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CAS No. : | 122306-01-8 | MDL No. : | MFCD04974508 |
Formula : | C6H6BrNO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QPPDKOIDAYZUHN-UHFFFAOYSA-N |
M.W : | 188.02 | Pubchem ID : | 6421249 |
Synonyms : |
6-Bromo-3-pyridinemethanol
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.17 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 38.06 |
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) : | -6.74 cm/s |
Log Po/w (iLOGP) : | 1.67 |
Log Po/w (XLOGP3) : | 0.99 |
Log Po/w (WLOGP) : | 1.18 |
Log Po/w (MLOGP) : | 0.65 |
Log Po/w (SILICOS-IT) : | 1.89 |
Consensus Log Po/w : | 1.28 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.06 |
Solubility : | 1.65 mg/ml ; 0.00877 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.27 |
Solubility : | 10.0 mg/ml ; 0.0532 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.71 |
Solubility : | 0.368 mg/ml ; 0.00196 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.6 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | 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 |
---|---|---|
> 95 %Chromat. | at 20℃; for 3 h; Sonication; Schlenk technique | First, Pd/AlO(OH) NP catalyst (40.0 mg, 0.16 mmol percent) and 1 mL of H2O/MeOH (v/v = 1/1) were added to a Schlenk tube. Next, the halogenated compound (0.25 mmol) was added. Finally, NaBH4 (0.75 mmol) was added to the reaction mixture and the vessel was closed. The reaction then continued during vigorous stirring under ultrasonic conditions at room temperature and was monitored by GC. Most of the reactions were completed over a time period of 1.5 - 4 h. After completion of the reaction, the catalyst was removed via simple centrifugation at 6000 rpm and then washed three times with methanol and water and allowed to dry for further use. The solvent was evaporated under vacuum. The products were purified by flash column chromatography and the dehalogenated products were then determined by 1H NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 20℃; for 3.5 h; | A solution of (6-bromo-3-ρyridinyl)methanol (50) (2.503 g, 13.3 mmol) and triphenylphosphine (4.026 g, 15.4 mmol) in anhydrous CH2Cl2 (100 mL) was carefully treated with recrystallized N-bromosuccinimide (2.732 g, 15.4 mmol) (water bath cooling), and the mixture was stirred at room temperature for 3.5 h. The resulting solution was concentrated, and then added to excess petroleum ether at the top of a silica gel column (100 g in petroleum ether), rinsing on with minimal extra CH2Cl2. Elution with petroleum ether firstly gave foreruns, and then further elution with 15-25percent Et2O/pentane gave pure 2-bromo-5-(bromomethyl)pyridine (51) (Schubert et al., 1999) (3.045 g, 91percent) as a lachrymatory white solid that was used directly in the next step; 1II NMR (CDCl3) δ 8.38 (d, J = 2.5 Hz, 1 H), 7.59 (dd, J - 8.2, 2.6 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 1 H), 4.42 (s, 2 H). |
91% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 20℃; for 3.5 h; | F. Synthesis of (6S)-6-[6-(4-fluorophenyl)-3-pyridinyl]methoxy}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (5) by the method of Scheme 4 A solution of (6-bromo-3-pyridinyl)methanol (50) (2.503 g, 13.3 mmol) and triphenylphosphine (4.026 g, 15.4 mmol) in anhydrous CH2Cl2 (100 mL) was carefully treated with recrystallized N-bromosuccinimide (2.732 g, 15.4 mmol) (water bath cooling), and the mixture was stirred at room temperature for 3.5 h. The resulting solution was concentrated, and then added to excess petroleum ether at the top of a silica gel column (100 g in petroleum ether), rinsing on with minimal extra CH2Cl2. Elution with petroleum ether firstly gave foreruns, and then further elution with 15-25percent Et2O/pentane gave pure 2-bromo-5-(bromomethyl)pyridine (51) (Schubert et al., 1999) (3.045 g, 91percent) as a lachrymatory white solid that was used directly in the next step; 1H NMR (CDCl3) δ 8.38 (d, J=2.5 Hz, 1H), 7.59 (dd, J=8.2, 2.6 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 4.42 (s, 2H). |
87% | With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃; Inert atmosphere | To a solution of (6-bromopyridin-3-yl)methanol (3.0 g, 16.0 mmol) in DCM (60 mL) was added triphenylphosphine (4.82 g, 18.4 mmol). After addition was completed, themixture was degassed three times under N2. Then a solution of CBr4 (5.84 g, 17.6 mmol) in DCM (15 mL) was added dropwise at 0°C, and the reaction was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1 to 15: 1) to give 2-bromo-5-(bromomethyl)pyridine (3.46 g, 87.0percent yield) as a white solid. LC10 MS: m/z 252 [M+Hj |
78% | With phosphorus tribromide In dichloromethane at 0 - 20℃; for 3 h; | To a stirred solution of (6-Bromopyridin-3-yl) methanol (2 g, 0.01 mol) in DCM (40 mL), PBr3 (14.3 g, 0.05 mol)) was added at 0°C and allowed to stir RT for 3 h. The reaction was monitored by TLC and LC S. The crude reaction mass was diluted with 20 mL of ice cold water and basified with sat. NaHC03 solution to a pH- 8 extracted with DCM (2 X 20 mL), washed with brine, the organic layer was dried over anhydrous NaaSC^, evaporated to get crude resiude that was purified in 100-200 silica gel in 10 percent EtOAc/Hexane to get 2.1 g (78percent) of the title compound as an off white gummy solid. (0771) LC-MS (method 23): R, = 1.91 min; m/z = 251.74 (M+H++2). |
62% | With phosphorus tribromide In diethyl ether at 20℃; for 1 h; | EXAMPLE 474-((6-(2-(2,4-Difluorophenyl)-l,l-difluoro-2-hydroxy-3-(lH-tetrazol-l- yl)propyl)pyridin-3-yl)methoxy)benzonitrile (79) and 4-((6-(2-(2,4-difluorophenyl)-l,l- difluoro-2-hydroxy-3-(2H-tetrazol-2-yl)propyl)pyridin-3-yl)methoxy)benzonitrile (80)To a stirred solution of compound J (prepared as in the first step of Example 17; 2.0 g, 10.75 mmol) in CH3OH (30 mL) was added NaBH4 (0.53 g, 13.97 mmol) portionwise at 0 °C and the reaction mixture was stirred at 0 °C for 1 h. After completion of the reaction (by TLC), CH3OH was removed under reduced pressure, and the reaction mixture was diluted with ice- cold water (75 mL) and extracted with EtOAc (2 x 75 mL). The combined organic layers were washed with water (75 mL) and brine (75 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 40percent EtOAc/hexanes) afforded compound AV (1.4 g, 7.44 mmol, 69percent) as a yellow solid. 1H NMR (400 MHz, CDC13): δ 8.35 (s, 1H), 7.59 (dd, J = 8.0, 2.4 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 4.71 (d, J = 6.0 Hz, 2H), 2.03 (t, J = 6.0 Hz, OH). MS (ESI): m/z 188 [M+] .To a stirred solution of compound AV (1.0 g, 5.31 mmol) in Et20 (20 mL) was added phosphorus tribromide (PBr3; 1.5 mL, 15.95 mmol) at 0 °C, and the mixture was stirred for 1 h at RT. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with ice-cold water (30 mL), adjusted to pH~8 using satd NaHC03 and extracted with EtOAc (2 x 100 mL). The combined orgainc extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (10percent EtOAc/hexanes) afforded compound AW (0.83 g, 3.30 mmol, 62percent) as a colorless liquid. 