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[ CAS No. 187804-79-1 ] {[proInfo.proName]}

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Chemical Structure| 187804-79-1
Chemical Structure| 187804-79-1
Structure of 187804-79-1 * Storage: {[proInfo.prStorage]}
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Product Details of [ 187804-79-1 ]

CAS No. :187804-79-1 MDL No. :MFCD07368680
Formula : C7H5BF4O3 Boiling Point : -
Linear Structure Formula :- InChI Key :VDEVIIGZNWVCOR-UHFFFAOYSA-N
M.W : 223.92 Pubchem ID :2783193
Synonyms :

Calculated chemistry of [ 187804-79-1 ]

Physicochemical Properties

Num. heavy atoms : 15
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.14
Num. rotatable bonds : 3
Num. H-bond acceptors : 7.0
Num. H-bond donors : 2.0
Molar Refractivity : 42.91
TPSA : 49.69 Ų

Pharmacokinetics

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) : -6.17 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 2.11
Log Po/w (WLOGP) : 2.08
Log Po/w (MLOGP) : 0.92
Log Po/w (SILICOS-IT) : 0.34
Consensus Log Po/w : 1.09

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.66
Solubility : 0.495 mg/ml ; 0.00221 mol/l
Class : Soluble
Log S (Ali) : -2.78
Solubility : 0.368 mg/ml ; 0.00164 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.2
Solubility : 1.41 mg/ml ; 0.00628 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.21

Safety of [ 187804-79-1 ]

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:

Application In Synthesis of [ 187804-79-1 ]

* 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.

  • Downstream synthetic route of [ 187804-79-1 ]

