* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] European Journal of Organic Chemistry, 2016, vol. 2016, # 22, p. 3679 - 3683
4
[ 18362-30-6 ]
[ 77-78-1 ]
[ 29866-54-4 ]
Reference：
[1] Journal of Organic Chemistry, 1964, vol. 29, p. 2693 - 2698
[2] Journal of Organic Chemistry, 1964, vol. 29, p. 2693 - 2698
5
[ 387-45-1 ]
[ 18362-30-6 ]
Yield
Reaction Conditions
Operation in experiment
62%
Stage #1: With potassium hydroxide In dimethyl sulfoxide at 0 - 20℃; for 18 h; Stage #2: With hydrogenchloride In water; dimethyl sulfoxide
Potassium hydroxide (10 g) was added slowly to a stirred solution of 2-chloro-6-fluoro- benzaldehyde (14.0 g, 88.3 mmol) in dimethylsulfoxide (20 mL) at 0°C, the reaction mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was diluted with water (100 mL) and acidified to pH 2 with concentrated HCl. The precipitates were filtered, washed with water (2x100 mL) and dried over anhydrous sodium sulfate, to give a residue which was used directly in the next step. Yield: 8.5 g (62percent). H NMR (400 MHz, CDCI3) δ ppm 6.85 - 7.02 (m, 2H) 7.39 - 7.47 (m, 1H) 10.41 (s, 1H) 11.95 (s, 1H).
61%
Stage #1: With potassium hydroxide In dimethyl sulfoxide at 0 - 20℃; Stage #2: With hydrogenchloride; water In dimethyl sulfoxide
2-chloro-6-hydroxybenzaldehyde To a solution of 2-chloro-6-fluorobenzaldehyde (2.44 g, 15.4 mmol) in DMSO (20 mL) at 0° C. was added potassium hydroxide (2.23 g, 33.8 mmol) slowly. The reaction mixture was allowed to stir and warm to rt overnight and then diluted with water (65 mL). The mixture was acidified to pH<1 with conc. HCl. A white solid formed and was filtered, washed with water, and dried to give 2-chloro-6-hydroxybenzaldehyde (1.48 g, 61percent). LCMS: (FA) ES-155.0.
Reference：
[1] European Journal of Organic Chemistry, 2018, vol. 2018, # 25, p. 3348 - 3351
[2] Patent: WO2012/87229, 2012, A1, . Location in patent: Page/Page column 14
[3] Patent: US2008/171754, 2008, A1, . Location in patent: Page/Page column 89
[4] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1993, # 12, p. 1345 - 1358
[5] Zeitschrift fuer Naturforschung, Teil B: Anorganische Chemie, Organische Chemie, Biochemie, Biophysik, Biologie, 1972, vol. 27, p. 663 - 674
[6] Journal of the Chemical Society, Chemical Communications, 1994, # 14, p. 1697 - 1698
[7] Patent: US5149357, 1992, A,
6
[ 29866-54-4 ]
[ 18362-30-6 ]
Yield
Reaction Conditions
Operation in experiment
80%
With boron tribromide In dichloromethane at -30 - 0℃; for 3 h;
Step 5:A solution of methyl ether 15e (720 mg, 4.2 mmol) in anhydrous CH2CI2 (20 mL) is added slowly to a precooled (-30 °C) solution of BBr3 (1 M, 8.4 mL, 8.4 mmol). The solution is warmed to 00C and is stirred for 3 h. The reaction is quenched carefully with methanol (1 mL) and washed with saturated NaHCO3 and then brine (25 mL each). The organic layer is dried over MgSO4, filtered and concentrated and the product is purified by CombiFlash.(R). Companion to give phenol 15f (530 mg, 80percent yield).
80%
Stage #1: With boron tribromide In dichloromethane at -30 - 0℃; for 3 h; Stage #2: With methanol In dichloromethane
A solution of methyl ether 15e (720 mg, 4.2 mmol) in anhydrous CH2CI2 (20 mL) is added slowly to a precooled (-300C) solution of BBr3 (1 M, 8.4 mL, 8.4 mmol). The solution is warmed to O0C and is stirred for about 3 h. The reaction is quenched carefully with methanol (1 mL) and washed with saturated NaHCO3 and then brine (25 mL each). The organic layer is dried over MgSO4, filtered and concentrated and the product is purified by CombiFlash.(R). Companion to give phenol 15f (530 mg, 80percent yield).
