* 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] Journal of Asian Natural Products Research, 2011, vol. 13, # 4, p. 330 - 340
[2] European Journal of Medicinal Chemistry, 2013, vol. 68, p. 222 - 232
2
[ 603-85-0 ]
[ 17056-99-4 ]
Reference：
[1] Helvetica Chimica Acta, 1951, vol. 34, p. 427,429
3
[ 603-85-0 ]
[ 59649-56-8 ]
Yield
Reaction Conditions
Operation in experiment
99%
With hydrogen In ethanol at 20℃; for 12 h;
Example 1 : 1 l-(3-chlorophenyl)-6-hydroxy-3,3-dimethyl-2,3,4,5,10,l 1-hexahydro- dibenzo|", e]\\ ,41diazepin- 1 -one (6).; Step l; A mixture of 2-amino-3-nitrophenol (10.0 g, 64.9 mmol), 10percent Pd/C in ethanol (150 mL), was hydrogenated at room temperature for 12 h. Then, the reaction mixture was degassed with nitrogen. The catalyst was removed by filtration and washed extensively with ethanol. The filtrate was evaporated to give 8.0 g (99percent) of the desired product as a black solid.
99%
With hydrogen In ethanol at 20℃; for 12 h;
Step 3. synthesis of 2,3-diaminophenol (4). ; <n="39"/>A mixture of 2-amino-3-nitrophenol (10.0 g, 64.9 mmol), 10percent Pd/C in ethanol (150 mL), was hydrogenated at room temperature for 12h. Then, the reaction mixture was degassed with nitrogen. The catalyst was removed by filtration and washed extensively with ethanol. The filtrate was evaporated to give 8.0 g (99percent) of the desired product as a black solid.
98%
at 20℃; for 6 h;
General procedure: To a solution of 4-amino-3-nitrophenol (28, 5.0 g, 32.44 mmol) was added cautiously Raney-Ni (1.0 g, wet weight) under N2 atmosphere. Then the suspended solution was degassed with H2 three times. The mixture was stirred for 6 h at room temperature under H2 balloon. The resulting reaction mixture was filtered through a celite pad. The filtrate was evaporated directly under reduced pressure to provide the intermediate 29 (3.83 g, 95percent yield) as a black solid which was used directly in the next step.
Reference：
[1] Journal of Medicinal Chemistry, 2018, vol. 61, # 8, p. 3309 - 3324
[2] Patent: WO2008/99019, 2008, A1, . Location in patent: Page/Page column 49
[3] Patent: WO2008/99022, 2008, A1, . Location in patent: Page/Page column 37-38
[4] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 380 - 396
[5] Helvetica Chimica Acta, 1951, vol. 34, p. 427,429
[6] Chemische Berichte, 1938, vol. 71, p. 34,41
[7] Bulletin de la Societe Chimique de France, 1927, vol. <4>41, p. 449
[8] Organic and Biomolecular Chemistry, 2008, vol. 6, # 18, p. 3256 - 3263
[9] Journal of Medicinal Chemistry, 2011, vol. 54, # 20, p. 7105 - 7126
[10] Archives of Pharmacal Research, 2017, vol. 40, # 4, p. 469 - 479
4
[ 603-85-0 ]
[ 67853-37-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 17, p. 5352 - 5362
[2] Journal of Organic Chemistry, 1988, vol. 53, # 6, p. 1170 - 1176
5
[ 603-85-0 ]
[ 603-84-9 ]
Yield
Reaction Conditions
Operation in experiment
62%
Stage #1: With hydrogenchloride; sodium nitrite In water at 0℃; for 0.5 h; Stage #2: With sulfuric acid; copper(l) chloride In water for 18 h;
Example 10 [:] Synthesis of [2-CHLORO-3- (2, 2-DIMETHYL-4-PHENETHYLSULFANYLMETHYL-1,] 2- dihydroquinoline-6-yl) phenol OH z O < \\ CI 8r OrB/ H H Suzuki OH OH ci ci \\I \\I I/ \\ \\ I \\ N N H H 10 To a suspension of 2-amino-3-nitrophenol (10 g, 65 mmol) in concentrated [HC1] (10 mL) at [0°C,] sodium nitrite (5.1 g, 73.3 mmol) in water (60 [ML)] was added dropwise. After stirring for 30 minutes at [0°C,] CuCl (12.8 g, [130] mmol) in 10percent [H2SO4] (3 mL) was added and the reaction was stirred for 18 hours. The heterogeneous mixture was filtered and washed with water. The filtrate was extracted three times with 70 mL portions of EtOAc. Evaporation of EtOAc extractions afforded 7 grams (62percent yield) of pure [2-CHLORO-3-NITROPHENOL,] 2-Chloro-3- nitrophenol (6 g, 35 mmol) was dissolved in methanol (100 [ML)] and treated with ammonium chloride (9.4 g, 175.7 mmol) and zinc dust (46 g, 702.8 mmol). The resulting mixture was refluxed for one hour. After filtration and evaporation, 2-chloro-3-aminophenol was collected (4.5 g, 90percent yield) as a purple solid. To a suspension of 2-chloro-3-aminophenol (4.5 g, 31 mmol) in concentrated [HCI] (10 mL) at [0°C] was added dropwise sodium nitrite (2.5 g, 35 mmol) in water (50 mL). After stirring for 30 minutes at [0°C,] [I (I] (10.4 g, 63 mmol) in 10percent [H2SO4] (3 mL) was added dropwise. The reaction was stirred at room temperature for 2 hours, then filtered, extracted with EtOAc, and concentrated in vacuo to afford 2-chloro-3-iodophenol as a dark purple solid (6 g, 75percent yield). 6-Bromo-2,2, [4-TRIMETHYL-1,] 2-dihydroquinoline (2.3 g, 9.2 mmol) (Example 8) and bis (pinacol) diborane (4.2 g, 16.5 mmol) were combined in DMSO (2 mL). [KOAC] (2.7 g, 27.4 mmol) was added, followed by [PDCL2] (dppf) (100 mg). The contents were placed into a microwave reaction vessel assembly and irradiated at [120°C] for 15 minutes. After cooling to room temperature, purification by chromatography afforded 2,2, [4-TRIMETHYL-6- (4,] 4,5, 5- tetramethyl- [1, 3,2] [DIOXABOROLAN-2-YL)-1,] 2-dihydroquinoline (2.3 g, [84percent] yield) as a white crystalline solid. 2,2, [4-TRIMETHYL-6- (4,] 4,5, [5-TETRAMETHYL- [1,] 3,2] [DIOXABOROLAN-2-YL)-1,] 2-dihydroquinoline [(308] mg) and 393 mg of 2-chloro-3-iodophenol were coupled using of 100 mg [OF PDCL2 (DPPF)] and [300 MG OF KOAC TO GIVE 250 MG OF 2-CHLORO-3- (2, 2, 4-TRIMETHYL-1, 2-DIHYDROQUINOLIN-6-YL) -] phenol. Using the procedures described in Example 7, this (85 mg) was reacted with NBS to give 56 mg [OF 3- (4-BROMOMETHYL-2, 2-DIMETHYL-1, 2-DIHYDROQUINOLIN-6-YL)-2-CHLOROPHENOL.] The product (50 mg) was coupled with 0.04 mL of 2-phenylethanethiol to give 40 mg of the title compound as an oil.
48%
Stage #1: With hydrogenchloride; sodium nitrite In 1,4-dioxane; water at 0 - 70℃; for 3.25 h; Stage #2: With copper(l) chloride In 1,4-dioxane; water at 0 - 60℃; for 0.5 h;
2-Amino-3-nitrophenol B1 (5 g; 32.4 MMOL) was dissolved in concentrated HCI (75 ML) and 1,4-dioxane (14. 7 mL). The mixture was heated to 70 C UNTIL most of the solids were in solution. The reaction mixture was cooled to 0 C (ice bath), and sodium nitrite (2.23 g; 32.3 MMOL) in H20 (5.4 mL) was added over a period of 3 hours to the brown solution. The temperature was maintained BELOW 10 C during the addition and the stirring was continued for an additional 15 min at 0°C. This diazonium intermediate was poured into a solution of Cu (I) CI (3.8 g; 38.9 MMOL) in H20 (18. 5 mL) and conc. HCI (18.5 mL) at 0 C. The reaction was stirred for 15 min at 0 C, WARMED TO 60 C, and stirred for an additional 15 min The reaction mixture was then brought to room temperature, and left to stir overnight. The reaction mixture was transferred to a separatory funnel and extracted with ether (3X 150 mL). The organic layers were combined, washed with brine (1X), dried (NA2SO4), filtered and concentrated to afford the crude product (5.83 g) as a red-brown oil. The crude material was purified by flash column chromatography (1 : 25 ultra pure silica gel, 230-400 mesh, 40-60 MM, 60 angstroms; 3: 1 hexane/EtOAcas the solvent) to afford pure 2-chloro-3-nitrophenol C2 (48percent; 2.7 g) as an orange solid. MS 171. 8 (MH)- : Homogeneity by HPLC (TFA) 220 nm: 96percent. Relevant literature for the Sandmeyer Reaction: J. Med. Chem, 1982,25 (4), 446- 451.
48%
Stage #1: With hydrogenchloride In 1,4-dioxane; water at 70℃; Stage #2: With sodium nitrite In 1,4-dioxane; water at 0 - 10℃; for 3.25 h; Stage #3: With hydrogenchloride; copper(l) chloride In 1,4-dioxane; water at 0 - 60℃; for 0.5 h;
Step A:; 2-Amino-3-nitrophenol 1b1 (5 g; 32.4 mmol) was dissolved in concentratedHCI (75 ml) and 1,4-dioxane (14.7 ml). The mixture was heated to 70°C until most ofthe solids were in solution. The reaction mixture was cooled to 0°C (ice bath), andsodium nitrite (2.23 g; 32.3 mmol) in H2O (5.4 ml) was added over a period of 3 hoursto the brown solution. The temperature was maintained below 10°C during theaddition and the stirring was continued for an additional 15 min. at 0°C. Thisdiazonium intermediate was poured into a solution of Cu(l)CI (3.8 g; 38.9 mmol) inH2O (18.5 ml_) and cone. HCI (18.5 mL) at 0°C. The reaction was stirred for 15 min. at0°C, warmed to 60°C, and stirred for an additional 15 min. The reaction mixture wasthen brought to room temperature, and left to stir overnight. The reaction mixture wastransferred to a separatory funnel and extracted with ether (3 X 150 mL). The organiclayers were combined, washed with brine (1 X), dried (Na2SO4), filtered andconcentrated to afford the crude product (5.83 g) as a red-brown oil. The crudematerial was purified by flash column chromatography (1:25 ultra pure silica gel, 230-400 mesh, 40-60mm, 60 angstroms; 3:1 hexane/EtOAc as the solvent) to afford pure2-chloro-3-nitrophenol 1c1 (48percent; 2.7 g) as an orange solid. MS 171.8 (MH)":Homogeneity by HPLC (TFA) (at) 220 nm: 96percent .