[ 187804-79-1 ] Synthesis Path-Downstream   1~50

  • 1
  • [ CAS Unavailable ]
  • [ 187804-79-1 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; water A solution of 4-bromo-2-fluoro-1-(trifluoromethoxy)benzene (1.0 g, 3.9 mmol) in THF (5 ml) was added slowly to n-BuLi (3.0 ml, 1.6M in hexane) in THF (5 ml) at -78° C. After 20 min, trimethyl borate (1.4 ml, 12 mmol) was added; the mixture was stirred at -78° C. for 2 hr. The cooling bath was removed, the reaction was allowed to warm up to room temperature (1-2 h). The reaction was then quenched with 2N HCl (10 ml) and stirred overnight. Solvent was removed under reduced pressure, and the residue dissolved in CH3CN-H2O-dioxane. Chromatography by reverse phase HPLC gave, after lyophilization, [3-fluoro-4-(trifluoromethoxy)phenyl]boronic acid as a fine powder. NMR (500 MHz, CDCl3) δ: 7.47(m, 1H); 7.99 (m, 2H).
  • 2
  • [ 105529-58-6 ]
  • [ 121-43-7 ]
  • [3-fluoro-4-(trifluoromethoxy)phenyl]boronic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
54% [Example 7] Synthesis of 4-[difluoro[(2,3'-difluoro-4'-trifluoromethoxy[1,1'-biphenyl]-4-yl)oxy]methyl]-4''-pentyl-2',3,5-trifluoro-1,1',4',1''-terphenyl (No. 1-3-70) [Synthesis of the Compound (T-14)] Well-dried magnesium (3.05 g) and THF (20.0 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated to 55 C. Then, <strong>[105529-58-6]1-bromo-3-fluoro-4-trifluoromethoxybenzene</strong> (T-13; 25.0 g) dissolved in THF (100 ml) was slowly added dropwise thereto in the temperature range of 47 C to 60 C, and stirred for additional 60 minutes. The obtained Grignard reagent was added dropwise to trimethyl borate (14.0 g) in a THF (100 ml) solution in the temperature range of -74 C to -65 C, and stirred for additional 180 minutes while allowing temperature to come to 25 C. After the reaction mixture had been cooled to -30 C, 6N-hydrochloric acid (90 ml) was slowly added dropwise and stirred for additional 180 minutes while temperature was allowed to come to 25 C. Then, the reaction mixture was poured into a vessel containing ice-water (250 ml) and 3,000 ml, and mixed. Ethyl acetate (300 ml) was added to separate the mixture into organic and aqueous layers, and an extraction operation was carried out. The obtained organic layer was fractionated, washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, whereby 11.7 g of 3-fluoro-4-trifluoromethoxy phenylboronic acid (T-14) was obtained. The yield based on the compound (T-13) was 54%.
  • 3
  • [ 105529-58-6 ]
  • [3-fluoro-4-(trifluoromethoxy)phenyl]boronic acid [ No CAS ]
  • C21H9B3F12O6 [ No CAS ]
  • 4
  • [ 187804-79-1 ]
  • [ 1257426-06-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: sodium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / toluene; ethanol; water / 2 h / 89 °C / Inert atmosphere 2: triphenylphosphine; N-Bromosuccinimide / dichloromethane / 3 h / 20 °C 3: sodium hydride / N,N-dimethyl-formamide / 0 - 20 °C / Inert atmosphere; Sealed tube
Multi-step reaction with 3 steps 1: sodium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / toluene; ethanol; water / 2 h / 89 °C / Inert atmosphere 2: triphenylphosphine; N-Bromosuccinimide / dichloromethane / 3 h / 20 °C 3: sodium hydride / N,N-dimethyl-formamide; mineral oil / 2.5 h / 0 - 20 °C / Inert atmosphere
  • 5
  • [ 187804-79-1 ]
  • [ 1263417-38-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: sodium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / toluene; ethanol; water / 2 h / 89 °C / Inert atmosphere 2: triphenylphosphine; N-Bromosuccinimide / dichloromethane / 3 h / 20 °C
Multi-step reaction with 2 steps 1: sodium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / toluene; ethanol; water / 2 h / 89 °C / Inert atmosphere 2: triphenylphosphine; N-Bromosuccinimide / dichloromethane / 3 h / 20 °C
  • 6
  • [3-fluoro-4-(trifluoromethoxy)phenyl]boronic acid [ No CAS ]
  • [ 88139-91-7 ]
  • [ 1263417-37-3 ]
YieldReaction ConditionsOperation in experiment
60% With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In ethanol; water; toluene; at 89℃; for 2h;Inert atmosphere; A stirred mixture of <strong>[88139-91-7](5-bromo-2-pyridinyl)methanol</strong> (105) (753 mg, 4.00 mmol), 3-fluoro-4-(trifluoromethoxy)phenylboronic acid (56) (see Example 2G) (1.165 g, 5.20 mmol) and Pd(dppf)Cl2 (366 mg, 0.50 mmol) in toluene (40 mL) and EtOH (20 mL) was degassed for 15 min (vacuum pump) and then N2 was added. An aqueous solution of 2M Na2CO3 (10 mL, 20.0 mmol) was added by syringe and the stirred mixture was again degassed for 15 min, and then N2 was added. The resulting mixture was stirred at 89 0C for 2 h, and then cooled, diluted with aqueous NaHCO3 (120 mL) and extracted with CH2Cl2 (6x 100 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 50-75% CH2Cl2/petroleum ether firstly gave foreruns, and then further elution with 75% CH2Cl2/petroleum ether and 0-0.5% MeOH/CH2Cl2 gave {5-[3-fluoro-4- (trifluoromethoxy)phenyl]-2-pyridinyI}methanol (106) (687 mg, 60%) as a light yellow-brown solid: mp 51-53 0C; 1H NMR (CDCl3) delta 8.76 (d, J = 1.9 Hz, 1 H), 7.84 (dd, J = 8.1, 2.3 Hz, 1 H), 7.46-7.34 (m, 4 H), 4.83 (d, J = 5.1 Hz, 2 H), 3.47 (t, J = 5.2 Hz, 1 H); HRESlMS calcd for CI3HI0F4NO2 mlz [M + H]+ 288.0642, found 288.0641.
60% With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In ethanol; water; toluene; at 89℃; for 2h;Inert atmosphere; Y. Synthesis of (6S)-6-({5-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-pyridinyl}methoxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (22) by the method of Scheme 17 A stirred mixture of <strong>[88139-91-7](5-bromo-2-pyridinyl)methanol</strong> (105) (753 mg, 4.00 mmol), 3-fluoro-4-(trifluoromethoxy)phenylboronic acid (56) (see Example 2G) (1.165 g, 5.20 mmol) and Pd(dppf)Cl2 (366 mg, 0.50 mmol) in toluene (40 mL) and EtOH (20 mL) was degassed for 15 min (vacuum pump) and then N2 was added. An aqueous solution of 2M Na2CO3 (10 mL, 20.0 mmol) was added by syringe and the stirred mixture was again degassed for 15 min, and then N2 was added. The resulting mixture was stirred at 89 C. for 2 h, and then cooled, diluted with aqueous NaHCO3 (120 mL) and extracted with CH2Cl2 (6*100 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 50-75% CH2Cl2/petroleum ether firstly gave foreruns, and then further elution with 75% CH2Cl2/petroleum ether and 0-0.5% MeOH/CH2Cl2 gave {5-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-pyridinyl}methanol (106) (687 mg, 60%) as a light yellow-brown solid: mp 51-53 C.; 1H NMR (CDCl3) delta 8.76 (d, J=1.9 Hz, 1H), 7.84 (dd, J=8.1, 2.3 Hz, 1H), 7.46-7.34 (m, 4H), 4.83 (d, J=5.1 Hz, 2H), 3.47 (t, J=5.2 Hz, 1H); HRESIMS calcd for C13H10F4NO2m/z [M+H]+ 288.0642, found 288.0641.
