* 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] Recueil des Travaux Chimiques des Pays-Bas, 1901, vol. 20, p. 169
3
[ 89-71-4 ]
[ 1975-50-4 ]
[ 77324-87-9 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1901, vol. 20, p. 169
4
[ 77324-87-9 ]
[ 1975-52-6 ]
Yield
Reaction Conditions
Operation in experiment
98%
With lithium hydroxide; water In tetrahydrofuran at 30℃; for 4 h;
To a solution of compound 3 (75.0 g, 0.46 mol) in THF (500 mL) was added 1 N aq. LiOH (1 L, 0.92 mol), then the mixture was stirred at 30°Cfor 4 hours. TLC (petroleum ether: ethyl acetate = 10:1 ) showed the reaction was complete, then the mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (200 mLx2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give compound 4 (67 g, 98percent) as a brown solid., which was used in the next step without further purification. 1H NMR (400 MHz, CDCI3): δ 8.93 (S, 1 H), 8.30-8.32 (d, J = 8.0 Hz, 1 H), 7.48- 7.50 (d, J = 8.0 Hz, 1 H), 2.79 (s, 3H).
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 20℃;
A solution of 2-methyl-5-nitrobenzoic acid (15 g, 82.8 mmole) in DMF (75 mL) was treated with methyl iodide (6.7 mL, 107.64 mmole) followed by powdered K2CO3 (17.2 g, 124.2 mmole) (extreme exotherm) and the suspension stirred at ambient temperature overnight. The reaction mixture was partitioned between EtOAc and water, the organics separated and washed with water and brine, dried (Na2SO4) and concentrated in vacuo to yield K1 (15.86 g, 98percent) in pure form as an off-white solid. The 1H NMR was consistent with that of the desired structure.
94%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
4.2.1 Methyl-2-methyl-5-nitrobenzoate (2) To a mixture of 2-methyl-5-nitrobenzoic acid (15 g, 82.8 mmol) and K2CO3 (17.2 g, 124.2 mmol) in 75 mL DMF was added iodomethane (6.7 mL). The mixture was stirred at room temperature overnight. Then, 500 mL water was added into the mixture, the aqueous phase was extracted with EA for three times. The combined organic phase was dried with Na2SO4, concentrated to afford the product 2 (15.3 g, 94percent) as yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.05 (s, 1H), 7.30 (s, 1H), 3.83 (s, 3H), 2.56 (s, 3H). ESI-MS m/z 196 [M+H]+.
Reference：
[1] Journal of the American Chemical Society, 2003, vol. 125, # 40, p. 12074 - 12075
[2] Patent: US6344465, 2002, B1, . Location in patent: Page column 32
[3] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 5881 - 5890
[4] Patent: US2005/43385, 2005, A1, . Location in patent: Page/Page column 14
[5] Patent: US2001/34343, 2001, A1,
[6] Patent: US5861417, 1999, A,
[7] Patent: EP946548, 2002, B1,
[8] Patent: US6194406, 2001, B1,
[9] Patent: US6423704, 2002, B1,
[10] Patent: US6211199, 2001, B1,
6
[ 67-56-1 ]
[ 201230-82-2 ]
[ 7745-92-8 ]
[ 77324-87-9 ]
Yield
Reaction Conditions
Operation in experiment
37%
With triethylamine; diphenylphosphinopropane In methanol at 110℃; for 18 h;
23.2 g (88 mmol) of 2-iodo-4-nitrotoluene are dissolved in 400 ml of anhydrous methanol and then placed in a steel reactor. 25 ml (177 mmol) of triethylamine, 1.97 g (8.8 mmol) of palladium diacetate and 7.3 g of diphenyphosphinopropane are added and the reaction medium is subjected to a carbon monoxide pressure of 4 bar and heated at 110° C. for 18 hours. The medium is then brought to ambient pressure and temperature, dissolved in dichloromethane and filtered on celite. After evaporation, the residue is purified by chromatography on a silica column. An orange-coloured powder is obtained (m=6.3 g, Y=37percent).
2-Methyl-5-nitrobenzoic Acid Methyl Ester (35). To a stirring MeOH (4 mL) in a round-bottom flask was added dropwise thionyl chloride (0.24 mL, 3.3 mmol) at 0° C. The mixture was added 2-methyl-5-nitrobenzoic acid 34 (300 mg, 1.7 mmol) at 0° C. and it was allowed to stir for 4 h at reflux temperature. The reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give corresponding compound 35 (320 mg, 99percent) as a colorless oil, Rf=0.85 (hexane:EtOAc=1:1). 1H NMR (400 MHz, CDCl3): δ 8.52 (s, 1H), 8.05 (s, 1H), 7.30 (s, 1H), 3.83 (s, 3H), 2.56 (s, 3H). 13CNMR(100 MHz, CDCl3): δ 165.4, 147.6, 145.6, 132.5, 130.1, 125.8, 125.3, 52.1, 21.5. MS (EI): m/z 195 [M]+. HRMS (EI), calcd for C9H9N04195.0532, found [M]+ 195.0539.
87%
for 36 h; Heating / reflux
2-Methyl-5-nitrobenzoate (5.0 g, 27.6 mmol) was dissolved in [MEOH] (0.4 L) followed by the addition of H2SO4 (7 mL). The mixture was heated at reflux for 36 h, then cooled [TO RT] and concentrated to ca 100 mL. The solution was diluted with [MTBE] neutralized with 6N [NAOH,] washed with 1N [NAOH,] brine, dried [(MGS04),] filtered and concentrated in vacuo to afford 4.72 g (87percent) of methyl [2-METHYL-5-NITROBENZOATE] as a white solid.
