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[ CAS No. 394-29-6 ] {[proInfo.proName]}

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Product Details of [ 394-29-6 ]

CAS No. :394-29-6 MDL No. :MFCD01631433
Formula : C7H3Cl2FO Boiling Point : -
Linear Structure Formula :- InChI Key :VWGAATKTEAKOCO-UHFFFAOYSA-N
M.W : 193.00 Pubchem ID :2773604
Synonyms :

Calculated chemistry of [ 394-29-6 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 41.59
TPSA : 17.07 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.15 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.87
Log Po/w (XLOGP3) : 3.28
Log Po/w (WLOGP) : 3.28
Log Po/w (MLOGP) : 3.05
Log Po/w (SILICOS-IT) : 3.4
Consensus Log Po/w : 2.98

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.44
Solubility : 0.07 mg/ml ; 0.000363 mol/l
Class : Soluble
Log S (Ali) : -3.31
Solubility : 0.0938 mg/ml ; 0.000486 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.86
Solubility : 0.0266 mg/ml ; 0.000138 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.44

Safety of [ 394-29-6 ]

Signal Word:Danger Class:8
Precautionary Statements:P280-P305+P351+P338-P310 UN#:3265
Hazard Statements:H314 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 394-29-6 ]

* 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 [ 394-29-6 ]

[ 394-29-6 ] Synthesis Path-Downstream   1~72

  • 2
  • [ 394-30-9 ]
  • [ 394-29-6 ]
YieldReaction ConditionsOperation in experiment
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h; 5-Chloro-2-fluorobenzoic acid (1 g, 5.73 mmol) was suspended in dichloromethane (10 imL) and DMF (1 drop) was added followed by dropwise addition of oxalyl chloride (0.75 ml_, 8.59 mmol). The mixture was stirred at ambient temperature for 1 h by which time gas evolution had ceased and a colourless solution resulted. This acid chloride was concentrated in vacuo, dissolved in dichloromethane (10 ml.) and added dropwise to aqueous ammonia (30%, 40 ml_). This mixture was stirred for a further 30 min and then extracted with dichloromethane (3 x 20 ml_). The combined extracts were dried (MgSO4) and concentrated in vacuo resulting in a white solid (900 mg, 91 %).
With Chloro-oxo-acetic acid; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h; 5-Chloro-2-fluorobenzoic acid (1 g, 5.73 mmol) was suspended in dichloromethane (10 mL) and DMF (1 drop) was added followed by dropwise addition of oxalyl chloride (0.75 mL, 8.59 mmol). The mixture was stirred at ambient temperature for 1 h by which time gas evolution had ceased and a colourless solution resulted.
13.50 g With thionyl chloride; at 85℃; for 10h; (1) equipped with magnetic stirring in 50 ml flask, add <strong>[394-30-9]5-chloro-2-fluoro-benzoic acid</strong> (CFBA) (12.5g, 71 . 61mmol) and 20 ml thionyl chloride. In 85 C reaction under 10h, to evaporate under the normal pressure of the excessive thionyl chloride, to continue to vacuum distillation, to obtain colorless liquid 5-chloro-2-fluoro-benzoyl chloride (CFBC) (13.50g).
900 g With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; To a stirred solution of <strong>[394-30-9]5-chloro-2-fluorobenzoic acid</strong> (900 g, 5. 17 mol) in5 DCM (10 L) vvas added oxalyl chloride (990 g, 7.8 mol) at 0 oc. After addition,DMF (3 mL) vvas added and the reaction mixture vvas stirred at ambienttemperature overnight. On completion, the solvent was removed under reducedpressure, the residue was dissolved in DCM (2 L) and the solution wasconcentrated again to dryness. The acid chloride thus obtained (900 g, 4.66 mol)10 was dissolved in DCM (6 L) a.nd N,O-dimethylhydroxylamine hydrochloride(682.27 g, 7 mmol) was added followed by a solution of triethylamine (2 7 L, 19.4mol) in DCM (4 L) dropwise at 0 oc. The reaction mixture vvas warmed slowly toambient temperature, and stirred overnight. The mixture '.vas then quenched withice v.·ater and the layers were separated. The aqueous layer wa.-.: extracted with15 DCM (2 x 3 L) and the combined organic layer was washed with 0.5 N HCl (4 L),lN NaOH (4 L), water (5 L) and brine (5 L) then it was dried over Na2S04 andconcentrated to afiord 5-chloro-2-fluoro-N-methoxy-N-methylbenzamide (900 g,80%) yield).

  • 3
  • [ 394-29-6 ]
  • [ 124-68-5 ]
  • [ 312494-00-1 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane at 25℃; for 3h;
  • 4
  • [ 394-29-6 ]
  • [ 180339-71-3 ]
  • 5-chloro-<i>N</i>-{3-chloro-4-[2-(5-chloro-2-fluoro-benzoyl)-4,5-dihydro-2<i>H</i>-9-thia-1,2,6-triaza-cyclopenta[<i>e</i>]azulene-6-carbonyl]-phenyl}-2-fluoro-benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dichloromethane
  • 6
  • [ 394-29-6 ]
  • 2-(4-chloro-2-fluoro-phenyl)-pteridin-4-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: pyridine 2: ammonia / ethanol / Heating 3: NaOH
  • 8
  • [ 394-29-6 ]
  • 2-(5-chloro-2-fluorophenyl)-4-(3-methyl-4-pyridylamino)pteridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: pyridine 2: ammonia / ethanol / Heating 3: NaOH 4: benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium*PF6
  • 9
  • [ 394-29-6 ]
  • 2-(5-chloro-2-fluorophenyl)-4-(3-ethyl-4-pyridylamino)pteridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: pyridine 2: ammonia / ethanol / Heating 3: NaOH 4: benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium*PF6
  • 10
  • [ 352-33-0 ]
  • [ 394-29-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 1.) n-BuLi / 1.) hexane/THF, -70 deg C, 4 h, 2.) RT, 16 h 2: SOCl2 / 0.5 h / Ambient temperature
  • 11
  • [ 394-29-6 ]
  • [ 82390-44-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: CH2Cl2 / 3 h / 25 °C 2: SOCl2 / 1 h / Ambient temperature
  • 12
  • [ 452-66-4 ]
  • [ 394-29-6 ]
  • 13
  • [ 67-56-1 ]
  • [ 394-29-6 ]
  • [ 57381-36-9 ]
YieldReaction ConditionsOperation in experiment
100% In dichloromethane at 0 - 20℃; for 3h; 107.1 Example 107; 5-Chloro-2-fluoro-benzoic acid hydrazide; Step 1: 5-CHLORO-2-FLUORO-BENZOIC acid methyl ester: Methanol (20 ml) was added to a solution 5-chloro-2-fluoro-benzoyl chloride (1.2 g, 6.2 mmol) in dichloromethane (10 ml) in an ice-bath. The reaction mixture was warmed to room temperature, stirred for 3 h and then concentrated to afford 5-chloro-2-fluoro-benzoic acid methyl ester (1.17 g, 100%). 1H NMR [(CDC13),] 8 (ppm): 7.93 (m, 1H), 7. 48 (m, [1H),] 7.12 (m, 1H), 3.96 (s, 3H).
