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CAS No. : | 105931-73-5 | MDL No. : | MFCD00010608 |
Formula : | C6H3BrFI | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XRMZKCQCINEBEI-UHFFFAOYSA-N |
M.W : | 300.89 | Pubchem ID : | 2724516 |
Synonyms : |
4-Bromo-2-fluoroiodobenzene
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 46.82 |
TPSA : | 0.0 Ų |
GI absorption : | Low |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.75 cm/s |
Log Po/w (iLOGP) : | 2.37 |
Log Po/w (XLOGP3) : | 3.36 |
Log Po/w (WLOGP) : | 3.61 |
Log Po/w (MLOGP) : | 4.37 |
Log Po/w (SILICOS-IT) : | 3.93 |
Consensus Log Po/w : | 3.53 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.32 |
Solubility : | 0.0145 mg/ml ; 0.0000483 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -3.04 |
Solubility : | 0.276 mg/ml ; 0.000916 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.47 |
Solubility : | 0.0103 mg/ml ; 0.0000341 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.22 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | 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 |
---|---|---|
96% | With [Cu2(2,7-bis(pyridin-2-yl)-l,8-naphthyridine)(OH)(CF3COO)3]; tetrabutylammomium bromide; ammonia; caesium carbonate In ethylene glycol at 140℃; for 16 h; Sealed tube | General procedure: A mixture of substrate (0.25 mmol), complex 1 (2.5 × 10− 3 mmol), Cs2CO3 (1 mmol), Conc. NH3(aq) (0.5 mL) and TBAB (0.25 mmol) in water (0.5 mL) were loaded in a sealed reaction tube. The reaction temperature was increased to 110–140 °C and the reaction mixture was stirred for 8–24 h. After cooling to RT, the reaction mixture was poured into a saturated NaCl solution, extracted with ethyl acetate and dried over anhydrous MgSO4. After removal of solvents, the residue was re-crystallized or chromatographed on silica gel. All products were characterized by NMR spectroscopy and were consistent with the literature data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate In 1,4-dioxane Heating; | |
88% | With potassium carbonate In 1,4-dioxane; water reflux; | 2.3 (4'-bromo-2,3,2'-trifluorobiphenyl-4-yl)trimethylsilane (7) A solution of 16.6 g (120 mmol) of K2CO3 in 50 ml of water is added to a solution of 15 g (50 mmol) of 4-bromo-2-fluoro-1-iodobenzene, 14.9 g (50 mmol) of 6 and 2.31 g (2 mmol) of [Pd(PPh3)4] in 100 ml of dioxane, and the mixture is refluxed overnight.The organic phase is washed with water and sat. NaCl, dried over MgSO4 and filtered through SiO2.The solvent is removed under reduced pressure, petroleum ether is added to the oily residue, and the product is recrystallized at -25° C. (yield: 88%, m.p. 78.0° C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With 2,2,6,6-tetramethyl-piperidine; n-butyllithium; bromine In tetrahydrofuran; hexane at -78 - 25℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With copper(l) iodide; potassium carbonate In dimethyl sulfoxide at 110℃; for 60h; | 29.1 Step 1 : 1,1-Dimethylethyl 4-[1 -(4-bromo-2-fluorophenyl)-1H-indol-4-yl]oxy}-1 - piperidinecarboxylate (78) A round-bottomed flask was charged under N2 with compound 63 (1.90 g, 6.0 mmol), CuI (171 mg, 0.9 mmol), K2CO3 (1.66 g, 12 mmol), 4-bromo-2-fluoro-1-iodobenzene (3.61 g, 12 mmol) and anhydrous DMSO (20 ml_). The reaction mixture was stirred at 110 0C for 60 h. The mixture was cooled to RT, diluted with EtOAC, filtered and the filtrate was concentrated under reduced pressure to afford the crude product, which was purified by flash column chromatography to give 1.96 g (75%) of the title product 78 as a mixture of two products. This material was used directly in the next step without purification. |
With potassium phosphate; copper(l) iodide; (1R,2R)-1,2-diaminocyclohexane at 20℃; for 15h; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With copper (I) iodide; N,N-diisopropylamine In tetrahydrofuran at 20℃; for 18h; | |
With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine In N,N-dimethyl-formamide at 20℃; | General procedure: To a suspension of the required aryl iodide (1.0 mmol), Pd(PPh3)2Cl2 (70.2 mg, 0.1 mmol) and CuI (38.1 mg, 0.2 mmol) in dry THF (20 mL) under argon was added TEA (202.4 mg, 2.0 mmol) and trimethylsilyl acetylene (147.3 mg, 1.5 mmol). The resulting mixture was stirred at rt overnight and then the catalyst was filtered. The filtrate was added TBAF (1M in THF, 1.5 mL) and stirred at rt for 30 min. The reaction was quenched with water (10 mL) and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, and reduced to dryness. The residue was purified on silica gel with petroleum ether to afford the corresponding substituted acetylene 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.8% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; benzene; for 37h;Heating / reflux; | First, 150 ml of ethanol containing 17.84 g of <strong>[143651-26-7]4-(trans-4-pentylcyclohexyl)phenylboronic acid</strong> dissolved therein, 150 ml of benzene containing 15.0 g of 4-bromo-2-fluoro-1-iodobenzene dissolved therein, 49.8 ml of a sodium carbonate aqueous solution with a concentration of 2.0 mol/l, and 1.44 g of tetrakis(triphenylphosphine)palladium(0) were put in an argon-replaced 500 ml flask, and stirred under reflux for 37 hours. After the reaction, water and ether were added to the reaction solution for extraction. The resultant ether layer was washed with a saturated brine and dried with sodium sulfate. The solvent was then distilled off. The residue was purified by silica gel column chromatography (eluent:hexane) and recrystallized from hexane, to obtain 13.6 g (Y: 67.8%) of 4-bromo-2-fluoro-4'-(trans-4-pentylcyclohexyl)biphenyl. The purity of the resultant compound was 99.5% as measured by GC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In methoxybenzene at 80℃; for 16h; | 201.a a) Preparation of 4, 4'-dibromo-2, 2'-difluoro-benzophenone Tetrakis (triphenylphosphine) palladium (0.15 g, 0.13 mmol) was dissolved in anisole (15 mL). [L-BROMO-3-FLUORO-4-IODOBENZENE] (2.0 g, 6.6 mmol), 4-bromo-2- fluorobenzeneboronic acid (1.45 g, 6.6 mmol) and potassium carbonate (2.7 g, 19.9 mmol) together with another 15 mL anisole were added. The above mixture was stirred for 16 h at [80°C] under 10 bar carbon monoxide pressure. The reaction mixture was allowed to cool, added to a toluene/water mixture (120 mL, 1: 1) the phases were separated and the water phase was extracted twice with toluene. Organic phases were pooled, washed with brine and the solvent was evaporated. Crystallization from hexane afforded the title compound as white crystals (1.17 g, 47%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 75℃; for 15h; | 2- (4-BROMO-2-FLUORO-PHENYL)-5-METHYL-THIOPHENE A mixture of 5-methyl-2-thiophene-boronic acid (1g, 7. 0MMOL), 1-bromo-3-fluoro-4- iodobenzene (1.77g, 5. 9MMOL), tetrakis (triphenylphosphine) palladium (0) (0.34g, 0. 3MMOL), 2M NA2CO3 (10 mL) in DME (10ML) was heated to 75 C under N2 for 15H. The reaction mixture was partitioned between 1 N HCI and EtOAc. The organic layer was washed with saturated NAHC03, brine, dried over NA2SO4AND concentrated. The residue was purified by silica gel chromatography (hexanes) to give the title compound (1.2g, 75percent). 1H NMR (CDCl3): No. 2.52 (s, 3H), 6.76 (s, 1H), 7.25 - 7.32 (m, 3H), 7.43 (t, 1H, J = 8.5 Hz). |
75% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 75℃; for 15h; | A mixture of 5-methyl-2-thiophene-boronic acid (1 g, 7.0 mmol), 1-bromo-3-fluoro-4-iodobenzene (1.77 g, 5.9 mmol), tetrakis(triphenylphosphine)palladium(0) (0.34 g, 0.3 mmol), 2M Na2CO3(10 mL) in DME (10 mL) was heated to 75° C. under N2 for 15 h. The reaction mixture was partitioned between 1 N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (hexanes) to give the title compound (1.2 g, 75percent). 1H NMR (CDCl3): delta 2.52 (s, 3H), 6.76 (s, 1H), 7.25-7.32 (m, 3H), 7.43 (t, 1H, J=8.5 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With sodium hydrogencarbonate In 1,2-dimethoxyethane; water at 80℃; for 72h; | A.10.1 Step 1 2- (4-Bromo-2-fluoro-phenyl)-benzo [b] thiophene A mixture of Benzo [b] thiophene-2-boronic acid (0. 71G, 4MMOL), 1-BROMO-3-FLUORO-4- iodobenzene (1g, 3. 3MMOL), bis (triphenylphospine) palladium (LI) chloride (46mg, 2MOL%), NAHC03 (0.83g, 9. 9MMOL) in DME (4mL) and H20 (4mL) was heated to 80 C under N2 for 72h. The reaction mixture was partitioned between 1 N HCI and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over NA2SO4AND concentrated. The residue was purified by silica gel chromatography (hexanes) to give the title compound as a white solid (0. 13G, 13%). 'H NMR (CDCL3) : No. 7.33-7. 41 (m, 4H), 7.57 (m, 1 H), 7.72 (s, 1 H), 1.80-7. 86 (m, 2H). |
13% | With sodium hydrogencarbonate In 1,2-dimethoxyethane; water at 80℃; for 72h; | A.10.1 A mixture of Benzo[b]thiophene-2-boronic acid (0.71 g, 4 mmol), 1-bromo-3-fluoro-4-iodobenzene (1 g, 3.3 mmol), bis(triphenylphospine)palladium(II) chloride (46 mg, 2 mol %), NaHCO3 (0.83 g, 9.9 mmol) in DME (4 mL) and H2O (4 mL) was heated to 80° C. under N2 for 72 h. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (hexanes) to give the title compound as a white solid (0.13 g, 13%). 1H NMR (CDCl3): δ 7.33-7.41 (m, 4H), 7.57 (m, 1H), 7.72 (s, 1H), 1.80-7.86 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 1.5h; | 45 To a solution of 1-bromo-3-fluoro-4-iodobenzene (2.5 g), 1-prop-2-ynylpiperidine (1.5 g), dichlorobis(triphenylphosphine)palladium(II) (300 mg) and copper(I) iodide (40 mg) in N,N-dimethylformamide (20 ml) was added triethylamine (10 ml) under a nitrogen atmosphere, and the solution was stirred for 1.5 hours at room temperature. A saturated aqueous solution of ammonium chloride was added thereto followed by stirring, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (1.1 g).1H-NMR (400MHz, CDCl3); δ (ppm): 1.41-1.49 (m, 2H), 1.58-1.68 (m, 4H), 2.48-2.62 (m, 4H), 3.51 (s, 2H), 7.21-7.31 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,4-dioxane at 50℃; for 72h; Heating / reflux; | 19.1a Under an argon atmosphere 17.9 mg (0.08 mmol) of palladium (II) acetate is added to a suspension of 800 mg (2.66 mmol) of 4-bromo-2-fluoro-1-iodobenzene, 447 mg (3.0 mmol) of 4-methyl-1-pyrrolidin-3-ylpiperidine (Amine A2), 1.21 g (40.0 mmol) of cesium carbonate, and 49.7 mg (0.08 mmol) of 2,2'-bis-(diphenylphosphino)-1,1'-binaphthalene in 15 mL of 1,4-dioxane and the reaction mixture is stirred overnight at 50° C. Another 49.7 mg (0.08 mmol) of 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene and 17.9 mg (0.08 mmol) of palladium (II) acetate are added and the mixture is refluxed for 3 days. After cooling, it is combined with water and EtOAc, the phases are separated, and the organic phase is washed several times with water and dried over sodium sulfate. After the desiccant and solvent have been eliminated, the residue is purified by chromatography (silica gel, DCM/MeOH/NH3 95:5:0.5). Yield: 250 mg (28.0% of theoretical); C16H22BrFN2 (M=341.262); calc.: molpeak (M+H)+: 341/343 (Br); found: molpeak (M+H)+: 341/343 (Br); retention time HPLC: 6.2 min (method A). |
28% | Stage #1: 4-methyl-1-pyrrolidin-3-yl-piperidine; 1-bromo-3-fluoro-4-iodobenzene With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,4-dioxane at 50℃; Stage #2: With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In 1,4-dioxane for 72h; Heating / reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | palladium; In fluorobenzene; nitrogen; | EXAMPLE 2 2.13 g (0.0175 mole) of phenylboronic acid, 3.00 g (0.01 mole) of 2-fluoro-4-bromoiodobenzene, 4.00 g (0.042 mole) fluorobenzene, 0.4 g of a palladium on carbon catalyst (5% Pd), and 10 ml of 2M Na2 CO3 were placed in a 25-ml round bottom flask (with a nitrogen purge) and heated to 50 C. for 18 hours. Gas chromatography (corrected for sensitivity factors) showed that the desired product, 2-fluoro-4-bromobiphenyl, was produced in 87% yield, with 8% starting material and 3% terphenyl also present. |
55% | Pd on carbon; palladium dichloride; In fluorobenzene; concentrated ethanol; | EXAMPLE 1 3 g of 2-fluoro-4-bromoiodobenzene, about 0.4 g of PdCl2 and 0.2 g or 5% Pd on carbon, 20 ml of fluorobenzene, and 10 ml of 2M Na2 CO3, were added to a 3-neck round bottom flask equipped with a slow nitrogen purge. The mixture was vigorously stirred and 1.21 g of phenylboronic acid in about 5 g of concentrated ethanol was added. The solution was then refluxed at 70-72 C. The resulting solution was then analyzed by gas chromatography (corrected for sensitivity factors) and it was determined that the desired product, 2-fluoro-4-bromobiphenyl, was produced in 55% yield with about 12% fluoroterphenyl. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; triethylamine | 39.1 Example 39 (1) In 150 ml of triethylamine, within nitrogen atmosphere, 10.0 g of 1-bromo-3-fluoro-4-iodobenzene and 4.6 g of 1-decyne were reacted for 8 hours at the room temperature in the presence of 18 mg of cuprous iodide(I) and 72 mg of dichlorobistriphenylphosphine palladium(II). After reaction, the triethyl amine was removed and the product was extracted with hexane. The hexane phase was washed with 1N-hydrochloric acid and then with water, followed by removing the hexane. The resulting liquid was dissolved in 200 ml of ethanol and hydrogenated using platinum dioxide. After confirming that no absorption of hydrogen was observed, the catalyst was removed, followed by removing the ethanol to obtain 8.9 g of 4-n-decyl-3-fluorobromobenzene. | |
