* 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.
With potassium permanganate In water for 3 h; Heating / reflux
To [A] solution of 2-fluoro-6-methyl-pyridine (2.5g, 22.5 [MMOL)] in water (170 ml) was added portionwise [KMN04] (2g, 12.65 mmol) and the mixture was heated to reflux. Then [KMN04] (8g, 50.63 [MMOL)] was added portionwise and the mixture was heated under reflux for 3 hours. On cooling, the precipitate was filtered and the filtrate was acidified with a solution of HCI and then concentrated under reduced pressure. The residue was triturated with hot EtOH, the solid was filtered and the filtrate was concentrated to dryness under reduced pressure. The title compound was obtained as a white solid (1.7g, 53percent); m. p. [137°C.]
53%
With potassium permanganate In water for 3 h; Heating / reflux
To a solution of 2-fluoro-6-methyl-pyridine (2.5g, 22.5 [MMOL)] in water (170 ml) was added portion-wise [KMN04] (2g, 12.65 [MMOL)] and the mixture was heated to reflux. [KMN04] [(8G,] 50.63 [MMOL)] was added portion-wise and the mixture was heated under reflux for 3 hours and then cooled. The precipitate was filtered and the filtrate was acidified with a solution of HCI and then concentrated under reduced pressure. The residue was triturated with hot [ETOH,] the solid filtered and the filtrate was concentrated to dryness under reduced pressure. The title compound was obtained as a white solid (1.7g, 53percent); m. p. [137°C.]
Reference：
[1] Patent: WO2004/13135, 2004, A1, . Location in patent: Page 46-47
[2] Patent: WO2004/13138, 2004, A2, . Location in patent: Page 22
[3] Journal of Fluorine Chemistry, 2011, vol. 132, # 8, p. 541 - 547
[4] Journal of the American Chemical Society, 1949, vol. 71, p. 4152
2
[ 407-22-7 ]
[ 67-63-0 ]
[ 402-69-7 ]
Yield
Reaction Conditions
Operation in experiment
45%
With potassium permanganate In chloroform; water
PREPARATION 233 6-Fluoropyridine-2-carboxylic acid To a heterogeneous solution of 2-fluoro-6-methyl-pyridine (9.65 g, 86.8 mmol) in water (400 mL) was added potassium permanganate (31.6 g, 200 mmol), and the reaction was heated to approximately 100° C. After 30 minutes, additional potassium permanganate (16.5 g, 104 mmol) was added, and the reaction heated at 100° C. overnight. The reaction was filtered through celite to remove manganese salts. The mother liquor was washed with ethyl ether (200 mL*3), neutralized to pH 7, and concentrated down to approximately 100 mL total volume. The aqueous solution was acidified to pH 2 with concentrated HCl and extracted with ethyl acetate, followed by 20percent i-PrOH/CHCl3 (*3). The combined organic layers were dried over MgSO4 and concentrated. The solids were suspended in chloroform, sonicated, then filtered to remove remaining side products. The mother liquor was concentrated to give 5.47 g as a white crystalline solid, 45percent yield. 1H NMR: consistent with structure. MS (ion spray) 140 (M-).
Reference：
[1] Patent: US2003/100576, 2003, A1,
3
[ 1824-81-3 ]
[ 407-22-7 ]
Reference：
[1] Tetrahedron, 1996, vol. 52, # 1, p. 23 - 36
[2] Journal of Fluorine Chemistry, 2011, vol. 132, # 8, p. 541 - 547
[3] Journal of the American Chemical Society, 1949, vol. 71, p. 4152
[4] Journal of Fluorine Chemistry, 1988, vol. 38, p. 435 - 438
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 80℃; for 3 h;
2-Fluoro-6-methylpyridine(4.32 g, 38.9 mmol), NBS (6 g, 33.7 mmol) and AIBN (0.56 g,3.4 mmol) were mixed and CCl 4 (50 mL) was added, followed by heating to 80 ° C. for 3 h. After cooling, the reaction mixture was filtered through Celite and filteredThe concentrated liquid was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 9/1) to give 4 g of a yellow oilShape, yield: 54percent.
37%
With N-Bromosuccinimide; 1,1'-azobis(1-cyanocyclohexanenitrile) In tetrachloromethane for 18 h; UV-irradiation
Preparation 442-Bromomethyl-6-fluoro-pyridineCombine 2-methyl-6-fluoro-pyridine (19.6 g, 176 mmol), l,l'-azobis- (cyclohexane-carbonitrile) (0.431 g, 1.77 mmol), and freshly recystallized N- bromo-succinimide (32.96 g, 185 mmol) in carbon tetrachloride (200 mL) and stir in a 1000 mL flask while radiating with UV light for 18 h. Allow to cool, then filter to remove succinimide and wash with dilute Na2S2O3 solution. Dry over Na2SO4, EPO <DP n="150"/>filter and evaporate to give an amber oil. Purify by silica gel chromatography, eluting with 0-30percent EtOAc/hexanes to obtain 12.3 g (37percent) of a clear oil. MS 100percent (m/e) 190 (EI); 1B. NMR (DMSO, 400 MHz): δ 8.03-7.95 (m, IH), 8.03-7.95 (m, IH), 7.48 (dd, IH, J=7.5, 2.6 Hz), 7.11 (dd, IH, J=7.9, 2.6 Hz), 4.63 (s, 2H).;
32.1%
With N-Bromosuccinimide In ethyl acetate at 20 - 65℃;
Add NBS (35.6 g, 0.20 mole) to a solution of 6-fluoro-2-methylpyridine (20 mL, 0.19 mole) in EtOAc (400 mL) at room temperature. When the temperature reaches 45° C., add AIBN (400 mg, 2.4 mmol). Heat the mixture at 65° C. for 6 h, then cool to room temperature and add hexane (1 L). Remove the white precipitate by filtration and wash the solid with hexane/EtOAc (1:1). Wash the filtrate with small amounts of aqueous Na2S2O3, NaHCO3, and brine. Dry the organics (Na2SO4), filter, then remove most of the solvent under vacuum at room temperature. Transfer the remaining solution to a distillation set-up. Remove the remaining solvent by distilling at atmospheric pressure, followed by the unreacted starting material at 80 mm (bp ca 70° C.; 11.2 g) and then the title product at 1 mm (bp ca 75° C.; 12.1 g, 32percent). NMR (300 MHz; CDCl3): 7.82 (1H; dd); 7.35 (1H; dd); 6.90 (1H; dd); 4.50 (2H; s).
