* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With 8-quinolinol; sodium hydroxide; copper dichloride In water at 20℃; for 0.333333 h; Sealed tube; Microwave irradiation
General procedure: In a 10 mL glass tube 2-iodobenzoic acid (1.0 mmol), acetamidine hydrochloride (1.2 mmol), CuCl2 (0.1 mmol), L2 (0.1 mmol), and NaOH (4.0 equiv.) and 3.0 mL water were placed. The vessel was then sealed with a septum and placed into the microwave cavity. Initial microwave irradiation of 120 W by using a CEM Discover microwave synthesizer was used at the room temperature for 20 min. The reaction mixture was stirred continuously during the reaction. After completion of the reaction, the solvent was removed in vacuo. The residue was purified by silica gel column chromatography to afford the corresponding product. All the products were confirmed by NMR and MS spectroscopic analysis.
5.00 g (21.6mmol) 2-Bromo-5-methoxy-benzoic acid, 620 mg (4.32mmol) copper (I) bromide and 2.63 g (32.4 mmol) potassium cyanate were dissolved in pyridine and boiled for 30 min. The solvent was removed and the residue was dissolved in 150 ml 2N hydrogen chloride acid and 150 ml ethyl acetate. The organic solvent was treated with water and brine, dried over magnesium sulfate and removed. The residue was digested with methanol. Yield: 2.50 g= 61percent Grey powder
Reference：
[1] Journal of the American Chemical Society, 2002, vol. 124, # 7, p. 1354 - 1363
[2] Journal of Organic Chemistry, 1993, vol. 58, # 17, p. 4579 - 4583
[3] Journal of the American Chemical Society, 2011, vol. 133, # 20, p. 7916 - 7925
[4] European Journal of Medicinal Chemistry, 2015, vol. 94, p. 149 - 162
[5] Chemistry - An Asian Journal, 2018, vol. 13, # 17, p. 2401 - 2404
10
[ 22921-68-2 ]
[ 71-43-2 ]
[ 60080-98-0 ]
Reference：
[1] European Journal of Organic Chemistry, 2014, vol. 2014, # 7, p. 1423 - 1430
[2] European Journal of Organic Chemistry, 2014, vol. 2014, # 7, p. 1423 - 1430
11
[ 22921-68-2 ]
[ 60080-98-0 ]
Reference：
[1] Tetrahedron, 2007, vol. 63, # 12, p. 2695 - 2711
[2] Organic and Biomolecular Chemistry, 2013, vol. 11, # 42, p. 7262 - 7266
12
[ 22921-68-2 ]
[ 58380-11-3 ]
Yield
Reaction Conditions
Operation in experiment
4.2 g
With aluminum (III) chloride In chlorobenzene for 2.5 h; Reflux
2-Bromo-5-methoxybenzoic acid5 g (manufactured by Wako Pure Chemical Industries, Ltd.) and 15 g of aluminum chloride were refluxed in 150 mL of chlorobenzene for 2.5 hours.After cooling, the reaction solution was transferred to ice water and extracted three times with 250 mL of diethyl ether. The obtained extract was concentrated under reduced pressure, diethyl ether was distilled off,4.2 g of 2-bromo-5-hydroxybenzoic acid was obtained.3.9 g of the obtained 2-bromo-5-hydroxybenzoic acid and 3.9 g of resorcinol (Tokyo Chemical Industry Co., Ltd.) were dissolved in 9 mL of 4 M NaOH aqueous solution at 60 ° C.,And heated for 30 minutes. To this reaction solution was added 1.8 mL of a 10percent aqueous solution of copper sulfate,Further,Heating was carried out for 10 minutes.The precipitate formed was collected by filtration,A white powder of urolitin A was obtained.
4.2 g
With aluminum (III) chloride In chlorobenzene for 2.5 h; Reflux
5g of 2-bromo-5-methoxybenzoic acid (manufactured by Wako Pure Chemical Industries, Ltd.) and 15 g of aluminum chloride were refluxed in 150 mL of chlorobenzene for 2.5 hours. After cooling, the reaction solution was transferred to ice water and extracted three times with 250 mL of diethyl ether. The obtained extract was concentrated under reduced pressure and diethyl ether was distilled off to obtain 4.2 g of 2-bromo-5-hydroxybenzoic acid. 3.9 g of the obtained 2-bromo-5-hydroxybenzoic acid and 3.9 g of resorcinol (Tokyo Chemical Industry Co., Ltd.) were heated in 9 mL of 4 M NaOH aqueous solution at 60 ° C. for 30 minutes. 1.8 mL of a 10percent aqueous solution of copper sulfate was added to the reaction solution, followed by further heating at 80 ° C. for 10 minutes. The precipitate formed was recovered by filtration to obtain a white powder of urolitin A.
4.2 g
With aluminum (III) chloride In chlorobenzene for 2.5 h; Reflux
5 g of 2-bromo-5-methoxybenzoic acid (manufactured by Wako Pure Chemical Industries, Ltd.) and 15 g of aluminum chloride were refluxed in 150 mL of chlorobenzene for 2.5 hours.After cooling,The reaction solution was transferred to ice water,Extraction was carried out three times with 250 mL of diethyl ether.The obtained extract was concentrated under reduced pressure, diethyl ether was distilled off,4.2 g of 2-bromo-5-hydroxybenzoic acid was obtained.
4.2 g
With aluminum (III) chloride In chlorobenzene for 2.5 h; Reflux
5 g of 2-bromo-5-methoxybenzoic acid (manufactured by Wako Pure Chemical Industries, Ltd.) and 15 g of aluminum chloride were refluxed in 150 mL of chlorobenzene for 2.5 hours.After cooling, the reaction solution was transferred to ice water and extracted three times with 250 mL of diethyl ether. The obtained extract was concentrated under reduced pressure and diethyl ether was distilled off to obtain 4.2 g of 2-bromo-5-hydroxybenzoic acid. 3.9 g of the obtained 2-bromo-5-hydroxybenzoic acid and 3.9 g of resorcinol (Tokyo Chemical Industry Co., Ltd.) were heated in 9 mL of 4 M NaOH aqueous solution at 60 ° C. for 30 minutes. 1.8 mL of a 10percent aqueous solution of copper sulfate was added to the reaction solution, followed by further heating at 80 ° C. for 10 minutes. The precipitate formed was recovered by filtration, and urineA white powder was obtained.
4.2 g
With aluminum (III) chloride In chlorobenzene for 2.5 h; Reflux
5 g of 2-bromo-5-methoxybenzoic acid (manufactured by Wako Pure Chemical Industries, Ltd.)And 15 g of aluminum chloride were refluxed in 150 mL of chlorobenzene for 2.5 hours. After cooling, the reaction solution was transferred to ice water,Extraction was carried out three times using 250 mL of diethyl ether.The obtained extract was concentrated under reduced pressure, diethyl ether was distilled off,4.2 g of 2-bromo-5-hydroxybenzoic acid was obtained.3.9 g of the obtained 2-bromo-5-hydroxybenzoic acid and resorcinol3.9 g (manufactured by Tokyo Chemical Industry Co., Ltd.) was heated in 9 mL of 4 M NaOH aqueous solution at 60 ° C. for 30 minutes.1.8 mL of a 10percent aqueous solution of copper sulfate was added to the reaction solution, and further 80 ° C.,Heating was carried out for 10 minutes. The precipitate formed was collected by filtration,A white powder of Urolithin A was obtained.
Reference：
[1] Yakugaku Zasshi, 1956, vol. 76, p. 1122,1125[2] Chem.Abstr., 1957, p. 3505
[3] Journal of Medicinal Chemistry, 2002, vol. 45, # 12, p. 2388 - 2409
[4] Patent: US5519133, 1996, A,
[5] Journal of Agricultural and Food Chemistry, 2008, vol. 56, # 2, p. 393 - 400
[6] Journal of Agricultural and Food Chemistry, 2009, vol. 57, # 21, p. 10181 - 10186
[7] Patent: WO2015/55736, 2015, A1, . Location in patent: Page/Page column 20
[8] Patent: EP2862568, 2015, A1, . Location in patent: Paragraph 0069
[9] Patent: JP2017/31108, 2017, A, . Location in patent: Paragraph 0084
[10] Patent: JP2017/7951, 2017, A, . Location in patent: Paragraph 0054
[11] Patent: JP2016/216378, 2016, A, . Location in patent: Paragraph 0056
[12] PLoS ONE, 2016, vol. 11, # 6,
[13] Patent: JP2017/14154, 2017, A, . Location in patent: Paragraph 0061
[14] Patent: JP2016/216443, 2016, A, . Location in patent: Paragraph 0063
13
[ 67-56-1 ]
[ 22921-68-2 ]
[ 35450-36-3 ]
Yield
Reaction Conditions
Operation in experiment
85%
for 18 h; Heating / reflux
To a stirred solution of 2-bromo-5-methoxybenzoic acid (Aldrich 384003; 5.0 g, 21.6 mmol) in methanol (80 mL) was added concentrated hydrochloric acid (2 mL) and the mixture was heated under reflux for 18 hours. The resulting solution was cooled, the solvent was removed in vacuo, water (100 mL) was added and the mixture was extracted with ethyl acetate (2 x 100 mL). The combined extracts were washed with saturated aqueous sodium hydrogen carbonate, dried over MgSO4, filtered and evaporated to obtain methyl 2-bromo-5-methoxybenzoate as a light brown oil (4.50 g, 85percent); NMR Spectrum δH (300 MHz, CDCl3) 7.53 (1 H, d, J 8.8 Hz, 3-H), 7.32 (1 H, d, J 3.0 Hz, 6-H), 6.89 (1 H, dd, J 3.0, 8.8 Hz, 4-H), 3.94 (3 H, s, Ar OCH3) and 3.82 <n="66"/>(3 H, s, CO2CH3) (data in accordance with published values, see Barhate, N. B.; Gajare, A. S.; Wakharkar, R. D.; Bedekar, A. V. Tetrahedron 1999, 55, 11127- 11142); vmjcnfl (thin film) 2951, 1732 (C=O), 1592, 1472, 1433, 1289, 1250, 1227, 1099, 1017, 975, 823, 792 (data in accordance with published values, see Barhate, N. B.; Gajare, A. S.; Wakharkar, R. D.; Bedekar, A. V. Tetrahedron 1999, 55, 11127-11142.); Rf (hexane - ethyl acetate 5:1) 0.58.
Reference：
[1] Tetrahedron, 1998, vol. 54, # 37, p. 11209 - 11234
[2] Journal of Organic Chemistry, 2003, vol. 68, # 11, p. 4586 - 4589
[3] Patent: WO2012/102985, 2012, A1, . Location in patent: Page/Page column 111
[4] Patent: WO2008/75048, 2008, A2, . Location in patent: Page/Page column 64-65
[5] Tetrahedron, 1995, vol. 51, # 37, p. 10115 - 10124
[6] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 17, p. 4601 - 4611
[7] Tetrahedron, 2016, vol. 72, # 24, p. 3454 - 3467
14
[ 22921-68-2 ]
[ 35450-36-3 ]
Reference：
[1] Yakugaku Zasshi, 1956, vol. 76, p. 1122,1125[2] Chem.Abstr., 1957, p. 3505
[3] Patent: US6514964, 2003, B1,
15
[ 22921-68-2 ]
[ 74-88-4 ]
[ 35450-36-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 1, p. 222 - 227
16
[ 75-91-2 ]
[ 22921-68-2 ]
[ 35450-36-3 ]
Reference：
[1] Dalton Transactions, 2015, vol. 44, # 14, p. 6546 - 6559
[2] Journal of Organic Chemistry, 2013, vol. 78, # 19, p. 9898 - 9905
17
[ 77152-08-0 ]
[ 22921-68-2 ]
[ 716-31-4 ]
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 22, p. 11126 - 11146
Dissolve 2-bromo-5-methoxy-benzoic acid (2.25 g, 9.7 mmol) in THF (10 mL) and cool to 0 [°C.] Add 1M borane in THF (48 mL, 48 mmol) and warm to room temperature. Upon completion, slowly pour reaction onto ice and saturated aqueous sodium bicarbonate. Extract with ethyl acetate and wash organic layer with water and saturated aqueous sodium bicarbonate. Dry with sodium sulfate, filter and concentrate in vacuo to yield 2.1 g (100percent) of the title [COMPOUND.APOS;H] NMR [(CDC13)] [O7.] 42 (d, J= 8.8 Hz, 1H), 7.06 (d, J = 3.1 Hz, 1H), 6.72 [(DD,] [J= 8.] 8,3. 1 Hz, [1H),] 4.71 (s, 2H), 3.81 (s, 3H).
96%
With borane In tetrahydrofuran for 1 h;
Under a nitrogen atmosphere, 25 g (0.11 mol) of 2-bromo-5-methoxybenzoic acid was dissolved in 100 mL of anhydrous THF. 140 mL (0.14 mol) of borane (1 M in THF) was added to this solution over a period of 1 hour. The reaction was allowed to stir and was carefully quenched with 1:1 THF: saturated K2CO3. Ether was added and the aqueous and organic layers were separated. The aqueous layer was extrated again with ether (2x100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford 23.0 g (96percent) of 2-bromo-5-methoxybenzyl alcohol (13). 1H NMR (CDCl3): 2.02 (t-1H; J=6.23 Hz), 3.79 (s-3H), 4.69 (d-2H; J=6.23 Hz), 6.70 (dd-1H; J=3.12, 8.72 Hz), 7.04 (d-1H; J=3.12 Hz), 7.39 (d-1H; J=8.72 Hz).