48%
Stage #1: With hydrogenchloride In 1,4-dioxane; water at 70℃; Stage #2: With sodium nitrite In 1,4-dioxane; water at 0 - 10℃; for 3.25 h; Stage #3: With copper(l) iodide In 1,4-dioxane; water at 0 - 60℃;
2-Amino-3-nitrophenol 2b1 (5 g; 32.4 mmol) was dissolved in concentratedHCI (75 ml) and 1,4-dioxane (14.7 ml_). The mixture was heated to 70°C until most ofthe solids were in solution. The reaction mixture was cooled to 0°C (ice bath), andsodium nitrite (2.23 g; 32.3 mmol) in H2O (5.4 ml) was added over a period of 3 hoursto the brown solution. The temperature was maintained below 10°C during theaddition and the stirring was continued for an additional 15 min. at 0°C. Thisdiazonium intermediate was poured into a solution of Cu(l)CI (3.8 g; 38.9 mmol) inH2O (18.5 ml) and cone. HCI (18.5 mL) at 0°C. The reaction was stirred for 15 min. at0°C, warmed to 60°C, and stirred for an additional 15 min. The reaction mixture wasthen brought to room temperature, and left to stir overnight. The reaction mixture wastransferred to a separatory funnel and extracted with ether (3 X 150 ml). The organiclayers were combined, washed with brine (1 X), dried (Na2SO4), filtered andconcentrated to afford the crude product (5.83 g) as a red-brown oil. The crudematerial was purified by flash column chromatography (1:25 ultra pure silica gel, 230-400 mesh, 40-60mm, 60 angstroms; 3:1 hexane/EtOAc as the solvent) to afford pure2-chloro-3-nitrophenol 2c1 (48percent; 2.7 g) as an orange solid. MS 171.8 (MH)":Homogeneity by HPLC (TFA) (at) 220 nm: 96percent .Relevant literature for the Sandmeyer Reaction: J. Med. Chem, 1982, 25(4), 446-451.
Reference：
[1] Journal of the Chemical Society, 1928, p. 3048
[2] Journal of the Chemical Society, 1927, p. 1057
10
[ 5467-64-1 ]
[ 603-85-0 ]
Reference：
[1] Journal of the Chemical Society, 1927, p. 1057
11
[ 66-56-8 ]
[ 14703-71-0 ]
[ 603-85-0 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1991, vol. 27, # 1, p. 21 - 31[2] Zhurnal Organicheskoi Khimii, 1991, vol. 27, # 1, p. 24 - 35
12
[ 7664-93-9 ]
[ 603-85-0 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1927, vol. <4>41, p. 449
13
[ 603-85-0 ]
[ 74-88-4 ]
[ 16554-45-3 ]
Yield
Reaction Conditions
Operation in experiment
91%
With potassium carbonate In N,N-dimethyl-formamide for 14 h;
Step 1: 2-methoxy-6~nitroaniline; A mixture of 2-amino-3-nitrophenol (1 1.66 g, 76 mmol) and K2C03 (12.55 g, 91 mmol) were stirred in DMF (100 ml) for 1 hour. Iodomethane (5.68 ml, 91 mmol) in DMF (lOmL) was added dropwise, and the mixture was stirred 14 hours. The reaction was diluted with H2 and extracted with EtOAc (2x). The organics were washed with brine, dried over Na2S04, filtered, concentrated to a dark solid. The crude solid was purified by crystallization from hexane to give the title compound as an orange solid (11 ,6g, 91percent). LCMS (ES+) m/z 169.0 (M+H)+.
90%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
To a mixture of 2-amino-3-nitrophenol (19.25 g) and K2CO3 (19 g) in DMF (100 mL) was added MeI (11 mL) at room temperature and the mixture was stirred over night and then poured into water. The resulting precipitate was collected by filtration and the solid was washed with water to afford the desired product (19 g, 90percent). 1H NMR (300 MHz, CDCl3) δ ppm 3.92 (s, 1H), 6.43 (br s, 1H), 6.61 (dd, 1H, J=7.5, 9.0 Hz), 6.89 (dd, 1H, J=0.9, 7.5 Hz), 7.73 (dd, 1H, J=0.9, 9.0 Hz); LC-MS: m/e=169 [M+1]+
89%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1.5 h;
The mixture of 2-amino-3-nitrophenol (308mg, 2mmol) and K2CO3 (552mg, 4mmol) in DMF (5mL) were stirred at room temperature for 30min before addition of MeI (0.15mL, 2.5mmol). After stirred at room temperature for 1h, the reaction mixture was diluted with water (30mL) and extracted with ethyl ether (15mL×3). The combined organic layer was washed with water and brine and then dried over anhydrous MgSO4, filtered and concentrated to give the crude product, which was purified by column chromatography on silica gel with petroleum ether/AcOEt (v/v=12:1). The title compound (300mg, 89percent yield) was afforded as salmon pink powder. M.p. 68–69°C; 1H NMR (CDCl3, 300MHz, δ ppm): 7.73 (1H, d, J=9.3Hz), 6.88 (1H, d, J=7.8Hz), 6.60 (1H, t, J=7.5Hz), 6.42 (2H, br s), 3.92 (3H, s); HRMS (ESI): m/z, calcd. For C7H9N2O3 [M+H]+: 169.0608, found 169.0607.
89%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16 h;
2-Methoxy-6-nitroaniline To a solution of 2-amino-3-nitrophenol (35 g, 227 mmol) in DMF (400 ml_), K2C03(37.7 g, 273 mmol) and Mel (17.04 ml_, 273 mmol) were added at RT. The reaction mixture was stirred at RT for 16 h. Then it was poured into water. The resulting precipitate was collected by filtration and the solid was washed with water to give 35 g (89percent) of the title compound. LC-MS m/z 168.9 (M+H)+, 1.71 (ret. time).
89%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16 h;
Intermediate 4 2-Methoxy-6-nitroaniline To a solution of 2-amino-3-nitrophenol (35 g, 227 mmol) in Ν,Ν-dimethylformamide (DMF) (400 mL), K2C03 (37.7 g, 273 mmol) and iodomethane (17.04 mL, 273 mmol) were added at ambient temperature. The reaction mixture was stirred at ambient temperature for 16 h. Then it was poured into water. The resulting precipitate was collected by filtration and the solid was washed with water to give 35 g (89percent) of the title compound. LC-MS m/z 168.9 (M+H)+, 1 .71 min (ret. time).
87%
With potassium hydroxide In N,N-dimethyl-formamide at 20℃;
c) 2-methoxy-6-nitro-phenylamine: 85percent potassium hydroxide solution (11.7 g, 0.179 mol) is added to a solution of 25 g (0.162 mol) 2-amino-3-nitro-phenol in 200 mL DMF. Then 11.1 mL (0.178 mol) iodomethane are added dropwise and the mixture is stirred overnight at ambient temperature. The reaction mixture is poured onto ice and stirred for one hour. The precipitated product is filtered off, washed with water and dried. Yield: 23.8 g (87percent); mass spectroscopy: [M+H]+=169.
87%
With potassium hydroxide In DMF (N,N-dimethyl-formamide) at 20℃;
85percent potassium hydroxide solution (11.7 g, 0.179 mol) is added to a solution of 25 g (0.162 mol) 2-amino-3-nitro-phenol in 200 mL DMF. Then 11.1 mL (0.178 mol) iodomethane are added dropwise and the mixture is stirred overnight at ambient temperature. The reaction mixture is poured onto ice and stirred for one hour. The precipitated product is filtered off, washed with water and dried. Yield: 23.8 g (87percent); mass spectroscopy: [M+H]+=169
87%
With potassium hydroxide In water; N,N-dimethyl-formamide at 0 - 20℃;
c) 2-methoxy-6-nitro-phenylamine 85percent potassium hydroxide solution (11.7 g, 0.179 mol) is added to a solution of 25 g (0.162 mol) 2-amino-3-nitro-phenol in 200 mL DMF. Then 11.1 mL (0.178 mol) iodomethane are added dropwise and the mixture is stirred overnight at ambient temperature. The reaction mixture is poured onto ice and stirred for one hour. The precipitated product is filtered off, washed with water and dried. Yield: 23.8 g (87percent); mass spectroscopy: [M+H]+=169.
81%
Stage #1: With potassium carbonate In N,N-dimethyl-formamide for 0.0833333 h; Stage #2: at 20℃; for 2 h;
To a solution of 2-amino-3-nitrophenol (2.55 g, 16.55 mmol) dissolved in N,Ndimethylformamide (35 mL) was added potassium carbonate (2.52 g, 18.20 mmol). The mixturewas stirred for 5 mm before iodomethane (1 .138 mL, 18.20 mmol) was added and the reactionallowed to stir at ambient temperature for 2 h. water75 mL) was added to quench the reactionand the precipitate product was collected by filtration, washed with water to afford the titlecompound 2-methoxy-6-nitroaniline (2.26 g, 81 percent). LC-MS m/z 168.9 (M+H), 0.74 mm (ret.time)
81%
at 20℃; for 2 h;
To a solution of 2-amino-3-nitrophenol (2.55 g, 16.55 mmol) dissolved in N,N- dimethylformamide (35 mL) was added potassium carbonate (2.52 g, 18.20 mmol). The mixture was stirred for 5 min before iodomethane (1.138 mL, 18.20 mmol) was added and the reaction allowed to stir at ambient temperature for 2 h. water75 mL) was added to quench the reaction and the precipitate product was collected by filtration, washed with water to afford the title compound 2-methoxy-6-nitroaniline (2.26 g, 81 percent). LC-MS m/z 168.9 (M+H)+, 0.74 min (ret. time)
76%
With potassium carbonate In water; N,N-dimethyl-formamide
Step 1. 2-Methoxy-6-nitrophenylamine. To a solution of 2-amino-3-nitrophenol (5 g, 32.4 mmol) in DMF (165 ml) were sequentially added potassium carbonate (9.0 g, 65 mmol) and methyl iodide (2.2 ml, 35 mmol). The mixture was heated at 50° C. overnight before it was cooled to room temperature, mixed with water (300 ml), and extracted with ethyl acetate (3*50 ml). The extracts were combined, washed with water (150 ml), brine (80 ml), and dried (MgSO4). Removal of the solvent under reduced pressure gave a dark orange solid that was triturated with 1:1 hexane/ether. The solids were collected by filtration to give product 136 as orange needles (4.1 g, 76percent).
