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CAS No. : | 13073-25-1 | MDL No. : | MFCD02683216 |
Formula : | C6H4BrNO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VEJSIOPQKQXJAT-UHFFFAOYSA-N |
M.W : | 218.00 | Pubchem ID : | 13545453 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 44.99 |
TPSA : | 66.05 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.05 cm/s |
Log Po/w (iLOGP) : | 1.64 |
Log Po/w (XLOGP3) : | 2.23 |
Log Po/w (WLOGP) : | 2.06 |
Log Po/w (MLOGP) : | 1.05 |
Log Po/w (SILICOS-IT) : | -0.1 |
Consensus Log Po/w : | 1.38 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.93 |
Solubility : | 0.254 mg/ml ; 0.00116 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.25 |
Solubility : | 0.122 mg/ml ; 0.000559 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.06 |
Solubility : | 1.89 mg/ml ; 0.00867 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.97 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P501-P270-P264-P280-P337+P313-P301+P312+P330 | UN#: | N/A |
Hazard Statements: | H302-H315-H319 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16 h; Stage #2: With ammonium chloride; zinc In ethanol at 20℃; for 6 h; |
[00162] Intermediate 9A. 3-Bromo-2-methoxyaniline: Potassium carbonate (6.47 g, 46.8 mmol) and methyl iodide (2.86 mL, 46.8 mmol) were added to a solution of 2- bromo-6-nitrophenol (5.10 g, 23.4 mmol) in DMF (100 mL) at room temperature and the resulting reaction mixture was stirred for 16 h. The reaction was quenched with water (100 mL) and diluted with EtOAc (500 mL). The aqueous layer was extracted with EtOAc. The combined organics were washed with saturated aHC03 solution and brine, dried over MgS04, filtered, and evaporated. The crude was dissolved in EtOH (100 mL) and zinc (15.30 g, 233.9 mmol) and ammonium chloride (12.52 g, 233.9 mmol) were added. The reaction mixture was stirred at room temperature for 6 h. The reaction was diluted with EtOAc, filtered through CELITE®, and evaporated. The crude was purified by flash chromatography (10-20percent EtOAc/hexanes) to give Intermediate 9A (4.6 g, 97percent) as a yellow oil. LCMS (ESI) m/z 202, 204 (M+H, M+2+H)+, RT = 1.38 min (Method A). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate In acetoneReflux | To a mixture of the compound represented by the structural formula (O-1) (19.6 g, 90.0 mmol) and potassium carbonate (24.9 g, 180 mmol) in acetone (400 mL), iodomethane (25.6 g, 180 mmol) was added. The mixture was refluxed overnight. After cooling, the mixture was filtered, and washed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, the solution was washed with brine, dried over Na2SO4, and concentrated to give 1-bromo-2-methoxy-3-nitrobenzene represented by the structural formula (O-2) as yellow solid (20.2 g, yield 97percent). 1H-NMR Spectrum (300MHz, DMSO-d6):δ (ppm): 3.92 (s, 3H), 7.32 (d, 1H, J=8.1Hz), 7.94-8.03 (m, 2H) |
96% | Stage #1: With potassium carbonate In N,N-dimethyl-formamide for 0.5 h; |
Stepi[00172j 2-Bromo-6-nitrophenol (5.0 g, 22.9 mmol) was dissolved in DMF (3 mL), potassium carbonate (4.75 g, 34.4 mmol) was added and the reaction was stirred for 30 minutes. Next iodomethane (2.15 mL, 34.4 mmol) was added and the reaction was stirred overnight. The crude reaction was filtered, diluted with ethyl acetate and washed with brine (twice) and water (twice). The organic layer was dried over sodium sulfate, filtered and concentrated to provide Int9 (5.12 g, 96percent). LC retention time 0.92 [J]. |
95% | Stage #1: With potassium carbonate In acetone at 70℃; for 1 h; Stage #2: for 8 h; Reflux |
A mixture of 2-Bromo-6-nitro-phenol (43.6 g, 0.2 mol), K2CO3 (82.9 g, 0.6 mol), acetone (600 mL) is stirred at 70° C. for 1 h. Then MeI (85.14 g, 0.6 mol) is slowly added to the reaction mixture and refluxed for 8 h. After reaction, filtered and the filtrate is extracted with ethyl acetate (3×1000 mL). The combined SnCl2 organic phase is washed with water and brine, dried over Na2SO4, concentrated in vacuo to obtain the desired product. Yield: 44 g (95percent) HPLC-MS: M+H=232/234; tRet=2.04 min; AM12 |
95% | Stage #1: With potassium carbonate In acetone at 70℃; for 1 h; Stage #2: for 8 h; Reflux |
l-Bromo-2-methoxy-3-nitro-benzene A mixture of 2-Bromo-6-nitro-phenol (43.6 g, 0.2mol), K2CO3 (82.9 g, 0.6 mol), acetone (600mL) is stirred at 70 °C for lh. Then Mel (85.14g, 0.6 mol) is slowly added to the reaction mixture and refluxed for 8h. After reaction, filtered and the filtrate is extracted with ethyl acetate (3 x lOOOmL). The combined SnC12organic phase is washed with water and brine, dried over Na2S04, concentrated in vacuo to obtain the desired product. Yield: 44g (95percent) HPLC-MS: M+H=232/234; tRet =2.04 min; AM12 |
90% | With potassium carbonate In acetone at 70℃; for 40 h; | Step 2 1-Bromo-2-methoxy-3-nitro-benzene; 2-Bromo-6-nitro-phenol 1b (46.55 g, 0.214 mol) was dissolved in 500 mL of acetone followed by addition of potassium carbonate (35.36 g, 0.256 mol) and iodomethane (20.1 mL, 0.32 mol). The reaction mixture was heated to reflux at 70 °C for 40 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure and diluted with 1300 mL of ethyl acetate and 500 mL of water. The aqueous layer was extracted with ethyl acetate (300 mL.x.2). The combined organic extracts were washed with 4 N hydrochloric acid and saturated aqueous sodium bicarbonate and then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 1-bromo-2-methoxy-3-nitro-benzene 1c (44.59 g, yield 90.0percent) as a brown solid. MS m/z (ESI): 234 [M+1] |
90% | With potassium carbonate In acetone at 70℃; for 40 h; | Step 2 1-Bromo-2-methoxy-3-nitro-benzene; 2-Bromo-6-nitro-phenol 1b (46.55 g, 0.214 mol) was dissolved in 500 mL of acetone followed by addition of potassium carbonate (35.36 g, 0.26 mol) and iodo- methane (20.1 mL, 0.32 mol). The reaction mixture was heated to reflux at 70°C for 40 hours. The reaction mixture was concentrated under reduced pressure and diluted with 1300 mL of ethyl acetate and 500 mL of water. The aqueous layer was extracted with ethyl acetate (300 mLx2). The combined organic extracts were washed with 4 M hydrochloric acid and saturated sodium bicarbonate solution and then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 1-bromo-2-methoxy-3-nitro-benzene 1c (44.59 g, yield 90.0percent) as a brown solid. MS m/z (ESI): 234 [M+1] |
90% | With potassium carbonate In acetone at 70℃; for 40 h; | 2-bromo-6-nitrophenol 1b (46.55g, 0.214mol) was dissolved in 500mL acetone. To this was added potassium carbonate (35.36g, 0.26mol) and iodomethane (20.1mL, 0.32mol) then the solution was heated at reflux 70°C for 40 hours. The reaction solution was concentrated under reduced pressure. Added 1300mL ethyl acetate and 500mL water. The aqueous phase was extracted with ethyl acetate (300mL × 2). The combined organic phases were washed with 4M hydrochloric acid and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The result was purified by column chromatography on silica gel to give 1-bromo-2-methoxy-3-nitrobenzene 1c (44.59g, brown solid). Yield: 90.0percent. |
89% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | Preparation 12 To a solution of 2-bromo-6-nitrophenol (5 g, 22.94 mmol) in DMF (18 ml) was added potassium carbonate (9.51 g, 68.8 mmol) and the resulting mixture was stirred for 15 min, then iodomethane (2.87 ml, 45.9 mmol) was added. The resulting mixture was stirred at rt overnight. HPLC and LCMS indicated complete conversion to product. Cold water added (75 mL), stir/sonicate, solid was collected by filtration. This material was then dissolved in EtOAc (150 mL). This solution was washed lx 10percent LiCl, lx brine. dried over sodium sulfate, then filtered and concentrated. Loaded onto a 120g silica gel cartridge, then purified by flash chromatography eluting with 0-50percent EtOAc in hexanes. Fractions containing the product were concentrated to afford a pale yellow solid as the product l-bromo-2-methoxy-3 -nitrobenzene (4.997 g, 20.46 mmol, 89percent yield). LCMS ave very weak MH+. |
89% | Stage #1: With potassium carbonate In N,N-dimethyl-formamide for 0.25 h; Stage #2: at 20℃; |
To a solution of 2-bromo-6-nitrophenol (5 g, 22.94 mmol) in DMF (18 ml) was added potassium carbonate (9.51 g, 68.8 mmol) and the resulting mixture was stirred for 15 min and then iodomethane (2.87 ml, 45.9 mmol). The resulting mixture was stirred overnight at rt. HPLC and LCMS instructions were fully converted to product. Add cold water (75 mL), perform agitation / sonic processing, and collect solids by filtration. The material was then dissolved in EtOAc (150 mL). The solution was washed with 10percent LiCl, washed 1x with brine, dried over sodium sulfate, filtered and concentrated. Was loaded onto a 120 g silica gel cartridge and then purified by flash chromatography eluting with 0-50percent EtOAc in hexanes. Concentrate the fractions containing the product to afford the product as a pale yellow solid 1-bromo-2-methoxy-3-nitrobenzene (4.997 g, 20.46 mmol, 89percent yield). |
83.6% | With potassium carbonate In acetoneHeating / reflux | To a mixture of 2-bromo-6-nitrophenol (5.0 g, 22.9 mmol) and potassium carbonate (6.3 g,45.8 mmol) in acetone (100 mL) was added iodomethane (2.85 mL, 45.8 mmol) under stirring and the mixture was then heated to reflux overnight. The mixture was cooled to room temperature, filtered through Celite, the filter cake washed with ethyl acetate, and the filtrate concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed 3x with IN NaOH, once with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was recrystallized twice from 2-propanol / water to give 4.45 g (83.6percent) of the title compound as beige, very fine needles.MS (ESI: 232 / 234 (M+H+) for C7H6BrNO1H-NMR (DMSO-d^ δ: ppm 3.98 (s, 3H); 7.39 (t, IH); 8.02 (dd, IH); 8.08 (dd, IH). |
2.1 g | With potassium carbonate In acetone at 80℃; for 6 h; | To a mixture of K2CO3 (2.54 g) and 2-bromo-6-nitrophenol (2 g) in acetone (15 mL) at room temperature was added Mel (3.442 mL). The reaction mixture was heated to 80° C. for 6 h, after cooling the reaction, the mixture was filtered and the filtrate was concentrated to afford 2-bromo-6-nitrophenyl methyl ether (D31) (2.1 g). δH (CDCl3, 400 MHz): 3.96 (3H, s), 4.91 (1H, m), 7.06 (1H, t), 7.19 (1H, s), 7.72 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With trichloroisocyanuric acid; bismuth subnitrate/charcoal In dichloromethane at 20℃; for 2h; regioselective reaction; | |
53% | With 5-methyl-1,4-dinitro-1H-imidazole In acetonitrile at 25℃; Irradiation; | |
42.8% | With sodium nitrate; sulfuric acid In water at 20 - 25℃; | 1.1 Step 1 2-Bromo-6-nitro-phenol; A solution of 60 mL of concentrated sulfuric acid diluted with 186 mL of water was cooled to room temperature. Sodium nitrate (79.2 g, 0.932 mol) was added to the solution. 2-Bromo-phenol 1a (60 mL, 0.516 mol) was added dropwise at such a rate that the reaction temperature was kept below 25 °C. The reaction mixture was reacted at room temperature for 2 hours and monitored by thin layer chromatography (TLC) until the disappearance of the starting materials. The precipitate was dissolved in 320 mL of ethyl acetate. The mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 2-bromo-6-nitro-phenol 1b (48.2 g, yield 42.8%) as a yellow solid. MS m/z (ESI): 218 [M+1] 1H NMR (400 MHz, CDCl3): δ 6.88∼7.02 (m, 1H), 7.89∼7.91 (d, J = 8 Hz, 1H), 8.12∼8.15 (m, 1H), 11.18 (s, 1H) |
42.8% | With sodium nitrate; sulfuric acid In water at 20 - 25℃; for 2h; | 1.1 Example 1: (Z)-2'-hydroxy-3'-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene)-hydrazino]-biphenyl-3-carboxylic acid bis-(ethanolamine); Step 1; 2-Bromo-6-nitro-phenol; A solution of 60 mL of concentrated sulfuric acid diluted with 186 mL of water was cooled to room temperature. Sodium nitrate (79.2 g, 0.93 mol) was added to the solution. 2-Bromo-phenol 1a (60 mL, 0.52 mol) was added dropwise at such a rate that the reaction temperature was kept below 25°C. The reaction mixture was stirred at room temperature for 2 hours. The precipitate was dissolved in 320 mL of ethyl acetate. The mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 2-bromo-6-nitro-phenol 1b (48.2 g, yield 42.8%) as a yellow solid. MS m/z (ESI): 218 [M+1] 1H NMR (400 MHz, CDCl3): δ 11.18 (s, 1H), 8.12-8.15 (m, 1H), 7.89-7.91 (m, 1H), 6.88-7.02 (m, 1H) |
42.8% | With sodium nitrate; sulfuric acid In water at 25℃; for 2h; | 1.1 Step one 2-bromo-6-nitrophenol 60mL of concentrated sulfuric acid diluted with 186mL of water was added sodium nitrate (79.2g, 0.93mol) at room temperature. Maintaining 25°C, o-bromophenol 1a (60mL, 0.52mol) was added and reacted at room temperature for 2 hours. 320mL of ethyl acetate was added to dissolve precipitated solids. I was then washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The result was purified by column chromatography on silica gel to give 2-bromo-6-nitrophenol 1b (48.2g, yellow solid). Yield: 42.8%. |