  • 7
  • [ 187804-79-1 ]
  • [ 1188329-26-1 ]
  • [ 1257426-25-7 ]
YieldReaction ConditionsOperation in experiment
89% With sodium carbonate In ethanol; water; toluene at 90℃; for 2h; 2.G A stirred mixture of bromide 52 (see Example 2F) (502 mg, 1.41 mmol), 3- fluoro-4-(trifluoromethoxy)phenylboronic acid (56) (450 mg, 2.01 mmol) and Pd(dppf)Cl2 (130 mg, 0.178 mmol) in toluene (20 mL) and EtOH (10 mL) was degassed for 12 min (vacuum pump) and then N2 was added. An aqueous solution of 2M Na2CO3 (3.8 mL, 7.6 mmol) was added by syringe and the stirred mixture was again degassed for 15 min, and then N2 was added. The resulting mixture was stirred at 90 0C for 2 h, and then cooled, diluted with aqueous NaHCO3 (100 mL) and extracted with CH2Cl2 (6x 100 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-0.5% MeOH/CH2Cl2 firstly gave foreruns, and then further elution with 0.5% MeOH/CH2Cl2 gave 21 (573 mg, 89%) as a cream solid: mp (CH2C l2/ρentane) 187-189 0C; 1H NMR (CDCl3) δ 8.62 (d, J = 1.5 Hz, 1 H), 7.90 (dd, J = 11.3, 2.1 Hz, 1 H), 7.78 (ddd, J = 8.6, 2.0, 1.3 Hz, 1 H), 7.75 (dd, J = 8.2, 2.2 Hz, 1 H), 7.71 (dd, J = 8.2, 0.8 Hz, 1 H), 7.41 (s, 1 H), 7.40 (ddq, J = 8.7, 7.6, 1.2 Hz, 1 H), 4.80 (d, J = 12.0 Hz, 1 H), 4.70 (d, J = 11.8 Hz, 1 H), 4.68 (ddd, J = 12.2, 3.5, 2.3 Hz, 1 H), 4.40 (dd, J = 12.2, 1.1 Hz, 1 H), 4.25 (dd, J = 13.3, 4.5 Hz, 1 H), 4.22-4.15 (m, 2 H). Anal. (C19H14F4N4O5) C, H, N.
89% With sodium carbonate In ethanol; toluene at 90℃; for 2h; Inert atmosphere; 2.G G. Synthesis of (6S)-6-({6-[3-fluoro-4-(trifluoromethoxy)phenyl]-3-pyridinyl}methoxy)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (21) by the method of Scheme 4 A stirred mixture of bromide 52 (see Example 2F) (502 mg, 1.41 mmol), 3-fluoro-4-(trifluoromethoxy)phenylboronic acid (56) (450 mg, 2.01 mmol) and Pd(dppf)Cl2 (130 mg, 0.178 mmol) in toluene (20 mL) and EtOH (10 mL) was degassed for 12 min (vacuum pump) and then N2 was added. An aqueous solution of 2M Na2CO3 (3.8 mL, 7.6 mmol) was added by syringe and the stirred mixture was again degassed for 15 min, and then N2 was added. The resulting mixture was stirred at 90° C. for 2 h, and then cooled, diluted with aqueous NaHCO3 (100 mL) and extracted with CH2Cl2 (6*100 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-0.5% MeOH/CH2Cl2 firstly gave foreruns, and then further elution with 0.5% MeOH/CH2Cl2 gave 21 (573 mg, 89%) as a cream solid: mp (CH2Cl2/pentane) 187-189° C.; 1H NMR (CDCl3) δ 8.62 (d, J=1.5 Hz, 1 H), 7.90 (dd, J=11.3, 2.1 Hz, 1H), 7.78 (ddd, J=8.6, 2.0, 1.3 Hz, 1H), 7.75 (dd, J=8.2, 2.2 Hz, 1H), 7.71 (dd, J=8.2, 0.8 Hz, 1H), 7.41 (s, 1H), 7.40 (ddq, J=8.7, 7.6, 1.2 Hz, 1H), 4.80 (d, J=12.0 Hz, 1H), 4.70 (d, J=11.8 Hz, 1H), 4.68 (ddd, J=12.2, 3.5, 2.3 Hz, 1H), 4.40 (dd, J=12.2, 1.1 Hz, 1H), 4.25 (dd, J=13.3, 4.5 Hz, l H), 4.22-4.15 (m, 2H). Anal. (C19H14E4N4O5) C, H, N.
  • 9
  • [ 187804-79-1 ]
  • [ 1599467-70-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: copper diacetate; N-ethyl-N,N-diisopropylamine; pyridine / dichloromethane / 12 h / 20 °C / Molecular sieve 2: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate / N,N-dimethyl-formamide / 18 h / 80 °C / Molecular sieve
  • 10
  • [ 187804-79-1 ]
  • [ 1599467-76-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: copper diacetate; N-ethyl-N,N-diisopropylamine; pyridine / dichloromethane / 12 h / 20 °C / Molecular sieve 2: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate / N,N-dimethyl-formamide / 18 h / 80 °C / Molecular sieve 3: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; N,N-dimethyl-formamide / 18 h / 85 °C
  • 11
  • [ 187804-79-1 ]
  • [ 1354745-81-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: copper diacetate; N-ethyl-N,N-diisopropylamine; pyridine / dichloromethane / 12 h / 20 °C / Molecular sieve 2: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate / N,N-dimethyl-formamide / 18 h / 80 °C / Molecular sieve 3: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / water; N,N-dimethyl-formamide / 18 h / 85 °C 4: acetic acid; hydrogen bromide / water / 24 h / 90 °C
  • 12
  • [ 105529-58-6 ]
  • [3-fluoro-4-(trifluoromethoxy)phenyl]boronic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.6 g n-BuLi (2.3 mL, 2.5M in hexanes, 1.50 equiv) was added dropwise into a solution of 4- bromo-2-fluoro- 1 -(trifluoromethoxy)benzene (1 g, 3.86 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) at -78C under nitrogen. After lh at-78C tris(propan-2-yl) borate (1.1 g, 5.85 mmol, 1.50 equiv) was added dropwise at -78C. The resulting solution was stirred for 14 h at room temperature and quenched by 3N NaOH. The resulting solution was stirred for 30 mm at room temperature. The pH value of the solution was adjusted to 7 with 3N aqueous hydrogen chloride. The resulting mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in the title compound (1.6 g) as yellow oil.
  • 13
  • [ 187804-79-1 ]
  • [ 1701433-00-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane; water / 14 h / 75 °C / Inert atmosphere 2: tris(dibenzylideneacetone)dipalladium(0) chloroform complex; 1,1'-bis-(diphenylphosphino)ferrocene / N,N-dimethyl-formamide / 1 h / 100 °C / Inert atmosphere; Microwave irradiation
  • 14
  • [ 1193-21-1 ]
  • [ 187804-79-1 ]
  • [ 1701432-99-6 ]
YieldReaction ConditionsOperation in experiment
23% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 75℃; for 14h; Inert atmosphere; 104.2 Step 2: Preparation of4-chloro-6- [3 -fluoro-4-(trifluoromethoxy)phenyl]pyrimidine A mixture of [3-fluoro-4-(trifluoromethoxy)phenyl]boronic acid (500 mg, 2.23 mmol, 1.00 equiv), 4,6-dichioropyrimidine (660 mg, 4.43 mmol, 2.00 equiv), Pd(dppf)C12 (82 mg, 0.11 mmol, 0.05 equiv), and potassium carbonate (616 mg, 4.46 mmol, 2.00 equiv) in water(1 mL)/1,4-dioxane (10 mL) was stirred for 14 h at 75°C under nitrogen. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column eluting with ethyl acetate/petroleum ether (1:10) to afford the title compound (150mg, 23%) as a white solid.
