* 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] ACS Catalysis, 2018, vol. 8, # 5, p. 4033 - 4043
[2] European Journal of Organic Chemistry, 2018, vol. 2018, # 4, p. 485 - 493
[3] Bulletin of the Chemical Society of Japan, 1964, vol. 37, p. 583 - 584
[4] Journal of the Indian Chemical Society, 2002, vol. 79, # 5, p. 420 - 425
[5] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 14, p. 3347 - 3351
[6] Journal of Heterocyclic Chemistry, 2010, vol. 47, # 1, p. 15 - 21
[7] Tetrahedron Letters, 2011, vol. 52, # 40, p. 5149 - 5152
[8] Tetrahedron, 2013, vol. 69, # 7, p. 1857 - 1871
7
[ 371-41-5 ]
[ 32315-10-9 ]
[ 38377-38-7 ]
Reference：
[1] Chemistry - A European Journal, 2013, vol. 19, # 42, p. 14047 - 14051
[2] Organic Letters, 2018, vol. 20, # 16, p. 4838 - 4842
8
[ 371-41-5 ]
[ 503-38-8 ]
[ 38377-38-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 8, p. 1716 - 1727
9
[ 371-41-5 ]
[ 42864-24-4 ]
[ 5724-56-1 ]
[ 394-33-2 ]
[ 52962-97-7 ]
[ 52911-59-8 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1983, p. 1003 - 1010
10
[ 371-41-5 ]
[ 42864-24-4 ]
[ 5724-56-1 ]
[ 394-33-2 ]
[ 52962-97-7 ]
[ 52911-65-6 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1983, p. 1003 - 1010
11
[ 371-41-5 ]
[ 67-66-3 ]
[ 347-54-6 ]
Yield
Reaction Conditions
Operation in experiment
22%
With sodium hydroxide In ethanol; water at 70℃; for 18 h; Heating
Example 82 3- [4- (3-hydroxy-4-methyl-phenoxy)-2-methyl-phenyl]-propionic acid ethyl ester Step A A solution of NaOH (78 g, 1950 mmol) in H20 (400 mL) is added to a solution of 4-fluorophenol (50 g, 446.43 mmol) in a mixture of H2O (200 mL) and EtOH (150 mL). After the mixture is warmed to 70°C, CHC13 (110 mL) is added dropwise (addition funnel, about 2 h), and the mixture is stirred at this temperature overnight (c. a. 16 h). It is allowed to reach r. t. and acidified with HCl (3M). The reaction is partitioned between brine and CH2Cl2, and the organic layer is dried, filtered and concentrated. The crude residue is flash chromatographed on Si02 (3percent EtOAc/hexanes) to afford 13.6 of the title compound (22percent, white solid).
21%
With sodium hydroxide In ethanol; water at 70℃;
Example 80 Synthesis of 5-fluoro-2-hydroxybenzaldehyde To a solution of 4-fluorophenol (25 mg, 223 mmol) in a mixed solvent of ethanol (100 mL) and H2O (75 mL) was added NaOH aqueous solution (39 g, 970 mmol, in 200 mL H2O). The resulted mixture was warmed up to 70° C. and added chloroform (55 mL, 691 mmol) dropwise during 2 h, and then the mixture was stirred at 70° C. for overnight. The reaction was cooled down to room temperature and quenched by addition of hydrochloric acid (6 M, 100 mL), and then the mixture was extracted with DCM (250 mL*2). The combined organic layer was washed with H2O and brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=25:1) to afford 5-fluoro-2-hydroxybenzaldehyde (6.5 g, yield: 21percent) as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ 10.01 (s, 1H), 9.88 (s, 1H), 7.26-7.32 (m, 2H), 7.00 (dd, J=4.0, 8.8 Hz, 1H).
Reference：
[1] Journal of the American Chemical Society, 1998, vol. 120, # 33, p. 8340 - 8347
[2] Patent: WO2005/37763, 2005, A1, . Location in patent: Page/Page column 126
[3] Patent: US2017/37038, 2017, A1, . Location in patent: Paragraph 0372; 0373; 0374
[4] Journal of the American Chemical Society, 1946, vol. 68, p. 2502
[5] European Journal of Medicinal Chemistry, 1996, vol. 31, # 6, p. 449 - 460
12
[ 50-00-0 ]
[ 371-41-5 ]
[ 347-54-6 ]
Reference：
[1] Organic Syntheses, 2005, vol. 82, p. 64 - 68
[2] Organic and Biomolecular Chemistry, 2017, vol. 15, # 6, p. 1530 - 1536
[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1994, # 13, p. 1823 - 1832
[4] Tetrahedron Letters, 2005, vol. 46, # 19, p. 3357 - 3358
[5] Tetrahedron Letters, 2005, vol. 46, # 32, p. 5285 - 5287
[6] Journal of Medicinal Chemistry, 2000, vol. 43, # 24, p. 4701 - 4710
[7] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 20, p. 5591 - 5593
[8] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 6, p. 1939 - 1943
[9] Chemistry - A European Journal, 2017, vol. 23, # 68, p. 17195 - 17198
[10] Organic Letters, 2017, vol. 19, # 23, p. 6340 - 6343
Reference：
[1] Chemical & Pharmaceutical Bulletin, 1983, vol. 31, # 5, p. 1751 - 1753
15
[ 108-95-2 ]
[ 371-41-5 ]
[ 367-12-4 ]
[ 367-27-1 ]
Yield
Reaction Conditions
Operation in experiment
41 %Spectr.
With Selectfluor; 1-(n-butyl)-3-methylimidazolium triflate In methanol at 80℃; for 5 h; Inert atmosphere
General procedure: A mixture of phenol (20 mg), F‐TEDA‐BF4 (1.1 equivalents), IL(0‐15 equivalents) and the organic solvent (5 mL) was stirred for 5 h at various temperatures under an argo atmosphere (Tables 1‐5). The mixture was evaporated at a reduced pressure and analysed by 1H, 19F NMR assolution in CDCl3 or CDCl3‐DMSO‐d6. Cl2CHCHCl2 and PhCF3 were used as internal standards for peakintegration.
Reference：
[1] Journal of the American Chemical Society, 1990, vol. 112, # 23, p. 8563 - 8575
[2] Tetrahedron Letters, 1986, vol. 27, # 37, p. 4465 - 4468
[3] Tetrahedron Letters, 1986, vol. 27, # 37, p. 4465 - 4468
[4] Journal of Organic Chemistry, 1998, vol. 63, # 10, p. 3379 - 3385
[5] Tetrahedron Letters, 1986, vol. 27, # 37, p. 4465 - 4468
[6] Journal of Organic Chemistry, 1998, vol. 63, # 10, p. 3379 - 3385
[7] Journal of Organic Chemistry, 1998, vol. 63, # 10, p. 3379 - 3385
[8] Russian Journal of Organic Chemistry, 2009, vol. 45, # 10, p. 1468 - 1473
[9] Arkivoc, 2017, vol. 2018, # 2, p. 60 - 71
16
[ 108-95-2 ]
[ 371-41-5 ]
[ 367-12-4 ]
[ 367-27-1 ]
[ 28177-48-2 ]
Reference：
[1] Patent: CN105753655, 2016, A, . Location in patent: Paragraph 0028; 0030; 0038; 0054-0058
17
[ 540-36-3 ]
[ 371-41-5 ]
[ 367-27-1 ]
[ 2713-31-7 ]
[ 7664-39-3 ]
Reference：
[1] Journal of the American Chemical Society, 2014, vol. 136, # 32, p. 11321 - 11330
18
[ 371-41-5 ]
[ 394-33-2 ]
Yield
Reaction Conditions
Operation in experiment
97%
With silica supported Al(NO3)3*9H2O In acetone at 20℃; for 0.5 h;
General procedure: To a solution of phenol (1 mmol) in acetone (5 mL) wasadded silica supported Al(NO3)3·9H2O (1 mmol) and theresulting mixture stirred at room temperature. After completionof the reaction, as indicated by TLC, the reaction masswas filtered and the residue (silica) was washed with ethylacetate (2 5 mL). The filtrate and the washing were collectivelyconcentrated under reduced pressure, and the crudecompound was purified by column chromatography oversilica gel (100-200 mesh) to afford the pure ortho-nitro phenol(95percent) and para- nitro phenol (3percent).
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1983, p. 75 - 82
[2] Synthetic Communications, 1997, vol. 27, # 19, p. 3301 - 3311
[3] Synlett, 2003, # 2, p. 191 - 194
[4] Synthetic Communications, 2005, vol. 35, # 2, p. 263 - 270
[5] Synthetic Communications, 1998, vol. 28, # 15, p. 2773 - 2781
[6] Mendeleev Communications, 2006, vol. 16, # 1, p. 41 - 42
[7] Letters in Organic Chemistry, 2015, vol. 12, # 2, p. 129 - 135
[8] Chinese Journal of Chemistry, 2011, vol. 29, # 4, p. 731 - 734
[9] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1983, p. 75 - 82
[10] Phosphorus, Sulfur and Silicon and the Related Elements, 2003, vol. 178, # 5, p. 1027 - 1035
[11] Synthetic Communications, 2003, vol. 33, # 5, p. 703 - 710
[12] Synthetic Communications, 1999, vol. 29, # 19, p. 3295 - 3302
[13] Tetrahedron, 2005, vol. 61, # 46, p. 10861 - 10867
[14] South African Journal of Chemistry, 2007, vol. 60, p. 109 - 112
[15] Turkish Journal of Chemistry, 2010, vol. 34, # 5, p. 753 - 759
[16] Chinese Chemical Letters, 2011, vol. 22, # 7, p. 827 - 830
[17] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2001, vol. 40, # 12, p. 1191 - 1195
[18] European Journal of Organic Chemistry, 2005, # 11, p. 2379 - 2384
[19] Synthetic Communications, 2008, vol. 38, # 19, p. 3366 - 3374
[20] Advanced Synthesis and Catalysis, 2003, vol. 345, # 11, p. 1197 - 1202
[21] Journal of Chemical Research - Part S, 2001, # 4, p. 140 - 142
[22] Chinese Chemical Letters, 2011, vol. 22, # 12, p. 1431 - 1434
[23] Bulletin des Societes Chimiques Belges, 1984, vol. 93, # 11, p. 961 - 972
[24] Phosphorus, Sulfur and Silicon and the Related Elements, 2003, vol. 178, # 9, p. 2019 - 2025
[25] Inorganic Chemistry, 2010, vol. 49, # 23, p. 11106 - 11117
[26] Molecules, 2001, vol. 6, # 7, p. 614 - 620
[27] Canadian Journal of Chemistry, 2009, vol. 87, # 8, p. 1144 - 1147
[28] Molecules, 2002, vol. 7, # 10, p. 734 - 742
[29] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1998, # 1, p. 1 - 6
[30] J. Gen. Chem. USSR (Engl. Transl.), 1975, vol. 45, p. 2372 - 2379[31] Zhurnal Obshchei Khimii, 1975, vol. 45, # 11, p. 2414 - 2422
[32] Synthetic Communications, 1989, vol. 19, # 1, 2, p. 233 - 238
[33] Recueil des Travaux Chimiques des Pays-Bas, 1916, vol. 35, p. 142[34] Chem. Zentralbl., 1913, vol. 84, # II, p. 760
[35] Patent: US5086062, 1992, A,
[36] Patent: US5149821, 1992, A,
[37] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 22, p. 6842 - 6851
[38] International Journal of Mass Spectrometry, 2013, vol. 345-347, p. 120 - 131
[39] Organic Process Research and Development, 2003, vol. 7, # 1, p. 95 - 97
[40] Bl. Acad. Belg., 1913, p. 265[41] Chem. Zentralbl., 1913, vol. 84, # II, p. 760
19
[ 540-80-7 ]
[ 371-41-5 ]
[ 394-33-2 ]
Yield
Reaction Conditions
Operation in experiment
65%
With water In tetrahydrofuran at 25℃; for 2.5 h; Schlenk technique
General procedure: To a Schlenk tube were added Phenol 1 (0.3 mmol), tert-Butyl nitrite 2a (0.6mmol), H2O (0.6 mmol), and THF (2 mL). Then the tube was stirred at 25 oC under airatmosphere for the indicated time until complete consumption of starting materialmonitored by TLC analysis. After the reaction was finished, the organic extracts weredried over anhydrous Na2SO4, concentrated in vacuum, and the resulting residue waspurified by silica gel column chromatography (hexane/ethyl acetate) to afford thedesired product 3.
