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[ CAS No. 33252-28-7 ]

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Chemical Structure| 33252-28-7
Chemical Structure| 33252-28-7
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CAS No. :33252-28-7 MDL No. :MFCD00084941
Formula : C6H3ClN2 Boiling Point : 236.4°C at 760 mmHg
Linear Structure Formula :- InChI Key :N/A
M.W :138.55 g/mol Pubchem ID :5152094
Synonyms :

Safety of [ 33252-28-7 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302+H312-H315-H319-H335 Packing Group:N/A
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Application In Synthesis of [ 33252-28-7 ]

  • Upstream synthesis route of [ 33252-28-7 ]
  • Downstream synthetic route of [ 33252-28-7 ]

[ 33252-28-7 ] Synthesis Path-Upstream   1~21

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Reference: [1] Patent: US5612340, 1997, A,
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  • [ 917-64-6 ]
  • [ 55676-22-7 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1931, vol. 487, p. 127,129
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  • [ 917-64-6 ]
  • [ 60-29-7 ]
  • [ 6271-78-9 ]
  • [ 55676-22-7 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1931, vol. 487, p. 127,129
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  • [ 3731-52-0 ]
  • [ 97004-04-1 ]
Reference: [1] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5885 - 5888
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  • [ 3731-52-0 ]
  • [ 23100-12-1 ]
  • [ 97004-04-1 ]
Reference: [1] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5885 - 5888
[2] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5885 - 5888
[3] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5885 - 5888
[4] Bulletin of the Chemical Society of Japan, 2000, vol. 73, # 5, p. 1227 - 1231
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  • [ 124-41-4 ]
  • [ 15871-85-9 ]
YieldReaction ConditionsOperation in experiment
100% for 20 h; Heating / reflux N-[4-(5-Cyano-2-methoxy-pyridin-3-yl)-benzyl]-2-trifluoromethoxy-benzenesulfonamide To a solution of 4-aminomethylphenylboronic acid hydrochloride (2.0 g, 13.2 mmol) in methanol (20 ml) was added di-tert-butyl dicarbonate (3.16 g, 15.5 mmol) and sodium bicarbonate (3.32 g, 19.8 mmol). The mixture was sonicated for 4 h then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and the solvent evaporated to give (4-bromo-benzyl)-carbamic acid tert-butyl ester (1.8 g, 13.2 mmol, 100percent) as a white solid. To 6-chloro-nicotinonitrile (15 g, 0.11 mol) under argon atmosphere was added 25percent sodium methoxide in methanol (11.7 g, 0.22 mol) and the mixture heated under reflux for 20 h. The methanol was evaporated and the residue partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over anhydrous magnesium sulfate and the solvent evaporated to give 6-methoxy-nicotinonitrile (17.0 g, 0.13 mol, 117percent) as a white solid. To 6-methoxy-nicotinonitrile (13.2 g, 99 mmol) in acetic acid (32 ml) was added sodium acetate (8.1 g, 99 mmol). The mixture was stirred and a solution of bromine (31.5 g, 197 mmol) in acetic acid (32 ml) added. The mixture was heated to 80° C. for 48 h. The reaction mixture was poured into water and extracted with diethyl ether. The organic phase was washed with 4M aqueous sodium hydroxide solution, 5percent sodium thiosulfate solution, dried over anhydrous potassium carbonate and the solvent was evaporated to give 5-bromo-6-methoxy-nicotinonitrile (11.9 g, 56 mmol, 57percent). To a solution of 2-methoxy-5-cyanopyridine-3-boronic acid (1.0 g, 4.0 mmol) in 1,2-dimethoxyethane (10 ml) was added (4-bromo-benzyl)-carbamic acid tert-butyl ester (0.42 g, 2.0 mmol), tetrakis(triphenylphosphine)palladium (0) (114 mg, 0.1 mmol) and 2M aqueous sodium carbonate (1 ml, 2.0 mmol). The reaction was heated to 150° C. for 10 min in a microwave over. The mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The organic phase was washed with water, then brine, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was purified on silica gel eluting with 5:1 heptane/ethyl acetate to give [4-(5-cyano-2-methoxy-pyridin-3-yl)-benzyl]-carbamic acid tert-butyl ester as a white solid (0.5 g, 1.47 mmol, 37percent). To a solution of [4-(5-cyano-2-methoxy-pyridin-3-yl)-benzyl]-carbamic acid tert-butyl ester (0.5 g, 1.5 mmol) in dichloromethane (5 ml) at 0° C. was added trifluoroacetic acid (5 ml, 28 mmol). The reaction mixture was stirred for 30 min at 0° C. before the solvent was evaporated and the residue purified on a SCX column (eluted with 2M ammonia in methanol) to give 5-(4-aminomethyl-phenyl)-6-methoxy-nicotinonitrile as a clear glass (0.39 g, 1.6 mmol, 107percent). To a solution of 5-(4-aminomethyl-phenyl)-6-methoxy-nicotinonitrile (57.3 mg, 0.24 mmol) in dichloromethane (2 ml) was added triethylamine (73.0 mg, 0.72 mmol) and 2-(trifluoromethoxy)benzenesulfonyl chloride. The reaction mixture was agitated for 20 hours and the solvent evaporated under reduced pressure. The crude product was taken up in dimethyl sulfoxide (1 ml) and purified by preparatory LCMS. The solvent was evaporated under reduced pressure to give the title compound (19.1 mg, 0.04 mmol, 17percent). 1H NMR (400 MHz, DMSO-d6): δ 8.68 (d, 1H), 8.47 (t, 1H), 8.15 (d, 1H), 7.90 (m, 1H), 7.73 (m, 1H), 7.45-7.55 (m, 4H), 7.31 (d, 2H), 4.19 (d, 2H), 3.96 (s, 3H) ppm; MS (ESI) m/z: 464.3 [M+H]+.
