* 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] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 524 - 530
[2] Patent: CN107880085, 2018, A,
2
[ 156-38-7 ]
[ 531-95-3 ]
Reference：
[1] Patent: US2015/57456, 2015, A1,
3
[ 156-38-7 ]
[ 1698-53-9 ]
[ 1698-60-8 ]
Reference：
[1] Patent: US4454318, 1984, A,
4
[ 156-38-7 ]
[ 4693-91-8 ]
Reference：
[1] Patent: CN106467499, 2017, A,
5
[ 156-38-7 ]
[ 108-46-3 ]
[ 17720-60-4 ]
Yield
Reaction Conditions
Operation in experiment
87%
With boron trifluoride diethyl etherate In toluene at 100 - 108℃; for 1.5 h; Inert atmosphere
Step 1: Reaction to produce l-(2,4-Dihydroxyphenyl)-2-(4-hydroxyphenyl)ethanone [00165] Resorcinol (1,3-dihydroxybenzene) (62.000 g, 563.1 mmol, 1.0 equiv.) and 4- Hydroxyphenylacetic acid (94.237 g, 619.4 mmol, 1.1 equiv.) were added to a 3 neck 2 L round bottomed flask fitted with a paddle, a pressure equalizing addition funnel and a thermometer and a heating mantle. Toluene (350 mL) was added to the flask to give a suspension. The reaction purged with nitrogen and the addition funnel filled with Boron trifluoride etherate (198.201 ml, 1578.0 mmol, 2.8 equiv.) via canula. The reaction was stirred at 150 rpm and boron trifluoride etherate was added in portions of 3-4 mL and the reaction heated. During addition the internal temperature rose to 100 °C. The reaction went through various changes in color from yellow to dark red. After complete addition of boron trifluoride etherate the addition funnel was removed and replaced with a condenser. The reaction was stirred for 1.5 h at an internal temperature of 108 °C. A sample was taken and HPLC analysis indicated the reaction was complete. The reaction was cooled and stirring stopped to give a biphasic solution. A 12 percent aqueous solution of sodium acetate (41 g, 336 mL) was slowly added to the reaction with stirring. The reaction was stirred for 16 hours. A precipitate formed overnight and was collected in a sintered glass funnel. The solid was dried on a vacuum oven for 16 h to give the product as a white powder (119.67 g, 87.0 percent).
87%
With boron trifluoride diethyl etherate In toluene at 100 - 108℃; for 1.5 h; Inert atmosphere
[00195] Resorcinol (1,3-dihydroxybenzene) (62.000 g, 563.1 mmol, 1.0 equiv.) and 4- Hydroxyphenylacetic acid (94.237 g, 619.4 mmol, 1.1 equiv.) were added to a 3 neck 2 L round bottomed flask fitted with a paddle, a pressure equalizing addition funnel and a thermometer and a heating mantle. Toluene (350 mL) was added to the flask to give a suspension. The reaction purged with nitrogen and the addition funnel filled with Boron trifluoride etherate (198.20 1 ml, 1578.0 mmol, 2.8 equiv.) via canula. The reaction was stirred at 150 rpm and boron trifluoride etherate was added in portions of 3-4 mL and the reaction heated. During addition the internal temperature rose to 100 °C. The reaction went through various changes in color from yellow to dark red. After complete addition of boron trifluoride etherate the addition funnel was removed and replaced with a condenser. The reaction was stirred for 1.5 h at an internal temperature of 108 °C. A sample was taken and HPLC analysis indicated the reaction was complete. The reaction was cooled and stirring stopped to give a biphasic solution. A 12 percent aqueous solution of sodium acetate (41 g, 336 mL) was slowly added to the reaction with stirring. The reaction was stirred for 16 hours. A precipitate formed overnight and was collected in a sintered glass funnel. The solid was dried on a vacuum oven for 16 h to give the product as a white powder (119.67 g,87.0 percent).
87%
With boron trifluoride diethyl etherate In toluene at 100 - 108℃; Inert atmosphere
Step 1 Reaction to produce l-(2,4-Dihydroxyphenyl)-2-(4-hydroxyphenyl)ethanone_:Resorcinol (1,3-dihydroxybenzene) (62.000 g, 563.1 mmol, 1.0 equiv.) and 4- Hydroxyphenyl acetic acid (94.237 619.4 mmol, 1.1 equiv.) were added to a 3 neck 2 L round bottomed flask fitted with a paddle, a pressure equalizing addition funnel and a thermometer and a heating mantle. Toluene (350 mL) was added to the flask to give a suspension. The reaction purged with nitrogen and the addition funnel filled with Boron trifluoride etherate (198.201 ml, 1578.0 mmol, 2.8 equiv.) via canula. The reaction was stirred at 150 rpm and boron trifluoride etherate was added in portions of 3-4 mL and the reaction heated. During addition the internal temperature rose to 100 °C. The reaction went through various changes in color from yellow to dark red. After complete addition of boron trifluoride etherate the addition funnel was removed and replaced with a condenser. The reaction was stirred for 1.5 h at an internal temperature of 108 °C. A sample was taken and HPLC analysis indicated the reaction was complete. The reaction was cooled and stirring stopped to give a biphasic solution. A 12 percent aqueous solution of sodium acetate (41 g, 336 mL) was slowly added to the reaction with stirring. The reaction was stirred for 16 hours. A precipitate formed overnight and was collected in a sintered glass funnel. The solid was dried on a vacuum oven for 16 h to give the product as a white powder (119.67 g, 87.0 percent).
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1991, # 12, p. 3005 - 3008
[2] Journal of Organic Chemistry, 2000, vol. 65, # 8, p. 2305 - 2308
[3] Journal of Agricultural and Food Chemistry, 1994, vol. 42, # 9, p. 1869 - 1871
[4] Tetrahedron Letters, 2006, vol. 47, # 47, p. 8375 - 8378
[5] Patent: WO2013/90921, 2013, A1, . Location in patent: Paragraph 00165
[6] Patent: WO2014/203129, 2014, A1, . Location in patent: Paragraph 00195
[7] Patent: WO2014/203132, 2014, A1, . Location in patent: Paragraph 00105; 00106
[8] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 11, p. 3703 - 3710
[9] Patent: EP1167364, 2002, A1, . Location in patent: Page 13
[10] Chemical and Pharmaceutical Bulletin, 2009, vol. 57, # 4, p. 346 - 360
[11] Tetrahedron Letters, 2012, vol. 53, # 49, p. 6697 - 6700,4
[12] Tetrahedron Letters, 2012, vol. 53, # 49, p. 6697 - 6700
[13] Journal of Medicinal Chemistry, 1997, vol. 40, # 14, p. 2117 - 2122
[14] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 13, p. 4360 - 4366
[15] Bulletin de la Societe Chimique de France, 1951, p. 82
[16] Patent: US6670346, 2003, B1, . Location in patent: Page column 31; 34
[17] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 2, p. 677 - 681
[18] Journal of Agricultural and Food Chemistry, 2010, vol. 58, # 18, p. 10027 - 10032
[19] Chemical and Pharmaceutical Bulletin, 2012, vol. 60, # 4, p. 513 - 520
[20] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 17, p. 5523 - 5526
[21] Patent: US2015/250802, 2015, A1, . Location in patent: Paragraph 0228
[22] Patent: EP3178480, 2017, A1, . Location in patent: Paragraph 0142
6
[ 156-38-7 ]
[ 108-46-3 ]
[ 17720-60-4 ]
Yield
Reaction Conditions
Operation in experiment
70%
Stage #1: at 50 - 60℃; Stage #2: With water In diethyl ether at 0 - 20℃;
EXAMPLE 62: Trihydroxybenzoin Resorcinol (100 g, 0.91 mol) and 4-hydroxyphenylacetic acid (138.4 g, 0.91 mol) were dissolved into BF3Et2O (346 ml, 2.73 mol) under N2. The mixture was stirred and heated at 50-60°C. After complete reaction, the mixture was cooled to room temperature and poured into a large volume of iced water. The crude product was filtered off and dried to yield trihydroxybenzoin (70 percent). mp 211°C. 1H-NMR (Acetone d6): 4.12 (s, 2H), 6.78 (d, 2H), 6.91 (d, 1H), 7.13 (d, 2H), 7.54-7.6 (m, 2H), 8.21 (s, 1H), 8.35 (s, 1H), 8.70 (s, 1H).
Reference：
[1] Synthetic Communications, 2000, vol. 30, # 3, p. 469 - 484
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 2000, vol. 4, p. 567 - 570
8
[ 156-38-7 ]
[ 85888-81-9 ]
[ 55453-87-7 ]
Yield
Reaction Conditions
Operation in experiment
79.3%
Stage #1: With potassium hydroxide In methanol at 20℃; for 1 h; Stage #2: Reflux Stage #3: at 80℃; for 2 h;
Reaction flask was added p-hydroxyphenyl acetic acid (150mmol) 22.67g, potassium hydroxide (200mmol) 11.22g, 90ml of methanol, stirred for 1 hour at room temperature, was added 2- (chloromethyl) benzoic acid (100mmol) 17.06g, heated at reflux The reaction, after the reaction was monitored by TLC, the solvent was distilled off under reduced pressure, 200ml of dichloromethane was added to dissolve, washed with water, dried, concentrated, Eaton reagent was added 7.5percent (mass concentration) 200ml, was heated to 80 deg.] C, stirred for 2 hours, the reaction was completed after addition of saturated sodium carbonate solution, filtration, and recrystallized from ethanol to give Isoxepac (79.3mmol) 21.27g, yield 79.3percent, HPLC purity of 99.9percent.
