* 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 N-Bromosuccinimide In acetonitrile at 20℃; for 5 h; Inert atmosphere
Example 2: preparation of 2-N,N-dimethylamino-5-hydroxy-4-methyl-6-(10- x decyl)-pyridine; 2-Amino-5-bromo-4,6-dimethylpyridine (13):To a stirred solution containing 2.00g (16.32 mmol) of 2-amino-4,6-dimethylpyridine in 25 mL of acetonitrile were added 2.90g (16.32 mmol) of N-bromosuccinimide. The reaction mixture was stirred at room temperature under argon atmosphere for 5 h. The formed precipitate was filtered and dried to afford the expected product as a white solid: yield 2.76g (84percent). 1H-NMR(CDC13) δ 6.22 (s, 1H), 4.39 (br, 2H), 2.48 (s, 3H), 2.25 (s, 3H);13C-NMR (CDC13) 5156.34, 155.23, 148.64, 112.26, 108.10, 25.10, 23.30.
84%
With N-Bromosuccinimide In acetonitrile at 20℃; for 5 h; Inert atmosphere
To a stirred solution containing 2.00 g (16.3 mmol) of 2-amino-4,6-dimethylpyridine in 25 mL of acetonitrile was added 2.90 g (16.3 mmol) of N-bromosuccinimide. The reaction mixture was stirred at room temperature for 5 h. The formed precipitate was filtered and dried to afford 6-amino-3-bromo-2,4-dimethylpyridine (8) as a colorless solid: yield 2.76 g (84percent); mp 143–145 °C; silica gel TLC Rf 0.15 (2:1 hexanes/ethyl acetate); 1H NMR (CDCl3) δ 2.25 (s, 3H), 2.48 (s, 3H), 4.39 (br s, 2H), and 6.22 (s, 1H); 13C NMR (CDCl3) δ 23.3, 25.1, 108.1, 112.3, 148.6, 155.2, and 156.3; mass spectrum (APCI), m/z 201.0032 (M+H)+ (C7H10N2Br requires 201.0027).
77%
With bromine In acetonitrile at 20℃; for 1 h;
A mixture of 4,6-dimethylpyridin-2-amine (3 g) and Bromine (1 .39 mL) taken up in Acetonitrile (30 mL) was stirred at ambient temperature for I h. The mixture was diluted with Water (100 mL) and the precipitate was collected by filteration and dried to afford the title product as a off white solid (3.8 g, 77percent). LCMS: Rt: 1.2 min; MS: mz = 203 (M+1) 1H NMR (300 MHz, Chloroform-d) 67.28 (5, IH), 6.37 (5, 2H), 2.43-2.12 (m, 6H).
76%
With dihydrogen peroxide; 1-butylpyridinium bromide; toluene-4-sulfonic acid In 1,2-dimethoxyethane at 80℃; for 24 h; Schlenk technique; Inert atmosphere; Green chemistry
General procedure: To a mixture of 2-aminopyridine (0.5 mmol, 1 equiv), p-TSA (0.4 mmol,0.8 equiv), 1-butylpyridinium bromide (1.5 mmol, 3 equiv) in a 50 mL Schlenk tube were added 1,2-dimethoxyethane (2 mL) under air. Then H2O2 (1.2 mmol, 2.4 equiv) was added. The mixture was stirred at 80°C for 24 h. And then the mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the products.
68%
at 20℃; for 1 h; Inert atmosphere
A solution of 2-amino-4,6-dimethylpyridine (1.22 g, 10 mmol) in 10 mL of glacial acetic acid under N2 was treated with a solution of 1.6 g (10 mmol) Br2 in 2 mL of glacial acetic acid over 15 minutes with water bath cooling keeping the temperature below 20°C. The solution became a solid mass and was allowed to stand at r.t. for 1h. After cooling in an ice bath, the material was made alkaline with 20percent cold NaOH solution. Then the mixture was extracted with CH2Cl2 three times, the combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on silica gel (Hexane-EtOAc, 2:1~1:1) to afford the product (1.37 g, 68percent) as a yellow solid.
