* 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.
Reference：
[1] Journal of the American Chemical Society, 2013, vol. 135, # 16, p. 6289 - 6299
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 1079 - 1089
2
[ 73781-91-6 ]
[ 26218-78-0 ]
Yield
Reaction Conditions
Operation in experiment
94%
With phosphorus(V) oxybromide In toluene at 90℃; for 3 h;
Dissolve 6-chloropyridine-3-carboxylic acid methyl ester (6.86 g, 40 mmol) in toluene (100 mL) and heat to 90°C. Add phosphorous oxybromide (25 g, 87 mmol) in several portions and continue heating for 3 hours. Cool the reaction to room temperature and pour onto ice water. Extract the reaction with ethyl acetate and wash organics again with water then NAHC03. COMBINE organics, dry over MGS04, filter, and evaporate to orange solid (8.1 g, 94percent) which is an 8: 1 mixture OF 6-BROMOPYRIDINE-3-CARBOXYLIC acid methyl ester : 6-CHLOROMOPYRIDINE-3-CARBOXYLIC acid methyl ester BY LH NMR. Combine the mixture as obtained above (0.225 g, 1.04 mmol) with hexamethylditin (0.375 g, 1.15 mmol), Pd (OAC) 2 (21 mg, 0.09 mmol), and triphenylphosphine (25 mg, 0.09 mmol) in toluene (5 mL). Purge with N2 and stir at 80°C for 18 hours. Cool reaction to room temperature. Add a solution of 1-BROM-2, 6- difluorobenzene (250 mg, 1.29 mmol) in toluene (1 mL) followed by Pd (OAC) 2 (21 mg, 0.09 mmol) and triphenylphosphine (25 mg, 0.09 mmol). Purge with N2 and stir at 80°C for an additional 18 hours. Cool reaction to room temperature. Evaporate the solvent and purify by column chromatography (silica, 10percent ethyl acetate in hexane) to give 50 mg (20percent yield) OF 6- (2, 6-difluorophenyl) pyridine-3-carboxylic acid ethyl ester. Hydrolyze the ester with IN sodium hydroxide solution (0.22 mL, 0.22 mmol) in methanol (3 mL) at room temperature for 3 days. Remove the volatiles under vacuum and combine the RESIDUE with IN hydrochloric acid solution. Collect the white solid by filtration, wash with water, and dry under vacuum to give 30 mg (63percent yield) of the title compound. MS (ES): m/z 235.9 (M+H).
Reference：
[1] Organic Process Research and Development, 2013, vol. 17, # 6, p. 940 - 945
[2] Organic Process Research and Development, 2013, vol. 17, # 6, p. 940 - 945
4
[ 5006-66-6 ]
[ 73781-91-6 ]
[ 56055-54-0 ]
Reference：
[1] Organic Process Research and Development, 2013, vol. 17, # 6, p. 940 - 945
5
[ 66171-50-4 ]
[ 73781-91-6 ]
[ 56055-54-0 ]
Reference：
[1] Organic Process Research and Development, 2013, vol. 17, # 6, p. 940 - 945
6
[ 885950-46-9 ]
[ 73781-91-6 ]
[ 56055-54-0 ]
Reference：
[1] Organic Process Research and Development, 2013, vol. 17, # 6, p. 940 - 945
7
[ 73781-91-6 ]
[ 54189-82-1 ]
Yield
Reaction Conditions
Operation in experiment
99.1%
With methylamine In methanol at 0 - 20℃; for 4 h;
A mixture of 6-chloronicotinic acid methyl ester(10.0 g, 58.3 mmol) was dissolved in 10 mL of methanol and stirred to form a pale yellow solution. A 40percent aqueous solution of methylamine (2.7 g, 87.5 mmol) was added dropwise at 0 ° C, and the reaction was carried out at room temperature for 4 h The The filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, crystallized, filtered and dried to give 9.4 g of pale yellow crystals, and the residue was washed with water, Yield 99.1percent. Μρ: 140-142 ° C.
6-chloronicotinic acid methyl ester (10.0g, 58.3mmol) was dissolved in 10mL 52 methanol to get light yellow solution, the 14 methylamine (2.7g, 87.5mmol) in 53 water solution was added dropwise at 0–5°C under stirring. The mixture was stirred at room temperature for 4h, and then concentrated in vacuum. Finally, 54 ethyl acetate (100mL) was added, and the resulting mixture was stirred at room temperature. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give light yellow crystalline (2) 9.4g, yield: 99.1percent, mp: 145–146°C. 1H NMR (DMSO‑d6, 400MHz): δ 2.75 (d, J=4.5Hz, 3H), 6.89 (d, J=8.8Hz, 1H), 8.16 (dd, J=8.7, 2.4Hz, 1H), 8.46 (br d, J=4.4Hz, 1H), 8.57 (d, J=2.3Hz, 1H). ESI-MS m/z 171.1 [M+H]+; Anal. Calcd for (C7H7ClN2O FW: 170.5); C, 49.28; H, 4.14; Cl, 20.78; N, 16.42. Found: C, 49.24; H, 4.16; Cl, 20.79; N, 16.43.
Reference：
[1] MedChemComm, 2015, vol. 6, # 5, p. 867 - 870
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 9, p. 2381 - 2391
9
[ 73781-91-6 ]
[ 1970-80-5 ]
Reference：
[1] Journal of Organic Chemistry, 1999, vol. 64, # 3, p. 1015 - 1021
[2] Angewandte Chemie - International Edition, 2012, vol. 51, # 32, p. 8097 - 8100
[3] Tetrahedron, 2013, vol. 69, # 14, p. 3019 - 3026
10
[ 73781-91-6 ]
[ 23100-12-1 ]
Reference：
[1] Organic Letters, 2005, vol. 7, # 14, p. 2965 - 2967
[2] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 9, p. 1571 - 1574
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 1079 - 1089
11
[ 73781-91-6 ]
[ 21543-49-7 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: With diisobutylaluminium hydride In tetrahydrofuran; toluene at -78 - 20℃; for 1 h; Stage #2: With rochelle salt In tetrahydrofuran; dichloromethane; water; toluene
To a solution of methyl 6-chloronicotinate (0.60 g, 3.50 mmol) in THF (10 niL) at - 78 °C was added a solution of DIBAL-H (1 M in toluene, 10.5 m-L, 10.5 mmol) and the reaction stirred from -78 0C to room temperature for 1 h. The reaction was diluted with a saturated aqueous solution of sodium potassium tartrate (25 mL) and CH2Cl2 (30 mL) and stirred vigorously overnight. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 x 15 mL). The combined organic extracts were dried (Na2SO4) and concentrated to afford the desired alcohol (0.48 g, 95percent) as a white solid.
70%
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 3 h; Inert atmosphere
a) (6-chloropyridin-3-yl)methanol To a suspension of LiAIH4(1.5 g, 40 mmol) in THF(80 mL) was added methyl 6-chloronicotinate (1.56 g, 10 mmol) slowly at 0-5 Π under N2atmosphere. The reaction mixture was stirred at rt for 3h before it was quenched with 15percent NaOH and water. The mixture was filtered through Celite® and the cake was washed with EtOAc (100 ml_x3). Thefiltrate was washed with brine (200 mL), dried and concentrated to give the desired product as yellow oil (1 g, 70percent). [LCMS: RtA = 0.88 min, m/z 144.2 [M+H]+].
70%
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 3 h; Inert atmosphere
a) (6-chloropyridin-3-yl)methanol To a suspension of LiAlH4 (1.5 g, 40 mmol) in THF (80 mL) was added methyl 6-chloronicotinate (1.56 g, 10 mmol) slowly at 0-5□ under N2 atmosphere. The reaction mixture was stirred at rt for 3 h before it was quenched with 15percent NaOH and water. The mixture was filtered through Celite and the cake was washed with EtOAc (100 mL*3). The filtrate was washed with brine (200 mL), dried and concentrated to give the desired product as yellow oil (1 g, 70percent). [LCMS: RtA=0.88 min, m/z 144.2 [M+H]+].
Reference：
[1] Organic Letters, 2005, vol. 7, # 14, p. 2965 - 2967
[2] Patent: WO2007/22371, 2007, A2, . Location in patent: Page/Page column 72
[3] Journal of the American Chemical Society, 2013, vol. 135, # 16, p. 6289 - 6299
[4] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 1079 - 1089
[5] Patent: WO2013/50987, 2013, A1, . Location in patent: Page/Page column 46; 47
[6] Patent: US2014/235609, 2014, A1, . Location in patent: Paragraph 0501-0502
[7] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 9, p. 1571 - 1574
[8] Journal of Medicinal Chemistry, 2000, vol. 43, # 18, p. 3386 - 3399
[9] Patent: EP1142587, 2001, A1,
12
[ 73781-91-6 ]
[ 70258-18-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2000, vol. 43, # 18, p. 3386 - 3399
[2] Journal of the American Chemical Society, 2013, vol. 135, # 16, p. 6289 - 6299
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 1079 - 1089
Stage #1: With sodium hydride In dimethyl sulfoxide at 0 - 20℃; for 1 h; Stage #2: at 20℃; for 6 h;
Example 7. Preparation of 0-(6-pyrazol-l-yl-pyridin-3-almethel)-hadroxylamine (Compound of formula (Xl)); Step 7a. Preparation of 6-Pyrazol-1-vl-nicotinic acid methyl ester (Compound of formula (XI-a)); To a solution of pyrazole (19.4g, 0. 28mol) in 100 mL anhydrous DMSO, which was at a temperature of 0°C, was added NaH (7. 5g, 0. 3mol) gradually over a period of 30 min. The resulting reaction mixture was allowed to warm to room temperature, at which the mixture continued to agitate for an additional 30 min. Methyl 6- chloronicotinate (35g, 0. 2mol) was added to the stirring reaction mixture and agitated vigorously for a period of 6 hr. The reaction mixture was subsequently cooled to a temperature of about 0°C and poured into a saturated aqueous, 0°C NH4C1 solution. The resulting precipitate was filtered, washed with water, and dried to give a compound of formula (XI-a) (38.3g, 93percent yield) as an off-white solid.
40%
Stage #1: With sodium hydride In N,N-dimethyl acetamide for 0.166667 h; Stage #2: at 95℃; Stage #3: With sodium hydroxide In water
Pyrazole (2.4 g, 35.4 mmol) was added to DMA (100 ml) and to this was slowly added NaH (1.85 g, 38.6 mmol). The reaction mixture was stirred for 10 mins under a nitrogen atmosphere. To the resulting anion was added methyl 6-chloropyridine-3-carboxylate (5.5 g, 32.2 mmol) and the reaction was heated at 95° C. overnight. The reaction mixture was evaporated to dryness, quenched with 2.0 N NaOH (100 ml), extracted with DCM (3.x.100 ml), dried (MgSO4) and the solvent removed in vacuo to yield a brown solid. This solid was purified via silica column chromatography, eluting with 0-40percent diethyl ether in iso-hexane. A white solid was obtained, which was dissolved in hot iso-hexane. On cooling a white solid was obtained which was filtered and dried (2.6 g, 40percent); 1H NMR (400.132 MHz, CDCl3) δ 3.96 (s, 3H), 6.50 (s, 1H), 7.77 (s, 1H), 8.05 (d, 1H), 8.40 (dd, 1H), 8.62 (d, 1H), 9.02 (d, 1H); MH+203.
Step 7a. Preparation of 6-Pyrazol-1-yl-nicotinic acid methyl ester (Compound of formula (XI-a)) To a solution of pyrazole (19.4 g, 0.28 mol) in 100 mL anhydrous DMSO, which was at a temperature of 0° C., was added NaH (7.5 g, 0.3 mol) gradually over a period of 30 min. The resulting reaction mixture was allowed to warm to room temperature, at which the mixture continued to agitate for an additional 30 min. Methyl 6-chloronicotinate (35 g, 0.2 mol) was added to the stirring reaction mixture and agitated vigorously for a period of 6 hr. The reaction mixture was subsequently cooled to a temperature of about 0° C. and poured into a saturated aqueous, 0° C. NH4Cl solution. The resulting precipitate was filtered, washed with water, and dried to give a compound of formula (XI-a) (38.3 g, 93percent yield) as an off-white solid.
64%
Stage #1: With sodium hydride In DMF (N,N-dimethyl-formamide) for 5 h; Stage #2: for 27 h;
Reference Example 54; Methyl 6-(1H-pyrazol-1-yl)nicotinate; To a suspension of pyrrole (0.356 g, 5.23 mmol) in DMF (20 ml) was added sodium hydride (60percent in oil, 0.233' g, 5.81 mmol). After stirring for 5 hrs. , methyl 6- chloronicotinate (1.00 g, 5.81 mmol) was added, and the mixture was further stirred for 27 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried (over anhydrous MgS04). After concentration under reduced pressure, the precipitated solid was collected by filtration and washed with hexane to give the title compound (0.683 g, 64percent) as a colorless powder. 1H-NMR (CDCl3) No.: 3.97 (3H, s), 6.51 (lH, dd, J=4.2,2.4 Hz), 7.75-7.81 (lH, m), 8.05 (lH, dd, J=12.6,0.9 Hz), 8.40 (lH, dd, J=12.6,3.3 Hz), 8.62 (lH, dd, J=4.2,1.2 Hz), 9.03 (lH, dd, J=3.3,0.9Hz).
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 110℃; for 2.33333h;Inert atmosphere;
Intermediate 9 (500 mg), Phenyl boronic acid (499 mg), Cs2CO3 (1.52 g), 8 ml 1,4-Dioxane and 0.5 ml water were added to a 3-neck 100 mL round bottom flask. Nitrogen was bubbled directly into the mixture for 20 minutes. Pd(dppf)Cl2.CH2Cl2 (238 mg, 0.1 eq.) was added and the mixture refluxed at 110 C. for 2 h under nitrogen. The reaction mixture was diluted with ethyl acetate/water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated to a residue. The residue was purified by column chromatography and isolated intermediate 10 as an off white solid (606 mg; 94% yield).
(4) 6-chloronicotinate methyl ester(7-1), 1.0 g, 5.85 mmol) was placed in THF (10 mL) and the temperature was dropped to 0 ° C.A solution of LiAlH4 (LAH, 244 mg, 6.44 mmol) in THF (10 mL) was obtained. After the dropwise addition, the reaction mixture was reacted at 20 ° C for 2 h.After completion of the reaction, it was quenched with NaOH solution (6.25 mol), then extracted twice with ethyl acetate (2×50 mL) and dried over anhydrous Na2SO4.Filter to dry to give a white solid6-chloro-3-methylhydroxypyridine(6-1), 780 mg, 5.59 mmol, yield 96percent),Used directly in the next step.
95%
To a solution of methyl 6-chloronicotinate (0.60 g, 3.50 mmol) in THF (10 niL) at - 78 °C was added a solution of DIBAL-H (1 M in toluene, 10.5 m-L, 10.5 mmol) and the reaction stirred from -78 0C to room temperature for 1 h. The reaction was diluted with a saturated aqueous solution of sodium potassium tartrate (25 mL) and CH2Cl2 (30 mL) and stirred vigorously overnight. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 x 15 mL). The combined organic extracts were dried (Na2SO4) and concentrated to afford the desired alcohol (0.48 g, 95percent) as a white solid.
70%
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 3h;Inert atmosphere;
a) (6-chloropyridin-3-yl)methanol To a suspension of LiAIH4(1.5 g, 40 mmol) in THF(80 mL) was added methyl 6-chloronicotinate (1.56 g, 10 mmol) slowly at 0-5 Pi under N2atmosphere. The reaction mixture was stirred at rt for 3h before it was quenched with 15percent NaOH and water. The mixture was filtered through Celite® and the cake was washed with EtOAc (100 ml_x3). Thefiltrate was washed with brine (200 mL), dried and concentrated to give the desired product as yellow oil (1 g, 70percent). [LCMS: RtA = 0.88 min, m/z 144.2 [M+H]+].
70%
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 3h;Inert atmosphere;
a) (6-chloropyridin-3-yl)methanol To a suspension of LiAlH4 (1.5 g, 40 mmol) in THF (80 mL) was added methyl 6-chloronicotinate (1.56 g, 10 mmol) slowly at 0-5? under N2 atmosphere. The reaction mixture was stirred at rt for 3 h before it was quenched with 15percent NaOH and water. The mixture was filtered through Celite and the cake was washed with EtOAc (100 mL*3). The filtrate was washed with brine (200 mL), dried and concentrated to give the desired product as yellow oil (1 g, 70percent). [LCMS: RtA=0.88 min, m/z 144.2 [M+H]+].
