* 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.
Step 1: Synthesis of methyl 4-formyl-3-hydroxybenzoate (239) 4-Formyl-3-hydroxybenzoic acid (1.2 g, 7.22 mmol) was dissolved in MeOH (10 ml). SOCl2 (1.054 ml, 14.45 mmol) was added, and the reaction was stirred at 60° C. for 3 hours to achieve completion. The reaction mixture was concentrated, and the crude was triturated in Hexane and filtered to give methyl 4-formyl-3-hydroxybenzoate (1.3 g, 7.22 mmol, 100percent yield). MS/ESI+ 181.04 [MH]+
85%
Reflux
4-Formyl-3-hydroxybenzoic acid (5 g, 30 mmol) was suspended in methanol (70 mL), and treated with thionyl chloride (3.29 mL 45 mmol) dropwise. The mixture was heated to reflux overnight. Concentrated to dryness, and 50 mL of toluene was added, and concentrated again. The residue was recrystallized from ethyl acetate-hexane. A total of 4.8 g (85percent) of methyl 4-formyl-3-hydroxybenzoate was obtained.
Reference：
[1] Patent: US2014/155391, 2014, A1, . Location in patent: Paragraph 0617; 0618
[2] Patent: US2012/245144, 2012, A1, . Location in patent: Page/Page column 105
[3] Journal of the American Chemical Society, 1955, vol. 77, p. 973,979
[4] Journal of Medicinal Chemistry, 1969, vol. 12, # 3, p. 420 - 424
[5] Bioorganic and Medicinal Chemistry, 2001, vol. 9, # 5, p. 1175 - 1183
2
[ 71780-40-0 ]
[ 24589-98-8 ]
Yield
Reaction Conditions
Operation in experiment
37%
With sodium tetrahydroborate; palladium 10% on activated carbon; oxygen; potassium carbonate In methanol; water
To a solution of 250 mg (1.37mmol) methyl3-hydroxy-4-(hydroxymethyl)benzoate in 3 mL 10percent aqueous methanol was added 73 mg (10percentloading, 0. 034 mmol, 2. 5 molpercent) Pd/C, 567 mg ( 4.11 mmol, 3 eq) potassium carbonate,and 5.2 mg (0.137, 0.1 eq) sodium borohydride, and the mixture was stirred under anatmosphere of oxygen overnight. Then, the mixture was diluted with dichloromethaneand filtered. The mixture was concentrated in vacuo, partitioned between ethyl acetateand water, and the aqueous layer extracted two more times with ethyl acetate. The combined organic phases were then dried over sodium sulfate. The solvent was removedunder reduced pressure and the product was purified by column chromatography. 92 mg(0.506 mmol, 37percent) of the methyl4-formyl-3-hydroxybenzoate were obtained as a whitesolid. Rf(25percent EtOAc, 75percent Hexanes) = 0.50; 1H NMR (600 MHz, Chloroform-d) 8 10.94(s, 1H), 9.98 (s, 1H), 7.69-7.63 (m, 3H), 3.94 (s, 3H). 13C NMR (126 MHz, Chloroform-d) 8196.44, 165.67, 161.24, 137.30, 133.62, 122.86, 120.40, 119.12, 52.69. HRMS: m/z(+H+). calc'd: 181.0495, found: 181.0494.
