4-DifluoroMethoxy-3-hydroxybenzaldehyde

The 138.1g (1mol) 3, 4- dihydroxybenzaldehyde was added to a concentration of 1L 7mol / L sodium hydroxide solution was added phase transfer catalyst tetrabutylammonium 16.6 g Ammonium, chloro-difluoro-acetic acid methyl ester 180.5g (1.3mol), stirred, solution was reacted at 60 -65 3 hours the reaction is complete, diluted with 1L of water and twice with 500mL ethyl acetate, the aqueous layer was collected, concentrated hydrochloric add was adjusted to pH 2 with 1.5L extracted three times with ethyl acetate, ethyl acetate layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to dryness and the residue with petroleum ether - ethyl acetate (3: l) recrystallization, white crystals 149.4g, yield 79.4percent, 99.45percent purity., Method (a): A suspension of 3, 4-dihydroxybenzaldehyde (1.38 g, 10 mmol) in an. DMF (15 mL) was stirred under nitrogen atmosphere for 10 min. The 4-(difiuoromethoxy)-3-hydroxybenzaidehyde was prepared with improved yield by the following microwave assisted procedure. To a solution of 3, 4-dihydroxybenzaIdehyde (0.415 g, 3 mmol) in an. DMF (5 mL), CS2CO3 (0.975 g, 3 mmol) and methyl chlorodifluoroacetate (0.520 g, 3.6 mmol) were added; then the mixture was irradiated with microwaves, under pressure, increasing the potency until 300 W in 2 minutes and cooling by compressed air to avoid the temperature increasing over 90 °C; the irradiation was carried on for further 3 minutes and then the mixture was cooled to room temperature, with compressed air, in 1 minute. The cycle was repeated five time for a total reaction time of 30 minutes, The mixture was poured into water (100 mL) and extracted with ethyl acetate (3 x 20 mL); the organic phase was washed with water (20 mL), brine (20 mL), dried (MgS0EXAMPLE 10 To a solution of 3, 4-hydroxybenzaldehyde [1 (Figure2), 1.38 g, 10 mmol] in dimethylformamide (DMF) (20 mL)were added methyl chlorodifluoroacetate (1.39 mL, 13 mmol)and cesium carbonate (4.23 g, 13 mmol). After the mixturerhad been stirred at 70 °C for 3 h under an air atmosphere, DMF was removed in vacuo. The residue was portionedbetween aqueous 3 N HCl and ethyl acetate. Layers wereseparated, and the aqueous layer was extracted with ethylacetate (3 × 30 mL). Combined organic layers were washedwith brine, dried over Na2SO4, and concentrated in vacuo. Thecrude product was purified by flash chromatography (5:1hexane/EtOAc) to afford compound 2 (0.61 g, 33percent) as awhite solid: 1H NMR (400 MHz, CDCl3) δ 9.92 (s, 1H), 7.55 (d, J = 4.0 Hz, 1H), 7.45 (dd, J = 4.0, 8.4 Hz, 1H), 7.28 (d, J =8.4 Hz, 1H), 6.67 (t, J = 72.8 Hz, 1H), 6.17 (br s, 1H).In a 100 ml round bottom flask, 3, 4-dihydroxybenzaldehyde (5.1 g, 36.9 mmol, 1.0 eq), NaTo a solution of 3, 4-dihydroxybenzaldehyde (1.66 g, 12 mmol)and sodium chlorodifluoroacetate (1.83 g, 12 mmol) in DMF (15 mL) and water (0.3 mL) was added sodium hydroxide (0.48 g, 12 mmol). Then, the mixture was heated at 120° C and stirred at this temperature for 2 h. The solvent was removed by vacuum distillation, and to the residue was added aqueous HCl (2 mL). The mixture was extracted with Et2O and washed with brine.The solvent was removed under reduced pressure, and the crude product was purified by chromatography on silica gel (petroleum ether/EtOAc = 80:20) to afford 12 as a white solid (1.05 g, 5.28 mmol, 46percent). ESI-MS (m/z): 187.4 ([MH]).A solution of 3, 4-dihydroxybenzaldehyde (16.6 g, 120 mmol) and