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Structure of 2973-80-0 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Chemical Communications, 2011, vol. 47, # 23, p. 6635 - 6637
2
[ 2973-80-0 ]
[ 14472-14-1 ]
Reference：
[1] Monatshefte fuer Chemie, 1954, vol. 85, p. 802,805
3
[ 2973-80-0 ]
[ 3964-56-5 ]
Reference：
[1] Monatshefte fuer Chemie, 1936, vol. 67, p. 320,322
4
[ 2973-80-0 ]
[ 3217-15-0 ]
Reference：
[1] Monatshefte fuer Chemie, 1936, vol. 67, p. 320,322
5
[ 100-83-4 ]
[ 2973-80-0 ]
Yield
Reaction Conditions
Operation in experiment
63%
With bromine In dichloromethane at 35 - 40℃;
3-Hydroxybenzaldehyde (120g, 0.98 moles) was suspended in 2400 ML OF CH2CL2 in a 5L 4-neck round bottom flask equipped with overhead stirrer, temperature probe, addition funnel, and condenser. The mixture was heated to 35-40° C in order to dissolve the starting material. Bromine (52 mL, 1.0 moles, 1.02 eq. ) was added dropwise through the addition funnel at a rate which maintained the reaction temperature between 35-38° C. The mixture was then allowed to stir overnight at 35 C. THE mixture was slowly cooled to-5-0° C over two hours and then allowed to stir at that temperature for lh more. The solid which formed was then collected by filtration through a Buchner funnel and the filter cake washed with 400mL of a cold 1 : 1 CHZCHEPTANE solution. The gray solid was then dried in vacuo (0.2mm Hg) at room temperature. Yield = 124.3g (63percent).
55%
at 15 - 22℃;
Example 1; 2-bromo-5-hydroxybenzaldehyde (3) 3-hydroxybenzaldehyde (10 g, 81.9 mmol) was dissolved in glacial acetic acid (50 mL) and cooled at 15° C. To the stirred solution, bromine (15.7 g, 98.2 mmol) was added dropwise while keeping the temperature below 22° C. After overnight stirring at room temperature, the volatiles were removed under vacuum without heating; the residue was co-evaporated three times with hexane (15 mL) and taken up in warm chloroform. Upon cooling, 9.05 g of 2-bromo-5-hydroxybenzaldehyde 3 were obtained as a white solid in two crops. Yield 55percent.1H NMR (300 MHz, CD3COCD3) δ ppm: 10.24 (s, 1H), 9.05 (s, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.34 (d, J=3.1 Hz, 1H), 7.10 (dd, J1=8.7 Hz, J2=3.1 Hz, 1H); 13C NMR (75 MHz, CD3COCD3) δ ppm: 192.8, 159.3, 136.7, 136.2, 125.1, 117.3, 117.2; HRMS (EI) m/z: calcd for C7H5BrO2: 199.9472, found: 199.9463; mp: 132-134° C.
55%
at 20℃;
To a stirred solution of 1.5 g (12.3 mmol) of 3-hydroxybenzaldehyde in 10 mL of glacialacetic acid at 22C was added 2.35 g (14.7 mmol) of bromine so as to keep the temperatureat or below 22. After stirring overnight at r.t., the volatiles were removed underreduced pressure. The residue was washed with hexane (3 £ 15 mL) and then taken up inwarm chloroform. After cooling, a total of 1.35 g (55percent) of 2-bromo-5-hydroxybenzaldehyde2 was obtained in two crops. Mp: 132–134C, lit. mp 134 C.27 1H RMN(300 MHz, CD3COCD3) d ppm: 10.24 (s, 1H), 9.05 (s, 1H), 7.58 (d, J D 8.7 Hz, 1H),7.34 (d, J D 3.1 Hz, 1H), 7.10 (dd, J1 D 8.7 Hz, J2 D 3.1 Hz, 1H); 13C RMN (75 MHz,CD3COCD3) d ppm: 192.8 (CHO), 159.3 (C-5), 136.7 (C-6), 136.2 (C-1), 125.1 (C-4),117.3 (C-3), 117.2 (C-2); HRMS (EI) m/z: Calcd for C7H5BrO2: 199.9472. Found:199.9463.
55%
With bromine In chloroform; acetonitrile at 20℃; for 4 h; Cooling with ice
A suspension of 3-hydroxybenzaldehyde (48.85 g, 400 mmol) in a 10:1 mixture of chloroformlacetonitril (330 mL) was cooled with an ice bath. Then, bromine (63.9 g, 1 equiv) was added dropwise and the bath was removed to stir the mixture at room temperature. After 4 h, the reaction was quenched with a saturated NaHCO3 solution (150 mL). The phases were separated and the organic layer was washed with water (150 mL). The concentrated organic phase was filtered through a thin pad of Celite and eluted with a 4:1 mixture of dichloromethane/ethyl acetate. Solvent was removed in vacuo and the remaining solid was crystallized several times from ethyl acetate/hexane to give 44.15 g of 2-bromo-5- hydroxybenzaldehyde as light brown needles. Yield 55percent; mp: 132-134 °C. ‘H NMR (300 MHz, CD3COCD3) ö ppm: 10.24 (s, 1H), 9.05 (s, 1H), 7.58 (d, J= 8.7 Hz, 1H), 7.34 (d, J= 3.1 Hz, 1H), 7.10 (dd, J, = 8.7 Hz, J2 = 3.1 Hz, 1H); ‘3C NMR (75 MHz, CD3COCD3) ö ppm: 192.8, 159.3, 136.7, 136.2, 125.1, 117.3, 117.2; HRMS (EI)mlz: calcd for C7H5BrO2: 199.9472, found: 199.9463.
50%
With bromine; sodium carbonate In chloroform
Preparation of 2-bromo-5-hydroxybenzaldehyde: A solution of 4.2 ml of bromine (82 mmol) in 30 ml of chloroform is slowly added to a solution of 10 g of 3-hydroxybenzaldehyde (82 mmol) in 100 ml of chloroform. The reaction solution is then combined with 50 ml of 6percent sodium carbonate solution and vigorously stirred. Once neutralisation is complete, the phases are separated and the solvent removed from the organic phase. The crude product is recrystallized with dilute acetic acid, whereupon 8.24 g of the product (7) are obtained as white needles at a yield of 50percent.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 8, p. 955 - 959
[2] Patent: US2004/19018, 2004, A1, . Location in patent: Page/Page column Sheet 2
[3] Journal of the Iranian Chemical Society, 2011, vol. 8, # 2, p. 531 - 536
[4] Tetrahedron Letters, 2009, vol. 50, # 9, p. 1007 - 1009
[5] Synthetic Communications, 2007, vol. 37, # 4, p. 581 - 585
[6] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 3, p. 1169 - 1172
[7] Journal of Organic Chemistry, 2002, vol. 67, # 26, p. 9248 - 9256
[8] Journal of Natural Products, 2008, vol. 71, # 11, p. 1938 - 1941
[9] Antimicrobial Agents and Chemotherapy, 2014, vol. 58, # 6, p. 3312 - 3326
[10] Chemical Communications, 2015, vol. 51, # 95, p. 16992 - 16995
[11] Organic Process Research and Development, 2017, vol. 21, # 10, p. 1625 - 1632
[12] Journal of Organic Chemistry, 1999, vol. 64, # 13, p. 4949 - 4952
[13] Acta Crystallographica Section C: Crystal Structure Communications, 2000, vol. 56, # 3, p. 354 - 355
[14] Organic Process Research and Development, 2004, vol. 8, # 5, p. 738 - 743
[15] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 24, p. 6328 - 6333
[16] Patent: WO2004/89890, 2004, A2, . Location in patent: Page 26-27; 32
[17] Organic letters, 2002, vol. 4, # 16, p. 2711 - 2714
[18] Organic Letters, 2018, vol. 20, # 17, p. 5177 - 5180
[19] Patent: US2011/105545, 2011, A1, . Location in patent: Page/Page column 17
[20] Organic Preparations and Procedures International, 2017, vol. 49, # 3, p. 265 - 272
[21] Patent: WO2017/134146, 2017, A1, . Location in patent: Page/Page column 44; 55; 100
[22] Tetrahedron Letters, 2004, vol. 45, # 26, p. 5091 - 5094
[23] Patent: US2002/16513, 2002, A1,
[24] Chemistry - A European Journal, 2016, vol. 22, # 29, p. 10194 - 10202
[25] Journal of Medicinal Chemistry, 1998, vol. 41, # 15, p. 2745 - 2753
[26] Synthesis, 2009, # 12, p. 2040 - 2060
[27] Journal of the Chemical Society, 1925, vol. 127, p. 876,877[28] Journal of the Chemical Society, 1926, p. 150
[29] Chemische Berichte, 1909, vol. 42, p. 4169
[30] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 4, p. 134
[31] Journal of the Indian Chemical Society, 1952, vol. 29, p. 363,364
[32] Journal of the American Chemical Society, 1994, vol. 116, # 18, p. 8392 - 8393
[33] Journal of the Chemical Society, 1925, vol. 127, p. 876,877[34] Journal of the Chemical Society, 1926, p. 150
[35] Patent: WO2013/174848, 2013, A2, . Location in patent: Page/Page column 18
6
[ 7507-86-0 ]
[ 2973-80-0 ]
Yield
Reaction Conditions
Operation in experiment
90.9%
With boron tribromide In dichloromethane at 0 - 25℃; for 3 h;
To a mixture of 2-bromo-5-methoxybenzaldehyde (2000.0 mg, 9.3 mmol) indichioromethane (10 mL) was added boron tribromide (2M in DCM; 4.65 mL, 9.3 mmol) slowly at 0 °C. The reaction was warmed up to 25 °C and stirred for 3 h. The reaction was quenched with water (10 mL) at 0°C and extracted with EtOAc (50 mL). The organic layer was washed with water (50 mL x 2) and brine (50 mL), dried over Mg504 and concentrated. The residue was purified by flash column chromatography (petroleum ether) to afford 2-bromo-5-hydroxybenzaldehyde (1.7 g, 90.9percent yield) as a colorless oil.
