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CAS No. : | 186593-54-4 | MDL No. : | MFCD08061303 |
Formula : | C5H3BrFNO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | APZDTSYBPUWQHB-UHFFFAOYSA-N |
M.W : | 191.99 | Pubchem ID : | 18458777 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 33.92 |
TPSA : | 33.12 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.32 cm/s |
Log Po/w (iLOGP) : | 1.28 |
Log Po/w (XLOGP3) : | 1.62 |
Log Po/w (WLOGP) : | 2.11 |
Log Po/w (MLOGP) : | 1.02 |
Log Po/w (SILICOS-IT) : | 2.05 |
Consensus Log Po/w : | 1.62 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.54 |
Solubility : | 0.548 mg/ml ; 0.00286 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.93 |
Solubility : | 2.27 mg/ml ; 0.0118 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.58 |
Solubility : | 0.5 mg/ml ; 0.00261 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.84 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319 | 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 |
---|---|---|
54.c 5-bromo-6-fluoro-3-(3-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride was prepared in the following manner. 54c. 3-bromo-2-fluoro-5-hydroxypyridine was then prepared as follows. The compound from step 54b above (3.0 g 15.9 mmol) is dissolved in 50 ml of HF pyridine (Aldrich) and cooled to 0° C. under nitrogen and sodium nitrite (1.09 g 15.8 mmol) is added in portions over 20 minutes. The reaction is heated to 50° C. for one hour, cooled to 0° C. and then basified with 20% sodium hydroxide. The aqueous phase is washed with methylene chloride (5*100 ml), neutralized with HCl (pH=7), and extracted with ethyl acetate (5*100 ml). These extracts are dried (MgSO4), filtered, and concentrated in vacuo to yield the title compound as a tan solid. MS (DCI/NH3) m/e 192-194 (M+H)+. 1H-NMR (DMSO-d6, 300 MHz) δ9.38 (d, J=2.6 Hz, 1H), 9.20-9.19 (d, J=2.6 Hz, 1H). | ||
106.c 106c. 106c. 3-bromo-2-fluoro-5-hydroxypyridine The compound from step 106b above (3.0 g 15.9 mmol) was dissolved in 50 ml of HF pyridine (Aldrich) and cooled to 0° C. under nitrogen and sodium nitrite (1.09 g 15.8 mmol) was added in portions over 20 min. The reaction was heated to 50° C. for one hour, cooled to 0° C. and then basified with 20% sodium hydroxide. The aqueous phase was washed with CH2 Cl2 (5*100 ml), neutralized with HCl (pH=7), and extracted with EtOAc (5*100 ml). These extracts were dried (MgSO4), filtered, and concentrated in vacuo yielding the title compound as a tan solid. MS (CI/NH3) m/e 192/194 (M+H)+. 1 H NMR (DMSO-d6, 300 MHz) δ9.38 (d, J=2.6 Hz, 1H), 9.20-9.19 (d, J=2.6 Hz, 1H). | ||
106.c 106c. 106c. 3-bromo-2-fluoro-5-hydroxypyridine The compound from step 106b above (3.0 g 15.9 mmol) was dissolved in 50 ml of HF pyridine (Aldrich) and cooled to 0° C. under nitrogen and sodium nitrite (1.09 g 15.8 mmol) was added in portions over 20 min. The reaction was heated to 50° C. for one hour, cooled to 0° C. and then basified with 20% sodium hydroxide. The aqueous phase was washed with methylene chloride (5*100 ml), neutralized with HCl (pH=7), and extracted with ethyl acetate (5*100 ml). These extracts were dried (MgSO4), filtered, and concentrated in vacuo yielding the title compound as a tan solid. MS (DCI/NH3) m/e 192-194 (M+H)+. 1 H NMR (DMSO-d6, 300 MHz) δ: 9.38 (d, J=2.6 Hz, 1H), 9.20-9.19 (d, J=2.6 Hz, 1H). |
106.c 106c. 106c. 3-Bromo-2-fluoro-5-hydroxypyridine The compound from step 106b above (3.0 g 15.9 mmol) was dissolved in 50 ml of HF pyridine (Aldrich) and cooled to 0° C. under nitrogen and sodium nitrite (1.09 g 15.8 mmol) was added in portions over 20 min. The reaction was heated to 50° C. for one hour, cooled to 0° C. and then basified with 20% sodium hydroxide. The aqueous phase was washed with CH2Cl2 (5*100 ml), neutralized with HCl (pH=7), and extracted with EtOAc (5*100 ml). These extracts were dried (MgSO4), filtered, and concentrated in vacuo yielding the title compound as a tan solid. MS (CI/NH3) m/e 192/194 (M+H)+. 1H NMR (DMSO-d6, 300 MHz) δ: 9.38 (d, J=2.6 Hz, 1H), 9.20-9.19 (d, J=2.6 Hz, 1H). | ||