Reference：
[1] Patent: CN106749268, 2017, A, . Location in patent: Paragraph 0729; 0730
[2] Patent: WO2007/2181, 2007, A2, . Location in patent: Page/Page column 148-149
[3] Patent: US2010/69404, 2010, A1, . Location in patent: Page/Page column 14
[4] Chemistry - A European Journal, 2016, vol. 22, # 5, p. 1602 - 1607
10
[ 407-22-7 ]
[ 100202-78-6 ]
[ 1243694-61-2 ]
Reference：
[1] Journal of Organic Chemistry, 2010, vol. 75, # 19, p. 6540 - 6548
11
[ 407-22-7 ]
[ 208110-81-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 1998, vol. 41, # 25, p. 5070 - 5083
[2] Patent: US2003/220348, 2003, A1,
[3] Journal of Fluorine Chemistry, 2011, vol. 132, # 8, p. 541 - 547
[4] Patent: US2003/69257, 2003, A1,
[5] Patent: WO2004/107863, 2004, A1, . Location in patent: Page 37
Reference：
[1] Journal of Organic Chemistry, 2000, vol. 65, # 23, p. 7718 - 7722
14
[ 407-22-7 ]
[ 315180-16-6 ]
Yield
Reaction Conditions
Operation in experiment
75%
With N-chloro-succinimide; dibenzoyl peroxide In acetic acid; acetonitrile at 85℃; for 22 h;
Step A: Preparation of 2-chloromethyl-6-fluoro-pyridine To a solution of 2-fluoro-6-methylpyridine (0.23 mL, 2.2 mmol) in acetonitrile (5 mL) was added N-chlorosuccinimide (440 mg, 3.3 mmol), benzoyl peroxide (14 mg, 0.044 mmol) and glacial acetic acid (10 uL). The solution was heated at 85° C. for four hours and at ambient temperature for eighteen hours. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The material was filtered and concentrated. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the chloromethyl compound as a colorless oil (240 mg, 75percent).
67%
With N-chloro-succinimide; dibenzoyl peroxide In acetonitrile at 85℃; for 3.5 h;
Manufacturing Example 45-1-1 2-Chloromethyl-6-fluoro-pyridine; A mixture of 2-fluoro-6-methylpyridine (420 mg, 3.78 mmol), N-chlorosuccimide (757 mg, 5.67 mmol), 75percent benzoyl peroxide (24.4 mg, 0.08 mmol), acetic acid (13 μL, 0.23 mmol) and acetonitrile (7 mL) was stirred for 3 hours and 30 minutes at 85° C. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (370.7 mg, 67percent).1H-NMR Spectrum (DMSO-d6) δ (ppm): 4.75 (2H, s), 7.17-7.19 (1H, m), 7.50-7.52 (1H, m), 8.02-8.08 (1H, m).
67%
With N-chloro-succinimide; acetic acid; dibenzoyl peroxide In acetonitrile at 85℃; for 3.5 h;
A mixture of 2-fluoro-6-methylpyridine (420 mg, 3.78 mmol), N-chlorosuccimide (757 mg, 5.67 mmol), 75percent benzoyl peroxide (24.4 mg, 0.08 mmol), acetic acid (13 μL, 0.23 mmol) and acetonitrile (7 mL) was stirred for 3 hours and 30 minutes at 85° C. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (370.7 mg, 67percent). 1H-NMR Spectrum (DMSO-d6) δ (ppm): 4.75 (2H, s), 7.17-7.19 (1H, m), 7.50-7.52 (1H, m), 8.02-8.08 (1H, m).
With potassium permanganate; In water; for 3h;Heating / reflux;
To [A] solution of 2-fluoro-6-methyl-pyridine (2.5g, 22.5 [MMOL)] in water (170 ml) was added portionwise [KMN04] (2g, 12.65 mmol) and the mixture was heated to reflux. Then [KMN04] (8g, 50.63 [MMOL)] was added portionwise and the mixture was heated under reflux for 3 hours. On cooling, the precipitate was filtered and the filtrate was acidified with a solution of HCI and then concentrated under reduced pressure. The residue was triturated with hot EtOH, the solid was filtered and the filtrate was concentrated to dryness under reduced pressure. The title compound was obtained as a white solid (1.7g, 53percent); m. p. [137°C.]
53%
With potassium permanganate; In water; for 3h;Heating / reflux;
To a solution of 2-fluoro-6-methyl-pyridine (2.5g, 22.5 [MMOL)] in water (170 ml) was added portion-wise [KMN04] (2g, 12.65 [MMOL)] and the mixture was heated to reflux. [KMN04] [(8G,] 50.63 [MMOL)] was added portion-wise and the mixture was heated under reflux for 3 hours and then cooled. The precipitate was filtered and the filtrate was acidified with a solution of HCI and then concentrated under reduced pressure. The residue was triturated with hot [ETOH,] the solid filtered and the filtrate was concentrated to dryness under reduced pressure. The title compound was obtained as a white solid (1.7g, 53percent); m. p. [137°C.]
