* 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.
Stage #1: With iodine; magnesium In tetrahydrofuran at 20℃; for 2 h; Stage #2: at -15 - 0℃; Inert atmosphere Stage #3: With ammonium chloride In tetrahydrofuran at 20℃; for 16 h;
THF (10 mL) was added to magnesium (abrasive) (24.3 g, 97.2 mmol) and two crystals of iodine (arbitrary amount), and the mixture was stirred at room temperature for 1 minute and then 4- (tetrahydro-2H- 2-yloxy) bromobenzene (25.0 g, 97.2 mmol) in THF (40.0 mL) was slowly added and the mixture was stirred at room temperature for 5 minutes under a nitrogen atmosphere, refluxed for 2 hours and returned to room temperature to obtain Grignard reagent Was prepared. Triethylborate (31.3 g, 292 mmol) and THF (600 mL) were added to another four-necked flask, and after purging with nitrogen, the mixture was cooled to -15 ° C.The Grignard reagent was cooled to 0 ° C. and added dropwise to a solution of triethylborate in THF over 30 minutes using a cannula. After completion of the dropwise addition, reaction was carried out for 1 hour while maintaining 0 ° C., whereby a gray solid precipitated. An ammonium chloride aqueous solution (10percent by weight, 150 mL) was added thereto, and the mixture was stirred at room temperature for 16 hours. Ethyl acetate (200 mL) was added and the mixture was stirred for a while. The organic layer was extracted, washed with water and saturated brine, dried over magnesium sulfate, magnesium sulfate was removed by filtration, and the solvent was distilled off under reduced pressure A pink solid was obtained. This was recrystallized from a mixed solvent of ethyl acetate and hexane 1: 10 (volume ratio) to obtain 4- (tetrahydro-2H-pyran-2-yloxy) phenylboronic acid (18.3 g) as a white solid (Yield 83percent).
Stage #1: With n-butyllithium In tetrahydrofuran at -40℃; for 2 h; Stage #2: at 20℃; for 8 h;
The compound obtained in Step 1(T-17) (723.7g, 2815.0mmol) in THF (3600ml)The solution was cooled to -40 ,Was added dropwise n-BuLi (1.59M, 2290ml, 3659.0mmol).At -40 for 2 hours,Solution of triisopropoxyborane (688.16g, 3659.0mmol).Stirred at room temperature for 8 hours.The reaction mixture was poured into saturated aqueous ammonium chloride (4000ml), andExtracted with ethyl acetate.The extracts were washed with water (3000ml) and saturated brine (2000ml) cleaning,Dried over anhydrous magnesium sulfate,Concentrated under reduced pressure.The residue was recrystallized (heptane) to give compound(T-18) (203.12g, 914.77mmol, 32.5percent).
Reference：
[1] New Journal of Chemistry, 2010, vol. 34, # 1, p. 34 - 43
[2] Patent: CN105358523, 2016, A, . Location in patent: Paragraph 0315; 0318; 0319
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[ 36603-49-3 ]
[ 182281-01-2 ]
Reference：
[1] Journal of Materials Chemistry, 2012, vol. 22, # 24, p. 12358 - 12368
[2] Chemistry - A European Journal, 2007, vol. 13, # 27, p. 7584 - 7594
[3] Macromolecules, 2002, vol. 35, # 15, p. 5808 - 5815
4
[ 36603-49-3 ]
[ 121-43-7 ]
[ 594-19-4 ]
[ 182281-01-2 ]
Reference：
[1] Patent: US5866568, 1999, A,
[2] Patent: US5668137, 1997, A,
5
[ 36603-49-3 ]
[ 121-43-7 ]
[ 7732-18-5 ]
[ 182281-01-2 ]
Yield
Reaction Conditions
Operation in experiment
24.3 g
Stage #1: With magnesium In tetrahydrofuranInert atmosphere Stage #2: for 3 h; Inert atmosphere Stage #3: Inert atmosphere
In a reaction vessel purged with nitrogen, magnesium 3.62 g (0.15 mol) and 6 mL of tetrahydrofuran were added. The compound represented by formula (I-1b) 29.4 g (0.11 mol) in tetrahydrofuran was gradually added to prepare a Grignard reagent. Trimethyl borate 17.8 g (0.17 mol) in tetrahydrofuran was added dropwise and the mixture was stirred for 3 hours. 10percent hydrochloric acid was added dropwise to make the reaction acidic. After washing with saline, By distilling off the solvent, the compound represented by formula (I-1c) 24.3 g (0.10 mol) was obtained.
