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CAS No. : | 1107627-14-4 | MDL No. : | MFCD18398719 |
Formula : | C8H6BrClO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | DBKFYOHGPURQCZ-UHFFFAOYSA-N |
M.W : | 249.49 | Pubchem ID : | 53751442 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 50.43 |
TPSA : | 26.3 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.63 cm/s |
Log Po/w (iLOGP) : | 2.36 |
Log Po/w (XLOGP3) : | 3.09 |
Log Po/w (WLOGP) : | 2.89 |
Log Po/w (MLOGP) : | 3.24 |
Log Po/w (SILICOS-IT) : | 3.01 |
Consensus Log Po/w : | 2.92 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.57 |
Solubility : | 0.0669 mg/ml ; 0.000268 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.31 |
Solubility : | 0.122 mg/ml ; 0.00049 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.95 |
Solubility : | 0.0282 mg/ml ; 0.000113 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.67 |
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 |
---|---|---|
A.2.27.1 Synthesis of <strong>[56961-26-3]2-bromo-3-chlorobenzoic acid</strong> methyl ester To a solution of <strong>[56961-26-3]2-bromo-3-chlorobenzoic acid</strong> (7.29 mmol) in 20 mL DCM and 1 mL DMF was added 1.06 mL thionyl chloride. After stirring at RT overnight, 5 mL MeOH were added and stirring was continued at RT for 1 h. The reaction mixture was cooled in an ice bath, quenched by adding a sat. aq. NaHC03 solution and extracted twice with DCM. The combined organic layers were dried over MgS04 and concentrated in vacuo to give the desired product as colorless oil. LC-MS (C): tR = 0.86 min; [M+CH3CN+H]+: 291 .94. | ||
To a solution of <strong>[56961-26-3]2-bromo-3-chlorobenzoic acid</strong> (7.29 mmol) in 20 mL DCM and 1 mL DMF was added 1.06 mL thionyl chloride. After stirring at RT overnight, 5 mL MeOH were added and stirring was continued at RT for 1 h. The reaction mixture was cooled in an ice bath, quenched by adding a sat. aq. NaHCO3 solution and extracted twice with DCM. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as colorless oil. LC-MS (C): tR=0.86 min; [M+CH3CN+H]+: 291.94. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 90 °C 2: zinc(II) chloride; lithium borohydride / tetrahydrofuran / 60 °C | ||
Multi-step reaction with 2 steps 1.1: N,N-dimethyl-formamide / 90 °C 1.2: 0.5 h / 20 °C 2.1: zinc(II) chloride; lithium borohydride / tetrahydrofuran / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.61% | In N,N-dimethyl-formamide at 90℃; for 1.2h; | 10.2 Step 2. methyl 3-chloro-2-cyanobenzoate (10.3) A solution of methyl 2-bromo-3-chlorobenzoate (10.2) (0.5 g, 2.008 mmol) in DMF (5 mL) were added CuCN (0.197 g, 2.2 mmol) and reaction mixture were heated at 90° C. temperature for 1.2 h. The reaction mixture was transferred into water (50 mL) and extracted with ethyl acetate (2×50 mL) and the combined organic phases were washed with brine (50 mL), dried with MgSO4, filtered, and then concentrated in vacuo. The residue was purified by column chromatography (0-50% gradient elution EtOAc in iso-hexane) to afford the title compound 10.3 (0.25 g, 63.61%). m/z 195 [M+H]+ |
In N,N-dimethyl-formamide at 90℃; | A.2.27.2 A.2.27.2 Synthesis of 3-chloro-2-cyanobenzoic acid methyl ester A.2.27.2 Synthesis of 3-chloro-2-cyanobenzoic acid methyl ester To a solution of 2-bromo-3-chlorobenzoic acid methyl ester (3.86 mmol) in 4 mL DMF was added CuCN (4.24 mmol) and the reaction mixture was heated to 90°C overnight. After cooling to 10°C, 10 mL EtOAc and 3 mL 1 M NaOH solution were added and stirring was continued at RT for 30 min. The aq. phase was separated and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgS04 and concentrated in vacuo. Purification by preparative LC-MS (method L) gives the desired product as white solid. LC-MS (C): tR = 0.78 min; [M+H]+: 196.02. | |
