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CAS No. : | 918524-63-7 | MDL No. : | MFCD07437995 |
Formula : | C16H26BN3O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KVQXFNGVIIPCSX-UHFFFAOYSA-N |
M.W : | 303.21 | Pubchem ID : | 2769618 |
Synonyms : |
|
Num. heavy atoms : | 22 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.69 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 96.97 |
TPSA : | 37.83 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.65 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 2.11 |
Log Po/w (WLOGP) : | 0.37 |
Log Po/w (MLOGP) : | 0.9 |
Log Po/w (SILICOS-IT) : | 0.87 |
Consensus Log Po/w : | 0.85 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.12 |
Solubility : | 0.231 mg/ml ; 0.00076 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.54 |
Solubility : | 0.884 mg/ml ; 0.00292 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.78 |
Solubility : | 0.0502 mg/ml ; 0.000166 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.39 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In dimethyl sulfoxide at 80℃; Inert atmosphere | A mixture of 15 (1.5 g, 5.9 mmol), bis(pinacolato)diboron (1.6 g, 6.5 mmol), potassium acetate(1.8 g, 18 mmol) and Pd(dppf)2Cl2[CH2Cl2] (0.73 g, 0.89 mmol) in DMSO (20 mL) was protected with nitrogen and stirred at 80 oC overnight. The mixture was diluted with water and extracted with EA. The organic solution was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EA, v/v = 3 to EA) to give 1.0 g of 16 (56percent yield) as a brown solid. MS: m/z 304 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With sodium carbonate In water; N,N-dimethyl-formamide for 3 h; Inert atmosphere; Reflux | Example 264 N-((4,6-dimethyl-2-oxo- 1 ,2-dihydropyridin-3-yl)methyl)- 1 -isopropyl-3-methyl-6-(6-(4- methylpiperazin- 1 -yl)pyridin- -yl)- 1 H-indole-4-carboxamide To a stirred solution of 6-bromo-N-((l,2-dihydro-4,6-dimethyl-2-oxopyridin-3- yl)methyl)-l-isopropyl-3 -methyl- lH-indole-4-carboxamide (2 g, 4.65 mmol) in DMF (100 mL) was added l-methyl-4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2- yl)piperazine (1.55 g, 5.12 mmol) followed by a solution of sodium carbonate (1.23 g, 11.62 mmol) in water (10 mL) and the contents were degassed with argon for 30 min. After that PdCl2(PPh3)2 (326 mg, 0.464 mmol) was added and the contents again degassed with argon for 10 min. The reaction mixture was stirred at reflux for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3x150 mL). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated to afford the crude product (2.8 g). The crude compound was purified by column chromatography over silica gel (100-200 mesh, eluent: 0-10percent MeOH: DCM), and the obtained product was further triturated with diethyl ether (100 mL) to afford the title compound as an off white solid (1.2 g, 50percent). 1H NMR (DMSO-d6, 400 MHz) : δ 1.493 (d, J = 6.4 Hz, 6H), 2.092 (s, 3H), 2.286 (s, 3H), 2.409 (s, 3H), 2.424 (s, 3H), 2.632 (s, 4H), 3.621 (s, 4H), 4.603-4.685 (m, 3H), 5.880 (s, 1H), 6.606 (d, J = 8.8 Hz ,1H), 7.016 (s, 1H), 7.261 (s, 1H), 7.433 (s, 1H), 7.675 - 7.704 (dd, J = 9 Hz, 2.4 Hz, 1H), 8.425 (d, J = 2.0 Hz, 1H), 11.699 (brs, 1H); LCMS (ES+): 525.23 [M-H]. |
50% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In water; N,N-dimethyl-formamide for 3 h; Inert atmosphere; Reflux | To a stirred solution of 6-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxamide (2 g, 4.65 mmol) in DMF (100 mL) was added 1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (1.55 g, 5.12 mmol) followed by a solution of sodium carbonate (1.23 g, 11.62 mmol) in water (10 mL) and the contents were degassed with argon for 30 min. After that PdCl2(PPh3)2 (326 mg, 0.464 mmol) was added and the contents again degassed with argon for 10 min. The reaction mixture was stirred at reflux for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to afford the crude product (2.8 g). The crude compound was purified by column chromatography over silica gel (100-200 mesh, eluent: 0-10percent MeOH: DCM), and the obtained product was further triturated with diethyl ether (100 mL) to afford the title compound as an off white solid (1.2 g, 50percent). 1H NMR (DMSO-d6, 400 MHz): δ 1.493 (d, J=6.4 Hz, 6H), 2.092 (s, 3H), 2.286 (s, 3H), 2.409 (s, 3H), 2.424 (s, 3H), 2.632 (s, 4H), 3.621 (s, 4H), 4.603-4.685 (m, 3H), 5.880 (s, 1H), 6.606 (d, J=8.8 Hz, 1H), 7.016 (s, 1H), 7.261 (s, 1H), 7.433 (s, 1H), 7.675-7.704 (dd, J=9 Hz, 2.4 Hz, 1H), 8.425 (d, J=2.0 Hz, 1H), 11.699 (brs, 1H); LCMS (ES+): 525.23 [M−H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 80 - 100℃; for 0.5 - 24h; | 6-[6-(4-Methyl-piperazin-l-yl)pyridin-3-yl]-l,2,3,4-tetrahydro- [ 1 ,8]naphthyridin-4-ol6-Bromo-l,2,3,4-tetrahydro-[l,8]naphthyridin-4-ol (89 mg) was reacted with l-methyl-4-[5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-piperazine (125 mg) as in General Procedure 13. Silica gel chromatography using a gradient of 0-10% (5% NH4OH in methanol)/methylene chloride as the eluting solvent gave the title compound as brown solids (22% yield). M.p. 124-128 0C, LCMS: m/z = 326 (M-I-H+), 1H-NMR (CDCl3, 400 MHz) delta2.00 (m, IH), 2.08 (s, IH), 2.62 (t, J= 5.0 Hz, 4H), 3.49 (m, 2H), 3.58 (m, 2H), 3.63 (t, J= 5.0 <n="193"/>Hz, 4H), 4.85 (t, J= 4.0 Hz, IH), 6.68 (s, IH), 6.71 (s, IH), 7.59 (dd, J= 2.6, 8.8 Hz, IH), 7.66 (d, J= 2.2 Hz, IH), 8.01 (d, J= 2.3 Hz, IH), 8.32 (d, J= 2.5 Hz, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 90℃; for 6h; | 4-(2,5-Difluorobenzyl)-6-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]-l,2,3,4- tetrahydro-[ 1 ,8]naphthyridine <n="201"/>Na2CO3 (2N, 53 muL) (4.0 eq) was added to a mixture of 6-bromo-4-(2,5-difluorobenzyl)- l,2,3,4-tetrahydro-[l,8]naphthyridine (9.0 mg) (1 eq), l-methyl-4-[5-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine (11.3 mg) (1.4 eq), and Pd(PPh3)4 (3.0 mg, 0.1 eq) in toluene/ethanol (4: 1, v/v, 2 mL). The reaction was heated at 9O0C for six (6) hours. The reaction mixture was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (15 mL) and washed with water (15 mL). The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica gel chromatography using a gradient of 0-20% methanol/CH2Cl2 as the eluting solvent to give the title compound as a yellow foam (26% yield). LCMS: m/z = 436 (M+H+), 1H-NMR (CDCl3, 400 MHz) delta 1.7-2.0 (m, 2H), 2.37 (s, 3H), 2.55-2.60 (m, 4H), 2.81 (dd, J= 9.1 and 13.3 Hz, IH), 2.98 (dd, J= 6.4 and 13.3 H, IH), 3.08-3.18 (m, IH), 3.40-3.50 (m, IH), 3.53-3.70 (m, 5H), 5.18 (bs, IH), 6.68 (d, J= 8.8 Hz, IH), 6.81-6.87 (m, IH), 6.89-6.96 (m, IH), 6.98-7.06 (m, IH), 7.16 (d, J= 1 Hz, IH), 7.50 (dd, J= 2.5 and 8.8 Hz, IH), 8.05 (d, J= 1 Hz, IH), 8.24 (d, J= 2.5 Hz, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With triphenylphosphine;palladium diacetate; In propan-1-ol; water; at 130℃; for 0.166667h;Microwave irradiation; | l-(2-Chloro-3,6-difluorobenzyl)-7-[6-(4-methylpiperazin-l-yl)pyridin-3-yl]- l,4-dihydro-2H-pyrido[2,3-b]pyrazin-3-oneA mixture of 7-bromo-l-(2-chloro-3,6-difiuorobenzyl)-l,4-dihydro-2H-pyrido[2,3-b]pyrazin- 3-one (42 mg, 0.11 mmol), l-methyl-4-[5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2- yl)pyridin-2-yl]piperazine (40 mg, 0.13 mmol), palladium (H) acetate (4 mg) and triphenylphosphine (14 mg) in n-propanol (1.0 mL) was degassed with argon while adding a 1.26 M aqueous solution OfNa2COs (0.12 mL) followed by water (0.38 mL). This mixture was heated in a microwave for 10 minutes at 1300C, cooled to room temperature and extracted into CH2Cb. The organic phase was passed through a plug OfNa2SO4, absorbed onto florisil and evaporated to dryness. This material was purified by silica gel chromatography by eluting with increasing amounts of 5% NHUOH/methanol in dichloromethane. The isolated material was recrystallized from methanol to give the title compound (15.4 mg, 29%). m.p. 235 -236 0C (dec); LCMS: m/z = 485/487 (M+H+); 1H-NMR (CDC13-rf6, 400 MHz) delta 8.22 (d, J= 2.4 Hz,IH), 7.89 (d, 7= 2.4 Hz, IH), 7.49-7.46 (m, IH), 7.16 (s, IH), 7.15-7.06 (m, IH), 7.05-6.93 <n="254"/>(m, IH), 6.69 (d, J=8.8, IH), 5.43, (s, 2H), 4.81 (s, IH), 4.24 (s, 2H), 3.61-3.59 (m, 4H), 2.55- 2.52 (m, 4H), 2.36 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of 1-(5-bromo-pyridin-2-yl)-4-methyl-piperazine (0.52 g, 2.3 mmol) in 15 ml THF is cooled to - 78 0C and n-butyllithium (1.7 ml, 1.6 M solution in hexane) is added dropwise. Stirring is continued for 30 minutes after which time 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2- dioxoborolan (511 mg, 2.7 mmol) is added. After 2 hours the mixture is allowed to warm to room temperature and quenched by addition of aq. NaHCO3. Extraction with ethylactetate, drying with Na2SO4 and removal of the solvent gives the desired boronate which was used as crude material in subsequent reactions.MS (ESI+) m/z: 304 [MH]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a 5 mL microwave tube was added N- [2-[(4-bromophenyl)methyl]-5-hydroxy-6-(l- methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 61, 31 mg, 0.073 mmol), 1 -methyl-4-[5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (22.16 mg, 0.073 mmol), potassium carbonate (30.3 mg, 0.219 mmol), and tetrakis(triphenylphosphine)palladium (0) (2.53 mg, 2.192 mumol) in 1,4-Dioxane (1.5 ml) andWater (0.500 ml). The mixture was irradiated at 100 0C for 20 minutes. The reaction mixture was diluted with water (4 ml) and acidified with IN HCl (1 ml) then filtered to remove any residue followed by purification by HPLC chromatography (ODS silica, gradient 10-75% acetonitrile/water (0.1% TFA)) to afford the title compound N- [5-hydroxy-6-(l -methylethyl)-2- ({4-[6-(4-methyl-l-piperazinyl)-3-pyridinyl]phenyl}methyl)-3-oxo-2,3-dihydro-4- pyridazinyljcarbonyl} glycine (23mg, 0.036 mmol, 49.7 % yield) as a white powder tfa salt. IH NMR (400 MHz, DMSO-^6) d ppm 15.87 (s, 1 H), 10.19 (t, J=5.68 Hz, 1 H), 9.94 (s, 1 H), 8.48 (d, J=2.53 Hz, 1 H), 7.94 (dd, J=9.09, 2.53 Hz, 1 H), 7.62 (d, J=8.34 Hz, 2 H), 7.38 (d, J=8.34 Hz, 2 H), 7.06 (d, J=9.09 Hz, 1 H), 5.28 (s, 2 H), 4.47 (d, J=13.39 Hz, 2 H), 4.10 (d, J=5.56 Hz, 2 H), 3.53 (dd, J=10.23, 6.44 Hz, 2 H), 2.99 - 3.26 (m, 5 H), 2.85 (s, 3 H), 1.22 (d, J=6.82 Hz, 6 H). MS(ES+) m/e 521 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.7% | To a 5 mL microwave tube was added N-[2-[(3-bromophenyl)methyl]-5-hydroxy-6-(l- methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 79, 31 mg, 0.073 mmol), 1 -methyl-4-[5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (22.16 mg, 0.073 mmol), potassium carbonate (303 mg, 2.192 mmol), and tetrakis(triphenylphosphine)palladium (0) (2.53 mg, 2.192 mumol) in 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100 0C for 20 minutes. The reaction mixture was diluted with water (4 ml) and acidified with IN HCl (1 ml) then filtered to remove any residue followed by purification by HPLC chromatography (ODS silica, gradient 10-75% acetonitrile/water (0.1% TFA)) to afford the title compound N- [5-hydroxy-6-(l -methylethyl)-2- ({3-[6-(4-methyl-l-piperazmyl)-3-pyridmyl]phenyl}methyl)-3-oxo-2,3-dihydro-4- pyridazinyljcarbonyl} glycine (32 mg, 0.048 mmol, 65.7 % yield) as a white powder. IH NMR(400 MHz, DMSO-(Z6) d ppm 15.88 (s, 1 H), 12.98 (br. s., 1 H), 10.18 (t, J=5.56 Hz, 1 H), 9.71 (br. s., 1 H), 8.46 (d, J=2.27 Hz, 1 H), 7.91 (dd, J=8.84, 2.53 Hz, 1 H), 7.52 - 7.61 (m, 2 H), 7.42 (t, J=8.08 Hz, 1 H), 7.23 (d, J=7.58 Hz, 1 H), 7.07 (d, J=9.09 Hz, 1 H), 5.32 (s, 2 H), 4.48 (d, J=12.63 Hz, 2 H), 4.09 (d, J=5.56 Hz, 2 H), 3.52 (d, J=10.36 Hz, 2 H), 3.00 - 3.26 (m, 5 H), 2.86 (d, J=4.04 Hz, 3 H), 1.21 (d, J=6.82 Hz, 6 H). MS(ES+) m/e 521 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | A sealed, degassed mixture of powdered KOH (123 mg, 2.2 mmol) and 1,2- dibromoethane (0.05 mL, 0.6 mmol) in anh THF (2 mL) under Ar was heated under microwave irradiation at 95 0C for 70 min. The reaction mixture was then cooled to rt and treated with Pd(OAc)2 (5.0 mg, 0.022 mmol), PPh3 (11.5 mg, 0.044 mmol), 1 -methyl-4-(5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (120 mg, 0.39 mmol) and degassed MeOH (2 mL). The sealed reaction mixture was heated again under microwave irradiation at 95 0C for 60 min. The crude mixture was concentrated under reduced pressure and purified by prepTLC (SiO2 10 % MeOH/DCM) to provide the title compound a colorless gum (0.18 g, quant): 1H NMR (400 MHz, CD3OD) delta ppm 8.07 (d, J=2.26 Hz, 1 H), 7.73 (dd, J=8.91, 2.38 Hz, 1 H), 6.82 (d, J=9.03 Hz, 1 H), 6.62 (dd, J=I 7.82, 11.04 Hz, 1 H), 5.63 (d, 1 H), 5.12 (d, J=10.79 Hz, 4 H), 3.52 - 3.66 (m, 4 H), 2.50 - 2.61 (m, 4 H), 2.35 (s, 3 H); MS ESI 204.0 [M + H]+, calcd for [Ci2H17N3+ H]+ 204.