With ammonium chloride; In tetrahydrofuran; hexane; water; pentane;
(ii) tert-Butyl lithium in pentane (1.7M, 200 ml) was added over 20 minutes to a solution of 2-(4-bromophenoxy)-2 H-tetrahydropyran (38.6 g) in dry tetrahydrofuran (450 ml) at -90 C. under argon. The solution was stirred at -90 C. for 30 minutes and then a solution of trimethyl borate (30 ml) in dry tetrahydrofuran (50 ml) was added over 15 minutes. The solution was stirred at -90 C. for 30 minutes and then allowed to warm to -30 C. Saturated ammonium chloride solution (100 ml) was added and the mixture was left to warm to room temperature. Water (100 ml) was added and the mixture was extracted with ether (2*250 ml). The extracts were washed with water (2*200 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was recrystallized from a mixture of ether and hexane to give 4-(2H-tetrahydropyran-2-yloxy)phenylboronic acid (23.4 g), m.p. 140-142 C.
With ammonium chloride; In tetrahydrofuran; hexane; water; pentane;
(b) tert-Butyl lithium in pentane (1.7M, 200 ml) was added over 20 minutes to a solution of 2-(4-bromophenoxy)-2 H-tetrahydropyran (38.6 g) in dry tetrahydrofuran (450 ml) at -90 C. under argon. The solution was stirred at -90 C. for 30 minutes and then a solution of trimethyl borate (30 ml) in dry tetrahydrofuran (50 ml) was added over 15 minutes. The solution was stirred at -90 C. for 30 minutes and then allowed to warm to -30 C. Saturated ammonium chloride solution (100 ml) was added and the mixture was left to warm to room temperature. Water (100 ml) was added and the mixture was extracted with ether (2*250 ml). The extracts were washed with water (2*200 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was recrystallized from a mixture of ether and hexane to give 4-(2-(2 H)-tetrahydropyranyloxy)phenylboronic acid (23.4 g), m.p. 140-142 C.
With potassium fluoride;palladium diacetate; In water; ethyl acetate; toluene;
(iii) A solution of potassium fluoride (6.5 g) in water (100 ml) was added to a solution of 2-chloro-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (7.8 g), 4-(2-(2 H)-tetrahydropyranyloxy)phenylboronic acid (10.0 g), tri-o-tolyl phosphine (0.73 g) and palladium acetate (0.25 g) in toluene (100 ml) and the mixture was heated under reflux under argon for 18 hours. Ethyl acetate (150 ml) was added and the organic phase was separated. The solution was washed with 2M sodium hydroxide solution (100 ml) and water (250 ml) and then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by flash chromatography, eluding with 25-50% ethyl acetatelhexane. The residue was crystallized from ethyl acetate/hexane to give N-(isobutoxycarbonyl)-2-[4-(2H-tetrahydropyran-2-yloxy)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (4.0 g), m.p. 142-144 C.
