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Structure of 71902-33-5 * Storage: {[proInfo.prStorage]}
* 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.
[0315] To a solution of 3,5-difluoropyridine (5.4 g, 46.8 mmol, 1 eq.) in MeOH (45 mL) was added NaOMe (7.5 g, 140.4 mmol). The mixture was divided into three microwave tubes and individually heated at 135 °C for 1 h in a microwave reactor. The three tubes were combined, concentrated, and diluted with a mixture EtOAc (100 mL) and brine (30 mL). The organic layerwas dried over Na2504 and concentrated. The crude was re-dissolved in MeOH (45 mL) and added NaOMe (7.5 g, 140.4 mmol). The mixture was again divided into three microwave tubes and individually heated at 135 °C for 1 h in a microwave reactor. The three tubes were combined and concentrated. The crude was dissolved in a mixture of EtOAc (200 mL) and brine (30 mL). The organic layer was dried over Na2SO4, concentrated, and purified on silica gelusing a mixture of EtOAc and hexanes as eluent to give 3,5-dimethoxypyridine (3.73 g, 57percent) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J— 2.4 Hz, 2H), 6.76 (t, J 2.4 Hz, 1H), 3.88 (s, 6H). LRMS (M+H+) m/z 140.1.
Step 1;To a solution of 3,5-difluoropyridine (5.4 g, 46.8 mmol, 1 eq.) in MeOH (45 mL) was added NaOMe (7.5 g, 140.4 mmol). The mixture was divided into three microwave tubes and individually heated at 135° C. for 1 h in a microwave reactor. The three tubes were combined, concentrated, and diluted with a mixture EtOAc (100 mL) and brine (30 mL). The organic layer was dried over Na2SO4 and concentrated. The crude was re-dissolved in MeOH (45 mL) and added NaOMe (7.5 g, 140.4 mmol). The mixture was again divided into three microwave tubes and individually heated at 135° C. for 1 h in a microwave reactor. The three tubes were combined and concentrated. The crude was dissolved in a mixture of EtOAc (200 mL) and brine (30 mL). The organic layer was dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3,5-dimethoxypyridine (3.73 g, 57percent) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=2.4 Hz, 2H), 6.76 (t, J=2.4 Hz, 1H), 3.88 (s, 6H). LRMS (M+H+) m/z 140.1.
Reference：
[1] Chemistry - A European Journal, 2005, vol. 11, # 6, p. 1903 - 1910
4
[ 2875-18-5 ]
[ 372-47-4 ]
[ 3512-18-3 ]
[ 76469-41-5 ]
[ 71902-33-5 ]
Yield
Reaction Conditions
Operation in experiment
24 %Spectr.
With triethylsilane; [Rh(μ-H)(1,3-bis(diisopropylphosphanyl)propane)]2 In benzene-d6 at 50℃; for 48 h; Inert atmosphere
General procedure: To a solution of fluoroarene (0.1 M) and HSiEt3 (0.1 M) in benzene-d6 in a PFA tube α,α,α-trifluorotoluene (1–2 μL) was added as internal standard. The PFA tube was closed by a Teflon plug, inserted into an NMR tube and an initial 19F{1H} NMR spectrum was recorded. Then [Rh(μ-H)(dippp)]2 (1) (0.005 M) was added and the reaction mixture was heated to 50 °C for 48 h. Hydrodefluorination of pentafluoropyridine gave 2,3,5,6-tetrafluoropyridine (11percent), 2,3,4,5-tetrafluoropyridine (11percent), 2,3,5-trifluoropyridine (8percent), 3,5-difluoropyridine (6percent) and 2-fluoropyridine (1percent) (TON = 11). Hydrodefluorination of 2,3,5,6-tetrafluoropyridine or 2,3,5,6-tetrafluoropyridine or 2,3,5,6-tetrafluoropyri-dine gave 2,3,5-trifluoropyridine (24percent), 2,3,6-trifluoropyridine (7percent), 3,5-difluoropyridine (15percent), 2,5-difluoropyridine (2percent) and 2-fluoropyridine (8percent) (TON = 18). Hydrodefluorination of hexafluoro-benzene or hexafluoroben-zene or hexa-fluorobenzene gave pentafluorobenzene (12percent) and 1,2,4,5-tetra-fluorobenzene or 1,2,4,5-tetrafluoro-benzene or 1,2,4,5-tetrafluoroben-zene (2percent) (TON = 3.1). Hydrodefluorination of pentafluorobenzene gave 1,2,4,5-tetrafluorobenzene (35percent), 1,2,3,4-tetrafluorobenzene (3percent), 1,2,4-trifluorobenzene (23percent) and 1,4-difluorobenzene (4percent) (TON = 19). Yields of organic hydrodefluorination products were determined from 19F{1H} NMR spectra by integration of product resonances versus the internal standard. Hydrodefluorination products were identified by NMR spectroscopy by comparison with literature data [23]. TON: number of hydrodefluorination steps/moles of 1.
Reference：
[1] Journal of Fluorine Chemistry, 2013, vol. 155, p. 132 - 142
5
[ 700-16-3 ]
[ 3512-16-1 ]
[ 2875-18-5 ]
[ 76469-41-5 ]
[ 71902-33-5 ]
Yield
Reaction Conditions
Operation in experiment
11 %Spectr.
With triethylsilane; [Rh(μ-H)(1,3-bis(diisopropylphosphanyl)propane)]2 In benzene-d6 at 50℃; for 48 h; Inert atmosphere
General procedure: To a solution of fluoroarene (0.1 M) and HSiEt3 (0.1 M) in benzene-d6 in a PFA tube α,α,α-trifluorotoluene (1–2 μL) was added as internal standard. The PFA tube was closed by a Teflon plug, inserted into an NMR tube and an initial 19F{1H} NMR spectrum was recorded. Then [Rh(μ-H)(dippp)]2 (1) (0.005 M) was added and the reaction mixture was heated to 50 °C for 48 h. Hydrodefluorination of pentafluoropyridine gave 2,3,5,6-tetrafluoropyridine (11percent), 2,3,4,5-tetrafluoropyridine (11percent), 2,3,5-trifluoropyridine (8percent), 3,5-difluoropyridine (6percent) and 2-fluoropyridine (1percent) (TON = 11). Hydrodefluorination of 2,3,5,6-tetrafluoropyridine or 2,3,5,6-tetrafluoropyridine or 2,3,5,6-tetrafluoropyri-dine gave 2,3,5-trifluoropyridine (24percent), 2,3,6-trifluoropyridine (7percent), 3,5-difluoropyridine (15percent), 2,5-difluoropyridine (2percent) and 2-fluoropyridine (8percent) (TON = 18). Hydrodefluorination of hexafluoro-benzene or hexafluoroben-zene or hexa-fluorobenzene gave pentafluorobenzene (12percent) and 1,2,4,5-tetra-fluorobenzene or 1,2,4,5-tetrafluoro-benzene or 1,2,4,5-tetrafluoroben-zene (2percent) (TON = 3.1). Hydrodefluorination of pentafluorobenzene gave 1,2,4,5-tetrafluorobenzene (35percent), 1,2,3,4-tetrafluorobenzene (3percent), 1,2,4-trifluorobenzene (23percent) and 1,4-difluorobenzene (4percent) (TON = 19). Yields of organic hydrodefluorination products were determined from 19F{1H} NMR spectra by integration of product resonances versus the internal standard. Hydrodefluorination products were identified by NMR spectroscopy by comparison with literature data [23]. TON: number of hydrodefluorination steps/moles of 1.
Reference：
[1] Journal of Fluorine Chemistry, 2013, vol. 155, p. 132 - 142
With potassium fluoride In sulfolane at 205℃; for 48 h;
Example 1; Preparation of 3,5-difluoropyridine; 1000 g of dichloropyridine and 1580 g of dry potassium fluoride were initially charged in 1700 ml of sulpholane in an autoclave. Subsequently, 84 g of CNC catalyst (compound (III-1)) were added, nitrogen was injected to 3 bar and the mixture was heated to 205° C. with stirring for 48 h. During the reaction, a maximum total pressure of 12.4 bar arose. Subsequently, the mixture was cooled to 10° C. and the product was distilled off at standard pressure. After redistillation, 473 g of dichloropyridine (60percent of theory) were obtained as a colourless liquid.
