* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2 h;
Method L:Step a: [00293] A mixture of 2-methyl-4-nitrobenzoic acid (l eq.) iodomethane (1.1 eq.), K2CO3 (1.5 eq.), and 10 mL of DMF is stirred for 2hrs at room temperature, then poured into water and extracted with AcOEt. The extract is washed with water and brine, dried over anhydrous MgSψ4, and evaporated to afford the expected compound in quantative yield.
89%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3 h;
A solution of 2-methyl-4-nitro-benzoic acid (10 g, 55 mmol), MeI (3.8 ml, 61 mmol) and K2CO3 (11.4 g, 83 mmol) in DMF was stirred for 3 h at RT after which the reaction was poured onto water and extracted in EtOAc. The organic fractions were washed with water and brine, dried over Na2SO4 and concentrated to give the desired product as an orange solid (9.57g, 89percent). 1H NMR (400 MHz, DMSO-^6) δ ppm 2.60 (s, 3 H), 3.88 (s, 3 H), 8.00 (d, J=8.70 Hz, 1 H), 8.10 - 8.16 (m, 1 H), 8.21 (d, J=2.29 Hz, I H).
Intermediate 5; Methyl 2-methyl-4-nitrobenzoate; SOCI2 was added to a solution of 2-methyl-4-nitrobenzoic acid (3 g, 16.5 mmol) in methanol dropwise. The reaction mixture was stirred at 70°C for 18 hours. The mixture was evaporated and the residue was diluted with diethyl ether, washed with water and NaOH 1 N. The organic phase was dried over Na2SO4, filtered and evaporated to give the title compound as dark yellow solid (3.25 g, quantitative yield). NMR1H NMR (300 MHz), CDCI3 δ: 7.95 (m, 3H), 3.86 (s, 3H), 2.59 (s, 3H).
98%
at 70℃; for 7 h;
Under ice bath was added SOCl2 dropwise anhydrous methanol (100ml) in. And then a solution of 2-methyl-4-nitrobenzoic acid (10.0 g, 55.2 mmol) in anhydrous methanol (70mL) solution, 1 hour addition was complete. This mixed system placed in an oil bath at 70 ° C 7 hours, TLC the reaction was complete. Cooling, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) was added saturated sodium bicarbonate (100 mL), separated, the aqueous phase was extracted once with ethyl acetate (50mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure, and dried under high vacuum to give a white solid 10.5g, 98percent yield
96%
for 15 h; Reflux
Example 1) l-MethyI-lH-imidazole-4-suIfonic acid (4-chloro-benzyI)-(2-ethyI-l- oxo-2,3-dihydro-lH-isoindol-5-yl)-amide (Method A)i) 2-Methyl-4-nitro-benzoic acid methyl ester2-Methyl-4-nitrobenzoic acid (2.00 g, 11.00 mmol) was stirred in concentrated sulfuric acid (0.6 ml) and methanol (25 ml) at reflux for 15 hrs. Reaction was cooled and the solvent evaporated. The resulting residue was partitioned between water and dichloromethane and the organic phase separated. The aqueous phase was extracted with dichloromethane (x3) and the combined organics washed with brine, then dried (MgSO4) and evaporated in vacuo to yield the title compound as a pale yellow solid (1.89 g, 96percent). HPLC retention time 4.39min.
95.3%
at 0 - 70℃; for 24.5 h;
Step 1: Synthesis of 2-Methyl-4-nitro-benzoic acid methyl ester To a solution of 2-methyl-4-nitro-benzoic acid (3 g, 16.56 mmole) in 30 ml methanol was added at 0° C. sulfuric acid (95-98percent, 10 ml) slowly for ½ hr. The reaction mixture was stirred at 70° C. for 24 hrs. Mixture was cooled down, a solid precipitated out, then the mixture was concentrated, diluted with 50 ml water, stirred for 10 minutes, filtered off, the solid was washed with water, dried to afford 3.08 g of brown solid, 95.3percent yield, pure by H NMR.
94.65%
for 15 h; Reflux
In a 250 mL, 3-neck round-bottomed flask, 2-methyl-4-nitrobenzoic acid (20 g, 93.8 mmol) was charged with methanol (100 mL) and sulfuric acid (4 mL). The reaction mixture was refluxed for 15 h. After completion, the reaction mixture was concentrated to obtain the crude product which was added water (200 mL) and basified to pH 7-8 with aqueous NaHC03 solution. Aqueous solution was extracted with dichloromethane (250 mL X 3), the organic layer was washed with saturated brine solution followed by drying over anhydrous sodium sulphate. The solvent was removed to obtain methyl 2-methyl-4- nitrobenzoate 1), 20 g; Yield: 94.65percent.
93%
at 0 - 80℃; for 2 h;
SOCl2 (2.6 g, 22.0 mmol) was slowly added to the solution of 2-methyl-4- nitrobenzoic acid (61.1) (2.0 g, 11.0 mmol) in MeOH (20 mL) at 0 °C. The resulting mixture was heated at 80 °C for 2 h. After cooling to room temperature, the reaction mixture was concentrated to afford methyl 2-methyl-4-nitrobenzoate (61.2) as a yellow oil (2.0 g, 93percent).
91.3%
at 12 - 20℃; for 12 h;
Thionyl chloride (4.3 g, 36.45 mmol) was added dropwise to a stirred solution of 18 (3 g, 16.57 mmol) in MeOH (25 mL) while maintaining the internal temperature below 12 °C. When the addition was complete the mixture was left to stand at room temperature for 12 h to result a white precipitation. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford white solid. The solid was washed with hexane and ethyl ether to afford 19 (2.95 g, 91.3percent); mp 153.7-154.4 °C (lit.39 mp 153-154 °C); Rf 0.43 (hexane/EtOAc 3:1); 1H NMR (CDCl3) δ 2.69 (s, 3H, CH3), 3.95 (s, 3H, COOCH3), 8.02-8.11 (m, 3H, C6H3).