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1983, p. 1003 - 1010
22
[ 371-41-5 ]
[ 42864-24-4 ]
[ 5724-56-1 ]
[ 394-33-2 ]
[ 52962-97-7 ]
[ 52911-65-6 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1983, p. 1003 - 1010
23
[ 371-41-5 ]
[ 7697-37-2 ]
[ 394-33-2 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1913, vol. 32, p. 65[2] Journal de Chimie Physique et de Physico-Chimie Biologique, 1919, vol. 17, p. 27[3] Chem. Zentralbl., 1912, vol. 83, # II, p. 1964
Reference：
[1] Patent: CN105753655, 2016, A, . Location in patent: Paragraph 0028; 0030; 0038; 0044-0048
26
[ 108-95-2 ]
[ 371-41-5 ]
[ 367-12-4 ]
[ 367-27-1 ]
[ 28177-48-2 ]
Reference：
[1] Patent: CN105753655, 2016, A, . Location in patent: Paragraph 0028; 0030; 0038; 0054-0058
27
[ 371-41-5 ]
[ 352-67-0 ]
Reference：
[1] Organic Letters, 2016, vol. 18, # 18, p. 4570 - 4573
[2] Journal of Fluorine Chemistry, 2017, vol. 203, p. 130 - 135
28
[ 17151-47-2 ]
[ 96898-10-1 ]
[ 462-06-6 ]
[ 371-41-5 ]
[ 352-67-0 ]
Reference：
[1] Journal of the American Chemical Society, 2011, vol. 133, # 34, p. 13308 - 13310
29
[ 371-41-5 ]
[ 399-97-3 ]
Reference：
[1] Inorganic Chemistry, 2010, vol. 49, # 23, p. 11106 - 11117
[2] International Journal of Mass Spectrometry, 2013, vol. 345-347, p. 120 - 131
30
[ 540-36-3 ]
[ 371-41-5 ]
[ 367-27-1 ]
[ 2713-31-7 ]
[ 7664-39-3 ]
Reference：
[1] Journal of the American Chemical Society, 2014, vol. 136, # 32, p. 11321 - 11330
31
[ 371-41-5 ]
[ 345-16-4 ]
Reference：
[1] European Journal of Organic Chemistry, 2001, # 15, p. 2911 - 2915
32
[ 371-41-5 ]
[ 344-20-7 ]
[ 496-69-5 ]
Yield
Reaction Conditions
Operation in experiment
86%
Stage #1: With toluene-4-sulfonic acid In methanol for 0.166667 h; Stage #2: With N-Bromosuccinimide In methanol for 0.416667 h;
General procedure: A solution of the starting material (~10 mmol) and pTsOH (10 mol percent) in MeOH (1.0 mL per mmol starting material) was stirred for 10 min, then a solution of NBS (100 mol percent; recrystallized from H2O) in MeOH (0.1 M) was added dropwise over 20 min from a foiled reaction flask. The reaction mixture was stirred for a further 5 min and then concentrated in vacuo. The resultant residue was purified using column chromatography (CH2Cl2, or 1percent MeOH in CH2Cl2). 3.3. Characterization of Products2-Bromo-4-methylphenol (10) [23]: 10.1 mmol; 1.73 g (92percent)
Reference：
[1] Molecules, 2016, vol. 21, # 1,
33
[ 371-41-5 ]
[ 496-69-5 ]
Reference：
[1] Tetrahedron Letters, 2010, vol. 51, # 2, p. 340 - 342
[2] Tetrahedron, 2010, vol. 66, # 34, p. 6906 - 6911
[3] Angewandte Chemie - International Edition, 2013, vol. 52, # 33, p. 8676 - 8680[4] Angew. Chem., 2013, vol. 125, # 33, p. 8838 - 8842,5
[5] Journal of Organic Chemistry, 2018, vol. 83, # 15, p. 7867 - 7877
[6] Journal of the American Chemical Society, 1959, vol. 81, p. 94,95, 97
[7] Bulletin of the Chemical Society of Japan, 1964, vol. 37, p. 583 - 584
[8] Patent: US4414208, 1983, A,
[9] Tetrahedron Letters, 2011, vol. 52, # 40, p. 5149 - 5152
[10] Tetrahedron, 2013, vol. 69, # 7, p. 1857 - 1871
34
[ 371-41-5 ]
[ 75-36-5 ]
[ 394-32-1 ]
Reference：
[1] Synthesis, 2007, # 8, p. 1154 - 1158
[2] Synthetic Communications, 1996, vol. 26, # 1, p. 67 - 74
[3] Journal of Medicinal Chemistry, 2007, vol. 50, # 9, p. 2108 - 2116
35
[ 371-41-5 ]
[ 394-32-1 ]
Reference：
[1] Synlett, 2005, # 9, p. 1465 - 1467
[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 2, p. 614 - 621
[3] Pharmacy and Pharmacology Communications, 1999, vol. 5, # 5, p. 323 - 329
[4] Pharmacy and Pharmacology Communications, 1999, vol. 5, # 3, p. 189 - 193
[5] Journal of Organic Chemistry, 1951, vol. 16, p. 1345,1348
[6] Journal of the American Chemical Society, 1939, vol. 61, p. 161,164
[7] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 11, p. 2826 - 2831
[8] MedChemComm, 2013, vol. 4, # 9, p. 1257 - 1266
[9] European Journal of Medicinal Chemistry, 2015, vol. 93, p. 64 - 73
[10] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2016, vol. 55B, # 4, p. 492 - 500
36
[ 371-41-5 ]
[ 64-19-7 ]
[ 394-32-1 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1998, # 10, p. 2678 - 2695
[2] Chemische Berichte, 1954, vol. 87, p. 194,201
37
[ 371-41-5 ]
[ 106-93-4 ]
[ 332-48-9 ]
Yield
Reaction Conditions
Operation in experiment
90%
With sodium hydroxide In water for 10 h; Reflux
Step 2: A 22.5percent aqueous sodium hydroxide solution (55 mL) was added to a mixture of 1,2-dibromoethane (112 g (0.60 mol)) and 4-fluorophenol (16.8 g (0.15 mol)), and the mixture was stirred 5 hours under heating at reflux. Sodium hydroxide (3.0 g (75 mmol)) was further added thereto and the mixture was stirred for 5 hours under heating at reflux. After completion of the reaction, the temperature was returned to room temperature, and the reaction solution was extracted three times with dichloromethane (100 mL). The whole organic layer was dried over Na2SO4 and the solvent was distilled away under reduced pressure. The residue was purified by a silica gel chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain 1-(2-bromoethoxy)-4-fluorobenzene (compound-03) (29.7 g, 0.136 mol, yield 90percent).
Reference：
[1] Patent: EP2357165, 2011, A1, . Location in patent: Page/Page column 18
[2] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 4, p. 495 - 500
[3] Russian Journal of Organic Chemistry, 2000, vol. 36, # 2, p. 254 - 257
[4] Archiv der Pharmazie, 2013, vol. 346, # 3, p. 180 - 188
[5] European Journal of Medicinal Chemistry, 1992, vol. 27, # 5, p. 545 - 549
[6] Izvestiya Vysshikh Uchebnykh Zavedenii, Khimiya i Khimicheskaya Tekhnologiya, 1958, vol. 1, # 2, p. 82[7] Chem.Abstr., 1959, p. 1243
[8] Bulletin de la Societe Chimique de France, 1956, p. 185,186
[9] Journal of medicinal chemistry, 1966, vol. 9, # 2, p. 197 - 203
[10] Journal of Medicinal Chemistry, 1982, vol. 25, # 1, p. 57 - 63
[11] Central European Journal of Chemistry, 2013, vol. 11, # 11, p. 1757 - 1767
[12] European Journal of Medicinal Chemistry, 2014, vol. 81, p. 89 - 94
38
[ 371-41-5 ]
[ 352-34-1 ]
[ 330-93-8 ]
Reference：
[1] Catalysis Science and Technology, 2016, vol. 6, # 6, p. 1701 - 1709
[2] Angewandte Chemie - International Edition, 2018, vol. 57, # 14, p. 3752 - 3757[3] Angew. Chem., 2018, vol. 130, p. 3814 - 3819,6
39
[ 371-41-5 ]
[ 330-93-8 ]
Reference：
[1] Journal of Organic Chemistry, 2001, vol. 66, # 2, p. 633 - 634
40
[ 371-41-5 ]
[ 109-70-6 ]
[ 1716-42-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 1989, vol. 32, # 1, p. 105 - 118
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 1, p. 517 - 523
[3] Indian Journal of Chemistry - Section B Organic Chemistry Including Medicinal Chemistry, 1990, vol. 29, # 1, p. 80 - 84
[4] Zhurnal Obshchei Khimii, 1959, vol. 29, p. 3708; engl. Ausg. S. 3664
41
[ 371-41-5 ]
[ 142-28-9 ]
[ 1716-42-3 ]
Reference：
[1] Angewandte Chemie - International Edition, 2015, vol. 54, # 32, p. 9347 - 9350[2] Angew. Chem., 2015, vol. 127, # 32, p. 9479 - 9482,4
[3] Angewandte Chemie - International Edition, 2016, vol. 55, # 18, p. 5550 - 5554[4] Angew. Chem., 2016, vol. 128, p. 5640 - 5644,5
42
[ 371-41-5 ]
[ 13675-18-8 ]
[ 71597-85-8 ]
Reference：
[1] Journal of the American Chemical Society, 2016, vol. 138, # 9, p. 2985 - 2988
43
[ 371-41-5 ]
[ 2713-29-3 ]
Yield
Reaction Conditions
Operation in experiment
67.8%
Stage #1: With sodium iodide; sodium hydroxide In methanol at 0 - 10℃; for 0.25 h; Inert atmosphere Stage #2: With sodium hypochlorite In methanol at 0 - 10℃; for 2.5 h;
To a round bottom flask, equipped with an addition funnel, and under N2 atmosphere at 0-10 °C, was added, methanol (200 mL), 4-fluorophenol (8.00 g, 71.37 mmol), Nal (12.84 g, 85.64 mmol) and NaOH (3.43 g, 85.64 mmol). This solution was allowed to stir for approximately 15 minutes, at 0-10 °C, before adding, dropwise, NaOCI (133 mL from 5percent v/v in commercial bleach, 92.77 mmol) over the period of 1.5 hours. After this bleach addition was complete, the reaction was allowed to stir for an additional hour at 0-10 °C. Next, 100 mL of 10 wtpercent aqueous sodium thiosulfate was added to the reaction mixture. The reaction mixture was then acidified with 5percent HC1, extracted into methylene chloride (500 mL), washed with 500 mL each of 10 wtpercent aqueous sodium thiosulfate, water, then brine, and then dried over anhydrous magnesium sulfate, filtered through a pad of silica gel, and then concentrated to give an oil. This crude was purified by recrystallization using hexanes, to afford 11.52 g (67.8percent) of pure compound as white crystals. 1H NMR (500 MHz, Chloroform-d) δ 7.36 (dd, J= 7.6, 2.9 Hz, 1H), 6.97 (ddd, J= 8.9, 7.7, 2.9 Hz, 2H), 6.92 (dd, J= 9.0, 4.9 Hz, 1H), 5.10 (s, 1H). 13C NMR (101 MHz, Chloroform-d) δ 156.42 (d, J= 243.0 Hz), 151.45 (d, J= 2.6 Hz), 124.34 (d, J= 25.3 Hz), 116.83 (d, J= 23.1 Hz), 115.08 (d, J= 7.8 Hz), 84.23 (d, J= 9.0 Hz). iyF NMR (376 MHz, Chloroform-d) δ -122.52 (td, J= 7.6, 4.9 Hz). MS m/e 238.
