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CAS No. : | 16063-70-0 | MDL No. : | MFCD00043007 |
Formula : | C5H2Cl3N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CNLIIAKAAMFCJG-UHFFFAOYSA-N |
M.W : | 182.44 | Pubchem ID : | 27666 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 39.27 |
TPSA : | 12.89 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.2 cm/s |
Log Po/w (iLOGP) : | 1.96 |
Log Po/w (XLOGP3) : | 3.11 |
Log Po/w (WLOGP) : | 3.04 |
Log Po/w (MLOGP) : | 2.28 |
Log Po/w (SILICOS-IT) : | 3.35 |
Consensus Log Po/w : | 2.75 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.42 |
Solubility : | 0.0688 mg/ml ; 0.000377 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.05 |
Solubility : | 0.163 mg/ml ; 0.000893 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.87 |
Solubility : | 0.0245 mg/ml ; 0.000134 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.77 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H312-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
99% | With trimethylsilyl bromide In propiononitrile at 100℃; for 14 h; | 2-bromo-3,5-dichloropyridine. A 100 mL round-bottom flask equipped with a condenser was charged with 1.82 g of compound 71 (10.0 mmol) and propiononitrile (20 mL), 3.06 g TMSBr (20.0 mmol) was slowly added to the above solution. The reaction mixture was stirred at 1000C under nitrogen for 14 hrs, then cooled to a temperature of about 250C and diluted with EtOAc (100 mL). The EtOAc layer was isolated, dried, and concentrated under reduced pressure to provide 72 as a yellowish solid (>99percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium fluoride; 18-crown-6 ether; potassium carbonate; cesium fluoride In sulfolane; dimethyl sulfoxide at 120 - 200℃; for 3 h; | 400 g of sulfolane and 400 g of dimethylsulfoxide were weighed into a 1000 mL flask and dehydrated to a temperature of less than 0.05percent at 200 ° C under a pressure of 0.07 MPa (negative pressure)96 g (1.66 mol) of cesium fluoride, 96 g (1.66 mol) of potassium fluoride, 120 g (0.67 mol) of trichloropyridine, 2 g of 18-crown ether and 3 g of potassium carbonate were weighed into a reaction flask at 120 ° C and heated to 200 ° C The product was collected in about 3 hours. 95 g (0.51 mol) of the product was obtained in 90percent yield. The purity was 96.8percent as determined by gas chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With copper(I) cyanide; tetraphenylphosphonium bromide; potassium iodide In diethylene glycol dimethyl ether for 113 h; Heating / reflux | [0169] In analogy to Troschuetz, R. et al., J. Heterocycl. Chem. 33, 1815-1821 (1996), 150 ml of diethylene glycol dimethyl ether, 47.68 g (0.261 mol) of 2,3,5-trichloro-pyridine, 2.0 g (0.005 mol) of tetraphenylphosphonium bromide, 4.0 g (0.024 mol) of finely powdered potassium iodide and 75.0 g (0.838 mol) of copper(I) cyanide are mixed under nitrogen and stirred under reflux for 24 hours. Then a further 100 ml of diethylene glycol dimethyl ether, 2.0 g (0.005 mol) of tetraphenylphosphonium bromide, 4.0 g (0.024 mol) of finely powdered potassium iodide and 75 g (0.838 mol) of copper(I) cyanide are added, and the mixture is stirred at reflux temperature for a further 89 hours. Cooling to room temperature is followed by filtration with suction, and the filtrate is distilled to remove most of the diethylene glycol dimethyl ether. The residue is taken up in toluene and washed with an aqueous solution of Mohr's salt and then with aqueous NaHCO3 solution (peroxide test). It is then washed with water to remove diethylene glycol dimethyl ether. After filtration through cellit, the filtrate is dried over magnesium sulfate, and the solution is concentrated. [0170] 18.0 g (40.0percent) of 2-cyano-3,5-dichloropyridine are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.2% | With