* 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 Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1990, # 9, p. 2409 - 2415
2
[ 131674-39-0 ]
[ 55676-21-6 ]
Yield
Reaction Conditions
Operation in experiment
81%
With chromium(VI) oxide In acetone at -30 - 20℃; for 3 h;
Step 2: 1-(2-Chloropyridin-3-yl)ethanone A solution of 1-(2-chloropyridin-3-yl)ethanone (10 g, 0.0635 mol) in dry acetone (200 mL) was introduced under argon into a 1 L flask. The mixture was cooled to -30° C. and pure, pulverized chromic anhydride (19 g, 0.19 mol) was added. The reaction mixture was kept at room temperature for 3 h. 2-Propanol (100 mL) was added, followed by aqueous sodium hydrogen carbonate to pH 8. After filtration, solids were washed with chloroform. The organic and aqueous layers were then separated and the aqueous layer was extracted with chloroform (2*100 mL). The combined organics were dried over anhydrous sodium sulfate and evaporated to yield the crude pyridyl ketone as an oil. This product was purified by column chromatography (8 g, 81percent). *1H NMR (CDCl3) 8.44 (dd, J=5 and 2 Hz, 1H) 7.91 (dd, J=7.5 and 2 Hz, 1H), 7.34 (dd, J=7.5 and 5 Hz, 1H), 2.68 (s, 3H).
81%
With chromium(VI) oxide In acetone at -30 - 20℃; for 3 h; Inert atmosphere
Step 2: l-(2-Chloropyridin-3-yl)ethanone.A solution of l-(2-chloropyridin-3-yl)ethanone (1O g, 0.0635 mol) in dry acetone (200 mL) was introduced under argon into a 1 L flask. The mixture was cooled to -30 0C and pure, pulverized chromic anhydride (19 g, 0.19 mol) was added. The reaction mixture was kept at room temperature for 3 h. 2-Propanol (100 mL) was added, followed by aqueous sodium hydrogen carbonate to pH 8. After filtration, solids were washed with chloroform. The organic and aqueous layers were then separated and the aqueous layer was extracted with chloroform (2x10OmL). The combined organics were dried over anhydrous sodium sulfate and evaporated to yield the crude pyridyl ketone as an oil. This product was purified by column chromatography (8 g, 81percent). *1H NMR (CDCl3) 8.44 (dd, J = 5 and 2 Hz, 1 H) 7.91 (dd, J = 7.5 and 2 Hz, 1 H), 7.34 (dd, J = 7.5 and 5 Hz, 1 H), 2.68 (s, 3 H).
77%
With chromium(VI) oxide In acetone at -30 - 20℃; for 3.25 h; Inert atmosphere
Step 2[00176] To a solution of l-(2-chloropyridin-3-yl)ethanol (II) in dry acetone at - 30°C under nitrogen was added in portions chromium (VI) oxide (1.80 g, 18 mmol). The solution was further stirred 15 min at -30°C and allowed to warm to room temperature. The solution was stirred for 3 h at room temperature before adding isopropanol (10 mL). The solution was made alkaline by slowly adding a saturated NaHC03 solution. The solution was filtered through a bed of Celite. The solids were washed by DCM. The organic phase of the filtrate was separated and the aqueous phase extracted with DCM (2 x 50 mL). The combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure to yield l-(2-chloropyridin-3-yl)ethanone (III) as a brown liquid (0.72 g, 4.63 mmol, 77percent yield). 1H NMR (CDC13) δ ppm 2.71 (s, 3 H), 7.35 (dd, J=7.63, 4.80 Hz, 1 H), 7.91 (dd, J=7.54, 1.88 Hz, 1 H), 8.55 (dd, J=4.71, 1.88 Hz, 1 H).
77%
With chromium(VI) oxide In acetone at -30 - 20℃; for 3.25 h; Inert atmosphere
To a solution of 1-(2-chloropyridin-3-yl)ethanol (XII) in dry acetone at −30° C. under nitrogen was added in portions chromium (VI) oxide (1.80 g, 18 mmol). The solution was further stirred 15 min at −30° C. and allowed to warm to room temperature. The solution was stirred for 3 h at room temperature before adding isopropanol (10 mL). The solution was made alkaline by slowly adding a saturated aqueous NaHCO3 solution. The solution was filtered through a bed of Celite. The solids were washed by DCM. The organic phase of the filtrate was separated and the aqueous phase extracted with DCM (2×50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to yield 1-(2-chloropyridin-3-yl)ethanone (XIII) as a brown liquid (0.72 g, 4.63 mmol, 77percent yield). 1H NMR (CDCl3) δ ppm 2.71 (s, 3H), 7.35 (dd, J=7.63 Hz, J=4.80 Hz, 1H), 7.91 (dd, J=7.54 Hz, J=1.88 Hz, 1H), 8.55 (dd, J=4.71 Hz, J=1.88 Hz, 1H).
77%
With chromium(VI) oxide In acetone at -30 - 20℃; for 3.25 h; Inert atmosphere
Step 2 To a solution of 1-(2-chloropyridin-3-yl)ethanol (X) in dry acetone at -30° C. under nitrogen was added in portions chromium (VI) oxide (1.80 g, 18 mmol). The solution was further stirred 15 min at -30° C. and allowed to warm to room temperature. The solution was stirred for 3 h at room temperature before adding isopropanol (10 mL). The solution was made alkaline by slowly adding a saturated aqueous NaHCO3 solution. The solution was filtered through a bed of Celite. The solids were washed by DCM. The organic phase of the filtrate was separated and the aqueous phase extracted with DCM (2*50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to yield 1-(2-chloropyridin-3-yl)ethanone (XI) as a brown liquid (0.72 g, 4.63 mmol, 77percent yield). 1H NMR (CDCl3) δ ppm 2.71 (s, 3H), 7.35 (dd, J=7.63 Hz, J=4.80 Hz, 1H), 7.91 (dd, J=7.54 Hz, J=1.88 Hz, 1H), 8.55 (dd, J=4.71 Hz, J=1.88 Hz, 1H).