Reference：
[1] Patent: CN105693685, 2016, A, . Location in patent: Paragraph 0050; 0051
9
[ 156-38-7 ]
[ 55453-87-7 ]
Reference：
[1] Patent: WO2011/128911, 2011, A2,
10
[ 335200-33-4 ]
[ 156-38-7 ]
[ 18699-02-0 ]
[ 335200-30-1 ]
Reference：
[1] Chemical Communications, 2001, # 1, p. 19 - 20
11
[ 106664-49-7 ]
[ 156-38-7 ]
[ 18699-02-0 ]
Reference：
[1] Chemical Communications, 2001, # 1, p. 19 - 20
12
[ 335200-29-8 ]
[ 156-38-7 ]
[ 18699-02-0 ]
[ 335200-30-1 ]
Reference：
[1] Chemical Communications, 2001, # 1, p. 19 - 20
13
[ 156-38-7 ]
[ 501-94-0 ]
Yield
Reaction Conditions
Operation in experiment
87%
Stage #1: With sulfuric acid In ethanol for 3 h; Reflux; Inert atmosphere Stage #2: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 25℃; for 12 h; Inert atmosphere
Step 1: The formation of 4-(2-hydroxyethyl)phenol. This compoundwas prepared following a literature procedure.54 To a solution of 2-(4-hydroxyphenyl)acetic acid (760 mg, 5 mmol) in ethanol (20 mL) wasadded sulfuric acid (27 μL, 0.5 mmol), and the resulting mixture washeated at reflux for 3 h. After completion monitored by TLC, the solventwas removed under reduced pressure, and the crude product was dissolvedin anhydrous THF (20 mL), followed by the addition of LiAlH4(228 mg, 6 mmol) slowly at 0 °C, and the resulting mixture was allowedto warm to RT for 12 h. After completion monitored by TLC, the solutionwas cooled to 0 °C, and quenched by Na2SO4·10H2O solid and filteredthrough Celite®. The solvent was removed under reduced pressureand the residue was diluted with H2O (20 mL) and extracted with ethylacetate (3×20 mL). The combined organic layers were dried overMgSO4 and concentrated in vacuo. The crude product was purified byflash chromatography (hexane/ethyl acetate 5:1→2:1) to give theproduct as an off-white solid (600 mg, 87percent). Rf (hexane/ethyl acetate2:1): 0.30; 1H NMR (400 MHz, CDCl3): δ 7.10 (2H, dd, J=2.0, 6.4 Hz),6.78 (2H, dd, J=2.0, 6.4 Hz), 4.83 (1H, br.s), 3.83 (2H, dd, J=6.4,15.0 Hz), 2.80 (2H, t, J=6.4 Hz); 13C NMR (100 MHz, CDCl3): δ 154.4,130.6, 130.3, 115.6, 64.0, 38.4. The spectroscopic data matched thatreported in the literature.54
Reference：
[1] Tetrahedron Letters, 2008, vol. 49, # 20, p. 3260 - 3263
[2] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2006, vol. 45, # 4, p. 1063 - 1066
[3] Journal of the American Chemical Society, 2001, vol. 123, # 35, p. 8618 - 8619
[4] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 22, p. 5852 - 5869
[5] Tetrahedron Letters, 2000, vol. 41, # 33, p. 6415 - 6418
[6] Chemical Communications (Cambridge, United Kingdom), 2012, vol. 48, # 85, p. 10514 - 10516,3
[7] Helvetica Chimica Acta, 1973, vol. 56, p. 2460 - 2479
[8] Journal of the Chemical Society, 1963, p. 2937 - 2943
[9] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 14, p. 3115 - 3120
[10] Journal of Medicinal Chemistry, 1995, vol. 38, # 12, p. 2130 - 2137
[11] Phytochemistry (Elsevier), 1990, vol. 29, # 5, p. 1653 - 1659
[12] Chemistry - A European Journal, 2016, vol. 22, # 9, p. 3009 - 3018
[13] Organic Letters, 2016, vol. 18, # 24, p. 6344 - 6347
[14] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 2, p. 131 - 134
14
[ 156-38-7 ]
[ 501-94-0 ]
[ 7339-87-9 ]
Reference：
[1] Chemical Communications (Cambridge, United Kingdom), 2012, vol. 48, # 85, p. 10514 - 10516,3
15
[ 156-38-7 ]
[ 52798-01-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 21, p. 5488 - 5492
16
[ 156-38-7 ]
[ 61439-59-6 ]
Reference：
[1] Carbohydrate Research, 2006, vol. 341, # 15, p. 2469 - 2477
[2] Journal of Organic Chemistry, 2016, vol. 81, # 4, p. 1367 - 1377
[3] Patent: CN107880085, 2018, A,
[4] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 22, p. 5852 - 5869
17
[ 156-38-7 ]
[ 17194-82-0 ]
Reference：
[1] Chemische Berichte, 1889, vol. 22, p. 2138
Reference：
[1] Tetrahedron Letters, 1983, vol. 24, # 44, p. 4847 - 4850
[2] Tetrahedron Letters, 1983, vol. 24, # 44, p. 4847 - 4850
[3] Bulletin of the Chemical Society of Japan, 1989, vol. 62, # 1, p. 148 - 152
21
[ 103-82-2 ]
[ 156-38-7 ]
[ 621-37-4 ]
[ 451-13-8 ]
[ 64700-73-8 ]
[ 614-75-5 ]
Reference：
[1] Agricultural and Biological Chemistry, 1987, vol. 51, # 3, p. 947 - 948
22
[ 87-41-2 ]
[ 156-38-7 ]
[ 55453-89-9 ]
Yield
Reaction Conditions
Operation in experiment
72.3%
Stage #1: With sodium methylate In methanol; N,N-dimethyl-formamide at 100 - 130℃; Stage #2: With water In methanol; N,N-dimethyl-formamide at 100℃; Stage #3: With hydrogenchloride In methanol; water; N,N-dimethyl-formamide at 10℃;
Example 1 Synthesis of the Intermediate 4-(2-Carboxybenzyloxy)Phenylacetic Acid (Olo-IM1) A solution of 4-hydroxyphenylacetic acid (90.0 g, 0.58 mol; assay >98percent) and phthalide (85.07 g, 0.63 mol) in DMF (323 g) was heated to an internal temperature of 130° C. The pressure was reduced to 800 mbar and sodium methoxide (224.6 g, 1.25 mol, assay: 30percent methanolic solution) was added slowly to the mixture maintaining the internal temperature above 100° C. During the addition methanol was distilled off, and after the addition the distillation was continued under normal pressure until the internal temperature increased to 130° C. again (260 g distillate). After stirring at this temperature for 6.5 h, phthalide (8.5 g, 0.06 mol) was added and the mixture was stirred overnight (16 h). Afterwards the mixture was cooled to 100° C. and hydrolyzed with water (1040 g). After cooling to <10° C., the pH of the mixture was adjusted to pH 1 with hydrochloric acid (163.5 g, 1.43 mol; assay: 32percent). The product was filtered off, washed with water (700 g) and dried under vacuum for 15 hours at 60° C. to give crude 4-(2-carboxybenzyloxy)phenylacetic acid (Olo-IM1) (yield: 174.6 g, 0.48 mol, 82.1percent; HPLC assay: 78.0percent). The crude Olo-IM1 (50.0 g, assay: 78.0percent, 0.14 mol) was recrystallized from acetonitrile/water (40 ml, 1/1). After filtration, the wet product washed successively with acetonitrile/water (98 ml, 1/1) and water (20 ml) to give slightly orange colored 4-(2-carboxybenzyloxy)phenylacetic acid (Olo-IM1) (yield: 35.27 g, 0.12 mol, 88.1percent; HPLC assay: 97.4percent; overall yield: 72.3percent).
Reference：
[1] Patent: US2007/232814, 2007, A1, . Location in patent: Page/Page column 23
[2] Patent: US4282365, 1981, A,
[3] Patent: WO2011/128911, 2011, A2, . Location in patent: Page/Page column 20-21
23
[ 156-38-7 ]
[ 34837-88-2 ]
Reference：
[1] Patent: WO2013/19682, 2013, A1,
24
[ 156-38-7 ]
[ 64-17-5 ]
[ 17138-28-2 ]
Yield
Reaction Conditions
Operation in experiment
100%
for 1 h; Heating / reflux
In a round-bottomed flask was placed 4-hydroxyphenyl acetic acid (10.0 g, 65.7 mmol), ethanol (120 ml) and cone. H2SO4 (1 ml). The mixture was heated at reflux for 1 hr and was then allowed to cool to room temperature. The mixture was carefully neutralized with aqueous NaHCC>3. Most of the ethanol was removed in vacuum. The aqueous phase was extracted with EtOAc, which was washed well with H2O and dried over Na2SC>4. Evaporation of the solvent gave the desired compound as an oil (11.8 g, 100percent). lB. NMR (400 MHz, CDCI3) 6 7.13 (d, 2H), 6.76 (d, 2H), 5.10 (s, 1H), 4.15 (q, 2H), 3.36 (s, 2H), 1.26 (t, 3H).
94%
Heating / reflux
A solution of 4-hydroxy phenyl acetic acid (4.5 g, 29.57 mmol) in benzene (60 mL) and ethanol (60 mL) was treated with concentrated sulfuric acid (2 mL) and heated to reflux overnight using a Dean-Stark water trap. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether (*2). The combined organic phase was washed with water (*1) and brine (*1), dried over anhydrous magnesium sulfate, filtered over a short bed of silica gel and evaporated in vacuo to afford the title product as an oil (5 g, 94percent). [0094] <1>H-NMR (300 MHz, CDCl3): [delta]1.23(t, J=6.7 Hz, 3H), 3.52(s, 2H), 4.14(q, J=6.7 Hz, 2H), 6.70(d, J=8.2 Hz, 2H), 7.06(d, J=8.5 Hz, 2H).
Reference：
[1] Patent: WO2006/20916, 2006, A2, . Location in patent: Page/Page column 79
[2] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 22, p. 8092 - 8105
[3] Synthesis, 2003, # 16, p. 2479 - 2482
[4] Patent: US2003/191181, 2003, A1, . Location in patent: Page/Page column 10; 15
[5] Journal of Medicinal Chemistry, 1988, vol. 31, # 8, p. 1651 - 1656
[6] Tetrahedron Asymmetry, 1995, vol. 6, # 6, p. 1345 - 1356
[7] Synlett, 2000, # 1, p. 59 - 60
[8] Journal of Organic Chemistry, 2003, vol. 68, # 3, p. 1165 - 1167
[9] Tetrahedron Letters, 2005, vol. 46, # 35, p. 5945 - 5947
[10] Chemische Berichte, 1889, vol. 22, p. 2138
[11] Journal of Medicinal Chemistry, 1989, vol. 32, # 8, p. 1910 - 1913
[12] Journal of Medicinal Chemistry, 2002, vol. 45, # 1, p. 115 - 126
[13] Journal of the Chinese Chemical Society, 2008, vol. 55, # 1, p. 201 - 208
[14] Patent: EP1229034, 2002, A1, . Location in patent: Page 119-120
[15] Combinatorial Chemistry and High Throughput Screening, 2011, vol. 14, # 2, p. 132 - 137
[16] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 3, p. 618 - 631
[17] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 24, p. 7699 - 7708
[18] Tetrahedron Letters, 2015, vol. 56, # 8, p. 981 - 985
[19] Patent: WO2007/146768, 2007, A2, . Location in patent: Page/Page column 11
25
[ 156-38-7 ]
[ 17138-28-2 ]
Reference：
[1] Patent: EP355830, 1994, B1,
[2] Patent: US5338482, 1994, A,
[3] Patent: US4909957, 1990, A,
[4] Patent: US4829086, 1989, A,
26
[ 156-38-7 ]
[ 144-55-8 ]
[ 17138-28-2 ]
Reference：
[1] Patent: US5849930, 1998, A,
27
[ 156-38-7 ]
[ 141-78-6 ]
[ 17138-28-2 ]
Reference：
[1] Synthesis, 2000, # 12, p. 1671 - 1672
[2] Synthesis, 2003, # 16, p. 2479 - 2482
Reference：
[1] Yakugaku Zasshi, 1933, vol. 53, p. 557,563; dtsch. Ref. S. 92[2] Chem.Abstr., 1933, p. 4223
32
[ 156-38-7 ]
[ 68641-16-7 ]
Reference：
[1] European Journal of Organic Chemistry, 2006, # 6, p. 1489 - 1498
[2] Australian Journal of Chemistry, 1967, vol. 20, p. 1413 - 1428
33
[ 156-38-7 ]
[ 10463-20-4 ]
Yield
Reaction Conditions
Operation in experiment
70%
With nitric acid In acetic acid
(a) 4-Hydroxy-3-nitrobenzene-acetic acid Fuming nitric acid (1.36 mL) was slowly added to an ice cooled solution of 4-hydroxy-benzeneacetic acid (4.00 gm, 26.3 mmol) in acetic acid (25 mL). The yellow solution was allowed to warm to room temperature over an hour as a brown precipitant formed. The solid was filtered and recrystallized from ethyl acetate/hexanes as yellow needles (3.61 gm, 70percent yield): 1 H-NMR δ (CDCl3 -d4 DMSO, 4:1) 3.50 (2H, s), 7.04 (1H, d, J=9 Hz), 7.46 (1H, dd, J=9, 3 Hz), 7.94 (1H, d, J=3 Hz).