90.9%
at 20 - 60℃;
EXAMPLE 75 2-Methyl-4-nitro-benzoic acid methyl ester (1) In accordance with general method S, 5.00 g (27.60 mmol) of 2-methyl-4-nitro-benzoic acid are dissolved in 20 ml of methanol, with heating, and 6 ml of concentrated sulfuric acid are added. The mixture is refluxed for 5 h. Yield: 4.90 g (90.9percent); melting point: 73.6° C. C9H9NO3(Mr=195.18); GC (method 1) 9.55 min 1H-NMR (CDCl3) in ppm: 8.19-8.09 (m, 2H, aryl H), 7.99 (d, 1H, J=8.52 Hz, aryl H), 3.87 (s, 3H, -OCH3), 2.59 (s, 3H, -CH3) 13C-NMR (CDCl3) in ppm: 166.35 (-C=O), 159.29 (C4), 141.79 (C2), 135.14 (C1), 131.43 (C6), 126.06 (C3), 120.48 (C5), 52.37 (-OCH3), 21.50 (-CH3) IR (ATR) (cm-1): 1722, 1523, 1432, 1348, 1260, 1081, 896, 821, 786, 730 MS m/z (percent): 195 (70), 164 (100), 134 (21), 118 (29), 63 (15). General Method SFor esterification of the acid group of the starting compound 2-methyl-4-nitro-benzoic acid, the stated amount is dissolved in methanol in a 100 ml one-necked flask at room temperature, concentrated H2SO4 is added and the mixture is refluxed at approx. 60° C. for 6 h. The excess alcohol is removed in vacuo, the residue is taken up in EtOAc and the mixture is deacidified repeatedly with 20percent strength sodium hydroxide solution. After drying (Na2SO4), the combined organic phases are concentrated in vacuo.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 3, p. 942 - 945
[2] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 3, p. 946 - 949
[3] Patent: WO2009/47240, 2009, A1, . Location in patent: Page/Page column 28
[4] Journal of Medicinal Chemistry, 1999, vol. 42, # 18, p. 3510 - 3519
[5] Patent: CN103804358, 2016, B, . Location in patent: Paragraph 0117
[6] Patent: WO2010/139953, 2010, A1, . Location in patent: Page/Page column 31-32
[7] Patent: US9138427, 2015, B2, . Location in patent: Page/Page column 286
[8] Patent: WO2016/81464, 2016, A1, . Location in patent: Paragraph 00117
[9] Patent: WO2016/90079, 2016, A1, . Location in patent: Paragraph 00866
[10] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 11, p. 3585 - 3594
[11] Patent: US2012/115862, 2012, A1, . Location in patent: Page/Page column 34-35
[12] Patent: WO2005/80388, 2005, A1, . Location in patent: Page/Page column 63
[13] Patent: WO2006/17443, 2006, A2, . Location in patent: Page/Page column 155-156
[14] Patent: US2010/15141, 2010, A1, . Location in patent: Page/Page column 26
[15] Patent: WO2011/19538, 2011, A1, . Location in patent: Page/Page column 127
[16] Patent: CN105218397, 2016, A, . Location in patent: Paragraph 0011
Preparation of 2-methyl-4-nitrobenzoic acid4-Nitro-o-xylene (0.15 g, 1 mmol), NHPI (0.05 g,0.3 mmol), nitric acid (40 percent; 1.26 g, 8 mmol),CoCl2 ·6H2O (7.1 mg, 0.03 mmol), Mn(OAc)2 ·4H2O(7.1 mg, 0.03 mmol) and a phase transfer catalyst(0.04 mmol) were added to a 50 mL three-neckedround bottomed flask equipped with a magnetic stirrerand a reflux condenser. The mixture was heated underreflux for 12 h at normal pressure. After the reactioncompletion the mixture was cooled to room temperatureand washed with 10 mL of water. The aqueousphase was extracted with ethyl acetate (3 × 5 mL)and the obtained organic phase was dried with anhydroussodium sulfate. Ethyl acetate was removedfrom the organic layer by rotary evaporation and thecrude products were determined by the HPLC analysisbased on the internal standard (2,4-dinitrotoluene).The crude products were re-crystallized (EtOH/H2Or = 3 : 1) to give pure 2-methyl-4-nitrobenzoic acid(0.13 g, 72 percent) in form of white needle crystals; m.p.:151–152C. IR, ν/cm−1, (KBr): 1702 cm−1.1H NMR(CDCl3, 500 MHz), δ: 2.79 (s, 3H, CH3 ), 8.13–8.17(m, 2H, Ar), 8.21 (d, 1H, J = 6.8 Hz, Ar). Anotherproduct is the 4-nitrophthalic acid which is separatedby column chromatography from ethyl acetate/hexane(r = 1 : 5) in form of light colored needle crystals;m.p.:163C. IR, ν/cm−1, (KBr): 1730 cm−1,1670 cm−1. 1H NMR (CDCl3, 500 MHz), δ: 7.86 (d,J = 8.6 Hz, 1H, Ar), 8.36 (dd, J1 = 8.6Hz, J2 = 2.0Hz,1H, Ar), 8.42 (d, J = 2.0 Hz, 1H, Ar) (Huntress et al.,1936).
62%
With oxygen; sodium hydroxide In methanol; water at 65℃; for 24 h; Autoclave
3,4-dimethyl-1-nitrobenzene (907 mg, 6 mmol, 1.0 eq)Sodium hydroxide (1.8 g, 45 mmol, 7.5 eq)Was added to a 100 ml autoclave,Add 10 ml of 50percent (v / v) methanol (5 ml of methanol, 5 ml of water)After charging oxygen three times,Passing oxygen gas (pressure 1.8MPa),In the oil bath temperature control 65 for 24 hoursAfter the reaction was diluted with methanol,Neutral and PH = 2-3,The solvent was removed under reduced pressure,After the addition of ethyl acetate,filter.Separated by chromatography,3,4-dimethyl-1-nitrobenzene recovered 72mg (0.47mmol),1,2-dimethyl-4-nitrobenzene conversion was 92percentTo give 673 mg (3.72 mmol) of 2-methyl-4-nitrobenzoic acid,The yield was 62percent.
Reference：
[1] Chemical Papers, 2015, vol. 69, # 4, p. 580 - 585
[2] Patent: CN106995374, 2017, A, . Location in patent: Paragraph 0043; 0044; 0045; 0046; 0047; 0048; 0049-0057
[3] Journal of Organic Chemistry, 2018, vol. 83, # 15, p. 8092 - 8103
[4] Patent: CN105777565, 2016, A, . Location in patent: Paragraph 0006
6
[ 99584-16-4 ]
[ 1975-51-5 ]
Yield
Reaction Conditions
Operation in experiment
89.5%
With hydrogenchloride In water for 20 h; Heating / reflux
A stirred mixture of 2-methyl-4-nitrobenzamide and 6N HC1 (1.3 L) was refluxed for 20 hours, then cooled. The resulting solid was filtered, washed with cold water, and dried on a lyophilizer to obtain the title compound as a solid. Yield: 160 g (Overall yield of last two steps was 89.50percent), Melting Point: 149- 150#x0;C.
Reference：
[1] Patent: WO2004/69245, 2004, A1, . Location in patent: Page/Page column 110
[2] Journal of Medicinal Chemistry, 1999, vol. 42, # 18, p. 3510 - 3519
[3] Bulletin de la Societe Scientifique de Bretagne, 1956, vol. 31, p. Sonderheft S.9,41
7
[ 89001-53-6 ]
[ 1975-51-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 1998, vol. 6, # 3, p. 271 - 282
[2] Chemische Berichte, 1919, vol. 52, p. 1083
[3] Journal fuer Praktische Chemie (Leipzig), 1915, vol. <2> 92, p. 145
[4] Journal of Medicinal Chemistry, 1999, vol. 42, # 18, p. 3510 - 3519
[5] Patent: WO2005/80388, 2005, A1, . Location in patent: Page/Page column 62-63
[6] Patent: WO2005/51366, 2005, A2, . Location in patent: Page/Page column 78
[7] Patent: WO2005/51366, 2005, A2, . Location in patent: Page/Page column 78
8
[ 6277-17-4 ]
[ 1975-51-5 ]
Reference：
[1] Patent: US5968942, 1999, A,
[2] Patent: US6046190, 2000, A,
[3] Patent: US6060476, 2000, A,
9
[ 2486-75-1 ]
[ 1975-51-5 ]
Reference：
[1] Angewandte Chemie - International Edition, 2006, vol. 45, # 47, p. 8016 - 8018
10
[ 99-52-5 ]
[ 1975-51-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 1999, vol. 42, # 18, p. 3510 - 3519
[2] Patent: CN105218375, 2016, A,
11
[ 108-88-3 ]
[ 1975-51-5 ]
Reference：
[1] Patent: CN105218375, 2016, A,
12
[ 22162-16-9 ]
[ 1975-51-5 ]
Reference：
[1] Die Pharmazie, 1969, vol. 24, # 1, p. 29 - 32
Reference：
[1] Chemische Berichte, 1884, vol. 17, p. 161
17
[ 7647-01-0 ]
[ 89001-53-6 ]
[ 64-19-7 ]
[ 1975-51-5 ]
Reference：
[1] Chemische Berichte, 1919, vol. 52, p. 1083
18
[ 99-51-4 ]
[ 7697-37-2 ]
[ 1975-51-5 ]
[ 1975-52-6 ]
Reference：
[1] Chemische Berichte, 1884, vol. 17, p. 161
19
[ 1975-51-5 ]
[ 578-39-2 ]
Reference：
[1] Chemische Berichte, 1884, vol. 17, p. 161
20
[ 1975-51-5 ]
[ 2486-75-1 ]
Yield
Reaction Conditions
Operation in experiment
98%
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.
With hydrogenchloride; In water; for 20h;Heating / reflux;
A stirred mixture of 2-methyl-4-nitrobenzamide and 6N HC1 (1.3 L) was refluxed for 20 hours, then cooled. The resulting solid was filtered, washed with cold water, and dried on a lyophilizer to obtain the title compound as a solid. Yield: 160 g (Overall yield of last two steps was 89.50%), Melting Point: 149- 150 C.
With thionyl chloride; for 4 - 6h;Heating / reflux;
Thionyl chloride (48 ml) was added slowly to <strong>[1975-51-5]2-methyl-4-nitro-benzoic acid</strong> (85g; 0.469 mol) and the reaction mixture was refluxed (4-6 h) to give a clear solution. It was brought to room temperature then chilled to 0C. Dry alcohol (150 ml) was added slowly with vigorous stirring and the reaction mixture was refluxed for 30 min. It was concentrated, treated with crushed ice, NaHC03 and extracted with EtOAc. The EtOAc layer was washed with water, brine, dried (Na2S04), concentrated, purified using flash chromatography (silica gel, 10% EtOAc-PE 60-80C) and crystallized using EtOAc-PE 60-80C to obtain the title compound as light yellow crystals. Yield, 83. 8 g (85.4%) ; mp, 68-71C ; IR: 2950,1720, 1525; MS (EI) : 209 (M, 192.181, 163 (100%), 89.
