* 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] Chemische Berichte, 1884, vol. 17, p. 161
5
[ 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).
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1901, vol. 20, p. 169
[2] Chemische Berichte, 1883, vol. 16, p. 1959[3] Chemische Berichte, 1884, vol. 17, p. 164
[4] Chemische Berichte, 1884, vol. 17, p. 161
[5] Justus Liebigs Annalen der Chemie, 1870, vol. 156, p. 235
[6] Justus Liebigs Annalen der Chemie, 1873, vol. 168, p. 246
[7] Chemische Berichte, 1883, vol. 16, p. 1959[8] Chemische Berichte, 1884, vol. 17, p. 164
[9] Gazzetta Chimica Italiana, 1935, vol. 65, p. 840,842
[10] Chemische Berichte, 1883, vol. 16, p. 1959[11] Chemische Berichte, 1884, vol. 17, p. 164
[12] Tetrahedron Letters, 2002, vol. 43, # 27, p. 4789 - 4791
[13] Tetrahedron Letters, 2008, vol. 49, # 28, p. 4449 - 4451
[14] Tetrahedron Letters, 2011, vol. 52, # 13, p. 1452 - 1455
7
[ 99-51-4 ]
[ 1975-52-6 ]
Reference：
[1] Chemical Communications, 1998, # 1, p. 73 - 74
8
[ 118-90-1 ]
[ 1975-52-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3420 - 3422
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 17, p. 5004 - 5008
9
[ 7745-93-9 ]
[ 1975-52-6 ]
Reference：
[1] Patent: WO2006/117669, 2006, A1,
10
[ 939-83-3 ]
[ 1975-52-6 ]
Reference：
[1] Journal of the Indian Chemical Society, 1937, vol. 14, p. 144,150
[2] Patent: WO2006/117669, 2006, A1,
11
[ 529-19-1 ]
[ 1975-52-6 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1873, vol. 168, p. 246
12
[ 95-47-6 ]
[ 1975-52-6 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1870, vol. 156, p. 235
13
[ 619-04-5 ]
[ 1975-52-6 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1870, vol. 156, p. 235
14
[ 89-71-4 ]
[ 59382-59-1 ]
[ 1975-52-6 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1901, vol. 20, p. 169
15
[ 99-51-4 ]
[ 7697-37-2 ]
[ 1975-51-5 ]
[ 1975-52-6 ]
Reference：
[1] Chemische Berichte, 1884, vol. 17, p. 161
16
[ 1975-52-6 ]
[ 74-88-4 ]
[ 77324-87-9 ]
Yield
Reaction Conditions
Operation in experiment
98%
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,
17
[ 67-56-1 ]
[ 1975-52-6 ]
[ 77324-87-9 ]
Yield
Reaction Conditions
Operation in experiment
99%
at 0℃; Reflux
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
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1984, vol. 23, # 11, p. 1098 - 1102
20
[ 1975-52-6 ]
[ 90725-68-1 ]
Reference：
[1] European Journal of Medicinal Chemistry, 1991, vol. 26, # 7, p. 699 - 707
[2] Patent: US2011/269834, 2011, A1,
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8561 - 8578
[4] Patent: WO2016/90079, 2016, A1,
21
[ 1975-52-6 ]
[ 103440-54-6 ]
Reference：
[1] Patent: WO2006/117669, 2006, A1,
22
[ 1975-52-6 ]
[ 54811-38-0 ]
Reference：
[1] Patent: WO2006/117669, 2006, A1,
23
[ 1975-52-6 ]
[ 18595-12-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 10, p. 2823 - 2827
[2] Journal of the American Chemical Society, 2003, vol. 125, # 40, p. 12074 - 12075
[3] Journal of Medicinal Chemistry, 2011, vol. 54, # 2, p. 635 - 654
[4] Patent: US2011/269834, 2011, A1,
24
[ 1975-52-6 ]
[ 2840-04-2 ]
Yield
Reaction Conditions
Operation in experiment
96%
With hydrogen In methanol at 40℃; for 3 - 4 h;
A mixture of compound 4 (30.0 g, 0.166 mol) and Pd/C (1.8 g) in dry methanol (1600 mL) was stirred under 50 Psi of H2 at 40sC for 3 to 4 hours. TLC (petroleum ether: ethyl acetate = 1 :2) showed the reaction was complete, then the mixture was filtered and the filtrate was concentrated in vacuo to give compound 5 (24 g, 96percent) as a white solid. 1H NMR (400 MHz, CDCI3): δ 7.10 (S, 1H), 6.89-6.91 (d, J = 8.0 Hz, 1 H), 6.64-6.66 (dd, J = 8.0 Hz, 1H), 2.31 (s, 3H).
95%
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.
Reference：
[1] Journal of Medicinal Chemistry, 1996, vol. 39, # 17, p. 3343 - 3356
[2] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 23, p. 6273 - 6278
[3] Patent: WO2006/117669, 2006, A1, . Location in patent: Page/Page column 41; 114
[4] Tetrahedron, 2018, vol. 74, # 47, p. 6795 - 6803
[5] Chemische Berichte, 1883, vol. 16, p. 1959[6] Chemische Berichte, 1884, vol. 17, p. 164
[7] Bulletin de la Societe Scientifique de Bretagne, 1956, vol. 31, p. Sonderheft S.9,41
[8] Bulletin de la Societe Chimique de France, 1966, p. 1848 - 1858
[9] Journal of Organic Chemistry, 1988, vol. 53, # 1, p. 98 - 104
[10] Tetrahedron Letters, 1991, vol. 32, # 39, p. 5379 - 5382
[11] Patent: EP2103620, 2009, A1, . Location in patent: Page/Page column 67
[12] Patent: WO2010/55083, 2010, A1, . Location in patent: Page/Page column 108
[13] Patent: US2007/72862, 2007, A1, . Location in patent: Page/Page column 70-71
[14] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8561 - 8578
[15] Patent: CN106083601, 2016, A, . Location in patent: Paragraph 0075-0078
With hydrogen;palladium on activated charcoal; In methanol; at 40℃; under 2585.81 Torr; for 3 - 4h;
A mixture of compound 4 (30.0 g, 0.166 mol) and Pd/C (1.8 g) in dry methanol (1600 mL) was stirred under 50 Psi of H2 at 40sC for 3 to 4 hours. TLC (petroleum ether: ethyl acetate = 1 :2) showed the reaction was complete, then the mixture was filtered and the filtrate was concentrated in vacuo to give compound 5 (24 g, 96%) as a white solid. 1H NMR (400 MHz, CDCI3): delta 7.10 (S, 1H), 6.89-6.91 (d, J = 8.0 Hz, 1 H), 6.64-6.66 (dd, J = 8.0 Hz, 1H), 2.31 (s, 3H).
