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CAS No. : | 1125828-26-3 | MDL No. : | MFCD14706004 |
Formula : | C10H8BrClN2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QYIGOGBGVKONDY-UHFFFAOYSA-N |
M.W : | 271.54 | Pubchem ID : | 25212417 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 11 |
Fraction Csp3 : | 0.1 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 61.24 |
TPSA : | 17.82 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.39 cm/s |
Log Po/w (iLOGP) : | 2.85 |
Log Po/w (XLOGP3) : | 3.61 |
Log Po/w (WLOGP) : | 3.6 |
Log Po/w (MLOGP) : | 3.28 |
Log Po/w (SILICOS-IT) : | 3.26 |
Consensus Log Po/w : | 3.32 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.31 |
Solubility : | 0.0132 mg/ml ; 0.0000486 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -3.67 |
Solubility : | 0.0579 mg/ml ; 0.000213 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.78 |
Solubility : | 0.00449 mg/ml ; 0.0000165 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.85 |
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: |
* 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 |
---|---|---|
83% | Stage #1: With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 20℃; for 0.25 h; Stage #2: at 50℃; for 5 h; |
A 3L 3-neck round bottom flask equipped with a mechanical stirrer, a temperature controller, and a nitrogen inlet was charged with potassium tert-butoxide (Aldrich 95percent, 84.6 g, 0.716 mol) and DMSO (400 mL, 4.x.) at room temperature and stirred for 15 minutes. To this solution was added pyrazole 2 (59 g, 0.719 mol) followed by a DMSO rinse (50 mL, 0.5.x.). The resulting orange turbid solution was stirred for 15 minutes and fluoride 1 (100 g, 0.477 mol) was added followed by a DMSO rinse (50 mL, 0.5.x.). This mixture was then heated to 50° C. and held for 5 hours at this temperature. After cooling to room temperature, the reaction mixture was diluted with MTBE (750 mL), and water (500 mL) was added to give a brown turbid mixture. After 15 minutes stirring, the organic layer was separated and sequentially washed with 1 N HCl (250 mL), brine (250 mL), and water (250 mL). Solution assay of organic layer was carried out using GC (conversion >99percent, solution yields of 3 and its regioisomer 4 were 83percent and 17percent, respectively). The MTBE solution was then concentrated under vacuum to a total volume of about 200 mL (KF showed 0.737percent water). THF (500 mL) was added, and concentrated to 2.x. solution (KF=0.158percent). THF addition-concentration sequence was repeated to give a 2.x. solution (KF=0.023percent), which used directly in the next step.Analytical samples of compounds 3 and 4 were purified by column chromatography and characterized: Compound 3: white crystals; M.p.: 76° C. (DSC onset temperature). 1H NMR (400 MHz, CDCl3) δ 7.80 (1H, d, J=2.3 Hz), 7.61 (1H, d, J=8.6 Hz), 7.58 (1H, d, J=2.5 Hz), 7.22 (1H, dd, J=8.6, 2.6 Hz), 6.27 (1H, d, J=2.5 Hz), 2.38 (3H, s); 13C NMR (100 MHz, CDCl3) δ 150.8, 140.6, 134.6, 134.1, 132.0, 129.0, 128.2, 115.4, 107.0, 13.6. Compound 4: white crystals; 1H NMR (400 MHz, CDCl3) δ 7.65 (1H, d, J=8.6 Hz), 7.62 (1H, d, J=1.5 Hz), 7.43 (1H, d, J=2.5 Hz), 7.35 (1H, dd, J=8.6, 2.2 Hz), 6.21 (1H, s), 2.19 (3H, s); 13C NMR (100 MHz, CDCl3) δ 140.6, 140.2, 140.0, 134.1, 133.9, 130.8, 130.2, 120.7, 105.9, 11.4. |
83 %Chromat. | Stage #1: With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 20℃; for 0.25 h; Stage #2: at 50℃; for 5 h; |
.1. Preparation of 1-(4-Chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanone A 3 L 3-neck round bottom flask equipped with a mechanical stirrer, a temperature controller, and a nitrogen inlet was charged with potassium tert-butoxide (Aldrich 95percent, 84.6 g, 0.716 mol) and DMSO (400 mL, 4.x.) at room temperature and stirred for 15 minutes. To this solution was added pyrazole 2 (59 g, 0.719 mol) followed by a DMSO rinse (50 mL, 0.5.x.). The resulting orange turbid solution was stirred for 15 min and fluoride 1 (100 g, 0.477 mol) was added followed by a DMSO rinse (50 mL, 0.5.x.). This mixture was then heated to 50° C. and