* 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.
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 25℃; for 0.5 h; Inert atmosphere Stage #2: at 50℃; for 2 h;
To a solution of 2-chloroisonicotinic acid (2.0 g, 0.0 12 mole) in DMF (5 mL)under N2 at 25 °C, was added sodium hydride (0.73 g, 0.0 15 mole) and stirred for 0.5hour. Methyl iodide (1.5 mL, 0.025 mole) was added at RT and the reaction mixturewas warmed to 50 °C for 2 hours. The reaction mixture was dissolved in ice water (50mL) and extracted with ethyl acetate (50 mL x 3). Organic layer was washed with brine solution (50 mL) and dried over Na2SO4. The organic phase was concentrated under vacuum to obtain methyl 2-chloroisonicotinate. Yield: 2.1 g (100 percent); Mass (mlz): 172.0 (M+H) , 174.0 (M+H) .
87%
With sodium hydrogencarbonate In N,N-dimethyl-formamide at 20℃; for 20 h;
Step 1: A mixture of 2-chloro-isonicotinic acid (4.0 g, 25.4 mmol), sodium bicarbonate (5.33 g, 63.48 mmol) and iodomethane (9.7 mL, 156.0 mmol) in N,N dimethyl formamide (60 mL) is stirred at room temperature for 20 hours. The mixture is poured into water and extracted with ether. The organic layer is washed with brine, dried over anhydrous sodium sulfate and filtered. Evaporation of the filtrate provides an oil which solidifies on standing to yield 3.8 g (87percent) of 2-chloro-isonicotinic acid methyl ester as a white solid. MS 172.0 [M+H].
2-Chloro-isonicotinic acid (5.10 g, 32.38 mmol) was dissolved in methanol (150 mL). Thionyl chloride (12 mL) was added. This suspension was stirred 5 h at 70 0C and concentrated in vacuo. The residue was dissolved in dichloromethane (250 mL) washed with a solution of 10 percent aqueous K2CO3 (2 x 150 mL) dried with MgSO4, filtered and evaporated. Methyl 2-chloropyridine-4-carboxylate SLA 07150 was obtained as a yellow solid (5.06 g, 91 percent).SLA 07150 MW: 171.58; Yield: 91 percent; Yellow Solid; Mp (0C): 33.0. Rf\\ 0.80 (MeOH:CH2CI2 = 10:90).1H-NMR (CDCI3, δ): 3.98 (s, 3H, CH3), 7.78 (dd, 1 H, J = 5.1 Hz, J = 1.3 Hz, ArH), 7.89 (d, 1 H, J = 0.6 Hz ArH), 8.55 (dd, 1 H, J = 5.1 Hz, J = 0.6 Hz, ArH).
81%
at 0 - 20℃; for 16 h;
To a solution of 2-chloroisonicotinic acid 19-1 A (5 g, 31.8 mmol) in MeOH (50 mL) was added SOCl2 (2.7 mL, 38.2 mmol) portion-wise at 0 °C, and the mixture was stirred at RT for 16 hr. Solvent was evaporated under reduced pressure. The reaction was quenched with saturated sodium carbonate and diluted with EtOAc (50 mL) washed with water (50 mL), brine (20 mL) and dried over Na2S04, and the organic phase was concentrated under reduced pressure. Obtained crude compound was purified using silica gel chromatography (15percent EtOAc in hexanes) to afford 19- 2A (4.4 g, 25.7 mmol, 81percent yield) as an off-white solid. MS (ESI): m/z 172.1 (M+l)+.
75%
for 3 h; Heating / reflux
Preparation 1; SYNTHESIS OF 2-[4-(5-FLUORO-2-TRIFLUOROMETHYLBENZOYL)PIPERAZIN-1-YL]ISONICOTINIC ACID METHYL ESTER; A. A mixture of 2-chloroisonicotinic acid (1.000 g, 6.340 mmol) and 5 drops of concentrated sulfuric acid in anhydrous methanol (50 mL) was refluxed for 3 hours. The reaction mixture was concentrated in vacuo, diluted with 20 mL of water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried and concentrated. The compound obtained was used for next step reaction without further purification. Yield 0.816 g, 75percent.
Reference：
[1] Patent: WO2008/11478, 2008, A2, . Location in patent: Page/Page column 76
[2] Patent: WO2016/154241, 2016, A1, . Location in patent: Paragraph 578; 579
[3] Patent: US2008/167321, 2008, A1, . Location in patent: Page/Page column 14
[4] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1988, p. 2785 - 2790
[5] Patent: EP1754706, 2007, A1, . Location in patent: Page/Page column 76
[6] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 11, p. 3615 - 3621
5
[ 6313-54-8 ]
[ 58481-11-1 ]
Yield
Reaction Conditions
Operation in experiment
73%
With thionyl chloride In methanol; toluene
Step 1 Preparation of Methyl-2-chloroisonicotinate To a solution of thionyl chloride (13.85 mL, 190.38 mmol) in toluene (50 mL) was added 2-chloropyridine-4-carboxylic acid (15 g, 95 mmol). The solution was heated to reflux for 3 hours. The resulting brown color solution was cooled to room temperature, and methanol (11.56 mL, 285.6 mmol) was added slowly dropwise. The mixture was brought to reflux for 15 minutes and became clear. The solution was then cooled to room temperature and poured into water (150 mL), basified with 50 percent sodium hydroxide and extracted with ethyl acetate (2*200 ml). The organic layer was separated and washed with brine, dried with magnesium sulfate, filtered and concentrated to yield the titled compound (11.93 g, 73percent) as a brown color solid. This was used in the next step without further purification.
83%
With thionyl chloride In methanol; water; toluene
Step 2 Preparation of Methyl 2-Chloroisonicotinate: To a solution of thionyl chloride (15.0 g, 0.127 mol) in 20 mL of toluene was added 2-chloroisonicotinic acid (10.0 g, 0.063 mol) and the reaction was heated at reflux until gas evolution ceased. Then a solution of methanol (7.7 mL, 0.19 mol) in 10 mL of toluene was added at room temperature over 15 min. The reaction mixture was then refluxed for 1 h and then cooled to room temperature. The clear solution was poured into 100 mL of water, basified with 40percent NaOH and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate filtered. The filtrate was concentrated in vacuo to give 8.2 g (83percent) of product as a brown oil which solidified upon standing, mp: 36-37 C.
Step 1 Preparation of Methyl 2-Methoxyisonicotinate A mixture of methyl 2-chloroisonicotinate (5.23 g, 0.030 mol) and sodium methoxide (2.47 g, 0.045 mol) in 15 mL of dioxane was heated at reflux for 1.5 hours. After the reaction mixture was cooled, water was added and the resulting mixture was extracted with methylene chloride. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 3.76 g (75percent) of product as a yellow oil: Anal. Calc'd. for C8H9NO3: C, 57.48; H, 5.43; N, 8.38. Found: C, 57.07; H, 5.54; N, 8.34.
Reference：
[1] Patent: US6509361, 2003, B1,
11
[ 58481-11-1 ]
[ 124-41-4 ]
[ 26156-51-4 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1988, p. 2785 - 2790
[2] Yakugaku Zasshi, 1952, vol. 72, p. 1639,1641[3] Chem.Abstr., 1953, p. 9325
[4] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 17, p. 5235 - 5246
12
[ 58481-11-1 ]
[ 100704-10-7 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: With diisobutylaluminium hydride In tetrahydrofuran; hexane at 0℃; for 2 h; Stage #2: With hydrogenchloride In tetrahydrofuran; hexane; water at 20℃; for 1 h; Stage #3: With sodium hydrogencarbonate In tetrahydrofuran; hexane; water
Reference Example 7 2-Chloropyridine-4-methanol (Reference compound No.7-1) A 0.95 M solution of diisobutylaluminum hydride in hexane (200 mL, 190 mmol) was added dropwise to a solution of 2-chloroisonicotinic acid methyl ester (11 g, 62 mmol) in anhydrous tetrahydrofuran (300 mL) under a nitrogen atmosphere under ice-cooling, and then the mixture was stirred under ice-cooling for 2 hours. After that, 1 N hydrochloric acid (200 mL) was added thereto, the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogencarbonate solution (400 mL) was added to the reaction mixture, then the whole was extracted with ethyl acetate (100 mL) three times. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to give 8.5 g of the title reference compound as a white solid. (Yield 95percent) 1H-NMR(500MHz,DMSO-d6) δ 4.56(d,J = 5.8 Hz,2H),5.54(t,J = 5.8 Hz,1H),7.34(d,J = 4.9 Hz,1H),7.41(s,1H),8.34(d,J = 4.9 Hz,1H)
94%
Stage #1: With diisobutylaluminium hydride In tetrahydrofuran; hexanes at -78 - 20℃; for 4.5 h; Stage #2: With ammonium chloride In tetrahydrofuran; hexanes; water
Methyl 2-chloropyridine-4-carboxylate (2.50 g, 14.60 mmol) was dissolved in anhydrous THF (50 mL) and this solution was cooled to -78 0C under N2 atmosphere. Diisobutylaluminium hydride 1.0 M in hexanes (63.3 mL, 63.30 mmol) was added dropwise stabilizing the temperature between - <n="79"/>50 0C and -70 0C. The reaction mixture was stirred 1 .5 h at -78 0C and allowed to stand at room temperature for 3 h. A solution of aqueous 10 percent NH4CI was slowly added and the mixture was extracted with ethyl acetate (3 x 300 ml_). The combined organic layers were washed with water (3 x 20 ml_), brine (2 x 20 ml_), dried over MgSO4, filtered and evaporated. (2- Chloropyridin-4-yl)methanol SLA 07152 was obtained as a yellow oil (1 .97 g, 94 percent yield).SLA 07152MW: 143.71 ; Yield: 94 percent; Yellow Oil. Rf : 0.35 (EtOAc:cyclohexane = 30:70).1H-NMR (CDCI3, δ): 2.95 (s broad, 1 H, OH), 4.75 (s, 2H, CH2O), 7.21 (dd, 1 H, J = 5.1 Hz, J = 1.2 Hz, ArH), 7.37 (d, 1 H, J = 1.2 Hz ArH), 8.29 (d, 1 H, J = 5.1 Hz, ArH).MS-ESI m/z (rel. int.): 144.0 ([MH]+, 100).HP LC: Method A, detection UV 254 nm, SLA 07152 RT = 3.45 min, peak area 99.9 percent.
71%
With lithium borohydride In tetrahydrofuran at 25 - 30℃; for 3 h; Inert atmosphere; Cooling
To a cooled solution of methyl 2-chloroisonicotinate (1.7 g, 0.009 mole) inTHF (30 mL) under N2, was added lithium borohydride (0.43 g, 0.019 mole) inportions. The reaction mixture was warmed to RT and stirred further for 3 hours. Thereaction mixture was concentrated under reduced pressure; residue was dissolved inice cold water (50 mL) and extracted with ethyl acetate (50 mL x 3). Organic layer was washed with brine solution (50 mL) and dried over Na2SO4. The organic phase was concentrated under vacuum to obtain the crude compound which was further purified by flash chromatography using ethyl acetate: n-hexane (40: 60) to afford (2-chloropyridin-4-yl)-methanol.Yield: 1.0 g (71 percent); ‘H - NMR (CDC13, 400MHz) ö ppm: 2.29 (bs, 1H), 4.75 (s, 2H),7.20 - 7.21 (d, J = 4.9 Hz, 1H), 7.31 (s, 1H), 8.32 - 8.33 (d, J = 5.0 Hz, 1H); Mass(m/z): 144.0 (M+H), 145.9 (M+H).
70.8%
Stage #1: With lithium borohydride In tetrahydrofuran; methanol at 0 - 20℃; for 4 h; Stage #2: With hydrogenchloride In tetrahydrofuran; methanol; water at 0℃;
A sample of methyl 2-chloroisonicotinate (5.00 g, 29.14 mmol) was dissolved in 10 niL THF, treated with 10 drops of methanol, and cooled to 0 0C. The solution was treated with lithium borohydride solution (21.86 mL of 1 M in THF, 43.71mmol) and then allowed to warm to room temp. After 4 h the solution was cooled to 0 0C and quenched with 1 N HCl solution. The pH was adjusted to pH 10 with 1 N NaOH solution, and the reaction mixture was extracted with EtOAc. The organic extracts were washed with brine and concentrated in vacuo yielding 2.96 g (70.8percent) of product.1H NMR (300 MHz, CD3CN) δ 8.32 (d, 1 H), 7.39 (s, 1 H), 7.29 (d, 1 H), 4.62 (s, 2 H) and 3.53 ppm (bs, 1 H).
70.8%
Stage #1: With methanol; lithium borohydride In tetrahydrofuran at 0 - 20℃; for 4 h; Stage #2: With hydrogenchloride; water In tetrahydrofuran; methanol at 0℃;
Intermediate T : Preparation of 2-chloro-4-(chloromethyl)pyridine; Step 1: Preparation of (2-chloropyridin-4-yl)methanol; A sample of methyl 2-chloroisonicotinate (5.00 g, 29.14 mmol) was dissolved in 10 mL THF, treated with 10 drops of methanol, and cooled to 0 °C. The solution was treated with lithium borohydride solution (21.86 mL of 1 M in THF, 43.71mmol) and then allowed to warm to room temp. After 4 h the solution was cooled to 0 °C and quenched with 1 N HC1 solution. The pH was adjusted to pH 10 with 1 N NaOH solution, and the reaction mixture was extracted with EtOAc. The organic extracts were washed with brine and concentrated in vacuo yielding 2.96 g (70.8percent) of product.'H NMR (300 MHz, CD3CN) 5 8.32 (d, 1 H), 7.39 (s, 1 H), 7.29 (d, 1 H), 4.62 (s, 2 H) and 3.53 ppm (bs, 1 H).
70.8%
With lithium borohydride In tetrahydrofuran; methanol at 20℃; for 4 h;
Preparation of (2-chloropyridin-4-yl)methanolA sample of methyl 2-chloroisonicotinate (5.00 g, 29.14 mmol) was dissolved in 10 mL THF, treated with 10 drops of methanol, and cooled to 0 C. The solution was treated with lithium borohydride solution (21.86 mL of 1 M in THF, 43.71 mmol) and then allowed to warm to room temp. After 4 h the solution was cooled to 0 C and quenched with 1 N HCl solution. The pH was adjusted to pH 10 with 1 N NaOH solution, and the reaction mixture was extracted with EtOAc. The organic extracts were washed with brine and concentrated in vacuo yielding 2.96 g (70.8percent) of product.1H NMR (300 MHz, CD3CN) ? 8.32 (d, 1 H), 7.39 (s, 1 H), 7.29 (d, 1 H), 4.62 (s, 2 H) and 3.53 ppm (bs, 1 H).
Step 1 Preparation of Methyl-2-chloroisonicotinate To a solution of thionyl chloride (13.85 mL, 190.38 mmol) in toluene (50 mL) was added 2-chloropyridine-4-carboxylic acid (15 g, 95 mmol). The solution was heated to reflux for 3 hours. The resulting brown color solution was cooled to room temperature, and methanol (11.56 mL, 285.6 mmol) was added slowly dropwise. The mixture was brought to reflux for 15 minutes and became clear. The solution was then cooled to room temperature and poured into water (150 mL), basified with 50 percent sodium hydroxide and extracted with ethyl acetate (2*200 ml). The organic layer was separated and washed with brine, dried with magnesium sulfate, filtered and concentrated to yield the titled compound (11.93 g, 73%) as a brown color solid. This was used in the next step without further purification.