94%
Stage #1: With dimethylsulfide borane complex In tetrahydrofuran Stage #2: at 60℃;
2-Bromo-5-methoxy benzoic acid (1 eq.) was dissolved in anhydrous THF (0.55M solution) and borane dimethylsulfide complex (2M in THF, 1 eq.) was added dropwise to the solution. The mixture was left stirring overnight, then HCl in MeOH was added and the mixture was warmed to 60 0C. All volatiles were evaporated and the residual material was dissolved in DCM. The solution was washed with IN HCl and with brine, then dried over Na2SO4 and evaporated in vacuo. A colorless oil was obtained (94percent), which was used without further characterization in the next reaction.
94%
Stage #1: With dimethylsulfide borane complex In tetrahydrofuran Stage #2: With hydrogenchloride In tetrahydrofuran; methanol at 60℃;
2-Bromo-5-methoxy benzoic acid (1 eq) was dissolved in anhydrous TηF (0.55M solution) and BH3 SMe2 complex (2M in THF, 1 eq) was added dropwise to the solution. The mixture was stirred overnight, then HCl in MeOH was added and the mixture was warmed to 60 0C. All volatiles were evaporated and the residual material was dissolved in DCM. The solution was washed with IN HCl and with brine, then dried over Na2SO4 and evaporated in vacuo. A colorless oil was obtained (94percent), which was used without further characterization in the next reaction.
94%
With dimethylsulfide borane complex In dichloromethane at 0 - 25℃; for 2 h;
18A (MW 231.05, 130 mmol, 30.0 g) in 300 mL CH2Cl2 at 00 C. Add BH3-SMe2 (3 equ, 25.2 mL) and age for 2 h at 250 C. Quench into aqueous 2 N HCl and separate layers. Dry organic (magnesium sulfate) and concentrate in vacuo to obtain 94percent yield of 18 (MW 217.06, 25.5 g).
96%
With borane In tetrahydrofuran
Preparation 9 2-bromo-5-methoxybenzyl alcohol (13) Under a nitrogen atmosphere, 25 g (0.11 mol) of 2-bromo-5-methoxybenzoic acid was dissolved in 100 mL of anhydrous THF. 140 mL (0.14 mol) of borane (1 M in THF) was added to this solution over a period of 1 hour. The reaction was allowed to stir and was carefully quenched with 1:1 THF: saturated K2CO3. Ether was added and the aqueous and organic layers were separated. The aqueous layer was extrated again with ether (2*100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford 23.0 g (96percent) of 2-bromo-5-methoxybenzyl alcohol (13). 1H NMR (CDCl3): 2.02 (t-1H; J=6.23 Hz), 3.79 (s-3H), 4.69 (d-2H; J=6.23 Hz), 6.70 (dd-1H; J=3.12, 8.72 Hz), 7.04 (d-1H; J=3.12 Hz), 7.39 (d-1H; J=8.72 Hz).
Reference：
[1] Patent: WO2004/9578, 2004, A2, . Location in patent: Page 31
[2] Journal of Organic Chemistry, 2005, vol. 70, # 2, p. 756 - 759
[3] European Journal of Medicinal Chemistry, 2015, vol. 94, p. 149 - 162
[4] Journal of Organic Chemistry, 1993, vol. 58, # 17, p. 4579 - 4583
[5] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 17, p. 4511 - 4514
[6] Patent: US2004/77853, 2004, A1, . Location in patent: Page 25
[7] Patent: WO2007/129119, 2007, A1, . Location in patent: Page/Page column 43
[8] Patent: WO2009/10783, 2009, A1, . Location in patent: Page/Page column 45
[9] Patent: US6353110, 2002, B1, . Location in patent: Page column 25
[10] Journal of Medicinal Chemistry, 2006, vol. 49, # 15, p. 4721 - 4736
[11] Journal of Organic Chemistry, 1999, vol. 64, # 26, p. 9658 - 9667
[12] Journal of Medicinal Chemistry, 2006, vol. 49, # 15, p. 4447 - 4450
[13] Tetrahedron, 1998, vol. 54, # 37, p. 11209 - 11234
[14] Patent: WO2004/48314, 2004, A1, . Location in patent: Page 50-52
[15] Patent: US2003/87891, 2003, A1,
[16] Patent: US5807897, 1998, A,
[17] Patent: EP883599, 2002, B1,
[18] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 12, p. 3193 - 3195
[19] Journal of the American Chemical Society, 2011, vol. 133, # 20, p. 7916 - 7925
[20] Chemistry - An Asian Journal, 2018, vol. 13, # 17, p. 2401 - 2404
With sodium chlorite; sodium dihydrogenphosphate; 2-methyl-but-2-ene; In tetrahydrofuran; water; tert-butyl alcohol; at 20℃; for 1.16667h;
). 2-Bromo-5-methoxybenzaldehyde (548 mg, 2.5 mmol), tert-butyl alcohol (30 mL), 2-methyl-2-butene (6 mL), and THF (30 mL) were addedto a round-bottom flask. NaClO2 (811 mg, 7.1 mmol) and NaH2PO4(2.14 g, 14 mmol) dissolved in water were gradually added over a period of 10min and the resulting mixture was stirred for 1.0 hr at room temperature. Afterthe removal of tert-butyl alcohol, 2-methyl-2-butene, and THF under reduced pressure, 2M HCl was added to the reaction mixture to acidify it (pH 2). The solution was thenextracted with ethyl acetate. The organic phase was washed with brine and driedover anhydrous Na2SO4. The solvent was removed underreduced pressure. The white solid (616 mg, quantitative yield) was identifiedas 2-bromo-5-methoxybenzoic acid (4a) on the basis of 1H-NMRand mass spectra. 1H-NMR (400 MHz, CDCl3): d 3.84 (s, -OCH3, 3H), 6.95 (dd, J=8.8 Hz, 3.0 Hz, 1H), 7.50 (d, J=3.0 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H); MS (ESI): m/z[M-H+2]- 231, [M-H]- 229.
72%
With potassium permanganate; In water; at 75℃; for 2h;
Commercially available 2-bromo-5-methoxybenzaldehyde (4.65mmol) was dissolved in 20mL of water. KMnO4 (6.51mmol, 1.4 eq.) was dissolved in 15mL of water and added dropwise to the reaction mixture. The reaction mixture was stirred at 75C for 2h, then a solution of KOH at 20% was added to obtain a strongly basic pH. The reaction mixture was filtered through a pleated filter, the filter washed with hot water and the aqueous filtrates were cooled to rt and filtered again to remove aldehyde residues. When the aqueous filtrates were acidified with HCl 37% the 2-bromo-5-methoxybenzoic acid 2b precipitated as white solid that was collected by filtration under reduced pressure (Yield: 72%, 773mg). No further purification was necessary. 1H NMR (300MHz, CDCl3): delta=7.58 (d, J=8.8Hz, 1H, arom.), 7.52 (d, J=3.1Hz, 1H, arom.), 6.95 (dd, J=8.8, 3.1Hz, 1H, arom.), 3.84 (s, 3H, -CH3). These data are in good agreement with literature values [27].
General procedure: To a solution of 4-fluoro-2-hydroxybenzoic acid (780.6 mg, 5 mmol) in MeCN (10 mL) was added con. H2SO4 (285 muL, 1.05 equiv.) at room temperature, the mixture was stirred for 5 min. Then, NBS (934.4 mg, 1.05 equiv.) was added to the mixture. The reaction was monitored using TLC analysis. The mixture was evaporated to dryness and MeCN (1 mL) was added to the flask. The mixture was stirred for 10 min and filtered. The filter cake was washed by water and dried to obtain the product as a white solid; yield: 85% (0.99 g).
90.8%
After putting 152.0 g (1.0 mol) of 3-methoxyben- zoic acid was into a 2.000 mE four-necked flask equipped with a stirrer, a thermometer, and a reflux cooling tube, 800 g of water was added thereto and stirred so as to disperse 3-methoxybenzoic acid. Subsequently, 273.3 g (2.05 mol) of a 30% sodium hydroxide aqueous solution was added. The liquid temperature was then reduced to 0 C., and 167.8 g (1.05 mol) of bromine was added dropwise at a liquid temperature of 0 to 5 C. Completion of the dropwise addition was followed by stirring for one hour at a liquid temperature of 0 to 5 C. Afier completion of the reaction, 1.28 g (0.01 mol) of sodium sulfite was added followed by addition of 100 g of toluene and raising the liquid temperature to 70 C. The organic phase was removed by a liquid separation operation, and 104.2 g (1.0 mol) of 35% hydrochloric acid was added dropwise to the acquired aqueous phase and stirred for one hour. Precipitated crystals were collected by filtration and dried under reduced pressure to acquire 237.3 g (99.9% purity, 90.8% yield) of 2-bromo-5- methoxybenzoic acid.
78%
With bromine; In acetic acid;
Reference Example 2-11 2-Bromo-5-methoxybenzoic acid The title compound was prepared according to the method described in JP 63-287756 A. To a solution of 3-methoxybenzoic acid (25.0 g, 164 mmol) in acetic acid (150 mL), a solution of bromine (26.5 g, 166 mmol) in acetic acid (75 mL) was added dropwise at room temperature, and the mixture was stirred at the same temperature for 8 hours. The mixture was poured into water, and the resulting crystals were collected by filtration, washed with water, and air dried to give the title compound (29.5 g, 78% yield). NMR (CDCl3) delta: 3.84 (3H, s), 6.95 (1H, dd, J=3.0 Hz, 8.8 Hz), 7.53 (1H, d, J=3.0 Hz), 7.58 (1H, d, J=8.8 Hz), hidden (1H).
72%
With bromine; acetic acid; In water; at 110℃; for 10h;
To a 250 mL round bottom flask equipped with a magnetic stirrer, m-methoxybenzoic acid (10 g, 55 mmol) was added and acetic acid (20 mL) was added to complete dissolution. A solution of bromine (3.4 mL) in water (10 mL) was slowly added to the flask and then water (60 mL) was added. The mixture was refluxed for 10 h and the TLC reaction was complete. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed twice with water to give a crude product. The crude product was recrystallized from acetic acid and water to give 10.9 g of pure white product in 72% yield. Melting point: 155-157 C; Literature value: 154-157 C (Tetrahedron 1963, 19, 1001-1010).
With bromine; In water; acetic acid;
(a) To m-anisic acid in acetic acid (1 L) is added dropwise bromine (85 ml), followed by water (1 L). The reaction mixture is heated to reflux, cooled in an ice-bath and then the product is collected by filtration, washed with cold water and dried to afford 2-bromo-5-methoxybenzoic acid, m.p. 154-156 C.
305.7 g (79%)
With bromine; In water; acetic acid;
(a) To a mixture of m-anisic acid (250 g, 1.67 mol) in acetic acid (1 L) was added bromine (85 mL) and then water (1 L). The mixture was heated to reflux, cooled in an ice bath and the product which precipitated was collected by filtration and washed with water to afford 305.7 g (79%) of 2-bromo-5-methoxybenzoic acid, m.p. 154-156 C.
With bromine; In water; acetic acid;
(a) To m-anisic acid in acetic acid (1 L) was added dropwise bromine (85 ml), followed by water (1 L). The reaction mixture was heated to reflux, cooled in an ice-bath and then the product was collected by filtration, washed with cold water and dried to afford 2-bromo-5-methoxybenzoic acid, m.p. 154-156 C.
305.7 g (79%)
With bromine; In water; acetic acid;
(a) To a mixture of m-anisic acid (250 g, 1.67 mol) in acetic acid (1 L) was added bromine (85 mL) and then water (1L). The mixture was heated to reflux, cooled in an ice bath and the product which precipitated was collected by filtration and washed with water to afford 305.7 g (79%) of 2-bromo-5-methoxybenzoic acid, m.p. 154-156 C.
General procedure: The title compounds synthesized within this study is shown inScheme 2 with the synthetic scheme.For the synthesis of UA, UB, and HMUA, a mixture of correspondingbenzoic acid derivative (2.3 mmol) and resorcinol(13.8 mmol) in sodium hydroxide aqueous solution (16.8 mmol,25 mL) was heated for 1 h under reflux. Then, aqueous CuSO4(28%, 15 mL) was added to the reaction mixture. The precipitatedproduct was cooled, filtered, and washed with ice water.
75%
Step 1: Ullmann Coupling Production: Batch RRO1L1O8AO. The production under GMP conditions was accomplished in a single batch. The production scale was 40.0 kg of commercially available 2-Bromo-5-methoxy benzoic acid. The standard equipment used in the Miniplant were a 450 L Hastelloy reactor, 1000 L stainless steel tank, 850 L stainless steel tank, 150 L stainless steel filter, QuadroComil, 100 mL brown-glass bottle and a stainless steel vacuumtray dryer.The solution of the catalyst was prepared by dissolving copper sulfate pentahydrate (4.4 g, 0.02 mol) in purified water (28 mL) at ambient temperature. The solution was stored in a glass bottle until use. The reactor was charged with 2-Bromo-5-methoxy benzoic acid (40.0 kg, 173.1 mol), 2.0 equiv. of resorcinol (38.8 kg, 352.4 mol), and 6.6 vol. of purifiedwater (265 L). Agitation was started and 2.2 equiv. of 50% caustic soda (31.0 kg, 387.6 mol) were added at a rate keeping the bulk temperature bellow 40 C (30 mm required). Stirring was continued for 5 mm at 25 C until a clear solution was obtained. The aqueous copper sulfate solution prepared previously was added at 25 C. The reaction mixture was heated to 70 C within 75 mm. The reaction mixture became very thick and viscous. The speed of stirring and mixing was significantly reduced. Therefore the mixture was diluted with additional 1.3 vol. of purified water (50 L). Stirring at 70-90 C was continued until InProcess Control by HPLC indicated conversion of 2-Bromo-5-methoxy benzoic acid to 8- methyl urolithin A 97 % (5 hours required). The reaction mixture was cooled from 89 C to 25 C within 20 mm and agitation was continued overnight (14 hours). The product was collected by filtration (48 hours required) and the filter cake was rinsed on the filter subsequently with 3.5 vol. of purified water (141 L, 60 hours required) and 1.8 vol. ofmethanol (56.0 kg, 71 L, 40 hours required). After combination of the mother liquor with the rinse solution the mixture was checked for residual product and discarded. The filter cake was dried in a flow of dry nitrogen and under reduced pressure at 30-50 C for 2 days until LOD = 0.3 %wt. Finally de-lumping of the material was accomplished in a QuadroComil using a 1.9 mm sieve.The product was received in a yield of 75 % corresponding to 31.3 kg of 8-methyl urolithin A.