pyridine; 5%-palladium/activated carbon; hydrogen; In methanol; water; at 50℃; under 3750.38 Torr; | With a thermometer, reflux condenser,300 g of 2-chloropyridine was added to a 500 mL glass reaction vial of a chlorine tube.15g supported catalyst Sn-AC, heated to 110 C,Chlorine gas (pressure 0.1MPa) was introduced at a flow rate of 200 ml/min, and after 20 hours of reaction, the temperature was lowered to 30 C or lower.Filter to remove the supported catalyst,The obtained filtrate (HPLC detection of <strong>[2808-86-8]2,3,4,5-tetrachloropyridine</strong> was 217 g) was placed in a glass reaction flask.And adding methanol-water mixed solvent 800mL (volume ratio 4:1),79 g of pyridine and 217 mg of activated carbon catalyst loaded with Pd (purchased from Xi'an Kaili New Materials Co., Ltd., grade 5% palladium carbon Pd/C, the same below), and the reaction system was repeatedly replaced with hydrogen three times.Then, it was heated to 50 C, and hydrogen gas (pressure 0.5 MPa) was introduced at a flow rate of 200 ml/min.At the same time, a 5% aqueous solution of Na2CO3 was added dropwise to maintain the pH of the reaction system at 8-10.HPLC analysis showed that the content of <strong>[2808-86-8]2,3,4,5-tetrachloropyridine</strong> in the material was less than 5%, and the hydrogen was stopped.The material is lowered to normal temperature. The catalyst was filtered, and the filtrate was evaporated under reduced pressure to remove methanol, and the precipitated white solid was collected by filtration.The filter cake was washed three times with 100 mL of 5% hydrochloric acid and dried to give 465 g of white solid.HPLC analysis showed that the crude product contained 5.8% dichloropyridine and 89.8% 2,3,5-trichloropyridine.<strong>[2808-86-8]2,3,4,5-tetrachloropyridine</strong> 4.4%. The crude product was subjected to distillation under reduced pressure to obtain 414 g of 2,3,5-trichloropyridine (yield: 86.2%).The purity is greater than 99%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; | EXAMPLE 6 Production of 2,3,5-trichloropyridine Hydrogen chloride is passed into a solution of 25.0 g (0.125 mol) of 2,4,4-trichloro-4-formylbutyronitrile in 50 mml of N,N-dimethylformamide at a rate such that the temperature of the reaction mixture does not exceed 120 C. After completion of the reaction, the reaction mixture is poured into ice water. The beige-coloured precipitate is filtered off and dried. There is obtained 15.1 g (66% of theory) of 2,3,5-trichloropyridine, m.p. 48-50 C. | |
With phosphorus pentachloride; In N-methyl-acetamide; | EXAMPLE 7 Production of 2,3,5-trichloropyridine 10.3 g of phosphorus pentachloride is added portionwise at a maximum of 60 C. to 40.0 g of dimethylformamide. The solution obtained is subsequently saturated with hydrogen chloride, whereupon the temperature rises to 95 C. After cooling to 50 C. there is added dropwise 20.0 g of 2,4,4-trichloro-4-formylbutyronitrile (produced according to Example 1(a) in such a manner that the temperature of 75 C. is not exceeded. After completion of the addition of 2,4,4-trichloro-4-formylbutyronitrile, the mixture is heated at 100 C. for 1 hour. The reaction mixture at 60 C. is subsequently poured onto ice, whereupon 2,3,5-trichloropyridine precipitates in solid form. After filtration and drying, the yield is 16.2 g (89% of theory) of 2,3,5-trichloropyridine, m.p. 49-51 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With hydrazine; In 1,4-dioxane; for 20h;Reflux; | (2) Synthesis of 3,5-dichloro-2-hydrazinylpyridine To a 500 mL flask, 2, 3, 5-trichloropyridine (20.00 g, 0.110 mol), 80% hydrazine (34.30 g, 0.550 mol) and dioxane (200 mL) were added sequentially. The reaction mixture was heated to reflux for 20 hours. Then the reaction mixture was cooled down to room temperature overnight and white crystal was precipitated. The white crystal was isolated via filtration and dried to give the product (14.0 g) as a white solid in 72% yield. Melting point: 187-189 C. 1H NMR (300 MHz, DMSO-d6): 8.123 (d, 1H), 7.849 (d, 1H). |
