* 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.
Stage #1: With potassium carbonate In acetone for 14 h; Heating / reflux Stage #2: With ammonia In methanol; water at 20℃; for 0.5 h;
Methyl 5-bromo-4-carboxymethyl-2-methoxybenzoate was synthesized according tothe method described in WO 01/35900. A 1 L 3-neck RBF, fitted with a droppingfunnel, a condenser and a magnetic stirring bar was charged with 4-methylsalicylicacid 10a (50 g, 0.33 mol), K2CO3 (91.1 g, 0.66 mol, 2 eq) and dry acetone (500 ml).This mixture was heated under reflux while dimethylsulfate (112.3 g, 0.891 mol, 2.7eq) was added dropwise. The reaction mixture was refluxed for -14 h (TLCindicated that the reaction was completed). The inorganic salts were filtered off andthe THF filtrate was evaporated under reduced pressure to obtain a yellow oil. Thisresidue was dissolved in 400 ml_ MeOH and a solution of cone. NH4OH (115 ml_)was added. The resulting mixture was stirred at RT for 30 min. The MeOH wasthen distilled off and the residue was diluted with water (500 ml_) and the oilyproduct was extracted with diethyl ether (3X300 mL). The combined organicextracts were dried over sodium sulfate and the diethyl ether was removed undervacuum to give pure methyl 2-methoxy-4-methylbenzoate 10b as a yellow oil (57 g,96percent yield). A dry 2 L 3-neck RBF fitted with an argon inlet, a thermometer, a magnetic stirringbar and a septum was charged with THF (220 mL) and diisopropylamine (54.6 mL,0.39 mol, 1.2 eq). The resulting mixture was cooled to -50°C and a solution of 2.5 Mn-BuLi (156 mL, 0.39 mol, 1.2 eq) was added slowly via cannula. After 30 min ofstirring at -50°C, the solution of LDA generated was cooled to -78°C and HMPA(67.8 mL, 0.39 mol, 1.2 eq) was added, followed by a solution of methyl 2-methoxy-4-methylbenzoate 10b (57 g, 0.32 mol) in THF (220 ml), while maintaining thetemperature at -78°C. The reaction mixture was stirred two more hours at -78°C,and then cannulated into a flask containing 100 g dry ice and THF (200 ml). After30 min stirring at -78°C, the reaction mixture was allowed to warm up slowly to RTand then poured into water (1.5 L). The organic layer was separated and theaqueous layer was further extracted with ether (3X1 L). The water layer wasacidified with a solution of 10percent H2SO4 (150 ml) and the reaction product wasextracted into CH2CI2 (3X1.5 L). The combined organic extracts were dried overanhydrous Na2SO4, the solvent was removed under reduced pressure and the crudeproduct was purified by flash chromatography (eluent EtOAc: hexane 3:7), followedby recrystallization from CH2CI2:hexane 1:1 to afford pure methyl 4-carboxymethyl-2-methoxybenzoate 10c (38.8 g, 54.7percent yield). Methyl 4-cafboxymethyl-2-methoxybenzoate 10c (12.7g, 0.0567 mol) was dissolved in glacial AcOH (100 ml_) and bromine (3.2 ml, 0.0624 mol, 1.1 eq) was added drop wise via a syringe, while maintaining the internal temperature between 20-25°C.iAfter stirring for 4 h at RT, the AcOH was evaporated and the orange oil co-evaporated twice with toluene to give an orange solid. This material was trituratedwith CH2CI2and some of the precipitated product was removed by filtration. The restof the product which remained in the filtrate was then concentrated, loaded on asilica gel column and eluted with 1percent AcOH in EtOAc:hexane (6:4 ratio). Theproduct was further purified by a second chromatography and re-crystallization fromEtOAc:hexane to give pure methyl 5-bromo-4-carboxymethyl-2-methoxybenzoate aswhite solid 10d (total amount 9 g, 52percent yield).
Reference：
[1] Patent: WO2004/108673, 2004, A2, . Location in patent: Page 45-46
[2] Bioorganic and medicinal chemistry, 2002, vol. 10, # 9, p. 3013 - 3021
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2334 - 2356
[4] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 19, p. 4987 - 4993
[5] Patent: WO2004/65367, 2004, A1, . Location in patent: Page 152 - 153; 157
5
[ 50-85-1 ]
[ 74-88-4 ]
[ 81245-24-1 ]
Yield
Reaction Conditions
Operation in experiment
91%
With potassium carbonate In DMF (N,N-dimethyl-formamide) for 18 h;
To a mixture of 2-hydroxy-4-methylbenzoic acid(30.43 g, 200 mmol) , K2CC>3 (62.19 g, 450 mmol) and DMF(600 mL) was added methyl iodide (28.01 mL, 450 mmol). Thereaction was stirred for 18 h, poured into ice/water(1.2 L), and extracted with EtOAc (2 X 300 mL). Thecombined organic layer was washed with brine, satd NaHCC>3and dried (MgSC>4) . The resulting solution was concentratedand distilled to give the title compound as a pale yellowliquid (32.73 g, 91percent, bp 120-4 °C/1333 Pa, 10 mm).(400MHz, CDCls): 5 2.40 (s, 3H), 3.90 (s, 3H), 3.93 (s,3H), 6.80 (m, 2H), 7.75 (d, J = 7.6 Hz, 1H).FIA-MS, m/e: 180.9 (m+1).
10 g
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 1 h; Stage #2: at 60℃; for 18 h;
To a solution of 2-hydroxy-4-methylbenzoic acid (10.00 g, 65 mmol) in DMF (10 mL) was added K2CO3 (13.6 g, 98 mmol). The reaction mixture was stirred at 60°C for 1 h. Methyl iodide (14.0 g, 98 mmol) was added to the reaction mixture and was stirred at 60°C for 18 h. The reaction mass was quenched in water and concentrated. The reaction mass was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 10.00 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 2.34 (s, 3H), 3.74 (s, 3H), 3.79 (s, 3H), 6.81 (d, J = 7.2 Hz, 1H), 6.97 (s, 1H), 7.56 (d, J = 7.8 Hz, 1H); MS (m/z): 180.95 (M+H)+.
11.0 g
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
To a mixture of 2-hydroxy-4-methylbenzoic acid (10.0 g, 65.7 mmol) and K2CO3 (22.7 g, 164.3 mmol) in DMF (200 mL) at room temperature was added methyl iodide (20.5 g, 144.5 mmol) over a period of 10 minutes. The resulting mixture was stirred at room temperature overnight, then diluted with DCM (150 mL) and filtered. The filtrate was washed with water (200 mL x 10) and brine (200 mL x 2), dried a2S04) and concentrated to give the intermediate as a yellow liquid (1 1.0 g)
With potassium carbonate In dimethyl sulfoxide at 20℃; for 19 h; Reflux
To a solution of 4-methylsalicylic acid (2.93 g, 19.1 mmol, 1 equiv) in acetone (34.8 mL) wasadded finely ground K2C03 (7.9 g, 57.2 mmol, 3 equiv) and Me2SO4 (5.42 mL, 57.2 mmol, 3equiv). The solution was stirred at rt for 18 h and under reflux for 1 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude residue was dissolved in EtOAc (100 mL) and Et3N (2.65 mL, 19.1 mmol, 1 equiv) was added. The reaction mixture was stirred at rt for 30 mm. The reaction mixture was successively washed with water, 2N HC1, and brine.The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel column (hexane/EtOAc 10:0 to 10:10 (v/v) in 30 mm) to afford a colorless liquid (3.37 g, 18.7 mmol, 98 percent).HPLC Purity = 99percent; tr = 4.02 mm; ‘H NMR (400 MHz, CDC13) ö 7.73 (d, J8.4 Hz, 1H),6.80-6.78 (m, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 2.39 (s, 3H); ‘3C NMR (101 MHz, CDC13) ö166.6, 159.3, 144.6, 131.8, 120.9, 116.9, 112.8, 55.9, 51.8, 21.9; MS (ESIj: mlz = 203[M+Na].
Example VI Preparation of N-Hydroxysuccinimidyl 3-(N-[3-hydroxy-4-(methoxycarbonyl)phenyl]methyl}carbamoyl)propionate STR24 Methyl 4-Methyl-2-hydroxybenzoate 4-Methyl-2-hydroxybenzoic acid (100 g, 658 mmoles) was dissolved in anhydrous methanol (500 mL) and concentrated sulfuric acid (25 mL) was added carefully. The solution was refluxed for 18 hours, then cooled to room temperature. The reaction mixture was concentrated to about 150 mL, and ethyl acetate (250 mL) was added. The ethyl acetate solution was washed twice with saturated aqueous sodium bicarbonate (250 mL portions) and then with saturated aqueous sodium chloride (100 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered, and evaporated to a clear, reddish-brown liquid. This crude product was vacuum distilled (oil pump) to afford a clear, viscous liquid that solidified on standing to afford 98.1 g (90percent yield) of methyl 4-methyl-2-hydroxybenzoate. 1 H NMR (300 MHz, CHCl3 -d) δ 2.32 (singlet, 3H, ArCH3), 3.91 (singlet, 3H, OCH3), 6.67 (doublet, J=8 Hz, 1H, ArH), 6.78 (singlet, 1H, ArH), 7.69 (doublet, J=8 Hz, 1H, ArH), 10.71 (singlet, 1H, OH). 13 C NMR (75 MHz, CHCl3 d) δ 21.8, 52.1, 110.0, 117.9, 120.6, 129.9, 147.3, 161.9, 170.9.
90%
With sulfuric acid In methanol; ethyl acetate
EXAMPLE IV Preparation of a Reagent of General Formula I Methyl 4-Succinylaminomethylsalicylate Succinimidyl Ester STR21 Methyl 4-Methylsalicylate 4-Methylsalicylic acid (100 g, 658 mmoles) was dissolved in anhydrous methanol (500 mL) and concentrated sulfuric acid (25 mL) was added carefully. The solution was refluxed for 18 hours, then cooled to room temperature. The reaction mixture was concentrated to about 150 mL, and ethyl acetate (250 mL) was added. The ethyl acetate solution was washed twice with saturated aqueous sodium bicarbonate (250 mL portions) and then with saturated aqueous sodium chloride (100 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered, and evaporated to a clear, reddish-brown liquid. This crude product was vacuum distilled (oil pump) to afford a clear, viscous liquid that solidified on standing to afford 98.1 g (90percent yield) of methyl 4-methylsalicylate. 1 H NMR (300 MHz, CHCl3 -d) δ2.32 (singlet, 3H, ArCH3), 3.91 (singlet, 3H, OCH3), 6.67 (doublet, J=8 Hz, 1H, ArH), 6.78 (singlet, 1H, ArH), 7.69 (doublet, J=8 Hz, 1H, ArH), 10.71 (singlet, 1H, OH). 13 C NMR (75 MHz, CHCl3 -d) δ21.8, 52.1, 110.0, 117.9, 120.6, 129.9, 147.3, 161.9, 170.9.
90%
With sulfuric acid In methanol; ethyl acetate
Methyl 4-Methylsalicylate 4-Methylsalicylic acid (100 g, 658 mmoles) was dissolved in anhydrous methanol (500 mL) and concentrated sulfuric acid (25 mL) was added carefully. The solution was refluxed for 18 hours, then cooled to room temperature. The reaction mixture was concentrated to about 150 mL, and ethyl acetate (250 mL) was added. The ethyl acetate solution was washed twice with saturated aqueous sodium bicarbonate (250 mL portions) and then with saturated aqueous sodium chloride (100 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered, and evaporated to a clear, reddish-brown liquid. This crude product was vacuum distilled (oil pump) to afford a clear, viscous liquid that solidified on standing to afford 98.1 g (90percent yield) of methyl 4-methylsalicylate. 1 H NMR (300 MHz, CHCl3- d) δ2.32 (singlet, 3H, ArCH3), 3.91 (singlet, 3H, OCH3), 6.67 (doublet,J=8 Hz, 1H, ArH), 6.78 (singlet, 1H, ArH), 7.69 (doublet, J=8 Hz, 1H, ArH), 10.71 (singlet, 1H, OH). 13 C NMR (75 MHz, CHCl3- d) δ21.8, 52.1, 110.0, 117.9, 120.6, 129.9, 147.3, 161.9, 170.9.
90%
With sulfuric acid In methanol; ethyl acetate
EXAMPLE IV Preparation of a Reagent of General Formula I Methyl 4-Succinylaminomethylsalicylate Succinimidyl Ester STR21 Methyl 4-Methylsalicylate. 4-Methylsalicylic acid (100 g, 658 mmoles) was dissolved in anhydrous methanol (500 mL) and concentrated sulfuric acid (25 mL) was added carefully. The solution was refluxed for 18 hours, then cooled to room temperature. The reaction mixture was concentrated to about 150 mL, and ethyl acetate (250 mL) was added. The ethyl acetate solution was washed twice with saturated aqueous sodium bicarbonate (250 mL portions) and then with saturated aqueous sodium chloride (100 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered, and evaporated to a clear, reddish-brown liquid. This crude product was vacuum distilled (oil pump) to afford a clear, viscous liquid that solidified on standing to afford 98.1 g (90percent yield) of methyl 4-methylsalicylate. 1 H NMR (300 MHz, CHCl3-d) δ 2.32 (singlet, 3H, ArCH3), 3.91 (singlet, 3H, OCH3), 6.67 (doublet, J=8 Hz, 1H, ArH), 6.78 (singlet, 1H, ArH), 7.69 (doublet, J=8 Hz, 1H, ArH), 10.71 (singlet, 1H, OH). 13 C NMR (75 MHz, CHCl3-d) δ 21.8, 52.1, 110.0, 117.9, 120.6, 129.9, 147.3, 161.9, 170.9.
Reference：
[1] Patent: US6156884, 2000, A,
[2] Patent: US5777148, 1998, A,
[3] Patent: US5837878, 1998, A,
[4] Patent: US5847192, 1998, A,
[5] Patent: US2003/219780, 2003, A1,
[6] Patent: US6150413, 2000, A,
[7] Patent: US2018/346438, 2018, A1,
11
[ 67-56-1 ]
[ 50-85-1 ]
[ 4670-56-8 ]
Yield
Reaction Conditions
Operation in experiment
95%
at 0℃; Inert atmosphere; Reflux
SOCl2 (10.9 mL, 150 mmol) was added dropwise into a solution of 193 4-methylsalicylic acid (5.0 g, 32.9 mmol, TCI reagent) in 27 MeOH (80 mL) at 0°C in a nitrogen atmosphere. A resulting mixture was stirred at reflux overnight. After a reaction was completed, a volatile solvent was evaporated under reduced pressure. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the 194 title compound (30-1) (5.18 g, 31.2 mmol, 95percent). (0238) 1H NMR (400 MHz, CDCl3); δ 10.70 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 6.79 (s, 1H), 6.69 (d, J = 8.4 Hz, 1H), 3.93 (s, 3H), 2.34 (s, 3H)
94%
at 20℃; for 5.5 h; Reflux
1 3A. Methyl 2-hydroxy-4-methyl-benzoateConcentrated H2504 (200 mL) was added dropwise over 30 minutes to a stirredsolution of 2-hydroxy-4-methyl-benzoic acid (100 g, 657 mmol) in MeOH (500 mL) at room temperature. The mixture was heated to reflux for 5 hours then allowed to cool to room temperature and carefully poured into ice cold saturated NaHCO3 solution(300 mL). The mixture was extracted with DCM (4 x 500 mL) and the combinedorganic extracts dried (Na2504) and evaporated under reduced pressure to give thetitle compound (100 g, 94percent) which was used without further purification.
84.6%
Reflux
General procedure: A mixture of organic acid (0.5 g) and methanol (100 ml) was heated under reflux in presence of sulphuric acid (0.8 ml) until the completion of the reaction which was checked by single spot TLC. Then, methanol was removed under reduced pressure a half and the solution was diluted with 20 ml of water. The product was extracted with ethyl acetate (30 ml). The organic phase was neutralized successively with NaHCO3 5percentand water, dried over anhydrous Na2SO4, and filtered. The ethyl acetate phase was separated, which on evaporation yielded the ester derivatives
72%
at 0 - 20℃; for 5 h; Heating / reflux
A 50 ml round-bottom flask equipped with a stir bar under a dry nitrogen atmosphere was charged with 4-methylsalicylic acid (1.5 g, 10.0 mmoles, 1.0 eq) followed by dry MeOH (15 ml). The reaction mixture was cooled to 0° C. on an ice bath and neat SOCl2 (1.1 ml, 15.0 mmoles, 1.5 eq) was added dropwise. The reaction was allowed to warm to room temperature and then stirred at reflux for 5 hrs. After that time, excess MeOH was removed in vacuo, the residue dissolved in EtOAc and extracted with saturated NaHCO3, the organic layer was dried with MgSO4 and filtered. Removal of excess solvent from the filtrate in vacuo provided 1.20 g (72percent) of the title compound as a clear oil. (1H CDCl3, 400 MHz): δ 10.71 (s, 1H), 7.70 (d, J=8.1 Hz, 1H), 6.75 (s, 1H), 6.69 (d, J=8.1 Hz, 1H), 3.93 (s, 3H), 2.34 (s, 3H).
Reference：
[1] Journal of the American Chemical Society, 2006, vol. 128, # 36, p. 11940 - 11947
[2] Journal of the Chemical Society - Series Chemical Communications, 1989, # 3, p. 186 - 187
[3] Patent: EP3404033, 2018, A1, . Location in patent: Paragraph 0237-0238
[4] Patent: WO2015/120390, 2015, A1, . Location in patent: Page/Page column 92; 138
[5] Organic and Biomolecular Chemistry, 2015, vol. 13, # 43, p. 10745 - 10750
[6] Journal of the American Chemical Society, 1994, vol. 116, # 6, p. 2629 - 2630
[7] Natural Product Research, 2018, vol. 32, # 5, p. 572 - 575
[8] Patent: US2005/143434, 2005, A1, . Location in patent: Page/Page column 9
[9] Chemische Berichte, 1890, vol. 23, p. 2953
[10] Bulletin de la Societe Chimique de France, 1908, vol. <4> 3, p. 730[11] Bulletin de la Societe Chimique de France, 1910, vol. <4> 7, p. 332
[12] Bioorganic and Medicinal Chemistry, 2000, vol. 8, # 1, p. 73 - 93
[13] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 2, p. 171 - 175
[14] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 24, p. 8618 - 8629
[15] European Journal of Medicinal Chemistry, 2012, vol. 47, # 1, p. 473 - 478
[16] Patent: WO2012/28629, 2012, A1, . Location in patent: Page/Page column 27
[17] Chemistry - A European Journal, 2012, vol. 18, # 16, p. 4859 - 4865
[18] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 11, p. 3615 - 3621
[19] Letters in Organic Chemistry, 2012, vol. 9, # 2, p. 114 - 117
[20] Journal of Medicinal Chemistry, 2014, vol. 57, # 12, p. 5282 - 5292
[21] Patent: WO2014/121291, 2014, A2, . Location in patent: Page/Page column 44; 45
[22] Tetrahedron Letters, 2016, vol. 57, # 48, p. 5301 - 5303
12
[ 50-85-1 ]
[ 74-88-4 ]
[ 4670-56-8 ]
Reference：
[1] Synthetic Communications, 2005, vol. 35, # 1, p. 145 - 152
[2] Journal of Chemical Research, Miniprint, 1997, # 1, p. 228 - 240
[3] Patent: EP2119718, 2009, A1, . Location in patent: Page/Page column 36
[4] Patent: WO2011/119549, 2011, A1, . Location in patent: Page/Page column 117-118
[5] Proceedings of the National Academy of Sciences of the United States of America, 2011, vol. 108, # 17, p. 6709 - 6714
13
[ 50-85-1 ]
[ 4670-56-8 ]
Yield
Reaction Conditions
Operation in experiment
90%
With sulfuric acid In methanol; ethyl acetate
Methyl 4-Methylsalicylate 4-Methylsalicylic acid (100 g, 658 mmoles) was dissolved in anhydrous methanol (500 mL) and concentrated sulfuric acid (25 mL) was added carefully. The solution was refluxed for 18 hours, then cooled to room temperature. The reaction mixture was concentrated to about 150 mL, and ethyl acetate (250 mL) was added. The ethyl acetate solution was washed twice with saturated aqueous sodium bicarbonate (250 mL portions) and thenwith saturated aqueous sodium chloride (100 mL). The ethyl acetate solutionwas dried over anhydrous sodium sulfate, filtered, and evaporated to a clear, reddish-brown liquid. This crude product was vacuum distilled (oil pump) to afford a clear, viscous liquid that solidified on standing to afford 98.1 g (90percent yield) of methyl 4-methylsalicylate. 1 H NMR (300 MHz, CHCl3 -d) δ2.32 (singlet, 3H, ArCH3), 3.91 (singlet, 3H, OCH3), 6.67 (doublet,J=8 Hz, 1H, ArH), 6.78 (singlet, 1H, ArH), 7.69 (doublet, J=8 Hz, 1H, ArH), 10.71 (singlet, 1H, OH). 13 C NMR (75 MHz, CHCl3 d) δ21.8, 52.1,110.0, 117.9, 120.6, 129.9, 147.3, 161.9, 170.9.
Reference：
[1] Patent: US5744627, 1998, A,
14
[ 7664-93-9 ]
[ 50-85-1 ]
[ 4670-56-8 ]
Reference：
[1] Patent: US5965741, 1999, A,
15
[ 50-85-1 ]
[ 4670-56-8 ]
Yield
Reaction Conditions
Operation in experiment
94%
With ethereal hydrochloric acid In methanol
(i) methyl 4-methylsalicylate To a suspension of 10 g (0.0651 mol) of 4-methylsalicylic acid in 150 mL of methanol was added 50 mL of ethereal hydrochloric acid. The reaction mixture was heated at 60° C. for 60 hours. The solvent was removed under vacuum. After adding hexane-ethyl acetate, the resulting solid was filtered and the filtrate was evaporated to give 10.2 g (94percent) of product as an oil.