95%
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 tetrahydrofuran; ethyl acetate; at 20℃;
To a solution of 2-methyl-5-nitrobenzoic acid (9.95 g) in ethyl acetate (100 mL)/tetrahydrofuran (100 mL) was added 10% palladium/activated carbon (50% water-containing product, 1.0 g) under hydrogen stream, and the mixture was stirred at room temperature overnight. The catalyst was filtered off, and the filtrate was concentrated. The obtained residue was filtered with ethyl acetate/hexane to give the title compound (8.17 g) as a colorless powder. 1H-NMR (DMSO-d6) delta: 2.32 (3H, s), 5.05 (2H, br s), 6.63 (1H, dd, J = 2.5 Hz, 8.1 Hz), 6.91 (1H, d, J = 8.1 Hz), 7.07 (1H, d, J = 2.5 Hz)
With hydrogen;5% Pd(II)/C(eggshell); In ethanol; at 20℃;
Step 1 : 5-Amino-2-methylbenzoic acid 5.24 g of 2-methyl-5-nitrobenzoic acid are dissolved in 250 ml of ethanol, 0.5 g palladium on charcoal (5%) are added, and the reaction mixture is stirred under an atmosphere of hydrogen at RT over night, until the reaction is completed according to TLC analysis. The mixture is filtered over a plug of celite, and the solvent is removed under reduced pressure resulting in the crude 5-amino-2-methylbenzoic acid, which is used for the next step without further purification.
With hydrogen;palladium 10% on activated carbon; In ethanol; ethyl acetate; under 760.051 Torr; for 44h;
To a 250 mL round-bottomed flask was added 2-methyl-5-nitrobenzoic acid (5.0 g, 28 mmol) and palladium 10% on carbon (1.5 g, 14 mmol). The mixture was taken up in EtOAc (30 mL) then EtOH (70 mL) was added. The mixture was purged with H2 then allowed to stir at 1 atm. H2 for 24 h. LCMS indicated about 10% conversion to product. About 0.5 g 10% Pd/C and ~30 mL MeOH was added to the reaction. The reaction was purged with H2 and let to stir at 1 atm H2 for 20 h. They reaction was monitored for complete conversion by LCMS. The mixture was passed through a pad of celite, washing with MeOH and concentrated to afford 5-amino-2-methylbenzoic acid as an off-white solid MS m/z found 152-1 (ESI, neg. ion).
With hydrogen; In isopropyl alcohol; at 50℃; for 1.16667h;Autoclave;
Example 14: Take 5.4ml Fe (NO3)2· 9H2O(0.03mol/L)5.7ml RuCl3 (0.01mol / L) 7.9ml Cu (NO3)2· 3H2O solution (0.03mol / L), silicon carbide and weighing 0.27g were mixed and stirred at room temperature for 12h, evaporated to dryness, and then dried at 110 deg.] C 12h, and finally placed in a tube furnace at 500 under with H2/ Ar (5:95) reducing 5h, gas flow rate was 20mL / min, to obtain 0.3g of iron loading of 3wt%, ruthenium 2wt%, 5wt% of copper supported metal iron carbide - Ru - copper catalyst, wherein the iron - ruthenium - copper ternary metal nanoparticle particle size of 63 nm. 13 g of 2-methyl-5-nitrobenzoic acid and 50 mL of isopropanol were mixed at a mass ratio of 0.33, and 0.3 g of the above catalyst (the mass ratio of the catalyst to 2-methyl-5-nitrobenzoic acid was 0.023 ), And the suspension was transferred to a high-pressure autoclave with a quartz window. The reactor was sealed and purged with hydrogen. The flow rate of hydrogen was maintained at 30 mL / min under normal pressure (total intake and 2-methyl-5-nitrobenzoic acid molar ratio of 1.31), the reaction was heated to 50 C under stirring, reacted with an artificial light source with simulated intensity of 3.5 W / cm2, Time 70min. The conversion of 2-methyl-5-nitrobenzoic acid was 82%, the selectivity of 2-methyl-5-aminobenzoic acid was 100%
With thionyl chloride; N,N-dimethyl-formamide; for 4h;Inert atmosphere; Reflux;
To a solution of <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (3.0 g, 16.6 mmol) in thionyl chloride (15 mL) kept under nitrogen atmosphere, was added N,N- dimethylformamide (1 drop). The mixture was heated to reflux for 4 h. The mixture was diluted with dichloromethane (20 mL) and concentrated to dryness to give a white solid (3.3 g, quantitative).
With hydrogenchloride; In thionyl chloride;
Part A. A 1-L flask equipped with a reflux condenser and a nitrogen sweep to an HCl gas scrubber was charged with <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (200 g, 1.10 mol). The reaction vessel was cooled in an ice bath and thionyl chloride (307 mL, 4.20 mol) was added in one portion. The ice bath was removed, and the reaction mixture was refluxed overnight. The excess thionyl chloride and the SO2 and HCl reaction side-products were removed by vacuum distillation to afford 2-methyl-5-nitrobenzoyl chloride as a solid residue, which was used without further purification.
With thionyl chloride; In hexane; toluene;
EXAMPLE 8 4,4'-[Ureylenebis(6-methyl-3,1-phenylenecarbonylimino)]bis[5-hydroxy-2,7-naphthalenedisulfonic acid]tetrasodium salt A mixture of 74.5 g of <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> and 160 ml of thionyl chloride is refluxed for 41/2 hours (complete solution after 11/2 hours). The mixture is evaporated in vacuo to an oil, then is reevaporated several times with toluene, finally about 300 ml of hexane is added resulting in formation of needles after standing at room temperature overnight. The material is collected by filtration and is washed with hexane to give 5-nitro-o-toluoyl chloride.
With thionyl chloride; In hexane; toluene;
EXAMPLE 10 4-Hydroxy-5-(5-nitro-o-toluamido)-2,7-naphthalenedisulfonic acid, disodium salt A mixture of 74.5 g of <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> and 160 ml of thionyl chloride is refluxed for 41/2 hours (complete solution after 11/2 hours). The mixture is evaporated in vacuo to an oil then is reevaporated several times with toluene, finally about 300 ml of hexane is added resulting in formation of needles after standing at room temperature overnight. The material is collected by filtration and is washed with hexane to give 5-nitro-o-toluoyl chloride.
With thionyl chloride; In hexane; toluene;
EXAMPLE 3 4,4'-[Ureylenebis[(6-methyl-3,1-phenylenecarbonyl)imino]]bis[5-hydroxy-2,7-naphthalenedisulfonic acid ] tetrasodium salt A mixture of 74.5 g of <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> and 160 ml of thionyl chloride is refluxed for 41/2 hours (complete solution after 11/2 hours). The mixture is evaporated in vacuo to an oil then is reevaporated several times with toluene, finally about 300 ml of hexane is added resulting in formation of needles after standing at room temperature overnight. The material is collected by filtration and is washed with hexane to give 5-nitro-o-toluoyl chloride.