31.d 31d. 31d. 3-Bromo-2-fluoro-5-hydroxypyridine The compound from 31c (3.0 g, 15.9 mmol) was dissolved in HF.pyridine (50 mL). The solution was cooled to 0° C. and stirred under nitrogen, then sodium nitrite (1.09 g, 15.8 mmol) was added in portions over 20 minutes. The mixture was heated to 50° C. for 1 hour, cooled to 0° C. and basified with 20% aqueous NaOH. The aqueous phase was washed with methylene chloride (5*100 mL), neutralized with HCl, and extracted with ethyl acetate (5*100 mL). The organic extracts were dried (MgSO4), filtered and concentrated in vacuo, yielding the title compound as a tan solid: MS (CI/NH3) m/z 192, 194 (M+H)+. 1 H NMR (DMSO-d6, 300 MHz) δ 9.38 (d, J=2.6 Hz, 1H), 9.20 (d, J=2.6 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate In butanone for 20h; Reflux; | 4 Preparation 4tert-Butyl(1-[(5-bromo-6-fluoropyridin-3-yl)oxy]methyl}cyclopropyl)methylcarbamate12.9 g of caesium carbonate are added to a solution of 10.5 g of the compound obtained in Step 4 of Preparation 1 and 5.8 g of 5-bromo-6-fluororopyridin-3-ol in 300 ml of butanone. The reaction mixture is heated for 20 hours at reflux and then filtered and concentrated. The residue is taken up in dichloromethane. After washing with saturated sodium chloride solution and drying over sodium sulphate, the organic phase is concentrated. Chromatography on silica gel (dichloromethane/butanone: 98/2) allows 10.7 g of the expected product to be obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: sulfuric acid; potassium nitrate / 16 h / 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 2.2: 16 h / 0 - 20 °C 3.1: iron; acetic acid / 2 h / 20 °C 4.1: dmap / 12 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: sulfuric acid; potassium nitrate / 16 h / 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 2.2: 16 h / 0 - 20 °C 3.1: iron; acetic acid / 2 h / 20 °C 4.1: potassium fluoride; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; dimethyl sulfoxide / 16 h / 120 °C / Inert atmosphere 5.1: dmap / 16 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With sulfuric acid; potassium nitrate at 20℃; for 16h; | A.31.1 Step 1- Synthesis of 5-bromo-6-fluoro-2-nitro-pyridin-3-ol X-31 a To a solution of H2S04 (15 ml) was added KN03 (0.63 g, 6.28 mmol) and the reactionmixture was stirred at room temperature for 20 min. 5-bromo-6-fluoro-pyridin-3-ol (0.60 g,3.14 mmol) was added and the reaction mixture was stirred at room temperature for 16h.Progress of reaction was monitored by TLC. After completion, the reaction mixture was25 poured into ice (1 00 ml) and extracted with EtOAc (3 x 80 ml). The organic layer wasseparated, washed with brine (120 ml), dried over anhydrous Na2S04 and concentratedunder vacuum to afford 5-bromo-6-fluoro-2-nitro-pyridin-3-ol X-31a (0.60 g) as an off-whitesolid.Yield: 56%1H NMR (400 MHz, DMSO-d6) o 8.11 (d, J=7.2 Hz, 1 H) 11.83 (brs, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sulfuric acid; potassium nitrate / 16 h / 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 2.2: 16 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: sulfuric acid; potassium nitrate / 16 h / 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 2.2: 16 h / 0 - 20 °C 3.1: iron; acetic acid / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: sulfuric acid; potassium nitrate / 16 h / 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 