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CAS No. : | 62802-38-4 | MDL No. : | MFCD07787364 |
Formula : | C4H2BrFN2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CTWZYPZCDJKBRS-UHFFFAOYSA-N |
M.W : | 176.97 | Pubchem ID : | 600690 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 29.69 |
TPSA : | 25.78 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.44 cm/s |
Log Po/w (iLOGP) : | 1.63 |
Log Po/w (XLOGP3) : | 1.33 |
Log Po/w (WLOGP) : | 1.8 |
Log Po/w (MLOGP) : | 0.81 |
Log Po/w (SILICOS-IT) : | 2.16 |
Consensus Log Po/w : | 1.54 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.33 |
Solubility : | 0.828 mg/ml ; 0.00468 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.47 |
Solubility : | 5.96 mg/ml ; 0.0337 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.78 |
Solubility : | 0.293 mg/ml ; 0.00166 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.58 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P264-P270-P301+P312+P330-P501 | UN#: | N/A |
Hazard Statements: | H302 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | Example 252-amino-5-[3-(2-fluoropyrimidin-5-yl)phenyl]-3-methyl-5-(4-trimethylsilylphenyl)imidazol-4-one; A mixture of 2-amino-5-(3-bromophenyl)-3-methyl-5-[4-(trimethylsilyl)phenyl]-3,5-dihydro-4H-imidazol-4-one (200 mg, 0.48 mmol), Potassium acetate (141 mg, 1.44 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct (1:1) (39 mg, 0.05 mmol) and Bis(pinacolato)diboron (134 mg, 0.53 mmol) in 1,2-dimethoxyethane (3 mL) was irradiated in a microwave reactor at 130 C. for 30 min. Then <strong>[62802-38-4]5-Bromo-2-fluoropyrimidine</strong> (85 mg, 0.48 mmol) was added together with water (1 mL) and the mixture run again at 150 C. for 20 min. When cooled to ambient temperature the mixture was diluted with brine, the organic phase separated and the water phase extracted with ethyl acetate. The combined organics were concentrated and purified by preparative HPLC. The combined HPLC fractions were concentrated under reduced pressure and the remaining aqueous phase was diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The combined organics were dried over sodium sulfate, filtered and concentrated to give 25 mg (25% yield) of the title compound; MS (ESI) m/z 434 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 3h; | To a vial is added R-12 (200 mg, 1.13 mmol) in DMF (5 ml), followed by the addition of K2CO3 (312 mg, 2.26 mmol) and isopropylamine (134 mg, 2.27 mmol). The reaction mixture is stirred at 70 C for 3 hours. The reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc, washed with water, brine, dried under anhy. Na2S04, fitered and concentrated to afford the title intermediate (221 mg); m/z 216.0/218.0 [M/M+2H] . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
221 mg | With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 3h; | Synthesis of (5-bromo-pyrimidin-2-yl)-tert-butyl-amine To a vial is added R-12 (200 mg, 1.13 mmol) in DMF (5 ml), followed by the addition of K2CO3 (312 mg, 2.26 mmol) and isopropylamine (134 mg, 2.27 mmol). The reaction mixture is stirred at 70 C. for 3 hours. The reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc, washed with water, brine, dried under anhy. Na2SO4, filtered and concentrated to afford the title intermediate (221 mg); m/z 216.0/218.0 [M/M+2H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29.3% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In toluene; at 110℃; for 16h;Inert atmosphere; | [00378] 65A: 2-fluoro-5-(2-fluoro-5-methoxyphenyl)pyrimidine. To a stirred solution of <strong>[62802-38-4]5-bromo-2-fluoropyrimidine</strong> (707 mg, 3.99 mmol) in Toluene (5.0 mL) was added (2- fluoro-5-methoxyphenyl)boronic acid (815 mg, 4.79 mmol), tetrakis(triphenylphosphine) palladium(O) (231 mg, 0.200 mmol) and potassium carbonate (1656 mg, 1 1.98 mmol). The resulting mixture was purged with argon and stirred at 1 10 C for 16h. After cooled to room temperature, the reaction mixture was diluted with water and extracted with DCM. The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give a solid which was purified by chromatography to afford 2-fluoro-5- (2-fluoro-5-methoxyphenyl)pyrimidine (265 mg, 1.169 mmol, 29.3 % yield) as a white solid. LC-MS Anal.Calc'd for CuH8F2N20 222.06, found [M+H] 223.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In 1,2-dimethoxyethane; ethanol; water; at 90℃; for 0.166667h;Sealed tube; | Preparation 67 tert-butyl (45,,65)-4-(2,4-difluoro-5-(2-fluoropyrimidin-5-yl)phenyl)-6-(3,5- dimethylisoxazol-4-yl)-4-methyl-5,6-dihydro-4H- 1 ,3 -thiazin-2-ylcarbamate To a solution of (5-((45',65)-2-((tert-butoxycarbonyl)amino)-6-(3,5- dimethylisoxazol-4-yl)-4-methyl-5,6-dihydro-4H-l,3-thiazin-4-yl)-2,4- difluorophenyl)boronic acid (Preparation 66, 30 mg, 0.062 mmol) and 5-bromo-2- fluoropyrimidine (22.06 mg, 0.125 mmol) in DME (1,2-dimethoxy ethane) (283 muKappa), EtOH (142 muKappa), and H20 (142 muKappa) was added Bis(triphenylphosphine)palladium(II) chloride (8.75 mg, 0.012 mmol) and cesium carbonate (40.6 mg, 0.125 mmol). The resulting mixture was brought to 90 C in a sealed tube and stirred for 10 min. The reaction mixture was then diluted with EtOAc (5 mL), washed with water (2 mL), brine (2 mL), dried over MgS04, filtered and concentrated in vacuo to give tert-butyl (45,65)- 4-(2,4-difluoro-5-(2-fluoropyrimidin-5-yl)phenyl)-6-(3,5-dimethylisoxazol-4-yl)-4- methyl-5,6-dihydro-4H-l,3-thiazin-2-ylcarbamate as the crude oil which was used without further purification; MS (M+H)+ : 534.