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1.5h;Inert atmosphere;
Example 111 Preparation of 2-methyl-4-nitrobenzamide (E111) To <strong>[1975-51-5]2-methyl-4-nitrobenzoic acid</strong> suspended in CH2Cl2 under Ar was added DMF then oxalyl chloride. The reaction was stirred at room temperature 1.5 hours then the solvent was evaporated. The residue was dissolved in THF and ammonia gas was bubbled through the reaction for 15 minutes. The solvent was evaporated and the residue partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The extracts were dried (MgSO4), filtered and evaporated. Column chromatography (SiO2, 0-100% EtOAc/Hex) gave pure 2-methyl-4-nitrobenzamide (E111).
With thionyl chloride;Reflux;
Thionyl chloride (48 ml) was added slowly to <strong>[1975-51-5]2-methyl-4-nitro-benzoic acid</strong> (85 g; 0.469 mol) and the reaction mixture was refluxed (4-6 h) to give a clear solution. It was brought to room temperature then chilled to 0 C. Dry alcohol (150 ml) was added slowly with vigorous stirring and the reaction mixture was refluxed for 30 min. It was concentrated, treated with crushed ice, NaHCO3 and extracted with EtOAc. The EtOAc layer was washed with water, brine, dried (Na2SO4), concentrated, purified using flash chromatography (silica gel, 10% EtOAc-PE 60-80 C.) and crystallized using EtOAc-PE 60-80 C. to obtain the title compound as light yellow crystals. Yield, 83.8 g (85.4%); mp, 68-71 C.; IR: 2950, 1720, 1525; MS (EI): 209(M+), 192. 181, 163 (100%), 89.
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 3h;
Example 2A 4-nitro-2-methylbenzamide A suspension of <strong>[1975-51-5]2-methyl-4-nitrobenzoic acid</strong> (50.0 g, 276.02 mmol), in dichloromethane (200 mL) at room temperature was treated with oxalyl chloride (30.1 mL, 345 mmol) and a few drops of DMF. After 1 hour another 5 drops of DMF were added. After a total of three hours the mix was concentrated under vacuum. A solution of the concentrate in THF (80 mL) was added to ice-cold aqueous concentrated NH4OH (100 mL) at 0 C. with rapid stirring. When the addition was complete, water (200 mL) was added and the mixture was stirred at 0 C. for 30 minutes. The resulting solid was collected by filtration and dried under vacuum at 45 C. for several hours to provide 46.38 g (93.3%) of the desired product as a slightly yellow powder. LCMS shows m/z at 181 (M+H)+.
With thionyl chloride; In benzene; for 3h;Heating / reflux;
2-Methyl-5-nitro-N-(lH-pyrrolo[2,3-b]pyridin-5-yl)-benzamide To a solution of <strong>[1975-51-5]2-methyl-4-nitrobenzoic acid</strong> (2 g, 11 mmol) in benzene (40 ml) was added thionyl chloride (2 ml) and refluxed for 3 h. The reaction mixture was concentrated, diluted with dry acetonitrile (20 ml). To this solution was added dry K2CO3 (2 g, 14 mmol) followed by a solution of lH-Pyrrolo[2,3-b]pyridin-5- ylamine (example c), 1.4 g, l lmmol) in acetonitrile (20 ml) and the reaction mixture and stirred for 16 h at RT. Solvent was removed under reduced pressure, diluted with water stirred for 15 min and filtered. The solid residue was washed with EtOAc to get 2.4 g of crude title product. LC-MS: (m/z 297)
With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20 - 40℃; for 2h;
[00147] To <strong>[1975-51-5]2-methyl-4-nitrobenzoic acid</strong> (10.5 g, 58.0 mmol) in CH2C12 (80 ml) was added 2.0 M oxalyl chloride in methylene chloride (39.9 ml, 80 mmol), followed by DMF (0.224 ml, 2.90 mmol). The mixture was stirred at 40 C for 1.5 h and then at rt for 0.5 h. Solvent was removed and the residue was put on high vacuum for 0.5 h. The acyl chloride prepared was then dissolved in methylene chloride (40mL) and cooled at 0 C, MeOH (40mL) was added and the mixture was stirred at 0 C for 0.5 h. Solvent was removed, the crude was diluted with EtOAc, washed with sat. sodium bicarbonate, brine. The organic layer was dried over sodium sulfate and concentrated to give Intermediate 3A (1 1.35 g, 58.2 mmol, 100% yield) as a white solid.1 NMR (400 MHz, chloroform-d) delta ppm 7.98 - 8.1 1 (m, 3 H) 3.93 (s, 3 H) 2.67 (s, 3 H).
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20 - 40℃; for 2h;
Intermediate 3A: 2-Methyl-4-nitro-benzoic acid methyl ester j00129j To <strong>[1975-51-5]2-methyl-4-nitrobenzoic acid</strong> (6.5 g, 35.9 mmol) in DCM (40 mL) was added 2.0 M oxalyl chloride in DCM (24.67 mL, 49.3 mmol), followed by DMF (0.139 mL, 1.794 mmol). The mixture was stirred at 40 C for 1.5 h and then at rt for 0.5 h. The solvent was removed and the residue was stored under high vacuum for 0.5 h. The intermediate acid chloride was then dissolved in DCM (40 mL) and cooled to 0 C,MeQH (40 mL) was then added and the mixture was stirred at 0 C for 0.5 h. Solvent was removed, the crude reaction mixture was diluted with EtOAc, washed with saturated NaHCO3 and brine. The organic layer was dried over sodium sulfate and concentrated to give Intermediate 3A (7.0 g, 35.9 mmol, 100 % yield) as a white solid. ?H NMR (400 MHz, CHLOROFORIVI-d) oe ppm 7.98 - 8.11 (m, 3 H) 3.93 (s, 3 H) 2.67 (s, 3 H).
13.3 g
With thionyl chloride; N,N-dimethyl-formamide; In toluene; for 4h;Reflux;
12.04 g (0.0664 mol) of <strong>[1975-51-5]4-nitro-2-methylbenzoic acid</strong> was added to a 100 ml one-necked flask,9.49 g (1.2 eq) of thionyl chloride and 12 ml of toluene were added, followed by the addition of 3 drops of DMF, refluxed for 4 hours,The solvent and excess thionyl chloride were distilled off under reduced pressure to give 13.3 g of a tan oil which was condensed to give a solid which was dissolved in 5 ml of acetonitrile.
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h;
To a solution of <strong>[1975-51-5]2-methyl-4-nitrobenzoic acid</strong> (1.66 g, 9.17 mmol) in DCM (15 mL) containing 5 drops of DMF was added oxalyl chloride (1.17 mL, 13.8 mmol) drop wise and the suspension was stirred at room temperature for 2 hours to form a clear solution. Volatiles were removed under vacuum and to the resulting crude acid chloride, was added a suspension of 2-aminophenol (1 g, 9.17 mmol) and triethylamine (3.3 mL, 22.9 mmol) in DCM (15 mL), drop wise, while vigorously stirring, and the reaction was continued at ambient temperature for 72 hours. The obtained suspension was filtered, and the filtrate volume was reduced to dryness under vacuum, taken up in dioxane (20 mL) and refluxed for 48 hours after adding methylsulfonic acid (1.8 mL, 27.6 mmol) to it. The reaction mixture was cooled down to room temperature, diluted with DCM, washed with saturated sodium bicarbonate, brine, and the organic liquor was dried over Na2SO4, decanted and evaporated under reduced pressure. The crude was purified by column chromatography on silica gel using 5:1 Hexane:EtOAc as mobile phase to give 2-(2-methyl-4-nitrophenyl)benzo[d]oxazole (0.72 g, 31%). UPLC-MS (Acidic Method, 2 min): rt 1.30 min, m/z 255.1 [M+H]+
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.