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h;
Example e) 2-Methyl-5-nitro-N-(2-phenyl-3H-imidazo[4,5-b]pyridin-6-yl)- benzamidel; Analogous to Example c) from 1.74 g 2-phenyl-3H-imidazo[4,5-b]pyridin-6- ylamine and 3,3 Ig 2-methyl-5-nitrobenzoyl chloride, which was prepared as follows: To 3.00 g <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> in 50 ml dichloromethane were added one drop of DMF and then dropwise at room temperature 2.52 g oxalyl chloride. The mixture was stirred for 2 hrs and then evaporated to give a residue of 3.558 g crude 2-methyl-5-nitrobenzoyl chloride. Yield 1.878 g of the title product
With thionyl chloride;N,N-dimethyl-formamide; In dichloromethane; at 80℃; for 3.5h;
Intermediate 7: 7-aminoisoquinolin-l(2H)-oneIntermediate; 7A: [00205] To <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (2.69 g, 14.85 mmol) in CH2Cl2 (40 mL) was added thionyl chloride (5.42 mL, 74.2 mmol) and DMF (0.5 mL). The mixture was stirred at 80 0C (oil bath) for 3.5 h. After it was cooled to rt, the solvent was removed and the residue was azeotroped with toluene. The crude solid acyl chloride was dried in vacuo for 20 min. It was then dissolved in CH2Cl2 (20 mL) and MeOH (10 mL) and stirred at rt for 30 min. Solvent was removed and the residue was diluted in EtOAc/hexanes, washed with sat. NaHCO3, brine, dried over Na2SO4. After evaporation of the solvent, Intermediate 7A (2.8 g) was obtained as a white solid. 1H NMR (400 MHz, CDCl3) delta ppm 2.70 (s, 3 H) 3.93 (s, 3 H) 7.42 (d, J=8.35 Hz, 1 H) 8.22 (dd, J=8.57, 2.42 Hz, 1 H) 8.76 (d, J=2.20 Hz, 1 H). It was used for next step without purification.
With thionyl chloride;N,N-dimethyl-formamide; In dichloromethane; at 80℃; for 3.5h;
Intermediate 3: 7-aminoisoquinolin-l(2H)-one; Intermediate 3A:; [00195] To <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (2.69 g, 14.85 mmol) in CH2Cl2 (40 mL) was added thionyl chloride (5.42 mL, 74.2 mmol) and DMF (0.5 mL). The mixture was stirred at 80 0C (oil bath) for 3.5 h. After it was cooled to rt, the solvent was removed and the residue was azeotroped with toluene. The crude solid acyl chloride was dried in vacuo for 20 min. It was then dissolved in CH2Cl2 (20 mL) and MeOH (10 mL) and stirred at rt for 30 min. Solvent was removed and the residue was diluted in EtOAc/hexanes, washed with sat. NaHCO3, brine, dried over Na2SO4. <n="90"/>After evaporation of the solvent, Intermediate 3 A (2.8 g) was obtained as a white solid that was used for next step without purification.
With thionyl chloride;pyridine; at 50℃; for 2h;
Preparation of intermediate 56; Intermediate 51; lambda/-(2-hydroxyethyl)-2-methyl-5-nitrobenzamide; <n="52"/>Thio?yl chloride (2.4 ml_, 33.0 mmol) and 1 drop of pyridine was added to 2-methyI- 5-nitrobenzoic acid (1 g, 5.5 mmol). The mixture was heated at 50 C for 2 h, and evaporated under reduced pressure to provide the acid chloride as a white solid. To a solution of the acid chloride in 5 mL CH2CI2 was slowly added 2-aminoethanol (0.6 g, 9.8 mmol). The reaction mixture was stirred at RT for 24 h, filtered, and washed with CH2CI2. The filtrate was washed with satd. aq. NaHCO3, dried (Na2SO4), and concentrated. The residue was purified by silica gel flash column chromatography (5?100% EtOAc : hexanes) to give 51 (670.1 mg, 54% yield) as a white solid. 1H NMR (400 MHz, MeOH-Cf4) delta 8.25 (d, J=2.56 Hz, 1 H), 8.18 (dd, J=8.42, 2.56 Hz, 1 H), 7.49 (d, J=8.42 Hz, 1 H), 3.71 (t, J=5.77 Hz, 2 H), 3.49 (t, J=5.68 Hz, 2 H), 2.50 (s, 3 H). ES-LCMS: m/z 225.2 (M+H).
With thionyl chloride; at 80℃; for 1h;Heating / reflux;
<strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (659 mg, 3.64 mmol) was heated to reflux in SOCl2 (6 mL) for 1 h. After cooling to room temperature and concentrating to dryness, the crude acid chloride was taken up in CH2Cl2 (25 mL). Pyrimidine-2,5-diamine 7 (400 mg, 3.64 mmol) was added to the solution and the mixture was allowed to stir at rt over night. The mixture became a thick white suspension. NEt3 (700 L, 4.73 mmol) was added. After 2 h, a thick-white suspension remained. The mixture was filtered through a Buchner funnel and washed with copious amounts of CH2Cl2 to remove NEt3HCl salt, affording N-(2-aminopyrimidin-5-yl)-2-methyl-5-nitrobenzamide 8 as an off-white solid.
With thionyl chloride; for 2h;Reflux;
General procedure: 4-Ethoxy-3-nitrobenzoic acid 55 (0.21 g, 1.1 mmol) was suspended in SOCl2 (5 mL) and the reaction mixture was heated to reflux for 2 h to give a clear solution. The volatiles were removed under reduced pressure to give 4-ethoxy-3-nitrobenzoyl chloride 56 as a light-yellow solid.
With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide; for 4h;Reflux;
Step 1: N,N,2-trimethyl-5-nitrobenzamide<strong>[1975-52-6]2-Methyl-5-nitrobenzoic acid</strong> (1 g, 5.5 mmol) was dissolved in 50C12 (15 mL), followed by addition of DMF (1 drop). The reaction mixture was refluxed for 4 hours. The solvent was removed under reduced pressure. DCM (10 mL) was added and then the reaction mixture was concentrated under reduced pressure. The DCM addition/concentration cycle was repeated three times to give a white solid. Me2NH.HCI (490 mg, 6.08 mmol) and TEA (1.67 g, 16.6 mmol) were dissolved in DCM (20 mL). 2-methyl-5-nitrobenzoyl chloride (1.09 g, 5.5 mmol) in DCM (5 mL) was added to the mixture slowly at 0C. Thereaction mixture was stirred at room temperature for 16 hours, washed with water (3 x30 mL) and the organics was dried (Na2SO4) and concentrated to give N,N,2-trimethyl-5-nitrobenzamide (600 mg, 52.2%) as a white solid. LCMS (Method B): 1.06 mm [MH]= 208.4.
With oxalyl dichloride; N,N-dimethyl-formamide; at 0 - 20℃;
2-Methyl-5-nitro-benzoyl chloride was prepared by dehydroxychlorination of commercially available <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (1.0 g, 5.5 mmol) in dichloromethane (DCM) (20 mL) with neat oxalyl chloride (C1CO-COC1) in DCM (1.4 mL, 2.1 g, 16.5 mmol mmol) in the presence of catalytic amounts (few small drops) of N,N-dimethylformamide (DMF) at about 0C (ice bath) to room temperature. After the suspension turned into a solution, volatile solvents and reaction products were removed under reduced pressure using a rotary evaporator to provide 1.1 g (-quant, yield) of the target compound as a yellow solid which was of sufficient purity to be used directly and without further isolation and purification procedures. Rf. -0.55 (EtOAc/hexane = 1 :4, v/v). 2-Methyl-5-nitro-benzoyl chloride is also commercially available.
With pyridine; thionyl chloride; at 50℃; for 3h;
Weighing 2 - methyl -5 - nitro benzoic acid 4.52g (25mmol) dissolved in 8 ml thionyl chloride in, dropping 3 drops of pyridine, then in 50 C stirring reaction under 3h, TLC tracking, raw material the reaction is complete, to stop the reaction. Pressure reducing and steaming and remove the thionyl chloride, without processing directly into the next step reaction.
