* 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.
benzooxazol-5-carboxylic acid: A mixture of 3-amino-4-hydroxybenzoic acid (500 mg, 3.26 mmol) and trimethyl orthoformate (5 mL) was heated at 65° C. for 2 h under argon. The reaction mixture was cooled to room temperature, filtered and washed with hexanes. The filtrate was concentrated in vacuo to afford the product as a white solid (78 mg, 15percent): 1H NMR (500 MHz, CDCl3): δ 8.57 (d, J=1.5 Hz, 1H), 8.20 (dd, J=8.4, 1.8 Hz, 1H), 8.20 (s, 1H), 7.67 (d, J=9.0 Hz, 1H). MS (M+H, 164).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 24, p. 8219 - 8248
[2] Patent: US2005/84506, 2005, A1, . Location in patent: Page/Page column 40
[3] Patent: EP1229027, 2002, A1, . Location in patent: Page 18
[4] Patent: EP1229028, 2002, A1, . Location in patent: Page 18
[5] Patent: EP1229037, 2002, A1, . Location in patent: Page 17
2
[ 122-51-0 ]
[ 1571-72-8 ]
[ 15112-41-1 ]
Yield
Reaction Conditions
Operation in experiment
92%
for 3 h; Reflux
A mixture of 3-amino-4-hydroxybenzoic acid (8.0 g, 1.0 eq) and 60 mL CH(OEt)3 was heated to reflux for 3 h, and then cooled to rt,. The remaining CH(OEt)3 was removed under reduced pressure to give the desired product (7.8 g, 92percent). 'H NMR (400 MHz, DMSO-c ) δ 13.00 (brs, 1H), 8.85 (s, 1H), 8.30 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H).
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 2, p. 521 - 533
6
[ 1445-45-0 ]
[ 1571-72-8 ]
[ 90322-32-0 ]
Yield
Reaction Conditions
Operation in experiment
80%
at 65℃; for 5 h;
2-methyl benzooxazol-5-carboxylic acid: A mixture of 3-amino-4-hydroxybenzoic acid (1.5 g, 9.79 mmol) and trimethyl orthoacetate (15 mL, large excess) was heated at 65° C. for 5 hrs under argon. The reaction mixture was cooled to room temperature, filtered, washed with hexanes. The filtrate was concentrated in vacuo to afford the product as a yellow solid (1.4 g, 80percent): 1H NMR (500 MHz, CD3OD) δ 8.26 (d, J=1.7 Hz, 1H), 8.07 (dd, J=8.5, 1.6 Hz, 1H), 7.67 (d, J=8.2 Hz, 1H), 2.67 (s, 1H); MS(APCI, M+1): 178.10.
Stage #1: With sodium hydrogencarbonate In chloroform; water at 0 - 20℃; for 48.83 h; Stage #2: With hydrogenchloride In chloroform; water
3-amino-4-hydroxybenzoic acid (4.0 g, 26.0 mmol) was dissolved in 168 mL of chloroform. 92 mL of saturated sodium bicarbonate solution was added and the new bi-phase mixture was stirred vigorously and cooled to 0° C. using an ice bath. Bromoacetylbromide (3.42 mL, 39 mmol) was added drop-wise. Fifteen minutes later the solution was removed from the ice bath and maintained at room temperature for 48 hours. HPLC (Eclipse XDB-C18, 4.6.x.250 mm, 5 micron, 1-99percent CH3CN/H2O with 0.1percent trifluoroacetic acid) chromatogram indicated that all of the starting material was gone and a new peak (Rt=3.7 min) had formed. The reaction mixture was quenched using concentrated hydrochloric acid until the solution reached a pH of 2. The organic layer was separated and the aqueous phase was extracted with 100 mL of chloroform. The combined organic layers were treated with 75 mL of 10percent hydrochloric acid solution and separated once again. The organic phase was dried over Na2SO4, filtered and concentrated to give 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (4.8 g, 24.7 mmol, 95percent) as an off-white amorphous solid. MS (ES) m/e 194 [M+H]+.
With potassium carbonate In tetrahydrofuran; water at 20℃; for 3 h;
To a solution of 3-amino-4-hydroxybenzoic acid (10 g, 66 mmol) in THF (25 mL) were added potassium carbonate (14.0 g, 100 mmol) and water (50 mL) and chloroacetyl chloride (8.0 mL, 100 mL) was added. The mixture was stirred at room temperature for 3 hrs. Concentrated hydrochloric acid was added to acidify the reaction solution. The precipitated crystals were collected by filtration. The obtained crystals were washed with water and diisopropyl ether and vacuum dried to give the title compound as brown crystals (9.4 g, yield 74percent). H NMR (300 MHz, DMSO-d6) 8 ppm: 4.65 (s, 2 H), 7.00 (d, J = 8.4 Hz, 1 H), 7.48-7. 52 (m, 2 H), 10.87 (s, 1 H), 12.77 (br, 1 H).
A solution (0.2 M) of acetyl chloride (3.0 eq. ) in MeOH was prepared at 0 °C then allowed to warm to 20 °C. 3-amino-4-hydroxybenzoic acid (1.0 eq. ) was added and the mixture was heated under reflux for 12 h then cooled and concentrated in VACUO. The residue was triturated with H20 and dried to afford the title compound (99percent) as a solid. H NMR (300 MHz, DMSO-D6, 300 K) 8 3.83 (s, 3H), 7.15 (d, J 8.5 Hz, 1H), 7.79 (dd, J2. 1, 8. 5 Hz, 1H), 7.93 (d, J 2. 1 Hz, 1H), 11.65 (br s, 1H).