Reference：
[1] Journal of the Brazilian Chemical Society, 2010, vol. 21, # 1, p. 3 - 6
[2] Chemical Communications, 2016, vol. 52, # 29, p. 5152 - 5155
[3] Organic and Biomolecular Chemistry, 2017, vol. 15, # 9, p. 1956 - 1960
[4] Patent: WO2016/89935, 2016, A1, . Location in patent: Page/Page column 27; 28
[5] Tetrahedron Letters, 2010, vol. 51, # 16, p. 2170 - 2173
[6] Synlett, 2007, # 14, p. 2227 - 2231
[7] Phosphorus, Sulfur and Silicon and the Related Elements, 2009, vol. 184, # 3, p. 651 - 659
[8] Patent: US2015/291713, 2015, A1,
[9] Chemistry Letters, 2017, vol. 46, # 5, p. 733 - 736
Example 1 A specific procedure for the synthesis of: N-[(4-fluoro)-5-phenoxythien-2-yl]methanesulfonamide (1) STR10 <strong>[13195-50-1]2-Nitro-5-bromothiophene</strong> (2.97 g, 14.2 mmol) was dissolved in dimethyl-formamide (40 mL). To this was added 4-fluorophenol (1.59 g, 14.2 mmol) and potassium carbonate (3.92 g, 28.4 mmol). This was stirred at 70° C. for 5 hours after which time the mix was poured into water and the crude solid was filtered and washed with water to give 2-Nitro-5(4-fluoro)phenoxythiophene 2.67 g (78percent), mp=69°-70° C.
1-(4-fluorophenoxy)-3-nitro-5-(trifluoromethyl)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With potassium phosphate; In N,N-dimethyl acetamide; at 100℃; for 12h;
To a round-bottomed flask equipped with a magnetic stir bar wasadded <strong>[454-73-9]1-fluoro-3-nitro-5-(trifluoromethyl)benzene</strong> (2.5 g, 12 mmol), 4-fluorophenol (12) (1.1 g, 10 mmol), potassium phosphate (4.2 g,20 mmol), and DMA (15 mL). The reaction vessel was immersed in a100 C preheated oil bath for 12 h until the reaction was completed asdetermined by TLC. After cooling, the reaction was diluted with waterand extracted with ethyl acetate. The ethyl acetate layer was washedwith saturated brine and dried over anhydrous MgSO4. After filtrationand concentration, the crude product was purified on a silica gelcolumn, eluted with hexane/ethyl acetate (50/1, V/V) to afford 13.Yield: 93%. 1H NMR (400 MHz, CDCl3) delta 8.17 (s, 1H), 7.89 (t,J=2.1 Hz, 1H), 7.52 (s, 1H), 7.21-7.12 (m, 2H), 7.12-7.05 (m, 2H).
2-(4-fluorophenoxy)-4-tert-butylbenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
With copper(I) trifluoromethanesulfonate benzene; 1-naphthalenecarboxylic acid; caesium carbonate; In ethyl acetate; toluene; at 110℃; for 16.0h;Molecular sieve;
A stirred suspension of <strong>[6332-96-3]4-tert-butyl-2-bromobenzoic acid</strong> (0.26 g, 1.0 mmol), 4-fluoro phenol (0.22 g, 2.0 mmol), cesium carbonate (0.65 g, 2.0 mmol), copper trifluoromethanesulfonate-benzene complex (13 mg, 25 mumol), 1-naphthoic acid (0.34 g, 2.0 mmol), and 4 molecular sieves (0.25 g) in toluene (10 mL) and EtOAc (5 muL) was heated at 110 C. for 16 h. The reaction was concentrated under reduced pressure and purified by silica gel chromatography (0%-5% MeOH-CH2Cl2) to afford 2-(4-fluorophenoxy)-4-tert-butylbenzoic acid (0.11 g, 39% yield) as a white solid. LC/MS: m/z 289.0 (M+H)+ at 3.58 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, CDCl3) delta 8.12 (d, J=8.3 Hz, 1H), 7.24 (d, J=1.7 Hz, 1H), 7.14-7.05 (m, 4H), 6.84 (d, J=1.6 Hz, 1H), 1.23 (s, 9H) ppm.
To a round bottom flask, equipped with an addition funnel, and under N2 atmosphere at 0-10 C, was added, methanol (200 mL), 4-fluorophenol (8.00 g, 71.37 mmol), Nal (12.84 g, 85.64 mmol) and NaOH (3.43 g, 85.64 mmol). This solution was allowed to stir for approximately 15 minutes, at 0-10 C, before adding, dropwise, NaOCI (133 mL from 5% v/v in commercial bleach, 92.77 mmol) over the period of 1.5 hours. After this bleach addition was complete, the reaction was allowed to stir for an additional hour at 0-10 C. Next, 100 mL of 10 wt% aqueous sodium thiosulfate was added to the reaction mixture. The reaction mixture was then acidified with 5% HC1, extracted into methylene chloride (500 mL), washed with 500 mL each of 10 wt% aqueous sodium thiosulfate, water, then brine, and then dried over anhydrous magnesium sulfate, filtered through a pad of silica gel, and then concentrated to give an oil. This crude was purified by recrystallization using hexanes, to afford 11.52 g (67.8%) of pure compound as white crystals. 1H NMR (500 MHz, Chloroform-d) delta 7.36 (dd, J= 7.6, 2.9 Hz, 1H), 6.97 (ddd, J= 8.9, 7.7, 2.9 Hz, 2H), 6.92 (dd, J= 9.0, 4.9 Hz, 1H), 5.10 (s, 1H). 13C NMR (101 MHz, Chloroform-d) delta 156.42 (d, J= 243.0 Hz), 151.45 (d, J= 2.6 Hz), 124.34 (d, J= 25.3 Hz), 116.83 (d, J= 23.1 Hz), 115.08 (d, J= 7.8 Hz), 84.23 (d, J= 9.0 Hz). iyF NMR (376 MHz, Chloroform-d) delta -122.52 (td, J= 7.6, 4.9 Hz). MS m/e 238.
With sodium perchlorate; In methanol;
Preparation of 4-fluoro-2-iodophenol To methanol (200 mL) at 0-10 C. was added 4-fluorophenol (8.00 g, 71.37 mmol), NaI (12.84 g, 85.64 mmol) and NaOH (3.43 g, 85.64 mmol). This solution was allowed to stir for 15 minutes at 0-10 C. before adding dropwise NaOCl (133 mL of 5 wt. % solution from commercial bleach, 92.77 mmol) over the period of 1 hour then allowed to stir for an additional hour at 0-10 C. The reaction was quenched with 10% wt. aqueous sodium thiosulfate (50 mL) then the reaction mixture was then acidified with 10% HCl. The organic solution was extracted into methylene chloride (300 mL), washed with 500 mL each of 10% wt. sodium thiosulfate, water then brine, dried over anhydrous magnesium sulfate, filtered through a pad of silica gel then concentrated to give crude compound. This crude was purified by recrystallization from hexanes to afford 11.52 g (67.8%) of compound as white crystals. 1H NMR (500 MHz, CDCl3) delta 7.36 (dd, J=7.6, 2.9 Hz, 1H), 6.97 (ddd, J=8.9, 7.7, 2.9 Hz, 2H), 6.92 (dd, J=9.0, 4.9 Hz, 1H), 5.10 (s, 1H). 13C NMR (101 MHz, Chloroform-d) delta 156.42 (d, J=243.0 Hz), 151.45 (d, J=2.6 Hz), 124.34 (d, J=25.3 Hz), 116.83 (d, J=23.1 Hz), 115.08 (d, J=7.8 Hz), 84.23 (d, J=9.0 Hz). 19F NMR (376 MHz, CDCl3) delta -122.52 (td, J=7.6, 4.9 Hz).