Reference：
[1] Patent: WO2017/84630, 2017, A1, . Location in patent: Paragraph 00976
[2] Journal of Medicinal Chemistry, 2000, vol. 43, # 4, p. 599 - 608
[3] Patent: WO2005/123668, 2005, A1, . Location in patent: Page/Page column 46
[4] Patent: WO2005/123668, 2005, A1, . Location in patent: Page/Page column 47
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1982, vol. 21, # 2, p. 95 - 97
13
[ 42454-06-8 ]
[ 2973-80-0 ]
Reference：
[1] Journal of the Chemical Society, 1925, vol. 127, p. 876,877[2] Journal of the Chemical Society, 1926, p. 150
14
[ 2973-80-0 ]
[ 74-88-4 ]
[ 7507-86-0 ]
Yield
Reaction Conditions
Operation in experiment
100%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 60 h;
To a solution of 2-bromo-5-hydroxybenzaldehyde (1000.0 mg, 4.975 mmol) in DMF (20 mL) were added methyl iodide (0.31 mL, 5.000 mmol) and potassium carbonate (1036.6 mg, 7.500 mmol). The reaction mixture was stirred at rt for 2.5 days. Water was added and the reaction mixture was extracted with hexanes-ether (1:1) solvent system. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum to yield 2-bromo-5-methoxybenzaldehyde (1069.8 mg, 100percent) as colorless oil. LC-MS (M+H)+=215.11. 1H NMR (500 MHz, DMSO-d6) δ 10.18 (s, 1H). 7.70 (d, J=10 Hz, 1H) 7.35 (d, J=3 Hz, 1H) 7.23 (dt, J1=7.0 Hz, J2=2.0 Hz, 1H) 3.83 (s, 3H).
Reference：
[1] Patent: US2008/194535, 2008, A1, . Location in patent: Page/Page column 30
[2] Organic letters, 2002, vol. 4, # 16, p. 2711 - 2714
[3] Journal of the Chemical Society, 1951, p. 181,184
With tetra-(n-butyl)ammonium iodide; potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃;
Example 396 : Synthesis of (1E,6E)-1-(5-benzyloxy-2-bromophenyl)-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione (CU531); (1) Synthesis of 5-benzyloxy-2-bromobenzaldehyde; To a suspension of 2-bromo-5-hydroxybenzaldehyde (100 mg, 0.50 mmol), potassium carbonate (138 mg, 1.00 mmol), and tetrabutylammonium iodide (18 mg, 0.05 mmol) in 1.0 mL of dry N,N-dimethylformamide was added benzyl bromide (89 μL, 0.74 mmol) at 0°C. After being stirred at room temperature overnight, the reaction mixture was diluted with diethyl ether, and the solution was washed with water, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate = 95/5 to 80/20) to obtain the title compound as a colorless oil (140 mg, 97percent).
97%
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃;
To a suspension of 2-bromo-5-hydroxybenzaldehyde (100 mg, 0.50 mmol), potassium carbonate (138 mg, 1.00 mmol), and tetrabutylammonium iodide (18 mg, 0.05 mmol) in 1.0 mL of dry N,N-dimethylformamide was added benzyl bromide (89 μL, 0.74 mmol) at 0° C. After being stirred at room temperature overnight, the reaction mixture was diluted with diethyl ether. The solution was washed with water, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 80/20) to obtain the title compound as a colorless oil (140 mg, 97percent).
Reference：
[1] Bulletin of the Korean Chemical Society, 2010, vol. 31, # 7, p. 2047 - 2050
[2] Patent: EP2123637, 2009, A1, . Location in patent: Page/Page column 110
[3] Patent: US2011/82295, 2011, A1, . Location in patent: Page/Page column 14
[4] Journal of Organic Chemistry, 2016, vol. 81, # 20, p. 10062 - 10070
[5] Journal of Organic Chemistry, 1999, vol. 64, # 13, p. 4949 - 4952
[6] Journal of the American Chemical Society, 1994, vol. 116, # 18, p. 8392 - 8393
[7] Patent: US2007/72833, 2007, A1, . Location in patent: Page/Page column 19
[8] Patent: WO2014/6020, 2014, A1, . Location in patent: Page/Page column 46
[9] Chemistry - A European Journal, 2017, vol. 23, # 62, p. 15775 - 15782
22
[ 2973-80-0 ]
[ 100-44-7 ]
[ 85604-06-4 ]
Yield
Reaction Conditions
Operation in experiment
96%
With potassium carbonate In acetone for 10 h; Reflux
201 g (1 mol) of 2-bromo-5-hydroxybenzaldehyde, 1000 ml of acetone, and 276 g of potassium carbonate (1.1 mol) were added to the reaction vessel, and 152 g (1.2 mol) of benzyl chloride was added thereto with stirring, and the mixture was refluxed for 10 hours to recover a solvent. Add 1000ml water, beaten, filter, reducePress drying to obtain 279 g of solid, yield 96percent;
Reference：
[1] Journal of Natural Products, 2008, vol. 71, # 11, p. 1938 - 1941
[2] Patent: CN108530476, 2018, A, . Location in patent: Paragraph 0046; 0090-0091
[3] Tetrahedron, 1992, vol. 48, # 5, p. 913 - 922
[4] Journal of Medicinal Chemistry, 2000, vol. 43, # 4, p. 599 - 608
23
[ 2973-80-0 ]
[ 906673-45-8 ]
Reference：
[1] Patent: WO2018/115362, 2018, A1,
24
[ 1194-02-1 ]
[ 2973-80-0 ]
[ 906673-54-9 ]
Yield
Reaction Conditions
Operation in experiment
71%
With potassium carbonate In N,N-dimethyl-formamide; toluene at 115℃; for 8 h; Inert atmosphere
In a round bottom flask, under nitrogen atmosphere, 2-bromo-5-hydroxybenzaldehyde (100 g, 497 mmol) and 4-fluorobenzonitrile (301 .2 g, 2487 mmol) were dissolved in DMF (250 ml) and toluene (500 ml). To the resulting dark solution, potassium carbonate (206.2 g, 1492 mmol) was added and the resulting mixture was stirred for 8 hours at 1 15 °C. After the reaction was completed by TLC, the heterogeneous mixture was filtered. The solvents and 4-fluoro-benzonitrile were distilled under reduced pressure from the obtained filtrate. Ethyl acetate (800 ml), water (500 ml) and brine (40 ml) were added and the formed phases were separated at 65-70 °C. The aqueous phase was extracted with ethyl acetate (150 ml) at 65-70 °C and the combined organic phase was washed with a mixture of water (225 ml) and brine (180 ml) at 65-70 °C. The obtained organic phase was evaporated under reduced pressure to give a brown solid. The solid was purified twice by recrystallization in a hot mixture of ethyl acetate and toluene to give 4-(4-bromo-3- formylphenoxy)benzonitrile (compound A) (107.5 g). Yield: 71 percent Purity by HPLC: >99percent 1H-NMR (200 MHz, CDCI3, δ ppm): 10.32 (1 H, s); 7.62-7.72 (3H, m); 7.57-7.59 (1 H, dd; J= 3, J= 1 ); 7.18- 7.23 (1 H, dd, J=8 Hz, J=3 Hz), 7.01 -7.08 (2H, m) 13C-NMR (50 MHz, CDCI3, δ ppm): 190.69; 160.08; 155.13; 135.59; 134.89; 134.39; 126.86; 121.81 ; 120.28; 1 18.68; 1 18.33; 107.32 DSC: Endothermic peak at 1 1 1.9 °C.
50 g
With potassium carbonate In N,N-dimethyl-formamide at 75 - 85℃; for 20 h;
A mixture of 2-bromo-5-hydroxybenzaldehyde (50g), 4-fluorobenzonitrile (75.3 lg) and potassium carbonate (103g) in dimethylformamide (500mL) was stirred at about 75°C to about 85°C for about 20h. The reaction mixture was filtered and the filtrate was quenched with water at about room temperature, stirred for about 2h, filtered and dried. The crude product was purified by ethyl acetate. Yield: 50g HPLC purity: >99percent
1.D28.01 Step :D28.01. Synthesis of (2E)-3-(2-Bromo-5-hydroxyphenyl)prop-2-enoic acid.
A round bottom flask fitted with a reflux condenser was charged with 4-bromo-3-formylphenol (25.3 g, 0.126 mol), pyridine (150 mL), malonic acid (15.7 g, 0.151 mol) and piperidine (1.50 mL). The reaction mixture was stirred at reflux for 6.5 h then allowed to cool. 2M Hydrochloric acid solution (500 mL) was added to the reaction mixture and the pH adjusted to <2 with concentrated hydrochloric acid solution. The mixture was stirred vigorously and cooled in an ice bath to <10°C. The resulting solids were collected on a Buchner funnel and washed with 2M hydrochloric acid solution (200 mL) and water (50 mL). The solids were partitioned between ethyl acetate (1.2 L) and 2M hydrochloric acid solution (200 mL). The aqueous layer was removed and the organics washed with brine (200 mL), dried over magnesium sulfate, filtered and concentrated to give the title compound as a pale purple powder (24.8 g, 81 %). H NMR (400MHz, DMSO-d6) δ ppm 12.53 (bs, 1 H), 9.90 (s, 1 H), 7.75 (d, J^15.8 Hz, 1 H), 7.47 (d, J^8.6 Hz, 1 H), 7.19 (d, J=2.9 Hz, 1 H), 6.80 (dd, J^8.7, 2.8 Hz, 1 H), 6.40 (d, J^15.8, 2.8 Hz, 1 H). LCMS [M]+ = 242.9, 244.9.
78%
With piperidine; pyridine for 4h; Reflux;
3 Preparation of (2E)-3-(2-Bromo-5-hydroxyphenyl)prop-2-enoic acid
Piperidine (1.47 mL) was added to a mixture of 4-bromo-3-formyi-phenoi (25.0 g, 0.124 moi) and maionic acid (15.53 g, 0.149 moi) in pyridine (150 mL) and heated to refiux for 4 h. The reaction mixture was cooied briefiy before adding hydrochioric acid (2 M, 500 mL) and acidified to pH 1-2 with concentrated hydrochioric acid (33%, ca. 50-1 00 mL). The suspension was cooied to approximateiy 10°C and the soiid coiiected by vacuum fiitration washing with hydrochioric acid (2 M, 60 mL) and dried under vacuum for 18 h. This crude materiai contained water and pyridine hydrochioride as indicated by 1H NMR, and was taken up in ethyi acetate (1.3 L) and washed with hydrochioric acid (2 M, 2 x 750 mL), dried over magnesium suifate and fiitered. The fiitrate was concentrated to dryness to give the titie compound as a grey powder (23.63 g, 0.0972 moi, 78%). 1H NMR (400 MHz, DMSO-d6) d ppm 12.62 (br. s., 1 H) 9.91 (s, 1 H) 7.76 (d, J=16.0 Hz, 1 H) 7.48 (d, J=8.6 Hz, 1 H) 7.19 (d, J=2.3 Hz, 1 H) 6.80 (dd, J=8.8, 2.5 Hz, 1 H) 6.41 (d, J=16.0 Hz, 1 H); HPLC (water/ACN + 0.1% TFA gradient) 98.9% at 220 nm; LCMS [M+H] = 242.9 , [M-Hr = 242.0. Ca 2-5 moi% of unknown impurities as indicated by 1H NMR anaiysis.