With pyridine; thionyl chloride; at 50℃; for 3h;
4.52 g (24.95 mmol) of <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> was dissolved in 8 mL of thionyl chloride,100 muL of pyridine was added dropwise,Heated to 50 reaction 3h,The thionyl chloride was distilled off under reduced pressure to give 2-methyl-5-nitrobenzoyl chloride (the reaction was carried out without isolation).
With thionyl chloride; In hexane; toluene;
EXAMPLE 10 4Hydroxy-5-(5-nitro-o-toluamido)-2,7-naphthlenedisulfonic acid, disodium salt A mixture of 74.5 g of <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> and 160 ml of thionyl chloride is refluxed for 41/2 hours (complete solution after 11/2 hours). The mixture is evaporated in vacuo to an oil then is reevaporated several times with toluene, finally about 300 ml of hexane is added resulting in formation of needles after standing at room temperature overnight. The material is collected by filtration and is washed with hexane to give 5-nitro-o-toluoyl chloride.
With thionyl chloride;Heating / reflux;
Example 2; Synthesis of substituted 2-methyl-N,N-dimethylbenzamides; a) Preparation of 2,N,N-trimethyl-5-nitrobenzamide (2)The preparation of 2N,N-trimethyl-5-nitrobenzamide utilized the procedure described in U.S. Pat. No. 4,942,163. The reaction mixture of <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (5 g, 27.6 mmol) and thionyl chloride (16.4 g, 138 mmol) was refluxed overnight. The excess thionyl chloride was removed by vacuum distillation to afford 2-methyl-5-nitro-benzoyl chloride as a solid residue.
With oxalyl dichloride; In toluene; at 20℃; for 5h;
To a solution of <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (2.45 g) in toluene (10 mL) was added oxalyl chloride (1.88 mL) under an atmosphere of argon and the mixture was stirred at room temperature for 5 hours. After the mixture was concentrated, the residue was dissolved in mixed solvent ofTHF (25 mL) and acetnitrile (25 mL). To the mixture was added trimethylsilyldiazomethane (2M hexane solution; 12.5 mL) under ice cooling and the mixture was stirred at 0 degrees for 1 hour. After removed the solvent, to the obtained residue were added benzyl alcohol (15 mL) and collidine (15 mL) and the mixture was stirred at 180 degrees for 2 hours. The reaction mixture was cooled to room temperature. To the mixture was added 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane : ethyl acetate = 9 : 1) to give the title compound (1.4 g) having the following physical data. TLC: Rf 0.60 (ethyl acetate : hexane = 3 : 7).
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 dimethylsulfide borane complex; In tetrahydrofuran; at 75℃;
General procedure: Adapting literature known protocols (Hay, et al., J. Chem. Soc., Perkin Trans. 1, 1999, 2759-2770; Fujikawa, et al., J. Am. Chem. Soc., 2008, 130, 14533-14543; Allen, et al., International Publication No. WO 2010/122089; and Gerspacher, et al., International Publication No. WO2008/031594), commercial borane dimethylsulfide (BH3.DMS, BH3.SMe2) (2.0 M in THF) (50 mL, 100 mmol) or borane tetrahydrofurane complex (BH3.THF) (1.0 M in THF) (100 mL, 100 mmol) is added dropwise at room temperature to a stirred solution of the nitrobenzoic acid (50 mmol) in anhydrous THF (250 mL). Optionally, the reaction is performed in the presence of trimethyl borate (B(OMe)3) (200 mmol). The solution is heated at reflux for 4-6 hours (75 C. oil bath temperature). The reaction is monitored by TLC and/or LCMS to completion. After cooling to about 5 C. (ice bath), the reaction is carefully quenched with a 1:1 (v/v) mixture of methanol (MeOH)/water (25 mL) followed by 5 N hydrochloric acid (HCl) (50 mL). The mixture is heated at about 50 C. for about 30-60 min and the majority of the volatile solvents are removed under reduced pressure. Water is added and the aqueous phase is extracted with ethyl acetate (3×). The combined organic extracts are successively washed with a saturated aqueous sodium hydrogencarbonate (NaHCO3) solution (1×) and with brine (1×), dried over anhydrous magnesium sulfate (MgSO4), filtered, and the solvents are evaporated to dryness under reduced pressure. If needed, the crude material is purified by silica gel column chromatography or is re-crystallized. (2-Methyl-5-nitro-phenyl)methanol (1a) Following the General Procedure of Description 1,2-methyl-5-nitro-phenyl)methanol (1a) was prepared from commercial 2-methyl-5-nitro benzoic acid (50.0 g, 276 mmol) with borane dimethylsulfide complex (2.0 M BH3.SMe2 in THF) (166 mL, 332 mmol) in anhydrous tetrahydrofuran (400 mL) to yield 44.0 g (?quantitative yield) of the target compound (1a) as a pale yellow solid which was of sufficient purity to be used directly in the next step without further isolation and purification. Rf: ?0.50 (EtOAc/Hxn=1:1 v/v). 1H NMR (300 MHz, CDCl3): delta 8.30 (d, J=2.4 Hz, 1H), 8.05 (dd, J=8.4, 2.4 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 4.78 (d, J=5.1 Hz, 2H), 2.41 (s, 3H), 1.87 (br. t, J=5.1 Hz, 1H) ppm. The compound is also commercially available.
100%
With dimethylsulfide borane complex; In tetrahydrofuran;Reflux;
General procedure: General Procedure for the Reduction of Benzoic Acids to Benzylic Alcohols [0557] Adapting literature known protocols (Hay, et al., J. Chem. Soc, Perkin Trans. 1, 1999, 2759-2770; Fujikawa, et al., J. Am. Chem. Soc, 2008, 130, 14533-14543; Allen, et al., International Application Publication No. WO 2010/122089; and Gerspacher, et al., International Application Publication No. WO2008/031594), commercial borane dimethylsulfide (BH3 DMS, BH3 SMe2) (2.0 M in THF) (50 mL, 100 mmol) or borane tetrahydrofurane complex (BH3 THF) (1.0 M in THF) (100 mL, 100 mmol) is added dropwise at room temperature to a stirred solution of the nitrobenzoic acid (50 mmol) in anhydrous THF (250 mL). Optionally, the reaction is performed in the presence of trimethyl borate (B(OMe)3) (200 mmol). The solution is heated at reflux for 4-6 hours (~75C oil bath temperature). The reaction is monitored by TLC and/or LCMS to completion. After cooling to about 5C (ice bath), the reaction is carefully quenched with a 1 : 1 (v/v) mixture of methanol (MeOH)/water (25 mL) followed by 5 N hydrochloric acid (HC1) (50 mL). The mixture is heated at about 50C for about 30-60 min and the majority of the volatile solvents are removed under reduced pressure. Water is added and the aqueous phase is extracted with ethyl acetate (3 chi). The combined organic extracts are successively washed with a saturated aqueous sodium hydrogencarbonate (NaHC03) solution (l x) and with brine (l x), dried over anhydrous magnesium sulfate (MgS04), filtered, and the solvents are evaporated to dryness under reduced pressure. If needed, the crude material is purified by silica gel column chromatography or is re-crystallized. Following the General Procedure of Description 1, 2-methyl-5-nitro- phenyl)methanol (la) was prepared from commercial 2-methyl-5-nitro benzoic acid (50.0 g, 276 mmol) with borane dimethylsulfide complex (2.0 M BH3 SMe2 in THF) (166 mL, 332 mmol) in anhydrous tetrahydrofuran (400 mL) to yield 44.0 g (-quant, yield) of the target compound (la) as a pale yellow solid which was of sufficient purity to be used directly in the next step without further isolation and purification. Rf: -0.50 (EtOAc/Hxn = 1 : 1, v/v). 1H MR (300 MHz, CDC13): delta 8.30 (d, J= 2.4 Hz, 1H), 8.05 (dd, J= 8.4, 2.4 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 4.78 (d, J= 5.1 Hz, 2H), 2.41 (s, 3H), 1.87 (br. t, J= 5.1 Hz, 1H) ppm.
