* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 1, p. 350 - 364
[2] Chemical Communications, 2012, vol. 48, # 94, p. 11558 - 11560
[3] Patent: US2012/277224, 2012, A1,
[4] Patent: WO2013/97773, 2013, A1,
3
[ 18595-14-7 ]
[ 25978-68-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4416 - 4420
4
[ 18595-14-7 ]
[ 3095-48-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 14, p. 3033 - 3044
5
[ 75-18-3 ]
[ 18595-14-7 ]
[ 3095-48-5 ]
Reference：
[1] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2010, vol. 75, # 1, p. 320 - 324
6
[ 18595-14-7 ]
[ 5471-81-8 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2010, vol. 352, # 9, p. 1451 - 1454
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4416 - 4420
7
[ 24078-21-5 ]
[ 18595-14-7 ]
Yield
Reaction Conditions
Operation in experiment
96%
With 5%-palladium/activated carbon; hydrogen In ethanolFlow reactor
General procedure: Before each run, the system (see Fig.4) was allowed to equilibrate by pumping solvent through for 30min with the Tube-in-Tube device at 16bar of hydrogen. An omnifit cartridge (20.0mm OD, 15.0mm ID) containing 1g of Pd-C catalyst was used. To avoid an overpressure of the system in the event of blockage, the upper pressure cut-off limit on the Knauer pump was set to 25bar. With the injection loop disconnected from the flow line, the loop was opened and filled manually (using a syringe) with 3.6mL of a 0.076M solution of starting material in ethanol (excess starting material solution exiting the loop was recovered for reuse). The injection loop was then closed off and switched into the flow stream. The outlet from the system (downstream of the back-pressure regulator) was collected for 120min. The solvent was removed under reduced pressure (using a rotary evaporator followed by a 2-stage rotary vane pump) to afford the product.
90%
Stage #1: With hydrogenchloride In water; ethyl acetate Stage #2: With zinc In water; ethyl acetate at 0 - 20℃; for 15.33 h; Stage #3: With sodium hydrogencarbonate In water; ethyl acetate
Methyl 3-methyl-4-nitrobenzoate (23 g, 117.84 mmol) was dissolved in ethyl acetate (400 mL) and cond HCl (58 mL). Then the solution was cooled to 0 °C and Zn powder (46.2 g, 707 mmol) was added in portions over 20 min with stirring. The mixture was allowed to warm up to room temperature and stirring was continued for 15 h. The reaction mixture was passed through a bed of Celite and washed with ethyl acetate (100 mL). The filtrate was washed with satd NaHCO3 solution (4 .x. 100 mL), water (3 .x. 100 mL) and brine (2 .x. 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to dryness to obtain the amino compound 5 (17.4 g, 90.0percent) as a colorless solid. mp 111-113 °C; 1H NMR (300 MHz, CDCl3) δ 2.18 (s, 3H), 3.85 (s, 3H), 4.02 (s, br, 2H), 6.65 (d, J = 8.1 Hz, 1H), 7.76-7.72 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 17.2, 51.7, 113.8, 119.5, 121.1, 129.4, 132.3, 149.5, 167.6; MS (ES) m/z 166 (M+1).
90%
With palladium on activated charcoal; hydrogen In methanol at 20℃;
To a solution of methyl 3-methyl-4-nitrobenzoate (50 g, 256.2mmol) in methanol (1.5L) was added palladium on carbon (2.5 g). Then H2 (g) was introduced and the reaction was stirred overnight at room temperature. The solids were filtered off and the resulting solution was concentrated in vacuo to afford methyl 4- amino- 3- methylbenzoate as a light yellow solid (38 g, 90percent). LCMS (ES, m/z): [M+H]+ 166.1
80%
With hydrogen In methanol at 20℃;
Step 2. Methyl 4-amino-3-methylbenzoate To a solution of methyl 3-methyl-4-nitrobenzoate (31 g, 158.83 mmol) in methanol (1000 mL) was added palladium on carbon (2 g), and the reaction was stirred overnight at room temperature under an atmosphere of H2(g). Then the solids were filtered out and filtrate was concentrated under vacuum to afford methyl 4-amino-3-methylbenzoate as a white solid (21 g, 80percent). LC/MS (ES, m/z): [M+H]+ 166.0 1H-NMR (300 MHz, CD3Cl) δ 7.74-7.77 (m, 2H), 6.52 (d, J=8.1 Hz, 1H), 4.09-4.11 (m, 2H), 3.87 (s, 3H), 2.20 (s, 3H)
62%
With iron; ammonium chloride In methanol; water for 4 h; Reflux
To a stirred solution of methyl 3-methyl-4-nitrobenzoate (50 g, 1.0 eq) in 1 L MeOH were added at rt a solution of NH4CI (137 g, 10 eq) in 60 mL H20 and Fe power (96 g, 7 eq), and the resulting mixture is heated at reflux for 4 h. The reaction mixture was allowed to cool to rt, filtered, and water was added. The mixture was extracted with EtOAc. The extract was dried, washed with water, and concentrated to give the desired product directly as a white solid (26 g, 62percent).
Reference：
[1] Tetrahedron, 2018, vol. 74, # 47, p. 6795 - 6803
[2] Journal of Heterocyclic Chemistry, 2003, vol. 40, # 6, p. 1107 - 1112
[3] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 14, p. 4582 - 4589
[4] Patent: WO2014/66795, 2014, A1, . Location in patent: Paragraph 0175
[5] Zeitschrift fur Anorganische und Allgemeine Chemie, 2014, vol. 640, # 1, p. 159 - 167
[6] Chemical Communications, 2012, vol. 48, # 94, p. 11558 - 11560
[7] Patent: US2012/277224, 2012, A1, . Location in patent: Page/Page column 34
[8] Asian Journal of Chemistry, 2014, vol. 26, # 7, p. 1921 - 1930
[9] Patent: WO2013/97773, 2013, A1, . Location in patent: Paragraph 0258
[10] Chemische Berichte, 1895, vol. 28, p. 597
[11] European Journal of Medicinal Chemistry, 1983, vol. 18, # 4, p. 307 - 314
[12] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4416 - 4420
[13] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 81 - 84
8
[ 3113-71-1 ]
[ 18595-14-7 ]
Yield
Reaction Conditions
Operation in experiment
99%
With H2 In methanol
(a) Methyl 4-amino-3-methylbenzoate. To a solution of 3-methyl-4-nitrobenzoic acid (6.50 g, 33.3 mmol) in 100 mL of MeOH was added 700 mg of 5percent Pd/C. The mixture was hydrogenated at 48 psi H2 for 24 hours, the catalyst was removed by suction filtration, and the filtrate was concentrated under reduced pressure. The title compound was obtained as a white solid (99percent). 1H NMR (CDCl3) δ: 2.19 (s, 3H), 3.85 (s, 3H), 4.20 (br s, 2H), 6.65 (d, 2H, J = 8.1Hz), 7.72 (d, 2H, J = 8.1Hz), 7.76 (s, 1H). Anal. (C9H11NO2) C, H, N.
Reference：
[1] Patent: EP1109560, 2003, B1,
[2] Journal of Heterocyclic Chemistry, 2003, vol. 40, # 6, p. 1107 - 1112
[3] Chemische Berichte, 1895, vol. 28, p. 597
[4] Chemical Communications, 2012, vol. 48, # 94, p. 11558 - 11560
[5] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 81 - 84
[6] Patent: US2012/277224, 2012, A1,
[7] Zeitschrift fur Anorganische und Allgemeine Chemie, 2014, vol. 640, # 1, p. 159 - 167
[8] Patent: WO2014/66795, 2014, A1,
[9] Asian Journal of Chemistry, 2014, vol. 26, # 7, p. 1921 - 1930
9
[ 67-56-1 ]
[ 2486-70-6 ]
[ 18595-14-7 ]
Yield
Reaction Conditions
Operation in experiment
95%
With thionyl chloride In dichloromethane at 80℃; for 3 h;
Step 1. Methyl 4-amino-3-methylbenzoate A solution of 4-amino-3-methylbenzoic acid (60 g, 396.92 mmol) and SOCl2 (141.9 g, 1.19 mol) in methanol (700 mL) was stirred 3 hours at 80° C. The resulting solution was concentrated in vacuo to afford a residue, which was dissolved in dichloromethane (500 mL) and washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford methyl 4-amino-3-methylbenzoate (62 g, 95percent) as a pink solid. LC/MS (ES, m/z): [M+H]+ 152.1 1H-NMR (300 MHz, CDCl3) δ 7.78 (d, J=0.6 Hz, 1H), 7.74 (d, J=2.1 Hz, 1H), 6.65 (d, J=8.1 Hz, 1H), 4.11 (s, 2H), 3.87 (s, 3H), 2.20 (s, 3H)
95%
at 20℃; for 12 h;
4-Amino-3-methylbenzoic acid (20 mmol) and 30 ml MeOH were placed in a flask, and SOCl2 (24 mmol) were added dropwise at -5 °C. The reaction kept for 12 h at room temperature. The solvent was evaporated and the residue was basified with NaHCO3 to PH 7 or 8, extracted with ethyl acetate (EA). The dried organic phase was concentrated to get the compound 4. White solid, yield 95percent, mp 119-120 °C; 1H NMR (400 Hz, CDCl3) δ (ppm): 2.07 (s, 3H, Ar-CH3), 3.73 (s, 3H, OCH3), 5.74 (s, 2H, NH2), 6.60 (d, 1H, JH = 8.0 Hz, Ar-H), 7.52 (dd, 1H, J12 = 2.0 Hz, J13 = 8.4 Hz, J34 = 2.0 Hz, Ar-H), 7.55 (s, 1H, Ar-H).