With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃; for 16h;
2-Methyl-4-nitrobenzoic acid (741 g, 5 mmol) was dissolved in methanol (20 mL), 10% palladium-carbon (100 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. The reaction solution was filtered through celite and, thereafter, the filtrate was concentrated under reduced pressure to obtain 4-amino-2-methylbenzoic acid as a crude material. In accordance with Reference Example 23 and Reference Example 14, from 4-amino-2-methylbenzoic acid obtained, there was obtained 4-[(tert- butyldimethylsilano yloxy)methyl]-3-methylaniline (0.33 g). LC/MS: M+1=252.2
With sulfuric acid; nitric acid; at 0 - 20℃; for 16h;Inert atmosphere;
To concd H2SO4 (50 mL) at 0 C was added concd HNO3 (50 mL) dropwise and the mixture was allowed to stir at 0 C for 10 min. Next, <strong>[1975-51-5]2-methyl-4-nitrobenzoic acid</strong> (8) (9.0 g, 49.71 mmol) was added portionwise.The resulting reaction mixture was allowed to stir at r.t. for 16 h. The mixture was poured into ice-cold H2O and the resulting solid was collected by filtration and dried to provide 2-methyl-4,5-dinitrobenzoic acid (9) (10 g, 89%) as an off-white solid. IR (KBr): 3431, 3005, 1693, 1538, 1363, 1275, 1260, 764, 750 cm-1. 1H NMR (400 MHz, DMSO-d6): delta = 14.06 (br s, 1 H), 8.50 (s, 1 H), 8.22 (s, 1 H), 2.67 (s, 3 H). 13C NMR (101 MHz, DMSO-d6): delta = 165.6, 147.6, 143.0, 138.7, 135.2, 128.0, 127.0, 20.9. MS (ESI+): m/z = 225.10 [M - H]+.
85%
With sulfuric acid; nitric acid; at 0 - 20℃; for 120h;
Step 1 : 2-Methyl-4,5-dinitrobenzoic acid To concentrated sulfuric acid (10 mL) at 0 C was added concentrated nitric acid (10 mL) dropwise and the mixture was allowed to stir at 0 C for 10 min. 2-Methyl-4- nitrobenzic acid (1.81 g, 10 mmol) was added and the mixture was allowed to stir at RT for 5 d. The mixture was poured into ice-cold water and the solid was removed by filtration and dried to give 2-methyl-4,5-dinitrobenzoic acid (1.93 g, 85%) as an off-white solid. LCMS (10 cm ESCI Formic MeCN): [M - H]" = 225 at 3.10 min. ? NMR (400 MHz, d6-DMSO): ? 8.53 (s, 1H), 8.26 (s, 1H), 2.71 (s, 3H). Step 2: 4-Methoxy-2-methyl-5-nitrobenzoic acid
72%
With sulfuric acid; potassium nitrate; at 25℃; for 16h;
<strong>[1975-51-5]2-Methyl-4-nitrobenzoic acid</strong> (10.0 g, 55.2 mmol) was dissolved in concentrated sulfuric acid (60 mL).A solution of potassium nitrate (8.4 g, 83.2 mmol) in concentrated sulfuric acid (40 mL) was added dropwise to the reaction mixture.25 C, 16 hours,It was poured into ice water, and a solid was precipitated, and dried under vacuum to give the title compound 9 g, yield: 72%.
Step 1 :; A solution of <strong>[89001-53-6]2-methyl-4-nitrobenzonitrile</strong> 11-1 (2.53 g, 15.6 mmol) in aqueous NaOH (10%, 31.0 mL) and aqueous H202 (10%, 16 mL) was stirred at reflux for 2.5 h. The water circulation in the cooling condenser was halted for 5-10 min (to allow removal of the dissolved ammonia), and then the water flow was restored and reflux continued for an additional 1. 5 h. The reaction mixture was cooled to RT, HCI (concentrated) was added drop-by-drop. until the pH was-3, at which point the carboxylic acid 11-2 precipitated as an orange-color solid (3.60 g). The carboxylic acid was used in step 2 without purification.
With hydrogenchloride; acetic acid; In water; at 150℃; for 8h;
A mixture of 3.04 g (18.7 mMol) of <strong>[89001-53-6]2-methyl-4-nitrobenzonitrile</strong> [preparation see: J. Med. Chem. 44 (2001), 3856], 26 mlHCI conc. and 26 mi acetic acid is heated in a sealed tube for8 h to 150 C. Filtration of the cool reaction mixture and washing with water gives the title compound: m. p.: 151-155 C ; MS: [M-1]+= 180.
Intermediate 5; Methyl 2-methyl-4-nitrobenzoate; SOCI2 was added to a solution of 2-methyl-4-nitrobenzoic acid (3 g, 16.5 mmol) in methanol dropwise. The reaction mixture was stirred at 70C for 18 hours. The mixture was evaporated and the residue was diluted with diethyl ether, washed with water and NaOH 1 N. The organic phase was dried over Na2SO4, filtered and evaporated to give the title compound as dark yellow solid (3.25 g, quantitative yield). NMR1H NMR (300 MHz), CDCI3 delta: 7.95 (m, 3H), 3.86 (s, 3H), 2.59 (s, 3H).
98%
With thionyl chloride; at 70℃; for 7h;
Under ice bath was added SOCl2 dropwise anhydrous methanol (100ml) in. And then a solution of 2-methyl-4-nitrobenzoic acid (10.0 g, 55.2 mmol) in anhydrous methanol (70mL) solution, 1 hour addition was complete. This mixed system placed in an oil bath at 70 C 7 hours, TLC the reaction was complete. Cooling, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) was added saturated sodium bicarbonate (100 mL), separated, the aqueous phase was extracted once with ethyl acetate (50mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure, and dried under high vacuum to give a white solid 10.5g, 98% yield
96%
With sulfuric acid; for 15h;Reflux;
Example 1) l-MethyI-lH-imidazole-4-suIfonic acid (4-chloro-benzyI)-(2-ethyI-l- oxo-2,3-dihydro-lH-isoindol-5-yl)-amide (Method A)i) 2-Methyl-4-nitro-benzoic acid methyl ester2-Methyl-4-nitrobenzoic acid (2.00 g, 11.00 mmol) was stirred in concentrated sulfuric acid (0.6 ml) and methanol (25 ml) at reflux for 15 hrs. Reaction was cooled and the solvent evaporated. The resulting residue was partitioned between water and dichloromethane and the organic phase separated. The aqueous phase was extracted with dichloromethane (x3) and the combined organics washed with brine, then dried (MgSO4) and evaporated in vacuo to yield the title compound as a pale yellow solid (1.89 g, 96%). HPLC retention time 4.39min.
95.3%
With sulfuric acid; at 0 - 70℃; for 24.5h;
Step 1: Synthesis of 2-Methyl-4-nitro-benzoic acid methyl ester To a solution of 2-methyl-4-nitro-benzoic acid (3 g, 16.56 mmole) in 30 ml methanol was added at 0 C. sulfuric acid (95-98%, 10 ml) slowly for ½ hr. The reaction mixture was stirred at 70 C. for 24 hrs. Mixture was cooled down, a solid precipitated out, then the mixture was concentrated, diluted with 50 ml water, stirred for 10 minutes, filtered off, the solid was washed with water, dried to afford 3.08 g of brown solid, 95.3% yield, pure by H NMR.
94.65%
With sulfuric acid; for 15h;Reflux;
In a 250 mL, 3-neck round-bottomed flask, 2-methyl-4-nitrobenzoic acid (20 g, 93.8 mmol) was charged with methanol (100 mL) and sulfuric acid (4 mL). The reaction mixture was refluxed for 15 h. After completion, the reaction mixture was concentrated to obtain the crude product which was added water (200 mL) and basified to pH 7-8 with aqueous NaHC03 solution. Aqueous solution was extracted with dichloromethane (250 mL X 3), the organic layer was washed with saturated brine solution followed by drying over anhydrous sodium sulphate. The solvent was removed to obtain methyl 2-methyl-4- nitrobenzoate 1), 20 g; Yield: 94.65%.
93%
With thionyl chloride; at 0 - 80℃; for 2h;
SOCl2 (2.6 g, 22.0 mmol) was slowly added to the solution of 2-methyl-4- nitrobenzoic acid (61.1) (2.0 g, 11.0 mmol) in MeOH (20 mL) at 0 C. The resulting mixture was heated at 80 C for 2 h. After cooling to room temperature, the reaction mixture was concentrated to afford methyl 2-methyl-4-nitrobenzoate (61.2) as a yellow oil (2.0 g, 93%).
