* 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, 1959, vol. 81, p. 740,742
2
[ 6635-88-7 ]
[ 42732-49-0 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 740,742
3
[ 6635-88-7 ]
[ 39891-09-3 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 740,742
4
[ 6635-88-7 ]
[ 39891-09-3 ]
[ 101012-32-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 1990, vol. 33, # 10, p. 2697 - 2706
5
[ 6635-88-7 ]
[ 39891-09-3 ]
[ 101012-32-2 ]
[ 142892-30-6 ]
Reference：
[1] Synthesis, 1992, # 6, p. 528 - 530
6
[ 6635-88-7 ]
[ 10025-87-3 ]
[ 99310-62-0 ]
[ 39891-09-3 ]
[ 101012-32-2 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 740,742
7
[ 6635-88-7 ]
[ 101012-32-2 ]
Yield
Reaction Conditions
Operation in experiment
42.9%
at 80℃; for 4.5 h; Heating / reflux
(1-oxypyridin-3-yl)acetonitrile (7.5 g, 35.9 mmol) is carefully added to vigorously stirred phosphorous oxychloride (100 mL). The mixture is slowly heated to 80° C. (in 5° C. increments) over 1.5 hr. (CAUTION. If heating is too quick, violent decomposition occurs at ca 70° C.) All the solids dissolved. The reaction is heated at reflux for 3 hr. The excess phosphorous oxychloride is removed and the residue is cautiously treated with cold water. Saturated sodium bicarbonate is added to make the mixture basic, then it is extracted with ethyl acetate (3.x.). The combined extract is washed with brine, dried, filtered and concentrated. The residue is purified by chromatography eluting with pentane-10 to 100percent ether. The second compound off the column is the desired (2-chloropyridin-3-yl)acetonitrile (2.35 g, 42.9percent yield) a light brown solid.
20%
for 3 h; Reflux
(1-Oxypyridin-3-yl)acetonitrile (1115) (4.00 g, 29.8 mmol) was added slowly to a stirred solution of POCI3 (50 mL). The mixture was heated to 80 °C in 5 - 7 °C increments every 10 -15 minutes. The reaction was then heated at reflux for 3 hours. Excess POCI3 was removed by distillation and the brown residue carefully poured on to cold water (200 mL). A saturated solution NaHC03 (300 mL) was then added carefully. Solid NaHC03 was added in portions to the aqueous mixture until the evolution of gas ceased. The aqueous layer was separated in to two portions (250 mL each) and each portion was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (200 mL) and dried over Na2S04. The solvent was removed and the residue purified by column chromatography on silica gel (0- 100percent EtOAc in petroleum benzine) to afford a mixture of two isomeric compounds. The mixture was re-purified by column chromatography on silica gel (0-40percent diethyl ether in petroleum benzine 40-80 °C) to afford the title compound (1116) (0.932 g, 20percent) as a white solid; 1 H NMR (400 MHz, CDCI3) 6 8.41 (dd, J = 4.8, 1.8 Hz, 1 H), 7.90 (ddt, J = 7,6, 1.7, 0.7 Hz, 1 H), 7.34 (dd, J = 7,6, 4.8 Hz, 1 H), 3.87 (s, 2H), LCMS Method C: rt 4,50 min; m/z 153 [M+H]+.