67.2%
at 5℃; for 0.916667 h;
4-Hydroxyphenylacetic acid 1 (31 g; 203.7 mmol) was dissolved in acetic acid (186 mL) and cooled to 5 Celsius on ice bath. Nitric acid (62 mL of 50-70percent) was added dropwise to a solution of 4-hydroxyphenylacetic acid for 40 min. and the reaction mixture was held at that temperature for 15 min. The reaction mixture was added into 600 mL of water and filtered precipitate, washed with water, dried. MW C8H7NO5 197.14 g/mol; yield: 27 g (67.2percent); (0200) H-NMR (CD3OD): δ 8.00 (d, 1H); 7.53 (dd, 1H); 7.10 (d, 1H); 3.63 (s, 2H).
65%
With nitric acid In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; acetic acid
In a first step, carried out according to Humel in Synth. Commun. 15, pages 1081-88 (1985), to a magnetically stirred solution of 100 g (0.65,mole) of 4-hydroxyphenyl acetic acid in 250 ml of glacial acetic acid was added dropwise a mixture of 40 ml of nitric acid (1.4 specific gravity) and 60 ml glacial acetic acid. The glacial acetic acid was warmed to about 45° C. to completely dissolve the 4-hydroxyphenyl acetic acid. Following addition of the nitric acid/acetic acid mixture, stirring of the resulting mixture was continued for one hour at 25° C. and then the flask was chilled in ice water for one hour. The resulting crystals were washed with cold water and air-dried at room temperature, the reaction providing 65percent of the theoretical yield of 3-nitro 4-hydroxyphenyl acetic acid.
63.9%
With nitric acid In water at 20℃;
General procedure: An appropriate phenol compound 8a–13a (1 mmol) was mixed with 60percent HNO3 (4.8 mmol). Theresulting suspension was stirred at room temperature for 10 min for 8a and 9a, for 30 min for 10a, 12aand 13a, or overnight for 11a, leading eventually to an intensively dark red solution. HPLC analysisconfirmed the absence of starting material and the presence of 3 major products corresponding mostlikely to nitro derivatives resulting from nitration at the o- and p-positions of the hydroxy group fromthe m-substituted phenols 8a, 10a and 12a, but only one product from the p-substituted phenols 9a,11a and 13a. The crude nitrophenol 8b or 9b was diluted with water (20 mL) and applied onto aDowex 50W-X2 (200–400 mesh) column (1.5 cm × 6 cm, H+ form, equilibrated with water).The column was washed with water (100 mL) and then the product was eluted with 2 M HCl(20 mL/fraction). Fractions containing the target compound were combined and evaporated to drynessto give a yellow powder. After the nitration of phenols 10a, 12a and 13a, the reaction mixture (10b,12b and 13b) was diluted with H2O (20 mL) and extracted with ethyl acetate (2 × 100 mL). Thecombined organic extract was washed with water (2 × 50 mL), dried with Na2SO4 and evaporatedunder reduced pressure. The nitration of 11a afforded 11b as an orange powder in the reaction mixture.After the filtration, the powder was washed with water and dried under reduced pressure to give a darkred powder 11b.
62%
at 10 - 15℃; for 2.5 h;
(a) The solution of (4-hydroxyphenyl)acetic acid (4.65 g, 300 mmol) in glacial acetic acid (366 mL) was cooled to 10-15 °C, and nitric acid (100.5 mL, 65 w/wpercent) was added dropwise over a period of 1 hour. A precipitate was formed, and the mixture was stirred for 90 min at 10- 15 °C. Cold water (1100 mL) was added and stirred for 1 hour at 10-15 °C. The precipitate was filtered, washed with cold water (5x30 mL), and dried. 1-(4-Hydroxy-3-nitrophenyl)acetic acid was obtained (36.1 g, 62percent), mp: 145-150 °C.
62%
With nitric acid; acetic acid In water at 10 - 15℃; for 2.5 h;
The solution of (4-hydroxyphenyl)acetic acid (4.65 g, 300 mmol) in glacial acetic acid (366 mL) was cooled to 10-15°C, and nitric acid (100.5 mL, 65 w/w percent) was added dropwise over a period of 1 hour A precipitate was formed and the mixture was stirred for 90 min at 10-15°C. Cold water (1100 mL) was added and stirred for 1 hour at 10-15°C. The precipitate was filtered, washed with cold water (5 x 30 mL) and dried. 1-(4-hydroxy-3-nitrophenyl)acetic acid was obtained (36.1 g, 62percent); mp: 145-150°CΞ;
39%
at 0℃; for 1 h;
2-(2-(3,5-dimethylisoxazol-4-yl)benzo[a) 2-(4-hydroxy-3-nitrophenyl)acetic acidTo a solution of 2-(4-hydroxyphenyl)acetic acid (10 g, 65.7 mmol) in AcOH (100 mL) at 0 °C was added concentrated HNO3 (5.3 mL, 118.4 mmol) dropwise and the reaction mixture was stirred for 1 h. The yellow solution was allowed to warm to rt. The resultant precipitate was collected by filtration and recrystallized from EtOAc/hexanes to provide the title compound (5.0 g, 39percent) as a yellow solid. H NMR (400 MHz, DMSO-d6) δ ppm 12.44 (br s, 1H), 10.87 (s, 1H), 7.80 (d, 1H), 7.44 (dd, 1H), 7.08 (d, 1H), 3.59 (s, 2H).
Reference：
[1] Synthetic Communications, 1985, vol. 15, # 12, p. 1075 - 1080
[2] Patent: US5229510, 1993, A,
[3] Journal of Medicinal Chemistry, 1987, vol. 30, # 7, p. 1166 - 1176
[4] Patent: US9995679, 2018, B2, . Location in patent: Page/Page column 52
[5] Patent: US5852191, 1998, A,
[6] Molecules, 2014, vol. 19, # 6, p. 8039 - 8050
[7] Patent: WO2015/110848, 2015, A1, . Location in patent: Page/Page column 16
[8] Patent: US2017/2020, 2017, A1, . Location in patent: Paragraph 0065
[9] Canadian Journal of Chemistry, 2001, vol. 79, # 5-6, p. 792 - 794
[10] Patent: WO2013/19682, 2013, A1, . Location in patent: Page/Page column 103
[11] Bioorg. Med. Chem. Lett., 1997, vol. 7, # 22, p. 2913 - 2918
[12] Bioscience, Biotechnology and Biochemistry, 1998, vol. 62, # 3, p. 448 - 452
[13] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1958, vol. 312, p. 168,182
[14] Bioscience, biotechnology, and biochemistry, 2000, vol. 64, # 8, p. 1751 - 1753
[15] Patent: US2003/158177, 2003, A1,
[16] Patent: US4593106, 1986, A,
[17] Patent: US4554284, 1985, A,
[18] Patent: WO2010/75469, 2010, A1, . Location in patent: Page/Page column 120
[19] Patent: US2011/9628, 2011, A1, . Location in patent: Page/Page column 41-42
[20] Patent: US2013/244891, 2013, A1, . Location in patent: Page/Page column
[21] Patent: WO2013/131408, 2013, A1, . Location in patent: Page/Page column 90
With boron trifluoride diethyl etherate; In toluene; at 100 - 108℃; for 1.5h;Inert atmosphere;
Step 1: Reaction to produce l-(2,4-Dihydroxyphenyl)-2-(4-hydroxyphenyl)ethanone [00165] Resorcinol (1,3-dihydroxybenzene) (62.000 g, 563.1 mmol, 1.0 equiv.) and 4- Hydroxyphenylacetic acid (94.237 g, 619.4 mmol, 1.1 equiv.) were added to a 3 neck 2 L round bottomed flask fitted with a paddle, a pressure equalizing addition funnel and a thermometer and a heating mantle. Toluene (350 mL) was added to the flask to give a suspension. The reaction purged with nitrogen and the addition funnel filled with Boron trifluoride etherate (198.201 ml, 1578.0 mmol, 2.8 equiv.) via canula. The reaction was stirred at 150 rpm and boron trifluoride etherate was added in portions of 3-4 mL and the reaction heated. During addition the internal temperature rose to 100 C. The reaction went through various changes in color from yellow to dark red. After complete addition of boron trifluoride etherate the addition funnel was removed and replaced with a condenser. The reaction was stirred for 1.5 h at an internal temperature of 108 C. A sample was taken and HPLC analysis indicated the reaction was complete. The reaction was cooled and stirring stopped to give a biphasic solution. A 12 % aqueous solution of sodium acetate (41 g, 336 mL) was slowly added to the reaction with stirring. The reaction was stirred for 16 hours. A precipitate formed overnight and was collected in a sintered glass funnel. The solid was dried on a vacuum oven for 16 h to give the product as a white powder (119.67 g, 87.0 %).