68%
at 20℃; for 1 h; Inert atmosphere
A solution of 2-amino-4,6-dimethylpyridine (1.22 g, 10 mmol) in 10 mL of glacial acetic acid under N2 was treated with a solution of 1.6 g (10 mmol) Br2 in 2 mL of glacial acetic acid over 15 min with water bath cooling to keep the reaction temperature below 20 °C. The solution became a solid mass and was allowed to stand at room temperature for 1 h. After cooling in an ice bath, the material was made alkaline with 20percent cold NaOH solution. Then the mixture was extracted with CH2Cl2 three times, the combined organic layer was dried over anhydrous Na2SO4, then filtered and concentrated. The residue was purified on silica gel (Hexane-EtOAc, 2:1 to 1:1) to afford the product (1.37 g, 68percent) as a yellow solid. Mp 143-144 °C. (lit. [40] 143 °C). 1H NMR (CDCl3) 6.24 (s, 1H), 4.32 (br, 2H), 2.50 (s, 3H), 2.28 (s, 3H).
55%
With sulfuric acid; bromine In water
Step 1 Preparation of 2-amino-4,6-dimethyl-5-bromopyridine 20 g(0.164 mole) of 2-amino-4, 6-dimethylpyridine was added into a mixture of 69 ml of water and 16.1 g(0.164 mole) of sulfuric acid and the resulting solution was cooled to 0° C., and thereto was added 8.45 ml(0.164 mole) of bromine gradually at 0° C. The resulting solution was stirred for 30 minutes, adjusted to pH 9 to 10 with aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous Na2 SO4 and concentrated under reduced pressure. The residue was purified with silica gel column chromatography to obtain 18.25 g of the title compound(yield 55percent) and 5.4 g of dibromo compound(yield 11.8percent).
48%
With N-Bromosuccinimide In acetonitrile at 20℃;
The mixture of 4,6-dimethylpyridin-2-amine (1 g, 8.2 mmol, 1.0 eq) and NBS (1.46 g, 8.2 mmol, 1.0 eq) in CH3CN (30 mL) was stirred at rt overnight. Then the mixture was concentrated, and the residue was purified on silica gel column (PE/EtOAc = 5/1) to afford 5-bromo-4,6-dimethylpyridin-2-amine as a yellow solid (800 mg, 48percent).
Reference：
[1] Organic Process Research and Development, 2012, vol. 16, # 1, p. 109 - 116
[2] Patent: WO2011/103536, 2011, A1, . Location in patent: Page/Page column 43-44
[3] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 17, p. 5188 - 5201
[4] Pharmacy and Pharmacology Communications, 1999, vol. 5, # 3, p. 233 - 238
[5] Patent: WO2018/108671, 2018, A1, . Location in patent: Page/Page column 178; 179
[6] Tetrahedron Letters, 2014, vol. 55, # 36, p. 5058 - 5061
[7] Journal of Medicinal Chemistry, 2015, vol. 58, # 21, p. 8743 - 8749
[8] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 15, p. 5093 - 5097
[9] European Journal of Medicinal Chemistry, 2012, vol. 55, p. 395 - 408,14
[10] European Journal of Medicinal Chemistry, 2012, vol. 55, p. 395 - 408
[11] Journal of Organic Chemistry, 2004, vol. 69, # 26, p. 9215 - 9223
[12] Journal of Heterocyclic Chemistry, 2003, vol. 40, # 4, p. 569 - 573
[13] Patent: US5849753, 1998, A,
[14] Patent: WO2015/103317, 2015, A1, . Location in patent: Page/Page column 154
[15] Journal of the American Chemical Society, 1952, vol. 74, p. 1916,1918
2
[ 128-08-5 ]
[ 5407-87-4 ]
[ 89856-44-0 ]
Reference：
[1] Patent: US5693812, 1997, A,
3
[ 5407-87-4 ]
[ 89856-44-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 1997, vol. 5, # 4, p. 673 - 678
[2] Bioorganic and Medicinal Chemistry, 1997, vol. 5, # 4, p. 673 - 678
4
[ 99179-94-9 ]
[ 89856-44-0 ]
Reference：
[1] Journal of the American Chemical Society, 1952, vol. 74, p. 1916,1918
5
[ 5407-88-5 ]
[ 89856-44-0 ]
Reference：
[1] Journal of the American Chemical Society, 1952, vol. 74, p. 1916,1918
Stage #1: With hydrogen bromide; sodium nitrite In water at 0 - 5℃; for 0.5 h; Stage #2: With bromine In water at 5℃; for 0.5 h;
To a solution of 2-amino-5-bromo-4,6-dimethylpyridine (201 mg, 1 mmol) in HBr (48percent, 3 mL) at 0°C, was added dropwise a solution of NaNO2 (172 mg, 2.5 mmol) in H2O (0.6 mL). Then the mixture was stirred at 0~5°C for 30 minutes, Br2 (448 mg, 2.8 mmol) was added, keeping the temperature below 5°C. After a further 30 minutes, the mixture was made alkaline with 20percent cold NaOH solution. Then the mixture was extracted with EtOAc three times, the combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on silica gel (Hexane-EtOAc, 10:1) to afford the product (243 mg, 92percent) as a pale yellow solid.