With triethylsilane; [Rh(μ-H)(1,3-bis(diisopropylphosphanyl)propane)]2 In benzene-d6 at 50℃; for 48 h; Inert atmosphere
General procedure: To a solution of fluoroarene (0.1 M) and HSiEt3 (0.1 M) in benzene-d6 in a PFA tube α,α,α-trifluorotoluene (1–2 μL) was added as internal standard. The PFA tube was closed by a Teflon plug, inserted into an NMR tube and an initial 19F{1H} NMR spectrum was recorded. Then [Rh(μ-H)(dippp)]2 (1) (0.005 M) was added and the reaction mixture was heated to 50 °C for 48 h. Hydrodefluorination of pentafluoropyridine gave 2,3,5,6-tetrafluoropyridine (11percent), 2,3,4,5-tetrafluoropyridine (11percent), 2,3,5-trifluoropyridine (8percent), 3,5-difluoropyridine (6percent) and 2-fluoropyridine (1percent) (TON = 11). Hydrodefluorination of 2,3,5,6-tetrafluoropyridine or 2,3,5,6-tetrafluoropyridine or 2,3,5,6-tetrafluoropyri-dine gave 2,3,5-trifluoropyridine (24percent), 2,3,6-trifluoropyridine (7percent), 3,5-difluoropyridine (15percent), 2,5-difluoropyridine (2percent) and 2-fluoropyridine (8percent) (TON = 18). Hydrodefluorination of hexafluoro-benzene or hexafluoroben-zene or hexa-fluorobenzene gave pentafluorobenzene (12percent) and 1,2,4,5-tetra-fluorobenzene or 1,2,4,5-tetrafluoro-benzene or 1,2,4,5-tetrafluoroben-zene (2percent) (TON = 3.1). Hydrodefluorination of pentafluorobenzene gave 1,2,4,5-tetrafluorobenzene (35percent), 1,2,3,4-tetrafluorobenzene (3percent), 1,2,4-trifluorobenzene (23percent) and 1,4-difluorobenzene (4percent) (TON = 19). Yields of organic hydrodefluorination products were determined from 19F{1H} NMR spectra by integration of product resonances versus the internal standard. Hydrodefluorination products were identified by NMR spectroscopy by comparison with literature data [23]. TON: number of hydrodefluorination steps/moles of 1.
Reference：
[1] Journal of Fluorine Chemistry, 2013, vol. 155, p. 132 - 142
12
[ 700-16-3 ]
[ 3512-16-1 ]
[ 2875-18-5 ]
[ 76469-41-5 ]
[ 71902-33-5 ]
Yield
Reaction Conditions
Operation in experiment
11 %Spectr.
With triethylsilane; [Rh(μ-H)(1,3-bis(diisopropylphosphanyl)propane)]2 In benzene-d6 at 50℃; for 48 h; Inert atmosphere
General procedure: To a solution of fluoroarene (0.1 M) and HSiEt3 (0.1 M) in benzene-d6 in a PFA tube α,α,α-trifluorotoluene (1–2 μL) was added as internal standard. The PFA tube was closed by a Teflon plug, inserted into an NMR tube and an initial 19F{1H} NMR spectrum was recorded. Then [Rh(μ-H)(dippp)]2 (1) (0.005 M) was added and the reaction mixture was heated to 50 °C for 48 h. Hydrodefluorination of pentafluoropyridine gave 2,3,5,6-tetrafluoropyridine (11percent), 2,3,4,5-tetrafluoropyridine (11percent), 2,3,5-trifluoropyridine (8percent), 3,5-difluoropyridine (6percent) and 2-fluoropyridine (1percent) (TON = 11). Hydrodefluorination of 2,3,5,6-tetrafluoropyridine or 2,3,5,6-tetrafluoropyridine or 2,3,5,6-tetrafluoropyri-dine gave 2,3,5-trifluoropyridine (24percent), 2,3,6-trifluoropyridine (7percent), 3,5-difluoropyridine (15percent), 2,5-difluoropyridine (2percent) and 2-fluoropyridine (8percent) (TON = 18). Hydrodefluorination of hexafluoro-benzene or hexafluoroben-zene or hexa-fluorobenzene gave pentafluorobenzene (12percent) and 1,2,4,5-tetra-fluorobenzene or 1,2,4,5-tetrafluoro-benzene or 1,2,4,5-tetrafluoroben-zene (2percent) (TON = 3.1). Hydrodefluorination of pentafluorobenzene gave 1,2,4,5-tetrafluorobenzene (35percent), 1,2,3,4-tetrafluorobenzene (3percent), 1,2,4-trifluorobenzene (23percent) and 1,4-difluorobenzene (4percent) (TON = 19). Yields of organic hydrodefluorination products were determined from 19F{1H} NMR spectra by integration of product resonances versus the internal standard. Hydrodefluorination products were identified by NMR spectroscopy by comparison with literature data [23]. TON: number of hydrodefluorination steps/moles of 1.
Reference：
[1] Journal of Fluorine Chemistry, 2013, vol. 155, p. 132 - 142
13
[ 30841-93-1 ]
[ 71902-33-5 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 10, p. 1705 - 1713
Reference：
[1] Chemistry - A European Journal, 2005, vol. 11, # 6, p. 1903 - 1910
[2] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 10, p. 1705 - 1713
19
[ 851179-05-0 ]
[ 71902-33-5 ]
Reference：
[1] Chemistry - A European Journal, 2005, vol. 11, # 6, p. 1903 - 1910
20
[ 2875-18-5 ]
[ 71902-33-5 ]
Reference：
[1] Chemistry - A European Journal, 2005, vol. 11, # 6, p. 1903 - 1910
21
[ 76469-41-5 ]
[ 71902-33-5 ]
Reference：
[1] Chemistry - A European Journal, 2005, vol. 11, # 6, p. 1903 - 1910
Reference：
[1] Journal of Organic Chemistry, 2014, vol. 79, # 12, p. 5827 - 5833
24
[ 700-16-3 ]
[ 372-47-4 ]
[ 2875-18-5 ]
[ 71902-33-5 ]
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 10, p. 1705 - 1713
25
[ 2457-47-8 ]
[ 71902-33-5 ]
[ 514797-99-0 ]
Reference：
[1] Journal of Organic Chemistry, 2014, vol. 79, # 12, p. 5827 - 5833
26
[ 107-31-3 ]
[ 71902-33-5 ]
[ 870234-98-3 ]
Yield
Reaction Conditions
Operation in experiment
81%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -70℃; for 0.5 h; Inert atmosphere Stage #2: at -70℃; for 1.5 h;
Example 113A 3,5-Difluoroisonicotinaldehyde Under argon and at -70° C., 44 ml of 2.5 M n-butyllithium solution in n-hexane (110 mmol, 1.1 equivalent) were slowly added dropwise to 15.4 ml of diisopropylamine (110 mmol, 1.1 equivalent) in 23 ml of THF. The solution formed was warmed to 0° C. and stirred at this temperature for 30 min. The reaction mixture was then brought to -70° C. and diluted with 23 ml of THF, and 11.5 g of 3,5-difluoropyridine (100 mmol, 1 equivalent) dissolved in 72 ml of THF, were added dropwise. The mixture was stirred at -70° C. for 30 min. 12.4 ml of methyl formate (200 mmol, 2 equivalent), dissolved in 23 ml of THF, were then slowly added dropwise. After 1.5 h at -70° C., the reaction solution was quickly poured into 230 ml of saturated aqueous sodium bicarbonate solution and extracted with a total of 460 ml of ethyl acetate. The combined organic phases were washed twice with in each case 115 ml of saturated aqueous sodium bicarbonate solution and twice with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated using a rotary evaporator. This gave 11.6 g (81percent of theory) of the title compound which were directly reacted further. GC-MS (Method 14): Rt=1.82 min MS (ESpos): m/z=144.0 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): δ=8.75 (br. s, 2H), 10.24 (br. s, 1H).