Stage #1: 2-bromo-3-chlorobenzoic acid methyl ester; copper(l) cyanide In N,N-dimethyl-formamide at 90℃; Stage #2: With sodium hydroxide In N,N-dimethyl-formamide at 20℃; for 0.5h; | A.2.27.2 A.2.27.2 Synthesis of 3-chloro-2-cyanobenzoic acid methyl ester To a solution of 2-bromo-3-chlorobenzoic acid methyl ester (3.86 mmol) in 4 mL DMF was added CuCN (4.24 mmol) and the reaction mixture was heated to 90° C. overnight. After cooling to 10° C., 10 mL EtOAc and 3 mL 1M NaOH solution were added and stirring was continued at RT for 30 min. The aq. phase was separated and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by preparative LC-MS (method L) gives the desired product as white solid. LC-MS (C): tR=0.78 min; [M+H]+: 196.02. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water for 8h; Heating; | 3.2 Step 2: Synthesis of methyl 3-chloro-2-(dibenzo[b,e][1,4]dioxin-2-yl)benzoate To a solution of 2- (dibenzo [b, e] [1,4] dioxin-2-yl) -4,4,5,5-tetramethyl-1,3,2-dioxabororane(73 g, 0.235 mol), methyl2-Bromo-3-chlorobenzoate (70.3 g, 0.282 mol) and Pd (PPh3) 4 (13.5 g, 0.011 mol), 2M Na2CO3 saturated aqueous solution (352 ml) and 1,4-dioxane (2 L) were added and dissolved therein, followed by heating and stirring for 8 hours. After completion of the reaction, distilled water was added and the organic layer was extracted with ethyl acetate. The obtained organic layer was dried over Na2SO4, distilled under reduced pressure and then purified by column chromatography to obtain methyl 3-chloro-2-(dibenzo[b,e][1,4]dioxin-2-yl)benzoate (75.4 g, yield 91%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: bis(pinacol)diborane With bis(1,5-cyclooctadiene)diiridium(I) dichloride; 4,4'-di-tert-butyl-2,2'-bipyridine In n-heptane at 85℃; Inert atmosphere; Stage #2: 2-bromo-3-chlorobenzoic acid methyl ester In n-heptane at 85℃; Inert atmosphere; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: bis(1,5-cyclooctadiene)diiridium(I) dichloride; 4,4'-di-tert-butyl-2,2'-bipyridine / n-heptane / 85 °C / Inert atmosphere 1.2: 85 °C / Inert atmosphere 2.1: copper dichloride; copper(l) chloride; potassium hexafluorophosphate; triethylamine / acetonitrile / 0.33 h / 0 °C 2.2: 42 h / 0 °C / Flow reactor 2.3: pH < 1 3.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / ethyl acetate / 30 °C / Inert atmosphere 4.1: lithium borohydride / 2-methyltetrahydrofuran; methanol / 2 h / 10 - 23 °C 5.1: triethylamine / dichloromethane / 18 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: bis(1,5-cyclooctadiene)diiridium(I) dichloride; 4,4'-di-tert-butyl-2,2'-bipyridine / n-heptane / 85 °C / Inert atmosphere 1.2: 85 °C / Inert atmosphere 2.1: copper dichloride; copper(l) chloride; potassium hexafluorophosphate; triethylamine / acetonitrile / 0.33 h / 0 °C 2.2: 42 h / 0 °C / Flow reactor 2.3: pH < 1 3.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / ethyl acetate / 30 °C / Inert atmosphere 4.1: lithium borohydride / 2-methyltetrahydrofuran; methanol / 2 h / 10 - 23 °C 5.1: 1H-imidazole / N,N-dimethyl-formamide / 18 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: bis(1,5-cyclooctadiene)diiridium(I) dichloride; 4,4'-di-tert-butyl-2,2'-bipyridine / n-heptane / 85 °C / Inert atmosphere 1.2: 85 °C / Inert atmosphere 2.1: copper dichloride; copper(l) chloride; potassium hexafluorophosphate; triethylamine / acetonitrile / 0.33 h / 0 °C 2.2: 42 h / 0 °C / Flow reactor 2.3: pH < 1 3.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / ethyl acetate / 30 °C / Inert atmosphere 4.1: lithium borohydride / 2-methyltetrahydrofuran; methanol / 2 h / 10 - 23 °C 5.1: pyridinium p-toluenesulfonate / ethyl acetate / 3 h / 55 °C 6.1: potassium carbonate; Trimethylacetic acid; cyclohexyldiphenylphosphine; tris(dibenzylideneacetone)dipalladium(0) chloroform complex / tetrahydrofuran; toluene / 4 h / 90 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: bis(1,5-cyclooctadiene)diiridium(I) dichloride; 4,4'-di-tert-butyl-2,2'-bipyridine / n-heptane / 85 °C / Inert atmosphere 1.2: 85 °C / Inert atmosphere 2.1: copper dichloride; copper(l) chloride; potassium hexafluorophosphate; triethylamine / acetonitrile / 0.33 h / 0 °C 2.2: 42 h / 0 °C / Flow reactor 2.3: pH < 1 3.