With copper(I) iodide In ethanol; dichlorobis(triphenylphosphine)palladium[II]; triethylamine | 49.1 Example 49 (1) In 150 ml of triethylamine, within nitrogen atmosphere, 10.0 g of 1-bromo-3-fluoro-4-iodobenzene and 4.6 g of 1-decyne were reacted for 8 hours at the room temperature in the presence of 72 mg of dichlorobistriphenylphosphine palladium(II) and 18 mg of cuprous iodide (I), followed by removing the triethylamine. The product was extracted with hexane. The hexane layer was washed with 1N-hydrochloric acid and then with water, and the hexane was removed. The product was dissolved in 200 ml of ethanol, and hydrogenated using 0.3 g of platinum dioxide. After confirming that no absorption of hydrogen was observed, the catalyst was removed by filtration, followed by removing the ethanol to obtain 8.8 g of 4-n-decyl-3-fluorobromobenzene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.68% | With potassium phosphate In ethylene glycol; butan-1-ol at 100℃; for 48h; | 50.3 A mixture of piperidin-3-yl-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate hydrochloride (1.67 g, 0.00574 mol), 4-bromo-2-fluoro- 1 -iodobenzene (2.07 g, 0.00689 mol), copper(I) iodide (0.11 g, 0.00057 mol), potassium phosphate (3.66 g, 0.0172 mol) and 1 ,2-ethanedioI (0.640 mL, 0.0115 mol) in 1-butanol (5.63 mL, 0.0616 mol) was heated at 100 0C under nitrogen for 2 days. The reaction mixture was treated with water, and then extracted with ether. The organic layers were combined, washed with water and brine respectively, dried and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 50% EtOAc in hexane, to give the desired product (1.98 g, 80.68%). LCMS (M+H) 427.1. The product was believed to have 3S stereochemistry and 3- endo configuration based on the starting materials. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate In toluene at 80℃; for 1h; | |
81% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene at 100℃; Inert atmosphere; | 14 4-(4-Bromo-2-fluorophenyl)morpholine: Into a 1-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-bromo-2-fluoro-1-iodobenzene (15 g, 49.85 mmol, 1.00 equiv) in toluene (300 mL). Pd2(dba)3 (1.3 g, 1.42 mmol, 0.03 equiv). Cs2CO3 (41 g, 125.45 mmol, 2.50 equiv). XantPhos (2.9 g, 5.01 mmol, 0.10 equiv). morpholine (4.3 g, 49.36 mmol, 1.00 equiv). The resulting solution was stirred overnight at 100°C. The reaction was then quenched by the addition of 150 mL of water. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:15). This resulted in 10.5 g (8 1%) of 4-(4- bromo-2-fluorophenyl)morpholine as a yellow solid. MS (ES, m/z): 260 (M+H). |
81% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene at 100℃; Inert atmosphere; | 11 4-(4-Bromo-2-fluorophenyl)morpholine Into a 1-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-bromo-2-fluoro-1-iodobenzene (15 g, 49.85 mmol, 1.00 equiv) in toluene (300 mL). Pd2(dba)3 (1.3 g, 1.42 mmol, 0.03 equiv). Cs2CO3 (41 g, 125.45 mmol, 2.50 equiv). XantPhos (2.9 g, 5.01 mmol, 0.10 equiv). morpholine (4.3 g, 49.36 mmol, 1.00 equiv). The resulting solution was stirred overnight at 100oC. The reaction was then quenched by the addition of 150 mL of water. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:15). This resulted in 10.5 g (81%) of 4-(4- bromo-2-fluorophenyl)morpholine as a yellow solid. MS (ES, m/z): 260 (M+H). |
81% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene at 100℃; Inert atmosphere; | 14 4-(4-Bromo-2-fluorophenyl)morpholine Into a 1-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-bromo-2-fluoro-1-iodobenzene (15 g, 49.85 mmol, 1.00 equiv) in toluene (300 mL). Pd2(dba)3 (1.3 g, 1.42 mmol, 0.03 equiv). Cs2CO3 (41 g, 125.45 mmol, 2.50 equiv). XantPhos (2.9 g, 5.01 mmol, 0.10 equiv). morpholine (4.3 g, 49.36 mmol, 1.00 equiv). The resulting solution was stirred overnight at 100oC. The reaction was then quenched by the addition of 150 mL of water. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:15). This resulted in 10.5 g (81%) of 4-(4- bromo-2-fluorophenyl)morpholine as a yellow solid. MS (ES, m/z): 260 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; at 80℃; | To a solution of 4-bromo-2-fluoro-l-iodobenzene (380 mg, 1.3 mmol) in THF (10 mL) was added tert-butyl [4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl]acetate (390 mg, 1.3 mmol), 2M sodium carbonate in water (2.5 mL) and tetrakis(triphenylphosphine)palladium (40 mg, 0.04 mmol). The solution was degassed with N2, and heated at 80 0C overnight. The mixture was cooled to RT, poured into water, extracted with EtOAc, washed with brine, dried over MgSO/t, filtered, and concentrated. The residue was purified by flash chromatograph on a silica gel column with EtOAc in Hexanes (30%) to afford the desired compound. LCMS: (M+57) = 299.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: 1-bromo-3-fluoro-4-iodobenzene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.75h; Stage #2: cyclobutanone In tetrahydrofuran; hexane at -78℃; for 1.5h; Stage #3: With water; ammonium chloride | 42.1 1-(4-bromo-2-fluorophenyl)cyclobutanol To a solution of 4-bromo-2-fluoro-1-iodobenzene (500 mg, 1.66 mmol) in tetrahydrofuran (5 mL) at -78° C. was added n-butyl lithium (2.5 M in hexane, 0.8 mL, 0.8 mmol) dropwise over 15 minutes. The reaction mixture was stirred at -78° C. for 30 minutes, treated with neat cyclobutanone (0.12 mL, 1.66 mmol) dropwise over 10 minutes, and stirred at -78° C. for an additional 1.5 hours. The reaction was quenched with saturated aqueous NH4Cl, warmed to room temperature and extracted with ethyl acetate (2*). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 300 mg yellow oil, which was purified by silica gel chromatography (12 g silica, 0-50% ethyl acetate/heptane, 21 column volumes). Product fractions were combined and concentrated in vacuo to afford the title compound as a colorless oil (215 mg, 53% yield). GCMS 244/246.(m/z) 1H NMR (500 MHz, CDCl3) δ 7.20-7.31 (m, 3H), 2.56-2.66 (m, 2H), 2.40-2.55 (m, 1H), 2.31-2.40 (m, 2H), 2.14 (m, 1H), 1.75 (m, 1H). |
Stage #1: 1-bromo-3-fluoro-4-iodobenzene With n-butyllithium In diethyl ether at -78 - -68℃; for 0.25h; Stage #2: cyclobutanone In diethyl ether at -78 - -68℃; for 0.25h; Stage #3: With water; ammonium chloride In diethyl ether | 60.A A 100 mL 3 -neck round bottom flask was charged with 4-bromo-2-fluoro-l- iodobenzene (1000 mg, 3.32 mmol) and diethyl ether (30 mL). The solution was cooled to - 78 0C, and n-butyllithium (1.329 mL, 3.32 mmol) was added dropwise, keeping the temperature below -68°C. After stirring for 15 min, cyclobutanone (0.249 mL, 3.32 mmol) was added dropwise, keeping temperature below -68°C. The solution was stirred at -78 0C for 15 min. The reaction was then quenched by the addition of saturated ammonium chloride (25 mL). The layers were separated, and the organic was washed with water (1 x 10 mL) and brine (1 x 10 mL). The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2 gel), eluting with 3% ethyl acetate / hexanes to give the desired product. 1H NMR (300 MHz, DMSO-de) δ ppm 1.55-1.69 (m, 1 H), 1.91.2.05 (m, 1 H), 2.19-2.28 (m, 2 H), 2.46- 2.55 (m, 2 H), 5.59 (s, 1 H), 7.33-7.40 (m, 2 H), 7.44-7.48 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
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54.2% | With potassium phosphate; ethylene glycol In butan-1-ol at 100℃; for 48h; | 1.7 Step 7: (5S)-7-(4-bromo-2-fluorophenyl)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one A mixture of (5S)-2-(cis-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (1.04 g, 0.00412 mol), 4-bromo-2-fluoro-1-iodobenzene (Aldrich, cat #: 283304) (1.85 g, 0.00615 mol), copper(I) iodide (Aldrich, cat #: 215554) (0.122 g, 0.000640 mol), potassium phosphate (2.63 g, 0.0124 mol) and 1,2-ethanediol (0.48 mL, 0.0086 mol) in 1-butanol (3.90 mL) was heated at 100° C. under nitrogen for 2 d. The reaction was quenched with water, and extracted with ether. The organic layers were combined, washed with water, brine, dried over Na2SO4, and filtered. The filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography on a silica gel column eluding with 0 to 5% methanol in DCM to yield the desired product (950 mg, 54.2%). LC/MS m/e 425.1/427.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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Stage #1: 2-acetamido-2-[2-[2-chloro-4-(5,5-dimethyl[1,3,2]dioxaborinan-2-yl)phenyl]ethyl]propane-1,3-diol diacetate; 1-bromo-3-fluoro-4-iodobenzene With sodium hydrogencarbonate In 1,2-dimethoxyethane; water at 100℃; for 9h; Stage #2: acetic anhydride With pyridine at 20℃; for 24h; | 23 N-[1,1-bis(acetoxymethyl)-3-(4'-bromo-3-chloro-2'-fluorobiphenyl-4-yl)propyl]acetamide Reference Example 23 N-[1,1-bis(acetoxymethyl)-3-(4'-bromo-3-chloro-2'-fluorobiphenyl-4-yl)propyl]acetamide A mixed solution of N-11,1-bis(acetoxymethyl)-3-[2-chloro-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]propyl}acetamide (2.05 g) of Reference Example 22, 1-bromo-3-fluoro-4-iodobenzene (1.39 g), sodium hydrogen carbonate (2.02 g) and tetrakistriphenylphosphine palladium (51 mg) in 1,2-dimethoxyethane (30 mL)-water (10 mL) was stirred at 100°C for 9 hr. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Pyridine (20 mL) and acetic anhydride (2 mL) were added to the residue, and the mixture was stood at room temperature for one day. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.30 g) as white crystals. 1H-NMR(CDCl3)δ(ppm):2.01(3H, s), 2.11(6H, s), 2.18-2.24(2H, m), 2.75-2.81(2H, m), 4.39(4H, s), 5.74(1H, s), 7.24-7.38(5H, m), 7.50(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-acetamide-4-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]-2-methylbutyl acetate; 1-bromo-3-fluoro-4-iodobenzene With sodium hydrogencarbonate In 1,2-dimethoxyethane; water at 100℃; for 14h; Stage #2: acetic anhydride With pyridine at 20℃; for 24h; | 29 2-acetamide-4-(4'-bromo-2'-fluorobiphenyl-4-yl)-2-methylbutyl acetate Reference Example 29 2-acetamide-4-(4'-bromo-2'-fluorobiphenyl-4-yl)-2-methylbutyl acetate A mixed solution of 2-acetamide-4-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]-2-methylbutyl acetate (1.44 g) of Reference Example 28, 1-bromo-3-fluoro-4-iodobenzene (1.21 g), sodium hydrogen carbonate (1.94 g) and tetrakistriphenylphosphine palladium (222 mg) in 1,2-dimethoxyethane (30 mL)-water (10 mL) was stirred at 100°C for 14 hr. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Pyridine (6 mL) and acetic anhydride (2 mL) were added to the residue, and the mixture was stood at room temperature for one day. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.88 g) as white crystals. 1H-NMR(CDCl3)δ(ppm):1.39(3H, s), 1.92-2.03(1H, m), 1.94(3H, s), 2.10(3H, s), 2.26-2.34(1H, m), 2.65(2H, t, J=8.7Hz), 4.19(1H, d, J=11.1Hz), 4.36(1H, d, J=11.4Hz), 5.39(1H, s), 7.26-7.36(5H, m), 7.43(2H, dd, J=1.2, 7.8Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-acetamide-4-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]-2-ethylbutyl acetate; 1-bromo-3-fluoro-4-iodobenzene With sodium hydrogencarbonate In 1,2-dimethoxyethane; water at 100℃; for 14h; Stage #2: acetic anhydride With pyridine at 20℃; for 24h; | 34 2-acetamide-4-(4'-bromo-2'-fluorobiphenyl-4-yl)-2-ethylbutyl acetate Reference Example 34 2-acetamide-4-(4'-bromo-2'-fluorobiphenyl-4-yl)-2-ethylbutyl acetate A mixed solution of 2-acetamide-4-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]-2-ethylbutyl acetate (1.63 g) of Reference Example 33, 1-bromo-3-fluoro-4-iodobenzene (1.32 g), sodium hydrogen carbonate (2.11 g) and tetrakistriphenylphosphine palladium (242 mg) in 1,2-dimethoxyethane (30 mL)-water (10 mL) was stirred at 100°C for 14 hr. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Pyridine (6 mL) and acetic anhydride (2 mL) were added to the residue, and the mixture was stood at room temperature for one day. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.02 g) as white crystals. 1H-NMR(CDCl3)δ(ppm):0.91(3H, t, J=7.5Hz), 1.70-2.25(4H, m), 1.96(3H, s), 2.10(3H, s), 2.61(2H, t, J=8.5Hz), 4.30(2H, d, J=11.4Hz), 4.36(2H, d, J=11.4Hz), 7.25-7.36(5H, m), 7.43(2H, dd, J=1.5, 8.2Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: N-[2,2-dimethyl-5-[2-[4-(5,5-dimethyl[1,3,2]dioxaborinan-2-yl)phenyl]ethyl]-1,3-dioxane-5-yl]acetamide; 1-bromo-3-fluoro-4-iodobenzene With sodium hydrogencarbonate In 1,2-dimethoxyethane; water for 8h; Heating / reflux; Stage #2: 1-bromo-3-fluoro-4-iodobenzene With sodium hydrogencarbonate In 1,2-dimethoxyethane; water at 100℃; for 15h; | 10 N-{5-[2-(4'-bromo-2'-fluorobiphenyl-4-yl)ethyl]-2,2-dimethyl-1,3-dioxan-5-yl}acetamide Reference Example 10 N-{5-[2-(4'-bromo-2'-fluorobiphenyl-4-yl)ethyl]-2,2-dimethyl-1,3-dioxan-5-yl}acetamide A mixed solution of N-(5-{2-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]ethyl}-2,2-dimethyl-1,3-dioxan-5-yl)acetamide (7.33 g) of Reference Example 6, 1-bromo-3-fluoro-4-iodobenzene (5.95 g), sodium hydrogen carbonate (9.48 g) and tetrakistriphenylphosphine palladium (434 mg) in 1,2-dimethoxyethane (120 mL)-water (40 mL) was heated under reflux for 8 hr. 1-Bromo-3-fluoro-4-iodobenzene (2.83 g) and tetrakistriphenylphosphine palladium (217 mg) were added to the reaction mixture, and the mixture was further stirred at 100°C for 15 hr. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography, and the obtained crude crystals were suspended in diisopropyl ether and collected by filtration to give the title compound (5.28 g) as white crystals. 1H-NMR(DMSO-d6)δ(ppm): 1.35(6H, s), 1.87(3H, s), 1.98-2.04(2H, m), 2.47-2.53(2H, m), 3.71(2H, d, J=11.8Hz), 3.97(2H, d, J=11.6Hz), 7.27(2H, d, J=8.1Hz), 7.44-7.53(3H, m), 7.61-7.66(2H, m). | |
