* 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.
Stage #1: With triethylamine; trifluoroacetic anhydride In dichloromethane at 0 - 20℃; Stage #2: With sodium hydroxide In dichloromethane; water
Pyrimidine-5-carbonitrile (SO3-067): To a suspension of pyrimidine-5-carboxamide (SOS- OSS) (262 mg, 2.12 mmol) and triethyl amine (481 mg, 4.24 mmol) in anhydrous dichoromethane (15 ml) was slowly added a solutionf of trifuoroacetic anhydride (0.36 ml in 4 ml dichloromethane) at 0°C. The reaction mixture was stirred at 0°C to RT for 2 h. and quenched with water (2ml) and washed with NaOH (1 N, 5 ml) and brine (2 x 5 ml). Organic solvent was dried (MgS04) and evaporated at less than 30°C to provide SO3-067 as a pale yellow solid. (1 74 mg, 78percent). 1 H NM R (400 M Hz, DMSO) δ 9.44 (s, 1 H), 9.31 (s, 2H).
Reference：
[1] Patent: WO2012/129564, 2012, A2, . Location in patent: Page/Page column 79
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 10, p. 3783 - 3805
[3] Journal of Organic Chemistry, 2015, vol. 80, # 5, p. 2676 - 2699
[4] Patent: WO2009/148452, 2009, A1, . Location in patent: Page/Page column 71
2
[ 4595-59-9 ]
[ 40805-79-6 ]
Yield
Reaction Conditions
Operation in experiment
95%
With 1-Butylimidazole In toluene at 160℃; for 16 h;
In an autoclave, 1 equiv. of aryl halide or heteroaryl halide, 2 equiv. of 1-alkylimidazole, 0.1 equiv. of CuI, 0.2 equiv. of dried K4[Fe(CN)6] (potassium hexacyanoferrate(II)), tetradecane as an internal standard for the GC analysis and a suitable amount of toluene were combined under argon and heated to 160 C. (The K4[Fe(CN)6] was dried by heating powdered K4[Fe(CN)6]x3H2O in a vacuum of 1 mbar to 80 C. for at least 24 hours.) After 16 hours, the reaction mixture was cooled to room temperature. Conversion and yield were determinable by means of gas chromatography. An isolation of the product took place according to the customary workup (distillation, crystallization or chromatography).
82%
With 1-methyl-1H-imidazole In toluene at 160℃; for 16 h;
In an autoclave, 1 equiv. of aryl halide or heteroaryl halide, 2 equiv. of 1-alkylimidazole, 0.1 equiv. of CuI, 0.2 equiv. of dried K4[Fe(CN)6] (potassium hexacyanoferrate(II)), tetradecane as an internal standard for the GC analysis and a suitable amount of toluene were combined under argon and heated to 160 C. (The K4[Fe(CN)6] was dried by heating powdered K4[Fe(CN)6]x3H2O in a vacuum of 1 mbar to 80 C. for at least 24 hours.) After 16 hours, the reaction mixture was cooled to room temperature. Conversion and yield were determinable by means of gas chromatography. An isolation of the product took place according to the customary workup (distillation, crystallization or chromatography).
Reference：
[1] Patent: US2009/62541, 2009, A1, . Location in patent: Page/Page column 4
[2] Patent: US2009/62541, 2009, A1, . Location in patent: Page/Page column 4
[3] New Journal of Chemistry, 2012, vol. 36, # 11, p. 2334 - 2339
[4] Synlett, 2007, # 4, p. 555 - 558
[5] Synthesis, 2008, # 20, p. 3351 - 3355
3
[ 17180-94-8 ]
[ 557-21-1 ]
[ 40805-79-6 ]
Yield
Reaction Conditions
Operation in experiment
60%
With dmap; 1,1'-bis-(diphenylphosphino)ferrocene; nickel(II) chloride hexahydrate; zinc In acetonitrile at 80℃; for 4 h; Inert atmosphere; Sealed tube
General procedure: Under argon protection, NiCl2·6H2O (0.05mmo 1,11.9mg), dppf (0.06mmol, 33.3mg), Ζn (0·2mmol, 13.0mg), DMAP (1.0mmol, 122.2mg), Ζn(CN)2 (0.8mmol) , 93.9mg),p-Chloroanisole (1.0 mmol, 140.6 mg) and acetonitrile (5.0 mL) were sequentially added in a 25.0 mL sealed tube, then directly put it into the oil bath at 60 °C, and heating was stopped after 6h, and cooled to room temperature, the reaction solution was directly filtered through a short silica gel column, washed with dichloromethane, concentrated and purified by silica gel column chromatography( given that the product is most easily pulled out, in order to avoid loss of sample mix, unless otherwise noted, both are wet method). Eluent: petroleum ether / ethyl acetate = 20:1, the product was 117.2 mg as a white solid, yield 88percent, and 1H NMR purity was greater than 98percent.