8.8 g Reflux A)
6-methoxynicotinonitrile
To a solution of 6-chloronicotinonitrile (10.0 g) in methanol (100 mL) was added sodium methoxide (7.80 g).
The reaction mixture was heated at reflux overnight, and the solvent was evaporated under reduced pressure.
To the residue was added water, and the mixture was extracted with ethyl acetate.
The extract was washed with saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (8.8 g).
1H NMR (400 MHz, DMSO-d6) δ 4.00 (3H, s), 6.83 (1H, dd, J= 8.8, 0.8 Hz), 7.78 (1H, dd, J= 8.6, 2.4 Hz), 8.50 (1H, d, J = 1.4 Hz).
Reference: [1] Patent: US2007/149577, 2007, A1, . Location in patent: Page/Page column 17-18
[2] Journal of the Chemical Society, 1948, p. 1939,1942
[3] Patent: EP2848618, 2015, A1, . Location in patent: Paragraph 0660
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Reference: [1] Organic Letters, 2014, vol. 16, # 4, p. 1060 - 1063
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  • [ 917-64-6 ]
  • [ 60-29-7 ]
  • [ 6271-78-9 ]
  • [ 55676-22-7 ]
Reference: [1] Justus Liebigs Annalen der Chemie, 1931, vol. 487, p. 127,129
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  • [ 75-86-5 ]
  • [ 20730-07-8 ]
Reference: [1] Organic Process Research and Development, 2016, vol. 20, # 8, p. 1540 - 1545
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  • [ 262295-96-5 ]
Reference: [1] Journal of the Chemical Society, 1948, p. 1939,1942
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  • [ 3939-12-6 ]
Reference: [1] Chemical Communications, 2018, vol. 54, # 7, p. 825 - 828
[2] Journal of Organic Chemistry, 2015, vol. 80, # 24, p. 12137 - 12145
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  • [ 201230-82-2 ]
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YieldReaction ConditionsOperation in experiment
98.95 g With dichloro [1,1'-bis(diphenylphosphino)propane]palladium(II); triethylamine In water; <i>tert</i>-butyl alcohol at 60℃; for 10 h; Autoclave; Inert atmosphere Example 15-Cyano-pyridine-2-carboxylic acid A 2 L stirred autoclave was charged under argon with PdC12(dppp) (2.13 g, 3.61 mmol), 6- chloro-nicotinonitrile (100 g, 0.722 mol), tert-butanol (800 ml), deionized water (200 ml) andtriethylamine (250 ml, 1.8 mol). The reaction vessel was closed, purged three times with carbonmonoxide (10 bar) and finally charged with carbon monoxide to 15 bar. The mixture was stirredvigorously at 60°C under constant pressure for 10 h; after this time no more carbon monoxideabsorption was observed. The reaction mixture was concentrated on a rotary evaporator such thatthe volatile organic components were removed. The resulting aqueous phase was filtered,extracted with dichloromethane and treated with active charcoal. After filtration, the pH of thesolution was reduced under stuffing at 60°C to ca. 0.7 by dropwise addition of hydrochloric acid.The resulting suspension was stirred at room temperature over night and then filtered. The filter cake was rinsed with water and dried in vacuo to constant weight to afford 5-cyano-pyridine-2- carboxylic acid (98.95 g) as a white solid, MS: mlz = 104 [M-C021, m.p.: 207 °C (dcc).