77%
With chromium(VI) oxide In acetone at -30 - 20℃; for 3.25 h;
To a solution of 1-(2-chloropyridin-3-yl)ethanol (X) in dry acetone at -30°C under nitrogen was added in portions chromium (VI) oxide (1.80 g, 18 mmol). The solution was further stirred 15 min at -30°C and allowed to warm to room temperature. The solution was stirred for 3 h at room temperature before adding isopropanol (10 mL). The solution was made alkaline by slowly adding a saturated aqueous NaHCCb solution. The solution was filtered through a bed of Celite. The solids were washed by DCM. The organic phase of the filtrate was separated and the aqueous phase extracted with DCM (2 x 50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to yield 1 -(2-chloropyridin-3 -yl)ethanone (XI) as a brown liquid (0.72 g, 4.63 mmol, 77percent yield). 1H NMR (CDCl3) δ ppm 2.71 (s, 3H), 7.35 (dd, J=7.63Hz, J=4.80Hz, 1H), 7.91 (dd, J=7.54Hz, J=1.88Hz, 1H), 8.55 (dd, J=4.71Hz, J=1.88Hz, 1H).
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1990, # 9, p. 2409 - 2415
[2] Patent: US2006/47126, 2006, A1, . Location in patent: Page/Page column 30
[3] Patent: WO2011/5759, 2011, A2, . Location in patent: Page/Page column 77
[4] Patent: WO2011/84486, 2011, A1, . Location in patent: Page/Page column 106; 110-111
[5] Patent: US2013/296302, 2013, A1, . Location in patent: Paragraph 0494
[6] Patent: US2016/68550, 2016, A1, . Location in patent: Paragraph 1056
[7] Patent: WO2016/40193, 2016, A1, . Location in patent: Paragraph 0703
[8] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1990, # 9, p. 2409 - 2415
3
[ 488149-34-4 ]
[ 676-58-4 ]
[ 55676-21-6 ]
Yield
Reaction Conditions
Operation in experiment
72%
Stage #1: at 0℃; for 1 h; Stage #2: With water In tetrahydrofuran
A solution of 2-chloro-N-methoxy-N-methyl-nicotinamide (23.6 g, 118 mmol) in tetrahydrofuran (350 mL, 0.34M) at 0° C. was treated dropwise via an addition funnel with methyl magnesium chloride (3.0M solution in tetrahydrofuran, 100 mL, 300 mmol). The reaction became a very thick opaque white mixture and was diluted with additional tetrahydrofuran (150 mL). The reaction was stirred at 0° C. for 1 h. At this time, the reaction was carefully quenched with water (250 mL) and then partitioned between additional water (250 mL) and ethyl acetate (250 mL). The aqueous layer was back extracted with ethyl acetate (2*250 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (250 mL), dried over magnesium sulfate, filtered, rinsed with ethyl acetate, and concentrated in vacuo. Flash chromatography (AnaLogix Intelliflash 280, 400 g silica gel column, 25-50percent ethyl acetate/hexanes) afforded 1-(2-chloro-pyridin-3-yl)-ethanone (13.17 g, 72percent) as a yellow oil.
Stage #1: at 0℃; for 0.5 h; Inert atmosphere Stage #2: With ammonium chloride In tetrahydrofuranInert atmosphere
General procedure: Methylmagnesium chloride (0.5 M in THF, 8.0 mL, 4.0 mmol) was added to a solution of 2-pyridyl 2-chloropyridine-3-carboxylate (2c, 939 mg, 4.0 mmol) in THF (12 mL) at 0 °C under argon atmosphere. After stirring for 0.5 h, the mixture was quenched with saturated NH4Cl solution (5 mL) and THF was evaporated in vacuo. The mixture was poured into saturated NH4Cl solution (30 mL) and extracted with dichloromethane (3 × 20 mL). The combined organic phases were dried overanhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by vacuum distillation using a Kugelrohr apparatus to give 3c (566 mg, 91percent).
Reference：
[1] Bulletin of the Korean Chemical Society, 2013, vol. 34, # 4, p. 1253 - 1256
5
[ 488149-34-4 ]
[ 917-54-4 ]
[ 55676-21-6 ]
Yield
Reaction Conditions
Operation in experiment
90%
at 0℃; for 1 h;
To a solution of 2 (473 mg, 3.0 mmol) in THF (8 mL) was added phenylethynyllithium, generated from phenylacetylene (306 mg, 3.0 mmol) and methyllithium (1.5 M in Et2O, 2.0 mL, 3.0 mmol) for 0.5 h at 0 C, or methyllithium (1.5 M in Et2O, 2.0 mL, 3.0 mmol) at 0 C. After being stirred for 0.5 h, the mixture was quenched with 0.5 N HCl (5 mL) and THF was evaporated in vacuo. The mixture was poured into 0.1 N HCl (30 mL) and extracted with dichloromethane(3 × 20 mL). The condensed residue was purified by silicagel column chromatography using 30percent EtOAc/n-hexane or vacuum distillation using a Kugelrohr apparatus to give 3a (616 mg, 85percent) and 6 (420 mg, 90percent), respectively.
90%
for 0.5 h;
Phenylacetylene (306 mg, 3.0 mmol) and methyl lithium (1.5 M in Et2O, 2.0 mL, 3.0 mmol) were reacted at 0 C for 0.5 hour Was added to a solution of compound 2 (473 mg, 3.0 mmol) in THF (8 mL). For 0.5 hours After mixing, the reaction was quenched by the addition of 0.5 N HCl (5 mL) and THF to the mixture and evaporated in vacuo. evaporation The resulting mixture was taken up in 0.1 N HCl (30 mL) and extracted with dichloromethane (3 x 20 mL). The concentrated residue was dissolved in 30percent The residue was purified by silica gel column chromatography using EtOAc / n-hexane as an extraction solvent to obtain Compound 3a (616 mg, 85percent) Respectively. Also, methyllithium (1.5 M in Et2O, 2.0 mL, 3.0 mmol) was added to a solution of compound 2 (473 mg, 3.0 mmol). After mixing for 0.5 h, the reaction was stopped by adding 0.5 N HCl (5 mL) to the mixture THF was evaporated in vacuo. The evaporated mixture was poured into 0.1 N HCl (30 mL) and added with dichloromethane (3 x 20 mL) . The concentrated residue was vacuum distilled using a Kugelrohr distillation column to yield compound 6 (420 mg, 90percent).