Reference：
[1] Organic Letters, 2017, vol. 19, # 8, p. 2118 - 2121
[2] Patent: CN108623495, 2018, A, . Location in patent: Paragraph 0043; 0045; 0189-0191
4
[ 4595-59-9 ]
[ 40805-79-6 ]
Reference：
[1] Chemistry - A European Journal, 2007, vol. 13, # 21, p. 6249 - 6254
5
[ 4595-59-9 ]
[ 40805-79-6 ]
Reference：
[1] Journal of the American Chemical Society, 2016, vol. 138, # 5, p. 1709 - 1716
6
[ 4595-59-9 ]
[ 40805-79-6 ]
Reference：
[1] Journal of Organic Chemistry, 2018, vol. 83, # 9, p. 4922 - 4931
7
[ 40929-50-8 ]
[ 40805-79-6 ]
Reference：
[1] Patent: WO2012/129564, 2012, A2,
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 10, p. 3783 - 3805
[3] Journal of Organic Chemistry, 2015, vol. 80, # 5, p. 2676 - 2699
[4] Patent: WO2009/148452, 2009, A1,
8
[ 75-05-8 ]
[ 109299-78-7 ]
[ 40805-79-6 ]
Reference：
[1] Chemistry - A European Journal, 2015, vol. 21, # 38, p. 13246 - 13252
With 1-Butylimidazole;copper(l) iodide; In toluene; at 160℃; for 16h;Product distribution / selectivity;
In an autoclave, 1 equiv. of aryl halide or heteroaryl halide, 2 equiv. of 1-alkylimidazole, 0.1 equiv. of CuI, 0.2 equiv. of dried K4[Fe(CN)6] (potassium hexacyanoferrate(II)), tetradecane as an internal standard for the GC analysis and a suitable amount of toluene were combined under argon and heated to 160 C. (The K4[Fe(CN)6] was dried by heating powdered K4[Fe(CN)6]x3H2O in a vacuum of 1 mbar to 80 C. for at least 24 hours.) After 16 hours, the reaction mixture was cooled to room temperature. Conversion and yield were determinable by means of gas chromatography. An isolation of the product took place according to the customary workup (distillation, crystallization or chromatography).
82%
With 1-methyl-1H-imidazole;copper(l) iodide; In toluene; at 160℃; for 16h;Product distribution / selectivity;
In an autoclave, 1 equiv. of aryl halide or heteroaryl halide, 2 equiv. of 1-alkylimidazole, 0.1 equiv. of CuI, 0.2 equiv. of dried K4[Fe(CN)6] (potassium hexacyanoferrate(II)), tetradecane as an internal standard for the GC analysis and a suitable amount of toluene were combined under argon and heated to 160 C. (The K4[Fe(CN)6] was dried by heating powdered K4[Fe(CN)6]x3H2O in a vacuum of 1 mbar to 80 C. for at least 24 hours.) After 16 hours, the reaction mixture was cooled to room temperature. Conversion and yield were determinable by means of gas chromatography. An isolation of the product took place according to the customary workup (distillation, crystallization or chromatography).
With hydroxylamine; In methanol; water; at 65℃; for 1h;
A solution of the product of Example 79B (5.47 g, 52 mmol) and aqueous hydroxylamine (Aldrich, 50%, 2.3 mL, 78 mmol) in methanol (50 mL) was stirred at 65 0C for 1 hour and then concentrated under reduced pressure to remove the volatiles. The residue was triturated with EtOAc (30 mL). The precipitates were collected by filtration and dried to give the titled compound. 1H NMR (300 MHz, DMSO-J6) delta 6.14 (s, 2 H), 9.03 (s, 2 H), 9.18 (s, 1 H), 10.06 (s, 1 H) ppm; MS (DCI/NH3) m/z 139 (M+H)+, 156 (M+NH4)+.