8.2 g (83%)
With thionyl chloride; In methanol; water; toluene;
Step 2 Preparation of Methyl 2-Chloroisonicotinate: To a solution of thionyl chloride (15.0 g, 0.127 mol) in 20 mL of toluene was added 2-chloroisonicotinic acid (10.0 g, 0.063 mol) and the reaction was heated at reflux until gas evolution ceased. Then a solution of methanol (7.7 mL, 0.19 mol) in 10 mL of toluene was added at room temperature over 15 min. The reaction mixture was then refluxed for 1 h and then cooled to room temperature. The clear solution was poured into 100 mL of water, basified with 40% NaOH and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate filtered. The filtrate was concentrated in vacuo to give 8.2 g (83%) of product as a brown oil which solidified upon standing, mp: 36-37 C.
With hydrogenchloride; sodium hydrogencarbonate; In methanol;
Step 1 2-Chloropyridine-4-carboxylic acid (15.5 g, 98 mmol) was suspended in methanol (175 ml) and anhydrous hydrogen chloride gas was slowly bubbled through the reaction mixture while cooling in a methanol/water (20/80) dry ice bath. Bubbling was continued for 40 min. during which time the suspension cleared to a partial solution. Ice bath was removed and the reaction mixture was heated to reflux under anhydrous conditions for 30 min. to give a clear yellow solution. The solution was cooled in an ice bath and saturated sodium bicarbonate was slowly added with stirring till the pH was neutral. The organics were removed in vacuo and the product was extracted into ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield 2-chloropyridine-4-carboxylic acid methyl ester as a brown liquid.
To methyl 2-chloroisonicotinate (18, 53.63 g) were added dioxane (150 mL) and sodium methoxide (25.32 g), and the mixture was stirred at reflux temperature for 26 h and then cooled down to room temperature. To the mixture was added acetic acid (28 mL), and the mixture was evaporated in vacuo. To the resulting residue were added ethyl acetate and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried, filtered, and the filtrate was evaporated in vacuo. The resulting residue was dissolved in THF (300 mL). Under an argon atmosphere, the solution was added dropwise to a suspension of lithium aluminum hydride (11.88 g) in THF (500 mL) at 0 C over 1 h. Then the reaction mixture was stirred at 0 C for 2 h. To the mixture was added water (30 mL) dropwise at 0 C, and then THF (270 mL) was added. The mixture was filtered over celite, and the filtrate was evaporated in vacuo to obtain 19 (33.55 g, 75%) as a orange oil: 1H NMR (DMSO-d6) delta 3.83 (3H, s), 4.49 (2H, d, J = 5.3 Hz), 4.70 (1H, t, J = 5.3 Hz), 6.73 (1H, s), 6.90 (1H, d, J = 5.4 Hz), 8.07 (1H, d, J = 5.4 Hz); EI-MS m/z 139 [(M)+].
2-Chloro-isonicotinic acid (5.10 g, 32.38 mmol) was dissolved in methanol (150 mL). Thionyl chloride (12 mL) was added. This suspension was stirred 5 h at 70 0C and concentrated in vacuo. The residue was dissolved in dichloromethane (250 mL) washed with a solution of 10 % aqueous K2CO3 (2 x 150 mL) dried with MgSO4, filtered and evaporated. Methyl 2-chloropyridine-4-carboxylate SLA 07150 was obtained as a yellow solid (5.06 g, 91 %).SLA 07150 MW: 171.58; Yield: 91 %; Yellow Solid; Mp (0C): 33.0. Rf 0.80 (MeOH:CH2CI2 = 10:90).1H-NMR (CDCI3, delta): 3.98 (s, 3H, CH3), 7.78 (dd, 1 H, J = 5.1 Hz, J = 1.3 Hz, ArH), 7.89 (d, 1 H, J = 0.6 Hz ArH), 8.55 (dd, 1 H, J = 5.1 Hz, J = 0.6 Hz, ArH).
81%
With thionyl chloride; at 0 - 20℃; for 16h;
To a solution of 2-chloroisonicotinic acid 19-1 A (5 g, 31.8 mmol) in MeOH (50 mL) was added SOCl2 (2.7 mL, 38.2 mmol) portion-wise at 0 C, and the mixture was stirred at RT for 16 hr. Solvent was evaporated under reduced pressure. The reaction was quenched with saturated sodium carbonate and diluted with EtOAc (50 mL) washed with water (50 mL), brine (20 mL) and dried over Na2S04, and the organic phase was concentrated under reduced pressure. Obtained crude compound was purified using silica gel chromatography (15% EtOAc in hexanes) to afford 19- 2A (4.4 g, 25.7 mmol, 81% yield) as an off-white solid. MS (ESI): m/z 172.1 (M+l)+.
75%
sulfuric acid; for 3h;Heating / reflux;
Preparation 1; SYNTHESIS OF 2-[4-(5-FLUORO-2-TRIFLUOROMETHYLBENZOYL)PIPERAZIN-1-YL]ISONICOTINIC ACID METHYL ESTER; A. A mixture of 2-chloroisonicotinic acid (1.000 g, 6.340 mmol) and 5 drops of concentrated sulfuric acid in anhydrous methanol (50 mL) was refluxed for 3 hours. The reaction mixture was concentrated in vacuo, diluted with 20 mL of water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried and concentrated. The compound obtained was used for next step reaction without further purification. Yield 0.816 g, 75%.
(1) 2-chloro-4-pyridinecarboxylic acid was dissolved in methanol, then thionyl chloride was added to the solution, and the mixture was stirred overnight at 80C. The obtained reaction solution was concentrated and then poured onto water, and the reaction solution was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried over anhydrous sodium sulfate, and the solvent was removed to obtain a methyl ester product [122-2]. [Show Image] The spectral data of the compound represented by the above Formula [122-2] is presented below. 1H-NMR (CDCl3) delta: 8.55 (1H, dd, J=0.8, 4.8 Hz), 7.90 - 7.80 (1H, m), 7.78 (1H, dd, J=1.2, 4.8 Hz), 3.98 (3H, s).
Step 1 Preparation of Methyl 2-Methoxyisonicotinate A mixture of methyl 2-chloroisonicotinate (5.23 g, 0.030 mol) and sodium methoxide (2.47 g, 0.045 mol) in 15 mL of dioxane was heated at reflux for 1.5 hours. After the reaction mixture was cooled, water was added and the resulting mixture was extracted with methylene chloride. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 3.76 g (75%) of product as a yellow oil: Anal. Calc'd. for C8H9NO3: C, 57.48; H, 5.43; N, 8.38. Found: C, 57.07; H, 5.54; N, 8.34.
methyl 2-(5-methyl-2-phenyl-4-oxazolyl)methoxy-4-pyridinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
14%
To a mixture of (5-methyl-2-phenyl-4-oxazolyl)methanol (9.46 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60percent, oil, 2.40 g) at room temperature and the reaction mixture was stirred at room temperature until generation of hydrogen ended. The mixture was added to a solution of <strong>[58481-11-1]methyl 2-chloropyridine-4-carboxylate</strong> (8.58 g) in tetrahydrofuran (50 ml) at room temperature and the resulting mixture was further stirred at room temperature for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals of methyl 2-(5-methyl-2-phenyl-4-oxazolyl)methoxy-4-pyridinecarboxylate from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless needle crystals (2.19 g, 14percent). melting point: 106-107 DEG C.
14%
Sodium hydride (60percent, oily, 2.40 g) was added to a solution of 5-methyl-2-phenyl-4-oxazolylmethanol (9.46 g) in N,N-dimethylformamide (50 ml) at 0°C, which was stirred for 15 minutes. A solution of <strong>[58481-11-1]methyl 2-chloro-4-pyridinecarboxylate</strong> (8.58 g) in tetrahydrofuran (50 ml) was added to the mixture. After being stirred at room temperature for 1 hour, the reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-4-pyridinecarboxylate (2190 mg, yield 14percent) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 106-107°C.
2-(furan-2-yl)-5-methyl-4-oxazolylmethanol[ No CAS ]
methyl 2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-4-pyridinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15%
With sodium hydride; In tetrahydrofuran; DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 2h;
Sodium hydride (60%, oily, 2.88 g) was added to a mixture of 2-(2-furyl)-5-methyl-4-oxazolylmethanol (10.80 g), <strong>[58481-11-1]methyl 2-chloro-4-pyridinecarboxylate</strong> (10.30 g), tetrahydrofuran (100 ml) and N,N-dimethylformamide (100 ml) at 0C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-4-pyridinecarboxylate (2.86 g, yield 15%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 80-81C
methyl 2-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)-4-pyridinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
18%
With sodium hydride; In DMF (N,N-dimethyl-formamide); at 20℃; for 3h;
Sodium hydride (60percent, oily, 2.00 g) was added to a mixture of 5-chloroimidazo[1,2-a]pyridin-2-ylmethanol (8.77g), <strong>[58481-11-1]methyl 2-chloro-4-pyridinecarboxylate</strong> (8.24 g) and N, N-dimethylformamide (150 ml) at 0C, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 2-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)-4-pydinecarboxylate (2.78 g, yield 18percent) as colorless crystals from the fraction eluted with tetrahydrofuran. This was recrystallized from tetrahydrofuran-hexane. Melting point: 157-158C
Reference Example 7 2-Chloropyridine-4-methanol (Reference compound No.7-1) A 0.95 M solution of diisobutylaluminum hydride in hexane (200 mL, 190 mmol) was added dropwise to a solution of <strong>[58481-11-1]2-chloroisonicotinic acid methyl ester</strong> (11 g, 62 mmol) in anhydrous tetrahydrofuran (300 mL) under a nitrogen atmosphere under ice-cooling, and then the mixture was stirred under ice-cooling for 2 hours. After that, 1 N hydrochloric acid (200 mL) was added thereto, the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogencarbonate solution (400 mL) was added to the reaction mixture, then the whole was extracted with ethyl acetate (100 mL) three times. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to give 8.5 g of the title reference compound as a white solid. (Yield 95percent) 1H-NMR(500MHz,DMSO-d6) delta 4.56(d,J = 5.8 Hz,2H),5.54(t,J = 5.8 Hz,1H),7.34(d,J = 4.9 Hz,1H),7.41(s,1H),8.34(d,J = 4.9 Hz,1H)
94%
Methyl 2-chloropyridine-4-carboxylate (2.50 g, 14.60 mmol) was dissolved in anhydrous THF (50 mL) and this solution was cooled to -78 0C under N2 atmosphere. Diisobutylaluminium hydride 1.0 M in hexanes (63.3 mL, 63.30 mmol) was added dropwise stabilizing the temperature between - <n="79"/>50 0C and -70 0C. The reaction mixture was stirred 1 .5 h at -78 0C and allowed to stand at room temperature for 3 h. A solution of aqueous 10 percent NH4CI was slowly added and the mixture was extracted with ethyl acetate (3 x 300 ml_). The combined organic layers were washed with water (3 x 20 ml_), brine (2 x 20 ml_), dried over MgSO4, filtered and evaporated. (2- Chloropyridin-4-yl)methanol SLA 07152 was obtained as a yellow oil (1 .97 g, 94 percent yield).SLA 07152MW: 143.71 ; Yield: 94 percent; Yellow Oil. Rf : 0.35 (EtOAc:cyclohexane = 30:70).1H-NMR (CDCI3, delta): 2.95 (s broad, 1 H, OH), 4.75 (s, 2H, CH2O), 7.21 (dd, 1 H, J = 5.1 Hz, J = 1.2 Hz, ArH), 7.37 (d, 1 H, J = 1.2 Hz ArH), 8.29 (d, 1 H, J = 5.1 Hz, ArH).MS-ESI m/z (rel. int.): 144.0 ([MH]+, 100).HP LC: Method A, detection UV 254 nm, SLA 07152 RT = 3.45 min, peak area 99.9 percent.
71%
With lithium borohydride; In tetrahydrofuran; at 25 - 30℃; for 3h;Inert atmosphere; Cooling;
To a cooled solution of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (1.7 g, 0.009 mole) inTHF (30 mL) under N2, was added lithium borohydride (0.43 g, 0.019 mole) inportions. The reaction mixture was warmed to RT and stirred further for 3 hours. Thereaction mixture was concentrated under reduced pressure; residue was dissolved inice cold water (50 mL) and extracted with ethyl acetate (50 mL x 3). Organic layer was washed with brine solution (50 mL) and dried over Na2SO4. The organic phase was concentrated under vacuum to obtain the crude compound which was further purified by flash chromatography using ethyl acetate: n-hexane (40: 60) to afford (2-chloropyridin-4-yl)-methanol.Yield: 1.0 g (71 percent); ?H - NMR (CDC13, 400MHz) oe ppm: 2.29 (bs, 1H), 4.75 (s, 2H),7.20 - 7.21 (d, J = 4.9 Hz, 1H), 7.31 (s, 1H), 8.32 - 8.33 (d, J = 5.0 Hz, 1H); Mass(m/z): 144.0 (M+H), 145.9 (M+H).
70.8%
A sample of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (5.00 g, 29.14 mmol) was dissolved in 10 niL THF, treated with 10 drops of methanol, and cooled to 0 0C. The solution was treated with lithium borohydride solution (21.86 mL of 1 M in THF, 43.71mmol) and then allowed to warm to room temp. After 4 h the solution was cooled to 0 0C and quenched with 1 N HCl solution. The pH was adjusted to pH 10 with 1 N NaOH solution, and the reaction mixture was extracted with EtOAc. The organic extracts were washed with brine and concentrated in vacuo yielding 2.96 g (70.8percent) of product.1H NMR (300 MHz, CD3CN) delta 8.32 (d, 1 H), 7.39 (s, 1 H), 7.29 (d, 1 H), 4.62 (s, 2 H) and 3.53 ppm (bs, 1 H).
70.8%
Intermediate T : Preparation of 2-chloro-4-(chloromethyl)pyridine; Step 1: Preparation of (2-chloropyridin-4-yl)methanol; A sample of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (5.00 g, 29.14 mmol) was dissolved in 10 mL THF, treated with 10 drops of methanol, and cooled to 0 °C. The solution was treated with lithium borohydride solution (21.86 mL of 1 M in THF, 43.71mmol) and then allowed to warm to room temp. After 4 h the solution was cooled to 0 °C and quenched with 1 N HC1 solution. The pH was adjusted to pH 10 with 1 N NaOH solution, and the reaction mixture was extracted with EtOAc. The organic extracts were washed with brine and concentrated in vacuo yielding 2.96 g (70.8percent) of product.'H NMR (300 MHz, CD3CN) 5 8.32 (d, 1 H), 7.39 (s, 1 H), 7.29 (d, 1 H), 4.62 (s, 2 H) and 3.53 ppm (bs, 1 H).
70.8%
With lithium borohydride; In tetrahydrofuran; methanol; at 20℃; for 4h;
Preparation of (2-chloropyridin-4-yl)methanolA sample of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (5.00 g, 29.14 mmol) was dissolved in 10 mL THF, treated with 10 drops of methanol, and cooled to 0 C. The solution was treated with lithium borohydride solution (21.86 mL of 1 M in THF, 43.71 mmol) and then allowed to warm to room temp. After 4 h the solution was cooled to 0 C and quenched with 1 N HCl solution. The pH was adjusted to pH 10 with 1 N NaOH solution, and the reaction mixture was extracted with EtOAc. The organic extracts were washed with brine and concentrated in vacuo yielding 2.96 g (70.8percent) of product.1H NMR (300 MHz, CD3CN) ? 8.32 (d, 1 H), 7.39 (s, 1 H), 7.29 (d, 1 H), 4.62 (s, 2 H) and 3.53 ppm (bs, 1 H).