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / ethyl acetate / 30 °C / Inert atmosphere 4.1: lithium borohydride / 2-methyltetrahydrofuran; methanol / 2 h / 10 - 23 °C 5.1: pyridinium p-toluenesulfonate / ethyl acetate / 3 h / 55 °C 6.1: palladium diacetate; potassium acetate; 1,4-di(diphenylphosphino)-butane / toluene / 18 h / 90 °C / Inert atmosphere; Glovebox 7.1: hydrogenchloride / acetonitrile; water / 3 h / 60 °C | ||
Multi-step reaction with 7 steps 1.1: bis(1,5-cyclooctadiene)diiridium(I) dichloride; 4,4'-di-tert-butyl-2,2'-bipyridine / n-heptane / 85 °C / Inert atmosphere 1.2: 85 °C / Inert atmosphere 2.1: copper dichloride; copper(l) chloride; potassium hexafluorophosphate; triethylamine / acetonitrile / 0.33 h / 0 °C 2.2: 42 h / 0 °C / Flow reactor 2.3: pH < 1 3.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / ethyl acetate / 30 °C / Inert atmosphere 4.1: lithium borohydride / 2-methyltetrahydrofuran; methanol / 2 h / 10 - 23 °C 5.1: pyridinium p-toluenesulfonate / ethyl acetate / 3 h / 55 °C 6.1: potassium carbonate; Trimethylacetic acid; cyclohexyldiphenylphosphine; tris(dibenzylideneacetone)dipalladium(0) chloroform complex / tetrahydrofuran; toluene / 4 h / 90 °C / Inert atmosphere 7.1: hydrogenchloride / acetonitrile; water / 3 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: bis(1,5-cyclooctadiene)diiridium(I) dichloride; 4,4'-di-tert-butyl-2,2'-bipyridine / n-heptane / 85 °C / Inert atmosphere 1.2: 85 °C / Inert atmosphere 2.1: copper dichloride; copper(l) chloride; potassium hexafluorophosphate; triethylamine / acetonitrile / 0.33 h / 0 °C 2.2: 42 h / 0 °C / Flow reactor 2.3: pH < 1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: bis(1,5-cyclooctadiene)diiridium(I) dichloride; 4,4'-di-tert-butyl-2,2'-bipyridine / n-heptane / 85 °C / Inert atmosphere 1.2: 85 °C / Inert atmosphere 2.1: Oxone / water; acetone / 20 - 30 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: bis(1,5-cyclooctadiene)diiridium(I) dichloride; 4,4'-di-tert-butyl-2,2'-bipyridine / n-heptane / 85 °C / Inert atmosphere 1.2: 85 °C / Inert atmosphere 2.1: copper dichloride; copper(l) chloride; potassium hexafluorophosphate; triethylamine / acetonitrile / 0.33 h / 0 °C 2.2: 42 h / 0 °C / Flow reactor 2.3: pH < 1 3.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / ethyl acetate / 30 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: bis(1,5-cyclooctadiene)diiridium(I) dichloride; 4,4'-di-tert-butyl-2,2'-bipyridine / n-heptane / 85 °C / Inert atmosphere 1.2: 85 °C / Inert atmosphere 2.1: copper dichloride; copper(l) chloride; potassium hexafluorophosphate; triethylamine / acetonitrile / 0.33 h / 0 °C 2.2: 42 h / 0 °C / Flow reactor 2.3: pH < 1 3.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / ethyl acetate / 30 °C / Inert atmosphere 4.1: lithium borohydride / 2-methyltetrahydrofuran; methanol / 2 h / 10 - 23 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: bis(1,5-cyclooctadiene)diiridium(I) dichloride; 4,4'-di-tert-butyl-2,2'-bipyridine / n-heptane / 85 °C / Inert atmosphere 1.2: 85 °C / Inert atmosphere 2.1: copper dichloride; copper(l) chloride; potassium hexafluorophosphate; triethylamine / acetonitrile / 0.33 h / 0 °C 2.2: 42 h / 0 °C / Flow reactor 2.3: pH < 1 3.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / ethyl acetate / 30 °C / Inert atmosphere 4.1: lithium borohydride / 2-methyltetrahydrofuran; methanol / 2 h / 10 - 23 °C 5.1: pyridinium p-toluenesulfonate / ethyl acetate / 3 h / 55 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: bis(1,5-cyclooctadiene)diiridium(I) dichloride; 4,4'-di-tert-butyl-2,2'-bipyridine / n-heptane / 85 °C / Inert atmosphere 1.2: 85 °C / Inert atmosphere 2.1: copper dichloride; copper(l) chloride; potassium hexafluorophosphate; triethylamine / acetonitrile / 0.33 h / 0 °C 2.2: 42 h / 0 °C / Flow reactor 2.3: pH < 1 3.