100% In dichloromethane at 0 - 20℃; for 3h; 54 Methanol (20 mL) was added to a solution 5-chloro-2-fluoro-benzoyl chloride (1.2 g, 6.2 mmol) in dichloromethane (10 mL) in an ice-bath. The reaction mixture was warmed to room temperature, stirred for 3 hours and then concentrated to afford 5-chloro-2-fluoro- benzoic acid methyl ester (1.17 g, [100%). LH NMR (CDC13), 6] (ppm): 7.93 (m, [1H),] 7.48 (m, 1H), 7.12 (m, [1H),] 3.96 (s, 3H).
  • 14
  • [ 180339-71-3 ]
  • [ 394-29-6 ]
  • N-[4-[(4,5-Dihydropyrazolo[3,4-d] thieno[3,2-b]azepin-6(1H)-yl)carbonyl]-3-chlorophenyl]-5-chloro-2-fluorobenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide; sodium hydrogencarbonate; triethylamine; citric acid In tetrahydrofuran; methanol; dichloromethane; chloroform; water 4 N-[4-[(4,5-Dihydropyrazolo[3,4-d] thieno[3,2-b]azepin-6(1H)-yl)carbonyl]-3-chlorophenyl]-5-chloro-2-fluorobenzamide EXAMPLE 4 N-[4-[(4,5-Dihydropyrazolo[3,4-d] thieno[3,2-b]azepin-6(1H)-yl)carbonyl]-3-chlorophenyl]-5-chloro-2-fluorobenzamide To an ice bath cooled mixture of 345 mg of 6-(2-chloro-4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-b]azepine in 3.5 ml of methylene chloride under argon is added 417 μl of triethylamine followed by a solution of 482 mg of 2-fluoro-5-chlorobenzoyl chloride in 1.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours under argon. An additional 40 ml of methylene chloride is added followed by 20 ml of water. The organic layer is washed with 20 ml each of 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried (Na2 SO4), filtered through hydrous magnesium silicate and the filtrate evaporated in vacuo to give 650 mg of the desired product as a solid residue. To a solution of 500 mg of the preceding compound in 4 ml methanol and 4 ml of tetrahydrofuran is added 1.51 ml of 1N NaOH. The reactants are stirred at room temperature for 18 hours. The reaction mixture is neutralized with 1N HCl and evaporated in vacuo to a residue which is diluted with 50 ml of chloroform and washed with water, brine and dried (Na2 SO4). The organic layer is passed through a pad of hydrous magnesium silicate. The filtrte is evaporated in vacuo to a residue which is crystallized from ethyl acetate containing ethyl alcohol. The collected solid is dried to give 215 mg of the desired product as an off white solid, m.p. 282°-288° C.
With sodium hydroxide; sodium hydrogencarbonate; triethylamine; citric acid In tetrahydrofuran; methanol; dichloromethane; chloroform; water 4 N-[4-[(4,5-Dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(1H)-yl)carbonyl]-3-chlorophenyl]-5-chloro-2-fluorobenzamide EXAMPLE 4 N-[4-[(4,5-Dihydropyrazolo[3,4-d]thieno[3,2-b]azepin-6(1H)-yl)carbonyl]-3-chlorophenyl]-5-chloro-2-fluorobenzamide To an ice bath cooled mixture of 345 mg of 6-(2-chloro-4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-b]azepine in 3.5 ml of methylene chloride under argon is added 417 μl of triethylamine followed by a solution of 482 mg of 2-fluoro-5-chlorobenzoyl chloride in 1.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours under argon. An additional 40 ml of methylene chloride is added followed by 20 ml of water. The organic layer is washed with 20 ml each of 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried (Na2 SO4), filtered through hydrous magnesium silicate and the filtrate evaporated in vacuo to give 650 mg of the desired product as a solid residue. To a solution of 500 mg of the preceding compound in 4 ml methanol and 4 ml of tetrahydrofuran is added 1.51 ml of 1N NaOH. The reactants are stirred at room temperature for 18 hours. The reaction mixture is neutralized with 1N HCl and evaporated in vacuo to a residue which is diluted with 50 ml of chloroform and washed with water, brine and dried (Na2 SO4). The organic layer is passed through a pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to a residue which is crystallized from ethyl acetate containing ethyl alcohol. The collected solid is dried to give 215 mg of the desired product as an off white solid, m.p. 282°-288° C.
  • 15
  • [ 394-29-6 ]
  • [ 159326-69-9 ]
  • [ 773140-19-5 ]
YieldReaction ConditionsOperation in experiment
21% With triethylamine In chloroform; acetonitrile at 20℃; M 1 -Amino- lH-pyrrole-2-carboxylic acid amide (1.25 g, 10 mmole) was partially dissolved in 45 ml acetonitrile, triethylamine (1.39 ml, 10 mmole) was added followed by dropwise addition of 5-chloro-2-fluorobenzoyl chloride ( 1.93 g, 10 mmole) in 3 ml chloroform. The reaction mixture was stirred at room temperature overnight, the solvent was removed under vacuum and the residue was taken up in chloroform, washed with 10% sodium bicarbonate, water, and dried over sodium sulfate (anh.). A solid crystallized from solution upon standing. Additional product was obtained by chromatographing the filtrate on silica gel eluting with 3% methanol/chloroform. 600 mg of product was obtained (yield: 21%)
  • 16
  • [ 41838-46-4 ]
  • [ 394-29-6 ]
  • 5-chloro-2-fluoro-N-(1-methyl-4-piperidinyl)-benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In water; benzene 2.a (a) (a) 5-chloro-2-fluoro-N-(1-methyl-4-piperidinyl)-benzamide A mixture of 23.9 g 4-amino-1-methyl-piperidine, 48.5 g 5-chloro-2-fluoro-benzoyl chloride, 44 ml triethylamine and 550 ml benzene is refluxed for 2 hours. Thereafter the solvent is evaporated off in vacuo and the residue is added dropwise under stirring to water. The solution is made alkaline and extracted with toluene. The toluene phase is dried and evaporated. The residue is recrystallized from methylene chloride/ether/petroleum ether to give the heading compound, m.p. 143°-145°.