95%
With borane; potassium carbonate; In tetrahydrofuran; water;
1. (2-Methyl-5-nitrophenyl)methanol 2-Methyl-5-nitrobenzoic acid (2.00 g, 11.0 mmol) was warmed under nitrogen, dissolved in anhydrous THF (25 mL), and treated with a 1N solution of borane in THF (16.5 mL). After stirring 18 hours at ambient temperature the reaction was quenched with a solution of potassium carbonate (1.8 g, 13 mmol) in water (50 mL), and the THF removed in vacuo. The remaining aqueous solution was extracted with DCM, and the organic layer washed with pH 7 buffer and brine, dried over sodium sulfate, and filtered. The evaporated filtrate gave the title compound as a pale yellow solid (1.76 g, 95%). 1H NMR (300 MHz, CDCl3) delta 8.29 (d, 1H, J=2.5 Hz), 8.04 (dd, 1H, J=8.3 Hz, 2.5 Hz), 7.31 (d, 1H, J=8.31 Hz), 4.77 (d, 2H, J=5.5 Hz), 2.41 (s, 3H), 2.09 (t, 1H, J=5.6 Hz).
94%
IF2a To a mixture of carboxylic acid IF1a (1.81 g, 10.0 mmol) and N-methylmorpholine (1.11 g, 11.0 mmol) in THF (20 mL) at 0 C. was added ethyl chloroformate (1.19 g, 11.0 mmol). The mixture was allowed to stir at 0 C. for an additional 30 min and filtered. The insoluble salt was washed with THF (5 mL*3). To the filtrate was added NaBH4 (1.13 g, 30 mmol) and the resulting mixture was then stirred at rt for 2 h. The reaction mixture was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous K2CO3, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/hexanes) to afford compound IF2a as a colorless oil (1.60 g, 94%). 1H NMR (CDCl3, 600 MHz) delta 8.31 (d, J=2.4 Hz, 1H), 8.06 (dd, J=8.1, 2.7 Hz, 1H), 7.32 (d, J=9.0 Hz, 1H), 4.79 (d, J=4.8 Hz, 2H), 1.57 (s, 3H).
Methyl 2-(5-amino-2-methylphenyl)acetate (7); [0124] 2-Methyl-5-nitrobenzoic acid 9 (125 g, 690 mmol) is dissolved in anhydrous THF (1.25 L). After adding borane (517 mL of a 2 M solution in THF, 1.04 mol), the reaction is stirred at rt for 18 h. The reaction is quenched using an aqueous solution of potassium carbonate (112.5 g in 2.5 L). After removing THF in vacuo, the aqueous solution is extracted with DCM and the combined organic layer is washed with brine and dried over sodium sulfate. After filtering and removing the solvent in vacuo, the product 10 is obtained as a pale yellow solid. 1H NMR (300MHz, CDCl3) delta 8.29 (d, J = 3 Hz, IH), 8.50 (m, IH), 7.29 (m, IH), 4.78 (s, 2H), 2.41 (s, 3H).
To a solution of 2-methyl-5-nitrobenzoic acid (3.0 g, 16.6 mmol, Acros) in THF (60 ml) at ambient temperature under nitrogen was added dropwise 1.0 M borane- tetrahydrofuran complex (33.1 ml, 33.1 mmol, Aldrich). The solution was heated to 80 0C for 1.5 h. To the solution at ambient temperature was slowly added methanol (20 ml) and then heated to 80 0C for 30 min. The solvent was removed in vacuo to leave an oil. The residue was dissolved in methanol (approximately 30 ml) and the solvent removed in vacuo to give (2-methyl-5-nitrophenyl)methanol as a yellow solid (3.18 g).
[00121] 2-Methyl-5-nitrobenzoic acid 9 (125 g, 690 mmol) was dissolved in anhydrous THF (1.25 L). After adding borane (517 mL of a 2 M solution in THF, 1.04 mol), the reaction was stirred at rt for 18 h. The reaction was quenched using an aqueous solution of potassium carbonate (112.5 g in 2.5 L). After removing THF in vacuo, the aqueous solution was extracted with DCM and the combined organic layer was washed with brine and dried over sodium sulfate. After filtering and removing the solvent in vacuo, the product 10 was obtained as a pale yellow solid. 1H NMR (300MHz, CDCl3) delta 8.29 (d, J = 3 Hz, IH), 8.50 (m, IH), 7.29 (m, IH), 4.78 (s, 2H), 2.41 (s, 3H).
With borane-THF; In tetrahydrofuran; at 20℃; for 18h;
2-Methyl-5-nitrobenzoic acid (5. 0g, 27. 5mmol) is dissolved in 50mL anhydrous THF. After adding 41.3mL 1M borane in THF solution (41.3mmol), the reaction is stirred in RT for 18 hours. The reaction is quenched by a solution of potassium carbonate (4. 5g) in 100mL water. After removing THF under vacuum, the aqueous solution is extracted with DCM and the combined organic layer is washed by brine and dried over sodium sulfate. After filtering and removing the solvent under the vacuum, the final product compound (12) (2-methyl-5-nitrophenyl) -methanol is the pale yellow solid, 4.3g.
With thionyl chloride; at 0 - 20℃;Heating / reflux;
EXAMPLE 1; [0093] This example illustrates a preparation of 6-methoxy-2-(l -methyl- lH-indol-5 - yl)isoindolin-l-one in an embodiment of the invention.; Step A: Synthesis of ethyl 2-methyl-5-nitrobenzoate as an intermediate <n="35"/>; [0094] A mixture of <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (10.0 g, 55.2 mmol) in ethanol (200 ml) was cooled to 0 0C with an ice bath, and thionyl chloride (16.0 mL, 220 mmol) was added dropwise over 10 min. After this time, the mixture was warmed to room temperature for 1 h, then transferred to an oil bath and heated to reflux overnight. The mixture was then cooled to room temperature and concentrated under reduced pressure. Purification by flash chromatography (silica, 9:1 hexanes/ethyl acetate) afforded ethyl 2-methyl-5-nitrobenzoate (12.4 g, quant.) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) delta 8.76 (d, J= 2.5 Hz, IH), 8.24 (dd, J= 8.5, 2.5 Hz, IH), 7.43 (d, J= 8.4 Hz, IH), 4.42 (q, J= 7.2 Hz, 2H), 2.72 (s, 3H), 1.44 (t, J= 7.1 Hz, 3H).