A mixture of 2-bromo-5-methoxybenzoic acid (5.6 grams), resorcinol (5.5 grams) and sodium hydroxide (2.2 grams) in water (25 ml) was heated under reflux for 30 minutes. After the addition of copper sulphate (5% aqueous solution, 10 ml), the mixture is refluxed again for 10 min when 3-hydroxy-8-methoxydibenzo-alpha-pyrone (3.7 grams) was precipitated as a straw colored powder. Crystallization from methanol and glacial acetic acid, in succession, afforded pale-yellow micro-crystals, m.p. 285-286 C. A suspension of this compound (2.18 grams) in a mixture of glacial acetic acid (120 ml) and azeotropic hydrobromic acid (60 ml) was heated under reflux for 11 hours. The starting material had dissolved within 2 hours and the desired product, 3,8-dihydroxydibenzo-alpha-pyrone (2), crystallized out after 6 hours as light yellow powder (1.9 grams). Recrystallization of the product from glacial acetic acid gave pale-yellow needles, m.p. 360-362 C. The purity of the products was determined by HPLC, and 1H-NMR spectra.
A mixture of 2-bromo-5-methoxybenzoic acid 1 (27.6 g; 119 mmol; 1.0 eq.), resorcinol 2 (26.3 g; 239 mmol; 2.0 eq.) and sodium hydroxide (10.5 g; 263 mmol; 2.2 eq.) in water (120 mL) was heated under reflux for 1 hour. A 5 % aqueous solution of copper sulphate (3.88 g of CuS04'5H20 in 50 mL water; 15.5 mmol; 0.1 eq.) was then added and the mixture was refluxed for additional 30 minutes. The mixture was allowed to cool to room temperature and the solid was filtered on a Buchner filter. The residue was washed with cold water to give a pale red solid which was triturated in hot MeOH. The suspension was left overnight at 4 C. The resultant precipitate was filtered and washed with cold MeOH to yield the title compound 3 as a pale brown solid.
A mixture of 2-bromo-5-methoxybenzoic acid 1(27.6 g; 119 mmol; 1.0 eq.), resorcinol 2(26.3 g; 239 mmol; 2.0 eq.) and sodium hydroxide (10.5 g; 263 mmol; 2.2 eq.) in water (120mL) was heated under reflux for 1 hour. A 5 % aqueous solution of copper sulphate (3.88 gof CuSO45H2O in 50 mL water; 15.5 mmol; 0.1 eq.) was then added and the mixture wasrefluxed for an additional 30 minutes. The mixture was allowed to cool to room temperature and the so lid was filtered on a Buechner filter. The residue was washed with cold water to give a pale red solid which was triturated in hot MeOH. The suspension was left overnight at 4 C. The resultant precipitate was filtered and washed with cold MeOH to yield the titlecompound 3 as a pale brown solid.
A mixture of 2-bromo-5-methoxybenzoic acid 1 (27.6 g; 119 mmol; 1.0 eq.), resorcinol 2 (26.3 g; 239 mmol; 2.0 eq.) and sodium hydroxide (10.5 g; 263 mmol; 2.2 eq.) in water (120 mL) was heated under reflux for 1 hour. A 5 % aqueous solution of copper sulphate (3.88 g of CuSO4*5H2O in 50 mL water; 15.5 mmol; 0.1 eq.) was then added and the mixture was refiuxed for additional 30 minutes. The mixture was allowed to cool to room temperature and the solid was filtered on a Buchner filter. The residue was washed with cold water to give a pale red solid which was triturated in hot MeOH. The suspension was left overnight at 4 C. The resultant precipitate was filtered and washed with cold MeOH to yield the title compound 3 as a pale brown solid.
A mixture of 2-bromo-5-methoxybenzoic acid 1(27.6 g; 119 mmol; 1.0 eq.), resorcinol 2(26.3 g; 239 mmol; 2.0 eq.) and sodium hydroxide (10.5 g; 263 mmol; 2.2 eq.) in water (120 mL) was heated under reflux for 1 hour. A 5 % aqueous solution of copper sulphate (3.88 g of CuSO45H2O in 50 mL water; 15.5 mmol; 0.1 eq.) was then added and the mixture was refluxed for an additional 30 minutes. The mixture was allowed to cool to room temperature and the solid was filtered on a Buechner filter. The residue was washed with cold water togive a pale red solid which was triturated in hot MeOH. The suspension was left overnight at4 C. The resultant precipitate was filtered and washed with cold MeOH to yield the title compound 3 as a pale brown solid.
A mixture of 2-bromo-5-methoxybenzoic acid 1 (27.6 g; 1 19 mmol; 1 .0 eq.), resorcinol 2 (26.3 g; 239 mmol; 2.0 eq.) and sodium hydroxide (10.5 g; 263 mmol; 2.2 eq.) in water (120 ml_) was heated under reflux for 1 hour. A 5 % aqueous solution of copper sulphate (3.88 g of CuSO4-5H2O in 50 ml_ water; 15.5 mmol; 0.1 eq.) was then added and the mixture was refluxed for additional 30 minutes. The mixture was allowed to cool to room temperature and the solid was filtered on a Buchner filter. The residue was washed with cold water to give a pale red solid which was triturated in hot MeOH. The suspension was left overnight at 4 C. The resultant precipitate was filtered and washed with cold MeOH to yield the title compound 3 as a pale brown solid.
A mixture of 2-bromo-5-methoxybenzoic acid 1 (27.6 g; 1 19 mmol; 1 .0 eq.), resorcinol 2 (26.3 g; 239 mmol; 2.0 eq.) and sodium hydroxide (10.5 g; 263 mmol; 2.2 eq.) in water (120 ml_) was heated under reflux for 1 hour. A 5 % aqueous solution of copper sulphate (3.88 g of CuSO4-5H2O in 50 ml_ water; 15.5 mmol; 0.1 eq.) was then added and the mixture was refluxed for additional 30 minutes. The mixture was allowed to cool to room temperature and the solid was filtered on a Buchner filter. The residue was washed with cold water to give a pale red solid which was triturated in hot MeOH. The suspension was left overnight at 4 C. The resultant precipitate was filtered and washed with cold MeOH to yield the title compound 3 as a pale brown solid.
A mixture of 2-bromo-5-methoxybenzoic acid 1 (27.6 g; 119 mmol; 1 .0 eq.),resorcinol 2 (26.3 g; 239 mmol; 2.0 eq.) and sodium hydroxide (10.5 g; 263 mmol;2.2 eq.) in water (120 mL) was heated under reflux for 1 hour. A 5% aqueoussolution of copper sulphate (3.88 g of CuSO45H2O in 50 mL water; 15.5 mmol; 0.1eq.) was then added and the mixture was refluxed for additional 30 minutes. Themixture was allowed to cool to room temperature and the solid was filtered on a Buechner filter. The residue was washed with cold water to give a pale red solidwhich was triturated in hot MeOH. The suspension was left overnight at 4 00 The resultant precipitate was filtered and washed with cold MeOH to yield the titlecompound 3 as a pale brown solid.
A mixture of 2-bromo-5-methoxybenzoic acid (5.6 grams), resorcinol (5.5 grams) and sodium hydroxide (2.2 grams) in water (25 ml) was heated under reflux for 30 minutes. After the addition of copper sulphate (5% aqueous solution, 10 ml), the mixture was refluxed again for 10 min when 3-hydroxy-8-methoxydibenzo-alpha-pyrone (3.7 grams) was precipitated as a straw colored powder. Crystallization from methanol and glacial acetic acid, in succession, afforded pale-yellow micro-crystals, m.p. 285-286 C. A suspension of this compound (2.18 grams) in a mixture of glacial acetic acid (120 ml) and azeotropic hydrobromic acid (60 ml) was heated under reflux for 1 hours. The starting material had dissolved within two hours and the desired product, 3,8-dihydroxydibenzo-alpha-pyrone, crystallized out after 6 hours as light yellow powder (1.9 grams). Recrystallization of the product from glacial acetic acid gave pale-yellow needles, m.p. 360-362 C. The purity of the products was determined by HPLC, and 1H-NMR spectra.
EXAMPLE 28 Preparation of 2-Bromo-5-hydroxybenzoic acid STR77 A mixture of 2-bromo-5-methoxybenzoic acid (10 g, 0.043 mol) in methylene chloride is cooled to -60 C., treated with boron tribromide (3.59 g, 0.143 mol), stirred at -60 C. for 1 hour, stirred at room temperature for 1 hour, cooled to -70 C., treated with additional boron tribromide (3.59 g, 0.143 mol), stirred at -70 C. for 1 hour, stirred at room temperature for 1 hour and poured into water. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product as a white solid which is identified by 1 H and 13 C-NMR spectral analyses.
With boron tribromide; In hexane; dichloromethane; at -20 - 0℃;
2-Bromo-5-hydroxybenzoic acid was obtained from commercially available 2-bromo-5- methoxybenzoic acid through demethylation by BBr3 (3 equiv.) in CE Cyhexane (3:2, v/v) at low temperature (-20 to 0 C).
With boron tribromide; In hexane; dichloromethane; at -20 - 0℃;
Urolithins A and B were synthesized by CuII-mediated coupling of 1,3-dihydroxybenzene and 2-bromo- 5-hydroxybenzoic acid (urolithin A) or 2-bromobenzoic acid (urolithin B) in concentrated aqueous NaOH according to already reported procedures (Bialonska D. et al., 20092-Bromo-5-hydroxybenzoic acid was obtained from commercially available 2-bromo-5-methoxybenzoic acid through demethylation by BBr3 (3 equiv.) in CH2Cl2/hexane (3:2, v/v) at low temperature (-20 to 0 C). Urolithins were isolated by precipitation and their purity checked by HPLC analysis. Their NMR and MS characteristics were in agreement with the literature. Urolithin C and D were purchased from Dalton Pharma Services (Toronto, Canada) and the certificates of analysis are available. Other compounds were commercially available.
4.2 g
With aluminum (III) chloride; In chlorobenzene; for 2.5h;Reflux;
2-Bromo-5-methoxybenzoic acid5 g (manufactured by Wako Pure Chemical Industries, Ltd.) and 15 g of aluminum chloride were refluxed in 150 mL of chlorobenzene for 2.5 hours.After cooling, the reaction solution was transferred to ice water and extracted three times with 250 mL of diethyl ether. The obtained extract was concentrated under reduced pressure, diethyl ether was distilled off,4.2 g of 2-bromo-5-hydroxybenzoic acid was obtained.3.9 g of the obtained 2-bromo-5-hydroxybenzoic acid and 3.9 g of resorcinol (Tokyo Chemical Industry Co., Ltd.) were dissolved in 9 mL of 4 M NaOH aqueous solution at 60 C.,And heated for 30 minutes. To this reaction solution was added 1.8 mL of a 10% aqueous solution of copper sulfate,Further,Heating was carried out for 10 minutes.The precipitate formed was collected by filtration,A white powder of urolitin A was obtained.
4.2 g
With aluminum (III) chloride; In chlorobenzene; for 2.5h;Reflux;
5g of 2-bromo-5-methoxybenzoic acid (manufactured by Wako Pure Chemical Industries, Ltd.) and 15 g of aluminum chloride were refluxed in 150 mL of chlorobenzene for 2.5 hours. After cooling, the reaction solution was transferred to ice water and extracted three times with 250 mL of diethyl ether. The obtained extract was concentrated under reduced pressure and diethyl ether was distilled off to obtain 4.2 g of 2-bromo-5-hydroxybenzoic acid. 3.9 g of the obtained 2-bromo-5-hydroxybenzoic acid and 3.9 g of resorcinol (Tokyo Chemical Industry Co., Ltd.) were heated in 9 mL of 4 M NaOH aqueous solution at 60 C. for 30 minutes. 1.8 mL of a 10% aqueous solution of copper sulfate was added to the reaction solution, followed by further heating at 80 C. for 10 minutes. The precipitate formed was recovered by filtration to obtain a white powder of urolitin A.
4.2 g
With aluminum (III) chloride; In chlorobenzene; for 2.5h;Reflux;
5 g of 2-bromo-5-methoxybenzoic acid (manufactured by Wako Pure Chemical Industries, Ltd.) and 15 g of aluminum chloride were refluxed in 150 mL of chlorobenzene for 2.5 hours.After cooling,The reaction solution was transferred to ice water,Extraction was carried out three times with 250 mL of diethyl ether.The obtained extract was concentrated under reduced pressure, diethyl ether was distilled off,4.2 g of 2-bromo-5-hydroxybenzoic acid was obtained.
With aluminum (III) chloride; In chlorobenzene; at 131℃; for 16h;
In a 500 ml round bottom flask, a solution of 2-bromo-5-methoxy benzoic acid (10gm, 0.043moles) and AlCl3 (17.26 gm, 0.129 moles) in chlorobenzene (230 ml) was added and the reactionwas refluxed for 16 hrs at 131C. The product obtained was extracted using ethylacetateand concentrated using rotary evaporator. In a two necked round bottom flask, the demethylatedproduct (2-bromo-5-hydroxy benzoic acid) obtained in reaction 1 (8.7 gms, 0.04 moles)along with resorcinol (4.414 gm, 0.04 moles), sodium hydroxide (4 gm, 0.10 moles) was mixedwith water (45.5 ml) and reaction was refluxed for 2 hrs at 100C. To the above mixture, 10%w/v CuSO4 (17 ml) was added and refluxed for another 2 hrs. Crude product was purified bycolumn chromatography. The desired compound was eluted with a solvent mixture of hexane:ethyacetate (50:50) followed by recrystallization in ethylacetate to ensure high purity. The purifiedUA (1 g) was concentrated and characterized by TLC, NMR spectroscopy, mass spectroscopyand HPLC (S1 Scheme).