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / ethyl acetate / 30 °C / Inert atmosphere 4.1: lithium borohydride / 2-methyltetrahydrofuran; methanol / 2 h / 10 - 23 °C 5.1: triethylamine; dmap / dichloromethane / 2 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: tris-(dibenzylideneacetone)dipalladium(0); dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium carbonate / toluene; ethanol; water / 90 °C / Inert atmosphere 2: sodium hydroxide / water / 10 h / 110 °C / Inert atmosphere 3: methanesulfonic acid / 3 h / 110 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: tris-(dibenzylideneacetone)dipalladium(0); dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium carbonate / toluene; ethanol; water / 90 °C / Inert atmosphere 2: sodium hydroxide / water / 10 h / 110 °C / Inert atmosphere 3: methanesulfonic acid / 3 h / 110 °C / Inert atmosphere 4: tetrahydrofuran / 2 h / 25 °C / Inert atmosphere 5: sodium hydride; chloro(2’-amino-1,1’-biphenyl-2-yl)palladium(II) dimer; C60H54NO5P / toluene / 12 h / 100 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: tris-(dibenzylideneacetone)dipalladium(0); dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium carbonate / toluene; ethanol; water / 90 °C / Inert atmosphere 2: sodium hydroxide / water / 10 h / 110 °C / Inert atmosphere 3: methanesulfonic acid / 3 h / 110 °C / Inert atmosphere 4: tetrahydrofuran / 2 h / 25 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: tris-(dibenzylideneacetone)dipalladium(0); dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium carbonate / toluene; ethanol; water / 90 °C / Inert atmosphere 2: sodium hydroxide / water / 10 h / 110 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate In ethanol; water; toluene at 90℃; Inert atmosphere; | Typical Procedure for synthesis of compound S2 (Typical Procedure A) General procedure: Under nitrogen atmosphere, methyl 2-bromo-3-methylbenzoate acid (6.87 g, 30.0 mmol, 1.0 equiv), o-tolylboronic acid (6.12 g, 45.0 mmol, 1.5 equiv), Pd2(dba)3 (0.229 g, 0.25 mmol, 0.83 mol%), S-Phos (0.410 g, 1.0 mmol, 3.3 mol%), K2CO3 (12.44 g, 90.0 mmol, 3.0 equiv) in a mixture of toluene (45.0 mL), EtOH (15.0 mL) and H2O (15.0 mL), was heated at 90°C for 10 h. After being cooled to room temperature, the solution was diluted with water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layer was washed with brine (20 mL × 3) and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation to give crude product S1, which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran; water at 90℃; for 12h; | I.1.2 (2) Synthesis of Sub 1-II-2 Sub 1-I-2 (13.00 g, 49.97 mmol) In methyl 2-bromo-3-chlorobenzoate (12.47 g, 49.47 mmol), Pd (PPh 3) 4 (1.73 g, 1.50 mmol), K 2 CO 3 (13.81 g, 99.94 mmol), THF (160ml), Add H 2 O (80 ml) and reflux at 90 ° C. for 12 hours. After the reaction is completed, the temperature of the reactant is cooled to room temperature, Extract with MC and wipe with water, The organic layer is dried over MgSO 4 and concentrated. after, The concentrate was separated using a silica gel column to give 11.95 g (79%) of product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / water; tetrahydrofuran / 65 °C / Sealed tube 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 20 °C / Inert atmosphere 4: lithium hydroxide monohydrate / water; tetrahydrofuran / 20 °C / Inert atmosphere 5: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 12 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / water; tetrahydrofuran / 65 °C / Sealed tube 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / water; tetrahydrofuran / 65 °C / Sealed tube 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 20 °C / Inert atmosphere 4: lithium hydroxide monohydrate / water; tetrahydrofuran / 20 °C / Inert atmosphere 5: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 12 h / 20 °C / Inert atmosphere 6: acetic acid / water / 85 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / water; tetrahydrofuran / 65 °C / Sealed tube 2.