To a suspension of lithium aluminum hydride (221 mg) in Et2O (10.0 mL) cooled to -40C was added <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (1.00 g) in Et2O (2 mL) dropwise and the mixture was stirred at -4 0C for 30 min and quenched with water. The aqueous layer was extracted with EtOAc three times. The combined organic layer was washed with aqueous saturated NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure to give (2-chloropyridin-4-yl)methanol (641 mg) as a pale brown solid.1HNMR (300 MHz, CDCl3, delta): 2.81-2.93 (m, IH), 4.72-4.80 (m, 2H), 7.17-7.26 (m, IH), 7.34-7.41 (m, IH), 8.30 (dd, J= 5.1, 0.6 Hz5 IH); ESI MS m/z 144 (M++., 100percent).
With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 90℃;
Degas with nitrogen a suspension containing <strong>[58481-11-1]2-chloro-isonicotinic acid methyl ester</strong> (2.15 g, 12.5 mmol), palladium acetate (281 mg, 1.25 mmol), racemic 2,2'- bis(diphenylphosphino)-1,1'-binaphthyl (780 mg, 1.25 mmol), cesium carbonate (4.95 g, 15 mmol), and (S) -sec-butylamine (1.5 mL, 15 mmol) in toluene (30 mL) and heat in a sealed tube at 90 °C overnight. Cool to room temperature and filter the solids through a filtering agent. Wash with ethyl acetate (30 mL), concentrate and purify (silica gel chromatography, eluting with 15: 85 to 30: 70 ethyl acetate: hexanes) to give the title compound.
With sodium methylate; In tetrahydrofuran; ethyl acetate; acetone;
Step 2 Preparation of 1-(2-Chloro-4-pyridinyl)-1,3-butanedione To a solution of methyl-2-chloroisonicotinate (11.93 g, 69.53 mmol) in THF (200 mL) was added acetone (14.19 mL, 153 mmol). The solution was warmed to 35° C. when sodium methoxide (94.13 g, 76.48 mmol) was added sequentially over 20 minutes. The mixture was stirred for 30 minutes, and then brought to reflux for 2.5 hours. The solvent was removed under reduced pressure and then taken up in ethyl acetate. The resulting solution was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated to yield 1-(2-chloro-4-pyridinyl)-1,3-butanedione (4.97 g, 76percent) as a light brown colored solid. This was used in the next step without further purification.
With sodium methylate; In tetrahydrofuran; water; acetone;
Step 3 Preparation of 1-(2-Chloroisonicotinyl)-1,3-butanedione: To solution of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (12.0 g, 0.07 mol) and acetone (12.2 g, 0.21 mol) in 100 mL of dry THF at 35 C was added sodium methoxide portionwise. After heating the reaction mixture at reflux for 4 h, the solvent was removed. The residue was dissolved with 500 mL of water, acidified with acetic acid to pH=6 and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 11.46 g (83percent yield) of product was a brown solid.
2-(furan-2-yl)-5-methyl-4-oxazolylmethanol[ No CAS ]
ethyl 2-[2-(furan-2-yl)-5-methyl-4-oxazolylmethoxy]-4-pyridinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15%
With sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; at 0 - 30℃; for 2h;
To a mixture of 2-(2-furyl)-5-methyl-4-oxazolylmethanol (10.8 g), <strong>[58481-11-1]methyl 2-chloro-4-pyridinecarboxylate</strong> (10.3 g) and a solution of tetrahydrofuran (100 mL) and N,N-dimethylformamide (100 mL) was added sodium hydride (60%, oil, 2.88 g) at 0 DEG C and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 2-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-4-pyridinecarboxylate (2.86 g, yield 15%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, v/v). The crystals were recrystallized from ethyl acetate-hexane. melting point: 80-81.
With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In toluene; at 150℃; for 0.333333h;Microwave;
Methyl 2-chloroisonicotinate (427mg), 4-(trifluoromethyl)phenylboronic acid (474mg), potassium phosphate (800mg), l,l-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (102mg), in PhMe (5ml) were placed in a microwave tube and the contents were heated in the microwave oven for 20min at 15O0C. The cooled mixture was filtered through Hyflo.(R). to remove inorganic material, the Hyflo.(R). was washed with EtOAc and the combined organic extracts were dispersed between H2O and EtOAc. The organic extracts were washed with brine, dried (MgSO4) and evaporated. The crude oil was purified by chromatography on silica using 10-25percent EtOAc in hexane to yield the product as a crystalline solid (560mg, 85percent). 1H NMR (400 MHz, CDCl3) delta: 4.01 (3H, s), 7.76 (2H, d, J 8.3), 7.84 (IH, dd, J 1.4, 4.9), 8.18 (2H, d, J 8.2), 8.33 (IH, t, J 1.1), 8.87 (IH, dd, J 0.6, 4.8).
70%
Methyl 2-chloroisonicotinate (5 g, 29.14 mmol), 4-(trifluoromethyl)phenylboronic acid (8.30 g, 43.71 mmol), potassium carbonate (6.04 g, 43.71 mmol) and PdCl2 (dppf) (0.633 g, 0.87 mmol) were mixed in methanol (30 mL) in two 20 mL microwave vials. Two drops of water were added to one of the vials and the vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. The solids were removed by filtration and the filtrate evaporated to yield a dark red slurry. DCM and water were added and the phases separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield a brown solid. The crude was dissolved in MTBE (180 mL) and solids filtered off. Hydrogen chloride (4 M in dioxane, (7.29 mL, 29.14 mmol) was added dropwise during stirring and a suspension was formed. The suspension was stirred at room temperature for 2.5 h. The solid was collected by filtration and washed with MTBE. MTBE and satd NaHCO3 was added to the solid, the organic phase dried (Na2SO4), filtered and evaporated to yield methyl 2-(4-(trifluoromethyl)phenyl)isonicotinate (5.75 g, 70percent) as a beige solid. 1H NMR (400 MHz, cdcl3) delta 4.00 (s, 3H), 7.75 (d, 2H), 7.84 (dd, 1H), 8.18 (d, 2H), 8.33 (s, 1H), 8.87 (dd, 1H). MS m/z 282 (M+H)+
With cesium fluoride;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane;Heating / reflux;
Reference Example 10 Cesium fluoride and tetrakis(triphenylphosphine)palladium were added to a 1,2-dimethoxyethane solution of <strong>[214210-21-6](3-cyano-4-fluorophenyl)boric acid</strong> and methyl 2-chloroisonicotinate, and the mixture was heated under reflux in an argon atmosphere to obtain methyl 2-(3-cyano-4-fluorophenyl)isonicotinate. F: 257.
To a solution of 2-chloroisonicotinic acid (2.0 g, 0.0 12 mole) in DMF (5 mL)under N2 at 25 C, was added sodium hydride (0.73 g, 0.0 15 mole) and stirred for 0.5hour. Methyl iodide (1.5 mL, 0.025 mole) was added at RT and the reaction mixturewas warmed to 50 C for 2 hours. The reaction mixture was dissolved in ice water (50mL) and extracted with ethyl acetate (50 mL x 3). Organic layer was washed with brine solution (50 mL) and dried over Na2SO4. The organic phase was concentrated under vacuum to obtain methyl 2-chloroisonicotinate. Yield: 2.1 g (100 %); Mass (mlz): 172.0 (M+H) , 174.0 (M+H) .
87%
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 20℃; for 20h;
Step 1: A mixture of 2-chloro-isonicotinic acid (4.0 g, 25.4 mmol), sodium bicarbonate (5.33 g, 63.48 mmol) and iodomethane (9.7 mL, 156.0 mmol) in N,N dimethyl formamide (60 mL) is stirred at room temperature for 20 hours. The mixture is poured into water and extracted with ether. The organic layer is washed with brine, dried over anhydrous sodium sulfate and filtered. Evaporation of the filtrate provides an oil which solidifies on standing to yield 3.8 g (87%) of 2-chloro-isonicotinic acid methyl ester as a white solid. MS 172.0 [M+H].
(RS)-2-Chloro-α-[[[(p-(2-ethoxyethoxy)phenethyl]amino]methyl]-4-pyridinemethanol[ No CAS ]
[ 101066-61-9 ]
Yield
Reaction Conditions
Operation in experiment
With diisobutylaluminium hydride; In toluene;
EXAMPLE 20 (RS)-2-Chloro-alpha-[[[(p-(2-ethoxyethoxy)phenethyl]amino]methyl]-4-pyridinemethanol, m.p. 76-78 C.; epsilon201 =25940, epsilon224 =13300, epsilon263 =3740, epsilon269 =3690, was obtained analogously to Example 14. The 2-chloro-4-(2-oxiranyl)pyridine, epsilon201 =15080, epsilon265 =2790, used as the starting material was prepared by reducing methyl 2-chloroisonicotinate with diisobutylaluminum hydride in toluene and reacting the resulting 2-chloroisonicotinic aldehyde, m.p 46-48 C.; epsilon264 =2810, epsilon200 =9950, with trimethylsulfoniummethyl sulfate in methylene chloride/50% NaOH.
(2) 18 g of the methyl ester product [122-2] and 21 mL of benzophenonimine were dissolved in 200 mL of toluene, then 47 g of cesium carbonate, 1.2 g of palladium acetate and 3.2 g of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl were added to the solution, and the mixture was stirred in a nitrogen atmosphere at 110°C for 5 hours. The obtained reaction solution was cooled to 0°C, then a methanol solution of hydrogen chloride was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, then the mixture was diluted with water, and sodium hydrogen carbonate was added to the dilution to neutralize the dilution. The aqueous phase was extracted with chloroform and dried, and the solvent was distilled off under reduced pressure. The residue was solidified from methanol and ether to obtain 4.6 g of a 2-aminopyridine product [122-3]. [Show Image] The spectral data of the compound represented by the above Formula [122-3] is presented below. 1H-NMR (CD3OD) delta: 8.17 (1H, d, J=5.6 Hz), 7.16 - 7.06 (1H, m), 7.06 - 7.05 (1H, m), 3.92 (3H, m)
Referential Example 12 Cesium fluoride and tetrakis(triphenylphosphine)-palladium were added to a 1,2-dimethoxyethane solution of <strong>[214210-21-6](3-cyano-4-fluorophenyl)boronic acid</strong> and methyl 2-chloroisonicotinate, followed by reaction under heating to reflux to obtain methyl 2-(3-cyano-4-fluorophenyl)isonicotinate. F: 257.
With cesium fluoride;
Reference Preparation Example 12 Cesium fluoride and tetrakis(triphenylphosphine)-palladium were added to a 1,2-dimethoxyethane solution of <strong>[214210-21-6](3-cyano-4-fluorophenyl)boronic acid</strong> and methyl 2-chloroisonicotinate, followed by reaction under heating to reflux to obtain methyl 2-(3-cyano-4-fluorophenyl)isonicotinate. F: 257.
With sodium hydride; In 1,2-dimethoxyethane; at 95℃;
Example 18; A. 3-[2-(2-chloropyridin-4-yl)-2-oxoethyl]isonicotinonitrile and 3-[2-(2-methoxypyridin- 4-yl)-2-oxoethyl]isonicotinonitrile.; In a three-necked round-bottomed flask equipped with a reflux cooler, 60 % NaH in mineral oil (1.35 g, 33.9 mmol) is added to DME (70 ml_). The suspension is heated to 95 0C and a solution of <strong>[7584-05-6]3-methylisonicotinonitrile</strong> (1.00 g, 8.47 mmol) and 2-chloroisonicotinic acid methyl ester (2.18 g, 12.71 mmol) in DME (15 mL) is added. The resulting reaction mixture is stirred overnight at 95 0C. After cooling down to room temperature the reaction mixture is partitioned between EtOAc and water. The aqueous phase is extracted with EtOAc and the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo to afford <n="182"/>a 1 : 2 mixture of 3-[2-(2-chloropyridin-4-yl)-2-oxoethyl]isonicotinonitrile and 3-[2-(2- methoxypyridin-4-yl)-2-oxoethyl]isonicotinonitrile as a brown solid (2.25 g, 8.47 mmol, 100%). 3-[2-(2-chloropyridin-4-yl)-2-oxoethyl]isonicotinonitrile: MS (ES+): 258 (M(C13H8CIN3OHH)+; 3-[2-(2-methoxy-pyridin-4-yl)-2-oxo-ethyl]-isonicotinonitrile: MS (ES+): 254 (M(C14H11N3O2HH)+ .
With sodium hydride; In 1,2-dimethoxyethane; at 95℃;
3-[2-(2-chloro-pyridin-4-yl)-2-oxo-ethyl]-isonicotinonitrile and 3-[2-(2-methoxy-pyridin-4-yl)-2- oxo-ethyl]-isonicotinonitrile; In a three-necked round-bottomed flask equipped with a reflux cooler, 60 % NaH in mineral oil (1.35 g, 33.9 mmol) is added to DME (70 ml_). The suspension is heated to 95 0C and a solution of <strong>[7584-05-6]3-methyl-isonicotinonitrile</strong> (1.00 g, 8.47 mmol) and 2-chloro-isonicotinic acid methyl ester (2.18 g, 12.71 mmol) in DME (15 ml_) is added. The resulting reaction mixture is stirred overnight at 95 0C. After cooling down to room temperature the reaction mixture is partitioned between EtOAc and water. The aqueous phase is extracted with EtOAc and the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo to afford a 1 : 2 mixture of 3-[2-(2-chloro-pyridin-4-yl)-2-oxo-ethyl]-isonicotinonitrile and 3-[2-(2- methoxy-pyridin-4-yl)-2-oxo-ethyl]-isonicotinonitrile as a brown solid (2.25 g, 8.47 mmol, 100%). 3-[2-(2-chloro-pyridin-4-yl)-2-oxo-ethyl]-isonicotinonitrile: MS (ES+): 258 (M(C13H8CIN3O)H-H)+; 3-[2-(2-methoxy-pyridin-4-yl)-2-oxo-ethyl]-isonicotinonitrile: MS (ES+): 254 (M(C14H11N3O2)H-H)+ .
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; at 100℃;
Reference Example 3 [4-(Benzyloxy)-3-cyanophenyl]boric acid and <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> were dissolved in a mixture liquid of toluene and an aqueous 2 M sodium carbonate solution, and in the presence of tetrakis(triphenylphosphine)palladium, the mixture was stirred under heating in an argon atmosphere at 100°C to obtain methyl 2-[4-(benzyloxy)-3-cyanophenyl]isonicotinate. F:345.
iron(III)-acetylacetonate; In tetrahydrofuran; 1-methyl-pyrrolidin-2-one; at 0℃; for 1h;
At 0 C, n-propylmagnesium chloride (16.0 mL of a 2.0 N solution in THF, 32.0 mmol) was added to a solution of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (4.77 g, 27.8 mmol), Fe(acac)3 (610 mg, 1.73 mmol), THF (150 mL) and NMP (17 mL) at 0 C. After 1 h, the reaction was diluted with MTBE (200 mL) and slowly quenched with1.0 N HCI (20 mL). The mixture was diluted with water (50 mL) and the phases were separated. The aqueous phase was extracted with MTBE (2x200 mL). The combined organic phase was dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude residue by flash column chromatography on 200 g silica gel (20percent hexanes/EtOAc) afforded 2.3 g (46percent) of methyl 2-propylisonicotinate.