91.3%
With thionyl chloride; at 12 - 20℃; for 12h;
Thionyl chloride (4.3 g, 36.45 mmol) was added dropwise to a stirred solution of 18 (3 g, 16.57 mmol) in MeOH (25 mL) while maintaining the internal temperature below 12 C. When the addition was complete the mixture was left to stand at room temperature for 12 h to result a white precipitation. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford white solid. The solid was washed with hexane and ethyl ether to afford 19 (2.95 g, 91.3%); mp 153.7-154.4 C (lit.39 mp 153-154 C); Rf 0.43 (hexane/EtOAc 3:1); 1H NMR (CDCl3) delta 2.69 (s, 3H, CH3), 3.95 (s, 3H, COOCH3), 8.02-8.11 (m, 3H, C6H3).
90.9%
With sulfuric acid; at 20 - 60℃;
EXAMPLE 75 2-Methyl-4-nitro-benzoic acid methyl ester (1) In accordance with general method S, 5.00 g (27.60 mmol) of 2-methyl-4-nitro-benzoic acid are dissolved in 20 ml of methanol, with heating, and 6 ml of concentrated sulfuric acid are added. The mixture is refluxed for 5 h. Yield: 4.90 g (90.9%); melting point: 73.6 C. C9H9NO3(Mr=195.18); GC (method 1) 9.55 min 1H-NMR (CDCl3) in ppm: 8.19-8.09 (m, 2H, aryl H), 7.99 (d, 1H, J=8.52 Hz, aryl H), 3.87 (s, 3H, -OCH3), 2.59 (s, 3H, -CH3) 13C-NMR (CDCl3) in ppm: 166.35 (-C=O), 159.29 (C4), 141.79 (C2), 135.14 (C1), 131.43 (C6), 126.06 (C3), 120.48 (C5), 52.37 (-OCH3), 21.50 (-CH3) IR (ATR) (cm-1): 1722, 1523, 1432, 1348, 1260, 1081, 896, 821, 786, 730 MS m/z (%): 195 (70), 164 (100), 134 (21), 118 (29), 63 (15). General Method SFor esterification of the acid group of the starting compound 2-methyl-4-nitro-benzoic acid, the stated amount is dissolved in methanol in a 100 ml one-necked flask at room temperature, concentrated H2SO4 is added and the mixture is refluxed at approx. 60 C. for 6 h. The excess alcohol is removed in vacuo, the residue is taken up in EtOAc and the mixture is deacidified repeatedly with 20% strength sodium hydroxide solution. After drying (Na2SO4), the combined organic phases are concentrated in vacuo.
With hydrogenchloride; In 1,4-dioxane; for 48h;Heating / reflux;
Step 2:; A solution of the acid 11-2 from step 1 (3.60 g, 15.6 mmol) in MeOH (30 mL) and HCI (4N HCI in dioxane, 2.0 mL) was heated to reflux for 48 h. The solvent was evaporated to dryness under vacuum and the residue obtained was re-dissolved in EtOAc (200 mL). The solution was washed with aqueous saturated NaHC03 (100 mL) and brine (100 mL), dried over anhydrous MgS04 and evaporated to dryness to give the ester intermediate 11-3 as a yellow-colored solid (2.38 g). This material was used in step 3 without purification.
With sulfuric acid; at 55℃; for 50h;
2-Methyl-4-nitrobenzoic acid methyl ester; [697] H2SO4 (98%, 0.030ml) was added dropwise into the MeOH (30mL) solutionof 2-methyl-4-nitrobenzoic acid at rt. The mixture was then heated at 55C. After 50h, thesolvent was removed in vacua and the residue was partitioned between EtOAc and H2O(25mL each). The aqueous layer was extracted with another portion of EtOAc (25mL). Thecombined extracts were washed with saturated NaHC03 (25mL), H2O (2 x 25mL), and brine(25mL), dried over MgS04, filtered and concentrated in vacua to give the title compound aslight-yellow solid. 'H NMR (CDC13,400 MHz): 5 = 2.69 (s, 3 H), 3.95 (s, 3 H), 8.03 - 8.12(m, 3 H). MS (ES+): m/z 196.25 (100) [MH4]. HPLC: /R= 3.29 min (ZQ2000, polar_5 min).
Preparation of 5-amino-2,3-dihydro-1H-isoindol-1-one A mixture of 2-methyl-4-nitrobenzoic acid (0.906 g, 5 mmol) in sulfurous dichloride (5.95 g, 50 mmol) was refluxed for 1 hour and concentrated. The residue was dissolved in methanol (30 mL, 741 mmol) and triethylamine (2 g, 19.76 mmol) was added. The mixture was stirred at room temperature for 1 hour, concentrated, and partitioned between ethyl acetate and water. The organic layer was separated, dried over MgSO4, and filtered through Magnesol to give 862 mg of methyl 2-methyl-4-benzoate as a tan solid.
sulfuric acid; In water; at 20 - 55℃;
Example 44Preparation of 5-[(2-((lS.2SV2-?-('5-chloropyrimidin-2-yl)piperidin-4- yl] cyclopropyl ) ethvDaminolisoindolin- 1 -oneStep 1 : methyl 2-methyl-4-nitrobenzoateSulfuric acid (6 ml, 113 mmol) was added to drop wise to a solution of the 2-methyl~4- nitrobenzoic acid (5 g, 27.6 mmol) in MeOH (138 ml) at RT. After the addition was complete the mixture was heated to 55 C overnight. The volatiles were removed in vacuum and the residue partitioned between EtOAc (100 ml) and water (100 ml). The layers were separated and aqueous phase extracted with EtOAc (2x100 ml). The organic fractions were combined, washed with saturated sodium bicarbonate (aqueous, 100ml), brine, dried over Na2SO4, filtered and the volatiles removed in vacuum to give the titled compound.
With sulfuric acid; for 10h;Reflux;
2-methyl-4-nitrobenzoic acid (1.81g, 10.0mmol) was dissolved in CH3OH (10mL), concentrated sulfuric acid (2.0mL, 3.7eq).The reaction system was heated to reflux, the reaction 10h.Completion of the reaction, cooled to room temperature, and thereto was added Na2CO3And sulfuric acid, and then filtered. The mother liquor after removal of methanol, to give compound I The crude yield of 89%, can be used directly in the next reaction.
With Trimethyl borate; dimethylsulfide borane complex; In tetrahydrofuran; at 65℃; for 2h;Inert atmosphere;
A flask was purged with nitrogen and charged with <strong>[1975-51-5]2-methyl-4-nitro-benzoic acid</strong> (45.3 g, 0.25 mol), trimethyl borate (103.9 g, 1.00 mol), and tetrahydrofuran (906 mL). Neat borane dimethyl sulfide complex (39.9 g, 49.8 mL, 0.525 mol) was added drop-wise at 20-35 C. over at least 30 min. An exotherm and effervescence were observed during this addition. When the addition was complete, the reaction mixture was stirred at 65 C. for at least 2 h or until in-process HPLC analysis showed that conversion was greater than 97%. The batch was quenched with cooling by drop-wise addition of methanol (46 mL), followed by a solution of 12.1 N aqueous hydrochloric acid (97 g, 82.1 mL, 1.00 mol) in water (138 mL) over at least 30 min. Batch temperature was held at 20-35 C. during quench; an exotherm and effervescence were observed during the quench. The mixture was stirred at 50 C. for at least 1 h and concentrated under reduced pressure to a volume of 230 mL (to remove tetrahydrofuran). The concentrate was diluted with water (453 mL) and extracted with ethyl acetate (2×453 mL). The organic layer was washed with saturated aqueous sodium chloride solution (230 mL), dried over anhydrous magnesium sulfate (23 g), filtered, and concentrated in vacuo to dryness to give the title compound as a beige solid (41 g, 98% yield).
To a solution of <strong>[1975-51-5]2-methyl-4-nitrobenzoic acid</strong> (5 g, 27.6 mmol, Aldrich) in THF) (95 ml) was added dropwise 1.0 M borane-tetrahydrofuran complex (55 ml, 55.0 mmol, Aldrich) at ambient temperature under nitrogen. The resulting red solution was heated to 80 0C for 2 h. To the solution at ambient temperature was added methanol (30 ml) and then heated to 80 0C for 30 min. The solvent was evaporated in vacuo to leave a yellow oil. The residue was dissolved in methanol (80 ml) and the solvent evaporated in vacuo to leave (2-methyl-4-nitrophenyl)methanol as a yellow solid (4.73 g).