40.5% | With sodium nitrate; sulfuric acid In water for 2h; Cooling with ice; | Preparation of 2-bromo-6-nitrophenol Take 5ml (0.078mol) concentrated sulfuric acid and slowly add 16ml of water along the wall of the cup.Add 6.6g (0.078mol) of sodium nitrate to the diluted sulfuric acid,Stir well until completely dissolved.Under ice bath conditions,Slowly add 7.46 g (0.043 mol) of o-bromophenol to the above solution,After finishing,Remove the ice bath.Reaction 2h,TLC is tracked until the reaction is complete,filter,The filter cake was washed with water (5ml × 4),Add ethyl acetate to dissolve,Dried over anhydrous magnesium sulfate,Filtered, and the filtrate was concentrated under reduced pressure,The obtained residue was purified by silica gel column chromatography,To give 2-bromo-6-nitrophenol (3.8 g of a yellow solid),Yield: 40.5%. |
34.1% | With nitric acid; acetic acid In ethanol; water | R.1 Synthesis of 2-halogeno-6-nitrophenol Reference Example 1 Synthesis of 2-halogeno-6-nitrophenol 51.9 g (0.3 mol) of 2-bromophenol and 300 ml of acetic acid were fed into a 1-liter four-necked flask provided with a reflux condenser, a stirrer and a thermometer. Thereto was dropwise added 29.7 g (0.33 mol) of 70% nitric acid at a temperature of 15° C. or below, with ice-cooling. The reaction mixture was stirred at a temperature of 10° C. or below for 1 hour and poured into 600 ml of water. The mixture was subjected to extraction with 400 ml of ether. The ether layer was washed with 150 ml of water. The ether layer was subjected to distillation. The residue was transferred into a 1-liter flask provided with a stirrer and a distillation apparatus. Azeotropic distillation was conducted while water was added gradually. The amount of water required for azeotropic distillation was 2,100 ml. The distillate obtained was subjected to extraction two times using 500 ml of ether. The ether layer was dried over anhydrous sodium sulfate and subjected to distillation to remove ether. The resulting crude product was mixed with 10 ml of ethanol. The mixture was heated and then allowed to cool. The formed crystals were collected by filtration and then dried to obtain 22.3 g of 2-bromo-6-nitrophenol (yield: 34.1%, purity: 99.6%). |
25% | With sodium nitrate In sulfuric acid; water | 5.a a a 2-Bromo-6-nitrophenol 2-Bromophenol (34.6 g, 0.2 mol) was added slowly to a cold (10° C.) solution of sodium nitrate (30.5 g, 0.3 6 mol) in conc. sulfuric acid (42 g) and water (74 mL) and the resulting mixture was allowed to stir at room temperature for 2 h. Water (210 mL) was added and the resulting mixture was extracted with diethyl ether and the extract was dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (silica gel, 10% ethyl acetate/hexanes) to afford first the title compound (10.9 g; 25%) as a bright, yellow solid. 1H NMR (300 MHz, CDCl3) δ11.10 (S, 1 h), 8.13 (d, J=7.9 Hz, 1H), 7.89 (d, J=7.9 Hz, 1H), 6.90 (t, J=7.9 Hz, 1H). |
durch Nitrierung; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With oxalic acid; silica gel; sodium nitrite; In dichloromethane; water; at 20℃; for 0.5h; | 2-bromophenol (20 g, 0.116 mol), sodium nitrite (48 g, 0.696 mol)Oxalic acid (43.7 g, 0.347 mol) was dissolved in 500 ml of dichloromethane,Add SiO211.5g under stirring, and then slowly add the water 11.5ml,After stirring, continue stirring at room temperature for 30 min. The reaction solution is directly filtered,The filter cake was washed twice with dichloromethane and 200 ml / time. The organic layer was dried over anhydrous sodium sulfate,Filtered and evaporated to dryness under reduced pressure to give 27.8 g of crude product,By petroleum ether column chromatography can get the main product 7.2g (TLC a main point, with a small amount of bit impurity). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bromine; acetic acid | ||
With bromine; acetic acid In water at 0 - 20℃; for 12h; | Synthesisof 2-bromo-6-nitrophenol (3) 2-nitrophenol(5 gm, 35.9 mmol) was dissolved in 1:1 acetic acid and water (50 mL) in a round bottam flask. The solutionwas cooled to 0-5 oC and bromine (1.1 mL, 43.1mmol) was added slowlyover a period of 10 min. The mixture was stirred for 12 hrs at roomtemperature. The yellow precipitate formed was filtered and the mixture waswashed with water (50 mL) to remove unreacted bromine. The yellow solid (7.2 g, 3.3mmol) wascollected and dried in the air. M.p.97-102οC. Anal. Calc. for C6H4BrNO3(218.0): C,33.06; H, 1.85; N, 6.42; O, 22.02; Br, 36.65. Found: C, 33.03; H, 1.83; N,6.40; O, 22.00; Br, 36.62. 1H NMR (CDCl3, 300 MHz) : δ10.49 (s, 2H ), 7.98 (d, 1H, J=2.4 Hz), 7.67 (dd, 1H, J=9.0, 2.4Hz), 7.08 (d, 1H, J=9.0 Hz) ppm. 13C-NMR (CDCl3, 75MHz): δ 151.5, 140.4, 134.5, 127.4, 121.8, 114.6 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen In acetic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 86% 2: 5% | With Oxone; potassium bromide In methanol at 20℃; for 24h; | |
With oxone; ammonium bromide In acetonitrile at 20℃; for 6.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With pyridine for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With caesium carbonate In acetonitrile at 75℃; | 138.A Step A 2-tert-Butyl-benzofuran-7-ylamine was prepared in 2 steps from 2-bromo-6-nitrophenol 2-Bromo-6-nitrophenol (500 mg, 2.29 mmol), bis(acetonitrile) palladium (II) chloride (12 mg, 0.05 mmol), 2-dicylohexylphosphino-2',4',6'-triisopropylbiphenyl (68 mg, 0.14 mmol), cesium carbonate (1.95 g, 6 mmol) and tert-butylacetylene (577 mg, 7 mmol) were dissolved 5 mL acetonitrile in a sealed tube and heated at 75° C. overnight. The reaction mixture was directly chromatographed (silica gel, heptane/ethyl acetate 9:1/4:1/1:1) to yield 2-tert-butyl-7-nitro-benzofuran as an off-white solid (185 mg, 37%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With ammonium chloride; zinc In methanol at 0 - 20℃; for 0.583333h; | B. Synthesis of 2-amino-6-bromophenol (29) To a solution of 2-bromo-6-nitrophenol (5.57 g, 25.5 mmol) in MeOH (128 mL) was added zinc (dust) (16.71 g, 255 mmol). Reaction mixture was cooled to 0 C in a ice/water bath followed by the addition of ammonium chloride (13.67 g, 255 mmol) portion wise over 5 min. The heterogeneous reaction mixture allowed to warm to RT and was stirred at RT for 30 min. Reaction was filtered through a plug of celite and concentrated to a dark brown solid. Solid partitioned between water and EtOAc. Aqueous phase extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to a dark solid of 2-amino-6-bromophenol (4.66 g, 24.78 mmol, 97 % yield). LCMS m/z 187.8 (MH+), Rt 0.34 min. |
97.4% | With palladium 10% on activated carbon; hydrogen In methanol at 20 - 30℃; for 6h; Autoclave; | 1.1 1. Preparation of a compound of formula II Add 1000 ml of methanol to a 2 L autoclave,100 g (0.46 mol) of 2-bromo-6-nitrophenol,5g of 10% palladium on carbon,Closed reactor,Replaced three times with nitrogen,Replaced with hydrogen three times,Keep the hydrogen pressure 0.1~0.2MPa,The reaction temperature is between 20 and 30 ° C, and the reaction is carried out for 6 hours.At the end of the reaction, the hydrogen was replaced with nitrogen three times, evacuated, the reaction vessel was opened, and the reaction solution was filtered.The filtrate was concentrated to dryness to give a brown solid (yield: 2-amino-6-bromophenol (II) 84 g, yield 97.4%, purity 92.265%. |
93% | Stage #1: 2-bromo-6-nitro-phenol With tin(II) chloride dihdyrate; water In tetrahydrofuran at 80℃; for 1h; Stage #2: With sodium hydrogencarbonate In tetrahydrofuran; water | 159.1 Step 1. 2-amino-6-bromophenol2-Bromo-6-nitrophenol (Aldrich, 0.25 g, 1.1 mmol) was dissolved in THF (6.4 mL), water (6.4 mL) and stannous chloride dihydrate (1.3 g, 5.7 mmol) were added. The mixture was heated to 80° C. for 1 h. Upon cooling to RT, sat'd sodium bicarbonate was added, followed by ethyl acetate. Insoluble material was filtered off. The layers were separated and the aqueous phase was extracted with two further portions of ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated to provide the desired product as an off-white crystalline solid, used without further purification (200 mg, 93%). LCMS (M+H)+: 188.0/190.0. |
93% | With hydrogen In methanol at 0 - 10℃; for 2h; | 4 Example 4 Preparation of 2-bromo-6-aminophenol 2-bromo-6-nitro-phenol, 15g (68.8mmol), 200 mL of methanol, Raney nickel 0.15g, stirring to dissolve, cooled to 0 ~ 10 , substituted with hydrogen, the reaction 2h, TLC the reaction was complete, filtered, and the filtrate was The solvent was evaporated to give 6-amino-2-bromo-phenol (compound I) 12.03g, yield 93%. |
90% | With sodium dithionite; water In ethanol | |
86% | With sodium dithionite; ethanol; water at 60℃; | 1; A1 To a mixture of 2-bromo-6-nitro-phenol (15.0 g, 68.8 mmol) in EtOH (200 mL) at 60° C. was added a warm solution of Na2S2O4 (50.0 g, 287 mmol) in water (180 mL) dropwise. Upon the addition of Na2S2O4 solution the reaction mixture turned to deep orange. After addition of about half of the Na2S2O4 solution, the deep orange changed to light yellow. The reaction mixture was allowed to cool to room temperature and EtOH was removed in vacuo. The residue was filtered, and the solid washed with water and dried under vacuum. The filtrate was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4) and concentrated. The solids were combined to give 11.1 g (86%) of Ala as a white crystalline material: 1H NMR (300 MHz, CDCl3) δ 6.87-6.83 (m, 1H), 6.66-6.63 (m, 2H), 5.39 (brs, 1H), 3.85 (brs, 2H); MS (ES) m/z: 188 (M+H+). |
86% | Stage #1: 2-bromo-6-nitro-phenol With hydrogenchloride; tin(ll) chloride In methanol; water at 20℃; Stage #2: With sodium hydroxide In methanol; water | 2-Amino-6-bromophenol: To a solution of 2-bromo-6-nitrophenol (1.0 g, 4.6 mmol) in methanol (20 mL) and concentrated hydrogen chloride (20 mL) was added SnCl2-H2O (4.9 g, 18.4 mmol) at room temperature in one portion. The mixture was stirred at room temperature overnight. Then the mixture was quenched with 2 N sodium hydroxide. The resulting mixture was filtered through a pad of celite. The filtrate was extracted with methylene chloride. The solvent was removed under vacuum afforded 0.69 g (86%) of the title product as a white solid. MS (ES) m/z 186.0 [M - H]". |
83% | With iron; acetic acid at 90℃; for 0.5h; | 37 5.1.37 2-Amino-6-bromophenol (56) To a solution of reduced iron (7.17 g, 128 mmol) in AcOH (30 mL) was added dropwise a solution of 2-bromo-6-nitrophenol (4.00 g, 18.3 mmol) in AcOH (20 mL) at 90 °C. The reaction mixture was stirred at 90 °C for 30 min and cooled to room temperature. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was diluted with EtOAc and aqueous saturated NaHCO3. The organic layer was separated, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by silica gel column chromatography using hexane/EtOAc (5:1, v/v) as eluent to give 56 (2.84 g, 83%) as a brown solid: mp 84-86 °C; 1H NMR (400 MHz, CDCl3) δ: 6.87-6.83 (1H, m), 6.65-6.63 (2H, m), 5.41 (1H, br s), 3.85 (2H, br s); IR (ATR) 3032, 1578, 1473, 1456, 1227 cm-1; HRMS (ESI) m/z calcd for C6H7BrNO [M+H]+ 187.9706; found 187.9704. |
79% | With tin(ll) chloride In ethanol at 70℃; for 1h; | 10 A mixture of 2-bromo-6-nitrophenol (4.00 g, 18.4 mmol) and tin (II) dihydrate (20.7 g, 91.7 rnmol) in ethanol (80 ml) was heated at 70 °C for 1 h. The mixture was poured into ice and the pH was made slightly basic (pH 7-8) by addition of IN sodium hydroxide solution in water. The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum to afford 2.74 g (79%) of the title compound. ¹H-NMR (CDC13) No.: 3.85 (m, 2H), 5.39 (m, 1H), 6.60-6.70 (m, 2H), 6.80-6.90 (m, 1H). MS Calcd. : 187; Found: 188 (M+H), 190. |
40% | With tin(II) chloride dihdyrate In ethanol at 70℃; for 1h; | |
25% | Stage #1: 2-bromo-6-nitro-phenol With tin(ll) chloride In ethanol at 70℃; for 0.0833333h; Inert atmosphere; Stage #2: In ethanol for 0.5h; Inert atmosphere; Cooling with ice; | |
With sodium dithionite In ethanol; water | ||
With hydrogen In tetrahydrofuran; methanol for 4h; | 1.c 5g (22.9mmol) 2-nitro-6-bromo-phenol (Fluka 67211) is hydrogenated in the presence of 0.1g Ra-Ni (B113W EtOH, Degussa) in 100ml of THF:MeOH = 1:1. for 4h. The reaction mixture is filtered (2 glass fiber filters used) and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, hexane: EtOAc = 2:1) to afford the title compound as a reddish oil which slowly solidifies. | |
With Raney-Ni In tetrahydrofuran; methanol | ||
With Raney-Ni In tetrahydrofuran; methanol | ||
