* 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.
With methanol In hexane; toluene at 0 - 20℃; for 1 h;
Example 7b: Preparation of 3-(2,2-Dibromovinyl)-4-hydroxybenzoic acid methyl esterTo a solution of 3-formyl-4-hydroxybenzoic acid (1.00 g, 5.9 mmol) in toluene-MeOH (2:1, 30 mL) was added (trirnethylsilyl)diazomethane (2.0 M solution in hexane, 16 mL, 32 mmol) at 0 0C, and the mixture was stirred for 1 h at rt. After evaporating the solvent, the resulting residue was filtrated through a plug of silica gel eluting with 15percent EtOAc in hexane to afford 3-formyl-4-hydroxybenzoate as a colorless solid (1.06 g, 99percent).
Reference：
[1] Green Chemistry, 2012, vol. 14, # 8, p. 2314 - 2320
[2] Chemical Communications, 2018, vol. 54, # 42, p. 5385 - 5388
[3] Dalton Transactions, 2010, vol. 39, # 8, p. 2070 - 2077
[4] Farmaco, 1991, vol. 46, # 5, p. 669 - 676
[5] Rend. Ist. super. Sanita, 1955, vol. 18, p. 750,760
[6] Journal of Medicinal Chemistry, 1969, vol. 12, # 3, p. 420 - 424
4
[ 100-97-0 ]
[ 99-96-7 ]
[ 584-87-2 ]
Yield
Reaction Conditions
Operation in experiment
36%
Stage #1: With copper(I) oxide In trifluoroacetic acid for 5 h; Reflux Stage #2: With hydrogenchloride In water at 20℃; for 1 h;
General procedure: To a solution of substrates (1a–1q, 0.15 mmol) in trifluoroacetic acid (5 ml), hexamethylenetetramine (0.3 mmol) and cuprous oxide (0.15 mmol) were added. The reaction mixture was refluxed for about 5 h, cooled to room temperature, followed by addition of hydrochloric acid (3 N, 5 ml). After stirring for another 1 h, the solution was concentrated under reduced pressure. The products were purified by silica gel column chromatography (200–300 mesh).
Reference：
[1] Bioconjugate Chemistry, 2018, vol. 29, # 9, p. 2909 - 2919
[2] Dalton Transactions, 2010, vol. 39, # 8, p. 2070 - 2077
[3] European Journal of Inorganic Chemistry, 2012, # 32, p. 5225 - 5238
[4] Research on Chemical Intermediates, 2015, vol. 41, # 11, p. 8147 - 8158
[5] Chemical Communications, 2018, vol. 54, # 42, p. 5385 - 5388
[6] Current Science, 1954, vol. 23, p. 331
[7] Journal of the Chinese Chemical Society, 1998, vol. 45, # 5, p. 611 - 617
[8] Journal of Natural Products, 2003, vol. 66, # 5, p. 690 - 692
[9] Journal of Coordination Chemistry, 2018, vol. 71, # 11-13, p. 1690 - 1703
5
[ 60-29-7 ]
[ 99-96-7 ]
[ 584-87-2 ]
Yield
Reaction Conditions
Operation in experiment
23%
With hydrogenchloride; sodium hydroxide; sodium hydrogensulfite In chloroform; water
EXAMPLE 36 3-Formyl-4-hydroxybenzoic acid 140 g (1.01 mol) of 4-hydroxybenzoic acid were added to a hot solution of 250 g (6.25 mol) of sodium hydroxide in 500 mL H2 O. 150 mL of CHCl3 were cautiously added to the hot solution, and after the foaming had ceased, the reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted to 4 L with H2 O, acidified to pH 1 by addition of about 300 mL of concentrated HCl, and extracted two times with 2 L and then three times with 1 L ethyl ether. The ether extracts were combined and a solution of 750 g sodium bisulfite in 3 L H2 O was added. This mixture was stirred thoroughly for 2 minutes, then the layers were separated and the aqueous layer was extracted two times with 500 ml ethyl ether. The aqueous layer was acidified by slow addition of a solution of 230 mL concentrated H2 SO4 in 230 mL H2 O. Vigorous SO2 evolution was noted. The solution was then heated on a steam bath, and a stream of N2 was blown through the hot solution for about 15 minutes until a large amount of crystals formed. The mixture was allowed to stand at room temperature overnight, then cooled to -10° C. for 1/20 hour, then filtered. The crystals were washed two times with H2 O and then dried under vacuum to yield 38.46 g of the title product as a tan powder. 23percent yield. 1 H NMR (300 m Hz, DMSO-d6): δ10.3 (s, 1H). MS (Cl, NH3): 183 M+17, 166 (M+), 165 Base.