Reference: [1] Patent: WO2014/173917, 2014, A1, . Location in patent: Page/Page column 13; 14
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Reference: [1] Patent: WO2014/173917, 2014, A1, . Location in patent: Page/Page column 15; 16
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  • [ 23100-12-1 ]
Reference: [1] Patent: US2002/77478, 2002, A1,
[2] Patent: US2002/128247, 2002, A1,
[3] Patent: US4317913, 1982, A,
[4] Patent: EP1138685, 2001, A2,
[5] Patent: WO2007/65669, 2007, A1, . Location in patent: Page/Page column 32
[6] Patent: EP1236723, 2002, A1, . Location in patent: Page 20
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  • [ 3731-52-0 ]
  • [ 23100-12-1 ]
  • [ 97004-04-1 ]
Reference: [1] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5885 - 5888
[2] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5885 - 5888
[3] Tetrahedron Letters, 1999, vol. 40, # 32, p. 5885 - 5888
[4] Bulletin of the Chemical Society of Japan, 2000, vol. 73, # 5, p. 1227 - 1231
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  • [ 139585-70-9 ]
YieldReaction ConditionsOperation in experiment
81% at 145℃; for 64 h; Example 29
6-Bromonicotinonitrile. 6-Chloronicotinonitrile (13.8 g, 100 mmol) was heated at 145° C. in phosphorus tribromide (150 mL) for 32 h.
After cooling, the mixture was concentrated in vacuo.
To the residue was added phosphorus tribromide (150 mL), and the mixture was heated at 145° C. for another 32 h.
After cooling, the mixture was concentrated in vacuo, and an ice-water mixture (500 mL) was added.
Sodium bicarbonate was added to neutralize the mixture, and the product was extracted with ethyl acetate (3*250 mL).
The combined organic extracts were washed with brine and dried over magnesium sulfate.
The solvent was removed in vacuo, and the residue was chromatographed (hexanes-ethyl acetate) to give 14.9 g (81 percent) of 6-bromonicotinonitrile as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=11.0 Hz, 1H), 7.80 (dd, J=3.1, 11.0 Hz, 1H), 8.67 (d, J=3.1 Hz, 1H); MS (M+H)+ m/z=183.0, 185.0.
81%
Stage #1: at 145℃; for 64 h;
Stage #2: With sodium hydrogencarbonate In water
Example 29Step A6-Bromonicotinonitrile. 6-Chloronicotinonitrile (13.8 g, 100 mmol) was heated at 145 °C in phosphorus tribromide (150 ml.) for 32 h. After cooling, the mixture was concentrated in vacuo. To the residue was added phosphorus tribromide (150 ml_), and the mixture was heated at 145 °C for another 32 h. After cooling, the mixture was concentrated in vacuo, and an ice-water mixture (500 ml.) was added. Sodium bicarbonate was added to neutralize the mixture, and the product was extracted with ethyl acetate (3 χ 250 ml_). The combined organic extracts were washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo, and the residue was chromatographed (hexanes-ethyl acetate) to give 14.9 g (81 percent) of 6-bromonicotinonitrile as a white solid: 1 H NMR (400 MHz, CDCI3) S 7.66 (d, J = 1 1.0 Hz, 1 H), 7.80 (dd, J = 3.1 , 1 1.0 Hz, 1 H), 8.67 (d, J = 3.1 Hz, 1 H); MS (M+H)+ m/z=183.0, 185.0.
Reference: [1] Patent: US2005/192302, 2005, A1, . Location in patent: Page/Page column 30
[2] Patent: WO2012/114223, 2012, A1, . Location in patent: Page/Page column 56
[3] Journal of Organic Chemistry, 2001, vol. 66, # 4, p. 1500 - 1502
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  • [ 67-63-0 ]
  • [ 195140-86-4 ]
Reference: [1] Patent: US2010/249071, 2010, A1, . Location in patent: Page/Page column 51
[2] Patent: WO2008/130320, 2008, A2, . Location in patent: Page/Page column 152-153
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Reference: [1] Patent: WO2008/130320, 2008, A2,
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  • [ 74879-18-8 ]
  • [ 1057682-03-7 ]
YieldReaction ConditionsOperation in experiment
69% With triethylamine In N,N-dimethyl-formamide at 20℃; for 14 h; Triethylamine (4.13 g, 3 niL, 40.8 mmol, 4 eq) is added to a solution of 6-chloro- nicotinonitrile (1.38 g, 10 mmol, leq), (S)-2-methyl- piperazine (1.0Og, 10 mmol, leq) in DMF (15 niL), and the resulting solution is stirred at rt for 14 h. A white precipitate of triethylamine hydrochloride forms in the course of the reaction. Water (15 mL) and EtOAc (100 mL) are added, the organic layer is separated, dried over sodium sulfate and concentrated under reduced pressure to a white residue. The solid is further dried under high vacuum to yield the desired product as a white solid (1.4 g, 69percent). 1H NMR (400 MHz, CHLOROFORM-cf) δ ppm 8.38 (s, 1 H), 7.58 (d, J=9.60 Hz, 1 H), 6.59 (d, J=9.09 Hz, 1 H), 4.19 - 4.31 (m, 2 H), 3.08 - 3.15 (m, 1 H), 2.92 - 3.04 (m, 1 H), 2.81 - 2.91 (m, 2 H), 2.57 - 2.65 (m, 1 H), 1.15 (d. J=6.32 Hz, 3 H).