98%
at 0 - 20℃; for 24 h;
Hydrogen chloride (1.25M in Methanol, lOOmL) was placed in a reactor at 0°C. Then 3- amino-4-hydroxybenzoic acid (5g, 0.032mo1) was added in portions. The reaction mixture was stirred 5 minutes at 0°C and 24 hours at room temperature. The solvent was removed under reduced pressure and the crude was partitioned between ethyl acetate and satu-rated bicarbonate. The organics layer were combined, dried, filtered and the solvent was removed under reduced pressure to obtain the title compound as a solid (5.38g, 98percent), which was used in the next step without further purification.LRMS (m/z): 168 (M+1)+
57%
at 55℃; for 48 h;
3-Amino-4-hydroxybenzoic acid (0.40 g, 2.61 mmol) was dissolved in anhydrous methanol (10 ml) and treated with TMSCl (0.75 ml, 5.94 mmol). The mixture was stirred at 55 °C for 2 days. After evaporation of the solvent, the obtained residue was purified by column chromatography on silica gel eluting with ethyl acetate (yield: 0.25 g, 1.50 mmol, 57percent, white solid). 0.20 g of the obtained methyl 3-amino-4-hydroxybenzoate, dissolved in anhydrous THF (10 ml), was mixed with TCDI (0.26 g, 1.46 mmol) under an inert atmosphere. The solution was stirred overnight at room temperature. After evaporation of the solvent the residue was treated with water (15 ml) and extracted with ethyl acetate (3 .x. 15 ml). The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The remaining crude product was recrystallized from ethanol yielding 0.22 g (1.05 mmol, 88percent) of methyl 2-sulfanylbenzo[d]oxazole-5-carboxylate (21) as a brown solid. Mp: 203-205 °C.
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 5, p. 1314 - 1317
[2] Patent: WO2004/87714, 2004, A1, . Location in patent: Page 53
[3] Patent: WO2014/95920, 2014, A1, . Location in patent: Page/Page column 66
[4] European Journal of Organic Chemistry, 2011, # 1, p. 100 - 109
[5] Heterocycles, 2011, vol. 83, # 12, p. 2851 - 2856
[6] MedChemComm, 2014, vol. 5, # 4, p. 474 - 488
[7] European Journal of Medicinal Chemistry, 2004, vol. 39, # 3, p. 291 - 298
[8] European Journal of Medicinal Chemistry, 2011, vol. 46, # 9, p. 4419 - 4429
[9] CrystEngComm, 2011, vol. 13, # 24, p. 7207 - 7211
[10] Justus Liebigs Annalen der Chemie, 1900, vol. 311, p. 55
[11] Patent: DE97333, , ,
[12] Xenobiotica, 1995, vol. 25, # 5, p. 501 - 510
[13] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 14, p. 6724 - 6731
[14] Patent: US2009/176775, 2009, A1, . Location in patent: Page/Page column 29-30
[15] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 14, p. 4001 - 4013
12
[ 75-36-5 ]
[ 1571-72-8 ]
[ 536-25-4 ]
Yield
Reaction Conditions
Operation in experiment
99%
at 0 - 20℃; for 12 h; Heating / reflux
A solution (0.2 M) of acetyl chloride (3.0 eq) in MeOH was prepared at 0 °C then allowed to warm to 20 °C. 3-amino-4-hydroxybenzoic acid (1.0 eq) was added and the mixture was heated under reflux for 12 h then cooled and concentrated in vacuo. The residue was triturated with H20 and dried to afford the title compound (99 percent) as a solid. 'H NMR (300 MHz, DMSO-d6) S 3.83 (s, 3H), 7.15 (d, J 8. 5 Hz, 1H), 7.79 (dd, J 2. 1, J 8.5 Hz, 1H), 7.93 (d, J 2.1 Hz, 1H), 11.65 (br s, 1H)
3-(dimethylamino)-4-hvdroxybenzoic acid: 3-Amino-4-hydroxybenzoic acid (459mg, 3 mmol) was dissolved in methanol (12ml) and toluene (36ml) was added. A 2.0M solution of (trimethylsilyl)diazomethane in hexanes (1.5ml, 3.0 mmol) was added dropwise and the mixture stirred for 0.5h. The reaction mixture was concentrated under vacuum and the residue purified by flash column chromatography on silica to afford methyl 3-amino-4-hydroxybenzoate as a pink solid (254mg, 51percent).A buffer solution at pH 5.5 was prepared by the addition of acetic acid to a 1M aqueous sodium acetate solution. Methyl 3-amino-4-hydroxybenzoate (254mg, 1.5 mmol) was dissolved in a mixture of buffer (1ml) and methanol (2ml). Formaldehyde solution (37percent by weight in water; 0.75ml, lOmmol) was added, the mixture stirred for 15 minutes, and then sodium cyanoborohydride (283mg, 4.5mmol) was added portionwise. The reaction mixture was stirred for an additional 0.5h and then concentrated. The residual oil was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with water, brine and dried over sodium sulfate. The solvent was removed and the crude product was purified by flash column chromatography on silica to give methyl 3-dimethylamino-4-hydroxybenzoate as a yellow gum (213mg, 73percent).To a solution of methyl 3-dimethylamino-4-hydroxybenzoate (210mg, 1.1 mmol) in 1,4-dioxane (2ml) was added 1 M LiOH (aq) (4mmol). After stirring for 4Oh, the mixture was acidified to pH 2 by addition of 1 M HCI (aq). The mixture was partitioned between water and ethyl acetate, and the aqueous layer was lyophilized to give a mixture of sodium chloride and 3-dimethylamino-4- hydroxybenzoic acid as a brown semi-solid (378mg). The crude material was used in the subsequent reaction.