Reference：
[1] Bulletin of the Korean Chemical Society, 2015, vol. 36, # 7, p. 1908 - 1911
[2] Patent: KR101766414, 2017, B1, . Location in patent: Paragraph 0078; 0079; 0081
After diluting the product in step b) with the appropriate amount of dry toluene,Slowly added to the stirred solution of step a) at room temperature.After stirring for 40 min, the solution was concentrated with concentrated HCl (261 g, 2.32 mol).The toluene layer was evaporated and cooled to give a pale yellow solid.To this solid was added DMSO (650 ml) and water (29 ml).The mixture was heated and maintained at 155 ° C for 3 hours and then heated until the reaction solution was cooled and poured into 2.5 L of cold water,A large amount of off-white solid precipitated, filtered and dried.To give 96 g of product 2-chloro-3-acetylpyridine in 72percent yield.
56%
With hydrogenchloride; water In dimethyl sulfoxide at 130℃; for 2 h;
Water (1.3 mL) was added to a solution of diethyl 2-(2-chloronicotinoyl)malonate (31.7 mmol) in dimethylsulfoxide (50 mL). The pH of the reaction mixture was added adjusted to 5-6 by the addition of hydrochloric acid and the reaction mixture was heated at 130° C. for 2 h. The reaction mixture was then quenched with ice water (300 mL) and the aqueous layer was extracted with ethyl acetate (3*50 mL). The combined organic layers were washed with brine, dried (sodium sulfate), and concentrated. The residue was purified by chromatography (1/20 ethyl acetate/petroleum ether to provide 1-(2-chloropyridin-3-yl)ethanone in 56percent yield as light yellow oil.
52%
With water In dimethyl sulfoxide at 130℃; for 3.5 h;
A solution of diethyl 2-(2-chloronicotinoyl)malonate (267 mmol) in dimethylsulfoxide (100 ml) was added dropwise over 1.5 h to a 130° C. solution of water (10 mL) in dimethylsulfoxide (260 mL). The reaction mixture was maintained at 130° C. for an additional 2 h and was allowed to cool to rt. The reaction mixture was diluted with cold (0° C.) water (500 mL) and was extracted with ethyl acetate (3*200 mL). The combined organic layers were washed with brine (5*200 mL), dried (sodium sulfate), and concentrated. The residue was purified by chromatography (10/1 petroleum ether/ethyl acetate) to provide 1-(2-chloropyridin-3-yl)ethanone 52percent yield as yellow oil.
Reference：
[1] Patent: CN106946770, 2017, A, . Location in patent: Paragraph 0070
[2] Patent: US2007/78147, 2007, A1, . Location in patent: Page/Page column 75
[3] Patent: US2007/78147, 2007, A1, . Location in patent: Page/Page column 73
[4] Patent: WO2005/61476, 2005, A2, . Location in patent: Page/Page column 89
8
[ 2942-59-8 ]
[ 75-16-1 ]
[ 55676-21-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 18, p. 7577 - 7589
[2] Patent: WO2011/79804, 2011, A1, . Location in patent: Page/Page column 24
[3] Patent: US2012/245178, 2012, A1, . Location in patent: Page/Page column 13
9
[ 49609-84-9 ]
[ 2942-59-8 ]
[ 79-37-8 ]
[ 594-27-4 ]
[ 144-55-8 ]
[ 55676-21-6 ]
Reference：
[1] Patent: US5688795, 1997, A,
10
[ 488149-34-4 ]
[ 75-16-1 ]
[ 55676-21-6 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 57, p. 311 - 322
[2] Patent: WO2016/132134, 2016, A1, . Location in patent: Page/Page column 74
11
[ 14188-94-4 ]
[ 55676-21-6 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2010, vol. 8, # 22, p. 5166 - 5173
[2] Canadian Journal of Chemistry, 1988, vol. 66, # 3, p. 420-428
12
[ 40134-18-7 ]
[ 75-16-1 ]
[ 55676-21-6 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1999, vol. 36, # 2, p. 445 - 452
13
[ 2942-59-8 ]
[ 55676-21-6 ]
Reference：
[1] ACS Medicinal Chemistry Letters, 2012, vol. 3, # 9, p. 764 - 768
[2] Patent: US2012/258982, 2012, A1,
[3] European Journal of Medicinal Chemistry, 2012, vol. 57, p. 311 - 322
[4] Bulletin of the Korean Chemical Society, 2013, vol. 34, # 4, p. 1253 - 1256
[5] Bulletin of the Korean Chemical Society, 2015, vol. 36, # 7, p. 1908 - 1911
[6] Patent: WO2006/123145, 2006, A1,
[7] Patent: WO2016/132134, 2016, A1,
[8] Patent: KR101766414, 2017, B1,
14
[ 6602-54-6 ]
[ 676-58-4 ]
[ 55676-21-6 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2010, vol. 8, # 22, p. 5166 - 5173
15
[ 109-09-1 ]
[ 55676-21-6 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1990, # 9, p. 2409 - 2415
[2] Patent: WO2011/5759, 2011, A2,
[3] Patent: WO2011/84486, 2011, A1,
[4] Patent: US2013/296302, 2013, A1,
[5] Patent: US2016/68550, 2016, A1,
[6] Patent: WO2016/40193, 2016, A1,
Reference：
[1] Canadian Journal of Chemistry, 1988, vol. 66, # 3, p. 420-428
18
[ 55676-21-6 ]
[ 65326-33-2 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1990, # 9, p. 2409 - 2415
19
[ 55676-21-6 ]
[ 124-41-4 ]
[ 131674-40-3 ]
Yield
Reaction Conditions
Operation in experiment
53%
for 4 h; Inert atmosphere
Sodium methoxide (0.065 g, 1.2 mmol) and 1-(2-chloropyridin-3-yl)ethanone (0.063 gm, 0.4 mmol) were stirred in anhydrous methanol (1.5 mL) in a 7 mL vial under a nitrogen atmosphere for 4 hours. The reaction was cooled to room temperature and 0.5 mL of H2O was added. The mixture was concentratedon a rotary evaporator to remove methanol and the resulting aqueous mixture was partitioned between dichloromethane (20 mL) and water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to provide the crude product as an orange oil (0.032 g, 53percent yield), which was used without further purification. 1H-NMR (CDCl3) δ 8.33 (dd, J = 4.8 and 2.0 Hz, 1H),8.13 (dd, J = 7.5 and 2.0 Hz, 1H), 7.00 (dd, J = 7.5 and 4.8 Hz, 1H), 4.08 (s,3H), 2.67 (s, 3H). MS (ESI+): m/z (M+H)+ = 152.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 17, p. 5352 - 5359
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1990, # 9, p. 2409 - 2415
[3] Patent: WO2015/187934, 2015, A1, . Location in patent: Paragraph 0218
20
[ 55676-21-6 ]
[ 116834-96-9 ]
Yield
Reaction Conditions
Operation in experiment
85%
With hydrazine In ethanol for 12 h; Heating / reflux
Step 3: 3-Methyl-1H-pyrazolo[3,4b]pyridine A solution of 1-(2-chloropyridin-3-yl)ethanone (22 g, 0.1415 mol) and hydrazine hydrate 98percent (113 g, 2.21 mol) in ethanol (300 mL) was refluxed for 12 h. About 80percent of the ethanol was distilled off under reduced pressure using a rotary evaporator. The residue was allowed to come to room temperature. The precipitated solid was filtered and washed with water. The product was dried at 90° C. to constant weight (16 g, 85percent) mp 152-154° C. 1H NMR (CDCl3) 8.62 (dd, J=4.5 and 1.4 Hz, 1H), 8.08 (dd, J=8.0 and 1.4 Hz, 1H), 7.15 (dd J=8.0 and 4.5 Hz, 1H), 2.64 (s, 3H). MS (FAB) m/z: 133 (M++1).
