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CAS No. : | 70951-85-8 | MDL No. : | MFCD13195703 |
Formula : | C7H11BrN2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KLLXOOSSATXFFY-UHFFFAOYSA-N |
M.W : | 203.08 | Pubchem ID : | 53216898 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.57 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 45.49 |
TPSA : | 17.82 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) : | -6.25 cm/s |
Log Po/w (iLOGP) : | 2.3 |
Log Po/w (XLOGP3) : | 1.81 |
Log Po/w (WLOGP) : | 2.4 |
Log Po/w (MLOGP) : | 1.84 |
Log Po/w (SILICOS-IT) : | 1.6 |
Consensus Log Po/w : | 1.99 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.54 |
Solubility : | 0.581 mg/ml ; 0.00286 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.8 |
Solubility : | 3.19 mg/ml ; 0.0157 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.48 |
Solubility : | 0.676 mg/ml ; 0.00333 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.62 |
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 |
---|---|---|
67% | With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h; | To a -78 0C solution of 4-bromo-l -7-butyI-lH-pyrazole (15 g, 74.3 mmol) in anhydrous THF (100 mL) was added /7-BuLi (2.5 M in hexane, 53 mL, 132 mmol) under N2, and the resulting mixture was stirred at -78°C for 30 min. Excess dry ice was added at -78 0C, and the mixture was warmed slowly to RT and stirred overnight. The reaction was concentrated in vacuo, water was added and the pH was adjusted to pH 3 by the addition of 2N aq HCI. The aqueous solution was extracted with EtOAc. The extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was recrystallized (EtO Ac-pet, ether) to give 1 -/-butyl- lH-pyrazole-4-carboxylic acid (8.0 g, 67 percent yield). 1H NMR (300 MHz, CDCl3): ^ 8.10 (s, 1 H), 8.03 (s, 1 H), 1.64 (s, 9 H); MS (ESI) m/z: 168.9 [M+Hf. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.4% | With N-Bromosuccinimide In dichloromethane at 0 - 20℃; Industry scale | To an ice cooled solution (0°C to 10°C) of 1 -(tert-butyl)pyrazole (1.75kg, 14.09mol) in dichloromethane (12.9kg) was added NBS (2.63kg ,14.79mol) portionwise. The solution was stirred at 0°C until the content of 1-(ie f-butyl)pyrazole <30percent (GC), then warmed to RT and stirred until the sample taken shows <1.0percent by GC. On receipt of a pass result, 10percent sodium bisulfite aqueous was added to the reaction mixture until Kl-starch did not turn to blue. The organic phase was then washed with 5percent NaCI solution and brine in sequence, then evaporated to give the title compound as a brown liquid (2.67kg, 93.4percentyield; GC purity 99.1 percenta/a). |
85% | With bromine; sodium carbonate In dichloromethane at 20℃; | To a suspension OfNa2CO3 (36 g, 339 mmol) in CH2Cl2 (300 mL) was added l-t- butyl-lH-pyrazoIe from Example B19 (21 g, 170 mmol) and Br2 (9 mL), and the resulting mixture was stirred at RT overnight. The solid was removed by Filtration and the filter cake was washed with CH2Cl2. The filtrates were washed with water and brine, dried (MgSO4), and concentrated to give crude 4-bromo-l- λ-butyl-lH-pyrazole (29 g, 85percent), used without further purification. 1H NMR (300 MHz, CDC13): δ 7.49 (s, 1 H), 7.45 (s, 1 H), 1.53 (s, 9 H); MS (ESI) m/z: 203 [M+H]+. |
85% | With sodium carbonate decahydrate; bromine In dichloromethane at 20℃; | To a suspension of Na2CO3 (3.6 g, 33.9 mmol) in CH2Cl2 (30 mL) was added 1-tert-butyl-1H-pyrazole (2.1 g, 17 mmol) and Br2 (0.9 mL). The mixture was stirred at roomtemperature overnight. The formed solid was removed by filtration and the filter cake waswashed with CH2Cl2 (30 mL). The filtrates were washed with water (20 mL) and brine (20 mL), dried (MgSO4), and concentrated under reduced pressure to afford crude 4-bromo-1-tert-butyl-1H-pyrazole (2.9 g, 85percent), which was used in next step without further purification. MS (ESI)m/z: 203 [M+H]+. |