With lithium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.5h;
58.A
To a solution of 2-chloro-4-pyridinecarboxylic acid (5.0 g, 31.7 mmol) in DCM (20 ml.) and MeOH (2 ml.) at 00C, (trimethylsilyl)diazomethane (2.0 M in ether, 16 ml.) was added dropwise. After stirring 15 min the reaction mixture was evaporated onto silica gel and chromatographed, 20-80% EtOAc in hexanes. The intermediate material, methyl 2-chloro-4-pyridinecarboxylate, was dissolved in THF (30 ml.) and cooled to 00C, LHMDS (1.0 M in THF, 57 ml_, 57 mmol) was added. A solution of 2-chloro-4- methylpyrimidine (3.47 g, 27.0 mmol) dissolved in THF (8 ml.) was added dropwise at 0°C and the reaction mixture was allowed to stir for 30 min. The reaction mixture was quenched at 00C with MeOH (50 ml_). Solvent was removed in vacuo. The residue was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4, filtered and evaporated. The title compound of Step A was purified by trituration with EtOAc. The title compound of Step A was obtained as a solid in 22% yield (1.75 g). MS (ESI): 268.2 [M+H]+.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; at 90℃; for 5h;
Production Example 10; To a mixture of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong>, Pd(PPh3)4, and [(E)-2-phenylvinyl]boric acid in dioxane was added a 2 M aqueous Na2CO3 solution, followed by stirring at 90°C for 5 hours. To the reaction mixture was added water, and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO4, and the filtrate was then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to obtain methyl 2-[(E)-2-phenylvinyl]isonicotinate as a pale yellow solid.
With sodium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 100℃; for 120h;
1. Synthesis of methyl 2-(thiazol-2-ylamino)isonicotinate A suspension of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (15.0 g, 87.42 mmol), 2-aminothiazole (10.50 g, 104.9 mmol), sodium carbonate (12.97 g, 122.4 mmol, 1.4 eq) and XANTPHOS (0.607 g, 1.049 mmol, 0.012 eq) in toluene (300 mL, bubbled with argon for 5 minutes) was bubbled again with argon for 5 additional minutes. Tris(dibenzylideneacetone)dipalladium (0) (0.320 g, 0.349 mmol, 0.004 eq) was then added to the suspension which was heated at 100° C. for 5 days. The mixture was cooled down to RT and filtered. The resulting solid was suspended in water and stirred for 1 hour. After filtration, the resulting solid was dried under vacuum overnight and afforded the title material (14.17, 69percent) as a solid. 1H NMR (400 MHz, DMSO-d6) delta (ppm): 3.90 (3H, s), 7.07 (1H, d, J=3.54), 7.32 (1H, dd, J=5.31, 1.26 Hz), 7.43 (1H, d, J=3.79 Hz), 7.61 (1H, s), 8.48 (1H, d, J=4.55 Hz), 11.56 (1H, s). LC/MS (M+H)+: 236. HPLC ret. time (Condition A): 1.182 min.
With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In toluene;Reflux; Inert atmosphere;
A suspension of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (1.00 g, 5.83 mmol), 2-aminopyridine (658 mg, 6.99 mmol), tris(dibenzylideneacetone)dipalladium(0) (107 mg, 0.17 mmol), dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (139 mg, 0.29 mmol) and tripotassium phosphate (3.09 g, 14.6 mmol) in toluene (30 mL) was heated under reflux under an argon atmosphere overnight. After cooling, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=9/1-2/3) and recrystallized from hexane/ethyl acetate to give the title compound (866 mg, yield 65percent) as colorless crystals.1H NMR (DMSO-d6) delta 3.89 (3H, s), 6.83-6.97 (1H, m), 7.29 (1H, d, J=4.9 Hz), 7.61-7.75 (2H, m), 8.26 (1H, d, J=4.9 Hz), 8.31 (1H, s), 8.39 (1H, d, J=5.3 Hz), 9.98 (1H, s).
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In methanol; at 100℃; for 0.5h;microwave irradiation;
A mixture of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (5 g, 29.14 mmol), 3,4-difluorophenylboronic acid (5.06 g, 32.05 mmol), potassium carbonate (2.416 g, 17.48 mmol) and PdCl2 (dppf) (1.066 g, 1.46 mmol) was stirred in methanol (30 mL) and heated in a single-node microwave reactor at 100° C. for 30 min. The solvent was evaporated in vacuo. DCM (400 mL) and 8percent NaHCO3 (aq) (400 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (400 mL). The combined organic phases were dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on three Biotage.(R). KP-SIL 100 g columns. A gradient from 5percent EtOAc in heptane over 2 CV followed by 5percent to 20percent of EtOAc in heptane over 9 CV was used as mobile phase. Methyl 2-(3,4-difluorophenyl)isonicotinate (5.82 g, 80percent) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) delta 4.00 (s, 3H), 7.23-7.33 (m, 1H), 7.76-7.84 (m, 2H), 7.90-8.00 (m, 1H), 8.21-8.27 (m, 1H), 8.82 (dd, 1H).
In a dried flask zinc powder (2.489 g, 38.07 mmol) was suspended in anhydrous tetrahydrofuran (50 mL) under nitrogen. The resulting suspension was warmed to 60 C., then 1,2-dibromoethane (0.126 mL, 1.46 mmol) was added and stirred at that temperature for 15 min. It was cooled to room temperature, then chlorotrimethylsilane (0.149 mL, 1.17 mmol) was added and stirred for 20 min. 1-(Bromomethyl)-2-(trifluoromethyl)benzene (4.46 mL, 29.28 mmol) in THF (2 mL) was added dropwise and stirring was continued at room temperature for 4 h. Stirring was switched off to let the precipitates settle. The supernatant was used in the next transformation. In a dried flask zinc powder (2.489 g, 38.07 mmol) was suspended in anhydrous tetrahydrofuran (50 mL) under nitrogen. The resulting suspension was warmed to 60 C., then 1,2-dibromoethane (0.126 mL, 1.46 mmol) was added and stirred at that temperature for 15 min. It was cooled to room temperature, then chlorotrimethylsilane (0.149 mL, 1.17 mmol) was added and stirred for 20 min. 1-(Bromomethyl)-2-(trifluoromethyl)benzene (4.46 mL, 29.28 mmol) in THF (2 mL) was added dropwise and stirring was continued at room temperature for 4 h. Stirring was switched off to let the precipitates settle. The supernatant was used in the next transformation.
Methyl 2-chloroisonicotinate (4 g, 23.31 mmol), 4-chloro-2-fluorophenylboronic acid (6.10 g, 34.97 mmol), potassium carbonate (2.416 g, 17.48 mmol) and PdCl2 (dppf) (0.506 g, 0.70 mmol) were mixed in methanol (30 mL) in two separate 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. Water and DCM were added and the phases were separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield a dark-orange solid. The solid was dissolved in MTBE and stirred for 15 minutes, then filtered. The orange MTBE layer was treated with hydrogen chloride (4 M in dioxane, 5.83 mL, 23.31 mmol) and stirred for 1 h at room temperature. The precipitate was collected by filtration to yield methyl 2-(4-chloro-2-fluorophenyl)isonicotinate hydrochloride (7.22 g, quant.) as a slightly orange solid. MS m/z 266 (M+H)+
Methyl 2-chloroisonicotinate (4.5 g, 26.23 mmol), 4-fluorophenylboronic acid (4.51 g, 32.26 mmol), potassium carbonate (2.247 g, 16.26 mmol) and PdCl2 (dppf) (0.380 g, 0.52 mmol) were mixed in methanol (30 mL) in two 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. The solids were removed by filtration and the filtrate evaporated to yield a dark red slurry. To the residue was added HCl (1.25 M in methanol, 100 mL). The mixture was stirred at 45° C. for 4 h, then concentrated. Satd NaHCO3 (100 mL) was added under ice cooling and extracted with DCM (3.x.100 mL) The combined organic phases were washed with brine, passed through a phase separator and evaporated to yield a brown solid. The crude was dissolved in MTBE (180 mL) and some solids were filtered off. Cooled with ice-water, hydrogen chloride (4 M in dioxane, 10 mL, 40 mmol) was added dropwise during stirring and a suspension was formed. The suspension was stirred at 0° C. for 10 min. The solid was collected by filtration and washed with MTBE to yield methyl 2-(4-fluorophenyl)isonicotinate hydrochloride (6.4 g, 91percent) as a beige solid. 1H NMR (400 MHz, cd3od) d 4.07 (s, 3H), 7.37-7.51 (m, 2H), 8.02-8.13 (m, 2H), 8.37 (dd, 1H), 8.71 (d, 1H), 8.97 (dd, 1H). MS m/z 232 (M+H)+
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In methanol; at 100℃; for 0.166667h;microwave irradiation;
Methyl 2-chloroisonicotinate (2.5 g, 14.57 mmol), phenylboronic acid (2.66 g, 21.86 mmol), potassium carbonate (3.02 g, 21.86 mmol) and PdCl2 (dppf) (0.316 g, 0.44 mmol) were mixed in methanol (15 mL) in a 20 mL microwave vial. Two drops of water were added and the vial was capped and heated at 100° C. for 10 min in a single node microwave reactor. The solids were removed by filtration and the filtrate partly evaporated to yield a dark red slurry. DCM and water were added and the phases separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield a dark red oil. The compound was purified via Biotage, SNAP 340 g KP-SIL, eluent isocratic heptane/ethyl acetate 9:1 for 2 CV, then linear gradient heptane/ethyl acetate 9:1 to 6:4 over 5 CV to give methyl 2-phenylisonicotinate (1.83 g, 58percent) as a colourless oil. 1H NMR (400 MHz, cdcl3) delta 3.98 (s, 3H), 7.39-7.54 (m, 3H), 7.76 (dd, 1H), 8.01-8.09 (m, 2H), 8.29 (s, 1H), 8.82 (d, 1H). MS m/z 214 (M+H)+
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In methanol; at 100℃; for 0.583333h;microwave irradiation;
Potassium carbonate (1.812 g, 13.11 mmol), methyl 2-chloroisonicotinate (3 g, 17.48 mmol), <strong>[68716-47-2]2,4-dichlorophenylboronic acid</strong> (5.00 g, 26.23 mmol), PdCl2 (dppf) (0.380 g, 0.52 mmol), and MeOH (30.6 mL) were split in two 20 mL microwave vials and heated to 100 C. for 35 min in a single node microwave reactor. The reaction mixture was diluted with water and DCM, extracted with DCM and evaporated. Purified by automated flash chromatography using 5% EtOAc in heptane ->30% EtOAc over 15 CV at 280 nm. Methyl 2-(2,4-dichlorophenyl)isonicotinate (2.3 g, 47%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) delta 3.98 (s, 3H), 7.37 (dd, 1H), 7.53 (d, 1H), 7.57 (d, 1H), 7.86 (dd, 1H), 8.20 (s, 1H), 8.87 (d, 1H). MS m/z 282 (M+H)+
Methyl 2-chloroisonicotinate (7 g, 40.80 mmol), 4-tert-butylphenylboronic acid (10 g, 56.17 mmol), potassium carbonate (3.5 g, 25.32 mmol) and PdCl2 (dppf) (0.9 g, 1.24 mmol) were mixed in methanol (30 mL) in two equal portions in 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. The solids were removed by filtration and the filtrate evaporated to yield a dark red slurry. DCM and brine were added and the phases separated. The water phase (pH 9) was extracted with DCM and the combined organic phases dried over MgSO4 and evaporated. The crude was dissolved in MTBE (180 mL) and the solids filtered off. Hydrogen chloride (4 M in dioxane, 10.20 mL, 40.80 mmol) was added dropwise during stirring and a suspension was formed. The suspension was stirred at room temperature for 1 h. The solid was collected by filtration and washed with MTBE. Methyl 2-(4-tert-butylphenyl)isonicotinate hydrochloride (9.6 g, 77percent) was isolated as a dark brown solid. 1H NMR (400 MHz, dmso) delta 1.30 (s, 9H), 3.92 (s, 3H), 7.53 (d, 2H), 7.80 (dd, 1H), 8.04 (d, 2H), 8.29 (s, 1H), 8.85 (d, 1H), 9.86 (br, 1H). MS m/z 270 (M+H)+
Zinc powder (2.81 g, 42.97 mmol) was suspended in THF (50 mL) under nitrogen and heated to 60 C. 1,2-dibromoethane (0.336 g, 1.79 mmol) was added and stirred for 15 min at 60 C. It was cooled to ambient temperature, TMSCl (0.156 g, 1.43 mmol) was added and stirred for 15 min at ambient temperature. 1-(Bromomethyl)-4-(methylsulfonyl)benzene (8.92 g, 35.81 mmol) dissolved in THF (50 mL) was added over 15 min and the resulting mixture was stirred at ambient temperature overnight. Stirring was stopped and the supernatant used in the next reaction. Methyl 2-chloroisonicotinate (5.12 g, 29.84 mmol) and Pd(PPh3)4 (1.379 g, 1.19 mmol) were dissolved in THF (50 mL) under nitrogen. Freshly prepared 4-(methylsulfonyl)benzyl)zinc(II) bromide (11.26 g, 35.81 mmol) in THF (100 mL) was added and the reaction mixture heated to 60 C. for 3 h. Water (20 mL) was added. It was diluted with NaHCO3 (aq) and extracted with diethylether. The organic layer was washed with NaCl (aq), dried over Na2SO4, filtered and evaporated. Purified using the Biotage equipment. Ethyl acetate and hexane used as eluent. Gradient 0% to 100% of ethyl acetate. Methyl 2-(4-(methylsulfonyl)benzyl)-isonicotinate (8.0 g, 88%) was isolated. 1H NMR (600 MHz, cdcl3) delta 3.00 (s, 3H), 3.92 (s, 3H), 4.28 (s, 2H), 7.45 (d, 2H), 7.68-7.72 (m, 2H), 7.85 (d, 2H), 8.69 (d, 1H). MS m/z 306 (M+H)+
In a dried flask was zinc powder (0.769 g, 11.76 mmol) suspended in anhydrous tetrahydrofuran (20 mL) under nitrogen. The resulting suspension was warmed to 60° C., then 1,2-dibromoethane (0.042 mL, 0.49 mmol) was added and stirred at that temperature for 15 min. It was cooled to room temperature, then chlorotrimethylsilane (0.050 mL, 0.39 mmol) was added and stirred at room temperature for 1 h. Then, 1-(bromomethyl)-4-(trifluoromethoxy)benzene (2.5 g, 9.80 mmol) in tetrahydrofuran (5 mL) was added over 2 min, then stirring continued at room temperature for 22 h. The stirring was switched off to let the solids settle. The supernatant was used in next transformation. To a solution of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (4.80 g, 28 mmol) and Pd(PPh3)4 (0.647 g, 0.56 mmol) in tetrahydrofuran (50 mL) under nitrogen in a dried flask was added a freshly prepared solution of (4-(trifluoromethoxy)benzyl)zinc(II) bromide (12.56 g, 39.20 mmol) in tetrahydrofuran (90 mL). The resulting bright yellow mixture was heated to 60° C. for 2 h 30 min, then cooled to room temperature. The reaction was quenched by the addition of 10percent aqueous NH4Cl. It was diluted with ethyl acetate. After phase separation, the organic layer was washed with brine, dried over MgSO4 and evaporated. The residue was suspended in 50 mL MTBE and sonicated, then the yellow insolubles were filtered off and washed with MTBE. The volume of the filtrate was increased to ca. 150 mL, then 5 mL MeOH was added, followed by hydrogen chloride (4 M in dioxane) (7.00 mL, 28.00 mmol). A colorless precipitate formed, which then dissolved again. The solvents were evaporated. The residue was dissolved in ca. 15 mL DCM and then MTBE and heptanes were added. An oil had formed that was triturated and after a few minutes a solid started to form. It was sonicated and then stirred at room temperature for 20 min. The formed solid was collected and washed with MTBE and dried. The solid was dissolved in DCM and washed with 10percent K2CO3. After phase separation, the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4 and evaporated. Methyl 2-(4-(trifluoromethoxy)benzyl)isonicotinate (8.04 g, 92percent) was isolated as a pale yellow oil. 1H NMR (400 MHz, cdcl3) delta 3.93 (s, 3H), 4.22 (s, 2H), 7.11-7.17 (m, 2H), 7.24-7.31 (m, 2H), 7.67-7.72 (m, 2H), 8.68-8.72 (m, 1H). MS m/z 312 (M+H)+
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In methanol; at 100℃; for 0.583333h;microwave irradiation;
Methyl 2-chloroisonicotinate (5 g, 29.14 mmol), 4-(methylsulfonyl)phenylboronic acid (7.58 g, 37.88 mmol), potassium carbonate (2.416 g, 17.48 mmol) and PdCl2 (dppf) (0.633 g, 0.87 mmol) were dissolved in methanol (30 mL) and divided up in two microwave vials. Each vial was heated to 100° C. in a single node microwave reactor for 35 min. DCM (250 mL) and water (250 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (250 mL). The combined organic phases were washed with brine (500 mL), dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on two Biotage.(R). KP-SIL 340 g columns. A gradient of 20-70percent EtOAc in heptane over 10 CV and then 70percent EtOAc in heptane over 5 CV was used as mobile phase. The product was collected using the wavelength 253 nm. The product fractions were collected and evaporated in vacuo yielding methyl 2-(4-(methylsulfonyl)phenyl)-isonicotinate (5.66 g, 66.7percent) as a white solid. 1H NMR (600 MHz, CDCl3) delta 3.09 (s, 3H), 3.98 (s, 3H), 7.85 (dd, 1H), 8.05 (d, 2H), 8.25 (d, 2H), 8.34 (s, 1H), 8.86 (t, 1H).