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; toluene; at 140℃;Inert atmosphere; Microwave irradiation; | General procedure: To a solution of 13 (30-90 mM) in toluene/EtOH (2:1) in a microwave vial under an argon atmosphere was added Pd(Ph3P)4 (5 mol%) and the mixture stirred for 10 min. An aqueous solution of 1M Na2CO3 (3 eq.) was then added followed by boronic acid (1.1 eq.) or boronic acid pinacol ester (1.1 eq.) and the mixture stirred for 5 min and then heated at 140 C for 21 min unless specified. The resultant mixture was cooled, poured onto ice and extracted with ethyl acetate. The organic extract was then dried (Na2SO4), filtered and solvent removed in vacuo to give the crude product. This was purified or used crude in the following trityl deprotection step as indicated. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.8% | With potassium phosphate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere; Sealed tube; | Example 2 N- [(4,6-Dimethyl-2-oxo- 1 ,2-dihydro-3 -pyridinyl)methyl] - 1 -( 1 -methylethyl)-6- [6-(4-methyl- l-piperazinyl)-3-pyridinyl]-lH-indole-4-carboxamideA mixture of 6-bromo-N-[(4,6-dimethyl-2-oxo-l,2-dihydro-3-pyridinyl)methyl]-l-(l- methylethyl)-lH-indole-4-carboxamide (0.10 g, 0.240 mmol), l-methyl-4-[5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (0.087 g, 0.288 mmol) and potassium phosphate (tribasic) (0.153 g, 0.721 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was degassed with N2 for 10 min, at which time PdCi2(dppf)-CH2Cl2 (0.029 g, 0.036 mmol) was added. The reaction was sealed and heated at 100 C for 2 h. The reaction was then allowed to cool to RT and sat overnight, at which time it was diluted with EtOAc, filtered through Celite, washed with EtOAc, and concentrated in vacuo. Purification of the residue by column chromatography (12 g Isco GOLD silica column; Gradient B: 5-90%; A: dichloromethane, B: 10% chloroform containing 2 M ammonia in methanol) gave N-[(4,6- dimethyl-2-oxo- 1 ,2-dihydro-3 -pyridinyl)methyl] - 1 -( 1 -methylethyl)-6- [6-(4-methyl- 1 - piperazinyl)-3-pyridinyl]-lH-indole-4-carboxamide (94 mg, 0.180 mmol, 74.8% yield). 1H NMR (400 MHz, DMSO-d6) delta ppm 1.46 (d, J=6.57 Hz, 6 H) 2.12 (s, 3 H) 2.17 - 2.28 (m, 6 H) 2.38 - 2.46 (m, 4 H) 3.49 - 3.57 (m, 4 H) 4.37 (d, J=5.05 Hz, 2 H) 4.86 - 4.98 (m, 1 H) 5.88 (s, 1 H) 6.87 (d, J=3.03 Hz, 1 H) 6.93 (d, J=8.84 Hz, 1 H) 7.58 (d, J=3.28 Hz, 1 H) 7.65 (d, J=1.26 Hz, 1 H) 7.87 (s, 1 H) 7.98 (dd, J=8.97, 2.65 Hz, 1 H) 8.28 (t, J=5.05 Hz, 1 H) 8.57 (d, J=2.27 Hz, 1 H) 11.55 (s, 1 H). MS(ES) [M+H]+ 513.3. |
74.8% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere; Sealed tube; | A mixture of 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indole-4-carboxamide (0.10 g, 0.240 mmol), <strong>[918524-63-7]1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine</strong> (0.087 g, 0.288 mmol) and potassium phosphate (tribasic) (0.153 g, 0.721 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was degassed with N2 for 10 min, at which time PdCl2(dppf)-CH2Cl2 (0.029 g, 0.036 mmol) was added. The reaction was sealed and heated at 100 C. for 2 h. The reaction was then allowed to cool to RT and sat overnight, at which time it was diluted with EtOAc, filtered through Celite, washed with EtOAc, and concentrated in vacuo. Purification of the residue by column chromatography (12 g Isco GOLD silica column; Gradient B: 5-90%; A: dichloromethane, B: 10% chloroform containing 2 M ammonia in methanol) gave N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1H-indole-4-carboxamide (94 mg, 0.180 mmol, 74.8% yield). 1H NMR (400 MHz, DMSO-d6) delta ppm 1.46 (d, J=6.57 Hz, 6H) 2.12 (s, 3H) 2.17-2.28 (m, 6H) 2.38-2.46 (m, 4H) 3.49-3.57 (m, 4H) 4.37 (d, J=5.05 Hz, 2H) 4.86-4.98 (m, 1H) 5.88 (s, 1H) 6.87 (d, J=3.03 Hz, 1H) 6.93 (d, J=8.84 Hz, 1H) 7.58 (d, J=3.28 Hz, 1H) 7.65 (d, J=1.26 Hz, 1H) 7.87 (s, 1H) 7.98 (dd, J=8.97, 2.65 Hz, 1H) 8.28 (t, J=5.05 Hz, 1H) 8.57 (d, J=2.27 Hz, 1H) 11.55 (s, 1H). MS(ES) [M+H]+ 513.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; for 3.0h;Inert atmosphere; Reflux; | Example 264 N-((4,6-dimethyl-2-oxo- 1 ,2-dihydropyridin-3-yl)methyl)- 1 -isopropyl-3-methyl-6-(6-(4- methylpiperazin- 1 -yl)pyridin- -yl)- 1 H-indole-4-carboxamide To a stirred solution of 6-bromo-N-((l,2-dihydro-4,6-dimethyl-2-oxopyridin-3- yl)methyl)-l-isopropyl-3 -methyl- lH-indole-4-carboxamide (2 g, 4.65 mmol) in DMF (100 mL) was added l-methyl-4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2- yl)piperazine (1.55 g, 5.12 mmol) followed by a solution of sodium carbonate (1.23 g, 11.62 mmol) in water (10 mL) and the contents were degassed with argon for 30 min. After that PdCl2(PPh3)2 (326 mg, 0.464 mmol) was added and the contents again degassed with argon for 10 min. The reaction mixture was stirred at reflux for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3x150 mL). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated to afford the crude product (2.8 g). The crude compound was purified by column chromatography over silica gel (100-200 mesh, eluent: 0-10percent MeOH: DCM), and the obtained product was further triturated with diethyl ether (100 mL) to afford the title compound as an off white solid (1.2 g, 50percent). 1H NMR (DMSO-d6, 400 MHz) : delta 1.493 (d, J = 6.4 Hz, 6H), 2.092 (s, 3H), 2.286 (s, 3H), 2.409 (s, 3H), 2.424 (s, 3H), 2.632 (s, 4H), 3.621 (s, 4H), 4.603-4.685 (m, 3H), 5.880 (s, 1H), 6.606 (d, J = 8.8 Hz ,1H), 7.016 (s, 1H), 7.261 (s, 1H), 7.433 (s, 1H), 7.675 - 7.704 (dd, J = 9 Hz, 2.4 Hz, 1H), 8.425 (d, J = 2.0 Hz, 1H), 11.699 (brs, 1H); LCMS (ES+): 525.23 [M-H]. |
50% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In water; N,N-dimethyl-formamide; for 3.0h;Inert atmosphere; Reflux; | To a stirred solution of 6-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxamide (2 g, 4.65 mmol) in DMF (100 mL) was added <strong>[918524-63-7]1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine</strong> (1.55 g, 5.12 mmol) followed by a solution of sodium carbonate (1.23 g, 11.62 mmol) in water (10 mL) and the contents were degassed with argon for 30 min. After that PdCl2(PPh3)2 (326 mg, 0.464 mmol) was added and the contents again degassed with argon for 10 min. The reaction mixture was stirred at reflux for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to afford the crude product (2.8 g). The crude compound was purified by column chromatography over silica gel (100-200 mesh, eluent: 0-10percent MeOH: DCM), and the obtained product was further triturated with diethyl ether (100 mL) to afford the title compound as an off white solid (1.2 g, 50percent). 1H NMR (DMSO-d6, 400 MHz): delta 1.493 (d, J=6.4 Hz, 6H), 2.092 (s, 3H), 2.286 (s, 3H), 2.409 (s, 3H), 2.424 (s, 3H), 2.632 (s, 4H), 3.621 (s, 4H), 4.603-4.685 (m, 3H), 5.880 (s, 1H), 6.606 (d, J=8.8 Hz, 1H), 7.016 (s, 1H), 7.261 (s, 1H), 7.433 (s, 1H), 7.675-7.704 (dd, J=9 Hz, 2.4 Hz, 1H), 8.425 (d, J=2.0 Hz, 1H), 11.699 (brs, 1H); LCMS (ES+): 525.23 [M?H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.2% | With sodium hydrogencarbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 85℃; for 1h;Inert atmosphere; Sealed tube; | e) N- { [4-(ethylamino)-6-methyl-2-oxo- 1 ,2-dihydro-3-pyridinyl]methyl} - 1 -( 1 -methylethyl)- 6-[6-(4-methyl- 1 -piperazinyl)-3-p ridinyl]- lH-indole-4-carboxamide To a 20 mL microwave vial was added 6-bromo-N-[4-(ethylamino)-6-methyl-2-oxo- l,2-dihydro-3-pyridinyl]methyl}-l-(l-methylethyl)-lH-indole-4-carboxamide (70 mg, 0.170 mmol), and l-methyl-4-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- pyridinyl]piperazine (59.9 mg, 0.198 mmol). PdC12(dppf)-CH2C12 adduct (14.67 mg, 0.018 mmol) and sodium bicarbonate (45.3 mg, 0.539 mmol) were added followed by 1,2- Dimethoxyethane (DME) (5 mL) and Water (2 mL). The vial was sealed and the reaction was heated to 85 C for 1 hr. The reaction was cooled and evaporated. The material was taken into Methanol/DMSO and was filtered through an acrodisk and purified by reverse phase Gilson HPLC (5-80% acetonitrile/water + 0.1% TFA, YMC ODS-A C18 Column 75 x30mm ID S-5um, 12nM Column, 6 minutes) the desired fractions were collected and evaporated from 0. IN NaOH which provided the desired product N- [4-(ethylamino)-6- methyl-2-oxo- 1 ,2-dihydro-3 -pyridinyljmethyl} - 1 -( 1 -methylethyl)-6- [6-(4-methyl- 1 - piperazinyl)-3-pyridinyl]-lH-indole-4-carboxamide (57 mg, 0.101 mmol, 56.2% yield). 1H NMR (400 MHz, DMSO-d6) delta ppm 10.68 (s, 1 H) 8.89 (t, J=5.94 Hz, 1 H) 8.66 (d, J=2.02 Hz, 1 H) 8.09 (dd, J=8.59, 2.02 Hz, 1 H) 7.91 (s, 1 H) 7.80 (s, 1 H) 7.60 (d, J=3.03 Hz, 1 H) 6.99 (d, J=8.84 Hz, 1 H) 6.89 - 6.96 (m, 2 H) 5.66 (s, 1 H) 4.85 - 4.98 (m, 1 H) 4.39 (d, J=5.81 Hz, 2 H) 3.63 (br. s., 4H) 3.11 - 3.24 (m, 2 H) 2.7 (bs, 4 H) 2.08 (s, 3 H) 1.47 (d, J=6.57 Hz, 6 H) 1.20 (t, 3 H). MS(ES) [M+H]+ 542.4. |