92%
With hydrogen bromide; bromine; sodium nitrite In water at 0 - 5℃; for 1 h;
To a solution of 1 (201 mg, 1 mmol) in HBr (48percent, 3 mL) at 0 °C, a solution of NaNO2 (172 mg, 2.5 mmol) in H2O (0.6 mL) was added dropwise. Then the mixture was stirred at 0-5 °C for 30 min, Br2 (448 mg, 2.8 mmol) was added, while keeping the temperature below 5 °C. After a further 30 min, the mixture was made alkaline with 20percent cold NaOH solution. Then the mixture was extracted with EtOAc three times, the combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on silica gel (Hexane-EtOAc, 10:1) to afford the product (243 mg, 92percent) as a pale yellow solid. Mp 62-63 °C. (lit. [41] 63 °C). 1H NMR (CDCl3) δ 7.20 (s, 1H), 2.65 (s, 3H), 2.37 (s, 3H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 15, p. 5093 - 5097
[2] European Journal of Medicinal Chemistry, 2012, vol. 55, p. 395 - 408,14
[3] European Journal of Medicinal Chemistry, 2012, vol. 55, p. 395 - 408
Stage #1: With hydrogenchloride; sodium nitrite In water at 0℃; for 0.166667 h; Stage #2: With copper(l) chloride In water at 0 - 35℃; for 4.33333 h;
Preparation Example 21 Synthesis of 3-bromo-6-chloro-2,4-dimethylpyridine 5-bromo-4,6-dimethylpyridin-2-amine (CAS No. 89856-44-0; Aldrich) (4.00 g) was added to a mixed solution of concentrated hydrochloric acid (24 mL) and water (24 mL). The solution was cooled to 0° C., and sodium nitrite (3.57 g) was added, followed by stirring at the same temperature for 10 minutes. Copper(I) chloride (5.91 g) was added to the solution, and the mixture was stirred at 0° C. for five minutes and at room temperature for four hours and 15 minutes. The reaction mixture was cooled to 0° C., and a 5 N aqueous sodium hydroxide solution was added to make the reaction mixture basic. Ethyl acetate was added to the reaction mixture, followed by filtration. The organic layer in the filtrate was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 5percent) to give the title compound (1.79 g). 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.39 (s, 3H), 2.65 (s, 3H), 7.06 (s, 1H).
Reference：
[1] Organic Process Research and Development, 2012, vol. 16, # 1, p. 109 - 116
[2] Organic and Biomolecular Chemistry, 2010, vol. 8, # 21, p. 4815 - 4818
[3] Patent: WO2012/58187, 2012, A1, . Location in patent: Page/Page column 66; 67
[4] Patent: US2013/143907, 2013, A1, . Location in patent: Paragraph 0388; 0389; 0390
[5] Patent: WO2014/22528, 2014, A1, . Location in patent: Page/Page column 92
[6] Patent: WO2014/19186, 2014, A1, . Location in patent: Page/Page column 78
[7] Patent: WO2015/89809, 2015, A1, . Location in patent: Page/Page column 46
[8] Patent: WO2015/95256, 2015, A1, . Location in patent: Page/Page column 46
Intermediate 60{(S)-6-[(R)-4-(1 ,2,4-Trimethyl-6-oxo-1 ,6-dihvdro-pyridin-3-yl)-indan-1 -yloxyl-2,3- dihydro-benzofuran-3-yl)-acetic acid methyl esterStep 1 : 5-bromo-4,6-dimethyl-pyridin-2-ol5-Bromo-4,6-dimethyl-pyridin-2-ylamine (2.01 g) in water (120 mL) and 32% aqueous HCI (40 mL) is heated to reflux temperature and the solution is filtered hot. NaN02 (2.00 g) dissolved in water (40 mL) is added to the hot filtrate with vigorous stirring. The resulting mixture is stirred at room temperature overnight. The mixture is cooled in an ice bath and the precipitate is separated by filtration. The precipitate is washed with water and dried to give the title compound. Yield: 1 .17 g (58% of theory); LC (method 1 ): tR = 0.82 min; Mass spectrum (EST): m/z = 202/204 (Br) [M+H]+.