Reference：
[1] Patent: WO2018/191360, 2018, A1, . Location in patent: Page/Page column 63
[2] Journal of Materials Chemistry, 2005, vol. 15, # 44, p. 4746 - 4752
3
[ 100-97-0 ]
[ 19438-10-9 ]
[ 24589-98-8 ]
[ 131524-43-1 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1994, vol. 42, # 10, p. 2170 - 2173
[2] Patent: EP1489078, 2004, A1, . Location in patent: Page 195
[3] Patent: EP1666478, 2006, A1, . Location in patent: Page/Page column 90
[4] Journal of the American Chemical Society, 2013, vol. 135, # 46, p. 17408 - 17416
4
[ 67-71-0 ]
[ 1560893-80-2 ]
[ 24589-98-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2334 - 2356
5
[ 6342-72-9 ]
[ 24589-98-8 ]
Reference：
[1] Journal of Materials Chemistry, 2005, vol. 15, # 44, p. 4746 - 4752
[2] Patent: WO2018/191360, 2018, A1,
6
[ 99-06-9 ]
[ 24589-98-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 1969, vol. 12, # 3, p. 420 - 424
7
[ 157942-12-6 ]
[ 24589-98-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2334 - 2356
Methyl 3-hydroxybenzoate (75.5 g) is dissolved in trifluoroacetic acid (2 L), thereto is added hexamethylenetetramine (141.4 g) at room temperature and the mixture is heated under reflux for 3 hours. The reaction solution is concentrated under reduced pressure, to the resulting residue is added water, the mixture is adjusted to pH 8 with potassium carbonate and sodium hydrogen carbonate, diluted with water and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 8/1, 5/1 followed by 2/1) to give methyl 2-formyl-3-hydroxybenzoate (54.6 g) (ESI-MS m/z: 179[M-H]-) and methyl 4-formyl-3-hydroxybenzoate (4.4 g) (ESI-MS m/z: 179[M-H]-).
at 20℃; for 3h;Heating / reflux;
Reference Example 118: Methyl 2-formyl-3-hydroxybenzoate and methyl 4-formyl-3-hydroxybenzoate; [Show Image] Methyl 3-hydroxybenzoate (75.5 g) is dissolved in trifluoroacetic acid (2 L), thereto is added hexamethylenetetramine (141.4 g) at room temperature, and the mixture is heated under reflux for 3 hours. The reaction solution is concentrated under reduced pressure and water is added to the resulting residue. The mixture is adjusted to pH 8 with potassium carbonate and sodium hydrogen carbonate, diluted with water and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate, and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 8/1, 5/1, and then 2/1) to give methyl 2-formyl-3-hydroxybenzoate (54.6 g) (ESI-MS m/z: 179[M-H]-) and methyl 4-formyl-3-hydroxybenzoate (4.4 g) (ESI-MS m/z: 179 [M-H]-).
With sodium tetrahydroborate; palladium 10% on activated carbon; oxygen; potassium carbonate; In methanol; water;
To a solution of 250 mg (1.37mmol) methyl3-hydroxy-4-(hydroxymethyl)benzoate in 3 mL 10% aqueous methanol was added 73 mg (10%loading, 0. 034 mmol, 2. 5 mol%) Pd/C, 567 mg ( 4.11 mmol, 3 eq) potassium carbonate,and 5.2 mg (0.137, 0.1 eq) sodium borohydride, and the mixture was stirred under anatmosphere of oxygen overnight. Then, the mixture was diluted with dichloromethaneand filtered. The mixture was concentrated in vacuo, partitioned between ethyl acetateand water, and the aqueous layer extracted two more times with ethyl acetate. The combined organic phases were then dried over sodium sulfate. The solvent was removedunder reduced pressure and the product was purified by column chromatography. 92 mg(0.506 mmol, 37%) of the methyl4-formyl-3-hydroxybenzoate were obtained as a whitesolid. Rf(25% EtOAc, 75% Hexanes) = 0.50; 1H NMR (600 MHz, Chloroform-d) 8 10.94(s, 1H), 9.98 (s, 1H), 7.69-7.63 (m, 3H), 3.94 (s, 3H). 13C NMR (126 MHz, Chloroform-d) 8196.44, 165.67, 161.24, 137.30, 133.62, 122.86, 120.40, 119.12, 52.69. HRMS: m/z(+H+). calc'd: 181.0495, found: 181.0494.
With formic acid; hydroxylamine hydrochloride; sodium formate; for 14h;Heating / reflux;
Methyl 4-formyl-3-hydroxybenzoate (1.96 g) obtained in Reference Example 146 is dissolved in formic acid (50 ml), thereto are added hydroxylammonium chloride (0.85 g) and sodium formate (0.85 g) and the mixture is heated under reflux for 14 hours. The reaction solution is concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is suspended chloroform/diisopropyl ether, and then the precipitates are collected by filtration to give the title compound (0.66 g). Furthermore, the filtrate is concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 3/2) to give the title compound (1.08 g). ESI-MS M/Z:176[M-H]-.