56.2% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium hydrogencarbonate; In 1,2-dimethoxyethane; water; at 85℃; for 1h;Inert atmosphere; Sealed tube; | To a 20 mL microwave vial was added 6-bromo-N-[4-(ethylamino)-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl]methyl}-1-(1-methylethyl)-1H-indole-4-carboxamide (70 mg, 0.170 mmol), and <strong>[918524-63-7]1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine</strong> (59.9 mg, 0.198 mmol). PdCl2(dppf)-CH2Cl2 adduct (14.67 mg, 0.018 mmol) and sodium bicarbonate (45.3 mg, 0.539 mmol) were added followed by 1,2-Dimethoxyethane (DME) (5 mL) and Water (2 mL). The vial was sealed and the reaction was heated to 85 C. for 1 hr. The reaction was cooled and evaporated. The material was taken into Methanol/DMSO and was filtered through an acrodisk and purified by reverse phase Gilson HPLC (5-80% acetonitrile/water+0.1% TFA, YMC ODS-A C18 Column 75×30 mm ID S-5 um, 12 nM Column, 6 minutes) the desired fractions were collected and evaporated from 0.1N NaOH which provided the desired product N-[4-(ethylamino)-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl]methyl}-1-(1-methylethyl)-6-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1H-indole-4-carboxamide (57 mg, 0.101 mmol, 56.2% yield). 1H NMR (400 MHz, DMSO-d6) delta ppm 10.68 (s, 1H) 8.89 (t, J=5.94 Hz, 1H) 8.66 (d, J=2.02 Hz, 1H) 8.09 (dd, J=8.59, 2.02 Hz, 1H) 7.91 (s, 1H) 7.80 (s, 1H) 7.60 (d, J=3.03 Hz, 1H) 6.99 (d, J=8.84 Hz, 1H) 6.89-6.96 (m, 2H) 5.66 (s, 1H) 4.85-4.98 (m, 1H) 4.39 (d, J=5.81 Hz, 2H) 3.63 (br. s., 4H) 3.11-3.24 (m, 2H) 2.7 (bs, 4H) 2.08 (s, 3H) 1.47 (d, J=6.57 Hz, 6H) 1.20 (t, 3H). MS(ES) [M+H]+ 542.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 110℃; for 4h; | Example 76N-((l,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-l-isopropyl-3-methyl-6-(6-(4- methylpiperazin-l-yl)pyridin-3-yl)-lH-indazole-4-carboxamideTo a stirred solution of 6-bromo-N-((l,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-l- isopropy 1-3 -methyl- lH-indazole-4-carboxamide (0.3 g, 0.69 mmol) in DMF (15 mL) was added 1- methyl-4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (0.25 g, 0.82 mmol) followed by PdCl2(PPh3)2 (0.097 g, 0.13 mmol) and the mixture stirred 5 min. Sodium carbonate (0.184 g, 1.73 mmol) dissolved in water (2 mL) was added and the resulting reaction mixture was stirred at 1 10 C for 4 h. The contents were then diluted with sodium bicarbonate solution and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine solution (20 mL), dried over anhydrous Na2S04, filtered, and concentrated to afford the crude product. The crude compound was purified by silica gel chromatography (eluent: 5% MeOHMDCM). The desired product was isolated as an off white solid with trace impurities. The impure compound was washed several times with cold water and triturated with hexane to afford the title compound as an off-white solid (80 mg, 22%). ¾ NM (DMSO-d6; 400 MHz) : delta 1.447 (d, J = 6.4 Hz, 6H), 2.112 (s, 3H), 2.235 (s, 6H), 2.41 1 (s, 7H), 3.551 (s, 4H), 4.363 (d, J = 4.4 Hz, 2H), 4.991-5.054 (m, 1H), 5.870 (s, 1H), 6.942 (d, J = 9.2 Hz, 1H), 7.321 (s, 1H), 7.880 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 8.403 (s, 1H ), 8.569 (s, 1H), 1 1.483 (brs, 1H). LCMS (ES+) m/z: 528.29. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With sodium hydrogencarbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 130℃; for 0.5h;Inert atmosphere; Sealed tube; Microwave irradiation; | Example 106V-[(4,6-Dimethyl-2-oxo-l,2-dihydro-3-pyridinyl)methyl]-l-(l-methylethyl)-6-[6-(4-methyl-l- piperazinyl)-3-pyridinyl]-l/ -indazole-4-carboxamideIn a 25 mL sealable tube under nitrogen were combined 6-bromo-N-[(4,6-dimethyl-2-oxo- l,2-dihydro-3-pyridinyl)methyl]-l-(l-methylethyl)-lH-indazole-4-carboxamide (100 mg, 0.24 mmol), l-methyl-4-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (109 mg, 0.36 mmol) in DME/water (3 mL: lmL). PdCl2(dppf)-CH2Cl2 (9.8 mg, 0.012 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (60.4 mg, 0.72 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave at 130 C for 30 min. Solvent was evaporated, DCM was added and it was purified by Si02 chromatography (eluent: gradient 100% DCM to 80:20:2 DCM/MeOH/NH4OH). Further purification by reversed- phase HPLC (C18, 15% to 80% CH3CN in water with 0.1% TFA, 12 minute gradient) afforded the TFA salt. The CH3CN was evaporated and the mixture was diluted with saturated sodium bicarbonate and EtOAc. The organic layer was separated and the aqueous layer was further extracted with DCM and DCM/isopropanol (80:20). The combined organic layers were washed with water, dried (MgS04), filtered and concentrated. EtOAc was added along with some hexanes, it was sonicated and the solids that precipitated were filtered and dried to afford the title compound (71 mg, 56%) as a white solid. ¾ NMR (400 MHz, DMSO-J6) delta ppm 1 1.55 (br. s., 1 H) 8.66 (d, =2.27 Hz, 1 H) 8.61 (t, J=4.93 Hz, 1 H) 8.36 (s, 1 H) 8.04 - 8.09 (m, 2 H) 7.84 (d, J=1.26 Hz, 1 H) 6.96 (d, J=8.84 Hz, 1 H) 5.89 (s, 1 H) 5.14 (quin, J=6.57 Hz, 1 H) 4.39 (d, J=5.05 Hz, 2 H) 3.52 - 3.60 (m, 4 H) 2.38 - 2.46 (m, 4 H) 2.22 (d, .7=4.55 Hz, 6 H) 2.13 (s, 3 H) 1.50 (s, 3 H) 1.49 (s, 3 H). MS(ES) [M+H]+ 514.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sodium hydrogencarbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 110℃; for 0.333333h;Inert atmosphere; Microwave irradiation; Sealed tube; | Example 16N-((4-ethyl-6-methyl-2-oxo-l,2-dihydropyridin-3-y])methyl)-l-isopropyl-6-(6-(4- methylpiperazin-l-yl)pyridin-3-yl)-lH-indazole-4-carboxamideIn a 25 mL sealable tube under nitrogen were combined 6-bromo-N-[(4-ethyl-6-methyl-2-oxo-l,2- dihydro-3-pyridinyl)methyl]-l-(l-methylethyl)-lH-indazole-4-carboxamide (90 mg, 0.21 mmol), 1- methyl-4-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (95 mg, 0.31 mmol) in dioxane/water (3 mL: lmL). PdCl2(dppf)-CH2Cl2 adduct (8.52 mg, 0.01 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (52.6 mg, 0.63 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave at 1 10 C for 20 min. The mixture was evaporated, DCM/MeOH (1 : 1) was added, and the contents pre-absorbed on silica gel and purified by Si02 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NE^OH).The collected product was further purified by reversed-phase HPLC (15% to 80% CH3CN in water with 0.1% TFA) which afforded the TFA salt. CH3CN was evaporated, and a saturated solution of sodium bicarbonate was added to the water layer along with EtOAc. The organic layer was separated, and the aqueous layer was further extracted with EtOAc, DCM and DCM/isopropanol (8:2). The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated. EtOAc was added along with some hexanes, and the contents were sonicated and then allowed sit overnight at room temperature. Solids that precipitated were filtered and dried to afford the title compound (84 mg, 76%) as a white solid. ¾ NMR (400 MHz, DMSO- 6) delta ppm 1 1.54 (br. s., 1 H) 8.65 (d, J=2.27 Hz, 1 H) 8.62 (t, J=4.80 Hz, 1 H) 8.36 (s, 1 H) 8.04 - 8.08 (m, 2 H) 7.82 - 7.85 (m, 1 H) 6.97 (d, .7=8.84 Hz, 1 H) 5.94 (s, 1 H) 5.14 (quin, J=6.57 Hz, 1 H) 4.42 (s, 1 H) 4.41 (s, 1 H) 3.52 - 3.59 (m, 4 H) 2.56 (q, .7=7.58 Hz, 2 H) 2.39 - 2.44 (m, 4 H) 2.23 (s, 3 H) 2.14 (s, 3 H) 1.50 (s, 3 H) 1.49 (s, 3 H) 1.10 (t, J=7.58 Hz, 3 H); LC-MS (ES) m/z = 486.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With sodium hydrogencarbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 110℃; for 0.333333h;Inert atmosphere; Microwave irradiation; Sealed tube; | Example 55l-cyclopent l-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl)methyl)-6-(6-(4- methylpiperazin-l-yl)pyridin-3-yl)-lH-indazole-4-carboxamideIn a 25 mL sealable tube under nitrogen were combined 6-bromo-l-cyclopentyl-N-[(6-methyl-2-oxo- 4-propyl-l,2-dihydro-3-pyridinyl)methyl]-lH-indazole-4-carboxamide (100 mg, 0.21 mmol), 1- methyl-4-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (96 mg, 0.32 mmol) in DME/water (3 mL: lmL). PdCl2(dppf)-CH2Cl2 adduct (8.7 mg, 0.01 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (53.5 mg, 0.64 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave at 1 10 C for 20 min. The mixture was evaporated, DCM/MeOH (1 : 1) was added, and the contents pre-absorbed on silica gel and purified by Si02 chromatography (eluent: gradient 0 to 80:20:2 DCM/MeOH/NH4OH).The collected product was further purified by reversed-phase HPLC (15% to 80% CH^CN in water with 0.1% TFA) which afforded the TFA salt. CH^CN was evaporated and a saturated solution of sodium bicarbonate was added. Solids that precipitated were filtered and dried to afford the title compound as a white solid (87 mg, 71%). *H NMR (400 MHz, DMSO-c/6) delta ppm 1 1.45 (br. s., 1 H) 8.68 (br. s., 1 H) 8.39 (s, 1 H) 8.24 (s, 1 H) 8.21 (d, J=5.30 Hz, 1 H) 7.84 - 7.88 (m, 1 H) 7.20 (s, 1 H) 7.13 (dd, J=5.31, 1.26 Hz, 1 H) 5.91 (s, 1 H) 5.38 (quin, J=7.07 Hz, 1 H) 4.43 (br. s., 1 H) 4.42 (br. s., 1 H) 3.55 - 3.63 (m, 4 H) 2.53 - 2.56 (m, 2 H) 2.41 - 2.46 (m, 4 H) 2.24 (s, 3 H) 2.12 - 2.20 (m, 5 H) 1.97 - 2.06 (m, 2 H) 1.86 - 1.95 (m, 2 H) 1.67 - 1.76 (m, 2 H) 1.48 - 1.57 (m, 2 H) 0.89 (t, J=7.33 Hz, 3 H); LC-MS (ES) m/z = 568.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | [0764] Synthesis of Compound A- 1 1 : N-((4,6-dimethyl-2-oxo- 1 ,2-dihydropyridin-3- yl)methyl)-l-isopropyl-6-(6-(4-methylpiperazin-l -yl)pyridin-3-yl)-lH-pyrazolo[3,4- b]pyridine-4-carboxamideCompound A- 1 1[0765] A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-l ,2-dihydropyridin-3-yl)methyl)- l -isopropyl-lH-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv), l -methyl-4-(5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1 ,4-dioxane was purged with argon for 10 min. Then, 2 M Na2C03 (3.6 equiv.) in water was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100 C for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give the desired compound (30% yield). LCMS: 515.20 (M + 1)+; HPLC: 98.36% (@ 254 nm), (Rt; 4.876); IH NMR (DMSO-d6, 400 MHz) delta 1 1.53 (s, IH), 9.01 (s, IH), 8.85 (t, IH), 8.36 (d, I H, J=8.8 Hz), 8.31 (s, I H), 8.07 (s, IH), 6.97 (d, IH, J=8.4 Hz), 5.89 (s, IH), 5.32-5.25 (m, IH), 4.40 (d, 2H, J=4.4 Hz), 3.61 (t, 4H), 2.41 (t, 4H), 2.22 (s, 6H), 2.12 (s, 3H), 1.53 (d, 6H, J=6.8 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33.6% | Step 4: Synthesis of 3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)benzamide A solution of 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((4-isopropyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (0.3 g, 0.99 mmol), respective boronic acid pinacol ester (0.216 g, 0.715 mmol), and tetrakis (0.068 g, 0.0596 mmol) in dioxane (10 mL) was purged with argon for 10 min. To this, aq. Na2CO3 (0.227 g, 2.14 mmol, 2 mL) was added and again degassed for 10 min. Reaction mixture was heated at 100 C. for 16 h. On completion, it was concentrated to obtain crude material which was purified using prep. HPLC to afford the title compound as a TFA salt (0.12 g, 33.6%). Analytical Data of TFA Salt: MS: 601.55 (M+1)+. HPLC: 96.78% (@ 210-370 nm) (Rt; 4.197; Method: Column: YMC ODS-A 150 mm×4.6 mm×5mu; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 muL, Col. Temp.: 30 C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) delta 11.49 (bs, 1H), 9.94 (bs, 1H), 8.493 (d, 1H, 6 Hz), 7.957 (bs, 1H), 7.65-7.258 (m, 3H), 7.056 (d, 1H, 8.4 Hz), 6.014 (s, 1H), 4.46 (d, 2H, 12.8 Hz), 4.349 (d, 2H, 4.8 Hz), 3.849 (d, 2H, 7.2 Hz), 3.530 (d, 2H, 10.8 Hz), 3.28-3.075 (m, 10H), 2.85 (s, 3H), 2.26 (bs, 3H), 2.14 (s, 3H), 1.64 (bs, 2H), 1.56 (bs, 2H), 1.14 (s, 3H), 1.12 (s, 3H), 0.845 (t, 3H, 7.6 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | Example 27V-[(4,6-Dimethyl-2-oxo-l,2-dihydro-3-pyridinyl)methyl]-3-methyl-l-(l-methylethyl)- 6- [6-(4-methyl- l-piperazinyl)-3-pyridinyl] - lH-pyrazolo [3,4-6] pyridine-4- carboxamideTo a 10-mL microwave vial were added 6-chloro-N-[(4,6-dimethyl-2-oxo-l,2- dihydro-3 -pyridiny l)methyl]-3 -methyl- 1 -( 1 -methylethyl)- 1 H-pyrazolo [3 ,4-b]pyridine-4- carboxamide (70 mg, 0.180 mmol),l-methyl-4-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-2-pyridinyl]piperazine (71.1 mg, 0.235 mmol) , DMSO (2.0 mL) and sodium carbonate (0.271 mL, 0.541 mmol) and the mixture was degassed for 10 min under nitrogen. Bis(triphenylphosphine)palladium(II) chloride (10.13 mg, 0.014 mmol) was added and the contents were sealed. The mixture was irradiated (microwave) at 140 C for 8 h. The reaction mixture was then quenched with water (5 mL) and filtered. The crude product was washed with water, dried, and then purified via silica gel chromatography (eluent: gradient of 0 to 15% (9 : 1 MeOH/NH4OH)/DCM). The resulting product was treated with MeOH and IN HCl. The mixture was concentrated in vacuo, dried under high vacuum and collected as the HCl salt, 42 mg (36%). LCMS E-S (M+H) = 529.0 1H NMR (400 MHz, DMSO-de) ? ppm 1.50 (d, 6 H), 2.13 (s, 3 H), 2.25 (s, 3 H), 2.42 (s, 3 H), 2.81 (d, J= 4.55 Hz, 3 H), 3.03 - 3.21 (m, 2 H), 3.41 (br. s., 2 H), 3.52 (d, J= 11.37 Hz, 2 H), 4.39 (d, J= 5.05 Hz, 2 H), 4.56 (d, J= 14.40 Hz, 2 H), 5.23 (quin, J= 6.63 Hz, 1 H), 5.91 (s, 1 H), 7.19 (d, J= 9.09 Hz, 1 H), 7.68 (s, 1 H), 8.50 (dd, J= 9.09, 2.27 Hz, 1 H) , 8.73 (t, J= 4.93 Hz, 3 H), 8.98 (d, J =2.02 Hz, 3 H), 10.97 - 11.21 (m, 2 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In ethanol; toluene; at 100℃; for 8h; | A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.75 g, 1.5 mmol), 1-Methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-piperazine (0.5 g, 17 mmol), Na2CO3 (2 M, 3.6 mL), and Pd(PPh3)2Cl2 (110 mg, 0.15 mmol) in toluene/ ethanol (1:1, 12 mL) was heated at 100 C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 6-(4-Methoxy-phenyl)-2-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as orange solid in 60% yield. |
60% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In ethanol; toluene; at 100℃; for 8h; | The corresponding intermediate 2-bromo-6- (4-methoxy-phenyl) -4- (2-trimethylsilane-ethoxymethyl) -4,7-dihydro- 4,5-diazo-cyclopenta [a] cyclopentadiene (0.75 g, 1.5 mmol)1-methyl-4 [5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -pyridin-2-yl]piperazine (0.5 g, 17 mmol), Na2CO3 (2 M, 3.6 mL) and Pd (PPh3) 2Cl2 (110 mg, 0.15 mmol) in toluene / ethanol (1: 1, 12 mL) was heated to 100 C 8 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The title product was obtained as an orange solid by gravity column chromatography (20% EtOAc in hexanes)6- (4-Methoxy-phenyl) -2- [6- (4-methyl-piperazin- 1 -yl) -pyridin-3-yl] -4- (2-trimethylsilane- Oxomethyl) -4,7-dihydro-1-thia-4,5-diazo-cyclopenta [a] cyclopentadiene in 60% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With tetrakis(triphenylphosphine) palladium(0); potassium fluoride dihydrate; In 1,2-dimethoxyethane; ethanol; water; at 110℃; for 0.833333h;Microwave irradiation; | General procedure: A vial was charged with 10a (200 mg, 0.50 mmol), 25c (140 mg, 0.50 mmol), KF·2H2O (143 mg, 1.51 mmol), Pd(PPh3)4 (29 mg, 0.25 mmol) and 5 mL of DME/H2O/EtOH (v/v/v, 7:3;2). Then the vial was capped and heated at 110 C for 50 min under microwave irradiation. The reaction mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by flash column chromatography (0-3% MeOH/CH2Cl2 gradient) and further separated by reverse HPLC (75-80% MeOH/H2O gradient) to afford compound 10c in 30% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With sodium 2'?(dicyclohexylphosphaneyl)?2,6?diisopropyl?[1,1'?biphenyl]?3?sulfonate; palladium diacetate; sodium carbonate; In isopropyl alcohol; at 90℃; for 2h;Inert atmosphere; | As shown in step 3-vii of Scheme 3, a solution of -chloro-N-(2-(3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)ethyl)pyrimidin-4-amine (60 mg, 0.197 mmol), 1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine (71.86 mg, 0.237 mmol), Na2CO3 (296.2 muL of 2M, 0.592 mmol), and [3-(2-dicyclohexylphosphanylphenyl)-2,4-dimethoxy-phenyl]sulfonyloxysodium (VPhos, 8.1 mg, 0.0158 mmol) in i-PrOH (1.6 mL) was degassed using a stream of N2 for 30 minutes. Pd(OAc)2 (0.88 mg, 0.0039 mmol) was added and the solution was heated to 90 C. for 2 hours. The solution was concentrated under reduced pressure and purified by medium pressure chromatography on silica gel (0 to 100% (10% MeOH/EtOAc) in hexanes) to give N-(2-(3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)ethyl)-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrimidin-4-amine (Compound 68, 32.4 mg, 36%) as a white solid: 1H NMR (400 MHz, CDCl3) delta 8.69 (s, 1H), 8.49 (s, 1H), 8.07 (d, J=8.1 Hz, 1H), 6.94-6.90 (m, 2H), 6.77 (t, J=7.3 Hz, 1H), 6.62 (d, J=8.9 Hz, 1H), 6.55 (s, 1H), 5.30 (s, 1H), 4.20 (s, 2H), 3.60 (s, 6H), 2.86 (t, J=6.4 Hz, 2H), 2.45 (s, 4H), 2.28 (s, 3H) and 1.27 (s, 6H) ppm; ESMS (M+H)=445.09. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With sodium 2'?(dicyclohexylphosphaneyl)?2,6?diisopropyl?[1,1'?biphenyl]?3?sulfonate; palladium diacetate; sodium carbonate; In isopropyl alcohol; at 90℃; for 4h;Inert atmosphere; | As shown in step 4-vi of Scheme 4, a mixture of 6-chloro-N-(2-(2-methoxyphenyl)propyl)pyrimidin-4-amine (75.0 mg, 0.270 mmol), 1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine (Compound 2007, 90.1 mg, 0.297 mmol), Pd(OAc)2 (1.21 mg, 0.00540 mmol), [3-(2-dicyclohexylphosphanylphenyl)-2,4-dimethoxy-phenyl]sulfonyloxysodium (VPhos, 11.1 mg, 0.0216 mmol), and Na2CO3 (405 muL of 2 M, 0.810 mmol) in IPA (2 mL) was degassed and back-filled with N2 (repeated 2*), then heated to 90 C. for 4 hours. The reaction mixture was filtered through diatomaceous earth and concentrated under reduced pressure. The residue was purified by medium pressure chromatography on silica gel (90-100% EtOAc in hexanes) to give N-(2-(2-methoxyphenyl)propyl)-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrimidin-4-amine as a clear, yellow oil (Compound 2013, 48.0 mg, 42% yield): 1H NMR (CDCl3) delta 8.77 (d, J=2.2 Hz, 1H), 8.56 (s, 1H), 8.15 (dd, J=9.0, 2.5 Hz, 1H), 7.28-7.21 (m, 2H), 7.01-6.89 (m, 2H), 6.72 (d, J=9.0 Hz, 1H), 6.60 (s, 1H), 5.09 (bs, 1H), 3.87 (s, 3H), 3.76-3.65 (m, 4H), 3.65-3.46 (m, 3H), 2.62-2.48 (m, 4H), 2.38 (s, 3H), 1.36 (d, J=6.7 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium hydrogencarbonate; In 1,4-dioxane; water; at 110℃; for 2h;Microwave irradiation; | To a 10 ml microwave vial was added 5-bromo-2-methyl-3-[(1-methylethyl)amino ]-N-[( 6-methyl-2-oxo-4-propyl-1 ,2-dihydro-3-pyridinyl)methyl]benzamide (130 mg, 0.299 mmol), 1-methyl-4-[5-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (127 mg, 0.389 mmol) then PdClz(dppf)- CH2Clz adduct (24.44 mg, 0.030 mmol) followed by 1,4-dioxane (10 mL). To the solutionwas added sodium bicarbonate (75 mg, 0.898 mmol) and water (2 mL). The vial wascapped and the reaction stirred on a hot plate at 110 oc for 2 h. The reaction was cooledand evaporated. The residue was filtered through an acrodisc and purified by reverse phaseGilson HPLC (10-70% acetonitrile/water+ 0.1% TFA, YMC ODS-A C18 Column 75 x30 mm ID S-5um, 12 nM Column 7 minutes). The title compound was isolated as an offwhite solid after extraction of the desired fractions with EtOAc/NaHC03 (sat aq),evaporation precipitation (from MeOH/ water (119)) and filtering. 1H NMR (400 MHz,DMSO-d6) 8 ppm 11.47 (br. s., 1 H) 8.36 (d, J=2.53 Hz, 1 H) 8.00 (t, J=4.93 Hz, 1 H) 7.77(dd, J=8.84, 2.53 Hz, 1 H) 6.88 (d, J=9.09 Hz, 1 H) 6.74 (d, J=1.01 Hz, 1 H) 6.65 (d,J=I.52 Hz, 1 H) 5.89 (s, 1 H) 4.47 (d, J=8.08 Hz, 1 H) 4.28 (d, J=4.80 Hz, 2 H) 3.70-3.81 (m, 1 H) 3.48- 3.54 (m, 4 H) 2.48- 2.49 (m, 2H) 2.39- 2.43 (m, 4 H) 2.22 (s, 3 H)2.12 (s, 3 H) 2.04 (s, 3 H) 1.49- 1.60 (m, 2 H) 1.20 (d, J=6.32 Hz, 6 H) 0.93 (t, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium acetate; | 2. Preparation of 1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine To 1,4-dioxane (20 mL) was successively added 1-(5-bromopyridin-2-yl)-4-methylpiperazine (0.67 g, 2.62 mmol), bis(pinacolato)diboron (1.00 g, 3.94 mmol), potassium acetate (0.65 g, 6.63 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichlormethane complex (15 mg). The resulting mixture was reacted under stirring in a nitrogen-protecting atmosphere at 90 C. for 12 hrs. The reaction mixture was cooled and directly used in the next step without a further treatment. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.6% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; at 90℃; for 16h;Cooling; Inert atmosphere; | 3. Preparation of 2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-10-(3-(trifluoromethyl)phenyl)pyrido [3,2-c][1,5]naphthyridin-9(10H)-one To the cooled reaction liquor of (1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)pyridin-2-yl)piperaz ine) obtained in the above step, were added 2-chloro-10-(3-(trifluoromethyl)phenyl)pyrido[3,2-c][1,5]naphthyridin-9(10H)-o ne (0.68g, 1.81mmol), palladium tetrakis(triphenylphosphine) (15mg) and 2N sodium carbonate solution (3.9mL). This system was reacted in a nitrogen-protecting atmosphere at 90 C for 16 h, cooled to the room temperature and filtered. The organic layer was separated out, concentrated in a reduced pressure, dissolved in dichlormethane, successively washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified with a silica-gel column chromatography (ethyl acetate) to produce 518 mg of the target compound in a yield of 55.6%. Formula: C28H23F3N6O MW: 516.19 MS(M+H): 517.3 1H-NMR(CDCl3, 400 MHz): delta 8.99 (1H, s), 8.35 (1H, d), 8.33 (1H, d), 8.02 (1H, d), 7.94 (1H, d), 7.76 (1H, d), 7.69 (1H, s), 7.63 (1H, t), 7.42 (1H, d), 6.99 (1H, d), 6.94 (1H, dd), 6.46 (1H, d), 3.75-3.67 (4H, m), 2.64-2.56 (4H, m), 2.40 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In dimethyl sulfoxide; at 80℃;Inert atmosphere; | A mixture of 15 (1.5 g, 5.9 mmol), bis(pinacolato)diboron (1.6 g, 6.5 mmol), potassium acetate(1.8 g, 18 mmol) and Pd(dppf)2Cl2[CH2Cl2] (0.73 g, 0.89 mmol) in DMSO (20 mL) was protected with nitrogen and stirred at 80 oC overnight. The mixture was diluted with water and extracted with EA. The organic solution was concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EA, v/v = 3 to EA) to give 1.0 g of 16 (56% yield) as a brown solid. MS: m/z 304 (M+H)+. |
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 90℃; for 12h;Inert atmosphere; | 2. Preparation of 1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine To 1,4-dioxane(20mL) was successively added 1-(5-bromopyridin-2-yl)-4-methylpiperazine (0.67g, 2.62mmol), bis(pinacolato)diboron (1.00g, 3.94mmol), potassium acetate (0.65g, 6.63mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium(II) chloride dichlormethane complex(15mg). The resulting mixture was reacted under stirring in a nitrogen-protecting atmosphere at 90C for 12hrs. The reaction mixture was cooled and directly used in the next step without a further treatment. | |