71%
Stage #1: malonic acid; 2-bromo-5-hydroxybenzaldehyde With pyridine at 100℃;
Stage #2: With hydrogenchloride In water
4
Example 4; (E)-3-(2-bromo-5-hydroxyphenyl)acrylic acid (8) A mixture of bromoaryl 3 (5.5 g, 27.0 mmol), malonic acid (2.85 g, 27.0 mmol), pyridine (15 mL) and piperidine (0.5 mL) as catalyst were stirred overnight at 100° C. Thereafter, water (5 mL) was added and the mixture was neutralized with concentrated HCl. The resulting precipitate was filtered and crystallized from methanol to give 4.72 g of 7 as a white solid. Yield 71%. 1H NMR (300 MHz, CD3COCD3) δ ppm: 7.95 (d, J=15.8 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.29 (d, J=3.0 Hz, 1H), 6.88 (dd, J1=8.4 Hz, J2=3.0 Hz, 1H), 6.44 (d, J=15.8 Hz, 1H), 2.88 (br s, 1H); 13C NMR (75 MHz, CD3COCD3) δ ppm: 168.2, 159.1, 144.4, 136.8, 135.9, 123.1, 121.2, 116.2, 104.2; HRMS (EI) m/z: calcd for C9H7BrO3: 241.9579, found: 241.9515; mp: 208-210° C.
With pyridine
47.6 g
With piperidine; pyridine at 100℃;
3 Ethyl (E)-3-(2-bromo-5-hydroxyphenyl)acrylate (6a)
A mixture of 2-bromo-5-hydroxybenzaldehyde (44.25 g), malonic acid (22.9 g, 1 equiv), pyridine (100 mL) and piperidine (5 mL) as catalyst were stirred overnight at 100 °C. Thereafter, ice-water (100 mL) was added and the mixture was acidified (pH= 1) with concentrated HC1. The resulting precipitate was filtered, washed with 1M HC1 solution (4x100 mL) and dried under vacuum to give 47.6 g of (E)-3-(2- bromo-5-hydroxyphenyl)acrylic acid as a brown solid. To a solution of this compound in dry ethanol (10( mL) was added a small quantity of H2S04 (1 mL) and the stirred mixture was refluxed overnight. The solvent was evaporated in vacuo and the crude was purified by crystallization from ethanol to give 48.83 g of compound 6a as light brown needles. Yield 82%; mp: 96-98 °C. ‘H RMN (300 MHz, CD3COCD3) ö ppm: 8.82 (br s, 1H), 7.94 (d, J= 16.1 Hz, 1H), 7.49 (d, J= 8.7 Hz, 1H), 7.28 (d, J= 2.9 Hz, 1H), 6.88 (dd, J, = 8.7 Hz, J2 = 2.9 Hz, 1H), 6.45 (d, J= 16.1 Hz, 1H), 4.24 (q, J= 7.1 Hz, 2H), 1.30 (t, J= 7.1 Hz, 3H); ‘3C RMN (75 MHz, CD3COCD3) ö ppm: 167.5, 159.1, 144.0, 136.7, 135.9, 123.0, 121.3, 116.2,115.8, 62.1, 15.6; HRMS (EI)mlz: calcd for C,,H,,Br03: 269.9892, found: 269.9886.
With methanol; sodium tetrahydroborate at 0 - 20℃; for 1h;
19.19w
To a solution of 4-bromo-3-formylphenol (20.1 g, 100 mmol) in methanol (200 mL) was added sodium borohydride (1.90 g, 50.0 mmol) portionwise at 0° C., and the mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure to a half volume, 6 M HCl (50 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 4-bromo-3-hydroxymethylphenol (19.4 g, 96%). (0703) 1H-NMR (300 MHz, DMSO-d6) δ (ppm) 4.39 (d, J=5.9 Hz, 2H), 5.35 (t, J=5.9 Hz, 1H), 6.56 (dd, J=8.5, 2.9 Hz, 1H), 6.97 (d, J=2.9 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 9.61 (s, 1H).
94%
With formic acid; C20H29ClIrN4(1+)*Cl(1-) In ethanol; water at 80℃; for 0.583333h; chemoselective reaction;
94%
With formic acid; C20H29ClIrN4(1+)*Cl(1-) In water at 80℃; for 0.583333h;
93%
With sodium tetrahydroborate In tetrahydrofuran at 0 - 20℃; for 2h; Inert atmosphere;
1 Example 1: Synthesis of 2-Bromo-5-hydroxybenzyl alcohol of Formula (III)
9.00 g (249 mmol) of NaBH4 are suspended under nitrogen atmosphere in 300 mL of THF. The suspension is cooled down to 0° C. and 100 g (497 mmol) of 2-bromo-5-hydroxy benzaldehyde of formula (VII) in 200 mL of THF are added over about an hour while maintaining the temperature below 15° C. The mixture is allowed to reach room temperature within one hour, then cooled down to about 0° C. and a solution of 5% HCl is added until reaching a pH value from 1 to 2. The biphasic solution is then concentrated under reduced pressure and the formed solid filtered off and washed with water until reaching a neutral pH value. The product is dried in an oven providing 94 g of 2-bromo-5-hydroxy-benzyl alcohol of formula (III) with a yield of 93%. 1H-NMR (DMSO-d6, 300 MHz) δ (ppm): 9.59 (1H, s), 7.27 (1H, d, J=8.7 Hz), 6.97 (1H, d, J=3.3 Hz), 6.55 (1H, dd, J=3.3, J=8.7), 5.33 (1H, t, J=5.7 Hz), 4.38 (2H, d, J=5.7 Hz).
92%
With methanol; sodium tetrahydroborate at 0℃; for 0.5h;
2.1 Step 1 Synthesis of Compound 6
NaBH4 (0.22 g, 5.97 mmol) was slowly added dropwise to compound 2 (1.0 g, 4.98 mmol) at 0 °C.In the methanol (15 ml) solution, the reaction was continued for 0.5 h after the completion of the dropwise addition.The reaction was quenched by the addition of 1 M hydrochloric acid (10 mL).Extraction with dichloromethane (20 ml × 2), combining the organic phases,Dry over anhydrous sodium sulfate and remove the solvent.The white solid product was 0.93 g, yield 92%.
91.6%
With methanol; sodium tetrahydroborate Cooling with ice;
1 Example 1 Synthesis of 2-bromo-5-hydroxybenzyl alcohol (III)
40 g (0.20 mol) of 2-bromo-5-hydroxybenzaldehyde (II) was added to the reaction flask. 400 mL of MeOH was stirred well; 5.6 g (0.15 mol) of sodium borohydride was added portionwise in an ice bath, and the reaction was kept for 0.5 h to 1.5 h. The basic reaction of TLC detection of raw materials is complete. It was quenched by the addition of 100 mL of EtOAc. Obtained as an off-white solid, and then added to 100 mL of dichloromethane at room temperature for 0.5 h, and filtered. The filter cake was air-dried to obtain 37.2 g of a white solid, which was 2-bromo-5-hydroxybenzyl alcohol (III), and the yield was 91.6%.
91%
With sodium tetrahydroborate; water; sodium hydroxide In tetrahydrofuran at 0 - 5℃; for 1h;
1 Synthesis of 4-bromo-3-(hydroxymethyl)phenol (Compound of Formula (IV) wherein X is -CH2OH)
2-Bromo-5-hydroxy benzaldehyde (compound of formula IV wherein X is -COH) (20.1 g, 100 mmol) was dissolved in THF (80 mL), and the solution was cooled to 0-5° C. A solution of NaBH4 (1.9 g, 50 mmol) in water (10 mL, stabilised with NaOH) was added in 30 min. The solution was stirred for a further 30 min. Acetone (25 mL) was added dropwise to the solution in 30 min. Water (50 mL) was then added, and THF was distilled off. The residual oil was extracted with AcOEt (200 mL). The organic phase was washed with saline solution (50 mL), then AcOEt was distilled off. The resulting solid was treated at 50° C. with 50 mL of toluene, and the suspension cooled to 20° C. The solid was filtered and dried at 65° C. to obtain the title compound as a white solid (18.6 g, 91%). 1H-NMR; 300 MHz, DMSO-d6. ι 9.64 (brs, 1H), 7.27 (d, 1H), 7.01 (d, 1H), 6.60 (dd, 1H), 5.37 (brs, 1H), 4.41 (s, 2H) 13C-NMR; 300 MHz, DMSO-d6. δ 157.5, 142.4, 132.9, 115.9, 115.6, 109.4, 63.0.
With sodium hydroxide; sodium tetrahydroborate
With sodium tetrahydroborate In ethanol at 20℃; Inert atmosphere;
91.82 g
With sodium tetrahydroborate In tetrahydrofuran at 0 - 5℃; for 2h;
1 Example-i: Preparation of 4-bromo-3-(hydroxymethyl)phenol (Formula-3a)
Sodium borohydride (9.4 gm) was slowly added to a pre-cooled mixture of 2-bromo- 5-hydroxy benzaldehyde compound of formula-2a (100 gm) and tetrahydrofuran (300 ml) at0-5°C and stirred the reaction mixture for 2 hr at the same temperature. Acidified the reaction mixture with aqueous hydrochloric acid solution at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C, ethyl acetate was added to it and stirred for 20 mm at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with ethyl acetate. Combined the organic layers and washed with water. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with dichloromethane. Dichloromethane (300 ml) was added to the obtained compound at 25-30°C and stirred the reaction mixture for 90 mm at the same temperature. Filtered the solid, washed with dichloromethane and dried the material to get the title compound.Yield: 91.82 gm; M.R.: 136.8-142.3°C.
With 1,3-di-n-butyl-1H-imidazol-3-ium tribromide at 20℃; for 0.133333h; Neat (no solvent); regioselective reaction;
92%
With 1-butyl-3-methylpyridinium tribromide at 20℃; for 0.25h;
80%
With 1,4-dioxane dibromide at 20℃; for 0.5h;
80%
With bromine; iron In acetic acid at 20℃;
78%
With bromine In chloroform; acetonitrile for 3.5h;
76%
With bromine In tetrachloromethane for 2.25h;
76%
With bromine In dichloromethane at 0 - 2℃; for 17h;
75%
With bromine In dichloromethane at 0 - 20℃; for 5h;
74%
With bromine In dichloromethane at -5 - 25℃; for 15h; Inert atmosphere; Large scale;
73%
With bromine In chloroform for 3h; Ambient temperature;
68%
With bromine In acetic acid for 3h;
65%
With bromine In dichloromethane Reflux; Large scale;
63%
With bromine In dichloromethane
63%
With bromine In dichloromethane at 35 - 40℃;
1; 1; 2 EXAMPLE 1: 6-bromo-3-hydroxybenzaldehyde; Scheme 1; Scheme 2
3-Hydroxybenzaldehyde (120g, 0.98 moles) was suspended in 2400 ML OF CH2CL2 in a 5L 4-neck round bottom flask equipped with overhead stirrer, temperature probe, addition funnel, and condenser. The mixture was heated to 35-40° C in order to dissolve the starting material. Bromine (52 mL, 1.0 moles, 1.02 eq. ) was added dropwise through the addition funnel at a rate which maintained the reaction temperature between 35-38° C. The mixture was then allowed to stir overnight at 35 C. THE mixture was slowly cooled to-5-0° C over two hours and then allowed to stir at that temperature for lh more. The solid which formed was then collected by filtration through a Buchner funnel and the filter cake washed with 400mL of a cold 1 : 1 CHZCHEPTANE solution. The gray solid was then dried in vacuo (0.2mm Hg) at room temperature. Yield = 124.3g (63%).
