 (m, 2H), 7.15 (m, 2H), 1.59 (s, 9H)
Reference：
[1] Journal of Organic Chemistry, 2017, vol. 82, # 6, p. 3245 - 3251
30
[ 456-22-4 ]
[ 1007-16-5 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 14, p. 1659 - 1664
[2] Journal of Organic Chemistry, 2005, vol. 70, # 4, p. 1501 - 1504
[3] Journal of Enzyme Inhibition and Medicinal Chemistry, 2012, vol. 27, # 5, p. 658 - 665,8
31
[ 456-22-4 ]
[ 403-16-7 ]
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 4, p. 1501 - 1504
32
[ 456-22-4 ]
[ 91590-90-8 ]
[ 1006-41-3 ]
Reference：
[1] Angewandte Chemie - International Edition, 2008, vol. 47, # 28, p. 5215 - 5219
33
[ 456-22-4 ]
[ 403-18-9 ]
Reference：
[1] Tetrahedron Letters, 2000, vol. 41, # 47, p. 9101 - 9104
[2] Russian Journal of Organic Chemistry, 2007, vol. 43, # 9, p. 1291 - 1296
[3] Russian Journal of Organic Chemistry, 2007, vol. 43, # 9, p. 1278 - 1281
[4] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 14, p. 1659 - 1664
[5] Patent: US5734073, 1998, A,
[6] Russian Journal of Organic Chemistry, 2008, vol. 44, # 6, p. 935 - 936
34
[ 456-22-4 ]
[ 403-18-9 ]
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 4, p. 1501 - 1504
[2] Journal of Organic Chemistry, 2005, vol. 70, # 4, p. 1501 - 1504
Reference：
[1] Journal of Organic Chemistry, 1990, vol. 55, # 7, p. 2034 - 2044
39
[ 456-22-4 ]
[ 329-59-9 ]
Reference：
[1] Chemistry - A European Journal, 2015, vol. 21, # 20, p. 7571 - 7581
40
[ 67-56-1 ]
[ 456-22-4 ]
[ 329-59-9 ]
Reference：
[1] Journal of Organic Chemistry, 1990, vol. 55, # 7, p. 2034 - 2044
41
[ 85407-77-8 ]
[ 456-22-4 ]
[ 29601-98-7 ]
Reference：
[1] Journal of the Indian Chemical Society, 1996, vol. 73, # 10, p. 540 - 541
42
[ 456-22-4 ]
[ 6638-79-5 ]
[ 116332-54-8 ]
Yield
Reaction Conditions
Operation in experiment
96%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 3 h;
General procedure: To a solution of 3-cyanobenzoic acid 8a (3.0 g, 19.7 mmol) in DMF was added N,O-dimethylhydroxylamine hydrochloride (2.0 g, 20.7 mmol), Et3N (2.88 mL, d = 0.73, 20.7 mmol) and EDC*HCl (4.0 g, 20.7 mmol). After the mixture was stirred for 3 h at room temperature, the solvent was removed in vacuo and the residue was dissolved in EtOAc, washed with 10percent citric acid, 10percent NaHCO3 and saturated NaCl, and dried over Na2SO4. Then, the solvent was removed to give a colorless oil of compound 9a (3.0 g, 79percent).
92%
Stage #1: With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In tetrahydrofuran; ethyl acetate at 0 - 5℃; for 0.166667 h; Inert atmosphere Stage #2: at 0 - 25℃; for 1.33333 h; Inert atmosphere
General procedure: To a solution of acid 1 (1.0g, 8.9 mmol) in THF (15 mL) was added Et3N (3.1 mL, 22.2 mmol), and T3P (50percent solution in EtOAc, 10.6mL, 17.7 mmol) at 0-5 °C and the solution was stirred for about 10 min under a nitrogen atmosphere. Then N,O-dimethylhydroxylaminehydrochloride salt (1.1g, 13.3 mmol) was added to the reaction mixture at 0-5 °C and the heterogeneous mixture was allowed to stir at room temperature till the completion of the reactionas indicated by TLC (see Table S-1). The mixture was then diluted with water(20 mL) followed by ethyl acetate (20 mL) and stirred for about 10 min. The separated organic layer was collected, washed with 5percent citric acid (2 x10 mL),5percent Na2CO3 (2 x 10 mL), and then brine solution. The collected organic layer was dried over anhydrous Na2SO4, filtered and concentrated under low vacuum. The crude product obtainedwas purified by flash column chromatography over silicagel (100-200 mesh) using 12-15percent EtOAc / n-hexane as eluent to affordthe desired compound.
79%
at 20℃; for 2 h;
Step 4a: 4-Fluoro-N-methoxy-N-methyl-benzamide (4a)To a solution of 4-fluorobenzoic acid (6.8 g, 48.57 mmole) in 100 mL of DMF at room temperature, is added diisopropylethylamine (25.3 mL, 145.7 mmole). After stirring at room temperature for 20 minutes, HOBT (7.22 g, 53.43 mmole), HBTU (20.26 g, 53.43 mmole) and N,O-dimethyl hydroxylamine hydrochloride (5.69 g, 58.29 mmole) are added to the reaction solution. After stirring at room temperature for 2 hours, the reaction solution is diluted with 200 mL of EtOAc and washed with 4.x.50 mL of water. The combined organic layers is concentrated and purified by flash column chromatography (hexane 70percent, EtOAc 30percent) to yield 4-fluoro-N-methoxy-N-methyl-benzamide (4a) (7.0 g, yield 79percent).
77%
Stage #1: With chloroformic acid ethyl ester; triethylamine In dichloromethane at 10℃; for 0.833333 h; Stage #2: With triethylamine In dichloromethane at 10℃; for 1 h;
Method C: a solution of ethyl chloroformate (3.40mL, 35.68mmol) in anhydrous dichloromethane (6mL) was added dropwise at 10°C to a solution of 4-fluorobenzoic acid (5.00g, 35.68mmol) and triethylamine (5mL, 35.68mmol) in anhydrous dichloromethane (50mL). This reaction mixture was stirred at 10°C for 50min, and then N,O-dimethylhydroxylamine hydrochloride (3.48g, 35.68mmol) and triethylamine (5mL, 35.68mmol) were added. The resulting mixture was stirred for 1h at 10°C and the suspension was taken up in water (150mL) and extracted with CH2Cl2 (150mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was finally chromatographed on silica gel eluting with ethyl acetate:petroleum ether (gradient from 0/100 to 20/80 v/v) to give 77percent of 3a as clear oil. 1H NMR (300MHz, CDCl3) δ 7.69 (m, 2H, F-Ph-2,6), 7.02 (m, 2H, F-Ph-3,5), 3.47 (d, 3H, J=1.2Hz, OCH3), 3.29 (d, 3H, J=1.2Hz, NCH3). 13C NMR (75MHz, CDCl3) δ 168.7, 164.0 (J=249Hz), 130.8 (2×C, J=9Hz), 129.8 (J=3Hz), 115.0 (2×C, J=22Hz), 61.0, 33.6.