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.2 g | With triethylamine; In isopropyl alcohol; at 150℃; for 0.333333h;Microwave irradiation; | As shown in step 6-i of Scheme 6, to a mixture of <strong>[62802-38-4]5-bromo-2-fluoro-pyrimidine</strong> (1 g, 5.651 mmol) in iPrOH (10 mL) was added TEA (1.143 g, 1.574 mL, 11.30 mmol) and trans-4-aminocyclohexan-1-ol (650.8 mg, 5.651 mmol). The mixture was microwaved for 20 min at 150 C., concentrated under reduced pressure, diluted with EtOAc, washed with water, and dried over Na2SO4. After removal of the volatiles under reduced pressure, the residue was purified by medium pressure silica gel chromatography (0-80% EtOAc/hexanes gradient) to provide (trans)-4-((5-bromopyrimidin-2-yl)amino)cyclohexanol (compound 1013, 1.2 g): 1H-NMR (300 MHz, CDCl3) delta 8.28 (s, 2H), 5.03 (d, J=8.1 Hz, 1H), 3.91-3.49 (m, 2H), 2.31-1.90 (m, 4H), 1.56-1.19 (m, 4H). |
1.2 g | With triethylamine; In isopropyl alcohol; at 150℃; for 0.333333h;Microwave irradiation; | As shown in step 6-i of Scheme 6, to a mixture of 5-bromo-2-fluoro- pyrimidine (1 g, 5.651 mmol) in iPrOH (10 mL) was added TEA (1.143 g, 1.574 mL, 11.30 mmol) and trans- 4-aminocyclohexan-l-ol (650.8 mg, 5.651 mmol). The mixture was microwaved for 20min at l50C, concentrated under reduced pressure, diluted with EtOAc , washed with water, and dried over Na2S04. After removal of the volatiles under reduced pressure, the residue was purified by medium pressure silica gel chromatography (0-80% EtO Ac/hexanes gradient) to provide {trans)- 4-((5- bromopyrimidin-2-yl)amino)cyclohexanol (compound 1013, 1.2 g): 1H-NMR (300 MHz, CDCl3) d 8.28 (s, 2H), 5.03 (d, J = 8.1 Hz, 1H), 3.91-3.49 (m, 2H), 2.31-1.90 (m, 4H), 1.56-1.19 (m, 4H).. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36 mg; 11 mg | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 65℃; for 2h;Microwave irradiation; | EXAMPLE W-16A AND W-16B [0668] [0669] A light yellow cloudy solution of (1S,1?S)-1,1?-(4,4?-([1,1?-biphenyl]-4,4?-diyl)bis(1H-imidazole-4,2-diyl))bis(2,2-dimethylpropan-1-amine), 4 HCl (60 mg, 0.100 mmol), <strong>[62802-38-4]5-bromo-2-fluoropyrimidine</strong> (42.3 mg, 0.239 mmol), and DIEA (0.122 mL, 0.697 mmol) in acetonitrile (1 mL) was heated in a microwave system at 65 C. for 2 h. The reaction mixture was purified by preparatory HPLC (MeOH/H2O/TFA) to afford Example W-16B (11 mg, TFA salt) as a white solid, LC/MS (Cond. L-1): [M+H]+ 615.5, Rt=1.23 min; and Example W-16A (36 mg, TFA salt) as a white solid, LC/MS (Cond. L-1): [M+H]+ 771.4, Rt=1.512 min. 1H NMR (400 MHz, MeOD-d4) delta ppm 8.40 (4H, s), 7.79-7.93 (10H, m), 4.99-5.06 (2H, m), 1.21 (18H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36 mg; 11 mg | A light yellow cloudy solution of (is, l?s)- 1,1 ?-(4,4?-([ 1,1 ?-biphenyl]-4,4?- diyl)bis( 1 H-imidazole-4,2-diyl))bis(2,2-dimethylpropan- i-amine), 4 HC1 (60 mg, 0.100 mmol), <strong>[62802-38-4]5-bromo-2-fluoropyrimidine</strong> (42.3 mg, 0.239 mmol), and DIEA (0.122mL, 0.697 mmol) in acetonitrile (1 mL) was heated in a microwave system at 65 C for 2 h. The reaction mixture was purified by preparatory HPLC (MeOHIH2O/TFA) to afford Example W-16B (11 mg, TFA salt) as a white solid, LC/MS (Cond. L-1):[M+H] 615.5, R = 1.23 mm; and Example W-16A (36 mg, TFA salt) as a white solid, LC/MS (Cond. L-i): [M+H] 771.4, R = i.5i2 mm. ?H NMR (400 MHz,MeOD-d4) ppm 8.40(4 H, s), 7.79-7.93 (10 H, m), 4.99-5.06(2 H, m), 1.21 (18 H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
361 mg | With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 20 - 100℃; for 58h;Inert atmosphere; | [Step 1] Production of 2-fluoro-5-(trimethylstannanyl)pyrimidine To <strong>[62802-38-4]5-bromo-2-fluoropyrimidine</strong> (300 mg), hexamethylditin (841 mg) and Pd(PPh3)4 (202 mg) was added 1,4-dioxane (33 mL), and the mixture was stirred under Ar atmosphere at 100C for 10 hours, and stirred at room temperature for 2 days. The solvent of the reaction mixture was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (361 mg) as colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
700 mg | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In N,N-dimethyl-formamide; at 100℃; for 24h;Inert atmosphere; Sealed tube; | tert-Butyl 2-(3-acetyl-5-((5-bromopyrimidin-2-yl)oxy)-1H-indol-1-yl)acetate A mixture of tert-butyl 2-(3-acetyl-5-hydroxy-1H-indol-1-yl)acetate 24 (700 mg), <strong>[62802-38-4]5-bromo-2-fluoropyrimidine</strong> (1 equiv), and Cs2CO3 (700 mg) in DMF (20 mL) was purged with argon in a pressure vessel for 5 min, then tris(dibenzylideneacetone)dipalladium(0) (0.01 equiv) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.01 equiv) were added under argon. The pressure vessel was sealed and heated at 100 C. for 24 h. The reaction mixture was cooled to rt and the solvent was removed under reduced pressure. The remaining residue was purified by column chromatography (eluted with DCM/MeOH) to give tert-butyl 2-(3-acetyl-5-((5-bromopyrimidin-2-yl)oxy)-1H-indol-1-yl)acetate (700 mg). |
