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CAS No. : | 850593-06-5 | MDL No. : | MFCD07363785 |
Formula : | C7H8BFO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QQPLHUGOUZKARP-UHFFFAOYSA-N |
M.W : | 153.95 | Pubchem ID : | 19261265 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 41.19 |
TPSA : | 40.46 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 : | No |
Log Kp (skin permeation) : | -6.32 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 1.29 |
Log Po/w (WLOGP) : | 0.23 |
Log Po/w (MLOGP) : | 1.05 |
Log Po/w (SILICOS-IT) : | 0.12 |
Consensus Log Po/w : | 0.54 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.94 |
Solubility : | 1.75 mg/ml ; 0.0114 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.74 |
Solubility : | 2.8 mg/ml ; 0.0182 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.94 |
Solubility : | 1.77 mg/ml ; 0.0115 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.77 |
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 Pd(2-[2-(benzylthio)phenyliminomethyl]-4-bromophenol-(H))Cl; potassium carbonate; In N,N-dimethyl-formamide; at 90.0℃; for 5.0h;Sealed tube; Inert atmosphere; | General procedure: A sealed tube was charged with sulfenyl chloride 2a (219mg, 1 mmol), phenylboronic acid (3a) (135 mg, 1 mmol),K2CO3 (254 mg, 2 mmol), catalyst 1a (2 mol%, 10 mg) andDMF (2 mL). The mixture was stirred at 90 C under an N2atm for 5 h. After completion of the reaction, the mixturewas cooled to r.t. and extracted with EtOAc (2 × 10 mL). The combined extracts were dried over anhydrous Na2SO4,filtered and the solvent removed under reduced pressure.The crude residue was purified by flash chromatographyover silica gel to provide product 4a (166 mg, 89%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21.72% | With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); caesium carbonate; copper(l) chloride; In 1,4-dioxane; at 50.0℃; for 1.0h;Inert atmosphere; | A 40-mL vial containing (P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (200 mg, 0.405 mmol), <strong>[850593-06-5](3-fluoro-5-methylphenyl)boronic acid</strong> (249 mg, 1.618 mmol), cesium carbonate (659 mg, 2.023 mmol), copper(I) chloride (160 mg, 1.618 mmol), and 1,1-bisR[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (57.3 mg, 0.081 mmol) was flushed with N2 and subsequently charged with dioxane (2 mL). After stirring for 1 h, the reaction was cooled to rt, quenched with 1 N HCl, and extracted thrice with EtOAc. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to an orange oil. Column chromatography (12 g Redisep Gold column, 0-80% [3:1 EtOAc/EtOH]/hept gradient with 10% DCM) afforded (P)-1-(2,3'-difluoro-5-methoxy-5'-methyl-4-biphenylyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide (46 mg, 0.088 mmol, 21.72% yield) as a white amorphous solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 2.44 (s, 3 H) 3.75 (s, 3 H) 6.46 (d, J=1.76 Hz, 1 H) 6.82 (d, J=9.64 Hz, 1 H) 6.88 (d, J=8.91 Hz, 1 H) 7.14-7.21 (m, 1 H) 7.32-7.43 (m, 3 H) 7.53 (d, J=10.37 Hz, 1 H) 7.87 (dd, J=8.97, 2.23 Hz, 1 H) 8.24 (d, J=9.64 Hz, 1 H) 8.39 (d, J=2.28 Hz, 1 H) 8.74 (d, J=1.76 Hz, 1H) 11.67 (s, 1 H). m/z (ESI) 524.