Reference：
[1] Patent: US2005/54631, 2005, A1, . Location in patent: Page/Page column 23-24
[2] Patent: WO2014/27199, 2014, A1, . Location in patent: Page/Page column 141
[3] Journal of the American Chemical Society, 1959, vol. 81, p. 740,742
[4] Patent: WO2012/110773, 2012, A1, . Location in patent: Page/Page column 138; 139
8
[ 6635-88-7 ]
[ 39891-09-3 ]
[ 101012-32-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 1990, vol. 33, # 10, p. 2697 - 2706
9
[ 6635-88-7 ]
[ 39891-09-3 ]
[ 101012-32-2 ]
[ 142892-30-6 ]
Reference：
[1] Synthesis, 1992, # 6, p. 528 - 530
10
[ 6635-88-7 ]
[ 10025-87-3 ]
[ 99310-62-0 ]
[ 39891-09-3 ]
[ 101012-32-2 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 740,742
11
[ 6635-88-7 ]
[ 61494-55-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 1990, vol. 33, # 10, p. 2697 - 2706
[2] Journal of the American Chemical Society, 1959, vol. 81, p. 740,742
[3] Patent: WO2012/110773, 2012, A1,
[4] Patent: WO2014/27199, 2014, A1,
12
[ 6635-88-7 ]
[ 7677-24-9 ]
[ 5912-34-5 ]
Yield
Reaction Conditions
Operation in experiment
66%
With N,N-Dimethylcarbamoyl chloride In dichloromethane at 20℃; for 72 h;
To a suspension of (1-oxy-pyridin-3-yl)-acetonitrile (10 g, 75 mmol) in anhydrous CH2Cl2 under a nitrogen atmosphere was added trimethylsilylcyanide (10.95 mL, 82 mmol) and dimethylcarbamoylchloride (7.55 mL, 82 mmol). The reaction mixture was stirred at room temperature for 72 hours and then concentrated. EtOAc (100 mL) was added to the residue and the organic phase was washed with 1 M NaOH (150 mL), dried over Na2SO4, filtered and concentrated. The resulting solid was purified by column chromatography (50percent EtOAc/hexanes) affording 7.08 g (66percent) of a yellow solid: mp 48-51 °C; MS (+) APCI m/z 144 [M+H]+. Ref: WO 9818796
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 9, p. 3331 - 3347
[2] Journal of Medicinal Chemistry, 2000, vol. 43, # 4, p. 675 - 682
[3] Patent: EP1147083, 2004, B1, . Location in patent: Page 49
[4] Organic Process Research and Development, 2010, vol. 14, # 4, p. 883 - 889
[5] Journal of Medicinal Chemistry, 2012, vol. 55, # 17, p. 7472 - 7479
13
[ 6635-88-7 ]
[ 7677-24-9 ]
[ 79-44-7 ]
[ 5912-34-5 ]
Reference：
[1] Patent: US6136821, 2000, A,
14
[ 6635-88-7 ]
[ 5912-35-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2000, vol. 43, # 4, p. 675 - 682
[2] Organic Process Research and Development, 2010, vol. 14, # 4, p. 883 - 889
[3] Journal of Medicinal Chemistry, 2011, vol. 54, # 9, p. 3331 - 3347
[4] Journal of Medicinal Chemistry, 2012, vol. 55, # 17, p. 7472 - 7479
With dihydrogen peroxide; acetic acid; In water; at 20 - 95℃; for 72h;
A solution of <strong>[6443-85-2]3-pyridylacetonitrile</strong> (11 g, 93.1 mmol), HOAc (55 mL), and 30% H2O2 (17 mL) was heated at 95C overnight, and at room temperature for 72 hours. H2O (50 mL) was added to the reaction mixture and the resulting solution was concentrated. This was repeated with additional H2O (100 mL). Toluene (2 x 100 mL) was used to remove residual H2O, and the resulting white solid was dried under vacuum overnight affording a waxy white solid: mp 120-125 C; MS (+) APCI m/z 135 [M+H]+. Ref: JACS 1959, 81 p. 740-743
With peracetic acid; In water; acetic acid; at 20 - 95℃; for 48h;
The title compound is prepared in accordance with the procedures as outlined in S. Okuda et al., J. Am. Chem. Soc., 81, 740, (1959). Peracetic acid (38%, 40 mL, 0.2 mol) is added to a stirred solution of <strong>[6443-85-2]3-pyridylacetonitrile</strong> (15.0 g, 127 mmol) in acetic acid (75 mL) and the reaction is heated at 95 C. for 24 hr, then stirred at room temperature for 24 hr. Water is added and the solvents are removed. More water (100 mL) is added and again removed. This process is repeated with toluene and with ether to give (1-oxypyridin-3-yl)acetonitrile as a cream solid.
With dihydrogen peroxide; acetic acid; at 20 - 95℃; for 92h;
30% Hydrogen peroxide (12 mL) was added to a solution of <strong>[6443-85-2]3-pyridylacetonitrile</strong> (7.50 g, 63.5 mmol) in acetic acid (40 mL) and the mixture heated at 95 C for 20 hours. The reaction mixture was then cooled and stirred at room temperature for 72 hours. Water (35 mL) was then added and the solution concentrated under reduced pressure. Water (2x 00 mL) was added to the residue and solution concentrated under reduced pressure. Residual water was removed azeotropically using toluene (2x100 mL) to yield the title compound (1115) (8.3 g, 97%) as a pale yellow solid which was used without further purification.
