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CAS No. : | 153254-09-2 | MDL No. : | MFCD01631349 |
Formula : | C8H5BF6O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WLYPBMBWKYALCG-UHFFFAOYSA-N |
M.W : | 257.93 | Pubchem ID : | 2782667 |
Synonyms : |
|
Num. heavy atoms : | 17 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 8.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 46.27 |
TPSA : | 40.46 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.03 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 2.59 |
Log Po/w (WLOGP) : | 3.71 |
Log Po/w (MLOGP) : | 2.39 |
Log Po/w (SILICOS-IT) : | 1.43 |
Consensus Log Po/w : | 2.02 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.13 |
Solubility : | 0.189 mg/ml ; 0.000734 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.09 |
Solubility : | 0.21 mg/ml ; 0.000816 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.06 |
Solubility : | 0.222 mg/ml ; 0.000861 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.05 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In 1,4-dioxane; water; | Example 2 1,3,6,8-Tetrakis-(2,4-bis-trifluoromethyl-phenyl)-pyrene 3.95 g (0.0116 mol) of 1,3,6,8-tetrachloro-pyrene, 15.0 g (0.0582 mol) of <strong>[153254-09-2]2,4-bis(trifluoromethyl)phenylboronic acid</strong>, 1.33 g (0.00145 mol) of tris(dibenzylideneacetone) dipalladium (0), 0.64 g (0.00276 mol) of di-tert-butyl-trimethylsilylmethyl-phosphane, 18.95 g (0.0582 mol) of cesium carbonate and 100 ml of dioxane were stirred at room temperature for 24 hours. The resultant mixture was poured into 200 ml of water and extracted twice with 200 ml of methylene chloride. The organic phase was dried over magnesium sulfate overnight and filtered. The solvent was removed on a roto-evaporator and the residue was purified by chromatography on silica gel with petroleum ether/ethyl ether (10/0.5) as eluent. Yield of 1,3,6,8-tetrakis-(2,4-bis-trifluoromethyl-phenyl)-pyrene: 1.08 g (8.85%) as a white solid with m.p. 290.00 C. 1H NMR (CDCl3) 7.45-8.30 (multiplets, 18H, arom-H). 19F NMR (CDCl3) -59.16, -63.27. The structure was confirmed by X-ray analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With potassium fluoride; tetra-(n-butyl)ammonium iodide;trans-bis(triphenylphosphine)palladium dichloride; In tetrahydrofuran; water; for 48h;Heating / reflux; | Example 15; 4-(2 ', 4 '-Bis(trifluoromethyl)phenyl)furan-2(5H)-one 15; A mixture containing 4-bromo-5(H)furanone (0.331 g, 2.031 mmol), (24'- bis(trifluoromethyl)phenyl)botauomc acid (0.641 g, 2.485 mmol), trans- dichlorobis(triphenylphosphine)palladium (II) (0.075 g, 1.069XlO*1 mmol), tetrabutylammonium iodide (0.037 g, 1.002XlO*1 mmol) and aqueous potassium fluoride (2M5 5 mL, 10.000 mmol) in tetrahydrofuran (15 mL) was refluxed for 48 h under nitrogen before the reaction mixture was allowed to cool to room temperature. Brine (50 mL) was added and the product extracted with dichloromethane (3x20 mL). The organic fractions were combined, washed with brine (3x20 mL), dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give a brown solid. The resulting solid was chromatographed (silica gel: eluent 50:50 dichloromethane/light petroleum) to give 4-(2',4'-bis(trifluoromethyl)phenyl)furan-2(5H)-one 15 (0.169 g, 28%) as a pale yellow powder. Recrystallisation from dichloromethane/light petroleum furnished <n="35"/>colourless needles, m.p. 116-1170C (ref. PDS-2-81). UV-Vis lambdamax (MeOH) 204(47498) nm; 1H NMR (CDCl3, 300 MHz) delta 8.05 (s, IH, H3'), 7.93 (d, IH, J= 7.9 Hz, H51), 7.56 (d, IH, J= 7.9 Hz, H61), 6.30 (t, IH, J= 1.9 Hz, H3), 5.09 (d, IH, J= 2.3 Hz, H5); 13C NMR (CDCl3, 75 MHz) delta 171.9 (C2), 161.4 (C4), 133.7 (Cl1), 132.6 (q, J= 33.9 Hz, C4'-CF3), 130.3 (C3), 129.2 (q, J = 32.5 Hz, C2'-CF3), 129.1 (d, J = 2.9 Hz, C5'), 124.6 (d, J = 2.2 Hz, C4'), 124.0 (ddd, J= 4.3 Hz, J = 7.9 Hz, J= 9.4 Hz, C6'), 121.4 (d, J= 2.2 Hz, C31), 121.0 (d, J= 2.9 Hz, C21), 73.3 (d, J= 2.2 Hz, C5); 19F NMR (CDCl3, 470 MHz) delta -59.04 (s, 3F, C2'-CF3), -63.66 (s, 3F, 04'-CF3); IR (KBr) 3138, 3104, 3057, 2938, 1792, 1742, 1649, 1624, 1584, 1510, 1466, 1438, 1353, 1315, 1281, 1269, 1205, 1168, 1144, 1128, 1087, 1068, 1042, 994, 918, 896, 882, 871, 859, 825, 762, 751, 733, 708, 687, 673, 661, 617, 583, 552, 479, 465 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41.9% | With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃; | Example 1.48; Preparation of (2',4'-Bis-trifluoromethyl-biphenyl-4-yl)-(4-bromo-2-methyl-2H-pyrazol-3- yl)-amine (Compound 34).A 20-mL scintillation vial was charged with (4-bromo-2-methyl-2H-pyrazol-3-yl)-(4- iodo-phenyl)-amine (80.0 mg, 0.21 mmol), 2,4-di-(trifluoromethyl)phenyl boronic acid (81.9 mg, 0.32 mmol), cesium carbonate (137.9 mg, 0.42 mmol), 1,2-dimeth?xyethane (1.5 mL) and water (0.2 mL). The reaction mixture was purged with argon, tetrakis(triphenylphosphine) palladium(O) (24.5 mg, 0.02 mmol) was added then the reaction vessel purged with argon again. The reaction mixture was heated at 800C overnight. Then, it was allowed to cool to ambient temperature, filtered and subjected to a purification by prep EtaPLC (0.05% TFA). The corresponding fractions were collected and lyophilized to afford Compound 34 as a white solid. Yield: 40.8 mg (41.9 %). LCMS m/z (%) =464 (M+Eta79Br, 90), 466 (M+HslBr, 100). 