87%
With boron trifluoride diethyl etherate; In toluene; at 100 - 108℃; for 1.5h;Inert atmosphere;
[00195] Resorcinol (1,3-dihydroxybenzene) (62.000 g, 563.1 mmol, 1.0 equiv.) and 4- Hydroxyphenylacetic acid (94.237 g, 619.4 mmol, 1.1 equiv.) were added to a 3 neck 2 L round bottomed flask fitted with a paddle, a pressure equalizing addition funnel and a thermometer and a heating mantle. Toluene (350 mL) was added to the flask to give a suspension. The reaction purged with nitrogen and the addition funnel filled with Boron trifluoride etherate (198.20 1 ml, 1578.0 mmol, 2.8 equiv.) via canula. The reaction was stirred at 150 rpm and boron trifluoride etherate was added in portions of 3-4 mL and the reaction heated. During addition the internal temperature rose to 100 C. The reaction went through various changes in color from yellow to dark red. After complete addition of boron trifluoride etherate the addition funnel was removed and replaced with a condenser. The reaction was stirred for 1.5 h at an internal temperature of 108 C. A sample was taken and HPLC analysis indicated the reaction was complete. The reaction was cooled and stirring stopped to give a biphasic solution. A 12 % aqueous solution of sodium acetate (41 g, 336 mL) was slowly added to the reaction with stirring. The reaction was stirred for 16 hours. A precipitate formed overnight and was collected in a sintered glass funnel. The solid was dried on a vacuum oven for 16 h to give the product as a white powder (119.67 g,87.0 %).
87.0%
With boron trifluoride diethyl etherate; In toluene; at 100 - 108℃;Inert atmosphere;
Step 1Reaction to produce l-(2,4-Dihydroxyphenyl)-2-(4-hydroxyphenyl)ethanone_:Resorcinol (1,3-dihydroxybenzene) (62.000 g, 563.1 mmol, 1.0 equiv.) and 4- Hydroxyphenyl acetic acid (94.237 619.4 mmol, 1.1 equiv.) were added to a 3 neck 2 L round bottomed flask fitted with a paddle, a pressure equalizing addition funnel and a thermometer and a heating mantle. Toluene (350 mL) was added to the flask to give a suspension. The reaction purged with nitrogen and the addition funnel filled with Boron trifluoride etherate (198.201 ml, 1578.0 mmol, 2.8 equiv.) via canula. The reaction was stirred at 150 rpm and boron trifluoride etherate was added in portions of 3-4 mL and the reaction heated. During addition the internal temperature rose to 100 C. The reaction went through various changes in color from yellow to dark red. After complete addition of boron trifluoride etherate the addition funnel was removed and replaced with a condenser. The reaction was stirred for 1.5 h at an internal temperature of 108 C. A sample was taken and HPLC analysis indicated the reaction was complete. The reaction was cooled and stirring stopped to give a biphasic solution. A 12 % aqueous solution of sodium acetate (41 g, 336 mL) was slowly added to the reaction with stirring. The reaction was stirred for 16 hours. A precipitate formed overnight and was collected in a sintered glass funnel. The solid was dried on a vacuum oven for 16 h to give the product as a white powder (119.67 g, 87.0 %).
With boron trifluoride diethyl etherate; In toluene; at 100℃; for 1h;
Step A: BF3.Et2O, toluene; 100 C.; 1 hour
With boron trifluoride diethyl etherate; at 95℃;Inert atmosphere;
General procedure: 12.5 mL of BF3-Et2O was added under nitrogen atmosphere to a mixture of resorcinol (550 mg, 5 mmol) and the appropriate phenylacetic acid (5 mmol). The solution was heated for 3-5 h in an oil bath at 95 oC, poured onto an ice-water mixture and extracted with ethyl acetate. The combined extracts were washed with water, brine, dried (Na2SO4) and evaporated in vacuo. The oily residue was purified by flash column chromatography on silica gel using as eluents CH2Cl2/MeOH to afford the respective deoxybenzoins 1-5 (yield 45-90%) as white solids.
With boron trifluoride diethyl etherate; In toluene; at 100℃; for 1h;
BF3.Et2O, toluene; 100 C.; 1 hour.
With boron trifluoride diethyl etherate; In toluene; at 100℃; for 1h;
With boron trifluoride diethyl etherate at 110℃; for 0.5h; Heating / reflux;
1.1
Stepl l-(2,4-Dihydroxy-3-methyl-phenyI)-2-(4-hydroxy-phenyl)-ethanone; EPO 2-Methylresorcinol (4.0Og, 1 equivalent) and 4-Hydroxyphenylacetic acid (5.0Og, 1 equivalent) were added to a round bottom flask. The round bottom flask was attached to a condenser and placed in an oil bath, the whole system was kept under nitrogen. Distilled BF3OEt2 (20ml, 5 equiv.) was added to the mixture while stirring. The mixture was refluxed (HO0C). A yellow solid formed at 20 minutes indicating that the reaction had gone to completion. The reaction was left on heat for a further 10 minutes and then cooled to room temperature. The yellow solid was collected by suction filtration and washed with distilled water (200ml) to remove any excess BF3OEt2 present. 1H NMR in d-DMSO indicated the yellow solid was l-(254-Dihydroxy-3-methyl-phenyl)-2-(4-hydroxy-phenyl)- ethanone in >95% purity. The solid was dried on a freeze dryer for 24hours (8.93g, 99%).
97%
With boron trifluoride diethyl etherate at 60 - 70℃; for 5h;
With boron trifluoride diethyl etherate at 110℃; for 2h; Inert atmosphere;
With ascorbic acid In aq. phosphate buffer at 25℃;
2.5. Reaction to produce 3,4-dihydroxyphenylacetic acid (DHPAA) from 4-hydroxyphenylacetic acid (HPAA)
A typical reaction was started by addition of 15.0 mg of tyrosinaseCLEAs into 20.0 mL of Na phosphate buffer (50 mM, pH 6.0) containing10.0mM HPAA and 15.0mM L-ascorbic acid in a 50 mL conical flask,which was placed in a shaking incubator with agitation of 200 rpm at25 °C. Periodically, a 0.15 mL sample was taken which was then fourtimes diluted with the buffer before subjected to HPLC analysis as describedbelow.
98%
With Agaricus bisporus; oxygen In aq. phosphate buffer; dichloromethane at 25℃; for 24h;
4.8 Oxidation of phenols and esters derivatives
General procedure: The reactions were performed under both homogeneous and heterogeneous conditions in CH2Cl2/buffer. As a general procedure, phenol (0.05mmol), tyrosinase (600IU) and the optimal amount of the Na-phosphate buffer 0.1M, pH 7 (CH2Cl2/buffer ratio ca. 1:0.1) were suspended in CH2Cl2 (2.5mL) at 25°C for 24h, and the mixture stirred under O2 atmosphere. The reactions were monitored by thin layer chromatography (TLC, n-hexane/EtOAc=2.0:1.0). After the disappearance of the substrate, the organic layer was recovered (eventually after filtration for immobilized enzyme), and evaporated under reduced pressure. The crude was treated with Na2S2O4 in equal volume of H2O and THF (2.0mL) with stirring for 5min. The mixture was diluted with EtOAc (4.0mL) and separated from H2O. The organic layer was dried on anhydrous Na2SO4 and evaporated under reduced pressure. When necessary the crude was purified by flash-chromatography. The products were characterized by 1H and 13C NMR, GC-MS (after silylation) and Elemental Analysis. GC-MS analysis was performed on a GC-MS QP5050 Shimadzu apparatus using an SPB column (25m×0.25mm and 0.25mm film thickness) and an isothermal temperature profile of 100°C for 2min, followed by a 10°Cmin-1 temperature gradient to 280°C for 25min. The injector temperature was 280°C. Chromatography-grade helium was used as the carrier gas with a flow of 2.7 mL×min-1. Mass spectra were recorded with an electron beam of 70eV. Quantitative analyses were performed by using dodecane as the internal standard. MS values are referred to full silylated derivatives with the only exception of 3c and 3d.
91%
With sodium dihydrogenphosphate at 25℃; for 0.25h; Glovebox;
88%
With Agaricus bisporus tyrosinase; oxygen; ascorbic acid In water at 20℃; for 24h; Na-phosphate buffer; Enzymatic reaction;
4.10. Phenols oxidation
General procedure: A panel of phenols (Fig. 7) were oxidized, including para-cresol 1, 4-ethyl phenol 2, 4-tert-butyl phenol 3, 4-sec-butyl phenol 4, 2,4-di-tert-butyl phenol 5, meta-cresol 6, 3,4-dimethyl phenol 7, 4-chloro phenol 8, 4-chloro-2-methyl phenol 9, 2-methoxy-4-methyl phenol 10, 2-methoxy phenol 11, 3-(4-hydroxyphenyl)propionic acid 12, 4-hydroxyphenylacetic acid 13, bis(4-hydroxyphenyl)methane 14 and tyrosol 15. As a general procedure phenol (0.05 mmol), tyrosinases (263-526 IU) and AA (1.5 equiv) were placed in 0.1 M Na-phosphate buffer pH 7.0 (5.0 mL) in vigorous stirring at room temperature. For insoluble aqueous phenols 3, 5, 14 substrates were dissolved in CH3CN (1.0 mL) and then added to the buffer solutions. Oxidations were performed using homogeneous and heterogeneous conditions. Reactions were monitored by thin layer chromatography (TLC). After the disappearance of the substrate, the reaction mixture was acidified with a solution of HCl 1.0 N and extracted twice with EtOAc. The organic extracts were treated with a saturated solution of NaCl and dried over anhydrous Na2SO4, then filtered and concentrated under vacuum to yield a colored crude. In the case of immobilized enzyme, biocatalyst was first recovered by filtration and the solution was subjected to the same work up described above. The obtained colored residue was treated with pyridine, HMDS and TMCS (HMDS-TMCS, 2:1 v/v) under vigorous stirring at room temperature for 30 min, then allowed to stand for 5 min.50 All products were identified by 1H NMR, 13C NMR and GC-MS. 1H NMR and 13C NMR were recorded on a Bruker 200 MHz spectrometer using CDCl3 as solvent. All chemical shift are expressed in parts per million (δ scale). GC-MS analysis were performed on a GCMS-QP5050 Shimadzu apparatus using a SPB column (25 m × 0.25 mm and 0.25 mm film thickness) and an isothermal temperature profile of 100 °C for 2 min, followed by a 10 °C/min temperature gradient to 280 °C for 25 min. The injector temperature was 280 °C. Chromatography-grade helium was used as the carrier gas with a flow of 2.7 mL/min. Mass spectra were recorded with an electron beam of 70 eV.
56%
With oxygen; ascorbic acid In aq. buffer at 30℃; for 4.4h; Enzymatic reaction;
2.6.2. Production of DHPAA without in situ adsorption
To examine the tyrosinase catalyzed production of DHPAA, dif-ferent amounts (0.1-0.9 g) of various matrix capsules (17-83 mgcdw/g, d = 0.9-1.3 mm) were incubated in 9 ml substrate solution(5 mM HPAA, 0-25 mM ascorbic acid, 0.1 M MES with pH 6 adjustedto with NaOH) under stirring and aeration at 30C. At certain timeintervals samples of the solution were withdrawn and the concen-trations of HPAA and DHPAA were quantified by HPLC. The yieldof DHPAA in these experiments was determined as the percent-age ratio of the amount of DHPAA in the reaction medium and theamount of HPAA initially used.
