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Stage #1: With trifluoroacetic acid In dichloromethane at 20℃; for 4 h; Stage #2: With sodium hydrogencarbonate In water
To the solution of (5-bromo-pyrimidin-2-yl)-cyano-acetic acid tert-butyl ester (3.2 g, 10 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated. To the residue was added water, and the "pH" of the mixture was adjusted to neutral by saturated aqueous NaHCO3 solution. The mixture was then extracted with ethyl acetate. Organic layer was separated, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:3, 1:2, 1;1) to give (5-bromo-pyrimidin-2-yl)-acetonitrile as a white solid (1.2 g, 71percent).
67.4%
at 70℃; for 2 h;
A mixture of tert-butyl 2- (5-bromopyrimidin-2-yl) -2-cyanoacetic acid tert-butyl ester (3.068,10.301111111), 4111001 /Of hydrochloric acid (20 mL) and acetic acid (20 mL)Followed by adding to 100 mL of the reaction flask,The reaction was warmed to 70 ° (2 hours to stop the reaction, the reaction solution was poured directly into ice water (150 mL)Ethyl acetate (50 mL X 3). The organic phases were combined, washed successively with water (50 mL X 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was directly subjected to silica gel column The title compound (yellow solid, 1.37 g, 67.40percent) was obtained by chromatography and purification (petroleum ether / ethyl acetate (ν / ν) = 5/1)
Reference:
[1] Patent: US2011/118283, 2011, A1, . Location in patent: Page/Page column 14
[2] Patent: CN106674207, 2017, A, . Location in patent: Paragraph 0201-0204
2
[ 65364-66-1 ]
[ 831203-15-7 ]
Yield
Reaction Conditions
Operation in experiment
43%
Stage #1: With sodium chloride In water; dimethyl sulfoxide at 120℃; for 3 h; Stage #2: With sodium hydroxide In water
Synthesis of(5-bromopyrιmιdιn-2-yl)acetomtrιleTo 2 7Og of ethyl (5-bromopyπmidin-2-yl)(cyano)acetate (9 970 mmol) in dimethylsulfoxyde (20 ml) was added 0 584g of sodium chloride (9 970 mmol) and 0 18mL of water (9 970 mmol) The mixture was heated at 1200C under a nitrogen atmosphere for 3 hours The mixture was poured into water ( 30OmL) and the resultant precipitate was collected by filtration to give 5-bromopynmidin-2- yl)acetomtπle (0 6g , yield = 30percent)The clear yellow filtrate was salted by the addition of a saturated solution of sodium chloride, neutralided with sodium hydroxide, to give a red solution which was then extracted with dichloromethane The organic phase was collected, dried over magnesium sulphate, and evaporated in vacuo to give a dark oil, wich was purified by flash chromatography using 2/1 heptane/ ethyl acetate as eluent, yieldidng to 5 bromopyπmidm-2-yl)acetonitπle (0 9g , yield = 43percent) 1H NMR S (PPm7 CDCl3) 9 0 (s, 2H), 425 (s, 2H)
43%
Stage #1: With sodium chloride In water; dimethyl sulfoxide at 120℃; for 3 h; Stage #2: With sodium hydroxide In water
Synthesis of(5-bromopyrimidin-2-yl)acetonitrileTo 2.7Og of ethyl (5-bromopyrimidin-2-yl)(cyano)acetate (9.970 mmol) in dimethylsulfoxyde (20 ml) was added 0.584g of sodium chloride (9.970 mmol) and 0.18mL of water (9.970 mmol). The mixture was heated at 1200C under a nitrogen atmosphere for 3 hours. The mixture was poured into water ( 30OmL) and the resultant precipitate was collected by filtration to give 5-bromopyrimidin-2- yl)acetonitrile (0.6g , yield = 30percent).The clear yellow filtrate was salted by the addition of a saturated solution of sodium chloride, neutralided with sodium hydroxide, to give a red solution which was then extracted with dichloromethane. The organic phase was collected, dried over magnesium sulphate, and evaporated in vacuo to give a dark oil, wich was purified by flash chromatography using 2/1 heptane/ ethyl acetate as eluent, yieldidng to 5-bromopyrimidin-2-yl)acetonitrile (0.9g , yield = 43percent). 1H NMR δ (ppm, CDCl3) : 9.0 (s, 2H); 4.25 (s, 2H).
