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CAS No. : | 247940-06-3 | MDL No. : | MFCD01862441 |
Formula : | C24H31P | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LCSNDSFWVKMJCT-UHFFFAOYSA-N |
M.W : | 350.48 | Pubchem ID : | 2734216 |
Synonyms : |
2-(Dicyclohexylphosphino)biphenyl
|
Chemical Name : | 2-(Dicyclohexylphosphino)biphenyl |
Num. heavy atoms : | 25 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 0.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 114.0 |
TPSA : | 13.59 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -3.65 cm/s |
Log Po/w (iLOGP) : | 4.28 |
Log Po/w (XLOGP3) : | 6.74 |
Log Po/w (WLOGP) : | 7.13 |
Log Po/w (MLOGP) : | 6.33 |
Log Po/w (SILICOS-IT) : | 7.23 |
Consensus Log Po/w : | 6.34 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 1.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -6.35 |
Solubility : | 0.000156 mg/ml ; 0.000000446 mol/l |
Class : | Poorly soluble |
Log S (Ali) : | -6.83 |
Solubility : | 0.0000518 mg/ml ; 0.000000148 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -7.86 |
Solubility : | 0.00000487 mg/ml ; 0.0000000139 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 4.31 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | 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 |
---|---|---|
81% | With bis(η3-allyl-μ-chloropalladium(II)); potassium hydroxide In water at 100℃; Inert atmosphere | General procedure: A mixture of L1 (0.05 or 0.10 mmol of P), [PdCl(η3-C3H5)]2 (0.025mmol), arylhalides (0.55 mmol) and dicyclohexylphosphine (0.50 mmol) in 20 M KOH aqueous solution (0.5-1.0 mL) under nitrogen atmosphere was shaken for several hours at 100 °C. The mixture was cooled and filtered. After being cooled, the reaction mixture was filtered and the aqueous filtrate was extracted with degassed toluene (2 mL x 2 times). Recovered catalyst resin beads were extracted with degassed toluene (2 mL x 4 times). The combined extract was dried over anhydrous Na2SO4 and concentrated in vacuo to give a crude residue. The residue was purified by silica-gel flash chromatography to give an aryl dicyclohexylphosphine 3. Chromatographic purification was carried out with the YAMAZEN medium pressure liquid chromatograph system using degassed eluent (n-hexane/Et2O = 10/0-9/1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 100℃; for 18.67 h; | A 50 cc glass vessel was equipped with a magnetic stirring bar, a pressure gauge, a syringe loading opening, a nitrogen valve and a vacuum valve. To the glass vessel were added 3.08 g (10.2 mmol) of biphenyl-2-yl-triflate, 3.12 g (20.5 mmol) of DBU, 262.7 mg (0.50 mmol) of Ni(dppe)Cl2, 20 cc of DMF and 2.98 g (15.0 mmol) of dicyclohexylphosphine under a nitrogen atmosphere. The reaction mixture was stirred and aged overnight (18 hours and 40 minutes) in an oil bath at 100° C. under a nitrogen atmosphere.The reaction solution was concentrated, and to the residue were added 20 cc of toluene and 10 g of 5percent hydrochloric acid, followed by shaking and separating. The resulting organic layer was washed with 10 cc of water, 20 g of 2.5percent sodium bicarbonate aqueous solution and 10 cc of water in this order. The organic layer was returned to a reaction flask, followed by concentrating to obtain a colored oil. The resulting colored oil was recrystallized and purified with 20 cc of methanol to obtain colorless powders (yield amount: 2.74 g (7.82 mmol)), yield: 77percent). The resulting colorless powders were confirmed to be 2-(dicyclohexylphosphino)biphenyl, which was an intended product. The analytical results of the resulting colorless powders are shown below. Quality: GC purity 98.0percent Characteristics: GC-MS: 349, 350 (FW350.48), mp: 103.4 to 104.6° C. 1H-NMR (CDCl3); 0.95-1.30 (10H, m), 1.50-1.75 (10H, m), 1.75-1.90 (2H, m), 7.25-7.44 (8H, m), 7.56-7.74 (1H, m) 31P-NMR; -12.6 |
8 %Chromat. | With 1,4-diaza-bicyclo[2.2.2]octane In N,N-dimethyl-formamide at 100℃; for 18.67 h; | A biphenyl-2-yl phosphine compounds were obtained in the same manner as Example 1 except for changing the type of a hydrogen-phosphine compound, catalyst, base and solvent used, as shown in Table 1.In addition, in all the Examples and Comparative Examples, biphenyl-2-yl-triflate was used as a biarylsulfonate compound, and 1.5 equivalents of a hydrogen-phosphine compound and 2 equivalents of a base were used, based on biphenyl-2-yl-triflate. Further, the reaction time was set to 16 to 24 hours (overnight).In Examples 1 to 5 and Comparative Examples 1 to 3, the compounds used and the results of the reaction yield and the like are shown in Table 1. |
90 %Chromat. | With 1,8-diazabicyclo[5.4.0]undec-7-ene In water; N,N-dimethyl-formamide at 100℃; for 18.67 h; | A biphenyl-2-yl phosphine compounds were obtained in the same manner as Example 1 except for changing the type of a hydrogen-phosphine compound, catalyst, base and solvent used, as shown in Table 1.In addition, in all the Examples and Comparative Examples, biphenyl-2-yl-triflate was used as a biarylsulfonate compound, and 1.5 equivalents of a hydrogen-phosphine compound and 2 equivalents of a base were used, based on biphenyl-2-yl-triflate. Further, the reaction time was set to 16 to 24 hours (overnight).In Examples 1 to 5 and Comparative Examples 1 to 3, the compounds used and the results of the reaction yield and the like are shown in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.07 g (46%) | With cesium fluoride;palladium diacetate; In 1,4-dioxane; hexane; ethyl acetate; | Step 3: A representative procedure for the mono-phasic bis-cross coupling reaction of bis-arylhalides with boronic acids is a modification of cross coupling reactions described by Buchwald, et al (J. Am. Chem. Soc. 1998, 120, 9722-9723). 3,6-Dibromocarbazole (1.52 g, 4.69 mmol), 2.73 g (11.72 mmol) 2-ethoxycarbonylindole-5-boronic acid, and 5.34 g (35.16 mmol) CsF were dissolved in 50 mL anhydrous dioxane under argon. Pd(OAc)2 (106 mg, 0.47 mmol) and 245 mg (0.70 mmol) dicyclohexylphosphinobiphenyl were dissolved in 20 mL dioxane under argon and added to the above mixture. The resulting mixture was stirred and refluxed under argon overnight, cooled to room temperature, diluted with 200 mL EtOAc and filtered through celite. The filtrate was washed with 3*75 mL H2O. The organic phase was dried over sodium sulfate and the solvent was evaporated. The residue was purified by flash-column chromatography using hexane/EtOAc (7:3-6:4) as eluent to yield 1.07 g (46%) of 3,6-Bis(5-indolyl)carbazole-2',2'-dicarboxylic acid diethyl ester. 1H NMR-1.41 (t, J=6.9 Hz, 6H), 4.41 (q, J=7.2 Hz, 4H), 7.26 (d, J=1.8 Hz, 2H), 7.59 (s, 2H), 7.62 (s, 2H), 7.77 (m, 2H), 7.80 (m, 2H), 8.08 (d, J=0.9 Hz, 2H), 8.61 (d, J=1.2 Hz, 2H), 11.34 (s, 1H), 11.96 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | palladium diacetate; In 1,2-dimethoxyethane; | 4-(4-Methoxy-3-nitro-phenyl)-morpholine 4-Bromo-2-nitroanisol (8.5 g, 36 mmol), morpholine (3.8 ml, 44 mmol), potassium phosphate (11 g, 51 mmol), 2-biphenyl-dicyclohexyl phosphine (960 mg, 2.7 mmol) and palladium(II)acetate (411 mg, 1.8 mmol) are dissolved in dimethoxyethane (80 ml) and stirred at 80 C. for 96 hours. The mixture is then cooled to room temperature, diluted with ethyl acetate (50 ml) and filtrated through dicalite. Flash chromatography on silica (eluent dichloromethane/methanol 99:1) affords the product as red solid (6.0 g, 69%). MS: m/e=238 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroacetic acid;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; | Example 75 3-[2-(2,4-Dichloro-Phenyl)-Ethoxy]-4-Methoxy-N-(6'-Methoxy-3,4,5,6-Tetrahydro-2H-[1,3']Bipyridinyl-4-Ylmethyl)-Benzamide A mixture of 100 mg (0.2 mmol) 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-ylmethyl-benzamide, 55 mg (0.32 mmol) 5-Brom-2-methoxypyridine, 70 mg sodium-t-butoxide in 5 ml dioxane were purged with argon for 10 min. Then 37 mg of 2-(Dicyclohexylphosphino)biphenyl and 20 mg Pd2(dba)3 were added under argon and the mixture refluxed overnight. The residue was taken up in 3 ml saturated NaHCO3 solution and filtered through a chem elut cartridge by elution with ethyl acetate. Subsequent removal of the solvent under reduced pressure and purification by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.5% TFA) the fractions containing the product were evaporated and lyophilised. The product was obtained as its trifluoroacetate salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroacetic acid;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; | Example 76 3-[2-(2,4-Dichloro-Phenyl)-Ethoxy]-4-Methoxy-N-(1-Phenyl-piperidin-4-Ylmethyl)-Benzamide A mixture of 100 mg (0.2 mmol) 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-ylmethyl-benzamide, 50 mg (0.32 mmol) Bromobenzene, 70 mg sodium-t-butoxide in 5 ml dioxane were purged with argon for 10 min. Then 37 mg of 2-(Dicyclohexylphosphino)biphenyl and 20 mg Pd2(dba)3 were added under argon and the mixture refluxed overnight. The residue was taken up in 3 ml saturated NaHCO3 solution and filtered through a chem elut cartridge by elution with ethyl acetate. Subsequent removal of the solvent under reduced pressure and purification by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.5% TFA) the fractions containing the product were evaporated and lyophilised. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroacetic acid;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; | Example 74 3-[2-(2,4-Dichloro-Phenyl)-Ethoxy]-4-Methoxy-N-(1-Pyrimidin-5-Yl-Piperidin-4-Ylmethyl)-Benzamide A mixture of 100 mg (0.2 mmol) 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-ylmethyl-benzamide, 50 mg (0.32 mmol) 4-Brompyrimidine, 70 mg sodium-t-butoxide in 5 ml dioxane were purged with argon for 10 min. Then 37 mg of 2-(Dicyclohexylphosphino)biphenyl and 20 mg Pd2(dba)3 were added under argon and the mixture refluxed overnight. The residue was taken up in 3 ml saturated NaHCO3 solution and filtered through a chem elut cartridge by elution with ethyl acetate. Subsequent removal of the solvent under reduced pressure and purification by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.5% TFA) the fractions containing the product were evaporated and lyophilised. The product was obtained as its trifluoroacetate salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
124.4 g (79.6%) | With potassium dihydrogenphosphate;palladium diacetate; In toluene; | N-tert-Butyldimethylsilyl-4-(4-Boc-piperazinyl)-indole (Scheme 1) The compound was prepared according to Method 2 from N-tert-butyldimethylsilyl -4-chloroindole (100 g, 376 mmol, 1 equiv.), tert-butyl 1-piperazinecarboxylate (84 g, 451 mmol), Palladium(II) acetate (1.26 g., 5.62 mmol, 2%), 2-(dicyclohexylphosphino)biphenyl (3.95 g., 11.28 mmol, 4 mol %), tert-BuONa (50 g, 520 mmol, 1.4 equiv.) in toluene. The solution was cooled to room temperature and KH2PO4 (150 mL, 13% aqueous solution) was added and pH was adjusted (pH=8-9) followed by extraction with toluene (2*100 mL), dried (MgSO4) and evaporated. The residue was crystallized from heptane to yield 124.4 g (79.6%). 1H NMR (CDCl3) delta 7.20 (d, J=8.4 Hz, 1H), 7.13 (d, J=3.2 Hz, 1H), 7.06 (t, 1H), 6.60-6.57 (m, 2H), 3.65 (t, 4H), 3.16 (t, 4H), 1.48 (s, 9H), 0.91 (s, 9H), 0.58 (s, 6H); 13C NMR (CDCl3) delta 155.0; 145.5; 142.2; 129.9; 124.9; 122.0; 109.3; 107.2; 102.9; 79.8; 77.3; 51.5; 28.5; 26.4; 19.5; -3.8; MS (ESI) 416.4 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroacetic acid;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; | (iii) N-[1-(4-Chloro-phenyl)-piperidin-4-yl]-3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methoxy-benzamide A mixture of 100 mg 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-yl-benzamide hydrochloride (0.2 mmol), 62 mg (0.33 mmol) 4-Bromochlorobenzene, 73 mg sodium-t-butoxide in 5 ml dioxane were purged with argon for 10 min. Then 37 mg of 2-(Dicyclohexylphosphino)biphenyl and 20 mg Pd2(dba)3 were added under argon and the mixture refluxed overnight. The residue was taken up in 3 ml saturated NaHCO3 solution and filtered through a chem elut cartridge by elution with ethyl acetate. Subsequent removal of the solvent under reduced pressure and purification by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.5% TFA) the fractions containing the product were evaporated and lyophilised. The product was obtained as its trifluroacetate salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30 mg (81%) | With sodium hydroxide; triethylamine; sodium t-butanolate;palladium diacetate; In toluene; | 27.1 A mixture of 30 mg (0.091 mmol) {4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methylamine, 2 mg (0.009 mmol) Pd(OAc)2, 7 mg (0.02 mmol) (dicyclohexylphosphino)-biphenyl, 44 mg (0.46 mmol) sodium tert-butoxide, and 20 mg (0.1 mmol) 4-bromopyridine hydrochloride in 1 ml of degassed toluene was stirred in a pressure tube at 120 C. during 16 hours. After cooling to room temperature the mixture was treated with 0.5M aqueous NaOH and extracted three times with Et2O. Drying of the combined organic layers with Na2SO4, evaporation of the solvent, and column chromatography on silica gel with EtOAc/NEt3 100:3 gave 30 mg (81%) of {4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-pyridin-4-yl-amine as a light yellow oil, MS: 390 (MH+). (In analogy to L. Buchwald et al. J. Org. Chem. 2000, 65, 1158-1174). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium t-butanolate;palladium diacetate; | Preparation 1.4. [5-Cyclobutyl-2-(4-methoxy-benzyl)-2H-pyrazol-3-yl]-(6-methoxy-pyridin-2-yl)-amine Procedure A: A dry toluene solution of 5-Cyclobutyl-2-(4-methoxy-benzyl)-2H-pyrazol-3-ylamine (Preparation 1.3, 2.27 g, 8.83 mmol), 2-chloro-6-methoxy pyridine (1.06 g, 7.36 mmol), sodium tert-butoxide (1.09 g, 10.3 mmol), 2-(dicyclohexylphosphino)-biphenyl (258 mg, 0.736 mmol), and palladium acetate (165 mg, 0.736 mmol), was heated to 120 C. for an hour and then cooled to rt. The reaction was then filtered through Celite pad and the filtrate was concentrated down and chromatographed using the Biotage Flash 45S system eluding with 20% EtOAc/hexanes to give the title compound of Preparation 1.4 as a peach colored solid (2 g, 74% yield). Rf 0.25 (20% EtOAc/Hexane), 1H NMR (400 MHz, CDCl3), delta 1.82-2.00 (m, 2H), 2.11-2.34 (m, 4H), 3.45-3.66 (dddd, J=8.7, 8.7, 8.7, 8.7 Hz, 1H), 3.71 (s, 3H), 3.80 (s, 3H), 5.10 (s, 2H), 6.01-6.03 (d, 1H), 6.07 (s, 1H), 6.14-6.16 (d, 1H), 6.75-6.78 (d, J=6.65 Hz, 2H), 7.03-7.06 (d, J=8.72 Hz, 2H), 7.29-7.33 (apt, 1H). LRMS m/z (APCl+) 365 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride;palladium diacetate; In tetrahydrofuran; | A. 2-Methyl-2-(4-{2-[5-methyl-2-(2'-trifluoromethyl-biphenyl-4-yl)-oxazol-4-yl]-ethoxy}-phenoxy)propionic acid ethyl ester A solution of 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (300 mg, 0.614 mmol) (see Ex. 2, part B), 2-trifluoromethylphenylboronic acid (0.921 mmol), potassium fluoride (88.6 mg, 1.84 mmol), palladium acetate (1.3 mg, 0.14 mumol), and 2-(dicyclohexylphosphino)biphenyl (12.3 mumol) were combined under N2, to which anhydrous THF (1.23 mL) was added. The yellow mixture was heated at reflux for 12 h. After cooling to room temperature, the mixture was partitioned between Et2O (20 mL) and 1M NaOH (10 mL). The layers were separated, and the aqueous phase was back-extracted with Et2O (10 mL). Combined organic phases were dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (25 g SiO2, 1:4 ethyl acetate:hexanes) to yield the desired product as an oil. Rf=0.47 in 1:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) delta7.98 (d, J=8.4 Hz, 2H), 7.73 (d, J=7.6 Hz, 1H), 7.55 (t, J=7.6 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.32 (d, J=7.6 Hz, 1H), 6.80-6.73 (m, 4H), 4.20 (q, J=7.2 Hz, 2H), 4.17 (t, J=6.6 Hz, 2H), 2.94 (t, J=6.6 Hz, 2H), 2.35 (s, 3H), 1.50 (s, 6H), 1.24 (t, J=7.2 Hz, 3H); MS (EI) 554.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride;palladium diacetate; In tetrahydrofuran; | A. 2-(4-{2-[2-(2'-Fluoro-biphenyl-4-yl)-5-methyloxazol-4-yl]-ethoxy}-phenoxy)-2-methylpropionic acid ethyl ester A solution of 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (300 mg, 0.614 mmol) (see Ex. 2, part B), 2-fluorophenylboronic acid (0.921 mmol), potassium fluoride (88.6 mg, 1.84 mmol), palladium acetate (1.3 mg, 0.14 mumol), and 2-(dicyclohexylphosphino)biphenyl (4.3 mg, 12.3 mumol) were combined under N2, to which anhydrous THF (1.23 mL) was added. The yellow mixture was heated at reflux for 12 h. After cooling to room temperature, the mixture was partitioned between Et2O (20 mL) and 1M NaOH (10 mL). The layers were separated, and the aqueous phase was back-extracted with Et2O (10 mL). Combined organic phases were dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (25 g SiO2, 1:4 ethyl acetate:hexanes) to yield the desired product as an oil. Rf=0.48 in 1:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) delta8.01 (d, J=8.0 Hz, 2H), 7.60 (d, J=8 Hz, 2H), 7.47-7.42 (m, 1H), 7.34-7.28 (m, 1H), 7.22-7.11 (m, 2H), 6.81-6.73 (m, 4H), 4.20 (q, J=6.8 Hz, 2H), 4.17 (t, J=6.6 Hz, 2H), 2.94 (t, J=6.6 Hz, 2H), 2.35 (s, 3H), 1.50 (s, 6H), 1.24 (t, J=6.8 Hz, 3H); MS (EI) 504.