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CAS No. : | 1029044-16-3 | MDL No. : | MFCD28900745 |
Formula : | C20H15ClF3N5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JGWRKYUXBBNENE-UHFFFAOYSA-N |
M.W : | 417.81 | Pubchem ID : | 25151352 |
Synonyms : |
PLX-3397;PLX3397
|
Num. heavy atoms : | 29 |
Num. arom. heavy atoms : | 21 |
Fraction Csp3 : | 0.15 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 104.94 |
TPSA : | 66.49 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -5.69 cm/s |
Log Po/w (iLOGP) : | 2.83 |
Log Po/w (XLOGP3) : | 4.45 |
Log Po/w (WLOGP) : | 6.04 |
Log Po/w (MLOGP) : | 2.96 |
Log Po/w (SILICOS-IT) : | 5.57 |
Consensus Log Po/w : | 4.37 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 1.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -5.37 |
Solubility : | 0.00177 mg/ml ; 0.00000423 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -5.57 |
Solubility : | 0.00114 mg/ml ; 0.00000272 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -9.47 |
Solubility : | 0.000000142 mg/ml ; 0.0000000003 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 2.89 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.4% | With triethylsilane; trifluoroacetic acid In acetonitrile at 15 - 82℃; | [0074] The reactor was charged with compound IV (663.3 gm, 1 eq.), compound V (623.2 gm, 2.0 eq.) and acetonitrile (13.3 L). The reaction mixture was stirred for about 5-10 minutes at room temperature. Triethylsilane (1531.6 gm, 7.4 eq.) was then added to the reactor over at least about 10 minutes at or less than about 30°C. Trifluoroacetic acid (1542.5 gm, 7.6 eq.) was added to the reactor over at least about 10 minutes at or less than about 30°C. The reaction mixture was stirred for at least about 30 minutes at about 15-30°C. It was then heated to about 70-82°C over at least about one hour and then stirred at about 70-82°C for about 20-48 hours. The reaction was monitored by HPLC. When the content of compound IV was less than about 1percent, the reaction was deemed complete. [0075] The reaction mixture was cooled to room temperature, the acetonitrile layer was separated and concentrated. Then water (7.96 L) was charged and the reaction mixture was concentrated to 6.64 L under vacuum providing a tri-phasic mixture. It was then cooled to 15- 25°C, charged with ethyl acetate (10.6 L) and stirred providing a biphasic mixture. It was cooled to 0-10°C, charged with a 25percent NaOH solution in water until a pH of about 8-9 was reached with vigorous stirring, heated to about 65-75°C and stirred at about 65-75° for about 30 minutes. The organic layer was separated, and water (3.98 L) was charged and the reaction mixture was heated at about 65-75°C. The organic layer was separated and concentrated to about 5.3-5.9 L under vacuum, heptane (11.9 L) was added and the slurry was heated to about 55-65°C and stirred for about 2 hours. The reaction mixture was cooled to about 15-30°C over at least about 2 hours and then stirred at about 15-30°C for at least about 1 hour. The precipitate was filtered, washed with heptane (1.99 L) and dried. The filter cake was charged into reactor with ethyl acetate (5.31L, 8 vol) and heptane (2.65 L, 4 vol), cooled to about 15-30°C over at least about 2 hours and then stirred at about 15-30°C for at least about 1 hour. The precipitate was filtered, washed with heptane and dried to provide Compound I as a light yellow solid (648.4 gm, 89.4percent yield, 99.4percent purity by HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogenchloride In ethanol; water at 30℃; | 1.4 Step 4: Conversion of I to II [0076] The reactor was charged with compound I (10 gm, 1 eq.), 110 mL ethanol was added and the reaction mixture was stirred. Concentrated hydrochloric acid (4.7 gm, 2 eq.) was slowly added to the reaction mixture while maintaining a temperature of about 30°C or less to form a clear solution. It was then filtered and washed with methanol (10 mL). It was again filtered and purified water (3 mL) was added to it at about 28-32°C. The mixture was stirred at about 28- 32°C for 1-3 hours and filtered, purified water (177 mL) was added to it at about 25-32°C. The reaction mixture was cooled at about 0-7 °C and stirred for at least about 2 hours. Optionally, seed crystals of compound II can be added in this step. The solids were filtered, rinsed with a cool (0-5°C) mixture of methanol (6 mL) and MTBE (24 mL), and with cool (0-5°C) MTBE (30 mL). The product was dried to provide Compound II (90% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: tetra(n-butyl)ammonium hydrogensulfate / isopropyl alcohol / 1 h / Large scale 1.2: 15 - 25 °C / Large scale 2.1: triethylsilane; trifluoroacetic acid / acetonitrile / 55 - 65 °C 3.1: triethylsilane; trifluoroacetic acid / acetonitrile / 15 - 82 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: tetra(n-butyl)ammonium hydrogensulfate / isopropyl alcohol / 1 h / Large scale 1.2: 15 - 25 °C / Large scale 2.1: triethylsilane; trifluoroacetic acid / acetonitrile / 55 - 65 °C 3.1: triethylsilane; trifluoroacetic acid / acetonitrile / 15 - 82 °C | ||
