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CAS No. : | 936250-20-3 | MDL No. : | MFCD08690235 |
Formula : | C10H17BN2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MSJAEFFWTBMIKT-UHFFFAOYSA-N |
M.W : | 208.07 | Pubchem ID : | 17750270 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.7 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 60.03 |
TPSA : | 47.14 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.43 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 1.6 |
Log Po/w (WLOGP) : | 1.02 |
Log Po/w (MLOGP) : | 0.3 |
Log Po/w (SILICOS-IT) : | 1.33 |
Consensus Log Po/w : | 0.85 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.32 |
Solubility : | 0.999 mg/ml ; 0.0048 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.2 |
Solubility : | 1.31 mg/ml ; 0.00629 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.23 |
Solubility : | 0.123 mg/ml ; 0.000592 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.85 |
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 |
---|---|---|
50% | With potassium acetate In dimethyl sulfoxide at 90℃; for 18 h; | [00612] B. 3-Methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaboroIan-2-yl)-lH- pyrazole. tert-Butyl 4-bromo-3-methyl-lH-pyrazole-l-carboxylate (0.48 g, 1.84 mmol), bis(pinacolato)diboron (0.535 g, 2.1 mmol), dichloro[l,l'- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.156 g, 0.19 mmol) and potassium acetate (0.56 g, 5.7 mmol) were placed in a sealed tube, in DMSO (5 mL). The system was flushed with nitrogen, sealed and heated to 90 °C for 18 h. The solvent was removed and the desired product isolated using silica gel chromatography (50percent ethyl acetate in hexanes) to afford the title compound (0.2 g, 50 percent yield). MS (ESI) m/z 209.1 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With triethylamine; In 1,4-dioxane; at 20℃; for 48h; | C. tert-Butyl 3-methyl-4-(4,4,5,5-tetramethyI-l,3,2-dioxaboroIan-2-yl)- lH-pyrazole-1-carboxylate. 3-Methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazole (0.2 g, 0.96 mmol), di-t-butyldicarbonate (0.4 g, 1.8 mmol) and triethylamine (0.18 g, 1.79 mmol) were placed in 1 ,4-dioxane (5 mL) and stirred, under nitrogen, at rt for two days. The solvent was removed and the desired product isolated using silica gel chromatography (25 % ethyl acetate in hexanes) to afford the title compound (0.175 g, 59 % yield). MS (ESI) m/z 309.4 [M+l]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dimethyl sulfoxide; at 90℃; for 18h; | [00612] B. 3-Methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaboroIan-2-yl)-lH- pyrazole. tert-Butyl 4-bromo-3-methyl-lH-pyrazole-l-carboxylate (0.48 g, 1.84 mmol), bis(pinacolato)diboron (0.535 g, 2.1 mmol), dichloro[l,l'- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.156 g, 0.19 mmol) and potassium acetate (0.56 g, 5.7 mmol) were placed in a sealed tube, in DMSO (5 mL). The system was flushed with nitrogen, sealed and heated to 90 C for 18 h. The solvent was removed and the desired product isolated using silica gel chromatography (50% ethyl acetate in hexanes) to afford the title compound (0.2 g, 50 % yield). MS (ESI) m/z 209.1 [M+l]+. |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In dimethyl sulfoxide; at 90℃; for 16h; | Compound 11 is prepared from compound 10 by reacting (1 eq), Boc2O (1.5 eq), Na2CO3 (2 eq) in DCM at RT for 16 h. After work up and the NMR showed characteristic peaks and was used as such for the next step. In subsequent step compound II (1 eq), and 12 (1.1 eq) in presence of PdCl2(dppf) (0.05 eq), KOAc (3 eq), DMSO was heated to 90 C., 16 h. After column purification LCMS showed 50% of desired mass of compound 11. Key intermediate 14 was prepared was prepared by reacting (1 eq), BH3-DMS (3 eq), THF, RT, 16 h. After work up LCMS showed 96% purity of the compound 14. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water; caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; industrial methylated spirit; at 140℃;Microwave irradiation; | Synthesis 32; [5-(3-Methyl-1 H-pyrazol-4-yl)-thiophen-3-yl]-(octahydro-quinolin-1-yl)-methanone (FF-15); (CIS ISOMERS); IMS, c/s-(5-Bromo-thiophen-3-yl)-(octahydro-quinolin-1-yl)-methanone (0.09 g, 0.27 mmol) was combined with 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1 H-pyrazole (62 <n="111"/>mg, 0.3 mmol), caesium carbonate (0.134 g, 0.41 mmol), and palladium tetrakis(triphenylphosphine) (0.031 g, 0.03 mmol) in DME (3 mL), IMS 0.6 mL) and water (0.3 mL). The reaction mixture was degassed then heated by microwave irradiation to 14O0C for 20 minutes then further quantities of 3-methyl-4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.062 g), caesium carbonate (0.067 g), and palladium tetrakis(triphenylphosphine) (0.031 g) were added. The mixture was heated by microwave irradiation to 1400C for 20 minutes followed by addition of 3-methyl-4-(4,4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazole (0.062 g) and further heating at 1400C for 20 minutes. Further quantities of 3-methyl-4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan- 2-yl)-1 H-pyrazole (0.062 g), caesium carbonate (0.097 g), and palladium tetrakis(triphenylphosphine) (0.031 g) were added and the mixture heated by microwave irradiation to 1400C for a final 20 minutes before diluting with water and extraction with DCM (x 3). The organic solution was dried over sodium sulfate, filtered and the solvent removed by evaporation. The residue was purified by chromatography on a silica Il cartridge, eluting with 10-50% ethyl acetate in cyclohexane and then was further purified by HPLC, eluting with 5%-98% acetonitrile in water (0.1 % formic acid) over 20 minutes. The fractions containing the desired product were freeze-dried to give the title compound as a white solid (0.027 g). LCMS m/z 330.30 [M+H]+ R.T. = 9.62 min (Analytical Method 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water; caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; industrial methylated spirit; at 140℃;Microwave irradiation; | Synthesis 33; (4,4-Dimethyl-azepan-1-yl)-[5-(3-methyl-1 H-pyrazol-4-yl)-thiophen-3-yl]-methanone(EE-24); IMS, (5-Bromo-thiophen-3-yl)-(4,4-dimethyl-azepan-1-yl)-methanone (0.105 g, 0.33 mmol) together with 3-methyl-4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazole (83 mg, 0.4 mmol), caesium carbonate (0.150 g, 0.46 mmol), and palladium tetrakis(triphenylphosphine) (0.057 g, 0.05 mmol) in DME (3 mL), IMS 1 mL) and water (0.5 mL) was degassed then heated by microwave irradiation to 140C for 20 minutes. Further quantities of 3-methyl-4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H- pyrazole (0.035 g), caesium carbonate (0.054 g), and palladium tetrakis(triphenylphosphine) (19 mg) were added and the mixture was heated by microwave irradiation to 1400C for 20 minutes before diluting with water and extracting with DCM (x 3). The organic solution was dried over sodium sulfate, filtered and the solvent evaporated. The residue was purified by chromatography on a silica Il cartridge, eluting with 10-60% ethyl acetate in cyclohexane and then was further purified by HPLC <n="112"/>using a phenyl hexyl column, eluting with 15%-95% acetonitrile in water (0.1% formic acid) over 20 minutes. The fractions containing the desired product were freeze-dried then taken up as a solution in methanol and dried to give the title compound as a colourless semi-solid (0.016 g). LCMS m/z 318.28 [M+H]+ RT. = 9.29 min (Analytical Method 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium acetate;bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); In water; butan-1-ol; at 120℃; for 0.5h;Sealed tube; Microwave irradiation; Inert atmosphere; | Example 129 (Method CB2) A- 1447- WO-PCT - 112 -Synthesis of (S)-2'-(3-methyl-lH-pyrazol-4-yl)-7'-(neopentyloxy)-5H-spiro [oxazole- 4,9'-xanthen]-2-amine 2,2,2-trifluoroacetateA 2-mL microwave vial was charged with (R)-2'-bromo-7'-(neopentyloxy)-5H- spiro[oxazole-4,9'-xanthen]-2-amine (50 mg, 120 mumol) in n-butanol (959 muL), 3-methyl- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (49.9 mg, 240 mumol), and potassium acetate (35.3 mg, 359 mumol) in water (240 muL). The vessel was purged with Ar. Bis(di-ter?-butyl(4-dimethylaminophenyl)phosphine(dichloropalladium (II) (1.7 mg, 2.4 mumol) was added and the reaction was heated to 120 0C for 30 min in a Biotage microwave initiator. The reaction was then cooled to room temperature and loaded an AccuBOND II SCX cartridge, washed with methanol (3 ml) and eluted with 2N ammonia in methanol (6 ml) to give the crude product. The crude mixture was then purified by reverse-phase preparative HPLC using a Gemini NX C18 column (150x30mm, 5 um), 0.1% TFA in acetonitrile/water, gradient 10% to 90% over 10 min to give the desired product as the TFA salt. MS m/z = 419.0 [M+H]+. Calc'd for C24H26N4O3: 418.20. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.3 g, 1.442 mmol) and potassium carbonate (0.996 g, 7.21 mmol) were suspended in acetonitrile (10 ml) and stirred overnight at RT. Additional iodomethane (0.5 ml) was added and the mixture was stirred overnight at RT. The mixture was diluted with EtOAc and the inorganic salts were removed by filtration. The filtrate was evaporated to yield an inseparable mixture (2:1) of 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole and 1 ,5-dimethyl-4-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)-1H-pyrazole (0.267 g, 83% yield). MS (ESI) m/z: 223.1 (M+H+). [0176] In a sealed tube, 4-(2-chloropyridin-4-yloxy)-2,5-difluoroaniline (0.257 g,1.00 mmol), a (2:1) mixture of 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole and 1 ,5-dimethyl-4-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)-1H-pyrazole (0.267 g, 1.20 mmol), potassium carbonate (0.415 g,3.01 mmol) and tetrakistriphenylphosphine palladium(O) (0.058 g, 0.050 mmol) were suspended in a mixture of dioxane (10 ml) and water (1.667 ml). The mixture was degassed with Ar and heated at 90 C overnight. The reaction was diluted with saturated aq. NaHCO3 (25 ml) and extracted with EtOAc (3 x 25 ml). The combined organic extracts were concentrated in vacuo and purified by silica gel chromatography (hexanes/EtOAc) to elute an inseparable (2:1) mixture of 4-(2-(1,3-dimethyl-1H- pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorobenzenamine and 4-(2-(l ,5 -dimethyl- 1H- pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorobenzenamine (0.31 g, 98% yield). MS (ESI) m/z: 317.1 (M+H+).; Example Bl (0.241 g, 1.078 mmol) was dissolved in thionyl chloride (4 ml, 54.8 mmol) and heated at 60 C for 3h. The reaction was azeotroped with toluene (3x). The crude acid chloride was dissolved in THF (5 ml) and added dropwise to a 0 C solution of Example A15 (0.31 g, 0.980 mmol) and N,N-diisopropylethylamine (0.171 ml, 0.980 mmol) in THF (5 ml). The mixture was stirred overnight at RT, saturated aq. NaHCO3 (25 ml) was added and the mixture extracted with EtOAc (3 x 25 ml). The combined organic extracts were dried (Na2SO4), evaporated and purified by silica gel chomatography (hexanes/EtOAc) to elute two products. N-(4-(2-(l,3- Dimethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-N'-(4- fluorophenyl)cyclopropane-l,l-dicarboxamide (278 mg; 54.4%) (eluted first) and N- (4-(2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-N'-(4- fluorophenyl)cyclopropane-l,l-dicarboxamide (81 mg; 16%) (eluted second). N-(4- (2-(1,3-Dimethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-N'-(4- fluorophenyl)cyclopropane-l,l-dicarboxamide: 1H NMR (400 MHz, DMSO-d6): delta 11.07 (s, 1H), 9.75 (s, 1H), 8.42 (d, 1H), 8.12-8.07 (m, 1H), 7.85 (s, 1H), 7.83-7.15 (m, 4H), 7.20-7.12 (m, 2H), 6.68-6.6.66 (m, 1H), 3.75 (s, 3H), 2.54 (s, 3H), 1.67-1.64 (m, 2H), 1.58-1.55 (m, 2H); MS (ESI) m/z: 522.2 (M+H+). N-(4-(2-(1,5-Dimethyl- 1 H-pyrazol-4-yl)pyridin-4-yloxy)-2 ,5 -difluorophenyl)-JV' -(4- fluorophenyl)cyclopropane-l,l-dicarboxamide: 1H NMR (400 MHz, DMSO-d6): delta 11.10 (s, 1H), 9.74 (s, 1H), 8.41 (d, 1H), 8.14-8.08 (m, 2H), 7.59-7.53 (m, 4H), 7.19- 7.14 (m, 1H), 7.07 (d, 1H), 6.72-6.70 (m, 1H), 3.75 (s, 3H), 2.36 (s, 3H), 1.67-1.64 (m, 2H), 1.58-1.55 (m, 2H); MS (ESI) m/z: 522.2 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; at 20℃; | 3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.3 g, 1.442 mmol) and potassium carbonate (0.996 g, 7.21 mmol) were suspended in acetonitrile (10 ml) and stirred overnight at RT. Additional iodomethane (0.5 ml) was added and the mixture was stirred overnight at RT. The mixture was diluted with EtOAc and the inorganic salts were removed by filtration. The filtrate was evaporated to yield an inseparable mixture (2:1) of 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole and 1 ,5-dimethyl-4-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)-1H-pyrazole (0.267 g, 83% yield). MS (ESI) m/z: 223.1 (M+H+). | |
Intermediate 25: 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [0459] A solution of <strong>[936250-20-3]3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (0.60 g; 2.9 mmol) and K2CO3 (2.0 g; 14 mmol) in MeCN (20 mL) was stirred overnight under nitrogen and added iodomethane (1.0 mL; 16 mmol). The reaction mixture was stirred overnight, diluted with EtOAc (20 mL), filtered, and concentrated to afford 727 mg of an inseparable mixture of the title compounds as a light yellow solid. [0460] LC-MS: m/z 223.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.3 g, 1.442 mmol) and potassium carbonate (0.996 g, 7.21 mmol) were suspended in acetonitrile (10 ml) and stirred overnight at RT. Additional iodomethane (0.5 ml) was added and the mixture was stirred overnight at RT. The mixture was diluted with EtOAc and the inorganic salts were removed by filtration. The filtrate was evaporated to yield an inseparable mixture (2:1) of 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole and 1 ,5-dimethyl-4-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)-1H-pyrazole (0.267 g, 83% yield). MS (ESI) m/z: 223.1 (M+H+). [0176] In a sealed tube, 4-(2-chloropyridin-4-yloxy)-2,5-difluoroaniline (0.257 g,1.00 mmol), a (2:1) mixture of 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole and 1 ,5-dimethyl-4-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)-1H-pyrazole (0.267 g, 1.20 mmol), potassium carbonate (0.415 g,3.01 mmol) and tetrakistriphenylphosphine palladium(O) (0.058 g, 0.050 mmol) were suspended in a mixture of dioxane (10 ml) and water (1.667 ml). The mixture was degassed with Ar and heated at 90 C overnight. The reaction was diluted with saturated aq. NaHCO3 (25 ml) and extracted with EtOAc (3 x 25 ml). The combined organic extracts were concentrated in vacuo and purified by silica gel chromatography (hexanes/EtOAc) to elute an inseparable (2:1) mixture of 4-(2-(1,3-dimethyl-1H- pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorobenzenamine and 4-(2-(l ,5 -dimethyl- 1H- pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorobenzenamine (0.31 g, 98% yield). MS (ESI) m/z: 317.1 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 110℃;Inert atmosphere; Sealed tube; | Example 11 Synthesis of (4-Hydroxy-piperidin-1-yl)-(4-{4-[4-(3-methyl-1H-pyrazol-4-yl)-benzotriazol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone (Compound 11) A mixture of (4-hydroxy-piperidin-1-yl)-{4-[4-(4-iodobenzotriazol-1-yl)-pyrimidin-2-yl-amino]-cyclohexyl}-methanone (274 mg) and 3-methyl-pyrazole-4-boronic acid pinacol ester (109 mg), Na2CO3 (2 M aq, 0.7 mL, degassed), toluene (9 mL, degassed) and EtOH (0.7 mL) was bubbled with argon in a screw cap pressure flask for 10 min. To this was added Pd(PPh3)4 (18 mg), the flask sealed, and the mixture stirred overnight at 110 C. The reaction mixture was allowed to cool to RT, then additional portions of 3-methyl-pyrazole-4-boronic acid pinacol ester (109 mg), Pd(PPh3)4 (20 mg), and EtOH (5 mL) were added, the flask sealed, and heated again at 110 C. for 6 h. An additional portion of 3-methyl-pyrazole-4-boronic acid pinacol ester (109 mg) and Pd(PPh3)4 (20 mg) was added, and the mixture stirred at 110 C. overnight. The reaction mixture was then cooled to RT, diluted in water, extracted in DCM, washed with water and brine, dried over Na2SO4, and the solvent stripped to yield a crude solid (311 mg). The crude product (52 mg) was chromatographed on silica, and eluted with 0-60% Magic Base/DCM, titurated in Et2O overnight, filtered, and dried to yield (4-hydroxy-piperidin-1-yl)-(4-{4-[4-(3-methyl-1H-pyrazol-4-yl)-benzotriazol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone (Compound 11, 28 mg). mp=190-195 C.; M+H=502. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 110℃;Sealed tube; | Example 10 Synthesis of (1-Methanesulfonyl-piperidin-4-yl)-{4-[4-(3-methyl-1H-pyrazol-4-yl)-benzotriazol-1-yl]-pyrimidin-2-yl}-amine (Compound 10) A mixture of [4-(4-iodobenzotriazol-1-yl)-pyrimidin-2-yl]-(1-methanesulfonyl-piperidin-4-yl)-amine (250 mg), 3-methyl-pyrazole-4-boronic acid pinacol ester (109 mg) and Na2CO3 (2 M aq, 0.7 mL, degassed), toluene (9 mL, degassed) and EtOH (0.7 mL) was added to a screw cap pressure flask. To this was added Pd(PPh3)4 (20 mg), the flask sealed, and the mixture stirred overnight at 110 C. The reaction mixture was then cooled to RT, and additional portions of 3-methyl-pyrazole-4-boronic acid pinacol ester (109 mg), Pd(PPh3)4 (20 mg), and EtOH (5 mL) added. The flask was again sealed and heated overnight at 110 C. The reaction mixture was then diluted in water, extracted in DCM, washed with water and brine, dried over Na2SO4, and the solvent stripped to yield a solid (0.34 g). The solid was chromatographed on silica, eluding with 0-60% Magic Base/DCM, then chromatographed again on silica using 0-60% Magic Base/DCM. The product was titurated with Et2O, filtered, and dried in vacuo overnight to provide (1-methanesulfonyl-piperidin-4-yl)-{4-[4-(3-methyl-1H-pyrazol-4-yl)-benzotriazol-1-yl]-pyrimidin-2-yl}-amine (Compound 10, 39 mg). Mp=231-232 C.; M+H=454. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 110℃;Sealed tube; | Example 12 Synthesis of (4-Hydroxy-piperidin-1-yl)-(4-{4-[4-(3-methyl-1H-pyrazol-4-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone (Compound 12) A mixture of {4-[4-(4-bromo-indol-1-yl)-pyrimidin-2-ylamino]-cyclohexyl}-(4-hydroxy-piperidin-1-yl)-methanone (0.51 g), 3-methyl-pyrazole-4-boronic acid pinacol ester (0.234 g) and Na2CO3 (2 M aq, 1.53 mL, degassed), toluene (18 mL, degassed) and EtOH (4 mL) was added to a screw cap pressure flask. To this was added Pd(PPh3)4 (0.035 g), the flask sealed, and the mixture stirred overnight at 110 C. The reaction mixture was then diluted in water, extracted in DCM, washed with water and brine, dried over Na2SO4, and the solvent stripped to yield a light yellow solid (0.45 g). The solid was flash chromatographed on silica, eluding with 0-60% Magic Base/DCM, then chromatographed again on silica using DCM:1% NH4OH-MeOH (1000:50) to provide (4-hydroxy-piperidin-1-yl)-(4-{4-[4-(3-methyl-1H-pyrazol-4-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone (Compound 12, 0.11 g, 22%) as an off-white powder. Mp=215-220 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With caesium carbonate;bis(tri-t-butylphosphine)palladium(0); In 1,4-dioxane; water; at 80℃; for 20h; | Example 13; Preparation of Lambda/-{(1 S)-2-amino-1-r(3,4-difluorophenyl)methyllethyl}-4-methyl-5-(3-methyl- 1 /-/-pyrazol-4-yl)-2-thiophenecarboxamide; a) methyl 4-methyl-5-(3-methyl-1 H-pyrazol-4-yl)-2-thiophenecarboxylate; To a solution of methyl 5-bromo-4-methyl-2-thiophenecarboxylate (940 mg, 4.0 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (832 mg, 4.00 mmol) and cesium carbonate (3910 mg, 12.00 mmol) in 1 ,4-Dioxane (12 ml.) and Water (3 ml.) was added bis(tri-t-butylphosphine)palladium(0) (204 mg, 0.400 mmol). The mixture was sealed and heated at 80 0C for 20 hrs. The mixture was concentrated and purified with silica gel