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Structure of 38275-57-9 * Storage: {[proInfo.prStorage]}
* 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.
With hydrogenchloride In water at 80℃; for 2 h; Inert atmosphere
To a solution of 5-bromopyrimidine-2-carbonitrile (3.0 g, 16 mmol) in MeOH (20 mL) was added concentrated HCl (19 mL). The reaction mixture was heated at 80° C. for 2 h. Upon cooling to rt, a precipitate formed. Filtration provided the desired product as a white solid (2.5 g, 71percent). MS (ESI): mass calcd. for C6H5BrN2O2, 216.0; m/z found, 217.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 9.20 (s, 2H), 3.92 (s, 3H).
With 1,4-diaza-bicyclo[2.2.2]octane In water; dimethyl sulfoxide at 20℃; for 18 h;
Preparation 63 5-Bromo-pyrimidine-2-carbonitrile A solution of 5-bromo-2-chloropyrimidine (10g, 51.8mmol) in dimethylsulfoxide (26ML)-WAS-ADDED TO : A MIXTURE, of sodium cyandie (2.59g, 51.8mmol) and triethylenediamine (1. 2g, 10. 4mmol) in dimethylsulfoxide (14mL) and water (28ML). THE RESULTING mixture was stirred for 18 hours at ROOM TEMPERATURE. THE ; mixture was-then diluted with water (130MOLY and extracted with diethyl ether (3x150mL) the combined organic solutions were dried over sodium sulfate and concentrated in vacuo to give a pale yellow solid. Re-crystallisation of the solid from hot dichloromethane afforded the title product in 99percent yield, 9.4g. 1HNMR (CDCL3, 400MHZ) No.: 8.84 (S, 2H).
88%
at 20℃;
Example 50; 2-Benzoyl-pyrimidine-5-carboxylic acid morpholin-4-ylamide; <n="95"/>Step 1 : 5-Bromo-2-chloropyrimidine (7.51 g, 38.83 mmol) is dissolved in DMSO (20 niL) is added to a mixture of NaCN (1.9 g, 38.83 mmol) and l,4-diazabicyclo[2,2,2]octane (0.87 g, 7.77 mmol) in DMSO (10 mL) and water (20 mL). The mixture is stirred at rt overnight, and then water (100 mL) is added. The mixture is extracted with ether (3x100 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo to afford 5 bromo-pyrimidine-2-carbonitrile (6.28 g, 88percent) as a solid. MS: 184 (M+H).
With 1,4-diaza-bicyclo[2.2.2]octane In water; dimethyl sulfoxide at 20℃;
To a solution of NaCN (0.849 g, 17.32 mmol) and DABCO (0.390 g, 3.48 mmol) in a mixture of DMSO (4 ml) and H2O (9 ml) was added a solution of 5-bromo-2-chloropyrimidine (3.05 g, 15.75 mmol) in DMSO (9 ml). The solution was stirred at room temperature overnight, and then diluted with water, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give 5-bromopyrimidine-2-carbonitrile (2.327 g, 12.01 mmol, 76percent yield, 1H NMR (CDCl3 500 MHz): δ 8.94 (s, 2H)).
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 2, p. 568 - 583
[2] Patent: US2014/107335, 2014, A1, . Location in patent: Paragraph 0170; 0171
[3] Patent: US2009/253708, 2009, A1, . Location in patent: Page/Page column 15
7
[ 32779-36-5 ]
[ 38275-57-9 ]
Yield
Reaction Conditions
Operation in experiment
84%
With 1,4-diaza-bicyclo[2.2.2]octane In water; dimethyl sulfoxide at 20℃;
A mixture of 5-bromo-2- chloropynmidine (20 g, 1 03.40 mmol, 1 .00 equiv), 1 , 4-diaza-bicyclo[2.2.2]octane (2.32 g), and potassium carbon itri le (6.72 g, 1 03.20 mmol, 1 .00 equiv) in water (54 2 mL) and DMSO (80 mL) was stirred overnight at rt. Water (50 mL) was then added and the resulting solution was extracted with 3 100 mL of ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1 6 g (84percent) of 5-bromopynmidine-2-carbonitri le as a yellow solid. 1HNMR (300 MHz, CDCl3) δ 8.94 (s, 2H).
Reference：
[1] Patent: WO2013/127267, 2013, A1, . Location in patent: Page/Page column 98
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 3, p. 529 - 541
8
[ 7677-24-9 ]
[ 36529-69-8 ]
[ 114969-66-3 ]
[ 38275-57-9 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1987, vol. 35, # 8, p. 3119 - 3126
9
[ 7677-24-9 ]
[ 36529-69-8 ]
[ 114969-66-3 ]
[ 38275-57-9 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1987, vol. 35, # 8, p. 3119 - 3126
10
[ 38275-57-9 ]
[ 87362-30-9 ]
Reference：
[1] Patent: US2014/275096, 2014, A1,
11
[ 75-16-1 ]
[ 38275-57-9 ]
[ 1189169-37-6 ]
Yield
Reaction Conditions
Operation in experiment
61%
at -78℃; for 3.5 h;
1-(5-Bromopyrimidin-2-yl)ethanone To a solution of 5-bromopyrimidine-2-carbonitrile (221 mg, 1.2 mmol) in THF (10 ml) was added methylmagnesium bromide (3.0 ml, 4.20 mmol, 1.4 molar, THF) at -78° C. under nitrogen. The solution was stirred at -78° C. for 3.5 hours, and then quenched with satd aq NH4Cl, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The reaction was purified by column chromatography on silica gel (petroleum ether: EtOAc=1:0 to 0:1) to afford 1-(5-bromopyrimidin-2-yl)ethanone (1.55 mg, 61percent yield). 1H NMR (CDCl3 500 MHz): δ 9.00 (s, 2H), 2.80 (s, 3H).