58%
With hydrogenchloride; sodium nitrite; In water; at 20℃;Reflux;
Intermediate 60{(S)-6-[(R)-4-(1,2,4-Trimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester Step 1: 5-bromo-4,6-dimethyl-pyridin-2-ol5-Bromo-4,6-dimethyl-pyridin-2-ylamine (2.01 g) in water (120 mL) and 32% aqueous HCl (40 mL) is heated to reflux temperature and the solution is filtered hot. NaNO2 (2.00 g) dissolved in water (40 mL) is added to the hot filtrate with vigorous stirring. The resulting mixture is stirred at room temperature overnight. The mixture is cooled in an ice bath and the precipitate is separated by filtration. The precipitate is washed with water and dried to give the title compound. Yield: 1.17 g (58% of theory); LC (method 1): tR=0.82 min; Mass spectrum (ESI+): m/z=202/204 (Br) [M+H]+.
13.7 g
With sulfuric acid; sodium nitrite; In water; at 0 - 35℃; for 1h;
(1) Synthesis of 5-bromo-4,6-dimethylpyridin-2-ol <strong>[89856-44-0]2-amino-5-bromo-4,6-dimethylpyridine</strong> (15 g) was dissolved in a mixed solution of sulfuric acid (14.2 mL) and water (212 mL). A solution of sodium nitrite (6.18 g) in water (31 mL) was added to the solution at 0 C. The reaction mixture was stirred at mom temperature for one hour, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was concentrated under reduced pressure. MTBE was added to the residue to precipitate the solid, followed by filtration. The filtration residue was washed with MTBE to give the title compound (13.7 g). ESI-MS m/z 204 [M+H]+
13.7 g
With sulfuric acid; sodium nitrite; In water; at 0 - 35℃; for 1h;
(1) Synthesis of 5-bromo-4,6-dimethylpyridin-2-ol 2-Amino-5-bromo-4,6-dimethylpyridine (15 g) was dissolved in a mixed solution of sulfuric acid (14.2 mL) and water (212 mL). A solution of sodium nitrite (6.18 g) in water (31 mL) was added to the solution at 0C. The reaction mixture was stirred for 1 hour at room temperature and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the desiccant was filtered out. The filtrate was concentrated under reduced pressure, MTBE was added to the residue, and the precipitated solid was deposited and then filtered out. The obtained solid was rinsed with MTBE to obtain the title compound (13.7 g). ESI-MS m/z 204 [M+H]+
With sulfuric acid; potassium nitrate; at -10 - 20℃; for 1.25h;
to a 50 mL round-bottom flask was added H2S04(2.0 mL) and the reaction system was cooled down to -10 C. At the same temperature, <strong>[89856-44-0]5-bromo-4,6-dimethylpyridin-2-amine</strong> (1.0 equiv, 2.49 mmol, 0.50 g) was added portion-wise over the period of 5 min, followed by the addition of KN03(1.4 equiv, 3.48 mmol, 0.4 g) portion-wise over the period of 10 min. The resulting solution was stirred at room temperature for 1 h. The reaction mixture was quenched with water/ice (30 mL) and saturated aqueous NaHC03was added until pH >7. Solid product precipitated out and the resulting suspension was filtered. Solids were collected and dried in oven under reduced pressure. This resulted in 0.45 g (73.5%) of 5-bromo-4,6-dimethyl-3-nitropyridin-2-amine as a yellow solid. (M+H)+= 245.9, 247.9
6-fluoro-2,4-dimethyl-nicotinic acid. To a suspension of <strong>[89856-44-0]2-amino-5-bromo-4,6-dimethylpyridine</strong> (4.02 g, 20.0 mmol) in HBF4 (48% in water, 15 mL) cooled in an ice bath was added a solution of NaNO2 (1.73 g, 25.0 mmol) in water (5 mL). The reaction mixture turned clear, and 10 min later a precipitate was formed. The precipitate was collected by filtration, dried under vacuum and added to hot heptane (100 mL) pre-heated at 90 C. After heated at 90 C. for 2 h the mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum to afford 3-bromo-2,4-dimethyl-6-fluoropyridine as a pale yellow solid (1.45 g, 36%). 1H NMR (CDCl3): delta 2.43 (s, 3H), 2.61 (s, 3H), 6.66 (d, 1H, J=3.0 Hz). 19F NMR (CDCl3): delta 3.24.