  • 15
  • [ 1255940-61-4 ]
  • [ 187804-79-1 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
1.4 g With bis(acetonitrile)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate In 1,4-dioxane at 80℃; for 12h; 6.1 Preparation of ethyl (S) -2 - (((S) -tert-butylsulfinyl) amino) -2- (3-fluoro-4- (trifluoromethoxy) phenyl) acetate (S, E) -ethyl 2 - ((tert-butylsulfinyl) imino) acetate(CAS No. 1255940-61-4) (1.93g), 3- fluoro-4-trifluoromethoxyphenyl boronic acid (1.40 g) 1,4-dioxane (40 ml) bis (acetonitrile) (1, 5-cyclooctadiene) rhodium (I) tetrafullofflovorate (0.24 g) at room temperature, and the mixture was stirred at 80 ° C. for 12 hours. The obtained reaction solution was concentrated and then purified by silica gel column chromatography (mobile phase: heptane: ethyl acetate = 90: 10-50: 50) to obtain the title compound (1.40 g) as a brown oil.
  • 16
  • [ 187804-79-1 ]
  • [ 2098454-56-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: bis(acetonitrile)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate / 1,4-dioxane / 12 h / 80 °C 2: hydrogenchloride / 1 h / 20 °C
  • 17
  • [ 187804-79-1 ]
  • [ 1646681-81-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: bis(acetonitrile)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate / 1,4-dioxane / 12 h / 80 °C 2: hydrogenchloride / 1 h / 20 °C 3: diethyl ether / 1.5 h / 20 °C / Cooling with ice
  • 18
  • [ 187804-79-1 ]
  • [ 2129135-41-5 ]
  • [ 2129135-47-1 ]
YieldReaction ConditionsOperation in experiment
28.5% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran for 12h; Reflux; Inert atmosphere; 19.9 g (0.038 mol) of 1,4-dibromo-2,5-difluoro-3,6-diiodobenzene (0.078 mol) of (3-fluoro-4-trifluoromethoxy) phenylboronic acid, 2.2 g of tetrakis (triphenylphosphine) palladium (0)2M potassium carbonate 114ml,Were mixed with 360 ml of tetrahydrofuran, and the mixture was refluxed under nitrogen for 12 hours. After cooling,Extraction with water and dichloromethane,The residue was further purified by silica gel column (developing solvent: ethyl acetate / hexane = 10/1)6.8 g (28.5%) of a white solid was obtained.
  • 19
  • [ 187804-79-1 ]
  • [ 63262-06-6 ]
  • [ 2129135-32-4 ]
YieldReaction ConditionsOperation in experiment
34% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran for 8h; Reflux; Inert atmosphere; 18.5 g (0.038 mol) of 1,4-dibromo-2,5-diiodobenzene,17.5 g (0.078 mol) of (3-fluoro-4-trifluoromethoxy) phenylboronic acid,2.2 g of tetrakis (triphenylphosphine) palladium (0)2M potassium carbonate 114ml,Were mixed with 360 ml of tetrahydrofuran,And the mixture was refluxed under nitrogen for 8 hours.After cooling,Extraction with water and dichloromethane,The residue was further purified by silica gel column (developing solvent: ethyl acetate / hexane = 10/1)7.6 g (34.0%) of a white solid was obtained.
  • 20
  • [ 187804-79-1 ]
  • [ 2133360-35-5 ]
  • [ 2133006-10-5 ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate In 1,2-dimethoxyethane at 150℃; for 0.5h; Inert atmosphere; Sealed tube; Microwave irradiation;
  • 21
  • [ 187804-79-1 ]
  • [ 1979137-13-7 ]
  • [ 1979136-16-7 ]
YieldReaction ConditionsOperation in experiment
11.68% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In 1,4-dioxane at 30 - 110℃; for 12h; Inert atmosphere; 11 (S)-2-((2-(3-Fluoro-4-(trifluoromethoxy)phenyl)-7,8-dihydro-1,6-naphthyridin-6(5H-yl )methyl)-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole The key intermediate B (62.32 mg, 178.17 μmol, 1.00 eq.) and [3-fluoro-4-(trifluoromethoxy)phenyl]boronic acid (39.90 mg, 178.17 μmol, 1.00 eq) were dissolved in dioxane (5.00 mL), Pd(dppf)Cl2 (13.04 mg, 17.82 μmol, 0.10 eq), sodium carbonate (47.21 mg, 445.42 μmol, 2.5 eq) were added at 30 °C under the nitrogen gas atmosphere. The mixed solution was stirred at 110 °C for 12 hours and then cooled and concentrated under reduced pressure at 45 °C. The residue was poured into water (10 mL) and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (30 mL * 3). The combined organic phases were washed with saturated brine (10 mL * 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was subjected to preliminary treatment by thin layer chromatography (petroleum ether / ethyl acetate = 1 / 2.5) and then separated and purified by preparative chromatography (GX-E; Column: Innoval C18 150*30mm*5μm; acetonitrile 30%-60%; water (0.225% fomic acid); 25mL/min) to deliver (S)-2-((2-(3-fluoro-4-(trifluoromethoxy)phenyl)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methyl)-2 -methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole compound 11 (10.70 mg, 20.82 μmol, 11.68% yield, 96% purity). 1H NMR (400 MHz, CDCl3): δ 7.86 (dd, J = 11.36, 2.07 Hz, 1H), 7.85 (d, J = 8.53 Hz, 1H), 7.72 (s, 1H), 7.52-7.49 (m, 1H), 7.47-7.39 (m, 2H), 4.43 (d, J = 9.66 Hz, 1H), 3.96 (d, J = 9.66 Hz, 1H), 3.91-3.83 (m, 2H), 3.20- 2.99 (m, 5H), 2.82 (d, J = 14.93 Hz, 1H), 1.69 (s, 3H). LCMS (ESI) m/z: 494 (M+1).
  • 22
  • [ 187804-79-1 ]
  • [ 2222986-96-9 ]
  • [ 2222660-44-6 ]
YieldReaction ConditionsOperation in experiment
95% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In ethanol; water; N,N-dimethyl-formamide; toluene at 87℃; for 2.25h; Inert atmosphere;
  • 23
  • [ 187804-79-1 ]
  • [ 2222641-64-5 ]
  • [ 2222639-60-1 ]
YieldReaction ConditionsOperation in experiment
83% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In ethanol; water; N,N-dimethyl-formamide; toluene at 87℃; for 2.33333h; Inert atmosphere;
  • 24
  • [ 187804-79-1 ]
  • [ 1379310-87-8 ]
  • [ 2227363-56-4 ]
YieldReaction ConditionsOperation in experiment
27.15 mg With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate In 1,4-dioxane; water at 90℃; for 16h; 75 Example 75. Synthesis of Compound 79 A mixture of A-72 (100 mg, 0.45 mmol), [3-fluoro-4-(trifluoromethoxy)phenyl]boronic acid (120.73 mg, 0.54 mmol), Pd(dppf)Cl2.DCM (73.39 mg, 0.09 mmol) and Cs2C03 (292.77 mg, 0.90 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was stirred at 90 C for 16 hours. After cooling to r.t, the mixture was filtered through silica gel and eluted with EtOAc (20 mL x 2). The filtrate was concentrated and diluted with EtOAc (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over Na2S04, filtered and concentrated to give the crude product, which was purified by prep-HPLC (Phenomenex Gemini (250 mm x 50 mm,10 _); A = _0 (0.05% NH4OH) and B = CH3CN; 60-70% B over 8 minutes) to afford Compound 79 (27.15 mg, 0.07 mmol) as a solid. H NMR (400MHz, CDC13) _ = 9.60 (d, 1H), 8.43 (s, 1H), 7.92 (dd, 1H), 7.79 (td, 1H), 7.53 - 7.47 (m, 1H). LCMS R, = 1.20 min using Method A, MS ESI calcd. for Ci3H6F7N40 [M+H]+ 367.0, found 366.9.
