* 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.
Stage #1: With triethylamine In diethyl ether; ethanol at 70℃; Inert atmosphere Stage #2: With hydrogenchloride; water In dichloromethane for 2 h;
Step 2 To a degassed solution of methyl 3-bromo-4-hydroxybenzoate (350 g, 1514.87 mmol) in ethanol (3 L) were added triethylamine (0.528 L, 3787.17 mmol), 1-(vinyloxy)butane (0.588 L, 4544.60 mmol), 1,1'-bis(diphenylphosphino)ferrocene (33.1 g, 60.6 mmol) and diacetoxypalladium (8.50 g, 37.9 mmol) under nitrogen. The mixture was heated at 70° C. overnight. The reaction was cooled down, filtered and the filtrate concentrated. The resulting solid was solubilized with DCM (2 L) and HCl 4N (1.14 L, 4544 mmol) was added under stirring. Stirring was maintained for 2 hrs, the organic phase was separated, dried over magnesium sulfate, filtered and concentrated to afford a solid which was stirred in diethyl ether (5 L) for 2 hrs. The solid was filtered off and the filtrate concentrated to dryness to afford methyl 3-acetyl-4-hydroxybenzoate (240 g, 82percent) as a beige powder. Mass spectrum: [M-H]- 193.
82%
Stage #1: With triethylamine In ethanol at 70℃; Inert atmosphere Stage #2: With hydrogenchloride In dichloromethane at 20℃; for 2 h;
To a degassed solution of methyl 3-bromo-4-hydroxybenzoate (350 g, 1514.87 mmol) in ethanol (3 L) were added triethylamine (0.528 L, 3787.17 mmol), l-(vinyloxy)butane (0.588 L, 4544.60 mmol), Ι,Γ-bis (diphenylphosphino)ferrocene (33.1 g, 60.6mmol) and diacetoxypalladium (8.50 g, 37.9 mmol) under nitrogen. The mixture was heated at 70°C overnight. The reaction was cooled down, filtered and the filtrate concentrated. The resulting solid was solubilized with DCM (2L) and HC1 4N (1.14 L, 4544 mmol) was added under stirring. Stirring was maintained for 2hrs, the organic phase was separated, dried over magnesium sulfate, filtered and concentrated to afford a solid which was stirred in diethyl ether (5 L) for 2hrs. The solid was filtered off and the filtrate concentrated to dryness to afford methyl 3-acetyl-4-hydroxybenzoate (240 g, 82percent) as a beige powder. Mass spectrum: ΓΜ-Η1" 193.
82%
With triethylamine In ethanol at 70℃; Inert atmosphere
Step 2To a degassed solution of methyl 3-bromo-4-hydroxybenzoate (350 g, 1514.87 mmol) in ethanol (3 L) were added triethylamine (0.528 L, 3787.17 mmol), l-(vinyloxy)butane (0.588 L, 4544.60 mmol), Ι,Γ-bis (diphenylphosphino)ferrocene (33.1 g, 60.6mmol) and diacetoxypalladium (8.50 g, 37.9 mmol) under nitrogen. The mixture was heated at 70°C overnight. The reaction was cooled down, filtered and the filtrate concentrated. The resulting solid was solubilized with DCM (2L) and HC1 4N (1.14 L, 4544 mmol) was added under stirring. Stirring was maintained for 2h, the organic phase was separated, dried over MgS04, filtered and concentrated to afford a solid which was stirred in ether(5 L) for 2h. The solid was filtered off and the filtrate concentrated to dryness to afford methyl 3-acetyl-4-hydroxybenzoate (240 g, 82percent) as a beige powder. Mass spectrum: m/z[M-H]- = 193.
82%
Stage #1: With triethylamine In ethanol at 70℃; Inert atmosphere Stage #2: With hydrogenchloride In dichloromethane for 2 h;
To a degassed solution of methyl 3-bromo-4-hydroxybenzoate (350 g, 1514.87 mmol) in ethanol (3 L) were added triethylamine (0.528 L, 3787.17 mmol), 1-(vinyloxy)butane (0.588 L, 4544.60 mmol), 1,1'-bis(diphenylphosphino)ferrocene (33.1 g, 60.6 mmol) and diacetoxypalladium (8.50 g, 37.9 mmol) under nitrogen. The mixture was heated at 70° C. overnight. The reaction was cooled down, filtered and the filtrate concentrated. The resulting solid was solubilized with DCM (2 L) and HCl 4N (1.14 L, 4544 mmol) was added under stirring. Stirring was maintained for 2 h, the organic phase was separated, dried over MgSO4, filtered and concentrated to afford a solid which was stirred in ether (5 L) for 2 h. The solid was filtered off and the filtrate concentrated to dryness to afford methyl 3-acetyl-4-hydroxybenzoate (240 g, 82percent) as a beige powder. Mass spectrum: m/z [M-H]-=193.
Intermediate T3T3.1[0304] Methyl 3-bromo-4-hydroxybenzoate (T3.1). To a stirred solution of 3- bromo-4-hydroxybenzoic acid (available from Alfa Aesar, Avocado, Lancaster) (50.0 g, 231 mmol) in MeOH (300 mL) was added a cold solution of sulfuric acid (2.50 mL, 47 mmol). The mixture was heated to 80°C and monitored by TLC. After 16.5 hours, the solvent was removed and the reaction mixture was diluted with EtOAc. The organic phase was washed carefully two times with saturated aqueous NaHCO3, once with brine, and then dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to yield T3.1 as a white solid (yield 100percent) that was used without purification.
100%
at 80℃; for 16.5 h;
Methyl 3-bromo-4-hydroxybenzoate (C.2). To a stirred solution of 3- bromo-4-hydroxybenzoic acid (C.l)(available from Alfa Aesar, Avocado, Lancaster) (50.0 g, 231 mmol) in MeOH (300 mL) was added a cold solution of sulfuric acid (2.50 mL, 47 mmol). The mixture was heated to 80°C and monitored by TLC. After 16.5 hours, the solvent was removed and the reaction mixture was diluted with EtOAc. The organic phase was washed carefully two times with saturated aqueous NaHCψ3, once with brine, and then dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to yield C.2 as a white solid (yield 100percent) that was used without purification.; Methyl 3-bromo-4-hydroxybenzoate (T6.5). To a stirred solution of 3- bromo-4-hydroxybenzoic acid (T6.4)(available from Alfa Aesar, Avocado, Lancaster) (50.0 g, 231 mmol) in MeOH (300 mL) was added a cold solution of sulfuric acid (2.50 mL, 47 mmol). The mixture was heated to 80°C and monitored by TLC. After 16.5 hours, the solvent was removed and the reaction mixture was diluted with EtOAc. The organic phase was washed carefully two times with saturated aqueous NaHCO3, once with brine, and then dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to yield T6.5 as a white solid (yield 100percent) that was used without purification.
94%
at 0 - 90℃; for 12 h; Inert atmosphere
Step 1) Synthesis of methyl 3-bromo-4-hydroxybenzoate3-Bromo-4-hydroxybenzoic acid (10.0 g, 46.1 mmol) and methanol (120 mL) were added toa 500 mL single neck flask, then thionyl chloride (7.35 mL, 101 mmol) was added dropwise at 0°C. The mixture was heated to 90 °C and stirred for 12 h under nitrogen. The resulting mixture was concentrated in vacuo to remove solvent. To the residue was added saturated aqueous sodium bicarbonate (200 mL), and the resulting mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) = 1/20) to give the title compound as a pale yellow solid (10.0 g, 94percent).MS (ES-API, neg. ion) m/z: 228.0 [M - 2].