In various solvent(s) at 30℃; for 170h; biosynthesis by Trichosporon cutaneum strains, other incubation times;
With mushroom tyrosinase In N,N-dimethyl-formamide at 25℃; aq. phosphate buffer; Enzymatic reaction;
With HpaB from Escherichia coli; sodium formate; flavin adenine dinucleotide; NADH; sodium chloride In aq. buffer at 35℃; Enzymatic reaction;
With hydrogenchloride; sodium hydroxide; In ethanol; water;
(1) 4-benzyloxyphenylacetic acid (b): At first, 291 g (1.91 moles) of 4-hydroxyphenylacetic acid (a) was added to a mixture of 161 g (4.02 moles) of sodium hydroxide, 250 ml of water and 800 ml of ethanol to prepare a homogeneous solution. Then, 240 ml (2.00 moles) of benzyl bromide was added dropwise to the solution at room temperature, and the solution as such was stirred overnight. Deposited white crystal was separated by filtration, washed with 200 ml of concentrated hydrochloric acid and then with 300 ml of water, and dried at 80 C. under reduced pressure to obtain 411 g of white crystal (yield-1). On the other hand, 500 ml of concentrated hydrochloric acid was added to the filtrate, and the resultant white precipitates were separated by filtration, washed with 200 ml of water, and dried at 80 C. under reduced pressure to obtain 50 g of the compound (b) as white crystal (yield-2). Sum of yield-1 and yield-2 was 461 g (99.4%). Melting point: 121-123 C. 1 H--NMR (CDCl3): delta10.9(bs, 1H), 7.4-6.7(m, 4H), 7.33 (s, 5H), 5.00(s, 2H), 3.53(s, 2H).
With boron trifluoride diethyl etherate; for 0.25h;Heating / reflux;
A mixture of 4-methoxyresorcinol (1.3 g, 9.29 mmol) and 4-hydroxyphenylacetic acid (1.27 g, 8.36 mmol) in BF3.Et2O (6.85 ml, 55.7 mmol) was heated at reflux temperature for 15 min under N2. After cooling to room temperature, the dark solution was poured into saturated aqueous sodium acetate (100 ml) and extracted with ethyl acetate (3×50 ml). The combined ethyl acetate layer was washed with 10% aq. NaHCO3 (50 ml) and water (100 ml), respectively, and dried with MgSO4. The solvent was evaporated under reduced pressure, and the dark brown oil was subjected to chromatography (CH2Cl2: EtOAc=8:2) to give the title compound as a yellow solid (1.1 g, 48%), mp 157-159 C. 1H NMR (300 MHz, DMSO-d6) delta 12.38 (s, 1H, OH), 10.48 (br s, 1H, OH), 9.29 (br s, 1H, OH), 7.40 (s, 1H, H-6), 7.08 (d, J=8.6 Hz, 2H, H-2', 6'), 6.69 (d, J=8.6 Hz, 2H, H-3', 5'), 6.30 (s, 1H, H-3), 4.16 (s, 2H, CH2), 3.76 (s, 1H, OCH3); 13C NMR (75 MHz, DMSO-d6) delta 202.2 (C-CO), 159.3 (C-4), 156.0 (C-4'), 155.4 (C-2), 141.0 (C-5), 130.4 (C-2',6'), 125.3 (C-1'), 115.6 (C-3',5'), 113.3 (C-6), 110.3 (C-1), 103.2 (C-2), 56.3 (C-OCH3), 43.6 (C-CH2). m/z=275 (M++1, 100%), 274 (16), 257 (9), 167 (18), 212; HRMS: C15H14O5 requires 274.9841 found 274.0829.
EDC (dimethylaminopropyl ethylcarbodiimide hydrochloride)[ No CAS ]
[ 156-38-7 ]
[ 32566-01-1 ]
[ 677297-11-9 ]
Yield
Reaction Conditions
Operation in experiment
In methanol; hexane; ethyl acetate; acetonitrile;
2-(4-Hydroxy-phenyl)-N-[2-(1H-indol-2-yl)-phenyl]-acetamide 1 g (4.8 mmol) 2-(2-Aminophenyl) indole was dissolved in 200 ml acetonitrile. 1.46 g (9.6 mmol, 2 eq) of 4-hydroxyphenylacetic acid were dissolved in 50 ml acetonitrile and added to the solution. To the mixture were added 1.84 g (9.6 mmol, 2 eq) of EDC (dimethylaminopropyl ethylcarbodiimide hydrochloride). The reaction mixture was stirred at 23 C. for 16 hours. The solvent was removed and the residue was dissolved in 100 ml ethylacetate:methanol (10:1). It was extracted twice with 100 ml of aqueous 1M HCl as well as 100 ml of aqueous, saturated sodium bicarbonate solution. The aqueous phases were re-extracted with EtOAc, respectively. The combined organic phases were dried over magnesium sulfate. The crude product was chromatographed on silica using a ethylacetate/hexane gradient (10%-50%) to obtain 1.23 g of the amide as a pink colored powder in an overall yield of 75%. 100% Purity by LC/MS (230 DAD) Mass-spec [M+H+]=343.9 1H NMR (MeOH-d4): 3.60 s (2H), 6.10 s (1H), 6.70 d, 8 Hz (2H), 7.03 t, 8 Hz (1H), 7.09-7.13 m (3H), 7.25 t, 7 Hz (1H), 7.34 m (2H), 7.49 d, 8 Hz (1H), 7.53 d, 8 Hz (1H), 7.95 d, 8 Hz (1H).
Into an Erlenmyer flask were poured p-hydroxyphenylacetic acid (1.52 g) and ethylace tate (50 ml).Into the flask was dropwise added a solution of amlopidine (4.0 g) in ethylacetate (100 ml), followed by stirring the solution at 23 C. for 3 hours to give precipitates.After being filtered off, the precipitates were washed with ethylacetate (50 ml) and then with hexane (50 ml) and dried at 23 C. under vacuum to allow 5.1 g of amlopidine p-hydroxyphenyacetate as a crystalline solid (Yield 92%). The element analysis and melting point of the amlodipine p-hydroxyphenylacetate prepared above were determined.
92%
In ethyl acetate; at 23℃; for 3h;
[INTO ALVERLENMYER FLASK_WERE POURED P-HYDROXYPHENYLACETIC] acid (1. [52 G)-AND-] ethylace tate (50 [ML).] Into the flask was dropwise added a solution of amlopidine (4. [0G)] in ethylacetate (100 ml), followed by stirring the solution at [23 C] for 3 hours to give precipitates. After being filtered off, the precipitates were washed with ethylacetate (50 ml) and then with hexane (50 [ML)] and dried at [23 C] under vacuum to allow 5.1 g of amlopidine p-hydroxyphenyacetate as a crystalline solid (Yield 92%).
6-O-p-OH-phenylacetyl-[(2-hydroxymethyl)phenyl]-β-D-glucopyranoside[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17%
With immobilized lipase B; In tert-butyl alcohol; at 60℃; for 34.0h;
5 mmol <strong>[138-52-3]D-(-)-salicin</strong> [2-hydroxymethyl)phenyl-delta-D-glucopyranoside], 7.5 mmol p-OH-phenylacetic acid, 4 g molecular sieve, 4 ml t-butanol and 2.5 g immobilized lipase B from Candida antarctica were incubated for 34 hours at 60 C. in a rotating 50 ml round-bottom flask. The reaction was monitored by thin-layer chromatography (silica gel 60 plates with fluorescence indicator; mobile solvent: chloroform/methanol/water 65/15/2 v/v/v; visualization: UV detection and with acetic acid/sulfuric acid/anisaldehyde (100:2:1 v/v/v) immersion reagent). The product was extracted with 20 ml of dichloromethane and purified by column chromatography (silica gel F60; mobile solvent: ethyl acetate/methanol 10/1 v/v). After purification, the yield was 17% (white solid). 13C-NMR (CD3OD): delta (ppm)=41.8 (C-2), 61.0 (C-7*), 65.0 (C-6'), 71.5 (C-4'), 74.9 (C-2'), 75.4 (C-5'), 77.8 (C-3'), 103.2 (C-1'), 117.1 (C-6*), 123.9 (C-4*), 129.4-132.3 (C-2*, C-3*, C-5*; C-4, C-5, C-7, C-8), 136.1 (C-3), 156.0-159.2 (C-1*, C-6), 173.31 (CO).
With caesium carbonate; In dimethyl sulfoxide; at 100℃;
Intermediate 87a: [4- (7-METHOXY-QUINOLIN-4-YLOXY)-PHENYL]-ACETIC acid A mixture of 4-CHLORO-7-METHOXY-QUINOLINE (200 mg, 1.036 MMOL), 4-HYDROXYPHENYLACETIC acid (158 mg, 1.036 MMOL), and Cs2CO3 (1.02 g, 3.11 MMOL) IN 2 mL of DMSO was heated at 100°C overnight. The mixture was then cooled to room temperature. EtOAc and water were added. The aqueous layer was acidified with 1 N HCI until a precipitate was formed. The solid was filtered and washed with water. The solid was dried in a vacuum-oven at 60°C overnight. The intermediate 87a (160 mg) was obtained as A brown solid NMR (300 MHz, CD30D) 8 8.63 (s, 1H), 8.39 (d, 1H, J= 9.04 Hz), 7.47-7. 28 (m, 4H), 7.16 (d, 2H, J= 7.72 Hz), 6.76 (s, 1H), 3.93 (s, 3H), 3.58 (s, 2H). LCMS (ESI+) [M+H]/Z Calc'd 310, found 310.
With sodium hydroxide; NaH; In water; N,N-dimethyl-formamide;
EXAMPLE 9 4-benzyloxyphenylacetic acid To a stirred slurry of 10 g (200 mmol) 60% NaH in oil (which had been washed with hexane) in 100 mL dry DMF under N2 atmosphere at 25 C. was added a solution of 15.2 g (100 mmol) of 4-hydroxyphenylacetic acid in 100 mL dry DMF over a 30 min. period. After addition was complete, the mixture was heated at 50 C. for 6 hours, 23.8 mL of benzyl bromide (200 mmol) was added at 40 C. and the mixture was stirred at 25 C. for 48 hours. The solvent was removed in vacuo and the residue partitioned between 400 mL EtOAc and 100 mL H2 O. The organic extract was washed repeatedly with H2O, dried over MgSO4 and concentrated to give 34 g of a tan solid. The crude ether ester was dissolved in 200 mL 95% EtOH and 8 g (200 mmol) solid NaOH was added. The solution was refluxed for 10 hours and the excess solvent was removed in vacuo. The residue was dissolved in H2 O, washed with ether, filtered, and acidified to pH=2. The solid was collected and vacuum dried to give 20.1 g (85 mmol) of acid; 1 H-NMR (DMSO) ppm delta 7.31 (M, 5 H) 7.14 (d, 2 H, J=7 Hz), 6.84 (d, 2 H, J=7 Hz), 5.15 (bs, 1 H), 5.02 (s, 2 H), 3.39 (s, 2 H).