57%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃;
To a solution of 4-fluorobenzoic acid (200 g, 1.43 mol), N,O-dimethylhydroxylamine hydrochloride (207 g, 2.14 mol) and EDCI (407 g, 2.14 mol) in dichloromethane (2 L) was added diisopropylethylamine (553 g, 4.28 mol) at 0° C. and the mixture was stirred at RT overnight. The reaction mixture was then washed with aqueous HCl (1 N, 1 L*4), water (1 L) and brine (1 L) sequentially. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give the title compound (150 g, yield 57percent). MS (ES+) C9H10FNO2 requires: 183. found 184 [M+H]+; purity: 90percent (UV254).
53.9%
Stage #1: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1 h; Stage #2: With triethylamine In dichloromethane at 20℃; for 2 h;
With potassium carbonate; p-toluenesulfonyl chloride; In acetonitrile; at 20℃; for 2.5h;
General procedure: TsCl (0.5 mmol, 0.10 g) was added to the mixture of carboxylic acid (1 mmol) and K2CO3 (1.5 mmol, 0.20 g) in dry CH3CN (5 mL), the reaction mixture was stirred at roomtemperature for the appropriate time (20-180 min, Table 2) until the TsCl was no longer detectable by TLC. After the completion of the reaction, CH2Cl2 or Et2O (2×10 mL) was added to the reaction mixture, stirred, filtered, and the organic layer was dried over CaCl2. The evaporation of the solvent afforded a highly pure product.
General procedure: The derivatives were synthesized by heating 2,4-diaminophenoldihydrochloride (1) (0.01 mol) with suitable acid (2a-2l) (0.01 mol) in polyphosphoric acid (PPA) (24 g) and stirring at170-200 Cfor 1.5-2.5 h.At the end of the reaction period, theresidue was poured into an ice-water mixture and neutralizedwith an excess of NaOH (10 %) solution, and the residue wasfiltered and boiled with charcoal (200 mg) in ethanol and filtered.After the evaporation of solvent in vacuo, the crudeproduct was obtained and recrystallized from ethanol-water(1:3) mixture (Yildiz-Oren et al., 2004a; Sener et al., 1987;Wynne et al., 2009).
General procedure: Trimethylacetyl chloride(1.21mL, 10mmol) and the excess of triethylamine (15mmol) were added to amixture of 2-fluorobenzoic acid (1.39g,10mmol) in CH2Cl2 (50mL). The resulting mixture wasstirred at r.t. until a clear solution was observed. A solution of piperazine (1.76g, 20mmol) in EtOH (50mL) was added,and the mixture was further stirred for 3-4h. Concd HCl (2mL) was added and theresulting mixture was extracted with CH2Cl2 (20mL). TheCH2Cl2 layer was discarded. NaOH (4.00g) was added to the aqueous solution and thenextracted with CH2Cl2 (150mL). The organic extract wasfurther washed with H2O (50mL) and then dried by Na2SO4.Evaporation of the solvent at reduced pressure yielded the crude productreserved for the next step. Compounds 6-2-6-10 were prepared by using thegeneral procedure described above.
N-[(2RS,3RS)-2,3-epoxy-3-phenylpropyl]-trifluoroacetamide[ No CAS ]
[ 456-22-4 ]
[ 7470-38-4 ]
N-[(2RS,3RS)-2,3-epoxy-3-phenylpropyl]-4-(dimethylamino)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; 1,1'-carbonyldiimidazole; In dichloromethane; water;
working as in Example 38 for the preparation of N-[(2RS,3RS)-2,3-epoxy-3-phenylpropyl]-4-(dimethylamino)benzamide, but starting with 4-morpholinobenzoic acid (3.44 g), carbonyldiimidazole (2.7 g), N-[(2RS,3RS)-2,3-epoxy-3-phenylpropyl]trifluoroacetamide (2.72 g), 3.5 N aqueous potassium hydroxide solution (3.2 cc) and dichloromethane (100 cc), and after recrystallization in ethyl acetate N-[(2RS,3RS)-2,3-epoxy-3-phenylpropyl]-4-morpholinobenzamide (1.9 g), m.p. 150 C., is obtained. 4-Morpholinobenzoic acid may be prepared in the following manner: a mixture of 4-fluorobenzoic acid (21 g) and morpholine (65 cc) is heated to a temperature of 180 C. for 20 hours. After the reaction mixture is cooled, water (100 cc) is added and the pH of the suspension obtained is adjusted to 6 by adding 5 N aqueous hydrochloric acid solution. The insoluble product is separated by filtration and then resuspended in distilled water (100 cc), and the pH of the suspension obtained is adjusted to 11 by adding caustic soda solution. The aqueous phase is extracted with dichloromethane (2*200 cc) and then acidified to pH 6 by adding 5 N aqueous hydrochloric solution, and the insoluble product is separated by filtration.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;
A mixture of (S)-3-hydroxy piperidine hydrochloride (0.2 g, 1.45 mmol), 4- fluoro benzoic acid (0.204 g, 1.45 mmol), EDCHCl (0.42 g, 2.18 mmol), HOBT (0.196 g, 1.45 mmol), triethylamine (320 uL, 4.36 mmol) in dichloromethane (10 mL) was stirred, under nitrogen atmosphere overnight at room temperature. The reaction mixture was diluted with dichloromethane (20 mL) and washed subsequently with 0.1 N HCl (2 times), 0.1 N NaOH (2 times) and then with brine. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to give a pale yellow oil (275 mg), which was used for the next step without further purification. Yield: 84%; LCMS (RT): 2.5 min (Method A); MS (ES+) gave m/z: 224.1.
Synthesis of tert-butyl 4-(4-fluorobenzamido)cyclohexylcarbamate (3.2) To a solution of compound 3.1 (1 equiv.) in dichloromethane, EDC (1.2 equiv.) and DMAP (1.5 equiv.) were added with stirring at 0 C. The resulting solution was stirred at this temperature for 15 min after which compound 1.2 (1.2 equiv.) was added, and the resulting mixture allowed to room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue treated with water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with 1N HCl, sat. NaHCO3 and brine, dried (sodium sulfate) and concentrated in vacuo. The residue was purified by silica gel column chromatography to obtain compound 3.2 as a solid.