92%
at 90℃; for 10 h;
To a solution of 4-amino-3-methylbenzoic acid (80 g, 529.23 mmol) in methanol (1000 mL) was added thionyl chloride (250 g) with stirring for 10 h at 90°C. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with H20 (200 mL), extracted with dichloromethane (3 x 150 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out to give the filtered, which was concentrated under vacuum to afford methyl 4-amino-3-methylbenzoate as a light yellow solid (80 g, 92percent). LCMS (ES, m/z): [M+H]+ 166.0 *H NMR (300 MHz, DMSO) δ 8.25 (brs, 2H), 7.60 (s, 1H), 7.59 (s, 1H), 6.86 (d, J = 8.40Hz, 1H), 3.76 (s, 3H), 2.16 (s, 2H)
Reference：
[1] Advanced Synthesis and Catalysis, 2010, vol. 352, # 9, p. 1451 - 1454
[2] Patent: US2012/277224, 2012, A1, . Location in patent: Page/Page column 39
[3] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 22, p. 6366 - 6379
[4] Patent: WO2014/66795, 2014, A1, . Location in patent: Paragraph 0175
[5] Journal of Organic Chemistry, 1996, vol. 61, # 17, p. 5804 - 5812
[6] Patent: EP1568688, 2005, A1, . Location in patent: Page/Page column 30
[7] Patent: US2004/132779, 2004, A1, . Location in patent: Page/Page column 17
[8] Journal of Photochemistry and Photobiology A: Chemistry, 2010, vol. 213, # 2-3, p. 164 - 170
10
[ 186581-53-3 ]
[ 2486-70-6 ]
[ 18595-14-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2001, vol. 44, # 25, p. 4416 - 4430
Stage #1: With sulfuric acid In water at 0℃; Stage #2: With sodium nitrite In water at 0℃; for 0.0833333 h;
4-Amino-3-methyl-benzoic acid methyl ester (5.25g, 32.0mmol) was treated with a 35percent solution of sulphuric acid (50ml) and the mixture was stirred and heated un;til dissolution then cooled to 0°C. Sodium nitrite (2.82g, 41.6mmol) in water (50ml) was added dropwise and the mixture was stirred for 5min at 0°C. Urea was added to destroy the excess nitrite. Copper nitrate (121g, 320mmol) in water (11) was added then copper ox;ide (4.25g, 32.0mmol). The mixture was warmed up to room temperature over 30 min and extracted with EtOAc (x 3). The organics were combined, washed with brine, dried and concentrated in vacuo. The residue was puri;fied by flash chromatography on silica gel (eluant; 30percent EtOAc:70percent hexane) to yield the title compound (2.2g, 42percent) .
Reference：
[1] Journal of Heterocyclic Chemistry, 2003, vol. 40, # 6, p. 1107 - 1112
[2] Journal of Medicinal Chemistry, 1993, vol. 36, # 25, p. 4040 - 4051
[3] European Journal of Medicinal Chemistry, 2016, vol. 115, p. 161 - 178
18
[ 18595-14-7 ]
[ 152628-02-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 1993, vol. 36, # 25, p. 4040 - 4051
[2] European Journal of Medicinal Chemistry, 2016, vol. 115, p. 161 - 178
19
[ 18595-14-7 ]
[ 144701-48-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 1993, vol. 36, # 25, p. 4040 - 4051
20
[ 18595-14-7 ]
[ 180624-25-3 ]
Reference：
[1] Journal of Organic Chemistry, 1996, vol. 61, # 17, p. 5804 - 5812
21
[ 18595-14-7 ]
[ 473416-12-5 ]
Yield
Reaction Conditions
Operation in experiment
62%
Stage #1: With hydrogenchloride; ammonium tetrafluoroborate; sodium nitrite In water for 0.583333 h; Stage #2: With 18-crown-6 ether; potassium acetate In chloroform; water at 20℃; for 2 h;
Step 3. Methyl 1H-indazole-5-carboxylate To a solution of methyl 4-amino-3-methylbenzoate (21 g, 133.18 mmol) in HCl (15 mL) and water (85 mL) was added NH4BF4 (20 g) and NaNO2 (10 g, 144.93). The mixture was stirred for 35 minutes, and the solids were collected by filtration and added in one portion to a stirred mixture of KOAc (16 g, 163.03 mmol) and 18-crown-6 (500 mg, 1.89 mmol) in CHCl3 (170 mL). After stirring for 2 hours at room temperature, the mixture was washed with water (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 30percent ethyl acetate in petroleum ether to afford methyl 1H-indazole-5-carboxylate as a white solid (14.5 g, 62percent). LC/MS (ES, m/z): [M+H]+ 177.0 1H-NMR (300 MHz, CDCl3) δ 8.58-8.59 (m, 1H), 8.23 (s, 1H), 8.09-8.13 (m, 1H), 7.54 (d, J=9.0 Hz, 1H), 3.98 (s, 3H)
55%
Stage #1: With tetrafluoroboric acid; sodium nitrite In water at 0 - 20℃; for 4 h; Stage #2: With 18-crown-6 ether; potassium acetate In chloroform; water at 0 - 20℃; for 3 h; Inert atmosphere
NaN02 (20 g, 0.29 mol) was added portion wise to a solution of methyl 4-amino-3- methylbenzoate (38 g, 0.23 mol) in aqueous HBF4 (48 wt, 200 mL) at 0°C. The reaction was allowed to stir for 4 h at room temperature. The solids were collected by filtration and washed with 3x200 mL of ether. The solids were dried in an oven under reduced pressure. Under an inert atmosphere of nitrogen, was placed CH3COOK (45 g, 0.46mol), 18-crown-6 (3 g, 0.012mol), and chloroform (200 mL). This was followed by the portion wise addition of the dried solid at 0°C. The reaction was stirred for 3 h at room temperature. Then 1 L of H20 was added and the resulting solution was extracted with 5x100 mL of DCM. The organic layers were dried over anhydrous sodium sulfate and the filtrate was concentrated in vacuo to afford a residue which was purified by silica gel column chromatography with 1percent methanol in CH2Cl2 to afford of methyl lH-indazole-5-carboxylate as a yellow solid (22 g, 55percent). LCMS (ES, m/z): [M+H]+ 177.1 *H NMR (300 MHz, DMSO) δ 13.41 (s, 1H), 8.50 (s, 1H), 8.26 (s, 1H), 7.94 - 7.90 (dd, / = 1.50, 8.70 Hz, 1H), 7.64 (d, / = 8.70 Hz, 1H), 3.90 (s, 3H)
30%
With acetic acid; sodium nitrite In water at 20℃; for 5 h;
A solution of sodium nitrite (836 mg, 59.1 mmol) in water (2 ml) was added to a solution of methyl 4-amino-3-methylbenzoate (2.00 g, 12.1 mmol) in acetic acid (80 ml) at room temperature and stirred at room temperature for 5 hours. The reaction solution was concentrated and the resulting residue was diluted with chloroform and washed with a 5percent aqueous sodium hydrogencarbonate solution and then a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate = 3/1) to obtain methyl 1H-indazole-5-carboxylate (645 mg, 30percent).1H-NMR (DMSO-d6) δ; 3.86 (3H, s), 7.61 (1H, d, J=8.8Hz), 7.91 (1H, d, J=8.8Hz), 8.25 (1H, s), 8.48 (1H, brs), 13.41 (1H, brs).
Reference：
[1] Patent: US2012/277224, 2012, A1, . Location in patent: Page/Page column 34
[2] Patent: WO2014/66795, 2014, A1, . Location in patent: Paragraph 0175
[3] Patent: EP1403255, 2004, A1, . Location in patent: Page 43-44
[4] Patent: WO2013/97773, 2013, A1,
[5] Asian Journal of Chemistry, 2014, vol. 26, # 7, p. 1921 - 1930
[6] Patent: WO2014/129796, 2014, A1,
[7] Patent: WO2014/143666, 2014, A1, . Location in patent: Paragraph 00190
22
[ 18595-14-7 ]
[ 108-24-7 ]
[ 473416-12-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 2016, vol. 59, # 4, p. 1556 - 1564
23
[ 18595-14-7 ]
[ 91367-05-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4416 - 4420
24
[ 18595-14-7 ]
[ 180636-50-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4416 - 4420
25
[ 18595-14-7 ]
[ 1092351-82-0 ]
Reference：
[1] Patent: WO2014/66795, 2014, A1,
26
[ 18595-14-7 ]
[ 108-24-7 ]
[ 239075-26-4 ]
Yield
Reaction Conditions
Operation in experiment
1.2 g
Stage #1: at 0 - 20℃; for 1 h; Stage #2: With potassium acetate; isopentyl nitrite In chloroform at 70℃; for 18 h;
4-Amino-3-methyl-benzoic acid methyl ester (2.0 g, 12.03 mmol) was dissolved in chloroform (25 mL) and then acetic anhydride (2.12 g, 30.07 mmol) was slowly added dropwise thereto at 0. The mixture was stirred for 1 hour at room temperature, and potassium acetate (250 mg, 3.61 mmol) and isoamyl nitrite (2.23 mL, 24.06 mmol) were added thereto. The mixture was stirred under reflux for 18 hours at 70 and added with excess dichloromethane. The mixture was washed with saturated sodium hydrogen carbonate aqueous solution, dried with anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure. The residue was separated by column chromatography to obtain the intermediate acetyl indazole (1.2 g, 5.50 mmol).
Reference：
[1] Chemical Communications, 2012, vol. 48, # 94, p. 11558 - 11560
[2] Patent: WO2014/129796, 2014, A1, . Location in patent: Paragraph 1225-1227
27
[ 18595-14-7 ]
[ 900019-52-5 ]
Yield
Reaction Conditions
Operation in experiment
83%
With N-Bromosuccinimide In dichloromethane at 20℃; for 3 h;
A mixture of compound 1 (429 mg, 0.0026 mol) and NBS (0.7 g, 0.0039 mol) in DCM was stirred at r.t. for 3 h. The mixture was concentrated to a residue, which was purified by Prep-TLC to obtain compound 2 (522 mg, 83percent) as a light yellow solid
With 5%-palladium/activated carbon; hydrogen; In ethanol; under 12001.2 Torr;Flow reactor;
General procedure: Before each run, the system (see Fig.4) was allowed to equilibrate by pumping solvent through for 30min with the Tube-in-Tube device at 16bar of hydrogen. An omnifit cartridge (20.0mm OD, 15.0mm ID) containing 1g of Pd-C catalyst was used. To avoid an overpressure of the system in the event of blockage, the upper pressure cut-off limit on the Knauer pump was set to 25bar. With the injection loop disconnected from the flow line, the loop was opened and filled manually (using a syringe) with 3.6mL of a 0.076M solution of starting material in ethanol (excess starting material solution exiting the loop was recovered for reuse). The injection loop was then closed off and switched into the flow stream. The outlet from the system (downstream of the back-pressure regulator) was collected for 120min. The solvent was removed under reduced pressure (using a rotary evaporator followed by a 2-stage rotary vane pump) to afford the product.