Reference：
[1] Patent: US5641789, 1997, A,
6
[ 67-66-3 ]
[ 99-96-7 ]
[ 584-87-2 ]
Reference：
[1] Dalton Transactions, 2012, vol. 41, # 4, p. 1252 - 1258
[2] Journal of Medicinal Chemistry, 1969, vol. 12, # 3, p. 420 - 424
[3] Chemistry - A European Journal, 2009, vol. 15, # 26, p. 6428 - 6434
[4] New Journal of Chemistry, 2017, vol. 41, # 20, p. 11619 - 11625
7
[ 24589-99-9 ]
[ 584-87-2 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2017, vol. 15, # 15, p. 3265 - 3275
General procedure: To a solution of substrates (1a-1q, 0.15 mmol) in trifluoroacetic acid (5 ml), hexamethylenetetramine (0.3 mmol) and cuprous oxide (0.15 mmol) were added. The reaction mixture was refluxed for about 5 h, cooled to room temperature, followed by addition of hydrochloric acid (3 N, 5 ml). After stirring for another 1 h, the solution was concentrated under reduced pressure. The products were purified by silica gel column chromatography (200-300 mesh).
19%
With trifluoroacetic acid; for 2h;Reflux; Inert atmosphere;
3-Formyl-4hydroxybenzoic acid synthesised as stated by theliterature [29] with slight modification (Scheme 2). 4-hydroxylbenzoicacid (22 mmol, 3.0 g) suspended in 10 mL trifluoroaceticacid (TFA) was added drop-wise to hexamethylenetetramine(22 mmol, 3.1 g) dissolved in trifluoroacetic acid and was refluxedby heating under argon atmosphere for 2 h. When cooled, theobtained solution was stirred using 4 M HCl (300 mL) for 3 h. Theyellowish powder was collected and washed with an excess ofbrine. Then it was dissolved in ether and dried. Yield: 3.5 g (19%).1H NMR (DMSO- d6): delta 12.86 (s, 1H, COOH), 11.47 (s, 1H, ArOH),10.29 (s, 1H, CHO), 8.23 (d, 1H, ArH), 8.04 (dd, 1H, ArH), 7.07 (d,1H, ArH).
With methanol; sodium tetrahydroborate; In tetrahydrofuran;
Compound 15 is treated with sodium borohydride in THF and methanol to form compound 16. Compound 16 is then treated first with N-hydroxysuccinimidein the presence of a carbodiimide crosslinking agent such as 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDAC), in DMF to form an activated acid (not shown). The activated acid compound is then reacted with 1-BOC pentanediamine in DMF and in the presence of a base such as triethylamine, to form compound 17. Compound 17 is then reacted with diethyl chlorophosphateand triethylamine in dichloromethane to form compound 18, by the method used to make compound 10 in Scheme 2, above. Compound 18 is then reacted with Deoxofluor in dichloromethane to form compound 19, which in turn, is reacted with trimethylsilyl bromide (TMSB) to form the deprotected amine compound 20. Compound 20 is then conjugated to biotin to form compound 21. The methods tomake compounds 19, 20 and 21 are the same as those used for compounds 12, 13 and 14 in Scheme 2, above.
With methanol; In hexane; toluene; at 0 - 20℃; for 1h;
Example 7b: Preparation of 3-(2,2-Dibromovinyl)-4-hydroxybenzoic acid methyl esterTo a solution of <strong>[584-87-2]3-formyl-4-hydroxybenzoic acid</strong> (1.00 g, 5.9 mmol) in toluene-MeOH (2:1, 30 mL) was added (trirnethylsilyl)diazomethane (2.0 M solution in hexane, 16 mL, 32 mmol) at 0 0C, and the mixture was stirred for 1 h at rt. After evaporating the solvent, the resulting residue was filtrated through a plug of silica gel eluting with 15% EtOAc in hexane to afford 3-formyl-4-hydroxybenzoate as a colorless solid (1.06 g, 99%).