81%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -70 - 0℃; for 0.5 h; Inert atmosphere Stage #2: at -70℃; for 1.5 h;
Example 25A 3,5-Difluoroisonicotinaldehyde Under argon and at -70° C., 44 ml of 2.5 M n-butyllithium solution in n-hexane (110 mmol, 1.1 equivalents) were slowly added dropwise to 15.4 ml of diisopropylamine (110 mmol, 1.1 equivalents) in 23 ml of THF. The resulting solution was warmed to 0° C. and stirred at this temperature for 30 min. The reaction mixture was then cooled to -70° C. and diluted with 23 ml of THF, and 11.5 g of 3,5-difluoropyridine (100 mmol, 1 equivalent), dissolved in 72 ml THF, were then added dropwise. The mixture was stirred at -70° C. for a further 30 min 12.4 ml of methyl formate (200 mmol, 2 equivalents), dissolved in 23 ml of THF, were then slowly added dropwise. After 1.5 h at -70° C., the reaction solution was slowly poured into 230 ml of saturated aqueous sodium bicarbonate solution and extracted with a total of 460 ml of ethyl acetate. The combined organic phases were washed twice with in each case 115 ml of saturated aqueous sodium bicarbonate solution and twice with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated on a rotary evaporator. This gave 11.6 g (81percent of theory) of the title compound, which were directly reacted further. GC-MS (Method 14): Rt=1.82 min MS (ESpos): m/z=144.0 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): δ=8.75 (br. s, 2H), 10.24 (br. s, 1H).
52%
Stage #1: With n-butyllithium; lithium diisopropyl amide In tetrahydrofuran; hexanes at -78 - -69℃; Inert atmosphere Stage #2: for 1.25 h;
Compound 13A: LDA (68 ml, 478 mmol) and THF (500 ml) were cooled to 0° C. while stirring under nitrogen and n-BuLi (192 ml, 478 mmol, 2.5 M in hexanes) was added dropwise. After 30 min, the mixture was cooled to -78° C. (dry ice/acetone bath) and 3,5-difluoropyridine (50 g, 434 mmol) dissolved in 500 ml of THF was added dropwise while maintaining the temperature below -69° C. After 4 h, methyl formate (54 ml, 868 mmol) dissolved in 135 ml of THF was added dropwise (completed addition in 1.25 h). In a separate flask, 1 L sat. NaHCO3 was cooled to 0° C. while stirring. The reaction mixture was added to the NaHCO3 solution while stirring and the mixture was allowed to warm to room temperature. The organic layer was separated and the water layer was extracted with ethyl acetate (4.x., 250 mL). The combined organic extracts were washed with sat. brine, dried over Na2SO4 and concentrated to obtain a dark purple oil. Purification using flash column chromatography gave 32.5 g (52percent yield) of compound 13A.
7.85 g
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78 - -70℃; for 3 h; Stage #2: at -78 - -75℃; for 0.75 h;
PREPARATION EXAMPLE 10: N-rri -(3.5-difluoro-4-DyridvncvcloDroDyllmethyll-2- (trifluoromethyl)pyridine-3-carboxamide (Compound A126)Step 1 : 3,5-difluoropyridine-4-carbaldehvdeAt 0°C A solution of LDA 2M in THF (47.792 mL, 95.58 mmol) was diluted with 50mL THF. It was cooled down to -78°C, then a solution of 3,5-Difluoropyridine (7.886 mL, 86.89 mmol) in 100mL THF was added dropwise while maintening the temperature below -70°C, (complete addition in 20 min). It gave a yellow suspension. The reaction mixture was stirred 3h at -78°C. A solution of Methyl formate (10.8 mL, 173.79 mmol) in 25mL THF was added dropwise in 15 min. The reaction mixture became a pale yellow solution. It was stirred 45 min at -75°C and then transferred via cannula to a stirred solution of 100mL sat aq NaHC03 held at about 0°C. It was extracted twice with EtOAc and the combined organic phases were washed with brine and dried with IS^SC^. The solvent was evaporated (165mbar, 30°C), 36.7 g of residue were obtained as a yellow liquid. The crude product was purified by flash chromatography (Solvent: CH2CI2). The product was isolated as a pale yellow oil (7.85 g), which crystallized upon standing.1H-NMR (CDCI3): 10.4 (s, 1 H), 8.57 (s, 2H).
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 1 h; Inert atmosphere Stage #2: at -78 - 0℃; for 2 h;
Under a nitrogen atmosphere, to a solution of diisopropylamine (9.67 g) in THF (100 mL) was added dropwise n-butyllithium hexane solution (1.6 M, 59.7 mL) at -78°C. After stirring for 20 min, a solution of 3,5-difluoropyridine (10.00 g) in THF (50 mL) was added dropwise while maintaining at -78°C. After stirring for 1 hr, ethyl formate (17.5 mL) was added dropwise, and the mixture was warmed to 0°C over 2 hr with stirring. Water was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.50 g). 1H NMR (300 MHz, CDCl3) δ 8.56 (2H, s), 10.42 (1H, s).
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.5 h; Stage #2: at -78℃; for 1.5 h; Stage #3: at -78 - 20℃; for 2 h;
INTERMEDIATE 63 : 3, 5-Difluoro-4-tributylstannanyl-pyridine [00224]. n-Butyl lithium (1.0 eq, 76 mmol, 47.6 mL, 1.6 M in hexanes) was added via dropping funnel to a solution of diisopropylamine (1.05 eq, 80 mmol, 11.2 mL) in THF (300 mL) at-78 °C under nitrogen (N2). The solution was stirred for 30 min at-78 °C, then a solution of 3,5- difluoropyridine (1.05 eq, 80 mmol, 9.2 g) in THF (20 mL) was added dropwise via syringe. A beige precipitate was observed to form. The reaction stirred at-78 °C for 90 min then tributyltin chloride (1.0 eq, 76 mmol, 20.7 mL) was added dropwise via syringe and the resulting solution allowed to warm to RT over 2 h. Water (5 mL) was added, then roughly 250 mL of THF was removed on a rotary evaporator. The resulting material was diluted with diethyl --139-- ether (350 mL) and washed successively with water (2X200 mL), saturated sodium chloride solution (1X150 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford the 3,5-Difluoro-4-tributylstannanyl-pyridine as a colourless oil (27.5 g, 88percent). This material was used crude without further purification. Retention Time (LC, method: ammonium acetate standard): 3.35 min. MS (M+H+) : 406.
88%
Stage #1: at -78℃; for 1.5 h; Stage #2: at -78 - 20℃; for 2 h;
Intermediate 63: 3,5-Difluoro-4-tributylstannanyl-pyridine n-Butyl lithium (1.0 eq, 76 mmol, 47.6 mL, 1.6 M in hexanes) was added via dropping funnel to a solution of diisopropylamine (1.05 eq, 80 mmol, 11.2 mL) in THF (300 mL) at -78° C. under nitrogen (N2). The solution was stirred for 30 min at -78° C., then a solution of 3,5-difluoropyridine (1.05 eq, 80 mmol, 9.2 g) in THF (20 mL) was added dropwise via syringe. A beige precipitate was observed to form. The reaction stirred at -78° C. for 90 min then tributyltin chloride (1.0 eq, 76 mmol, 20.7 mL) was added dropwise via syringe and the resulting solution allowed to warm to RT over 2 h. Water (5 mL) was added, then roughly 250 mL of THF was removed on a rotary evaporator. The resulting material was diluted with diethyl ether (350 mL) and washed successively with water (2*200 mL), saturated sodium chloride solution (1*150 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford the 3,5-Difluoro-4-tributylstannanyl-pyridine as a colourless oil (27.5 g, 88percent). This material was used crude without further purification. Retention Time (LC, method: ammonium acetate standard): 3.35 min. MS (M+H+): 406.
Example A3 In NMP (15 mL) was placed 3-amino-4-chlorophenol (1.70 g, 11.8 mmol) and potassium t-butoxide (1.40 g, 12.4 mmol) and the mixture was stirred overnight at RT. The dark solution was treated with the <strong>[71902-33-5]3,5-difluoropyridine</strong> (2.73 g, 23.7 mmol) and powdered potassium carbonate (818 mg, 5.92 mmol) and the mixture was then warmed to 80 C. and stirred for 24 h. The resulting black mixture was cooled to RT, diluted with brine (100 mL) and extracted with ethyl acetate (3*50 mL). The combined ethyl acetate extracts were washed with saturated sodium bicarbonate (50 mL), water (50 mL) and brine (50 mL), dried (Na2SO4), concentrated in vacuo and purified via column chromatography to yield 2-chloro-5-(5-fluoropyridin-3-yloxy)benzenamine as a thick oil which was used without further purification. 1H-NMR (DMSO-d6): delta 5.57 (br s, 2H), 6.26-6.30 (dd, 1H), 6*50 (s, 1H), 7.19-7.22 (m, 1H), 7.45-7.50 (m, 1H), 8.26 (s, 1H), 8.39 (s, 1H). MS (ESI) m/z: 239.0 (M+H+).