90%
Methyl 3-methyl-4-nitrobenzoate (23 g, 117.84 mmol) was dissolved in ethyl acetate (400 mL) and cond HCl (58 mL). Then the solution was cooled to 0 C and Zn powder (46.2 g, 707 mmol) was added in portions over 20 min with stirring. The mixture was allowed to warm up to room temperature and stirring was continued for 15 h. The reaction mixture was passed through a bed of Celite and washed with ethyl acetate (100 mL). The filtrate was washed with satd NaHCO3 solution (4 × 100 mL), water (3 × 100 mL) and brine (2 × 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to dryness to obtain the amino compound 5 (17.4 g, 90.0%) as a colorless solid. mp 111-113 C; 1H NMR (300 MHz, CDCl3) delta 2.18 (s, 3H), 3.85 (s, 3H), 4.02 (s, br, 2H), 6.65 (d, J = 8.1 Hz, 1H), 7.76-7.72 (m, 2H); 13C NMR (75 MHz, CDCl3) delta 17.2, 51.7, 113.8, 119.5, 121.1, 129.4, 132.3, 149.5, 167.6; MS (ES) m/z 166 (M+1).
90%
With palladium on activated charcoal; hydrogen; In methanol; at 20℃;
To a solution of <strong>[24078-21-5]methyl 3-methyl-4-nitrobenzoate</strong> (50 g, 256.2mmol) in methanol (1.5L) was added palladium on carbon (2.5 g). Then H2 (g) was introduced and the reaction was stirred overnight at room temperature. The solids were filtered off and the resulting solution was concentrated in vacuo to afford methyl 4- amino- 3- methylbenzoate as a light yellow solid (38 g, 90%). LCMS (ES, m/z): [M+H]+ 166.1
80%
With hydrogen;palladium on activated charcoal; In methanol; at 20℃;
Step 2. Methyl 4-amino-3-methylbenzoate To a solution of <strong>[24078-21-5]methyl 3-methyl-4-nitrobenzoate</strong> (31 g, 158.83 mmol) in methanol (1000 mL) was added palladium on carbon (2 g), and the reaction was stirred overnight at room temperature under an atmosphere of H2(g). Then the solids were filtered out and filtrate was concentrated under vacuum to afford methyl 4-amino-3-methylbenzoate as a white solid (21 g, 80%). LC/MS (ES, m/z): [M+H]+ 166.0 1H-NMR (300 MHz, CD3Cl) delta 7.74-7.77 (m, 2H), 6.52 (d, J=8.1 Hz, 1H), 4.09-4.11 (m, 2H), 3.87 (s, 3H), 2.20 (s, 3H)
62%
With iron; ammonium chloride; In methanol; water; for 4h;Reflux;
To a stirred solution of <strong>[24078-21-5]methyl 3-methyl-4-nitrobenzoate</strong> (50 g, 1.0 eq) in 1 L MeOH were added at rt a solution of NH4CI (137 g, 10 eq) in 60 mL H20 and Fe power (96 g, 7 eq), and the resulting mixture is heated at reflux for 4 h. The reaction mixture was allowed to cool to rt, filtered, and water was added. The mixture was extracted with EtOAc. The extract was dried, washed with water, and concentrated to give the desired product directly as a white solid (26 g, 62%).
General procedure: Methyl 4-amino-3-methylbenzoate (6) (10.00g, 60.58mmol) was acylated with alkyl acyl chloride (90.87mmol) and triethylamine (16.79mL, 121.16mmol) in DCM at 0C. The resulting amide was reacted with fuming nitric acid in sulfuric acid (60%) at-20C. The resulting nitro-compound was reduced with hydrogen (5bar) and Raney Ni (0.79g, 13.34mmol) in methanol at 100C. The resulting amino compound was dissolved in glacial acetic acid and heated under reflux for 1h. After evaporation of the acetic acid, water was added and the pH was adjusted to 9 by addition of concentrated ammonia. This solution was extracted with ethyl acetate (3×100mL). The combined organic layers were washed with aqueous NaHCO3 solution and dried over MgSO4. After filtration, the solvent was removed under reduced pressure.
With thionyl chloride; In dichloromethane; at 80℃; for 3h;
Step 1. Methyl 4-amino-3-methylbenzoate A solution of <strong>[2486-70-6]4-amino-3-methylbenzoic acid</strong> (60 g, 396.92 mmol) and SOCl2 (141.9 g, 1.19 mol) in methanol (700 mL) was stirred 3 hours at 80 C. The resulting solution was concentrated in vacuo to afford a residue, which was dissolved in dichloromethane (500 mL) and washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford methyl 4-amino-3-methylbenzoate (62 g, 95%) as a pink solid. LC/MS (ES, m/z): [M+H]+ 152.1 1H-NMR (300 MHz, CDCl3) delta 7.78 (d, J=0.6 Hz, 1H), 7.74 (d, J=2.1 Hz, 1H), 6.65 (d, J=8.1 Hz, 1H), 4.11 (s, 2H), 3.87 (s, 3H), 2.20 (s, 3H)
95%
With thionyl chloride; at 20℃; for 12h;
4-Amino-3-methylbenzoic acid (20 mmol) and 30 ml MeOH were placed in a flask, and SOCl2 (24 mmol) were added dropwise at -5 C. The reaction kept for 12 h at room temperature. The solvent was evaporated and the residue was basified with NaHCO3 to PH 7 or 8, extracted with ethyl acetate (EA). The dried organic phase was concentrated to get the compound 4. White solid, yield 95%, mp 119-120 C; 1H NMR (400 Hz, CDCl3) delta (ppm): 2.07 (s, 3H, Ar-CH3), 3.73 (s, 3H, OCH3), 5.74 (s, 2H, NH2), 6.60 (d, 1H, JH = 8.0 Hz, Ar-H), 7.52 (dd, 1H, J12 = 2.0 Hz, J13 = 8.4 Hz, J34 = 2.0 Hz, Ar-H), 7.55 (s, 1H, Ar-H).
92%
With thionyl chloride; at 90℃; for 10h;
To a solution of <strong>[2486-70-6]4-amino-3-methylbenzoic acid</strong> (80 g, 529.23 mmol) in methanol (1000 mL) was added thionyl chloride (250 g) with stirring for 10 h at 90C. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with H20 (200 mL), extracted with dichloromethane (3 x 150 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out to give the filtered, which was concentrated under vacuum to afford methyl 4-amino-3-methylbenzoate as a light yellow solid (80 g, 92%). LCMS (ES, m/z): [M+H]+ 166.0 *H NMR (300 MHz, DMSO) delta 8.25 (brs, 2H), 7.60 (s, 1H), 7.59 (s, 1H), 6.86 (d, J = 8.40Hz, 1H), 3.76 (s, 3H), 2.16 (s, 2H)
With thionyl chloride; at 80℃; for 14h;
Thionyl chloride (2.64 mL) was added to a mixture of <strong>[2486-70-6]4-amino-3-methylbenzoic acid</strong> (5.0 g) and methanol (50 mL), followed by stirring at 80C for fourteen hours. After cooling to room temperature, the reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, concentrated under reduced pressure and was extracted with ethyl acetate. The organic layer was sequentially washed with saturated aqueous sodium hydrogen carbonate solution and brine and was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, to yield the titled compound (5.50 g) as crystals.
Preparation of Intermediate 4-Amino-3-methyl-benzoic acid methyl ester (I-1b): A solution of methanol (200 ml) was chilled to 0 C. acetyl chloride (47.1 g, 600 mmols) was then added dropwise to the stirring mixture to make a 3N HCl solution of methanol.To this solution was added <strong>[2486-70-6]4-amino-3-methyl-benzoic acid</strong> (10.0 g, 66 mmols).The mixture was then refluxed for 5 hours.The mixture was cooled to room temperature and 100 ml of diethyl ether was added.A white precipitate formed and this was collected by suction filtration and washed with ether.The dry product weighed 13.14 g (65 mmols).
With 1-pyridin-1-ium-1-yliodanuidylpyridin-1-ium tetrafluoroborate; In dichloromethane; for 3.5h;
To a solution of methyl 4-amino-3-methyl-benzoate (12.17 g, 73.70 mmol) in DCM (135 mL) was added 1-pyridin-1-ium-1-yliodanuidylpyridin-1-ium (Boron Tetrafluoride Ion) (30.14 g, 81.00 mmol). The reaction mixture was stirred for 1.5h, then 1-pyridin-1-ium-1- yliodanuidylpyridin-1-ium (Boron Tetrafluoride Ion) (2.740 g, 7.367 mmol) was added and the mixture was stirred for another 2h, then quenched with aqueous saturated NaHCO3 (100 mL).The layers were separated. The aqueous layer was extracted with DCM (2 x 100 mL). The combined organic extracts were washed with aqueous 1M Na2S2O3 (100 mL) and dried over Na2SO4, filtered and concentrated. The crude residue was co-evaporated with heptane (2x) and purified by flash chromatography on a BiotageTM snap 340g silica cartridge, using a gradient of EtOAc (0-25%) in Hex as eluent. The fractions were combined and concentrated to provide thetitle compound (18.0 g, 84% yield). ?H NMR (400 MHz, CDC13) oe 8.23 (s, 1H), 7.71 (s, 1H),4.51 (s, 2H), 3.85 (s, 3H), 2.25 (s, 3H).
(a) Methyl 4-amino-3-methylbenzoate. To a solution of 3-methyl-4-nitrobenzoic acid (6.50 g, 33.3 mmol) in 100 mL of MeOH was added 700 mg of 5% Pd/C. The mixture was hydrogenated at 48 psi H2 for 24 hours, the catalyst was removed by suction filtration, and the filtrate was concentrated under reduced pressure. The title compound was obtained as a white solid (99%). 1H NMR (CDCl3) delta: 2.19 (s, 3H), 3.85 (s, 3H), 4.20 (br s, 2H), 6.65 (d, 2H, J = 8.1Hz), 7.72 (d, 2H, J = 8.1Hz), 7.76 (s, 1H). Anal. (C9H11NO2) C, H, N.
