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CAS No. : | 433939-27-6 | MDL No. : | MFCD07783710 |
Formula : | C6H4BrFO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JCPJGUPQZDEZQH-UHFFFAOYSA-N |
M.W : | 191.00 | Pubchem ID : | 21904636 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 36.12 |
TPSA : | 20.23 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) : | -5.79 cm/s |
Log Po/w (iLOGP) : | 1.72 |
Log Po/w (XLOGP3) : | 2.36 |
Log Po/w (WLOGP) : | 2.71 |
Log Po/w (MLOGP) : | 2.67 |
Log Po/w (SILICOS-IT) : | 2.48 |
Consensus Log Po/w : | 2.39 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.0 |
Solubility : | 0.189 mg/ml ; 0.00099 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.43 |
Solubility : | 0.718 mg/ml ; 0.00376 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.96 |
Solubility : | 0.211 mg/ml ; 0.00111 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.42 |
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 |
---|---|---|
94% | Stage #1: With 2-(methylsulfonyl)ethyl alcohol; potassium <i>tert</i>-butylate In dimethyl sulfoxide at 0 - 20℃; for 3 h; Stage #2: With hydrogenchloride In water; dimethyl sulfoxide Stage #3: With sodium hydroxide In diethyl ether; water |
To a solution of l-bromo-3,5-difluorobenzene (30.6 mL, 0.266 mole) and 2-(methylsulfonyl)ethanol (66 g, 0.531 mole) in DMSO (240 mL) was added potassium tert-butoxide (76.6 g, 0.682 mole) at 00C. The resulting mixture was stirred at room temperature for 3h and quench with 4N HCl slowly to pH < 1. The desired product was extracted with Et2O (12 L) until no product was detected in the aqueous layer. The Et2O was evaporated under reduced pressure to one third the amount of the <n="223"/>solvent and washed with IN NaOH (12 L). Then, the NaOH solution was adjusted to pH= 3 and extracted with Et2O until no desired product was detected in the aqueous layer. The Et2O was evaporated under reduced pressure and passed through an Al2O3 column eluted with Et2O to afford 3-bromo-5-fluorophenol as a colorless oil (48 g, 94percent yield). LC-MS 190.33 (M+H); Analytical HPLC = 2.26 minutes (0-100percent CH3CN in H2O witfi 0.1percent TFA in a 4-min run); 1H NMR (400 MHz, CD3OD) δ ppm 6.88 - 6.64 (m, 2H), 6.58 - 6.30 (m, 1 H), 4.99 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: With aluminum (III) chloride; <i>N</i>,<i>N</i>-dimethyl-aniline In dichloromethane at 0℃; for 2.16667 h; Stage #2: With hydrogenchloride In dichloromethane; water |
To a solution of 1-bromo-3-fluoro-5-benzyloxybenzene (110.0 g, 0.39 mol; see step (i) above) and N,N-dimethylaniline (474.0 g, 3.92 mol) in anhydrous CH2Cl2 (1.0 L) at 0° C. was added aluminium chloride (156.0 g, 1.17 mol). After 10 min, the ice bath was removed and the stirring was continued for 2 h. The reaction was quenched by the cautious addition of 3N HCl (600 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2*150 mL). The combined organic extracts were washed with 2N HCl (250 mL) and H2O (3*250 mL). To the organic layer was added 15percent KOH (500 mL), and the layers were separated. The organic layer was further extracted with 2 N KOH (2*70 mL). The combined aqueous layers were washed with CH2Cl2 (3*100 mL) and then acidified with 4N HCl. The aqueous layer was extracted with Et2O (3*125 mL) then, the combined Et2O extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the sub-title compound (69.0 g, 92percent) as a brown oil that was used without further purification. Mp: 33-35° C. Rf=0.25 (CHCl3) 1H NMR (300 MHz, DMSO-d6) δ10.38 (s, 1H), 6.90 (dd, JH-F=11 Hz, J=2 Hz, 1H), 6.81 (s, 1H), 6.59 (dt, JH-F=11 Hz, J=2 Hz, 1H). |
92% | With aluminum (III) chloride; <i>N</i>,<i>N</i>-dimethyl-aniline In dichloromethane at 0℃; for 2.16667 h; | To a solution of 1-bromo-3-fluoro-5-benzyloxybenzene (110.0 g, 0.39 mol; see step (i) above) and N, N-dimethylaniline (474.0 g, 3.92 mol) in anhydrous [CH2CI2] (1.0 L) at [0°C] was added aluminium chloride (156.0 g, 1.17 mol). After 10 min, the ice bath was removed and the stirring was continued for 2 h. The reaction was quenched by the cautious addition of 3N HC1 (600 mL). The layers were separated, and the aqueous layer was extracted with [CH2CI2] (2 x 150 mL). The combined organic extracts were washed with 2N HCI (250 mL) and [H2O] (3 x 250 mL). To the organic layer was added 15percent KOH (500 mL), and the layers were separated. The organic layer was further extracted with 2 N KOH (2 x 70 mL). The combined aqueous layers were washed with [CH2CI2] (3 x 100 [ML)] and then acidified with 4N HCI. The aqueous layer was extracted with [ET,] O [X 1 ? 5] mL) then, the combined Et20 extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the sub-title compound (69.0 g, 92percent) as a brown oil that was used without further purification. Mp: [33-35°C] Rf = 0.25 (CHC13) 'H NMR (300 MHz, DMSO-d6) 8 10.38 (s, 1H), 6.90 (dd, [JH-F] = [11 HZ, J] = 2 Hz, 1H), 6.81 (s, [1H),] 6.59 (dt, JH-F = 11 Hz, [J] = 2 Hz, [1H).] APCI-MS: (M-1) = 189 m/z |
66.6% | Stage #1: With aluminum (III) chloride; <i>N</i>,<i>N</i>-dimethyl-aniline In dichloromethane at 0 - 20℃; for 2.16667 h; Stage #2: With hydrogenchloride In dichloromethane; water |
3-bromo-5-fluoro-phenol Add aluminum chloride (13.51 g, 101.38 mmol) to 1-benzyloxy-3-bromo-5-fluoro-benzene (9.50 g, 33.79 mmol, prepared according to WO 03/101956) and dimethylaniline (40.96 g, 337.92 mmol) in dichloromethane (84 mL) at -0° C. under nitrogen and stir 10 minutes. Remove ice-bath and stir 2 hours. Add 60 mL 2N hydrochloric acid dropwise. Separate layers and wash the organic layer with 2N hydrochloric acid (4*50 mL). Extract the organic layer with 3N potassium hydroxide (4*50 mL). Acidify with 5N hydrochloric acid and extract with dichloromethane (3*50 mL). Dry the dichloromethane layer (sodium sulfate) and concentrate to give 4.3 g (66.6percent) of the desired compound as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: With boron tribromide In dichloromethane at -30 - 5℃; for 3 h; Stage #2: With water; sodium hydrogencarbonate In dichloromethane |
Step 2 3-Bromo-5-fluorophenol To a solution of 1-bromo-3-fluoro-5-methoxybenzene (3.0 g, 0.015 mol) in dry CH2Cl2 (80 mL) under an inert atmosphere and cooled to -30° C. was added 1 M BBr3 (4.27 mL, 0.045 mol) in 21 mL of CH2Cl2 dropwise while maintaining temperature at -30° C. The reaction was stirred for 3 h at 0-5° C. and then the reaction mixture was quenched with aqueous saturated NaHCO3. Water was added and the mixture was extracted with CH2CO2 three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to give the title compound (2.54 g, 91percent). |
85% | With boron tribromide In dichloromethane at -78 - 20℃; for 3 h; | To a stirred suspension of l-bromo-3-fluoro-5-methoxybenzene (5.0 g, 25 mmol) in DCM (50 mL) was added BBr3 (12.2 g, 50 mmol) at -78°C. The resulting mixture was stirred at -78°C to r.t for 3hrs, then the mixture was poured into ice-water and extracted with EtOAc. The organics was dried and concentrated to give 3-bromo- 5-fluorophenol (4 g, 85percent yield) as yellow oil. lH NMR: (CDC13 400MHz) δ 6.82- 6.80 (m, 2H), 6.53-6.51(m, 1H), 6.20-6.15(m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium hydroxide; In water; isopropyl alcohol; at 20 - 85℃; for 18h; | A mixture of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong>. (6.1 g, 31.0 mmol; see step (ii) above) and chlorodifluoromethane (13.0 g, 150.0 mmol) in i-PrOH (100 mL) and 30% KOH (80 mL) was heated in a sealed flask for 18 h at 80-85 C. The reaction mixture was cooled to room temperature and the layers were separated. The organic layer was concentrated in vacuo to afford a colourless oil. The aqueous layer was extracted with Et2O (3*30 mL). The crude oil and the combined organic extracts were washed with 2N NaOH (3*30 mL) and H2O (3*30 mL). The organics were then dried (Na2SO4), filtered through a small silica gel plug, and concentrated in vacuo to afford the sub-title compound (6.1 g, 79%) as a colourless oil that was used without further purification. 1H NMR (300 MHz, CDCl3) delta7.11-7.14 (m, 2H), 6.84 (dt, J=9 Hz, J=2 Hz, 1H), 6.50 (t, JH-F=72 Hz, 1H). |
79% | With potassium hydroxide; In water; isopropyl alcohol; at 80 - 85℃; for 18h; | A mixture of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (6.1 g, 31.0 mmol ; see step (ii) above) and chlorodifluoromethane (13.0 g, 150.0 mmol) in i-PrOH (100 mL) and 30% KOH (80 mL) was heated in a sealed flask for 18 h at [80-85C.] The reaction mixture was cooled to room temperature and the layers were separated. The organic layer was concentrated in vacuo to afford a colourless oil. The aqueous layer was extracted with Et20 (3 x 30 mL). The crude oil and the combined organic extracts were washed with 2N [NAOH] (3 x 30 mL) and H20 (3 x 30 mL). The organics were then dried [(NA2SO4),] filtered through a small silica gel plug, and concentrated in vacuo to afford the sub-title compound (6.1 g, 79%) as a colourless oil that was used without further purification. 'H NMR (300 MHz, [CDCI3)] [5] 7. 11-7. 14 (m, 2H), 6.84 (dt, [J] = 9 Hz, J = 2 Hz, [I H),] 6.50 (t, [JH-F = 72 HZ, 1 H).] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | To a solution of 1-bromo-3-fluoro-5-benzyloxybenzene (110.0 g, 0.39 mol; see step (i) above) and N,N-dimethylaniline (474.0 g, 3.92 mol) in anhydrous CH2Cl2 (1.0 L) at 0 C. was added aluminium chloride (156.0 g, 1.17 mol). After 10 min, the ice bath was removed and the stirring was continued for 2 h. The reaction was quenched by the cautious addition of 3N HCl (600 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2*150 mL). The combined organic extracts were washed with 2N HCl (250 mL) and H2O (3*250 mL). To the organic layer was added 15% KOH (500 mL), and the layers were separated. The organic layer was further extracted with 2 N KOH (2*70 mL). The combined aqueous layers were washed with CH2Cl2 (3*100 mL) and then acidified with 4N HCl. The aqueous layer was extracted with Et2O (3*125 mL) then, the combined Et2O extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the sub-title compound (69.0 g, 92%) as a brown oil that was used without further purification. Mp: 33-35 C. Rf=0.25 (CHCl3) 1H NMR (300 MHz, DMSO-d6) delta10.38 (s, 1H), 6.90 (dd, JH-F=11 Hz, J=2 Hz, 1H), 6.81 (s, 1H), 6.59 (dt, JH-F=11 Hz, J=2 Hz, 1H). | |
