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[ CAS No. 944396-07-0 ] {[proInfo.proName]}

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Chemical Structure| 944396-07-0
Chemical Structure| 944396-07-0
Structure of 944396-07-0 * Storage: {[proInfo.prStorage]}
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Product Details of [ 944396-07-0 ]

CAS No. :944396-07-0 MDL No. :MFCD18251596
Formula : C18H21F3N6O2 Boiling Point : -
Linear Structure Formula :- InChI Key :CWHUFRVAEUJCEF-UHFFFAOYSA-N
M.W : 410.39 Pubchem ID :16654980
Synonyms :
BKM120;NVP-BKM120

Calculated chemistry of [ 944396-07-0 ]

Physicochemical Properties

Num. heavy atoms : 29
Num. arom. heavy atoms : 12
Fraction Csp3 : 0.5
Num. rotatable bonds : 4
Num. H-bond acceptors : 8.0
Num. H-bond donors : 1.0
Molar Refractivity : 106.12
TPSA : 89.63 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -7.74 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.64
Log Po/w (XLOGP3) : 1.5
Log Po/w (WLOGP) : 2.21
Log Po/w (MLOGP) : 0.68
Log Po/w (SILICOS-IT) : 1.96
Consensus Log Po/w : 1.8

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.37
Solubility : 0.174 mg/ml ; 0.000425 mol/l
Class : Soluble
Log S (Ali) : -2.99
Solubility : 0.42 mg/ml ; 0.00102 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.61
Solubility : 0.0101 mg/ml ; 0.0000246 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 3.46

Safety of [ 944396-07-0 ]

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 [ 944396-07-0 ]

* 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 [ 944396-07-0 ]