Methyl 2-chloroisonicotinate (3 g, 17.48 mmol), 2,4-difluorophenylboronic acid (4.14 g, 26.23 mmol), potassium carbonate (1.812 g, 13.11 mmol) and PdCl2 (dppf) (0.380 g, 0.52 mmol) were mixed in methanol (30 mL) in two separate 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. Water and DCM were added and the phases were separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield a brown solid. The solid was dissolved in MTBE and stirred for 15 minutes, then filtered. The orange MTBE layer was treated with hydrogen chloride (4 M in dioxane, 4.37 mL, 17.48 mmol) and stirred for 1 h at room temperature. The formed solid was collected by filtration. Methyl 2-(2,4-difluorophenyl)isonicotinate hydrochloride (4.0 g, 80percent) was isolated as a slightly orange solid. MS m/z 250 (M+H)+
Methyl 2-chloroisonicotinate (3.5 g, 20.40 mmol), <strong>[313545-72-1]2-chloro-4-fluorophenylboronic acid</strong> (3.91 g, 22.44 mmol), potassium carbonate (2.114 g, 15.30 mmol) and PdCl2 (dppf) (0.443 g, 0.61 mmol) were mixed in methanol (30 mL) in two separate 20 mL microwave vials. The vials were capped and heated at 100 C. for 10 min in a single node microwave reactor. Water and DCM were added and the phases were separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield a dark-brown solid. The solid was dissolved in MTBE and stirred for 15 minutes, then filtered. The MTBE layer was treated with hydrogen chloride (4 M in dioxane, 5.10 mL, 20.40 mmol) and stirred for 1 h at room temperature. The precipitate was collected by filtration. Methyl 2-(2-chloro-4-fluorophenyl)isonicotinate (2.350 g, 38.1%) was obtained as a light yellow solid. 1H NMR (400 MHz, cdcl3) delta 4.13 (s, 3H), 7.24-7.33 (m, 1H), 7.36 (d, 1H), 7.82-8.03 (m, 1H), 8.34 (s, br., 1H), 8.56 (s, br., 1H), 9.08 (s, br., 1H). MS m/z 266 (M+H)+
In a dried flask was zinc powder (2.493 g, 38.13 mmol) suspended in anhydrous tetrahydrofuran (23 mL) under nitrogen. The resulting suspension was warmed to 60° C., then 1,2-dibromoethane (0.137 mL, 1.59 mmol) was added and stirred at that temperature for 15 min. It was cooled to room temperature, then chlorotrimethylsilane (0.161 mL, 1.27 mmol) was added and stirred at room temperature for 45 min. Then, 1-(bromomethyl)-3,5-di-tert-butylbenzene (9 g, 31.77 mmol) dissolved in anhydrous tetrahydrofuran (23.00 mL) was added over 10 min. Stirring continued at room temperature for 16 h, then stirring was switched off to let the solids settle. The supernatant was used in the next transformation. To a solution of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (4 g, 23.31 mmol) and Pd(PPh3)4 (0.539 g, 0.47 mmol) in tetrahydrofuran (120 mL) under nitrogen in a dried flask was added a freshly prepared solution of (3,5-di-tert-butylbenzyl)zinc(II) bromide (11.08 g, 31.78 mmol) in tetrahydrofuran (46 mL). The resulting bright yellow solution was heated to 60° C. for 35 min, then stirred at room temperature for 1 h. The reaction was quenched by addition of methanol (50 mL). The solution was diluted with EtOAc and washed with NH4Cl. The organic layer was dried over MgSO4, filtered and evaporated to yield a brown oil. The crude was redissolved in MTBE (180 mL) and solids were filtered off. Hydrogen chloride (4 M in dioxane, 6.42 mL, 25.66 mmol) was added dropwise during stirring and a suspension was formed. The suspension was stirred at room temperature for 10 min. The solid was collected by filtration and washed with MTBE. Redissolved in MTBE/satd NaHCO3. The phases were separated, the organic phase dried over Na2SO4, filtered and evaporated to yield methyl 2-(3,5-di-tert-butylbenzyl)isonicotinate (7.132 g, 90percent) as a brown oil. 1H NMR (600 MHz, cdcl3) delta 1.28 (s, 18H), 3.89 (s, 3H), 4.19 (s, 2H), 7.11 (d, 2H), 7.27 (t, 1H), 7.64 (dd, 1H), 7.71 (s, 1H), 8.68 (d, 1H). MS m/z 340 (M+H)+
tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 60℃; for 18h;Inert atmosphere;
Methyl 2-chloroisonicotinate (5.2 g, 30.31 mmol) and Pd(PPh3)4 (0.700 g, 0.61 mmol) were dissolved under nitrogen in THF (100 mL) and (2-fluorobenzyl)zinc(II) chloride (0.5 M in THF) (90 mL, 45.00 mmol) was added and the brown solution was stirred at 60° C. for 18 h. The reaction was quenched by addition of methanol (50.0 mL). The solution was diluted with EtOAc, washed with NH4Cl (aq) and dried over Na2SO4, then evaporated. The compound was purified in 2 runs via Biotage, SNAP 340 g KP-SIL, eluent isocratic heptane/ethyl acetate 8:2 for 2 CV, then linear gradient heptane/ethyl acetate 8:2 to 5:5 over 5 CV to give methyl 2-(2-fluorobenzyl)isonicotinate (5.42 g, 73percent) as a yellow oil. 1H NMR (400 MHz, cdcl3) 3.92 (s, 3H), 4.25 (s, 2H), 7.00-7.13 (m, 2H), 7.18-7.30 (m, 2H), 7.64-7.74 (m, 2H), 8.69 (d, 1H). MS m/z 246 (M+H)+
2-(4-chloro-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane[ No CAS ]
[ 58481-11-1 ]
[ 1251843-74-9 ]
Yield
Reaction Conditions
Operation in experiment
79%
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In methanol; at 100℃; for 0.25h;microwave irradiation;
Methyl 2-chloroisonicotinate (1.2 g, 6.99 mmol), potassium carbonate (0.580 g, 4.20 mmol) and PdCl2 (dppf) (0.122 g, 0.17 mmol) were combined in a microwave vial. 2-(4-Chloro-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.1 g, 8.19 mmol) dissolved in MeOH (15 mL) was added. The reaction mixture was heated in a single node microwave reactor at 100° C. for 15 min. DCM (125 mL) and water (125 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (125 mL). The combined organic phases were washed with brine (250 mL), dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on a Biotage.(R). KP-SIL 100 g column. A gradient of 10percent EtOAc in heptane over 3 CV and then 10 to 50percent EtOAc in heptane over 12 CV was used as mobile phase. The product was collected using the wavelength 253 nm. Methyl 2-(4-chloro-3-fluorophenyl)isonicotinate (1.473 g, 79percent) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) delta 4.00 (s, 3H), 7.48-7.54 (m, 1H), 7.76-7.83 (m, 2H), 7.88-7.94 (m, 1H), 8.24-8.27 (m, 1H), 8.83 (dd, 1H).
2-(3-(tert-butyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane[ No CAS ]
[ 58481-11-1 ]
[ 1251843-42-1 ]
Yield
Reaction Conditions
Operation in experiment
70%
Methyl 2-chloroisonicotinate (1.7 g, 9.91 mmol), 2-(3-tert-butylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.393 g, 13.04 mmol), potassium carbonate (2.054 g, 14.86 mmol) and PdCl2 (dppf) (0.215 g, 0.30 mmol) were mixed in methanol (14 mL) in a 20 mL microwave vial. The vial was capped and heated at 100° C. for 10 min in a single node microwave reactor. The reaction mixture was suspended in methanol, the solids removed by filtration and the filtrate evaporated to yield a dark red slurry. DCM and water were added and the phases separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to a brown solid. The solid was dissolved in MTBE (100 mL) and the solids were filtered off. Hydrogen chloride(4 M in dioxane, 3.50 mL, 13.99 mmol) was added dropwise during stirring and a suspension was formed. The suspension was stirred at room temperature for 3 days. The solid was collected by filtration and washed with MTBE to yield methyl 2-(3-tert-butylphenyl)isonicotinate hydrochloride (2.14 g, 70percent) as a slightly brown solid. 1H NMR (600 MHz, cd3od) delta 1.41 (s, 9H), 4.07 (s, 3H), 7.62 (t, 1H), 7.77-7.80 (m, 2H), 8.00-8.02 (m, 1H), 8.37-8.40 (m, 1H), 8.69-8.71 (m, 1H), 8.94-8.97 (m, 1H).
tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 60℃; for 19h;Inert atmosphere;
Methyl 2-chloroisonicotinate (5.6 g, 32.64 mmol) and Pd(PPh3)4 (0.754 g, 0.65 mmol) were dissolved under nitrogen in THF (100 mL) and (4-fluorobenzyl)zinc(II) chloride (0.5 M in THF) (100 mL, 50.00 mmol) was added. The brown solution was stirred at 60° C. for 19 h. The reaction was quenched by addition of methanol (50.0 mL). The solution was diluted with EtOAc and washed with NH4Cl (aq) and water. The organic layer was evaporated, dissolved in DCM and washed with NH4Cl (aq) and then dried by passage through a phase separator. The solvent was evaporated to yield a brown oil. The compound was purified in 2 runs via Biotage, SNAP 340 g KP-SIL, eluent isocratic heptane/ethyl acetate 8:2 for 2 CV, then linear gradient heptane/ethyl acetate 8:2 to 5:5 over 5 CV to yield methyl 2-(4-fluorobenzyl)isonicotinate 7.08 g (88percent) as a yellow oil. 1H NMR (400 MHz, cdcl3) delta 3.92 (s, 3H), 4.18 (s, 2H), 6.94-7.02 (m, 2H), 7.19-7.27 (m, 2H), 7.65-7.69 (m, 2H), 8.68-8.71 (m, 1H). MS m/z 246 (M+H)+
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In methanol; at 100℃; for 0.333333h;microwave irradiation;
Potassium carbonate (2.416 g, 17.48 mmol), <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (5 g, 29.14 mmol), 2-(3,5-dichlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.34 g, 37.88 mmol), PdCl2 (dppf) (0.633 g, 0.87 mmol), and MeOH (45.7 mL) were split in three 20 mL microwave-vials and heated to 100° C. in a single node microwave reactor for 20 min. The reaction mixture was diluted with water and DCM, the aqueous layer extracted with DCM and the combined organic layers were evaporated. Purified by automated flash chromatography using 5percent EtOAc in heptane ->30percent EtOAc over 15 CV at 280 nm. Methyl 2-(3,5-dichlorophenyl)isonicotinate (6.1 g, 74percent) was isolated as a white powder. 1H NMR (400 MHz, cdcl3) delta 4.01 (s, 3H), 7.44 (t, 1H), 7.84 (dd, 1H), 7.96 (d, 2H), 8.23-8.28 (m, 1H), 8.85 (dd, 1H).