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 3h;
2-Fluoro-6-methylpyridine(4.32 g, 38.9 mmol), NBS (6 g, 33.7 mmol) and AIBN (0.56 g,3.4 mmol) were mixed and CCl 4 (50 mL) was added, followed by heating to 80 C. for 3 h. After cooling, the reaction mixture was filtered through Celite and filteredThe concentrated liquid was purified by silica gel column chromatography (eluent: PE / EtOAc (v / v) = 9/1) to give 4 g of a yellow oilShape, yield: 54%.
37%
With N-Bromosuccinimide; 1,1'-azobis(1-cyanocyclohexanenitrile); In tetrachloromethane; for 18h;UV-irradiation;
Preparation 442-Bromomethyl-6-fluoro-pyridineCombine 2-methyl-6-fluoro-pyridine (19.6 g, 176 mmol), l,l'-azobis- (cyclohexane-carbonitrile) (0.431 g, 1.77 mmol), and freshly recystallized N- bromo-succinimide (32.96 g, 185 mmol) in carbon tetrachloride (200 mL) and stir in a 1000 mL flask while radiating with UV light for 18 h. Allow to cool, then filter to remove succinimide and wash with dilute Na2S2O3 solution. Dry over Na2SO4, EPO <DP n="150"/>filter and evaporate to give an amber oil. Purify by silica gel chromatography, eluting with 0-30% EtOAc/hexanes to obtain 12.3 g (37%) of a clear oil. MS 100% (m/e) 190 (EI); 1B. NMR (DMSO, 400 MHz): delta 8.03-7.95 (m, IH), 8.03-7.95 (m, IH), 7.48 (dd, IH, J=7.5, 2.6 Hz), 7.11 (dd, IH, J=7.9, 2.6 Hz), 4.63 (s, 2H).;
32.1%
With N-Bromosuccinimide;2,2'-azobis(isobutyronitrile); In ethyl acetate; at 20 - 65℃;
Add NBS (35.6 g, 0.20 mole) to a solution of 6-fluoro-2-methylpyridine (20 mL, 0.19 mole) in EtOAc (400 mL) at room temperature. When the temperature reaches 45 C., add AIBN (400 mg, 2.4 mmol). Heat the mixture at 65 C. for 6 h, then cool to room temperature and add hexane (1 L). Remove the white precipitate by filtration and wash the solid with hexane/EtOAc (1:1). Wash the filtrate with small amounts of aqueous Na2S2O3, NaHCO3, and brine. Dry the organics (Na2SO4), filter, then remove most of the solvent under vacuum at room temperature. Transfer the remaining solution to a distillation set-up. Remove the remaining solvent by distilling at atmospheric pressure, followed by the unreacted starting material at 80 mm (bp ca 70 C.; 11.2 g) and then the title product at 1 mm (bp ca 75 C.; 12.1 g, 32%). NMR (300 MHz; CDCl3): 7.82 (1H; dd); 7.35 (1H; dd); 6.90 (1H; dd); 4.50 (2H; s).
With potassium permanganate; In chloroform; water;
PREPARATION 233 6-Fluoropyridine-2-carboxylic acid To a heterogeneous solution of 2-fluoro-6-methyl-pyridine (9.65 g, 86.8 mmol) in water (400 mL) was added potassium permanganate (31.6 g, 200 mmol), and the reaction was heated to approximately 100° C. After 30 minutes, additional potassium permanganate (16.5 g, 104 mmol) was added, and the reaction heated at 100° C. overnight. The reaction was filtered through celite to remove manganese salts. The mother liquor was washed with ethyl ether (200 mL*3), neutralized to pH 7, and concentrated down to approximately 100 mL total volume. The aqueous solution was acidified to pH 2 with concentrated HCl and extracted with ethyl acetate, followed by 20percent i-PrOH/CHCl3 (*3). The combined organic layers were dried over MgSO4 and concentrated. The solids were suspended in chloroform, sonicated, then filtered to remove remaining side products. The mother liquor was concentrated to give 5.47 g as a white crystalline solid, 45percent yield. 1H NMR: consistent with structure. MS (ion spray) 140 (M-).
A. 2-Methoxy-6-methylpyridine Sodium (31.0 g, 1.35 mol) was added portionwise to methanol (500 mL) over 30 min with stirring in a flask equipped with a reflux cindenser. After the addition was complete, the reaction mixture was allowed to cool to ambient temperature. 2-Fluoro-6-methylpyridine (50 g, 450 mmol) was added portionwise with stirring. The reaction mixture was then heated to reflux temperature and stirred for 48 h. The mix was then cooled to ambient temperature and solvent was removed in vacuo to provide a yellow oil. The residue was taken up in water (500 mL) and three extractions with ether (200 mL) were performed. The combined organic layers were dried over MgSO4, filtered and solvent was removed in vacuo from the filtrate to give a yellow liquid: 1H-NMR(CDCl3, 300 MHz): delta 7.44 (dd, 1H, J=8,7), 6.71 (d, 1H, J=7), 6.53 (d, 1H, J=8), 3.91 (s, 3H), 2.45 (s, 3H).