Multi-step reaction with 5 steps 1: triethyl borane; tetrakis(triphenylphosphine) palladium(0) / hexane; tetrahydrofuran / 24 h / 55 °C / Inert atmosphere 2: dmap / dichloromethane 3: dichloromethane / 3 h / 20 °C / Sealed tube 4: 4,4'-di-tert-butyl-2,2'-bipyridine; bis(1,5-cyclooctadiene)nickel (0); triethylamine / acetone / 36 h / 20 °C / Glovebox; Sealed tube; Irradiation 5: trifluoroacetic acid / dichloromethane / 20 °C | ||
Multi-step reaction with 7 steps 1: triethyl borane; tetrakis(triphenylphosphine) palladium(0) / hexane; tetrahydrofuran / 24 h / 55 °C / Inert atmosphere 2: dmap / dichloromethane 3: dichloromethane / 3 h / 20 °C / Sealed tube 4: 4,4'-di-tert-butyl-2,2'-bipyridine; bis(1,5-cyclooctadiene)nickel (0); triethylamine / acetone / 36 h / 20 °C / Glovebox; Sealed tube; Irradiation 5: dichloromethane / 3 h / 20 °C / Sealed tube 6: 4,4'-di-tert-butyl-2,2'-bipyridine; bis(1,5-cyclooctadiene)nickel (0); triethylamine / acetone / 36 h / 20 °C / Glovebox; Sealed tube; Irradiation 7: trifluoroacetic acid / dichloromethane / 20 °C |
Multi-step reaction with 3 steps 1: <i>N</i>,<i>N</i>-dimethyl-aniline / tetrahydrofuran / 1 h / Inert atmosphere 2: chloro(1,5-cyclooctadiene)(1,10-phenanthroline)iridium(I) THF adduct / n-heptane; isopropyl alcohol / 60 min / 70 °C / Inert atmosphere; Sealed tube 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / isopropyl alcohol / 8 h / 70 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: triethylsilane; trifluoroacetic acid / acetonitrile / 55 - 65 °C 2: triethylsilane; trifluoroacetic acid / acetonitrile / 15 - 82 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.4% | With triethylsilane; trifluoroacetic acid; In acetonitrile; at 15 - 82℃; | [0074] The reactor was charged with compound IV (663.3 gm, 1 eq.), compound V (623.2 gm, 2.0 eq.) and acetonitrile (13.3 L). The reaction mixture was stirred for about 5-10 minutes at room temperature. Triethylsilane (1531.6 gm, 7.4 eq.) was then added to the reactor over at least about 10 minutes at or less than about 30C. Trifluoroacetic acid (1542.5 gm, 7.6 eq.) was added to the reactor over at least about 10 minutes at or less than about 30C. The reaction mixture was stirred for at least about 30 minutes at about 15-30C. It was then heated to about 70-82C over at least about one hour and then stirred at about 70-82C for about 20-48 hours. The reaction was monitored by HPLC. When the content of compound IV was less than about 1%, the reaction was deemed complete. [0075] The reaction mixture was cooled to room temperature, the acetonitrile layer was separated and concentrated. Then water (7.96 L) was charged and the reaction mixture was concentrated to 6.64 L under vacuum providing a tri-phasic mixture. It was then cooled to 15- 25C, charged with ethyl acetate (10.6 L) and stirred providing a biphasic mixture. It was cooled to 0-10C, charged with a 25% NaOH solution in water until a pH of about 8-9 was reached with vigorous stirring, heated to about 65-75C and stirred at about 65-75 for about 30 minutes. The organic layer was separated, and water (3.98 L) was charged and the reaction mixture was heated at about 65-75C. The organic layer was separated and concentrated to about 5.3-5.9 L under vacuum, heptane (11.9 L) was added and the slurry was heated to about 55-65C and stirred for about 2 hours. The reaction mixture was cooled to about 15-30C over at least about 2 hours and then stirred at about 15-30C for at least about 1 hour. The precipitate was filtered, washed with heptane (1.99 L) and dried. The filter cake was charged into reactor with ethyl acetate (5.31L, 8 vol) and heptane (2.65 L, 4 vol), cooled to about 15-30C over at least about 2 hours and then stirred at about 15-30C for at least about 1 hour. The precipitate was filtered, washed with heptane and dried to provide Compound I as a light yellow solid (648.4 gm, 89.4% yield, 99.4% purity by HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.1% | With 5%-palladium/activated carbon; hydrogen; ammonium chloride In methanol at 30 - 35℃; for 6h; Autoclave; Green chemistry; | 8; 9 Example 8: Preparation of pexidartinib (I) Add to a 500 ml stainless steel autoclave200 grams of methanol,23.5 g (0.05 mol) of compound V,0.5 g of 5% palladium on carbon catalyst,1.5 grams of ammonium chloride,After replacing the nitrogen three times, hydrogen is introduced to maintain the hydrogen pressure at 0.2-0.3 MPa.The reaction was carried out at 30-35 ° C for 6 hours.Displaced three times with nitrogen, filtered to remove palladium carbon, and the filtrate was concentrated.Dry 20.5 grams of pyroxibinib,The yield was 98.1%, and the liquid phase purity was 99.