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Chemical Structure| 935534-47-7 Chemical Structure| 935534-47-7
Chemical Structure| 935534-47-7

5-Bromo-4-(trifluoromethyl)pyrimidin-2-amine

CAS No.: 935534-47-7

4.5 *For Research Use Only !

Cat. No.: A334229 Purity: 95%

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Product Details of [ 935534-47-7 ]

CAS No. :935534-47-7
Formula : C5H3BrF3N3
M.W : 242.00
SMILES Code : NC1=NC=C(Br)C(C(F)(F)F)=N1
MDL No. :MFCD09261254
Boiling Point : No data available
InChI Key :FAMGPURZLOTOKD-UHFFFAOYSA-N
Pubchem ID :45382152

Safety of [ 935534-47-7 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Calculated chemistry of [ 935534-47-7 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 6
Fraction Csp3 0.2
Num. rotatable bonds 1
Num. H-bond acceptors 5.0
Num. H-bond donors 1.0
Molar Refractivity 39.14
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

51.8 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

1.42
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

1.47
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

3.0
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

1.29
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

1.98
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.83

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-2.57
Solubility 0.651 mg/ml ; 0.00269 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-2.16
Solubility 1.66 mg/ml ; 0.00685 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-3.04
Solubility 0.221 mg/ml ; 0.000914 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

Yes
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.73 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

1.81

Application In Synthesis [ 935534-47-7 ]

* 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 [ 935534-47-7 ]

[ 935534-47-7 ] Synthesis Path-Upstream   1~1

  • 1
  • [ 16075-42-6 ]
  • [ 935534-47-7 ]
YieldReaction ConditionsOperation in experiment
85% With N-Bromosuccinimide In acetonitrile at 20℃; for 4.5 h; Darkness To a solution of 2-amino-4-trifluoromethylpyrimidine (25 g, 0.15 mol) in CH3CN (800 mL) was added dropwise (over 2.5 hours) NBS (34.8 g, 0.195 mol) dissolved in 200 mL of CH3CN in the dark.
The mixture was stirred 4.5 h at RT in the dark and then the solvent was evaporated.
The residue was dissolved in EtOAc and H2O and the binary mixture was transferred into a separating funnel.
The aqueous layer was separated and extracted with EtOAc.
The organic layers were washed with H2O and brine, dried with Na2SO4, filtered and evaporated.
The residue was purified by chromatography on silica gel using a gradient of hexane/EtOAc 9:1 to 3:2.
The combined pure fractions were evaporated and the residue suspended in 40 mL hexane, stirred for 10 min., filtered and washed with 2*20 mL of hexane to give the title product as a beige solid (31.2 g, 85percent).
tR: 0.82 min (LC-MS 1).
85% With N-Bromosuccinimide In acetonitrile for 7 h; Darkness To a solution of 2-amino-4-trifluoromethylpyrimidine (25 g, 0.15 mol) in CH3CN (600 mL) was added in the dark a solution of N-bromosuccinimide (34.8 g, 195 mmol) in acetonitrile (200 mL) over a period of 2.5 h.
The reaction mixture was stirred for 4.5 h at RT and then concentrated.
The residue was dissolved in EtOAc and H2O, the organic solvents were separated, washed with H2O and brine, dried over Na2SO4, filtered and concentrated.
The residue was purified by column chromatography using EtOAc in hexane from 10percent to 40percent to provide the title compound as a beige solid (31.2 g, 85percent). LC-MS: Rt 0.82 min; (LCMS method 2).
82% With N-Bromosuccinimide In chloroform for 20 h; Method 9; Synthesis of 5-bromo-4-(trifluoromethyl)pyrimidin-2-amine; [0249] To a solution of 2-amino-4-trifluoromethylpyrimidine (8.0 g, 49.1 mmol) in chloroform (300 mL) was added N-bromosuccinimide (8.9 g, 50 mmol). The solution was stirred in the dark for 16 hours, at which time additional N-bromosuccinimide (4.0 g,22.5 mmol) was added. After stirring for an additional 4 hours the solution was added toCH2Cl2 (200 mL) and IN NaOH (200 mL). Upon mixing, the layers were separated and the organic layer was washed with NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated, yielding 10.9 g (82percent) of 5-bromo-4-(trifluoromethyl)-2-pyrimidylamine:LCMS (m/z): 242/244 (MH+); 1H NMR (CDCl3): δ 8.52 (s, IH), 5.38 (bs, 2H).
82%
Stage #1: With N-Bromosuccinimide In chloroform for 20 h;
Stage #2: With sodium hydroxide In dichloromethane; chloroform; water
[0250] To a solution of 2-amino-4-trifluoromethylpyrimidine (8.0 g, 49.1 mmol) in chloroform (300 mL) was added N-bromosuccinimide (8.9 g, 50 mmol). The solution was stirred in the dark for 16 hours, at which time additional N-bromosuccinimide (4.0 g, 22.5 mmol) was added. After stirring for an additional 4 hours the solution was added to CH2CI2 (200 mL) and IN NaOH (200 mL). Upon mixing, the layers were separated and <n="97"/>the organic layer was washed with NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated, yielding 10.9 g (82percent) of 5-bromo-4-(trifluoromethyl)-2-pyrimidylamine. LCMS (m/z): 242/244 (MH+). 1H NMR (CDCl3): δ 8.52 (s, IH), 5.38 (bs, 2H).
82%
Stage #1: With N-Bromosuccinimide In chloroform for 20 h; Darkness
Stage #2: With sodium hydroxide In dichloromethane; chloroform
[0092] Synthesis -bromo-4-(trifluoromethyl)pyrimidin-2-amine[0093] To a solution of 2-amino-4-trifluoromethylpyrimidine (8.0 g, 49.1 mmol) in chloroform (300 mL) was added N-bromosuccinimide (8.9 g, 50 mmol). The solution was stirred in the dark for 16 hours, at which time additional N-bromosuccinimide (4.0 g, 22.5 mmol) was added. After stirring for an additional 4 hours the solution was added to CH2C12 (200 mL) and IN NaOH (200 mL). Upon mixing, the layers were separated and the organic layer was washed with NaCl(sat.) (100 mL), dried over Na2S04, filtered and concentrated, yielding 10.9 g (82percent) of 5-bromo-4-(trifluoromethyl)-2-pyrimidylamine. LCMS im/z): 242/244 (MH ). 3/4 NMR (CDC13): δ 8.52 (s, 1H), 5.38 (bs, 2H).
75% With N-Bromosuccinimide In chloroform at 20 - 50℃; for 20 h; 4-(Trifluoromethyl)pyrimidin-2-ylamine (2 g, 12.3 mmol) was suspended in chloroform (70 ml) followed by the addition of N-bromosuccinimide (3.3 g, 18.4 mmol) and the resulting mixture was stirred at 50° C. for 5 hours and then at room temperature for 15 hours. A mixture of methylene chloride (50 ml) and 1 M sodium hydroxide (50 ml) was added, the resulting mixture was stirred, and then the organic layer was fractionated and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (2.2 g, 75percent) as a pale orange solid.1H-NMR (CDCl3) δ: 5.37 (2H, brs), 8.52 (1H, s).
73% With N-Bromosuccinimide In dichloromethane at 25℃; for 48 h; Darkness To a solution of compound 31(500mg, 3.06 mmol) in DCM (60 mL) was added NBS (1.66g, 9.32 mmol). The solution was stirred in the dark for 2d at rt. Then the reaction was quenched with iN NaOH (50 mL) and extracted with DCM (50 mL). The organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give the title compound 32 as a white solid (530 mg, 73percent yield), which was used directly in the next step without further purification. ‘H NIVIR (CDC13): 8.52(s, 1H), 5.29(bs, 2H).

References: [1] Patent: US2013/225574, 2013, A1, . Location in patent: Paragraph 0506; 0507.
[2] Patent: US2014/135330, 2014, A1, . Location in patent: Paragraph 0217.
[3] Patent: WO2008/98058, 2008, A1, . Location in patent: Page/Page column 63.
[4] Patent: WO2007/84786, 2007, A1, . Location in patent: Page/Page column 94-95.
[5] ACS Medicinal Chemistry Letters, 2011, vol. 2, # 10, p. 774 - 779.
[6] Patent: WO2012/109423, 2012, A1, . Location in patent: Page/Page column 20-21.
[7] Patent: US2010/130492, 2010, A1, . Location in patent: Page/Page column 77.
[8] Patent: WO2017/219800, 2017, A1, . Location in patent: Paragraph 00216; 00217.
 

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