92% | With aluminum (III) chloride; N,N-dimethyl-aniline; In dichloromethane; at 0℃; for 2.16667h; | To a solution of 1-bromo-3-fluoro-5-benzyloxybenzene (110.0 g, 0.39 mol; see step (i) above) and N, N-dimethylaniline (474.0 g, 3.92 mol) in anhydrous [CH2CI2] (1.0 L) at [0C] was added aluminium chloride (156.0 g, 1.17 mol). After 10 min, the ice bath was removed and the stirring was continued for 2 h. The reaction was quenched by the cautious addition of 3N HC1 (600 mL). The layers were separated, and the aqueous layer was extracted with [CH2CI2] (2 x 150 mL). The combined organic extracts were washed with 2N HCI (250 mL) and [H2O] (3 x 250 mL). To the organic layer was added 15% KOH (500 mL), and the layers were separated. The organic layer was further extracted with 2 N KOH (2 x 70 mL). The combined aqueous layers were washed with [CH2CI2] (3 x 100 [ML)] and then acidified with 4N HCI. The aqueous layer was extracted with [ET,] O [X 1 ? 5] mL) then, the combined Et20 extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the sub-title compound (69.0 g, 92%) as a brown oil that was used without further purification. Mp: [33-35C] Rf = 0.25 (CHC13) 'H NMR (300 MHz, DMSO-d6) 8 10.38 (s, 1H), 6.90 (dd, [JH-F] = [11 HZ, J] = 2 Hz, 1H), 6.81 (s, [1H),] 6.59 (dt, JH-F = 11 Hz, [J] = 2 Hz, [1H).] APCI-MS: (M-1) = 189 m/z |
66.6% | 3-bromo-5-fluoro-phenol Add aluminum chloride (13.51 g, 101.38 mmol) to 1-benzyloxy-3-bromo-5-fluoro-benzene (9.50 g, 33.79 mmol, prepared according to WO 03/101956) and dimethylaniline (40.96 g, 337.92 mmol) in dichloromethane (84 mL) at -0 C. under nitrogen and stir 10 minutes. Remove ice-bath and stir 2 hours. Add 60 mL 2N hydrochloric acid dropwise. Separate layers and wash the organic layer with 2N hydrochloric acid (4*50 mL). Extract the organic layer with 3N potassium hydroxide (4*50 mL). Acidify with 5N hydrochloric acid and extract with dichloromethane (3*50 mL). Dry the dichloromethane layer (sodium sulfate) and concentrate to give 4.3 g (66.6%) of the desired compound as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoromethanesulfonic acid anhydride; | Step 1: 5-fluoro-3-hydroxymethylbromobenzene. The desired compound was prepared by reaction of 5-fluoro-3-hydroxybromobenzene with trifluoromethanesulfonic anhydride andpyridine, followed by reaction of the resulting triflate with 1,1-bis(diphenylphosphino)ferrocene, Pd(II)acetate, and CO as described inU.S. Pat. No. 5,227,399, Example 2, steps 1 and 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | To a solution of l-bromo-3,5-difluorobenzene (30.6 mL, 0.266 mole) and 2-(methylsulfonyl)ethanol (66 g, 0.531 mole) in DMSO (240 mL) was added potassium tert-butoxide (76.6 g, 0.682 mole) at 00C. The resulting mixture was stirred at room temperature for 3h and quench with 4N HCl slowly to pH < 1. The desired product was extracted with Et2O (12 L) until no product was detected in the aqueous layer. The Et2O was evaporated under reduced pressure to one third the amount of the <n="223"/>solvent and washed with IN NaOH (12 L). Then, the NaOH solution was adjusted to pH= 3 and extracted with Et2O until no desired product was detected in the aqueous layer. The Et2O was evaporated under reduced pressure and passed through an Al2O3 column eluted with Et2O to afford 3-bromo-5-fluorophenol as a colorless oil (48 g, 94% yield). LC-MS 190.33 (M+H); Analytical HPLC = 2.26 minutes (0-100% CH3CN in H2O witfi 0.1% TFA in a 4-min run); 1H NMR (400 MHz, CD3OD) delta ppm 6.88 - 6.64 (m, 2H), 6.58 - 6.30 (m, 1 H), 4.99 (s, 1 H). | |
EXAMPLE 5; (R)-N-(l-(5-chloropyridin-2-yl)-l-(3-fluoro-5-(l,l,2,2-tetrafluoroethoxy)phenyl)- 2-phenyIethyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine; Procedure 8; [00201] A solution of l-bromo-3,5-difluorobenzene (20.0 g, 104 mmole) was cooled in a water bath and 2-(methylsulfonyl)ethanol (26.0 g, 207 mmol) in DMSO (100 mL) was added. KOtBu (29.0 g, 260 mmole) was added to this reaction mixture in portions. The reaction mixture turned dark. After the addition was complete, the water bath was removed and the reaction was stirred at room temperature for 1 h. The pH was adjusted to 1 using 1 N HCl, and the reaction was extracted with ether (3 x 200 mL). The combined organic portions were washed with aqueous IN NaOH (2 x 200 mL). The NaOH layer was acidified to pH 1 and extracted with ether (3 x 200 mL). The combined organic layers were dried over sodium sulfate and filtered. The filtrate solvent volume was concentrated NOT to complete dryness due to volatility of the 3-bromo-5-fluorophenol and was used directly in the next step without further purification. NMR: 400 MHz 1H (CDCl3) 6.81 ppm, 1 H, dt, J=8.35Hz and 1.98 Hz; 6.78 ppm, 1 H, m; 6.50 ppm, 1 H, dt, J=9.67 Hz and 2.20 Hz.; EXAMPLE 81; (S)-N-(l-(4-fluoro-3-methoxyphenyl)-l-(3-?uoro-5-(l,l,2,2- tetrafluoroethoxy)phenyl)-2-phenylethyl)-5-methyl-4-(trifluoromethyl)thiazoI-2- amine; Procedure 21; [00224] A solution of l-bromo-3,5-difluorobenzene (20.0 g, 104 mmole) was cooled in a water bath and 2-(methylsulfonyl)ethanol (26.0 g, 207 mmol) in DMSO (100 mL) was added. Potassium 2-methylpropan-2-olate (29.0 g, 260 mmole) was added to this reaction mixture in portions. The reaction mixture turned dark. After the addition was complete, the water bath was removed and the reaction was stirred at room temperature for 1 h. The pH was adjusted to 1 using 1 N HCl, and the reaction mixture was extracted with ether (3 x 200 mL). The combined organic portions were washed with aqueous IN NaOH (2 x 200 mL). The NaOH layer was separated, acidified to pH 1 and extracted with ether (3 x 200 mL). The combined organic layers were dried over sodium sulfate and filtered. The filtrate solvent volume was concentrated, but NOT to complete dryness, due to volatility of 3~bromo-5- fluorophenol and was used directly in the next step without further purification. NMR: 400 MHz 1H (CDCl3) 6.81ppm, 1 H, dt, J=8.35Hz and 1.98 Hz; 6.78ppm, 1 H, m; 6.50ppm, 1 H, dt, J=9.67Hz and 2.20 Hz. | ||
A solution of 1-bromo-3,5-difluorobenzene (20.0 g, 104 mmole) was cooled in a water bath and 2-(methylsulfonyl)ethanol (26.0 g, 207 mmol) in DMSO (100 mL) was added. KOtBu (29.0 g, 260 mmole) was added to this reaction mixture in portions. The reaction mixture turned dark. After the addition was complete, the water bath was removed and the reaction was stirred at room temperature for 1 h. The pH was adjusted to 1 using 1 N HCl, and the reaction was extracted with ether (3×200 mL). The combined organic portions were washed with aqueous 1N NaOH (2×200 mL). The NaOH layer was acidified to pH 1 and extracted with ether (3×200 mL). The combined organic layers were dried over sodium sulfate and filtered. The filtrate solvent volume was concentrated NOT to complete dryness due to volatility of 3-bromo-5-fluorophenol and was used directly in the next step without further purification. NMR: 400 MHz 1H (CDCl3) 6.81 ppm, 1H, dt, J=8.35 Hz and 1.98 Hz; 6.78 ppm, 1H, m; 6.50 ppm, 1H, dt, J=9.67 Hz and 2.20 Hz. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With 1H-imidazole; In tetrahydrofuran; at 0 - 20℃; for 18h; | To a solution of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (5.7 g, 30 mmol), prepared as described in Procedure 3, and imidazole (4.0 g, 60 mmol, 2 eq) in anhydrous THF (100 mL) at 00C was added tert-butyldiphenyl-silyl chloride (9.6 mL, 1.3 eq). The <n="320"/>resulting mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with water and extracted with hexane/EtOAc (1: 1). The combined organic layers were washed with H2O (2 x) and sat. NaCl (2 x), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexanes/EtOAc) to give (3-bromo~5-fluorophenoxy)(tert- butyl)diphenylsilane as colorless oil (7.5 g, yield 58 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate; In dimethyl sulfoxide; at 70℃; for 16h; | To a solution of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (47 g, 0.249 mole) and 2,2,3,3- tetrafluoroethyliodme (68 g, 0.298 mole) in DMSO (260 mL) was added potassium carbonate (137 g, 0.992 mole). The resulting mixture was stirred at 700C for 16h. The inorganic salt was removed by filtration and the filter cake was washed with Et2O (500 mL). The filtrate was diluted with 500 mL OfH2O and extracted with excess Et2O (1.5 L). The Et2O layer was washed with 0.5 N NaOH (250 mL), H2O, brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude product was passed through an Al2O3 column using Et2O as the eluting solvent to afford l-bromo-3-fluoro-5-(l,l,2,2-tetrafluoroethoxy)benzene (63 g, yield: 87%) as yellowish oil. LC-MS (ESI): 290.21 (M+H), retention time = 3.66 minutes (0-100% MeOH in H2O with 0.1% TFA in a 4-min run); 1H NMR (400 MHz5 CD3OD) delta ppm 7.45 - 7.22 (m, 2 H), 7.10 (d, J=9.23 Hz, 1 H), 6.59 - 5.94 (m, 1 H). |