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride;palladium diacetate; In tetrahydrofuran; | A. 2-(4-{2-[2-(2'-Methoxy-biphenyl-4-yl)-5-methyloxazol-4-yl]-ethoxy}-phenoxy)-2-methylpropionic acid ethyl ester A solution of 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (300 mg, 0.614 mmol) (see Ex. 2, part B), o-methoxyphenylboronic acid (140 mg, 0.921 mmol), potassium fluoride (88.6 mg, 1.84 mmol), palladium acetate (1.3 mg, 0.14 mumol), and 2-(dicyclohexylphosphino)biphenyl (4.3 mg, 12.3 mumol) were combined under N2, to which anhydrous THF (1.23 mL) was added. The yellow mixture was heated at reflux for 12 h. After cooling to room temperature, the mixture was partitioned between Et2O (20 mL) and 1M NaOH (10 mL). The layers were separated, and the aqueous phase was back-extracted with Et2O (10 mL). Combined organic phases were dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (25 g SiO2, 1:4 ethyl acetate:hexanes) to yield 100.5 mg (32%) as an oil. Rf=0.38 in 1:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) delta7.97 (d, J=8.0 Hz, 2H), 7.57 (d, J=8.0 Hz, 2H), 7.33-7.29 (m, 2H), 7.01 (t, J=7.2 Hz, 1H), 6.97 (d, J=7.6 Hz, 1H), 6.80-6.74 (m, 4H), 4.20 (q, J=7.2 Hz, 2H), 4.17 (t, J=6.8 Hz, 2H), 3.80 (s, 3H), 2.94 (t, J=6.8 Hz, 2H), 2.34 (s, 3H), 1.50 (s, 6H), 1.24 (t, J=7.2 Hz, 3H); MS (EI) 538.2 (M+Na)+, 516.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride;palladium diacetate; In tetrahydrofuran; | A. 2-Methyl-2-(4-{2-[5-methyl-2-(2'-methyl-biphenyl-4-yl)-oxazol-4-yl]-ethoxy}-phenoxy)propionic acid ethyl ester A solution of 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (300 mg, 0.614 mmol) (see Ex. 2, part B), 2-methylphenylboronic acid (0.921 mmol), potassium fluoride (88.6 mg, 1.84 mmol), palladium acetate (1.3 mg, 0.14 mumol), and 2-(dicyclohexylphosphino)biphenyl (4.3 mg, 12.3 mumol) were combined under N2, to which anhydrous THF (1.23 mL) was added. The yellow mixture was heated at reflux for 12 h. After cooling to room temperature, the mixture was partitioned between Et2O (20 mL) and 1M NaOH (10 mL). The layers were separated, and the aqueous phase was back-extracted with Et2O (10 mL). Combined organic phases were dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (25 g SiO2, 1:4 ethyl acetate:hexanes) to yield the desired product as an oil. Rf=0.44 in 1:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) delta7.99 (d, J 8.6 Hz, 2H), 7.36 (d, J 8.6 Hz, 2H), 7.26-7.21 (m, 4H), 6.81-6.74 (m, 4H), 4.20 (t, J=6.6 Hz, 2H), 4.19 (q, J=7.2 Hz, 2H), 2.94 (t, J=6.6 Hz, 2H), 2.35 (s, 3H), 2.26 (s, 3H), 1.50 (s, 6H), 1.25 (t, J=7.2 Hz, 3H); MS (EI) 500.2 (M+H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride;palladium diacetate; In tetrahydrofuran; | A. 2-(4-{2-[2-(2',6'-Difluoro-biphenyl-4-yl)-5-methyloxazol-4-yl]-ethoxy}-phenoxy)-2-methylpropionic acid ethyl ester A solution of 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}-phenoxy)-2-methylpropionic acid ethyl ester (300 mg, 0.614 mmol) (see Ex. 2, part B), 2,6-difluorophenylboronic acid (0.921 mmol), potassium fluoride (88.6 mg, 1.84 mmol), palladium acetate (1.3 mg, 0.14 mumol), and 2-(dicyclohexylphosphino)biphenyl (4.3 mg, 12.3 mumol) were combined under N2, to which anhydrous THF (1.23 mL) was added. The yellow mixture was heated at reflux for 12 h. After cooling to room temperature, the mixture was partitioned between Et2O (20 mL) and 1M NaOH (10 mL). The layers were separated, and the aqueous phase was back-extracted with Et2O (10 mL). Combined organic phases were dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (25 g SiO2, 1:4 ethyl acetate:hexanes) to yield the desired product as an oil. 1H NMR (400 MHz, CDCl3) delta8.02 (d, J=8.0 Hz, 2H), 7.51 (d, J=8 Hz, 2H), 7.34-7.28 (m, 1H), 6.98-6.91 (m, 2H), 6.81-6.73 (m, 4H), 4.20 (q, J=6.8 Hz, 2H), 4.17 (t, J=6.6 Hz, 2H), 2.93 (t, J=6.6 Hz, 2H), 2.33 (s, 3H), 1.50 (s, 6H), 1.24 (t, J=6.8 Hz, 3H); MS (EI) 522.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium fluoride;palladium diacetate; In tetrahydrofuran; | A. 2-(4-{2-[2-(2',6'-Dichloro-biphenyl-4-yl)-5-methyloxazol-4-yl]-ethoxy}-phenoxy)-2-methylpropionic acid ethyl ester A solution of 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (300 mg, 0.614 mmol) (see Ex. 2, part B), 2,6-dichlorophenylboronic acid (0.921 mmol), potassium fluoride (88.6 mg, 1.84 mmol), palladium acetate (1.3 mg, 0.14 mumol), and 2-(dicyclohexylphosphino)biphenyl (4.3 mg, 12.3 mumol) were combined under N2, to which anhydrous THF (1.23 mL) was added. The yellow mixture was heated at reflux for 12 h. After cooling to room temperature, the mixture was partitioned between Et2O (20 mL) and 1M NaOH (10 mL). The layers were separated, and the aqueous phase was back-extracted with Et2O (10 mL). Combined organic phases were dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (25 g SiO2, 1:4 ethyl acetate:hexanes) to yield the desired product as an oil. Rf=0.50 in 1:4 ethyl acetate:hexanes; MS (EI) 554.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); In 1,2-dimethoxyethane; | The starting material was prepared as follows: A solution of 191 mg (0.4 mmol) of 6-iodo-3-carboxaldehyde-1-[2-(trimethyl-silanly)-ethoxymethyl]-1H-indazole (from Example 33(a), step(ii)), methyl anthranilate (120.1 mg, 0.8 mmol), 2-(dicyclohexylphosphino) biphenyl (28 mg, 0.08 mmol), Pd2(dba)3 (18.4 mg, 0.02 mmol), K3PO4 (212.3 mg, 1.0 mmol), dissolved in dry DME (1.0 mL), was vacuum flushed with argon (3*), then stirred under an argon atmosphere for 3d in an oil bath at 80 C. The crude mixture was filtered through a plug of SiO2 eluted with ethyl acetate, then purified by "chromatotron" radial chromatography eluted with 25% CH3CN/CH2Cl2. The mass of the fractions that were pure was 42 mg. An addition 120 mg of product that was ~90% pure was also collected. The total yield of N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-6-ylamino]-benzamide was 162 mg or ~81%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 4-chloro-2-methyl-indene; | EXAMPLE 2 Preparation of 2-Methyl-4-(2,6-dimethylphenyl) Indene from 2-Methyl-4-Bromoindene A flask is charged with palladium (II) acetate (60.8 mg, 0.27 mmol), 2-(dicyclohexylphosphino)-biphenyl (321 mg, 0.9 mmol), (2,6-dimethylphenyl) boronic acid (1.0 g, 6.6 mmol), and potassium phosphate (2.3 g, 10.8 mmol). The flask is filled with nitrogen before addition of dry deoxygenated toluene (14.8 g) and 2-methyl-4-bromoindene (1.0 g, 4.7 mmol) (prepared in analogous fashion to 2-methyl-4-chloroindene) via syringe. The mixture was stirred at 87-95 C. for 20 hours under nitrogen. Analysis of an aliquot by GC/MS revealed a 67% yield of desired product and 32% of starting 2-methyl-4-bromoindene. Work up and purification as described in Example 1 provided a 55% yield of 2-methyl-4-(2,6-dimethylphenyl) indene as 1:1 mixture of two olefin isomers. MS observed 234. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With triethylamine;palladium diacetate; | e [3-Amino-5-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic acid 2-trimethylsilanyl-ethyl ester Palladium acetate (106 mg, 0.47 mmol), 2-(dicyclohexylphosphino)biphenyl (658 mg, 1.88 mmol), (3-amino-4-bromo-5-methyl-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (Example 294: step d (3.24 g, 9.38 mmol)) were combined in a flask and placed under an argon atmosphere. p-Dioxane (40 mL) was added, followed by triethylamine (5.23 mL, 38 mmol) and pinacolborane (4.08 mL, 28 mmol). The solution was stirred at 80 C. for lh during which a precipitate appeared. The solvent was removed in vacuo and the residue was partitioned between EtOAc (100 mL) and aq. NH4Cl (50 mL). The organic layer was further extracted with NH4Cl (2*30 mL), NaHCO3 (30 mL), and brine (50 mL). The organic layer was dried (MgSO4), concentrated in vacuo, and the residue was purified by SiO2 flash column chromatography (8:2 Hex/EtOAc) to afford the product (2.44 g, 66%) as a brown solid. 1H NMR (CDCl3) delta 6.77 (s, 1H), 6.38 (s, 1H), 6.28 (d, 1H, J=1.9 Hz), 4.91 (s, 2H), 4.23 (m, 2H), 2.42 (s, 3H), 1.32 (s, 12H), 1.03 (m, 2H), 0.05 (s, 9H). |