51%
for 0.5 h;
4.14 3-(dimethylamino)-4-hvdroxybenzoic acid; 3-Amino-4-hydroxybenzoic acid (459 mg, 3 mmol) was dissolved in methanol (12 ml) and toluene (36 ml) was added. A 2.0 M solution of (trimethylsilyl)diazomethane in hexanes (1.5 ml, 3.0 mmol) was added dropwise and the mixture stirred for 0.5h. The reaction mixture was concentrated under vacuum and the residue purified by flash column chromatography on silica to afford methyl 3-amino-4-hydroxybenzoate as a pink solid (254 mg, 51 percent).
Reference：
[1] Archiv der Pharmazie, 2008, vol. 341, # 6, p. 386 - 392
15
[ 616-82-0 ]
[ 1571-72-8 ]
Yield
Reaction Conditions
Operation in experiment
98%
at 0℃; for 1 h; Reflux
To tin(II) chloride (207 mg, 1.09 mmol), 12N-HCl (1.5 mL) and 4-hydroxy-3-nitrobenzoic acid (100 mg, 0.55 mmol) were added successively at 0°C, and the reaction mixture was refluxed for 1 h. After addition of water, the reaction mixture was adjusted to pH 1 using 2N NaOH. The precipitates obtained were filtered and washed with water. The filtrate was concentrated in vacuo, and methanol was added to the residue. The formed precipitate was filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using methylene chloride and methanol (5:1) as eluent to obtain compound 1 (82 mg, 98percent) as a brown solid [1H NMR (500 MHz, DMSO-d6) δ 11.30 (brs, 1 H), 9.42 (brs, 3 H), 7.79 (s, 1 H), 7.60 (d, 1 H, J = 8.0 Hz), 7.07 (d, 1 H, J = 8.0 Hz)].
98%
With hydrogenchloride; tin(ll) chloride In tetrahydrofuran; water at 0℃; for 1 h;
Concentrated hydrochloric acid (12N-HCl, 1.5 mL)Tin tailored to 0 (II) chloride (tin (II) chloride, 207 mg, 1.09 mmol)After the addition to the,4-hydroxy-3-nitrobenzoic acid (100 mg, 0.55 mmol)And the mixture was stirred under reflux for 1 hour. Then,Water was added and the pH was adjusted to 1 by addition of 2N-NaOH.The resulting solid was filtered, washed with water, and the filtrate was concentrated under reduced pressure,Methanol was added and filtered again.The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methylene chloride: methanol = 5: 1) to obtain Compound 57 (82 mg, 98percent) as a brown solid.
95%
With palladium on activated charcoal; hydrogen In methanol at 20℃;
A mixture of 4-hydroxy-3-nitrobenzoic acid (10 g, 1.0 eq) and 2 g Pd/C in 100 mL MeOH was stirred at rt under H2 (1 atm) overnight, and then filtered. The filtrate was concentrated under reduced pressure to afford the desired product (8.0 g, 95percent). :H NMR (400 MHz, DMSO-c ) δ 10.00 (brs, 1H), 7.19 (s, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 4, p. 684 - 688
[2] Patent: KR2018/117068, 2018, A, . Location in patent: Paragraph 0084; 0283; 0286; 0288; 0289
[3] Patent: WO2013/97773, 2013, A1, . Location in patent: Paragraph 0267
[4] Chemische Berichte, 1896, vol. 29, p. 1758
[5] Zeitschrift fuer Chemie, 1866, p. 648
[6] Journal of the Chemical Society, 1935, p. 196,199
[7] Journal of Organic Chemistry, 1989, vol. 54, # 15, p. 3740 - 3744
16
[ 861550-32-5 ]
[ 1571-72-8 ]
Reference：
[1] Journal of the American Chemical Society, 1929, vol. 51, p. 508
17
[ 91004-38-5 ]
[ 1571-72-8 ]
Reference：
[1] Journal of the American Chemical Society, 1953, vol. 75, p. 6237
18
[ 23685-91-8 ]
[ 1571-72-8 ]
Reference：
[1] Journal of the American Chemical Society, 1953, vol. 75, p. 2770
19
[ 94-26-8 ]
[ 1571-72-8 ]
Reference：
[1] Journal of the American Chemical Society, 1953, vol. 75, p. 2770
20
[ 96-99-1 ]
[ 1571-72-8 ]
Reference：
[1] Patent: WO2013/97773, 2013, A1,
21
[ 99-96-7 ]
[ 1571-72-8 ]
Reference：
[1] Journal of the Chemical Society, 1935, p. 196,199
[2] Chemische Berichte, 1896, vol. 29, p. 1758
22
[ 536-25-4 ]
[ 1571-72-8 ]
Reference：
[1] Journal of the Society of Chemical Industry, London, 1945, vol. 64, p. 212,214
23
[ 13052-92-1 ]
[ 1571-72-8 ]
Reference：
[1] Chemische Berichte, 1897, vol. 30, p. 991
24
[ 99-42-3 ]
[ 1571-72-8 ]
Reference：
[1] Journal of the Society of Chemical Industry, London, 1945, vol. 64, p. 212,214
25
[ 19013-10-6 ]
[ 1571-72-8 ]
Reference：
[1] Chemische Berichte, 1897, vol. 30, p. 991
26
[ 140648-39-1 ]
[ 63-74-1 ]
[ 1571-72-8 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1992, vol. 57, # 2, p. 268 - 275
With hydrogenchloride; tin(ll) chloride; at 0℃; for 1h;Reflux;
To tin(II) chloride (207 mg, 1.09 mmol), 12N-HCl (1.5 mL) and <strong>[616-82-0]4-hydroxy-3-nitrobenzoic acid</strong> (100 mg, 0.55 mmol) were added successively at 0C, and the reaction mixture was refluxed for 1 h. After addition of water, the reaction mixture was adjusted to pH 1 using 2N NaOH. The precipitates obtained were filtered and washed with water. The filtrate was concentrated in vacuo, and methanol was added to the residue. The formed precipitate was filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using methylene chloride and methanol (5:1) as eluent to obtain compound 1 (82 mg, 98%) as a brown solid [1H NMR (500 MHz, DMSO-d6) delta 11.30 (brs, 1 H), 9.42 (brs, 3 H), 7.79 (s, 1 H), 7.60 (d, 1 H, J = 8.0 Hz), 7.07 (d, 1 H, J = 8.0 Hz)].