5.28 g | With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate In 1,2-dimethoxyethane; water at 100℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium carbonate In 1,4-dioxane; water at 80℃; | 30.1 A mixture of compound 6W (1 g, 3.23 mmol), 4-bromo-2-fluoro-1-iodo-benzene (1.46 g, 4.85 mmol), potassium carbonate (1.4 g, 9.69 mmol), Pd(dppf)CI2 (0.264 g, 0.323 mmol) and 4/1 /dioxane/water (10 ml) was degassed for 15 minutes. Then it was heated at 80 °C for overnight. Cooled to room temperature and diluted with EtOAc (200 ml). The organic layer was washed with water (100 ml), dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel eluting with 1/10 EtOAc/hexane to give the desired product 7W (0.9 g, 78%). |
78% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate In 1,4-dioxane; water at 110℃; for 2h; | 26.1 Step 1 : tert-Butyl 4-(4-bromo-2-fluoro-phcnyl )-3,6-dihydro-2H-nyridinc- 1 -carboxylatc 4-Bromo-2-fluoro-l-iodo-benzene (CAS 105931-73-5) (2.19 g, 7.28 mmol, 1.5 equiv.) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l- carboxylate (CAS 286961-14-6) (1.50 g, 4.85 mmol) were dissolved in 20 ml of dioxane. Sodium carbonate (2M in water) (7.28 ml, 14.6 mmol, 3.0 equiv.) and PdCl2(dppf)-CH2Cl2 adduct (355 mg, 0.485 mmol, 0.1 equiv.) were added and the reaction mixture was stirred at 110 °C for 2 hours. The reaction mixture was cooled to room temperature and then extracted with ethyl acetate and saturated NaHCCb-solution. The aqueous layer was backextracted with ethyl acetate. The organic layers were washed with water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with an ethyl acetate:heptane 0: 100 to 70:30 gradient. The desired tert-butyl 4-(4-bromo-2-fluoro-phenyl)-3,6-dihydro-2H-pyridine-l- carboxylate (1.35 g, 78 % yield) was obtained as a colorless oil, MS: m/e = 300.0/302.0 (M- tBu+H+). |
Stage #1: 1-bromo-3-fluoro-4-iodobenzene; tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate In ethanol; water; toluene for 0.166667h; Inert atmosphere; Stage #2: With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In 1,2-dimethoxyethane; water at 85℃; for 2h; Inert atmosphere; | 70.i Step-i: tert -butyl 4-( 4-bromo-2-fluorophenyl)-5 ,6-dihydropyridine-1 (2H)-carboxylate Using similar reaction conditions as described in step i of intermediate 9, 4-bromo-2-fluoro-1-iodobenzene (500mg, 1.95 mmol) was coupled with tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5 ,6-dihydropyridine-1 (2H)-carboxylate ( 660mg, 2.14 mmol) usingsodium carbonate (620mg, 5.85mmol) and PdCh(PPh3)z (69mg, 0.097 mmol) in DME/water5 (10/2 ml) at 85°C for 2 hours to afford 300mg (50.5%) of the crude product after purificationwith (60/120 silica gel) column chromatography using 20% ethyl acetate in hexane as eluent.MS: m/z = 300.0 (M+ 1) (t-butyl cleaved mass was observed) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 1h; Stage #2: 1-bromo-3-fluoro-4-iodobenzene In tetrahydrofuran; hexane at -78℃; for 1h; Stage #3: methyl iodide In tetrahydrofuran; hexane | 1 1-bromo-3-fluoro-4-iodo-2-methylbenzene Reference Example 1 1-bromo-3-fluoro-4-iodo-2-methylbenzene A solution of diisopropylamine (6.06 mL) in THF (100 mL) was cooled to -78° C., n-butyllithium-hexane (24.9 mL, 1.6 mol/L) was added dropwise and, after the completion of the dropwise addition, the mixture was stirred at -78° C. for 1 hr. Subsequently, a solution of 4-bromo-2-fluoro-1-iodobenzene (10.0 g) in THF (50 mL) was added dropwise, and the mixture was further stirred at -78° C. for 1 hr. Methyl iodide (2.90 mL) was added dropwise at -78° C. and the mixture was further stirred at -78° C. for 2 hr, and the mixture was warmed to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a brown oil (yield: 10.5 g, yield: 100%). 1H-NMR(CDCl3)δ:2.37(3H,d,J=2.6 Hz), 7.10(1H,dd,J=8.5,1.1 Hz), 7.39-7.46(1H,m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With zinc(II) chloride In tetrahydrofuran at -5 - 20℃; for 4.16 - 6.16h; | 1.3.1; 1 To a 72 L round bottomed flask was added zinc chloride THF solution (0.5 M, 33.2 L, 16.62 mol). The solution was cooled to -5° C. and vinyl magnesium chloride THF solution (1.6 M, 20.80 L, 33.24 mol) was added slowly, maintaining temperature at less than 20° C. Triphenylphosphine (149.5 g, 0.570 mol) was added, followed by Pd(PPh3)2Cl2 (200 g, 0.285 mol). The mixture was stirred for 10 min, and 1-Bromo-3-fluoro-4-iodobenzene was added. The reaction mixture was stirred at ambient temperature for 4-6 h until the reaction was complete by HPLC. Mixing zinc chloride and vinyl magnesium chloride THF solutions was exothermic. The temperature was controlled by adjusting the addition rate and the cooling bath temperature. The coupling reaction after the addition of aryl iodide (1) was slightly exorthermic. The temperature rose from 11° C. to 37° C. without a cooling bath in about 1 h and it cooled down thereafter. The reaction mixture was quenched into a pre-cooled (0° C.) mixture of pentane (20 L), water (12 L), and concentrated HCl (1.0 L) in a 200 L extractor. The two layers were separated. The organic layer was diluted with pentane (20 L), washed with water (16 L), and concentrated under reduced pressure. Compound 2 was quite volatile, and 20% was lost during rotavap concentration. Assay of the product before concentration normally gave product yield of 80-85%. The product was further purified in this way: The residue was taken up with pentane (10 L). The resulting suspension was filtered. The solid was washed with pentane (1.0 L). The combined filtrate and wash were concentrated. The crude oil was purified by vacuum distillation at 0.1-0.2 mm Hg. Purified product was light yellow with a boiling point of 45-50° C. at 0.1-0.2 mm Hg. Distillation recovery was 95%. Product was 93-95 wt %. The residue in the distillation pot was liquid at the end of distillation, but solidified upon cooling |
80% | Stage #1: vinylmagnesium chloride With zinc(II) chloride In tetrahydrofuran at -5 - 20℃; for 0.166667h; Stage #2: 1-bromo-3-fluoro-4-iodobenzene In tetrahydrofuran at 11 - 37℃; for 4 - 6h; | 3.1 3.1. Preparation of Styrene Compound 2; Materials MW Amount Moles 1-Bromo-3-fluoro-4-iodobenzene 300.89 5.0 kg 16.62 Vinyl magnesium chloride3 1.6 M in THF 20.80 L 33.24 Zinc chloride 0.5 M in THF 33.2 L 16.62Pd(PPh3)2Cl2 701.89 200 g 0.285PPh3 262.29 149.5 g 0.570 Pentane 40 L To a 72 L round bottomed flask was added zinc chloride THF solution (0.5 M, 33.2 L, 16.62 mol). The solution was cooled to -5° C. and vinyl magnesium chloride THF solution (1.6 M, 20.80 L, 33.24 mol) was added slowly, maintaining temperature at less than 20° C. Triphenylphosphine (149.5 g, 0.570 mol) was added, followed by Pd(PPh3)2Cl2 (200 g, 0.285 mol). The mixture was stirred for 10 min, and 1-Bromo-3-fluoro-4-iodobezene was added. The reaction mixture was stirred at ambient temperature for 4-6 h until the reaction was complete by HPLC. Mixing zinc chloride and vinyl magnesium chloride THF solutions was exothermic. The temperature was controlled by adjusting the addition rate and the cooling bath temperature. The coupling reaction after the addition of aryl iodide (1) was slightly exorthermic. The temperature rose from 11° C. to 37° C. without a cooling bath in about 1 h and it cooled down thereafter. The reaction mixture was quenched into a pre-cooled (0° C.) mixture of pentane (20 L), water (12 L), and concentrated HCl (1.0 L) in a 200 L extractor. The two layers were separated. The organic layer was diluted with pentane (20 L), washed with water (16 L), and concentrated under reduced pressure. Compound 2 was quite volatile, and 20% was lost during rotavap concentration. Assay of the product before concentration normally gave product yield of 80-85%. The product was further purified in this way: The residure was taken up with pentane (10 L). The resulting suspension was filtered. The solid was washed with pentane (1.0 L). The combined filtrate and wash were concentrated. The crude oil was purified by vacuum distillation at 0.1-0.2 mm Hg. Purified product was light yellow with a boiling point of 45-50° C. at 0.1-0.2 mm Hg. Distillation recovery was 95%. Product was 93-95 wt %. The residue in the distillation pot was liquid at the end of distillation, but solidified upon cooling |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.8% | With potassium carbonate In Solmix A-11; water; toluene for 2h; Inert atmosphere; Reflux; | 7.1 First Step: 4-Bromo-2-fluoro-iodobenzene (21) (5.0 g), 4-ethoxy-2,3-difluoro-1,1'-biphenyl-4'-boronic acid (6) (4.7 g), potassium carbonate (6.9 g), Pd(Ph3P)2Cl2 (0.4 g), toluene (100 ml), Solmix A-11 (100 ml), and water (100 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated under reflux for 2 hours. The reaction mixture was cooled to 25 °C, and then poured into water (500 ml) and toluene (500 ml), and mixed. Subsequently, the mixture was allowed to stand until it had separated into two phases of organic and aqueous phases, and an extractive operation into an organic phase was carried out. The organic phase obtained was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and heptane (volume ratio; toluene: heptane= 1:1) as the eluent and silica gel as the stationary phase powder. The residue was further purified by means of recrystallization from a mixed solvent of ethyl acetate/Solmix A-11 (volume ratio; ethyl acetate: Solmix A-11= 2:1), and dried, giving 5.6 g of 4'-bromo-4-ethoxy-2,3,2"-trifluoro-1,1'-terphenyl (22). The yield based on a compound (21) was 82.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In ethanol; water; toluene at 120℃; Sealed tube; | 51.1 To a sealed tube were added 4-bromo-2-fluoro-l-iodobenzene 207-1 (600 mg, 2.0 mmol), 2-fluoropyridin-4-ylboronic acid 205-4 (282 mg, 2.0 mmol), Pd(PPh3)4 (116 mg, 0.1 mmol), Na2CO3 ( 636 mg, 6.0 mmol), toluene (2 mL),H2O (2 mL) and ethanol (0.5 mL). The reaction mixture was stirred at 120 °C overnight. After cooling to room temperature, the solvents were evaporated and the residue was redissolved in water (5 ml) and extracted with ethyl acetate (8 mL x 3). The combined organic phases were dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography and eluted with 15% ethyl acetate in hexane to give 4-(4-bromo-2-fluorophenyl)-2-fluoropyridine 207-3. MS m/z 270.1 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium carbonate In water; toluene for 10h; Reflux; Inert atmosphere; | 26 ; Under the atmosphere of argon gas, 1000 ml of toluene and 500 ml of 2 M concentration sodium carbonate aqueous solution was added to 120.0 g (399 mmol) of 1-bramo-3-fluaro-4-iodobromobenzene, 72.7 g (479 mmol) of 2-methoxyphenyl boronic acid sand 9.2 g (7.96 mmol) of tetrakis(triphenylphosphine) palladium (0), and the resultant mixture solution was heated while being refluxed for 10 hours. After the reaction was completed, extraction with toluene was carried out immediately and a water layer was removed. After drying the organic layer over sodium sulfate, the resultant was condensed. The residue was subjected to a chromatography purification using a silica gel column to obtain 89.6 g of 4-bromo-2-fluoro-2'-methoxybiphenyl in the state of white crystal (yield: 80%). Under the atmosphere of argon gas, of 900 ml of dichloromethane was added to 89.6 g (319 mmol) of 4-bromo-2-fluoro-2'-methoxybiphenyl, and the resultant mixture solution was stirred while cooling with ice. After adding 95.9 g (382 mmol) of boron tribromide by dropping, the solution was stirred at a room temperature for 12 hours. After completion of the reaction, 200 ml of water was added, and the resultant mixture solution was stirred for 1 hour, followed by removing a water layer. After drying the organic layer over magnesium sulfate, the resultant was condensed. The residue was subjected to a chromatography purification using a silica gel column to obtain 68.1 g of 4-bromo-2-fluoro-2'-hydroxybiphenyl in the state of white crystal (yield: 70%). Onto 68.1 g (255 mmol) of 4-bromo-2-fluoro-2'-hydroxybiphenyl and 70.4 g (510 mmol) of potassium carbonate, 1500 ml of N-methylpyrrolidone was added and the resultant solution was stirred at 180°C for 3 hours. After completion of the reaction, water was added and extraction by toluene was conducted. After drying an organic layer over sodium sulfate, the resultant was condensed. The resultant residue was re-crystallized through toluene and 44.2 g of 3-bromodibenzofuran in the state of white crystal was obtained (yields:60%). Under the atmosphere of argon gas, 350 ml of toluene and 170 ml of 2 M concentration sodium carbonate aqueous solution was added to 34.2 g (138 mmol) of 3-bromobenzofram, 26.0 g (166 mmol) of 4-chlorophenyl boronic acid and 3.2 g (2.77 mmol) of tetrakis(triphenylphasphine)palladium (0), and the resultant mixture solution was heated while being refluxed for 12 hours. After the reaction was completed, filtration was carried out immediately and a water layer was removed. After drying the organic layer over sodium sulfate, the resultant was concentrated. The residue was subjected to a chromatography purification using a silica gel column to obtain 23.1 g of white crystal (yield:60%). The resultant white crystal was identified as Intermediate 26 from the result in accordance with the FD-MS analysis. |