4.2 g
With aluminum (III) chloride; In chlorobenzene; for 2.5h;Reflux;
5 g of 2-bromo-5-methoxybenzoic acid (manufactured by Wako Pure Chemical Industries, Ltd.) and 15 g of aluminum chloride were refluxed in 150 mL of chlorobenzene for 2.5 hours.After cooling, the reaction solution was transferred to ice water and extracted three times with 250 mL of diethyl ether. The obtained extract was concentrated under reduced pressure and diethyl ether was distilled off to obtain 4.2 g of 2-bromo-5-hydroxybenzoic acid. 3.9 g of the obtained 2-bromo-5-hydroxybenzoic acid and 3.9 g of resorcinol (Tokyo Chemical Industry Co., Ltd.) were heated in 9 mL of 4 M NaOH aqueous solution at 60 C. for 30 minutes. 1.8 mL of a 10% aqueous solution of copper sulfate was added to the reaction solution, followed by further heating at 80 C. for 10 minutes. The precipitate formed was recovered by filtration, and urineA white powder was obtained.
4.2 g
With aluminum (III) chloride; In chlorobenzene; for 2.5h;Reflux;
5 g of 2-bromo-5-methoxybenzoic acid (manufactured by Wako Pure Chemical Industries, Ltd.)And 15 g of aluminum chloride were refluxed in 150 mL of chlorobenzene for 2.5 hours. After cooling, the reaction solution was transferred to ice water,Extraction was carried out three times using 250 mL of diethyl ether.The obtained extract was concentrated under reduced pressure, diethyl ether was distilled off,4.2 g of 2-bromo-5-hydroxybenzoic acid was obtained.3.9 g of the obtained 2-bromo-5-hydroxybenzoic acid and resorcinol3.9 g (manufactured by Tokyo Chemical Industry Co., Ltd.) was heated in 9 mL of 4 M NaOH aqueous solution at 60 C. for 30 minutes.1.8 mL of a 10% aqueous solution of copper sulfate was added to the reaction solution, and further 80 C.,Heating was carried out for 10 minutes. The precipitate formed was collected by filtration,A white powder of Urolithin A was obtained.
4.2 g
With aluminum (III) chloride; In chlorobenzene; for 2.5h;Reflux;
In 150 mL of chlorobenzene, 5 g of 2-bromo-5-methoxybenzoic acid (manufactured by Wako Pure Chemical Industries, Ltd.) and 15 g of aluminum chloride were refluxed for 2.5 hours. After cooling, the reaction liquid was transferred to ice water, and extraction was carried out using 250 mL of diethyl ether three times. The obtained extract was concentrated under reduced pressure to evaporate diethyl ether, to obtain 4.2 g of 2-bromo-5-hydroxybenzoic acid. In 9 mL of 4 M aqueous NaOH solution, 3.9 g of the obtained 2-bromo-5-hydroxybenzoic acid and 3.9 g of resorcinol (manufactured by Tokyo Chemical Industry Co., Ltd.) were heated at 60 C. for 30 minutes. To this reaction liquid, 1.8 mL of 10% aqueous copper sulfate solution was added, and heating was further carried out at 80 C. for 10 minutes. The resulting precipitate was collected by filtration to obtain white powder of urolithin A.
21.A Step A
Step A Methyl 2-bromo-5-methoxybenzoate Sulfuric acid (2 eq) was added to a solution of 2-bromo-5-methoxybenzoic acid (1 eq) in methanol (0.30 M) at 0° C. under N2. The solution was allowed to warm to RT and then refluxed for 5 h. After cooling to RT, the solution was concentrated in vacuo, the residue dissolved in ethyl acetate and washed with 1N NaOH solution (2*). The combined aqueous layers were extracted with ethyl acetate and the combined organics dried over MgSO4. Concentration in vacuo gave methyl 2-bromo-5-methoxybenzoate as a clear oil. EI-MS m/z 245, 247 (M+H)+
Dissolve 2-bromo-5-methoxy-benzoic acid (2.25 g, 9.7 mmol) in THF (10 mL) and cool to 0 [C.] Add 1M borane in THF (48 mL, 48 mmol) and warm to room temperature. Upon completion, slowly pour reaction onto ice and saturated aqueous sodium bicarbonate. Extract with ethyl acetate and wash organic layer with water and saturated aqueous sodium bicarbonate. Dry with sodium sulfate, filter and concentrate in vacuo to yield 2.1 g (100%) of the title [COMPOUND.'H] NMR [(CDC13)] [O7.] 42 (d, J= 8.8 Hz, 1H), 7.06 (d, J = 3.1 Hz, 1H), 6.72 [(DD,] [J= 8.] 8,3. 1 Hz, [1H),] 4.71 (s, 2H), 3.81 (s, 3H).
96%
With borane; In tetrahydrofuran; for 1h;
Under a nitrogen atmosphere, 25 g (0.11 mol) of 2-bromo-5-methoxybenzoic acid was dissolved in 100 mL of anhydrous THF. 140 mL (0.14 mol) of borane (1 M in THF) was added to this solution over a period of 1 hour. The reaction was allowed to stir and was carefully quenched with 1:1 THF: saturated K2CO3. Ether was added and the aqueous and organic layers were separated. The aqueous layer was extrated again with ether (2x100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford 23.0 g (96%) of 2-bromo-5-methoxybenzyl alcohol (13). 1H NMR (CDCl3): 2.02 (t-1H; J=6.23 Hz), 3.79 (s-3H), 4.69 (d-2H; J=6.23 Hz), 6.70 (dd-1H; J=3.12, 8.72 Hz), 7.04 (d-1H; J=3.12 Hz), 7.39 (d-1H; J=8.72 Hz).
94%
2-Bromo-5-methoxy benzoic acid (1 eq.) was dissolved in anhydrous THF (0.55M solution) and borane dimethylsulfide complex (2M in THF, 1 eq.) was added dropwise to the solution. The mixture was left stirring overnight, then HCl in MeOH was added and the mixture was warmed to 60 0C. All volatiles were evaporated and the residual material was dissolved in DCM. The solution was washed with IN HCl and with brine, then dried over Na2SO4 and evaporated in vacuo. A colorless oil was obtained (94%), which was used without further characterization in the next reaction.
94%
2-Bromo-5-methoxy benzoic acid (1 eq) was dissolved in anhydrous TetaF (0.55M solution) and BH3 SMe2 complex (2M in THF, 1 eq) was added dropwise to the solution. The mixture was stirred overnight, then HCl in MeOH was added and the mixture was warmed to 60 0C. All volatiles were evaporated and the residual material was dissolved in DCM. The solution was washed with IN HCl and with brine, then dried over Na2SO4 and evaporated in vacuo. A colorless oil was obtained (94%), which was used without further characterization in the next reaction.
94%
With dimethylsulfide borane complex; In dichloromethane; at 0 - 25℃; for 2h;
18A (MW 231.05, 130 mmol, 30.0 g) in 300 mL CH2Cl2 at 00 C. Add BH3-SMe2 (3 equ, 25.2 mL) and age for 2 h at 250 C. Quench into aqueous 2 N HCl and separate layers. Dry organic (magnesium sulfate) and concentrate in vacuo to obtain 94% yield of 18 (MW 217.06, 25.5 g).
With borane-THF; In tetrahydrofuran; at -5 - 20℃; for 12h;
D. N, N-DIMETHYL-5-METHOXY-2-BROMOPHENYLACETAMIDE 5-Methoxy-2-bromobenzoic acid (85 g, 0.37 mol) is dissolved in anhydrous THF (100 mL) and cooled in an ice-salt bath until the temperature REACHES-5 C. Borane-THF complex is added dropwise as a 1.0 M solution in THF (736 mL, 0.74 mol) AT-5C. After addition is complete, the reaction mixture is slowly warmed to room temperature and stirred for 12 hours. Water (40 mL) is slowly added dropwise and the reaction mixture stirred for 30 minutes. Additional water (350 mL) is added and the mixture is concentrated by rotary evaporator to remove most of the THF. The remaining material is extracted with EtOAc (800 mL). The organic layer is washed with saturated NAHCO3 (500 mL), brine (250 mL) and then dried (NA2SO4). UPON REMOVAL of the solvent by rotary evaporator, 5-methoxy-2- bromobenzyl alcohol is obtained as a white solid. 5-Methoxy-2-bromobenzyl alcohol (79.5 g, 0.37 mol) is dissolved in 48% HBr (400 mL) and heated to reflux temperature for 4 hours. The reaction mixture is cooled to room temperature and poured into water (1500 mL). The solution is extracted with EtOAc (2 x 500 mL). The combined organic layers are dried (MGS04) and concentrated by rotary evaporator. The crude material is then purified using flash chromatography (CH2CI2/hexanes, from 1: 1 to 4: 1) to give 5-methoxy-2-bromobenzyl bromide. 5-METHOXY-2-BROMOBENZYL bromide (72.8 g, 0.26 mol) is dissolved in EtOH (280 mL) and stirred at room temperature. Sodium cyanide (38.2 g, 0.78 mol) is dissolved in water and added to the solution of the bromide. The reaction mixture is heated to reflux temperature for 3 hours and then cooled to room temperature. Most of the ethanol is removed by rotary evaporator. A solid forms which is isolated by filtration and washed with water (500 mL). The crude material is purified using flash chromatography (CH2CI2/HEXANES, 1: 1) to give 5-methoxy-2-bromophenylacetonitrile (53 g). 5-Methoxy-2-bromophenylacetonitrile (52.8 g, 0.23 mol) is dissolved in ethanol (250 mL) and stirred at room temperature. Sodium hydroxide (9.3 g, 0.47 mol) is dissolved in water (150 mL) and added to the solution of the nitrile. The mixture is heated to reflux temperature for 12 hours and then cooled to room temperature. Most of the ethanol is removed using a rotary evaporator and the residual aqueous solution adjusted to pH 4 with 3 N HCI. The solid which forms is isolated by filtration and washed with water. Air drying gives 5-methoxy-2-bromophenylacetic acid. 5-Methoxy-2-bromophenylacetic acid (56 g, 0.23 mol) is dissolved in CH2CI2 (350 mL) and a catalytic amount of DMF is added and the solution stirred and cooled to 0C. Thionyl chloride (41 mL, 0.34 mol) is added dropwise. The reaction mixture is heated at reflux temperature overnight and then cooled to room temperature. Solvents are removed by rotary evaporator. Twice benzene (500 mL) is added to the residual oil and the benzene solution is evaporated by rotary evaporator to remove any additional volatile components. The residual oil is crystallized from hexanes to give 5-methoxy-2-bromophenylacetyl chloride. 5-Methoxy-2-bromophenylacetyl chloride (60 g, 0.23 mol) is dissolved in anhydrous ET20 (400 mL), stirred and cooled in an ice bath. A 2 M solution of DIMETHYLAMINE (228 mL, 0.46 mol) is added dropwise and the mixture allowed to warm to room temperature and stirred for 2 hours. Additional ET20 (500 mL) is added. The organic solution is washed with 1 N HCI (2 x 500 mL), saturated NAHCO3 (500 mL) and brine (500 mL). The organic layer is dried (NA2SO4) and concentrated by rotary evaporator. The residue is purified using flash chromatography (hexanes/EtOAc, from 7: 3 to 1: 9). Trituration of the crude product with ET20/HEXANES gives N, N-DIMETHYL-5-METHOXY-2-BROMOPHENYLACETAMIDE AS a white crystalline solid (m. p. 88-90C).
23.0 g (96%)
With borane; In tetrahydrofuran;
Preparation 9 2-bromo-5-methoxybenzyl alcohol (13) Under a nitrogen atmosphere, 25 g (0.11 mol) of 2-bromo-5-methoxybenzoic acid was dissolved in 100 mL of anhydrous THF. 140 mL (0.14 mol) of borane (1 M in THF) was added to this solution over a period of 1 hour. The reaction was allowed to stir and was carefully quenched with 1:1 THF: saturated K2CO3. Ether was added and the aqueous and organic layers were separated. The aqueous layer was extrated again with ether (2*100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford 23.0 g (96%) of 2-bromo-5-methoxybenzyl alcohol (13). 1H NMR (CDCl3): 2.02 (t-1H; J=6.23 Hz), 3.79 (s-3H), 4.69 (d-2H; J=6.23 Hz), 6.70 (dd-1H; J=3.12, 8.72 Hz), 7.04 (d-1H; J=3.12 Hz), 7.39 (d-1H; J=8.72 Hz).
With borane; In tetrahydrofuran; water;
a. 2-Bromo-5-methoxybenzyl Alcohol A solution of 2-bromo-5-methoxybenzoic acid (10.00 g, 43.3 mmol) in dry THF (40 ml) was treated with borane in THF (65 ml of 1.0M solution, 65 mmol) at room temperature under nitrogen. After stirring for 4 h, no starting material was detectable by tic. Excess borane was quenched by careful addition of water over 30 min, and the solvent was evaporated under reduced pressure. The residue was partitioned between ether and 5% Na2 CO3. The ether layer was washed with 5% Na2 CO3, water, and brine, and dried over MgSO4. Filtration and removal of solvent left a colorless oil which solidified (9.11 g, 97%); tlc (silica gel, CH2 Cl2, Rf 0.25). This material was used without further purification.
