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CAS No. : | 871332-95-5 | MDL No. : | MFCD08056360 |
Formula : | C7H5BClNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PRPLADNLEYNYFZ-UHFFFAOYSA-N |
M.W : | 181.38 | Pubchem ID : | 44119831 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 45.99 |
TPSA : | 64.25 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.58 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 1.17 |
Log Po/w (WLOGP) : | -0.11 |
Log Po/w (MLOGP) : | 0.24 |
Log Po/w (SILICOS-IT) : | -0.12 |
Consensus Log Po/w : | 0.24 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.01 |
Solubility : | 1.79 mg/ml ; 0.00987 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.11 |
Solubility : | 1.39 mg/ml ; 0.00768 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.99 |
Solubility : | 1.86 mg/ml ; 0.0102 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.95 |
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 |
---|---|---|
40% | With sodium hydrogencarbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; tert-butyl alcohol; at 90.0℃; for 4.0h;Sealed tube; Inert atmosphere; | Methyl (S)-1-((S)-2-(5-iodo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (215 mg, 0.512 mmol), <strong>[871332-95-5]4-Chloro-3-cyanophenylboronic acid</strong> (purchased from Combiblock, 102 mg, 0.563 mmol), PdCl2(DPPF) (94 mg, 0.128 mmol) and NaHCO3 (129 mg, 1.536 mmol) were mixed in a sealable tube. Then 4 ml t-BuOH/H2O(v/v 10:1)) was added to the mixture. The resulting suspension was bubbled with a stream of nitrogen for 3 min. Then the tube was sealed and heated in a 90 C. oil-bath for 4 h with stirring. The reaction mixture was cooled to room temperature and was filtered through Celite and washed with dichloromethane. The filtrate was evaporated under vacuum. The residue was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (2*). The combined organic phases were evaporated. The residue was purified by flash silica gel column separation (EtOAc/Hexane 0-70% gradient, then 70%) to obtain 89 mg(40% yield) of ((S)-1-{(S)-2-[5-(4-Chloro-3-cyano-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester as light brown powder. ESI-LCMS m/e calcd. for C21H24ClN5O3 429.2 [M+], found 430.0 [M+H+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With potassium fluoride; tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 100.0℃; for 6.0h; | To 100.0 mg (0.16 mmol) tert-butyl 4-{3-[(3R)-3-[1-(5-bromopyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 8c) in 4 ml toluene were added 3.8 mg tetrakis(triphenylphosphine)palladium(0), 35.7 mg (0.20 mmol) (4-chloro-3-cyano-phenyl)boronic acid in 1.0 ml ethanol and 29.6 mg (0.51 mmol) potassium fluoride in 1.0 ml water. The mixture was stirred at 100 C for 6 hours, diluted with water and saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-95/5-90/10) gave 44 mg (36 %) tert-butyl 4-{3-[(3R)-3-({1-[5-(4-chloro-3-cyanophenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate. UPLC (ACN-HCOOH): Rt. = 1.27 min MS (ES+): m/e = 668.6 ( M+H+) MS (ES-): m/e = 664.5 (M - H), 710.5 (M + HCOO-) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47.6% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 50.0℃; | P)-perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (5.66 g, 9.52 mmol), <strong>[871332-95-5](4-chloro-3-cyanophenyl)boronic acid</strong> (1.900 g, 10.48 mmol), potassium carbonate (3.95 g, 28.6 mmol), and Pd(PPh3)4 (1.101 g, 0.952 mmol) were combined in 1,4-dioxane (35.7 ml) and water (11.91 ml). The reaction was heated to 50 C. overnight at which point it was cooled to RT and water was added. The product was extracted with DCM (*3), dried via phase separator and concentrated in vacuo. The crude material was purified via MPLC, eluting with 0-100% ethyl acetate in heptanes (with a 10% DCM additive) to yield product as a dark brown oily solid. To remove some of the impurities, the material was dissolved in DCM and loaded onto a 50-g SCX-2 column. (P)-perfluorophenyl 1-(4'-chloro-3'-cyano-2-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (2.95 g, 4.53 mmol, 47.6% yield) eluted off with the methanol wash as a light yellow solid after concentration in vacuo. m/z (ESI) 651.