Reference：
[1] Journal of Medicinal Chemistry, 2009, vol. 52, # 16, p. 5228 - 5240
[2] Patent: US2011/269834, 2011, A1, . Location in patent: Page/Page column 28-29
[3] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 10, p. 2823 - 2827
[4] Patent: WO2004/18414, 2004, A2, . Location in patent: Page 109-110
[5] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8561 - 8578
[6] European Journal of Medicinal Chemistry, 1991, vol. 26, # 7, p. 699 - 707
[7] Patent: WO2005/80388, 2005, A1, . Location in patent: Page/Page column 55
[8] Patent: WO2006/63805, 2006, A1, . Location in patent: Page/Page column 75
[9] Patent: WO2007/71955, 2007, A1, . Location in patent: Page/Page column 52
[10] Patent: US2009/239859, 2009, A1, . Location in patent: Page/Page column 298
[11] Patent: WO2005/9940, 2005, A1, . Location in patent: Page 174
[12] Patent: US2010/81643, 2010, A1, . Location in patent: Page/Page column 37
[13] Patent: WO2010/47982, 2010, A1, . Location in patent: Page/Page column 77-78
[14] Journal of Medicinal Chemistry, 2011, vol. 54, # 2, p. 635 - 654
[15] Patent: WO2014/167444, 2014, A1, . Location in patent: Page/Page column 46; 47
[16] Patent: WO2016/90079, 2016, A1, . Location in patent: Paragraph 00883-00884
8
[ 67-56-1 ]
[ 939-83-3 ]
[ 77324-87-9 ]
Yield
Reaction Conditions
Operation in experiment
82%
With hydrogenchloride In dichloromethane; water for 96 h; Heating / reflux
To a solution of compound 2 (64.0 g, 0.39 mol) in MeOH (1500 mL), H2O (50 mL) and CH2CI2 (500 mL) was purged with HCI gas till the solution was saturated. The mixture was left standing for 48 hours, then refluxed for 48 hours. TLC (petroleum ether: ethyl acetate = 10:1) showed the reaction was complete, then the mixture was concentrated in vacuo to give crude product, which was purified by column chromatography (first petroleum ether, then petroleum ether: ethyl acetate 1 :1) to afford compound 3 (33 g, yield: 82percent) as a yellow solid and recover compound 2 (42 g) as a grey solid. 1H NMR (400 MHz, CDCI3): 1H NMR δ 8.76 (S, 1 H), 8.22- 8.24 (dd, J = 8.0 Hz, 1 H), 7.42-7.44 (d, J = 8.0 Hz, 1 H), 3.95 (s, 3H), 2.71 (s, 3H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 23, p. 6273 - 6278
[2] Patent: WO2006/117669, 2006, A1, . Location in patent: Page/Page column 41; 114
Reference：
[1] Chemische Berichte, 1911, vol. 44, p. 1122
16
[ 89-71-4 ]
[ 1975-50-4 ]
[ 77324-87-9 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1901, vol. 20, p. 169
17
[ 186581-53-3 ]
[ 1975-52-6 ]
[ 77324-87-9 ]
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1984, vol. 23, # 11, p. 1098 - 1102
18
[ 89-71-4 ]
[ 7697-37-2 ]
[ 59382-59-1 ]
[ 77324-87-9 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1901, vol. 20, p. 169
19
[ 77324-87-9 ]
[ 90725-68-1 ]
Yield
Reaction Conditions
Operation in experiment
95.5%
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 83℃; for 5 h;
To a solution of methyl 2-methyl-5-nitrobenzoate (6.4 g, 32.76 mmol) in CCI4 (80 ml_) were added NBS (6.4 g, 36.1 mmol) and BPO (794 mg, 3.28 mol). The resulting mixture was stirred at 83°C for 5 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with EtOAc (150 mL), washed with H2O (120 ml_ x 3). The organic phase was dried and concentrated to give methyl 2-(bromomethyl)-5-nitrobenzoate (8.5 g, 95.5 percent) as a brown oil which was used directly for the next step without further purification. LCMS (method B): 2.59 min [M+Na]+= 295.9,297.9
89%
With N-Bromosuccinimide In tetrachloromethane for 34 h; Reflux
2-Bromomethyl-5-nitrobenzoic Acid Methyl Ester (36). Compound 35 (100 mg, 0.53 mmol) was dissolved in CCl4 (4 mL), followed by addition of NBS (100 mg, 0.58 mmol) and a catalytic amount of benzoyl peroxide. The mixture was stirred at reflux for 24 h. Another portion, of dibenzoyl peroxide (40 mg, 0.23 mmol) was added and then the mixture was stirred and heated at reflux for another 10 h. The mixture was allowed to cool to 23° C. and was filtered. The filtrate was washed with NaHCO3, dried over Na2SO4, and the solvent evaporated in vacuo. The residue was purified by silica gel column chromatography to afford compound 36 in 89percent yield. 1H NMR (400 MHz, CDCl3): δ 8.81 (d, 1H, J=2.5 Hz), 8.33 (dd, 1H, J=8.5, 2.5 Hz), 7.68 (d, 1 H, 8.5 Hz), 5.00 (s, 2H), 4.01 (s, 3H).
85%
With N-Bromosuccinimide; azobisisobutyronitrile In 1,1-dichloroethane for 3 h; Photoirradiation
Methyl 2-methyl-5-nitrobenzoate (2.0 g, 10.2 mmol) NBS (2.73 g, 15.3 mmol) and AIBN (50 mg) were dissolved in dichloroethane (100 mL). The mixture was irratiated with a photolamp for 3h. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by silica gel chromatography [(HEPTANE/ETOAC] 1/0,19/1, 9/1) to afford 2. 40 g (85percent) of methyl [2- (BROMOMETHYL)-5-NITROBENZOATE.]
61%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 18 h; Heating / reflux
Part A. Preparation of methyl 2-((diethoxyphosphoryl)methyl)-5-nitrobenzoate.; [00689] To a solution of methyl 2-methyl-5-nitrobenzoate (0.40 g, 2.05mmol) in CCl4 (20ml) was addedN-bromosuccinimide (365mg, 2.05mmol) and 2,2'-azobisisobutyronitrile (34mg, 0.21mmol). The resulting mixture was stirred at reflux for 18h, cooled to room temperature and partitioned betweenEtOAc (50ml) and H2O (50ml). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 1:3 EtOAc:hexanes as the eluent to give the bromide as an oil (345mg, 61percent).
1.9 g
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 90℃; for 5 h;
To a solution of methyl 2-methyl-5-nitrobenzoate (62.2) (1.5 g, 7.7 mmol) in carbon tetrachloride (30 mL) was added N-bromosuccinimide (NBS) (1.5 g, 8.42 mmol) and azobisisobutyronitrile (AIBN) (124 mg, 0.76 mmol). The reaction mixture was stirred at 90 °C for 5 h. TLC showed the reaction was complete. The reaction mixture was filtered, and the filtrate was quenched with the addition of water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated to afford the crude product. The crude product was purified by column chromatography (DCM) to afford methyl 2-(bromomethyl)-5-nitrobenzoate (62.3) as a yellow solid (1.9 g, 90percent). [00887] LCMS: 314.0 [M+1]+.