With 1,4-diaza-bicyclo[2.2.2]octane; In water; dimethyl sulfoxide; at 20℃; for 18h;
Preparation 63 5-Bromo-pyrimidine-2-carbonitrile A solution of 5-bromo-2-chloropyrimidine (10g, 51.8mmol) in dimethylsulfoxide (26ML)-WAS-ADDED TO : A MIXTURE, of sodium cyandie (2.59g, 51.8mmol) and triethylenediamine (1. 2g, 10. 4mmol) in dimethylsulfoxide (14mL) and water (28ML). THE RESULTING mixture was stirred for 18 hours at ROOM TEMPERATURE. THE ; mixture was-then diluted with water (130MOLY and extracted with diethyl ether (3x150mL) the combined organic solutions were dried over sodium sulfate and concentrated in vacuo to give a pale yellow solid. Re-crystallisation of the solid from hot dichloromethane afforded the title product in 99% yield, 9.4g. 1HNMR (CDCL3, 400MHZ) No.: 8.84 (S, 2H).
88%
1,4-diaza-bicyclo[2.2.2]octane; In water; dimethyl sulfoxide; at 20℃;
Example 50; 2-Benzoyl-pyrimidine-5-carboxylic acid morpholin-4-ylamide; <n="95"/>Step 1 : 5-Bromo-2-chloropyrimidine (7.51 g, 38.83 mmol) is dissolved in DMSO (20 niL) is added to a mixture of NaCN (1.9 g, 38.83 mmol) and l,4-diazabicyclo[2,2,2]octane (0.87 g, 7.77 mmol) in DMSO (10 mL) and water (20 mL). The mixture is stirred at rt overnight, and then water (100 mL) is added. The mixture is extracted with ether (3x100 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo to afford 5 bromo-pyrimidine-2-carbonitrile (6.28 g, 88%) as a solid. MS: 184 (M+H).
With 1,4-diaza-bicyclo[2.2.2]octane; In water; dimethyl sulfoxide; at 20℃; for 2h;
Sodium cyanide (270mg, 5.43mmol) was dissolved in water (3ml) and DABCO(87mg, 0.8mmol) added, followed by DMSO (3ml). To this mixture was added a solution of 5- bromo-2-chloropyrimidine (Ig, 5.17mmol) in DMSO (3ml), and the resulting mixture stirred at room temperature for 2 hours. The mixture was diluted with EtOAc (75ml) and washed with water, IN HCl, sat. NaHCO3, filtered and evaporated to give of the title compound. 1HNMR (50025 MHz, CDCl3) delta: 8.96 (s, 2H).
In DMF (N,N-dimethyl-formamide); at 20℃; for 18h;
Sodium cyanide (2.30 g, 46.6 MMOL) was dissolved in dimethylformamide (60 ml) and treated with 5-bromo-2-chloropyrimidine (6.0 g, 31.1 MMOL). The resulting mixture was stirred at room temperature for 18 hours, diluted with water and extracted with dichloromethane. The DICHLOROMETHANE extracts were combined, washed with water, dried (magnesium sulphate), filtered and concentrated in vacuo. The crude product was purified by column chromatography eluting with a mixture of ethyl acetate: hexane (1: 4) to afford the title compound (D38).
With sodium hydroxide; water; at 60℃; for 1h;Heating;
Preparation 64 5-BROMO-PYRIMIDINE-2-CARBOXCVLIC ACID mixture of sodium hydroxide (4. 88G ; 120MMOL) and the product of preparation. 63 (7.5g, 40. 8mmol) in water (122mL) was heated at 60C FOR SI. HOUR-THE mixture was then. acidified with 1 M hydrochloric acid, extracted with ethyl acetate AND DICHTOROMETHANE and concentrated in vacuo to afford some title compound as a white solid, 300mg. The aqueous solution-was also evaporated under reduced pressure and the residue was extracted into dichloromethane methanol, 90. 10J THE precipitate was-filtered off and the filtrate was concentrated in vacuo to afford further title compound as a white solid, 5.5g. 'HNMR (DMSO-D6, 400MHZ) No. : 9. .10(s, 2H), 13.8(brs, 1H). MS APCI+ m/z 203 [MH]+
A mixture of <strong>[38275-57-9]5-bromopyrimidine-2-carbonitrile</strong> (5.74g, 31.20 mmol) and sodium hydroxide (3.75 g, 93.59 mmol) in water (100 ml) was heated at 6O0C for lhr. The reaction 5 mixture was then acidified with IM HCl and the volume of aqueous reduced in vacuo. The residue was extracted into 90:10 DCM:MeOH and the extracts evaporated to give a yellow solid. This was triturated with ethyl acetate was and the resulting yellow solid filtered off and washed well with more ethyl acetate. The filtrate was dried (MgSO4), filtered, combined with the solid and the solvent removed in vacuo to give 5-bromopyrimidine-2- 0 carboxylic acid as EPO <DP n="104"/>a yellow solid. 4.72g, 1H NMR (400 MHz, DMSO-d6) delta 9.18 (s, 2H), 13.76 (s, IH); the spectrum also shows signals due to an unidetified impurity, approx. 10 mol % .