In NMP (15 mL) was placed 3-amino-4-chlorophenol (1.70 g, 11.8 mmol) and potassium t-butoxide (1.40 g, 12.4 mmol) and the mixture was stirred overnight at RT. The dark solution was treated with the <strong>[71902-33-5]3,5-difluoropyridine</strong> (2.73 g, 23.7 mmol) and powdered potassium carbonate (818 mg, 5.92 mmol) and the mixture was then warmed to 80 C and stirred for 24 h. The resulting black mixture was cooled to RT, diluted with brine (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined ethyl acetate extracts were washed with saturated sodium bicarbonate (50 mL), water (50 mL) and brine (50 mL), dried (Na2SC>4), concentrated in vacuo and purified via column chromatography to yield 2-chloro-5-(5-fluoropyridin-3-yloxy)benzenamine as a thick oil which was used without further purification. -NMR (DMSO-i: delta 5.57 (br s, 2H), 6.26-6.30 (dd, 1H), 6.50 (s, 1H), 7.19-7.22 (m, 1H), 7.45-7.50 (m, 1H), 8.26 (s, 1H), 8.39 (s, 1H). MS (ESI) m z: 239.0 (M+H+).
With potassium fluoride;1,3-dimethyl-2-(N',N',N",N"-tetramethylguanidino)-4,5-dihydro-3H-imidazolium chloride; In sulfolane; at 205℃; under 2250.23 - 9300.93 Torr; for 48h;
Example 1; Preparation of 3,5-difluoropyridine; 1000 g of dichloropyridine and 1580 g of dry potassium fluoride were initially charged in 1700 ml of sulpholane in an autoclave. Subsequently, 84 g of CNC catalyst (compound (III-1)) were added, nitrogen was injected to 3 bar and the mixture was heated to 205° C. with stirring for 48 h. During the reaction, a maximum total pressure of 12.4 bar arose. Subsequently, the mixture was cooled to 10° C. and the product was distilled off at standard pressure. After redistillation, 473 g of dichloropyridine (60percent of theory) were obtained as a colourless liquid.
5-(5-Fluoro-pyridin-3-ylamino)-2-methyl-thiazole-4-carboxylic acid (2-methyl-pyridin-4-yl)-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With caesium carbonate; In N,N-dimethyl-formamide; at 150℃; for 0.75h;Microwave irradiation;
E) 5-Amino-2-methyl-thiazole-4-carboxylic acid (2-methyl-pyridin-4-yl)-amide (0.15 g, 0.605 mmol) was dissolved in 5 mL fry DMF. 3,5-Difluoropyridine (0.213 g, 1.85 mmol) and cesium carbonate (0.59 g, 1.85 mmol) were added. The reaction mixture was irradiated in the microwave at 150° C. for 45 min, diluted with 100 mL water and extracted three times with ethyl acetate (50 mL each). The organic phases were pooled, dried with sodium sulfate and evaporated. The crude product was flash-chromatographed on silica gel with heptane/ethyl acetate 100:0-->0:100 gradient to yield the title compound as an off-white solid (0.135 g, 65percent)
3-(5-Fluoro-pyridin-3-ylamino)-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
24%
With caesium carbonate; In N,N-dimethyl-formamide; at 120 - 160℃; for 73h;Microwave irradiation;
EXAMPLE 7 3-(5-Fluoro-pyridin-3-ylamino)-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide In a 5 ml microwave reaction vessel were dissolved 70 mg (0.29 mmol) 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide (Example 5) and 266 mg (2.31 mmol, 8.0 equiv.) of <strong>[71902-33-5]3,5-difluoropyridine</strong> in 1.5 ml of DMF. Cesium carbonate (376 mg, 1.16 mmol, 4.0 equiv.) was added and the suspension was sonicated under argon for 10 min. The mixture was heated for 72 h at 120° C. in an oil bath and then 1 h at 160° C. under microwave irradiation. The dark brown suspension was filtered over Dicalite which was washed with ethyl acetate. The filtrate was evaporated to dryness in vaccuo, and the residue dissolved in 200 ml of ethyl acetate, which was washed once with brine. After drying over magnesium sulfate and concentration in vaccuo, the residue (90 mg) was purified by flash chromatography (gradient heptane/ethyl acetate 1:1 to 0:1) to yield the title compound, light yellow solid, (23 mg, 24percent). MS (ISP): m/e=338.1 (M+H+).
3-Amino-pyrazine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide hydrochloride[ No CAS ]
[ 71902-33-5 ]
3-(5-Fluoro-pyridin-3-ylamino)-pyrazine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
16%
With caesium carbonate; In N,N-dimethyl-formamide; at 180℃; for 1h;microwave irradiation;
3-Amino-pyrazine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide hydrochloride (120 mg, 0.47 mmol), <strong>[71902-33-5]3,5-difluoropyridine</strong> (500 mg, 4.4 mmol), cesium carbonate (610 mg, 1.89 mmol) and 1 mL N,N-dimethylformamide were mixed and stirred under microwave irradiation for 60 minutes at 180° C. The reaction mixture was extracted with sat. NaHCO3- solution and three times ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 90:10->30:70 gradient). The desired compound was obtained as a yellow solid (24 mg, 16percent), MS: m/e=314.0 (M+H+).
4-trans(5-fluoro-pyridin-3-yloxy)cyclohexylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With NaH; In N,N-dimethyl-formamide; mineral oil;
Example 62A 4-trans(5-fluoro-pyridin-3-yloxy)cyclohexylamine To a stirred solution of trans-4-aminocyclohexanol (460 mg, 4 mmol) in DMF (5 mL) at 0° C. was added 60percent NaH in mineral oil (480 mg, 12 mmol). The reaction mixture was stirred at 0° C. for 1/2 hour and then <strong>[71902-33-5]3,5-difluoro-pyridine</strong> (560 mg, 4.8 mmol) was added. It was heated to 60° C. for 2 hours and stirred for 12 hours at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water (3 times) and brine. The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide the titled compound. MS (DCI) m/z 211 (M+H)+.
With chloro-trimethyl-silane; lithium diisopropyl amide; In tetrahydrofuran;
3,5-Difluoropyridine (5.0 g, 43.45 mmol) in THF was cooled to -720C (external -8O0C). LDA (23.9 mL, 1.1 eq.) was added drop-wise so that the internal temp did not increase more than 30C during addition. The reaction mixture turned into a deep brownish, thick phase and was stirred for 30 minutes at this temperature. TMS-Cl (43.4 mL, 43.45 mmol) was added drop-wise in a relatively fast fashion. The reaction became a clear and light yellow solution. LDA (23.9 mL, 1.1 eq.) was added drop-wise in a quicker version, and the reaction mixture was allowed to stir for 2h. Methyl 2-methoxyacetate (5.59 mL, 56.48 mmol) was added quickly through a syringe. The reaction mixture was quenched at -780C by adding 20 ml of saturated NH4Cl solution. Evaporation of the organic extracts under reduced pressure gave a colored residue. Purification utilizing ISCO (0-25percent EtOAc/hexanes), gave the title compound (3 g). LCMS: 188 [M+H]+.
Intermediate 30 l-(3,5-Difluoropyridin-2-yl)-2-methoxyethanone3,5-Difluoropyridine (5.0 g, 43.45 mmol) in THF was cooled to -720C (external -8O0C). LDA (23.9 mL, 1.1 eq.) was added drop-wise at such rate that the internal temp did not increase more than 30C during addition. The reaction mixture turned into a deep brownish, thick phase and was stirred for 30 minutes at this temperature. TMS-Cl (43.4 mL, 43.45 mmol) was added via syringe in a relatively fast fashion. The reaction became a clear and light yellow solution. LDA (23.9 mL, 1.1 eq.) was added drop-wise in a quicker version, and the reaction mixture was allowed to stir for 2 hours. Methyl 2-methoxyacetate (5.59 mL, 56.48 mmol) was added quickly through a syringe. The reaction mixture was quenched at -780C by adding 20 ml of saturated NH4Cl solution. Evaporation of the organic extracts under reduced pressure gave a colored residue. Purification utilizing ISCO (0-^25percent EtOAc/hexanes), gave the title product (3 g). LCMS: 188 [M+H]+.