80% | With sodium carbonate In water; toluene for 10h; Reflux; Inert atmosphere; | 1-37 Under an argon atmosphere, 1,000 mL of toluene and 500 mL of an aqueous solution of sodium carbonate having a concentration of 2 M were added to 120.0 g (399 mmol) of 1-bromo-3-fluoro-4-iodobenzene, 72.7 g (479 mmol) of 2-methoxyphenyl boronic acid, and 9.2 g (7.96 mmol) of tetrakis(triphenylphosphine)palladium(0), and then the mixture was heated while being refluxed for 10 hours. Immediately after the completionof the reaction, the resultant was filtrated, and then the aqueous layer was removed. The organic layer was dried with sodium sulfate, and was then concentrated. The residue was purified by silica gel column chromatography. Thus, 89.6 g of a white crystal of 4-bromo-2-fluoro-2'-methoxybiphenyl were obtained (in 80% yield) |
80% | With sodium carbonate In water; toluene for 10h; Inert atmosphere; Reflux; | 27 Under an argon atmosphere, 1,000 mL of toluene and 500 mL of an aqueous solution of sodium carbonate having a concentration of 2 M were added to 120.0 g (399 mmol) of 1-bromo-3-fluoro-4-iodobenzene, 72.7 g (479 mmol) of 2-methoxyphenyl boronic acid, and 9.2 g (7.96 mmol) of tetrakis(triphenylphosphine)palladium(0), and then the mixture was heated while being refluxed for 10 hours. Immediately after the completion of the reaction, the resultant was filtrated, and then the aqueous layer was removed. The organic layer was dried with sodium sulfate, and was then concentrated. The residue was purified by silica gel column chromatography. Thus, 89.6 g of a white crystal of 4-bromo-2-fluoro-2'-methoxybiphenyl were obtained (in 80% yield). |
80% | With sodium carbonate In water; toluene for 10h; Inert atmosphere; Reflux; | 5 Synthesis Example 5 (synthesis of intermediate 5)> Under an argon atmosphere, 1,000 mL of toluene and 500 mL of an 2M aqueous solution of sodium carbonate were added to 120.0 g of 1-bromo-3-fluoro-4-iodobenzene, 72.7 g of 2-methoxyphenylboronic acid, and 9.2 g of tetrakis(triphenylphosphine)palladium(0), and then the reaction mixture was heated at reflux for 10 hours. Immediately after the completion of the reaction, the resultant was filtrated, and then the aqueous layer was removed. The organic layer was dried with sodium sulfate, and was then concentrated. The residue was purified by silica gel column chromatography. Thus, 89.6 g of the white crystal of 4-bromo-2-fluoro-2'-methoxybiphenyl were obtained (in 80% yield). Under an argon atmosphere, 900 mL of dichloromethane were added to 89.6 g of 4-bromo-2-fluoro-2'-methoxybiphenyl, and then the mixture was stirred under ice cooling. 95.9 g of boron tribromide were added dropwise to the mixture, and then the whole was stirred at room temperature for 12 hours. After the completion of the reaction, 200 mL of water were added to the resultant, and then the mixture was stirred for 1 hour. After that, the aqueous layer was removed. The organic layer was dried with magnesium sulfate, and was then concentrated. The residue was purified by silica gel column chromatography. Thus, 68.1 g of the white crystal of 4-bromo-2-fluoro-2'-hydroxybiphenyl were obtained (in 70% yield). 1,500 mL of N-methylpyrrolidone were added to 68.1 g of 4-bromo-2-fluoro-2'-hydroxybiphenyl and 70.4 g of potassium carbonate, and then the mixture was stirred at 180 °C for 3 hours. After the completion of the reaction, water was added to the resultant, and then the mixture was extracted with toluene. The organic layer wasdriedwithsodiumsulfate, and was then concentrated. The residue was recrystallized from toluene and purified. Thus, 44.2 g of the white crystal of 3-bromodibenzofuran were obtained (in 60% yield) . The white crystal was identified as the intermediate 5 by FD-MS analysis. |
80% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In water; toluene for 10h; Reflux; Inert atmosphere; | 6 Synthesis of Intermediate 6 Under an argon atmosphere, 1000 mL of toluene and 500 mL of 2 M sodium carbonate aqueous solution were added to 120.0 g of 1-buromo-3-fluoro-4-iodobenzene (399 millimoles), 72.7 g of 2-methoxyphenylboronic acid (479 millimoles) and 9.2 g of tetrakis(triphenylphosphine)palladium (0) (7.96 millimoles), and the mixture was heated under reflux for 10 hours.After completion of a reaction, the reacted mixture was immediately subjected to filtration and the water phase was then removed. The organic phase was dried with sodium sulfate and concentrated. The residual concentrate was purified with silica gel column chromatography to obtain 89.6 g of 4-buromo-2-fluoro-2′-methoxybiphenyl white crystals (yield 80%). |
70% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane; water at 77℃; for 42h; Inert atmosphere; | A-1 (A-1) Synthesis of Intermediate A-1 In argon atmosphere, a mixture of 1-bromo-3-fluoro-4-iodobenzene (1037 g, 3.45 mol), 2-methoxyphenylboronic acid (620 g, 4.14 mol), tetrakis(triphenylphosphine)palladium(0) (80 g, 69 mmol), sodium carbonate (1096 g, 10.3 mol), 1,2-dimethoxyethane (DME) (5.2 L), and water (5.2 L) was stirred at 77° C. for 42 h. The reaction liquid was cooled to room temperature. After adding water, the reaction liquid was extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain Intermediate A-1 (685 g). The yield was 70%. |
With sodium carbonate In water; toluene for 10h; Inert atmosphere; Reflux; | 40 Under an argon atmosphere, 120.0 g of 1-bromo-3-fluoro-4-iodobenzene, 72.7 g of 2-methoxyphenyl boronic acid, and 9.2 g of tetrakis(triphenylphosphine)palladium, 1,000 ml of toluene, and 500 ml of an aqueous solution of sodium carbonate having a concentration of 2 M were loaded into a 2,000-ml three-necked flask, and then the mixture was heated for 10 hours while being refluxed. Immediatelyafter the completion of the reaction, the resultant was filtrated, and then the aqueous layer was removed. The organic layer was dried with sodium sulfate, and was then concentrated. The residue was purified by silica gel column chromatography. Thus, 89.6 g of a white crystal of 4-bromo-2-fluoro-2'-methoxybiphenyl were obtained. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine In N,N-dimethyl-formamide at 60℃; for 1h; | B1.19.A Step A. tert-butyl (4-((4-bromo-2-fluorophenyl)ethynyl)phenyl)carbamate. To a suspension of 4-bromo-2-fluoro-1-iodobenzene (13.35 g, 44.4 mmol), PdCl2(PPh)3 (779 mg, 1.11 mmol), CuI (211 mg, 1.11 mmol) in DMF (50 mL) was added Et3N (8.3 mL, 60 mmol) followed by tert-butyl (4-ethynylphenyl)carbamate (8.22 g, 37 mmol). The mixture was heated at 60 C for 1 h. The mixture was then cooled and pooled to water and extracted with EtOAc. The combined organic layers were washed with water, dried and concentrated under reduced pressure. The residue was chromatographied by a silica gel column (0-15% EtOAc/Hexane) to offer 6.1 g of title compound as a brown solid |
Yield | Reaction Conditions | Operation in experiment |
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Stage #1: trimethyl(pentafluoroethyl)silane With potassium fluoride; copper(I) bromide In N,N-dimethyl-formamide at -5 - 20℃; for 13.5h; Inert atmosphere; Stage #2: 1-bromo-3-fluoro-4-iodobenzene In 1,3-dimethyl-2-imidazolidinone; N,N-dimethyl-formamide at 75℃; for 14h; Inert atmosphere; | A.3-145.1 Step 1: Synthesis of 3-fluoro-4-(pentafluoroethyl)bromobenzene13.2 g (91.9 mmol) of copper(I) bromide were cooled to -5° C. in 80 ml of dry N,N-dimethylformamide. Under nitrogen, 14.7 g (76.7 mmol) of trimethyl-(pentafluoroethyl)silane were added. 4.45 g (76.7 mmol) of potassium fluoride (spray-dried) were added in portions over the course of 30 minutes at a rate such that the internal temperature remained below 0° C. The mixture was stirred at 0° C. for 1 hour and was then warmed to 20° C. over the course of 12 hours. Thereafter 10 ml of dry 1,3-dimethyl-2-imidazolidinone and 22 g (73.1 mmol) of 3-fluoro-4-iodo-bromobenzene were added. The contents were stirred at 75° C. for 14 hours. Then all of the volatile constituents were distilled off to dryness, the distillate being collected in a cold trap cooled with liquid nitrogen. The distillate was subsequently warmed to 20° C. and dissolved in 500 ml of diethyl ether. This solution was washed with four times 100 ml of water and then with two times 100 ml of saturated aqueous NaCl solution. The organic phase was then dried, and the solvent was removed on a Vigreux column. Subsequent distillation of the residue on a Vigreux column gave 16.1 g of product (boiling point: 86-87° C. (75 mmHg)) with a purity of 99% by weight. | |
Stage #1: trimethyl(pentafluoroethyl)silane With potassium fluoride; copper(I) bromide In N,N-dimethyl-formamide at -5 - 20℃; for 13.5h; Inert atmosphere; Stage #2: 1-bromo-3-fluoro-4-iodobenzene In 1,3-dimethyl-2-imidazolidinone; N,N-dimethyl-formamide at 75℃; for 14h; Inert atmosphere; | A.1-153.1 Step 1: Synthesis of 3-fluoro-4-(pentafluoroethyl)bromobenzene13.2 g (91.9 mmol) of copper(I) bromide were cooled to -5° C. in 80 ml of dry N,N-dimethylformamide. Under nitrogen, 14.7 g (76.7 mmol) of trimethyl-(pentafluoroethyl)silane were added. 4.45 g (76.7 mmol) of potassium fluoride (spray-dried) were added in portions over the course of 30 minutes at a rate such that the internal temperature remained below 0° C. The mixture was stirred at 0° C. for 1 hour and was then warmed to 20° C. over the course of 12 hours. Thereafter 10 ml of dry 1,3-dimethyl-2-imidazolidinone and 22 g (73.1 mmol) of 3-fluoro-4-iodo-bromobenzene were added. The contents were stirred at 75° C. for 14 hours. Then all of the volatile constituents were distilled off to dryness, the distillate being collected in a cold trap cooled with liquid nitrogen. The distillate was subsequently warmed to 20° C. and dissolved in 500 ml of diethyl ether. This solution was washed with four times 100 ml of water and then with two times 100 ml of saturated aqueous NaCl solution. The organic phase was then dried, and the solvent was removed on a Vigreux column. Subsequent distillation of the residue on a Vigreux column gave 16.1 g of product (boiling point: 86-87° C. (75 mmHg)) with a purity of 99% by weight. |
Yield | Reaction Conditions | Operation in experiment |
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48.5% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 40h;Inert atmosphere; Reflux; | Synthesis of Compound S1-4) 64.5 g of 3-chloro-5-fluorophenylboric acid (S1-2), 110.0 g of 1-bromo-3-fluoro-5-iodobenzene (S1-3), 6.0 g of tetrakis(triphenylphosphine)palladium, 130.0 g of potassium carbonate, and 1000 ml of a mixed solvent of toluene/ethanol/water 3/3/1 (volume ratio) were added into a reactor under nitrogen atmosphere, and refluxed for 40 hrs. The reaction solution was cooled to room temperature, added with toluene, and then washed with 1N hydrochloric acid, and water. Afterwards, the solution was dried over magnesium sulfate, and then distilled under vacuum to remove the solvent. Then, the product was purified by silica-gel column chromatography with heptane as a developing solvent, and then dried under vacuum to obtain 53.8 g of (S1-4). The yield of Compound (S1-4) from (S1-3) was 48.5%. |
Yield | Reaction Conditions | Operation in experiment |