93%
at 60℃; for 5 h;
3-Bromo-4-hydroxybenzoic acid (1.50 g, 6.77 mmol) was dissolved in 15 mL of methanol and acetyl chloride (0.59 mL, 8.12 mmol) was added. The mixture was stirred at 60°C for 5 h. The solution was allowed to cool and was evaporated. Ethyl acetate was added to the residue, the organic phase was washed twice with water, brine and dried over magnesium sulphate. Filtration and evaporation gave 1.51 g (6.53 mmol, 93percent) of the title compound as a white solid. Purity 96percent. HPLC/MS (9 min) retention time 5.36 min. LRMS: m/z 232 (M+1)
90%
for 18 h; Reflux
70C. methyl 3-bromo-4-hydroxybenzoate: To 3-bromo-4-hydroxybenzoic acid (10.85 g, 50 mmol) in MeOH (60 mL), sulfuric acid (0.533 mL, 10.00 mmol) was added and the reaction was refluxed for 18 h. The reaction mixture was concentrated and diluted with EtOAc. The mixture was washed with sat. NaHCO3, brine, dried and concentrated to give 70C (white solid, 10.4 g, 90percent yield). HPLC RT=2.66 min.
90%
for 12 h; Reflux
[00120] 3-Bromo-4-hydroxybenzoic acid (BHBA) (250 g, 1.81 mol) was dissolved in MeOH (1.5 L), the mixture cooled to 15 to 25 °C, and SOCl2 (35 g) added drop wise (T<25 °C). The reaction mixture was then refluxed for 12 h. The reaction mixture was concentrated under vacuum and the white solid thus formed was washed with deionized water until pH ~7. Drying under vacuum at 50-55 °C gave the desired product as a white solid (239 g, 90percent; 99.52percent purity). XH NMR (400 MHz, CDCI3): δ = 8.2 (s, 1H), 7.8-8.0 (d, J = 8 Hz, 1H), 6.9-7.0 (d, J = 8 Hz, 1H), 4.92 (brs, 1H), 3.87 (s, 3H) ppm. 1 C NMR (100 MHz, CDC13): 165.95, 158.63, 134.5, 133.38, 130.05, 122.28, 115.30, 109.27, 51.17 ppm.
85%
for 24 h; Heating / reflux
methyl 3-bromo-4-hydroxybenzoate A solution of 3-bromo-4-hydroxybenzoic acid (50.4 g, 232 mmol) and conc. sulfuric acid (17 mL) in methanol (330 mL) was heated under reflux for 24 hrs. The reaction mixture was neutralized with aqueous sodium hydroxide solution. Methanol was removed under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crystals were washed with diethyl ether/hexane to give the title compound (45.5 g, yield 85percent) as pale-pink crystals. MS m/z 231 (MH+)
85%
for 24 h; Heating / reflux
A solution of 3-bromo-4-hydroxybenzoic acid (50.4 g, 232 mmol) and concentrated sulfuric acid (17 mL) in methanol (330 mL) was heated under reflux for 24 hr. The reaction mixture was neutralized with aqueous sodium hydroxide solution, methanol was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with diethyl ether/hexane to give the title compound (45.5 g, yield 85percent) as pale-pink crystals. MS m/z 231 (MH+).
With bromine In dichloromethane at 0 - 20℃; Inert atmosphere
Dibromine (0.185 L, 3614.92 mmol) was added dropwise a stirred suspension of methyl 4- hydroxybenzoate (500 g, 3286 mmol) in DCM (4 L) at 0°C under N2. The mixture was left to stir for 24 hrs at RT under N2 (need to trap HBr). A solution of sodiummetabisulfite (62.5 g, 329 mmol) in 2L of water was then added, while keeping the temperature around 15°C, followed by 500 mL of MeOH. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered and concentrated to dryness to afford methyl 3-bromo-4-hydroxybenzoate (710 g, 94percent) as a white solid. NMR Spectrum (CDC13): 3.89 (s, 3H), 5.95 (s, 1H), 7.05 (d, 1H), 7.92 (dd, 1H), 8.19 (d, 1H).
94%
With bromine In dichloromethane at 0 - 20℃; for 36 h; Inert atmosphere
Step 1Dibromine (0.185 L, 3614.92 mmol) was added dropwise a stirred suspension of methyl 4- hydroxybenzoate (500 g, 3286 mmol) in DCM (4 L) at 0°C under N2. The mixture was left to stir for 24 h at r.t. under N2. A solution of sodium metabisulfite (62.5 g, 329 mmol) in 2L of water was then added, while keeping the temperature around 15°C, followed by 500 mL of MeOH. The organic layer was washed with water, brine, dried over MgS04, filtered and concentrated to dryness to afford methyl 3-bromo-4-hydroxybenzoate (710 g,94percent) as a white solid. Proton NMR Spectrum (CDC13): 3.89 (s, 3H), 5.95 (s, 1H), 7.05 (d, 1H), 7.92 (dd, 1H), 8.19 (d, 1H).
81%
With bromine In dichloromethane at 0 - 20℃; for 6 h;
The compound (5 g, 32.9 mmol) obtained in was dissolved in dichloromethane (350 mL), and a solution obtained by dissolving Br2 (1.7 mL, 32.9 mmol) in dichloromethane (50 mL) was slowly added thereto at 0°C, and stirred at ambient temperature for 1 hour. The mixture was stirred at ambient temperature for another 5 hours, and water and a Na2S2O3 aqueous solution were added thereto. The mixture was extracted with dichloromethane, washed with saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified using silica gel chromatography to obtain the title compound (white solid, 6.18 g, and 81 percent yield). (0110) 1H NMR (300 MHz, CDCl3) δ 8.19 (d, 1H), 7.92 (dd, 1H), 7.05 (d, 1H), 5.93 (s, 1H), 3.89 (s, 3H).
78.2%
With bromine; acetic acid In dichloromethane at 20 - 30℃; for 32 h;
To methylparaben (21.42g, 0.148mol, 1eq) in dichloromethane (300ml) was added glacial acetic acid (90ml, 0.155mol, 1.1eq), stirring until completely dissolved, the ice bath to cool to 5 , to the reaction mixture was slowly added dropwise liquid bromine (8.0ml, 0.155mol, 1.1eq), added dropwise in the temperature of the process control 0 ~ 5 , addition was complete, 32h is reacted at room temperature, the reaction process to receive exhaust HBr.After completion of the reaction, the reaction mixture was added Na2S2O3The aqueous solution (35.2g, 264ml), stirred for 1h, then methanol (200ml), extracted several layers washed with water twice, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a white solid which was toluene (4:1) recrystallized to give a white solid 20.4 g, yield 78.2percent.