Stage #1: 2-bromo-6-nitro-phenol With acetic acid; zinc In methanol at 20℃; for 0.25h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water | A Intermediate 1 : 2-Amino-6-bromophenolMethod A To a solution of 2-bromo-6-nitrophenol (5g; Aldrich) in MeOH (459ml) and acetic acid (115ml) was added portionwise with stirring zinc powder (7.5Og), and the reaction mixture stirred at room temperature for fifteen minutes. The reaction mixture was filtered through a pad of celite and washed with water (500ml) and the filtrate evaporated to remove the methanol. The aqueous layer was extracted with DCM (2x 500ml) and the combined organic layers washed with saturated sodium bicarbonate (2x 500ml) and brine (500ml), then dried and evaporated to afford the title compound (3.45g) as a dark brown solid, m/z [M+H]+: 188.0 /190.0. Retention time 0.51 min (LC/MS method 3). | |
With sodium dithionite; water In ethanol at 60℃; | B Method BTo a solution of 2-bromo-6-nitrophenol (25g) in ethanol (250ml) was added dropwise with stirring a solution of sodium hydrosulfite (8Og) in water (500ml), and the reaction mixture stirred at 6O0C for three hours then cooled overnight. The reaction mixture was evaporated to remove the ethanol. The aqueous was extracted with DCM (500ml and 250ml) and the combined organic layers washed with brine (300ml), then dried and evaporated to afford the title compound (13.2g) as a brown solid. | |
Stage #1: 2-bromo-6-nitro-phenol With acetic acid; zinc In methanol at 20℃; for 0.25h; Stage #2: With sodium hydrogencarbonate In dichloromethane | 1.A To a solution of 2-bromo-6-nitrophenol (5g; Aldrich) in MeOH (459ml) and acetic acid(115ml) was added portionwise with stirring zinc powder (7.5Og), and the reaction mixture stirred at room temperature for fifteen minutes. The reaction mixture was filtered through a pad of celite and washed with water (500ml) and the filtrate evaporated to remove the methanol. The aqueous layer was extracted with DCM (2x 500ml) and the combined organic layers washed with saturated sodium bicarbonate (2x 500ml) and brine (500ml), then dried and evaporated to afford the title compound (3.45g) as a dark brown solid, m/z [M+H]+: 188.0 /190.0. Retention time 0.51 min (LC/MS method 3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: Na2S2O4 / ethanol; H2O 2: BH3-DMS / tetrahydrofuran / Heating 3: pyridine / CH2Cl2 4: BINAP; t-BuONa / Pd2(dba)3 / toluene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: Na2S2O4 / ethanol; H2O 2: BH3-DMS / tetrahydrofuran / Heating 3: pyridine / CH2Cl2 4: BINAP; t-BuONa / Pd2(dba)3 / toluene 5: HCl / ethanol / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: Na2S2O4 / ethanol; H2O 2: BH3-DMS / tetrahydrofuran / Heating 3: pyridine / CH2Cl2 4: BINAP; t-BuONa / Pd2(dba)3 / toluene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: Na2S2O4 / ethanol; H2O 2: BH3-DMS / tetrahydrofuran / Heating 3: pyridine / CH2Cl2 4: BINAP; t-BuONa / Pd2(dba)3 / toluene 5: HCl / ethanol / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33.4% | With sodium hydroxide In water | 1 Example 1 Example 1 Into a 200-ml four-necked flask provided with a reflux condenser, a stirrer and a thermometer were fed 4.36 g (0.02 mol) of 2-bromo-6-nitrophenol, 16.7 g (0.1 mol) of 24% sodium hydroxide, 20 ml of 1,4-dioxane and 7 ml of water. The mixture was heated to 80° C. The mixture was stirred at that temperature for 11 hours with heating while chlorodifluoromethane (flon 22) was blown thereinto from a bomb. The reaction mixture was cooled and then subjected to extraction two times each using 20 ml of ether. The ether layer was washed with 20 ml of 12% sodium hydroxide and then with the same volume of water. Then, the ether layer was dried over anhydrous sodium sulfate and then subjected to distillation to obtain 1.79 g of 3-bromo-2-difluoromethoxynitrobenzene (yield: 33.4%, purity: 98.8%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-bromo-6-nitro-phenol With iron; ammonium chloride In tetrahydrofuran; ethanol; water at 100℃; for 3.5h; Stage #2: With hydrogenchloride In ethyl acetate | 51.1 step 1 Production of 2-amino-6-bromophenol hydrochloride 2-Bromo-6-nitrophenol (12 g) was dissolved in tetrahydrofuran (40 mL), ethanol (70 mL) and water (60 mL), ammonium chloride (14.7 g) and iron (15.4 g) were added, and the mixture was stirred with heating at 100° C. for 3.5 hr. The insoluble material was removed by celite filtration, and the filtrate was concentrated and extracted with ethyl acetate and tetrahydrofuran. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the obtained residue was dissolved in 4N hydrogen chloride (ethyl acetate solution). The precipitated solid was collected by filtration to give the title compound (6.56 g) as an ocher solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate In acetone Reflux; | 13 Synthesis of the compound represented by the structural formula (15) (compound J-157) To a mixture of the compound represented by the structural formula (O-1) (19.6 g, 90.0 mmol) and potassium carbonate (24.9 g, 180 mmol) in acetone (400 mL), iodomethane (25.6 g, 180 mmol) was added. The mixture was refluxed overnight. After cooling, the mixture was filtered, and washed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, the solution was washed with brine, dried over Na2SO4, and concentrated to give 1-bromo-2-methoxy-3-nitrobenzene represented by the structural formula (O-2) as yellow solid (20.2 g, yield 97%). 1H-NMR Spectrum (300MHz, DMSO-d6):δ (ppm): 3.92 (s, 3H), 7.32 (d, 1H, J=8.1Hz), 7.94-8.03 (m, 2H) |
96% | Stage #1: 2-bromo-6-nitro-phenol With potassium carbonate In N,N-dimethyl-formamide for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide | 3.1 Stepi[00172j 2-Bromo-6-nitrophenol (5.0 g, 22.9 mmol) was dissolved in DMF (3 mL), potassium carbonate (4.75 g, 34.4 mmol) was added and the reaction was stirred for 30 minutes. Next iodomethane (2.15 mL, 34.4 mmol) was added and the reaction was stirred overnight. The crude reaction was filtered, diluted with ethyl acetate and washed with brine (twice) and water (twice). The organic layer was dried over sodium sulfate, filtered and concentrated to provide Int9 (5.12 g, 96%). LC retention time 0.92 [J]. |
95% | Stage #1: 2-bromo-6-nitro-phenol With potassium carbonate In acetone at 70℃; for 1h; Stage #2: methyl iodide In acetone for 8h; Reflux; | 16 1-Bromo-2-methoxy-3-nitro-benzene A mixture of 2-Bromo-6-nitro-phenol (43.6 g, 0.2 mol), K2CO3 (82.9 g, 0.6 mol), acetone (600 mL) is stirred at 70° C. for 1 h. Then MeI (85.14 g, 0.6 mol) is slowly added to the reaction mixture and refluxed for 8 h. After reaction, filtered and the filtrate is extracted with ethyl acetate (3×1000 mL). The combined SnCl2 organic phase is washed with water and brine, dried over Na2SO4, concentrated in vacuo to obtain the desired product. Yield: 44 g (95%) HPLC-MS: M+H=232/234; tRet=2.04 min; AM12 |
95% | Stage #1: 2-bromo-6-nitro-phenol With potassium carbonate In acetone at 70℃; for 1h; Stage #2: methyl iodide In acetone for 8h; Reflux; | 16.1 l-Bromo-2-methoxy-3-nitro-benzene l-Bromo-2-methoxy-3-nitro-benzene A mixture of 2-Bromo-6-nitro-phenol (43.6 g, 0.2mol), K2CO3 (82.9 g, 0.6 mol), acetone (600mL) is stirred at 70 °C for lh. Then Mel (85.14g, 0.6 mol) is slowly added to the reaction mixture and refluxed for 8h. After reaction, filtered and the filtrate is extracted with ethyl acetate (3 x lOOOmL). The combined SnC12organic phase is washed with water and brine, dried over Na2S04, concentrated in vacuo to obtain the desired product. Yield: 44g (95%) HPLC-MS: M+H=232/234; tRet =2.04 min; AM12 |
90% | With potassium carbonate In acetone at 70℃; for 40h; | 1.2 Step 2 1-Bromo-2-methoxy-3-nitro-benzene; 2-Bromo-6-nitro-phenol 1b (46.55 g, 0.214 mol) was dissolved in 500 mL of acetone followed by addition of potassium carbonate (35.36 g, 0.256 mol) and iodomethane (20.1 mL, 0.32 mol). The reaction mixture was heated to reflux at 70 °C for 40 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure and diluted with 1300 mL of ethyl acetate and 500 mL of water. The aqueous layer was extracted with ethyl acetate (300 mL×2). The combined organic extracts were washed with 4 N hydrochloric acid and saturated aqueous sodium bicarbonate and then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 1-bromo-2-methoxy-3-nitro-benzene 1c (44.59 g, yield 90.0%) as a brown solid. MS m/z (ESI): 234 [M+1] |
90% | With potassium carbonate In acetone at 70℃; for 40h; | 1.2 Step 2 1-Bromo-2-methoxy-3-nitro-benzene; 2-Bromo-6-nitro-phenol 1b (46.55 g, 0.214 mol) was dissolved in 500 mL of acetone followed by addition of potassium carbonate (35.36 g, 0.26 mol) and iodo- methane (20.1 mL, 0.32 mol). The reaction mixture was heated to reflux at 70°C for 40 hours. The reaction mixture was concentrated under reduced pressure and diluted with 1300 mL of ethyl acetate and 500 mL of water. The aqueous layer was extracted with ethyl acetate (300 mLx2). The combined organic extracts were washed with 4 M hydrochloric acid and saturated sodium bicarbonate solution and then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 1-bromo-2-methoxy-3-nitro-benzene 1c (44.59 g, yield 90.0%) as a brown solid. MS m/z (ESI): 234 [M+1] |
90% | With potassium carbonate In acetone at 70℃; for 40h; | 1.2 Step two 1-bromo-2-methoxy-3-nitrobenzene 2-bromo-6-nitrophenol 1b (46.55g, 0.214mol) was dissolved in 500mL acetone. To this was added potassium carbonate (35.36g, 0.26mol) and iodomethane (20.1mL, 0.32mol) then the solution was heated at reflux 70°C for 40 hours. The reaction solution was concentrated under reduced pressure. Added 1300mL ethyl acetate and 500mL water. The aqueous phase was extracted with ethyl acetate (300mL × 2). The combined organic phases were washed with 4M hydrochloric acid and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The result was purified by column chromatography on silica gel to give 1-bromo-2-methoxy-3-nitrobenzene 1c (44.59g, brown solid). Yield: 90.0%. |
89% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | 12.1 Preparation 12 Preparation 12 To a solution of 2-bromo-6-nitrophenol (5 g, 22.94 mmol) in DMF (18 ml) was added potassium carbonate (9.51 g, 68.8 mmol) and the resulting mixture was stirred for 15 min, then iodomethane (2.87 ml, 45.9 mmol) was added. The resulting mixture was stirred at rt overnight. HPLC and LCMS indicated complete conversion to product. Cold water added (75 mL), stir/sonicate, solid was collected by filtration. This material was then dissolved in EtOAc (150 mL). This solution was washed lx 10% LiCl, lx brine. dried over sodium sulfate, then filtered and concentrated. Loaded onto a 120g silica gel cartridge, then purified by flash chromatography eluting with 0-50% EtOAc in hexanes. Fractions containing the product were concentrated to afford a pale yellow solid as the product l-bromo-2-methoxy-3 -nitrobenzene (4.997 g, 20.46 mmol, 89% yield). LCMS ave very weak MH+. |
89% | Stage #1: 2-bromo-6-nitro-phenol With potassium carbonate In N,N-dimethyl-formamide for 0.25h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃; | 12.1 step 1 To a solution of 2-bromo-6-nitrophenol (5 g, 22.94 mmol) in DMF (18 ml) was added potassium carbonate (9.51 g, 68.8 mmol) and the resulting mixture was stirred for 15 min and then iodomethane (2.87 ml, 45.9 mmol). The resulting mixture was stirred overnight at rt. HPLC and LCMS instructions were fully converted to product. Add cold water (75 mL), perform agitation / sonic processing, and collect solids by filtration. The material was then dissolved in EtOAc (150 mL). The solution was washed with 10% LiCl, washed 1x with brine, dried over sodium sulfate, filtered and concentrated. Was loaded onto a 120 g silica gel cartridge and then purified by flash chromatography eluting with 0-50% EtOAc in hexanes. Concentrate the fractions containing the product to afford the product as a pale yellow solid 1-bromo-2-methoxy-3-nitrobenzene (4.997 g, 20.46 mmol, 89% yield). |
89% | Stage #1: 2-bromo-6-nitro-phenol With potassium carbonate In N,N-dimethyl-formamide for 0.25h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃; | 422.1 Step 1 : To a solution of 2-bromo-6-nitrophenol (5 g, 22.94 mmol) in DMF (18 ml) was added potassium carbonate (9.51 g, 68.8 mmol). The resulting mixture was stirred for 15 minutes, then iodomethane (2.87 ml,45.9 mmol) was added. The resulting mixture was stirred at room temperature overnight. HPLC and LC-MS indicated complete conversion to product. Cold water was added (75 mL), and the resulting mixture was stirred and sonicated. Next, the solid was collected with filtration. This material was then dissolved in EtOAc (l50mL). This solution was washed lx with 10% LiCl and lx with brine. The reaction mixture was dried over sodium sulfate, then filtered and concentrated. This was loaded onto a l20g ISCO column, then purified by flash chromatography eluting with 0-50% EtOAc in hexanes. The reaction afforded a pale yellow solid, l-bromo-2-methoxy-3-nitrobenzene (4.997 g, 20.46 mmol, 89 % yield) HPLC /R 0.92 min (analytical HPLC Method A). |
86% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | 10.2 Second step To a solution of compound 10c (10.80 g, 49.54 mmol) and potassium carbonate (10.40 g, 75.25 mmol) in 150 mL N,N-dimethylformamide was added methyl iodide (10.70 g, 75.38 mmol). The resulting reaction solution was reacted overnight at room temperature. After the reaction is over, filter, add ethyl acetate (100mL) to dilute, wash the organic phase with water (50mL×2), dry with anhydrous sodium sulfate, filter, the filtrate was concentrated under reduced pressure to obtain compound 10d (10.00 g), yield: 86%. |
83.6% | With potassium carbonate In acetone Heating / reflux; | 17 To a mixture of 2-bromo-6-nitrophenol (5.0 g, 22.9 mmol) and potassium carbonate (6.3 g,45.8 mmol) in acetone (100 mL) was added iodomethane (2.85 mL, 45.8 mmol) under stirring and the mixture was then heated to reflux overnight. The mixture was cooled to room temperature, filtered through Celite, the filter cake washed with ethyl acetate, and the filtrate concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed 3x with IN NaOH, once with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was recrystallized twice from 2-propanol / water to give 4.45 g (83.6%) of the title compound as beige, very fine needles.MS (ESI: 232 / 234 (M+H+) for C7H6BrNO1H-NMR (DMSO-d^ δ: ppm 3.98 (s, 3H); 7.39 (t, IH); 8.02 (dd, IH); 8.08 (dd, IH). |
With potassium carbonate In acetone at 80℃; for 6h; | Description for D312-bromo-6-nitrophenyl methyl ether (D31)To a mixture of K2C03 (2.54 g) and 2-bromo-6-nitrophenol (2g) in acetone (15 mL) at room temperature was added Mel (3.442 mL). The reaction mixture was heated to 80 °C for 6 h, after cooling the reaction, the mixture was filtered and the filtrate was concentrated to afford 2-bromo-6-nitrophenyl methyl ether (D31) (2.1 g). δΗ (CDCI3, 400MHz): 3.96 (3H, s), 4.91 (1H, m), 7.06 (1 H, t), 7.19 (1H, s), 7.72 (1H, m). | |
2.1 g | With potassium carbonate In acetone at 80℃; for 6h; | D31 Description for D31 [0202] 2-bromo-6-nitrophenyl methyl ether (D31) To a mixture of K2CO3 (2.54 g) and 2-bromo-6-nitrophenol (2 g) in acetone (15 mL) at room temperature was added Mel (3.442 mL). The reaction mixture was heated to 80° C. for 6 h, after cooling the reaction, the mixture was filtered and the filtrate was concentrated to afford 2-bromo-6-nitrophenyl methyl ether (D31) (2.1 g). δH (CDCl3, 400 MHz): 3.96 (3H, s), 4.91 (1H, m), 7.06 (1H, t), 7.19 (1H, s), 7.72 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium carbonate In acetonitrile for 2h; Reflux; | 71A.1 Step 1: 2-(Benzyloxy)-1-bromo-3-nitrobenzene Step 1: 2-(Benzyloxy)-1-bromo-3-nitrobenzene A mixture of 5.22 g (23.9 mmol) of 2-bromo-6-nitrophenol, 3.0 ml (25.1 mmol) of benzyl bromide and 3.64 g (26.3 mmol) of potassium carbonate in 50 ml of acetonitrile was heated under reflux for 2 h. After cooling to RT, the solid was filtered off and the filtrate was freed from the solvent on a rotary evaporator. The residue obtained was dissolved in ethyl acetate and washed successively with water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate, the mixture was filtered and the filtrate was concentrated on a rotary evaporator. The residue that remained was dried under high vacuum. This gave 7.53 g (99% of theory) of the title compound. 1H NMR (400 MHz, CDCl3, δ/ppm): 7.84 (dd, 1H), 7.79 (dd, 1H), 7.57-7.53 (m, 2H), 7.44-7.36 (m, 3H), 7.16 (t, 1H), 5.20 (s, 2H). |
94% | With potassium carbonate In acetonitrile at 20 - 70℃; | 41.a 2-Bromo-6-nitrophenol (1.59 g, 7.29 mmol), benzyl bromide (0.87 mL, 7.32 mmol), potassium carbonate (2.5 g, 18.1 mmol), and acetonitrile (15 mL) were combined in a round bottom flask and the mixture was heated at 70 0C with stirring under a nitrogen atmosphere for 3 h. The reaction mixture was allowed to stand at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was separated, washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give 2.12 g (94%) of l-bromo-3-nitro-2-[(phenylmethyl)oxy]benzene as a yellow liquid which solidified upon standing to a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.83 (dd, J = 8, 2 Hz, IH), 7.78 (dd, J = 8, 2 Hz, IH), 7.55 (m, 2H), 7.35-7.43 (m, 3H), 7.15 (t, J = 8 Hz, IH), 5.19 (s, 2H). |
94% | With potassium carbonate In acetonitrile at 70℃; for 3h; Inert atmosphere; |
93% | With potassium carbonate In acetone Reflux; | 4.5.2.1 1-Benzyloxy-2-bromo-6-nitrobenzene19 2-Bromo-6-nitrophenol (2.00g, 9.2mmol), anhydrous potassium carbonate (3.80g, 27.5mmol), and benzyl bromide (1.90g, 11.1mmol) were stirred in acetone (60ml) under reflux. Once the complete conversion was detected, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate) to give the title compound as a light yellow solid (2.59g, 93%). |
6.2 g | With potassium carbonate In acetone at 20℃; for 8h; | Synthesisof 2-(benzyloxy)-1-bromo-3-nitrobenzene (4) Toa solution of bromo phenol 3 (5 gm, 22.9mol) in acetone (50 mL) wasadded potassium carbonate (6.33gm, 45.8 mmol), benzyl bromide (2.72ml, 22.9mmol and the resultant red color solution was stirred at room temperature for 8hrs. The reaction mixture was filtered, washed the precipitate with acetone (30mL). The solvent was removed under reduced pressure,diluted with Ethyl acetate (100mL) and the organic layer was washed with water (3X50 mL), followed by withbrine solution. The organic layer was dried over MgSO4, filtered and the solvent was removed underreduced pressure to afford a brown color compound which was purified bytriturating with hot hexane to yield yellow color solid (6.2g, 20.1 mmol). M.P:83οC.Anal. Calc. for C13H10BrNO3 (308.0): C, 50.67;H, 3.27; N, 4.55; O, 15.58; Br, 25.93. Found: C, 50.63; H, 3.23; N, 4.53; O,15.54; Br, 25.90. 1H NMR (CDCl3, 300 MHz) : δ 7.97 (d,1H, J=2.4 Hz), 7.58 (dd, 1H, J=9.0, 2.4 Hz), 7.37 (m, 5H) ), 7.00(d, 1H, J=9.0Hz), 5.22 (s, 2H )ppm. 13C-NMR (CDCl3, 75 MHz): δ151.16, 140 .75, 136.82,135.19 , 128.93, 128.56, 128. 48, 127.12, 116.9, 112.38, 71.62 ppm. |
With potassium carbonate In acetonitrile | 24.1 Step 1: Preparation of 2-(benzyloxy)-1-bromo-3-nitrobenzene To 2-bromo-6-nitrophenol(5.2 g, 23.9 mmol) and K2CO3(3.6 g, 26.3 mmol) in acetonitrile(100 mL) was benzyl bromide(4.3 g, 25.3 mmol). The mixture was stirred at 100°C for 3 hour. TLC(PE:EA=10:1) detected and showed that the reaction was completed. The reaction mixture was filtered and the solid was eluted with ethyl acetate(10 mL*3). After the filtrate was spun dry, the residue was dissolved in ethyl acetate, and washed with water(20 m/L) and saturated salt water(20 mL). The organic phase was dried with anhydrous sodium sulfate, filtered and spun dry to give a yellow solid of 2-(benzyloxy)-1-bromo-3-nitrobenzene(7.50 g, 91.51% yield) as a crude product which was directly used in the next step without further purification. 1H NMR (400 MHz, CDCl3)□7.84 (d, J=8.03 Hz, 1 H), 7.79 (d, J=8.03 Hz, 1 H), 7.56 (d, J=6.53 Hz, 2 H), 7.37 - 7.45 (m, 3 H), 7.16 (t, J=8.28 Hz, 1 H), 5.21 (s, 2 H). MS (ESI) Calcd. for C13H10BrNO3 [M+H]+ 308, Found 308. | |
With potassium carbonate In acetonitrile for 3h; Reflux; | 1.1 Example 1 (1) (10.9 g, 50 mmol) 2-nitro-6-bromophenol (I), (9 g, 52 mmol) benzyl bromide (II) and potassium carbonate (7.6 g, 55 mmol) were mixed in acetonitrile (120 ml) The reaction was refluxed for 3 hours, cooled to room temperature, filtered, concentrated to dryness, dissolved in ethyl acetate (100 ml), washed with water (50 ml) and saturated sodium chloride solution (50 ml) successively, anhydrous sulfuric acid was used. The sodium is filtered after being dried, filtered and concentrated to dryness to give yellow crystals of oxybenzylidene bromide-3-nitrobenzene (III). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 1,4-diaza-bicyclo[2.2.2]octane In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-bromo-6-nitro-phenol With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere; Stage #2: Ethyl bromodifluoroacetate In N,N-dimethyl-formamide at 0 - 30℃; for 3.5h; | 3.B To a solution of 2-amino-6-bromophenol (2.00 g, 10.70 mmol, may be prepared as described in intermediate 1 ) in DMF (20 ml) was added sodium hydride (60%, 560 mg, 13.90 mmol) at 00C under nitrogen. The mixture was stirred for 30 min then ethyl bromo(difluoro)acetate (2.61 g, 12.84 mmol, Aldrich) was added dropwise at 00C and stirred for 30 min at 00C, then stirred for 3 hr at 300C. The mixture was diluted with EtOAc (50 ml), washed with water three times, then washed with brine, dried over sodium sulfate, filtered and concentrated. It was purified via column chromatography on silica gel (eluting with petroleum ether / ethyl acetate 10:1 ) to give the title compound (1.18 g) as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: zinc; acetic acid / methanol / 0.25 h / 20 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Reflux; Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C / Inert atmosphere 4.2: -78 - 20 °C 4.3: pH 1 5.1: Chiralpak AS / Resolution of racemate 6.1: potassium carbonate / potassium iodide / N,N-dimethyl-formamide / 20 °C | ||
Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 1.2: 3.5 h / 0 - 30 °C 2.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C / Inert atmosphere 2.2: -78 - 20 °C 2.3: pH 1 3.1: Chiralpak AS / Resolution of racemate 4.1: potassium carbonate / potassium iodide / N,N-dimethyl-formamide / 20 °C | ||
Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 1.2: 3.5 h / 0 - 30 °C 2.1: n-butyllithium / cyclohexane; diethyl ether / 1.58 h / -73 °C / Inert atmosphere 2.2: 2 h / -73 °C 2.3: 25 °C / pH 5 3.1: (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / toluene; tetrahydrofuran / 1.25 h / 25 °C 4.1: potassium carbonate / potassium iodide / N,N-dimethyl-formamide / 20 °C |
Multi-step reaction with 6 steps 1.1: zinc; acetic acid / methanol / 0.25 h / 20 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Reflux; Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / cyclohexane; diethyl ether / 1.58 h / -73 °C / Inert atmosphere 4.2: 2 h / -73 °C 4.3: 25 °C / pH 5 5.1: (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / toluene; tetrahydrofuran / 1.25 h / 25 °C 6.1: potassium carbonate / potassium iodide / N,N-dimethyl-formamide / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: zinc; acetic acid / methanol / 0.25 h / 20 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Reflux; Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C / Inert atmosphere 4.2: -78 - 20 °C 4.3: pH 1 5.1: Chiralpak AS / Resolution of racemate 6.1: potassium carbonate / potassium iodide / N,N-dimethyl-formamide / 20 °C | ||
Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 1.2: 3.5 h / 0 - 30 °C 2.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C / Inert atmosphere 2.2: -78 - 20 °C 2.3: pH 1 3.1: Chiralpak AS / Resolution of racemate 4.1: potassium carbonate / potassium iodide / N,N-dimethyl-formamide / 20 °C | ||
Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 1.2: 3.5 h / 0 - 30 °C 2.1: n-butyllithium / cyclohexane; diethyl ether / 1.58 h / -73 °C / Inert atmosphere 2.2: 2 h / -73 °C 2.3: 25 °C / pH 5 3.1: (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / toluene; tetrahydrofuran / 1.25 h / 25 °C 4.1: potassium carbonate / potassium iodide / N,N-dimethyl-formamide / 20 °C |
Multi-step reaction with 6 steps 1.1: zinc; acetic acid / methanol / 0.25 h / 20 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Reflux; Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / cyclohexane; diethyl ether / 1.58 h / -73 °C / Inert atmosphere 4.2: 2 h / -73 °C 4.3: 25 °C / pH 5 5.1: (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / toluene; tetrahydrofuran / 1.25 h / 25 °C 6.1: potassium carbonate / potassium iodide / N,N-dimethyl-formamide / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 4.2: -78 - 20 °C 5.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 6.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 7.1: Chiracel OJ column / n-heptane; ethanol / Resolution of racemate | ||
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 3.2: -78 - 20 °C 4.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 5.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 6.1: Chiracel OJ column / n-heptane; ethanol / Resolution of racemate | ||
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 3.2: 2 h / -73 °C 3.3: 25 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 5.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 6.1: Chiracel OJ column / n-heptane; ethanol / Resolution of racemate |