eluting with 0 - 60% ethyl acetate / hexane to afford the desired product as a brown oil [731.1 mg, 75%]: LC-MS (ES) m/z 237 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3% | Example 170: trans-4-[4-[6-(3-methyl-1H-pyrazol-4-yl)-1,3-benzothiazol-2-yl]amino}-6-(phenylmethyl)-2-pyrimidinyl]amino}cyclohexanol trifluoroacetate (salt) A mixture of trans-4-[4-[(6-bromo-1,3-benzothiazol-2-yl)amino]-6-(phenylmethyl)-2-pyrimidinyl]amino}cyclohexanol (50mg, O.i mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (42mg, 0.2mmol), 2'-(dimethylamiono)-2-biphenyl- palladium(ll) chloride dinorbornylphosphine complex (2.2mg, 0.004mmol) and potassium phosphate (0.15mmol, 32mg) in 1 ,4-dioxane (0.8mL) and water (0.2ml_) was sealed and heated in a CEM "Discover" microwave at 1 100C for 20 minutes. After cooling additional 3-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (0.2mmol, 42mg) and 2'-(dimethylamiono)-2-biphenyl-palladium(ii) chloride dinorbornylphosphine complex (2.2mg, 0.004mmol) was added and the vessel sealed and heated at 1 100C for an additional 30 minutes, then at 135C for 5 minutes, then at 1400C for a further 5 minutes. The reaction mixture was then loaded onto a C18 solid-phase extraction cartridge (preconditioned with acetonitrile/0.1 % trifluoroacetic acid) and the cartridge was eluted with acetonitrile/0.1 % trifluoroacetic acid. The product-containing fractions were evaporated to dryness and the product was purified using mass-directed automated preparative HPLC (TFA modifier) to afford the title compound (1.4mg, 0.0027mmol, 3% yield). LCMS (Method A): Rt 0.68 minutes; m/z 512 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; for 24h;Inert atmosphere; Reflux; | A mixture of 6-bromo-l, 2, 2-trimethyl-2, 3- dihydrothieno[3,2-d]pyrimidin-4 (IH) -one (138 mg, 0.50 mmol) , 3-methyl-4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) - lH-pyrazole (208 mg, 1.00 mmol), cesium carbonate (489 mg, 1.50 mmol), 1, 2-dimethoxyethane (5 mL) and water (1 mL) was purged with argon. Then, 1,1'- bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon again. This mixture was refluxed for 18 h. After cooling to room temperature, 3- methyl-4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -IH- pyrazole (0.208 g, 1.00 mmol), Cs2CO3 (0.489 g, 1.50 mmol), 1, 2-dimethoxyethane (5 mL) and water (1 mL) were added. The mixture was purged with argon. Then, 1,1'- bis (diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (0.041 g, 0.050 mmol) was added, and the mixture was purged with argon again. The mixture was refluxed for 6 h. Then, the mixture was poured into saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc(100 mL) , and the extract was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. This residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc). The obtained yellow solid was triturated with EtOAc and collected by filtration to afford the title compound (52.7 mg, 38%) as a pale yellow solid:1H NMR (300 MHz, DMSO-d6) delta 1.40 (6H, s) , 2.40 (3H, br s) , 2.88 (3H, s), 6.86 (IH, s) , 7.44 (IH, br s) , 7.77 (0.6H, br s), 8.10 (0.4H, br s) , 12.86 (IH, m) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With N-ethyl-N,N-diisopropylamine;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 120℃; for 2.5h;Microwave irradiation; | EXAMPLE 4: 4-(3-Methyl-1H-pyrazol-4-yl)-2-(6-methylpyridin-2-yloxy)thiazole (Final Compound 1.11) According to Scheme 4: A mixture of 2-(4-bromothiazol-2-yloxy)-6-methylpyridine (0.37 mmol, 100 mg), <strong>[936250-20-3]3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (0.44 mmol, 92 mg), Pd (dppf) (37 mumol, 30 mg) and N-ethyl-N-isopropylpropan-2-amine (0.74 mmol, 0.13 mL) in dioxane/water (1 :1, 2.5 mL) was stirred at 120C for 1 hour under microwave conditions. To complete the reaction, PdCl2(dppf) (37 mumol, 30 mg) and <strong>[936250-20-3]3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (0.44 mmol, 92 mg) were added and the reaction mixture was stirred at 120C for 1.5 hour under microwave conditions. The reaction mixture was filtered through a pad of celite and was washed with DCM. The organic phase was washed with water, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude mixture was purified by flash chromatography over silica gel using DCM/EtOEta/NuEta3 (100:0:0 to 93:6.4:0.6) as eluent to yield 4-(3 -methyl-1H-pyrazol-4-yl)-2-(6-methylpyridin-2-yloxy)thiazole (95 mumol, 26 mg, 26%) as an orange solid.M. p.: 138-139C;UPLC-MS: RT = 0.85 min; MS m/z ES+= 273;1H-NMR (300MHz, DMSO): 7.84 (s, IH), 7.80-7.76 (m, IH), 7.14 (d, J=8.0 Hz, IH), 7.02 (d, J=8.0 Hz, IH), 7.01 (s, IH), 2.54 (s, 3H), 2.47 (s, 3H). |
26% | With N-ethyl-N,N-diisopropylamine;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 120℃; for 1.5h;Microwave irradiation; | Example 4 4-(3-Methyl-1H-pyrazol-4-yl)-2-(6-methylpyridin-2-yloxy)thiazole (Final Compound 1.11) According to Scheme 4: A mixture of 2-(4-bromothiazol-2-yloxy)-6-methylpyridine (0.37 mmol, 100 mg), <strong>[936250-20-3]3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (0.44 mmol, 92 mg), Pd (dppf) (37 mumol, 30 mg) and N-ethyl-N-isopropylpropan-2-amine (0.74 mmol, 0.13 mL) in dioxane/water (1:1, 2.5 mL) was stirred at 120 C. for 1 hour under microwave conditions. To complete the reaction, PdCl2(dppf) (37 mumol, 30 mg) and <strong>[936250-20-3]3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (0.44 mmol, 92 mg) were added and the reaction mixture was stirred at 120 C. for 1.5 hour under microwave conditions. The reaction mixture was filtered through a pad of celite and was washed with DCM. The organic phase was washed with water, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude mixture was purified by flash chromatography over silica gel using DCM/EtOH/NH3 (100:0:0 to 93:6.4:0.6) as eluent to yield 4-(3-methyl-1H-pyrazol-4-yl)-2-(6-methylpyridin-2-yloxy)thiazole (95 mumol, 26 mg, 26%) as an orange solid. M.p.: 138-139 C.; UPLC-MS: RT=0.85 min; MS m/z ES+=273; 1H-NMR (300 MHz, DMSO): 7.84 (s, 1H), 7.80-7.76 (m, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 7.01 (s, 1H), 2.54 (s, 3H), 2.47 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; N,N-dimethyl-formamide; at 80℃; for 12.5h;Inert atmosphere; | Example 79 2-(1-(4-amino-3-(3-methyl-1H-indazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one To a solution of Example 57c (0.400 g, 0.758 mmoles) in DMF (4 ml), ethanol (2 ml) and water (2 ml), 3-Methylindazole-6-boronic acid pinacol ester 97 (0.391 g, 1.517 mmoles) and sodium carbonate (0.401 g, 3.79 mmoles) were added and the system is degassed for 30 min. Tetrakistriphenylphosphine Palladium (0.172 g, 0.149 mmoles) was added under nitrogen atmosphere and heated to 80 C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as yellow solid (0.095 g, 23% yield). MP: 214-217 C. 1H-NMR (delta ppm, DMSO-d6, 400 MHz): delta 12.75 (s, 1H), 8.08 (s, 1H), 8.05 (dd, J=7.9, 1.4 Hz, 1H), 7.86 (m, 2H), 7.68 (d, J=8.3 Hz, 1H), 7.62 (s, 1H), 7.53 (t, J=7.3 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.31 (br s, 1H), 7.07 (dt, J=8.9, 2.1 Hz, 1H), 6.93 (m, 2H), 6.07 (q, J=6.7 Hz, 1H), 2.51 (s, 3H), 1.91 (d, J=7.0 Hz, 3H). Mass: 532.03 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium acetate;bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); In water; butan-1-ol; at 120℃; for 0.5h;Inert atmosphere; Microwave irradiation; | Example 14Synthesis of (S)-2'-(3-methyl-lH-pyrazol-4-yl)-7'-(neopentyloxy)-5H-spiro[oxazole- 4,9'-xanthen]-2-amine 2,2,2-trifluoroacetateA 2-mL microwave vial was charged with (R)-2'-bromo-7'-(neopentyloxy)-5H- spiro[oxazole-4,9'-xanthen]-2 -amine (50 mg, 120 muetaiotaomicron) in n-butanol (959 mu), 3-methyl- 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (49.9 mg, 240 muetaiotaomicron), and potassium acetate (35.3 mg, 359 muetaiotaomicron) in water (240 xL). The vessel was purged with Ar. Bis(di-?er?-butyl(4-dimethylaminophenyl)phosphine(dichloropalladium (II) (1.7 mg, 2.4 muetaiotaomicron) was added and the reaction was heated to 120 C for 30 min in a Biotage microwave initiator. The reaction was then cooled to room temperature and loaded an AccuBOND II SCX cartridge, washed with methanol (3 ml) and eluted with 2N ammonia in methanol (6 ml) to give the crude product. The crude mixture was then purified by reverse-phase preparative HPLC using a Gemini NX CI 8 column (150x30mm, 5 um), 0.1 % TFA in acetonitrile/water, gradient 10% to 90% over 10 min to give the desired product as the TFA salt. MS m/z = 419.0 [M+H]+. Calc'd for C24H26N4O3: 418.20 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17%; 13% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 20℃;Inert atmosphere; | Step B: Preparation of 3-(3-methyl-4-(7-(l-methyl-lH-pyrazol-4- yl)imidazorL2-clpyrimidin-5-yl -lH-pyrazol-l-yl)propanenitrile: To a flask charged with 7- (1 -methyl- lH-pyrazol-4-yl)-5 -(3 -methyl- lH-pyrazol-4-yl)imidazo[l ,2-c]pyrimidine (0.025 g, 0.090 mmol) and acrylonitrile (0.032 mL, 0.49 mmol) was added 1 mL of acetonitrile and DBU (0.027 mL, 0.18 mmol) and the flask was sealed under nitrogen and allowed to proceed at ambient temperature overnight. The reaction was diluted with 3 mL of DCM, loaded directly onto a silica gel column and eluted with 1% MeOH in EtOAc containing 1% NH4OH to afford a mixture of regioisomers from alkylation at N-l and N-2. The mixture was purified by silica gel chromatography, eluting with a gradient of 1.0-5.0%) MeOH in DCM with 0.5% NH4OH to afford the title compound (5.0 mg, 0.0150 mmol, 17% yield). MS (apci) m/z = 333.1 (M+H). The structure and regioisomer were confirmed by observed nOe signals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41.2% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; | Step B: Preparation of 3 -cyclopentyl-3 -(3 -methyl-4-(7-f 4-morpholinophenyl) imidazor 1 ,2-c1pyrimidin-5 -yl)- 1 H-pyrazol- 1 -vDpropanenitrile : 4-(4-(5-(3-methyl-lH- pyrazol-4-yl)imidazo[l,2-c]pyrimidin-7-yl)phenyl)morpholine (0.0690 g, 0.191 mmol), 3- cyclopentylacrylonitrile (Table 1, compound g; 0.0696 g, 0.574 mmol) and DBU 0.0661 mL, 0.479 mmol) were suspended in DMF (3 mL) and stirred overnight. The reaction mixture was partitioned between saturated aqueous NaHCC>3 and EtOAc. The organics were washed with brine, dried, MgS04 and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 0.5 - 2 percent (9:1, MeOH:NH4OH)/DCM) to furnish 3-cyclopentyl-3-(3-methyl-4-(7-(4-mophiholinophenyl) imidazo[l,2-c]pyrimidin-5-yl)-lH-pyrazol-l-yl)propanenitrile (0.0380 g, 0.078905 mmol, 41.2percent yield). MS (apci) m/z = 482.