85%
With hydrazine hydrate In ethanol for 12 h; Reflux
Step 3: 3-Methyl-lH-pyrazolo[3,4b]pyridine. A solution of l-(2-chloropyridin-3-yl)ethanone (22 g, 0.1415 mol) and hydrazine hydrate 98percent (113 g, 2.21 mol) in ethanol (300 mL) was refluxed for 12 h. About 80percent of the ethanol was distilled off under reduced pressure using a rotary evaporator. The residue was allowed to come to room temperature. The precipitated solid was filtered and washed with water. The product was dried at 90 0C to constant weight (16 g, 85percent) mp 152-154 0C. 1H NMR (CDCl3) 8.62 (dd, J = 4.5 and 1.4 Hz, 1 H), 8.08 (dd, J = 8.0 and 1.4 Hz, 1 H), 7.15 (dd J = 8.0 and 4.5 Hz, 1 H), 2.64 (s, 3 H). MS (FAB) m/z: 133 (M+ +1).
72%
With hydrazine hydrate In butan-1-olReflux
Step 3[00177] To a solution of l-(2-Chloropyridin-3-yl)ethanone (III) (0.311 g, 2 mmol) in n-butanol (10 mL) was added hydrazine hydrate (1.45 mL, 30 mmol). The reaction was refluxed overnight. The solution was cooled and the solvent was evaporated under vacuum. The residue was dissolved in DCM and washed successively by water and brine. The organic layers were dried over MgS04, filtered and concentrated under reduced pressure to give 3-methyl-lH-pyrazolo[3,4-.pound.]pyridine (IV) as a white solid (192 mg, 1.44 mmol, 72percent yield). 1H NMR (CDC13) δ ppm 2.64 (s, 3 H), 7.14 (dd, J=8.01, 4.62 Hz, 1 H), 8.14 (dd, J=7.54, 1.88 HZ, 1 H), 8.59 (dd, J=4.52, 1.32 HZ, 1 H), 11.68 (brs, 1H).
72%
With hydrazine hydrate In butan-1-olReflux
To a solution of 1-(2-Chloropyridin-3-yl)ethanone (XIII) (0.311 g, 2 mmol) in n-butanol (10 mL) was added hydrazine hydrate (1.45 mL, 30 mmol). The reaction was refluxed overnight. The solution was cooled and the solvent was evaporated under vacuum. The residue was dissolved in DCM and washed successively by water and brine. The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give 3-methyl-1H-pyrazolo[3,4-b]pyridine (XIV) as a white solid (192 mg, 1.44 mmol, 72percent yield). 1H NMR (CDCl3) δ ppm 2.64 (s, 3H), 7.14 (dd, J=8.01 Hz, J=4.62 Hz, 1H), 8.14 (dd, J=7.54 Hz, J=1.88 Hz, 1H), 8.59 (dd, J=4.52 Hz, J=1.32 Hz, 1H), 11.68 (brs, 1H)
72%
With hydrazine hydrate In butan-1-olReflux
Step 3 To a solution of 1-(2-chloropyridin-3-yl)ethanone (XI) (0.311 g, 2 mmol) in n-butanol (10 mL) was added hydrazine hydrate (1.45 mL, 30 mmol). The reaction was refluxed overnight. The solution was cooled and the solvent was evaporated under vacuum. The residue was dissolved in DCM and washed successively by water and brine. The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give 3-methyl-1H-pyrazolo[3,4-b]pyridine (XII) as a white solid (192 mg, 1.44 mmol, 72percent yield). 1H NMR (CDCl3) δ ppm 2.64 (s, 3H), 7.14 (dd, J=8.01 Hz, J=4.62 Hz, 1H), 8.14 (dd, J=7.54 Hz, J=1.88 Hz, 1H), 8.59 (dd, J=4.52 Hz, J=1.32 Hz, 1H), 11.68 (brs, 1H).
72%
With hydrazine hydrate In butan-1-olReflux
To a solution of 1-(2-chloropyridin-3-yl)ethanone (XI) (0.31 1 g, 2 mmol) in n-butanol (10 mL) was added hydrazine hydrate (1.45 mL, 30 mmol). The reaction was refluxed overnight. The solution was cooled and the solvent was evaporated under vacuum. The residue was dissolved in DCM and washed successively by water and brine. The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give 3-methyl-1H-pyrazolo [3,4-b]pyridine (XII) as a white solid (192 mg, 1.44 mmol, 72percent yield). 1H NMR (CDCl3) δ ppm 2.64 (s, 3 H), 7.14 (dd, J=8.01Hz, J=4.62Hz, 1H), 8.14 (dd, J=7.54Hz, J=1.88Hz, 1H), 8.59 (dd, J=4.52Hz, J=1.32Hz, 1H), 1 1.68 (brs, 1H).