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.0% | With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); potassium carbonate; In 1,4-dioxane; water; at 100.0℃; for 2.0h;Sealed tube; Inert atmosphere; | To a mixture of [1-(3-chloro-6-methoxy-[1,5]naphthyridin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (1.0 g, 2.53 mmol), <strong>[850593-06-5]3-fluoro-5-methylphenylboronic acid</strong> (0.78 g, 5.06 mmol), Pd[t-Bu2P(4-NMe2C6H4)]2Cl2) (0.21 g, 0.25 mmol), and K2CO3 (1.05 g, 7.59 mmol) in a sealed tube was added dioxane (20 mL) and water (2 mL). The reaction mixture was bubbled with N2 for 10 min and then heated at 100 C. for 1 hr. Due to unreacted starting material, the reaction was continued to heat at 100 C. for 1 hr after more <strong>[850593-06-5]3-fluoro-5-methylphenylboronic acid</strong> (0.78 g, 5.06 mmol), Pd[t-Bu2P(4-NMe2C6H4)]2Cl2) (0.211 g, 0.253 mmol), and K2CO3 (1.049 g, 7.590 mmol) were added. The mixture was concentrated and purified by silica gel column chromatography and and then C18 reversed-phase column chromatography. Pure fractions were combined, basified with saturated NaHCO3 (aq) and concentrated to remove MeCN. The solid from aqueous residue was collected by vacuum filtration and washed with water to afford the title compound (0.8 g, 68.0% yield) as a light yellow solid. MS (M+H)+=467.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
118 mg | With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); potassium carbonate; In 1,4-dioxane; at 100.0℃; for 1.0h;Inert atmosphere; | Step 7-3, preparation of {1-[6-(3-cyano-5-fluoro-2-methoxymethoxy-phenyl)-3-(3-fluoro-5-methyl-phenyl)-quinolin-4-yl]-azetidin-3-ylmethyl}-carbamic acid tert-butyl ester: to a dioxane (3 mL) solution of {1-[3-chloro-6-(3-cyano-5-fluoro-2-methoxymethoxy-phenyl)-quinolin-4-yl]-azetidin-3-ylmethyl}-carbamic acid tert-butyl ester (0.3 mmol, 160 mg) was added Pd[t-Bu2P(4-NMe2C6H4)]2Cl2) (0.2 eq., 0.06 mmol, 42 mg), 3-fluoro-5-methylphenyl boronic acid (4.0 eq., 1.2 mmol, 186 mg) and K2CO3 (5.0 eq., 1.5 mmol, 207 mg). N2 was bubbled through the reaction solution for 5 min and 0.3 mL water was added. The resulting mixture was heated at 100 C. for 1 h and LCMS analysis showed that starting material was completely consumed. The reaction solution was diluted with ethyl acetate (20 mL) and washed with brine. The organic layer was dried with Na2SO4, filtered and concentrated. The residue obtained was purified by silica gel chromatography eluting with ethyl acetate/hexane (0?50%) to give 118 mg of the desired product as yellow foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
314 mg | With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); potassium carbonate; In 1,4-dioxane; water; at 100.0℃; for 1.0h;Inert atmosphere; | to a dioxane (10 mL) solution of 3-[3-chloro-4-(3-hydroxymethyl-azetidin-1-yl)-quinolin-6-yl]-5-fluoro-2-methoxymethoxy-benzonitrile (1.065 mmol, 456 mg) was added Pd[t-Bu2P(4-NMe2C6H4)]2Cl2) (0.2 eq., 0.21 mmol, 151 mg), 3-fluoro-5-methylphenyl boronic acid (3.0 eq., 3.2 mmol, 492 mg) and K2CO3 (5.0 eq., 5.3 mmol, 735 mg). N2 was bubbled through the reaction solution for 5 min and 1.0 mL water was added. The resulting mixture was heated at 100 C. for 1 h and LCMS analysis showed that starting material was fully consumed. The reaction solution was diluted with ethyl acetate (40 mL) and washed with brine. The organic layer was dried with Na2SO4, filtered and concentrated. The residue obtained was purified by silica gel chromatography eluting with ethyl acetate/dichloromethane (0?85%) to give 314 mg of the desired product as yellow foam. MS (M+H)+=502.