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: potassium <i>tert</i>-butylate / 2-methyltetrahydrofuran / 6 h / 35 - 40 °C / Green chemistry 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 2-methyltetrahydrofuran / 4 h / 40 - 45 °C / Green chemistry 2.2: 2 h / 20 - 25 °C / Green chemistry 3.1: 5%-palladium/activated carbon; ammonium chloride; hydrogen / methanol / 6 h / 30 - 35 °C / 1500.15 - 2250.23 Torr / Autoclave; Green chemistry |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: potassium <i>tert</i>-butylate / tetrahydrofuran / 3 h / 40 - 60 °C / Green chemistry 2.1: potassium <i>tert</i>-butylate / 2-methyltetrahydrofuran / 6 h / 35 - 40 °C / Green chemistry 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 2-methyltetrahydrofuran / 4 h / 40 - 45 °C / Green chemistry 3.2: 2 h / 20 - 25 °C / Green chemistry 4.1: 5%-palladium/activated carbon; ammonium chloride; hydrogen / methanol / 6 h / 30 - 35 °C / 1500.15 - 2250.23 Torr / Autoclave; Green chemistry |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: sodium ethanolate / 2-methyltetrahydrofuran / 6 h / 50 - 55 °C / Green chemistry 2.1: potassium <i>tert</i>-butylate / 2-methyltetrahydrofuran / 6 h / 35 - 40 °C / Green chemistry 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / 2-methyltetrahydrofuran / 4 h / 40 - 45 °C / Green chemistry 3.2: 2 h / 20 - 25 °C / Green chemistry 4.1: 5%-palladium/activated carbon; ammonium chloride; hydrogen / methanol / 6 h / 30 - 35 °C / 1500.15 - 2250.23 Torr / Autoclave; Green chemistry |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Stage #1: 5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-amine With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Inert atmosphere; Stage #2: C19H22N2O9 In N,N-dimethyl-formamide at 0 - 20℃; for 18h; Inert atmosphere; | 9 Pexidartinib-TCO-Glycine conjugate via BSA-protection method: To a solution of compound 13 (418 mg, 1.0 mmol) in DMF (10 mL) at 0 °C was added NaH (ca. 60%, 44 mg, 1.1 mmol). The reaction mixture was stirred under N2 for 1 h before Bis-NHS-TCO (398 mg, 1.0 mmol) was added. The resulting mixture was stirred at room temperature for 18 h. The reaction was quenched with water (10 mL). The product was extracted with ethyl acetate (2 x 40 mL). The combined organic layers were washed with water (4 x 15 mL), and brine (15 mL), dried (MgSCL) and evaporated in vacuo. The product was purified by flash chromatography on silica gel eluting with EA/Hex (0% - 100%) to give the intermediate 14 (463 mg, 64%) as a white solid. LCMS: Rt = 1.281, m/z 725 [M+l]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 1 h / 0 °C / Inert atmosphere 1.2: 18 h / 0 - 20 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine; N,O-bis-(trimethylsilyl)-acetamide / dichloromethane; N,N-dimethyl-formamide / 16 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.8% | With potassium carbonate In 1,4-dioxane; water at 120℃; for 7h; Large scale; | 1-3 Dissolve raw material 3 (2.11Kg, 1.2eq) in 3L 1,4-dioxane, dissolve potassium carbonate (2.06Kg, 1.5eq) in 3L of water, and then warm the reaction system of the previous step to 120°C At the same time, the raw material 3 solution and the potassium carbonate aqueous solution were added dropwise, the addition time was 2 hours, and the reaction was stirred for 5 hours after the addition was completed. After HPLC detected that the alkylated intermediate disappeared, the reaction solution was filtered while hot, and then the filtrate was reduced Pressure distillation, recover most of 1,4-dioxane (15L) and apply it to the concentrated reaction solution, add 20L of ethyl acetate, wash with saturated brine, and dry and spin-dry the organic phase with ethanol: water = 1:2 Recrystallization to obtain the product pexidartinib, 3.3Kg, yield 78.8%, HPLC purity 99.