67% With potassium carbonate In N,N-dimethyl acetamide at 60℃; for 2 h; To a stirred solution of (2S)-2-methylpiperazine (0.30 g, 2.1 mmol) in DMA (6 mL), 6-chloropyridine-3-carbonitrile (0.29 g, 2.3 mmol) and K2C03 were added. The resultantreaction mixture was heated to 60 °C for 2 h (TLC indicated complete consumption ofstarting material). The reaction mixture was diluted with cold water (20 mL) and extractedwith EtOAc (3 x 25 mL). The combined organic extracts were washed with cold water (20mL) and brine (2 x 20 mL). The organic layer was separated, dried over Na2S04 andconcentrated under reduced pressure to give the crude residue which was purified by columnchromatography (100-200 silica gel, 10 g, 10percent MeOH-DCM) to furnish 6-[(3S)-3-methylpiperazin-1-yl]pyridine-3-carbonitrile (0.29 g, 67percent) as an off-white solid.LCMS: m/z: 203.4 [M+Ht.
Reference: [1] Journal of Medicinal Chemistry, 2009, vol. 52, # 13, p. 3954 - 3968
[2] Patent: WO2008/110611, 2008, A1, . Location in patent: Page/Page column 34
[3] Patent: WO2018/125961, 2018, A1, . Location in patent: Page/Page column 110; 113
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YieldReaction ConditionsOperation in experiment
69% With potassium carbonate In acetonitrile at 20 - 60℃; for 2 h; To a mixture of 6-chloropyridine-3-carbonitrile (10 g, 0.06 mol) and (2R)-2-methylpiperazine(6.35 g, 0.06 mol) in acetonitrile (80 mL), K2C03 (12.0 g, 0.09 mol) was added at RT. Theresulting mixture was stirred at 60°C for 2 h (TLC indicated complete consumption ofstarting material). The reaction was brought toRT, quenched with water (150 mL) andextracted with EtOAc (3 x 80 mL). The combined organic extracts were dried over anhydrousNa2S04 and concentrated under reduced pressure. The residue was purified by columnchromatography (100-200 silica gel, 5percent MeOH-DCM) to afford 6-[(3R)-3-methylpiperazine-1-yl]-pyridine-3-carbonitrile (10.0 g, 69percent yield).
59% With triethylamine In N,N-dimethyl-formamide at 20℃; for 36 h; Triethylamine (5.51 g, 4 mL, 54.6 mmol, 2.7 eq) is added to a solution of 6-chloro- nicotinonitrile (2.76 g, 20 mmol, 1 eq), (i?)-2-methyl- piperazine (2.0Og, 20 mmol, 1 eq) in DMF (15 mL), and the resulting solution is stirred at rt for 36 h. A white precipitate of triethylamine hydrochloride forms in the course of the reaction. Water (15 mL) and EtOAc (100 mL) are added, the organic layer is separated, dried over sodium sulfate and concentrated under reduced pressure to a white residue. The solid is further dried under high vacuum to yield the desired product as a white solid (2.3 g, 59percent). IH NMR (400 MHz, CHLOROFORM-*/) δ ppm 8.32 (d, J=2.40 Hz, 1 H), 7.52 (dd, J=9.09, 2.27 Hz, 1 H), 6.52 (d, J=8.97 Hz, 1 H), 4.14 - 4.24 (m, 2 H), 3.01 - 3.07 (m, 1 H), 2.72 - 2.94 (m, 3 H), 2.52 (dd, J=12.76, 10.36 Hz, 1 H), 1.07 (d, J=6.32 Hz, 3 H).
Reference: [1] Patent: WO2018/125961, 2018, A1, . Location in patent: Page/Page column 80
[2] Journal of Medicinal Chemistry, 2009, vol. 52, # 13, p. 3954 - 3968
[3] Patent: WO2008/110611, 2008, A1, . Location in patent: Page/Page column 34
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  • [ 1245913-20-5 ]
Reference: [1] Journal of the American Chemical Society, 2013, vol. 135, # 32, p. 12122 - 12134
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