2-Bromo-3-hydroxy-4-methoxybenzaldehyde

Off-White Solid

3-Hydroxy-4-methoxybenzaldehyde (10.0 g, 65.7 mmol) in CH2Cl2(150 mL) was treated with NBS (11.7 g, 65.7 mmol) for 30 min at r.t. togive 2-bromo-3-hydroxy-4-methoxybenzaldehyde (14.1 g, 93percent).40Isovanillin 10.00g (65.73mmol) dissolved in 200ml glacial acetic acid was added to a 500ml round bottom flask. To this was added sodium acetate 0.78g (131.45mmol), iron powder 0.37g (6.57mmol). Liquid bromine 3.4ml (65.73mmol) containing 20ml of glacial acetic acid was then added to a constant pressure funnel. In an ice bath, it was slowly added dropwise to the round bottom flask with stirring. After dropping, it was reacted at 23°C for 8h. TLC detection. Completion of the reaction. The reaction system was added to 500ml of ice water. After stirring for a few minutes, it was left to stand for 10min then filtered. Ice water washed free of acetic acid. The filter cake was dried and weighed giving 13.40g of white solid 2-bromo-3-hydroxy-4-methoxybenzaldehyde (Compound 2), yield 88.74percent; m.p.206-207°C.Example 33 N-(2-cyano- 1 -(1 -hydroxy-7-phenoxy-l .3-dihydrobenzo[c] [ 1.2]oxaborol-6-yloxy)propan- 2-yl)-4-(trifluoromethoxy)benzamide 3-Hydroxy-4-methoxybenzaldehyde (30.4g, 0.2mol), 1, 4-dioxane (250ml) and water (100ml) are mixed, and N-bromosuccinimide (37.38g, 0.21mol) is added over 30 minutes at 0°C. After 2h, water (400ml) is added, and the precipitated crystals are collected by filtration. The crystals are washed with water (1000ml) to give the desired product (38.5g, yield 83percent) as a white solid.20.0 g (132 mmol) of 3-hydroxy-4-methoxybenzaldehyde (4), 21.59 g (263 mmol) of sodium acetateAnd 0.68 g (12 mmol) of iron powderPlaced in a 500 ml three-necked flask, 120 ml of glacial acetic acid was added, Stirring for 30 min at room temperature;After completion of the stirring, Control temperature 23 ~ 25 , (140 mmol) of liquid bromine was added dropwise in advanceAnd 30mL glacial acetic acid mixed with the preparation of the solution, After the temperature drops 23 ~ 25 to continue stirring 3h;Then 250 mL of ice water was added, Stirring 1h;filter, Solid evaporated, Ethanol recrystallization, To give 24.70 g of 2-bromo-3-hydroxy-4-methoxybenzaldehyde (5)Yield 82percent;To a mixture of isovanillin (1) (20.0 g, 132 mmol), NaOAc(21.59 g, 263 mmol) and iron powder (0.68 g, 12 mmol) was added glacial acetic acid (120 mL). The mixture was stirred atroom temperature for 30 min. Br2 (7.0 mL, 140 mmol) in glacial acetic acid (30 mL) was added dropwise into the abovemixture at 23–26C. The mixture was stirred at the same temperature for 3 h. Ice water (250 mL) was added and the mixturestirred for another 1 h and filtered. The solid obtained was dried and recrystallized from EtOH to give 4 (24.59 g, 81percent) as agray solid.2-Bromo-3-Hydroxy-4-Methoxy-Benzaldehyde (8)To a stirred suspension of isovanillin (10 g, 66 mmol), powdered anhydrous sodium acetate (10.82 g, 0.132 mol) and iron powder (0.3 g, 5.4 mmol) in glacial acetic acid (60 mL) under argon, was added drop-wise over 15 min a solution Of BrTo a solution of isovanillin (2) (5.0 g, 32.9 mmol) in CHCl3(1000 mL), DBDMH (5.2 g, 18.2 mmol) was portionwise added, and the mixture was stirred for 9 h at ambient temperature.After the addition of water (300 mL), the organic layer wasseparated, washed with brine, and dried over MgSO4. Theorganic solvent was removed in vacuo to give a crude material which was purified by recrystallization from AcOEt. Thetitle compound (3, 5.8 g, 25.1 mmol, 77percent) was obtained as apale orange powder, mp 200.2–201.0 °C (AcOEt) [lit.15) mp206–207 °C (EtOH)]. 