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With potassium phosphate; bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); In water; toluene; at 100.0℃; for 10.0h;Inert atmosphere; | to a 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-[cis-1-[3-chloro-6-(3-fluoro-2-formylphenyl)quinolin-4-yl]-3-hydroxypiperidin-4-yl]carbamate (100 mg, 0.20 mmol, 1.00 equiv), <strong>[850593-06-5](3-fluoro-5-methylphenyl)boronic acid</strong> (62 mg, 0.40 mmol, 2.00 equiv), Pd(amphos)Cl2 (9 mg, 0.05 equiv), K3PO4 (65 mg, 0.31 mmol, 3.00 equiv), toluene/H2O (2 mL). The resulting solution was stirred for 10 h at 100 C. and then concentrated under vacuum. The residue was purified by a silica gel column eluting with ethyl acetate/petroleumether (1:3) yielding 60 mg (52%) of the title compound as a light yellow solid. MS (M+1)+=574.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.3% | With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); potassium carbonate; In 1,4-dioxane; water; at 100.0℃; for 2.0h;Sealed tube; Inert atmosphere; | To a mixture of tert-butyl N-[l-(5-chloro- 3-hydroxypyridazin-4-yl)piperidin-4-yl]carbamate (4.00 g, 12.17 mmol), (3-fluoro-5- methylphenyl)boronic acid (3.748 g, 24.34 mmol), Pd[t-Bu2P(4- Me2C6H4)]2Cl2) (0.86 g, 1.22 mmol), and K2C03 (5.41 g, 39.12 mmol) in a sealed tube was added dioxane (40 mL) and water (4.0 mL). The mixture was bubbled with N2 (g) for 10 min and then heated at 100C for 2 hrs. The mixture was concentrated in vacuo to dryness and purified by silica gel column chromatography to afford the title compound (2.81 g, 57.3 % yield) as an off-white solid. MS (M+H)+= 403.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; In tetrahydrofuran; water; at 30.0℃; for 2.0h;Inert atmosphere; | into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed benzyl N-[l-(2-amino-5-bromo- 3-formylpyridin-4-yl)piperidin-4-yl]carbamate (3.9 g, 9.00 mmol, 1.00 equiv), (3-fluoro-5- methylphenyl)boronic acid (2.8 g, 18.19 mmol, 2.00 equiv), Pd2(dba)3 (200 mg, 0.22 mmol, 0.02 equiv), t-Bu3P (400 mg), K3P04 (5.7 g, 3.00 equiv), THF (50 mL), waterQO mL). The resulting solution was stirred for 2 hrs at 30 C, diluted with 200 mL of H20 and then extracted with 3x200 mL of ethyl acetate. The organics were dried over anhydrous sodium sulfate. After filtration to remove the solids, the solution was concentrated under vacuum and the resulted crude was purified by silica gel column chromatography eluted with ethyl acetate/petroleum ether (3 : 1 to yield 3.1 g (74%) of the title compound as a light yellow solid. MS (M+H)+= 463.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; potassium phosphate; tri tert-butylphosphoniumtetrafluoroborate; In water; toluene; at 80.0℃; for 2.0h;Inert atmosphere; | into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-[l-[5- bromo-3-formyl-2-(methylsulfanyl)pyridin-4-yl]piperidin-4-yl]carbamate (1.0 g, 2.32 mmol, 1.00 equiv), <strong>[850593-06-5](3-fluoro-5-methylphenyl)boronic acid</strong> (546 mg, 3.55 mmol, 1.50 equiv), K3PO4 (1.5 g, 7.07 mmol, 3.00 equiv), Pd2(dba)3.CHCl3 (240 mg, 0.10 equiv), P(t-Bu)3.BHF4 (135 mg, 0.20 equiv), toluene (15 mL), water (1.5 mL). The resulting solution was stirred for 2 hrs at 80 C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether which resulted in 700 mg (66%) of the title compound as a yellow solid. MS (M+H)+= 460.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