With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In methanol; at 100℃; for 0.166667h;Inert atmosphere; microwave irradiation;
Methyl 2-chloroisonicotinate (5.5 g, 32.05 mmol), (E)-4-fluorostyrylboronic acid (7.98 g, 48.08 mmol), potassium phosphate (3.93 mL, 48.08 mmol) and PdCl2 (dppf) (0.464 g, 0.64 mmol) were split into 5 equal portions and each portion was placed in a microwave reaction vessel. The vessels were evacuated and backfilled with nitrogen. Methanol (15 mL) was added to each vessel, the vessels were sealed and heated in a single node microwave reactor at 100° C. for 10 min each. The contents of the vessels was pooled and water and DCM were added, the phases separated and the aqueous layer was extracted with DCM. The combined organic layers were filtered through a phase separator and evaporated. The residue was purified by automated flash chromatography on a Biotage.(R). KP-SIL 340 g column. A gradient from 6:1 to 4:1 of EtOAc in heptane over 15 CV was used as mobile phase. (E)-Methyl 2-(4-fluorostyryl)isonicotinate (3.88 g, 47percent) was isolated. 1H NMR (400 MHz, cdcl3) delta 3.98 (s, 3H), 7.04-7.18 (m, 3H), 7.52-7.62 (m, 2H), 7.63-7.71 (m, 2H), 7.93 (s, 1H), 8.74 (d, 1H). MS m/z 258 (M+H)+
4-(bromomethyl)-2-fluoro-1-(trifluoromethyl)benzene[ No CAS ]
[ 1251845-25-6 ]
Yield
Reaction Conditions
Operation in experiment
In a dried flask was zinc powder (3.05 g, 46.69 mmol) suspended in anhydrous tetrahydrofuran (25 mL) under nitrogen. The resulting suspension was warmed to 60° C., then 1,2-dibromoethane (0.168 mL, 1.95 mmol) was added and stirred at that temperature for 15 min. It was cooled to room temperature, then chlorotrimethylsilane (0.2 mL, 1.58 mmol) was added and stirred at room temperature for 1 h 15 min. Then, 4-(bromomethyl)-2-fluoro-1-(trifluoromethyl)benzene (10 g, 38.91 mmol) in tetrahydrofuran (5 mL) was added in 6 equal portions every 10 minutes under ice-cooling. After complete addition the ice-bath was removed and the reaction mixture stirred at room temperature for 18 h. Then was stirring switched off to let the solids settle. The supernatant was used in next transformation. To a solution of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (5.15 g, 30 mmol) and Pd(PPh3)4 (0.693 g, 0.60 mmol) in tetrahydrofuran (40 mL) under nitrogen in a dried flask was added freshly prepared (3-fluoro-4-(trifluoromethyl)benzyl)zinc(II) bromide (12.55 g, 38.91 mmol) in tetrahydrofuran (50 mL). The resulting bright yellow mixture was heated to 60° C. for 2 h 20 min, then cooled to room temperature. The reaction was quenched by the addition of 10percent NH4Cl. It was diluted with ethyl acetate. After phase separation, the organic layer was washed with brine, dried over MgSO4 and evaporated. The residue was suspended in 150 mL MTBE and sonicated, then the yellow insolubles were filtered off and washed with MTBE. The volume of the filtrate was increased to ca. 200 mL, then hydrogen chloride (7.50 mL, 30.00 mmol) (4M in dioxane) was added dropwise. A colorless precipitate formed. The resulting suspension was stirred for ca. 1 h, then sonicated for 2 min. The formed solid was collected and washed with MTBE and dried. The solid was dissolved in DCM and washed with 10percent K2CO3. After phase separation, the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4 and evaporated. Methyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)isonicotinate (8.26 g, 88percent) was isolated as a pale orange oil. 1H NMR (400 MHz, cdcl3) delta 3.94 (s, 3H), 4.24 (s, 2H), 7.06-7.18 (m, 2H), 7.52 (t, 1H), 7.69-7.75 (m, 2H), 8.68-8.75 (m, 1H). MS m/z 314 (M+H)+
Zinc powder (2.62 g, 40.00 mmol) and lithium chloride (1.696 g, 40.00 mmol) were added to a dried flask and heated to 150 C. under vacuum for 30 min. The flask was allowed to reach room temperature. THF (20 mL) and 1,2-dibromoethane (0.115 mL, 1.33 mmol) were added. The mixture was heated until boiling occurred and the flask was then allowed to reach room temperature. Chlorotrimethylsilane (0.034 mL, 0.27 mmol) was added and the mixture was again heated until boiling occurred. The flask was cooled with an ice-bath and <strong>[220141-72-0]5-(bromomethyl)-1,2,3-trifluorobenzene</strong> (6 g, 26.67 mmol) dissolved in THF (5 mL) was then added dropwise. The ice-bath was removed and the reaction stirred at room temperature for 20 h. Solids were allowed to settle and the supernatant used in the next transformation. Methyl 2-chloroisonicotinate (3.5 g, 20.40 mmol) was dissolved in THF (30 mL) under a nitrogen atmosphere. Bis(tri-tert-butylphosphine)Pd(0) (0.208 g, 0.41 mmol) was added. Freshly made (3,4,5-trifluorobenzyl)zinc(II) bromide (1.06 M in THF) (25.1 mL, 26.65 mmol) was then added and the reaction mixture stirred at 60 C. for 3 h. Water (15 mL) was added and THF was evaporated. The reaction mixture was diluted with satd NaHCO3 and extracted with EtOAc (3×). The combined organic phases were washed with satd NaHCO3, water, NH4Cl and brine, and dried with Na2SO4, filtered and evaporated in vacuo yielding a red oil (5 g). MTBE (70 mL) was added, insolubles filtered off and washed with MTBE (10 mL). To the filtrate was added hydrogen chloride (4 M in dioxane, 5.10 mL, 20.40 mmol) dropwise, an orange precipitate formed. The mixture was cooled with an ice-bath. The precipitate was filtered off, washed with cold MTBE and dried in vacuo yielding methyl 2-(3,4,5-trifluorobenzyl)isonicotinate hydrochloride (4.00 g, 61.7%) as an orange solid. 1H NMR (600 MHz, CD3OD) delta 4.02 (s, 3H), 4.45 (s, 2H), 7.13-7.22 (m, 2H), 8.24-8.32 (m, 2H), 8.87-8.93 (m, 1H). MS m/z 282 (M+H)+
tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 60℃;Inert atmosphere;
Methyl 2-chloroisonicotinate (5.6 g, 32.64 mmol) and Pd(PPh3)4 (0.754 g, 0.65 mmol) were dissolved in THF (100 mL) under nitrogen. (3,4-Difluorobenzyl)zinc(II) bromide (0.5 M in THF) (100 mL, 50.00 mmol) was added and the brown solution was stirred at 60° C. overnight. The reaction was quenched by addition of methanol (50 mL). The solution was diluted with EtOAc and washed with NH4Cl (aq). The organic layer was dried over MgSO4, filtered and evaporated to yield a yellow oil. The compound was purified via Biotage, SNAP 340 g KP-SIL, eluent isocratic heptane/ethyl acetate 8:2 for 2 CV, then linear gradient heptane/ethyl acetate 8:2 to 5:5 over 6 CV to yield methyl 2-(3,4-difluorobenzyl)isonicotinate (7.7 g, 90percent) as a yellow oil. 1H NMR (400 MHz, cdcl3) delta 3.93 (s, 3H), 4.16 (s, 2H), 6.94-7.01 (m, 1H), 7.02-7.12 (m, 2H), 7.66-7.71 (m, 2H), 8.70 (dd, 1H). MS m/z 264 (M+H)+
Methyl 2-chloroisonicotinate (2.8 g, 16.32 mmol), <strong>[503309-11-3]2-fluoro-4-(trifluoromethyl)phenylboronic acid</strong> (5.09 g, 24.48 mmol), potassium carbonate (1.692 g, 12.24 mmol) and PdCl2 (dppf) (0.354 g, 0.49 mmol) were mixed in methanol (30 mL) in two separate 20 mL microwave vials. The vials were capped and heated at 100 C. for 10 min in a single node microwave reactor. Water and DCM were added and the phases were separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield a dark-orange solid. The solid was dissolved in MTBE and stirred for 15 minutes, then filtered. The orange MTBE layer was treated with hydrogen chloride (4 M in dioxane, 4.08 mL, 16.32 mmol) and stirred for 1 h at room temperature. The precipitate was collected by filtration. Methyl 2-(2-fluoro-4-(trifluoromethyl)phenyl)isonicotinate hydrochloride (5.4 g, 99%) was isolated as a slightly orange solid. MS m/z 300 (M+H)+
In a dried flask was zinc powder (1.526 g, 23.34 mmol) suspended in anhydrous THF (12.5 mL) under nitrogen. The resulting suspension was warmed to 60° C., then 1,2-dibromoethane (0.084 mL, 0.97 mmol) was added and stirred at that temperature for 15 min. It was cooled to room temperature, then chlorotrimethylsilane (0.099 mL, 0.78 mmol) was added and stirred at room temperature for 20 min. Then, 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (5 g, 19.45 mmol) dissolved in anhydrous THF (12.5 mL) was added over 7 min and stirring continued at room temperature for 1 h, then stirring was switched off to let the solids settle. The supernatant was used in the next transformation. Methyl 2-chloroisonicotinate (3.0 g, 17.48 mmol) and Pd(PPh3)4 (0.606 g, 0.52 mmol) were dissolved in THF (50 mL) under nitrogen. Freshly prepared (3-fluoro-5-(trifluoromethyl)benzyl)zinc(II) bromide (5.41 g, 19.45 mmol) in THF (25 mL) was added to the yellow solution and the flask was warmed to 60° C. overnight. The reaction mixture was quenched by adding methanol. The solution was diluted with ethyl acetate and washed with NH4Cl and water. The organic layer was dried with Na2SO4, filtered through celite, and the solvent was evaporated. The residue was chromatographed using the Biotage equipment.Eluent ethyl acetate-heptane, started 20-80 and linear gradient until 60-40. Methyl 2-(3-fluoro-5-(trifluoromethyl)benzyl)isonicotinate (4.1 g, 75percent yield) was isolated. 1H NMR (400 MHz, cdcl3) delta 3.94 (s, 3H), 4.25 (s, 2H), 7.13-7.22 (m, 2H), 7.33 (s, 1H), 7.69-7.75 (m, 2H), 8.70-8.74 (m, 1H). MS m/z 314 (M+H)+
Zinc powder (1.43 g, 21.87 mmol) was added to a dried flask and was heated at 70 C. under vacuum for 30 minutes. Dry DMA (29 mL) and iodine (0.092 g, 0.37 mmol) were added and the mixture was heated at 70 C. until the red-brown colour had disappeared (approx. 5 minutes). 4-(Bromomethyl)-1,1-difluorocyclohexane (3.1 g, 14.55 mmol) was added and heating was continued for ca. 42 h. The resulting solution was used in the next transformation. To methyl-2-chloroisonicotinate (1.664 g, 9.7 mmol) and bis(tri-tert-butylphosphine)palladium(0) (198 mg, 0.38 mmol) under nitrogen was added tetrahydrofuran (10 mL). To the resulting solution was added freshly prepared ((4,4-difluorocyclohexyl)methyl)zinc(II) bromide (14.55 mmol, 0.5 M in 29 mL DMA) and the resulting brown mixture heated to 60 C. for 4 h. The reaction mixture was diluted with ethyl acetate and washed with satd NaHCO3 (2 times), satd NH4Cl and brine. The organic layer was dried over MgSO4, filtered and evaporated. The residue was dissolved in DCM and added onto an SCX-2 cation exchange column. The column was washed with DCM, MeOH and then eluted with NH3/MeOH. The NH3/MeOH layer was evaporated leaving methyl 2-((4,4-difluorocyclohexyl)methyl)isonicotinate (2 g, 67%) as a yellow oil. 1H NMR (400 MHz, cdcl3) delta 1.30-1.46 (m, 2H), 1.58-1.79 (m, 4H), 1.87-2.14 (m, 3H), 2.82 (d, 2H), 3.96 (s, 3H), 7.65-7.73 (m, 2H), 8.70 (d, 1H). MS m/z 270 (M+H)+
Methyl 2-chloroisonicotinate (3.25 g, 18.94 mmol), 2,4,5-trifluorophenylboronic acid (5.00 g, 28.41 mmol), potassium carbonate (3.93 g, 28.41 mmol) and PdCl2 (dppf) (0.411 g, 0.57 mmol) were mixed in methanol (20 mL) in two 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. The reaction mixture was suspended in methanol, filtered and the filtrate evaporated to yield a dark red slurry. DCM and water were added and the phases separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield a brown solid. The crude brown solid was dissolved in MTBE (120 mL) and solids filtered off. Hydrogen chloride (4 M in dioxane, 4.74 mL, 18.94 mmol) was added dropwise and a suspension was formed. The suspension was stirred at room temperature for 45 min. The solid was collected by filtration and washed with MTBE. MTBE and satd NaHCO3 were added. The organic phase was dried over Na2SO4, filtered and evaporated to yield methyl 2-(2,4,5-trifluorophenyl)isonicotinate (1.676 g, 33percent) as a beige solid. The MTBE-filtrate was washed with satd NaHCO3, dried over Na2SO4, filtered and evaporated to yield a brown solid. The residue was purified via Biotage (0=>20percent EtOAc in heptane, 6 CV; Biotage.(R). KP-SIL 100 g column) to yield methyl 2-(2,4,5-trifluorophenyl)-isonicotinate (0.86 g, 17percent) as a white solid. 1H NMR (600 MHz, cdcl3) delta 3.97 (s, 3H), 7.00-7.07 (m, 1H), 7.81 (dd, 1H), 7.90-7.97 (m, 1H), 8.32-8.33 (m, 1H), 8.83 (dd, 1H). MS m/z 268 (M+H)+
tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 60℃; for 18h;Inert atmosphere;
Methyl 2-chloroisonicotinate (5.2 g, 30.31 mmol) and Pd(PPh3)4 (0.700 g, 0.61 mmol) were dissolved in THF (100 mL) under nitrogen and (2,4-difluorobenzyl)zinc(II) chloride (0.5 M in THF, 90 mL, 45.00 mmol) was added and the brown solution was stirred at 60° C. overnight (18 h). The reaction was quenched by addition of methanol (50.0 mL). The solution was diluted with EtOAc and washed with NH4Cl (aq) and brine and dried over Na2SO4 to give a red oil. The crude was redissolved in MTBE (200 mL) and solids were filtered off. Hydrogen chloride (4 M in dioxane, 7.58 mL, 30.31 mmol) was added dropwise during stirring and a suspension was formed. The suspension was stirred at room temperature for 15 min. The solid was collected by filtration and washed with MTBE. The solid was dissolved in MTBE/satd NaHCO3. The phases were separated, the organic phase dried over Na2SO4, filtered and evaporated to yield methyl 2-(2,4-difluorobenzyl)isonicotinate (7.011 g, 88percent) as a red oil. 1H NMR (400 MHz, cdcl3) delta 3.93 (s, 3H), 4.20 (s, 2H), 6.77-6.88 (m, 2H), 7.18-7.25 (m, 1H), 7.62-7.73 (m, 2H), 8.69 (dd, 1H). MS m/z 264 (M+H)+
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In methanol; at 100℃; for 0.166667h;microwave irradiation;
Methyl 2-chloroisonicotinate (2.86 g, 16.67 mmol), PdCl2 (dppf) (0.278 g, 0.38 mmol) and potassium carbonate (1.161 mL, 19.24 mmol) were distributed equally over 3 microwave reaction vials. 2-(3-Fluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane (3.72 g, 12.82 mmol) dissolved in methanol (45 mL) was split into 3 equal portions and added to the vials. The vials were capped and heated in a single node microwave reactor at 100° C. for 10 min each. The contents of the vials was combined and the solvent evaporated. The residue was dissolved in DCM and washed with water. The organic phase was filtered through a phase separator and evaporated. The residue was purified by automated flash chromatography on a Biotage.(R). KP-SIL 340 g column. 7:1 of heptane:EtOAc over 10 CV was used as mobile phase. Crude methyl 2-(3-fluoro-4-(trifluoromethyl)phenyl)isonicotinate (2.92 g, 76percent) was isolated. MS m/z 300 (M+H)+
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In methanol; at 100℃; for 0.666667h;microwave irradiation;
Methyl 2-chloroisonicotinate (1,838 g, 10.71 mmol), potassium carbonate (0.888 g, 6.43 mmol) and PdCl2 (dppf) (0.233 g, 0.32 mmol) were added to a microwave vial. 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.3 g, 10.71 mmol) dissolved in MeOH (15 mL) was added and the reaction heated in a single node microwave reactor at 100 C. for a total of 40 min. DCM (100 mL) and water (100 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (100 mL). The combined organic phases were washed with brine (200 mL), dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on a Biotage KP-SIL 100 g column. A gradient from 5% EtOAc in heptane over 3 CV followed by 5% to 30% of EtOAc in heptane over 9 CV was used as mobile phase. The product was collected using the wavelength 250 nm. Methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)isonicotinate (1.810 g, 53%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) delta 3.99 (s, 3H), 7.74 (d, 2H), 7.86-7.89 (m, 1H), 8.27 (s, 1H), 8.86 (d, 1H).
tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 60℃; for 4h;Inert atmosphere;
Methyl 2-chloroisonicotinate (5.600 g, 32.64 mmol) and Pd(PPh3)4 (0.754 g, 0.65 mmol) were dissolved in THF (100 mL) under nitrogen and (2,6-difluorobenzyl)zinc(II) bromide (0.5 M in THF, 100 mL, 50.00 mmol) was added and the resulting solution was stirred at 60° C. for 4 h before it was cooled to room temperature and quenched with methanol (50.0 mL). The mixture was diluted with EtOAc and washed with satd NH4Cl. The organic phase was dried with MgSO4, filtered and evaporated. The crude product was dissolved in MTBE (200 mL), solids were filtered off, and HCl (4 M in dioxane, 8.16 mL, 32.64 mmol) was added dropwise. The mixture was stirred for 10 minutes before the precipitate was filtered off, washed with MTBE and dissolved in MTBE/satd NaHCO3. The organic layer was dried with MgSO4, filtered and evaporated to give methyl 2-(2,6-difluorobenzyl)isonicotinate (5.03 g, 58.6percent) as a white solid. 1H NMR (400 MHz, cdcl3) delta 3.92 (s, 3H), 4.29 (s, 2H), 6.87-6.97 (m, 2H), 7.18-7.29 (m, 1H), 7.61-7.73 (m, 2H), 8.63-8.70 (m, 1H). MS m/z 264 (M+H)+
tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 60℃;Inert atmosphere;
Methyl 2-chloroisonicotinate (8.1 g, 47.21 mmol) and Pd(PPh3)4 (1.091 g, 0.94 mmol) were dissolved in THF (150 mL) under nitrogen. (3-Trifluoromethyl)benzyl)zinc(II) chloride (0.5 M in THF) (142 mL, 71 mmol) was added to the orange solution and the flask was warmed to 60° C. overnight. The reaction mixture was quenched by adding methanol (50 mL) and most of the solvent was removed by evaporation. The residue was diluted with ethyl acetate and washed with NH4Cl (aq) and water. The organic layer was dried with Na2SO4, filtered through celite, and the solvent was evaporated. The crude was chromatographed using the Biotage equipment. Eluent ethyl acetate-heptane, started 20-80 and linear gradient until 40-60. Methyl 2-(3-(trifluoromethyl)benzyl)isonicotinate (12.83 g, 92percent) was isolated. 1H NMR (400 MHz, cdcl3) delta 3.93 (s, 3H), 4.27 (s, 2H), 7.37-7.56 (m, 4H), 7.66-7.75 (m, 2H), 8.67-8.76 (m, 1H).