98%
With hydrogenchloride; tin(ll) chloride; In tetrahydrofuran; water; at 0℃; for 1h;
Concentrated hydrochloric acid (12N-HCl, 1.5 mL)Tin tailored to 0 (II) chloride (tin (II) chloride, 207 mg, 1.09 mmol)After the addition to the,<strong>[616-82-0]4-hydroxy-3-nitrobenzoic acid</strong> (100 mg, 0.55 mmol)And the mixture was stirred under reflux for 1 hour. Then,Water was added and the pH was adjusted to 1 by addition of 2N-NaOH.The resulting solid was filtered, washed with water, and the filtrate was concentrated under reduced pressure,Methanol was added and filtered again.The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methylene chloride: methanol = 5: 1) to obtain Compound 57 (82 mg, 98%) as a brown solid.
98%
With hydrogenchloride; tin(ll) chloride; In water; at 0℃; for 1h;Reflux;
1) [3-Amino-4-hydroxybenzoic acid] (57) Concentrated hydrochloric acid (12N-HCl, 1.5 mL) was added to tin (II) chloride (207 mg, 1.09 mmol) at 0 C, <strong>[616-82-0]4-hydroxy-3-nitrobenzoic acid</strong> (100 mg, 0.55 mmol) was added thereto, and the mixture was stirred under reflux for 1 hour. Then, water was added and 2N-NaOH was added to adjust to pH 1. The resulting solid was filtered, washed with water, the filtrate was concentrated under reduced pressure, methanol was added and the mixture was filtered again. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (methylene chloride:methanol = 5:1) to obtain Compound 57 (82 mg, 98%) as a brown solid. 1H NMR (500 MHz, DMSO-d6) delta 11.30 (brs, 1 H), 9.42 (brs, 3 H), 7.79 (s, 1 H), 7.60 (d, 1 H, J = 8.0 Hz), 7.07 (d, 1 H, J = 8.0 Hz).
95%
With palladium on activated charcoal; hydrogen; In methanol; at 20℃; under 760.051 Torr;
A mixture of <strong>[616-82-0]4-hydroxy-3-nitrobenzoic acid</strong> (10 g, 1.0 eq) and 2 g Pd/C in 100 mL MeOH was stirred at rt under H2 (1 atm) overnight, and then filtered. The filtrate was concentrated under reduced pressure to afford the desired product (8.0 g, 95%). :H NMR (400 MHz, DMSO-c ) delta 10.00 (brs, 1H), 7.19 (s, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H).
With sulfuric acid; at 0℃; for 12h;Inert atmosphere; Reflux;
To a stirred solution of 3-amino-4-hydroxybenzoic acid (9) (1.0 g, 6.53 mmol) in EtOH (10 mL) was added concentrated H2SO4 (3.0 mL) at 0C under nitrogen atmosphere. After completion of addition, the reaction mixture was warmed and then refluxed for 12 h. After completion of the reaction, the reaction mixture was cooled to room temperature, poured into crushed ice and neutralized with aqueous saturated NaHCO3 solution. The reaction mixture was extracted with EtOAc (3 × 45 mL). The combined organic layer was washed with H2O (2 × 20 mL) and brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography (EtOAc:hexane = 1:2) to afford the pure product 10 (1.01 g, 85%) as pale orange color solid; mp 96-98C; Rf = 0.33 (EtOAc/hexane = 1/2); 1H NMR (300 MHz, CDCl3) delta 7.44 (1H, d, J = 1.8 Hz), 7.41 (1H, dd, J = 7.8, 1.8 Hz), 6.75 (1H, d, J = 7.8 Hz), 4.32 (2H, q, J = 7.2 Hz) 1.37 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) delta 167.0, 148.6, 134.1, 123.3, 122.2, 118.2, 114.6, 61.0, 14.7.