24.07 g | With hydrazine; In ethanol; at 100℃; | (1) 2,3,5-trichloro-pyridine (25g), was added hydrazine monohydrate (109.8g) in ethanol (20) and stirred at 100 C, was cooled to room temperature. By collecting the generated solid was filtered to give the 3,5-dichloro-2-yl hydrazine (24.07g). |
With hydrazine hydrate; In ethanol; for 10h;Reflux; | General procedure: 2,6-dichloropyrazine (10.49 g, 70.38 mmol) was dissolved in 150 mL of ethanol. After stirring for 5 min, 80% hydrazine hydrate (7.05 g, 0.147 mol) was added. The reaction was heated to 80 C and refluxed for 10 h until the solution became clear. The resulting mixture was cooled to room temperature, and a yellow solid was precipitated. The suspension was filtered, and the filtrate was concentrated under reduced pressure to afford a yellow solid 9.1 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride; In sulfolane; at 155 - 160℃; for 8h; | To bring a thermometer,Into a four-necked flask with a reflux condenser and a stirrer, 93.1 g of 2,3,5-trichloropyridine (98% by mass, 0.50 mol),300mL sulfolane,32.2g of powdered potassium fluoride (99% by mass, 0.55mol),Heating to a temperature of 155-160 C and maintaining it for 8h,Sampling and analysis, at this time the content of 2,3,5-trichloropyridine is less than 1.0%, stop the reaction, cool to room temperature, filter, and wash the solid three times with sulfolane (10 mL each time).The filtrate and washings were combined. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | Step 1 : Preparation of ter-butyl cyano (3 , 5-dichloro-2 pyridinyl) acetate To 50 ml of dimethoxyethane was slowly added portionwise at 0C, 8.8 g (0.22 mol) of sodium hydride (60% dispersion in mineral oil). To this suspension, was further added dropwise at 5C, 17 g (0.12 mol) ofter-butyl cyanoacetate in 50 ml of dimethoxyethane. The suspension was stirred for 45 mn at room temperature. To the suspension were successively added 20 g (0.11 mol) of <strong>[16063-70-0]2,3,5-trichloropyridine</strong>, 0.59 g (1.1 mmol) of (S)-(+)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyl-ter-butylphosphine, and 1,2g (2.2 mmol) of bis(dibenzylideneacetone)palladium(0). The black mixture was heated at reflux for 5 hours. After cooling, the reaction mixture was poured into 100 ml of 1N hydrochloric acid. The aqueous phase was filtered on supersel and was extracted with ethyl acetate (3 x 200 ml). The organic phase was washed with brine and dried over magnesium sulphate. The solvent was evaporated under reduced pressure to give 38.5 g of the crude product as a brown oil. The crude product was purified by flash chromatography on silica gel (eluent: heptane/chloroforme: 6/4) to give ter-butyl cyano(3,5-dichloro-2-pyridinyl)acetate: 13 g (41%) as a yellow oil; mass spectrum: 287 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.7% | With potassium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,2-dimethoxyethane; at 85℃; for 2.5h; | In a 300-ml four-necked flask, under a nitrogen atmosphere, 2, 3, 5-trichloropyridine (10.0 g, 54.81 mmol), palladium acetate (383 mg, 16.44 mmol), 4,5- bis (diphenylphosphino) -9, 9-dimethylxanthene (Xantphos) (906 mg, 16.44 mmol), potassium carbonate (14.4 g, 109.62 mmol), 1,2- dimethoxyethane (100 ml) and o-anisidine (6.43 g, 52.21 mmol) were mixed. The mixture was stirred for 2.5 hours at an external temperature of 85C. After completion of the reaction, the reaction solution was cooled to room temperature. Ethyl acetate (100 ml) and water (100 ml) were added thereto, and the insoluble was dissolved. This