Reference：
[1] Patent: US6359136, 2002, B1, . Location in patent: Example 1C
23
[ 50-85-1 ]
[ 6623-35-4 ]
Yield
Reaction Conditions
Operation in experiment
89%
With bromine In methanol at -20 - 20℃; for 1.5 h;
To a mixture of 2-hydroxy-4-methylbenzoic acid (24.5 g, 161 mmol) in methanol (300 mL) was added dropwise a solution of bromine (28 g, 180 mmol) in methanol (50 mL) at -20 °C and the reaction mixture was stirred for 0.5 h, then warmed to rt and stirred for another 1 h. The reaction was quenched with saturated aquous sodium sulfite (100 mL). The reaction mixture was concentrated to remove methanol and the residue was diluted with water (50 mL).The mixture was filtered and the filtrate was dried to give a red-brown solid (33 g, 89 percent).MS (ESI, pos. ion) m/z: 231.1 [M+H]t
6.78 g
With bromine In acetic acid at 10 - 35℃; for 5.5 h;
A) 5-bromo-2-hydroxy-4-methylbenzoic acid To a solution of 2-hydroxy-4-methylbenzoic acid (5.00 g) in acetic acid (70.0 mL) was added dropwise bromine (1.68 mL) , and the mixture was stirred at room temperature for 5.5 hr. To the reaction mixture was added water, and the precipitate was collected by filtration, and dried under reduced pressure to give the title compound (6.78 g) . MS: [M-H]+ 229.0.
126 g
at 10 - 35℃;
To a mixture of 2-hydroxy-4-methylbenzoic acid (100 g) and acetic acid (1100 mL) was added dropwise bromine (34 mL) at room temperature, and the mixture was stirred at roomtemperature overnight. Water (800 mL) was added thereto, and the mixture was stirred at room temperature for 30 min. The precipitates were collected by filtration and washed with water to give the title compound (126 g) .MS: [M-H]~228.9, 230.9.
Reference：
[1] Patent: WO2018/24224, 2018, A1, . Location in patent: Page/Page column 80; 81
[2] Patent: US2018/127370, 2018, A1, . Location in patent: Paragraph 0892
[3] Journal of the Chemical Society, 1914, vol. 105, p. 1891
[4] Journal fuer Praktische Chemie (Leipzig), 1915, vol. <2> 91, p. 388
[5] Patent: EP1391451, 2004, A1, . Location in patent: Page 84
[6] Patent: WO2015/163485, 2015, A1, . Location in patent: Paragraph 0349
[7] Patent: WO2016/208775, 2016, A1, . Location in patent: Paragraph 0393
Reference：
[1] Journal of the Chemical Society, 1914, vol. 105, p. 1891
26
[ 50-85-1 ]
[ 7732-18-5 ]
[ 64-19-7 ]
[ 4619-74-3 ]
[ 29666-53-3 ]
[ 6623-35-4 ]
[ 6623-36-5 ]
Reference：
[1] Journal of the Chemical Society, 1914, vol. 105, p. 1891
27
[ 74-96-4 ]
[ 50-85-1 ]
[ 88709-17-5 ]
Yield
Reaction Conditions
Operation in experiment
100%
With potassium carbonate In dimethyl sulfoxide at 35 - 40℃; for 11 h;
Potassium carbonate (68.0 g, 0.492 mole) was added to a well-stirred solution of 4-methylsalicylic acid (25 g, 0.164 mole) in dimethylsulfoxide (75 ml ). The mixture was stirred at 35-40° C. and 1st lot of ethyl bromide (27.0 g, 0.247 mole) was added slowly over a period of 30 minutes then stirred for two hours and a second lot of ethyl bromide (27.0 g, 0.247 mole) was added over a period of 30 minutes at 35-40° C. The reaction mixture was further stirred at 35-40° C. for eight hours, cooled to 20-25° C., and diluted with dichloromethane (50 ml). The inorganics were removed by filtration and washed with dichloromethane. The combined filtrate and washings were diluted with water (50 ml), stirred for 30 minutes, and the organic layer was separated. The aqueous layer was further extracted with dichloromethane and the combined dichloromethane layer was washed with water (2.x.50 ml). The solvent was removed under vacuum to afford ethyl 2-ethoxy-4-methylbenzoate 34.2 g (quantitative yield).
88%
With potassium carbonate In dimethyl sulfoxide at 40℃; for 10.5 h;
To a mixture of 2-hydroxy-4-methylbenzoic acid (20.0 g, 131.5 mmol) and K2CO3 (54.5 g, 394.5 mmol) in DMSO (50 mL) at 40 °C was added bromoethane (21 .5 g, 197.2 mmol) over 30 minutes. The reaction was then stirred at 40 C for 2 hours. Further bromoethane (21.5 g, 197.2 mmol) was then added dropwise and the reaction stirred at 40 °C for 8 hours. DCM (200 mL) was added and the mixture was filtered. The organic layer was washed with water (4 x 150 mL), dried (Na2SO.i) and concentrated to give the title compound (24.1 g, 88percent) as a clear oil. LCMS-C: RT 2.77 min; m/z 209.1 [M+H] +
Reference：
[1] Patent: US6686497, 2004, B1, . Location in patent: Page column 3-4
[2] Organic Process Research and Development, 2002, vol. 6, # 2, p. 184 - 186
[3] Patent: WO2016/34673, 2016, A1, . Location in patent: Page/Page column 103
[4] Journal of Medicinal Chemistry, 1998, vol. 41, # 26, p. 5219 - 5246
28
[ 50-85-1 ]
[ 75-03-6 ]
[ 88709-17-5 ]
Yield
Reaction Conditions
Operation in experiment
90%
With potassium carbonate In dimethyl sulfoxide at 40℃; for 11 h;
To a mixture of 2-hydroxy-4-methylbenzoic acid (8.2 g, 54 mmol) and K2CO3 (22.4 g, 162 mmol) in DMSO (70 mL) at 40 C was added ethyl iodide (12.6 g, 80.8 mmol) drop-wise over a period of 30 minutes. The reaction was stirred for 2 hours then further ethyl iodide (12.6 g, 80.8 mmol) was added over 30 minutes. The resulting mixture was stirred for another 8 hours at 40 C, then diluted with DCM (150 mL) and filtered. The filtrate was washed with water (200 mL χ 10) and brine (200 mL 2), dried ( a2S04) and concentrated to give the desired compound (10.1 g, 90percent yield) as a yellow liquid. LCMS-C: RT 2.70 min; m/z 209.1 [M+H]*
90%
With potassium carbonate In dimethyl sulfoxide at 40℃; for 11 h;
To a mixture of 2-hydroxy-4-methylbenzoic acid (8.2 g, 53.9 mmol) and K2CO3 (22.4 g, 161.7 mmol) in dimethylsulfoxide (70 mL) at 40 ^C was added and ethyl iodide (12.6 g, 80.8 mmol) dropwise over a period of 30 min. The reaction was stirred for 2 h then further ethyl iodide (12.6 g, 80.8 mmol) was added over 30 min. The resulting mixture was stirred a further 8 h at 40 ^C, then diluted with CH2Cl2 (150 mL) and filtered. The filtrate was washed with water (200 mL x 10) and brine (200 mL x 2), dried (Na2SO4) and concentrated to give the desired compound as a yellow liquid (10.1 g, 90percent): LCMS: RT 2.70min; m/z 209.1 [M+H]+.
90%
With potassium carbonate In dimethyl sulfoxide at 40℃; for 11 h;
To a mixture of 2-hydroxy-4-methylbenzoic acid (8.2 g, 53.9 mmol) and K2CO3 (22.4 g, 161 .7 mmol) in dimethylsulfoxide (70 mL) at 40 °C was added ethyl iodide (12.6 g, 80.8 mmol) dropwise over a period of 30 min. The reaction was stirred for 2 hours then further ethyl iodide (12.6 g, 80.8 mmol) was added over 30 min. The resulting mixture was stirred a further 8 hours at 40 °C, diluted with CH2CI2 CI 5O mL) and filtered. The filtrate was washed with water (200 mL x 10) and brine (200 mL x 2), dried (Na2SC>4), filtered and concentrated to give the desired compound as a yellow liquid (10.1 g, 90percent): LCMS: RT 2.70min; m/z 209.1 [M+H]+.
85%
With potassium carbonate In acetone at 20℃; for 72 h;
[00463] Intermediate 48: Synthesis of ethyl 2-ethoxy-4-formylbenzoate[00464] Step 1: Synthesis of ethyl 2-ethoxy-4-methylbenzoate: To a mixture of 2- hydroxy-4-methylbenzoic acid (5.0 g, 32.9 mmol), K2C03 (18.9 g, 136.6 mmol) and acetone (50 mL) was added ethyl iodide (41.0 g, 263.2 mmol). The mixture was stirred at room temperature for 3 days. After filtration, the organic layer was concentrated to afford ethyl 2- ethoxy-4-methylbenzoate as colorless oil (5.7 g, 85percent), which was used directly for next step.
With potassium carbonate In toluene at 25 - 45℃; for 21 - 31.5 h; Heating / reflux
Added 260 ml (3.0 mol) of diethyl sulfate to the mixture of 1000 ml of toluene, 272.5 g (3.0 mol) of potassium carbonate and 100 g (1.0 mol) of 2-Hydroxy-4-methyl-benzoic acid at 25-45° C. for 1 hr to 1 hr 30 min. Heated the reaction mass to azeotropic reflux for 20-30 hr. Cooled the reaction mixture to 25-35° C. and collected the unwanted material by filtration, washed the unwanted material with 500 ml of toluene. Combined filtrate was washed with water (1.x.1000 ml and 1.x.500 ml) at 80-85° C. Total organic layer was concentrated to residue under vacuum at below 70° C. The yield of the title compound is 128 g (94.11percent). [0036] The obtained product was characterised by analytical techniques like IR, Mass and 1H-NMR
87%
With potassium carbonate In acetonitrile for 12 h; Heating / reflux
4-Methyl salicylic acid (5 g, 32.89 mmol), diethyl sulfate (20.26 g, 0.131 mole) and anhydrous potassium carbonate (18.15 g, 0.132 mole) were mixed thoroughly in dry acetonitrile and mixture was refluxed for 12 hr. Reaction mixture was cooled and filtered through Celite bed. Filtrate was concentrated under vacuum. Residue was purified by fractional distillation at 0.5 mm vacuum. 1st fraction dis tilled at 48-51 C. (oil bath temperature 80 C.). Product (ethyl-2-ethoxy-4-methylbenzoate) 3 distilled at 90-93 C. (oil bath temperature 120 C.) Yield=6 g (87percent).
84%
With potassium carbonate In 1,4-dioxane for 16 h; Heating / reflux
4-Methyl salicylic acid (5 g, 32.89 mmol), diethyl sulfate (20.26 g, 0.131 mole) and anhydrous potassium carbonate (18.15 g, 0.132 mole) were mixed thoroughly in dry dioxane and mixture was refluxed for 16 hr. Reaction mixture was cooled and filtered through Celite bed. Filtrate was concentrated under vacuum. Residue was purified by fractional distillation at 0.5 mm vacuum. 1st fraction dis tilled at 48-51 C. (oil bath temperature 80 C.). Product (ethyl-2-ethoxy-4-methylbenzoate) 3 distilled at 90-93 C. (oil bath temperature 120 C.) Yield=5.8 g (84percent).
75%
With potassium carbonate In acetone for 16 h; Heating / reflux
4-Methyl salicylic acid (5 g, 32.89 mmol), diethyl sulfate (20.26 g, 0.131 mole) and anhydrous potassium carbonate (18.15 g, 0.132 mole) were mixed thoroughly in dry acetone and mixture was refluxed for 16 hr. Reaction mixture was cooled and filtered through Celite bed. Filtrate was concentrated under vacuum. Residue was purified by fractional distillation at 0.5 mm vacuum. 1st fraction dis tilled at 48-51 C. (oil bath temperature 80 C.). Product (ethyl-2-ethoxy-4-methylbenzoate) 3 distilled at 90-93 C. (oil bath temperature 120 C.) Yield=5.2 g (75percent)
Intermediate 13: Methyl 2-hydroxy-4-methylbenzoate (1-13)
To a solution of 2-hydroxy-4-methyl-benzoic acid (10 g, 0.065 mol) in methanol (50 mL) was added thionylchloride (15 mL, mole) at 0°C. The reaction mixture was heated at 80°C for 12 h, cooled to RT, concentrated under vacuum to obtain the crude .To the crude 200 mL of water was added and basified with aqueous ammonia, and extracted with dichloromethane (200 mL x 3). Organic layer was washed with brine solution (50 mL) anddried over Na2SO4. Organic layer was concentrated under vacuum to afford the titlecompound.Yield: 10.7 g (98.1%); ‘H - NMR (CDC13, 400 MHz) ö ppm: 2.34 (s, 3H), 3.92 (s, 3H), 6.68-6.70 (d, J=8 Hz, 1H), 6.79 (s, 1H), 7.69-7.71 (d, J=8.12 Hz, 1H), 10.71 (s, 1H); Mass (mlz):167.1 (M+H).
97%
With hydrogen cation
95%
With thionyl chloride at 0℃; Inert atmosphere; Reflux;
30.1 Step 1. Synthesis of methyl 2-hydroxy-4-methylbenzoate (30-1)
SOCl2 (10.9 mL, 150 mmol) was added dropwise into a solution of 193 4-methylsalicylic acid (5.0 g, 32.9 mmol, TCI reagent) in 27 MeOH (80 mL) at 0°C in a nitrogen atmosphere. A resulting mixture was stirred at reflux overnight. After a reaction was completed, a volatile solvent was evaporated under reduced pressure. A resulting residue was purified by means of a silica gel column chromatography, so as to obtain the 194 title compound (30-1) (5.18 g, 31.2 mmol, 95%). (0238) 1H NMR (400 MHz, CDCl3); δ 10.70 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 6.79 (s, 1H), 6.69 (d, J = 8.4 Hz, 1H), 3.93 (s, 3H), 2.34 (s, 3H)
94%
With sulfuric acid at 20℃; for 5.5h; Reflux;
13A 1 3A. Methyl 2-hydroxy-4-methyl-benzoate
1 3A. Methyl 2-hydroxy-4-methyl-benzoateConcentrated H2504 (200 mL) was added dropwise over 30 minutes to a stirredsolution of 2-hydroxy-4-methyl-benzoic acid (100 g, 657 mmol) in MeOH (500 mL) at room temperature. The mixture was heated to reflux for 5 hours then allowed to cool to room temperature and carefully poured into ice cold saturated NaHCO3 solution(300 mL). The mixture was extracted with DCM (4 x 500 mL) and the combinedorganic extracts dried (Na2504) and evaporated under reduced pressure to give thetitle compound (100 g, 94%) which was used without further purification.
92%
With sulfuric acid for 5h; Reflux;
85%
With sulfuric acid at 70℃;
85%
With sulfuric acid for 12h; Reflux;
4.3. Synthesis of ester from 4-methyl salicylic acid
Ester of 4-methyl salicylic acid was prepared by refluxing methanolicsolution of salicylic acid (6.57 mmol, 0.5 g) with catalytic amountof concentrated sulphuric acid for 12 h. Excess acid was quenched usingsodium bicarbonate solution (10%). Ethyl acetate (20 mL × 3) wasused to extract the ester from aqueous layer. Anhydrous MgSO4 wasadded to remove water from organic layer. Filtration was performed toremove MgSO4 and filtrate was evaporated to get ester (57) as an oilyproduct with 85% yield [20].Yield: 85%; Rf = 0.8 (n-Hexane/EtOAc = 7:3); m.p (oC):Oil.
84.6%
With sulfuric acid Reflux;
3.1 General procedure for the synthesis of compounds
General procedure: A mixture of organic acid (0.5 g) and methanol (100 ml) was heated under reflux in presence of sulphuric acid (0.8 ml) until the completion of the reaction which was checked by single spot TLC. Then, methanol was removed under reduced pressure a half and the solution was diluted with 20 ml of water. The product was extracted with ethyl acetate (30 ml). The organic phase was neutralized successively with NaHCO3 5%and water, dried over anhydrous Na2SO4, and filtered. The ethyl acetate phase was separated, which on evaporation yielded the ester derivatives
82%
With sulfuric acid for 24h; Inert atmosphere; Reflux;
2.1 Compound 10 synthesis method
Experimental procedure1L four-necked flask, 2-hydroxy-4-methylbenzoic acid (100g, 0.657mol) was added to the reaction flask under nitrogen protection, and then 800mL of methanol was added. After stirring and dissolving the material, concentrated sulfuric acid was slowly added to the reaction bottle. In the middle, about 20min is dripped. After the completion of the dropwise addition, the mixture was heated with an oil bath to start refluxing of methanol. After 24 hours, the oil bath was removed, cooled to room temperature, and the solution was transferred to a 2 L single-mouth bottle, and the flask was rinsed with a small amount of methanol and incorporated into a single-mouth bottle. After concentrating under reduced pressure and removing 400-500 ml of methanol, water and ethyl acetate were added to the bottle, and the organic phase was washed successively with water, saturated sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, and evaporated. Dry for 2h,90 g of a yellow liquid were obtained. Yield 82%
82.41%
With sulfuric acid at 80℃; for 12h;
Methyl 2-hydroxy-4-methylbenzoate
Step 1 Methyl 2-hydroxy-4-methylbenzoate 2-hydroxy-4-methylbenzoic acid (5.00 g, 32.86 mmol) was dissolved in methanol (50.00 mL), added with sulfuric acid (4.83 g, 49.29 mmol, 2.63 mL), and then stirred at 80° C. for 12 hours. The reaction was quenched with 50 mL saturated sodium bicarbonate solution and extracted with dichloromethane (50 mL*3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give methyl 2-hydroxy-4-methylbenzoate (a white solid, 4.5 g, yield: 82.41%). 1H NMR (400 MHz, CDCl3) 10.78 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 6.79 (s, 1H), 6.69 (d, J=8.4 Hz, 1H), 3.93 (s, 3H), 2.35 (s, 3H).
79%
With sulfuric acid for 21h; Reflux;
72%
With thionyl chloride at 0 - 20℃; for 5h; Heating / reflux;
1 2-Hydroxy-4-methyl-benzoic acid methyl ester:
A 50 ml round-bottom flask equipped with a stir bar under a dry nitrogen atmosphere was charged with 4-methylsalicylic acid (1.5 g, 10.0 mmoles, 1.0 eq) followed by dry MeOH (15 ml). The reaction mixture was cooled to 0° C. on an ice bath and neat SOCl2 (1.1 ml, 15.0 mmoles, 1.5 eq) was added dropwise. The reaction was allowed to warm to room temperature and then stirred at reflux for 5 hrs. After that time, excess MeOH was removed in vacuo, the residue dissolved in EtOAc and extracted with saturated NaHCO3, the organic layer was dried with MgSO4 and filtered. Removal of excess solvent from the filtrate in vacuo provided 1.20 g (72%) of the title compound as a clear oil. (1H CDCl3, 400 MHz): δ 10.71 (s, 1H), 7.70 (d, J=8.1 Hz, 1H), 6.75 (s, 1H), 6.69 (d, J=8.1 Hz, 1H), 3.93 (s, 3H), 2.34 (s, 3H).
With hydrogenchloride
With sulfuric acid
With dicyclohexyl-carbodiimide In diethyl ether at 20℃;
With sulfuric acid at 70℃;
With sulfuric acid at 20℃; for 48h; Reflux;
With sulfuric acid for 6h; Reflux;
With thionyl chloride at 50℃; for 24h;
1
Description 1Methyl 2-hydroxy-4-methylbenzoate (D1 )Thionyl chloride (2.16 ml, 29.6 mmol) was added dropwise to a solution of 2-hydroxy-4- methylbenzoic acid (3 g, 19.72 mmol) in methanol (20 ml). The solution was heated at 50°C for 24 hours. The solution was cooled, the solvent was removed in vacuo and the residue was dissolved in dichloromethane (20 ml), washed with water (15 ml) and saturatedNaHC03 solution (2 x 10 ml), dried and the solvent removed in vacuo to yield the title compound as an oil. 3.28 g.1 H NMR (DMSO-de): 2.30 (3 H, s), 3.80 (3 H, s), 6.61 - 6.88 (2 H, m), 7.68 (1 H, d, J=7.89 Hz), 10.48 (1 H, s)
With sulfuric acid Inert atmosphere; Reflux;
With sulfuric acid Reflux;
With sulfuric acid Heating;
With sulfuric acid for 24h; Reflux;
With sulfuric acid for 24h; Reflux;
Synthesis of W,2-dihydroxy-4-methylbenzamide
4-Methylsalicylic acid (252.5 mg, 1 .66 mmol) was dissolved with 20 mL of MeOH in a 50 mL round bottom flask. 0.5 mL of concentrated sulfuric acid was added while stirring. The flask was connected to a partial condenser (T=5°C) and set in an oil bath (T=85°C). The solution was stirred and allowed to react under reflux for 24 hours. The reaction wasquenched by adding 100 mL of water to the solution. The intermediate was extracted with ethyl ether (3 x 30 mL). The organic phases were combined and washed with a saturated sodium bicarbonate solution (2 x 100 mL). The ether was evaporated in vacuo and the intermediate was dissolved in 0.5 mL of THF. In a separate vial, 6.72 mL of 1 .64 M hydroxylamine in water was added to 8.38 mL of 3 M NaOH. The intermediate solution was added drop wise to the NaOH/NhbOH solution while stirring. The reaction was allowed to proceed at room temperature for 24 hours. After 24 hours, the reaction was cooled to 0°C using an Ice bath, and the pH was adjusted to pH = 5 with 10 M HCI. The solution was allowed to warm to room temperature before extracting the product with ethyl acetate (3 x 15 mL). The organic layers were combined and the solvent was evaporated. Mass spec analysis shows [M+H] = 168.071 1 m/z.