1H NMR (400 MHz, CDC13): δ 8.38 (d, J = 2.4 Hz, 1H), 7.59 (dd, J = 8.0, 2.4 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 4.41 (s, 2H).To a stirred suspension of 4-hydroxybenzonitrile (0.39 g, 3.30 mmol) and Cs2C03 (1.62 g, 4.96 mmol) in DMF (10 mL) was added compound AW (0.83 g, 3.30 mmol) at RT, and the mixture was stirred for 4 h. After completion of the reaction (by TLC), the reaction mixture was quenched with ice-cold water (25 mL) and extracted with EtOAc (4 x 50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 10percent EtOAc/hexanes) afforded compound AX (0.90 g, 3.11 mmol, 94percent) as a pale yellow solid. 1H NMR (500 MHz, CDC13): δ 8.44 (d, J = 2.0 Hz, 1H), 7.64-7.61 (m, 3H), 7.54 (d, J = 8.5 Hz, 1H), 7.01 (d, J = 8.5 Hz, 2H), 5.08 (s, 2H). MS (ESI): m/z 291 [M+2]+.To a stirred suspension of copper powder (1.55 g, 6.22 mmol) in DMSO (10 mL) was added ethyl 2-bromo-2,2-difluoroacetate (0.63 g, 3.11 mmol) at RT and the mixture was stirred for 1 h. A solution of compound AX (0.9 g, 3.11 mmol) in DMSO (5 mL) was added to the reaction mixture and stirring was continued for another 16 h at RT. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with satd NH4C1 solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 25percent EtOAc/hexane) afforded compound AY (0.5 g, 1.5 mmol, 49percent) as a pale yellow solid. 1H NMR (500 MHz, CDC13): δ 8.71 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 9.0 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 5.18 (s, 2H), 4.38 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H). MS (ESI): m/z 334 [M+2]+.To a stirred solution of l-bromo-2,4-difluorobenzene (348 mg, 1.80 mmol) in Et20 (10 mL) was added w-BuLi (1.6 M in hexane; 0.7 mL, 1.80 mmol) at -78 °C, and the mixture was stirred for 30 min under inert atmosphere. A solution of compound AY (500 mg, 1.50 mmol) in Et20 (30 mL) was added to the reaction mixture at -78 °C and stirring was continued for another 2 h. After completion of the reaction (by TLC), the reaction mixture was quenched with satd NH4C1 solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the crude AZ (1.5 g) as a brownish liquid. This crude material was used in the next step without any further purification. MS (ESI): m/z 401 [M+H]+.To a stirred solution of crude AZ (650 mg, crude) in Et20 (100 mL) was added freshly prepared diazomethane [prepared by dissolving NMU (1.67 g, 16.25 mmol) in a 1 : 1 mixture of 10percent KOH solution (100 mL) and Et20 (100 mL) at 0 °C followed by separation and drying of the organic layer using KOH pellets] at -5 °C and the mixture was stirred for 2 h. The resulting reaction mixture was allowed to warm to RT and stirring was continued for another 16 h; progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 25percent EtOAc/hexanes) afforded compound BA (250 mg, 0.60 mmol, 37percent) as a yellow liquid. 