50%
With caesium carbonate In tetrahydrofuran at 18 - 25℃; for 144 h;
In the case of SM Ic an additional step needed to be carried out as shown below: 2-amino-3-nitro-6methoxybenzene:Into a 250ml round bottom flask was fed 2-amino-3-nitrophenol (2.04g, 13.24mmol) and 50ml anhydrous THF. Cesium carbonate (18.98g, 58.26mmol) was added into the solution followed by methyl iodide (2.07g, 14.56mmol). The mixture was stirred 6 days at room temperature. The resulting mixture was filtered and washed with DCM. The solvent was removed on a rotary evaporator. The crude material was purified by silica gel chromatography (gradient elution; EtOAc: Hexane 20percent) to afford title compound (l.lg, 50percent) M/Z 168.
29.4 g
With tetra-(n-butyl)ammonium iodide; sodium hydroxide In tetrahydrofuran; water at 20℃;
INTERMEDIATE (7-Bromo-5 -methoxy-3 -methyl-quinoxalin-2-yl)-hydrazine (Ilq). 2-Amino-3-nitrophenol (25 g) and NaOH (25.0 g) were dissolved in a mixture of THF (500 mL) and water (200 mL). TBAI (2.5 g) and methyl iodide (21.2 mL) were added. The mixture was stirred overnight at ambient temperature. Most of the THF was removed in vacuo. The residue was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO i, filtered, and concentrated in vacuo to afford 2-methoxy-6-nitro-phenyl amine (29.4 g). 22 g of this material and NaOAc (17.8 g) were mixed in acetic acid (300 mL) at ambient temperature. Bromine (6.9 mL) in acetic acid (5 mL) was added drop-wise over 15 min. The precipitated solid was filtered off, washed with water and heptanes, and dried to afford 4-bromo-2-methoxy-6-nitro-phenylamine (25.5 g). 2.47 g of this material dissolved in DCM (100 mL). DMAP (1.22 g) and Boc20 (2.62 g) were added, and the mixture was overnight at ambient temperature. The volatiles were removed in vacuo. The residue was purified by chromatography on silica gel (eluent: heptanes→ EtOAc). Fractions containing the desired material were pooled and most of the EtOAc was removed in vacuo. The residual solution was diluted with heptanes, and the resulting mixture was allowed to stand at ambient temperature overnight. The precipitated solid was filtered off and dried to afford (4-bromo- 2-methoxy-6-nitro-phenyl)-iminocarbonicacid-bis-(tert-butyl ester) (3.94 g). A larger portion of this material (25.6 g) prepared in a similar manner was dissolved in ethanol (700 mL). 5percent Platinum on charcoal (4.0 g) was added, and the mixture was treated with hydrogen gas (1 bar) for 45 min using a Parr shaker instrument. The catalyst was filtered off. The filtrate was concentrated in vacuo. The residual solid was suspended in heptanes, filtered, and dried to afford 6-amino-4-bromo-2-methoxy- phenyl)-iminocabonicacid-bis (fert-butyl ester) (22.0 g). This material was dissolved in DCM (250 mL) and treated with TFA (5 mL) overnight at ambient temperature. The volatiles were removed in vacuo. The residue was partitioned between EtOAc and 2M aq NaOH (until pH was 9). The organic layer was dried over MgSO i, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent: heptanes→ EtOAc) to afford the mono-deprotected material (ca 11 g). This material was dissolved in a mixture of DCM (100 mL) and TFA (50 mL) and stirred overnight at ambient temperature. The volatiles were removed in vacuo. The residue was partitioned between EtOAc and 2M NaOH (until pH 9). The organic layer was dried over MgSO i, filtered, and concentrated in vacuo to afford 5-bromo-3-methoxy-benzene-l,2-diamine (3.63 g). This material was dissolved in methanol (200 mL). 2-Oxo-propanoic acid methyl ester (2.0 g) was added, and the mixture was stirred overnight at ambient temperature. The precipitated 7-bromo-5-methoxy-3- methyl-lH-quinoxalin-2-one was filtered off. The filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent: heptanes→ EtOAc) to afford more 7-bromo- 5-methoxy-3-methyl-lH-quinoxalin-2-one as the first eluting isomer followed by 6-bromo-8- methoxy-3-methyl-lH-quinoxalin-2-one as the second eluting isomer. The two crops of 7-bromo-5- methoxy-3-methyl-lH-quinoxalin-2-one were mixed and washed with a little acetone to afford 7- bromo-5-methoxy-3 -methyl- lH-quinoxalin-2-one (1.7 g) sufficiently pure for the next step. The fractions containing the second eluting isomer were pooled and concentrated in vacuo; the residual solid was washed with a little acetone to afford 6-bromo-8-methoxy-3-methyl-lH-quinoxalin-2-one (0.61 g) sufficiently pure for the next step. The structure of the isomers were elucidated by identifying the nitrogen carrying a proton by 2D HSQC and comparing with the shift of the nitrogen having long range correlation to an aromatic proton in 2D HMBC. 7-Bromo-5- methoxy-3-methyl-lH-quinoxalin-2-one (1.7 g) was refluxed in phosphoryl chloride (23 mL) for 2h. The volatiles were removed in vacuo. The residue was partitioned between DCM and ice/water. The mixture was basified with 2M aq Na2C03. The organic layer was dried over MgSO i, filtered, and concentrated in vacuo to afford 7-bromo-2-chloro-5-methoxy-3-methyl-quinoxaline (0.61 g). This material was dissolved in ethanol (38 mL). Hydrazine hydrate (3 mL) was added and the mixture was refluxed for 2h. The volatiles were removed in vacuo. The residual solid was suspended in water, filtered off, washed with heptanes, and dried to afford Ilq (0.58 g) sufficiently pure for the next step.
29.4 g
With tetra-(n-butyl)ammonium iodide; sodium hydroxide In tetrahydrofuran; water at 20℃;
INTERMEDIATE 6-Bromo-8-methoxy-3-methyl-quinoxalin-2-yl)-hydrazine (Ilf). 2-Amino-3-nitrophenol (25 g) and NaOH (25.0 g) were dissolved in a mixture of THF (500 mL) and water (200 mL). TBAI (2.5 g) and methyl iodide (21.2 mL) were added. The mixture was stirred overnight at ambient temperature. Most of the THF was removed in vacuo. The residue was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO i, filtered, and concentrated in vacuo to afford 2-methoxy-6-nitro-phenyl amine (29.4 g). 22 g of this material and NaOAc (17.8 g) were mixed in acetic acid (300 mL) at ambient temperature. Bromine (6.9 mL) in acetic acid (5 mL) was added drop-wise over 15 min. The precipitated solid was filtered off, washed with water and heptanes, and dried to afford 4-bromo-2-methoxy-6-nitro- phenylamine (25.5 g). 2.47 g of this material dissolved in DCM (100 mL). DMAP (1.22 g) and B0C2O (2.62 g) were added, and the mixture was overnight at ambient temperature. The volatiles were removed in vacuo. The residue was purified by chromatography on silica gel (eluent: heptanes→ EtOAc). Fractions containing the desired material were pooled and most of the EtOAc was removed in vacuo. The residual solution was diluted with heptanes, and the resulting mixture was allowed to stand at ambient temperature overnight. The precipitated solid was filtered off and dried to afford (4-bromo-2-methoxy-6-nitro-phenyl)-iminocarbonicacid-bis-(tert-butyl ester) (3.94 g). A larger portion of this material (25.6 g) prepared in a similar manner was dissolved in ethanol (700 mL). 5percent Platinum on charcoal (4.0 g) was added, and the mixture was treated with hydrogen gas (1 bar) for 45 min using a Parr shaker instrument. The catalyst was filtered off. The filtrate was concentrated in vacuo. The residual solid was suspended in heptanes, filtered, and dried to afford 6-amino-4-bromo-2-methoxy-phenyl)-iminocabonicacid-bis (tert- butyl ester) (22.0 g). This material was dissolved in DCM (250 mL) and treated with TFA (5 mL) overnight at ambient temperature. The volatiles were removed in vacuo. The residue was partitioned between EtOAc and 2M aq NaOH (until pH was 9). The organic layer was dried over MgSO i, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent: heptanes→ EtOAc) to afford the mono-deprotected material (ca 11 g). This material was dissolved in a mixture of DCM (100 mL) and TFA (50 mL) and stirred overnight at ambient temperature. The volatiles were removed in vacuo. The residue was partitioned between EtOAc and 2M NaOH (until pH 9). The organic layer was dried over MgS04, filtered, and concentrated in vacuo to afford 5-bromo-3-methoxy-benzene-l,2-diamine (3.63 g). This material was dissolved in methanol (200 mL). 2-Oxo-propanoic acid methyl ester (2.0 g) was added, and the mixture was stirred overnight at ambient temperature. The precipitated 7-bromo-5-methoxy-3-methyl-lH- quinoxalin-2-one was filtered off. The filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent: heptanes→ EtOAc) to afford more 7-bromo-5-methoxy- 3-methyl-lH-quinoxalin-2-one as the first eluting isomer followed by 6-bromo-8-methoxy-3- methyl-lH-quinoxalin-2-one as the second eluting isomer. The two crops of 7-bromo-5-methoxy- 3-methyl-lH-quinoxalin-2-one were mixed and washed with a little acetone to afford 7-bromo-5- methoxy-3-methyl-lH-quinoxalin-2-one (1.7 g) sufficiently pure for the next step. The fractions containing the second eluting isomer were pooled and concentrated in vacuo; the residual solid was washed with a little acetone to afford 6-bromo-8-methoxy-3-methyl-lH-quinoxalin-2-one (0.61 g) sufficiently pure for the next step. The structure of the isomers were elucidated by identifying the nitrogen carrying a proton by 2D ^N-'H HSQC and comparing with the shift of the nitrogen having long range correlation to an aromatic proton in 2D ^N-'H HMBC. 6-bromo- 8-methoxy-3-methyl-lH-quinoxalin-2-one (1.7 g) was dissolved in phosphoryl chloride (23 mL) was refluxed for 2h. The volatiles were removed in vacuo. The residue was partitioned between DCM and a little ice. The biphasic mixture was basified with 2M aq Na2C03 and was filtered. The organic part of the filtrate was dried over MgSO i, filtered, and concentrated in vacuo to afford 7- bromo-3-chloro-5-methoxy-2-methyl-quinoxaline (1.1 g). This material was dissolved in ethanol (38 mL). Hydrazine hydrate (3 mL) was added, and the mixture was refluxed for 2h. The volatiles were removed in vacuo. The residue was suspended in water (50 mL). The solid was filtered off, washed with heptanes and dried to afford Ilf (1.6 g) sufficiently pure for the next step.