With sulfuric acid for 16h; Reflux;
With thionyl chloride at 0 - 65℃; for 48h;
With sulfuric acid at 80℃;
General procedure for the preparation of compounds 2 (2a as a model).
General procedure: To a solution of 1a (5 mmol) in CH3OH (25 mL) concentrated sulfuric acid was added dropwise (10 drops). After stirring under reflux for 12 h, the reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3 solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (petroleum ether/ethyl acetate = 5:1) to afford 2a.
With thionyl chloride at 0 - 65℃; for 48.16h;
4.1.3. General procedure for the synthesis of intermediates 6a-6h
General procedure: Methyl 4-bromosalicylate (1 mol) was dissolved in methanol(25 mL), and thionyl chloride was added dropwise under ice-cooling,after 10 min, The mixture was stirred at 65 °C for 48 h. and monitoredby TLC. After the reaction was completed, excess methanol was evaporated,the residue was extracted with ethyl acetate and aqueous sodiumcarbonate, and the organic phase was added to anhydrous sodiumsulfate and concentrated to obtain intermediate 6a.The compounds 6b-6h were prepared analogously.
With thionyl chloride at 0 - 20℃; for 15h; Inert atmosphere;
With methanesulfonic acid; phosphorus pentoxide at 90℃; for 0.25h;
70.1%
With zinc(II) chloride; trichlorophosphate at 75℃; Microwave irradiation;
2 5.2.3. Synthesis of 1,3-dihydroxyxanthones (2a ~ i)
General procedure: The synthesis refers to a procedure described in the literature [43]. To a 50-mL flask 8mL phosphorus oxychloride (POCl3) and anhydrous zinc chloride (6.8g, 0.05mol) were added. The suspension was stirred at 70°C until ZnCl2 was completely dissolved into phosphorus oxychloride. The mixture was then cooled down to room temperature (r.t.). Afterwards, salicylic acids (1a-i) (l.0mmol) and 1,3,5-trihydroxybenzene (1.1mmol) were added, respectively, and the mixture was heated with microwave reactor with a programmed procedure of 75°C for 30min, where the power was 200W. Then the mixture was cooled down to r. t. and pulled into ice water stirring for 20min. The mixed solution was filtered, washed with cold water. The solid residues were collected and purified by flash column liquid chromatography. 5.2.3.1. Synthesis of 1,3-dihydroxy-6-methyl-9H-xanthen-9-one (2a).Light yellow powder, m. p. 193e195 C, yield 70.1%. 1H NMR(DMSO-d6, 300 MHz) d: 10.85 (s, 1H, OH), 10.29 (s, 1H, OH), 7.96 (d,J 8.1 Hz,1H, H-8), 7.71 (d, J 2.1 Hz, 1H, H-5), 7.34 (t, J 8.1 Hz,1H,H-7), 6.43 (d, J 1.8 Hz, 1H, H-4), 6.22 (d, J 1.8 Hz, 1H, H-2), 2.42(s, 3H, CH3). 13C NMR (DMSO-d6, 75 MHz) d: 180.4 (C-9), 166.4 (C-3), 163.2 (C-1), 157.7 (C-4a), 154.1 (C-4b), 136.7 (C-6), 127.1 (C-8),124.2 (C-7), 123.2 (C-8a), 120.1 (C-5), 102.4 (C-8b), 98.6 (C-2), 94.6(C-4), 15.6 (-CH3); MS-ESI m/z: 243.1 [MH].
44.6%
With zinc(II) chloride; trichlorophosphate at 70℃; for 3.5h;
1 1,3-dihydroxy-6-methyl-9H-xanthone
The amount of taking 100ml of phosphorus oxychloride, weighed 30g of zinc chloride, added to the three-necked flask 250ml, stir until heated to 60 ° C,After 1 h of reaction, 15.2 g of 4-methylsalicylic acid and 18.4 g of phloroglucinol (both dried) were added,After the reaction temperature was stable, it was slowly heated to 70 ° C. After 3.5 hours of reaction, the sample was sampled. After TLC detection (petroleum ether:Ethyl acetate = 2: 1). The reaction was complete and the reaction was stopped. After cooling, the mixture was poured into about 1500 ml of ice water, stirred,Filtered and washed to neutral. The filter cake was dried and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1)10.8 g of a pale yellow powder was obtained in a yield of 44.6%.
With zinc(II) chloride; trichlorophosphate
With methanesulfonic acid; phosphorus pentoxide at 80℃;
With Eaton′s Reagent at 80℃; for 3h;
6.1.1. Synthesis of substituted 1,3-dihydroxy-9H-xanthen-9-ones (32)
General procedure: To a mixture of commercially available phloroglucinol (1.2 equiv) and an appropriate substituted salicylic acid (1 equiv), 20 mL of Eaton's reagent (P2O5-CH3SO3H) was added slowly. The mixture was stirred for 3 h at 80 °C, cooled to rt, and poured onto ice. After vigorous stirring at rt for 2 h, a brown solid was precipitated. The solid was collected by filtration, washed with water (pH ∼ 6), and dried at 60 °C. In most instances, this intermediate 1,3-dihydroxy-9H-xanthen-9-one was used without further purification.
With methanesulfonic acid; phosphorus pentoxide at 100℃; for 0.25h;
Intermediate compound 247: ethyl 2-hydroxy-4-methylbenzoate
To a solution of 2-hydroxy-4-methylbenzoic acid (65.7 mmol, 10000 mg) in EtOH (178 ml), sulfuric acid (89.0 mmol, 8700 mg) was added. The mixture was refluxed for 16h. Solvent was evaporated. It was washed twice with EtAcO /satured NaHC03 aqueous solution. The combined organic layers were dried over Na2S04, filtered and evaporated. (7702 mg, yield: 65%). LC-MS: tR = 2.51 [M+H]+ = 181 (method 6)
With hydrogenchloride
With sulfuric acid for 48h; Heating;
With sulfuric acid Reflux;
With sulfuric acid
With sulfuric acid Reflux;
With sulfuric acid Reflux;
1
Take 1mmol 4-methyl salicylic acid added to 50mL absolute ethanol, and add 5mL of concentrated sulfuric acid, refluxed overnight. About a fifth of the remaining vacuum distillation, adding 20mL of water, extracted with ethyl acetate,Washed sequentially with saturated NaHCO3 and saturated NaCl and finally dried over anhydrous MgSO4,Decompression distillation to give 4 - methyl salicylicester;Dissolve 4-methyl salicylate in 50 mL of absolute ethanol, add 15 mL of hydrazine hydrate and reflux overnight.The solvent after the reaction was distilled under reduced pressure, until no liquid out, add water,To obtain 4-methyl salicyloyl hydrazide; hydrazide into a 50mL round bottom flask, was dissolved in 30mL absolute ethanol, adding an equal molar mass of carbon disulfide, under basic conditions (potassium hydroxide) was refluxed for 24 hours,The crude reaction product is dried and recrystallized to obtain a series of 2-thio-1,3,4-oxadiazole derivatives.An equal molar mass of 2-thio-1,3,4-oxadiazole derivative and 2-bromoacetophenone were put into a 25 mL round bottom flask and dissolved in 5 mL of 80% ethanol and stirred at room temperature for 4- 6h,The excess solvent was distilled off under reduced pressure, then the crude reaction was poured into ice water, allowed to stand for 1-2 hours, filtered and washed with water. The resulting precipitate was dried and recrystallized from methanol to give the title compound. White powder,Yield 83%,
With nitrosylsulfuric acid; nitric acid at 30 - 40℃;
With nitric acid; acetic anhydride; acetic acid In dichloromethane; water at 0 - 20℃; for 1.18333h;
51
4-Methylsalicylic acid (17 g, 112 mmol) was suspended in methylene chloride (120 mL) and acetic anhydride (35 mL) was added together with acetic acid (7 mL).The mixture was cooled using an ice bath. Nitric acid (7mL, 90%) was added over 1 minute, the mixture was stirred for 10 min and nitric acid (4 mL) was added slowly until the reaction mixture was clear. The stirring was continued for 60 min at ambient temperature during which a precipitate formed. Hexane (120 mL) was added and the stirring was continued for 10 min. The solids were collected by filtration and washed with a small amount of hexane. The remaining solvent was removed under high vacuum to give 7.5 g of a white solid. This reaction was repeated to give more starting material for further synthesis.The 5-nitro-4-methylsalicylic acid (9.7 g, 49 mmol) was dissolved in ethanol (150 mL) and thionyl chloride (9 mL) was added. The mixture was heated to reflux for 24 hr. The solvent was removed under vacuum and the residue was dissolved in a solution of sodium bicarbonate (200 mL) in ethyl acetate (200 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (200 mL). The organic phases were combined, dried over sodium sulfate and concentrated under vacuum to give 10.7 g (48 mmol) of solid ethyl ester intermediate. The solid was dissolved in a mixture of dioxane (100 mL) and toluene (200 mL) and the volume was reduced under vacuum to about 80 mL. DMF (20 mL) and toluene (150 mL) were added together with potassium carbonate (20 g) and 4-methoxybenzyl chloride (9.0 g, 57 mmol). Sodium iodide (1.0 g) was added and the mixture was stirred for three days. The solids were removed by filtration and washed with ethyl acetate (2 * 100 mL). The filtrate was concentrated under vacuum, dissolved in a small amount of chloroform, then purified using flash chromatography (17O g silica gel, hexane: chloroform: ethyl acetate, 60:35:5). Clean product fractions and mixed fractions eluted. The product fractions were combined and concentrated under vacuum. Hexane was added to dissolve residue and crystals formed as the solution was slowly concentrated. The crystals were collected by filtration to give 12.4 g of the 4-methoxybenzyl ether derivative. Another 0.94 g was recovered from the mother liquor and the mixed fractions by performing further purification using flash chromatography. The product from the previous step (13.3 g, 38.6 mmol) and N,N-dimethylformamide dimethyl acetal (25 g) were added to DMF (10 mL) and kept at 125 0C for 18 hr. The solvent was removed under vacuum and the residue was dissolved in THF (120 mL). A solution of sodium periodate (30 g, 140 mmol) in water (250 mL) was added and the mixture was stirred for 30 min. Ethyl acetate (100 mL) was added, the solids were removed by filtration. The phases were separated and the aqueous phase was extracted with ethyl acetate (200 mL). The organic phases were combined, dried over sodium sulfate and concentrated to give a brown, sticky solid. Methanol (100 mL) was added and the insoluble material was collected by filtration (2.45 g). The filtrate was concentrated to give a sticky, brown oil (12.9 g). It was dissolved in a small amount of chloroform and evaporated onto silica gel (15 g). The silica gel was transferred to a column (100 g silica gel) and purified using 500 mL hexane:chloroform:ethyl acetate, 60:35:5, then 40:55:5. The product fractions were concentrated under vacuum and crystals started to form when a small volume remained. Methanol (100 mL) was added and the solids were collected by filtration. The solids were dried under high vacuum to give 3.4 g of an off white solid. An additional 4.45g were recovered from the motherliquor. A total of 7.95 g of nitro aldehyde intermediate was thus collected.The nitro aldehyde derivative (3.4 g, 9.5 mmol) from the previous step was dissolved in dry DMF (50 mL) and oxone (6.76 g, 11 mmol) was added. The mixture was stirred for 18 hours and chloroform (150 mL) was added. The solids were removed by filtration and the filtrate was concentrated by vacuum to a remaining volume of about 30 mL. To this DMF solution was added DMAP (1.16 g, 9.5 mmol), HOBT (1.28 g, 9.5 mmol), triethylamine (3 mL, 22 mmol), 3-fluorophenethylamine (1.7 g, 12.2 mmol) and EDCI (5 g, 26 mmol). The mixture was stirred at ambient temperature over night. The solvent was removed under vacuum and water (300 mL) was added together with 2M sulfuric acid (enough to bring pH to 2). The solution was extracted with ethyl acetate (2 x 250 mL) and the organic phase was washed with sodium bicarbonate solution (100 mL). The organic phase was dried over sodium sulfate, and concentrated to about 12 mL. A little chloroform was added (to keep the product in solution) and the product was purified using flash chromatography (100 g silica gel, ethyl acetate:hexane, 500 mL 40:60, 250 mL 50:50, 250 mL 60:40). The product fractions were combined and concentrated under vacuum to start crystallization of the amide derivative as a white solid (3.45 g).The reduction of the nitro group to the amine, using 1Og Zn/Cu and the following ring closure using isoamylnitrite was carried out as in Example 3 using 1.13 g (2.27 mmol) of the product from the previous step. The reaction gave 0.93 g of a yellowish solid. The triazinone from the previous step (0.93 g, 1.95 mmol) was dissolved in methylene chloride (50 mL) and trifluoroacetic acid (1.5 mL, 19 mmol) was added. The mixture was stirred for 60 min at ambient temperature. The solvent was removed under vacuum, chloroform (20 mL) was added and the solvent was again evaporated. The residue was dissolved in THF (10 mL) and methanol (15 mL) and a solution of potassium hydroxide (3.0 g, 53 mmol, 15 mL) was added. The mixture was left at ambient temperature for 90 min. The organic solvents were removed under vacuum and the aqueous residue was washed with methyl t-butylether (30 mL). Hydrochloric acid was added until pH reached 3 and the product started precipitating. The product was extracted with chloroform:THF, 3:1 (2 x 40 mL) and concentrated under vacuum (followed by high vacuum) to a constant weight to give 624 mg of a yellow solid. This step in the synthesis was repeated to give more starting material for the next step.The salicylic acid from the previous step (0.781 g, 2.37 mmol) was dissolved in chloroform (30 mL) and ethyl acetate (20 mL). CDI (2.0 g, 12.3 mmol) was added followed by DMF (about 10 mL) until a clear solution was obtained. The solution was stirred for 2 hr at ambient temperature after which ethanolamine (5 mL in 20 mL THF) was added. The mixture was stirred for three days. The solvent was removed under vacuum and 2N hydrochloric acid (40 mL) was added. The product was extracted with chloroform:methanol, 5:1 (2 * 75 mL) and the solvent was removed under vacuum (followed by high vacuum) to give 1.09 g (<2.9 mmol) of crude amide derivative. The crude product from the previous step (1.09 g) was dissolved in a mixture of toluene (100 mL) and dioxane (30 mL). The solution was placed in a distillation apparatus. Toluene sulfonic acid (50 mg) was added as a catalyst and the solution was heated until distillation started. Trimethylorthoformate (4 mL in 6 mL toluene) was added over 10 min. A total of about 90 mL had distilled off at the completion of the reaction. The solution was cooled to ambient temperature and ethyl acetate (100 mL) was added. The reaction mixture was washed with sodium bicarbonate solution (50 mL), dried over sodium sulfate and concentrated to the point when crystals started forming. After crystallization was complete, the crystals were collected and dissolved in chloroform (12 mL) and filtered through 2 mm of silica gel. The silica was washed with a small amount of chloroform, then ethyl acetate was added to the filtrate and the solution was slowly concentrated until crystals started to form. The supernatant was removed and the crystals were dried under high vacuum to give 170 mg of product. It was combined with product from repeated syntheses, purified further using flash chromatography (50 g silica gel, chloroform:THF 96:4) and crystallized from chloroform:methyl t-butylether to give a white solid with the following properties: MP: 191- 193 0C; 1H NMR (300 MHz, CDCl3) δ 8.74 (IH, s), 7.95 (IH, s), 7.29 - 6.89 (4H, m), 6.35 (IH, s), 4.71-4.66 (2H, m), 4.42-4.27 (3H, m), 3.73-3.63 (IH, m) and 3.25-3.20 ppm (2H, m).
With bromine; In methanol; at -20 - 20℃; for 1.5h;
To a mixture of 2-hydroxy-4-methylbenzoic acid (24.5 g, 161 mmol) in methanol (300 mL) was added dropwise a solution of bromine (28 g, 180 mmol) in methanol (50 mL) at -20 C and the reaction mixture was stirred for 0.5 h, then warmed to rt and stirred for another 1 h. The reaction was quenched with saturated aquous sodium sulfite (100 mL). The reaction mixture was concentrated to remove methanol and the residue was diluted with water (50 mL).The mixture was filtered and the filtrate was dried to give a red-brown solid (33 g, 89 %).MS (ESI, pos. ion) m/z: 231.1 [M+H]t
With bromine; In methanol; at -20 - 20℃; for 2.0h;
After dissolving 2-hydroxy-4-methylbenzoic acid (24.54 g, 161.29 mmol) in methanol (300 ml), the solution was cooled to -20C. A solution of bromine (26.03 g) in methanol (50 ml) was added dropwise over 1 hour. The reaction mixture was stirred at room temperature for 1 hour and then concentrated. The residue was heated to dissolution in methanol (100 ml) and water (40 ml) was added. The precipitated crystals were filtered off and washed with 50% methanol-water. The precipitated crystals in the filtrate were also filtered off and washed with 50% methanol-water. The crystals were combined and dried to yield the title compound (24.8 g) as white crystals.1H-NMR(CDCl3)δ(ppm) 2.37(3H,s), 6.85(1H,s), 7.98(1H,s).
6.78 g
With bromine; In acetic acid; at 10 - 35℃; for 5.5h;
A) 5-bromo-2-hydroxy-4-methylbenzoic acid To a solution of 2-hydroxy-4-methylbenzoic acid (5.00 g) in acetic acid (70.0 mL) was added dropwise bromine (1.68 mL) , and the mixture was stirred at room temperature for 5.5 hr. To the reaction mixture was added water, and the precipitate was collected by filtration, and dried under reduced pressure to give the title compound (6.78 g) . MS: [M-H]+ 229.0.
126 g
With bromine; acetic acid; at 10 - 35℃;
To a mixture of 2-hydroxy-4-methylbenzoic acid (100 g) and acetic acid (1100 mL) was added dropwise bromine (34 mL) at room temperature, and the mixture was stirred at roomtemperature overnight. Water (800 mL) was added thereto, and the mixture was stirred at room temperature for 30 min. The precipitates were collected by filtration and washed with water to give the title compound (126 g) .MS: [M-H]~228.9, 230.9.
With N-Bromosuccinimide; sulfuric acid; for 2.0h;
Taking compound 1 b (761 mg, 5 mmol) is dissolved in concentrated sulfuric acid (5 ml), under ice bath is added in batches N - bromosuccinimide (979 mg, 5.5 mmol). Reaction 2 h TLC monitoring display after the completion of the reaction. The reaction liquid dropping slowly adding 40 ml ice water, white solid precipitated, filtered, solid to ice water (10 ml) washing, drying, to obtain compound 2 b crude product (white solid, 820 mg, crude yield 71%). The crude product without further purification directly used for the next step reaction.
With sulfuric acid at 20℃; for 1h; Inert atmosphere;
8.B3 Example 8: Synthesis procedures B3: 4Me-NO-ASA
In an inert 250 mL three-necked round bottom flask 6.00 g (39.4 mmol, 1.00 eq) 2-hydroxy-4-methylbenzoic acid and 13.1 g (159 mmol, 12.1 mL, 3.26 eq) acetic acid anhydride were mixed. To this suspension a catalytic amount (69.5 mg (990 μηιοΙ, 52.5 il, 0.03 eq)) of concentrated sulphuric acid was added. After 1 hour 83.7 mL water were added and stirring was continued for additional 13 h. The precipitate was filtered off, washed with 200 mL water. The title compound was obtained as a colourless solid in 6.79 g (34.9 mmol, 89 %).
With pyridine; diethyl ether
With quinoline
With sulfuric acid at 90℃;
Heating;
With sulfuric acid
With sulfuric acid
With phosphoric acid at 80℃; for 0.5h;
With phosphoric acid
With triethylamine In tetrahydrofuran at 20℃; Inert atmosphere; Cooling with ice;
With tetrabutylammomium bromide; sodium hydroxide In ethanol; dichloromethane; water at 20 - 100℃; for 4h;
1 Step 1 :
To the biphasic mixture of 2-hydroxy-4-methylbenzoic acid (10.0 g, 65.7 mmol), TBAB (2.1 g, 6.6 mmol) and NaOH (7.9 g, 197 5 mmol) in 3:2 v/v CH2CI2-water (100 rnL), BnBr (23.4 rnL, 197 5 mmol) was added dropwise and stirred at rt. After 3 h, the organic phase was separated and concentrated in vacuo. The residue was dissolved in EtOH, 2M NaOH solution (66 mL, 131 .5 mmol) was added and heated at 100 °C for 1 h. The reaction mixture was concentrated in vacuo , diluted with water and extracted with Et20 twice. The aqueous layer was acidified with 6N aqueous HC solution, extracted with EtOAc thrice. The combined organic solution was washed with brine solution, dried over anhydrous Na2SG4 and concentrated in vacuo to afford 2-(benzyloxy)-4-meihyibenzoic acid (15.0 g, 94% yield) as a white solid. 1 H N R (300 MHz, CDCI3) d ppm 10.74 (brs, 1 H), 8.08 (d, J= 7.8 Hz, 1 H), 7.45 - 7.36 (m, 5H), 6.78 - 6.94 (m, 2H), 5.27 (s, 2H), 2.42 (s, 3H).