  • 17
  • [ 3866-32-8 ]
  • [ 394-29-6 ]
  • 2-chloro-10-(1-methyl-piperidin-4-yl)-dibenzo[b,f][1,4]thiazepin-11(10H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide; potassium carbonate; triethylamine In tetrahydrofuran; <i>N</i>-methyl-acetamide; benzene 1.b (b) (b) 2-Chloro-10-(1-methyl-piperidin-4-yl)-dibenzo[b,f][1,4]thiazepin-11(10H)-one A solution of 243 g 1'-methyl-spiro[benzothiazolin-2,4'-piperidine] in 500 ml absolute tetrahydrofuran is added dropwise at 0° to a stirred suspension of 30.4 g lithium aluminium hydride in 1.5 l of tetrahydrofuran. The mixture is stirred 2 hours at 0° and then treated under ice-cooling with 182 ml of a saturated solution of potassium carbonate. The precipitate is filtered off and washed with ether. 543 g of the dried precipitate containing a compound of formula IV, wherein Z'=S, R1 '=CH3 and R2 =H, 235 g 5-chloro-2-fluorobenzoyl chloride, 152 ml triethylamine and 1.6 l benzene are refluxed for 16 hours. The mixture is evaporated in vacuo, the residue treated with 2.2 l of 2 N sodium hydroxide and boiled at reflux for 5 hours. The cooled reaction mixture is extracted with methylene chloride, the organic phase dried and evaporated. The resulting residue containing a compound of formula III, wherein Z'=S, R1 '=CH3, R2 =H, R3 =5-Cl and X=F, is dissolved in 350 ml dimethylformamide, treated with 7.0 g of a 55% sodium hydride/oil dispersion and stirred at 80° for 9 hours. The solvent is evaporated in vacuo and the residue partitioned between 2 N hydrochloric acid and toluene. The acid phase is made alkaline with sodium hydroxide and extracted with methylene chloride. After drying the organic phase is evaporated in vacuo and the residue recrystallized from ether to give the heading compound, m.p. 164°-165°.
  • 18
  • [ 394-29-6 ]
  • [ 261762-57-6 ]
YieldReaction ConditionsOperation in experiment
91% With ammonia In dichloromethane; water for 0.5h; a 5-Chloro-2-fluorobenzamide This acid chloride was concentrated in vacuo, dissolved in dichloromethane (10 mL) and added dropwise to aqueous ammonia (30%, 40 mL). This mixture was stirred for a further 30 min and then extracted with dichloromethane (3 20 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo resulting in a white solid (900 mg, 91%).
With ammonia In dichloromethane; water for 0.5h; a 5-Chloro-2-fluorobenzoic acid (1 g, 5.73 mmol) was suspended in dichloromethane (10 imL) and DMF (1 drop) was added followed by dropwise addition of oxalyl chloride (0.75 ml_, 8.59 mmol). The mixture was stirred at ambient temperature for 1 h by which time gas evolution had ceased and a colourless solution resulted. This acid chloride was concentrated in vacuo, dissolved in dichloromethane (10 ml.) and added dropwise to aqueous ammonia (30%, 40 ml_). This mixture was stirred for a further 30 min and then extracted with dichloromethane (3 x 20 ml_). The combined extracts were dried (MgSO4) and concentrated in vacuo resulting in a white solid (900 mg, 91 %).
  • 19
  • [ 1029971-71-8 ]
  • [ 394-29-6 ]
  • [ 1029970-78-2 ]
YieldReaction ConditionsOperation in experiment
With dmap; triethylamine In ISOPROPYLAMIDE at 20℃; 110 Example 110(2Z)-2-(3-butyl-4.5-dimethyl-1.3-thiazol-2(3H)-ylideDe)-l-(5-chtoϖ)-2- fluorophenyPethanoneIn a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 5-chloro-2-fluorobenzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1 : 1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.93 (t, 3 H) 1.33 - 1.42 (m, 2 H) 1.61 - 1.68 (m, 2 H) 2.19 (s, 3 H) 2.23 (s, 3 H) 3.94 - 4.01 (m, 2 H) 6.36 (s, 1 H) 7.27 - 7.35 (m, 1 H) 7.47 - 7.53 (m, 1 H) 7.75 - 7.81 (m, 1 H); MS (ESI) m/z 340 (M+H)+.
  • 20
  • [ 1029971-83-2 ]
  • [ 394-29-6 ]
  • [ 1029972-15-3 ]
YieldReaction ConditionsOperation in experiment
With dmap In dichloromethane at 20℃; 60 Example 60 (2Z)-2-(3-butyl-4-methyl-1.3-thiazol-2(3H)-ylidene)-l-(5-chloro-2- fluorophenyDethanoneIn a 20 mL vial a solution of 3-butyl-2,4-dimethylthiazol-3-ium iodide (47.92 mg, 0.16mmol) dissolved in CH2Cl2 (0.5 mL) was added, followed by the addition of DMAP (49.24 mg, 0.40 mmol) dissolved in CH2Cl2 ( 0.8 mL). Then, to the solution was added 5-chloro-2-fluorobenzoyl chloride (30.9 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL). The vial was capped and shaken overnight at room temperature. The residue was dissolved in 1 : 1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.95 (t, 3 H) 1.31 - 1.41 (m, 2 H) 1.57 - 1.77 (m, 2 H) 2.28 - 2.34 (m, 3 H) 3.95 - 4.02 (m, 2 H) 6.37 - 6.41 (m, 1 H) 6.55 - 6.68 (m, 1 H) 7.28 - 7.35 (m, 1 H) 7.48 - 7.54 (m, 1 H) 7.76 - 7.80 (m, 1 H); MS (ESI) positive ion 326 (M+H).
  • 21
  • [ 1065639-64-6 ]
  • [ 394-29-6 ]
  • [ 1065640-23-4 ]
YieldReaction ConditionsOperation in experiment
With triethylamine In tetrahydrofuran at 20℃; for 3h; 51.51A Example 51A (Z)-N-(5-tert-butyl-3-isobutylthiazol-2(3H)-ylidene)-5-chloro-2-fluorobenzamide 5-tert-Butyl-3-isobutylthiazol-2(3H)-imine (Example 16A, 1.5 g, 7.1 mmol) was dissolved in 10 mL of THF. 5-Chloro-2-fluorobenzoyl chloride (1.4 g, 7.1 mmol) was added then triethylamine (3 mL, 21.6 mmol) and the mixture stirred at room temperature for 3 hours. The reaction was diluted with EtOAc, washed with water, brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash chromatography using a gradient from 0 to 40% EtOAc in hexanes afforded the title compound. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 0.98 (d, J=6.74 Hz, 6H) 1.36 (s, 9H) 2.19-2.39 (m, 1H) 4.01 (d, J=7.14 Hz, 2H) 6.63 (s, 1H) 7.05 (dd, J=10.31, 8.72 Hz, 1H) 7.35 (ddd, J=8.73, 3.97, 2.78 Hz, 1H) 8.10 (dd, J=6.74, 2.78 Hz, 1H). MS (DCI/NH3) m/z 369.2 (M+H)+.