9.85 g
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2 h;
C) 2-Methoxy-6-nitroaniline To a solution of 2-amino-3-nitrophenol (9.12 g) and potassium carbonate (13.6 g) in DMF (100 mL), iodomethane (4.44 mL) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture at room temperature. The deposited solid was collected by filtration and washed with water and hexane to obtain the title compound (9.85 g). 1H NMR (300MHz, DMSO-d6) δ 3.88 (3H, s), 6.61 (1H, dd, J = 8.9, 7.7 Hz), 6.95-7.17 (3H, m), 7.59 (1H, dd, J = 8.9, 1.3 Hz).
Reference：
[1] Patent: WO2012/40040, 2012, A1, . Location in patent: Page/Page column 47-48
[2] Journal of Medicinal Chemistry, 2006, vol. 49, # 17, p. 5352 - 5362
[3] Patent: US2012/88767, 2012, A1, . Location in patent: Page/Page column 16; 22
[4] Journal of Asian Natural Products Research, 2011, vol. 13, # 4, p. 330 - 340
[5] European Journal of Medicinal Chemistry, 2013, vol. 68, p. 222 - 232
[6] Patent: WO2015/92713, 2015, A1, . Location in patent: Page/Page column 69; 154; 155
[7] Journal of Medicinal Chemistry, 2016, vol. 59, # 8, p. 3991 - 4006
[8] Patent: WO2016/203400, 2016, A1, . Location in patent: Page/Page column 45; 46
[9] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3515 - 3527
[10] Patent: US2007/249595, 2007, A1, . Location in patent: Page/Page column 8-9
[11] Patent: US2006/63817, 2006, A1, . Location in patent: Page/Page column 12
[12] Patent: US2007/203125, 2007, A1, . Location in patent: Page/Page column 35
[13] Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 4003 - 4015
[14] Patent: US6369235, 2002, B1, . Location in patent: Example 46
[15] Patent: WO2016/203401, 2016, A1, . Location in patent: Page/Page column 102
[16] Patent: WO2016/202253, 2016, A1, . Location in patent: Page/Page column 129
[17] Patent: WO2018/104766, 2018, A1, . Location in patent: Page/Page column 102
[18] Patent: US2005/54850, 2005, A1,
[19] Patent: WO2008/56150, 2008, A1, . Location in patent: Page/Page column 180
[20] Journal of Medicinal Chemistry, 1993, vol. 36, # 12, p. 1772 - 1784
[21] Patent: WO2005/70906, 2005, A1, . Location in patent: Page/Page column 21
[22] Patent: US5128356, 1992, A,
[23] Patent: WO2008/42282, 2008, A2, . Location in patent: Page/Page column 131
[24] Patent: US6353010, 2002, B1, . Location in patent: Page column 9
[25] Patent: WO2005/65680, 2005, A1, . Location in patent: Page/Page column 79
[26] Helvetica Chimica Acta, 2009, vol. 92, # 11, p. 2159 - 2172
[27] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 17, p. 5161 - 5164
[28] Patent: WO2008/32027, 2008, A1, . Location in patent: Page/Page column 100
[29] Patent: WO2013/34755, 2013, A1, . Location in patent: Page/Page column 26
[30] Patent: WO2013/34758, 2013, A1, . Location in patent: Page/Page column 19
[31] Patent: EP3287441, 2018, A1, . Location in patent: Paragraph 0490
14
[ 603-85-0 ]
[ 112970-44-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 17, p. 5352 - 5362
[2] Journal of Organic Chemistry, 1988, vol. 53, # 6, p. 1170 - 1176
15
[ 603-85-0 ]
[ 101935-40-4 ]
Yield
Reaction Conditions
Operation in experiment
56%
Stage #1: With hydrogen bromide In 1,4-dioxane; water at 80℃; for 0.5 h; Stage #2: With sodium nitrite In 1,4-dioxane; water at 0℃; Stage #3: With hydrogen bromide; copper(I) bromide In 1,4-dioxane; water at 0 - 60℃;
Example 11 : Preparation of 2-Bromo-3-nitro-phenol; 2-Amino-3-nitrophenol (commercially available) (24.6g, 160 mmol) is suspended in mixture of water (150 ml) and dioxane (75 ml). At 800C hydrobromic acid (48percent, 85 ml) is added dropwise. This mixture is stirred at reflux temperature for 30 minutes and then cooled to 00C. A solution of sodium nitrite (11.04 g, 160 mmol) in Water (100ml) is added dropwise and the reaction mixture is stirred at 00C for 1 hour. The reaction mixture is added dropwise to a solution of CuBr (26.4g, 184 mmol) in Water (150 ml) and hydrobromic acid (48percent, 85 ml). The resulting suspension is stirred at 00C for 30 minutes and at 60°C for 1 hour. The reaction mixture is cooled to room temperature, diluted with Water and extracted three times with ethyl acetate. <n="71"/>The combined organic phases are dried over sodium sulfate and concentrated. The residue is purified by column chromatography on silica gel (eluent: dichloromethane / cyclohexane 7:3) to give 2-Bromo-3-nitro-phenol (19.5g, 56 percent yield) as a yellow solid. 1H-NMR (CDCI3, 400 MHz): 7.50 (d, 1 H), 7.35 (t, 1 H), 7.25 (d, 1 H), 6.05 (s, 1 H) ppm.
56%
Stage #1: With hydrogen bromide In 1,4-dioxane; water at 80℃; Reflux Stage #2: With sodium nitrite In 1,4-dioxane; water at 0℃; Stage #3: With hydrogen bromide In 1,4-dioxane; water at 0 - 60℃;
2-Amino-3-nitrophenol (24.6g, 160 mmol) is suspended in mixture of water (150 ml) and dioxane (75 ml). At 800C hydrobromic acid (48percent, 85 ml) is added dropwise. This mixture is stirred at reflux temperature for 30 minutes and then cooled to 00C. A solution of sodium nitrite (1 1.04 g, 160 mmol) in water (100ml) is added dropwise and the reaction mixture is stirred at 0°C for 1 hour. The reaction mixture is added dropwise to a solution of CuBr (26.4g, 184 mmol) in water (150 ml) and hydrobromic acid (48percent, 85 ml). The resulting suspension is stirred at 00C for 30 minutes and at 600C for 1 hour. The reaction mixture is cooled to room temperature, diluted with water and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. The residue is purified by column <n="67"/>chromatography on silica gel (eluent: dichloromethane / cyclohexane 7:3) to give 2-Bromo-3- nitro-phenol (19.5g, 56 percent yield) as a yellow solid. 1H-NMR (CDCI3, 400 MHz): 7.50 (d, 1 H), 7.35 (t, 1 H), 7.25 (d, 1 H), 6.05 (s, 1 H) ppm.
45%
Stage #1: With hydrogen bromide In 1,4-dioxane; water for 0.25 h; Heating / reflux Stage #2: With sodium nitrite In 1,4-dioxane; water at 0℃; for 0.25 h; Stage #3: With copper(I) bromide In 1,4-dioxane; water at 0 - 60℃; for 0.5 h;
2-Amino-3-nitrophenol B1 (5 g; 32.4 MMOL) was dissolved in H20 (29.5 ML) and 1,4- dioxane (14.7 mL). The mixture was heated to reflux and hydrobromic acid (48percent; 16.7 mL; 147 MMOL) was added dropwise over a period of 20 min. Upon completion of the addition, the reflux was maintained an additional 15 min. The reaction was cooled to 0 C (ice bath), and sodium nitrite (2.23 g; 32.3 MMOL) in H20 (20 mL) was added over a period of 30 min. The stirring was continued for 15 min at 0 C, then the mixture was transferred to a jacketed dropping FUNNEL (0 C) and added dropwise to a stirred mixture of Cu (I) Br (5.34 g; 37.2 MMOL) in H20 (29.5 mL) and HBr (48percent; 16.7 mL; 147 MMOL) at 0°C. The reaction was stirred for 15 min at 0°C, warmed to 60 C, stirred for an additional 15 min, cooled to room temperature, and left to stir overnight. The reaction mixture was transferred to a separatory funnel and extracted with ether (3x 150 mL). The organic layers were combined, washed with brine (1X), dried (Na2SO), filtered and concentrated to afford the crude product (7. 99 g) as a red-brown oil. The crude material was purified by flash column chromatography (1: 25 ultra pure silica gel, 230-400 mesh, 40-60 mm, 60 angstroms; CH2CL2AS the solvent) to afford pure 2-bromo-3-nitrophenol B2 (45percent; 3.16 g) as an orange-brown solid. MS 217. 8 (MH) . Homogeneity by HPLC (TFA) 220 nm: 97percent.
45%
Stage #1: With hydrogen bromide In 1,4-dioxane; water for 0.583333 h; Heating / reflux Stage #2: With sodium nitrite In 1,4-dioxane; water at 0℃; for 0.75 h; Stage #3: With hydrogen bromide; copper(I) bromide In 1,4-dioxane; water at 0 - 60℃; for 0.5 h;
Step A:; 2-Amino-3-nitrophenol 1b1 (5 g; 32.4 mmol) was dissolved in H2O (29.5 ml)and 1,4-dioxane (14.7 mL). The mixture was heated to reflux and hydrobromic acid(48percent; 16.7 mL; 147 mmol) was added dropwise over a period of 20 min. Uponcompletion of the addition, the reflux was maintained an additional 15 min. Thereaction was cooled to 0°C (ice bath), and sodium nitrite (2.23 g; 32.3 mmol) in H2O(20 mL) was added over a period of 30 min. The stirring was continued for 15 min. at0°C, the mixture transferred to a jacketed dropping funnel (0°C) and added dropwiseto a stirred mixture of Cu(l)Br (5.34 g; 37.2 mmol) in H2O (29.5 mL) and HBr (48percent;16.7 mL; 147 mmol) at 0°C. The reaction was stirred for 15 min. at 0°C, warmed to60°C, stirred for an additional 15 min., cooled to room temperature, and left to stirovernight. The reaction mixture was transferred to a separatory funnel and extractedwith ether (3 X 150 mL). The organic layers were combined, washed with brine (1 X),dried (Na2SO4), filtered and concentrated to afford the crude product (7.99 g) as a red-brown oil. The crude material was purified by flash column chromatography (1:25 ultrapure silica gel, 230-400 mesh, 40-60mm, 60 angstroms; CH2CI2 as the solvent) toafford pure 2-bromo-3-nitrophenol 1b2 (45percent; 3.16 g) as an orange-brown solid. MS217.8 (MM)'. Homogeneity by HPLC (TFA) (at) 220 nm: 97percent.