With N-chloro-succinimide; dibenzoyl peroxide; In acetic acid; acetonitrile; at 85℃; for 22h;
Step A: Preparation of 2-chloromethyl-6-fluoro-pyridine To a solution of 2-fluoro-6-methylpyridine (0.23 mL, 2.2 mmol) in acetonitrile (5 mL) was added N-chlorosuccinimide (440 mg, 3.3 mmol), benzoyl peroxide (14 mg, 0.044 mmol) and glacial acetic acid (10 uL). The solution was heated at 85 C. for four hours and at ambient temperature for eighteen hours. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The material was filtered and concentrated. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the chloromethyl compound as a colorless oil (240 mg, 75%).
67%
With N-chloro-succinimide; dibenzoyl peroxide; In acetonitrile; at 85℃; for 3.5h;
Manufacturing Example 45-1-1 2-Chloromethyl-6-fluoro-pyridine; A mixture of 2-fluoro-6-methylpyridine (420 mg, 3.78 mmol), N-chlorosuccimide (757 mg, 5.67 mmol), 75% benzoyl peroxide (24.4 mg, 0.08 mmol), acetic acid (13 muL, 0.23 mmol) and acetonitrile (7 mL) was stirred for 3 hours and 30 minutes at 85 C. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (370.7 mg, 67%).1H-NMR Spectrum (DMSO-d6) delta (ppm): 4.75 (2H, s), 7.17-7.19 (1H, m), 7.50-7.52 (1H, m), 8.02-8.08 (1H, m).
67%
With N-chloro-succinimide; acetic acid; dibenzoyl peroxide; In acetonitrile; at 85℃; for 3.5h;
A mixture of 2-fluoro-6-methylpyridine (420 mg, 3.78 mmol), N-chlorosuccimide (757 mg, 5.67 mmol), 75% benzoyl peroxide (24.4 mg, 0.08 mmol), acetic acid (13 muL, 0.23 mmol) and acetonitrile (7 mL) was stirred for 3 hours and 30 minutes at 85 C. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (370.7 mg, 67%). 1H-NMR Spectrum (DMSO-d6) delta (ppm): 4.75 (2H, s), 7.17-7.19 (1H, m), 7.50-7.52 (1H, m), 8.02-8.08 (1H, m).
With N-chloro-succinimide; acetic acid; benzoic peroxyanhydride; In acetonitrile; at 85℃; for 12h;
To a solution of 2-fluoro-6-methylpyridine (8.00 g, 72.0 mmol, 7.41 mL, 1.00 eq) in acetonitrile (200 mL) was added l-chloropyrrolidine-2,5-dione (24.0 g, 180 mmol, 2.50. eq), benzoic peroxyanhydride (2.09 g, 8.64 mmol, 0.120 eq) and acetic acid (0.400 mL). The mixture was stirred at 85 C for 12 h. The mixture was concentrated to afford a residue. The residue was diluted with water (50.0 mL) and extracted with ethyl acetate (3 c 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 1/0 - 10/1) to afford 2-(chloromethyl)-6-fluoropyridine (4.50 g, 30.9 mmol, 43% yield) as a colorless oil. MS (ESI) rn/z 145.9 (M il
With caesium carbonate In dimethyl sulfoxide at 110℃; for 16h;
40.1
Example 40; Synthesis of 4-(3-(6-methylpyridin-2-yloxy)benzylidene)-N-(pyridin-3-yl)piperidine-1-carboxamide; Step 1; (3-(6-Methylpyridin-2-yloxy)phenyl)methanol; 3-Hydroxymethyl-phenol (3.69 g, 29.7 mmol), 2-fluoro-6-methyl-pyridine (3.00 g, 27 mmol,) and cesium carbonate (9.68 g, 29.7 mmol) were suspended in dimethylsulfoxide (25 mL) and heated to 110° C. After stirring for 16 h, the reaction was partitioned between water (250 mL) and ethyl acetate (250 mL). The organic layer was separated and the aqueous was extracted again with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10-50%, EtOAc:heptane) to afford the title compound (3.72 g, 64% yield) as an off-white solid.
Stage #1: 4-bromobenzenemethanol With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #2: 2-fluoro-6-methylpyridine In N,N-dimethyl-formamide at 0 - 20℃; for 5h;
3.1.1
Manufacturing Example 3-1-1 2-(4-Bromo-benzyloxy)-6-methyl-pyridine; To a solution of (4-bromo-phenyl)-methanol (4.54 g, 24.3 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride (999 mg, 25 mmol, 60% in oil) under nitrogen atmosphere on an ice bath (0° C.), which was stirred for 30 minutes at room temperature. 2-Fluoro-6-methylpyridine (1.8 g, 16.2 mmol) was then added to the reaction mixture on an ice bath (0° C.), and stirred for 5 hours at room temperature. The reaction mixture was partitioned into water and ethyl acetate on the ice bath (0° C.). The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:15) to obtain the title compound (3.65 g, 81%).1H-NMR Spectrum (CDCl3) δ (ppm): 2.44 (3H, s), 5.32 (2H, s), 6.57-6.59 (1H, m), 6.71-6.74 (1H, m), 7.26-7.35 (2H, m), 7.44-7.49 (3H m).
81%
Stage #1: 4-bromobenzenemethanol With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h;
Stage #2: 2-fluoro-6-methylpyridine In N,N-dimethyl-formamide at 0 - 50℃; for 5h;
3.1.1
To a solution of (4-bromo-phenyl)-methanol (4.54 g, 24.3 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride (999 mg, 25 mmol, 60% in oil) under nitrogen atmosphere on an ice bath (0° C.), which was stirred for 30 minutes at room temperature. 2-Fluoro-6-methylpyridine (1.8 g, 16.2 mmol) was then added to the reaction mixture on an ice bath (0° C.), and stirred for 5 hours at room temperature. The reaction mixture was partitioned into water and ethyl acetate on the ice bath (0° C.). The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:15) to obtain the title compound (3.65 g, 81%). 1H-NMR Spectrum (CDCl3) δ (ppm): 2.44 (3H, s), 5.32 (2H, s), 6.57-6.59 (1H, m), 6.71-6.74 (1H, m), 7.26-7.35 (2H, m), 7.44-7.49 (3H m).