57%
With bromine; acetic acid
56%
With bromine In dichloromethane at 20℃; for 1.5h; Inert atmosphere;
55%
With bromine; acetic acid at 15 - 22℃;
1
Example 1; 2-bromo-5-hydroxybenzaldehyde (3) 3-hydroxybenzaldehyde (10 g, 81.9 mmol) was dissolved in glacial acetic acid (50 mL) and cooled at 15° C. To the stirred solution, bromine (15.7 g, 98.2 mmol) was added dropwise while keeping the temperature below 22° C. After overnight stirring at room temperature, the volatiles were removed under vacuum without heating; the residue was co-evaporated three times with hexane (15 mL) and taken up in warm chloroform. Upon cooling, 9.05 g of 2-bromo-5-hydroxybenzaldehyde 3 were obtained as a white solid in two crops. Yield 55%.1H NMR (300 MHz, CD3COCD3) δ ppm: 10.24 (s, 1H), 9.05 (s, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.34 (d, J=3.1 Hz, 1H), 7.10 (dd, J1=8.7 Hz, J2=3.1 Hz, 1H); 13C NMR (75 MHz, CD3COCD3) δ ppm: 192.8, 159.3, 136.7, 136.2, 125.1, 117.3, 117.2; HRMS (EI) m/z: calcd for C7H5BrO2: 199.9472, found: 199.9463; mp: 132-134° C.
55%
With bromine; acetic acid at 20℃;
2-Bromo-5-hydroxybenzaldehyde (2)10
To a stirred solution of 1.5 g (12.3 mmol) of 3-hydroxybenzaldehyde in 10 mL of glacialacetic acid at 22C was added 2.35 g (14.7 mmol) of bromine so as to keep the temperatureat or below 22. After stirring overnight at r.t., the volatiles were removed underreduced pressure. The residue was washed with hexane (3 £ 15 mL) and then taken up inwarm chloroform. After cooling, a total of 1.35 g (55%) of 2-bromo-5-hydroxybenzaldehyde2 was obtained in two crops. Mp: 132-134C, lit. mp 134 C.27 1H RMN(300 MHz, CD3COCD3) d ppm: 10.24 (s, 1H), 9.05 (s, 1H), 7.58 (d, J D 8.7 Hz, 1H),7.34 (d, J D 3.1 Hz, 1H), 7.10 (dd, J1 D 8.7 Hz, J2 D 3.1 Hz, 1H); 13C RMN (75 MHz,CD3COCD3) d ppm: 192.8 (CHO), 159.3 (C-5), 136.7 (C-6), 136.2 (C-1), 125.1 (C-4),117.3 (C-3), 117.2 (C-2); HRMS (EI) m/z: Calcd for C7H5BrO2: 199.9472. Found:199.9463.
55%
With bromine In chloroform; acetonitrile at 20℃; for 4h; Cooling with ice;
3 2-bromo-5-hydroxybenzaldehyde (1)
A suspension of 3-hydroxybenzaldehyde (48.85 g, 400 mmol) in a 10:1 mixture of chloroformlacetonitril (330 mL) was cooled with an ice bath. Then, bromine (63.9 g, 1 equiv) was added dropwise and the bath was removed to stir the mixture at room temperature. After 4 h, the reaction was quenched with a saturated NaHCO3 solution (150 mL). The phases were separated and the organic layer was washed with water (150 mL). The concentrated organic phase was filtered through a thin pad of Celite and eluted with a 4:1 mixture of dichloromethane/ethyl acetate. Solvent was removed in vacuo and the remaining solid was crystallized several times from ethyl acetate/hexane to give 44.15 g of 2-bromo-5- hydroxybenzaldehyde as light brown needles. Yield 55%; mp: 132-134 °C. ‘H NMR (300 MHz, CD3COCD3) ö ppm: 10.24 (s, 1H), 9.05 (s, 1H), 7.58 (d, J= 8.7 Hz, 1H), 7.34 (d, J= 3.1 Hz, 1H), 7.10 (dd, J, = 8.7 Hz, J2 = 3.1 Hz, 1H); ‘3C NMR (75 MHz, CD3COCD3) ö ppm: 192.8, 159.3, 136.7, 136.2, 125.1, 117.3, 117.2; HRMS (EI)mlz: calcd for C7H5BrO2: 199.9472, found: 199.9463.
51%
With bromine In tetrachloromethane at 20℃; for 2h;
50%
With bromine; sodium carbonate In chloroform
Preparation of 2-bromo-5-hydroxybenzaldehyde:
Preparation of 2-bromo-5-hydroxybenzaldehyde: A solution of 4.2 ml of bromine (82 mmol) in 30 ml of chloroform is slowly added to a solution of 10 g of 3-hydroxybenzaldehyde (82 mmol) in 100 ml of chloroform. The reaction solution is then combined with 50 ml of 6% sodium carbonate solution and vigorously stirred. Once neutralisation is complete, the phases are separated and the solvent removed from the organic phase. The crude product is recrystallized with dilute acetic acid, whereupon 8.24 g of the product (7) are obtained as white needles at a yield of 50%.
49%
With bromine In dichloromethane at 25℃; for 12h; Inert atmosphere;
45%
With bromine In dichloromethane for 3h; Ambient temperature;
35%
With bromine; acetic acid at 10 - 20℃; for 2.66667h; Inert atmosphere;
durch Bromierung;
With chloroform; bromine
With bromine; acetic acid
With bromine In chloroform at 25℃;
Multi-step reaction with 2 steps
1: bei der Nitrierung
2: Na2S2O4; water / Diazotieren in bromwasserstoffsaurer Loesung und nachfolgende Behandlung mit Kupfer(I)-bromid
With bromine
1
Compound 2 is prepared as described in Bioorganic & Medicinal Chemistry Letters, 20(3), 1 169-1 172; 2010 or according to Journal of Organic Chemistry, 67(26), 9248-9256; 2002.
With potassium carbonate; In acetone; for 10h;Reflux;
201 g (1 mol) of 2-bromo-5-hydroxybenzaldehyde, 1000 ml of acetone, and 276 g of potassium carbonate (1.1 mol) were added to the reaction vessel, and 152 g (1.2 mol) of benzyl chloride was added thereto with stirring, and the mixture was refluxed for 10 hours to recover a solvent. Add 1000ml water, beaten, filter, reducePress drying to obtain 279 g of solid, yield 96%;
96%
With potassium carbonate; In acetone; for 10h;Reflux;
201 g (1 mol) of 2-bromo-5-hydroxybenzaldehyde (compound of formula I),1000 ml of acetone and 276 g of potassium carbonate (1.1 mol) were added to the reaction vessel, and 152 g (1.2 mol) of benzyl chloride was added thereto with stirring, and the mixture was refluxed for 10 hours to recover the solvent.Add 1000 ml of waterbath added,filter and dry under reduced pressure to obtain 279 g of a solid, yield 96%.
With tetra-(n-butyl)ammonium iodide; potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃;
Example 396 : Synthesis of (1E,6E)-1-(5-benzyloxy-2-bromophenyl)-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione (CU531); (1) Synthesis of 5-benzyloxy-2-bromobenzaldehyde; To a suspension of 2-bromo-5-hydroxybenzaldehyde (100 mg, 0.50 mmol), potassium carbonate (138 mg, 1.00 mmol), and tetrabutylammonium iodide (18 mg, 0.05 mmol) in 1.0 mL of dry N,N-dimethylformamide was added benzyl bromide (89 muL, 0.74 mmol) at 0C. After being stirred at room temperature overnight, the reaction mixture was diluted with diethyl ether, and the solution was washed with water, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate = 95/5 to 80/20) to obtain the title compound as a colorless oil (140 mg, 97%).
97%
With potassium carbonate;tetra-(n-butyl)ammonium iodide; In N,N-dimethyl-formamide; at 0 - 20℃;
To a suspension of 2-bromo-5-hydroxybenzaldehyde (100 mg, 0.50 mmol), potassium carbonate (138 mg, 1.00 mmol), and tetrabutylammonium iodide (18 mg, 0.05 mmol) in 1.0 mL of dry N,N-dimethylformamide was added benzyl bromide (89 muL, 0.74 mmol) at 0 C. After being stirred at room temperature overnight, the reaction mixture was diluted with diethyl ether. The solution was washed with water, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 80/20) to obtain the title compound as a colorless oil (140 mg, 97%).
With 15-crown-5; sodium hydride; In N,N-dimethyl-formamide; at 90℃; for 3h;
EXAMPLE 8A A solution of 2-bromo-5-hydroxybenzaldehyde (400 mg), 60% oily NaH (88 mg), and 15-crown-5 (0.435 mL) in DMF (6 mL) was treated with benzyl bromide (0.260 mL), stirred at 90 C. for 3 hours, cooled, poured into diethyl ether, washed with 1M HCl, 1M NaOH, water and brine, and concentrated.
With potassium carbonate; In acetone; at 20℃;
Specifically, to a solution of2-bromo-5-hydroxybenzaldehyde (1.0 eq.) inanhydrous acetone were added potassium carbonate (2 eq.) and benzyl bromide (1.1 eq.).The reaction mixture was stirred overnight at room temperature (r.t.), filtered andthe solvent was removed under reduced pressure. The resulting crude reaction product wassuspended in water and extracted with AcOEt. The combined organic layers were driedover Na2S04, filtered and the volatiles were removed in vacuo to yield 5-(benzyloxy)-2-bromo benzaldehyde.