1H NMR (400MHz, CDCl3): delta 3.77 (s, 3H), 5.39 (s, IH), 6.66 (dd, J=6.6, 1.8 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 7.56 (s, IH), 7.80 (d, J=7.6 Hz, IH), 7.99(s, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With Ba(OH)2;Pd(PPh3)4; | Step A Tert-butyl (8aS,12aR)-2-[2,4-bis(trifluoromethyl)phenyl]-4,5,6,7,8a,9,10,11,12,12a-decahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.047 g, 17%) was prepared by the general method of Example 319, step A from tert-butyl (8aS,12aR)-2-bromo-4,5,6,7,9,10,12,12a-octahydroazepino[3,2,1-hi]pyrido[4,3-b]indole-11(8aH)-carboxylate (0.20 g, 0.50 mmol), <strong>[153254-09-2]2,4-bis(trifluoromethyl)phenylboronic acid</strong> (0.26 g, 1.0 mmol), Pd(PPh3)4 (12 mg, 0.010 mmol), and Ba(OH)2 (2 M, 1.0 mL, 2.0 mmol) as a white foam. MS (ESI): 541 (base, M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With sodium carbonate;Pd(PPh3)2Cl2; | Step A Tert-butyl (7aS,11aR)-2-[2,4-bis(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (0.029 g, 11%) was prepared by the general method of Example 89, step C from tert-butyl (7aS,11aR)-2-bromo-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (0.20 g, 0.50 mmol), <strong>[153254-09-2]2,4-bis(trifluoromethyl)phenylboronic acid</strong> (0.26 g, 1.0 mmol), Pd(PPh3)2Cl2 (17 mg, 0. 025 mmol), Na2CO3 (2.0 M, 1.0 mL, 2.0 mmol) as a white foam. MS (ESI): 527 (base, M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; water; at 120℃; for 0.333333h;microwave irradiation; | In a microwave tube was placed 3-(1-chlorophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide (0.097 g, 0.29 mmol), <strong>[153254-09-2]2,4-bis(trifluoromethyl)benzeneboronic acid</strong> (0.074 g, 0.29 mmol), tetrakis(triphenylphosphine)palladium (0) (0.033 g, 0.029 mmol) and 2M potassium carbonate (0.43 mL, 0.86 mmol) in 1.5 mL of DME/EtOH (4/1). The mixture was heated in the microwave at 120 C. for 20 minutes. After cooling, water was added and the mixture was extracted with DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude product was purified by HPLC to give 3-(1-(2,4-bis(trifluoromethyl)phenyl)phthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide as an off-white solid. MS (ES+)=516.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With triethylamine;copper diacetate; In 1,2-dichloro-ethane; at 50℃; for 3h; | Step 1: N'-(2,4-Bis-trifluoromethyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 1.00 g, 6.8 mmol), <strong>[153254-09-2]2,4-bis(trifluoromethyl)phenylboronic acid</strong> (Ryscor; 1.75 g, 6.8 mmol), copper(II) acetate (1.24 g, 6.8 mmol) and triethylamine (960 muL, 6.8 mmol) in 1,2-dichloroethane (15 mL) was heated in an oil bath at 50 C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluding with 10% ethyl acetate/hexanes, to give N'-(2,4-bis-trifluoromethyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (646 mg, 36%) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 170℃; for 0.25h;microwave irradiation; | To a solution of methyl 3-bromo-4-(4-(trifluoromethyl)phenyl)phenylacetate (.5g ; 1.34mmol) and <strong>[153254-09-2]2,4-bis(trifluoromethyl)benzeneboronic acid</strong> (.52g; 2.00mmol) in 1,4-dioxan (4ml) and saturated sodium carbonate solution (ImI) was added [1,1'- bis(diphenylphosphino)ferrocene]palladium(?) chloride (0.049g ; 0.067mmol). The reaction mixture was heated in a microwave reactor at 1700C for fifteen minutes then poured onto water and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with brine, dried over magnesium sulphate filtered and evaporated under reduced pressure to give an oil. The oil was absorbed onto silica and purified by flash chromatography using a gradient elution iso-hexane to iso-hexane/ethyl acetate (10:1) as eluant. The appropriate fractions were combined and evaporated under reduced pressure to give the title compound Yield = 0.5g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a reactor, containing 2,4-bis(trifluoromethyl)bromobenzene (1.00 eq) and tetrahydrofuran (THF), was charged Isopropyl magnesium chloride (1PrMgCl) (2 M in THF, 1.14 eq) while maintaining the content at -10 C. The mixture