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | Stage #1: 5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-amine With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Inert atmosphere; Stage #2: trans-cyclooctenol p-nitrobenzene In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | 8 Example 8 General Procedure for Preparing TCO-Pexidartinib To a solution of pexidartinib (PLX3397) (373 mg, 0.89 mmol) in DMF (4.0 mL) at 0°C.Sodium hydride (about 60%, 39 mg, about 0.96 mmol) was added and the reaction mixture was stirred under nitrogen for 1 h before the TCO-PNB ester (200 mg, 0.68 mmol).Was added. The resulting mixture was stirred overnight at rt., Evaporated in vacuo. Dilute the reaction mixture with water (30 mL),Extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo.The residue is converted to dichloromethane,Then purify by flash chromatography on silica gel eluting with MeOH-CH2Cl2 (0-5%),TCO-pexidartinib (145 mg, 37%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: tetrahydrofuran / 0 - 20 °C / Inert atmosphere 1.2: 2 h / 10 °C / Inert atmosphere 2.1: palladium diacetate; tris-(o-tolyl)phosphine; silver carbonate; N-ethyl-N,N-diisopropylamine / dimethylsulfoxide-d6 / 24 h / 70 - 100 °C / Inert atmosphere 3.1: potassium hydroxide / methanol / 4 h / 70 °C 4.1: hydrogenchloride / methanol / 8 h / 70 °C 5.1: triethylsilane; trifluoroacetic acid / acetonitrile / 36 h / 65 °C | ||
Multi-step reaction with 5 steps 1.1: tetrahydrofuran / 0 - 20 °C / Inert atmosphere 1.2: 2 h / 10 °C / Inert atmosphere 2.1: palladium diacetate; tris-(o-tolyl)phosphine; N-ethyl-N,N-diisopropylamine / dimethyl amine / 24 h / 100 °C / Inert atmosphere 3.1: potassium hydroxide / methanol / 4 h / 70 °C 4.1: hydrogenchloride / methanol / 8 h / 70 °C 5.1: triethylsilane; trifluoroacetic acid / acetonitrile / 36 h / 65 °C | ||
Multi-step reaction with 6 steps 1: tetrahydrofuran / 5 h / 0 - 150 °C / Inert atmosphere 2: tetrahydrofuran / 1 h / 0 °C / Inert atmosphere 3: palladium diacetate; tris-(o-tolyl)phosphine; silver carbonate; N-ethyl-N,N-diisopropylamine / dimethylsulfoxide-d6 / 24 h / 70 - 100 °C / Inert atmosphere 4: potassium hydroxide / methanol / 4 h / 70 °C 5: hydrogenchloride / methanol / 8 h / 70 °C 6: triethylsilane; trifluoroacetic acid / acetonitrile / 36 h / 65 °C |
Multi-step reaction with 6 steps 1: tetrahydrofuran / 5 h / 0 - 150 °C / Inert atmosphere 2: tetrahydrofuran / 1 h / 0 °C / Inert atmosphere 3: palladium diacetate; tris-(o-tolyl)phosphine; N-ethyl-N,N-diisopropylamine / dimethyl amine / 24 h / 100 °C / Inert atmosphere 4: potassium hydroxide / methanol / 4 h / 70 °C 5: hydrogenchloride / methanol / 8 h / 70 °C 6: triethylsilane; trifluoroacetic acid / acetonitrile / 36 h / 65 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: palladium diacetate; tris-(o-tolyl)phosphine; N-ethyl-N,N-diisopropylamine / dimethyl amine / 24 h / 100 °C / Inert atmosphere 2: potassium hydroxide / methanol / 4 h / 70 °C 3: hydrogenchloride / methanol / 8 h / 70 °C 4: triethylsilane; trifluoroacetic acid / acetonitrile / 36 h / 65 °C | ||
Multi-step reaction with 4 steps 1: palladium diacetate; tris-(o-tolyl)phosphine; silver carbonate; N-ethyl-N,N-diisopropylamine / dimethylsulfoxide-d6 / 24 h / 70 - 100 °C / Inert atmosphere 2: potassium hydroxide / methanol / 4 h / 70 °C 3: hydrogenchloride / methanol / 8 h / 70 °C 4: triethylsilane; trifluoroacetic acid / acetonitrile / 36 h / 65 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium hydroxide / methanol / 4 h / 70 °C 2: hydrogenchloride / methanol / 8 h / 70 °C 3: triethylsilane; trifluoroacetic acid / acetonitrile / 36 h / 65 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: palladium diacetate; tris-(o-tolyl)phosphine; N-ethyl-N,N-diisopropylamine / dimethyl amine / 24 h / 100 °C / Inert atmosphere 2: potassium hydroxide / methanol / 4 h / 70 °C 3: hydrogenchloride / methanol / 8 h / 70 °C 4: triethylsilane; trifluoroacetic acid / acetonitrile / 36 h / 65 °C | ||
Multi-step reaction with 4 steps 1: palladium diacetate; tris-(o-tolyl)phosphine; silver carbonate; N-ethyl-N,N-diisopropylamine / dimethylsulfoxide-d6 / 24 h / 70 - 100 °C / Inert atmosphere 2: potassium hydroxide / methanol / 4 h / 70 °C 3: hydrogenchloride / methanol / 8 h / 70 °C 4: triethylsilane; trifluoroacetic acid / acetonitrile / 36 h / 65 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: hydrogenchloride / methanol / 8 h / 70 °C 2: triethylsilane; trifluoroacetic acid / acetonitrile / 36 h / 65 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: methylmagnesium chloride / tetrahydrofuran / 0.5 h / 0 - 10 °C / Inert atmosphere 1.2: 48 h / 0 - 24 °C 2.1: palladium diacetate; tris-(o-tolyl)phosphine; N-ethyl-N,N-diisopropylamine / dimethyl amine / 24 h / 100 °C / Inert atmosphere 3.1: potassium hydroxide / methanol / 4 h / 70 °C 4.1: hydrogenchloride / methanol / 8 h / 70 °C 5.1: triethylsilane; trifluoroacetic acid / acetonitrile / 36 h / 65 °C | ||