Intermediate 49 l-(3,5-Difluoropyridin-2-yl)-2-methoxyethanone3,5-Difluoropyridine (5.0 g, 43.45 mmol) in THF was cooled to -72°C (external -800C). LDA (23.9 mL, 1.1 eq.) was added drop-wise so that the internal temp did not increase more than 3°C during addition. The reaction turned into a deep brownish, thick phase. The reaction was stirred for 30 minutes. TMS-Cl (43.4 mL, 43.45 mmol) was added drop-wise in a relatively fast fashion. The reaction became a clear and light yellow solution. LDA (23.9 mL, 1.1 eq.) was added drop- wise in a quicker version, and the reaction was allowed to stir for 2h. Methyl 2-methoxyacetate (5.59 mL, 56.48 mmol) was added quickly through a syringe. The reaction was quenched at - 78°C by adding 20 ml of saturated NH4Cl solution. Evaporation of the organic extracts under reduced pressure gave a colored residue. Purification by ISCO (0-25percent EtOAc/hexanes), gave the title compound (3 g). LCMS: 188 [M+H]+.
3,5-Difluoropyridine (5.0 g, 43.45 mmol) in THF was cooled to -72°C (external -800C). LDA (23.9 rnL, 1.1 eq.) was added drop-wise so that the internal temperature did not increase more than 3°C during addition. The reaction mixture turned into a deep brownish, thick phase. The reaction mixture was stirred for 30 mins. TMS-Cl (43.4 mL, 43.45 mmol) was added in a relatively fast fashion. The reaction became a clear and light yellow solution. LDA (23.9 mL, 1.1 eq.) was added drop-wise in a quicker version, and the reaction mixture was allowed to stir for 2 hours. Methyl 2-methoxyacetate (5.59 mL, 56.48 mmol) was added quickly through a syringe. The reaction mixture was quenched at -78°C by adding 20 ml of saturated NH4Cl solution. Evaporation of the organic extracts under reduced pressure gave a colored residue. Purification by ISCO (0- 25percent EtOAc/hexanes), gave the title product (3 g). LCMS: 188 [M+H]+.
4-trans(5-fluoro-pyridin-3-yloxy)cyclohexylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a stirred solution of trans-4-aminocyclohexanol (460 mg, 4 mmol) in DMF (5 mL) at 0 [°C] was added 60percent NaH in mineral oil (480 mg, 12 mmol). The reaction mixture was stirred at 0 [°C] for [percent 2 HOUR] and then <strong>[71902-33-5]3,5-difluoro-pyridine</strong> (560 mg, 4.8 mmol) was added. It was heated to 60 [°C] for 2 hours and stirred for 12 hours at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water (3 times) and brine. The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide the titled compound. MS (DCI) m/z 211 (M+H) +.
Example 113A 3,5-Difluoroisonicotinaldehyde Under argon and at -70° C., 44 ml of 2.5 M n-butyllithium solution in n-hexane (110 mmol, 1.1 equivalent) were slowly added dropwise to 15.4 ml of diisopropylamine (110 mmol, 1.1 equivalent) in 23 ml of THF. The solution formed was warmed to 0° C. and stirred at this temperature for 30 min. The reaction mixture was then brought to -70° C. and diluted with 23 ml of THF, and 11.5 g of <strong>[71902-33-5]3,5-difluoropyridine</strong> (100 mmol, 1 equivalent) dissolved in 72 ml of THF, were added dropwise. The mixture was stirred at -70° C. for 30 min. 12.4 ml of methyl formate (200 mmol, 2 equivalent), dissolved in 23 ml of THF, were then slowly added dropwise. After 1.5 h at -70° C., the reaction solution was quickly poured into 230 ml of saturated aqueous sodium bicarbonate solution and extracted with a total of 460 ml of ethyl acetate. The combined organic phases were washed twice with in each case 115 ml of saturated aqueous sodium bicarbonate solution and twice with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated using a rotary evaporator. This gave 11.6 g (81percent of theory) of the title compound which were directly reacted further. GC-MS (Method 14): Rt=1.82 min MS (ESpos): m/z=144.0 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): delta=8.75 (br. s, 2H), 10.24 (br. s, 1H).
81%
Example 25A 3,5-Difluoroisonicotinaldehyde Under argon and at -70° C., 44 ml of 2.5 M n-butyllithium solution in n-hexane (110 mmol, 1.1 equivalents) were slowly added dropwise to 15.4 ml of diisopropylamine (110 mmol, 1.1 equivalents) in 23 ml of THF. The resulting solution was warmed to 0° C. and stirred at this temperature for 30 min. The reaction mixture was then cooled to -70° C. and diluted with 23 ml of THF, and 11.5 g of <strong>[71902-33-5]3,5-difluoropyridine</strong> (100 mmol, 1 equivalent), dissolved in 72 ml THF, were then added dropwise. The mixture was stirred at -70° C. for a further 30 min 12.4 ml of methyl formate (200 mmol, 2 equivalents), dissolved in 23 ml of THF, were then slowly added dropwise. After 1.5 h at -70° C., the reaction solution was slowly poured into 230 ml of saturated aqueous sodium bicarbonate solution and extracted with a total of 460 ml of ethyl acetate. The combined organic phases were washed twice with in each case 115 ml of saturated aqueous sodium bicarbonate solution and twice with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated on a rotary evaporator. This gave 11.6 g (81percent of theory) of the title compound, which were directly reacted further. GC-MS (Method 14): Rt=1.82 min MS (ESpos): m/z=144.0 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): delta=8.75 (br. s, 2H), 10.24 (br. s, 1H).
52%
Compound 13A: LDA (68 ml, 478 mmol) and THF (500 ml) were cooled to 0° C. while stirring under nitrogen and n-BuLi (192 ml, 478 mmol, 2.5 M in hexanes) was added dropwise. After 30 min, the mixture was cooled to -78° C. (dry ice/acetone bath) and <strong>[71902-33-5]3,5-difluoropyridine</strong> (50 g, 434 mmol) dissolved in 500 ml of THF was added dropwise while maintaining the temperature below -69° C. After 4 h, methyl formate (54 ml, 868 mmol) dissolved in 135 ml of THF was added dropwise (completed addition in 1.25 h). In a separate flask, 1 L sat. NaHCO3 was cooled to 0° C. while stirring. The reaction mixture was added to the NaHCO3 solution while stirring and the mixture was allowed to warm to room temperature. The organic layer was separated and the water layer was extracted with ethyl acetate (4.x., 250 mL). The combined organic extracts were washed with sat. brine, dried over Na2SO4 and concentrated to obtain a dark purple oil. Purification using flash column chromatography gave 32.5 g (52percent yield) of compound 13A.
7.85 g
PREPARATION EXAMPLE 10: N-rri -(3.5-difluoro-4-DyridvncvcloDroDyllmethyll-2- (trifluoromethyl)pyridine-3-carboxamide (Compound A126)Step 1 : <strong>[71902-33-5]3,5-difluoropyridine</strong>-4-carbaldehvdeAt 0°C A solution of LDA 2M in THF (47.792 mL, 95.58 mmol) was diluted with 50mL THF. It was cooled down to -78°C, then a solution of 3,5-Difluoropyridine (7.886 mL, 86.89 mmol) in 100mL THF was added dropwise while maintening the temperature below -70°C, (complete addition in 20 min). It gave a yellow suspension. The reaction mixture was stirred 3h at -78°C. A solution of Methyl formate (10.8 mL, 173.79 mmol) in 25mL THF was added dropwise in 15 min. The reaction mixture became a pale yellow solution. It was stirred 45 min at -75°C and then transferred via cannula to a stirred solution of 100mL sat aq NaHC03 held at about 0°C. It was extracted twice with EtOAc and the combined organic phases were washed with brine and dried with IS^SC^. The solvent was evaporated (165mbar, 30°C), 36.7 g of residue were obtained as a yellow liquid. The crude product was purified by flash chromatography (Solvent: CH2CI2). The product was isolated as a pale yellow oil (7.85 g), which crystallized upon standing.1H-NMR (CDCI3): 10.4 (s, 1 H), 8.57 (s, 2H).