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 20 °C / Inert atmosphere 4.1: lithium hydroxide monohydrate / water; tetrahydrofuran / 20 °C / Inert atmosphere 5.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 20 °C / Inert atmosphere 5.2: 85 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / water; tetrahydrofuran / 65 °C / Sealed tube 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / water; tetrahydrofuran / 65 °C / Sealed tube 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 20 °C / Inert atmosphere 4: lithium hydroxide monohydrate / water; tetrahydrofuran / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran; water at 65℃; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: diethyl ether / 3 h / 20 °C 2: sulfuric acid; acetic acid 3: palladium diacetate; triphenylphosphine; potassium acetate / tetrahydrofuran / 110 °C / Schlenk technique; Inert atmosphere 4: bis(cycloocta-1,5-diene)rhodium(I) trifluoromethanesulfonate; (S)-(+)-5,5’-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4’-bi-1,3-benzodioxole; hydrogen / dichloromethane / 6 h / 20 °C / 38002.6 Torr / Inert atmosphere; Glovebox; Autoclave |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: diethyl ether / 3 h / 20 °C 2: sulfuric acid; acetic acid 3: palladium diacetate; triphenylphosphine; potassium acetate / tetrahydrofuran / 110 °C / Schlenk technique; Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: diethyl ether / 3 h / 20 °C 2: sulfuric acid; acetic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In diethyl ether at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; water; toluene for 12h; Reflux; | 15 [Preparation Example 15] Synthesis of methyl 3-chloro-2-(spiro[cyclohexane-1,1'-inden]-2'-yl)benzoate The desired compound of Preparation Example 2 (100.0 g, 322.3 mmol), methyl 2-bromo-3-chlorobenzoate (104.5 g, 419.0 mmol) and Pd(PPh3)4(18.6 g, 16.1 mmol), K2CO3(133.6 g, 967.0 mmol) was added to 500 ml of Toluene, 100 ml of EtOH, and 100 ml of H2O and heated to reflux for 12 hours.After completion of the reaction, the mixture was extracted with methylene chloride, MgSO4was added and filtered.After removing the solvent of the filtered organic layer, the target compound is methyl 3-chloro-2-(spiro[cyclohexane-1,1'-inden]-2'-yl)benzoate (97.8 g, yield 86%) using column chromatography. ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; water; toluene Inert atmosphere; | a a. Under the protection of inert gas, the compound 3-chloro-2-bromobenzoic acid methyl ester, potassium carbonate, purified water,Mix the toluene evenly, add tetrakistriphenylphosphine palladium, add dropwise ethanol solution of o-methoxyphenylboronic acid under temperature control,Incubate for 2-20h and the reaction is complete. After washing with water, column passing and recrystallization, compound A is obtained,Total yield: 55.0-75.0%, GC: ≥99.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / toluene; ethanol; water / Inert atmosphere 2: tetrahydrofuran / Inert atmosphere 3: 1,2-dichloro-ethane / Inert atmosphere 4: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / Inert atmosphere 5: potassium carbonate; palladium diacetate; xanthene / toluene / Inert atmosphere 6: boron tribromide / 1,2-dichloro-ethane / Inert atmosphere 7: potassium carbonate / N,N-dimethyl-formamide / Inert atmosphere 8: triphenylphosphine / 1,2-dichloro-benzene / Inert atmosphere 9: sodium t-butanolate; tris-(dibenzylideneacetone)dipalladium(0); XPhos / toluene / 10 h / 85 - 95 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / toluene; ethanol; water / Inert atmosphere 2: tetrahydrofuran / Inert