Multi-step reaction with 5 steps 1.1: methylmagnesium chloride / tetrahydrofuran / 0.5 h / 0 - 10 °C / Inert atmosphere 1.2: 48 h / 0 - 24 °C 2.1: palladium diacetate; tris-(o-tolyl)phosphine; silver carbonate; N-ethyl-N,N-diisopropylamine / dimethylsulfoxide-d6 / 24 h / 70 - 100 °C / Inert atmosphere 3.1: potassium hydroxide / methanol / 4 h / 70 °C 4.1: hydrogenchloride / methanol / 8 h / 70 °C 5.1: triethylsilane; trifluoroacetic acid / acetonitrile / 36 h / 65 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: tetrahydrofuran / 1 h / 0 °C / Inert atmosphere 2: palladium diacetate; tris-(o-tolyl)phosphine; silver carbonate; N-ethyl-N,N-diisopropylamine / dimethylsulfoxide-d6 / 24 h / 70 - 100 °C / Inert atmosphere 3: potassium hydroxide / methanol / 4 h / 70 °C 4: hydrogenchloride / methanol / 8 h / 70 °C 5: triethylsilane; trifluoroacetic acid / acetonitrile / 36 h / 65 °C | ||
Multi-step reaction with 5 steps 1: tetrahydrofuran / 1 h / 0 °C / Inert atmosphere 2: palladium diacetate; tris-(o-tolyl)phosphine; N-ethyl-N,N-diisopropylamine / dimethyl amine / 24 h / 100 °C / Inert atmosphere 3: potassium hydroxide / methanol / 4 h / 70 °C 4: hydrogenchloride / methanol / 8 h / 70 °C 5: triethylsilane; trifluoroacetic acid / acetonitrile / 36 h / 65 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 0.5 h / 0 - 20 °C / Inert atmosphere 1.2: 0.5 h / 0 °C / Inert atmosphere 1.3: 1 h / 0 - 20 °C / Inert atmosphere 2.1: tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2.2: 2 h / 10 °C / Inert atmosphere 3.1: palladium diacetate; tris-(o-tolyl)phosphine; silver carbonate; N-ethyl-N,N-diisopropylamine / dimethylsulfoxide-d6 / 24 h / 70 - 100 °C / Inert atmosphere 4.1: potassium hydroxide / methanol / 4 h / 70 °C 5.1: hydrogenchloride / methanol / 8 h / 70 °C 6.1: triethylsilane; trifluoroacetic acid / acetonitrile / 36 h / 65 °C | ||
Multi-step reaction with 6 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 0.5 h / 0 - 20 °C / Inert atmosphere 1.2: 0.5 h / 0 °C / Inert atmosphere 1.3: 1 h / 0 - 20 °C / Inert atmosphere 2.1: tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2.2: 2 h / 10 °C / Inert atmosphere 3.1: palladium diacetate; tris-(o-tolyl)phosphine; N-ethyl-N,N-diisopropylamine / dimethyl amine / 24 h / 100 °C / Inert atmosphere 4.1: potassium hydroxide / methanol / 4 h / 70 °C 5.1: hydrogenchloride / methanol / 8 h / 70 °C 6.1: triethylsilane; trifluoroacetic acid / acetonitrile / 36 h / 65 °C | ||
Multi-step reaction with 7 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 0.5 h / 0 - 20 °C / Inert atmosphere 1.2: 0.5 h / 0 °C / Inert atmosphere 1.3: 1 h / 0 - 20 °C / Inert atmosphere 2.1: tetrahydrofuran / 5 h / 0 - 150 °C / Inert atmosphere 3.1: tetrahydrofuran / 1 h / 0 °C / Inert atmosphere 4.1: palladium diacetate; tris-(o-tolyl)phosphine; silver carbonate; N-ethyl-N,N-diisopropylamine / dimethylsulfoxide-d6 / 24 h / 70 - 100 °C / Inert atmosphere 5.1: potassium hydroxide / methanol / 4 h / 70 °C 6.1: hydrogenchloride / methanol / 8 h / 70 °C 7.1: triethylsilane; trifluoroacetic acid / acetonitrile / 36 h / 65 °C |
Multi-step reaction with 7 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 0.5 h / 0 - 20 °C / Inert atmosphere 1.2: 0.5 h / 0 °C / Inert atmosphere 1.3: 1 h / 0 - 20 °C / Inert atmosphere 2.1: tetrahydrofuran / 5 h / 0 - 150 °C / Inert atmosphere 3.1: tetrahydrofuran / 1 h / 0 °C / Inert atmosphere 4.1: palladium diacetate; tris-(o-tolyl)phosphine; N-ethyl-N,N-diisopropylamine / dimethyl amine / 24 h / 100 °C / Inert atmosphere 5.1: potassium hydroxide / methanol / 4 h / 70 °C 6.1: hydrogenchloride / methanol / 8 h / 70 °C 7.1: triethylsilane; trifluoroacetic acid / acetonitrile / 36 h / 65 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: sodium tris(acetoxy)borohydride; acetic acid / acetic acid; dichloromethane / 6 h / 0 - 20 °C / Cooling with ice 2.1: isopropylmagnesium chloride / tetrahydrofuran / 0.5 h / 0 - 20 °C / Inert atmosphere 2.2: 0.5 h / 0 °C / Inert atmosphere 2.3: 1 h / 0 - 20 °C / Inert atmosphere 3.1: tetrahydrofuran / 0 - 20 °C / Inert atmosphere 3.2: 2 h / 10 °C / Inert atmosphere 4.1: palladium diacetate; tris-(o-tolyl)phosphine; N-ethyl-N,N-diisopropylamine / dimethyl amine / 24 h / 100 °C / Inert atmosphere 5.1: potassium hydroxide / methanol / 4 h / 70 °C 6.1: hydrogenchloride / methanol / 8 h / 70 °C 7.1: triethylsilane; trifluoroacetic acid / acetonitrile / 36 h / 65 °C | ||