With sodium sulfate; In tetrahydrofuran;
Reference example 1. 6-chloropyridine-3-carboaldehyde 0.20g (1.17mmol) of methyl 6-chloronicotinate (Lancaster) was dissolved in 4ml of tetrahydrofuran anhydrous, and 0.045g (1.17mmol) of lithium aluminum hydride was added thereto under ice bath cooling, followed by stirring for 30 minutes. Sodium sulfate 10 hydrate was added to the reaction mixture until no foam appeared, and after stirring for 2 hours, filtration with Celite was performed. The filtrate was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate) to obtain 0.090g of 6-chloropyridine-3-methyl alcohol. 1H NMR (CDCl3, 300MHz) delta 3.79(1H, brs), 4.70 (2H, s), 7.31 (1H, d, J = 8.3Hz), 7.69 (1H, dd, J = 2.4, 8.3Hz), 8.28 (1H,d, J= 2.4Hz) mass spectrum EIMS, m/z:143(M+)
Stage #1: 6-Chloronicotinic acid methyl ester; 4-Fluorophenol With caesium carbonate In dimethyl sulfoxide at 130 - 150℃;
Stage #2: With hydrogenchloride; water In diethyl ether
14.A
Description 14: Alternative Method (A); 6-[(4-Fluorophenyl)oxy]-3-pyridinecarboxylic acid (D14); A mixture of 4-fluorophenol (96.8g), methyl 6-chloropyridine-3-carboxylate (3Og) and cesium carbonate (285.3g) in DMSO (875mL) was stirred and heated to 130cC over a period of 1.75h then cooled overnight. The reaction mixture was reheated to -15O0C over a period of 1.5h, kept at this temperature for ~1h, then cooled to ~40°C and poured into water (4L). The aqueous solution was extracted with ether (1.0L) then adjusted to pH7-8 by addition of 2M HCI. The solution was extracted with further ether (2x1.0L), then adjusted to pH 2 by addition of 2M HCI causing precipitation of a solid. The precipitate was collected by filtration, washed with water and dried overnight at 4O0C in vacuo to give the title compound as a beige/pink solid (36.7g).
With phosphorus pentachloride; trichlorophosphate; at 30 - 95℃;
To 63 g of the previous crude material was added with mechanical stirring phosphorus oxychloride (75 mL) and then phosphorus pentachloride (120 g) in portions so that the temperature did not rise above 30 C. The mixture was stirred overnight at 95 C. and concentrated in vacuo. The residue was dissolved in dichloromethane (150 mL) and methanol (150 mL) was added dropwise. The mixture was boiled for 2 h and the solvents were removed in vacuo. The residue was partitioned between diethyl ether and sodium bicarbonate solution. Organic phases were pooled, dried with MgSO4 and the solvent was evaporated. The residue was purified by column chromatography on silica (n-heptane/ethyl acetate 6:1) to yield 4 g of the title compound as a colorless solid, mp 78-79 C.
With sodium hydride In DMF (N,N-dimethyl-formamide) at 0℃; for 0.5h;
30 Reference Example 30
To a solution of 2-phenyl-4-thiazolylmethanol (6.69 g) and methyl 6-chloro-3-pyridinecarboxylate (6.01 g) in N,N-dimethylformamide (100 ml) was added sodium hydride (60% in oil, 1.40 g) at 0°C and the mixture was stirred for 30 min. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. To a solution of the residue in tetrahydrofuran (150 ml) was added aluminum lithium hydride (1.33 g) at 0°C and the mixture was stirred at room temperature for 10 min. Sodium sulfate 10 hydrate (11.3 g) was added to the reaction mixture and the mixture was stirred at room temperature for 30 min. The precipitate was filtered off and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and 2-(2-phenyl-4-thiazolylmethoxy)-5-pyridylmethanol (5.81 g, yield 56%) was obtained as colorless crystals from a fraction eluted with tetrahydrofuran. The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 134-135°C.
With sodium hydride In DMF (N,N-dimethyl-formamide) at 0℃; for 0.5h;
Reference Example 109
Sodium hydride (60%, oily, 1.40 g) was added to a solution of 2-phenyl-4-thiazolylmethanol (6.69 g) and methyl 6-chloro-3-pyridinecarboxylate (6.01 g) in N,N-dimethylformamide (100 ml) at 0°C, and the mixture was stirred for 30 minutes. 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. Lithium aluminium hydride (1.33 g) was added to a solution of the residue in tetrahydrofuran (150 ml) at 0°C, which was stirred at room temperature for 10 minutes. Sodium sulfate decahydrate (11.3 g) was added to the reaction mixture, which was stirred for 30 minutes at room temperature. The precipitate was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethanol (5.81 g, yield 56%) as colorless crystals from the fraction eluted with tetrahydrofuran. This was recrystallized from tetrahydrofuran-hexane. Melting point: 134-135°C
To a cooled (0 ° C.) solution of 7 6-chloronicotinic acid 6 (200 mg, 1.29 mmol) in 8 CH2Cl2 (5 mL), 2 drops of 9 DMF and 10 oxalyl Chloride (0.13 mL, 1.52 mmol) was added drop wise. The reaction mixture was stirred at room temperature for 16 h and the volatiles were removed under reduced pressure. The residue was cooled to 0° C. and dissolved in CH2Cl2 (5 mL), 11 methanol (1 mL) and heated to 40° C. (monitored by TLC). After 15 min, the solvents were removed under vacuo, diluted with ether. The organic layer was washed with water and brine solution. The organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure, to afford 12 methyl 6-chloronicotinate 7 (200 mg, 91percent) as off-white solid. 1H NMR (400 MHz, CDCl3): delta 9.00 (s, 1H), 8.26 (d, J=8.4 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 3.96 (s, 3H).
With hydrogenchloride; for 5h;Heating / reflux;
6-Chloronicotinic acid (2,0 g) was dissolved in methanol and concentrated hydrochloric acid (3,0 ml) was added. The reaction mixture was refluxed for 5 hours and methanol was removed in vacuum. Ethyl acetate was added and the resulting solution was washed with saturated sodium bicarbonate solution, water and brine NMR (400 MHZ,) 8 : 8.92 (d, 1H, J 2.1 Hz), 8.32 (dd, 1H, J 8.4, 2.1 Hz), 7.70 (d, 1H, J 8.4 Hz), 3.90 (s, 3H).
1. 6-Chloronicotinic acid, methyl ester. To a solution of 6-chloronicotinic acid (20.0 g, 0.127 mol) in CH2Cl2(250 mL) was added oxalyl chloride (123.3 mL, 0.15 mol) with 1-5 drops of DMF. The solution was stirred 18 h and concentrated in vacuo. The residue was dissolved in CH2Cl2 (100 mL) and cooled in an ice bath. To this was added MeOH (20 mL) and the solution was stirred for 15 min while maintaining a temp below 40° C. The solvent was removed in vacuo, and the residue was dissolved in Et2O, washed with H2O and brine, dried with Na2SO4, and filtered through SiO2. The solvent was removed in vacuo to yield 6-chloronicotinic acid, methyl ester (21 g) as an off-white solid: 1H-NMR (300 MHz, CDCl3) delta 9.02 (d, J=13.8 Hz, 1H), 8.51-8.06 (m, 1H), 7.76-7.30 (m, 1H), 4.01 (s, 3H); EIMS m/z 171 ([M]+), which was used in Step 2 without further purification.
With diazomethyl-trimethyl-silane; In toluene; at 20℃; for 0.5h;
To a solution of 6-chloronicotinic acid (0.78 g, 5.00 mmol) in toluene (50 mL) and CH3OH (10 mL) was slowly added a solution of trimethylsilyldiazomethane (2.75 mL, 2.0 M in ether). After stirring at room temperature for 30 min, AcOH (0.5 mL) was added, and the solution was concentrated to dryness to yield crude 6-chloronicotinic acid methyl ester. The crude ester was dissolved in CH3CN (50 mL) and phenol (1.10 g, 11.0 mmol), Cs2C03 (0.98 g), and K2C03 (0.74 g) were then added. The mixture was refluxed overnight. The reaction showed incomplete conversion, so the solvent was replaced with DMF (10 mL), K2C03 (0.91 g) and phenol (0.64 g) were added, and the mixture was refluxed for 1 h. The mixture was poured into ice and extracted with Et20 (3 chi 25 mL). The combined organic layers were washed with aqueous Na2C03 and brine, dried (Na2S04), and concentrated to yield crude 20.
With sulfuric acid; at 65℃;Reflux;
A solution of 6-chloronicotinic acid (0.785 g,0.005 mol) in anhydrous methanol was added dropwise 98percent sulfuric acid. The mixture was gradually heated to reflux at 65°C. The solvent was evaporated in vacuum.The mixture was neutralized to pH=8 with saturated sodium bicarbonate solution and then extracted with ethyl acetate, dried by sodium sulfate. The mixture was filtered and the filtrate was concentrated in vacuum to give compound 11 as a pale yellow solid.
With sodium hydride; In DMF (N,N-dimethyl-formamide); at 0℃; for 1h;
Sodium hydride (60%, oily, 1.58g) was added to a solution of <strong>[1780-17-2]2-quinolylmethanol</strong> (6.29 g) and methyl 6-chloro-3-pyridinecarboxylate (6.78g) in N,N-dimethylformamide (100 ml) at 0C, and the mixture was stirred 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. Lithium aluminium hydride (1.50 g) was added to a solution of the residue in tetrahydrofuran (150 ml) at 0C, which was stirred at room temperature for 10 minutes. Sodium sulfate decahydrate (12.7 g) was added to the reaction mixture, which was stirred at room temperature for 1 hour. The precipitate was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 2-(2-quinolylmethoxy)-5-pyridylmethanol (5.31 g, yield 50%) as colorless crystals from the fraction eluted with ethyl acetate. This was recrystallized from ethyl acetate-hexane. Melting point: 124-125C
With N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 120℃; for 2h;
Example 15 1 -mesyl-4-(5-methoxycarbonyl-2-pyridyl)piperazine 1-Mesylpiperazine hydrochloride (4.24 g) was added to a solution of methyl 6-chloronicotinate (1.7 g) and N,N-diisopropylethylamine (6.3 ml) in dimethylacetamide (20 ml) and the mixture was heated at 120 C. for 2 hours.. The mixture was allowed to cool to ambient temperature and poured onto crushed ice/water (50 ml) to precipitate a tan solid.. The solid was collected by filtration and dried at 80 C. for 18 hours in a vacuum oven, to give 1-mesyl-4-(5-methoxycarbonyl-2-pyridyl)piperazine (2.05 g), mp 205-207 C. NMR (d6-DMSO): 2.90 (s, 3H), 3.20 (m, 4H), 3.78 (m, 3H), 3.80 (s, 3H), 6.92 (d, 1H), 8.00 (dd, 1H), 8.67 (d, 1H), m/z 300 (M+1).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In DMF (N,N-dimethyl-formamide); at 95℃; for 2h;
To a solution the 6-chloro-nicotinic acid methyl ester (410 mg, 2.40 mmol) and the compound from 1B (602 mg, 2.0 mmol) in 10 mL of dry N,N-dimethylformamide was added potassium carbonate (663 mg, 4.8 mmol) and followed by Pd(PPh3)4 (115 mg, 0.10 mmol). After the reaction mixture was stirred at 95° C. for 2 hours, the reaction mixture was allowed to cool to room temperature. The solvent was removed under reduced pressure. The residue was diluted with 100 mL of ethyl acetate and washed with water (10 mL) and brine (10 mL), dried over MgSO4, and the solvents were evaporated. The residue was purified by chromatography (hexanes:ethyl acetate=1:1) to give the desired product as a colorless solid (320 mg, 52percent). [0250] HPLC (4 minute gradient) tR=1.91 min; MS m/z 311 (M+H).
<strong>[73781-91-6]6-Chloronicotinic acid methyl ester</strong> (500mg ; 2. 93mmol) was suspended in 1,4- dioxane (3ml) in a 5ml reaction vial. To the vessel was added dichlorobis (triphenylphosphine) palladium (II) (70mg; 3molpercent), copper iodide (12mg), N, N- diisopropylethylamine (0. 63ml ; 3.5mmol) and 3, 3-dimethylbut-1-yne (0. 44ml ; 3. 5mmol). The vessel was sealed and the mixture was heated at 80°C for 24hrs. The solvents were evaporated to dryness and 20ml of tetrahydrofuran and 20ml of 1ON NaOH was added. The mixture was stirred at room temperature for 30 minutes and the solvent was evaporated. The basic layer was acidified with concentrated HCl and extracted three times with EtOAc. The organic layers were washed with brine and dried over Na2SO4, filtered and evaporated to give the desired product as a brown powder (590mg ; 99percent). MS: MH+= 204
Under an argon atmosphere, to 4 ml 1,2-dimethoxyethane are added methyl 6-chloronicotinate (230 mg, 1.06 mmol), [4- (trifluoromethoxy) phenyl] boronic acid (268 mg, 1.31 mmol), 1.28 ml of a 2M aqueous sodium carbonate solution and tetrakis- (triphenylphosphin) palladium (0) (62 mg, 0.05 mmol). The mixture is stirred at 80 °C for 16h, cooled and quenched with water. After threefold extraction with ethyl acetate, the combined organic layers are washed with brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue is purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate 7: 1). Yield: 180 mg (57 percent). 'H NMR (400 MHz, DMSO-d6) 8 3.92 (s, 3H), 7.53 (d, 2H), 8.17 (d, 1H), 8.30 (d, 2H), 8.40 (dd, 1H), 9. 18 (d, 1H). MS (ESIF) : 298 [M+H] + HPLC : Retention time 5.01 min (method B)
With phosphorus(V) oxybromide; In toluene; at 90℃; for 3h;
Dissolve 6-chloropyridine-3-carboxylic acid methyl ester (6.86 g, 40 mmol) in toluene (100 mL) and heat to 90C. Add phosphorous oxybromide (25 g, 87 mmol) in several portions and continue heating for 3 hours. Cool the reaction to room temperature and pour onto ice water. Extract the reaction with ethyl acetate and wash organics again with water then NAHC03. COMBINE organics, dry over MGS04, filter, and evaporate to orange solid (8.1 g, 94%) which is an 8: 1 mixture OF 6-BROMOPYRIDINE-3-CARBOXYLIC acid methyl ester : 6-CHLOROMOPYRIDINE-3-CARBOXYLIC acid methyl ester BY LH NMR. Combine the mixture as obtained above (0.225 g, 1.04 mmol) with hexamethylditin (0.375 g, 1.15 mmol), Pd (OAC) 2 (21 mg, 0.09 mmol), and triphenylphosphine (25 mg, 0.09 mmol) in toluene (5 mL). Purge with N2 and stir at 80C for 18 hours. Cool reaction to room temperature. Add a solution of 1-BROM-2, 6- difluorobenzene (250 mg, 1.29 mmol) in toluene (1 mL) followed by Pd (OAC) 2 (21 mg, 0.09 mmol) and triphenylphosphine (25 mg, 0.09 mmol). Purge with N2 and stir at 80C for an additional 18 hours. Cool reaction to room temperature. Evaporate the solvent and purify by column chromatography (silica, 10% ethyl acetate in hexane) to give 50 mg (20% yield) OF 6- (2, 6-difluorophenyl) pyridine-3-carboxylic acid ethyl ester. Hydrolyze the ester with IN sodium hydroxide solution (0.22 mL, 0.22 mmol) in methanol (3 mL) at room temperature for 3 days. Remove the volatiles under vacuum and combine the RESIDUE with IN hydrochloric acid solution. Collect the white solid by filtration, wash with water, and dry under vacuum to give 30 mg (63% yield) of the title compound. MS (ES): m/z 235.9 (M+H).
