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CAS No. : | 401815-98-3 | MDL No. : | MFCD04112534 |
Formula : | C5H5BFNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WXGBZJJAGLSBPR-UHFFFAOYSA-N |
M.W : | 140.91 | Pubchem ID : | 2783396 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 34.02 |
TPSA : | 53.35 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.02 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 0.19 |
Log Po/w (WLOGP) : | -0.68 |
Log Po/w (MLOGP) : | -0.93 |
Log Po/w (SILICOS-IT) : | -0.72 |
Consensus Log Po/w : | -0.43 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.21 |
Solubility : | 8.66 mg/ml ; 0.0615 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.87 |
Solubility : | 19.1 mg/ml ; 0.135 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.17 |
Solubility : | 9.57 mg/ml ; 0.0679 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.85 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | at 100℃; for 10 h; | A 25 mL reaction flask was charged with trifluoromethylhydrazine (0.05 mmol)2-fluoropyridine-4-boronic acid (0.5 mmol)Potassium tert-butoxide (1.0 mmol)And polyethylene glycol-400 (2.0 g).The mixture was reacted at 100 ° C until the reaction was complete. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The product was separated by column chromatography to yield 99percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With n-butyllithium In tetrahydrofuran; hexane; toluene at -78℃; for 1 h; Inert atmosphere | [00178] Step 1 : To a solution of anhydrous toluene and tetrahydrofuran ("THF") (4:1, 250 mL) were added 4-bromo-2-fluoropyridine 1 (30.0 g, 0.17 mol) and triisopropyl borate (38.4 g, 0.20 mol). The mixture was cooled to -78 °C under a nitrogen atmosphere. Then, n- butyllithium (80 mL, 0.20 mol) (2.5 M in hexanes) was added dropwise over 30 minutes, followed by stirring at the same temperature for an additional 30 minutes. The mixture was finally warmed up to -20 °C over 1 hour. Thin layer chromatography ("TLC") (petroleum ether ("PE"):ethyl acetate ("EtOAc") = 1 :1) indicated that the starting material was consumed. The reaction mixture was acidified to a pH of 2 with 3N HCl (50 mL) and then stirred at room temperature for 15 minutes. The mixture was partitioned between EtOAc (150 mL) and water (150 mL). The organic layer was isolated, washed with water, brine, dried over anhydrous MgS04, then filtered and evaporated to provide (2-fluoropyridin-4-yl)boronic acid (22.0 g, 91percent) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.2% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In 1,2-dimethoxyethane; water for 2 h; Reflux | A solution of 6g (771 mg, 2.012 mmol), (2-fluoro-4-pyridinyl)boronic acid (425 mg, 3.02 mmol),bis(triphenylphosphine)palladium(II) chloride (70.6 mg, 0.101 mmol) and Na2CO3 (1066 mg,10.06 mmol) in DME (20 mL) and water (2 mL) was stirred at reflux for 2 hours. The mixturewas then diluted with EA (50 mL) and water (50 mL). The organic layer was separated and theaqueous layer was extracted with ethyl acetate (50 mL*2). The combined organic layer wasconcentrated and the crude was purified by silica gel eluting with 0-10percent MeOH/DCM (1percentammonia) to give the title compound 8i (500 mg, 1.252 mmol, 62.2 percent yield) as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; water; at 150℃; for 0.416667h;Microwave irradiation; | Step 21.1 : 6-(2.4-Dichloro-phenvpi-3-(2-fluoro-pyridin-4-yl)-8-isobutoxy-imidazoH .2- <n="142"/>aipyridine-7-carbonitrile.In a sealed tube, a mixture of 3-bromo-6-(2,4-dichloro-phenyl)-8-isobutoxy-imidazo[1 ,2- a]pyridine-7-carbonitrile (115 mg, 0.25 mmol, prepared according to Example 35, Step 20.2), 2-fluoro-4-pyridine-boronic acid (45.3 mg, 0.32 mmol), PdCI2(PPh3)2 (9.6 mg, 0.014 mmol) and Na2CO3 (2.0 M solution in water, 0.43 mL) in DME (1 mL) was heated at 1500C for 25 min in a microwave oven. The reaction mixture was cooled to RT, diluted in AcOEt (20 mL) and washed with water (2 x 10 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to dryness. The remaining residue was purified by Combi-Flash Companion.(TM). (Isco Inc.) column chromatography (SiO2; gradient elution, hexane / TBME 95:5 --> 6:4) to yield the title compound (46.6 mg, 0.10 mmol, 41 percent) as a white solid. MS: 455 [M+1]+ ; HPLC: \\et = 3.18; TLC: RF 0.25 (hexane / TBME 1:1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | lntermediate-4 (prepared by Step 1.4) Suzuki coupling [2-[Bis-(4-fluorophenyl)methyl]-4-(2-fluoropyridin-4-yl)thiazol-5-yl]acetic acid. lntermediate-3 (1.0 g, 2.0 mmol), 2-fluoropyridine-4-boronic acid (0.57 g, 4.1 mmol) and sat. Na2CO3 solution (2.0 mL) was suspended in dry dioxane (9 ml). The reaction mixture was flushed with N2 for 15 min. PdCI2(dppf) (82 mg, 0.10 mmol) was added under under N2. The reaction mixture was stirred at 90 °C for 2 h. 1 N HCI was added and then the mixture was extracted with DCM. The organic phase was passed through a phase-separation filter and concentrated. The residue was purified on a PEAX SPE column (equilibrated with 100percent MeOH and then eluted with 10percent AcOH in MeOH) to give the product (500 mg, 56percent). LC/MS (an20p5): Rt = 2.9 min, m/z 441 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With n-butyllithium; In tetrahydrofuran; hexane; toluene; at -78℃; for 1h;Inert atmosphere; | [00178] Step 1 : To a solution of anhydrous toluene and tetrahydrofuran ("THF") (4:1, 250 mL) were added 4-bromo-2-fluoropyridine 1 (30.0 g, 0.17 mol) and triisopropyl borate (38.4 g, 0.20 mol). The mixture was cooled to -78 °C under a nitrogen atmosphere. Then, n- butyllithium (80 mL, 0.20 mol) (2.5 M in hexanes) was added dropwise over 30 minutes, followed by stirring at the same temperature for an additional 30 minutes. The mixture was finally warmed up to -20 °C over 1 hour. Thin layer chromatography ("TLC") (petroleum ether ("PE"):ethyl acetate ("EtOAc") = 1 :1) indicated that the starting material was consumed. The reaction mixture was acidified to a pH of 2 with 3N HCl (50 mL) and then stirred at room temperature for 15 minutes. The mixture was partitioned between EtOAc (150 mL) and water (150 mL). The organic layer was isolated, washed with water, brine, dried over anhydrous MgS04, then filtered and evaporated to provide (2-fluoropyridin-4-yl)boronic acid (22.0 g, 91percent) as a solid. |
33% | With n-butyllithium; | The reaction carried out in the third step of the synthesis of the 2-fluoropyridine-4-boronic acid utilized in this experimental procedure can be depicted as follows: In this step of the synthesis process, a wide variety of electrophiles can again be used in place of triisopropylborate, B(OiPr)3, actually used in this experimental procedure. For instance other suitable electrophiles including, but not limited to CO2, SO2, a wide variety of dialkylcarbonates, ureas, formamides, amides, carboxylic acid esters, mono- and dihaloalkyls, halogens (such as, but not limited to, chlorine, fluorine, bromine, and iodine), metallic salts, sulfones, sulfonyls, aldehydes, ketones, anhydrides, nitrites, and electrophilic boron compounds including, but not limited to, boron trialkoxides and boron trihalides (see, March, Advanced Organic Chemistry, Reactions, Mechanisms, and Structures, 5th Ed., 2001, the teachings of which are incorporated herein by reference in their entirety. |
Step 1a.Synthesis of 2-fluoropyridine boronic acid A flame-dried flask was charged with toluene and tetrahydrofuran (4:1) and then with 4-bromo-2-fluoropyridine(1 eq) and triisopropylborate (1.2 eq) and the flask was cooled to -70° C. Then n-butyllithium (1.2 eq) was added dropwise over 0.5 h and the mixture was stirred for 0.5 h at -70° C. The reaction mixture was then brought to -20° C. and 2N hydrochloric acid was added to it.Formation of 2-fluoropyridine boronic acid was seen by LC/MS on warming the mixture to ambient temperature.The mixture was partitioned between ethyl acetate and water.The organic layer was dried with sodium sulfate and concentrated to yield 2-fluoropyridine boronic acid. MS: MH+=141. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In DMF (N,N-dimethyl-formamide); water; at 100℃; for 12h; | 8-Bromo-N-cyclopentyl-2- (methylsulfanyl)-7-phenylpyrazolo [1, 5-a] [1,3, 5] triazin-4- amine (0.20 g, 0.50 mmol) was dissolved in N, N-dimthylformamide. To this solution was added dichlorobis (triphenylphosphine) palladium (II] (70 mg, 0.2 equiv), anhydrous sodium carbonate (105 mg, 2 equiv), 2-fluoro-4-pyridinylboronic acid (91 mg, 1.3 equiv) and a few drops of water. The reaction mixture was heated at 100 °C for 12 hours, at which time no starting material remained in the reaction mixture. Ethyl acetate and water were added to the reaction mixture. The phases were separated and the organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (ethyl acetate: hexane 1: 1) gave 70 mg (33 percent) of N-cyclopentyl-8- (2-fluoro-4-pyridinyl)-2- (methylsulfanyl)-7- phenylpyrazolo [1, 5-a] [1, 3, 5] triazin-4-amine as a white foam.'H-NMR (CDCI3) : 8 8.10 (d, 1 H), 7.60 (m, 2H), 7.52 (m, 3H), 7. 37 (m, 1 H), 7.29 (s, 1 H), 6.55 (d, 1 H), 4.63 (m, 1 H), 2.66 (s, 3H), 2.3-2. 1 (m, 2H), 2.0-1. 6 (m, 6H) ; F-NMR (CDCl3) : 8-69. 01 ; MS m/z 421 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With water; sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In DMF (N,N-dimethyl-formamide); at 110℃; for 24h; | 3-Bromo-2-phenyl-7-pyrrolidin-1-ylpyrazolo [1, 5-a] pyrimidine (150 mg, 0.44 mmol) was dissolved in N, N-dimethylformamide (4 mL). To this solution was added dichlorobis (tripenylphosphine) palladium (II) (60 mg, 0.09 mmol), 2-fluoropyridin-4- ylboronic acid (92 mg, 0.66 mmol), sodium carbonate (185 mg, 1.76 mmol) and a few drops of water. The resulting solution was heated at 110 °C for 24 hours. The resulting mixture was diluted with dichloromethane and washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated. The resulting black residue was purified bysilica gel chromatography (ethyl acetate: hexane 1: 1) to give 50 mg (32 percent) of the title compound as a white solid.'H NMR (CDCi3) : 8 8. 17 (d, 1 H), 8.08 (d, 1 H), 7.60 (m, 2H), 7.41 (m, 4H), 7.24 (broad s, 1 H), 5.87 (d, 1 H), 4.06 (broad s, 4H), 2.07 (broad s, 4H) ;"F NMR (CDCI3) : 8-69. 34; MS m/z360 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With sodium carbonate; lithium chloride;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 80℃; for 1h; | Add 3-(5-bromo-benzo[]thiophen-2-ylmethyl)-l-cyclohexyl-pyrrolidin-2-one (250 mg, 0.64 mmol), 2-fluoropyridine-4-boronic acid (200 mg, 1 mmol), LiCl (10 eq) and Pd(PPh3)4 (0.05 eq) into a solution of dioxane (10 mL) and 2M Na2CO3 (2 niL) and heat at 8O0C for 1 hour. Pour the reaction mixture into water and extract with ethyl acetate. Dry over sodium sulfate, filter, and concentrate. Purify by silica gel (20-50percent ethyl acetate in hexanes) to give the title compound as a pale yellow powder (260 mg, 58percent): MS (APCI-pos mode) m/z (rel intensity): 409.2 (M+H, 100percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium carbonate; lithium chloride;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃; for 1h; | Add 7-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)naphthalen-2-yl trifluoromethanesulfonate (150 mg, 0.33 mmol), 2-fluoropyridine-4-boronic acid (0.2 g, 0.51 mmol), LiCl (450 mg, 10.7 mmoL) and Pd(PPh3)4 (60 mg, 0.05 mmol) into a solution of dioxane (20 mL) and 2M Na2CO3 (aq, 5 mL) and heat at 80°C for 1 hour. Pour the reaction into water and extract with ethyl acetate. Wash the organic layer with NaHCO3 and brine. Dry, filter and concentrated to obtain the crude mixture. Purify the residue by column chromatography to afford the title compound as a white solid (100 mg, 75 percent): MS (APCI-pos mode) m/z (rel intensity): 403.2 (M+H, 100percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium carbonate; lithium chloride;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃; for 1h; | Add 3-((5-bromonaphthalen-2-yl)niethyl)-1-cyclohexylpyrrolidin-2-one (300 mg, 0.66 mmol), 2-fluoropyridine-4-boronic acid (0.4 g, 1.1 mmol), LiCl (450 mg, 10.7 mmoL) and Pd(PPh3 )4 (60 mg, 0.05 mmol) into a solution of dioxane (20 mL) and 2M Na2CO3 (aq, 5 mL) and heat at 80°C for 1 hour. Pour the reaction into water and extract with ethyl acetate. Wash the organic layer with NaHCO3 and brine. Dry, filter and concentrated to obtain the crude mixture. Purify the residue by column chromatography to afford the title compound as a white solid (200 mg, 75 percent): MS (APCI-pos mode) m/z (rel intensity): 403.2 (M+H, 100percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl acetamide; water; at 80℃; for 1.5h;Inert atmosphere; | Step E-5-[5-(2-Fluoro-4-pyridinyl)-1H-benzimidazol-1-yl]-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxamide; 2-Fluoropyridine-4-boronic acid (0.497 g, 3.53 mmol), 5-(5-bromo-1H-benzimidazol-1-yl)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)thiophene-2-carboxamide (1.50 g, 2.94 mmol), and sodium carbonate (1 N in water, 10.3 mL) were combined in N,N-dimethylacetamide (30 mL). 1,1'-bisdiphenylphosphino-ferrocene dichloropalladium (II) (0.24 g, 0.3 mmol) was added and the reaction mixture was stirred under nitrogen while heating at 80° C. for 1.5 h. The mixture was then cooled and partitioned between DCM and water. The aqueous layer was extracted with DCM. The combined organics were dried over MgSO4, concentrated onto silica gel and purified by column chromatography (0 to 50percent EtOAc:hexanes) to afford 1.52 g (97percent) of the title compound as a light tan solid after trituration in diethyl ether. 1H NMR (400 MHz, CDCl3): delta 8.29 (d, 1H, J=5.3 Hz), 8.12 (s, 2H), 7.68 (m, 4H), 7.51 (m, 3H), 7.21 (s, 1H), 7.18 (s, 1H), 6.71 (s, 1H), 5.85 (m, 2H), 1.82 (d, 3H, J=5.9 Hz); MS (ESI): 527.0 [M+H]+. |
67% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl acetamide; water; at 80℃; for 2h; | Step B - 5-[5-(2-Fluoro-4-pyridinyl)- 1H-benzimidazol- 1-yl]-3-({(1R)- 1-[2- (trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarhoxamide; EPO <DP n="48"/>2-Fluoropyridine-4-boronic acid (0.21 g, 1.5 mmol), 5-(5-bromo-1 A'- benzimidazol-1-yl)-3-({(1 /t)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)thiophene- 2-carboxamide (0.505 g, 0.99 mmol), and sodium carbonate (1 N in water, 3.4 mL) were combined in Lambda/.LambdaAdimethylacetamide (10 mL). 1,1'- bisdiphenylphosphino-ferrocene dichloropalladium (II) (0.078 g, 0.1 mmol) was added and the reaction mixture was stirred under N2 while heating at 80 0C for 2 h. The mixture was then cooled and partitioned between EtOAc and water. The aqueous layer was extracted twice with EtOAc. The combined organics were dried over MgSO4, concentrated onto silica gel and purified by column chromatography (0 to 70percent EtOAsigma.hexanes) to afford 0.343 g (67percent) of the title compound as a light tan solid. 1H NMR (400 MHz, CDCI3): delta 8.29 (d, 1H, J= 5.3 Hz), 8.12 (s, 2H), 7.68 (m, 4H), 7.51 (m, 3H), 7.21 (s, 1H)1 7.18 (s, 1H), 6.71 (s, 1H), 5.85 (m, 2H), 1.82 (d, 3H, J= 5.9 Hz); MS (ESI): 527.2 [M+H]+. |
67% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl acetamide; water; at 80℃; for 2h; | 2-Fluoropyridine-4-boronic acid (0.21 g, 1.5 mmol), 5-(5-bromo-1 H- benzimidazol-1 -yI)-3-({(1 R)-lambda -[2-(trifluoromethyl)phenyl]ethyl}oxy)thiophene-2- carboxamide (0.505 g, 0.99 mmol), and sodium carbonate (1 N in water, 3.4 mL) were combined in Lambda/,Lambda.pound.dimethylacetamide (10 ml_). 1 ,1'- bisdiphenylphosphino-ferrocene dichloropalladium (II) (0.078 g, 0.1 mmol) was added and the reaction mixture was stirred under nitrogen while heating at 80 °C for 2 h. The mixture was then cooled and partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organics were dried over magnesium sulfate, concentrated onto silica gel and purified by column chromatography (0 to 70percent ethyl acetate:hexanes) to afford 0.343 g (67percent) of the title compound as a light tan solid. 1H NMR (400 MHz, CDCI3): delta 8.29 (d, 1 H, J = 5.3 Hz), 8.12 (s, 2H), 7.68 (m, 4H), 7.51 (m, 3H), 7.21 (s, 1 H), 7.18 (s, 1H), 6.71 (s, 1 H), 5.85 (m, 2H), 1.82 (d, 3H, J= 5.9 Hz); MS (ESI): 527.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl acetamide; water; at 80℃; for 2h;Inert atmosphere; | Step E-3-[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-[5-(2-fluoropyridin-4-yl)-1H-benzimidazol-1-yl]thiophene-2-carboxamide; 2-Fluoropyridine-4-boronic acid (0.440 g, 3.15 mmol), 5-(5-bromo-1H-benzimidazol-1-yl)-3-[(1R)-1-(2-chlorophenyl)ethyl]oxy}thiophene-2-carboxamide (1.0 g, 2.10 mmol), 1,1' bisdiphenylphosphinoferrocene dichloropalladium (II) (0.171 g, 0.21 mmol), and sodium carbonate (1N in water, 7.4 mL) were combined in N,N-dimethylacetamide (25 mL). The reaction mixture was stirred under nitrogen while heating at 80° C. for 2 h after which time the mixture was cooled and partitioned between DCM and water. The aqueous layer was extracted (.x.5) with DCM. The combined organics were dried over MgSO4, concentrated onto silica gel and purified by column chromatography (10-100percent EtOAc in hexanes) to afford 0.735 g (71percent) as a tan solid. 1H NMR (400 MHz, CDCl3): delta 8.33 (d, 1H, J=5.3 Hz), 8.11 (d, 2H, J=16.0 Hz), 7.50 (m, 7H), 7.26 (s, 1H), 7.23 (br s, 1H), 6.71 (s, 1H), 5.94 (q, 1H, J=6.3 Hz), 5.82 (br s, 1H), 1.84 (d, 3H, J=6.5 Hz); MS (ESI): 493.1 [M+H]+. |
71% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl acetamide; water; at 80℃; for 2h; | 2-Fluoropyridine-4-boronic acid (0.440 g, 3.15 mmol), 5-(5~bromo-1 H benzimidazol-1 -yl)-3-[(1 R)A -(2-chlorophenyl)ethyl]oxy}thiophene-2- carboxamide (1.0 g, 2.10 mmol), and sodium carbonate (1 N in water, 7.4 mL) were combined in Lambda/,Lambda.pound.dimethylacetamide (25 mL). 1 ,1'- bisdiphenylphosphino-ferrocene dichloropalladium (II) (0.171 g, 0.21 mmol) EPO <DP n="88"/>was added and the reaction mixture was stirred under nitrogen while heating at 80 °C for 2 h. The mixture was then cooled and partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (5x). The combined organics were dried over magnesium sulfate, concentrated onto silica gel and purified by column chromatography (10 to 100percent ethyl acetate:hexanes) to afford 0.735 g (71percent) of the title compound as a tan solid. 1H NMR (400 MHz, CDCI3): delta 8.33 (d, 1 H, J= 5.3 Hz), 8.11 (d, 2H, J= 16.0 Hz)1 7.50 (m, 7H), 7.26 (s, 1 H), 7.23 (br s, 1 H), 6.71 (s, 1 H), 5.94 (q, 1 H, J= 6.3 Hz), 5.82 (br s, 1 H), 1.84 (d, 3H, J= 6.5 Hz); MS (ESI): 493.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; acetonitrile; at 150℃; for 0.0833333h;Microwave irradiation; | A microwave vial (2 ml) was charged with (S)-3-(4-{2-amino-6-[(S)-1-(4-bromo-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidin-4-yl}-phenyl)-2-tert-butoxycarbonylamino-propionic acid (139 mg, 0.23 mmol), 2-fluoropyridine-4-boronic acid (40 mg, 0.27 mmol) 1 ml of acetonitrile, and 0.7 ml of water. To this mixture, 0.4 ml of aqueous sodium carbonate (1M) was added, followed by 14 mg (5 mol percent) of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness, and the residue was dissolved in 2.5 ml of methanol. The product was purified with Preparative HPLC to give 70 mg of (S)-3-[4-(2-amino-6-{(S)-2,2,2-trifluoro-1-[4-(2-fluoro-pyridin-4-yl)-phenyl]-ethoxy}-pyrimidin-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid. The above product (70 mg) was dissolved in 5 ml 30percent TFA in DCM. The reaction mixture was stirred at r.t. overnight. Removal of solvent gave crude product which was purified by preparative HPLC to give 52 mg of (S)-2-amino-3-[4-(2-amino-6-{(S)-2,2,2-trifluoro-1-[4-(2-fluoro-pyridin-4-yl)-phenyl]-ethoxy}-pyrimidin-4-yl)-phenyl]-propionic acid. 1H NMR (300 MHz, CD3OD) delta (ppm) 8.17 (d, J=5.7 Hz, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.77 (d, J=6.9 Hz, 2H), 7.67 (d, J=8.2 Hz, 2H), 7.53 (m, 1H), 7.38 (d, J=8.4 Hz, 2H), 7.30 (s, 1H), 6.76 (m, 2H), 4.21 (t, 1H), 3.2 (m, 2H). | |
70 mg | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In water; acetonitrile; at 150℃; for 0.0833333h;Sealed tube; Microwave irradiation; | A microwave vial (2 ml) was charged with (S) -3- (4- {2-amino-6 - [(S) -1- (4-bromo-phenyl) -2,2,2-Yl) -phenyl) -2-tert-butoxycarbonylamino-propionic acid (139 mg, 0.23 mmol)2-fluoropyridine-4-boronic acid (40 mg, 0.27 mmol), 1 ml of acetonitrile, and 0.7 ml of water. To the mixture was added 0.4 ml of an aqueous solution of sodium carbonate (1 M), followed by14 mg (5 molpercent) of dichlorobis (triphenylphosphine) palladium (II) was added. The reaction vessel was sealed and heated to 150 ° C with microwave irradiation,Lasted 5 minutes. After cooling, the reaction mixture was evaporated to dryness and the residue was dissolved in 2.5 ml of methanol. The product was prepared using preparative HPLCLine to give 70 mg(S) -3- [4- (2-amino-6 - {(S) -2,2,2-trifluoro-l- [4- (2-fluoro-pyridine-4-yl) -Phenyl] -ethoxy} -pyrimidin-4-yl) -phenyl] -2-tert-butoxycarbonylamino-propionic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.4% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 3h;Inert atmosphere; | 1002621 Step A: Sodium carbonate (4.91 g, 46.3 mmol) was added to <strong>[401815-98-3]2-fluoropyridin-4-ylboronic acid</strong> (2.61 g, 18.5 mmol) and 2,4-dichloropyrimidine (77.2 mL, 15.4 mmol) in dioxane/water (77 mL, 4:1), and the suspension was purged with argon. PdC12(dppf)*DCM (0.630 g, 0.772 mmol) was added to the mixture, and the mixture was heated at 80°C under argon. After 3 hours, the reaction mixture was diluted with water, and the resulting solid was collected by vacuum filtration to yield 2-chloro-4-(2-fluoropyridin-4-yl)pyrimidine (3.12 g, 14.9 mmol, 96.4percent yield) with minor impurities. |
50% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 90℃; for 4h;Inert atmosphere; | [00179] Step 2: To a solution of dioxane and water (5: 1, 300 mL) was added (2- fluoropyridin-4-yl)boronic acid (20.0 g, 141.94 mmol), 2,4-dichloropyrimidine (22.2 g, 149.03 mmol), cesium carbonate (69.3 g, 212.90 mmol) and Pd(dppf)Cl2 (5.2 g, 7.1 mmol). The reaction mixture was heated at 90 °C with stirring under a nitrogen atmosphere for 4 hours. TLC (PE:EtOAc = 5: 1) indicated that the starting material was consumed. The mixture was cooled to room temperature, and then the filtrate was partitioned between EtOAc (200 mL) and water (100 mL). After separation, the organic layer was washed with water, brine, dried over anhydrous MgS04, filtered, concentrated and purified by column chromatography on silica gel (PE:EtOAc = 20:1 to about 5:1) to provide 2-chloro-4-(2-fluoropyridin-4- yl)pyrimidine (15.0 g, 50percent) as a solid. |
44% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80 - 85℃; for 4h; | Example 1; Representative procedure for the synthesis of compounds type (VIII); Preparation of Intermediates (III); Example 1a; 2-Chloro-4-(2-fluoro-pyridin-4-yl)-pyrimidine (llla); To a degassed solution of 2,4-dichloropyrimidine (Ia) (0.85 g, 4.71 mmol) and 2- fluoropyridine-4-boronic acid (Ha) (1g, 7.14 mmol) in 1,2 dimethoxy ethane (20 mL) were added, sequentially, aqueous Na2CO3 (1.21 g, 11.42 mmol) and Pd(PPh3J4 (132 mg, 1.14 mmol). The resultant mixture was stirred at 80-85 O0C for 4 h, cooled to O0C and quenched with saturated NH4CI The product was extracted with CH2CI2 thrice and the combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was column purified (EtOAc/Hexane 1/5) to furnish 0.410 g of (Ilia) in 44percent yield. LC-MS (ESI positive mode) m/z 210 ([M+H]+); 1H NMR (400MHz, CDCI3): delta 8.85 (d, 1H), 8.47 (d, 1H)1 7.87 (dt, 1H), 7.75 (d, 1H), 7.67-7.68 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.4% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 3h;Inert atmosphere; Sealed tube; | 1003201 Step A: Sodium carbonate (0.575 g, 5.43 mmol) was added to <strong>[401815-98-3]2-fluoropyridin-4-ylboronic acid</strong> (0.306 g, 2.17 mmol) and 2,4-dichloro-5-methylpyrimidine (0.212 mL, 1.81 mmol) in dioxane/water (10 mL; 4:1), and the suspension was purged with nitrogen. PdC12(dppf)*DCM (0.0739 g, 0.0905 mmol)was added, and the vial was sealed and heated at 80°C. After 3 hours, the cooled reaction mixture was partitioned between water and EtOAc. The EtOAc was washed with brine, dried over MgSO4, filtered, and evaporated to yield a crude product (0.50 g) as a solid. The crude product was absorbed on silica gel and chromatographed on a 50 g Biotage SNAP column with 1:1 hexane/EtOAc. Fractions 16-34 contained 2-chloro-4-(2-fluoropyridin-4-yl)-5 -methylpyrimidine (0.22 g, 0.984 mmol, 54.4percent yield) with minor impurities. |
25% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80 - 85℃; for 4h; | Example 1b; 2-Chloro-4-(2-fluoro-pyridin-4-yl)-5-methyl-pyrimidine (HIb)(Ib); (HIb) <n="61"/>To a degassed solution of (Ib) (1.5 g, 9.2 mmol) and (Ha) (1 62g, 11.50 mmol) in 1,2 dimethoxy ethane (50 mL) were added, sequentially, aqueous Na2CO3 (1.90 g, 18.420 mmol) and Pd(PPh3)4 (0.53 g, 0.46 mmol). The resultant mixture was stirred at 80-85 O0C for 4 h, cooled to O0C and quenched with saturated NH4CI. The product was extracted with CH2CI2 thrice and the combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was column purified (EtOAc/Hexane 1/5) to furnish 0.500 g of (UIb) in 25 percent yield. LC-MS (ESI positive mode) m/z 224 ([IvHH]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere; Reflux; | 3,6-Dibromopyrazolo[l,5-alpha]pyrimidine (3.80 g, 13.7 mmol) was mixed with 2-fluoropyridin-4- yl-4-boronic acid (2.51 g, 17.80 mmol). Dioxane (100 mL) and IM Na2CO3 (27.4 mL) were added. The mixture was evacuated and flushed with nitrogen under stirring, then Pd(Ph3P)4 (0.81 g, 0.70 mmol) was added in a counter flow of nitrogen. The reaction mixture was refluxed under stirring for 16 h, cooled, and poured into a 5 -fold excess of water. The product was extracted thrice with CHCl3. The organic layer was washed with brine, dried with MgSO4, filtered, and evaporated. The residue was purified by column chromatography (silica gel,CHCl3/MeOH, 10:1). Yield 3-bromo-6-(2-fluoropyridin-4-yl)pyrazolo[l,5-alpha]pyrimidine: 2.16 g(54percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 20 - 80℃; | Example 13Synthesis of 3-Methoxy-1 -(2-(4-[4-(1 -methyl-1 H-M ,2.41triazol-3-vn-phenyl1-3.6- dihvdro-2H-pyridin-1-yl)-2-oxo-ethyl)-pyrrolidine-3-carboxylic acid T3-(2- methoxy-pyridin-4-yl)-1 H-indazol-5-vll-amide Step 1 :Synthesis of 3-(2-Fluoro-pyridin-4-yl)-5-nitro-1-trityl-1 H-indazole 3-Bromo-5-nitro-1 -trityl-1 H-indazole 3Bl (15.64g, 32.3 mmol), 2-fluoro-4- pyridine boronic acid 2BV (5.Og, 35.5 mmol), K3PO4 (IT1Ig, 80.7 mmol) andPd(dppf)CI2 (2.64g, 3.23 mmol) was mixed in dioxane/H2O (240 ml_760 ml_) at rt and heated at 80 0C overnight. The reaction mixture was cooled to rt and concentrated to a small volume. The residue was partitioned between ethyl acetate (200 ml_) and brine (150 ml_). The organic layer was washed with brine, dried (MgSO4) and filtered. The resulting filtrate was concentrated and the residue was purified on silica gel column eluting with hexanes, 5percent ethyl acetate in hexanes, 10percent ethyl acetate in hexanes sequentially to yield a yellow solid 3BV (3.33g, 64percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Synthesis 64; 5-(2-Fluoro-pyridin-4-yl)-thiophene-3-carboxylic acid; IMS, A mixture of delta-bromo-thiophene-S-carboxylic acid (0.71 g, 4.4 mmol), 2-fluoropyridine-4- boronic acid (0.619 g, 4.4 mmol), caesium carbonate (2.9 g, 8.8 mmol), and palladium tetrakis(triphenylphosphine) (0.469 g, 0.44 mmol) in DME (40 mL), IMS 20 mL) and water (10 mL) was divided across three microwave vials and each was heated by microwave irradiation to 1200C for 20 minutes. The batches were combined and concentrated and the residue was partitioned between saturated aqueous sodium carbonate and DCM. The aqueous phase was isolated and filtered to obtain the title compound as a grey precipitate (0.168 g) and the filtrate was acidified using dilute HCI (pH 2) then re-filtered to obtain a further amount of the title compound as an off-white solid (0.114 g). LCMS m/z 224.06 [MH-H]+ RT. = 2.77min (Analytical Method 8). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 110℃; | 4-(6-bromopyridine-2-carbonyl)-piperazine-1-carboxylic acid te/f-butyl ester (500 mg, 1.35 mmol), 2-fluoro-4-pyridine boronic acid (286 mg, 2.03 mmol) and 2.0 M Na2CO3 solution (2.0 ml_, 4.06 mmol) in DME (15.0 ml.) are stirred. Added Pd(PPh3)4 (156 mg, 0.13 mmol) and heated the reaction in a sealed pressure vessel at 1 10 0C until reaction is complete. Reaction is then diluted with EtOAc (15 ml.) and extracted between organic and saturated NaHCO3 (x2). The organic layer is washed with brine, dried over anhydrous Na2SO4 and then evaporated under reduced pressure to provide a crude residue that is purified via flash chromatography (SiO2, EtOAc/heptanes gradient) to afford the compound as a pale yellow solid (418 mg, 80percent). MS (ESI) m/z 387.1 (M+1 ). 1H-NMR (400 MHz, CD2CI2) delta ppm 8.36 (d, J=5.3 Hz, 1 H), 7.98 - 8.05 (m, 1 H), 7.94 (dd, 1 H), 7.85 (dt, J=5.3, 1.6 Hz, 1 H), 7.76 (dd, J=7.6, 1.0 Hz, 1 H), 7.61 (s, 1 H), 3.76 - 3.84 (m, 2 H), 3.56 - 3.67 (m, 4 H), 3.48 - 3.55 (m, 2 H), 1.49 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In ethanol; toluene; at 110℃; for 16h; | 4-(6-Chloro-3-ethoxycarbonyl-pyridin-2-yl)-piperazine-1 -carboxylic acid te/f-butyl ester (1.11 g, 3.00 mmol) and 2-fluoropyridine-4-boronic acid (0.63 g, 4.50 mmol) are dissolved in toluene/EtOH (10:1 , 30 ml_). To this mixture is added 2.0 M Na2CO3 solution (3.0 ml_, 6.0 mmol) and Pd(dppf)CI2 DCM complex (0.24 g, 0.30 mmol). This above suspension is heated at 110 0C for 16 h. The reaction mixture is then diluted with EtOAc (300 ml_), washed with water (100 ml_), dried over Na2SO4, and concentrated. The crude residue is purified via FCC with EtOAc/heptanes (1/2) to afford the above product as a yellow solid (0.85 g, 66percent). MS (ESI) m/z 431.3 (M+1 ). 1H-NMR (400 MHz, CDCI3) delta ppm 8.31 (d, J=5.3 Hz, 1 H), 8.15 (d, J=7.8 Hz, 1 H), 7.76 (m, 1 H), 7.55 (s, 1 H), 7.28 (d, J=7.8 Hz, 1 H), 4.39 (q, J=7.1 Hz, 2 H), 3.60 - 3.62 (m, 4 H), 3.49 - 3.52 (m, 4 H), 1.49 (s, 9 H), 1.41 (t, J=7.1 Hz, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In ethanol; toluene; at 110℃; for 16h; | 4-(6-Chloro-5-ethoxycarbonyl-pyridin-2-yl)-piperazine-1 -carboxylic acid te/f-butyl ester (0.82 g, 2.22 mmol) and 2-fluoropyridine-4-boronic acid (0.47 g, 3.33 mmol) are dissolved in toluene/EtOH (10/1 , 22 ml_). To this mixture is added 2.0 M Na2CO3 solution (2.2 ml_, 4.40 mmol) and Pd(dppf)CI2 DCM complex (0.18 g, 0.22 mmol). This above suspension is heated at 110 0C for 16 h. The reaction mixture is then diluted with EtOAc (200 ml_), washed with water (100 ml_), dried over Na2SO4, and concentrated. The crude residue is purified via FCC with EtOAc/heptanes (1/2) to afford the above product as a light brown solid (0.73 g, 76percent). MS (ESI) m/z 431.3 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 90℃;Inert atmosphere; | A mixture of 4-(6-bromo-4-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid te/f-butyl ester (1.9 g, 4.9 mmol), 2-fluoropyridine-4-boronic acid (0.9 g, 6.37 mmol), Pd(dppf)CI2. CH2CI2 (0.2 g, 0.245 mmol), aqueous solution of Na2CO3(5.0 ml_, 2.0 M) and DME (45 ml.) is sparged with argon for 10 min and then heated to 90 0C for 3 h under argon. The mixture is then allowed to cool to room temperature, diluted with CH2CI2 and washed with saturated NaHCO3 (x 2), and dried (Na2SO4), filtered and concentrated. The residue is then separated via flash chromatography (SiO2, 20-30percent EtOAc/heptane gradient) to give the title compound 4-(2'-Fluoro-4-nitro-[2,4']bipyridinyl-6-yl)-piperazine-1-carboxylic acid te/f-butyl ester.. MS (ESI) m/z 404.0 (M+1 ). 1H NMR (400 MHz, CDCI3) delta ppm 8.36 (d, J=5.3 Hz, 1 H), 7.75 - 7.81 (m, 2 H), 7.56 - 7.60 (m, 1 H), 3.78 (dd, J=6.3, 4.0 Hz, 4 H), 3.60 - 3.67 (m, 4 H), 1.51 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 80℃; for 4h; | 4-(6-Bromo-4-methoxycarbonyl-pyridin-2-yl)-piperazine-1 -carboxylic acid te/f-butyl (2.0 g, 5.01 mmol), Example 4B, and 2-fluoro-4-pyridine boronic acid (0.85 g, 6.01 mmol) are dissolved in DME (40 ml_). To this is added 2.0 M Na2CO3 solution (7.5 ml_, 15.03 mmol) and Pd(dppf)CI2-CH2CI2 (0.41 g, 0.50 mmol). This above suspension is heated to 80 0C for 4 h. Reaction is diluted with EtOAc (25.0 ml.) and extracted between organic and saturated NaHCO3 (x2). The organic layer is washed with brine, dried over anhydrous Na2SO4 and then evaporated under reduced pressure to provide a crude residue that is purified via flash chromatography (SiO2, EtOAc/heptanes gradient) to afford the title compound as a pale yellow solid (1.80 g, 90percent). MS (ESI) m/z 417.1 (M+1 ). 1H-NMR (400 MHz, CDCI3) delta ppm 8.32 (d, J=5.3 Hz, 1 H), 7.81 (dt, J=5.2, 1.5 Hz, 1 H), 7.70 (s, 1 H), 7.60 (s, 1 H), 7.35 (s, 1 H), 4.00 (s, 3 H), 3.70 - 3.78 (m, 4 H), 3.58 - 3.67 (m, 4 H), 1.52 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 4h;Inert atmosphere; | Method C; Step h; 2-fluoro-4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyridine; 1 g (2.3 mmol) of 4-iodo-1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1 H-pyrazole (prepared as decribed in Example 27) were dissolved in a mixture of 20 ml of dioxane and 5 ml of water in a nitrogen atmosphere. 750 mg (2.3 mmol) of cesium carbonate, 350 mg (0.3 mmol) of palladium tetrakis and 486 mg (3.45 mmol) of 2-fluoro-pyridyl boronic acid were added and the reaction stirred at 1000C for 4 hours. The mixture was then filtered through a celite pad and the filtrate evaporated under reduced pressure. The residue was re-dissolved with dichloromethane and washed with water. The organic layer was dried over sodium sulphate and evaporated. 680 mg (73percent) of the title compound crystallized from diethylether. 1H NMR (401 MHz, DMSO-d6) delta = 3.74 (s, 3 H) 5.36 (s, 2 H) 6.91 - 6.99 (m, 2 H) 7.16 - 7.18 (m, 1 H) 7.34 - 7.39 (m,2 H) 7.45-7.48 (m, 1 H) 7.68 (dd, J=8.79, 7.81 Hz, 1 H) 7.78 - 7.83 (m, 1 H) 8.15 (d, J=5.25 Hz, 1 H) 8.20 - 8.28 (m, 2 H) 8.43 (s, 1 H).HRMS(ESI): calcd for C22H18FN4O3[M+H]+ 405.1358 found 405.1369. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 150℃; for 0.25h;Microwave irradiation; | To a degassed solution of Part B Compound (120 mg, 0.322 mmol) in DME (1.6 mL)/H2O (0.4 mL) were successively added <strong>[401815-98-3]2-fluoropyridin-4-ylboronic acid</strong> (91 mg, 0.645 mmol), K2CO3 (89 mg, 0.645 mmol) and (Ph3P)4Pd (0) (18.6 mg, 0.016 mmol). The reaction was heated at 150° C. in an Emrys Optimizer.(R). (microwave) for 15 min, then was cooled to RT. The reaction mixture was partitioned between EtOAc (100 mL) and H2O (10 mL). The organic phase was washed with brine (10 mL), dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed (SiO2; 12 g; continuous gradient from 100percent hex to 1:1 hex:EtOAc over 25 min, then held at 1:1 hex:EtOAc for 15 min) to give Part C Compound (100 mg, 80percent yield) as a white solid. LCMS Method A (ESI, positive ion spectrum): (M+H)/z=389, tR=2.99 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 140℃; for 0.25h;Microwave irradiation; | [00475] Step 8: Ethyl 4-cyano-3-(2,4-dichlorophenyl)-5-(2-fluoropyridin-4-yl)thiophene- 2-carboxylate[00476] A mixture of ethyl 4-cyano-3-(2,4-dichlorophenyl)-5-iodothiophene-2-carboxylate (1.81 g, 0.00400 mol), 2-Fluoro-4-pyridinylboronic acid (1.13 g, 0.00801 mol), Tetrakis(triphenylphosphine)palladium(O) (0.231 g, 0.0002 mol) and sodium carbonate (1.27 g, 0.0120 mol) in 1,2-Dimethoxyethane (20 mL) and Water (10 mL) was heated under microwave irradiation at 140 0C for 15 min. The reaction mixture was diluted with EtOAc and sat. NaHCO3. The layers were separated and MPI09-013Pl RNWOM PCT FILING the aqueous layer was extracted 2x with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to in vacuo to brown oil. The residue was loaded onto a 24g Analogix silica gel column and eluted with hexane (3min) to 50percent EtOAc in hexanes (25min gradient). The appropriate fractions were concentrated to a white solid (1.25 g, 74percent). LCMS: (FA) ES+, 421, 423. 1H NMR (400MHz, d6-DMSO) 58.42 (d, J = 5.28 Hz, IH), 7.65 (td, J = 5.27, 1.51, 1.51 Hz, IH), 7.57 (d, J = 2.00 Hz, IH), 7.45-7.34 (m, IH), 7.29 (d, J = 8.26 Hz, IH), 4.34-4.17 (m, IH), 1.21 (t, J = 7.14, 7.14 Hz, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In iso-butanol; at 100℃; for 10h;Inert atmosphere; | To a flask containing <strong>[197376-47-9]ethyl 2-(6-chloropyridin-3-yl)acetate</strong> 208-1 (300 mg, 1.5 mmol), 2-fluoropyridin-4-ylboronic acid 205-4 (318 mg, 2.25 mmol), Pd(OAc)2 (17 mg, 0.075 mmoL), 2-dicyclohexylphosphino-2',6'-dimethoxyybiphenyl (62 mg, 0.15 mmol), K3PO4 (800 mg, 9 mmol) under argon was added 2-butanol (1.5 rnL). The reaction mixture was stirred at 100 0C for 10 hours. After cooled to room temperature, the mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation. The crude was purified by silica gel flash chromatography, eluted with 40% ethyl acetate in dichloromethane to give ethyl 2-(2'-fluoro-2,4'-bipyridin-5-yl)acetate 208-2 as a yellow solid. MS m/z 261.1 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In ethanol; water; toluene at 120℃; Sealed tube; | 51.1 To a sealed tube were added 4-bromo-2-fluoro-l-iodobenzene 207-1 (600 mg, 2.0 mmol), 2-fluoropyridin-4-ylboronic acid 205-4 (282 mg, 2.0 mmol), Pd(PPh3)4 (116 mg, 0.1 mmol), Na2CO3 ( 636 mg, 6.0 mmol), toluene (2 mL),H2O (2 mL) and ethanol (0.5 mL). The reaction mixture was stirred at 120 °C overnight. After cooling to room temperature, the solvents were evaporated and the residue was redissolved in water (5 ml) and extracted with ethyl acetate (8 mL x 3). The combined organic phases were dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography and eluted with 15% ethyl acetate in hexane to give 4-(4-bromo-2-fluorophenyl)-2-fluoropyridine 207-3. MS m/z 270.1 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 120℃; | To a sealed tube were added <strong>[121554-10-7]5-bromo-2-iodobenzonitrile</strong> 206-1 (500 mg, 1.6 mmol), 2-fluoropyridin-4-ylboronic acid 