methyl 4-hydroxy-3-(2-phenethyl)benzoate[ No CAS ]
[ 24589-99-9 ]
Yield
Reaction Conditions
Operation in experiment
84%
In methanol;
Reference Example 58 Preparation of methyl 4-hydroxy-3-(2-phenethyl)benzoate A suspension of <strong>[584-87-2]3-formyl-4-hydroxybenzoic acid</strong> (3.9 g, 23.5 mmol) in of methanol (50 ml) was cooled below 0 C. To the suspension was added concentrated H2 SO4 (3 ml) and the reaction was allowed to warm to ambient temperature and stirred for 60 hours. The reaction was heated to reflux for 12 hours, the solvent evaporated and residue subjected to chromatography (eluant: ethyl ether/hexane) to give methyl 3-formyl-4-hydroxybenzoate as a white solid (3.55 g, 84%). NMR (200 MHz, DMSO-d6): delta11.53 (s, 1H), 10.30 (s, 1H), 8.25 (d, 1H), 8.06 (dd, lH), 7.10 (d, 1H), 3.84 (s, 3H).
EXAMPLE 37 3-Formyl-4-methoxybenzoic acid methyl ester 24.8 mL (398 mmol) of methyl iodide were added dropwise to a room temperature suspension of 30.0 g (181 mmol) of <strong>[584-87-2]3-formyl-4-hydroxybenzoic acid</strong> (from Example 36) and 75 g (542 mmol) of K2 CO3 in 250 mL of dry dimethylformamide (DMF). After stirring 4 hours at room temperature, the reaction mixture was diluted with 2 L H2 O and extracted four times with 750 mL ethyl acetate. The ethyl acetate extracts were washed three times with 500 mL H2 O, one time with 300 mL 1N NaOH, one time with 500 mL H2 O, one time with 250 mL brine, and dried over Na2 SO4. Filtration, concentration of filtrate and drying under vacuum gave 20.35 g of pure product as pale yellow needles. 58% yield. 1 H NMR (300 m Hz, CDCl3): delta4.01 (s, 3H); 3.90 (s, 3H).
With hydrogenchloride; sodium hydroxide; sodium hydrogensulfite; In chloroform; water;
EXAMPLE 36 3-Formyl-4-hydroxybenzoic acid 140 g (1.01 mol) of 4-hydroxybenzoic acid were added to a hot solution of 250 g (6.25 mol) of sodium hydroxide in 500 mL H2 O. 150 mL of CHCl3 were cautiously added to the hot solution, and after the foaming had ceased, the reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted to 4 L with H2 O, acidified to pH 1 by addition of about 300 mL of concentrated HCl, and extracted two times with 2 L and then three times with 1 L ethyl ether. The ether extracts were combined and a solution of 750 g sodium bisulfite in 3 L H2 O was added. This mixture was stirred thoroughly for 2 minutes, then the layers were separated and the aqueous layer was extracted two times with 500 ml ethyl ether. The aqueous layer was acidified by slow addition of a solution of 230 mL concentrated H2 SO4 in 230 mL H2 O. Vigorous SO2 evolution was noted. The solution was then heated on a steam bath, and a stream of N2 was blown through the hot solution for about 15 minutes until a large amount of crystals formed. The mixture was allowed to stand at room temperature overnight, then cooled to -10 C. for 1/20 hour, then filtered. The crystals were washed two times with H2 O and then dried under vacuum to yield 38.46 g of the title product as a tan powder. 23% yield. 1 H NMR (300 m Hz, DMSO-d6): delta10.3 (s, 1H). MS (Cl, NH3): 183 M+17, 166 (M+), 165 Base.
Example 1-1 Preparation of 3-formyl-4-hydroxybenzoic acid In a reactor 20g of 4-hydroxybenzoic acid and 36g of sodium hydroxide were loaded, and nitrogen replacement was carried out for 10 minutes at room temperature. To the mixture 100ml of water was added, and the mixture was heated at 70C while being stirred. Next, 20ml of chloroform was added dropwise through a funnel, and precipitate of brown color was obtained. To the mixture 300ml of water was added, and a homogeneous solution was obtained. Then, hydrochloric acid was added until the solution exhibited acidity. As a result, white colored precipitate was obtained. The white precipitate was extracted with diethylether, and the solvent was evaporated. As a result of concentration, brownish white solid was obtained.