A mixture of intermediate 22 (1.8 g, 9.57 mmol) and 4-fluoro-benzoic acid (1.34 g, 9.57 mmol) in polyphosphoric acid (25 g) was stirred and heated at 180 0C for Ih. The r.m. was cooled to r.t, and water was added. The resulting sol. was neutralized with K2CO3, and the resulting precipitate was filtered off and washed with water. Yield: 1 g of crude intermediate 23, which was used as such in the next step.
b) Preparation of intermediate 34A mixture of intermediate 33 (1.8 g, 9.57 mmol) and 4-fluoro-benzoic acid (1.34 g, 9.57 mmol) in polyphosphoric acid (25 g) was stirred and heated for 1 h at 180 0C. The r.m. was cooled to r.t, and water was added. The resulting sol. was neutralized with K2Ctheta3, and the resulting precipitate was filtered off and washed with water. Yield: 1 g of crude intermediate 34, which was used as such in the next reaction step.
With oxygen; sodium hydride; In tetrahydrofuran; mineral oil; at 25℃; under 760.051 Torr; for 0.5h;
General procedure: To a solution of benzoins 1 (0.5 mmol) in distilled THF (5 mL) was added NaH (60% dispersion in mineral oil, 1.0 mmol) at 0 C. While stirring, the dark-blue solution was allowed to warm to room temperature. After stirring under O2 (1 atm), until TLC analysis indicated complete consumption of the starting material, the reaction mixture was quenched by adding 0.1 N HCl to a final pH of 1-2 and extracted with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography to give 2.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 3h;
General procedure: To a solution of 3-cyanobenzoic acid 8a (3.0 g, 19.7 mmol) in DMF was added N,O-dimethylhydroxylamine hydrochloride (2.0 g, 20.7 mmol), Et3N (2.88 mL, d = 0.73, 20.7 mmol) and EDC·HCl (4.0 g, 20.7 mmol). After the mixture was stirred for 3 h at room temperature, the solvent was removed in vacuo and the residue was dissolved in EtOAc, washed with 10% citric acid, 10% NaHCO3 and saturated NaCl, and dried over Na2SO4. Then, the solvent was removed to give a colorless oil of compound 9a (3.0 g, 79%).
92%
General procedure: To a solution of acid 1 (1.0g, 8.9 mmol) in THF (15 mL) was added Et3N (3.1 mL, 22.2 mmol), and T3P (50% solution in EtOAc, 10.6mL, 17.7 mmol) at 0-5 C and the solution was stirred for about 10 min under a nitrogen atmosphere. Then N,O-dimethylhydroxylaminehydrochloride salt (1.1g, 13.3 mmol) was added to the reaction mixture at 0-5 C and the heterogeneous mixture was allowed to stir at room temperature till the completion of the reactionas indicated by TLC (see Table S-1). The mixture was then diluted with water(20 mL) followed by ethyl acetate (20 mL) and stirred for about 10 min. The separated organic layer was collected, washed with 5% citric acid (2 x10 mL),5% Na2CO3 (2 x 10 mL), and then brine solution. The collected organic layer was dried over anhydrous Na2SO4, filtered and concentrated under low vacuum. The crude product obtainedwas purified by flash column chromatography over silicagel (100-200 mesh) using 12-15% EtOAc / n-hexane as eluent to affordthe desired compound.
79%
With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; at 20℃; for 2h;
Step 4a: 4-Fluoro-N-methoxy-N-methyl-benzamide (4a)To a solution of 4-fluorobenzoic acid (6.8 g, 48.57 mmole) in 100 mL of DMF at room temperature, is added diisopropylethylamine (25.3 mL, 145.7 mmole). After stirring at room temperature for 20 minutes, HOBT (7.22 g, 53.43 mmole), HBTU (20.26 g, 53.43 mmole) and N,O-dimethyl hydroxylamine hydrochloride (5.69 g, 58.29 mmole) are added to the reaction solution. After stirring at room temperature for 2 hours, the reaction solution is diluted with 200 mL of EtOAc and washed with 4×50 mL of water. The combined organic layers is concentrated and purified by flash column chromatography (hexane 70%, EtOAc 30%) to yield 4-fluoro-N-methoxy-N-methyl-benzamide (4a) (7.0 g, yield 79%).
77%
Method C: a solution of ethyl chloroformate (3.40mL, 35.68mmol) in anhydrous dichloromethane (6mL) was added dropwise at 10C to a solution of 4-fluorobenzoic acid (5.00g, 35.68mmol) and triethylamine (5mL, 35.68mmol) in anhydrous dichloromethane (50mL). This reaction mixture was stirred at 10C for 50min, and then N,O-dimethylhydroxylamine hydrochloride (3.48g, 35.68mmol) and triethylamine (5mL, 35.68mmol) were added. The resulting mixture was stirred for 1h at 10C and the suspension was taken up in water (150mL) and extracted with CH2Cl2 (150mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was finally chromatographed on silica gel eluting with ethyl acetate:petroleum ether (gradient from 0/100 to 20/80 v/v) to give 77% of 3a as clear oil. 1H NMR (300MHz, CDCl3) delta 7.69 (m, 2H, F-Ph-2,6), 7.02 (m, 2H, F-Ph-3,5), 3.47 (d, 3H, J=1.2Hz, OCH3), 3.29 (d, 3H, J=1.2Hz, NCH3). 13C NMR (75MHz, CDCl3) delta 168.7, 164.0 (J=249Hz), 130.8 (2×C, J=9Hz), 129.8 (J=3Hz), 115.0 (2×C, J=22Hz), 61.0, 33.6.
75%
General procedure: A. To a mixture of benzoic acid (50 mg, 0.41 mmol, 1 equiv), PPh3 (160 mg, 0.61 mmol, 1.5 equiv) and NBS (108.5 mg, 0.61 mmol, 1.5 equiv), CH2Cl2 (2 ml) was added and the reaction was stirred at 0 C for 15 min. The reaction was brought to room temperature and N,O-dimethylhydroxylamine hydrochloride (59.5 mg, 0.61 mmol, 1.5 equiv) and Et3N (45.5 mg, 63 mul, 0.45 mmol, 1.1 equiv) were added and reaction was stirred for 1 h at room temperature. The reaction mixture was quenched with aqueous sodium bicarbonate solution and diluted with CH2Cl2. The bicarbonate washings were again extracted with CH2Cl2 and the combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. Column chromatography was performed using EtOAc/Petroleum ether (1:5).