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 57, p. 311 - 322
[2] Patent: US2006/47126, 2006, A1, . Location in patent: Page/Page column 30
[3] Patent: WO2011/5759, 2011, A2, . Location in patent: Page/Page column 77-78
[4] Canadian Journal of Chemistry, 1988, vol. 66, # 3, p. 420-428
[5] Patent: WO2011/84486, 2011, A1, . Location in patent: Page/Page column 106; 111
[6] Patent: US2013/296302, 2013, A1, . Location in patent: Paragraph 0495
[7] Patent: US2016/68550, 2016, A1, . Location in patent: Paragraph 1057
[8] Patent: WO2016/40193, 2016, A1, . Location in patent: Paragraph 0704
[9] Patent: WO2005/9958, 2005, A1, . Location in patent: Page 180
[10] Patent: WO2011/79804, 2011, A1, . Location in patent: Page/Page column 24
[11] Patent: US2012/245178, 2012, A1, . Location in patent: Page/Page column 13
[12] Journal of Medicinal Chemistry, 2014, vol. 57, # 18, p. 7577 - 7589
21
[ 55676-21-6 ]
[ 116855-03-9 ]
Reference：
[1] Canadian Journal of Chemistry, 1988, vol. 66, # 3, p. 420-428
A solution of 62 (1.9 g, 13.9 mmol) in phosphorus oxychloride (23 mL, 249 mmol) was heated at 100 C for 2 h. Excess phosphorus oxychloride was removed under a stream of nitrogen and to the residue was added ice-water (200 mL) and the mixture extracted with diethyl ether (3 × 100 mL). The combined organic extracts were washed with water (2 × 100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The product was isolated by flash column chromatography using ethyl acetate, hexane (1:4) as an eluent to obtain the title compound 63 (1.1 g, 50%) as a yellow oil, Rf: 0.55 (1:1 ethyl acetate, hexane); IR (vmax (neat)): 3020, 1683, 1574, 1559, 1395, 1276, 1116, 1063, 803 cm-1; 1H NMR (300 MHz, CDCl3): delta 2.69 (3H, s), 7.34 (1H, dd, J = 7.6, 4.8 Hz), 7.90 (1H, dd, 7.6, 2.0 Hz), 8.49 (1H, dd, J = 4.8, 2.0 Hz), 8.69 (1H, s) ppm; 13C NMR (75 MHz, CDCl3): delta 26.9, 124.7, 126.2, 135.8, 139.5, 142.4, 193.8 ppm.
With chromium(VI) oxide; In acetone; at -30 - 20℃; for 3h;Inert atmosphere;
Step 2: l-(2-Chloropyridin-3-yl)ethanone.A solution of l-(2-chloropyridin-3-yl)ethanone (1O g, 0.0635 mol) in dry acetone (200 mL) was introduced under argon into a 1 L flask. The mixture was cooled to -30 0C and pure, pulverized chromic anhydride (19 g, 0.19 mol) was added. The reaction mixture was kept at room temperature for 3 h. 2-Propanol (100 mL) was added, followed by aqueous sodium hydrogen carbonate to pH 8. After filtration, solids were washed with chloroform. The organic and aqueous layers were then separated and the aqueous layer was extracted with chloroform (2x10OmL). The combined organics were dried over anhydrous sodium sulfate and evaporated to yield the crude pyridyl ketone as an oil. This product was purified by column chromatography (8 g, 81%). *1H NMR (CDCl3) 8.44 (dd, J = 5 and 2 Hz, 1 H) 7.91 (dd, J = 7.5 and 2 Hz, 1 H), 7.34 (dd, J = 7.5 and 5 Hz, 1 H), 2.68 (s, 3 H).
81%
With chromium(VI) oxide; In acetone; at -30 - 20℃; for 3h;
Step 2: 1-(2-Chloropyridin-3-yl)ethanone A solution of 1-(2-chloropyridin-3-yl)ethanone (10 g, 0.0635 mol) in dry acetone (200 mL) was introduced under argon into a 1 L flask. The mixture was cooled to -30 C. and pure, pulverized chromic anhydride (19 g, 0.19 mol) was added. The reaction mixture was kept at room temperature for 3 h. 2-Propanol (100 mL) was added, followed by aqueous sodium hydrogen carbonate to pH 8. After filtration, solids were washed with chloroform. The organic and aqueous layers were then separated and the aqueous layer was extracted with chloroform (2*100 mL). The combined organics were dried over anhydrous sodium sulfate and evaporated to yield the crude pyridyl ketone as an oil. This product was purified by column chromatography (8 g, 81%). *1H NMR (CDCl3) 8.44 (dd, J=5 and 2 Hz, 1H) 7.91 (dd, J=7.5 and 2 Hz, 1H), 7.34 (dd, J=7.5 and 5 Hz, 1H), 2.68 (s, 3H).
77%
With chromium(VI) oxide; In acetone; at -30 - 20℃; for 3.25h;Inert atmosphere;
Step 2[00176] To a solution of l-(2-chloropyridin-3-yl)ethanol (II) in dry acetone at - 30C under nitrogen was added in portions chromium (VI) oxide (1.80 g, 18 mmol). The solution was further stirred 15 min at -30C and allowed to warm to room temperature. The solution was stirred for 3 h at room temperature before adding isopropanol (10 mL). The solution was made alkaline by slowly adding a saturated NaHC03 solution. The solution was filtered through a bed of Celite. The solids were washed by DCM. The organic phase of the filtrate was separated and the aqueous phase extracted with DCM (2 x 50 mL). The combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure to yield l-(2-chloropyridin-3-yl)ethanone (III) as a brown liquid (0.72 g, 4.63 mmol, 77% yield). 1H NMR (CDC13) delta ppm 2.71 (s, 3 H), 7.35 (dd, J=7.63, 4.80 Hz, 1 H), 7.91 (dd, J=7.54, 1.88 Hz, 1 H), 8.55 (dd, J=4.71, 1.88 Hz, 1 H).
77%
With chromium(VI) oxide; In acetone; at -30 - 20℃; for 3.25h;Inert atmosphere;
To a solution of 1-(2-chloropyridin-3-yl)ethanol (XII) in dry acetone at -30 C. under nitrogen was added in portions chromium (VI) oxide (1.80 g, 18 mmol). The solution was further stirred 15 min at -30 C. and allowed to warm to room temperature. The solution was stirred for 3 h at room temperature before adding isopropanol (10 mL). The solution was made alkaline by slowly adding a saturated aqueous NaHCO3 solution. The solution was filtered through a bed of Celite. The solids were washed by DCM. The organic phase of the filtrate was separated and the aqueous phase extracted with DCM (2×50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to yield 1-(2-chloropyridin-3-yl)ethanone (XIII) as a brown liquid (0.72 g, 4.63 mmol, 77% yield). 1H NMR (CDCl3) delta ppm 2.71 (s, 3H), 7.35 (dd, J=7.63 Hz, J=4.80 Hz, 1H), 7.91 (dd, J=7.54 Hz, J=1.88 Hz, 1H), 8.55 (dd, J=4.71 Hz, J=1.88 Hz, 1H).