With borane; In tetrahydrofuran; water;
a. 2-Bromo-5-methoxybenzyl alcohol A solution of 2-bromo-5-methoxybenzoic acid (10.00 g, 43.3 mmol) in dry THF (40 ml) was treated with borane in THF (65 ml of 1.0 M solution, 65 mmol) at room temperature under nitrogen. After stirring for 4 h, no starting material was detectable by tlc. Excess borane was quenched by careful addition of water over 30 min, and the solvent was evaporated under reduced pressure. The residue was partitioned between ether and 5% Na2CO3. The ether layer was washed with 5% Na2CO3, water, and brine, and dried over MgSO4. Filtration and removal of solvent left a colorless oil which solidified (9.11g, 97%); tlc (silica gel, CH2Cl2, Rf 0.25). This material was used without further purification.
To the three-neck flask B was added 11.55 g (0.05 mol) of <strong>[22921-68-2]2-bromo-5-methoxybenzoic acid</strong>,60g (0.5mol) thionyl chloride, three-neck flask with calcium chloride drying tube, thermometer,Tail gas absorption device, the mixture was stirred at 80 C for 2 hours,At the end of the reaction, the product was distilled off with atmospheric distillation to give 11.23 g of 2-bromo-5-methoxybenzoyl chloride.Colorless oily liquid, yield 89.8%, purity 97.3%.
With thionyl chloride;
Example 166 PREPARATION OF 2- [2- (4 -CVANO-4-METHOXV-BIPHEN-2-YL)-QUINOLIN-6YLL-1-CYCLOHEXYL-1 H- BENZOIMIDAZOLE-5-CARBOXYLIC ACID (COMPOUND 365) Step 1: 2-[2-(2-BROMO-5-METHOXY-PHENYL)-QUINOLIN-6-YL]-1-CYCLOHEXYL-LH- benzoimidazole-5-carboxylic acid (Compound 365a); [0614] Following the procedure and workup for Compound 354, Compound 354e (2.28g, 5. 83MMOL) was reacted with 1- (2-BROMO-5-METHOXY-PHENYL)- ethanone (1.335g, 5.83mmol) (the ethanone was prepared by reacting 1- (2-BROMO-5- methoxy) benzoic acid with thionyl chloride to give 1- (2-BROMO-5-METHOXY) benzoyl chloride which is further reacted with dimethyl zinc to give the ethanone) in ethanol (45mL) using 10% w/v KOH in ethanol (11. 57m, 17. 5MMOL) to the title intermediate (2.80g, 86% yield). [0615] MS: 557.14 (M+H+) ; HPLC Procedure C, retention time=2.82min
With thionyl chloride; for 2.5h;Heating / reflux;
A mixture of <strong>[22921-68-2]2-bromo-5-methoxybenzoic acid</strong> (8.0 g) and thionyl chloride (20 ml) was refluxed for 2.5 hours, the reaction mixture was concentrated in vacuo. To a solution of the resulting 2-bromo-5-methoxybenzoyl chloride crude product in dichloromethane (50 ml) were sequentially added (4-nitrobenzyl) phenyl ether (8.0 g) and aluminum chloride (4.6 g), the solution was stirred for 13 hours at room temperature. To the reaction mixture was added ice, the solution was extracted with dichloromethane, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo, the resulting crude crystal was washed with hexane-ethyl acetate to provide the title compound (light gray powder) (13.1 g).1H-NMR (400MHz, CDCl3); delta (ppm): 3.80 (s, 3H), 5.25 (s, 2H), 6.85 (d, 1H), 6.89 (dd, 1H), 7.01 (d, 2H), 7.50 (d, 1H), 7.61 (d, 2H), 7.82 (2H, d), 8.26 (2H, d)
With oxalyl dichloride; N,N-dimethyl-formamide; In benzene; for 0.5h;Inert atmosphere;
General procedure: To a solution under argon of the appropriate acid (1 equiv.) in anhydrous benzene (3 mL/1 mmol of acid) was added oxalyl chloride (1.5 equiv.), followed by N,N-dimethylformamide (2 drops). When gas evolution had ceased (30 min.), the reaction mixture was concentrated under vacuum to afford the crude acyl chloride, which was used without further purification. Triethylamine (3 equiv.) was added to a solution under argon of the appropriate amine (1 equiv.) in anhydrous CH2Cl2 (2 mL / 1 mmol of acid). The acyl chloride (1 equiv.) in anhydrous CH2Cl2 (2 mL / 1 mmol of acid) was added dropwise to this mixture. After 60 min, the reaction mixture was concentrated and the crude product was directly purified by chromatography on silica gel to yield the expected amide.
With oxalyl dichloride;N,N-dimethyl-formamide; In toluene; at 50℃; for 1h;
Example 13<strong>[22921-68-2]2-Bromo-5-methoxy-benzoic acid</strong> tert-butyl ester Oxalyl chloride (1.08 mL, 12.33 mmol) and two drops of DMF were added to a solution of <strong>[22921-68-2]2-bromo-5-methoxy benzoic acid</strong> (2.5 g, 10.82 mmol) in toluene (35 mL). The resulting mixture was heated at 50 C. for 1 h.The reaction was quenched with water (3 mL) and the mixture was extracted with diethyl ether (2×10 mL). The organic layer was dried (MgSO4), filtered and the solvent was evaporated under vacuum.Then the reaction was concentrated to dryness under vacuum and the residue was re-dissolved in THF (20 mL). The solution was added to a suspension of potassium tert-butoxide (1.5 g, 13.42 mmol) in THF (30 mL) and the mixture was stirred at room temperature for 16 h,After that time, water (25 mL) was added followed by a saturated solution of ammonium chloride (25 mL). The mixture was extracted with diethyl ether (50 mL) and the organic layer was washed with Brine, dried (MgSO4), filtered and the solvent was evaporated under vacuum to isolate the title compound as a colorless solid. (Yield=63%)1H-NMR (CDCl3, 300 MHz): 7.49 (d, 1H, J=8.8 Hz, ArH), 7.24 (d, 1H, J=2.4 Hz, ArH), 6.85 (dd, 1H, J=8.8, 2.4 Hz, ArH), 3.83 (s, 3H, ArOCH3), 1.63 (s, 9H, CO2tBu).
With thionyl chloride; for 2h;Reflux;
General procedure: A solution of 2-bromo-4,5-dimethoxybenzoic acid (4 mmol, 1.04 g) or <strong>[22921-68-2]2-bromo-5-dimethoxybenzoic acid</strong> (4 mmol, 0.92 g) in SOCl2 was reflux for 2 h. Evaporation of SOCl2 provided crude acid chlorides which were directly used in next synthesis step.
With oxalyl dichloride; In chloroform; N,N-dimethyl-formamide; at 20℃; for 2h;
The compound <strong>[22921-68-2]2-bromo-5-methoxybenzoic acid</strong> (6.45 g) and DMF (0.429 mL) were placed in chloroform (77 mL) and after adding oxalyl chloride (4.79 mL), the mixture was stirred at room temperature for 2 hours and the reaction mixture was concentrated under reduced pressure. To the resulting residue, triethylamine (11.6 mL), (3-chlorophenyl)hydrazine hydrochloride (5.00 g) and THF (64 mL) were added and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with chloroform (50 mL) and washed with saturated aqueous sodium hydrogencarbonate (150 mL) and saturated brine (150 mL) consecutively. After drying the organic layer with Na2SO4, the desiccant was separated by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (SNAP Cartridge HP-Sil; mobile phase: chloroform/methanol=100/0-90/10; v/v). The resulting roughly purified product was washed in suspension with IPE and filtered to give the titled compound (5.19 g as colorless solids). MS (ESI pos.) m/z: 355([M+H]+)
With thionyl chloride; In N,N-dimethyl-formamide; toluene; at 0 - 80℃; for 2.25h;
General procedure: 2-bromobenzoic acid derivatives (8 mmol), toluene (40 mL) were added to a 100 mL round-bottom flask. After cooled to 0 oC, DMF (0.1 eq., 0.8 mmol) was added to the mixture. SOCl2 (1.2 eq., 9.6 mmol) was slowly added to the flask with more than 10 min. After performed at 0 oC for 5 min, the reaction was warmed to 23 oC for 10 min. At last the mixture was performed at 80 oC for 2 h. After evaporated the solvent and dried by vacuum pump, the crude product of 2,4-dibromobenzoyl chloride derivatives were provided as a oil. After 2,4-dibromobenzoyl chloride derivative (6 mmol) was added to it, the tube evacuated and recharged with N2 for 3 times. Before the mixture was cooled to -78 oC, THF (20 mL) was added to the tube. MeMgCl (6 mmol) was dropwised to the mixture. The reaction was performed for 1h at -78 oC, 2 h at 0 oC, 5 to 10 h at rt. 20 mL water was added to the tube and the mixture was extracted with Et2O (30 mL x 3),dried by anhydrous Na2SO4. Evaporation of the solvent followed by purification on silica gel provided 1-(2-bromophenyl)ethanone derivative, yield 60-70%.
General procedure: The proper 2-haloarylcarboxylic acid (12mmol) was dissolved in 60mL of methanol and to this solution 8mL (12 equiv.) of concentrated sulfuric acid were then added dropwise. Then the reaction mixture was stirred at reflux until no more starting product was detected by TLC analysis. The reaction mixture was then cooled to rt and concentrated under reduced pressure. The residue was diluted with EtOAc (20mL) and washed with a saturated aqueous solution of NaHCO3 (3×30mL). The organic phase was dried over Na2SO4, filtered and the solvent was removed at reduced pressure to yield the corresponding methyl 2-haloarylcarboxylates.
85%
hydrogenchloride; In water; for 18h;Heating / reflux;
To a stirred solution of 2-bromo-5-methoxybenzoic acid (Aldrich 384003; 5.0 g, 21.6 mmol) in methanol (80 mL) was added concentrated hydrochloric acid (2 mL) and the mixture was heated under reflux for 18 hours. The resulting solution was cooled, the solvent was removed in vacuo, water (100 mL) was added and the mixture was extracted with ethyl acetate (2 x 100 mL). The combined extracts were washed with saturated aqueous sodium hydrogen carbonate, dried over MgSO4, filtered and evaporated to obtain methyl 2-bromo-5-methoxybenzoate as a light brown oil (4.50 g, 85%); NMR Spectrum deltaH (300 MHz, CDCl3) 7.53 (1 H, d, J 8.8 Hz, 3-H), 7.32 (1 H, d, J 3.0 Hz, 6-H), 6.89 (1 H, dd, J 3.0, 8.8 Hz, 4-H), 3.94 (3 H, s, Ar OCH3) and 3.82 <n="66"/>(3 H, s, CO2CH3) (data in accordance with published values, see Barhate, N. B.; Gajare, A. S.; Wakharkar, R. D.; Bedekar, A. V. Tetrahedron 1999, 55, 11127- 11142); vmjcnfl (thin film) 2951, 1732 (C=O), 1592, 1472, 1433, 1289, 1250, 1227, 1099, 1017, 975, 823, 792 (data in accordance with published values, see Barhate, N. B.; Gajare, A. S.; Wakharkar, R. D.; Bedekar, A. V. Tetrahedron 1999, 55, 11127-11142.); Rf (hexane - ethyl acetate 5:1) 0.58.
With sulfuric acid; for 24h;Reflux;
General procedure: 4.2.1. General procedures I for the synthesis of starting materials 1 a-n. Compounds 1a-g, i-n were synthesized according to general procedures I. Compound 1h was commercially available. Method A:16, 17 A two-necked round-bottomed flask equipped with a reflux condenser and a magnetic stir bar was charged withthe 2-bromobenzoic acid (20 mmol) and freshly distilled methanol(25 mL). The solution was heated in a hot water bath, conc. H2SO4(8 mmol) was added slowly and the reaction mixture was refluxed for 24 h. After cooling to room temperature around half of theamount of the solvent was removed in vacuo and the residue was partitioned between water (50 mL) and diethyl ether (70 mL). The organic layer was separated and washed with saturated NaHCO3(250 mL), water (50 mL) and brine (50 mL), dried over anhydrous MgSO4 and the volatiles were removed under reduced pressure.The crude product thus obtained was purified by flash chromatographyon silica gel to afford the alkyl-2-halobenzoate.In a two-necked round-bottomed flask equipped with a reflux condenser and a magnetic stir bar the alkyl 2-halobenzoate(22.5 mmol) was dissolved in freshly distilled dry THF (30 mL) under argon. The solution was cooled to 0 C using an ice bath and NaH (60% in mineral oil, 15 mmol) was added portion wise. After stirring for 15 min a solution of the alkyl acetate (15 mmol) in dry THF (30 mL) was added dropwise to the reaction mixture at 0 C.The mixture was warmed up, stirred at room temperature for 2 h and heated under reflux for 24 h. After cooling to room temperature around half of the amount of the solvent was removed in vacuo and the reaction mixture was diluted with toluene (50 mL). The resulting mixture was washed with 2N HCl (50 mL), saturated NH4Cl (50 mL), dried over anhydrous MgSO4 and the volatiles were removed under reduced pressure. The crude product was purifiedby flash column chromatography on silica gel to afford the alkyl 3-(20-halophenyl)-3-oxo-propanoate 1.