Step 3. Methyl 1H-indazole-5-carboxylate To a solution of methyl 4-amino-3-methylbenzoate (21 g, 133.18 mmol) in HCl (15 mL) and water (85 mL) was added NH4BF4 (20 g) and NaNO2 (10 g, 144.93). The mixture was stirred for 35 minutes, and the solids were collected by filtration and added in one portion to a stirred mixture of KOAc (16 g, 163.03 mmol) and 18-crown-6 (500 mg, 1.89 mmol) in CHCl3 (170 mL). After stirring for 2 hours at room temperature, the mixture was washed with water (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 30% ethyl acetate in petroleum ether to afford methyl 1H-indazole-5-carboxylate as a white solid (14.5 g, 62%). LC/MS (ES, m/z): [M+H]+ 177.0 1H-NMR (300 MHz, CDCl3) delta 8.58-8.59 (m, 1H), 8.23 (s, 1H), 8.09-8.13 (m, 1H), 7.54 (d, J=9.0 Hz, 1H), 3.98 (s, 3H)
55%
NaN02 (20 g, 0.29 mol) was added portion wise to a solution of methyl 4-amino-3- methylbenzoate (38 g, 0.23 mol) in aqueous HBF4 (48 wt, 200 mL) at 0C. The reaction was allowed to stir for 4 h at room temperature. The solids were collected by filtration and washed with 3x200 mL of ether. The solids were dried in an oven under reduced pressure. Under an inert atmosphere of nitrogen, was placed CH3COOK (45 g, 0.46mol), 18-crown-6 (3 g, 0.012mol), and chloroform (200 mL). This was followed by the portion wise addition of the dried solid at 0C. The reaction was stirred for 3 h at room temperature. Then 1 L of H20 was added and the resulting solution was extracted with 5x100 mL of DCM. The organic layers were dried over anhydrous sodium sulfate and the filtrate was concentrated in vacuo to afford a residue which was purified by silica gel column chromatography with 1% methanol in CH2Cl2 to afford of methyl lH-indazole-5-carboxylate as a yellow solid (22 g, 55%). LCMS (ES, m/z): [M+H]+ 177.1 *H NMR (300 MHz, DMSO) delta 13.41 (s, 1H), 8.50 (s, 1H), 8.26 (s, 1H), 7.94 - 7.90 (dd, / = 1.50, 8.70 Hz, 1H), 7.64 (d, / = 8.70 Hz, 1H), 3.90 (s, 3H)
30%
With acetic acid; sodium nitrite; In water; at 20℃; for 5h;
A solution of sodium nitrite (836 mg, 59.1 mmol) in water (2 ml) was added to a solution of methyl 4-amino-3-methylbenzoate (2.00 g, 12.1 mmol) in acetic acid (80 ml) at room temperature and stirred at room temperature for 5 hours. The reaction solution was concentrated and the resulting residue was diluted with chloroform and washed with a 5% aqueous sodium hydrogencarbonate solution and then a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate = 3/1) to obtain methyl 1H-indazole-5-carboxylate (645 mg, 30%).1H-NMR (DMSO-d6) delta; 3.86 (3H, s), 7.61 (1H, d, J=8.8Hz), 7.91 (1H, d, J=8.8Hz), 8.25 (1H, s), 8.48 (1H, brs), 13.41 (1H, brs).
With acetic acid; isopentyl nitrite; at 20 - 80℃; for 6h;
Isoamyl nitrite (26.8 g, 22.8 mmol) was added to a mixture of methyl 4-amino-3-methylbenzoate (3.4 g, 20.8 mmol) in acetic acid (AcOH, (20 mL). The reaction mixture was stirred at room temperature for lh then at 80 C for 5 h. It was concentrated and the residue was purified by silica gel column chromatography (Hexanes/EtOAc 10: 1 to 2: 1) to give pure methyl lH-indazole-5-carboxylate.
1.50 g (9.08 mmol) methyl 4-amino-3-methyl-benzoate are dissolved in 250 ml dioxane combined with 1.3 ml (10.7 mmol) trichloromethyl-chloroformate and refluxed for 5. 5 hours with stirring. Then the mixture is evaporated down i. vac. and the residue is further reacted without any more purification. Yield: 1.74 g (quantitative) C10H9NO3 (191.19)
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 16h;
A solution of 2.14 g (10 mmol) 6-bromo-hexanoylchloride in 5.0 ml THF is slowly added dropwise with stirring at ambient temperature to 1.65 g (10 mmol) methyl 4-amino-3-methyl-benzoate in 50 ml THF with 2 ml DIPEA. After 16 hours stirring at ambient temperature the mixture is evaporated down i. vac., the residue is dissolved in dichloromethane, washed twice with water and dried over sodium sulphate. The residue remaining after evaporation i. vac. is further reacted without any more purification. Yield: 3.30 g (96%) Rf value: 0.40 (silica gel; petroleum ether/ethyl acetate=4:1) C15H20BrNO3 (342.24)
100 mg (0.61 mmol) methyl 4-amino-3-methyl-benzoate dissolved in 3 ml of pyridine are combined with 82 mul (0.67 mmol) 3-chloropropanesulphonic acid chloride and stirred for 16 hours at ambient temperature. The reaction solution is combined with water and ethyl acetate and then the aqueous phase is again extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down i. vac. The residue is further reacted without any more purification. Yield: 170 mg (92%) C12H16ClNO4S (305.78) Mass spectrum: (M+H)+=306/308 (chlorine isotope) Rf value: 0.10 (silica gel; petroleum ether/ethyl acetate=8:2)
1.70 g (10.3 mmol) methyl 4-amino-3-methyl-benzoate in 10 ml THF are combined with 2.84 ml (20.6 mmol) triethylamine and stirred for 20 minutes at ambient temperature. Then a solution of 1.78 g (10.4 mmol) 3-(2-chloro-ethoxy)-propionic acid-chloride in 25 ml THF is added dropwise and the mixture is stirred for a further 2.5 hours at ambient temperature. Then water is added and the mixture is extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down completely i. vac. The residue is purified by chromatography on silica gel (eluting gradient: petroleum ether/ethyl acetate=7:3->6:4). Yield: 1.25 g (41%) C14H18ClNO4 (299.75) Mass spectrum: (M+H)+=300/302 (chlorine isotope) Rf value: 0.15 (silica gel; petroleum ether/ethyl acetate=7:3)
4-(methoxycarbonyl)-2-methylbenzenediazonium tetrafluoroborate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With tetrafluoroboric acid; sodium nitrite; In water; at 0 - 20℃; for 0.25h;
To an aqueous solution of NaN02 (12.54 g, 2.0 eq) in 75 mL H20 at 0 C was added dropwise cooled solution of <strong>[18595-14-7]methyl 4-amino-3-methylbenzoate</strong> (15 g, 1.0 eq) in HBF4(aq)(40% in water). After addition, the mixture was stirred for 15 min at ambient temperature. The precipitate was filtered, washed with ice-cold water, and dried, to give the desired product as a white solid (16 g, 90%).
A solution of sodium nitrite (4.60 g, 66.6 mmol, 1.10 equiv) in water (50 mL) was added slowly to a pre-cooled (-10 C) mixture of <strong>[18595-14-7]methyl 4-amino-3-methylbenzoate</strong> (12-1, 10.0 g, 60.5 mmol, 1 equiv) and concentrated aqueous hydrochloric acid solution (12 M, 15.1 mL, 182 mmol, 3.00 equiv) in water (75 mL) at a rate that kept the reaction mixture temperature below 0 C. Following the addition, the reaction mixture was stirred at -5 C for 30 min, then filtered. A solution of sodium tetrafluoroborate (20.0 g, 182 mmol, 3.00 equiv) in water (100 mL) was immediately added to the cold filtrate. The precipitate was filtered and washed with ice-cold water (70 mL). The remaining solid was air-dried to give 4-(methoxycarbonyl)-2-methylbenzenediazonium tetrafluoroborate as a white solid. A suspension of this product (16.0 g, 60.6 mmol, 1 equiv), potassium acetate (14.9 g, 152 mmol, 2.50 equiv) and 18- crown-6 (1.60 g, 6.06 mmol, 0.100 equiv) in chloroform (300 mL) was stirred at 23 C for 5 h. The reaction mixture was filtered and concentrated. The residue was partitioned between water and EtOAc (300 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated to give methyl lH-indazole-5-carboxylate (12-2) as a light orange solid. LRMS m/z (M+Eta) 177.1 found, 177.1 required.
4-Amino-3-methyl-benzoic acid methyl ester (5.25g, 32.0mmol) was treated with a 35% solution of sulphuric acid (50ml) and the mixture was stirred and heated until dissolution then cooled to 0C. Sodium nitrite (2.82g, 41.6mmol) in water (50ml) was added dropwise and the mixture was stirred for 5min at 0C. Urea was added to destroy the excess nitrite. Copper nitrate (121g, 320mmol) in water (11) was added then copper oxide (4.25g, 32.0mmol). The mixture was warmed up to room temperature over 30 min and extracted with EtOAc (x 3). The organics were combined, washed with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 30% EtOAc:70% hexane) to yield the title compound (2.2g, 42%) .
With sodium hydroxide; potassium acetate; acetic anhydride; In methanol; hydrochloric acid-methanol; water; chlorobenzene;
Intermediate 2: 1H-5-Indazolecarboxylic acid Methyl 4-amino-3-methylbenzoate (0.85 g), potassium acetate (1.47 mg), and acetic anhydride (1.42 ml) were suspended in chlorobenzene (20 ml), and isoamyl nitrate (1.17 g) was added to the suspension at 80C. The reaction mixture was stirred at the same temperature for 18 hr. Water (20 ml) was then added thereto, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was dissolved in hydrochloric acid-methanol (20 ml), and the mixture was then stirred at 80C for 5 hr. A saturated aqueous sodium hydrogencarbonate solution (20 ml) was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel [chloroform/methanol] to give intermediate A. Intermediate A was dissolved in methanol (20 ml), and a 3 N aqueous sodium hydroxide solution (3 ml) was added thereto. The reaction mixture was stirred at room temperature for 18 hr. The solvent was then removed by distillation under the reduced pressure, and the residue was purified by ODS chromatography [water/acetonitrile] to give the title compound (0.32 g). Mass spectrum (ESI-MS, m/z): 161 (M+-1)
With potassium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In ISOPROPYLAMIDE; at 60℃;Combinatorial reaction / High throughput screening (HTS);
Step 2. Catalytic amination of the solid supported 8-iodo-l-methyl-4,5-dihydro- lH-pyrazolo [4,3-h] quinazoline-3-carboxamide; <n="82"/>Using a 4 niL Argonaut Trident synthesizer cassette, 200 mg (0.11 mmol) of the resin from step 1 above, were charged into separate vials. To each of the reactor vials flushed with argon, finely divided potassium carbonate (0.15 g, 1.1 mmol), palladium acetate [Pd(OAc)2] (2.5mg, 0.011 mmol, 10%), (HK)-BINAP (6.8 mg, 0.011 mmol, 10%) and the corresponding amine (0.22 mmol, 2 equivalents) in degassed (argon) dimethyacetamide (2 mL) were added. The resulting mixture was agitated at 600C for 10 hours on the Argonaut Trident Automated Library Synthesizer (ALS) station. The Trident ALS station was programmed to continuously mechanically agitate the resin at 6O0C while a nitrogen gas "sparge" was incorporated to re-suspend the scarcely soluble potassium carbonate. Nitrogen gas sparging was incorporated once per hour, for a 30 second duration, throughout the 16-hour heating cycle.The resin was drained from the synthesis cocktail and washed using the Argonaut Trident External Agitation Thermal Unit (EATU) synthesis station with DMA (3 x 2 mL, 5 min.). The above catalytic amination cycle was repeated a second time using the previously described procedure.Upon completion of the second amination cycle, the resin was drained from the synthesis cocktail and washed using the Argonaut Trident EATU synthesis station with DMF (1 x 2 mL, 5 min.), with water (1 x 2 mL, 5 min.), with DMF/water (1 : 1) (3 x 2 mL, 5 min.), with DMF (3 x 2 mL, 5 min.), with methanol (3 x 2 mL, 5 min.) and with DCM (3 x 2 mL, 5 min.).