To a suspension of sodium hydride (55% dispersion in mineral oil, 48 mg, 1.1 mmol) in THF (1.5 mL) was added a solution of <strong>[18718-79-1](5-methyl-3-phenyl-isoxazol-4-yl)-methanol</strong> (189 mg, 1.0 mmol) in THF (3 mL) at 0 C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of 2-fluoro-6-methylpyridine (122 mg, 1.1 mmol) in THF (3 mL) was added dropwise at 0 C. and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 4:1) afforded the title compound (135 mg, 48%) which was obtained as a yellow oil. MS: m/e=281.1 [M+H]+.
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 60℃; for 22h;
Under stirring, N-bromosuccinimide (1.65 g, 9.27 mmol, 1.0 eq.) and alpha,alpha?-azobisisobutyronitrile (152mg, 0.93 mmol, 0.1 eq.) were added to a solution of 10-4b (1.0 g, 9.00 mmol, 1.0 eq.) in carbon tetrachloride (30 mL). The mixture was heated at 60C for 22 hours. After cooling to rt, water (60mL) was added and the aqueous layer was extracted with dichloromethane (2 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The crude residue was purified by column chromatography (SiO2, dichloromethane/cyclohexane, 1/1, v/v) to give by order of elution: 2-dibromomethyl-6-fluoropyridine (0.31 g, 1.17 mmol, 13%) and the desired product (0.60 g, 3.16mmol, 35%) as colorless oils.
2.1. Typical Procedure A solution of ethylpyridine (1.6 mL, 14 mmol) in THF (50 mL) was cooled to -78 C. A solution of n-butyllithium in hexane (4.8 mL, 12 mmol) was added within 15 min, keeping the temperature below - 60 C during the addition. The resulting deep red solution was stirred at -78 C for 30 min. The temperature was then raised to -20 C, at which point 2-fluoropyridine (0.5 mL, 12 mmol) was added dropwise, keeping the temperature below -10 C. After raising the temperature to r. t. within 20 min, the mixture was refluxed for 1 h. After cooling to r. t., the electrophile (6 mmol) was added and the solution refluxed for 1 h (4), 2 h (5), 16 h (7), 36 h (6), or 48 h (8 and 1), respectively. After cooling to r. t., the reaction mixture was quenched with water and extracted three times with MTBE. Volatiles were then removed in vacuo and hexane was added to the oily residue. After stirring overnight, the precipitated solid was filtered off, washed with hexane and dried in vacuo. The products were obtained as slightly off-white solids.
With (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; 4,4'-di-tert-butyl-2,2'-bipyridine In tetrahydrofuran at 80℃; for 18h; Inert atmosphere; Glovebox; Overall yield = 75 %; Overall yield = 117 mg;
4 Example 4 Borylation of Pyridines Borylation of 2-Fluoro-6-Methylpyridine
Example 4Borylation of PyridinesBorylation of 2-Fluoro-6-MethylpyridineAn oven-dried 3 mL screw-cap Wheaton vial was charged inside a nitrogen-filled glovebox with [Ir(OMe)cod]2 (3.3 mg, 0.005 mmol) and dtbpy (2.7 mg, 0.01 mmol). THF (1.5 mL) was added, followed by B2pin2 (127 mg, 0.5 mmol) and 2-fluoro-6-methylpyridine (103 μL, 1.0 mmol). The vial was capped and heated outside of the glovebox at 80° C. for 18 h. 19F NMR analysis of the crude reaction mixture showed 78% conversion of starting material and formation of a 1:1.8 ratio of 3-Bpin:4-Bpin compounds. The reaction solvent was removed on a rotary evaporator, and the residue was purified by flash column chromatography using pentane-EtOAc mixtures as eluent providing a 1:3 mixture of 3- and 4-Bpin isomers, 2-fluoro-6-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine and 2-fluoro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, as a colorless oil (177 mg 75%): 1H NMR (500 MHz, CDCl3) δ 8.04 (dd, J=8.1, 7.8 Hz, 1H, Ha), 7.36 (d, J=2.3 Hz, 1H, He), 7.07-7.06 (s, 1H, Hd), 7.02 (dd, J=7.8, 2.2 Hz, 1H, Hb), 2.50 (s, 3H, 3-Bpin isomer), 2.49 (s, 3H, 4-Bpin isomer), 1.34 (s, 12H, both isomers); 19F NMR (470 MHz, CDCl3) δ -58.43 (d, J=8.1 Hz, 3-Bpin isomer), -69.80 (4-Bpin isomer)
tert-butyl (1-(6-(4-cyano-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)carbamate[ No CAS ]
tert-butyl (1-(6-(4-cyano-2-(6-methylpyridin-2-yl)-2H-indazol-6-yl)pyridin-2-yl)ethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: To a mixture of tert-butyl (l-(6-(4-cyano-l-(6-methylpyridin-2-yl)-lH-indazol-6- yl)pyridin-2-yl)ethyl)carbamate and tert-butyl (l-(6-(4-cyano-2-(6-methylpyridin-2-yl)-2H- indazol-6-yl)pyridin-2-yl)ethyl)carbamate (120 mg, 0.34 mmol, 1.0 eq) and TEA (51.4 mg, 0.51 mmol, 1.5 eq) in DCM (20 mL) was added (Boc)20 (88 mg, 0.41 mmol, 1.2 eq) at rt. The mixture was stirred at rt for 2 h and diluted with water (10 mL). The organic phase was washed with brine and dried over Na2S04. After filtration and concentration, the residue was directly used for next step without further purification. 123 mg, as yellow oil, Y: 80%. EST MS (M+H) +: 455.1.