Multi-step reaction with 7 steps 1.1: sodium tris(acetoxy)borohydride; acetic acid / acetic acid; dichloromethane / 6 h / 0 - 20 °C / Cooling with ice 2.1: isopropylmagnesium chloride / tetrahydrofuran / 0.5 h / 0 - 20 °C / Inert atmosphere 2.2: 0.5 h / 0 °C / Inert atmosphere 2.3: 1 h / 0 - 20 °C / Inert atmosphere 3.1: tetrahydrofuran / 0 - 20 °C / Inert atmosphere 3.2: 2 h / 10 °C / Inert atmosphere 4.1: palladium diacetate; tris-(o-tolyl)phosphine; silver carbonate; N-ethyl-N,N-diisopropylamine / dimethylsulfoxide-d6 / 24 h / 70 - 100 °C / Inert atmosphere 5.1: potassium hydroxide / methanol / 4 h / 70 °C 6.1: hydrogenchloride / methanol / 8 h / 70 °C 7.1: triethylsilane; trifluoroacetic acid / acetonitrile / 36 h / 65 °C | ||
Multi-step reaction with 8 steps 1.1: sodium tris(acetoxy)borohydride; acetic acid / acetic acid; dichloromethane / 6 h / 0 - 20 °C / Cooling with ice 2.1: isopropylmagnesium chloride / tetrahydrofuran / 0.5 h / 0 - 20 °C / Inert atmosphere 2.2: 0.5 h / 0 °C / Inert atmosphere 2.3: 1 h / 0 - 20 °C / Inert atmosphere 3.1: tetrahydrofuran / 5 h / 0 - 150 °C / Inert atmosphere 4.1: tetrahydrofuran / 1 h / 0 °C / Inert atmosphere 5.1: palladium diacetate; tris-(o-tolyl)phosphine; N-ethyl-N,N-diisopropylamine / dimethyl amine / 24 h / 100 °C / Inert atmosphere 6.1: potassium hydroxide / methanol / 4 h / 70 °C 7.1: hydrogenchloride / methanol / 8 h / 70 °C 8.1: triethylsilane; trifluoroacetic acid / acetonitrile / 36 h / 65 °C |
Multi-step reaction with 8 steps 1.1: sodium tris(acetoxy)borohydride; acetic acid / acetic acid; dichloromethane / 6 h / 0 - 20 °C / Cooling with ice 2.1: isopropylmagnesium chloride / tetrahydrofuran / 0.5 h / 0 - 20 °C / Inert atmosphere 2.2: 0.5 h / 0 °C / Inert atmosphere 2.3: 1 h / 0 - 20 °C / Inert atmosphere 3.1: tetrahydrofuran / 5 h / 0 - 150 °C / Inert atmosphere 4.1: tetrahydrofuran / 1 h / 0 °C / Inert atmosphere 5.1: palladium diacetate; tris-(o-tolyl)phosphine; silver carbonate; N-ethyl-N,N-diisopropylamine / dimethylsulfoxide-d6 / 24 h / 70 - 100 °C / Inert atmosphere 6.1: potassium hydroxide / methanol / 4 h / 70 °C 7.1: hydrogenchloride / methanol / 8 h / 70 °C 8.1: triethylsilane; trifluoroacetic acid / acetonitrile / 36 h / 65 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | Stage #1: 5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-amine With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Inert atmosphere; Stage #2: (2E)-cyclooct-2’-en-1’-yl 4-nitrophenyl carbonate In N,N-dimethyl-formamide at 20℃; | A2 General Procedure for the Preparation of TCO-pexidartinib To a solution of Pexidartinib (PLX3397) (373 mg, 0.89 mmol) in DMF (4 .0 mL) 0 °C was added sodium hydride (ca. 60%, 39 mg, ca. 0.96 mmol); and reaction mixture was stirred under nitrogen for 1 h before TCO-PNB ester (200 mg, 0.68 mmol) was added. The resulting mixture was stirred at rt overnight and evaporated in vacuo. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine, dried (Na2S04) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with di chi orom ethane followed by MeOH-CH2CL (0-5%) to give TCO- pexidartinib (14 5 mg, 37%). LC-MS: 571 [M+H]+ 1HNMR (300 MHz, CDCh) d 8.72 (s, 1 H), 8.4 1 (s, 1 H), 8.05 (s, 1 H), 7.85 (d, J= 6.9 Hz, 1 H), 7.66 (s, 1 H), 7.62 (d, J= 7.8 Hz, 1 H), 7.56 (s, 1 H), 7.29 (d, J= 2.4 Hz, 1 H), 6.37 (d, J= 8.4 Hz, 1 H), 6.15 (m, 1 H), 5.74 (s, 1 H), 5.60 (d, J= 6.0 Hz, 1 H), 4.88 (t, J= 6.0 Hz, 1 H), 4.67 (d, J= 6.0 Hz, 2 H), 3.87 (s, 1 H), 2.50 (m 1 H), 2.30 (m, 1 H), 2.10 -0.80 (m, 8 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 20 °C 1.2: 2 h / 20 °C 2.1: 4,4'-di-tert-butyl-2,2'-bipyridine; bis(1,5-cyclooctadiene)nickel (0); triethylamine / acetone / 36 h / 20 °C / Glovebox; Sealed tube; Irradiation 3.1: trifluoroacetic acid / dichloromethane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: dmap / dichloromethane 2: dichloromethane / 3 h / 20 °C / Sealed tube 3: 4,4'-di-tert-butyl-2,2'-bipyridine; bis(1,5-cyclooctadiene)nickel (0); triethylamine / acetone / 36 h / 20 °C / Glovebox; Sealed tube; Irradiation 4: trifluoroacetic acid / dichloromethane / 20 °C | ||