9 g
With borane-THF; In tetrahydrofuran; methanol; at 80℃; for 6.66667h;
(A) (2-Methyl-4-nitrophenyl)methanol A 1.0 M solution of borane-THF complex in THF (110 mL) was added dropwise to a mixture of <strong>[1975-51-5]2-methyl-4-nitrobenzoic acid</strong> (10 g) and THF (200 mL) at room temperature, and the resulting mixture was stirred at 80 C. for 5.5 hours. The reaction mixture was cooled to room temperature, then methanol (50 mL) was added thereto, and the mixture was stirred at room temperature 10 minutes and then stirred at 80 C. for 1 hour. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue. The reaction mixture was washed with 0.5 N hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure to obtain the title compound (9.0 g). 1H NMR (300 MHz, CDCl3) delta 1.81 (1H, t, J=5.6 Hz), 2.40 (3H, s), 4.80 (2H, d, J=5.6 Hz), 7.62 (1H, d, J=8.4 Hz), 8.00-8.11 (2H, m).
9 g
With borane-THF; In tetrahydrofuran; at 80℃; for 5.5h;
At room temperature,A 1.0 M borane-THF complex was addedTHF solution (110 mL)Was added dropwise to a mixture of <strong>[1975-51-5]2-methyl-4-nitrobenzoic acid</strong> (10 g) and THF (200 mL)The resulting mixture was stirred at 80 C for 5.5 hours.The reaction mixture was cooled to room temperature,Methanol (50 mL) was added thereto, and the mixture was stirred at room temperature for 10 minutes and then at 80 C for 1 hour.The solvent was removed by distillation under reduced pressure, and ethyl acetate was added to the residue. The reaction mixture was washed with 0.5N hydrochloric acid, saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain the title compound (9.0 g).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;
Method L:Step a: [00293] A mixture of 2-methyl-4-nitrobenzoic acid (l eq.) iodomethane (1.1 eq.), K2CO3 (1.5 eq.), and 10 mL of DMF is stirred for 2hrs at room temperature, then poured into water and extracted with AcOEt. The extract is washed with water and brine, dried over anhydrous MgStheta4, and evaporated to afford the expected compound in quantative yield.
89%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;
A solution of 2-methyl-4-nitro-benzoic acid (10 g, 55 mmol), MeI (3.8 ml, 61 mmol) and K2CO3 (11.4 g, 83 mmol) in DMF was stirred for 3 h at RT after which the reaction was poured onto water and extracted in EtOAc. The organic fractions were washed with water and brine, dried over Na2SO4 and concentrated to give the desired product as an orange solid (9.57g, 89%). 1H NMR (400 MHz, DMSO-^6) delta ppm 2.60 (s, 3 H), 3.88 (s, 3 H), 8.00 (d, J=8.70 Hz, 1 H), 8.10 - 8.16 (m, 1 H), 8.21 (d, J=2.29 Hz, I H).
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 4h;
To a solution of7A (50 g, 0.27 mol) in DMF(500 mL) was added K2C03 (65 g, 0.54 mol). The mixture was cooled to 0C, CH31 wasadded dropwise. The reaction mixturewas stirred 4 hr at room temperature. The mixture was extracted with EtOAc and washedwith water, dried over Na2S04to afford crude7B (55 g) as yellow oil.
To a solution of <strong>[1975-51-5]2-methyl-4-nitrobenzoic acid</strong> 120.0 g, 0.662 mol) in ethanol (1.0 L) was added concentrated sulfuric acid (1.0 mL) and the mixture was heated at reflux for 24 hours and evaporated. The residue was dissolved in ethyl acetate (1.0 L), washed with saturated aqueous NAHCO3 solution (2 X 100 mL) and brine (1 X 200 mL), dried over anhydrous sodium sulfate, filtered and evaporated under vacuum to give the title compound, which was used in the next step without further purification. Yield: 115G (82.99%), Melting Point: 71-72 C.
sulfuric acid;Reflux;
<strong>[1975-51-5]2-Methyl-4-nitrobenzoic acid</strong> (1Og, 55.2mmol) in EtOH (20OmL) was treaed with sulfuric acid (2mL) and stirred at reflux until the reaction was complete. The mixture was worked-up and purified to give the title compound.
palladium(II) dichloride bis(triphenylphosphine)[ No CAS ]
[ 6277-17-4 ]
[ 1975-51-5 ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In diethyl ether; hexane; water; pyrographite; ethyl acetate; N,N-dimethyl-formamide;
Part A. Preparation of 4-Nitro-2-methylbenzoic Acid. A mixture of 1.0 g (3.8 mmol) of 2-iodo-nitrotoluene, 2.1 g (15.2 mmol) potassium carbonate and 27 mg (0.038 mmol) of palladium(II) dichloride bis(triphenylphosphine) in a mixture of 5 mL of water and 10 mL of N,N-dimethylformamide. This was placed in a Fisher/Porter bottle under 15 psig of carbon monoxideand heated at 70 C. for 16 hours. The solution became homogeneous when heated. The reaction was cooled, diethyl ether and water was added, the organic layer separated and discarded. The aqueous layer was acidified with IN hydrohloric acid, extracted with ethyl acetate, washed with water, brine, dried over magnesium sulfate, filtered and concentrated to yield 0.5 g of crude material. This dissolved in ethyl acetate, hexane added and the resulting brown solid discarded. The filtrate was concentrated, and then recrystallized fom diethyl ether/hexane to afford 215 mg of 4-nitro-2-methylbenzoic acid, m/e=182 (M+H).
With potassium carbonate; In diethyl ether; hexane; water; pyrographite; ethyl acetate; N,N-dimethyl-formamide;
Part A. Preparation of 4-Nitro-2-methylbenzoic Acid A mixture of 1.0 g (3.8 mmol) of 2-iodo-nitrotoluene, 2.1 g (15.2 mmol) potassium carbonate and 27 mg (0.038 mmol) of palladium(II) dichloride bis(triphenylphosphine) in a mixture of 5 mL of water and 10 mL of N,N-dimethylformamide. This was placed in a Fisher/Porter bottle under 15 psig of carbon monoxideand heated at 70 C. for 16 hours. The solution became homogeneous when heated. The reaction was cooled, diethyl ether and water was added, the organic layer separated and discarded. The aqueous layer was acidified with 1N hydrohloric acid, extracted with ethyl acetate, washed with water, brine, dried over magnesium sulfate, filtered and concentrated to yield 0.5 g of crude material. This dissolved in ethyl acetate, hexane added and the resulting brown solid discarded. The filtrate was concentrated, and then recrystallized fom diethyl ether/hexane to afford 215 mg of 4-nitro-2-methylbenzoic acid, m/e=182(M+H).
With potassium carbonate; In diethyl ether; hexane; water; pyrographite; ethyl acetate; N,N-dimethyl-formamide;
Part A. Preparation of 4-Nitro-2-methylbenzoic Acid. A mixture of 1.0 g(3.8 mmol) of 2-iodo-nitrotoluene, 2.1 g(15.2 mmol) potassium carbonate and 27 mg(0.038 mmol) of palladium(II) dichloride bis(triphenylphosphine) in a mixture of 5 mL of water and 10 mL of N,N-dimethylformamide. This was placed in a Fisher/Porter bottle under 15 psig of carbon monoxideand heated at 70 C for 16 hours. The solution became homogeneous when heated. The reaction was cooled, diethyl ether and water was added, the organic layer separated and discarded. The aqueous layer was acidified with iN hydrohloric acid, extracted with ethyl acetate, washed with water, brine, dried over magnesium sulfate, filtered and concentrated to yield 0.5 g of crude material. This dissolved in ethyl acetate, hexane added and the resulting brown solid discarded. The filtrate was concentrated, and then recrystallized fom diethyl ether/hexane to afford 215 mg of 4-nitro-2-methylbenzoic acid, m/e=182(M+H).