  • 25
  • [ 187804-79-1 ]
  • [ 40971-95-7 ]
  • [ 1262619-21-5 ]
YieldReaction ConditionsOperation in experiment
35.5 mg With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate In 1,4-dioxane; water at 90℃; for 16h; 31 Example 31 : Synthesis of Compound 31 A mixture of A-1 (150.00 mg, 673.98 mmol), [3-fluoro-4-(trifluoromethoxy)phenyl]boronic acid (181.10 mg, 808.78 mmol), Pd(dppf)Cl2.CH2Cl2 (82.56 mg, 101.10 mmol) and Cs2C03 (439.19 mg, 1.35 mmol) in dioxane (3 mL) and H20 (300 _) was stirred at 90 C for 16 hours. The mixture was cooled to room temperature, diluted with EtOAc (30 mL), filtered through silica gel and eluted with EtOAc (10 mL). The filtrate was concentrated to give a residue that was purified by prep-HPLC (Xtimate Ci8 (150 mm x 25 mm, 5 _); A = H20 (0.05% NH4OH) and B = CH3CN; 46-76 %B over 10 minutes) to afford Compound 31 (35.50 mg) as a solid. 1H NMR (400MHz, CDC13) _ = 8.37 (d, 1H), 7.93 (dd, 1H), 7.87 - 7.82 (m, 1H), 7.74 (d, 1H), 7.54 (t, 1H). LCMS R, = 1.21 min using Method A, MS ESI calcd. for Ci3H6F7N40 [M+H]+ 367.0, found 366.9.
  • 26
  • [ 187804-79-1 ]
  • [ 2378329-11-2 ]
  • [ 2378329-13-4 ]
YieldReaction ConditionsOperation in experiment
66% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 100℃; Inert atmosphere; 10.C Step C:
Benzyl (1-(6-(3-fluoro-4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)azetidin-3-yl)carbamate Step C: Benzyl (1-(6-(3-fluoro-4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)azetidin-3-yl)carbamate A solution of benzyl (1-(6-chloropyrimidin-4-yl)azetidin-3-yl)carbamate (86 mg, 0.27 mmol), (3-fluoro-4-(trifluoromethoxy)phenyl)boronic acid (63 mg, 0.27 mmol), K2CO3 (276 mg, 1.9 mmol), and Pd(dppf)Cl2.CH2Cl2 (11 mg, 0.013 mmol), in dioxane (1.8 mL) and water (0.22 mL) was degassed with a stream of nitrogen for 5 minutes then heated to 100° C. overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered through Celite. Purification via silica gel chromatography (0% to 100% [10% (NH3 in MeOH, 2M)/DCM] in DCM) gave the title compound (82 mg, 66%). MS (ESI): mass calcd. for C22H18F4N4O3, 462.1; m/z found, 463.1 [M+H]+.
  • 27
  • [3-fluoro-4-(trifluoromethoxy)phenyl]boronic acid [ No CAS ]
  • [ 34941-91-8 ]
  • 4-fluoro-2-(3-fluoro-4-(trifluoromethoxy)phenyl)pyridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 100℃; Inert atmosphere; 11.A Step A:
4-Fluoro-2-(3-fluoro-4-(trifluoromethoxy)phenyl)pyridine Step A: 4-Fluoro-2-(3-fluoro-4-(trifluoromethoxy)phenyl)pyridine A solution of 2-chloro-4-fluoropyridine (209 mg, 1.5 mmol), (3-fluoro-4-(trifluoromethoxy)phenyl)boronic acid (359 mg, 1.5 mmol), K2CO3 (1.6 g, 11.4 mmol), and Pd(dppf)Cl2.CH2Cl2 (63 mg, 0.08 mmol), in dioxane (10 mL) and water (1.3 mL, 70 mmol) was degassed with a stream of nitrogen for 5 minutes then heated to 100° C. overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered through Celite. Purification via silica gel chromatography (0-10% EtOAc in heptane) gave the title compound (295 mg, 70%). MS (ESI): mass calcd. for C12H6F5NO, 275.0; m/z found, 276.0 [M+H]+.
  • 28
  • [ 187804-79-1 ]
  • [ 2378329-20-3 ]
  • [ 2378320-77-3 ]
YieldReaction ConditionsOperation in experiment
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 100℃; Inert atmosphere; 15.B Step B:
N-[1-[5-Fluoro-2-[3-fluoro-4-(trifluoromethoxy)phenyl]-4-pyridyl]-4-piperidyl]acetamide Step B: N-[1-[5-Fluoro-2-[3-fluoro-4-(trifluoromethoxy)phenyl]-4-pyridyl]-4-piperidyl]acetamide A solution of N-(1-(2-chloro-5-fluoropyridin-4-yl)piperidin-4-yl)acetamide (74 mg, 0.27 mmol), (3-fluoro-4-(trifluoromethoxy)phenyl)boronic acid (83 mg, 0.35 mmol), K2CO3 (188 mg, 1.36 mmol), and Pd(dppf)Cl2.CH2Cl2 (11 mg, 0.014 mmol), in dioxane (2.7 mL) and water (0.22 mL) was degassed with a stream of nitrogen for 5 minutes then heated to 100° C. overnight. The reaction mixture was filtered through a pad a Celite and rinsed with EtOAc. The solvent was removed under reduced pressure. The crude product was taken up in MeOH and filtered through a cartridge Silicycle Silia Prep Thiol to remove Pd. Solvent was concentrated under reduced pressure, crude purified by basic prep HPLC (Agilent, Waters XBridge C18 5 um 50*100 mm column, 5-90% MeCN/20 mM NH4OH over 15 min, 80 mL/min). MS (ESI): mass calcd. for C19H18F5N3O2, 415.1; m/z found, 416.1 [M+H]+. 1H NMR (500 MHz, Chloroform-d) δ ppm 8.26 (d, J=5.1 Hz, 1H), 7.75 (dd, J=11.2, 2.2 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.36 (t, J=8.1 Hz, 1H), 7.09 (d, J=7.2 Hz, 1H), 5.44 (d, J=7.6 Hz, 1H), 4.07-3.96 (m, 1H), 3.77 (d, J=12.6 Hz, 2H), 3.07-2.95 (m, 2H), 2.14-2.06 (m, 2H), 2.00 (s, 3H), 1.64-1.52 (m, 2H).
  • 29
  • [ 187804-79-1 ]
  • [ 2378329-30-5 ]
  • [ 2378329-32-7 ]
YieldReaction ConditionsOperation in experiment
30% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 100℃; for 16h; Inert atmosphere; 18.B Step B: Step B: tert-butyl (1-(2-(3-Fluoro-4-(trifluoromethoxy)phenyl)pyridin-4-yl)-2-methylpiperidin-4-yl)carbamate tert-Butyl (1-(2-chloropyridin-4-yl)-2-methylpiperidin-4-yl)carbamate (25 mg, 0.086 mmol), (3-fluoro-4-(trifluoromethoxy)phenyl)boronic acid (20 mg, 0.086 mmol), K2CO3 (59 mg, 0.43 mmol), and Pd(dppf)Cl2.CH2Cl2 (3.5 mg, 0.004 mmol), dioxane (1.2 mL) and water (71 μL, 3.9 mmol) was combined, degassed with a stream of nitrogen for 5 minutes, and heated to 100° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered through Celite. Purification via silica gel chromatography (0-100% [10% (NH3 in MeOH, 2M)/DCM] in DCM) gave the title compound (12 mg, 30%). MS (ESI): mass calcd. for C23H27F4N3O3, 469.2; m/z found, 470.9 [M+H]+.
  • 30
  • [ 42779-56-6 ]
  • [3-fluoro-4-(trifluoromethoxy)phenyl]boronic acid [ No CAS ]