1-(4-fluorophenyl)-5-[4-(tetrahydropyran-2-yloxy)phenyl]pyrazolo[3,4-f]isoquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃;
EXAMPLE 2; 1 -(4-Fluo rophenyl)-5-[4-(tetrahyd ropy ran-2-yloxy)phenyl]pyrazolo[3,4-/]isoquinoline; To a suspension of 5-bromo-1 -(4-fluorophenyl)pyrazolo[3,4-f]isoquinoline (0.2 g, 0.6 mmol, obtained in example 1 ), [4-(tetrahydropyran-2-yloxy)phenyl]boronic acid (0.19 g, 0.9 mmol), anhydrous K2CO3 (0.16 g, 1.2 mmol), Pd(PPh3)4 (4.7 mg) in 1 ,2-dimethoxyethane (4 imL) under argon, water (0.12 imL) was added. The reaction mixture was heated at 80 0C overnight. It was allowed to cool and water and CH2CI2 were added. The phases were separated and the aqueous phase was reextracted 3 times with CH2CI2. The combined organic phases were dried over Na2SO4 and the solvent was evaporated. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 0.25 g of the title compound (yield: 97 %). LC-MS (method 1 ): tR = 10.10 min; m/z = 440.1 [M+H]+.
With sodium hydrogencarbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; isopropyl alcohol; at 150℃; for 0.166667h;Microwave irradiation;
Intermediate 24-Nitro-2-(tetrahydro-2H-pyran-2-yl)-6-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2H- indazole 6-Bromo-4-nitro-2-(tetrahydro-2H-pyran-2-yl)-2/-/-indazole (500 mg, 1.53 mmol), Pd(dppf)CI2 (125 mg, 0.153 mmol), [4-(tetrahydro-2H-pyran-2-yloxy)phenyl]boronic acid (51 1 mg, 2.3 mmol), saturated sodium hydrogen carbonate (aq) (3 ml) and isopropyl alcohol (12 ml) were added to each of 5 microwave vessels. All 5 reactions were heated at 150 0C for 10 mins in a Biotage microwave. The reaction mixtures were combined and water (250 ml) and ethyl acetate (250 ml) were added. The mixture was filtered and the organic layer collected. The organic layer was washed with water, then brine, dried over magnesium sulphate, filtered and dried in vacuo. The residue was purified using silica gel chromatography, eluting with 0 - 25% ethyl acetate in cyclohexane. Appropriate fractions were combined and the solvent was removed in vacuo to give the title compound, 2.3 g. LC/MS (Method A) Rt = 3.85 mins, MH+ = 424.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene;Inert atmosphere; Reflux;
Compound 52B (165 mg, 0.84 mmol) in toluene (5 ml) was treated sequentially with <strong>[182281-01-2]4-(tetrahydro-2H-pyran-2-yloxy)phenylboronic acid</strong> (280 mg, 1.26 mmol), tetrakis(triphenylphosphine)palladium(0) (48.6 mg, 0.042 mmol) and sodium carbonate (2N aq.) (1.26 ml, 2.52 mmol). The reaction vessel was purged with nitrogen and heated at reflux overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by column chromatography on silica gel eluting with a gradient of 0 to 5% MeOH in CH2Cl2: 1H NMR (300 MHz, DMSO-d6) delta ppm 8.92 (1 H, s), 8.83 (2 H, m), 8.74 (1 H, s), 7.22 (2 H, m), 5.63 (1 H, t), 4.92 (1 H, septet), 3.79 (1 H, ddd), 3.60 (1 H, m), 1.82 (4 H, m), 1.60 (6 H, d), 1.55 (2 H, m).
The compound obtained in Step 1(T-17) (723.7g, 2815.0mmol) in THF (3600ml)The solution was cooled to -40 ,Was added dropwise n-BuLi (1.59M, 2290ml, 3659.0mmol).At -40 for 2 hours,Solution of triisopropoxyborane (688.16g, 3659.0mmol).Stirred at room temperature for 8 hours.The reaction mixture was poured into saturated aqueous ammonium chloride (4000ml), andExtracted with ethyl acetate.The extracts were washed with water (3000ml) and saturated brine (2000ml) cleaning,Dried over anhydrous magnesium sulfate,Concentrated under reduced pressure.The residue was recrystallized (heptane) to give compound(T-18) (203.12g, 914.77mmol, 32.5%).