700 mg | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In N,N-dimethyl-formamide; at 100℃; for 24h;Inert atmosphere; | tert- utyl 2-(3-acetyl-5-((5-bromopyrimidin-2-yl)oxy)-lH-indol-l-yl)acetate (92). [0587] A mixture of ter -butyl 2-(3-acetyl-5-hydroxy-lH-indol-l-yl)acetate 70 (700 mg), <strong>[62802-38-4]5-bromo-2-fluoropyrimidine</strong> (1 equiv), and CS2CO3 (700 mg) in DMF (20 mL) was purged with argon in a pressure vessel for 5 min, then tris(dibenzylideneacetone) dipalladium(O) (0.01 equiv) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.01 equiv) were added under argon. The pressure vessel was sealed and heated at 100 C for 24 h. The reaction mixture was cooled to rt and the solvent was removed under reduced pressure. The remaining residue was purified by column chromatography (eluted with DCM/MeOH) to give fert-butyl 2-(3-acetyl-5-((5- bromopyrimidin-2-yl)oxy)- lH-indol- 1 -yljacetate (700 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h;Inert atmosphere; | To a stirred solution of lH-pyrrolo[2,3-c]pyridine (0.73 g, 6.22 mmol) and <strong>[62802-38-4]5-bromo-2-fluoropyrimidine</strong> (1 g, 5.65 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (1.56 g, 11.30 mmol). The resulting mixture was stirred for 16 hours at 80 C under nitrogen atmosphere. After cooling down to ambient temperature, the resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers was washed with brine (4 x 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 1-2% methanol in dichloromethane to afford l-(5- bromopyrimidin-2-yl)-lH-pyrrolo[2,3-c]pyridine as a yellow solid: MS (ESI, m/z): 275.1, 277.1 [M + 1]+; 1H NMR (400 MHz, CDC13) delta 9.91 (s, 1H), 8.42 (d, J= 4.8 Hz, 1H), 8.28 (d, J= 5.2 Hz, 1H), 8.01 (s, 2H), 7.52 (t, J= 4.4 Hz, 1H), 6.69 (d, J= 4.8 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In acetonitrile; at 20℃; for 24h;Inert atmosphere; UV-irradiation; | General procedure: A solution of diazine derivative (1 equiv, 0.5 mmol) and the appropriate phosphite (1.1 equiv, 0.55 mmol) in acetonitrile (5 mL) is stirred at room temperature during 24 h under irradiation (distance 8-10 cm, 100 W). The solvent is removed under vacuum. GP A: water (5 mL) is added and the solution is extracted with dichloromethane (3×5 mL). Organic phases are dried over magnesium sulfate and the solvent is removed under vacuum. The crude mixture is purified by flash chromatography on silica gel with appropriate eluent. GP B: The crude mixture is purified by flash chromatography on silica gel with appropriate eluent and without aqueous work-up. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 5-ethyl-4-nitro-1H-pyrazole (350 mg, 2.5 mmol) and 3,4- dihydro-2H-pyran (319 mg, 3.8 mmol) in DCM (20 mE) at 0 C was addedp-TsOH(43 mg, 0.25 mmol), and the mixture was stirred at 0 C for lh and then at rt overnight. DCM (100 mL) was added, and the mixture was washed with water and brine, dried over Na2 SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with petroleum ether/EtOAc (10:1 to 1:1) to afford a mixture of 3-ethyl-4-nitro-1- (tetrahydro-2H-pyran-2-yl)- 1JJ-pyrazole and 5 -ethyl-4-nitro- 1 -(tetrahydro-2H-pyran-2-yl)- 1H- pyrazole.; To a solution of 3-ethyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1JJ-pyrazole and5-ethyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1ff-pyrazole (557 mg, 2.5 mmol) in MeOH (20 mE) at 0C was added 10 % Pd/C (50 mg), and the mixture was stirred under H2 overnight at rt. DCM (20 mE) was added and the mixture was filtered through the Celite. The filtrate was concentrated under reduced pressure to afford a mixture of 3-ethyl-1-(tetrahydro-2H-pyran-2- yl)- 1H-pyrazol-4-amine and 5-ethyl-i -(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-4-amine, which was used in the next step without further purification; To a solution of 3-ethyl-1-(tetrahydro-2H-pyran-2-yl)-iH-pyrazol-4-amine, - ethyl-1-(tetrahydro-2J1-pyran-2-yl)-1H-pyrazol-4-amine (252 mg, 1.03 mmol) and 5-bromo-2- fluoro-pyrimidine (166 mg, 0.94 mmol) in DMSO (7 mL) was added DIEA (243 mg, 1.88 mmol), and the mixture was stirred at 100 C for 1.5 h. DCM (100 mE) was added, and the mixture was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with petroleum ether EtOAc (10:1 to 2:1) to afford a mixture of 5-bromo-N-(3 -ethyl-i -(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-4-yl)pyrimidin-2-amine and 5-bromo-N-(5-ethyl- i -(tetrahydro-2H-pyran-2-yl)- 1H- pyrazol-4-yl)pyrimidin-2-amine; To a solution of 5-bromo-N-(3-ethyl-i-(tetrahydro-2H-pyran-2-yl)-IH- pyrazol-4-yl)pyrimidin-2-amine, 5-bromo-N-(5-ethyl- i -(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol- 4-yl)pyrimidin-2-amine (100 mg, 0.28 mmol), 2-(2-fluoro-4-(4,4, 5,5 -tetramethyl- 1,3,2- dioxaborolan-2-yl)phenyl)-N-(5-( 1 -(trifluoromethyl)cyclopropyl)i soxazol-3 -yl)acetamide (127 mg, 028 mmol), and Na2CO3 (89 mg, 0.84 mmol) in CH3CN (10 mL) and H20 (2 mL) was added Pd(dppf)C12DCM (21 mg, 0.026 mmol). The mixture was stirred at 70 C under N2 overnight and concentrated under reduced pressure. DCM (100 mL) was added and the organic layer was washed with brine, dried over Na2 SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether/EtOAc (10:1 to 1:1) to afford