[ 944396-07-0 ] Synthesis Path-Downstream   1~4

  • 1
  • [ 10244-24-3 ]
  • [ 944401-57-4 ]
  • 4-(trifluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
95% With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 90℃; for 15.33h; [0390] Argon gas was bubbled through a heterogeneous mixture of 2,4- dimophiholino-6-chloropyrimidine (4.1 g, 14.3 mmol) and 4-(trifluoromethyl)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridm-2-amine (16.5 g, 57.3 mmol) in 1,2- dimethoxyethane and 2M Na2Ctheta3 (3:1) for 20 minutes. 1,1'-Bis(diphenylphosphino)ferrocene palladium (IT) chloride (292 mg, 0.36 mmol) was added and the high pressure glass vessel containing the mixture was sealed. The reaction mixture was then heated at 900C for 15 hours, cooled and diluted with EtOAc (300 mL). The organic solution was washed with 300 mL of a mixture of water: Na2Ctheta3(sat.):NH4thetaH(conc.) = 5:4:1, then NH4Cl(sat), and brine (2x), dried over Na2SO4, filtered and concentrated. The crude material was purified by SiO2 chromatography (50- 90% EtOAc/hexanes with 0.1% TEA) resulting in 5.62 g (95%) of 4-(trifluoromethyl)-5- (2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine as an off-white solid. LCMS (m/z): 411.3 (MH+); 1H NMR (CDCl3): delta 8.27 (s, IH), 6.78 (s, IH), 5.97 (s, IH), 4.77 (bs, 2H), 3.59-3.80(m, 12H), 3.58-3.61(m, 4H).
4-(Trifluoromethyl)-5-(2,6-dimophiholinopytauimidin-4-yl)pyridin-2-amine [00133] Argon gas was bubbled through a heterogeneous mixture of 2,4-dimorpholino-6- chloropyrimidine (4.1 g, 14.3 mmol) and 4-(trifluoromethyl)-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-amine (16.5 g, 57.3 mmol) in 1 ,2-dimethoxyethane and 2MNa2C03 (3:1) for 20 minutes. 1 , 1 '-Bis(diphenylphosphino)ferrocene palladium (II) chloride (292 mg, 0.36 mmol) was added and the high pressure glass vessel containing the mixture was sealed. The reaction mixture was then heated at 90 C for 15 hours, cooled and diluted with EtOAc (300 mL). The organic solution was washed with 300 mL of a mixture of water: Na2C03(Sat.):NH40H(ConC.) = 5:4:1, then NH4Cl(sat.), and brine (2x), dried over Na2S04, filtered and concentrated. The crude material was purified by Si02 chromatography (50-90% EtOAc/hexanes with 0.1% TEA) resulting in 5.62 g (95%) of 4-(trifluoromethyl)-5-(2,6- dimo holinopyrimidin-4-yl)pyridin-2-amine as an off-white solid. LCMS (m/z) 411.3 (MH ); ¾ NMR (CDC13): delta 8.27 (s, 1H), 6.78 (s, 1H), 5.97 (s, 1H), 4.77 (bs, 2H), 3.59- 3.80(m, 12H), 3.58-3.61 (m, 4H).
  • 2
  • [ 944401-56-3 ]
  • [ 1370351-45-3 ]
  • 4-(trifluoromethyl)-5-(2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% With caesium carbonate;dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); In tetrahydrofuran; water; at 45℃; for 0.75h;Inert atmosphere; Example 4: 5-(2,6-Di-4-morpholinyl^^yrimidinyl)-^trifluoromethylpyridin-2-ami^ (5); Charge a 500 mL round bottom 3-neck flask that equipped with a thermocouple, mechanical stirrer, nitrogen inlet/outlet and cooling bath with 202.8 g (0.622 mol) of cesium carbonate and 260 g (260 mL) of water. Stir and cool the resulting solution to 22 +/- 3 C. Transfer the solution to the addition funnel. Charge a nitrogen-flushed 3 L reactor that equipped with an overhead stirrer, condenser, pH probe, nitrogen inlet/outlet and 500 mL addition funnel with 50.0 g (0.207 mol) of 5-bromo-4-(trifluoromethyl) pyridin-2-amine 4a, 190.9 g (0.456 mol) of 4,4'-[6-(4,4,5,5- tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyrimidine-2,4-diyl]di[morpholine] 4, 6.75 g (0.0103 mol) of 1,1'-bis(di-ferf-butylphosphino) ferrocene palladium dichloride and 556 g (625 mL) of thf. Stir the slurry at 22 +/- 3 C. Add the aqueous cesium carbonate solution via the addition funnel to the slurry over 1 - 2 min. Stir rapidly (to ensure good mixing), heat to 45 +/- 3 C over 15 min and hold at this temperature for at least 30 minutes. Check for completeness of the reaction. Cool to 22 +/- 3 C. Separate the phases. Partially concentrate the THF (25 C, 90 mbar) to a volume of 400 mL. Add 654 g (750 mL) of isopropyl acetate, resume the vacuum distillation and concentrate to a volume of 400 mL. Add 610 g (700 mL) of isopropyl acetate, stir and filter the hazy solution through a 25 g pad of Celite. Wash the reactor and filter cake with 87 g (100 mL) of isopropyl acetate and add the wash to the batch. Add 1 L of 0. 25N aqueous N-acetyl-L- cysteine solution and stir at 60 +/- 3 C for 1 h. Cool to 22 +/- 3 C and drain the aqueous wash. Add 1 L of 0.25N aqueous N-acetyl-L-cysteine pH = 7 solution and stir at 60 +/- 3 C for 1 h. Cool to 22 +/- 3 C and drain the aqueous wash. Again, add 1 L of 0.25N aqueous N-acetyl-L-cysteine pH = 7 solution and stir at 60 +/- 3 C for 1 h. Cool to 22 +/- 3 C and drain the aqueous wash. Charge 34.5 g of Si-Thiol functionalized silica gel and stir the suspension at 60 +/- 3 C for 1 h. Cool to 22 +/- 3 C and filter to remove the silica gel. Add 1 L of 1 N aqueous hydrochloric acid solution and stir for 15 minutes. Separate the phases and retain the aqueous phase which now contains product. Extract the organic phase again by adding 500 mL of 1N aqueous HCI solution and stirring for 15 minutes. Separate the phases and combine the aqueous extracts. Adjust the pH to 2.3 +/- 0.2 by the addition of ~280 mL of 4N aqueous sodium hydroxide solution. Charge 17.2 g of Si-Thiol functionalized silica gel and stir the suspension at 50 +/- 3 C for 1 h. Cool to 22 +/- 3 C and filter to remove the silica gel. Adjust the pH to 5.0 +/- 0.2 by the slow addition of ~75 mL of 4N aqueous sodium hydroxide solution maintaining a batch temperature of 15 +/- 3 C. Stir the slurry for at least 16 h at 22 +/- 3 C to allow the product to completely solidify. Filter the solids and wash the filter cake once with 250 g (250 mL) of water. Dry the solids (50 C, 35 mbar) for 16 h to obtain 75 g (89% yield) of 5 as a tan solid. Following this procedure, Compound 5 is the hemihydrate polymorph form HA of the Compound of Formula A.
24.4% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In tetrahydrofuran; at 45℃; for 1h;Inert atmosphere; The 4,4 ' - (6 - (4, 4, 5, 5-tetramethyl -1, 3, 2- two oxygen boron fifth heavenly stem link -2-yl) pyrimidine -2,4-diyl) two morpholine (414 mg, 1 . 1mmol) and 5-bromo-4 - (trifluoromethyl) pyridin -2 amine (120.5 mg, 0 . 5mmol) were dissolved in tetrahydrofuran (25 ml) stirred cesium carbonate (489 mg, 1 . 5mmol) aqueous solution (10 ml), under the protection of nitrogen added the 1 [...] -bis (mortars; concrete ; artificial stone) ferrocene palladium dichloride (20 mg, 0 . 027mmol), slowly increased the temperature to 45 C and maintained for 1 hour. after reducing pressure and evaporating tetrahydrofuran, by adding ethyl acetate (80 ml) extraction, separation, the organic phase is dried with anhydrous sodium sulfate, concentrated, crude product by silica gel column chromatography (petroleum ether: ethyl acetate: triethylamine = 1:1: 0.01) purification, to obtain the title compound (50 mg, yield 24.4%).
24.4% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In tetrahydrofuran; water; at 45℃; for 1h;Inert atmosphere; The 4,4 ' - (6 - (4, 4, 5, 5-tetramethyl -1, 3, 2- two oxygen boron fifth heavenly stem link -2-yl) pyrimidine -2,4-diyl) two morpholine (414 mg, 1 . 1mmol) and 5-bromo-4 - (trifluoromethyl) pyridin -2 amine (120.5 mg, 0 . 5mmol) dissolved in tetrahydrofuran (25 ml) in, stirring cesium carbonate (489 mg, 1 . 5mmol) aqueous solution (10 ml), under the protection of nitrogen by adding 1, the 1 [...] -bis (mortars; concrete ; artificial stone) ferrocene palladium dichloride (20 mg, 0 . 027mmol), slowly increasing the temperature to 45 C, reaction 1 hour, after reducing pressure and evaporating tetrahydrofuran, by adding ethyl acetate (80 ml) extraction, separation, the organic phase is dried with anhydrous sodium sulfate, concentrated, crude product by silica gel column chromatography (petroleum ether: ethyl acetate: triethylamine = 1:1: 0.01) purification, to obtain the title compound (50 mg, yield 24.4%).
  • 3
  • [ CAS Unavailable ]
  • [ 1370351-47-5 ]
  • [ 944396-07-0 ]
YieldReaction ConditionsOperation in experiment
84.9% Stage #1: 6-acetamido-4-(trifluoromethyl)pyridin-3-ylboronic acid With potassium carbonate In 1,2-dimethoxyethane at 70 - 90℃; for 5h; Stage #2: With hydrogenchloride; water at 20 - 75℃; Stage #3: With sodium hydroxide In Isopropyl acetate; water 9 Example 9: 5-(2,6-Di-4-morpholiny -pyrimidinyl)^4rifluoromethylpyridin-2-amine (5); B3The reactor was charged at 20 °C with 111.7 g 4,4'-(6-chloropyrimidine-2,4-diyl)dimorpholine 3, 108.5 g K2C03 and 4.54 g Tetrakis(Triphenylphosphin)Palladium (0). 125 ml water and 500 ml 1 ,2-Dimethoxyethan were added. The white suspension was warmed within 30 min to 90 °C. A solution of 100 g 6-acetamido-4-(trifluoromethyl)pyridin-3-ylboronic acid B3 in 450 ml 1,2- Dimethoxyethan was constantly added within a period of 4 ½ h. The funnel was washed with 50 ml ,2-Dimethoxyethan. The reaction mixture was cooled to 70 °C within 30 min. 1000 ml water were added. 1000 ml solvent was removed by distillation (70 °C, 400 mbar to 260 mbar). 1000 ml water was added. 1000 ml solvent was removed by distillation (70 °C, 400 mbar to 260 mbar). The reaction mixture was cooled to 20 °C within 30 min. The precipitate was collected by filtration and washed with 300 ml water. The reactor was charged with the precipitate and 1900 g 1 N HCI were added. The reaction mixture was warmed to 75 °C within 30 min. The reaction mixture was stirred for 3 h at 75 °C. The reaction mixture cooled to 20 °C within 1 h and stirred over night at 20 °C. The precipitate was removed by filtration and washed with 200 ml water. The reactor was charged with the filtrate and everything was rinsed with 100 ml water. pH was adjusted to pH11.9. 1800 ml Isopropylacetate were added and the mixture was stirred. The phases were separated and the organic layer was collected. Solvent was removed (70 °C, 280 mbar) until the volume was reduced to 725 ml. 1800 ml Isopropylacetate were added and the mixture was stirred. The phases were separated and the organic layer was collected. Solvent was removed (70 °C, 280 mbar) until the volume was reduced to 725 ml. The reaction mixture was cooled to 20 °C within 30 min and stored over the week end. The reaction mixture was filtered over a bed of HYO and washed with 225 ml Isopropylacetate. The reactor was charged with the filtrate and 735. 5 g of solution 1 (61.2 g N-Acetyl-cystein and 600 g water, pH adjusted to pH 7 with 4 N NaOH) were added. The reaction mixture was warmed to 64 °C within 15 min. The reaction mixture was stirred at 64 °C for 2 h. The reaction mixture was cooled to 20 °C within 45 min. The phases were separated and the aqueous layer was removed. 926.5 ml 1 N HCI were added and the mixture was stirred for 15 min. The phases were separated and the aqueous layer was collected. 947 ml 1 N HCI were added and the mixture was stirred for 15 min. The phases were separated and the aqueous layer was collected. The organic layer was removed from the reactor. The reactor was charged with the combined aqueous layers. pH was adjusted to pH 2.3. 39 g Silabond were added. The reaction mixture was warmed to 64 °C within 20 min. The reaction mixture was stirred for 2 h at 64 °C. The reaction mixture was colled to 20 °C within 30 min. The precipitate was removed by filtration. The residue was washed with 500 g water. The reactor was charged with the combined filtrates. pH was adjusted to pH 5.0 with 4 N NaOH The reaction mixture was cooled to 0 °C. The reaction mixture was stirred for 60 min. The product was collected by filtration and washed with 500 g cold (~10 °C) water. The product was dried until constant weight was obtained to yield 136.8 g (84.9 %) 5-(2,6-Di-4-morpholinyl-4-pyrimidinyl)-4-trifluoromethylpyridin-2-amine 5.
  • 4
  • [ 1607826-40-3 ]
  • [ 944396-07-0 ]
YieldReaction ConditionsOperation in experiment
85% With hydrogenchloride In water at 70 - 75℃; for 3h; 4 Example 4: Preparation of 5-(2,6-Di-4-morpholinyl-4-pyrimidin-4-yl)-4(trifluoromethyl) pyridin-2-amine (Compound A) Example 4: Preparation of 5-(2,6-Di-4-morpholinyl-4-pyrimidin-4-yl)-4(trifluoromethyl) pyridin-2-amine (Compound A)N-(5-(2,6-dimorpholinopyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)acetamide (36.1 g, 76.52 mmol) was suspended in demineralized water (180 mL). The suspension was treated with aqueous 2N HCI (180 mL) and the mixture was heated to 70°C -75°C. The reaction mixture was stirred at 75°C for 3 hours at this temperature. The reaction mixture was then cooled down to 25°C and clear filtered. The filter cake is washed with water (2x50 mL). Isopropylacetate (IPA, 100 mL) was added to the filtrate and the pH of the biphasic solution was adjusted to 1 .75 by slow addition of aq. 2N NaOH (105 g) under intense stirring. Stirring was continued for additional 15 minutes at 20-25 °C and the phases were separated. The aqueous phase was extracted with additional IPA (2x50 mL) and the phases were separated. The pH of the aqueous phase was adjusted to 9.1 by slow addition of 2N NaOH (114 g). A suspension was formed. Isopropylacetate (400 mL) was added to the suspension and the mixture was heated to 40 °C under stirring to obtain a biphasic solution. The phases were separated and the water phase was extracted again with isopropylacetate (50 mL). The organic phases were combined. An aqueous solution of N-Acetyl-L-cysteine (140 mL) was added to the organic phase and the mixture was stirred at 50°C for 1 hour. The phases were separated. The organic phase was treated again with an aqueous solution of N-Acetyl-L-cysteine (140 mL) for additional 1 hour at 60°C and the phases are separated. Finally, the organic phase was washed with demineralized water (70 mL) and the temperature was cooled down to 20 °C. Aqueous 1 N HCI solution (200 mL) was added slowly to the organic phase, maintaining the temperature at 20-25°C. The mixture was intensively stirred for 10 minutes and the phases were separated. The organic phase was extracted again with aqueous 1 N HCI solution (50 mL) and with water (50 mL). The aqueous HCI and water phases were clear filtered and combined. The pH of the combined aqueous phase was adjusted to 7.1 by slow addition of aqueous 2N NaOH solution (123 g) and the formed suspension was stirred for at least 3 hours at 20-25°C. The product was isolated by filtration and the filter cake was washed with demineralized water (3x100 mL). The product was dried in vacuo at 50°C over night to obtain 5-(2,6-Di-4-morpholinyl-4-pyrimidin-4-yl)-4- (trifluoromethyl)pyridin-2-amine (>99.5 a% purity as determined by HPLC) and 85% overall yield.
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NVP-BKM120 Hydrochloride

Reason: Free-salt