With potassium carbonate; In dimethyl sulfoxide; at 70℃; for 18h; | To a solution of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (104 mmol crude), prepared as described in Step 1, Procedure 7, and iodo-1,1,2,2,-tetrafluoroethane (28.4 g, 125 mmol) in DMSO (80 mL) was added K2CO3 (57.0 g, 420 mmol). The reaction mixture was sealed in a thick walled glass pressure round bottom flask and heated at 70 C. for 18 h. The reaction mixture was cooled to rt, diluted with water (500 mL) and extracted with ether (3×200 mL). The combined ether layers were washed with 1N NaOH (2×200 mL), water (2×200 mL) and sat. NaCl (200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue. The residue was dissolved in ether (150 mL) and filtered through a plug of activated basic alumina. The filtrate was concentrated under reduced pressure to give 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene as a pale yellow oil (27.2 g, 88% for two steps) which was used without further purification. LCMS: RT=1.91 min, [M+H] No Ionizable peak (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.76 min (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm, Purity 100%); NMR: 400 MHz 1H (CDCl3) ppm 7.19 (m, 2H), 6.92 (d, J=8.35Hz, 1H), 5.88 (tt; J=52.95 Hz and J=2.64 Hz, 1H). | |
With potassium carbonate; In dimethyl sulfoxide; at 70℃; for 18h; | To a solution of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (104 mmol crude) and iodo- 1,1,2,2,-tetrafluoroethane (28.4 g, 125 mmol) in DMSO (80 niL) was added K2CO3 (57.0 g, 420 mmol). The reaction mixture was sealed in a thick walled glass pressure round bottom flask and heated at 700C for 18 h. The reaction mixture was allowed to cool to room temperature, diluted with water (500 mL) and extracted with ether (3 x 200 mL). The combined ether layers were washed with IN NaOH (2 x 200 mL), water (2 x 200 mL) and brine (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in ether (150 mL) and filtered through a plug of activated basic alumina. The filtrate was concentrated to give l-bromo-3-fluoro-5-(l,l,2,2-tetrafluoroethoxy)benzene as a pale yellow oil (27.2 g, 88% for two steps) which was used without further purification LCMS: 1.91 min, [M+l] No Ionizable peak (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.76 min (4 min gradient, MeOH/H2O 0.2% PPA) Purity 100%; NMR: 400 MHz 1H (CDCl3) 7.19 ppm, 2H, m; 6.92 ppm, IH, d, J=8.35Hz; 5.88 ppm, IH, tt; J=52.95Hz and J=2.64Hz.; To a solution of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (104 mmol crude) and iodo- 1,1,2,2,-tetrafluoroethane (28.4 g, 125 mmol) in DMSO (80 mL) was added K2CO3 (57.0 g, 420 mmol). The reaction mixture was sealed in a thick walled glass pressure round bottom flask and heated at 70 0C for 18 h. The reaction mixture was allowed to cool to room temperature, diluted with water (500 mL) and extracted with ether (3 x 200 mL). The combined ether layers were washed with IN NaOH (2 x 200 mL), water (2 x 200 mL) and saturated NaCl (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in ether (150 mL) and filtered through a plug of activated basic alumina. The filtrate was concentrated to give l-bromo-3-fluoro-5-(l,l,2,2-tetrafluoroethoxy)benzene as a pale yellow oil (27.2 g, 88% for two steps) which was used without further purification LCMS: RT = 1.91 min, [M+H] No Ionizable peak (Phenomenex Luna Cl 8 column, 4.6 x 30 mm eluting with 10-90% MeOHTH2O over 2 minutes containing 0.1% TFA; 5 niL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) 7.19ppm, 2H, m; 6.92ppm, IH, d, J=8.35Hz; 5.88ppm, IH, tt; J=52.95Hz and 2.64Hz. |
With potassium carbonate; In dimethyl sulfoxide; at 70℃; for 18h; | To a solution of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (104 mmol crude) and iodo-1,1,2,2,-tetrafluoroethane (28.4 g, 125 mmol) in DMSO (80 mL) was added K2CO3 (57.0 g, 420 mmol). The reaction mixture was sealed in a thick walled glass pressure round bottom flask and heated at 70 C. for 18 h. The reaction mixture was allowed to cool to room temperature, diluted with water (500 mL) and extracted with ether (3×200 mL). The combined ether layers were washed with 1N NaOH (2×200 mL), water (2×200 mL) and brine (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in ether (150 mL) and filtered through a plug of activated basic alumina. The filtrate was concentrated to give 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene as a pale yellow oil (27.2 g, 88% for two steps) which was used without further purification LCMS: 1.91 min, [M+1] No Ionizable peak (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.76 min (4 min gradient, MeOH/H2O 0.2% PPA) Purity 100%; NMR: 400 MHz 1H (CDCl3) 7.19 ppm, 2H, m; 6.92 ppm, 1H, d, J=8.35 Hz; 5.88 ppm, 1H, tt; J=52.95 Hz and J=2.64 Hz. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.8% | With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 50℃; for 2h; | 1-bromo-3-fluoro-5-propoxy-benzene Add propyl iodide (5.74 g, 33.77 mmol) to <strong>[433939-27-6]3-bromo-5-fluoro-phenol</strong> (4.30 g, 22.51 mmol) and cesium carbonate (11.00 g, 33.77 mmol) in N,N-dimethylformamide (75 mL) and stir at room temperature 1 hour, then heat at 50 C. for 1 hour. Cool to room temperature and dilute with hexanes. Wash (water, IN lithium chloride, saturated aqueous sodium chloride), dry (magnesium sulfate), filter and concentrate to give the desired compound as a colorless oil, 4.40 g (83.8%). 1H-NMR (400 MHz, CDCl3) delta 6.85-6.80 (m, 2H), 6.55 (dt, 1H, J=6.4, 3.5 Hz), 3.88 (t, 2H, J=6.6 Hz), 1.84-1.75 (m, 2H), 1.02 (t, 3H, J=7.5 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Step 3 2-(3-Bromo-5-fluorophenoxy)-5-(trifluoromethyl)pyridine To a solution of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (2.54 g, 0.013 mol) in DMF (12 mL) under a N2 atmosphere was added potassium carbonate (3.59 g, 0.026 mol) and the reaction was stirred for 20 min at RT. 2-Chloro-5-trifluoromethylpyridine (2.4 g, 0.013 mol) was added and the reaction mixture was refluxed at 110 C. overnight. Water was added and the mixture was extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by silica gel column chromatography (10% ethyl acetate in hexane) to give the title compound (4.28 g, 96%). 1H NMR (500 MHz, CDCl3): delta 8.45 (s, 1H), 7.96 (dd, J=2 Hz, J=8.5 Hz, 1H), 7.16-7.15 (m, 2H), 7.08 (d, J=8.5 Hz, 1H), 6.89-6.85 (m, 1H); m/z (337.9, M+ H+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Step 2 3-Bromo-5-fluorophenol To a solution of <strong>[29578-39-0]1-bromo-3-fluoro-5-methoxybenzene</strong> (3.0 g, 0.015 mol) in dry CH2Cl2 (80 mL) under an inert atmosphere and cooled to -30 C. was added 1 M BBr3 (4.27 mL, 0.045 mol) in 21 mL of CH2Cl2 dropwise while maintaining temperature at -30 C. The reaction was stirred for 3 h at 0-5 C. and then the reaction mixture was quenched with aqueous saturated NaHCO3. Water was added and the mixture was extracted with CH2CO2 three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness to give the title compound (2.54 g, 91%). | |
85% | With boron tribromide; In dichloromethane; at -78 - 20℃; for 3h; | To a stirred suspension of l-bromo-3-fluoro-5-methoxybenzene (5.0 g, 25 mmol) in DCM (50 mL) was added BBr3 (12.2 g, 50 mmol) at -78C. The resulting mixture was stirred at -78C to r.t for 3hrs, then the mixture was poured into ice-water and extracted with EtOAc. The organics was dried and concentrated to give 3-bromo- 5-fluorophenol (4 g, 85% yield) as yellow oil. lH NMR: (CDC13 400MHz) delta 6.82- 6.80 (m, 2H), 6.53-6.51(m, 1H), 6.20-6.15(m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In dimethyl sulfoxide; at 20℃;Cooling; | A solution of 1-bromo-3,5-difluorobenzene (20.0 g, 104 mmol) was cooled in an ice water bath and 2-(methylsulfonyl)ethanol (26.0 g, 207 mmol) in DMSO (100 mL) was added. KOtBu (29.0 g, 260 mmol) was added to the reaction mixture in portions. The reaction mixture turned dark. After the addition was complete, the ice water bath was removed and the reaction mixture was stirred at rt for 1 h. At the conclusion of this period, the solution was brought to pH 1 by addition of 1 N HCl, and the reaction mixture was extracted with ether (3×200 mL). The combined organic portions were washed with aqueous 1N NaOH (2×200 mL). The combined NaOH layers were acidified to pH 1 and extracted with ether (3×200 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate solvent volume was concentrated under reduced pressure, but care was taken not to concentrate to complete dryness due to volatility of 3-bromo-5-fluorophenol. The mixture was used directly in the next step without further purification. NMR: 400 MHz 1H (CDCl3) ppm 6.81 (dt, J=8.35 Hz and 1.98 Hz, 1H), 6.78 (m, 1H), 6.50 (dt, J=9.67 Hz and 2.20 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With 1H-imidazole; In dichloromethane; at 20℃; for 2h; | General procedure: To a solution of bromophenol (10 mmol) and imidazole (1.7 g, 25 mmol) indimethylformamide (38 mL) was added tert-butyldimethylsilyl chloride (1.81 g, 12mmol). The reaction was stirred for 2 h at ambient temperature before being quenchedby the addition of saturated aqueous ammonium chloride. The mixture was diluted withethyl acetate and following separation, the aqueous layer was extracted twice with thesame solvent. The combined organic layers were washed with brine, dried overmagnesium sulfate, filtered, and concentrated in vacuo. The crude material waspurified using flash column chromatography (gradient 0-5% ethyl acetate/hexanes) togive the title compounds as a yellow oils, in nearly quantitative yield. |