45%
Stage #1: With hydrogen bromide In 1,4-dioxane; water for 0.583333 h; Heating / reflux Stage #2: With sodium nitrite In 1,4-dioxane; water at 0℃; for 0.75 h; Stage #3: With hydrogen bromide; copper(I) bromide In 1,4-dioxane; water at 0 - 60℃;
2-Amino-3-nitrophenol 1b1 (5 g; 32.4 mmol) was dissolved in H2O (29.5 mL) and 1,4-dioxane (14.7 mL). The mixture was heated to reflux and hydrobromic acid (48percent; 16.7 mL; 147 mmol) was added dropwise over a period of 20 min. Upon completion of the addition, the reflux was maintained an additional 15 min. The reaction was cooled to 0° C. (ice bath), and sodium nitrite (2.23 g; 32.3 mmol) in H2O (20 mL) was added over a period of 30 min. The stirring was continued for 15 min. at 0° C., the mixture transferred to a jacketed dropping funnel (0° C.) and added dropwise to a stirred mixture of Cu(I)Br (5.34 g; 37.2 mmol) in H2O (29.5 mL) and HBr (48percent; 16.7 mL; 147 mmol) at 0° C. The reaction was stirred for 15 min. at 0° C., warmed to 60° C., stirred for an additional 15 min., cooled to room temperature, and left to stir overnight. The reaction mixture was transferred to a separatory funnel and extracted with ether (3*150 mL). The organic layers were combined, washed with brine (1*), dried (Na2SO4), filtered and concentrated to afford the crude product (7.99 g) as a red-brown oil. The crude material was purified by flash column chromatography (1:25 ultra pure silica gel, 230-400 mesh, 40-60mm, 60 angstroms; CH2Cl2as the solvent) to afford pure 2-bromo-3-nitrophenol 1b2 (45percent; 3.16 g) as an orange-brown solid. MS 217.8 (MH)-. Homogeneity by HPLC (TFA)at;220 nm: 97percent.
45%
Stage #1: With hydrogen bromide In 1,4-dioxane; water for 0.583333 h; Heating / reflux Stage #2: With sodium nitrite In 1,4-dioxane; water at 0℃; for 0.75 h; Stage #3: With copper(I) bromide In 1,4-dioxane; water at 0 - 60℃;
2-Amino-3-nitrophenol 2b1 (5 g; 32.4 mmol) was dissolved in H2O (29.5 ml)and 1,4-dioxane (14.7 ml). The mixture was heated to reflux and hydrobromic acid(48percent; 16.7 ml 147 mmol) was added dropwise over a period of 20 min. Uponcompletion of the addition, the reflux was maintained an additional 15 min. Thereaction was cooled to 0°C (ice bath), and sodium nitrite (2.23 g; 32.3 mmol) in H2O(20 mL) was added over a period of 30 min. The stirring was continued for 15 min. at0°C, the mixture transferred to a jacketed dropping funnel (0°C) and added dropwiseto a stirred mixture of Cu(l)Br (5.34 g; 37.2 mmol) in H2O( 29.5 mL) and HBr (48percent;16.7 mL; 147 mmol) at 0°C. The reaction was stirred for 15 min. at 0°C, warmed to60°C, stirred for an additional 15 min., cooled to room temperature, and left to stirovernight. The reaction mixture was transferred to a separatory funnel and extractedwith ether (3 X 150 mL). The organic layers were combined, washed with brine (1 X),dried (Na2SO4), filtered and concentrated to afford the crude product (7.99 g ) as ared-brown oil. The crude material was purified by flash column chromatpgraphy (1:25ultra pure silica gel, 230-400 mesh, 40-60mm, 60 angstroms; CH2CI2as the solvent)to afford pure 2-bromo-3-nitrophenol 2b2 (45percent; 3.16 g ) as an orange-brown solid.MS 217.8 (MH)'. Homogeneity by HPLC (TFA) (at) 220 nm: 97percent.
45%
Stage #1: With hydrogen bromide In 1,4-dioxane; water for 0.583333 h; Heating / reflux Stage #2: With sodium nitrite In 1,4-dioxane; water at 0℃; for 0.75 h; Stage #3: With hydrogen bromide; copper(I) bromide In 1,4-dioxane; water at 0 - 60℃;
EXAMPLE 2B; Synthesis of 2-bromo-3-methoxy aniline (2B4); Step A; 2-Amino-3-nitrophenol 2B1 (5 g; 32.4 mmol) was dissolved in H2O (29.5 mL) and 1 ,4-dioxane (14.7 mL). The mixture was heated to reflux and hydrobromic acid (48percent; 16.7 mL; 147 mmol) was added dropwise over a period of 20 min. Upon completion of the addition, the reflux was maintained an additional 15 min. The reaction was cooled to 00C (ice bath), and sodium nitrite (2.23 g; 32.3 mmol) in H2O (20 mL) was added over a period of 30 min. The stirring was continued for 15 min. at 00C, the mixture EPO <DP n="36"/>transferred to a jacketed dropping funnel (00C) and added dropwise to a stirred mixture of Cu(I)Br (5.34 g; 37.2 mmol) in H2O (29.5 mL) and HBr (48percent; 16.7 ml 147 mmol) at 00C. The reaction was stirred for 15 min. at O0C, warmed to 60°C, stirred for an additional 15 min., cooled to room temperature, and left to stir overnight. The reaction mixture was transferred to a separatory funnel and extracted with ether (3 X 150 mL). The organic layers were combined, washed with brine (1 X), dried (Na2SO4), filtered and concentrated to afford the crude product (7.99 g) as a red-brown oil. The crude material was purified by flash column chromatography (1 :25 ultra pure silica gel, 230-400 mesh, 40-60mm, 60 angstroms; CH2CI2 as the solvent) to afford pure 2-bromo-3-nitro-phenol 2B2 (45percent; 3.16 g) as an orange-brown solid. MS 217.8 (MH)-. Homogeneity by HPLC (TFA) (at) 220 nm: 97percent.
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 42, p. 9996 - 10000
[2] Patent: JP2005/522501, 2005, A, . Location in patent: Page/Page column 18
[3] Patent: WO2009/92590, 2009, A2, . Location in patent: Page/Page column 69-70
[4] Patent: WO2009/109539, 2009, A2, . Location in patent: Page/Page column 65; 66
[5] Patent: WO2004/103996, 2004, A1, . Location in patent: Page 40
[6] Patent: WO2006/7700, 2006, A1, . Location in patent: Page/Page column 61-62
[7] Patent: US2006/19905, 2006, A1, . Location in patent: Page/Page column 24
[8] Patent: WO2006/85, 2006, A1, . Location in patent: Page/Page column 75-76
[9] Patent: WO2007/9227, 2007, A1, . Location in patent: Page/Page column 34-35
[10] Journal of Organic Chemistry, 1988, vol. 53, # 6, p. 1170 - 1176
16
[ 603-85-0 ]
[ 100367-36-0 ]
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, # 6, p. 1170 - 1176
[2] Chemistry - A European Journal, 2017, vol. 23, # 42, p. 9996 - 10000
17
[ 603-85-0 ]
[ 89521-55-1 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1983, vol. 20, # 6, p. 1525 - 1532
[2] Archives of Pharmacal Research, 2017, vol. 40, # 4, p. 469 - 479
[3] Patent: WO2016/200840, 2016, A1,
[4] Journal of Medicinal Chemistry, 2018, vol. 61, # 8, p. 3309 - 3324
With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; for 12h;
Example 1 : 1 l-(3-chlorophenyl)-6-hydroxy-3,3-dimethyl-2,3,4,5,10,l 1-hexahydro- dibenzo|", e]\\ ,41diazepin- 1 -one (6).; Step l; A mixture of 2-amino-3-nitrophenol (10.0 g, 64.9 mmol), 10percent Pd/C in ethanol (150 mL), was hydrogenated at room temperature for 12 h. Then, the reaction mixture was degassed with nitrogen. The catalyst was removed by filtration and washed extensively with ethanol. The filtrate was evaporated to give 8.0 g (99percent) of the desired product as a black solid.
99%
With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; for 12h;
Step 3. synthesis of 2,3-diaminophenol (4). ; <n="39"/>A mixture of 2-amino-3-nitrophenol (10.0 g, 64.9 mmol), 10percent Pd/C in ethanol (150 mL), was hydrogenated at room temperature for 12h. Then, the reaction mixture was degassed with nitrogen. The catalyst was removed by filtration and washed extensively with ethanol. The filtrate was evaporated to give 8.0 g (99percent) of the desired product as a black solid.
98%
With hydrogen; at 20℃; for 6h;
General procedure: To a solution of 4-amino-3-nitrophenol (28, 5.0 g, 32.44 mmol) was added cautiously Raney-Ni (1.0 g, wet weight) under N2 atmosphere. Then the suspended solution was degassed with H2 three times. The mixture was stirred for 6 h at room temperature under H2 balloon. The resulting reaction mixture was filtered through a celite pad. The filtrate was evaporated directly under reduced pressure to provide the intermediate 29 (3.83 g, 95percent yield) as a black solid which was used directly in the next step.
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 2h;
General procedure: In a 250 mL parr shaker vessel, a mixture of the corresponding alkyl substituted nitro aminophenol 3 (3.99 mmol) in methanol (30 mL) was placed and then added 10percent Pd?C (20percent w/w). The resulting solution was stirred at ambient temperature for 2 h in the presence of hydrogen gas. After completion of the reaction, the mixture was filtered through celite bed and washed with methanol, and then the filtrate was evaporated under vacuum to afford the title compounds. These compounds were used for the next step without further purification.