33 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; N,N-dimethyl-formamide; at 95℃;Inert atmosphere; | Step 2: A mixture of compound 1b-2 (37.5 g, 146.4 mmol), compound Pd(dppf)Cl2 (4.3 g, 5.86 mmol), compound 1b.2 (81.8 g, 322.0 mmol), potassium acetate (57.5 g, 585.6 mmol), 1,4-dioxane (300 mL) and DMF (200 mL) was stirred under argon atmosphere at 95 C. overnight. The reaction solution was filtered, concentrated and purified by combiflash (EA:MeOH=90:10) to give a solid compound 1b (33 g, 75%). MS m/z (ESI): 304.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.2% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃;Inert atmosphere; Sealed tube; | In a sealed tube, Pd(PPh3)4 (0.016 g, 0.014 mmol), K2C03 (0.115 g, 0.834 mmol), Example A3 (0.100 g, 0.278 mmol), and 2-(4-methylpiperazino)pyridine-5-boronic acid pinacol ester (0.126 g, 0.417 mmol) were suspended in dioxane (6 mL) and water (1.5 mL). The mixture was degassed with Ar and heated at 90 C overnight. The reaction mixture was partitioned between EtOAc and IN NaOH and extracted with EtOAc (2x). The EtOAc extracts were combined and washed with brine. The aqueous extracts were combined and back-extracted with DCM (3x). The DCM extracts were combined with the EtOAc extracts, dried, and evaporated. The crude product was purified by silica gel preparatory TLC (DCM/MeOH(10% NEt3)) to give the desired product, which was dissolved in acetonitrile/water, frozen and lyophilized to yield 3- (tert-butyl)- 1 -(6-methyl-5-((6'-(4-methylpiperazin- 1 -yl)-[2,3'-bipyridin]-4-yl)oxy)pyridin-2-yl)- lH-l ,2,4-triazol-5(4H)-one (49 mg, 35.2%). 1H NMR (400 MHz, DMSO-de): delta 1 1.99 (s, 1 H), 8.85 (d, J = 2.5 Hz, 1 H), 8.49 (d, J = 5.7 Hz, 1 H), 8.27 (dd, J = 9.0, 2.5 Hz, 1 H), 7.86 (d, J = 8.8 Hz, 1 H), 7.71 (d, J = 8.8 Hz, 1 H), 7.56-7.54 (m, 1 H), 7.03 (d, J = 9.0 Hz, 1 H), 6.77-6.75 (m, 1 H), 4.51-4.49 (m, 2 H), 3.56-3.46 (m, 2 H), 3.22-3.20 (m, 2 H), 3.08-3.05 (m, 2 H), 2.81 (d, J = 4.5 Hz, 3 H), 2.35 (s, 3 H), 1.27 (s, 9 H); MS (ESI) m/z: 501.3 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In water; N,N-dimethyl-formamide; at 120℃;Inert atmosphere; | Example 190: N-((4,6-Dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-6-(6-(4-methylpiperazin- 1 -yl)pyridin-3-yl)-1 -oxo-2,3-dihydro-1 H-indene-4-carboxamide A mixture of the compound of example 189 (0.055 g, 0.141 mmol), 1 -methyl- 4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (0.064 g, 0.212 mmol), and potassium carbonate (0.039 g, 0.283 mmol) in DMF:H20 (2:1 ) (12 ml_) were sonicated for two minutes and the reaction mixture was stirred under argon atmosphere at an ambient temperature. The dichlorobis(triphenylphosphine) Palladium(ll) (4.96 mg, 0.014 mmol) was added to the reaction mixture and stirred at 120 C till the reaction was complete. The reaction mixture was diluted with EtOAc (50 ml_) and filtered through a celite bed. The filtrate was washed with water (20 ml_), brine (5 ml_). The organic layer was dried over anhydrous Na2S04, filtered, concentrated and the residue obtained was purified by column chromatography (silica gel, 5 % methanol in chloroform) to obtain the title compound. Yield: 0.069 g (97 %); 1H NMR (300 MHz, DMSO-d6): delta 1 1 .52 (br. s, 1 H), 8.54-8.52 (m, 2H), 8.09 (m, 1 H), 7.99 (dd, J = 8.7 and 2.4 Hz, 1 H), 7.86 (m, 1 H), 6.94 (d, J = 8.7 Hz, 1 H), 5.87 (s, 1 H), 4.34 (d, J = 1 .8 Hz, 2H), 3.54 (m, 4H), 3.30-3.20 (m, 2H), 2.60-2.50 (m, 2H), 2.45-2.35 (m, 4H), 2.21 -2.20 (m, 6H), 2.1 1 (s, 3H); MS (ESI+): m/z 486 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 3h;Inert atmosphere; | Example 66:Methyl 3-(ethyl(tetrahyd ro-2H-pyran-4-yl)ami no)-2-methyl-5-(6-(4-methyl piperazin-1 -yl)pyridin-3-yl)benzoateThe compound of example 19 (2 g, 5.61 mmol) was added to a stirredsolution of 1 -methyl-4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (1 .702 g, 5.61 mmol), PdCI2(dppf)-CH2CI2 adduct (0.458 g, 0.561 mmol) and Na2003 (1.785 g, 16.84 mmol) in 1 ,4-dioxane (5 mL) and water (1 .667 mL). The reaction mixture was stirred at 80 C for 3h under nitrogen atmosphere. The resulting mixture was cooled, diluted with water and extracted with ethylacetate. The ethyl acetate layer was washed with water and brine and dried over anhydrous sodium sulphate to obtain a crude material, which was purified by column chromatography (silica gel, 10-20 % methanol in chloroform) to yield the title compound.Yield: 2.08 g (78 %); 1H NMR (DMSO-d6, 300 MHz): 68.42 (5, 1H), 7.85-7.83 (m, 1 H), 7.65 (5, 1 H), 7.51 (5, 1 H), 6.90 (d, J= 9.0 Hz, 1 H), 3.84 (5, 3H), 3.83-3.73 (m, 2H), 3.53-3.41 (m, 4H), 3.29-3.22 (m, 2H), 3.11-3.01 (m, 3H), 2.49-2.42(m, 4H), 2.41 (5, 3H), 2.23 (5, 3H), 1.68-1.13 (m, 4H), 0.81 (t, J= 6.9 Hz, 3H); MS(ESl+): m/z 453.3 [M+H] HPLC Purity: 95.67 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19.41% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere; | Example 28: 3-( Ethyl(tetrahyd ro-2H-pyran-4-yI)am i no)-2-methyl-N-((4-methyl-2-oxo-3,5,6,7,8,9-hexahydro-2H-cyclohepta[c]pyridin-1 -yI)methyl)-5-(6-(4-methyl pi perazin-1 -yI)pyridi n-3-yI)benzamideThe compound of example 24 (175 mg, 0.329 mmol) was added to a stirredsolution of 1 -methyl-4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (150 mg, 0.494 mmol), Pd012(dppf)-0H2012 adduct (26.9 mg, 0.033 mmol) and Na2003 (105 mg, 0.988 mmol) in 1,4-dioxane (5 mL) and water (1.667 mL). The reaction mixture was stirred at 80 00 for 2 h under nitrogen atmosphere. The reaction mixture was cooled, diluted with water and extracted with ethylacetate. The ethyl acetate layer was washed with water and brine; and dried overanhydrous sodium sulphate. The organic layers were concentrated to obtain acrude material, which was purified by using column chromatography (silica gel, 0-15 % MeOH/0H013) to yield the title compound.Yield: 0.041 g (19.41%); 1H NMR (DMSO-d6, 300 MHz): 6 8.39 (5, 1H),7.82-7.79 (m, 1H), 7.34 (5, 1H), 7.16 (5, 1H), 6.90-6.87 (m, 1H), 4.37 (d, J= 4.2Hz, 2H), 3.83-3.80 (m, 2H), 3.52-3.48 (m, 4H), 3.24 (t, J= 11 .4 Hz, 2H), 3.08-3.05(m, 3H), 2.64-2.63 (m, 2H), 2.36-2.39 (m, 6H), 2.28 (5, 3H), 2.21 (5, 6H), 1.73-1.48 (m, 1OH), 0.81(t, J= 6.6 Hz, 3H); MS (ESl+): m/z 627.4 [M+H] HPLC Purity:97.73 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24.43% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere; | Example 37: 3-( Ethyl(tetrahyd ro-2H-pyran-4-yI)am i no)-2-methyl-N-((8-methyl-6-oxo-3,4,6,7-tetrahydro-1 H-pyrano[3,4-c]pyridi n-5-yI)methyl)-5-(6-(4- methyl piperazin-1 -yI)pyridi n-3-yI)benzamideThe compound of example 35(100mg, 0.193 mmol) was added to a stirredsolution of 1 -methyl-4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (88 mg, 0.289 mmol), PdCI2(dppf)-CH2Cl2adduct (15.75 mg, 0.019 mmol) and Na2CO3 (61 .3 mg, 0.579 mmol) in 1 ,4-dioxane (5 mL) and water (1 .667 mL). The reaction mixture was stirred at 80C for 2h under nitrogen atmosphere. The reaction mixture was cooled, diluted with water and extracted with ethylacetate. The ethyl acetate layer was washed with water and brine; and dried overanhydrous sodium sulphate. The organic layers were concentrated to obtain acrude mixture, which was purified by using column chromatography (silica gel, 0-15 % MeOH/CHCI3) to yield the title compound.Yield: 0.030 g (24.43 %); 1H NMR (DMSO-d6, 300 MHz): 6 11.57 (5, 1H),8.41 (5, 1H), 8.19 (5, 1H), 7.84 (d, J= 3.9 Hz, 1H), 7.36 (5, 1H), 7.18 (5, 1H), 6.94(d, J= 5.4 Hz, 1H), 4.45 (5, 2H), 4.28 (5, 2H), 3.84-3.78 (m, 4H), 3.52-3.44 (m,4H), 3.25 (t, J= 6.9 Hz, 2H), 3.09-3.02 (m, 3H), 2.81-2.83 (m, 2H), 2.61-2.65 (m,4H), 2.41 (5, 3H), 2.22 (5, 3H), 2.04 (5, 3H), 1.67-1.36 (m, 4H), 0.82 (t, J= 6.6 Hz,3H); MS (ESl+): m/z 615.6 [M+H] HPLC Purity: 96.55 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 3h;Inert atmosphere; | Example 43:3-(Ethyl(tetrahydro-2H-pyran-4-yI)ami no)-2-methyl-5-(6-(4-methyl pi perazi n-i - yl)pyridi n-3-yl)-N-((3-oxo-2,3,5,6,7,8-hexahydroisoqui noli n-4-yl)methyl)benzamideThe compound of example 40(100mg, 0.199 mmol) was added to a stirredsolution of 1 -methyl-4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (91 mg, 0.299 mmol), PdCI2(dppf)-CH2CI2 adduct (16.25 mg, 0.020 mmol) and Na2003 (63.3 mg, 0.597 mmol) in 1 ,4-dioxane (5 mL) and water (1 .667 mL). The reaction mixture was stirred at 80 C for 3h under nitrogen atmosphere. The reaction mixture was cooled, diluted with water and extracted with ethylacetate. The ethyl acetate layer was washed with water and brine, and dried overanhydrous sodium sulphate. The organic layers were concentrated to obtain acrude material, which was purified by using column chromatography (silica gel, 0-15 % MeOH/CHCI3) to yield the title compound.Yield: 0.016 g (12.73 %); 1H NMR (DMSO-d6, 300 MHz): 6 11.39 (5, 1H),8.54 (5, 1H), 8.42(s, 1H), 7.85-7.82 (m, 1H), 7.39 (5, 1H), 7.29 (5, 1H), 7.08 (5,1H), 6.90 (d, J= 8.7 Hz, 1H), 4.16 (d, J= 5.1 Hz, 2H), 3.84-3.81 (m, 2H), 3.54-3.50 (m, 4H), 3.21 (t, J= 11.4 Hz, 2H), 3.13-3.08 (m, 3H), 2.39-2.30 (m, 8H), 2.26 (5, 3H), 2.21 (s, 3H), 1.68-1.34 (m, 8H), 0.83 (t, J= 6.9 Hz, 3H); MS (ESI+): m/z 599.6 [M+H] HPLC Purity: 94.78 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 3h;Inert atmosphere; | Example 48:N-((1 -ethoxy-3-oxo-2,3,5,6,7,8-hexahydroisoquinol i n-4-yl)methyl)-3-(ethyl (tetrahyd ro-2H-pyran-4-yl)ami no)-2-methyl-5-(6-(4-methyl pi perazi n-i -yl)pyridi n-3-yl)benzamideThe compound of example 46 (150 mg, 0.274 mmol) was added to a stirred solution of 1 -methyl-4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2- yl)piperazine (125 mg, 0.412 mmol), PdCI2(dppf)-CH2CI2 adduct (22.41 mg, 0.027 mmol) and Na2003 (87 mg, 0.823 mmol) in 1 ,4-dioxane (5 mL) and water (1 .667 mL). The reaction mixture was stirred at 80 C for 3h under nitrogen atmosphere.The reaction mixture was cooled, diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with waterand brine and dried over anhydrous sodium sulphate to obtain a crude material, which was purified by column chromatography (silica gel, 10-20 % methanol in chloroform) to yield the title compound.Yield: 0.008 g (4.10 %); 1H NMR (DMSO-d6, 300 MHz): 6 10.25 (5, 1H),8.40 (5, 1H), 8.38 (5, 1H), 7.82 (d, J= 5.4 Hz, 1H), 7.37 (5, 1H), 7.17 (5, 1H), 6.90(d, J= 5.4 Hz, 1 H), 4.31 (d, J= 3.3 Hz, 2H), 4.26 (q, J= 4.8 Hz, 2H), 3.83 (d, J= 6.0Hz, 2H),3.58-3.52 (m, 4H), 3.25 (t, J= 6.6 Hz, 2H), 3.09-2.98 (m, 3H), 2.73 (5,2H), 2.42-2.36 (m, 6H), 2.23 (5, 6H), 1.67-1.52 (m, 8H), 1.28 (t, J= 4.2 Hz, 3H),0.82 (t, J= 3.9 Hz, 3H); MS (ESl+): m/z 643.4 [M+H] HPLC Purity: 90.48 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.017 g | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 3h;Inert atmosphere; | Example 52:3-( Ethyl(tetrahyd ro-2H-pyran-4-yl)am i no)-2-methyl-N-((6-methyl-2-oxo-1 ,2- di hydropyridi n-3-yl)methyl)-5-(6-(4-methyl pi perazi n-i -yl)pyrid i n-3- yl)benzamideThe compound 1 -methyl-4-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (197 mg, 0.649 mmol) was added to a stirred solution ofthe compound of example 50 (200 mg, 0.433 mmol), PdCI2(dppf)-CH2CI2 adduct (35.3 mg, 0.043 mmol) and Na2CO3 (138 mg, 1.298 mmol) in 1,4-dioxane (5 mL) and water (1.667 mL). The reaction mixture was stirred at 80 C for 3h under nitrogen atmosphere. The resultingmixture was cooled, diluted with water andextracted with ethyl acetate. The ethyl acetate layer was washed with water and brine and dried over anhydrous sodium sulphate to obtain a crude material, which was purified by column chromatography (silica gel, 10-15 % methanol in chloroform ) to yield the title compound. Yield: 0.017 g (6.66 %); 1H NMR (DMSO-d6, 300 MHz): 6 11.66 (s, 1H),8.56 (s, 1 H), 8.49 (s, 1 H), 7.94 (d, J= 9.0 Hz, 1 H), 7.41 (s, 1 H), 7.32 (s, 1 H), 7.26(d, J= 6.9 Hz, 1H), 7.03 (d, J= 8.7 Hz, 1H), 5.99 (d, J= 6.9 Hz, 1H), 4.16 (s, 2H),3.84-3.82 (m, 2H),3.25-3.15 (m, 4H), 3.18-3.02 (m, 6H),2.82-2.76 (m, 3H), 2.26 (s,3H), 2.15 (s, 3H), 1.65-1.42 (m, 4H), 1.17 (t, J= 7.2 Hz, 3H), 0.83 (t, J= 6.9 Hz,3H); MS (ESl+): m/z 559.4 [M+H] HPLC Purity: 96.17%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.9% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 20 - 80℃; for 3.33333h;Inert atmosphere; | To a solution