80%
Stage #1: With boron tribromide In dichloromethane at -30 - 0℃; for 3 h; Stage #2: With water; sodium hydrogencarbonate In methanol; dichloromethane
A solution of methyl ether 15e (720 mg, 4 2 mmol) in anhydrous CH2Cl2 (20 mL) is added slowly to a precooled (-300C) solution of BBr3 (1 M, 8 4 mL, 8 4 mmol) The solution is warmed to 0°C and is stirred for 3 h The reaction is quenched carefully with methanol (1 mL) and washed with saturated NaHCO3 and then brine (25 mL each) The organic layer is dried over MgSO4, filtered and concentrated and the product is purified by CombiFlash.(R). Companion to give phenol 15f (530 mg, 80percent yield)
80%
Stage #1: With boron tribromide In dichloromethane at -30 - 0℃; for 3 h; Stage #2: With methanol In dichloromethane
A solution of methyl ether 15e (720 mg, 4.2 mmol) in anhydrous CH2CI2 (20 mL) is added slowly to a precooled (-300C) solution of BBr3 (1 M, 8.4 mL, 8.4 mmol). The solution is warmed to 0°C and is stirred for 3 h. The reaction is quenched carefully with methanol (1 mL) and washed with saturated NaHCO3 and then brine (25 mL <n="88"/>each). The organic layer is dried over MgSO4, filtered and concentrated and the product is purified by CombiFlash.(R). Companion to give phenol 15f (530 mg, 80percent yield).
Reference：
[1] Journal of Organic Chemistry, 2015, vol. 80, # 2, p. 1229 - 1234
17
[ 110-89-4 ]
[ 18362-30-6 ]
[ 105-53-3 ]
[ 70384-83-7 ]
Yield
Reaction Conditions
Operation in experiment
58%
With acetic acid In ethanol
EXAMPLE 19 4-amino-9-chloro-2-methyl-1,2,3,4,4a,10a-hexahydro[10 H]benzopyrano[3,2-c]pyrid-10-ylacetic acid lactam. C15 H17 ClN2 O2. Molecular weight=292.77. 19.1 Ethyl 5-chlorocoumarin-3-carboxylate C12 H9 ClO4. Molecular weight 252.5. 15 g (0.0958 mole) of 2-chloro-6-hydroxy-benzaldehyde, 16.7 g (0.105 mole) ethyl malonate, 40 mL ethanol, 0.6 mL piperidine and 0.1 mL acetic acid are refluxed for 5 hours. After cooling the resultant product is dried. After drying, 14 g of ethyl 5-chlorocoumarin-3-carboxylate are obtained. (Yield=58percent). Melting pointG =142°-144° C. IRνC=0: 1720 cm-1. C=0: 1760 cm-1. NMR (CDCl3)δppm relative to TMS.
Potassium hydroxide (10 g) was added slowly to a stirred solution of 2-chloro-6-fluoro- benzaldehyde (14.0 g, 88.3 mmol) in dimethylsulfoxide (20 mL) at 0°C, the reaction mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was diluted with water (100 mL) and acidified to pH 2 with concentrated HCl. The precipitates were filtered, washed with water (2x100 mL) and dried over anhydrous sodium sulfate, to give a residue which was used directly in the next step. Yield: 8.5 g (62percent). H NMR (400 MHz, CDCI3) delta ppm 6.85 - 7.02 (m, 2H) 7.39 - 7.47 (m, 1H) 10.41 (s, 1H) 11.95 (s, 1H).
61%
2-chloro-6-hydroxybenzaldehyde To a solution of 2-chloro-6-fluorobenzaldehyde (2.44 g, 15.4 mmol) in DMSO (20 mL) at 0° C. was added potassium hydroxide (2.23 g, 33.8 mmol) slowly. The reaction mixture was allowed to stir and warm to rt overnight and then diluted with water (65 mL). The mixture was acidified to pH<1 with conc. HCl. A white solid formed and was filtered, washed with water, and dried to give 2-chloro-6-hydroxybenzaldehyde (1.48 g, 61percent). LCMS: (FA) ES-155.0.
