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[ CAS No. 373-88-6 ] {[proInfo.proName]}

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Chemical Structure| 373-88-6
Chemical Structure| 373-88-6
Structure of 373-88-6 * Storage: {[proInfo.prStorage]}
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Product Details of [ 373-88-6 ]

CAS No. :373-88-6 MDL No. :MFCD00012875
Formula : C2H5ClF3N Boiling Point : -
Linear Structure Formula :- InChI Key :ZTUJDPKOHPKRMO-UHFFFAOYSA-N
M.W : 135.52 Pubchem ID :9772
Synonyms :

Calculated chemistry of [ 373-88-6 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 7
Num. arom. heavy atoms : 0
Fraction Csp3 : 1.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 21.59
TPSA : 26.02 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.39 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 1.04
Log Po/w (WLOGP) : 2.57
Log Po/w (MLOGP) : 0.96
Log Po/w (SILICOS-IT) : 0.86
Consensus Log Po/w : 1.08

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 3.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.27
Solubility : 7.29 mg/ml ; 0.0538 mol/l
Class : Very soluble
Log S (Ali) : -1.18
Solubility : 9.02 mg/ml ; 0.0666 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.73
Solubility : 25.2 mg/ml ; 0.186 mol/l
Class : Soluble

Medicinal Chemistry

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

Safety of [ 373-88-6 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P264-P280-P337+P313-P302+P352+P312-P304+P340+P312 UN#:N/A
Hazard Statements:H302+H312+H332-H315-H319 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 373-88-6 ]

* 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.

  • Upstream synthesis route of [ 373-88-6 ]
  • Downstream synthetic route of [ 373-88-6 ]

[ 373-88-6 ] Synthesis Path-Upstream   1~7

  • 1
  • [ 753-90-2 ]
  • [ 373-88-6 ]
YieldReaction ConditionsOperation in experiment
96.3% With hydrogenchloride In ethanol; water at 25 - 50℃; for 1 h; Add 100 g to a three-necked flaskEthanol and 33 gTrifluoroethylamine,At temperatures below 25 ° C, 35 g of saturated hydrochloric acid solution was slowly added dropwise,After the drop was completed, the temperature was raised to 50 ° C for one hour.The reaction solution in the system after the vacuum of 0.98MPa,The control temperature is 45 ± 5 ° C,After 5 hours of distillation under reduced pressure, the water and ethanol were removed,To give trifluoroethylamine hydrochloride 43. 5 g,The product yield was 96. 30percent. The obtained trifluoroethylamine hydrochloride was a white powdery crystalline solid,The water content was 0.13percent.
Reference: [1] Patent: CN105801428, 2016, A, . Location in patent: Paragraph 0016; 0017
  • 2
  • [ 100-46-9 ]
  • [ 76-05-1 ]
  • [ 373-88-6 ]
Reference: [1] Tetrahedron Letters, 2002, vol. 43, # 31, p. 5449 - 5452
  • 3
  • [ 348-08-3 ]
  • [ 373-88-6 ]
Reference: [1] Tetrahedron Letters, 2002, vol. 43, # 31, p. 5449 - 5452
  • 4
  • [ 373-88-6 ]
  • [ 182438-97-7 ]
  • [ 182438-98-8 ]
YieldReaction ConditionsOperation in experiment
76.1%
Stage #1: With oxalyl dichloride In dichloromethane at 25℃; for 2 h; Inert atmosphere
Stage #2: With triethylamine In dichloromethane at 25℃; for 2 h;
In a thermometer,In a three-necked flask of a dropping funnel,(25.0 g, 73 mmol), methylene chloride (250 ml), oxalyl chloride (11.0 g, 87 mol) and DMF (5 drops) under nitrogen atmosphere at room temperature for 2 h and the solvent was evaporated under reduced pressure , The residue was dissolved in dichloromethane (50 ml)A solution of trifluoroethylamine hydrochloride (10.9 g, 80 mmol)And triethylamine (31 ml, 220 mmol) in dichloromethane (100 ml). The organic phase was washed with water, 1N HCl solution, saturated aqueous NaHCO3 solution and saturated brine (200 ml x 3 times each), dried over anhydrous Na2SO4, and evaporated to remove the solvent. The residue was purified by silica gel column chromatography (eluent: To give a light yellow oil which was recrystallized from anhydrous ethanol (200 ml) at -5 ° C and the solid was collected to give the title compound as an intermediate (4) (23.7 g, 76.1percent) as a white solid,
73%
Stage #1: With 4-methyl-morpholine; isobutyl chloroformate In dichloromethane at 0 - 5℃; for 0.25 h; Inert atmosphere
Stage #2: With 4-methyl-morpholine In dichloromethane at 20℃;
To a solution of 9-(4-bromobutyl)-9H-fluorene-9-carboxylic acid (200 gm, 0.579 moles) in dichloromethane (4 L) was charged N-methyl morpholine (87.88 gm, 0.87 moles). The reaction mass was cooled to about 0-5°C under nitrogen atmosphere and isobutylchloroformate (102.68 gm, 0.75 moles) was added slowly at about 0-5°C. The reaction mass was stirred for about 15 min at same temperature and a suspension of 2,2,2-trifluoroethylamine hydrochloride (94.2 gm, 0.70 moles) and N-methyl morpholine (87.88 gm, 0.868 moles) in dichloromethane (1 L) was slowly added. The reaction mass was stirred for about 8-12 hrs at room temperature. After completion of the reaction, water was added to the reaction mass at about 25-30°C and the layers were separated. The organic layer was washed with dilute hydrochloric acid followed by water. The organic layer was distilled off under vacuum at about 35-40°C to afford a residue. Water was added to the solution of residue in methanol and the obtained mass was stirred. The precipitated solid was filtered and dried under vacuum at about 50-55°C for about 12 hrs to afford 180 gm of 9-(4-bromobutyl)-N-(2,2,2-trifluroethyl)-9H-fluorene-9-carboxamide as pale yellow solid (Yield 73 percent, HPLC purity 95.40 percent).
71%
Stage #1: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 1.66667 h;
Stage #2: With triethylamine In dichloromethane at 0℃; for 1 h;
To a solution of Part A(1) acid (60 g, 173 mmol) and DMF (100 μL) in CH2Cl2 (600 mL) under argon at 0°C was added oxalyl chloride (104 mL, 2.0M in CH2Cl2, 208 mmol) dropwise. The reaction was stirred at 0°C for 10 min, then warmed to room temperature and stirred for 1.5 h. The reaction was concentrated in vacuo to give the crude acid chloride as a yellow oil. To a suspension of 2,2,2-trifluoroethylamine hydrochloride (25.9 g, 191 mmol) in CH2Cl2 (500 mL) at 0°C under argon was added triethylamine (73 mL, 521 mmol) followed by dropwise addition of a solution of the crude acid chloride in CH2Cl2 (15 mL). The reaction was stirred at 0°C for 1 h, diluted with CH2Cl2 (500 mL), and washed with water (2 x 300 mL), 1N HCl (2 x 300 mL), saturated NaHCO3 (2 x 300 mL), and brine (2 x 300 mL), then dried over MgSO4. Evaporation gave 80 g of a oil which was purified by flash chromatography on silica gel (2.5 kg). The crude product was loaded in a mixture of CH2Cl2 and hexane, and eluted with a step gradient of 10percent EtOAc/hexane (4L) to 15percent EtOAc/hexane (2L) to 20percent EtOAc/hexane (4L). Pure fractions were combined and evaporated to give title compound (52.5 g, 71percent) as a white solid (mp 88-92°C).
Reference: [1] Patent: CN106146385, 2016, A, . Location in patent: Paragraph 0037; 0038
[2] Patent: WO2016/55934, 2016, A1, . Location in patent: Paragraph 0124; 0133
[3] Patent: EP904262, 2004, B1, . Location in patent: Page 145
  • 5
  • [ 373-88-6 ]
  • [ 331767-53-4 ]
  • [ 182438-98-8 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 20, p. 5067 - 5070
[2] Journal of Medicinal Chemistry, 2001, vol. 44, # 6, p. 851 - 856
[3] Patent: US2003/166637, 2003, A1,
[4] Patent: US2003/114442, 2003, A1,
[5] Patent: US6818644, 2004, B1,
[6] Patent: WO2016/71849, 2016, A1, . Location in patent: Page/Page column 15; 16
  • 6
  • [ 110-52-1 ]
  • [ 1989-33-9 ]
  • [ 373-88-6 ]
  • [ 182438-98-8 ]
YieldReaction ConditionsOperation in experiment
155 g
Stage #1: With sodium t-butanolate In toluene at 5 - 30℃; for 3 h; Inert atmosphere
Stage #2: With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 25 - 30℃; for 2 h;
Stage #3: With sodium carbonate In dichloromethane; water at 5 - 10℃; for 0.75 h;
A mixture of 9H-fluorene-9-carboxylic acid compound of formula-2a (100 gm), 1,4-dibromobutane (308 gm) and toluene (1000 ml) was stirred for 15 mm at 25-30°C undernitrogen atmosphere. Cooled the reaction mixture to 5-10°C, sodium tert.butoxide (100.5 gm) was slowly added to it and stirred the reaction mixture for 3 hrs at the same temperature. Water was added to the reaction mixture at 25-30°C and stirred for 15 mm at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with water. Both the organic and aqueous layers were separated and washed the aqueouslayer with toluene. Acidified the aqueous layer using aqueous hydrochloric acid solution at25-30°C aiid stirred the reaction mixture for 20 mm at the same temperature. Dichioromethane was added to the reaction mixture at 25-30°C and stirred for 15 mm at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with aqueous citric acid solution. Distilled off the solvent completely from theorganic layer. Dichioromethane (500 ml) was added to the reaction mixture at 25-30°C and stirred for 15 mm at the same temperature. N,N-dimethylformamide (6.9 gm) followed by oxalyl chloride (66.4 gm) were slowly added to the reaction mixture at 25-30°C and stirred for 2 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture under nitrogen atmosphere and co-distilled with dichloromethane under reducedpressure. Dichloromethane (500 ml) was added to the obtained compound at 25-30°C and stirred for .15 mm at the same temperature. The obtained compound was slowly added to a pre-cooled mixture of water (500 ml), 2,2,2-trifluoroethylamine hydrochloride (64.4 gm) and sodium carbonate (75.6 gm) at 5-10°C and stirred the reaction mixture for 45 mm at the same temperature. Both the organic and aqueous layers were separated and washed the organiclayer with aqueous hydrochloric acid solution followed by with aqueous sodium bicarbonate solution and then finally washed with water. Distilled off the solvent completely from the organic layer and then co-distilled with n-heptane under reduced pressure. n-Heptane (100 ml) and isopropanol (5 ml) were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 1 hr at the same temperature. Cooled the reaction ttiture to 25-30°C and stirred for 1 hr at the same temperature. Filtered the precipitatedsolid, washed with n-heptäne and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-5.Yield: 155.0 gm; M.R: 95-102°C.
Reference: [1] Patent: WO2017/98522, 2017, A1, . Location in patent: Page/Page column 18; 19; 24; 25
  • 7
  • [ 373-88-6 ]
  • [ 79-04-9 ]
  • [ 170655-44-4 ]
YieldReaction ConditionsOperation in experiment
100%
Stage #1: With tert-butyl methyl ether; sodium hydroxide In water at 20℃; for 0.5 h;
Stage #2: at 5 - 10℃; for 1 h;
To a 500 ml four-necked flask, 30.4 g (759.3 mmol) of sodium hydroxide and 50 g of water were added, dissolved at room temperature, and then cooled to 5 ° C. A solution prepared by dissolving 50 g (370.4 mmol) of 2,2,2-trifluoroethylamine hydrochloride in 60 g of water was added dropwise thereto at 5 ° C. After 85 g of tert-butyl methyl ether was added and stirred for 30 minutes, a solution of 43.9 g (388.9 mmol) of chloroacetyl chloride dissolved in 15 g of tert-butyl methyl ether was added dropwise while keeping at 5 ° C. The reaction solution was heated to 10 ° C. and stirred for 1 hour. After disappearance of 2,2,2-trifluoroethylamine was confirmed by gas chromatography, the temperature was raised to room temperature and liquid separation was carried out. The aqueous layer was extracted with 100 g of tert-butyl methyl ether, the organic layers were combined, the solvent was distilled off under reduced pressure to adjust the liquid volume, and 2-chloro-N- (2,2,2-trifluoroethyl) acetamide Of a tert-butyl methyl ether solution was obtained. As a result of the internal standardization by high performance liquid chromatography, the yield was 65 g, the yield was 100percent, and the concentration was 25.1 wtpercent. The melting point of 2-chloro-N- (2,2,2-trifluoroethyl) acetamide taken out by dropping the obtained solution in heptane and crystallizing it was 53.8 ° C. (DSC).
Reference: [1] Patent: JP5652628, 2015, B2, . Location in patent: Paragraph 0057
[2] Inorganic Chemistry, 2018, vol. 57, # 17, p. 11252 - 11263
[3] Chemical Communications, 2016, vol. 52, # 96, p. 13885 - 13888
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