100%
With thionyl chloride; at 0 - 20℃;Reflux;
EXAMPLE 2; This example illustrates the preparation of 2-(4-(1-oxo-6-propylisoindolin-2-yl)phenyl)propanoic acid; Step A: Synthesis of ethyl 2-methyl-5-nitrobenzoate as an Intermediate; A mixture of <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (10.0 g, 55.2 mmol) in ethanol (200 ml) was cooled to 0 C. with an ice bath and thionyl chloride (16.0 mL, 220 mmol) was added dropwise over 10 min. After this time, the mixture was warmed to room temperature for 1 h, then transferred to an oil bath and heated to reflux overnight. The mixture was then cooled to room temperature and concentrated under reduced pressure. Purification by flash chromatography (silica, 9:1 hexanes/ethyl acetate) afforded ethyl 2-methyl-5-nitrobenzoate (12.4 g, quant.) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) delta 8.76 (d, J=2.5 Hz, 1H), 8.24 (dd, J=8.5, 2.5 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 2.72 (s, 3H), 1.44 (t, J=7.1 Hz, 3H).
With sulfuric acid; at 80℃;
Step 1: synthesis of ethyl 2-methyl-5-nitrobenzoate (101).To a solution of <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (27.6 mmol, 5 g) in ethanol (100 mL), sulfuric acid (138 mmol, 7.36 ml) was added slowly and stirred overnight at 80C. The reaction mixture was neutralized with saturated solution of Na2C03, extracted with diethyl ether (3x), organic layers were washed with brine, dried and concentrated under reduced pressure to yield crude product ethyl 2-methyl-5-nitrobenzoate 101 (5.4g, 95%). NMR (400 MHz, CDC13) 1.44 (t, J = 7.0 Hz, 3H), 2.72 (s, 3H), 4.42 (q, J = 7.04 Hz, 2H), 7.43 (d, J = 8.6 Hz, 1H), 8.23 (dd, J = 8.6 Hz and 2.7 Hz, 1H), 8.76 (d, J = 2.7 Hz, 1H).
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).
EXAMPLE 49. Synthesis of N-f2-(3-(2-rPyrrolidin-l- yOEthoxy)Phenylamino)Pyrimidin-5-ylV5-Amino-2-Methylbenzamide (Intermediate30}30[0197] To a solution of <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (0.93 g, 5.13 mmol) in anhydrous CH2Cl2 (50 mL) was added 2-chloro-4,6-diimethyoxy-l,3,5-triazine (CDMT, 0.9 g, 5.13 mmol), and 4-methylmopholine (NMM, 1.54 mL, 14 mmol). The mixture was stirred for 0.5 h at room temperature followed by adding intermediate 29 (Example 45) (1.02 g, 3.42 mmol). The mixture was stirred overnight at room temperature. The saturated NaHCtheta3 (40 mL) was added and the mixture was stirred for 5 min. The organic layer was separated and aqueous was extracted with CH2CI2 (3 x 20 mL). The combined organic solution was dried (Na2SO4). The solvent was removed in vacuo.[0198] The crude product was purified by flash column (SiO2ZCH2Cl2, then CH2Cl2 : MeOH : NH3-H2O = 100 : 10 : 1). The obtained yellow solid was dissolved in MeOH (200 mL) and bubbled with Ar for 2 min before adding 10% Pd-C. The mixture was hydrogenated for Ih at room temperature. The catalyst was filtered off and washed with MeOH. The filtrate was concentrated in vacuo. The desired product was obtained as a yellow solid (1.36 g, 92%).
<strong>[1975-52-6]2-Methyl-5-nitrobenzoic acid</strong> (10.00 g, 55.2 mmol), iodine (5.6O g, 22.1 mmol, 0.4 equiv) and sodium iodate (4.37 g, 22.1 mmol, 0.4 equiv) were dissolved in 96% sulfuric acid (40 ml), and the solution was stirred at 30 to 40C for 2 hours. The reaction solution was cooled to near room temperature. While adjusting the internal temperature of the reaction solution not to exceed 50C, sodium sulfite (17.40 g, 138.0 mmol, 2.5 equiv) /water (100 ml) and methanol (40 ml) were added dropwise sequentially. The reaction solution was stirred for 2 hours while maintaining the internal temperature of the reaction solution at 20 to 30C. Precipitated crystals were collected by filtration, and washed twice with 67% hydrous ethanol (20 ml) . The crystals were dried in a vacuum at 50C, to yield the title compound (15.80 g) (yield 93.2%).1H-NMR (300 MHz, TMS, DMSOd6) delta (ppm): 2.69 (s, 3H), 8.44 (d, J = 2.2 Hz, IH), 8.70 (d, J = 2.3 Hz, IH). 13C-NMR (300 MHz, TMS, DMSO-d6) delta (ppm): 26.5, 104.5, 124.0, 133.5, 135.3, 145.3, 148.4, 167. Mass analysis (C8H6INO4) <n="166"/>Theoretical value: 306.9342 Measured value: 306.9333 Melting point: 178.3C
With 1,1'-carbonyldiimidazole; In tetrahydrofuran;
(1) Carbonyldiimidazole (4.9 g, 30.4 mmol) was added to a solution of 2-methyl-5-nitrobenzoic acid (5 g, 27.6 mmol) in tetrahydrofuran (50 ml) at room temperature. After stirred at room temperature for 6 hours, a magnesium salt of malonic acid monoethyl ester (4.4 g, 15.2 mmol) was added. This mixture was stirred at 60 C. for 1.5 hours, the reaction solution was diluted with ethyl acetate (100 ml), and washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and saturated brine, dried with sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent:hexane-ethyl acetate (4:1)] to obtain ethyl 3-(2-methyl-5-nitrophenyl)-3-oxopropionate (5.4 g, 21.5 mmol, 78%) as a colorless oil. IR numax (KBr) cm-1: 3100-2600 (br, OH), 1741, 1699 (C=O). 1H-NMR (CDCl3) delta: 1.264 (3/5*3H, t, J=7.0 Hz), 1.354 (2/5*3H, t, J=7.0 Hz), 2.572 (2/5*3H, s), 2.647 (3/5*3H, s), 4.017 (3/5*2H, s), 4.213 (3/5*2H, q, J=7.0 Hz), 4.297 (2/5*2H, q, J=7.0 Hz), 5.361 (2/5*1H, s), 7.38-8.52 (3H, m).