was agitated at -10 C. until the reaction was completed by HPLC analysis. The resultant mixture was transferred to the second reactor, containing trimethyl borate (2.26 eq) and THF held at a temperature of -10 C. The reaction was then monitored by HPLC until 1,3-bis(trifluoromethyl)benzene was not more than 2%. Aq. HCl (aqueous hydrochloric acid), prepared from water and concentrated 37% hydrochloric acid (HCl) were then added to quench the reaction while maintaining the content at not more than 25 C. After agitating the content for 1-2 h and settling for ca. 30 minutes, the layers were separated. The organic layer was washed with brine solution mixed with water and then concentrated under vacuum. Heptane was charged and the content was further concentrated under vacuum. The operations were repeated one more time. Heptane was then charged and the resultant slurry is cooled to 3 C., and agitated at the temperature for 4-6 h.The product was filtered, washed with heptane twice and dried under vacuum at a maximum of 40 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3-Chloro-6-methylpyridazine (1.00 eq), 2-(dicyclohexylphosphino)biphenyl (0.05 eq), <strong>[153254-09-2]2,4-bis(trifluoromethyl)phenylboronic acid</strong> (1.85 eq), 1,2-dimethoxyethane and aqueous potassium carbonate solution were all charged into a reactor. After degassing three times with nitrogen, palladium acetate (0.025 eq) was charged and the content is heated and agitated under reflux until the reaction was deemed complete.The reaction mixture was cooled to 22 C. Heptane was charged, followed by addition of Celite. After agitating for ca. 30 minutes at 22 C., the mixture was filtered into the first reactor, rinsing forward with a mixture of 1,2-dimethoxyethane and Heptanes. The layers of the filtrate are separated.To the organic layer was charged borane trimethylamine complex (0.03 eq), water, and acetic acid. The resultant mixture with a pH at maximum 4 was agitated for 1-2 h at 22 C. and then refluxed at ca. 80 C. for 2-3 h. After cooling back to 22 C., the mixture was adjusted to pH 10-11 with addition of 5% aq. sodium hydroxide while maintaining the content at 22 C. and then agitated for 1-2 h. The mixture was filtered and the layers were separated. The aq. layer was disposed of and the organic layer was filtered through ZetaCarbon cartridges into the in-process cleaned first reactor, rinsing forward with 1,2-dimethoxyethane through the carbon cartridges.The filtrate was concentrated under vacuum with a maximum jacket setting of 60 C. Heptane was charged and the contents were further concentrated under vacuum with a maximum jacket setting of 60 C. Additional Heptane was charged to the concentrate and the 1,2-dimethoxyethane (DME) content (maximum 0.5%) of the mixture was checked by NMR. After adjusting to 85 C. and agitating for ca. 1 h, the mixture was polished filtered hot through a filter into the second reactor.The filtrate in the second reactor was adjusted to reflux and then agitated for 1 h. With ramp cooling and moderate agitation, the mixture is cooled from reflux to 0 to 6 C. over a period of minimum 4 h and then agitated at 0 to 6 C. for 1 h.The product was filtered, washed with ambient temperature Heptanes and dried under vacuum at a maximum of 40 C. until loss on drying is maximum 1%. w/w Mole v/w Materials M.W. Ratio Ratio Ratio 2,4-Bis(trifluoromethyl)phenyl- 257.92 4.00 1.85 - boronic acid Borane trimethylamine complex 72.92 0.018 0.03 - 3-Chloro-6-methylpyridazine 128.56 1.00 1.00 - Diatomaceous earth (celite) N/A 0.30 - - Di(cyclohexyl)phosphinobiphenyl 350.49 0.14 0.05 - 1,2-Dimethoxyethane 90.12 12.00 - 13.80 Drinking water 18.02 3.75 - 3.75 Glacial acetic acid 60.05 0.05 0.10 - Heptanes 100.21 20.40 - 29.80 Palladium (II) acetate 224.49 0.044 0.025 - Potassium carbonate, 138.21 2.15 2.00 - Sodium hydroxide, 5% solution 40.00 - - - | ||
With sodium carbonate;tetrakis(triphenylphosphine)palladium (0); In toluene; | Step 2. 3-(2,4-Bis-trifluoromethyl-phenyl)-6-methyl-pyridazine A solution of 3-chloro-6-methyl-pyridazine (2.56 g, 20 mmol), 2,4-bis-trifluoromethyl-phenyl-boronic acid (7.7 g, 30 mmol), tetrakistriphenylphosphine palladium(0) (5 mol %, 1.1 g) in toluene: 2N Na2CO3 (4:1, 100 mL total) was sparged with argon for 3 minutes then heated to 100 C. for 20 hours. The reaction was partitioned, the aqueous phase washed with EtOAc (2*50 mL) and the organics combined, dried (brine, Na2SO4) and purified on silica gel eluding with 10-60% hexanes:EtOAc, yielding the product (1.9 g) as a brown solid. | |