66%
With bromine; acetic acid In tetrachloromethane at 20℃; for 8 h;
To a stirred solution of methyl 4-hydroxybenzoate (10.0 g, 84.935 mmol) in CCU (30 mL) was added AcOH (20 mL, 2 VoI). Br2 (1.80 mL, 71.428 mmol) was then added slowly at 0 0C. After the addition was completed, the reaction mixture was brought to RT and stirred for 8 h. Reaction mixture was quenched with water (50 mL), neutralized with saturated NaHCC^ solution and extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with water (2 x 50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to obtain crude product. The crude material was purified via silica gel column chromatography eluting with 5percent EtOAc- 95percent hexanes to afford methyl 3-bromo-4-hydroxybenzoate (10.0 g, 66 percent) as a brown solid.
65%
With bromine In dichloromethane at -5 - 20℃; for 4.5 h; Inert atmosphere
To a solution of 36 (3.15 g, 20.7 mmol) in DCM (230 mL) was added slowly at −5 °C a solution of bromine (1.1 mL, 21 mmol) in DCM (50 mL). The mixture was stirred for 4.5 h at room temperature. The reaction mixture was diluted with EtOAc and the organic layer was washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/EtOAc) to give 37 (3.10 g, 65percent) as colorless solid. The compound was used, without structure determination, directly for the next step.
Reference：
[1] Tetrahedron, 2010, vol. 66, # 34, p. 6906 - 6911
[2] Helvetica Chimica Acta, 1989, vol. 72, p. 594 - 607
[3] Tetrahedron, 2003, vol. 59, # 46, p. 9173 - 9177
[4] Synlett, 2011, # 11, p. 1537 - 1542
[5] Tetrahedron, 2011, vol. 67, # 34, p. 6300 - 6307
[6] Patent: WO2011/51704, 2011, A1, . Location in patent: Page/Page column 99
[7] Patent: WO2012/140419, 2012, A1, . Location in patent: Page/Page column 84
[8] Journal of Medicinal Chemistry, 2015, vol. 58, # 2, p. 943 - 962
[9] Journal of the American Chemical Society, 2001, vol. 123, # 49, p. 12202 - 12206
[10] Journal of the American Chemical Society, 2000, vol. 122, # 51, p. 12907 - 12908
[11] Patent: EP2963027, 2016, A1, . Location in patent: Paragraph 0108; 0109; 0110
[12] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 10, p. 2621 - 2625
[13] Patent: CN103467296, 2016, B, . Location in patent: Paragraph 0027; 0028
[14] Tetrahedron Letters, 1996, vol. 37, # 14, p. 2395 - 2398
[15] Patent: WO2009/158393, 2009, A1, . Location in patent: Page/Page column 108
[16] European Journal of Medicinal Chemistry, 2013, vol. 61, p. 26 - 40
[17] Journal of the Society of Chemical Industry, London, 1945, vol. 64, p. 212,214
[18] Yakugaku Zasshi, 1930, vol. 50, p. 224,227; dtsch. Ref. S. 27[19] Chem.Abstr., 1930, p. 3513
[20] Patent: US2011/98271, 2011, A1, . Location in patent: Page/Page column 37
[21] Patent: US2012/184587, 2012, A1, . Location in patent: Page/Page column 19
[22] Patent: US2012/264731, 2012, A1, . Location in patent: Page/Page column 33
Reference：
[1] Journal of Organic Chemistry, 1997, vol. 62, p. 4504 - 4506
[2] Journal of Organic Chemistry, 1997, vol. 62, p. 4504 - 4506
7
[ 99-96-7 ]
[ 29415-97-2 ]
Reference：
[1] Patent: EP2963027, 2016, A1,
8
[ 14348-41-5 ]
[ 29415-97-2 ]
Reference：
[1] Monatshefte fuer Chemie, 1901, vol. 22, p. 437
9
[ 67201-23-4 ]
[ 29415-97-2 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1981, p. 2415 - 2434
10
[ 29415-97-2 ]
[ 29922-56-3 ]
Yield
Reaction Conditions
Operation in experiment
68%
Stage #1: With diisobutylaluminium hydride In tetrahydrofuran; dichloromethane at -78℃; for 1 h; Stage #2: With water In tetrahydrofuran; methanol; dichloromethane
To a solution of 12 (0.185 g, 0.80 mmol) in dry CH2Cl2 (14 mL), a solution of DIBAL-H in THF (1.0 M) (1.92 mL, 1.92 mmol) was added at -78 °C. The solution was stirred for 1 h and then it was quenched by addition of MeOH and water. A saturated solution of Na+ and K+ tartrate was added; the mixture was stirred for an additional hour and the aqueous layer was extracted with ethyl acetate (3.x.20 mL). The organic layers were combined and washed with a 10percent aqueous solution of NaHCO3 and water, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (ethyl acetate/hexane 1:1) to afford 13 as white solid (0.111 g, 68percent). Mp 125 °C; [Found: C, 41.45; H, 3.42. C7H7BrO2 requires C, 41.41; H, 3.48]; Rf 0.6 (ethyl acetate/hexane 65:35); IR νmax (Nujol) 3510, 3060, 2982, 1610, 1505, 1425, 1270, 905, 750, 710 cm-1; 1H NMR (300 MHz, DMSO-d6) δ: (s, 1H), 7.38 (d, J 2.0 Hz, 1H), 7.08 (dd, J 2.0, 8.2 Hz, 1H), 6.87 (d, J 8.2 Hz, 1H), 5.07 (t, J 5.7 Hz, 1H), 4.34 (d, J 5.7 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ: 153.3, 135.4, 131.6, 127.6, 116.5, 109.4, 62.5.
To a stirred solution of methyl 3-bromo-4-hydroxybenzoate (2.50 g, 10.775 mmol) in NMP (7.5 mL) was added CuCN (1.05 g, 11.853 mmol) at RT under an inert atmosphere. <n="110"/>The reaction mixture was then heated at 200 0C for 4 h., cooled to RT, diluted with water (10 mL) and stirred for 10 min. The precipitated solid was filtered off and the filtrate was concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford methyl 3-cyano-4-hydroxybenzoate (1 .50 g, 78percent) as a yellow solid.
13 g
With copper(l) iodide In N,N-dimethyl-formamide at 120℃;
Methyl 3-cyano-4-hydroxybenzoate: To a solution of methyl 3-bromo-4- hydroxybenzoate (26 g, 112.53 mmol, 1.00 equiv) in DMF (160 mL) was added Cul (2.1 g, 11.1 1 mmol, 0.10 equiv) and CuCN (30 g, 337.08 mmol, 3.00 equiv). The resulting solution was stirred overnight at 120 °C. The reaction mixture was cooled and diluted with water (300 mL). The resulting solution was extracted with dichloromethane (3 x 100 mL), and the organic layers were combined. The reaction mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column eluting with ethyl acetate/ petroleum ether (1 : 1) to afford 13 g of methyl 3-cyano-4- hydroxybenzoate as a white solid.