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37% | With potassium phosphate;copper(l) iodide; In 1,4-dioxane; for 15h;Reflux; Inert atmosphere; | Step E - Synthesis of Compound Int-9e; A suspension of compound Int-9d (2 g, 8.8 mmol), aryl iodide (2.6 g, 8.8 mmol),Cul (67 mg, 0.35 mmol) and K3PO4 (2.4 g, 17.6 mmol) in dioxane (50 mL) was put under N2 atmosphere, heated to reflux, and allowed to stir at this temperature for about 15 hours. The reaction was cooled to room temperature and filtered and the filtrate was washed with water (50 mL) and extracted with EtOAc (200 mL). The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue obtained was purified using column chromatography to provide compound Int-9e (1.3 g, 37%). MS (ESI) m z (M+H)+: 400. |
37% | With potassium phosphate;copper(l) iodide; In 1,4-dioxane; for 15h;Inert atmosphere; Reflux; | Synthesis of Compound Int-9eInt 9d Int 9eA suspension of compound Int-9d (2 g, 8.8 mmol), aryl iodide (2.6 g, 8.8 mmol), Cul (67 mg, 0.35 mmol) and K3P04 (2.4 g, 17.6 mmol) in dioxane (50 mL) was put under N2 atmosphere, heated to reflux, and allowed to stir at this temperature for about 15 hours. The reaction was cooled to room temperature and filtered and the filtrate was washed with water (50 mL) and extracted with EtOAc (200 mL). The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue obtained was purified using column chromatography to provide compound Int-9e (1.3 g, 37%). MS (ESI) m/z (M+H)+: 400. |
Yield | Reaction Conditions | Operation in experiment |
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96% | With [Cu2(2,7-bis(pyridin-2-yl)-l,8-naphthyridine)(OH)(CF3COO)3]; tetrabutylammomium bromide; ammonia; caesium carbonate; In ethylene glycol; at 140℃; for 16.0h;Sealed tube; | General procedure: A mixture of substrate (0.25 mmol), complex 1 (2.5 × 10- 3 mmol), Cs2CO3 (1 mmol), Conc. NH3(aq) (0.5 mL) and TBAB (0.25 mmol) in water (0.5 mL) were loaded in a sealed reaction tube. The reaction temperature was increased to 110-140 C and the reaction mixture was stirred for 8-24 h. After cooling to RT, the reaction mixture was poured into a saturated NaCl solution, extracted with ethyl acetate and dried over anhydrous MgSO4. After removal of solvents, the residue was re-crystallized or chromatographed on silica gel. All products were characterized by NMR spectroscopy and were consistent with the literature data. |
Yield | Reaction Conditions | Operation in experiment |
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77% | With bis(triphenylphosphine)palladium(II) dichloride; tetrabutylammomium bromide; potassium carbonate; triphenylphosphine In ethanol; toluene at 80℃; for 6h; Inert atmosphere; | 1.1-1 (Stage 1-1) Synthesis of Compound (S1-03) Under a nitrogen flow, a mixed solution of 21.5 g (71.6 mmol) of 1-bromo-3-fluoro-4-iodobenzene (S1-01), 11.3 g (71.6 mmol) of 3,5-difluorophenylboric acid (S1-02), 0.503 g (0.716 mmol) of (bistriphenylphosphine)palladium dichloride, 0.375 g (1.43 mmol) of triphenylphosphine, 14.8g (107 mmol) of potassium carbonate, 5.71g (17.9 mmol) of tetrabutylammonium bromide, 100 mL of ethanol and 100 mL of toluene was heated and stirred at 80°C for 6 hours. The reaction solution was poured in water and then extracted twice with 300 mL of toluene. The organic phase was washed three times with water and then concentrated under a reduced pressure. Then, the residue was purified through silica-gel column chromatography using heptane as a solvent to obtain 15.8 g (55.1 mmol, yield: 77%) of the compound (S1-03). |
Yield | Reaction Conditions | Operation in experiment |
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80.2% | Stage #1: 1-bromo-3-fluoro-4-iodobenzene With n-butyllithium In tetrahydrofuran at -70℃; for 1h; Inert atmosphere; Stage #2: 4-propyl-cyclohexanone In tetrahydrofuran at -70 - 20℃; | 6.1 First step Under a nitrogen atmosphere, n-BuLi (108.0 mL, 174.0 mmol) was slowly added dropwise, at -70°C or lower, to a THF (300 mL) solution of 4-bromo-2-fluoro-1-iodobenzene (67) (50.0 g, 166.0 mmol). The reaction mixture was agitated at -70°C or lower for 1 hour, and then 4-propylcyclohexanone (66) (24.5 g, 174.0 mmol) was slowly added dropwise thereto. The reaction mixture was returned to room temperature, and then quenched with 200 mL of 1 N hydrochloric acid aqueous solution, and extracted with 100 mL of toluene three times. Combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was purified by silica gel column chromatography, and thus 1-(4-bromo-2-fluorophenyl)-4-propylcyclohexanol (68) (42.0 g, yield 80.2%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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87% | With 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0) In tetrahydrofuran at 65℃; for 1h; Inert atmosphere; Sealed tube; chemoselective reaction; | 4.3 General procedure for the Reformatsky-Negishi coupling employing ethyl 2-bromozincacetate (2a) General procedure: To a 20 mL vial with a stir bar was added aryl halide 1 (2.00 mmol), Pd(dba)2 (28.8 mg, 2.5 mol %), Xantphos (28.9 mg, 2.5 mol %). The vial was sealed with a Teflon-lined cap and THF (6.0 mL) was added. The mixture was vacuumed and backfilled with nitrogen (3×). A solution of ethyl 2-bromozincacetate (2a) in THF (0.40 M, 6.0 mL, 1.2 equiv) filtered through a Target Nylon 0.45 μm filter (1.25-inch OD) was syringed in and the reaction mixture was then heated to 65 °C and monitored by HPLC. Upon reaction completion based on HPLC analysis (≥95% conversion unless the reaction was stalled), the mixture was cooled to room temperature and quenched with 1 M aq HCl (5.0 mL), followed by addition of brine (5.0 mL). The organic layer was separated and concentrated in vacuum. The residue was purified by silica gel column chromatography using gradient EtOAc in hexanes. |
Yield | Reaction Conditions | Operation in experiment |
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With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; toluene; at 99℃; for 8h;Inert atmosphere; | In an inertized (N2) reaction vessel at internal temperature 20C and under exclusion of humidity and air, Compound 1 (1.0 eq.) and Compound 2 (1.2 eq.) are reacted in the presence of cesium carbonate (2.4 eq.), tris(dibenzylidenaceton) dipalladium(O) (0.035 eq.) and Xantphos (0.07 eq.) in a mixture of toluene and 1 ,4-dioxane at internal temperature of 99C. After 8 hours, the mixture is cooled to internal temperature of 60C. Subsequently, dimethylformamide (DMF), filter aid (CEFOK) and activated charcoal (EKNS) are added, and the mixture is stirred and cooled to internal temperature of 35 C. The solids are filtered off and washed with a mixture of dimethylformamide and toluene. To the filtrate, which contains the product Compound 3, is introduced at internal temperature of25 C hydrogen chloride gas (CLC) whereupon the HQ salt of Compound 3 crystallizes. The palladium residue mainly remains in solution. After warming to 60 C and cooling to 0C, the solids are filtered using a centrifuge and are washed with a mixture of toluene and dimethylformamide. The damp Compound 3 HC1 salt is charged to a reactor (equipped with pH probe) together with dimethylformamide and is heated to 60C. By adding a 4 wt% of aqueous tripotassium phosphate solution, the pH is adjusted to a pH range of 6.8-7.6 (with a target of pH 7.2) while Compound 3 crystallizes as free base. After cooling to 22C and stirring, the solids are filtered using a centrifuge and are washed with drinking water. The moist solids are dried at 50 C under vacuum to give dry, crude Compound 3. In order to remove residual palladium, dry, crude Compound 3 is dissolved in dimethylformamide at internal temperature of 60C and stirred together with Smopex-234 (commercially available from Johnson Matthey) and activated charcoal for 90 minutes. The solids are filtered off at internal temperature of 60C and are washed with dimethylformamide. To the filtrate are added drinking water and Compound 3 seed crystals. More drinking water is added while Compound 3 crystallizes. After cooling to internal temperature of 20 C, the solids are filtered using a centrifuge and are washed with a mixture of deionized water and dimethylformamide and with deionized water. The moist solids are dried at 50C under vacuum, providing 6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3- methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (Compound 3). |
Yield | Reaction Conditions | Operation in experiment |
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To a 100 ml jacketed reactor equipped with a mechanical stirrer was charged 4-bromo-2-fluoro1-iodobenzene "Compound (A)" (5 g, 1.0 eq) and THF (25 ml). The solution was cooled to -5 C. 2 M isopropyl magnesium chloride in THF (10.8 ml, 1.3 eq) was slowly added maintaining the internal temperature below 0 C. The mixture was stirred at 0 C. for 1 h. Di-tert-butyl dicarbonate (5.44 g, 1.5 eq) in THF (10 ml) was added. After 1 h, the solution was quenched with 10% citric acid (10 ml), and then diluted with 25% NaCl (10 ml). The layers were separated and the organic layer was concentrated to near dryness and chased with THF (3*10 ml). The crude oil was diluted with THF (5 ml), filtered to remove inorganics, and concentrated to dryness. The crude oil (6.1 g, potency=67%, potency adjusted yield=88%) was taken to the next step without further purification. 1H NMR (DMSO-d6): delta 1.53 (s, 9H), 7.50-7.56 (m, 1H), 7.68 (dd, J=10.5, 1.9 Hz, 1H), 7.74 (t, J=8.2 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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80.96% | Stage #1: 1-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]-1H-[1,2,4]triazole; 1-bromo-3-fluoro-4-iodobenzene With potassium phosphate In 1,4-dioxane; water for 0.25h; Inert atmosphere; Stage #2: With tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; water at 100℃; for 12h; Inert atmosphere; | P6.3 Step-3 i -(4’-bromo-2’-fluorobiphenyl-4-yI)-i H-i, 2, 4-triazole To a stirred solution of compound 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboralon-2- yl)phenyl)-1H-1,2,4-triazole (0.8 g, 2.95 mmol) in 1,4-dioxane/Water (10.0/3 mL), 4- bromo-2-fluoro-1-iodobenzene (0.887 g, 2.95 mmol) and K3P04 tribasic (1.88 g,8.85 mmol) was added and degassed with argon atmosphere. After 15mm Tetrakis (0.170 g, 0.148 mmol) was added to the reaction mixture under argon and again degassed for 5 min.The reaction mixtures was heated at 10000 12h. After cooling, the reaction mixture was quenched with ice and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and concentratedunder reduced pressure, to yield the title compound (0.76 g, 80.96%) as a pale yellow solid. LOMS: (M-H) + = 320.0 1H NMR: (DMSO-d6, 300MHz ) 6 9.38(s, 1H), 8.28(s, 1 H), 7.90 (d, 2H), 7.76(d, 2H),7.69(s, 1 H)7.57 (d, 2H). |
80.96% | Stage #1: 1-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]-1H-[1,2,4]triazole; 1-bromo-3-fluoro-4-iodobenzene With potassium phosphate In 1,4-dioxane; water for 0.25h; Inert atmosphere; Stage #2: With tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; water at 100℃; for 12.0833h; Inert atmosphere; | 3 Step-3 I -(4’-bromo-2’-fluorobiphenyl-4-yI)-1 H-I, 2, 4-triazole To a stirred solution of compound 1 -(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxoboralon-2- yl)phenyl)-1 H-i ,2,4-trizole (0.8 g, 2.95 mmol) in 1 ,4-dioxane/Water (10.0/3 mL) was added 4-bromo-2-fluoro-i-iodobenzene (0.887 g, 2.95 mmol) and K3P04 (1.88 g,8.85 mmol) degassed with argon atmosphere. After 15mm tetrakis (0.170 g, 0.148 mmol) was added to the reaction mixture under Argon and again degassed for 5min.The reaction mixtures was heated at 10000 12h. After cooling, the reaction mixture was quenched with ice and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure, to yield the title compound (0.76 g, 80.96%) as a pale yellow solid.LOMS: (M-H) + = 320.0 1H NMR: (DMSO-d6, 300MHz ) 6 9.38(s, 1H), 8.28(s, 1H),7.90 (d, 2H), 7.76(d, 2H),7.69(s, 1 H)7.57 (d, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | Stage #1: 5-amino-2-bromopyrazine; bis(pinacol)diborane With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 90℃; for 60h; Inert atmosphere; Stage #2: 1-bromo-3-fluoro-4-iodobenzene With potassium carbonate In 1,4-dioxane at 80℃; for 48h; Inert atmosphere; | A Step A: 5-(4-Bromo-2-fluorophenyl)pyrazin-2-amine Step A: 5-(4-Bromo-2-fluorophenyl)pyrazin-2-amine (0172) To a solution of 5-bromopyrazin-2-amine (1.74 g, 10.0 mmol) in 1,4-dioxane (40 mL) were added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.65 g, 10.5 mmol) and KOAc (1.96 g, 20.0 mmol). The mixture was sparged with N2 several times before adding Pd(dppf)Cl2.CH2Cl2 (0.41 g, 0.5 mmol). The resultant mixture was stirred at 90° Celsius for 60 hours under N2. After cooling to rt, 4-bromo-2-fluoro-1-iodobenzene (4.5 g, 15.0 mmol), K2CO3 (2.76 g, 20.0 mmol) and another portion of Pd(dppf)Cl2.CH2Cl2 (0.41 g, 0.5 mmol) were added. The resultant mixture was sparged with N2 again, and stirred at 80° Celsius for 48 hours under N2. The mixture was then cooled to rt, diluted with THF (30 mL) and filtered. The filtrate was concentrated to dryness and the residue purified by FCC to give 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine (0.4 g, 15%). 1H NMR (300 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.01 (s, 1H), 7.82 (m, 1H), 7.63 (dd, J=11.1, 2.1, 1H), 7.50 (dd, J=8.4, 2.1, 1H), 6.75 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine In tetrahydrofuran at 60℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1-bromo-3-fluoro-4-iodobenzene With isopropylmagnesium chloride In tetrahydrofuran at -20℃; for 0.833333h; Inert atmosphere; Stage #2: 2,2-dimethyl-5-(propan-2-ylidene)-1,3-dioxane-4,6-dione In tetrahydrofuran; toluene at -20 - 0℃; for 3h; | 282.1 1M Isopropylmagnesium chloride THF solution (183 mL, 182.79 mmol) was added dropwise to a solution of 4-bromo-2-fluoro-1-iodobenzene (50.0 g, 166.17 mmol) in anhydrous THF (96 mL) over 20 min at -20°C under argon gas atmosphere. The reaction mixture was stirred at -20°C for 30 min, and added dropwise to a solution of 5-isopropylidene-2,2-dimethyl-1,3-dioxane-4,6-dione in anhydrous toluene (84 mL) at -20°C over 20 min, and the container was washed with THF (24 mL). The reaction mixture was stirred at 0°C for 3 hr, 10% aqueous citric acid solution (200 mL) was added thereto at 0°C, and the mixture was extracted with toluene (200 mL). The organic layer was concentrated under reduced pressure to give 5-(2-(4-bromo-2-fluorophenyl)propan-2-yl)-2,2-dimethyl-1,3-dioxane-4,6-dione as a pale yellow oil | |