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 3.2: -78 - 20 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 5.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 6.1: Chiracel OJ column / n-heptane; ethanol / Resolution of racemate | ||
Multi-step reaction with 7 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 4.2: -78 - 20 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 6.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 7.1: Chiracel OJ column / n-heptane; ethanol / Resolution of racemate | ||
Multi-step reaction with 7 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 4.2: 2 h / -73 °C 4.3: 25 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 6.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 7.1: Chiracel OJ column / n-heptane; ethanol / Resolution of racemate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 4.2: -78 - 20 °C 5.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 6.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 20 °C / Inert atmosphere | ||
Multi-step reaction with 5 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 3.2: -78 - 20 °C 4.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 5.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 20 °C / Inert atmosphere | ||
Multi-step reaction with 5 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 3.2: 2 h / -73 °C 3.3: 25 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 5.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 20 °C / Inert atmosphere |
Multi-step reaction with 5 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 3.2: -78 - 20 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 5.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 20 °C / Inert atmosphere | ||
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 4.2: 2 h / -73 °C 4.3: 25 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 6.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 20 °C / Inert atmosphere | ||
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 4.2: -78 - 20 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 6.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 4.2: -78 - 20 °C 5.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 3.2: 2 h / -73 °C 3.3: 25 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C | ||
Multi-step reaction with 4 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 3.2: -78 - 20 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C |
Multi-step reaction with 4 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 3.2: -78 - 20 °C 4.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere | ||
Multi-step reaction with 5 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 4.2: 2 h / -73 °C 4.3: 25 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C | ||
Multi-step reaction with 5 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 4.2: -78 - 20 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 4.2: -78 - 20 °C 5.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 6.1: Chiralcel OJ column / n-heptane; trifluoroacetic acid; ethanol / Resolution of racemate | ||
Multi-step reaction with 5 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 3.2: -78 - 20 °C 4.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 5.1: Chiralcel OJ column / n-heptane; trifluoroacetic acid; ethanol / Resolution of racemate | ||
Multi-step reaction with 5 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 3.2: 2 h / -73 °C 3.3: 25 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 5.1: Chiralcel OJ column / n-heptane; trifluoroacetic acid; ethanol / Resolution of racemate |
Multi-step reaction with 5 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 3.2: -78 - 20 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 5.1: Chiralcel OJ column / n-heptane; trifluoroacetic acid; ethanol / Resolution of racemate | ||
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 4.2: -78 - 20 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 6.1: Chiralcel OJ column / n-heptane; trifluoroacetic acid; ethanol / Resolution of racemate | ||
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 4.2: 2 h / -73 °C 4.3: 25 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 6.1: Chiralcel OJ column / n-heptane; trifluoroacetic acid; ethanol / Resolution of racemate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 4.2: -78 - 20 °C 5.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 6.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 20 °C | ||
Multi-step reaction with 5 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 3.2: 2 h / -73 °C 3.3: 25 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 5.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 20 °C | ||
Multi-step reaction with 5 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 3.2: -78 - 20 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 5.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 20 °C |
Multi-step reaction with 5 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 3.2: -78 - 20 °C 4.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 5.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 20 °C | ||
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 4.2: 2 h / -73 °C 4.3: 25 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 6.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 20 °C | ||
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 4.2: -78 - 20 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 6.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 4.2: -78 - 20 °C 5.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 6.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 20 °C 7.1: Chiralpak IA column / n-heptane; ethanol / Resolution of racemate | ||
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 3.2: -78 - 20 °C 4.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 5.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 20 °C 6.1: Chiralpak IA column / n-heptane; ethanol / Resolution of racemate | ||
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 3.2: 2 h / -73 °C 3.3: 25 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 5.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 20 °C 6.1: Chiralpak IA column / n-heptane; ethanol / Resolution of racemate |
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 3.2: -78 - 20 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 5.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 20 °C 6.1: Chiralpak IA column / n-heptane; ethanol / Resolution of racemate | ||
Multi-step reaction with 7 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 4.2: 2 h / -73 °C 4.3: 25 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 6.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 20 °C 7.1: Chiralpak IA column / n-heptane; ethanol / Resolution of racemate | ||
Multi-step reaction with 7 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 4.2: -78 - 20 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 6.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 20 °C 7.1: Chiralpak IA column / n-heptane; ethanol / Resolution of racemate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 4.2: -78 - 20 °C 5.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 6.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C | ||
Multi-step reaction with 5 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 3.2: 2 h / -73 °C 3.3: 25 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 5.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C | ||
Multi-step reaction with 5 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 3.2: -78 - 20 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 5.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C |
Multi-step reaction with 5 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 3.2: -78 - 20 °C 4.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 5.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C | ||
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 4.2: 2 h / -73 °C 4.3: 25 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 6.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C | ||
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 4.2: -78 - 20 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 6.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 4.2: -78 - 20 °C 5.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 6.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 20 °C | ||
Multi-step reaction with 5 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 3.2: 2 h / -73 °C 3.3: 25 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 5.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 20 °C | ||
Multi-step reaction with 5 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 3.2: -78 - 20 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 5.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 20 °C |
Multi-step reaction with 5 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 3.2: -78 - 20 °C 4.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 5.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 20 °C | ||
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 4.2: 2 h / -73 °C 4.3: 25 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 6.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 20 °C | ||
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 4.2: -78 - 20 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 6.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 4.2: -78 - 20 °C 5.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 6.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C | ||
Multi-step reaction with 5 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 3.2: 2 h / -73 °C 3.3: 25 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 5.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C | ||
Multi-step reaction with 5 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 3.2: -78 - 20 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 5.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C |
Multi-step reaction with 5 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 3.2: -78 - 20 °C 4.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 5.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C | ||
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 4.2: 2 h / -73 °C 4.3: 25 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 6.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C | ||
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 4.2: -78 - 20 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 6.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 4.2: -78 - 20 °C 5.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 6.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 7.1: Chiralpak AD column / n-heptane; ethanol / Resolution of racemate | ||
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 3.2: -78 - 20 °C 4.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 5.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 6.1: Chiralpak AD column / n-heptane; ethanol / Resolution of racemate | ||
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 3.2: 2 h / -73 °C 3.3: 25 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 5.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 6.1: Chiralpak AD column / n-heptane; ethanol / Resolution of racemate |
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 3.2: -78 - 20 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 5.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 6.1: Chiralpak AD column / n-heptane; ethanol / Resolution of racemate | ||
Multi-step reaction with 7 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 4.2: 2 h / -73 °C 4.3: 25 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 6.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 7.1: Chiralpak AD column / n-heptane; ethanol / Resolution of racemate | ||
Multi-step reaction with 7 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 4.2: -78 - 20 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 6.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 7.1: Chiralpak AD column / n-heptane; ethanol / Resolution of racemate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 4.2: -78 - 20 °C 5.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 6.1: Chiralcel OJ column / n-heptane; trifluoroacetic acid; ethanol / Resolution of racemate 7.1: potassium carbonate / N,N-dimethyl-formamide / 25 °C | ||
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 3.2: -78 - 20 °C 4.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 5.1: Chiralcel OJ column / n-heptane; trifluoroacetic acid; ethanol / Resolution of racemate 6.1: potassium carbonate / N,N-dimethyl-formamide / 25 °C | ||