66% | With triethylamine;palladium diacetate; | e) [3-Amino-5-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic acid 2-trimethylsilanyl-ethyl ester Palladium acetate (106 mg, 0.47 mmol), 2-(dicyclohexylphosphino)biphenyl (658 mg, 1.88 mmol), (3-amino-4-bromo-5-methyl-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester ((Example 2: step d) 3.24 g, 9.38 mmol) were combined in a flask and placed under an argon atmosphere. p-Dioxane (40 mL) was added, followed by triethylamine (5.23 mL, 38 mmol) and pinacolborane (4.08 mL, 28 mmol). The solution was stirred at 80 C. for 1 h during which a ppt appeared. The solvent was removed in vacuo and the residue was partitioned between EtOAc (100 mL) and aq. NH4Cl (50 mL). The organic layer was further washed with NH4Cl (2*30 mL), NaHCO3 (30 mL), and brine (50 mL). The organic layer was dried (MgSO4), concentrated in vacuo, and the residue was purified by SiO2 column chromatography (8:2 Hex/EtOAc) to afford the product (2.44 g, 66%) as a brown solid. 1H NMR (CDCl3): delta 6.77 (s, 1H), 6.38 (s, 1H), 6.28 (d, 1H, J=1.9 Hz), 4.91 (s, 2H), 4.23 (m, 2H), 2.42 (s, 3H), 1.32 (s, 12H), 1.03 (m, 2H), 0.05 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine;palladium diacetate; In 1,4-dioxane; | 2-Bromo-5-chloro-3-methyl-phenylamine (595 mg, 2.7 mmol, Example 135: step c), Pd(OAc)2 (30.3 mg, 0.14 mmol), 2-(dicyclohexylphosphino)biphenyl (189.2 mg, 0.54 mmol) and Et3N (1.5 mL, 10.8 mmol) were dissolved into dioxane (10 mL). To this was added 4,4,5,5-Tetramethyl-[1,3,2]dioxaborolane (1.2 mL, 8.1 mmol) slowly. The reaction was heated to 80 C. overnight. The solvents were removed in vacuo and the resulting residue was dissolved into EtOAc and washed with brine. The combined organic layers were dried (MgSO4) and removal of the solvents in vacuo resulted in a mixture of the title compound and 3-Methyl-2,5-bis-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine were obtained and used with out further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine;palladium diacetate; In 1,4-dioxane; ethyl acetate; | d 5-Methoxy-3-methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine A solution of 2-bromo-5-methoxy-3-methyl-phenylamine ((Example 198: step c) 2.04 g, 6.18 mmol) in dry dioxane (100 mL) was treated with triethylamine (5.26 mL, 37.7 mmol), 2-(dicyclohexylphosphino)biphenyl (0.662 g, 1.89 mmol), and Pd(OAc)2 (0.106 g, 0.472 mmol). 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (4.09 mL, 28.3 mmol) was added slowly and the mixture heated to reflux for 1 h. The dioxane was evaporated in vacuo. The residue was taken up in EtOAc and washed with water (2*75 mL). The organic layer was filtered by gravity to remove the palladium residue, dried over MgSO4 and concentrated in vacuo. Silica gel chromatography (10-25% EtOAc in hexanes raised in 5% increments) afforded the product 5-methoxy-3-methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (1.61 g, 98%) as a light brown solid. 1H NMR (CDCl3): delta 7.361 (d, 1H, J=7.6 Hz), 7.279 (d, 1H, J=8.0 Hz), 3.815 (s, 3H), 2.46 (s, 3H), 1.356 (s, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 145 4-(3,4-diethoxyphenyl)-N-[4-(2-hydroxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (2-hydroxyphenyl)boronic acid (17.2 mg) as starting materials and in the same manner as in Example 119, 4-(3,4-diethoxyphenyl)-N-[4-(2-hydroxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide (5.1 mg) was obtained. HPLC (220 nm) purity 92% (retention time 1.89 min) MS (ESI+, m/e) 511 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 177 4-(2,3-dihydro-1-benzofuran-5-yl)-N-[4-(2-hydroxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (2-hydroxyphenyl)boronic acid (17.2 mg) as starting materials and in the same manner as in Example 119, 4-(2,3-dihydro-1-benzofuran-5-yl)-N-[4-(2-hydroxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide (10.6 mg) was obtained. HPLC (220 nm) purity 81% (retention time 1.86 min) MS (ESI+, m/e) 465 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 139 methyl 3-(2-[4-(3,4-diethoxyphenyl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)benzoate Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and [3-(methoxycarbonyl)phenyl]boronic acid (22.5 mg) as starting materials and in the same manner as in Example 119, methyl 3-(2-[4-(3,4-diethoxyphenyl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)benzoate (13.9 mg) was obtained. HPLC (220 nm) purity 97% (retention time 2.14 min) MS (ESI+, m/e) 553 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 170 methyl 3-(2-[4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)benzoate Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and [3-(methoxycarbonyl)phenyl]boronic acid (22.5 mg) as starting materials and in the same manner as in Example 119, methyl 3-(2-[4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)benzoate (13.6 mg) was obtained. HPLC (220 nm) purity 99% (retention time 2.09 min) MS (ESI+, m/e) 507 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); In water; toluene; | Example 112 methyl 4-(2-[4-(3,4-diethoxyphenyl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)benzoate To a solution of N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (190 mg) in toluene (5 mL) were added tris(dibenzylideneacetone)dipalladium (9 mg), biphenyl-2-yl(dicyclohexyl)phosphine (22 mg), aqueous potassium phosphate solution (267 mg) and [4-(methoxycarbonyl)phenyl]boronic acid (151 mg), and the mixture was heated overnight at 100C under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-hexane to give methyl 4-(2-[4-(3,4-diethoxyphenyl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)benzoate (131 mg) as crystals. 1H-NMR (CDCl3) delta: 1.43 - 1.54 (6 H, m, J=8.76, 7.02, 7.02 Hz), 2.90 (2 H, t, J=6.41 Hz), 3.44 (2 H, t, J=6.41 Hz), 3.95 (3 H, s), 4.10 - 4.21 (4 H, m, J=7.16, 7.16, 7.16, 7.16 Hz), 6.89 (1 H, d, J=8.48 Hz), 7.42 - 7.57 (4 H, m), 7.61 - 7.72 (2 H, m), 7.78 (2 H, d, J=8.48 Hz), 7.99 - 8.10 (2 H, m), 8.13 (2 H, d, J=8.48 Hz), 8.35 (1 H, s), 8.44 (1 H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 140 N-[4-(3-acetylphenyl)-6-phenylpyridin-2-yl]-4-(3,4-diethoxyphenyl)-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (3-acetylphenyl)boronic acid (20.5 mg) as starting materials and in the same manner as in Example 119, N-[4-(3-acetylphenyl)-6-phenylpyridin-2-yl]-4-(3,4-diethoxyphenyl)-4-oxobutanamide (14.1 mg) was obtained. HPLC (220 nm) purity 96% (retention time 2.08 min) MS (ESI+, m/e) 537 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 171 N-[4-(3-acetylphenyl)-6-phenylpyridin-2-yl]-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (3-acetylphenyl)boronic acid (20.5 mg) as starting materials and in the same manner as in Example 119, N-[4-(3-acetylphenyl)-6-phenylpyridin-2-yl]-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide (12.4 mg) was obtained. HPLC (220 nm) purity 99% (retention time 2.02 min) MS (ESI+, m/e) 491 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 143 4-(3,4-diethoxyphenyl)-4-oxo-N-{6-phenyl-4-[3-(trifluoromethoxy)phenyl]pyridin-2-yl}butanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and [3-(trifluoromethoxy)phenyl]boronic acid (25.7 mg) as starting materials and in the same manner as in Example 119, 4-(3,4-diethoxyphenyl)-4-oxo-N-{6-phenyl-4-[3-(trifluoromethoxy)phenyl]pyridin-2-yl}butanamide (15.0 mg) was obtained. HPLC (220 nm) purity 94% (retention time 2.28 min) MS (ESI+, m/e) 579 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 175 4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxo-N-{6-phenyl-4-[3-(trifluoromethoxy)phenyl]pyridin-2-yl}butanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and [3-(trifluoromethoxy)phenyl]boronic acid (25.7 mg) as starting materials and in the same manner as in Example 119, 4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxo-N-{6-phenyl-4-[3-(trifluoromethoxy)phenyl]pyridin-2-yl}butanamide (14.1 mg) was obtained. HPLC (220 nm) purity 97% (retention time 2.23 min) MS (ESI+, m/e) 533 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