  • 22
  • [ 301673-16-5 ]
  • [ 394-29-6 ]
  • [ 1000782-02-4 ]
YieldReaction ConditionsOperation in experiment
75.5% With triethylamine; In tetrahydrofuran; at 10 - 30℃; for 1h; To a solution of <strong>[301673-16-5]tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate</strong> (500 mg, 2.31 mmol) and triethylamine (0.483 ml, 3.47 mmol) in tetrahydrofuran (10 ml) was added 5-chloro-2-fluorobenzoyl chloride (0.366 ml, 2.77 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the object product (650 mg, 75.5percent) as an oil. 1H-NMR (CDCl3) delta; 1.48 (9H, s), 2.99 (3H, br s), 3.31 (1H, br s), 3.64 (1H, br s), 3.77 (1H, br s), 4.15 (2H, br s), 4.48-4.51 (1H, m), 4.83 (1H, br s), 7.02-7.08 (1H, m), 7.35-7.39 (2H, m).
  • 23
  • [ 1140917-46-9 ]
  • [ 394-29-6 ]
  • [ 1217420-07-9 ]
YieldReaction ConditionsOperation in experiment
52% With triethylamine In tetrahydrofuran at 20℃; for 3h; 89G Triethylamine (1.2 mL, 8.8 mmol) was added to a solution of 5-chloro-2-fluorobenzoyl chloride (0.57 g, 2.95 mmol) and Example 89F (0.7 g, 2.95 mmol) in THF (6 mL) at room temperature. The reaction mixture was stirred for 3 hours then partitioned between EtOAc (15 mL) and saturated NaHCO3 (1 mL). The organic extract was washed with water and brine, dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (SiO2, solvent A=hexane:EtOAc:Et3N (1:3:0.2), solvent B=hexane:EtOAc:MeOH:Et3N (1:3:1:0.2), 0 to 20% solvent B/solvent A gradient over 300 mL then isocratic for 180 mL) to afford the title compound (0.6 g, 1.5 mmol, 52% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.38 (s, 9H), 1.67-1.82 (m, 3H), 1.84-1.96 (m, 1H), 3.59-3.67 (m, 1H), 3.71-3.79 (m, 1H), 3.91 (s, 3H), 4.14-4.23 (m, 1H), 4.32-4.46 (m, 2H), 6.82 (s, 1H), 7.14-7.23 (m, 1H), 7.42 (ddd, J=8.5, 3.6, 3.4 Hz, 1H), 7.78 (dd, J=6.3, 3.2 Hz, 1H); MS (DCI/NH3) m/z 394.2 (M+H)+
52% With triethylamine In tetrahydrofuran at 20℃; for 3h; 116 Example 116; N-{(3E)-5-tert-butyl-1-methyl-2-[2R)-tetrahydrofuran-2-ylmethyl]-1,2-dihydro-3H-pyrazol-3-ylidene}-5-chloro-2-fluorobenzamide; Triethylamine (1.2 mL, 8.8 mmol) was added to a mixture of 5-chloro-2-fluorobenzoyl chloride (0.57 g, 2.95 mmol) and Example 14C (0.7 g, 2.95 mmol) in 6 mL of THF. The mixture was stirred at room temperature for 3 hours, diluted with EtOAc, washed with saturated NaHCO3, water, brine, dried with MgSO4, filtered, and concentrated. Purification by chromatography (SiO2, solvent A=hexane:EtOAc:triethylamine (1:3:0.2); solvent B=hexane:EtOAc:MeOH:triethylamine (1:3:1:0.2); a gradient from 100% solvent A to 20% Solvent B over 300 mL then isocratic for 180 mL) afforded the title compound (0.6 g, 1.5 mmol, 52% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.38 (s, 9H), 1.67-1.82 (m, 3H), 1.84-1.96 (m, 1H), 3.59-3.67 (m, 1H), 3.71-3.79 (m, 1H), 3.91 (s, 3H), 4.14-4.23 (m, 1H), 4.32-4.46 (m, 2H), 6.82 (s, 1H), 7.14-7.23 (m, 1H), 7.42 (ddd, J=8.5, 3.6, 3.4 Hz, 1H), 7.78 (dd, J=6.3, 3.2 Hz, 1H). MS (DCI/NH3) m/z 394.2 (M+H)+.
52% With triethylamine In tetrahydrofuran at 20℃; for 3h; 89G Triethylamine (1.2 mL, 8.8 mmol) was added to a solution of 5-chloro-2-fluorobenzoyl chloride (0.57 g, 2.95 mmol) and Example 89F (0.7 g, 2.95 mmol) in THF (6 mL) at room temperature. The reaction mixture was stirred for 3 hours then partitioned between EtOAc (15 mL) and saturated NaHCO3 (1 mL). The organic extract was washed with water and brine, dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (SiO2, solvent A=hexane:EtOAc:Et3N (1:3:0.2), solvent B=hexane:EtOAc:MeOH:Et3N (1:3:1:0.2), 0 to 20% solvent B/solvent A gradient over 300 mL then isocratic for 180 mL) to afford the title compound (0.6 g, 1.5 mmol, 52% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.38 (s, 9H), 1.67-1.82 (m, 3H), 1.84-1.96 (m, 1H), 3.59-3.67 (m, 1H), 3.71-3.79 (m, 1H), 3.91 (s, 3H), 4.14-4.23 (m, 1H), 4.32-4.46 (m, 2H), 6.82 (s, 1H), 7.14-7.23 (m, 1H), 7.42 (ddd, J=8.5, 3.6, 3.4 Hz, 1H), 7.78 (dd, J=6.3, 3.2 Hz, 1H); MS (DCI/NH3) m/z 394.2 (M+H)+
  • 24
  • [ 3891-07-4 ]
  • [ 394-29-6 ]
  • [ 1161741-92-9 ]
YieldReaction ConditionsOperation in experiment
71% With pyridine; N,N,N,N,-tetramethylethylenediamine at 20℃; for 18h;
  • 25
  • [ 394-29-6 ]
  • [ 1303557-95-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 - 34 °C 2.1: potassium <i>tert</i>-butylate / <i>tert</i>-butyl alcohol / 20 h / 75 °C 2.2: pH 1 - 2 / Cooling with ice
  • 26
  • [ 394-29-6 ]
  • [ 1303557-96-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 - 34 °C 2.1: potassium <i>tert</i>-butylate / <i>tert</i>-butyl alcohol / 20 h / 75 °C 2.2: pH 1 - 2 / Cooling with ice 3.1: phosphorus(V) oxybromide / 1-methyl-pyrrolidin-2-one / 4.5 h / 20 - 95 °C