205-4 (229mg, 1.6 mmol), Pd(PPh3)4 (94 mg, 0.08 mmol), Na2CO3 ( 516 mg, 4.9 mmol), toluene (2 mL),H2O (2 mL) and ethanol (0.5 mL). The reaction mixture was stirred at 120 C overnight. After cooling to room temperature, the solvents were evaporated and the residue was redissolved in water (5 ml) and extracted with ethyl acetate (8 mL x 3). The combined organic phases were dried over Na2SO4, and concentrated. The residue was purified by silica gel flash chromatography and eluted with 15% ethyl acetate in hexane to give 5-bromo-2-(2-fluoropyridin-4-yl)benzonitrile 206-3. MS m/z 277 '.1 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In iso-butanol; at 100℃; for 2h; | To a reaction vial was added 2-(6-chloro-5-methylpyridin-3-yl)acetic acid 74- 4 (185 mg, 1 mmol), <strong>[401815-98-3]2-fluoropyridin-4-ylboronic acid</strong> 193-1 (220mg, 1.5 mmol), Pd(OAc)2 (12 mg, 0.05 mmol), S-Phos (41 mg, 0.1 mmol) and K3PO4 (636 mg, 3 mmol) in 1 mL 2-butanol. The reaction was heated to 100°C and stirred for 2 hours. The reaction was cooled down to room temperature and then diluted to DMSO. The reaction mixture was filtered and the filtrate was purified by reverse-phase HPLC to give 2-(2'-fluoro-3-methyl-2,4'-bipyridin-5-yl)acetic acid 193-2 as white solid. MS m/z 247.2 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 105℃; for 6h; | Step 2. Preparation of 2'-fluoro-N-(3-fluorobenzyl)-4-(trifluoromethyl)-2,4'-bipyridin-6-amine; To 6-chloro-N-(3-fluorobenzyl)-4-(trifluoromethyl)pyridin-2-amine (70 mg, 0.230 mmol) was added <strong>[401815-98-3]2-fluoropyridin-4-ylboronic acid</strong> (58.3 mg, 0.414 mmol), PdCl2(dppf).CH2Cl2 adduct (22.52 mg, 0.028 mmol), DME (1.2 ml), and 2M sodium carbonate (0.460 ml, 0.919 mmol). The resulting reaction mixture was stirred at 105° C. until completion as indicated by LCMS, about 6 hours. The reaction mixture was cooled, 15 ml of ethyl acetate and 5 ml of methanol was added, filtered and concentrated to yield a crude solid. The solid was purified by prep LC. The product was free-based using 200 ml of ethyl acetate and washed with saturated sodium bicarbonate (1.x.), water (2.x.), saturated salt solution (1.x.), dried sodium sulfate, filtered and concentrated to a constant mass, yielding 35 mg of titled compound as free base. LCMS (m/z): 366.2 (MH+), retention time=1.20 min. | |
With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 105℃; for 6h; | Step 2. Preparation of 2'-fluoro-N-(3-fluorobenzyl)-4-(trifluoromethyl)-2,4'-bipyridin-6- amine:To 6-chloro-N-(3-fluorobenzyl)-4-(trifluoromethyl)pyridin-2-amine (70 mg, 0.230 mmol) was added <strong>[401815-98-3]2-fluoropyridin-4-ylboronic acid</strong> (58.3 mg, 0.414 mmol),PdCl2(dppf).CH2Cl2 adduct (22.52 mg, 0.028 mmol), DME (1.2 ml), and 2M sodium carbonate (0.460 ml, 0.919 mmol). The resulting reaction mixture was stirred at 105 °C until completion as indicated by LCMS, about 6 hours. The reaction mixture was cooled, 15 ml of ethyl acetate and 5 ml of methanol was added, filtered and concentrated to yield a crude solid. The solid was purified by prep LC. The product was free-based using 200 ml of ethyl acetate and washed with saturated sodium bicarbonate (1x), water (2x), saturated salt solution (1x), dried sodium sulfate, filtered and concentrated to a constant mass, yielding 35 mg of titled compound as free base. LCMS (m/z): 366.2 (MH+), retention time = 1.20 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.2% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; for 2.0h;Reflux; | A solution of 6g (771 mg, 2.012 mmol), (2-fluoro-4-pyridinyl)boronic acid (425 mg, 3.02 mmol),bis(triphenylphosphine)palladium(II) chloride (70.6 mg, 0.101 mmol) and Na2CO3 (1066 mg,10.06 mmol) in DME (20 mL) and water (2 mL) was stirred at reflux for 2 hours. The mixturewas then diluted with EA (50 mL) and water (50 mL). The organic layer was separated and theaqueous layer was extracted with ethyl acetate (50 mL*2). The combined organic layer wasconcentrated and the crude was purified by silica gel eluting with 0-10% MeOH/DCM (1%ammonia) to give the title compound 8i (500 mg, 1.252 mmol, 62.2 % yield) as an off-white solid. |
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 2.0h;Reflux; | (2-Fluoro-4-pyridinyl)boronic acid (425 mg, 3.02 mmol),bis(triphenylphosphine)palladium(ll) chloride (70.6 mg, 0.10 mmol) and sodium carbonate (1066 mg, 10.06 mmol) as a solution in 2 ml of water was added to a solution of 5-bromo-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in example 2; 771 mg, 2.01 mmol) in 1 ,2-dimethoxyethane (20 ml). The mixture was heated to reflux for 2 hours. The mixture was diluted with ethyl acetate (50 ml) and water (50 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 50 ml). The organics were combined and evaporated. The residue was purified by chromatography on silica eluting with 0- 0% methanol/ dichloromethane 1 % ammonia to yield the title compound as an off-white solid. 500 mg. MS (electrospray): m/z [ +H]+ = 400H NMR (400 MHz, CHLOROFORM-tf) 5.36 (2 H, s), 7.18 - 7.32 (2 H, m), 7.32 - 7.44 (2 H, m), 7.49 - 7.66 (6 H, m) ,7.89 (1 H, dd, J=8.55, 2.19 Hz), 8.01 (1 H, d, J=7.45 Hz), 8.12 (1 H, d, J=1.53 Hz), 8.25 (2 H, t, J=5.04 Hz), 8.60 (1 H, d, J=2.19 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 140℃; for 0.666667h;microwave irradiation; | To a solution of intermediate B (300 mg, 1.2 mmol) in 6 mL of DME and 2 mL of water, 2-(fluoro)pyridin-4-ylboronic acid (719 mg, 5.1 mmol), Pd(dppf)Ci2 (160 mg, 0.13 mmol), and 2M a2C03 (324 mg, 3.06 mL) were added. The mixture was microwave heated at 140 C for about 40 min. The mixture was concentrated under reduced pressure and extracted with EtOAc. The combined organic phase was 8576.98-304 dried with Na2S04 and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography (PE: EA=75%) to give the title compound as a white solid (200 mg, 65% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 100℃; for 2h; | 3 : 4-Amino-N-(i7"fln1s-4-hydroxycyclohexyl)-7-(2-fluoro-4-pyridinyl)pyrrolo [2,1- fj [l,2,4]triazine-5-carboxamide[00139] A suspension of 3A (39 mg, 0.11 mmol), <strong>[401815-98-3]2-fluoropyridin-4-ylboronic acid</strong> (31 mg, 0.22 mmol) and aq. potassium carbonate (0.14 mL, 0.21 mmol) in 2 mL of degassed DMF was treated with 6 mg (0.006 mmol) oftetraA;/i(triphenylphosphine)palladium(0). The mixture was stirred at 100 °C for 2h, cooled to RT, and diluted with water. The resulting mixture was extracted three times with 9:1 chloroform-ethanol, and the combined organic extracts dried andconcentrated. Trituration from ether afforded 3 (8 mg, 18 percent yield) as a white powder. HPLC: 5.88 min (YMC S5 ODS, 4.5 x 50 mm. 4 mL/min, 10-90percent methanol-water 0.2percent H3PO4, gradient over 12 min). MS (ES): m/z= 371 [M+H]+. 3/4 NMR (400 MHz, DMSO-d6) 5 ppm 10.49(br. s, IH); 8.36-8.44(m, 3H); 8.16(s, IH); 8.15(s, IH); 8.01-8.04(m, IH); 7.95(s, IH); 4.65(d, IH, J = 4.3 Hz); 3.75-3.86(m, IH); 3.40- 3.5 l(m. IH); 1.85-1.96(m, 4H); 1.23-1.49(m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In iso-butanol; at 100℃;Inert atmosphere; | Example 10N-((2'-fluoro-r2,4'-bipyridinl-5-yl)methyl)-4-(pyrazin-2-yl)benzamide (24) [0179] Step 1: A mixture of (2-fluoropyridin-4-yl)boronic acid 24-1 (200 mg, 1.42 mmol), <strong>[97004-04-1](6-chloropyridin-3-yl)methanamine</strong> 18-1 (142 mg, 1.00 mmol), Pd(OAc)2 (12 mg, 0.05 mmol), dicyclohexyl(2',6'-dimethoxy-[l,l'-biphenyl]-2-yl)phosphine (41 mg, 0.1 mmol) and K3PO4 (424 mg, 2.00 mmol) in 2-butanol (1 mL) was stirred at 100 °C under argon overnight. After cooling to room temperature, the mixture was filtered through celite (washed with ethyl acetate), concentrated by rotavap and the residue subjected to silica gel columnchromatography with 7percent ammonia- saturated methanol in dichloromethane as eluent to give (2'-fluoro-[2,4'-bipyridin]-5-yl)methanamine 24-2 as an oil. | |
With potassium phosphate;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In iso-butanol; at 100℃; for 10h;Inert atmosphere; | Example 146'-(Dimethylamino)-N-((2'-fluoro-2^'-bipyridin-5-yl)methyl)-3 '-bipyridine-6-carboxamide(38)38-4 38-5 Compound 38[0192] Step 1 : To a flask containing <strong>[97004-04-1](6-chloropyridin-3-yl)methanamine</strong> 33-2 (642 mg, 4.50 mmol), 2-fluoropyridin-4-ylboronic acid 38-1 (634 mg, 4.50 mmol), Pd(OAc)2 (51 mg, 0.23 mmol), S-Phos (186 mg, 0.45 mmol) and potassium phosphate (2.85 g, 13.50 mmol) under argon was added 2-butanol (5 mL). The mixture was stirred at 100 °C for 10 hours. After cooling to room temperature, the mixture was filtered through celite cake. The filtrate was diluted with ethyl acetate, washed with H20 and brine, dried over Na2S04, and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flashchromatography, eluted with 5percent methanol containing ~ 7N ammonia in dichloromethane to give (2'-fluoro-2,4'-bipyridin-5-yl)methanamine 38-2 as yellow solid. MS m/z 204.1 (M + 1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.3% | With potassium phosphate;bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); In 1,4-dioxane; water; at 100℃; for 0.5h;Inert atmosphere; microwave; | A microwave vial was charged with 3-chloro-l -fluoro-7-(2-fluoropyridin-3- yl)spiro[chromeno[2,3-c]pyridine-5, -isoindol]-3'-amine 2,2,2-trifluoroacetate (43 mg, 0.077 mmol, step 3), 2-fluoropyridine-4-boronic acid (27.0 mg, 0.192 mmol, Aldrich), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (5.43 mg, 7.67 muiotaetaomicron, Aldrich) and potassium phosphate (48.8 mg, 0.230 mmol, Aldrich). The vial was evacuated and backfilled with N2 gas (2x). Dioxane (0.6 mL) and water (0.2 mL) were added, and the vial was heated in the microwave for 30 min at 100 °C. The reaction mixture was partitioned between EtOAc and water. The organic phase was separated and the solvent was removed under reduced pressure. The residue was purified by reversed- phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 1 10 A, 100 x 50 mm, 0.1 percent TFA in CH3CN/H20, gradient 10percent to 100percent over 20 min to obtain the title product (23 mg, 0.037 mmol, 48.3 percent yield) as a light-yellow solid. MS m/z = 508.1 [M+H]+. Calculated for CzgHjgFaNjOCzHFaOz: 621.49 (TFA salt). 'H-NMR (300 MHz, MeOH) delta ppm 7.14 (t, .7=1.61 Hz, 1 H) 7.30 - 7.39 (m, 1 H) 7.39 - 7.48 (m, 1 H) 7.53 - 7.70 (m, 3 H) 7.72 - 7.86 (m, 4 H) 7.92 (ddd, J=9.94, 7.75, 1.90 Hz, 1 H) 8.16 (d, J=4.97 Hz, 1 H) 8.22 (d, .7=5.41 Hz, 1 H) 8.26 - 8.37 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium carbonate;palladium diacetate; tris-(o-tolyl)phosphine; In 1,2-dimethoxyethane; water; at 80℃; for 5h;Inert atmosphere; | To a resealable reaction vessel under nitrogen was added 1.0 equiv of the bromo derivative 7, Pd(OAc)2 (0.1 equiv), P(o-tolyl)3 (0.2 equiv), sodium carbonate (2.0 equiv) and the respective pyridinyl boronic acid (1.6 equiv), DME (6 mL) and water (0.7 mL). The mixture was degassed through bubbling nitrogen and heated at 80 °C for 5 h. The mixture was cooled, poured into 20 mL of a saturated aqueous solution of NaHC03 and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over MgS04, filtered through Celite and the solvent removed under reduced pressure. The resultant residue was purified by flash chromatography (CHC13/ MeOH, 50/1 to 10/1).7-ferf-Butoxycarbonyl-2-i?.v0-|2 '-amino-3 '-(2-fluoropyridin-4-yl)-5 '-pyridnyl|-7- azabicyclo 12.2.1 j heptane (8a).The reagents were compound 7 and 2-fluoropyridine-4-boronic acid. .H NMR (300 MHz, CDCI3) delta 1.4 (br s, 9H), 1.52-1.59 (m, 2H), 1.82-1.84 (m, 3H), 1.94-1.98 (m, 1H), 2.79-2.84 (m, 1H), 4.16 (s, 1H), 4.36 (br s, 1H), 4.77 (s, 2 NH), 7.06 (s, 1H), 7.34 (ddd, J = 1.6, 5.13, 8.4 Hz, 1H), 7.41 (d, J = 2.3 Hz, 1H), 8.0 (d, J = 2.3 Hz, 1H), 8.26 (d, J = 5.16 Hz, 1H); MS (ESI) m/z 385.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.7% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; methanol; water; at 140℃; for 0.666667h;Inert atmosphere; microwave oven; | Example 74 The reaction was executed under an argon-atmosphere.To 100 mg (0.24 mmol) of example 33 and 70.0 mg (0.50 mmol) <strong>[401815-98-3]2-fluoropyridin-4-ylboronic acid</strong>, 3 mL dioxane and 2 mL methanol, 350 muL (0.70 mmol) of a aqueous sodium carbonate solution (2 mol/L) and 18.0 mg (0.02 mmol) 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) were added. The reaction mixture was heated to 140° C. for 40 min in a microwave oven. After cooling to room temperature the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by preparative HPLC (eluent A: water+0.13percent TFA, eluent B: acetonitrile). 47.4 mg (45.7percent) of the product were obtained.HPLC-MS (Method1): Rt=1.49 minMS (ESI pos): m/z=440 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 110℃; for 3h; | To 6-chloro-N-(3-fluorobenzyl)pyrazin-2-amine (140 mg, 0.589 mmol) was added 2- fluoropyridin-4-ylboronic acid (125 mg, 0.884 mmol), PalladiumTetrakis (82 mg, 0.071 mmol), DME (3.3 ml), and 2M sodium carbonate (1.031 ml, 2.062 mmol) . The resulting reaction mixture was stirred at 1 10 °C until completion as indicated by LCMS, about 3 hours. The reaction mixture was cooled to room temperature, diluted with 20 ml of ethyl acetate, filtered and concentrated to yield a crude solid. The solid was dissolved in DMSO, filtered and purified by prep LC. After lyophilization, 72 mg of the title compound was obtained as a TFA salt,. LCMS (m/z): 299.1 (MH+), retention time = 0.89 min. | |