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In toluene; at 100℃; for 20h;Inert atmosphere; | Step 2. 3-(2,4-Bis-trifluoromethyl-phenyl)-6-methyl-pyridazine A solution of 3-chloro-6-methyl-pyridazine (2.56 g, 20 mmol), 2,4-bis-trifluoromethyl-phenyl-boronic acid (7.7 g, 30 mmol), tetrakistriphenylphosphine palladium(0) (5 mol %, 1.1 g) in toluene: 2N Na2CO3 (4:1, 100 nIL total) was sparged with argon for 3 minutes then heated to 100 C. for 20 hours. The reaction was partitioned, the aqueous phase washed with EtOAc (2*50 mL) and the organics combined, dried (brine, Na2SO4) and purified on silica gel eluding with 10-60% hexanes:EtOAc, yielding the product (1.9 g) as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃; for 72h;Product distribution / selectivity; | Compound A was dissolved in dimethoxyethane (DME). To this solution was added 2,4-bis(trifluromethyl)phenylboronic acid and a 2N aq. Na2CO3 solution. To the resulting biphasic mixture was added Pd(PPh3)4 and the reaction was then heated at 80 C. for 72 hrs. The reaction was cooled to room temperature and filtered through Celite and the Celite washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified on 6 g SiO2 using MeOH/CH2Cl2 to elute compound. The compound thus obtained was contaminated with PPh3(O). The product was repurified on a 1 mm Chromatotron plate with 0 to 5% MeOH/CH2Cl2 in 1% steps. The pure fractions were combined and concentrated in vacuo, then dried on high vacuum for 12 hrs. 11.8 mg of the free base of compound (1) was obtained with no PPh3 contamination. 1H NMR (300 MHz, CD3OD) 6.20 (s, 2) 7.32 (m, 3) 7.52 (m, 1) 7.78 (d, 1) 7.89 (d, 1) 7.95 (s, 2) 8.15 (m, 3) 8.35 (d, 1) 9.12 (s, 1) LC/MS M+H=518 | |
11.8 mg | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 72h; | Example 1 : 5-({6-[2,4-bis(trifluoromethyl)phenyl]pyridazin-3-yl}methyl)-2-(2-fluorophenyl)-5H- imidazo[4,5-c]pyridi Compound 103 was dissolved in dimethoxyethane (DME). To this solution was added 2,4-bis(trifluromethyl)phenylboronic acid 105 and a 2N aq. Na2C03 solution. To the resulting biphasic mixture was added Pd(PPh3)4 and the reaction was then heated at 80C for 72 hrs. The reaction was cooled to room temperature and filtered through Celite and the Celite washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified on 6g Si02 using MeOH/CH2CI2 to elute compound. The compound thus obtained was contaminated with PPh3(0). The product was repurified on a 1 mm Chromatotron plate with 0 to 5% MeOH/CH2CI2 in 1 % steps. The pure fractions were combined and concentrated in vacuo, then dried on high vacuum for 12 hrs. 11.8 mg of the free base of compound 1 was obtained with no PPh3 contamination. 1H NMR (300MHz,CD3OD) delta 6.20 (s, 2), 7.32 (m, 3), 7.52 (m, 1 ), 7.78 (d, 1), 7.89 (d, 1), 7.95 (s, 2), 8.15 (m, 3), 8.35 (d, 1), 9.12 (s, 1); LC/MS M+H = 518. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 57 5-(2',4'-Bis-trifluoromethyl-biphenyl-4-ylmethyl)-2-(2,3-difluoro-phenyl)-5H-imidazo[4,5-d]pyridazine (Compound 244) From 5-(4-Bromo-benzyl)-2-(2,3-difluoro-phenyl)-5H-imidazo[4,5-d]pyridazine and 2,4-Bis-trifluoromethyl-phenylboronic acid following general procedure A. MS 535 (M+H+); H1 NMR (DMSO-d6): delta(ppm) 10.52 (s, 1H), 9.72 (s, 1H), 8.15 (m, 3H), 7.7-7.38 (m, 7H), 6.01 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6-(2,4-Bis-trifluoromethyl-phenyl)-3-[2-(2,3-difluoro-phenyl)-imidazo[4,5-d]pyridazin-5-ylmethyl]-pyridin-2-ylamine (Compound 360) From {6-Chloro-3-[2-(2,3-difluoro-phenyl)-imidazo[4,5-d]pyridazin-5-ylmethyl]-pyridin-2-yl}-carbamic acid tert-butyl ester and 2,4-Bis-trifluoromethyl-phenylboronic acid following general procedure A. MS 551 (M+H+); H1 NMR (DMSO-d6): delta(ppm) 10.18 (s, 1H), 9.59 (s, 1H), 8.17 (m, 3H), 7.78-7.38 (m, 4H), 6.71 (m, 1H), 5.85 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5-[6-(2,4-Bis-trifluoromethyl-phenyl)-pyridin-3-ylmethyl]-2-(2,3-difluoro-phenyl)-5H-imidazo[4,5-d]pyridazine (Compound 130) From 5-(6-Chloro-pyridin-3-ylmethyl)-2-(2,3-difluoro-phenyl)-5H-imidazo[4,5-d]pyridazine and 2,4-bistrifluoromethyl-phenylboronic acid following general procedure A. MS 536.0 (M+H+); H1 NMR (DMSO-d6): delta(ppm) 10.14 (s, 1H), 9.46 (s, 1H), 8.85 (m, 1H), 8.16 (m, 3H), 8.01 (m, 1H), 7.80 (m, 1H), 7.68-7.52 (m, 2H), 7.34 (m, 1H), 5.98 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 69 5-(2',4'-Bis-trifluoromethyl-biphenyl-3-ylmethyl)-2-(2,3-difluoro-phenyl)-5H-imidazo[4,5-d]pyridazine (Compound 256) From 5-(3-Bromo-benzyl)-2-(2,3-difluoro-phenyl)-5H-imidazo[4,5-d]pyridazine and 2,4-Bis-trifluoromethyl-phenylboronic acid following general procedure A. MS 535 (M+H+); H1 NMR (DMSO-d6): delta(ppm) 10.30 (s, 1H), 9.58 (s, 1H), 8.11 (s, 3H), 7.70-7.23 (m, 7H), 6.09 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 70 2-(2,3-Difluoro-phenyl)-5-(3-fluoro-2',4'-bis-trifluoromethyl-biphenyl-4-ylmethyl)-5H-imidazo[4,5-d]pyridazine (Compound 257) From 5-(4-Bromo-2-fluoro-benzyl)-2-(2,3-difluoro-phenyl)-5H-imidazo[4,5-d]pyridazine and 2,4-Bis-trifluoromethyl-phenylboronic acid following general procedure A. MS 553 (M+H+); H1 NMR (DMSO-d6): delta(ppm) 10.25 (s, 1H), 9.55 (s, 1H), 8.08 (m, 3H), 7.60-7.33 (m, 7H), 6.00 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5-{1-[5-(2,4-Bis-trifluoromethyl-phenyl)-pyridin-2-yl]-ethyl}-2-(2,3-difluoro-phenyl)-5H-imidazo[4,5-d]pyridazine (Compound 305) From <strong>[153254-09-2]2,4-bis(trifluoromethyl)phenylboronic acid</strong> and 5-[1-(5-bromo-pyridin-2-yl)-ethyl]-2-(2,3-difluoro-phenyl)-5H-imidazo[4,5-d]pyridazine following general procedure A. MS: 550.1 (M+H+); H1 NMR (DMSO-d6): delta(ppm) 10.49 (s, 1H), 9.70 (s, 1H), 8.51-8.53 (m, 1H), 8.10-8.21 (m, 3H), 7.90-7.98 (m, 1H), 7.65-7.76 (m, 3H), 7.41-7.52 (m, 1H), 6.53 (q, 1H), 2.17 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With PS-DIPEA;bis-triphenylphosphine-palladium(II) chloride; tri tert-butylphosphoniumtetrafluoroborate; In water; acetonitrile; for 8h;Reflux; | A solution of 5-bromo-2-(quinolin-4-ylmethyl)aminosulfonyl-benzoic acid methyl ester (0.50 g, 1.2 mmol, prepared according to 1.1.2) and 2,4-bis(trifluoromethyl)phenyl- boronic acid (0.34 g, 1.3 mmol) in acetonitrile (5 ml) and water (2 ml) was refluxed for 8 hours in the presence of immobilized diisopropylethylamine (1.20 g, 4.08 mmol, PS- DIPEA, from Novabiochem), tri-tert-butylphosphoniumtetrafluoroborat (0.017 g, 0.06 mmol) and bis(triphenylphosphino)palladium-ll-chloride (0.025 g, 0.04 mmol). The obtained reaction mixture was filtered, the retained solid was rinsed with acetonitrile (10 ml) and the obtained filtrate was concentrated in vacuo. The residue was purified by column chromatography (gradient: cyclohexane/ethyl acetate; 90 : 10 to 40 : 60) to yield 5-(2,4-bis(trifluoromethyl)phenyl)-1 ,1-dioxo-2-quinolin-4-ylmethyl-1 ,2-dihydro- 1-benzo[d]isothiazol-3-one (0.096 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 90℃; for 16h; | Reference Production Example 15 ; To 6 ml of 1,4-dioxane was added 0.5 g of 4-chloropyridine-2-carbonitrile, 1.1 g of potassium carbonate, 0.13 g of tetrakis(triphenylphosphinepalladium) and 1.12 g of <strong>[153254-09-2]2,4-bis(trifluoromethyl)phenylboronic acid</strong>, and the mixture was stirred at 90C for 16 hours. Thereafter, the resultant reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with t-butyl methyl ether three times. The organic layers obtained by extraction were combined and washed with saturated saline, dried over anhydrous magnesium sulfate, then, concentrated. The resultant residue was subjected to silica gel column chromatography to obtain 0.74 g of 4-[2,4-bis(trifluoromethyl)phenyl]pyridine-2-carbonitrile. [Show Image] 1H-NMR:7.47(d, 1H), 7.50(dd, 1H), 7.67(s, 1H), 7.95(d, 1H), 8.09(s,1 H), 8.82(dd, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Pd(PPh3)4; In methanol; 1,2-dimethoxyethane; dichloromethane; | Step 3 The compound SM3 (obtained as described in step 2) was dissolved in dimethoxyethane (DME). To this solution was added 2,4-bis(trifluromethyl)phenylboronic acid and a 2N aq. Na2CO3 solution. To the resulting biphasic mixture was added Pd(PPh3)4 and the reaction was then heated at 80 C. for 72 hrs. The reaction was cooled to room temperature and filtered through Celite and the Celite washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified on 6 g SiO2 using MeOH/CH2Cl2 to elute compound. The compound thus obtained was contaminated with PPh3(O). The product was repurified on a 1 mm Chromatotron plate with 0 to 5% MeOH/CH2Cl2 in 1% steps. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 20 - 80℃; | Example 270A 6-(2,4-bis(trifluoromethyl)phenyl)picolinaldehyde To a solution of 6-bromopicolinaldehyde (1.00 g, 5.38 mmol) in dioxane (30 mL) at ambient temperature was added <strong>[153254-09-2]2,4-bis(trifluoromethyl)phenylboronic acid</strong> (1.38 g, 5.38 mmol), 2M cesium carbonate (8.0 mL, 16 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.220 g, 0.269 mmol). The mixture was degassed (3* vacuum/purge N2), then heated at 80 C. overnight. The mixture was cooled to room temperature and concentrated and the residue then partitioned between water and CH2Cl2. The organic layer concentrated and purified by chromatography (20% ethyl acetate:hexanes) to provide the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 95℃;Inert atmosphere; | Compound number 301 was prepared as follows. To a solution of <strong>[335349-57-0]5-chloro-4-iodo-2-nitroaniline</strong> (6 g, 20.1 mmol) in dioxane (100 ml) and water (10 ml) which was purged and maintained with an inert atmosphere of nitrogen