1H NMR (400 MHz, CDC13): δ 8.73 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.65-7.53 (m, 3H), 7.38-7.36 (m, 1H), 7.03 (d, J = 8.0 Hz, 2H), 6.86-6.71 (m, 2H), 5.18 (s, 2H), 3.45 (d, J = 5.2 Hz, 1H), 2.98 (t, J = 5.2 Hz, 1H). MS (ESI): m/z 415 [M+H]+.To a stirred solution of compound BA (250 mg, 0.60 mmol) in dry DMF (8 mL) was added iH-tetrazole (62.5 mg, 0.90 mmol) followed by K2C03 (83.3 mg, 0.60 mmol) at RT under inert atmosphere. The reaction mixture was heated to 65 °C and stirred for 16 h. After completion of the reaction (by TLC), the reaction mixture was quenched with ice-cold water and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography afforded 80 (40 mg, 0.15 mmol, 13percent; eluent: 35percent EtOAc/hexanes) as a yellow liquid and 79 (75 mg, 0.28 mmol, 25percent; eluent: 60percent EtOAc/hexanes) as a thick yellow solid. Compound 79: 1H NMR (400 MHz, CDC13): δ 8.74 (s, 1H), 8.58 (s, 1H), 7.90 (dd, J = 8.0, 2,0 Hz, 1H), 7.66-7.62 (m, 3H), 7.45 (br s, OH), 7.40-7.34 (m, 1H), 7.02 (d, J = 8.0 Hz, 2H), 6.80-6.65 (m, 2H), 5.52 (d, J = 14.0 Hz, 1H), 5.18 (d, J = 14.0 Hz, 1H), 5.16 (s, 2H). MS (ESI): m/z 485 [M+H]+. HPLC: 97percent. Compound 80: 1H NMR (400 MHz, CDC13): δ 8.63 (s, 1H), 8.31 (s, 1H), 7.90 (dd, J = 8.4, 1.6 Hz, 1H), 7.66-7.62 (m, 3H), 7.44-7.38 (m, 1H), 7.03 (d, J = 8.4 Hz, 2H), 6.83-6.67 (m, 2H), 6.63 (br s, OH), 5.82 (d, J = 14.0 Hz, 1H), 5.40 (d, J = 14.0 Hz, 1H), 5.16 (s, 2H). MS (ESI): m/z 485 [M+H]+. HPLC: 97percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium tetrahydroborate In methanol at 20 - 30℃; for 2 h; | To a solution of 6-bromonicotinaldehyde (20.0 g, 0.1 1 mol) in MeOH (108 mL) was added portionwise NaBH4 (4.88 g, 0.026 mol) at 20-30°C and the reaction mixture was stirred at room temperature for 2 hours then diluted with saturated aqueous NH4CI solution. The combined mixture was concentrated to remove MeOH and resultant aqueous solution was extracted with EtOAc. The extract was washed with saturated aqueous NaHC03 solution, brine, dried over MgS04, filtered and concentrated to afford title compound 94 (18.61 g, 92 percent yield) as an pale yellow solid. ?-NMR (300 MHz, CDC13) ? (ppm): 8.36 (d, J = 2.7 Hz, 1 H), 7.60 (dd, J = 8.1 , 2.7 Hz, 1 H), 7.49 (d, J = 8.1 Hz, 1H), 4.72 (s, 2H), 1.95 (s, 1 H). |
69% | at 0℃; | EXAMPLE 474-((6-(2-(2,4-Difluorophenyl)-l,l-difluoro-2-hydroxy-3-(lH-tetrazol-l- yl)propyl)pyridin-3-yl)methoxy)benzonitrile (79) and 4-((6-(2-(2,4-difluorophenyl)-l,l- difluoro-2-hydroxy-3-(2H-tetrazol-2-yl)propyl)pyridin-3-yl)methoxy)benzonitrile (80)To a stirred solution of compound J (prepared as in the first step of Example 17; 2.0 g, 10.75 mmol) in CH3OH (30 mL) was added NaBH4 (0.53 g, 13.97 mmol) portionwise at 0 °C and the reaction mixture was stirred at 0 °C for 1 h. After completion of the reaction (by TLC), CH3OH was removed under reduced pressure, and the reaction mixture was diluted with ice- cold water (75 mL) and extracted with EtOAc (2 x 75 mL). The combined organic layers were washed with water (75 mL) and brine (75 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 40percent EtOAc/hexanes) afforded compound AV (1.4 g, 7.44 mmol, 69percent) as a yellow solid. 1H NMR (400 MHz, CDC13): δ 8.35 (s, 1H), 7.59 (dd, J = 8.0, 2.4 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 4.71 (d, J = 6.0 Hz, 2H), 2.03 (t, J = 6.0 Hz, OH). MS (ESI): m/z 188 [M+] .To a stirred solution of compound AV (1.0 g, 5.31 mmol) in Et20 (20 mL) was added phosphorus tribromide (PBr3; 1.5 mL, 15.95 mmol) at 0 °C, and the mixture was stirred for 1 h at RT. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with ice-cold water (30 mL), adjusted to pH~8 using satd NaHC03 and extracted with EtOAc (2 x 100 mL). The combined orgainc extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (10percent EtOAc/hexanes) afforded compound AW (0.83 g, 3.30 mmol, 62percent) as a colorless liquid. 