With sodium carbonate; In 1,2-dimethoxyethane; at 110℃; for 3h; | Step 2. Preparation of N-(3-fluorobenzyl)-6-(2-fluoropyridin-4-yl)pyrazin-2-amine: To 6-chloro-N-(3-fluorobenzyl)pyrazin-2-amine (140 mg, 0.589 mmol) was added 2- fluoropyridin-4-ylboronic acid (125 mg, 0.884 mmol), PalladiumTetrakis (82 mg, 0.071 mmol), DME (3.3 ml), and 2M sodium carbonate (1.031 ml, 2.062 mmol) . The resulting reaction mixture was stirred at 1 10 °C until completion as indicated by LCMS, about 3 hours. The reaction mixture was cooled to room temperature, diluted with 20 ml of ethyl acetate, filtered and concentrated to yield a crude solid. The solid was dissolved in DMSO, filtered and purified by prep LC. After lyophilization, 72 mg of the title compound was obtained as a TFA salt,. LCMS (m/z): 299.1 (MH+), retention time = 0.89 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 105℃; for 6h; | To 6-chloro-N-(3-fluorobenzyl)-4-(trifluoromethyl)pyridin-2-amine (70 mg, 0.230 mmol) was added <strong>[401815-98-3]2-fluoropyridin-4-ylboronic acid</strong> (58.3 mg, 0.414 mmol),PdCl2(dppf).CH2Cl2 adduct (22.52 mg, 0.028 mmol), DME (1.2 ml), and 2M sodium carbonate (0.460 ml, 0.919 mmol). The resulting reaction mixture was stirred at 105 °C until completion as indicated by LCMS, about 6 hours. The reaction mixture was cooled, 15 ml of ethyl acetate and 5 ml of methanol was added, filtered and concentrated to yield a crude solid. The solid was purified by prep LC. The product was free-based using 200 ml of ethyl acetate and washed with saturated sodium bicarbonate (1x), water (2x), saturated salt solution (1x), dried sodium sulfate, filtered and concentrated to a constant mass, yielding 35 mg of titled compound as free base. LCMS (m/z): 366.2 (MH+), retention time = 1.20 min. | |
With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 105℃; for 6h; | Step 2. Preparation of 2'-fluoro-N-(3-fluorobenzyl)-4-(trifluoromethyl)-2,4'-bipyridin-6- amine:To 6-chloro-N-(3-fluorobenzyl)-4-(trifluoromethyl)pyridin-2-amine (70 mg, 0.230 mmol) was added <strong>[401815-98-3]2-fluoropyridin-4-ylboronic acid</strong> (58.3 mg, 0.414 mmol),PdCl2(dppf).CH2Cl2 adduct (22.52 mg, 0.028 mmol), DME (1.2 ml), and 2M sodium carbonate (0.460 ml, 0.919 mmol). The resulting reaction mixture was stirred at 105 °C until completion as indicated by LCMS, about 6 hours. The reaction mixture was cooled, 15 ml of ethyl acetate and 5 ml of methanol was added, filtered and concentrated to yield a crude solid. The solid was purified by prep LC. The product was free-based using 200 ml of ethyl acetate and washed with saturated sodium bicarbonate (1x), water (2x), saturated salt solution (1x), dried sodium sulfate, filtered and concentrated to a constant mass, yielding 35 mg of titled compound as free base. LCMS (m/z): 366.2 (MH+), retention time = 1.20 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 90℃; for 1h;Inert atmosphere; | Step 1. Methyl 2-(2-fluoropyridin-4-yl)-3-(isopropyl(methyl)amino)quinoxaline-6- carboxylateTo a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (300.0 mg, 1.02 mmol) in dioxane (5 mL) was added <strong>[401815-98-3]2-fluoropyridin-4-ylboronic acid</strong> (289.0 mg, 2.06 mmol), K3P04 (435.0 mg, 2.05 mmol), Pd(PPh3)4 (60 mg, 0.05 mmol) and three drops water under an inert atmosphere of nitrogen. The resulting solution was stirred for 1 h at 90°C and then quenched by the addition of water (50 mL). The resulting solution was extracted with dichloromethane (5 x 20 mL) and the organic layers combined, dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 1 percent - 5percent ethyl acetate in petroleum ether to afford methyl 2-(2-fluoropyridin-4-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a yellow solid (250 mg, 69percent).LC/MS(ES, m z):[M+H]+ 355.0 'H-NMR (300 MHz, CDCI3), delta 8.58 (d, / = 1.5 Hz, 1H), 8.38 (d, / = 5.1 Hz, 1H), 8.09 - 8.12 (m, 1H), 7.98 (d, / = 8.7 Hz, 1H), 7.72 - 7.74 (m, 1H), 7.51 (s, 1H), 4.22 - 4.26 (t, / = 6.6 Hz, 1H), 4.07 (s, 3H), 2.78 (s, 3H), 1.15 (d, / = 6.6 Hz, 6H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; at 150℃; for 0.75h;Microwave irradiation; | 9. GENERAL PROCEDURE 5a. PREPARATION OF 2-((4-ETHYL-5-(2-FLUOROPYRIDIN-4-YL)-4H-1,2,4- TRIAZOL-3-YL)THIO)-N-(4-ISOPROPYLPHENYL)ACETAMIDE (VU0458428).[00583] To a solution of 2-((5-bromo-4-ethyl-4H-l,2,4-triazol-3-yl)thio)-N-(4- isopropylphenyl)acetamide (30 mg, 0.078 mmol) in 7.8 mL of (4: 1) THF:H20 was added cesium carbonate (31.0 mg, 0.094 mmol), Pd(PPh3)4 (9.0 mg, 0.008 mmol) and (2- fluoropyridin-4-yl)boronic acid (13.2 mg, 0.094 mmol). The resulting slurry was heated in a microwave reactor at 150°C for 45 min. After cooling to room temperature, the reaction mixture was filtered over a celite plug and concentrated. The resulting residue was purified by HPLC with H20/MeCNto afford 16 mg (51percent) of the desired product. XH NMR (CDC13) delta 9.98 (s, 1H), 8.43 (d, J = 5.0 Hz, 1H), 7.49 (m, 3H), 7.16 (d, J = 8.4 Hz, 2 H), 4.08 (q, J = 7.2 Hz, 2H), 4.02 (s, 2H), 2.86 (m, 1H), 1.43 (t, 7.2, 3H), 1.21 (d, J = 6.9 Hz). LRMS calculated for C20H22FN5OS (M+H)Vz: 400.15 Measured 400.2 m/z. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; benzene; at 120℃; for 1h;microwave irradiation; | (i)Preparation of 22b: (4aS,6aS,6bR,8aR,13aR,15bS)-benzyl 12-amino-15-(2-fluoropyridin-4-yl)-2,2,6a,6b,9,9,13a-heptamethyl-2,3,4,4a,5,6,6a,6b,7,8,8a,9,11,13,13a,13b,14,15b-octadecahydro-1H-chryseno[1,2-f]indazole-4-a-carboxylateA mixture of II (500 mg, 0.75 mmol), <strong>[401815-98-3]2-fluoropyridin-4-ylboronic acid</strong> (210 mg, 1.50 mmol), Pd(PPh3)4 (80 mg, 0.075 mmol) and K2CO3 (310 mg, 2.25 mmol) in benzene (4.0 mL) and EtOH (1.0 mL) was sealed and heated to 120° C. by microwave for 1 hour.The reaction mixture was diluted with EtOAc (100 mL).The organic phase was washed with brine then dried (MgSO4), filtered and concentrated to dryness.The residue was purified by column chromatography (silica, 0-10percent MeOH in CH2Cl2) to afford the sub-title compound (448 mg, 88percent) as a brown solid. APCI MS (Positive Mode) m/z 679 [C43H55FN4O2+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Step 1: preparation of compound 44-2: To a solution of D (150 mg, 0.65 mmol) in dioxane (20 mL), was added TEA (300 mg, 3.0 mol), and PyBroP (400 mg, 1.0 mmol). After the mixture was stirred at r.t. for 1 h, Pd(PPh3)4 (80 mg, 0.07 mmol), boronic acid 44-1 (180 mg, 1.3 mmol), K2C03 (200 mg, 1.3 mmol), and H20 (5 mL) was added. After the mixture was stirred at 90°C for 3 h under N2, it was extracted with EtOAc (50 mL X 2), washed with sat NaCl (50 mL), dry over Na2S04, and concentrated to give the crude product as brown solid. The solid was washed with EtOH (10 mL) to give the yellow solid as product: ethyl 8-arnino-2-(2-fluoropyridin-4-yl)-l,7-naphthyridine-5-carboxylate 44-2 (100 mg, yield 50percent). NMR (400MHz, CDC13) delta 9.27 (d, J= 9.2 Hz, 1H), 8.67 (s, 1H), 8.56 (d, J= 9.2 Hz, 1H), 8.43 (br, 1H), 8.38 (m, 3H), 8.13 (br, 1H), 4.30 (q, 2H), 1.32 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.3% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 6h;Inert atmosphere; | (002821 Step B: Sodium carbonate (4.24 g, 40.0 mmol) was added to 2-fluoropyridin- 4-ylboronic acid (2.26 g, 16.0 mmol) and 6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4- amine (2.85 g, 13.3 mmol) in 4:1 dioxane/water (100 mL), and the suspension was purged with argon. PdC12(dppf)*DCM (0.545 g, 0.667 mmol) was added, and the mixture was heated at 80°C under nitrogen. After agitating for 6 hours, the reaction mixture was cooled, diluted with water and extracted with ethyl acetate two times. The extract was washed with water, brine, dried and evaporated. Purified by chromatography on silica gel, eluted with 50-70percent ethyl acetate/hexane to give 6-(2-fluoropyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin- 4-amine (2.50 g, 9.11 mmol, 68.3percent yield) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.3% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 6h;Inert atmosphere; | 1002851 Step B: Sodium carbonate (0.989 g, 9.33 mmol) was added to <strong>[401815-98-3]2-fluoropyridin-4-ylboronic acid</strong> (0.570 g, 4.04 mmol) and 4-bromo-N-(tetrahydro-2H-pyran-4-yl)pyridin-2- amine (0.80 g, 3.11 mmol) in 4:1 dioxane/water (25 mE), and the suspension was purged with nitrogen. PdC12(dppf)*DCM (0.127 g, 0.156 mmol) was added, and the mixture was heated at 80°C under nitrogen. After agitating for 6 hours, the reaction mixture was cooled, diluted with water and extracted with ethyl acetate (2 X). The extract was washed with water, brine, dried and evaporated. Purified by chromatography on silica gel, eluted with 5 0-70percent ethyl acetate/hexane to give 2?-fluoro-N-(tetrahydro-2H-pyran-4-yl)-4,4?-bipyridin-2-amine (0.64 g, 2.34 mmol, 75.3percent yield) as a solid. |
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 85℃; for 2.0h;Inert atmosphere; | Step A: A suspension of <strong>[959236-97-6]4-bromo-2-(methylthio)pyrimidine</strong> (7.00 g, 34.1 mmol), 2-fluoropyridin-4-ylboronic acid (5.05 g, 35.8 mmol), Na2C03 (10.9 g, 102 mmol) and Pd(dppf)Cl2 CH2C12 (1.40 g, 1.71 mmol) in dioxane/H20 (100 mL; 1 :1) was heated to 85C under an Ar balloon for 2 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate (200 mL) and water (100 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (IX). The organics were dried, filtered and concentrated. The crude product was purified via column chromatography, eluting with hexanes/ethyl acetate (3:1) to give 4-(2-fluoropyridin-4-yl)-2- (methylthio)pyrimidine (6.83 g, 90%) as a solid. 1H NM (400 MHz, (CD3)2SO) delta 8.85 (d, J=5.2 Hz, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.1 1 (m, 1H), 7.96 (d, J=5.2 Hz, 1H), 7.92 (s, 1H), 2.62 (s, 3H); m/z (APCI-pos) M+l = 222.1. |
90% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 85℃; for 2.0h;Inert atmosphere; | step 1: A suspension of <strong>[959236-97-6]4-bromo-2-(methylthio)pyrimidine</strong> (7.00 g, 34.1 mmol), 2-fluoropyridin- 4-ylboronic acid (5.05 g, 35.8 mmol), Na2C03 (10.9 g, 102 mmol) and Pd(dppf)Cl2 CH2C12 (1.40 g, 1.71 mmol) in dioxane/H20 (100 mL; 1:1) was heated to 85C under an Ar balloon for 2 h. The reaction mixture was cooled to RT and concentrated. The residue was diluted with ethyl acetate (200 mL) and water (100 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (IX). The organics were dried, filtered and concentrated. The crude product was purified via column chromatography, eluting with hexanes/ethyl acetate (3: 1) to give 4-(2-fluoropyridin-4-yl)-2-(methylthio)pyrimidine (6.83 g, 90%) as a solid. XH NMR (400 MHz, (CD3)2SO) delta 8.85 (d, J=5.2 Hz, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.11 (m, 1H), 7.96 (d, J=5.2 Hz, 1H), 7.92 (s, 1H), 2.62 (s, 3H); m/z (APCI-pos) M+l = 222.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 1.5h;Inert atmosphere; Sealed tube; | (002651 Step A: Sodium carbonate (1.3 g, 13 mmol) to <strong>[401815-98-3]2-fluoropyridin-4-ylboronic acid</strong> (0.71 g, 5.0 mmol) and 2,4-dichloro-5-fluoropyrimidine (0.70 g, 4.2 mmol) in dioxane/water (17 mL, 4:1), and the mixture was purged with nitrogen. PdC12(dppf)*DCM (0.17 g, 0.21 mmol) was added to the mixture, and the sealed vial was heated at 80°C. After 1.5 hours, the cooled reaction mixture was partitioned between water and EtOAc. The EtOAc was washed with brine, dried over MgSO4, filtered, and evaporated to yield a crude product (1.7 g) as an oil. The crude product was absorbed on silica gel and chromatographed on a 50 g Biotage SNAP column with 2:1 hexane/EtOAc. Fractions 14-17 contained 2-chloro-5- fluoro-4-(2-fluoropyridin-4-yl)pyrimidine (0.82 g, 3.6 mmol, 86percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In ethanol; toluene; at 105℃;Inert atmosphere; | In a 15 mL pressure vessel, a solution of <strong>[149849-94-5]methyl 2-chloropyrimidine-4-carboxylate</strong> (0.048 g, 0.278 mmol), (2-fluoropyridin-4-yl)boronic acid (0.060 g, 0.426 mmol) and Pd(dppf)Cl2.DCM (0.013 g, 0.016 mmol) in a mixture of toluene (4 mL) and ethanol (3 mL) was degassed under high vacuum and back-filled with nitrogen three times. An aqueous solution of sodium carbonate (2 M, 0.18 mL, 0.360 mmol) was then added and the mixture was heated at 105 C overnight. The cooled mixture was diluted with water and the resulting mixture was washed with ethyl acetate (x3). The aqueous layer was separated, acidified to pH 1 with 1 M hydrochloric acid and extracted with ethyl acetate (xl) and then dichloromethane (x2). The combined organic extract was washed once with brine, dried over anhydrous Na2SO4 and concentrated. The crude residue was taken up in THF (3 mL) and treated with a solution of diazomethane (0.77 M in Et20, 1 mL, 0.77 mmol) and the mixture was stirred at room temperature for 64 h. The volatiles were then removed in vacuo and the residue was purified on the ISCO using a REDISEP 4 g column (elution with hexanes-EtOAc) to give the title compound (0.020 g, 31%) as a white solid. LC (Method B): 1.691 min. LCMS (APCI): calcd for C11H9FN3O2 [M+H]+ m/z 234.067, found 234.2. 