7.402 g | With N-Bromosuccinimide In dichloromethane at 20℃; for 18 h; | Intermediate 10: 4-Bromo-1-(1,1-dimethylethyl)-1H-pyrazole[0393]1-(1,1-dimethylethyl)-1H-pyrazole (6.1 g, 49.1 mmol) in dichloromethane (DCM) (200 ml) was added N-bromosuccinimde (8.74 g, 49.1 mmol). This was warmed to ambient temperature and stirred for 18 h. There was no starting material present and so the reaction mixture was quenched with aqueous sodium thiosulfate. The organics were washed with water (2×500 ml) and passed through a hydrophobic frit. The filtrate was concentrated in vacuo to yield an orange-brown oil which turned purple on standing (7.402 g).[0395]LCMS (Method B): Rt=1.03 min, MH+=203, 205 |
34 g | With N-Bromosuccinimide In dichloromethane at 0 - 10℃; for 0.5 h; | To a mixture of 21.9 g of 1-tert-butyl-pyrazole in 150 mL DOM was added 31.5 g Nbromosuccinimide in portions between 0 and 10 00 The resulting mixture was stirred for 30 mm. The reaction mixture was allowed to reach ambient temperature. The precipitate was filtered off and washed with DOM. The combined organic extracts were washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuo to yield 34.0 g of 4-bromo-1-tert-butyl-pyrazole as oil.Analysis: HPLC-MS: R1 = 1 .35 mm (method B), M+H = 203 I 205 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.5% | Stage #1: With n-butyllithium In tetrahydrofuran at -85 - -75℃; for 1 h; Industry scale Stage #2: for 3 h; |
To a 20L four-neck bottle, 4-bromo-(tert-butyl)pyrazole (1.15kg, 5.66mol) and THF (9.2L) were added, then the mixture was cooled to between -78°C and -85°C and treated with nBuLi (6.23mol) dropwise at that temperature. After addition the solution was stirred at the same temperature for 1 h and /sopropyl pinacol borate (1.47kg, 7.92mol) was added dropwise. The reaction was complete after stirring for ~3h (starting material <1.0percenta/a by GC) then water (2.3L) was added to quench the reaction; and the pH adjusted to 8-9 by addition of 3.45kg 1 M HCI. The aqueous phase was extracted with TBME (3.45L x 2), and the combined organic phase washed with 5percent NaCI (3.45L x 2) and water (3.45L) in sequence. The organic phase was evaporated to give the crude product. After subsequent recrystallization from heptanes the pure product was obtained as a white solid (GC purity 99.7percenta/a) in a 63.5percentth overall yield. (Two 20L reactions were run, then combined in the heptane recrystallization). |
63.5% | Stage #1: With n-butyllithium In tetrahydrofuran at -85 - -78℃; Large scale Stage #2: for 0.3 h; Large scale |
Stage d) Preparation of 1-(1,1-Dimethylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Intermediate 11) To a 20 L four-neck bottle, 4-bromo-(tert-butyl)pyrazole (1.15 kg, 5.66 mol) and THF (9.2 L) were added, then the mixture was cooled to between -78° C. and -85° C. and treated with nBuLi (6.23 mol) dropwise at that temperature. After addition the solution was stirred at the same temperature for 1 h and isopropyl pinacol borate (1.47 kg, 7.92 mol) was added dropwise. The reaction was complete after stirring for ˜3 h (starting material<1.0percent a/a by GC) then water (2.3 L) was added to quench the reaction; and the pH adjusted to 8-9 by addition of 3.45 kg 1M HCl. The aqueous phase was extracted with TBME (3.45 L*2), and the combined organic phase washed with 5percent NaCl (3.45 L*2) and water (3.45 L) in sequence. The organic phase was evaporated to give the crude product. After subsequent recrystallization from heptanes the pure product was obtained as a white solid (GC purity 99.7percent a/a) in a 63.5percent th overall yield. (Two 20 L reactions were run, then combined in the heptane recrystallization). |
44.26 g | Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -60℃; for 0.0833333 h; Inert atmosphere Stage #2: at -60 - 20℃; |