methyl 4-(3-(8-(3,4-dimethoxyphenylamino)imidazo[1,2-a]pyrazin-6-yl)benzamido)-3-methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
A mixture of 3-(8-(3,4-dimethoxyphenylamino)imidazo[1,2-a]pyrazin-6-yl)benzoic acid hydrochloride salt (80 mg, 0.187 mmol), <strong>[18595-14-7]methyl 4-amino-3-methylbenzoate</strong> (46 mg, 0.281 mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (124 mg, 0.281 mmol) and 4-methylmorpholine (95 mg, 0.937 mmol) in DMF (1.5 mL) was stirred at ambient temperature for 18 h. The mixture was then stirred at 45 C. for 6 h before additional <strong>[18595-14-7]methyl 4-amino-3-methylbenzoate</strong> (46 mg, 0.281 mmol) was added and the resulting mixture was stirred at ambient temperature for 18 h. To the reaction mixture was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (97 mg, 0.187 mmol) and the resulting mixture was stirred at 45 C. for 18 h and then at ambient temperature for 6 d. After this time, the reaction was diluted with ethyl acetate (50 mL) and washed with water (30 mL) then 5% aqueous lithium chloride solution (30 mL). The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 39:1 methylene chloride/methanol) to afford methyl 4-(3-(8-(3,4-dimethoxyphenylamino)imidazo[1,2-a]pyrazin-6-yl)benzamido)-3-methylbenzoate (36 mg, 36%): ESI MS m/z 538 [M+H]+
With toluene-4-sulfonic acid; In 1,4-dioxane; at 130℃; for 3h;Microwave irradiation;
[00547] 4-(6-Cyclohexylamino-9H-purin-2-ylamino)-3-methyl-benzoic acid(81): A suspension of (2-chloro-9H-purin-6-yl)cyclohexylamine 1 (0.20 g, 0.80 mmol), 4- amino-3-methylbenzoic acid methyl ester (0.20 g, 1.20 mmol), and /?-TSA (0.15 g, 0.80 mmol) in of 1,4-dioxane (1.0 mL) was irradiated at 130 0C for 3 hours in a microwave and then was concentrated and purified by silica gel chromatography to provide intermediate ester (0.11 g, 36%). The above ester was hydrolyzed in a solution of lithium hydroxide (10 equiv.) in THF:MeOH:water (2: 1 : 1) The solution was stirred for 16 hours at room temperature, then cooled in an ice bath and then 2 N HCl solution was slowly added to afford a precipitate. The precipitate 81 was collected, dried, and then used in the next reaction without purification.
Into a 500-mL round-bottom flask was placed a solution of <strong>[18595-14-7]methyl 4-amino-3-methylbenzoate</strong> (4.00 g, 24.2 mmol, 1.00 equiv) and NaSCN (7.00 g, 86.4 mol, 3.57 equiv) in AcOH (90 mL) that was cooled to 0 C. This was followed by the addition of a solution of Br2 (3.9 g, 25 mmol, 1.0 equiv) in AcOH (25 mL) dropwise, maintaining at 0 C over 20 min. The resulting solution was allowed to warm to RT on its own accord (over approximately 10 min.) and stirred for 48 hrs at RT. At this time, the solids of the reaction were filtered out. The resulting solution was diluted with 100 mL H20. The pH value of the solution was adjusted to 8-9 with ammonia (using Whatman PH strip paper to monitor PH adjustment) which furnished an immediate precipitation. The solids were collected by filtration and washed once with ice cold MeOH (50 mL) to afford as a yellow solid. MS m/z 223.0 (M+l). 1H NMR (400 MHz, MeOH- 4) delta 8.17 (app d, J = 1.0 Hz, 1H), 8.03 (br s, 2H, NH2), 7.68 (s, 1H), 3.82 (s, 3H), 2.42 (s, 3H).
With bromine; acetic acid; at 0 - 30℃; for 16h;
To a 500 mL rotmd-hottom f1ask vas added methyl4-amino-3-methylbenzoate A-6a(1 0.0 g, 60.54 mmol, 1.0 equiv.), AcOFf (200 mL), and NaSCN (19.6 g, 4.0 equiv.) follo·wed10 by the dropwise addition of a solution ofbromine (9.7 g, 60.70 mmol, 1.0 equiv.) in AcOH(100 mL) at 0 C. 111e resulting mixture was stirred at 30 C for 16 hand then quenched bythe addition of 500 mL of ice water. The pH value of the aqueous solution was adjusted to 9using sodi1m1 hydroxide. The aqueous mixture was extracted with ethyl acetate (500 mL x3), and the combined organic layers vvere w·ashed with brine (500 mL x 3), dried over15 anhydrous sodium sulfate, filtered, and concentrated 1..mder reduced pressure to afford 15 g ofrnethyl 2-amino-4-methyl-1,3-benzothiazole-6-ca.rboxylate A-6a as a yellow solid (crude)The crude product was carried onto the next step without further purification.
With bromine; acetic acid; at 0 - 30℃; for 16h;
To a 500 mL round-bottom flask was added <strong>[18595-14-7]methyl 4-amino-3-methylbenzoate</strong> A-6a (10.0 g, 60.54 mmol, 1.0 equiv.), AcOH (200 mL), and NaSCN (19.6 g, 4.0 equiv.), followed by the dropwise addition of bromine (9.7 g, 60.70 mmol, 1.0 equiv.) in AcOH (100 mL) at 0 C. The resulting mixture was stirred at 30 C for 16 h and then quenched with ice water (500 mL), The pH value of the solution was adjusted to 9 using sodium hydroxide. The aqueous mixture was extracted with ethyl acetate (500 mL x 3), and the combined organic layers were washed with brine (500 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford methyl 2-amino-4-methyl-l,3-benzothiazole-6-carboxylate A-6b (15 g) as a yellow solid. The product was carried on to the next step without further purification.
With ytterbium(III) triflate; In acetonitrile; at 90℃; for 20h;sealed tube;
To a stirred solution of <strong>[18595-14-7]4-amino-3-methyl-benzoic acid methyl ester</strong> (11.55 g, 70 mmol) and 3-bromobenzaldehyde (8.2 mL, 70 mmol) in acetonitrile (150 mL) were added isobutene (17 mL, 242 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.2 g, 8.4 mmol). The resulting mixture was stirred at 90 C. for 20 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(3-bromo-phenyl)-4,4,8-trimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (8.15 g, 30%) as a light yellow solid: MS (ESI) M+1=388.0 & 390.0.
30%
ytterbium(III) triflate; In acetonitrile; at 90℃; for 20h;Sealed tube;
Example 66Cyclopropanesulfonic acid [4,4,8-trimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4- tetrahydro-quinoline-6-carbonyl]-amideTo a stirred solution of <strong>[18595-14-7]4-amino-3-methyl-benzoic acid methyl ester</strong> (11.55 g, 70mmmol) and 3-bromobenzaldehyde (8.2 mL, 70 mmol) in acetonitrile (150 mL) were added isobutene (17 mL, 242 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.2 g, 8.4 mmol). The resulting mixture was stirred at 90C for 20 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL x 2) and brine (100 mL x 2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10 - 50% ethyl acetate in petroleum ether) to afford 2-(3-bromo-phenyl)- 4,4,8-trimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (8.15 g, 30%) as a light yellow solid: MS(ESI) M+l = 388.0 & 390.0.A mixture solution of 2-(3-bromo-phenyl)-4,4,8-trimethyl-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid methyl ester (1.4 g, 3.6 mmol), morpholine (4.3 mL, 50 mmol), copper(I) iodide (274 mg, 1.44 mmol), N,N-dimethylglycine hydrochloride (0.3 g, 2.16 mmol), and potassium carbonate (1.49 g, 10.8 mmol) in dimethyl sulfoxide (10 mL) was stirred at 120C for 16 h. Then the reaction mixture was cooled to room temperature. The reaction mixture was extracted with ethyl acetate (150 mL x 2), washed with saturated aqueous ammonium chloride solution (50 mL x 3) and brine (50 mL x 2), dried over anhydrous sodium sulfate and then concentrated in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 30 - 50% ethyl acetate in petroleum ether) to afford 4,4,8-trimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid methyl ester (1.4 g, 98%) as a white solid: MS(ESI) M+l = 394.2.To a stirred mixture solution of 4,4,8-trimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4- tetrahydro-quinoline-6-carboxylic acid methyl ester (1.4 g, 3.55 mmol) in methanol (5 mL) and tetrahydrofuran (10 mL) was added 30% sodium hydroxide in water (5 mL). The reaction mixture was stirred at 60C for 16 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2 x 50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 4,4,8-trimethyl-2-(3-morpholin-4-yl-phenyl)- l,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.9 g, 66%) as a light white solid which was used for next step without further purification: MS(ESI) M+l = 381.0.To a suspension of 60% sodium hydride (664 mg, 16.6 mmol) in N,N-dimethylformamide (5 mL) was added cyclopropanesulfonic acid amide (2.01 g, 16.6 mmol) at room temperature. The resulting mixture was stirred at 25C for 1 h to afford Solution A66. A solution of 4,4,8-trimethyl-2-(3-morpholin-4-yl-phenyl)- l,2,3,4-tetrahydro-quinoline-6- carboxylic acid (0.9 g, 2.37 mmol) and Iota, Gamma-carbonyldiimidazole (768 mg, 4.74 mmol) in N,N-dimethylformamide (5 mL) was stirred at 70C for 1 h and cooled to roomtemperature to afford Solution B66. Solution B66 was added to Solution A66 and the resulting mixture was stirred at 25C for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm x 100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [4,4,8-trimethyl-2-(3- morpholin-4-yl-phenyl)-l, 2,3, 4-tetrahydro-quinoline-6-carbonyl] -amide (107 mg, 9%) as a brown solid: MS(ESI) M+l
4-Amino-3-methyl-benzoic acid methyl ester (2.0 g, 12.03 mmol) was dissolved in chloroform (25 mL) and then acetic anhydride (2.12 g, 30.07 mmol) was slowly added dropwise thereto at 0. The mixture was stirred for 1 hour at room temperature, and potassium acetate (250 mg, 3.61 mmol) and isoamyl nitrite (2.23 mL, 24.06 mmol) were added thereto. The mixture was stirred under reflux for 18 hours at 70 and added with excess dichloromethane. The mixture was washed with saturated sodium hydrogen carbonate aqueous solution, dried with anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure. The residue was separated by column chromatography to obtain the intermediate acetyl indazole (1.2 g, 5.50 mmol).