1H NMR (400 MHz, MeOH-d4: delta 9.20 (d, J= 4.70 Hz, 1H), 8.33-8.41 (m, 2H), 8.10 (s, 1H), 8.08 (d, J= 4.70 Hz, 1H), 4.06 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 4h; | In a pressure tube Intermediate 7 (1.7 g, 4.63 mmol) and (2-fluoropyridin-4-yl)-acid (935 mg, 6.64 mmol) were dissolved in 1,4-dioxane (10 mL) and a 2Mof K2C03 in water (7 mL) was added. The mixture was flushed with nitrogenbis[3 -(diphenylphosphanyl)cyclopenta-2,4-dien- 1 -yl]iron dichloropalladium dichloromethane complex (300 mg, 0.37 mmol) was added. The mixture was heated atfor 4 h. The mixture was diluted with ethyl acetate (20 mL), then washed with(2 x 10 mL) and brine (10 mL). The organic layer was dried over sodium sulfateconcentrated under vacuum. The resulting dark brown solid was purified by FCC,with a gradient of 70-100percent ethyl acetate in heptane followed by 0-10percent methanolDCM, to afford the title compound (1.55 g, 87percent) as a light pink solid. oH (250 MHz,CD3OD) 8.52-8.49 (m, 1H), 8.24 (d, J5.4 Hz, 1H), 7.63 (d, J 1.8 Hz, 1H), 7.60 (d, J0.91H), 7.56-7.52 (m, 1H), 7.33 (s, 1H), 7.3 1-7.25 (m, 1H), 7.24-6.64 (m, 4H), 4.43 (s,2.44 (s, 3H). Method D HPLC-MS: MH+ m/z 384, RT 3.29 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With potassium phosphate; In 1,4-dioxane; water; at 90℃; for 4h;Inert atmosphere; | SiliaCat DPP-Pd (0.26 mmol/g loading, from Silicycle, 100 mg, 0.67 mmol),ethyl2-(6-bromobenzo[d]thiazol-2-yl)acetate (described in W02011/074560, 200 mg,0.67 mmol), potassium phosphate (348 mg, 2.00 mmol) and <strong>[401815-98-3](2-fluoropyridin-4-yl)boronic acid</strong> (141 mg, 1.00 mmol) in dioxane (5 mL)/water (0.2 mL) were purged with10 argon for 5 minutes and then heated at 90 °C. After 4 hours, the reaction mixture wasdiluted with water (50 mL), extracted with DCM (3 X 50 mL), dried over MgS04, andconcentrated under reduced pressure. The residue was purified by silica gelchromatography (0 to 100percent ethyl acetate/hexanes over 15 minutes) to give CompoundB23a (120 mg, 57percent yield) as a brown solid. HPLC: RT = 0.95 min (LCMS Method M).15 MS (ES): m/z = 316.9 [M+H( 1H NMR (500MHz, DMSO-d6) 8 8.68 (d, 1=1.7 Hz,IH), 8.35 (d, 1=5.2 Hz, IH), 8.12 (d, 1=8.5 Hz, IH), 8.02 (dd, 1=8.5, 1.9 Hz, IH), 7.81 (d,1=5.2 Hz, IH), 7.64 (s, IH), 4.38 (s, 2H), 4.19 (q, 1=7.1 Hz, 2H), 1.24 (t, 1=7.0 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; benzene; at 120℃; for 1h;Microwave irradiation; Sealed tube; | (i) Preparation of 22b: (4aS,6aS,6bR,8aR,13aR,15bS)-Benzyl 12-amino-15-(2-fluoropyridin-4-yl)-2,2,6a,6b,9,9,13a-heptamethyl-2,3,4,4a,5,6,6a,6b,7,8,8a,9,11,13,13a,13b,14,15b-octadecahydro-1H-chryseno[1,2-f]indazole-4a-carboxylate A mixture of II (500 mg, 0.75 mmol), <strong>[401815-98-3]2-fluoropyridin-4-ylboronic acid</strong> (210 mg, 1.50 mmol), Pd(PPh3)4 (80 mg, 0.075 mmol) and K2CO3 (310 mg, 2.25 mmol) in benzene (4.0 mL) and EtOH (1.0 mL) was sealed and heated to 120 °C by microwave for 1 hour. The reaction mixture was diluted with EtOAc (100 mL). The organic phase was washed with brine then dried (MgSO4), filtered and concentrated to dryness. The residue was purified by column chromatography (silica, 0-10percent MeOH in CH2Cl2) to afford the sub-title compound (448 mg, 88percent) as a brown solid. APCI MS (Positive Mode) m/z 679 [C43H55FN4O2 + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.5% | With sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 0.5h;Microwave irradiation; | [11241 Step 1: Synthesis of methyl4-(((25 .6R?)-4-(3-(2-fluoropvridin-4-vlThenzovl?)-2.6-dimethvlpiperazin- 1 -vl?)methvl?)benzoate[11251 1,2-Dimethoxyethane/water (v/v=3/1) (3 mL) were added to a mixture of methyl 4-(((2S ,6R)-4-(3-iodobenzoyl)-2,6-dimethylpiperazin- 1 -yl)methyl)benzoate (formula15-1, 0.400 g, 0.8 12 mmol), <strong>[401815-98-3](2-fluoropyridin-4-yl)boronic acid</strong> (0.172 g, 1.219 mmol), Pd(dbpf)C12 (0.026 g, 0.04 1 mmol) and Na2CO3 (0.25 8 g, 2.437 mmol), and heated by microwave irradiation at 120 °C for 30 minutes, followed by cooling to room temperature. Then, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (silicon dioxide; ethyl acetate/hexane = from 10 percent to 50 percent) and concentrated to afford the desired compound (0.366 g, 97.5 percent) as a brown oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With palladium diacetate; sodium carbonate; tris-(o-tolyl)phosphine; In 1,2-dimethoxyethane; water; at 80℃; for 5h;Inert atmosphere; | General procedure: To a resealable reaction vessel under nitrogen was added1.0 equiv of compound 7, Pd(OAc)2 (0.1 equiv), P(o-tolyl)3(0.2 equiv), sodium carbonate (2.0 equiv) and the respective pyridinylboronic acid (1.6 equiv), DME (6 mL) and water (0.7 mL).The mixture was degassed through bubbling nitrogen for 40 min,sealed and heated in an oil bath at 80 C for 5 h. The mixture wascooled, poured into 20 mL of a saturated aqueous solution ofNaHCO3 (20 mL) and extracted with EtOAc (3 30 mL). The combinedorganic layers were dried over MgSO4, filtered through Celite and the solvent removed under reduced pressure. The resultantresidue was purified on a silica gel ISCO column and elutedwith EtOAc/hexanes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.4% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; toluene; at 80℃; for 2h; | General procedure: The mixture of 5b (2.9 g, 6.7 mmol), 4-chlorophenylboronic acid (1.36 g, 10.1 mmol), tetrakis(triphenylphosphine)palladium (0.7 g, 0.6 mmol) and sodium carbonate (2.8 g, 26.8 mmol) in toluene (29 mL) and water (2.9 mL) was degassed and heated at 80 °C for 2 h. Filter, the filtrate was diluted with EA (50 mL), washed with water, dried over sodium sulfate, concentrated under vacuum to yield yellow oil. The oil was purified by silica gel column (ethyl acetate: petroleum ether, 1:10, v/v) to afford off-white solid 6a (2.7 g, 87.2percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; ethanol; at 85℃; for 8h; | Example 44 Synthesis of tert-butyl cyclopropyl(5-(2-fluoropyridin-4-yl)-3-formylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate To tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (1 g, 3 mmol) in 29 mL of a 2:1 mixture of 1,2-dimethoxyethane/EtOH was added 2-Fluoropyridine-4-boronic acid (500 mg, 3.55 mmol), tetrakis(triphenylphosphine)palladium(0) (173 mg, 0.15 mmol), and 2M aqueous solution of Na2CO3 (4.4 mL, 8.9 mmol). The mixture was stirred at 85° C. for 8 hours. The volatiles were removed by rotary evaporation and the residue was purified by silica gel chromatography (35percent EtOAc/Hexanes) to provide 324 mg tert-butyl cyclopropyl(5-(2-fluoropyridin-4-yl)-3-formylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (28percent yield). LCMS (M+1=398) |
28% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 85℃; for 8h; | To tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (1 g, 3 mmol) in 29 mL of a 2:1 mixture of 1,2-dimethoxyethane/EtOH was added 2-Fluoropyridine-4-boronic acid (500 mg, 3.55 mmol), tetrakis(triphenylphosphine)palladium(0) (173 mg, 0.15 mmol), and 2M aqueous solution of Na 2CO 3 (4.4 mL, 8.9 mmol). The mixture was stirred at 85° C. for 8 hours. The volatiles were removed by rotary evaporation and the residue was purified by silica gel chromatography (35percent EtOAc/Hexanes) to provide 324 mg tert-butyl cyclopropyl(5-(2-fluoropyridin-4-yl)-3-formylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (28percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 1h;Inert atmosphere; | General procedure: [0156] The quinolizine scaffold (1 eq.), boronate (1.3 eq.)and cesium carbonate (3 eq.) were added to a 3:1 mixtureof 1,2-dimethoxyethane and water. Themixture was degassed with argon. 1,1?-Bis-diphenylphosphine ferrocenepalladium(II) dichloride (0.1 eq.) was added andthe mixture was heated at 90 °C under an argon atmosphere for 1h. Thereaction mixture was cooled. Themixture was diluted with CH2Cl2 (3 mL) and water was added (3 mL). The layers wereseparated using a phase separator andthe aqueous layer was extracted with CH2Cl2 (2 x 5 mL). The combined organiclayers were dried over sodium sulfateand concentrated in vacuo. The crude productwas purified by flash silica columnchromatography and dried in vacuo to afford the desiredproduct. Methyl 1-cyclopropyl-8-(2-fluoro-pyridin-4-yl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 2-fluoro-pyridin-4-yl-boronic acid (72 mg, 0.51 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (107 mg, 89percent). ESI-MS m/z: 353 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In 1,4-dioxane; water; at 85℃; for 7h;Inert atmosphere; | A round bottom flask under nitrogen was charged with 2'-bromo-6',8'-dihydro-2H-spiro[benzofuran-3,9'- pyrido[3',2':4,5]imidazo[2,l-c][l,4]oxazine] (1 g, 2.79 mmol, Preparation 85), (2-fluoropyridin-4- yl)boronic acid (0.433 g, 3.07 mmol), CS2CO3 (2.00 g, 6.14 mmol) and bis(triphenylphosphine)palladium(II)dichloride (0.196 g, 0.279 mmol) in a mixture of 1,4-dioxane and water. Then the yellowish reaction mixture was degased for 10 min by a flow of nitrogen. Next the reaction was heated in an oil bath to 85 °C. After 7 h reaction was cooled then diluted with about 100 mL of EtOAc. The organic layer was washed with water and brine, dried over MgS04, filtered and evaporated under reduced pressure to provide a solid. The solid was triturated with MeOH affording a solid which was separated by filtration to give the title compound (0.75g, 70percent); LC/MS (Table 1, Method i) = 0.89 min; MS m/z: 375 (M+ H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In 1,4-dioxane; water; at 85℃; for 1.5h;Inert atmosphere; | 7-Bromo-4-(2-methoxyphenyl)-3,4-dihydro-2H-pyrano[2',3':4,5]imidazo[l,2- ]pyridine (445 mg, 1.239 mmol, Preparation 91), <strong>[401815-98-3](2-fluoropyridin-4-yl)boronic acid</strong> (209 mg, 1.487 mmol), PdCl2(PPh3)2 (87 mg, 0.124 mmol), and CS2CO3 (1009 mg, 3.10 mmol) were flushed with N2, 1,4-dioxane (10 mL) and water (2 mL) were added, and the mixture was heated at 85 °C for 1.5 h. 200 mL EtOAc was added, the solution was washed with 100 mL water, and dried over Na2S04. The residue was purified on a Grace Reveleris 40 g column, eluted with 0-100percent 3: 1 EtOAc :EtOH in 1 : 1 DCM:heptane (40 mL/min), affording the title compound (414.8 mg, 89percent); lH NMR (400 MHz, DMSO- 6) delta 8.20 (d, J= 5.3 Hz, 1H), 8.06 (dd, J= 1.9, 1.0 Hz, 1H), 7.62 (dd, J = 9.3, 1.9 Hz, 1H), 7.60 - 7.48 (m, 2H), 7.40 - 7.37 (m, 1H), 7.21 (ddd, J = 8.2, 7.3, 1.7 Hz, 1H), 7.07 (dd, J = 8.3, 1.1 Hz, 1H), 6.74 (td, J = 7.4, 1.1 Hz, 1H), 6.45 (dd, J = 7.6, 1.7 Hz, 1H), 4.82 (dd, J = 6.2, 3.4 Hz, 1H), 4.27 (ddd, J = 11.3, 4.8, 3.2 Hz, 1H), 3.95 (td, J = 11.0, 2.1 Hz, 1H), 3.87 (s, 3H), 2.37 (dddd, J = 14.0, 10.6, 6.1, 3.1 Hz, 1H), 2.10 - 2.02 (m, 1H). MS (ESI+) m/z 376.1 (M+H). LC/MS (Table 1, ab) Rt = 0.87 min; MS m/z: 376 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium carbonate; bis(dibenzylideneacetone)-palladium(0); tricyclohexylphosphine; In water; N,N-dimethyl-formamide; at 130℃; for 0.5h;Microwave irradiation; Inert atmosphere; | 6-bromo-l-(3,4-methylenedioxyphenyl)-lH-benzo[d] imidazole (0.315 mmol, 100 mg), 2-fluro- pyridine-4-boronic acid (1.0 eq., 0.315 mmol, 45.8 mg), Na2C03 (4.0 eq., 1.26 mmol, 134 mg), and a mixture of 4: 1 DMF/water (3.5 mL) were added to a microwave vial. The vial was purged with Ar(g) then tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3, 0.01 eq., 3.2 muiotatauiotaomicron, 3.0 mg) and tricyclohexylphosphine (0.03 eq., 9.5 muiotatauiotaomicron, 2.8 mg) was added. The reaction was microwave irradiated under Ar (g) at 130 °C for 30 min. then filtered through celite washing down with CH2CI2 and MeOH. The filtrate was evaporated in vacuo and DMF was removed by azeotroping with toluene. The crude material was purified via flash chromatography eluting with a hexanes/EtOAc gradient to obtain 67 (0.270 mmol, 90.5 mg). Yield: 86percent, light purple solid. XH NMR (400 MHz, DMSO-d6) delta 8.57 (s, 1H), 8.27 (d, J= 5.3 Hz, 1H), 7.94 (d, J= 1.7 Hz, 1H), 7.88 (d, J= 8.5 Hz, 1H), 7.79 - 7.72 (m, 2H), 7.60 (s, 1H), 7.41 (d, J= 2.2 Hz, 1H), 7.20 (dd, J= 8.2, 2.2 Hz, 1H), 7.14 (d, J= 8.2 Hz, 1H), 6.17 (s, 2H). 