With potassium carbonate; In N,N-dimethyl-formamide;
<strong>[1975-51-5]2-Methyl-4-nitrobenzoic acid</strong> was treated with benzyl bromide in the presence of potassium carbonate in DMF to give the corresponding benzyl ester
<strong>[1975-51-5]2-Methyl-4-nitrobenzoic acid</strong> (700 mg, 3.86 mmol) was dissolved in pyridine (8 mL), p-toluenesulfonyl chloride (1.47 g, 7.74 mmol) was added, then tert-butanol (0.369 mL, 3.86 mmol) was added under ice cooling, and the mixture was stirred at 0C for 2 hours and at room temperature for 2 hours, tert-Butanol (0.369 mL, 3.86 mmol) was further added, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, water was added, then the mixture was extracted with ethyl acetate (x 3), and the organic layer was washed with 1 N hydrochloric acid, a 1 N aqueous sodium hydroxide solution, water, and saturated sodium chloride solution. The organic layer was dried with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, a solution of the resulting residue in ethyl acetate (40 mL) was added to 10% palladium-carbon (dry; 222 mg), the atmosphere in the system was replaced with a hydrogen atmosphere, and then the mixture was stirred at room temperature for 2 hours. The atmosphere in the system was replaced with a nitrogen atmosphere, and then the mixture was filtered through celite. The solvent was evaporated under reduced pressure to give the title compound (835 mg; yield, 100%) as a brown solid. 1H NMR (CDCl3, 400 MHz): delta 1.57 (9H, s), 2.52 (3H, s), 6.70-6.72 (2H, m), 7.78 (1H, d, J=8.1Hz). MS (APCI) m/z: 208 (M+H)+.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;
[0582] Preparation Example 148: Preparation of (4-amino-2-methylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone[0583][0584] <strong>[1975-51-5]2-Methyl-4-nitrobenzoic acid</strong> (500 mg), 1-(2,4-dimethylphenyl)piperazine (523 mg) and 1-hydroxybenzotriazole1 hydrate (373 mg) were dissolved in N,N-dimethylformamide (13 mL), 1-ethyl-3-(3?-dimethylaminopropyl)carbodiimidehydrochloride (531 mg) was added, and the mixture was stirred at room temperature. Water was added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and thesolvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give[4-(2,4-dimethylphenyl)piperazin-1-yl](2-methyl-4-nitrophenyl)methanone (771 mg). Then, to a mixed solution of ethanol(11 mL) and water (3 mL) were added ammonium chloride (660 mg) and iron (480 mg), and the obtained [4-(2,4-dimethylphenyl)piperazin-1-yl](2-methyl-4-nitrophenyl)methanone (771 mg) was added while stirring at 60C - 70C.After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. Tothe obtained residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethylacetate. The solvent was evaporated from the organic layer to give the title compound (833 mg).MS (ESI) m/z:324(M+H)+.
First take 10mLThe mass fraction is69%Of nitric acidAnd 5mL mass fraction98% sulfuric acid,Into a reaction vessel,The control temperature was 65 C,Speed is 200r / min,Stirring mixing,The mixed acid was cooled to 20 C,40 mL of toluene was slowly added dropwise at a rate of 5 g /Stirring 30min,Placed in hot water bath reaction 45min,And then hot filter,The filtrate was poured into cold water, cooled to room temperature,Washed with 40 mL of sodium hydrogencarbonate solution to basicity,Then rinse with water,To give 2,5-dinitrotoluene;Then, 40 g of tin dichloride and 5 g of iron powder were added to the above 2,5-dinitrotoluene,While adding 30mL of glacial acetic acid, speed set to 700r / min,Stirring 30min,Upon completion of the stirring,The control temperature is 85 ,To this was added dropwise 20 mL of 35% hydrochloric acid,Increase speed 1200r / min,Stirring 50min,Amino-5-nitrotoluene;Then, 30 mL of the 2-amino-5-nitrotoluene obtained above was placed in a 70 mL three-necked flask,Add 20mL of acetic acid, control the temperature of 60 , stirring 50min, while stirring to drop 15mL of 98% sulfuric acid, keep the temperature constant, magnetic stirring 2h, 2-methyl-4-nitroacetyl Aniline; 2-methyl-4-nitroacetanilide obtained above was added with 15 mL of hydrogen peroxide and 7 g of sodium perborate at a temperature of 300 C and a pressure of 3 MPa for 2 hours, and 20 mL of acetic acid was added thereto, 70 C, stirring 50min, when stirring is completed, placed in ice water 5min, washed with deionized water, in 2-methyl-4-nitrophenylacetamide; Finally, the above 2-methyl 4- Nitrobenzeneacetamide into the 100mL reaction flask, respectively, to which 5g of potassium permanganate and 20mL of sodium hypochlorite, the temperature of 80 , speed 900r / min, stirring 40min, stirring slowly dropping 20mL quality 30% hydrochloric acid, until the drop is completed, the reaction 2h, standing filter, dried to 2-methyl-4-nitrobenzoic acid. The method has the advantages of simple synthesis process, low cost and less by-products. The yield of the product is up to 97.5% and the purity is up to 99.36%.
(S)-dibenzyl 2-(2-ethoxy-4-(5-((((R)-2-((R)-1-(N-hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)furan-2-yl)benzamido)succinate[ No CAS ]
(S)-dibenzyl 2-(2-ethoxy-4-(5-((((R)-2-((R)-1-(N-((2-methyl-4-nitrobenzoyl)oxy)formamido)propyl)heptanamido)methyl)carbamoyl)furan-2-yl)benzamido)succinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With 4-methyl-morpholine; HATU; In N,N-dimethyl-formamide; acetonitrile; at 50℃; for 16h;
Step 1 : (S)-dibenzyl 2-(2-ethoxy-4-(5-((((R)-2-((R)-1-(N-((2-methyl-4- nitrobenzoyl)oxy)formamido)propyl)heptanamido)methyl)carbamoyl)furan-2- yl)benzamido)succinate To a solution containing (S)-dibenzyl 2-(2-ethoxy-4-(5-((((R)-2-((R)-1-(N- hydroxyformamido)propyl)heptanamido)methyl)carbamoyl)furan-2-yl)benzamido)succinate (91.2 mg, 0.1 12 mmol), <strong>[1975-51-5]2-methyl-4-nitrobenzoic acid</strong> (24.39 mg, 0.135 mmol), and HATU (64.0 mg, 0.168 mmol) in MeCN (0.5 mL) and DMF (0.5 mL) at RT was added N- methylmorpholine (0.037 mL, 0.337 mmol). The reaction was stirred at 50 C for 16 h. The mixture was partitioned between EtOAc and water, then the organic layer was washed with brine. It was then dried over MgS0 , filtered, and concentrated. Purification by Si (0-100% EtOAc/Hex) afforded the title compound. (107 mg, 98% yield). MS (m/z) 976.9 (M+H)+
With N-hydroxyphthalimide; cobalt(II) chloride hexahydrate; nitric acid; manganese (II) acetate tetrahydrate; under 760.051 Torr; for 12h;Reflux;
Preparation of 2-methyl-4-nitrobenzoic acid4-Nitro-o-xylene (0.15 g, 1 mmol), NHPI (0.05 g,0.3 mmol), nitric acid (40 %; 1.26 g, 8 mmol),CoCl2 ·6H2O (7.1 mg, 0.03 mmol), Mn(OAc)2 ·4H2O(7.1 mg, 0.03 mmol) and a phase transfer catalyst(0.04 mmol) were added to a 50 mL three-neckedround bottomed flask equipped with a magnetic stirrerand a reflux condenser. The mixture was heated underreflux for 12 h at normal pressure. After the reactioncompletion the mixture was cooled to room temperatureand washed with 10 mL of water. The aqueousphase was extracted with ethyl acetate (3 × 5 mL)and the obtained organic phase was dried with anhydroussodium sulfate. Ethyl acetate was removedfrom the organic layer by rotary evaporation and thecrude products were determined by the HPLC analysisbased on the internal standard (2,4-dinitrotoluene).The crude products were re-crystallized (EtOH/H2Or = 3 : 1) to give pure 2-methyl-4-nitrobenzoic acid(0.13 g, 72 %) in form of white needle crystals; m.p.:151-152C. IR, nu/cm-1, (KBr): 1702 cm-1.1H NMR(CDCl3, 500 MHz), delta: 2.79 (s, 3H, CH3 ), 8.13-8.17(m, 2H, Ar), 8.21 (d, 1H, J = 6.8 Hz, Ar). Anotherproduct is the 4-nitrophthalic acid which is separatedby column chromatography from ethyl acetate/hexane(r = 1 : 5) in form of light colored needle crystals;m.p.:163C. IR, nu/cm-1, (KBr): 1730 cm-1,1670 cm-1. 1H NMR (CDCl3, 500 MHz), delta: 7.86 (d,J = 8.6 Hz, 1H, Ar), 8.36 (dd, J1 = 8.6Hz, J2 = 2.0Hz,1H, Ar), 8.42 (d, J = 2.0 Hz, 1H, Ar) (Huntress et al.,1936).