tert-butyl (1-(6-(4-(aminomethyl)-1-(6-methylpyridin-2-yl)-1H-indazol-6-yl)pyridin-2-yl)ethyl)carbamate[ No CAS ]
tert-butyl (1-(6-(4-(aminomethyl)-2-(6-methylpyridin-2-yl)-2H-indazol-6-yl)pyridin-2-yl)ethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: The preparation of tert-butyl (l-(6-(4-(aminomethyl)-l-(6-methylpyridin-2-yl)-lH- indazol-6-yl)pyridin-2-yl)ethyl)carbamate and tert-butyl (l-(6-(4-(aminomethyl)-2-(6- methylpyridin-2-yl)-2H-indazol-6-yl)pyridin-2-yl)ethyl)carbamate was the same as that of 5- (4-(aminomethyl)-l-(6-(trifluoromethyl)pyridin-2-yl)-lH-indazol-6-yl)pyridin-3-amine. 100 mg, as yellow oil, ESI-MS (M+H) +: 459.1.
6-(6-acetylpyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carbonitrile[ No CAS ]
6-(6-acetylpyridin-2-yl)-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: The preparation of 6-(6-acetylpyridin-2-yl)-l-(6-methylpyridin-2-yl)-lH-indazole-4- carbonitrile and 6-(6-acetylpyridin-2-yl)-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonitrile was the same as that of tert-butyl (6-(6-acetylpyridin-2-yl)-l-(6-methylpyridin-2-yl)-lH- indazol-4-yl)carbamate. 262 mg, as a white solid, Y: 51 . The mixture of 6-(6-acetylpyridin- 2-yl)-l-(6-methylpyridin-2-yl)-lH-indazole-4-carbonitrile and 6-(6-acetylpyridin-2-yl)-2-(6- methylpyridin-2-yl)-2H-indazole-4-carbonitrile was difficult to be purified due to poor solubility. The mixture was directly used for next step. ESI-MS (M+H) +: 354.1.
(Z)-6-(6-(1-(hydroxyimino)ethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carbonitrile[ No CAS ]
(Z)-6-(6-(1-(hydroxyimino)ethyl)pyridin-2-yl)-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: The preparation of (Z)-6-(6-(l-(hydroxyimino)ethyl)pyridin-2-yl)-l-(6- methylpyridin-2-yl)-lH-indazole-4-carbonitrile and (Z)-6-(6-(l-(hydroxyimino)ethyl)pyridin- 2-yl)-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonitrile was the same as that of 2-(l-(6- (trifluoromethyl)pyridin-2-yl)-lH-indazol-6-yl)-5H-cyclopenta[b]pyridin-7(6H)-one oxime. 208 mg, as a white solid, Y: 76%. The mixture of (Z)-6-(6-(l-(hydroxyimino)ethyl)pyridin-2- yl)- 1 -(6-methylpyridin-2-yl)- lH-indazole-4-carbonitrile and (Z)-6-(6-(l - (hydroxyimino)ethyl)pyridin-2-yl)-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonitrile was difficult to be purified due to poor solubility. The mixture was directly used for next step. ESI-MS (M+H) +: 369.1.
6-(6-(1-aminoethyl)pyridin-2-yl)-1-(6-methylpyridin-2-yl)-1H-indazole-4-carbonitrile[ No CAS ]
6-(6-(1-aminoethyl)pyridin-2-yl)-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: The preparation of 6-(6-(l-aminoethyl)pyridin-2-yl)-l-(6-methylpyridin-2-yl)-lH- indazole-4-carbonitrile and 6-(6-(l-aminoethyl)pyridin-2-yl)-2-(6-methylpyridin-2-yl)-2H- indazole-4-carbonitrile was the same as that of 2-(l-(6-(trifluoromethyl)pyridin-2-yl)-lH- indazol-6-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-amine. 208 mg, as a white solid, Y: 43%. The mixture of 6-(6-(l-aminoethyl)pyridin-2-yl)-l-(6-methylpyridin-2-yl)-lH- indazole-4-carbonitrile and 6-(6-(l-aminoethyl)pyridin-2-yl)-2-(6-methylpyridin-2-yl)-2H- indazole-4-carbonitrile was difficult to be purified due to poor solubility. The mixture was directly used for next step. ESI-MS (M+H) +: 355.1.
tert-butyl (6-bromo-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)(methyl)carbamate[ No CAS ]
tert-butyl (6-bromo-2-(6-methylpyridin-2-yl)-2H-indazol-4-yl)(methyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: To a mixture of tert-butyl (6-bromo-l-(6-methylpyridin-2-yl)-lH-indazol-4- yl)(methyl)carbamate and tert-butyl (6-bromo-2-(6-methylpyridin-2-yl)-2H-indazol-4- yl)(methyl)carbamate (650 mg, 1.60 mmol, 1.0 eq) in anhydrous THF (10 mL) was added NaH (39 mg, 1.60 mmol, 1.0 eq) at rt. The mixture was stirred at rt for 5 min, then Mel (273 mg, 1.92 mmol, 1.2 eq) was added into the mixture. The mixture was stirred at 40 C for 1 h. After concentration, the residue was purified by column chromatography on silica gel (PE/EA = 10/1) to give a mixture of tert-butyl (6-bromo-l-(6-methylpyridin-2-yl)-lH- indazol-4-yl)(methyl)carbamate and tert-butyl (6-bromo-2-(6-methylpyridin-2-yl)-2H- indazol-4-yl)(methyl)carbamate as a white solid. 439 mg, Y: 65%. ESI-MS (M+H) +: 417.2.