To a stirred and cooled (0 C) slurry of commercially available <strong>[18595-14-7]methyl 4-amino-3-methylbenzoate</strong> (2 g, 12.12 mmol) in 6 N HCl (12 mL) was added NaNO2 (0.92 g, 13.33 mmol) in water (2 mL) drop wise maintaining a temperature of <15 C during the addition. The mixture was stirred an additional 1.5 h affording a light yellow, homogeneous solution. To the mixture was carefully added 4.58 g (24.24 mmol) of anhydrous SnCl2. The temperature during the addition was kept <10 C. The mixture was stirred at 0 C for 1 h. The precipitated solid was collected by filtration, dried under vacuum to afford methyl 4-hydrazinyl-3-methylbenzoate hydrochloride 4 (1.75 g 81%) as a brown solid: mp 224-226 C; 1H NMR (CDCl3, 500 MHz) delta ppm 2.22 (s, 3H), 3.80 (s, 3H), 6.99 (d, J = 8.5 Hz, 1H), 7.70 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H); MS (ESI): m/z calcd for C9H12N2O2 ([M+H]+) 181.0932; found 181.0911 ([M+H]+).
73%
Step 1. Methyl 4-hydrazinyl-3-methylbenzoate hydrochloride To a solution of methyl 4-amino-3-methylbenzene carboxylate (1.02 g, 6.17 mmol) in concentrated HCl(aq) (6.0 mL) and water (2.0 mL) was added a solution of sodium nitrite (0.640 g, 9.28 mmol) in water (2.0 mL) slowly at 0 C. After the reaction mixture was stirred at 0 C. for 1 h, a solution of tin(II) chloride (3.51 g, 18.5 mmol) in concentrated HCl(aq) (3.0 mL) was added. The solution was stirred for another 3 h at room temperature. The solids were collected by filtration and washed with cold water and n-hexane to give methyl 4-hydrazinyl-3-methylbenzoate hydrochloride (0.980 g, 73%) as a lightly yellow solid. 1H NMR (DMSO-d6, 300 MHz) delta 8.50-8.10 (br, 1H), 7.77 (d, 1H), 7.69 (s, 1H), 6.90 (d, 1H), 3.76 (s, 3H), 2.18 (s, 3H).
With N-Bromosuccinimide; In dichloromethane; at 20℃; for 3h;
A mixture of compound 1 (429 mg, 0.0026 mol) and NBS (0.7 g, 0.0039 mol) in DCM was stirred at r.t. for 3 h. The mixture was concentrated to a residue, which was purified by Prep-TLC to obtain compound 2 (522 mg, 83%) as a light yellow solid
3.66 g
With N-Bromosuccinimide; acetic acid; for 1h;
To a stirred solution of methyl 4-amino-5-methylbenzoate (85) (2.48 g, 15 mmol) in 25 mL of AcOH, NBS (3.0 g, 17 mmol)was added portionwise, the mixture was stirred for 1 h, diluted with water, extracted with DCM, washed with a saturated NaHCO3 solution, dried over a2S04, and rotovapped to yield 3.66 g of methyl 4-amino-3-bromo-5-methylbenzoate (86). XH NMR (CDC13, 400 MHz) delta 8.03 (s, 1H), 7.71 (s, 1H), 4.50 (brs, 2H), 3.87 (s, 3H), 2.25 (s, 3H).
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 3h;
To a solution of compound 4 (20 mmol) in 100 mL of tetrahydrofuran (THF) at0 C, lithium aluminium hydride (30 mmol) was added in smallportions. Monitored with TLC, the reaction kept stirring at 0 Cfor 3 h, then excessive dosage of Na2SO4 10H2O was added with vigorous stirring for 30 min. The suspension was filtered and the filtrate was evaporated. The residue was applied to a flash column chromatography by eluting with petroleum ether/ethyl acetate (2:1) to give the compound 5 as a yellow solid. Yield 75%, mp215-216 C; 1H NMR (400 Hz, CDCl3) d (ppm): 2.16 (s, 3H, CH3),3.62 (s, 2H, NH2), 4.52 (s, 2H, OCH2), 6.65 (d, 1H, JH = 7.6 Hz,Ar-H), 7.03 (d, 1H, JH = 8.0 Hz, Ar-H), 7.06 (s, 1H, Ar-H)
methyl 4-(2,5-dichlorobenzenesulfonamido)-3-methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With pyridine; at 25℃; for 12h;
General procedure: To a solution of amine (1 mmol) in 3 mL of pyridine at 0C was slowly added the appropriate benzenesulfonyl chloride (1.1 mmol, 1.1 equiv). The mixture was stirred for 12 h at 25C. The mixture was quenched with 2N HCl, extracted with EtOAc, dried over anhydrous MgSO4, and concentrated in vacuum. The crude product was purified by recrystallization and/or chromatography as noted below.
methyl 4-(2,6-dichlorophenylsulfonamido)-3-methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With pyridine; at 25℃; for 12h;
General procedure: To a solution of amine (1 mmol) in 3 mL of pyridine at 0C was slowly added the appropriate benzenesulfonyl chloride (1.1 mmol, 1.1 equiv). The mixture was stirred for 12 h at 25C. The mixture was quenched with 2N HCl, extracted with EtOAc, dried over anhydrous MgSO4, and concentrated in vacuum. The crude product was purified by recrystallization and/or chromatography as noted below.
General procedure: Methyl 4-amino-3-methylbenzoate (6) (10.00g, 60.58mmol) was acylated with alkyl acyl chloride (90.87mmol) and triethylamine (16.79mL, 121.16mmol) in DCM at 0C. The resulting amide was reacted with fuming nitric acid in sulfuric acid (60%) at-20C. The resulting nitro-compound was reduced with hydrogen (5bar) and Raney Ni (0.79g, 13.34mmol) in methanol at 100C. The resulting amino compound was dissolved in glacial acetic acid and heated under reflux for 1h. After evaporation of the acetic acid, water was added and the pH was adjusted to 9 by addition of concentrated ammonia. This solution was extracted with ethyl acetate (3×100mL). The combined organic layers were washed with aqueous NaHCO3 solution and dried over MgSO4. After filtration, the solvent was removed under reduced pressure.
General procedure: Methyl 4-amino-3-methylbenzoate (6) (10.00g, 60.58mmol) was acylated with alkyl acyl chloride (90.87mmol) and triethylamine (16.79mL, 121.16mmol) in DCM at 0C. The resulting amide was reacted with fuming nitric acid in sulfuric acid (60%) at-20C. The resulting nitro-compound was reduced with hydrogen (5bar) and Raney Ni (0.79g, 13.34mmol) in methanol at 100C. The resulting amino compound was dissolved in glacial acetic acid and heated under reflux for 1h. After evaporation of the acetic acid, water was added and the pH was adjusted to 9 by addition of concentrated ammonia. This solution was extracted with ethyl acetate (3×100mL). The combined organic layers were washed with aqueous NaHCO3 solution and dried over MgSO4. After filtration, the solvent was removed under reduced pressure.
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h;
TEA (1.2 mmol) and the commercially available benzoyl chloride (1.1 mmol) wereadded at 000 to a solution of the corresponding aniline (1 mmol) in DCM (0.16M). The reaction mixture was left stirring at room temperature for 2h. Sat. solution of NaHCO3 (500m1) was added. The phases were separated and the aqueous layer was extracted with DCM (3 times). The combined organic layers were evaporated and purified by flash chromatography eluting with DCM/EtOAc to obtain the compounds of examples16-18,20,21 reported in Table 4.