240 mg | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; In water; toluene; at 70.0℃; for 2.0h;Inert atmosphere; | under N2, in toluene (10 ml), tert- butyl N-[l-[5-bromo-3-formyl-2-(morpholin-4-yl)pyridin-4-yl]piperidin-4-yl]carbamate (280 mg, 0.60 mmol, 1.00 equiv), <strong>[850593-06-5](3-fluoro-5-methylphenyl)boronic acid</strong> (275 mg, 1.79 mmol, 3.00 equiv), Pd2(dba)3 (30 mg, 0.03 mmol, 0.05 equiv), P(t-Bu)3 (60 mg), water (1 mL), and K3P04 (379 mg, 3.00 equiv) were mixed and stirred for 2 h at 70 C and then cooled to room temperature. The crude was extracted with ethyl acetate, dried and concentrated. The residual was purified via silica gel chromatography eluted with ethyl acetate/petroleum ether to afford the title compound as a light yellow solid (240 mg). MS: [M+H] += 449.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; toluene; at 80.0℃; for 2.0h;Inert atmosphere; | a mixture of tert-butyl N-[l-(5-bromo-3- formyl-2-methylpyridin-4-yl)piperidin-4-yl]carbamate (50 mg, 0.13 mmol), (3-fluoro-5- methylphenyl)boronic acid (58 mg, 0.38 mmol), Pd(dppf)Cl2 (10 mg, 0.01 mmol), K2C03 (52 mg, 0.38 mmol, 3.00 equiv), toluene (1 mL), H20 (0.1 mL) was stirred for 2 hrs at 80 C under an inert atomsphere. The resulting mixture was concentrated and purified via a silica gel column, eluted with ethyl acetate/petroleum ether to afford tert-butyl N-[l-[5-(3-fluoro-5- methylphenyl)-3-formyl-2-methylpyridin-4-yl]piperidin-4-yl]carbamate as a yellow solid (30 mg). MS: [M+H] += 428.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); potassium carbonate; In 1,4-dioxane; water; at 80.0℃; for 1.2h;Inert atmosphere; Sealed tube; | A mixture of tert-butyl N-[l-(2-amino-5- bromo-3-formylpyridin-4-yl)piperidin-4-yl]carbamate (1.6 g, 4.0 mmol), 3-fluoro-5- methylboronic acid (1,0 g, 1.7 eq.), PdCl2(t-Bu2PPhNMe2)2 (280 mg, 0.4 mmol), and K2C03 (1.1 g, 2 eq.) in dioxane/H20 (10/1 = 20 mL/2.0 mL) was degassed with N2 for 5 min, and then sealed. The reaction mixture was stirred for 1.2 h at 80 C and cooled to room temperature. The reaction was filtered through a pad of celite, and the volatile solvent was removed under vacuum. The residue was purified by column chromatography to afford the title compound (1.35 g, 79 %). MS (M+H)+ = 429.4. |
5 g | With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; potassium phosphate; water; tri tert-butylphosphoniumtetrafluoroborate; In toluene; at 70.0℃; for 2.0h;Inert atmosphere; | Step 1-5, preparation of tert-butyl N-{1-[2-amino-5-(3-fluoro-5-methylphenyl)-3-formylpyridin-4-yl]piperidin-4-yl}carbamate into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-{1-(2-amino-5-bromo-3-formylpyridin-4-yl)piperidin-4-yl}carbamate (5.0 g, 12.5 mmol, 1.0 equiv), <strong>[850593-06-5](3-fluoro-5-methylphenyl)boronic acid</strong> (2.9 g, 18.8 mmol, 1.5 equiv), Pd2(dba)3HCCl3 (1.3 g, 1.4 mmol, 0.10 equiv), K3PO4 (8.0 g, 37.7 mmol, 3.00 equiv), P(t-Bu)3HBF4 (1.1 g, 0.3 equiv), toluene (50 mL), water (5 mL). The resulting solution was stirred for 2 hrs at 70 C., and then was concentrated under vacuum. The residue was chromatographied on a silica gel column eluted with ethyl acetate/petroleum ether (1:2) resulting in the title compound as a brown