Multi-step reaction with 2 steps 1: dichloromethane 2: phosphorus(V) oxybromide / 1-methyl-pyrrolidin-2-one
  • 27
  • [ 394-29-6 ]
  • [ 1303556-78-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 - 34 °C 2.1: potassium <i>tert</i>-butylate / <i>tert</i>-butyl alcohol / 20 h / 75 °C 2.2: pH 1 - 2 / Cooling with ice 3.1: phosphorus(V) oxybromide / 1-methyl-pyrrolidin-2-one / 4.5 h / 20 - 95 °C 4.1: potassium phosphate; 4a,9a-dihydro-9,9-dimethyl-4,5-bis(diphenylphosphino)-xanthene / tris-(dibenzylideneacetone)dipalladium(0) / tert-Amyl alcohol / 6.5 h / 100 - 117 °C / Inert atmosphere
  • 28
  • [ 394-29-6 ]
  • [ 1303556-79-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 - 34 °C 2.1: potassium <i>tert</i>-butylate / <i>tert</i>-butyl alcohol / 20 h / 75 °C 2.2: pH 1 - 2 / Cooling with ice 3.1: phosphorus(V) oxybromide / 1-methyl-pyrrolidin-2-one / 4.5 h / 20 - 95 °C 4.1: potassium phosphate; 4a,9a-dihydro-9,9-dimethyl-4,5-bis(diphenylphosphino)-xanthene / tris-(dibenzylideneacetone)dipalladium(0) / tert-Amyl alcohol / 6.5 h / 100 - 117 °C / Inert atmosphere 5.1: hydrogen / tetrahydrofuran
  • 29
  • [ 394-29-6 ]
  • [ 1303556-94-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 - 34 °C 2.1: potassium <i>tert</i>-butylate / <i>tert</i>-butyl alcohol / 20 h / 75 °C 2.2: pH 1 - 2 / Cooling with ice 3.1: phosphorus(V) oxybromide / 1-methyl-pyrrolidin-2-one / 4.5 h / 20 - 95 °C 4.1: potassium phosphate; 4a,9a-dihydro-9,9-dimethyl-4,5-bis(diphenylphosphino)-xanthene / tris-(dibenzylideneacetone)dipalladium(0) / tert-Amyl alcohol / 6.5 h / 100 - 117 °C / Inert atmosphere 5.1: hydrogen / tetrahydrofuran 6.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 °C 7.1: hydrogen / 5% Pd(II)/C(eggshell) / methanol
  • 30
  • [ 394-29-6 ]
  • [ 1303557-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 - 34 °C 2.1: potassium <i>tert</i>-butylate / <i>tert</i>-butyl alcohol / 20 h / 75 °C 2.2: pH 1 - 2 / Cooling with ice 3.1: phosphorus(V) oxybromide / 1-methyl-pyrrolidin-2-one / 4.5 h / 20 - 95 °C 4.1: potassium phosphate; 4a,9a-dihydro-9,9-dimethyl-4,5-bis(diphenylphosphino)-xanthene / tris-(dibenzylideneacetone)dipalladium(0) / tert-Amyl alcohol / 6.5 h / 100 - 117 °C / Inert atmosphere 5.1: hydrogen / tetrahydrofuran 6.1: triethylamine; hydrogen / palladium on carbon / tetrahydrofuran / 20 °C / 760.05 Torr
  • 31
  • [ 394-29-6 ]
  • [ 1303557-53-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 - 34 °C 2.1: potassium <i>tert</i>-butylate / <i>tert</i>-butyl alcohol / 20 h / 75 °C 2.2: pH 1 - 2 / Cooling with ice 3.1: phosphorus(V) oxybromide / 1-methyl-pyrrolidin-2-one / 4.5 h / 20 - 95 °C 4.1: caesium carbonate; 4a,9a-dihydro-9,9-dimethyl-4,5-bis(diphenylphosphino)-xanthene / tris-(dibenzylideneacetone)dipalladium(0) / 1,4-dioxane / 85 °C / Inert atmosphere
  • 32
  • [ 394-29-6 ]
  • [ 551-93-9 ]
  • [ 1019367-42-0 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20 - 34℃; 3 EXAMPLE 3: Synthesis of N-(2-Acetyl-phenyl)-5-chloro-2-fluoro-benzamide (M 291.71)70 g 2-amino acetophenone were reacted at ambient temperature in 2.5 I THF in presence of 177 ml N-ethyl diisopropylamine with 100 g 5-cloro-2-fluoro-benzoylchloride while temperature rose from 20 to 34°C and white precipitate appeared. After one more night the suspension was filtered and the filtrate concentrated. Solution in THF at 80°C was slowly diluted with water. After a night at ambient temperature precipitate was filtered and washed with water. After drying 149 g product was obtained as pinkish needles with Rt~ 2.49 min and correct M+H+ 292 in LC-MS system 1.
  • 33
  • [ 394-29-6 ]
  • [ 1303556-83-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 - 34 °C 2.1: potassium <i>tert</i>-butylate / <i>tert</i>-butyl alcohol / 20 h / 75 °C 2.2: pH 1 - 2 / Cooling with ice 3.1: phosphorus(V) oxybromide / 1-methyl-pyrrolidin-2-one / 4.5 h / 20 - 95 °C 4.1: potassium phosphate; 4a,9a-dihydro-9,9-dimethyl-4,5-bis(diphenylphosphino)-xanthene / tris-(dibenzylideneacetone)dipalladium(0) / tert-Amyl alcohol / 6.5 h / 100 - 117 °C / Inert atmosphere 5.1: hydrogen / tetrahydrofuran 6.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 °C
  • 34
  • [ 394-29-6 ]
  • [ 613-89-8 ]
  • [ 1303557-95-0 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane 27 EXAMPLE 27 Synthesis of 4-bromo-2-(5-chloro-2-fluoro-phenyl)-quinoline Commercial 2-aminoacetophenone was acylated with commercial 5-chloro-2-fluoro-benzoylchloride to give the corresponding 4-hydroxy-2-phenyl-quinoline (aka its tautomer 2-(5-chloro-2-fluoro-phenyl)-1H-quinolin-4-one), which was brominated with phosphoroxytribromide in N-methylpyrrolidone to give the product 4-bromo-2-(5-chloro-2-fluoro-phenyl)-quinoline with correct LC-MS: M+H+ 338 and Rt˜2.50 min.