With dihydrogen peroxide; In acetonitrile; at 95℃; for 20h;
30% Hydrogen peroxide (12 mL) was added to a solution of <strong>[6443-85-2]3-pyridylacetonitrile</strong> (7.50 g, 63.5 mmol) in acetic acid (40 mL) and the mixture heated at 95 C for 20 hours. The reaction mixture was then cooled and stirred at room temperature for 72 hours. Water (35 mL) was then added and the solution concentrated under reduced pressure. Wafer (2x100 mL) was added to the residue and solution concentrated under reduced pressure. Residual water was removed azeotropically using toluene (2x100 mL) to yield the title compound (1115) (8.3 g, 97%) as a pale yellow solid which was used without further purification.
With 3-chloro-benzenecarboperoxoic acid; In chloroform; at 20℃;
] A solution of 2-(pyridin-3-yl)acetonitrile (625 mg, 5.3 mmol) and m-CPBA(1.36 g, 7.95 mmol) in CHC13 (20 mL) was stirred at room temperature for overnight. The reaction mixture was quenched by sat.NaHCO3 and extracted by DCM and MeOH (DCM / MeOH = 10/1). The combined organic layers were dried over anhydrous Na2504, filtered and dried in vacuo to give the crude product as a white solid (780 mg, >100%), which was used to the next step without further purification. MS [MH] calcd for C7H6N20 135.0 found 135.0.
With trichlorophosphate; at 80℃; for 4.5h;Heating / reflux;
(1-oxypyridin-3-yl)acetonitrile (7.5 g, 35.9 mmol) is carefully added to vigorously stirred phosphorous oxychloride (100 mL). The mixture is slowly heated to 80 C. (in 5 C. increments) over 1.5 hr. (CAUTION. If heating is too quick, violent decomposition occurs at ca 70 C.) All the solids dissolved. The reaction is heated at reflux for 3 hr. The excess phosphorous oxychloride is removed and the residue is cautiously treated with cold water. Saturated sodium bicarbonate is added to make the mixture basic, then it is extracted with ethyl acetate (3×). The combined extract is washed with brine, dried, filtered and concentrated. The residue is purified by chromatography eluting with pentane-10 to 100% ether. The second compound off the column is the desired (2-chloropyridin-3-yl)acetonitrile (2.35 g, 42.9% yield) a light brown solid.
20%
With trichlorophosphate; for 3h;Reflux;
(1-Oxypyridin-3-yl)acetonitrile (1115) (4.00 g, 29.8 mmol) was added slowly to a stirred solution of POCI3 (50 mL). The mixture was heated to 80 C in 5 - 7 C increments every 10 -15 minutes. The reaction was then heated at reflux for 3 hours. Excess POCI3 was removed by distillation and the brown residue carefully poured on to cold water (200 mL). A saturated solution NaHC03 (300 mL) was then added carefully. Solid NaHC03 was added in portions to the aqueous mixture until the evolution of gas ceased. The aqueous layer was separated in to two portions (250 mL each) and each portion was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (200 mL) and dried over Na2S04. The solvent was removed and the residue purified by column chromatography on silica gel (0- 100% EtOAc in petroleum benzine) to afford a mixture of two isomeric compounds. The mixture was re-purified by column chromatography on silica gel (0-40% diethyl ether in petroleum benzine 40-80 C) to afford the title compound (1116) (0.932 g, 20%) as a white solid; 1 H NMR (400 MHz, CDCI3) 6 8.41 (dd, J = 4.8, 1.8 Hz, 1 H), 7.90 (ddt, J = 7,6, 1.7, 0.7 Hz, 1 H), 7.34 (dd, J = 7,6, 4.8 Hz, 1 H), 3.87 (s, 2H), LCMS Method C: rt 4,50 min; m/z 153 [M+H]+.
