* 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.
Reference:
[1] Journal of Heterocyclic Chemistry, 1995, vol. 32, # 1, p. 259 - 263
2
[ 38841-54-2 ]
[ 129432-25-3 ]
Yield
Reaction Conditions
Operation in experiment
91.8%
With sodium hydroxide; sodium hypobromide; bromine In water
A solution of 204.4g (5.11 mole) of sodium hydroxide in 1950ml of water was stirred and cooled to 0-5° C. 78.8ml (1.53 mole) of bromine was then added dropwise to the solution over 30 minutes, maintaining the temperature of the resultant solution at 0-5° C., to produce a sodium hypobromite solution. To the sodium hypobromite solution, Was added 275g (1.34 mole) of 2,6-dichloro-4-methyl-3-pyridinecarboxamide over 10 minutes, maintaining the temperature of resultant mixture at 0-5° C. The resultant mixture was slowly brought to room temperature over one hour and then heated at 70-75° C. for one hour, to produce a suspension. The suspension was cooled to room temperature, and stirred overnight. The resultant precipitate was filtered, washed with 21 of water and dried at 60° C., to give 217.9g (91.8percent) of 2,6-dichloro-4-methyl-3-aminopyridine (mp 83-85° C.).
86.3%
With sodium hydroxide; bromine In water; Petroleum ether
A)PREPARATION OF 2,6-DICHLORO-4-METHYL-3-AMINOPYRIDINE STR11 A solution of 89.2g (2.23 mole) of sodium hydroxide in 850ml of water was stirred and cooled to 0° C. in an ice/salt bath. 34.4 g (0.668 mole) of bromine was added dropwise, maintaining the temperature at 0° C. 120g (0.585 mole) of 2,6-dichloro-4-methyl-3-pyridinecarboxamide was then added at once keeping the temperature at 0° C. -5° C. The solution was slowly, over one-half hour, brought to room temperature and then heated at 70° C.-75° C. for one hour. The resulting suspension was cooled to room temperature, diluted further with 1l of water, and stirred overnight. The solid was filtered, back-washed with 1l of water, followed by 300 ml of petroleum ether and dried at 60° C. to give 89.4g (86.3percent) (mp: 80° C.-83° C.) of tan crystalline 2,6-dichloro-4-methyl-3-aminopyridine.
Reference:
[1] Journal of Heterocyclic Chemistry, 1995, vol. 32, # 1, p. 259 - 263
[2] Journal of Medicinal Chemistry, 1995, vol. 38, # 24, p. 4830 - 4838
[3] Patent: US5200522, 1993, A,
[4] Patent: US5571912, 1996, A,
3
[ 875-35-4 ]
[ 129432-25-3 ]
Reference:
[1] Journal of Medicinal Chemistry, 1995, vol. 38, # 24, p. 4830 - 4838
With water; sodium hydroxide; at 30 - 35℃; for 1.0h;
The reactor is filled with water, the hydrolyzate is dried, and then the sodium hydroxide is added to the mixture, and the temperature is controlled at 30-35 C, and the temperature is kept at this temperature for 1 hour.Then, the sodium hypochlorite was added dropwise at a temperature of 25-30 C, and the system was clarified. After the solution was clarified, the activated carbon was added and stirred for 1 hour, followed by pressure filtration.The filtrate was incubated at 30-35 C for 2 hours, then warmed to 50-55 C, then filtered for 10-12 hours with suction, and the filter cake was washed with water.Further, three batches of the crude product were placed in the reaction vessel, and then water and granules were added, and the mixture was heated to 50-55 C, stirred for 2 hours, and centrifuged, and the filter cake was washed with water.The molar ratio of the components is: hydroxyl species: chlorine gas: concentrated sulfuric acid: sodium hypochlorite = 1: 2.24: 3.03: 3.84.5. The finally obtained verapate intermediate 2,6-dichloro-3-amino-4-methylpyridine.The molar yield was 90.1%, and the purity was 98.2% as determined by HPLC.
