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[ CAS No. 1446817-84-0 ] {[proInfo.proName]}

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Chemical Structure| 1446817-84-0
Chemical Structure| 1446817-84-0
Structure of 1446817-84-0 * Storage: {[proInfo.prStorage]}
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Product Details of [ 1446817-84-0 ]

CAS No. :1446817-84-0 MDL No. :MFCD31735112
Formula : C20H22F9N3O2 Boiling Point : -
Linear Structure Formula :- InChI Key :SQZJGTOZFRNWCX-UHFFFAOYSA-N
M.W : 507.39 Pubchem ID :71657619
Synonyms :
ABX-1431
Chemical Name :1,1,1,3,3,3-Hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate

Calculated chemistry of [ 1446817-84-0 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 34
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.65
Num. rotatable bonds : 9
Num. H-bond acceptors : 12.0
Num. H-bond donors : 0.0
Molar Refractivity : 113.07
TPSA : 36.02 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -5.69 cm/s

Lipophilicity

Log Po/w (iLOGP) : 4.11
Log Po/w (XLOGP3) : 5.22
Log Po/w (WLOGP) : 7.43
Log Po/w (MLOGP) : 3.8
Log Po/w (SILICOS-IT) : 4.45
Consensus Log Po/w : 5.0

Druglikeness

Lipinski : 1.0
Ghose : None
Veber : 0.0
Egan : 1.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -5.81
Solubility : 0.000784 mg/ml ; 0.00000155 mol/l
Class : Moderately soluble
Log S (Ali) : -5.72
Solubility : 0.000957 mg/ml ; 0.00000189 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -5.24
Solubility : 0.00293 mg/ml ; 0.00000577 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 3.0
Synthetic accessibility : 3.11

Safety of [ 1446817-84-0 ]

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:

Application In Synthesis of [ 1446817-84-0 ]

* 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 [ 1446817-84-0 ]