With phosphorus(V) oxybromide; In toluene; at 90℃; for 3h;Heating / reflux;
Dissolve 6-CHLOROPYRIDINE-3-CARBOXYLIC acid methyl ester (6.86 g, 40 mmol) in toluene (100 mL) and heat to 90C. Add phosphorous oxybromide (25 g, 87 mmol) in several portions and continue heating for 3 hours. Cool the reaction to room temperature and pour onto ice water. Extract the reaction with ethyl acetate and wash organics again with water then NAHC03. COMBINE organics, dry over MGS04, filter, and evaporate to orange solid (8.1 g, 94%) which is an 8: 1 mixture of 6-bromopyridine-3-carboxylic acid methyl ester: 6-chloromopyridine-3-carboxylic acid methyl ester BY H NMR. Combine the mixture as obtained above (0.225 g, 1.04 mmol) with hexamethylditin (0.375 g, 1.15 mmol), Pd (OAc) 2 (21 mg, 0.09 mmol), and triphenylphosphine (25 mg, 0.09 mmol) in toluene (5 mL). Purge with N2 and stir at 80C for 18 hours. Cool reaction to room temperature. Add a solution of 1-BROMO-2, 6- difluorobenzene (250 mg, 1.29 mmol) in toluene (1 mL) followed by Pd (OAC) 2 (21 mg, 0.09 mmol) and triphenylphosphine (25 mg, 0.09 mmol). Purge with N2 and stir at 80C for an additional 18 hours. Cool reaction to room temperature. Evaporate the solvent and purify by column chromatography (silica, 10% ethyl acetate in hexane) to give 50 mg (20% yield) OF 6- (2, 6-difluorophenyl) pyridine-3-carboxylic acid ethyl ester. Hydrolyze the ester with IN sodium hydroxide solution (0.22 mL, 0.22 mmol) in methanol (3 mL) at room temperature for 3 days. Remove the volatiles under vacuum and combine the residue with IN hydrochloric acid solution. Collect the white solid by filtration, wash with water, and dry under vacuum to give 30 mg (63% yield) of the title compound. MS (ES): M/Z 235.9 (M+H).
With phosphorus(V) oxybromide; In toluene; at 90℃; for 3h;
Dissolve 6-chloropyridine-3-carboxylic acid methyl ester (6.86 g, 40 mmol) in toluene (100 mL) and heat to 90C. Add phosphorous oxybromide (25 G, 87 mmol) in several portions and continue heating for 3 hours. Cool the reaction to room temperature and pour onto ice water. Extract the reaction with ethyl acetate and wash organics again with water then sodium hydrogencarbonate. Combine organics, dry over magnesium sulfate, filter, and evaporate to orange solid (8.1 g, 94%) which is an 8: 1 mixture of 6- bromopyridine-3-carboxylic acid methyl ester: 6-chloromopyridine-3-carboxylic acid methyl ester BY LH NMR. Combine the mixture as obtained above (0.225 g, 1.04 mmol) with hexamethylditin (0.375 g, 1.15 mmol), Pd (OAC) 2 (21 mg, 0.09 mmol), and triphenylphosphine (25 mg, 0.09 mmol) in toluene (5 mL). Purge with N2 and stir at 80C for 18 hours. Cool reaction to room temperature. Add a solution of 1-BROM-2, 6- difluorobenzene (250 mg, 1.29 mmol) in toluene (1 mL) followed by Pd (OAC) 2 (21 mg, 0.09 mmol) and triphenylphosphine (25 mg, 0.09 mmol). Purge with N2 and stir at 80C for an additional 18 hours. Cool reaction to room temperature. Evaporate the solvent and purify by column chromatography (SILICA,} 0% ethyl acetate in hexane) to give 50 mg (20% yield) OF 6- (2, 6-difluorophenyl) PYRIDINE-3-CARBOXYLIC acid ethyl ester. Hydrolyze the ester with 1 N sodium hydroxide solution (0.22 mL, 0.22 mmol) in methanol (3 mL) at room temperature for 3 days. Remove the volatiles under vacuum and combine the residue with 1 N hydrochloric acid solution. Collect the white solid by filtration, wash with water, and dry under vacuum to give 30 mg (63% yield) of the title compound. MS (m/e): 235.9 (MH+).
Step 7a. Preparation of 6-Pyrazol-1-yl-nicotinic acid methyl ester (Compound of formula (XI-a)) To a solution of pyrazole (19.4 g, 0.28 mol) in 100 mL anhydrous DMSO, which was at a temperature of 0 C., was added NaH (7.5 g, 0.3 mol) gradually over a period of 30 min. The resulting reaction mixture was allowed to warm to room temperature, at which the mixture continued to agitate for an additional 30 min. Methyl 6-chloronicotinate (35 g, 0.2 mol) was added to the stirring reaction mixture and agitated vigorously for a period of 6 hr. The reaction mixture was subsequently cooled to a temperature of about 0 C. and poured into a saturated aqueous, 0 C. NH4Cl solution. The resulting precipitate was filtered, washed with water, and dried to give a compound of formula (XI-a) (38.3 g, 93% yield) as an off-white solid.
64%
Reference Example 54; Methyl 6-(1H-pyrazol-1-yl)nicotinate; To a suspension of pyrrole (0.356 g, 5.23 mmol) in DMF (20 ml) was added sodium hydride (60% in oil, 0.233' g, 5.81 mmol). After stirring for 5 hrs. , methyl 6- chloronicotinate (1.00 g, 5.81 mmol) was added, and the mixture was further stirred for 27 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried (over anhydrous MgS04). After concentration under reduced pressure, the precipitated solid was collected by filtration and washed with hexane to give the title compound (0.683 g, 64%) as a colorless powder. ¹H-NMR (CDCl3) No.: 3.97 (3H, s), 6.51 (lH, dd, J=4.2,2.4 Hz), 7.75-7.81 (lH, m), 8.05 (lH, dd, J=12.6,0.9 Hz), 8.40 (lH, dd, J=12.6,3.3 Hz), 8.62 (lH, dd, J=4.2,1.2 Hz), 9.03 (lH, dd, J=3.3,0.9Hz).
There was dissolved, in methanol (50 mL), methyl 6-chloro-nicotinate (4.00 g, 23.3 mM), then morpholine (6.10 mL, 69.9 mM) was added to the solution and the solution was stirred for 14 hours while refluxing the same with heating. The solvent was distilled off from this reaction liquid, the resulting residue was diluted with water and then extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate, the solvent was distilled off to thus obtain methyl 6-(morpholin-4-yl)-nicotinate (4.07 g, yield: 79percent). Subsequently, acetonitrile (1.61 mL, 30.6 mM) was added to a solution of 18-crown-6 (476 mg, 1.80 mM) and potassium tert-butoxide (1M THF solution, 27.0 mL, 27.0 mM) in THF (10 mL) at 60° C. and then the mixture was stirred for 5 minutes. To this solution, there was added the methyl 6-(morpholin-4-yl)-nicotinate (4.00 g, 18.0 mM) prepared above and the mixture was stirred for 30 minutes. This suspension was filtered and the resulting solid was washed with diethyl ether.
71%
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 100℃; for 6h;
Reference Example 53; Methyl 6-morpholin-4-ylnicotinate; A mixture of methyl 6-chloronicotinate (1.02 g, 5.93 mmol), morpholine (0.57 ml, 6.52 mmol), potassium carbonate (1.06 g, 7.71 mmol) and DMF (20 ml) was stirred at 100°C for 6 hrs. The reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried (over anhydrous MgS04), and concentrated under reduced pressure. The obtained solid was collected by filtration and washed with diisopropy ether to give the title compound (0.93 c 71percent) as a colorless powder. 1 H-NMR (CDCl3) No.: 3.64-3.70 (4H, m), 3.78-3.85 (4H, m), 3.88 (3H, s) , 6.57 (lH, dd, J=9.0,0.6 Hz) , 8. 05 (1H, dc J=9.0,2.4 Hz), 8.81 (lH, dd, J=2.4,0.6 Hz).
With cesium fluoride;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 100℃;
Preparation 12; [6-(4-Trifluoromethyl-phenyl)-pyridin-3-yl]-methanol ;Step A. 6-(4-Trifluoromethyl-phenyl)-nicotinic acid methyl ester; To an ambient temperature solution of 6-chloro-nicotinic acid methyl ester (12.4 g, 72 mmol) and 4- (trifluoromethyl)phenylboronic (15 g, 79 mmol) in dioxane (270 mL) is added CsF (38.3 g, 252 mmol) and the reaction mixture is degassed with nitrogen. PdCl2(dppf) (1.5 g) is added and the reaction mixture is heated to 100 C over weekend. The reaction mixture was diluted with ethyl acetate, filtered through celite. The filtrate is concentrated. Purification of the crude product by column on silica gel (hexanes/ethyl acetate) gives 6- (4-trifluoromethyl-phenyl)-nicotinic methyl ester (18.3 g, 82.3% yied).
2.35 g
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; cesium fluoride; In 1,4-dioxane; at 100℃; for 48h;Inert atmosphere;
In a 200 mL round-bottomed flask were added methyl 6-chloronicotinate (2 g, 11.66 mmol) and (4- (trifluoromethyl)phenyl)boronic acid (2.435 g, 12.82 mmol) in dioxane (43.7 ml) to give a tan solution. Cesium fluoride (6.20 g, 40.8 mmol) was added. Nitrogen was bubbled in the flask for 5 minutes. Pd(dppf)CI2*DCM (0.286 g, 0.350 mmol) was added. Nitrogen was bubbled in the flask for 5 minutes. Heated to 100°C for 2 days. Diluted the reaction mixture with EtOAc (50 mL). Filtered the mixture over celite and rinsed with EtOAc (2 x 25 mL). Concentrated to dryness and the residue was purified on ISCO using a RediSep® Gold column (Hex-EtOAc; 0-40percent) to give 2.35g of the title compound. 1H NMR (400 MHz, DMSO-cf6) delta ppm 9.21 (d, J = 2.0 Hz, 1 H), 8.34 - 8.46 (m, 3H), 8.25 (d, J = 8.6 Hz, 1 H), 7.90 (d, J = 8.2 Hz, 2H), 3.92 (s, 3H).
To a solution of methyl 6-chloronicotinate (5.0 g, 29.1 mmol), ferricacetylacetonate (1.0 g, 2.83 mmol) in tetrahydrofuran (160 mL) and NMP (1 mL) was added slowly a solution of ethylmagnesium bromide (1M in tetrahydrofuran, 1.09 mL, 7.27 mmol). The reaction mixture was stirred at 25 C for 3 hrs. The reaction mixture was diluted with saturated aqueous ammonium chloride solution and stirred for additional 30 min. The mixture was diluted with EtOAc, the separated organic layer was washed with saturated aqueous ammonium chloride solution, water and brine. The organic phase was dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, 80 g,EtOAc/heptane = 0/100 to 30/70] providing methyl 6-ethylnicotinate (2.48 g) as an oil. LCMS (m/z): 166.1 [M+H]+; Rt = 0.32 min.
iron(III)-acetylacetonate; In tetrahydrofuran; 1-methyl-pyrrolidin-2-one; at 25℃; for 3h;
To a solution of methyl 6-chloronicotinate (5.0 g, 29.1 mmol), ferricacetylacetonate (1.0 g, 2.83 mmol) in tetrahydrofuran (160 mL) and NMP (1 mL) was added slowly a solution of ethylmagnesium bromide (1 M in tetrahydrofuran, 1.09 mL, 7.27 mmol). The reaction mixture was stirred at 25 C for 3 hrs. The reaction mixture was diluted with saturated aqueous ammonium chloride solution and stirred for additional 30 min. The mixture was diluted with EtOAc, the separated organic layer was washed with saturated aqueous ammonium chloride solution, water and brine. The organic phase was dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, 80 g,EtOAc/heptane = 0/100 to 30/70] providing methyl 6-ethylnicotinate (2.48 g) as an oil. LCMS (m/z): 166.1 [M+H]+; Rt = 0.32 min.
iron(III)-acetylacetonate; In tetrahydrofuran; 1-methyl-pyrrolidin-2-one; at 25℃; for 3h;
To a solution of methyl 6-chloronicotinate (5.0 g, 29.1 mmol), ferric acetylacetonate (1 .0 g, 2.83 mmol) in tetrahydrofuran (160 mL) and NMP (1 mL) was added slowly a solution of ethylmagnesium bromide (1 M in tetrahydrofuran, 1 .09 mL, 7.27 mmol). The reaction mixture was stirred at 25 C for 3 hrs. The reaction mixture was diluted with saturated aqueous ammonium chloride solution and stirred for additional 30 min. The mixture was diluted with EtOAc, the separated organic layer was washed with saturated aqueous ammonium chloride solution, water and brine. The organic phase was dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, 80 g, EtOAc/heptane = 0/100 to 30/70] providing methyl 6-ethylnicotinate (2.48 g) as an oil. LCMS (m/z): 166.1 [M+H]+; Rt = 0.32 min
2.7 g
With 1-methyl-pyrrolidin-2-one; iron(III)-acetylacetonate; In tetrahydrofuran; at 0 - 20℃; for 0.5h;
To a mixture of methyl 6-chioronicotinate (5.5 g) and ferric acetylacetonate (0.5 g) in THF (100mL) and NMP (10 mL) was added dropwise ethylmagnesium bromide (1 M in THF, 40 mL) at 0C.After addition the mixture was stirred at RT for 30 minutes and then poured into ice/water (300mL). The mixture was extracted with EA (2x 100 ml). The combined organic layers were dried overNa2SO4 and evaporated to give the crude product, which was purified by column chromatography(eluting with EA:PE = 5%) to afford the title compound (2.7 g) as clear oil. MS (ESI): C9H1 ,N02requires 162; found 163 [M+H].
With 1-methyl-pyrrolidin-2-one;iron(III)-acetylacetonate; In tetrahydrofuran; for 0.166667h;
A flame-dried flask is charged under N2 with methyl-6-chloronicotinate (11 g, 64.1 mmol), Fe(acac)3 (1.13 g, 3.19 mmol), anhydrous THF (200 mL) and N-methylpyrrolidinone (20 mL). A solution of ethylmagnesium bromide (1M in THF, 76.9 mL, 76.9 mmol) is added. The resulting mixture is stirred for 10 min. The reaction is quenched with 1:1 water-saturated brine and extracted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue is treated with aqueous NaOH (5N, 64 mL) and EtOH (64 mL) at room temperature overnight. EtOH is then removed under reduced pressure. The pH of the aqueous solution is adjusted to 4-5 with 6N HCl, and extracted with EtOAc. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by silica gel chromatography with EtOAc as the eluent to afford the title compound as a white solid. 1HNMR (400 MHz, CDCl3) delta: 9.29 (d, 1H), 8.37 (dd, 1H), 8.10 (bs, 1H), 7.34 (d, 1H), 2.99 (q, 2H), 1.37 (t, 3H). LC-MS m/z (M+H): 152.
ferrous acetylacetonate; In tetrahydrofuran; 1-methyl-pyrrolidin-2-one; at 25℃; for 3h;
To a solution of methyl 6-chloronicotinate (5.0 g, 29.1 mmol), ferricacetylacetonate (1.0 g, 2.83 mmol) in tetrahydrofuran (160 mL) and NMP (1 mL) was added slowly a solution of ethylmagnesium bromide (1M in tetrahydrofuran, 1.09 mL, 7.27 mmol). The reaction mixture was stirred at 25 C for 3 hrs. The reaction mixture was diluted with saturated aqueous ammonium chloride solution and stirred for additional 30 min. The mixture was diluted with EtOAc, the separated organic layer was washed with saturated aqueous ammonium chloride solution, water and brine. The organic phase was dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, 80 g, EtOAc/heptane = 0/100 to 30/70] providing methyl 6-ethylnicotinate (2.48 g) as an oil. LCMS (m/z): 166.1 [M+H]+; Rt = 0.32 min.
Methyl 6-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
12%
With sodium t-butanolate;tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene](benzylidene)Ru(II) dichloride; In Oxygen-free THF; for 3h;Heating / reflux;
To a solution of <strong>[861673-68-9]2-(2-tert-butylphenoxy)pyridin-3-amine</strong> (Intermediate 1) (100 mg, 0.413 mmol) and methyl 6-chloronicotinate (355 mg, 2.07 mmol) in oxygen-free THF (2 mL) was added Nolan catalyst (10 mg) followed by sodium tert-butoxyde (39 mg, 0.41mmol). The reaction was stirred at refluxed for 3 h and partitioned between H2O and AcOEt. The organic phase was dried (MgSO4) and concentrated to give crude material. Purification by flash chromatography (silica gel, 15% AcOEt/hexanes the CH2Cl2) provided Example 215 (18 mg, 12%). (M+H)+=378.1817; 1H NMR (400 MHz, CDCl3) delta ppm 1.38 (s, 9 H), 3.93 (s, 3 H), 6.75 (d, J=8.0 Hz, 1 H), 6.95 (dd, J=7.9, 1.3 Hz, 1 H), 7.05 (dd, J=8.1, 5.0 Hz, 1 H), 7.16 (dt, J=7.8, 1.5 Hz, 1 H), 7.23 (dd, J=7.9, 1.8 Hz, 1 H), 7.43 (bs, 1 H), 7.46 (dd, J=7.8, 1.8 Hz, 1 H), 7.81 (dd, J=4.8, 1.8 Hz, 1 H), 8.13 (dd, J=8.6, 2.2 Hz, 1 H), 8.80 (dd, J=7.8, 1.8 Hz, 1 H), 8.93 (d, J=1.8, 1 H).