solid (5.0 g). MS [M+H]=429.2. H-NMR (300 MHz, DMSO-d6, ppm): delta 10.02 (s, 1H), 7.87 (s, 1H), 7.65 (br, 1H), 7.02 (d, J=9.6 Hz, 1H), 6.96-6.77 (m, 3H), 3.25 (s, 1H), 3.10 (d, J=12.5 Hz, 2H), 2.77 (t, J=11.6 Hz, 2H), 2.38 (s, 3H), 1.65-1.61 (m, 2H), 1.44-1.37 (m, 11H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); potassium carbonate; In 1,4-dioxane; water; at 75.0℃; for 1.5h;Inert atmosphere; Sealed tube; | A mixture of tert-butyl N-[l-(2-amino- 5-bromopyridin-4-yl)piperidin-4-yl]carbamate (0.11 g, 0.29 mmol), 3-fluoro-5- methylboronic acid (91 mg, 2.0 eq.), PdCl2(t-Bu2PPh Me2)2 (21 mg, 0.03 mmol), and K2C03 (82 mg, 2 eq.) in dioxane/H20 (10/1 = 3 mL/0.3 mL) was degassed with N2 for 5 min, and then sealed. The reaction mixture was stirred for 1.5 h at 75 C and cooled to room temperature. The reaction was filtered through a pad of celite, and the volatile solvent was removed under vacuum. The residue was purified by column chromatography to afford the title compound (0.1 g, 83 %). MS (M+H)+ = 401.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); potassium carbonate; In 1,4-dioxane; at 90.0℃; for 2.0h;Inert atmosphere; Sealed tube; | A mixture of the material obtained from the above step, <strong>[850593-06-5]3-fluoro-5-methylphenylboronic acid</strong> (30 mg), Pd (0694) (amphos)Cl? (5 mg), K2C03 (30 mg) was bubbled with N2 for 10 min and then heated at 90C in dioxane (1 ml) under sealed condition for 2 hrs, then extracted with ethyl acetate. The organic layer was separated, concentrated and used for next step without further purification. MS (M+l)+: 582.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.45 g | With tris-(dibenzylideneacetone)dipalladium(0); potassium phosphate monohydrate; tri tert-butylphosphoniumtetrafluoroborate; In tetrahydrofuran; water; for 2.08333h;Sealed tube; | to 6-chloro-3-trifluoromethanesulfonyloxy-quinoline-4-carboxylic acid methyl ester (1.85 g, 5.0 mmol), <strong>[850593-06-5]3-fluoro-5-methylphenylboronic acid</strong> (1.16 g, 7.5 mmol), K3P04.H20 (2.3 g, 10 mmol), Pd2dba3/t-Bu3P (1/1.2, 276 mg, 0.21 mmol ) in THF/water (20 ml/2 ml) for 5 min. The mixture was sealed and stirred for 2 hrs. The crude was extracted with ethyl acetate, then washed with brine, and concentrated. The resulted oil was purified by silica gel column chromatography eluted with hexane/ethyl acetate to yield the desired compound (1.45g). MS (M+H)+: 330.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23 mg | With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); potassium carbonate; In 1,4-dioxane; water; at 100.0℃; for 1.5h;Inert atmosphere; | to a dioxane solution (1.5 mL) of benzyl N-{ l-[l-(3-bromo-5-formylpyridin-4-yl)azetidin-3-yl]-2-hydroxyethyl}carbamate (1.0 equiv, 0.10 mmol, 47 mg) was added Pd(Amphos)Cl2(0.15 equiv, 0.015 mmol, 11 mg), 3-fluoro-5-methylphenyl boronic acid (3.0 equiv, 0.30 mmol, 50 mg) and K2C03(3.0 equiv, 0.30 mmol, 42 mg). N2was bubbled through the reaction solution for 5 min and 0.15 mL water was added. The resulting mixture was heated at 100 C for 1.5 hrs and LCMS analysis showed that starting material was completely consumed. The reaction solution was concentrated with silica gel and the residue obtained was applied onto a silica gel chromatography eluting with ethyl acetate/hexane(0-100%) to give 23 mg of the desired product. MS (M+H)+= 464.