57%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;
To a solution of 4-fluorobenzoic acid (200 g, 1.43 mol), N,O-dimethylhydroxylamine hydrochloride (207 g, 2.14 mol) and EDCI (407 g, 2.14 mol) in dichloromethane (2 L) was added diisopropylethylamine (553 g, 4.28 mol) at 0 C. and the mixture was stirred at RT overnight. The reaction mixture was then washed with aqueous HCl (1 N, 1 L*4), water (1 L) and brine (1 L) sequentially. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give the title compound (150 g, yield 57%). MS (ES+) C9H10FNO2 requires: 183. found 184 [M+H]+; purity: 90% (UV254).
N-(9-fluorenylmethoxycarbonyl)-3-(β-naphthyl)-L-alanine[ No CAS ]
(S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-ureidopentanoic acid[ No CAS ]
Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine[ No CAS ]
C111H167FN36O28S2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: Protected peptide resins were manually constructed according to the standard procedure using NovaSyn TGR-resin 21 (96.2 mg, 0.025 mmol). 4-Methyltrityl (Mtt) group was employed for the protection of the d-Lys epsilon-amino group. The N-terminal amino group was acylated by treatment with Ac2O (0.012 mL, 0.125 mmol)/pyridine (0.020 mL, 0.250 mmol) for 1 h at room temperature for peptides 26a,b, and with 4-fluorobenzoic acid (17.5 mg, 0.125 mmol)/DIC (0.019 mL, 0.125 mmol)/HOBt·H2O (19.2 mg, 0.125 mmol) for 1.5 h at room temperature for peptide 26c. Subsequently, the resin 22 was treated with CH2Cl2/1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP)/trifluoroethanol (TFE)/triethylsilane (TES) [65:20:10:5; 5 mL] for 2 h at room temperature. The DTPA group was incorporated using the identical procedure employed for the synthesis of the octreotide derivative 19a. Treatment of the resins (25a: 178 mg, 25b: 165 mg, 25c: 162 mg) with a TFA/1,2-ethandithiol(EDT)/H2O (95:2.5:2.5; 5 mL) cocktail for 2 h at room temperature followed by air oxidation and purification provided the peptides Compound 26a (14.6 mg, 15.4%), 26b (6.67 mg, 8.7%) and 26c (7.4 mg, 9.5%) as white powders.
With triethylamine; HATU; In N,N-dimethyl-formamide;
A. Methyl 2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate, 9c. A solution of 1.0 g (4.9 mmol) of <strong>[17672-21-8]methyl 2-amino-3-hydroxybenzoate</strong> 9a, 1.03 g (7.4 mmol) of 4-fluorobenzoic acid 9b, 10 mL DMF and 2.9 mL (20.6 mmol) of TEA were placed into a flask and stirred for 10 min. HATU (7.4 mmol, 2.8 g) was added and the reaction was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organics were washed with water and brine and the solvent was evaporated to give 1.2 g of crude product, methyl 2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate, 9c, which was used without purification. MS m/z (M+H+) 290.1.
With triethylamine; HATU; In N,N-dimethyl-formamide;
A solution of 1.0 g (4.9 mmol) of <strong>[17672-21-8]methyl 2-amino-3-hydroxybenzoate</strong> 8a, 1.03 g (7.4 mmol) of 4-fluorobenzoic acid 8b, 10 mL DMF and 2.9 mL (20.6 mmol) of TEA were placed into a flask and stirred for 10 min. HATU (7.4 mmol, 2.8 g) was added and the reaction was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organics were washed with water and brine and the solvent was evaporated to give 1.2 g of crude product, methyl 2-(4-fluoro-benzoylamino)-3-hydroxy-benzoate, 8c, which was used without purification. MS m/z (M+H+) 290.1
General procedure for the synthesis of test compounds by solid phase peptide synthesis (SPPS); All the compounds were synthesized using Fmoc based solid-phase peptide synthesis protocol. Rink amide MBHA resin preloaded with Fmoc-Proline (750 mg, 0.58 mmol/g) was swollen in DMF for 20 min and washed with DMF (3 X 25 ml). Fmoc group of the resin bound Proline was removed by agitating peptidyl resin in 20% piperidine solution (25 ml, 1 X 5 min and 1 X 30 min) for the next coupling reaction. Fmoc--Ala-OH/ Fmoc-GABA-OH/ <strong>[185116-43-2]Fmoc-PABA-OH</strong> were coupled to the peptidyl resin by agitating their respective preactivated solutions under N2 atmosphere. (i.e. Fmoc-XX-OH (4 equiv), HOBt (4 equiv), and DIC (4 equiv) in DMF (5 mL) for 30 min.). After completion of the coupling reaction confirmed by Kaiser ninhydrin and TNBS tests, peptidyl resin was washed with DMF, DCM and ether (3 X 25 ml each) and treated with 20% piperidine solution (25 ml, 1 X 5 min and 1 X 30 min) to remove Fmoc group. Peptidyl resin was then washed with DMF, DCM and ether (3 X 25 ml each) and swollen in DMF for 30 min for the coupling of benzoic acids. Substituted benzoic acids were incorporated to the respective peptidyl resin by agitating peptidyl rasine in the preactivated coupling solution of respective benzoic acid under N2 atm. over a period of 2-4hrs. Completion of coupling was confirmed by Kaiser ninhydrin and TNBS tests, whenever coupling was found incomplete one more coupling cycle was performed. Then, the resin was washed with DMF, DCM and ether (5 X 25ml each) and dried under vacuum for the global cleavage to get the desired peptidomimetics. Cleavage; The desired peptidomimetics were cleaved and deprotected from their respective peptidyl-resins by treatment with TFA cleavage mixture as follows. A solution of TFA / Water / Triisopropylsilane (95: 2.5: 2.5) (10 ml / 100 mg of peptidyl-resin) was added to peptidyl-resins and the mixture was kept at room temperature with occasional starring. The resin was filtered, washed with a cleavage mixture and the combined filtrate was evaporated to dryness. Residue obtained was triturated with ether (20 ml each) to yield crude compounds, typically in >100% yield (Ca 200-230 mg). Crude compounds thus obtained were purified by preparative HPLC as follows: Purification; Preparative HPLC was carried out on a Shimadzu LC-8A liquid chromatograph. A solution of crude compounds dissolved in water: ACN (1:1, 5ml) or Methanol (5ml) was injected into a semi-Prep column (Luna 10 mu; C18; 210-220 nm), dimension 250 X 21.20 mm and eluted with a linear gradient of ACN in water, both buffered with 0.1 % TFA, using a flow rate of 15 ml / min, with effluent monitoring by PDA detector at 220 nm. A typical gradient of 20 % to 70 % of water-ACN mixture, buffered with 0.1 % TFA was used, over a period of 100 minutes, with 1% gradient change per minute. The desired product eluted were collected in a single 50-80 ml fraction and pure peptidomimetics were obtained as white solids either by lyophilisation of respective HPLC fractions or by normal work up procedure after evaporation of ACN from the fractions and extraction with DCM.