3-bromo-4-[2-(5-ethyl-10-methyl-11-oxo-10,11-dihydro-5<i>H</i>-4,5,6,10-tetraaza-dibenzo[<i>a</i>,<i>d</i>]cyclohepten-2-yl)-ethoxy]-benzoic acid methyl ester[ No CAS ]
3-bromo-4-[2-(5-ethyl-10-methyl-11-oxo-10,11-dihydro-5<i>H</i>-4,5,6,10-tetraaza-dibenzo[<i>a</i>,<i>d</i>]cyclohepten-2-yl)-ethoxy]-benzoic acid[ No CAS ]
2-{4-Methoxymethoxy-3-[(E)-3-methyl-5-((4aS,8aS)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8a-octahydro-naphthalen-1-yl)-pent-2-enyl]-benzyloxy}-tetrahydro-pyran[ No CAS ]
In methanol; hexanes; dichloromethane; at 20℃; for 2h;
PREPARATION OF CARBOXYLIC ACID INTERMEDIATES CARBOXYLIC ACID 1 3-Cyano-4-isopropyloxybenzoic acid; Step A: Methyl 3-bromo-4-hydroxybenzoate; A solution of 3.9 g (18. 0 mmol) of 3-bromo-4-hydroxybenzoic acid in 20 mL of 3: 1 v/v CH2Cl2/CH30H was treated with 10.8 mL of 2.0 M (trimethylsilyl) diazomethane solution in hexanes. The mixture was stirred at rt for 2 h, then concentrated to give 4.6 g of the title compound : 1H NMR (500 MHz, CDCl3) 8 3.90 (s, 3H), 5.93 (bs, 1H), 7.05 (d, J = 8.5, 1H), 7.92 (dd, J = 2. 1,8. 5,1H), 8.19 (d, J = 2. 0, 1H).
With potassium carbonate;potassium iodide; In DMF (N,N-dimethyl-formamide); at 80℃; for 2h;
methyl 3-bromo-4-isopropoxybenzoate To a solution of <strong>[29415-97-2]methyl <strong>[29415-97-2]3-bromo-4-hydroxybenzoate</strong></strong> (15.0 g, 64.9 mmol), 2-bromopropane (7.68 mL, 77.9 mmol) and potassium iodide (1.0 g, 6.49 mmol) in N, N-dimethylformamide (200 mL) was added potassium carbonate (13.5 g, 97.4 mmol) and the mixture was stirred at 80C for 2 hrs. The reaction mixture was concentrated under reduced pressure. Brine was added to the obtained residue and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-hexane/ethyl acetate=9/1) to give the title compound (14.6 g, yield 83%) as a colorless oil. 1H NMR (CDC13) 5 : 1.41 (6H, d, J=6. 0Hz), 3.89 (3H, s), 4.59-4. 75 (1H, m), 6.90 (1H, d, J=8.9Hz), 7.94 (1H, dd, J=8. 7,2. 1Hz), 8.23 (1H, d, J=2. lHz).
83%
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 80℃; for 2h;
To a solution of <strong>[29415-97-2]methyl <strong>[29415-97-2]3-bromo-4-hydroxybenzoate</strong></strong> (15.0 g, 64.9 mmol), 2-bromopropane (7.68 mL, 77.9 mmol) and potassium iodide (1.0 g, 6.49 mmol) in N,N-dimethylformamide (200 mL) was added potassium carbonate (13.5 g, 97.4 mmol), and the mixture was stirred at 80C for 2 hr. The reaction mixture was concentrated under reduced pressure, brine was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-hexane/ethyl acetate=9/1) to give the title compound (14.6 g, yield 83%) as a colorless oil. 1H NMR (CDCl3) delta: 1.41 (6H, d, J=6.0Hz), 3. 89 (3H, s), 4.59-4.75(1H, m), 6.90(1H, d, J=8.8Hz), 7.94(1H, dd, J=8.8, 2.1Hz), 8.23(1H, d, J=2.1Hz).
With potassium carbonate; In N,N-dimethyl-formamide; at 10℃; for 16h;
Compound 23-1 (6.00 g, 26.0 mmol) was dissolved in N,N-dimethylformamide (100 mL). Compound 23-2 (3.83 g, 31.2 mmol) and potassium carbonate (10.8 g, 77.9 mmol) were added at 10 C. The mixture was stirred at this temperature for 16 hours. The reaction solution was concentrated. The residue was added into dichloromethane (100 mL) and stirred for 1 hour. The mixture was filtered. The filtrate was concentrated to afford compound 23-3.1H NMR: (400 MHz, CDCl3) delta 8.23 (d, J=2.0 Hz, 1H), 7.94 (dd, J=2.0, 8.8 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 4.75-4.61 (m, 1H), 3.89 (s, 3H), 1.42 (d, J=6.0 Hz, 6H).
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 65℃; for 3h;
Step B : Methyl 3-bromo-4-isopropyloxybenzoate; A mixture of 4.6 g (19.9 mmol) of <strong>[29415-97-2]methyl <strong>[29415-97-2]3-bromo-4-hydroxybenzoate</strong></strong> (from Step A), 2.2 mL (21.9 mmol) of 2-iodopropane and 5.5 g (39.8 mmol) of potassium carbonate in 10 mL of DMF was stirred at 65 C for 3 h. The mixture was diluted with 20 mL of EtOAc and washed with sat'd NaCl, H20 (3x), and sat'd NaCl. The organic layer was dried over MgS04 and concentrated. Chomatography on a Biotage 40M cartridge using 24: 1 v/v hexanes/EtOAc gave 4.3 g of the title compound : 1H NMR (500 MHz, CDCl3) 8 1.44 (d, J = 6.2, 6H), 3.91 (s, 3H), 4. 71-4. 79 (m, 1H), 6.99 (d, J = 8.9, 1H), 8.18 (dd, J = 2.2, 8.8, 1H), 8.24 (d, J = 2.1, 1H).
With potassium carbonate; In N,N-dimethyl-formamide;
Preparation 13 Methyl 3-Bromo-4-iso-propoxybenzoate Methyl <strong>[29415-97-2]3-bromo-4-hydroxybenzoate</strong> (2.5 g, 10.8 mmol) in DMF (35 ml) was treated with potassium carbonate (3.0 g, 21.6 mmol), 2-iodopropane (2.76, 21.6 mmol) and then stirred at 25 C. for 48 h. Work-up with ethyl acetate gave the title compound (3.0 g). 1H NMR (250MHz, CDCl3) delta: 1.41 (6H, d, J=7 Hz), 3.89 (3H, s), 4.66 (1H, m), 6.90 (1H, d, J=8 Hz), 7.93 (1H, dd, J=8.2 Hz), 8.22 (1H, d, J=2 Hz).
With potassium carbonate; In N,N-dimethyl-formamide;
PREPARATION 8 Methyl 3-Bromo-4-iso-propoxybenzoate Methyl <strong>[29415-97-2]3-bromo-4-hydroxybenzoate</strong> (2.5 g, 10.8 mmol) in DMF (35 ml) was treated with potassium carbonate (3.0 g, 21.6 mmol), 2-iodopropane (2.76, 21.6 mmol) and then stirred at 25 C. for 48 h. Work-up with ethyl acetate gave the title compound (3.0 g). 1H NMR (250 MHz, CDCl3) delta: 1.41 (6H, d, J=7 Hz), 3.89 (3H, s), 4.66 (1H, m), 6.90 (1H, d, J=8 Hz), 7.93 (1H, dd, J=8, 2 Hz), 8.22 (1H, d, J=2 Hz).
