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CAS No. : | 1196154-25-2 | MDL No. : | MFCD13190301 |
Formula : | C11H16BrN3O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | AHUXCBVCMJGTTD-UHFFFAOYSA-N |
M.W : | 302.17 | Pubchem ID : | 72212688 |
Synonyms : |
|
Num. heavy atoms : | 17 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.64 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 71.41 |
TPSA : | 47.36 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.18 cm/s |
Log Po/w (iLOGP) : | 2.84 |
Log Po/w (XLOGP3) : | 1.35 |
Log Po/w (WLOGP) : | 1.86 |
Log Po/w (MLOGP) : | 1.57 |
Log Po/w (SILICOS-IT) : | 1.04 |
Consensus Log Po/w : | 1.74 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.58 |
Solubility : | 0.788 mg/ml ; 0.00261 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.95 |
Solubility : | 3.42 mg/ml ; 0.0113 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.32 |
Solubility : | 1.46 mg/ml ; 0.00483 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.73 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-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 |
---|---|---|
86.1% | With N-Bromosuccinimide In dichloromethane at 20℃; for 2h; | 139 (e) A mixture of tert-butyl 6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate (223 mg, 1 mmol) and NBS (190 mg, 1.05 mmol) in DCM was stirred at r.t. for 2 h. The mixture was diluted with DCM followed by washing successively with water and brine. The organic layer was dried over sodium sulfate, concentrated in vacuum, and the residue was purified through flash chromatography on silica gel eluted with 40% ethyl acetate in hexane to give 260 mg of tert-butyl 3-bromo-6,7-dihydropyrazolo[l,5-a]pyrazine-5(4H)-carboxylate as a colorless oil, yield:86.1%. LC/MS: (ESI) [M+H]+= 303.4 |
With N-Bromosuccinimide In dichloromethane at 20℃; for 2h; | ||
450 mg | With N-Bromosuccinimide In dichloromethane at 20℃; | 392.4 Step 4: 3-Bromo-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester A solution of the title compound from Step 3 (400 mg, 1.8 mmol) and NBS (318 mg, 1.8 mmol) in DCM (200 mL) at room temperature was stirred overnight at room. The mixture was diluted with saturated NH4Cl aqueous solution (50 mL) and extracted with DCM (30 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (450 mg, 1.5 mmol) which was used without further purification in the next step. LCMS (M+H)+ 302. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 100℃; for 12h; Inert atmosphere; | tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (I-76) To a mixture of tert-butyl 3- bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (5.0 g, 16 mmol),bis(pinacolato)diboron (4.6 g, 18 mmol) and [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (1.4 g, 1.6 mmol) in 1,4-dioxane (20 mL, 200 mmol) was added potassium acetate (4.9 g, 50 mmol). The mixture was degassed for 15 min and stirred under N2for 12 hours at 100 °C. The reaction was cooled to room temperature and quenched with saturated NaHCO3aqueous solution, and then extracted with ethyl acetate. The organic phase was separated and combined, washed with brine, and dried over anhydrous Na2SO4. The dried organic solution was concentrated and the residue was chromatographed on silica gel with ethyl acetate / heptane ( 0 to 70%) to give tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (2.7 g; Yield: 42%).1H NMR (400 MHz, CHLOROFORM-d) d 7.75 (s, 1H), 4.75 - 4.87 (m, 2H), 4.12 - 4.22 (m, 2H), 3.82 - 3.95 (m, 2H), 1.50 (s, 9H), 1.22 - 1.31 (m, 16H); LC/MS: RT - 1.71 min, MS: (M+H)+: 350.2. |
40.82% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In N,N-dimethyl-formamide at 100℃; for 12h; Inert atmosphere; | 1.1 step 1:In {3-bromo-4H,6H,7H-pyrrole[1,5-a]piperazin-5-yl}carboxylic acid tert-butyl ester 1a (1.50g, 4.90mmol)Add Bis(pinacolato)diboron (1.49g, 5.80mmol) to the mixture of DMF (20.0mL),[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.36g, 0.4mmol) and potassium acetate (1.44g, 14.70mmol),Then the reaction solution was stirred at 100°C for 12 hours under a nitrogen atmosphere.LCMS monitored the completion of the reaction, cooled to room temperature, and added 50 mL of brine to the reaction mixture.Extract with ethyl acetate (100 mL),The extracted organic phase was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product obtained after passing through column chromatography (SiO2, petroleum ether: ethyl acetate = 1:9)After separation and purification, a yellow solid compound 1b (0.875 g, 40.82%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In acetonitrile at 300℃; | |