With isopropylmagnesium chloride In tetrahydrofuran; toluene at -20 - 0℃; for 3.16667h; Inert atmosphere; | 6.8 A solution (183 niL, 182.79 mrnol) of 1M isopropylmagnesiumchloride in THF was added dropwise to a solution of 4-bromo-2-fluoro-l-iodobenzene (50.0 g, 166.17 rnmol) in anhydrous THE’ (96 mL) over 20 mm at -20°C under argon atmosphere. The reaction mixture was stirred at -20°C for 30 mm, and added dropw±se to a solution of 5-isopropylidene-2,2-dimethyl-1,3- dioxane-4,6-dione in anhydrous toluene (84 mL) over 20 mm at-20°C, and then the used container was washed with THE’ (24 mL) The reaction mixture was stirred at 0°C for 3 hr, 10% aqueous citric acid solution (200 mL) was added thereto at 0°C, and the mixture was extracted with toluene (200 mL). The organic layer was concentrated under reduced pressure to give 5-(2-(4-bromo-2-fluorophenyl)propan-2-yl) -2, 2-dimethyl-1 3-dioxane-4, 6-dione as a pale-yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With tris-(dibenzylideneacetone)dipalladium(0); trifuran-2-yl-phosphane In tetrahydrofuran at 20℃; Inert atmosphere; | 3-100.1 (1) Under an argon gas atmosphere, at room temperature 1-bromo-3-fluoro-4-iodobenzene (3.0g)In tetrahydrofuran (34mL) solution,Tri (2-furyl) phosphine (696mg),Tris (dibenzylideneacetone) palladium (0) (916mg)And 0.5 M 4- ethoxy-4-oxobutyl zinc bromide tetrahydrofuran solution (26 mL) was added and stirred overnight at the same temperature.The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 62: 38 → 0: 100) to give the ethyl 4- (4-bromo-2-fluorophenyl) butanoate (750 mg, 26%) as a pale yellow as an oily substance. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With bis-triphenylphosphine-palladium(II) chloride In tetrahydrofuran for 12h; Reflux; | 3 3.1.5. tert-butyl 4-(4-(4-bromo-2-fluorophenyl)thiazol-2-yl)piperazin-1-carboxylate (8) A mixture of 7 (346 mg, 0.62 mmol), 1-bromo-3-fluoro-4-iodobenzene (153 mg, 0.51 mmol) and PdCl2(PPh3)2 (22 mg,0.031 mmol) were dissolved in THF (5 mL) and the resulting mixture was refluxed for 12 h. After cooled to room temperature, the reaction mixture was extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatographyon silica gel including 10% K2CO3 using n-hexane/ethyl acetate(15:1, v/v) and then (5:1, v/v) to give 8 (186 mg, 83%) as a colorless crystal. mp: 111-113° C. 1H NMR (300 MHz, CDCl3) d:1.49 (s, 9H), 3.51-3.60 (m, 8H), 7.09 (d, J = 2.6 Hz, 1H), 7.25-7.34(m, 2H), 8.00-8.05 (m, 1H). 13C NMR (75 MHz, CDCl3) d: 28.4,42.9, 48.3, 80.3, 107.4 (d, JC-F = 15.4 Hz), 119.3 (d, JC-F = 25.9 Hz),120.7 (d, JC-F = 9.2 Hz), 121.8 (d, JC-F = 11.1 Hz), 127.5 (d, JC-F =3.7 Hz), 131.0 (d, JC-F = 4.3 Hz), 144.4 (d, JC-F = 2.5 Hz), 154.6,159.9 (d, JC-F = 252.8 Hz), 169.8. FAB-MS: m/z 442 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.5% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene at 100℃; for 12h; Green chemistry; | 1.D Preparation of N- (2- tert-butoxy ethoxy) -6 - [(4-bromo-2-fluorophenyl) amino] -7-fluoro -3H- benzimidazole-5-carboxamide: N- (2- tert-butoxy-ethoxy) -6-amino-7-fluoro -3H- benzimidazole-5-carboxamide (21.0g, 0.07mol) was dissolved in toluene (270mL), was added 4-bromo 2-fluoro-1-iodo-benzene (24.4g, 0.08mol), cesium carbonate (52.9g, 0.16mol), tris(dibenzylideneacetone)dipalladium (2.2g, 2.4mmol), 4,5-bis diphenylphosphino-methyl-9,9-xanthene (2.7g, 4.7mmol), the reaction mixture was stirred for the reaction 100°C 12h, TLC plates to determine the point of completion of the reaction, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated by rotary evaporation to dryness, a mixed solvent of ethyl acetate and n-hexane and recrystallized to give N- (2- tert-butoxyethoxy) -6 - [(4-bromo-2-fluorophenyl) amino] -7-fluoro -3H- benzimidazole-5-carboxamide, an off-white solid (27.0 g of the), a yield of 82.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.1% | With potassium hydroxide In N,N-dimethyl-formamide at 60℃; for 5h; Cooling with ice; | 4.1 Then, 3-fluoro-4-iodo-bromobenzene (T-20) (300 g, 997 mmol; Tokyo Chemical Industry Co., Ltd), potassium hydroxide (112 g, 1.996 mol) and DMF (800 mL) were mixed, and the resulting mixture was ice-cooled. Into the solution, 2,2,2-trifluoroethanol (200 g, 1.992 mmol) was added dropwise under ice-cooling, and then the reaction mixture was slowly heated, and stirred at 60° C. for 5 hours. The reaction mixture was allowed to cool to room temperature, and then poured into water (800 mL), and subjected to extraction with heptane (500 mL). The extracted layer was washed with water (500 mL) and saturated brine (300 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain compound (T-21) (270 g, 708.8 mmol, 71.1%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.4% | Stage #1: benzyl alcohol With sodium hydride In N,N-dimethyl-formamide at 90℃; for 0.5h; Stage #2: 1-bromo-3-fluoro-4-iodobenzene In N,N-dimethyl-formamide at 90℃; for 10h; | 5.1 Sodium hydride (60%, 21.9 g, 547 mmol) was added to DMF (800 mL), and then benzyl alcohol (59.3 g, 548.4 mmol) was added thereto, and the resulting mixture was stirred at 90° C. for 30 minutes. Into the reaction mixture that was allowed to cool to room temperature, 3-fluoro-4-iodo-bromobenzene (T-20) (150.0 g, 498.5 mmol; Tokyo Chemical Industry Co., Ltd) was added dropwise, and the resulting mixture was stirred at 90° C. for 10 hours. The reaction mixture was allowed to cool to room temperature, and concentrated under reduced pressure. Water (800 mL) was added dropwise to the residue at 80° C., and then the resulting mixture was cooled to 0° C. The precipitated solid was obtained by filtration, and then washed with water, and recrystallized from isopropanol (450 mL) and toluene (25 mL) to obtain compound (T-27) (125 g, 321.3 mmol, 64.4%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; water; toluene at 80℃; for 14h; Inert atmosphere; | 4.1 1) compound I-3-2 synthesis of Weighing 3g embodiment 2 I-2 of synthetic compound, 3.06 g1-bromo-3-fluoro-4-iodophenylamino, 0.2g four-triphenylporphyrin phosphorus arrowhead, 2.8g potassium carbonate, the volume 30 ml toluene, 15 ml ethanol, 15 ml water. All of the above material into 250 ml three-mouth bottle, the nitrogen three times, heating to 80 °C reflux reaction 14h, TLC shows the reaction is complete. Reaction liquid cooling to room temperature, add 20 ml water, ethyl acetate extraction three times, combined with the organic layer, water to neutral, dry anhydrous sodium sulfate, concentrated dry solvent, crude the post, the obtained crude product with ethyl acetate-petroleum ether recrystallization to obtain 2.7g white solid I-3-2. MSm/z: 340 (M +), yield: 80%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine In N,N-dimethyl-formamide at 95℃; for 3.5h; Inert atmosphere; | 21.1 Step 1: (5-(4-Bromo-2-fluorophenyl)-1,4-dimethyl-1H- 1,2,3-triazole A 100 niL round-bottomed flask was charged with 4-bromo-2-fluoro-1-iodobenzene (765.3 mg, 2.54 mmol), 1,4-dimethyl-5-(tributylstannyl)-1H-1,2,3-triazole (1.08 g, 2.80 mmol), and triethylamine (0.71 mL, 5.09 mmol) in DMF (25 mL), purgedwith N2 by bubbling through solution over 5 mm. To the mixture was added Pd(PPh3)4 (287.2 mg, 0.249 mmol) and copper(I) iodide (101.6 mg, 0.533 mmol), the flask was sealed with a septum then heated to 95 °C with stirring for 3.5 h. The reaction mixture was cooled to room temperature and then concentrated in vacuo. The residue was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, gradient of 0% to100% using solvent AIB=hexanes/EtOAc over 12 column volumes, RediSep 5i02 80 g, loaded as DCM solution). The product, 5-(4-bromo-2-fluorophenyl)-1,4-dimethyl-1H- 1,2,3-triazole (316.4 mg, 46%) was obtained as a cream solid: HPLC: RT=0.84 mm (Waters Acquity UPLC BEH C18 1.7 um 2.0 x 50 mm, CH3CN/H20/0.05%TFA, 1 mm gradient, wavelength=254nm); MS (ES): m/z= 270/272 79Br/8’Br [M+1f ‘H NMR(400MHz, CDC13) ö 7.49 - 7.44 (m, 2H), 7.16 (dd, J=8.3 (H-H), 7.6 Hz (H-F), 1H), 3.92 (d, J0.9 Hz, 3H), 2.29 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: 1-bromo-3-fluoro-4-iodobenzene; 4-cyanophenylboronic acid With potassium carbonate In 1,2-dimethoxyethane; water for 0.25h; Sonication; Stage #2: With 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride-chloroform adduct In 1,2-dimethoxyethane; water at 60 - 80℃; | 2.1 4-Bromo-2-fluoroiodobenzene (72.2g, 240mmol), 4-cyanobenzeneboronic acid (35.2g, 240mmol), dimethoxyethane (300ml), water (150ml) and potassium carbonate (50g, 362mmol) were ultrasonicated for 15 minutes.[1 ,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (1.2g,1.7mmol) was added and the mixture heated to 80°C for 2.5 hours and a further 17 hours at 60C. The mixture was cooled, water (360ml) was added and the mixture acidified cautiously with concentrated HCl (60ml). The two layers were separated and the aqueous layer extracted with MTBE (1000ml and 2 x 200ml). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and the solvent from the filtrate removed in vacuo. The residue was purified by vacuum flashchromatography eluting with toluene/heptane 1 :1. The fractions containing the product were combined and the solvent removed in vacuo to give the desired product (35.4g, 53% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In Dimethyl ether; water at 60℃; for 10h; Inert atmosphere; | 1.1 Preparation of compound 2 9.5 g of the compound of Formula 1, 8 g of 1-bromo-3-fluoro-4-iodobenzene, 0.6 g of tetra-triphenylphosphonium palladium, Measuring 100mLDME (dimethyl ether), 27 g aqueous potassium carbonate solution (2 mol / L), All of the above materials were added to a 250 mL single-necked flask, replaced with nitrogen for 5 times, at 60 ° C for 10 h, and TLC showed trace amounts of feedstock.After treatment: add 100mL of water, 100mL ethyl acetate extraction, the organic layer, washed with water to neutral, anhydrous sodium sulfate drying, concentrated dry solvent, petroleum ether eluent column chromatography to get 10.2g white needle crystal compound 2.yield: 80% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium phosphate; copper(l) iodide; N<SUP>1</SUP>,N<SUP>2</SUP>-bis(pyridin-2-ylmethyl)oxalamide In dimethyl sulfoxide at 75℃; for 24h; Inert atmosphere; Sealed tube; Schlenk technique; chemoselective reaction; | |
66% | With potassium phosphate monohydrate; 3,4,7,8-Tetramethyl-o-phenanthrolin; copper diacetate In dimethyl sulfoxide at 80℃; for 3h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate In toluene at 120℃; for 6h; Inert atmosphere; Sealed tube; | Step-i: Synthesis of tert-butyl 4-(4-bromo-2-fluorophenyl)piperazine-1-carboxylate To a stirred solution of 4-bromo-2-fluoro- 1 -iodobenzene (1g, 3.23 mmol), N-Boc piperazine (0.63 g, 3.39 mmol) in toluene (20 mL) was added NaOtBu (0.93 g, 9.63 mmol) and degassed with nitrogen for 15 min followed by Pd2(dba)3 (0.146g, 0.16 mmol) and Xantphos (0.09g, 0.16 mmol) was added and the reaction mixture was heated for 6 h at 120 °C in sealed tube. Once the reaction was completed (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated under vacuum to give the residue which was purified by combiflash column chromatography using 60% ethyl acetate in hexane as eluent to afford the title compound as off-white solid (0.65g, 54%). 1H NMR (400 MHz, CDCl3): δ 7.44 (d, J = 11.6 Hz 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.00 (t, J = 8.8 Hz, 1H), 3.45 (m, 4H), 2.94 (m, 4H), 1.44 (s, 9H); LC-MS: m/z 358.9 (M+H). |
54% | With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate In toluene at 120℃; for 6h; Inert atmosphere; Sealed tube; | Step-i: Synthesis of tert-butyl 4-(4-bromo-2-fluorophenyl)piperazine-1-carboxylate To a stirred solution of 4-bromo-2-fluoro- 1 -iodobenzene (1g, 3.23 mmol), N-Boc piperazine (0.63 g, 3.39 mmol) in toluene (20 mL) was added NaOtBu (0.93 g, 9.63 mmol) and degassed with nitrogen for 15 min followed by Pd2(dba)3 (0.146g, 0.16 mmol) and Xantphos (0.09g, 0.16 mmol) was added and the reaction mixture was heated for 6 h at 120 °C in sealed tube. Once the reaction was completed (monitored by TLC), the reaction mixture was diluted with EtOAc. The combined organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated under vacuum to give the residue which was purified by combiflash column chromatography using 60% ethyl acetate in hexane as eluent to afford the title compound as off-white solid (0.65g, 54%). 1H NMR (400 MHz, CDCl3): δ 7.44 (d, J = 11.6 Hz 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.00 (t, J = 8.8 Hz, 1H), 3.45 (m, 4H), 2.94 (m, 4H), 1.44 (s, 9H); LC-MS: m/z 358.9 (M+H). |
44% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 100℃; for 16h; Inert atmosphere; | 9 Preparation of tert-butyl 4-(4-bromo-2-fiuorophenyl) piperaime-I-carboxylate (AH) To a stirred solution of 4-bromo-2-fmoro- 1 -iodobenzene AF (2.5 g- 8.30 mmol) in 1 ,4- dioxane (50 mL) under argon atmosphere were added fer/-btityi piperazine- 1 -carboxylate (AG, 1.8 g, 9.96 mmol), Xantphos (240 mg, 0.41 mmol) and cesium carbonate (4 g, 12,45 mmol). The reaction was purged with argon for 10 mm at RT, then P ^t'ciba)* (379 mg, 0.41 mmol) was added and the reaction was stirred at 100 °C for 16 h. The reaction was cooled to RT, diluted with water (20 mL), and the product was extracted with EtOAc (2 x 20 ml). The combined organic extracts were washed with water (20 niL), dried ewer anhydrous NaiSO-j and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 3 % EtOAc Hexane) to afford Compound AH (1.3 g, 3.63 mmol, 44 %) as a pale yellow solid. 1H NMR (500 MHz, DMSO-*): δ 7.84-7.77 (in, 1H), 7.51-7.36 (in, 1H), 7.00 (t, J = 9.0 Hz, IH), 3,47-3,45 (in, 4H), 3.00-2.88 (in, 4H), 1.42 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate In toluene at 80℃; for 2h; Inert atmosphere; | 44.1 Step 1. Benzyl 4-(4-bromo-2-fluorophenyl)piperazine~l-carboxylate Step 1. Benzyl 4-(4-bromo-2-fluorophenyl)piperazine~l-carboxylate (1155) [00386] Into a 100-mL round-bottom flask, purged and maintained under an inert atmosphere of nitrogen, was added 4-bromo-2-fluoro-l-iodobenzene (3.00 g, 10.0 mmol), benzyl piperazine- 1-carboxylate (2.60 g, 11.8 mmol), Pd2(dba)3 (0.458 g, 0,500 mmol), XantPhos (0.595 g, 1.00 mmol), and NaOtBu (2.88 g, 30.0 mmol). Toluene (30 mL) was added and the reaction mixture was stirred for 2 h at 80 °C then concentrated in vacuo to a crude material that was purified by FCC eluting with ethyl acetate/petroleum ether (1 : 10) to afford benzyl 4-(4-bromo-2- fluorophenyl)piperazine-l-carboxylate as a brown oil (2.5 g, 64%). LCMS (ESI, m z): 393[ i i l |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of 4-bromo-2-fluoro-l-iodo-benzene (CAS 105931-73-5, 20.6 g, 68.5 mmol) in tetrahydrofuran (200 mL) was added a solution of w-BuLi/hexane (2.5 M, 34.24 mL) dropwise at -70 C under nitrogen atmosphere. The resultant mixture was stirred for 30 min, then to the solution was added a solution of 2-methyl-7Y-(oxetan-3-ylidene)propane-2-sulfinamide (10.0 g, 57.1 mmol) in tetrahydrofuran (100 mL) dropwise. The mixture was warmed to -20 C and stirred for 2 hrs. On completion, to the mixture was added ammonium chloride solution (50 mL, sat.), and the mixture was extracted with ethyl acetate (3 X 100 mL). The combined organic phase was washed with brine (300 mL), dried over sodium sulfate, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1 to 2: 1) to give the title compound. 1HNMR (400 M, DMSO-t 6) delta = 7.61 (dd, J = 10.4, 1.6 Hz, 1H), 7.52 (dd, J = 8.4, 1.6 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 6.47 (br, s, 1H), 5.14 (d, J = 6.8 Hz, 1H), 4.99 (d, J= 6.0 Hz, 1H), 4.93 (d, J= 6.4 Hz, 2H), 1.11 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 70℃; for 3h;Inert atmosphere; | mixture of tert-butyl 3 -(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)-5,6-dihydropyridine- 1 (2H)-carboxylate (4.3 g, 13.9 mmol), 4-bromo-2-fluoro- 1 -iodobenzene (6.2520.8 mmol), [1,1 ?-Bis(diphenylphosphino)ferrocene] dichloropalladium(II) (2.54 g, 2.78 mmol) and potassium carbonate (5.75 g, 41.7 mmol) in dioxane/H20 (L/10 mL) was degassed withNitrogen for three times and then heated at 70 °C for 3 h. The reaction mixture was cooled to room temperature and concentrated to get crude product, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 4/1) to afford the title compound (3.7 g, yield 75percent) as a brown oil. MS (ES+) C16H19BrFNO2 requires: 355, found: 300 [M-56+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine; triphenylphosphine In tetrahydrofuran at 80℃; for 24h; Inert atmosphere; | 1,4-Bis[4-(heptyl)phenyl]ethynyl-2-fluorobenzene [bistolane-(F)-C] General procedure: In a 50 mL two-way flask, a mixture of 4-ethynylheptylbenzene (2.52 mmol, 505 mg), TEA(10 mL) and THF (10 mL) was bubbled with argon. 1-Bromo-4-iodobenzene (1.17 mmol,330 mg), Pd(PPh3)4 (125 μmol, 144 mg), CuI (120 μmol, 22.8 mg) and PPh3 (117 μmol,30.6 mg) were put in another 50 mL two-way flask which was filled with argon. Then, theliquid mixture in the former flask was added into the latter flask, and it was stirred at 80°Cfor 24h. After cooling to room temperature, insoluble salts were filtered off and the filtratewas extracted with ethyl acetate and washed with water, 2M HCl aq and brine, and dried withMgSO4. After filtration and evaporation under reduced pressure, the crude was purified silicagel on a column chromatography (eluent: hexane) after solving with a small amount ofdichloromethane, and recrystallized with hexane, to afford a colorless solid (176 mg, 32%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.3% | With tetrakis(triphenylphosphine) palladium(0); tetrabutylammomium bromide; potassium carbonate; In ethanol; water; toluene; for 8h;Inert atmosphere; Reflux; | In a reaction vessel under a nitrogen atmosphere, (4-pen-tylphenyl)boronic acid (E-1) (26.8 g, 139.58 mmol),4-bromo-2-fluoro-1-iodobenzene (E-2) (40.0 g, 132.94mmol), tetrakistriphenyl phosphine palladium (1.54 g, 1.33 mmol), potassium carbonate (27.6 g, 199.41 mmol) andtetrabutylammonium bromide (10.71 g, 33.23 mmol) wereput in a mixed solvent of 200 mE of toluene, 50 mE ofethanol and 200 mE of water, and the resulting mixture was refluxed for 8 hours. The resulting react ion mixture was subjected to extraction using toluene. A combined organiclayer was washed with water and saturated brine, and driedover magnesium sulfate, and then a solvent was distilled oilusing an evaporator. The resulting residue was purified by silica gel colunm chromatography and recrystallized to give 4-bromo-2-fluoro-4?-pentyl-l , 1 ?-biphenyl (E-3) (35.1 g, yield: 78.3percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran; toluene at 20℃; for 12h; | 31.1 Step 1: Step 1: Synthesis of 3-(4-bromo-2-fluorophenyl)-N,N-dimethylprop-2-yn-1-amine To a solution of 4-bromo-2-fluoro-1-iodobenzene (3 g, 1 eq) in a mixture of THF (10 ml)/toluene (10 ml) was added with CuI (0.19 g, 0.1 eq), Pd(PPh3)2Cl2(0.7 g, 0.1 eq), Et3N (4.2 ml, 3 eq) and N,N-dimethylprop-2-yn-1-amine (1.61 ml, 1.5 eq). The mixture was stirred for 12 hr at room temperature and extracted with ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified with column chromatography to prepare the title compound (1.87 g, 73%). 1H NMR (600 MHz, CDCl3-d1); δ7.29-7.22 (m, 3H), 3.49 (s, 2H), 2.36 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | Stage #1: 1-bromo-3-fluoro-4-iodobenzene With 2,2,6,6-tetramethyl-piperidine; n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h; Inert atmosphere; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran; hexane at -78 - 20℃; for 1h; Inert atmosphere; | 3.7 BCD-BTK-35-9 In a round-bottom flask, equipped with a stirrer, thermometer and reflux condenser, mix under nitrogen in the specified order: 60 mL of dry THF and 3.067 g (0.0217 mol) of 2,2,6,6-tetramethylpiperidine. Cool the mixture to - 78 °C, add 8.69 mL (0.0217 mol) of 2.5M butyllithium in hexane, and allow to stand. After 20 minutes, add a solution of 6 g (0.01974 mol) of 3-fluoro-4- iodobromobenzene in 6 mL of THF, maintaining the temperature -78 °C. Allow the mixture to stand for 1 hour and add 4.56 mL (0.059 mol) of DFM. Stop cooling and allow the mixture to warm to room temperature. Allow to stand for another hour. Add, while cooling the reaction mixture, 3 mL of methanol and 15 mL of NH4Cl aqueous solution. Allow to stand for 30 minutes. To the reaction mass add 100 mL of water, 50 mL of dichloromethane, and transfer to a separatory funnel. Separate the organic layer; re-extract the aqueous layer twice using 25 mL of dichloromethane. Combine the organic layers, wash with water, dry with sodium sulfate, and distill off the solvent. Purify the resulting product by column chromatography, eluent hexane : dichloromethane (9:1). Yield: 3.1 g (47%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In water; toluene for 8h; Inert atmosphere; Reflux; | 1 Preparation of Intermediate A-1 Compound I-1 (22.7 g, 105 mmol), Compound a (30.0 g, 100 mmol), Pd(PPh3)4 (2.31g, 2 mmol), toluene (300 ml) were sequentially added to the flask under argon atmosphere. Aqueous sodium carbonate (2M, 150 mL) was stirred at reflux for 8 h. After the reaction mixture was cooled to room temperature, the mixture was extracted with toluene, and the organic phase was combined. The organic phase was washed with saturated brine, and the organic phase was dried and concentrated. 1 (26.1 g, 72%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In water; toluene for 8h; Inert atmosphere; Reflux; | 4 Preparation of Intermediate D-3 Compound D-2 (15.2 g, 55 mmol), Compound a (16.5 g, 55 mmol), Pd (PPh3) 4 (1.27 g, 1.1 mmol), toluene (180 ml) were sequentially added to the flask under argon atmosphere. The aqueous sodium carbonate solution (2M, 90 ml) was stirred at reflux for 8 hours. After the reaction solution was cooled to room temperature, the mixture was extracted with toluene, and the organic phase was combined. The organic phase was washed with saturated brine, and then dried and concentrated. Intermediate D-3 (17.8 g, 80%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With potassium phosphate; copper(l) iodide; In 1,2-dimethoxyethane; butan-1-ol; at 100℃; for 16h;Inert atmosphere; | Under an argon atmosphere,<strong>[120737-78-2]tert-butyl 2-methylpiperazine-1-carboxylate</strong>(1.28 g, 6.40 mmol), 1-bromo-3-fluoro-4-iodobenzene (2.31 g, 7.68 mmol), copper iodide (122 mg, 0.640 mmol)Triopotassium phosphate (4.08 g, 25.6 mmol),Ethylene glycol (716 muL, 12.8 mmol) inA solution of 1-butanol (6 mL) was stirred at 100 C. for 16 h.Water was added to the reaction solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (767 mg, 32%).Clear oil |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; toluene;Inert atmosphere; Reflux; | <strong>[104115-76-6]3-methoxy-2-naphthalene boronic acid</strong> (21.2 g, 105 mmol), 1-bromo-3-fluoro-4-iodobenzene (30.0 g, 100 mmol), Pd (PPh3) were sequentially added to the flask under argon atmosphere. 4 (2.31 g, 2 mmol), toluene (300 ml), aqueous sodium carbonate (2M,150 ml), stirred under reflux for 8 hours. After cooling the above reaction solution to room temperature, extraction with toluene, combining the organic phases, there will beThe organic phase is washed with saturated brine, and the organic phase is dried and concentrated, and then subjected to column chromatography using silica gel as a stationary phase to obtain a compound.A1 (23.2 g, 70%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17%; 8.8% | With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 90℃;Inert atmosphere; | Cuprous iodide (3.6 g, 18 mmol) was added to a mixture of tert-butyl (R)-(2- oxopiperidin-3-yl)carbamate (10 g, 47 mmol), 4-bromo-2-fluoro-l-iodobenzene (14 g, 47 mmol), and potassium phosphate tribasic (15 g, 70 mmol) in dioxane (100 mL), and the mixture was purged with nitrogen for 20 minutes. N^V-dimethylethylenediamine (2.0 mL, 18.7 mmol) was added, and the reaction mixture was stirred at 90 C overnight. The reaction mixture was filtered through celite, washed with ethyl acetate and concentrated in vacuo. The crude product was purified by column chromatography (30% ethyl acetate in pet ether). The mixture was further purified by SFC to give tert- butyl (i?)-(l-(4-bromo- 2-fluorophenyl)-2-oxopiperidin-3-yl)carbamate (3.0 g, 7.8 mmol, 17 % yield) and tert- butyl (i?)-(l-(3-fluoro-4-iodophenyl)-2-oxopiperidin-3-yl)carbamate (1.8 g, 4.1 mmol, 8.8 % yield). Analytical data for Intermediate 2: NMR (300 MHz, CDCh):? ppm 7.30 - 7.37 (m, 2H), 7.10 - 7.18 (m, 1H), 5.46 (s, 1H), 4.27 (m, 1H), 3.53 - 3.68 (m, 2H), 2.54 - 2.66 (m, 1H), 2.01 - 2.12 (m, 2H), 1.46 (s, 9H) ; 19FNMR: -117, MS(ESI) m/z: (0151) 387.2/389.2 (M+H)+. Analytical data for Intermediate 3: NMR (300 MHz, CDCh-d) ? ppm 7.49 - 7.00 (m, 2H), 6.92 - 7.00 (m, 1H), 5.46 (s, 1H), 4.27 (dt, J=11.71, 6.00Hz, 1H), 3.54 - 3.68 (m, 2H), 2.54 -2.66 (m, 1H), 2.01 - 2.12 (m, 2H), 1.74(m, 1H), 1.46 (s, 9H) ; 19F NMR: -117, MS(ESI) m/z: 435.