Example 1 Synthesis of the Intermediate 4-(2-Carboxybenzyloxy)Phenylacetic Acid (Olo-IM1) A solution of 4-hydroxyphenylacetic acid (90.0 g, 0.58 mol; assay >98%) and phthalide (85.07 g, 0.63 mol) in DMF (323 g) was heated to an internal temperature of 130 C. The pressure was reduced to 800 mbar and sodium methoxide (224.6 g, 1.25 mol, assay: 30% methanolic solution) was added slowly to the mixture maintaining the internal temperature above 100 C. During the addition methanol was distilled off, and after the addition the distillation was continued under normal pressure until the internal temperature increased to 130 C. again (260 g distillate). After stirring at this temperature for 6.5 h, phthalide (8.5 g, 0.06 mol) was added and the mixture was stirred overnight (16 h). Afterwards the mixture was cooled to 100 C. and hydrolyzed with water (1040 g). After cooling to <10 C., the pH of the mixture was adjusted to pH 1 with hydrochloric acid (163.5 g, 1.43 mol; assay: 32%). The product was filtered off, washed with water (700 g) and dried under vacuum for 15 hours at 60 C. to give crude 4-(2-carboxybenzyloxy)phenylacetic acid (Olo-IM1) (yield: 174.6 g, 0.48 mol, 82.1%; HPLC assay: 78.0%). The crude Olo-IM1 (50.0 g, assay: 78.0%, 0.14 mol) was recrystallized from acetonitrile/water (40 ml, 1/1). After filtration, the wet product washed successively with acetonitrile/water (98 ml, 1/1) and water (20 ml) to give slightly orange colored 4-(2-carboxybenzyloxy)phenylacetic acid (Olo-IM1) (yield: 35.27 g, 0.12 mol, 88.1%; HPLC assay: 97.4%; overall yield: 72.3%).
With sodium hydroxide; In water; benzene;
Step A 4-(2-Carboxybenzyloxy)phenylacetic Acid Prepare the disodium salt of p-hydroxyphenylacetic acid by mixing 15 ml. of 40% aqueous sodium hydroxide and 11.41 gm. of p-hydroxyphenylacetic acid. Evaporate the mixture to dryness and treat with benzene to eliminate residual water. Evaporate to dryness. Stir the solid residue with 10 gm. of phthalide at 180 C. for 30 minutes, then at 210 C. for 2.5 hours. Cool and dissolve in 300 ml. of water. Acidify with hydrochloric acid and separate the precipitate by filtration to obtain the title product as a cream colored solid (m.p. 171-174 C. lit. 181-183 C., cryst.).
Example 10: Preparation of 2-((4-(carboxymethyl)phenoxy)methyl)benzoic acid compound of formula-7A mixture of p-hydroxy phenylacetic acid (50 g), dimethylformamide (180 ml) and phthalide (47 g) was heated to 130-135C for about 45 minutes and then cooled to 120-125C. 25% methanolic sodium methoxide (136 g) was added to the reaction mixture slowly at 120-125C and then stirred for 10 minutes at 120-125C. Distilled off methanol completely from the reaction mixture and then heated the reaction mixture to 130-135C. Phthalide (10 g) was added to the reaction mixture and stirred for 12 hours at 130-135C. The reaction mixture was cooled to 5-10C and then quenched it with 10% hydrochloric acid. Water was added to the reaction mixture and temperature of the reaction mixture was raised to 25-30C. Stirred the reaction mixture for 45 minutes at 25- 30C. Filtered the precipitated solid, washed with water and then dried to get the title compound. Cyclohexane (250 ml) was added to the obtained solid. Heated the reaction mixture to 75-80C and stirred for 45 minutes at same temperature. Cooled the reaction mixture to 25-30C. Filtered the solid, washed with cyclohexane and then dried to get the pure title compound.Yield: 80 grams;MR: 172-175C
EXAMPLE 1 4,5-Dichloro-2-phenyl-pyridazinone (2.41 g), 4-hydroxyphenyl-acetic acid (1.0 g) and 20% aqueous ammonia (20 ml) were heated to 100-110 C. with stirring in a small autoclave for 4 hours. The reaction mixture was then cooled to room temperature, and the resulting precipitate of 4-chloro-5-amino-2-phenyl-3(2H)-pyridazinone was isolated by filtration, washed with water and dried. 1.86 g of pure 4-chloro-5-amino-2-phenyl-3(2H)-pyridazinone were obtained, m.p. 206-207 C.
EXAMPLE 5 In accordance with the process of Example 1, a reaction of methyl 4-chlorophenylacetate with sodium hydroxide was performed in the presence of bis(8-quinolinolate) copper (II) complex. The amount of methyl 4-chlorophenylacetate was 18.5 g. (0.1 mol) and the amount of 13% aqueous solution of sodium hydroxide was 185 g. (0.6 mol) and the other condition was the same as that of Example 1. The reaction mixture was treated by the same process to obtain 14.6 g. of a white platy crystal of 4-hydroxyphenylacetic acid having a melting point of 148-149 C. (yield of 96%).
EXAMPLE 19 1-Adamantaneethanol (10 g, 0.05 mol), 4-hydroxyphenylacetic acid (8.43 g, 0.05 mol) and p-toluenesulfonic acid (1 g, 0.006 mol) were refluxed in benzene (100 mL) with continuous water separation for 8 hours, then allowed to stir overnight. The residue was washed, first with 5% aqueous sodium bicarbonate solution (50 mL) and then twice with water (50 mL), then was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo. The product, (adamant-1-yl)ethyl 4-hydroxyphenylacetate, was taken up in epichlorohydrin (50 mL) and refluxed for 2 hours in the presence of DBU (1 mL, 0.007 mol).
EXAMPLE 20 <strong>[770-71-8]1-Adamantanemethanol</strong> (8.31 g, 0.05 mol), 4-hydroxyphenylacetic acid (7.6 g, 0.05 mol) and p-toluenesulfonic acid (1 g, 0.006 mol) were refluxed in benzene (100 mL) with continuous water separation for 8 hous. The reaction mixture was allowed to cool with stirring overnight, then was washed, first with water (100 mL), then with aqueous 5% NaHCO3 solution (100 mL), then twice more with water (100 mL). Drying over anhydrous MgSO4, filtering and concentrating in vacuo afforded (adamant-1-yl)methyl 4-hydroxyphenylacetate, which was then combined with epichlorohydrin (50 mL) and refluxed for 2 hours in the presence of DBU (1 mL, 0.007 mol).
2-[4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)phenyl]acetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A mixture of <strong>[417721-36-9]4-chloro-7-methoxyquinoline-6-carboxamide</strong> (1.26 g), 5 2-(4-hydroxyphenyl)acetic acid (0.85 g), caesium carbonate (5.47 g) and DMF (15 ml) was stirred and heated to 1000C for 14 hours. The mixture was cooled to ambient temperature and diethyl ether (50 ml) was added. The precipitate was isolated and dissolved in water and the solution was acidified to pH4.5 by the addition of 6N aqueous hydrochloric acid. The resultant precipitate was isolated, washed with water and with diethyl ether and dried under 0 vacuum. There was thus obtained the required starting material (0.98 g); 1HNMR: (DMSOd6) 4.04 (s, 3H), 6.48 (d, IH), 7.25 (d, 2H)5 7.42 (d, 2H), 7.52 (s, IH), 7.73 (br s, IH), 7.86 (br s, <n="135"/>IH)5 8.67 (m, 2H); Mass Spectrum: M+H+353.
Step-1Preparation of 2-[4-(acetyloxy)phenyl]-3-(3-methyl-4-fluorophenyl)acrylic acidA mixture of <strong>[135427-08-6]3-methyl-4-fluorobenzaldehyde</strong> (2 g, 14.4 mmol) and 4- hydroxyphenylacetic acid (2.2 g, 14.4 mmol) was dissolved under stirring with acetic anhydride (8 mL). DIPEA (diisopropylethyl amine) (6.5 mL, 50.5 mmol) was added to the reaction mixture dropwise and stirred for 12 hours. Upon completion (as monitored by TLC using 1 :1 hexane: ethyl acetate as eluent), the reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (75 mL x 2). The combined ethyl acetate layers were washed with water (two times), dried over anhydrous Na2SO4, concentrated and dried to afford a sticky compound (4.34 g, 96 % yield).
96%
With N-ethyl-N,N-diisopropylamine;
Step-1 Preparation of 2-[4-(acetyloxy)phenyl]-3-(3-methyl-4-fluorophenyl)acrylic acid A mixture of <strong>[135427-08-6]3-methyl-4-fluorobenzaldehyde</strong> (2 g, 14.4 mmol) and 4-hydroxyphenylacetic acid (2.2 g, 14.4 mmol) was dissolved under stirring with acetic anhydride (8 mL). DIPEA (diisopropylethyl amine) (6.5 mL, 50.5 mmol) was added to the reaction mixture dropwise and stirred for 12 hours. Upon completion (as monitored by TLC using 1:1 hexane:ethyl acetate as eluent), the reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (75 mL*2). The combined ethyl acetate layers were washed with water (two times), dried over anhydrous Na2SO4, concentrated and dried to afford a sticky compound (4.34 g, 96% yield).
Stage #1: 4-hydroxyphenylacetate; N-(3-aminopropyl)-1,4-diaminobutane With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 22h; Inert atmosphere;
Stage #2: trifluoroacetic acid In methanol; water
General procedure for preparation of amide analogues 1-21
General procedure: To a solution of the appropriate carboxylic acid (2 equiv.), diamine (1 equiv.) and PyBOP (2 equiv.) in DMF (1.0 mL) was added TEA (6 equiv.). The reaction mixture was allowed to stir under N2 at room temperature for 22 h. The crude product was concentrated under vacuum and subjected to purification by combinations of reversed-phase C2, C8 and/or C18 flash column chromatography using H2O (+0.05% TFA) - MeOH solvent mixtures.
N,N'-(3,3'-(butane-1,4-diylbis(azanediyl))bis(propane-3,1-diyl))bis(2-(4-hydroxyphenyl)acetamide) di(trifluoroacetic acid) salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
General procedure: To a solution of the appropriate carboxylic acid (2 equiv.), diamine (1 equiv.) and PyBOP (2 equiv.) in DMF (1.0 mL) was added TEA (6 equiv.). The reaction mixture was allowed to stir under N2 at room temperature for 22 h. The crude product was concentrated under vacuum and subjected to purification by combinations of reversed-phase C2, C8 and/or C18 flash column chromatography using H2O (+0.05% TFA) - MeOH solvent mixtures.