Stage #1: With sodium hydride In dimethyl sulfoxide at 20℃; for 1 h; Inert atmosphere Stage #2: at 20℃; for 8 h; Inert atmosphere Stage #3: With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 16 h;
To a suspension of sodium hydride (53 mg (60percent oil suspension), 1.34 mmol) in DMSO (2 ml) at room temperature under a nitrogen atmosphere was added tert-butyl cyanoacetate (197 mg, 39 mmol) in DMSO (1 ml) was added dropwise over 15 minutes and then stirred at room temperature for 1 hour.5-Bromo-2-chloropyrimidine (100 mg, 0.52 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 8 hours. Next, a saturated aqueous solution of ammonium chloride was added to the reaction system, extracted with ethyl acetate, washed with water, and then concentrated under reduced pressure to obtain a crude product.Subsequently, trifluoroacetic acid (1.8 ml) was added to a solution of the dried crude product in dichloromethane (2.3 ml) at 0 ° C., and the mixture was stirred for 1 hour and then allowed to warm to room temperature and stirred for 15 hours did.The reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered and concentrated under reduced pressure to obtain a crude product of (5-bromopyrimidin-2-yl) acetonitrile.The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain (5-bromopyrimidin-2-yl) acetonitrile. Yield 46 mg, yield 45percent, white solid.
Reference:
[1] Patent: JP2017/178911, 2017, A, . Location in patent: Paragraph 0152; 0153
Synthesis of(5-bromopyriotamiotadiotan-2-yl)acetomtriotaleTo 2 7Og of ethyl (5-bromopy?midin-2-yl)(cyano)acetate (9 970 mmol) in dimethylsulfoxyde (20 ml) was added 0 584g of sodium chloride (9 970 mmol) and 0 18mL of water (9 970 mmol) The mixture was heated at 1200C under a nitrogen atmosphere for 3 hours The mixture was poured into water ( 30OmL) and the resultant precipitate was collected by filtration to give 5-bromopynmidin-2- yl)acetomt?le (0 6g , yield = 30%)The clear yellow filtrate was salted by the addition of a saturated solution of sodium chloride, neutralided with sodium hydroxide, to give a red solution which was then extracted with dichloromethane The organic phase was collected, dried over magnesium sulphate, and evaporated in vacuo to give a dark oil, wich was purified by flash chromatography using 2/1 heptane/ ethyl acetate as eluent, yieldidng to 5 bromopy?midm-2-yl)acetonit?le (0 9g , yield = 43%) 1H NMR S (PPm7 CDCl3) 9 0 (s, 2H), 425 (s, 2H)
43%
Synthesis of(5-bromopyrimidin-2-yl)acetonitrileTo 2.7Og of ethyl (5-bromopyrimidin-2-yl)(cyano)acetate (9.970 mmol) in dimethylsulfoxyde (20 ml) was added 0.584g of sodium chloride (9.970 mmol) and 0.18mL of water (9.970 mmol). The mixture was heated at 1200C under a nitrogen atmosphere for 3 hours. The mixture was poured into water ( 30OmL) and the resultant precipitate was collected by filtration to give 5-bromopyrimidin-2- yl)acetonitrile (0.6g , yield = 30%).The clear yellow filtrate was salted by the addition of a saturated solution of sodium chloride, neutralided with sodium hydroxide, to give a red solution which was then extracted with dichloromethane. The organic phase was collected, dried over magnesium sulphate, and evaporated in vacuo to give a dark oil, wich was purified by flash chromatography using 2/1 heptane/ ethyl acetate as eluent, yieldidng to 5-bromopyrimidin-2-yl)acetonitrile (0.9g , yield = 43%). 1H NMR delta (ppm, CDCl3) : 9.0 (s, 2H); 4.25 (s, 2H).
To the solution of (5-bromo-pyrimidin-2-yl)-cyano-acetic acid tert-butyl ester (3.2 g, 10 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for 4 h. The mixture was concentrated. To the residue was added water, and the ?pH? of the mixture was adjusted to neutral by saturated aqueous NaHCO3 solution. The mixture was then extracted with ethyl acetate. Organic layer was separated, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:3, 1:2, 1;1) to give (5-bromo-pyrimidin-2-yl)-acetonitrile as a white solid (1.2 g, 71%).
67.4%
With hydrogenchloride; acetic acid; at 70℃; for 2h;
A mixture of tert-butyl 2- (5-bromopyrimidin-2-yl) -2-cyanoacetic acid tert-butyl ester (3.068,10.301111111), 4111001 /Of hydrochloric acid (20 mL) and acetic acid (20 mL)Followed by adding to 100 mL of the reaction flask,The reaction was warmed to 70 (2 hours to stop the reaction, the reaction solution was poured directly into ice water (150 mL)Ethyl acetate (50 mL X 3). The organic phases were combined, washed successively with water (50 mL X 3) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was directly subjected to silica gel column The title compound (yellow solid, 1.37 g, 67.40%) was obtained by chromatography and purification (petroleum ether / ethyl acetate (nu / nu) = 5/1)
tert-butyl 2-(3-acetyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)acetate[ No CAS ]
tert-butyl 2-(3-acetyl-5-(2-(cyanomethyl)pyrimidin-5-yl)-1H-indazol-1-yl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 5h;
To a solution of <strong>[831203-15-7]2-<strong>[831203-15-7](5-bromopyrimidin-2-yl)acetonitrile</strong></strong> (S2, 1 equiv) in DMF/H2O (9:1, 10 vol) was added compound S1 (1 equiv), K2CO3(2 equiv), and tetrakis(triphenylphosphine)palladium (0.1 equiv). The reaction mixture was stirred at 90 C. for 5 h and then concentrated under reduced pressure. The remaining residue was purified by column chromatography on silica gel to give compound S3.