500 mg
With fluoroboric acid; sodium nitrite; In water; at 0℃; for 0.166667h;
Preparation Example 38 Synthesis of 3-bromo-6-fluoro-2,4-dimethylpyridine <strong>[89856-44-0]2-amino-5-bromo-4,6-dimethylpyridine</strong> (2 g) was suspended in fluoroboric acid (48% aqueous solution, 7.5 mL). Sodium nitrite (890 mg) dissolved in water (3 mL) was added to the solution at 0 C. The reaction mixture was stirred at 0 C. for 10 minutes. The precipitated solid was collected by filtration and suspended in n-heptane (100 mL). The solution was stirred with heating under reflux for two hours. After cooling to room temperature, the precipitated solid was collected by filtration. The resulting solid was dried under reduced pressure to give the title compound (500 mg). 1H-NMR (400 MHz, CDCl3) delta (ppm): 2.43 (s, 3H), 2.62 (s, 3H), 6.67 (s, 1H).
Step A Preparation of 2-amino-5-bromo-4,6-lutidine STR4 2-Amino-4,6-lutidine (101.0 g, 0.827 mole) is dissolved in acetone at 25 C. and the solution cooled to -15 C. N-Bromosuccinimide (137.5 g, 0.778 mole) is added in 10*13.75 g portions over 1.5 hours, maintaining a temperature of -10 C. After addition is complete, the slurry is aged at -10 C. for 0.5 hours. Water (1820 mL) is added over 0.5 hours, allowing the temperature to rise to 20-25 C. The resulting slurry is recooled to 5-10 C. and aged for 1 hour then filtered and the product washed with cold water (500 mL, 5-10 C.) and dried under vacuum to yield 141.3 g of 2-amino-5-bromolutidine (4) at a purity of 96.9% (HPLC wt %) for a yield of 82.3%. The crystallization as described removes succinimide (water soluble), 2-amino-4,6-lutidine (3) (water soluble) and 2-amino-3-bromo-4,6-lutidine (10).
N-(5-BROMO-4,6-DIMETHYL-2-PYRIDYL)-2-THIENYLACETAMIDE[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 4 N-(5-BROMO-4,6-DIMETHYL-2-PYRIDYL)-2-THIENYLACETAMIDE By performing the process as in Example 2, but replacing the 2-ethylamino-4,6-dimethylpyridine by <strong>[89856-44-0]2-amino-5-bromo-4,6-dimethylpyridine</strong> obtained in Stage A of the preparation, the title product is obtained. Recrystallization solvent: acetone Yield: 86% Melting point: 192 C.
A stirred solution of <strong>[89856-44-0]2-amino-5-bromo-4,6-dimethylpyridine</strong> (65 g, 323 mmol) in 37% hydrochloric acid (780 ml) was cooled to -10 C. Sodium nitrite (66.9 g, 970 mmol) was added in small portions over 10 min. The reaction was stirred for 15 min at -10 C and then warmed to room temperature. After stirring for 1 hour at r.t., the reaction was quenched by pouring into ice/water (4L). The mixture was stirred for 5 minutes and then extracted with EtOAc (4L). The organic extract was washed with water (4L) and brine (2L). The organic layer was dried over Na2S04, filtered, and concentrated. The resulting white solid was dissolved in CH2CI2 (200 mL) and heptanes (700 mL) were added. The solution was stirred for 20 minutes and then filtered to remove solids. The filtrate was concentrated and the residue was purified by flashchromatography on silica gel with 0 to 15% EtOAc/heptanes to afford 3-bromo~6-chloro-2,4- dimethylpyridine. LCMS = 21 .9 and 221.9 (M+H)+ 1H NMR (CDC13, 500 MHz) delta 7.05 (s, 1H), 2.65 (s, 3H), 2.39 (s, 3H).
1.79 g
Preparation Example 21 Synthesis of 3-bromo-6-chloro-2,4-dimethylpyridine <strong>[89856-44-0]5-bromo-4,6-dimethylpyridin-2-amine</strong> (CAS No. 89856-44-0; Aldrich) (4.00 g) was added to a mixed solution of concentrated hydrochloric acid (24 mL) and water (24 mL). The solution was cooled to 0 C., and sodium nitrite (3.57 g) was added, followed by stirring at the same temperature for 10 minutes. Copper(I) chloride (5.91 g) was added to the solution, and the mixture was stirred at 0 C. for five minutes and at room temperature for four hours and 15 minutes. The reaction mixture was cooled to 0 C., and a 5 N aqueous sodium hydroxide solution was added to make the reaction mixture basic. Ethyl acetate was added to the reaction mixture, followed by filtration. The organic layer in the filtrate was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 5%) to give the title compound (1.79 g). 1H-NMR (400 MHz, CDCl3) delta (ppm): 2.39 (s, 3H), 2.65 (s, 3H), 7.06 (s, 1H).