was added[2,4-bis(trifluoromethyl)phenyl]boronic acid (10.3 g, 40.01 mmol), K3PO4 (8.6 g, 40.70 mmol) and Pd(pph3)4 (2.3 g, 2.04 mmol) at room temperature. The resulting solution was stirred overnight at 95 C. in an oil bath. The resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column, eluting with 2% to 3% ethyl acetate in petroleum ether to produce 4-[2,4-bis(trifluoromethyl)phenyl]-5-chloro-2-nitroaniline as a crude light yellow solid (2.2 g, crude). Next, to a solution of 4-[2,4-bis(trifluoro-methyl)phenyl]-5-chloro-2-nitroaniline (2.2 g, crude) in ethanol (50 ml) was added hydrogen chloride (conc, 1.5 ml) and Zn powder (2.2 g, 33.85 mmol). The resulting solution was stirred for 2 h at 90 C. in an oil bath. The reaction was then quenched by the addition of water (300 ml), adjusted pH to 8 with aqueous sodium carbonate and then extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine (200 ml), dried and concentrated under vacuum to produce 4-[2,4-bis(trifluoromethyl) phenyl]-5-chlorobenzene-1,2-diamine as a crude brown solid (1.75 g, crude). Finally, a Solution of 4-[2,4-bis(trifluoromethyl)phenyl]-5-chlorobenzene-1,2-diamine (300 mg, crude) in trifluoroacetic acid (10 ml) and hydrogen chloride (conc, 2 ml) was stirred overnight at 80 C. in an oil bath. The solution was evaporated and dissolved in water (30 ml), adjusted to pH 8 with aqueous sodium carbonate and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to produce 6-[2,4-bis(trifluoromethyl)phenyl]-5-chloro-2-(trifluoromethyl)-1H-1,3-benzodiazole as a off-white solid (132.4 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.8 mg | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 72h; | Example 1 5-({6-[2,4-bis(trifluoromethyl)phenyl]pyridazin-3-yl}methyl)-2-(2-fluorophenyl)-5H imidazo[4,5-c]pyridine 1 Compound 104 was dissolved in dimethoxyethane (DME). To this solution was added <strong>[153254-09-2]2,4-bis(trifluoromethyl)phenylboronic acid</strong> 105 and a 2N aq. Na2CO3 solution. To the resulting biphasic mixture was added Pd(PPh3)4 and the reaction was then heated at 80 C. for 72 hrs. The reaction was cooled to room temperature and filtered through Celite and the Celite washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified on 6 g SiO2 using MeOH/CH2Cl2 to elute compound. The compound thus obtained was contaminated with PPh3(O). The product was repurified on a 1 mm Chromatotron plate with 0 to 5% MeOH/CH2Cl2 in 1% steps. The pure fractions were combined and concentrated in vacuo, then dried on high vacuum for 12 hrs. 11.8 mg of the free base of compound 1 was obtained with no PPh3 contamination. 1H NMR (300 MHz, CD3OD) delta 6.20 (s, 2), 7.32 (m, 3), 7.52 (m, 1), 7.78 (d, 1), 7.89 (d, 1), 7.95 (s, 2), 8.15 (m, 3), 8.35 (d, 1), 9.12 (s, 1); LC/MS M+H=518. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 165℃; for 0.333333h;Microwave irradiation; | General procedure: Method B: A solution of K2CO3 (346 mg, 2.5 mmol) in H2O (3 mL)was added to a mixture of a 5-bromopyrimidine (1) (159 mg,1.0 mmol), the corresponding (hetero)arylboronic acid (2a-k)(1.2 mmol) and Pd(PPh3)4 (58 mg, 5 mol %) in 1,4-dioxane (4 mL). The resulting mixture was irradiated in a microwave apparatusat 165C (250 W) for 20 min. After that solvent was distilled off in vacuo, and the residue was purified by flash column chromatography(hexane/ethyl acetate, 1:3) to afford the desired cross-coupling products (3a-k). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 165℃; for 0.333333h;Microwave irradiation; | General procedure: A solution of K2CO3 (346 mg, 2.5 mmol) in 3 mL H2O was addedto a mixture of 5-bromo-4-(thien-2-yl)pyrimidine (8) [or 5-bromo-4-(furan-2-yl)pyrimidine (9)] (0.5 mmol), the corresponding arylboronic acid (2a-k) (0.6 mmol) and Pd(PPh3)4 (29 mg, 5 mol %) in 1,4-dioxane (4 mL). The resulting mixture was irradiated in a microwave apparatus at 165C (250 W) for 20 min. After that solvent was distilled off in vacuo, and the residue was purified by flash column chromatography (hexane/ethyl acetate, 1:3) to afford the desired 5-aryl-4-(hetero)arylpyrimidines 6a-k and 7a-k. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 165℃; for 0.333333h;Microwave irradiation; | General procedure: A solution of K2CO3 (346 mg, 2.5 mmol) in 3 mL H2O was addedto a mixture of 5-bromo-4-(thien-2-yl)pyrimidine (8) [or 5-bromo-4-(furan-2-yl)pyrimidine (9)] (0.5 mmol), the corresponding arylboronic acid (2a-k) (0.6 mmol) and Pd(PPh3)4 (29 mg, 5 mol %) in 1,4-dioxane (4 mL). The resulting mixture was irradiated in a microwave apparatus at 165C (250 W) for 20 min. After that solvent was distilled off in vacuo, and the residue was purified by flash column chromatography (hexane/ethyl acetate, 1:3) to afford the desired 5-aryl-4-(hetero)arylpyrimidines 6a-k and 7a-k. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 20℃; for 1h; | In the above scheme 7 and as, 250 ml 2-neck (neck) flask in Scheme 6 from the compound obtained (0.6 g, 2.1 mmol), 2,4 -bis(trifluoromethyl)phenylboronic acid(0.65 g, 2.5 mmol), potassium carbonate (potassium carbonate) (0.87 g, 6.3 mmol), and tetrakis (tetrakis) (triphenyl phosphine (triphenylphosphine)) palladium (palladium) (0) ( 0.12 g, 0.1 mmol) and the mixture of 1,4-dioxane (dioxane) and the mixture was stirred at room temperature for 1 hour and dissolved in 30 ml water and 10 ml. The distillation was stirred at 90 further 1 hour, extracted with dichloromethane (dichloromethane) and salt water (brine) and the solvent under reduced pressure. To give the compound in dichloromethane (Dichloromethane) hexane and 0.5 g (54%) by column chromatography using the calligraphy (hexane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 2h; | 500ml 2-neck flask in the compound E-1 (5.0 g, 20.6 mmol), 2,4-bis (trifluoromethyl) phenylboronic acid (5.3 g, 20.6 mmol), potassium carbonate (8.5 g, 61.7 mmol), tetrakis (triphenylphosphine) palladium (0) (1.19 g, 1.0 mmol) into a stirred 1 hour at room temperature and dissolved in 1,4-dioxane (200 ml) and water (70 ml). After stirring at 90 C further 1 hour, extracted with dichloromethane and brine, and was evaporated the solvent under reduced pressure. Column by using Dichloromethane and hexane to give the compound E-2 (4.7 g). (Yield = 61%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; for 0.666667h;Reflux; | 500ml 2-neck flask in the 2- bromo-l, 4-benzoquinone (2-Bromo-1,4-benzoquinone) (3.14g, 16.8mmol), 2,4- bis (trifluoromethyl) phenyl Boro acid ( 2,4-Bis (trifluoromethyl) phenyl boronic acid) (4.3g, 16.8mmol), tetrakis (triphenylphosphine) palladium (0) (1.0g, 0.84mmol), potassium carbonate (7.0g, 50.6mmol) and into a mixed solution of 1,4-Dadi dioxane (120ml) and water (40ml), refluxed and stirred for 40 minutes. After the reaction, extracted with water and dichloromethane and the column with dichloromethane and n- hexane to give the compound B-1 1.6g (30%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; for 10h;Inert atmosphere; Reflux; | General procedure: A solution of K2CO3 (346 mg, 2.5 mmol) in H2O (4 mL) was added to a mixture of 5-bromo-4-(5-nitrofuran-2-yl)-pyrimidine (2) (270 mg, 1.0 mmol), phenylboronic (3a) [2-fluorobenzeneboronic (3b), 3-fluorobenzeneboronic (3c), 4-fluorobenzeneboronic (3d), 2,4-difluorobenzeneboronic (3e), 3,5-difluorobenzeneboronic (3f), 2-(trifluoromethyl)benzeneboronic (3g), 3-(trifluoromethyl)benzeneboronic (3h), 4-(trifluoromethyl)benzeneboronic (3i) 2,4-bis(trifluoromethyl)benzeneboronic (3j), or 3,5-bis(trifluoromethyl)benzeneboronic (3k)] acid (1.2 mmol) and Pd(PPh3)4 (58 mg, 5 mol%) in 1,4-dioxane (20 mL). The mixture was refluxed under argon for 10 h. Ethyl acetate (20 ml × 3) and water (20 mL) was added and the organic layer was separated, washed sequentially with water and brine (5 mL × 3), dried over sodium sulfate, concentrated in vacuo and purified by silica gel column chromatography (eluent: hexanes/ethyl acetate, 1:3) to give the desired products (4a-k). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In ethanol; benzene; for 16h;Reflux; Inert atmosphere; | In accordance with the following formula, a C-N ligand (3) was obtained by reacting <strong>[153254-09-2]2,4-bis(trifluoromethyl)phenylboronic acid</strong> with 2-iodopyridine. A mixture of <strong>[153254-09-2]2,4-bis(trifluoromethyl)phenylboronic acid</strong> (2.31 g, 8.96 mmol), 2-iodopyridine (1.16 g, 5.66 mmol), benzene (25 mL), ethanol (10 mL), K2CO3 (7.31 g, 52.9 mmol) and PdCl2(PPh3)2 (0.383 g, 0.546 mmol) was heated and refluxed for 16 hours under a nitrogen atmosphere. After being allowed to cool, the reaction mixture was transferred to a separating funnel. After diluting with an appropriate amount of chloroform, the mixture was washed with water and a saturated saline, and the organic layer was dried on anhydrous magnesium sulfate. After removal of the magnesium sulfate by filtration, the solvent was distilled off with a rotary evaporator. The C-N ligand (3) was obtained in a yield of 59% (0.978 g, 3.36 mmol) by purifying the residue with a silica gel chromatography (development solvent; chloroform). The 1H NMR property of the thus synthesized compound was as follows. 