atmosphere 3: 1,2-dichloro-ethane / Inert atmosphere 4: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / Inert atmosphere 5: potassium carbonate; palladium diacetate; xanthene / toluene / Inert atmosphere 6: boron tribromide / 1,2-dichloro-ethane / Inert atmosphere 7: potassium carbonate / N,N-dimethyl-formamide / Inert atmosphere 8: triphenylphosphine / 1,2-dichloro-benzene / Inert atmosphere 9: sodium t-butanolate; tris-(dibenzylideneacetone)dipalladium(0); XPhos / toluene / 13 h / 95 - 100 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / toluene; water / Inert atmosphere 2: tetrahydrofuran / Inert atmosphere 3: 1,2-dichloro-ethane / Inert atmosphere 4: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / Inert atmosphere 5: potassium carbonate; palladium diacetate; tricyclohexylphosphine / toluene; water; tetrahydrofuran / Inert atmosphere 6: triphenylphosphine / 1,2-dichloro-benzene / Inert atmosphere 7: palladium dichloride / dimethyl sulfoxide / Inert atmosphere 8: sodium t-butanolate; tris-(dibenzylideneacetone)dipalladium(0); XPhos / toluene / 15 h / 95 - 105 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / toluene; water / Inert atmosphere 2: tetrahydrofuran / Inert atmosphere 3: 1,2-dichloro-ethane / Inert atmosphere 4: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / Inert atmosphere 5: potassium carbonate; palladium diacetate; tricyclohexylphosphine / toluene; water; tetrahydrofuran / Inert atmosphere 6: triphenylphosphine / 1,2-dichloro-benzene / Inert atmosphere 7: palladium dichloride / dimethyl sulfoxide / Inert atmosphere 8: sodium t-butanolate; tris-(dibenzylideneacetone)dipalladium(0); XPhos / toluene / 14 h / 100 - 110 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / toluene; water / Inert atmosphere 2: tetrahydrofuran / Inert atmosphere 3: 1,2-dichloro-ethane / Inert atmosphere 4: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / Inert atmosphere 5: potassium carbonate; palladium diacetate; tricyclohexylphosphine / toluene; water; tetrahydrofuran / Inert atmosphere 6: triphenylphosphine / 1,2-dichloro-benzene / Inert atmosphere 7: palladium dichloride / dimethyl sulfoxide / Inert atmosphere 8: sodium t-butanolate; tris-(dibenzylideneacetone)dipalladium(0); XPhos / toluene / 6 h / 80 - 90 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / toluene; ethanol; water / Inert atmosphere 2: tetrahydrofuran / Inert atmosphere 3: 1,2-dichloro-ethane / Inert atmosphere 4: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / Inert atmosphere 5: potassium carbonate; palladium diacetate; xanthene / toluene / Inert atmosphere 6: boron tribromide / 1,2-dichloro-ethane / Inert atmosphere 7: potassium carbonate / N,N-dimethyl-formamide / Inert atmosphere 8: triphenylphosphine / 1,2-dichloro-benzene / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / toluene; water / Inert atmosphere 2: tetrahydrofuran / Inert atmosphere 3: 1,2-dichloro-ethane / Inert atmosphere 4: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / Inert atmosphere 5: potassium carbonate; palladium diacetate; tricyclohexylphosphine / toluene; water; tetrahydrofuran / Inert atmosphere 6: triphenylphosphine / 1,2-dichloro-benzene / Inert atmosphere 7: palladium dichloride / dimethyl sulfoxide / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / toluene; ethanol; water / Inert atmosphere 2: tetrahydrofuran / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / toluene; ethanol; water / Inert atmosphere 2: tetrahydrofuran / Inert atmosphere 3: 1,2-dichloro-ethane / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / toluene; ethanol; water / Inert atmosphere 2: tetrahydrofuran / Inert atmosphere 3: 1,2-dichloro-ethane / Inert atmosphere 4: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / toluene; ethanol; water / Inert atmosphere 2: tetrahydrofuran / Inert atmosphere 3: 1,2-dichloro-ethane / Inert atmosphere 