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 3.2: 2 h / -73 °C 3.3: 25 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 5.1: Chiralcel OJ column / n-heptane; trifluoroacetic acid; ethanol / Resolution of racemate 6.1: potassium carbonate / N,N-dimethyl-formamide / 25 °C |
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 3.2: -78 - 20 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 5.1: Chiralcel OJ column / n-heptane; trifluoroacetic acid; ethanol / Resolution of racemate 6.1: potassium carbonate / N,N-dimethyl-formamide / 25 °C | ||
Multi-step reaction with 7 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 4.2: -78 - 20 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 6.1: Chiralcel OJ column / n-heptane; trifluoroacetic acid; ethanol / Resolution of racemate 7.1: potassium carbonate / N,N-dimethyl-formamide / 25 °C | ||
Multi-step reaction with 7 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 4.2: 2 h / -73 °C 4.3: 25 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 6.1: Chiralcel OJ column / n-heptane; trifluoroacetic acid; ethanol / Resolution of racemate 7.1: potassium carbonate / N,N-dimethyl-formamide / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 4.2: -78 - 20 °C 5.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 6.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 20 °C 7.1: Chiralpak IA column / isopropyl alcohol; n-heptane / Resolution of racemate | ||
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 3.2: -78 - 20 °C 4.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 5.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 20 °C 6.1: Chiralpak IA column / isopropyl alcohol; n-heptane / Resolution of racemate | ||
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 3.2: 2 h / -73 °C 3.3: 25 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 5.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 20 °C 6.1: Chiralpak IA column / isopropyl alcohol; n-heptane / Resolution of racemate |
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 3.2: -78 - 20 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 5.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 20 °C 6.1: Chiralpak IA column / isopropyl alcohol; n-heptane / Resolution of racemate | ||
Multi-step reaction with 7 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 4.2: -78 - 20 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 6.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 20 °C 7.1: Chiralpak IA column / isopropyl alcohol; n-heptane / Resolution of racemate | ||
Multi-step reaction with 7 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 4.2: 2 h / -73 °C 4.3: 25 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 6.1: potassium carbonate / N,N-dimethyl-formamide / 1 h / 20 °C 7.1: Chiralpak IA column / isopropyl alcohol; n-heptane / Resolution of racemate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 4.2: -78 - 20 °C 5.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 6.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 7.1: Chiralpak IA column / isopropyl alcohol; n-heptane / Resolution of racemate | ||
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / hexane; diethyl ether / 0.5 h / -78 °C 3.2: -78 - 20 °C 4.1: cesium fluoride / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 5.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 6.1: Chiralpak IA column / isopropyl alcohol; n-heptane / Resolution of racemate | ||
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 3.2: 2 h / -73 °C 3.3: 25 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 5.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 6.1: Chiralpak IA column / isopropyl alcohol; n-heptane / Resolution of racemate |
Multi-step reaction with 6 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere 2.2: 3.5 h / 0 - 30 °C 3.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 3.2: -78 - 20 °C 4.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 5.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 6.1: Chiralpak IA column / isopropyl alcohol; n-heptane / Resolution of racemate | ||
Multi-step reaction with 7 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / diethyl ether / 0.5 h / -78 °C / Inert atmosphere 4.2: -78 - 20 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 6.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 7.1: Chiralpak IA column / isopropyl alcohol; n-heptane / Resolution of racemate | ||
Multi-step reaction with 7 steps 1.1: water; sodium dithionite / ethanol / 60 °C 2.1: triethylamine / ethyl acetate / 2 h / 90 °C / Inert atmosphere 3.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 50 °C 4.1: n-butyllithium / tert-butyl methyl ether / 2.17 h / -70 - 73 °C / Inert atmosphere 4.2: 2 h / -73 °C 4.3: 25 °C 5.1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; borane-THF / tetrahydrofuran / 2.25 h / 25 °C 6.1: potassium carbonate / N,N-dimethyl-formamide / 20 °C 7.1: Chiralpak IA column / isopropyl alcohol; n-heptane / Resolution of racemate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine In dichloromethane at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With triethylamine In dichloromethane at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine In dichloromethane at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 6 h / 80 °C 2: caesium carbonate; tri-tert-butyl phosphine / tris-(dibenzylideneacetone)dipalladium(0) / tetrahydrofuran / 20 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 6 h / 80 °C 2: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; tri-tert-butyl phosphine / tetrahydrofuran / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 6 h / 80 °C 2: caesium carbonate; tri-tert-butyl phosphine / tris-(dibenzylideneacetone)dipalladium(0) / tetrahydrofuran / 20 °C / Inert atmosphere 3: hydrogen / Raney nickel / ethanol / 20 °C | ||
Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 6 h / 80 °C 2: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; tri-tert-butyl phosphine / tetrahydrofuran / 20 °C / Inert atmosphere 3: hydrogen / ethanol / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: potassium carbonate / acetone / 6 h / 80 °C 2.1: caesium carbonate; tri-tert-butyl phosphine / tris-(dibenzylideneacetone)dipalladium(0) / tetrahydrofuran / 20 °C / Inert atmosphere 3.1: hydrogen / Raney nickel / ethanol / 20 °C 4.1: sodium nitrite; hydrogen bromide / water / 0.17 h / 0 - 5 °C 4.2: 0.17 h / 80 °C 4.3: 16 h / 90 °C / Inert atmosphere | ||
Multi-step reaction with 5 steps 1.1: potassium carbonate / acetone / 6 h / 80 °C 2.1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; tri-tert-butyl phosphine / tetrahydrofuran / 20 °C / Inert atmosphere 3.1: hydrogen / ethanol / 20 °C / Inert atmosphere 4.1: hydrogen bromide / water / 0 - 5 °C 4.2: 0.17 h / 0 - 5 °C 4.3: 0.17 h / 80 °C 5.1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / N,N-dimethyl-formamide / 16 h / 90 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: potassium carbonate / acetone / 6 h / 80 °C 2.1: caesium carbonate; tri-tert-butyl phosphine / tris-(dibenzylideneacetone)dipalladium(0) / tetrahydrofuran / 20 °C / Inert atmosphere 3.1: hydrogen / Raney nickel / ethanol / 20 °C 4.1: sodium nitrite; hydrogen bromide / water / 0.17 h / 0 - 5 °C 4.2: 0.17 h / 80 °C 4.3: 16 h / 90 °C / Inert atmosphere 5.1: potassium phosphate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 0.25 h / 130 °C / Inert atmosphere; Sealed; Microwave irradiation | ||
Multi-step reaction with 6 steps 1.1: potassium carbonate / acetone / 6 h / 80 °C 2.1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; tri-tert-butyl phosphine / tetrahydrofuran / 20 °C / Inert atmosphere 3.1: hydrogen / ethanol / 20 °C / Inert atmosphere 4.1: hydrogen bromide / water / 0 - 5 °C 4.2: 0.17 h / 0 - 5 °C 4.3: 0.17 h / 80 °C 5.1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / N,N-dimethyl-formamide / 16 h / 90 °C / Inert atmosphere 6.1: potassium phosphate; tetrakis(triphenylphosphine) palladium(0) / water; 1,2-dimethoxyethane / 0.25 h / 130 °C / Inert atmosphere; Sealed tube; Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: potassium carbonate / acetone / 6 h / 80 °C 2.1: caesium carbonate; tri-tert-butyl phosphine / tris-(dibenzylideneacetone)dipalladium(0) / tetrahydrofuran / 20 °C / Inert atmosphere 3.1: hydrogen / Raney nickel / ethanol / 20 °C 4.1: sodium nitrite; hydrogen bromide / water / 0.17 h / 0 - 5 °C 4.2: 0.17 h / 80 °C 4.3: 16 h / 90 °C / Inert atmosphere 5.1: potassium phosphate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 0.25 h / 130 °C / Inert atmosphere; Sealed; Microwave irradiation 6.1: potassium phosphate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 0.25 h / 130 °C / Inert atmosphere; Sealed; Microwave irradiation | ||
Multi-step reaction with 7 steps 1.1: potassium carbonate / acetone / 6 h / 80 °C 2.1: tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; tri-tert-butyl phosphine / tetrahydrofuran / 20 °C / Inert atmosphere 3.1: hydrogen / ethanol / 20 °C / Inert atmosphere 4.1: hydrogen bromide / water / 0 - 5 °C 4.2: 0.17 h / 0 - 5 °C 4.3: 0.17 h / 80 °C 5.1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / N,N-dimethyl-formamide / 16 h / 90 °C / Inert atmosphere 6.1: potassium phosphate; tetrakis(triphenylphosphine) palladium(0) / water; 1,2-dimethoxyethane / 0.25 h / 130 °C / Inert atmosphere; Sealed tube; Microwave irradiation 7.1: potassium phosphate; tetrakis(triphenylphosphine) palladium(0) / water; 1,2-dimethoxyethane / 0.25 h / 130 °C / Inert atmosphere; Sealed tube; Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 40 h / 70 °C 2: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 43 h / 105 °C | ||
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 40 h / 70 °C 2: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane / 43 h / 105 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 40 h / 70 °C 2: potassium acetate / tetrakis(triphenylphosphine) palladium(0) / etheroxalic acid dimethyl ether / 17 h / Reflux | ||
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 40 h / 70 °C 2: potassium acetate; tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane / 17 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: potassium carbonate / acetone / 40 h / 70 °C 2.1: potassium acetate / tetrakis(triphenylphosphine) palladium(0) / etheroxalic acid dimethyl ether / 17 h / Reflux 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 2.5 h / Reflux 3.2: pH 3 | ||
Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 40 h / 70 °C 2: potassium acetate; tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane / 17 h / Reflux 3: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 2.5 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: potassium carbonate / acetone / 40 h / 70 °C 2.1: potassium acetate / tetrakis(triphenylphosphine) palladium(0) / etheroxalic acid dimethyl ether / 17 h / Reflux 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 2.5 h / Reflux 3.2: pH 3 4.1: ammonium formate / palladium 10% on activated carbon / ethyl acetate / 3.5 h / Reflux | ||
Multi-step reaction with 4 steps 1: potassium carbonate / acetone / 40 h / 70 °C 2: potassium acetate; tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane / 17 h / Reflux 3: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 2.5 h / Reflux 4: palladium 10% on activated carbon; ammonium formate / ethyl acetate / 3.5 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: potassium carbonate / acetone / 40 h / 70 °C 2.1: potassium acetate / tetrakis(triphenylphosphine) palladium(0) / etheroxalic acid dimethyl ether / 17 h / Reflux 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 2.5 h / Reflux 3.2: pH 3 | ||
Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 40 h / 70 °C 2: potassium acetate; tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane / 17 h / Reflux 3: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 2.5 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: potassium carbonate / acetone / 40 h / 70 °C 2.1: potassium acetate / tetrakis(triphenylphosphine) palladium(0) / etheroxalic acid dimethyl ether / 17 h / Reflux 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 2.5 h / Reflux 3.2: pH 3 4.1: ammonium formate / palladium 10% on activated carbon / ethyl acetate / 3 h / Reflux | ||