With potassium phosphate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 80℃; for 1h;
2) Production of 2-(1-t-butoxycarbonylpiperidin-4-yloxy)-5-(2-cyanopyrimidin-5-yl)pyrimidine: 2-Cyano-5-bromopyrimidine (20 mg, 0.11 mmol), bis(diphenylphosphino)ferrocene-palladium(II) dichloride, dichloromethane (4.0 mg, 0.005 mmol), potassium phosphate (53 mg, 0.25 mmol) were added to a dimethylformamide (2.0 ml) solution of 2-(1-t-butoxycarbonylpiperidin-4-yloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxobororan-2-yl)pyri midine (20 mg, 0.049 mmol), and stirred in a nitrogen atmosphere at 80C for 1 hour. The reaction mixture was cooled to room temperature, and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and saturated saline solution in that order, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through partitioning thin-layer column chromatography (ethyl acetate:hexane = 1:1) to obtain the entitled compound (9.3 mg, 49 %).
5-(2-fluoro-phenoxy)-2-pyrazin-2-yl-6-(2-cyano-pyrimidin-5-yloxy)-1H-benzimidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With Ce2CO3; In 1-methyl-pyrrolidin-2-one; at 90℃; for 0.25h;
7.0 mg of <strong>[38275-57-9]5-bromo-2-cyano-pyrimidine</strong> and 15 mg of cesium carbonate were added to an N-methylpyrrolidinone (0.5 ml) solution of 7.0 mg of 5-(2-fluorophenoxy)-6-hydroxy-2-pyrazin-2-yl-1H-benzimidazole obtained in the step 1, and the reaction liquid was stirred at 90C for 15 minutes. The reaction mixture was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1 % trifluoroacetic acid]. The resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound a colorless solid. 1H-NMR(CD3OD)delta: 7.01-7.58(5H,m), 7.64-7.82(1H,m), 8.52(2H,s), 8.67(1H,s), 8.74(1H,s), 9.44(1H,s) ESI-MS(m/e):426[M+H]
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In toluene; at 100℃; for 22h;
Example II:; A mixture of 4-bromo-2-cyanopyrimidine (280 mg, 1.52 mmol), Pd[PPh3J4 (86 mg,0.074 mmol) and Cs2CO3 (628 mg, 1.93 mmol) was evacuated and purged with nitrogen. Toluene (15 mL) was then added followed by TIPS-SH (413 muL, 1.92 mmol). The mixture was heated at 1000C for 22 h and the resulting orange suspension was then cooled to O0C. 2,4-Dichloro-5-methylpyrimidine (267 muL, 2.28 mmol) was then added followed by tetrabutyl ammonium fluoride (1.0 M in THF. 3.8 mL, 3.8 mmol) dropwise. The mixture was stirred at O0C for 30 min then allowed to warm to room temperature and stirred for 6 h. The reaction was quenched with saturated aqueousNH4CI and the mixture was extracted three times with EtOAc. The combined extracts <n="102"/>were washed with water, brine then dried (Na2SO.)). Solvent removal under reduced pressure and purification by silica gel chromatography w ith 100% dichloromethane then 1 % EtOAc/dichloromethane as eluent gave 5-(2-chloro-5-methylpy?midin-4- ylthio)pyrimidiotane-2-carbonitrile (327 mg, 82%) as a pale yellow solid: 1 H NMR (300 5 MHz, CDCl3): delta 8.97 (s, 2H), 8.25 (s, I H), 2.35 (s, 3H); Std LC-MS; rt 6.30 mm. m/z 264.1 [M+H]+; purity 96% at 254 nm.
Step 2: 5-Bromo-pyrimidine-2-carbonitrile(2.5 g, 13.59 mmol) is dissolved ether (30 mL), and PhMgBr (3 ether solution, 13.59 mmol, 4.53 mL) is added dropwise at rt. The mixture is heated to reflux for 3 h under N2, and then cooled to rt. THF (30 mL) is added followed by the addition of 2 N aqueous HCl (10 mL). The resulting solution is stirred at rt for 30 min, and water (30 mL) is added. The aqueous layer is extracted with EtOAc (3x20 mL). The combined organic layer is washed with saturated aqueous NaHCO3 (15 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting 70% EtOAc in heptane to afford (5-bromo-pyrimidine-2-yl)-phenyl-methanone (3.01 g, 84%) as a solid. MS: 264 (M+H).
1-(5-Bromopyrimidin-2-yl)ethanone To a solution of <strong>[38275-57-9]5-bromopyrimidine-2-carbonitrile</strong> (221 mg, 1.2 mmol) in THF (10 ml) was added methylmagnesium bromide (3.0 ml, 4.20 mmol, 1.4 molar, THF) at -78 C. under nitrogen. The solution was stirred at -78 C. for 3.5 hours, and then quenched with satd aq NH4Cl, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The reaction was purified by column chromatography on silica gel (petroleum ether: EtOAc=1:0 to 0:1) to afford 1-(5-bromopyrimidin-2-yl)ethanone (1.55 mg, 61% yield). 1H NMR (CDCl3 500 MHz): delta 9.00 (s, 2H), 2.80 (s, 3H).