Stage #1: 2-bromo-5-methoxy-benzoic acid With borane In tetrahydrofuran
Stage #2: benzyl bromide With tetra-(n-butyl)ammonium iodide; sodium hydride
Stage #3: vinylboronic acid dibutyl ester With sodium ethanolate Title compound not separated from byproducts;
Stage #1: 2-bromo-5-methoxy-benzoic acid With sodium carbonate In water at 50 - 75℃;
Stage #2: With water at 80℃; for 4h;
Stage #3: With hydrogenchloride In water at 20℃;
21; 22
Under nitrogen, 2 mmol of the halogen-substituted benzoic acid indicated in Table 6 was stirred with a solution of 3 mmol Na2CO3 at 50-75° C. until all of the halogen-substituted benzoic acid was dissolved. Subsequently, 0.02 mmol CuSO4 and 0.04 mmol rac-trans-N,N'-dimethylcyclohexane-1,2-diamine (Ligand F) dissolved in 1 mL deionized water were added and the reaction mixture was heated at 80-100° C. for 4 h. After cooling to ambient temperature the reaction mixtures were carefully acidified with 35% aqueous HCl.In isolation method A, the products were extracted from the aqueous layer twice with ethyl acetate, the ethyl acetate fractions were combined and the crude reaction product was isolated by evaporation of ethyl acetate under vacuum. In isolation method B, the products were isolated by filtration, washed with water and dried under vacuum. The crude reaction product was analyzed by 1H NMR (d6-dmso). The results are summarized in Table 6. TABLE 6 Examples 8~23 Starting material Halogenated Benzoic Acid Isolation CONV SEL Example Benzoic Acid Product T (° C.) Method (%) (%) 8 2,5-dibromo- 2-hydroxy-5- 80 B >99 >99 bromo- 9 2-bromo-5-nitro- 2-hydroxy-5- 80 B >99 >99 nitro- 10 2-bromo-5-nitro- 2-hydroxy-5- 100 A >99 >99 nitro- 11 2-bromo-5-methyl- 2-hydroxy-5- 80 B >99 >99 methyl- 12 2-bromo-5-methyl- 2-hydroxy-5- 100 A >99 >99 methyl- 13 4-bromo- 4-hydroxy- 100 A >99 >99 14 4-chloro- 4-hydroxy- 80 B >99 >99 15 2,4-dichloro- 2-hydroxy-4- 100 A 70 >99 chloro- 16 2,5-dichloro- 2,5-dihydroxy- 80 B 93 >99 17 2-chloro-5-nitro- 2-hydroxy-5- 100 A 74 >99 nitro- 18 2-chloro-3,5-dinitro- 2-hydroxy-3,5- 100 A >99 >99 dinitro- 19 2-chloro-3,5-dinitro- 2-hydroxy-3,5- 80 B >99 >99 dinitro- 20 2-chloro-5-methyl- 2-hydroxy-5- 100 A >99 >99 methyl- 21 2-bromo-5- 2-hydroxy-5- 100 A >99 >99 methoxy- methoxy- 22 2-bromo-5- 2-hydroxy-5- 80 B >99 >99 methoxy- methoxy- 23 2-chloro-5-bromo- 2-hydroxy-5- 80 B 73 >99 bromo-
2-[(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)amino]-5-methoxybenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
31%
A mixture of 2-bromo-5-methoxy benzoic acid (2.26 g, 9.79 MMOL), potassium carbonate (1.49 g, 10.8 MMOL), 5-amino-3-tert-butyl-1-methylpyrazole (1.50 g, 9.79 MMOL), and copper (II) acetate (35 mg, 0.20 MMOL) in DMF (20 mL) was heated (150C) in a sealed tube for 16 h. After cooling, the reaction mixture was diluted with water (10 mL) and acidified to pH = 4 with acetic acid. This mixture was extracted with DICHLOROMETHANE (3 x 20 mL), and then the combined organic extracts were washed with water (2 x 30 mL), dried over NA2SO4, filtered, and concentrated under reduced pressure. HPLC purification of the residue (YMC propack C18 column, 150 x 20 mm ID, 30%-80% acetonitrile in water gradient) afforded the title compound (973 mg, 31%) as a pale yellow SOLID.'H NMR (300 MHz, DMSO-d6) 8 13.22 (br s, 1 H), 9.24 (br s, 1 H), 7.38 (d, 1 H), 7.10 (dd, 1 H), 6.80 (d, 1 H), 5.95 (s, 1 H), 3.70 (s, 3 H), 3.55 (s, 3 H), 1.21 (s, 9 H); ES- MS M/Z 304.2 (MH'), HPLC RT (min) 2.58.
With potassium carbonate;copper; In N,N-dimethyl-formamide; at 180℃; for 1h;
Example 79 Preparation of Intermediate 79 Step 1: To a solution of <strong>[22921-68-2]2-bromo-5-methoxybenzoic acid</strong> (1.68 g, 7.27 mmol) in DMF (50 mL) in a medium pressure flask (Chemglass) was added benzamidine (1.25 g, 8.00 mmol), K2CO3 (6.0 g, 43.6 mmol), and copper powder (336 mg, 1.45 mmol). The reaction mixture was heated to 180 C. for 1 hour. Copper and excess K2CO3 were removed by vacuum filtration and washed with MeOH. The filtrate was concentrated and the resulting crude was purified by flash column chromatography (SiO2, 5% MeOH in DCM) to give a light green solid (1.55 g, 84% yield): 1H NMR (DMSO-d6) delta 3.84 (s, 3H), 7.26 (d, J=7.8 Hz, 1H), 7.46 (br s, 5H), 7.57 (s, 1H), 8.38 (br s, 1H); MS m/z (MH+) 253.
84%
With potassium carbonate;copper; In N,N-dimethyl-formamide; at 180℃; for 1h;
To a solution of <strong>[22921-68-2]2-bromo-5-methoxybenzoic acid</strong> (1.68 g, 7.27 mmol) in DMF (50 mL) in a medium pressure flask (Chemglass) was added benzamidine (1.25 g, 8.00 mmol), K2CO3 (6.0 g, 43.6 mmol), and copper powder (336 mg, 1.45 mmol). The reaction mixture was heated to 180 C. for 1 h. Copper and excess K2CO3 were removed by vacuum filtration and washed with MeOH. The filtrate was concentrated and the resulting crude was purified by flash column chromatography (SiO2, 5% MeOH in DCM) to give a light green solid (1.55 g, 84% yield): 1H NMR (DMSO-d6) delta 3.84 (s, 3H), 7.26 (d, J=7.8 Hz, 1H), 7.46 (br s, 5H), 7.57 (s, 1H), 8.38 (br s, 1H); MS m/z (MH+) 253.
84%
With potassium carbonate;copper; In DMF (N,N-dimethyl-formamide); at 180℃; for 1h;
To a solution of <strong>[22921-68-2]2-bromo-5-methoxybenzoic acid</strong> (1.68g, 7. 27mmol) in DMF (50mL) in a medium pressure flask (Chemglass) was added benzamidine (1.25g, 8.00mmol),K2CO3 (6. 0g, 43.6mmol), and copper powder (336mg, 1. 45mmol). The reaction mixture was heated to180C for lh. Copper and excessK2CO3 were removed by vacuum filtration and washed with MeOH. The filtrate was concentrated and the resulting crude was purified by flash column chromatography(Si02, 5% MeOH in DCM) to give a light green solid(1.55g, 84% yield) : 1H NMR (DMSO-d6)8 3.84 (s, 3H), 7.26 (d, J = 7.8 Hz,1H), 7.46 (br s,5H), 7.57 (s, 1H), 8.38 (br s,1 H); MSm/z(MH+) 253.
84%
With copper; potassium carbonate; In N,N-dimethyl-formamide; at 180℃; for 1h;
Step 1 To a solution of <strong>[22921-68-2]2-bromo-5-methoxybenzoic acid</strong> (1.68 g, 7.27 mmol) in DMF (50 mL) in a medium pressure flask (Chemglass) was added benzamidine (1.25 g, 8.00 mmol), K2CO3 (6.0 g, 43.6 mmol), and copper powder (336 mg, 1.45 mmol). The reaction mixture was heated to 180 C for 1 h. Copper and excess K2CO3 were removed by vacuum filtration and washed with MeOH. The filtrate was concentrated and the resulting crude was purified by flash column chromatography (SiO2, 5% MeOH in DCM) to give a light green solid (1.55 g, 84% yield): 1H NMR (DMSO-d6) delta 3.84 (s, 3H), 7.26 (d, J=7.8 Hz, 1H), 7.46 (br s, 5H), 7.57 (s, 1H), 8.38 (br s, 1 H); MS m/z (MH+) 253.
84%
With copper; potassium carbonate; In N,N-dimethyl-formamide; at 180℃; for 1h;
To a solution of <strong>[22921-68-2]2-bromo-5-methoxybenzoic acid</strong> (1.68 g, 7.27 mmol) in DMF (50 mL) in a medium pressure flask (Chemglass) was added benzamidine (1.25 g, 8.00 mmol), K2CO3 (6.0 g, 43.6 mmol), and copper powder (336 mg, 1.45 mmol). The reaction mixture was heated to 180 C. for 1 h. Copper and excess K2CO3 were removed by vacuum filtration and washed with MeOH. The filtrate was concentrated and the resulting crude was purified by flash column chromatography (SiO2, 5% MeOH in DCM) to give a light green solid (1.55 g, 84% yield): 1H NMR (DMSO-d6) delta 3.84 (s, 3H), 7.26 (d, J=7.8 Hz, 1H), 7.46 (br s, 5H), 7.57 (s, 1H), 8.38 (br s, 1H); MS m/z (MH+) 253.
84%
With copper; potassium carbonate; In N,N-dimethyl-formamide; at 180℃; for 1h;
To a solution of <strong>[22921-68-2]2-bromo-5-methoxybenzoic acid</strong> (1.68 g, 7.27 mmol) in DMF (50 mL) in a medium pressure flask (Chemglass) was added benzamidine (1.25 g, 8.00 mmol), K2CO3 (6.0 g, 43.6 mmol), and copper powder (336 mg, 1.45 mmol). The reaction mixture was heated to 180 C. for 1 h. Copper and excess K2CO3 were removed by vacuum filtration and washed with MeOH. The filtrate was concentrated and the resulting crude was purified by flash column chromatography (SiO2, 5% MeOH in DCM) to give a light green solid (1.55 g, 84% yield): 1H NMR (DMSO-d6) delta 3.84 (s, 3H), 7.26 (d, J=7.8 Hz, 1H), 7.46 (br s, 5H), 7.57 (s, 1H), 8.38 (br s, 1H); MS m/z (MH+) 253.
A mixture of 2-bromo-5-methoxy benzoic acid (1.31 g, 5.7 MMOL), potassium carbonate (859 mg, 6.2 MMOL), 5-AMINO-1-PHENYL-PYRAZOLE (900 mg, 5.7 MMOL), and copper (II) acetate (21 mg, 0.11 MMOL) in DMF (12 mL) was heated (150C) in a sealed tube for 16 h. After cooling, the reaction mixture was diluted with water (5 mL), and then acidified to pH 4 with acetic acid. The mixture was extracted with DICHLOROMETHANE (3 X 10 mL), and then the combined organic extracts were washed with water (2 x 10 mL), dried over NA2SO4, filtered, and concentrated under reduced pressure. HPLC purification of the residue (YMC propack C18 column, 150 x 20 mm ID, 30%-80% acetonitrile in water gradient) afforded 5-METHOXY-2- [ (1-PHENYL-1 H-PYRAZOL-5-YL) AMINO] BENZOIC acid (450 mg, 26%) as a pale yellow solid :'H NMR (300 MHz, DMSO-d6) 8 13.33 (br s, 1 H), 9.62 (br s, 1 H), 7.64 (d, 1 H), 7.34-7. 58 (m, 6 H), 7.00-7. 11 (m, 2 H), 6.30 (d, 1 H), 3.69 (s, 3 H); ES-MS m/z 310.1 (MH+) ; HPLC RT (min) 2.74.
Example 5; 3-(7-Bromo-l-oxoisoquinolin-2(lH)-yl)-iV-cyclopropyl-4-methylbenzamide; To a solution of 3-(7-bromo-l,3-dioxo-3,4-dihydroisoquinolin-2(lH)-yl)-N- cyclopropyl-4-methylbenzamide (1.13 g) in methanol (19 ml) and methylene chloride (45 ml) under an atmosphere of argon was added NaBH4 (114 mg) portionwise and the reaction stirred at room temperatue for 17 hours. Concentrated hydrochloric acid (0.2 ml) was added and the reaction stirred for a further 1 hour. The reaction mixture was concentrated and the residue resuspended in methylene chloride, washed 2N HCl, dried (magnesium sulfate) and concentrated to give 3-(7-bromo-l-oxoisoquinolin-2(lH)-yl)-N- cyclopropyl-4-methylbenzamide as a brown solid (157 mg); NuMR Spectrum: (DMSOd6) 0.55 (m, 2Eta), 0.70 (m, 2H), 2.10 (s, 3H), 2.85 (m, IH), 6.80 (d, IH), 7.42 (d, IH), 7.51 (d, IH), 7.78 (d, IH), 7.79 (s, IH), 7.89 (d, IH), 7.97 (d, IH), 8.35 (s, IH), 8.44 (d, IH); Mass Spectrum: M+H* 421.3 -(7-Bromo- 1 ,3 -dioxo-3 ,4-dihydroisoquinolin-2(lH)-yl)-N-cyclopropyl-4- methylbenzamide used as starting material was prepared as follows:-Sodium hydride (1.2 g) was added portionwise to a stirred suspension of 2-bromo- 5-methoxybenzoic acid (3.50 g) and copper (I) bromide (100 mg) in ethylacetoacetate (15 ml). After the addition was complete the reaction was stirred under an argon atmosphere at 8O0C for 30 minutes. The reaction mixture was cooled to room temperature and poured into water (100 ml) and extracted with diethyl ether (x2). To the aqueous layer was added NuaOEta (10 g) and the solution stirred at room temperature for 18 hours. The solution was washed with methylene chloride and the pEta adjusted to pEta 1 with concentrated EPO <DP n="66"/>hydrochloric acid and extracted with methylene chloride. The combined organic layers were dried (magnesium sulfate) and concentrated to a brown solid. The solid was triturated with ethyl acetate to yield 2-(carboxymethyl)-5-bromobenzoic acid as a brown solid (2.38 g); NMR Spectrum: (DMSOd6) 3.98 (s, 2H), 7.37 (d, IH), 7.76 (d, IH), 8.04 (s, 1 H); Mass Spectrum: M+Na+ 281.To a suspension of 2-(carboxymethyl)-5-bromobenzoic acid (2.37 g) in acetone (20 ml) was added acetyl chloride (2.60 ml) and the reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated and azeotroped with toluene (x3). The resultant solid was triturated with diethyl ether to yield 7-bromo-lH-isochromene- l,3(4H)-dione as a brown solid (2.20 g); NMR Spectrum: (DMSOd6) 4.24 (s, 2Eta), 7.42 (d, IH), 7.94 (d, IH), 8.13 (s, IH).A suspension of 7-bromo-lH-isochromene-l,3(4H)-dione (1.09 g) and 3-amino-N- cyclopropyl-4-methylbenzamide (0.91 g) in a mixture of toluene (8 ml) and acetic acid (2.5 ml) was heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300W magnetron) at 15O0C for 60 minutes. This was process was repeated and the batches combined, diluted with ethyl acetate and washed with IN HCl, saturated NaHCO3 solution, water, brine, dried (magnesium sulfate) to yield 3-(7-bromo-l,3-dioxo- 3,4-dihydroisoquinolin-2(lH)-yl)-N-cyclopropyl-4-methylbenzamide as a brown solid (1.13 g); NuMR Spectrum: (DMSOd6) 0.60 (m, 2Eta), 0.71 (m, 2H), 2.12 (s, 3H), 2.89 (m, IH), 4.34 (d, IH), 4.42 (d, IH), 7.48 (d, IH)3 7.53 (d, IH), 7.70 (s, IH), 7.85 (d, IH), 7.99 (d, IH), 8.20 (s, IH), 8.45 (d, IH); Mass Spectrum: M+Nua+ 435.