a mixture of 2-(4-(2-((3 -ethyl-i -(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-4-yl)amino)pyrimidin-5-yl)-2-fluorophenyl)-N-(5-( i - (trifluoromethyl)cyclopropyl)i soxazol-3 -yl)acetamide and 2-(4-(2-((5 -ethyl-i -(tetrahydro-2H- pyran-2-yl)- 1H-pyrazol-4-yl)amino)pyrimidin-5 -yl)-2-fluorophenyl)-N-(5-( 1- (trifluoromethyl)cyclopropyl)i soxazol-3 -yl)acetamide; To a solution of 2-(4-(2-((3-ethyl- 1 -(tetrahydro-2H-pyran-2-yl)- 1JJ-pyra.zol-4- yl)amino)pyrimidin-5-yl)-2-fluorophenyl)-N-(5 -(1 -(trifluoromethyl)cyclopropyl)isoxazol-3 - yl)acetamide and 2-(4-(2-((5 -ethyl-i -(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-4- yl)amino)pyrimidin-5-yl)-2-fluorophenyl)-N-(5 -(1 -(trifluoromethyl)cyclopropyl)isoxazol-3 - yl)acetamide (136 mg, 0.23 mmol) in DCM (10 mL) was added TEA (3 mE), and the mixture was stirred at it for 1 h and concentrated under reduced pressure. DCM (100 mE) was added and the mixture was washed with saturated NaHCO3, water, and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether/EtOAc (10:1 to 1:1), followed by preparative TEC, eluting with petroleum ether/EtOAc (1:1). The product was further purified by reverse-phase preparative HPLC (Xunion C18 5 jim, 20x150 mm, 20-75% B, A: H20 (5 mmol NH4HCO3), B: acetonitrile, flow rate 20 mL/min, UV 214 nm) to afford 2-(4-(2-((3-ethyl-1H-pyrazol-4-yl)amino)pyrimidin- 5 -yl)-2-fluorophenyl)-N-(5-( 1 -(trifluoromethyl)cyclopropyl)isoxazol-3 -yl)acetamide. ?H NIVIR (400 MHz, DMSO-d5) 5 12.27 (br s, 1H), 1140 (s, 1H), 8.85 (s, 1H), 8.72 (s, 2H), 7.66 (br s, 1H), 7.54 (d, J= 11.6 Hz, 1H), 7.50-7.40 (m, 2H), 6.92 (s, 1H), 3.80 (s, 2H), 2.58 (t, J 7.2 Hz, 2H), 1.54-1.51 (m, 2H), 1.48-1.45 (m, 2H), 1.14 (t, J= 7.6 Hz, 3H). LCMS (ES+APCI) m/z 516 (M-1-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 5-ethyl-4-nitro-1H-pyrazole (350 mg, 2.5 mmol) and 3,4- dihydro-2H-pyran (319 mg, 3.8 mmol) in DCM (20 mE) at 0 C was addedp-TsOH(43 mg, 0.25 mmol), and the mixture was stirred at 0 C for lh and then at rt overnight. DCM (100 mL) was added, and the mixture was washed with water and brine, dried over Na2 SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with petroleum ether/EtOAc (10:1 to 1:1) to afford a mixture of 3-ethyl-4-nitro-1- (tetrahydro-2H-pyran-2-yl)- 1JJ-pyrazole and 5 -ethyl-4-nitro- 1 -(tetrahydro-2H-pyran-2-yl)- 1H- pyrazole.; To a solution of 3-ethyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1JJ-pyrazole and5-ethyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1ff-pyrazole (557 mg, 2.5 mmol) in MeOH (20 mE) at 0C was added 10 % Pd/C (50 mg), and the mixture was stirred under H2 overnight at rt. DCM (20 mE) was added and the mixture was filtered through the Celite. The filtrate was concentrated under reduced pressure to afford a mixture of 3-ethyl-1-(tetrahydro-2H-pyran-2- yl)- 1H-pyrazol-4-amine and 5-ethyl-i -(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-4-amine, which was used in the next step without further purification; To a solution of 3-ethyl-1-(tetrahydro-2H-pyran-2-yl)-iH-pyrazol-4-amine, - ethyl-1-(tetrahydro-2J1-pyran-2-yl)-1H-pyrazol-4-amine (252 mg, 1.03 mmol) and 5-bromo-2- fluoro-pyrimidine (166 mg, 0.94 mmol) in DMSO (7 mL) was added DIEA (243 mg, 1.88 mmol), and the mixture was stirred at 100 C for 1.5 h. DCM (100 mE) was added, and the mixture was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with petroleum ether EtOAc (10:1 to 2:1) to afford a mixture of 5-bromo-N-(3 -ethyl-i -(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-4-yl)pyrimidin-2-amine and 5-bromo-N-(5-ethyl- i -(tetrahydro-2H-pyran-2-yl)- 1H- pyrazol-4-yl)pyrimidin-2-amine; To a solution of 5-bromo-N-(3-ethyl-i-(tetrahydro-2H-pyran-2-yl)-IH- pyrazol-4-yl)pyrimidin-2-amine, 5-bromo-N-(5-ethyl- i -(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol- 4-yl)pyrimidin-2-amine (100 mg, 0.28 mmol), 2-(2-fluoro-4-(4,4, 5,5 -tetramethyl- 1,3,2- dioxaborolan-2-yl)phenyl)-N-(5-( 1 -(trifluoromethyl)cyclopropyl)i soxazol-3 -yl)acetamide (127 mg, 028 mmol), and Na2CO3 (89 mg, 0.84 mmol) in CH3CN (10 mL) and H20 (2 mL) was added Pd(dppf)C12DCM (21 mg, 0.026 mmol). The mixture was stirred at 70 C under N2 overnight and concentrated under reduced pressure. DCM (100 mL) was added and the organic layer was washed with brine, dried over Na2 SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether/EtOAc (10:1 to 1:1) to afford a mixture of 2-(4-(2-((3 -ethyl-i -(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-4-yl)amino)pyrimidin-5-yl)-2-fluorophenyl)-N-(5-( i - (trifluoromethyl)cyclopropyl)i soxazol-3 -yl)acetamide and 2-(4-(2-((5 -ethyl-i -(tetrahydro-2H- pyran-2-yl)- 1H-pyrazol-4-yl)amino)pyrimidin-5 -yl)-2-fluorophenyl)-N-(5-( 1- (trifluoromethyl)cyclopropyl)i soxazol-3 -yl)acetamide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 4h; | To a solution of <strong>[62802-38-4]5-bromo-2-fluoropyrimidine</strong> (742 mg, 4.2 mmol) and tert- butyl (2-(2-methoxyethoxy)thiazol-5-yl)carbamate (765 mg, 2.8 mmol) in DMF (10 mL) was added K2C03 (800 mg, 5.8 mmol), and the mixture was stirred at 100 C for 4 h. The mixture was cooled to rt and purified by reverse phase chromatography (Welch Ultimate XB-C18, 40-70 muiotaeta), eluting with a gradient of 30-95% acetonitrile in