With potassium carbonate; In acetonitrile;Reflux;
To a solution of <strong>[29415-97-2]methyl <strong>[29415-97-2]3-bromo-4-hydroxybenzoate</strong></strong> (44 g, 192.14 mmol) (Description 2) in acetonitrile (1 L) was added potassium carbonate (79.5 g, 576.4 mmol) and 2-iodopropane (58 mL, 576.4 mmol), the reaction mixture was heated to reflux overnight. The mixture was filtered and the filtrate was concentrated. The residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with water, dried over sodium sulfate and concentrated to afford the title compound (52.4 g). H N R (CDCI3, 400MHz) delta ppm: 1.41 (6H, d, J 6.5 Hz), 3.89 (3H, s), 4.66 (1 H, m), 6.90 (1H, d, J 8.5 Hz), 7.94 (1 H, dd, J 8.5, 2.0 Hz), 8.23 (1 H, d, J 2.0 Hz
With potassium carbonate; In acetonitrile;Reflux;
Description 3: Methyl 3-bromo-4-[(1-methylethyl)oxy]benzoate To a solution of <strong>[29415-97-2]methyl <strong>[29415-97-2]3-bromo-4-hydroxybenzoate</strong></strong> (44 g, 192.14 mmol) (Description 2) in acetonitrile (1 L) was added potassium carbonate (79.5 g, 576.4 mmol) and 2-iodopropane (58 mL, 576.4 mmol), the reaction mixture was heated to reflux overnight. The mixture was filtered and the filtrate was concentrated. The residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with water, dried over sodium sulfate and concentrated to afford the title compound (52.4 g). 1H NMR (CDCl3, 400 MHz) 5 ppm: 1.41 (6H, d, J=6.5 Hz), 3.89 (3H, s), 4.66 (1H, m), 6.90 (1H, d, J=8.5 Hz), 7.94 (1H, dd, J 8.5, 2.0 Hz), 8.23 (1H, d, J=2.0 Hz).
With potassium carbonate; In acetonitrile; for 5h;Heating / reflux;
Methyl <strong>[29415-97-2]3-bromo-4-hydroxybenzoate</strong> [prepared as per Tetrahedron, 2003, 59, 9173] (3.47 g, 15.0 mmol) was dissolved in acetonitrile (50 ml), anhydrous potassium carbonate (3.11 g, 22.5 mmol) was added and the stirred mixture was treated with benzyl bromide (3.08 g, 18.0 mmol) and held at reflux for 5 hours. Upon cooling the solvent was removed in vacuo and the mixture partitioned between water and dichloromethane. The organic layer was separated, the solvent removed in vacuo and the residue subjected to column chromatography on silica. Elution with 10% ethyl acetate in petroleum ether afforded methyl 4-benzyloxy-3-bromobenzoate (3.6 g, 75%) as a colourless solid. 1H NMR (DMSOd6) 8.12 (1H, d), 7.96 (1 H, dd), 7.51 (2H, m), 7.43 (2H, t), 7.35 (2H, m), 5.32 (2H, s), 3.84 (3H, s).
75%
With potassium carbonate; In acetonitrile; for 5h;Heating / reflux;
Methyl <strong>[29415-97-2]3-bromo-4-hydroxybenzoate</strong> [prepared as per Tetrahedron, 2003, 59, 9173] (3.47 g, 15.0 mmol) was dissolved in acetonitrile (50 ml), anhydrous potassium carbonate (3.11 g, 22.5 mmol) was added and the stirred mixture was treated with benzyl bromide (3.08 g, 18.0 mmol) and held at reflux for 5 hours. Upon cooling the solvent was removed in vacuo and the mixture partitioned between water and dichloromethane. The organic layer was separated, the solvent removed in vacuo and the residue subjected to column chromatography on silica. Elution with 10% ethyl acetate in petroleum ether afforded methyl 4-benzyloxy-3-bromobenzoate (3.6 g, 75%) as a colourless solid. 1H NMR (DMSO-d6) 8.12 (1 H, d), 7.96 (1 H, dd), 7.51 (2H, m), 7.43 (2H, t), 7.35 (2H, m), 5.32 (2H, s), 3.84 (3H, s).
75%
With potassium carbonate; In acetonitrile; for 5h;Heating / reflux;
Methyl <strong>[29415-97-2]3-bromo-4-hydroxybenzoate</strong> [prepared as per Tetrahedron, 2003, 59, 9173] (3.47 g, 15.0 mmol) was dissolved in acetonitrile (50 ml), anhydrous potassium carbonate (3.11 g, 22.5 mmol) was added and the stirred mixture was treated with benzyl bromide (3.08 g, 18.0 mmol) and held at reflux for 5 hours. Upon cooling the solvent was removed in vacuo and the mixture partitioned between water and dichloromethane. The organic layer was separated, the solvent removed in vacuo and the residue subjected to column chromatography on silica. Elution with 10% ethyl acetate in petroleum ether afforded methyl 4-benzyloxy-3-bromobenzoate (3.6 g, 75%) as a colourless solid. 1H NMR (DMSOd6) 8.12 (1H, d), 7.96 (1 H, dd), 7.51 (2H1 m), 7.43 (2H1 1), 7.35 (2H, m), 5.32 (2H, s), 3.84 (3H, s).
75%
With potassium carbonate; In acetonitrile; for 5h;Heating / reflux;
Methyl <strong>[29415-97-2]3-bromo-4-hydroxybenzoate</strong> [prepared as per Tetrahedron, 2003, 59, 9173] (3.47 g, 15.0 mmol) was dissolved in acetonitrile (50 ml), anhydrous potassium carbonate (3.11 g, 22.5 mmol) <n="115"/>was added and the stirred mixture was treated with benzyl bromide (3.08 g, 18.0 mmol) and held at reflux for 5 hours. Upon cooling the solvent was removed in vacuo and the mixture partitioned between water and dichloromethane. The organic layer was separated, the solvent removed in vacuo and the residue subjected to column chromatography on silica. Elution with 10% ethyl acetate in petroleum ether afforded methyl 4-benzyloxy-3-bromobenzoate (3.6 g, 75%) as a colourless solid. 1H NMR (DMSO-d6) 8.12 (1 H, d), 7.96 (1 H, dd), 7.51 (2H, m), 7.43 (2H, t), 7.35 (2H1 m), 5.32 (2H, s), 3.84 (3H, s).
75%
With potassium carbonate; In acetonitrile; for 5h;Reflux;
Methyl <strong>[29415-97-2]3-bromo-4-hydroxybenzoate</strong> [prepared as per Tetrahedron, 2003, 59, 9173] (3.47 g, 15.0 mmol) was dissolved in acetonitrile (50 ml), anhydrous potassium carbonate (3.11 g, 22.5 mmol) was added and the stirred mixture was treated with benzyl bromide (3.08 g, 18.0 mmol) and held at reflux for 5 hours. Upon cooling the solvent was removed in vacuo and the mixture partitioned between water and dichloromethane. The organic layer was separated, the solvent removed in vacuo and the residue subjected to column chromatography on silica. Elution with 10% ethyl acetate in petroleum ether afforded methyl 4-benzyloxy-3-bromobenzoate (3.6 g, 75%) as a colourless solid. 1H NMR (DMSO-d6) 8.12 (1H, d), 7.96 (1H, dd), 7.51 (2H, m), 7.43 (2H, t), 7.35 (2H, m), 5.32 (2H, s), 3.84 (3H, s).