Pyrimidine-5-carbonitrile (SO3-067): To a suspension of pyrimidine-5-carboxamide (SOS- OSS) (262 mg, 2.12 mmol) and triethyl amine (481 mg, 4.24 mmol) in anhydrous dichoromethane (15 ml) was slowly added a solutionf of trifuoroacetic anhydride (0.36 ml in 4 ml dichloromethane) at 0C. The reaction mixture was stirred at 0C to RT for 2 h. and quenched with water (2ml) and washed with NaOH (1 N, 5 ml) and brine (2 x 5 ml). Organic solvent was dried (MgS04) and evaporated at less than 30C to provide SO3-067 as a pale yellow solid. (1 74 mg, 78%). 1 H NM R (400 M Hz, DMSO) delta 9.44 (s, 1 H), 9.31 (s, 2H).
To a suspension of the product of Example 79A (6.75 g, 54.8 mmol) and triethylamine (Aldrich, 15.28 mL, 110 mmol) in anhydrous CH2Cl2 (Aldrich, 400 mL) was slowly added a solution of trifluoroacetic anhydride (Aldrich, 9.30 mL, 65.8 mmol) in anhydrous CH2Cl2 (100 mL) at 0-10 0C over 1 hours. It was then stirred at 0 0C to ambient temperature for 2 hours. The reaction was then quenched with water (10 mL) and washed with NaOH (1 N, 20 mL) and brine (2 x 10 mL) before being concentrated under reduced pressure at less than 30 0C to supply the titled compound. 1H NMR (300 MHz, DMSO-J6) delta 9.34 (s, 2 H), 9.47 (s, 1 H) ppm; MS (DCI/NH3) m/z 123 (M+NH4)+.
To a stirred suspension of <strong>[40805-79-6]5-cyanopyrimidine</strong> (5.0 g, 47 mmol) in methanol (50 mL) was added 25% by weight sodium methoxide in methanol (1.2 g, 23 mmol). The mixture was stirred at room temperature for 17 h under nitrogen atmosphere and then acetic acid (2.72 ml, 47 mmol) was added dropwise. The resulting mixture was stirred for 4 h and then evaporated under reduced pressure to remove methanol and yield a residue. The residue was dissolved in ether (150 mL) and the solids were removed by filtration. The filtrate was concentrated under reduced pressure to yield methyl pyrimidine-5-carbimidate (4.9 g, 75% yield). The crude product was used without further purification. XH NMR (400 MHz, DMSO-d6, delta): 3.83 (s, 3H); 9.18 (s, 2H); 9.30 (s, 1H); 9.54 (s, 1H). ES-MS: [M++l] = 138.
In a 250 mL round-bottomed flask, <strong>[40805-79-6]pyrimidine-5-carbonitrile</strong> (1.5 g, 14.3 mmol), pyridine (0.339 g, 0.35 ml, 28.5 mmol), and 2-mercaptopropionic acid (1.51 g, 14.3 mmol) were combined to give a light yellow solution. The reaction mixture was heated to 100 C. and stirred for 2 h. Upon cooling, the thick yellow mixture was diluted with 100 mL ethanol and stirred for 30 min. The slurry was then filtered, and washed with diethyl ether (2*100 mL) to give 5-Methyl-2-(pyrimidin-2-yl)-thiazol-4-ol (2.33 g, 85%) as yellow solid which was used directly without further purification.
With sodium hydrogencarbonate; In methanol; at 60℃; for 15h;pH 6.0;Aqueous phosphate buffer;
Example O(R,S)-4,5-Dihydro-N-(pyrimidin-2-ylmethyl)-2-(5-pyrimidinyl)-1,3-thiazole-5-carboxamideStage 1: (R,S)-4,5-Dihydro-2-(5-pyrimidinyl)-1,3-thiazole-5-carboxylic acid 1.00 g (9.51 mmol) of <strong>[40805-79-6]5-cyanopyrimidine</strong> were initially charged with 1.04 g (12.3 mmol) of sodium bicarbonate in 50 ml of phosphate buffer solution (pH 6), and admixed with 1.95 g (12.3 mmol) of isocysteine hydrochloride (preparation in analogy to Ch. Dose, O. Seitz Org. Biomol. Chem. 2004, 2, 59-65; Bioorg. Med. Chem. 2008, 16, 65-77), dissolved in 50 ml of methanol. Thereafter, the reaction mixture was stirred at 60 C. for 15 hours. After cooling, the mixture was concentrated under reduced pressure and the remaining residue was stirred successively with acetonitrile, acetone, N,N-dimethylformamide and chloroform. The remaining solid was purified by means of medium-pressure chromatography (RP column, eluent: water).HPLC-MS: logP (HCOOH)=0.30; mass (m/z) 210.0 (M+H)+;1H NMR (d6-DMSO) 4.28-4.71 (m, 3H), 9.06 (d, 1H), 9.30 ppm (d, 2H).