  • 35
  • [ 394-29-6 ]
  • [ 1323916-53-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: dichloromethane 2: phosphorus(V) oxybromide / 1-methyl-pyrrolidin-2-one 3: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / water; 1,4-dioxane / 1.25 h / Inert atmosphere; Reflux
  • 36
  • [ 394-29-6 ]
  • [ 100-66-3 ]
  • [ 133436-34-7 ]
YieldReaction ConditionsOperation in experiment
76% With aluminum (III) chloride at 0 - 50℃; for 3h;
  • 37
  • methyl 3-(4-(2-aminoethyl)phenyl)propanoate [ No CAS ]
  • [ 394-29-6 ]
  • C18H17ClFNO3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 3 h / 0 - 20 °C / Inert atmosphere 2: lithium hydroxide; water / tetrahydrofuran / 0 - 20 °C
  • 38
  • methyl 3-(4-(2-aminoethyl)phenyl)propanoate [ No CAS ]
  • [ 394-29-6 ]
  • C19H19ClFNO3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere;
  • 39
  • [ 394-29-6 ]
  • [ 1586041-29-3 ]
  • 40
  • [ 394-29-6 ]
  • [ 1270034-43-9 ]
YieldReaction ConditionsOperation in experiment
46 Intermediate 132 5-((tert-butoxycarbonyl)amino)-2-(5-chloro-2-fluorophenyl)thiazole-4-carboxylic acid Intermediate 132 5-((tert-butoxycarbonyl)amino)-2-(5-chloro-2-fluorophenyl)thiazole-4-carboxylic acid Following procedures from Examples 1-9, 5-chloro-2-fluorobenzoyl chloride was converted to the title compound.
  • 41
  • [ 394-29-6 ]
  • [ 100-66-3 ]
  • [ 1097106-69-8 ]
YieldReaction ConditionsOperation in experiment
16.50 g With aluminum (III) chloride at 50℃; for 3h; Cooling with ice; 1-2 example 1-2 (2) in a fully dried 100 ml three-port flask, add AlCl3(9.12g, 68 . 4mmol) and 90.0 ml anisole, ice-bath to 0 °C, to the constant pressure dropping funnel dropwise CFBC (13.50g, 69 . 95mmol), the temperature rising to the reaction liquid 50 °C, reaction 3h. The reaction solution is poured into a few drops of HCl with ice water, and extracting with chloroform. Using anhydrous MgSO4drying, rotary evaporation, recrystallized with ethanol, to obtain 5-chloro-2-fluoro-1 - (4 the [...] -methoxybenzoyl) benzene (CFMBP) (16.50g).
  • 42
  • [ 394-29-6 ]
  • [ 6638-79-5 ]
  • 5-chloro-2-fluoro-N-methoxy-N-methylbenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
900 g With triethylamine In dichloromethane at 0 - 20℃; 1 STEP 1: 5-CHLOR0-2-FLUORO-N-METHOXY-N-METHYLBENZAMIDE To a stirred solution of 5-chloro-2-fluorobenzoic acid (900 g, 5. 17 mol) in5 DCM (10 L) vvas added oxalyl chloride (990 g, 7.8 mol) at 0 oc. After addition,DMF (3 mL) vvas added and the reaction mixture vvas stirred at ambienttemperature overnight. On completion, the solvent was removed under reducedpressure, the residue was dissolved in DCM (2 L) and the solution wasconcentrated again to dryness. The acid chloride thus obtained (900 g, 4.66 mol)10 was dissolved in DCM (6 L) a.nd N,O-dimethylhydroxylamine hydrochloride(682.27 g, 7 mmol) was added followed by a solution of triethylamine (2 7 L, 19.4mol) in DCM (4 L) dropwise at 0 oc. The reaction mixture vvas warmed slowly toambient temperature, and stirred overnight. The mixture '.vas then quenched withice v.·ater and the layers were separated. The aqueous layer wa.-.: extracted with15 DCM (2 x 3 L) and the combined organic layer was washed with 0.5 N HCl (4 L),lN NaOH (4 L), water (5 L) and brine (5 L) then it was dried over Na2S04 andconcentrated to afiord 5-chloro-2-fluoro-N-methoxy-N-methylbenzamide (900 g,80%) yield).
  • 43
  • N-methyl-3-(morpholin-4-ylsulfonyl)aniline [ No CAS ]
  • [ 394-29-6 ]
  • 5-chloro-2-fluoro-N-methyl-N-[3-(morpholin-4-ylsulfonyl)phenyl]benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
3.6 g With triethylamine In dichloromethane at 0 - 30℃; for 1h; 4.1 ST E P-i: Synthesis 5-chloro-N-methyl-N-[3-(morphol i n-4-ylsulfonyl)phenyl]-1 H -ndazol-3-ami ne To a stirred solution of N-methyl-3-(morphol i n-4-ylsulfonyl )ani line (2.2gm, 8.6mmol) in di chl oromethane, tn ethyl amine (4 ml ,27.7mmol) was added and allowed to cool upto 0°C.To the reaction mixture, a solution of 5-chl oro-2-fl uorol benzoyl chloride (1.8gm, 9.3mmol) in dichloromethane was added in drop wise manner and stirred for 1 hour at 30°C. The reaction mixture was diluted with 2N hydrochloric acid and extracted with dichloromethane. The organic layer was washed with water, followed by sodium bicarbonate solution and then dried over sodium sulphate. It was concentrated underreduced pressure to prav’ide 3.6 gm of 5-chloro-2-fluoro-N-methyl-N-[3-(morpholin-4- ylsulfonyl) phenyl] benzamide.
  • 44
  • [ 394-29-6 ]
  • 5-chloro-2-fluoro-N-methyl-N-[3-(morpholin-4-ylsulfonyl)phenyl]benzene [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 1 h / 0 - 30 °C 2: Lawessons reagent / toluene / 1 h / 100 °C
  • 45
  • [ 394-29-6 ]
  • 5-chloro-N-methyl-N-[3-(morpholin-4-ylsulfonyl)phenyl]-1H-indazol-3-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 1 h / 0 - 30 °C 2: Lawessons reagent / toluene / 1 h / 100 °C 3: hydrazine hydrate / dimethyl sulfoxide / 6 h / 100 °C
  • 46
  • [ 394-29-6 ]
  • ethyl (5-chloro-3-{methyl[3-(morpholin-4-ylsulfonyl)phenyl]amino}-1H-indazol-1-yl)acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 1 h / 0 - 30 °C 2: Lawessons reagent / toluene / 1 h / 100 °C 3: hydrazine hydrate / dimethyl sulfoxide / 6 h / 100 °C 4: caesium carbonate / N,N-dimethyl-formamide / 3 h / 0 - 5 °C
  • 47
  • [ 394-29-6 ]
  • (5-chloro-3-{methyl[3-(morpholin-4-ylsulfonyl)phenyl]amino}-1H-indazol-1-yl)acetic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: triethylamine / dichloromethane / 1 h / 0 - 30 °C 2: Lawessons reagent / toluene / 1 h / 100 °C 3: hydrazine hydrate / dimethyl sulfoxide / 6 h / 100 °C 4: caesium carbonate / N,N-dimethyl-formamide / 3 h / 0 - 5 °C 5: water; lithium hydroxide / methanol
  • 48
  • [ 394-29-6 ]
  • 4-[5-(5-chloro-2-fluoro-phenyl)-[1,3,4]oxadiazol-2-ylmethyl]-piperazine-1-carboxylic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: dichloromethane / 3 h / 0 - 20 °C 2: hydrazine / ethanol / 20 °C 3: 1 h / 120 °C 4: potassium carbonate / acetonitrile
  • 49
  • [ 394-29-6 ]
  • 4-{1-[5-(5-chloro-2-fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethyl}-piperazine-1-carboxylic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: dichloromethane / 3 h / 0 - 20 °C 2: hydrazine / ethanol / 20 °C 3: 1.5 h / 60 - 120 °C 4: potassium carbonate / acetonitrile
  • 50
  • [ 394-29-6 ]
  • [ 657424-44-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: dichloromethane / 3 h / 0 - 20 °C 2: hydrazine / ethanol / 20 °C
  • 51
  • [ 394-29-6 ]
  • [ 657424-50-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: dichloromethane / 3 h / 0 - 20 °C 2: hydrazine / ethanol / 20 °C 3: 1.5 h / 60 - 120 °C
  • 52
  • [ 394-29-6 ]
  • [ 657424-48-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: dichloromethane / 3 h / 0 - 20 °C 2: hydrazine / ethanol / 20 °C 3: 1 h / 120 °C
  • 53
  • [ 394-29-6 ]
  • [ 100-01-6 ]
  • C13H8ClFN2O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dichloromethane
  • 54
  • [ 394-29-6 ]
  • C13H10ClFN2O [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane 2: tin(II) chloride dihdyrate / ethanol / 16 h / Reflux
  • 55
  • [ 394-29-6 ]
  • N-(4-(2H-pyrazolo[3,4-c]pyridin-2-yl)phenyl)-5-chloro-2-fluorobenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane 2: tin(II) chloride dihdyrate / ethanol / 16 h / Reflux 3: diphenylsilane; 3-Methyl-1-phenyl-2-phospholene 1-oxide / toluene / 24 h / 110 °C / Sealed tube
  • 56
  • [ 394-29-6 ]
  • N-(3-aminophenyl)-5-chloro-2-fluorobenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane 2: tin(II) chloride dihdyrate / ethanol / 16 h / Reflux
  • 57
  • [ 394-29-6 ]
  • N-(3-(2H-pyrazolo[3,4-c]pyridin-2-yl)phenyl)-5-chloro-2-fluorobenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane 2: tin(II) chloride dihdyrate / ethanol / 16 h / Reflux 3: diphenylsilane; 3-Methyl-1-phenyl-2-phospholene 1-oxide / toluene / 24 h / 110 °C / Sealed tube
  • 58
  • [ 394-29-6 ]
  • [ 99-09-2 ]
  • 5-chloro-2-fluoro-N-(3-nitrophenyl)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dichloromethane
  • 59
  • [ 394-29-6 ]
  • C13H12N4O [ No CAS ]
  • 5-chloro-2-fluoro-N-(4-(5-methoxy-2H-pyrazolo[3,4-c]pyridin-2-yl)phenyl)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
63 mg With triethylamine In dichloromethane
  • 60
  • [ 394-29-6 ]
  • C13H12N4O [ No CAS ]
  • 5-chloro-2-fluoro-N-(3-(5-methoxy-2H-pyrazolo[3,4-c]pyridin-2-yl)phenyl)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
56 mg With triethylamine In dichloromethane
  • 61
  • [ 107-10-8 ]
  • [ 394-29-6 ]
  • 5-chloro-2-fluoro-N-propylbenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
81% Stage #1: propylamine With potassium carbonate In acetonitrile at 70℃; Stage #2: 5-chloro-2-fluoro-benzoyl chloride In acetonitrile at 70℃; for 4h; A typical procedure for the synthesis of 1a: General procedure: A mixture of propylamine (0.885 g, 15.0 mmol), K2CO3 (2.070 g, 15.0 mmol) andCH3CN (25 mL) in a 100-mL round-bottomed flask was stirred at 70 °C for a few minutes,and then 2-fluorobenzoyl chloride (1.585 g, 10.0 mmol) was added dropwise to the mixture(ca. 0.5 h). The obtained reaction mixture was heated for additional 4 h and then cooled toroom temperature, water (50 mL) was added and the mixture was extracted with ethyl acetate(3 × 50 mL). The combined organic phases were dried over MgSO4.The filtered solution wasconcentrated under reduced pressure, and the crude residue was purified by columnchromatography on silica gel with the use of petroleum ether/ethyl acetate (gradient mixtureratio from 20:1 to 4:1 in volume) to afford 1a as a pale yellow oil in 90% yield (1.635 g).1b ~ 1m were prepared in 2.0 mmol-scale of benzoyl chlorides.
  • 62
  • [ 394-29-6 ]
  • 7-chloro-N-propyl-3-methyl-1,4-benzoxazepin-5(4H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium carbonate / acetonitrile / 70 °C 1.2: 4 h / 70 °C 2.1: potassium hydroxide / dimethyl sulfoxide / 24 h / 30 - 50 °C / Sealed tube
  • 63
  • [ 394-29-6 ]
  • 6-chloro-N-propyl-2-vinyl-2,3-dihydro-1,3-benzoxazin-4(4H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium carbonate / acetonitrile / 70 °C 1.2: 4 h / 70 °C 2.1: potassium hydroxide / acetonitrile / 24 h / 30 - 50 °C / Sealed tube
  • 64
  • [ 4096-21-3 ]
  • [ 394-29-6 ]
  • (5-chloro-2-fluorophenyl)(1-phenylpyrrolidin-2-yl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
71% With (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile; potassium propionate In dichloromethane at 25℃; for 3h; Inert atmosphere; Irradiation;
  • 65
  • [ 394-29-6 ]
  • [ 76981-71-0 ]
  • C17H15ClFNO3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 3 h / 20 °C / Cooling with ice 2: ethanol; sodium hydroxide / 3 h / Reflux
  • 66
  • [ 394-29-6 ]
  • [ 76981-71-0 ]
  • 2-(2-fluoro-5-chloro)benzamide-6-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dichloromethane at 20℃; for 3h; Cooling with ice; 26.2 Weigh 1 eq of 2-amino-6-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ethyl ester, add dichloromethane and 2 eq of triethylamine, and place in an ice bath Stir. The above-mentioned benzoyl chloride solution was added dropwise, and after the dropping was completed, the mixture was stirred at room temperature for 3 hours until the reaction was completed as detected by TLC. Dichloromethane and dilute hydrochloric acid were added to the reaction solution to wash 3 times, the organic layer was collected, and then washed 3 times with saturated sodium bicarbonate solution, and once with saturated brine. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and reduced. Press and concentrate to obtain crude product. Add ethanol to the crude product, heat and reflux until all the solids are dissolved, then slowly drop to room temperature, and filter under reduced pressure to obtain the intermediate2-(2-Fluoro-5-chloro)benzamide-6-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ethyl ester derivative.