solution was moved to a separating funnel, and the organic layer was separated by extraction. The aqueous layer was re-extracted twice with ethyl acetate (100 ml) . The organic layers were combined and washed with saturated brine (100 ml) , dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Methanol (100 ml) was added to the concentrate residue, and the mixture was heated to reflux for 1 hour, and then water (100 ml) was added dropwise thereto. The mixture was stirred for 1 hour at room temperature and with ice cooling for 45 minutes. A precipitate was collected by filtration with a glass filter, washed with methanol/water (1/1, 100 ml), and dried under reduced pressure at 50C, to yield the title compound (13.86 g, 51.49 mmol) as a ocher solid (yield 94.7%).1H-NMR (CDCl3, TMS, 300 MHz) delta (ppm) : 3.96 (s, 3H), 6.92- 6.96 (m, IH), 7.00-7.03 (m, 2H), 7.60 (d, IH, J = 2.3 Hz), 7.80 (m, IH), 8.13 (d, IH, J = 2.3 Hz), 8.51-8.54 (m, IH).13C-NMR (CDCl3, TMS, 300 MHz) delta (ppm): 55.97, 110.46, 116.94, 118.36, 120.64, 121.01, 122.04, 129.35, 136.10, 144.07, 148.21, 149.72.High resolution mass spectrometry (Ci2Hi0CI2N2O) Theoretical value: 268.0171 [M+] <n="177"/>Measured value : 268 . 0173 [M+]Melting point : 123 . 4C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.6% | With potassium carbonate;palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,2-dimethoxyethane; at 50 - 85℃; for 6.5h; | Under a nitrogen atmosphere, in a 50-ml flask, 2,3,5- trichloropyridine (345 mg, 1.09 mmol), palladium acetate (16.8 mg, 0.055 mmol), 4, 5-bis (diphenylphosphino) -9, 9- dimethylxanthene (Xantphos) (43.3 mg, 0.055 mmol), 1,2- dimethoxyethane (10 ml), methyl 5-amino-3' - (ethylsulfonyl) -4- methylbiphenyl-3-carboxylate monohydrochloride (500 mg, 1.04 mmol) and potassium carbonate (724 mg, 3.64 mmol) were mixed, and the mixture was stirred at an external temperature of 500C for 30 minutes and at 85C for 6 hours. The reaction solution was cooled to room temperature, and water (5 ml) was added thereto. The organic layer was separated by extraction using ethyl acetate (10 ml), and the aqueous layer was re-extracted twice with ethyl acetate (10 ml) . The organic layers were combined, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Diisopropyl ether (10 ml)/ n-hexane (5 ml) was added to the concentrated residue. The mixture was stirred at room temperature for 1 hour. A precipitate was collected by filtration, washed twice with n-hexane (5 ml), and dried under reduced pressure at 50C, to yield the title compound (605 mg, 1.26 mmol) as a yellow solid (yield 80.6%).1H-NMR (CDCl3, TMS, 300 MHz) delta (ppm) : 1.31 (s, 3H, J = 7.4 Hz), 2.54 (s, 3H), 3.17 (q, 2H, J = 7.4 Hz), 3.95 (s, 3H), 6.92 (s, IH), 7.62-7.67 (m, 2H), 7.87-7.92 (m, 3H), 8.05 (d, IH, J = 2.0 Hz) , 8.15 (s, IH) , 8.32 (d, IH, J = 1.6 Hz).13C-NMR (CDCl3, TMS, 300 MHz) 5 (ppm): 7.54, 14.85, 50.76, 52.39, 116.57, 121.59, 124.76, 124.80, 126.61, 127.20, 129.90, 131.65, 132.22, 132.54, 136.59, 136.91, 139.28, 139.37, 141.46, 144.48, 150.13, 168.14.High resolution mass spectrometry (C22H20Cl2N2O4S) <n="195"/>Theoretical value: [M+] 478.0521 Measured value: [M+] 478.0515 Melting point: 160.4C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium fluoride; C6H10BNO4; In dimethyl sulfoxide; at 60℃; for 5h; | 36.5 g of 2,3,5-trichloropyridine (0.2 mol) was added to a dry reactor.292 g of dimethyl sulfoxide, 34.8 g of potassium fluoride (0.62 mol),0.32 g of boron-containing compound I-1 (0.019 mol), and the mixture was heated to 60 C for 5 h.After the reaction of the raw materials is completed, the residue potassium chloride is removed by centrifugation.The mother liquid was removed under reduced pressure of the solvent dimethyl sulfoxide, and 29.5 g of 2,3-difluoro-5-chloropyridine was extracted with dichloromethane to give a qualitative content of 96%, yield 95%.The molar ratio of the fluorinated halogen to the fluorinating reagent in the raw material is 1:1.55, the molar ratio of the reactant (the material to be fluorinated) to the boron-containing compound is 1:0.1, and the weight ratio of the raw materials to the solvent other than the solvent is 1: 4. |