92% | With 1H-imidazole; In tetrahydrofuran; at 0 - 20℃; | To a solution of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (1.50 g, 7.88 mmol) in THF (15 ml) was added tert-butyldimethylsilyl chloride (1.54 g, 10.2 mmol) and imidazole (1.07 g, 15.8 mmol) at 0 C. After stirring for 3 h at room temperature, the reaction mixture was quenched with aqueous citric acid. The mixture was extracted with EtOAc (50 ml, twice), the combined organic layers were washed with brine, dried over MgSO4, and concentrated. The residue was purified by flash column chromatography to give the title compound (2.21 g, 7.23 mmol, 92%) as a white solid.1H NMR delta (CDCl3) 6.89-6.84 (1H, m), 6.81-6.79 (1H, m), 6.52-6.46 (1H, m), 0.98 (9H, s), 0.22 (6H, s). |
30 g | With 1H-imidazole; In N,N-dimethyl-formamide; at 0 - 20℃; | Example 26 N-(l -(7-chloro-4-fluoro- 1 -hydroxy- 1 ,3-dihydrobenzo[cl [ 1 ,2"|oxaborol-6-yloxy)-2-cvanop ropan-2-yl)-4-(trifluoromethoxy)benzamide To a solution of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (19 g, 100 mmol) and imidazole (15 g, 220 mmol) in DMF (80 mL) is added TBDMSC1 (16.5 g, 110 mmol) at 0C, and the mixture is stirred at rt overnight. Water is added at 0C, and aqueous layer is extracted with DCM. The organic layer is washed with brine, dried over Na2S04 and evaporated in vacuo. The residue is purified by silica gel chromatography (PE:EA= 100:1) to give the desired product as colorless oil (30 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.5% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; | Preparation of Compound Int-17blnt-17a lnt-17b500 mL flask was added Int-17a (25.0 g, 130 mmol), drydichloromethane (250 mL) and DIPEA (25.37 g, 195 mmol). The solution was cooled to 0 C and acetyl chloride (13.27g, 169 mmol, in 30 mL dry dichloromethane) was added dropwise. The resulting reaction was allowed to stir at 0 C for one hour and then at room temperature for about 15 hours. The solution was diluted with EtOAc and washed with water. The organic phase was dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The product was purified using silica gel chromatography (330g, 0% to 50% of EtOAc in Hexane) to provide Int-17b (22.58 g, 74.5%) |
74.5% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 16h; | To a 500 mL flask was added Int-17a (25.0 g, 130 mmol), dry dichloromethane (250 mL) and DIPEA (25.37 g, 195 mmol). The solution was cooled to 0 C and acetyl chloride (13.27g, 169 mmol, in 30 mL dry dichloromethane) was added dropwise. The resulting reaction was allowed to stir at 0 C for one hour and then at room temperature for about 15 hours. The solution was diluted with EtOAc and washed with water. The organic phase was dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue obtained was purified using flash columnchromatography on silica gel (330g, 0% to 50% of EtOAc in Hexane) to provideCompound Int-17b (22.58 g, 74.5%) |
74.5% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 15h; | To a 500 mL flask was added Int-17a (25.0 g, 130 mmol), drydichloromethane (250 mL) and DIPEA (25.37 g, 195 mmol). The solution was cooled to 0 C and acetyl chloride (13.27g, 169 mmol, in 30 mL dry dichloromethane) was added dropwise. The resulting reaction was allowed to stir at 0 C for one hour and then at room temperature for about 15 hours. The solution was diluted with EtOAc and washed with water. The organic phase was dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue obtained was purified using silica gel chromatography (330g, 0% to 50% of EtOAc in Hexane) to provide Compound Int-17b (22.58 g, 74.5%) |
74.5% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; | Preparation of Compound Int-17blnt-17a lnt-17b500 mL flask was added Int-17a (25.0 g, 130 mmol), drydichloromethane (250 mL) and DIPEA (25.37 g, 195 mmol). The solution was cooled to 0 C and acetyl chloride (13.27g, 169 mmol, in 30 mL dry dichloromethane) was added dropwise. The resulting reaction was allowed to stir at 0 C for one hour and then at room temperature for about 15 hours. The solution was diluted with EtOAc and washed with water. The organic phase was dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The product was purified using silica gel chromatography (330g, 0% to 50% of EtOAc in Hexane) to provide Int-17b (22.58 g, 74.5%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With di-tert-butyl-diazodicarboxylate; dibenzyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; | Step 5. tert-butyl 4-(3-bromo-5-fluorophenoxy)piperidine-l-carboxylateTo a mixture of triphenylphosphine (1.75 g, 6.66 mmol) and 3-bromo-5- fluorophenol (795 mg, 4.16 mmol) and tert-butyl 4-hydroxypiperidine-l-carboxylate (922 mg, 4.58 mmol) in THF (20. mL) was added di-tert-butyl azodicarboxylate (1.53 g, 6.66 mmol) (DBAD) at 0C. The reaction was stirred overnight at room temperature. The solvent was removed and the residue was dissolved in methanol and purified by preparative-LCMS (CI 8 column eluting with a gradient of ACN/H20 containing 0.15% NH4OH) to give the desired product (1.09 g, 70%). LCMS (M+Na)+: 396.0, 398.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In toluene; at 20℃; | To a mixture of <strong>[433939-27-6]3-fluoro-5-bromophenol</strong> (4.13 g), Compound I (3.78 g), triphenylphosphine (5.66 g) and toluene (60 mL) was added diisopropyl azodicarboxylate (4.3 mL), and the resulting mixture was stirred at room temperature overnight. The reaction solution was washed successively with 1M aqueous sodium hydroxide solution, 1M hydrochloric acid, and brine. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=6/1) to giv Compound II (6.84 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | A reaction vessel containing <strong>[433939-27-6]3-fluoro-5-bromophenol</strong> (69mg, 0.36mmol), Et3N (1.5ml), dichlorobis(triphenylphosphine)palladium (II) (8.4mg, 0.012mmol) and copper (I) iodide (4.6mg, 0.024mmol) in DMF (1ml) was sealed, degassed, and flushed with nitrogen. The mixture was stirred at rt for 30 min. A solution of (S)-2[(4,6-dimethyl-2-prop-2-ynylamino-pyrimidine-5- carbonyl)-amino]-3-[(thiophene-2-carbonyl)-amino]-propionic acid methyl ester (lOOmg, 0.24mmol) in DMF (1 mL) was added at rt. The reaction mixture was stirred at rt over the weekend. The mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography with 10% MeOH in DCM to give pure product (51 mg, 40% yield). MS m/e 525.9 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With copper(l) iodide; potassium carbonate; L-proline; In dimethyl sulfoxide; at 100℃; for 24h;Inert atmosphere; | Nitrogen was bubbled through a solution of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (10 g, 51 .31 mmol) in dry dimethyl sulfoxide (70 ml) for 10 min after which sodium methanesulfinate (8.27 g, 76.96 mmol), cupper(l)iodide (5.86 g, 30.79 mmol), L- proline (7.09 g, 61 .57 mmol) and potassium carbonate (4.25 g, 30.79 mmol) was added. The nitrogen flow was continued for an additional 10 min after which the mixture was heated at 100C for 24 h. Ethyl acetate (100 ml) and water (100 ml) was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2 x 100 ml), the combined organic phase was washed with aqueous lithium chloride (100 ml, 5%) and aqueous hydrochloric acid (100 ml, 5%), dried (Na2S04) and evaporated. Purification by flash column chromatography (ethyl acetate/isooctane, 0: 1 to 1 : 1 ) gave the title compound (7.17 g, 73%). MS m/z (relative intensity, 70 eV) 190 (M+, 81 ), 175 (27), 128 (50), 1 1 1 (bp), 83 (58). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With potassium carbonate; In acetonitrile; at 85℃; for 1h; | Example 15. Synthesis of 1-546-1. Into a 50-mL round-bottom flask, was placed <strong>[55876-84-1]methyl 5-(bromomethyl)picolinate</strong> (500 mg, 2.17 mmol, 1.00 equiv), 3-bromo-5-fluorophenol (440 mg, 2.30 mmol, 1.06 equiv), CH3CN (6 mL), and potassium carbonate (900 mg, 6.52 mmol, 3.00 equiv). The resulting solution was stirred for 60 min at 85°C. The mixture was concentrated under vacuum and the residue was diluted with 20 mL of H20. The resulting solution was extracted with 3x20 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 0.62 g (77percent) of methyl 5-((3-bromo-5- fluorophenoxy)methyl)picolinate as a yellow solid.LC-MS: ( + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (0.5 g, 2.6 mmol) in DMF (4.5 mL) was added K2C03 (0.9 g, 6.54 mmol) and stirred at 25 C for 10 min. Water (0.5 mL) was added to the above mixture followed by addition of 2-Chloro-2,2,-difluoroacetic acid sodium salt (0.6 g, 3.93 mmol) and stirring was continued at 100 C for 3 h. The reaction mixture was cooled to 25 C and diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by column chromatography (using silica gel and 2% ethyl acetate in Hexane as eluent) to afford the desired compound (Int-45). 1H NMR (400MHz, CDC13) delta ppm 7.2-6.9 (2H, m), 6.8-6.7 (1H, d), 6.7-6.2 (1H, m). | ||
To a solution of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (0.5 g, 2.6 mmol) in DMF (4.5 mL) was added K2CO3 (0.9 g, 6.54 mmol) and stirred at 25 C. for 10 min. Water (0.5 mL) was added to the above mixture followed by addition of 2-Chloro-2,2-difluoroacetic acid sodium salt (0.6 g, 3.93 mmol) and stirring was continued at 100 C. for 3 h. The reaction mixture was cooled to 25 C. and diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by column chromatography (using silica gel and 2% ethyl acetate in Hexane as eluent) to afford the desired compound (Int-45). 1H NMR (400 MHz, CDCl3) delta ppm 7.2-6.9 (2H, m), 6.8-6.7 (1H, d), 6.7-6.2 (1H, m). | ||