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27.7% | With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 20 - 100℃;Inert atmosphere; | Step A: Preparation of 7-( 1 -methyl- 1 H-pyrazol-4-yD-5 -(3 -methyl- 1 H-pyrazol-4-yl imidazo[l,2-clpyrimidine: To a flask charged with 5-chloro-7-(l-methyl-lH-pyrazol-4- yl)imidazo[l,2-c]pyrimidine (Preparation J; 0.650 g, 2.78 mmol), 3-methyl-4-(4,4,5,5- tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (0.868 g, 4.17 mmol), and 2 M K3PO4 (4.17 mL, 8.35 mmol)was added 20 mL of DME and argon was bubbled through for 15 minutes before tetrakis(triphenylphosphine)palladium (0) (0.321 g, 0.278 mmol) was added. The flask was sealed and the reaction was heated to 100 C for 4 hours, then allowed to cool to ambient temperature and stirred overnight. The reaction mixture was diluted with EtOAc (300 mL) and washed with aqueous saturated sodium bicarbonate (50 mL). The organic layer was washed with brine (50 mL), dried over MgS04, filtered, and concentrated under reduced pressure. The crude material was taken up in DCM in preparation for chromatography when a precipitate began to form and continued to thicken over time. The addition of minimal MeOH (0.5 mL) did not dissolve the precipitate. The solid was collected by vacuum filtration and retained. The rinse was purified by means of silica gel chromatography eluting with a gradient of 5-10% MeOH in EtOAc containing 1% NH4OH. This was successful at generating material that was combined with the solid above to afford 7-(l-methyl-lH-pyrazol-4-yl)-5-(3-methyl-lH-pyrazol-4-yl)imidazo[l ,2-c]pyrimidine (0.215 g, 0.770 mmol, 27.7% yield). MS (apci) m/z = 280.1 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In 1,4-dioxane; water; at 100℃; for 0.5h;microwave irradiation; | Example 1 3-[(1S)-1-(2-Chloro-3-fluoro-6-methoxyphenyl)ethyl]-5-(3-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine A mixture of 5-Bromo-3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (12 mg, 0.031 mmol), <strong>[936250-20-3]3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole</strong> (13.0 mg, 0.0626 mmol), potassium carbonate (0.0130 g, 0.0938 mmol) and 4:1 Dioxane:water (4:1,1,4-Dioxane:H2O, 0.31 mL, 3.1 mmol) were added to a microwave vessel and the vessel was degassed 3*. The reaction was heated in the microwave at 100 C. for 30 min. Reaction mixture was concentrated in vacuo and purified by HPLC to afford the title compound. 1H NMR (400 MHz, CD3OD): delta=1.82 (d, J=7.3 Hz, 3H), 2.23 (s, 3H), 3.66 (br. s., 3H), 5.12 (d, J=6.8 Hz, 1H), 6.91 (dd, J=9.0, 4.2 Hz, 1H), 7.10 (t, J=9.0 Hz, 1H), 7.36 (d, J=1.3 Hz, 1H), 7.48 (s, 1H), 7.62 (br. s., 1H), 8.18 (d, J=1.8 Hz, 1H). MS (ES+): m/z=384.96/386.94 (100/65) [MH+]. HPLC: tR=3.19 min (ZQ3, polar-5 min). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 1h;Microwave irradiation; | To a microwave vial containing ethyl A/-[6-chloro-2-(2-pyridinyl)-4-pyrimidinyl]-p-alaninate (100 mg, 0.33 mmol) was added 3-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazole (102 mg, 0.49 mmol) then cesium carbonate (212 mg, 0.65 mmol), palladium tetrakis (37.7 mg, 0.033 mmol) and a solution of 1 ,4-Dioxane (1 ml) in water (0.50 ml). The reaction mixture was heated 100C for 1 hr using a microwave then concentrated under reduced pressure then diluted with IPA (<1 ml_) and neutralised using 2M HCI (aq). The neutralised reaction mixture was loaded onto an SCX cartridge, washed five times with IPA then product eluted with a solution of 10% ammonia in IPA. Ammonia washes were combined and concentrated under reduced pressure to afford the crude product as an orange oil. The oil dissolved in DMSO then purified by MDAP (Method E) and the resulting product was dissolved in methanol and passed down a thiol SPE cartridge, eluting the product with methanol. The appropriate fractions were combined and concentrated under reduced pressure to afford the title compound as a white solid, 35mg (29%).LCMS (Method B): Rt = 0.79 min, MH+ = 353.2 (Method A) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 80℃; for 12h; | Compound 60C: 1 -({3-[(Benzyloxy)methyl]oxetan-3-yl}methyl)-3-methyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazoleA solution of (4-(tetramethyl-1 ,3,2-dioxaborolan-2yl)-1 H-3-methyl pyrazole (3.0 g, 14.4 mmol) in DMF (10 mL) was treated with sodium hydride (60% dispersion in oil, 519 mg, 12.98 mmol) and {3-[(benzyloxy)methyl]oxetan-3-yl}methyl methanesulfonate (Compound 44D, 4.15 g, 21 .6 mmol) at RT and heated to 80 C for 12 hrs. The Reaction mixture was cooled to RT, poured into water (100 mL) and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, concentrated to give a residue which was purified by column chromatography (Si02, 0.5 % methanol in dichloromethane) to give 1.6 g (36%) of the title compound as the predominant regioisomer. 1H NMR (400 MHz, CDCI3) delta: 7.51 (s, 1 H), 7.25 -7.32 (m, 5H), 4.52 (d, J = 5.6 Hz, 2H), 4.36-448 (m, 6H), 3.45 (s, 2H), 2.35 (s, 3H), 1.27 (s, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 80℃; for 1h;Inert atmosphere; | A mixture of 9-bromo-2-iodo-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (200 mg, 0.51 mmol), <strong>[936250-20-3]3-methylpyrazole-4-boronic acid pinacol ester</strong> (117 mg, 0.56 mmol), PdCl2dppf.DCM (42 mg, 0.05 mmol) and Cs2CO3 (416 mg, 1.28 mmol) in dioxane (4 mL) and H2O (1 mL) was purged with argon and heated at 80 C. for 1 h. The reaction mixture was loaded onto an Isolute SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-3% MeOH in DCM) affording 9-Bromo-2-(3-methyl-1H-pyrazol-4-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (53 mg, 30%). LCMS: RT 2.21 min [M+H]+ 345.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 100℃; for 0.25h;microwave irradiation; | To a solution of //-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-i)]pyridin-4-yl}-3- chlorobenzenesulfonamide (Example 33) (100 mg, 0.191 mmol) in 1 ,4-dioxane (2 mL) was added 3-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (59.6 mg, 0.286 mmol), bis(triphenylphosphine)palladium(ll) chloride (13.40 mg, 0.019 mmol) and potassium carbonate (79 mg, 0.573 mmol). Water (1 mL) was added and the mixture heated at 100C in a microwave for 15 min (x 2). The solvent was removed in vacuo and the residue dissolved in ethyl acetate (20 mL) and washed with water (20 mL). The aqueous phase re-extracted with ethyl acetate (2 x 20 mL). All organic phases were combined, dried over MgS04, filtered and concentrated. The residue was purified on silica, eluting with a gradient of 0-80% ethyl acetate in cyclohexane and then further purified using MDAP (acidic conditions), to give the title compound (15 mg). LCMS (A) m/z: 525 [M+1]+, Rt 1 .23 min (acidic). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; at 135℃; for 0.333333h;Microwave irradiation; | A mixture of 6-bromo-N-(2-methyl-5-(5-methyl-1 ,2,4-oxadiazol-3- yl)phenyl)imidazo[1 ,2-a]pyridine-3-carboxamide (42) (50 mg, 0.121 mmol), 3-methyl-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (30 mg, 0.146 mmol), [1 ,1 '- Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (9 mg, 0.024 mmol) and a solution of 2M sodium carbonate (150 uL) in anhydrous dioxane (1 ml_) was heated in the microwave at 135 C for 20 minutes. The crude product was purified by reverse phase preparative HPLC to obtain 6-(3-methyl-1 H-pyrazol-4-yl)-N-(2-methyl-5-(5-methyl-1 ,2,4- oxadiazol-3-yl)phenyl)imidazo[1 ,2-a]pyridine-3-carboxamide (F257) as a white solid. 1 H NMR (400MHz, c/6-DMSO) delta 10.14 (s, 1 H), 9.59 (s, 1 H), 8.66 (s, 1 H), 8.04 (d, J = 1 .7 Hz, 1 H), 7.96 (s, 1 H), 7.89 (d, J = 9.3 Hz, 1 H), 7.82 (dd, J = 1 .8, 8.0 Hz, 2H), 7.50 (d, J = 8.1 Hz, 1 H), 2.66 (s, 3H), 2.40 (s, 3H), 2.36 (s, 3H), 2.07 (s, 1 H). MS m/z 413.1 6 (M+1 )+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In 1,4-dioxane; water; at 150℃; for 12h;Microwave irradiation; | A solution of (S)-tert-butyl (1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)carbamate (1.15 g, 3.25 mmol), tetrakis(triphenylphosphine)palladium (0) (0.188 g, 0.162 mmol) and <strong>[936250-20-3]3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (2.026 g, 9.74 mmol) in dioxane/saturated aqueous NaHCO3 (1 : 1 , 20 mL) was heated to 150C in a microwave reactor for 12 hours. After cooling to RT, the solvent was removed, and the reaction mixture was purified by silica gel column chromatography eluting with 20- 100% EtOAc in hexane over 1.5 hours. The intermediate was taken up in dioxane and 4 M HCl (1 :1). The mixture was stirred at RT for 1 hour. The volatiles were removed to give the title compound as an HCl salt of the title compound, which was used without further purification (58%). ESI-MS m/z [M+H]+ calc'd for C14H17N5, 256; found 256. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 1h;Microwave irradiation; | A solution of the compound (300 mg, 0.59 mmol) obtained in Example 16-4), <strong>[936250-20-3]3-methyl-1H-pyrazole-4-boronic acid pinacol ester</strong> (135 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.06 mmol), and potassium carbonate (163 mg, 1.18 mmol) in 1,2-dimethoxyethane (3 mL) and water (1.5 mL) was stirred at 120C for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature, water (3 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol = 30:70) to obtain the title compound (213 mg, 71%) in an orange oily form. 1H-NMR (400 MHz, CDCl3) delta: 0.04 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.19 (3H, s), 1.41-1.50 (2H, m), 1.56-1.63 (2H, m), 2.43 (3H, s), 2.54 (1H, dd, J = 14.5, 7.0 Hz), 2.69 (1H, dd, J = 16.4, 7.4 Hz), 3.39 (2H, s), 3.51 (1H, d, J = 10.0 Hz), 3.55 (1H, d, J = 10.0 Hz), 4.06-4.15 (1H, m), 4.34 (1H, dd, J = 14.5, 7.4 Hz), 7.11 (2H, d, J = 8.2 Hz), 7.32 (2H, d, J = 8.2 Hz), 7.65 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19.5 mg | With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); sodium t-butanolate; In ethanol; water; toluene; at 120℃; for 1.5h;Inert atmosphere; | To the compound 0001-5 (30 mg), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (45.2 mg), bis(di-tert-butyl (4-dimethylaminophenyl)-phosphine)dichloropalladium (II) (6.3 mg), and sodium carbonate (19.0 mg) were added 1,4-dioxane (0.5 mL) and water (0.05 mL) under a nitrogen atmosphere, and the mixture was stirred at 120C for 1.5 hours. The reaction solution was cooled to room temperature and purified by silica gel column chromatography (chloroform-methanol, NH silica). The solvent was evaporated under reduced pressure and the obtained solid was washed with ethyl acetate to obtain a compound 0001 (19.5 mg) as a white solid. 1H-NMR (DMSO-d6) delta: 9.79 (1H, s), 9.37 (1H, s), 9.19 (1H, bd), 9.09 (1H, d), 8.25 (1H, d), 8.18 (1H, d), 7.55 (1H, d), 7.43 (1H, d), 7.32 (1H, dd), 6.95 (1H, d), 4.03-4.18 (1H, m), 3.91 (3H, s), 1.85-2.05 (2H, m), 1.51-1.84 (6H, m). MS m/z (M+H): 379. <Example 43> - Synthesis of Compound 0043 - The same method as in Example 1 except for using <strong>[936250-20-3]3-methylpyrazole-4-boronic acid pinacol ester</strong> instead of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol used for the synthesis of the compound 0001 in Example 1, using sodium tert-butoxide instead of sodium carbonate used for the synthesis of the compound 0001 in Example 1, and using ethanol and toluene instead of 1,4-dioxane used for the synthesis of the compound 0001 in Example 1 was used to obtain a compound 0043 (24.3 mg) as a white solid. 1H-NMR (DMSO-d6) delta: 9.80 (1H, s), 9.40-9.19 (1H, m), 8.95 (1H, d), 8.23 (1H, d), 8.08-7.88 (2H, m), 7.50 (1H, d), 4.19-4.00 (1H, m), 2.01-1.84 (2H, m), 1.84-1.52 (6H, m). MS m/z (M+H): 337. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Into a round bottom flask was placed 3-methyl-4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-lH-pyrazole 117 (0.7 g, 3.36 mmol) in dimethylformamide (10 ml), and cooled in an ice-water bath. Sodium hydride (60% in mineral oil, 0.34 g, 8.41 mmol) was added and the mixture was stirred for 60 minutes. To this mixture was added 3-iodooxetane 118 (0.3 ml, 3.49 mmol) under nitrogen dropwise. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with methanol and concentrated to dryness. The resulting liquid crude product solidified to a toffee consistency 119. The material was used for subsequent reaction without purification. MS ESI [M+H+]+ = 264.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); In 1,4-dioxane; water; at 85℃; for 1h;Sealed tube; | To a solution of Example 30A (20 mg, 0.043 mmol) in Dioxane (1.5 mL) were added 3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (13.47 mg, 0.065 mmol), potassium phosphate (1 M, 0.108 mL, 0.108 mmol) and chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl- 1 , 1 '-biphenyl)[2-(2'-amino- 1,1'- biphenyl)]palladium(II) (2nd generation X-Phos-Precatalyst,1.70 mg, 2.158 muiotaetaomicron) at RT. The reaction was stirred in a sealed vial at 85 C for lh. The reaction was partitioned between EtOAc and water. Organic phase was separated and solvent was removed. To this residue was added DCM (1 mL) followed by addition of TFA (0.5 ml). After stirred at RT for 1 hr, solvent was removed. Purification by reverse phase chromatography afforded Example 30 (16.2 mg, 78% yield). LCMS (ESI) m/z: 365.1 (M+H)+; XH NMR (500MHz, DMSO-d6) delta 10.56 (s, 1H), 8.35 (br. s., 3H), 7.56 (br. s., 1H), 7.36 - 7.28 (m, 3H), 7.28 - 7.24 (m, 1H), 7.22 (d, J=4.4 Hz, 4H), 4.03 (br. s., 1H), 3.76 (s, 3H), 2.74 - 2.65 (m, 2H), 2.18 (s, 3H), 2.16 - 2.04 (m, 2H); Analytical HPLC RT = 1.06 min (Method C), 1.25 min (Method D). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With [1,1?-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium (II); cesium fluoride; In water; tert-butyl alcohol; at 85℃; for 48h; | To a microwave vial were charged with tert-butyl alcohol (1.2 mL), and water (1.2 mL), cesium fluoride (683 mg, 4.50 mmol), ethyl 4-bromo-1-{3-(cyanomethyl)-1-[2,5-difluoro-4-([(1S)-2,2,2-trifluoro-1-methylethyl]amino}carbonyl)phenyl]azetidin-3-yl}-1H-pyrazole-3-carboxylate (725 mg, 1.28 mmol) and <strong>[936250-20-3]3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (401 mg, 1.93 mmol), followed by Pd-127 (49 mg, 0.064 mmol) (from Johnson Mathew). The reaction mixture was heated at 85 C. for 48 h. The reaction was cooled to room temperature, diluted with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over Na2SO4, concentrated. The resulting residue was purified with flash chromatography (eluting with 30-100% ethyl acetate in hexanes) to give the desired product as an oil.LCMS calculated for C25H25F5N7O3 (M+H)+: m/z=566.2. Found: 566.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 60℃; for 2h; | A mixture of <strong>[936250-20-3]3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (1.06 g, 5.10 mmol), tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (1.00 g, 5.15 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.38 mL, 2.6 mmol) in acetonitrile (20 mL) was heated at 60 C. for 2 h. After cooling, the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexanes (0-60%) to afford the desired product. LCMS cacld. for C16H24BN4O4 (M-55)+: m/z=347.2. Found: 347.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1.5h; | Preparation of intermediatesExample A1a) Preparation of intermediate 1A mixture of <strong>[936250-20-3]3-methylpyrazole-4-boronic acid pinacol ester</strong> (0.50 g, 2.40 mmol), 2- (trimethylsilyl)ethoxymethyl chloride (0.53 ml, 3.00 mmol) and DIPEA (1.3 ml, 7.21 mmol) in DCM (10 ml) was stirred at ambient temperature for 1.5 hours. The mixture was partitioned between DCM and water. The organic phase was washed with brine, dried over Na2S04and concentrated in vacuo to afford the desired product as a pale brown oil (0.81 g, 100%, mixture of two regioisomers).LCMS (Method D): Rt= 4.21 and 4.32 min, m/z [M+H]+= 339. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 25: 1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [0459] A solution of <strong>[936250-20-3]3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (0.60 g; 2.9 mmol) and K2CO3 (2.0 g; 14 mmol) in MeCN (20 mL) was stirred overnight under nitrogen and added iodomethane (1.0 mL; 16 mmol). The reaction mixture was stirred overnight, diluted with EtOAc (20 mL), filtered, and concentrated to afford 727 mg of an inseparable mixture of the title compounds as a light yellow solid. [0460] LC-MS: m/z 223.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In acetonitrile; for 23h;Reflux; | To a solution of 3-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (300mg, 1.442mmol) in MeCN (10ml) was added cesium carbonate (1.4g, 4.33mmol) followed by 4-(2- chloroethyl)morpholine (402mg, 2.163mmol) and the reaction was heated at reflux for 5 hours followed by stirring at RT for 18h. The reaction was filtered under reduced pressure to remove cesium carbonate. The filtrate was concentrated under reduced pressure. The product mixture was purified by flash chromatography on silica gel (24g) using ISCO combiflash (GPE-15) eluting with DCM/Methanol gradient (0-15%) to give the title compound and it's regioisomer. LCMS: RT 0.70 mins; MS m/z 323.6 [M+H]+; Method2minl_owpHv01 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 3-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (300mg, 1.442mmol) in MeCN (10ml) was added cesium carbonate (1.4g, 4.33mmol) followed by 4-(2- chloroethyl)morpholine (402mg, 2.163mmol) and the reaction was heated at reflux for 5 hours followed by stirring at RT for 18h. The reaction was filtered under reduced pressure to remove cesium carbonate. The filtrate was concentrated under reduced pressure. The product mixture was purified by flash chromatography on silica gel (24g) using ISCO combiflash (GPE-15) eluting with DCM/Methanol gradient (0-15%) to give the title compound and it's regioisomer. LCMS: RT 0.70 mins; MS m/z 323.6 [M+H]+; Method2minl_owpHv01 (0592) Step 2: 4-{2-[4-(6-Bromo-pyrazin-2-yl)-3-methyl-pyrazol-1 -yl]-ethyl}-morpholine (0593) To a solution of 4-(2-(3-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-1- yl)ethyl)morpholine and the regioisomer (step 1 ) (302mg, 0.799mmol) in Toluene/EtOH (2:1 ; 9ml) was added 2,6-dibromopyrazine (190mg, 0.799mmol) followed by Pd(PPh3)2CI2 (28.0mg, 0.040mmol) followed by 2M aqueous sodium carbonate (1 .2 ml, 2.396mmol). The reaction was heated in the microwave at 80C for 1 hour. The organic layer of the reaction was isolated and concentrated under reduced pressure to a yellow oil. The product was purified by flash chromatography on silica gel (24g) using ISCO combiflash (GPE-15) eluting with DCM/MeOH gradient (0-10%) to give two products as a yellow oil which were separated by reverse phase preparative HPLC (Method; 10-35% gradient LowpH). To give the title compound. This was the second compound eluted. The stereochemistry was identified by NOE; the first compound showed a through space interaction between the methyl and methylene whilst the required compound did not. (0594) LCMS: RT 0.61 mins; MS m/z 354.1 [M+H]+; Method2minLowpH. (0595) 1 H NMR (400 MHz, d6-DMSO) delta 8.88 (1 H, s), 8.58 (1 H, s), 8.45 (1 H, s), 4.20 (2H, t), 3.54 (4H, m), 3.32 (3H, s), 2.72 (2H, t), 2.45 (4H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 70℃; | To a solution of 3-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (1.5 g, 7.2 mmol) in DMF (30 mL) were added 1-bromo-3-methoxypropane (4.5 g, 29 mmol) , potassium iodide (1.2 g, 7.2 mmol) and Cs2CO3(12 g, 36.8 mmol) . The mixture was stirred at 70 overnight. The reaction mixture was concentrated to remove DMF. The residue was diluted with water (20 mL) . The resulting mixture was extracted with EtOAc (30 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by pre-HPLC to give a colorless oily product (1.2 g, 30) .