With hydroxylamine hydrochloride; sodium formate; for 14h;Heating / reflux;
Reference Example 119: Methyl 4-cyano-3-hydroxybenzoate Methyl 4-formyl-3-hydroxybenzoate (1.96 g) obtained in Reference Example 118 is dissolved in formic acid (50 ml), thereto are added hydroxylammonium chloride (0.85 g) and sodium formate (0.85 g) and the mixture is heated under reflux for 14 hours. The reaction solution is concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is suspended in chloroform/diisopropyl ether, and the precipitates are collected by filtration to give the title compound (0.66 g). Furthermore, the filtrate is concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 3/2) to give the title compound (1.08 g). ESI-MS M/Z:176[M-H]-
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]chromane-7-carboxamide fumarate[ No CAS ]
[ 527681-26-1 ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In acetone;
EXAMPLE 15 N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]chromane-7-carboxamide-fumarate To a stirred solution of <strong>[24589-98-8]methyl 4-formyl-3-hydroxybenzoate</strong> [see: Harayama, Chem. Pharm. Bull. 1994, 2170] (0.8 g, 4.1 mmol) and anhydrous K2CO3 (1.1 g, 8.0 mmol) in acetone (12 mL) is added allyl bromide (0.70 mL, 8.1 mmol). The mixture is heated in a 48 C. oil bath for 2 h. The reaction mixture is cooled to rt and filtered. The mother liquor is concentrated in vacuo to a brown oil. The crude product is purified by flash chromatography on SiO2. Elution with hexanes-EtOAc (85:15) gives 0.85 g (49%) of methyl 3-(allyloxy)-4-formylbenzoate as a clear solid: 1H NMR (400 MHz, CDCl3) delta10.6, 7.9, 7.7, 6.1, 5.5, 5.4, 4.8, 4.0.
methyl 3-hydroxy-4-[4-(2-hydroxyethyl)benzyl]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; methanol; water;
Reference Example 4 Methyl 3-hydroxy-4-[4-(2-hydroxyethyl)benzyl]benzoate To a solution of 2-(bromophenyl)ethylalchol (1.7g) in tetrahydrofuran (100mL) was added 1.45mol/L tert-butyllithium n-pentane solution (12.6mL) under an argon atmosphere at -78C. After the mixture was stirred at -78C for 10 minutes, a solution of <strong>[24589-98-8]methyl 4-formyl-3-hydroxybenzoate</strong> (0.50g) in tetrahydrofuran (10mL) was added to the reaction mixture. After the reaction mixture was stirred for 30 minutes under ice-cooling, a saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate = 1/3) to give a diphenylmethanol compound (0.28g). The obtaineddiphenylmethanol compound (0.28g) was dissolved in methanol (5mL), and 10% palladium-carbon powder (0.14g) was added to the solution. After the mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate = 1/1) to give methyl 3-hydroxy-4-[4-(2-hydroxyethyl)benzyl]-benzoate (0.26g). 1H-NMR (CDCl3) delta ppm: 1.37 (1H, t, J=5.9Hz), 2.84 (2H, t, J=6.5Hz), 3.75-3.95 (5H, m), 4.01 (2H, s), 5.10 (1H, s), 7.05-7.25 (5H, m), 7.47 (1H, d, J=1.6Hz), 7.56 (1H, dd, J=1.6, 7.8Hz)
With hydrogenchloride; In tetrahydrofuran; methanol; water;
Reference Example 2 Methyl 4-(4-ethylbenzyl)-3-hydroxybenzoate To a solution of 1-bromo-4-ethylbenzene (0.41mL) in tetrahydrofuran (15mL) was added 1.45mol/L tert-butyllithium n-pentane solution (2.3mL) under an argon atmosphere at -78C. After the mixture was stirred at -78C for 10 minutes, a solution of <strong>[24589-98-8]methyl 4-formyl-3-hydroxybenzoate</strong> (0.18g) in tetrahydrofuran (5mL) was added to the reaction mixture. After the mixture was stirred under ice-cooling for 45 minutes, a saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate = 3/1) to give a diphenylmethanol compound (0.27g). The obtained diphenylmethanol compound (0.27g) was dissolved in methanol (5mL), and concentrated hydrochloric acid (0.08mL) and 10% palladium-carbon powder (54mg) were added to the solution. After the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hours, the catalyst was removed by filtration, and the filtrate was concentrated under reducedpressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate = 3/1) to give methyl 4-(4-ethylbenzyl)-3-hydroxybenzoate (0.20g). 1H-NMR (CDCl3) delta ppm: 1.22 (3H, t, J=7.6Hz), 2.62 (2H, q, J=7.6Hz), 3.89 (3H, s), 4.00 (2H, s), 5.01 (1H, s), 7.05-7.25 (5H, m), 7.47 (1H, d, J=1.6Hz), 7.56 (1H, dd, J=1.6, 7.8Hz)
methyl 3-hydroxy-4-(4-propoxybenzyl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; methanol; water;
Reference Example 3 Methyl 3-hydroxy-4-(4-propoxybenzyl)benzoate To a solution of 1-allyloxy-4-bromobenzene (3.1g) in tetrahydrofuran (70mL) was added 1.45mol/L tert-butyllithium n-pentane solution (11mL) under an argon atmosphere at -78C. After the mixture was stirred at -78C for 5 minutes, a solution of <strong>[24589-98-8]methyl 4-formyl-3-hydroxybenzoate</strong> (0.89g) in tetrahydrofuran (15mL) was added to the reaction mixture. After the mixture was stirred for 30 minutes under ice-cooling, a saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate = 3/1) to give a diphenylmethanol compound (0.99g). The obtained diphenylmethanol compound (0.99g) was dissolved in methanol (10mL), and 10% palladium-carbon powder (0.30g) was added to the solution. After the mixture was stirred under a hydrogenatmosphere at room temperature for 24 hours, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate = 3/1) to give methyl 3-hydroxy-4-(4-propoxybenzyl)benzoate (0.50g). 1H-NMR (CDCl3) delta ppm: 1.02 (3H, t, J=7.4Hz), 1.70-1.85 (2H, m), 3.80-3.95 (5H, m), 3.97 (2H, s), 4.99 (1H, s), 6.75-6.90 (2H, m), 7.05-7.20 (3H, m), 7.47 (1H, d, J=1.5Hz), 7.56 (1H, dd, J=1.5, 7.8Hz)
Reference Example 4 methyl 3-hydroxy-4-[4-(2-hydroxyethyl)benzyl]benzoate To a solution of 2-(4-bromophenyl)ethylalchol (1.7g) in tetrahydrofuran (100ML) was added 1.45mol/L tert-butyllithium n-pentane solution (12.6ML) under an argon atmosphere at -78C. After the mixture was stirred at -78C for 10 minutes, a solution of <strong>[24589-98-8]methyl 4-formyl-3-hydroxybenzoate</strong> (0.50g) in tetrahydrofuran (10ML) was added to the reaction mixture.. After the reaction mixture was stirred for 30 minutes under ice-cooling, a saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate.. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure.. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate = 1/3) to give a diphenylmethanol compound (0.28g).. The obtained diphenylmethanol compound (0.28g) was dissolved in methanol (5ML), and 10% palladium-carbon powder (0.14g) was added to the solution.. After the mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure.. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate = 1/1) to give methyl 3-hydroxy-4-[4-(2-hydroxyethyl)benzyl]benzoate (0.26g).1H-NMR (CDCl3) delta ppm: 1.37 (1H, t, J=5.9Hz), 2.84 (2H, t, J=6.5Hz), 3.75-3.95 (5H, m), 4.01 (2H, s), 5.10 (1H, s), 7.05-7.25 (5H, m), 7.47 (1H, d, J=1.6Hz), 7.56 (1H, dd, J=1.6, 7.8Hz)