With di-tert-butyl peroxide; copper(II) bis(trifluoromethanesulfonate); In 1,2-dichloro-ethane; at 130℃; for 12h;Sealed tube;
General procedure: A 50 mL sealed tube (with a Teflon high pressure valve) equipped with a magnetic stir bar was charged with Cu(OTf)2 (0.05 mmol), followed by carboxylic acid (0.5 mmol), formamide (2.0 mmol), tert-butyl peroxide (DTBP, 1 mmol), and DCE (1 mL). After the reaction mixture was stirred at 130 C for 12 h, it was allowed to cool to ambient temperature. The reaction mixture was diluted with ethyl acetate, and then filtered through a small pad of Celite. The filtrate was washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL, twice). The organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel preparative TLC to give the corresponding product.
To a solution of 4-fluorobenzoic acid (700 mg, 5.0 mmol) in 1 ,2-dichloroethane (30 mL) was added EDCI (2.38 g, 12.5 mmol), DMAP (1 .52 mg, 12.5 mmol) and N,N- diisopropylethylamine (2.17 mL, 12.5 mmol) and stirred for 20 minutes at room temperature. Lambda/,/V-dimethylaminosulfonamide (1 .24 g, 10.0 mmol) was added to the solution and the mixture heated at 60 °C for 2.5 hours. The mixture was cooled, diluted with water (20 mL) and 2M HCI (20 mL) and extracted with DCM (3 x 30 mL), washed with water (20 mL) and dried over MgSO . The solvent was removed in vacuo to afford the title compound as a white solid (585 mg, 47percent). No further purification was necessary. 1 H NMR (400 MHz, CDCI3) delta ppm 3.02 (s, 6H), 7.15 (dd, 2H), 7.90 (dd, 2H). 19F NMR (400 MHz, CDCI3) delta ppm -104 (s, 1 F). LCMS Rt = 2.35 minutes MS m/z 247 [MH]+
With dmap; In tert-butyl alcohol; at 0 - 20℃; for 4h;
Tert-butyl 4-fluorobenzoate. To the solution of 4-fluorobenzoic acid (10 g, 0.07 mol) in tert-Butanol (200 ml) was added 4-di methylaminopyridine (4.36 g, 35.7 mmol), then Pyrocarbonic acid di-tert-butyl ester (31.1 g, 0.14 mol) was added at C, the solution was stirred for 4h at room temperature, then water (200 ml) was added and extracted with dichloromethane, evaporated the solvent purified by column chromatography (silica gel, Petroleum ether / ethyl acetate = 20: 1) to give tert-butyl 4-fluorobenzoate (10.2 g, 74%) H- NMR (300 MHz, CD3OD) 1H-NMR (300 MHz, CD3OD) delta 7.98(m, 2H), 7.15 (m, 2H), 1.59 (s, 9H)
74%
With dmap; In tert-butyl alcohol; at 0 - 20℃; for 4h;
To the solution of 4-fluorobenzoic acid (10 g, 0.07 mol) in tert-Butanol (200 ml) was added 4-di methylaminopyridine (4.36 g, 35.7 mmol), then Pyrocarbonic acid di-tert-butyl ester (31.1 g, 0.14 mol) was added at 0 C., the solution was stirred for 4 h at room temperature, then water (200 ml) was added and extracted with dichloromethane, evaporated the solvent purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=20:1) to give tert-butyl 4-fluorobenzoate (10.2 g, 74%) H-NMR (300 MHz, CD3OD) 1H-NMR (300 MHz, CD3OD) delta 7.98 (m, 2H), 7.15 (m, 2H), 1.59 (s, 9H)
15 g
With dmap; In tert-butyl alcohol; at 0 - 20℃; for 16h;
35.0 g of p-fluorobenzoic acid and 15.0 g of dimethylaminopyridine were dissolved in 500 mL of t-butanol and cooled to 0 C.107.50 g of di-tert-butyl dicarbonate was added to the mixture, followed by stirring at room temperature for 16 h.Purification by column chromatography to obtain a colorless oily product.The oily product was combined with 15.0 g of the intermediate product represented by formula (III).60.0 g of cesium carbonate was dissolved in 300 mL of dimethyl sulfoxide and heated continuously at 110 C for 16 h.Dimethyl sulfoxide was removed by distillation under reduced pressure. Add 200 mL of water to the residue.It was extracted with dichloromethane, dried over sodium sulfate and concentrated, and the residue was purified by column chromatography eluting with methanol/dichloromethane (50:1 by volume).The product of 6.0 g of a white solid was obtained at room temperature with hydrochloric acid/tetrahydrofuran (12 mol/L concentrated hydrochloric acid)A mixture of 10 ml and tetrahydrofuran (90 ml) was stirred for 16 h.The pH was adjusted to pH 9 with sodium bicarbonate and the mixture was filtered to give a crude material. The crude product was further crystallized three times with methanol to give 2.6 g of the pure product as a white solid, which was the ribavirin hapten of the formula (I), yield 55%. The specific synthetic route is shown in Figure 1.
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; water;Cooling with ice;
The amino acid having non-radioactive FB (hereinafter referred to as ?[19F]FB?) introduced into the side chain of lysine was prepared as follows. Specifically, Fmoc-Lys (5 g, 13.6 mmol) was dissolved in water:THF (1:9, 30 ml), to which DIEA (4.7 ml, 27.1 mmol, diisopropylethylamine) was then added, followed by adding FB-Cl (1.53 ml, 12.9 mmol, 4-F-benzoic acid chloride) thereto with stirring under ice cooling. Thereafter, the reaction solution was stirred a whole day and night, and then added to a 0.5 mol/L hydrochloric acid aqueous solution (300 ml), followed by extracting the title derivative of interest with 300 ml of ethyl acetate. The resulting ethyl acetate layer was dried with sodium sulfate and concentrated under reduced pressure to provide a white solid powder. This was used as an amino acid derivative raw material for the appropriate peptide synthesis (hereinafter referred to as ?Lys-epsilon([19F]FB)?).