Reference：
[1] Organic and Biomolecular Chemistry, 2017, vol. 15, # 48, p. 10172 - 10183
[2] Patent: WO2016/127213, 2016, A1, . Location in patent: Page/Page column 106
[3] Journal of Medicinal Chemistry, 2009, vol. 52, # 16, p. 5228 - 5240
[4] Patent: US2011/269834, 2011, A1, . Location in patent: Page/Page column 29
[5] Patent: WO2004/18414, 2004, A2, . Location in patent: Page 110
[6] Patent: WO2009/39135, 2009, A1, . Location in patent: Page/Page column 133
[7] European Journal of Medicinal Chemistry, 1991, vol. 26, # 7, p. 699 - 707
[8] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 11, p. 1625 - 1630
[9] Patent: US5665723, 1997, A,
[10] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 814 - 819
[11] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8561 - 8578
[12] Inorganic Chemistry, 2014, vol. 53, # 6, p. 2932 - 2942
[13] Patent: WO2016/90079, 2016, A1, . Location in patent: Paragraph 00886-00887
20
[ 128-08-5 ]
[ 77324-87-9 ]
[ 90725-68-1 ]
Reference：
[1] Patent: EP514133, 1992, A1,
21
[ 77324-87-9 ]
[ 103440-54-6 ]
Reference：
[1] Patent: WO2006/117669, 2006, A1,
22
[ 77324-87-9 ]
[ 54811-38-0 ]
Reference：
[1] Patent: WO2006/117669, 2006, A1,
23
[ 77324-87-9 ]
[ 18595-12-5 ]
Yield
Reaction Conditions
Operation in experiment
100%
With hydrogen In ethanol for 20 h;
Methyl 2-methyl-5-nitrobenzoate (5.0 g, 25.6 mmol) was dissolved in [ETOH] with Raney nickel under a 35 psi atmosphere of H2. The reaction was stirred for 20 h, then filtered through Celite washed with [MEOH] and concentrated in vacuo to afford 4.2 g (100percent) of methyl [5-AMINO-2-METHYLBENZOATE.]
99%
With hydrogen In ethyl acetate at 23℃; for 16 h;
5-Amino-2-methylbenzoic Acid Methyl Ester (41). To a solution of nitro 35 (635 mg, 3.3 mmol) in EtOAc (10 mL) was added 10percent Pd-C (30 mg) and it was allowed to stir for 16 h at 23° C. under H2 atmosphere. The reaction was filtered through a celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to furnish compound 41 (536 mg, >99percent) as a colorless oil, Rf=0.57 (hexane:EtOAc=1:1). 1HNMR(400 MHz, CDCl3): δ 7.21 (d, 1H, J=2.5 Hz), 6.97 (d, 1H, J=8.1 Hz), 6.69 (dd, 1H, J=2.5 and 8.1 Hz), 3.82 (s, 3H), 3.64 (s, 2H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 168.1, 144.1, 132.3, 129.8, 129.5, 118.8, 116.7, 51.6, 20.6. MS (EI): m/z 165.20 [M]+. HRMS (EI), calcd for C9H11NO2165.0790, found [M]+ 165.0787.
86%
With hydrogen In methanol at 80℃; for 14 h;
6.3 g (32 mmol) of methyl 2-methyl-5-nitrobenzoate are dissolved in 80 ml of anhydrous methanol and then transferred into a steel reactor. The mixture is degassed with nitrogen and then 630 mg of Pd/C (5percent) are added. The reaction medium is then subjected to a hydrogen pressure of 4 bar and to a temperature of 80° C. for 14 hours and then brought to ambient pressure and temperature and filtered. The residue, after evaporation, is purified by chromatography on a silica column. A brown oil is obtained (m=4.6 g, Y=86percent).
860 mg
With palladium 10% on activated carbon; hydrogen In ethanol at 20℃; for 3 h;
153.1 5-Amino-2-methyl-benzoic acid methyl ester To a solution of 2-methyl-5-nitrobenzoic acid methyl ester (1015 mg) in EtOH (33 mL) was added 10percent palladium on charcoal (175 mg) and the reaction mixture was stirred under an atmospheric pressure of hydrogen for 3 h at RT. It was filtered over a pad of celite and the filtrate was concentrated in vacuo to give 860 mg of the titled compound as an orange oil. 1H NMR (CDCl3) δ: 7.27 (d, J=2.6 Hz, 1H), 7.05 (d, J=8.1 Hz, 1H), 6.77 (dd, J1=8.1 Hz, J2=2.6 Hz, 1H), 3.89 (s, 3H), 3.64 (s, 2H), 2.49 (s, 3H)
Reference：
[1] Journal of the American Chemical Society, 2003, vol. 125, # 40, p. 12074 - 12075
[2] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 10, p. 2823 - 2827
[3] Patent: WO2004/18414, 2004, A2, . Location in patent: Page 110
[4] Journal of Medicinal Chemistry, 2009, vol. 52, # 16, p. 5228 - 5240
[5] Patent: US2011/269834, 2011, A1, . Location in patent: Page/Page column 29
[6] Journal of Medicinal Chemistry, 2011, vol. 54, # 2, p. 635 - 654
[7] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 2, p. 634 - 639
[8] Journal of Medicinal Chemistry, 1991, vol. 34, # 7, p. 2176 - 2186
[9] Tetrahedron, 2008, vol. 64, # 14, p. 3253 - 3267
[10] Patent: US6689922, 2004, B1, . Location in patent: Page column 86
[11] Bulletin de la Societe Scientifique de Bretagne, 1956, vol. 31, p. Sonderheft S.9,41
[12] Patent: US2005/43385, 2005, A1, . Location in patent: Page/Page column 14
[13] Patent: WO2006/63805, 2006, A1, . Location in patent: Page/Page column 76
[14] Patent: WO2007/71955, 2007, A1, . Location in patent: Page/Page column 52
[15] Patent: US2009/239859, 2009, A1, . Location in patent: Page/Page column 298
[16] Patent: WO2005/9940, 2005, A1, . Location in patent: Page 175
[17] Patent: US2010/81643, 2010, A1, . Location in patent: Page/Page column 37
[18] Patent: WO2010/47982, 2010, A1, . Location in patent: Page/Page column 78
[19] Patent: WO2012/114268, 2012, A1, . Location in patent: Page/Page column 134
[20] Patent: US2014/73651, 2014, A1, . Location in patent: Paragraph 0984; 0985
24
[ 77324-87-9 ]
[ 2840-04-2 ]
Reference：
[1] Patent: WO2006/117669, 2006, A1,
25
[ 77324-87-9 ]
[ 421551-82-8 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 10, p. 2823 - 2827
With hydrogen;nickel; In ethanol; under 1810.07 Torr; for 20h;
Methyl 2-methyl-5-nitrobenzoate (5.0 g, 25.6 mmol) was dissolved in [ETOH] with Raney nickel under a 35 psi atmosphere of H2. The reaction was stirred for 20 h, then filtered through Celite washed with [MEOH] and concentrated in vacuo to afford 4.2 g (100%) of methyl [5-AMINO-2-METHYLBENZOATE.]
> 99%
With hydrogen;palladium 10% on activated carbon; In ethyl acetate; at 23℃; for 16h;
5-Amino-2-methylbenzoic Acid Methyl Ester (41). To a solution of nitro 35 (635 mg, 3.3 mmol) in EtOAc (10 mL) was added 10% Pd-C (30 mg) and it was allowed to stir for 16 h at 23 C. under H2 atmosphere. The reaction was filtered through a celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to furnish compound 41 (536 mg, >99%) as a colorless oil, Rf=0.57 (hexane:EtOAc=1:1). 1HNMR(400 MHz, CDCl3): delta 7.21 (d, 1H, J=2.5 Hz), 6.97 (d, 1H, J=8.1 Hz), 6.69 (dd, 1H, J=2.5 and 8.1 Hz), 3.82 (s, 3H), 3.64 (s, 2H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3): delta 168.1, 144.1, 132.3, 129.8, 129.5, 118.8, 116.7, 51.6, 20.6. MS (EI): m/z 165.20 [M]+. HRMS (EI), calcd for C9H11NO2165.0790, found [M]+ 165.0787.