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In methanol; at 100℃; for 0.166667h;microwave irradiation;
Methyl 2-chloroisonicotinate (3 g, 17.48 mmol), 2-(2-fluoro-4-(trifluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.37 g, 17.55 mmol), potassium carbonate (1.812 g, 13.11 mmol) and PdCl2 (dppf) (0.380 g, 0.52 mmol) were mixed in methanol (30 mL) in two separate 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. Water and DCM were added and the phases were separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated to yield a dark-brown solid. The residue was purified by automated flash chromatography on a Biotage.(R). KP-SIL 340 g column. A gradient from 8:1 to 3:1 of EtOAc in heptane over 10 CV was used as mobile phase. Methyl 2-(2-fluoro-4-(trifluoromethoxy)phenyl)isonicotinate (4.48 g, 81percent) was yielded as a colorless solid. 1H NMR (600 MHz, cdcl3) delta 3.96 (s, 3H), 7.07 (d, 1H), 7.14 (d, 1H), 7.79-7.84 (m, 1H), 8.03-8.09 (m, 1H), 8.31 (s, 1H), 8.82-8.88 (m, 1H). MS m/z 316 (M+H)+
6-(trifluoromethyl)-3-pyridinylboronic acid[ No CAS ]
[ 58481-11-1 ]
[ 1251843-54-5 ]
Yield
Reaction Conditions
Operation in experiment
57%
Methyl 2-chloroisonicotinate (3 g, 17.48 mmol), 6-(trifluoromethyl)pyridin-3-yl boronic acid (5.01 g, 26.23 mmol), potassium carbonate (1.450 g, 10.49 mmol) and PdCl2 (dppf) (0.380 g, 0.52 mmol) were mixed in methanol (30 mL) in two separate 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. Water and DCM were added and the phases were separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield an orange solid. The solid was diluted with MTBE, then HCl (4 M in dioxane) was added to give a suspension. The solids were collected by filtration to yield methyl 6'-(trifluoromethyl)-2,3'-bipyridine-4-carboxylate hydrochloride (3.2 g, 57percent). MS m/z 283 (M+H)+
tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 60℃; for 4h;Inert atmosphere;
Methyl 2-chloroisonicotinate (5.6 g, 32.64 mmol) and Pd(PPh3)4 (0.754 g, 0.65 mmol) were dissolved in THF (100 mL) under nitrogen and (3-fluorobenzyl)zinc(II) chloride (0.5 M in THF) (100 mL, 50.00 mmol) was added. The brown solution was stirred at 60° C. for 4 h. The reaction was quenched by addition of methanol (50 mL), diluted with EtOAc and washed with NH4Cl. The organic layer was dried over Na2SO4, filtered and evaporated to yield a yellow oil. The compound was purified in 2 runs via Biotage, SNAP 340 g KP-SIL, eluent isocratic heptane/ethyl acetate 8:2 for 2 CV, then linear gradient heptane/ethyl acetate 8:2 to 5:5 over 5 CV to yield methyl 2-(3-fluorobenzyl)isonicotinate (6.766 g, 85percent) as a yellow oil. 1H NMR (400 MHz, cdcl3) delta 3.93 (s, 3H), 4.21 (s, 2H), 6.88-7.00 (m, 2H), 7.02-7.07 (m, 1H), 7.22-7.30 (m, 1H), 7.66-7.73 (m, 2H), 8.68-8.73 (m, 1H). MS m/z 246 (M+H)+
Potassium carbonate (2.66 g, 19.23 mmol), <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (5.5 g, 32.05 mmol), 2-methyl-4-(trifluoromethyl)phenylboronic acid (8.50 g, 41.67 mmol), PdCl2 (dppf) (0.696 g, 0.96 mmol), and MeOH (50.3 mL) were split into three microwave vials and heated in a single node microwave reactor to 100° C. for 20 min. Diluted with DCM, filtered and evaporated. Purified by flash chromatography using 5percent EtOAc in heptane ->20percent EtOAc over 10 CV at 280 nm. The residue was dissolved in ether and hydrogen chloride (4 M in dioxane, 8.01 mL, 32.05 mmol) was added and the solvents evaporated to yield methyl 2-(2-methyl-4-(trifluoromethyl)phenyl)isonicotinate hydrochloride (9.15 g, 86percent) as a white solid. 1H NMR (400 MHz, cd3od) delta 2.41 (s, 3H), 4.03 (s, 3H), 7.63-7.76 (m, 3H), 8.27 (dd, 1H), 8.33 (dd, 1H), 8.99 (dd, 1H). MS m/z 296 (M+H)+
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In methanol; at 100℃; for 0.5h;microwave irradiation;
Methyl 2-chloroisonicotinate (175 mg, 1.02 mmol), 2-(5-tert-butylthiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 mg, 1.13 mmol), K2CO3 (85 mg, 0.61 mmol) and PdCl2 (dppf) (37.3 mg, 0.05 mmol) was stirred in methanol (2 mL) and heated in a single node microwave reactor to 100° C. for 30 min. DCM (50 mL) and water (50 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (50 mL). The combined organic phases were dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on a Biotage.(R). KP-SIL 50 g column. A gradient from 5percent EtOAc in heptane over 2 CV followed by 5percent to 20percent of EtOAc in heptane over 9 CV was used as mobile phase. The product was collected using the wavelength 295 nm. The product fractions were collected and evaporated in vacuo yielding methyl 2-(5-tert-butylthiophen-2-yl)isonicotinate (213 mg, 76percent). 1H NMR (600 MHz, cdcl3) delta 1.41 (s, 9H), 3.96 (s, 3H), 6.85 (d, 1H), 7.50 (s, 1H), 7.61 (d, 1H), 8.13 (s, 1H), 8.64 (d, 1H). MS m/z 276 (M+H)+
Methyl 2-chloroisonicotinate (3.01 g, 17.53 mmol), PdCl2 (dppf) (0.317 g, 0.44 mmol) and potassium carbonate (1.322 mL, 21.91 mmol) were distributed equally over 3 microwave reaction vials. 2-(4-Chloro-3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.01 g, 14.61 mmol) was dissolved in methanol (45 mL) to give a colorless solution. The solution was split into 3 equal portions and added to the vials. The vials were capped and heated in a single node microwave reactor at 100° C. for 10 min each. The content of the vials was combined and the solvent evaporated. The residue was dissolved in DCM and washed with water. The organic phase was filtered through a phase separator and evaporated. The residue was dissolved in MTBE and solids were filtered off. Hydrogen chloride (4 M in dioxane, 3.65 mL, 14.61 mmol) was added and the precipitate collected to yield methyl 2-(4-chloro-3,5-difluorophenyl)isonicotinate hydrochloride (1.72 g, 42percent) as a solid. 1H NMR (400 MHz, cdcl3) delta 4.06 (s, 3H), 7.86 (d, 2H), 8.09 (d, 1H), 8.39 (s, 1H), 8.96 (d, 1H). MS m/z 284 (M+H)+
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In methanol; at 100℃; for 0.166667h;microwave irradiation;
Methyl 2-chloroisonicotinate (0.996 g, 5.80 mmol), potassium carbonate (1.042 g, 7.54 mmol), 4,4,5,5-tetramethyl-2-(3-methyl-4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (1.66 g, 5.80 mmol) and PdCl2 (dppf) (0.105 g, 0.15 mmol) were mixed in methanol (20 mL) in two microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. The solution was partitioned between water and ethyl acetate. The organic layer was isolated, dried over Na2SO4, filtered through celite and the solvent was evaporated. Automated column chromatography using the Biotage equipment. Gradient eluation using heptane-ethyl acetate, 0percent to 50percent. Methyl 2-(3-methyl-4-(trifluoromethyl)phenyl)-isonicotinate (1.22 g, 71percent) was isolated. 1H NMR (600 MHz, cdcl3) delta 2.57 (s, 3H), 3.99 (s, 3H), 7.70 (d, 1H), 7.81 (dd, 1H), 7.91 (d, 1H), 7.98 (s, 1H), 8.29 (s, 1H), 8.84 (d, 1H).
tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 60℃;Inert atmosphere;
Methyl 2-chloroisonicotinate (18 g, 104.91 mmol) and Pd(PPh3)4 (2.43 g, 2.10 mmol) were dissolved in THF (300 mL). (4-Trifluoromethyl)benzyl)zinc(II) chloride (0.5 M in THF) (273 mL, 137 mmol) was added to the yellow solution and the flask was warmed to 60° C. overnight. The reaction mixture was quenched by adding methanol. The solution was diluted with ethyl acetate and washed with NH4Cl (aq) and water. The organic layer was dried with Na2SO4, filtered through celite, and the solvent was evaporated. The crude was chromatographed using the Biotage equipment. Eluent ethyl acetate-heptane, started 0-100 and linear gradient until 100-0. Methyl 2-(4-(trifluoromethyl)benzyl)isonicotinate (11.5 g, 37.1percent) was isolated. 1H NMR (600 MHz, cdcl3) delta 3.91 (s, 3H), 4.25 (s, 2H), 7.36 (d, 2H), 7.54 (d, 2H), 7.66-7.70 (m, 2H), 8.68 (d, 1H).
tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 60℃;Inert atmosphere;
To a solution of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (5.6 g, 32.64 mmol) and Pd(PPh3)4 (0.754 g, 0.65 mmol) in anhydrous THF (100 mL) was added (2,5-difluorobenzyl)zinc(II) bromide (0.5 M in THF) (100 mL, 50.00 mmol) dropwise under nitrogen. The reaction mixture was heated at 60° C. for 15 h. The reaction mixture was quenched by addition of methanol (50 mL) and then filtered. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with satd NH4Cl solution and brine, then dried. The solvent was evaporated under reduced pressure. The residue was suspended in ethanol, filtered and the solid washed with ethanol. The filtrate was concentrated. The residue was dissolved in MTBE (150 mL), then HCl (4 M in dioxane, (8.15 mL) and MeOH (7.5 mL) were added. The resulting suspension was stirred for 20 min, the solid collected, washed with MTBE (.x.2) and air dried. The solid was dissolved in DCM (200 mL) and washed with satd NaHCO3. The organic phase was dried using a phase separator and evaporated to yield methyl 2-(2,5-difluorobenzyl)isonicotinate (6.8 g, 79percent). MS m/z 264 (M+H)+
tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 60℃; for 3h;Inert atmosphere;
Methyl 2-chloroisonicotinate (5.600 g, 32.64 mmol) and Pd(PPh3)4 (0.754 g, 0.65 mmol) were dissolved in THF (100 mL) under nitrogen, then (3,5-difluorobenzyl)zinc(II) chloride (0.5 M in THF, 100 mL, 50.00 mmol) was added and the resulting solution was stirred at 60° C. for 3 h before it was cooled to room temperature and quenched with methanol (50.0 mL). The mixture was diluted with EtOAc and washed with satd NH4Cl. The organic phase was dried and concentrated. The residue was purified by automated flash chromatography on a Biotage.(R). KP-SIL 340 g column, eluent isocratic heptane/EtOAc 8:2 for 2 CV, then a gradient from 20percent to 50percent of EtOAc in heptane over 6 CV was used as mobile phase. Methyl 2-(3,5-difluorobenzyl)isonicotinate (7.42 g, 86percent) was isolated as an oil. 1H NMR (400 MHz, cdcl3) delta 3.94 (s, 3H), 4.18 (s, 2H), 6.66 (tt, 1H), 6.74-6.82 (m, 2H), 7.67-7.75 (m, 2H), 8.67-8.75 (m, 1H). MS m/z 264 (M+H)+
With lithium hexamethyldisilazane; In tetrahydrofuran; at -50℃; for 0.5h;
General procedure: To the solution of ethyl acetate (60 mol), aryl ester (10 mol) in dry THF (20 mL), LiHMDS (30 mol) was added quickly at -50 °C and stirred at this temperature for 30 min. The reaction was monitored by TLC and it was quenched with acetic acid (20 mol) and water (25 mL), basified with sat. solution of sodium bicarbonate (20 ml) and extracted with ethyl acetate (2 .x. 20 mL). The combined organic extract was washed with water (10 mL) and brine solution (10 mL) and dried over anhyd Na2SO4. The crude product was purified by column chromatography (hexane/ethyl acetate, 20:80) to get the pure product
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate;palladium diacetate; In N,N-dimethyl-formamide; at 60℃;Inert atmosphere;
To 35 ml of anhydrous DMF under argon in a sealed tube were added tripotassium phosphate (9.28 g, 43.71 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxy-biphenyl (SPhos, 0.239 g, 0.58 mmol), palladium(ll) acetate (0.065 g, 0.29 mmol) and then methyl 2-chloro-pyhdine-4-carboxylate (2.50 g, 14.57 mmol) and B-benzyl-9- borabicyclo[3.3.1]nonane (6.80 g, 32.05 mmol). The mixture was heated overnight at 60 0C. After cooling to room temperature, the mixture was diluted into 200 ml of EA, the solution washed three times with 100 ml of a 1 N sodium hydroxide solution and twice with 100 ml of brine. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was then purified by chromatography on silica gel (cyclohexane/EA, 100:0, then 80:20) to give 2.784 g of the title compound as an orange oil.
With tetrakis(triphenylphosphine) palladium(0); In toluene; at 110℃; for 16h;Inert atmosphere;
To a stirred solution of methyl 2chloro isonicotinate (2 g, 0.012 mol) in toluene (20 mL) was added hexamethylditin (4.5 g, 0.014 mol), the mixture was degassed with argon for 10 minutes, then Pd(PPh3)4 (1.35 g, 0001 mol) was added, the mixture was degassed again for 5 minutes and the resulting reaction mixture was heated at 110°C for 16h. The progress of the reaction was monitored by LCMS. The reaction mixture was cooled to RT, filtered through the Celite pad, washed with EtOAc and the filtrate was concentrated to get acrude compound. The crude compound was purified by column chromatography using neutral alumina and eluted with 5percentEtOAc/pet ether to afford the title compound (1.5 g, 42percent) as a colorless liquid.LCMS (method 1): R = 1.20 mm; m/z = 301 .99(M+H].