85%
With sulfuric acid; at 0℃; for 12h;Inert atmosphere; Reflux;
3-amino-4-hydroxybenzoic acid (compound 9) (1.0 g, 6.53 mmol) was added to EtOH (10 mL) and stirred at 0 C, Concentrated H2SO4 (3.0 mL) was added under nitrogen atmosphere. after the reaction was completed, the mixture was warmed and refluxed for 12 hours. After completion of the reaction, the mixture was cooled to room temperature, placed in crushed ice, and neutralized with saturated aqueous NaHCO3 solution. The reaction mixture was extracted with EtOAc (3 x 45 mL).The mixed organic solvent layer was washed with H2O (2 × 20 mL), brine (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude compound was purified by column chromatography (EtOAc: Hexane = 1: 2) to give a pale orange solid compound 10 (1.01 g, 85%). Melting point 96-98 C;
85%
With sulfuric acid; at 0℃; for 12h;Reflux; Inert atmosphere;
3-Amino-4-hydroxybenzoic acid (Compound 9) (1.0 g, 6.53 mmol) was added to EtOH (10 mL), and concentrated H2SO4 (3.0 mL) was added to a stirred solution under a nitrogen atmosphere at 0 C.After the reaction was completed, the mixture was warmed and refluxed for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, placed in crushed ice, and neutralized with saturated aqueous NaHCO 3 solution. The reaction mixture was extracted with EtOAc (3 x 45 mL). The mixed organic solvent layer was washed with H 2 O (2 × 20 mL), brine (20 mL), dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The crude compound was purified by column chromatography (EtOAc: Hexane = 1: 2) to give a pale orange solid compound 10 (1.01 g, 85%). Melting point 96-98 C.
85%
With sulfuric acid; at 0℃; for 12h;Inert atmosphere; Reflux;
3-Amino-4-hydroxybenzoic acid (Compound 9) (1.0 g, 6.53 mmol) was added to EtOH (10 mL), and concentrated H2SO4 (3.0 mL) was added to a stirred solution under a nitrogen atmosphere at 0 C. After the reaction was completed, the mixture was warmed and refluxed for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, placed in crushed ice, and neutralized with saturated aqueous NaHCO 3 solution. The reaction mixture was extracted with EtOAc (3 x 45 mL). The mixed organic solvent layer was washed with H 2 O (2 × 20 mL), brine (20 mL), dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The crude compound was purified by column chromatography (EtOAc: Hexane = 1: 2) to give a pale orange solid compound 10 (1.01 g, 85%).
3-Amino-4-hydroxybenzoic acid (10.00 g; 65.30 mmol) was dissolved in cone, hydrochloric acid (100 mL, and a solution of sodium nitrite (4.73 g; 68.56 mmol) in water (30 mL) was added dropwise at 00C. The reaction mixture was stirred at 0C for 30 min, and subsequently, a solution of potassium iodide (54.20 g; 326.5 mmol) in water (100 mL) was added dropwise at 00C. After stirring at 00C for 30 min, the reaction mixture was heated to 700C until no more gas evolved (ca. 1 hr). The mixture was extracted with ether (3 times 250 mL), and the combined organic layers were washed with 1 M NaHSO3 (100 mL). The aqueous layer was back-extracted with ether (150 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to dryness. The remaining solid was recrystallized from a mixture of methanol (30 mL) and water (70 mL) to yield the product as brown crystals (8.95 g; 52%). 1H-NMR (MeOD): delta 8.34 (d, IH, J=2.2 Hz), 7.85 (dd, IH, J=2.2, 8.6 Hz), 6.86 (d, IH, J=8.6 Hz) ppm. FT-IR (ATR): V 3271, 1679, 1574, 1362, 1288, 1239,1195,767 cm"1.
15%
3-Amino-4-hydroxybenzoic acid (1.0 g, 6.53 mmol) is dissolved in 10 ml HCI cone, and cooled to 0C in an ice bath. Under vigorous stirring NaN02 (540 mg, 7.84 mmol) dissolved in 2 ml of water is added drop wise and the mixture stirred at room temperature for 40 min. The mixture is subsequently filtered through glass-wool into a solution of Kl (10.82 g, 65 mmol) in 14 ml H20. The solution is stirred for 1.5 h diluted with CH2CI2 (150 ml) and washed twice with 50 ml Na2S03 sat., 50 ml water, and 50 ml of brine. The organic layer is dried over MgS04 and the solvent evaporated. The residue is purified by flash column chromatography (cyclohexane:ethyl acetate 10:1) to yield 250 mg (0.95 mmol, 15%) of the title compound as a colorless solid. ESI-MS 265.3 [M+H]+.
benzooxazol-5-carboxylic acid: A mixture of 3-amino-4-hydroxybenzoic acid (500 mg, 3.26 mmol) and trimethyl orthoformate (5 mL) was heated at 65 C. for 2 h under argon. The reaction mixture was cooled to room temperature, filtered and washed with hexanes. The filtrate was concentrated in vacuo to afford the product as a white solid (78 mg, 15%): 1H NMR (500 MHz, CDCl3): delta 8.57 (d, J=1.5 Hz, 1H), 8.20 (dd, J=8.4, 1.8 Hz, 1H), 8.20 (s, 1H), 7.67 (d, J=9.0 Hz, 1H). MS (M+H, 164).
11
A solution of 3-amino-4-hydroxybenzoic acid (0.142 g, 0.927 mmol) and the acyl chloride prepared from acid 74 (in 84% yield) (0.259 g, 1.019 mmol) in DCM (5 ml) and pyridine (6 ml) was stirred at room temperature for under at for 24 h. The solvent was removed under reduced pressure. HCl (aq, 4 M, 6 ml) was added and the precipitate was filtered, washed with water (10 ml) and dried under vacuum. Trituration with methanol (15 ml) and acetone (10 ml) afforded 75 as an off-white solid (0.084 g, 0.230 mml, 25%). 1H NMR (400 MHz5 DMSO-d6) δ 3.92 (3H, s), 7.00 (IH, d, J 8.4 Hz), 7.67 (IH, d, J 8.8 Hz), 8.04- 8.10 (2H, m), 8.16-8.27 (2H, m ), 8.33 (IH, s), 8.70-8.66 (2H, m), 9.80 (IH, s), 10.55 (IH, bs). 13C NMR (100 MHz, DMSOd6) δ 53.09, 116.18, 122.59, 125.94, 126.45, 126.26, 126.80, 128.45, 128.48, 129.19, 130.35, 130.40, 130.93, 134.13, 134.66, 134.94, 154.61, 165.85, 166.84, 167.73. vmax (solid^cm'1) 3059, 1716, 1666, 1592, 1541, 1283, 1247, 1132, 759.