To a solution of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (0.5 g, 2.6 mmol) in DMF (4.5 mL) was added K2CO3 (0.9 g, 6.54 mmol) and stirred at 25 C. for 10 min. Water (0.5 mL) was added to the above mixture followed by addition of 2-Chloro-2,2,-difluoroacetic acid sodium salt (0.6 g, 3.93 mmol) and stirring was continued at 100 C. for 3 h. The reaction mixture was cooled to 25 C. and diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by column chromatography (using silica gel and 2% ethyl acetate in Hexane as eluent) to afford the desired compound. 1H NMR (400 MHz, CDCl3) delta ppm 7.2-6.9 (2H, m), 6.8-6.7 (1H, d), 6.7-6.2 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetone; at 20℃; for 2h; | Step 1: Intermediate 98-b To a solution of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong>, 98-a (25.00 g, 131.0 mmol), in acetone (654 ml) were sequentially added K2C03 (27.10 g, 196.0 mmol) and chloro(methoxy)methane (11.59 g, 144.0 mmol). The reaction was stirred at room temperature for 2 hours and then filtered. The filtrate was concentrated under reduced pressure to provide intermediate 98-b as a yellow oil. | |
With potassium carbonate; In acetone; at 20℃; for 2h; | Step 1: Intermediate 98-b [0383] To a solution of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong>, 98-a (25.00 g, 131.0 mmol), in acetone (654 ml) were sequentially added K2CO3 (27.10 g, 196.0 mmol) and chloro(methoxy)methane (11.59 g, 144.0 mmol). The reaction was stirred at room temperature for 2 hours and then filtered. The filtrate was concentrated under reduced pressure to provide intermediate 98-b as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With potassium carbonate; In acetone; at 60℃; for 16h; | A solution of <strong>[19047-31-5]2-chloro-N-cyclopropylacetamide</strong> (2.8 g, 20.9 mmol), 3-bromo- 5-fluorophenol (4.0 g, 20.9 mmol) and K2CO3 (4.3 g, 31.4 mmol) in 40 mL of acetone was heated at 60 C for 16 h. The mixture was filtered and concentrated to give a residue, which was purified by column chromatography (PE/EA, 3/1) to give the title compound (4.3 g, 71%) as a yellow solid, m/e 288 (M+H)+. |
71% | With potassium carbonate; In acetone; at 60℃; for 16h; | Example 84 2-(3-Bromo-5-fluorophenoxy)-N-cyclopropylacetamide A solution of <strong>[19047-31-5]2-chloro-N-cyclopropylacetamide</strong> (2.8 g, 20.9 mmol), 3-bromo-5- fluorophenol (4.0 g, 20.9 mmol) and K2CO3 (4.3 g, 31.4 mmol) in 40 mL of acetone was heated at 60 C for 16 h. The mixture was filtered and concentrated to give a residue, which was purified by column chromatography (PE/EA, 3/1) to give the title compound (4.3 g, 71%) as a yellow solid, m/e 288 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With caesium carbonate; In tert-butyl alcohol; at 80℃; for 16h;Inert atmosphere; | Example 26: 1-Bromo-3-(trans-4-tert-butylcyclohexyloxy)-5-fluorobenzene [00172] A mixture of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (908 mg, 4.8 mmol, 1.0 eq), 2-methyl- 2-(cis-4-(methylsulfonyloxy)cyclohexyl)propan- 1-ylium (1.1 g, 4.8 mmol, 1.0 eq) and Cs2CO3 (3.1 g, 9.6 mmol, 2.0 eq) in t-BuOH (10 mL) was stuffed at 80 C under N2 for 16 h. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (PE, 100%) to give the title compound as a white solid (800 mg, 51% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.6% | With triethylamine; In dichloromethane; at 0℃; for 1h; | To a solution of compound 521a (15.8 g, 0.083 mol), Et3N (12.1 g, 0.12 mol) in DCM (125 mL) was added butyryl chloride (10.6 g, 0.1 mol) at 0C. The mixture was allowed to stir for 1 hour. The crude product was washed with IN HCl, NaHC03, and brine. The organics were separated, dried over Na2S04, filtered, and the filtrate was concentrated in vacuo, evaporated in vacuo to provide compound 521b (18.5 g, 85.6% yield). LC/MS: Anal. Calcd. For [M+H]+ C10H10BrFO2:259.98 found 262.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With toluene-4-sulfonic acid; In dichloromethane; at 20℃; for 16h; | 36A. 2-(3-Bromo-5-fluorophenoxy)tetrahydro-2H-pyran A solution of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (1.64 g, 8.59 mmol), 3,4-dihydro-2H-pyran (1.56 mL, 17.2 mmol) and PPTS (0.216 g, 0.859 mmol) in DCM (10 mL) was stirred for 16 h at rt. The reaction was concentrated in vacuo. The residual crude oil was purified by chromatography (SiO2) using a 0% to 20% EtOAc/hexane over 15 min to give the title compound (2.24 g, 8.14 mmol, 95% yield) as a clear oil. 1H NMR (CDCl3) delta: 7.05 (dd, J=2.8, 2.1 Hz, 1H), 6.90 (ddd, J=8.0, 2.2, 1.8 Hz, 1H), 6.77 (dt, J=10.6, 2.2 Hz, 1H), 5.41 (t, J=3.1 Hz, 1H), 3.91-3.81 (m, 1H), 3.72-3.58 (m, 1H), 2.05-1.92 (m, 1H), 1.92-1.82 (m, 2H), 1.81-1.58 (m, 3H); 19F NMR (CDCl3) delta: -110.28 (s); 13C NMR (CDCl3) delta: 164.22 (s), 162.24 (s), 158.78 (d, J=11.8 Hz), 122.41 (d, J=12.5 Hz), 115.88 (d, J=3.3 Hz), 112.33 (s), 112.13 (s), 103.42 (s), 103.22 (s), 96.67 (s), 61.97 (s), 30.05 (s), 25.01 (s), 18.39 (s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With copper(l) iodide; potassium carbonate; trans-N,N'-dimethylcyclohexane-1,2-diamine; In toluene; at 150℃; for 3.5h;Microwave irradiation; Inert atmosphere; | a. 3-(5-Amino-3-tert-butyl-pyrazol-1-yl)-5-fluoro-phenol (Intermediate Wa) Degassed toluene (sparged with argon for 25 mins, 10.0 mL) was added to a mixture of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (1.00 g, 5.23 mmol), 3-tert-butyl-1H-pyrazole-5-amine (728 mg, 5.23 mmol), copper (I) iodide (50.0 mg, 0.26 mmol) and potassium carbonate (1.52 g, 11.0 mmol). Trans-N,N'-dimethylcyclohexanediamine (165 muL, 1.05 mmol) was added and the reaction heated to 150 C. for 3.5 h using microwave irradiation. The mixture was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3*). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-75% EtOAc in cyclohexane, to give the title compound (488 mg, 37%). LCMS (Method 4): Rt 2.49 min, m/z 250 [MH+]. |
37% | With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; potassium carbonate; In toluene; at 150℃; for 3.5h;Microwave irradiation; | Degassed toluene (sparged with argon for 25 mins, 10.0 mL) was added to a mixture of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (1.00 g, 5.23 mmol), 3-tert-butyl-lH-pyrazole-5- amine (728 mg, 5.23 mmol), copper (I) iodide (50.0 mg, 0.26 mmol) and potassium carbonate (1.52 g, 11.0 mmol). Trans-N,N'-dimethylcyclohexanediamine (165 mu, 1.05 mmol) was added and the reaction heated to 150 C for 3.5 h using microwave irradiation. The mixture was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3 x). The combined organic layers were washed with brine, dried (MgS04), filtered and evaporated in vacuo. The residue was purified by FCC, using 0- 75% EtOAc in cyclohexane, to give the title compound (488 mg, 37%). LCMS (Method 4): Rt 2.49 min, m/z 250 [MH+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With cesium bicarbonate; In 1-methyl-pyrrolidin-2-one; at 150℃; for 7h;Microwave irradiation; Sealed tube; Inert atmosphere; | Cesium hydrogen carbonate (142 mg, 0.73 mmol) was added all at once to 4'-fluoro-7'-methylsulfonyl-spiro[l ,3-dioxolane-2, -indane] (100 mg, 0.37 mmol) and <strong>[433939-27-6]3-bromo-5-fluoro-phenol</strong> (105 mg, 0.55 mmol) in l-methyl-2-pyrrolidone (1.5 mL) at room temperature in a microwave reaction vial equipped with a stir bar. The flask was flushed with nitrogen then sealed with a crimp cap. The reaction was heated to 150 C for 7 hours, cooled to ambient temperature then purified directly on reverse phase silica gel (25+M, 14 CV, 20-100% MeCN/water) affording 4'-(3-bromo-5-fluoro-phenoxy)-7'- methylsulfonyl-spiro[l ,3-dioxolane-2, l '-indane] (1 18 mg, 0.26 mmol, 72% yield). |
72% | With cesium bicarbonate; In 1-methyl-pyrrolidin-2-one; at 20 - 150℃; for 7h;Microwave irradiation; Sealed tube; Inert atmosphere; | Cesium hydrogen carbonate (142 mg, 0.73 mmol) was added all at once to 4'-fluoro-7'-methylsulfonyl-spiro[l,3-dioxolane-2,r-indane] (100 mg, 0.37 mmol) and <strong>[433939-27-6]3-bromo-5-fluoro-phenol</strong> (105 mg, 0.55 mmol) in 1 -methyl-2-pyrrolidone (1.5 mL) at room temperature in a microwave reaction vial equipped with a stir bar. The flask was flushed with nitrogen then sealed with a crimp cap. The reaction was heated to 150 C for 7 hours, cooled to ambient temperature then purified directly on reverse phase silica gel (25+M, 14 CV, 20-100% MeCN/water) affording 4'-(3-bromo-5-fluoro-phenoxy)-7'- methylsulfonyl-spiro[l,3-dioxolane-2,l'-indane] (118 mg, 0.26 mmol, 72% yield). |
72% | With cesium bicarbonate; In 1-methyl-pyrrolidin-2-one; at 150℃; for 7h;Inert atmosphere; Sealed tube; | 1005021 Step A: Preparation of 4?-(3 -bromo-5 -fluoro-phenoxy)-7?-methyl sulfonyl-spirol 1,3- dioxolane-2.1?-indanel: Cesium hydrogen carbonate (142 mg, 0.73 mmol) was added all at once to 4?-fluoro-7?-methylsulfonyl-spiro[ 1,3 -dioxolane-2, 1 ?-indane] (100 mg, 0.37 mmol) and <strong>[433939-27-6]3-bromo-5-fluoro-phenol</strong> (105 mg, 0.55 mmol) in 1-methyl-2-pyrrolidone (1.5 mL) at room temperature in a microwave reaction vial equipped with a stir bar. The flask was flushed with nitrogen then sealed with a crimp cap. The reaction was heated to 150 C for 7 hours, cooled to ambient temperature then purified directly on reverse phase silica gel (25+M, 14 CV, 20-100% MeCN/water) affording 4?-(3 -bromo-5 -fluoro-phenoxy)-7?-methyl sulfonylspiro[ 1,3 -dioxolane-2, 1 ?-indane] (118 mg, 0.26 mmol, 72% yield). |