Multi-step reaction with 4 steps 1: potassium carbonate / acetone / 40 h / 70 °C 2: potassium acetate; tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane / 17 h / Reflux 3: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 2.5 h / Reflux 4: ammonium formate; palladium on activated charcoal / ethyl acetate / 3 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: potassium carbonate / acetone / 40 h / 70 °C 2.1: potassium acetate / tetrakis(triphenylphosphine) palladium(0) / etheroxalic acid dimethyl ether / 17 h / Reflux 3.1: potassium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 2.5 h / Reflux 3.2: pH 3 4.1: ammonium formate / palladium 10% on activated carbon / ethyl acetate / 3 h / Reflux 5.1: boron tribromide / dichloromethane / 4.5 h / 20 °C | ||
Multi-step reaction with 5 steps 1: potassium carbonate / acetone / 40 h / 70 °C 2: potassium acetate; tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane / 17 h / Reflux 3: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 2.5 h / Reflux 4: ammonium formate; palladium on activated charcoal / ethyl acetate / 3 h / Reflux 5: boron tribromide / dichloromethane / 4.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 40 h / 70 °C 2: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 43 h / 105 °C 3: ammonium formate / palladium 10% on activated carbon / ethanol / 0.33 h / 80 °C | ||
Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 40 h / 70 °C 2: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane / 43 h / 105 °C 3: palladium 10% on activated carbon; ammonium formate / ethanol / 0.33 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: potassium carbonate / acetone / 40 h / 70 °C 2.1: potassium acetate / tetrakis(triphenylphosphine) palladium(0) / etheroxalic acid dimethyl ether / 17 h / Reflux 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 2.5 h / Reflux 3.2: pH 3 4.1: ammonium formate / palladium 10% on activated carbon / ethyl acetate / 3.5 h / Reflux 5.1: boron tribromide / dichloromethane / 1 h / 20 °C 5.2: 1 h 6.1: hydrogenchloride; sodium nitrite / water / 0.33 h / Cooling with ice 6.2: 20 °C / pH 8 - 9 / Cooling with ice 6.3: pH 3 - 4 7.1: water; tetrahydrofuran / 2 h / 20 °C | ||
Multi-step reaction with 7 steps 1.1: potassium carbonate / acetone / 40 h / 70 °C 2.1: potassium acetate; tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane / 17 h / Reflux 3.1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 2.5 h / Reflux 4.1: palladium 10% on activated carbon; ammonium formate / ethyl acetate / 3.5 h / Reflux 5.1: boron tribromide / dichloromethane / 1 h / 20 °C 6.1: hydrogenchloride; sodium nitrite / water / 0.33 h / Cooling with ice 6.2: 20 °C / pH 8 - 9 7.1: water; tetrahydrofuran / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: potassium carbonate / acetone / 40 h / 70 °C 2.1: potassium acetate / tetrakis(triphenylphosphine) palladium(0) / etheroxalic acid dimethyl ether / 17 h / Reflux 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.5 h / Reflux 3.2: pH 3 | ||
Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 40 h / 70 °C 2: potassium acetate; tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane / 17 h / Reflux 3: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 0.5 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: potassium carbonate / acetone / 40 h / 70 °C 2.1: potassium acetate / tetrakis(triphenylphosphine) palladium(0) / etheroxalic acid dimethyl ether / 17 h / Reflux 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 0.5 h / Reflux 3.2: pH 3 4.1: ammonium formate / palladium 10% on activated carbon / ethyl acetate / 3 h / Reflux | ||
Multi-step reaction with 4 steps 1: potassium carbonate / acetone / 40 h / 70 °C 2: potassium acetate; tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane / 17 h / Reflux 3: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 0.5 h / Reflux 4: palladium 10% on activated carbon; ammonium formate / ethyl acetate / 3 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: potassium carbonate / acetone / 40 h / 70 °C 2.1: potassium acetate / tetrakis(triphenylphosphine) palladium(0) / etheroxalic acid dimethyl ether / 17 h / Reflux 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 2.5 h / Reflux 3.2: pH 3 4.1: ammonium formate / palladium 10% on activated carbon / ethyl acetate / 3.5 h / Reflux 5.1: boron tribromide / dichloromethane / 1 h / 20 °C 5.2: 1 h 6.1: hydrogenchloride; sodium nitrite / water / 0.33 h / Cooling with ice 6.2: 20 °C / pH 8 - 9 / Cooling with ice 6.3: pH 3 - 4 | ||
Multi-step reaction with 6 steps 1.1: potassium carbonate / acetone / 40 h / 70 °C 2.1: potassium acetate; tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane / 17 h / Reflux 3.1: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; 1,4-dioxane / 2.5 h / Reflux 4.1: palladium 10% on activated carbon; ammonium formate / ethyl acetate / 3.5 h / Reflux 5.1: boron tribromide / dichloromethane / 1 h / 20 °C 6.1: hydrogenchloride; sodium nitrite / water / 0.33 h / Cooling with ice 6.2: 20 °C / pH 8 - 9 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: potassium carbonate / acetone / 40 h / 70 °C 2.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane; water / 43 h / 105 °C 3.1: ammonium formate / palladium 10% on activated carbon / ethanol / 0.33 h / 80 °C 4.1: hydrogen bromide / water / 120 °C 5.1: hydrogenchloride; sodium nitrite / water / Cooling with ice 5.2: 20 °C / pH 8 / Cooling with ice | ||
Multi-step reaction with 5 steps 1: potassium carbonate / acetone / 40 h / 70 °C 2: sodium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane / 43 h / 105 °C 3: palladium 10% on activated carbon; ammonium formate / ethanol / 0.33 h / 80 °C 4: hydrogen bromide / water / 120 °C 5: hydrogenchloride; sodium nitrite; sodium hydrogencarbonate / water; ethanol / 20 °C / pH 8 / Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With 1,1'-bis(diphenylphosphanyl)ferrocene In toluene at 150℃; for 24h; Inert atmosphere; | |
66.3% | With 1,1'-bis(diphenylphosphanyl)ferrocene In 5,5-dimethyl-1,3-cyclohexadiene at 130℃; Inert atmosphere; | 8 Preparation of compound K-a Under the protection of nitrogen,Weighed 30 g of 2-bromo-6-nitrophenol (137.6 mmol) in turn,37.2 g of benzyl alcohol (344.1 mmol) was added to 10 g of DPPF.Add the mixture with xylene and heat to 130 ° C.The temperature is refluxed to the sampling point plate to show that there is no remaining of 2-bromo-6-nitrophenol, concentrated and de-dryed, activated carbon, petroleum ether passed through a silica gel column, and the solvent is dehydrated to a fraction without distillation, and refined with petroleum ether.Drying to obtain 25 g of compound K-a,The yield is 66.3%.GC: 98.7%. |
64% | With 1,1'-bis(diphenylphosphanyl)ferrocene In 5,5-dimethyl-1,3-cyclohexadiene at 125 - 135℃; for 36h; Inert atmosphere; | 1.1 (1) Synthesis of reactant B-1 To be equipped with mechanical stirring, thermometer,The three-necked flask of the spherical condenser is filled with nitrogen (0.100L/min) for 15min,Add 2-bromo-6-nitrophenol (50.0g, 229.3mmol) sequentially,Benzyl alcohol (29.76g, 275.2mmol),1,1'-bis(diphenylphosphine)ferrocene (3.71g, 6.8mmol) and xylene (500mL) are stirred and heated,When the temperature rises to 125-135, reflux and react for 36h,Stop stirring and heating after the reaction is completed, and start the treatment reaction when the temperature drops to room temperature;Add toluene and water to extract the reaction solution, combine the organic phases,Dry the organic layer with anhydrous magnesium sulfate, filter, and concentrate;Use dichloromethane/n-heptane system to purify the crude product by silica gel column chromatography,A solid compound reactant B-1 (40.23 g, 64%) was obtained. |
64% | With 1,1'-bis(diphenylphosphanyl)ferrocene In 5,5-dimethyl-1,3-cyclohexadiene at 125 - 135℃; for 36h; Inert atmosphere; | (1) Synthesis of Intermediate M-1 Introduce nitrogen (0.100L/min) into the three-necked flask equipped with mechanical stirring, thermometer and spherical condenser for 15min,2-Bromo-6-nitrophenol (50.0 g, 229.3 mmol), benzyl alcohol (29.76 g, 275.2 mmol) were added successively,1,1'-bis(diphenylphosphino)ferrocene (3.71 g, 6.8 mmol) and xylene (500 mL) were stirred and heated,When the temperature rises to 125-135 , reflux reaction for 36h, stop stirring and heating after the reaction is completed,When the temperature drops to room temperature, the treatment reaction is started;Toluene and water were added to extract the reaction solution, the organic phases were combined, the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated;The crude product was purified by silica gel column chromatography using a dichloromethane/n-heptane system to obtain a solid compound Intermediate M-1 (40.23 g, yield 64%). |
48% | With ferric(III) chloride; 1,1'-bis(diphenylphosphanyl)ferrocene In toluene at 150℃; for 24h; | 1-(1) Synthesis of [Intermediate 1-a] 100ml round bottom flask was charged benzyl alcohol (31.0g, 0.286mol), 2- bromo-6-nitro-phenol (25.0g, 0.115mol), iron chloride (III) (0.93g, 5.7mmol), 1,1'- bis(diphenylphosphino) ferrocene (1.27g, 2mmol), into 25ml of toluene was refluxed understirring for 24 hours at 150 ° C. After the reaction was complete, it cooled at room temperature and concentrated underreduced pressure and column separation. Recrystallized from petroleum ether to give the [intermediate 1-a]. (15.0g, 48%). |
48.6% | With 1,1'-bis(diphenylphosphanyl)ferrocene In 5,5-dimethyl-1,3-cyclohexadiene at 130℃; for 24h; | 1.1.2.1 Synthesis of intermediate B-1-1 Add 2-bromo-6-nitrophenol (15.0g, 68.8mmol),Benzyl alcohol (9.67g, 89.4mmol),Dppf (1.14g, 2.06mmol), .xylene (150mL),Put it into a round bottom flask, heat up to 130°C and stir for 24h.After the temperature of the reaction solution drops to room temperature, the organic phase is separated by washing with water,Use anhydrous magnesium sulfate to dry the organic phase,And remove the solvent in the organic phase under reduced pressure to obtain a crude product;Using dichloromethane/n-heptane as the eluent, the crude product was purified by silica gel column chromatography,B-1-1 (8.75 g, yield 48.6%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.04 g | With potassium carbonate; caesium carbonate In N,N-dimethyl-formamide at 40℃; for 48h; Inert atmosphere; | 8 Method 21 2-Isopropoxy-3-(4-methylpiperazine-1-yl)phenylamine 1.23 g of potassium carbonate, 14.6 g of caesium carbonate, 22 ml of dimethylformamide and 1.0 g of 2-bromo-6-nitrophenol are successively introduced into a three-necked round-bottomed flask under argon. The resulting suspension is stirred at ambient temperature for 10 min, and then 0.91 ml of 2-iodopropane is added in one go. The round-bottomed flask is rinsed with 10 ml of dimethylformamide and then the reaction mixture is heated at 40° C. for 48 h. After cooling to ambient temperature, the mixture is treated with 50 ml of water and extracted four times with 30 ml of ethyl acetate. The organic extracts are combined and washed with 30 ml of saturated brine and then 30 ml of water. The organic phase is then dried over magnesium sulfate and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 30 g silica cartridge, elution being carried out with a 95/5 v/v cyclohexane/ethyl acetate mixture at a flow rate of 30 ml/min, so as to obtain 1.04 g of 1-bromo-2-isopropoxy-3-nitrobenzene in the form of a yellow oil. |
1.04 g | With potassium carbonate; caesium carbonate In N,N-dimethyl-formamide at 40℃; for 48h; Inert atmosphere; | III.8.21 1 .23 g of potassium carbonate, 14.6 g of caesium carbonate, 22 ml of dimethylformamide and 1 .0 g of 2-bromo-6-nitrophenol are successively introduced into a three-necked round-bottomed flask under argon. The resulting suspension is stirred at ambient temperature for 10 min, and then 0.91 ml of 2-iodopropane is added in one go. The round- bottomed flask is rinsed with 10 ml of dimethylformamide and then the reaction mixture is heated at 40 °C for 48 h. After cooling to ambient temperature, the mixture is treated with 50 ml of water and extracted four times with 30 ml of ethyl acetate. The organic extracts are combined and washed with 30 ml of saturated brine and then 30 ml of water. The organic phase is then dried over magnesium sulfate and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 30 g silica cartridge, elution being carried out with a 95/5 v/v cyclohexane/ethyl acetate mixture at a flow rate of 30 ml/min, so as to obtain 1 .04 g of 1 -bromo-2-isopropoxy-3-nitrobenzene in the form of a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 13h; | |