With potassium hydroxide; In water; dimethyl sulfoxide;
Step D Synthesis of 6-chlorosalicylaldehyde as an intermediate A stirred solution of 40.0 grams (0.252 mole) of 2-chloro-6-fluorobenzaladehyde in 300 mL of dimethylsulfoxide was cooled to 15° C., and 36.6 grams (0.555 mole) of powdered 85percent potassium hydroxide was added portionwise at a rate to maintain the reaction mixture temperature below 25° C. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 18 hours. After this time the reaction mixture was poured into 1000 mL of water and was acidified with concentrated hydrochloric acid, with stirring. The resultant solid was collected by filtration, washed with water, and dried to yield 30.1 grams of 6-chlorosalicylaldehyde; m.p. 50°-52° C.
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃;
tert-Butyl 4-(tosyloxy)piperidine-1-carboxylate (1.42 g, 4.0 mmol) and 2-chloro-6- hydroxybenzaldehyde (620 mg, 3.3 mmol) were dissolved in N,N-dimethylformamide (20 mL) and potassium carbonate (552 mg, 4.0 mmol ) was added. The reaction mixture was allowed to stir at 60 °C overnight. Ice was added and the mixture was acidified with 6N hydrochloric acid. The mixture was extracted with ethyl acetate and the organic layer was washed with brine. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography, on silica gel, eluting with 2: 8 ethyl acetate: hexanes to give tert-butyl 4-(3-chloro-2-formylphenoxy)piperidine-1- carboxylate (430 mg) as a white solid. 1H NMR (CDCI3): 10.50 (s, 1H), 7.35 (t, 1H), 7.05 (d, 1H), 6.90 (d, 1H), 4.60 (m, 1H), 3.65 (m, 2H), 3.45 (m, 2H), 1.85 (m, 4H),1.40 ppm (s, 9H).
(R)-2-chloro-6-(2,3-epoxypropoxy)benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N-methyl-acetamide; dichloromethane; water; Petroleum ether;
EXAMPLE 2 A stirred mixture of <strong>[18362-30-6]2-chloro-6-hydroxybenzaldehyde</strong> (4.4 g), (R)-glycidyl 4-toluenesulphonate (5.0 g) and potassium carbonate (3.9 g) in dimethylformamide (120 ml) was heated at 60° C. for 5 hours then allowed to stand at ambient temperature for 18 hours. The solvent was removed in vacuo, water (60 ml) was added and the mixture extracted with ether (3*100 ml). The combined extracts were dried over magnesium sulphate and the solvent evaporated. The residue was purified by flash chromatography on silica eluding with a 1:1 mixture of petroleum ether (b.p. 60-80° C.) and dichloromethane followed by a 19:1 mixture of dichloromethane and industrial methylated spirit. Appropriate fractions were combined and the solvent was removed in vacuo to give (R)-2-chloro-6-(2,3-epoxypropoxy)benzaldehyde (2.8 g) m.p. 62-64° C.
With potassium carbonate; In N-methyl-acetamide; dichloromethane; water; Petroleum ether;
EXAMPLE 9 A mixture of <strong>[18362-30-6]2-chloro-6-hydroxybenzaldehyde</strong> (4.4 g), (R)-glycidyl 4-toluenesulphonate (5.0 g) and potassium carbonate (3.9 g) in dimethylformamide (120 ml) was stirred and heated at 60° C. for 5 hours and allowed to cool over 18 hours. The solvent was removed in vacuo, water (60 ml) was added to the residue and the mixture extracted with ether (3*100 ml). The combined extracts were dried over magnesium sulphate and the solvent was evaporated. The residual oil was purified by flash chromatography on silica eluding with a 1:1 mixture of petroleum ether (b.p. 40-60° C.) and dichloromethane, followed by neat dichloromethane then a 19:1 mixture of dichloromethane and industrial methylated spirit. Appropriate fractions were combined and the solvent removed in vacuo to give (R)-2-chloro-6-(2,3-epoxypropoxy)benzaldehyde as a pale yellow solid (2.8 g). Other, incompletely purified, fractions gave material which was subjected to repeat chromatography, providing a second crop of product (0.5 g).