methyl 2-amino-3-(4-((2,6-dichlorophenyl)carbonylamino)-2-oxohydropyrimidinyl)propionate (232) TFA salt[ No CAS ]
[ 1975-52-6 ]
[ 144-55-8 ]
[ 21900-37-8 ]
methyl (2S)-3-(4-((2,6-dichlorophenyl)carbonylamino)-2-oxohydropyrimidinyl)-2-((2-methyl-5-nitrophenyl)carbonylamino)propionate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With triethylamine In dichloromethane
245 Methyl (2S)-3-(4-((2,6-dichlorophenyl)carbonylamino)-2-oxohydropyrimidinyl)-2-((2-methyl-5-nitrophenyl)carbonylamino)propionate (245)
Example 245 Methyl (2S)-3-(4-((2,6-dichlorophenyl)carbonylamino)-2-oxohydropyrimidinyl)-2-((2-methyl-5-nitrophenyl)carbonylamino)propionate (245) To a solution of 100 mg (0.200 mmol) of methyl 2-amino-3-(4-((2,6-dichlorophenyl)carbonylamino)-2-oxohydropyrimidinyl)propionate (232) TFA salt in 3 ml of dichloromethane, were added 0.28 ml (0.400 mmol) of triethylamine and 3 ml of a solution of 2,6-dimethylbenzoyl chloride (prepared from 72 mg (0.40 mmol) of 2-methyl-5-nitrobenzoic acid and 0.042 ml of oxalyl chloride) in dichloromethane, and the mixture was stirred at room temperature for 1.5 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the resulting mixture was extracted with chloroform. Organic layers were combined, washed with 1N hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel; chloroform/methanol = 60/1-40/1) to obtain 107 mg of methyl (2S)-3-(4-((2,6-dichlorophenyl)carbonylamino)-2-oxohydropyrimidinyl)-2-((2-methyl-5-nitrophenyl)carbonylamino)propionate (245) (yield: 98%). LR-MS (m/z): 546 [(M-H)-] IR (KBr): 3263, 3078, 2956, 1719, 1663, 1561, 1491, 1433, 1348, 1304, 1243, 1194, 1135, 1079, 1042, 1007, 902 cm-1 1H-NMR (300MHz, CD3OD, δppm): 2.53(3H, s), 3.79(3H, s), 4.38-4.57(2H, m), 5.01-5.08(1H, m), 7.33-7.37(4H, m), 7.54(1H, d, J= 7.5 Hz), 7.82(1H, d, J= 7.5 Hz), 8.12(1H, dd, J= 2.4, 8.1 Hz), 8.26(1H, s), 8.28(1H, d, J= 2.7 Hz), 8.87(1H, s) [α]D20= -120° (c = 0.048, CH3OH)
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 29h;
DIEA 225 μL (1.29 mmol) was added to a solution of 4-(p- fluorophenoxy)-piperidine 250 mg (1.280 mmol), HOBWH2O 250 mg (1.63 mmol), 2-methyl-5-nitrobenzoic acid 255 mg (1.40 mmol) and EDOHCI 268 mg (1.40 mmol) in anhydrous DMF (1.5 ml_) and the mixture was stirred for 29 hours. The mixture was diluted with ethyl acetate (100 ml_), washed twice with saturated NaHCθ3 (2 x 100 ml_) and the aqueous phases were re-extracted with ethyl acetate (100 mL). The combined organic extracts were dried (MgSO4) and evaporated. The residue was purified on a column of silica (40 g) in a hexane-ethyl acetate gradient (0-60% EtOAc). The obtained purified nitro-intermediate was dissolved in a mixture of ethanol (99%, 20 mL) and acetic acid (2 mL). SnCl2*2H2O 1.58 g (6.00 mmol) was added and the mixture was refluxed under Ar for 1 h on oil bath (95 0C). The mixture was cooled, diluted with dichloromethane 50 mL, 1M aq. NaOH 200 mL was added and the mixture was stirred vigorously for Vz hour. The mixture was extracted twice with dichloromethane (2 x 200 mL), and the organic extracts were washed with saturated NaCI (200 mL), combined, dried (MgSO4) and evaporated. Y = 335 mg of amino-substituted intermediate (79.5%) as a pale- yellow amorphous glassy solid.
To a mixture of <strong>[1975-52-6]2-methyl-5-nitro-benzoic acid</strong> (50 g) in dichloromethane (330 ml_) is added oxalyl chloride (25.5 mi_) followed by dimethylformamide (0.5 ml_). The reaction mixture is stirred at ambient temperature for 14 h, then filtered and separated from ail volatile constituents in a rotary evaporator. The residue is dissolved in dichloromethane (100 mL), the resulting solution is cooled to -5 0C1 and anisole (31 mL) is added. Then aluminum trichloride (37.5 g) is added batchwise so that the temperature maintains below 5 0C. The solution is stirred for another 1 h at 1 to 5 0C and then poured onto crushed ice. The organic phase is separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with aqueous hydrochloric acid (1 mol/L), twice with aqueous sodium hydroxide solution (1 mol/L) and with brine. The organic phase is dried (sodium sulphate), the solvent is removed and the residue is recrystallised from ethanol. Yield: 65.8 g (88% of theory); Mass spectrum (ESI+): m/z = 272 [M+H]+
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 2h;
1
Intermediate C4-[l-(5-amino-2-methyl-benzoyl)-4-piperidyl]benzonitrile4-[ 1 -(2-methyl-5-nitro-benzoyl)-4-piperidyl]benzonitrileA mixture of 2-methyl-5-nitrobenzoic acid (5g, 27.6mmol), 4-(4'-cyanophenyl)piperidine (5.14g, 27.6mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (5.82g, 30.36mmol) and DMAP (338mg, 2.76 mmol) in DMF (50 mL) was stirred at room temperature for 2 hrs. Ethyl acetate (200ml) was added and the resulting solution washed with dilute hydrochloric acid (100 mL of IM), NaHCO3, brine (100 mL). At this point a colourless solid precipitated, which was isolated by filtration and dried. The filtrate was dried (MgSO4), filtered and reduced in vacuo to give a white solid. This was chromatographed (12O g silica column, Companion, eluting with a gradient consisting of 0- 50% ethyl acetate in isohexane) to give a colourless solid which was identical to that isolated previously. The solids were combined to give the title compound (4 g), *H NMR (300.072 MHz, CDCl3) δl.64 - 2.11 (4H, m),2.42 - 2.53 (3H, m),2.79 - 3.00 (2H, m),3.09 - 3.23 (IH, m),3.55 (IH, d),4.98 (IH, d),7.29 - 7.36 (2H, m),7.42 (IH, d),7.63 (2H, d),8.04 - 8.18 (2H, m), m/z 348 (M-H)".
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 18 - 25℃; for 2h;
D.1
Intermediate D; 4- [ 1 -(5 -amino-2-methyl-benzoyl)-4-piperidyl]benzonitrile; 4-[l-(2-methyl-5-nitro-benzoyl)-4-piperidyl]benzonitrile; A mixture of 2-methyl-5-nitrobenzoic acid (5g, 27.6mmol), 4-(4'-cyanophenyl)piperidine (5.14g, 27.6mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (5.82g, 30.36mmol) and DMAP (338mg, 2.76 mmol) in DMF (50 mL) was stirred at room temperature for 2 hrs. Ethyl acetate (200ml) was added and the resulting solution washed with dilute hydrochloric acid (100 mL of IM), NaHCO3, brine (100 mL). At this point a colourless solid precipitated, which was isolated by filtration and dried . The filtrate was dried (MgSO4), filtered and reduced in vacuo to give a white solid. This was chromatographed (12O g silica column, Companion, eluting with a gradient consisting of 0- 50% ethyl acetate in isohexane) to give a colourless solid which was identical to that isolated previously. The solids were combined to give the title compound (4 g), 1H NMR (300.072 MHz, CDCl3) δl.64 - 2.11 (4H, m),2.42 - 2.53 (3H, m),2.79 - 3.00 (2H, m),3.09 - 3.23 (IH, m),3.55 (IH, d),4.98 (IH, d),7.29 - 7.36 (2H, m),7.42 (IH, d),7.63 (2H, d),8.04 - 8.18 (2H, m), m/z 348 (M-H)-.