Multi-step reaction with 6 steps 1: dmap / dichloromethane 2: dichloromethane / 3 h / 20 °C / Sealed tube 3: 4,4'-di-tert-butyl-2,2'-bipyridine; bis(1,5-cyclooctadiene)nickel (0); triethylamine / acetone / 36 h / 20 °C / Glovebox; Sealed tube; Irradiation 4: dichloromethane / 3 h / 20 °C / Sealed tube 5: 4,4'-di-tert-butyl-2,2'-bipyridine; bis(1,5-cyclooctadiene)nickel (0); triethylamine / acetone / 36 h / 20 °C / Glovebox; Sealed tube; Irradiation 6: trifluoroacetic acid / dichloromethane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 20 °C 1.2: 2 h / 20 °C 2.1: 4,4'-di-tert-butyl-2,2'-bipyridine; bis(1,5-cyclooctadiene)nickel (0); triethylamine / acetone / 36 h / 20 °C / Glovebox; Sealed tube; Irradiation 3.1: trifluoroacetic acid / dichloromethane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 4,4'-di-tert-butyl-2,2'-bipyridine; bis(1,5-cyclooctadiene)nickel (0); triethylamine / acetone / 36 h / 20 °C / Glovebox; Sealed tube; Irradiation 2: dichloromethane / 3 h / 20 °C / Sealed tube 3: 4,4'-di-tert-butyl-2,2'-bipyridine; bis(1,5-cyclooctadiene)nickel (0); triethylamine / acetone / 36 h / 20 °C / Glovebox; Sealed tube; Irradiation 4: trifluoroacetic acid / dichloromethane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 4,4'-di-tert-butyl-2,2'-bipyridine; bis(1,5-cyclooctadiene)nickel (0); triethylamine / acetone / 36 h / 20 °C / Glovebox; Sealed tube; Irradiation 2: trifluoroacetic acid / dichloromethane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 4,4'-di-tert-butyl-2,2'-bipyridine; bis(1,5-cyclooctadiene)nickel (0); triethylamine / acetone / 36 h / 20 °C / Glovebox; Sealed tube; Irradiation 2: trifluoroacetic acid / dichloromethane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: dichloromethane / 3 h / 20 °C / Sealed tube 2: 4,4'-di-tert-butyl-2,2'-bipyridine; bis(1,5-cyclooctadiene)nickel (0); triethylamine / acetone / 36 h / 20 °C / Glovebox; Sealed tube; Irradiation 3: trifluoroacetic acid / dichloromethane / 20 °C | ||
Multi-step reaction with 5 steps 1: dichloromethane / 3 h / 20 °C / Sealed tube 2: 4,4'-di-tert-butyl-2,2'-bipyridine; bis(1,5-cyclooctadiene)nickel (0); triethylamine / acetone / 36 h / 20 °C / Glovebox; Sealed tube; Irradiation 3: dichloromethane / 3 h / 20 °C / Sealed tube 4: 4,4'-di-tert-butyl-2,2'-bipyridine; bis(1,5-cyclooctadiene)nickel (0); triethylamine / acetone / 36 h / 20 °C / Glovebox; Sealed tube; Irradiation 5: trifluoroacetic acid / dichloromethane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: dichloromethane / 3 h / 20 °C / Sealed tube 2: 4,4'-di-tert-butyl-2,2'-bipyridine; bis(1,5-cyclooctadiene)nickel (0); triethylamine / acetone / 36 h / 20 °C / Glovebox; Sealed tube; Irradiation 3: trifluoroacetic acid / dichloromethane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With trifluoroacetic acid In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: tetrabutylammonium hydrogensulfate; potassium 2-methyl-2-butoxide / isopropanol; cyclohexane / 48 h / 25 - 40 °C 2: triethylsilane; trifluoroacetic acid / acetonitrile / 12 h / 85 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.36% | With triethylsilane; trifluoroacetic acid In acetonitrile at 85℃; for 12h; | 1-6 Synthesis of pecidatinib: In a 100ml one-necked flask, 60mg of compound (V) was dissolved in 10mL of acetonitrile,After stirring for 30 min, 0.85 mL of triethylsilane and 0.38 mL of trifluoroacetic acid were added in sequence,Keep the reaction temperature at 85°C, reflux for 12h,The reaction solution was slowly poured into 50mL of 5(wt)% sodium hydroxide solution,Extract with 50 mL of ethyl acetate, take the organic phase, wash the organic phase with 50 mL of saturated brine, and after washing, concentrate and dry the organic phase.The concentrated product was recrystallized with a mixed solvent of ethanol:water=1:2,After filtration, drying was performed to obtain a crude product. The crude product was dissolved in a mixed solvent of ethanol: water = 1:4, and 0.2 g of activated carbon was added for decolorization. After decolorization, cooling and crystallization were completed.The dried product gave 33.5 mg of percidatinib, and the calculated yield was 71.36%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: acetonitrile / 0.33 h 1.2: 24 h / 85 °C 2.1: sodium bis(2-methoxyethoxy)aluminium dihydride / tetrahydrofuran / 4 h / 60 °C / Inert atmosphere 3.1: Dess-Martin periodane / tetrahydrofuran / 5 h / 25 °C / Inert atmosphere 4.1: triethylamine; dmap / dichloromethane / 36 h / 25 °C 5.1: tetra(n-butyl)ammonium hydrogensulfate; potassium 2-methylbutan-2-olate / isopropyl alcohol; cyclohexane / 48 h / 25 - 40 °C 6.1: triethylsilane; trifluoroacetic acid / acetonitrile / 12 h / 85 °C | ||