Reference Example 2 methyl 4-(4-ethylbenzyl)-3-hydroxybenzoate To a solution of 1-bromo-4-ethylbenzene (0.41 ML) in tetrahydrofuran (15 ML) was added 1.45 mol/L tert-buthyllithium n-pentane solution (2.3 ML) under an argon atmosphere at -78 C. After the mixture was stirred at -78C for 10 minutes, a solution of <strong>[24589-98-8]methyl 4-formyl-3-hydroxybenzoate</strong> (0.18g) in tetrahydrofuran (5ML) was added to the reaction mixture.. After the mixture was stirred under ice-cooling for 45 minutes, a saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate.. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure.. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate = 3/1) to give a diphenylmethanol compound (0. 27g).. The obtained diphenylmethanol compound (0.27g) was dissolved in methanol (5ML), and concentrated hydrochloric acid (0.08ML) and 10% palladium-carbon powder (54mg) were added to the solution. After the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hours, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure.. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate = 3/1) to give methyl 4-(4-ethylbenzyl)-3-hydroxybenzoate (0.20g).1H-NMR (CDCl3) delta ppm: 1.22 (3H, t, J=7.6Hz), 2.62 (2H, q, J=7.6Hz), 3.89 (3H, s), 4.00 (2H, s), 5.01 (1H, s), 7.05-7.25 (5H, m), 7.47 (1H, d, J=1.6Hz), 7.56 (1H, dd, J=1.6, 7.8Hz)
Reference Example 3 methyl 3-hydroxy-4-(4-propoxybenzyl)benzoate To a solution of 1-allyloxy-4-bromobenzene (3.1g) in tetrahydrofuran (70ML) was added 1.45mol/L tert-butyllithium n-pentane solution (11ML) under an argon atmosphere at -78C. After the mixture was stirred at -78C for 5 minutes, a solution of <strong>[24589-98-8]methyl 4-formyl-3-hydroxybenzoate</strong> (0.89g) in tetrahydrofuran (15ML) was added to the reaction mixture.. After the mixture was stirred for 30 minutes under ice-cooling, a saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate.. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure.. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate = 3/1) to give a diphenylmethanol compound (0.99g).. The obtained diphenylmethanol compound (0.99g) was dissolved in methanol (10ML), and 10% palladium-carbon powder (0.30g) was added to the solution.. After the mixture was stirred under a hydrogen atmosphere at room temperature for 24 hours, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure.. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate = 3/1) to give methyl 3-hydroxy-4-(4-propoxybenzyl)benzoate (0.50g).1H-NMR (CDCl3) delta ppm: 1.02 (3H, t, J=7.4Hz), 1.70-1.85 (2H, m), 3.80-3.95 (5H, m), 3.97 (2H, s), 4.99 (1H, s), 6.75-6.90 (2H, m), 7.05-7.20 (3H, m), 7.47 (1H, d, J=1.5Hz), 7.56 (1H, dd, J=1.5, 7.8Hz)
(Example 68) 5-Hydroxymethyl-2-[4-(3-hydroxypropyl)benzyl]phenyl 7-deoxy-D-glycero-beta-D-gluco-heptopyranoside (Example Compound No. 1-137); (68a) Methyl 4-[4-(3-benzyloxypropyl)phenyl]hydroxymethyl}-3-hydroxybenzoate; 1-Bromo-4-(3-benzyloxypropyl)benzene (2.71 g, 8.88 mmol) was dissolved in tetrahydrofuran (50 mL), the mixture was cooled to -78C, a solution of 2.6 mol/L n-butyllithium hexane (3.4 mL, 8.84 mmol) was added dropwise, and the mixture was stirred at -78C for 10 min. A solution of 2-hydroxy-4-methoxycarbonyl benzaldehyde (0.40 g, 2.22 mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction mixture, and the mixture was stirred from -70 to 0C for 1 h. Aqueous ammonium chloride was added to the reaction mixture, the mixture was extracted with ethyl acetate, and then the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 5:1 to 3:1 to 2:1, v/v) to obtain the title compound (0.45 g, yield 50%) as a pale yellow oil.