75%
With potassium carbonate; In acetonitrile; for 5h;Heating / reflux;
PREPARATION B7; Synthesis of (Z)-4-benzyloxy-3-(l-methyl-propenyl)-benzoic acid; Methyl <strong>[29415-97-2]3-bromo-4-hydroxybenzoate</strong> [prepared as per Tetrahedron, 2003, 59, 9173] (3.47 g, 15.0 mmol) was dissolved in acetonitrile (50 ml), anhydrous potassium carbonate (3.11 g, 22.5 mmol) was added and the stirred mixture was treated with benzyl bromide (3.08 g, 18.0 mmol) and held at reflux for 5 hours. Upon cooling the solvent was removed in vacuo and the mixture partitioned between water and dichloromethane. The organic layer was separated, the solvent removed in vacuo and the residue subjected to column chromatography on silica. Elution with 10% ethyl acetate in petroleum ether afforded methyl 4-benzyloxy-3-bromobenzoate (3.6 g, 75%) as a colourless solid. 1H NMR (DMSO-d6) 8.12 (IH, d), 7.96 (IH, dd), 7.51 (2H, m), 7.43 (2H, t), 7.35 (2H, m), 5.32 (2H, s), 3.84 (3H, s).Methyl 4-benzyloxy-3-bromobenzoate (1.61 g, 5.0 mmol), caesium carbonate (4.89 g, 15.0 mmol), (E)-2- buten-2-yl boronic acid (600 mg, 6.0 mmol) and [l,l'-bis(diphenylphosphino)ferrocenyl] palladium (II) chloride (204 mg, 0.25 mmol) were dissolved in anhydrous tetrahydrofuran (100 ml), water (10 ml) was added and the mixture was stirred and held at reflux under an atmosphere of nitrogen for 16 hours. Upon cooling the solvent was removed in vacuo and the mixture partitioned between dichloromethane and water. The organic layer was separated, the solvent removed in vacuo and the residue subjected to column chromatography on silica. Elution with 5% ethyl acetate in petroleum ether afforded methyl (Z)- 4-ben2yloxy-3-(l-methyl-propenyl)-benzoate (600 mg, 41%) as a colourless solid. 1H NMR (DMSO-d6) 7.88 (IH, dd), 7.59 (IH, d), 7.40 (4H, m), 7.34 (IH, m), 7.23 (IH, d), 5.57 (IH, q), 5.21 (2H, s), 3.82 (3H, s), 1.94 (3H, s), 1.38 (3H, d).Methyl (Z)-4-benzyloxy-3-(l-methyl-propenyl)-benzoate (592 mg, 2.0 mmol) was dissolved in methanol (20 ml), a solution of potassium hydroxide (336 mg, 6.0 mmol) in water (7 ml) was added and the mixture was stirred and held at reflux for 3 hours. Upon cooling the solvent was removed in vacuo and the mixture acidified to pH 2 or below by the addition of 2M hydrochloric acid. The mixture was extracted with dichloromethane, the organic layer was separated and the solvent removed in vacuo to afford (Z)-4-benzyloxy-3-(l-methyl-propenyl)-benzoic acid (460 mg, 82%) as a colourless solid. 1H NMR (DMSOd6) 7.85 (IH, dd), 7.57 (IH, d), 7.40 (4H, m), 7.34 (IH, m), 7.18 (IH, d), 5.57 (IH, q), 5.21 (2H, s), 1.96 (3H, s), 1.40 (3H, d). MS: [M+H]+ 283.
With caesium carbonate; In dimethyl sulfoxide; at 20℃;Ice water bath;
Methyl 4-(benzyloxy)-3-bromobe?zoate (T18.3). To a solution of T3.1(53.2 g, 230 mmol) in DMSO (45.0 mL) was added 1 -(bromomethyl)benzene (35.6 mL, 299 mmol). After cooling in an ice water bath, CS2CO3 (128 g, 391 mmol) was carefully added to the mixture, and the mixture was allowed to warm to room temperature. After overnight stirring, the mixture was diluted with water and extracted three times with EtOAc. The organic layers were combined and then washed with brine. After drying over anhydrous magnesium sulfate and filtration, the organic solvent was removed under reduced pressure to yield T18.3 as a white solid.
With caesium carbonate; In dimethyl sulfoxide; at 20℃;Cooling with ice;
Methyl 4-(benzyloxy)-3-bromobenzoate (T7.3). To a solution of T6.5(53.2 g, 230 mmol) in DMSO (45.0 mL) was added 1 -(bromomethyl)benzene (35.6 mL, 299 mmol). After cooling in an ice water bath, cesium carbonate (128 g, 391 mmol) was carefully added to the mixture, and the mixture was allowed to warm to room temperature. After overnight stirring, the mixture was diluted with water and extracted three times with EtOAc. The organic layers were combined and then washed with brine. After drying over anhydrous magnesium sulfate and filtration, the organic solvent was removed under reduced pressure to yield T7.3 as a white solid.
48.7 g
With potassium carbonate; In N,N-dimethyl-formamide; at 80 - 90℃;
40 g of compound 9 (0.173 mol) was placed in 320 ml of DMF.Add 35.8 g of potassium carbonate (0.259 mol),35.5 g of benzyl bromide (0.208 mol) was added dropwise at room temperature.After the dropwise addition, the temperature is raised to 80 to 90 C for 10 to 12 hours.The TLC monitors the reaction completely. Filtered, and the filtrate was concentrated to dryness under reduced pressure.Add 500ml of water, stir and filter,Drying gave 48.7 g of compound 10.
With toluene-4-sulfonic acid; In dichloromethane; water; at 20℃; for 2h;
Methyl 3-bromo-4-(tetrahydro-2H-pyran-2-yloxy)be?zoate(T3.2). To a stirred solution of T3.1 (38 g, 164 mmol) and 3,4-dihydro-2H-pyran (45 niL, 493 mmol) in DCM (355 mL,) was added 4-methylbenzenesulfonic acid hydrate (0.63 g, 3.30 mmol). The mixture was stirred at room temperature and monitored by TLC. After 2 hours, the solution was washed with a mixed aqueous solution of saturated aqueous sodium bicarbonate/brine/water (1 : 1 :2). The aqueous layer was extracted three times with ether. After drying over anhydrous sodium sulfate and then filtering, the organic solvent was removed under reduced pressure. The residue was purified on silica gel (0- 10% EtOAc in hexanes) to yield a white solid. The product was recrystallized from MeOH to provide T3.2 (yield 90%). 1H NMR (400 MHz, CDCl3) delta 8.24 (1 H, d, J=2.0 Hz), 7.93 (1 H, dd, J=8.6, 2.0 Hz), 7.17 (1 H, d, J=8.6 Hz), 5.62 (1 H, t, J=2.5 Hz), 3.90 (3 H, s), 3.83 (1 H, td, J=I L l, 2.9 Hz), 3.66 (1 H, m), 2.18 (1 H, m), 2.04 (1 H, m), 1.94 (1 H, m), 1.79 (2 H, m), 1.67 (1 H, m).)