Example 1-1 Preparation of 3-formyl-4-hydroxybenzoic Acid In a reactor 20 g of 4-hydroxybenzoic acid and 36 g of sodium hydroxide were loaded, and nitrogen replacement was carried out for 10 minutes at room temperature. To the mixture 100 ml of water was added, and the mixture was heated at 70 C. while being stirred. Next, 20 ml of chloroform was added dropwise through a funnel, and precipitate of brown color was obtained. To the mixture 300 ml of water was added, and a homogeneous solution was obtained. Then, hydrochloric acid was added until the solution exhibited acidity. As a result, white colored precipitate was obtained. The white precipitate was extracted with diethylether, and the solvent was evaporated. As a result of concentration, brownish white solid was obtained.
57
[ 926025-92-5 ]
[ 584-87-2 ]
[ 926028-18-4 ]
Yield
Reaction Conditions
Operation in experiment
25%
With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; diisopropyl-carbodiimide; In tetrahydrofuran; at 0 - 20℃;
Example 22Atert-butyl {3-[(4-fluorobenzyl)(3-formyl-4-hydroxybenzoyl)amino]propyl}carbamate; 1.5 g (5.59 mmol) tert-butyl {3-[(4-fluorobenzyl)amino]propyl}carbamate are dissolved in 15 ml THF. 1.02 g (6.15 mmol) <strong>[584-87-2]3-formyl-4-hydroxybenzoic acid</strong>, 906 mg (6.71 mmol) HOBT and2.24 ml (12.86 mmol) diisopropylethylamine are added. The stirred mixture is cooled to 0-50C and1 ml (6.43 mmol) N,N-diisopropylcarbodiimid are added. The mixture is allowed to warm up to rt and is stirred over night, before poured onto water. The aqueous layer is acidified with IN hydrochloric acid and then extracted three times with ethyl acetate. The combined organic layers are washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by column chromatography on silica gel followed by preparative reverse phase HPLC(water - acetonitrile) to afford 610 mg (25% of th.) of the title compound.LC-MS (method 5): R, = 2.23 min; m/z = 331 (M+H-Boc)+1H-NMR (300 MHz, DMSO-(I6): delta = 11.12 (bs, IH), 10.26 (s, IH), 7.68 (d, IH), 7.57 (dd, IH), 7.49-7.13 (m, 4H), 7.04 (d, IH), 6.70 (m, IH), 4.58 (m, 2H), 3.19 (m, 2H), 2.80 (m, 2H), 1.65 (m, 2H), 1.30 (s, 9H).
With potassium hydrogencarbonate; In N,N-dimethyl-formamide; at 20℃;
To a stirred solution of 3-formyl-4-hydroxybenzoicacid (6.83 g, 41 mmol) and benzyl bromide (5.16g, 41 mmol) in DMF (50 mL) was added potassium hydrogen carbonate (5.00 g, 50mmol). The mixture was stirred at room temperature overnight. The mixture waspoured to iced dilute hydrochloric acid, then triturated with ethyl acetate.The organic phase was washed with brine, and dried over sodium sulfate. Afterevaporation of the solvent, the residue was purified with column chromatography(petroleum/ethyl acetate, 8:1) to afford compound 3 (4.69 g, 45%) as a whitesolid. M.p.: 106-106.5 C. 1H NMR (300 M, CDCl3): d 5.34 (s, 2 H), 7.01 (d, J= 9.17 Hz, 1 H), 7.35-7.45 (m, 5 H), 8.20 (d, J = 9.16 Hz, 1 H), 8.31 (s, 1 H),9.92 (s, 1 H), 11.39 (s, 1 H). MS (EI) (m/e): 256 (M+).
39%
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;
[0646] To a solution of the <strong>[584-87-2]3-formyl-4-hydroxybenzoic acid</strong> (5 g, 43.06 mmol) in DMF (100 mL) was added benzyl bromide (5.1 mL, 43.06 mmol) and NaHCO3 (2.53 g, 43.06 mmol) at room temperature under N2 atmosphere. The mixture was stirred overnight at room temperature under N2 atmosphere. The reaction was diluted with water (100 mL) and extracted with EA (200 mL2). The obtained organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound Int-TG1-1 (2.56 g, 39%). [0647] 1H NMR (400 Hz, CDCl3) delta 11.41 (s, 1H), 9.95 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.23 (dd, J=6.4 Hz, 2.4 Hz, 1H), 7.46-7.35 (m, 5H), 7.04 (d, J=9.2 Hz, 1H), 5.37 (s, 2H).
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