86%
With hydrogen;5%-palladium/activated carbon; In methanol; at 80℃; under 3000.3 Torr; for 14h;
6.3 g (32 mmol) of methyl 2-methyl-5-nitrobenzoate are dissolved in 80 ml of anhydrous methanol and then transferred into a steel reactor. The mixture is degassed with nitrogen and then 630 mg of Pd/C (5%) are added. The reaction medium is then subjected to a hydrogen pressure of 4 bar and to a temperature of 80 C. for 14 hours and then brought to ambient pressure and temperature and filtered. The residue, after evaporation, is purified by chromatography on a silica column. A brown oil is obtained (m=4.6 g, Y=86%).
A mixture of 15, methanol (40 mL) and 10% palladium on charcoal (0.1 g) was stirred under hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered and evaporated to give 16 (1.88 g, 2 steps quant.).
With hydrogen;palladium 10% on activated carbon; In methanol; for 48h;
Method 22; Methyl 5-amino-2-methgammalbenzoate; A solution of methyl 2-methyl-5-nitrobenzoate (Method 23; 3.4 g) and 10% palladium on carbon (672 mg) in MeOH (20 ml) was treated with H2 for 48 hours. The reaction mixture was then filtered through diatomaceous earth and washed with MeOH (20 ml) and EtOAc (10 ml). The solvents were removed under reduced pressure to give 2.7 g of a brown oil.1H NMR: 7.11 (d, 1 H), 6.94 (d, 1 H), 6.69 (dd, 1 H), 5.13 (s, 2 H), 3.78 (s, 3 H), 2.33 (s, 3 H); m/z: 165.
With hydrogen;palladium 10% on activated carbon; In methanol;
Methyl 2-methyl-5-nitrobenzoate (5.06 g) was suspended in methanol (100 ml). The mixture was degassed by bubbling nitrogen for 15 minutes. Pd/C 10% wet Degussa type E101 NE/WW (260 mg) was added and the mixture stirred under hydrogen atmosphere (balloon) overnight. The suspension was filtered and the solvents evaporated to afford methyl 5-amino-2-methylbenzoate as an orange oil (4.18 g, 97% yield).
With hydrogen;5%-palladium/activated carbon; In ethanol; at 20℃; under 760.051 Torr; for 3h;
Compound 497 (26. 5 G, 135.78 MMOL) in ethanol (200 ML) was hydrogenated under 1 atmosphere at room temperature in the presence of Pd/C 5% (2.00 G) for 3 h. After reaction, the catalyst was filtered off. The filtrate was concentrated in vacuo, providing the title compound as a brownish oil.
With hydrogen;palladium on activated carbon; In methanol; under 1551.49 - 2585.81 Torr; for 1h;
Step B Methyl 5-amino-2-methylbenzoate. To a solution of methyl 2-methyl-5-nitrobenzoate (60 g, 307 mmol) in MeOH (600 mL) was added Pd (10 wt % on carbon) (1.6 g). The reaction was shaken under hydrogen (30-50 psi) for 1 h, filtered through a celite pad and concentrated to afford the desired product as a red paste, which was used in the next step without purification.
With hydrogen;palladium 10% on activated carbon; In methanol; under 1551.49 - 2585.81 Torr; for 1h;
To a solution of methyl 2-methyl-5-nitrobenzoate (6Og, 307 mmol) in MeOH (600 mL) was added Pd (10 wt% on carbon) (1.6 g). The reaction was shaken under hydrogen (30-50 psi) for 1 h, filtered through a cehte pad and concentrated to afford the desired product as a red paste, which was used in the next step without purification.
With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; for 3h;
Example 153 5-[(2-Chloro-pyrimidin-4-yl)-methyl-amino]-N-(1 -hydroxy- cyclohexylmethyl)-2-methyl-benzamide153.1 5-Amino-2-methyl-benzoic acid methyl esterTo a solution of 2-methyl-5-nitrobenzoic acid methyl ester (1015 mg) in EtOH (33 mL) was added 10% palladium on charcoal (175 mg) and the reaction mixture was stirred under an atmospheric pressure of hydrogen for 3h at RT. It was filtered over a pad of celite and the filtrate was concentrated in vacuo to give 860 mg of the titled compound as an orange oil.1H NMR (CDCIs) delta: 7.27 (d, J = 2.6 Hz, 1 H), 7.05 (d, J = 8.1 Hz, 1 H), 6.77 (dd, Ji = 8.1 Hz, J2 = 2.6 Hz, 1 H), 3.89 (s, 3 H), 3.64 (s, 2 H), 2.49 (s, 3 H)
860 mg
With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃; under 760.051 Torr; for 3h;
153.1 5-Amino-2-methyl-benzoic acid methyl ester To a solution of 2-methyl-5-nitrobenzoic acid methyl ester (1015 mg) in EtOH (33 mL) was added 10% palladium on charcoal (175 mg) and the reaction mixture was stirred under an atmospheric pressure of hydrogen for 3 h at RT. It was filtered over a pad of celite and the filtrate was concentrated in vacuo to give 860 mg of the titled compound as an orange oil. 1H NMR (CDCl3) delta: 7.27 (d, J=2.6 Hz, 1H), 7.05 (d, J=8.1 Hz, 1H), 6.77 (dd, J1=8.1 Hz, J2=2.6 Hz, 1H), 3.89 (s, 3H), 3.64 (s, 2H), 2.49 (s, 3H)
2-Methyl-5-nitrobenzoic Acid Methyl Ester (35). To a stirring MeOH (4 mL) in a round-bottom flask was added dropwise thionyl chloride (0.24 mL, 3.3 mmol) at 0 C. The mixture was added <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> 34 (300 mg, 1.7 mmol) at 0 C. and it was allowed to stir for 4 h at reflux temperature. The reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give corresponding compound 35 (320 mg, 99%) as a colorless oil, Rf=0.85 (hexane:EtOAc=1:1). 1H NMR (400 MHz, CDCl3): delta 8.52 (s, 1H), 8.05 (s, 1H), 7.30 (s, 1H), 3.83 (s, 3H), 2.56 (s, 3H). 13CNMR(100 MHz, CDCl3): delta 165.4, 147.6, 145.6, 132.5, 130.1, 125.8, 125.3, 52.1, 21.5. MS (EI): m/z 195 [M]+. HRMS (EI), calcd for C9H9N04195.0532, found [M]+ 195.0539.