With diisopropylamine;
Example 25A 3,5-Difluoroisonicotinaldehyde Under argon and at -70° C., 44 ml of 2.5 M n-butyllithium solution in n-hexane (110 mmol, 1.1 equivalents) were slowly added dropwise to 15.4 ml of diisopropylamine (110 mmol, 1.1 equivalents) in 23 ml of THF. The resulting solution was warmed to 0° C. and stirred at this temperature for 30 min. The reaction mixture was then cooled to -70° C. and diluted with 23 ml of THF, and 11.5 g of <strong>[71902-33-5]3,5-difluoropyridine</strong> (100 mmol, 1 equivalent), dissolved in 72 ml THF, were then added dropwise. The mixture was stirred at -70° C. for a further 30 min. 12.4 ml of methyl formate (200 mmol, 2 equivalents), dissolved in 23 ml of THF, were then quickly added dropwise. After 1.5 h at -70° C., the reaction solution was quickly poured into 230 ml of saturated aqueous sodium bicarbonate solution and extracted with a total of 460 ml of ethyl acetate. The combined organic phases were washed twice with in each case 115 ml of saturated aqueous sodium bicarbonate solution and twice with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated. This gave 11.6 g (81percent of theory) of the title compound, which were directly reacted further. GC-MS (Method 14): Rt=1.82 min MS (ESpos): m/z=144.0 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): delta=8.75 (br. s, 2H), 10.24 (br. s, 1H).
3,5-Difluoro-pyridine-4-carboxaldehyde Diisopropylamine (13.4 mL, 95.6 mmol) in THF (40 mL) was stirred at about 0 °C under an atmosphere of nitrogen and n-butyllithium (1.6M in hexanes, 60 mL, 96 mmol) was added while maintaining reaction temperature below about 10 °C. The mixture was stirred for about 30 minutes at about 0 °C and then was diluted with THF (150 mL) and cooled to about-78 °C. A solution of <strong>[71902-33-5]3,5-difluoro-pyridine</strong> (10.0 g, 86.9 mmol) in THF (100 mL) was added dropwise while maintaining the reaction temperature below about-75 °C. The solution was stirred at about-78 °C for about 1 hour and a solution of methyl formate (10.7 mL, 174 mmol) in THF (30 mL) was added over about 30 minutes. The mixture was stirred for about 0.75 hr and then transferred via cannula to a stirred solution of saturated aqueous NaHC03 (200 mL) held at about 0 °C. The product was extracted with EtOAc (100 mL) and the combined organic extracts were washed with saturated aqueous brine solution (2 x 100 mL) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure (165 mbar, bath temperature about 30 °C). The crude material was purified by flash chromatography on silica gel using DCM as the mobile phase. Fractions containing the desired product were combined and concentrated under reduced pressure. Crystallization from heptane afforded 3,S-difluoro-pyridine-4-carboxaldehyde as an off-white solid (4.44 g, 31.0 mmol) ; (at)H NMR (DMSO-d6, 300 MHz) 10.23 (s, 1H), 8.75 (s, 2H) ; RP-HPLC (Table 1, Method m) Rt 0.62 min.
INTERMEDIATE 63 : 3, 5-Difluoro-4-tributylstannanyl-pyridine [00224]. n-Butyl lithium (1.0 eq, 76 mmol, 47.6 mL, 1.6 M in hexanes) was added via dropping funnel to a solution of diisopropylamine (1.05 eq, 80 mmol, 11.2 mL) in THF (300 mL) at-78 °C under nitrogen (N2). The solution was stirred for 30 min at-78 °C, then a solution of 3,5- difluoropyridine (1.05 eq, 80 mmol, 9.2 g) in THF (20 mL) was added dropwise via syringe. A beige precipitate was observed to form. The reaction stirred at-78 °C for 90 min then tributyltin chloride (1.0 eq, 76 mmol, 20.7 mL) was added dropwise via syringe and the resulting solution allowed to warm to RT over 2 h. Water (5 mL) was added, then roughly 250 mL of THF was removed on a rotary evaporator. The resulting material was diluted with diethyl --139-- ether (350 mL) and washed successively with water (2X200 mL), saturated sodium chloride solution (1X150 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford the 3,5-Difluoro-4-tributylstannanyl-pyridine as a colourless oil (27.5 g, 88percent). This material was used crude without further purification. Retention Time (LC, method: ammonium acetate standard): 3.35 min. MS (M+H+) : 406.
88%
Intermediate 63: 3,5-Difluoro-4-tributylstannanyl-pyridine n-Butyl lithium (1.0 eq, 76 mmol, 47.6 mL, 1.6 M in hexanes) was added via dropping funnel to a solution of diisopropylamine (1.05 eq, 80 mmol, 11.2 mL) in THF (300 mL) at -78° C. under nitrogen (N2). The solution was stirred for 30 min at -78° C., then a solution of <strong>[71902-33-5]3,5-difluoropyridine</strong> (1.05 eq, 80 mmol, 9.2 g) in THF (20 mL) was added dropwise via syringe. A beige precipitate was observed to form. The reaction stirred at -78° C. for 90 min then tributyltin chloride (1.0 eq, 76 mmol, 20.7 mL) was added dropwise via syringe and the resulting solution allowed to warm to RT over 2 h. Water (5 mL) was added, then roughly 250 mL of THF was removed on a rotary evaporator. The resulting material was diluted with diethyl ether (350 mL) and washed successively with water (2*200 mL), saturated sodium chloride solution (1*150 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford the 3,5-Difluoro-4-tributylstannanyl-pyridine as a colourless oil (27.5 g, 88percent). This material was used crude without further purification. Retention Time (LC, method: ammonium acetate standard): 3.35 min. MS (M+H+): 406.
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 17h;
t-Butyl 4-hydroxypiperidine-1-carboxylate (1.04 g, 5.00 mmol) was added to a N,N-dimethylformamide suspension (5.0 ml) of 60percent sodium hydride (229 mg, 6.00 mmol), at 0°C, and stirring was carried out at room temperature for 30 minutes. Further, at 0°C, <strong>[71902-33-5]3,5-difluoropyridine</strong> (645 mg, 5.50 mmol) was added, and stirring was carried out for 16.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed sequentially with water and saline, and then dried over anhydrous sodium sulfate. The organic layer was concentrated and the resulting residue was purified by silica gel column chromatography to afford t-butyl 4-[(5-fluoropyridin-3-yl)oxy]piperidine-1-carboxylate (1.48 g, yield 99percent) as a colorless oil. 1H-NMR (CDCl3, 400 MHz) delta: 8.16-8.11 (2H, m), 6.96 (1H, dt, J=10.2, 2.3 Hz), 4.52-4.47 (1H, m), 3.73-3.67 (2H, m), 3.39-3.33 (2H, m), 1.99-1.73 (4H, m), 1.47 (9H, s). MS (ESI, m/z): 297 (M+H)+.
With lithium hexamethyldisilazane; In tetrahydrofuran; at -30 - -15℃; for 1h;Industry scale;
EXAMPLE 1 : 3,5-Difiuoroisonicotinaldehyde [0084] Anhydrous DMF (2.0 L) and anhydrous THF (5.0 L) were combined and the resulting mixture was cooled to -20°C. LiHMDS (10.4 L, 1.2 equiv) was added while maintaining the temperature between -15 and -25°C. The mixture was cooled to -30°C and then <strong>[71902-33-5]3,5-difluoropyridine</strong> (1.0 kg, 8.69 mol) was added while maintaining the temperature between -20° and -25°C. After one hour, the reaction mixture was added to a mixture of brine (4.0 kg NaCl in 16 L of DI water), THF (10 L), and concentrated aqueous HC1 (2.2 L) at 0°C. The mixture was stirred for one hour and then the layers were separated. The pH of the aqueous layer was adjusted to about 7.5 with 2 N HC1 solution (about 100 mL) and was extracted with MTBE/THF (1 : 1, 10 L). The organic layers were combined, washed with brine (1.0 kg NaCl in 4 L of DI water), and concentrated under reduced pressure to give the title compound as a yellow-orange, oily slurry.