77%
With chromium(VI) oxide; In acetone; at -30 - 20℃; for 3.25h;Inert atmosphere;
Step 2 To a solution of 1-(2-chloropyridin-3-yl)ethanol (X) in dry acetone at -30 C. under nitrogen was added in portions chromium (VI) oxide (1.80 g, 18 mmol). The solution was further stirred 15 min at -30 C. and allowed to warm to room temperature. The solution was stirred for 3 h at room temperature before adding isopropanol (10 mL). The solution was made alkaline by slowly adding a saturated aqueous NaHCO3 solution. The solution was filtered through a bed of Celite. The solids were washed by DCM. The organic phase of the filtrate was separated and the aqueous phase extracted with DCM (2*50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to yield 1-(2-chloropyridin-3-yl)ethanone (XI) as a brown liquid (0.72 g, 4.63 mmol, 77% yield). 1H NMR (CDCl3) delta ppm 2.71 (s, 3H), 7.35 (dd, J=7.63 Hz, J=4.80 Hz, 1H), 7.91 (dd, J=7.54 Hz, J=1.88 Hz, 1H), 8.55 (dd, J=4.71 Hz, J=1.88 Hz, 1H).
77%
With chromium(VI) oxide; In acetone; at -30 - 20℃; for 3.25h;
To a solution of 1-(2-chloropyridin-3-yl)ethanol (X) in dry acetone at -30C under nitrogen was added in portions chromium (VI) oxide (1.80 g, 18 mmol). The solution was further stirred 15 min at -30C and allowed to warm to room temperature. The solution was stirred for 3 h at room temperature before adding isopropanol (10 mL). The solution was made alkaline by slowly adding a saturated aqueous NaHCCb solution. The solution was filtered through a bed of Celite. The solids were washed by DCM. The organic phase of the filtrate was separated and the aqueous phase extracted with DCM (2 x 50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to yield 1 -(2-chloropyridin-3 -yl)ethanone (XI) as a brown liquid (0.72 g, 4.63 mmol, 77% yield). 1H NMR (CDCl3) delta ppm 2.71 (s, 3H), 7.35 (dd, J=7.63Hz, J=4.80Hz, 1H), 7.91 (dd, J=7.54Hz, J=1.88Hz, 1H), 8.55 (dd, J=4.71Hz, J=1.88Hz, 1H).
With triethylamine; In acetonitrile; at 20 - 180℃; for 0.333333h;Microwave irradiation;
Example 4 A. 3-Methyl-thieno[2,3-b]pyridine-2-carboxlic acid ethyl ester. To a solution of Compound 4a (0.637 g; 4.1 mmol), dissolved in MeCN (3.0 mL), at ambient temperature, is added TEA (0.743 mL; 5.3 mmol), followed by Compound 3a (0.542 g; 4.5 mmol) and the reaction was heated under microwave radiation at 180° C. for 20 min. The crude reaction was diluted with EtOAc, washed sequentially with 3N NaOH, H2O, and brine, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 4b. 1H-NMR (300 MHz, DMSO-d6): delta 8.72-8.74 (m, 1H), 8.28-8.42 (m, 1H), 7.36-7.67 (m, 1H), 4.21-4.49 (q, 2H), 1.21-1.36 (t, 3H); LC/MS: C11H11NO2S: m/z 222.0 (M+1).
With triethylamine; In acetonitrile; at 180℃; for 0.333333h;Microwave irradiation;
A.3-Methyl-thieno[2,3-b]pyridine-2-carboxlic acid ethyl ester.To a solution of Compound 4a (0.637 g; 4.1 mmol), dissolved in MeCN (3.0 mL), at ambient temperature, is added TEA (0.743 mL; 5.3 mmol), followed by Compound 3a (0.542 g; 4.5 mmol) and the reaction was heated under microwave radiation at 180° C. for 20 min.The crude reaction was diluted with EtOAc, washed sequentially with 3N NaOH, H2O, and brine, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure.The crude residue was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 4b. 1H-NMR (300 MHz, DMSO-d6): delta 8.72-8.74 (m, 1H), 8.28-8.42 (m, 1H), 7.36-7.67 (m, 1H), 4.21-4.49 (q, 2H), 1.21-1.36 (t, 3H); LC/MS: C11H11NO2S: m/z 222.0 (M+1).
With triethylamine; In acetonitrile; at 180℃; for 0.333333h;Microwave irradiation;
To a solution of Compound 4a (0.637 g; 4.1 mmol), dissolved in MeCN (3.0 ml_), at ambient temperature, is added TEA (0.743 ml 5.3 mmol), followed by Compound 3a (0.542 g; 4.5 mmol) and the reaction was heated under microwave radiation at 180 0C for 20 min. The crude reaction was diluted with EtOAc, washed sequentially with 3N NaOH, H2O, and brine, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 4b. 1H-NMR (300 MHz, DMSO-d6): delta 8.72-8.74 (m, 1 H), 8.28- 8.42 (m, 1 H), 7.36-7.67 (m, 1 H), 4.21 -4.49 (q, 2H), 1.21 -1.36 (t, 3H); LC/MS: CiiHiiNO2S: m/z 222.0 (M+1 ).
trans-(3R,13bS,Sa)-13b-methyl-3-phenyl-2,3-dihydro-13bH-benz[e]oxazolo[3,2-a]-6-(4,5-dihydro-4,4-dimethyloxazol-2-yl)-pyrido[2,3-c]azepin-5-one[ No CAS ]
Triethylamine (7.4g, 73mmol) was added to a solution of diethyl malonate (5.6g, 35mmol) and anhydrous magnesium chloride (1.9g, 20mmol) in toluene (15ml) under inert atmosphere. After stirring for lhr at room temperature, a solution of 2-chloro nicotinoyl chloride (5.2g, 29mmol) in toluene (5ml) was added and the reaction mixture was stirred at room temperature for a further lhr. The reaction was quenched with ice cold 2N hydrochloric acid (20ml), and the organic layer was separated and concentrated to dryness. The resultant residue was dissolved in a mixture of 3 :2 DMSO-water and heated at 120-1300C for 6hr. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100ml). The organic layer was washed once with bicarbonate solution, then several times with water, and finally with brine. The organic layer was then dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to yield l-(2-chloro-pyridin-3-yl) ethanone (Ig5 25percent) as oil.