72% | With cesium bicarbonate; In 1-methyl-pyrrolidin-2-one; at 150℃; for 7h;Microwave irradiation; Inert atmosphere; | Cesium hydrogen carbonate (142 mg, 0.73 mmol) was added all at once to 4'-fluoro-7'-methylsulfonyl-spiro[l,3-dioxolane-2, -indane] (100 mg, 0.37 mmol) and 3- bromo-5-fluoro-phenol (105 mg, 0.55 mmol) in l-methyl-2-pyrrolidone (1.5 mL) at room temperature in a microwave reaction vial equipped with a stir bar. The flask was flushed with nitrogen then sealed with a crimp cap. The reaction was heated to 150 C for 7 hours, cooled to ambient temperature then purified directly on reverse phase silica gel (25+M, 14 CV, 20-100% MeCN/water) affording 4'-(3-bromo-5-fluoro-phenoxy)-7'-methylsulfonyl-spiro[l,3-dioxolane- 2, l'-indane] (1 18 mg, 0.26 mmol, 72% yield). |
72% | With cesium bicarbonate; In 1-methyl-pyrrolidin-2-one; at 150℃; for 7h;Microwave irradiation; Sealed tube; | Cesium hydrogen carbonate (142 mg, 0.73 mmol) was added all at once to 4'-fluoro-7'-methylsulfonyl-spiro[1,3-dioxolane-2,1'-indane] (100 mg, 0.37 mmol) and <strong>[433939-27-6]3-bromo-5-fluoro-phenol</strong> (105 mg, 0.55 mmol) in 1-methyl-2-pyrrolidone (1.5 mL) at room temperature in a microwave reaction vial equipped with a stir bar. The flask was flushed with nitrogen then sealed with a crimp cap. The reaction was heated to 150 C. for 7 hours, cooled to ambient temperature then purified directly on reverse phase silica gel (25+M, 14 CV, 20-100% MeCN/water) affording 4'-(3-bromo-5-fluoro-phenoxy)-7'-methylsulfonyl-spiro[1,3-dioxolane-2,1'-indane] (118 mg, 0.26 mmol, 72% yield). |
72% | With cesium bicarbonate; In 1-methyl-pyrrolidin-2-one; at 150℃; for 7h; | Cesium hydrogen carbonate (142 mg, 0.73 mmol) was added all at once to 4'-fluoro-7'-methylsulfonyl-spiro[l,3-dioxolane-2,r-indane] (100 mg, 0.37 mmol) and <strong>[433939-27-6]3-bromo-5-fluoro-phenol</strong> (105 mg, 0.55 mmol) in l-methyl-2-pyrrolidone (1.5 mL) at room temperature in a microwave reaction vial equipped with a stir bar. The flask was flushed with nitrogen then sealed with a crimp cap. The reaction was heated to 150 C for 7 hours, cooled to ambient temperature then purified directly on reverse phase silica gel (25+M, 14 CV, 20-100% MeCN/water) affording 4'-(3-bromo-5-fluoro-phenoxy)-7'- methylsulfonyl-spiro[l,3-dioxolane-2,l'-indane] (118 mg, 0.26 mmol, 72% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; tricyclohexylphosphine; In tetrahydrofuran; at 20℃; | To a solution of Intermediate <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> 59-e (2.5 g, 13.2 mmol) and Intermediate 59-d (3.2 g, 14.5 mmol) in THF (13.2 ml), were sequentially added triphenylphosphine (5.2 g, 19.7 mmol), and DIAD (4.26 g, 21.1 mmol) at room temperature, and the reaction was then stirred overnight. Volatiles were removed under reduced pressure. Purification by silica gel chromatography provided Intermediate 59-f as a yellow oil. | |
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; | To a solution of Intermediate <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> 21-e (2.5 g, 13.2 mmol) and intermediate 21-d (3.2 g, 14.5 mmol) in THF (13.2 ml) were sequentially added triphenylphosphine (5.2 g, 19.7 mmol), and DIAD (4.26 g, 21.1 mmol) at room temperature, and the reaction was then stirred overnight. Volatiles were removed under reduced pressure. Purification by silica gel chromatography provided Intermediate 21-f as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; | To a solution of Intermediate <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> 21-e (170 mg, 0.9 mmol) and intermediate 23-c (200 mg, 0.9 mmol) in THF (1.0 ml) were sequentially added triphenylphosphine (351 mg, 19.7 mmol), and DIAD (277 pI, 1.4 mmol) at room temperature, and the reaction was then stirred overnight. Volatiles were removed under reduced pressure. Purification by silica gel chromatography provided Intermediate 23-d as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 5h; | General procedure: In a round bottom flask, DIAD (1-1.2 equiv) and N-tBoc-ethanolamine(1.3 equiv) were dissolved in THF (15 mL). Then the 3-bromo-5-hydroxypyridine (1 equiv) and the triphenylphosphine(1.2-1.5 equiv) were added. The reaction mixture was stirred atroom temperature for 5 h. The solvent was removed under reducedpressure and the residue was used without any further purificationfor deprotection. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63 mg | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In ethanol; at 100℃; for 2h;Inert atmosphere; | [Step 1] Production of 3-fluoro-5-[2-(pyridin-2-ylmethoxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]phenol To 2-(pyridin-2-ylmethoxy)-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)-6,7-dihydro-5H-cyclopenta[b]py ridine (100 mg), <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (82 mg), Pd(OAc)2 (2.6 mg) and S-Phos (9.4 mg) was added ethanol (1.4mL), and the mixture was degassed, and stirred under Ar atmosphere at 100C for 2 hours. After the reaction mixture was allowed to return to room temperature, diluted with ethyl acetate, filtered through Celite, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (63 mg) as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.9% | With potassium hydroxide; In water; acetonitrile; at -78 - 20℃; for 0.333333h;Inert atmosphere; | A MeCN (6.5 mL)/H2O (6.5 mL) mixture of potassium hydroxide (1469 mg, 26.2 mmol) and <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (250 mg, 1.309 mmol) was cooled to -78 C. in an open 50-mL teardrop flask, and bromodifluoromethyl diethylphosphonate (465 mul, 2.62 mmol) was added. The cooling bath was removed, and the white slurry was allowed to warm to rt. After 20 min, the reaction was diluted with EtOAc and the layers were separated. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to a colorless oil. Column chromatography (12 g Redisep Gold column, 0-80% EtOAc/hept) afforded 1-bromo-3-(difluoromethoxy)-5-fluorobenzene (189 mg, 0.784 mmol, 59.9% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) delta ppm 7.15-7.59 (m, 4 H). 19F NMR (376 MHz, DMSO-d6) delta ppm-108.47 (s, 2F)-83.75 (s, 1F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With sodium hydroxide; In water; at 120℃; for 120h; | To 3-bromo-5-fluoro-phenol (9.0 g, 47 mmol), and 1-chloro-2-methyl-propan-2-ol (5.116 g, 47.12 mmol), aqueous sodium hydroxide (37.69 g, 94.24 mmol) was added and the reaction mixture was heated at 120° C. for 5 days in a pressure vessel. The reaction was cooled and then extracted three times with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified on 220 g of silica gel utilizing a gradient of 0 to 10percent ethyl acetate in dichloromethane. The impure product was repurified on 220 g of gold silica gel utilizing a gradient of 0 to 10percent ethyl acetate in dichloromethane to yield 1-(3-bromo-5-fluoro-phenoxy)-2-methyl-propan-2-ol (4.75 g, 18.0 mmol, 38percent). ESI-MS m/z calc. 262.00046. found 263.0 (M+1)+. Retention time: 1.57 minutes (3 min run). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.3% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 55℃; for 18h; | To a stirred solution of <strong>[433939-27-6]3-bromo-5-fluoro-phenol</strong> (2.270 g, 11.88 mmol), 2-methylpropane-1,3-diol (1.071 g, 11.88 mmol) and triphenylphosphane (3.428 g, 3.028 mL, 13.07 mmol) in tetrahydrofuran (71.82 mL) at 0 C. was added diisopropyl azodicarboxylate (2.643 g, 2.532 mL, 13.07 mmol). The ice bath was removed and the reaction was stirred at 55 C. for 18 h. The reaction was diluted with ethylacetate and washed twice with sodium bicarbonate and twice with brine. The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The crude product was purified on 220 g of silica gel utilizing a gradient of 0 to 15% ethyl acetate in dichloromethane to yield 3-(3-bromo-5-fluoro-phenoxy)-2-methyl-propan-1-ol (1.73 g, 6.57 mmol, 55.3%) as a colorless liquid. 1H NMR (400 MHz, DMSO-d6) delta 7.09-7.03 (m, 1H), 7.03-6.98 (m, 1H), 6.87 (dt, J=11.2, 2.3 Hz, 1H), 4.57 (t, J=5.3 Hz, 1H), 3.97 (dd, J=9.5, 5.9 Hz, 1H), 3.85 (dd, J=9.5, 6.3 Hz, 1H), 3.48-3.34 (m, 2H), 2.05-1.84 (m, 1H), 0.94 (d, J=6.8 Hz, 3H). ESI-MS m/z calc. 262.00046. found 265.0 (M+1)+; Retention time: 1.58 minutes (3 min run). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | To <strong>[433939-27-6]3-bromo-5-fluoro-phenol</strong> (6.00 g, 31.41 mmol) in DMF (60 mL) was slowly added NaH (1.38 g, 34.55 mmol) and the reaction mixture was stirred at ambient temperature for 15 min. To the mixture was added NaI (1.18 g, 7.85 mmol), followed 2-(bromomethyl)-1,1,1,2,3,3,3-heptadeuterio-propane (5.05 g, 34.55 mmol). The reaction mixture was stirred at 80 C. for 6 h. The reaction mixture was cooled to ambient temperature and slowly quenched with water (120 mL). The reaction mixture was extracted with EtOAc (240 mL) and the organic phase separated. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude light yellow oil was purified by silica gel column chromatography eluting with 0-100% EtOAc/hexanes to give 1-bromo-3-fluoro-5-[2,3,3,3-tetradeuterio-2-(trideuteriomethyl)propoxy]benzene (6.8 g, 85%). 1H NMR (400 MHz, Chloroform-d) delta 6.90-6.77 (m, 2H), 6.55 (dt, J=10.7, 2.2 Hz, 1H), 3.75-3.61 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With sodium hydrogencarbonate; In 1-methyl-pyrrolidin-2-one; at 160℃; for 10h;Inert atmosphere; | To a stirred solution of 7'-fluorospiro[l,3-dioxolane-2,3'-indane]-4'- sulfonamide (490 mg, 1.79 mmol) and <strong>[433939-27-6]3-bromo-5-fluoro-phenol</strong> (685 mg, 3.59 mmol) in NMP (6 mL) was added sodium bicarbonate (452 mg, 5.38 mmol). The reaction mixture was heated at 160 C under nitrogen for 10 hours. After cooling, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by C18 reverse phase flash chromatography (20-95% MeCN/water) to give 7'-(3-bromo-5-fluoro-phenoxy)spiro[l,3-dioxolane-2,3'-indane]-4'-sulfonamide (85 mg, 11 %). LCMS ESI (+) m/z 444, 446 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h; | Step 1: To a solution of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (1.0 g, 5.26 mmol) in DMF (20 mL) was added potassium carbonate (0.73 g, 5.26 mmol) and methyl 2,4-dibromobutanoate (1.36 g, 5.26 mmol) and the mixture was heated at 60C for 3 h, cooled to rt and extracted with EtOAc (3 x 100 mL). The organic portion was washed with brine, dried over Na2S04, concentrated and purified by column chromatography (PE/EA = 10:1 ) to yield methyl 4-bromo-2-(3-bromo-5-fluoro- phenoxy)butanoate lnt-12a-1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