1 C NMR (100 MHz, DMSO- d6) delta 165.25, 162.93, 153.81 (d, J= 8.6 Hz), 148.30, 147.91 (d, J= 15.9 Hz), 147.04, 145.36, 144.71, 134.12, 131.50 (d, J= 3.5 Hz), 129.50, 121.74, 120.42, 120.09 (d, J= 3.7 Hz), 117.89, 109.76, 108.89, 107.10, 106.72, 105.92, 102.03; [M+H]+ = 334.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In 1,4-dioxane at 85℃; for 16h; Alkaline conditions; Inert atmosphere; | Step 9 1. Charge compound 6-2, XIII, Pd-catalyst and sodium bicarbonate to a four-necked jacketed flask with paddle stirrer under N2 2. Charge water and 1,4-dioxane (5.0V., KF<0.02%) to the flask 3. Stir the suspension at 85° C. for 16 hrs 4. Filter through the silica-gel (2.0×) and diatomaceous earth (0.5×) 5. Remove the 1,4-dioxane by distillation under a vacuum 6. Partition between water (2.0V) and EtOAc (5.0V) 7. Separate the organic phase and concentrate 8. Purify by re-crystallization from PE and EtOAc |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 14h;Inert atmosphere; | A mixture of (2-fiuoropyridin-4-yl)boronic acid (0.02 g, 0.142 mmol), (S)- tert-bu yl (l-((6-chloro-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2- yl)carbamate (prepared in similar fashion as described in Example 226) (0.051 g, 0.142 mmol), and CS2CO3 (0.116 g, 0.355 mmol) in 1,4-dioxane (1 mL) and water (0.2 mL). The mixture was purged with nitrogen for 15 min. PdCk(dppf)-CH2Ci2 adduct (0.012 g, 0.014 mmol) was added and the mixture purged for a further 5 min then reaction mixture was heated to 100 °C for 14 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (20 mL) and filtered through diatomaceous earth (Celite®). The bed was washed with 20 mL of ethyl acetate. The filtrate was concentrated under reduced pressure to afford (S)-tert-buty\ (l-((2'-fluoro-4-methyl-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-yl)carbamate (0.05 g, 0.089 mmol, 62percent yield) as a yellow semi-solid. LCMS (ESI) m/e 418.7 [(M+H) +, calcd for C23H33FN3O3, 418.2]; LC/MS retention time (method B); fe. = 1.18 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 120℃; for 16h;Inert atmosphere; | To a stirred solution of N-({5-bromo-2-[(3-{ [(tert-butyldimethylsilyl)oxy]methyl}pyridin2-yl) sulfanyl] -3-chlorophenyl } methyl)-2-methylpropane-2- sulfinamide( 10. 0g, 17. 3mmol) in dioxan (5OmL) were added <strong>[401815-98-3](2-fluoropyridin-4-yl)boronic acid</strong> (2.93g, 20.8mmol), Na2CO3 (5.51g, S2mmol),water (25mL) and degassed for 10 mm in argon atmosphere. Then to it was added Pd(PPh3)4 (2.Og, 1 .73mmol) and again degassed for 5 mm. The reaction mass was heatedto 120°C for 16 h. Reaction mixture was then cooled to 25°C, filtered through celite pad and washed with EtOAc. The separated organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to get the crude which was purified by column chromatography (Si02 100-200 mesh; 50-90percent EtOAc/Hexanes) to get N-({2-[(3- { [(tert-butyldimethylsilyl)oxy] methyl }pyridin-2-yl) sulfanyl] -3-chloro-5- (2-fluoropyridin-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide (7.5g, 72percent) as off white solid. LC-MS: 593.9 [M+H] + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 120℃; for 16h;Inert atmosphere; | To a stirred solution of N-({6-bromo-2-[(3-{ [(tert-butyldimethylsilyl)oxy]methyl}pyridin2-yl) sulfanyl] -3-chlorophenyl } methyl)-2-methylpropane-2- sulfinamide (4. Og, 6 .93mmol) in dioxan (30mL) were added <strong>[401815-98-3](2-fluoropyridin-4-yl)boronic acid</strong> (1. 17g, 8.3mmol), Na2CO3 (2.2g, 20.8mmol),water (l5mL) and degassed for 10 mm in argon atmosphere. Then to it was added Pd(PPh3)4 (80 1mg, 0.69mmol) and again degassed for 5 mm. The reaction mass was heated to120°C for 16 h. Reaction mixture was then cooled to 25°C, filtered through celite pad and washed with EtOAc. The separated organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to get the crude which was purified by column chromatography (Si02 100-200 mesh; 40-80percent EtOAc/Hexane) to get N-({2-[(3-[(tert- butyldimethylsilyl)oxy] methyl }pyridin-2-yl) sulfanyl] -3-chloro-6- (2-fluoropyridin-4-yl)phenyl}methyl)-2-methylpropane-2-sulfinamide (2g, 48percent) as light yellow sticky solid. LCMS: 593.8 [M+H] + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With trifluoromethylhydrazine; potassium tert-butylate; at 100℃; for 10h; | A 25 mL reaction flask was charged with trifluoromethylhydrazine (0.05 mmol)2-fluoropyridine-4-boronic acid (0.5 mmol)Potassium tert-butoxide (1.0 mmol)And polyethylene glycol-400 (2.0 g).The mixture was reacted at 100 ° C until the reaction was complete. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The product was separated by column chromatography to yield 99percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 115℃; for 6h; | To a mixture of degassed 1 ,4-dioxane (4.3 mL) and water (1 mL) in a microwave vial was added [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (0.0084 g, 0.01 mmol), followed by the title compound from Preparative Example A (0.05 g, 0.2 mmol), <strong>[401815-98-3](2-fluoropyridin-4-yl)boronic acid</strong> (0.035 g, 0.245 mmol) and cesium carbonate (0.133 g, 0.41 mmol). The reaction mixture was then heated at ~115C in a sand-bath for 6 hours. The reaction mixture was diluted with ethyl acetate (60 mL) and water (20 mL), the organic phase was separated, dried over Na2S04, filtered and the solvents were evaporated in vacuo. The dark residue was purified by chromatography on silica (25 g HP-SIL) using a Biotage Isolera system employing a dichloromethane/methanol gradient (100/0 -> 95/5 -> 90/10 -> 80/20) to afford the title compound F-3a as an off-white solid (0.033 g, 63 %). (0203) 1H-NMR (400 MHz, DMSO-d6) delta = 12.50 (br-s, 1H), 9.45 (s, 1 H), 8.83 (d, 1 H), 8.56-8.52 (m, 1H), 8.43-8.39 (m, 1 H), 8.19-8.14 (m, 2H), 7.92 (s, 1H), 7.54-7.50 (m, 1 H) (0204) MS (ESI): m/z = 265.04 [M+H]+ |
63% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 115℃; for 6h;Microwave irradiation; Inert atmosphere; | To a mixture of degassed 1 ,4-dioxane (4.3 ml_) and water (1 ml_) in a microwave vial was added [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (0.0084 g, 0.01 mmol), followed by the title compound of Preparative Example A (0.05 g, 0.2 mmol), <strong>[401815-98-3](2-fluoropyridin-4-yl)boronic acid</strong> (0.035 g, 0.245 mmol) and cesium carbonate (0.133 g, 0.41 mmol). The reaction mixture was then heated at ~1 15C in a sand-bath for 6 hours. The reaction mixture was diluted with ethyl acetate (60 mL) and water (20 mL), the organic phase was separated, dried over Na2S04, filtered and the solvents were evaporated in vacuo. The dark residue was purified by chromatography on silica (25 g HP-SIL) using a Biotage Isolera system employing a dichloromethane/methanol gradient (100/0 -> 95/5 -> 90/10 -> 80/20) to afford the title compound 1 (lb) as an off-white solid (0.033 g, 63 %). (0289) 1H-NMR (400 MHz, DMSO-d6) d = 12.50 (br-s, 1 H), 9.45 (s, 1 H), 8.83 (d, 1 H), 8.56-8.52 (m, 1 H), 8.43-8.39 (m, 1 H), 8.19-8.14 (m, 2H), 7.92 (s, 1 H), 7.54-7.50 (m, 1 H) (0290) MS (ESI): m/z = 265.04 [M+H]+ |
63% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 115℃; for 6h; | To a mixture of degassed 1 ,4-dioxane (4.3 mL) and water (1 ml_) in a microwave vial was added [1 ,T-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (0.0084 g, 0.01 mmol), followed by the title compound of Preparative Example A (0.05 g, 0.2 mmol), <strong>[401815-98-3](2-fluoropyridin-4-yl)boronic acid</strong> (0.035 g, 0.245 mmol) and cesium carbonate (0.133 g, 0.41 mmol). The reaction mixture was then heated at ~115C in a sand-bath for 6 hours. The reaction mixture was diluted with ethyl acetate (60 mL) and water (20 mL), the organic phase was separated, dried over Na2S04, filtered and the solvents were evaporated in vacuo. The dark residue was purified by chromatography on silica (25 g HP-SIL) using a Biotage Isolera system employing a dichloromethane/methanol gradient (100/0 -> 95/5 -> 90/10 -> 80/20) to afford the title compound 1 as an off-white solid (0.033 g, 63 %).1H-NMR (400 MHz, DMSO-d6) d = 12.50 (br-s, 1 H), 9.45 (s, 1 H), 8.83 (d, 1 H), 8.56-8.52 (m, 1 H), 8.43-8.39 (m, 1 H), 8.19-8.14 (m, 2H), 7.92 (s, 1 H), 7.54-7.50 (m, 1 H)MS (ESI): m/z = 265.04 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 3h;Inert atmosphere; | To a solution of 2-chloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-pyrrolo[2,3-b:4,5-cdipyridine (i3) (0.20 g, 0.60 mmol) and 2-Fluoropyridine-4-Boronic Acid (0.12 g, 0.84 mmol) in dioxane (4 mL)and H20 (1 mL)was added Na2CO3 (0.19 g, 1.80 mmol) and reaction was purged with argon for30 mi PdCI2(dppf).DCM (0.05 g, 0.06 mmol) was added, purged with argon for 15 mm. The reaction mixture was heated at 100°C for 3h. Progress of the reaction was monitored byTLC and LCMS. After completion, the reaction mixture was concentrated in vacuo. The crude obtained was purified by column chromatography (silica, 230-400 mesh, 0 to 1percent MeOH in DCM) to afford 2-(2-fluoropyridin-4-yl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9 H-pyrrolo[2,3-b:4,5-d]dipyridine (i4) (0.23 g, 97percent) as a brown solid.MS (ESI) m/e (M+1): 395.001H NMR (400 MHz, DMSO-d6) 6 -0.20 (s, 9H) 3.57 ? 3.66 (m, 2H) 0.85 ? 0.94 (m, 2H) 6.02 (s, 2H) 7.80 (d, J = 5.7 Hz, 1 H) 8.03 (s, 1 H) 8.22-8.88 (m, 2H) 8.42 (d, J = 5.3 Hz, 1 H) 8.63 (d, J =5.7 Hz, 1H) 8.87 (d, J= 8.1 Hz, 1H) 9.49 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | 4.2.11 N-[2-(3-Fluoro-phenyl)-ethyl]-3-(2-fluoro-pyridin-4-yl)-5-trifluoromethyl-benzenesulfonamide (10) Compound 10 was obtained as a white solid following the general procedure using 2-fluoropyridine-4-boronic acid. RP-HPLC tR?=?26.4?min, gradient condition: from 5percent B to 100percent B in 50?min. 1H NMR (CDCl3, 400?MHz): 8.31 (d, J?=?5.2?Hz, 1H); 8.11 (bs, 1H); 8.06 (bs, 1H); 7.96 (bs, 1H); 7.35 (dt, J?=?5.3, 1.6?Hz, 1H); 7.14 (td, J?=?8.0, 6.0?Hz, 1H); 7.08 (s, 1H); 6.79 (m, 2H); 6.68 (dt, J?=?9.6, 2.1?Hz, 1H); 4.68 (t, J?=?6.2?Hz, 1H); 3.28 (q, J?=?6.5?Hz, 2H); 2.76 (t, J?=?6.7?Hz, 2H). ESMS: m/z calcd for C20H16F5N2O2S [M+ H]+: 443.08; found 443.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate; In dichloromethane; ethyl acetate; at 60℃; for 2h; | General procedure: A solution of triene urushiol (314 mg, 1 mmol) and phenylboronic acid (1.0 eq) was dissolved in DCM/EA (0.5 mL) and heated to 60 °C for 2 h in a pressure tube. After being concentrated in a vacuum, pure compound 4 (400 mg, 100percent) was obtained. Repeat the step above to get compounds 5, 6, and 7, and their yields were 70?80percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In tetrahydrofuran; water; at 60℃;Inert atmosphere; | General procedure: The TBS protected steroid triflate 722 or 1224 (1.00 equiv.), cesiumcarbonate (2.00 equiv.) and the boronic acid (1.05 equiv.) was individuallyplaced in a flame dried 10 mL round bottomed flask anddissolved in a 1:1 mixture of water and THF (6.00?8.00 mL). Then Pd(PPh3)4 (5 mol percent) was added and the reaction mixture was stirred at60 °C under argon atmosphere overnight. The reaction mixture wasthen brought to room temperature, added brine (10 mL) and extractedwith ethyl acetate (4×5.00 mL). The combined organic phases weredried over MgSO4 and evaporated in vacuo. The residue was purified byflash column chromatography (silica gel, 10?20percent EtOAc in heptane) toobtain the pure TBS-ethers of 9a-9e or 13a-13b as light yellow oils. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium phosphate; palladium diacetate; triphenylphosphine; In 1,2-dimethoxyethane; N,N-dimethyl-formamide; at 100℃; for 1.66667h;Inert atmosphere; Microwave irradiation; | Compound 13 (50 mg, 0.17 mmol), 2-fluoropyridine-4-boronic acid (36 mg,0.26 mmol), triphenylphosphine (17 mg, 0.065 mmol), potassium phosphate (108 mg, 0.51 mmol) and palladium acetate (8 mg, 0.036 mmol) were weighed in a vial, and kept under vacuum. 