[1830]MS (ESI, pos. ion) m/z: 281.3 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; | A mixture of 3-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (1.5 g, 7.2 mmol) , methyl 2-bromo-2-methylpropanoate (1.4 mL, 10.8 mmol) and Cs2CO3 (4.5 g, 14 mmol) in DMF (15 mL) was stirred at 70 overnight. The reaction mixture was concentrated in vacuo to remove DMF. The residue was diluted with water (20 mL) . The resulting mixture was extracted with DCM (30 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 9/1 to give a colorless oily product (1.3 g, 58) .[1557]MS (ESI, pos. ion) m/z: 309.3 [M+1] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 10h; | A mixture of 3-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (1.5 g, 7.2 mmol) , ethyl 2-bromo-2-methylpropanoate (1.7 mL, 11 mmol) and Cs2CO3(4.5 g, 14 mmol) in DMF (15 mL) was stirred at 70 overnight. The reaction mixture was concentrated in vacuo to remove DMF. The residue was diluted with water (20 mL) . The resulting mixture was extracted with DCM (30 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 9/1 to give a colorless oily product (1.4 g, 60) .[1746]MS (ESI, pos. ion) m/z: 323.3 [M+1]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 70℃; | A mixture of 3-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (1.5 g, 7.2 mmol) , 4- (3-chloropropyl) morpholine (1.7 mL, 2.7 mmol) , potassium iodide (0.5 g, 2.7 mmol) and Cs2CO3(4.5 g, 14 mmol) in DMF (30 mL) was stirred at 70 overnight. The reaction mixture was concentrated in vacuo to remove DMF. The residue was diluted with water (30 mL) . The resulting mixture was extracted with DCM (50 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by pre-HPLC to give a light yellow oily product (0.9 g, 50) .[1759]MS (ESI, pos. ion) m/z: 336.0 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 70℃; | A mixture of 3-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (2 g, 9.7 mmol) , 2-bromoethanol (2.5 mL, 28.8 mmol) , KI (0.8 g, 4.8 mmol) and Cs2CO3(7.9 g, 24 mmol) in DMF (30 mL) was stirred at 70 overnight. The reaction mixture was concentrated to remove DMF. The residue was diluted with water (30 mL) . The resulting mixture was extracted with DCM (50 mL × 3) . The combined organic layers were dried over anhydrous Na2SO4and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE/EtOAc (v/v) 9/1 to give a white solid product (1.5 g, 62) .[1907]MS (ESI, pos. ion) m/z: 253.1 [M+1]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 2h;Inert atmosphere; | To a suspension of (4) (200mg, 0.50mmol), 3-methyl-4-(tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (104mg, 0.5mmol) and Cs2C03 (326mg, I .Ommol) in DMF (4m L) and H20 (1 mL) was added Pd(PPh3)4 (58mg, 0.05mmol). The reaction mixture was flushed with N2(g) and heated up to 90C for 2h. It was then re-treated with 3-methyl-4-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (104mg, 0.5mmol), Cs2C03 (326mg, I .Ommol) and Pd(PPh3)4 (58mg, 0.05mmol). The reaction mixture was flushed with N2(g) and heated up to 90C for another 2h. Once cooled down, it was partitioned between H20 (10ml_) and CH2CI2 (2 x 30mL). The combined organic extracts were dried over MgS04, filtered and concentrated in vacuo. Purification by flash column chromatography with CH2CI2/MeOH (1 :0-4:1) yielded (5) (67mg, 33%). 1 H NMR (500 MHz, DMSO-cfe), deltaEta ppm: 8.69 (d, J=1.5 Hz, 1 H), 8.24-8.29 (m, 2H), 8.10 (d, J=2.7 Hz, 1 H), 7.87 (d, J^8.3 Hz, 2H), 7.60 (s, 1 H), 7.48 (d, J^8.4 Hz, 2H), 7.34 (s, 1 H), 7.19 (m, 1 H), 5.98 (br. s., 1 H), 5.52 (s, 2H), 3.81 (s, 3H), 2.30 (s, 3H). LCMS (ES): Found 401.5 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | A mixture of <strong>[936250-20-3]3-methylpyrazole-4-boronic acid pinacol ester</strong> (0.50 g, 2.40 mmol), 2- (trimethylsilyl)ethoxymethyl chloride (0.53 ml, 3.00 mmol) and DIPEA (1.3 ml, 7.21mmol) in DCM (10 ml) was stirred at ambient temperature for 1.5 hours. The mixture was partitioned between DCM and water. The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo to afford the desired product as a pale brown oil (0.81 g, 100%, mixture of two regioisomers). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In N,N-dimethyl-formamide; at 90℃; for 1h; | A degassed solution of 1C (20 mg, 0.045 mmol), <strong>[936250-20-3]3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (18.82 mg, 0.090 mmol), PdC12(dppf)-CH2C12 adduct (3.69 mg, 4.52 imol) and potassium phosphate tribasic 2M solution (0.068 mL, 0.136 mmol) in DMF (0.5 mL) was heated to 90 C for 1 h. The reaction mixture was purified on preparative HPLC to give 1 (14.8 mg, 74% yield). ?H NMR (500 MHz, DMSO-d6) oe 7.94 (d, J5.7 Hz, 1H), 7.63 - 7.54 (m, 1H), 7.41 (dd, J8.1, 5.7 Hz, 2H), 7.21 - 7.09 (m, 3H), 6.88 (dd,J=8.6, 5.2 Hz, 1H), 5.45 (s, 2H), 3.41 (br. s., 2H), 2.80 (t, J=6.6 Hz, 2H), 2.50 (s, 3H merge with DMSO). MS(ESI) m/z 444.1 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.7% | Synthesis of (4S)-N-(4-(3-methyl-lH-pyrazol-4-yl) pyridin-2-yl)-7-(2-methylpyridin-4- -3, 4-dihydro-l, 4-methanopyrido [2, 3-b] [1, 4] diazepine-5(2H)-carboxamideTo a stirred solution of (4,S)-N-(4-bromopyridin-2-yl)-7-(2-methylpyridin-4-yl)-3,4- dihydro-l,4-methanopyrido[2,3-^][l,4]diazepine-5(2H)-carboxamide (300 mg, 0.665 mmol) in 1,4-Dioxane (40 mL) and Water (10 mL) were added 3-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (207 mg, 0.997 mmol) and K3PO4 (423 mg, 1.994 mmol) at RT and degassed for 15 min. Then Pd2(dba)3 (60.9 mg, 0.066 mmol) and x-phos (63.4 mg, 0.133 mmol) were added to the reaction mixture again degassed for 10 min, then the reaction mixture was stirred at 80 C for 16 h. (TLC System: 10% methanol in DCM, Rr0.2; UV active). The reaction mixture was cooled to RT and partitioned between water and ethyl acetate (3x30 mL). The combined organic layer was washed with brine solution, dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain crude compound. The crude compound was purified by flash column chromatography (using neutral alumina and eluted at 20% ethyl acetate in Pet ether) to afford the desired compound (4,S)-N-(4-(3-methyl-lH-pyrazol-4-yl)pyridin-2-yl)-7-(2- methylpyridin-4-yl)-3,4-dihydro-l,4-methanopyrido[2,3-^][l,4]diazepine-5(2H)- carboxamide (139 mg, 0.304 mmol, 45.7 % yield) as a pale brown solid. LCMS (m/z): 453.21 [Mu+Eta]+, = 1.36 min.1H NMR (400 MHz, CDC13): delta ppm 13.59 (s, 1 H), 10.35 (br s, 1 H), 8.63 (d, J=5.26 Hz, 1 H), 8.44 - 8.16 (m, 3 H), 7.87 (s, 1 H), 7.73 (d, J=3.95 Hz, 1 H), 7.63 (d, J=8.11 Hz, 1 H), 7.49 (d, J=7.89 Hz, 1 H), 7.10 (dd, J=5.15, 1.43 Hz, 1 H), 5.72 (dd, J=5.70, 3.07 Hz, 1 H), 3.36 - 3.16 (m, 3 H), 3.02 (dd, J=12.06, 3.07 Hz, 1 H), 2.76 (s, 3 H), 2.59 (s, 3 H), 2.42 - 2.29 (m, 1 H), 2.10 (dt, J=14.03, 7.02 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17.8% | With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h;Microwave irradiation; | A mixture of 2,2-difluoroethyl trifluoromethanesulfonate 1b (8.23 g, 0.38 mol), <strong>[936250-20-3]3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (500 mg, 1.92 mmol) and CS2CO3 (1.25 g, 3.84 mmol) in DMF (10 mL) was heatedin microwave at 100C for 1 h. The reaction mixture was cooled to room temperature quenched with H2O (30 mL) andextracted with EA (20 mL*3), the organic layers were combined and washed with water (10 mL*2) and brine (10 mL*2),dried over Na2SO4, evaporated. The residue was purified by silica column to afford 1-(2,2-difluoroethyl)-3-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole (117 mg, white solid), yield: 17.8 %.1H NMR (400 MHz, CDCl3) delta 7.63 (s, 1H), 6.23-5.89 (m, 1H), 4.41-4.31 (m, 1H), 2.36 (s, 3H), 1.28 (s, 12H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 80℃; for 8h;Inert atmosphere; | Compound 2 (250mg, 2.1mmol) and the compound 10 (400mg, 2.1mmol) placed in 50mL single-neck flask under nitrogen, a solution of DBU at room temperature (1g, 4.2mmol), stir. Then heated to 80 , reaction 8h. After completion of the reaction, the solvent spin dry column chromatography (ethyl acetate: petroleum ether = 5: 1) to give a white solid 250mg, 36percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; lithium chloride; In ethanol; at 120℃; for 1.5h;Microwave irradiation; | Intermediate 19-7 6-(3-Methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic acid (1376) (1377) Analogously to the synthesis of Intermediate 19-2, 216 mg of methyl 6-bromopyridine-2-carboxylate were reacted with 250 mg of <strong>[936250-20-3]3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> in the microwave at 120 C. for 90 min. This gave, after purification by HPLC, 68 mg (33% of theory) of the title compound mixed with methyl 6-(3-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylate. (1378) UPLC-MS (Method A1): Rt=0.50 min (1379) MS (ESIpos): m/z=204 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.1 g | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium hydrogencarbonate; In water; N,N-dimethyl-formamide; at 120℃; for 1.5h;Inert atmosphere; Micellar solution; | Step b. A solution of Intermediate B (l .Og, 2.53 mmol), 3-methylpyrazole-4-boronic acid, pinacol ester (CAS Number 936250-20-3) (0.63g, 3.03mmol) and NaHC03 (0.63g, 7.5mmol) in DMF : water (8:2, 15ml) was stirred at rt in a microwave tube. The reaction mixture and degassed for 15 min. Pd(dppf)Cl2 (0.19g, 0.25 mmol) was added and the reaction mixture was heated at 120C for 1.5 h in microwave. The resulting reaction mixture was combined with 22 other batches prepared on the same scale by an identical method, then poured into water (500 ml). The resulting mixture was extracted with EtOAc (3 x 500 ml). The combined organic phase was dried over Na2S04, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (70% EtOAc in hexane) yielding tert-butyl (S)-2-(4-(5-methyl-lH-pyrazol-4-yl)indoline-l- carbonyl)pyrrolidine-l-carboxylate (11. lg, 28.01mmol). LCMS: Method C, 2.033 min, MS: ES+ 397.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