With N,N,N,N,N,N-hexamethylphosphoric triamide In tetrahydrofuran
59%
Stage #1: 2-bromo-5-hydroxybenzaldehyde; tert-butylmagnesium chloride In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide; hexane at -78℃; for 3h;
Stage #2: With methanol In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide; hexane
1.a; 2
Under nitrogen, to a solution of 2-bromo-5-hydroxybenzaldehyde (14) (8.04 g, 40 m) in 80 mL of anhydrous THF and 20 mL of HMPA at -78° C., is added t-BuMgCl (44 mL, 2.0 M in Hexane, 88 mmol). 3 hours later, this reaction is quenched by 20 mL of MeOH. The resulting mixture is diluted with water (200 mL), and extracted with EtOAc (100 mL×2). The combined organic layer is washed with brine, and dried over MgSO4. After filtration, the filtrate is concentrated and crystallized from hexane/EtOAc=3/1, giving white solid 6.1 g (59%) (15). [0124] 1H NMR (DMSO-d6) δ9.55 (s, 1H), 7.28 (d, 1H, J=8.1 Hz), 6.94 (d, 1H, J=3.0 Hz), 6.58 (dd, 1H, J=3.0, 8.1 Hz), 5.31 (d, 1H, J=4.2 Hz), 4.61 (d, 1H, J=4.2 Hz), 0.89 (s, 9H).
Stage #1: 2-bromo-5-hydroxybenzaldehyde; dimethyl amine In tetrahydrofuran; 1,2-dichloro-ethane at 20℃; for 1h;
Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran; 1,2-dichloro-ethane for 3h;
Stage #3: With sodium hydrogencarbonate In tetrahydrofuran; water; 1,2-dichloro-ethane
82.A
A. 4-Bromo-3-dimethylaminomethyl-phenol. 2-Bromo-5-hydroxy-benzaldehyde (5.0 g, 24.9 mmol, 1.0 equiv) and 2.0 M dimethylamine in THF (31 mL, 62 mmol, 2.5 equiv) were stirred in dichloroethane (50 mL) at rt for 1.0 h. Sodium triacetoxyborohydride (15.8 g, 75 mmol, 3.0 equiv) was added, and the mixture was stirred for 3.0 h then poured into satd. aq. NaHCO3. The aqueous mixture was extracted three times with chloroform and the combined extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by Method 2 to afford 2.12 g (38%) of the title compound. 1H NMR (400 MHz, CD3OD): 7.36 (dd, J=8.6, 1.8 Hz, 1H), 6.91-6.90 (m, 1H), 6.67-6.62 (m, 1H), 3.53 (d, J=1.3 Hz, 1H), 2.30 (m, 6H).
With caesium carbonate; In dimethyl sulfoxide; at 20.0℃; for 2.0h;
2-Bromo-5-hydroxybenzaldehyde (0.96 g, 4.8 mmol) was dissolved in anhydrous DMSO (10 mL). Iodoethane (0.50 niL, 6.2 mmol) and Cs2CO3 (1.9 g, 6.3 mmol) were added and the mixture stirred at room temperature for 1.5 hours. Additional Cs2CO3 (1.45 g, 4.8 mmol) was added to the reaction mixture and then was stirred for 30 minutes. The reaction mixture was diluted with H2O and EtOAc and the layers were separated. Brine was added to the aqueous layer and it was extracted twice with EtOAc. The combined organics were washed with IM NaOH twice and brine thrice, and then was dried over MgSO4. The solution was vacuum-filtered through Celite.(R). and concentrated in vacuo to give 1.08 g of 2-bromo-5- ethoxybenzaldehyde.
With potassium carbonate; In N,N-dimethyl-formamide; at 50.0℃;
Step A: Synthesis of 2-Bromo-5-ethoxybenzaldehyde To a solution of 2-bromo-5-hydroxybenzaldehyde (5 g, 24.87 mmol) in DMF (20 ml) K2CO3 (6.88 g, 49.7 mmol) was added portion wise. To this, iodoethane (5.82 g, 37.3 mmol) was added slowly and the resulting reaction mixture was stirred overnight at 50 0C. After cooling down to ambient temperature, the reaction mixture was diluted with 100 mL ether/heaxane(l : 1 ) and 100 mL water. Layers were separated. The organic layer was washed with 100 mL brine, dried over sodium sulfate, filtered and concentrated to give the desired product as a white solid. 1H-NMR (CDCl3): delta: 10.3 (s, 1H), 7.51 (d, J=9.0 Hz, 1H), 7.39 (d, J= 3.0 Hz, 1H) 7.02 (dd, J = 3.5 Hz, J=8.5 Hz, 1H), 4.06 (q, 2H), 1.42 (t, J= 6.5 Hz, 3H).
With potassium carbonate; In N,N-dimethyl-formamide; at 50.0℃;
To a solution of 2-bromo-5-hydroxybenzaldehyde (5 g, 24.87 mmol) in DMF (20 mL), K2CO3 (6.88 g, 49.7 mmol) was added portion-wise. lodoethane (5.82 g, 37.3 mmol) was added slowly and the resulting reaction mixture was stirred at 50 °C overnight After cooling the reaction to ambient temperature, it was diluted with 100 mL of ether/hexanes (1 : 1) and 100 mL of water. The organic layer was washed with 100 mL of brine, dried over sodium sulfate, filtered and concentrated to give the title compound 2-bromo-5-ethoxybenzaIdehyde as a white solid.lH NMR (CDC13, 500 MHz): delta 10.3 (s, 1H), 7.51 (d, J= 9.0 Hz, 1H), 7.39 (d, J- 3.0 Hz, 1H) 7.02 (dd, J = 3.5 Hz, J - 8.5 Hz, 1H), 4.06 (q, 2H), 1.42 (t,'J= 6.5 Hz, 3H).
With potassium carbonate; In N,N-dimethyl-formamide; at 50.0℃;
Example 4-1 4-{8-[(4-Ethoxy-2',4,,5'-trifluorobiphenyl-2-yl)methyl]-2-oxo-l-oxa-3;>8-diazaspiro[4.5]dec-3- yl} benzoic acid, TFA salt Step 1. Synthesis of 2-bromo-5-ethoxybenzaldehyde (CAS. 43192-34-1 ) To a solution of 2-bromo~5-hydroxybenzaidehyde (5g, 24.87 mmol) in DMF (20 mL) was added iodoethane (5.82g, 37.3 mmol) and K2C03 (6.88g, 49.7 mmol) portion wise. The resulting reaction mixture was stirred at 50 °C overnight. After cooling, the mixture was diluted with EtOAc/hexanes (1 :1) and water. Layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give the title intermediate (4.6 g) as white solid. -NM (CDC13): delta 10.3 (s, 1H), 7.51 (d, J= 9.0 Hz, 1H), 7.39 (d, J= 3.0 Hz, 1H) 7.02 (dd, J = 3.5 Hzs J- 8.5 Hz, 1H), 4.06 (q, J- 6.5 Hz, 2H), 1.42 (t, J- 6.5 Hz, 3H).
With potassium carbonate; In N,N-dimethyl-formamide; at 50.0℃; for 1.0h;
Potassium carbonate (560 mg, 4.05 mmol) and iodoethane (243 mul, 3.03 mmol) were added to a solution of 2-bromo-5-hydroxybenzaldehyde (406 mg, 2.02 mmol) in DMF (1.6 ml), and it was stirred at 50°C for one hour. Water was added to the reaction mixture, followed by extraction with tert-butyl methyl ether/n-hexane (1:1). The organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, followed by concentration under reduced pressure to yield the title compound as a crude product. LCMS: m/z 268 [M+H]+ HPLC retention time: 0.93 min (analysis condition K)
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 10.0h;
Compound 1 (2.0 g, 16.5 mmol), Compound 2 (3.3 g, 16.5 mmol) and potassium carbonate were sequentially placed.(3.4 g, 24.8 mmol) was added to a solution of DMF (20 ml), and the mixture was stirred at 100 C for about 10 h, and analyzed by spotting until the starting material was completely reacted.The reaction solution was cooled to room temperature.The reaction was quenched with water (15 mL)EtOAcThe organic phase was washed twice with saturated sodium chloride. The organic phase was collected, dried over anhydrous sodium sulfate and evaporated.The concentrate was subjected to column separation (eluent: petroleum ether/ethyl acetate (v/v) = 10:1),The white solid product was obtained in 3.8 g, yield 76%.
71%
With potassium carbonate; In N,N-dimethyl-formamide; toluene; at 115℃; for 8.0h;Inert atmosphere;
In a round bottom flask, under nitrogen atmosphere, 2-bromo-5-hydroxybenzaldehyde (100 g, 497 mmol) and 4-fluorobenzonitrile (301 .2 g, 2487 mmol) were dissolved in DMF (250 ml) and toluene (500 ml). To the resulting dark solution, potassium carbonate (206.2 g, 1492 mmol) was added and the resulting mixture was stirred for 8 hours at 1 15 C. After the reaction was completed by TLC, the heterogeneous mixture was filtered. The solvents and 4-fluoro-benzonitrile were distilled under reduced pressure from the obtained filtrate. Ethyl acetate (800 ml), water (500 ml) and brine (40 ml) were added and the formed phases were separated at 65-70 C. The aqueous phase was extracted with ethyl acetate (150 ml) at 65-70 C and the combined organic phase was washed with a mixture of water (225 ml) and brine (180 ml) at 65-70 C. The obtained organic phase was evaporated under reduced pressure to give a brown solid. The solid was purified twice by recrystallization in a hot mixture of ethyl acetate and toluene to give 4-(4-bromo-3- formylphenoxy)benzonitrile (compound A) (107.5 g). Yield: 71 % Purity by HPLC: >99% 1H-NMR (200 MHz, CDCI3, delta ppm): 10.32 (1 H, s); 7.62-7.72 (3H, m); 7.57-7.59 (1 H, dd; J= 3, J= 1 ); 7.18- 7.23 (1 H, dd, J=8 Hz, J=3 Hz), 7.01 -7.08 (2H, m) 13C-NMR (50 MHz, CDCI3, delta ppm): 190.69; 160.08; 155.13; 135.59; 134.89; 134.39; 126.86; 121.81 ; 120.28; 1 18.68; 1 18.33; 107.32 DSC: Endothermic peak at 1 1 1.9 C.
With sodium hydride; In dimethyl sulfoxide; at 120℃; for 2.0h;
EXAMPLE 10A A solution of 2-bromo-5-hydroxybenzaldehyde (400 mg), 60% oily NaH (88 mg) and 4-fluorobenzonitrile (241 mg) in DMSO (5 mL) at 120 C. was stirred for 2 hours, cooled, poured into 1M NaOH (30 mL) and extracted with diethyl ether. The extract was concentrated, and the concentrate was flash chromatographed on silica gel with 10% ethyl acetete/hexanes.