tert-butyl methyl(1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-4-yl)carbamate[ No CAS ]
tert-butyl methyl(2-(6-methylpyridin-2-yl)-6-(4,4,5 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-4-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: The preparation of tert-butyl methyl(l-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-indazol-4-yl)carbamate and tert-butyl methyl(2-(6- methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-indazol-4- yl)carbamate was the same as that of l-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-indazole. 465 mg, as a white solid, Y: 80%. The mixture of tert-butyl methyl(l-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazol- 4-yl)carbamate and tert-butyl methyl(2-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-2H-indazol-4-yl)carbamate was directly used for next step without further purification. ESI-MS (M+H) +: 465.1.
tert-butyl (6-bromo-1-(6-methylpyridin-2-yl)-1H-indazol-4-yl)carbamate[ No CAS ]
tert-butyl (6-bromo-2-(6-methylpyridin-2-yl)-2H-indazol-4-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: The preparation of 6-bromo-l-(6-methylpyridin-2-yl)-lH-indazole-4-carboxylic acid and 6-bromo-2-(6-methylpyridin-2-yl)-2H-indazole-4-carboxylic acid was the same as that of 6-bromo-l-(6-methylpyridin-2-yl)-lH-indazole. 810 mg, as a light brown solid, Y: 60%. The mixture of of 6-bromo-l-(6-methylpyridin-2-yl)-lH-indazole-4-carboxylic acid and 6-bromo- 2-(6-methylpyridin-2-yl)-2H-indazole-4-carboxylic acid was difficult to be purified due to poor solubility. The mixture was directly used for next step. ESTMS (M+H) +: 332.9.
tert-butyl (1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-4-yl)carbamate[ No CAS ]
tert-butyl (2-(6-methylpyridin-2-yl)-6-(4,4,5 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-4-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: The preparation of tert-butyl (l-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-indazol-4-yl)carbamate and tert-butyl (2-(6-methylpyridin-2-yl)-6- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-indazol-4-yl)carbamate was the same as that of l-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- indazole. 206 mg, as a white solid, Y: 80%. The mixture of tert-butyl (l-(6-methylpyridin-2- yl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazol-4-yl)carbamate and tert-butyl (2-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-indazol-4- yl)carbamate was directly used for next step without further purification. ESTMS (M+H) +: 451.1.
6-bromo-N,N-dimethyl-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine[ No CAS ]
6-bromo-N,N-dimethyl-2-(6-methylpyridin-2-yl)-2H-indazol-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: The preparation of 6-bromo-N,N-dimethyl-l-(6-methylpyridin-2-yl)-lH-indazol-4- amine and 6-bromo-N,N-dimethyl-2-(6-methylpyridin-2-yl)-2H-indazol-4-amine was the same as tert-butyl (6-bromo-l-(6-methylpyridin-2-yl)-lH-indazol-4-yl)(methyl)carbamate. 250 mg, as white solid, Y: 67%. ESI-MS (M+H) +: 331.2
N,N-dimethyl-1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-4-amine[ No CAS ]
N,N-dimethyl-2-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: The preparation of N,N-dimethyl- l-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- lH-indazol-4-amine and N,N-dimethyl-2-(6-methylpyridin-2-yl)-6- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-indazol-4-amine was the same as that of 1- (6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole. 246 mg, as a white solid, Y: 86%. The mixture of N,N-dimethyl-l-(6-methylpyridin-2-yl)-6-(4,4,5,5- tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-indazol-4-amine and N,N-dimethyl-2-(6- methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-2H-indazol-4-amine was directly used for next step without further purification. ESTMS (M+H) +: 379.1.
6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxylic acid[ No CAS ]
6-bromo-2-(6-methylpyridin-2-yl)-2H-indazole-4-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: The preparation of 6-bromo-l-(6-methylpyridin-2-yl)-lH-indazole-4-carboxylic acid and 6-bromo-2-(6-methylpyridin-2-yl)-2H-indazole-4-carboxylic acid was the same as that of 6-bromo-l-(6-methylpyridin-2-yl)-lH-indazole. 810 mg, as a light brown solid, Y: 60%. The mixture of of 6-bromo-l-(6-methylpyridin-2-yl)-lH-indazole-4-carboxylic acid and 6-bromo- 2-(6-methylpyridin-2-yl)-2H-indazole-4-carboxylic acid was difficult to be purified due to poor solubility. The mixture was directly used for next step. ESTMS (M+H) +: 332.9.
6-bromo-1-(6-methylpyridin-2-yl)-1H-indazol-4-amine[ No CAS ]
6-bromo-2-(6-methylpyridin-2-yl)-2H-indazol-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: The preparation of 6-bromo-l-(6-methylpyridin-2-yl)-lH-indazol-4-amine and 6- bromo-2-(m-tolyl)-2H-indazol-4-amine was the same as 6-(6-(l-aminoethyl)pyridin-2-yl)-l- (6-methylpyridin-2-yl)-lH-indazol-4-amine. 340 mg, as a light brown solid, Y: 85%. ESI-MS (M+H)+: 303.1.