783 mg | With potassium carbonate; In acetonitrile; at 70℃; for 16h; | [0440] To a mixture of 2-chloro-N-(pentan-3-yl)acetamide (500.00 mg, 3.06 mmol) and <strong>[433939-27-6]3-bromo-5-fluoro-phenol</strong> (530.54 mg, 2.78 mmol) in MeCN (30.00 mL) was added K2C03 (767.82 mg, 5.56 mmol). The mixture was stirred at 70 C for 16 h. TLC (petroleum ether/EtOAc=5: 1, Rf=0.57) showed one new main spot. The reaction mixture was cooled to room temperature and diluted with water (30 mL). The resulting mixture was extracted with EtOAc (30 mLX 3). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, petroleum ether/EtOAc=l :0 to 8: 1) to give the title compound (783 mg, 88%) as a yellow solid. 1H NMR (400 MHz, DMSO-i/6) delta 7.74 (d, J= 8.8 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.04 (s, 1H), 6.90-6.86 (m, 1H), 4.57 (s, 2H), 3.62-3.55 (m, 1H), 1.48-1.43 (m, 2H), 1.38-1.33 (m, 2H), 0.79 (t, J= 7.2 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | Nitrogen was passed through a solution of dioxane/H2O (4/1) and this solution (2.0 mL) was then added to a mixture of the (1-(4-(3,4-dichlorophenyl)-5- (isopropylthio)thiazol-2-yl)-5-(methoxycarbonyl)-3-methyl-1H-pyrazol-4-yl)boronic acid (50 mg, 0.10 mmol), <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (23 mg, 0.12 mmol) and Na2CO3 (55 mg, 0.52 mmol) followed by the addition of the catalyst Pd(PPh3)4 (12 mg, 0.010 mmol). The reaction mixture was heated at 85 oC for 16 hours. Add LiOH (12 mg, 0.51 mmol) and the reaction mixture was stirred in the microwave at 110 oC for 15 min. Evaporated in vacuo. The crude product was purified by semi-prep HPLC-MS (column X-Bridge 30x50, eluted with 55-75% MeCN/NH4CO2H 10 mM, pH 3.8/Flow 45 ml/min/10 min) and afforded the title compound (12 mg, 0.022 mmol, 21%) as a yellow solid after lyophilization. [490] 1H NMR (500 MHz, DMSO) delta 10.05 (s, 1H), 8.24 (d, J = 2.1 Hz, 1H), 8.04 (dd, J = 8.5, 2.1 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.09 (bs, 1H), 6.80- 6.73 (m, 2H), 6.56-6.49 (m, 1H), 3.39- 3.31 (m, 1H), 2.28 (s, 3H), 1.23 (d, J = 6.7 Hz, 6H). MS (m/z): 538.0 [M+1]+. | |
21% | Nitrogen was passed through a solution of dioxane/H20 (4/1) and this solution (2.0 mL) was then added to a mixture of the (1-(4-(3,4-dichlorophenyl)-5- (isopropylthio)thiazol-2-yl)-5-(methoxycarbonyl)-3-methyl- 1 H-pyrazol-4-yl) boronic acid (50 mg, 0.10 mmol), <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (23 mg, 0.12 mmol) and Na2003 (55 mg, 0.52 mmol) followed by the addition of the catalyst Pd(PPh3)4 (12 mg, 0.010 mmol). The reaction mixture was heated at 85 0 for 16 hours. Add LiOH (12 mg, 0.51 mmol) and the reaction mixture was stirred in the microwave at 11000 for 15 mm. Evaporated in vacuo. The crude product was purified by semi-prep HPLC-MS (column X-Bridge 30x50, eluted with 55-75% MeCN/NH4002H 10 mM, pH 3.8/Flow 45 mI/min/lO mm) and afforded the title compound (12 mg, 0.022 mmol, 21%) as a yellow solid after lyophilization. 1H NMR (500 MHz, DMSO) O 10.05 (5, 1H), 8.24 (d, J= 2.1 Hz, 1H), 8.04 (dd, J= 8.5, 2.1 Hz, 1H), 7.73(d, J= 8.5 Hz, 1H), 7.09 (bs, 1H), 6.80-6.73(m, 2H), 6.56-6.49(m, 1 H), 3.39 - 3.31 (m, 1 H), 2.28 (5, 3H), 1.23 (d, J = 6.7 Hz, 6H). MS (m/z): 538.0 [M+1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 18h; | Diisopropyl diazocarboxylate (318 mg, 1.57 mmol) was added to a solution of 3- bromo-5-fluorophenol (200 mg, 1.05 mmol), oxetan-3-ol (97 mg, 1.3 mmol) and triphenylphosphine (412 mg, 1.57 mmol) in THF (4.6 mL). The reaction mixture was stirred at r.t. for 18 h. Ethyl acetate was added and the mixture was washed with 1N NaOH (3x). The organic layer was dried with sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a solution of ethyl acetate in hexanes (10 to 20%) to give the title compound (186 mg, 0.753 mmol, 72%) as a colorless oil. |
72% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 18h; | Diisopropyl diazocarboxylate (318 mg, 1.57 mmol) was added to a solution of 3- bromo-5-fluorophenol (200 mg, 1.05 mmol), oxetan-3-ol (97 mg, 1.3 mmol) and triphenylphosphine (412 mg, 1.57 mmol) in THF (4.6 mL). The reaction mixture was stirred at r.t. for 18 h. Ethyl acetate was added and the mixture was washed with 1 N NaOH (3x). The organic layer was dried with sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel using a solution of ethyl acetate in hexanes (10 to 20%) to give the title compound (186 mg, 0.753 mmol, 72%) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; | This molecule was prepared with the synthetic method described in the above scheme. The title compound was isolated as a white solid. lU NMR (400 MHz, CD3OD): delta 0.80 (d, / = 6.8 Hz, 3H), 1.12 (d, / = 6.4 Hz, 3H), 1.54 (d, J = 6.8 Hz, 3H), 1.67 (s, 3H), 1.96-2.06 (s, 2H), 2.17-2.23 (m, IH), 2.44 (s, 3H), 2.50 (s, 3H), 2.56-2.61 (m, IH), 2.69 (s, 3H), 3.27-3.28 (m, IH), 3.47-3.65 (m, 2H), 3.78-3.91 (m, 3H), 4.15-4.17 (m, 2H), 4.48-4.67 (m, 3H), 5.04-5.09 (m, IH), 6.58-6.60 (m, IH), 6.95-7.00 (m, 2H), 7.22-7.24 (m, 2H), 7.38-7.48 (m, 5H), 7.85 (s, IH), 8.20 (s, IH), 8.69-8.71 (m, IH), 8.90 (s, IH); LC/MS 1017.00 [M+H]+; tR = 2.898 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetra-(n-butyl)ammonium iodide; caesium carbonate; In N,N-dimethyl-formamide; at 90℃; for 18h; | To a solution of 3bromo-5 fluorophenol (10.00 g, 52.4 mmoi) in DMF (50 ni) was added bromocyciobutane (14.14 g, 105 rnmol),Bu4NI (19.34 g, 52.4 mrnol) and Cs2CO3 (17.06 g, 52.4 mniol). Then the mixture was stirred at90C for 18 h. The mixture was diluted with water (400 mL) and extracted with EtOAc (3 x80 niL). The organic layer was dried and concentrated in vacuo. The residue was purified via silica gel chromatography (PE) to afford the title compound |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.6% | With caesium carbonate; In acetonitrile; at 80℃; for 3h; | To a stirred suspension of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (4.5 g, 23.7 mmol) was added Cs2C03 (15.5 g, 47.4 mmol) and BnBr (4.5 g, 26 mmol) in dry CH3CN (50 mL). The resulting mixture was stirred at 80C 3 h, and then, the mixture was poured into water and extracted with EtOAc. The organics was dried and concentrated to give a residue, which was purified by silica gel chromatography (petrolem ether : EtOAc = 100: 1 to 6: 1) to give l-(benzyloxy)-3-bromo-5-fluorobenzene (4 g, 61.6% yield) as a white oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate; | Step 1: Methyl 4-(3-bromo-5-fluorophenoxy)butanoate To a solution of <strong>[433939-27-6]3-bromo-5-fluoro-phenol</strong> (5.24 mmol, 1.0 g) in acetone (20 mL) was added potassium iodide (0.26 mmol, 43 mg), potassium carbonate (5.76 mmol, 800 mg) and methyl 4-bromobutanoate (5.76 mmol, 0.73 mL). The reaction was heated at reflux overnight. The mixture was partitioned between ethyl acetate and water and the phases were separated. The aqueous layer was extracted with ethyl acetate, the organic extracts were combined, washed with brine, dried over sodium sulfate and the solvent was evaporated. The residue was purified by silica gel chromatography (solvent gradient: 0-30% ethyl acetate in heptanes) to afford 1370 mg (90%) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With triphenylphosphine; 1,1'-azodicarbonyl-dipiperidine; In chloroform; at 0 - 25℃; for 16h; | 2.00 g of compound 16 (6.66 mmol), 1.53 g of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> 15 (7.99 mmol) at 0C.And 3.84 g of triphenylphosphine (14.65 mmol)Dissolved in 15 ml of chloroform, a solution of 3.70 g of azodipiperidine (14.65 mmol) in chloroform (10 ml) was added dropwise.The reaction mixture was stirred at 25 C for 16 hours.Add 15 ml of water and extract with dichloromethane (50 ml x 3). The organic phase was dried over anhydrous sodium sulfate, spin-dried and purified by silica gel column (petroleum ether:ethyl acetate (volume ratio)=30:1 to 10:1) to obtain 2.30 g of white solid compound 17 (Yield: 73.0%) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.71% | With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 8h;Inert atmosphere; | <strong>[369-25-5]Methyl 3,4-difluorobenzoate</strong> (211 mg, 1.23 mmol) was added to a 25 mL single-mouth bottle.3-bromo-5-fluorophenol (256 mg, 1.34 mmol), potassium carbonate (539 mg, 3.9 mmol) and anhydrous DMF (4 mL), and the reaction was heated to 120 C under nitrogen for 8 h.After the reaction was completed, the temperature was cooled to room temperature, ethyl acetate (30 mL) andDilute with water (15 mL), separate the organic phase, and wash the organic phase with saturated brine for 4 times.Dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure.The title compound was obtained as a white solid(310 mg, 73.71%). |