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 1h;
(Example 58) 2-(4-Difluoromethoxybenzyl)-5-hydroxymethylphenyl 7-deoxy-D-glycero-beta-D-gluco-heptopyranoside (Example Compound No. 1-128); (58a) Methyl 4-(diethoxyphosphoryloxymethyl)-3-methoxymethoxybenzoate; Potassium carbonate (9.9 g, 71.6 mmol) and chloromethyl methyl ether (4.3 g, 53.4 mmol) were successively added to a solution of <strong>[24589-98-8]methyl 4-formyl-3-hydroxybenzoate</strong> (5.2 g, 28.9 mmol) in N,N-dimethylformamide (60 mL) in an ice water bath, and the mixture was stirred at room temperature for 1 h. The reaction mixture was filtered using Celite, and the filtrate was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain a crude product (5.99 g, yield 92%).
(Example 66) 5-Hydroxymethyl-2-(4-methylsulfanylbenzyl)phenyl 7-deoxy-D-glycero-beta-D-gluco-heptopyranoside (Example Compound No. 1-135); (66a) Methyl 3-hydroxy-4-[hydroxy-(4-methylsulfanylphenyl)methyl]benzoate; 4-Bromothioanisole (9.02 g, 44.4 mmol) was dissolved in tetrahydrofuran (50 mL), followed by addition of magnesium (1.08 g, 44.4 mmol) and a catalytic amount of iodine, and the mixture was stirred at room temperature for 30 min and further heated to reflux for 1 h. The reaction mixture was added dropwise to a solution of 2-hydroxy-4-methoxycarbonylbenzaldehyde (2.00 g, 11.1 mmol) in tetrahydrofuran (40 mL) at -50C, and the mixture was stirred from -50 to 2C for 1 h. Aqueous ammonium chloride was added to the reaction mixture, the mixture was extracted with ethyl acetate, and then the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 3:1 to 2:1, v/v) to obtain the title compound (3.38 g, yield 100%) as a yellow oil. 1H NMR (400 MHz, CDCl3): delta 2.48 (3H, s), 2.89 (1H, d, J=3.1 Hz), 3.89 (3H, s), 6.04 (1H, d, J=3.1 Hz), 6.96 (2H, d, J=7.8 Hz), 7.25 (2H, d, J=8.6 Hz), 7.31 (2H, d, J=8.6 Hz), 7.49 (1H, dd, J=7.8 and 1.6 Hz), 7.56 (1H, d, J=1.6 Hz), 8.00 (1H, s); MS (FAB)m/z: 304 (M)+.
A mixture of <strong>[24589-98-8]methyl 4-formyl-3-hydroxybenzoate</strong> (4.8 g, 27 mmol), 40% aqueous solution of ethanedial (11.6 g, 79.93 mmol) and 50% aqueous ammonia (6.8 g, 399 mmol) in methanol (50 mL) was stirred for 2 hours or longer until the reaction is done. The solvent was removed by rotary evaporation, and the residue was partitioned between ethyl acetate and water. The mixture was filtered to remove the precipitates. pH was adjusted to 5-6 by careful addition of 1 N HCl. The aqueous layer was extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried over MgSO4. The residue was purified by flash chromatography to yield methyl 3-hydroxy-4-(1H-imidazol-2-yl)benzoate as a yellow solid (4 g, 71%)
With dimethylsulfide; oxygen; ozone; In dichloromethane; at -78℃;
General procedure: C: Methyl hydroxyl-4-vinylbenzoate (1.0 mmol) was dissolved in DCM (0.4 M)in a flask open to air. The reaction mixture was cooled to -78 C and a stream of 02 (g)was passed through it for 5 mm. At this time, 03 (g) was bubbled into the mixture until the color turned blue. The resulting solution was then purged with 02 (g) for an additional 5 mm before being treated with dimethylsulfane (3.0 equiv) and allowed to warm to rt overnight. The mixture was concentrated in vacuo and purified using flashcolumn chromatography on Si02 (Hexanes/EtOAc: 6/1) to yield the desired product.; Methyl 4-formyl-2-hydroxybenzoate (161 6-07b). Compound 161 6-07b was prepared viaProcedure C from 1616-07a (0.49 g, 2.8 mmol) to afford a white solid (0.30 g, 60%).