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); potassium carbonate; In tetrahydrofuran; at 90.0℃; for 18.0h; | Degassed THF (2 mL) was added to a mixture of methyl 4-bromo-1-(4-bromo-5- (isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate (75.0 mg, 0.165 mmol), (4- chloro-3-cyanophenyl)boronic acid (30 mg, 0.16 mmol), [1,1?-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) (8.2 mg, 0.016 mmol) and potassium carbonate (114 mg, 0.824 mmol). The reaction mixture was heated at 90 oC for 18 hours. Water was added and the mixture was extracted with ethyl acetate (2x). The combined organic layers were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel using a solution of ethyl acetate in hexanes (2 to 5%) to give the title compound (35 mg, 0.068 mmol, 42%) as a pale orange oil |
42% | With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); potassium carbonate; In tetrahydrofuran; at 90.0℃; for 18.0h; | Degassed THF (2 mL) was added to a mixture of methyl 4-bromo-l-(4-bromo-5- (isopropylthio)thiazol-2-yl)-3-methyl- 1 H-pyrazole-5-carboxylate (75.0 mg, 0.165 mmol), (4- chloro-3-cyanophenyl)boronic acid (30 mg, 0.16 mmol), [1 ,1?-Bis(di-teit- butylphosphino)ferrocene]dichloropalladium(ll) (8.2 mg, 0.016 mmol) and potassium carbonate (114 mg, 0.824 mmol). The reaction mixture was heated at 90 00 for 18 hours. Water was added and the mixture was extracted with ethyl acetate (2x). The combined organic layers were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel using a solution of ethyl acetate in hexanes (2 to 5%) to give the title compound (35 mg, 0.068 mmol, 42%) as a pale orange oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With pyridine; copper diacetate; In dichloromethane; at 40.0℃; for 18.0h; | (4-Chloro-3-cyanophenyl)boronic acid (287 mg, 1.58 mmol), lH-imidazole (215 mg, 3.16 mmol), copper (II) acetate (632 mg, 3.48 mmol) and pyridine (0.64 ml, 7.90 mmol) were combined in DCM (16 ml) and heated open vessel at 40C for 18 h. The reaction mixture was cooled to rt and filtered through a celite pad, washing through with DCM. The filtrate was evaporated and purified by flash column chromatography (0-50 % EtOAc in hexane) to give 2-chloro-5-(lH-imidazol-l-yl)benzonitrile (64 mg, 20 %). LCMS (Method R): rt 2.00 min, m/z 204 [M+H]+; NMR (400 MHz, CDC13) delta ppm 7.88 (br s, 1H), 7.72 (d, 1H), 7.66 (d, 1H), 7.59 (dd, 1H), 7.25-7.30 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18.2% | With potassium phosphate; bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); In 1,4-dioxane; water; at 80.0℃; for 1.0h;Inert atmosphere; Sealed tube; Microwave irradiation; | A vial was charged with f^^cj-l-(4-bromo-5-fluoro-2-methoxypheny 1)-N-(isoxazol-3-yl)-2-oxo-l,2,7,84etrahydro-l,6-naphthyridine-6(5H)-sulfonamide (See Example 15, step 1, 64.2 mg, 0.129 mmol), <strong>[871332-95-5](4-chloro-3-cyanophenyl)boronic acid</strong> (Aururm Pharmatech, 46.6 mg, 0.26 mmol), l,l-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (9.10 mg, 0.013 mmol), and potassium phosphate (82 mg, 0.386 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (514 |xL) and water (129 |xL) were added. The vial was sealed and heated to 80 C for 1 h in a Biotage Initiator microwave reactor. LCMS showed a mix of product, over-coupling, and something else. The organic layer was separated, and the aq. layer was diluted with 2N aq. HCI and extracted with EtOAc (2x) and 10% MeOH/EtOAc. The combined organic extracts were concentrated. The residue was concentrated from MeOH, then taken up in MeOH and filtered. The filtrate was concentrated. The residue was purified by chromatography on silica gel (25-g SNAP Ultra column with 2070% of a 3:1 EtOAc/EtOH mixture in heptane with 10% DCM) to give 30 mg of a solid. The material was dissolved in MeOH and purified by reverse-phase HPLC (25-70% CH3CN/H2Owith 0.1% TFA). Fractions containing the desired product were combined with saturated aq. sodium bicarbonate solution and extracted with DCM (3x). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to give (rac)-1-(4'-chloro-3'-cyano-2-fluoro-5-methoxy-[1,1'-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2,7,8-tetrahydro-1,6-naphthyridine-6(5H)-sulfonamide (13 mg, 0.02 mmol, 18.2 % yield) as an off-white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; acetonitrile; at 95.0℃; for 6.0h;Inert atmosphere; | <strong>[871332-95-5]4-Chloro-3-cyanophenylboronic acid</strong> (1.94 g, 10.7 mmol), PdCl2(dppf).CH2Cl2 (218 mg, 0.270 mmol) and K2CO3 (2.5 M aq. solution, 6.42 mL, 16.0 mmol) were added to a solution of bromide compound Intermediate A1 (1.00 g, 5.35 mmol) in CH3CN (2 mL) under Ar atmosphere. The reaction mixture was stirred at 95 C. for 6 h. The reaction mixture was filtered (to remove water) and the solid was dissolved in CHCl3:iPrOH (2:1) solution. After filtration the solution was concentrated. The residue was purified on ISCO (0-10% MeOH in CH2Cl2) to provide the desired product (480 mg, 37% yield): 1H NMR (400 MHz, MeOH-d4) delta 8.08 (t, J=2.2 Hz, 1H), 7.94 (dd, J=2.2, 8.6 Hz, 1H), 7.58 (d, J=8.6 Hz, 1H), 7.56 (s, 1H), 4.08 (t, J=7.1 Hz, 2H), 2.89 (t, J=7.0 Hz, 2H), 2.65 (pent, J=7.6 Hz, 2H); LC-MS, >98% (215, 254 nm), Rt=0.688, m/z=244.1 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12.6 g | at 20.0℃; for 24.0h;Molecular sieve; | A suspension of 10.0 g (55.1 mmol) of <strong>[871332-95-5](4-chloro-3-cyanophenyl)boronic acid</strong>, 6.52 g (55.1 mmol) of pinacol and molecular sieves were stirred at room temperature for 24 h. The reaction solution was filtered over celite and the solvent was removed under reduced pressure. The residue was purified chromatographically by MPLC on silica gel (gradient: ethyl acetate/cyclohexane 0:100-50:50). 12.6 g of 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile were thus obtained. HPLC-MSa): log P=4.19, mass (m/z)=264 [(M+H)]+ 1H-NMR (400 MHz. d6-DMSO): delta=8.065 (0.8); 8.062 (0.9); 7.953 (0.5); 7.950 (0.4); 7.933 (0.6); 7.929 (0.6); 7.786 (0.9); 7.765 (0.7); 3.320 (8.9); 2.512 (3.7); 2.507 (8.0); 2.503 (11.4); 2.498 (8.7); 2.494 (4.3); 1.311 (16.0); 0.000 (0.7). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.57 g | With sodium hydrogencarbonate; In 1,4-dioxane; water; at 80.0℃; for 16.0h;Inert atmosphere; | 21.7 ml of a saturated aqueous sodium hydrogencarbonate solution were added to a solution of 2.0 g (3.9 mmol) of 1-[2,6-dichloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)phenyl]-4-iodo-1H-pyrazole and 0.83 g (4.6 mmol) of (4-chloro-3-cyanophenyl)boric acid in 65 mL of dioxane under argon. The reaction mixture was stirred at 80 C. for 16 h. The organic solvent was removed under reduced pressure and the aqueous phase was extracted repeatedly with ethyl acetate. The combined organic phases were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was separated chromatographically by MPLC on silica gel (gradient: ethyl acetate/cyclohexane 0:100-20:80). 1.57 g of 2-chloro-5-{1-[2,6-dichloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)phenyl]-1H-pyrazol-4-yl}benzonitrile were thus obtained. HPLC-MSa): log P=5.3, mass (m/z)=518 [(M+H)]+. 1H-NMR (400 MHz, d6-DMSO): 8.107 (9.7); 7.886 (10.1); 7.842 (5.8); 7.837 (6.2); 7.751 (16.0); 7.722 (2.9); 7.717 (2.7); 7.701 (3.8); 7.696 (3.6); 7.570 (6.3); 7.548 (4.7); 7.263 (15.7); 5.301 (0.6); 2.045 (0.6); 1.592 (20.7); 1.259 (0.4); 0.000 (14.8); -0.001 (14.2). |
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