With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 12h;
Example 19Preparation of 3-chloro-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-amineTo a stirred solution of 5-chloro-1H-pyrazol-4-amine, HCl (2 g, 12.99 mmol) and cesium carbonate (8.89 g, 27.3 mmol) in DMF (13 mL) was added <strong>[71902-33-5]3,5-difluoropyridine</strong> (1.794 g, 15.58 mmol) and the mixture heated at 70° C. for 12 h.The mixture was cooled to room temperature and filtered.The solids were washed with copious amount of ethyl acetate.The filtrates was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to give a brown solid.This solid was dissolved in ethyl acetate and the resulting solution was saturated with hexanes to precipitate 3-chloro-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-amine (2.31 g, 10.32 mmol, 79percent yield) as a brown solid: 1H NMR (400 MHz, DMSO-d6) delta 8.89-8.82 (m, 1H), 8.45 (d, J=2.5 Hz, 1H), 8.07 (d, J=10.4 Hz, 1H), 7.94 (s, 1H), 4.51 (s, 2H); EIMS (m/z) 213 ([M+1]+).3-Bromo-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-amine was prepared from the corresponding pyrazole as described in Example 19: mp 164-165° C.; 1H NMR (400 MHz, CDCl3) delta 8.65 (d, J=1.7 Hz, 1H), 8.36 (d, J=2.5 Hz, 1H), 7.76 (dd, J=5.9, 3.6 Hz, 1H), 7.48 (s, 1H), 3.22 (s, 2H).
79%
With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 12h;
Example 19 Preparation of 3-chloro-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-amine To a stirred solution of 5-chloro-1H-pyrazol-4-amine, HCl (2 g, 12.99 mmol) and cesium carbonate (8.89 g, 27.3 mmol) in DMF (13 mL) was added <strong>[71902-33-5]3,5-difluoropyridine</strong> (1.794 g, 15.58 mmol) and the mixture heated at 70° C. for 12 h. The mixture was cooled to room temperature and filtered. The solids were washed with copious amount of ethyl acetate. The filtrates was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to give a brown solid. This solid was dissolved in ethyl acetate and the resulting solution was saturated with hexanes to precipitate 3-chloro-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-amine (2.31 g, 10.32 mmol, 79percent yield) as a brown solid: 1H NMR (400 MHz, DMSO-d6) delta 8.89-8.82 (m, 1H), 8.45 (d, J=2.5 Hz, 1H), 8.07 (d, J=10.4 Hz, 1H), 7.94 (s, 1H), 4.51 (s, 2H); EIMS (m/z) 213 ([M+1]+). 3-Bromo-1-(5-fluoropyridin-3-yl)-1H-pyrazol-4-amine was prepared from the corresponding pyrazole as described in Example 19: mp 164-165° C.; 1H NMR (400 MHz, CDCl3) delta 8.65 (d, J=1.7 Hz, 1H), 8.36 (d, J=2.5 Hz, 1H), 7.76 (dd, J=5.9, 3.6 Hz, 1H), 7.48 (s, 1H), 3.22 (s, 2H).
Under argon gas atmosphere, n-butyllithium (1.6 M THF solution, 0.7 mL) was added dropwise to a mixture of <strong>[71902-33-5]3,5-difluoropyridine</strong> (123 mg) and THF (3 mL) at -78° C., followed by stirring at the same temperature for one hour. Then, zinc chloride (146 mg) was added, and stirred for an additional hour. Methyl 4-chloro-1-[(trifluoromethyl)sulfonyl]oxy}isoquinoline-7-carboxylate (330 mg) and tetrakis(triphenylphosphine)palladium (206 mg) were added thereto, followed by heating under stirring in an oil bath at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and purified under silica gel column chromatography (hexane/ethyl acetate) to obtain methyl 4-chloro-1-(3,5-difluoropyridin-4-yl)isoquinoline-7-carboxylate (62 mg).
Under argon gas atmosphere, n-butyllithium (1.6 M THF solution, 1.3 mL) was added dropwise to a mixture of <strong>[71902-33-5]3,5-difluoropyridine</strong> (238 mg) and THF (4 mL) at -78° C., followed by stirring at the same temperature for one hour. Then, zinc chloride (0.5 M THF solution, 3.8 mL) was slowly added stirried at the same temperature for 30 minutes and further for an additional hour at room temperature. Tris(dibenzylideneacetone)dipalladium (73 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (148 mg), and ethyl 2,3-dimethyl-4-[(trifluoromethyl)sulfonyl]oxy}quinoline-6-carboxylate (300 mg), were added to the reaction mixture and heated under stirring in an oil bath at 70° C. for 15 hours. The reaction mixture was returned to room temperature, and the insoluble materials were separated by filtration. Then, the precipitate was concentrated under reduced pressure, and the resulting residue was purified under silica gel column chromatography (hexane/ethyl acetate) to obtain ethyl 4-(3,5-difluoropyridin-4-yl)-2,3-dimethylquinoline-6-carboxylate (51 mg).
With potassium carbonate;dihydrogen dichloro-bis(di-tert-butylphosphinito-kappaP)palladium(2-); In N,N-dimethyl-formamide; at 120℃; for 12h;Inert atmosphere;
43 mg (0.37 mmol) of <strong>[71902-33-5]3,5-difluoropyridine</strong>, 99 mg (0.37 mg) of the pyrazolylpyridine, 6 mg (0.01 mmol) of dihydrogen dichloro bis(di-t-butylphosphinito-kP)palladate(2-) (POPd, from CombiPhos, USA) and 102 mg (0.74 mmol) of potassium carbonate were stirred in 5 ml of dimethylformamide under argon at 120° C. for 12 h.For workup, the mixture was concentrated and purified by means of column chromatography on silica gel (eluent: dichloromethane/methanol).Yield: 35 mg (26percent of theory)HPLC-MS: logP(HCOOH): 1.98; mass (m/z): 362.1 (M+H)+;1H NMR (d6-DMSO): 3.40 (s, 3H), 7.98 (m, 1H), 8.08 (m, 2H), 8.2 (m, 1H), 8.58 (m, 1H), 8.70 (m, 1H), 9.08 (m, 1H), 9.40 (m, 1H) ppm.
3,5-difluoro-α-[4-[(trifluoromethyl)thio]phenyl]-4-pyridinemethanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6.0 g
A solution of 2,2,6,6-tetramethylpiperidinyl magnesium chloride lithium chloride complex solution (25 mL, 1.0 M in toluene/tetrahydrofuran) was slowly added to a stirred solution of <strong>[71902-33-5]3,5-difluoropyridine</strong> (2.4 g, 20.9 mmol) in tetrahydrofuran (60 mL) at -78 °C. After stirring at -40 °C to -20 °C for 1 hr, the reaction mixture was treated with 4-(trifluoromethylthio)benzyaldehyde (4.3 g, 20.9 mmol) in tetrahydrofuran (10 mL) at - 78 °C. After stirring for another 1 hr at -78 °C, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with water and saturated aqueous NaCl solution, dried with anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel using hexanes/ethyl acetate (70:30 to 20:80) as eluent to afford the title product as a colorless oil (6.0 g, 18.7 mmol). H NMR (CDCI3) delta 8.35 (s, 2H), 7.66 (d, 2H), 7.48 (d, 2H), 6.29 (s, 1H), 3.00 (s, br. 1H).
With triethylsilane; [Rh(mu-H)(1,3-bis(diisopropylphosphanyl)propane)]2; In benzene-d6; at 50℃; for 48h;Inert atmosphere;
General procedure: To a solution of fluoroarene (0.1 M) and HSiEt3 (0.1 M) in benzene-d6 in a PFA tube alpha,alpha,alpha-trifluorotoluene (1?2 muL) was added as internal standard. The PFA tube was closed by a Teflon plug, inserted into an NMR tube and an initial 19F{1H} NMR spectrum was recorded. Then [Rh(mu-H)(dippp)]2 (1) (0.005 M) was added and the reaction mixture was heated to 50 °C for 48 h. Hydrodefluorination of pentafluoropyridine gave 2,3,5,6-tetrafluoropyridine (11percent), 2,3,4,5-tetrafluoropyridine (11percent), 2,3,5-trifluoropyridine (8percent), 3,5-difluoropyridine (6percent) and 2-fluoropyridine (1percent) (TON = 11). Hydrodefluorination of 2,3,5,6-tetrafluoropyridine or 2,3,5,6-tetrafluoropyridine or 2,3,5,6-tetrafluoropyri-dine gave 2,3,5-trifluoropyridine (24percent), 2,3,6-trifluoropyridine (7percent), 3,5-difluoropyridine (15percent), 2,5-difluoropyridine (2percent) and 2-fluoropyridine (8percent) (TON = 18). Hydrodefluorination of hexafluoro-benzene or hexafluoroben-zene or hexa-fluorobenzene gave pentafluorobenzene (12percent) and 1,2,4,5-tetra-fluorobenzene or 1,2,4,5-tetrafluoro-benzene or 1,2,4,5-tetrafluoroben-zene (2percent) (TON = 3.1). Hydrodefluorination of pentafluorobenzene gave 1,2,4,5-tetrafluorobenzene (35percent), 1,2,3,4-tetrafluorobenzene (3percent), 1,2,4-trifluorobenzene (23percent) and 1,4-difluorobenzene (4percent) (TON = 19). Yields of organic hydrodefluorination products were determined from 19F{1H} NMR spectra by integration of product resonances versus the internal standard. Hydrodefluorination products were identified by NMR spectroscopy by comparison with literature data [23]. TON: number of hydrodefluorination steps/moles of 1.