2.2: 16 h / 0 - 20 °C 3.1: iron; acetic acid / 2 h / 20 °C 4.1: potassium fluoride; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; dimethyl sulfoxide / 16 h / 120 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.3% | With triphenylphosphine; In tetrahydrofuran; | 31a. 5-((2S)-azetidinylmethoxy)-3-bromo-2-fluoropyridine dibenzoate To a solution of diethyl azodicarboxylate (0.7 mL, 4.4 mmol) in THF (25 mL) was added triphenylphosphine (1.19 g, 4.4 mmol) at 0 C., and the reaction mixture was stirred for 0.5 hour. 1-t-Butyloxycarbonyl-(2S)-azetidinemethanol (0.85 g, 4.5 mmol, Example 7c) and 5-bromo-6-fluoropyridin-3-ol (0.75 g, 4.0 mmol, Step 31d) were then added. The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The solvent was removed, and the residue was chromatographed (silica gel, hexane/ethyl acetate, 5:1) to afford 5-bromo-6-fluoro-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (1.02 g, 72.3%): MS (CI/NH3) m/z 362, 379 (M+H)+, (M+NH4+); 1 H NMR (CDCl3 300 MHz) δ 7.82 (m, 1H), 7.60 (dd, J=3.1, 7.1 Hz 1H), 4.51 (m, 1H), 4.35 (m, 1H), 4.11 (dd, J=3.1, 10.2 Hz, 1H), 3.88 (m, 2H), 2.33 (m, 2H), 1.45 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 4h; | A.A.4.1 Step-1 : Synthesis of 3-bromo-2-fluoro-5-methoxy-pyridine X-4a: To a solution of 5-bromo-6-fluoro-pyridin-3-ol (0.80 g, 4.17 mmol) and NaH (0.33 g, 8.33 mmol) in DMF (15 mL) was added CH3I (0.31 mL, 5.00 mmol) drop wise at 0 °C. The reaction mixture was stirred at room temperature for 4h. Progress of reaction was monitored by TLC and LCMS. After completion, the reaction mixture was poured into cold H20 (20 mL) and extracted with EtOAc (2 c 30 mL). The organic layer was separated, washed with brine (20 mL), dried over anhydrous Na2S04 and concentrated under vacuum. The crude obtained was purified by combi-flash column chromatography (30% EtOAc in hexane) to afford 3-bromo-2-fluoro-5-methoxy-pyridine X-4a (0.80 g) as a pale yellow solid. Yield: 93%. (0762) Basic LCMS Method 2 (ES+): 206 (M+H)+, 99% purity. (0763) 1H NMR (400 MHz, DMSO-cfe) d 3.85 (s, 3H), 7.92 (t, J=2.20 Hz, 1 H), 7.99 (dd, J=7.34, 2.20 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 4 h / 0 - 20 °C 2.1: urea hydrogen peroxide / dichloromethane / 0.17 h / 0 °C 2.2: 16 h / 0 - 20 °C 3.1: trichlorophosphate / dichloromethane; N,N-dimethyl-formamide / 16 h / 0 - 20 °C 4.1: caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 0.33 h / Inert atmosphere 4.2: 16 h / 100 °C / Inert atmosphere 5.1: hydrogenchloride / methanol / 3 h / 0 - 20 °C 6.1: dmap; pyridine / 16 h / 90 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 4 h / 0 - 20 °C 2.1: urea hydrogen peroxide / dichloromethane / 0.17 h / 0 °C 2.2: 16 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 4 h / 0 - 20 °C 2.1: urea hydrogen peroxide / dichloromethane / 0.17 h / 0 °C 2.2: 16 h / 0 - 20 °C 3.1: trichlorophosphate / dichloromethane; N,N-dimethyl-formamide / 16 h / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 4 h / 0 - 20 °C 2.1: urea hydrogen peroxide / dichloromethane / 0.17 h / 0 °C 2.2: 16 h / 0 - 20 °C 3.1: trichlorophosphate / dichloromethane; N,N-dimethyl-formamide / 16 h / 0 - 20 °C 4.1: caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 0.33 h / Inert atmosphere 4.2: 16 h / 100 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 4 h / 0 - 20 °C 2.1: urea hydrogen peroxide / dichloromethane / 0.17 h / 0 °C 2.2: 16 h / 0 - 20 °C 3.1: trichlorophosphate / dichloromethane; N,N-dimethyl-formamide / 16 h / 0 - 20 °C 4.1: caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 0.33 h / Inert atmosphere 4.2: 16 h / 100 °C / Inert atmosphere 5.1: hydrogenchloride / methanol / 3 h / 0 - 20 °C |
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