1H NMR (400 MHz, CDC13): δ 8.38 (d, J = 2.4 Hz, 1H), 7.59 (dd, J = 8.0, 2.4 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 4.41 (s, 2H).To a stirred suspension of 4-hydroxybenzonitrile (0.39 g, 3.30 mmol) and Cs2C03 (1.62 g, 4.96 mmol) in DMF (10 mL) was added compound AW (0.83 g, 3.30 mmol) at RT, and the mixture was stirred for 4 h. After completion of the reaction (by TLC), the reaction mixture was quenched with ice-cold water (25 mL) and extracted with EtOAc (4 x 50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 10percent EtOAc/hexanes) afforded compound AX (0.90 g, 3.11 mmol, 94percent) as a pale yellow solid. 1H NMR (500 MHz, CDC13): δ 8.44 (d, J = 2.0 Hz, 1H), 7.64-7.61 (m, 3H), 7.54 (d, J = 8.5 Hz, 1H), 7.01 (d, J = 8.5 Hz, 2H), 5.08 (s, 2H). MS (ESI): m/z 291 [M+2]+.To a stirred suspension of copper powder (1.55 g, 6.22 mmol) in DMSO (10 mL) was added ethyl 2-bromo-2,2-difluoroacetate (0.63 g, 3.11 mmol) at RT and the mixture was stirred for 1 h. A solution of compound AX (0.9 g, 3.11 mmol) in DMSO (5 mL) was added to the reaction mixture and stirring was continued for another 16 h at RT. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with satd NH4C1 solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 25percent EtOAc/hexane) afforded compound AY (0.5 g, 1.5 mmol, 49percent) as a pale yellow solid. 1H NMR (500 MHz, CDC13): δ 8.71 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 9.0 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 5.18 (s, 2H), 4.38 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H). MS (ESI): m/z 334 [M+2]+.To a stirred solution of l-bromo-2,4-difluorobenzene (348 mg, 1.80 mmol) in Et20 (10 mL) was added w-BuLi (1.6 M in hexane; 0.7 mL, 1.80 mmol) at -78 °C, and the mixture was stirred for 30 min under inert atmosphere. A solution of compound AY (500 mg, 1.50 mmol) in Et20 (30 mL) was added to the reaction mixture at -78 °C and stirring was continued for another 2 h. After completion of the reaction (by TLC), the reaction mixture was quenched with satd NH4C1 solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the crude AZ (1.5 g) as a brownish liquid. This crude material was used in the next step without any further purification. MS (ESI): m/z 401 [M+H]+.To a stirred solution of crude AZ (650 mg, crude) in Et20 (100 mL) was added freshly prepared diazomethane [prepared by dissolving NMU (1.67 g, 16.25 mmol) in a 1 : 1 mixture of 10percent KOH solution (100 mL) and Et20 (100 mL) at 0 °C followed by separation and drying of the organic layer using KOH pellets] at -5 °C and the mixture was stirred for 2 h. The resulting reaction mixture was allowed to warm to RT and stirring was continued for another 16 h; progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 25percent EtOAc/hexanes) afforded compound BA (250 mg, 0.60 mmol, 37percent) as a yellow liquid. 1H NMR (400 MHz, CDC13): δ 8.73 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.65-7.53 (m, 3H), 7.38-7.36 (m, 1H), 7.03 (d, J = 8.0 Hz, 2H), 6.86-6.71 (m, 2H), 5.18 (s, 2H), 3.45 (d, J = 5.2 Hz, 1H), 2.98 (t, J = 5.2 Hz, 1H). MS (ESI): m/z 415 [M+H]+.To a stirred solution of compound BA (250 mg, 0.60 mmol) in dry DMF (8 mL) was added iH-tetrazole (62.5 mg, 0.90 mmol) followed by K2C03 (83.3 mg, 0.60 mmol) at RT under inert atmosphere. The reaction mixture was heated to 65 °C and stirred for 16 h. After completion of the reaction (by TLC), the reaction