Methyl 4-amino-3-methylbenzoate (30 g, 0.18 mOl) in concentrated hydrochloric acid (120 mL) and glacial acetic acid (40 mL)An aqueous solution (40 mL) of sodium nitrite (21 g, 0.27 mol) was added at a rate such that the solution temperature did not exceed 0 C.After the addition, the mixture was stirred at -10 C. for a further 45 minutes to form the diazonium salt.The three-necked flask was filled with glacial acetic acid (100 ml) and bubbled with sulfur dioxide gas for 30 minutes.Thereafter, copper dichloride (25 g, 0.14 mol) was added to the above colorless solution and sulfur dioxide gas was bubbled in for 30 minutes until the solution turned light yellow.The previously prepared diazonium salt was added at a rate such that the solution temperature did not exceed 30 C. and then stirred at room temperature for 1 hour. The reaction mixture was poured into an ice bath to give a precipitate which was extracted with dichloromethane.The organic layer was washed with water and brine, dried over sodium sulfate and then concentrated to give methyl 4- (chlorosulfonyl) -3-methylbenzoate (20 g, 44%).
methyl 4-amino-3-methylcyclohexanecarboxylate hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 5% rhodium-on-charcoal; hydrogen; acetic acid; In ethanol; at 80℃; under 9000.9 Torr; for 22h;Autoclave;
An autoclave was charged with a mixture of <strong>[18595-14-7]methyl 4-amino-3-methylbenzoate</strong> (10.0 g, 60.5 mmol, Cas No18595-14-7), rhodium 5% on charcoal (3.74 g, 50% wet), acitic acid (5.2 ml)and ethanol (100 ml) and pressurized with hydrogen (12 bar). The mixture was stirred at 80C for 22 h. For work-up, the catalyst was filtrate d off, washed with ethanol and the filtratewas concentrated under reduced pressure. The residue was dissolved in dichloromethane(250 ml) and hydrochloric acid (30 ml, 120 mmol, 4 M in dioxane) was added. The mixturewas concentrated und reduced pressure and the residue was codestilled with toluene (2x) togive the crude product as a mixture of isomers which was used without further purification.
methyl 4-[(chloroacetyl)amino]-3-methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
In tetrahydrofuran; at 20℃; for 20h;
Step 1. Methyl 4-[(chloroacetyl)amino]-3-methylbenzoate A solution of methyl 4-amino-3-methylbenzene carboxylate (1.01 g, 6.11 mmol) and chloroacetyl chloride (0.980 mL, 6.11 mmol) in THF (10 mL) was stirred at room temperature for 20 h. The solvent was concentrated and dried under high vacuum to give methyl 4-[(chloroacetyl)amino]-3-methylbenzoate (1.48 g, 100%) as a white solid. 1H NMR (CDCl3, 400 MHz) delta 8.42 (br s, 1H), 8.19 (d, 1H), 7.94-7.91 (m, 2H), 4.26 (s, 2H), 3.91 (s, 3H), 2.37 (s, 3H); LC-MS (ESI) m/z 264.0 [M+Na]+.
methyl 4-[(4-fluorobenzoyl)amino]-3-methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h;
Step 1. Synthesis of methyl 4-[(4-fluorobenzoyl)amino]-3-methylbenzoate Following standard procedure, 4-fluorobenzoic acid (0.510 g, 3.63 mmol), <strong>[18595-14-7]methyl 4-amino-3-methylbenzoate</strong> (0.500 g, 3.03 mmol), EDCI · HCl (1.16 g, 6.06 mmol), DMAP (0.930 g, 7.57 mmol) and CH2Cl2 (7.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give methyl 4-[(4-fluorobenzoyl)amino]-3-methylbenzoate (0.380 g, 44%). 1H NMR (CDCl3, 400 MHz) delta 8.23 (d, 1H), 7.96-7.88 (m, 4H), 7.75 (br s, 1H), 7.20 (td, 2H), 3.91 (s, 3H), 2.39 (s, 3H).
methyl 3-methyl-4-[4-oxo-2-(pyridin-2-yl)-1,3-thiazolidin-3-yl]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
13%
Example 472 Methyl 3-methyl-4-[4-oxo-2-(pyridin-2-yl)-1,3-thiazolidin-3-yl]benzoate To a solution of <strong>[18595-14-7]methyl 4-amino-3-methylbenzenecarboxylate</strong> (0.300 g, 1.82 mmol), Na2SO4 (0.260 g, 1.82 mmol) and pyridine-2-carbaldehyde (0.260 mL, 2.73 mmol) in toluene (10.0 mL) was stirred at 110 C. for 6 h, followed by addition of thioglycolic acid (0.250 mL, 3.63 mmol) in one portion. The reaction mixture was refluxed overnight, then partitioned between ethyl acetate and H2O. The organic layer was dried over MgSO4 (s) and concentrated to give a crude product which was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give methyl 3-methyl-4-[4-oxo-2-(pyridin-2-yl)-1,3-thiazolidin-3-yl]benzoate (75.0 mg, 13%). 1H NMR (CDCl3, 400 MHz) delta 8.56 (br d, 1H), 7.88 (br s, 1H), 7.70 (br d, 1H), 7.61 (t, 1H), 7.22-7.18 (m, 2H), 6.95 (br s, 1H), 5.85 (br s, 1H), 4.19 (d, 1H), 3.85 (s, 3H), 3.79 (d, 1H), 2.30 (br s, 3H); LC-MS (ESI) m/z 329.2 [M+H]+.
methyl 3-methyl-4-[4-oxo-2-(pyridin-3-yl)-1,3-thiazolidin-3-yl]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
19%
Example 473 Methyl 3-methyl-4-[4-oxo-2-(pyridin-3-yl)-1,3-thiazolidin-3-yl]benzoate To a solution of <strong>[18595-14-7]methyl 4-amino-3-methylbenzenecarboxylate</strong> (0.300 g, 1.82 mmol), Na2SO4 (0.260 g, 1.82 mmol) and nicotinaldehyde (0.290 mL, 2.73 mmol) in toluene (10.0 mL) was stirred at 110 C. for 24 h, followed by addition of thioglycolic acid (0.250 mL, 3.63 mmol) in one portion. The reaction mixture was refluxed overnight, then partitioned between ethyl acetate and H2O. The organic layer was dried over MgSO4(s) and concentrated to give a crude product which was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give methyl 3-methyl-4-[4-oxo-2-(pyridin-3-yl)-1,3-thiazolidin-3-yl]benzoate (0.115 g, 19%). 1H NMR (CDCl3, 400 MHz) delta 8.50 (br d, 1H), 8.45 (s, 1H), 7.84 (br s, 1H), 7.74-7.71 (m, 2H), 7.25-7.21 (m, 1H), 7.18-6.60 (br, 1H), 5.99 (br s, 1H), 4.01 (d, 1H), 3.92 (d, 1H), 3.84 (s, 3H), 2.29-1.85 (br, 3H); LC-MS (ESI) m/z 329.1 [M+H]+.
methyl 3-methyl-4-[4-oxo-2-(1,3-thiazol-2-yl)-1,3-thiazolidin-3-yl]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
21%
Example 474 Methyl 3-methyl-4-[4-oxo-2-(1,3-thiazol-2-yl)-1,3-thiazolidin-3-yl]benzoate To a solution of <strong>[18595-14-7]methyl 4-amino-3-methylbenzenecarboxylate</strong> (0.300 g, 1.82 mmol), Na2SO4 (0.260 g, 1.82 mmol) and thiazole-2-carbaldehyde (0.240 mL, 2.73 mmol) in toluene (5.0 mL) was stirred at 110 C. for 16 h, followed by addition of thioglycolic acid (0.250 mL, 3.63 mmol) in one portion. The reaction mixture was refluxed overnight, then partitioned between ethyl acetate and H2O. The organic layer was dried over MgSO4 (s) and concentrated to give a crude product which was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give methyl 3-methyl-4-[4-oxo-2-(1,3-thiazol-2-yl)-1,3-thiazolidin-3-yl]benzoate (0.130 g, 21%). 1H NMR (CDCl3, 400 MHz) delta 7.92 (br s, 1H), 7.82-7.76 (m, 1H), 7.64 (d, 1H), 7.36 (d, 1H), 7.04 (br s, 1H), 6.23 (br s, 1H), 4.11 (d, 1H), 3.88-3.84 (m, 4H), 2.23 (br s, 3H); LC-MS (ESI) m/z 357.1 [M+Na]+.
methyl 4-[2-(1-benzofuran-2-yl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17%
Example 475 Methyl 4-[2-(1-benzofuran-2-yl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate To a solution of <strong>[18595-14-7]methyl 4-amino-3-methylbenzenecarboxylate</strong> (0.300 g, 1.82 mmol), Na2SO4 (0.310 g, 2.18 mmol) and benzofuran-2-carbaldehyde (0.330 mL, 2.73 mmol) in toluene (10.0 mL) was stirred at 110 C. for 7 h, followed by addition of thioglycolic acid (0.250 mL, 3.63 mmol) in one portion. The reaction mixture was refluxed overnight, then partitioned between ethyl acetate and H2O. The organic layer was dried over MgSO4 (s) and concentrated to give a crude product which was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give methyl 4-[2-(1-benzofuran-2-yl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.115 g, 17%). 1H NMR (CDCl3, 400 MHz) delta 7.91 (br s. 1H), 7.74 (br d, 1H), 7.52-7.46 (m, 2H), 7.33 (t, 1H), 7.24-7.20 (m, 1H), 6.95 (br s, 1H), 6.54 (s, 1H), 5.92 (br s, 1H), 4.23 (d, 1H), 3.93-3.81 (m, 4H), 2.32 (br s, 3H); LC-MS (ESI) m/z 368.2 [M+H]+.
methyl 3-methyl-4-[4-oxo-2-(thiophen-3-yl)-1,3-thiazolidin-3-yl]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22%
Example 476 Methyl 3-methyl-4-[4-oxo-2-(thiophen-3-yl)-1,3-thiazolidin-3-yl]benzoate To a solution of <strong>[18595-14-7]methyl 4-amino-3-methylbenzenecarboxylate</strong> (0.300 g, 1.82 mmol), Na2SO4 (0.260 g, 1.82 mmol) and thiophene-3-carbaldehyde (0.240 mL, 2.73 mmol) in toluene (5.0 mL) was stirred at 110 C. for 16 h, followed by addition of thioglycolic acid (0.250 mL, 3.63 mmol) in one portion. The reaction mixture was refluxed overnight, then partitioned between ethyl acetate and H2O. The organic layer was dried over MgSO4 (s) and concentrated to give a crude product which was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give methyl 3-methyl-4-[4-oxo-2-(thiophen-3-yl)-1,3-thiazolidin-3-yl]benzoate (0.134 g, 22%). 1H NMR (CDCl3, 300 MHz) delta 7.88 (s, 1H), 7.77 (br d, 1H), 7.26-7.25 (m, 1H), 7.12-7.08 (m, 2H), 6.93 (br s, 1H), 6.03 (br s, 1H), 3.99 (d, 1H), 3.96-3.85 (m, 4H), 2.17 (br s, 3H); LC-MS (ESI) m/z 334.1 [M+H]+.
methyl 4-[4-(4-fluorophenyl)-4-oxobutanoyl]amino}-3-methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h;
Step 1. Synthesis of methyl 4-[4-(4-fluorophenyl)-4-oxobutanoyl]amino}-3-methylbenzoate To a solution of methyl 4-amino-3-methylbenzene carboxylate (0.814 g, 4.93 mmol), 3-(4-fluorobenzoyl)propionic acid (0.966 g, 4.93 mmol), and DMAP (1.20 g, 9.86 mmol) in CH2Cl2 (15 mL) was added EDCI?HCl (1.89 g, 9.86 mmol) at room temperature. The reaction mixture was stirred for 16 h and diluted with CH2Cl2. The solution was washed with 2 N HCl(aq). The organic layer was dried over MgSO4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-45% ethyl acetate in n-hexane) to give methyl 4-[4-(4-fluorophenyl)-4-oxobutanoyl]amino}-3-methylbenzoate (1.08 g, 64%) as a white solid. 1H NMR (CDCl3, 300 MHz) delta 8.13 (br d, 1H), 8.04 (dd, 2H), 7.88-7.87 (m, 2H), 7.79 (br s, 1H), 7.15 (t, 2H), 3.88 (s, 3H), 3.45 (dd, 2H), 2.87 (dd, 2H), 2.36 (s, 3H).