90%
With toluene-4-sulfonic acid; In dichloromethane; at 20℃; for 2h;
Methyl 3-bromo-4-(tetrahydro-2H-pyran-2-yloxy)benzoate(C3). To a stirred solution of C.2 (38 g, 164 mmol) and 3,4-dihydro-2H-pyran (45 mL, 493 mmol) in DCM (355 mL,) was added 4-methylbenzenesulfonic acid hydrate (0.63 g, 3.30 mmol). The mixture was stirred at room temperature and monitored by TLC. After 2 hours, the solution was washed with a mixed aqueous solution of saturated aqueous sodium bicarbonate/brine/water (1 :1 :2). The aqueous layer was extracted three times with ether. After drying over anhydrous sodium sulfate and then filtering, the organic solvent was removed under reduced pressure. The residue was purified on silica gel (0-10% EtOAc in hexanes) to yield a white solid. The product was recrystallized from MeOH to provide C.3 (yield 90%). 1H NMR (400 MHz, CDCl3) delta 8.24 (1 H, d, J=2.0 Hz), 7.93 (1 H, dd, J=8.6, 2.0 Hz), 7.17 (1 H, d, J=8.6 Hz), 5.62 (1 H, t, J=2.5 Hz), 3.90 (3 H, s), 3.83 (1 H, <n="106"/>td, J=I Ll, 2.9 Hz), 3.66 (1 H, m), 2.18 (1 H, m), 2.04 (1 H, m), 1.94 (1 H, m), 1.79 (2 H, m), 1.67 (I H, m).).; Methyl 3-bromo-4-(tetrahydro-2H-pyran-2-yloxy)benzoate (T6.6).To a stirred solution of T6.5 (38 g, 164 mmol) and 3,4-dihydro-2H-pyran (45 mL, 493 mmol) in DCM (355 mL,) was added 4-methylbenzenesulfonic acid hydrate (0.63 g, 3.30 mmol). The mixture was stirred at room temperature and monitored by TLC. After 2 hours, the solution was washed with a mixed aqueous solution of saturated aqueous sodium bicarbonate/brine/water (1 :1 :2). The aqueous layer was extracted three times with ether. After drying over anhydrous sodium sulfate and then filtering, the organic solvent was removed under reduced pressure. The crude material was purified on silica gel (0-10% EtOAc in hexanes) to yield a white solid. The product was recrystallized <n="144"/>from MeOH to provide T6.6 (yield 90%). 1H NMR (400 MHz, CDCl3) delta ppm 8.24 (1 H, d, J=2.0 Hz), 7.93 (1 H, dd, J=8.6, 2.0 Hz), 7.17 (1 H, d, J=8.6 Hz), 5.62 (1 H, t, J=2.5 Hz), 3.90 (3 H, s), 3.83 (1 H, td, J=I Ll, 2.9 Hz), 3.66 (1 H, m), 2.18 (1 H, m), 2.04 (1 H, m), 1.94 (1 H, m), 1.79 (2 H, m), 1.67 (1 H, m).)
24.4%
With toluene-4-sulfonic acid; In dichloromethane; at 20℃; for 1.5h;
70D. methyl 3-bromo-4-(tetrahydro-2H-pyran-2-yloxy)benzoate To a solution of 70C (5.4 g, 23.37 mmol) and 3,4-dihydro-2H-pyran (6.40 mL, 70.1 mmol) in CH2Cl2 (50 mL) was added 4-toluenesulfonic acid monohydrate (0.089 g, 0.467 mmol). The reaction was stirred at room temperature for 1.5 h. The mixture was washed with NaHCO3 (aq) and water and dried and concentrated. Chromatography on silica gel (ISCO) using 0 to 10% hexane/EtOAc gradient provided 70D (1.8 g, 24.4% yield). HPLC RT=3.78 min.
With 1,1'-bis-(diphenylphosphino)ferrocene; sodium carbonate;palladium diacetate; In N,N-dimethyl acetamide; at 125 - 130℃; for 43.5h;Inert atmosphere;
A mixture of <strong>[29415-97-2]methyl <strong>[29415-97-2]3-bromo-4-hydroxybenzoate</strong></strong> (Journal of Organic Chemistry (1997), 62(13), 4504-4506; 3.47 g, 15.0 mmol), potassium ferrocyanide trihydrate (1.394 g, 3.30 mmol), palladium acetate (0.034 g, 0.150 mmol), 1 ,1'- bis(diphenylphosphino)ferrocene (0.166 g, 0.300 mmol), and sodium carbonate (1.590 g, 15.00 mmol) in dry N,N-dimethylacetamide (DMA) (30 ml) was degassed by evacuation and refilling with nitrogen, and the mixture was heated under nitrogen at 125 for 18h. More potassium ferrocyanide trihydrate (700mg), palladium acetate (34mg) and 1 ,1 '-bis(diphenylphosphino)ferrocene (166mg) were added, and stirring was continued under nitrogen at 130 for 21.5h. More sodium carbonate (1.59g), palladium acetate (0.034 g, 0.150 mmol) and 1 ,1 '-bis(diphenylphosphino)ferrocene (0.166 g, 0.300 mmol) was added, and heating was continued at 130 with stirring under nitrogen for 4h. The solvent was evaporated in vacuo and the residue treated with glacial acetic acid (3ml) and partitioned between water (100ml) and ethyl acetate (100ml). The layers separated poorly, hence the mixture was filtered through Celite filter aid, and the aqueous layer was further extracted with ethyl acetate (70ml). The combined organic layers were washed with saturated aqueous sodium chloride, dried (MgSC>4) and evaporated in vacuo to give a black solid which was purified by flash chromatography on silica, eluting with 0-50% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow solid (1 .01 g) MS (ES) C9H7NO3 requires 177; found 176 [M-H]+.
In 1-methyl-pyrrolidin-2-one; at 200℃; for 4.0h;Inert atmosphere;
To a stirred solution of <strong>[29415-97-2]methyl <strong>[29415-97-2]3-bromo-4-hydroxybenzoate</strong></strong> (2.50 g, 10.775 mmol) in NMP (7.5 mL) was added CuCN (1.05 g, 11.853 mmol) at RT under an inert atmosphere. <n="110"/>The reaction mixture was then heated at 200 0C for 4 h., cooled to RT, diluted with water (10 mL) and stirred for 10 min. The precipitated solid was filtered off and the filtrate was concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford methyl 3-cyano-4-hydroxybenzoate (1 .50 g, 78%) as a yellow solid.
In 1-methyl-pyrrolidin-2-one; at 200℃; for 2.0h;Microwave irradiation;
Step A: Preparation of Methyl 3-cyano-4-hydroxybenzoate.To a mixture of <strong>[29415-97-2]methyl <strong>[29415-97-2]3-bromo-4-hydroxybenzoate</strong></strong> (1.78 g, 7.70 mmol) and copper(I) cyanide (0.897 g, 10.02 mmol) was added NMP (10 mL). The mixture was heated to 200 0C for 2 h under microwave irradiation. The mixture was diluted with ethyl acetate and quenched with 1 N aqueous HCl solution. After the addition of brine, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography. The combined fractions were concentrated under reduced pressure and triturated with cold water to provide the title compound as an off-white solid (0.63 g). LCMS m/z = 178.2 [M+H]+; 1H NMR (400 MHz, CDCl3) delta ppm 3.92 (s, 3H), 6.55 (bs, IH), 7.04 (d, J = 8.72 Hz, IH), 8.15 (dd, J= 8.72, 2.15 Hz, IH), 8.23 (d, J= 1.89 Hz, IH).