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100.0℃; for 1.0h;Inert atmosphere; | to a dioxane solution (2.0 mL) of benzyl N-{ l-[l-(3- bromo-5-formylpyridin-4-yl)azetidin-3-yl]propyl}carbamate (1.0 equiv, 0.19 mmol, 81 mg) was added Pd(dppf)Cl2(0.20 equiv, 0.038 mmol, 28 mg), 3-fluoro-5-methylphenyl boronic acid (3.0 equiv, 0.57 mmol, 96 mg) and K2C03(5.0 equiv, 0.95 mmol, 130 mg). N2was bubbled through the reaction solution for 5 min and 0.20 mL water was added. The resulting mixture was heated at 100 C for 1 h and LCMS analysis showed that starting material was completely consumed. The reaction solution was concentrated and the residue obtained was purified by silica gel chromatography eluting with ethyl acetate/dichlorom ethane (0-100%) to give 20 mg of the title compound. MS (M+H)+= 462.4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; potassium phosphate; tri tert-butylphosphoniumtetrafluoroborate; In 1,4-dioxane; water; at 70.0℃; for 1.0h;Inert atmosphere; | to a 250-mL round-bottom flask was placed tert-butyl N- [[l-(3-bromo-5-formylpyridin-4-yl)azetidin-3-yl]methyl]carbamate (1.0 equiv, 5.4 mmol, 2 g), 3- fluoro-5-methylphenyl)boronic acid (1.2 equiv, 6.5 mmol, 1.0 g), K3P04(3.0 equiv,), 22.1 mmol , 4.7 g), Pd2(dba)3CHCl3(0.05 equiv, 0.27 mmol, 280 mg ), P(t-Bu)3HBF4(0.10 equiv, 0.54 mmol, 157 mg), l,4-dioxane (20 mL) and water (2.0 mL). The resulting solution was purged with nitrogen and stirred at 70 C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether to afford 2.1 g (97%) of tert-butyl N-([l-[3-(3-fluoro-5-methylphenyl)-5- formylpyridin-4-yl]azetidin-3-yl]methyl)carbamate as a yellow solid. LCMS (M+H)+= 400.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83 mg | With tris-(dibenzylideneacetone)dipalladium(0); potassium phosphate monohydrate; tri tert-butylphosphoniumtetrafluoroborate; In tetrahydrofuran; water; at 20.0℃; for 2.58333h;Inert atmosphere; | to a THF (4.0 mL) solution of benzyl N-[l-(3- bromo-5-formylpyridin-4-yl)-3-hydroxyazetidin-3-yl]methyl}carbamate (1.0 equiv, 0.41 mmol, 172 mg) and 3-fluoro-5-methylphenyl boronic acid (3.0 equiv, 1.23 mmol, 189 mg) was added tris(dibenzylideneacetone)dipalladium/tri-tert-butyl phosphonium tetrafluorob orate mixture (mole ratio: 1/1.2) complex (0.05 equiv, 0.021 mmol, 27 mg) and K3PO4 20 (3.0 equiv, 1.23 mmol, 282 mg). N2was bubbled through the reaction solution for 5 min and 0.4 mL of water was added. The resulting mixture was stirred at rt for 1.5 hrs and LCMS analysis showed incomplete conversion. 3-fluoro-5-methylphenyl boronic acid (3.0 equiv, 1.23 mmol, 189 mg), tris(dibenzylideneacetone)dipalladium/tri-tert-butyl phosphonium tetrafluorob orate mixture (mole ratio: 1/1.2) complex (0.05 equiv, 0.021 mmol, 27 mg) and K3RO42O (3.0 eq., 1.23 mmol, 282 mg) were added under N2.The resulting mixture was stirred at rt for 1 h and LCMS analysis showed complete consumption of starting material. The reaction solution was diluted with ethyl acetate (50 mL) and washed with water and brine. The organic layer was dried with Na2S04,filtered and concentrated. The residue obtained was purified by silica gelchromatography eluting with ethyl acetate/dichlorom ethane (0-50%) to give 83 mg of the title compound. MS (M+H)+= 450.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