held for 5 hours at this temperature. After cooling to room temperature, the reaction mixture was diluted with MTBE (750 mL), and water (500 mL) was added to give a brown turbid mixture. After 15 min stirring, the organic layer was separated and sequentially washed with 1 N HCl (250 mL), brine (250 mL), and water (250 mL). Solution assay of organic layer was carried out using GC (conversion >99percent, solution yields of 3 and its regioisomer 4 were 83percent and 17percent, respectively). The MTBE solution was then concentrated under vacuum to a total volume of about 200 mL (KF showed 0.737percent water). THF (500 mL) was added, concentrated to 2.x. solution (KF=0.158percent). THF addition-concentration sequence was repeated to give a 2.x. solution (KF=0.023percent) which used directly in the next step.Analytical samples of compounds 3 and 4 were purified by column chromatography and characterized: Compound 3: white crystals; 1H NMR (400 MHz, CDCl3) δ 7.80 (1H, d, J=2.3 Hz), 7.61 (1H, d, J=8.6 Hz), 7.58 (1H, d, J=2.5 Hz), 7.22 (1H, dd, J=8.6, 2.6 Hz), 6.27 (1H, d, J=2.5 Hz), 2.38 (3H, s); 13C NMR (100 MHz, CDCl3) δ 150.8, 140.6, 134.6, 134.1, 132.0, 129.0, 128.2, 115.4, 107.0, 13.6. Compound 4: white crystals; 1H NMR (400 MHz, CDCl3) δ 7.65 (1H, d, J=8.6 Hz), 7.62 (1H, d, J=1.5 Hz), 7.43 (1H, d, J=2.5 Hz), 7.35 (1H, dd, J=8.6, 2.2 Hz), 6.21 (1H, s), 2.19 (3H, s); 13C NMR (100 MHz, CDCl3) δ 140.6, 140.2, 140.0, 134.1, 133.9, 130.8, 130.2, 120.7, 105.9, 11.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at 0 - 10℃; for 1.5 h; Stage #2: at -20 - 0℃; for 1.25 h; |
The above THF solution was transferred to a jacketed 3L 3-neck round bottom flask equipped with a mechanical stirrer, a temperature controller, and a nitrogen inlet. After diluting with THF (800 mL), the water content in the solution was checked by KF (0.053percent). To the above solution was added a solution of i-PrMgCl in THF (Aldrich 2 M, 286 mL, 0.572 mol) at 0-10° C. over 1 hours. The resulting solution was stirred for 30 minutes at 10° C. (GC showed the completion of magnesium-bromine exchange reaction). Ethyl trifluoroacetate (74 mL, 0.620 mol) was then added to the Grignard solution between -20 and -10° C. over 45 minutes, slowly warmed to 0° C., and stirred for 30 minutes at the same temperature. The reaction mixture was poured into 2 N HCl (300 mL) at 0° C., and stirred for 30 minutes at room temperature. The organic layer was diluted with MTBE (500 mL), and washed with brine (250 mL) followed by water (250 mL). Solution assay of organic layer was carried out using GC (Compound 5: 67percent solution yield, the corresponding regioisomer 6 was present at about 20percent relative to 5). The solution was then concentrated under vacuum to 2.x. solution. To remove water, THF (500 mL) was added, and evaporated to 2.x. solution. THF addition-concentration was repeated to give a 2.x. solution. Heptane (500 mL) was added, concentrated to 2.x. solution to exchange the solvent for recrystallization. Heptane (500 mL) was again added, concentrated to 3.5.x. solution.The 3.5.x. heptane solution was then transferred to a 1L 3-neck jacketed round bottom flask equipped with a mechanical stirrer, a temperature controller, and a nitrogen inlet. The solution was heated at 60° C., and the resulting homogeneous solution was slowly (1-2 h) cooled to room temperature with stirring, further cooled to 0° C. and stirred for 30 minutes at the same temperature. The crystals were collected and washed with ice-cold heptane (200 mL), dried under vacuum at 50° C. to afford a pale yellow solid (Compound 5, 85.7 g, 99percent pure by GC, 62percent yield from fluoride 1). M.p.: 83° C. (DSC onset temperature) 1H NMR (400 MHz, CDCl3) δ 7.85 (1H, d, J=2.5 Hz), 7.48 (1H, d, J=1.7 Hz), 7.38 (1H, d, J=8.3 Hz), 7.31 (1H, dd, J=8.1, 1.8 Hz), 6.33 (1H, d, J=2.5 Hz), 2.30 (3H, s); 13C NMR (100 MHz, CDCl3) δ 184.2 (q, JC-F=36.6 Hz), 151.7, 138.7, 138.5, 130.7, 126.4, 125.7, 124.5, 116.8, 116.1 (q, JC-F=289.8 Hz), 109.7, 13.0; 19F NMR (376 MHz, CDCl3) δ=-76.8 (s). |
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