of methyl 4-bromo-l -ethyl-7-methyl-lH-indole-6-carboxylate (Intermediate 1-3, 1.8 g, 6.08 mmol) in dioxane (20 mL) and water (10 mL), were added 1- methyl-4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (2.396 g, 7.90 mmol) and 2.0 M solution of sodium carbonate (9.12 mL, 18.23 mmol). Argon was bubbled through the mixture for 20 minutes at room temperature. To this mixture was added PdCl2(dppf)-CH2Cl2 adduct (0.496 g, 0.608 mmol) and heated to 80 C for 3 hours. After completion of the reaction, it was cooled to room temperature, filtered through celite, and concentrated. Water was added and extracted with ethyl acetate and concentrated. Further purification by column chromatography using 2-5 % MeOH in chloroform provided the title compound (1.5 g, 3.82 mmol, 62.9 % yield) as a solid. JH NMR (DMSO-d6, 300 MHz) delta ppm: 8.34 (s, 1H), 7.77 (d, J=8.5 Etazeta,IotaEta), 7.56 (d, J=3 Etazeta,IotaEta), 7.36 (s, 1H), 6.96 (d, J=5.4 Hz, 1H), 6.52 (d, J=2.5 Etazeta,IotaEta), 4.52 (m, 2H), 3.84 (s, 3H), 3.54 (bs, 4H), 2.86 (s, 3H), 2.42 (bs, 4H), 2.23 (s,3H), 1.38 (t, J=7 Hz 3H). MS (ESI- ): 393.4 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; at 20 - 85℃; for 1.25h;Inert atmosphere; | To a solution of 4-bromo-l-ethyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3- yl)methyl)-lH-indole-6-carboxamide (Example 22, 125 mg, 0.290 mmol) and l-methyl-4- (5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (114 mg, 0.378 mmol) in 1,4-dioxane (2 mL) was added 2 M solution of Na2C03 (0.436 mL, 0.871 mmol) and stirred at RT for 15 minutes with argon bubbling. PdCi2(dppf)-CH2Ci2 adduct (23.72 mg, 0.029 mmol) was added and stirred at 85 C for 1 h. After completion of the reaction, the reaction mixture was cooled to RT and filtered through celite, water was added and extracted with ethyl acetate. The organic layer was washed with water and concentrated which was further purified by column chromatography (5-10 % MeOH in chloroform) to obtain the title compound. Yield: 68 mg (43 ); JH NMR (DMSO-d6; 300 MHz): delta 11.51 (s, 1H), 8.43 (s, 1H), 8.38 (s, 1H), 7.99 (s, 1H), 7.86 (d, J = 9 Hz, 1H), 7.57 (s, 2H), 6.96 (d, J= 8.7 Hz, 1H), 6.54 (d, J= 3 Hz, 1H), 5.89 (s, 1H), 4.38 (d, J= 4.5 Hz, 2H), 4.28 (q, J= 6.9 Hz, 2H), 3.54 (s, 4H), 2.49 (m, 2H), 2.41 (s, 4H), 2.22 (s, 3H), 2.11 (s, 3H), 1.46-1.53 (m 2H), 1.38 (t, J= 7.2 Hz, 3H), 0.86 (t, J= 7.2 Hz, 3H); MS (ESI+): 527.5 [M+H]+; HPLC purity: 96.98 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 20 - 80℃; for 5.16667h;Inert atmosphere; | To a solution of 4-bromo-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-7- methyl-lH-indole-6-carboxamide (Example 25, 125 mg, 0.322 mmol) and l-methyl-4-(5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (127 mg, 0.419 mmol) in 1,4-dioxane (5 mL) and water (5 mL) was added 2M Na2C03 (0.483 mL, 0.966 mmol) and argon was bubbled at RT for 10 minutes and added PdCl2(dppf)-CH2Ci2 Adduct (26.3 mg, 0.032 mmol) catalyst and stirred the reaction mixture at 80 C for 5 h. After completion of the reaction, cooled the reaction mixture to RT, filtered through celite, water was added, extracted with ethyl acetate and concentrated to obtain the crude product. The crude product obtained was stirred in ethyl acetate and filtered to obtain the title compound. Yield: 70 mg (43 %); JH NMR (DMSO-d6; 300 MHz): delta 11.48 (s, 1H), 11.33 (s, 1H), 8.41 (s, 1H), 8.05 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.46 (s, 1H), 7.00 (s, 1H), 6.93 (d, J= 8.7 Hz, 1H), 6.53 (s, 1H), 5.86 (s, 1H), 4.30 (d, J= 4.8 Hz, 2H), 3.52 (s, 4H), 2.52 (s, 3H), 2.41 (s, 4H), 2.22 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H); MS (ESI+): 485.2 [M+H]+; HPLC purity: 96.29 %. Example 28: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; at 20 - 90℃; for 4.16667h;Inert atmosphere; | To a solution of 4-bromo-7-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydropyridin-3-yl) methyl)- l-(2,2,2-trifluoroethyl)-lH-indole-6-carboxamide (Example 68, 50 mg, 0.100 mmol) in dioxane (2 mL) was added l-methyl-4-(5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl)piperazine (42.6 mg, 0.140 mmol) and PdCl2(dppf)- CH2CI2 adduct (2.458 mg, 3.01mupiiotaomicron1) under nitrogen atmosphere and stirred at RT for 10 minutes. 2 M Na2CC>3 solution (0.151 mL, 0.301 mmol) was added and the reaction mixture was heated to 90 C for 4 h. After completion of the reaction, reaction mixture was cooled to RT, filtered through celite, the filtrate was concentrated, added water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to obtain crude. The crude was purified by flash chromatography using 1 :9 MeOH:CHCl3 to obtain the title compound. Yield: 26 mg (43 ); JH NMR (DMSO-de, 300 MHz): delta 11.47 (s, 1H), 8.31 (s, 1H), 8.12 (s, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.43 (s, 1H), 6.93 (m, 3H), 6.59 (s, 1H), 5.87 (s, 1H), 5.37 (m, 1H), 4.30 (d, J = 3.9 Hz, 2H), 3.51 (bs, 4H), 2.60 (s, 3H), 2.52 (m, 2H), 2.39 (bs, 4H), 2.20 (s, 3H), 2.09 (s, 3H), 1.54 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H); MS (ESI+): 595.3 [M+H]+; HPLC purity: 97.87 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.6% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 20 - 80℃; for 16.5h;Inert atmosphere; | To a solution of 7-bromo-3-(dimethylamino)-4-methyl-N-((6-methyl-2-oxo-4-propyl-l,2- dihydropyridin-3-yl)methyl)-2,3-dihydro-lH-indene-5-carboxamide (Example 79, 20 mg, 0.043 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added l-methyl-4-(5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (18.44 mg, 0.061 mmol) and 2 M solution of sodium carbonate (13.81 mg, 0.130 mmol) and argon gas was bubbled for 30 minutes at room temperature. PdCl2(dppf) (3.18 mg, 4.34 mupiiotaomicron) was added and the reaction mass was heated to 80 C for 16 h. After completion of reaction, the reaction mass was cooled to room temperature, filtered through celite, the filtrate was concentrated, added water, extracted with ethyl acetate, concentrated and purified by column chromatography to obtain the title compound. Yield: 12 mg (49.6 ); JH NMR (DMSO-d6, 300 MHz): delta 11.46 (s, 1H), 8.20 (s, 1H), 8.10 (bs, 1H), 7.66 (d, 1H, J=7.8 Hz), 7.09 (s,lH), 6.88 (d, 1H, J=9Hz), 5.87 (s, 1H), 4.27 (bs, 3H), 3.50 (bs, 4H), 2.97 (m, 1H), 2.73 (m, 1H), 2.40 (bs, 4H), 2.35 (s, 3H), 2.22 (s, 3H), 2.10 (bs, 8H), 1.71 (m, 1H), 1.51 (m, 2H), 1.32 (bs, 1H), 1.22 (bs, 3H), 0.92 (m, 3H); MS (ESI+): m/z 557 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; at 20 - 90℃; for 4.16667h;Inert atmosphere; | To a solution of 7-bromo-2-isopropyl-4-methyl-N-((6-methyl-2-oxo-4-propyl-l,2-dihydro pyridin-3-yl)methyl)benzo[d]thiazole-5-carboxamide (Example 92, 70 mg, 0.147 mmol) in dioxane (2.8 mL) was added l-methyl-4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yl)piperazine (62.4 mg, 0.206 mmol), PdCl2(dppf)-CH2Ci2 adduct (3.60 mg, 4.41 mupiiotaomicron) under nitrogen atmosphere and stirred at RT for 10 minutes. 2 M Na2CC>3 solution (0.220 mL, 0.441 mmol) was added and reaction mixture was heated to 90 C for 4 h. After completion of reaction, reaction mixture was cooled to RT, filtered through celite, filtrate was concentrated, water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated to obtain crude and the crude obtained was purified by flash chromatography using 1 :9 methanohdichloromethane to obtain the title compound. Yield: 62 mg (74 ); JH NMR (DMSO-de, 500 MHz): delta 11.51 (s, IH), 8.44 (s, IH), 8.32 (s, IH), 7.86 (d, J = 9.0 Hz, IH), 7.33 (s, IH), 6.99 (d, J = 9.0 Hz, IH), 5.90 (s, IH), 4.34 (d, J = 5.0 Hz, 2H), 3.57 (bs, 4H), 3.43 (m, IH), 2.69 (s, 3H), 2.55 (m, 2H), 2.42 (s, 4H), 2.23 (s, 3H), 2.12 (s, 3H), 1.56 (m, 2H), 1.42 (d, J = 7.2 Hz, 6H), 0.93 (t, J = 7.2 Hz, 3H); MS (ESI+): m/z 573.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 20 - 78℃; for 3.33333h;Inert atmosphere; | To a solution of methyl 4-bromo-7-methyl-l-((tetrahydro-2H-pyran-4-yl)methyl)-lH- indole-6-carboxylate (Intermediate 1-26, 350 mg, 0.956 mmol) and l-methyl-4-(5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (435 mg, 1.433 mmol) in 1,4- dioxane (10 mL) and water (5 mL) was added 2 M Na2C( (1.433 mL, 2.87 mmol) and argon was bubbled for 20 minutes at RT. To the reaction mixture, was added PdCl2(dppf)- CH2CI2 adduct (78 mg, 0.096 mmol) and stirred at 78 C for 3 h. After completion of the reaction, the reaction mixture was cooled to RT, filtered through celite, the solid obtained was washed with MeOH and purified by column chromatography (silica gel, 2-3 % MeOH in chloroform) to obtain the title compound. Yield: 398 mg (90 ); JH NMR (CDC13; 300 MHz): delta 8.32 (d, J= 2.4 Hz, 1H), 7.75 (dd, J = 8.7 & 2.4 Hz, 1H), 7.51 (d, J= 3.3 Hz, 1H), 7.35 (s, 1H), 6.93 (d, J= 8.7 Hz, 1H), 6.48 (d,J= 3 Hz, 1H), 4.31 (d, J= 6.9 Hz, 2H), 3.82 (s, 3H), 3.76-3.81 (m, 2H), 3.52 (s, 4H), 3.10-3.18 (m, 2H), 2.83 (s, 3H), 2.40 (s, 4H), 2.21 (s, 3H), 1.85-1.92 (m, 1H), 1.21-1.28 (m, 4H); MS (ESI+): 463.3 [M+H]+; HPLC purity 99.66 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.2 g | With sodium carbonate; In 1,4-dioxane; water; at 20℃; for 0.5h;Inert atmosphere; | To a solution of methyl 4-bromo-7-methyl-lH-indole-6-carboxylate (Intermediate 1-2, 1.5 g, 5.59 mmol) and l-methyl-4-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2- yl)piperazine (2.54 g, 8.39 mmol) in 1,4-Dioxane (25 mL) and water (12.50 mL) was added 2M Na2CC>3 (8.39 mL, 16.78 mmol) solution and argon was bubbled for 30 minutes at RT. After completion of the reaction, the reaction mixture was cooled to RT and filtered through celite, extracted with ethyl acetate and DCM and purified by column chromatography (silica gel, 1-2 % MeOH in CHCI3) to obtain the title compound. Yield: 1.2 g; JH NMR (DMSO-de; 300 MHz): delta 11.62 (s, 1H), 8.40 (s, 1H), 7.81 (d, J = 5.1 Hz, 1H), 7.61 (s, 1H), 7.54 (s, 1H), 6.96 (d, J= 5.4 Hz, 1H), 6.60 (s, 1H), 3.84 (s, 3H), 3.54 (s, 4H), 2.76 (s, 3H), 2.43 (s, 4H), 2.23 (s, 3H); MS (ESI+): 365.3 [M+H]+; HPLC purity: 99.08 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In N,N-dimethyl-formamide; at 140℃; for 0.5h;Inert atmosphere; Micellar solution; | A mixture of 13 (133 mg, 0.33 mmol), 16 (200 mg, 0.66 mmol), Pd(dppf)2Cl2[CH2Cl]2 (41 mg, 0.050 mmol) and Cs2CO3 (215 mg, 0.66 mmol) in DMF (5 mL) was protected with argon and irradiated with microwave at 140 oC for 30 minutes. The mixture was diluted with ethyl acetate and filtered through Celite. The filtrate was concentrated and the residue was purified by flash chromatography and prep-HPLC (HCOOH system) to give 55 mg of JQEZ5 (31% yield) as a dark solid. MS: m/z 543.4 (M+H)+; 1H NMR (500 MHz, CDCl3) delta 9.00 (d, J = 2.5 Hz, 1H), 8.33 (s, 1H), 8.31 (dd, J = 9.0 and 2.5 Hz, 1H), 8.14 (t, J = 6.0 Hz, 1H), 7.87 (s, 1H), 6.75 (d, J = 9.0 Hz, 1H), 6.02 (s, 1H), 5.38 (m, 1H), 4.69 (d, J = 6.0 Hz, 2H), 3.88 (m, 4H), 2.92 (m, 4H), 2.75 (m, 2H), 2.62 (s, 3H), 2.27 (s, 3H), 1.67 (m, 2H), 1.62 (d, J = 6.5 Hz, 6H), 1.05 (t, J = 7.0 Hz, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 110℃; for 1h;Inert atmosphere; Microwave irradiation; | 150 mg (0.37 mmol) 7-chloro-N- [(4-ethoxy-6-methyl-2-oxo- 1 ,2-dihydropyridin-3-yl)methyl] -1- isopropylimidazo[1,5-a]pyridine-5-carboxamide (intermediate 201A), 124.2 mg (0.41 mmol) 1- methyl-4- [5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine and 43 mg (37pmol) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. 