With hydrogenchloride; sodium nitrite; In water; at -5 - 20℃; for 25.5h;
Step A: 3 -Bromo-6-chloro-2,4-dimethylpyridine (3-1)To a mixture of <strong>[89856-44-0]2-amino-5-bromo-4,6-dimethylpyridine</strong> (5.03 g, 25 mmol) in cone. HC1 (30 mL), which was cooled to -5 C, was added dropwise a solution of sodium nitrite (5.18 g, 75 mmol) in water (20 mL) over 30 mm, while maintaining the reaction temperature between -5 C and 5 C.After the addition was complete, the reaction was stirred for 1 h. Then the cooling bath was removed and the reaction was warmed to room temperature and stirred for 24 h. The reaction was then poured into ice and SN NaOH was added to adjust the pH of resulting mixture to pH 7. The mixture was extracted with EtOAc three times. The combined organic layers were dried over anhydrous Na2504, filtered and concentrated. The resulting residue was purified by flashchromatography on silica gel with PE:EA=20: 1 to afford 3-bromo-6-chloro-2,4- dimethylpyridine. MS (ESI) mle (M+Hj: 222.0/220.0.
With hydrogenchloride; sodium nitrite; In water; at -5 - 20℃; for 25.5h;
To a mixture of<strong>[89856-44-0]2-amino-5-bromo-4,6-dimethylpyridine</strong> (5.03 g, 25 mmol) in cone. HCl (30 mL),which was cooled to -5 C, was added dropwise a solution of sodium nitrite (5.18 g, 75 mmol) inwater (20 mL) over 30 min, while maintaining the reaction temperature between -5 oc and 5 C.10 After the addition was complete, the reaction was stirred for 1 h. Then the cooling bath wasremoved and the reaction was warmed to room temperature and stirred for 24 h. The reactionwas then poured into ice and 5N NaOH was added to adjust the pH of resulting mixture to pH 7.The mixture was extracted with EtOAc three times. The combined organic layers were dried overanhydrous Na2S04, filtered and concentrated. The resulting residue was purified by flash15 chromatography on silica gel with PE:EA=20: 1 to afford 3-bromo-6-chloro-2,4-dimethylpyridine.MS (ESI) m/e (M+H+): 222.0/220.0.
With hydrogenchloride; sodium nitrite; In water; at -5 - 20℃; for 25.5h;
Step A. 3-Bromo-6-chloro-2,4-dimethylpyridine To a mixture of <strong>[89856-44-0]2-amino-5-bromo-4,6-dimethylpyridine</strong> (5.03 g, 25 mmol) in cone HC1 (30 mL) which was cooled to -5C, was added a solution of sodium nitrite (5.18 g, 75 mmol) in water (20 mL) dropwise over 30 min, while maintaining the temperature of the reaction between -5C and 5C. After the addition was complete, the reaction was stirred for lh, and then the cooling bath was removed and the reaction was warmed to room temperature and stirred for 24 hrs. The reaction was poured into ice and 5N NaOH was added to adjust the PH of solution to 7. The mixture was extracted with EtOAc for three times. The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by flash chromatography on silica gel with PE:EA=20: 1 to the title compound. MS (ESI) m/e (M+H ): 222.0/220.0.
With toluene-4-sulfonic acid; In toluene;Reflux; Inert atmosphere;
2-(2,5-Dimethyl-lH-pyrrol-l-yl)-5-bromo-4,6-dimethylpyridine (14):; To a stirred solution containing 2.76g (13.75 mmol) of 2-amino-5-bromo-4,6- dimethylpyridine (13) in 25 mL of toluene were added 2.02 mL (17.18 mmol) of 2,5- hexadienone followed by 130 mg (0.68 mmol) of /^-toluene sulfonic acid. The reaction mixture was stirred at reflux overnight under argon atmosphere. The reaction mixture was poured into 150 mL of water and then extracted with a portion of 200 mL of ethyl acetate. The organic solution was washed with a portion of 150 mL of brine, dried (MgS04) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with hexanes-ethyl acetate 5: 1 gave the expected product as an orange oil: yield 2.37 g (62%). 1H-NMR(CDC13) delta 6.93 (s, 1H), 5.88 (s, 2H), 2.70 (s, 3H), 2.47 (s, 3H), 2.12 (s, 6H);13C-NMR (CDC13) delta 157.35, 149.32, 128.42, 122.49, 121.22, 25.58, 23.41, 13.10.