water, to afford fer/-butyl (5- bromopyrimidin-2-yl)(2-(2-methoxyethoxy)thiazol-5-yl)carbamate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; for 2h;Inert atmosphere; | To a solution of <strong>[62802-38-4]5-bromo-2-fluoro-pyrimidine</strong> (1.0 g, 4.93 mmol) and 6,7- dihydro-5H-pyrrolo[l,2-a]imidazol-2-amine (0.87 g, 4.93 mmol) in DMSO (20 mL) was added DIEA (1.27 g, 9.86 mmol), and the mixture was stirred at 100 C for 2 h under 2 before it was allowed to cool to rt. The mixture was purified by reverse phase column chromatography (Welch Ultimate XB-C18, 40-70 muiotaeta) eluting with a gradient of 20-95% acetonitrile in water to afford N-(5-bromopyrimidin-2-yl)-6,7-dihydro-5H-pyrrolo[l,2- ]imidazol-2-amine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; for 2h;Inert atmosphere; | To a solution of <strong>[62802-38-4]5-bromo-2-fluoro-pyrimidine</strong> (1 12 mg, 0.64 mmol) and 2-(4- amino-l-methyl-lH-pyrazol-3-yl)-ethanol (90 mg, 0.64 mmol) in DMSO (lOmL) was added DIEA (165 mg, 1.28 mmol), and the mixture was stirred at 100 C for 2 h under N2. The mixture was allowed to cool to rt and was purified by reverse phase column chromatography (Welch Ultimate XB-C18, 40-70 mutaueta) eluting with a gradient of 20-95% acetonitnle in water to afford 2-[4-(5-bromo-pyrimidin-2-ylamino)-l-methyl-lH-pyrazol-3-yl]-ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 120℃; for 2h; | Step 3: A mixture of <strong>[64517-88-0]1,3-dimethyl-1H-pyrazol-4-amine</strong> (453 mg, 4.66 mmol), 5- bromo-2-fluoropyrimidine (750 mg, 4.24 mmol) and DWA (1.62 mL, 21.8 mmol) in DM50 (5 mE) was heated with at 120 C for 2 h. The resulting mixture was cooled to it and quenched with water. The yellow solid was collected via filtration, washed with water, and dried in vacuum oven to give 5-bromo-N-(1,3-dimethyl-1H-pyrazol-4-yl)pyrimidin-2-amine (1.08 g, 99%). LC-MS (ESI) m/z 268, 270 (M+Hjb. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 5-ethyl-4-nitro-1H-pyrazole (350 mg, 2.5 mmol) and 3,4- dihydro-2H-pyran (319 mg, 3.8 mmol) in DCM (20 mE) at 0 C was addedp-TsOH(43 mg, 0.25 mmol), and the mixture was stirred at 0 C for lh and then at rt overnight. DCM (100 mL) was added, and the mixture was washed with water and brine, dried over Na2 SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with petroleum ether/EtOAc (10:1 to 1:1) to afford a mixture of 3-ethyl-4-nitro-1- (tetrahydro-2H-pyran-2-yl)- 1JJ-pyrazole and 5 -ethyl-4-nitro- 1 -(tetrahydro-2H-pyran-2-yl)- 1H- pyrazole.; To a solution of 3-ethyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1JJ-pyrazole and5-ethyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1ff-pyrazole (557 mg, 2.5 mmol) in MeOH (20 mE) at 0C was added 10 % Pd/C (50 mg), and the mixture was stirred under H2 overnight at rt. DCM (20 mE) was added and the mixture was filtered through the Celite. The filtrate was concentrated under reduced pressure to afford a mixture of 3-ethyl-1-(tetrahydro-2H-pyran-2- yl)- 1H-pyrazol-4-amine and 5-ethyl-i -(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-4-amine, which was used in the next step without further purification; To a solution of 3-ethyl-1-(tetrahydro-2H-pyran-2-yl)-iH-pyrazol-4-amine, - ethyl-1-(tetrahydro-2J1-pyran-2-yl)-1H-pyrazol-4-amine (252 mg, 1.03 mmol) and 5-bromo-2- fluoro-pyrimidine (166 mg, 0.94 mmol) in DMSO (7 mL) was added DIEA (243 mg, 1.88 mmol), and the mixture was stirred at 100 C for 1.5 h. DCM (100 mE) was added, and the mixture was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with petroleum ether EtOAc (10:1 to 2:1) to afford a mixture of 5-bromo-N-(3 -ethyl-i -(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-4-yl)pyrimidin-2-amine and 5-bromo-N-(5-ethyl- i -(tetrahydro-2H-pyran-2-yl)- 1H- pyrazol-4-yl)pyrimidin-2-amine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; | A mixture of 5-bromo-2-fluoropyrimidine (239 mg, 1.35 mmol), tert-butyl thiazol-2-ylcarbamate (180 mg, 0.9 mmol) and K2C03 (621 mg, 4.5 mmol) in DMF (8 mL) was stirred at 100 C overnight. After cooling to it, the mixture was poured into cold water and extracted with EtOAc (2x 50 mL). The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with EtOH to afford tert-butyl (5-bromopyrimidin-2-yl)(thiazol-2- yl)carbamate as a solid (220 mg, 44% yield). H NMR (400 IVIHz, DMSO-d6) 3 9.22 (s, 2H), 7.60 (d, J 4.4 Hz, 1H), 7.03 (d, J 4.4 Hz, IH), 1.40 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 80℃; for 3h; | A mixture of 3-ethoxy-1-methyl-1H-pyrazol-5-amine (210 mg, 1.49 mmol), 5- bromo-2-fluoropyrimidine (270 mg, 1.53 rnmol), and DIEA (1.5 mL) in DMSO (5 mL) was stirred at 80 C for 3 h. The mixture was cooled to rt and purified by flash column chromatography (Welch Ultimate XB-C 18, 40-70 jim) eluting with a gradient of 15-95% acetonitrile in water to afford 5-bromo-N-(3-ethoxy- 1-methyl- 1H-pyrazol-5 -yl)pyrimidin-2- amine as a yellow solid (66 mg, 15 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 120℃; for 2h;Inert atmosphere; | To a solution of 5-bromo-2-fluoro-pyrimidinc (870 mg, 4.92 mmol) and 4- amino-1-methyl-1H-pyrazole-3-carbonitrile (600 mg, 4.92 mmol) in DMSO (20 mL) was added DIEA (1.3 g, 4.92 mmol), and the mixture was stirred at 120 C for 2 h under N2 After cooling to