1 ,2- dimethoxyethane (0.73 mL) and DMF (0.37 mL) (sparged with nitrogen for 5 min) were added. The vial was filled with nitrogen, and was heated in Biotage® microwave synthesizer at 100 °C for 100 min. The mixture was cooled to room temperature, filtered through a silica gel plug, and eluted with EtOAc. The filtrate was washed with water. The organic extract was dried with Na2S04, and concentrated. The residue was purified by flash chromatography (silica gel, eluting with 0percent to 20percent EtOAc in hexanes) to give compound 14e (58 mg, 96percent yield) as a white solid, m/z = 356 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 90℃; for 2h;Inert atmosphere; | Under argon atmosphere, 50?mg of 4 (0.196?mmol, 1.0?eq.) and 41?mg of 2-fluoropyridine-4-boronic acid (0.294?mmol, 1.5?eq., from OXCHEM Corporation, USA) was suspended in a mixture of 3.6?mL 1,4-dioxane and 0.3?mL of a 2?M Cs2CO3 solution. Afterwards, 7.2?mg (0.010?mmol, 0.05?eq.) Pd(dppf)Cl2 was added and the mixture was heated for 2?h at 90?°C. After pouring the mixture into 100?mL water and extraction with ethyl acetate (3?*?25?mL), the combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (SiO2, dichloromethane/methanol, 39/1, v/v) to obtain 5b with a yield of 99percent (44?mg, 0.196?mmol). Rf (SiO2, dichloromethane/methanol, 39/1, v/v): 0.52; 1H NMR (DMSO?d6, 300?MHz) delta: 7.36 (s, 2H), 7.41 (m, 1H), 7.66 (ddd, J?=?5.3?Hz, J?=?2.1?Hz, J?=?1.4?Hz, 1H), 7.95 (s, 1H), 8.27 (d, J?=?5.3?Hz, 1H) ppm; 13C NMR (DMSO?d6, 100?Hz) delta: 108.9 (d, J?=?39.3?Hz), 121.9 (d, J?=?3.8?Hz), 131.2, 133.1 (d, J?=?4.2?Hz), 144.7, 147.8 (d, J?=?15.6?Hz), 150.5 (d, J?=?8.8?Hz), 155.6, 163.7 (d, J?=?234.2?Hz) ppm; 19F NMR (DMSO?d6, 376?MHz) delta: -68.9?ppm; ESI-MS m/z calcd. for C9H7N4FCl+ [M+H]+ 225.03, found 225.03, m/z calcd. for C9H6N4FClNa+ [M+Na]+ 247.02, found 247.02. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 2h;Inert atmosphere; | A mixture of 55-bromo-54-fluoro- l4H-6-oxa-3-aza-2(2,6)-pyridina- l(3,4)-triazola-5(l,2)- benzenacyclodecaphan-4-one (80 mg, 0.18 mmol), <strong>[401815-98-3](2-fluoropyridin-4-yl)boronic acid</strong> (26 mg, 0.18 mmol), Pd(dppf)Cl2 (13.5 mg, 0.018 mmol), K2C03 (51 mg, 0.37 mmol) in dioxane/H20 (5/1, 12 mL) was degassed by bubbling N2 through the mixture. The reaction was then stirred at 90 °C for 2 h. After this time the solvent was removed and the residue was purified by column chromatography on silica gel eluting with DCM/MeOH (100/1 to 20/1) to give the title compound (62 mg, 59percent) as a yellow solid. 1H NMR (400 MHz, DMSO- 6) delta ppm 10.98 (s, 1H), 8.67 (s, 1H), 8.32 - 8.34 (d, 7=5.2 Hz, 1H), 8.19 - 8.22 (d, 7=9.2 Hz, 1H), 8.04 - 8.08 (m, 1H), 7.85 - 7.87 (m, 2H), 7.58 - 7.59 (m, 1H), 7.42 - 7.45 (m, 2H), 4.37 - 4.40 (m, 2H), 4.23 - 4.27 (m, 2H), 2.44 - 2.47 (m, 2H), 1.93 - 1.95 (m, 2H). MS (ESI): 449.0 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; at 120℃; for 0.25h; | General procedure: To 6 (150 mg, 0.65 mmol) was added crude solution of 126 (166 mg, 0.648 mmol) in DME (3 mL) followed by the addition of 2M sodiumcarbonate (0.75 mL, 1.5 mmol) and [1,1?-bis(diphenylphosphino) ferrocene]dichloropalladium(II)·DCM (52.9 mg, 0.065 mmol). The reactionmixture was heated in microwave at 120 C for 15 min. The crudereaction mixture was partitioned between ethyl acetate and water. Theorganic layer was separated, dried over sodium sulfate, filtered andconcentrated. The crude was tried to dissolved in CH2Cl2. The solidobserved was filtered and dried to give 13 (100 mg; 55% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 80℃; for 3h;Inert atmosphere; | A solution of 5-bromo-6-fluoro-3- (2-methylpyridin-4-yl) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (250 mg, 0.64 mmol) , (2-fluoropyridin-4-yl) boronic acid (90 mg, 0.64 mmol) Pd(dppf) Cl2·DCM (52 mg, 0.064 mmol) and Na2CO3(135 mg, 1.28 mmol) in dioxane/H2O (5/1 ml) was stirred at 80 under N2protection for 3 h. The mixture was cooled to room temperature and diluted with EA (50 mL) , washed by H2O (20 mL x2) and brine (20 mL) . The organic layer was dried over anhydrous Na2SO4, filtered off, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (PE/EA=1/1) to give the title compound (200 mg, 76percentyield) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; at 85℃; for 5h;Inert atmosphere; | A mixture of 5-bromo-1- (1-ethoxyethyl) -3- (2-methylpyridin-4-yl) -1H-pyrazolo- [3, 4-b] pyridine (320 mg, 0.89 mmol) , (2-fluoropyridin-4-yl) boronic acid (150 mg, 1.06 mmol) , Pd(dppf) Cl2·DCM (36 mg, 0.04 mmol) and Na2CO3(284 mg, 2.67 mmol) in dioxane (4 mL) /H2O (2 mL) was stirred at 85 under N2protection for 5 h. The mixture was cooled to room temperature and diluted with EtOAc (30 mL) washed with water (10 mL) , brine (10 mL) . The organic layer was dried over anhydrous Na2SO4, filtered off, and concentrated in vacuo. The crude product was purified by silica gel flash column chromatography eluting with ethyl acetate in hexane (20 percent) to give the title compound (210 mg, 63percent) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With C33H49P*C13H12N(1-)*Pd(2+)*CH3O3S(1-); caesium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 0.416667h;Microwave irradiation; | In a 20 mL microwave vial were added (trans)-4-(5-(2-fluoropyridin-4-yl)-2-(((S)-1- methoxypropan-2-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)cyclohexanol (600 mg, 1.57 mmol), cesium carbonate (1.24 g, 3.76 mmol) and <strong>[401815-98-3]2-fluoropyridin-4-yl-boronic acid</strong> (331 mg, 2.35 mmol). DME (10 mL) and water (4 mL) were then added and the resulting mixture was sparged with argon for 8 minutes in the sonication bath. Finally, XPhos Palladacycle Gen.4 (27.5 mg,31.3 mumol) was added, the vial was sealed and the reaction mixture was irradiated in a microwave apparatus at 90 °C for 25 min. The mixture was diluted with EtOAcconcentrated to dryness. The crude product was purified on a 40 g silica column (dry pack) eluting with (A) DCM and (B) 20percent IPA in DCM (gradient from 5percent to 60percent). The product was dissolved in a minimum of ACN and then water was added. The cloudy solution was frozen and lyophilized, affording the title product as a yellow powder obtained (515 mg, 82 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.95% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 12h;Inert atmosphere; | (2-Fluoropyridin-4-yl)boronic acid 5a (48.64 mg, 0.35 mmol, prepared according to the method disclosed in the patent application "WO2015103137"), compound 1f (70 mg, 0.23 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (17.07 mg, 0.023 mmol) and potassium carbonate (63.61 mg, 0.46 mmol) were dissolved in 5 mL of a mixed solvent of 1,4-dioxane and water (V/V = 4:1), then the reaction solution was warmed up to 80C and stirred for 12 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound 5b (70 mg, yield: 94.95%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 102 - 108℃;Inert atmosphere; | General procedure: brominated compound (1 eq), boronic acid derivative (BA, 8a-8f, 9a-9c, 1.1-1.3 eq), and K2CO3(2-3 eq) were combined in a mixture of 1,4-dioxane and water (4:1). The suspension was degassedwith argon for 5-10 min, and Pd(PPh3)4 (5-10 mol%) was added. The mixture was refluxed (bathtemperature 102-108 C) for 1-2 days until completion of the reaction (as indicated by TLC). Thesolvent was removed, and the residue was partitioned between CHCl3 and water. The aqueous layerwas extracted twice with CHCl3, and the combined organic layers were dried (Na2SO4) and thesolvent evaporated. Unless stated otherwise, the obtained residue was purified by flashchromatography on silica gel using CHCl3/MeOH (10:1) as the eluent. The following productswere isolated: 8-(2-Fluoropyridin-4-yl)-3-methylbenzo[e]imidazo[5,1-c][1,2,4]triazine (6a): Based on GeneralProcedure A of Suzuki coupling, a mixture of compound 5 (101 mg, 0.38 mmol,1 eq), BA 8a(65 mg,0.46 mmol, 1.2 eq), and K2CO3 (131 mg, 0.95 mmol, 2.5 eq), in dioxane/water (5 mL) werereacted in the presence of Pd(PPh3)4 (44 mg, 10 mol%) to give after purification compound 6a(81 mg, 76%) as a yellow solid. TLC (hexane/ethyl acetate (1:1)): Rf = 0.25. 1H NMR (400 MHz,DMSO-d6) deltaH = 9.28 (s, 1H), 8.92 (d, J = 1.9 Hz, 1H), 8.52 (d, J = 8.5 Hz, 1H), 8.46 (d, J = 5.3 Hz, 1H), 8.25(dd, J = 8.5, 1.9 Hz, 1H), 7.97 (dt, J = 5.3, 1.8 Hz, 1H), 7.82 (s, 1H), 2.79 (s, 3H). LR-MS (ESI+): m/z = 280,(calcd. 280 for C15H11FN5+ [M + H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; XPhos In 1,4-dioxane; water at 60 - 90℃; for 1h; Inert atmosphere; | Step A: methyl 2-(2-chloro-6-(2-fluoropyridin-4-yl)phenyl)acetate A solution of K2CO3 (44.9 g, 325 mmol) in water (50 mL) was added to methyl 2-(2,6- dichlorophenyl)acetate (17.8 g, 81 mmol), (2-fluoropyridin-4-yl)boronic acid (11.45 g, 81 mmol), XPhos (3.87 g, 8.13 mmol) and Pd2(dba)3(3.72 g, 4.06 mmol) in dioxane (500 mL) and the suspension was evacuated and backfilled with N2 three times whilst stirring at 60 °C, then the reaction was stirred at 90 °C for 1 h. The mixture was diluted with EtOAc (200 mL) and washed with water (200 mL) and brine (200 mL). The organic layer was separated, dried (MgSO4) and the product was purified by FC (0-20% EtOAc/isohexane) to afford the title compound (11.5 g, 47%) as a white solid. LCMS m/z 280.1/282.2 (M+H)+(ES+).1H NMR (CDCl3) d 8.33 (d, J = 5.1 Hz, 1H), 7.61 (dd, J = 8.1, 1.3 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.33 - 7.30 (m, 1H), 7.30 - 7.26 (m, 1H), 7.14 (br s, 1H), 3.72 (s, 2H), 3.59 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; potassium carbonate In 1,4-dioxane; water monomer at 80℃; for 2h; | 6 Typical procedure 6, exemplified by the preparation of Intermediate 4, 2-fluoro-4-(3- (trifluoromethyl)benzyl)pyridine 1-(Bromomethyl)-3-(trifluoromethyl)benzene (0.14 mL, 0.88 mmol) was added to a suspension of 2-fluoropyridine-4-boronic acid (150 mg, 1.06 mmol), K2CO3 (146 mg, 1.06 mmol) and PdCI2(dppf).DCM (129 mg, 0.18 mmol) in 1,4-dioxane (4 mL )/water (0.4 mL) and the reaction mixture heated at 80 °C for 2 hours. The reaction mixture was partitioned between water (6 mL) and EtOAc (6 mL) and the organic layer removed. The aqueous layer was extracted with EtOAc (2×6 mL), the combined organic layers dried (phase separator) and the solvent removed in vacuo. The residue was purified by gradient flash column chromatography eluting with 0-50% EtOAc in /-hexane to afford 2-fluoro-4-(3- (trifluoromethyl)benzyl)pyridine as a yellow liquid (167 mg, 74%). Data in table 2. |
74% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; potassium carbonate In 1,4-dioxane; water monomer at 80℃; for 2h; Inert atmosphere; | 2 Intermediate 2, 2-fluoro-4-(3-(trifluoromethyl)benzyl)pyridine 1-(bromomethyl)-3-(trifluoromethyl)benzene (0.14 mL, 0.88 mmol) was added to a suspension of 2-fluoropyridine-4-boronic acid (150 mg, 1.06 mmol), potassium carbonate (146 mg, 1.06 mmol) and PdCl2(dppf).DCM (129 mg, 0.18 mmol) in 1,4-dioxane (4 mL)/water (0.4 mL) and the resultant reaction mixture heated at 80 °C for 2 h. The reaction mixture was partitioned between water (6 mL) and EtOAc (6 mL) and the organic layer removed. The aqueous layer was extracted with EtOAc (2x6 mL), the combined organic layers dried (phase separator) and the solvent removed in vacuo. The residue was purified by gradient flash column chromatography eluting with 0-50% EtOAc in /-hexane to afford 2-fluoro-4-(3- (trifluoromethyl)benzyl)pyridine as a yellow liquid (167 mg, 74%). Data in table 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 90℃; for 18h; Inert atmosphere; | B Step B: 5-(2-fluoropyridin-4-yl)-2,3-dihydro-1H-inden-4-ol (2-fluoropyridin-4-yl)boronic acid (2.6 g, 19 mmol) was added to a stirred mixture of 5-bromo-2,3-dihydro-1H-inden-4-ol (4.0 g, 19 mmol), Pd(dppf)Cl2.CH2Cl2(0.77 g, 0.94 mmol) and K2CO3(7.8 g, 56 mmol) in 9:11,4-dioxane:water (11 mL). The mixture was degassed with a stream of nitrogen gas for 15 min then heated to 90 °C for 18 h. The mixture was left to cool to RT and filtered through a pad of Celite, washing through with EtOAc (2 x 15 mL). The filtrate was concentrated to dryness on silica (30 g). The crude product was purified by FC (0-30% EtOAc/isohexane (elution ~10%)) to afford a yellow/green solid. The material was triturated with 1:4 MTBE:heptane (100 mL) and filtered to afford the title compound (1.39 g, 23%) as an off-white solid.LCMS m/z 230.3 (M+H)+(ES+); 228.6 (M-H)- (ES-).1H NMR (500 MHz, DMSO-d6) δ 9·08 (s, 1H), 8.21 (d, J = 5.3 Hz, 1H), 7.52 (ddd, J = 5.3, 2.3, 1.4 Hz, 1H), 7.30 (d, J = 1.3 Hz, 1H), 7.19 (d, J = 7.7 Hz, 1H), 6.85 (d, J = 7.7 Hz, 1H), 2.87 (td, J = 7.3, 5.2 Hz, 4H), 2.03 (p, J = 7.4 Hz, 2H).19F NMR (471 MHz, DMSO-d6) δ -69.86. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With tetrakis-(triphenylphosphine)-palladium; anhydrous sodium carbonate In ethanol; water monomer; toluene for 16h; Inert atmosphere; Reflux; |
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