90%
With sodium hydroxide In dichloromethane at 20℃; for 3h;
(a) 2-Methoxy-4-methylbenzoic acid A stirred mixture of 2-hydroxy-4-methylbenzoic acid (75 g, 0.50 mol), sodium hydroxide (42 g, 1.0 mol) and water (250 ml) was cooled to 10 C. and treated dropwise with dimethyl sulphate (126 g, 1.0 mol). The mixture was stirred for 6 days, poured into water (4000 ml), acidified with sulfuric acid and extracted with dichloromethane (4*600 ml). The extracts were combined, washed with water, dried over sodium sulfate and the solvent was evaporated off under reduced pressure. The resulting oil was treated with aqueous sodium hydroxide (1000 ml of 2M) and heated under reflux for 2 hours. The mixture was acidified with hydrochloric acid and extracted with dichloromethane (3*300 ml). The combined extracts were dried over sodium sulfate and the solvent was evaporated off under reduced pressure to give the crude product as an oil. The crude product was purified by column chromatography (silica gel, chloroform) and recrystallized from chloroform-hexane to yield 2-methoxy-4-methylbenzoic acid as a colorless crystalline solid, having a melting point of 108-109 C.
With sodium hydroxide; In water;
a) 2-Methoxy-4-methylbenzoic acid . A stirred mixture of 2-hydroxy-4-methylbenzoic acid (75 g, 0.50 mol), sodium hydroxide (42 g, 1.0 mol) and water (250 ml) was cooled to 10C and treated dropwise with dimethyl sulphate (126 g, 1.0 mol). The mixture was stirred for 6 days, poured into water (4000 ml), acidified with sulfuric acid and extracted with dichloromethane (4 x 600 ml). The extracts were combined, washed with water, dried over sodium sulfate and the solvent was evaporated off under reduced pressure. The resulting oil was treated with aqueous sodium hydroxide (1000 ml of 2M) and heated under reflux for 2 hours. The mixture was acidified with hydrochloric acid and extracted with dichloromethane (3 x 300 ml). The combined extracts were dried over sodium sulfate and the solvent was evaporated off under reduced pressure to give the crude product as an oil. The crude product was purified by column chromatography (silica gel, chloroform) and recrystallized from chloroform-hexane to yield 2-methoxy-4-methylbenzoic acid as a colorless crystalline solid, having a melting point of 108-109C.
4-methyl salicylic acid (5 mmol of) was dissolved in 15mL of distilled water, 37 C water bath, adjusted with 30% NaOH solution to pH 10, stirred for 30min, slowly added dropwise 2 mL of dimethyl sulfate, the reaction until the solution becomes pH 7, then 30% NaOH solution pH was adjusted to 10, after the reaction I H, dimethyl sulfate dropwise slowly again I mL, the reaction solution until the pH becomes 7, and then 30% NaOH solution pH was adjusted 10, the reaction I h, at 80 C for hydrolysis water bath 15 min, TLC monitoring progress of the reaction (eluent, ethyl acetate: petroleum ether = 1: 1~1: 4), cooled to room temperature, 10% HCl adjusted to pH 5, white gray precipitate formed, 50 (: precipitate washed with distilled water, and the precipitate was dried in vacuo; the dried precipitate was dissolved in IOmL of dichloromethane, was added two drops of DMF and 0.5mL of thionyl chloride, 40 C in an oil bath heated at reflux for 0.5 h, dichloromethane was distilled off under reduced pressure, and thionyl chloride, dissolved in IOmL of acetone, was added 5,6,7-trimethoxy-1 obtained in Example 4 '- hydroxyflavone 80mg, by ImL of triethylamine was added dropwise, the reaction 3 h, filtration, recovery of acetone, purified by silica gel column chromatography, eluent: ethyl acetate: petroleum ether = 1: 1~1: 4, to give compound 4_ (5 6,7-trimethoxy-4-oxo -4H- chromen-2-yl) phenyl 2-methoxy-4-methylbenzoate. Pale yellow powder, 47% yield
Dissolve 7.60g of raw material 2-hydroxy-4-methylbenzoic acid in 60ml of acetone, add 10.4g of potassium carbonate and stir at room temperature for 10minThen, at room temperature, 5ml of methyl iodide was added dropwise to the reaction bottle, the dropwise addition was completed within 5 minutes, and then the reaction was refluxed for 4h,Cooled to room temperature, suction filtered, the mother liquor was removed from the acetone on a rotary evaporator, and dried to obtain 8.84 g of white solid with a yield of 98.2%.
93%
Potassium carbonate (817.5 mg; 5.92 mmol; 3.00 eq.) was added to a solution of 4-methylsalicylic acid (300.0 mg; 1.97 mmol; 1.00 eq.) in DMF (6.00 ml) and the mixture was stirred 10 min at rt. Then, methyl iodide (368 pi; 5.92 mmol; 3.00 eq.) was added and the mixture was stirred 19h at rt. The mixture was then extracted with EtOAc and the organic layer washed with brine, dried over MgS04, filtered and concentrated under vacuum to give methyl 2-methoxy-4-methyl-benzoate (330.3 mg; 93 %) as an orange oil.
91%
With potassium carbonate; In DMF (N,N-dimethyl-formamide); for 18h;
To a mixture of 2-hydroxy-4-methylbenzoic acid(30.43 g, 200 mmol) , K2CC>3 (62.19 g, 450 mmol) and DMF(600 mL) was added methyl iodide (28.01 mL, 450 mmol). Thereaction was stirred for 18 h, poured into ice/water(1.2 L), and extracted with EtOAc (2 X 300 mL). Thecombined organic layer was washed with brine, satd NaHCC>3and dried (MgSC>4) . The resulting solution was concentratedand distilled to give the title compound as a pale yellowliquid (32.73 g, 91%, bp 120-4 C/1333 Pa, 10 mm).(400MHz, CDCls): 5 2.40 (s, 3H), 3.90 (s, 3H), 3.93 (s,3H), 6.80 (m, 2H), 7.75 (d, J = 7.6 Hz, 1H).FIA-MS, m/e: 180.9 (m+1).
86%
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 40℃; for 12h;
Step 1: To a mixture of 2-hydroxy-4-methylbenzoic acid (80 g, 0.5 mol) and K2C03 (218 g, 1.58- mol) in DMF (300 mL) was added iodomethane (224 g, 1.5 mol) dropwise at 0 C. The resulting mixture was stirred at 40 C for 12 h. The reaction mixture was filtered, and the filtrate was partitioned into water (1,500 ml) and ethyl acetate (800 ml). The organic layer was collected, washed with water (300 ml x 2) and brine (300 ml), dried over Na2SO4 and concentrated under reduce pressure to give a crude product which was purified through silica gel flash column chromatography (cyclohexane/ethyl acetate = 10/i) to afford methyl 2-methoxy-4- methylbenzoate as a yellow oil (82 g, 86%). LC/MS (ES) calcd for C10-H1203: 180.1; found:181.0 [M+H]. ?HNMR (400 MHz, CDC13): 7.72 (d, J= 8.0 Hz, 1H), 6.78-6.79 (m, 211), 3.89 (s, 3H), 3.86 (s, 3H), 2.38 (s, 311).
86%
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 40℃; for 12h;
Step 1: To a mixture of 2-hydroxy-4-methylbenzoic acid (80 g, 0.5 mol) and K2CO3 (218 g, 1.58 mol) in DMF (300 mL) was added iodomethane (224 g, 1.5 mol) dropwise at 0 C. The resulting mixture was stirred at 40 C for 12 h. The reaction mixture was filtered, and the filtrate was partitioned into water (1,500 mL) and ethyl acetate (800 mL). The organic layer was collected, washed with water (300 mL x 2) and brine (300 mL), dried over Na2S04, and concentrated under reduce pressure to give a crude product which was purified through silica gel flash column chromatography (cyclohexane/ethyl acetate = 10/1) to afford methyl 2-methoxy-4- methylbenzoate as a yellow oil (82 g, 86%). LC/MS (ES+) calcd for C10H12O3: 180.1; found: 181.0 [M+H] NMR (400 MHz, CDCb): d 7.72 (d, J= 8.0 Hz, 1H), 6.78-6.79 (m, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 2.38 (s, 3H).
86%
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 40℃; for 12h;
To a mixture of 2-hydroxy-4-methylbenzoic acid (80 g, 0.5 mol) and K2CO3 (218 g, 1.58 mol) in DMF (300 mL) was added iodomethane (224 g, 1.5 mol) dropwise at 0 C. The resulting mixture was stirred at 40 C. for 12 h. The reaction mixture was filtered, and the filtrate was partitioned into water (1,500 mL) and ethyl acetate (800 mL). The organic layer was collected, washed with water (300 mL*2) and brine (300 mL), dried over Na2SO4, and concentrated under reduce pressure to give a crude product which was purified through silica gel flash column chromatography (cyclohexane/ethyl acetate=10/1) to afford methyl 2-methoxy-4-methylbenzoate as a yellow oil (82 g, 86%). LC/MS (ES+) calcd for C10H12O3: 180.1; found:181.0 [M+H]. 1H NMR (400 MHz, CDCl3): delta 7.72 (d, J=8.0 Hz, 1H), 6.78-6.79 (m, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 2.38 (s, 3H).
With potassium carbonate; In N-methyl-acetamide;
Methyl 2-methoxy-4-methylbenzoate: Methyl iodide (123 mL, 1.95 mole) was added to a stirred suspension of potassium carbonate (360.0 g, 2.60 mole) in a solution of 2-hydroxy-4-methylbenzoic acid (100.0 g, 0.651 mole) in dimethylformamide (1500 mL) at room temperature. After stirring overnight, the reaction mixture was poured onto ice water (1000 mL) and the aqueous mixture extracted several times with ethyl acetate. The organic layers were combined, dried (Na2 SO4), and stripped in vacuo to give a brown oil. After passage over silica gel using 20% ethyl acetate/hexane as the eluent, there was obtained 116.7 g of the title compound as an oil which was a single spot on thin layer chromatography (Rf 0.35, 20% ethyl acetate/hexane). NMR (CDCl3, 300 MHz, ppm): 2.4 (s, 3H); 3.87 (s, 3H); 3.9 (s, 3H); 6.78 (s, 1H); 6.8 (d, 1 =J Hz, 1 h); 7.72 (d, J= 7 Hz, 1H).
With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 25℃; for 5h;
EXAMPLE 1-2: Production of 5-(2-amino-6-chloropyrimidin-4-yl)-2-methoxy-4-methylbenzoic acid methyl ester (Compound 1-2) [Show Image] Step 1: Preparation of 2-methoxy-4-methylbenzoic acid methyl ester [Show Image] Commercially available 2-hydroxy-4-methylbenzoic acid (1.5 g, 10.0 mmol) and cesium carbonate (13.0 g, 40.0 mmol) were placed in a reaction vessel, and then N,N-dimethylformamide (40 ml) and methyl iodide (2.5 ml) were added thereto. The resulting mixture was stirred at room temperature for 5 hours. The reaction solution was filtered through celite and washed with ethyl acetate (300 ml). The filtrate was sequentially washed with water (100 ml) and a saturated aqueous sodium chloride solution (200 ml). Then, the filtrate was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 2-methoxy-4-methylbenzoic acid methyl ester (1.4 g) as a pale yellow oily material. Physicochemical properties of 2-methoxy-4-methylbenzoic acid methyl ester: Molecular weight: 180.ESI (LC/MS positive mode): m/z = 181 (M+H+).Chemical shift value delta in 1H-NMR (400 MHz, in dimethylsulfoxide d-6): 2.35 (3H,s), 3.75 (3H, s), 3.80 (3H, s), 6.83(1H, dd, J=4Hz, 8Hz), 6.97 (1H, d, J=4Hz), 7.56 (1H, d, J=8Hz).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;
Example 62 6-Amino-2-ethoxy-9-(3-methoxy-4-morpholin-4-ylmethylbenzyl)-7,9-dihydropurin-8-one 2-Hydroxy-4-methylbenzoic acid (600 mg, 4 mmol), methyl iodide (1.4 g, 10 mmol) and potassium carbonate (1.4 g, 10 mmol) were added to DMF (10 mL), and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and to the residue were added ethyl acetate and water. The mixture was separated, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and to the residue were added NBS (700 mg, 5 mmol), benzoyl peroxide (100 mg) and carbon tetrachloride (6 mL), and the mixture was stirred at 80C for 5 hours. The insoluble materials were separated by filtration, and the filtrate was washed with sodium thiosulfate and water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was added to 2-ethoxy-8-methoxyadenine TFA salt (250 mg, 0.8 mmol), potassium carbonate (420 mg, 3 mmol) and DMF (5 mL), and the mixture was stirred at room temperature overnight. The solvent was removed by evaporation, and water and chloroform were added to the residue, and the mixture was separated. The organic phase was dried over magnesium sulfate, and purified by silica gel column chromatography (CHCl3/MeOH=50/1) to give a white solid (310 mg). This solid and lithium aluminum hydride (74 mg, 2 mmol) were added to THF (10 mL), and the mixture was stirred under ice-cooling for 2 hours. The insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue were added thionyl chloride (0.3 mL) and dichloromethane (5 mL), and the mixture was stirred at 40C for 2 hours. The solvent was removed by evaporation, and to the residue were added morpholine (0.2 mL), diisorpopylethylamine (0.5 mL) and DMF (5mL), and the mixture was heated at 80C with stirring for 2 hours. The solvent was removed by evaporation, and the residue was purified by silica gel column chromatography (CHCl3/MeOH/28 % NH3=100/3/2) to give the title compound (46 mg). 1H NMR (DMSO-d6) delta 9.95 (1H, s), 7.22 (1H, d, J = 8.0 Hz), 7.00 (1H, d, J = 1.2 Hz), 6.78 (1H, dd, J = 1.4, 8.0 Hz), 6.46 (2H, s), 4.83 (2H, s), 4.20 (2H, q, J = 7.0 Hz), 3.74 (3H, s), 3.54 (4H, t, J = 4.6 Hz), 3.40 (3H, s), 2.34 (4H, m), 1.25 (3H, t, J = 7.0 Hz).
With potassium carbonate; In acetone; at 50℃; for 5h;
Description 42Methyl 4-methyl-2-(methyloxy)benzoate (D42)To a suspension of 2-hydroxy-4-methylbenzoic acid (2.5 g, 16.43 mmol) in acetone (25 ml) was added potassium carbonate (7.49 g, 54.2 mmol) and iodomethane (4.32 ml, 69.0 mmol). The mixture was heated at 50C for 5 hours, cooled and the acetone was removed in vacuo. The mixture was partitioned between ethyl acetate (30 ml) and water (20 ml). The organic layer was separated, dried (MgS04) and the solvent removed in vacuo. Purification by column (Si02, 6: 1 cyclohexane/ethyl acetate) gave the title compound as a solid. 2.51 g. MS (electrospray): m/z [M+H]+ 181
With potassium carbonate; In acetone; for 48h;Reflux;
To a solution of 2-hydroxy-4-methylbenzoic acid (25 g, 0.164 mol) in acetone (350 mL) was added K2CO3 (68 g, 0.492 mmol) followed by MeI (41 mL, 0.656 mmol) and the reaction mixture heated at reflux for 48 hrs. After cooling to r.t. the reaction mixture was filtered and the filtrate was evaporated to give the crude methyl 2-methoxy-4-methylbenzoate. KOH (11.3 g, 1.2 eq) was dissolved in MeOH (300 mL) and the crude ester was added to the mixture and the solution heated at reflux 48 hrs. After cooling the reaction mixture was acidified with aq. HCl (1N) and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was triturated with Ethyl acetate/Hexane to give 20 g of 2-methoxy-4-methylbenzoic acid as a cream white solid (85% yield)
10 g
To a solution of 2-hydroxy-4-methylbenzoic acid (10.00 g, 65 mmol) in DMF (10 mL) was added K2CO3 (13.6 g, 98 mmol). The reaction mixture was stirred at 60C for 1 h. Methyl iodide (14.0 g, 98 mmol) was added to the reaction mixture and was stirred at 60C for 18 h. The reaction mass was quenched in water and concentrated. The reaction mass was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 10.00 g of desired product. 1H NMR (300 MHz, DMSO d6): delta 2.34 (s, 3H), 3.74 (s, 3H), 3.79 (s, 3H), 6.81 (d, J = 7.2 Hz, 1H), 6.97 (s, 1H), 7.56 (d, J = 7.8 Hz, 1H); MS (m/z): 180.95 (M+H)+.
11.0 g
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
To a mixture of 2-hydroxy-4-methylbenzoic acid (10.0 g, 65.7 mmol) and K2CO3 (22.7 g, 164.3 mmol) in DMF (200 mL) at room temperature was added methyl iodide (20.5 g, 144.5 mmol) over a period of 10 minutes. The resulting mixture was stirred at room temperature overnight, then diluted with DCM (150 mL) and filtered. The filtrate was washed with water (200 mL x 10) and brine (200 mL x 2), dried a2S04) and concentrated to give the intermediate as a yellow liquid (1 1.0 g)
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
Reference Example 15; Methyl 2-methoxy-4-methylbenzoate; [Show Image] To a solution of 2-hydroxy-4-methylbenzoic acid (4.56 g) in DMF (70 ml) were added potassium carbonate (16.6 g) and methyl iodide (12.8 g), and the mixture was stirred at room temperature overnight. Then, the reaction mixture was poured into ice water (50 ml), and extracted with ethyl acetate. The organic layer was washed with water, then a saturated saline, and then dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [hexane:ethyl acetate = 2:1] to give the titled compound (5.41 g) as a pale yellow oil. 1H-NMR(CDCl3): delta 2.39(3H, s), 3.87(3H, s), 3.90(3H, s), 6.79(2H, m), 7.73(1H, d, J=8.4)
With potassium hydrogencarbonate In N,N-dimethyl-formamide at 40℃;
86%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile
With potassium hydrogencarbonate In N,N-dimethyl-formamide at 40℃; for 4h;
1-3.1
EXAMPLE 1-3: Production of 5-(2-amino-6-chloropyrimidin-4-yl)-2-ethoxy-4-methylbenzoic acid methyl ester (Compound 1-3) [Show Image] Step 1: Preparation of 2-hydroxy-4-methylbenzoic acid methyl ester [Show Image] Commercially available 2-hydroxy-4-methylbenzoic acid (1.0 g, 7.0 mmol) and potassium bicarbonate (841 mg, 8.4 mmol) were placed in a reaction vessel, and then N,N-dimethylformamide (10 ml) and methyl iodide (0.65 ml, 10.5 mmol) were added thereto. The resulting mixture was stirred at 40°C for 4 hours. The reaction solution was diluted with ethyl acetate (200 ml), and sequentially washed with water (70 ml), with a saturated aqueous sodium bicarbonate solution (70 ml), twice with water (70 ml), and with a saturated aqueous sodium chloride solution (70 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to yield 2-hydroxy-4-methylbenzoic acid methyl ester (1.1 g) as a pale yellow oily material. Physicochemical properties of 2-hydroxy-4-methylbenzoic acid methyl ester: Molecular weight: 166.ESI (LC/MS positive mode): m/z = 167 (M+H+).Chemical shift value δ in 1H-NMR (400 MHz, in dimethylsulfoxide d-6): 2.30 (3H, s), 3.88 (3H, s), 6.77 (1H, dd, J=4Hz, 8Hz), 6.81 (1H, d, J=4Hz), 7.67 (1H, d, J=8Hz), 10.49 (1H, s).
With lithium carbonate In N,N-dimethyl-formamide at 23 - 60℃; for 3.5h;
00416] Methyl 2-hydroxy-4-methylbenzoate. Iodomethane (22.6 mL, 362 mmol, 1 . 1 equiv) was added to a suspension of 4-methylsalicylic acid (50.0 g, 329 mmol, 1 equiv) and lithium carbonate (26.8 g, 362 mmol, 1.1 equiv) in dimethylformamide (450 mL) at 23 °C. The reaction flask was heated in an oil bath at 60 °C. After 3.5 h, the warm suspension was partitioned carefully between ice water (500 mL) and ethyl acetate (800 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (800 mL). The organic layers were combined. The combined solution was washed sequentially with water (2 x 500 mL) then saturated aqueous sodium chloride solution (500 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. A small sample of the product (-50 mg) was purified by flash-column chromatography (2% ethyl acetate-hexanes) and was characterized by NMR, , 3C N R, IR, and HRMS. The balance of the product, methyl 2-hydroxy-4-methylbenzoate, was used directly in the next reaction without purification. TLC: (2% ethyl acetate-hexanes) R/ = 0.15 (CAM); NMR (500 MHz, CDCb) δ: 10.70 (s, 1 H), 7.70 (d, 1 H, J = 8.4 Hz), 6.79 (s, 1 H), 6.69 (d, 1 H, J = 7.7 Hz), 3.92 (s, 3H), 2.34 (s, 3H); l 3C NMR ( 125 MHz, CDCh) δ: 170.5, 161.5, 147.0, 129.6, 120.4, 1 17.7, 109.8, 52.0, 21.8; FTIR (neat), cm-1 : 3186 (m), 2956 (m), 1672 (s), 1623 (m), 1579 (m), 1504 (m), 1441 (s), 1338 (s), 1298 (s), 1250 (s), 1215 (s), 1 157 (s), 1096 (s), 906 (s), 780 (s); HRMS (ESI): Calcd for (C9H,o03+H)+ 167.0703, found 167.0698.
With potassium carbonate; In dimethyl sulfoxide; at 35 - 40℃; for 11h;
Potassium carbonate (68.0 g, 0.492 mole) was added to a well-stirred solution of 4-methylsalicylic acid (25 g, 0.164 mole) in dimethylsulfoxide (75 ml ). The mixture was stirred at 35-40 C. and 1st lot of ethyl bromide (27.0 g, 0.247 mole) was added slowly over a period of 30 minutes then stirred for two hours and a second lot of ethyl bromide (27.0 g, 0.247 mole) was added over a period of 30 minutes at 35-40 C. The reaction mixture was further stirred at 35-40 C. for eight hours, cooled to 20-25 C., and diluted with dichloromethane (50 ml). The inorganics were removed by filtration and washed with dichloromethane. The combined filtrate and washings were diluted with water (50 ml), stirred for 30 minutes, and the organic layer was separated. The aqueous layer was further extracted with dichloromethane and the combined dichloromethane layer was washed with water (2×50 ml). The solvent was removed under vacuum to afford ethyl 2-ethoxy-4-methylbenzoate 34.2 g (quantitative yield).