Synthesis of 1 -tert-Butyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazole 4.19 To a stirred mixture of 50 g of 4-bromo-1 -tert-butyl-pyrazole 3J. in 230 mL THF was added dropwise 100 mL 2.5M N-butyllithium solution in hexane under argon atmosphere below - 60 °C, then the mixture was stirred at this temperature for 5 min, before 52 mL 2-isopropoxy- 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane were added dropwise below -60 °C. The reaction mixture was allowed to reach ambient temperature. The mixture was cooled with an ice bath and diluted with aqueous phosphate buffer solution and water and neutralized with 2M aqueous hydrochloric acid. The organic solvent was removed by destination and the residue was extracted with DCM. The combined organic extracts were washed with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield 44.26 g of 1 -tert-butyl-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazole as solid.Analysis: HPLC-MS: Rt = 0.904 min (method F), M+H = 251 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 100℃; for 8 h; Inert atmosphere | To a solution of 4-bromo-1-tert-butyl-1H-pyrazole (2.40 g, 9.836 mmol) and bis(pinacolato)diboron (1 .64 g, 7.995 mmol) in dioxane (30 mL) was added potassium acetate (2.54 g, 29.5 mmol) at room temperature. Nitrogen gas was bubbled through the mixture for 5 mins and 1,1 '-bis(diphenylphosphino)-ferrocenepalladium(ll) chloride (125 mg, 0.153 mmol) was then added. The mixture was heated at 100 ° C for 8 hours. The reaction mixture was diluted with EtOAc (50 mL), filtered over Celite and washed with EtOAc (50 mL). The filtrate was concentrated at reduced pressure and the residue was purified by Biotage Isolera™ chromatography [SNAP Cartridge KP-Sil 100 g; eluting with a gradient of eluents; 0-100percent EtOAc in heptane] giving the title product (0.65 g, 29percent yield) as white solid. 1H NMR (500 MHz, chloroform-d) δ [ppm] 7.78 (d, J = 0.6 Hz, 1 H), 7.76 (s, 1 H), 1 .53 (s, 9H), 1 .26 (s, 12H). LCMS (Analytical Method A): Rt = 1 .18 mins; MS (ESIPos) m/z = 251 .05 (M+H)\ |
25% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane for 15 h; Reflux | A mixture of 4-bromo-1-tert-butyl-1H-pyrazole (3.3 g, 16.3 mmol), bis(pinacolato)diboron (8.3 g, 32.6 mmol), PdCl2(dppf) (1.8 g, 2.4 mmol), and KOAc (3.2 g, 32.6 mmol) in 1,4-dioxane (60 mL) was heated at reflux for 15 hours. After the completion of the reaction, the mixture was filtered and the filter cake was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using heptane/ethyl acetate (10percent to 50percent) as eluting solvents to afford 1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as white solid (1.0 g, 25percent). MS (ESI) m/z: 251 [M+H]+. |
1.68 g | With tris-(dibenzylideneacetone)dipalladium(0); potassium acetate; XPhos In 1,4-dioxane at 110℃; for 1.5 h; Inert atmosphere; Microwave irradiation | Intermediate 11: 1-(1,1-Dimethylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole[0396]4-bromo-1-(1,1-dimethylethyl)-1H-pyrazole (2.4 g, 11.82 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (3.00 g, 11.82 mmol), potassium acetate (2.90 g, 29.5 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.108 g, 0.118 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.225 g, 0.473 mmol) in 1,4-dioxane (30 ml) was degassed with nitrogen. The reaction mixture was spilt into 2 microwave vials and heated at 110° C. in a microwave for 1.5 h. There was no starting material remaining so the reactions were filtered through a bond elut reservoir and the residue was washed with ethyl acetate. The filtrate was concentrated in vacuo to yield the crude product. This was dissolved in DCM and purified through silica (50 g) eluting with 0-50percent ethyl acetate in DCM gradient. Appropriate fractions were combined and concentrated in vacuo to yield the title compound as a beige solid (1.68 g).[0398]LCMS (Method B): Rt=1.08 min, MH+=250.8 |
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