In N,N-dimethyl-formamide; at 150℃; for 16.0h;
(b) Synthesis of methyl 3-cyano-4-hydroxybenzoateMethyl <strong>[29415-97-2]3-bromo-4-hydroxybenzoate</strong> (37.81 g) was dissolved in N,N-dimethylformamide (250 mL), and copper cyanide (22.03 g) was added to the solution. After stirring the mixture at 150 C. for 16 hours, potassium carbonate (68.00 g) and chloromethyl methyl ether (14.8 mL) were added to the solution under ice cooling, and then the mixture was stirred for 2 hours. The reaction solution was filtered and water was added, and then the reaction mixture was extracted with ethyl acetate. After the operation of adding water to the organic layer, stirring the mixture, filtering the mixture and separating the organic layer was repeated three times, the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was dissolved in chloroform (30 mL). Trifluoroacetic acid (30 mL) was added to the solution, and then the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and the obtained residue was washed with a mixture of n-hexane and ethyl acetate in a mixing ratio of 2:1 to obtain the title compound (6.53 g) as a pale yellow crystal.
13 g
With copper(l) iodide; In N,N-dimethyl-formamide; at 120℃;
Methyl 3-cyano-4-hydroxybenzoate: To a solution of methyl 3-bromo-4- hydroxybenzoate (26 g, 112.53 mmol, 1.00 equiv) in DMF (160 mL) was added Cul (2.1 g, 11.1 1 mmol, 0.10 equiv) and CuCN (30 g, 337.08 mmol, 3.00 equiv). The resulting solution was stirred overnight at 120 C. The reaction mixture was cooled and diluted with water (300 mL). The resulting solution was extracted with dichloromethane (3 x 100 mL), and the organic layers were combined. The reaction mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column eluting with ethyl acetate/ petroleum ether (1 : 1) to afford 13 g of methyl 3-cyano-4- hydroxybenzoate as a white solid.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 0.5h;
(Example 11) In Example 11, (2S,4S)-4-(2-bromo-4-carboxyphenoxy)pyrrolidine-2- carboxylate (IIc) was synthesized according to the reaction scheme shown below. 1) Mitsunobu Reaction [Show Image] The above Mitsunobu reaction was first performed. Specifically, to a solution of methyl(2S,4R)-1-benzoyl-4-hydroxypyrrolidine-2-carboxylate (42.3 mg, 170 mu mol) in THF (500 mu L), triphenylphosphine (111 mg, 423 mu mol) and methyl<strong>[29415-97-2]3-bromo-4-hydroxybenzoate</strong> (78.6 mg, 340 mu mol) were added under the argon atmosphere. Diisopropyl azodicarboxylate (88.0 mu L, 447 mu mol) was slowly added dropwise to the reaction solution at room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated in vacuo, and the residue was sequentially purified by column chromatography (silica gel 60, hexane/ethyl acetate = 1/3) and thin layer chromatography (silica gel 60, 0.5 mm, toluene/methanol/chloroform= 8/1/1) to obtain the compound of interest (77.7 mg, 99%). TLC and 1H NMR data are shown below. TLC: Rf = 0.37 (silica gel, hexane/ethyl acetate= 1/3) 1H NMR (400 MHz, CDCl3) : (two rotamers) delta (ppm) 2.52-2.8 (complex, 2H), 3.73 and 3.82 and 3.89 (s, 6H), 3.89-4.03 (complex), 4.31-4.39 (br dd, J = 5.4 and 14.2 Hz), 4.58 (d, J = 8.5 Hz), 4.96-5.03 (complex), 5.06-5.13 (complex), 6.75 (d, J = 9.0 Hz) and 6.81 (d, J = 8.8 Hz) (1H), 7.36-7.49 and 7.56-7.62 (complex, 5H), 7.9-8.0 (m, 1H), 8.24 (d, J = 2.0 Hz, 1H)
Step 2 To a stirred suspension of <strong>[29415-97-2]methyl <strong>[29415-97-2]3-bromo-4-hydroxybenzoate</strong></strong> (270 g, 1168 mmol) in DCM (1.5 L) was added pyridine (150 mL). Acetyl chloride (87 mL, 1227 mmol) was then added dropwise at room temperature and under nitrogen. The mixture was left to stir for 2 hrs at room temperature. Water (1 L) was then added followed by HCl 2N until pH 1. The organic layer was then washed with water, brine, dried over magnesium sulfate, filtered and evaporated to dryness to afford methyl 4-acetoxy-3-bromobenzoate (300 g, 94%) as a white powder. NMR Spectrum: (DMSOd6) 2.34 (s, 3H), 3.87 (s, 3H), 7.47 (d, 1H), 8.01 (dd, 1H), 8.20 (d, 1H).
94%
With pyridine; In dichloromethane; at 20℃;Inert atmosphere;
To a stirred suspension of <strong>[29415-97-2]methyl <strong>[29415-97-2]3-bromo-4-hydroxybenzoate</strong></strong> (270 g, 1168 mmol) in DCM (1.5 L) was added pyridine (150 mL). Acetyl chloride (87 mL, 1227 mmol) was then added dropwise at room temperature and under nitrogen. The mixture was left to stir for 2 hrs at room temperature. Water (1 L) was then added followed by HCl 2N until pH 1. The organic layer was then washed with water, brine, dried over magnesium sulfate, filtered and evaporated to dryness to afford methyl 4-acetoxy-3-bromobenzoate (300 g, 94 %) as a white powder. NMR Spectrum: (DMSOdg) 2.34 (s, 3H), 3.87 (s, 3H), 7.47 (d, 1H), 8.01 (dd, 1H), 8.20 (d, 1H).
94%
With pyridine; In dichloromethane; at 20℃; for 2h;Inert atmosphere;
Step 2To a stirred suspension of <strong>[29415-97-2]methyl <strong>[29415-97-2]3-bromo-4-hydroxybenzoate</strong></strong> (270 g, 1168 mmol) in DCM (1.5 L) was added pyridine (150 mL). Acetyl chloride (87 mL, 1227 mmol) was then added dropwise at room temperature and under nitrogen. The mixture was left to stir for 2 h at room temperature. Water (1 L) was then added followed by HCl 2N until pH 1. The organic layer was then washed with water, brine, dried over MgS04, filtered and evaporated to dryness to afford methyl 4-acetoxy-3-bromobenzoate (300 g, 94%) as a white powder.Proton NMR Spectrum: : (DMSO-d6) 2.34 (s, 3H), 3.87 (s, 3H), 7.47 (d, 1H), 8.01 (dd, 1H), 8.20 (d, 1H).
94%
With pyridine; In dichloromethane; at 20℃; for 2h;Inert atmosphere;
To a stirred suspension of <strong>[29415-97-2]methyl <strong>[29415-97-2]3-bromo-4-hydroxybenzoate</strong></strong> (270 g, 1168 mmol) in DCM (1.5 L) was added pyridine (150 mL). Acetyl chloride (87 mL, 1227 mmol) was then added dropwise at room temperature and under nitrogen. The mixture was left to stir for 2 h at room temperature. Water (1 L) was then added followed by HCl 2N until pH 1. The organic layer was then washed with water, brine, dried over MgSO4, filtered and evaporated to dryness to afford methyl 4-acetoxy-3-bromobenzoate (300 g, 94%) as a white powder.Proton NMR Spectrum:(DMSO-d6) 2.34 (s, 3H), 3.87 (s, 3H), 7.47 (d, 1H), 8.01 (dd, 1H), 8.20 (d, 1H).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