With N-iodomorpholine-hydrogen iodide; potassium carbonate; In water; at 20℃; for 3h;Inert atmosphere;
General procedure: According to the reported procedure,S4 to a solution of morpholine (653 mg, 7.50 mmol) in H2O (7.5 mL) wereslowly added a solution of iodine (2.39 g, 9.42 mmol) and potassium iodide (4.37 g, 26.3 mmol) dissolved in H2O (3.8mL) at room temperature. After stirring for 20 min at the same temperature, the resulting orange solid was collected byfiltration and washed with H2O (10 mL) on a funnel. The wet orange solid containing 4-iodomorpholin-4-ium iodidewas used in the following reaction without further purification.To a mixture of 2-bromo-4-methylphenol (935 mg, 5.00 mmol) and potassium carbonate (2.07 g, 15.0 mmol) in H2O(5.0 mL) were added four portions of 4-iodomorpholin-4-ium iodide (ca. 1.9 mmol each; total ca. 7.5 mmol) at roomtemperature with 15 min intervals. After stirring for 3 h at the same temperature, to the mixture was added aqueoussaturated sodium thiosulfate (5 mL) and extracted with EtOAc (10 mL × 3). The combined organic extract was washedwith brine (5 mL), dried (Na2SO4), and after filtration, the filtrate was concentrated under reduced pressure. The residuewas purified by flash column chromatography (silica-gel 40 g, n-hexane/EtOAc = 5/1) to give2-bromo-6-iodo-4-methylphenol (1.48 g, 4.75 mmol, 94.9%) as a colorless oil.
With iodine; ammonium hydroxide; In water; at 20℃; for 2.5h;
To a solution of 4-fluorophenol (1.90 g, 16.9 mmol) in concentrated ammonium hydroxide (20 ml) at room temperature was added a solution of iodine (4.30 g, 16.9 mmol) and potassium iodide (14.0 g, 84.5 mmol) in water (20 ml) and the resulting mixture was stirred for 2.5 hours. The solution is acidified to pH 2-3 with 1N hydrochloric acid, diluted with ether, washed with 1N hydrochloric acid (2x), dried over anhydrous sodium sulfate, and concentrated. The residue is purified on a 40 g silica column (0 to 100% ethyl ACETATE/HEXANES over 25 minutes) to give 3.42 g of product. NMR analysis indicated an 8: 2 MIXTURE OF MONOIODO and diiodo product. GC-MS M/Z 238 (M+)
With potassium carbonate; In acetonitrile; at 85℃; for 120h;
Step B: 3-(4-Fluoro-phenoxy)-pyrrolidine-l-carboxylic acid tert-butyl esterTo a solution of the product from Step A (1.06 g, 8.60 mmol) in acetonitrile (25 mL) is added 4-fluorophenol (0.55 g, 8.98 mmol) and potassium carbonate (0.86 g, 6.23 mmol). The mixture is heated at 85 0C for 5 days. Analysis of the reaction by TLC shows the formation of the product. The mixture is then diluted with water and extracted with ethyl acetate. Organic layer is then condensed in vacuo and purified by flash chromatography (20-100% ethyl acetate in heptanes) to give the product (0.72 g, 64 %).
With sodium hydride; In DMF (N,N-dimethyl-formamide); at 20 - 60℃; for 18h;
3- (4-fluoro-phenoxy)-pyrrolidine-l-carboxylic acid ter-butyl ester; Sodium hydride (554 mg, 13. 84 mmol) is added to a solution of 4-fluorophenol (1.60 g, 14.20 mmol) in DMF (20 ml) and the mixture is stirred at room temperature for 2 minutes. 3-Methanesulphonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester is added and the mixture heated at 60 C for 18 hours. Water (50 ml) is then added and the resulting product is extracted using diethyl ether (3 x 30 ml). The organic extracts are dried (using MgS04), filtered and evaporated to give a white solid, which is purified using column chromatography over silica gel (ethyl acetate/isohexane 1: 9 v/v) to give the title compound.
With potassium carbonate; In dimethyl sulfoxide; at 60℃; for 16h;
Manufacturing Example 91-1-1 5-(4-Fluoro-phenoxy)-thiophene-2-carbonitrile; To a dimethyl sulfoxide (100 mL) solution of 5-nitro-2-thiophene carbonitrile (5.00 g, 32.4 mmol) were added 4-fluorophenol (5.45 g, 48.6 mmol) and potassium carbonate (11.2 g, 81.0 mmol) under nitrogen atmosphere, which was stirred for 16 hours at 60 C. The reaction solution was cooled to room temperature and water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:10?1:5) to obtain the title compound (6.10 g, 85.9%).1H-NMR Spectrum (CDCl3) delta (ppm): 6.40 (1H, d, J=4.4 Hz), 7.07-7.16 (4H, m), 7.36 (1H, d, J=4.4 Hz).
With potassium carbonate; In dimethyl sulfoxide; at 60℃; for 0.5h;
Preparation Example 27. 5-(4-Fluorophenoxy)thiophene-2-carbonitrile 5-Nitrothiophene-2-carbonitrile (2.0g, 13mmol), 4-fluorophenol (2.9g, 26mmol) and potassium carbonate (5.4g, 39mmol) were suspended in dimethylsulfoxide (30mL), and the mixture was stirred for 30 minutes at 60C. Water and ethyl acetate were added to the reaction mixture, which was then separated, the organic layer was washed with water twice, then, NH silica gel was added to the organic layer, the solvent was evaporated in vacuo for adsorption, purification was carried out by NH silica gel column chromatography (hexane: ethyl acetate = 20: 1), and the title compound (3.7g, containing 4-fluorophenol) was obtained as a brown oil. 1H-NMR Spectrum (DMSO-d6) delta (ppm): 6.68-6.76 (2H, m), 7.26-7.38 (3H, m), 7.74-7.80 (1 H, m).
With potassium carbonate; In dimethyl sulfoxide; at 60℃; for 0.5h;
5-Nitrothiophene-2-carbonitrile (2.0g, 13mmol), 4-fluorophenol (2.9g, 26mmol) and potassium carbonate (5.4g, 39mmol) were suspended in dimethylsulfoxide (30mL), and the mixture was stirred for 30 minutes at 60C. Water and ethyl acetate were added to the reaction mixture, which was then separated, the organic layer was washed with water twice, then, NH silica gel was added to the organic layer, the solvent was evaporated in vacuo for adsorption, purification was carried out by NH silica gel column chromatography (hexane : ethyl acetate = 20 : 1), and the title compound (3.7g, containing 4-fluorophenol) was obtained as a brown oil. 1H-NMR Spectrum (DMSO-d6) delta(ppm) : 6.68-6.76 (2H, m), 7.26-7.38 (3H, m), 7.74-7.80 (1 H, m).
With sodium periodate; sodium sulfate; In hexane; dichloromethane; sodium hydrogencarbonate; ethyl acetate;
Part 2: Ethyl (2E,4S)-4,5-isopropylidenedioxy-2-pentenoate (Scheme VIII; 4): A solution of 1,2:5,6- di-O-isopropylidene-(D)-mannitol 2 (100 g, 0.38 mol) in CH2Cl2 (1000 mL) containing saturated NaHCO3 solution (40 mL) was cooled to 0 C., treated with NaIO4 (123 g, 0.57 mol) and allowed to stir at 0C. to 20 C. After 2 to 3 h (TLC analysis), solid Na2SO4 (35 g) was added and the reaction mixture was stirred further for 15 min. The reaction mixture was filtered and concentrated (below 25 C. bath temperature) to half the volume. The above solution of (R)-glyceraldehyde 3 in CH2Cl2 (500 mL) was cooled to below 10 C. and treated with (carbethoxymethylene) triphenyl phosphorane (132 g, 0.38 mol) in portions. After stirring at room temperature for 3-4 h, the solvent was evaporated, the residue treated with hexane (500 mL) and the solution decanted through silica gel. The residue was further treated with 10% EtOAc in hexane (4*500 mL) and decanted through silica gel. Evaporation of solvent afforded ethyl (2E,4S)-4,5-isopropylidenedioxy-2-pentenoate 4 (105 g) in 73 % yield as a colorless liquid. 1H-NMR (CDCl3, 200 MHz): delta1.2 (t, 3H, J 7.1 Hz, CH3), 1.3, 1.35 (2s, 6H, CH3), 3.48 (dd, 1H, J 6.1 Hz, H-5), 4.05 (q, 2H, J 7.1 Hz, OCH2), 4.25 (dd, 1H, J 8.0 Hz, H-5a), 5.3-5.40 (m, 1H, H-4), 5.72 (dd, 1H, J 2.3, 11.0Hz, H-2), 6.72 (dd, 1H, J 6.1, 12.2 Hz, H-3).
In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide;
Part 1 (S)-Glycidyl-4-fluorophenyl ether (Scheme I; 4) In a 100 ml two-necked round bottom flask equipped with magnetic stir bar, nitrogen inlet and a septum, was taken sodium hydride (60% dispersion in oil, 0.742 g, 0.0185 mol) and 10 mL of dry dimethyl formamide (DMF). The reaction mixture was cooled to 0 C. and 4-fluorophenol 2 (1.9 g, 0.017 mol) in dry DMF (20 mL) was introduced. The reaction mixture was stirred at room temperature for 1 hour and cooled to 0 C. <strong>[113826-06-5](S)-Glycidyl tosylate</strong> 3 (3.52 g, 0.015 mol) in DMF (10 mL) was added, and the reaction mixture was stirred at room temperature and monitored by TLC (EtOAc-light petroleum ether 1:4, Rf=0.5). After 4 hours, the reaction mixture was quenched by addition of ice-water (1 mL) and extracted with (2*25 mL) ethyl ether. The ever layer was washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure to afford (S)-glycidyl-4-fluorophenyl ether 4, crude yield 3.6 g. The crude compound was purified by distillation at 160-170 C./9 mm, to yield 1.98 g (76%) of purified product 4, [alpha]D+4.96 (c 2.335, CHCl3). 1H NMR (200 MHz, CDCl3): delta 2.68 (dd, J=4.5, 2.2 Hz, 1 H), 2.85 (t, J=4.5 Hz, 1 H), 3.27 (m, 1 H), 3.89 (dd, J=15.7, 6.7 Hz, 1 H), 4.11 (dd, J=15.7, 4.5 Hz, 1 H), 6.74-7.02 (m, 4 H).
In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide;
Part 1 (S)-Glycidyl-4-fluorophenyl ether (Scheme I; 4) In a 100 ml two-necked round bottom flask equipped with magnetic stir bar, nitrogen inlet and a septum, was taken sodium hydride (60% dispersion in oil, 0.742 g, 0.0185 mol) and 10 mL of dry dimethyl formamide (DMF). The reaction mixture was cooled to 0 C. and 4-fluorophenol 2 (1.9 g, 0.017 mol) in dry DMF (20 mL) was introduced. The reaction mixture was stirred at room temperature for 1 hour and cooled to 0 C. <strong>[113826-06-5](S)-Glycidyl tosylate</strong> 3 (3.52 g, 0.015 mol) in DMF (10 mL) was added, and the reaction mixture was stirred at room temperature and monitored by TLC (EtOAc-light petroleum ether 1:4, Rf=0.5). After 4 hours, the reaction mixture was quenched by addition of ice-water (1 mL) and extracted with (2*25 mL) ethyl ether. The ether layer was washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure to afford (S)-glycidyl-4-fluorophenyl ether 4, crude yield 3.6 g. The crude compound was purified by distillation at 160-170 C./9mm, to yield 1.98 g (76%) of purified product 4, [alpha]D+4.96 (c2.335, CHCl3). 1H NMR (200 MHz, CDCl3): delta 2.68 (dd, J=4.5, 2.2 Hz, 1 H), 2.85 (t, J=4.5 Hz, 1 H), 3.27 (m, 1 H), 3.89 (dd, J=15.7, 6.7 Hz, 1 H), 4.11 (dd, J=15.7, 4.5 Hz, 1 H), 6.74-7.02 (m, 4 H).