50 g
With potassium carbonate; In N,N-dimethyl-formamide; at 75 - 85℃; for 20.0h;
A mixture of 2-bromo-5-hydroxybenzaldehyde (50g), 4-fluorobenzonitrile (75.3 lg) and potassium carbonate (103g) in dimethylformamide (500mL) was stirred at about 75C to about 85C for about 20h. The reaction mixture was filtered and the filtrate was quenched with water at about room temperature, stirred for about 2h, filtered and dried. The crude product was purified by ethyl acetate. Yield: 50g HPLC purity: >99%
With anhydrous potassium acetate In (methylsulfinyl)methane at 70℃; for 16h;
71.a
Step (a) 5-hydroxy-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzaldehyde1 , 1 '-bis(diphenylphosphino)ferrocenedichloro-palladium(ii) dichloromethane complex (1.009 g, 1.24 mmol) and l,l'-bis(diphenylphosphino)ferrocene (0.685 g, 1.24 mrαol) were stirred in DMSO (40 mL) at rt. for 10 min. 2-bromo-5-hydroxybenzaldehyde (5.00 g, 24.87 mmol), potassium acetate (7.28 g, 74.18 mmol) and diboron pinacol ester (8.16 g, 32.14 mmol) were added under nitrogen. The reaction was stirred for 16 h at 7O0C, cooled and poured onto water (300 mL) . The resulting mixture was extracted into diethyl ether and washed with brine and dried over sodium sulfate to give the title compound (6.7g, 109%) as a purple gum. Used in the next step without purification or analysis
67%
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate In 1,4-dioxane at 100℃; for 2h; Inert atmosphere;
51%
With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous potassium acetate In 1,4-dioxane Cooling with ethanol-dry ice;
2.1 Example 2: Preparation of 5-(5-fluorobenzothiazol-2-oxy)benzo[c][1,2]oxaborol-1(3H)-alcohol (S2)
Step 1. Under nitrogen protection, 3.0 g, 14.9 mmol of 2-bromo-5-hydroxy-benzaldehyde was dissolved in 30 mL of 1,4-dioxane.Then add 5.68 g, 22.35 mmol of dipinacol borate,1.09g, 1.49mmol PdCl2 (dppf) and4.4g, 44.7mmol potassium acetate,The mixture was stirred at 80 ° C overnight, then cooled, filtered, and the filtrate was concentrated. The residue was purified by column chromatography to give 5-hydroxy-2-(4,4,5,5-tetramethyl-1,3,2 - Dioxaborolan-2-yl)benzaldehyde, 1.89 g of a white solid, yield 51%.
45%
With anhydrous potassium acetate In 1,4-dioxane at 100℃; for 2h; Inert atmosphere;
1
Intermediate I: BenzofcJ [1 ,2]oxaborole-l ,5(3H)-diol[0502] Into a 250-mL 3 -necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen were placed a solution of 2-bromo-5- hydroxybenzaldehyde (5 g, 25.00 mmol, 1.00 equiv) in 1,4-dioxane (lOOmL), 4,4,5,5- tetramethyl-2-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 ,3 ,2-dioxaborolane (12.7 g, 50.0 mmol, 2.00 equiv), Pd(dppf)2Cl2 (1.83 g, 2.50 mmol, 0.10 equiv) and KOAc (7.35 g, 75.0 mmol, 3.00 equiv). The resulting mixture was stirred for 2 h at 100 °C. The reaction mixture was cooled and filtered. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1/10). This resulted in 3.12 g (45%) of 5-hydroxy-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzaldehyde as a white solid.[0503] Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 5-hydroxy-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzaldehyde (5.5 g, 22 mmol, 1.0 equiv) in methanol (25 mL). This was followed by the addition of NaBH4 (1.24 g, 32.6 mmol, 1.5 equiv) in several batches at 0 °C. The resulting solution was stirred for 10 min at 0 °C, then it was concentrated under vacuum to get rid of half methanol at low temperature. To the residual solution was added water (6 mL) and HC1 (6M, 14.5 mL) dropwise at 0 °C. The resulting solution was stirred overnight at room temperature. Then it was concentrated under vacuum at low temperature to remove MeOH. The solid was collected by filtration. This resulted in 2.0 g of benzo[c][l,2]oxaborole- l,5(3H)-diol as a white solid. Intermediate
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; anhydrous potassium acetate In 1,4-dioxane at 90℃; for 12h; Schlenk technique; Inert atmosphere;
With sodium carbonate In water; N,N-dimethyl-formamide at 20℃; Inert atmosphere;
51.1
To a suspension of 2-bromo-5-hydroxybenzaldehyde (300 mg, 1.49 mmol), sodium carbonate (190 mg, 1.79 mmol), and 1-naphthaleneboronic acid (384 mg, 2.23 mmol) in 3.0 mL of N,N-dimethylformamide/water (2:1) was added palladium acetate (18 mg, 80 μmol) under nitrogen. After being stirred at room temperature overnight, the reaction mixture was filtered. The filtrate was diluted with ethyl acetate, and the solution was washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=85/15 to 75/25) to obtain the title compound as a white solid (274 mg, 74%).
65%
With palladium diacetate; potassium carbonate In tetrahydrofuran; water at 20℃;
With potassium carbonate In N,N-dimethyl-formamide at 150℃; for 10h;
21.1
To a solution of 2-bromo-5-hydroxybenzaldehyde (62; 5 g, 0.025 mol) in DMF (100 ml) was added (R)-4-(chloromethyl)-2,2-dimethyl-l,3-dioxolane (63; 4.87 g, 0.032 mol) and K2CO3(7.0 g, 0.05 mol). The resulting reaction mixture was stirred at 150 0C for 1O h, cooled to room temperature, diluted with water, and then extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ether/EtOAc=10:l to afford the desired product, namely (S)-2-bromo-5-((2,2-dimethyl-l,3-dioxolan-4- yl)methoxy)benzaldehyde 64 (4.1 g, 56%).
56%
With potassium carbonate In N,N-dimethyl-formamide at 150℃; for 10h;
19.1
Example 19. Synthesis of (R)-2-(2-(difluoromethyl)-4-(2,3- dihydroxypropoxy)phenyI)-N-(thiazol-2-yl)-[l,2,4]triazolo[l,5-a]pyridine-8- carboxamide (Compound 249):Step 1) Preparation of (S)-2-bromo-5-((2,2-dimethyl-l,3-dioxolan-4- yl)methoxy)benzaldehyde (82): To a solution of 2-bromo-5-hydroxybenzaldehyde (81; 5 g, 0.025 mol) in DMF (100 ml) was added (R)-4-(chloromethyl)-2,2-dimethyl-l,3-dioxolane (4.87 g, 0.032 mol) and K2CO3(7.0 g, 0.05 mol). The resulting reaction mixture was stirred at 150 0C for 10 h, cooled to room temperature, diluted with water, and then extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ether/EtO Ac= 10:1) to afford the desired product, namely (S)-2-bromo-5-((2,2-dimethyl-l,3-dioxolan-4- yl)methoxy)benzaldehyde 82 (4.1 g, 56%).
With potassium carbonate In N,N-dimethyl-formamide at 80℃; Inert atmosphere;
19.19cj
To a solution of 6-chloro-nicotinonitrile (3.5 g, 25.0 mmol, 1.0 eq.), 2-bromo-5-hydroxy-benzaldehyde (5.0 g, 25.0 mmol, 1.0 eq.) in DMF (40.0 mL) was added K2CO3 (4.1 g, 30.0 mmol, 1.2 eq.) under nitrogen atmosphere. The mixture was heated at 80° C. overnight. After cooling to room temperature, the mixture was poured into EtOAc (30 mL) and H2O (30 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×20 mL). Combined organic extracts was washed with brine (30 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give 6-(4-bromo-3-formyl-phenoxy)-nicotinonitrile as a white solid. 1H NMR (CHLOROFORM-d) δ: 10.35 (s, 1H), 8.43 (dd, J=2.3, 0.6 Hz, 1H), 7.98 (dd, J=8.6, 2.3 Hz, 1H), 7.69-7.77 (m, 2H), 7.30 (dd, J=8.6, 3.0 Hz, 1H), 7.12 (dd, J=8.6, 0.8 Hz, 1H). Amount obtained, 5.92 g, 78% yield.
With potassium carbonate In N,N-dimethyl-formamide at 65 - 80℃; for 30.5h; Inert atmosphere;
With bis[chloro(1,2,3-trihapto-allylbenzene)palladium(II)]; dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine; sodium dodecyl-sulfate; cesium fluoride In toluene at 110℃; for 12h; Inert atmosphere;
With tetrakis(triphenylphosphine) palladium(0); potassium phosphate monohydrate; In 1,2-dimethoxyethane; at 150℃; for 1.5h;Microwave irradiation;
General procedure: To degassed solutions of 1 equiv of substituted 2-bromo-benzaldehydes 10, 13 or 14 in DME were added 1.5 equiv of boronic species, 3 equiv of K3PO4·H2O and 0.05 equiv of Pd(PPh3)4; the suspensions were heated under microwave irradiation (6 bars, 80-150 watts) for 1 h 30 min at 150 C. The resulting mixtures were filtered (washed with Et2O or EtOAc) and concentrated under reduced pressure. The crude products were then purified by flash chromatography.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; acetonitrile;Reflux;
2-bromo-5-hydroxybenzaldehyde ( 1 mmo 1 ), 3 -chloro-4-methoxyphenylboronicacid (1 mmol) and Na2C03 (2 mmol) were dissolved in AcN/H20 (7:3). Then, palladiumtetrakistriphenylphosfine (0.03 mmol) was added and the resulting mixture was refluxeduntil completion. After concentrating the mixture in vacuo the residue was taken up inwater and extracted with AcOEt. The combined organic fractions were dried over Na2S04, filtered, and evaporated. The crude reaction product was purified by means of flashchromatography on silica gel (hexane/ AcOEt 5:1) to yield 3 '-chloro-4-hydroxy-4'methoxybiphenyl-2-carbaldehyde as a white solid (93%); m.p.: 168-170 C.
2-(4-bromo-3-formylphenoxy)-5-fluorobenzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 19h;Inert atmosphere;
To a solution of 2-bromo-5-hydroxybenzaldehyde (5.0 g, 25 mmol, 1.0 eq) and <strong>[64248-64-2]2,5-difluorobenzonitrile</strong> (6.9 g, 50 mmol, 2.0 eq) in DMSO (25 mL) was added K2C03325 mesh (2.4 g, 17 mmol, 0.70 eq). The mixture was warmed to 80 C for 19 hours, after which the reaction was determined to be > 99.5 a% complete by HPLC. The heat source was removed and the reaction was cooled to ambient temperature. CH3CN (40 mL, 8 mL/g) and water (40 mL, 8 mL/g) were added. The mixture was allowed to stir at ambient temperature for 20 hours and the solids were removed by filtration, washed with 1 :1 CH3CN:water (2 x 2 mL/g), and dried to give 5.95 g (75%) of the title product. Loss to filtrate was calculated to be 1.2 g (15%). Solid was 98.8a% pure and 99.7 wt%.
methyl 5-(4-bromo-3-formylphenoxy)-2-cyanobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃;
A mixture of <strong>[606080-43-7]methyl 2-cyano-5-fluorobenzoate</strong> (4.48 g, 25.0 mmol), 2-bromo-5-hydroxybenzaldehyde (5.03 g, 25.0 mmol), and potassium carbonate (4.14 g, 30.0 mmol) in N,N-dimethylformamide (50 mL) was stirred at 80 C. overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (chloroform) to give methyl 5-(4-bromo-3-formylphenoxy)-2-cyanobenzoate (5.35 g, 71%). (0643) 1H-NMR (300 MHz, CDCl3) delta (ppm) 3.98 (s, 3H), 7.18-7.24 (m, 2H), 7.58 (d, J=2.9 Hz, 1H), 7.66 (d, J=2.6 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 10.3 (s, 1H).