62%
With toluene-4-sulfonic acid; In toluene; for 14h;Reflux; Inert atmosphere;
To a stirred solution containing 2.76 g (13.8 mmol) of <strong>[89856-44-0]6-amino-3-bromo-2,4-dimethylpyridine</strong> (8) in 25 mL of toluene were added 2.02 mL (1.98 g; 17.2 mmol) of 2,5-hexanedione followed by 130 mg (0.68 mmol) of p-toluenesulfonic acid. The cooled reaction mixture was stirred at reflux for 14 h. The cooled reaction mixture was poured into 150 mL of water and then extracted with 200 mL of ethyl acetate. The organic phase was washed with 150 mL of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (15 × 6 cm). Elution with 6:1 hexanes/ethyl acetate afforded 3-bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)-2,4-dimethylpyridine (9) as an orange oil: yield 2.37 g (62%); silica gel TLC Rf 0.70 (6:1 hexanes/ethyl acetate); 1H NMR (CDCl3) delta 2.12 (s, 6H), 2.47 (s, 3H), 2.70 (s, 3H), 5.88 (s, 2H), and 6.93 (s, 1H); 13C NMR (CDCl3) delta 13.1, 23.4, 25.6, 106.9, 121.16, 121.24, 122.5, 128.4, 149.6, and 157.4; mass spectrum (APCI), m/z 279.0502 (M+H)+ (C13H16N2Br requires 279.0497).
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃;Inert atmosphere;
Preparation of 2-N,N-dimethylamino-5-hydroxy-4,6-dimethylpyrimidine (21); 2-N,N-dimethylamino-5-bromo-4,6-dimethylpyridine (20):; To a stirred solution containing 1.12 g (5.57 mmol) of 2-amino-5-bromo-4,6- dimethylpyridine (13) in 20 mL of anhydrous THF were added 1.04 mL (16.71 mmol) of methyl iodide followed by 668 mg (16.71 mmol) of 60 % suspension of sodium hydride in mineral oil. The reaction mixture was stirred at room temperature under argon atmosphere overnight. The reaction mixture was poured into 100 mL of water and extracted with two portions 100 mL of ether. The combined organic solution was dried (MgS04) and the concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with hexanes-ether 9: 1 gave the expected product as colorless oil: yield 700 mg (55%).1H-NMR(CDC13) delta 6.22 (s, 1H) , 3.01 (s, 6H), 2.51 (s, 3H), 2.30 (s, 3H);13C-NMR (CDC13) 5156.34, 155.23, 148.64, 112.26, 108.10, 74.40, 25.10, 23.30.
General procedure: The appropriate (hetero) aromatic amine (1.0 mmol) and 2',6'-/3',5'-dihalo-substituted (hetero/aromatic) aldehyde (1.5 mmol) were stirred in dry toluene under reflux condition followed by addition of mercaptoaceticacid (2.0 mmol). The reaction mixture was refluxed with a Dean-Stark trap for 24-48 h until the complete consumption of (hetero) aromatic amine. The reaction mixture was concentrated to dryness under reduced pressure and the residue was taken up in ethyl acetate. The organic layer was successively washed with 5% aq citric acid, water, 5% aq sodium hydrogen carbonate, and then finally with brine. The organic layer was dried over sodium sulfate and solvent was removed under reduced pressure to get a crude product that was purified by column chromatography on silica-gel (230-400 mesh) using hexane-ethyl acetate as eluent. The structures of synthesized compounds were characterized by means of TLC, IR, ESI-MS, 1H NMR, 13C NMR, elemental analyses and HRMS.
General procedure: The appropriate (hetero) aromatic amine (1.0 mmol) and 2',6'-/3',5'-dihalo-substituted (hetero/aromatic) aldehyde (1.5 mmol) were stirred in dry toluene under reflux condition followed by addition of mercaptoaceticacid (2.0 mmol). The reaction mixture was refluxed with a Dean-Stark trap for 24-48 h until the complete consumption of (hetero) aromatic amine. The reaction mixture was concentrated to dryness under reduced pressure and the residue was taken up in ethyl acetate. The organic layer was successively washed with 5% aq citric acid, water, 5% aq sodium hydrogen carbonate, and then finally with brine. The organic layer was dried over sodium sulfate and solvent was removed under reduced pressure to get a crude product that was purified by column chromatography on silica-gel (230-400 mesh) using hexane-ethyl acetate as eluent. The structures of synthesized compounds were characterized by means of TLC, IR, ESI-MS, 1H NMR, 13C NMR, elemental analyses and HRMS.
