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Chemical Structure| 1254981-27-5 Chemical Structure| 1254981-27-5

Structure of 1254981-27-5

Chemical Structure| 1254981-27-5

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Product Details of [ 1254981-27-5 ]

CAS No. :1254981-27-5
Formula : C13H9ClF3NO
M.W : 287.67
SMILES Code : FC(C1=C(OCC2=CC=CC=C2)C=CN=C1Cl)(F)F
MDL No. :MFCD22420292

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Application In Synthesis of [ 1254981-27-5 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 1254981-27-5 ]

[ 1254981-27-5 ] Synthesis Path-Downstream   1~2

  • 1
  • [ 1186194-98-8 ]
  • [ 100-51-6 ]
  • [ 1254981-27-5 ]
YieldReaction ConditionsOperation in experiment
50% A solution of benzyl alcohol (commercially available, 1.201 mL, 11.55 mmol) was added to a mixture of 60% sodium hydride dispersion in mineral oil (0.484 g, 12.10 mmol) and DMF (30 mL) in an ice bath at 0 C. The mixture was allowed to stir at 0 C for 30 min, then a solution of <strong>[1186194-98-8]2,4-dichloro-3-(trifluoromethyl)pyridine</strong>30 (2.376 g, 11 mmol) in DMF (3 mL) was quickly added. The resulting mixture was stirred at 0 C for 1 h, then quenched by the addition of water. The aqueous mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (5:1 hexanes/ethyl acetate) to afford 4-(benzyloxy)-2-chloro-3-(trifluoromethyl)pyridine (1.59 g, 50% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 5.9 Hz, 1H), 7.47-7.37 (m, 6H), 6.95 (d, J = 5.6 Hz, 1H), 5.28 (s, 2H); LC-MS (M+H)+ 288.1.
38% To a solution of NaH (60% in oil, 24 g, 600 mmol) in DMF (2 L) at 0 C was added benzyl alcohol (35 g, 325 mmol), then the reaction was stirred for 2 mm. Intermediate(160 mg, 741 mmol) was added in one portion, and stirred at 0 C for 1 h. The reaction was diluted by the addition of H20 and extracted with Et20. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/EtOAc = 20/1). The pure fractions were collected and the solvent was evaporated to yield intermediate 3(lOOg,38%).
38% To a solution of NaH (60% in oil, 24 g, 600 mmol) in DMF (2 L) at 0 C was added benzyl alcohol (35 g, 325 mmol), then the reaction was stirred for 2 mm. Intermediate 2(160 mg, 741 mmol) was added in one portion, and stirred at 0 C for 1 h. The reaction was diluted by the addition of H20 and extracted with Et20. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/EtOAc = 20/1). The pure fractions were collected and the solvent was evaporated to yield intermediate 3(100 g, 38%).
33% Description 74-benzyloxy-3-trifluoromethyl-2-chloro-pyridine (D7)To a suspension of NaH (0.487 g, 12.732 mmol, 60% mineral oil) in DMF (50 ml) cooled at 0 0C, was added benzyl alcohol (1.262 ml, 12.2 mmol). The resulting mixture was stirred for 2 min. Then, intermediate compound D6 (2.5 g, 11.575 mmol) was added. The resulting reaction mixture was gradually warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with water and extracted with Et2O.The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; Heptane/DCM gradient as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D7 (1.1 g, 33%).
33% To a suspension of NaH (0.487 g, 12.732 mmol, 60% mineral oil) in DMF (50 ml) cooled at 0 0C, was added benzyl alcohol (1.262 ml, 12.2 mmol). The resulting mixture was stirred for 2 min. Intermediate compound D13 (2.5 g, 11.575 mmol) was then added. The resulting reaction mixture was stirred for 1 h while gradually allowing it to warm to r.t., quenched with water and extracted with Et2O. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; Heptane/DCM gradient as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D14 (l.l g, 33%).
33% To a suspension of NaH (0.487 g, 12.732 mmol, 60% mineral oil) in DMF (50 ml) cooled at 0 0C, was added benzyl alcohol (1.262 ml, 12.2 mmol). The resulting mixture was stirred for 2 min., then, intermediate compound D25 (2.5 g, 11.575 mmol) was added. The resulting reaction mixture was gradually warmed to r.t. and stirred for 1 h. The reaction mixture was quenched with water and extracted with Et2O. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; Heptane/DCM gradient as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D26 (1.1 g, 33%).
33% 4-Benzyloxy-2-chloro-3 -trifluoromethyl-pyridine (1-7)To a suspension of NaH (0.49 g, 12.73 mmol, 60% mineral oil) in DMF (50 mL) cooled at 0 C, was added benzyl alcohol (1.26 mL, 12.2 mmol). The resulting mixture was stirred for 2 min then; intermediate 1-6 (2.5 g, 11.57 mmol) was added. The resulting r.m. was gradually warmed to r.t. and stirred for 1 h. The r.m. was quenched with water and extracted with Et20. The organic layer was separated, dried (Na2S04) and concentrated in vacuo. The crude product was purified by column chromatography (silica; DCM in Heptane 0/100 to 100/0). The desired fractions were collected and concentrated in vacuo to yield intermediate 1-7 (1.1 g, 33%).