0.37 ml (0.75 mmol) aqueous sodium carbonate solution (2N), 1.5 ml ethanol und 2 ml toluene were added and the resulting mixture heated for lh to 110 C in a Biotage Initiator microwave oven. The reaction mixture was concentrated in vacuo and the residue purified by silica gel column chromatography (eluent: gradient of methanol in dichloromethane) toyield 92 mg of the slightly impure target compound. Further purification by preparative HPLC (see subsequent box for details) provided 49 mg (24%) of the target compound in pure form.System:Waters Autopurificationsystem: Pump 254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3100Column:XBrigde C18 5pm 100x30 mmSolvent:A = H20 + 0.1% HCOOH (99%)B = acetonitrileGradient:0-8 mm 1-99% BFlow:70 ml/minTemperature:room temperature?H NMR (300 MHz, DMSO-d6) oe [ppm] = 1.24 (t, 3 H), 1.29 (d, 6 H), 2.17 (s, 3 H), 2.21 (s, 3 H),2.38-2.41 (m, 4 H), 3.43 (m, 1H), 3.51-3.54 (m, 4 H), 4.08 (q, 2H), 4.33 (d, 2 H), 6.08 (s, 1 H),6.91 (d ,1 H), 7.44 (s, 1 H), 7.95 (s, 1 H), 8.01 (dd, 1H), 8.59 (d, 1H), 8.69 (t, 1 H), 8.82 (s, 1 H),11.45 (s, 1 H).LCMS (conditions 2.2): R 0.51mm; MS (ESI): [M + H] = 544.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 110℃; for 1h;Inert atmosphere; Microwave irradiation; | 80 mg (0.19 mmol) 7-chloro-N- [(4-ethoxy-6-methyl-2-oxo- 1 ,2-dihydropyridin-3-yl)methyl] -1- isopropyl-3-methylimidazo [1 ,5-a]pyridine-5-carboxamide (intermediate 203A, 68.82 mg, 0.23mmol) 1 -methyl-4- [5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine and 22 mg (19 pmol) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. 0.192 ml (0.384 mmol) aqueous sodium carbonate solution (2N), 1.5 ml ethanol und 1.5 ml 1 ,2-dimethoxyethane were added and the resulting mixture heated for 1 h to 110C in a Biotage Initiator microwave oven. The reaction mixture was concentrated in vacuo andthe residue purified by preparative HPLC (Preparative HPLC conditions 2 (basic)) provided 60.7 mg (52%) of the target compound in pure form.?H-NMR (300MHz, DMSO-do): oe [ppm]= 1.22 - 1.34 (m, 9H), 2.17 (s, 3H), 2.22 (s, 3H), 2.37 - 2.43 (m, 4H), 2.46 (s, 3H), 3.35 - 3.44 (m, 1H), 3.48 - 3.57 (m, 4H), 4.10 (q, 2H), 4.29 (d, 2H),6.08 (s, 1H), 6.86 - 6.93 (m, 2H), 7.78 (d, 1H), 7.94 (dd, 1H), 8.51 (d, 1H), 8.67 (t, 1H), 11.44 (s,1H).MS (ESI): [M + H] = 558.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 130℃; for 0.5h;Inert atmosphere; Microwave irradiation; | 50 mg (0.12 mmol) rae-i -sec-butyl-7-chloro-N- [(4-ethoxy-6-methyl-2-oxo- 1 ,2-dihydropyridin-3-yl)methyl]imidazo[i,5-a]pyridine-5-carboxamide (intermediate 204A), 64.4 mg (0.216 mmol) 1- methyl-4- [5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine and 20.8 mg (18 pmol) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under an atmosphere of argon. 0.12 ml (0.24 mmol) aqueous sodium carbonate solution (2N), 0.75 ml ethanol und 0.75 ml toluene were added and the resulting mixture heated for 30 mm to 130 C in aBiotage Initiator microwave oven. The reaction mixture was filtered and concentrated. The crude product was purified by preparative HPLC (Preparative HPLC conditions 1) to provide 38.2 mg (57%) of the target compound in pure form.?H-NMR (400MHz, DMSO-do): oe [ppm]= 0.76 (t, 3H), 1.22 - 1.30 (m, 6H), 1.59 - 1.78 (m, 2H),2.18 (s, 3H), 2.23 (s, 3H), 2.39 - 2.45 (m, 4H), 3.12 - 3.22 (m, 1H), 3.51 - 3.57 (m, 4H), 4.10 (q,2H), 4.34 (d, 2H), 6.09 (s, 1H), 6.92 (d, 1H), 7.44 (d, 1H), 7.93 (d, 1H), 8.01 (dd, 1H), 8.59 - 8.62(m, 1H), 8.69 (t, 1H), 8.83 (s, 1H), 11.45 (br. s, 1H).MS (ESI): [M + H] = 558.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 130℃; for 0.5h;Inert atmosphere; Microwave irradiation; | 50 mg (0.117 mmol) 7-chioro- 1 -cyclopentyl-N- [(6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3-yl)methyl]imidazo[1,5-a]pyridine-5-carboxamide (intermediate 214A), 63.9 mg (0.21 mmol) 1-methyl-4- [5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine and 20.3 mg (18pmol) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vial under anatmosphere of argon. 0.117 ml (0.233 mmol) aqueous sodium carbonate solution (2N), 1.5 ml ethanol und 1.5 ml 1 ,2-dimethoxyethane were added and the resulting mixture heated for 30 mm to 130 C in a Biotage Initiator microwave oven. The reaction mixture was filtered and concentrated. The crude product was purified by preparative HPLC (conditions 1) to provide 28.8mg (38%) of the target compound in pure form.?H-NMR (400MHz, DMSO-do): oe [ppm]= 0.89 (t, 3H), 1.52 (sxt, 2H), 1.62 - 1.71 (m, 2H), 1.75 -1.88 (m, 4H), 1.94 - 2.04 (m, 2H), 2.14 (s, 3H), 2.23 (s, 3H), 2.42 (t, 4H), 3.49 - 3.58 (m, 5H), 4.40(d, 2H), 5.92 (s, 1H), 6.93 (d, 1H), 7.49 (d, 1H), 7.96 (d, 1H), 8.02 (dd, 1H), 8.61 (d, 1H), 8.82 (s,1H), 8.91 (t, 1H), 11.54 (s, 1H)) (3 H obscured by solvent signal).LCMS (conditions 2.5): R = 0.79 mm; MS (ESI): [M + H] = 568.38 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 110℃; for 1h;Inert atmosphere; Microwave irradiation; | 80 mg (0.181 mmol) 7-chloro-N- { [4-(cyclobutylmethoxy)-6-methyl-2-oxo- 1 ,2-dihydropyridin-3- yl]methyl } -1 -isopropylimidazo [1 ,5-a]pyridine-5-carboxamide (intermediate 222A), 71.2 mg (0.24mmol) 1 -methyl-4- [5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine and20.8 mg (18 pmol) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwave vialunder an atmosphere of argon. Aqueous sodium carbonate solution (2N; 0.226 ml; 0.452 mmol),1.5 ml ethanol und 1.5 ml 1,2-dimethoxyethane were added and the resulting mixture was heatedfor 1 h to 110 C in a Biotage Initiator microwave oven. The reaction mixture was filtered andconcentrated. The crude product was purified by preparative HPLC (conditions 2) to provide 32 mg(31%) of the target compound in pure form.1H-NMR (400MHz, DMSO-d6): oe [ppm]= 1.30 (d, 6H), 1.72 - 1.86 (m, 4H), 1.88 - 2.00 (m, 2H),2.18 (s, 3H), 2.22 (s, 3H), 2.40 (t, 4H), 2.57 - 2.66 (m, 1H), 3.44 (dt, 1H), 3.49 - 3.58 (m, 4H), 4.00(d, 2H), 4.34 (d, 2H), 6.11 (s, 1H), 6.92 (d, 1H), 7.46 (d, 1H), 7.96 (d, 1H), 8.01 (dd, 1H), 8.60 (d,1H), 8.68 (t, 1H), 8.84 (s, 1H), 11.48 (s, 1H).MS (ESI): [M + H] = 584.5 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 110℃; for 1h;Inert atmosphere; Microwave irradiation; | 90 mg (0.21 mmol) 7-chloro-N- [(4-methoxy-6-methyl-2-oxo- 1 ,2-dihydropyridin-3-yl)methyl] -1-(tetrahydro-2H-pyran-4-yl)imidazo [1 ,5-a]pyridine-5-carboxamide (intermediate 225A), 76.0 mg(0.25 mmol) 1 -methyl-4- [5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazineand 24 mg (21 pmol) tetrakis(triphenylphosphine)palladium(0) were weighed into a microwavevial under an atmosphere of argon. Aqueous sodium carbonate solution (2N; 0.26 ml; 0. 52 mmol),1.5 ml ethanol und 1.5 ml 1,2-dimethoxyethane were added and the resulting mixture was heated for 1 h to 110 C in a Biotage Initiator microwave oven. The reaction mixture was filtered and concentrated. The crude product was purified by preparative HPLC (conditions 2) to provide 38 mg (31%) of the target compound in pure form.1H-NMR (400MHz, DMSO-d6): oe [ppm]= 1.70 (d, 2H), 1.92 (m, 2H), 2.19 (s, 3H), 2.22 (s, 3H),2.37 - 2.43 (m, 4H), 3.44 - 3.62 (m, 7H), 3.81 (s, 3H), 3.97 (dd, 2H), 4.31 (d, 2H), 6.13 (s, 1H),6.93 (d, 1H), 7.47 (d, 1H), 7.97 - 8.12 (m, 2H), 8.63 (d, 1H), 8.71 (t, 1H), 8.84 (s, 1H), 11.51 (br. s.,1H).MS (ESI): [M + H] = 572.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | 40 mg (86 pmol) 7-chloro-N- { [4-(difluoromethoxy)-6-methyl-2-oxo- 1 ,2-dihydropyridin-3- yl]methyl } -1 -(tetrahydro-2H-pyran-4-yl)imidazo[ 1 ,5-a]pyridine-5-carboxamide (intermediate 226A), 31.2 mg (103 pmol) 1 -methyl-4- [5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-2- yl]piperazine and 9.9 mg (9 pmol) tetrakis(triphenylphosphine)palladium(0) were weighed into amicrowave vial under an atmosphere of argon. Aqueous sodium carbonate solution (2N; 0.107 ml;0.214 mmol), 1.5 ml ethanol und 1.5 ml 1 ,2-dimethoxyethane were added and the resulting mixture was heated for 1 h to 110 C in a Biotage Initiator microwave oven. The reaction mixture was filtered and concentrated. The crude product was purified by preparative HPLC (conditions 2) to yield 12 mg of impure product, which was further purified by preparative HPLC (conditions: seebelow) to provide 3 mg (6 %) of the trifluoroacetate salt of the target compound in pure form.Conditions for final preparative HPLC:Column: Waters XBrigde C18 5 pm 100 x 30 mm;Eluent: A: water + 0.2% vol. trifluoroacetic acid (99%); B: acetonitrile;Gradient: 0.0-0.5 mm 5% B, 0.5 1-5.5 mm 5-50% B1H-NMR (400MHz, DMSO-d6): oe [ppm]= 1.71 (d, 2H), 1.87 - 2.01 (m, 2H), 2.22 (s, 3H), 2.86 (d,3H), 3.04 - 3.22 (m, 5H), 3.40 - 3.57 (m, 6H, overlain by water signal), 3.99 (dd, 2H), 4.36 (d, 2H),4.50 (d, 2H), 6.11 (s, 1H), 7.09 (d, 1H), 7.64 (br. s., 1H), 8.16 (dd, 1H), 8.20 (s, 1H), 8.72 (d, 1H),8.97 (t, 1H), 9.15 (br. s., 1H), 9.73 (br. s., 1H).MS (ESI): [M + H] = 608.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; dimethyl sulfoxide; at 110℃; for 1.5h;Microwave irradiation; | Example 113A N-alpha-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide 3-Bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide (150 mg, 0.24 mmol) and <strong>[918524-63-7]1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine</strong> (109 mg, 0.36 mmol) were dissolved in dimethyl sulphoxide (2 ml), and tetrakis(triphenylphosphine)palladium(0) (28 mg, 24 mumol), sodium carbonate (76 mg, 0.72 mmol) and water (0.36 ml, 20 mmol) were added. The reaction mixture was stirred at 110 C. in a microwave (Biotage Initiator) for 90 min, cooled, filtered and purified by chromatography via HPLC (Method 10). This gave 70 mg (40% of theory) of the title compound. LC-MS (Method 4): Rt=0.89 min; MS (ESIpos): m/z=723.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | Example 78A N-alpha-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-4-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide formate 27.7 mg (23.9 mumol) of tetrakis(triphenylphosphine)palladium(0), 76.1 mg (0.72 mmol) of sodium carbonate and 0.36 ml (20.0 mmol) of water were added to a solution of 150 mg (0.24 mmol) of 4-bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide and 108.9 mg (0.36 mmol) of <strong>[918524-63-7]1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine</strong> in 1.8 ml of DMSO. The mixture was treated in the microwave at 110 C. for 2.5 h. The mixture was filtered and purified by preparative HPLC (Method 10). 49 mg (28% of theory) of the title compound were obtained. LC-MS (Method 4): Rt=0.89 min; MS (ESIpos): m/z=723.6 [M+H-HCOOH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.37% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In water; toluene; at 80℃; for 10h; | 2- (1-Naphthylmethoxy)-6-bromo-3-iodoquinoline (100 mg, 0.21 mmol) was dissolved in 3 mL of toluene, Followed by adding1,1 - bis (diphenylphosphino) ferrocene dichloropalladium dichloromethane complex (8.6 mg, 0.01 mmol), sodium carbonate (43 mg, 0.4 lmmo 1) in 1 mL of water, (6- (4-methylpiperazin-l-yl) pyridin-3-yl) boronic acid pinacol ester(Dichloromethane / methanol 15: 1). The reaction mixture was stirred at 80 C for 10 hours, then 5 mL of water was added and the mixture was extracted three times with dichloromethane. The organic phase was combined and purified by column chromatography (dichloromethane / methanol 15: 1)To give 75 mg of a yellow solid, yield 66.37% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium phosphate; dicyclohexylphosphino-2?,6?