With hydrogenchloride In 1,4-dioxane; dichloromethane at 20℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.7% | Stage #1: 3-bromo-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester With hydrogenchloride In 1,4-dioxane; dichloromethane at 20℃; for 1h; Stage #2: formaldehyd With formic acid at 100℃; for 8h; | 13 Preparation of 3-bromo-5-methyl-4,5,6,7-tetrahydropvyrazolo[1,5-a]pyrazine HCl (4 M in dioxane; 3.31 mL, 13.24 mmol) was added in one portion to tert-butyl 3-bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (0.400 g, 1.32 mmol) in DCM (6 mL) at 20° C. The resulting mixture was stirred at 20° C. for 60 minutes. A white solid formed. The mixture was concentrated under reduced pressure, and the resulting residue was redissolved in formic acid (12.7 mL, 331 mmol) and treated with formaldehyde (0.64 mL, 8.6 mmol). This new mixture was heated at 100° C. for 8 h before being concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (25 mL) and then washed with saturated aqueous sodium hydrogencarbonate (2×25 mL); the combined aqueous layers were then extracted with EtOAc (2×25 mL). The combined organic layers were concentrated under reduced pressure, and the resulting crude residue was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 3-bromo-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.185 g, 64.7%) as a colourless oil. 1H NMR (400 MHz, CDCl3, 30° C.) 2.45 (3H, s), 2.75-2.85 (2H, m), 3.48 (2H, s), 4.05-4.15 (2H, m), 7.35 (1H, s). m/z: ES+[M+H]+ 218 (81Br isotope). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate In 1,4-dioxane; water at 100℃; Inert atmosphere; | 64.2 Step 2, feff-Butyl 3-(4-(2-(((benzyloxy)carbonyl)amino)ethyl)phenyl)-6,7-dihydropyrazolo [l,5-a]pyrazine-5(4fl)-carboxylate (1364) [00442] Into a 50-mL round-bottom flask was added tert-hutyl 3-bromo~4H,5H,6H H- pyrazoio[l,5-a]pyrazine-5-carboxyiate (0.300 g, 0.99 mmol), benzyl (4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenethyl)carbamate (0.380 g, 1.00 mmol), Pd (dppfJCh-C fcC (0.073 g, 0.10 mmol), CS2CO3 (0.972 g, 2.98 mmol), dioxane (5 mL), and water (0.5 mL). The reaction mixture was sparged with nitrogen and stirred overnight at 100 °C, and then cooled and concentrated in vacuo. The resulting crude product was purified by FCC eluting with ethyl acetate/petroleum ether (1 : 1) to afford fe/ -butyl 3-(4-(2-(((benzyloxy)carbonyl)amino)ethyl) (1365) 180 (1366) 144628010 vl phenyl)-6,7-dihydropyrazoio[l,5- ]pyrazine-5(4H)-carboxylate as a yellow oil (300 mg, 63%). LCMS (ESI, m/z): Ml [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
103 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In 1,4-dioxane; water at 110℃; for 4h; Inert atmosphere; | 392.5 Step 5: 3-(4-Ethoxy-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester A mixture of the title compound from Step 4 (210 mg, 0.70 mmol), 4-ethoxy-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (190 mg, 0.69 mmol), Pd(dppf)Cl2 (50 mg, 0.07 mmol) and Na2CO3 (288 mg, 2.7 mmol) in a dioxane/H2O mixture (15 mL/3 mL) under N2 was stirred at 110° C. for 4 hours. The mixture was cooled down to room temperature and extracted with DCM (30 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative-TLC eluting with DCM/MeOH (30:1) to afford the title compound (103 mg, 0.28 mmol). LCMS (M+H)+ 375. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; sodium acetate In water; acetonitrile at 90℃; for 1h; | 182.1 Step 1: tert-butyl 3-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate A mixture of [7-fluoro-8-(isopropoxycarbonylamino)-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]boronic acid (100 mg, 0.21 mmol), tert-butyl 3-bromo-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (120 mg, 0.40 mmol), potassium phosphate (40 mg, 0.19 mmol), sodium acetate (50 mg, 0.61 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (40 mg, 0.05 mmol) in acetonitrile (10 mL) and water (1 mL) was stirred at 90° C. for 1 hour. After filtration, the filtrate was concentrated under vacuum. The residue was purified by Prep-TLC with ethyl acetate/methanol (50/1) to afford tert-butyl 3-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(6-methyl-7-oxo-5,8-dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-2-yl)amino]-6-isoquinolyl]-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (43 mg, 0.065 mmol) as yellow solid. LCMS (ESI) [M+H]+=662. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.7% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; water; at 105℃; for 1h;Inert atmosphere; | (d) Ethyl 2-((3-bromoimidazo[l,2-a]pyridin-6-yl)(tert-butoxycarbonyl)amino)acetate (8 mg, 0.02 mmol) and <strong>[219735-99-6](2-chloro-4-methoxyphenyl)boronic acid</strong> (5.2 mg, 0.028 mmol) were dissolved in a mixture of DMF:H20 = 4: 1. To the mixture, PdCl2(dppf) DCM (2 mg) and K2C03(5.6 mg, 0.04 mmol) were added. The mixture was heated at 105 C for 1 h under N2. The solvent was removed under reduced pressure, and the residue was extracted with DCM. The organic layer was dried over sodium sulfate, concentrated in vacuum, and the residue was purified through flash chromatography on silica gel eluted with 80% ethyl acetate in hexane to give ethyl 2-((tert-butoxycarbonyl)(3-(2-chloro-4-methoxyphenyl)imidazo[l,2-a]pyridin-6- yl)amino)acetate 8 mg, yield: 87.0%. LC/MS: (ESI) [M+H]+= 460.8 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14.59% | Stage #1: 3-bromo-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid tert-butyl ester With n-butyllithium In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -78℃; for 2h; Inert atmosphere; | 1.1 Step 1: tert-Butyl 3-formyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate To a solution of tert-butyl 3-bromo-6,7-dihydro-4H-pyrazolo[1 ,5-a]pyrazine-5-carboxylate (3000 mg, 9.93 mmol) in THF (30 ml_) was added n-BuLi (2.5 M, 8.34 ml_) under N2 at -78 °C and stirred at -78 °C for 0.5 hr. DMF (798.27 mg, 10.92 mmol, 840.28 uL) was then added and the resulting mixture was stirred at -78 °C for another 2 hrs. The reaction mixture was quenched with water (200 ml_) and the products were extracted with EA (200 ml_ * 2). The combined organic layers were washed with brine (200 ml_), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, PE/EA=1 :1) to give the title compound (400 mg, 1.45 mmol, 14.59% yield) as a light yellow oil. LCMS (ESI) m/z: [M+H]+ = 252.2. 1H NMR (400 MHz, CDCI3) d = 9.88 (s, 1 H), 7.95 (s, 1 H), 4.92 (s, 2H), 4.23 (t, J = 5.2 Hz, 2H), 3.93 (t, J = 5.2 Hz, 2H), 1.51 (s, 9H) ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.51% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In 1,4-dioxane; water at 100℃; for 15h; | 2.1 Step 1: Add to the mixed solution of 1,4-dioxane/water = 10:1 (10mL) in a round bottom flask4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-7hydro-pyrrole[2,3-d]pyridine 2b (96.94mg, 0.397 mmol),3-bromo-6,7-dihydropyrazole[1,5-a]piperazine-5(4H)-carboxylic acid tert-butyl ester 2a (100mg, 0.331mmol),[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (24.21mg, 0.033mmol) and Na2CO3 (70.16mg, 0.662mmol),The resulting mixture was stirred at 100°C for 15 h.LCMS monitors the end of the reaction, cools to room temperature, adds 100 mL of brine to the reaction mixture,It was extracted with ethyl acetate (2X100 mL), and the extracted organic phase was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was passed through column chromatography(SiO2, petroleum ether: ethyl acetate = 1:1) separation and purification to obtain a white solid compound(4-{7H-pyrrole[2,3-d]pyrimidin-4-yl}-4H,6H,7H-pyrazole[1,5-a]piperazin-5-yl)tert-butyl carboxylate 2c (50mg, yield 44.51%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis-(triphenylphosphine)-palladium; Cs2CO3 In 1,4-dioxane; lithium hydroxide monohydrate at 80℃; for 2h; Inert atmosphere; | 11.A Step A Tetrakis(triphenylphosphine)palladium(0) (76.48 mg, 0.066 mmol, 0.08 equiv.) was added to a suspension of tert-butyl-3-bromo-6,7-dihydro-4H-pyrazolo[1 ,5-a]pyrazine- 5-carboxylate (250 mg, 0.827 mmol, 1 equiv.), (3-cyanophenyl)boronic acid (145.88 mg, 0.99 mmol, 1.2 equiv.) and cesium carbonate (808.7 mg, 2.48 mmol, 3 equiv.) in 9 mL 1 :2 water/dioxane. The reaction mixture was degassed and stirred at 80°C for 2 hours. Then it was diluted with EtOAc and filtrated over Celite. The organic phase was washed with water (twice), dried over Na2SO4, filtered and concentrated under reduced pressure. Crude was used for the next step without any purification. | |
With tetrakis-(triphenylphosphine)-palladium; Cs2CO3 In 1,4-dioxane; lithium hydroxide monohydrate at 80℃; for 2h; Inert atmosphere; | 11.A Step A Tetrakis(triphenylphosphine)palladium(0) (76.48 mg, 0.066 mmol, 0.08 equiv.) was added to a suspension of tert-butyl-3-bromo-6,7-dihydro-4H-pyrazolo[1 ,5-a]pyrazine- 5-carboxylate (250 mg, 0.827 mmol, 1 equiv.), (3-cyanophenyl)boronic acid (145.88 mg, 0.99 mmol, 1.2 equiv.) and cesium carbonate (808.7 mg, 2.48 mmol, 3 equiv.) in 9 mL 1 :2 water/dioxane. The reaction mixture was degassed and stirred at 80°C for 2 hours. Then it was diluted with EtOAc and filtrated over Celite. The organic phase was washed with water (twice), dried over Na2SO4, filtered and concentrated under reduced pressure. Crude was used for the next step without any purification. |
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