6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole-4-carboxamide[ No CAS ]
6-bromo-2-(6-methylpyridin-2-yl)-2H-indazole-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: The preparation of 6-bromo-l-(6-methylpyridin-2-yl)-lH-indazole-4-carboxamide and 0-(6-bromo-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonyl)hydroxylamine was the same as that of 6-bromo-l-(6-methylpyridin-2-yl)-lH-indazole-4-carboxamide and 0-(6- bromo-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonyl)hydroxylamine. 1.5 g, as a yellow solid, Y: 60%. The mixture of 36-bromo-l-(6-methylpyridin-2-yl)-lH-indazole-4- carboxamide and 0-(6-bromo-2-(6-methylpyridin-2-yl)-2H-indazole-4- carbonyl)hydroxylamine was difficult to be purified due to poor solubility. The mixture was directly used for next step. ESI-MS (M+H) +: 331.1.
6-bromo-1-(6-methylpyridin-2-yl)-1H-indazole-4-carbonitrile[ No CAS ]
6-bromo-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: The preparation of 6-bromo-l-(6-methylpyridin-2-yl)-lH-indazole-4-carbonitrile and 6-bromo-2-(6-methylpyridin-2-yl)-2H-indazole-4-carbonitrile was the same as that of N-(5- (4-cyano-l-(6-(trifluoromethyl)pyridin-2-yl)-lH-indazol-6-yl)pyridin-3-yl)-2,2,2- trifluoroacetamide. 596 mg, as a white solid, Y: 42%. The mixture of 6-bromo-l-(6- methylpyridin-2-yl)- lH-indazole-4-carbonitrile and 6-bromo-2-(6-methylpyridin-2-yl)-2H- indazole-4-carbonitrile was difficult to be purified due to poor solubility. The mixture was directly used for next step. ESI-MS (M+H) +: 313.1.
1-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-4-carbonitrile[ No CAS ]
2-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-4-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: The preparation of l-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)- lH-indazole-4-carbonitrile and 2-(6-methylpyridin-2-yl)-6-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-indazole-4-carbonitrile was the same as that of l-(6- methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole. 523 mg, as a white solid, Y: 76%. The mixture of l-(6-methylpyridin-2-yl)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)- lH-indazole-4-carbonitrile and 2-(6-methylpyridin-2-yl)-6-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-2H-indazole-4-carbonitrile was difficult to be purified due to poor solubility. The mixture was directly used for next step. ESTMS (M+H) +: 361.1.
With bis(η4-1,5-cyclooctadiene)-di-μ-methoxy-diiridium(I); 4,4'-di-tert-butyl-2,2'-bipyridine In tert-butyl methyl ether at 80℃; for 14h; Inert atmosphere;
3 Intermediate 3A: 2-fluoro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine
To a solution of 2-fluoro-6-methylpyridine (0.5 g, 4.50 mmol) in MTBE (20 mL) were added BISPIN (2.285 g, 9.00 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (0.085 g, 0.315 mmol). The mixture was degasified with argon followed by the addition of (1,5- cyclooctadiene)(methoxy)iridium(I) dimer (0.089 g, 0.135 mmol) under an argon atmosphere. The reaction mixture was heated at 80 °C for 14 hours. The resulting black suspension was concentrated under vacuum to afford a black oil which was analyzed by LCMS. The crude product was chromatographed using snap-40g and 9:1 CHCl3:MeOH. Product spot was isolated at 10% MeOH as white semi solid (0.75g, 70.3%). White solid was obtained on keeping at 5 °C for a day. LCMS retention time 1.16 min [D]. MS (E-) m/z: 238.1 (M+H).
25 %Spectr.
With C29H35CoN4Si at 23℃; for 18h; Inert atmosphere; Glovebox; regioselective reaction;
Stage #1: 2-fluoro-6-methylpyridine With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - 0℃; for 0.5h; Inert atmosphere;
Stage #2: propyl bromide In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere;
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h;
Intermediate 9.3
After stirring a mixture of 3-methylcyclobutan-1 -l (0.25 mL, 2.7 mmol) and sodium hydride (55%, 236 mg, 5.4 mmol) in DMF (5 ml, 61.5 mmol) for 10 mm 2-fluoro-6-methylpyridine (300 mg, 2.7 mmol) was added and the mixture was stirred for 1 h at rt. H20 was added and extracted with diethylether. The combined organic layers were dried and concentrated and the resulting crude product was used without further purification.MS (ESI): (M+H) 178/179HPLC: RT = 0.54 mm, Method F
tert-butyl 3-cyano-3-(6-methylpyridin-2-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hexamethylsilazane In tetrahydrofuran at -70 - 25℃; for 12h; Inert atmosphere;
To a solution of tert-butyl 3-cyanopiperidine-1-carboxylate (3.00 g, 14.3 mmol, 1.0 eq.) and 2-fluoro-6-methylpyridine (1.66 g, 14.9 mmol, 1.05 eq.) in THF (30 mL) was added dropwise KHMDS (17 mL, 17 mmol, 1.2 eq., 1M in THF) at -70 C under N2 atmosphere. The resulting mixture was allowed to warm to 25C and stirred for 12 hours. The reaction was quenched with water (50 mL), and extracted with EtOAc (30 mLx3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by combi flash (20% EtOAc in PE) to give tert-butyl 3-cyano-3-(6-methylpyridin-2-yl)piperidine-1- carboxylate (177-1).1H NMR (400 MHz, CDCl3) d ppm 7.64 (t, J = 7.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 4.61-4.14 (m, 2H), 3.54-3.21 (m, 1H), 2.94-2.73 (m, 1H), 2.55 (s, 3H), 2.40-2.24 (m, 1H), 2.23-2.12 (m, 1H), 2.06-1.92 (m, 1H), 1.84-1.75 (m, 1H), 1.51 (s, 9H). LC-MS: [M+H]+ =302.0.
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