42%
With tetrakis(triphenylphosphine) palladium(0); In toluene; at 110℃; for 16h;
To a stirred solution of methyl 2-chloro isonicotinate (2 g, 12 mmol) in toluene (20 mL), hexamethylditin (4.5 g, 14 mmol) was added. The reaction mixture was degassed with argon for 10 minutes, then Pd(PPI)4 (1.35 g, 10 mmol) was added, it was degassed again for 5 minutes and the resulting reaction mixture was heated at 110°C for 16h. The progress of the reaction was monitored by LCMS. The reaction mixture was cooled to RT, filtered through the Celite pad, washed with EtOAc and the filtrate was concentrated to dryness. The crude compound was purified by column chromatography using neutral alumina and eluted with 5percentEtOAc/pet ether to afford the title compound (1.5 g, 42percent) as a colorless liquid. LC-MS (method 1): R, = 1.20 min; m/z = 301.99 (M+H+)
42%
With tetrakis(triphenylphosphine) palladium(0); In toluene; at 110℃; for 16h;Inert atmosphere;
To a stirred solution of methyl 2-chloro isonicotinate (2 g, 0.0116 mol) in toluene (20 mL) was added hexamethylditin (4.5 g, 0.0140 mol). the mixture was degassed with argon for 10 minutes, then Pd(PPhs)i (1.35 g, 0.00116 mol) was added and the mixture was degassed again for 5 minutes. The resulting reaction mixture was heated at 110°C for 16h. The progress of the reaction was monitored by LCMS. The reaction mixture was cooled to RT, filtered through a Celite pad, washed with EtOAc, the filtrate was concentrated to get crude compound. The crude compound was purified by column chromatography using neutral alumina and eluted with 5percentEtOAc/pet ether to afford the title compound (1.5 g, 42percent) as a colorless liquid. (0533) LC-MS (method 1): R, = 1.20 min; m/z = 301.99 (Mu+Eta').
tetrakis(triphenylphosphine) palladium(0); In toluene; for 3h;Reflux;
c)Methyl 2-(trimethylstannyl)isonicotinate (12).Hexamethyldistannane (210 muL, 334 mg, 1.02 mmol) and tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.06 mmol) were added to a solution of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (11) (100 mg, 0.58 mmol) in toluene (10 ml) and the resulting mixture was refluxed for 3 h. AcOEt (50 mL) and water (100 mL) were then added.The layers were separated and the organic layer was washed with water (5 x 100 mL), dried (Na2SO4), and the solvent removed by rotary evaporation to leave (12) as an oily residue which was used in the next step without further purification.
tetrakis(triphenylphosphine) palladium(0); In toluene; for 3h;Reflux;
Hexamethyldistannane (210 \\L, 334 mg, 1.02 mmol) and tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.06 mmol) were added to a solution of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (11) (100 mg, 0.58 mmol) in toluene (10 ml) and the resulting mixture was ref uxed for 3 h. AcOEt (50 mL) and water (100 mL) were then added. The layers were separated and the organic layer was washed with water (5 x 100 mL), dried (Na2S04), and the solvent removed by rotary evaporation to leave (12) as an oily residue which was used in the next step without further purification.
With potassium carbonate; In dimethyl sulfoxide; toluene; at 100℃; for 18h;
Example 74 Synthesis of (Z)-5-((2-(4-(p-tolyl)piperazin-1-yl)pyridin-4-yl)methylene)thiazolidine-2,4-dione A 40 mL round-bottomed vial was charged with <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (200 mg, 1.17 mmol, 1 equiv.) and 1-(p-tolyl)piperazine (205 mg, 1.17 mmol, 1 equiv.). Toluene (3 mL) and DMSO (3 mL) were added followed by potassium carbonate (403 mg, 2.9 mmol, 2.5 equiv.). The mixture was shaken for 18 h at 100° C. LC-MS after 18 h showed a peak at 1.68 min with the desired mass (M+1=312) with the chloropyridine starting material co-eluting (M+1=172). The reaction mixture was diluted with water (5 mL) and the aqueous layer was extracted with CH2Cl2 (3.x.10 mL). The combined organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The crude mixture was purified on silica gel (10 g, Hexanes/EtOAc 9:1 to 1:1) to provide the desired product as white crystals (27 mg, 67 mg theoretical, 40percent).
Under N2, <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (CAS 58481-11-1) (1.000 g, 5.83 mmol, Eq: 1.00) was dissolved in THF (35.0 ml) and NMP (4.00 ml). Iron III acetylacetonate (106 mg, 291 mumol, Eq: 0.05) (red solution) was added. At 0 C., ethylmagnesium bromide 1M in THF (11.7 ml, 11.7 mmol, Eq: 2) was added dropwise. The RM became dark brown. The RM was stirred at RT over 30 minutes. Control with TLC: the reaction was finished. 50 ml sat. NH4Cl-solution and 10 ml water were added. The RM was extracted. The water layer was extracted with DCM. The combined organics layers were dried over MgSO4; filtered; concentrated in vacuo (200 mbar). The crude material was purified by flash chromatography (silica gel, 70 g, DCM).Under N2, the residue was diluted in DCM (20 ml). m-CPBA (1.51 g, 8.74 mmol, Eq: 1.50) was added and the RM was stirred at RT overnight. Control with TLC: the reaction was finished. The solvent was evaporated. The crude material was purified by flash chromatography (silica gel, 100 g, 35% to 100% EtOAc in heptane; then DCM; then MeOH). Brown oil. MS (ISP): 182.1 ([M+H]+)
With (1,1'-bis(diphenylphosphine)ferrocene)palladium(0); In tetrahydrofuran; 1,4-dioxane; at 100℃; for 18h;Inert atmosphere;
To a solution of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (4.59 g, 26.7 mmol) in dry dioxane (120 mL),Pd(dppt) (2.18 g, 2.67 mmol) is added under argon. To this red-brown suspension 3-pentylzink (11.6 g, 53.5 mmol, 107 mL of a 0.5 M solution in THF) is added and the mixture is stirred at 100°C for 18 h. The black solution is cooled to rt, diluted with EA (200 mL) and washed with water (100 mL) and 2 N aq. HCI. The washings are extracted four times with DCM (4x100 mL). The combined org. extracts are dried over MgSO4, filtered andconcentrated. The crude product is purified by MPLC on silica gel eluting with a gradient of EA in heptane to give methyl 2-(pentan-3-yl)isonicotinate (1.15 g, 21percent) as brownish oil containing a few percent of methyl 2-(pentan-2-yl)isonicotinate; LC-MS: tR = 0.62 mm; [M+1] = 208.30. This material is dissolved in THF (30 mL) and 25percent aq. HCI (25 mL) and the mixture is stirred at 70°C for 18 h before it is concentrated and dried to give the title compound (467 mg, 37percent) as a beige solid; LC-MS: tR = 0.35 mi [M+1] = 194.28; 1HNMR (CD3OD): 8.74 (d, J = 5.2 Hz, 1 H), 7.97 (5, 1 H), 7.96 (d, J = 6.0 Hz, 1 H), 2.74-2.84 (m, 1 H), 1.71-1.91 (m, 4 H), 0.83 (t, J = 7.4 Hz, 6 H).
To a solution of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (4.59 g, 26.7 mmol) in dry dioxane (120 mL),Pd(dppt) (2.18 g, 2.67 mmol) is added under argon. To this red-brown suspension 3-pentylzink (11.6 g, 53.5 mmol, 107 mL of a 0.5 M solution in THF) is added and the mixture is stirred at 100°C for 18 h. The black solution is cooled to rt, diluted with EA (200 mL) and washed with water (100 mL) and 2 N aq. HCI. The washings are extracted four times with DCM (4x100 mL). The combined org. extracts are dried over MgSO4, filtered andconcentrated. The crude product is purified by MPLC on silica gel eluting with a gradient of EA in heptane to give methyl 2-(pentan-3-yl)isonicotinate (1.15 g, 21percent) as brownish oil containing a few percent of methyl 2-(pentan-2-yl)isonicotinate; LC-MS: tR = 0.62 mm; [M+1] = 208.30. This material is dissolved in THF (30 mL) and 25percent aq. HCI (25 mL) and the mixture is stirred at 70°C for 18 h before it is concentrated and dried to give the title compound (467 mg, 37percent) as a beige solid; LC-MS: tR = 0.35 mi [M+1] = 194.28; 1HNMR (CD3OD): 8.74 (d, J = 5.2 Hz, 1 H), 7.97 (5, 1 H), 7.96 (d, J = 6.0 Hz, 1 H), 2.74-2.84 (m, 1 H), 1.71-1.91 (m, 4 H), 0.83 (t, J = 7.4 Hz, 6 H).
2-cyclobutylisonicotinic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With copper(l) iodide; palladium bis[bis(diphenylphosphino)ferrocene] dichloride; In tetrahydrofuran; 1,4-dioxane; at 80℃; for 1h;Inert atmosphere;
General procedure Ill: Negeshi coupling: cross-coupling reaction of a halide and anorganozinc derivative.Under inert atmosphere, a mixture of halide, (1.0 equiv.), organozinc derivative (1.5 - 4.0 equiv.), PdCI2(dppf)2 (0.1 equiv.) and Cul (0.2 equiv.) in Dioxane (C=0.1 molL1) was heated for 1 hour at 80°C. After cooling, the reaction mixture was hydrolysed and extracted with EtOAc orDCM. The organic layers were combined, washed with brine, dried over MgSO4, concentrated and purified to afford the product.:_Compound 59: 2-Cyclobutyl-isonicotinic acid methyl ester.Compound 59 was obtained according to general procedure Ill starting from 2-Chloro-isonicotinic acid methyl ester in presence of cyclobutylzinc bromide (in THE 0.5M ? 3.0 equiv.).Purification by flash-chromatography (EtOAc in Cyclohexane, 0 to 80percent) afforded compound 59as yellow oil in 46percent yield.1H-NMR (400 MHz, DMSO): 1.80-1.90 (m, 1H, CH); 1.96-2.08 (m, 1H, CH); 2.25-2.33 (m, 4H,2CH2); 3.76 (quint, J 8.6 Hz, 1H, CCH); 3.90 (s, 3H, OCH3); 7.63-7.65 (m, 2H, Ar); 8.73 (d, J4.9 Hz, 1H, Ar).MZ (M+H) = 192.1.
methyl 2-(2-(4-fluorophenyl)propanamido)isonicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃;Inert atmosphere;
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-(4-fluorophenyl)propanamide (317.6 mg, 1.90 mmol, 1.00 equiv), dioxane (20 mL), Cs2CO3 (930 mg, 2.85 mmol, 1.50 equiv), Xantphos (55 mg, 0.10 mmol, 0.05 equiv). This was followed by the addition of <strong>[58481-11-1]methyl 2-chloropyridine-4-carboxylate</strong> (650 mg, 3.79 mmol, 2.00 equiv). After 5 minutes, Pd2(dba)3 (30 mg, 0.03 mmol, 0.01 equiv) was added. The resulting solution was stirred overnight at 100 oC then concentrated under vacuum. The resulting solution was extracted with 500 mL of ethyl acetate and the extracts were washed with 3x100 mL of aqueous sodium chloride. After concentrating under vacuum, the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:1) and chromatographed to provide 314 mg (55percent) of methyl 2-[2-(4- fluorophenyl)propanamido]pyridine-4-carboxylate as a white solid
methyl 2-(1-methyl-1H-pyrazol-4-yl)pyridine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With potassium dihydrogenphosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); In tetrahydrofuran; water; at 20℃; for 1h;Inert atmosphere;
To a stirred solution of <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (1.26 g, 7.12 mmol) intetrahydrofuran (20 mL) and water (15 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.72 g, 7.84 mmol), 2nd generation XPhos precatalyst (0.llg, 0.14 mmol), and potassium phosphate tribasic (4.63 g, 21.37 mmol). The mixture wasdegassed under vacuum/backfilled with nitrogen (x 3), and then it was allowed to stir at room temperature. After 1 h, the yellow solution was diluted with water (75 mL). The mixture was extracted with ethyl acetate (3 x 75 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification of the crude product (CombiFlash, 24 g silica gel gold column, 1-5% methanol/dichloromethane elute)afforded 1.28 g (83%) of methyl 2-(1-methyl-1H-pyrazol-4-yl)isonicotinate a white solid.
61%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 0.5h;Microwave irradiation;
To a stirred suspension of K-1 a (60 mg, 3.43 mmol), H-1 a (840 mg, 3.96 mmol, 1.15 eq.) and Cs2C03 (3.3 g, 10.1 mmol, 2.9 eq.) in a DME/water mixture (3:1 , 16 mL) is added [1 ,T-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane (150 mg, 0.2 mmol, 5 mol%). The reaction mixture is stirred under microwave irradiation at 90 C for 30 min. After full conversion the solvents are evaporated under reduced pressure and taken up in water. The mixture is extracted with DCM, the combined organic phases are dried over MgS04, filtrated and the solvent is evaporated under reduced pressure. The crude product is purified using normal phase chromatography (DCM/MeOH/NH3, 100:10:1 ) to afford pure product L-1 a (yield: 61 % - 455 mg, 2.1 mmol; HPLC-MS: (M+H)+ = 218, tRet. = 0.72 min, method VAB).
7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-(di-tert-butoxycarbonyl)amine[ No CAS ]
methyl 2-(2-((bis-(tert-butoxycarbonyl))amino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)isonicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
In sealed 40 mL tube, a mixture of bis-Boc-7-bromo-[ 1 ,2,4jtriazolo [1,5-al pyridin-2-amine(375 mg, 0.907 mmol), bis(pinacolato)diboron (288 mg, 1.134 mmol), potassium acetate (267 mg, 2.72 mmol) and [1,1 ?-bis(diphenylphosphino)ferrocenej dichloropalladium(II) (33.2 mg, 0.045 mmol) in 1,4-dioxane (5 mL) was stirred at 100 C 1 h. The reaction mixture was cooled to rt and concentrated to a solid. To the crude solid was added <strong>[58481-11-1]methyl 2-chloroisonicotinate</strong> (175 mg, 1.020 mmol),1,1?-bis(di-tert-butylphosphino)ferrocene palladium dichloride (27.7 mg, 0.042 mmol) and dioxane (8 mL). The mixture was degassed by sparging with nitrogen for 5 mm. 2M K3P04 (aq) (1.275 mL, 2.55 mmol) was added and the reaction mixture heated at 100C for 25 mm. After cooling to rt, the reaction mixture was concentrated onto Celite.Using a 24 g ISCO column, the cmde material was purified by flash chromatography,eluting with 0-100% EtOAc in hexanes. Afforded methyl2-(2-((bis-tert-butoxycarbonyl)amino)-[ 1 ,2,4jtriazolo [1 ,5-ajpyridin-7-yl)isonicotinate (367 mg, 0.743 mmol, 87 % yield) as a tan solid. Material carried forward into subsequent chemistry as is.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In methanol; at 100℃; for 0.166667h;Inert atmosphere; Microwave irradiation; Sealed tube;
Methyl 2-chloroisonicotinate (1.00 g, 5.83 mmol), (3-chlorophenyl)boronic acid (0.91 g, 5.83 mmol), and potassium carbonate (1.21 g, 8.75 mmol) were weighed out into a Biotage microwave tube. Methanol (6 mL) was added and the mixture was bubbled with nitrogen for 5 minutes. After two drops of water and [Iota, - bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with DCM (190 mg, 0.23 mmol) were added, the vessel was capped and irradiated to 100C for 10 minutes in a Biotage Initiator microwave. The reaction mixture was diluted with dichloromethane (100 mL) and filtered through a pad of Celite. The filtrate was washed twice with saturated aqueous sodium bicarbonate (60 mL), dried over magnesium sulfate, filtered, and evaporated to dryness. Purification by silica gel chromatography (5 - 30% ethyl acetate in hexanes) yielded Compound 55 A (0.75 g, 52%). 1H NMR (CDC13) delta 8.85 (m, 1H), 8.29 (m, 1H), 8.09 (m, 1H), 7.94 (m, 1H), 7.82 (m, 1H), 7.44 (m, 2H), 4.01 (s, 1H).
methyl 2-[(3R)-3-benzyl-5-oxomorpholin-4-yl]pyridine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With palladium diacetate
19.a.B B)
B) methyl 2-[(3R)-3-benzyl-5-oxomorpholin-4-yl]pyridine-4-carboxylate A mixture of methyl 2-chloroisonicotinate (305 mg), (5R)-5-benzyl morpholin-3-one (374 mg), palladium acetate (24 mg), XANTPHOS (86 mg), cesium carbonate (875 mg) and DME (10 mL) was irradiated with microwave at 100° C. for 3 hr. The reaction solution was partitioned between ethyl acetate-water, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (425 mg). MS: [M+H]+ 327.2.
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