6-(4-bromo-3-formylphenoxy)pyridine-2,3-dicarboxylic acid dimethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.14 g
With caesium carbonate In N,N-dimethyl-formamide at 80℃;
19.19ar 6-(4-Bromo-3-formyl-phenoxy)-pyridine-2,3-dicarboxylic acid dimethyl ester (19)
6-(4-Bromo-3-formyl-phenoxy)-pyridine-2,3-dicarboxylic acid dimethyl ester (19) (0789) To a solution of 6-chloro-pyridine-2,3-dicarboxylic acid dimethyl ester (18, 4.0 g, 17.42 mmols) and 2-bromo-5-hydroxy-benzaldehyde (3.5 g, 17.42 mmol) in DMF (30 mL) was added cesium carbonate (11.35 g, 34.84 mmols). The resulting mixture was heated at 80° C. overnight. DMF was removed under reduced pressure, diluted with EtOAc (100 mL), washed with water (2×25 mL) and brine (50 mL) solution. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give crude product which was purified by column chromatography (Silica gel 20% EtOAc in hexane) to yield title compound 19 (1.14 g, 15%) as a light yellow oil. 1H NMR 400 MHz (DMSO-d6) δ: 10.18 (s, 1H), 8.38 (d, J=8.6 Hz, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.66 (s, 1H), 7.55-7.52 (m, 1H), 7.36 (d, J=8.6 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 3H); MS (ES) m/z: 394 (M+1)+, 396 (M+3)+.
With caesium carbonate In N,N-dimethyl-formamide at 80℃;
19.19as 3-Bromo-6-(4-bromo-3-formyl-phenoxy)-pyridine-2-carboxylic acid ethyl ester (23)
3-Bromo-6-(4-bromo-3-formyl-phenoxy)-pyridine-2-carboxylic acid ethyl ester (23) (0794) To a solution of 3-bromo-6-chloro-pyridine-2-carboxylic acid ethyl ester (22, 8.0 g, 30.24 mmol) and 2-bromo-5-hydroxy-benzaldehyde (7.29 g, 36.29 mmol) in DMF (100 mL) was added cesium carbonate (22.6 g, 69.55 mmol). The resulting mixture was heated at 80° C. overnight. DMF was removed under reduced pressure, and the residue was diluted with EtOAc (200 mL), washed with water (2×50 mL) and brine (50 mL) solution. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give crude product which was purified by column chromatography (Silica gel 20% EtOAc in hexane) to yield title compound 23 (4.0 g, 31%) as transparent oil. 1H NMR 400 MHz (DMSO-d6) δ: 10.18 (s, 1H), 8.27 (d, J=8.6 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.65 (s, 1H), 7.51 (dd, J=8.7, 2.9 Hz, 1H), 7.26 (d, J=8.9 Hz, 1H), 4.29 (q, J=7.1 Hz, 2H), 1.25 (t, J=7.0 Hz, 3H); MS (ES) m/z: 430 (M+1)+.
6-[3-formyl-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenoxy]-2-methoxynicotinonitrile[ No CAS ]
2-[3-formyl-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenoxy]-6-methoxynicotinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6-[3-Formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-2-methoxy-nicotinonitrile and 2-[3-Formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-6-methoxy-nicotinonitrile (31 and 32) (0802) To a degassed solution (30 min with nitrogen) of 6-(4-bromo-3-formyl-phenoxy)-2-methoxy-nicotinonitrile and 2-(4-bromo-3-formyl-phenoxy)-6-methoxy-nicotinonitrile (29 and 30, 4.80 g, 14.40 mmol) in 1,4-dioxane (70 mL) was added bis(pinacolato)diboron (5.48 g, 21.61 mmol), potassium acetate (4.24 g, 43.20 mmol), and [1,1?-bis(diphenylphosphino)ferrocene]palladium(II)chloride (0.54 g, 0.72 mmol). Degassed again (10 min with nitrogen), and the suspension was heated at 90 C. overnight. The mixture was passed through Celite and concentrated under reduced pressure to give crude product, which was purified by column chromatography (silica gel, 25% EtOAc in hexane) to yield the title compounds 31 and 32 in a ratio of 1:1.5 (4.60 g, 85%) as a colorless oil. 1H NMR 400 MHz (DMSO-d6) delta: 10.37 (s, 2H), 8.28-8.24 (m, 2H), 7.83-7.57 (m, 4H), 7.64-7.57 (m, 2H), 6.80-6.73 (m, 2H), 3.71 (s, 3H), 3.61 (s, 3H), 1.39 (s, 24H).
6-(4-bromo-3-formylphenoxy)-2-chloronicotinonitrile[ No CAS ]
2-(4-bromo-3-formylphenoxy)-6-chloronicotinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In 1,2-dichloro-ethane; at 70℃; for 18h;Sealed tube;
6-(4-Bromo-3-formyl-phenoxy)-2-chloro-nicotinonitrile (3) (0998) Triethylamine (11.0 mL, 78.0 mmol) was added to a solution of 2-bromo-5-hydroxy-benzaldehyde (1) (7.84 g, 39.0 mmol) and 2,6-dichloro-nicotinonitrile (2) (7.42 g, 42.9 mmol) in a sealable reaction vessel. The reaction vessel was sealed with a teflon cap and heated at 70 C. for 18 hr. The reaction was left to cool to room temperature and concentrated to give an orange oil (18.0 g). The oil was diluted with CH2Cl2 (200 mL) followed by the addition of silica gel (70 g, 230-400 mesh) and concentrated to dryness. This was loaded onto a silica gel column (70 g, 230-400 mesh) and eluted with gradient 5-40% EtOAc/hexanes. Isolated a mixture of 6-(4-bromo-3-formyl-phenoxy)-2-chloro-nicotinonitrile (3) and 2-(4-bromo-3-formyl-phenoxy)-6-chloro-nicotinonitrile (4) in a ratio of 2:1, respectively (5.80 g) as a clear oil which later solidified to a white solid. The mixture was carried forward with further purification. (0999) 6-(4-bromo-3-formyl-phenoxy)-2-chloro-nicotinonitrile (3) 1H NMR 400 MHz (CDCl3) 810.35 (s, 1H), 7.99 (d, J=8.6 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.69 (d, J=2.7 Hz, 1H), 7.30 ppm (dd, J=8.6, 2.7 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H). 2-(4-bromo-3-formyl-phenoxy)-6-chloro-nicotinonitrile (4) 1H NMR 400 MHz (CDCl3) delta 10.35 (s, 1H), 7.97 (d, J=7.8 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.73 (d, J=2.3 Hz, 1H), 7.34 (dd, J=7.8, 2.3 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H).
6-(4-bromo-3-formylphenoxy)-2-methoxynicotinonitrile[ No CAS ]
2-(4-bromo-3-formylphenoxy)-6-methoxynicotinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6-(4-Bromo-3-formyl-phenoxy)-2-methoxy-nicotinonitrile and 2-(4-Bromo-3-formyl-phenoxy)-6-methoxy-nicotinonitrile (29 and 30) (0801) To a mixture of 6-chloro-2-methoxy-nicotinonitrile and 2-chloro-6-methoxy-nicotinonitrile (27 and 28, 5.0 g, 29.65 mmol) and 2-bromo-5-hydroxy-benzaldehyde (5.96 g, 29.65 mmol) in DMF (100 mL) was added potassium carbonate (6.14 g, 44.47 mmol). The resulting mixture was heated at 80 C. overnight. DMF was removed under reduced pressure, residue was dissolved in EtOAc (150 mL), washed with water (2×50 mL) and brine (50 mL) solution, dried over Na2SO4, filtered, and concentrated to give brown oil, which was recrystallized from diethyl ether (50 mL) to give inseparable mixture of compounds 29 and 30 in a ratio of 1:2 (5.8 g, 60%) as white solid. 1H NMR 400 MHz (DMSO-d6) delta: 10.17 (s, 2H), 8.28-8.23 (m, 2H), 7.87 (dd, J=8.5, 2.7 Hz, 2H), 7.75 (d, J=2.7 Hz, 1H), 7.71 (d, J=3.1 Hz, 1H), 7.62-7.55 (m, 2H), 6.79 (d, J=8.2 Hz, 1H), 6.73 (d, J=8.6 Hz, 1H), 3.71 (s, 3H), 3.61 (s, 3H); MS (ES) m/z: 335 (M+1)+.
6-(4-bromo-3-formylphenoxy)-2-dimethylaminonicotinonitrile[ No CAS ]
2-(4-bromo-3-formylphenoxy)-6-dimethylaminonicotinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6-(4-Bromo-3-formyl-phenoxy)-2-dimethylamino-nicotinonitrile (5) (1001) A mixture of 6-(4-bromo-3-formyl-phenoxy)-2-chloro-nicotinonitrile (3) and 2-(4-bromo-3-formyl-phenoxy)-6-chloro-nicotinonitrile (4) in a ratio of 2:1, respectively (2.47 g, 7.34 mmol) was dissolved in 1,2-dichloroethane (40 mL) in a sealable reaction vessel. Then dimethylamine (18.3 mL, 36.7 mmol) was added and the reaction vessel was sealed with a teflon cap. The reaction was heated at 70 C. for 4 hr [Note: A white precipitate formed overtime]. The reaction mixture was cooled to room temperature and then concentrated to give an orange coloured solid which contained a mixture of 6-(4-bromo-3-formyl-phenoxy)-2-dimethylamino-nicotinonitrile (5) and 2-(4-bromo-3-formyl-phenoxy)-6-dimethylamino-nicotinonitrile (6) in a ratio of 2:1, respectively (2.80 g). The solid was dissolved with CH2Cl2 (200 mL) followed by the addition of silica gel (50 g, 230-400 mesh) and concentrated to dryness. This was loaded onto a silica gel column (100 g, 230-400 mesh) and eluted with gradient 5-10% EtOAc/hexanes. Pure fractions were combined and concentrated to give the title compound (5) as a white solid (1.10 g, 43% isolated yield). (1002) 6-(4-bromo-3-formyl-phenoxy)-2-dimethylamino-nicotinonitrile (5) 1H NMR 400 MHz (CDCl3) 610.34 (s, 1H), 7.78 (d, J=2.7 Hz, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.27 (dd, J=8.6, 2.7 Hz, 1H), 6.24 (d, J=8.2 Hz, 1H), 3.11 (s, 6H). (1003) 2-(4-bromo-3-formyl-phenoxy)-6-dimethylamino-nicotinonitrile (6) 1H NMR 400 MHz (CDCl3) delta 10.35 (s, 1H), 7.85 (d, J=2.7 Hz, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.32 (dd, J=8.6, 2.7 Hz, 1H), 6.19 (d, J=8.6 Hz, 1H), 2.95 (s, 6H).