ii, the mixture was treated with water (10 mL) and extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by reverse phase chromatography (Welch Ultimate XB-C18, 40-70 jim) eluting with a gradient of 20-95% acetonitrile in water to afford 4-((5-bromopyrimidin-2-yl)amino)- 1-methyl-i H-pyrazole-3 -carbonitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In N,N-dimethyl-formamide; at 100℃; for 24h;Inert atmosphere; | Step 1 : tert- utyl 2-(3-acetyl-5-((5-fluoropyrimidin-2-yl)oxy)-lH-indoI-l-yl)acetate (218) [0704] A mixture of tert-hutyl 2-(3-acetyl-5-hydroxy-lH-indol-l-yl)acetate 70 ( 1 equiv), <strong>[62802-38-4]5-bromo-2-fluoropyrimidine</strong> (1 equiv), and CS2CO3 (2 equiv) in DMF (10 vol) was purged with argon in a pressure vessel for 5 min, then tris(dibenzylideneacetone) dipalladium(O) (0.01 equiv) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.01 equiv) were added under argon. The pressure vessel was sealed and heated at 100 C for 24 h. The reaction mixture was cooled to rt and the solvent was removed under reduced pressure. The residue was purified by coluran chromatography on silica gel (MeOH/DCM) to give compound 218. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 5h; | To a solution of <strong>[62802-38-4]5-bromo-2-fluoropyrimidine</strong> (S2, 1 equiv) in DMF/H2O (9:1, 10 vol) was added compound S1 (1 equiv), K2CO3(2 equiv), and tetrakis(triphenylphosphine)palladium (0.1 equiv). The reaction mixture was stirred at 90 C. for 5 h and then concentrated under reduced pressure. The remaining residue was purified by column chromatography on silica gel to give compound S3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20 - 60℃; for 3h;Inert atmosphere; | In -60 C, Ar under protection, NaH (60%, 130 mg, 5.4mmol) adding (S)-2 - nitro - 6, 7 - dihydro - 5H - imidazole [2,1 - the b] [1, 3] oxazine -6 - alcohol (500 mg, 2 . 7mmol) and 5 - bromo -2 - fluoro pyrimidine (570 mg, 3 . 2mmol) of DMF (5 ml) solution. The solution stirring at room temperature 3 hours, inverted water (50 ml) in. Filtering, solid dissolved in EtOAc, salt water washing, drying (Na2SO4). Evaporate the solvent to obtain the white solid product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With triethylamine; In 1-methyl-pyrrolidin-2-one; at 180℃; for 0.5h; | To <strong>[62802-38-4]5-bromo-2-fluoro-pyrimidine</strong> (1, 0.600 g, 3.39 mmol) in NMP (10 ml) was added pyrazolo[1,5-a]pyridin-3-amine dihydrochloride (42, 0.301 g, 1.46 mmol) and triethylamine (1 mL). The reaction mixture was allowed to stir at 180 C. for 30 minutes. The reaction mixture was diluted with water and saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. This provided 0.4 g (94% yield) of compound 43 as brownish viscous liquid that solidified after several days. MS ESI [M+H+]+=292.00. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.342 g | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 120℃; for 19h;Inert atmosphere; | To 1-methylpyrazol-4-amine (2, 2.43 g, 25.0 mmol), <strong>[62802-38-4]5-bromo-2-fluoro-pyrimidine</strong> (1, 5.31 g, 30.0 mmol) and N,N-diisopropylethylamine (9.69 g, 75.0 mmol) was added dimethyl sulfoxide (12.5 mL). The reaction flask was placed under nitrogen gas and allowed to stir at 120 C. for 19 hours. The brownish solution was diluted with water (200 mL) and extracted with ethyl acetate (5×100 mL). The combined organic layers were washed with water (2×100 mL) and 5 M sodium chloride (1×100 mL) and the aqueous layer back extracted with ethyl acetate (1×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the product triturated with diethyl ether (1×100 mL). The precipitate was collected by vacuum filtration and washed with diethyl ether (1×100 mL), giving 5.58 g of compound 3 as a yellow solid. MS ESI [M+H+]+=254.05. The brownish orange filtrate was evaporated and purified by silica gel flash column chromatography eluting with 0-10% methanol in dichloromethane. This provided an additional 762 mg of compound 3. MS ESI [M+H+]+=254.05. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate; In dimethyl sulfoxide; at 70℃; for 24h;Schlenk technique; | General procedure: 5-Bromo-2-fluoropyridine (0.5 mmol), an N-heterocyclic amine (1.0 mmol) and K2CO3 (1.0 mmol) were added to a 25-mL Schlenk tube, followed by addition of DMSO (2 mL). The reaction mixture was heated to 70 C for 24 h under air atmosphere. Then, the reaction mixture was added to brine (15 mL) and this mixture was extracted with CH2Cl2 (3 × 15 mL). The combined extracts were concentrated under reduced pressure and the product was isolated by flash chromatography on a silica gel (200-300 mesh) column. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate; In dimethyl sulfoxide; at 70℃; for 24h;Schlenk technique; | General procedure: 5-Bromo-2-fluoropyridine (0.5 mmol), an N-heterocyclic amine (1.0 mmol) and K2CO3 (1.0 mmol) were added to a 25-mL Schlenk tube, followed by addition of DMSO (2 mL). The reaction mixture was heated to 70 C for 24 h under air atmosphere. Then, the reaction mixture was added to brine (15 mL) and this mixture was extracted with CH2Cl2 (3 × 15 mL). The combined extracts were concentrated under reduced pressure and the product was isolated by flash chromatography on a silica gel (200-300 mesh) column. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium carbonate; In dimethyl sulfoxide; at 70℃; for 24h;Schlenk technique; | General procedure: 5-Bromo-2-fluoropyridine (0.5 mmol), an N-heterocyclic amine (1.0 mmol) and K2CO3 (1.0 mmol) were added to a 25-mL Schlenk tube, followed by addition of DMSO (2 mL). The reaction mixture was heated to 70 C for 24 h under air atmosphere. Then, the reaction mixture was added to brine (15 mL) and this mixture was extracted with CH2Cl2 (3 × 15 mL). The combined extracts were concentrated under reduced pressure and the product was isolated by flash chromatography on a silica gel (200-300 mesh) column. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With potassium carbonate; In dimethyl sulfoxide; at 70℃; for 24h;Schlenk technique; | General procedure: 5-Bromo-2-fluoropyridine (0.5 mmol), an N-heterocyclic amine (1.0 mmol) and K2CO3 (1.0 mmol) were added to a 25-mL Schlenk tube, followed by addition of DMSO (2 mL). The reaction mixture was heated to 70 C for 24 h under air atmosphere. Then, the reaction mixture was added to brine (15 mL) and this mixture was extracted with CH2Cl2 (3 × 15 mL). The combined extracts were concentrated under reduced pressure and the product was isolated by flash chromatography on a silica gel (200-300 mesh) column. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With potassium carbonate; at 140℃; for 2h;Sealed tube; Inert atmosphere; | (4aR6aR6bR8aS, llR, llaR, 11 bR, 13aR, 13bR)-4,4,6a,6b, 13b-pentamethyl-ll-(prop-len-2-y l)icosahydro-lH -cyclopenta[ 5, 6]naphtho [2, 1-f] isoquinoline-8a-carbaldehyde (90. 0mg, 0.211 mmol), <strong>[62802-38-4]5-bromo-2-fluoropyrimidine</strong> (374 mg, 2.114 mmol) and potassiumcarbonate (58.4 mg, 0.423 mmol) were added to small pressure vessel. The vessel was sealed and warmed to 140C for 2 hours. The resulted mixture was diluted withmethylene chloride, washed with water, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude material was purified by flashchromatography using a 0.1-3 % ethy 1 acetatehexanes gradient. After concentrating thefractions, the title product was isolated as a white solid (0.095g, 0.163 mmol, 77%). LCMS: m/e 582.4 and 584.4 (M+H)+, 3.82 min (method 8B) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.7 g | A mixture of ((lr,3r)-3-fluoro-l-(3-fluoropyridin-2-yl)cyclobutyl)methanamine (37.6 g, 190 mmol), <strong>[62802-38-4]5-bromo-2-fluoropyrimidine</strong> (32.0 g, 181 mmol), DIPEA (71 mL, 407 mmol), and NMP (200 mL) was stirred at rt overnight. The reaction mixture was then diluted with EtOAc (1500 mL) and washed with saturated sodium bicarbonate (500 mL). The organic layer was separated, dried over Na2S04, and concentrated. The resultant solid was dissolved in THF (600 mL), followed by the slow addition of DMAP (14 g, 90 mmol) and Boc20 (117.3 g, 542 mmol). The reaction was heated to 60 C. and stirred for 3 h. The reaction mixture was then concentrated and purified by silica gel chromatography (0273) (EtO Ac/hex) to give 59.7 g oft-butyl 5-bromopyrimidin-2-yl((trans-3-fluoro-l-(3- fluoropyridin-2-yl)cyclobutyl)methyl)carbamate as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; palladium diacetate; tricyclohexylphosphine; In toluene; at 100℃; for 10h; | To a solution of <strong>[62802-38-4]5-bromo-2-fluoro-pyrimidine</strong> (5 g, 28.25 mmol) and cyclopropylboronic acid (2.91 g, 33.90 mmol) in toluene (100 mL) was added K3PO4 (17.99 g, 84.76 mmol), PCy3 (916 muL, 2.83 mmol) and Pd(OAc)2 (317 mg, 1.41 mmol) and the resulting mixture was stirred at 100 C. for 10 h and then cooled to rt. The mixture was poured into H2O and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by normal phase silica gel chromatography to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 70℃; for 1h; | To a mixture of <strong>[62802-38-4]5-bromo-2-fluoro-pyrimidine</strong> (42 mg, 239 mumol) in 4:1 THF/ H2O (2 mL) was added (S)-2-amino-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid trifluoroacetate (100 mg, 217 mumol) and NaHCO3 (55 mg, 651 mumol) and the resulting mixture was stirred at 70 C. for 1 h and then allowed to cool to rt and then concentrated in vacuo. The crude residue was purified by reverse phase prep-HPLC to give the title compound. LCMS (ESI+): m/z=503.1 (M+H)+. 1H NMR (400 MHz, D2O): delta ppm 8.39 (s, 2H) 7.49 (d, J=7.34 Hz, 1H) 6.52 (br d, J=6.24 Hz, 1H) 4.52 (dd, J=8.93, 4.89 Hz, 1H) 3.23-3.53 (m, 6H) 2.58-2.90 (m, 5H) 2.40-2.54 (m, 1H) 2.23-2.39 (m, 1H) 1.57-1.96 (m, 6H) 0.84-1.05 (m, 4H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 70℃; for 1h; | To a mixture of (S)-2-amino-4-((2-phenoxyethyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid (100 mg, 234 mumol) in 4:1 THF/ H2O (2 mL) was added <strong>[62802-38-4]5-bromo-2-fluoropyrimidine</strong> (46 mg, 258 mol) and NaHCO3 (59 mg, 703 mumol) and the resulting mixture was stirred at 70 C. for 1 h and then allowed to cool to rt and then concentrated in vacuo. The crude residue was purified by reverse phase prep-HPLC to give the title compound. LCMS (ESI+): m/z=583.