In tetrahydrofuran; toluene; at 0℃; for 2h;
At 0 C, methylmagnesium bromide (1.4 M solution in toluene/THF (75:25, 21.35 mL, 29.9 mmol) was added to a THF (54.3 mL) solution containing <strong>[38275-57-9]5-bromo-2-cyanopyrimidine</strong> (5 g, 27.2 mmol). The resulting mixture was stirred for 2 h at 0 C. Next, a saturated aqueous ammonium chloride solution was added followed by 3.0 N HCl to adjust the pH to 1. This solution was allowed to stir overnight. The pH was then adjusted to 7-8 with a saturated aqueous solution of K2CO3and the material was extracted with EtOAc and concentrated in vacuo. The product thus obtained was purified on silica gel eluting with a hexanes/EtOAc gradient (0-100%). Desired fractions were then pooled and concentrated in vacuo to provide the title compound. LCMS-ESI (pos.) m/z: 200.9 (M+H)t
D. 1-(5-bromopyrimidin-2-yl)ethanone To a 50 mL 1 neck flask equipped with magnetic stirrer, nitrogen inlet and thermometer was charged 0.68 grams (g) of 5-Bromo-pyrimidine-2-carbonitrile (3.7 mmol), and 20 mL of anhydrous ether. The solution was cooled to ~0 C., and the methyl magnesium bromide solution 3.0M in ether; 1.1 ml, 3.3 mmol) was added dropwise. Allowed to slowly warm to room temperature, and quenched with aqueous ammonium chloride solution. Extracted with 3*50 mls of ether and washed with brine. Dried over anhydrous magnesium sulfate, and concentrated under vacuum on a rotary evaporator. The crude product thus obtained was chromatographed on silica gel with ethyl acetate and hexane. afforded 0.22 g of a white solid which was consistent with the title compound upon analysis by NMR. The NMR data is as follows: 300 MHz 1H NMR (CDCl3, TMS=0 ppm) 2.75 (s, 3H); 9.00 (s 2H).
With 1,4-diaza-bicyclo[2.2.2]octane; In water; dimethyl sulfoxide; at 20℃;
To a solution of NaCN (0.849 g, 17.32 mmol) and DABCO (0.390 g, 3.48 mmol) in a mixture of DMSO (4 ml) and H2O (9 ml) was added a solution of 5-bromo-2-chloropyrimidine (3.05 g, 15.75 mmol) in DMSO (9 ml). The solution was stirred at room temperature overnight, and then diluted with water, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give 5-bromopyrimidine-2-carbonitrile (2.327 g, 12.01 mmol, 76% yield, 1H NMR (CDCl3 500 MHz): delta 8.94 (s, 2H)).
In dimethyl sulfoxide; at 5 - 20℃;Inert atmosphere;
To a 50 mL 1 neck flask equipped with magnetic stirrer, nitrogen inlet and thermometer was charged 3.16 grams (g) of 5-bromo-2-chloropyrimidine (16.3 mmol), and 20 mL of anhydrous dimethylsulfoxide. The solution was cooled to 5 C. (began to freeze), and the sodium cyanide (0.8 g 16.3 mmol) was added in one portion. Allowed to slowly warm to room temperature, and stirred for another 3 hours. Then the solution was poured into 100 ml of water and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum on a rotary evaporator. Silica gel column chromatography (ethyl acetate/hexane) afforded 0.85 g of a white solid which was consistent with the title compound upon analysis by NMR. The NMR data is as follows: 300 MHz 1H NMR (CDCl3, TMS=0 ppm) 8.95 (s 2H);
5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrimidinecarbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
3-Cyclobutyl-2, 3,4, 5-TETRAHYDRO-1H-3-BENZAZEPIN-7-OL (E3) (1.81 g, 8.33 MMOL) was dissolved in pyridine (40 ml) and sodium hydride (60% in mineral oil, 0.40 g, 10.0 MMOL) was added with stirring under argon at 0 C. The mixture was left to stir for 5 minutes. Copper (I) bromide (1.68 g, 11.7 MMOL) was added and the mixture allowed to warm to room temperature over 30 minutes. 5-Bromo-2-pyrimidinecarbonitrile (D38) (2.30 g, 12.5 MMOL) in pyridine (8 ml) was added and the mixture heated at 100 C for 1 hour. The mixture was allowed to cool to room temperature and the solvent removed in vacuo. The crude product was purified by column chromatography, eluting with a mixture of 0.880 ammonia: methanol : dichloromethane (0.2 : 1.8 : 98) to afford the title compound (E177A) ; MS (ES+) m/e 321 [M+H] +.
With 1,4-diaza-bicyclo[2.2.2]octane; In water; dimethyl sulfoxide; at 20℃;
A mixture of 5-bromo-2- chloropynmidine (20 g, 1 03.40 mmol, 1 .00 equiv), 1 , 4-diaza-bicyclo[2.2.2]octane (2.32 g), and potassium carbon itri le (6.72 g, 1 03.20 mmol, 1 .00 equiv) in water (54 2 mL) and DMSO (80 mL) was stirred overnight at rt. Water (50 mL) was then added and the resulting solution was extracted with 3 100 mL of ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1 6 g (84%) of 5-bromopynmidine-2-carbonitri le as a yellow solid. 1HNMR (300 MHz, CDCl3) delta 8.94 (s, 2H).
With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 100℃; for 2h;
A mixture of 5- bromopyrimidine-2-carbonitrile (2.0 g, 1 0.87 mmol, 1 .00 equiv), benzenethiol ( 1 .1 g, 9 98 mmol, 0.92 equiv), and cesium carbonate (7.08 g, 2 1 .73 mmol, 2 00 equiv) in 1 - methylpyrrolidin-2-one ( 1 0 mL) was stirred for 2 h at 1 00 C. The resulting solution was di luted with 50 mL of water and extracted with 3x50 mL of ether The organic layers were combined was washed with 3x50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether ( 1 :30) to give 1.1 g (47%) of 5- (phenylsulfanyl) pyrimidine-2-carbonitrile as an off-white solid. 1HNMR (300 MHz, CDCl3) delta 8.74 (s, 2H), 7.64-7.58 (m, 2H), 7 56-7.49 (m, 3H).