33% Intermediate 3 (1-3)4-Benzyloxy-2-chloro-3-trifluoromethyl-pyridine (1-3)To a suspension of NaH (0.49 g, 12.73 mmol, 60% mineral oil) in DMF (50 mL) cooled at 0 C, was added benzyl alcohol (1.26 mL, 12.2 mmol). The resulting mixture was stirred for 2 min. then; intermediate compound 1-2 (2.5 g, 11.57 mmol) was added. The resulting reaction mixture was gradually warmed to r.t. and stirred for 1 h. The reaction mixture was quenched with water and extracted with diethyl ether. The organic layer was separated, dried (Na2SC>4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM in Heptane 0/100 to 100/0). The desired fractions were collected and concentrated in vacuo to yield intermediate compound 1-3 (1.1 g, 33%).
33% With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 1h; Intermediate 9(1-9)-3-trifluoromethyl-pyridine (1-9)To a suspension of NaH (0.49 g, 12.73 mmol, 60% mineral oil) in DMF (50 mL) cooled at 0 C, was added benzyl alcohol (1.26 mL, 12.2 mmol). The resulting mixture was stirred for 2 min. then; intermediate compound 1-8 (2.5 g, 11.57 mmol) was added. The resulting reaction mixture was gradually warmed to r.t. and stirred for 1 h. The reaction mixture was quenched with water and extracted with Et20. The organic layer was separated, dried (Na2S04) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM in Heptane 0/100 to 100/0). The desired fractions were collected and concentrated in vacuo to yield intermediate compound 1-9 (1.1 g, 33%).
33% Intermediate 3 (1-3)-3-trifluoromethyl-pyridine (1-3)To a suspension of NaH (0.49 g, 12.73 mmol, 60% mineral oil) in DMF (50 mL) cooled at 0 C, was added benzyl alcohol (1.26 mL, 12.2 mmol). The resulting mixture was stirred for 2 min. then; intermediate compound 1-2 (2.5 g, 11.57 mmol) was added. The resulting reaction mixture was gradually warmed to r.t. and stirred for 1 h. The reaction mixture was quenched with water and extracted with diethyl ether. The organic layer was separated, dried (Na2S04) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM in Heptane 0/100 to 100/0). The desired fractions were collected and concentrated in vacuo to yield intermediate compound 1-3 (1.1 g, 33%).
33% With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 1h; 4-Benzyloxy-2-chloro-3-trifluoromethyl-pyridine (I-3) To a suspension of NaH (0.49 g, 12.73 mmol, 60% mineral oil) in DMF (50 mL) cooled at 0 C., was added benzyl alcohol (1.26 mL, 12.2 mmol). The resulting mixture was stirred for 2 min. then; intermediate compound I-2 (2.5 g, 11.57 mmol) was added. The resulting reaction mixture was gradually warmed to r.t. and stirred for 1 h. The reaction mixture was quenched with water and extracted with diethyl ether. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM in Heptane 0/100 to 100/0). The desired fractions were collected and concentrated in vacuo to yield intermediate compound I-3 (1.1 g, 33%).
33% With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; 4-Benzyloxy-2-chloro-3-trifluoromethyl-pyridine (I-7) To a suspension of NaH (0.49 g, 12.73 mmol, 60% mineral oil) in DMF (50 mL) cooled at 0 C., was added benzyl alcohol (1.26 mL, 12.2 mmol). The resulting mixture was stirred for 2 min then; intermediate I-6 (2.5 g, 11.57 mmol) was added. The resulting r.m. was gradually warmed to r.t. and stirred for 1 h. The r.m. was quenched with water and extracted with Et2O. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica; DCM in Heptane 0/100 to 100/0). The desired fractions were collected and concentrated in vacuo to yield intermediate I-7 (1.1 g, 33%).
33% To a suspension of NaH (0.487 g, 12.732 mmol, 60% mineral oil) in DMF (50 mL) cooled at 0 C, was added benzyl alcohol (1.262 mL, 12.2 mmol). The resulting mixture was stirred for 2 min, then, 1-2 (2.5 g, 11.575 mmol) was added. The resulting reaction mixture was gradually warmed to rt and stirred for 1 h. The reaction mixture was quenched with water and extracted with Et20. The organic layer was separated, dried (Na2S04) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; Heptane/DCM gradient as eluent). The desired fractions were collected and concentrated in vacuo to yield 1-3 (1.1 g, 33%).
30% Asolutionofbenzylalcohol(2.4g,22mM)wasaddedtoamixtureof60%sodiumhydride dispersioninmineraloil(0.97mg,24mM)anddimethylformamide(80mL)inanicebathat0C. Themixturewasallowedtostirat0Cfor30min,andthenasolutionof2,4-dichloro-3- (trifluoromethyl)pyridine(C1,5.0g,23mM)indimethylformamide(10mL)wasquicklyadded. Theresultingmixturewasstirredat0Cfor1h,thenquenchedbytheadditionofwater.The aqueousmixturewasextractedwithethylacetate.Thecombinedorganiclayerswerewashed withbrine,driedovermagnesiumsulfate,filtered,andconcentratedinvacuo.Theresiduewas purifiedbysilica-gelcolumnchromatography(5:1hexanes/ethylacetate)toafford4-(benzyloxy)- 2-chloro-3-(trifluoromethyl)pyridine(C3,1.9g,6.9mM)in30%yield.ToasuspensionofC3(1.09 g,3.79mM)in1,4-dioxane(9mL),wasaddedhydrazinemonohydrate(3.68mL,75.8mM).The reactionmixturewasheatedat160Cfor30minundermicrowaveirradiation.Afterthemixture wascooledtoroomtemperature,thevolatileswereevaporatedinvacuo.Theresiduethus obtainedwasdissolvedindichloromethaneandwashedwithsaturatedsodiumbicarbonate aqueoussolution.Theorganiclayerwasseparated,driedoversodiumsulfate,concentratedin vacuoandpurifiedbysilica-gelcolumnchromatographytogive4-(benzyloxy)-2-hydrazineyl-3- (trifluoromethyl)pyridine(C4,0.86g,3.03mM)in80%yield.

 

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