sodium chlorodifluoroacetate (18.3 g, 120 mmol) in dimethylformamide (150 ml) and water (3 ml) was added with sodium hydroxide (4.8 g, 120 mmol), heated to 120° C. and stirred at this temperature for 2 hrs. Production Example 19-1 To a solution of 3, 4-dihydroxybenzaldehyde (41.52 g, 0.3 mol, 1.0 eq) and sodium chloro(difluoro)acetate (45.75 g, 0.3 mol, 1.0 eq) in DMF (375 ml) and water (7.5 ml) was added NaOH (12 g, 0.3 mol, 1.0 eq) and the resulting mixture was heated at 120 °C for 2 h. The solvent was removed by vacuum distillation and aqueous HCl was added to the residue. The mixture was extracted with EA (500 ml x 2) and the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel (PE/EA from 10/1 to 8/1) to afford 4-(difluoromethoxy)-3-hydroxybenzaldehyde (20.86 g, 37percent yield, 99.8percent purity) as a white solid.To a solution of 3, 4-dihydroxybenzaldehyde (41.52 g, 0.3 mol, 1.0 eq) and sodium chloro(difluoro)acetate (45.75 g, 0.3 mol, 1.0 eq) in DMF (375 ml) and water (7.5 ml) was added NaOH (12 g, 0.3 mol, 1.0 eq) and the resulting mixture was heated at 120 °C for 2 h. The solvent was removed by vacuum distillation and HCl and water were added to the residue. The mixture was extracted with EA (500 ml x 2) and the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel (PE/EA from 10/1 to 8/1) to furnish Intermediate 1 (20.86 g, 36.9percent yield, 99.8percent purity) as a white solid.3, 4-Dihydroxybenzaldehyde (20 g, 145 mmol), chlorodifluoroacetic acid sodium salt (55.19 g, 362 mmol) and sodium hydroxide (5.50 g, 138 mmol) were stirred in DMF (1200 mL) at 55°C under nitrogen for 16 hours. The pH was adjusted to 1.0 by the addition of 10 percent aqueous HC1 followed by extraction with ethyl acetate (3x 500 mL). The combined extracts were evaporated under vacuum. The residue was purified on silica gel using a 10-20percent ethyl acetate/hexane gradient. 4-difluoromethoxy-3- hydroxybenzaldehyde was isolated in 24percent yield (6.62 G). IH NMR (CDC13, 400 MHz) 8 6.1 (br s, 1H), 6.48-6. 85 (t, 1H OCHF2), 7.26 (d, 1H), 7.44 (d, 1H), 7.55 (s, 1H), 9.91 (s, 1H).Intermediate E Synthesis of 4-difluoromethoxy-3-hydroxybenzaldehyde 3, 4-Dihydroxybenzaldehyde (20 g, 145 mmol), chlorodifluoroacetic acid sodium salt (55.19 g, 362 mmol) and sodium hydroxide (5.50 g, 138 mmol) were stirred in DMF (1200 mL) at 55° C. under nitrogen for 16 hours. The pH was adjusted to 1.0 by the addition of 10percent aqueous HCl followed by extraction with ethyl acetate (3.x.500 mL). The combined extracts were evaporated under vacuum. The residue was purified on silica gel using a 10-20percent ethyl acetate/hexane gradient. 4-difluoromethoxy-3-hydroxybenzaldehyde was isolated in 24percent yield (6.62 g). Preparation of 3-hydroxy-4-difluoromethoxybenzaldehydeBenzyltriethyl ammonium chloride (4.12 g, 0.0182 mol) was added to a solution of 3, 4-dihydroxy benzaldehyde (5 g, 0.0362 mol) in dimethylformamide (35 mL). Sodium hydroxide solution (0.0905 mol of 30percent solution) was added dropwise to the resulting reaction mixture for about 10 minutes with a continuous flow of chloro-difluoro methane. The reaction mixture was acidified with dilute hydrochloric acid and then diluted with water. It was extracted with ethyl acetate, washed with saturated solution of sodium chloride and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using 10percent ethyl acetate in hexane to furmish the title compound. Yield: 2.5 g (37percent).To