Example 11 : Preparation of 2-Bromo-3-nitro-phenol; 2-Amino-3-nitrophenol (commercially available) (24.6g, 160 mmol) is suspended in mixture of water (150 ml) and dioxane (75 ml). At 800C hydrobromic acid (48%, 85 ml) is added dropwise. This mixture is stirred at reflux temperature for 30 minutes and then cooled to 00C. A solution of sodium nitrite (11.04 g, 160 mmol) in Water (100ml) is added dropwise and the reaction mixture is stirred at 00C for 1 hour. The reaction mixture is added dropwise to a solution of CuBr (26.4g, 184 mmol) in Water (150 ml) and hydrobromic acid (48%, 85 ml). The resulting suspension is stirred at 00C for 30 minutes and at 60C for 1 hour. The reaction mixture is cooled to room temperature, diluted with Water and extracted three times with ethyl acetate. <n="71"/>The combined organic phases are dried over sodium sulfate and concentrated. The residue is purified by column chromatography on silica gel (eluent: dichloromethane / cyclohexane 7:3) to give 2-Bromo-3-nitro-phenol (19.5g, 56 % yield) as a yellow solid. 1H-NMR (CDCI3, 400 MHz): 7.50 (d, 1 H), 7.35 (t, 1 H), 7.25 (d, 1 H), 6.05 (s, 1 H) ppm.
56%
2-Amino-3-nitrophenol (24.6g, 160 mmol) is suspended in mixture of water (150 ml) and dioxane (75 ml). At 800C hydrobromic acid (48%, 85 ml) is added dropwise. This mixture is stirred at reflux temperature for 30 minutes and then cooled to 00C. A solution of sodium nitrite (1 1.04 g, 160 mmol) in water (100ml) is added dropwise and the reaction mixture is stirred at 0C for 1 hour. The reaction mixture is added dropwise to a solution of CuBr (26.4g, 184 mmol) in water (150 ml) and hydrobromic acid (48%, 85 ml). The resulting suspension is stirred at 00C for 30 minutes and at 600C for 1 hour. The reaction mixture is cooled to room temperature, diluted with water and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. The residue is purified by column <n="67"/>chromatography on silica gel (eluent: dichloromethane / cyclohexane 7:3) to give 2-Bromo-3- nitro-phenol (19.5g, 56 % yield) as a yellow solid. 1H-NMR (CDCI3, 400 MHz): 7.50 (d, 1 H), 7.35 (t, 1 H), 7.25 (d, 1 H), 6.05 (s, 1 H) ppm.
45%
2-Amino-3-nitrophenol B1 (5 g; 32.4 MMOL) was dissolved in H20 (29.5 ML) and 1,4- dioxane (14.7 mL). The mixture was heated to reflux and hydrobromic acid (48%; 16.7 mL; 147 MMOL) was added dropwise over a period of 20 min. Upon completion of the addition, the reflux was maintained an additional 15 min. The reaction was cooled to 0 C (ice bath), and sodium nitrite (2.23 g; 32.3 MMOL) in H20 (20 mL) was added over a period of 30 min. The stirring was continued for 15 min at 0 C, then the mixture was transferred to a jacketed dropping FUNNEL (0 C) and added dropwise to a stirred mixture of Cu (I) Br (5.34 g; 37.2 MMOL) in H20 (29.5 mL) and HBr (48%; 16.7 mL; 147 MMOL) at 0C. The reaction was stirred for 15 min at 0C, warmed to 60 C, stirred for an additional 15 min, cooled to room temperature, and left to stir overnight. The reaction mixture was transferred to a separatory funnel and extracted with ether (3x 150 mL). The organic layers were combined, washed with brine (1X), dried (Na2SO), filtered and concentrated to afford the crude product (7. 99 g) as a red-brown oil. The crude material was purified by flash column chromatography (1: 25 ultra pure silica gel, 230-400 mesh, 40-60 mm, 60 angstroms; CH2CL2AS the solvent) to afford pure 2-bromo-3-nitrophenol B2 (45%; 3.16 g) as an orange-brown solid. MS 217. 8 (MH) . Homogeneity by HPLC (TFA) 220 nm: 97%.
45%
Step A:; 2-Amino-3-nitrophenol 1b1 (5 g; 32.4 mmol) was dissolved in H2O (29.5 ml)and 1,4-dioxane (14.7 mL). The mixture was heated to reflux and hydrobromic acid(48%; 16.7 mL; 147 mmol) was added dropwise over a period of 20 min. Uponcompletion of the addition, the reflux was maintained an additional 15 min. Thereaction was cooled to 0C (ice bath), and sodium nitrite (2.23 g; 32.3 mmol) in H2O(20 mL) was added over a period of 30 min. The stirring was continued for 15 min. at0C, the mixture transferred to a jacketed dropping funnel (0C) and added dropwiseto a stirred mixture of Cu(l)Br (5.34 g; 37.2 mmol) in H2O (29.5 mL) and HBr (48%;16.7 mL; 147 mmol) at 0C. The reaction was stirred for 15 min. at 0C, warmed to60C, stirred for an additional 15 min., cooled to room temperature, and left to stirovernight. The reaction mixture was transferred to a separatory funnel and extractedwith ether (3 X 150 mL). The organic layers were combined, washed with brine (1 X),dried (Na2SO4), filtered and concentrated to afford the crude product (7.99 g) as a red-brown oil. The crude material was purified by flash column chromatography (1:25 ultrapure silica gel, 230-400 mesh, 40-60mm, 60 angstroms; CH2CI2 as the solvent) toafford pure 2-bromo-3-nitrophenol 1b2 (45%; 3.16 g) as an orange-brown solid. MS217.8 (MM)'. Homogeneity by HPLC (TFA) (at) 220 nm: 97%.
45%
2-Amino-3-nitrophenol 1b1 (5 g; 32.4 mmol) was dissolved in H2O (29.5 mL) and 1,4-dioxane (14.7 mL). The mixture was heated to reflux and hydrobromic acid (48%; 16.7 mL; 147 mmol) was added dropwise over a period of 20 min. Upon completion of the addition, the reflux was maintained an additional 15 min. The reaction was cooled to 0 C. (ice bath), and sodium nitrite (2.23 g; 32.3 mmol) in H2O (20 mL) was added over a period of 30 min. The stirring was continued for 15 min. at 0 C., the mixture transferred to a jacketed dropping funnel (0 C.) and added dropwise to a stirred mixture of Cu(I)Br (5.34 g; 37.2 mmol) in H2O (29.5 mL) and HBr (48%; 16.7 mL; 147 mmol) at 0 C. The reaction was stirred for 15 min. at 0 C., warmed to 60 C., stirred for an additional 15 min., cooled to room temperature, and left to stir overnight. The reaction mixture was transferred to a separatory funnel and extracted with ether (3*150 mL). The organic layers were combined, washed with brine (1*), dried (Na2SO4), filtered and concentrated to afford the crude product (7.99 g) as a red-brown oil. The crude material was purified by flash column chromatography (1:25 ultra pure silica gel, 230-400 mesh, 40-60mm, 60 angstroms; CH2Cl2as the solvent) to afford pure 2-bromo-3-nitrophenol 1b2 (45%; 3.16 g) as an orange-brown solid. MS 217.8 (MH)-. Homogeneity by HPLC (TFA)a220 nm: 97%.
45%
2-Amino-3-nitrophenol 2b1 (5 g; 32.4 mmol) was dissolved in H2O (29.5 ml)and 1,4-dioxane (14.7 ml). The mixture was heated to reflux and hydrobromic acid(48%; 16.7 ml 147 mmol) was added dropwise over a period of 20 min. Uponcompletion of the addition, the reflux was maintained an additional 15 min. Thereaction was cooled to 0C (ice bath), and sodium nitrite (2.23 g; 32.3 mmol) in H2O(20 mL) was added over a period of 30 min. The stirring was continued for 15 min. at0C, the mixture transferred to a jacketed dropping funnel (0C) and added dropwiseto a stirred mixture of Cu(l)Br (5.34 g; 37.2 mmol) in H2O( 29.5 mL) and HBr (48%;16.7 mL; 147 mmol) at 0C. The reaction was stirred for 15 min. at 0C, warmed to60C, stirred for an additional 15 min., cooled to room temperature, and left to stirovernight. The reaction mixture was transferred to a separatory funnel and extractedwith ether (3 X 150 mL). The organic layers were combined, washed with brine (1 X),dried (Na2SO4), filtered and concentrated to afford the crude product (7.99 g ) as ared-brown oil. The crude material was purified by flash column chromatpgraphy (1:25ultra pure silica gel, 230-400 mesh, 40-60mm, 60 angstroms; CH2CI2as the solvent)to afford pure 2-bromo-3-nitrophenol 2b2 (45%; 3.16 g ) as an orange-brown solid.MS 217.8 (MH)'. Homogeneity by HPLC (TFA) (at) 220 nm: 97%.
45%
EXAMPLE 2B; Synthesis of 2-bromo-3-methoxy aniline (2B4); Step A; 2-Amino-3-nitrophenol 2B1 (5 g; 32.4 mmol) was dissolved in H2O (29.5 mL) and 1 ,4-dioxane (14.7 mL). The mixture was heated to reflux and hydrobromic acid (48%; 16.7 mL; 147 mmol) was added dropwise over a period of 20 min. Upon completion of the addition, the reflux was maintained an additional 15 min. The reaction was cooled to 00C (ice bath), and sodium nitrite (2.23 g; 32.3 mmol) in H2O (20 mL) was added over a period of 30 min. The stirring was continued for 15 min. at 00C, the mixture EPO <DP n="36"/>transferred to a jacketed dropping funnel (00C) and added dropwise to a stirred mixture of Cu(I)Br (5.34 g; 37.2 mmol) in H2O (29.5 mL) and HBr (48%; 16.7 ml 147 mmol) at 00C. The reaction was stirred for 15 min. at O0C, warmed to 60C, stirred for an additional 15 min., cooled to room temperature, and left to stir overnight. The reaction mixture was transferred to a separatory funnel and extracted with ether (3 X 150 mL). The organic layers were combined, washed with brine (1 X), dried (Na2SO4), filtered and concentrated to afford the crude product (7.99 g) as a red-brown oil. The crude material was purified by flash column chromatography (1 :25 ultra pure silica gel, 230-400 mesh, 40-60mm, 60 angstroms; CH2CI2 as the solvent) to afford pure 2-bromo-3-nitro-phenol 2B2 (45%; 3.16 g) as an orange-brown solid. MS 217.8 (MH)-. Homogeneity by HPLC (TFA) (at) 220 nm: 97%.