Step 1 : To a mixture <strong>[40805-79-6]pyrimidine-5-carbonitrile</strong> (2.0 g, 19.0 mmoL) and 2-mercapto-propionic acid (2.1 g, 19.0 mmol) was added pyridine (0.5 mL, 6.28 mmol) and the mixture was heated to 100 C for 2h. The mixture was cooled to rt and EtOH (100 mL) was added to the RM which was stirred at rt for 30 min. The formed precipitate was isolated though filtration and was washed with hexane and was dried under reduced pressure to yield the desired compound (2.0 g, 54%) LC-MS (Method 3): m/z [M+H]+ = 194.2 (MW calc. = 193.23); R, = 1.99 min.
C-pyridin-3-yl-C-pyrimidin-5-yl-methylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
11.3%
3-Bromo-pyridine (0.92 ml; 9.51 mmol; 2.00 eq.) and anhydrous THF (8 mL) are added in a dry flask. The solution is purged with nitrogen for 30 min. Isopropylmagnesium chloride/LiCI solution 1 .3 M in THF (7.32 mL; 9.51 mmol; 2.00 eq.) is added dropwise to the reaction flask over a period of 10 min, and the mixture is stirred for 4 h at RT. The resulting solution of 3- pyridylmagnesium bromide is treated with solid <strong>[40805-79-6]pyrimidine-5-carbonitrile</strong> (0.50 g; 4.76 mmol; 1.00 eq.) at RT and to the resulting mixture NaBH4 (0.72 g; 19.03 mmol; 4.00 eq.) is added, followed by water (0.2 mL, after 30 minutes) The mixture is stirred overnight. Next portion of water (10 mL) is added and the mixture concentrated in vacuo. The residue is dissolved in EtOAc and filtered. Oily residue is purified by FCC (DCM/MeOH; gradient) provided C- pyridin-3-yl-C-pyrimidin-5-yl-methylamine (100.00 mg; yield 1 1.3 %; yellow oil).
With dmap; 1,1'-bis-(diphenylphosphino)ferrocene; nickel(II) chloride hexahydrate; zinc; In acetonitrile; at 80℃; for 4h;Inert atmosphere; Sealed tube;
General procedure: Under argon protection, NiCl2·6H2O (0.05mmo 1,11.9mg), dppf (0.06mmol, 33.3mg), Zetan (0·2mmol, 13.0mg), DMAP (1.0mmol, 122.2mg), Zetan(CN)2 (0.8mmol) , 93.9mg),p-Chloroanisole (1.0 mmol, 140.6 mg) and acetonitrile (5.0 mL) were sequentially added in a 25.0 mL sealed tube, then directly put it into the oil bath at 60 C, and heating was stopped after 6h, and cooled to room temperature, the reaction solution was directly filtered through a short silica gel column, washed with dichloromethane, concentrated and purified by silica gel column chromatography( given that the product is most easily pulled out, in order to avoid loss of sample mix, unless otherwise noted, both are wet method). Eluent: petroleum ether / ethyl acetate = 20:1, the product was 117.2 mg as a white solid, yield 88%, and 1H NMR purity was greater than 98%.
Into a 250ml three-necked flask, add a magnetic stirrer and protect it with nitrogen.Then add 1.65 ml (2.0 mol / L) of dimethylamine and 50 ml of anhydrous ether, and slowly add 2.06 ml (1.6 mol / L) of butyl lithium at room temperature.The reaction liquid changed from clear to white turbid liquid. After stirring at room temperature for 20 minutes,Quickly add 0.55 g of p-bromobenzonitrile as a solid. After the reaction is continued for 1 hour, 0.66 g of m-bromopyrimidine is added quickly.After the reaction was continued for 4 hours under the protection of nitrogen, the nitrogen protection was removed. After the reaction was continued for 1 hour under the air atmosphere,Filter under reduced pressure, wash the filter cake with diethyl ether, recrystallize the filter plate with ethanol: water (1: 2),The product was filtered and dried under vacuum. The product was directly reacted without further purification.
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