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tris-(dibenzylideneacetone)dipalladium(0); In 1,2-dimethoxyethane; water; | Example 117 4-(3,4-diethoxyphenyl)-N-[4-(3-furyl)-6-phenylpyridin-2-yl]-4-oxobutanamide To a solution of N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg) and biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg) in DME (1 mL) were added 1N aqueous potassium carbonate solution (0.1 mL) and 3-furylboronic acid (14.0 mg), and the mixture was reacted using microwave (250 W) at 150C for 5 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and concentrated under reduced pressure. The obtained residue was subjected to a reversed-phase preparative high performance liquid chromatography (Gilson UniPoint System, Column Capcellpak C18 UG120 20 x 50 mm, manufactured by SHISEIDO), and the fraction eluted with acetonitrile (containing 0.1 % trifluoroacetic acid)-water (20:80, v/v) was concentrated under reduced pressure to give 4-(3,4-diethoxyphenyl)-N-[4-(3-furyl)-6-phenylpyridin-2-yl]-4-oxobutanamide (3.7 mg). HPLC (220 nm) purity 89% (retention time 1.98 min) MS (ESI+, m/e) 485 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium carbonate; triphenylphosphine; In 1,4-dioxane; ethanol; chloroform; water; ethyl acetate; acetone; toluene; | A mixture of 6-chloro-N*2*-(4-chloro-phenyl)-pyrimidine-2,4-diamine (0.077 g, 0.30 mmol), 5-chloro-2-methoxy-phenyl boronic acid (0.112 g, 0.60 mmol), palladium (II) acetate (0.017 g, 0.075 mmol), 2-(dicyclohexylphosphino)biphenyl (0.105 g, 0.30 mmol) and potassium phosphate (0.254 g, 1.2 mmol) in dry toluene (3.5 ml) was heated at 90-100 C. under an argon atmosphere for 18 hours. After cooling to room temperature, ether (20 ml) was added and the mixture was washed with aqueous sodium hydroxide solution (1.0 M, 10 ml), with saturated aqueous sodium chloride solution (10 ml), and dried over magnesium sulfate. After concentrating under reduced pressure, the residue was purified by flash chromatography on silica gel eluding with ethyl acetate-hexane (1:3) to provide the title compound (0.032 g, 30% yield) as a white powder. Alternatively, to a mixture of 2,6-dichloro-pyrimidin-4-yl-amine (1.64 g, 10.0 mmol), 5-chloro-2-methoxy-phenyl boronic acid (1.84 g, 10.0 mmol), palladium (II) acetate (0.337 g, 1.0 mmol) and triphenylphosphine (0.786 g, 3.0 mmol) was added a solution of sodium carbonate (5.3 g, 50.0 mmol) in water (10 ml) followed by glyme (50 ml). The mixture was stirred under an argon atmosphere for 24 hours. After addition of acetone (50 ml), filtration and concentration of the filtrate provided the crude product which was treated with chloroform (50 ml) and stirred for 1 hour. Filtration provided a solid which was dissolved in ethanol (50 ml). A solution of hydrogen chloride in dioxane (4.0 M, 5 ml) was added and volatiles were evaporated under reduce pressure. The residue was treated with ethyl acetate (25 ml) and stirred for 2 hours. Filtration provided the hydrochloride salt of 2-chloro-6-(5-chloro-2-methoxy-phenyl)-pyrimidin-4-yl-amine (0.42 g, 14% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 118 tert-butyl 2-(2-[4-(3,4-diethoxyphenyl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)-1H-pyrrole-1-carboxylate Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and [1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl] boronic acid (26.4 mg) as starting materials and in the same manner as in Example 117, tert-butyl 2-(2-[4-(3,4-diethoxyphenyl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)-1H-pyrrole-1-carboxylate (1.6 mg) was obtained. HPLC (220 nm) purity 84% (retention time 2.17 min) MS (ESI+, m/e) 584 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 155 4-(2,3-dihydro-1-benzofuran-5-yl)-N-[4-(4-methoxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (4-methoxyphenyl)boronic acid (19.0 mg) as starting materials and in the same manner as in Example 119, 4-(2,3-dihydro-1-benzofuran-5-yl)-N-[4-(4-methoxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide (12.0 mg) was obtained. HPLC (220 nm) purity 92% (retention time 1.98 min) MS (ESI+, m/e) 479.(M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium phosphate;palladium diacetate; In toluene; | EXAMPLE 401 6-(4-Methoxy-phenyl)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile A mixture of Example 397 (24 mg, 0.049 mmol), 4-methoxybenzeneboronic acid (11 mg, 0.072 mmol), Pd(OAc)2 (1.0 mg, 0.0045 mmol), 2-(dicyclohexylphosphino) biphenyl (5.0 mg, 0.014 mmol) and K3PO4 (20 mg, 0.10 mmol) in toluene (0.5 ml) was degassed with argon. The mixture was heated at 90 C. for 20 min, then directly purified by silica gel flash column chromatography to give title compound (20 mg, 92%)(10% EtOAc-hexanes). LCMS Found: (M+H)+=447.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); In 1,2-dimethoxyethane; water; | (2) 4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxo-N-(6' -phenyl-3,4' - bipyridine-2'-yl)butanamide To a solution of N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (200 mg) in DME (3 mL) were added tris(dibenzylideneacetone)dipalladium (92 mg), biphenyl-2-yl(dicyclohexyl)phosphine (105 mg), 2N aqueous potassium carbonate solution (0.2 mL) and 3-pyridylboronic acid (122 mg), and the mixture was reacted using microwave (250 W) at 150C for 5 min. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [developing solvent: n-hexane-ethyl acetate (9:1?1:1)], and the obtained crystals were recrystallized from chloroform to give 4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxo-N-(6'-phenyl-3,4'-bipyridine-2'-yl)butanamide (78 mg) as crystals. 1H-NMR (CDCl3) delta: 2.91 (2 H, t, J=6.41 Hz), 3.26 (2 H, t, J=8.85 Hz), 3.42 (2 H, t, J=6. 31 Hz), 4.67 (2 H, t, J=8.76 Hz), 6.82 (1 H, d, J=8.29 Hz), 7.39 - 7.54 (4 H, m), 7.67 (1 H, d, J=1.32 Hz), 7.86 - 7.92 (2 H, m), 7.96 - 8.09 (3 H, m), 8.39 (2 H, d, J=12.43 Hz), 8.68 (1 H, dd, J=4.90, 1.51 Hz), 8.96 (1 H, d, J=2.26 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With sodium hydroxide; sodium carbonate;dichlorobis(triphenylphosphine)palladium[II]; In hydrogenchloride; dichloromethane; water; | Example 12F 2-[2-(2-(R)-Methyl-pyrrolidin-1-yl)-ethyl]-6-pyridin-3-yl-benzothiazole A mixture of 6-bromo-2-[2-(2-(R)-methyl-pyrrolidin-1-yl)-ethyl]-benzothiazole (0.3 g, 0.9 mmol), 3-pyridinyl boronic acid (0.17 g, 1.4 mmol) and 2-(dicyclohexylphosphino)biphenyl (65 mg, 0.2 mmol) in 15 mL of IPA was purged with nitrogen. Dichlorobis(triphenylphosphine)palladium II (65 mg, 0.1 mmol) was added. Sodium carbonate (0.15 g, 1.35 mmol) was dissolved in 5 g of water, purged with nitrogen, and added to the above mixture. The mixture was heated to 65 C. under nitrogen for 16 hr. After cooling to room temperature 20 mL of methylene chloride was added and the solid was filtered off. The filtrate was concentrated to oil and dissolved in 10 mL of 2N HCl. The acidic aqueous layer was washed with 10 mL methylene chloride, the pH adjusted with 4N NaOH to pH 10, and the product free base was extracted with 20 mL methylene chloride. The methylene chloride layer was concentrated to dryness and purified by column chromatography (silica gel, 10:90 MeOH:CHCl3) to give the pure 2-[2-(2-Methyl-pyrrolidin-1-yl)-ethyl]-6-pyridin-3-yl-benzothiazole (0.2 g, 67% yield). 1H NMR (CDCl3, 400 MHz) delta 1.14 (d, 3H, J=8 Hz), 1.42-1.51 (m, 1H), 1.71-1.86 (m, 2H), 1.92-2.00 (m, 1H), 2.27 (q, 1H, J=8 Hz), 2.41-2.48 (m, 1H), 2.60-2.67 (m, 1H), 3.22-3.37 (m, 4H), 7.36-7.39 (m, 1H), 7.64 (broad d, 1 H, J=8 Hz), 7.90 (broad d, 1H, J=8 Hz), 8.03-8.05 (m, 2H), 8.60 (d, 1H, J=4 Hz), 8.89 (d, 1H, J=1.5 Hz); 13C NMR (CDCl3, 400 MHz) delta 19.3, 22.2, 33.0, 34.0, 52.7, 53.8, 59.9, 119.7, 122.6, 123.3, 125.0, 134.2, 135.9, 136.2, 148.0, 148.1, 152.3, 170.7; (DCl/NH3) m/z 324 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 124 4-(3,4-diethoxyphenyl)-N-{4-[4-(hydroxymethyl)phenyl]-6-phenylpyridin-2-yl}-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (4-hydroxymethylphenyl)boronic acid (19.0 mg) as starting materials and in the same manner as in Example 119, 4-(3,4-diethoxyphenyl)-N-{4-[4-(hydroxymethyl)phenyl]-6-phenylpyridin-2-yl}-4-oxobutanamide (11.7 mg) was obtained. HPLC (220 nm) purity 95% (retention time 1.89 min) MS (ESI+, m/e) 525 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 156 4-(2,3-dihydro-1-benzofuran-5-yl)-N-{4-[4-(hydroxymethyl)phenyl]-6-phenylpyridin-2-yl}-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (4-hydroxymethylphenyl)boronic acid (19.0 mg) as starting materials and in the same manner as in Example 119, 