87%
With sulfuric acid; for 36h;Heating / reflux;
2-Methyl-5-nitrobenzoate (5.0 g, 27.6 mmol) was dissolved in [MEOH] (0.4 L) followed by the addition of H2SO4 (7 mL). The mixture was heated at reflux for 36 h, then cooled [TO RT] and concentrated to ca 100 mL. The solution was diluted with [MTBE] neutralized with 6N [NAOH,] washed with 1N [NAOH,] brine, dried [(MGS04),] filtered and concentrated in vacuo to afford 4.72 g (87%) of methyl [2-METHYL-5-NITROBENZOATE] as a white solid.
sulfuric acid; for 72h;Heating / reflux;
Step 1 :; A solution of <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> 6-1 (10.0 g, 55.2 mmol) in MeOH (200 mL) and H2SO4 (1.0 mL) was heated to reflux while stirring for-3 days. The solvent was evaporated under vacuum and the residue was re-dissolved in EtOAc (-200 mL), washed with cold H2O (-50 mL), cold saturated aqueous NaHC03 (-50 mL) and cold brine (-50 mL). The organic layer was then dried over anhydrous MgS04 and concentrated to dryness to give the methyl ester 6-2 as a white solid, which was used without purification in step 2.
With hydrogenchloride; at 65℃; for 24.16h;
Method 23; Methyl 2-methyl-5-nitrobenzoate; A solution of <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (3.9 g, 21.5 mmol) in MeOH (20 ml) was treated with HCl gas for 10 min. The reaction was then refluxed in a sealed tube at 65 0C for 24 hours. The solvent was evaporated giving a cream coloured solid (4.8 g), which was dissolved in EtOAc (200 ml), washed with water (200 ml), brine (200 ml), and dried (MgSO4). The solvents were removed under reduced pressure to give 3.4 g of a white solid.1H NMR: 8.48 (d, 1 H), 8.27 (dd, 1 H), 7.60 (d, 1 H), 3.87 (s, 3 H), 2.60 (s, 3 H); m/z: 196.
With sulfuric acid; In methanol;Reflux;
<strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (24 g) was dissolved in methanol (240 ml) and concentrated sulfuric acid (8 ml). The mixture was stirred at reflux overnight. Upon cooling the ester crystallized out. The material was isolated by filtration to afford methyl 2-methyl-5-nitrobenzoate as a white solid (19.0 g, 74% yield). A second crop of material (4.92 g, 19% yield) was isolated upon concentration and addition of water to the mother liquor.
Acetyl chloride (15 ml) was added to MeOH (500 ml) at room temperature. After 10 min, <strong>[1975-52-6]2-methyl-5-nitro-benzoic acid</strong> (25.00 g, 138.00 MMOL) was added. The reaction solution was heated for reflux for 18 h. The solution was then concentrated in vacuo. The residue was dissolved in diethyl ether and washed with H20 and saturated aqueous solution of NAHC03 respectively. The organic phase was dried over MGS04 and concentrated in vacuo to provide the title compound as a white solid.
With hydrogenchloride; In 1,4-dioxane;Reflux;
Step A Methyl 2-methyl-5-nitrobenzoate. To a solution of <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (60 g, 331 mmol) in MeOH (400 mL) was added HCl (4 M in dioxane) (10 mL). The mixture was heated at reflux over night. Volatiles were removed and the residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3 and brine, dried (MgSO4) and concentrated to afford the desired product as white powder.
With hydrogenchloride; In 1,4-dioxane;Reflux;
To a solution of <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (6O g, 331 mmol) in MeOH (400 mL) was added HCl (4 M in dioxane) (10 mL). The mixture was heated at reflux over night. Volatlles were removed and the residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3 and brine, dried (MgSO4) and concentrated to afford the desired product as white powder.
With sulfuric acid; for 16h;Reflux;
To a solution of <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (1.0 g, 5.52 mmol) in methanol (10 mL) was added cone. H2S04 (0.5 mL) and the reaction mixture was heated at reflux for 16 h. Then the reaction mixture was concentrated and the residue was diluted with EtOAc. Then the mixture was washed with saturated aqueous NaHC03 solution, water and brine. The organic layer was separated, dried, filtered and concentrated to afford 1.0 g of methyl 2-methyl-5-nitrobenzoate which was used for the next step without further purification. A mixture of methyl 2-methyl-5-nitrobenzoate (1.0 g, 5.12 mmol) and l-ie/t-butoxy- N,N,N',N'-tetramethylmethanediamine (2.23 g, 12.81 mmol) was heated at 1 15 C for 2 h. Then the reaction mixtuer was concentrated and purified by column chromatography to afford 600 mg of (E)-methyl 2-(2-(dimethylamino)vinyl)-5- nitrobenzoate. To a solution of (E)-methyl 2-(2-(dimethylamino)vinyl)-5- nitrobenzoate (600 mg, 2.40 mmol) in toluene (5 mL) was added (2,4- dimethoxyphenyl)methanamine (602 mg, 3.60 mmol) and the reaction mixture was heated at 120 C for 2 h. Then the reaction mixture was concentrated and the residue was triturated with EtOAc: Et20 (1 :9) and the solid precipitate was filtered and dried to afford 700 mg of the title product. 1H NMR (400 MHz, DMSO- 6): delta 9.32-9.31 (d, = 2.4 Hz, 1H), 8.41-8.38 (dd, = 2.4, 8.8 Hz, 1H), 7.62-7.60 (d, = 9.6 Hz, 1H), 7.48-7.46 (d, J = 7.2 Hz, 1H), 7.44-7.42 (d, J = 8.0 Hz, 1H), 6.52-6.49 (m, 3H), 5.15 (s, 2H), 3.86 (s, 3H), 3.82 (s, 3H).
With thionyl chloride; at 70℃; for 3h;
To a solution of <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (62.1) (3.0 g, 16.6 mmol) in methanol (30 mL) was added thionyl chloride (10 mL). The reaction mixture was stirred at 70 C for 3 h. TLC showed the reaction was complete. The excess thionyl chloride was removed. The reaction mixture was quenched with the addition of water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated to afford the crude product. The crude methyl 2-methyl-5-nitrobenzoate (62.2) was used in the next step without further purification (3.18 g, 98%). [00884] 1HNMR (400 MHz, CDCl3): delta 2.72 (s, 3H), 3.95 (s, 3H), 7.43 (d, 1H), 8.23 (dd, 1H), 8.78 (d, 1H).