N-(1-ethylpyrazol-5-yl)-5-methoxyanthranilic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44.37 g (62%)
With potassium carbonate;Cu(OAc)2; In N,N-dimethyl-formamide;
(b) A mixture of 2-bromo-5-methoxybenzoic acid (39.3 g, 0.17 mol), DMF (150 ml), 5-amino-1-ethylpyrazole (18.5 g, 0.17 mol), potassium carbonate (23.5 g, 0.17 mol) and Cu(OAc)2 (0.6 g) is refluxed for about 2 days. The reaction mixture is cooled, poured into water and acidified to a pH of 5. A precipitate forms which is collected by filtration, washed with water and dried to afford 44.37 g (62%) of N-(1-ethylpyrazol-5-yl)-5-methoxyanthranilic acid.
44.37 g (62%)
With potassium carbonate;Cu(OAc)2; In N,N-dimethyl-formamide;
(b) A mixture of 2-bromo-5-methoxybenzoic acid (39.3 g, 0.17 mol), DMF (150 ml), 5-amino-1-ethylpyrazole (18.5 g, 0.17 mol), potassium carbonate (23.5 g, 0.17 mol) and Cu(OAc)2 (0.6 g) was refluxed for about 2 days. The reaction mixture was cooled, poured into water and acidified to a pH of 5. A precipitate formed which was collected by filtration, washed with water and dried to afford 44.37 g (62%) of N-(1-ethylpyrazol-5-yl)-5-methoxyanthranilic acid.
With potassium carbonate;Cu(OAc)2; In N,N-dimethyl-formamide;
(a) A mixture of 2-bromo-5-methoxybenzoic acid (141.5 g, 0.61 mol), 5-amino-1-ethylpyrazole (68 g, 0.61 mol), K2CO3 (84.2 g, 0.61 mol), DMF (500 ml) and Cu(OAc)2 (3 g) is refluxed for about 2 days. The reaction mixture is cooled and then is poured into water (1500 ml). The mixture is acidified with acetic acid, and the resulting solid is collected by filtration and dried to afford 110 g of N-(1-ethylpyrazol-5-yl)-5-methoxyanthranilic acid.
N-(1-ethylpyrazol-5-yl)-5-methoxyanthranilic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Cu(OAc)2; In N,N-dimethyl-formamide;
(a) A mixture of 2-bromo-5-methoxybenzoic acid (141.5 g, 0.61 mol), 5-amino-1-ethylpyrazole (68 g, 0.61 mol), K2 CO3 (84.2 g, 0.61 mol), DMF (500 mL) and Cu(OAc)2 (3 g) was refluxed for about 2 days. The reaction mixture was cooled and then was poured into water (1500 mL). The mixture was acidified with acetic acid and the resulting solid was collected by filtration and dried to afford 110 g of N-(1-ethylpyrazol-5-yl)-5-methoxyanthranilic acid.
With potassium carbonate; acetic acid; In N-methyl-acetamide; water;
(a) 2-(4-Benzyloxyphenylamino)-5-methoxybenzoic acid. To a 5 L 3-neck flask was added 282 g (2.06 moles) milled potassium carbonate and 1.0 L dimethylformamide. While stirring the resulting mixture at room temperature, 250 g (1.06 moles) <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> was added portionwise over 15 minutes. After this was completed, 231 g (1.0 mole) 2-bromo-5-methoxybenzoic acid was added over 15 minutes and the mixture was stirred for another 15 minutes. The suspension was cooled to 10-15 C. and 13.8 g cupric acetate monohydrate (0.06 moles) was added portionwise over 20 minutes. Gas evolved slowly and after stirring 15 minutes at room temperature the reaction was warmed on a steam bath over 40 minutes to 70 C. whereupon a vigorous evolution of carbon dioxide was observed. Stirring and heating was continued for 90 minutes at 80-85 C., heat was removed and the mixture was allowed to cool to room temperature. The brownish red suspension was transferred to a 12 L flask containing 1 L ice-cold water. Acetic acid (650 ml) was added dropwise and the dark green precipitate was stirred vigorously until homogenous. After filtering and washing well with water, the crude product was dried overnight at 55-60 C. in a vacuum oven. The crude product (approximately 350 g) was diluted with 5.8 L toluene, heated to reflux temperature and filtered. The dark green filtrate was alowed to cool to room temperature for 2-3 hours, and the solid product was collected by filtration and rinsed with cold (5-10 C.) toluene. The bright yellow crystalline product was obtained in 80% yield.
80%
With potassium carbonate; acetic acid; In N-methyl-acetamide; water;
(a) 2-(4-Benzyloxyphenylamino)-5-methoxybenzoic acid To a 5 L 3-neck flask was added 284 g (2.06 moles) milled potassium carbonate and 1.0 L dimethylformamide. While stirring the resulting mixture at room temperature, 250 g (1.06 moles) <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> was added portionwise over 15 minutes. After this was completed, 231 g (1.0 mole) 2-bromo-5-methoxybenzoic acid was added over 15 minutes and the mixture was stirred for another 15 minutes. The suspension was cooled to 10-15 C. and 13.8 g cupric acetate monohydrate (0.06 moles) was added portionwise over 20 minutes. Gas evolved slowly and after stirring 15 minutes at room temperature the reaction was warmed on a steam bath over 40 minutes to 70 C. whereupon a vigorous evolution of carbon dioxide was observed. Stirring and heating was continued for 90 minutes at 80-85C., heat was removed and the mixture was allowed to cool to room temperature. The brownish red suspension was transferred to a 12 L flask containing 1 L ice-cold water. Acetic acid (650 ml) was added dropwise and the dark green precipitate was stirred vigorously until homogeneous. After filtering and washing well with water, the crude product was dried overnight at 55-60 C. in a vacuum oven. The crude product (approximately 350 g) was diluted with 5.8 L toluene, heated to reflux temperature and filtered. The dark green filtrate was allowed to cool to room temperature for 2-3 hours, and the solid product was collected by filtration and rinsed with cold (5-10 C.) toluene. The bright yellow crystalline product was obtained in 80% yield. A sample of the compound had the m.p. 167-168 C. when recrystallized from a benzene-cyclohexane mixture.
copper(I) bromide; In pyridine; for 3h;Heating / reflux;
5.00 g (21.6mmol) 2-Bromo-5-methoxy-benzoic acid, 620 mg (4.32mmol) copper (I) bromide and 2.63 g (32.4 mmol) potassium cyanate were dissolved in pyridine and boiled for 30 min. The solvent was removed and the residue was dissolved in 150 ml 2N hydrogen chloride acid and 150 ml ethyl acetate. The organic solvent was treated with water and brine, dried over magnesium sulfate and removed. The residue was digested with methanol. Yield: 2.50 g= 61% Grey powder
Step 1: 2-bromo-5-methoxybenzamide To a solution of <strong>[22921-68-2]2-bromo-5-methoxybenzoic acid</strong> (21.6 mmol) in DMF (20 mL) was added N,N-carbonyldiimidazole (54.1 mmol). The reaction mixture was allowed to stir at rt for 30 min and then ammonium carbonate (97.4 mmol) was added in portions over several minutes. The reaction mixture was allowed to stir until for 5 days and then poured into water. A white precipitate formed. The mixture was extracted with EtOAc. The organic solutions were combined, washed sequentially with water, 1N HCl, sat. aq. NaHCO3 and brine, dried over Na2SO4 filtered and concentrated to give 2-bromo-5-methoxybenzamide (18.5 mmol, 85%), which was used without further purification.
3.2. 5-methoxy-2-(4-methoxybenzoyl)benzoic acid; A solution of 18.5 g (80 mmol) of 2-bromo-5-methoxybenzoic acid in 150 mL of tetrahydrofuran is stirred under nitrogen at -78 C. in a bath of cardice/acetone. 100 mL (160 mmol) of a 1.6M solution of n-butyllithium in hexane are added dropwise over about 1 hour, while taking care to ensure that the temperature does not exceed -70 C. About half way through the introduction, the formation of a beige-coloured precipitate that corresponds to the formation of the lithium carboxylate is noted. After the addition, the mixture is stirred at -78 C. for 1 hour, and a solution of 15.9 g (80 mmol) of N,4-dimethoxy-N-methylbenzamide in 20 mL of THF is added dropwise. The reaction medium is stirred at -78 C. for 1 hour and the bath of cardice/acetone is then removed and the reaction medium is stirred, while allowing the temperature to return gradually to room temperature, for 18 hours. The mixture is hydrolysed with 100 mL of water, basified to pH =12 with 2N NaOH solution and then extracted with tert-butyl methyl ether. The aqueous phase containing the carboxylate is acidified with 5N HCl solution to pH 1 and extracted with dichloromethane. The dichloromethane phase is washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. The product is crystallized from isopropyl ether; after filtering and drying, 14.6 g of white crystals are obtained (yield=64%). m.p.=170 C. (Mettler FP62) LC/MS: MH+=287 (Rt=7.07 minutes) 1H NMR delta in ppm (DMSO d 6): 3.85 (s, 3H); 3.90 (s, 3H); 7.03 (d, J=8.5 Hz, 2H); 7.24 (dd, J1=8.5 Hz, J2=2.5 Hz, 1H); 7.35 (d, J=8.5 Hz, 1H); 7.42 (d, J=2.5 Hz, 1H); 7.61 (d, J=8.5 Hz, 2H); 13.1 (s, 1H, COOH).
2.4. 5-Methoxy-2-(4-methoxybenzoyl)benzoic Acid A solution of 18.5 g (80 mmol) of 2-bromo-5-methoxybenzoic acid in 150 mL of THF is stirred under nitrogen at -78 C. 100 mL (160 mmol) of a 1.6 M solution of n-butyllithium in hexane are added dropwise over about one hour while taking care to ensure that the temperature does not exceed -70 C. After the addition, the mixture is stirred at -78 C. for one hour, and a solution of 15.9 g (80 mmol) of N-4-dimethoxy-N-methylbenzamide in 20 mL of THF is then added dropwise. The reaction medium is stirred at -78 C. for one hour and then at room temperature for 18 hours. The mixture is hydrolyzed with 100 mL of water, basified to pH=12 with 2 N NaOH solution and extracted with tert-butyl methyl ether. The aqueous phase containing the carboxylate is acidified with 5 N HCl solution to pH=1 and extracted with dichloromethane. The dichloromethane phase is washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. The product is crystallized from isopropyl ether; after filtering off and drying, 14.6 g of white crystals are obtained.m.p.=170 C. (M)LC/MS: MH+=287 (Rt=7.07 minutes, pH 3.1)1H NMR (DMSO-d6, 250 MHz) delta ppm: 3.85 (s, 3H); 3.90 (s, 3H); 7.03 (d, J=8.5 Hz, 2H); 7.24 (dd, J1=8.5 Hz, J2=2.5 Hz, 1H); 7.35 (d, J=8.5 Hz, 1H); 7.42 (d, J=2.5 Hz, 1H); 7.61 (d, J=8.5 Hz, 2H); 13.1 (s, 1H, COOH).
To a solution of 2-bromo-5-methoxybenzoic acid (1 01 g, 439 mmol) in DCM (15 mL) at -78 C was added boron tnbromide in DCM (9 8 mL, 9 8 mmol) The reaction mixture was warmed to rt and stirred for 3 h. Methanol (15 mL) was added to the reaction mixture and stirred for additional 30 mm. Concentrated sulfuric acid was then added and heated at 50 C over night The reaction was concentrated and then diluted with DCM (100 mL) The organic layer was washed with H2O (2x50 mL), dried over Na2SO4 and concentrated to yield the desired product as an off-white solid (900mg) NMR (CDC13) delta 7 53 (d, 1H), 733 (d, 1H), 6 88 (dd, 1H), 3 96 (s, 3H) Step B Methyl 2-bromo-5-(4-fluorobenzyloxy1benzoate
Preparation 8; 2-Bromo-5-hydroxybenzoic acid methyl ester (P8); 2-Bromo-5-methoxybenzoic acid (30.0 g, 130 mmol, Aldrich) was stirred under argon in dry dichloromethane (600 mL), cooled in Dry Ice/acetone, as boron tribromide (1M in dichloromethane, 280 mL, 280 mmol) was added over 15 minutes. The mixture was then stirred at ambient temperature for 2.5 hours, yielding a precipitate. Methanol (300 mL) was then cautiously added dropwise (CARE: initially strongly exothermic, and with effervescence) over 30 minutes, finally giving a dark homogeneous solution, to which was added concentrated sulphuric acid (15 mL). The solution was stirred at reflux for 1 hour, cooled, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (500 mL), washed with brine (500 mL), dried over magnesium sulfate, filtered and concentrated at reduced pressure to yield the title compound as a solid ; LC/MS (ES+ve): [M+H] + at m/z 231,233 (C8H7BrO3 requires [M+H] + at m/z 231,233).; 2-Bromo-5-hydroxybenzoic acid methyl ester A solution of boron tribromide (18 mL, 190.5 mmol) in dichloromethane (18 mL) was added to a stirred suspension of 2-bromo-5-methoxybenzoic acid (from Wychem, 20 g, 86.6 mmol) in dichloromethane (200 mL) at-15 to-10 C. The yellow suspension was allowed to warm to 0C. HPLC analysis showed complete consumption of acid. The reaction was quenched by addition of methanol (100 mL). The clear dark solution was stirred at reflux (approximately 45C) for 12 hours, evaporated to near dryness, partitioned between water (400 mL) and ethyl acetate (500 mL), and separated. The organic solution was washed with brine (250 mL) and evaporated to yield the title compound as a cream solid.