3-amino-4-hydroxybenzoic acid (4.0 g, 26.0 mmol) was dissolved in 168 mL of chloroform. 92 mL of saturated sodium bicarbonate solution was added and the new bi-phase mixture was stirred vigorously and cooled to 0 C. using an ice bath. Bromoacetylbromide (3.42 mL, 39 mmol) was added drop-wise. Fifteen minutes later the solution was removed from the ice bath and maintained at room temperature for 48 hours. HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) chromatogram indicated that all of the starting material was gone and a new peak (Rt=3.7 min) had formed. The reaction mixture was quenched using concentrated hydrochloric acid until the solution reached a pH of 2. The organic layer was separated and the aqueous phase was extracted with 100 mL of chloroform. The combined organic layers were treated with 75 mL of 10% hydrochloric acid solution and separated once again. The organic phase was dried over Na2SO4, filtered and concentrated to give 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (4.8 g, 24.7 mmol, 95%) as an off-white amorphous solid. MS (ES) m/e 194 [M+H]+.
With potassium carbonate; In tetrahydrofuran; water; at 20℃; for 3h;
To a solution of 3-amino-4-hydroxybenzoic acid (10 g, 66 mmol) in THF (25 mL) were added potassium carbonate (14.0 g, 100 mmol) and water (50 mL) and chloroacetyl chloride (8.0 mL, 100 mL) was added. The mixture was stirred at room temperature for 3 hrs. Concentrated hydrochloric acid was added to acidify the reaction solution. The precipitated crystals were collected by filtration. The obtained crystals were washed with water and diisopropyl ether and vacuum dried to give the title compound as brown crystals (9.4 g, yield 74%). H NMR (300 MHz, DMSO-d6) 8 ppm: 4.65 (s, 2 H), 7.00 (d, J = 8.4 Hz, 1 H), 7.48-7. 52 (m, 2 H), 10.87 (s, 1 H), 12.77 (br, 1 H).
With potassium carbonate; In tetrahydrofuran; water; at 0 - 25℃;Inert atmosphere;
To a solution of 3-amino-4-hydroxybenzoic acid (10.0 g, 65.3 mmol) and potassium carbonate (10.83 g, 78.36 mmol) in THF (15 mL) and water (30 mL) cooled at 0C was added chloroacetyl chloride (8.85 g, 78.36 mmol) and the reaction mixture was then stirred at 25 C overnight. The reaction was quenched using concentrated hydrochloric acid until pH of 2. The solid precipitate was filtered off, washed with water (50 mL) and MeOH (5 mL) to give the crude title compound (8.6 g, 65%) as light yellow solid. MS: 194.1 (M+H+).
With potassium carbonate; In tetrahydrofuran; water; at 0 - 25℃;Inert atmosphere;
To a solution of 3-amino-4-hydroxybenzoic acid (10.0 g, 65.3 mmol) and potassium carbonate (10.83 g, 78.36 mmol) in THF (15 mL) and water (30 mL) cooled at 0 C was added chloroacetyl chloride (8.85 g, 78.36 mmol) and the reaction mixture was then stirred at 25 C overnight. The reaction was quenched using concentrated hydrochloric acid until pH of 2. The solid precipitate was filtered off, washed with water (50 mL) and MeOH (5 mL) to give the crude title compound (8.6 g, 65%) as light yellow solid. MS (ESI): m/z = 194.1 [M+H]+.
2-methyl benzooxazol-5-carboxylic acid: A mixture of 3-amino-4-hydroxybenzoic acid (1.5 g, 9.79 mmol) and trimethyl orthoacetate (15 mL, large excess) was heated at 65° C. for 5 hrs under argon. The reaction mixture was cooled to room temperature, filtered, washed with hexanes. The filtrate was concentrated in vacuo to afford the product as a yellow solid (1.4 g, 80percent): 1H NMR (500 MHz, CD3OD) delta 8.26 (d, J=1.7 Hz, 1H), 8.07 (dd, J=8.5, 1.6 Hz, 1H), 7.67 (d, J=8.2 Hz, 1H), 2.67 (s, 1H); MS(APCI, M+1): 178.10.
Stage #1: 3-amino-4-hydroxybenzoic acid With sodium carbonate In water at 45℃;
Stage #2: methyl chloroformate In water at 45 - 80℃;
Stage #3: With hydrogenchloride In water Cooling with ice;
1.1
(1) Benzoxazolin-2-one-5-carboxylic acid 7.8g (0.05mol) of 3-amino-4-hydroxybenzoic acid was weighed, and added under stirring to 45mL aqueous solution in which 8.5g (0.08mol) of anhydrous sodium carbonate was dissolved. The mixture was heated in a 45°C oil bath, and added dropwise with 7.1g of methyl chloroformate. After the addition, the reaction was carried out under stirring for 0.5 h, and then the temperature was elevated to 80°C to keep the reaction overnight. In the next day, an acidification was carried out under cooling in an ice-water bath to pH 2-3, and a solid was filtered out, washed with a small amount of cold water, and dried to obtain a light brown powdery solid 7.5g (83.3%), mp: 329-331°C. 1H-NMR (ppm, d6-DMSO) δ: 7.385(d, 1H,J=8.40Hz, 7-H), 7.566(d,1H,J=1.68Hz, 4-H), 7.74(dd,1H, J1= 8.40Hz,J2=1.68Hz,6-H), 11.868(br-s, 1H,NH), 13.006(br-s, 1H, CO2H).