4: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / Inert atmosphere 5: potassium carbonate; palladium diacetate; xanthene / toluene / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / toluene; ethanol; water / Inert atmosphere 2: tetrahydrofuran / Inert atmosphere 3: 1,2-dichloro-ethane / Inert atmosphere 4: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / Inert atmosphere 5: potassium carbonate; palladium diacetate; xanthene / toluene / Inert atmosphere 6: boron tribromide / 1,2-dichloro-ethane / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In water; toluene Inert atmosphere; | a a. Under the protection of inert gas, the compound 3-chloro-2-bromobenzoic acid methyl ester, sodium carbonate, purified water,Toluene and phenylboronic acid are mixed uniformly, tetrakistriphenylphosphine palladium is added, and the reaction is completed after keeping the temperature for 2-20 hours.After the post-treatment, the compound H is obtained by washing with water, passing through a column, and recrystallizing. The total yield: 70.0-90.0%, GC: ≥99.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; toluene at 60℃; for 8h; Inert atmosphere; | 12.1 (1) Synthesis of Intermediate 1-313: Take a 50 ml three-necked flask, put it in the stir bar and the upper reflux tube, and fill it with nitrogen.Raw material B-2 (2.48 g, 0.1 mol), raw material N-3 (2.35 g, 0.1 mol),Potassium carbonate (0.12mol), tetrakis(triphenylphosphine)palladium (5mmol), toluene (8ml),Water (2ml), under the protection of nitrogen, react at 60 degrees Celsius for 8 hours,After the reaction is completed, it is cooled to room temperature and quenched by adding 3 ml of ice water.Dichloromethane (3×15 ml) was extracted, and the obtained extract was added with magnesium sulfate to dry,Filter and spin dry, the crude product is purified by chromatography (dichloromethane/n-hexane, 1/15 (volume ratio)),The intermediate 1-313 (1.01 g, yield 28%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With potassium phosphate; palladium diacetate; ruphos In water; toluene at 110℃; for 2.5h; Inert atmosphere; | 1 Example 1: compound (7) in Table I According to procedure (E), a solution of methyl 2-bromo-3-chlorobenzoate (500 mg, 2.0 mmoles, 1 eq) and potassium cyclopropyltrifluoroborate (445 mg, 3.0 mmoles, 1.5 eq.) in toluene (10 mL) and water (2 mL) was degassed with argon during 5 minutes then tripotassium phosphate (1.08 g, 5.0 mmoles, 2.5 eq.), RuPhos (37.4 mg, 80 pmoles, 0.04 eq.) and palladium(II) acetate (9.1 mg, 40 pmoles, 0.02 eq.) were added. The reaction mixture was heated at 110°C and stirred for 2h30 under inert atmosphere. Upon cooling down to room temperature, it was filtered over a pad of celite and the pad was washed with EtOAc. A saturated aqueous solution of brine was then added to the filtrate and the mixture was extracted with EtOAc. The combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give methyl 3-chloro-2-cyclopropylbenzoate (201 mg, 47%). NMR (400 MHz, e-DMSO) d 7.59 (dd, J= 8.0, 1.3 Hz, 1H), 7.46 (dd, J = 7.7, 1.3 Hz, 1H), 7.35 (t, 7= 7.8 Hz, 1H), 3.86 (s, 3H), 1.94 (tt, J= 8.5, 5.8 Hz, 1H), 1.08 - 0.93 (m, 2H), 0.47 - 0.34 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.14% | With potassium carbonate; at 20℃; for 2h; | A mixture of <strong>[56961-26-3]2-bromo-3-chlorobenzoic acid</strong> (10.1) (10.0 g, 42.9 mmol) in DMF (100 mL) were added K2CO3 (11.8 g, 85.8 mmol) and CH3I (3.96 mL, 63.0 mmol) and stirred at RT for 2 h. The reaction mixture was transferred into water (500 mL) and extracted with ethyl acetate (2×500 mL) and the combined organic phases were washed with brine (500 mL), dried with MgSO4, filtered, and then concentrated in vacuo. The residue was purified by column chromatography (0-50% gradient elution EtOAc in iso-hexane) to afford the title compound 10.2 (10 g, 95.14%). m/z 247.1 [M+H]+. |
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