With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 1h;
6.a (a) N-((4-chlorophenyl)(phenyl)methyl)-2-(4-hydroxyphenyl)acetamide
To a solution of (4-chlorophenyl)(phenyl)methanamine (3.0 g, 11.8 mmol) in DMF (15.0 mL) was added DMAP (2.62 g, 21.4 mmol), EDC (2.72 g, 14.1 mmol), HOBt (2.17 g, 14.1 mmol) followed by 2-(4-hydroxyphenyl)acetic acid (1.63 g, 10.7 mmol) and the reaction mixture was stirred at rt for 1 h. After completion of the reaction, the reaction mixture was concentrated, diluted with EtOAc (50 mL), washed with water (25 mL) and brine (25 mL). After drying (Na2SO4) and conceniration of the combined organic layers, the product was purified by silica gel column chromatography (40% EtOAc/Hexane) to provide the title compound (4.5 g, 65.2%). MS (ESI+) 352.0 [M + H]. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.25 (s, 1H), 8.94-8.96, (d, 1H), 3.37-3.39 (d, 2H), 7.28-7.34 (m, 3H), 7.24-7.26 (m, 3H), 7.04-7.06 (d, 2H), 6.65-6.67 (d, 2H), 6.07-6.09 (d, 1H), 4.08 (s, 2H).
With boron trifluoride diethyl etherate; for 0.25h;Reflux;
[00155] A mixture of Fluoro resorcinol (2) (9 g, 70 mmol ) and 4- hydroxyphenylaceticacid (9.62 g, 63 mmol) in BF3-Et20 (26.7ml, 210 mmol ) were stirred under reflux for 15 min T. After completion of the reaction (monitored by TLC, using 30% ethyl acetate and pet ether as eluting solvent) the reaction mixture was cooled in an ice bath and poured into excess of ice-water and extracted with ethyl acetate (3 x 100 mL). The combined ethyl acetate layer was dried over anhyd Na2S04 and concentrated under vacuum to get the crude product as mixture of regioisomers. Preparative HPLC purification afforded the require isomer (3) as beige colored solid. Yield: 4.5 g (25%>).
With potassium carbonate; In acetic anhydride; at 135℃; for 5h;
A mixture of compound 10 (2.5 g, 11.7 mmol), 4-hydroxyphenyl acetic acid (3.8 g, 25.0 mmol), acetic anhydride (Ac2O, 25 mL), K2CO3 (3.0 g, 21.7 mmol) was refluxed at 135 C for 5 h. Then,the mixture was poured into 100 mL of ice water, and extracted with EtOAc (75 mL × 3). The organic layer was then sequentially washed with water, satd NaCl solution, and dried over anhydrous MgSO4, evaporated to dryness under reduced pressure. The residue was recrystalizedfrom ethanol/water to afford the white needles 11 in yield of 67%, mp 167-169 oC; 1H NMR(CDCl3, 600 MHz) delta (ppm): 7.35-7.29 (m, 3H, ArH), 7.25 (d, J = 8.4 Hz, 1H, ArH), 7.23 (d, J =2.4 Hz, 1H, ArH), 7.16 (s, 1H, ArH), 7.14-7.12 (m, 3H, ArH), 6.99-6.94 (m, 3H, ArH), 2.37 (s,3H, CH3), 2.26 (s, 3H, CH3); MS (ESI), m/z: 437 ([M+Na]+); Anal. Calcd for C25H18O6: C, 72.46;H, 4.38. Found: C, 72.55; H, 4.51.
With dihydrogen peroxide In water at 24.84℃; Green chemistry;
2.3. Phenyl acetic acid conversion
Phenylacetic acid oxidation was carried out in a 100 mlPyrex reactor equipped with a magnetic stirrer. The solidcatalystwas introduced into 50mL of PAA aqueous solution(500 mg L1), under continuous stirring. The desiredquantity of H2O2 (0.02 M) was added indicating the start ofthe reaction. During the experiments, aliquots were withdrawnat regular intervals with the purpose of monitoringthe conversion of PAA to p-HPAA and then to 3,4-DHPAAafter being immediately filtered to completely removecatalyst particles.
4-Hydroxyphenylacetic acid (40 mg, 0.263 mmol) and cinchonidine (77.4 mg, 0.263 mmol) were dissolved in isopropanol (IPA). The solution was left to evaporate and crystals were obtained after one week
4-Hydroxyphenylacetic acid(40 mg, 0.263 mmol) and cinchonidine (77.4 mg, 0.263 mmol) were both dissolved in ethyl methyl ketone. Crystals were obtained afterone week.
Reaction flask was added p-hydroxyphenyl acetic acid (150mmol) 22.67g, potassium hydroxide (200mmol) 11.22g, 90ml of methanol, stirred for 1 hour at room temperature, was added 2- (chloromethyl) benzoic acid (100mmol) 17.06g, heated at reflux The reaction, after the reaction was monitored by TLC, the solvent was distilled off under reduced pressure, 200ml of dichloromethane was added to dissolve, washed with water, dried, concentrated, Eaton reagent was added 7.5percent (mass concentration) 200ml, was heated to 80 deg.] C, stirred for 2 hours, the reaction was completed after addition of saturated sodium carbonate solution, filtration, and recrystallized from ethanol to give Isoxepac (79.3mmol) 21.27g, yield 79.3percent, HPLC purity of 99.9percent.
4-((4-methoxy-1H-benzo[d]imidazol-2-yl)methyl)phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In water; for 16h;Reflux;
General procedure: To a solution of the corresponding substituted alkyloxybenzene-1,2-diamine 4 (2.26 mmol) in 6N HCl (10 mL), corresponding acid 5 (6.80 mmol) was added. The resulting solution was refluxed for 16 h. The reaction mixture was cooled to 0 C, diluted with EtOAc, and then pH was adjusted to ~ 7 by using solid NaHCO3, extracted with EtOAc. The combined organic extracts were washed with brine solution, dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The crude mixture was subjected to flash silica gel (230-400 mesh) column chromatography to afford the title compounds 6a-f and 6h-s.
4-((4-(benzyloxy)-1H-benzo[d]imidazol-2-yl)methyl)phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22%
With boric acid; In 5,5-dimethyl-1,3-cyclohexadiene; for 48.0h;Reflux;
To a stirred solution of <strong>[89521-55-1]3-(benzyloxy)benzene-1,2-diamine</strong> 4g (4.67 mmol) in xylenes (10 mL), 2-(4-hydroxyphenyl) acetic acid (9.34 mmol) and boric acid (0.46 mmol) were added. The resulting solution was refluxed for 48 h. After cooling to room temperature, the reaction was concentrated under reduced pressure and diluted with EtOAc. The organic phase was washed with saturated NaHCO3 solution, dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by flash silica gel (230-400 mesh) column chromatography to afford the title compounds 6g. Yield 22%; White solid; mp 105-109 C; IR (neat) 3400-2600 (br., peak), 2921, 2850, 1594, 1515, 1442, 1245, 1172,1098, 1022, 837, 784, 732; 1H NMR (300 MHz, Methanol-d4) δ 7.46-7.57 (m, 2H), 7.26-7.40 (m, 3H), 7.06-7.14 (m,4H), 6.75-6.80 (m, 1H), 6.68-6.74 (m, 2H), 5.23 (s, 2H),4.08 (s, 2H); 13C NMR (100 MHz, Methanol-d4) δ 157.7,155.3, 149.1, 138.9, 131.0, 129.7, 129.4, 129.2, 129.1,124.1, 116.8, 116.7, 108.8, 105.7, 71.6, 35.2; HRMS (ESI) Calcd for C21H18N2O2 [M + H]+ 331.1446, found 331.1471.
2-(4-hydroxybenzyl)-1H-benzo[d]imidazol-4-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In water; for 16h;Reflux;
General procedure: To a solution of the corresponding substituted alkyloxybenzene-1,2-diamine 4 (2.26 mmol) in 6N HCl (10 mL), corresponding acid 5 (6.80 mmol) was added. The resulting solution was refluxed for 16 h. The reaction mixture was cooled to 0 °C, diluted with EtOAc, and then pH was adjusted to ~ 7 by using solid NaHCO3, extracted with EtOAc. The combined organic extracts were washed with brine solution, dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The crude mixture was subjected to flash silica gel (230?400 mesh) column chromatography to afford the title compounds 6a?f and 6h?s.
A, condensation reaction:Step 1: Check the reaction kettle, dry and anhydrous, 75kg of p-hydroxyphenylacetic acid, 75kg of resorcinol and 50kg of zinc chloride are added to the reaction kettle, the reactor is 200L enamel kettle, Heating the steam, the bottom of the material began to melt when the start of mixing, the kettle material after the whole solution, start the vacuum valve, control the vacuum at 0.08MPa or more, the temperature control at 140 , the reaction for 20 minutes, after the end of the reaction closed the vacuum valve;Step 2: Add 150L of dissolved water to the reaction. The reactor was cooled by cold water until the temperature in the autoclave reached below 30 . The crystals were stirred for 2 hours, dried in a centrifuge and the mother liquor was collected. Water washing and then into the centrifuge in the dry, get a condensate one, and collect the washing liquid;Step 3: The mother liquor and lotion are added to the reaction kettle, the steam in the interlayer is heated and the vacuum valve is started. The vacuum degree is controlled above 0.08MPa, the temperature is controlled at 140 , the reaction is carried out for 20 minutes, and the vacuum valve is closed after the reaction.Step 4: Add 150L of dissolved water to the reaction, and the reactor interlayer is cooled by cold water until the temperature inside the autoclave reaches below 30 C. The crystals are stirred for 2 hours, dried in a centrifuge and washed with 150 L of water. Into the centrifuge in the dry, get condensate two;Step 5: The condensate one and the condensate two are mixed to obtain a condensate which is dried at 100 C until the water content is 0.5% or less;B, cyclization reaction:Step 1: Check the reaction kettle, dry and anhydrous, DMF300L, 50kg of condensate, 54.5kg of triethyl orthoformate, 10kg of forest and 12kg of glacial acetic acid are added to the reaction kettle. The reactor is 500L enamel , The reaction of the reactor in the steam, the temperature control at 140 , reflux reaction 5 hours, the reactor connected to the fractionation tower, distillation reaction product ethanol recovery, distillation tower outlet temperature of 75 , first with the top of the first valve , With the amount of alcohol production and then gradually open the following valve;Step 2: After the reaction is completed, the temperature of the reactor is cooled to the temperature of the reactor to 50 or less, start the vacuum valve, keep the vacuum above 0.08MPa, and recover the dimethylformamide by distillation.Step 3: The reaction vessel was cooled to below 100 C, 240 L of ethanol dissolved in 80% volume was added, heated by steam, controlled at 140 C for 2 hours, then cooled to below 25 C, stirred for 2 hours , Into the centrifuge to dry, filter cake with 30L ethanol washing, into the centrifuge in the dry, filter cake and then washed with 100L dilute hydrochloric acid, into the centrifuge in the dry, filter cake and then wash with 300L water, put Into the centrifuge in the dry, was crude;Step 4: The crude product is dried at 93 C to a moisture content of 0.5% or less;C, refined:Step 1: Ethanol 800L was added to the reaction kettle, and the reactor was a 1000L glass-lined kettle. The dried crude product was 7 kg and the activated carbon was 2.5 kg. The autoclave was heated in a temperature range of 140C, Hour, material one;Step 2: the material in a vacuum of 0.06MPa above the conditions of the filter with the filter filter, the material two, filter with the bottom of the filter canvas double layer pad, the penultimate layer for the white cloth pad, the penultimate Layer for the canvas pad, the top layer for the canvas bag;Step three: the material two at 140 under the conditions of steam, steamed to the remaining material to 70L when the stop the steam, the material was cooled three;Step four: the material three into the centrifuge in the dry, filter cake washed with 10L water, then into the centrifuge in the dry, and then 10L water washing, drying after the material four;Step five: the material four at 93 under the conditions of drying to a moisture content of 0.5% or less, was fine
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In dichloromethane; for 6h;
2- (4-Hydroxyphenyl) acetic acid 9a (5 g, 33 mmol) was dissolved in 150 mL of dichloromethane,2- (7-AzoBenzotriazole) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (14.74 g, 39 mol),Methylamine (19.7 ml, 39 mol)And triethylamine (13.7 mL, 98 mmol) were added and reacted for 6 hours. The reaction solution was washed with saturated sodium bicarbonate solution (200 mL × 3),Saturated sodium chloride solution (200 mL X 3), the combined organic phases were dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with siliconThe residue was purified by column chromatography on eluent System A to afford the title 2- (4-hydroxyphenyl) -N-methylacetamide% (2.77g, yellow oil), yield: 51.0%.
