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Structure of 54109-16-9
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 54109-16-9 |
Formula : | C9H6BrF3O |
M.W : | 267.04 |
SMILES Code : | FC(F)(F)C1=C(C=CC=C1)C(=O)CBr |
MDL No. : | MFCD03094304 |
InChI Key : | KWZCBMKXNYOQAK-UHFFFAOYSA-N |
Pubchem ID : | 2778430 |
GHS Pictogram: |
![]() |
Signal Word: | Danger |
Hazard Statements: | H314 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Class: | 8 |
UN#: | 3265 |
Packing Group: | Ⅱ |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.22 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 49.51 |
TPSA ? Topological Polar Surface Area: Calculated from |
17.07 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.86 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.28 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.44 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.24 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.75 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.31 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.68 |
Solubility | 0.0556 mg/ml ; 0.000208 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.31 |
Solubility | 0.13 mg/ml ; 0.000486 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.49 |
Solubility | 0.00862 mg/ml ; 0.0000323 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
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) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.6 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.99 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[0475] [CHEMMOL-00023] [0476] The title compound was synthesised from [3-(3-Dimethylaminomethylene-thioureido)-propyl]-carbamic acid tert-butyl ester and 2-trifluoromethyl phenacylbromide (literature: EP 432040) according to the procedure described for Example 25. MS (m/e): 429.9 (MH+, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[0487] [CHEMMOL-00029] [0488] The title compound was synthesised from [3-(3-Dimethylaminomethylene-thioureido)-propyl]-carbamic acid tert-butyl ester 2-Trifluoromethyl-phenacyl bromide (literature: EP432040) according to the procedure described for Example H. [0489] MS (m/e): 330.4 (MH+, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With triethylamine; In ethanol; at 20℃; for 16h; | To a mixture of 801 mg (5 mmol) 3-cyanophenylthioisocyanate in 5 ml IN [NAOH] at [0C] was added 473 mg acetamidine hydrochloride in 10 ml THF and allowed to stirr at 0C for 16 h. The mixture was extracted with ethylacetate and the cornbined organic layers [ARERE] dried with [MGS04] and evaporated to dryness. The residue was purified by flash [COLUENN] chromatography on silica [ELUTINGWITH ETHYLACETATE/CYCLOHEX : ANE 1] : 2 to yield [510] mg (47%) of 1-(1-Amino-ethylidene)-3-(3-cyano-phenyl)-thiourea. (MS (m/e): 219.2 [(M+H,] 100%). A mixture of 50 mg (0.23 mrnol) [1- (1-AMINO-ETHYLIDENE)-3- (3-CYANO-PHENYZ)-] thiourea, 92 mg (0.345 mmol) [2-BROMO-1- (2-TRIFLUOROMETHYL-PHENYL)-ETHANONE AND-48] ul triethylamine in 1 ml ethanol was stirred for 16 h at room temperature. The mixtures were diluted with methanol and directly subjected to preparative HPLC separation on reversed phase eluting with an [ACETONITRILE/WATER] gradient. Evaporation of the product fractions yielded 10.4 mg (12%) of the title compound. (MS (m/e): 386.2 (M-H, 100%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | at 140 - 150℃; for 4.5h; | Combine 2-BROMO-1- (2-TRIFLUOROMETHYL-PHENYL)-ETHANONE (6.6 g, 24.7 mmol) with 5-carbamoyl-pentanoic acid methyl ester (7. 8 g, 49 mmol) and heat the neat mixture in a sealed vessel at 140-150C for about 4.5 hours. Cool the mixture, dilute with water, and extract with EtOAc. Dry the combined extracts over NA2S04 and concentrate. Chromatography over silica gel (CH2C12) allows for recovery of 5- [4- (2-TRIFLUOROMETHYL- PHENYL)-OXAZOL-2-YL]-PENTANOIC acid methyl ester (3.47 g, 43 %). MS (ES): (M+1) + 328. 2 M/Z. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With copper(ll) bromide; In chloroform; ethyl acetate; for 5h;Heating / reflux; | Dissolve 2'- (trifluoromethyl)-acetophenone (5.0 g, 26.6 mmol) in CHCl3 (25 ML) and add this mixture to a warmed slurry of CuBr2 (11.86 g, 53.2 mmol) in EtOAc (75 mL). Heat the resulting mixture near reflux for approx. 5 hours. Cool and filter the mixture and concentrate the resulting filtrate. Chromatograph the resulting residue over silica gel (CH2Cl2) to allow for isolation of 2-Bromo-1- (2-trifluoromethyl-phenyl)- ethanone (6.6 g, 93 %). |
With bromine; In diethyl ether; chloroform; at 20 - 25℃; for 1h; | Reference Example 5 ethyl 2-cyano-4-oxo-4-[(2-trifluoromethyl)phenyl]butanoate; 2'-(Trifluoromethyl)acetophenone (10.0 g) was dissolved in chloroform (30 mL) and diethyl ether (30 mL), a solution of bromine (8.50 g) in chloroform (20 mL) was added dropwise while maintaining the reaction temperature at not higher than 25 C. After the dropwise addition, the mixture was stirred at room temperature for 1 hr, water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, concentration under reduced pressure to give crude 2-bromo-1-(2-trifluoromethylphenyl)ethanone. Potassium carbonate (13.82 g) was added to ethyl cyanoacetate (44.44 g), and the mixture was stirred at 45 C. for 1 hr. A solution of crude 2-bromo-1-(2-trifluoromethylphenyl)ethanone in acetone (100 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hr, and stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→7:1) to give the title compound as an oil (yield 10.43 g, from 2'-(trifluoromethyl)acetophenone, yield 66%). 1H-NMR (CDCl3) δ: 1.36 (3H, t, J=7.2 Hz), 3.34-3.46 (1H, m), 3.59-3.70 (1H, m), 4.08-4.22 (1H, m), 4.32 (2H, q, J=7.2 Hz), 7.57-7.80 (4H, m). | |
With bromine; In diethyl ether; at 0 - 20℃; | To a solution of l-[2-(trifluoromethyl)phenyl]ethanone (1 g) in diethyl ether (10 mL) cooled at 0 C was added bromine (0.288 mL) dropwise. The resulting mixture was allowed to warm to room temperature. After stirring for 2 hours, the reaction was complete. Solvent was removed in vacuo to afford 2-bromo-l-[2-(trifluoromethyl)phenyl]ethanone (1.488 g) as a yellow oil. MS(ES+) m/z 267 (MH+). |
With hydrogen bromide; bromine; acetic acid; In chloroform; for 0.5h; | To a solution of l-(2-(trifluoromethyl)phenyl)ethanone (71.0 g, 377.0 mmol)and HBr (2.0 mL, 45% solution of AcOH) in chloroform (500.0 mL) was added the solution of dibromide (60.3 g, 377.0 mmol) in chloroform (200.0 mL). After addition, the solution was stirred for 30 min, then the solvent was evaporated and the residue was used in the next step directly. MS (ESI) calcd for C9H6BrF30: 265.96. | |
With bromine; In diethyl ether; chloroform; at 10 - 35℃; for 1h; | Reference Example 25 Ethyl 2-cyano-4-oxo-4-[(2-trifluoromethylphenyl)butanoate 2'-(Trifluoromethyl)acetophenone (10.0 g) was dissolved in chloroform (30 mL) and diethyl ether (30 mL), a solution of bromine (8.50 g) in chloroform (20 mL) was added dropwise while maintaining the reaction temperature at not higher than 25C. After the dropwise addition, the mixture was stirred at room temperature for 1 hr, water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give crude 1-bromo-1-(2-trifluoromethylphenyl)ethanone. | |
With bromine; In diethyl ether; at 20℃; for 0.5h; | General procedure: To a stirred solution of 2-methylacetophenone 8b (13.42 g, 100 mmol) in Et2O (100 mL) was added dropwise bromine (16.0 g, 100 mmol), and the mixture was stirred at room temperature for 30 min, poured into ice H2O, extracted with Et2O. The extract was washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to obtain an crude oil of 2-bromo-1-(2-methylphenyl)ethanone. | |
With N-Bromosuccinimide; toluene-4-sulfonic acid; In water; acetonitrile; at 80℃; for 4h;Inert atmosphere; | A 200 mL flask was charged with 2′-trifluoromethylacetophenone (9.41 g, 50 mmol), N-bromosuccinimide (9.79 g, 55 mmol, 1.1 eq.), p-toluenesulfonic acid (10.46 g, 55 mmol, 1.1 eq.) and MeCN (100 mL) under nitrogen stream and the mixture was stirred for 4 hours at 80 C. The mixture was allowed to cool to room temperature and then MeCN was removed by an evaporator. CHCl3 (150 mL) and H2O (50 mL) were added to the residue and the lower layer was separated and then washed with saturated aqueous NaHCO3 (50 mL) twice and brine (50 mL). The solution was dried over anhydrous MgSO4 and filtered and then solvents were removed in an evaporator to obtain the crude product as yellow oil (13.66 g) in >99.9% yield. This product was identified as 2-Bromo-2′-trifluoromethylacetophenone contaminated with some dibromo compound. 1H-NMR (CDCl3), delta (ppm): 4.36 (s, 2H), 7.48-7.50 (m, 1H), 7.60-7.64 (m, 2H), 7.72-7.75 (m, 1H), 19F-NMR (CDCl3), delta in ppm, standard: C6F6=-162.2 ppm: -58.68. | |
With bromine; In dichloromethane; for 1.5h; | 2-Amino-4-(2-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (V.17); Step 1; To a solution of 20.00 g (0.11 mole) of 2'-(trifluoromethyl)acetophenone in 200 mL of dichloromethane was added 5.5 mL (0.11 mole) of bromine over 90 minutes. A stream of nitrogen was bubbled through the reaction mixture for 15 minutes. The mixture solvent was removed under reduced pressure. The residue was dissolved with ethanol, and then concentrated under reduced pressure to give 27.25 g of 2-bromo-1-(2-trifluoromethyl-phenyl)-ethanone as a yellow oil, which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 1h; | Example 126. Mixture of (3R,4R; 3S. 4S)-f2-((3-r4-(4-Chloro-phenyl)-4-hvdroxy- piperidin-l-vn-4-hvdroxy-pyrrolidm-l-yl)-l-(2-trifluoromethyl-phenyl)-ethanone bistrifluoroacetat; [00366] A mixture of (3R.4R; 3S,4S)-4-(4-chloro-phenyl)-l-(4-hydroxy-pyrroridin-3-yl)- piperidin-4-ol bistrifluoroacetate (see Example 1 for preparation) (12.7 mg, 0.024 mmol), 2-Bromo-l- (2-trifluoromethyl-phenyl)-ethanone (8 mg, 1.2 eq.), diisopropyl ethyl amine (26 μL, 6 eq.) were dissolved into DMF (0.8 mL) at O0C. The solution was warmed to RT and stirred for Ih. The mixture was purified by preparative LC-MS to yield 15 mg of the title compound as the bistrifluoroacetate salt. ESDVIS ([M+H]*): 483.3 (100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; N,N-dimethyl-formamide; | EXAMPLE 15 A mixture of methyl 4-carbamoylbenzoate (896 mg), 2-trifluoromethylphenacyl bromide (2.22 g) and N,N-dimethylformamide (5 ml) was stirred at 130 C. for 2 hours. Hot ethanol was added to the reaction mixture, which was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was concentrated, and the residue was subjected to a silica gel column chromatography to obtain methyl 4-[4-(2-trifluoromethylphenyl)-2-oxazolyl]benzoate as an oil from a fraction eluted with ethyl acetate-hexane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.44 g (36%) | In acetonitrile; | Example 15 2,3-Dimethyl -7(2-trifluoromethylphenacyl)-pyrrolo[2,3-b]pyridine hydrobromide The title compound was made according to the general method from Example 14. 2,3 -dimethyl-pyrrolo[2,3-b]pyridine (438 mg, 3 mmol), 2-trifluoromethylphenacyl bromide (798 mg, 3 mmol) in acetonitrile (5 ml). Yield 0.44 g (36%). (1 H-NMR, 300 MHz, DMSO-d6), 2.45(s,3H), 2.50(s,3H), 6.55(s,2H),7.65(t,1H), 7.95(t,1H), 8.05(m,2H), 8.40(d,2H), 8.65 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Reference Example 5 ethyl 2-cyano-4-oxo-4-[(2-trifluoromethyl)phenyl]butanoate; 2'-(Trifluoromethyl)acetophenone (10.0 g) was dissolved in chloroform (30 mL) and diethyl ether (30 mL), a solution of bromine (8.50 g) in chloroform (20 mL) was added dropwise while maintaining the reaction temperature at not higher than 25 C. After the dropwise addition, the mixture was stirred at room temperature for 1 hr, water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, concentration under reduced pressure to give crude 2-bromo-1-(2-trifluoromethylphenyl)ethanone. Potassium carbonate (13.82 g) was added to ethyl cyanoacetate (44.44 g), and the mixture was stirred at 45 C. for 1 hr. A solution of crude 2-bromo-1-(2-trifluoromethylphenyl)ethanone in acetone (100 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hr, and stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→7:1) to give the title compound as an oil (yield 10.43 g, from 2'-(trifluoromethyl)acetophenone, yield 66%). 1H-NMR (CDCl3) δ: 1.36 (3H, t, J=7.2 Hz), 3.34-3.46 (1H, m), 3.59-3.70 (1H, m), 4.08-4.22 (1H, m), 4.32 (2H, q, J=7.2 Hz), 7.57-7.80 (4H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; water; at 20℃; | Step 2; A solution of 26.04 g (0.40 mole) of potassium cyanide in 30 mL of water was added to a stirring solution of 27.00 g (0.10 mole) of 2-bromo-1-(2-trifluoromethyl-phenyl)-ethanone in 500 mL of ethanol. The mixture was stirred at room temperature overnight. Water and dichloromethane were added to the mixture. The mixture was then acidified with acetic acid (pH=5-6). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Recrystallization of the residue with ether and hexane gave 14.97 g of 3-oxo-3(2-trifluoromethyl-phenyl)-propionitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10.43 g | Potassium carbonate (13.82 g) was added to ethyl cyanoacetate (44.44 g), and the mixture was stirred at 45C for 1 hr. A solution (100 mL) of crude 1-bromo-1-(2-trifluoromethylphenyl)ethanone in acetone was added dropwise. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hr, and stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→7:1) to give the title compound as an oil (yield 10.43 g, from 2'-(trifluoromethyl)acetophenone, 66%).1H-NMR (CDCl3)δ: 1.36 (3H, t, J=7.2 Hz), 3.34-3.46 (1H, m), 3.59-3.70 (1H, m), 4.08-4.22 (1H, m), 4.32 (2H, q, J=7.2 Hz), 7.57-7.80 (4H, m). | |
General procedure: K2CO3 powder (27.6 g, 200 mmol) was added to ethyl cyanoacetate (79.2 g 700 mmol), and the mixture was stirred at 43-45 C for 45 min. To this stirred suspension was added a solution of crude 2-bromo-1-(2-methylphenyl)ethanone in acetone (150 mL) over a period of 30 min, and then the mixture was stirred at room temperature for 16 h, filtered and concentrated under reduced pressure. The residue was taken up with EtOAc, washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (n-hexane/EtOAc = 10/1-8/1)to |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 85℃; for 0.5h;Inert atmosphere; | A solution of 2-bromo-l-[2-(trifluoromethyl)phenyl]ethanone (intermediate 6a, 381 mg) and N- [(-(methyloxy)phenyl]methyl}amino)carbonothioyl]benzamide (intermediate lb, 400 mg) in NN-dimethylformamide (DMF) (4 mL) was stirred at 85 C under nitrogen for 30 mins. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo and the residue was stirred in TFA (7 mL) at 80 C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2S04. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-70 %) to afford (2-amino-4-phenyl-l,3-thiazol-5-yl)[2-(trifluoromethyl)phenyl]methanone (336 mg) as a yellow solid. MS(ES+) m/z 349 (MH+). |
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