1H NMR (CDCl3): delta7.33 (ddd, J=7.8, 7.7 and 1.1 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.64 (d, J=7.7 Hz, 1H), 7.76 (ddd, J=7.7, 7.7 and 1.9 Hz, 1H), 7.86 (d, J=8.3 Hz, 1H), 8.01 (s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 6h;Inert atmosphere; | Under argon atmosphere, 2,4-ditrifluoromethylphenylboronic acid (9.0 g, 35 mmol) was added to a 250 mL round bottom flask.Chlothiophene [2,3-d]pyrimidine (5.1 g, 30 mmol), Pd(dppf)Cl2 (440 mg, 0.6 mmol), K2CO3 (5.5 g, 40 mmol), 60 mL 1,4-dioxane and 20 mL water, The mixture was heated at 90 C with stirring for 6 h. Cool to room temperature, quench with water, extract with dichloromethane, and remove the solvent on a rotary evaporator. Purification by column chromatography. A white solid (8.6 g, 83%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; for 5h;Reflux; | After dissolving Compound P6 (2.0 g, 3.84 mmol) and <strong>[153254-09-2](2,4-bis(trifluoromethyl)phenyl)boronic acid</strong> (1.50 g, 5.81 mmol) in toluene and ethanol, potassium carbonate (K2CO3, 1.60 g, 11.5 mmol) was added to the reaction solution with water, and tetrakis(triphenylphosphine)palladium (0.2 g, 0.16 mmol) was added thereto. The result was stirred under reflux for 5 hours, cooled to room temperature, and extracted with chloroform. The result was dried with anhydrous magnesium sulfate, filtered, and vacuum distilled to remove the solvent. Red solid Compound P11 (1.80 g, 77%) was obtained through a silica-gel column. (0232) [M-F]+=587 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In methanol; water; at 120℃;Microwave irradiation; Inert atmosphere; | General procedure: To a microwave reaction vessel were added compound 37a or 37b (36 mg, 0.1 mmol), arylboronic acid (2 equiv), Pd(PPh3)4 (5 mol %), K2CO3 (2 equiv) and MeOH/H2O (9/1, 2 mL). The reaction mixture was irradiated under argon at 120 C for the appropriate time. The reaction mixture was then concentrated and the residue was extract with DCM, washed by H2O and dried over Na2SO4. The organic layer was concentrated and the residue was purified by Combiflash (MeOH/DCM, 1%-3%) to give product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.8% | With lithium 2,2,6,6‐tetramethylpiperidide at -60 - 20℃; for 7h; Acidic conditions; | 2.2; 3.2; 4.2 The second step boronation reaction: 1,3-ditrifluorotoluene (107g, 0.5mol) was slowly added dropwise to Intermediate A, and the temperature was controlled from -60°C to -40°C. After the dropwise addition, the reaction was carried out for 2 hours; Triisopropyl borate (113g, 0.6mol) was added, and after the reaction was incubated for 2 hours, the temperature was naturally raised to room temperature and stirred for 3 hours; the reaction solution was rotary evaporated to obtain a viscous oil, which was placed in a four-necked round-bottomed flask, 500 g of methyl tert-butyl ether was added, the temperature was controlled at 0--10° C., 470 g of 10% hydrochloric acid was added dropwise, the pH was adjusted to 2-3, and the aqueous layer was separated. The aqueous layer was extracted once with 100 ml of ethyl acetate. The oil layers were combined and washed twice with 100 g of 3% hydrochloric acid. Wash once with 100 g of saturated brine. Rotary evaporated to dryness, added 300 g of heptane, beating for 1 hour, suction filtered, rinsed to obtain 103 g of an off-white solid with a yield of 79.8%. The liquid content was measured to be 98.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.6% | With lithium 2,2,6,6‐tetramethylpiperidide at -60 - 20℃; for 5h; Acidic conditions; | 1.2 The second step boronation reaction: slowly drop 1,3-ditrifluorotoluene (107g, 0.5mol) into Intermediate A, control the temperature from -60°C to -40°C, and react for 1 hour after dropping; Trimethyl borate (62.4g, 0.6mol) was added, and after the reaction was incubated for 1 hour, the temperature was naturally raised to room temperature, and stirred for 3 hours; the reaction solution was rotary-evaporated to obtain a viscous oil, which was placed in a four-necked round-bottomed flask, 500 g of ethyl acetate was added, the temperature was controlled at 0--10° C., 470 g of 10% hydrochloric acid was added dropwise, the pH was adjusted to 2-3, and the aqueous layer was separated. The aqueous layer was extracted once with 100 ml of ethyl acetate. The oil layers were combined and washed twice with 100 g of 5% hydrochloric acid. Wash once with 100 g of saturated brine. Rotary-evaporated to dryness, added 300 g of petroleum ether, beating for 1 hour, suction filtered, rinsed to obtain 91 g of off-white solid with a yield of 70.6%. The liquid content was measured to be 98.1%, |
Tags: 153254-09-2 synthesis path| 153254-09-2 SDS| 153254-09-2 COA| 153254-09-2 purity| 153254-09-2 application| 153254-09-2 NMR| 153254-09-2 COA| 153254-09-2 structure
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P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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