EXAMPLE 15 If the procedure is as described in Example 13, except that 50.1 g (0.175 mol) of 2,3-dichloro-4,4'-difluorobenzophenone and 10 g of 90 percent hydrogen peroxide, solution are used, 11.8 g (0.105 mol, 60%) of 4-fluorophenol and 28.3 g (0.136 mol, 78%) of 2,3-dichloro-4-fluorobenzoic acid are obtained.
30
[ 371-41-5 ]
[ 169457-73-2 ]
[ 897666-34-1 ]
Yield
Reaction Conditions
Operation in experiment
98%
With tetra-(n-butyl)ammonium iodide; potassium carbonate; In acetone;Heating / reflux;
EXAMPLE 22.1 Tert-butyl-4-[2-(4-fluorophenoxy)ethyl]piperidine-1-carboxylate To a solution of tert-butyl-4-(2-bromoethyl)piperidine-1carboxylate (600 mg, 2.05 mmol) in acetone (30 ml), 4-fluorophenol (230 mg, 2.05 mmol), potassium carbonate (1.12 g, 8.2 mmol) and tetrabutylammonium iodide (45 mg, 0.123 mmol) was added. The resulting mixture was refluxed overnight. After removal of acetone, the residue was partitioned between water and water. The organic layer was washed with 1N NaOH three times, water, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to provide a yellow oil (700 mg, 98%). 1H NMR (300 MHz, CDCL3): 6.89-6.94 (m, 2H), 6.75-6.80 (m, 2H), 4.07 (br, 2H), 3.91 (t, 2H), 2.61 (br, 2H), 165-1.68 (m, 5H), 1.43 (s, 9H), 1.02-1.18 (m, 2H).
98%
With potassium carbonate;tetra-(n-butyl)ammonium iodide; In acetone;Heating / reflux;
Example 15.1; 4-[2-(4-Fluoro-phenoxy)-ethyl]-piperidine-1-carboxylic Acid tert-butyl Ester; 4-Fluoro-phenol (230 mg, 2.05 mmol), potassium carbonate (1.11 g, 8.04 mmol), tetrabutyl ammonium iodide (45 mg, 0.123 mmol) were added to the solution of 4-(2-bromo-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (600 mg, 2.05 mmol) in acetone. The reaction mixture was refluxed for overnight. The reaction mixture was concentrated in vacuo; the residue was partitioned between ethyl acetate and water. Organic layer was washed with 1N sodium hydroxide aqueous solution (3×20 mL), water and brine. The organic phase was dried over anhydrous sodium sulfate; filtered and condensed to dryness. Yellow oil was obtained as product (700 mg, 98%). This product was used directly in the subsequent step to generate the corresponding amine in situ, which reacted with 2-Chloromethyl-1-methyl-1H-benzoimidazole in Example 13 to give the final compound 2-{4-[2-(4-Fluoro-phenoxy)-ethyl]-piperidin-1-ylmethyl}-1-methyl-1H-benzoimidazole (Example 1.1).1HNMR (300 MHz, CDCl3): (ppm) 6.94 (t, 2H), 6.77 (m, 2H), 4 (br, 2H), 3.9 (t, 2H), 2.62 (br, 2H), 1.61 (br, 5H), 1.43 (s, 9H), 1.16 (br, 2H)
95.8%
With potassium carbonate;tetra-(n-butyl)ammonium iodide; In acetone;Heating / reflux;
The phenol (1.0 equiv), tetrabutylammonium iodide (O.Oequiv), and potassium carbonate (2.0 equiv) was added to a solution of 4-(2-bromo-ethyl)-piperine-l-carboxylic acid tert-butyl ester (1.0 equiv) in acetone. The reaction mixture was refluxed overnight. After removing acetone, the residue was partitioned between ethyl acetate and water. The organic layer was washed with IN sodium hydroxide aqueous solution, water, brine and dried over anhydrous sodium sulfate. The product was purified with flash chromatography on silica gel (20% ethyl acetate in hexanes). IH NMR was used to confirm the purity of the product.; 4- [2-(4-Fuoro-phenoxy)-ethyl] -piperidine- 1-carboxylic acid tert-butyl ester was obtained from 4-fluoro-phenol (1.37mmol, 0.153g), tetrabutylammonium iodide (0.081mmol, 0.03g), 4-(2-bromo-ethyl)-piperine- 1-carboxylic acid tert-butyl ester (1.37mmol, 0.4g) and potassium carbonate (2.74mmol, 0.946g) in acetone (10ml) as a off white solid (0.423g 95.8%). 1H NMR (300MHz5 CDC13): delta(ppm) 6.88-6.94 (m, 2H), 6.75-6.79 (m, 2H), 4.01-4.06 (m, 2H), 3.90(t, 2H), 2.62 (t, 2H)3 1.59-1.67 (m, 5H), 1.42 (s, 9H), 1.12-1.15(m, 2H).
REFERENCE EXAMPLE 6 Preparation of 2,8-difluoro-6,11-dihydrodibenz[b,e]oxepin-11-one: To a solution of 2.0 g of sodium metal in 100 ml of ethanol is added 10.0 g of 4-fluorophenol and the solvent is distilled off under reduced pressure. To the residue is added 12 g of <strong>[700-85-6]5-fluorophthalide</strong> [Coll. Czech. Commun., 32, 2021 (1967)]and the mixture is stirred with heating at 200 C. for 1 hour. The mixture is cooled to 100 C. and dissolved in 300 ml of water. This solution is made acidic by adding 10% hydrochloric acid under ice cooling to precipitate crystals of the objective compound, which are collected by filtration, washed with water and dried to give 17 g of 4-fluoro-2-[(4-fluorophenyloxy)methyl]benzoic acid. Mass spectrum m/z: 264(M+).
methyl 2-(4-fluorophenoxy)-5-iodonicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of 4-fluorophenol (224 mg, 2.0 mmol) in DMF (5.0 mL) was added sodium hydride (48 mg, 2.0 mmol) at room temperature. After stirring for 10 min, methyl <strong>[59782-86-4]2-chloro-5-iodonicotinate</strong> (J. Org. Chem. 1989, 54, 3618-3624, 594 mg, 2.0 mmol) was added to the reaction mixture. The reaction mixture was stirred under reflux for 16 h. Then the reaction mixture was poured into water (50 mL) and extracted with ether (50 mL x 3). The combined organic extracts were washed with brIne (50 m(at)-) and dr*(at)--d, (sod.uTY: s.1l(at)a(at)e). After removal o4 the 3ci'.3(at)f:(at) t'e (at)3(at):::(at)(at) <";zs ;'.(at)-Z?"(at)'(at)(at)3(at) hy7 '(at):(at):1B(at)(at) xt(at)l:r- :-;(at)(at)(at)(at)(at).(at)5..t:;,?"£;:(at).;/ 8(at)(at)(at)0E. £ ,q], L .-.."I.: -'-(at)2(at)::'(at)0/;:/::*-(at),(at)(at) ::_=J'(at)(at)'(at)(at)- (J.>,'. ] .:: ilf=No.= (at):<.No...---'(at) (I? lflXJ i:.: ..:.:,i .::":.1 compound: (at)H-NMR (CDCl3) No. 8.51 (1 H, d, J=2.3 Hz), 8.41 (1 H, s), 7.09 (4H, d, J=6.2 Hz), 3.95 (3H, s) ; MS (ESI) m/z 374 (M + H)+.
Intermediate 19; 2-(4-Fluoro-phenoxy)-imidazo[2,1-b][1,3,4]thiadiazole; A mixture of <strong>[1137142-58-5]2-bromo-imidazo[2,1-b][1,3,4]thiadiazole</strong> (1.0 g, 4.90 mmol) and 4- fluorophenol (2.2 g, 19.60 mmol) was heated under microwave irradiation at 135C for 3.5 hours. On cooling, the mixture was diluted with dichloromethane (7 mL), adsorbed in silica and purified by column chromatography (Biotage/Flash, silica, methanol:dichloromethane 0.2:9.8 to 2:8) to give 2-(4-fluoro-phenoxy)- imidazo[2,1-b][1 ,3,4]thiadiazole as a white solid (610 mg, 53% yield).1H-NMR (300 MHz, CDCI3): delta 7.54 (d, J = 1.3 Hz, 1 H), 7.29 (m, 2H), 7.21 (d, J =1.2 Hz, 1 H), 7.14 (m, 2H).MS (ES+) m/z 236 (M+H)+ (MW: 235.24).
methyl 2-(4-fluorophenoxy)-5-iodonicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
EXAMPLE 56 4-F {12-(4-FLUOROPHENOXY)-5-(TRIFLUOROMETHYL) PYRIDIN-3- YLLCARBONYL} INO) METHYLLBENZOIC ACID STEP 1. Methyl 2- (4-FLUOROPHENOXY)-5-IODONICOTINATE; To a solution of 4-fluorophenol (224 mg, 2.0 mmol) in DMF (5.0 mL) was added sodium hydride (48 mg, 2.0 mmol) at room temperature. After stirring for 10 min, <strong>[78686-83-6]methyl 2-chloro-5-iodonicotinate</strong> (J. Org. Chem. 1989, 54, 3618,594 mg, 2.0 mmol) was added to the reaction mixture. The reaction mixture was stirred under reflux for 16 h. Then the reaction mixture was poured into water (50 mL) and extracted with ether (50 mL x 3). The combined organic extracts were washed with brine (50 mL) and dried (sodium sulfate). After removal of the solvent, the residue was purified by flash column chromatography on silica gel (50 g) eluting with hexane/ethyl acetate (2/1) to afford 644 mg (86%) of the title compound : H-NMR (CDCL3) o 8.51 (1H, d, J = 2.3 Hz), 8.41 (1H, s), 7.09 (4H, d, J = 6.2 Hz), 3.95 (3H, s); MS (ESI) M/Z 374 (M + H) +.
To an N,N-dimethylformamide (40.0 mL) solution of 4-fluorophenol (3.00 g, 26.8 mmol) was added sodium hydride (1.00 g, 25.0 mmol, 60percent in oil) on an ice bath (0° C.) under nitrogen atmosphere, which was stirred for 20 minutes at room temperature. To the reaction solution was then added a mixture of <strong>[936342-91-5]5-bromo-2-chloromethyl-pyridine hydrochloride</strong> (4.6 g, 22.3 mmol) described in Manufacturing Example 54-1-2 and triethylamine (30.6 mL, 20.4 mmol), which was stirred for 10 minutes at room temperature. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. This organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated from the filtrate under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:4) to obtain the title compound (4.0 g, 63.6percent). 1H-NMR Spectrum (CDCl3) delta (ppm): 5.10 (2H, s), 6.88-6.91 (2H, m), 6.95-6.99 (2H, m), 7.40-7.42 (1H, m), 7.81-7.84 (1H, m), 8.64-8.65 (1H, m).