2-amino-N-(5-methoxycarbonyl-pyridin-2-yl)-2-methylpropylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 80℃; for 48h;
56
Reference example 56:; 2-Amino-N-(5-methoxycarbonyl-2-pyridyl)-2-methyl-amine [0263] To a solution of methyl 6-chloronicotinate (3.42 g, 20.0 mmol) in 2-propanol(20 mL) were added diisopropylethylamine (4.18 mL, 24.0 mmol) and 1,2-diamino-2-methylpropane (3.14 mL, 30.0 mmol), and the mixture was refluxed at 80 DEG C for 48 hours. The reaction mixture was concentrated under reduced pressure, and chloroform and aqueous potassium carbonate solution were added to the residue. The aqueous layer was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Chromatorex (registered trademark) NH, Fuji Silysia, hexane/ethyl acetate =5/1) to obtain the title compound (2.31 g, 10.3 mmol).yield: 52%<1>H NMR (CDCl3) delta (ppm): 8.71 (1H, d, J = 2.3 Hz), 7.95 (1H, dd, J = 8.9, 2.3 Hz), 6.40 (1H, d, J = 8.9 Hz), 5.53 (1H, t, J = 5.9 Hz), 3.86 (3H, s), 3.27 (2H, d, J = 5.9 Hz), 1.30 (2H, br s), 1.18 (6H, s).APCIMS (m/z): 224 (M + H)
1) 2-(6-Chloro-3-pyridyl)-2-propanol To a solution of methyl 6-chloronicotinate (1.72 g, 10.0 mmol) in THF (30 mL) was added a 3 mol/L solution of methyl magnesium bromide in THF (7.33 mL, 22.0 mmol) at -30 DEG C, and the mixture was stirred at 0 DEG C for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=40/1) to obtain 2-(6-chloro-3-pyridyl)-2-propanol (1.71 g, 10.0 mmol).yield: quantitative<1>H NMR (CDCl3) delta (ppm): 8.49 (1H, d, J = 2.6 Hz), 7.79 (1H, dd, J = 8.4, 2.6 Hz), 7.29 (1H, d, J = 8.4 Hz), 1.60 (6H, s).APCIMS (m/z): 172 (M + H)<+>
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 2h;
Procedure: To a stirring solution of methyl-6-chloronicotinate (200mg, 1.17mmol) and potassium carbonate (483mg, 3.5mmol) in N,N-dimethylformamide (6mL), add A- trifluoromethoxy-benzenethiol (340mg, 1.75mmol) and heat to 100°C for two hours. After this time, remove the heat and wash the reaction with water while extracting with dichloromethane. Dry the organics with sodium sulfate, filter and concentrate in vacuo. Purify via radial chromatography eluting with ethyl acetate and hexane. EPO MS (m/e): 330.1 (M+l).
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 9h;
A solution of 858 mg of methyl 6-chloronicotinate in 13 ml of N, N-dimethylformamide was added 0.67 ml of 1-methylpiperazine and 5 ml of N, N-diisopropylethylamine, The reaction mixture was heated to 80 ° C and stirred for 9 hours. After heating, the reaction solution was diluted with 65 ml of water and extracted with ethyl acetate. The organic phases were combined and washed with saturated aqueous sodium chloride solution five times, dried over anhydrous sodium sulfate, filtered The residue was purified by column chromatography (dichloromethane: methanol = 99: 1-97: 3, v / v) to give 1.063 g of an orange solid,Yield 90.4percent.
88%
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 100℃;Inert atmosphere;
A mixture of methyl 6-chioronicotinate (500 mg,2.92 mmol), 1 -methylpiperazine (900 mg, 9 mmol), DIPEA(774 mg, 6 mmol) in 1,4-dioxane (15 mE) was stirred at100° C. under N2 atmosphere for overnight. The mixturewas cool and EA (50 mE) and water (40 mE) were added,stirred for 30 mm, the organic layer was separated, dried,concentrated to get a residue, which was washed with PE (30mE) to afford as yellow solid (650 mg, 88percent).
77%
With diisopropylamine;sodium iodide; In water; N,N-dimethyl-formamide;
EXAMPLES 5-21 Preparation of methyl 6-(4-methyl-1-piperazinyl)nicotinate (compound 5) To a solution of 5.15 g of methyl 6-chloronicotinate, 3.15 g of 1-methylpiperazine and 3.18 g of diisopropylamine in 50 ml of DMF was added a catalytic amount of NaI. The mixture was heated to 120°-130° C. and stirred for 4 hours. The resulting mixture was poured into 250 ml of water followed by extraction with ethyl acetate. The extract was washed twice with water, and once with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate and concentrated. Purification of the concentrate by column chromatography (silica gel; chloroform:methanol=3:1) afforded 5.39 g of methyl 6-(4-methyl-1-piperazinyl)nicotinate (yield 77percent). The same procedure as mentioned above was repeated but replacing 1-methylpiperazine by piperazine, 1-ethylpiperazine, 1-phenylpiperazine, 1-benzylpiperazine, 1-(o-methoxyphenyl)piperazine, 1-(3,4-dimethoxybenzyl)piperazine, 1-(1-pyrrolidinylcarbonylmethyl)piperazine and homopiperazine, respectively, to give methyl 6-(1-piperazinyl)nicotinate (compound 6), methyl 6-(4-ethyl-1-piperazinyl)nicotinate (compound 7), methyl 6-(4-phenyl-1-piperazinyl)nicotinate (compound 8), methyl 6-(4-benzyl-1-piperazinyl)nicotinate (compound 9), methyl 6-(4-(2-methoxyphenyl)-1-piperazinyl)nicotinate (compound 10), methyl 6-[4-(3,4-dimethoxybenzyl)-1-piperazinyl]nicotinate (compound 11), methyl 6-(4-(1-pyrrolidinylcarbonylmethyl)-1-piperazinyl]nicotinate (compound 12) and methyl 6-(1-homopiperazinyl)nicotinate (compound 13), respectively.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 80℃; for 5h;
<strong>[73781-91-6]Methyl 6-chloronicotinate</strong> (5.0 g) was dissolved in DMF (75 ml) at r.t. under an argon atmosphere. 1-Methylpiperazine (3.66 ml) and diisopropylethylamine (30.7 ml) were added and the solution was stirred for 5 hours at 80° C. The reaction was quenched with water. The solution was extracted with EtOAc. The water phase was twice washed with EtOAc. The combined organic layers were washed with water and sat. aq. NaCl, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2-->CH2Cl2/MeOH 9:1) to give 6-(4-methyl-piperazin-1-yl)-nicotinic acid methyl ester (5.59 g) as light yellow solid.MS (ISP): 236.1 ([M+H]+).
6-(2-tritylsulfanylethylamino)nicotinic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; dichloromethane; water; at 120℃;
<strong>[73781-91-6]Methyl 6-chloronicotinate</strong> (0.20 g, 1.17 mmol), 2-tritylsulfanylethylamine (0.56 g, 1.75 mmol), cesium carbonate (0.95 g, 2.91 mmol), and [1 ,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(ll) complex with dichloromethane (1 :1) (0.24 g, 0.29 mmol) were heated to 120°C overnight in 1 ,4-dioxane (4.0 mL) and water. Upon cooling to rt, the reaction mixture was filtered through Celite.(R)., concentrated in vacuo, and purified by Biotage column chromatography (5percent EtOAc/Hexanes). This yielded 0.3442 g of a white solid. The material was recrystallized from 10percent EtOAc/Hexanes, yielding 0.272 g (51percent) of the desired product as a white solid.
51%
With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; dichloromethane; at 120℃;
<strong>[73781-91-6]Methyl 6-chloronicotinate</strong> (0.20 g, 1.17 mmol), 2-tritylsulfanylethylamine (0.56 g, 1.75 mmol), cesium carbonate (0.95 g, 2.91 mmol), and [1 ,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(ll) complex with dichloromethane (1 :1 ) (0.24 g, 0.29 mmol) were heated to 1200C overnight in 1 ,4-dioxane (4.0 mL) and water. Upon cooling to rt, the reaction mixture was filtered through Celite.(R)., concentrated in vacuo, and purified by Biotage column chromatography (5percent EtOAc/Hexanes). This yielded 0.3442 g of a white solid. The material was recrystallized from 10percent EtOAc/Hexanes, yielding 0.272 g (51 percent) of the desired product as a white solid. Rf = 0.42 (20percent EtOAc/Hexanes). 1H NMR (400 MHz, CD2CI2) delta 2.0 (bs, 1 H), 2.45 (t, 2H), 3.40 (t, 2H), 3.92(s, 3H), 7.15-7.30 (m, 10H), 7.42-7.50 (m, 6H), 8.02 (d, 1 H), 8.90 (s, 1 H).
51%
With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; dichloromethane; water; at 120℃;
<strong>[73781-91-6]Methyl 6-chloronicotinate</strong> (0.20 g, 1.17 mmol), 2-tritylsulfanylethylamine (0.56 g, 1.75 mmol), cesium carbonate (0.95 g, 2.91 mmol), and [1 ,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(ll) complex with dichloromethane (1 :1) (0.24 g, 0.29 mmol) were heated to 120°C overnight in 1 ,4-dioxane (4.0 mL) and water. Upon cooling to rt, the reaction mixture was filtered through Celite.(R)., concentrated in vacuo, and purified by Biotage column chromatography (5percent EtOAc/Hexanes). This yielded 0.3442 g of a white solid. The material was recrystallized from 10percent EtOAc/Hexanes, yielding 0.272 g (51percent) of the desired product as a white solid.
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 10h;
Preparation 1; A mixture of methyl 6-chloronicotinate (5.0g), l-benzyl-3-aminopyrrolidine (6.16g) and K2C03 (4.83g) in DMF (20ml) wasstirred at 100 C for 10 hours under atmospheric pressure ofnitrogen. The reaction mixture was poured into a mixture of AcOEtand water and the organic layer was washed with brine and driedover MgSO4. The solvent was evaporated in vacuo and the residuewas chromatographed on silicagel eluting with AcOEt-MeOH (97:3).The eluted fractions containing the desired product were collectedand evaporated in vacuo to give methyl 6-[(l-benzylpyrrolidin-3-yl)amino]nicotinate (4.17g)NMR (DMSO-d6, d): 1.58-1.71 (1H, m), 2.17-2.34 (1H, m), 2.37-2.89(4H, m), 3.51 (2H, s), 3.65 (2H, s), 4.39 (1H, m), 6.42 (1H, d, J=8.80HZ), 7.19-7.33 (5H, m), 7.59 (1H, d, J= 6.78Hz), 7.80 (1H, dd,J= 2.20Hz and 8.80Hz), 8.56 (1H, d, J= 2.20Hz)
With potassium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 70℃; for 2h;
Methyl 6-(6-Methyl-pyridin-3-ylamino)-nicotinateTo 5-amino-2-methylpyridine (2.22 g, 20.56 mmol) and finely ground anhydrous K2CO3 (11.9 g, 85.2 mmol) is added dry toluene (30 mL) under argon. Then, a solution of palladium(ll) acetate (79 mg, 0.34 mmol) and BINAP (218 mg, 0.34 mmol) in dry toluene (10 mL) is added. The reaction mixture is placed in an oil bath (70 0C) and a solution of methyl 6- chloronicotinate (3.0 g, 17.1 mmol) in dry toluene (20 mL) is added dropwise within 30 min. After 1.5 h the oilbath is removed and the reaction flask is placed in an ice bath. After stirring for 15 min the product is filtered off. The filter cake is triturated three times with THF / MeOH 1:1 (100 mL). The combined extracts are evaporated to dryness to give a brown powder. Flash chromatography (gradient MTBE-MeOH 100:0 - MTBE-MeOH 85:15) followed by crystallization from ether gives the product as light pink crystals (1.86 g, 45percent).
t-butyl 8-[5-(methoxycarbonyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 16; 8-(5-[(4-Aminobiphenyl-3-yl)amino]carbonyl}pyridin-2-yl)-N-(2-phenylethyl)-2,8-diazaspiro[4.5]decane-2-carboxamide; To a solution of methyl 6-chloronicontinate (200 mg, 1.16 mmol) in DMSO/PhMe (2 mL of a 1:1 solution) was added t-butyl-2,8-diazaspiro[4.5]decane-2-carboxylate (700 mg, 2.91 mmol). The reaction mixture was heated at 85 C. for 6 hours and then diluted with EtOAc (10 mL). The organic layer was washed with NaHCO3 (1×5 mL) and brine (1×5 mL), dried over Na2SO4, and then concentrated. The crude residue was purified by reverse-phase flash chromatography (10-100% MeCN/H2O with 0.05% TFA) to give t-butyl 8-[5-(methoxycarbonyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate: MS (ESI+): cal'd [M+H]+ 376.2, obs'd 376.2.
With potassium carbonate; In dimethyl sulfoxide; at 150℃; for 0.333333h;Microwave irradiation;
EXAMPLE 15; Pyridin-3-ylmethyl 7-(5-[(2-Aminophenyl)amino]carbonyl}pyridin-2-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate; 2-Benzyl-2,7-diazaspiro[4.4]nonane was purchased from Clariant Ltd. For synthesis and manipulation of this spirocycle, see Culbertson, T. P. et al., Quinolone antibacterial agents substituted at the 7-position with spiroamines. Synthesis and structure-activity relationships. J. Med. Chem. 1990, 33, 2270. A mixture of <strong>[885275-27-4]2-benzyl-2,7-diazaspiro[4.4]nonane</strong> (1.00 g, 4.68 mmol), methyl 6-chloronicotinate (800 mg, 4.68 mmol) and K2CO3 (700 mg, 5.07 mmol) in 5 mL of DMSO was stirred under microwave irradiation for 20 min at a temperature of 150 C. The mixture was poured into EtOAc and washed with sat'd NaHCO3, dried (Na2SO4), filtered and concentrated, giving methyl 6-(7-benzyl-2,7-diazaspiro[4.4]non-2-yl)nicotinate. A bottle containing a suspension of the benzyl amine and 20% Pd(OH)2/C (600 mg, 0.857 mmol) in 20 mL of EtOH was evacuated and purged with H2 gas three times. Using a Parr shaker apparatus, the suspension was agitated under 50 psi of H2 for 20 h. The pressure was released and the mixture filtered through a pad of Celite and concentrated, giving methyl 6-(2,7-diazaspiro[4.4]non-2-yl)nicotinate: 1H NMR (600 MHz, DMSO-d6) delta 8.59 (d, J=2.1 Hz, 1 H), 7.89 (dd, J=9.1, 2.3 Hz, 1 H), 7.27 (d, J=4.4 Hz, 1 H), 6.44 (d, J=8.8 Hz, 1 H), 3.74 (s, 3 H), 3.13 (br s, 4 H), 2.89 (t, J=7.3 Hz, 2 H), 2.72 (AB, J=7.6 Hz, 2 H), 1.92 (br m, 2 H), 1.69 (AB, J=7.3 Hz, 2 H).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃; for 10h;
To a round bottom flask containing (2-hydroxyphenyl)boronic acid (1.37 g, 9.9 mmol) in 1,4-dioxane : water (8:1, 40 ml) was added methyl 6-chloronicotinate (1.71 g, 10.0 mmol), potassium carbonate (4.14g, 30.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.3g, 0.26 mmol) and the resulting mixture stirred at 80 C. for 10 h, then stood at r.t. for 72 h. The solution was acidifed to pH 1 with aqueous 2 N HCl and concentrated in vacuo to a volume of approximately 5 ml. This solution was then partitioned between saturated sodium hydrogen carbonate (30 ml) and dichloromethane:methanol (95:5, 150 ml). The layers were separated and the aqueous layer extracted with dichloromethane (50 ml). The organic layers were combined and dried with anhydrous MgSO4, filtered and concentrated to afford a yellow solid. The solid was recrystallised from ethyl acetate/methanol to give the title compound as a yellow solid (1.14g) (50%). 1H NMR (400 MHz, CDCl3) ppm 9.16 (1 H, s), 8.46-8.40 (1 H, m), 8.02-7.96 (1 H, m ), 7.86-7.80 (1 H, m), 7.39-7.33 (1 H, m), 7.10-7.04 (1 H, m), 6.96-6.90 (1 H, m), 4.00 (3 H, s). LRMS: AP m/z 230 [M+H]+.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃; for 5h;
To a degassed mixture of 1,4-dioxane:water (4:1, 15 mis) was added <strong>[259209-20-6](5-fluoro-2-hydroxyphenyl)boronic acid</strong> (0.781 g, 5.0 mmol), methyl 6-chloronicotinate (0.86 g, 5.0 mmol), potassium carbonate (2.08 g, 15.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.05 mmol) and the resulting mixture stirred at 80° C. for 2h. After this time additional tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.05 mmol) was added and then heating continued at 80° C. for 3h. The mixture was then stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue suspended in ethyl acetate (50 ml). The suspension was filtered through a plug of arbocel and the filtrate concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (100 ml) and washed with saturated aqueous sodium carbonate (3.x.100 ml). The aqueous washings were combined and extracted with ethyl acetate (3.x.50 ml). The ethyl acetate layers were combined, dried with anhydrous MgSO4 and concentrated in vacuo to afford a solid which was recrystallised from dichloromethane/heptane to afford the title compound as a yellow solid (0.71 g) (57percent). 1H NMR (400 MHz, CDC3) ppm 9.14 (1 H, s), 8.46-8.40 (1 H, m), 7.91-7.86 (1 H, m) 7.53-7.46 (1 H, m), 7.11-7.03 (1 H, m), 7.02-6. 96 (1 H, m), 3.99 (3 H, s). LRMS: AP m/z 248 [M+H]+.