With palladium diacetate; potassium carbonate; triphenylphosphine; In ethanol; toluene; at 60℃; for 12h;Inert atmosphere;
General procedure: The general procedure for the preparation of N-(3-phenyl)-2,2-dichloroacetamide heterocyclic derivatives was as follows. A mixture of 0.2mmol 2,2-dichloro-N-(3,5-diiodo-phenyl)acetamide, 0.6 mmol substituted phenylboronic acid, 0.8 mmol K2CO3, 0.16mmol triphenyl phosphine, and 0.04 mmol palladium acetate were stirred in 3 mL toluene and 3 mL ethanol at 60? under a argon atmosphere. The progress of the reaction was monitored by TLC (petroleum ether/ethyl acetate). After the reaction finished, the reaction mixture was filtered. The filtrate was concentrated to dryness and subjected to flash column chromatography (silica gel), eluting with petroleum ether/ethyl acetate, to give N-([1,1':3',1''-terphenyl]-5'-yl)-2,2-dichloroacetamide derivatives.
With tetrakis(triphenylphosphine) palladium(0); cesium fluoride; In N,N-dimethyl-formamide; toluene; at 100℃;Inert atmosphere;
(f) 3-Methyl-4-{3-methyl-1 -(tetrahydropyran-2-yl)-6-[4-(tetrahydro-pyran-2-yloxy)- phenyl]-1 H-pyrazolo[3,4-b]pyridine-4-carbonyl}-3-phenyl-piperazine-1 -carboxylic acid tert-butyl ester4-[6-Chloro-3-methyl-1 -(tetrahydro-pyran-2-yl)-1 H-pyrazolo[3,4-b]pyridine-4-carbonyl]- 3-methyl-3-phenyl-piperazine-1 -carboxylic acid tert-butyl ester (255 mg) and 4-(tetra- hydro-2H-pyran-2-yloxy)phenylboronic acid (153 mg) were dissolved in DMF/toluene (v/v = 1/1 , 7.5 ml_). After inertisation of the mixture with argon, cesium fluoride (140mg) and tetrakis(triphenylphosphine)palladium(0) (27 mg) were added. The mixture was stirred at 100C overnight. The mixture was filtered through a 0.2??? membrane syringe filter, the filtrate was diluted with ethyl acetate and washed three times with water (15 ml_ each) and once with brine (10 ml_). The organic phase was dried over magnesium sulfate and concentrated. The residue was absorbed on silica and purified by flash chromatography (heptane/ethylacetate v/v = 1/1 ). 300 mg (94%) of the title compound were obtained.LC/MS (Method LC1 ): Rt = 1 .48 min; m/z = 696.5 [M+H]+.
94%
With tetrakis(triphenylphosphine) palladium(0); cesium fluoride; In N,N-dimethyl-formamide; toluene; at 100℃;Inert atmosphere;
4-[6-Chloro-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-3-methyl-3-phenyl-piperazine-1-carboxylic acid tert-butyl ester (255 mg) and <strong>[182281-01-2]4-(tetrahydro-2H-pyran-2-yloxy)phenylboronic acid</strong> (153 mg) were dissolved in DMF/toluene (v/v=1/1, 7.5 mL). After inertisation of the mixture with argon; cesium fluoride (140 mg) and tetrakis(triphenylphosphine)palladium(0) (27 mg) were added. The mixture was stirred at 100 C. overnight. The mixture was filtered through a 0.2 mum membrane syringe filter, the filtrate was diluted with ethyl acetate and washed three times with water (15 mL each) and once with brine (10 mL). The organic phase was dried over magnesium sulfate and concentrated. The residue was absorbed on silica and purified by flash chromatography (heptane/ethylacetate v/v=1/1). 3000 g (94%) of the title compound were obtained. LC/MS (Method LC1): Rt=1.48 min; m/z=696.5 [M+H]+.
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