With sulfuric acid; bromine; In acetic acid; at 75℃; for 2h;
Example 37b: 2-Bromo/chloro-3- (bromoacetvl)-pvridine; Bromine (0.89 ml, 17.35 mmol) in acetic acid (10 ml) is added dropwise to 3-acetyl-2- chloro-pyridine (2.7 g, 17.35 mmol) in acetic acid (20 ml). After the addition of sulfuric acid (0.7 ml) the mixture is heated at 75°C for 2 hours. The acetic acid is evaporated under reduced pressure. The residue is diluted with water and the pH adjusted by addition of 1 M aqueous sodium hydroxide to pH 7. The product is extracted using chloroform, then purified by flash chromatography to give the title compound as a crystalline 1: 1 mixture of 2-bromo-3- (bromoacetyl)-pyridine and 2-chloro-3- (bromoacetyl)-pyridine ;'H-NMR (CDC13, 300 MHz): 8.55 (dd, 0.5H) ; 8.50 (dd, 0.5H) ; 7.94 (dd, 0.5H) ; 7.79 (dd, 0.5H) ; 7.43-7. 37 (m, 1 H) ; 4.56 (s, 1H) ; 4.53 (s, 1H).
After diluting the product in step b) with the appropriate amount of dry toluene,Slowly added to the stirred solution of step a) at room temperature.After stirring for 40 min, the solution was concentrated with concentrated HCl (261 g, 2.32 mol).The toluene layer was evaporated and cooled to give a pale yellow solid.To this solid was added DMSO (650 ml) and water (29 ml).The mixture was heated and maintained at 155 ° C for 3 hours and then heated until the reaction solution was cooled and poured into 2.5 L of cold water,A large amount of off-white solid precipitated, filtered and dried.To give 96 g of product 2-chloro-3-acetylpyridine in 72percent yield.
56%
With hydrogenchloride; water; In dimethyl sulfoxide; at 130℃; for 2h;pH 5 - 6;Product distribution / selectivity;
Water (1.3 mL) was added to a solution of diethyl 2-(2-chloronicotinoyl)malonate (31.7 mmol) in dimethylsulfoxide (50 mL). The pH of the reaction mixture was added adjusted to 5-6 by the addition of hydrochloric acid and the reaction mixture was heated at 130° C. for 2 h. The reaction mixture was then quenched with ice water (300 mL) and the aqueous layer was extracted with ethyl acetate (3*50 mL). The combined organic layers were washed with brine, dried (sodium sulfate), and concentrated. The residue was purified by chromatography (1/20 ethyl acetate/petroleum ether to provide 1-(2-chloropyridin-3-yl)ethanone in 56percent yield as light yellow oil.
52%
With water; In dimethyl sulfoxide; at 130℃; for 3.5h;Product distribution / selectivity;
A solution of diethyl 2-(2-chloronicotinoyl)malonate (267 mmol) in dimethylsulfoxide (100 ml) was added dropwise over 1.5 h to a 130° C. solution of water (10 mL) in dimethylsulfoxide (260 mL). The reaction mixture was maintained at 130° C. for an additional 2 h and was allowed to cool to rt. The reaction mixture was diluted with cold (0° C.) water (500 mL) and was extracted with ethyl acetate (3*200 mL). The combined organic layers were washed with brine (5*200 mL), dried (sodium sulfate), and concentrated. The residue was purified by chromatography (10/1 petroleum ether/ethyl acetate) to provide 1-(2-chloropyridin-3-yl)ethanone 52percent yield as yellow oil.
With water; In dimethyl sulfoxide; at 140 - 150℃; for 4h;
Example 37c: 3-AcetvI-2-chloroPYridine; A mixture of 2-chloronicotinic acid (2-chloro-3-pyridylcarboxylic acid, 4.0 g, 25.4 mmol), oxalyl chloride (2.28 mi, 26.65 mmol) and two drops of DMF are stirred in chloroform (60 ml) for 30 minutes and subsequently refluxed for 45 minutes. The volatiles are distilled under reduced pressure to give crude 2-chloronicotinoyl chloride. This crude product is added to a mixture of diethyl malonate (3.85 ml, 25.38 mmol), magnesium chloride (2.4 g, 25.38 mmol) and triethylamine (7 ml, 50.77 mmol) in acetonitrile (25 ml) with cooling, such that the temperature does not rise above 15°C. After stirring for 24 hours the reaction mixture is diluted with ether and washed repeatedly with 1 M hydrochloric acid and brine. Drying of the organic phase over magnesium sulfate, filtering and evaporation of the solvents gives crude diethyl 2- (2-chloronicotinoyl)-malonate. This crude product is dissolved in DMSO (40 ml) and water (3 ml), and is heated at 140-150°C for four hours. The mixture is poured onto crushed ice and the product is extracted using ether. Filtering of the ether phase over a pad of silicagel gives 3-acetyl-2-chloropyridine as a yellow oil ; 'H-NMR (CDCI3, 300MHz) : 8.50 (dd, 1 H) ; 7.91 (dd, 1 H) ; 7.34 (ddd, 1 H) ; 2.71 (s, 3H).
1-(2-chloro-pyridin-3-yl)-3-dimethylamino-propenone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
at 85℃; for 1.5h;
Step 1. Preparation of 1-(2-Chloro-pyridin-3-yl)-3- dimethylamino-propenone; 1- (2-Chloro-pyridin-3-yl)-ethanone ([Kuo, D. L. Tetrahedron, 48,42, 9233-9236](21.7 g, 139 mmol) in 46 mL N,N- dimethylformamide, dimethyl acetal (42 g, 350 mmol) was heated under a drying tube at 85 °C for 1.5 h and concentrated. The residue was purified by suction filtration chromatography (using 150 g silica in a Buchner funnel, with rapid collection of fractions eluting with 10: 1 and then 5:1 CH2Cl2/IpOH) to provide the title compound as a yellow solid. MS m/z = 211 [M+H]+. Calc'd for C10H11ClN2O: 210.66.