mixture was quenched with ice-cold water and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography afforded 80 (40 mg, 0.15 mmol, 13percent; eluent: 35percent EtOAc/hexanes) as a yellow liquid and 79 (75 mg, 0.28 mmol, 25percent; eluent: 60percent EtOAc/hexanes) as a thick yellow solid. Compound 79: 1H NMR (400 MHz, CDC13): δ 8.74 (s, 1H), 8.58 (s, 1H), 7.90 (dd, J = 8.0, 2,0 Hz, 1H), 7.66-7.62 (m, 3H), 7.45 (br s, OH), 7.40-7.34 (m, 1H), 7.02 (d, J = 8.0 Hz, 2H), 6.80-6.65 (m, 2H), 5.52 (d, J = 14.0 Hz, 1H), 5.18 (d, J = 14.0 Hz, 1H), 5.16 (s, 2H). MS (ESI): m/z 485 [M+H]+. HPLC: 97percent. Compound 80: 1H NMR (400 MHz, CDC13): δ 8.63 (s, 1H), 8.31 (s, 1H), 7.90 (dd, J = 8.4, 1.6 Hz, 1H), 7.66-7.62 (m, 3H), 7.44-7.38 (m, 1H), 7.03 (d, J = 8.4 Hz, 2H), 6.83-6.67 (m, 2H), 6.63 (br s, OH), 5.82 (d, J = 14.0 Hz, 1H), 5.40 (d, J = 14.0 Hz, 1H), 5.16 (s, 2H). MS (ESI): m/z 485 [M+H]+. HPLC: 97percent. |
1.9 g | With sodium tetrahydroborate In tetrahydrofuran at 0 - 20℃; for 2 h; | At 0 °C ice bath, add NaBH4 (1.640 g) to a solution of 2-bromo-5-mercaptopyridine (2.010 g) in THF (20 mL), after adding NaBH4, remove the ice bath, warm naturally to room temperature. After stirring at room temperature for 2 hours, The reaction mixture was quenched with water (50 mL) Extracted with EA (50 mL × 2), The combined organic phases were dried over anhydrous Na2SO4 and concentrated. Purified by column chromatography (PE/EA=5/1), 1.900 g of (6-bromopyridin-3-yl)methanol were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.5% | Stage #1: With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0℃; for 0.333333 h; Stage #2: With sodium tetrahydroborate In tetrahydrofuran; water at 0℃; for 1.83333 h; |
After dissolving 6-bromonicotinic acid (65.7 g, 0.325 mol) in tetrahydrofuran (1600 ml), triethylamine (54 ml, 0.39 mol) and ethyl chloroformate (32.6 ml, 0.341 mol) were added while stirring on ice. The mixture was stirred for 20 minutes while cooling on ice, and the white crystals which precipitated upon filtration were removed and washed with tetrahydrofuran. The filtrate was stirred while cooling on ice, and an aqueous solution (211 ml) of sodium borohydride (18.4 g, 0.488 mol) was gradually added dropwise over a period of 30 minutes. After continued stirring for 1 hour and 20 minutes while cooling on ice, 800 ml of water was added and extraction was performed with ethyl acetate (600 ml x 2), and then after washing the combined organic layers with brine (300 ml) and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to yield the title compound (45.5 g, 74.5percent). This was used without further purification for the following reaction.1H-NMR(CDCl3)δ(ppm) 4.70(2H,s), 7.46(1H,d,J=8.0Hz), 7.59(1H,d,J=8.0Hz), 8.34(1H,brs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 1 h; | 6-bromonicotinic acid methyl ester (1.00g, 4.63mmol) was dissolved in tetrahydrofuran (20 mL), and at 0°C, was added lithium aluminum lithium aluminum hydride (351mg, 9.26mmol), the reaction for one hour. Was added water (10 mL) to quench the reaction. Extracted with ethyl acetate (20mLx3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure by silica gel column chromatography separation and purification: to give (6-bromo (11 petroleum ether / ethyl acetate, Rf = 0.3) 3-yl) methanol (600mg, yellow oil). yield: 69percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With BH3 In tetrahydrofuran; water | Step 2) 