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 83℃; for 5.0h;
To a solution of methyl 2-methyl-5-nitrobenzoate (6.4 g, 32.76 mmol) in CCI4 (80 ml_) were added NBS (6.4 g, 36.1 mmol) and BPO (794 mg, 3.28 mol). The resulting mixture was stirred at 83C for 5 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with EtOAc (150 mL), washed with H2O (120 ml_ x 3). The organic phase was dried and concentrated to give methyl 2-(bromomethyl)-5-nitrobenzoate (8.5 g, 95.5 %) as a brown oil which was used directly for the next step without further purification. LCMS (method B): 2.59 min [M+Na]+= 295.9,297.9
89%
With N-Bromosuccinimide;dibenzoyl peroxide; In tetrachloromethane; for 34.0h;Reflux;
2-Bromomethyl-5-nitrobenzoic Acid Methyl Ester (36). Compound 35 (100 mg, 0.53 mmol) was dissolved in CCl4 (4 mL), followed by addition of NBS (100 mg, 0.58 mmol) and a catalytic amount of benzoyl peroxide. The mixture was stirred at reflux for 24 h. Another portion, of dibenzoyl peroxide (40 mg, 0.23 mmol) was added and then the mixture was stirred and heated at reflux for another 10 h. The mixture was allowed to cool to 23 C. and was filtered. The filtrate was washed with NaHCO3, dried over Na2SO4, and the solvent evaporated in vacuo. The residue was purified by silica gel column chromatography to afford compound 36 in 89% yield. 1H NMR (400 MHz, CDCl3): delta 8.81 (d, 1H, J=2.5 Hz), 8.33 (dd, 1H, J=8.5, 2.5 Hz), 7.68 (d, 1 H, 8.5 Hz), 5.00 (s, 2H), 4.01 (s, 3H).
85%
With N-Bromosuccinimide; azobisisobutyronitrile; In 1,1-dichloroethane; for 3.0h;Photoirradiation;
Methyl 2-methyl-5-nitrobenzoate (2.0 g, 10.2 mmol) NBS (2.73 g, 15.3 mmol) and AIBN (50 mg) were dissolved in dichloroethane (100 mL). The mixture was irratiated with a photolamp for 3h. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by silica gel chromatography [(HEPTANE/ETOAC] 1/0,19/1, 9/1) to afford 2. 40 g (85%) of methyl [2- (BROMOMETHYL)-5-NITROBENZOATE.]
84%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In benzene;Reflux;
N- B ro m os ucc i n i m i de (5.0 g, 28 mmol, 1.1 eq.) was added to a solution of methyl 2-methyl-5-nitrobenzoate (5.0 g, 25 mmol, 1.0 eq.) and AIBN (410 mg, 2.5 mmol, 0.1 eq.) in benzene (40 mL) and the mixture refluxed overnight. The suspension was cooled to room temperature, the solvent evaporated under reduced pressure and the residue partitioned between EtOAc (50 mL) and H20 (50 mL). The organic phase was washed with brine (100 mL), dried (MgSC ), filtered and the solvent evaporated under reduced pressure. The residue was purified by column chromatography (0- 100% EtOAc:hexane) to give methyl 2-(bromomethyl)-5-nitrobenzoate (EC2-053) as an off- white solid (5.9 g, 84%). lH NMR (500 MHz, DMSO- e) d 8.59 (d, 7 = 2.6 Hz, 1H), 8.43 (dd, 7 = 8.5, 2.6 Hz, 1H), 7.91 (d, 7 = 8.5 Hz, 1H), 5.10 (s, 2H), 3.94 (s, 3H); HPLC-MS (ESI+): m/z 296.0 and 298.0 [40%, (M+Na)+] (See WO2017/197056.)
61%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 18.0h;Heating / reflux;
Part A. Preparation of methyl 2-((diethoxyphosphoryl)methyl)-5-nitrobenzoate.; [00689] To a solution of methyl 2-methyl-5-nitrobenzoate (0.40 g, 2.05mmol) in CCl4 (20ml) was addedN-bromosuccinimide (365mg, 2.05mmol) and 2,2'-azobisisobutyronitrile (34mg, 0.21mmol). The resulting mixture was stirred at reflux for 18h, cooled to room temperature and partitioned betweenEtOAc (50ml) and H2O (50ml). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 1:3 EtOAc:hexanes as the eluent to give the bromide as an oil (345mg, 61%).
57%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In 1,2-dichloro-ethane; at 80℃; for 1.0h;
To a solution of methyl 2-methyl-5-nitrobenzoate (compound 7.1, 10.00 g, 51.24 mmol) in 1 ,2-dichloroethane (100 mL) was added NBS (13.678 g, 76.86 mmol) and AIBN (420.68 mg, 2.56 mmol). The reaction mixture was stirred at 80 C for 1 hour. TLC (15% EtOAc in petroleum ether, Rf = 0.6) showed the starting material consumed, two new spots found. The mixture was concentrated and purified by flash chromatography (0-10% EtOAc in petroleum ether) to afford methyl 2-(bromomethyl)-5-nitro-benzoate (compound 7.2, 8.00 g, 57%) as a yellow solid. NMR (400 MHz,CDCl3) delta 8.82-8.81 (d, J = 2.8 Hz, 1H), 8.34-8.31 (m, 1H), 7.69-7.67 (d, J = 8.4 Hz, 1H), 4.99 (s, 2H), 4.00 (s, 3H).
57%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In 1,2-dichloro-ethane; at 80℃; for 1.0h;
To a solution of methyl 2-methyl-5-nitrobenzoate (comound 9.1, 10.00 g, 51.24 mmol) in 1 ,2-dichloroethane (100 mL) was added NBS (13.678 g, 76.86 mmol) and AIBN (420.68 mg, 2.56 mmol). The reaction mixture was stirred at 80 C for 1 hour. TLC (15% EtOAc in petroleum ether, Rf = 0.6) showed the starting material consumed, two new spots found. The mixture was concentrated and purified by flash chromatography (0-10% EtOAc in petroleum ether) to afford methyl 2-(bromomethyl)-5-nitro-benzoate (compound 9.2, 8.00 g, 57%) as a yellow solid. lH NMR (400 MHz,CDCl3) delta 8.82-8.81 (d, J = 2.8 Hz, 1H), 8.34-8.31 (m, 1H), 7.69-7.67 (d, J = 8.4 Hz, 1H), 4.99 (s, 2H), 4.00 (s, 3H).
57%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In 1,2-dichloro-ethane; at 80℃; for 1.0h;
[0337] To a solution of Compound 15.1 (10.00 g, 51.24 mmol) in l,2-dichloroethane (100 mL) was added NBS (13.678 g, 76.86 mmol) and AIBN (420.68 mg, 2.56 mmol). The reaction mixture was stirred at 80 C for 1 hour. TLC (15% EtOAc in petroleum ether, Rf = 0.6) showed the starting material consumed, two new spots found. The mixture was concentrated and purified by flash chromatography (0-10% EtOAc in petroleum ether) to afford Compound 15.2 (8.00 g, 57%) as a yellow solid. 1H NMR (400 MHz, CDCl3) d 8.82-8.81 (d, J= 2.8 Hz, 1H), 8.34-8.31 (m, 1H), 7.69-7.67 (d, J= 8.4 Hz, 1H), 4.99 (s, 2H), 4.00 (s, 3H).