6-chloro-2-(4,6-dimethoxypyrimidin-2-yloxy)benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N-methyl-acetamide;
Step E Synthesis of 6-chloro-2-(4,6-dimethoxypyrimidin-2-yloxy)benzaldehyde as an intermediate Under a nitrogen atmosphere a solution of 2.0 grams (0.013 mole) of 6-chlorosalicylaldehyde in 10 mL of dimethylformamide was stirred, and 1.94 grams (0.0141 mole) of potassium carbonate was added. The reaction mixture was then stirred for 10 minutes, and a solution of 2.6 grams (0.013 mole) of 4,6-dimethoxy-2-methylsulfonylpyrimidine (prepared in Steps A-C) in 15 mL of dimethylformamide was added dropwise during a 10 minute period. Upon completion of addition, the reaction mixture was warmed to 60° C. where it was stirred for 18 hours. The reaction mixture was poured into 150 mL of water, cooled, and the pH was adjusted to 12 with aqueous 50percent sodium hydroxide, with stirring. The mixture was stirred for 15 minutes, and the resultant solid was collected by filtration to yield 1.62 grams of 6-chloro-2-(4,6-dimethoxypyrimidin-2-yloxy)benzaldehyde. The nmr spectrum was consistent with the proposed structure.
4-(2-Chloro-6-hydroxyphenyl)but-3-en-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; sodium hydroxide; In acetone;
(a) 4-(2-Chloro-6-hydroxyphenyl)but-3-en-2-one <strong>[18362-30-6]2-Chloro-6-hydroxybenzaldehyde</strong> (20.57 g) was treated with 10% sodium hydroxide solution (52.5 ml) and the mixture was shaken. Acetone (44.6 ml) and a further portion of 10% sodium hydroxide (71 ml) were added. After shaking again, the mixture was diluted with water (500 ml) and stirred overnight at room temperature. The mixture was acidified to pH 1 by the addition of 2 N hydrochloric acid and the solid product was collected by filtration, washed with water and dried (24.68 g). A small sample was purified by preparative-layer chromatography on silica gel using a chloroform methanol mixture for elution, and recrystallisation from methylene chloride, to give the title compound as pale yellow needles m.p. 153-155.
4-amino-9-chloro-2-methyl-1,2,3,4,4a,10a-hexahydro[10 H]benzopyrano[3,2-c]pyrid-10-ylacetic acid lactam[ No CAS ]
[ 70384-83-7 ]
Yield
Reaction Conditions
Operation in experiment
58%
With acetic acid; In ethanol;
EXAMPLE 19 4-amino-9-chloro-2-methyl-1,2,3,4,4a,10a-hexahydro[10 H]benzopyrano[3,2-c]pyrid-10-ylacetic acid lactam. C15 H17 ClN2 O2. Molecular weight=292.77. 19.1 Ethyl 5-chlorocoumarin-3-carboxylate C12 H9 ClO4. Molecular weight 252.5. 15 g (0.0958 mole) of <strong>[18362-30-6]2-chloro-6-hydroxy-benzaldehyde</strong>, 16.7 g (0.105 mole) ethyl malonate, 40 mL ethanol, 0.6 mL piperidine and 0.1 mL acetic acid are refluxed for 5 hours. After cooling the resultant product is dried. After drying, 14 g of ethyl 5-chlorocoumarin-3-carboxylate are obtained. (Yield=58percent). Melting pointG =142°-144° C. IRnuC=0: 1720 cm-1. C=0: 1760 cm-1. NMR (CDCl3)deltappm relative to TMS.
With 1,4-diaza-bicyclo[2.2.2]octane; for 5h;Heating / reflux;
Step 6:A mixture of the aldehyde 15f (1.1 g, 7.2 mmol), acrylonitrile (2.4 mL, 36 mmol) and DABCO (190 mg, 1.7 mmol) are refluxed for 5 h. The reaction mixture is cooled to RT, diluted with EtOAc (50 mL) and washed with 1 N NaOH (20 mL) and then with 1 N HCI (20 mL). The organic phase is dried over MgSO4 and concentrated to <n="75"/>dryness. The product is purified by CombiFlash.(R). Companion to afford the nitrile 15g (650 mg, 47percent yield).
47%
With 1,4-diaza-bicyclo[2.2.2]octane; for 5h;Heating / reflux;
A mixture of the aldehyde 15f (1.1 g, 7.2 mmol), acrylonitrile (2.4 mL, 36 mmol) andDABCO (190 mg, 1.7 mmol) are refluxed for about 5 h. The reaction mixture is cooled toRT, diluted with EtOAc (50 mL) and washed with 1 N NaOH (20 mL) and then with 1 NHCI (20 mL). The organic phase is dried over MgSO4 and concentrated to dryness. The product is purified by CombiFlash.(R). Companion to afford the nitrile 15g 650 mg, 47percent yield).