2-(3-fluorobenzoyl)-5-methoxybenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
2-(3-fluorobenzoyl)-5-methoxybenzoic acid A -78 C. solution of 2-bromo-5-methoxybenzoic acid (26.0 g, 112.5 mmol) in THF (100 mL) was treated with n-BuLi (1.6 M in hexane) (140 mL, 225 mmol) and stirred at -78 C. for 1 h. <strong>[226260-01-1]3-fluoro-N-methoxy-N-methylbenzamide</strong> (15.3 g, 83.8 mmol) in THF (40 mL) was added dropwise then warmed to rt for 16 h. The reaction mixture was diluted with water (100 mL), acidified with 5N HCl (25 mL) and extracted with EtOAc (3*200 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain 2-(3-fluorobenzoyl)-5-methoxybenzoic acid (21.0 g, 68%) (274.83 [M+H]); 1H NMR: (400 MHz, DMSO) delta: 3.89 (s, 3H), 7.26-7.29 (m, 1H), 7.37-7.45 (m, 4H), 7.50-7.55 (m, 2H).
6,6'-azanediylbis(3-methoxybenzoic acid)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With copper(I) oxide; copper; potassium carbonate In N,N-dimethyl-formamide Inert atmosphere; Reflux;
With copper(I) oxide; copper; potassium carbonate In N,N-dimethyl-formamide at 80℃;
7.1 (1) Synthesis of compound 3 ':
To commercially available raw materials 1 '(2.00g, 8.66mmol), 2' (1.59g, 9.52mmol) were added Cu (0.11g, 1.73mmol),Cu2O (0.12g, 0.87mmol), potassium carbonate (3.59g, 25.97mmol), DMF 15ml, the reaction was stirred at 80 ° C overnight.The reaction solution was cooled to room temperature, and 2M dilute hydrochloric acid was added thereto until the system became acidic, and a large amount of solid precipitated.The precipitated solid was suction filtered, washed with water, and dried to obtain compound 3 (2.00 g, 73%), and directly participated in the subsequent reaction without purification.
[Ho(2-bromine-5-methoxybenzoate)3(2,2:6′,2″-terpyridine)(H2O)][ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57.52%
With sodium hydroxide In ethanol for 6h;
2.3.1 Preparation of Ho(2-Br-5-MOBA)3(terpy)(H2O)
A mixture of 2-Br-5-MOHBA (0.6mmol) and terpy (0.2mmol) was dissolved in 6mL 95% ethanol solution and the pH of the resulting solution was adjusted to 5-7 with 1molL-1 NaOH solution. This mixture was then added dropwise to an aqueous solution of HoCl3·6H2O (0.2mmol) under stirring and then the stirring was continued for about 6h. Powders of title complexes were obtained after standing for 12h, filtering and drying. Single crystals were collected from the mother liquor after two weeks at room temperature. For 1, yield: 57.52%, Elemental analyses for C39H31Br3N3O10Ho (%), Calcd: C, 43.04; H, 2.68; N, 3.86; Ho, 15.15. Found: C, 42.98; H, 2.65; N, 3.82; Ho, 15.11.
[Ho(2-bromine-5-methoxybenzoate)3(5,5′-dimethy-2,2′-bipyridine)]2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37.9%
With sodium hydroxide In ethanol for 6h;
2.3.1 Preparation of Ho(2-Br-5-MOBA)3(terpy)(H2O)
General procedure: A mixture of 2-Br-5-MOHBA (0.6mmol) and terpy (0.2mmol) was dissolved in 6mL 95% ethanol solution and the pH of the resulting solution was adjusted to 5-7 with 1molL-1 NaOH solution. This mixture was then added dropwise to an aqueous solution of HoCl3·6H2O (0.2mmol) under stirring and then the stirring was continued for about 6h. Powders of title complexes were obtained after standing for 12h, filtering and drying. Single crystals were collected from the mother liquor after two weeks at room temperature. For 1, yield: 57.52%, Elemental analyses for C39H31Br3N3O10Ho (%), Calcd: C, 43.04; H, 2.68; N, 3.86; Ho, 15.15. Found: C, 42.98; H, 2.65; N, 3.82; Ho, 15.11.
General procedure: To a solution of the acid (1 equiv.) in DCM (0.2 M) were added DCC (1.1 equiv.) and DMAP (0.5 equiv.) at 0 C. After the mixture was stirred for 10 min, t-BuOH (1.5equiv.) was added. The reaction was stirred overnight at room temperature, then filtered through a pad of Celite and washed with Et2O three times. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography on silica gel to give the desired product.
2-ethyl-3-(2-bromo-5-methoxybenzoyl)benzofuran[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
24%
Stage #1: 2-bromo-5-methoxy-benzoic acid With thionyl chloride for 2h; Reflux;
Stage #2: 2-ethylbenzofuran With tin(IV) chloride In dichloromethane at 20℃; for 4.5h; Inert atmosphere;
2-Ethyl-3-(2-bromo-5-methoxybenzoyl)benzofuran.
. 2-Bromo-5-methoxybenzoic acid(287 mg, 1.24 mmol) and SOCl2 (6.58 g, 55 mmol) were added to around-bottom flask. The reaction mixture was heated while refluxing for 2.0 hrand the solvent was removed under reduced pressure. The residue was dilutedwith CH2Cl2 (7 mL) and SnCl4 (446 mg, 1.71mmol) , after which 2-ethylbenzofuran (200 mg, 1.37 mmol) was added in an N2atmosphere. The resulting mixture wasstirred for 4.5 hr at room temperature and cooled in an ice bath, followed bythe addition of water (20 mL) to quench the reaction. The product was extractedwith CH2Cl2 and washed with brine. The organic phase wasdried over anhydrous Na2SO4 and the solvent was removedunder reduced pressure. The product was purified using silica gel columnchromatography. The purple oil (106 mg, 24% yield) was identified as 2-ethyl-3-(2-bromo-5-methoxybenzoyl)benzofuranon the basis of 1H-NMR and mass spectra. 1H-NMR (400 MHz,CDCl3): d 1.30 (t, J=7.5 Hz, -CH2-CH3,3H), 2.82 (q, J=7.5 Hz, -CH2-CH3,2H), 3.81 (s, -OCH3, 3H), 6.91 (d, J=3.0 Hz, Ar H, 1H), 6.93 (dd, J=8.6,3.0 Hz, Ar H, 1H), 7.22 (dt, J=7.5,1.2 Hz, Ar H, 1H), 7.29 (dt, J=7.5,1.2 Hz, Ar H, 1H), 7.42 (dd, J=7.8,0.8 Hz, Ar H, 1H), 7.46 (dd, J=7.8,0.8 Hz, Ar H, 1H), 7.54 (d, J=8.6 Hz,Ar H, 1H); MS (ESI): m/z [M+Na+2]+383, [M+Na]+ 381.
With 8-quinolinol; sodium hydroxide; copper dichloride; In water; at 20℃; for 0.333333h;Sealed tube; Microwave irradiation;
General procedure: In a 10 mL glass tube 2-iodobenzoic acid (1.0 mmol), acetamidine hydrochloride (1.2 mmol), CuCl2 (0.1 mmol), L2 (0.1 mmol), and NaOH (4.0 equiv.) and 3.0 mL water were placed. The vessel was then sealed with a septum and placed into the microwave cavity. Initial microwave irradiation of 120 W by using a CEM Discover microwave synthesizer was used at the room temperature for 20 min. The reaction mixture was stirred continuously during the reaction. After completion of the reaction, the solvent was removed in vacuo. The residue was purified by silica gel column chromatography to afford the corresponding product. All the products were confirmed by NMR and MS spectroscopic analysis.
With copper(I) oxide; copper; potassium carbonate; In N,N-dimethyl-formamide; at 95℃; for 12h;
General procedure: The starting material 2-amino-5-methoxy-3,4-dimethyl-benzoic acid8c was synthesized according to a method previously reported in theliterature.[25] To a magnetically stirred solution of 2-(2-bromophenyl)acetic acid 7a (0.61g, 2.8 mmol) and 8c (0.5g, 2.6 mmol) in DMF wasadded powdered Cu (0.02g), Cu2O (0.02g) and K2CO3 (0.28g, 2 mmol)successively. The reaction mixture was heated to 95 for 12 h. Uponremoval of the solvents, the residue was triturated with 1 N NaOHsolution. The whole mixture was filtered off and the alkaline solutionwas acidified with conc. HCl, and then collected the precipitate. Thedried residue was subjected to column purification (PE/EA 4:1) tofurnish the desired compound. A solution of 2-((2-(carboxymethyl)phenyl) amino)-5-methoxy-3,4-dimethyl-benzoic acid in Eaton?s reagent(P2O5 -CH3SO3H) (5 ml) at room temperature was heated to90 C for 1 h. After cooling to room temperature, the mixture was addedslowly to the saturated aqueous NaHCO3 solution. The crude was accumulatedby filtration followed by purification with silica gel columnchromatography to give 0.3g product: the dark brown solid, yield 37.5%. 1H NMR (400 MHz, CHLOROFORM-D) delta (ppm): 8.17 (d,J = 8.0 Hz, 1H), 7.81 (s, 1H), 7.62 (dd, J = 7.1, 0.9 Hz, 1H), 7.42 -7.36 (m, 1H), 3.99 (s, 3H), 3.92 (s, 2H), 2.39 (s, 3H), 2.37 (s, 3H). 13CNMR (101 MHz, DMSO-D 6) delta (ppm): 173.51, 161.50, 155.21, 153.01,139.05, 134.15, 132.91, 125.57, 124.99, 122.86, 121.12, 120.42,119.14, 101.45, 55.73, 38.54, 13.16, 13.02. HRMS (ESI) m/z [M+H] + calculated for C18H15NO3: 294.1130 found: 294.1123.
Stage #1: 3-Bromophenol; 2-bromo-5-methoxy-benzoic acid With sodium hydroxide In water for 1h; Reflux;
Stage #2: With copper(ll) sulfate pentahydrate In water for 0.5h; Reflux;
1.1 Step 1:
A mixture of 2-bromo-5-methoxybenzoic acid 1 (27.6 g; 119 mmol; 1.0 eq.), resorcinol 2 (26.3 g; 239 mmol; 2.0 eq.) and sodium hydroxide (10.5 g; 263 mmol; 2.2 eq.) in water (120 mL) was heated under reflux for 1 hour. A 5% aqueous solution of copper sulphate (3.88 g of CuSO4.5H2O in 50 mL water; 15.5 mmol; 0.1 eq.) was then added and the mixture was refluxed for additional 30 minutes. The mixture was allowed to cool to room temperature and the solid was filtered on a Buchner filter. The residue was washed with cold water to give a pale red solid which was triturated in hot MeOH. The suspension was left overnight at 4° C. The resultant precipitate was filtered and washed with cold MeOH to yield the title compound 3 as a pale brown solid.
3-(methylsulfonamido)phenyl 2-bromo-5-methoxybenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: 2-bromo-5-methoxy-benzoic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1h;
Stage #2: N-(3-hydroxyphenyl)methanesulfonamide With triethylamine In dichloromethane; N,N-dimethyl-formamide for 4h;
2 3-(Methylsulfonamido)phenyl 2-bromo-5-methoxybenzoate (Intermediate 1)
To a suspension of 2-bromo-5-methoxybenzoic acid (642 mg, 2.78 mmol) in DCM (10 mL) was added oxalyl chloride (0.27 mL, 3.06 mmol) dropwise and 1 drop of DMF. The solution was stirred at RT for 1 h and the solvent was removed in vacuo. The resultant mixture was re- dissolved in DCM (5 mL) and a suspension of N-(3-hydroxyphenyl)methanesulfonamide (520 mg, 2.78 mmol) in DCM (5 mL) was added followed by TEA (0.58 mL, 4.17 mmol). The resulting mixture was stirred for 4 h, then diluted with DCM and washed with saturated aq. NH4Cl. The organic extracts were filtered through PTFE and concentrated in vacuo and the crude product was purified by chromatography on silica (ISCO 12 g) using 0-50% EtOAc in cyclohexane as eluant to give the product 3-(methylsulfonamido)phenyl 2-bromo-5- methoxybenzoate as colourless oil (1 g, 90%). LCMS (Method 5): Rt 1.43 min; m/z 398.0/400.0 [M-H]-.1H NMR (400 MHz, CDCl3) δ 7.61 (1H, d, J=8.9 Hz), 7.52 (1H, d, J=3.1 Hz), 7.41 (1H, t, J=8.1 Hz), 7.19-7.08 (3H, m), 6.98 (1H, dd, J=8.9, 3.1 Hz), 6.77 (1H, s), 3.87 (3H, s), 3.07 (6H, s).
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