2-((5-(4-fluorophenyl)pyrimidine)-2-yl)acetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80.1%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In toluene; at 100℃; for 8h;Inert atmosphere;
A solution of 2- (5-bromopyrimidin-2-yl) acetonitrile (0.1 (^, 0.50%)4-fluorophenylboronic acid (0.088, 0.601111111)Potassium carbonate (0.21 g, 1.50 mmol),Tetrakis (triphenylphosphine) palladium (0.3 g, 0.30 mmol)And toluene (10 mL) were successively added to a 50 mL reaction flask,The reaction was carried out with nitrogen and the reaction was carried out at 100 C for 8 hours.The reaction was quenched and the solvent was removed by distillation under reduced pressure. The remaining solid was extracted with dichloromethane (10 mL X), washed with organic phase, saturated brine (20 mL) and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The title compound (white solid, 0.088, 80.1%) was obtained by silica gel column chromatography (petroleum ether / acetone (nu / nu) = 20/1)
2-(5-(4-chloro-2-fluorophenyl)pyrimidin-2-yl)acetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62.2%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In toluene; at 100℃; for 15h;Inert atmosphere;
General procedure: The title compound of this step was prepared by the method described in Example 1, Step 3,2- (5-bromopyrimidin-2-yl) acetonitrile (0.724 g, 3.66 mmol), 4-chloro-2-fluorophenylboronic acid (0.829 g, 4.75 mmol)Potassium carbonate (1.517 g, 10.98 mmol),Tetrakis (triphenylphosphine) palladium (0.338 g, 0.292 mmol)In toluene (15 mL) with nitrogen at 100 C for 15 hours.The crude product was directly purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / V) = 5/1)The compound (orange solid, 563 g, 62.2%)
[5-(1-octynyl)pyrimidin-2-yl]acetonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With copper(l) iodide; triethylamine; triphenylphosphine; palladium dichloride; at 40℃; for 3h;Inert atmosphere;
At room temperature, under a nitrogen atmosphere,(5-bromopyrimidin-2-yl) acetonitrile (150 mg, 0.76 mmol),1-octyne (167 mg, 1.51 mmol),PdCl2 (13 mg, 0.08 mmol),Triphenylphosphine (40 mg, 0.15 mmol),CuI (7 mg, 0.04 mmol),Triethylamine (0.81 ml) and THF (1.8 ml) were added and the mixture was stirred at 40 C. for 3 hours.Thereafter, filtration with celite was carried out, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified using thin layer column chromatography (hexane: ethyl acetate = 2: 1) to obtain [5- (1-octynyl) pyrimidin-2-yl] acetonitrile. Yield 138 mg, yield 80%, yellow liquid.
To a suspension of sodium hydride (53 mg (60% oil suspension), 1.34 mmol) in DMSO (2 ml) at room temperature under a nitrogen atmosphere was added tert-butyl cyanoacetate (197 mg, 39 mmol) in DMSO (1 ml) was added dropwise over 15 minutes and then stirred at room temperature for 1 hour.5-Bromo-2-chloropyrimidine (100 mg, 0.52 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 8 hours. Next, a saturated aqueous solution of ammonium chloride was added to the reaction system, extracted with ethyl acetate, washed with water, and then concentrated under reduced pressure to obtain a crude product.Subsequently, trifluoroacetic acid (1.8 ml) was added to a solution of the dried crude product in dichloromethane (2.3 ml) at 0 C., and the mixture was stirred for 1 hour and then allowed to warm to room temperature and stirred for 15 hours did.The reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered and concentrated under reduced pressure to obtain a crude product of (5-bromopyrimidin-2-yl) acetonitrile.The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain (5-bromopyrimidin-2-yl) acetonitrile. Yield 46 mg, yield 45%, white solid.
(E)-2-(5-bromopyrimidin-2-yl)-3-ethoxy-prop-2-enenitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79.6%
at 120℃; for 5h;
Add acetic anhydride (2.50 g, 23.7 mmol) to a solution of2-(5-bromopyrimidin-2yl)acetonitrile (950 mg, 4.75 mmol) and triethyl orthoformate (3 mL, 17.7 mmol), the reaction mixture is stirred at 120 oc for 5 h. The reaction mixture is concentrated to afford 10 title compound (0.96 g, 79.6%) as brown crude. LCMS (m/z): 255.9 [M+Ht.