90% | With potassium fluoride; 18-crown-6 ether; potassium carbonate; cesium fluoride; In sulfolane; dimethyl sulfoxide; at 120 - 200℃; for 3h; | 400 g of sulfolane and 400 g of dimethylsulfoxide were weighed into a 1000 mL flask and dehydrated to a temperature of less than 0.05% at 200 C under a pressure of 0.07 MPa (negative pressure)96 g (1.66 mol) of cesium fluoride, 96 g (1.66 mol) of potassium fluoride, 120 g (0.67 mol) of trichloropyridine, 2 g of 18-crown ether and 3 g of potassium carbonate were weighed into a reaction flask at 120 C and heated to 200 C The product was collected in about 3 hours. 95 g (0.51 mol) of the product was obtained in 90% yield. The purity was 96.8% as determined by gas chromatography. |
With potassium carbonate; cesium fluoride; In dimethyl sulfoxide; | EXAMPLE 13 PREPARATION OF 5-CHLORO-2,3-DIFLUOROPYRIDINE Cesium fluoride (125 g, 0.82 mol) and DMSO (300 ml) were placed in a fluorination flask equipped with a mechanical stirrer, a thermometer, and a distilling head. About 50 ml DMSO were distilled off, under vacuum, to dry the system. 2,3,5-Trichloropyridine (50 g, 0.27 mol) and potassium carbonate (2.5 g, 0.018 mol) were added and the mixture was heated at 130-140 C. for 7 hours, with vigorous stirring. The product was distilled directly out of the reaction mixture, under vacuum. The DMSO was watered out and the product was redistilled to give a clear, colorless liquid (11.9 g, 29% of theoretical, b.p. 70-73 C. a 85 mmHg). |
With potassium carbonate; In dimethyl sulfoxide; | EXAMPLE 13 PREPARATION OF 5-CHLORO-2,3-DIFLUOROPYRIDINE Cedium fluoride (125 g, 0.82 mol) and DMSO (300 ml) were placed in a fluorination flask equipped with a mechanical stirrer, a thermometer, and a distilling head. About 50 ml DMSO were distilled off, under vacuum, to dry the system. 2,3,5-Trichloropyridine (50 g, 0.27 mol) and potassium carbonate (2.5 g, 0.018 mol) were added and the mixture was heated at 130-140 C. for 7 hours, with vigorous stirring. The product was distilled directly out of the reaction mixture, under vacuum. The DMSO was watered out and the product was redistilled to give a clear, colorless liquid (11.9 g, 29% of theoretical, b.p. 70-73 C.a85 mmHg). | |
With potassium carbonate; cesium fluoride; In dimethyl sulfoxide; | EXAMPLE 13 Preparation of 5-Chloro-2,3-Difluoropyridine Cesium fluoride (125 g, 0.82 mol) and DMSO (300 ml) were placed in a fluorination flask equipped with a mechanical stirrer, a thermometer, and a distilling head. About 50 ml DMSO were distilled off, under vacuum, to dry the system. 2,3,5-Trichloropyridine (50 g, 0.27 mol) and potassium carbonate (2.5 g, 0.018 mol) were added and the mixture was heated at 130-140 C. for 7 hours, with vigorous stirring. The product was distilled directly out of the reaction mixture, under vacuum. The DMSO was watered out and the product was redistilled to give a clear, colorless liquid (11.9 g, 29% of theoretical, b.p. 70-73 C. a 85 mmHg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With copper(I) cyanide; tetraphenylphosphonium bromide; potassium iodide; In diethylene glycol dimethyl ether; for 113h;Heating / reflux; | [0169] In analogy to Troschuetz, R. et al., J. Heterocycl. Chem. 33, 1815-1821 (1996), 150 ml of diethylene glycol dimethyl ether, 47.68 g (0.261 mol) of <strong>[16063-70-0]2,3,5-trichloro-pyridine</strong>, 2.0 g (0.005 mol) of tetraphenylphosphonium bromide, 4.0 g (0.024 mol) of finely powdered potassium