4-[3′-[4″-(4‴-fluorobenzoyl)piperazine-1″-carbonyl]-4′-fluorobenzyl]-2H-phthalazin-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In acetonitrile; for 0.0833333h;
To 20 mg (54.5 muiotaetaomicronIota) of 4-(4-fluoro-3-(piperazine-l-carbonyl)benzyl)phthalazin-l(2H)-one dissolved in 1 mL of MeCN, 9.2 mg (65.5 muiotaetaomicronIota) 4-fluorobenzoic acid was added followed by 24.8 mg (65.5 muiotaetaomicronIota) of HBTU and 18 mu (131 muiotaetaomicronIota) of Et3N. The reaction mixture was stirred for 5 minutes and purified by H PLC to yield the compound as an orange solid (11.5 mg, 23.5 muiotaetaomicronIota, 43%). 1H-NM R (500 M Hz, CDC delta = 10.74 (s, 1H), 8.51-8.49 (d, 1H), 7.83-7.76 (m, 2H), 7.82 (s, 1H), 7.45-7.44 (m, 2H), 7.38-7.36 (m, 2H), 7.14-7.08 (m, 3H), 4.33 (s, 2H), 3.75-3.39 (m, 8H). MS-ES m/z [M + Na]+ = 511.2. H RMS-ESi m/z calculated for [C27 H22 N4 03 F2 Naf 511.1558, found 511.1569 [M + Na]+.
(2S)-1-acetyl-N-[(1S)-1-[[(1S)-3-[(4-fluorobenzoyl)amino]-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methylbutyl]-N-methylpyrrolidine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.8 eq of commercially available <strong>[204316-32-5]Fmoc-L-Dab(Alloc)-OH</strong> and DIEA (4 eq) are added to the resin in 2 mL DMF. The mixture is intermittently stirred manually during 1 hour. After that, 0.5 mL/g of MeOH are added to the reaction mixture to cap the remaining reactive points of the resin. After 15 minutes, the solution is filtered off and the resin is washed thoroughly with DCM, DMF and MeOH. Fmoc removal is achieved by treating the resin with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15'). For the coupling of Na-Fmoc-L-iso leucine (Fmoc-L-Ile-OH), 3 eq of the amino acid, 3 eq of the coupling agent TBTU and 6 eq of DIEA dissolved in a small amount of DMF and premixed for 2 minutes. After which, the mixture is added to the resin and the reaction is allowed to react for 90 minutes. To extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15'). For the N-methylation of the amino group of the lle moiety, the free amino group is protected with ortho-nitro benzene sulfonyl chloride (4 eq) using collidine (10 eq) as a base in DMF, which are allowed to react with the resin for 30 minutes. Then, the resin is rinsed with DMF and DCM, and the protection step is repeated again under the same conditions. The extent of the protection is monitored using the Kaiser test. The N-methylation of the amino group is achieved by treating the resin with 3 eq of 7-methyl-l,5,7-triazabicyclo[4.4.0]dec-5-ene and 4 eq of para- nitrobencensulfonate in DMF for 30 minutes (3 treatments). Between treatments the resin is washed thoroughly with DMF and DCM. After the N-methylation of the lle amino group, the ortho-nitro benzene sulfonyl protecting group is removed by treating the resin with 10 eq of beta-mercaptoethanol and 5 eq of DBU (1 x 10' and 1 x 40'). The removal of the ortho-nitro benzene sulfonyl group is assessed using the chloranil test. Then, Fmoc-L-Pro-OH is attached, for that purpose 3 eq of the amino acid, 3 eq of the coupling agent TBTU and 6 eq of DIEA dissolved in a small amount of DMF and premixed for 2 minutes. After which, the mixture is added to the resin and the reaction is allowed to react for 90 minutes. The extent of the reaction is monitored using the Kaiser test. The Fmoc group is then removed by treatments with 20% piperidine in DMF (1 x 5', 1 x 10' and 1 x 15') and additional treatment with a mixture of piperidine/DBU/toluene/DMF (5:5:20:70) (1 x 5'). For the acetylation of the N-part terminal part of the peptide, 20 eq of acetic anhydride and 20 eq of DIEA are added to the resin. The mixture is allowed to react for 30 minutes and the extent of the reaction is monitored using the chloranil test. For the removal of the Alloc group, 10 eq of phenylsilane in DCM are added to the resin while N2 is bubbled through the mixture. Then, 0.1 eq of Pd(PPh3)4 are added maintaining the N2 bubbling while mixing everything well. Then the reaction vessel is sealed and shaken for 15 minutes. After this time, the reaction is filtered and the resin washed thoroughly. The same treatment is repeated two more times. After the last treatment, the resin is washed thoroughly with DCM, MeOH and DMF. For the coupling of the 4-fluorobenzoic acid on the side chain of the Dab moiety, 3 eq of said acid, 3 eq of TBTU and 6 eq of DIEA in DMF are added to the resin. The reaction is allowed to react for 60 minutes. After this time, the resin is washed with DMF and DCM and the extent of the reaction is monitored the Kaiser test. For the cleavage of the peptide, the resin is washed several times with DCM and dried by suction. The linear side-chain protected peptide is cleaved from the resin by adding a solution of HFIP/DCM (1 :4), the mixture is allowed to react for 15 min. Then the reaction mixture is filtered and the resin rinsed with HFIP/DCM. This cleavage procedure is repeated for a second time. All the filtrates are pooled and the solvent is evaporated under vacuum. The crude peptide is used for the formation of the hydroxamide in solution without prior purification. The peptide is dissolved in DCM. After which, 3.5 eq of 0-(2,4-dimethoxybenzyl)hydroxylamine, 5 eq of 4- methylmorpholine, 1.3 eq of the coupling agent EDC HCl and 1.3 eq of the additive HO At are added and the mixture is allowed to react under a N2 atmosphere overnight. The extent of the reaction is monitored using HPLC. Once the desired product is obtained, the mixture is washed with IN HC1, water and brine. The organic layer is dried over magnesium sulfate, filtered and evaporated. After that, a mixture of TFA/water/TIS (95:2.5:2.5) is added to the peptide crude and the mixture is lightly stirred during 2 hours. Afterwards, TFA is evaporated under a N2 flow, yielding example 1. The compound is purified using reverse-phase chromatography
With di-tert-butyl dicarbonate; potassium carbonate; magnesium chloride; nickel dichloride; zinc; In tetrahydrofuran; at 20℃; for 20h;
Weigh 1mmol of p-fluorobenzoic acid and 0.5mmol of p-methylbenzeneboronic acid in the reaction flask, With tetrahydrofuran as solvent, 6.5 mg of nickel chloride (0.05 mmol) 98 mg zinc powder (1.5 mmol), 8 mg of bipyridine (0.05 mmol), 138 mg of potassium carbonate (1.0 mmol), 143 mg of magnesium chloride (1.5 mmol), 109 mg of di-tert-butyl dicarbonate (0.5 mmol), The reaction was stirred at room temperature for 20h, to give the desired product isolated 58mg, yield 54percent