Example 7. Preparation of 0-(6-pyrazol-l-yl-pyridin-3-almethel)-hadroxylamine (Compound of formula (Xl)); Step 7a. Preparation of 6-Pyrazol-1-vl-nicotinic acid methyl ester (Compound of formula (XI-a)); To a solution of pyrazole (19.4g, 0. 28mol) in 100 mL anhydrous DMSO, which was at a temperature of 0°C, was added NaH (7. 5g, 0. 3mol) gradually over a period of 30 min. The resulting reaction mixture was allowed to warm to room temperature, at which the mixture continued to agitate for an additional 30 min. Methyl 6- chloronicotinate (35g, 0. 2mol) was added to the stirring reaction mixture and agitated vigorously for a period of 6 hr. The reaction mixture was subsequently cooled to a temperature of about 0°C and poured into a saturated aqueous, 0°C NH4C1 solution. The resulting precipitate was filtered, washed with water, and dried to give a compound of formula (XI-a) (38.3g, 93percent yield) as an off-white solid.
40%
Pyrazole (2.4 g, 35.4 mmol) was added to DMA (100 ml) and to this was slowly added NaH (1.85 g, 38.6 mmol). The reaction mixture was stirred for 10 mins under a nitrogen atmosphere. To the resulting anion was added methyl 6-chloropyridine-3-carboxylate (5.5 g, 32.2 mmol) and the reaction was heated at 95° C. overnight. The reaction mixture was evaporated to dryness, quenched with 2.0 N NaOH (100 ml), extracted with DCM (3.x.100 ml), dried (MgSO4) and the solvent removed in vacuo to yield a brown solid. This solid was purified via silica column chromatography, eluting with 0-40percent diethyl ether in iso-hexane. A white solid was obtained, which was dissolved in hot iso-hexane. On cooling a white solid was obtained which was filtered and dried (2.6 g, 40percent); 1H NMR (400.132 MHz, CDCl3) delta 3.96 (s, 3H), 6.50 (s, 1H), 7.77 (s, 1H), 8.05 (d, 1H), 8.40 (dd, 1H), 8.62 (d, 1H), 9.02 (d, 1H); MH+203.
Example 1; 6-((5-Methyl-3-phenyl-isoxazol-4-yl)-methoxy)-nicoti?ic acid hydrazidea) 6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl esterTo a solution of <strong>[18718-79-1](5-methyl-3-phenyl-isoxazol-4-yl)-methanol</strong> (263 mg, 1.39 mmol) in THF (3 mL) was added sodium hydride (55% dispersion in mineral oil, 66.7 mg, 1.53 mmol). After stirring for 15 min at room temperature methyl 6-chloronicotinate (286 mg, 1.67 mmol) was added and the reaction mixture was stirred for 18 h. The mixture was then diluted with ethyl acetate (10 mL), washed with aqueous citric acid (10%, 10 mL), water (10 mL) and aqueous sodium chloride (saturated, 10 mL). The combined aqueous layers were extracted with ethyl acetate (10 mL) and the combined organic extracts dried over sodium sulfate. Filtration and concentration followed by purification by chromatography (silica, heptane:ethyl acetate 1 :0 to 7:3) afforded the title compound (191 mg, 42 %) as a colorless oil MS: m/e = 325.3 [M+H]+.
42%
With sodium hydride; In mineral oil; at 20℃; for 5h;
Example 7 6-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid To a solution of <strong>[18718-79-1](5-methyl-3-phenyl-isoxazol-4-yl)-methanol</strong> (200 mg, 1.06 mmol) was added sodium hydride (55% dispersion in mineral oil, 996 mg, 22.8 mmol). After stirring for 0.5 h at ambient temperature methyl 6-chloronicotinate (1.06 mmol) was added and the reaction mixture was stirred for 5 h at ambient temperature. It was diluted with ethyl acetate (10 mL), washed with aqueous citric acid (10%, 10 mL), water (10 mL) and aqueous sodium chloride (saturated, 10 mL). The combined aqueous layers were extracted with ethyl acetate (10 mL). After drying over sodium sulfate and concentration purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 70:30) afforded 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (191 mg, 42%) as a white solid.
42%
To a solution of <strong>[18718-79-1](5-methyl-3-phenyl-isoxazol-4-yl)-methanol</strong> (200 mg, 1.06 mmol) was added sodium hydride (55% dispersion in mineral oil, 996 mg, 22.8 mmol). After stirring for 0.5 h at ambient temperature methyl 6-chloronicotinate (1.06 mmol) was added and the reaction mixture was stirred for 5 h at ambient temperature. It was diluted with ethyl acetate (10 mL), washed with aqueous citric acid (10%, 10 mL), water (10 mL) and aqueous sodium chloride (saturated, 10 mL). The combined aqueous layers were extrated with ethyl acetate (10 mL). After drying over sodium sulfate and concentration purification by chromatography (Si02, heptane:ethyl acetate = 100:0 to 70:30) afforded 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)- nicotinic acid methyl ester (191 mg, 42%) as a white solid.
To a suspension of sodium hydride (55percent dispersion in mineral oil, 852 mg, 20 mmol) in THF (27 mL) was added a solution of [3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (3.68 g, 18 mmol) in THF (54 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (3.35 g, 20 mmol) in THF (1.5 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=7:3) afforded the title compound (4.1 g, 68percent) which was obtained as a white solid. MS: m/e=343.1 [M+H]+.
68%
With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 20℃;
Example 8 6-[3-(3-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid To a suspension of sodium hydride (55percent dispersion in mineral oil, 852 mg, 20 mmol) in THF (27 mL) was added a solution of [3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (3.68 g, 18 mmol) in THF (54 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (3.35 g, 20 mmol) in THF (1.5 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=7:3) afforded 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (4.1 g, 68percent) which was obtained as a white solid.
68%
To a suspension of sodium hydride (55percent dispersion in mineral oil, 852 mg, 20 mmol) in THF (27 mL) was added a solution of [3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl] -methanol (3.68 g, 18 mmol) in THF (54 mL) at 0 °C and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (3.35 g, 20 mmol) in THF (1.5 mL) was added dropwise at 0 °C and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (Si02, heptane:ethyl acetate = 7:3) afforded 6-[3-(3-fluoro-phenyl)-5-methyl- isoxazol-4-ylmethoxy] -nicotinic acid methyl ester (4.1 g, 68percent) which was obtained as a white solid.
A solution of (5-methyl-3-pyridin-4-yl-isoxazol-4-yl)-methanol (1.00 g, 5.26 mmol) in THF (15 mL) was cooled to 0° C. and sodium hydride (55percent dispersion in mineral oil, 252 mg, 5.78 mmol) was added carefully under an atmosphere of nitrogen. After the resulting suspension was stirred for 0.5 h at ambient temperature methyl 6-chloronicotinate (1.08 g, 6.31 mmol) was added and the suspension was stirred for 18 h at this temperature.The reaction mixture was treated with a aqueous sodium hydroxide (1 N, 15.8 mL, 15.8 mmol) and stirred for 0.5 h at 70° C. The solution was cooled to ambient temperature, diluted with water (15 mL) and washed with tert-butylmethylether (15 mL). The organic layers were extracted with water (20 mL) and the combined aqueous layers were acified to pH=4 with a aqueous hydrochloric acid (25 percent). After the resulting suspension was stirred for 0.5 h at ambient temperature it was filtered off and washed with water (20 mL) affording the title compound (1.60 g, 97percent) which was obtained as a white solid MS: m/e=310.2 [M+H]+.
6-(2,6-difluorophenyl)-pyridine-3-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20%
Dissolve 6-chloropyridine-3-carboxylic acid methyl ester (6.86 g, 40 mmol) in toluene (100 mL) and heat to 90C. Add phosphorous oxybromide (25 G, 87 mmol) in several portions and continue heating for 3 hours. Cool the reaction to room temperature and pour onto ice water. Extract the reaction with ethyl acetate and wash organics again with water then sodium hydrogencarbonate. Combine organics, dry over magnesium sulfate, filter, and evaporate to orange solid (8.1 g, 94%) which is an 8: 1 mixture of 6- bromopyridine-3-carboxylic acid methyl ester: 6-chloromopyridine-3-carboxylic acid methyl ester BY LH NMR. Combine the mixture as obtained above (0.225 g, 1.04 mmol) with hexamethylditin (0.375 g, 1.15 mmol), Pd (OAC) 2 (21 mg, 0.09 mmol), and triphenylphosphine (25 mg, 0.09 mmol) in toluene (5 mL). Purge with N2 and stir at 80C for 18 hours. Cool reaction to room temperature. Add a solution of 1-BROM-2, 6- difluorobenzene (250 mg, 1.29 mmol) in toluene (1 mL) followed by Pd (OAC) 2 (21 mg, 0.09 mmol) and triphenylphosphine (25 mg, 0.09 mmol). Purge with N2 and stir at 80C for an additional 18 hours. Cool reaction to room temperature. Evaporate the solvent and purify by column chromatography (SILICA,} 0% ethyl acetate in hexane) to give 50 mg (20% yield) OF 6- (2, 6-difluorophenyl) PYRIDINE-3-CARBOXYLIC acid ethyl ester. Hydrolyze the ester with 1 N sodium hydroxide solution (0.22 mL, 0.22 mmol) in methanol (3 mL) at room temperature for 3 days. Remove the volatiles under vacuum and combine the residue with 1 N hydrochloric acid solution. Collect the white solid by filtration, wash with water, and dry under vacuum to give 30 mg (63% yield) of the title compound. MS (m/e): 235.9 (MH+).
20%
Dissolve 6-chloropyridine-3-carboxylic acid methyl ester (6.86 g, 40 mmol) in toluene (100 mL) and heat to 90C. Add phosphorous oxybromide (25 g, 87 mmol) in several portions and continue heating for 3 hours. Cool the reaction to room temperature and pour onto ice water. Extract the reaction with ethyl acetate and wash organics again with water then NAHC03. COMBINE organics, dry over MGS04, filter, and evaporate to orange solid (8.1 g, 94%) which is an 8: 1 mixture OF 6-BROMOPYRIDINE-3-CARBOXYLIC acid methyl ester : 6-CHLOROMOPYRIDINE-3-CARBOXYLIC acid methyl ester BY LH NMR. Combine the mixture as obtained above (0.225 g, 1.04 mmol) with hexamethylditin (0.375 g, 1.15 mmol), Pd (OAC) 2 (21 mg, 0.09 mmol), and triphenylphosphine (25 mg, 0.09 mmol) in toluene (5 mL). Purge with N2 and stir at 80C for 18 hours. Cool reaction to room temperature. Add a solution of 1-BROM-2, 6- difluorobenzene (250 mg, 1.29 mmol) in toluene (1 mL) followed by Pd (OAC) 2 (21 mg, 0.09 mmol) and triphenylphosphine (25 mg, 0.09 mmol). Purge with N2 and stir at 80C for an additional 18 hours. Cool reaction to room temperature. Evaporate the solvent and purify by column chromatography (silica, 10% ethyl acetate in hexane) to give 50 mg (20% yield) OF 6- (2, 6-difluorophenyl) pyridine-3-carboxylic acid ethyl ester. Hydrolyze the ester with IN sodium hydroxide solution (0.22 mL, 0.22 mmol) in methanol (3 mL) at room temperature for 3 days. Remove the volatiles under vacuum and combine the RESIDUE with IN hydrochloric acid solution. Collect the white solid by filtration, wash with water, and dry under vacuum to give 30 mg (63% yield) of the title compound. MS (ES): m/z 235.9 (M+H).
Description 26 1,1-Dimethylethyl 7-((5-[(methyloxy)carbonyl]-2-pyridinyl)oxy)-1,2,4,5-tetrahydro-3H- 3-benzazepine-3-carboxylate (D26); Sodium hydride (540 mg of 60percent dispersion; 13.7 mmol) was added to a solution of 1,1- dimethylethyl 7-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (3 g; 11.4 mmol; obtainable by the process described in Description 3 from WO 02/40471) in dry dimethylformamide (20 ml) and the reaction stirred at room temperature for 45 minutes. Methyl 6-chloro-3-pyridinecarboxylate (3.9 g; 22.8 mmol) was added and the mixture stirred at 100 °C for 18 hours. The mixture was poured into water and extracted with ethyl acetate. The extracts were combined, dried (sodium sulphate) and evaporated. The residue was purified by silica column chromatography eluting with 3-1 pentane - ethyl acetate to afford a white powder (3.7 g; 82percent) MS (AP+), m/e 399 [M+H].
Example 17 3-(Cyclopropylmethyl)-7-[5-(3-methyl-1,2,4-oxadiazol-5-yl)-2-pyridinyl]oxy}-2,3,4,5- tetrahydro-1H-3-benzazepine (E17) Step 1: 1,1-Dimethylethyl 7-({5-[(methyloxy)carbonyl)-2-pyridinyl}oxy)-1,2,4,5- tetrahydro-3H-3-benzazepine-3-carboxylate; 1,1-Dimethylethyl 7-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Description 3 of WO 02/40471) (3 g, 11.4 mmole) was dissolved in dry dimethylformamide (20 ml), cooled to 0°C and treated with sodium hydride (60percent in mineral oil, 540 mg, 13.7 mmole). The mixture was allowed to warm to room temperature over 60 minutes. Methyl 6- chloro-3-pyridinecarboxylate (2.4 g, 13.7 mmole) was added and the mixture stirred at 100 °C for 18 hours. The mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layers were combined, dried (sodium sulphate) and evaporated in vacuo. The residue was purified by column chromatography eluting with ethyl acetate/pentane (1: 4) to afford the title compound. MS (AP+) m/e 399 [M+H]+.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃;
Step 1. Preparation of methyl 6-(4-fluorophenyl)niotacotiotanate (C119). To a degassed suspension of methyl 6-chloronicotinate (5.0 g, 29 mmol), 4-fluorophenylboronic acid (4 89 g, 43 7 mmol) and sodium carbonate (7.50 g, as a solution in 35.4 ml of water, 70 8 mmol) in dimethoxyethane (45 mL) was added tetrakis(tnphenylphosph.ne)pa.ladium(0) (1 68 g, 1 46 mmol), and the reaction was stirred and heated to reflux (-80°C) overnight The reaction was allowed to cool to 25°C1 solvent was removed in vacuo, and the residue was partitioned between ethyl acetate and ice water. The organic layer was washed with water and saturated aqueous sodium chlonde solution, dried over magnesium sulfate, filtered and concentrated The residue was purified by silica gel column chromatography (Gradient- 10 1 hexanes ethyl acetate to 1.1 hexanes ethyl acetate) to yield C119 Yield beta 60 g, 98percent. 1H NMR (400 MHz,CDCb) * 3 94 (S, 3H). 7.15 (m, 2H), 7.73 (dd, J=Q 3, 0.9 Hz, 1H), 8 02 (m, 2H), 8 30 (dd, J=8 3, 2 2 Hz, 1 H), 9.22 (dd, J=2 2, 0.9 Hz, 1 H)
With triethylamine; In N,N-dimethyl-formamide; at 80℃; for 4.5h;
Intermediate Preparation 26; 4-Hvdroxy-3A5,6-tetrahvdro-2H-ri,2'1bipyridinyl-5'-carboxylic acid methyl ester; To a solution of methyl 6-chloronicotinate (890 mg, 1.00 equiv; 5.03 mmol) in dry DMF (30 mL) is added 4-hydroxypiperidine (1.5 equiv; 7.55 mmol; 778.95 mg) and triethylamine (1.05 mL; 1.5 equiv; 7.55 mmol). The system is flushed with N2 and heated at 80 0C for 4.5 h. The reaction is allowed to reach room temperature and is diluted with water/EtOAc. The aqueous layer is extracted with ethyl acetate (3x). The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue is purified via chromatography eluting with hexane/EtOAc 2: 1 to 1:2 to yield an orange solid. The solid is triturated with hexane/EtOAc 4: 1 and filtered to provide the title compound (1.023 g, 86percent) as a white solid. ES/MS m/z 237.0 (M+l)
With toluene-4-sulfonic acid; In 1,4-dioxane; at 111℃; for 14h;Inert atmosphere;
b. Methyl 6-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino)nicotinate (75). To a 100 mL, one-neck, round-bottomed flask equipped with a magnetic stir bar and charged with 74 (0.8047 g, 3.958 mmol), methyl 6-chloronicotinate (0.6897, 4.02 mmol), and p-TsOH (0.7605 g,4.0 mmol) was added 1 ,4-dioxane (15 mL). The flask was fitted with a reflux condenser, evacuated and back-filled with nitrogen, heated to reflux and stirred in an oil bath at 111 °C for 14 h. After cooling the reaction to r.t., the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to yield a crude product that was purified by column chromatography (150 mL Si02, 10percent ethyl acetate:hexanes) to give 75 (0.8152 g, 61percent) as a white crystalline solid, m.p. 167-171 °C: ?H NMR (400 MHz, CDC13) oe 8.81 (dd, J 2.0, 0.4, 1H), 8.02 (dd, J_ 8.8, 2.0, 1H), 7.94 (s, 111), 7.31 (a, J 7.6, 111), 7.21 (d, J 2.4, 1H), 7.12 (dd, J 8.4, 2.4, 1H), 6.82 (dd, J 8.8, 0.4, 1H), 3.87 (s, 3H), 1.70 (s, 411), 1.29 (s, 12H); ?3C NMR (100.6 MHz, CDC13) oe 166.0, 159.4, 151.2, 146.3, 141.5, 138.9, 136.1, 127.5, 120.4, 120.0, 116.3, 106.0, 51.6, 35.0, 34.9, 34.3, 33.9, 31.8, 31.7; IR (neat) 3224, 2954, 1715, 1597, 1535, 1261 cm?; ES-MS (M+Na)+ caled for C21H26N7O2Na 361.1892, found 361.1899.