methyl 4-{2-[4-fluoro-2,3,5,6-d4-phenyl]-4-oxo-1,3-thiazolidin-3-yl}-3-methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29%
Example 428 Methyl 4-{2-[4-fluoro-2,3,5,6-d4-phenyl]-4-oxo-1,3-thiazolidin-3-yl}-3-methylbenzoate A solution of <strong>[18595-14-7]methyl 4-amino-3-methylbenzoate</strong> (0.846 g, 5.12 mmol), Na2SO4 anhydrous (1.46 g, 10.2 mmol), and 4-fluorobenzaldehyde-2,3,5,6-d4 (0.722 g, 5.63 mmol) in toluene (30 mL) was reflux for 24 h. Then 2-mercaptoacetic acid (0.840 mL, 12.0 mmol) was added to the reaction mixture, and it was stirred at 100 C. for 16 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solution was washed with 10% NaOH(aq) and 3 N HCl(aq). The organic layer was dried over MgSO4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give methyl 4-{2-[4-fluoro-2,3,5,6-d4-phenyl]-4-oxo-1,3-thiazolidin-3-yl}-3-methylbenzoate (0.503 g, 29%) as a white foam. 1H NMR (CDCl3, 400 MHz) delta 7.86 (br s, 1H), 7.74 (br d, 1H), 7.10-6.80 (br, 1H), 6.10-5.80 (br, 1H), 4.01 (d, 1H), 3.93 (d, 1H), 3.87 (s, 3H), 2.17 (br s, 3H); LC-MS (ESI) m/z 350.1 [M+H]+.
methyl 4-[2-(4-fluorophenyl)-4-oxo-2-d-1,3-thiazolidin-3-yl]-3-methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
19%
Step 1. Synthesis of methyl 4-[2-(4-fluorophenyl)-4-oxo-2-dl-1,3-thiazolidin-3-yl]-3-methylbenzoate A solution of <strong>[18595-14-7]methyl 4-amino-3-methylbenzoate</strong> (390 mg, 2.36 mmol), Na2SO4 anhydrous (503 mg, 3.54 mmol), and 4-fluorobenaldehyde-d1 (325 mg, 2.60 mmol) in toluene (10 mL) was reflux for 18 h. Then 2-mercaptoacetic acid (0.296 mL, 4.24 mmol) was added to the reaction mixture, and it was stirred at 90-100 C. for 18 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solution was washed with 10% NaOH(aq). The organic layer was dried over MgSO4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give methyl 4-[2-(4-fluorophenyl)-4-oxo-2-d-1,3-thiazolidin-3-yl]-3-methylbenzoate (152 mg, 19%) as a lightly yellow foam. 1H NMR (CDCl3, 400 MHz) delta 7.86 (br s, 1H), 7.73 (br s, 1H), 7.30 (dd, 2H), 6.95 (br t, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 3.87 (s, 3H), 2.19 (br s, 3H); LC-MS (ESI) m/z 347.1 [M+H]+.
2-isopropyl-5,5-dimethylcyclohexane carboxylic acid[ No CAS ]
methyl 4-(2-isopropyl-5,5-dimethylcyclohexanecarboxamido)-3-methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29%
Under a nitrogen atmosphere, to a 100-mL four-necked flask were added 5-methylmenthyl carboxylic acid (rac-11a) (600 mg, 3.03 mmol) obtained in Synthesis Example 7, 8, 9, or 19, thionyl chloride (0.33 mL, 1.50 eq.), and a catalytic amount of DMF, followed by stirring at room temperature for 3 hours. The solution in the system was distilled off under reduced pressure, and toluene (2 mL) was added thereto. The inside of the system was cooled to 10 C. or lower in an ice bath, and <strong>[18595-14-7]3-methyl-4-aminobenzoic acid methyl ester</strong> (1.50 g, 3.0 eq.) was added slowly thereto. After two and a half hours, completion of the reaction was confirmed by GC-MS, and a post-treatment was performed. The reaction solution was transferred to a separating funnel, and tap water and chloroform were added thereto to effect washing. The oil layer was washed twice with dilute hydrochloric acid, and further washed once with a saturated saline solution, and then dried with anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure, and then isolation and purification were performed by column chromatography (heptane/ethyl acetate=4/1), whereby an amorphous solid was obtained (306 mg, yield: 29%). HRMS: mass: 345.2304 actual measurement value: 345.2298 1H-NMR (500 MHz, CDCl3): delta0.85-0.98 (m, 12H), 1.20-1.33 (m, 3H), 1.45-1.65 (m, 4H), 1.82 (quid, 1H, J=6.6, 2.1 Hz), 2.29-2.40 (m, 4H), 7.05 (br, 1H), 7.86-7.90 (m, 2H), 8.14 (d, 1H, J=8.2 Hz)
With triethylamine; In dichloromethane; at 20℃; for 1h;Cooling with ice;
General procedure: To a solution of arylamine (6 mmol) and triethylamine (911mg, 9 mmol) in dichloromethane (15 ml) was dropped a solution of bromoacetyl bromide (1.57g, 7.8 mmol) in dichloromethane (5 ml) with icecooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water and extracted with dichloromethane. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was recrystallized from hexane to provide 85-91% yield of 2-bromo-N-arylacetamide as white powdery crystals.
methyl 3-methyl-4-(1-methyl-1H-pyrazole-5-carboxamido)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
To a solution of 1-methyl-1H-pyrazole-5-carboxylic acid (compound 4A, 4.58 g, 36.3 mmol), DIEA (13.7 g, 106 mmol) in CH2Cl2 (30 mL) was added EDCI (11.6 g, 60.5 mmol) and DMAP (4.44 g, 36.3 mmol) at -5 C., the mixture was stirred at -5 C. for 30 min. Then <strong>[18595-14-7]methyl 4-amino-3-methylbenzoate</strong> (compound 11, 5.00 g, 30.3 mmol) was added, stirred at -5 C. for 30 min. The mixture was warmed to 25 C., stirred for 11 hrs. TLC (petroleum ether:ethyl acetate=1:1, Rf=0.52) showed starting material consumed completely. The mixture was concentrated in vacuum to give light yellow oil. The oil was purified by silica gel column chromatography (petroleum ether:ethyl acetate=90:10 to 50:50) to give methyl 3-methyl-4-(1-methyl-1H-pyrazole-5-carboxamido)benzoate (compound 12, 5.70 g, 69% yield) as light yellow solid.
methyl 4-(8-chloro-4-oxochromene-2-carboxamido)-3-methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26.6%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 18h;
To a solution of 8-chloro-4-oxo-chromene-2-carboxylic acid (Int-1, 250 mg, 1.11 mmol) in DCM (20 mL) was added <strong>[18595-14-7]methyl 4-amino-3-methylbenzoate</strong> (184 mg, 1.11 mmol), DIPEA (230 mg, 1.78 mmol) and HATU (635 mg, 1.67 mmol) at room temperature and the resulting mixture was then stirred at room temperature for 18 hours. After the reaction was completed, the mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL) three times. The combined organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by silica gel flash chromatography (elution with PE/EtOAc=lO: 1-1:5) to give methyl 4-(8-chloro-4-oxo-chromene-2-carboxamido)-3- methylbenzoate (110 mg, 26.6 %) as a yellow foam. MS obsd. (ESE) [(M+H)+]: 372.1.
5.1 1.Preparation of methyl 2-amino-4-methylbenzo[d]thiazole-6-carboxylate
1. Preparation of methyl 2-amino-4-methylbenzo[d]thiazole-6-carboxylate Methyl 4-amino-3-methylbenzoate (33.0 g, 0.2 mol) and KSCN (68.0 g, 0.7 mol) were added to glacial acetic acid (200 mL) at 0 °C, and bromine (31.9 g, 0.2 mol) was slowly added dropwise at 0 °C. After the dropwise addition was completed, the mixture solution was heated to 25 °C and reacted for 10 hrs. The reaction solution was then poured into an ice water, and pH of the solution was adjusted to 8 with ammonium hydroxide. A solid was precipitated, filtered out under reduced pressure, and dried. The resulted solid would be directly used in the next step.
methyl 4-(2-Chloro-2-fluoroacetamido)-3-methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In dichloromethane; ethyl acetate; at 0 - 20℃; for 2.0h;
General procedure: To a stirred solution of 5-amino-1-naphthol (126 mg, 0.792 mmol) and <strong>[70395-35-6]sodium chlorofluoroacetate</strong> (159 mg,1.18 mmol) in dichloromethane (8 mL) was added T3P (50 wt%solution in AcOEt, 701 μL, 1.18 mmol) and N,N-diisopropylethylamine(DIPEA) (273 μL, 1.57 mmol) at 0C. Afterstirred at ambient temperature for 1 h, the reaction mixturewas diluted with water and extracted thrice with CHCl3. Thecombined organic layers were washed with brine, dried overNa2SO4, filtered and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (hexane/AcOEt = 3 : 1) to afford the title compound (37.2 mg, 18% yield) as a pale purple solid.
With N-chloro-succinimide; In dichloromethane; at 20.0℃;
Methyl 4-amino-3-methyl benzoate (5.0 g, 30.3 mmol) and dry dichloromethane (50 mL) were added in a threeneckedflask and stirred. N-chlorosuccinimide (4.85 g, 36.3 mmol) was added and the mixture was allowed to reactovernight at room temperature. The reaction mixture was poured into water (100 mL), extracted three times with dichloromethane.The organic phase was combined, dried with anhydrous sodium sulfate, filtered, concentrated to dry, andpurified by column to obtain the target compound (5.1 g, 82%) as a white solid.1H NMR (400 MHz, CDCl3): δ 7.85 (s, 1H), 7.67 (s, 1H), 4.33 (brs, 2H), 3.86 (s, 3H), 2.22 (s, 3H).
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