5.00 mL of 1 M benzene solution of lambda/-Boc-3-methyl-4- hydroxypiperidine from step 1 and triphenylphosphine 1.575 g (6.00 mmol) was dissolved in anhydrous THF (2.5 mL) and cooled to 0 0C. 40% DEAD solution in toluene 2.3 mL (6.00 mL of a 40% solution) was added dropwise over 10 minutes. After additional 15 minutes at 0 0C, p-fluorophenol 673 mg (6.00 mmol, solid) was added in one portion. The mixture was stirred at 0 CC to room temperature for 45 min and then at room temperature for 21 hours. Ether (40 mL) and 50% H2O2 (1 mL) was added and the stirring continued for 15 minutes. The mixture was diluted with additional ether (40 mL), washed twice with 1M NaOH (2 x 50 mL), the aqueous phases were re-extracted with ether (100 mL). The combined organic extracts were dried (MgSO4) and evaporated. The residue was purified on a column of silica (120 g), with hexane-ethyl acetate gradient (0-40%). The Boc-protected intermediate 574 <n="37"/>mg (37% Y) was obtained as a colorless honey, a 1:1 mixture of diastereomers.
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h;
FreparatioH 63: 6-(4-F oroplieMoxy)pyridiMe-2-earboiiItrik To <strong>[33252-29-8]6-chloropyridine-2-carbonitrile</strong> (LOg, 7.22mmol) in DMF (40rnL) was added K2CO3 (1.50g, lO.Smmol) and 4-fluorophenol (0.81g, 7.22mmol). The mixture was heated at 100C for 16h before the solvent was removed in vacuo. The mixture was partitioned between EtOAc and water, the aqueous phase re-extracted with EtOAc, the combined organic phase was dried (MgS04) and the solvent removed in vacuo. The residue was purified by column chromatography (25:75 EtOAc :Hexa.ne) to give, after removal of the solvent in vacuo, the title compound: RT = 3.52min; m/z (ES+) ==: 215.1 [M+ H]+.
Preparation 76: 2-Amino-5-(4-fluorophenoxy)nicotinic add methyl ester To 2-aminonicotimc acid methyl eater (5.5g, 36.2mmol) in DMF (70mL) was added N-iodosuccinimide (9.8g, 43.7rmnol). After 16h the mixture was poured into sat. sodium thiosulfite solution and then extracted with Et20. The organic phase was washed with water, brine, dried (MgS04) and the solvent was removed in vacuo to give <strong>[1227048-78-3]2-amino-5-iodonicotinic acid methyl ester</strong>. To 4-fluorophenol (2.4g, 21.6mmol) in dioxane (50mL) was addedCS2CO3 (6g, 25.2mmol) and the mixture was heated to 50C. After 20min Cul (0.56g, 3.0mmol) and 2-ammo-5-iodonicotrriic acid methyl ester (2g, 7.2mmol) were added and the mixture heated under reflux for 16h. After cooling the solvent removed in vacuo, the residue was partitioned between EtOAc and 4N HQ, the organic phase was extracted with 6N HC1 and the organic phase discarded. The combined aqueous phase was basified with NH4OH and re-extracted with EtOAc. The organic phase was dried (MgS04) and the solvent was removed in vacuo. The residue was purified by column chromatography (1 :3EtOAcrHexane) to give, after removal of the solvent in vacuo, the title compound: RT= 3.30min; m/z (ES+) = 263.2 [M+ Iff".
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 3.5h;
Step 1 : A solution of 1 -(5-fluoropyrimidin-2-yl)ethanone (700 mg, 5.0 mmol) and 4- fluorophenol (616 mg, 5.50 mmol) in 6 mL DMF was treated with potassium carbonate (829 mg 6.0 mmol) and heated to 50C for 3.5 h. The reaction mixture was poured into 20 mL water, and extracted with EtOAc (2 x 20 mL). Organics were washed with 20 mL each water, brine, and dried over Na2S04. Mixture was filtered and concentrated on silica gel. Column chromatography (10 - 100% EtOAc/hept) gave 295 mg (25%) 1 -(5-(4- fluorophenoxy)pyrimidin-2-yl)ethanone as a white solid used directly in the following step. MS m/z 233.2 (M + H)+. 1H NMR (400 MHz, CDCI3) delta 8.55 (s, 2H), 7.23 - 7.07 (m, 4H), 2.78 (s, 3H).
25%
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 3.5h;
Step 1: A solution of <strong>[905587-44-2]1-(5-fluoropyrimidin-2-yl)ethanone</strong> (700 mg, 5.0 mmol) and 4- fluorophenol (616 mg, 5.50 mmol) in 6 mL DMF was treated with potassium carbonate (829 mg 6.0 mmol) and heated to 5000 for 3.5 h. The reaction mixture was poured into 20 mL water, and extracted with EtOAc (2 x 20 mL). Organics were washed with 20 mL each water, brine,and dried over Na2SO4. Mixture was filtered and concentrated on silica gel. Column chromatography (10 - 100% EtOAc/hept) gave 295 mg (25%) 1-(5-(4-fluorophenoxy)pyrimidin- 2-yl)ethanone as a white solid used directly in the following step. MS mlz 233.2 (M + H)+. 1H NMR (400 MHz, CDCI3) O 8.55 (5, 2H), 7.23 - 7.07 (m, 4H), 2.78 (5, 3H).
4-Fluorophenol (98%, 2.37 g, 21.1 mmol) was dissolved in DMF (50 mL), NaH (60% in paraffin oil, 0.89 g, 22.2 mmol) was added at RT in small portions and stirred for 1 h at RT. To this suspension 3-Bromo-5-iodopyridine (3.00 g, 10.6 mmol) was added at RT and stirring was continued for 2 h at 90C. After cooling the solvent was removed under reduced pressure. The residue was redissolved in ethyl acetate, washed with diluted sodium hydroxide solution, water and saturated NaCI solution. It was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue containing of a 1 :1 mixture of the bromo- and iodo- intermediate was used without further purification. According to the procedures (s.) and (t.) compound 31 was obtained in 52% yield over 2 steps. As an alternative, instead of pyridine, 3-5-dibromopyridine-N-oxide was reacted as described in (a.), (s.) and (t.) to obtain compound 31. The reduction of the N-oxide to the pyridine under the condition described in (t.) required an extended reaction time of 37 h.
4-Fluorophenol (98%, 2.37 g, 21.1 mmol) was dissolved in DMF (50 mL), NaH (60% in paraffin oil, 0.89 g, 22.2 mmol) was added at RT in small portions and stirred for 1 h at RT. To this suspension 3-Bromo-5-iodopyridine (3.00 g, 10.6 mmol) was added at RT and stirring was continued for 2 h at 90C. After cooling the solvent was removed under reduced pressure. The residue was redissolved in ethyl acetate, washed with diluted sodium hydroxide solution, water and saturated NaCI solution. It was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue containing of a 1 :1 mixture of the bromo- and iodo- intermediate was used without further purification.
methyl 4-(1-(4-fluorophenoxy)ethyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 12h;
Methyl 4-(l-(4-fluorophenoxy)ethyl)benzoate. To a solution of methyl 4-(l- hydroxyethyl)benzoate (0.9 g, 5 mmol), 4-fluorophenol (627 mg, 5.6 mmol), triphenylphosphine (2.2 g, 8.4 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (1.7 g, 8.4 mmol) at 0C. The mixture was stirred at 20C for 12 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL x 3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 5: 1) to give methyl 4-(l-(4-fluorophenoxy)ethyl)benzoate (490 mg, 35%).
35%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 12h;
To a solution of methyl 4-(1-hydroxyethyl)benzoate (0.9 g, 5 mmol), 4-fluorophenol (627 mg, 5.6 mmol), triphenylphosphine (2.2 g, 8.4 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (1.7 g, 8.4 mmol) at 0 C. The mixture was stirred at 20 C. for 12 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give methyl 4-(1-(4-fluorophenoxy)ethyl)benzoate (490 mg, 35%).
4-fluorophenoxy-3-formylpyridine To a solution of 4-fluorophenol (455 mg, 4.06 mmol) in THF [5 mL] was added HNa (162 mg, 4.06 mmol). After stirring for 0.5 hour, <strong>[114077-82-6]4-chloronicotinaldehyde</strong> (500 mg, 3.53 mmol) was added and the reaction mixture was heated at 65 C for 3 hours. Then the reaction mixture was diluted with water and brine, extracted with MTBE, dried over MgS04 and concentrated under reduced pressure to give 617 mg of an oily compound (Yield: 64%) APCI-MS: (M+H)+ =218
With sodium hydride; In N,N-dimethyl acetamide; mineral oil; at 250℃; for 0.25h;Inert atmosphere; Microwave irradiation;
A solution of <strong>[60290-21-3]4-chloro-1H-pyrrolo[3,2-c]pyridine</strong>(100 mg, 0.66 mmol) and 4-fluorophenol (367 mg, 3.28 mmol) in DMA(2.0 mL) was stirred under nitrogen. Sodium hydride (52.4 mg, 1.31 mmol; 60% in mineral oil) was added to the solution and then stirred for 5 minutes before heating under microwave irradiation at 250C for 10 minutes. The mixture was diluted withTHF (10 mL) and quenched with water and ice (2 mL). The solution was filtered through a Varian ChemElute cartridge and concentrated. The material was partially purified by flash chromatography with a gradient elution of heptane,ethyl acetate and methanol (1:1:0 to 1:1:1) to give a gum. The material was further purified by reverse phase preparative HPLC to provide the desired material (41.0mg, 27.4 %) as a solid. HPLC Purity: >99%(215 nM), >98% (254 nM), >99% (280 nM). 1H NMR (400 MHz, DMSO-d6) d ppm 6.55 (dd, J=3.1,0.8 Hz, 1 H), 7.10 - 7.28 (m, 5 H), 7.41 (d, J=3.1 Hz, 1 H), 7.59 - 7.69 (m, 1H), 11.65 (br. s., 1 H). HRMS m/z calcd for C13H9FN2O[M+H]+ 229.0775, found 229.0772.