[ 1446817-84-0 ] Synthesis Path-Downstream   1~11

YieldReaction ConditionsOperation in experiment
Stage #1: With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h; Stage #2: In dichloromethane at 20℃; for 2h; 82.4 Step 4: l,l,l?3,3,3-hexafluoropropan-2-yl 4-[[2-(morpholin-4-yl)-3- (trifluoromethyl)phenyl]methyl]piperazine-l-carboxylate General procedure: A 50 mL round-bottom flask was charged with l, l, l,3,3,3-hexafluoropropan-2- ol (168 mg, 1.00 mmol, 1.10 equiv), triphosgene (99.0 mg, 0.330 mmol, 0.33 equiv), dichloromethane (10 mL). N,N-Diisopropylethylamine (381 mg, 2.95 mmol, 3.24 equiv) was added dropwise. The mixture was stirred at room temperature for 2 h. 4-[2-(Piperazin-l- ylmethyl)-5-(trifluoromethyl)phenyl]morpholine (300 mg, 0.910 mmol, 1.00 equiv) was added. The resulting solution was stirred for 2 hours at room temperature and diluted with dichloromethane (20 mL). The resulting mixture was washed with H20 (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/3). Thecrude product (337 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% over 0.1 min, and holding at 20% for 1.9 min, on a waters 2767-5 chromatograph. Column: X-bridge Prep Ci8, 19* 150mm 5um; Mobile phase: Phase A: aqueous NH4HCO3(0.05%); Phase B: CH3CN; Detector, UV220 & 254nm. Purification resulted in 171.9 mg (35% yield) of 1, 1,1,3,3,3- hexafluoropropan-2-yl 4-[[2-(morpholin-4-yl)-3-(trifluoromethyl)phenyl]methyl]piperazine-l- carboxylate as light yellow oil. XH NMR 300 MHz (CDC13) δ 7.54-7.623 (m, 1H), 7.33-7.42 (m, 2H), 5.72-5.85 (m, 1H), 3.84-3.87 (m, 4H), 3.64 (s, 2H), 3.56-3.57 (m, 4H), 2.96-3.00 (m, 4H), 2.51-2.52 (m, 4H). LCMS (ESI, m/z): 524 [M+H]+.
  • 2
  • [ 1446817-84-0 ]
  • 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate mono-hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
91.4% With hydrogenchloride In water; isopropyl alcohol at 38 - 42℃; Large scale; 12.d; 13.d Example 12: Formation of Compound I-HCl Form 2 Step d): Compound I (16.29 kg) was charged in a vessel followed by isopropanol (84.3 kg) and stirred at 38-40° C. for approx. 20 minutes. Solution was filtered in a second vessel and isopropanol (2.4 kg) was used as rinse from first to second vessel; temperature was maintained in the range 38-42° C. Approx. 6M HCl in isopropanol (1.1 kg) was added over approx. 15 minutes under stirring maintaining the temperature in the range 38-42° C. Seed (30 g) of Compound I-HCl form 2 was added followed by a second portion of 6M HCl in isopropanol (2.7 kg in approx. 15 minutes. The suspension was stirred at 38-42° C. for approx. 35 minutes. A third portion of 6M HCl in isopropanol (0.8 kg was added in approx. 15 minutes and the suspension was stirred for further approx. 70 minutes at 38-42° C., then cooled in approx. 60 minutes to 30° C., stirred for approx. 90 minutes, cooled to 20° C. in approx. 60 minutes and stirred at this temperature for up to 13 hours. Solid was isolated and washed with isopropanol (2×16 kg) and the wet solid was air dried at 35-40° C. for approx. 9 hours to end up with the desired product Compound I-HCl form 2 (15.96 kg, 91.4%). 1H-NMR (DMSO-d6): δ(ppm) 1.90-1.93 (4H, t), 3.22-3.25 (8H, t), 3.82 (4H, bs), 4.49 (2H, bs), 6.60-6.67 (1H, m), 7.24-7.25 (2H, m), 7.92-7.94 (1H, d), 11.40 (1H, bs).
90% With hydrogenchloride In tert-butyl methyl ether; water at 35℃; 2 Example 2. Preparation of Compound 2 (Form 1) jjmono-HC111 To Compound 1 (20.0 g) in 9 v/w of tert-butylmethyl ether was added conc. HC1 (1.06 eq) at 3 5°C. The suspension was cooled to room temperature and the solid was collected by filtration and washed with tert-butylmethyl ether. The solid was dried to give Compound 2 (19.3 g, 90%).
  • 3
  • [ 75-75-2 ]
  • [ 1446817-84-0 ]
  • C20H22F9N3O2*CH4O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
85.3% In tert-butyl methyl ether at 40℃; for 1.25h; Mesylate salt (Compound 5) j00513J 300 mg of Compound 1 were weighed into a 20 mL glass scintillation vial. The solid was fully dissolved in tert-butylmethyl ether (6.0 mL) at 40°C. 1.0 equivalent of neat methane sulfonic acid (38.4 1iL) was added to the free base solution. Precipitation was observed within minutes from the addition. The mixture was stirred at 40°C for 1 hour following by cooling to room temperature. The resulting solid was isolated by centrifugation (Crop 1) and the remaining slurry from the vial was left to slowly evaporate. This yielded more solid (Crop 2). Both crops were dried in a desiccator for 3 hours and analyzed separately by XRPD and HPLC. According to XRPD analysis, Crop 1 and 2 both corresponded to the same form and had similar levels of crystallinity. Moreover, XRPD analysis confirmed that the mesylate salt obtained from the secondary screen corresponded to the form obtained in the primary screen. The combined crop yield was 8 5.3%. Crop 1 was used for the full characterization of the salt.
  • 4
  • [ 1446817-84-0 ]
  • [ 110-17-8 ]
  • (x)C4H4O4*C20H22F9N3O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
In ethanol; acetonitrile at 40℃; for 1h; Fumarate salt (Compound 6), Form 1 j00520J 300 mg of Compound 1 were weighed into a 20 mL glass scintillation vial. The solid was fully dissolved in MeCN (1.5 mL) at 40°C. 1.05 equivalents of fumaric acid (72.06 mg) were weighed out in a different vial and the solid was fully dissolved in EtOH (2.4 mL) at 40°C. The fumaric acid solution was added to the free base solution and the mixture was stirred at 40°C for 1 hour. The mixture was cooled to room temperature and the solution was subjected to slow evaporation for 2 days. Afterwards, the vial was stored at 5°C for a further 3 days to aid precipitation. The resulting solid was isolated by centrifugation (Crop 1) and the resulting mother liquor was left to slowly evaporate. This yielded more solid (Crop 2). Both crops were dried in a desiccator for 3 hours and analyzed by XRPD and HPLC.
  • 5
  • [ 89763-93-9 ]
  • [ 1446817-84-0 ]
  • 6
  • [ 1374603-97-0 ]
  • [ 1446817-84-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: 0.5 h / 20 °C / Inert atmosphere 1.2: 20 °C / Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 18 h / 0 - 20 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 20 °C / Inert atmosphere 3.2: 2 h / 20 °C / Inert atmosphere
  • 7
  • [ 1446819-16-4 ]
  • [ 1446817-84-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: trifluoroacetic acid / dichloromethane / 18 h / 0 - 20 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 20 °C / Inert atmosphere 2.2: 2 h / 20 °C / Inert atmosphere
  • 8
  • [ 32315-10-9 ]
  • [ 920-66-1 ]
  • [ 1446819-17-5 ]
  • [ 1446817-84-0 ]
YieldReaction ConditionsOperation in experiment
79% Stage #1: bis(trichloromethyl) carbonate; 1,1,1,3',3',3'-hexafluoro-propanol With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h; Inert atmosphere; Stage #2: 1-[[2-(pyrrolidin-1-yl)-4-(trifluoromethyl)phenyl]methyl]piperazine In dichloromethane at 20℃; for 2h; Inert atmosphere;
  • 9
  • [ 1374603-97-0 ]
  • 1,1,1,3,3,3-hexafluoropropan-2-yl piperazine-1-carboxylate, 2,2,2-trifluoroacetate salt [ No CAS ]
  • [ 1446817-84-0 ]
YieldReaction ConditionsOperation in experiment
92% Stage #1: 1,1,1,3,3,3-hexafluoropropan-2-yl piperazine-1-carboxylate, 2,2,2-trifluoroacetate salt With triethylamine In ethyl acetate at 20 - 25℃; for 1.25h; Large scale; Stage #2: 2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzaldehyde In ethyl acetate at 20 - 25℃; for 3.25h; Inert atmosphere; Large scale; Stage #3: With sodium tris(acetoxy)borohydride In ethyl acetate at 20 - 25℃; Inert atmosphere; Large scale; 9.c Example 9: Synthesis of Compound I Via TFA Route Step c) via TFA route: A3-TFA (16.2 kg) was charged in a vessel at 20-25° C. followed by EtOAc (57 kg) at 20-25° C. obtaining a suspension. TEA (4.4 kg) was added over 15 min and the mixture was stirred at 20-25° C. for 1 hour. The A5 solution obtained in example 5 (20.5 kg) was added under nitrogen over 15 min at 20-25° C. and the mixture was stirred at 20-25° C. for 3 hours. STAB (9.8 kg) was added in 4 equal portions, waiting about 30 minutes between every portion and the following one while maintaining the temperature between 20 and 25° C. Subsequently, the suspension was stirred for 12 hours, followed by the addition of a further portion of STAB (1.4 kg) and a further stirring period of 2 hours. Subsequently, a further portion of STAB (0.3 kg) was added to the suspension followed by stirring for 2 hours. Purified water (13.5 kg) was added at 20° C. over 2 hours to form a phase separation. The organic phase was diluted with EtOAc (12.3 kg) and washed with purified water (63.2 kg). The organic phase was concentrated under vacuum below 40° C. to approx. 25 l. Methanol (21.4 kg) was added and solution was concentrated under vacuum to approx. 25 l. Methanol (48.2 kg) was added and the solution heated to 48-52° C. Purified water (81.2 kg) was slowly added in approx. 2 hours obtaining a suspension that was stirred at 48-52° C. for 30 minutes, followed by cooling to 20° C. over 3 hours and stirred at 20° C. for 3 hours. Suspension was centrifugated and washed with purified water/methanol mixture (27.1 kg/47.6 kg), the wet solid (18.49 kg) was dried under nitrogen flow for no less than 8 hours in a static drier affording Compound 1 (17.29 kg, 92% yield). 1H-NMR (DMSO-d6): δ(ppm) 1.86-1.89 (4H, t), 2.39 (4H, m), 3.24-3.27 (4H, t), 3.56 (2H, s), 6.53-6.63 (1H, m), 7.01-7.02 (1H, d), 7.09-7.11 (1H, dd), 7.53-7.55 (1H, d).
  • 10
  • [ 1374603-97-0 ]
  • 1,1,1,3,3,3-hexafluoropropan-2-yl piperazine-1-carboxylate hydrochloride [ No CAS ]
  • [ 1446817-84-0 ]
YieldReaction ConditionsOperation in experiment
92% Stage #1: 1,1,1,3,3,3-hexafluoropropan-2-yl piperazine-1-carboxylate hydrochloride With triethylamine In ethyl acetate at 20 - 25℃; for 1.25h; Large scale; Stage #2: 2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzaldehyde In ethyl acetate at 20 - 25℃; for 3h; Inert atmosphere; Large scale; Stage #3: With sodium tris(acetoxy)borohydride In ethyl acetate at 20 - 25℃; for 15.5h; Inert atmosphere; Large scale; 10.c; 11.c Example 10: Synthesis of Compound I Via HCl Route Step c) via HCl route: A3-HCl (12.9 kg, 1.43 wt. %) was charged in vessel at 20-25° C. followed by EtOAc (57 kg) at 20-25° C. obtaining a suspension. TEA (4.4 kg) was added over 15 min and the mixture was stirred at 20-25° C. for 1 hour. Water (102 g) was added to the A5 solution from example 4 (20.5 kg at 44% w/w). The A5 solution was then added under nitrogen over 15 min at 20-25° C. and the mixture was stirred at 20-25° C. for 3 hours. STAB (9.8 kg) was added in 4 equal portions waiting about 30 minutes between every portion and the following one while maintaining the temperature between 20-25° C. The suspension was stirred for 15 hours. Purified water (13.5 kg) was added at 20° C. over 2 hours to obtain a phase separation. The organic phase was diluted with EtOAc (12.3 kg) and washed with purified water (63.2 kg). The organic phase was concentrated under vacuum below 40° C. to approx. 25 l. Methanol (21.4 kg) was added and solution was concentrated again under vacuum to approx. (25 l). Methanol (48.2 kg) was added and the solution was heated to 48-52° C. Purified water (81.2 kg) was slowly added over approx. 2 hours obtaining a suspension that was stirred at 48-52° C. for 30 minutes then cooled to 20° C. over 3 hours and stirred at 20° C. for approx. 3 hours. Suspension was centrifugated and washed with a purified water/methanol mixture (27.1 kg/47.6 kg). The wet solid (18.33 kg) was dried under nitrogen flow in a static drier for about 8 hours affording Compound 1 (17.33 kg, yield 92%). 1H-NMR (DMSO-d6): δ(ppm) 1.86-1.89 (4H, t), 2.39 (4H, m), 3.24-3.27 (4H, t), 3.56 (2H, s), 6.53-6.63 (1H, m), 7.01-7.02 (1H, d), 7.09-7.11 (1H, dd), 7.53-7.55 (1H, d).
  • 11
  • [ 1446817-18-0 ]
  • [ 1446817-84-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: hydrogenchloride / water; Isopropyl acetate / 1 h / 15 - 23 °C / Large scale 2.1: triethylamine / ethyl acetate / 1.25 h / 20 - 25 °C / Large scale 2.2: 3 h / 20 - 25 °C / Inert atmosphere; Large scale 2.3: 15.5 h / 20 - 25 °C / Inert atmosphere; Large scale
Multi-step reaction with 2 steps 1.1: 2 h / 25 °C / Large scale 2.1: triethylamine / ethyl acetate / 1.25 h / 20 - 25 °C / Large scale 2.2: 3.25 h / 20 - 25 °C / Inert atmosphere; Large scale 2.3: 20 - 25 °C / Inert atmosphere; Large scale
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