With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 25℃; for 17h; Inert atmosphere;
1 Intermediate-1: Preparation of (R)-2-methyl-N-(1-(naphthalen-1-yl)ethyl)-5- nitrobenzamide
To a solution of 2-methyl-5-nitrobenzoic acid (0.6 g, 3.31 mmol) in DCM (20 ml), (R)-1-(naphthalen-1-yl)ethan-1-amine (0.567 g, 3.31 mmol), EDC (0.794 g, 4.14 mmol), HOBT (0.634 g, 4.14 mmol) and DIPEA (2.256 ml, 12.92 mmol) were added one by one and reaction mixture was stirred under N2 atm. at 25 °C for 17 h. Completion of reaction checked by TLC. The reaction was concentrated in vacuo and diluted with water, solid was filtered and washed it with water. Crude product was purified by column chromatography (ethyl acetate : n-hexane) (gradient) to yield, (R)-2-methyl-N-(1-(naphthalen-1-yl)ethyl)-5- nitrobenzamide (1.06 g, 3.17 mmol, 96 % yield). 1H NMR (400 MHz, DMSO-d6): δ = 8.24 (d, J = 8.4 Hz, 1H), 8.16 - 8.12 (m ,2H), 7.93 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.64 - 7.48 (m, 4H), 7.38 (d, J = 8.4 Hz, 1H), 6.18 - 6.09 (m, 2H), 2.55 (s, 3H), 1.86 (d, J = 6.4 Hz, 3H); MS (TOF): m/z (%) = 335.1386 (100%) (M+H)+.
96%
With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 25℃; for 17h; Inert atmosphere;
1 Intermediate-1: Preparation of (R)-2-methyl-N-(1-(naphthalen-1-yl)ethyl)-5- nitrobenzamide
To a solution of 2-methyl-5-nitrobenzoic acid (0.6 g, 3.31 mmol) in DCM (20 ml), (R)-1-(naphthalen-1-yl)ethan-1-amine (0.567 g, 3.31 mmol), EDC (0.794 g, 4.14 mmol), HOBT (0.634 g, 4.14 mmol) and DIPEA (2.256 ml, 12.92 mmol) were added one by one and reaction mixture was stirred under N2 atm. at 25 °C for 17 h. Completion of reaction checked by TLC. The reaction was concentrated in vacuo and diluted with water, solid was filtered and washed it with water. Crude product was purified by column chromatography (ethyl acetate : n-hexane) (gradient) to yield, (R)-2-methyl-N-(1-(naphthalen-1-yl)ethyl)-5- nitrobenzamide (1.06 g, 3.17 mmol, 96 % yield). 1H NMR (400 MHz, DMSO-d6): δ = 8.24 (d, J = 8.4 Hz, 1H), 8.16 - 8.12 (m ,2H), 7.93 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.64 - 7.48 (m, 4H), 7.38 (d, J = 8.4 Hz, 1H), 6.18 - 6.09 (m, 2H), 2.55 (s, 3H), 1.86 (d, J = 6.4 Hz, 3H); MS (TOF): m/z (%) = 335.1386 (100%) (M+H)+.
95%
With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 23℃; Combinatorial reaction / High throughput screening (HTS); Inert atmosphere;
83%
With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 12h;
Stage #1: 2-Methyl-5-nitrobenzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 23℃;
Stage #2: (R)-1-(1-Naphthyl)ethylamine With triethylamine
2-methyl-5-nitro-N-(pyrimidin-5-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In a 2 L round bottom flask with mechanical stirring was charged with 2-methyl-5-nitrobenzoic acid (20 g), HATU (38 g) and diisopropylamine (32 mL) in DMF (90 mL). This mixture was stirred for 30 min then <strong>[591-55-9]pyrimidin-5-amine</strong> was added and the reaction was stirred for 18 hr. The LCMS showed complete conversion. DMF was removed under vacuum as much as possible then water was added and a solid precipitated out (use mechanical stirring). The tan solid was filtered and rinsed with water, then taken up in EtOAc, washed with brine, dried over MgSO4, filtered and concentrated down. The crude was taken up in EtOAc and the product 45 precipitated out. This was filtered and the filtrate was concentrated down and taken up in EtOAc/Hex. After standing overnight, more solids were filtered and were combined with the first crop. 2-methyl-5-nitro-N-(pyrimidin-5-yl)benzamide 45 was obtained as a light yellow solid.
EXAMPLE 57. Synthesis of 5-Amino-2-Methyl-N-(2-(Pyridin-3-vtamino)Pyrimidin-5- ylVBenzamide (Intermediate 31)31; [0220] To a solution of <strong>[1975-52-6]2-methyl-5-nitrobenzoic acid</strong> (1.05 g, 5.77 mmol) in anhydrous CH2Cl2 (50 mL) was added 2-chloro-4,6-dimethyoxy-l,3,5-triazine (CDMT, 0.9 g, 5.13 mmol), and 4-methylmopholine (NMM, 1.54 mL, 14 mmol). The mixture was stirred for 0.5 h at room temperature followed by adding intermediate 9 (Example 15) (0.9 g, 4.8 mmol). The mixture was stirred overnight at room temperature. The saturated NaHCCb (40 mL) was added and the mixture was stirred for 5 min. The organic layer was separated and aqueous was extracted with CH2CI2 (3 x 20 mL). The combined organic solution was dried (Na2SO4). The solvent was removed in vacuo.[0221] The crude product was purified by flash column (SiO2/CH2Cl2, then CH2Cl2 : MeOH : NH3-H2O = 100 : 10 : 1). The obtained yellow solid was dissolved in MeOH (200 mL) and bubbled with Ar for 2 min before adding Raney Ni. The mixture was hydrogenated for Ih at room temperature. The catalyst was filtered off and washed with MeOH. The filtrate was concentrated in vacuo. The desired product was obtained as a yellow solid (1.24 g, 81%).
Step I: (2-Methyl-5-nitro-phenyl)methanol (5i) Following the General Procedure of Description 6, 2-methyl-5-nitro-phenyl)methanol (5i) was prepared from commercial 2-methyl-5-nitro benzoic acid (50.0 g, 276 mmol) with borane dimethylsulfide complex (2.0 M BH3.SMe2 in THF) (166 mL, 332 mmol) in anhydrous tetrahydrofuran (400 mL) to yield 44.0 g (?quantitative yield) of the target compound (5i) as a pale yellow solid which was of sufficient purity to be used directly in the next step without further isolation and purification procedures. Rf: ?0.50 (EtOAc/Hxn=1:1 v/v). 1H NMR (300 MHz, CDCl3): delta 8.30 (d, J=2.4 Hz, 1H), 8.05 (dd, J=8.4, 2.4 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 4.78 (d, J=5.1 Hz, 2H), 2.41 (s, 3H), 1.87 (br. t, J=5.1 Hz, 1H) ppm.
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