With tetrakis(triphenylphosphine) palladium(0); In water; toluene; at 80℃; for 16h;Inert atmosphere;
Step 3 Preparation of 5-[4-(2-Cyano-pyrimidin-5-yl)-phenyl]-4-fluoromethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester To the solution of 4-Fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-oxazolidine-3-carboxylic acid tert-butyl ester (1 g, 2.298 mmol, 1.0 eq) in toluene/water (3:1-24 mL) is added 5-Bromo-pyrimidine-2-carbonitrile (0.42 g, 2.282 mmol, 1.20 eq), Na2CO3 (0.48 g, 4.528 mmol) and degassed with nitrogen for 15 minutes followed by addition of Tetrakis(triphenylphosphine)palladium(0) (0.132 g, 0.114 mmol) and heated reaction mixture to 80 C. for 16 hours. Solvent is evaporated in vacuo to get the crude which is purified by column chromatography eluting from 10% ethyl acetate/hexane to give title compound (0.45 g): 1H-NMR (400 MHz, DMSO-d6) 1.43 (s, 9H), 1.51 (s, 3H), 1.63 (s, 3H), 3.85-3.92 (m, 1H), 4.47-4.59 (m, 1H), 4.76-4.96 (m, 1H), 5.17 (d, 1H, J=7.16), 7.67 (d, 2H, J=8.24 Hz), 7.96 (d, 2H, J=8.24 Hz), 9.40 (s, 2H).). m/z M-H 410.8.
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 90℃;Inert atmosphere;
[0660] Synthesis of 5-(pyrrolidin-l-yl) pyrimidine-2-carbonitrile: [0661] To a stirred solution of <strong>[38275-57-9]5-bromopyrimidine-2-carbonitrile</strong> (150 mg, 0.81 mmol) in DMF (6 mL) under argon atmosphere were added pyrrolidine (82.7 mg, 1.21 mmol), diisopropyl ethyl amine (0.28 mL, 1.62 mmol) at RT; heated to 90 C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with CH2CI2 (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 30% EtOAc/ Hexanes to afford 5-(pyrrolidin- 1-yl) pyrimidine-2-carbonitrile (32 mg, 21%) as an off- white solid. [0662] 1H-NMR (CDCI3, 400 MHz): delta 8.02 (s, 2H), 3.40-3.38 (m, 4H), 2.11-2.09 (m, 4H); LC-MS: 99%; 175.1 (M++l); (column; Eclipse XDB C18, (150 4.6 mm, 5.0 mupiiota); RT 7.46 min. 0.05% TFA (aq.): ACN; 1.0 mL/min); TLC: 30% EtOAc/ Hexanes (R 0.2).
In N,N-dimethyl-formamide; at 0℃; for 1h;Inert atmosphere;
[0684] Synthesis of 5-(methylthio) pyrimidine-2-carbonitrile: [0685] To a stirred solution of <strong>[38275-57-9]5-bromopyrimidine-2-carbonitrile</strong> (1 g, 5.40 mmol) in DMF (20 mL) under argon atmosphere was added sodium methanethiolate (454 mg, 6.48 mmol) at 0 C and stirred for 1 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ Hexanes to afford 5-(methylthio) pyrimidine-2-carbonitrile (350 mg, 42%) as white solid. [0686] 1H-NMR (CDCI3, 500 MHz): delta 8.60 (s, 2H), 2.63 (s, 3H); LC-MS: 99.56%; 151.8 (M++l); (column; X-bridge C-18, (50 3.0 mm, 3.5 mu); RT 2.58 min. 0.05% TFA (aq.): ACN; 0.8 mL/min); TLC: 20% EtOAc/ Hexanes (R 0.3).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;
A mixture of AI-1 (11.0 g, 59.8 mmol), K2CO3 (10.7 g, 77.4 mmol) and sodium ethanethiolate (5.5 g, 65.4 mmol) in DMF (100 mL) is stirred at room temperature under nitrogen overnight. The mixture is diluted with water and extracted with EtOAc. The organic layers are dried with anhydrous Na2SO4, evaporated under reduced pressure and purified by silica gel column chromatography to yield intermediate AI-2.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h;Inert atmosphere;
A mixture of AH-1 (113 g, 0.62 mol), K2C03 (171 g, 1.24 mol) and sodium ethanethiolate (67 g, 0.80 mol) in DMF (2 L) is stirred at rt under N2 for 18 h. The mixture is diluted with H20 and extracted with EtOAc. The organic layers are dried (Na2S04), decanted and concentrated. The resulting residue is purified by Si02 flash chromatography to yield AH-2.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h;Inert atmosphere;
Under N2, stir AH-1 (113 g, 0.62 mol) at rt,K2 CO3 (171 g, 1.24 mol)And sodium ethanethiolate (67 g, 0.80 mol)Mixture in DMF (2 L) for 18 h.The mixture was diluted with H2O and extracted with EtOAc. The organic layer was dried (Na2SO4), evaporated and concentrated. The resulting residue was purified by flash chromatography on SiO2 to yield AH-2.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h;Inert atmosphere;
A mixture of AH-1 (113 g, 0.62 mol), K2C03 (171 g, 1.24 mol) and sodium ethanethiolate (67 g, 0.80 mol) in DMF (2 L) is stirred at rt under N2 for 18 h. The mixture is diluted with H20 and extracted with EtOAc. The organic layers are dried (Na2S04), decanted and concentrated. The resultant residue is purified by Si02 flash chromatography to yield AH- 2.