iodide and 75.0 g (0.838 mol) of copper(I) cyanide are mixed under nitrogen and stirred under reflux for 24 hours. Then a further 100 ml of diethylene glycol dimethyl ether, 2.0 g (0.005 mol) of tetraphenylphosphonium bromide, 4.0 g (0.024 mol) of finely powdered potassium iodide and 75 g (0.838 mol) of copper(I) cyanide are added, and the mixture is stirred at reflux temperature for a further 89 hours. Cooling to room temperature is followed by filtration with suction, and the filtrate is distilled to remove most of the diethylene glycol dimethyl ether. The residue is taken up in toluene and washed with an aqueous solution of Mohr's salt and then with aqueous NaHCO3 solution (peroxide test). It is then washed with water to remove diethylene glycol dimethyl ether. After filtration through cellit, the filtrate is dried over magnesium sulfate, and the solution is concentrated. [0170] 18.0 g (40.0%) of 2-cyano-3,5-dichloropyridine are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium hydride; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 3.5h; | Reference Example 196 To a solution of3-isopropyl-4- [3- (methoxymethoxy) propyl]-lH-pyrazole (0.90 g) in N, N- <Desc/Clms Page number 212>dimethylformamide (30 ml) was added sodium hydride (60%, in oil, 0.19 g) at0 C, and the mixture was stirred at room temperature for 30 minutes. 2,3, 5-Trichloropyridine (0.89 g) was added at room temperature, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried(MgS04) and concentrated. The residue was subjected to silica gel column chromatography, and1- (3, 5- dichloro-2-pyridyl)-3-isopropyl-4- [3- (methoxymethoxy) propyl]- 1H-pyrazole (1.19 g, yield 78%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1: 5, volume ratio). 1H-NMR (CDC13) $ : 1.34 (6H, d, J=7 Hz), 1.85-2. 00 (2H, m), 2.55- 2.65 (2H, m), 2.95-3. 15 (1H, m), 3.38 (3H, s), 3.62 (2H, t, J=6 Hz), 4.65 (2H, s), 7.84 (1H, s), 7.86 (1H, d, J=2 Hz), 8.35 (1H, d, J=2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In DMF (N,N-dimethyl-formamide); water; at 65℃; for 16h; | step 2 A mixture of 2-METHYL-7- (4, 4,5, 5-tetramethyl- [1, 3,2] DIOXABOROLAN-2-YL)-2H-INDAZOLE (0.040 g, 0.15 mmol), 2,3, 5-trichloropyridine (0.274 g, 1.50 mmol), (PH3P) 4Pd (0) (0.019 g, 0.017 mmol), 2 mL of DMF, and 2 mL of a 2 M K3P04 solution was stirred at 65 C for 16 h then allowed to cool. Water (10 mL) was added, and the mixture was extracted with three 5 mL portions of ethyl acetate. The combined organic layers were dried over NA2SO4, filtered, and concentrated to a brown solid. Column chromatography (0-50% EtOAc/hexanes) afforded of 7-(3, 5-dichloro-pyridin-2-yl) -2-methyl-2H-indazole (7: R = Me; R'= H; Ar = 3,5-dichloro-pyridin-2-yl ; 0.042 g; 93%). To a solution OF 7- (3, 5-DICHLORO-PYRIDIN-2-YL)-2-METHYL-2H-INDAZOLE (0.042 g) in ether was added a 2 M solution OF HCL in ether. The mixture was filtered to afford 0.039 g of 7- (3, 5-Dichloro-pyridin-2-yl) -2-methyl-2H-indazole hydrochloride as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | SYNTHESIS EXAMPLE 11; Synthesis of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-<strong>[16063-70-0]2,3,5-trichloropyridine</strong> (compound No. 186); (a); 17.2 ml (26.7 mmol) of n-butyllithium (1.56 M hexane solution) was dropwise added to a diethyl ether (20 ml) solution of 2.7 g (26.7 mmol) of diisopropylamine at 0 C., followed by stirring for 1 hour. The solution was cooled to -78 C., a toluene solution of 4.8 g (26.7 mmol) of <strong>[16063-70-0]2,3,5-trichloropyridine</strong> was dropwise added thereto, and then a toluene solution of 5.0 g (24.0 mmol) of 2,3,4-trimethoxy-6-methylbenzaldehyde was dropwise added thereto, followed by stirring for 30 minutes. The temperature was recovered to room temperature, and stirring was carried out further for 1 hour. 30 mP of water