83.3%
Stage #1: 3-amino-4-hydroxybenzoic acid With sodium carbonate In water Heating;
Stage #2: methyl chloroformate In water at 80℃;
Stage #3: In water Cooling with ice; Acidic conditions;
1.1
(1) Benzoxazolin-2-one-5-carboxylic acid 7.8 g (0.05 mol) of 3-amino-4-hydroxybenzoic acid was weighed, and added under stirring to 45 mL aqueous solution in which 8.5 g (0.08 mol) of anhydrous sodium carbonate was dissolved. The mixture was heated in a 45° C. oil bath, and added dropwise with 7.1 g of methyl chloroformate. After the addition, the reaction was carried out under stirring for 0.5 h, and then the temperature was elevated to 80° C. to keep the reaction overnight. In the next day, an acidification was carried out under cooling in an ice-water bath to pH 2-3, and a solid was filtered out, washed with a small amount of cold water, and dried to obtain a light brown powdery solid 7.5 g (83.3%), mp: 329-331° C. 1H-NMR (ppm, d6-DMSO) δ: 7.385 (d, 1H, J=8.40 Hz, 7-H), 7.566 (d, 1H, J=1.68 Hz, 4-H), 7.74 (dd, 1H, J1=8.40 Hz, J2=1.68 Hz, 6-H), 11.868 (br-s, 1H, NH), 13.006 (br-s, 1H, CO2H).
83.3%
With sodium carbonate In water at 45 - 80℃;
1.1 (1) benzoxazolin-2-one-5-carboxylic acid:
Weigh 7.8 g (0.05 mol) of 3-amino-4-hydroxybenzoic acid,Add to a solution of 8.5 g (0.08 mol) of anhydrous sodium carbonate in 45 mL of water with stirring.Heating in a 45 ° C oil bath, adding 7.1 g of methyl chloroformate dropwise, plus,Stirring was continued for half an hour and then allowed to warm to 80 ° C overnight. The next day,Acidified to pH 2~3 under ice water cooling, filtered solids, washed with a small amount of cold water.Drying a light brown powdery solid 7.5 g (83.3%),
To a stirred suspension of 3-amino-4-hydroxybenzoic acid (2.0 g, 13 mmol) in 6 M HCl (aq.) (10 mL) was added acrylaldehyde (1.1 g, 20 mmol) dropwise. The reaction was stirred at 100 C. for 2 h. The reaction was cooled to rt, conc. NH4OH was added until pH 9, and the reaction mixture was filtered to remove the solid. The filtrate was acidified with glacial AcOH to pH 4-5, and the solid was collected by vacuum filtration. The solid was suspended in 1:1 acetone/water (30 mL), and the product was collected by vacuum filtration to provide the desired acid (1.5 g) as a light brown solid.
The Schiff-base was prepared by condensation reaction betweenan aldehyde and a primary amine. An ethanolic solution(10 mL) of 3-amino-4-hydroxy benzoic acid (10 mmol) was addeddropwise to an ethanolic solution (15 mL) of 2,6-diformyl-4-methyl-phenol (10 mmol) with constant stirring. The resultantmixture was refluxed for 6 h and the solvent was reduced by rotaryevaporator. The solid mass thus obtained was recrystallised severaltimes from dry ethanol to get the pure ligand. 1H NMR (300 MHz, DMSO-d6, 25 C) d = 15.107 (s, 1H, COOH),14.728 (br, 1H, OHa), 10.395 (s, 1H, CHO), 10.293 (br, 1H, OHb),9.142 (s, 1H, N(at)CH), 7.894 (s, 1H, Hc), 7.803, 7.809 (sb, He), 7.768(s, 1H, Hd), 7.687, 7.680 (d, 1H, Hf), 7.018, 7.000 (d, 1H, Hg), d2.221 (s, 3H, CH3).FT-IR m (KBr) [cm 1] = 1683(s), 1634(s), 1598(s), 1462(s).ESI-MS m/z = 300.2496 (calculated for 12C16H13NO5 + H+:300.2859).
The Schiff-base was prepared by condensation reaction betweenan aldehyde and a primary amine. An ethanolic solution(10 mL) of 3-amino-4-hydroxy benzoic acid (10 mmol) was addeddropwise to an ethanolic solution (15 mL) of 2,6-diformyl-4-methyl-phenol (10 mmol) with constant stirring. The resultantmixture was refluxed for 6 h and the solvent was reduced by rotaryevaporator. The solid mass thus obtained was recrystallised severaltimes from dry ethanol to get the pure ligand. It was prepared by adopting similar procedure as for L1 where the aldehyde used was 2,6-diformyl-4-tert-butyl-phenol instead of2,6-diformyl-4-methyl-phenol.Yield: 72%. Anal. Calcd. for C19H19NO5: C, 66.85; H, 5.61; N, 4.10.Found: C, 66.83; H, 5.60; N, 4.08%.1H NMR (300 MHz, DMSO-d6, 25 C) d = 15.109 (s, 1H, COOH),14.734 (br, 1H, OHa), 10.389 (s, 1H, CHO), 10.287 (br, 1H, OHb),9.026 (s, 1H, NH), 7.968 (s, 1H, Hc), 7.812, 7.809 (sb, 1H, He),7.768 (s, 1H, Hd), 7.674, 7.650 (d, 1H, Hf), 6.987, 6.965 (d, 1H, Hg),1.152 (s, 9H, C(CH3)3).FT IR m (KBr) [cm 1] = 1685(s), 1623(s), 1516(s), 1460(s).ESI-MS m/z = 342.3321 (calculated for 12C19H19NO5 + H+:342.3659).