88%
With potassium carbonate; In dimethyl sulfoxide; at 40℃; for 10.5h;
To a mixture of 2-hydroxy-4-methylbenzoic acid (20.0 g, 131.5 mmol) and K2CO3 (54.5 g, 394.5 mmol) in DMSO (50 mL) at 40 C was added bromoethane (21 .5 g, 197.2 mmol) over 30 minutes. The reaction was then stirred at 40 C for 2 hours. Further bromoethane (21.5 g, 197.2 mmol) was then added dropwise and the reaction stirred at 40 C for 8 hours. DCM (200 mL) was added and the mixture was filtered. The organic layer was washed with water (4 x 150 mL), dried (Na2SO.i) and concentrated to give the title compound (24.1 g, 88%) as a clear oil. LCMS-C: RT 2.77 min; m/z 209.1 [M+H] +
With potassium carbonate;Inert atmosphere; Reflux;
To a solution of 4-methylsalicylic acid (1) (6.00 g,39.4 mmol, 1.0 equiv) in acetonitrile (130 mL) were added K2CO3 (22.0 g, 157 mmol, 4.0 equiv), followed by dimethyl sulfate (13.1 mL, 138 mmol, 3.5 equiv) at room temperature. The reaction mixture was refluxed overnight. After cooling to room temperature, the suspension was filtered, and the filtrate was concentrated. The crude residue was purified by column chromatography (20% hexane/dichloromethane) to give compound 2 as a white solid (6.50 g, 99%).
96%
Methyl 5-bromo-4-carboxymethyl-2-methoxybenzoate was synthesized according tothe method described in WO 01/35900. A 1 L 3-neck RBF, fitted with a droppingfunnel, a condenser and a magnetic stirring bar was charged with 4-methylsalicylicacid 10a (50 g, 0.33 mol), K2CO3 (91.1 g, 0.66 mol, 2 eq) and dry acetone (500 ml).This mixture was heated under reflux while dimethylsulfate (112.3 g, 0.891 mol, 2.7eq) was added dropwise. The reaction mixture was refluxed for -14 h (TLCindicated that the reaction was completed). The inorganic salts were filtered off andthe THF filtrate was evaporated under reduced pressure to obtain a yellow oil. Thisresidue was dissolved in 400 ml_ MeOH and a solution of cone. NH4OH (115 ml_)was added. The resulting mixture was stirred at RT for 30 min. The MeOH wasthen distilled off and the residue was diluted with water (500 ml_) and the oilyproduct was extracted with diethyl ether (3X300 mL). The combined organicextracts were dried over sodium sulfate and the diethyl ether was removed undervacuum to give pure methyl 2-methoxy-4-methylbenzoate 10b as a yellow oil (57 g,96% yield). A dry 2 L 3-neck RBF fitted with an argon inlet, a thermometer, a magnetic stirringbar and a septum was charged with THF (220 mL) and diisopropylamine (54.6 mL,0.39 mol, 1.2 eq). The resulting mixture was cooled to -50C and a solution of 2.5 Mn-BuLi (156 mL, 0.39 mol, 1.2 eq) was added slowly via cannula. After 30 min ofstirring at -50C, the solution of LDA generated was cooled to -78C and HMPA(67.8 mL, 0.39 mol, 1.2 eq) was added, followed by a solution of methyl 2-methoxy-4-methylbenzoate 10b (57 g, 0.32 mol) in THF (220 ml), while maintaining thetemperature at -78C. The reaction mixture was stirred two more hours at -78C,and then cannulated into a flask containing 100 g dry ice and THF (200 ml). After30 min stirring at -78C, the reaction mixture was allowed to warm up slowly to RTand then poured into water (1.5 L). The organic layer was separated and theaqueous layer was further extracted with ether (3X1 L). The water layer wasacidified with a solution of 10% H2SO4 (150 ml) and the reaction product wasextracted into CH2CI2 (3X1.5 L). The combined organic extracts were dried overanhydrous Na2SO4, the solvent was removed under reduced pressure and the crudeproduct was purified by flash chromatography (eluent EtOAc: hexane 3:7), followedby recrystallization from CH2CI2:hexane 1:1 to afford pure methyl 4-carboxymethyl-2-methoxybenzoate 10c (38.8 g, 54.7% yield). Methyl 4-cafboxymethyl-2-methoxybenzoate 10c (12.7g, 0.0567 mol) was dissolved in glacial AcOH (100 ml_) and bromine (3.2 ml, 0.0624 mol, 1.1 eq) was added drop wise via a syringe, while maintaining the internal temperature between 20-25C.iAfter stirring for 4 h at RT, the AcOH was evaporated and the orange oil co-evaporated twice with toluene to give an orange solid. This material was trituratedwith CH2CI2and some of the precipitated product was removed by filtration. The restof the product which remained in the filtrate was then concentrated, loaded on asilica gel column and eluted with 1% AcOH in EtOAc:hexane (6:4 ratio). Theproduct was further purified by a second chromatography and re-crystallization fromEtOAc:hexane to give pure methyl 5-bromo-4-carboxymethyl-2-methoxybenzoate aswhite solid 10d (total amount 9 g, 52% yield).
With potassium carbonate; In acetone; for 28h;Heating / reflux;
4-methylsalicylic acid (100 g, 0.66 mol) was dissolved in acetone (1 L) and K2CO3 (227 g, 1.64 mol, 2.5 equiv. ) was added in portions. The mixture was heated to reflux and dimethylsulfate (155 mL, 1.64 mol, 2.5 equiv. ) was added dropwise over 1 h. The mixture was refluxed overnight. Additional K2CO3 (90 g) and dimethylsulfate (60 mL) were added and the mixture refluxed for an additional 20 h. K2CO3 (20 g) and dimethylsulfate (15 mL) were again added and after refluxing for 7 h, the reaction was judged complete by TLC. Solids were removed by filtration using acetone for washings and the filtrate concentrated to a volume of 200 mL. The solution was diluted with MEOH (1 L) and stirred with ammonium hydroxide (300 mL) for 30 min. MEOH was removed under reduced pressure and the residue extracted with EtOAc (2 x 400 mL). The extract was washed with brine (500 ML) and dried (NA2SO4). Removal of volatiles gave the desired product as a yellow oil (119 g).
With thionyl chloride; N,N-dimethyl-formamide In n-heptane at 60℃;
With thionyl chloride In toluene at 47℃; for 4h;
With oxalyl dichloride In dichloromethane at 0 - 20℃; for 2h;
With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 4h;
Stage #1: 2-hydroxy-p-toluic acid With N,N-dimethyl-formamide In dichloromethane at 0 - 5℃; Inert atmosphere;
Stage #2: With oxalyl dichloride In dichloromethane at 0 - 25℃; for 7h; Inert atmosphere;
With thionyl chloride In dichloromethane at 40℃; for 1h;
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 25℃; for 12h;
Method B
General procedure: Thionyl chloride (1.46 mL, 20.0 mmol) was added to a suspension of salicylic acid (4.0 mmol) in DCM (20 mL), followed by a catalytic amount of DMF (0.80 mmol). The reaction mixture was stirred overnight at room temperature. The solvent and residual thionyl chloride were removed under reduced pressure and the crude residue was used immediately without further purification. The crude was resuspended in DCM (20 mL), 4-aminobenzonitrile (945 mg, 8.0 mmol) was added and the reaction mixture was stirred overnight at room temperature. The mixture was diluted with DCM, washed with 1M HCl solution, brine, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography (hexanes in ethyl acetate 0-100%) afford the salicylamides.
With thionyl chloride In dichloromethane at 40℃; for 1h;
With pyridine; thionyl chloride In dichloromethane Reflux;
With thionyl chloride In tetrahydrofuran for 2h; Reflux;
With thionyl chloride at 60℃; for 2h;
4.1.1. General procedure of amide bond formation
General procedure: The benzoic acid derivatives (0.75 mmol) was added to thionylchloride (2.0 mL, 0.10 mol) and heated to 60 C with stirring. After2 h, the mixture was cooled to rt and concentrated under reducedpressure to give the solid acyl chloride which was advanced to thenext step without further purification. The crude acyl chlorideresidue and the aniline derivative (1.5 mmol) were suspended inanhydrous DCM (5.0 mL) under nitrogen atmosphere, and themixture was stirred overnight at rt. The mixture was diluted withDCM, washed with 1 M HCl solution, brine, dried overMgSO4andconcentrated under reduced pressure. The crude residue was purifiedby recrystallization or column chromatography to affordbenzamide derivative.
With potassium hydrogencarbonate In N,N-dimethyl-formamide at 40℃;
86%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h;
89
To a stirring solution of 4-methyl salicyclic acid (152 mg, 1 mmol) in DMF (3 inL) was added benzyl bromide (120 μ, 1 mmol) and potassium carbonate (138 mg, 1 mmol). The resulting mixture was stirred at room temperature for 2 hours. After that, the reaction mixture was diluted with water (20 inL) and extracted by EtOAc (2 χ 20 mL). The combined organic layers were washed by brine (30 mL) and dried over anhydrous sodium sulphate. After removal of EtOAc, benzyl 2-hydroxy-4- methylbenzoate was obtained as a light yellow liquid without further purification (207 mg, yield: 86%).
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h;
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h;
With trifluoroacetic acid; trifluoroacetic anhydride at 0 - 20℃; for 72.0333h;
2,2,7-Trimethyl-benzo[1,3]dioxin-4-one 11; Trifluoroacetic acid (50 ml) and acetone (12 ml) were added to the 4-methysalicylic acid (10 g, 65.72 mmol, 1 eq). Reaction mixture was cooled to 0° C. and trifluoroacetic anhydride (30 ml) was added dropwise over 2 min. Reaction mixture was stirred for 3 days at room temperature and then the volatiles were removed in vacuo. The residues were purified through a dry-flash silica plug eluted with DCM (800 ml). The oil was then additionally purified through another dry-flash silica gel plug eluted with toluene (1 L). This gave the product as a yellow waxy solid (10.475 g, 83%).
70%
With sulfuric acid; acetic anhydride at -8℃; for 12h;
58%
With trifluoroacetic acid; trifluoroacetic anhydride at 20℃;
46%
With trifluoroacetic acid; trifluoroacetic anhydride at 20℃; for 72h;
27%
With trifluoroacetic acid; trifluoroacetic anhydride at 65℃; for 20h;
52.a
Example 52; 4- 3 3-(at)h fbu'iai(at)io=(at):l-(at).4(at) . 4(at)hex 1 hen 1 eth 1 arililmo ) methvl)-2- hydroxybenzoic acid, N-methyl-D-glucamine (i.e. 1-deoxy-1- fmethpnol I(at) ucitoll salt; Step a); Formation of 2,2,7 trimethyl-4H 1,(at)-be(at)zodioxi(at)-4-one; To a stirred suspension of 4-znethylsalicylic acid (50 g, Aldrich) in TFA (320 mL) under nitrogen was added TFAA (105 mL) followed by dry acetone (60 mL). The reaction mixture was heated to 65°C for 5 hours. At this time was added another portion of acetone (50 mL) and heating was continued for 15 hours. The solvent was removed ,under reduced pressure and the residue was taken up with Et20 (250 mL). The organic layer was washed with a 10% aqueous solution of NaHC03 (2x100 mL), brine and dried over MgS04. The solvent was removed under reduced pressure. The residue was purified by chromatography (Pet Ether/ EtOAc 98/2) to give 17 g (27%) of the titled compound as a liquid.
With acetic anhydride at 0℃; for 1.5h;
200 g (1.31 mol) of 4-methylsalicylic acid 1 are dissolved in 2 l of acetone and 400 ml of acetic anhydride. Under an argon atmosphere, 50 ml of conc. sulfuric acid are added dropwise at 0° C. The reaction solution is stirred at 0° C. for 90 minutes. Then about 1 l of acetate is distilled out, and the residue is mixed with 1 l of n-heptane/ethyl:acetate (4:1) and 1 l of water. The aqueous phase is separated off and extracted once more with 1 l of n-heptane/ethyl acetate (4:1). The collected organic phase is washed twice with 500 ml of 10% strength sodium hydroxide solution, filtered through 250 ml of silica gel and concentrated. The oily residue is dissolved in a little n-heptane and seeded with seed crystals. 137.5 g of crystalline acetonide 2 are obtained.
Under nitrogen, 1.86 g (10.0 mmol) of <strong>[7697-25-8]2-chloro-4-methylbenzoic acid</strong> was combined with 10 g of H2O. 1.11 g (15 mmol) of Ca(OH)2 was then added. The mixture was heated at 85° C. under stirring for 60 min, remaining under a nitrogen atmosphere. Separately, 43 mg of CuBr and 94 mg of rac-trans-N,N'-dimethylcyclohexane-1,2-diamine (Ligand F) were combined with 1 mL deionized water under nitrogen. The resulting mixture was stirred under an air atmosphere until the CuBr was dissolved to give a blue solution. This solution was added to the stirred reaction mixture via syringe at 80° C. under nitrogen and stirred for 24 h at 80° C. After cooling to 25° C., the reaction mixture was acidified with 15percent HCl, producing a white precipitate. The white precipitate was filtered and washed with water. After drying, a total of 1.45 g (9.5 mmol, 95percent yield) of 2-hydroxy-4-methylbenzoic acid was collected. The purity was determined by 1H NMR to be >99percent.
With sodium tetrahydroborate; Trimethyl borate; dimethyl sulfate In tetrahydrofuran at 20℃; for 4.5h;
Multi-step reaction with 2 steps
1: 99 percent / H2SO4 / 24 h / Heating
2: 64 percent / LiAlH4 / tetrahydrofuran / 1 h / 20 °C
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 60℃; Inert atmosphere;
Preparation of 2-(Cyanomethyl)phenols 3
General procedure: To a solution of LiAlH4 (2.1 g, 55 mmol) in THF (100 mL) was added salicylic acid (6.9 g, 50 mmol) at 0 °C, and stirred at 60 °C overnight. The reaction mixture was cooled to 0 °C, and then degassed water (2.0 mL), 15 wt% NaOH aqueous solution (2.0 mL), and water (6.0 mL) were successively added. After stirring at room temperature for 1 h, the mixture was filtered and washed with Et2O (50 mL×3). The combined organic layer was washed with brine and dried over MgSO4. The organic solvent was removed under reduced pressure to afford 2-hydroxymethyl phenol (4.5 g, 33.5 mmol, 67% yield) as a colorless oil.
With potassium carbonate; In toluene; at 25 - 45℃; for 21 - 31.5h;Heating / reflux;
Added 260 ml (3.0 mol) of diethyl sulfate to the mixture of 1000 ml of toluene, 272.5 g (3.0 mol) of potassium carbonate and 100 g (1.0 mol) of 2-Hydroxy-4-methyl-benzoic acid at 25-45 C. for 1 hr to 1 hr 30 min. Heated the reaction mass to azeotropic reflux for 20-30 hr. Cooled the reaction mixture to 25-35 C. and collected the unwanted material by filtration, washed the unwanted material with 500 ml of toluene. Combined filtrate was washed with water (1×1000 ml and 1×500 ml) at 80-85 C. Total organic layer was concentrated to residue under vacuum at below 70 C. The yield of the title compound is 128 g (94.11%). [0036] The obtained product was characterised by analytical techniques like IR, Mass and 1H-NMR
87%
With potassium carbonate; In acetonitrile; for 12h;Heating / reflux;
4-Methyl salicylic acid (5 g, 32.89 mmol), diethyl sulfate (20.26 g, 0.131 mole) and anhydrous potassium carbonate (18.15 g, 0.132 mole) were mixed thoroughly in dry acetonitrile and mixture was refluxed for 12 hr. Reaction mixture was cooled and filtered through Celite bed. Filtrate was concentrated under vacuum. Residue was purified by fractional distillation at 0.5 mm vacuum. 1st fraction dis tilled at 48-51 C. (oil bath temperature 80 C.). Product (ethyl-2-ethoxy-4-methylbenzoate) 3 distilled at 90-93 C. (oil bath temperature 120 C.) Yield=6 g (87%).
84%
With potassium carbonate; In 1,4-dioxane; for 16h;Heating / reflux;
4-Methyl salicylic acid (5 g, 32.89 mmol), diethyl sulfate (20.26 g, 0.131 mole) and anhydrous potassium carbonate (18.15 g, 0.132 mole) were mixed thoroughly in dry dioxane and mixture was refluxed for 16 hr. Reaction mixture was cooled and filtered through Celite bed. Filtrate was concentrated under vacuum. Residue was purified by fractional distillation at 0.5 mm vacuum. 1st fraction dis tilled at 48-51 C. (oil bath temperature 80 C.). Product (ethyl-2-ethoxy-4-methylbenzoate) 3 distilled at 90-93 C. (oil bath temperature 120 C.) Yield=5.8 g (84%).
75%
With potassium carbonate; In acetone; for 16h;Heating / reflux;
4-Methyl salicylic acid (5 g, 32.89 mmol), diethyl sulfate (20.26 g, 0.131 mole) and anhydrous potassium carbonate (18.15 g, 0.132 mole) were mixed thoroughly in dry acetone and mixture was refluxed for 16 hr. Reaction mixture was cooled and filtered through Celite bed. Filtrate was concentrated under vacuum. Residue was purified by fractional distillation at 0.5 mm vacuum. 1st fraction dis tilled at 48-51 C. (oil bath temperature 80 C.). Product (ethyl-2-ethoxy-4-methylbenzoate) 3 distilled at 90-93 C. (oil bath temperature 120 C.) Yield=5.2 g (75%)
tert-butyl cis-4-aminocyclohexylcarbamate[ No CAS ]
[ 50-85-1 ]
cis-[4-(2-hydroxy-4-methyl-benzoylamino)-cyclohexyl]-carbamic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 72h;
76 Preparation 76, syn-[4-(2-Hydroxy-4-methyl-benzoylamino)-cyclohexyl]-carbamic acid tert-butyl ester
4-Methylsalicylic acid (3.5 g, 23 mmol) was added to a mixture of the amine from preparation 5 (5.35 g, 25 mmol) 1-hydroxybenzotriazole hydrate (3.88 g, 28.8 mmol) 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (6.23 g, 32.5 mmol) and N-diisopropylethylamine (4.84 g, 37.5 mmol) in dichloromethane (65 ml). The mixture was stirred at room temperature for 72 hours and was diluted with dichloromethane (100 ml). Water (150 ml) was added and the aqueous layer was acidified to pH 3 by addition of 2M hydrochloric acid. The phases were separated and the organic phase was washed with water (2×100 ml) and dried (MgSO4). The organic solution was concentrated in-vacuo and the residue was triturated with hot ethyl acetate to give the title compound, 5.2 g. [0570] LRMS: m/z ES+ 371 [MNa+]
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 48h;
13
Preparation 13; SYN-F4- (2-HYDROXY-4-METHYL-BENZOYLAY MINO)-CYCLOHEXYL]-CARBAMIC acid tert-butyl ester; The amine of preparation 2 (17.14g, 80. Ommol) was dissolved in DICHLOROMETHANE (180ML) and the solution treated with N-ETHYIDIISOPROPYLAMINE (20.9mL, 120MOL), 1-HYDROXYBENZOTRIAZOLE hydrate (12.97g, 96MOL), 1- (3-DIMETHYLAMINOPROPYL)-3- ethylcarbodiimide hydrochloride (19. 94g, 104MMOL) and 4-methyl-salicylic acid (10. 96g, 72MOL). The reaction mixture was stirred at room temperature for 48 hours and then diluted with DICHLOROMETHANE (300mL) and water (450mL). The aqueous layer was acidified to pH 3 by dropwise addition of 2M hydrochloric acid and the organic layer washed with water (2X300ML), dried over magnesium sulphate and concentrated in vacuo. The residue was triturated from ethyl acetate to yield the title product as a white solid, 17.59g. HNMR (CDCI3, 400MHZ) : 6 = 1.46 (s, 9H), 1.87 (m, 10H), 2.33 (s, 3H), 3.67 (m, 1 H), 4. 10 (m, 1H), 6.09 (m, 1H), 6.80 (m, 1H), 7.12 (m, 1H) ppm MS ES+ M/Z 349 [MH] +
7.a
Acetic anhydride (32 mL, 34.5 g, 0.338 mol, 1.03 eq), 4-methylsalicylic acid (50 g, 0.329 mmol, 1.00 eq), and xylenes (100 mL) are added to a 1 L, four-neck flask fitted with a magnetic stir bar, a thermometer, and a condenser. The flask is placed in a sand bath and heating of the cloudy white mixture begun. The reaction mixture clears to a yellow solution around 90° C. Most of the volatile organics (xylenes and acetic acid) are distilled into the Dean-Stark trap over three hours (135-146° C.). Distillation is continued for another hour (a total of 110 mL distilled), during which the pot temperature slowly rises to 204° C. and the distillate slows to a trickle. The residue is poured off while still hot into an aluminum tray. Upon cooling a brittle yellow glass forms. The solid is ground to a fine powder. The oligo(4-methylsalicylate) received is used without further purification.