76%
With bromine; sodium hydroxide; In water; at 0 - 75℃; for 2.0h;
To a solution of NaOH (3.7 g, 93 mmol) in H20 (100 mL) was added Br2 (4.7g, 29.4 mmol) dropwise at 0 C. The mixture was stirred at 0 C for 1 h before adding 2,6-dichloro-4- methylnicotinamide (5 g, 24.5 mmol). The mixture was allowed to warm to room temperature gradually over 1 h. The mixture was then heated to 75 C for lh. The resulting suspension was cooled to room temperature with stirring overnight. The suspension was filtered. The collected solid material was washed with water to afford 2,6-dichloro-4-methylpyridin-3-amine (3.3 g, 76%). MS m/z 176.9, 178.9 [M+H]+.
217.9g (91.8%)
With sodium hydroxide; sodium hypobromide; bromine; In water;
A solution of 204.4g (5.11 mole) of sodium hydroxide in 1950ml of water was stirred and cooled to 0-5 C. 78.8ml (1.53 mole) of bromine was then added dropwise to the solution over 30 minutes, maintaining the temperature of the resultant solution at 0-5 C., to produce a sodium hypobromite solution. To the sodium hypobromite solution, Was added 275g (1.34 mole) of 2,6-dichloro-4-methyl-3-pyridinecarboxamide over 10 minutes, maintaining the temperature of resultant mixture at 0-5 C. The resultant mixture was slowly brought to room temperature over one hour and then heated at 70-75 C. for one hour, to produce a suspension. The suspension was cooled to room temperature, and stirred overnight. The resultant precipitate was filtered, washed with 21 of water and dried at 60 C., to give 217.9g (91.8%) of 2,6-dichloro-4-methyl-3-aminopyridine (mp 83-85 C.).
89.4g (86.3%)
With sodium hydroxide; bromine; In water; Petroleum ether;
A)PREPARATION OF 2,6-DICHLORO-4-METHYL-3-AMINOPYRIDINE STR11 A solution of 89.2g (2.23 mole) of sodium hydroxide in 850ml of water was stirred and cooled to 0 C. in an ice/salt bath. 34.4 g (0.668 mole) of bromine was added dropwise, maintaining the temperature at 0 C. 120g (0.585 mole) of 2,6-dichloro-4-methyl-3-pyridinecarboxamide was then added at once keeping the temperature at 0 C. -5 C. The solution was slowly, over one-half hour, brought to room temperature and then heated at 70 C.-75 C. for one hour. The resulting suspension was cooled to room temperature, diluted further with 1l of water, and stirred overnight. The solid was filtered, back-washed with 1l of water, followed by 300 ml of petroleum ether and dried at 60 C. to give 89.4g (86.3%) (mp: 80 C.-83 C.) of tan crystalline 2,6-dichloro-4-methyl-3-aminopyridine.
a 5-Bromo-2-chloro-N-(2,6-dichloro-4-methyl-3-pyridinyl)-3-pyridinecarboxamide 3-Amino-2,6-dichloro-4-methylpyridine (0.51 g, 2.85 mmol) was dissolved in toluene (35 mL) and pyridine (0.27 mL, 3.28 mmol) was added. 5-Bromo-2-chloro-3-pyridinecarbonyl chloride (0.80 g, 3.14 mmol) was then added dropwise over 30 min. The resulting mixture was stirred at room temperature for 1 h, diluted with water and extracted with toluene (2*). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The resulting thick oil was triturated with CH2Cl2, and the white solid collected via suction filtration to give the title compound (0.41 g, 36% yield).
Recovery of 3-amino-2,6-dichloro-4-methylpyridine: The organic phase of the first extraction of the above-described synthesis is worked up as follows. The organic phase is mixed with 6 kg of 45% sodium hydroxide solution and 80 liters of water and extracted, the lower organic phase is separated off and the aqueous phase is mixed once more with 25 liters of methylene chloride. From the combined organic phase, after conventional working up, 7.1 kg =4% of theory of 3-amino-2,6-dichloro-4-methylpyridine are obtained, which can be reused in the reaction.