With triethylsilane; [Rh(mu-H)(1,3-bis(diisopropylphosphanyl)propane)]2; In benzene-d6; at 50℃; for 48h;Inert atmosphere;
General procedure: To a solution of fluoroarene (0.1 M) and HSiEt3 (0.1 M) in benzene-d6 in a PFA tube alpha,alpha,alpha-trifluorotoluene (1?2 muL) was added as internal standard. The PFA tube was closed by a Teflon plug, inserted into an NMR tube and an initial 19F{1H} NMR spectrum was recorded. Then [Rh(mu-H)(dippp)]2 (1) (0.005 M) was added and the reaction mixture was heated to 50 °C for 48 h. Hydrodefluorination of pentafluoropyridine gave 2,3,5,6-tetrafluoropyridine (11percent), 2,3,4,5-tetrafluoropyridine (11percent), 2,3,5-trifluoropyridine (8percent), 3,5-difluoropyridine (6percent) and 2-fluoropyridine (1percent) (TON = 11). Hydrodefluorination of 2,3,5,6-tetrafluoropyridine or 2,3,5,6-tetrafluoropyridine or 2,3,5,6-tetrafluoropyri-dine gave 2,3,5-trifluoropyridine (24percent), 2,3,6-trifluoropyridine (7percent), 3,5-difluoropyridine (15percent), 2,5-difluoropyridine (2percent) and 2-fluoropyridine (8percent) (TON = 18). Hydrodefluorination of hexafluoro-benzene or hexafluoroben-zene or hexa-fluorobenzene gave pentafluorobenzene (12percent) and 1,2,4,5-tetra-fluorobenzene or 1,2,4,5-tetrafluoro-benzene or 1,2,4,5-tetrafluoroben-zene (2percent) (TON = 3.1). Hydrodefluorination of pentafluorobenzene gave 1,2,4,5-tetrafluorobenzene (35percent), 1,2,3,4-tetrafluorobenzene (3percent), 1,2,4-trifluorobenzene (23percent) and 1,4-difluorobenzene (4percent) (TON = 19). Yields of organic hydrodefluorination products were determined from 19F{1H} NMR spectra by integration of product resonances versus the internal standard. Hydrodefluorination products were identified by NMR spectroscopy by comparison with literature data [23]. TON: number of hydrodefluorination steps/moles of 1.
methyl 5-fluoro-8-[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydroisoquinoline-2(1H)-carboxylate[ No CAS ]
[ 71902-33-5 ]
methyl 8-(3,5-difluoropyridin-4-yl)-5-fluoro-3,4-dihydroisoquinoline-2(1h)-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
112 mg
General procedure: In an argon gas atmosphere, n-butyllithium (2.6 M hexane solution, 0.77 mL) was added to a mixture of <strong>[71902-33-5]3,5-difluoropyridine</strong> (225 mg) and THF (4.2 mL) under cooling at -78° C., followed by stirring for 0.5 hours at the same temperature. Thereafter, zinc(II) chloride (277 mg) was added thereto under cooling at -78° C., followed by stirring for 0.5 hours at the same temperature, and then the temperature was raised to room temperature. An N-methylpyrrolidone (5.6 mL) solution of methyl 5-fluoro-8-[(trilfluoromethyl)sulfonyl]oxy}-3,4-dihydroisoquinoline-2(1H)-carboxylate (140 mg), and tetrakis(trifluorophosphine)palladium (90 mg) were added to the reaction liquid, followed by stirring for 15 hours under heating at an oil temperature of 100° C. After the reaction liquid was cooled to room temperature, 1 M hydrochloric acid and ethyl acetate were added thereto to perform liquid separation. The organic layer was washed with water and then dried, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining methyl 8-(3,5-difluoropyridin-4-yl)-5-fluoro-3,4-dihyroisoquinoline-2(1H)-carboxylate (112 mg).
ethyl 4-(3,5-difluoropyridin-4-yl)benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80 mg; 83 mg
Preparation Example 8 Lithium diisopropylamide (2.0 M heptane/THF/ethylbenzene solution, 5.57 mL) was added to a THF (7.5 mL) solution of <strong>[71902-33-5]3,5-difluoropyridine</strong> (1.26 g) under an argon gas atmosphere at -78° C. with dry ice/acetone, followed by stirring for 0.5 hours, and then zinc chloride (1.55 g) was added thereto, followed by stirring again for 0.5 hours at the same temperature. After the temperature was elevated to room temperature, a N-methylpyrrolidin-2-one (NMP) (7.5 mL) solution of ethyl 4-bromobenzoate (0.50 g) and tetrakis(triphenylphosphine)palladium (0.50 g) were added thereto, followed by stirring under heating for 8 hours at an oil temperature of 100° C., and cooling to room temperature. 1 M hydrochloric acid was added to the reaction liquid, and then the generated solid was collected by filtration, thereby obtaining 4-(3,5-difluoropyridin-4-yl)benzoic acid (Preparation Example 8-1, 80 mg). The filtrate was diluted with ethyl acetate and then washed with saturated brine, followed by drying and then concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining ethyl 4-(3,5-difluoropyridin-4-yl)benzoate (Preparation Example 8-2, 83 mg).
(1S,3S,5R)-3-cyano-8-aza-bicyclo[3.2.1]oct-6-ene-8-carboxylic acid tert-butyl ester[ No CAS ]
[ 71902-33-5 ]
tert-butyl (1R,5S)-3-cyano-3-(5-fluoro-3-pyridyl)-8-azabicyclo[3.2.1]oct-6-ene-8-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With lithium hexamethyldisilazane; In tetrahydrofuran; at -50 - 20℃;Inert atmosphere;
tert-Butyl (1 R,5S)-3-cyano-8-azabicyclo[3.2. 1]oct-6-ene-8-carboxylate (10.0 g, 42.7 mmol)was dissolved in anhydrous tetrahydrofuran (100 mL) in a dry 500 mL three neck flask and<strong>[71902-33-5]3,5-difluoropyridine</strong> (5.15 g, 44.8 mmol) was added to the stirred solution under nitrogen. The reaction mixture was cooled down to -50 °C and lithium bis(trimethylsilyl)amide (47 mL of a 1 M solution in THF) was added dropwise. An exotherm was observed and the solution became brown in colour. Stirring was continued at -50 °C for 1 h, then allowed to warm toroom temperature and stirred overnight. The reaction mixture was slowly poured into water (700 mL). The aqueous phase was extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulphate and concentrated under reduced pressure to give the crude product. Purification by flash chromatography (5i02, ethyl acetate/cyclohexane gradient) furnished tert-butyl (1 R, 5S)-3-cyano-3-(5-fluoro-3-pyridyl)-8-azabicyclo [3.2.1] oct-6-ene-8-carboxylate as a white solid.LC MS (method I): 330 [M+H].1H NMR (400 MHz, CDCI3, TMS) s/ppm: 1.46-1.50 (m, 2H), 1.52 (s, 9H), 2.11-2.30 (m, 3H),2.34-2.49 (m, 1 H), 4.67-4.86 (m, 2H), 6.36-6.48 (m, 2H), 7.50-7.57 (m, 1 H), 8.43-8.48 (m,1 H) 8.53-8.58 (m, 1 H).
Under a nitrogen atmosphere, to a solution of diisopropylamine (9.67 g) in THF (100 mL) was added dropwise n-butyllithium hexane solution (1.6 M, 59.7 mL) at -78°C. After stirring for 20 min, a solution of <strong>[71902-33-5]3,5-difluoropyridine</strong> (10.00 g) in THF (50 mL) was added dropwise while maintaining at -78°C. After stirring for 1 hr, ethyl formate (17.5 mL) was added dropwise, and the mixture was warmed to 0°C over 2 hr with stirring. Water was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.50 g). 1H NMR (300 MHz, CDCl3) delta 8.56 (2H, s), 10.42 (1H, s).
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