a well stirred suspension of 3, 4-dihydroxy benzaldehyde (100 gm) and anhydrous potassium carbonate (120 gm) in dry N, N-dimethyl formamide (1.0 lit) was passed chlorodifluoromethane gas for about 30 minutes at about 80-850C. After an hour another lot of anhydrous potassium carbonate (25.0 gm) was added and stirred for about one and half hours. The third lot of anhydrous potassium carbonate (25.0 gm) was added and stirred for about one and half hours. The reaction mixture was then stirred for about 5-6 hours at an ambient temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue obtained was diluted with water (500 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product obtained was purified through silica gel column to give 4-difluoromethoxy-3 -hydroxy benzaldehyde. Yield: 25-30 percent.Example 47: Synthesis of ethyl 2-(4-(difluoromethoxy)-8-nitrodibenzo[b, d]furan- l-yl)-l, 3-oxazoIe-4-carboxylate; Step 1: Synthesis of 4-(difluoromethoxy)-3-hydroxy benzaldehyde; To a stirred solution of 3, 4-dihydroxybenzaldehyde (25 g, 0.181 mol) in DMF (75 mL), potassium carbonate (70 g, 0.507 mol) was added. It was refluxed to 75-80 1) hydroxylamine (50wtpercent aqueous solution) (16.5g), 3, 4-hydroxybenzaldehyde (60.8g, 500mmol), Difluoro methyl bromoacetate (106.6g, 525mmol)Acetonitrile was added to 45 Contacting the reaction is carried out, After completion of the reaction, The reaction solution was added water, Extracted with dichloromethane, concentrate, Recrystallized from petroleum ether to give 3-hydroxy-4-fluoro-methoxybenzaldehyde84.9g, Yield 90.3percent, Purity of 98.66percent.Step 2: Methyl chlorodifluoroacetate (15.3 mL, 145 mmol) was added to a suspension of 3, 4- dihydroxybenzaldehyde (5.0 g, 36 mmol) and potassium carbonate (20.0 g, 145 mmol) in DMF (10 mL). The suspension was heated to 60 Methyl chlorodifluoroacetate (15.3 mL, 145mmol) was added to a suspension of 3, 4-dihydroxybenzaldehyde (11) (5.0 g, 36 mmol) and potassiumcarbonate (20.0 g, 145 mmol) in DMF (10 mL). The suspension was heated to 60 °C for 16 h and then diluted with water. The aqueous phase wasextracted with EtOAc and the combined organic fractions were washed withsaturated aqueous NaHCOTo the reaction flask was added DMF (75 mL) Lithium chloride (1.9 g, 0.045 mol) and 3-methoxy-4-difluoromethoxybenzaldehyde (3.0 g, 0.015 mol) Stir and warm to reflux, HPLC detection of 3-methoxy-4-difluoromethoxybenzaldehyde after the disappearance of raw materials to stop heating. After the reaction system was reduced to room temperature, hydrochloric acid was added to adjust the pH to 1 and extracted with ethyl acetate. The organic phase was washed successively with saturated sodium bicarbonate, water and saturated brine, dried over anhydrous sodium sulfate. The crude product was concentrated with acetic acid Ethyl ester and n-hexane to give 3-hydroxy-4-difluoromethoxybenzaldehyde as a white solid (0.78 g, 28percent yield, 97.9percent purity, HPLC chromatogram as shown in Fig. 2)3, 4-Dihydroxybenzaldehyde (20 g, 145 mmol), chlorodifluoroacetic acid sodium salt (55.19 g, 362 mmol) and sodium hydroxide (5.50 g, 138 mmol) were stirred in DMF (1200 mL) at 55PREPARATION 19

Molecular Weight:188.13
XLogP3:1.9
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:3
Exact Mass:188.02850037
Monoisotopic Mass:188.02850037
Topological Polar Surface Area:46.5
Heavy Atom Count:13
Complexity:175
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes