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CAS No. : | 130191-91-2 | MDL No. : | MFCD08062385 |
Formula : | C6H3BrF2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HHGOLZGZHXELSW-UHFFFAOYSA-N |
M.W : | 208.99 | Pubchem ID : | 7172027 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 36.08 |
TPSA : | 20.23 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.83 cm/s |
Log Po/w (iLOGP) : | 1.65 |
Log Po/w (XLOGP3) : | 2.46 |
Log Po/w (WLOGP) : | 3.27 |
Log Po/w (MLOGP) : | 3.1 |
Log Po/w (SILICOS-IT) : | 2.9 |
Consensus Log Po/w : | 2.68 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.13 |
Solubility : | 0.155 mg/ml ; 0.000742 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.53 |
Solubility : | 0.619 mg/ml ; 0.00296 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.24 |
Solubility : | 0.121 mg/ml ; 0.000577 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.4 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-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 |
---|---|---|
86.1% | With potassium carbonate In acetone at 60℃; | A mixture of 4-bromo-3,5-difiuoro-phenol (0.4 g, 1.91 mmol), l-bromo-2- methoxyethane (0.80 g, 5.74 mmol), and potassium carbonate (1.07 g, 7.66 mmol) in acetone (10 mL) was heated to 60 °C overnight. The reaction mixture was filtered and concentrated in vacuo. Flash chromatography (20% ethyl acetate/hexane) afforded 2-bromo-l,3-difluoro-5-(2-methoxy- ethoxy)-benzene (0.44 g, 86.1%) as a pale yellow oil. H NMR (400 MHz, DMSO-d6) ppm 3.29 (s, 3 H) 3.59 - 3.71 (m, 2 H) 4.07 - 4.19 (m, 2 H) 6.89 - 7.06 (m, 2 H) |
80% | With potassium carbonate In acetone |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 80 percent / K2CO3 / acetone 2: Pd(OAc)2; tBuONa; Pd(tBu)3 / toluene | ||
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / 60 °C 2: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 110 °C / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 80 percent / K2CO3 / acetone 2: Pd(OAc)2; tBuONa; Pd(tBu)3 / toluene 3: KI; K2CO3 / acetonitrile |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium carbonate / acetonitrile / 20 °C 2: tetrakis(triphenylphosphine) palladium(0) / toluene / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium carbonate / acetonitrile / 20 °C 2: tetrakis(triphenylphosphine) palladium(0) / toluene / 100 °C 3: phenyltrimethylammonium tribromide / methanol; dichloromethane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: potassium carbonate / acetonitrile / 20 °C 2: tetrakis(triphenylphosphine) palladium(0) / toluene / 100 °C 3: phenyltrimethylammonium tribromide / methanol; dichloromethane / 20 °C 4: potassium carbonate / acetonitrile / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: potassium carbonate / acetonitrile / 20 °C 2: tetrakis(triphenylphosphine) palladium(0) / toluene / 100 °C 3: phenyltrimethylammonium tribromide / methanol; dichloromethane / 20 °C 4: potassium carbonate / acetonitrile / 20 °C 5: palladium 10% on activated carbon; hydrogen / ethyl acetate / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: potassium carbonate / acetonitrile / 20 °C 2: tetrakis(triphenylphosphine) palladium(0) / toluene / 100 °C 3: phenyltrimethylammonium tribromide / methanol; dichloromethane / 20 °C 4: potassium carbonate / acetonitrile / 20 °C 5: palladium 10% on activated carbon; hydrogen / ethyl acetate / 20 °C 6: 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium carbonate In N,N-dimethyl-formamide at 50 - 60℃; for 14h; Microwave irradiation; | 2.1 2.1 Prepration of 5-(benzyloxy)-2-bromo-1,3-difluorobenzene 4-bromo -3,5-difluoro-phenol 7 g (33.49 mmol), benzyl bromide and 4 ml (40.18 mmol), K2CO3 13.8 g (100.47mmol) was dissolved in the DMF 83 ml. After stirring for 50 to 60 14 at hours was cooled to room temperature. It was diluted in EA (200 ml) and washed three times with water. The organic layer was dehydrated with Na2SO4, and concentrated under reduced pressure to give the title compound in 9.6 g (32.09 mmol, 96%) as a yellow liquid. |
With potassium carbonate In acetonitrile at 20℃; | ||
9.6 g | With potassium carbonate In N,N-dimethyl-formamide at 50 - 60℃; for 14h; Microwave irradiation; | 3.1 3.1. 5-(Benzyloxy)-2-bromo- 1 ,3-difluorobenzene A mixture of 4-bromo-3,5-difluorophenol (7 g, 33.49 mmol), benzyl bromide (4.0 mL, 40.18 mmol) and K2C03 (13.8 g, 100.47 mmol) in DMF (83 mL) was heated at 50°C to 60°C under microwave heating condition for 14 h. After cooling down to rt, the reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to afford the desired product (9.6 g) as a yellow oil.LC-MS (ESI, mlz) = 299.0 (M+H÷). |
9.6 g | With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 14h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With acetic acid; potassium bromide; In water; acetic acid; at 35℃; | General procedure: 0.11 g (1.0 mmol) of 4-methylphenol, 5 mL of acetic acid, 0.5 mL of water, and 0.12 g (1.0 mmol)potassium bromide were placed in round-bottomed flask. Then, 0.19 g (0.2 mmol)ZnAl-BrO3--LDHs was added in the flask under stirring at 35 C. After the addition, stirring wascontinued to the end of reaction (monitored by thin layer chromatography). The residualZnAl-BrO3--LDHs were removed by centrifugation. The product was extracted with 3 × 10 mLdichloromethane. The combined extract was washed with sodium sulfite solution, brine, and dried(Na2SO4). Evaporation of the solvent left the crude product. The crude product was purified bycolumn chromatography over silica gel (ethyl acetate-petroleum ether) to obtain pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran; toluene at 60℃; | 123.A To a solution of 4-bromo-3, 5-difluorophenol (5.0 g) , tert-butyl [ (IS) -2-hydroxy-l-methylethyl] carbamate (5 g) and triphenylphosphine (7.5 g) in THF (50 mL) was addeddiisopropyl azodicarboxylate (1.9 in toluene, 14 mL)dropwise at room temperature. The reaction mixture was stirred at 60 °C overnight and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford the title compound (5.1 g) . ¾ NMR (300 MHz, DMSO-d6) δ 1.10 (3H, d, J = 6.5 Hz), 1.33-1.42 (9H, m), 3.71-3.99 (3H, m) , 6.80-7.03 (3H, m) .MS (ESI+) : [M+H]+ 266.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / toluene; tetrahydrofuran / 60 °C 2.1: triethylamine / copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / toluene / 100 °C / Inert atmosphere 2.2: 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / toluene; tetrahydrofuran / 60 °C 2.1: triethylamine / copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / toluene / 100 °C / Inert atmosphere 2.2: 1 h / 20 °C 3.1: triethylamine / copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / toluene / 100 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / toluene; tetrahydrofuran / 60 °C 2.1: triethylamine / copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / toluene / 100 °C / Inert atmosphere 2.2: 1 h / 20 °C 3.1: triethylamine / copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / toluene / 100 °C / Inert atmosphere 4.1: perchloric acid; ethyl O-(2-mesitylenesulfonyl)acetohydroxamate / N,N-dimethyl-formamide; tetrahydrofuran / 0.83 h / 0 - 20 °C 4.2: 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: triphenylphosphine; di-isopropyl azodicarboxylate / toluene; tetrahydrofuran / 60 °C 2.1: triethylamine / copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / toluene / 100 °C / Inert atmosphere 2.2: 1 h / 20 °C 3.1: triethylamine / copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride / toluene / 100 °C / Inert atmosphere 4.1: perchloric acid; ethyl O-(2-mesitylenesulfonyl)acetohydroxamate / N,N-dimethyl-formamide; tetrahydrofuran / 0.83 h / 0 - 20 °C 4.2: 20 °C 5.1: hydrogenchloride / ethyl acetate / 0.5 h / 20 °C 5.2: 0.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine In dichloromethane at 20℃; Inert atmosphere; | 210.B 2-((liS',2i?)-2-(l-(5-methoxypyrimidin-2-yl)piperidin-4-yl)cyclopropyl)ethanol (1.4 g, 5.05 mmol), 4-bromo-3,5-difluorophenol (1.26 g, 6.06 mmol) and triphenylphosphine (1.98 g, 7.57 mmol) were dissolved in dichloromethane (25 ml). The mixture was stirred at RT under N2 for 5 min and diisopropyl azodicarboxylate (1.53 g, 7.57 mmol) added. The mixture was stirred at RT overnight. The mixture was diluted with DCM (50 ml), washed with 0.5 N NaOH (50 ml), brine, dried over sodium sulfate and the volatiles removed in vacuo. The residue was purified by silica gel column chromatography (50 g SNAP, 10-40% EtOAc in hexane) to afford 1.86 g (79%) of the titled compound. LC/MS (m/z) 469 (Μ+Η)+· Rf was 0.3 30% EtOAc in hexanes (blue spot on CAM stain) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine In dichloromethane at 0 - 20℃; for 3h; | 229.B Step B: 2-(4-{(li?,2S)-2-[2-(4-bromo-3,5-difluorophenoxy)ethyl]cyclopropyl}piperidin-l-yl)-5- ethoxypyrimidine DIAD (2.45 mL, 12.6 mmol) was slowly added to a solution of 2-((lS,2i?)-2-(l-(5- ethoxypyrimidin-2-yl)piperidin-4-yl)cyclopropyl)ethanol (2.45 g, 8.41 mmol), 4-bromo-3,5- difluorophenol (1.93 g, 9.25 mmol), and triphenylphosphine (3.31 g, 12.6 mmol) in DCM (30 mL) that had been cooled to 0 °C. The ice bath was removed and the resulting mixture was stirred at rt for 3 hrs. The reaction mixture was diluted with DCM (20 mL) and washed with a 2 N NaOH solution (30 mL x 1). The organic phase was dried over MgS04, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (KP-Sil 100 g SNAP column, Biotage system) eluting with 5-40% EtOAc:hexanes 12 CV to afford the title compound. LC/MS (m/z): 482 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In dichloromethane; at 20℃; | Example 94 6-[4-[2 6-difluoro-4-(oxetan-3-yloxy)phenyl]piperazin- 1 -yl]- 1 -methyl-5H-pyrazolo[3 4- d]pyrimidin-4-one (1-85) Condensation of <strong>[26272-83-3]3-(4-methylbenzenesulfonate)-3-oxetanol</strong> (CASRN 26272-83-3) and 4- bromo-3,5-difluorophenol under Mirsunobu conditions (PPh3,DIAD, DCM, RT) afforded 3-(4- bromo-3,5-difluoro-phenoxy)-oxetane which was condensed teri-butyl piperazine-l-carboxylate utilizing palladium coupling described in Intermediate I. Removal of the boc (TFA/DCM) and condensation with Intermediate A (DIPEA, EtOH, 140 C) affords the title compound: H NMR (300MHz, DMSO-i delta ppm 10.96 (s, 1H), 7.80 (s, 1H), 6.61 (d, J = 10.8 Hz, 2H), 5.30-5.26 (m, 1H), 4.95-4.91 (m, 2H), 4.54-4.50 (m, 2H), 3.76-3.74 (m, 7H), 3.10-3.09 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: potassium carbonate / acetone / 60 °C 2.1: n-butyllithium / diethyl ether; hexane / 2 h / -78 °C / Inert atmosphere 2.2: 2 h / -78 - 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: potassium carbonate / acetone / 60 °C 2: caesium carbonate; copper(l) iodide; 2-Picolinic acid / 1,4-dioxane 3: hydrogenchloride 4: sodium hydride / mineral oil; N,N-dimethyl-d<SUB>6</SUB>-formamide 5: hydrogenchloride / methanol 6: N-ethyl-N,N-diisopropylamine / ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 60 °C 2: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 110 °C / Heating 3: N-ethyl-N,N-diisopropylamine / ethanol / 0.5 h / 140 °C / Microwave irradiation; Sealed tube |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); 2,6-di-tert-butyl-4-methyl-phenol; potassium carbonate; tricyclohexylphosphine In 1,4-dioxane at 100℃; for 1h; Inert atmosphere; | 35 3,5-Difluoro-4-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazoI-4-yl]-phenol A mixture of 4-bromo-2,3-difluorophenol (707 mg), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yI)-1 H-pyrazol-1 -yl)propan-2-ol (900 mg), potassium carbonate(1 .40 g), 2,6-di-tert-butyl-4-methylphenol (373 mg), tricyclohexylphosphine (76 mg), and tris(dibenzylideneacetone)dipalladium(0) (124 mg) inl,4-dioxane (4 mL) and water (1.5 mg) is heated in a microwave oven under a nitrogen atmosphere to 100 °C for 1 h. The reaction mixture is diluted with water and extracted with ethyl acetate. The combined extracts are concentrated in vacuo and the residue chromatographedon silica gel (cyclohexane/ethyl acetate 100:0-÷60:40) to give the title compound. Mass spectrum (EDj: mlz = 268 [M]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate In acetonitrile for 2h; Inert atmosphere; Reflux; | A22.a a- Synthesis of Int. 71 a- Synthesis of Int. 71: Under N2, a sol. of 4-bromo-3,5-difluorophenol (3.0 g, 14.4 mmol) in ACN (37 mL) was treated with K2CO3 (4.0 g, 29 mmol) and 8 (2.4 mL, 14.4 mmol) and the r.m. was stirred under reflux for 2h. The sol. was filtered and concentrated to give 4.9 g of Int. 71, colorless oil (100%). The product was used like this in the next step |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 14 h / 50 - 60 °C / Microwave irradiation 2: sodium t-butanolate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 0.33 h / 130 °C / Microwave irradiation 3: palladium 10% on activated carbon; hydrogen / methanol / 3 h / 20 °C | ||
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 14 h / 90 °C / Microwave irradiation 2: sodium t-butanolate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 0.33 h / 130 °C / Microwave irradiation 3: palladium 10% on activated carbon; hydrogen / methanol / 3 h / 20 °C | ||
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 14 h / 50 - 60 °C / Microwave irradiation 2: sodium t-butanolate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 0.33 h / 130 °C / Microbiological reaction 3: hydrogen; palladium 10% on activated carbon / methanol / 3 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 14 h / 50 - 60 °C / Microwave irradiation 2: sodium t-butanolate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 0.33 h / 130 °C / Microwave irradiation 3: palladium 10% on activated carbon; hydrogen / methanol / 3 h / 20 °C 4: potassium carbonate / N,N-dimethyl-formamide / 17 h / 50 - 60 °C | ||
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 14 h / 90 °C / Microwave irradiation 2: sodium t-butanolate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 0.33 h / 130 °C / Microwave irradiation 3: palladium 10% on activated carbon; hydrogen / methanol / 3 h / 20 °C 4: potassium carbonate / N,N-dimethyl-formamide / 17 h / 50 - 60 °C | ||
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 14 h / 50 - 60 °C / Microwave irradiation 2: sodium t-butanolate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 0.33 h / 130 °C / Microbiological reaction 3: hydrogen; palladium 10% on activated carbon / methanol / 3 h 4: potassium carbonate / N,N-dimethyl-formamide / 17 h / 50 - 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: potassium carbonate / N,N-dimethyl-formamide / 14 h / 50 - 60 °C / Microwave irradiation 2: sodium t-butanolate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 0.33 h / 130 °C / Microwave irradiation 3: palladium 10% on activated carbon; hydrogen / methanol / 3 h / 20 °C 4: potassium carbonate / N,N-dimethyl-formamide / 17 h / 50 - 60 °C 5: hydrogenchloride / water; dichloromethane; methanol / 4 h / 20 °C | ||
Multi-step reaction with 5 steps 1: potassium carbonate / N,N-dimethyl-formamide / 14 h / 50 - 60 °C / Microwave irradiation 2: sodium t-butanolate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 0.33 h / 130 °C / Microbiological reaction 3: hydrogen; palladium 10% on activated carbon / methanol / 3 h 4: potassium carbonate / N,N-dimethyl-formamide / 17 h / 50 - 60 °C 5: hydrogenchloride / methanol; dichloromethane / 4 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: potassium carbonate / N,N-dimethyl-formamide / 14 h / 50 - 60 °C / Microwave irradiation 2: sodium t-butanolate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 0.33 h / 130 °C / Microwave irradiation 3: palladium 10% on activated carbon; hydrogen / methanol / 3 h / 20 °C 4: potassium carbonate / acetonitrile / 12 h / Reflux | ||
Multi-step reaction with 5 steps 1: potassium carbonate / N,N-dimethyl-formamide / 14 h / 50 - 60 °C / Microwave irradiation 2: sodium t-butanolate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 0.33 h / 130 °C / Microbiological reaction 3: hydrogen; palladium 10% on activated carbon / methanol / 3 h 4: potassium carbonate / acetonitrile / 12 h / Reflux 5: caesium carbonate / N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 14 h / 50 - 60 °C / Microwave irradiation 2: sodium t-butanolate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 0.33 h / 130 °C / Microwave irradiation 3: palladium 10% on activated carbon; hydrogen / methanol / 3 h / 20 °C 4: potassium carbonate / N,N-dimethyl-formamide / 21 h / 20 °C | ||
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 14 h / 90 °C / Microwave irradiation 2: sodium t-butanolate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 0.33 h / 130 °C / Microwave irradiation 3: palladium 10% on activated carbon; hydrogen / methanol / 3 h / 20 °C 4: potassium carbonate / N,N-dimethyl-formamide / 17 h / 20 °C | ||
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 14 h / 50 - 60 °C / Microwave irradiation 2: sodium t-butanolate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 0.33 h / 130 °C / Microbiological reaction 3: hydrogen; palladium 10% on activated carbon / methanol / 3 h 4: potassium carbonate / N,N-dimethyl-formamide / 17 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 14 h / 50 - 60 °C / Microwave irradiation 2: sodium t-butanolate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 0.33 h / 130 °C / Microwave irradiation 3: palladium 10% on activated carbon; hydrogen / methanol / 3 h / 20 °C 4: potassium carbonate / acetonitrile / 12 h / Reflux | ||
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 14 h / 90 °C / Microwave irradiation 2: sodium t-butanolate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 0.33 h / 130 °C / Microwave irradiation 3: palladium 10% on activated carbon; hydrogen / methanol / 3 h / 20 °C 4: potassium carbonate / acetonitrile / 12 h / Reflux | ||
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 14 h / 50 - 60 °C / Microwave irradiation 2: sodium t-butanolate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 0.33 h / 130 °C / Microbiological reaction 3: hydrogen; palladium 10% on activated carbon / methanol / 3 h 4: potassium carbonate / acetonitrile / 12 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.75 g | With potassium carbonate In acetonitrile at 80℃; for 4h; | 42 Reference Preparation Example 42 A mixture of 1.35g of 14A (mentioned in the Reference Preparation Example 14), 1.00g of 4-bromo-3,5-difluorophenol, 1.32g of potassium carbonate, and 19mL of acetonitrile was heated and stirred at 80°C for 4 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The residue thus obtained was washed with methyl tert-butyl ether and hexane to obtain 1.75g of 1-[2-(4-bromo-3,5-difluorophenoxymethyl)-3-methylphenyl]-4-methyl-1,4-dihydrotetrazol-5-one (Referred to as 42A). |
1.75 g | With potassium carbonate In acetonitrile at 80℃; for 4h; | 42 Reference Production Example 42 Reference Production Example 42 (0701) A mixture of 1.35 g of 14A mentioned in Reference Production Example 14, 1.00 g of 4-bromo-3,5-difluorophenol, 1.32 g of potassium carbonate, and 19 mL of acetonitrile was stirred with heating at 80° C. for 4 hours. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue thus obtained was washed with hexane and methyl tert-butyl ketone to obtain 1.75 g of 1-[2-(4-bromo-3,5-difluorophenoxymethyl)-3-methylphenyl]-4-methyl-1,4-dihydrotetrazol-5-one (referred to as 42A). (0702) 1H-NMR (CDCl3) δ: 7.47-7.40 (2H, m), 7.29 (1H, dd, J=7.6, 1.4 Hz), 6.55-6.49 (2H, m), 4.98 (2H, s), 3.67 (3H, s), 2.47 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-tert-butyl-diazodicarboxylate In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 15h; | 11 Preparation of 3-(4-bromo-3,5-difluorophenoxy)-l-propylazetidine To a tetrahydrofuran (10 mL) solution of l-propylazetidin-3-ol (1.479 g, 12.8 mmol, 1.0 equiv.), 4-bromo-3,5-difluorophenol (3.220 g, 15.4 mmol, 1.2 equiv.) were added triphenylphosphine (4.042 g, 15.4 mmol, 1.2 equiv.), and diisopropyl azodicarboxylate (3.034 ml, 15.4 mmol, 1.2 equiv.) at 0 C. The resulting mixture was stirred at room temperature for 3 h. TLC analysis (5% MeOH/DCM) indicated that the starting phenol still was present with strong UV absorbance. The mixture was stirred at room temp, for an additional 12 h. The mixture was concentrated and dissolved in DCM and loaded on to a silica gel column (40 g, 0-5% MeOH/DCM). Fractions 7-13 were collected and concentrated under reduced pressure to give a white solid. IHNMR indicated product along with triphenylphosphine oxide. The residue was dissolved in EA (100 mL) and 4 N HC1 in dioxane (10 mL) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated to an oil. This oil was cooled in an ice water bath and diethylether (100 mL) was added at which point a white solid formed. The mixture was sonicated and stirred. The white solid was filtered and rinsed with diethylether. The resulting solid was added sat'd sodium bicarbonate solution and EA and stirred at room temperature for 30 min and layers were separated. Organic layer was washed with brine, dried over anhy. sodium sulfate, filtered and concentrated to afford the title compound as a pale yellow oil. IHNMR (300 MHz, CDC13), δ 6.40 (d, J = 7.5 Hz, 2H), 4.74 - 4.67 (m, 1H), 3.78 (t, J = 7.2 Hz, 2H), 3.07 (dt, J = 7.4, 3.0 Hz, 2H), 2.46 (t, J = 7.5 Hz, 2H), 1.45 - 1.33 (m, 2H), 0.90 (t, J = 7.5 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8% | With palladium diacetate; cesium fluoride; catacxium A In 1,4-dioxane; water at 80℃; for 1h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate In tetrahydrofuran at 70℃; for 4h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate In N,N-dimethyl-formamide at 90℃; for 2h; | A Step A: 2-bromo-5- (difluoromethoxy) -1, 3-difluorobenzene. Cs2CO3(2339 mg, 7.18 mmol) was added to a mixture of 4-bromo-3, 5-difluorophenol (1000 mg, 4.78 mmol) and sodium 2-chloro-2, 2-difluoroacetate (1459 mg, 9.57 mmol) in DMF (9570 μl) at 90 C and then stirred for 2 h. Then the mixture was filtered to remove the solid, and washed with Et2O. The filtrate was concentrated to remove solvent. The resulting residue was purified by silica gel column chromatography to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.72% | With caesium carbonate In acetonitrile at 80℃; for 12h; | 13.B Step B: Cesium carbonate (2.34g, 7.18mmol, 1.00eq) and 1,2-dibromoethane (6.74g, 35.90mmol, 2.71mL,5.00eq) were added to a solution of compound 40 (1.50g, 7.18mmol, 1.00eq) in acetonitrile (10.00mL), the reactionsolution was stirred at 80°C for 12 hours, then poured into 50mL water, extracted twice with 50mL ethyl acetate eachtime. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified bysilica gel column chromatography (PE/EA=10/1) to give the product 41 as a yellow oil (1.40g, 4.43mmol, yield 61.72%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2 g | With boron tribromide In dichloromethane at 25℃; for 12h; | 13.A Embodiment 13 Step A: Boron tribromide (6.74g, 26.91mmol, 2.59mL, 3.00eq) was added dropwise to a solution of compound39 (2.00g, 8.97mmol, 1.00eq) in dichloromethane (20.00mL). After completion of the addition, the reaction solution wasstirred at 25°C for 12 hours, then quenched by the dropwise addition of 40mL methanol, concentrated to give a crudeproduct, which was purified by silica gel column chromatography to give the product 40 as a brown oil (2g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With sodium t-butanolate In tetrahydrofuran at 25℃; for 3h; | 3 4-Bromo-3,5-difluorophenyl trifluoromethanesulfonate To a solution of 4-bromo-3,5-difluorophenol (300 mg, 1.44 mmol) in THF (5 mL) is added NaOtBu (276 mg, 2.9 mmol) and PhN(SC CF3)2 (569 mg, 1.6 mmol) at 25 °C. The resulting mixture is stirred at 25 °C for 3 h. The reaction is quenched with water (10 mL), extracted with EtOAc (20 mL x 3), and dried over Na2S04. The solvent is concentrated under reduced pressure, and the residue purified by silica gel chromatography, eluting with EtOAc in petroleum ether (0-10%) to give 4-bromo-3,5-difluorophenyl trifluoromethanesulfonate (120 mg, 25% yield) as a colorless oil. Formula: C7FhBrF503S Exact Mass; 339.88, Molecular Weight: 341.05. MS (ESI+) [M+H]+ calcd for (C7H2BrF503SH+) 340.89, no MS signal. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.67% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; anhydrous sodium carbonate In tetrahydrofuran; methanol; lithium hydroxide monohydrate at 100℃; for 12.3333h; Inert atmosphere; | 41.1 Step 1: To a stirred solution of 4-bromo-3,5-difluoro-phenol (2.5 g, 11.96 mmol) in THF (20 mL) Methanol (5 mL) and Water (5 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxylate (5.55 g, 17.94 mmol) and degassed with N2 for 20 minutes. Pd(dppf)C12 .Dichloromethane (0.98 g, 1.20 mmol), Sodium carbonate (3.80 g, 35.89 mmol, 1.50 mL) were added to the reaction mixture and heated at 100 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to get crude which was purified by column chromatography on silica gel eluted with 20 % ethyl acetate in petroleum ether to yield tert-butyl 4-(2,6-difluoro-4-hydroxy-phenyl)-3,6-dihydro-2H-pyridine-l-carboxylate (3.0 g, 8.09 mmol, 67.67% yield) as an off white solid. LCMS (ESI-): 310.1 [M-H]-. |
67.67% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; anhydrous sodium carbonate In tetrahydrofuran; methanol; lithium hydroxide monohydrate at 100℃; for 12.3333h; Inert atmosphere; | 41.1 Step 1: To a stirred solution of 4-bromo-3,5-difluoro-phenol (2.5 g, 11.96 mmol) in THF (20 mL) Methanol (5 mL) and Water (5 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxylate (5.55 g, 17.94 mmol) and degassed with N2 for 20 minutes. Pd(dppf)C12 .Dichloromethane (0.98 g, 1.20 mmol), Sodium carbonate (3.80 g, 35.89 mmol, 1.50 mL) were added to the reaction mixture and heated at 100 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to get crude which was purified by column chromatography on silica gel eluted with 20 % ethyl acetate in petroleum ether to yield tert-butyl 4-(2,6-difluoro-4-hydroxy-phenyl)-3,6-dihydro-2H-pyridine-l-carboxylate (3.0 g, 8.09 mmol, 67.67% yield) as an off white solid. LCMS (ESI-): 310.1 [M-H]-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.3% | at 25 - 30℃; for 2h; | 6 At room temperature (25-30°C), 41.0g (0.5mol) N-methylimidazole and 104.5g (0.5mol) 3,5-difluoro-4-bromophenol were added to a 500mL three-necked flask, and nitrogen was passed under stirring. After evacuating the air, add 75.4g (0.5mol) tert-butyldimethylsilyl chloride dropwise (the rate of dripping is subject to the control system temperature of 25-30°C), after about 1 hour of dropwise addition, continue at this temperature Reaction for 1h to the end of the reaction, then the mixture in the three-necked flask was placed in a 1L separatory funnel to stand for separation, and the upper layer was 2,6-difluoro-4-(tert-butyldimethylsiloxy)bromobenzene , the lower layer is N-methylimidazole hydrochloride. 2,6-difluoro-4-(tert-butyldimethylsiloxy)bromobenzene was washed with water (50 mL×1, the washed aqueous phase was used to prepare the subsequent aqueous sodium tetrafluoroborate solution), and dried over sodium sulfate to obtain 2,6-Difluoro-4-(tert-butyldimethylsiloxy)bromobenzene 147.5g, the yield is 91.3%, and the purity is more than 99.1% detected by GC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium carbonate In N,N-dimethyl-formamide at 90℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere 2: tetrakis-(triphenylphosphine)-palladium; potassium carbonate / toluene; lithium hydroxide monohydrate; ethanol / Inert atmosphere; Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere 2: tetrakis-(triphenylphosphine)-palladium; potassium carbonate / toluene; lithium hydroxide monohydrate; ethanol / Inert atmosphere; Reflux 3: bromine / chloroform / 2 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere 2: tetrakis-(triphenylphosphine)-palladium; potassium carbonate / toluene; lithium hydroxide monohydrate; ethanol / Inert atmosphere; Reflux 3: bromine / chloroform / 2 h / 0 - 20 °C 4: tris-(dibenzylideneacetone)dipalladium(0); tris-(o-tolyl)phosphine / toluene / 6 h / Inert atmosphere; Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 90 °C / Inert atmosphere 2: tetrakis-(triphenylphosphine)-palladium; potassium carbonate / toluene; lithium hydroxide monohydrate; ethanol / Inert atmosphere; Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 90 °C / Inert atmosphere 2: tetrakis-(triphenylphosphine)-palladium; potassium carbonate / toluene; lithium hydroxide monohydrate; ethanol / Inert atmosphere; Reflux 3: bromine / chloroform / 2 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: potassium carbonate / N,N-dimethyl-formamide / 90 °C / Inert atmosphere 2: tetrakis-(triphenylphosphine)-palladium; potassium carbonate / toluene; lithium hydroxide monohydrate; ethanol / Inert atmosphere; Reflux 3: bromine / chloroform / 2 h / 0 - 20 °C 4: tris-(dibenzylideneacetone)dipalladium(0); tris-(o-tolyl)phosphine / toluene / 6 h / Inert atmosphere; Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: potassium carbonate / N,N-dimethyl-formamide / 90 °C / Inert atmosphere 2: tetrakis-(triphenylphosphine)-palladium; potassium carbonate / toluene; lithium hydroxide monohydrate; ethanol / Inert atmosphere; Reflux 3: bromine / chloroform / 2 h / 0 - 20 °C 4: tris-(dibenzylideneacetone)dipalladium(0); tris-(o-tolyl)phosphine / toluene / 6 h / Inert atmosphere; Reflux 5: NBS / tetrahydrofuran / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 16h; | 15 Synthesis of compound 15-2 At room temperature, compound 15-1 (50 g, 240.46 mmol), N,N-diisopropylethylamine (59.3 mL, 359 mmol)It was dissolved in dichloromethane (1000 mL), chloromethyl methyl ether (21.8 mL, 289.73 mmol) was slowly added at 0°C, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was poured into saturated aqueous sodium carbonate solution (1000 mL), and extracted with dichloromethane (1000 mL×3). The organic phases were combined, washed successively with 1M hydrochloric acid (2000 mL) and saturated brine (2000 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was separated by column chromatography (SiO2, petroleum ether/ethyl acetate=1/1) to obtain compound 15-2. |