61%
With toluene-4-sulfonic acid; In 1,4-dioxane; at 111℃;Inert atmosphere;
To a 100 mL, one-neck, round-bottomed flask equipped with a magnetic stir bar and charged with 33 (0.8047 g, 3.958 mmol), methyl 6-chloronicotinate (34) (0.6897, 4.02 mmol), and p-TsOH (0.7605 g, 4.0 mmol) was added 1,4-dioxane (15 mL). The flask was fitted with a reflux condenser, evacuated and back-filled with nitrogen, heated to reflux and stirred in an oil bath at 111° C. for 14 hours. After cooling the reaction to room temperature, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to yield a crude product that was purified by column chromatography (150 mL SiO2, 10percent ethyl acetate:hexanes) to give compound 35 (0.8152 g, 61percent) as a white crystalline solid, m.p. 167-171° C.: 1H NMR (400 MHz, CDCl3) delta 8.81 (dd, J=2.0, 0.4, 1H), 8.02 (dd, J=8.8, 2.0, 1H), 7.94 (s, 1H), 7.31 (d, J=7.6, 1H), 7.21 (d, J=2.4, 1H), 7.12 (dd, J=8.4, 2.4, 1H), 6.82 (dd, J=8.8, 0.4, 1H), 3.87 (s, 3H), 1.70 (s, 4H), 1.29 (s, 12H); 13C NMR (100.6 MHz, CDCl3) delta 166.0, 159.4, 151.2, 146.3, 141.5, 138.9, 136.1, 127.5, 120.4, 120.0, 116.3, 106.0, 51.6, 35.0, 34.9, 34.3, 33.9, 31.8, 31.7; IR (neat) 3224, 2954, 1715, 1597, 1535, 1261 cm-1; ES-MS (M+Na)+ calcd for C21H26N2O2Na 361.1892, found 361.1899.
c) 6-[3-(4-Fluoro-phenyl)-5-((E)-styryl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester; To a suspension of sodium hydride (813 mg, 18.6 mmol) in 28 mL THF was added a solution of [3-(4-fluoro-phenyl)-5((E)-styryl)-isoxazol-4-yl]-methanol (5.00 g, 16.9 mmol) in THF (52 mL) and stirring was continued for 1 h at room temperature. A solution of methyl 6-chloronicotinate (3.26 g, 18.6 mmol) in THF (52 mL) was added. The mixture was stirred at room temperature for 3 h. Then water (50 mL) was added cautiously and then saturated ammonium chloride solution (150 mL) and water (100 mL). Extraction with ethyl acetate and chromatography (silica, ethyl acetate:heptane=1:4 to 1:1) afforded the title compound (3.88 g, 94percent) as a white solid. MS: m/e=431.3 [M+H]+.
Stage #1: 2,2,2-trifluoroethanol With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5h;
Stage #2: 6-Chloronicotinic acid methyl ester In tetrahydrofuran; acetonitrile; mineral oil at 70℃; for 1.5h;
To a stirred solution of 2,2,2-trifluoroethanol (1.0 mL, 14 mmol) in THF (25 mL) was added sodium hydride (60% dispersion in oil, 0.56 g, 14 mmol). The reaction mixture was stirred at r.t. for 30 minutes prior to the addition of 6-chloronicotinic acid methyl ester (1.71 g, 10 mmol) in MeCN (5 mL). The reaction mixture was heated at 7O0C for 1.5 h, then partitioned between EtOAc (50 mL) and saturated ammonium chloride solution (50 mL). The aqueous layer was extracted with EtOAc (30 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated in vacuo. The resulting white solid was dissolved in THF (5 mL) and water (5 niL). Lithium hydroxide (200 mg) was added and the reaction mixture was stirred at r.t. for 2 h, then taken to pH 6 with HCl (2M aqueous). The reaction mixture was concentrated in vacuo, yielding the title compound (0.7 g, 32%) as a white solid. δH (de-DMSO) 8.62 (d, J 2.0 Hz, IH), 8.17 (dd, J8.6, 2.3 Hz, IH), 6.86 (d, J8.3 Hz, IH), 5.00 (q, J9.1 Hz, 2H). LCMS (ES+) 222 (M+H)+.
Stage #1: 2,2,2-trifluoroethanol With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5h;
Stage #2: 6-Chloronicotinic acid methyl ester In tetrahydrofuran; mineral oil at 70℃; for 1.5h;
6-(2,2,2-Trifluoro-ethoxy)-nicotinic Acid Methyl Ester
To a stirred solution of 2,2,2-trifluoroethanol (4.2 g) in THF (100 mL) was added sodium hydride (60% dispersion in oil, 1680 mg). The reaction mixture was stirred at RT for 30 minutes prior to the addition of 6-chloronicotinic acid methyl ester (5.1 g) in THF (5 mL). The reaction mixture was heated at 70° C. for 1.5 hours, then partitioned between EtOAc (50 mL) and saturated ammonium chloride solution (50 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried (sodium sulphate), filtered and concentrated in vacuo. The resulting white solid was purified by SGC (PE/EA=5:1) to provide 6-(2,2,2-trifluoro-ethoxy)-nicotinic acid methyl ester. MS ESI+: m/z=236 [M+H]+.
3.24 g of 4-trifluoromethylphenol was dissolved in 30 ml of dimethylsulfoxide and 0.88 g of 60% sodium hydride was added thereto under ice cooling. The reaction solution was stirred at room temperature for 30 minutes, 3.43 g of methyl 6-chloronicotinate was added thereto under ice cooling, and the resulting mixture was stirred at 70 C. overnight. The reaction solution was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine. Thereafter, the resultant was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate) to obtain 5.36 g of a target compound. Yield: 90%. 1H-NMR (CDCl3, delta ppm) 3.92 (3H, s), 7.01 (1H, d), 7.26 (2H, d), 7.67 (2H, d), 8.32 (1H, d), 8.80 (1H, s)
2. 6-(4-Trifluoromethylphenoxy)-nicotinic acid methyl ester. To a suspension of NaH (60% dispersion in oil; 1.2 g, 30 mmol) in 30 mL of DMSO was added a solution of 4-(trifluoromethyl)phenol (1.86 g, 30 mmol) in 20 mL of DMSO and the mixture was stirred for 30 min To this was added methyl 6-chloronicotinate (5.13 g, 30 mmol) and the solution was heated overnight at 70 C. The reaction was cooled to room temperature and then diluted with Et2O. The solution was washed with H2O, brine, dried with Na2SO4, suction filtered, and the solvent removed in vacuo. The residue was purified via normal phase column chromatography over SiO2using 15% Et2O/pentane to yield 6-(4-trifluoromethylphenoxy)-nicotinic acid methyl ester (4.5 g) as a colorless solid: 1H-NMR (300 MHz, CDCl3) delta 8.81 (dd, J=2.5, 0.6 Hz, 1H), 8.33 (dd, J=8.6, 2.4 Hz, 1H), 7.69 (d, J=8.5 Hz, 2H), 7.31-7.24 (m, 2H), 7.02 (dd, J=8.5, 0.6 Hz, 1H), 3.93 (s, 3H); EIMS m/z 297 ([M]+).
To a suspension of NaH (60% dispersion in oil; 1.2 g, 30 mmol) in 30 mL of DMSO was added a solution of 4- (trifluoromethyl)phenol (1.86 g, 30 mmol) in 20 mL of DMSO and the mixture was stirred for 30 min. To this was added methyl 6-chloronicotinate (5.13 g, 30 mmol) and the solution was heated overnight at 700C. The reaction was cooled to room temperature and then diluted with Et2O. The solution was washed with H2O, brine, dried with Na2SO4, suction filtered, and the solvent removed in vacuo. The residue was purified via normal phase column chromatography over SiO2 using 15% Et2O/pentane to yield 6-(4-trifluoromethylphenoxy)- nicotinic acid methyl ester (4.5 g) as a colorless solid: 1H-NMR (300 MHz, CDCl3) delta 8.81 (dd, J = 2.5, 0.6 Hz, IH), 8.33 (dd, J = 8.6, 2.4 Hz, IH), 7.69 (d, J = 8.5 Hz, 2H), 7.31 - 7.24 (m, 2H), 7.02 (dd, J = 8.5, 0.6 Hz, IH), 3.93 (s, 3H); EIMS m/z 297 ([M]+).
With N-ethyl-N,N-diisopropylamine In acetonitrile at 140℃; for 1h; Microwave irradiation;
1.1.3.1.3.1
1.3.1 ntermediate 10 6- [(3 S)-3 -Methoxypyrrol idin- 1 -yl]pyridine-3 -carboxy late A microwave vial was charged with methyl 6-chloronicotinate (1.3 g, 7.4 mmol), (S)-3- methoxypyrrolidine (0.9 g, 8.9 mmol), diisopropylethylamine (3.9 mL, 22.2 mmol) and acetonitrile (10 mL) and heated for one hour at 140 °C in the microwave. The mixture was diluted with EtOAc (50 mL) and washed with saturated sodium carbonate (30 mL). The aqueous was further extracted with EtOAc (30 mL) and the combined organics were washed with brine (50 mL). The organic layers were combined and dried over MgS04, filtered and concentrated. The crude residue was purified by column chromatography using silica and eluting 12-100% EtOAc in petrol to yield methyl 6-[(3S)-3-methoxypyrrolidin-l -yl]pyridine-3- carboxylate (880 mg, 50% yield) as an off white solid. NMR (400 MHz, CD3OD) δ 8.60 - 8.74 (m, 1 H), 7.98 - 8.08 (m, 1H), 6.49 - 6.60 (m, 1 H), 4.13 - 4.21 (m, 1 H), 3.87 (s, 3H), 3.47 - 3.73 (m, 4H), 3.36 - 3.42 (m, 3H), 2.06 - 2.33 (m, 2H)MS ES+ 237
With lithium chloride;dichlorobis(tri-O-tolylphosphine)palladium; In N,N-dimethyl-formamide; at 100℃; for 2h;
step 1<strong>[73781-91-6]Methyl 6-chloronicotinate</strong> (1.51 g, 8.79 mmol) was dissolved in DMF (35 mL), vinyltributyltin (3.32 mL, 11.4 mmol), dichlorobis(tri-o-tolylphosphine)palladium (206 mg, 0.262 mmol) and lithium chloride (554 mg, 13.1 mmol) were added and the mixture was stirred at 100°C for 2 hr.The mixture was allowed to cool to room temperature, and an aqueous potassium fluoride solution was added thereto.The mixture was filtered through celite and the residue was washed with ethyl acetate.To the obtained filtrate was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30) to give methyl 6-vinylnicotinate (1.22 g, 85percent) as a colorless transparent oil. 1H NMR (CDCl3, deltappm): 3.95 (s, 3H), 5.63 (dd, J = 1.1, 10.8 Hz, 1H), 6.35 (dd, J = 1.1, 17.4 Hz, 1H), 6.87 (dd, J = 10.8, 17.4 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 8.25 (dd, J = 2.1, 8.2 Hz, 1H), 9.15-9.18(m, 1H).
85%
With lithium chloride;dichlorobis(tri-O-tolylphosphine)palladium; In N,N-dimethyl-formamide; at 100℃; for 2h;
step 1<strong>[73781-91-6]Methyl 6-chloronicotinate</strong> (1.51 g, 8.79 mmol) was dissolved in DMF (35 mL), vinyltributyltin (3.32 mL, 11.4 mmol), dichlorobis(tri-o-tolylphosphine)palladium (206 mg, 0.262 mmol) and lithium chloride (554 mg, 13.1 mmol) were added and the mixture was stirred at 100°C for 2 hr.The mixture was allowed to cool to room temperature, and an aqueous potassium fluoride solution was added thereto.The mixture was filtered through Celite and the residue was washed with ethyl acetate.To the obtained filtrate was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30) to give methyl 6-vinylnicotinate (1.22 g, 85percent) as a colorless transparent oil.1H NMR (CDCl3, deltappm): 3.95 (s, 3H), 5.63 (dd, J = 1.1, 10.8 Hz, 1H), 6.35 (dd, J = 1.1, 17.4 Hz, 1H), 6.87 (dd, J = 10.8, 17.4 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 8.25 (dd, J = 2.1, 8.2 Hz, 1H), 9.15-9.18(m, 1H).
85%
With dichlorobis(tri-O-tolylphosphine)palladium; lithium chloride; In N,N-dimethyl-formamide; at 100℃; for 2h;
step 1 <strong>[73781-91-6]Methyl 6-chloronicotinate</strong> (1.51 g, 8.79 mmol) was dissolved in DMF (35 mL), vinyltributyltin (3.32 mL, 11.4 mmol), dichlorobis(tri-o-tolylphosphine)palladium (206 mg, 0.262 mmol) and lithium chloride (554 mg, 13.1 mmol) were added and the mixture was stirred at 100°C for 2 hr. The mixture was allowed to cool to room temperature, and an aqueous potassium fluoride solution was added thereto. The mixture was filtered through Celite and the residue was washed with ethyl acetate. To the obtained filtrate was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30) to give methyl 6-vinylnicotinate (1.22 g, 85percent) as a colorless transparent oil. 1H NMR (CDCl3, deltappm) : 3.95 (s, 3H), 5.63 (dd, J = 1.1, 10.8 Hz, 1H), 6.35 (dd, J = 1.1, 17.4 Hz, 1H), 6.87 (dd, J = 10.8, 17.4 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 8.25 (dd, J = 2.1, 8.2 Hz, 1H), 9.15-9.18 (m,1H).
[3-(4-Fluoro-phenyl)-5-methyl-3H-[1,2,3]-triazol-4-yl]-methanol[ No CAS ]
[ 1374672-54-4 ]
Yield
Reaction Conditions
Operation in experiment
88%
With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 20℃; for 20.5h;
f)6-[3-(4-Fluoro-phenyl)-5-methyl-3H-[1,2,3]-triazol-4-ylmethoxy]-nicotinic acid methyl esterA solution of [3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-yl]-methanol (425 mg, 2.05 mmol) in THF (3 mL) was added dropwise at 0° C. to a suspension of NaH (55percent in oil, 100 mg, 2.05 mmol) in THF (6 mL) and the reaction mixture was then stirred at room temperature for 30 min.Then a solution of methyl 6-chloronicotinate (390 mg, 8.0 mmol) in THF (3 mL) was added dropwise at 0° C. and the reaction mixture stirred at room temperature for 20 h.The mixture was then poured into water extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated.Purification by chromatography (silica, 10 to 50percent ethyl acetate in heptane) afforded the title compound (621 mg, 88percent) as a white solid. MS: m/e=343.3 [M+H]+.