47%
1-n-propylpiperazine; for 5h;Heating / reflux;
A mixture of the aldehyde 15f (1 1 g, 7 2 mmol), acrylonitrile (2 4 mL, 36 mmol) and DABCO (190 mg, 1 7 mmol) are refluxed for 5 h The reaction mixture is cooled to RT, diluted with EtOAc (50 mL) and washed with 1 N NaOH (20 mL) and then with 1 N HCI (20 mL) The organic phase is dried over MgSO4 and concentrated to dryness The product is purified by CombiFlash.(R). Companion to afford the nitrile 15g (650 mg, 47percent yield)
47%
1,4-diaza-bicyclo[2.2.2]octane; for 5h;Heating / reflux;
A mixture of the aldehyde 15f (1.1 g, 7.2 mmol), acrylonitrile (2.4 mL, 36 mmol) and DABCO (190 mg, 1.7 mmol) are refluxed for 5 h. The reaction mixture is cooled to RT, diluted with EtOAc (50 mL) and washed with 1 N NaOH (20 mL) and then with 1 N HCI (20 mL). The organic phase is dried over MgSO4 and concentrated to dryness. The product is purified by CombiFlash.(R). Companion to afford the nitrile 15g (650 mg, 47percent yield).
With boron tribromide; In dichloromethane; at -30 - 0℃; for 3h;
Step 5:A solution of methyl ether 15e (720 mg, 4.2 mmol) in anhydrous CH2CI2 (20 mL) is added slowly to a precooled (-30 °C) solution of BBr3 (1 M, 8.4 mL, 8.4 mmol). The solution is warmed to 00C and is stirred for 3 h. The reaction is quenched carefully with methanol (1 mL) and washed with saturated NaHCO3 and then brine (25 mL each). The organic layer is dried over MgSO4, filtered and concentrated and the product is purified by CombiFlash.(R). Companion to give phenol 15f (530 mg, 80percent yield).
80%
A solution of methyl ether 15e (720 mg, 4.2 mmol) in anhydrous CH2CI2 (20 mL) is added slowly to a precooled (-300C) solution of BBr3 (1 M, 8.4 mL, 8.4 mmol). The solution is warmed to O0C and is stirred for about 3 h. The reaction is quenched carefully with methanol (1 mL) and washed with saturated NaHCO3 and then brine (25 mL each). The organic layer is dried over MgSO4, filtered and concentrated and the product is purified by CombiFlash.(R). Companion to give phenol 15f (530 mg, 80percent yield).
80%
A solution of methyl ether 15e (720 mg, 4 2 mmol) in anhydrous CH2Cl2 (20 mL) is added slowly to a precooled (-300C) solution of BBr3 (1 M, 8 4 mL, 8 4 mmol) The solution is warmed to 0°C and is stirred for 3 h The reaction is quenched carefully with methanol (1 mL) and washed with saturated NaHCO3 and then brine (25 mL each) The organic layer is dried over MgSO4, filtered and concentrated and the product is purified by CombiFlash.(R). Companion to give phenol 15f (530 mg, 80percent yield)
80%
A solution of methyl ether 15e (720 mg, 4.2 mmol) in anhydrous CH2CI2 (20 mL) is added slowly to a precooled (-300C) solution of BBr3 (1 M, 8.4 mL, 8.4 mmol). The solution is warmed to 0°C and is stirred for 3 h. The reaction is quenched carefully with methanol (1 mL) and washed with saturated NaHCO3 and then brine (25 mL <n="88"/>each). The organic layer is dried over MgSO4, filtered and concentrated and the product is purified by CombiFlash.(R). Companion to give phenol 15f (530 mg, 80percent yield).
With potassium carbonate; In ISOPROPYLAMIDE; at 150℃; for 0.25h;Microwave irradiation;
Example 30; STEP A; A reaction mixture of <strong>[18362-30-6]2-chloro-6-hydroxybenzaldehyde</strong> (31.3 mg, 0.2 mmol), compound 1-1 (26 mg, 0.1 mmol) and potassium carbonate (55 mg, 0.4 mmol) in DMA was stirred in microwave at 150 0C for 15 minutes. Compound30-1 was purified using reverse phase HPLC.
