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Structure of 54127-31-0
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 54127-31-0 |
Formula : | C6H4Cl3N |
M.W : | 196.46 |
SMILES Code : | ClCC1=CN=C(Cl)C(Cl)=C1 |
MDL No. : | MFCD00125365 |
InChI Key : | XJCSQVBPRZIYPY-UHFFFAOYSA-N |
Pubchem ID : | 10176536 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H314 |
Precautionary Statements: | P501-P260-P264-P280-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P405 |
Class: | 8 |
UN#: | 3261 |
Packing Group: | Ⅱ |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | In ethanol;Heating / reflux; | Potassium cyanide (0.47 g, 0.00714 mol) was added to a flask containing Preparatory Compound P in ethanol (25 mL). The mixture was heated at reflux overnight. The mixture was dissolved in dichloromethane and washed twice with water. The organic phase was dried over magnesium sulfate and concentrated in vacuo to obtain a reddish oil. The oil was purified by silica gel chromatography using 50% ethyl acetate/hexanes as eluents. Fractions containing the desired product were isolated and concentrated in vacuo to yield Preparatory Compound Q, (5, 6-dichloropyridin-3-yl) acetonitrile, as a purple solid. (0.450 g, 39%). 1 H NMR 8 8.28 (d, 1H, J=2.1 Hz), 7.83 (dd, 1H, J=0.7 Hz and J=1.6 Hz), 3.78 (s, 2H). MS (ESI) NIZ 190 ([M+4] +, 10), 188 ( [M+2] +, 64), 186 ([M]+, 99), 151 (100), 124 (39). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With acetic acid; zinc; In methanol; at -5℃; for 4h; | 2, 3-dichloro-5-trichloromethylpyridine (36.60 g, 0.139 mol) was added to a flask containing acetic acid (53.50 g, 0.892 mol) and methanol (200 mL). The mixture was cooled to-5 C, and zinc dust (20.01 g, 0.308 mol) was added in small portions at 10 minute intervals. The mixture was stirred mechanically for 4 hours, filtered, and concentrated in vacuo. The residue was dissolved in dichloromethane and washed with brine, followed by saturated aqueous sodium bicarbonate, followed by a second brine wash. The organic phase was dried over magnesium sulfate and concentrated in vacuo to yield 21.55 g (79%) of Preparatory Compound P, 2, 3-DICHLORO-5- (CHLOROMETHYL) pyridine, as a yellow liquid (about 65% PURITY). 1H NMR No. 8.31 (d, 1H, J=2.3 Hz), 7.85 (q, 1H, J=0.4 Hz and J=2.2 Hz), 4.56 (s, 2H). MS (ESI) NIZ 199 ([M+4] +, 8), 197 ([M+2]+, 27), 195 ([M]+, 28), 164 (11), 162 (66), 160 (100), 124 (19) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine; thionyl chloride; at 0 - 20℃; for 2.0h; | (Referential Example 9) Synthesis of 5-chloromethyl-2,3-dichloropyridine (referential compound 9) Pyridine (1.0 ml, 12 mmol) and 18 ml (250 mmol) of thionyl chloride were gradually added, at 0C, to a solution of 30 g (168 mmol) of 5,6-dichloro-3-pyridinemethanol in 250 ml of chloroform and the mixture was stirred for 2 hours at room temperature. After the reaction was finished, the reaction solution was poured into a mixed solvent of chloroform and water and potassium carbonate was added thereto so that pH of an aqueous layer was made alkaline. The organic layer was separated therefrom and dried over anhydrous sodium sulfate and concentrated in vacuo to give 37 g of the title compound as a light brown oily substance (yield: quantitative). Rf value: 0.80 (n-hexane: ethyl acetate = 9:1 (v/v)) Mass spectrum (CI, m/z): 196 (M+ + 1) 1H-NMR spectrum (CDCl3, δ ppm): 4.54-4.55 (m, 2H), 7.84-7.85 (m, 1H), 8.30-8.31 (m, 1H) |
77.4% | With pyridine; trichlorophosphate; In dichloromethane; at 20℃; for 2.0h; | To a stirred solution of 2,3-dichloro-5-hydroxymethylpyridine (4.4 g, 25 mmol) and pyridine (2.61 g, 33 mmol) in dichloromethane (75 mL) was added rapidly phosphorous oxychloride (4.91 g, 32 mmol). An exothermic reaction sufficient to boil the reaction mixture ensued. After stirring at room temperature for 2 h, 1 N HCl aqueous solution (50 mL) was carefully added to the reaction mixture and the stirring continued for 10 min. The organic phase was separated and the aqueous phase extracted with dichloromethane (50 mL). The combined organic phase