418 mg | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; CyJohnPhos; In 1,2-dimethoxyethane; water; at 80℃;Inert atmosphere; | In a nitrogen atmosphere, 80 C, A solution of (2E) -3- (4-chloropyridin-3-yl) -N- (4- (N-morpholinylmethyl) phenyl) acrylamide (500 mg) Methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (581 mg) 2- (dicyclohexylphosphino) biphenyl (61.2 mg), Pd2 (dba) 3 (64 mg), 2M aqueous cesium carbonate solution (1.75 mL) and DME (8 mL) was stirred overnight. The reaction mixture was concentrated under reduced pressure, And the residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate) to obtain the title compound (418 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18%; 35% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; for 18h;Inert atmosphere; | To a solution of <strong>[936250-20-3]3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (600 mg, 2.88 mmol) and 3-(cyanomethylene)cyclobutane-1-carbonitrile (Preparation 27, 341 mg, 2.88 mmol) in MeCN (28.8 mL) was added DBU (439 mg, 2.88 mmol) at about 20 C. After about 18 hrs at about 20 C., the mixture was poured into EtOAc and 10% aq. K2HPO4. The EtOAc was separated and the aqueous phase was extracted twice more with EtOAc. The combined EtOAc extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by column chromatography to afford (1r,3r)-3-(cyanomethyl)-3-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile (trans isomer, 325 mg, 35%) 1H NMR (400 MHz, CDCl3) delta: 7.79 (s, 1H), 3.17-3.28 (m, 3H), 3.16 (s, 2H), 2.81-2.89 (m, 2H), 2.39 (s, 3H), 1.32 (s, 12H).LCMS m/z=327.2 [MH]+and (1s, 3s)-3-(cyanomethyl)-3-(3-methyl-4-(4,4, 5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutane-1-carbonitrile (cis isomer, 171 mg, 18%).1H NMR (400 MHz, CDCl3) delta: 7.75 (s, 1H), 3.18-3.28 (m, 1H), 3.08-3.18 (m, 2H), 3.05 (s, 2H), 2.93-3.02 (m, 2H), 2.39 (s, 3H), 1.32 (s, 12H).LCMS m/z=327.2 [MH]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 130℃; for 0.333333h;Microwave irradiation; | A mixture of methyl 2-(( 4-bromophenoxy)methyl)cyclopropanecarboxylate (SS mg, 0.31 mmol), 3-methyl-4-( 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H -pyrazole(96 mg, 0.463 mmol), K2C03 (171 mg, 1.23 mmol), andPd(Ph3 P)4 (36 mg, 0.031 mmol) in THF (1.5 mL) and water(0.5 mL) was heated in a microwave reactor at 130 C. for20 min, then was cooled to rt. The mixture was extractedwith EtOAc (3x3 mL). The combined organic extracts weredried over MgS04 , and concentrated in vacuo. This crudeproduct was purified by preparative HPLC (YMC reversephase ODS-A-5 30xl00 mm column; flow rate=40 mL/min,0 to I 00% Solvent B over 30 min, hold to 40 min, whereSolvent A=90:10:0.1 H20:MeCN:TFA and Solvent B=90:10:0.1 CH3CN:H20:TFA) to give trans-methyl 2-((4-(3-methyl-IH-pyrazol-4-yl)phenoxy) methyl)cyclopropanecarboxy late ( 40 mg, 45% yield) as a white solid. LCMS,[M+Hr=2S7.1. 1H NMR (500 MHz, CDCI3 ) o 11.50 (s,2H), 7.74 (s, lH), 7.32-7.27 (m, 2H), 7.00-6.SS (m, 2H),4.00 (dd, 1=10.1, 5.9 Hz, lH), 3.SS (dd, 1=10.1, 6.6 Hz, lH),3.71 (s, 3H), 2.50 (s, 3H), 1.93 (dqd, 1=12.6, 6.3, 4.0 Hz,lH), 1.74 (dt, 1=S.S, 4.6 Hz, lH), 1.33 (dt, 1=9.2, 4.7 Hz,lH), 1.02 (ddd, 1=S.4, 6.2, 4.5 Hz, lH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.85% | With caesium carbonate; In acetone; at 60℃; for 8h; | 5- (Chloromethyl) thiazole (502 mg, 3.76 mmol) and <strong>[936250-20-3]3-methylpyrazole-4-boronic acid pinacol ester</strong> (820 mg,3.94 mmol) was dissolved in acetone (10 mL), Cs2CO3 (402 mg, 1.23 mmol) was added to the system,The reaction was warmed to 60 C for 8 h.The reaction mixture was filtered, and the concentrated crude product was purified by silica gel column chromatography (PE / EtOAc (v / v) = 1/1)The isomer mixture was obtained as a yellow oil of 652 mg, yield: 56.85% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.64% | With caesium carbonate; In acetone; at 60℃; for 8h; | 2- (Chloromethyl) pyrazine (107 mg, 0.83 mmol) and <strong>[936250-20-3]3-methylpyrazole-4-boronic acid pinacol ester</strong> (180 mg,0.87 mmol) was dissolved in acetone (10 mL). Cs 2 CO 3 (402 mg, 1.23 mmol) was added to the system, and the mixture was heated to 60 C. for 8 h.The reaction mixture was filtered, and the concentrated crude product was purified by silica gel column chromatography (PE / EtOAc (v / v) = 1/1) to give isomersThe mixture was 189 mg of a yellow oil, yield: 75.64%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.01% | With caesium carbonate; In acetone; at 60℃; for 6h; | 2- (Chloromethyl) thiazole (302 mg, 2.26 mmol) and <strong>[936250-20-3]3-methylpyrazole-4-boronic acid pinacol ester</strong> (463 mg,2.23 mmol) was dissolved in acetone (10 mL). Cs 2 CO 3 (1.12 g, 3.44 mmol) was added to the system and heated to 60 C. for 6 h.The reaction mixture was filtered, and the concentrated crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 5/1) to give483 mg of yellow oil, yield: 70.01% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.88% | With caesium carbonate; In acetone; at 60℃; for 6h; | The compound 5- (chloromethyl) -2-methylthiazole (241 mg, 1.63 mmol) and 3-methylpyrazole-4-boronic acidAlcohol ester (340 mg, 1.63 mmol) was dissolved in acetone (10 mL). Cs2CO3 (1.3 g, 4.0 mmol) was added to the system and the temperature was raised to 60 reaction 6h. The reaction mixture was filtered, and the concentrated crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) =3/1) to give 312 mg of a yellow oil, yield: 59.88%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; | To a solution of <strong>[936250-20-3]3-methylpyrazole-4-boronic acid pinacol ester</strong> (0.50 g, 2.4 mmol) in DMF (25 mL) was added (4-2-yl) methyl methanesulfonate (0.62 g, 3.1 mmol) and K2CO3 (1.3 g, 4.0 mmol) were added and then reacted at 100 C overnight. The reaction solution was concentrated under reduced pressure to remove DMF, water (40 mL) was added thereto and extracted with methylene chloride (50 mL × 3). The organic phase was washed with anhydrousThe crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 7/3) to give0.18 g of light yellow oil, yield: 24%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With caesium carbonate; potassium iodide; In acetone; at 60℃; | To <strong>[936250-20-3]3-methylpyrazole-4-boronic acid pinacol ester</strong>(1.50 g, 7.2 mmol) in acetone (40 mL) was added 2- (bromoMethyl) -6-methylpyridine (2 g, 10.8 mmol), Cs2CO3 (5.9 g, 18.0 mmol) and KI (0.6 g, 4 mmol)Then reacted at 60 C overnight. The reaction solution was cooled, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatographyAgent: PE / EtOAc (v / v) = 3/2) to give 1.5 g of a yellow solid in a yield of 66%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 70℃; | To a solution of <strong>[936250-20-3]3-methylpyrazole-4-boronic acid pinacol ester</strong> (1.01 g, 4.85 mmol) in DMF (40 mL) was added 4-Methyl) pyrimidine (1.2 g, 6.9 mmol), Cs 2 CO 3 (3.9 g, 12 mmol) and KI (0.4 g, 2 mmol)Then reacted at 70 C overnight. The reaction solution was concentrated under reduced pressure to remove DMF, extracted with water (40 mL) and extracted with dichloromethane (50 mL × 3). The organic phase was dried over anhydrous Na 2 SO 4 and the concentrated crude product was purified by silica gel column chromatography (eluent: / MeOH (v / v) = 20/1)0.8 g of a yellow oil, yield: 50%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 70℃; | To a solution of <strong>[936250-20-3]3-methylpyrazole-4-boronic acid pinacol ester</strong> (1.01 g, 4.85 mmol) in DMF (40 mL)Added to the solution2-Chloromethyl-4-amino-pyrimidine(1.1 g, 7.7 mmol), Cs2CO3 (5.5 g, 17 mmol) and KI (0.4 g, 2 mmol)Then reacted at 70 C overnight. The reaction mixture was concentrated under reduced pressure to remove DMF, water (40 mL)Dichloromethane (50 mL x 3), the organic phase was dried over anhydrous Na2SO4,The concentrated crude product was purified by silica gel column chromatography (eluent: CH2Cl2 / MeOH (v / v) = 20 /1) to give 0.48 g of a yellow solid, yield: 31%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 70℃; for 15h;Inert atmosphere; | 3-Methyl-4-pyrazole boronic acid pinacol ester(1.50 g, 7.2 mmol) were dissolved in DMF (15 mL) and added sequentially2- (Chloromethyl) -5-methylpyrimidine(1.5 g, 11 mmol), Cs2CO3 (8.2 g, 25 mmol) and potassium iodide (0.6 g, 3.6 mmol). Then replace nitrogen,Under nitrogen protection, heated to 70 C, the reaction 15h. Stop heatingThe reaction was cooled to room temperature. Celite was filtered, concentrated under reduced pressure, the filtrate was freed from DMF, water (60 mL) was added,Dichloromethane (30 mL x 3)The organic phase was dried over anhydrous Na2SO4 and the concentrated crude product was isolated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1 /1) to give 943 mg of a pale yellow oil product (containing isomers), which was isolated and purified by preparative workup.This gave 645 mg of a light yellow oil, yield: 28%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 70℃; for 10h; | To a solution of <strong>[936250-20-3]3-methylpyrazole-4-boronic acid pinacol ester</strong> (1.40 g, 6.73 mmol) in DMF (40 mL) was added2- (bromomethyl) pyridine hydrobromide (2.5 g, 9.9 mmol), Cs2CO3 (3.91 g, 12.0 mmol) and KI (0.41 g, 2.4 mmol)The reaction was carried out at 70 C for 10 h. The reaction mixture was concentrated under reduced pressure to remove DMF, extracted with water (40 mL) and extracted with methylene chloride (50 mL × 3), and then the organicThe phases were dried over anhydrous Na2SO4. The concentrated crude product was isolated by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1 /1) to give 1.3 g of a yellow oil, yield: 65%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; | To a solution of <strong>[936250-20-3]3-methylpyrazole-4-boronic acid pinacol ester</strong> (1.00 g, 4.81 mmol) in DMF (40 mL) was added (6-(Trifluoromethyl) pyridin-2- yl) methyl methanesulfonate (1.9 g, 7.4 mmol) and K2CO3 (2.5 g, 7.7 mmol) C overnight. The reaction solution was concentrated under reduced pressure to remove DMF, and water (40 mL) and dichloromethane (50 mL × 3) were added for extraction. The organic phaseAfter drying over anhydrous Na2SO4, the concentrated crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 4 /1) to give 0.7 g of product as a light yellow oil, yield: 40%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; | To a solution of <strong>[936250-20-3]3-methylpyrazole-4-boronic acid pinacol ester</strong> (0.91 g, 4.4 mmol) in DMF (25 mL) was added pyrimidine-2-ylmethyl methanesulfonate (1.2 g, 6.4 mmol) and Cs2CO3 (2.3 g, 7.1 mmol) were added and then reacted at 100 C overnight. anti-The solution was concentrated under reduced pressure to remove DMF, extracted with water (40 mL) and extracted with dichloromethane (50 mL × 3). The organic phase was dried over anhydrous Na 2 SO 4,The concentrated crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 3/2) to give 1.1 g of a yellow oilShape, yield: 84%. . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 70℃; | To a solution of <strong>[936250-20-3]3-methylpyrazole-4-boronic acid pinacol ester</strong> (1.01 g, 4.85 mmol) in DMF (40 mL) was added 2-Methyl) -4- fluoropyridine (1.2 g, 6.3 mmol), Cs2CO3 (5.5 g, 17 mmol) and KI (0.4 g, 2 mmol) were added and then reacted at 70 C overnight. The reaction solution was concentrated under reduced pressure to remove DMF, water (40 mL) was added thereto and extracted with methylene chloride (50 mL × 3). The organic phase was washed with noWater and dried over Na 2 SO 4. The concentrated crude product was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 1/1)To 1 g of a yellow oil, yield: 65%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 6h; | General procedure: Pd(pph3)4 (30 mg, 0.026 mmol), 1H-pyrazole-4-boronic acid (58.2 mg, 0.52 mmol),NaCO3 (82.6 mg, 0.78 mmol) and compound o (90.5 mg, 0.26 mmol) were added to the reaction tube.Then, H2O (0.39 ml) and 1,4-dioxane (0.65 ml, 0.4 M) were added to remove nitrogen three times, and the mixture was heated to 90C and stirred for 6 hours.Cool to room temperature, dilute with water, extract twice with ethyl acetate, and wash with saturated brine.After drying over anhydrous sodium sulfate, it was concentrated and purified by silica gel column (PE:EA=2:1) to obtain 35 mg of white solid, namely SKLB-C4573, yield: 40.1%. |
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 6h; | General procedure: Under N2 atmosphere, a mixture of 6 (100.0 mg, 0.26 mmol),Pd(pph3)4 (30.0 mg, 0.026 mmol), 2.0M aq Na2CO3 (0.29 ml,0.78 mmol) and 1-Methyl-1H-pyrazole-5-boronic acid pinacolester (108.2 mg, 0.52 mmol) in 1,4-Dioxane (0.65 ml) was heated to90 C and stirred for 6 h. The reaction mixture was cooled, dilutedwith ethyl acetate, washed with water, dried over anhydrousNa2SO4, filtered and concentrated under vacuum. Purification onsilica using a solvent gradient of 10-30% ethyl acetate in hexanesyielded the desired compound 1j (77.0 mg, 77.5%). Compounds 1akwere prepared according to general procedure as described forcompound 1j using corresponding aryl bromide 2-4 and theappropriate boronic acid or boronic acid pinacol ester. The characterizationdata for compounds 1a-k were provided below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | At room temperature, 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (49a) (1.00 g, 3.52 mmol) and <strong>[936250-20-3]3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (1.10 g, 5.28 mmol) were dissolved in dioxane (30 mL), water (4 mL) and potassium carbonate (1.20 g) were then added, nitrogen replacement was performed, and the reaction was stirred at room temperature for 10 min. Pd(dppf)Cl2 (140 mg) was added under protection of nitrogen. The reaction system was stirred in an oil bath at 90C overnight. After TLC indicated the substrate disappeared, the reaction solution was quenched by slowly pouring into ice-water, extracted with EA, the organic phase was dried over anhydrous sodium sulfate, and purified by preparative flash chromatography (PE:EA=1:1), to afford compound (49b) (200 mg, yellow solid), yield: 18%. MS m/z: 330 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | A mixture of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-S -(4-(4-fluorophenethoxy)phenyl)-2-methyl-6-(((trifluoromethyl)sulfonyl)oxy)pyridin-3 -yl)acetate (0.025 g, 0.034 mmol), 3 -methyl-4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)-1H-pyrazole (0.0 14 g, 0.068 mmol), Pd(Ph3P)4 (7.82 mg, 6.77 .imol), and 2 MNa2CO3 (0.042 ml, 0.085 mmol) in toluene (1 mL) and ethanol (1 mL) was degassed. Thereaction was heated at 90 C in a sealed tube for 2 h. The reaction mixture was filtered through a pad of celite and concentrated in vacuo. The residue was taken up in ethanol (1 mL). 5 M NaOH (0.068 mL, 0.338 mmol) was added and the mixture was heated at 80 C for 3 h, cooled to ambient temperature, and filtered. The cmde mixture was then purifiedvia preparative HPLC to afford the desired product (3.1 mg, 15%). ?H NMR (500 MHz,DMSO-d6) 7.37 (dd, J= 8.4, 5.9 Hz, 2H), 7.15 (q, J= 8.9 Hz, 3H), 7.08 - 7.01 (m, 1H),6.95 (d, J= 8.4 Hz, 1H), 6.90 - 6.84 (m, 1H), 6.32 (s, 1H), 5.79 (br. s., 1H), 4.27 -4.16(m, 2H), 3.05 (t, J= 6.8 Hz, 2H), 2.88 - 2.79 (m, 1H), 2.55 (s, 6H), 2.28 (s, 3H), 1.91 (s,2H), 1.53 (br. s., 1H), 1.31 (br. s., 1H), 1.20 - 1.11 (m, 1OH), 1.01 (d, J 12.5 Hz, 1H),0.85 (s, 3H), 0.61 (s, 3H). LCMS (M+1) = 629.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); cesium fluoride; In water; tert-butyl alcohol; at 60 - 100℃; | A flask was charged with 3-bromo-5-chloropyrazin-2-amine (0.24 g, 1.2 mmol, D-L Chiral Chemicals), <strong>[936250-20-3]3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (0.24 g, 1.2 mmol, Aldrich), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.041 g, 0.058 mmol), and cesium fluoride (0.53 g, 3.5 mmol). tert-Butyl alcohol (6.1 mL) and water (1.6 mL) were added, and the mixture was degassed and heated to 60 C. for 1.5 hours, then at 70 C. overnight, then at 100 C. for 1.5 hours. Upon cooling, the reaction mixture was partitioned between water and EtOAc, and the layers were separated. The aqueous layer was extracted with two additional portions of EtOAc and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The product was purified by flash chromatography, eluting with a gradient of 0-10% MeOH in DCM to afford a pale yellow solid (0.14 g, 58%). LCMS for C8H9ClN5 (M+H)+: calculated m/z=210.1; found 210.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.16% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 100℃;Inert atmosphere; | A mixture of 5-bromopyridin-3-ol (10 g, 54.599 mmol, 1 equiv, 95%), Pd(dppf)Cl2.CH2Cl2 (2.35 g, 2.730 mmol, 0.05 equiv, 95%), K2CO3 (11.91 g, 81.898 mmol, 1.50 equiv, 95%) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (14.35 g, 65.518 mmol, 1.2 equiv, 95%) in dioxane (150.01 mL, 1682.194 mmol, 30.81 equiv, 95%) and H2O (29.99 mL, 1664.971 mmol, 28.97 equiv, 95%) was stirred for overnight at 100 degrees C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to afford 5-(3-methyl-1H-pyrazol-4- yl)pyridin-3-ol (6.5g,61.16%) as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In acetonitrile; at 90℃; for 4h;Inert atmosphere; | An exemplary Intermediate D, Intermediate D-l, may be used to synthesize compounds of formula I wherein R1 is a disubstituted heteroaryl. A mixture of 3-methyl-4-(4, 4, 5, 5- tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-pyrazole (370 mg, 1.78 mmol, 1.00 equiv), 2- iodopropane (907 mg, 5.33 mmol, 533 uL, 3.00 equiv) and cesium carbonate (2.32 g, 7.11 mmol, 4.00 equiv) in acetonitrile (7.00 mL) was purged with nitrogen and subsequently stirred at 90 C for 4 h. The reaction mixture was filtered and concentrated under reduced pressure to provide a residue. The crude material was purified by column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 3 / 1) to afford a mixture of l-isopropyl-3-methyl-4- (4, 4, 5, 5- tetramethyl-l, 3, 2-dioxaborolan-2-yl)pyrazole (170 mg, 34.4% yield, 90.0% purity) and l-isopropyl-5-methyl-4- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)pyrazole (170 mg, 34.4% yield, 90.0% purity) as a light yellow oil. LCMS [M+l]: 251.4. 1H NMR (400MHz, CDCl3) d = 7.73 (s, 0.6H), 7.65 (s, 1H), 4.50 - 4.36 (m, 2H), 2.45 (s, 2H), 2.40 (s, 3H), 1.50-1.44 (m, 12H), 1.31 (s, 22H). |
Tags: 936250-20-3 synthesis path| 936250-20-3 SDS| 936250-20-3 COA| 936250-20-3 purity| 936250-20-3 application| 936250-20-3 NMR| 936250-20-3 COA| 936250-20-3 structure
[ 1046832-21-6 ]
1,3-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
Similarity: 0.91
[ 269410-08-4 ]
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
Similarity: 0.88
[ 857530-80-4 ]
3,5-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
Similarity: 0.86
[ 761446-44-0 ]
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
Similarity: 0.80
[ 1002334-06-6 ]
1-Methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
Similarity: 0.80
[ 1046832-21-6 ]
1,3-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
Similarity: 0.91
[ 269410-08-4 ]
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
Similarity: 0.88
[ 857530-80-4 ]
3,5-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
Similarity: 0.86
[ 761446-44-0 ]
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
Similarity: 0.80
[ 1002334-06-6 ]
1-Methyl-3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
Similarity: 0.80
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