150 g
Condensation reaction: will be 153 g P-hydroxy-acetic acid dissolved in 200 ml in chloroform, 0 C dropping under 120 g thionyl chloride, reflux stirring 5 hours to TLC detection reaction finishes, cooling the lower is dripped into the 40% methylamine aqueous solution 800 ml in, then completing insulation stirring 2 hours, filtered, the filter cake is washed with water to, be 150 g yellow solid intermediate;
EXAMPLE 62: Trihydroxybenzoin Resorcinol (100 g, 0.91 mol) and 4-hydroxyphenylacetic acid (138.4 g, 0.91 mol) were dissolved into BF3Et2O (346 ml, 2.73 mol) under N2. The mixture was stirred and heated at 50-60C. After complete reaction, the mixture was cooled to room temperature and poured into a large volume of iced water. The crude product was filtered off and dried to yield trihydroxybenzoin (70 %). mp 211C. 1H-NMR (Acetone d6): 4.12 (s, 2H), 6.78 (d, 2H), 6.91 (d, 1H), 7.13 (d, 2H), 7.54-7.6 (m, 2H), 8.21 (s, 1H), 8.35 (s, 1H), 8.70 (s, 1H).
2-(4-hydroxyphenyl)-N-(4-octylphenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h; Inert atmosphere;
General Procedure for Synthesis of FTY720 Derivatives 2-10
General procedure: EDCI (3 eq), N,N-dimethyl-4-aminopyridine (DMAP) (0.5 eq), and the acid intermediates (1.5 eq) were added to a stirred solution of 4-n-octylaniline (100 mg, 0.49 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred under nitrogen for 12 h. The solvent was removed in vacuo and the resulting residue was purified by flash column chromatography to afford the desired products 2-10.
(S)-2-(2-(4-hydroxyphenyl)acetamido)-N-((R)-3-methyl-1-((3aS,4S ,6 S,7aR)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)butyl)-3-phenylpropanamide[ No CAS ]
3-(4-((4-bromobenzyl)oxy)phenyl)-2-(4-hydroxyphenyl)acrylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7%
With acetic anhydride; triethylamine; for 5h;Reflux;
General procedure: The titlecompounds were prepared by a Knoevenangel reaction, as shown in Scheme 1, according to literaturemethods [17-19]. A suitable aldehyde (0.015 mol) was condensed with 4-bromophenylacetic acidor 4-hydroxyphenylacetic acid (0.015 mol) and acetic acid anhydride (10 mL) in the presence oftriethylamine (5 mL). The reaction mixture was refluxed for approximately 5 h (while monitoringcompletion of the reaction). The solution was poured into 2 N HCl, and ice and the precipitate formedwas collected by filtration and recrystallized from 50% v/v aqueous ethanol. In case that no precipitatewas formed an extraction with 3 x 100 mL CHCl3 was made and the organic phase was collected,dried over MgSO4 and evaporated to dryness affording a residue that was recrystallized from 50%aqueous ethanol.
With copper(I) oxide; 1D-1-O-Methyl-muco-inostol; sodium hydroxide; In water; at 100℃; for 6h;
In the l00mL hydrothermal synthesis reactor,Add sodium hydroxide (3 mmol), water (5 mL), stir and dissolve,Add <strong>[1798-06-7]p-iodophenylacetic acid</strong> (0.5 mmol), cuprous oxide (0.05 mmol),White lignan (0.05 mmol), the reaction was stirred at 100 C for 6 hours.After cooling, the pH was adjusted to 2 with dilute hydrochloric acid and extracted with ethyl acetate.The extract is concentrated and subjected to column chromatography to obtain p-hydroxyphenylacetic acid.63.8 mg, yield 84%.
84%
With copper(I) oxide; 1-D-O-Methyl-chiro-inositol; sodium hydroxide; In water; at 100℃; for 6h;
A 100 mL hydrothermal synthesis reactor equipped with a magnetic stirring bar was charged with sodium hydroxideand water, and then stirred at ambient temperature. After the dissolution of sodium hydroxide, cuprous oxide, L-Queand aryl iodides were added. The reaction mixture was stirred at appropriate temperature until the hydrolysis of aryliodides completes by TLC analysis. Then the reaction mixture was cooled to ambient temperature, acidified by theaddition of 2 M hydrochloric acid, and extracted with ethyl acetate. The combined organic phase was dried overanhydrous magnesium sulfate and the solvent was removed under reduced pressure. The crude products were purifiedby flash column chromatography on silica gel to afford the desired product. The identity of the products was confirmedby comparison with literature melting point and spectroscopy data.
Multi-step reaction with 6 steps
1.1: sulfuric acid / 0.5 h / Reflux; Green chemistry
2.1: potassium carbonate / N,N-dimethyl-formamide / 12 h / 80 °C / Green chemistry
3.1: sodium hydroxide; water / methanol / 2 h / Reflux; Green chemistry
4.1: thionyl chloride / 1 h / Reflux; Green chemistry
4.2: 1 h / 0 °C / Green chemistry
5.1: N-Bromosuccinimide; 1,8-diazabicyclo[5.4.0]undec-7-ene / 70 °C / Green chemistry
6.1: potassium hydroxide / ethanol / Reflux; Green chemistry
With Candida antarctica lipase B immobilized on acrylic resin In hexane; butanone at 35℃; for 48h; Molecular sieve; Enzymatic reaction;
1.I Example 1: Transesterification of HPA and triglyceride
Reaction I: 10 ml of nhexane/2-butanone mixture (75:25, v/v) containing 40 mM HPA, 240 mM TON, 200 mg molecular sieve, and 1 unit (200 mg) CalB lipase. Reaction II: 5 ml of hexane/2-butanone mixture containing 40 mM HPA, 240 mM FO, 200 mg molecular sieve, and 1 unit CalB lipase (85:15, v/v). The reaction mixture was reacted at 35 °C and 210 rpm for 48 hours, and the reaction was stopped by removing the lipase from the mixture. As a result of monitoring the conversion rate over time using an optimized reaction system, the conversion rate increased up to 24 hours, and the obtained conversion rates were 87% and 59% for HPA-DON and HPA-dFO, respectively (Fig. 2c). After 24 hours, the conversion rate was stably maintained until 72 hours, and this result indicates that as the forward reaction using HPA and triglyceride proceeded, fatty acids were accumulated and the reverse reaction using HPA-diglyceride and fatty acid started. After 24 hours, the conversion rate was stably maintained until 72 hours, and this result indicates that as the forward reaction using HPA and triglyceride proceeded, fatty acids were accumulated and the reverse reaction using HPA-diglyceride and fatty acid started.
N-(3,5-dibromophenyl)-2-(4-hydroxyphenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
With Orthoboric acid In toluene at 140℃; for 12h;
4.2.1. N-(3,5-dimethylphenyl)-2-(4-hydroxyphenyl)acetamide (12a)
General procedure: To a stirring solution of 3,5-dimethylaniline 10a (2.7 g, 15.6 mmol) in toluene (25 mL)were add 2-(4-hydroxyphenyl)acetic acid 11a (2.0 g, 13 mmol) and boric acid (0.08 g,0.13 mmol) at room temperature. The reaction mixture was refluxed at 140°C with a waterseparator for 12 h. Upon completion, the mixture was cooled to room temperature andfiltered, and the filter cake was washed with toluene (3 20 mL) and water (3 20 mL),respectively. Then, the filter cake was dried in a vacuum drying oven to give 12a as a whitesolid (3.0g, 90.5%).
2-(4-hydroxyphenyl)-N-(4-(methylthio)phenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41.7%
With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 20℃; for 8h;
4.2.2. N-(3,5-dimethylphenyl)-4-hydroxybenzamide (12b)
General procedure: To a stirring solution of 4-hydroxybenzoic acid 11b (0.73 g, 6 mmol), EDCl (1.44 g,7.5 mmol) and HOBT (0.81 g, 6 mmol) in dry DCM (20 mL) at room temperature was added3,5-dimethylaniline 10a (0.73 g, 6 mmol) for 8 h. Upon completion, the mixture was washedwith water (3 20 mL) and dried over anhydrous sodium sulfate before concentrationin vacuo. The crude product was purified with silica gel column chromatography usingpetroleum ether (PE)/ethyl acetate (EA) (5:1 to 3:1) as eluent to afford 12b as a white solid(0.53 g, 44%).
N-([1,1'-biphenyl]-3-yl)-2-(4-hydroxyphenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67.3%
With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 20℃; for 8h;
4.2.2. N-(3,5-dimethylphenyl)-4-hydroxybenzamide (12b)
General procedure: To a stirring solution of 4-hydroxybenzoic acid 11b (0.73 g, 6 mmol), EDCl (1.44 g,7.5 mmol) and HOBT (0.81 g, 6 mmol) in dry DCM (20 mL) at room temperature was added3,5-dimethylaniline 10a (0.73 g, 6 mmol) for 8 h. Upon completion, the mixture was washedwith water (3 20 mL) and dried over anhydrous sodium sulfate before concentrationin vacuo. The crude product was purified with silica gel column chromatography usingpetroleum ether (PE)/ethyl acetate (EA) (5:1 to 3:1) as eluent to afford 12b as a white solid(0.53 g, 44%).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