Stage #1: syn-N-(4-amino-cyclohexyl)-2-(tetrahydrothiopyran-4-yloxy)-nicotinamide hydrochloride; 2-hydroxy-p-toluic acid With benzotriazol-1-ol; triethylamine In Isopropyl acetate for 2h; Heating / reflux;
Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In Isopropyl acetate at 40℃; for 24h; Heating / reflux;
Stage #3: With water In Isopropyl acetate at 0 - 25℃; for 19h;
1 Example 1:
Example 1: Preparation of Form C (crystalline monohydrate form) 2.45 kg (8.5 ml/g) of isopropyl acetate was charged to the reaction vessel. The following were then added with stirring: 4-methyl salicylic acid (113 g, 0.743 M), the amine of preparation 18 (see below for obtention of the amine of preparation 18 - 290 g 0.746 M), 1-Hydroxybenzotriazole.hydrate (90.3 g, 0.599 M) and triethylamine (151 g, 1.492 M). Reaction was heated to reflux for 2 hours, then cooled to 40°C and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSCDI) (177 g, 0.923 M) was added. Once added the reaction was heated back to reflux and left to react for 24 hours. In-process check by fast liquid chromatography after 24 hours found the reaction to be complete with less than 5% of 4-methyl salicylic acid remaining. The reaction was cooled to 25°C and 2.26 L of water (7.8 ml/g) was added. The product then precipitated from the reaction. This mixture was left to stir at room temperature for 18 hours and was then cooled to 0°C and granulated for 1 hour. The recovered solid was filtered and washed with 0.23 L (0.8 ml/g) of isopropylacetate followed by 1.13 L (4 ml/g) of water. The damp cake was dried in a vacuum oven at 55°C for 18 hours. 299 g of the crude of cis-5-Fluoro-N-[4-(2-hydroxy-4-methylbenzamido)cyclohexyl]-2-(tetrahydro-thiopyran-4-yloxy)-nicotinamide was then obtained (recovery: 82.14%). 1H-NMR (CDCl3, 400MHz) δ: 1.60-2.10 (m, 10H), 2.30-2.50 (m, 5H), 2.70-2.94 (m, 4H), 4.06-4.34 (m, 2H), 5.46 (m, 1 H), 6.28 (m, 1 H), 6.68 (1 H, d), 6.80 (s, 1 H), 7.32 (d, 1 H), 8.00-8.18 (m, 2H), 8.28 (m, 1 H), 12.20 (brs, 1 H) PXRD The PXRD pattern for Form C is shown in Figure 1. The main characteristic peaks are at 17.7, 18.3, 20.5, 21.7 and 24.3 degrees 2-theta and are further given in table 1. The calculated PXRD pattern is illustrated in Figure 2. The main characteristic peaks from the calculated pattern for Form C are shown in table 2. Table 1: Characteristic PXRD Peaks for Form C Angle 2-Theta (Degrees) Intensity (%) Angle 2-Theta (Degrees) Intensity (%) 8.1 17.6 20.5 79.0 10.5 30.0 21.0 26.4 12.5 19.3 21.7 66.7 12.7 28.9 23.9 38.0 14.2 21.0 24.3 76.3 15.3 26.3 25.0 19.5 16.1 30.2 25.4 44.1 16.3 16.1 27.0 24.9 17.7 100.0 28.9 24.5 18.3 59.5 30.9 16.0Table 2: Characteristic PXRD Peaks from calculated pattern for Form C Angle 2-Theta (Degrees) Intensity (%) Angle 2-Theta (Degrees) Intensity (%) 8.1 17.6 20.5 100.0 10.5 36.9 21.0 30.1 11.3 16.6 21.7 83.3 12.5 27.7 22.8 15.0 12.7 33.7 23.9 44.4 14.2 25.1 24.3 92.0 14.4 18.1 25.0 24.7 15.3 33.6 25.4 53.7 16.1 35.4 27.0 28.8 16.2 23.4 29.0 29.5 17.7 98.1 31.0 16.5 18.3 67.4 31.5 18.4DSC DSC analysis of a 3.050 mg sample of Form C was performed as described above. The DSC thermogram for Form C is shown in Figure 3. Form C shows an endothermic peak at 110°C +/- 5°C. This is due to dehydration of Form C.
VI Preparation of N-Hydroxysuccinimidyl 3-(N-[3-hydroxy-4-(methoxycarbonyl)phenyl]methyl}carbamoyl)propionate STR24 Methyl 4-Methyl-2-hydroxybenzoate
Example VI Preparation of N-Hydroxysuccinimidyl 3-(N-[3-hydroxy-4-(methoxycarbonyl)phenyl]methyl}carbamoyl)propionate STR24 Methyl 4-Methyl-2-hydroxybenzoate 4-Methyl-2-hydroxybenzoic acid (100 g, 658 mmoles) was dissolved in anhydrous methanol (500 mL) and concentrated sulfuric acid (25 mL) was added carefully. The solution was refluxed for 18 hours, then cooled to room temperature. The reaction mixture was concentrated to about 150 mL, and ethyl acetate (250 mL) was added. The ethyl acetate solution was washed twice with saturated aqueous sodium bicarbonate (250 mL portions) and then with saturated aqueous sodium chloride (100 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered, and evaporated to a clear, reddish-brown liquid. This crude product was vacuum distilled (oil pump) to afford a clear, viscous liquid that solidified on standing to afford 98.1 g (90% yield) of methyl 4-methyl-2-hydroxybenzoate. 1 H NMR (300 MHz, CHCl3 -d) δ 2.32 (singlet, 3H, ArCH3), 3.91 (singlet, 3H, OCH3), 6.67 (doublet, J=8 Hz, 1H, ArH), 6.78 (singlet, 1H, ArH), 7.69 (doublet, J=8 Hz, 1H, ArH), 10.71 (singlet, 1H, OH). 13 C NMR (75 MHz, CHCl3 d) δ 21.8, 52.1, 110.0, 117.9, 120.6, 129.9, 147.3, 161.9, 170.9.
90%
With sulfuric acid In methanol; ethyl acetate
IV Preparation of a Reagent of General Formula I Methyl 4-Succinylaminomethylsalicylate Succinimidyl Ester STR21 Methyl 4-Methylsalicylate
EXAMPLE IV Preparation of a Reagent of General Formula I Methyl 4-Succinylaminomethylsalicylate Succinimidyl Ester STR21 Methyl 4-Methylsalicylate 4-Methylsalicylic acid (100 g, 658 mmoles) was dissolved in anhydrous methanol (500 mL) and concentrated sulfuric acid (25 mL) was added carefully. The solution was refluxed for 18 hours, then cooled to room temperature. The reaction mixture was concentrated to about 150 mL, and ethyl acetate (250 mL) was added. The ethyl acetate solution was washed twice with saturated aqueous sodium bicarbonate (250 mL portions) and then with saturated aqueous sodium chloride (100 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered, and evaporated to a clear, reddish-brown liquid. This crude product was vacuum distilled (oil pump) to afford a clear, viscous liquid that solidified on standing to afford 98.1 g (90% yield) of methyl 4-methylsalicylate. 1 H NMR (300 MHz, CHCl3 -d) δ2.32 (singlet, 3H, ArCH3), 3.91 (singlet, 3H, OCH3), 6.67 (doublet, J=8 Hz, 1H, ArH), 6.78 (singlet, 1H, ArH), 7.69 (doublet, J=8 Hz, 1H, ArH), 10.71 (singlet, 1H, OH). 13 C NMR (75 MHz, CHCl3 -d) δ21.8, 52.1, 110.0, 117.9, 120.6, 129.9, 147.3, 161.9, 170.9.
90%
With sulfuric acid In methanol; ethyl acetate
IV Methyl 4-Methylsalicylate
Methyl 4-Methylsalicylate 4-Methylsalicylic acid (100 g, 658 mmoles) was dissolved in anhydrous methanol (500 mL) and concentrated sulfuric acid (25 mL) was added carefully. The solution was refluxed for 18 hours, then cooled to room temperature. The reaction mixture was concentrated to about 150 mL, and ethyl acetate (250 mL) was added. The ethyl acetate solution was washed twice with saturated aqueous sodium bicarbonate (250 mL portions) and then with saturated aqueous sodium chloride (100 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered, and evaporated to a clear, reddish-brown liquid. This crude product was vacuum distilled (oil pump) to afford a clear, viscous liquid that solidified on standing to afford 98.1 g (90% yield) of methyl 4-methylsalicylate. 1 H NMR (300 MHz, CHCl3- d) δ2.32 (singlet, 3H, ArCH3), 3.91 (singlet, 3H, OCH3), 6.67 (doublet,J=8 Hz, 1H, ArH), 6.78 (singlet, 1H, ArH), 7.69 (doublet, J=8 Hz, 1H, ArH), 10.71 (singlet, 1H, OH). 13 C NMR (75 MHz, CHCl3- d) δ21.8, 52.1, 110.0, 117.9, 120.6, 129.9, 147.3, 161.9, 170.9.
90%
With sulfuric acid In methanol; ethyl acetate
IV Preparation of a Reagent of General Formula I Methyl 4-Succinylaminomethylsalicylate Succinimidyl Ester STR21 Methyl 4-Methylsalicylate.
EXAMPLE IV Preparation of a Reagent of General Formula I Methyl 4-Succinylaminomethylsalicylate Succinimidyl Ester STR21 Methyl 4-Methylsalicylate. 4-Methylsalicylic acid (100 g, 658 mmoles) was dissolved in anhydrous methanol (500 mL) and concentrated sulfuric acid (25 mL) was added carefully. The solution was refluxed for 18 hours, then cooled to room temperature. The reaction mixture was concentrated to about 150 mL, and ethyl acetate (250 mL) was added. The ethyl acetate solution was washed twice with saturated aqueous sodium bicarbonate (250 mL portions) and then with saturated aqueous sodium chloride (100 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered, and evaporated to a clear, reddish-brown liquid. This crude product was vacuum distilled (oil pump) to afford a clear, viscous liquid that solidified on standing to afford 98.1 g (90% yield) of methyl 4-methylsalicylate. 1 H NMR (300 MHz, CHCl3-d) δ 2.32 (singlet, 3H, ArCH3), 3.91 (singlet, 3H, OCH3), 6.67 (doublet, J=8 Hz, 1H, ArH), 6.78 (singlet, 1H, ArH), 7.69 (doublet, J=8 Hz, 1H, ArH), 10.71 (singlet, 1H, OH). 13 C NMR (75 MHz, CHCl3-d) δ 21.8, 52.1, 110.0, 117.9, 120.6, 129.9, 147.3, 161.9, 170.9.
With sulfuric acid In methanol
23 Example 23
Example 23 In this example, one method for the synthesis of a bis(salicylhydroxamic acid) affinity linker with amine handle is provided (as depicted in). Briefly, 4-methylsalicylic acid (compound 1, 5 g, 33 mmol) was added slowly to a chilled solution of concentrated H2SO4 (4.3 ml, 78 mmol) in 45 ml of methanol. The solution was refluxed for 5 hours, concentrated under reduced pressure, and partitioned between 50 mM NaHCO3 (100 ml) and EtOAc (100 ml). The organic layer was dried with anhydrous Na2SO4 and the volatiles evaporated under reduced pressure to give methyl 4-methyl salicylate (compound 2) as a colorless oil.
13.a (a)
(a) Methyl 2-hydroxy-4-methylbenzoate: In a similar manner to that of Example 12(a) starting with 30.43 g (200.0 mmol) of 2-hydroxy-4-methylbenzoic acid, and after refluxing for 72 hours, 29.49 g (89%) of the expected compound are obtained in the form of a colourless liquid which crystallizes slowly, with a melting point of 20-25° C. 1 H NMR (CDCl3) δ 2.34 (s, 3H), 3.92 (s, 3H), 6.69 (d, 1H, J=8.2 Hz), 6.79 (s, 1H), 7.70 (d, 1H, J=8.1 Hz).
28 Preparation of 4-(2-(2-phenethyl)phenoxymethyl)-2-hydroxybenzoic Acid
EXAMPLE 28 Preparation of 4-(2-(2-phenethyl)phenoxymethyl)-2-hydroxybenzoic Acid A solution of 2-hydroxy-4-methylbenzoic acid (20.0 g, 0.132 mol) in methanol (200 ml) was cooled in an ice bath. Concentrated, H2 SO4 (20 ml) was added cautiously and the reaction heated to reflux and held at reflux for 48 hours. The reaction was allowed to cool to ambient temperature, the solvent evaporated and the residue purified by chromatography (eluant: CH2 Cl2) to give methyl 2-hydroxy-4-methylbenzoate (19.76 g, 90%). NMR (200 MHz, DMSO-d6): δ10.47 (s, 1H), 7.64 (d, 1H), 6.78 (m, 2H), 3.86 (s, 3H), 2.3 (s, 3H).
102.i (i)
(i) methyl 4-methylsalicylate To a suspension of 10 g (0.0651 mol) of 4-methylsalicylic acid in 150 mL of methanol was added 50 mL of ethereal hydrochloric acid. The reaction mixture was heated at 60° C. for 60 hours. The solvent was removed under vacuum. After adding hexane-ethyl acetate, the resulting solid was filtered and the filtrate was evaporated to give 10.2 g (94%) of product as an oil.
With tetrabutylammomium bromide In sodium hydroxide; ethanol; water
G 4-Methyl-2-phenylmethoxybenzoic acid (XII: R3 =4-CH3)
4-Methyl-2-phenylmethoxybenzoic acid (XII: R3 =4-CH3) A two-phase mixture of 45.6 g (0.3 mol) 4-methylsalicylic acid, NaOH (36 g, 0.9 mol), benzyl bromide (154 g, 0.9 mol) and tetrabutylammonium bromide (10 g, 30 mmol) in water (200 ml) and CH2 Cl2 (200 ml) was stirred at room temperature for 3 hours. The layers were separated and the CH2 Cl2 was removed from the organic fraction. The residue was dissolved in a mixture of ethanol (250 ml) and 2N NaOH (50 ml), and the mixture was heated under reflux for 30 min. The ethanol was removed under vacuum and the residue was diluted with water and washed with ethyl acetate. The aqueous layer was separated and acidified with dilute HCl to give a precipitate of 4-methyl-2-phenylmethoxybenzoic acid (65.3 g, 90%) m.p. (MeOH aq) 105°-107° C. Anal (C15 H14 O3) C,H,O. 4-Methyl-2-phenylmethoxybenzenemethanol (XIII: R3 =4-CH3, Z=OH)
IV Methyl 4-Methylsalicylate
Methyl 4-Methylsalicylate 4-Methylsalicylic acid (100 g, 658 mmoles) was dissolved in anhydrous methanol (500 mL) and concentrated sulfuric acid (25 mL) was added carefully. The solution was refluxed for 18 hours, then cooled to room temperature. The reaction mixture was concentrated to about 150 mL, and ethyl acetate (250 mL) was added. The ethyl acetate solution was washed twice with saturated aqueous sodium bicarbonate (250 mL portions) and thenwith saturated aqueous sodium chloride (100 mL). The ethyl acetate solutionwas dried over anhydrous sodium sulfate, filtered, and evaporated to a clear, reddish-brown liquid. This crude product was vacuum distilled (oil pump) to afford a clear, viscous liquid that solidified on standing to afford 98.1 g (90% yield) of methyl 4-methylsalicylate. 1 H NMR (300 MHz, CHCl3 -d) δ2.32 (singlet, 3H, ArCH3), 3.91 (singlet, 3H, OCH3), 6.67 (doublet,J=8 Hz, 1H, ArH), 6.78 (singlet, 1H, ArH), 7.69 (doublet, J=8 Hz, 1H, ArH), 10.71 (singlet, 1H, OH). 13 C NMR (75 MHz, CHCl3 d) δ21.8, 52.1,110.0, 117.9, 120.6, 129.9, 147.3, 161.9, 170.9.
2-Hydroxy-4-methylbenzoic acid was reacted with K2 CO3 and dimethyl sulfate to give methyl 2-methoxy-4-methybenzoate (boiling point at 0.7 mm=100 C.). Hydrolysis with 2N sodium hydroxide solution provided 2-methoxy-4-methylbenzoic acid (melting point 103-104 C.).
With N-Bromosuccinimide; CH3I; potassium carbonate;azobisisobutyronitrile; In tetrachloromethane; diethyl ether; acetone;
C. Methyl 4-Bromomethyl-2-methoxybenzoate. A mixture of 4-methylsalicylic acid (20 g, 131.5 mmol), CH3I (74.7 g, 526.3 mmol), and K2CO3 (36.2 g, 262 mmol) in 250 mL of acetone was maintained at reflux for 4 days. After filtering, the filtrate was concentrated under reduced pressure and the resulting residue taken up in Et2O and washed with 2 N NaOH. The organic extract was concentrated under reduced pressure. From this crude material, 10 g (55.6 mmol) was taken up in 100 mL of CCl4; and N-bromo-succinimide (10.8 g, 61.1 mmol) and a catalytic amount of AIBN were added. The mixture was heated at reflux for 4 h and then diluted 10 fold with Et2O. The organics were washed with 25% NaOH (aq.) and concentrated under reduced pressure. Crude product was recrystallized from EtOAc-hexanes, giving 14.2 g (99%) of the desired bromide. 1H NMR (CDCl3) delta 7.77 (d, J=8.3 Hz, 1H), 7.01 (d, J=2.6 Hz, 1H), 6.99 (s, 1H), 4.47 (s, 2H), 3.94 (s, 3H), 3.91(s, 3H).
51.A
To a solution of 2-hydroxy-4-methylbenzoic acid (1.52 g, 10 mmol) in toluene (6 mL) and methanol (2 mL) at 0 0C is added trimethylsilyldiazomethane (2 M in hexane, 6 mL, 12 mmol) dropwise. The mixture is then warmed up to ambient temperature and it is stirred for 2 h. The solvent is removed under reduced pressure and the residue is purified by flash chromatography to give the title compound as a colorless oil.
Stage #1: 2-hydroxy-p-toluic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 24h;
Stage #2: Cyclopropylamine With triethylamine In dichloromethane for 72h;
1
4-Methylsalicylic acid (21.3 g, 140 mmol) was dissolved in methylene chloride (120 mL) followed by CDI (22.7 g, 140 mmol) in portions. The mixture was stirred at room temperature for 24 hr, and then briefly heated to boiling. A solution of cyclopropylamine (8.0 g, 140 mmol) in triethylamine (5 mL, 36 mmol) was added to the mixture, which was stirred for 3 days. Water (200 mL) was added and the pH was adjusted to 2 using 12 M hydrochloric acid. The phases were separated and the aqueous phase was extracted with chloroform (200 mL). The combined organic phases were washed with sodium bicarbonate solution (100 mL) and dried over sodium sulfate. Concentration gave 22.7 g of amide as an off white solid.
Stage #1: 2-hydroxy-p-toluic acid With 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 24h; Heating / reflux;
Stage #2: Cyclopropylamine With triethylamine In dichloromethane for 72h;
55
4-Methylsalicylic acid (21.3 g, 140 mmol) was dissolved in methylene chloride (120 mL) and CDI (22.7 g, 140 mmol) was added portion wise causing release of CO2. The mixture was stirred at ambient temperature for 24 hr, then briefly heated to boiling. A solution of cyclopropylamine (8.O g, 140 mmol) in triethylamine (5 mL, 36 mmol) was added to the mixture, which was stirred for 3 days. Water (200 mL) was added and the pH was adjusted to 2 using 12 M hydrochloric acid. The phases were separated and the aqueous phase was extracted with chloroform (200 mL). The combined organic phases were washed with sodium bicarbonate solution (100 mL) and dried over sodium sulfate. Concentration gave 22.7 g of amide as an off white solid. NMR showed some contaminants.The crude amide (22.7 g, 119 mmol) and trioxane (36 g, 0.4 mol) were dissolved in chloroform (250 mL), which was stirred at ambient temperature. Sodium sulfate (32 g) and concentrated sulfuric acid (80 drops) were added and the mixture was refluxed for 30 min, after which cone, sulfuric acid (40 drops) was added. After 90 min, the solids were removed by filtration and washed with ethyl acetate. The solvent was removed under vacuum to give 30 g of oil. The oil was purified using flash chromatography (250 g silica gel, ethyl acetate:hexane 30:70, then 40:60) to give 20.1 g of benzoxazinone as a colorless oil.The nitration of the benzoxazinone was carried out as in Example 1 using 16 g (79 mmol) of the oil from the previous step, 30 mL Ac2O and 14 mL nitric acid (90%). 9.4 g of the clean 5- nitro derivative were obtained as an off white solid after crystallization from chloroform/ethyl 5 acetate.The formation of the nitro acid was carried out following the procedure in Example 52 using 9.4 g (37.8 mmol) of the solid from the previous step, 60 mL Dimethylformamide dimethylacetal, 22.5g (105 mmol) NaIO4 and 37.7g KMnO4. The reaction resulted in 7.5 g of a beige/orange acid.10 To reduce the nitro group, the nitro acid (1.4 g, 5.0 mmol) from the previous step was dissolved in chlorofornrTHF (50 mL and 50 mL) and palladium on carbon (10%, 590 mg) was added. The mixture was hydrogenated at ambient temperature for 18 hr. The catalyst was filtered off and the filtrate was concentrated under vacuum to give 2.0 g of a yellow solid, which was used without further purification.15 The formation of the amide was carried out as in Example 27 using 2.0 g of the product from the previous reaction, 611 mg (5 mmol) DMAP, 676 mg (5 mmol) HOBT, 1 mL NEt3, 2.Og (10.4 mmol) EDCI and 2-methoxyethylamine (3 mL, 35 mmol). The reaction yielded 575 mg of the amide as a yellow oil.The amide from the previous step (0.575 g, 1.88 mmol) was dissolved in DMF (6 mL) and 20 isoamyl nitrite (2 mL) and allowed to stand at ambient temperature for 18 hr. The solvent was removed under vacuum and the residuepurified using flash chromatography (ethyl acetate :hexane, 8:2). The product fractions were combined and concentrated to about 1 mL. Methyl t-butyl ether (8 mL) was added and the solvent was slowly evaporated to yield 206 mg of white crystals with the following properties: MP: 103-105 0C; 1H NMR (300 MHz, CDCl3) 25 δ 8.80 (IH, s), 7.84 (IH, s), 5.32 (2H, s), 4.64 (2H, m), 3.87 (2H, m), 3.37 (3H, s), 2.76 (IH, m) and 1.1-0.8 ppm (4H, m).