With N-Bromosuccinimide; azobisisobutyronitrile; In chloroform;
Methyl 6-Bromomethyl-3-nitrobenzoate (2-3) 3-Nitro-6-methylbenzoic acid (2-1) (Aldrich) was converted into methyl 3-nitro-6-methylbenzoate (2-2) using the standard procedure of MeOH and HCl gas. To a mixture of methyl 3-nitro-6-methylbenzoate (2-2) (2.0 g, 10.3 mmol) and N-bromosuccinimide (1.64 g, 9.23 mmol) in CHCl3 was added AIBN (20 mg) and this was then photolysed at reflux for 4 hours. The reaction was cooled, filtered and the filtrate evaporated to dryness. Chromatography of the residue (silica, hexane/EtOAc 92:8) afforded 2-3 as a solid (1.56 g). Rf (silica; hexane/EtOAc 10:1)=0.25. STR57
1.9 g
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 90℃; for 5.0h;
To a solution of methyl 2-methyl-5-nitrobenzoate (62.2) (1.5 g, 7.7 mmol) in carbon tetrachloride (30 mL) was added N-bromosuccinimide (NBS) (1.5 g, 8.42 mmol) and azobisisobutyronitrile (AIBN) (124 mg, 0.76 mmol). The reaction mixture was stirred at 90 C for 5 h. TLC showed the reaction was complete. The reaction mixture was filtered, and the filtrate was quenched with the addition of water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, and concentrated to afford the crude product. The crude product was purified by column chromatography (DCM) to afford methyl 2-(bromomethyl)-5-nitrobenzoate (62.3) as a yellow solid (1.9 g, 90%). [00887] LCMS: 314.0 [M+1]+.
With lithium hydroxide; water; In tetrahydrofuran; at 30℃; for 4h;
To a solution of compound 3 (75.0 g, 0.46 mol) in THF (500 mL) was added 1 N aq. LiOH (1 L, 0.92 mol), then the mixture was stirred at 30Cfor 4 hours. TLC (petroleum ether: ethyl acetate = 10:1 ) showed the reaction was complete, then the mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (200 mLx2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give compound 4 (67 g, 98%) as a brown solid., which was used in the next step without further purification. 1H NMR (400 MHz, CDCI3): delta 8.93 (S, 1 H), 8.30-8.32 (d, J = 8.0 Hz, 1 H), 7.48- 7.50 (d, J = 8.0 Hz, 1 H), 2.79 (s, 3H).
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃;
A solution of <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (15 g, 82.8 mmole) in DMF (75 mL) was treated with methyl iodide (6.7 mL, 107.64 mmole) followed by powdered K2CO3 (17.2 g, 124.2 mmole) (extreme exotherm) and the suspension stirred at ambient temperature overnight. The reaction mixture was partitioned between EtOAc and water, the organics separated and washed with water and brine, dried (Na2SO4) and concentrated in vacuo to yield K1 (15.86 g, 98%) in pure form as an off-white solid. The 1H NMR was consistent with that of the desired structure.
94%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
4.2.1 Methyl-2-methyl-5-nitrobenzoate (2) To a mixture of <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (15 g, 82.8 mmol) and K2CO3 (17.2 g, 124.2 mmol) in 75 mL DMF was added iodomethane (6.7 mL). The mixture was stirred at room temperature overnight. Then, 500 mL water was added into the mixture, the aqueous phase was extracted with EA for three times. The combined organic phase was dried with Na2SO4, concentrated to afford the product 2 (15.3 g, 94%) as yellow solid. 1H NMR (400 MHz, CDCl3) delta 8.52 (s, 1H), 8.05 (s, 1H), 7.30 (s, 1H), 3.83 (s, 3H), 2.56 (s, 3H). ESI-MS m/z 196 [M+H]+.
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 40℃; for 1h;
A mixture of 6 (2.0 g, 9.6 mmol) iodomethane (1.2 mL), potassium carbonate (4.0 g) and DMF (10 mL) was stirred at 40 C. for 1 hour. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water twice (100 mL each) followed by brine (100 mL), dried (Na2SO4), and evaporated to give ester 15.
With potassium carbonate; In acetone;
PREPARATION 33 2-Methyl-5-(1H-tetrazol-1-yl)benzoic Acid Combine <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (4.98 g, 27.5 mmol), potassium carbonate (1.93 g, 14.0 mol), and methyl iodide (7.80 g, 55.0 mmol) in acetone (100 mL). Heat to reflux. After 4 hours, cool the reaction mixture, dilute with water, and extract five times with ethyl acetate. Combine the organic layers, extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give methyl 2-methyl-5-nitrobenzoate: Rf=0.61 (silica gel, ethyl acetate/hexane 1/1).
With potassium carbonate; In acetone;
PREPARATION 8 2-Methyl-5-(1H-tetrazol-1-yl)benzoic acid Combine <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (4.98 g, 27.5 mmol), potassium carbonate (1.93 g, 14.0 mol), and methyl iodide (7.80 g, 55.0 mmol) in acetone (100 mL). Heat to reflux. After 4 hours, cool the reaction mixture, dilute with water, and extract five times with ethyl acetate. Combine the organic layers, extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over Na2 SO4, filter, and evaporate in vacuo to give methyl 2-methyl-5-nitrobenzoate: Rf =0.61 (silica gel, ethyl acetate/hexane 1/1).
With potassium carbonate; In acetone;
PREPARATION 8 2-Methyl-5-(1H-tetrazol-1-yl)benzoic acid Combine <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (4.98 g, 27.5 mmol), potassium carbonate (1.93 g, 14.0 mol), and methyl iodide (7.80 g, 55.0 mmol) in acetone (100 mL). Heat to reflux. After 4 hours, cool the reaction mixture, dilute with water, and extract five times with ethyl acetate. Combine the organic layers, extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give methyl 2-methyl-5-nitrobenzoate: Rf=0.61 (silica gel, ethyl acetate/hexane 1/1).
With potassium carbonate; In acetone;
Preparation 33 2-Methyl-5-(1H-tetrazol-1-yl)benzoic Acid Combine <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (4.98 g, 27.5 mmol), potassium carbonate (1.93 g, 14.0 mol), and methyl iodide (7.80 g, 55.0 mmol) in acetone (100 mL). Heat to reflux. After 4 hours, cool the reaction mixture, dilute with water, and extract five times with ethyl acetate. Combine the organic layers, extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give methyl 2-methyl-5-nitrobenzoate: Rf=0.61 (silica gel, ethyl acetate/hexane 1/1).