With trichlorophosphate; at 80℃; for 3h;
(1-Oxypyridin-3-yl)acetonitrile (1115) (4.00 g, 29.8 mmol) was added slowly to a stirred solution of POCI3 (50 mL). The mixture was heated to 80 C in 5 - 7 C increments every 10 -15 minutes. The reaction was then heated at reflux for 3 hours. Excess POCI3 was removed by distillation and the brown residue carefully poured on to cold water (200 mL). A saturated solution NaHC03 (300 mL) was then added carefu)iy. Solid NaHC03 was added in portions to the aqueous mixture until the evolution of gas ceased. The aqueous layer was separated in to two portions (250 mL each) and each portion was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (200 mL) and dried over Na2S04. The solvent was removed and the residue purified by column chromatography on silica gel (0- 100% EtOAc in petroleum benzine) to afford a mixture of two isomeric compounds. The mixture was re-purified by column chromatography on silica gel (0-40% diethyl ether in petroleum benzine 40-60 C) to afford the title compound (1116) (0.932 g, 20%) as a white solid; 1H NMR (400 MHz, CDCI3) delta 8.41 (dd, J = 4.8, 1.8 Hz, 1 H),7.90 (ddt, J = 7.6, 1 .7, 0.7 Hz, 1 H), 7.34 (dd, J = 7.6, 4.8 Hz, 1 H), 3.87 (s, 2H). LCMS Method C: rt 4.50 min; m/z 153 [M+H]+.
With N,N-Dimethylcarbamoyl chloride; In dichloromethane; at 20℃; for 72h;
To a suspension of (1-oxy-pyridin-3-yl)-acetonitrile (10 g, 75 mmol) in anhydrous CH2Cl2 under a nitrogen atmosphere was added trimethylsilylcyanide (10.95 mL, 82 mmol) and dimethylcarbamoylchloride (7.55 mL, 82 mmol). The reaction mixture was stirred at room temperature for 72 hours and then concentrated. EtOAc (100 mL) was added to the residue and the organic phase was washed with 1 M NaOH (150 mL), dried over Na2SO4, filtered and concentrated. The resulting solid was purified by column chromatography (50% EtOAc/hexanes) affording 7.08 g (66%) of a yellow solid: mp 48-51 C; MS (+) APCI m/z 144 [M+H]+. Ref: WO 9818796
A. 2-Cyano-3-pyridylacetonitrile To a stirred suspension of 3-cyanomethylpyridine-N-oxide (30 g, 0.22 mol; for synthesis see Shigenobu Okuda, Michael M. Robison, J. Am. Chem. Soc. 81, 740 (1959)) in dichloromethane (200 ml) is added trimethylsilanecarbonitrile (26 g, 0.26 mol). To this suspension is added dimethylcarbamyl chloride (28 g, 0.26 mol). The mixture is stirred for 45 h. The solvent is removed and the residue dissolved in ethyl acetate. The solution is washed with 1 N NaOH and water and concentrated in vacuo. The product is purified by flash column chromatography on silica gel (15:2 toluene/acetone) affording the title compound. Mass M+H 144.1. Melting point 62-63 C.
Multi-step reaction with 3 steps
1.1: trichlorophosphate / 3 h / 80 °C
2.1: sodium hydroxide; water / 0.58 h / Reflux
2.2: 1 h / 0 °C / pH 1
3.1: acetyl chloride / 20 h / Reflux
Multi-step reaction with 3 steps
1: trichlorophosphate / 3 h / Reflux
2: sodium hydroxide / 0.58 h / Reflux
3: acetyl chloride / 20 h / Reflux
(E)-3-(1-cyano-2-(3,4-dihydroxy-5-nitrophenyl)vinyl)pyridine-1-oxide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
18%
With ammonium acetate; In methanol; for 3h;Reflux;
A solution of 3-(cyanomethyl)pyridine 1-oxide (400 mg, 3.0 mmol), 3,4-dihydroxy-5- nitro- benzaldehyde (270 mg, 1.5 mmol) and NH4OAc (693 mg, 9 mmol) in MeOH (10 mL) was heated to reflux for overnight. LCMS showed no <strong>[116313-85-0]3,4-dihydroxy-5-nitrobenzaldehyde</strong> left. The reaction mixture was cooled to room temperature. The solid was filtered and washed by MeOH and H20. The solid was re-dissolved in MeOH (5 mL). 5 mL of iN aqueous HC1 was added to adjust pH 34. The desired product was obtained by filter as a bright solid (110 mg, 18%). ?H NIVIR (301 IVIHz, DMSO) 13.71 (s, 1H), 10.89 (s, 2H), 8.65 (s, 1H), 8.26 (d, J=6.2 Hz, 1H), 8.14 (s, 1H), 7.99 (d, J= 2.0 Hz, 1H), 7.84 (d, J= 2.0 Hz, 1H), 7.67- 7.50 (m, 2H). MS [MFT] calcd for C,4H9N305 300.0 found 300.0.
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