2-Bromo-5-hydroxymethylpyridine To a cooled (0° C.), stirred suspension of 6-bromonicotinic acid (13.8 g, 0.068 mol), prepared according to Campbell, et al. Aust. J. Chem. 1971, 24, 277, in THF (20 mL) was added 1.0M BH3 in THF (204 mL, 0.204 mol). The mixture was stirred at room temperature for 3 h, recooled to 0° C., and saturated aqueous K2 CO3 and water were added. The mixture was extracted with EtOAc, and the combined extracts were washed with water, dried (MgSO4), and concentrated to give a yellow oil. Purification by flash chromatography (2percent MeOH/CH2 Cl2) gave 7.5 g (59percent) of a yellow solid, mp 49°-51° C. 1 H NMR (DMSO-d6): d 4.50 (d, J=5.7 Hz, 2H), 5.40 (t, J=5.7 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.70 (dd, J=8.3 Hz, 1.5 Hz, 1H), 8.35 (d, J=1.5 Hz, 1H). |
59% | With BH3 In tetrahydrofuran; water | Step 1) 2-Bromo-5-hydroxymethylpyridine To a cooled (0° C.), stirred suspension of 6-bromonicotinic acid (13.8 g, 0.068 mol), prepared according to Campbell, et al. Aust. J. Chem. 1971, 24, 277, in THF (20 mL) was added 1.0M BH3 in THF (204 mL, 0.204 mol). The mixture was stirred at room temperature for 3 h, recooled to 0° C., and saturated aqueous K2 CO3 and water were added. The mixture was extracted with EtOAc, and the combined extracts were washed with water, dried, and concentrated to give a yellow oil. Purification by flash chromatography (2percent MeOH/CH2 Cl2) gave 7.5 g (59percent) of a yellow solid, mp 49°-51° C. 1 H NMR (DMSO-d6) δ 4.50 (d, J=5.7 Hz, 2H), 5.40 (t, J=5.7 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.70 (dd, J=8.3, 1.5 Hz, 1H), 8.35 (d, J=1.5 Hz, 1H). |
59% | With BH3 In tetrahydrofuran; water | Step 2 2-Bromo-5-hydroxymethylpyridine To a cooled (0° C.), stirred suspension of 6-bromonicotinic acid (13.8 g, 0.068 mol), prepared according to Campbell, et al. Aust. J. Chem. 1971, 24, 277, in THF (20 mL) was added 1.0M BH3 in THF (204 mL, 0.204). The mixture was stirred at room temperature for 3 h, recolled to 0° C., and saturated aqueous K2 CO3 and water were added. The mixture was extracted with EtOAc, and the combined extracts were washed with water, dried (MgSO4), and concentrated to give a yellow oil. Purification by flash chromatography (2percent MeOH/CH2 Cl2) gave 7.5 g (59percent) of a yellow solid, mp 49°-51° C. 1 H NMR (DMSO-d6): δ 4.50 (d, J=5.7 Hz, 2H), 5.40 (t, J=5.7 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.70 (dd, J=8.3 Hz, 1.5 Hz, 1H), 8.35 (d, J=1.5 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.05 g | With thionyl chloride In dichloromethane at 0 - 20℃; for 2 h; | A solution of (6-bromopyridin-3-yl)methanol (1.000 g) in DCM (10 mL) was cooled to EtOAc. Ethylene was added dropwise thionylchloride (1.260 g) in remove the ice bath after the addition. Stir for 2 hours to allow the solution to naturally warm to room temperature. Direct concentration gave 1.050 g of 2-bromo-5-(chloromethyl)pyridine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With thionyl chloride In dichloromethane at 20℃; for 2 h; | Synthesis of 2-bromo-5-(chloromethyl)pyridine hydrochloride (264): (6- Bromopyridin-3-yl)methanol (1) (1.0 g, 5.3 mmol) was dissolved in CH2C12 (15 mL), SOCl2 (3 mL, 42 mmol) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to give 2-bromo-5- (chloromethyl)pyridine hydrochloride (263) as white solid (1.3 g, 98percent yield). LCMS: m/z 205.1 [M+H]+; = 1.78 min. |
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