  • 67
  • [ 4506-71-2 ]
  • [ 394-29-6 ]
  • C16H13ClFNO3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 3 h / 20 °C / Cooling with ice 2: ethanol; sodium hydroxide / 3 h / Reflux
  • 68
  • [ 4506-71-2 ]
  • [ 394-29-6 ]
  • 2-(2-fluoro-5-chloro)benzamido-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dichloromethane at 20℃; for 3h; Cooling with ice; 17.2 Weigh 1 eq of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ethyl ester, add dichloromethane and 2 eq of triethylamine, and stir in an ice bath. The above-mentioned benzoyl chloride solution was added dropwise, and after the dropping was completed, the mixture was stirred at room temperature for 3 hours until the reaction was completed as detected by TLC. Dichloromethane and dilute hydrochloric acid were added to the reaction solution and washed 3 times. The organic layer was collected, washed 3 times with saturated sodium bicarbonate solution and once with saturated brine. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and reduced. After pressing and concentrating, the crude product is obtained. Add ethanol to the crude product, heat and reflux until all the solids are dissolved, then slowly drop to room temperature, and filter under reduced pressure to obtain the intermediate 2-(2-fluoro-5-chloro)benzamide-4,5,6,7-Tetrahydrobenzo[b]thiophene-3-carboxylic acid ethyl ester derivative.
  • 69
  • [ 394-29-6 ]
  • 2,4-benzoyl-(8a-methyl-6-oxo-3,4,4a,5,6,8a-hexahydro-2H-chromen-3-yl)-3-chloro-6-fluoro-Nmethoxybenzamide [ No CAS ]
  • 2,4-benzoyl-(8a-methyl-6-oxo-3,4,4a,5,6,8a-hexahydro-2H-chromen-3-yl)-3-chloro-6-fluoro-Nmethoxybenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate / ethyl acetate; water / 0 - 20 °C 2: dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; cesium acetate / tetrahydrofuran / 12 h / 80 °C / Inert atmosphere
  • 70
  • [ 394-29-6 ]
  • [ 593-56-6 ]
  • 5-chloro-2-fluoro-N-methoxybenzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
1.9 g With potassium carbonate In water; ethyl acetate at 0 - 20℃;
  • 71
  • [ 1140917-46-9 ]
  • [ 394-29-6 ]
  • [ 1217403-77-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: triethylamine / tetrahydrofuran / 3 h / 20 °C 2.1: potassium-t-butoxide / tetrahydrofuran / 0.17 h 2.2: 20 h
  • 72
  • [ 394-29-6 ]
  • [ 65234-09-5 ]
  • C20H14Cl2FNO3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine In dichloromethane at 20℃; 4.1.2 Syntheses of 4-arylthiophene-3-carboxylic acid derivatives General procedure: Taking 2-(1-naphthamido)-4-(4-chlorophenyl) thiophene-3-carboxylic acid (6) as an example. Step a: 18.55g (120mmol) 4-chloroacetophenone, 16.29g (144mmol) ethyl cyanoacetate, 7.12g (120mmol) acetic acid, 23.00g (264mmol) morpholine, and 500mL ethanol were added into a round bottom flask and stirred for 3h under an argon atmosphere at 70°C. Then 4.91g (144mmol) sulfur was added and stirred for 48h. The solution was evaporated, and the residue was purified by column chromatography to afford 2-aminothiophene-3-carboxylate acid ethyl ester (yield 21%). Step b: 0.195g (0.73mmol) 2-aminothiophene-3-carboxylate acid ethyl ester was dissolved in 10mL DCM and 0.125g (0.66mmol) 1-naphthyl chloride which was dissolved in 10mL DCM was dropped it into the solution at 0°C. Stirred for 8h at room temperature, followed by evaporation and recrystallization using DCM/petroleum ether. White powder intermediate Ethyl 2-(1-naphthamido)-4-(4-chlorophenyl)thiophene-3-carboxylate 0.227g (0.54mmol) was obtained (yield 75%) as white powder. Step c: 0.143g (0.34mmol) ethyl 2-(1-naphthamido)-4-(4-chlorophenyl)thiophene-3-carboxylate and 0.068g (1.7mmol) NaOH were dissolved in THF/methanol/water solution and stirred for 8h at room temperature. Adjusted pH to neutral by acetic acid and precipitated by adding water. 0.094g (0.23mmol) colorless crystal compound 6 was obtained
With triethylamine In dichloromethane at 20℃; 4.1.2 Syntheses of 4-arylthiophene-3-carboxylic acid derivatives General procedure: Taking 2-(1-naphthamido)-4-(4-chlorophenyl) thiophene-3-carboxylic acid (6) as an example. Step a: 18.55g (120mmol) 4-chloroacetophenone, 16.29g (144mmol) ethyl cyanoacetate, 7.12g (120mmol) acetic acid, 23.00g (264mmol) morpholine, and 500mL ethanol were added into a round bottom flask and stirred for 3h under an argon atmosphere at 70°C. Then 4.91g (144mmol) sulfur was added and stirred for 48h. The solution was evaporated, and the residue was purified by column chromatography to afford 2-aminothiophene-3-carboxylate acid ethyl ester (yield 21%). Step b: 0.195g (0.73mmol) 2-aminothiophene-3-carboxylate acid ethyl ester was dissolved in 10mL DCM and 0.125g (0.66mmol) 1-naphthyl chloride which was dissolved in 10mL DCM was dropped it into the solution at 0°C. Stirred for 8h at room temperature, followed by evaporation and recrystallization using DCM/petroleum ether. White powder intermediate Ethyl 2-(1-naphthamido)-4-(4-chlorophenyl)thiophene-3-carboxylate 0.227g (0.54mmol) was obtained (yield 75%) as white powder. Step c: 0.143g (0.34mmol) ethyl 2-(1-naphthamido)-4-(4-chlorophenyl)thiophene-3-carboxylate and 0.068g (1.7mmol) NaOH were dissolved in THF/methanol/water solution and stirred for 8h at room temperature. Adjusted pH to neutral by acetic acid and precipitated by adding water. 0.094g (0.23mmol) colorless crystal compound 6 was obtained
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