With oxygen; potassium acetate; palladium diacetate; p-benzoquinone In N,N-dimethyl acetamide at 115℃; for 15h;
82%
With tert.-butylhydroperoxide; (2S,3S)-N-acetyl-2-amino-3-methylpentanoic acid; potassium acetate; palladium diacetate; p-benzoquinone In 1,2-dimethoxyethane; water at 100℃;
<strong>[137-09-7]2,4-Diaminophenol dihydrochloride</strong> (6.43 g, 32.7 mmol) and 4-methylsalicylic acid (4.97 g, 32.7 mmol) were mixed in PPA (150 mL) in a 1 L round-bottomed flask. The reaction mixture was heated to 150 C and was then stirred for 12 h. The resulting mixture was cooled to room temperature and poured into ice-water with vigorous stirring. The solution was neutralized by adding sodium bicarbonate. The crude product was collected by filtration and recrystallized in ethanol. Further purification was carried out with column chromatography using an ethyl acetate-toluene mixture as a mobile phase. After evaporation, the product was dried in vacuo (yield: 2.03 g, 26%); 1H NMR (300 MHz, DMSO-d6): delta = 11.31 (s, OH, 1H), 7.94 (s, Ar-H, 1H), 6.92 (d, Ar-H, 1H), 6.90 (d, Ar-H, 1H), 6.85 (d, Ar-H, 2H), 6.67 (d, Ar-H, 1H), 4.52 (s, NH, 2H), 2.35 (s, 3H).
2-[3-(2-bromo-5-methoxyphenyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl]-5-methylphenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With trichlorophosphate at 80℃; for 5h;
5.4. General procedure for the conventional synthesis of 3-(2-bromo-5-methoxyphenyl)-6-(substituted)[1,2,4]triazolo[3,4-b][1,3,4] thiadiazole (5a-j)
General procedure: An equimolar mixture of compound (4) (0.0035 mol) and appropriate mono or disubstituted aromatic carboxylic acids (0.0035 mol) in phosphorus oxychloride (15 mL) was refluxed for 5 h. The reaction mixture was cooled to room temperature and poured onto crushed ice (50 g) with stirring. Finally, to remove the excess of phosphorus oxychloride powdered potassium carbonate and the required amount of potassium hydroxide were added till the pH of the mixture was raised to 8. The solid was collected by vacuum filtration, dried and recrystallized from appropriate solvent.
To a solution of 4-methylsalicylic acid (2.5 g, 16.4 mmol) in DMF (16.4 mL) was added K2CO3 (4.6 g, 32.9 mmol) and the reaction mixture was stirred at 25 C for 30 min before EtI (5.3 mL, 65.7 mmol) was added. The mixture was stirred at 55 C for 20 hours, after which LC-MS showed that starting material was consumed completely and that a new UV peak with the desired m/z was the major peak. The reaction mixture was cooled down to room temperature, poured into water (75 mL) and aqueous phase was extracted with EtOAc (3 × 35 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford ethyl 2-ethoxy-4-methylbenzoate (3.4 g, 99%) as an amber oil.
90%
With potassium carbonate; In dimethyl sulfoxide; at 40℃; for 11h;
To a mixture of 2-hydroxy-4-methylbenzoic acid (8.2 g, 54 mmol) and K2CO3 (22.4 g, 162 mmol) in DMSO (70 mL) at 40 C was added ethyl iodide (12.6 g, 80.8 mmol) drop-wise over a period of 30 minutes. The reaction was stirred for 2 hours then further ethyl iodide (12.6 g, 80.8 mmol) was added over 30 minutes. The resulting mixture was stirred for another 8 hours at 40 C, then diluted with DCM (150 mL) and filtered. The filtrate was washed with water (200 mL chi 10) and brine (200 mL 2), dried ( a2S04) and concentrated to give the desired compound (10.1 g, 90% yield) as a yellow liquid. LCMS-C: RT 2.70 min; m/z 209.1 [M+H]*
90%
With potassium carbonate; In dimethyl sulfoxide; at 40℃; for 11h;
To a mixture of 2-hydroxy-4-methylbenzoic acid (8.2 g, 53.9 mmol) and K2CO3 (22.4 g, 161.7 mmol) in dimethylsulfoxide (70 mL) at 40 ^C was added and ethyl iodide (12.6 g, 80.8 mmol) dropwise over a period of 30 min. The reaction was stirred for 2 h then further ethyl iodide (12.6 g, 80.8 mmol) was added over 30 min. The resulting mixture was stirred a further 8 h at 40 ^C, then diluted with CH2Cl2 (150 mL) and filtered. The filtrate was washed with water (200 mL x 10) and brine (200 mL x 2), dried (Na2SO4) and concentrated to give the desired compound as a yellow liquid (10.1 g, 90%): LCMS: RT 2.70min; m/z 209.1 [M+H]+.
90%
With potassium carbonate; In dimethyl sulfoxide; at 40℃; for 11h;
To a mixture of 2-hydroxy-4-methylbenzoic acid (8.2 g, 53.9 mmol) and K2CO3 (22.4 g, 161 .7 mmol) in dimethylsulfoxide (70 mL) at 40 C was added ethyl iodide (12.6 g, 80.8 mmol) dropwise over a period of 30 min. The reaction was stirred for 2 hours then further ethyl iodide (12.6 g, 80.8 mmol) was added over 30 min. The resulting mixture was stirred a further 8 hours at 40 C, diluted with CH2CI2 CI 5O mL) and filtered. The filtrate was washed with water (200 mL x 10) and brine (200 mL x 2), dried (Na2SC>4), filtered and concentrated to give the desired compound as a yellow liquid (10.1 g, 90%): LCMS: RT 2.70min; m/z 209.1 [M+H]+.
85%
With potassium carbonate; In acetone; at 20℃; for 72h;
[00463] Intermediate 48: Synthesis of ethyl 2-ethoxy-4-formylbenzoate[00464] Step 1: Synthesis of ethyl 2-ethoxy-4-methylbenzoate: To a mixture of 2- hydroxy-4-methylbenzoic acid (5.0 g, 32.9 mmol), K2C03 (18.9 g, 136.6 mmol) and acetone (50 mL) was added ethyl iodide (41.0 g, 263.2 mmol). The mixture was stirred at room temperature for 3 days. After filtration, the organic layer was concentrated to afford ethyl 2- ethoxy-4-methylbenzoate as colorless oil (5.7 g, 85%), which was used directly for next step.
With samarium(III) trifluoromethanesulfonate In ethanol; water at 80℃; for 5h;
General procedure for the synthesis of benzoxazoles/benzothiazole
General procedure: To a mixture of o-aminophenol/o-aminothiophenol (1 mmol) and carboxylic acids (1 mmol) in ethanol:water (2:2 mL) under open atmosphere, 10 mol% of samarium triflate catalyst were added. The resulting mixture was stirred at 80 °C. After completion of the reaction, as monitored by TLC, the reaction mixture was diluted with 1:1 mixture of water/ethyl acetate (10 mL) and catalyst recovered by simplefiltration. The reaction mixture was extracted with diethyl ether (2 x 10 mL) and dried with anhydrous sodium sulfate. Finally, crude product was recrystallized from ethyl acetate or methanol. All the pure products were confirmed by their 1 HNMR, 13C NMR, IR, and mass spectroscopy data.
45%
With phosphoric acid at 150℃; for 12h;
2 2.2. Synthesis of 2-(2'-hydroxy-4'-methylphenyl)benzoxazole (BZ 1)
2-Aminophenol (3.57 g, 32.7 mmol) and 4-methylsalicylic acid (4.97 g, 32.7 mmol) were mixed in PPA (150 mL) in a 1 L round-bottomed flask. The reaction mixture was heated to 150 °C and was then stirred for 12 h. The resulting mixture was cooled to room temperature and poured into ice-water with vigorous stirring. The solution was neutralized by adding sodium bicarbonate. The crude product was collected by filtration and was recrystallized in ethanol. Further purification was carried out with column chromatography using an ethyl acetate-toluene mixture as a mobile phase. After chromatography, the product was dried in vacuo (yield: 3.23 g, 45%); 1H NMR (300 MHz, CDCl3-d6): δ = 11.45 (s, OH, 1H), 7.92 (d, Ar-H, 1H), 7.72 (m, Ar-H, 1H), 7.60 (m, Ar-H, 1H), 7.38 (m, Ar-H, 2H), 6.95 (s, Ar-H, 1H),6.84 (d, Ar-H, 1H), 1.56 (s, 3H).
Stage #1: 2-hydroxy-p-toluic acid; diethylamine With triphenylphosphine In toluene at 22℃; for 0.166667h; Inert atmosphere;
Stage #2: With di-isopropyl azodicarboxylate In toluene for 18h; Reflux; Inert atmosphere;
General procedure: Triphenylphosphine (1.20 eq), diethylamine (1.20 eq), and the benzoic acid(1.00 eq) were dissolved in toluene (0.2Msolution) at room temperature and allowedto stir for 10 min. Diisopropylazodicarboxylate (1.20 eq) was then added dropwiseand the reaction was heated to reflux overnight (18 h), at which time the reactionwas diluted with EtOAc and washed with 1M NaOH brine. The combined organiclayers were dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and theresulting residue was purified by flash column chromatography (EtOAc=hexanes2:1) to afford the desired benzamides.
Cu(4-methylsalicylate)<SUB>2</SUB>(N-methylnicotinamide)<SUB>2</SUB>(H<SUB>2</SUB>O)<SUB>2</SUB>[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; for 1h;
General procedure: N-methylnicotinamide (1 mmol) was added to an aqueous solution (5 mL) of copper acetate (0.5 mmol) and after few minutes 4-methysalicylic acid (1 mmol) was washed down with ethanol (about 20 mL). The reaction system was heated about one hour using water bath. The dark green precipitate was formed during heating, it was filtered off and the mother liquid was left to crystallizeat room temperature. Green crystals were then separated andthey were suitable for X-ray structure determination. [Cu(4-Mesal)2(mna)2(H2O)2]2EtOHAnal Calc: C, 53.29; H, 6.05; N, 7.31.
dipotassium 5-[{4'-[(5'-carboxylato-4'-hydroxy-2'-methylphenyl)diazenyl]biphenyl-4-yl}diazenyl]-2-hydroxy-4-methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53.2%
Stage #1: p,p'-diaminobiphenyl With hydrogenchloride; potassium nitrite In water at 0 - 5℃; for 1h;
Stage #2: 2-hydroxy-p-toluic acid With potassium carbonate In water at 5 - 20℃;
Potassium 5-[{4'-[(5'-carboxy-4'-hydroxy-2'-methylphenyl)diazenyl]biphenyl-4-yl}diazenyl]-2-hydroxy-4-methylbenzoate (I)
A mixture of1.84 g (0.01 mol) of benzidine, 4.8 mL (0.06 mol) of hydrochloric acid, and 10 mL of distilled water wasstirred for 20 min to get homogeneous suspension.Then 45 mL of boiling water was added at vigorous stirring to achieve complete dissolution of benzidine.After cooling to 0°C, a solution of potassium nitrite[1.75 g (0.021 mol) in 5 mL of water] was addedwithin 20 sec. The obtained mixture was stirred for 1 hat 5°C. Next, the prepared diazo solution was addeddropwise within 45 min to a solution of 2.9 g(0.021 mol) of 4-methylsalicylic acid in 50 mL of water and 9.66 g (0.07 mol) of potassium carbonate cooled to 5°C. The reaction mixture was stirred for 3 hand left overnight. The prepared dye was salted out with potassium chloride, filtered off, washed with 17% solution of potassium chloride, dried at room temperature, and chromatographed eluting with ethanol-water mixture (4 : 1). The obtained powderlike substance was dissolved in 50 mL of DMF and reprecipitated by adding 300 mL of diethyl ether. The precipitate formed was filtered off, washed with diethyl ether and dried in a vacuum at 40°C. Yield 53.2%. IR spectrum (KBr): ν, cm-1: 3424.7, 2923.91, 1637.35, 1586.02, 1492.25 1460.46, 1427.75, 1378.74,1265.33, 1173.96, 1064.42, 1002.8, 920.1, 852.35, 739.1, 626.55, 525.85. 1H NMR spectrum (DMSO-d6),δ, ppm: 8.17 s (2H), 7.94 d.d (8, J1 = J2 = 90 Hz),6.64 s (2), 2.63 s (6), 17.80 s (OH). 13C NMR spectrum (DMSO-d6), δ, ppm: 17.45, 116.77, 117.9, 122.59, 127.50, 140.14, 140.82, 143.41, 152.16, 162.25, 168.51, 170.97.
Stage #1: p,p'-diaminobiphenyl With hydrogenchloride; potassium nitrite In water at 0℃;
Stage #2: 2-hydroxy-p-toluic acid With potassium carbonate In water at 5℃;
5-formyl-2-hydroxy-4-methyl-benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1: 27.3%
2: 13.7%
Stage #1: hexamethylenetetramine; 2-hydroxy-p-toluic acid With copper(I) oxide In trifluoroacetic acid for 5h; Reflux;
Stage #2: With hydrogenchloride In water at 20℃; for 1h; regioselective reaction;
General procedure for the synthesis of target compounds
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).
Stage #1: 2-hydroxy-p-toluic acid; 2-Aminophenyl disulfide In toluene at 70℃; for 2.5h; Inert atmosphere;
Stage #2: With phosphorus trichloride In toluene at 30 - 100℃; Inert atmosphere;
General procedure for the synthesis of benzothiazole derivatives 3a-3p, D.
General procedure: 2,2'-Disulfanediyldianiline 1a or 6,6'-disulfanediylbis(3-chloroaniline) 1b (0.5 mmol) and carboxylic acid (1.0 mmol, except 0.5mmol for 2k) were added to a three-neck flask under an atmosphere of Ar, and 5 mL dry toluene was added, then the mixture was stirred for 2.5 h at 70 °C to allow the solid to dissolve in toluene solvent completely. After the reaction solution was cooled down to 30 °C, PCl3 (1.2 mmol, 0.165 g) was added dropwise. When the PCl3 was added completely, the reaction mixture was further stirred for 4 - 6 h at 100°C until no 2,2'-disulfanediyldianiline or 6,6'-disulfanediylbis(3-chloroaniline) was detected by TLC analysis. The reaction solution was washed with saturated aqueous sodium bicarbonate solution and extracted with CH2Cl2. The collected organic layers were dried over anhydrous MgSO4. After filtered toremove the MgSO4 and the solvent was removed under reduced pressure. The crude product was purifiedby flash chromatography on silica gel using PE / EtOAc.
potassium 3,7-bis(4-hydroxy-3-carboxylate-6-methylphenylazo)-5,5'-dioxodibenzothiophene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
Stage #1: 3,7-dibenzothiophenediamine, 5,5-dioxide With hydrogenchloride In water at 90℃; for 0.25h;
Stage #2: With potassium nitrite In water at 0℃; for 1.5h;
Stage #3: 2-hydroxy-p-toluic acid With potassium carbonate In water at 5℃;
Azo Dyes of Benzeneazo-5,5'-dioxodibenzothiophene Series
We placed 2.46 g of benzidine sulfone 2, 4.8 mL (0.06 mol) of concentrated hydrochloric acid and 30 mL of distilled water into a beaker equipped with a mechanical stirrer, thermometer, and dropping funnel. The mixture was heated under stirring at 90°C for 15 min. The resulting suspension was cooled to 0°C and a solution of 1.87 g of potassium nitrite in 5 mL of water was added dropwise, followed by stirring the mixture for 1.5 h. Solution 3 of diazo salt was added dropwise to asolution of 0.022 mol of 4-methylsalicylic acid and 9.66 g (0.07 mol) of potassium carbonate in 50 mL of water at a temperature of 5°C for 45 min, and the mixture was stirred for 5 h and kept overnight. The dye was then isolated and purified according to the known procedure [14]. FtF-2. Potassium 3,7-bis(4-hydroxy-3-carboxylate-6-methylphenylazo)-5,5'-dioxodibenzothiophene(Fig. 1). Yield, 54.0%. 1H NMR (500 MHz, DMSOd6,δ): 2.65, s (6H); 6.65, s (2H); 8.24, m (6H); 8.41, d(J = 8 Hz, 2H). 13C NMR (125 MHz, DMSO-d6, δ):17.63, 112.94, 117.37, 117.67, 118.58, 124.11, 129.98,130.43, 138.89, 140.59, 144.86, 154.17, 170.53, 170.76.IR (ν, cm-1): 3424, 2923, 1634, 1582, 1492, 1456,1373, 1298, 1194, 1062, 830, 741.
sodium 3,7-bis(4-hydroxy-3-carboxylate-6-methylphenylazo)-5,5'-dioxodibenzothiophene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
Stage #1: 3,7-dibenzothiophenediamine, 5,5-dioxide With hydrogenchloride In water at 90℃; for 0.25h;
Stage #2: With potassium nitrite In water at 0℃; for 1.5h;
Stage #3: 2-hydroxy-p-toluic acid With sodium carbonate In water at 5℃;
Azo Dyes of Benzeneazo-5,5'-dioxodibenzothiophene Series
General procedure: FtF-1. Sodium 3,7-bis(4-hydroxy-3-carboxylate-6-methylphenylazo)-5,5'-dioxodibenzothiophene. The compound was synthesized and isolated via the same procedures, but sodium salts of the reagents were used. Yield, 50%. 1H NMR (500 MHz, DMSO-d6, δ): 2.65,s (6H); 6.65, s (2H); 8.24, m (6H); 8.41, d (J = 8.5 Hz,2H); 17.98, br. s (OH). 13C NMR (125 MHz, DMSOd6,δ): 17.63, 113.06, 117.39, 117.68, 118.55, 124.14,129.96, 130.47, 138.9, 140.70, 144.86, 154.15, 170.24,170.91. IR (ν, cm-1): 3424, 2922, 1634, 1582, 1532,1446, 1370, 1298, 1254, 1053, 836, 795, 731. We placed 2.46 g of benzidine sulfone 2, 4.8 mL (0.06 mol) of concentrated hydrochloric acid and 30 mL of distilled water into a beaker equipped with a mechanical stirrer, thermometer, and dropping funnel. The mixture was heated under stirring at 90°C for 15 min. The resulting suspension was cooled to 0°C and a solution of 1.87 g of potassium nitrite in 5 mL of water was added dropwise, followed by stirring the mixture for 1.5 h. Solution 3 of diazo salt was added dropwise to asolution of 0.022 mol of 4-methylsalicylic acid and 9.66 g (0.07 mol) of potassium carbonate in 50 mL of water at a temperature of 5°C for 45 min, and the mixture was stirred for 5 h and kept overnight. The dye was then isolated and purified according to the known procedure [14].
With carbon dioxide at 185℃; for 7h; Autoclave; regioselective reaction;
General procedure: A glass reactor placed into a steel autoclave and equipped with a stirrer, electric heating, and carbondioxide gas inlet (outlet) fittings, was loaded with4.33 g (0.04 mol) of pcresol and 2.24 g (0.02 mol)of sodium ethyl carbonate (reactants ratios was[pcresol] : [sodium ethyl carbonate] = 2 : 1); the autoclave was pressurized; purged twice with 2 toremove air; and filled with 2 to a pressure of 10 atm;after which stirring and heating were switched on. Thereaction mixture was heated to 185°C over 4 h (at aheating rate of 40°C/h) and held at this temperatureand a 2 pressure of 10 atm for 3 h. After that, stirring and heating were stopped and the autoclave was cooled down to room temperature. The reaction mixture was treated with water. The obtained aqueous solution was extracted with ether to separate unreacted pcresol. From the ether phase, 2.2 g of unreacted pcresol was recovered.
With zinc(II) chloride; trichlorophosphate at 75℃; for 0.5h; Microwave irradiation;
5.2.2. Synthesis of xanthones (3-1~3-33)
General procedure: The synthesis refers to a procedure described in literature [32].To a 50-mL flask 8 mL phosphorus oxychloride (POCl3) and anhydrouszinc chloride (6.8 g, 0.05 mol) were added. The suspensionwas stirred at 70 °C until ZnCl2 was completely dissolved intophosphorus oxychloride. The mixture was then cooled down toroom temperature (r.t.). Afterwards, salicylic acids (1a-l) (l.0 mmol)and phenolics (2a-d) (1.1 mmol) were added, respectively, and themixture was heated with microwave reactor with a programmedprocedure of 75 °C for 30 min. Then the mixture was cooled downto r.t. and pulled into ice water stirring for 20 min. The mixed solutionwasfiltered,washed with coldwater. The solid residues werecollected and purified by flash column liquid chromatography.
With zinc(II) chloride; trichlorophosphate at 75℃; for 0.5h; Microwave irradiation;
5.2.2. Synthesis of xanthones (3-1~3-33)
General procedure: The synthesis refers to a procedure described in literature [32].To a 50-mL flask 8 mL phosphorus oxychloride (POCl3) and anhydrouszinc chloride (6.8 g, 0.05 mol) were added. The suspensionwas stirred at 70 °C until ZnCl2 was completely dissolved intophosphorus oxychloride. The mixture was then cooled down toroom temperature (r.t.). Afterwards, salicylic acids (1a-l) (l.0 mmol)and phenolics (2a-d) (1.1 mmol) were added, respectively, and themixture was heated with microwave reactor with a programmedprocedure of 75 °C for 30 min. Then the mixture was cooled downto r.t. and pulled into ice water stirring for 20 min. The mixed solutionwasfiltered,washed with coldwater. The solid residues werecollected and purified by flash column liquid chromatography.