88%
f) 6-r3-(4-Fluoro-phenyl)-5-methyl-3H-ri,2,31triazol-4-ylmethoxyl-nicotinic acid methyl esterA solution of [3-(4-fluoro-phenyl)-5-methyl-3H-[l,2,3]triazol-4-yl]-methanol (425 mg, 2.05 mmol) in THF (3 mL) was added dropwise at 0 °C to a suspension of NaH (55percent in oil, 100 mg, 2.05 mmol) in THF (6 mL) and the reaction mixture was then stirred at room temperature for 30 min. Then a solution of methyl 6-chloronicotinate (390 mg, 8.0 mmol) in THF (3 mL) was added dropwise at 0 °C and the reaction mixture stirred at room temperature for 20 h. The mixture was then poured into water extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 10 to 50percent ethyl acetate in heptane) afforded the title compound (621 mg, 88percent) as a white solid. MS: m/e = 343.3 [M+H]+.
With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 20℃; for 16.5h;
e)6-[5-(4-Fluoro-phenyl)-3-methyl-3H-[1,2,3]-triazol-4-ylmethoxy]-nicotinic acid methyl esterA solution of [5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-methanol (380 mg, 2.02 mmol) in THF (5.5 mL) was added dropwise at 0° C. to a suspension of NaH (55percent in oil, 88 mg, 2.02 mmol) in THF (2.7 mL) and the reaction mixture was then stirred at room temperature for 30 min.Then a solution of methyl 6-chloronicotinate (346 mg, 2.02 mmol) in THF (5.5 mL) was added dropwise at 0° C. and the reaction mixture stirred at room temperature for 16 h.The mixture was then poured into water extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated.Purification by chromatography (silica, 0 to 100percent ethyl acetate in heptane) afforded the title compound (449 mg, 72percent) as a white solid. MS: m/e=343.1 [M+H]+.
72%
e) 6-r5-(4-Fluoro-phenyl)-3-methyl-3H-rL2,31triazol-4-ylmethoxyl-nicotinic acid methyl esterA solution of [5-(4-fluoro-phenyl)-3-methyl-3H-[l,2,3]triazol-4-yl]-methanol (380 mg, 2.02 mmol) in THF (5.5 mL) was added dropwise at 0 °C to a suspension of NaH (55percent in oil, 88 mg, 2.02 mmol) in THF (2.7 mL) and the reaction mixture was then stirred at room temperature for 30 min. Then a solution of methyl 6-chloronicotinate (346 mg, 2.02 mmol) in THF (5.5 mL) was added dropwise at 0 °C and the reaction mixture stirred at room temperature for 16 h. The mixture was then poured into water extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100percent ethyl acetate in heptane) afforded the title compound (449 mg, 72percent) as a white solid. MS: m/e = 343.1 [M+H]+.
With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 20℃; for 16.5h;
d)Methyl 6-((4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methoxy)nicotinateA solution of (4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methanol (100 mg, 0.48 mmol) in THF (1.4 mL) was added dropwise at 0° C. to a suspension of NaH (60percent in oil, 21 mg, 0.53 mmol) in THF (0.7 mL) and the reaction mixture was then stirred at room temperature for 30 min.Then a solution of methyl 6-chloronicotinate (91 mg, 0.53 mmol) in THF (1 mL) was added dropwise at 0° C. and the reaction mixture stirred at room temperature for 16 h.The mixture was then poured into water extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated.Purification by chromatography (silica, 0 to 100percent ethyl acetate in heptane) afforded the title compound (110 mg, 67percent) as a colourless gum. MS: m/e=343.1 [M+H]+.
67%
d) Methyl 6-((4-(2-fluorophenyl)- 1-methyl- 1H- 1 ,2,3-triazol-5-yl)methoxy)nicotinateA solution of (4-(2-fluorophenyl)-l-methyl-lH-l,2,3-triazol-5-yl)methanol (100 mg, 0.48 mmol) in THF (1.4 mL) was added dropwise at 0 °C to a suspension of NaH (60percent in oil, 21 mg, 0.53 mmol) in THF (0.7 mL) and the reaction mixture was then stirred at room temperature for 30 min. Then a solution of methyl 6-chloronicotinate (91 mg, 0.53 mmol) in THF (1 mL) was added dropwise at 0 °C and the reaction mixture stirred at room temperature for 16 h. The mixture was then poured into water extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100percent ethyl acetate in heptane) afforded the title compound (110 mg, 67percent) as a colourless gum. MS: m/e = 343.1 [M+H]+
With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 20℃; for 18.5h;
f)6-(3-Methyl-5-pyridin-2-yl-3H-[1,2,3]-triazol-4-ylmethoxy)-nicotinic acid methyl esterA solution of (3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-yl)-methanol (158 mg, 0.83 mmol) in THF (2.4 mL) was added dropwise at 0° C. to a suspension of NaH (60percent in oil, 40 mg, 0.91 mmol) in THF (1.2 mL) and the reaction mixture was then stirred at room temperature for 30 min.Then a solution of methyl 6-chloronicotinate (157 mg, 0.91 mmol) in THF (2.4 mL) was added dropwise at 0° C. and the reaction mixture stirred at room temperature for 18 h.The mixture was then poured into water extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated.Purification by chromatography (silica, 0 to 100percent ethyl acetate in heptane) afforded the title compound (209 mg, 77percent) as a white solid. MS: m/e=326.1 [M+H]+.
77%
f) 6-(3-Methyl-5-pyridin-2-yl-3H-ri,2,31triazol-4-ylmethoxy)-nicotinic acid methyl esterA solution of (3-methyl-5-pyridin-2-yl-3H-[l,2,3]triazol-4-yl)-methanol (158 mg, 0.83 mmol) in THF (2.4 mL) was added dropwise at 0 °C to a suspension of NaH (60percent in oil, 40 mg, 0.91 mmol) in THF (1.2 mL) and the reaction mixture was then stirred at room temperature for 30 min. Then a solution of methyl 6-chloronicotinate (157 mg, 0.91 mmol) in THF (2.4 mL) was added dropwise at 0 °C and the reaction mixture stirred at room temperature for 18 h. The mixture was then poured into water extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100percent ethyl acetate in heptane) afforded the title compound (209 mg, 77percent) as a white solid. MS: m/e = 326.1 [M+H]+.
To a solution of methyl 6-chloronicotinate (0.70 g, 4.08 mmol), iron(III) acetylacetonate (0.14 g, 0.41 mmol) and 1-methyl-2-pyrrolidinone (0.23 mL, 2.39 mmol) in THF (23 mL) is added (3,3,3-trifluoropropyl)magnesium bromide (8.16 mL, 8.16 mmol, Step-1), and the mixture is stirred at rt for 30 minutes. The reaction mixture is poured into water, and the aqueous layer is extracted with EtOAc. The seprated organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with hexane / EtOAc (3:1) to give 0.95 g (99percent yield) of the title compound as a white solid. 1H-NMR (300 MHz, CDCl3) delta 9.14 (1H, d, J = 2.2 Hz), 8.22 (1H, dd, J = 8.1, 2.2 Hz), 7.27 (1H, d, J = 8.1 Hz), 3.95 (3H, s), 3.13-3.08 (2H, m), 2.71-2.55 (2H, m), MS (ESI) m/z: 234 (M+H)+.
Magnesium (0.30 g, 12.4 mmol) is added to flame dried flask. 3-bromo-1,1,1-trifluoropropane (1.2 mL, 11.3 mmol) and tetrahydrofuran (11 mL) is added to the flask and refluxed with stirring for 2 hours. This material is used for the next reaction (Step-2).[0425] <Step-2>:methyl 6-(3,3,3-trifluoropropyl)nicotinate(3,3,3-trifluoropropyl)magnesium bromide (8.16 mL, 8.16 mmol, Step-1) is added to a solution of methyl 6-chloronicotinate (0.70 g, 4.08 mmol), iron(III) acetylacetonate (0.14 g, 0.41 mmol) and 1-methyl-2-pyrrolidinone (0.23 mL, 2.39 mmol) in tetrahydrofuran (23 mL) and stirred at room temperature for 30 minutes. The reaction mixture is poured into water, extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane / ethyl acetate (3:1) to give 0.95 g (99percent yield) of the title compound as a white solid.1H-NMR (300 MHz, CDCl3) delta 9.14 (1H, d, J = 2.2 Hz), 8.22 (1H, dd, J = 8.1, 2.2 Hz), 7.27 (1H, d, J = 8.1 Hz), 3.95 (3H, s), 3.13-3.08 (2H, m), 2.71-2.55 (2H, m), MS (ESI) m/z: 234 (M+H)+.
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 3h;Inert atmosphere; Sealed flask;
Example 20 Methyl 6-(4-(4-(2-fluorophenyl)-l-methyl-lH-l,2,3-triazol-5-yl)-lH-imidazol-l- yl)nicotinate A mixture of 4-(2-fluorophenyl)-5-(lH-imidazol-4-yl)-l-methyl-lH-l,2,3-triazole (233 mg,0.958 mmol), methyl 6-chloronicotinate (164 mg, 0.988 mmol) and potassium carbonate (265 mg, 1.92 mmol) in DMF (5.0 mL) was stirred under Ar in a sealed flask and heated at 120 °C for 3 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 50 to 100percent ethyl acetate in heptane) afforded the title compound (303 mg, 79percent) as a white solid. MS: m/e = 379.2 [M+H]+.
79%
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 3h;Inert atmosphere;
A mixture of 4-(2-fluorophenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-1,2,3-triazole (233 mg, 0.958 mmol), methyl 6-chloronicotinate (164 mg, 0.988 mmol) and potassium carbonate (265 mg, 1.92 mmol) in DMF (5.0 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 3 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 50 to 100percent ethyl acetate in heptane) afforded the title compound (303 mg, 79percent) as a white solid. MS: m/e=379.2 [M+H]+.
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 3h;Inert atmosphere; Sealed flask;
e) Methyl 6-(4-(4-(2-chlorophenyl)-l-methyl-lH-l,2,3-triazol-5-yl)-lH-imidazol-l- vPnicotinate A mixture of 4-(2-chlorophenyl)-5-(lH-imidazol-4-yl)-l-methyl-lH-l,2,3-triazole (322 mg, 1.24 mmol), methyl 6- chloronicotinate (213 mg, 1.24 mmol) and potassium carbonate (343 mg, 2.48 mmol) in DMF (7 mL) was stirred under Ar in a sealed flask and heated at 120 °C for 3 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 30 to 100percent ethyl acetate in heptane) afforded the title compound (370 mg, 76percent) as a white solid. MS: m/e = 395.1 [M+H]+.
76%
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 3h;Inert atmosphere; sealed flask;
A mixture of 4-(2-chlorophenyl)-5-(1H-imidazol-4-yl)-1-methyl-1H-1,2,3-triazole (322 mg, 1.24 mmol), methyl 6-chloronicotinate (213 mg, 1.24 mmol) and potassium carbonate (343 mg, 2.48 mmol) in DMF (7 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 3 h. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 30 to 100percent ethyl acetate in heptane) afforded the title compound (370 mg, 76percent) as a white solid. MS: m/e=395.1 [M+H]+.
Intermediate 596-(5-Methyl-1 H-1 ,2,3,4-tetrazoH -yl)pyridine-3-carboxylic acid To a solution of methyl 6-aminopyhdine-3-carboxylate (1 .52 g) in dichloromethane (10 mL) and pyridine (3 mL) is added acetic anhydride (2 g) and the solution is stirred at r.t. overnight. After concentration water and dichloromethane are added and the organic layer is separated, washed with saturated aqueous CuSO4, then water, dried over MgSO4 and concentrated. The N-acyl compound is dissolved in MeCN (20 mL) and sodium azide (4 g) and SiCI4 (4 mL) are added and the mixture is stirred at r.t. overnight. The reaction is quenched by slow addition to an ice/NaHCO3 mixture and extracted with ethyl acetate. The organic extracts are dried over MgSO4 and concentrated. The crude ester is dissolved in MeOH (30 mL) and 4 M NaOH (3 mL) is added and stirred at r.t. for 2 h. The mixture is neutralized to pH 7 with 6 M HCI, concentrated and then acidified with 6 M HCI and the precipitate is filtered off washing with water and dried by suction to give the title compound. LC (method 20): tR = 1 .52 min; Mass spectrum (APCI): m/z = 206 [M+H]+.
With sodium hydride; In tetrahydrofuran; mineral oil; at 20℃; for 2h;
Example 11 6-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid To a suspension of sodium hydride (55percent dispersion in mineral oil, 1.16 g, 26.5 mmol) in THF (30 mL) was added a solution of [3-(4-chloro-phenyl)-isoxazol-4-yl]-methanol (24.1 mmol) in THF (60 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (4.65 g, 26.5 mmol) in THF (60 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=4:1 to 2:1) afforded 6-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (72percent) which was obtained as a light yellow solid.
72%
To a suspension of sodium hydride (55percent dispersion in mineral oil, 1.16 g, 26.5 mmol) in THF (30 mL) was added a solution of [3-(4-chloro-phenyl)-isoxazol-4-yl]-methanol (24.1 mmol) in THF (60 mL) at 0 °C and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (4.65 g, 26.5 mmol) in THF (60 mL) was added dropwise at 0 °C and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (Si02, heptane:ethyl acetate = 4: 1 to 2: 1) afforded 6-[3-(4-Chloro-phenyl)-isoxazol-4-ylmethoxy]- nicotinic acid methyl ester (72percent) which was obtained as a light yellow solid.
With methylmagnesium chloride; In tetrahydrofuran; at 0 - 20℃; for 0.5h;
The methylmagnesium chloride (58.3ml, 174.8mmol) was added to a 1L 3-neck flash and diluted with 100ml THF and cooled to 0°C. The methyl 6-chloronicotinate, 33-a, (lOg, 58.3mmol) was dissolved in THF (50ml) and added dropwisely to the Grignard reagent. The reaction solution was stirred at room temperature for 30 mins while being monitored by TLC. The reaction mixture was poured into 500ml of IN HC1 and extracted with ether (2 x 200 mL). The combined organic extracts were washed with brine, dried with MgS04, and concentrated under vacuum to give 33-b (lOg, 100percent)
Step e: 6-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester To a suspension of sodium hydride (55percent dispersion in mineral oil, 852 mg, 20 mmol) in THF (27 mL) was added a solution of [3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (103 mg, 0.55 mmol) (3.68 g, 18 mmol) in THF (54 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (3.35 g, 20 mmol) in THF (1.5 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=7:3) afforded the title compound (81 mg, 47percent) which was obtained as a light yellow solid. MS: m/e=343.3 [M+H]+.
47%
To a suspension of sodium hydride (55percent dispersion in mineral oil, 852 mg, 20 mmol) in THF (27 mL) was added a solution of [3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (103 mg, 0.55 mmol) (3.68 g, 18 mmol) in THF (54 mL) at 0 °C and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (3.35 g, 20 mmol) in THF (1.5 mL) was added dropwise at 0 °C and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (Si02, heptane:ethyl acetate = 7:3) afforded the title compound (81 mg, 47percent) which was obtained as a light yellow solid. MS: m/e = 343.3 [M+H]+.