was washed successively with water (25 mL), 1 N aqueous NaOH solution (25 mL) and saturated aqueous NaCl solution (25 mL), dried over anhydrous MgSO4, filtered, and concentrated to give 3.80 g of the desired 2,3-dichloro-5-chloromethylpyridine as yellow oil (77.4% yield) which solidified upon standing at room temperature. GC-MS: mass calcd for C6H5Cl2NO [M]+ 178. Found 178 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2,3-Dichloro-5-hydroxymethyl-pyridine is reacted in a known manner with thionyl chloride to give 5-chloromethyl-2,3-dichloro-pyridine and the latter is reacted with sodium cyanide, without additional purification (for example analogously to L. A. Carlson et al., Acta Pharm. Suecica 9, 411 (1972)). 5,6-Dichloro-pyridine-3-acetonitrile, thus obtained, melts at 72-75 C. after recrystallisation from ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; In methanol; water; | Example 1(a) Preparation of 2,3-dichloro-5-(methoxymethyl)pyridine Under argon and at room temperature, 4.14 g (23 mmol) of sodium methoxide (30 percent strength solution in methanol) was added dropwise within 5 minutes to a solution of 4.11 g (20.9 mmol) of <strong>[54127-31-0]2,3-dichloro-5-(chloromethyl)-pyridine</strong> [prepared from 2,3-dichloro-5-(hydroxymethyl)-pyridine by reaction with thionyl chloride] in 40 ml of methanol. The reaction mixture was subsequently heated to 60 C. for 3 hours. After the reaction had ended, the solvent was distilled off and the residue was admixed with 100 ml of water and extracted with dichloromethane (3*75 ml). The organic phase was dried over magnesium sulfate and evaporated. The yield of the product was 4.06 g (90.4 percent) of a yellow oil, purity (GC) 90.8 percent. For analysis, the product was chromotographed over silica gel using hexane/ethyl acetate (3:1). MS (m/z): 192 (M+); 176; 161; 148; 124; 112. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In tetrahydrofuran; at 20℃; for 3.0h; | To a stirred solution of 2,3-dichloro-5-chloromethylpyridine (3.75 g, 19.1 mmol) in THF (30 mL) was added solid sodium thiomethoxide (2.01 g, 29 mmol) in one portion and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with ether (100 mL), washed with 0.1 N aqueous HCl (50 mL) solution and brine (50 mL), dried over anhydrous MgSO4, filtered, concentrated, and dried to give 3.55 g of 2,3-dichloro-5-methylthio-methylpyridine as a dark yellow liquid in 89% crude yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 4.0h; | 2-Butylaminoadenine (300 mg, 1.5 mmol), 5-chloromethyl-2, 3-dimethylpyridine (400 mg, 2 mmol) and potassium carbonate (420 mg, 3 mmol) were added to DMF (5 mL), and the mixture was heated at 60C for 4 hours, and the solvent was evaporated. To the residue were added water and chloroform, and the mixture was separated. The organic phase was dried over magnesium sulfate. The residue was purified by silica gel column chromatography (CHC13/MeOH=50/1) to give a white solid (480 mg). The obtained solid and bromine (320 mg, 2 mmol) were added to chloroform (10 mL), and the mixture was stirred under ice-cooling for 2 hours. The precipitated yellow solid was collected by filtration, and thereto was added 12N hydrochloric acid, and the mixture was refluxed for 6 hours. The solvent was evaporated under reduced pressure, and neutralized with a 28 % aqueous ammonia to give 2-butylamino-9-(5, 6-dichloropyridin-3-ylmethyl)-8-oxoadenine as a white solid (350 mg). This solid (200 mg, 0.5 mmol) and N-methylpiperazine (5 mL) were heated at 130 for 3 hours. The solvent was evaporated under reduced pressure, and thereto was added water. The precipitated solid was collected by filtration, and purified by silica gel column chromatography (CHCl3/MeOH=100/3) to give the title compound (114 mg, 50 %). 1H NMR (DMSO-d6) δ 9.64 (1H, s), 8.19 (1H, d, J = 1.8 Hz), 7.73 (1H, d, J = 1.8 Hz), 6.24 (1H, t, J = 5.6 Hz), 6.02 (2H, s), 4.75 (2H, s), 3.18 (4H, m), 2.44 (4H, t, J = 4.4 Hz), 2.21 (3H, s), 1.47 (2H, m), 1.30 (2H, m), 0.88 (3H, t, J = 7.2 Hz). |
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