90% | With potassium carbonate; potassium iodide In acetone for 15h; Inert atmosphere; Reflux; | 1 Example 1: Synthesis of benzyl 2-bromo-6-nitrophenyl ether of formula (IV) 2-bromo-6-nitrophenol (100 g, 0.459 mol), K2CO3 (74.2 g, 0.537 mol), KI (3.81 g, 23 mmol) and benzyl chloride (62.7 g, 0.495 mol) are suspended in acetone (600 ml) in a 2 L flask with mechanical stirrer, condenser and thermometer, purged under nitrogen atmosphere. The reaction mixture is heated at reflux temperature for 15 hours, and then cooled to about 25°C and filtered through a Celite bed. The panel is further washed with acetone, and the organic phases are combined and concentrated at low pressure. The residue thus obtained is crystallised from hexane (600 ml). The solid product is filtered and stove-dried at 40°C at low pressure. 126 g of benzyl 2-bromo-6-nitrophenyl ether (IV) is obtained, with a yield of 90%. [0055] The compound of formula (IV) thus obtained presents an XRPD spectrum substantially as reported in Figure 2, wherein the most intense peaks expressed in 2θ are found at about 12.09; 13.21; 13.49; 15.42; 16.55; 17.81; 19.84; 21.28; 22.64; and 22.85 ± 0.2° in 20. [0056] 1H-NMR (CDCl3, 300 MHz), δ: 7.86-7.75 (m, 2H); 7.67-7.50 (m, 2H) 7.46-7.32 (m, 3H); 7.14 (t, J=8.2 Hz, 1H); 5.19 (s 2H). |
87% | With tetra-(n-butyl)ammonium iodide; potassium carbonate at 25 - 80℃; for 3h; | 1 Example 1: Preparation of 2-(benzyloxy)-1-bromo-3-nitrobenzene [Benzyl Proctected Bromonitrophenol] In a 2 L round bottom flask, anhydrous potassium carbonate (76 g), tetrabutylammonium iodide (5 g) and benzyl chloride (61 g) were added at 25-35° C. to a stirred solution of 2-bromo-6-nitrophenol (100 g) in acetonitrile (1000 mL) at 25-30° C. The resulting suspension was refluxed at 80±2° C. for 3 h. After completion of reaction (HPLC monitored), the reaction mass was concentrated at atmospheric pressure at 80-90° C. Thereafter, concentrated mass was cooled at 40-50° C. and water (1600 mL) and cycloxehane (600 mL) were added. The Reaction mass was stirred at 50-60° C. for -30 minutes. The layers were separated. Organic layer was washed with 200 mL of water at 50-60° C. The obtained organic layer was cooled to 25-30° C. and stirred for 30 minutes then further cooled to 12-18° C. and continued stirring at this temperature for another 2 h to complete the precipitation of the product. Product was filtered and washed with pre-cooled cyclohexane (100 mL). The obtained wet product was dried at 40-45° C. under reduced pressure (50 mm Hg) for 10 h to furnish 123.0 g (87% yield) as an off white powder with >99% purity, by HPLC. (0092) 1H NMR (500 MHz, CDCl3) 7.83(dd, J=1.5 Hz & 6.5 Hz, 1H), 7.77(dd, J=1.5 Hz & 8.5 Hz, 1H), 7.54(d, J=7.0 Hz, 2H), 7.44-7.36(m, 3H), 7.15(t, J=8.5 Hz, 1H), 5.25(s, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | [00162] Intermediate 9A. 3-Bromo-2-methoxyaniline: Potassium carbonate (6.47 g, 46.8 mmol) and methyl iodide (2.86 mL, 46.8 mmol) were added to a solution of 2- bromo-6-nitrophenol (5.10 g, 23.4 mmol) in DMF (100 mL) at room temperature and the resulting reaction mixture was stirred for 16 h. The reaction was quenched with water (100 mL) and diluted with EtOAc (500 mL). The aqueous layer was extracted with EtOAc. The combined organics were washed with saturated aHC03 solution and brine, dried over MgS04, filtered, and evaporated. The crude was dissolved in EtOH (100 mL) and zinc (15.30 g, 233.9 mmol) and ammonium chloride (12.52 g, 233.9 mmol) were added. The reaction mixture was stirred at room temperature for 6 h. The reaction was diluted with EtOAc, filtered through CELITE, and evaporated. The crude was purified by flash chromatography (10-20% EtOAc/hexanes) to give Intermediate 9A (4.6 g, 97%) as a yellow oil. LCMS (ESI) m/z 202, 204 (M+H, M+2+H)+, RT = 1.38 min (Method A). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | Stage #1: NH-pyrazole; 2-bromo-6-nitro-phenol With copper(I) oxide; caesium carbonate In N,N-dimethyl-formamide at 100℃; Inert atmosphere; Sealed tube; Stage #2: With potassium carbonate In N,N-dimethyl-formamide for 0.5h; Stage #3: methyl iodide In N,N-dimethyl-formamide for 2h; | 5.1; 5.2 Step 1[00176j A vial containing 2-bromo-6-nitrophenol (290 mg, 1.33 mmol), 1H-pyrazole (136 mg, 2.00 mmol) and copper(I) oxide (190 mg, 1.33 mmol) in DMF (3 mL) was purged with nitrogen for 5 minutes. Cesium carbonate (867 mg, 2.66 mmol) was thenadded and the vessel was sealed and heated to 100 °C overnight. The reaction was filtered, concentrated and carried on without further purification. Step 2[00177j The crude product of Step 1 was dissolved in DMF (3 mL), potassiumcarbonate (269 mg, 2.0 mmol) was added and the reaction was stirred for 30 minutes.Next iodomethane (0.12 mL, 2.0 mmol) was added and the reaction was stirred for 2 hours. The crude product was filtered, concentrated and purified by automated chromatography providing 1 -(2-methoxy-3 -nitrophenyl)- 1H-pyrazole (115 mg, 39% yield). LC retention time 1.34 [J]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium carbonate In acetonitrile at 70℃; for 24h; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With di-tert-butyl (E)-azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With di-isopropyl azodicarboxylate; triphenylphosphine In dichloromethane at 20℃; for 15h; Inert atmosphere; | 115.1 Step 1: To a solution of 2-bromo-6-nitrophenol (2.0 g,9.17 mmol),(S)-methyl 2-hydroxypropanoate (1.15 g,11.01 mmol)and triphenylphosphine (3.61 g,13.76 mmol)in DCM(20 mL)was added DIAD (2.78 mL,13.76 mmol)dropwise. The reaction mixture was stirred at15 room temperature for 15 h under a nitrogen atmosphere. The mixture was concentrated in vacuo.20EtOAc (80 mL)was added,washed with brine (30 mL x 3),dried over anhydrous Na2S04,filtered and concentrated in vacuo. The crude residue was purified by silica gel columnchromatography (petroleum ether/EtOAc = 7:3)to give the title compound (2.5 g,81%)as awhite solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With pyridine In dichloromethane at 0 - 30℃; for 0.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: N-(p-tolylsulfonyl)-2-phenylaziridine; 2-bromo-6-nitro-phenol With lithium perchlorate In acetonitrile at 85℃; for 3h; Inert atmosphere; Stage #2: With copper(l) iodide; potassium carbonate In N,N-dimethyl-formamide at 120℃; for 10h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1) Take 2-nitro-6-bromophenol 12%, potassium carbonate 5% and benzyl bromide 7% in turn, and pour into 120 ml of acetonitrile solution for reflux reaction.After the reflux reaction was heated to 90 C and the temperature was maintained at 90 C for 3 hours, the reflux was continued.The reflux apparatus was cooled to room temperature, the resulting solution was filtered and concentrated to a dry solid, and the solid was placed in a 100 ml glass dish, and 40 ml of a triethylamine liquid was added to continuously heat the glass dish.Until white crystals appear on the solid surface,The glass dish is cooled, the solid is washed and dried with water, and the above materials are reserved for use; 2) The material obtained in the step 1) is dissolved in 100 ml of ethyl acetate, washed successively with 50 ml of water and 50 ml of a saturated sodium chloride solution, and after washing, anhydrous sodium sulfate crystals are added for moisture absorption and drying. The solution is filtered and concentrated to dry crystals, and the above materials are reserved for use; 3) Take 5% potassium carbonate, 6% 3-carboxybenzeneboronic acid, 5% palladium dichloride,20 ml of dioxane and 40 ml of water were placed in a 100 ml glass dish to react with the material prepared in step 2).After heating to 50 C in the reaction state, keep the temperature at 50 C and a pressure of 1 MPa was added to the nitrogen to carry out a protective reaction for four hours.Then, the temperature is lowered, the liquid in the glass dish is filtered, and after distilling off the dioxane under reduced pressure, water and a 1 mol/L hydrochloric acid solution are added to adjust the pH.The solution was filtered to obtain a solid, and placed in a 100 ml glass dish, 80 ml of isopropanol and an aqueous solution prepared in a ratio of 3:1 were added to carry out recrystallization, and the above materials were reserved for use; 4) The material prepared in the step 3) is placed in a 350 ml solution of ethyl acetate, 2% of palladium on carbon is placed in the solution, and hydrogen is reacted for 10 hours.The solution was filtered and concentrated to dry crystals, placed in a 100 ml glass dish, 80 ml of methanol was added to recrystallize, and the above materials were reserved for use;5) Take <strong>[277299-70-4]2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one</strong> 8% in order and mix in a ratio of 1:1:2 70ml of sodium nitrate,Sodium bicarbonate and an aqueous solution are placed in a 100 ml glass dish to react with the material prepared in step 4).After the reaction is completed, 20 ml of ethanolamine is added and hydrogen is introduced to carry out the reaction to obtain Eltrombopag; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With palladium on activated charcoal; potassium carbonate In methanol; water for 6h; Inert atmosphere; Reflux; | Preparation of 3'-nitro-2'-hydroxybiphenyl-3-carboxylic acid Take 5g (0.022mol) 1-bromo-2-hydroxy-3-nitrobenzene with the reaction flask,Add 7.15g (0.043mol) of m-carboxyphenylboronic acid,11.89g (0.086mol) potassium carbonate,50ml of methanol, 50ml of water, stir well under the protection of argon,Another 150 mg of palladium on carbon was added and heated to reflux reaction.The reaction took about 6 hours, and the reaction was followed by TLC.The heating was stopped, the palladium carbon was recovered by suction filtration, and the filter cake was washed with 50 ml of water.The filtrate was concentrated under reduced pressure, and the reaction pH was adjusted to about 5 with 6N hydrochloric acid.Stirring was continued for half an hour, suction filtration, the filter cake was washed with dilute hydrochloric acid, and air-dried to obtain 3'-nitro-2'-hydroxybiphenyl-3-carboxylic acid (5.42 g) as a white solid product, yield: 92% . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With potassium carbonate In acetone for 16h; Reflux; | 1 The synthesis of 2-(2-bromo-6-nitrophenoxy)-A,A-dimethylethanamine (25- 1): A mixture of 25-1 (4.0 g, 18.4 mmol), 2-chloro-A,A-dimethylethanamine hydrochloride (5.3 g, 36.8 mmol) and K2CO3 (7.6 g, 55.2 mmol) in acetone (50 mL) was heated to reflux for 16 h. The mixture was diluted with EtOAc (150 mL). The organic layer was successively washed with water (100 mL), saturated bicarbonate solution (100 mL), and brine (100 mL). The organic layer was then dried with MgSC and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether/EtOAc (0246) = 1/4) to give 25-2 (2.3 g, 43% yield) as an oil. MS Calcd.: 288.0; MS Found: 289.1 [M + H] +. |
28% | With potassium carbonate; sodium iodide In acetone at 60℃; for 16h; | 9 The synthesis of 2-(2-bromo-6-nitrophcnoxy)-N,N-dimethylethanamine (47-1): The mixture of 2-bro a m i n c hydrochloride (2.2 g, 15.0 mmol), K2CO3 (3.8 g, 27.3 mmol) and Nal (1.0 g, 6.8 mmol) in acetone (25 mL) was stirred at 60 °C for 16 h. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was diluted with water (50 mL) and then extracted with EtOAc (30 mL x 5). The organic layer was washed with brine and concentrated to dryness to give 47-1 (1.1 g, about 28% yield) as an oil. MS Calcd.: 288.0; MS Found: 289.1 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate In N,N-dimethyl-formamide at 60℃; | 44 The synthesis of l-(2-(2-bromo-6-nitrophenoxy)ethyl)- 1/7- 1,2, 4-triazole (55- A mixture of 55-1 (2.2 g, 10.09 mmol), l-(2-bromoethyl)-l /- 1,2, 4-triazole (2.1 g, 12.11 mmol) and K2CO3 (2.1 g, 15.14 mmol) in DMF (50 mL) was stirred at 60 °C overnight. The reaction mixture was cooled to room temperature and poured into water (100 mL) and extracted with EtOAc (70 mL x 3). The organic layer was washed with brine and concentrated. The residue was purified by column chromatography (CFLCL/MeOH = 100/1-20/1) to give 55-2 (2.2 g, about 70% yield) as an oil. MS Calcd.: 312.0; MS Found: 313.0 [M + H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With sodium hydroxide In dimethyl sulfoxide at 20℃; for 3h; | 11.A Step A: 2-(2-bromo-6-nitrophenoxy)-1-(4-chloro-2-fluorophenyl)ethan-1-one. A mixture of 2-bromo-6-nitrophenol (1.09 g, 5.00 mmol), 2-bromo-1-(4-chloro-2-fluorophenyl)ethan-1-one (1.38 g, 5.50 mmol), NaOH (202 mg, 5.50 mmol) in DMSO (5 mL) was stirred at 20 °C for 3 h. LCMS showed the reaction was completed. The mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was dried and concentrated. The residue was purified with silica gel column chromatography (PE/EA = 5: 1) to give 2-(2-bromo-6-nitrophenoxy)-1-(4-chloro-2-fluorophenyl)ethan-1-one (1.28 g, 3.30 mmol, 66% yield) as a yellow solid. 1H NMR (400 MHz, CDCl 3) δ ppm 8.01 -8.10 (m, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.31 (dd, J = 8.4, 1.6 Hz, 1H), 7.15 -7.24 (m, 2H), 5.39 (d, J = 3.6 Hz, 2H). LC-MS: m/z = 388.0, 390.0 (M+H) +. |
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P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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