47%
Step e: 6- r3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxyl -nicotinic acid methyl ester: To a suspension of sodium hydride (55percent dispersion in mineral oil, 852 mg, 20 mmol) in THF (27 mL) was added a solution of [3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (103 mg, 0.55 mmol) (3.68 g, 18 mmol) in THF (54 mL) at 0 °C and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (3.35 g, 20 mmol) in THF (1.5 mL) was added dropwise at 0 °C and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (Si02, heptane:ethyl acetate = 7:3) afforded the title compound (81 mg, 47percent) which was obtained as a light yellow solid. MS: m/e = 343.3 [M+H]+.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium tetrahydroborate; N,N,N,N,-tetramethylethylenediamine; In tetrahydrofuran; at 25℃; for 2h;Inert atmosphere;
General procedure: PdCl2(dppf), PdCl2(tbpf) and (A.caPhos)PdCl2. A mixture of the halogenated heterocycle (0.66 mmol) in anhydrous THF (13.2 mL) was degassed by bubbling argon for few minutes. Then, PdCl2(dppf) (27.0 mg, 0.033 mmol, 5.0 molpercent), TMEDA (0.130 g, 1.12 mmol, 1.7 equiv) and finally NaBH4 (42.4 mg, 1.12 mmol, 1.7 equiv) were introduced in sequence. The mixture was stirred at room temperature under argon for the proper time and then worked up as described above.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 110℃;Inert atmosphere;
General procedure: To 1,4-dioxane (15 mL) were added chloro-substituted N-heterocycles(10.0 mmol), aromatic boronic acid (or pinacol ester, 12.0 mmol), Pd(dppf)Cl2 (0.73 g, 1.0mmol) and aqueous Cs2CO3 (2 N, 10 mL, 20.0 mmol) under N2 atmosphere. The content washeated and kept at 110 °C overnight. The reaction mixture was cooled to room temperature after the completion of the reaction. Dioxane was removed under reduced pressure. The resultant aqueous solution was extracted with EtOAc. The combined organic phase was washed with water and saturated brine for three times, and dried over Na2SO4. After the removal of the solvent under reduced pressure, the residue was charged to flash chromatography, which gave the pure product.
methyl 6-(thiazol-4-ylmethoxy)nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22%
Preparation of Compound 93, methyl 6-(thiazol-4-ylmethoxy)nicotinate[00114] 4-(Hydroxymethyl)-1 ,3-thiazole (0.187 mL, 2.17 mmol) was added to a suspension of NaH (60%, 0.054 g, 2.3 mmol) in dry THF (6 mL) at 0 C. After a few minutes, the reaction mixture was allowed to warm to rt, stirred for 20 min before methyl 6-chloropyridine-3-carboxylate (0.339 g, 1 .97 mmol) was added and the reaction mixture was heated at reflux for 4.5 h, cooled, concentrated, added water and saturated NaHC03. The mixture was extracted with DCM (3x). The organic phase was dried (Na2S04), filtered and concentrated. The crude material was purified by silica gel column chromatography using a gradient of 20 to 25% EtOAc in PE to afford the title compound (106 mg, 22%) as a white solid.1H NMR (500 MHz, CDCl3) delta 8.87-8.84 (m, 2H), 8.18 (dd, J = 8.7, 2.4 Hz, 1 H), 7.43 (dd, J = 1 .9, 0.9 Hz, 1 H), 6.86 (dd, J = 8.5, 0.8 Hz, 1 H), 5.64 (d, J = 0.7 Hz, 2H), 3.91 (s, 3H). HRMS (ESI+): calcd for C11H11N2O3S (M + H)+, 251 .0485; found 251 .0487.
6-chloronicotinic acid methyl ester (10.0g, 58.3mmol) was dissolved in 10mL 52 methanol to get light yellow solution, the 14 methylamine (2.7g, 87.5mmol) in 53 water solution was added dropwise at 0-5C under stirring. The mixture was stirred at room temperature for 4h, and then concentrated in vacuum. Finally, 54 ethyl acetate (100mL) was added, and the resulting mixture was stirred at room temperature. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give light yellow crystalline (2) 9.4g, yield: 99.1%, mp: 145-146C. 1H NMR (DMSO-d6, 400MHz): delta 2.75 (d, J=4.5Hz, 3H), 6.89 (d, J=8.8Hz, 1H), 8.16 (dd, J=8.7, 2.4Hz, 1H), 8.46 (br d, J=4.4Hz, 1H), 8.57 (d, J=2.3Hz, 1H). ESI-MS m/z 171.1 [M+H]+; Anal. Calcd for (C7H7ClN2O FW: 170.5); C, 49.28; H, 4.14; Cl, 20.78; N, 16.42. Found: C, 49.24; H, 4.16; Cl, 20.79; N, 16.43.
tert-butyl 4-(5-(methoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96.7%
With triethylamine; In N,N-dimethyl-formamide; at 80℃; for 14h;
A stirred solution of 1-Boc piperazine (9.5g, 51.28 mmol, Symax fine chemicals) in dry DMF (80 mL), TEA (12.9 mL, 93.24 mmol) and methyl 6-chloronicotinate (8 g, 46.62 mmol, combi block chemicals) were added. The reaction mixture was stirred at 80 °C for 14 h.The resulting reaction mixture was cooled to rt and poured in to water (100 mL). The formed precipitate was filtered to afford the title product. Yield: 96.7percent (14.5 g, off white solid). 1H NMR (400 MHz, DMSO-d6): 68.66 (d, J = 2.2 Hz, IH), 7.97 (dd, J = 9.1, 2.4 Hz, IH), 6.88 (d, J = 9.1 Hz, IH), 3.79 (5, 3H), 3.66 (t, J = 4.7 Hz, 4H), 3.43 (t, J = 5.2 Hz, 4H), 1.43 (5, 9H). LCMS: (Method A) 322.3 (M +H), Rt. 2.42 mm, 99.42percent (Max).
96.7%
With triethylamine; In N,N-dimethyl-formamide; at 80℃; for 14h;
A stirred solution of 1-Boc piperazine (9.5g, 51.28 mmol, Symax fine chemicals) in dry DMF (80 mL), TEA (12.9 mL, 93.24 mmol) and methyl 6-chloronicotinate (8 g, 46.62 mmol, combi block chemicals) were added. The reaction mixture was stirred at 80 °C for 14 h. The resulting reaction mixture was cooled to rt and poured in to water (100 mL). The formed precipitate was filtered to afford the title product. Yield: 96.7percent (14.5 g, off white solid). 1H NMR (400 MHz, DMSO-d6): delta 8.66 (d, J = 2.2 Hz, 1 H), 7.97 (dd, J = 9.1, 2.4 Hz, 1 H), 6.88 (d, J = 9.1 Hz, 1 H), 3.79 (s, 3H), 3.66 (t, J = 4.7 Hz, 4H), 3.43 (t, J = 5.2 Hz, 4H), 1.43 (s, 9H). LCMS: (Method A) 322.3 (M +H), Rt. 2.42 min, 99.42percent (Max).
91%
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 95℃;Inert atmosphere;
A mixture of methyl 6-chloronicotinate (1.7 g, 10 mmol), tert-butyl piperazine-1-carboxylate (5.58 g, 30 mmol), DIPEA (6.45 g, 50 mmol) in 1,4-dioxane (30 mE) was stirred at 95° C. under N2 atmosphere for overnight. The mixture was cool and EA (100 mE) and water (100 mE) were added, stirred for 30 mm, the organic layer was separated, dried, concentrated to get a residue, which was washed by PE (100 mE) to obtain compound 2 (2.9 g, 91percent) as a light yellow solid.
54%
With dmap; potassium carbonate; In N,N-dimethyl-formamide; at 20 - 80℃; for 0.5h;Microwave irradiation;
To a stirred solution of methyl6-chloropyridine-3-carboxylate (500 mg, 2.91 mmol) in DMF(5 mL), tert-butyl piperazine-1-carboxylate (720 mg, 3.87 mmol), K2C03 (1.2 g, 8.74 mmol)and DMAP (35 mg, 0.29 mmol) were added at RT. The reaction mixture was heated in aCEM microwave at 80 °C for 30 min (TLC showed the complete consumption of startingmaterial) and diluted with water (20 mL) during which solid was precipitated out. The solidwas filtered and dissolved in EtOAc (50 mL), dried over Na2S04, concentrated under reducedpressure to give the crude compound which was purified by flash chromatography (100-200silica gel, 5 g, 30percent EtOAc-Hexane) to afford tert-butyl4-(5-methoxycarbonyl-2-pyridyl)piperazine-1-carboxylate (510 mg, 54percent) as a white solid.LCMS: m/z: 322.63 [M+Ht.
With dmap; potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 24h;
A solution of compound 11 (0.5 g, 0.003 mol) and 1-boc-piperazine (0.5 g, 0.004 mol) in DMF was added potassium carbonate (1.242 g,0.009 mol) and 10percent DMAP. The reaction mixture was heated to 100°C and stirred for 24 hours. The mixture was poured into water and extracted with ethyl acetate, dried over sodium sulfate.The mixture was filtered, the filtrate was concentrated in vacuum and chromatographed on a silica gel column, eluted with petroleum ether /ethyl acetate (5:1-3:1,V/V)) to give compound 12 as a white solid.
methyl 6-[2-(trifluoromethyl)morpholin-4-yl]nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
11%
With potassium carbonate In acetonitrile at 60℃; for 20h;
19.A Methyl 6-[2-(trifluoromethyl)morpholin-4-yl]nicotinate
250 mg (1.5 mmol) of methyl 6-chioronicotinate were initially charged in 3 ml of acetonitrile, 705 mg (5.1 mmol) of potassium carbonate and 331 mg (2.2 mmol) of 2-(trifluoromethyl)morpholine hydrochloride (1:1) were added and the mixture was stirred at 60° C. for 20 h. Water was then added, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulphate, filtered and concentrated. The crude product was purified on silica gel (mobile phase: cyclohexane/ethyl acetate 8:1-5:1). This gave 47 mg (11% of theory) of product. LC-MS [Method 1]: Rt=1.02 mm; MS (ESIpos):mlz=291 (M+H)
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 2h;
Step 1: Compound 250-2 (1.14 g, 10 mmol) was added into a solution of compound 250-1 (1.71 g, 10 mmol) and K2CO3 (2.78 g, 20 mmol) in DMF (20 mL), the reaction mixture was stirred at 110°C for 2h, monitored by LCMS till completion. Then the mixture was poured into H2O, extracted with EtOAc, the organic phase was dried over anhydrous sodium sulfate, concentrated to give a crude product. The crude product was purified by silica gel column chromatography (PE:EtOAc=1:1) to deliver compound 250-3 (2.3 g, yield 92percent) as oil. MS ESI calcd for C13H19N3O2[M+H]+ 250, found 250.
methyl 6-[3-(trifluoromethoxy)phenoxy]pyridine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 5h;
General procedure: A mixture of 2-chloro-5-(trifluoromethyl)pyridine (5.45 g,30 mmol), ethyl 3-hydroxybenzoate (5.5 g, 33 mmol), K2CO3(4.98 g, 36 mmol) and DMF (20 mL) was stirred at 100 C for 5 h.After cooling to room temperature, the reaction mixture wasdiluted with water and extracted with AcOEt. The organic layerwas washed with brine, dried over Na2SO4 and concentrated invacuo. The resulting residue was purified by silica gel chromatography(hexane-AcOEt) to give 10a
methyl 6-{methyl[4-(trifluoromethoxy)phenyl]amino}pyridine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%
With acetic acid; at 180℃; for 0.5h;Microwave irradiation;
Step A: A mixture of methyl 6-chloronicotinate (0.34 g,2.0 mmol), N-methyl-p-trifluoromethoxyaniline (0.38 g, 2.0 mmol)and acetic acid (3.0 mL) was heated at 180 C with microwaveassistancefor 30 min with stirring. After cooling to room temperature,the mixture was diluted with 1 M NaOH aq. and extractedwith AcOEt. The organic layer was washed with brine, dried overNa2SO4 and concentrated in vacuo. The resulting residue was purifiedby silica gel chromatography (hexane-AcOEt) to give methyl6-{methyl[4-(trifluoromethoxy)phenyl]amino}pyridine-3-carboxylate(0.066 g, 10%) as a colorless solid. 1H NMR (CDCl3) d: 8.88 (1H,d, J = 2.3 Hz), 7.91 (1H, dd, J = 9.0, 2.3 Hz), 7.31 (4H, s), 6.44 (1H, dd,J = 9.0, 0.8 Hz), 3.88 (3H, s), 3.53 (3H, s). MS (ESI+) m/z: 327 (M+H)+.
With methylamine; In methanol; at 0 - 20℃; for 4h;
A mixture of 6-chloronicotinic acid methyl ester(10.0 g, 58.3 mmol) was dissolved in 10 mL of methanol and stirred to form a pale yellow solution. A 40% aqueous solution of methylamine (2.7 g, 87.5 mmol) was added dropwise at 0 C, and the reaction was carried out at room temperature for 4 h The The filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, crystallized, filtered and dried to give 9.4 g of pale yellow crystals, and the residue was washed with water, Yield 99.1%. Murho: 140-142 C.
With tert-butylhypochlorite; sodium carbonate; sodium chloride; In dichloromethane; at 100℃; for 20h;Schlenk technique;
Weighing 5-methylpyridine-2-carboxylic acid (54.3 mg, 0.3 mmol),Sodium carbonate (64.0 mg, 0.6 mmol), NaCl (17.6 mg, 0.3 mmol), tert-butyl hypochlorite (32 muL, 0.3 mmol) into a 25 mL of Schlenk reaction bottle, Then add CH2Cl2 (1mL) in a 100 C oil bath for 20h reaction. After completion of the reaction, the solvent was removed under reduced pressure and eluted with petroleum ether / ethyl acetate.The solvent was separated on a silica gel column, The yield of 2-chloro-3-nitropyridine was 30%.
methyl 6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-2-yl)pyridine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.76 g
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane for 24h; Reflux; Inert atmosphere;
35 Reference Example 35
A mixture of 1,2,3,4-tetrahydroisoquinolin-1-one (1.0 g), 1,4-dioxane (10.0 mL), methyl 6-chloronicotinate (1.39 g), Pd2(dba)3 (0.124 g), xantphos (0.197 g), and Cs2CO (2.88 g) was stirred for 1 day under heating to reflux under nitrogen atmosphere. After cooled to room temperature, water was added to the reaction solution and the mixture was extracted with AcOEt. The organic layer was dried over anhydrous Na2SO , and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane/AcOEt) to give methyl 6-( 1 -oxo- 1,2,3 ,4-tetrahydroisoquinolin-2-yl)pyridine-3-carboxylate (1.76 g).
methyl 6-(2,4-dioxo-1,3,8-triazaspiro[4.5]decan-8-yl)nicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 16h;
General procedure: To a suspension of l ,3,8~triazaspiro[4.5]decane-2,4-dione (CAS 13625-39-3, 20 mg, 1 18 mhio, eq. 1) and DIPEA (45.8 mg, 61.9 m, 355 pmol, eq. 3) in AVV-dimethylformamide (0.5 ml) was added 2-chlorobenzo[d]thiazole (22.1 mg, 130 mtho, eq 1.1) The reaction mixture was stirred at 120 C for 2 hours. The reaction mixture was poured into a mixture of ethylacetate/tetrahydrofuran (1 : 1) and the organic layer was washed with water and brine, dried over NazSCri and concentrated in vacuo. The crude material was purified by flash column chromatography (silica gel, eluent: 0 to 5% of methanol in dichloromethane) to afford 8- (benzo[d]thi azol-2-yl)- 1 ,3 , 8-tri azaspiro[4.5]decane-2,4-di one (11 mg, 36.4 mtho, 30.8 %) as a white solid. MS (ISP): 303.1 {I M 1 1 | }.
6-chloro-N-(5-cyano-4-phenylthiazol-2-yl) nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95.5%
With caesium carbonate
Intermediate 20: 6-chloro-N-(5-cyano-4-phenylthiazol-2-yl) nicotinamide
Intermediate 20: 6-chloro-N-(5-cyano-4-phenylthiazol-2-yl) nicotinamide A solution of 0.300 g (1.50 mmol) of 2-amino-4-phenylthiazole-5-carbonitrile, 0.281 g (0.64 mmol) of methyl 6-chloronicotinate and 0.583 g (1.79 mmol) of cesium carbonate in 0.8 mL of DMF is stirred at 60° C. for two days. Then, the reaction mixture is poured into cold water, the precipitate forming is filtered under vacuum. The solid obtained is washed twice with water and dried to obtain 0.485 g (95.50%) of the desired nicotinamide derivative. 1H-NMR (400 MHz, DMSO-d6): δ=13.84 (s, 1H), 9.10 (d, J=2.5 Hz, 1H), 8.50 (dd, J=8.4, 2.6 Hz, 1H), 8.04 (dd, J=8.2, 1.4 Hz, 2H), 7.76 (d, J=8.4 Hz, 1H), 7.58 (m, 3H). HPLC-MS: Rt 3.173, m/z 341.0 (MH+).
With potassium carbonate; In N,N-dimethyl acetamide; at 100℃;
Methyl 6-chloronicotinate (23, 5.56 g), <strong>[138007-24-6]ter<strong>[138007-24-6]t-butyl piperidine-4-carboxylate</strong></strong>(5.50 g), dipotassium carbonate (11.2 g), and N,N-dimethylformamide(80 mL) were mixed, followed by stirring at 100 Covernight. The mixture was cooled to room temperature and dilutedwith ethyl acetate. The insoluble materials were separated by filtrationand the filtrate was washed with water and a saturated aqueous sodiumchloride solution, and dried over anhydrous magnesium sulfate. Theinsoluble materials were separated by filtration and the filtrate wasconcentrated under reduced pressure. The obtained solid was washedwith diisopropyl ether and dried to obtain a white solid (7.97 g).
With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride; potassium <i>tert</i>-butylate In 1,2-dimethoxyethane Inert atmosphere; Heating;
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