Multi-step reaction with 4 steps 1: trifluoroacetic acid / toluene / 4 h / Dean-Stark; Inert atmosphere; Reflux 2: potassium <i>tert</i>-butylate; C26H35Cl2NPRuS2; hydrogen / toluene; ethanol / 10 h / 65 - 120 °C 3: sodium methylate / methanol / 4 h / Inert atmosphere; Dean-Stark; Reflux 4: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / isopropyl alcohol / 8 h / 70 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: acetonitrile / 0.33 h 1.2: 24 h / 85 °C 2.1: sodium bis(2-methoxyethoxy)aluminium dihydride / tetrahydrofuran / 4 h / 60 °C / Inert atmosphere 3.1: Dess-Martin periodane / tetrahydrofuran / 5 h / 25 °C / Inert atmosphere 4.1: triethylamine; dmap / dichloromethane / 36 h / 25 °C 5.1: tetra(n-butyl)ammonium hydrogensulfate; potassium 2-methylbutan-2-olate / isopropyl alcohol; cyclohexane / 48 h / 25 - 40 °C 6.1: triethylsilane; trifluoroacetic acid / acetonitrile / 12 h / 85 °C | ||
Multi-step reaction with 4 steps 1: trifluoroacetic acid / toluene / 4 h / Dean-Stark; Inert atmosphere; Reflux 2: potassium <i>tert</i>-butylate; C26H35Cl2NPRuS2; hydrogen / toluene; ethanol / 10 h / 65 - 120 °C 3: sodium methylate / methanol / 4 h / Inert atmosphere; Dean-Stark; Reflux 4: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / isopropyl alcohol / 8 h / 70 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: sodium bis(2-methoxyethoxy)aluminium dihydride / tetrahydrofuran / 4 h / 60 °C / Inert atmosphere 2: Dess-Martin periodane / tetrahydrofuran / 5 h / 25 °C / Inert atmosphere 3: triethylamine; 4-dimethylaminopyridine / dichloromethane / 36 h / 25 °C 4: tetrabutylammonium hydrogensulfate; potassium 2-methyl-2-butoxide / isopropanol; cyclohexane / 48 h / 25 - 40 °C 5: triethylsilane; trifluoroacetic acid / acetonitrile / 12 h / 85 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: Dess-Martin periodane / tetrahydrofuran / 5 h / 25 °C / Inert atmosphere 2: triethylamine; dmap / dichloromethane / 36 h / 25 °C 3: tetra(n-butyl)ammonium hydrogensulfate; potassium 2-methylbutan-2-olate / isopropyl alcohol; cyclohexane / 48 h / 25 - 40 °C 4: triethylsilane; trifluoroacetic acid / acetonitrile / 12 h / 85 °C | ||
Multi-step reaction with 2 steps 1: sodium methylate / methanol / 4 h / Inert atmosphere; Dean-Stark; Reflux 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / isopropyl alcohol / 8 h / 70 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: triethylamine; 4-dimethylaminopyridine / dichloromethane / 36 h / 25 °C 2: tetrabutylammonium hydrogensulfate; potassium 2-methyl-2-butoxide / isopropanol; cyclohexane / 48 h / 25 - 40 °C 3: triethylsilane; trifluoroacetic acid / acetonitrile / 12 h / 85 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: potassium <i>tert</i>-butylate; C26H35Cl2NPRuS2; hydrogen / toluene; ethanol / 10 h / 65 - 120 °C 2: sodium methylate / methanol / 4 h / Inert atmosphere; Dean-Stark; Reflux 3: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate / isopropyl alcohol / 8 h / 70 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81 % | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In isopropyl alcohol at 70℃; Inert atmosphere; | 6 Example 6: Preparation of methyl 5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-amine (Compound 6) To a flask, (dippf)PdCl2 (13.1 mg, 0.022 mmol, 2.5 mol%), Compound 5 (0.15 g, 0.38 mmol, 1 equivalent), K2CO3 (0.27 g, 0.76 mmol, 2 equivalents), and Compound 9 (0.365 g, 0.42 mmol, 1.1 equivalents) were measured. The flask was then sealed with septa and then evacuated and refilled with nitrogen. The purging process was repeated three times and then wet isopropanol (1.1 mL, 0.35 M), degassed by sparging with nitrogen for 2 hours, was added to the flask. Agitation was started and then the reactor was heated to 70 oC for 8 hours. After this time, the reaction mixture was cooled and extracted with ethyl acetate. The extract was then evaporated to dryness. The crude material was analyzed by 1H NMR and found to have greater than 95% conversion to the desired product. Purification of the material by column chromatography (0-10% MeOH/CH2Cl2) gave Compound 6 (0.297 g, 0.712 mmol, 81%). 1H NMR (400 MHz, Chloroform-d) δ 9.63 (s, 1H), 8.72 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 2.3 Hz, 1H), 8.10 - 7.99 (m, 1H), 7.91 - 7.81 (m, 1H), 7.73 (dd, J = 2.3, 0.7 Hz, 1H), 7.63 (dd, J = 8.1, 0.8 Hz, 1H), 7.28 (dd, J = 8.4, 2.3 Hz, 1H), 7.09 (dd, J = 2.4, 1.2 Hz, 1H), 6.35 (dd, J = 8.5, 0.8 Hz, 1H), 5.04 (t, J = 6.1 Hz, 1H), 4.65 (d, J = 6.1 Hz, 2H), 3.91 (s, 2H). 19F NMR (376 MHz, CDCl3) δ -67.74. |
Tags: 1029044-16-3 synthesis path| 1029044-16-3 SDS| 1029044-16-3 COA| 1029044-16-3 purity| 1029044-16-3 application| 1029044-16-3 NMR| 1029044-16-3 COA| 1029044-16-3 structure
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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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