6-ethyl-3,4-dihydro-2H-chromen-4-aminium chloride[ No CAS ]
[ 38275-57-9 ]
5-[(6-ethyl-3,4-dihydro-2H-chromen-4-yl)amino]pyrimidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
8%
With triethylamine; In N,N-dimethyl acetamide; at 200℃; for 2h;Microwave irradiation;
0.20 g (1.09 mmol) of <strong>[38275-57-9]5-bromo-2-cyanopyrimidine</strong> (ABCR 245244), 0.325 g (1.52 mmol) of 6-ethyl-3,4-dihydro-2H-chromen-4-aminium chloride and 0.35 g (3.3 mmol) of triethylamine in 1.5 ml of N,N-dimethylacetamide are heated in a closed cuvette in the microwave at 200 C. for 120 minutes (Biotage Initiator, http://www.biotage.com/DynPage.aspx?id=22001). The crude mixture obtained in this manner is applied to silica gel and purified by column chromatography using the mobile phase heptane/ethyl acetate. Concentration gives 0.03 g of 5-[(6-ethyl-3,4-dihydro-2H-chromen-4-yl)amino]pyrimidine-2-carbonitrile (wax-like) (yield 8% at a purity of 80%).
a) Preparation of Int. 272 1 , l'-Bis(diphenylphosphino)ferrocenedichloro palladium(II) (0.75 g; 1.022 mmol) was added to Int. 249 (8 g; 32.779 mmol) and <strong>[38275-57-9]5-bromopyrimidine-2-carbonitrile</strong> (7.237 g; 39.335 mmol) in dioxane (160 ml) at r.t. The reaction mixture was stirred at 80 C for 30 min. A Na2C03 solution in H20 (24.584 ml; 49.169 mmol) was added to the reaction mixture at 80 C. The reaction mixture was stirred at 80 C for 1 h. The reaction mixture was poured on ice/water. The water layer was stirred at r.t. for 1 h. The precipitate was filtered off and dried under vacuum yielding 9.2 g of Int. 272 (92.53 %).
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In acetonitrile; at 120℃; for 0.0833333h;Microwave irradiation; Sealed tube; Inert atmosphere;
General procedure: A sealed 10mL glass tube containing substrate 1a-1s (1.5mmol), trimethylsilylacetylene (1.5mmol), triethylamine (7.5mmol), Pd(PPh3)2Cl2 (5mol%), CuI (10mol%), and acetonitrile (1mL) was placed in the cavity of a microwave reactor and irradiated for 2-10min, at 120C and power 150W. After cooling to room temperature by an N2-flow, the tube was removed from the rotor. The reaction mixture was combined with dichloromethane (30mL) and water (30mL). The organic layer was separated and washed with water (2×30mL), dried over sodium sulfate, and concentrated. Purification by column chromatography, eluting with petroleum ether gave 1-aryl-2-(trimethylsilyl)acetylenes (2a-2s) as coloured oils or solids. All the products 2a-2s were characterized by 1H NMR and EI-MS. (See Supporting Information file for characterization data of 1H NMR and EI-MS spectrum.)
5-bromo-N’-hydroxypyrimidine-2-carboximidamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.8 g
With hydroxylamine hydrochloride; sodium hydroxide; In ethanol; water; at 20℃; for 19h;
Step 1: To a stirred suspension of <strong>[38275-57-9]5-bromopyrimidine-2-carbonitrile</strong> (CAS 38275-57-9, 2.84 g) in ethanol (23.0 ml), hydroxylamine hydrochloride (1.13 g) and sodium hydroxide solution, 1M in H20 (15.6 ml) were added. The reaction mixture was stirred at room temperature for 19 h. The product was collected by filtration, washed with cold H20 and dried in high vacuo to give 5-bromo-N'-hydroxypyrimidine-2-carboximidamide (2.80 g) as a yellow solid. MS: m/z = 217.0 [M+H]+.
With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); XPhos; In water; toluene; at 60℃;Sealed tube;
[0214] A mixture of <strong>[38275-57-9]5-bromopyrimidine-2-carbonitrile</strong>(640 mg, 3.5 mmol), cyclopropylboronic acid (601 mg, 7 mmol), Pd2(dba)3 (640 mg, 0.7 mmol), X-Phos (668 mg, 1.4 mmol) and K3P04 H20 (2.79 g, 10.5 mmol) in toluene (10 mL) was heated in a sealed tube at 60C for overnight. After cooling to room temperature, the reaction mixture was filtered and concentrated to give a crude product which was by column chromatography on a silica gel with ethyl acetate/hexane (1/1) to give 5-cyclopropylpyrimidine-2-carbonitrile as a solid. LC/MS = 146 [M+l].
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; cesium fluoride; In toluene; at 100℃; for 12h;Inert atmosphere;
To a solution of 148 <strong>[38275-57-9]5-bromopyrimidine-2-carbonitrile</strong> (2 g, 10.87 mmol, 1.00 equiv) in 64 toluene (15 mL) under an inert atmosphere of 8 nitrogen was added 149 trimethyl-1,3,5,2,4,6-trioxatriborinane (975.4 mg, 16.31 mmol, 1.5 equiv), 150 CsF (1.66 g, 21.74 mmol, 2.0 equiv), 151 K3PO4.3H2O (4 g, 29.89 mmol, 2.75 equiv) and Pd(dppf)Cl2.CH2Cl2 (799.7 mg, 2.17 mmol, 0.2 equiv). The reaction solution was stirred for 12 h at 100 C. The solid was filtered out. The filtrate was concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/26 petroleum ether (1:1) to afford 0.5 g (38.6%) of 147 5-methylpyrimidine-2-carbonitrile as white solid. 1H NMR (300 MHz, DMSO-d6) delta: 8.33 (s, 2H), 2.40 (s, 3H).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; cesium fluoride; In water; toluene; at 60℃;Sealed tube;
[0212] A mixture of <strong>[38275-57-9]5-bromopyrimidine-2-carbonitrile</strong>(800 mg, 4.37 mmol), 2,4,6-trimethyl- l,3,5,2,4,6-trioxatriborinane(l . l g, 8.74 mmol), Pd(dppf)Cl2 (639 mg, 0.87 mmol) and CsF (763 mg, 8.74 mmol) and K3PO4 H2O (3.2 g, 12 mmol) in toluene (10 mL) was heated in a sealed tube at 60C for overnight. After cooling to room temperature, the reaction mixture was filtered and concentrated to give a crude product which was purified by column chromatography on a silica gel with ethyl acetate/hexane (1/1) to give 3-cyclopropylpyrazine-2-carbonitrile as a solid. LC/MS = 146 [M+l].