6-(4-bromo-3-formylphenoxy)-2-pyrrolidin-1-ylnicotinonitrile[ No CAS ]
2-(4-bromo-3-formylphenoxy)-6-pyrrolidin-1-ylnicotinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%; 10%
6-(4-Bromo-3-formyl-phenoxy)-2-pyrrolidin-1-yl-nicotinonitrile (5) (1016) A mixture of 6-(4-bromo-3-formyl-phenoxy)-2-chloro-nicotinonitrile (3): 2-(4-bromo-3-formyl-phenoxy)-6-chloro-nicotinonitrile (4) in a ratio of 2.0:1 (1.14 g, 3.39 mmol) and pyrrolidine (723 mg, 0.85 mL, 10.2 mmol) in 1,2-dichloroethane (30 mL) in a sealed reaction vessel was heated to 80 C. for 90 min. The reaction was cooled to room temperature and concentrated to give a mixture of 6-(4-bromo-3-formyl-phenoxy)-2-pyrrolidin-1-yl-nicotinonitrile (5) and 2-(4-bromo-3-formyl-phenoxy)-6-pyrrolidin-1-yl-nicotinonitrile (6) in a ratio of 2:1 (2.10 g). TLC of 6-(4-bromo-3-formyl-phenoxy)-2-pyrrolidin-1-yl-nicotinonitrile (5) gave Rf=0.6 and 2-(4-bromo-3-formyl-phenoxy)-6-pyrrolidin-1-yl-nicotinonitrile (6) gave Rf=0.4 when eluted with 25% EtOAc/hexanes and rendered with UV lamp or a solution of phosphomolybdic acid in ethanol. The mixture was fractionated by dry-pack column chromatography as follows: The oil was diluted with 10% MeOH/CH2Cl2 (100 mL) followed by the addition of silica gel (10 g, 230-400 mesh) and concentrated to dryness. This was loaded onto a silica column (30 g, 230-400 mesh) and eluted with 10% EtOAc/hexanes. The mixture was separable and gave 5 (550 mg, white solid, 43% yield) and 6 (120 mg, white solid, 10% yield). (1017) Compound 5: 1H NMR 400 MHz (CDCl3) 810.34 (s, 1H), 7.79 (d, J=3.1 Hz, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.65 (d, J=8.6 Hz. 1H), 7.28 (dd, J=9.0, 3.1 Hz, 1H), 6.18 (d, J=8.2 Hz, 1H), 3.60-3.52 (4H), 1.93-1.87 (4H). (1018) Compound 6: 1H NMR 400 MHz (CDCl3) 810.35 (s, 1H), 7.88 (d, J=2.7 Hz, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.60 (d, J=8.6 Hz, 1H), 7.33 (dd, J=8.2, 2.7 Hz, 1H), 6.05 (d, J=8.6 Hz, 1H), 3.40-3.20 (4H), 2.13-1.81 (4H).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water;Inert atmosphere; Heating;
compound represented by Formula (1-125-1) , a compound represented by Formula (1-125-2) , potassium carbonate, ethanol, water, and tetrakis (triphenyiphosphine) palladium (0) were put into a reaction container under a nitrogen atmosphere, followed by heating and stirring. After ordinary post-treatment was performed,purification was performed by column chromatography (silica gel) to obtain a compound represented by Formula (1-125-3).
4.8 g
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol;Inert atmosphere; Reflux;
5.0 g of the compound represented by Formula (I-23-1), 4.1 g of the compound represented by Formula (I-23-2), 5.2 g of potassium carbonate, and 50 mL of ethanol were added to the reaction container. After substituting nitrogen in the reaction container, 0.3 g of tetrakis (triphenylphosphine) palladium (0) was added thereto and the mixture was heated under reflux. After diluting with ethyl acetate and washing with a 5% hydrochloric acid and a saline solution, purification was performed by column chromatography (silica gel, ethyl acetate) to obtain 4.8 g of a compound represented by Formula (I-23-3).
4.8 g
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol;Inert atmosphere; Reflux;
5.0 g of the compound represented by (I-21-1), 4.1 g of the compound represented by the formula (I-21-2), 5.2 g of potassium carbonate and 50 mL of ethanol were placed in a reaction container.After the reaction vessel was subjected to nitrogen substitution, 0.3 g of hydrazine (triphenylphosphine)palladium (0) was added, and the mixture was heated under reflux.After diluting with ethyl acetate, washing with 5% hydrochloric acid and brine, and then purified by column chromatography (purified gel, ethyl acetate), 4.8 g of compound of formula (I-21-3) .
With potassium carbonate In N,N-dimethyl-formamide at 80℃; Inert atmosphere;
2.1 Step 1 Synthesis of intermediate 1
Compound SM (1.5 g, 8.26 mmol) was dissolved in DMF (25 mL) and 2-bromo-5-hydroxybenzaldehyde (1.66 g, 8.26 mmol) and K2CO3 (1.71 g, 12.4 mmol) were added with stirring. Under nitrogen, the reaction was carried out at 80 ° C overnight. TLC showed the reaction was completed. Cool to room temperature, add H20 (40 mL) and extract with EA (25 mL x 3). The combined organic phases were washed with saturated sodium chloride (25 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated and purified (SiO2, PE: EA = 100: 1) to give the title compound (2.3 g, 80.4%).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2.5h;Inert atmosphere;
Intermediate 1 (1.42 g, 7.22 mmol) was dissolved in DMF (25 mL) and 2-bromo-5-hydroxybenzaldehyde (1.21 g, 6.02 mmol) and K2CO3 (998.0 mg, 7.22 mmol) were added with stirring. Under nitrogen, the reaction was carried out at room temperature for 2.5 hours. TLC showed the reaction was completed. H2O (60 mL) was added and EA extracted (25 mL x 4). The combined organic phases were washed with saturated sodium chloride (25 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated and purified (SiO2, PE: EA = 10: 1) to give the title compound (1.75 g, 91.7%).
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1.5h; Inert atmosphere;
5.3 Step 3 Synthesis of intermediate 3
Intermediate 2 (447.8 mg, 1.49 mmol) was dissolved in DMF (6 mL) and 2-bromo-5-hydroxybenzaldehyde (250.0 mg, 1.24 mmol) and K2CO3 (206.3 mg, 1.49 mmol) were added with stirring. Under nitrogen, the reaction was carried out at room temperature for 1.5 hours and TLC showed the reaction was completed. H2O (15 mL) was added and EA extracted (15 mL x 3). The combined organic phases were washed with saturated sodium chloride (15 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated and purified (SiO2, PE: EA = 40: 1) to give the title compound (420.0 mg, 93.8%).
5-(1-methyl-1H-benzimidazole-2-oxy)-2-bromobenzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With sodium hydride; In N,N-dimethyl-formamide; at 120℃;
Step 2: Under nitrogen protection,1.20 g, 5.97 mmol of 2-bromo-5-hydroxybenzaldehyde and1.00 g, 6.00 mmol of 1-methyl-2-chlorobenzimidazole,Dissolved in 10 mL of N.N-dimethylformamide,Then add 60%, 264mg, 6.60mmol sodium hydride solution,The mixture was stirred at 120 C overnight.Then, it is cooled, filtered, and the filtrate is successively added with water and ethyl acetate, and the organic phase is concentrated, and the residue is purified by column chromatography.Obtaining 5-((1-methyl-1H-benzimidazole-2)-oxy)-2-bromobenzaldehyde,White solid 0.99 g, yield 50%.
5-(1-benzyl-1H-benzimidazole-2-oxy)-2-bromobenzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
With sodium hydride; In N,N-dimethyl-formamide; at 120℃;Inert atmosphere;
Step 2: Under a nitrogen atmosphere, 1.56 mg, 7.76 mmol of 2-bromo-5-hydroxybenzaldehyde and 1.88 g of 7.75 mmol of <strong>[43181-78-8]1-benzyl-2-chlorobenzimidazole</strong> were dissolved in NN-dimethylformamide. In 10 mL, then add 60%, 341 mg, 8.53 mmol of sodium hydride, and the mixture was stirred at 120 C overnight, then cooled, filtered, and the filtrate was added with water and ethyl acetate.The organic phase is concentrated, and the residue is purified by column chromatography to give 5-((1-benzyl-1H-benzimidazole-2)-oxy)-2-bromobenzaldehyde.The white solid was 0.95 g and the yield was 30%.
9-hydroxy-7H-dibenzo[de,g]quinolin-7-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
General procedure: A round-bottom flask was charged with aryl halide (1.0 mmol),aryl boronic acid (1.1 equiv.), K2CO3 (3 equiv.), PdCl2 (0.08 equiv.)and Na2SO4 (0.08 equiv.). The mixture was then stirred in anhydrous i-PrOH (4 mL) at 85 C for 8 h. After 8 h of reaction, themixture was filtered and the solvent was removed. Then, themixture in the flask was dissolved in DCE (2.0 mL), and TFA (3.0equiv.), TBHP (4.0 equiv.) and FeSO4 (0.03 equiv.) were added to thissolution. After the mixture was reacted at 90 C for 10 h, the solution was treated with saturated aqueous NaHCO3. The mixturewas extracted with ethyl acetate (3 10 mL), and the combinedorganic layer was dried over anhydrous Na2SO4 and concentrated invacuum. The residue was purified by chromatography (silica gel, ethyl acetateehexane: 1: 5) to obtain the desired products (yellowpowder).
With toluene-4-sulfonic acid In dichloromethane at 10 - 15℃;
1-9 Example 8
At room temperature, 2-bromo-5-hydroxybenzaldehyde (SM-1, 20.10g, 0.10mol), MED (15.10g, 0.13mol), p-toluenesulfonic acid (1.72g, 0.01mol) were added to dry dichloromethane (300ml), control the temperature at 1015 to the end of the reaction, add saturated sodium bicarbonate solution (250ml), stir for 1015min, separate the layers to take the organic layer, wash with purified water (150ml×3), and wash with saturated brine (150ml). ), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 4-bromo-3-(1,3-dioxolan-2-yl)phenol with a yield of 97.7% and a purity of 99.73%.
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