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) delta ppm 8.16 (s, 2H) 7.29 (d, J=7.45 Hz, 1H) 7.16-7.25 (m, 2H) 6.90 (t, J=7.24 Hz, 1H) 6.84 (d, J=7.89 Hz, 2H) 6.46 (d, J=7.45 Hz, 1H) 4.32 (t, J=6.14 Hz, 1H) 4.18 (t, J=5.26 Hz, 2H) 3.33-3.43 (m, 2H) 3.05-3.27 (m, 4H) 2.94 (br s, 2H) 2.59-2.75 (m, 4H) 2.05-2.27 (m, 2H) 1.69-1.93 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 70℃; for 1h; | (S)-2-amino-4-(((S)-2-fluoro-3-methoxypropyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid hydrochloride (100 mg, 231 mumol) in THF (1 mL) and H2O (0.25 mL) was added NaHCO3 (58 mg, 693 mumol) and <strong>[62802-38-4]5-bromo-2-fluoropyrimidine</strong> (49 mg, 277 mumol) and the resulting mixture was stirred at 70 C. for 1 h and then allowed to cool to rt. The mixture was adjusted to pH=6 by the addition of 1 M aq. HCl and then concentrated in vacuo. The crude residue was purified by reverse phase prep-HPLC to give the title compound. LCMS (ESI+): m/z=553.2 (M+H)+. 1H NMR (400 MHz, Methanol-d4) delta ppm 8.24 (s, 2H) 7.40 (d, J=7.50 Hz, 1H) 6.52 (d, J=7.28 Hz, 1H) 4.77 (br d, J=3.53 Hz, 1H) 4.36 (t, J=6.17 Hz, 1H) 3.58 (d, J=4.41 Hz, 1H) 3.52 (d, J=4.19 Hz, 1H) 3.35-3.44 (m, 2H) 3.33 (s, 3H) 2.83-2.95 (m, 4H) 2.66-2.76 (m, 6H) 2.05-2.18 (m, 2H) 1.84-1.91 (m, 3H) 1.75-1.83 (m, 1H) 1.61-1.71 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 70℃; for 1h; | To a mixture of (S)-2-amino-4-((2-(2,2-difluoroethoxy)ethyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid hydrochloride (150 mg, 333 mumol) in THF (1.6 mL) and H2O (0.4 mL) was added NaHCO3 (140 mg, 1.66 mmol) and then <strong>[62802-38-4]5-bromo-2-fluoropyrimidine</strong> (65 mg, 366 mumol) and the resulting mixture was heated to 70 C. for 1 h, cooled to rt, adjusted to pH=6 by the addition of 1 M aq. HCl, and then concentrated in vacuo. The crude residue was purified by prep-HPLC to give the title compound. LCMS (ESI+): m/z=571.1 (M+H)+. 1H NMR (400 MHz, Methanol-d4) delta ppm 8.41 (s, 2H) 7.60 (d, J=7.34 Hz, 1H) 6.64 (d, J=7.46 Hz, 1H) 5.80-6.22 (m, 1H) 4.64 (dd, J=8.62, 5.07 Hz, 1H) 3.95 (br t, J=4.65 Hz, 2H) 3.78 (td, J=14.67, 1.83 Hz, 2H) 3.47-3.55 (m, 4H) 3.32-3.46 (m, 3H) 3.25-3.30 (m, 1H) 2.75-2.86 (m, 4H) 2.41-2.52 (m, 1H) 2.21-2.34 (m, 1H) 1.96 (dt, J=11.77, 6.04 Hz, 2H) 1.80 (br d, J=2.81 Hz, 4H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With triethylamine; In ethanol; at 120℃; for 0.5h;Microwave irradiation; | A solution of 2-fluoro-5-bromo-pyrimidine (0.500 g, 2.8248 mmol, 1.0 eq), (R)- 3 fluoro- pyrrolidine hydrochloride (390 mg, 3.1073 mmol) and triethylamine (1.2 mL, 8.4745 mmol) in ethanol (5mL) was heated at 120C for 30 min under microwave irradiation. Then, the reaction mixture was cooled to room temperature. The reaction mixture was filtered, washed with cold ethanol and pentane, dried under reduced pressure to give the desired product (0.370 g, 53 %). 1H-NMR (500 MHz, DMSO-d6) d 8.4 (s, 2H), 5.49-5.37 (m, 1 H), 3.80-3.57 (m, 3H), 3.04 (q, 1 H), 2.10-2.30 (m, 2H). MS (ESI); m/z = 245.9 [M+Hf |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; diisopropylamine; at 40℃; for 16h;Sealed tube; Inert atmosphere; | In a sealed tube, <strong>[62802-38-4]5-bromo-2-fluoropyrimidine</strong> (175 mg, 0.989 mmol), bis(triphenyphosphine)pailadiura(H) chloride (17.35 mg, 0.025 mmol), copper(I) iodide (4.71 mg, 0.025 mmol) and diisopropylamine (1691 m, 11.87 mmol) were combined under nitrogen. Ethynyltrimethyl silane (151 m, 1.088 mmol) was then added and the reaction mixture was stirred at 40 C for 16 h. The reaction mixture was quenched with water and extracted with CH2CI2 (3 x 20 rnL). The combined organic layers were dried 9 1 over magnesium sulfate and concentrated under vacuum. The crude product was purified by column chromatography on silica gel (0% 30% ethyl acetate in hexanes; 40 g column) to afford 2-fluoro-5-((trimethylsilyl)ethynyl)pyrimidine (128 mg, 0.659 mmol, 67% yield). NMR (400 MHz, CHLOROFORM-d) 6 8.70 (d, .>=1 5 Hz, 21 1), 0.29 (s, 9H); LC/MS (ESI) m/e 195.0 [(M+H)+, calcd for C9H12FN2S1 195.1], fe = 1.89 min (Method 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With TEA In N,N-dimethyl-formamide at 85℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 80℃; for 14h; Inert atmosphere; | 20 3-(5-Fluoropyrimidin-2-yl)-2-methoxyaniline: In a round bottom flask, add 4-chloro-N-methyl-1-tolyl-1H-pyrrolo[2,3-b ]pyridine-5-carboxamide (1.08g), 3-(5-fluoropyrimidin-2-yl)-2-methoxyaniline (0.7g), tetrakistriphenylphosphine palladium (0.46g) and potassium carbonate ( 1.36 g) and then dioxane (10 mL) and water (2 mL) were added. The reaction system was heated to 80°C under argon protection for 14h. After the reaction, the solvent was evaporated to dryness under reduced pressure, and the resultant was dissolved in ethyl acetate. The organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated to dryness under reduced pressure to obtain the crude product. The crude product was purified by pressurized silica gel column chromatography to obtain pure product, |
[ 903131-29-3 ]
5-Bromo-2,4-difluoropyrimidine
Similarity: 0.81
[ 903131-29-3 ]
5-Bromo-2,4-difluoropyrimidine
Similarity: 0.81
[ 31402-54-7 ]
5-Bromo-N-methylpyrimidin-2-amine
Similarity: 0.68
[ 903131-29-3 ]
5-Bromo-2,4-difluoropyrimidine
Similarity: 0.81
[ 31402-54-7 ]
5-Bromo-N-methylpyrimidin-2-amine
Similarity: 0.68
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