was added to the mixture to terminate the reaction, and ethyl acetate was added for extraction. The organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain 6.7 g (yield 72%) of amorphous (2,3,4-trimethoxy-6-methylphenyl)(2,3,5-trichloro-4-pyridyl)methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.7%Chromat.; 77.8%Chromat. | With ammonium chloride; zinc; In 1,4-dioxane; water; at 90 - 92℃; for 12h;Product distribution / selectivity; | 2,3,5,6-Tetrachloropyridine (1 g) was charged to a reaction tube containing water (2 ml), 1,4-dioxane (6 ml), ammonium chloride (0.8 g) and zinc powder (1.5 g). Agitation was commenced (magnetic follower) and the reaction tube heated to 90-92° C. for 12 hours. Gas chromatography of the reaction mixture showed that it comprised: 3,5-dichloropyridine 77.8%, 2,3,5-trichloropyridine 7.7% and 2,3,5,6-terachloropyridine 14.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.3% | With acetic acid; zinc; In water; at 65 - 95℃; for 1 - 5.25h;Product distribution / selectivity; | <strong>[16063-70-0]2,3,5-Trichloropyridine</strong> (3.6 g) was charged to a round bottomed flask containing water (9.0 ml) and acetic acid (2.0 ml). The mixture was agitated with a magnetic follower, zinc metal powder (2.5 g) added and the mixture was heated to 95° C. The reaction was monitored by chromatography and after 1 hour all of the <strong>[16063-70-0]2,3,5-trichloropyridine</strong> had been consumed. The mixture was steam distilled to give water plus an oil that solidified on cooling. The solid was dissolved in dichloromethane (20 ml), the organic phase was separated, dried by passage under gravity through a filter paper and evaporated under reduced pressure to give the title compound as a low melting point solid (2.51 g, yield of 87.3%). Material confirmed as 3,5-dichloropyridine by comparative chromatography and 1 H NMR. To approximately half the crude reaction mass from Step 1 was added water (15 ml), zinc metal powder (2.0 g) and acetic acid. The mixture was heated to 65° C. After 2 hours 25 minutes a further quantity of zinc metal (0.5 g) was added and heating was continued for a further 2 hours 50 minutes. The resulting mixture was steam distilled until approximately 8 mls of distillate had been collected. The addition of water (10 ml) to the distillate caused a white solid to precipitate. The resulting distillate mixture was extracted with dichloromethane (20 ml) and the organic and inorganic phases were added to water (50 ml). The organic phase was separated and the aqueous phase re-extracted with a further quantity of dichloromethane (20 ml). The organic extracts were combined, washed with water (50 ml), dried over magnesium sulphate, the drying agent was filtered off and washed with dichloromethane. The filtrate was evaporated under reduced pressure to give the title compound as a white solid (0.531 g, approximate yield of 42% based on acrylonitrile charged). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium hydroxide; In dimethyl sulfoxide; | 5-(3,5-Dichloro-pyridin-2-yloxy)-2-methoxy-pyridine A solution of <strong>[51834-97-0]5-hydroxy-2-methoxypyridine</strong> (1.25 g, 10.0 mmol), 2,3,5-trichloropyridine (1.82 g, 10.0 mmol) and potassium hydroxide (85% pure, 1.08 g, 10.0 mmol) in dimethyl sulfoxide (25 mL) was heated at 90 C. for 1.5 hours. The solution was poured slowly into water (200 mL). The precipitate was collected by suction, washed thoroughly with water and dried in a vacuum oven at 45 C., yielding the title compound (2.39 g, 88% yield). 1H NMR (300 MHz, CDCl3): =3.95 (s, 3H), 6.80 (d, 1H), 7.41 (dd, 1H), 7.77 (d, 1H), 7.93 (d, 1H), 8.03 (d, 1H); HPLC-MS (Method A): m/z=271 (M+H)+; Rt=4.18 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | The yield of 2,3,5-trichloropyridine was calculated based on 2,3,5-trichloro-6-hydrazinopyridine. As a result, the yield was 95%. | |