General procedure: Thearyl acid (1 eq) was dissolved into DMF (1-3 mL/1 mmol) and cooled to 0C. HATU(1.2 eq) and DIPEA (3.5 eq) were then added and reaction was stirred at 0C for5-10 min. The amino acid methyl ester (1 eq) was then added and reaction wasallowed to warm and stir at room temperature overnight. Reaction was pouredinto water,and extracted with EtOAc. The organic layers were combined andwashed with a 1N HCl(aq) solution, sat. NaHCO3 (aq)solution, and brine, dried over MgSO4, and concentrated in vacuo.The crude material was purified by flash chromatography (0-100% EtOAc:Hexanes gradient).9-99%
methyl (S)-3-cyclohexyl-2-(4-fluorobenzamido)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
General procedure: Thearyl acid (1 eq) was dissolved into DMF (1-3 mL/1 mmol) and cooled to 0C. HATU(1.2 eq) and DIPEA (3.5 eq) were then added and reaction was stirred at 0C for5-10 min. The amino acid methyl ester (1 eq) was then added and reaction wasallowed to warm and stir at room temperature overnight. Reaction was pouredinto water,and extracted with EtOAc. The organic layers were combined andwashed with a 1N HCl(aq) solution, sat. NaHCO3 (aq)solution, and brine, dried over MgSO4, and concentrated in vacuo.The crude material was purified by flash chromatography (0-100% EtOAc:Hexanes gradient).9-99%
With sodium hydride; In tert-butyl methyl ether; water; at 90℃;
Methyl 4-fluorobenzoate (50 g)Was added to a suspension of sodium hydride in methyl-tert-butyl ether (MTBE)(2 eq.) At 90 C.4-fluorobenzoylacetonitrile was obtained in about 64% yield.4-fluorobenzoic acid with a purity of 81%, 17.5%4-methoxybenzoylacetonitrile was about 3%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide;
General procedure: To a solution of corresponding acids (RCOOH, 0.63 mmol), HOBt (170 mg, 1.26 mmol), EDCI (242 mg, 1.26 mmol), and DIPEA (0.208 mL, 1.26 mmol) were added to DMA (60 mL), and then 4 (186 mg, 1.26mmol) were added, the mixture was stirred overnight. The mixture was dissolved in water, then the aqueous solution was extracted with ethyl acetate (50 mL 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by column chromatography to give N-(4-nitrophenethyl)amide (5) in a good yield. And to a solution of 5 in MeOH was added 10% Pd/C under H2 at reflux overnight, then the mixture was dissolved in water, then the aqueous solution was extracted with ethyl acetate (50 mL 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by column chromatography to give N-(4-aminophenethyl)amide (6) in a good yield. Then the mixture of 3 and 6 was added NaCNBH3 in MeOH and the solution was stirred under reflux overnight. After reaction completed, the solvent was removed under reduced pressure and the residue was dissolved in water, the aqueous solution was extracted with ethyl acetate (50 mL 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by column chromatography to afford the corresponding compounds (7-26) in good yields.
N-(6-bromo-3-isoquinolyl)-4-fluoro-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96.9%
With dmap; 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 80℃; for 17h;
To a suspension of <strong>[891785-28-7]6-bromoisoquinolin-3-amine</strong> (XV) (2.0 g, 8.97 mmol), 4-fluorobenzoic acid (XCVII) (1.51 g, 10.76 mmol), DMAP (1.1 g, 8.97 mmol) and HATU (4.09 g, 10.76 mmol) in DMF (30 mL) was added DIPEA (6.25 mL, 35.86 mmol). The resulting mixture was heated at 80 C. for 2 h. An additional 1.2 eq. of HATU was added and the mixture stirred at 80 C. for additional 15 h. The reaction mixture was poured into water (250 mL) and the resulting solid filtered, washed with water and dried to produce N-(6-bromo-3-isoquinolyl)-4-fluoro-benzamide (XCVIII) as a brown solid (3.0 g, 8.69 mmol, 96.9% yield). ESIMS found for C16H10BrFN2O m/z 345.0 (M+H).
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 15h;Inert atmosphere;
General procedure: A solution of 1-chloro-2-fluorobenzene(0.30 g, 2.3 mmol) in DMF (4 mL) was rapidly added to <strong>[16545-68-9]cyclopropanol</strong> (0.20 g, 3.6 mmol) in a 25 mLsingle-necked round-bottom flask. After that, the mixture was stirred and Cs2CO3 (1.12 g, 3.5 mmol)was put into the flask at nitrogen atmosphere. Then the mixture was refluxed under nitrogen andstirred at 135 C for 15 h. After completion of the reaction, the resulting mixture was diluted withH2O (30 mL) and extracted with AcOEt (10 mL×3). Then the combined organic phase was washedwith saturated aqueous NaCl (10 mL×3) and dried over Na2SO4 for 0.5 h. After that, the organicphase was concentrated under reduced pressure to give crude product. The crude product waspurified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100/1) togive desired product as a light yellow liquid in 39.6% yield (0.15g)
N-(1-(4-bromophenyl)cyclopropyl)-4-fluorobenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; 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 16h;
To a stirred solution of 4-fluorobenzoic acid (290 mg, 2.070 mmol) in DMF (8 mL) were added HATU (905 mg, 2.380 mmol), l-(4-bromophenyl)cyclopropanamine (505 mg, 2.380 mmol) and TEA (0.87 mL, 6.24 mmol) at RT and the reaction was stirred RT for 16 h. Then the mixture was diluted with water (50 mL), extracted with EtOAc (30 mLx3), and the organic layers were collected, washed with brine, dried over Na^SO^ and filtered. After filtration, the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography to afford the title compound as a solid. MS (ESI) m/z: 333.9 [M+H+]
Trimethylacetyl chloride (2.42 mL, 20 mmol) and Et3N (4.60 mL,30 mmol) were added to a mixture of 4-fluorobenzoic acid(20 mmol) in dry CH2Cl2 (80 mL). The resulting mixture was stirredat room temperature for 0.5e1 h until a clear solution wasobserved. A solution of piperazine (3.44 g, 40 mmol) in EtOH(80 mL) was added, and the mixture was further stirred for 3 h.Then the reaction solution was evaporated to remove solvents. Theresidue was dissolved in 20 mL H2O, and concd HCl (4 mL) wasadded. The resulting mixture was extracted with CH2Cl2 (5 mL) toremove bisadduct. NaOH (8 g) was added to the aqueous solutionand then extracted with CH2Cl2 (30 mL 3). The organic extractwas further washed with H2O (30 mL) and then dried over Na2SO4.Evaporation of the solvent at reduced pressure yielded the residuewhich was further used in next step. EI-MS (m/z) 208[M].The intermediates 5b-5e were prepared by commercially benzoicacids bearing different substituents and piperazine using thesame method as described above.