General procedure: The Schiff-base was prepared by condensation reaction betweenan aldehyde and a primary amine. An ethanolic solution(10 mL) of 3-amino-4-hydroxy benzoic acid (10 mmol) was addeddropwise to an ethanolic solution (15 mL) of 2,6-diformyl-4-methyl-phenol (10 mmol) with constant stirring. The resultantmixture was refluxed for 6 h and the solvent was reduced by rotaryevaporator. The solid mass thus obtained was recrystallised severaltimes from dry ethanol to get the pure ligand. 1H NMR (300 MHz, DMSO-d6, 25 C) d = 15.105 (s, 1H, COOH),14.730 (br, 1H, OHa), 10.392 (s, 1H, CHO), 10.285 (br, 1H, OHb),9.049 (s, 1H, NH), 7.995 (s, 1H, Hc), 7.806, 7.804 (sb, He), 7.767 (s,1H, Hd), 7.561, 7.558 (d, Hf), 7.018, 7.001 (d, Hg).FT IR m (KBr) [cm 1] = 1680(s), 1629(s), 1528(s), 1384(s).ESI-MS m/z = 320.7762 (calculated for 12C15H10NO5Cl + H+:320.7049).
A mixture of 3-amino-4-hydroxybenzoic acid (8.0 g, 1.0 eq) and 60 mL CH(OEt)3 was heated to reflux for 3 h, and then cooled to rt,. The remaining CH(OEt)3 was removed under reduced pressure to give the desired product (7.8 g, 92%). 'H NMR (400 MHz, DMSO-c ) delta 13.00 (brs, 1H), 8.85 (s, 1H), 8.30 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H).
With sodium pyrophosphate; ATP-dependent adenylase AsuA2, 51 kDa; tris-(2-carboxyethyl)-phosphine hydrochloride; magnesium chloride; In aq. buffer; at 25℃; for 0.333333h;pH 7.5;Enzymatic reaction;Kinetics;
The assays were performed in 100mul of reaction mixture that contains 50mM Tris buffer (pH 7.5), 2mM MgCl2, 5mM <strong>[56-65-5]ATP</strong>, 1mM Na4PPi (containing 250-400 kcpm of Na4[32P]PPi), 1mM TCEP, 5mM aromatic substrate, and 1muM AsuA2 at 25C. Reactions were initiated by adding AsuA2 and quenched with 500mul of a charcoal suspension (100mM Na4PPi, 350mM HClO4, and 16 g/l charcoal) after 60min. The pellets were collected by centrifugation and washed twice with 500mul of washing solution (100mM Na4PPi and 350mM HClO4). AsuA2 kinetic analysis was carried out in 500mul of reaction mixture as described above except for a varying concentration of 3,4-AHBA (5, 10, 20, 50, 100, or 250muM). Reactions were initiated by adding AsuA2 and quenched with 500mul of a charcoal suspension at 0, 5, 10, 15, and 20min. The rate of substrate consumption was calculated as the incorporation rate of the charcoal-bound [32P]-<strong>[56-65-5]ATP</strong> measured on a Beckman LS 6500 scintillation counter. The resulting data were fitted to the Michaelis-Menten equation in GraphPad Prism to obtain estimates for kcat and Km.
3-amino-4-hydroxybenzoic acid 5.0 g (32.7 mmol)Was dissolved in methanol (327 mL, 0.1 M) Of concentrated hydrochloric acid at 0 (16.3 mL, 2.0 M)Was slowly added.After the reaction mixture was reacted at 80 DEG C for 12 hours,300 mL of distilled water was added to dilute the solution, and 1.0 N NaOH aqueous solution was gradually added at 0 C to terminate the reaction.Separation three times with chloroform / methanol (10: 1, 100 mL)And the water of the organic layer was removed with sodium sulfate,The solvent was concentrated with a vacuum distillation apparatus. The residue is then transferred to a microwave tube,Was dissolved in trimethyl orthoformate (32.7 mL, 1.0 M) and reacted with microwave at 150 C for 1 hour under 200W condition.After the reaction, the solvent was concentrated using a vacuum distillation apparatus,The residue was purified by silica gel chromatography to give the title compoundMethylbenzo [d]Oxazole-5-carboxylateThe agent was obtained.
2-(2-hydroxy-3,5-dimethyl-phenyl)-benzooxazole-5-carboxylicacid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
Stage #1: 3,5-dimethylsalicylaldehyde; 3-amino-4-hydroxybenzoic acid In N,N-dimethyl-formamide at 20℃;
Stage #2: With sodium cyanide In N,N-dimethyl-formamide for 18h;
2-(3,5-dichloro-2,6-dihydroxyphenyl)benzoxazole-5-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
Stage #1: 3,5-dichloro-2,6-dihydroxybenzaldehyde; 3-amino-4-hydroxybenzoic acid In N,N-dimethyl-formamide at 20℃;
Stage #2: With sodium cyanide In N,N-dimethyl-formamide for 18h;
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