4-(2,3-dihydro-1-benzofuran-5-yl)-N-{4-[4-(hydroxymethyl)phenyl]-6-phenylpyridin-2-yl}-4-oxobutanamide (12.9 mg) was obtained. HPLC (220 nm) purity 92% (retention time 1.82 min) MS (ESI+, m/e) 479 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 146 4-(3,4-diethoxyphenyl)-N-[4-(2-methoxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (2-methoxyphenyl)boronic acid (19.0 mg) as starting materials and in the same manner as in Example 119, 4-(3,4-diethoxyphenyl)-N-[4-(2-methoxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide (7.5 mg) was obtained. HPLC (220 nm) purity 95% (retention time 2.05 min) MS (ESI+, m/e) 525 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 178 4-(2,3-dihydro-1-benzofuran-5-yl)-N-[4-(2-methoxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (2-methoxyphenyl)boronic acid (19.0 mg) as starting materials and in the same manner as in Example 119, 4-(2,3-dihydro-1-benzofuran-5-yl)-N-[4-(2-methoxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide (14.0 mg) was obtained. HPLC (220 nm) purity 96% (retention time 1.99 min) MS (ESI+, m/e) 479 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 148 2-(2-[4-(3,4-diethoxyphenyl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)benzoic acid Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and 2-(dihydroxyboryl)benzoic acid (20.7 mg) as starting materials and in the same manner as in Example 119, 2-(2-[4-(3,4-diethoxyphenyl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)benzoic acid (4.4 mg) was obtained. HPLC (220 nm) purity 99% (retention time 1.93 min) MS (ESI+, m/e) 539 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 180 2-(2-[4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)benzoic acid Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and 2-(dihydroxyboryl)benzoic acid (20.7 mg) as starting materials and in the same manner as in Example 119, 2-(2-[4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)benzoic acid (2.6 mg) was obtained. HPLC (220 nm) purity 92% (retention time 1.86 min) MS (ESI+, m/e) 493 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 125 3-[4-(2-[4-(3,4-diethoxyphenyl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)phenyl]propanoic acid Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and [4-(2-carboxyethyl)phenyl]boronic acid (24.2 mg) as starting materials and in the same manner as in Example 119, 3-[4-(2-[4-(3,4-diethoxyphenyl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)phenyl]propanoic acid (2.9 mg) was obtained. HPLC (220 nm) purity 80% (retention time 1.92 min) MS (ESI+, m/e) 567 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 157 3-[4-(2-[4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)phenyl]propanoic acid Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and [4-(2-carboxyethyl)phenyl]boronic acid (24.2 mg) as starting materials and in the same manner as in Example 119, 3-[4-(2-[4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)phenyl]propanoic acid (5.2 mg) was obtained. HPLC (220 nm) purity 94% (retention time 1.86 min) MS (ESI+, m/e) 521 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 123 4-(3,4-diethoxyphenyl)-N-[4-(4-hydroxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (4-hydroxyphenyl)boronic acid (17.2 mg) as starting materials and in the same manner as in Example 119, 4-(3,4-diethoxyphenyl)-N-[4-(4-hydroxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide (4.6 mg) was obtained. HPLC (220 nm) purity 82% (retention time 2.12 min) MS (ESI+, m/e) 511 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 136 4-(3,4-diethoxyphenyl)-N-{4-[3-(hydroxymethyl)phenyl]-6-phenylpyridin-2-yl}-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (3-hydroxymethylphenyl)boronic acid (19.0 mg) as starting materials and in the same manner as in Example 119, 4-(3,4-diethoxyphenyl)-N-{4-[3-(hydroxymethyl)phenyl]-6-phenylpyridin-2-yl}-4-oxobutanamide (15.6 mg) was obtained. HPLC (220 nm) purity 98% (retention time 1.91 min) MS (ESI+, m/e) 525 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 167 4-(2,3-dihydro-1-benzofuran-5-yl)-N-{4-[3-(hydroxymethyl)phenyl]-6-phenylpyridin-2-yl}-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (3-hydroxymethylphenyl)boronic acid (19.0 mg) as starting materials and in the same manner as in Example 119, 4-(2,3-dihydro-1-benzofuran-5-yl)-N-{4-[3-(hydroxymethyl)phenyl]-6-phenylpyridin-2-yl}-4-oxobutanamide (6.8 mg) was obtained. HPLC (220 nm) purity 99% (retention time 1.84 min) MS (ESI+, m/e) 479 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 138 3-(2-[4-(3,4-diethoxyphenyl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)benzoic acid Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and 3-(dihydroxyboryl)benzoic acid (20.7 mg) as starting materials and in the same manner as in Example 119, 3-(2-[4-(3,4-diethoxyphenyl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)benzoic acid (3.4 mg) was obtained. HPLC (220 nm) purity 86% (retention time 2.16 min) MS (ESI+, m/e) 539 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 169 3-(2-[4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)benzoic acid Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and 3-(dihydroxyboryl)benzoic acid (20.7 mg) as starting materials and in the same manner as in Example 119, 3-(2-[4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)benzoic acid (1.9 mg) was obtained. HPLC (220 nm) purity 93% (retention time 2.10 min) MS (ESI+, m/e) 493 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 128 4-(2-[4-(3,4-diethoxyphenyl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)benzamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (4-aminocarbonylphenyl)boronic acid (20.6 mg) as starting materials and in the same manner as in Example 119, 4-(2-[4-(3,4-diethoxyphenyl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)benzamide (10.5 mg) was obtained. HPLC (220 nm) purity 99% (retention time 1.85 min) MS (ESI+, m/e) 538 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); In 1,2-dimethoxyethane; water; | Example 116 4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxo-N-(6-phenyl-4,4'-bipyridin-2-yl)butanamide To a solution of N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (200 mg) in DME (2.5 mL) were added tris(dibenzylideneacetone)dipalladium (23 mg), biphenyl-2-yl(dicyclohexyl)phosphine (26 mg), 2N aqueous potassium carbonate solution (0.2 mL) and 4-pyridylboronic acid (122 mg), and the mixture was reacted using microwave (250 W) at 150C for 5 min. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [developing solvent: n-hexane-ethyl acetate (9:1?1:1)], and the obtained crystals were recrystallized from chloroform to give 4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxo-N-(6-phenyl-4,4'-bipyridin-2-yl)butanamide (29 mg) as crystals. 1H-NMR (CDCl3) delta: 2.91 (2 H, t, J=6.31 Hz), 3.25 (2 H, t, J=8.76 Hz), 3.42 (2 H, t, J=6.41 Hz), 4.67 (2 H, t, J=8.76 Hz), 6.82 (1 H, d, J=8.29 Hz), 7.42 - 7.55 (3 H, m), 7.58 - 7.64 (2 H, m), 7.68 (1 H, d, J=1.32 Hz), 7.78 - 7.96 (2 H, m), 7.97 - 8.05 (2 H, m), 8.39 - 8.50 (2 H, m), 8.70 - 8.77 (2 H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 131 4-(3,4-diethoxyphenyl)-N-{4-[4-(dimethylamino)phenyl]-6-phenylpyridin-2-yl}-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (4-dimethylaminophenyl)boronic acid (20.6 mg) as starting materials and in the same manner as in Example 119, 4-(3,4-diethoxyphenyl)-N-{4-[4-(dimethylamino)phenyl]-6-phenylpyridin-2-yl}-4-oxobutanamide (3.9 mg) was obtained. HPLC (220 nm) purity 92% (retention time 1.90 min) MS (ESI+, m/e) 538 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 162 4-(2,3-dihydro-1-benzofuran-5-yl)-N-{4-[4-(dimethylamino)phenyl]-6-phenylpyridin-2-yl}-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (4-dimethylaminophenyl)boronic acid (20.6 mg) as starting materials and in the same manner as in Example 119, 4-(2,3-dihydro-1-benzofuran-5-yl)-N-{4-[4-(dimethylamino)phenyl]-6-phenylpyridin-2-yl}-4-oxobutanamide (2.4 mg) was obtained. HPLC (220 nm) purity 85% (retention time 1.83 min) MS (ESI+, m/e) 492 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 120 N-[4-(1,3-benzodioxol-5-yl)-6-phenylpyridin-2-yl]-4-(3,4-diethoxyphenyl)-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (1,3-benzodioxol-5-yl)boronic acid (20.7 mg) as starting materials and in the same manner as in Example 119, N-[4-(1,3-benzodioxol-5-yl)-6-phenylpyridin-2-yl]-4-(3,4-diethoxyphenyl)-4-oxobutanamide (9.7 mg) was obtained. HPLC (220 nm) purity 98% (retention time 2.04 min) MS (ESI+, m/e) 539 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 134 4-(3,4-diethoxyphenyl)-N-[4-(3-hydroxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (3-hydroxyphenyl)boronic acid (17.2 mg) as starting materials and in the same manner as in Example 119, 4-(3,4-diethoxyphenyl)-N-[4-(3-hydroxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide (11.0 mg) was obtained. HPLC (220 nm) purity 91% (retention time 1.94 min) MS (ESI+, m/e) 511 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 165 4-(2,3-dihydro-1-benzofuran-5-yl)-N-[4-(3-hydroxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (3-hydroxyphenyl)boronic acid (17.2 mg) as starting materials and in the same manner as in Example 119, 4-(2,3-dihydro-1-benzofuran-5-yl)-N-[4-(3-hydroxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide (11.5 mg) was obtained. HPLC (220 nm) purity 91% (retention time 1.88 min) MS (ESI+, m/e) 465 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 147 4-(3,4-diethoxyphenyl)-N-{4-[2-(hydroxymethyl)phenyl]-6-phenylpyridin-2-yl}-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and [2-(hydroxymethyl)phenyl]boronic acid (19.0 mg) as starting materials and in the same manner as in Example 119, 4-(3,4-diethoxyphenyl)-N-{4-[2-(hydroxymethyl)phenyl]-6-phenylpyridin-2-yl}-4-oxobutanamide (12.0 mg) was obtained. HPLC (220 nm) purity 98percent (retention time 1.95 min) MS (ESI+, m/e) 525 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 179 4-(2,3-dihydro-1-benzofuran-5-yl)-N-{4-[2-(hydroxymethyl)phenyl]-6-phenylpyridin-2-yl}-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and [2-(hydroxymethyl)phenyl]boronic acid (19.0 mg) as starting materials and in the same manner as in Example 119, 4-(2,3-dihydro-1-benzofuran-5-yl)-N-{4-[2-(hydroxymethyl)phenyl]-6-phenylpyridin-2-yl}-4-oxobutanamide (6.5 mg) was obtained. HPLC (220 nm) purity 99percent (retention time 1.88 min) MS (ESI+, m/e) 479 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 150 4-(3,4-diethoxyphenyl)-4-oxo-N-[6-phenyl-4-(3,4,5-trimethoxyphenyl)pyridin-2-yl]butanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (3,4,5-trimethoxyphenyl)boronic acid (26.5 mg) as starting materials and in the same manner as in Example 119, 4-(3,4-diethoxyphenyl)-4-oxo-N-[6-phenyl-4-(3,4,5-trimethoxyphenyl)pyridin-2-yl]butanamide (16.9 mg) was obtained. HPLC (220 nm) purity 100% (retention time 2.05 min) MS (ESI+, m/e) 585 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 182 4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxo-N-[6-phenyl-4-(3,4,5-trimethoxyphenyl)pyridin-2-yl]butanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (3,4,5-trimethoxyphenyl)boronic acid (26.5 mg) as starting materials and in the same manner as in Example 119, 4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxo-N-[6-phenyl-4-(3,4,5-trimethoxyphenyl)pyridin-2-yl]butanamide (17.7 mg) was obtained. HPLC (220 nm) purity 93% (retention time 1.98 min) MS (ESI+, m/e) 539 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 144 N-[4-(2-cyanophenyl)-6-phenylpyridin-2-yl]-4-(3,4-diethoxyphenyl)-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (2-cyanophenyl)boronic acid (18.4 mg) as starting materials and in the same manner as in Example 119, N-[4-(2-cyanophenyl)-6-phenylpyridin-2-yl]-4-(3,4-diethoxyphenyl)-4-oxobutanamide (9.0 mg) was obtained. HPLC (220 nm) purity 94% (retention time 2.10 min) MS (ESI+, m/e) 520 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 176 N-[4-(2-cyanophenyl)-6-phenylpyridin-2-yl]-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (2-cyanophenyl)boronic acid (18.4 mg) as starting materials and in the same manner as in Example 119, N-[4-(2-cyanophenyl)-6-phenylpyridin-2-yl]-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide (7.8 mg) was obtained. HPLC (220 nm) purity 88% (retention time 2.04 min) MS (ESI+, m/e) 474 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 149 4-(3,4-diethoxyphenyl)-N-[4-(4-hydroxy-3-methoxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and 2-(4-hydroxy-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (31.3 mg) as starting materials and in the same manner as in Example 119, 4-(3,4-diethoxyphenyl)-N-[4-(4-hydroxy-3-methoxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide (6.5 mg) was obtained. HPLC (220 nm) purity 99% (retention time 1.87 min) MS (ESI+, m/e) 541 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 181 4-(2,3-dihydro-1-benzofuran-5-yl)-N-[4-(4-hydroxy-3-methoxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and 2-(4-hydroxy-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (31.3 mg) as starting materials and in the same manner as in Example 119, 4-(2,3-dihydro-1-benzofuran-5-yl)-N-[4-(4-hydroxy-3-methoxyphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide (13.3 mg) was obtained. HPLC (220 nm) purity 91% (retention time 1.79 min) MS (ESI+, m/e) 495 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 151 4-(3,4-diethoxyphenyl)-N-[4-(4-hydroxy-3,5-dimethylphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (31.0 mg) as starting materials and in the same manner as in Example 119, 4-(3,4-diethoxyphenyl)-N-[4-(4-hydroxy-3,5-dimethylphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide (12.3 mg) was obtained. HPLC (220 nm) purity 84% (retention time 1.93 min) MS (ESI+, m/e) 539 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 183 4-(2,3-dihydro-1-benzofuran-5-yl)-N-[4-(4-hydroxy-3,5-dimethylphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (31.0 mg) as starting materials and in the same manner as in Example 119, 4-(2,3-dihydro-1-benzofuran-5-yl)-N-[4-(4-hydroxy-3,5-dimethylphenyl)-6-phenylpyridin-2-yl]-4-oxobutanamide (7.3 mg) was obtained. HPLC (220 nm) purity 94% (retention time 1.86 min) MS (ESI+, m/e) 493 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 121 4-(3,4-diethoxyphenyl)-N-[4-(1H-indol-5-yl)-6-phenylpyridin-2-yl]-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (30.3 mg) as starting materials and in the same manner as in Example 119, 4-(3,4-diethoxyphenyl)-N-[4-(1H-indol-5-yl)-6-phenylpyridin-2-yl]-4-oxobutanamide (7.1 mg) was obtained. HPLC (220 nm) purity 89% (retention time 1.90 min) MS (ESI+, m/e) 534 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 154 4-(2,3-dihydro-1-benzofuran-5-yl)-N-[4-(1H-indol-5-yl)-6-phenylpyridin-2-yl]-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (30.3 mg) as starting materials and in the same manner as in Example 119, 4-(2,3-dihydro-1-benzofuran-5-yl)-N-[4-(1H-indol-5-yl)-6-phenylpyridin-2-yl]-4-oxobutanamide (5.1 mg) was obtained. HPLC (220 nm) purity 80% (retention time 1.74 min) MS (ESI+, m/e) 488 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 141 3-[3-(2-[4-(3,4-diethoxyphenyl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)phenyl]propanoic acid Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and [3-(2-carboxyethyl)phenyl]boronic acid (24.2 mg) as starting materials and in the same manner as in Example 119, 3-[3-(2-[4-(3,4-diethoxyphenyl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)phenyl]propanoic acid (11.6 mg) was obtained. HPLC (220 nm) purity 91% (retention time 1.95 min) MS (ESI+, m/e) 567 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 172 3-[3-(2-[4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)phenyl]propanoic acid Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and [3-(2-carboxyethyl)phenyl]boronic acid (24.2 mg) as starting materials and in the same manner as in Example 119, 3-[3-(2-[4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)phenyl]propanoic acid (9.7 mg) was obtained. HPLC (220 nm) purity 90% (retention time 1.89 min) MS (ESI+, m/e) 521 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 174 (2E)-3-[3-(2-[4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)phenyl]acrylic acid Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (2E)-3-[3-(dihydroxyboryl)phenyl]acrylic acid (24.0 mg) as starting materials and in the same manner as in Example 119, (2E)-3-[3-(2-[4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)phenyl]acrylic acid (4.4 mg) was obtained. HPLC (220 nm) purity 96% (retention time 1.91 min) MS (ESI+, m/e) 519 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 137 4-(3,4-diethoxyphenyl)-N-{4-[3-(3-hydroxypropyl)phenyl]-6-phenylpyridin-2-yl}-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and [3-(3-hydroxypropyl)phenyl]boronic acid (22.5 mg) as starting materials and in the same manner as in Example 119, 4-(3,4-diethoxyphenyl)-N-{4-[3-(3-hydroxypropyl)phenyl]-6-phenylpyridin-2-yl}-4-oxobutanamide (11.3 mg) was obtained. HPLC (220 nm) purity 100% (retention time 2.22 min) MS (ESI+, m/e) 553 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 168 4-(2,3-dihydro-1-benzofuran-5-yl)-N-{4-[3-(3-hydroxypropyl)phenyl]-6-phenylpyridin-2-yl}-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and [3-(3-hydroxypropyl)phenyl]boronic acid (22.5 mg) as starting materials and in the same manner as in Example 119, 4-(2,3-dihydro-1-benzofuran-5-yl)-N-{4-[3-(3-hydroxypropyl)phenyl]-6-phenylpyridin-2-yl}-4-oxobutanamide (5.0 mg) was obtained. HPLC (220 nm) purity 89% (retention time 1.90 min) MS (ESI+, m/e) 507 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 135 N-[4-(3-butoxyphenyl)-6-phenylpyridin-2-yl]-4-(3,4-diethoxyphenyl)-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (3-butoxyphenyl)boronic acid (24.3 mg) as starting materials and in the same manner as in Example 119, N-[4-(3-butoxyphenyl)-6-phenylpyridin-2-yl]-4-(3,4-diethoxyphenyl)-4-oxobutanamide (14.9 mg) was obtained. HPLC (220 nm) purity 96% (retention time 2.for 35 min) MS (ESI+, m/e) 567 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 166 N-[4-(3-butoxyphenyl)-6-phenylpyridin-2-yl]-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (3-butoxyphenyl)boronic acid (24.3 mg) as starting materials and in the same manner as in Example 119, N-[4-(3-butoxyphenyl)-6-phenylpyridin-2-yl]-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide (11.5 mg) was obtained. HPLC (220 nm) purity 91% (retention time 2.26 min) MS (ESI+, m/e) 521 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); In 1,2-dimethoxyethane; water; | Example 119 4-(3,4-diethoxyphenyl)-N-[4-(1-methyl-1H-pyrazol-4-yl)-6-phenylpyridin-2-yl]-4-oxobutanamide To a solution of N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg) and biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg) in DME (1 mL) were added 1N aqueous potassium carbonate solution (0.1 mL) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (26.0 mg), and the mixture was reacted using microwave (250 W) at 150C for 5 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and concentrated under reduced pressure. The obtained residue was subject to a reversed-phase preparative high performance liquid chromatography (Gilson, UniPoint System, Column Capcellpak C18 UG120 20 x 50 mm, manufactured by SHISEIDO), and the fraction eluted with acetonitrile (containing 0.1% formic acid)-water (20:80, v/v) was concentrated under reduced pressure to give 4-(3,4-diethoxyphenyl)-N-[4-(1-methyl-1H-pyrazol-4-yl)-6-phenylpyridin-2-yl]-4-oxobutanamide (6.9 mg). HPLC (220 nm) purity 97% (retention time 1.75 min) MS (ESI+, m/e) 499 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 153 4-(2,3-dihydro-1-benzofuran-5-yl)-N-[4-(1-methyl-1H-pyrazol-4-yl)-6-phenylpyridin-2-yl]-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (26.0 mg) as starting materials and in the same manner as in Example 119, 4-(2,3-dihydro-1-benzofuran-5-yl)-N-[4-(1-methyl-1H-pyrazol-4-yl)-6-phenylpyridin-2-yl]-4-oxobutanamide (2.2 mg) was obtained. HPLC (220 nm) purity 100% (retention time 1.87 min) MS (ESI+, m/e) 453 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 133 N-{4-[3-(cyanomethyl)phenyl]-6-phenylpyridin-2-yl}-4-(3,4-diethoxyphenyl)-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetonitrile (30.4 mg) as starting materials and in the same manner as in Example 119, N-{4-[3-(cyanomethyl)phenyl]-6-phenylpyridin-2-yl}-4-(3,4-diethoxyphenyl)-4-oxobutanamide (12.0 mg) was obtained. HPLC (220 nm) purity 81% (retention time 2.04 min) MS (ESI+, m/e) 534 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 164 N-{4-[3-(cyanomethyl)phenyl]-6-phenylpyridin-2-yl}-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and [3-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetonitrile (30.4 mg) as starting materials and in the same manner as in Example 119, N-{4-[3-(cyanomethyl)phenyl]-6-phenylpyridin-2-yl}-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide (10.7 mg) was obtained. HPLC (220 nm) purity 99% (retention time 1.99 min) MS (ESI+, m/e) 488 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 152 4-(3,4-diethoxyphenyl)-N-{4-[(1E)-octa-1-en-1-yl]-6-phenylpyridin-2-yl}-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (1E)-octa-1-en-1-ylboronic acid (19.5 mg) as starting materials and in the same manner as in Example 119, 4-(2,3-dihydro-1-benzofuran-5-yl)-N-{4-[(lE)-octa-1-en-1-yl]-6-phenylpyridin-2-yl}-4-oxobutanamide (5.9 mg) was obtained. HPLC (220 nm) purity 83% (retention time 2.26 min) MS (ESI+, m/e) 529 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 132 N-[4-(3-cyanophenyl)-6-phenylpyridin-2-yl]-4-(3,4-diethoxyphenyl)-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (3-cyanophenyl)boronic acid (18.4 mg) as starting materials and in the same manner as in Example 119, N-[4-(3-cyanophenyl)-6-phenylpyridin-2-yl]-4-(3,4-diethoxyphenyl)-4-oxobutanamide (15.4 mg) was obtained. HPLC (220 nm) purity 90% (retention time 2.11 min) MS (ESI+, m/e) 520 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 126 methyl 3-[4-(2-[4-(3,4-diethoxyphenyl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)phenyl]propanoate Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and [4-(2-methoxycarboxyethyl)phenyl]boronic acid (26.0 mg) as starting materials and in the same manner as in Example 119, methyl 3-[4-(2-[4-(3,4-diethoxyphenyl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)phenyl]propanoate (11.1 mg) was obtained. HPLC (220 nm) purity 97% (retention time 2.08 min) MS (ESI+, m/e) 581 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 127 methyl (2E)-3-[4-(2-[4-(3,4-diethoxyphenyl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)phenyl]acrylate Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and [4-(E-3-methoxy-3-oxo-1-propen-1-yl)phenyl]boronic acid (25.8 mg) as starting materials and in the same manner as in Example 119, methyl (2E)-3-[4-(2-[4-(3,4-diethoxyphenyl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)phenyl]acrylate (15.8 mg) was obtained. HPLC (220 nm) purity 96% (retention time 2.16 min) MS (ESI+, m/e) 579 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 142 methyl 3-[3-(2-[4-(3,4-diethoxyphenyl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)phenyl]propanoate Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and [3-(2-methoxycarboxyethyl)phenyl]boronic acid (26.0 mg) as starting materials and in the same manner as in Example 119, methyl 3-[3-(2-[4-(3,4-diethoxyphenyl)-4-oxobutanoyl]amino}-6-phenylpyridin-4-yl)phenyl]propanoate (16.7 mg) was obtained. HPLC (220 nm) purity 93% (retention time 2.11 min) MS (ESI+, m/e) 581 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 122 N-[4-(4-cyanophenyl)-6-phenylpyridin-2-yl]-4-(3,4-diethoxyphenyl)-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(3,4-diethoxyphenyl)-4-oxobutanamide obtained in Example 43-(3) (22.6 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (4-cyanophenyl)boronic acid (18.3 mg) as starting materials and in the same manner as in Example 119, N-[4-(4-cyanophenyl)-6-phenylpyridin-2-yl]-4-(3,4-diethoxyphenyl)-4-oxobutanamide (6.8 mg) was obtained. HPLC (220 nm) purity 99% (retention time 2.12 min) MS (ESI+, m/e) 520 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tris-(dibenzylideneacetone)dipalladium(0); | Example 184 4-(2,3-dihydro-1-benzofuran-5-yl)-N-{4-[(1E)-octa-1-en-1-yl]-6-phenylpyridin-2-yl}-4-oxobutanamide Using N-(4-chloro-6-phenylpyridin-2-yl)-4-(2,3-dihydro-1-benzofuran-5-yl)-4-oxobutanamide obtained in Example 114-(1) (20.3 mg), tris(dibenzylideneacetone)dipalladium (1.1 mg), biphenyl-2-yl(dicyclohexyl)phosphine (1.8 mg), 1N aqueous potassium carbonate solution (0.1 mL) and (1E)-octa-1-en-1-ylboronic acid (19.5 mg) as starting materials and in the same manner as in Example 119, 4-(2,3-dihydro-1-benzofuran-5-yl)-N-{4-[(1E)-octa-1-en-1-yl]-6-phenylpyridin-2-yl}-4-oxobutanamide (5.4 mg) was obtained. HPLC (220 nm) purity 90% (retention time 2.21 min) MS (ESI+, m/e) 483 (M+H) |
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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