-di-i-propoxy-1,1?-biphenyl; In water; N,N-dimethyl-formamide; at 75℃; for 1h; | 4-Chloro-N-[(4-isopropoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-2,8-dimethyl- quinoline-7-carboxamide (example 20) (135 mg, 0.33 mmol) and l-methyl-4-[5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine (128.6 mg, 0.42 mmol) were solved in N,N-dimethylformamide (2 ml) and treated with RuPhos-Pd-G2 (51 mg, 0.065 mmol) and 0.5 M aqeous potassium phosphate solution (1.96 ml, 0.98 mmol). The reaction mixture was stirred at 75C for 60 min. Purification via HPLC (method 14) gave 117 mg (65% of theory) of the title compound. NMR (400 MHz, DMSO-d6) delta ppm 1.28 (d, 6 H) 2.16 (s, 3 H) 2.24 (s, 3 H) 2.43 (m, 4 H) 2.70 (s, 3 H) 2.73 (s, 3 H) 3.56 - 3.63 (m, 4 H) 4.29 (d, 2 H) 4.62 - 4.72 (m, 1 H) 6.09 (s, 1 H) 7.02 (d, 1 H) 7.35 (d, 1 H) 7.37 (s, 1 H) 7.66 - 7.75 (m, 2 H) 8.03 - 8.10 (m, 1 H) 8.26 (d, 1 H) 11.26 - 11.41 (m, 1 H). UPLC (method 1) [M+H]+ 555.3, 0.70 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With potassium phosphate; dicyclohexylphosphino-2?,6?-di-i-propoxy-1,1?-biphenyl; In water; N,N-dimethyl-formamide; at 75℃; for 1h; | 4-Chloro-2,8-dimemyl-N-[(6-memyl-2-oxo-4-pro carboxamide (example 21) (100 mg, 0.25 mmol) and l-methyl-4-[5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl]piperazine (99.1 mg, 0.33 mmol) were solved in N,N- dimethylformamide (2 ml) and treated with RuPhos-Pd-G2 (39 mg, 0.05 mmol) and 0.5 M aqeous potassium phosphate solution (1.5 ml, 0.75 mmol). The reaction mixture was stirred at 75C for 60 min. Purification via HPLC (method 8) gave 54 mg (40% of theory) of the title compound. NMR (400 MHz, DMSO-d6) delta ppm 0.95 (t, 3 H) 1.52 - 1.63 (m, 2 H) 2.13 (s, 3 H) 2.24 (s, 3 H) 2.43 (m, 4 H) 2.53 - 2.58 (m, 2 H) 2.70 (2s, 6 H) 3.58 - 3.63 (m, 4 H) 4.35 (d, 2 H) 5.91 (s, 1 H) 7.02 (d, 1 H) 7.33 (d, 1 H) 7.37 (s, 1 H) 7.64 - 7.78 (m, 2 H) 8.14 - 8.32 (m, 2 H) 11.38 - 11.66 (m, 1 H). UPLC (method 1) [M+H]+ 539.3, 0.75 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With potassium phosphate; dicyclohexylphosphino-2?,6?-di-i-propoxy-1,1?-biphenyl; In water; N,N-dimethyl-formamide; at 75℃; for 2h; | 4-Chloro-N-[(4-isobutyl-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-2,8-dimethylquinoline- 7-carboxamide (example 22) (157 mg, 0.38 mmol) and l-methyl-4-[5-(4,4,5,5-tetramefhyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl]piperazine (150.2 mg, 0.49 mmol) were solved in N,N- dimethylformamide (2 ml) and treated with RuPhos-Pd-G2 (59 mg, 0.076 mmol) and 0.5 M aqeous potassium phosphate solution (2.3 ml, 1.14 mmol). The reaction mixture was stirred at 75C for 120 min. Purification via HPLC (method 14) gave 83 mg (40% of theory) of the title compound. NMR (400 MHz, DMSO-d6) delta ppm 0.93 (d, 6 H) 1.82 - 1.94 (m, 1 H) 2.13 (s, 3 H) 2.24 (s, 3 H) 2.40 - 2.45 (m, 4 H) 2.47 (d, 2 H) 2.70 (s, 6 H) 3.57 - 3.63 (m, 4 H) 4.34 (d, 2 H) 5.88 (s, 1 H) 7.02 (d, 1 H) 7.33 (d, 1 H) 7.38 (s, 1 H) 7.67 - 7.74 (m, 2 H) 8.20 - 8.25 (m, 1 H) 8.26 (d, 1 H) 11.40 - 11.59 (m, 1 H). UPLC (method 1) [M+H]+ 553.3, 0.80 min. - - |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With potassium phosphate; dicyclohexylphosphino-2?,6?-di-i-propoxy-1,1?-biphenyl; In water; N,N-dimethyl-formamide; at 75℃; for 2h; | 4-Chloro-N- { [4-( 1 , 1 -difluoro-2-methylpropyl)-6-methyl-2-oxo- 1 ,2-dihydropyridin-3-yl]methyl } - 2,8-dimethylquinoline-7-carboxamide (example 23) (200 mg, 0.45 mmol) and l-methyl-4-[5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine (176 mg, 0.58 mmol) were solved in N,N-dimethylformamide (2 ml) and treated with RuPhos-Pd-G2 (69.4 mg, 0.09 mmol) and 0.5 M aqeous potassium phosphate solution (2.7 ml, 1.34 mmol). The reaction mixture was stirred at 75C for 120 min. Purification via HPLC (method 14) gave 68 mg (26% of theory) of the title compound. H NMR (400 MHz, DMSO-d6) delta ppm 1.01 (d, 6 H) 2.21 (s, 3 H) 2.24 (s, 3 H) 2.41 - 2.45 (m, 4 H) - - 2.69 - 2.72 (m, 6 H) 3.57 - 3.63 (m, 4 H) 4.37 - 4.42 (m, 2 H) 6.06 (s, 1 H) 7.02 (d, 1 H) 7.33 (d, 1 H) 7.38 (s, 1 H) 7.67 - 7.76 (m, 2 H) 8.13 - 8.21 (m, 1 H) 8.23 - 8.30 (m, 1 H) 11.92 - 12.19 (m, 1 H). UPLC (method 1) [M+H]+ 589.3, 0.84 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | With potassium phosphate; dicyclohexylphosphino-2?,6?-di-i-propoxy-1,1?-biphenyl; In water; N,N-dimethyl-formamide; at 75℃; for 2h; | N-[(4-sec-butoxy-6-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl]-4-chloro-2,8-dimethyl- quinoline-7-carboxamide (example 24) (37.5 mg, 0.09 mmol) and l-methyl-4-[5-(4,4,5,5- tetramethyl- l,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine (34.5 mg, 0.11 mmol) were solved in Nu,Nu-dimethylformamide (1 ml) and treated with RuPhos-Pd-G2 (13 mg, 0.02 mmol) and 0.5 M aqeous potassium phosphate solution (0.53 ml, 0.26 mmol). The reaction mixture was stirred at 75C for 120 min. Purification via HPLC (method 9) gave 5 mg (9% of theory) of the title compound. - - H NMR (400 MHz, DMSO-d6) delta ppm 0.90 - 0.97 (m, 3 H) 1.24 (d, 3 H) 1.57 - 1.71 (m, 2 H) 2.16 (s, 3 H) 2.24 (s, 3 H) 2.41 - 2.46 (m, 4 H) 2.70 (s, 3 H) 2.72 (s, 3 H) 3.57 - 3.63 (m, 4 H) 4.27 - 4.33 (m, 2 H) 4.43 - 4.52 (m, 1 H) 6.09 (s, 1 H) 7.03 (d, 1 H) 7.34 (d, 1 H) 7.38 (s, 1 H) 7.66 - 7.74 (m, 2 H) 8.01 - 8.08 (m, 1 H) 8.25 - 8.28 (m, 1 H). UPLC (method 2) [M+H]+ 569.3, 1.13 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Toa solution of 3-bromo-6-(3-cyclopropyl-5-methyl-1H-pyrazol-4-yl)-1H-indazole(190 mg, 0.599 mmol) in acetonitrile (20 mL) in a round-bottom flask were added di-tert-butyldicarbonate (288 mg, 1.32 mmol), triethylamine (0.332 mL, 2.40 mmol) and 4-dimethylaminopyridine (7.3 mg, 0.0599 mmol). The resulting mixturewas stirred at room temperature for 1 hour, then concentrated under reducedpressure. Purification byflash chromatography on silica gel (0% to 20% AcOEt/n-hexane linear gradient) provided the title compound (275 mg, 0.532 mmol, 89% yield):To a solution of tert-butyl 3-bromo-6-[1-(tert-butoxycarbonyl)-3-cyclopropyl-5-methyl-1H-pyrazol-4-yl]-1H-indazole-1-carboxylate (or tert-butyl 3-bromo-6-[1-(tert-butoxycarbonyl)-5-cyclopropyl-3-methyl-1H-pyrazol-4-yl]-1H-indazole-1-carboxylate) (130 mg, 0.251 mmol) in 1,2-dimethoxyethane (5 mL) in a round-bottom flask were added <strong>[918524-63-7]1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine</strong> (152 mg, 0.503 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (20.5 mg, 0.0251 mmol), tripotassium phosphate hydrate (174 mg, 0.754 mmol), and water (2 mL). The resulting mixture was stirred for 1 hour at 100oC and thereaction mixture was addedwater.The resulting solution was extracted with AcOEt. The organic extracts were combined, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Purificationby flash chromatography on NH-silicagel (0% to 67%AcOEt/n-hexane linear gradient) provided the title compound (128 mg, 0.209 mmol, 83% yield); tert-butyl 6-[1-(tert-butoxycarbonyl)-3-cyclopropyl-5-methyl-1H-pyrazol-4-yl]-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1H-indazole-1-carboxylate (or tert-butyl 6-[1-(tert-butoxycarbonyl)-5-cyclopropyl-3-methyl-1H-pyrazol-4-yl]-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1H-indazole-1-carboxylate) (128 mg, 0.209mmol) was dissolved in 4mol/L hydrogen chloride in1,4-dioxane (9.58 mL, 313 mmol). The resulting mixture was stirred at 60 oCfor 1 hour, then concentrated under reduced pressure. The residue wasadded saturated aqueous sodium hydrogen carbonate solution and the resultingsolid was collected. The solidwas washed with waterand dried under reduced pressure at 50C. The title compound was obtained as a white solid. (58.0mg,0.140 mmol, 67% yield): 1H NMR (500 MHz, DMSO-d6) d 13.00 (s,1H), 12.23 (brs, 1H), 8.72 (s, 1H), 8.09 (d, J= 8.7Hz, 1H), 7.99 (d, J= 8.3 Hz, 1H), 7.45 (brs,1H),7.19 (d, J = 8.7Hz, 1H), 6.96 (d, J= 8.3 Hz, 1H), 3.59-3.51(m, 4H), 2.42-2.37 (m, 4H), 2.23 (brs, 3H), 2.21 (s, 3H),1.83-1.76(m, 1H), 0.80-0.74 (m, 4H); LCMS m/z 414 [M + H]+ ; HRMS (Positive ESI) m/z 414.2411 (414.2328 calcd for C24H27N7 + H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In ethanol; water; toluene; at 80℃;Schlenk technique; | General procedure: Method A: AbA iodide (3-1) (75 to 100 mg), tetrakis (triphenylphosphine)palladium(O) (0.2 equiv.), coupling reagent as boronic acid or pinacol ester (2 to 6 equiv.), and cesium carbonate (3 to 6 equiv.) were combined in a 10 mL Schlenk apparatus. The apparatus was evacuated and filled with dry nitrogen three times. Toluene (2 mL) and 0.6M ethanol in water (0.25 mL) were added. The resulting mixture was sparged with dry nitrogen for one minute and then heated to 80 C with rapid stirring and the reaction was monitored by HPLC analysis. Once the reaction was complete, the mixture was cooled, and partitioned between toluene and /or ethyl acetate and water. The layers were separated, and the organic layer was washed with brine, dried with sodium sulfate, filtered through Magnesol filtration media, and the solvent was removed in vacuo. The residue was purified by reverse-phase chromatography (C I 8 silica gel, 95% water with 0.1 %v/v TFA to 95% acetonitrile with 0.07%v/v TFA) to give the desired products. Method B: Method A was used, substituting [l, -Bis(diphenylphosphino)ferrocene] dichloropalladium(II) (1 : 1) for tetrakis (triphenylphosphine)palladium(O). Using Method B, compound 3-1 (104 mg) was coupled with 5-[2-(4-methylpiperazin- l-yl)]pyridineboronic acid pinacol ester (4 equiv.) using [1, - Bis(diphenylphosphino)ferrocene] dichloropalladium(II) (1:1) (17%mol), cesium carbonate (5 equiv.), toluene (2 mL), and 0.6M ethanol in water (0.3 mL) to give Compound No. 20 in 31% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); caesium carbonate; In 1,4-dioxane; water; at 50℃; for 16h;Inert atmosphere; | A vial was charged with <strong>[918524-63-7]1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine</strong> (20.4 mg, 0.067 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2, 5.3 mg, 6.74 mumol) and cesium carbonate (53.3 mg, 0.164 mmol). The vial was sealed, evacuated and backfilled with nitrogen (this process was repeated a total of three times). A solution of tert-butyl 6-cyano-5-(2-fluoro-6-methylphenyl)-3-iodo-1H-pyrazolo[4,3-b]pyridine-1-carboxylate (20.0 mg, 0.042 mmol) in 1,4-dioxane (2.00 ml) was added, followed by water (200.0 muL). The reaction mixture was heated to 50 C. for 16 h. The reaction mixture was concentrated. To the resultant residue was added CH2Cl2 (2.0 mL) followed by TFA (2.0 mL). The mixture was stirred at room temperature for 15 min, and then concentrated. The residue was purified using prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) to afford the desired product. LCMS calculated for C24H23FN7 (M+H)+: m/z=428.2; found: 428.2. |
Tags: 918524-63-7 synthesis path| 918524-63-7 SDS| 918524-63-7 COA| 918524-63-7 purity| 918524-63-7 application| 918524-63-7 NMR| 918524-63-7 COA| 918524-63-7 structure
A256090[ 936353-84-3 ]
(6-(4-Methylpiperazin-1-yl)pyridin-3-yl)boronic acid
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