General procedure: The appropriate (hetero) aromatic amine (1.0 mmol) and 2',6'-/3',5'-dihalo-substituted (hetero/aromatic) aldehyde (1.5 mmol) were stirred in dry toluene under reflux condition followed by addition of mercaptoaceticacid (2.0 mmol). The reaction mixture was refluxed with a Dean-Stark trap for 24-48 h until the complete consumption of (hetero) aromatic amine. The reaction mixture was concentrated to dryness under reduced pressure and the residue was taken up in ethyl acetate. The organic layer was successively washed with 5% aq citric acid, water, 5% aq sodium hydrogen carbonate, and then finally with brine. The organic layer was dried over sodium sulfate and solvent was removed under reduced pressure to get a crude product that was purified by column chromatography on silica-gel (230-400 mesh) using hexane-ethyl acetate as eluent. The structures of synthesized compounds were characterized by means of TLC, IR, ESI-MS, 1H NMR, 13C NMR, elemental analyses and HRMS.
General procedure: The appropriate (hetero) aromatic amine (1.0 mmol) and 2',6'-/3',5'-dihalo-substituted (hetero/aromatic) aldehyde (1.5 mmol) were stirred in dry toluene under reflux condition followed by addition of mercaptoaceticacid (2.0 mmol). The reaction mixture was refluxed with a Dean-Stark trap for 24-48 h until the complete consumption of (hetero) aromatic amine. The reaction mixture was concentrated to dryness under reduced pressure and the residue was taken up in ethyl acetate. The organic layer was successively washed with 5% aq citric acid, water, 5% aq sodium hydrogen carbonate, and then finally with brine. The organic layer was dried over sodium sulfate and solvent was removed under reduced pressure to get a crude product that was purified by column chromatography on silica-gel (230-400 mesh) using hexane-ethyl acetate as eluent. The structures of synthesized compounds were characterized by means of TLC, IR, ESI-MS, 1H NMR, 13C NMR, elemental analyses and HRMS.
With dimethylbromosulphonium bromide; In acetonitrile; at 20℃; for 1.5h;
General procedure: A mixture of aromatic aldehyde (1mmol), amidine (1mmol) and isocyanide (1mmol) was taken in 2 mL acetonitrile. Then, the catalyst bromodimethylsulfonium bromide (0.022 g, 0.1mmol) was added into it and the reaction mixture was kept for stirring at room temperature till the completion of the reaction as indicated by TLC. The solid product came out slowly which was filtered through a Buchner funnel and the solid precipitate was washed with acetonitrile. Finally it was dried under reduced pressure.
With dimethylbromosulphonium bromide; In acetonitrile; at 20℃; for 1h;
General procedure: A mixture of aromatic aldehyde (1mmol), amidine (1mmol) and isocyanide (1mmol) was taken in 2 mL acetonitrile. Then, the catalyst bromodimethylsulfonium bromide (0.022 g, 0.1mmol) was added into it and the reaction mixture was kept for stirring at room temperature till the completion of the reaction as indicated by TLC. The solid product came out slowly which was filtered through a Buchner funnel and the solid precipitate was washed with acetonitrile. Finally it was dried under reduced pressure.
To a solution of <strong>[89856-44-0]2-amino-5-bromo-4,6-dimethylpyridine</strong> (201 mg, 1 mmol) in HBr (48%, 3 mL) at 0C, was added dropwise a solution of NaNO2 (172 mg, 2.5 mmol) in H2O (0.6 mL). Then the mixture was stirred at 0~5C for 30 minutes, Br2 (448 mg, 2.8 mmol) was added, keeping the temperature below 5C. After a further 30 minutes, the mixture was made alkaline with 20% cold NaOH solution. Then the mixture was extracted with EtOAc three times, the combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on silica gel (Hexane-EtOAc, 10:1) to afford the product (243 mg, 92%) as a pale yellow solid.
92%
With hydrogen bromide; bromine; sodium nitrite; In water; at 0 - 5℃; for 1h;
To a solution of 1 (201 mg, 1 mmol) in HBr (48%, 3 mL) at 0 C, a solution of NaNO2 (172 mg, 2.5 mmol) in H2O (0.6 mL) was added dropwise. Then the mixture was stirred at 0-5 C for 30 min, Br2 (448 mg, 2.8 mmol) was added, while keeping the temperature below 5 C. After a further 30 min, the mixture was made alkaline with 20% cold NaOH solution. Then the mixture was extracted with EtOAc three times, the combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on silica gel (Hexane-EtOAc, 10:1) to afford the product (243 mg, 92%) as a pale yellow solid. Mp 62-63 C. (lit. [41] 63 C). 1H NMR (CDCl3) delta 7.20 (s, 1H), 2.65 (s, 3H), 2.37 (s, 3H).
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