  • 4-chloro-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-methylpyridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% With 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; caesium carbonate; In 1,4-dioxane; water; at 70℃; for 16h;Inert atmosphere; Step A: 4-Chloro-2-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-methylpyridine A solution of <strong>[42779-56-6]2,4-dichloro-6-methylpyridine</strong> (150 mg, 0.93 mmol), (3-fluoro-4-(trifluoromethoxy)phenyl)boronic acid (212 mg, 0.93 mmol), palladium(II) acetate (10 mg, 0.046 mmol), cesium carbonate (754 mg, 2.3 mmol), and DPPF (26 mg, 0.046 mmol), in dioxane (4.6 mL) and water (1 mL), was degassed with nitrogen for 5 minutes, then heated to 70 C. for 16 hours. The reaction mixture was partitioned between EtOAc and a saturated aqueous solution of NaCl. The aqueous phase was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered and evaporated. Purification via silica gel chromatography (0-20% EtOAc in hexanes) gave the title compound (170 mg, 60%). MS (ESI): mass calcd. for C13H8ClF4NO, 305.0; m/z found, 306.0 [M+H]+.
  • 31
  • [ 187804-79-1 ]
  • [ 856163-79-6 ]
  • [ 2378329-50-9 ]
YieldReaction ConditionsOperation in experiment
72% With 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; caesium carbonate In 1,4-dioxane; water at 70℃; for 16h; Inert atmosphere; 25.A Step A: Step A: (4-Chloro-6-(3-fluoro-4-(trifluoromethoxy)phenyl)pyridin-2-yl)methanol A solution of (4,6-dichloropyridin-2-yl)methanol (80 mg, 0.45 mmol), (3-fluoro-4-(trifluoromethoxy)phenyl)boronic acid (103 mg, 0.45 mmol), palladium(II) acetate (5 mg, 0.022 mmol), cesium carbonate (366 mg, 1.12 mmol), and DPPF (12 mg, 0.022 mmol), in dioxane (2.2 mL) and water (0.5 mL), was degassed with nitrogen for 5 minutes then heated to 70° C. for 16 hours. The reaction mixture was partitioned between EtOAc and a saturated aqueous solution of NaCl. The aqueous phase was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered and evaporated. Purification via silica gel chromatography (0-20% EtOAc in hexanes) gave the title compound (104 mg, 72%). MS (ESI): mass calcd. for C13H8ClF4NO2, 321.0; m/z found, 322.9 [M+H]+.
  • 32
  • [ 187804-79-1 ]
  • [ 2378320-51-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate / 1,4-dioxane; water / 100 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / butan-1-ol / 48 h / 130 °C / Inert atmosphere
  • 33
  • [ 187804-79-1 ]
  • [ 2378329-40-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate / 1,4-dioxane; water / 100 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / butan-1-ol / 16 h / 150 °C / Inert atmosphere
  • 34
  • [ 187804-79-1 ]
  • [ 2378329-52-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: caesium carbonate; palladium diacetate; 1,1'-bis-(diphenylphosphino)ferrocene / 1,4-dioxane; water / 16 h / 70 °C / Inert atmosphere 2: tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 1.5 h / 150 °C / Inert atmosphere; Microwave irradiation
  • 35
  • [ 187804-79-1 ]
  • [ 2378321-40-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: caesium carbonate; palladium diacetate; 1,1'-bis-(diphenylphosphino)ferrocene / 1,4-dioxane; water / 16 h / 70 °C / Inert atmosphere 2: tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 1,4-dioxane / 1.5 h / 150 °C / Inert atmosphere; Microwave irradiation 3: trifluoroacetic acid / dichloromethane / 16 h / 20 °C / Inert atmosphere 4: sodium carbonate / water; tetrahydrofuran / 24 h / 20 °C / Inert atmosphere
  • 36
  • [ 187804-79-1 ]
  • [ 2378327-17-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate / 1,4-dioxane; water / 100 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / butan-1-ol / 48 h / 130 °C / Inert atmosphere
  • 37
  • [ 187804-79-1 ]
  • [ 2378327-28-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate / 1,4-dioxane; water / 100 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / butan-1-ol / 48 h / 130 °C / Inert atmosphere
  • 38
  • [ 187804-79-1 ]
  • [ 2378328-52-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate / 1,4-dioxane; water / 100 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / butan-1-ol / 120 h / 130 °C / Inert atmosphere
  • 39
  • [ 58530-53-3 ]
  • [3-fluoro-4-(trifluoromethoxy)phenyl]boronic acid [ No CAS ]
  • 4-bromo-2-(3-fluoro-4-(trifluoromethoxy)phenyl)pyridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
39% With palladium diacetate; triphenylphosphine; potassium hydroxide; In acetonitrile; at 70℃; for 18h;Inert atmosphere; Step A: 4-Bromo-2-(3-fluoro-4-(trifluoromethoxy)phenyl)pyridine A solution of <strong>[58530-53-3]2,4-dibromopyridine</strong> (700 mg, 2.96 mmol), 3-fluoro-4-(trifluoromethoxy)phenylboronic acid (742 mg, 3.25 mmol), KOH (331 mg, 5.91 mmol), triphenylphosphine (155 mg, 0.59 mmol), and Pd(OAc)2 (33 mg, 0.15 mmol) in MeCN (30 mL) was degassed and placed under atmosphere of nitrogen. The reaction mixture was heated at 70 C. for 18 hours then filtered through Celite and the solvent was evaporated. Purification via silica gel chromatography (0-15% EtOAc in hexanes) gave the title compound (390 mg, 39%). MS (ESI): mass calcd. for C12H6BrF4NO, 335.0; m/z found, 335.9 [M+H]+. 1H NMR (500 MHz, Chloroform-d) delta ppm 8.53 (dd, J=5.3, 0.6 Hz, 1H), 7.93-7.88 (m, 2H), 7.78 (ddd, J=8.6, 2.1, 1.3 Hz, 1H), 7.48 (dd, J=5.2, 1.8 Hz, 1H), 7.46-7.40 (m, 1H).
  • 40
  • [ 1780-26-3 ]
  • [ 187804-79-1 ]
  • [ 2378329-05-4 ]
YieldReaction ConditionsOperation in experiment
49% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 100℃; Inert atmosphere; 7.A Step A:
4-Chloro-6-(3-fluoro-4-(trifluoromethoxy)phenyl)-2-methylpyrimidine Step A: 4-Chloro-6-(3-fluoro-4-(trifluoromethoxy)phenyl)-2-methylpyrimidine A solution of 4,6-dichloro-2-methylpyrimidine (573 mg, 3.45 mmol), (3-fluoro-4-(trifluoromethoxy)phenyl)boronic acid (309 mg, 1.38 mmol), K2CO3 (1.4 g, 10.2 mmol), and Pd(dppf)Cl2.CH2Cl2 (225 mg, 0.28 mmol), in dioxane (11.5 mL) and water (1.14 mL, 63 mmol) was degassed with a stream of nitrogen for 5 minutes then heated to 100° C. overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered through Celite. Purification via silica gel chromatography (0-10% EtOAc in hexanes) gave the title compound (208 mg, 49%). MS (ESI): mass calcd. for C12H7ClF4N2O, 306.0; m/z found, 307.0 [M+H]+.
  • 41
  • [ 187804-79-1 ]
  • [ 1244949-68-5 ]
  • [ 2378329-03-2 ]
YieldReaction ConditionsOperation in experiment
42% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 100℃; Inert atmosphere; 5.A Step A:
(4-Chloro-6-(3-fluoro-4-(trifluoromethoxy)phenyl)pyrimidin-2-yl)methanol Step A: (4-Chloro-6-(3-fluoro-4-(trifluoromethoxy)phenyl)pyrimidin-2-yl)methanol A solution of (4,6-dichloropyrimidin-2-yl)methanol (78 mg, 0.44 mmol), (3-fluoro-4-(trifluoromethoxy)phenyl)boronic acid (100 mg, 0.44 mmol), K2CO3 (302 mg, 2.2 mmol), and Pd(dppf)Cl2.CH2Cl2 (18 mg, 0.02 mmol), in dioxane (3 mL) and water (0.36 mL, 20 mmol) was degassed with a stream of nitrogen for 5 minutes then heated to 100° C. overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered through Celite. Purification via silica gel chromatography (0-40% EtOAc in heptane) gave the title compound (60 mg, 42%). MS (ESI): mass calcd. for C12H7ClF4N2O2, 322.0; m/z found, 323.0 [M+H]+.
  • 42
  • [ 187804-79-1 ]
  • [ 2378329-24-7 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
59% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 100℃; Inert atmosphere; 16.C Step C:
(trans)-N-[3-Fluoro-1-[2-[3-fluoro-4-(trifluoromethoxy)phenyl]-4-pyridyl]-4-piperidyl]acetamide Step C: (trans)-N-[3-Fluoro-1-[2-[3-fluoro-4-(trifluoromethoxy)phenyl]-4-pyridyl]-4-piperidyl]acetamide A solution of N-((3,4-trans)-1-(2-chloropyridin-4-yl)-3-fluoropiperidin-4-yl)acetamide (42 mg, 0.16 mmol), (3-fluoro-4-(trifluoromethoxy)phenyl)boronic acid (47 mg, 0.20 mmol), K2CO3 (107 mg, 0.77 mmol), and Pd(dppf)Cl12.CH2Cl2 (6 mg, 0.008 mmol), in dioxane (1 mL) and water (0.13 mL, 7 mmol) was degassed with a stream of nitrogen for 5 minutes then heated to 100° C. overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered through Celite. Purification by basic prep HPLC (Agilent, Waters XBridge C18 5 um 50*100 mm column, 5-90% MeCN/20 mM NH4OH over 15 min, 80 mL/min) gave the title compound (38 mg, 59%). MS (ESI): mass calcd. for C19H18F5N3O2, 415.1; m/z found, 416.1 [M+H]+. 1H NMR (500 MHz, Chloroform-d) δ ppm 8.35 (d, J=5.9 Hz, 1H), 7.78 (dd, J=11.3, 2.1 Hz, 1H), 7.72-7.64 (m, 1H), 7.39-7.32 (m, 1H), 7.02 (d, J=2.5 Hz, 1H), 6.67 (dd, J=6.0, 2.5 Hz, 1H), 5.90 (d, J=7.7 Hz, 1H), 4.52-4.34 (m, 1H), 4.23-4.08 (m, 2H), 3.80 (d, J=12.9 Hz, 1H), 3.16-3.02 (m, 2H), 2.30-2.21 (m, 1H), 2.01 (s, 3H), 1.62-1.48 (m, 1H).
  • 43
  • [ 187804-79-1 ]
  • [ CAS Unavailable ]
  • [ 2378328-09-5 ]
YieldReaction ConditionsOperation in experiment
22% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 100℃; for 16h; Inert atmosphere; 17.C Step C:
(*R/*R)-N-[3-fluoro-1-[5-fluoro-2-[3-fluoro-4-(trifluoromethoxy)phenyl]-4-pyridyl]-4-piperidyl]acetamide Step C: (*R/*R)-N-[3-fluoro-1-[5-fluoro-2-[3-fluoro-4-(trifluoromethoxy)phenyl]-4-pyridyl]-4-piperidyl]acetamide A solution of N-((3,4-trans)-1-(2-chloro-5-fluoropyridin-4-yl)-3-fluoropiperidin-4-yl)acetamide (32 mg, 0.11 mmol), (3-fluoro-4-(trifluoromethoxy)phenyl)boronic acid (34 mg, 0.14 mmol), K2CO3 (76 mg, 0.55 mmol), and Pd(dppf)Cl2.CH2Cl2 (5 mg, 0.006 mmol), in dioxane (1.1 mL) and water (0.1, 5 mmol), was degassed with a stream of nitrogen for 5 minutes, then heated to 100° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered through Celite. Purification by basic prep HPLC (Agilent, Waters XBridge C18 5 um 50*100 mm column, 5-90% MeCN/20 mM NH4OH over 15 min, 80 mL/min) gave the racemic title compound (26 mg, 54%). The racemic compound was then separated via SFC chiral separation (Stationary phase: Chiralpak IF 5 μm 250*21 mm, Mobile phase: 18% methanol, 82% CO2, 2 mL/min, 150 Bar, retention time: 3.30 min at 254 nM) to afford the tile compound (11 mg, 22%). MS (ESI): mass calcd. for C19H17F6N3O2, 433.1; m/z found, 434.1 [M+H]+. 1H NMR (500 MHz, Chloroform-d) δ ppm 8.31 (d, J=4.7 Hz, 1H), 7.77 (dd, J=11.2, 2.1 Hz, 1H), 7.68-7.63 (m, 1H), 7.40-7.34 (m, 1H), 7.11 (d, J=7.1 Hz, 1H), 5.61 (d, J=7.7 Hz, 1H), 4.53 (dtd, J=49.4, 9.4, 4.8 Hz, 1H), 4.22-4.10 (m, 1H), 4.08-4.00 (m, 1H), 3.72-3.65 (m, 1H), 3.12-3.00 (m, 2H), 2.36-2.26 (m, 1H), 2.05 (s, 3H), 1.72-1.61 (m, 1H).
  • 44
  • [ 187804-79-1 ]
  • [ 1912896-55-9 ]
  • [ 2378320-18-2 ]
YieldReaction ConditionsOperation in experiment
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water; N,N-dimethyl-formamide at 100℃; Inert atmosphere; 2.B Step B: N-[1-[6-[3-Fluoro-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]-4-piperidyl]acetamide N-(1-(6-chloropyrimidin-4-yl)piperidin-4-yl)acetamide (3.6 g, 14.3 mmol), 3-fluoro-4-(trifluoromethoxy)phenylboronic acid (3.7 g, 15.8 mmol), and Pd(PPh3)4 (414 mg, 0.358 mmol) was combined in 1,4-dioxane (60 mL) DMF (15 mL) and 2M Na2CO3 (aq) (18 mL). The resulting mixture was degassed with N2 and heated overnight at 100° C. The reaction was cooled to room temperature and partitioned between DCM and H2O. The layers were separated and the aqueous was extracted with DCM (3×). The organic layers were combined and washed with brine (2×50 mL), dried over MgSO4, filtered and concentrated. The crude residue was dissolved in 50 mL of DMF and SiliaMetS Thiol Pd scavenger (1.1 g, 1.28 mmol/g) was added as a powder. The resulting suspension was capped and stirred at room temperature overnight. The suspension was filtered through a pad of Celite and 100 mL of H2O was added to the solution. The resulting precipitate was collected and via filtration to obtain a yellow solid. These solids were suspended in a mixture of 4:1 Hexanes:EtOAc (100 mL) and stirred vigorously for 30 minutes. The mixture was filtered and the solids were dried under vacuum to obtain a pale yellow solid. These solids were dissolved in 1:1 DCM:MeOH (100 mL) and activated charcoal was added. The suspension was stirred overnight at room temperature. The activated charcoal was removed via filtration and the filtrate was concentrated and dried under vacuum to obtain the title compound as a white solid (3.6 g, 63%). MS (ESI): mass calcd. for C18H18F4N4O2, 398.1; m/z found, 399.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.58 (d, J=1.1 Hz, 1H), 8.30 (dd, J=12.0, 2.1 Hz, 1H), 8.15 (ddd, J=8.6, 2.1, 1.1 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.72-7.66 (m, 1H), 7.44 (d, J=1.2 Hz, 1H), 4.44 (d, J=12.9 Hz, 2H), 3.94-3.83 (m, 1H), 3.15 (ddd, J=13.8, 11.2, 2.6 Hz, 2H), 1.87-1.77 (m, 5H), 1.40-1.27 (m, 2H).
  • 45
  • [ 187804-79-1 ]
  • [ 40314-71-4 ]
  • [ 2378329-36-1 ]
YieldReaction ConditionsOperation in experiment