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h;
Step 1: Synthesis of methyl 3-(cyclopropylmethoxy)-4-formylbenzoate (125) To a solution of <strong>[24589-98-8]methyl 4-formyl-3-hydroxybenzoate</strong> (50 mg, mmol) in DMF (1 ml), cyclopropylbromide (0.5 ml, mmol) and potassium carbonate (50 mg, mmol) were added at RT. The reaction was stirred at 60 degrees for 3 hours, then poured onto water and the aqueous phase extracted with AcOEt twice. The combined organic phases were dried over Na2SO4, and the solvent was removed under reduced pressure to yield 50 mg of the title compound (mmol, yield %), which was used for the next step without further purification. MS/ESI+ 180.04 [MH]+
Step-2 A solution of <strong>[24589-98-8]methyl 4-formyl-3-hydroxybenzoate</strong> (0.05 g, 0.27 mmol) and NaH2PO4.2H2O (0.11 g, 0.69 mmol) in DMSO: water, 2:1 (7.5 ml) was charged with sodium chlorite (0.075 g, 0.66 mmol) at 0 C. The reaction mixture was allowed to stir at room temperature for 12 hours. The reaction mixture was acidified with 1N HCl until pH=2. The precipitated white solid was filtered, washed with water several times and dried to give 2-hydroxy-4-(methoxycarbonyl)benzoic acid. Yield: (0.035 g, 65%). Molecular Weight: 196. MS (ES+): m/z=197.2 [MH+].
In water; dimethyl sulfoxide;
Step-2 A solution of <strong>[24589-98-8]methyl 4-formyl-3-hydroxybenzoate</strong> (0.05 g, 0.27 mmol) and NaH2PO4.2H2O (0.11 g, 0.69 mmol) in DMSO:water, 2:1 (7.5 ml) was cooled to 0 C. and charged with sodium chlorite (0.075 g, 0.66 mmol). The reaction mixture was allowed to stir at room temperature for 12 hr. then acidified to pH 2 with 1N HCl. The precipitated white solid was filtered, washed with water several times and dried to give 2-hydroxy-4-(methoxycarbonyl)benzoic acid. Yield: (0.035 g, 65%). Molecular Weight: 196. MS (ES+): m/z=197.2 [MH+].
(S)-4-(2-(4-(4-(tert-butoxycarbonylamino)cyclohexylcarbamoyl)-3-(cyclopropylmethoxy)benzoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl) ethyl)-3,5-dichloropyridine 1-oxide[ No CAS ]
4-((S)-2-(4-((1s,4R)-4-aminocyclohexylcarbamoyl)-3-(cyclopropylmethoxy)benzoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide hydrochloride[ No CAS ]
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 4h;
Step-1 [0429] Required ortho hydroxy aromatic aldehydes with carbethoxy/methoxy functionality were synthesized either by esterification of corresponding carboxylic acid available commercially using reaction conditions described in method-A step-1 (for 4-formyl-3-hydroxy methyl benzoate) or synthesized as per methods in the literature (JACS, 131, 15608-15609, 2009 for methyl 3-formyl-4-hydroxybenzoate; Syn. Comm, 29, 2061-2068,1999. for 3-formyl-4-hydroxy ethyl cinnamate). (E)-ethyl 3-(3-formyl-4-hydroxyphenyl)acrylate was synthesized as per methods in the literature (Syn. Comm. 30 1003-1008 2000). Aldehyde functionality was reduced either by catalytic hydrogenation or using sodium borohydride in methanol. The details of compounds synthesized are as below in Table 27. 10% Pd/C (10% w/w.), Hydrogen (balloon pressure), Methanol (50 vol), 4 h, RT, 79%
With sodium chlorite; sodium dihydrogenphosphate dihydrate; dihydrogen peroxide; In water; acetonitrile; at 0 - 20℃;