With sodium hydroxide; benzyltri(n-butyl)ammonium chloride In dichloromethane; water at 20℃; for 96h;
10
Example 10; 7-(β-D-Glucopyranosyloxy)-1-(4-methylbenzyl)-1H-benzimidazole; [Show Image] To a mixture of 2-amino-3-nitrophenol (0.5g), 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (1.88 g) and benzyltri (n-butyl) ammonium chloride (1.01g) in methylene chloride (15 mL) was added 5 mol/L aqueous sodium hydroxide solution (3.24 mL), and the mixture was stirred at room temperature for 4 days. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with 0.5 mol/L hydrochloric acid, water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 4/1) to give 2-amino-3-nitrophenyl, 2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranoside(0.99 g). This material was dissolved in tetrahydrofuran (15 mL). To the solution was added 10% palladium-carbon powder (500 mg) , and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 3/1 - 1.5/1) to give 2, 3-diaminophenyl 2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranoside (0.53 g). To the obtained 2,3-diaminophenyl 2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranoside (0.2g) were added triethyl orthoformate (0.24 g) and a catalytic amount of p-toluenesulfonic acid monohydrate, and the mixture was stirred at 130°C for 3 minutes. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 1/1 - 1/2) to give 4-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-benzimidazole (0.16 g). To this material were added cesium carbonate (0.13 g), 4-methylbenzyl chloride (40mg), a catalytic amount of sodium iodide and N,N-dimethylformamide (4 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give a mixture (0.16 g) of 1-(4-methylbenzyl)-7-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-benzimidazole and 1-(4-methylbenzyl)-4-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-benzimidazole. This material was dissolved in methanol (2 mL). To the solution were added water (0.2 mL) and lithium hydroxide monohydrate (43 mg), and the mixture was stirred at roomtemperature for 8 hours. After purification of the reaction mixture by column chromatography on silica gel (eluent: methylene chloride/methanol=5/1), the crystals obtained by concentration of the fractions were treated with methanol. The precipitated isomer was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (12 mg). 1H-NMR (CD3OD) δ ppm: 2.29 (3H, s), 3 . 3-3 . 55 (4H, m), 3.68 (1H, dd, J=12.4Hz, 6.2Hz), 3.88 (1H, dd, J=12.4Hz, 2.2Hz), 5.08 (1H, d, J=7.5Hz), 5.61 (1H, d, J=15.3Hz), 5.86 (1H, d, J=15.3Hz), 7.05-7.2 (6H, m), 7.33 (1H, d, J=8.0Hz), 8.09 (1H, s).
Example 10 [:] Synthesis of [2-CHLORO-3- (2, 2-DIMETHYL-4-PHENETHYLSULFANYLMETHYL-1,] 2- dihydroquinoline-6-yl) phenol OH z O < CI 8r OrB/ H H Suzuki OH OH ci ci I I I/ I N N H H 10 To a suspension of 2-amino-3-nitrophenol (10 g, 65 mmol) in concentrated [HC1] (10 mL) at [0C,] sodium nitrite (5.1 g, 73.3 mmol) in water (60 [ML)] was added dropwise. After stirring for 30 minutes at [0C,] CuCl (12.8 g, [130] mmol) in 10% [H2SO4] (3 mL) was added and the reaction was stirred for 18 hours. The heterogeneous mixture was filtered and washed with water. The filtrate was extracted three times with 70 mL portions of EtOAc. Evaporation of EtOAc extractions afforded 7 grams (62% yield) of pure [2-CHLORO-3-NITROPHENOL,] 2-Chloro-3- nitrophenol (6 g, 35 mmol) was dissolved in methanol (100 [ML)] and treated with ammonium chloride (9.4 g, 175.7 mmol) and zinc dust (46 g, 702.8 mmol). The resulting mixture was refluxed for one hour. After filtration and evaporation, 2-chloro-3-aminophenol was collected (4.5 g, 90% yield) as a purple solid. To a suspension of 2-chloro-3-aminophenol (4.5 g, 31 mmol) in concentrated [HCI] (10 mL) at [0C] was added dropwise sodium nitrite (2.5 g, 35 mmol) in water (50 mL). After stirring for 30 minutes at [0C,] [I (I] (10.4 g, 63 mmol) in 10% [H2SO4] (3 mL) was added dropwise. The reaction was stirred at room temperature for 2 hours, then filtered, extracted with EtOAc, and concentrated in vacuo to afford 2-chloro-3-iodophenol as a dark purple solid (6 g, 75% yield). 6-Bromo-2,2, [4-TRIMETHYL-1,] 2-dihydroquinoline (2.3 g, 9.2 mmol) (Example 8) and bis (pinacol) diborane (4.2 g, 16.5 mmol) were combined in DMSO (2 mL). [KOAC] (2.7 g, 27.4 mmol) was added, followed by [PDCL2] (dppf) (100 mg). The contents were placed into a microwave reaction vessel assembly and irradiated at [120C] for 15 minutes. After cooling to room temperature, purification by chromatography afforded 2,2, [4-TRIMETHYL-6- (4,] 4,5, 5- tetramethyl- [1, 3,2] [DIOXABOROLAN-2-YL)-1,] 2-dihydroquinoline (2.3 g, [84%] yield) as a white crystalline solid. 2,2, [4-TRIMETHYL-6- (4,] 4,5, [5-TETRAMETHYL- [1,] 3,2] [DIOXABOROLAN-2-YL)-1,] 2-dihydroquinoline [(308] mg) and 393 mg of 2-chloro-3-iodophenol were coupled using of 100 mg [OF PDCL2 (DPPF)] and [300 MG OF KOAC TO GIVE 250 MG OF 2-CHLORO-3- (2, 2, 4-TRIMETHYL-1, 2-DIHYDROQUINOLIN-6-YL) -] phenol. Using the procedures described in Example 7, this (85 mg) was reacted with NBS to give 56 mg [OF 3- (4-BROMOMETHYL-2, 2-DIMETHYL-1, 2-DIHYDROQUINOLIN-6-YL)-2-CHLOROPHENOL.] The product (50 mg) was coupled with 0.04 mL of 2-phenylethanethiol to give 40 mg of the title compound as an oil.
48%
2-Amino-3-nitrophenol B1 (5 g; 32.4 MMOL) was dissolved in concentrated HCI (75 ML) and 1,4-dioxane (14. 7 mL). The mixture was heated to 70 C UNTIL most of the solids were in solution. The reaction mixture was cooled to 0 C (ice bath), and sodium nitrite (2.23 g; 32.3 MMOL) in H20 (5.4 mL) was added over a period of 3 hours to the brown solution. The temperature was maintained BELOW 10 C during the addition and the stirring was continued for an additional 15 min at 0C. This diazonium intermediate was poured into a solution of Cu (I) CI (3.8 g; 38.9 MMOL) in H20 (18. 5 mL) and conc. HCI (18.5 mL) at 0 C. The reaction was stirred for 15 min at 0 C, WARMED TO 60 C, and stirred for an additional 15 min The reaction mixture was then brought to room temperature, and left to stir overnight. The reaction mixture was transferred to a separatory funnel and extracted with ether (3X 150 mL). The organic layers were combined, washed with brine (1X), dried (NA2SO4), filtered and concentrated to afford the crude product (5.83 g) as a red-brown oil. The crude material was purified by flash column chromatography (1 : 25 ultra pure silica gel, 230-400 mesh, 40-60 MM, 60 angstroms; 3: 1 hexane/EtOAcas the solvent) to afford pure 2-chloro-3-nitrophenol C2 (48%; 2.7 g) as an orange solid. MS 171. 8 (MH)- : Homogeneity by HPLC (TFA) 220 nm: 96%. Relevant literature for the Sandmeyer Reaction: J. Med. Chem, 1982,25 (4), 446- 451.
48%
Step A:; 2-Amino-3-nitrophenol 1b1 (5 g; 32.4 mmol) was dissolved in concentratedHCI (75 ml) and 1,4-dioxane (14.7 ml). The mixture was heated to 70C until most ofthe solids were in solution. The reaction mixture was cooled to 0C (ice bath), andsodium nitrite (2.23 g; 32.3 mmol) in H2O (5.4 ml) was added over a period of 3 hoursto the brown solution. The temperature was maintained below 10C during theaddition and the stirring was continued for an additional 15 min. at 0C. Thisdiazonium intermediate was poured into a solution of Cu(l)CI (3.8 g; 38.9 mmol) inH2O (18.5 ml_) and cone. HCI (18.5 mL) at 0C. The reaction was stirred for 15 min. at0C, warmed to 60C, and stirred for an additional 15 min. The reaction mixture wasthen brought to room temperature, and left to stir overnight. The reaction mixture wastransferred to a separatory funnel and extracted with ether (3 X 150 mL). The organiclayers were combined, washed with brine (1 X), dried (Na2SO4), filtered andconcentrated to afford the crude product (5.83 g) as a red-brown oil. The crudematerial was purified by flash column chromatography (1:25 ultra pure silica gel, 230-400 mesh, 40-60mm, 60 angstroms; 3:1 hexane/EtOAc as the solvent) to afford pure2-chloro-3-nitrophenol 1c1 (48%; 2.7 g) as an orange solid. MS 171.8 (MH)":Homogeneity by HPLC (TFA) (at) 220 nm: 96% .
48%
2-Amino-3-nitrophenol 2b1 (5 g; 32.4 mmol) was dissolved in concentratedHCI (75 ml) and 1,4-dioxane (14.7 ml_). The mixture was heated to 70C until most ofthe solids were in solution. The reaction mixture was cooled to 0C (ice bath), andsodium nitrite (2.23 g; 32.3 mmol) in H2O (5.4 ml) was added over a period of 3 hoursto the brown solution. The temperature was maintained below 10C during theaddition and the stirring was continued for an additional 15 min. at 0C. Thisdiazonium intermediate was poured into a solution of Cu(l)CI (3.8 g; 38.9 mmol) inH2O (18.5 ml) and cone. HCI (18.5 mL) at 0C. The reaction was stirred for 15 min. at0C, warmed to 60C, and stirred for an additional 15 min. The reaction mixture wasthen brought to room temperature, and left to stir overnight. The reaction mixture wastransferred to a separatory funnel and extracted with ether (3 X 150 ml). The organiclayers were combined, washed with brine (1 X), dried (Na2SO4), filtered andconcentrated to afford the crude product (5.83 g) as a red-brown oil. The crudematerial was purified by flash column chromatography (1:25 ultra pure silica gel, 230-400 mesh, 40-60mm, 60 angstroms; 3:1 hexane/EtOAc as the solvent) to afford pure2-chloro-3-nitrophenol 2c1 (48%; 2.7 g) as an orange solid. MS 171.8 (MH)":Homogeneity by HPLC (TFA) (at) 220 nm: 96% .Relevant literature for the Sandmeyer Reaction: J. Med. Chem, 1982, 25(4), 446-451.