70.1%
With zinc(II) chloride; trichlorophosphate at 85℃; for 3h;
1.1-4.1 (1) Synthesis of 6-methyl-1,3-dihydroxyxanthone:
Measure POCl3 (8mL) and mix it with anhydrous ZnCl2 (3.6g).Add a mixed powder of 4-methylsalicylic acid (0.152g, 1.0mmol) and resorcinol (0.151g, 1.2mmol). After reacting at 85 ° C for 3h, cool to room temperature.Pour the cooled product into ice water, stir for 1 h, leave it for 1 h, suction filter,Extracted with ethyl acetate (3 × 50mL), washed the filter cake to neutrality,The filter residue was dried and separated by column chromatography (mobile phase: petroleum ether-ethyl acetate).0.17 g of a pale yellow powder solid was obtained with a yield of 70.1%.
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 19h;Reflux;
To a solution of 4-methylsalicylic acid (2.93 g, 19.1 mmol, 1 equiv) in acetone (34.8 mL) wasadded finely ground K2C03 (7.9 g, 57.2 mmol, 3 equiv) and Me2SO4 (5.42 mL, 57.2 mmol, 3equiv). The solution was stirred at rt for 18 h and under reflux for 1 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude residue was dissolved in EtOAc (100 mL) and Et3N (2.65 mL, 19.1 mmol, 1 equiv) was added. The reaction mixture was stirred at rt for 30 mm. The reaction mixture was successively washed with water, 2N HC1, and brine.The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel column (hexane/EtOAc 10:0 to 10:10 (v/v) in 30 mm) to afford a colorless liquid (3.37 g, 18.7 mmol, 98 %).HPLC Purity = 99%; tr = 4.02 mm; ?H NMR (400 MHz, CDC13) oe 7.73 (d, J8.4 Hz, 1H),6.80-6.78 (m, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 2.39 (s, 3H); ?3C NMR (101 MHz, CDC13) oe166.6, 159.3, 144.6, 131.8, 120.9, 116.9, 112.8, 55.9, 51.8, 21.9; MS (ESIj: mlz = 203[M+Na].
3-methyl-12H-benzo[e]benzo[4,5]imidazo[2,1-b][1,3]oxazine-12-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With pyridine; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; copper(I) bromide In para-xylene at 120℃; for 36h; Schlenk technique; Green chemistry;
13 Example 13, Prepartion of 3-Methyl-12H-benzo[e]benzo[4,5]imidazo[2,1-b][1,3]oxazine-12-one (Compound III-12)
CuBr 6 mg (0.04 mmol), TEMPO 5 mg (0.03 mmol), compounded in a 25 mL Schlenk reaction tubeBenzimidazole 47 mg (0.4 mmol),4-methyl salicylic acid 31 mg (0.2 mmol), p-xylene (0.5 mL), and then pyridine 33 μL (0.4 mmol) was added and the temperature was kept at 120°C. The reaction was stirred and refluxed for 36 hours.Cool to room temperature, transfer all to a 25 mL flask, spin off the solvent on a rotary evaporator, add an appropriate amount of silica gel, spin dry, and then use a 300-400 mesh silica gel column. The developing solvent used is petroleum ether:ethyl acetate=16: 1 to 6:1, namely compound III-12 35mg, yield 70%; white solid
7-methyl-2-(2-carbonylpropyl)-2-phenyl-4-hydro-benzo[d][1,3]dioxin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With morpholine In dichloromethane at 20℃; for 24h;
75%
With acridine In tetrahydrofuran at 25℃; Green chemistry;
3 Example 3: Synthesis of 7-Methyl-2-(2-carbonylpropyl)-2-phenyl-4-hydro-benzo[d] [1, 3] dioxin-4-one
To a solution of 4-methylsalicylic acid (0.3 mmol) and 4-phenyl-3-butyn-2-one (0. 3 mmol) in tetrahydrofuran (2 mL), acridine (5m0%) was added dropwise with stirring ), react at room temperature (25 ° C) overnight. The reaction solution was dried and purified by column chromatography to give the desired product 7-methyl-2-(2-carbonylpropyl)-2-phenyl-4-hydro-benzo[d][1,3]dioxin 4-ketone: 66.62 mg, yield: 75%, colorless oily liquid.
2.2.1 Typical preparation procedure
General procedure: A solution of Zn(CH3COO)2·2H2O (0.022g, 0.10mmol) in 5mL EtOH was added to an EtOH solution (10mL) containing Hdmpz (0.019g, 0.20mmol) and 2-bromobenzoic acid (HL1) (0.0804g, 0.40mmol) under continuous stirring for about 2h at room temperature. The solution became turbid then a few drops of conc. ammonia were added till the solution became clear completely. The clear solution was filtered into the test tube, after several days colorless block crystals precipitated, which was filtered off, washed with EtOH and dried under vacuum to afford 0.042g of [Zn(Hdmpz)2(L1)2] (1).
2-hydroxy-N-[2-(1H-indol-3-yl)-ethyl]-4-methylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82.63%
Stage #1: 2-hydroxy-p-toluic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetone at 20℃; for 4h;
Stage #2: tryptamine In acetone at 20℃; for 24h;
75%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 8h;
4.3. General procedure for the preparation of 1-9, 11-14, 16,19-20, 22-27
General procedure: To a solution of tryptamine derivatives (0.62 mmol) indichloromethane (3 mL), EDCIHCl (144 mg, 0.75 mmol) and HOBT(110 mg, 0.81 mmol), Et3N (0.22 mL, 1.56 mmol), salicylic acid derivatives(0.69 mmol) were added at room temperature and stirredfor 8 h. After completion of the reaction detected by TLC, the reactionliquid was removed by rotary evaporation under reducedpressure. Then the resulting residue was purified by silica gel flashcolumn chromatography to afford the desired product as a solid(70%-90%).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 10h; Inert atmosphere;
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃;
4.3. general procedure for the preparation of compounds and the characterization data of new compounds
General procedure: For compounds with oxygen or nitrogen atoms substituted at 14position, the synthetic procedure is shown as follows: a test tubeequipped with a magnetic stir bar was charged with tryptamine (1 mmol), 2-(phenylamino)benzoic acid (1 mmol), EDCl (1.2 mmol), HOBt(1.2 mmol), triethylamine (2.5 mmol) and DCM (10 mL). The resultingmixture was stirred for 10 h at room temperature, then added 25 mL ofwater and 10 mL of saturated brine solution and extracted with DCM for3 times (3 × 25 mL). The combined organic extracts were concentratedand the resulting residue was purified by column chromatography onsilica gel (petroleum ether/ethyl acetate = 3/1) to give intermediates aswhite solid. For compounds with sulfur atom substituted at 14 position,a test tube equipped with a magnetic stir bar was charged with tryptamine(1.2 mmol), methyl 2-mercaptobenzoate (1 mmol), AlMe3 (1.2mmol), DCM (10 mL) at 0 C. The resulting mixture was moved to roomtemperature and stirred for 12 h, then quenched with HCl (5 M) aqueoussolution, and extracted with DCM for 3 times (3 × 25 mL), the combinedorganic extracts were concentrated and the resulting residue was purifiedby column chromatography on silica gel (petroleum ether/ethylacetate = 2/1) to give intermediates as white solid. The next step is thata mixture of the above intermediates (0.1 mmol) was triethyl orthoformate(0.30 mmol), BF3•Et2O (0.05 mmol, 0.5 eq) and DMF (1.0 mL)were added and stirred at 100 C for 5 h under an argon atmosphere.Then, the mixture was added 25 mL of water and 10 mL of saturatedbrine solution and extracted with ethyl acetate for 3 times (3 × 25 mL).The extract was dried over anhydrous Na2SO4 and concentrated underreduced pressure. The crude product was purified by column chromatography(petroleum ether/ ethyl acetate = 4/1) to afford the productsas white solid. (compounds 1-3 were obtained at 135 C; compounds 4 -5 were obtained at room temperature in DCM.)
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 2h; Inert atmosphere;
4.3 General procedure for the preparation of compound L1-L22
General procedure: A mixture of salicylic acid derivatives (1.0mmol, 1.0eq), tryptamine derivatives (1.0mmol, 1.0eq), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCIHCl, 1.2mmol, 1.2eq), 1-Hydroxybenzotriazole (HOBt, 1.1mmol, 1.1eq), triethylamine (Et3N, 2.0mmol, 2.0eq) and dichloromethane (DCM, 2.0mL) were stirred at room temperature for 2h under argon condition. After completion of the reaction detected by thin layer chromatography (TLC), the reaction liquid was removed by rotary evaporation under reduced pressure. Then the resulting residue was purified by silica gel flash column chromatography to afford the desired product as a solid (68-93%).
N-[2-(5-chloro-1H-indol-3-yl)ethyl]-2-hydroxy-4-methylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80.46%
Stage #1: 2-hydroxy-p-toluic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetone at 20℃; for 4h;
Stage #2: 5-chlorotryptamine In acetone at 20℃; for 24h;
77%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 2h; Inert atmosphere;
4.3 General procedure for the preparation of compound L1-L22
General procedure: A mixture of salicylic acid derivatives (1.0mmol, 1.0eq), tryptamine derivatives (1.0mmol, 1.0eq), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCIHCl, 1.2mmol, 1.2eq), 1-Hydroxybenzotriazole (HOBt, 1.1mmol, 1.1eq), triethylamine (Et3N, 2.0mmol, 2.0eq) and dichloromethane (DCM, 2.0mL) were stirred at room temperature for 2h under argon condition. After completion of the reaction detected by thin layer chromatography (TLC), the reaction liquid was removed by rotary evaporation under reduced pressure. Then the resulting residue was purified by silica gel flash column chromatography to afford the desired product as a solid (68-93%).
2-hydroxy-4-methyl-N-[2-(5-methyl-1H-indol-3-yl)ethyl]benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 2h; Inert atmosphere;
4.3 General procedure for the preparation of compound L1-L22
General procedure: A mixture of salicylic acid derivatives (1.0mmol, 1.0eq), tryptamine derivatives (1.0mmol, 1.0eq), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCIHCl, 1.2mmol, 1.2eq), 1-Hydroxybenzotriazole (HOBt, 1.1mmol, 1.1eq), triethylamine (Et3N, 2.0mmol, 2.0eq) and dichloromethane (DCM, 2.0mL) were stirred at room temperature for 2h under argon condition. After completion of the reaction detected by thin layer chromatography (TLC), the reaction liquid was removed by rotary evaporation under reduced pressure. Then the resulting residue was purified by silica gel flash column chromatography to afford the desired product as a solid (68-93%).
79.78%
Stage #1: 2-hydroxy-p-toluic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetone at 20℃; for 4h;
Stage #2: 5-methyltryptamine In acetone at 20℃; for 24h;
Stage #1: 2-hydroxy-p-toluic acid With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 0 - 20℃; for 1h;
Stage #2: <i>tert</i>-butyl alcohol With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 20℃; for 5h;
To a solution of 2-hydroxy-4-methylbenzoic acid (1) (10.0g, 66mmol) in 30mL dry DMF at 0°C, N,'N-carbonyldiimidazole (11.7g, 72mmol) was added, and stirred at room temperature for 1h. Then DBU (15mL, 100mmol) and tert-butanol (13mL, 130mmol) were added in sequence, and stirred at room temperature for 5h. The resulting mixture was diluted with H2O and then extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was removed to afford the crude product. It was purified by flash chromatography to afford tert-butyl 2-hydroxy-4-methylbenzoate as light yellow oil (12.6g, 91%).
With pyridine; thionyl chloride In 5,5-dimethyl-1,3-cyclohexadiene at 130 - 140℃; for 2h;
2.2. General procedure for synthesis of 3,5-diphenyl-1,2,4-triazole
General procedure: Substituted benzoic acid (1.2e2.0 g, 10 mmol) and o-hydroxybenzamide (1.5e2.3 g, 11 mmol) were added into 20 mL of xylene,then anhydrous pyridine (catalytic amount) was added, and thionylchloride (1.5 mL, 20 mmol) in xylene (8 mL) was added dropwiseover 30 mins at room temperature. After that, stirring was undertakenat 130e140 C. The mixturewas stirred for 2 h (TLC show acidwas consumed) and the solvent was distilled off under reducedpressure to obtain intermediate. The intermediate, 4-hydrazinobenzene-1-sulfonamide hydrochloride (1.1 g, 5 mmol)and triethylamine (1.0 g,10 mmol), were added to 15 mL of absoluteethanol, and the mixture was stirred at 80 C for 18 h. When thereaction was complete, the solution was filtered, and saturatedsodium bicarbonate was added to adjust pH to 7. The solution wasextracted with ethyl acetate, and the organic layer was washedwith 20 mL of saturated brine and dried over anhydrous sodium.The solvent was evaporated under reduced pressure to obtain thetarget compounds. The target compounds were recrystallized frommethanol.
With pyridine; thionyl chloride In 5,5-dimethyl-1,3-cyclohexadiene at 140℃; for 18h;
2.3. General procedure for the synthesis of 3,5-disubstituted phenyl-1,2,4-oxadiazole (compounds 11-27)
General procedure: Substituted o-hydroxybenzoic acid (1.1 eq, 11 mmol) and substitutedo-hydroxy benzamide (1 eq, 10 mmol) were added to 20 mL of xylene,anhydrous pyridine (catalytic amount) was added, and thionyl chloride(2 eq, 20.6 mmol) in xylene was added dropwise over 2 h. Afterwards,the mixture was stirred at 140 C for 16 h. The solvent was distilled offunder reduced pressure, and the residue was recrystallized with ethanolto yield the intermediates. The intermediates (1eq, 2 mmol) and hydroxylaminehydrochloride (1.1eq, 2.2mol) and triethylamine (catalyticamount) were added to 10 mL of absolute ethanol, and the mixture wasrefluxed for 8 h. When the reaction was complete, the formed precipitatewas collected by filtration and washed with EtOH and water. The targetcompounds were recrystallized in ethanol.
2-(2-hydroxy-4-methylphenyl)-4H-benzo[e][1,3]oxazin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; thionyl chloride In 5,5-dimethyl-1,3-cyclohexadiene at 130 - 140℃; for 2h;
2.2. General procedure for synthesis of 3,5-diphenyl-1,2,4-triazole
General procedure: Substituted benzoic acid (1.2e2.0 g, 10 mmol) and o-hydroxybenzamide (1.5e2.3 g, 11 mmol) were added into 20 mL of xylene,then anhydrous pyridine (catalytic amount) was added, and thionylchloride (1.5 mL, 20 mmol) in xylene (8 mL) was added dropwiseover 30 mins at room temperature. After that, stirring was undertakenat 130e140 C. The mixturewas stirred for 2 h (TLC show acidwas consumed) and the solvent was distilled off under reducedpressure to obtain intermediate. The intermediate, 4-hydrazinobenzene-1-sulfonamide hydrochloride (1.1 g, 5 mmol)and triethylamine (1.0 g,10 mmol), were added to 15 mL of absoluteethanol, and the mixture was stirred at 80 C for 18 h. When thereaction was complete, the solution was filtered, and saturatedsodium bicarbonate was added to adjust pH to 7. The solution wasextracted with ethyl acetate, and the organic layer was washedwith 20 mL of saturated brine and dried over anhydrous sodium.The solvent was evaporated under reduced pressure to obtain thetarget compounds. The target compounds were recrystallized frommethanol.
With pyridine; thionyl chloride In 5,5-dimethyl-1,3-cyclohexadiene at 140℃; for 18h;
2.2. General procedure for the synthesis of 3,5-disubstituted phenyl-1,2,4-triazole (compounds 1-10)
General procedure: Substituted o-hydroxybenzoic acid (1 eq, 10 mmol) and o-hydroxybenzamide (1.1 eq, 11 mmol) were added to 20 mL of xylene, anhydrouspyridine (catalytic amount) was added, and thionyl chloride (2 eq, 20.6mmol) in xylene was added dropwise over 2 h. Afterwards, the mixturewas stirred at 140 C for 16 h. The solvent was distilled off underreduced pressure, and the residue was recrystallized with ethanol toyield the intermediates. The intermediates (1 eq, 2 mmol) and hydrazinehydrate (2.05 eq, 4.1 mmol) were added to 10 mL of absolute ethanol,and the mixture was refluxed for 2 h. When the reaction was complete,the formed precipitate was collected by filtration and washed with EtOHand water. The target compounds were recrystallized in ethanol.2.2.1.
2-hydroxy-4-methyl-N-(2-oxo-2H-chromen-3-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
With phosphorus trichloride In acetonitrile Reflux;
4.1.3 General procedure for the synthesis of compounds 5a-p
General procedure: The 3-aminocoumarin 3 (1mmol) and appropriate carboxylic acid 4a-p (1.1mmol) were dissolved in 3mL CH3CN and the mixture was stirred at room temperature for half an hour. The PCl3 (1mmol) was added dropwise in the reaction mixture and the reaction mixture was again refluxed for 5-6h but in case of compounds 5c and 5p 8h refluxing was required. After completion the reaction was quenched by adding ice cold water (5mL) and the solvent was evaporated under reduced pressure. The residue was dissolved in chloroform (10mL) and washed twice with water (2×20mL) and then with saturated NaHCO3 solution (10mL) and finally with brine (20mL). The organic layer was dried over Na2SO4 and the solvent was evaporated under vacuum. The solid products obtained in case of compounds 5a, 5b, 5d, 5f, 5h, and 5p were recrystallized from acetone while those in case of compounds 5c, 5i and 5l were recrystallized in acetone and DMSO mixture (3:1). The crude products obtained in case of compounds 5e, 5g, 5j, 5k and 5m-5o were purified by silica gel column using chloroform:methanol (9:1) as eluent.
With 2,6-dimethylpyridine In acetonitrile at 0 - 22℃; for 16h; Inert atmosphere;
General Experimental Procedure A.
General procedure: To a mixture of salicylic acid (1.00 eq) in acetonitrile (1.0 M solution) at 0 C was added 2,6-lutidine (4.00 eq) followed by the dropwise addition of di-tert-butylsilyl bis(trifluoromethansulfonate) (2.00 eq). The reaction was warmed to room temperature and allowed to stir overnight (16 h). The reaction was poured into H2O, extracted with EtOAc, and washed with brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and the resulting residue was purified by medium pressure flash chromatography (Silicycle SiliaSep Si column, 25 g, 1.0% EtOAc:hexanes, 25 mL/min detected at 254 nm) to afford the desired di-tert-butylsilylenes.
tert-butyl (4-(4-methyl-2-hydroxybenzoyl))aminobenzylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran for 12h; Reflux;
1 General Procedure for the Synthesis of Compounds 7-12
General procedure: 103 mg of EDCI (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.45 mmol, 1 equivalent) and 1 equivalent of tert-butyl-(4-aminobenzyl)carbamate (0.45 mmol), synthesized according to the method described by V. Famiglini et al., Eur. J. Med. Chem. 2014, 80, 101-111, are added to a solution of 100 mg of the appropriate carboxylic acid derivative (0.45 mmol), dissolved in 2.5 ml of THF (tetrahydrofuran). The solution is stirred, then brought to reflux for 12 hours. After a return to ambient temperature, the solution is evaporated to dryness. The residue is dissolved in 20 ml of ethyl acetate and the resulting solution is washed with a 1N (3×20 ml) aqueous hydrochloric acid solution, then with 20 ml of a saturated aqueous sodium hydrogen carbonate solution. The organic phase is dried over anhydrous sodium sulfate, filtered and then evaporated under vacuum. The residue is then purified, either by washing (2×5 ml) with diethyl ether (compound 10), or by washing (2×5 ml) with dichloromethane (compound 9), or chromatographed on silica gel for the other compounds. Tert-butyl (4-(4-methyl-2-hydroxybenzoyl)aminobenzylcarbamate (Compound 7) Eluent: nHex/AcOEt 1/2 v/v. Pale yellow solid (mass: 131 mg, yield: 82%); 1H NMR (CDCl3, 400 MHz): δ ppm 1.45 (s, 9H), 2.33 (s, 3H), 4.28 (d, 2H, J=5.5 Hz), 4.84 (bs, 1H), 6.70 (dd, 1H, J=8.1 Hz, 1.1 Hz), 6.82 (d, 1H, J=1.1 Hz), 7.27 (d, 2H, J=8.4 Hz), 7.39 (d, 1H, J=8.1 Hz), 7.50 (d, 2H, J=8.4 Hz), 7.93 (bs, 1H), 11.94 (s, 1H); 13C NMR (CDCl3, 100 MHz): δ ppm 21.9, 28.6, 44.4, 79.9, 112.1, 119.3, 120.3, 121.6, 125.5, 128.4, 136.1, 136.2, 146.1, 156.1, 162.1, 168.6; HPLC, Tr=1.90 min; MS (ESI+): m/z 357.2 [M+H]+, 379.1 [M+Na]+, 301.2 [M-tBu]+
82%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran for 12h; Reflux;
5‐chloropyridin‐3‐yl 2‐hydroxy‐4‐methylbenzoate[ No CAS ]
5‐chloropyridin‐3‐yl 2‐((2‐hydroxy‐4‐methylbenzoyl)oxy)‐4‐methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1: 15%
2: 3%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 23℃; Inert atmosphere;
Synthesis of 6-chloropyridin-2-yl 2-acetoxybenzoate (6a).
General procedure: To a stirred solution of 2-acetoxybenzoicacid (150 mg, 0.83 mmol) in DCM (3 mL), 5-chloropyridin-3-ol (129.4 mg, 0.10 mmol), EDC (240 mg,1.25 mmol) and DMAP (102 mg, 0.83 mmol) were added. The resulting reaction mixture was stirredat 23 °C for 10 h. After this period, the reaction mixture was washed with saturated aqueous Na-HCO3. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressureto give a crude residue. The residue was purified via silica gel column chromatography (30%ethyl acetate in hexanes) to afford the title ester 6a (30 mg, 12%) as an amorphous solid.
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