1H-NMR (400 MHz, CDCl3) δ: 10.26 (d, 1H, CHO), 7.58 (d, J=8.8 Hz, 1H, ArH), 6.93 (d, J=8.8 Hz, 1H, ArH), 6.07 (s, 1H, OH), 4.01 (s, 3H, OMe).PREPARATIVE EXAMPLE 88 To a mixture of 1 (10.0 g, 0.066 mol), NaOAc (10.8 g, 0.132 mol), Fe powder (0.34 g, 0.006 mol) was added acetic acid (60 mL), and then the mixture was stirred for 30 min at room temperature. Liquid Br2 (36.85 g, 11.6 mL, 225mmol, 1.5 equiv.) was added dropwise at a rate of 0.1 mL/min over a period of 2 hours, using a syringepump or addition funnel, to a three-neck flask, equipped with septum and overhead stirring assembly, containing a solution of isovanillin, 3-hydroxy-4-methoxybenzaldehyde (22.8g, 150 mmol), in 75 mL ofCCl4 and 75 mL of CHCl3. The reaction mixture was allowed to stir overnight (approximately 12 hours) atroom temperature. The resulting reddish brown precipitate was vacuum filtered and rinsed with 50 mLof a 1:1 solution of CCl4 and CHCl3. After removing solvent under reduced pressure, the precipitate wasdissolved in 300 mL of ethyl acetate (EtOAc) to give a bright yellow solution. This extract was washedwith 150 mL of brine, 50 mL of 10percent w/v sodium thiosulfate, and twice more with brine (2 x 150 mLportions).The organic phase was dried with MgSO4, vacuum-filtered, and solvent was removed by underreduced pressure at room temperature. The recovered white solid was recrystallized in ethanol andvacuum filtered to afford 22.11 g (60percent) of a fine, grainy, white solid, 2-bromo-3-hydroxy-4-methoxybenzaldehyde (mp = 204.5–210.4°C). 1H-NMR (300 MHz, DMSO-d6): 10.11 (s, 1H, CHO), 9.94 (s, 1H, OH), 7.42 (d, J =8.6 Hz, 1H, Ar-H), 7.15 (d, J = 8.6 Hz, 1H, Ar-H), 3.93 (s, 3H, OMe); EI-MSm/z: 232 (M+2), 231(100percent), 230 (M+), 229, 214, 201, 189, 187, 173, 161, 159, 150, 143, 131, 122, 107, 94, 79, 78, 77, 63, 51; UV-Vis: 215.3, 239.1, 297.4 nm.Compound 8 (iso-vanillin, 3 g, 19.7 mmol) was dissolved in 20 ml of glacial acetic acid under argon and sodium acetate was added.(3.2 g, 39.4 mmol), reduced iron powder (110 mg, 1.96 mmol).After bromine (1.1ml, 21.1mmol) of glacial acetic acidThe (5 ml) solution was gradually added to the above reaction solution, and stirred vigorously at room temperature for 1 hour.. The reaction was monitored by TLC until compound 8 was completely reacted.The reaction mixture was poured into 150 ml of ice water and washed, and then filtered to give a colorless crystals.After recrystallization from ethanol, 2.1 g of light brown needle-like crystalline solid compound 7 was obtained.The next reaction can also be carried out without further purification.Dissolving isocoumarin X (60.86 g, 400 mmol), NBS (74.76 g) in dioxane/water (500 ml/200 ml) in, then stirring the reaction mixture at room temperature for 3 hours, TLC shows the reaction is complete, the addition of water, filtered, the filter cake is dried under vacuum to obtain compound IXa (81.9 g).

Taspine intermediate.

Molecular Weight:231.04
XLogP3:1.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:229.95786
Monoisotopic Mass:229.95786
Topological Polar Surface Area:46.5
Heavy Atom Count:12
Complexity:162
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes