Structure of 62980-03-4
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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. : | 62980-03-4 |
Formula : | C8H8ClF3N2 |
M.W : | 224.61 |
SMILES Code : | Cl.FC(C1=CC=CC(=C1)C(=N)N)(F)F |
MDL No. : | MFCD00179830 |
Boiling Point : | No data available |
InChI Key : | JRWQLKZLTWPEBO-UHFFFAOYSA-N |
Pubchem ID : | 2730243 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.12 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 49.67 |
TPSA ? Topological Polar Surface Area: Calculated from |
49.87 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.19 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.94 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.97 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.13 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.45 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.43 |
Solubility | 0.0839 mg/ml ; 0.000374 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.91 |
Solubility | 0.0277 mg/ml ; 0.000123 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.02 |
Solubility | 0.215 mg/ml ; 0.000955 mol/l |
Class? Solubility class: Log S scale |
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) |
No |
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 |
-5.41 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 |
0.0 |
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 |
2.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.44 |
* 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 |
---|---|---|
With sodium hydroxide; In dichloromethane; water; | EXAMPLE 1 3-(Trifluoromethyl)-N-(3-phenyl-1,2,4-oxadiazol-5-yl)benzamidine In a 500 ml flask provided with a condenser, a thermometer and a stirring device are added 22.4 g (0.1 mole) <strong>[62980-03-4]3-trifluoromethylbenzamidine hydrochloride</strong> and 100 ml water. Complete solubilization is obtained. Methylene chloride (50 ml) followed by 10 N sodium hydroxide solution (20 ml; 0.2 mole) are then added thereto. The reaction mixture is cloudy, whitish. A solution of 18 g (0.1 mole) 3-phenyl-5-chloro-oxadiazole in 50 ml methylene chloride is then added. The temperature increases gradually to 41 C. (refluxing temperature of methylene chloride) while a white solid is produced. The reaction mixture is stirred for a further period of time of 5 hours, and is then left quiescent overnight. The solid material is filtered off, and washed successively with water, methylene chloride and ethanol. After drying, it is recrystallized from 5 volumes Cellosolve, to give 27 g (81%) of the title compound. M.p. (cap.)=224 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 119 Preparation of m-Trifluoromethylphenylamidine hydrochloride. A mixture of m-trifluoromethylphenyliminoethyl ester hydrochloride (119 g) and absolute ethanol (595 ml) is stirred and ammonia gas bubbled in slowly at room temperature for 0.5 hours, then let stand overnight. Then the addition of ammonia gas is resumed at 30 C. until solution occurs. Ether is added, the precipitated material filtered, washed with ether and dried to afford 119.48 g of title product, m.p. 181-182 C. Analysis calculated for C8 H8 N2 ClF3: C 42.78; H 3.59; N 12.47; Cl 15.78; F 25.37; Found: C 42.40; H 3.71; N 12.36; Cl 16.34; F 25.43. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; | EXAMPLE 120 Preparation of cis and trans 4,5-dimethyl-2-(alpha,alpha,alpha-trifluoro-m-tolyl)-2-imidazoline-4,5-diol hydrochloride 2,3-Butanedione (49.1 ml) is added dropwise over 30 minutes to a warm (45 C.) solution of <strong>[62980-03-4]m-trifluoromethylphenylamidine hydrochloride</strong> (110.48 g; 0.53 mole) in water (480 ml). The reaction mixture is stirred overnight at room temperature, and then stripped at 40 C. The isolated crude solid contains about 77.3 g of amidine. The amidine, water (100 ml) and 2,3-butanedione (31 ml) are mixed and reacted in an ice bath for 2 hours. The mixture is then filtered, washed with hexane to afford 55.96 g of title product. Total yield: 119.0 g. Analysis calculated for C12 H14 N2 ClF3 O2: C 46.39; H 4.54; N 9.02; Cl 11.41; F 18.34; Found: C 45.03; H 4.78; N 9.65; Cl 12.57; F 18.07. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | A) 4,6-Dimethyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester A solution of 5.31 g (23.6 mmol) <strong>[62980-03-4]3-trifluoromethyl-benzamidine HCl</strong> in 60 ml EtOH was treated with 2.34 g (23.6 mmol) of sodium tert-butoxide. After 4 min, 4.40 g (23.6 mmol) of crude (E,Z)-2-acetyl-3-methoxy-but-2-enoic acid ethyl ester [McCombie, S. W.; Tagat, J. R.; Vice, S. F.; Lin, S.-I.; Steensma, R.; Palani, A.; Neustadt, B. R.; Baroudy, B. M.; Strizki, J. M.; Endres, M.; Cox, K.; Dan, N.; Chou, C.-C. Bioorganic & Medicinal Chemistry Letters (2003), 13(3), 567-571] in 40 ml of EtOH was added. Then, the reaction mixture was stirred for 65 hours at RT. Subsequently, the solvents were evaporated and the residue poured into crashed ice, acidified with HCl (25% in water) and extracted three times with Et2O; the organic phases were dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (heptane/EtOAc 99:1) to give 4.95 g (65%) of the title compound as colorless oil. MS:=325.2 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | A) 4-Cyclopropyl-6-methyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester 2-Cyclopropanecarbonyl-3-oxo-butyric acid ethyl ester [Jung, J.-C.; Watkins, E. B.; Avery, M. A. Tetrahedron (2002), 58(18), 3639-3646] (4.7 g, 24 mmol) was dissolved in acetonitrile (40 ml) and cooled to 0 C. Cesium carbonate (7.8 g, 24 mmol) was added and the reaction stirred for 0.5 h before the addition of trifluoro-methanesulfonic acid methyl ester (2.6 ml, 24 mmol) and the reaction stirred for a further 2 h. The reaction mixture was diluted with EtOAc, washed with water, brine, dried (Na2SO4) and concentrated to afford a crude mixture of (E,Z)-2-cyclopropanecarbonyl-3-methoxy-but-2-enoic acid ethyl ester and/or 2-[1-cyclopropyl-1-methoxy-meth-(E,Z)-ylidene]-3-oxo-butyric acid ethyl ester (6.3 g, quant). A third of this material (2.1 g, 8 mmol) was dissolved in ethanol (10 ml) and added dropwise to a solution of <strong>[62980-03-4]3-trifluoromethyl-benzamidine hydrochloride</strong> (1.8 g, 8 mmol) and sodium tert-butoxide (0.8 g, 8 mmol) and the mixture stirred overnight. The reaction was concentrated, re-dissolved in EtOAc, washed with 1N hydrochloric acid solution, dried (Na2SO4) and concentrated. Purification by flash column chromatography (EtOAc/Heptane 1:9) afforded the title product (1.2 g, 42%) as clear oil. MS: 351.2 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | A solution of ethyl delta-acetyl-thiophene^-carboxylate (0.5g, 2.52mmol) in DMF.DMA (2ml) was heated at 1000C for I hour, then cooled and concentrated under reduced pressure. The solid residue was dissolved in EtOH (20ml). Then 3-trifluoromethylbenzamidine.HCI (Interchim, 0.567g, 2.52mmol) and EtONa (0.206g, 3.03mmol) were added and the mixture <n="34"/>was heated at 800C for 16 hours and then poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH2CI2). The title compound was obtained as a white solid (0.69g, yield= 72%). LC/MS (method B): Rt= 4.35mins; MH+ 379.1 ; H1 NMR (300MHz, CDCI3, ppm): 8.86 (d, 1 H), 8.82 (s, 1 H), 8.76 (d, 1 H), 7.85 (d, 1 H), 7.8 (m, 2H), 7.67 (t, 1 H), 7.55 (d, 1 H), 4.42 (q, 2H), 1.45 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A] 4-Cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester To a solution of 0.953 g (4.24 mmol) commercially available <strong>[62980-03-4]3-trifluoromethyl-benzamidine hydrochloride</strong> in 10 ml of ethanol was added 0.408 g (4.25 mmol) of sodium tert-butoxide. Two Min. later, 0.901 g (4.25 mmol) of crude (E,Z)-2-cyclopropane-carbonyl-3-ethoxy-acrylic acid methyl ester (example 27C], containing