With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate; In toluene; at 110℃; for 10h;
Step 1 synthesis of 5-benzyloxy-2-cyano-pyrimidine The <strong>[38275-57-9]5-bromo-2-cyano-pyrimidine</strong> (10g, 54mmol) and benzyl alcohol (17.5g, 162mmol) are respectively dissolved in 100 ml in toluene, and then respectively adding cesium carbonate (35g, 108mmol), cuprous iodide (1g, 5.4mmol), 1,10-phenanthroline (2g, 11.34mmol) (here the added cuprous iodide and 1,10-phenanthroline as a catalyst, to a minimum amount, the addition of which is <strong>[38275-57-9]5-bromo-2-cyano-pyrimidine</strong> 10% and 20%). The reaction was stirred at 110 C for 4 hours. TLC detection reaction is complete. The reaction was cooled to room temperature (20-25 C), concentrated reaction solution, column chromatography purification, to obtain white solid 5-benzyloxy-2-cyano-pyrimidine 10.3g, the yield is about 90%.
6-fluoro-2-(piperazin-1-yl)-1H-benzimidazole-4-carboxamide[ No CAS ]
[ 38275-57-9 ]
2-(4-(2-cyano-pyrimidine-5-yl)piperazin-1-yl)-6-fluoro-1H-benzimidazole-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
With triethylamine; In N,N-dimethyl-formamide; at 100℃; for 8h;
A solution of Compound d: 2- (piperazin-1-yl) -1 Hydrogen - Add benzimidazole-4-carboxamide (74mg, 0.3mmol) in dimethylformamide (5mL) of 2-chloro-pyrimidine ( 34mg, 0.3mmol) and triethylamine (30mg, 0.3mmol), was heated to 100 deg.] C, the reaction was cooled after 8 hours, the solvent was removed under reduced pressure, the residue was purified by flash column chromatography (methylene chloride: methanol = 10: 1 ) to give the compound (1): 2- (4- (pyrimidin-2-yl) piperazin-1-yl) -1 hydrogen - benzimidazole-4-carboxamide (32mg, 33% yield). Using embodiment 1 preparation of the compound (1) step 5 the similar method, through compound l:6-fluoro-2 - (piperazin-1-yl) - 1 H-benzimidazole-4-carboxamide with <strong>[38275-57-9]5-bromo-2-cyano-pyrimidine</strong> generating aromatic nucleophilic substitution reaction to prepare compound (38): 2 - (4 - (2-cyano-pyrimidin-5-yl) piperazin-1-yl) - 6-fluoro -1 H-benzimidazole-4-carboxamide (18 mg, yield 26%). Using embodiment 1 preparation of the compound (1) step 5 the similar method, through compound l:6-fluoro-2 - (piperazin-1-yl) - 1 H-benzimidazole-4-carboxamide with <strong>[38275-57-9]5-bromo-2-cyano-pyrimidine</strong> generating aromatic nucleophilic substitution reaction to prepare compound (38): 2 - (4 - (2-cyano-pyrimidin-5-yl) piperazin-1-yl) - 6-fluoro -1 H-benzimidazole-4-carboxamide (18 mg, yield 26%).
(2S,6R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-2,6-dimethylpiperazine-1-carboxamide[ No CAS ]
[ 38275-57-9 ]
(2S,6R)-N-[2-(1-benzylpiperidin-4-yl)ethyl]-4-(2-cyanopyrimidin-5-yl)-2,6-dimethylpiperazine-1-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 45℃;
Step 23 A: (2S.6R)-N-r2-(l-benzylpiperidin-4-yl)ethyll-4-(2-cvanopyrimidin-5-yl)- 2.6-dimethylpiperazine- 1 -carboxamide (0909) To a solid mixture of (2S,6R)-N-[2-(l-benzylpiperidin-4-yl)ethyl]-2,6- dimethy lpiperazine- 1 -carboxamide 4b (30 mg, 0.08 mmol, 1.0 eq), 5-bromopyrimidine- 2-carbonitrile (22 mg, 0.12 mmol, 1.5 eq) and cesium carbonate (39 mg, 0.12 mmol, 1.5 eq) was added NMP (1 mL) and reaction mixture stirred at 45 C over the weekend. The resulting suspension was cooled, passed through an HPLC filter diluting to 1 mL with MeOH and submitted for directly for preparative chromatography yielding (2S,6R)-N-[2-(l-benzylpiperidin-4-yl)ethyl]-4-(2-cyanopyrimidin-5-yl)-2,6- dimethy lpiperazine- 1 -carboxamide 23-1.