With potassium carbonate; In acetone;
PREPARATION 33 2-Methyl-5-(1H-tetrazol-1-yl)benzoic acid Combine <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (4.98 g, 27.5 mmol), potassium carbonate (1.93 g, 14.0 mol), and methyl iodide (7.80 g, 55.0 mmol) in acetone (100 mL). Heat to reflux. After 4 hours, cool the reaction mixture, dilute with water, and extract five times with ethyl acetate. Combine the organic layers, extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give methyl 2-methyl-5-nitrobenzoate: Rf=0.61 (silica gel, ethyl acetate/hexane 1/1).
With triethylamine; diphenylphosphinopropane;palladium diacetate; In methanol; at 110℃; under 3000.3 Torr; for 18.0h;
23.2 g (88 mmol) of <strong>[7745-92-8]2-iodo-4-nitrotoluene</strong> are dissolved in 400 ml of anhydrous methanol and then placed in a steel reactor. 25 ml (177 mmol) of triethylamine, 1.97 g (8.8 mmol) of palladium diacetate and 7.3 g of diphenyphosphinopropane are added and the reaction medium is subjected to a carbon monoxide pressure of 4 bar and heated at 110 C. for 18 hours. The medium is then brought to ambient pressure and temperature, dissolved in dichloromethane and filtered on celite. After evaporation, the residue is purified by chromatography on a silica column. An orange-coloured powder is obtained (m=6.3 g, Y=37%).
With hydrogenchloride; In dichloromethane; water; for 96.0h;Heating / reflux;
To a solution of compound 2 (64.0 g, 0.39 mol) in MeOH (1500 mL), H2O (50 mL) and CH2CI2 (500 mL) was purged with HCI gas till the solution was saturated. The mixture was left standing for 48 hours, then refluxed for 48 hours. TLC (petroleum ether: ethyl acetate = 10:1) showed the reaction was complete, then the mixture was concentrated in vacuo to give crude product, which was purified by column chromatography (first petroleum ether, then petroleum ether: ethyl acetate 1 :1) to afford compound 3 (33 g, yield: 82%) as a yellow solid and recover compound 2 (42 g) as a grey solid. 1H NMR (400 MHz, CDCI3): 1H NMR delta 8.76 (S, 1 H), 8.22- 8.24 (dd, J = 8.0 Hz, 1 H), 7.42-7.44 (d, J = 8.0 Hz, 1 H), 3.95 (s, 3H), 2.71 (s, 3H).
With dibenzoyl peroxide; In tetrachloromethane; water;
Step 2: Sodium 2-carbomethoxy-4-nitrobenzyl sulphonate : A mixture of methyl 2-methyl-5-nitrobenzoate (2.51g, 12.9mmol) and benzoyl peroxide (containing approx. 25% water) (164mg, 0.51mmol) in carbon tetrachloride (50ml) was purged with nitrogen before removing 12ml of the solvent by distillation. N-Bromosuccinimide (2.30g, 12.9mmol) was then added in small portions to the refluxing mixture under irradiation (60W) and the mixture heated at reflux for 2.5h under nitrogen. The succinimide was removed by filtration and the filtrate evaporated in vacuoto give crude methyl 2-bromomethyl-5-nitrobenzoate (3.67g) as a yellow oil.
7.B
Intermediate 7B: [00206] A mixture of Intermediate 7A (2.38 g, 12.19 mmol) and l-tert- butoxy-N,N,N',N'-tetramethylmethanediamine (5.79 mL, 28.0 mmol) was heated at 115 0C (no solvent) for 3.5 h. After the mixture was cooled to rt, it was triturated with hexanes/EtOAc (6 : 1). After over night standing at room temperature, the precipitate was collected by filtration to give solid Intermediate 7B (2.73 g, 90% yield). 1H NMR (400 MHz, CDCl3) δ ppm 2.99 (s, 6 H) 3.89 (s, 3 H) 6.39 (d, J=13.18 Hz, 1 H) 7.17 (d, J=13.62 Hz, 1 H) 7.43 (d, J=9.23 Hz, 1 H) 8.03 (dd, J=9.23, 2.64 Hz, 1 H) 8.70 (d, J=2.64 Hz, 1 H).
90%
at 115℃; for 3.5h; Neat (no solvent);
Intermediate 3B:; [00196] A mixture of Intermediate 3A (2.38 g, 12.19 mmol) and -tert- butoxy-N,N,N',N'-tetramethylmethanediamine (5.79 mL, 28.0 mmol) was heated at 115 0C (no solvent) for 3.5 h. After the mixture was cooled to rt, it was triturated with hexanes/EtOAc (6 : 1). After over night standing at rt, the precipitate was collected by filtration to give solid Intermediate 3B (2.73 g, 90% yield).
90%
In neat (no solvent) at 115℃; Inert atmosphere;
600 mg
at 115℃; for 2h;
1 Step 1: Preparation of 2-(2,4-dimethoxybenzyl)-7-nitroisoquinolin-1(2H)-one
To a solution of 2-methyl-5-nitrobenzoic acid (1.0 g, 5.52 mmol) in methanol (10 mL) was added cone. H2S04 (0.5 mL) and the reaction mixture was heated at reflux for 16 h. Then the reaction mixture was concentrated and the residue was diluted with EtOAc. Then the mixture was washed with saturated aqueous NaHC03 solution, water and brine. The organic layer was separated, dried, filtered and concentrated to afford 1.0 g of methyl 2-methyl-5-nitrobenzoate which was used for the next step without further purification. A mixture of methyl 2-methyl-5-nitrobenzoate (1.0 g, 5.12 mmol) and l-ie/t-butoxy- N,N,N',N'-tetramethylmethanediamine (2.23 g, 12.81 mmol) was heated at 1 15 °C for 2 h. Then the reaction mixtuer was concentrated and purified by column chromatography to afford 600 mg of (E)-methyl 2-(2-(dimethylamino)vinyl)-5- nitrobenzoate. To a solution of (E)-methyl 2-(2-(dimethylamino)vinyl)-5- nitrobenzoate (600 mg, 2.40 mmol) in toluene (5 mL) was added (2,4- dimethoxyphenyl)methanamine (602 mg, 3.60 mmol) and the reaction mixture was heated at 120 °C for 2 h. Then the reaction mixture was concentrated and the residue was triturated with EtOAc: Et20 (1 :9) and the solid precipitate was filtered and dried to afford 700 mg of the title product. 1H NMR (400 MHz, DMSO- 6): δ 9.32-9.31 (d, = 2.4 Hz, 1H), 8.41-8.38 (dd, = 2.4, 8.8 Hz, 1H), 7.62-7.60 (d, = 9.6 Hz, 1H), 7.48-7.46 (d, J = 7.2 Hz, 1H), 7.44-7.42 (d, J = 8.0 Hz, 1H), 6.52-6.49 (m, 3H), 5.15 (s, 2H), 3.86 (s, 3H), 3.82 (s, 3H).
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