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The starting material 5 2-fluoro-4-iodo-1-(4-pentyl-phenyl)-benzene was prepared according to a literature procedure by Suzuki-coupling of 5-pentylbenzene boronic acid and 4-bromo-2-fluoro-1-iodo-benzene followed by bromine-lithium exchange and reaction of the lithiated intermediate with iodine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; sodium t-butanolate; In toluene; at 110℃; for 24h;Inert atmosphere; | 1) In a 250 ml three-necked flask,Add 10g (49.5mmol) of <strong>[59557-91-4]4-bromo-2-methoxyaniline</strong>,15 g (49.9 mmol) of 1-bromo-3-fluoro-4-iodobenzene, 9.5 g (99 mmol) of sodium tert-butoxide,0.5g palladium acetate,2.48g of 1,1'-bis(diphenylphosphino)ferrocene, 150ml toluene,Under nitrogen protection, heat to 110 reflux for 24 hours; the reaction is completed,It was cooled to room temperature, vacuum-dried, and extracted with 600 ml of petroleum ether.Distilling petroleum ether,Spinning to obtain pure first intermediate 16.4g, yield 88%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 100℃; Inert atmosphere; | 2 2) N,N-dimethyl-1-(4-bromo-2-fluorophenyl)piperidin-4-amine 4-bromo-2-fluorophenyl iodide (700 mg, 2.33 mmol), N,N-dimethylaminopiperidine (359 mg, 2.80 mmol), tris(dibenzylideneacetone)dipalladium (213 mg, 0.23 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (270 mg, 0.47 mmol) and cesium carbonate (1.89 g. 5.83 mmol) were added to dioxane (15 mL) at room temperature. After the atmosphere in the reaction system was replaced with nitrogen three times, the reaction mixture was stirred overnight at 100 °C. The reaction solution was cooled to rt filtered, and concentrated at reduced pressure to remove the organic solvent, thereby producing a crude product. Isolation and purification by column chromatography (silica gel, DCM: MeOH = 15:1 as an eluant) were performed to produce the targeted compound (350 mg, 49% yield, yellow liquid). LC-MS (ESI): m/z (M+1) 301.32. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: 1-bromo-3-fluoro-4-iodobenzene With n-butyllithium In tetrahydrofuran; hexane at -76℃; for 1h; Stage #2: N-tert-butyloxycarbonylpiperidin-4-one In tetrahydrofuran at -76℃; for 2h; | 33.1 Step 1 : tert-Butyl 4-('4-bromo-2-fluoro-phcnyl )-4-hydroxy-pipcridinc- 1 -carboxyl ate 4-Bromo-2-fluoro-l-iodo-benzene (CAS 105931-73-5) (5 g, 16.6 mmol, 1.1 equiv.) was dissolved in 80 ml of THF and n-butyllithium (1.6 M solution in hexanes) (10.4 ml, 16.6 mmol, 1.1 equiv.) was added dropwise at -76 °C. The reaction mixture was stirred at -76 °C for 1 hour. A solution of tert-butyl 4-oxopiperidine-l-carboxylate (CAS 79099-07-3) (3 g, 15.1 mmol) dissolved in 40 ml of THF was added dropwise at -76 °C. After the addition was complete, the reaction mixture was stirred without cooling bath for 2 hours. The reaction mixture was extracted with ethyl acetate and saturated NaHCCb-solution. The aqueous layer was backextracted with ethyl acetate. The organic layers were washed with water and brine. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a heptane:ethyl acetate 100:0 to 0:100 gradient to obtain the desired tert-butyl 4-(4-bromo-2-fluoro-phenyl)-4-hydroxy- piperidine-l-carboxylate (5.3 g, 94 % yield) as a white solid, MS: m/e = 272.1/274.1 (M- BOC+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With silver carbonate; palladium dichloride; CyJohnPhos In N,N-dimethyl acetamide at 150℃; for 2h; Inert atmosphere; | B.2.2.1 Ethyl 2-(4-bromo-2-fluorophenyl)-4-cyclopropylthieno[2,3-b]pyridine-6-carboxylate A mixture of intermediate D3 (390 mg, 1.14 mmol, purity 85%), 1-bromo-3-fluoro-4- iodobenzene (342 mg, 1.14 mmol), Ag2CO3 (941 mg, 3.41 mmol) in DMA (15 mL) was purged with N2. PdCl2 (20 mg, 0.114 mmol) and CyJohnPhos (80 mg, 0.228 mmol) were added. The mixture was purged with N2 then stirred at 150°C for 2 h. The mixture was cooled down to rt then water and EtOAc were added and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, evaporated and purified by preparative LC (irregular SiOH 15-40 µm, 24 g (0158) GraceResolv, mobile phase gradient: from Heptane/EtOAc 100:0 to 0:100). The fractions containing product were combined and evaporated under vacuum then the residue was purified again by reverse phase (spherical C1825 µm, 40 g YMC-ODS-25, mobile phase gradient 0.2% aq. NH4+HCO3-/MeCN from 50:50 to 0:100). The fractions containing product were combined and evaporated under vacuum to give intermediate D4 (46 mg, 10%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; toluene for 5h; Reflux; | 1.1-1; 1.5-1 General procedure: Methyl-2-bromobenzoate (40 g, 152.6 mmol), 1-naphthalenylboronic acid (31.5 g, 183.2 mmol), and tetrakis(triphenylphosphine)palladium (8.8 g, 7.62 mmol) were added to 1 L of toluene. Stirred. 2 M potassium carbonate (228 mL, 458 mmol) and 228 mL of ethanol were added and refluxed for 5 hours. After cooling to room temperature, it was extracted with ethyl acetate. Separated by column chromatography to obtain Intermediate 1-a (35 g, 87%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: 1-(phenylsulfonyl)bicyclo[1.1.0]butane With phenyllithium In tetrahydrofuran; dibutyl ether at -78℃; Stage #2: With zinc(II) chloride In tetrahydrofuran; dibutyl ether at -78 - 20℃; Stage #3: 1-bromo-3-fluoro-4-iodobenzene With trifuran-2-yl-phosphane; bis(dibenzylideneacetone)-palladium(0) In tetrahydrofuran at 40℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | Stage #1: 1-bromo-3-fluoro-4-iodobenzene With n-butyllithium In tetrahydrofuran; hexane at -70℃; for 0.5h; Stage #2: 1-Methyl-4-piperidone In tetrahydrofuran; hexane at -70℃; for 1h; | 11.1 Step 1. 4-(4-Bromo-2-fiuoro-phenyl)-1-methyl-piperidin-4-ol To a solution of 4-bromo-2-fiuoro-1-iodo-benzene {24.0 g, 79.7 mmol) in THF (400 mL) at -70 °C was added dropwise n-butyliitbium (2.5 M in hexane, 31.9 mL, 79.7 mmol). After stirring at -70 °C for 30 min, a solution of 1-methyipiperidin-4-one (9.01 g, 79.7 mmol) in THF (20 mL) was added dropwise. After stirring at -70 °C for 1 h, the reaction mixture was poured into sat. ammonium chloride solution and extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 5-66% ethyl acetate in petroleum ether to give the title compound (13.0 g, 57%). MS m/z: 289.8 [M•1j+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In tetrahydrofuran for 12h; Reflux; | P.1.a (a) Preparation of Compound Q-1 Bromo-3-fluoro-4-iodobenzene (50 g, 166.6 mmol) and 5-chloro-2-methoxyphenylboronic acid (31.1 g, 166.6 mmol) were dissolved in tetrahydrofuran (THF) (800 mL). 2 M sodium carbonate (Na2CO3) solution (250 mL) and tetrakis(triphenylphosphine)palladium (0) [Pd(PPh3)4] (3.8 g, 3 mol %) were added and the mixture was refluxed for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted three times with water and toluene. The toluene layer was separated, then dried over magnesium sulfate, filtered, and the filtrate was distilled under reduced pressure. The resulting mixture was recrystallized three times with chloroform and ethanol to give Compound Q-1 (27.5 g, yield: 51%, MS: [M+H]+=314). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In tetrahydrofuran; water for 24h; Reflux; | 7.7-1 Synthesis Example 7-1. Synthesis of compound 7-a After dissolving 4-bromo-2-fluoro-1-iodobenzene (100 g, 332 mmol) and (5-chloro-2-hydroxyphenyl) boronic acid (57.3 g, 332 mmol) in THF (1500 ml),Pd(PPh3)4 (7.68 g, 6.6 mmol) and 300 ml of 2M Na2CO3 aqueous solution were added and stirred under reflux for 24 hours.The reaction solution was cooled, and the organic layer was extracted with ethyl acetate and dried over anhydrous magnesium sulfate.The organic solvent was removed under reduced pressure and purified by column chromatography to obtain compound 7-a (69 g, yield 69%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene for 12h; Reflux; | 10.10-2 Synthesis Example 10-2. Synthesis of [Intermediate 10-b] In a round-bottom flask, [Intermediate 10-a] (20.8 g, 110 mmol), 1-bromo 3-fluoro 4-iodobenzene (28.7 g, 95 mmol), tetrakis(triphenylphosphine)palladium (33 g, 29 mmol), and sodium carbonate (30.3 g, 290 mmol) were put, followed by toluene (200 ml), ethanol (60 ml), and water (60 ml). The solution was stirred for 12 hours under reflux. After completion of the reaction, the reaction mixture was cooled to room temperature, extracted, and concentrated in a vacuum. Isolation of the concentrate by column chromatography afforded [Intermediate 10-b]. (22.3 g, 63%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In tetrahydrofuran for 12h; Reflux; | A.1 1) Preparation of Compound R-1 1-bromo-3-fluoro-4-iodobenzene (50 g, 166.6 mmol) and (5-chloro-2-methoxyphenyl) boronic acid (31.1 g, 166.6 mmol) were dissolved in 800 ml of tetrahydrofuran (THF). A 2 M sodium carbonate (Na2CO3) solution (250 mL) and tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4] (3.8 g, 3 mol %) were added thereto and refluxed for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, and the resulting mixture was extracted three times with water and toluene. After separating the toluene layer and drying with magnesium sulfate, the filtrate was distilled under reduced pressure, and the mixture obtained was recrystallized three times using chloroform and ethanol to obtain compound R-1 (29.7 g, yield 55%). MS: [M+H]+=314 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | With copper (I) iodide; potassium carbonate; <i>L</i>-proline In dimethyl sulfoxide at 90℃; for 3h; Inert atmosphere; | A Step A: 1-(4-bromo-2-fluorophenyl)-4-(dimethoxymethyl)piperidine Under an atmosphere of nitrogen, was placed 4-bromo-2-fluoro-1-iodobenzene (11.00 g, 36.79 mmol), DMSO (150 mL), 4-(dimethoxymethyl)piperidine (5.85 g, 36.7 mmol ), K2CO3(10.12 g, 73.33 mmol), L-proline (421 mg, 3.66 mmol), copper (I) iodide (700 mg, 3.66 mmol). The resulting solution was stirred for 3 hours at 90oC. The reaction mixture was cooled. The resulting solution was diluted with water (300 mL). The resulting solution was extracted with ethyl acetate (3 x 100 mL). The resulting mixture was washed with brine (2 x 50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated. Purification by silica gel column chromatography (1:5 ethyl acetate:petroleum ether) afforded 1.03 g (9%) of 1-(4-bromo- 2-fluorophenyl)-4-(dimethoxymethyl)piperidine as a light yellow solid. MS (ESI): m/z 286.10 [M+H]+ |
9% | With copper (I) iodide; potassium carbonate; <i>L</i>-proline In dimethyl sulfoxide at 90℃; for 3h; Inert atmosphere; | A Step A: 1-(4-bromo-2-fluorophenyl)-4-(dimethoxymethyl)piperidine Under an atmosphere of nitrogen, was placed 4-bromo-2-fluoro-1-iodobenzene (11.00 g, 36.79 mmol), DMSO (150 mL), 4-(dimethoxymethyl)piperidine (5.85 g, 36.7 mmol ), K2CO3(10.12 g, 73.33 mmol), L-proline (421 mg, 3.66 mmol), copper (I) iodide (700 mg, 3.66 mmol). The resulting solution was stirred for 3 hours at 90oC. The reaction mixture was cooled. The resulting solution was diluted with water (300 mL). The resulting solution was extracted with ethyl acetate (3 x 100 mL). The resulting mixture was washed with brine (2 x 50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated. Purification by silica gel column chromatography (1:5 ethyl acetate:petroleum ether) afforded 1.03 g (9%) of 1-(4-bromo- 2-fluorophenyl)-4-(dimethoxymethyl)piperidine as a light yellow solid. MS (ESI): m/z 286.10 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With tetrakis-(triphenylphosphine)-palladium; anhydrous sodium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 80 - 120℃; Inert atmosphere; | 2 Intermediate S1 (50 g, 0.23 mol) was added containing 350 ml of dioxane,In a 1000ML reactor of 150ml water,Then add 4-bromo-2-fluoroiodobenzene (75.9g, 0.25mol) to the system,Sodium carbonate (72.9g, 0.69mol),and replaced with nitrogen three times,Then add tetrakis(triphenylphosphine)palladium(1.2 g, 0.5%),The system was added to 80 - 120 °C,Fully react for 5-20h,Monitor the reaction with the liquid phase,Stop the reaction when the raw material is less than 1%,The temperature was lowered to below 50°C, introduced into 1000ml of water, and then extracted with dichloromethane to obtain an organic phase, which was dried with anhydrous sodium sulfate, and passed through a diatomaceous earth column to obtain a filtrate, which was concentrated under reduced pressure, and then used ethyl acetate. Recrystallization to obtain intermediate S4: 3-(2-fluoro-4-bromophenyl)-2-methylthioethernaphthalene, 62.1 g, HPLC=99.4%, yield 78%; |
[ 1235865-75-4 ]
Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate
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P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
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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