(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyne-2-ol[ No CAS ]
[ 38275-57-9 ]
(2R,3S)-2-(2,4-difluorophenyl)-3-methyl-5-(2-cyanopyrimidin-5-yl)-1-(1H-1,2,4-triazol-1-yl)pentan-4-yn-2-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 60℃; for 12h;Inert atmosphere;
he compound 5 (1 mmol),The compound <strong>[38275-57-9]5-bromo-2-cyanopyrimidine</strong> (1 mmol)Dissolved in NMP (10 mL)CuI (20 mmol%) was added,Pd (PPh3) 2Cl2 (5 mmol%),DIEA (5 mmol).Under nitrogen protection,60 reaction 12h.TCL monitoring reaction is complete,Extracted three times with ethyl acetate,Combine organic phase,Washed twice with saturated NaCl,Anhydrous Na2SO4 dry.Spin dry,Column chromatography gave compound 7f.
cis-3-[8-dimethylamino-1-[(1-hydroxycyclobutyl)methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]propionamide[ No CAS ]
[ 38275-57-9 ]
cis-N-(2-cyanopyrimidin-5-yl)-3-[8-dimethylamino-1-[(1-hydroxycyclobutyl)methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]propionamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15%
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 18.25h;Inert atmosphere;
CIS-3-[8-Dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide (SC_5002) (0.270 g, 0.631 mmol) was dissolved in 1,4 dioxane (30 mL) at RT and purged with nitrogen. To the reaction mixture were added <strong>[38275-57-9]5-bromopyrimidine-2-carbonitrile</strong> (0.173 g, 0.946 mmol), Cs2CO3 (0.410 g, 1.262 mmol), Xanthphos (0.055 g, 0.095 mmol), Pd2(dba)3 (0.029 g, 0.032 mmol) and the resulting suspension was again purged with nitrogen for 15 minutes. The reaction mixture was stirred at 90 C. for 18 h, then cooled to RT and diluted with EtOAc (60 mL.). The insoluble solid was filtered off and the clear filtrate was concentrated under reduced pressure. The crude product was purified preparative TLC using 3% MeOH in DCM as a mobile phase to afford 52 mg (15%) of CIS-N-(2-cyano-pyrimidin-5-yl)-3-[8-dimethylamino-1-[(1-hydroxy-cyclobutyl)-methyl]-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl]-propionamide (SC_5022) as an off-white solid (TLC system: 10% MeOH in DCM; Rf: 0.56). [M+H]+ 532.3
cis-8-(dimethylamino)-8-phenyl-1,3-diazaspiro[4.5]decan-2-one[ No CAS ]
[ 38275-57-9 ]
5-(cis-8-(dimethylamino)-2-oxo-8-phenyl-1,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.4 g
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 16h;Inert atmosphere;
[0123] Cs2CO3 (1.1 g, 3.66 mmol) was added to the solution of CIS-8-(dimethylamino)-8-phenyl-1,3- diazaspiro[4.5]decan-2-one (INT-976) (0.5 g, 1.83 mmol), Xanthphos (0.158 g, 0.274 mmol), Pd2(dba)3 (0.083 g, 0.091 mmol) and <strong>[38275-57-9]5-bromopyrimidine-2-carbonitrile</strong> (0.52 g, 2.74 mmol) in 1 ,4-dioxane (20 mL) under argon atmosphere. The reaction mixture was stirred for 16 h at 90C, then cooled to RT and concentrated under reduced pressure. The residue was suspended in EtOAc (20 mL) and filtered through a plug of celite. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash chromatography on silica gel to afford 5-(cis-8-(dimethylamino)-2-oxo-8-phenyl- 1 ,3-diazaspiro[4.5]decan-3-yl)pyrimidine-2- carbonitrile (INT-600) (0.4 g) as a white solid.
In dimethyl sulfoxide; at 100℃; for 20h;Inert atmosphere;
A mixture of <strong>[38275-57-9]5-bromopyrimidine-2-carbonitrile</strong> (1.00 g, 5.43 mmol), sodium methanesulfinate (844 mg, 8.27. mmol) and DMSO (10 mL) was stirred at 100 C under nitrogen atmosphere for 20 h. After being cooled, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 20% - 50% EtOAc in hexane) , followed by suspending in IPE. The precipitate was collected by filtration and dried in vacuo to give the title compound (0.572 g, 3.12 mmol, 57.5%) as pale yellow solids. (4171) 1H NMR (300 MHz, CDC13) 5:3.23 (3H, s), 9.34 (2H, s) .
2,6-difluoro-4-(4-hexylphenyl)boronic acid[ No CAS ]
[ 38275-57-9 ]
5-[4-(4-hexylphenyl)-2,6-difluorophenyl]pyrimidine-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With bis(tri-tert-butylphosphine)platinum(0); sodium carbonate; In tetrahydrofuran; water; at 20℃;Inert atmosphere; Reflux;
40 ml of water, 4.4 g (52.2 mmol) of sodium carbonate, 10 g (31 mmol) of 2,6-difluoro-4-(4-hexylphenyl)benzoic acid and 4.8 g (26 mmol) in an inert atmosphere <strong>[38275-57-9]2-cyano-5-bromopyrimidine</strong> was dissolved in 80 ml of THF, and 27 mg of bis(tributylphosphonium)palladium(0) (52 mmol) was added. The reaction was refluxed for 4 h and stirred at room temperature overnight. The solvent was removed in vacuo and the crude product was purified by column chromatography with toluene gel. Crystallization from isopropanol gave 5-[4-(4-hexylphenyl)-2,6-difluoro-phenyl]pyrimidine-2-carbonitrile (PUM-6-N) as colorless crystals.
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