1.0 g of 6-chlorosalicylaldehyde 9 is dissolved in 30 ml of DMF, 0.26 g of NaH (60percent suspension in paraffin oil) is carefully added with cooling, and the mixture is stirred at RT for 45 min. 1.30 g of 2-iodoacetamide 2 are then added, and the reaction mixture is stirred overnight. The mixture is subsequently subjected to conventional work-up, giving 1.28 g (90percent) of 2-(3-chloro-2-formylphenoxy)acetamide 10 ; MS-EI (M+)=213
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 21h;
General procedure: Anhydrous K2CO3 (39.0 g, 283 mmol) was added to a stirred solution of 11 (11.5 g, 10.0 mL, 94.2 mmol) and PMB-Cl (19.2 g, 16.6 mL, 122 mmol) in DMF (95 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h, and then warmed to room temperature. The mixture was stirred for 20 h, whereupon the reaction was partitioned between H2O (200 mL) and PhCH3 (100 mL). The layers were separated, and the aqueous layer was washed with PhCH3 (2.x.50 mL). The combined organic layers were washed with brine (1.x.100 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to afford 20.7 g (91percent yield).
With pyrrolidine; In dimethyl sulfoxide; at 25℃; for 78h;
Step 1(E)-4-Oxo-but-2-enoic acid ethyl ester (4.60 mL, 38.32 mmol), 2-nitrobenzoic acid (1.08 g, 6.39 mmol), and pyrrolidine (0.53 mL, 6.39 mmol) were added simultaneously to a solution of commercially available <strong>[18362-30-6]2-chloro-6-hydroxy-benzaldehyde</strong> (5.0 g, 31.93 mmol) in dimethysulfoxide (30 mL) at 25°C and the solution was stirred for 78 hours at 25°C. The reaction was quenched by the addition of water. The reaction mixture was then partitioned between water and ethyl acetate. The combined organics were washed with a saturated brine solution, dried over anhydrous sodium sulfate, filtered, rinsed and concentrated in vacuo. The residue obtained was purified on a silica gel Flash column chromatography using ethyl acetate- hexanes (1 :1.2) as eluents, yielding 5-chloro-3-formyl-2H-chromene-2-carboxylic acid ethyl ester as a solid (2.08 g, 49.5percent).
Example 8Preparation of 4-chlorobenzoic acid [1-(2-chloro-6-hydroxyphenyl)-methylidene]-hydrazide (Compound 70) A suspension of <strong>[18362-30-6]2-chloro-6-hydroxybenzaldehyde</strong> (0.10 g, 0.64 mmol) and 4-chlorobenzoic acid hydrazide (0.10 g, 0.61 mmol) in EtOH (3 mL) was agitated and heated to 60° C. for 16 h. The reaction mixture was cooled to room temperature and H2O (1-2 mL) was added portionwise to precipitate the product. The solid was collected via suction filtration and rinsed with ethanol to furnish the title compound as an off-white solid (0.18 g, 95percent): mp 273-277° C.; 1H NMR (400 MHz, DMSO-d6) delta 12.53 (s, 1H), 12.51 (s, 1H), 9.04 (s, 1H), 8.03-7.95 (m, 2H), 7.71-7.63 (m, 2H), 7.34 (t, J=8.2 Hz, 1H), 7.07 (dd, J=7.9, 0.9 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H); ESIMS m/z 309 ([M+H]+), 307 ([M-H]-).
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 1.5h;
Ethyl chloroacetate (8.0 mL, 1.3eq.) was added to a mixture of 2-chloro-6-hydroxy- benzaldehyde (Example la), 9.0 g, 57 mmol) and potassium carbonate (16.0 g, 114 mmol) inDMF (100 mL) at rt. The reaction mixture was heated at +120°C for 1.5 h, cooled to room temperature and filtered through a short bed of Celite. The filtrate was acidified to pH 2 with 5 M HC1 and the solution was extracted with dichloromethane (2x100 mL). The combined organic extracts was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography by using hexane/ethyl acetate (9/1) as eluent to give the title compound.Yield: 10 g ( 77percent ). H NMR (400 MHz, CDC13) delta ppm 1.44 (t, 3H) 4.56 (q, 2H) 7.29 - 7.32(m, 1H) 7.35 - 7.40 (m, 1H) 7.49 - 7.52 (m, 1H) 7.60 (s, 1H).
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