With toluene-4-sulfonic acid In diethylene glycol dimethyl ether at 80℃;
2
2-(Chloromethyl)-4-nitrobenzo[d]oxazole. To a RT solution of 2-amino-3- nitrophenol (14.7 g, 95 mmol, 1.0 equiv) in 2-methoxyethylether (136 mL) was added 2-chloro- 1,1,1-triethoxyethane (19.1 g, 97.3 mmol, 1.02 equiv) andp-toluene sulfonic acid hydrate (25 mg, 0.13 mmol, 0.2 equiv). The resulting mixture was heate to relflux overnight. After the reaction was cooled to RT, the solvent was removed in vacuo. The solid was suspended in methanol (40 mL), stirred and filtered to provide the desired product as a red solid (3.61 g). The filtrate provided an additional 9.8 g of the title compound through an additional methanol treatment (13.4 g, 98% combined).
474.A A.
A. 2-Methyl-4-nitrobenzoxazole (474A) To 2-amino-3-nitrophenol (6.17 g, 40.0 mmol) was added triethylorthoacetate (25.96 g, 160.0 mmol) and the mixture was heated at 100° C. for 12 h to give a dark red solution. Cooling to room temperature produced a crystalline mass which was filtered and washed with hexane to give compound 474A (6.78 g, 95%) as light maroon needles. HPLC: 98.1% at 1.86 min (retention time) (YMC S5 ODS column, 4.6*50 mm, eluding with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 179.08 [M+H]+.
91%
at 100℃; for 1h;
46.a a) 2-Methyl-4-nitrobenzoxazole
A suspension of 2-amino-3-nitrophenol (6.16 g, 40.00 mmol) and ethyl orthoacetate (12 mL) was stirred at 100° C. 1 for hour. After the reaction mixture was left to cool, diisopropyl ether was added to the reaction mixture, and the resulting crystals were collected by filtration to obtain crystals of the title compound (6.49 g, yield 91%). 1H-NMR (CDCl3) δ: 2.79 (3H, s), 7.46 (1H, t, J=8.2 Hz), 7.82 (1H, dd, J=1.0 Hz, 8.2 Hz), 8.18 (1H, dd, J=1.0 Hz, 8.2 Hz)
Example 1. Synthesis of N-(2-(3-(trifluoromethoxy)phenyl)benzo[rf]oxazol-4- yl)thiazole-4-carboxamide (Compound 104):Step 1) Preparation of4-nitro-2-(3-(trifluoromethoxy)phenyl)benzo[d]oxazole (2): 2-Amino-3-nitrophenol (1; 2.00 g, 0.0130 mol) was taken up in 10 mL of polyphosphoric acid (PPA) along with <strong>[1014-81-9]3-trifluoromethoxybenzoic acid</strong> (50; 2.67 g. 0.0130 mol). The reaction mixture was stirred at 165 0C for 3 h. It was then cooled to about 100 0C and poured carefully into 300 mL of water. Enough solid NaOH was added to produce a pH = 6. The resulting solids were collected by filtration, washed with water, and dried to afford 800 mg of 4-nitro-2-(3- (trifluoromethoxy)phenyl)benzo[
Multi-step reaction with 4 steps
1.1: pyridine / acetonitrile / 21 h / 5 °C
2.1: triethylamine / acetonitrile / 6 h / 70 °C
2.2: 14 h / 20 °C
3.1: palladium 10% on activated carbon; hydrogen / methanol / 30 °C / 760.05 Torr
4.1: pyridine / 72 h / 20 °C
Multi-step reaction with 4 steps
1.1: potassium carbonate / N,N-dimethyl-formamide / 16 h / 20 °C
2.1: acetic acid; sodium acetate; bromine / 0.33 h / 20 °C
3.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C
4.1: acetic acid; zinc / 0.33 h / 20 °C
4.2: 0.5 h / 4 °C
Multi-step reaction with 5 steps
1: potassium carbonate / N,N-dimethyl-formamide / 16 h / 20 °C
2: acetic acid; sodium acetate; bromine / 0.33 h / 20 °C
3: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C
4: acetic acid; zinc / 10 h / 20 °C
5: sulfuric acid; sodium nitrite / 0.83 h / 0 °C
Multi-step reaction with 5 steps
1.1: potassium carbonate / N,N-dimethyl-formamide / 16 h
2.1: sodium acetate; bromine / acetic acid / 0.33 h / 20 °C
3.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C
3.2: 0.5 h / 0 °C
4.1: zinc; acetic acid / 10 h / 20 °C
5.1: sulfuric acid; sodium nitrite / water / 0.83 h / 0 °C
Multi-step reaction with 5 steps
1.1: potassium carbonate / N,N-dimethyl-formamide / 16 h / 20 °C
2.1: acetic acid; sodium acetate; bromine / 0.33 h / 20 °C
3.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C
3.2: 0.5 h
4.1: acetic acid; zinc / 10 h / 20 °C
5.1: sulfuric acid; sodium nitrite / water / 0.83 h / 0 °C
Multi-step reaction with 4 steps
1.1: potassium carbonate / N,N-dimethyl-formamide / 0.08 h
1.2: 2 h / 20 °C
2.1: bromine; acetic acid; sodium acetate / 0.5 h / 20 °C
3.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C
4.1: acetic acid; zinc / 3 h / 20 °C
4.2: 1.75 h / 0 °C
Multi-step reaction with 4 steps
1.1: potassium carbonate / N,N-dimethyl-formamide / 0.08 h
1.2: 2 h / 20 °C
2.1: bromine; sodium acetate; acetic acid / 0.5 h / 20 °C
3.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C
4.1: zinc; acetic acid / 3 h / 20 °C
4.2: 1.75 h / 0 °C
Multi-step reaction with 4 steps
1.1: N,N-dimethyl-formamide / 2 h / 20 °C
2.1: bromine; acetic acid; sodium acetate / 0.5 h / 20 °C
3.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C
4.1: acetic acid; zinc / 3 h / 20 °C
4.2: 1.75 h / 0 °C
Multi-step reaction with 5 steps
1.1: potassium carbonate / N,N-dimethyl-formamide / 16 h / 20 °C
2.1: bromine; sodium acetate / acetic acid / 0.33 h / 20 °C
3.1: sodium hydride / N,N-dimethyl-formamide / 1 h / 0 °C
4.1: tin(II) chloride hydrate / ethanol / 2 h / 75 °C
4.2: pH 14
5.1: sodium nitrite; sulfuric acid / 0.83 h / 0 °C
2-(3,5-dimethyl-4-methoxyphenyl)-4-nitrobenzoxazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With toluene-4-sulfonic acid; In 5,5-dimethyl-1,3-cyclohexadiene; for 18h;Reflux;
3,5-Dimethyl-4-methoxybenzoic acid (164 mg, 0.907 mmol), 2-amino-3-nitrophenol (116 mg, 0.750 mmol), andp-TsOH?H2O (737 mg, 3.87 mmol)were refluxed in xylenes (5 mL).After 18 h, the reaction was cooled, extracted into EtOAc (50 mL), and washed with saturated H2O (2x25 mL) and brine (25 mL), dried over Na2SO4, filtered, and concentrated.Flash chromatographic purification over silica (2:1 hexanes:EtOAc) afforded 2-(3,5-dimethyl-4-methoxyphenyl)-4-nitrobenzoxazole, which was then stirred with boron tribromide (2.25 mL of 1 M BBr3in hexanes, 2.25 mmol) in anhydrous CH2Cl2(10 mL) at R.T. under an argon atmosphere.After 18 h, the reaction was quenched with MeOH (5 mL), extracted into EtOAc (50 mL), and washed with 1 N HCl (25 mL), sat. NaHCO3(25 mL), and brine (25 mL).The organics were dried over Na2SO4, filtered, and concentrated.Flash chromatographic purification over silica (2:1 hexanes:EtOAc gradient elution), followed by prep-HPLC purification afforded 2-(3,5-dimethyl-4-hydroxyphenyl)-4-nitrobenzoxazole (200)as alight tan solid (82.4 mg, 39%).1H-NMR (500 MHz,d6-DMSO)d9.15 (s, 1H), 7.72 (s, 2H), 7.51 (s, 1H), 5.84 (s, 2H), 2.25 (s, 6H;13C-NMR (125 MHz,d6-DMSO)d161.33, 157.06, 147.62, 137.65, 130.11, 129.48, 127.48, 125.11, 116.53, 100.67, 86.54, 16.56; ESI-TOF 283.0723m/z[M-H+]-, C15H11N2O4requires283.0724; RP-HPLC: 99% pure.
5-nitro-3-(pyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2-Bromo-1-pyridin-2-ylethanone hydrobromide (135 g, 480 mmol) was suspended in acetonitrile (1700 mL) at rt and potassium carbonate (135 g, 977 mmol) was added. The reaction was stirred for 1 h and then was heated to 60 C. and 2-amino-3-nitrophenol (67.5 g, 438 mmol) was added slowly portionwise as a solid over 30 minutes. The reaction became a dark red slurry. This mixture was stirred at 60 C. for an additional 1 h. The reaction was diluted with water (6500 mL) and stirred vigorously for 1 h to give a precipitate. The solids were collected and washed with water and dried to give the product as a dark brown solid 134 g. The solid was suspended in ethyl acetate (2500 mL) and heated to 75 C. in an oil bath to dissolve the product. To the reaction mixture was added activated charcoal (40 g). The mixture was stirred for 30 minutes and filtered hot through celite to give a yellow-red solution. The solution was concentrated in vacuo to give a crystalline residue. This was triturated with ethyl ether, filtered and the solids were washed with ethyl ether to give the crude desire product, 5-nitro-3-(pyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-ol (1x, 100 g, 83%) as a yellow orange crystalline solid. The mother liquor was concentrated to give an additional 10.0 g of the crude desired product as a yellow orange solid. The crude desired product was directly utilized in the subsequent reactions without further purification.
Chemistry
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Material Science
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