31% With 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; caesium carbonate In 1,4-dioxane; water at 70℃; for 16h; Inert atmosphere; 20.A Step A: Step A: 4-Chloro-6-(3-fluoro-4-(trifluoromethoxy)phenyl)picolinonitrile A solution of (4,6-dichloropyridine-2-carbonitrile) (150 mg, 0.87 mmol), (3-fluoro-4-(trifluoromethoxy)phenyl)boronic acid (198 mg, 0.87 mmol), palladium(II) acetate (9.7 mg, 0.043 mmol), cesium carbonate (706 mg, 2.17 mmol), and DPPF (24 mg, 0.043 mmol), in dioxane (4.3 mL) and water (0.94 mL), was degassed with nitrogen for 5 minutes, then heated to 70° C. for 16 hours. The reaction mixture was partitioned between EtOAc and a saturated aqueous solution of NaCl. The aqueous phase was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered and evaporated. Purification via silica gel chromatography (0-20% EtOAc in hexanes) gave the title compound (86 mg, 31%). 1H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J=1.8 Hz, 1H), 8.38 (d, J=1.7 Hz, 1H), 8.32-8.27 (m, 1H), 8.16-8.11 (m, 1H), 7.79-7.70 (m, 1H).
  • 46
  • [ 187804-79-1 ]
  • [ 2091605-25-1 ]
  • [ 2472972-29-3 ]
YieldReaction ConditionsOperation in experiment
77.1% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; N,N-dimethyl-formamide at 70℃; for 3h; Inert atmosphere; 2.1 (1) Synthesis of compound BYLC-02-1: Under the protection of nitrogen, add 65.2g compound (0.291mol), 67.5g compound (0.291mol) into the reaction flask,200ml N,N-dimethylformamide, 100ml deionized water,72.8g of anhydrous potassium carbonate (0.53mol), 0.5g of tetrakistriphenylphosphine palladium, heated to 70°C for 3 hours.Routine post-treatment, purification by chromatography, elution with n-hexane, and recrystallization from ethanolObtained a white solid (compound BYLC-02-1, 0.224mol) 83.8g, GC: 99.8%,Yield: 77.1%.
  • 47
  • [ 187804-79-1 ]
  • [ 33035-41-5 ]
  • [ CAS Unavailable ]
  • [ 2380214-36-6 ]
YieldReaction ConditionsOperation in experiment
74% Stage #1: [3-fluoro-4-(trifluoromethoxy)phenyl]boronic acid With boron trifluoride diethyl etherate In dichloromethane at 0℃; for 0.166667h; Sealed tube; Inert atmosphere; Stage #2: 2-(diacetoxyiodo)mesitylene In dichloromethane at 0 - 20℃; Sealed tube; Inert atmosphere; Stage #3: sodium tosylate In dichloromethane; water for 0.005h; Inert atmosphere;
  • 48
  • [ 187804-79-1 ]
  • [ 2638530-69-3 ]
  • [ 2638530-04-6 ]
YieldReaction ConditionsOperation in experiment
36% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate monohydrate In 1,4-dioxane; water at 100℃; for 24h; Preparation of compound 1 A mixture of intermediate A4 (300 mg, 0.845 mmol), 3 -fluoro-4-(trifluorom ethoxy) phenylboronic acid (CAS [187804-79-1], 227 mg, 1.01 mmol) and Potassium phosphate monohydrate (584 mg, 2.53 mmol) in 1,4-Dioxane (3.2 mL) and water (0.80 mL) was purged with argon (vacuum/argon: 3 times). [1,1- Bis(diphenylphosphino)ferrocene] dichloropalladium(II) (61.8 mg, 84.5 pmol) was added and the reaction mixture was purged with argon (vacuum/argon: 3 times). The resulting mixture was stirred at 100°C for 24 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL), filtered through a glass frit to collect after rinsing with water (3 x 5 mL) a black solid, 0.41 g. It was purified by flash chromatography on silica gel (25 g), DCM/Methanol 100/0 to 98/2 over 50 min to afford an off-white solid, 0.311 g. It was triturated with methanol (2 x 3 mL) and dried under high vacuum at 50°C (for 18 h) to afford Compound 1 as a white solid, 0.289 g, 75%. NMR (400 MHz, DMSO-d6) d ppm 11.91 (s, 1H), 9.64-9.61 (m, 1H), 8.24 (dd, J = 9.3 Hz, 1.8 Hz, 1H), 8.17-8.09 (m, 3H), 7.93 (d, J = 8.3 Hz, 1H), 7.89-7.84 (m, 1H), 7.76 (t, J = 8.0 Hz, 1H), 7.69-7.63 (m, 1H), 7.36-7.30 (m, 1H), 2.42 (s, 3H).
  • 49
  • [ 187804-79-1 ]
  • [ 1831116-38-1 ]
  • [ 2750005-05-9 ]
YieldReaction ConditionsOperation in experiment
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 110℃; for 2h; Microwave irradiation; Sealed tube; Inert atmosphere;
  • 50
  • [ 187804-79-1 ]
  • [ 2529550-24-9 ]
  • [ 2529550-28-3 ]
YieldReaction ConditionsOperation in experiment
92% With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate In ethylene glycol dimethyl ether; lithium hydroxide monohydrate at 58℃; for 18h; Inert atmosphere; 207D Example 207D: tert-butyl (3-(4-(3-fluoro-4-(trifluoromethoxy)phenyl)-1H-pyrazol-1- yl)bicyclo[1.1.1]pentan-1-yl)carbamate Potassium carbonate (105 mg, 0.762 mmol), tris(dibenzylideneacetone)dipalladium(0) (42 mg, 0.046 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (27 mg, 0.092 mmol), 3-fluoro-4-(trifluoromethoxy)phenylboronic acid (82 mg, 0.366 mmol, Combi- Blocks), and the product of Example 207C (100 mg, 0.305 mmol) were combined with 1,2- dimethoxyethane (5 mL) and water (0.5 mL) in a 20 mL vial. The vial was sealed and degassed three times with a nitrogen backflush each time. It was then heated at 58 °C for 18 hours. The reaction mixture was cooled to ambient temperature, and then partitioned between dichloromethane (2 × 30 mL) and aqueous sodium carbonate (1.0 M, 30 mL). The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC [YMC TriArt C18 Hybrid 5 μm column, 50 × 100 mm, flow rate 140 mL/minute, 15-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (0.12 g, 0.28 mmol, 92% yield). MS (APCI+) m/z 428 (M+H)+.
92% With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate In ethylene glycol dimethyl ether; lithium hydroxide monohydrate at 58℃; for 18h; Inert atmosphere; 207D Example 207D: tert-butyl (3-(4-(3-fluoro-4-(trifluoromethoxy)phenyl)-1H-pyrazol-1- yl)bicyclo[1.1.1]pentan-1-yl)carbamate Potassium carbonate (105 mg, 0.762 mmol), tris(dibenzylideneacetone)dipalladium(0) (42 mg, 0.046 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (27 mg, 0.092 mmol), 3-fluoro-4-(trifluoromethoxy)phenylboronic acid (82 mg, 0.366 mmol, Combi- Blocks), and the product of Example 207C (100 mg, 0.305 mmol) were combined with 1,2- dimethoxyethane (5 mL) and water (0.5 mL) in a 20 mL vial. The vial was sealed and degassed three times with a nitrogen backflush each time. It was then heated at 58 °C for 18 hours. The reaction mixture was cooled to ambient temperature, and then partitioned between dichloromethane (2 × 30 mL) and aqueous sodium carbonate (1.0 M, 30 mL). The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC [YMC TriArt C18 Hybrid 5 μm column, 50 × 100 mm, flow rate 140 mL/minute, 15-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (0.12 g, 0.28 mmol, 92% yield). MS (APCI+) m/z 428 (M+H)+.
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