560 mg | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tri-tert-butyl phosphine; water; In toluene; at 70.0℃; for 0.5h;Inert atmosphere; | Step 2-4, Preparation of tert-butyl N-[1-[2-(dimethylamino)-5-(3-fluoro-5-methylphenyl}-3-formylpyridin-4-yl]piperidin-4-yl]carbamate into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-[1-(5-bromo-2-(dimethylamino)-3-formylpyridin-4-yl]piperidin-4-yl]carbamate (550 mg, 1.29 mmol), <strong>[850593-06-5](3-fluoro-5-methylphenyl)boronic acid</strong> (396 mg. 2.57 mmol, 2.0 equiv), Pd2(dba)3 (25 mg, 0.03 mmol. 0.02 equiv), P(t-Bu)3 (50 mg), K3PO4 (817 mg, 3.85 mmol, 3.0 equiv), toluene (10 ml). water (1 mL). The resulting solution was stirred for 30 min at 70 C. The reaction mixture was cooled to rt, concentrated. The residue was chromatagraphied onto a silica gel column eluted with ethyl acetate/petroleum ether (1:1) to afford the title compound (560 mg) as a yellow solid. MS (M+H)+=457.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
250 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; water; potassium carbonate; In 1,4-dioxane; at 60.0℃; for 2.0h;Inert atmosphere; | Step 3-2, Preparation of tert-butyl N-[1-[2-chloro-5-(3-fluoro-5-methylphenyl)-3-formylpyridin-4-yl]piperidin-4-yl]carbamate Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-[1-(5-bromo-2-chloro-3-formylpyridin-4-yl)piperidin-4-yl]carbamate (250 mg, 0.60 mmol), <strong>[850593-06-5](3-fluoro-5-methylphenyl)boronic acid</strong> (92 mg, 0.60 mmol, 1.0 equiv), Pd(dppf)Cl2 (50 mg, 0.07 mmol, 0.12 equiv), K2CO3 (165 mg, 1.2 mmol, 2.0 equiv), dioxane (5 mL), H2O (0.5 mL). The resulting mixture was stirred for 2 hrs at 60 C. and then concentrated under vacuum. The residue was chromatographied on a silica gel column, eluted with ethyl acetate/petroleum ether to produce the title compound as a yellow solid (250 mg). MS [M+H]+=448.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium carbonate; In 1,4-dioxane; at 110.0℃; for 2.0h;Inert atmosphere; Sealed tube; | General procedure: A suspension of 2-bromo-3-chloro-5,5-dimethyl-2-cyclohexenone (3a, 0.5 g, 2.11 mmoles); or 3-bromo-2-chloro-5,5-dimethyl-2-cyclohexenone (3b, 0.5 g, 2.11 mmoles), aryl boronic acid (4a-i, 1.1 mmolar equivalent), K2CO3 (0.87 g, 6.32 mmoles), Pd(dppf)2Cl2 catalyst (5 mg, 0.0068 mmoles, 0.32 mol%) in 6 mL of 1,4-dioxane was taken in a 15 mL Sigma-Aldrich ace pressure tube along with a magnetic pellet. The suspension was purged over 5 minutes with nitrogen gas and sealed. The pressure tube was introduced into a pre-heated oil bath at 110 C and magnetically stirred for a period of 4 hours. Aliquots indicated the reaction to be completed within the duration of time as indicated in Table 1. The reaction was allowed to attain ambient temperature, transferred to a beaker and diluted with ethyl acetate (20 mL). The extract was filtered over a bed of CeliteVR. The filtrate was concentrated on a rotary evaporator and the crude product was purified by column chromatography using silica gel (Merck, 60-120 mesh) as the stationary phase and ethyl acetate: petroleum benzine (60-74 C) as mobile phase to isolate the compounds 2-aryl-3-chloro-5,5-dimethyl-2-cyclohexenones 5a-i and 3-aryl-2-chloro-5,5-dimethyl-2-cyclohexenones 6a-i in greater than 90% yields. The novel compounds were characterized by spectral analysis and the yields are reported in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium carbonate; In 1,4-dioxane; at 110.0℃; for 4.0h;Inert atmosphere; Sealed tube; | General procedure: A suspension of 2-bromo-3-chloro-5,5-dimethyl-2-cyclohexenone (3a, 0.5 g, 2.11 mmoles); or 3-bromo-2-chloro-5,5-dimethyl-2-cyclohexenone (3b, 0.5 g, 2.11 mmoles), aryl boronic acid (4a-i, 1.1 mmolar equivalent), K2CO3 (0.87 g, 6.32 mmoles), Pd(dppf)2Cl2 catalyst (5 mg, 0.0068 mmoles, 0.32 mol%) in 6 mL of 1,4-dioxane was taken in a 15 mL Sigma-Aldrich ace pressure tube along with a magnetic pellet. The suspension was purged over 5 minutes with nitrogen gas and sealed. The pressure tube was introduced into a pre-heated oil bath at 110 C and magnetically stirred for a period of 4 hours. Aliquots indicated the reaction to be completed within the duration of time as indicated in Table 1. The reaction was allowed to attain ambient temperature, transferred to a beaker and diluted with ethyl acetate (20 mL). The extract was filtered over a bed of CeliteVR. The filtrate was concentrated on a rotary evaporator and the crude product was purified by column chromatography using silica gel (Merck, 60-120 mesh) as the stationary phase and ethyl acetate: petroleum benzine (60-74 C) as mobile phase to isolate the compounds 2-aryl-3-chloro-5,5-dimethyl-2-cyclohexenones 5a-i and 3-aryl-2-chloro-5,5-dimethyl-2-cyclohexenones 6a-i in greater than 90% yields. The novel compounds were characterized by spectral analysis and the yields are reported in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
200 mg | With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; potassium phosphate; water; tri tert-butylphosphoniumtetrafluoroborate; In toluene; at 70.0℃; for 2.0h; | Step 6-3, Preparation of Benzyl (4alphaS,8alphaS)-6-[2-amino-5-(3-fluoro-5-methylphenyl)-3-formylpyridin-4-yl]-octahydro-1H-pyrido[3,4-b]morpholine-1-carboxylate into a 50-mL 3-necked round-bottom flask purged and maintained with nitrogen, was placed benzyl (4alphaS,8alphaS)-6-(2-amino-5-bromo-3-formylpyridin-4-yl)-octahydro-1H-pyrido[3,4-b]morpholine-1-carboxylate (300 mg, 0.63 mmol, 1.0 equiv), <strong>[850593-06-5](3-fluoro-5-methylphenyl)boronic acid</strong> (192 mg, 1.25 mmol, 2.0 equiv), Pd2(dba)3.CHCl3 (65 mg, 0.06 mmol, 0.10 equiv), P(t-Bu)3.HBF4 (37 mg, 0.13 mmol, 0.2 equiv), toluene (3 mL), water (0.3 mL), K3PO4 (402 mg, 3.0 equiv). The resulting mixture was stirred for 2 hrs at 70 C., and concentrated under vacuum after cooling to rt. The residue was chromatographied by a silica gel column eluted with ethyl acetate/petroleum ether to give the title compound as a yellow solid (200 mg). MS [M+H]+=505.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; anhydrous sodium carbonate; In water monomer; N,N-dimethyl-formamide; at 100℃; for 2h;Inert atmosphere; | General procedure: Under N2, to a solution of compound 2 (1.7 g, 10.0 mmol) in a mixture of DMF(30 mL) and H2O (5 mL) were added the appropriate compound 3 (14.0 mmol), sodiumcarbonate (2.1 g, 20.0 mmol) and Pd(dppf)Cl2 (366 mg, 0.50 mmol). The mixture wasstirred at 100 C for 2 h. The mixture was diluted with water (60 mL) and extractedwith ethyl acetate (3100 mL). The organic layer was washed with brine, dried andconcentrated under reduced pressure. The residue was purified by flash chromatography(CH2Cl2:MeOH, 20:1 - 10:1) to provide the target compound. |
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