27.4%
With sodium hydride; In N,N-dimethyl acetamide; mineral oil; at 250℃; for 0.166667h;Inert atmosphere; Microwave irradiation;
A solution of <strong>[60290-21-3]4-chloro-1H-pyrrolo[3,2-c]pyridine</strong>(100 mg, 0.66 mmol) and 4-fluorophenol (367 mg, 3.28 mmol) in DMA (2.0 mL) wasstirred under nitrogen. Sodium hydride (52.4 mg, 1.31 mmol; 60% in mineral oil)was added to the solution and then stirred for 5 minutes before heating under microwaveirradiation at 250 Cfor 10 minutes. The mixture was diluted with THF (10 mL) and quenched withwater and ice (2 mL). The solution was filtered through a Varian ChemElutecartridge and concentrated. The material was partially purified by flashchromatography with a gradient elution of heptane, ethyl acetate and methanol(1:1:0 to 1:1:1) to give a gum. The material was further purified by reversephase preparative HPLC to provide the desired material (41.0 mg, 27.4 %) as asolid. HPLC Purity: >99% (215 nM), >98% (254 nM), >99% (280 nM). 1HNMR (400 MHz, DMSO-d6) d ppm 6.55 (dd, J=3.1, 0.8 Hz, 1 H), 7.10 - 7.28 (m, 5 H), 7.41 (d,J=3.1 Hz, 1 H), 7.59 - 7.69 (m, 1 H), 11.65 (br. s., 1 H). HRMSm/z calcd for C13H9FN2O [M+H]+ 229.0775,found 229.0772.
With sodium hydride; In N,N-dimethyl acetamide; mineral oil; at 20 - 200℃; for 0.3h;Inert atmosphere; Microwave irradiation;
A solution of <strong>[21560-29-2]1-chloro-6,7-dimethoxyisoquinoline</strong> (50 mg, 0.22 mmol) and 4-fluorophenol (25.06mg, 0.22 mmol) in DMA (3 mL) was stirred under a nitrogen atmosphere for 5 minutes.Sodium hydride (22.35 mg, 0.56 mmol; 60% in mineral oil) was added to the reaction mixture and stirred at ambient temperature for 15 minutes. Next the mixture was stirred and heated at 200C for 3 minutes under microwave irradiation. The reaction mixture was quenched with methanol (0.5 mL) and the crude material was purified by flash column chromatography eluting with a gradient of ethyl acetate and methanol (1:0 to 1:1) to give a gum. The product was purified by reverse phase chromatography and the desired product (33.0 mg,49.3%) was obtained as a solid. HPLC purity:>99% (215 nM), >99% (254 nM), >99% (280 nM). 1H NMR (400MHz, DMSO-d6) d ppm 3.94 (s, 3 H), 3.92 (s, 3 H), 7.23- 7.31 (m, 4 H), 7.36 - 7.43 (m, 2 H), 7.58 (s, 1 H), 7.76 (d, J=5.5 Hz, 1 H).HRMS m/z calcd for C17H14FNO3 [M+H]+300.1031, found 300.1030.
49.3%
A solution of <strong>[21560-29-2]1-chloro-6,7-dimethoxyisoquinoline</strong>(50 mg, 0.22 mmol) and 4-fluorophenol (25.06 mg, 0.22 mmol) in DMA (3 mL) wasstirred under a nitrogen atmosphere for 5 minutes. Sodium hydride (22.35 mg,0.56 mmol; 60% in mineral oil) was added to the reaction mixture and stirred atambient temperature for 15 minutes. Next the mixture was stirred and heated at 200C for 3 minutes undermicrowave irradiation. The reaction mixture was quenched with methanol (0.5 mL)and the crude material was purified by flash column chromatography eluting witha gradient of ethyl acetate and methanol (1:0 to 1:1) to give a gum. Theproduct was purified by reverse phase chromatography and the desired product (33.0mg, 49.3%) was obtained as a solid. HPLCpurity: >99% (215 nM), >99% (254 nM), >99% (280 nM). 1H NMR(400 MHz, DMSO-d6) dppm 3.94 (s, 3 H), 3.92 (s, 3 H), 7.23 - 7.31 (m, 4 H), 7.36- 7.43 (m, 2 H), 7.58 (s, 1 H), 7.76 (d, J=5.5 Hz, 1 H). HRMS m/z calcd for C17H14FNO3[M+H]+ 300.1031, found 300.1030.
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h;
Example 6 Preparation of 5-(2-(4-fluorophenoxy)-4-(trifluoromethyl)benzamido)picolinic acid (56) [embedded image] To a solution of <strong>[89763-93-9]2-fluoro-4-(trifluoromethyl)benzaldehyde</strong> (1.0 g, 5.20 mmol) and 4-fluorophenol (583.5 mg, 5.20 mmol) in DMF (5.0 mL) was added dicesium carbonate (1.7 g, 5.20 mmol) and the mixture was heated at 100 C. for 1 hour. The reaction was cooled to room temperature. The reaction was diluted with ethyl acetate (5 ml) and water (10 ml). The organic layer was washed with water (210 mL), dried with MgSO4, filtered and evaporated to yield a brown oil that was purified by column chromatography using a gradient of ethyl acetate in hexanes (0-25%) to yield 2-(4-fluorophenoxy)-4-(trifluoromethyl)benzaldehyde (1.16 g, 78%). 1H NMR (400 MHz, CDCl3) - 10.58 (s, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.42 (d, J=7.5 Hz, 1H), 7.18-7.04 (m, 5H) ppm.To a solution of 2-(4-fluorophenoxy)-4-(trifluoromethyl)benzaldehyde (1.16 g, 4.08 mmol) in tBuOH (11.60 mL), water (7.30 mL), acetonitrile (7.30 mL) was added sodium dihydrogen phosphate (1.47 g, 12.25 mmol), 2-methyl-2-butene (2.16 mL, 20.42 mmol) and sodium chlorite (1.11 g, 12.25 mmol) and the reaction mixture was stirred at 25 C. for 2 hours. The reaction was acidified with 1N HCl and diluted with ethyl acetate. Sodium sulfide was added to remove the slightly yellow color. The 2 layers were separated and the aqueous layer extracted 2 additional times with ethyl acetate. The organics were combined, dried with MgSO4, filtered and evaporated to give 2-(4-fluorophenoxy)-4-(trifluoromethyl)benzoic acid (1.0 g, 82%) as a yellow solid that was used in the next step without further purification. 1H NMR (400 MHz, DMSO) - 8.01 (d, J=8.0 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.33-7.18 (m, 3H), 7.14-7.01 (m, 2H) ppm.A solution of methyl 5-aminopicolinate (15.2 mg, 0.1 mmol), 2-(4-fluorophenoxy)-4-(trifluoromethyl)benzoic acid (33.0 mg, 0.12 mmol), N-methylmorpholine (22 -L, 0.2 mmol) and HATU (45.6 mg, 0.12 mmol) in DMF (0.4 mL) was stirred at 40 C. for 16 hours. Aqueous NaOH (166.7 -L, 3M) and methanol (0.2 mL) were added and the mixture was stirred at 40 C. for 1 hour. The reaction mixture was diluted with MeOH, filtered and purification by reverse phase HPLC using a gradient of ACN in Water (1-99%) and HCl as a modifier to give 54244-fluorophenoxy)-4-(trifluoromethyl)benzamido)picolinic acid (56) (9.95 mg, 33%). ESI-MS m/z calc. 420.07. found 421.29 (M+1)+. Retention time: 1.60 minutes (3 minutes run). 1H NMR (400 MHz, DMSO) - 13.15-12.96 (m, 1H), 11.09 (s, 1H), 8.90 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.36-7.13 (m, 5H) ppm.
3-bromo-4-(4-fluoro-phenoxymethyl)-pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
600 mg
With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 16h;
To a solution of <strong>[146679-66-5](3-bromo-pyridin-4-yl)-methanol</strong> (650 mg, 3.5 mmol), 4-fluoro-phenol (260 mg, 2.3 mmol) and PPh3 (1.7 g, 6.4 mmol) in THF (50 mL) is added a solution of di-tert-butyl azodicarboxylate (1.2 g, 5 mmol) in THF at 0 C. After addition, the mixture is stirred at room temperature for 16 hrs. The solvent is removed and the residue is purified by flash column chromatography to give 600 mg of 3-bromo-4-(4-fluoro-phenoxymethyl)-pyridine.
General procedure: DCC (1.3 equiv.) was added to a solution of <strong>[3482-49-3]fusidic acid</strong> 1 (1.0 equiv.) in dichloromethane (15 mL) and resulting reaction mixture was stirred at 25C for 10 min followed by addition of alcohol (1.3 equiv.) and catalytic amount of DMAP. The resulting mixture was stirred at 25C for 2h, after which the solvent was evaporated under reduced pressure. The crude mixture was washed with distilled water (3×15 ml) and extracted with dichloromethane (3×15 ml). The combined organic layers were dried over MgSO4. The crude product was subjected to column chromatography on silica gel using ethyl acetate/hexane as eluent to furnish the target compounds.
With di-isopropyl azodicarboxylate; triphenylphosphine; In toluene; at 0 - 20℃;Inert atmosphere;
Preparation of intermediate EV A solution of DIAD (0.74 mL, 3.75 mmol) in toluene (5 mL) was added to a solution of 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (CAS [1147557-97-8], 0.8 g, 3.75 mmol), 4-fluorophenol (0.421 g, 3.75 mmol) and triphenylphosphine (1.48 g, 5.63 mmol) in toluene (35 mL) at 0 °C under N2. The reaction mixture was then allowed to warm up to room temperature slowly overnight. Additional 4-fluorophenol (0.21 g, 1.88 mmol) was added and the reaction was stirred further at room temperature for 3d. The reaction mixture was evaporated to dryness, then dissolved in a minimum of diethyl ether and cooled to 0 °C. A large excess of heptane was added and the resulting mixture was evaporated under vacuum which induced the precipitation of PPh30, which was filtered off and washed with diethyl ether. The filtrate was evaporated to dryness and purified by preparative LC (irregular SiOH, 15-40 muiotaeta, 40 g, Grace, dry loading (silica), mobile phase gradient: Heptane/EtOAc from 90/10 to 50/50) to give 1.07 g of intermediate EV as a yellow solid (not obtained pure but engaged as such in the next step).
General procedure: Under inert atmosphere (N2, Schlenk flask), to a suspension of sodiumhydride (8.3 g, 346 mmol, 3.6 equiv) in freshly distilled dioxane (125 mL), phenols (144 mmol, 1.5 equiv) were introduced slowly (exothermic reaction and evolves H2 gas). To this mixture, the chlorodifluoroacetic acid (8.1 mL, 96.0 mmol, 1.0 equiv) was slowly addedat 0 C. Then, the solution was immersed in a temperature controlled oilbath to achieve a gentle reflux. The reaction progress was monitored by19F NMR. After 20-24 h, the acid was completely consumed and the mixture was concentrated in a rotary evaporator. The residue was dissolved in water (400 mL), and acidified with conc. HCl to reach pH= 1. Subsequenlty, the mixture was basified with NaHCO3 to reachpH= 8, and washed with DCM to remove the unreacted phenol. The solution was then acidified to pH= 1 and extracted with DCM(4 × 200 mL). After drying the combined organic layer with MgSO4 and filtration, the solvent was removed by rotary evaporation to obtain the compounds listed in Table 1.