some Et-ester) was added and the reaction allowed to proceed over night at RT. The mixture was then poured onto crashed ice/AcOEt/HCl dil., the aqueous phase extracted again with AcOEt, the combined organic layers were washed with water, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=9/1) yielded finally 1.253 g of title compound as white waxy solid (mixture of Me/Et-ester). MS: 322.1, 336.0 (M)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | In N,N-dimethyl-formamide; at 150℃; for 0.75h;Microwave irradiation; | Example 21 5-(4-Chlorophenyl)-4-cyclopropyl-2-({5-[3-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one 100 mg (0.33 mmol) of the compound from Example 21A were dissolved in 1.6 ml of DMF, 109 mg (0.49 mmol) of <strong>[62980-03-4]3-trifluoromethylbenzamidine hydrochloride</strong> were added and the mixture was stirred in a microwave oven at 150 C. for 45 min. After cooling, the reaction was concentrated under reduced pressure on a rotary evaporator and the residue that remained was purified chromatographically [Method 19]. This gave 70 mg (47% of theory) of the target compound as a colorless solid. LC/MS [Method 7]: Rt=2.33 min; MS [ESIpos]: m/z=461 (M+H)+ 1H-NMR (400 MHz, CDCl3): delta=0.74-0.84 (m, 2H), 0.99-1.10 (m, 2H), 2.96-3.06 (m, 1H), 5.28 (s, 2H), 7.45 (d, 2H), 7.53 (t, 1H), 7.64 (d, 1H), 7.68 (d, 2H), 8.25 (d, 1H), 8.36 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | In N,N-dimethyl-formamide; at 220℃; for 0.5h;Microwave irradiation; | Example 25 5-(5-Chlorothiophen-2-yl)-4-(2-fluorobenzyl)-2-({5-[3-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one 100 mg (0.26 mmol) of the compound from Example 22A were dissolved in 1.0 ml of DMF, 88 mg (0.39 mmol) of 3-(trifluoromethyl)benzenecarboximidamide hydrochloride were added and the mixture was stirred in a microwave oven at 220 C. for 30 min. After cooling, the reaction was concentrated under reduced pressure on a rotary evaporator, and the residue was purified chromatographically [Method 19]. This gave 71 mg (51% of theory) of the target compound as a colorless resin. MS [ESIpos]: m/z=535 (M+H)+ 1H-NMR (400 MHz, CDCl3): delta=5.14 (s, 2H), 5.34 (s, 2H), 6.85 (s, 1H), 6.95 (s, 1H), 7.04-7.16 (m, 3H), 7.28-7.37 (m, 1H), 7.50-7.60 (m, 1H), 7.61-7.70 (m, 1H), 8.20-8.30 (m, 1H), 8.35 (s, 1H), 12.00 (br. s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With 1,10-Phenanthroline; copper diacetate; potassium carbonate; In N,N-dimethyl-formamide; at 130℃; for 24h;Inert atmosphere; Schlenk technique; | General procedure: To a round-bottom flask (25 mL) equipped with a spherical condenser (40 cm length) were added amidine hydrochloride 1 (1.0 mmol), Cu(OAc)2 (0.2 equiv), K2CO3 (2.0 equiv), 1,10-phenanthroline (0.1 equiv) and anhyd DMF (2.0 mL). Then the mixture was well stirred at 130C under an inert atmosphere. After cooling off, the mixture was filtered through a pad of celite eluting with CH2Cl2 (3×6 mL). The volatiles were removed under reduced pressure and the residue was purified by a short flash silica gel column chromatography to give compound 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With iodine; caesium carbonate; In 1,2-dichloro-benzene; at 130℃; for 16h; | General procedure: To a stirred solution of amidine hydrochloride 1 (1.0 mmol) in o-dichlorobenzene (3.0 mL) was added Cs2CO3 (651 mg, 2.0 mmol) followed by iodine (508 mg, 2.0 mmol) at room temperature. The reaction mixture was stirred at 130 C for 16 h. After cooling to room temperature the reaction mixture was diluted with 10% aqueous Na2S2O3 (4.0 mL) and the product was extracted with EtOAc (2 × 15 mL). The combined organic layers were dried over anhydrous Na2SO4, filteredand evaporated in vacuum. The crude product was purified by flash column chromatography over silica gel using EtOAc/n-Hexane as the eluent to afford the desired product |
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