73.71% | With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 8h; | To a 25 mL single neck flask was added <strong>[369-25-5]methyl 3,4-difluorobenzoate</strong> (211 mg, 1.23 mmol), 3-bromo-5-fluorophenol (256 mg, 1.34 mmol), potassium carbonate(539 mg, 3.9 mmol) and anhydous DMF (4 mL), the mixture was stirred at 120 C for 8 hours. After the reaction was complete, the mixture was cooled to rt, and diluted with EtOAc (30 mL) and water (15 mL). The separated organic layer was washed with saturated aqueous NaC1 4 times and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a white solid (310 mg, 73.71%). ?H N1VIR (400 1VIHz, DMSO-d6) 7.87 (dd, J 11.3, 1.8 H4 1H), 7.83 - 7.77 (m, 1H), 7.76 - 7.70 (m, 1H), 7.33 - 7.22 (m, 2H),6.92 (dd, J= 8.8, 2.0 Hz, 1H), 3.85 (s, 3H?). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32.5% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 10.0h;Inert atmosphere; Cooling with ice; | 3-Bromo-5-fluoro-phenol (110 mg, 0.58 mmol) was added to a 25 mL three-necked flask.Methyl 4-hydroxycyclohexanoate (100 mg, 0.631 mmol),Triphenylphosphine (208 mg, 0.79 mmol) and anhydrous THF (3 mL),Under a nitrogen atmosphere and under ice cooling, DIAD (178 mg, 0.86 mmol) in THF (2.0 mL) was added dropwise, and the reaction was allowed to warm to room temperature.10h. After the reaction, the solvent was concentrated under reduced pressure.Column residue chromatography(PE/EtOAc (V/V) = 20/1),The title compound was obtained as a colorless oil (yield: 62mg, 32.50percent). |
32.5% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 10.0h;Inert atmosphere; | [00280]. To a 25 mLthree-neck flask were added 3-bromo-5-fluoro-phenol (110 mg, 0.58 mmol),<strong>[3618-03-9]methyl 4-hydroxycyclohexanecarboxylate</strong> (100 mg, 0.63 1 mmol), triphenylphosphine (208 mg,0.79 mmol) and anhydrous THF (3 mL). To the mixture was added a solution of DIAD (178 mg,0.86 mmol) in THF (2.0 mL) dropwise under N2 in an ice bath. After the addition, the mixturewas warmed naturally to rt and stirred for 10 hours. After the reaction was complete, the mixture was concentrated. The residue was purified by silica gel column chromatography (PE/EtOAc (V/V) = 20/1) to give the title compound as colorless oil (62 mg, 32.50percent). ?H N1VIR (400 1VIFIz, CDC13) 6.90-6.76 (m, 2H), 6.62 - 6.50 (m, 1H), 4.52 - 4.35 (m, 1H), 3.71 (s, 3H), 2.50 - 2.32 (m, 1H), 2.21 -2.05 (m, 1H), 2.04 - 1.85 (m, 3H), 1.84 - 1.71 (m, 2H), 1.71 - 1.58 (m, 2H?). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.8% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 12h;Inert atmosphere; | After <strong>[433939-27-6]3-bromo-5-fluoro-phenol</strong> (1.39 g, 7.28 mmol) was dissolved in anhydrous THF (25 mL),Methyl (1r, 4r)-4-hydroxycyclohexanecarboxylate (1.38 g, 8.72 mmol), PPh3 (2.34 g, 8.74 mmol) and DIAD(1.80 g, 8.72 mmol). The reaction was stirred under nitrogen for 12 h at room temperature.Purification by chromatography (PE/EA (V/V) = 20/1),The title compound was obtained as a colorless oil (1.61 g, 66.80%). |
66.8% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 12h;Inert atmosphere; | [00284]. 3-Bromo-5-fluoro-phenol (1.39 g, 7.28 mmol) was dissolved in anhydrous THF (25mL), to the solution was added (lr,4r)-methyl 4-hydroxycyclohexanecarboxylate (1.38 g 8.72mmol), PPh3 (2.34 g, 8.74 mmol) and DIAD (1.80 g, 8.72 mmol) under N2 in one portion. The reaction mixture was stirred at rt for 12 hours under N2 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as coloeless (1.61 g, 66.80%). ?H N1VIR (400 MH4 CDC13) 6.88 - 6.78 (m, 2H), 6.58 - 6.53 (m, 1H), 4.43 (s, lET?), 3.69 (s, 3H), 2.46 - 2.37 (m, 1H), 2.03 - 1.86 (m, 4H), 1.82 -1.71 (m, 2H?), 1.64 (t, J= 12.5Hz, 2H?). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.2% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 12h;Inert atmosphere; | After <strong>[433939-27-6]3-bromo-5-fluoro-phenol</strong> (1.37 g, 7.17 mmol) was dissolved in anhydrous THF (25 mL), (1 s, 4 s) methyl 4-hydroxycyclohexanecarboxylate (1.36) g, 8.60 mmol), PPh3 (2.30 g, 8.59 mmol) and DIAD(1.78 g, 8.63 mmol). Under nitrogen protection, the reaction was stirred at room temperature for 12 h.Then concentrated under reduced pressure, and the residue obtained was applied to silica gel column chromatography(PE/EA(V/V)=20/1) purified,The title compound was obtained as a colorless oily material (1.05 g, 44.2%). |
44.2% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 12h;Inert atmosphere; | 3-Bromo-5-fluoro-phenol (1.37 g, 7.17 mmol) was dissolved in anhydrous THF (25 mL), to the solution was added (ls,4s)-methyl 4-hydroxycyclohexanecarboxylate (1.36 g 8.60 mmol), PPh3 (2.30 g 8.59 mmol) and DIAD (1.78 g, 8.63 mmol) under N2. The reaction mixture was stirred at rt for 12 hours under N2 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as coloeless (1.05 g, 44.2%). ?H NMR (400 MH4 CDC13) 6.86 - 6.79 (m, 2H), 6.56 - 6.50 (m, 1H), 4.43 (s, 1H), 3.69 (s, 3H), 2.43 - 2.37 (m, 1H), 2.03 - 1.87 (m, 4H), 1.81 - 1.72 (m, 2H),1.69- 1.60 (m, 2H?). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; | A solution of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (200 mg, 1.047 mmol) and 1- (methylsulfonyl)piperidin-4-yl methanesulfonate (054) (404 mg, 1.571 mmol) in DMF (5 mL) was charged into a 10 mL vial with a magnetic stir bar. Cesium carbonate (682 mg, 2.094 mmol) was added. The resulting dispersion was heated to 70 C and stirred overnight. The reaction was cooled to room temperature andpartitioned between EtOAc (10 mL) and water (10 mL). The solution was extract with EtOAc (3 X 10 mL), washed with brine (10 mL), dried with MgS04, filtered, and evaporated under vaccuum. The crude product was dry loaded onto 2 g. silica and purified by column chromatography (ISCO normal phase, 24 g. gold column, 0-60% EtOAc/hexanes gradient) to isolate 4-(3- bromo-5-fluorophenoxy)-l-(methylsulfonyl)piperidine (055) (108 mg, 0.307 mmol, 29%). 1H NMR (400 MHz, CDCL) d ppm 1.97 - 2.08 (m, 4 H) 2.84 (s, 3 H) 3.36 - 3.43 (m, 4 H) 4.48 - 4.58 (m, 1 H) 6.59 (dt, 7=10.45, 2.24 Hz, 1 H) 6.87 - 6.93 (m, 2 H). LCMS: 353.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With magnesium(II) perchlorate; at 50 - 65℃; for 6.33333h;Inert atmosphere; | To <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (500 mg) were sequentially added di-tert-butyl dicarbonate (1.14 g) and magnesium perchlorate (58 mg) at room temperature under argon flow. The reaction mixture was stirred at 50 C. for 1 hour 20 minutes. To the reaction mixture was added at 50 C. di-tert-butyl dicarbonate. The reaction mixture was stirred at 50 C. for 1 hour and further stirred at 65 C. for 1 hour, and then cooled to room temperature. To the reaction mixture was added at room temperature di-tert-butyl dicarbonate. The reaction mixture was stirred at 65 C. for 3 hours. The reaction mixture was cooled to room temperature, and thereto was added a mixed solution of n-hexane/ ethyl acetate (1/1). The reaction mixture was sequentially washed with 3N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and brine, and then dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 20/1) to give the title compound (437 mg) in the yield of 68%. (0174) 1H-NMR (CDCl3) delta: 1.35 (s, 9H), 6.62-6.66 (m, 1H), 6.92-6.98 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; | To a solution of <strong>[433939-27-6]3-bromo-5-fluorophenol</strong> (0.58 g, 3.0 mmol, 1 equiv.) in dry THF (40 mL) under anhydrous conditions was added 4-hydroxy- 1 -piperidine carboxylate (0.75 g, 3.2 mmol,1.05 equiv.) and triphenyl phosphine (1.6 g, 6.1 mmol, 2 equiv.). The reaction mixture was then cooled in an ice bath, and DIAD (1.2 mL, 6.2 mmol, 2.05 equiv.) dissolved in THF (10 mL) was added dropwise. The reaction mixture was stirred overnight at room temperature under argon. Upon completion the reaction was diluted with ethyl acetate. The organic layer was washed with water, brine, dried over Na2S04, and concentrated under reduced pressure. The residue was then purified by column chromatography (0 - 20% C^CUhexanes) to yield 104 (0.796 g, 64% yield). lH NMR (500 MHz, CDCL) d 7.44 - 7.27 (m, 5H), 6.90 - 6.80 (m, 2H), 6.56 (dt, J = 10.5, 2.2 Hz, 1H), 5.16 (d, J = 3.9 Hz, 2H), 4.45 (tt, J = 6.9, 3.5 Hz, 1H), 3.72 (ddd, J = 13.6, 8.1, 3.8 Hz, 2H), 3.53 - 3.42 (m, 2H), 1.92 (t, J = 9.5 Hz, 2H), 1.77 (p, J = 6.9 Hz, 2H); 13C NMR (126 MHz, CDCL) d 163.51 (d, 7 = 249.6 Hz), 159.01 (d, J = 11.7 Hz), 155.30, 136.80, 128.59, 128.13, 127.97, 122.90 (d, J = 12.5 Hz), 115.29 (d, J = 3.2 Hz), 111.92 (d, J = 24.9 Hz), 102.79 (d, J = 24.5 Hz), 72.65, 67.29, 40.65, 30.24; LRMS-ESI: Exact mass calcd for CigHigFNNaCL [M + Na]+: 430.0; found: 430.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 4 h / 0 - 12 °C 2: Aluminum Chloride / dichloromethane / 0.5 h / 0 °C 3: sodium hydride / mineral oil; tetrahydrofuran / 2.5 h / 0 - 15 °C 4: diisobutylaluminium hydride / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere |
Tags: 433939-27-6 synthesis path| 433939-27-6 SDS| 433939-27-6 COA| 433939-27-6 purity| 433939-27-6 application| 433939-27-6 NMR| 433939-27-6 COA| 433939-27-6 structure
[ 29578-39-0 ]
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P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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