Ortho hydroxy aromatic aldehydes, with carbethoxy or methoxy functionality at suitable position were oxidized to get o-carboxy phenols which were then converted to amide by reaction either with ammonia/o-Methyl hydroxylamine. Ester functionality was then hydrolyzed to get required o-Hydroxy amido carboxylic acid, which upon coupling with tert-butyl 3-(piperidin-4-yl)benzylcarbamate and subsequent deprotection in acidic media afforded the title compounds. Step-1 [0443] Desired Carbmethoxy hydroxy benzaldehyde was dissolved in Acetonitrile and aq solution of di-sodium hydrogen phosphate & 30% hydrogen peroxide was then added and reaction mass cooled to 0 C. Aq. solution of Sodium chlorite was added to the reaction mass drop wise and reaction mass was allowed to warm to room temperature. Stirring continued at room temperature and reaction was monitored by LCMS till maximum starting was consumed. Reaction mass was then concentrated, residue was acidified with aq. HCl and product extracted in ethyl acetate. Ethyl acetate extract dried over sodium sulfate and concentrated to get the crude product which was sufficient pure for the use in next step. The details of the compounds synthesized are as below in Table 31. 4-Formyl, 3-Hydroxy methyl benzoate, (1 eq) ACN (65 V), NaH2PO4?2H2O (0.32 eq in 11 V water), H2O2 30% solution (5 eq) NaClO2 (1.4 eq in 10 V of water) RT 2 h. Yield - 35.46%
4-formyl-3-(2-methoxy-ethoxy)-benzoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.88 g
With potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 18h;Inert atmosphere;
A mixture of <strong>[24589-98-8]4-formyl-3-hydroxy-benzoic acid methyl ester</strong> (1.80 g, 9.99 mmol) and K2CO3 (2.76 g, 19.97 mmol) in DMF (20 mL) was treated with 1-bromo-2-methoxy-ethane (1.20 mL, 12.77 mmol) and heated to 75 C. for 18 h under nitrogen. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and water. The aqueous extract was further extracted with EtOAc (×2) and the combined organic extract was washed with water and brine, then dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as an dark brown waxy solid (1.88 g).1H NMR (400 MHz, CDCl3) delta 10.56 (1H, d, J=0.5 Hz), 7.88 (1H, dd, J=7.8, 0.5 Hz), 7.70-7.69 (1H, m), 7.68 (1H, s), 4.39-4.28 (2H, m), 3.95 (3H, s), 3.85-4.81 (2H, m), 3.4 (3H, s).
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 60℃; for 12.5h;
Under ice-cooling,2-hydroxy-benzaldehyde 4-carboxylate (1.80g, 10mmol) and anhydrous K2CO3(1.66g, 12mmol) was dissolved DMF (25ml) at, was slowly added dropwise ethylbromoacetate (1.67g, 10mmol). Completion of the dropwise addition, 0 C wasstirred for 30min, then at 60 C in an oil bath, the reaction 12h. Thereaction solution was poured into ice water , Filtered solids dissolved inchloroform, dried over anhydrous Na2SO4, filtered, and spin dry the solvent bysilica gel column chromatography After chromatographic separation to give ayellow solid 2.03g (82%), which was dissolved in tetrahydrofuran: methanol = 4to 1 mixture solution Solution (20ml) was added sodium hydroxide (0.43g,10.7mmol), stirred at room temperature 3h, the solution was evaporated todryness, The remaining liquid was poured into ice water, washed withdichloromethane, adjusting the PH value to 2, filtered, and the solid wascollected, washed with methanol weight Crystallized solid to give 1.42g (79%yield), which was dissolved in dichloromethane (25ml), was added DIC (0.98g,7.77mmol), Stirred for 1h at room temperature after added DMAP (0.24g,1.94mmol) and hydroxymethyl phosphonic aciddiethyl ester (1After .20g, 7.12mmol), was heatedunder reflux for 6h, the reaction with water and brine solution, dried overanhydrous magnesium sulfate Dry, filtered, evaporated to dryness, ethyl acetate- petroleum ether system recrystallized product, 6-benzofuran-carboxylatePyran-2-carboxylic acid (2'-phosphonic acid dimethyl ester) ester 1.80 g (75%yield).
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