62%
With oxygen; sodium hydroxide; In methanol; water; at 65℃; under 13501.4 Torr; for 24h;Autoclave;
3,4-dimethyl-1-nitrobenzene (907 mg, 6 mmol, 1.0 eq)Sodium hydroxide (1.8 g, 45 mmol, 7.5 eq)Was added to a 100 ml autoclave,Add 10 ml of 50% (v / v) methanol (5 ml of methanol, 5 ml of water)After charging oxygen three times,Passing oxygen gas (pressure 1.8MPa),In the oil bath temperature control 65 for 24 hoursAfter the reaction was diluted with methanol,Neutral and PH = 2-3,The solvent was removed under reduced pressure,After the addition of ethyl acetate,filter.Separated by chromatography,3,4-dimethyl-1-nitrobenzene recovered 72mg (0.47mmol),1,2-dimethyl-4-nitrobenzene conversion was 92%To give 673 mg (3.72 mmol) of 2-methyl-4-nitrobenzoic acid,The yield was 62%.
With manganese(IV) oxide; nitric acid; for 1h;
In a three-necked flask equipped with a stirrer, a dropping funnel and a thermometer, 3 g o-xylene was added, and 5 mL of trifluoroacetic acid was added dropwise to the flask through a dropping funnel,Control the drop rate so that it dripping within 1min finished; after the drop is completed,Start the stirrer to 200r / min speed stirring 20min, and then into the bottle into the nitrogen dioxide gas,Access rate of 10mL / min, ventilation time of 5min, ventilated after the end into the microwave reactor,To 600W of power, 0.2MPa pressure microwave reaction 30min; after the end of the reaction,The reaction was terminated by the dropwise addition of 5 mL of a sodium bicarbonate solution having a mass concentration of 30%The reaction was extracted three times with dichloromethane and the combined organic phases were washed with deionized water to pH to neutral,After drying over anhydrous sodium sulfate, the filtrate was placed in a rotary evaporator, heated to 80 C,Steamed to remove methylene chloride, get viscous liquid; the viscous liquid into the 500mL beaker,50 mL of a nitric acid solution having a mass concentration of 65% and 2 g of manganese dioxide were added,Placed in shaking on the shaking reaction 1h, the mixture into the Buchner funnel, washed with deionized water 3 times,The filtrate was separated; the mixture was transferred to a water bath and heated to 40 C,Add 5g potassium permanganate particles, stirring with a glass rod lOmin mixed solution;To the above mixture was added 20 mL of an acetic acid solution having a mass concentration of 30% and 3 g of iron powder,Into the ultrasonic oscillator, the ultrasonic oscillation reaction 30min,Ultrasonic power of 100W, ultrasonic frequency of 25 Kappa Eta zeta, after the end of ultrasound with n-hexane extraction of the reaction solution, the organic phase separation, into the distillation device, heated to 85 C, distilled n-hexane to remove 2 - Aminobenzoic acid.
With potassium permanganate; at 40℃; for 0.166667h;
In a three-necked flask equipped with a stirrer, a dropping funnel and a thermometer, 3 g o-xylene was added, and 5 mL of trifluoroacetic acid was added dropwise to the flask through a dropping funnel,Control the drop rate so that it dripping within 1min finished; after the drop is completed,Start the stirrer to 200r / min speed stirring 20min, and then into the bottle into the nitrogen dioxide gas,Access rate of 10mL / min, ventilation time of 5min, ventilated after the end into the microwave reactor,To 600W of power, 0.2MPa pressure microwave reaction 30min; after the end of the reaction,The reaction was terminated by the dropwise addition of 5 mL of a sodium bicarbonate solution having a mass concentration of 30%The reaction was extracted three times with dichloromethane and the combined organic phases were washed with deionized water to pH to neutral,After drying over anhydrous sodium sulfate, the filtrate was placed in a rotary evaporator, heated to 80 C,Steamed to remove methylene chloride, get viscous liquid; the viscous liquid into the 500mL beaker,50 mL of a nitric acid solution having a mass concentration of 65% and 2 g of manganese dioxide were added,Placed in shaking on the shaking reaction 1h, the mixture into the Buchner funnel, washed with deionized water 3 times,The filtrate was separated; the mixture was transferred to a water bath and heated to 40 C,Add 5g potassium permanganate particles, stirring with a glass rod lOmin mixed solution;To the above mixture was added 20 mL of an acetic acid solution having a mass concentration of 30% and 3 g of iron powder,Into the ultrasonic oscillator, the ultrasonic oscillation reaction 30min,Ultrasonic power of 100W, ultrasonic frequency of 25 Kappa Eta zeta, after the end of ultrasound with n-hexane extraction of the reaction solution, the organic phase separation, into the distillation device, heated to 85 C, distilled n-hexane to remove 2 - Aminobenzoic acid.
2-(trimethylsilyl)ethyl 2-methyl-4-nitrobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75 g
A) 2-(Trimethylsilyl)ethyl 2-methyl-4-nitrobenzoate 4-Dimethylaminopyridine (67.4 g) and WSC hydrochloride (95.46 g) were added to a mixture of <strong>[1975-51-5]2-methyl-4-nitrobenzoic acid</strong> (50 g) and dichloromethane (600 mL) at room temperature, followed by stirring at room temperature for 30 minutes. 2-(Trimethylsilyl)ethanol (58.79 g) was then added thereto at room temperature, followed by stirring at room temperature for 5 hours. After completion of the reaction, the reaction mixture was diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated saline solution, and was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to obtain the title compound (75 g). 1H NMR (400 MHz, CDCl3) delta 0.08 (9H, s), 1.13-1.17 (2H, m), 2.68 (3H, s), 4.41-4.45 (2H, m), 7.95 (1H, d, J=8.7 Hz), 8.05-8.08 (1H, m), 8.10 (1H, s).
With hydrogen fluoride; acetic acid; sodium nitrite; In dichloromethane; water; at 5 - 25℃; for 1h;
36.5 g of <strong>[1975-51-5]2-methyl-4-nitrobenzoic acid</strong> and 200 mL of glacial acetic acid were placed in the reactor, and then slowly cooled to 5 C or lower and then 17 g of sodium nitrite was added. After completion, 14 g of hydrofluoric acid was added dropwise. After the addition is completed, the fluorination reaction is carried out under the control temperature of 5 C or less. After confirming the completion of the reaction of the raw materials, the temperature is further raised at 20 C to 25 C for 30 min, and then 150 mL of dichloromethane and 50 mL of water are added, and stirred. After 30 min, it was allowed to stand and layered, and a dichloromethane solution containing the compound of the formula II was directly used for the next reaction, and the single step yield reached 95.8%;
With N-ethyl-N,N-diisopropylamine; HATU; In 2,2,2-trifluoroethanol; at 25 - 40℃;
General procedure: To a solution of tert-butyl 4-aminopiperidine-1-carboxylate (1 equiv) and appropriate acids (1 equiv) in CH2Cl2 at rt, HATU (1.2 equiv) and DIEA (1.5 equiv) were added. The resulting mixture was warmed to 25C-40C and stirred until completion of the reaction. The mixture was diluted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and purified by chromatography to yield the intermediates 30a-h. Intermediates 30a-h (1 equiv) were dissolved in ethanol, and Pd/C (0.1 equiv) was added. The flask was flushed with H2 and stirred for 3hat 40C. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated to dryness, yielding intermediates 31a-h.
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 - 40℃;
General procedure: HATU (1.2 equiv) and DIEA (1.5 equiv) were added to a solutionof 2-fluoro-4-nitrobenzoic acid (1 equiv) and R6-NH2 (1 equiv) inCH2Cl2 at rt. The resulting mixture was heated to 25e40 C andstirred until the reaction was complete. The mixture was dilutedwith ethyl acetate, and the organic layer was washed with saline,dried over anhydrous Na2SO4 and filtered. The filtrate wasconcentrated and purified using chromatography to yield the intermediates33a-g. Intermediates 33a-g (1 equiv) were dissolved inethanol, and Pd/C (0.1 equiv)was added. The flask was flushed withH2 and stirred for 6 h at 40 C. The reaction mixture was filteredthrough a Celite pad and the filtrate was concentrated to dryness,yielding intermediates 34a-g.
Chemistry
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