With potassium fluoride;bis(benzonitrile)palladium(II) chloride; In N,N,N,N,N,N-hexamethylphosphoric triamide; dichloromethane; water; N,N-dimethyl-formamide;
EXAMPLE 18 3-Acetyl-2-chloropyridine The following is the preparation of a compound of Formula 2 in which t is 0, L is chloro, Y is N, Z is CH and R3 is acetyl. A mixture of 2-chloronicotinic acid (20 g, 0.127 mmol) and oxalyl chloride (13.3 mL, 0.152 mmol) in 2 drops of DMF and 200 mL of methylene chloride was stirred at room temperature for approximately 14 hours. The mixture was stirred at reflux temperature for 1 hour. The solution was cooled and partitioned between 100 mL of ice-cold aqueous sodium bicarbonate and 300 mL of methylene chloride. The organic layer was washed with brine, dried (Na2 SO4) and concentrated to give 2-chloronicotinic acid chloride (8.8 g, 49.5 mmol). A mixture of 2-chloronicotinic acid chloride (8.8 g, 49.5 mmol), tetramethyltin (5.5 mL, 40 mmol) and bis(benzonitrile)palladium(II) chloride (0.385 g) in 20 mL of hexamethylphosphoramide was stirred at room temperature for 20 hours. The mixture was stirred with 50 mL of 10percent potassium fluoride and then poured into 50 mL of water. The mixture was extracted with diethyl ether (4*50 mL) and the combined extracts were washed with water, saturated sodium bicarbonate and sodium chloride, dried (Na2 SO4) and concentrated. The residue was purified on silica gel by column chromatography eluding with hexanes/ethyl acetate (3:1) to give 3-acetyl-2-chloropyridine (4.2 g, 27 mmol).
1-[2-({4-[(E)-2-(2,4-difluorophenyl)vinyl]phenyl}sulfonyl)pyridin-3-yl]ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
In dimethyl sulfoxide; at 160℃; for 1 - 2h;Microwave;Product distribution / selectivity;
Example 19 l-[2-({4-[(.pound.)-2-(2,4-difluorophenyl)vinyl]plienyl}sulfonyl)pyridin-3-yl]etlianolSodium 4-[(E)-2-(2,4-difluorophenyl)vinyl]benzenesulfinate (prepared according to the method of Example 7 Steps 1-3 using 2,4-difluorostyrene in step 2, 302 mg, 1 mmol) and l-(2-chloropyridin-3-yl)ethanone (prepared according to the method in patent WO 2003094918, 155 mg, 1 mmol) were dissolved in dimethylsulfoxide (4 mL) and heated to 1600C in a microwave for 1 hour. The cooled reaction was poured into water. Extraction with ethyl acetate was attempted but the product did not dissolve so the solid residue and ethyl acetate were washed in a flask and azeotroped with toluene to give 399 mg. This was suspended in tetrahydrofuran (5 mL) and ethanol (5 mL). Excess sodium borohydride was added and the reaction was stirred for two hours before being poured into water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 30percent ethyl acetate/isohexane to give the title compound (58 mg, 14percent). deltaH (500 MHz, d6 DMSO): 8.40 (1 H, d, J = 3.2 Hz), 8.29 (1 H, d, J = 7.8 Hz), 7.90-7.85 (5 H, m), 7.65 (1 H, dd, J = 4.4, 7.8 Hz), 7.46-7.38 (2 H, m), 7.31 (1 H, t, J = 9.8 Hz), 7.16 (1 H, t, J = 7.8 Hz), 5.81 (1 H, t, J = 4.6 Hz), 5.60 (1 H, d, J = 4.0 Hz), 1.41 (3 H, d, J = 6.2 Hz).; Step 2Sodium 4-[(E)-2-(2,4-difluorophenyl)vinyl]benzenesulfinate (prepared according to the method of Example 7 Steps 1-3 using 2,4-difluorostyrene in step 2, 3 g, 9.93 mmol) and l-(2-chloropyridin-3-yl)ethanone (Step 1, 1.54 g, 9.93 mmol) were dissolved in dimethylsulfoxide (10 mL) and heated to 1600C for 2 hours. The reaction was poured into water and extracted with ethyl acetate, dichloromethane and methanol mixtures. The organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography on silica, eluting with ethyl acetate/isohexane and 5percent diethyl ether/dichloromethane. The solid obtained was recrystallised from ethyl acetate to yield the title compound (1.3g, 33percent). deltaH (500 MHz, d6 DMSO): 8.74-8.71 (1 H, m), 8.15-8.12 (1 H, m), 7.91-7.84 (5 H, m), 7.79-7.73 (1 H, m), 7.46-7.34 (2 H, m), 7.31-7.26 (1 H, m), 7.16-7.11 (1 H, m), 2.67 (3 H, s).
With ammonia; sulfur; In methanol; water; at 110℃; for 24.1667h;Product distribution / selectivity;
Ammonium hydroxide (368 mL) was added to a mixture of sulfur (386 mmol) and <strong>[55676-21-6]1-(2-chloropyridin-3-yl)ethanone</strong> (350 mmol) and the slurry was diluted with methanol (960 mL). Ammonia gas was bubbled through the reaction mixture for 10 min and the reaction mixture was heated at 110° C. for 24 h. The reaction mixture was concentrated to dryness and the residue was extracted with water (3*500 mL). The aqueous layer was extracted with ethyl acetate (5*500 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated. The residue was purified by chromatography (1/25 ethyl acetate/petroleum ether to provide 3-methylisothiazolo[5,4-b]pyridine in 67percent yield as a light yellow solid.
22%
With ammonia; sulfur; In ethanol; water; at 130℃; for 16h;Product distribution / selectivity;
A solution of <strong>[55676-21-6]1-(2-chloropyridin-3-yl)ethanone</strong> (129 mmol) in ammonium hydroxide (130 mL) and ethanol (500 mL) was added to a 1 L high pressure steel vessel under an atmosphere of ammonia. Sulfur (129 mmol) was added to the reaction mixture, the vessel was sealed, and the reaction mixture was heated at 130° C. for 16 h. The reaction mixture was filtered through Celite and the eluent was extracted with ethyl acetate (300 mL). The organic layer was washed with brine (100 mL), dried (sodium sulfate) and concentrated. The residue was purified by chromatography (20/1 petroleum ether/ethyl acetate) to provide 3-methylisothiazolo[5,4-b]pyridine in 22percent yield as a white solid.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