18
[ 108-24-7 ]
[ 129432-25-3 ]
N-(2,6-dichloro-4-methylpyridin-3-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22%
With potassium acetate; In toluene; at 70℃; for 48.0h;
To a solution of <strong>[129432-25-3]2,6-dichloro-4-methylpyridin-3-amine</strong> (3 g, 17 mmol) in toluene (50 mL) was added KOAc (2 g, 20.4 mmol) and Ac20 (6.9 g, 68 mmol). The mixture was stirred at 70 C for 48 h. The mixture was cooled to room temperature, and then poured into ice water (100 mL). The water was extracted with EtOAc (60 mL X 3). The combined organic phases were concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 25% EtOAc in petroleum ether to afford N-(2,6-dichloro-4-methylpyridin-3-yl) acetamide (842 mg, 22%) as a yellow solid. MS m/z 219.0, 221.0 [M+H]+.
5-chloro-7-methylthiazolo[5,4-b]pyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With hydrogenchloride; In ethanol; at 100℃; for 75.0h;
To a mixture of <strong>[129432-25-3]2,6-dichloro-4-methylpyridin-3-amine</strong> (0.50 g, 2.8 mmol) and potassium thiocyanate (0.82 g, 8.5 mmol) in ethanol (7.5 mL) at room temperature was added concentrated hydrochloric acid (10.0 mL, 330 mmol) dropwise. The mixture was heated at 100 C for 44 h. Additional potassium thiocyanate (0.82 g, 8.5 mmol) was added, and the mixture was heated at 100 C for additional 31 h. The reaction mixture was cooledto room temperature and concentrated under vacuum to dryness. To the residue was added 1N aqueous NaOH (10 mL) followed by solid K2C03 until the mixture became basic (pH =9-10). The mixture was extracted with dichloromethane (4 x 40 mL). The combined organicextracts were dried over anhydrous Na2504, filtered and concentrated to dryness in vacuo.The residue was loaded onto an Isco solid load cartridge and purified by flashchromatography on 5i02 (0-6% MeOH/DCM) to give 5-chloro-7-methylthiazolo[5,4-bjpyridin-2-amine (0.33 g, 1.7 mmol, 59% yield) as a tan solid. MS (ESI) m/z: 199.9 [M+Hf ?H NMR (500 MI-Tz, DMSO-d6) oe 7.90 (s, 2H), 7.22 (s, 1H), 2.41 (s, 3H).
58.7%
With hydrogenchloride; In ethanol; water; at 100℃; for 75.0h;
To a mixture of <strong>[129432-25-3]2,6-dichloro-4-methylpyridin-3-amine</strong> (0.500 g, 2.82 mmol) and potassium thiocyanate (0.823 g, 8.47 mmol) in ethanol (7.5 mL) at rt was added concentrated hydrochloric acid (10.04 mL, 330 mmol) dropwise. The mixture was heated at 100 C for 44 h. Additional potassium thiocyanate (0.823 g, 8.47 mmol) was added and the mixture was heated at 100 C for additional 31 h. The reaction mixture was concentrated under vacuum to dryness. To the residue was added 1 N NaOH solution (10 mL), followed by solid K2CO3, until the mixture became basic (pH = 9-10). The mixture was extracted with dichloromethane (4 x 40 mL). The combined extracts were dried over anhydrous Na2S04, filtered, and concentrated under vacuum. The residue was purified by flash chromatograph (80 g silica gel, solid loading, 0-6% methanol/dichloromethane) to provide 5-chloro-7-methylthiazolo[5,4-b]pyridin-2-amine (0.331 g, 1.658 mmol, 58.7 % yield) as a tan solid. MS (ESI) m/z: 199.9 [M+H]+; NMR (500 MHz, DMSO-de) delta 7.90 (s, 2H), 7.22 (s, 1H), 2.41 (s, 3H).