(2S)-1-acetyl-N-[(1S)-1-[[(1S)-3-[(4-fluorobenzoyl)amino]-1-(hydroxycarbamoyl)propyl]carbamoyl]-2-methylbutyl]-N-methylpyrrolidine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12%
General procedure: The compounds were synthesized manually by SPPS following theFmoc/tert-butyl (Fmoc/tBu) strategy and using 2-chlorotrityl resin (IrisBiotech) in polypropylene syringes, each fitted with a polyethyleneporous disk. Solvents and soluble reagents were removed by suction.Prior to starting the synthesis, the resin was conditioned by swelling indichloromethane (DCM, 15 min) and washings with dimethylformamide(DMF, 3×30 s). The incorporation of hydroxylamine linker wasperformed by adding N-Fmoc-hydroxylamine (1.5 eq) and N,N-diisopropylethylamine(10 eq) to the resin in DCM for 24 h [50]. After this,the unreacted points of the resin were capped with methanol (0.8 mL/ gresin, 10 min). The Fmoc protecting groups were removed using 20%piperidine (Carlo Erba) solution in DMF (Carlo Erba) (2x1 min, 1x10min). The coupling reactions were performed in DMF using Fmocaminoacids (3 eq) and oxyma pure (3 eq, Iris Biotech) in the presenceof diisopropylcarbodiimide (3 eq) for 90 min. This mixture is known toproduce couplings with high efficiency and extremely low or null racemization[51]. The reaction was monitored by colorimetric tests: theKaiser colorimetric test [52] was used for the detection of primaryamines, while the chloranil test was used for secondary amines boundto the solid-phase [53]. The Alloc group was removed by adding phenylsilane(10 eq) and Pd(PPh3)4 (0.1 eq) in DCM (3×15 min). Peptideswere cleaved from the resin using 30% trifluoroacetic acid (TFA,Fluorochem) in DCM (3×15 min). After cleavage, filtrates and DCMwashes (3×5 min) were evaporated and lyophilized. The crude productobtained was purified by reverse-phase column chromatographyusing a Combi flash ISCO RF provided with dual ultraviolet detectionusing a high performance RediSep Rf Gold C18 column (Teledyne isco).The purity of the purified compounds was determined at lambda=220 nmby analytical HPLC (Waters Alliance 2695 separation module equippedwith a 2487 photodiode array detector, a Sunfire C18 column(100×4.6mm×5 mum, 100 A, Waters), and Empower software). Flowrate 1 mL/min, mobile phase H2O (0.036% TFA) and acetonitrile(0.045% TFA). Compound identity was assessed by analytical HPLC-MS(Waters Alliance 2695 separation module system equipped with aWaters 2998 photodiode array detector electrospray ionization (ESI)-MS micromass ZQ and a Sunfire C18 column (2.1×100mm×3.5 mum,100 A, Waters), and Masslynx software. Flow rate 0.3 mL/min, mobilephase H2O (0.1% formic acid (FA)) and acetonitrile (0.07% FA). Thepurity of all final compounds was 95% or higher, as measured by HPLC.The exact mass for compound 40 was measured in a LCT-Premier XE(Waters-Micromass) coupled to UPLC (Acquity, Waters).
Complex 1 was prepared by the reaction of an aqueous solution of copper(II) acetate monohydrate (1mmol, 0.20g) with N-methylnicotinamide (2mmol, 0.27g) followed by addition of 4-fluorobenzoic acid (2mmol, 0.28g). The reaction mixture was stirred until a blue product was precipitated (3days). The fine blue microcrystals were filtered off, washed with a small portion of water and dried at ambient temperature. The mother liquor obtained from filtration were left to crystallize. The blue crystals suitable for X-ray structure determination were separated after several days. Yield: 0.41g (65%). Anal calc. for C28H26CuF2N4O7 (Mr=632.07): C 53.21, H 4.15, N 8.64. Found: C 52.84, H 4.18, N 8.52. IR (cm-1): 3321 (vs), 3120 (w), 1669 (s), 1605 (m), 1599 (w), 1536 (s), 1504 (m), 1481 (m), 1428 (w), 1408 (m), 1387 (s), 1378 (m), 1349 (w), 1302 (s), 1219 (m), 1200 (w), 1167 (w), 1157 (m), 1139 (w), 1113 (w), 1090 (m), 1066 (w), 1012 (w), 967 (w), 933 (w), 861 (m), 847 (w), 829 (w), 784 (s), 740 (m), 692 (s), 655 (w), 621 (s), 553 (w), 499 (m), 457 (w), 429 (w).
tert-butyl (2S,5R)-4-(4-fluorobenzoyl)-2,5-dimethylpiperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70.1%
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 4h;
To a solution of 4-fluorobenzoic acid (0.98 g, 7 mmol) in DMF (10 mL) were added TEA (1.95 mL, 14.0 mmol), BOP (2.06 g, 4.67 mmol) and tert-butyl (2S,5R)-2,5- dimethylpiperazine-1-carboxylate (1.0 g, 4.67 mmol). The reaction mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the crude compound was purified by flash chromatography (12 g column silica, eluted with 25-40% ethyl acetate/ Pet ether) to obtain tert-butyl (2S,5R)-4-(4-fluorobenzoyl)-2,5- dimethylpiperazine-1-carboxylate (1.1 g, 70.1 % yield) as an off white solid; LCMS: m/z, 337.2 (M+H); rt 1.95 min. LCMS Method Column Name: AQUITY UPLC BEH C18(3.0 x 50 mm) 1.7 ^m Buffer: 10 mM ammonium acetate Mobile phase A:Buffer acetonitrile (95:5) Mobile phase B: Buffer: acetonitrile (5:95) Method:%B: 0 min-20:2 min -100:2.2 min-100 Flow: 0.7 mL/min
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