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 5h;Inert atmosphere; Schlenk technique; Green chemistry;
General procedure: Under an argon atmosphere, a Schlenk tube was charged with MCM-41-2N-Cu(OAc)2(46 mg, 0.025 mmol), nitroarene 1 (0.5 mmol), phenol 2 (1.0 mmol), Cs2CO3 (1.0 mmol) and DMF (3 mL). The reaction mixture was stirred at 100 C for 5 h under Ar. After being cooled to room temperature, the mixture was diluted with ethyl acetate (20 mL) and filtered. The MCM-41-2N-Cu(OAc)2 catalyst was washed with distilled water (2 × 5 mL), DMF (2 × 5 mL) and EtOH (2 × 5 mL) and could be reused in the next run. The filtrate was washed with water (2 × 10 mL) and dried over anhydrous MgSO4. After removal of the solvent under reduced pressure, the residue was purified by column chromatography (EtOAc/hexane) on silica gel to afford the desired product 3.
With caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 40℃;
Take a 150mL eggplant-shaped bottle,Weigh 1.0 g of intermediate III-2 (5.0 mmol; 1.0 equiv),0.56 g of 4-fluorophenol (5.0 mmol; 1.0 equiv),2.5 g cesium carbonate (7.5 mmol; 1.5 equiv),0.6g potassium iodide (3.0mmol; 0.6equiv),40mL of N,N-dimethylformamide added to the bottle,Stir well,Then it was heated to 40C and reacted overnight.Thin layer TLC board,An ultraviolet analyzer (254 nm) monitors the progress of the reaction.Then the reaction solution was filtered and evaporated to dryness.The resulting residue was treated with 2 mol/L NaOH aqueous solution,The ethyl acetate was re-dissolved and added to a separatory funnel.The aqueous phase is extracted 2 to 3 times with an equal volume of ethyl acetate.Combine the ethyl acetate layers,Add saturated aqueous sodium chloride,Then,The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight.Filter out the desiccant,Weigh about 5g of 60-100 mesh silica gel powder into the filtrate.Rotary to dry sand,Silica gel column chromatography separation,The elution system selected was petroleum ether:ethyl acetate = 10:1.The resulting etherification reaction product is collected,A total of 0.39g of pale yellow solid IV-4c was obtained.Yield: 31.2%.
(S)-tert-butyl 3-(4-fluorophenoxy)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.4 g
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 12h;Inert atmosphere;
A. To a solution of (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (3 g, 14.91 mmol) in THF (30 mL) was added 4-fluorophenol (1.67 g, 14.91 mmol) and triphenylphosphine (3.91 g, 14.91 mmol). DIAD (3.01 g, 14.91 mole) was added dropwise at 0 C under N2. Then the reaction was stirred at room temperature for 12 h. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to provide the product 2.4 g as yellow oil.
tert-butyl 4-(4-fluorophenoxy)azepane-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
440 mg
A. To a solution of <strong>[478832-21-2]tert-butyl 4-hydroxyazepane-1-carboxylate</strong> (400 mg, 1.86 mmol) in THF (8 mL) was added 4-fluorophenol (210 mg, 1.86 mmol), triphenylphosphine (0.73 g, 2.79 mmol). The reaction was stirred at ambient temperature for 5 min. Diisopropyl azodiformate (0.41 g, 2.05 mmol) was added to the above mixture dropwise. The reaction was stirred at ambient temperature for 3 h. TLC showed the starting material was consumed. The combined organics were concentrated in vacuo. The resulting oil was purified by flash column chromatography with an isocratic elution of EtOAc (10%) and hexanes (90%) to provide tert-butyl 4-(4-fluorophenoxy)azepane-1-carboxylate (440mg) as a colorless oil.
a dry 50 ml reaction flask was vacuumed three times with nitrogen, then added 4-methoxyphenol (124 mg, 1.0 mmol, 1.0 equiv) to the reaction flask, and 3.0 ml of dried THF was added. Stir until all the 4-methoxyphenol was dissolved, then add NaH (28.8 mg, 1.2 mmol, 1.2 equiv, sodium hydride content 60percent) to the reaction flask under ice bath.It was suspended in mineral oil and reacted for 30 min in an ice bath; then <strong>[10320-42-0]2-chloro-5-nitropyrimidine</strong> (0.1593 g, 1.0 mmol, 1.0 equiv) was added to the reaction flask. The entire mixture was slowly raised to a temperature of 50 ° C for 12 hours. The reaction was monitored by TLC, and the reaction was stopped if it was detected that all of the phenol was completely reacted. The experimental treatment was to drain the solution in the reaction; dissolve the solute in the reaction flask with ethyl acetate, transfer it to a 100 ml round bottom flask, and cook it in a round bottom.Add 3 ml (200-300 mesh) of silica gel to the flask and spin dry (petroleum ether and ethyl acetate) over silica gel on the column. The intermediate product was white crystals of 2-(4-methoxyphenoxy)-5-nitropyrimidine (207 mg, 90percent yield).
With sodium hydride; In N,N-dimethyl-formamide; at 80℃; for 10.0h;Inert atmosphere;
General procedure: NaH (12.0mmol) was added to a solution of 1 or 722 (1.88g, 10.0mmol) and substituted phenol (12.0mmol) in DMF (50mL) at room temperature under N2, and the mixture was stirred at 80C for 10h. Water was added to the cooled mixture, and the mixture was extracted with EtOAc several times. The combined organic layers were washed with water, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography to obtain purified compound 2, or crude 2 was used directly for the next reaction without further purification.
2-((4-fluorophenoxy)methyl)benzo[d]oxazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83.13%
With potassium carbonate; In acetone; for 4h;Reflux;
General procedure: To a solution of various substituted phenols (1 mmol) in dry acetone (30 mL) K2CO3 (1 mmol)and compound 3 or 4 (1 mmol) were added. After being stirred for 4 h at reflux temperature, thereaction mixture was cooled, filtered, and concentrated under vacuum. Then the residue was dilutedwith 30 mL ethyl acetate and sequentially washed with 30 mL 1 M HCl, aq. NaHCO3 solution andbrine in order. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification of theresidue by chromatography on silica gel furnished target compounds. 1H-NMR, 13C-NMR and massspectroscopy (MS) of compounds 5a-m and 6a-m are shown in Supplementary Materials.
4-(4-fluorophenoxy)-3,5,6-trifluorophthalonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With potassium fluoride; In acetone; at 0℃; for 0.5h;
In a 50 ml reactor, 7 g of <strong>[1835-65-0]tetrafluorophthalonitrile</strong>,2.25 g of potassium fluoride and 30 g of acetone were added and stirred at 0 ° C. A solution prepared by mixing 3.9 g of 4-fluorophenol with 5 g of acetone was dropped there, and kept at 0 ° C. for 30 minutes.After raising the temperature to 25 ° C., the reaction solution is suction filtered.The solvent was distilled off from the filtrate under reduced pressure, and then crystallization was performed by adding methanol.The crystallized material is collected by filtration and then dried under reduced pressure.5.72 g (yield 56 molpercent based on <strong>[1835-65-0]tetrafluorophthalonitrile</strong>) of 4- (4-fluorophenoxy) -3,5,6-trifluorophthalonitrile was obtained.5 g of 4- (4-fluorophenoxy) -3,5,6-trifluorophthalonitrile thus obtained,2.61 g of potassium carbonate, 1.56 g of ethyl 3,4-dihydroxybenzoate and 50 g of acetonitrile were charged into a 100 ml reactor and reacted at 80 ° C. for 2 hours.Thereafter, 3.84 g of 4-fluorophenol and 5.21 g of potassium carbonate were further added, and reacted at 80 ° C. for about 7 hours.The reaction solution is filtered while hot to remove inorganic components,The solvent was distilled off under reduced pressure from the filtrate to obtain 9.21 g of phthalonitrile mixture (A) (yield: 98 molpercent based on 4- (4-fluorophenoxy) -3,5,6-trifluorophthalonitrile).
3-(4-fluorophenoxy)pyridine-4-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
18%
With copper(l) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 110℃; for 18h;
Example 64 Synthesis of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-3-(4-fluorophenoxy)isonicotinamide Compound 35a. To a stirred solution of <strong>[13959-02-9]3-bromopyridine-4-carboxylic acid</strong> (1.0 g, 5.0 mmol, 1 equiv) in DMF (10 mL), was added 4-fluorophenol (0.560 g, 5.0 mmol, 1 equiv), CuI (1.90 g, 10.0 mmol, 2 equiv) and Cs2CO3 (3.260 g, 10.0 mmol, 2 equiv). Heated the reaction mixture at 110 C. for 18 h. Reaction progress was checked by LCMS. The reaction mixture was diluted with water (20 mL) and added few drops of dil. HCl till pH was slightly acidic. The aqueous layer was extracted with ethyl acetate (50 mL*2). Combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain 3-(4-fluorophenoxy)pyridine-4-carboxylic acid (0.200 g, 18% Yield)
2-(4-fluorophenoxy)-4-chloro-6-methoxy-1,3,5-triazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 0.5h;
General procedure: Phenol (ca. 500 mg, 1.0 eq) in dichloromethane(5 mL) and N,N-diisopropylethylamine (1.0 eq) in dichloromethane(5 mL) were added dropwise to a solution of 2 (1.0 eq)in dichloromethane (10 mL). The mixture was stirred for30 min at room temperature, washed with aqueous hydrochloricacid and brine, dried over sodium sulfate and concentrated.The residue was purified by silica gel column chromatographyor recrystallization.
methyl 2-fluoro-4-(4-fluorophenoxy)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29%
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 4h;
Methyl 2,4-difluorobenzoate (1.00 g; 5.81 mmol), 4-fluorophenol (0.72 g; 6.39 mmol) and potassium carbonate (1.61 g; 11.62 mmol) in DMF (20 mL) are stirred at 90C for 4 hours. The reaction mixture is diluted with water and extracted three times with DCM. The combined organic layers are dried over MgSC , filtered and concentrated under reduced pressure. The residue is purified by RP-HPLC (ACN/water + TFA). Yield: 0.45 g (29%) ESI-MS: m/z = 265 [M+H]+ Rt(HPLC): 1.15 min (method 1)
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 12h;
Dissolve <strong>[52092-47-4]2-nitro-5-chloropyridine</strong> (3.17g, 20mmol), p-fluorophenol (2.24g, 20mmol), and potassium carbonate (4.14g, 30mmol) in 50mL of DMF solution. The reaction was carried out at 100 C for 12 hours. The reaction was cooled to room temperature, and 100 mL of ice water was added and stirred. A solid precipitated out, filtered with suction, washed with water, and dried.The target compound was obtained (brown solid, 4.03 g, yield: 86%).
Chemistry
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