95% | With sodium hypochlorite; sodium hydroxide; In water; at 70 - 75℃; for 1h;Green chemistry; | To a 1000 ml four-necked flask, 100 g of 2,3,5-trichloro-6-hydrazinylpyridine, 50 g of a 5% aqueous sodium hydroxide solution, and the temperature was raised to 70 to 75 C, and 387.6 g of a 10% sodium hypochlorite aqueous solution was added dropwise. Insulation at 70-75 C, reaction for 1 hour, the reaction is completed, the temperature is lowered to 5 ~ 10 C, stirred for 1 hour, filtered to obtain crude 2,3,5-trichloropyridine, distilled under reduced pressure, the product is obtained as a pale yellow solid, yield: 95%, content: 98%. |
93% | The yield of 2,3,5-trichloropyridine was calculated based on 2,3,5-trichloro-6-hydrazinopyridine. As a result, the yield was 93%. |
84% | The yield of 2,3,5-trichloropyridine was calculated based on 2,3,5-trichloro-6-hydrazinopyridine. As a result, the yield was 84%. | |
23% | The yield of 2,3,5-trichloropyridine was calculated based on 2,3,5-trichloro-6-hydrazinopyridine. As a result, the yield was 23%. | |
With N-benzyl-N,N,N-triethylammonium chloride; dihydrogen peroxide; sodium hydrogencarbonate; In water; toluene; | Example 1 50 kg of 2,3,5-trichloro-6-hydrazinopyridine as a starting material, 45 kg of toluene as an organic solvent, 100 kg of water, 50 kg of sodium hydrogencarbonate as a basic substance and 3 kg of benzyltriethylammonium chloride as a phase transfer catalyst were charged in order in a reaction vessel. The reaction system was heated to 75C and 27 kg of aqueous 35% hydrogen peroxide was added dropwise in the reaction vessel over 10 hours. After the completion of the reaction, the reaction solution was allowed to stand for about 30 minutes and then observed visually. As a result, the interface between the organic layer and aqueous layer was clear and the separation property was good. This organic layer was concentrated by fractional distillation to obtain 2,3,5-trichloropyridine. | |
339 kg | With N-benzyl-N,N,N-triethylammonium chloride; dihydrogen peroxide; sodium hydroxide; In water; at 70 - 75℃;Large scale; | In a 3000 liter reactor, add 1200 kg of water, 434 kg of 2,3,5,6-tetrachloropyridine, and 80% hydrazine hydrate.Kilograms, 43 kg of n-butanol, 319 kg of sodium carbonate,Then, the reactor is heated to 90-95 degrees Celsius, and stirred for 4-5 hours to form a trichloropyridinium group;Then, the temperature was lowered to 70-75 degrees Celsius, and then 43 kg of 30% sodium hydroxide and 2.2 kg of benzyltriethylammonium chloride were added thereto, and 450 kg of 30% hydrogen peroxide was slowly added dropwise thereto for 6-8 hours.After completion of the reaction, the organic layer was separated by phase separation, and the organic layer was washed with water and distilled to yield 339 kg of 2,3,5-trichloropyridine. The GC content (gas chromatography analysis) of the obtained product was determined to be 99.3%, and the yield was 93.1%. |
With sodium hydroxide; sodium hypochlorite; In toluene; | EXAMPLE VI -- Preparation of 2,3,5-trichloropyridine To a stirred mixture of 53.1 grams (0.25 mole) of 2,3,5-trichloro-6-hydrazinopyridine, 250 milliliters of toluene and 500 milliliters of 1.0N sodium hydroxide, under reflux at 88 C., was added over a 20 minute period 350 milliliters of 6.25 percent sodium hypochlorite. After the addition was complete, the mixture was stirred for an additional 10 minutes and then cooled to room temperature. The organic (toluene) phase was separated and concentrated and cooled. The 2,3,5-trichloropyridine was recovered in a yield of 45.3 grams (99.3 percent of theoretical) and had a purity of 97.6 percent. The product was recrystallized from hexane, filtered through activated carbon and was found to melt at 48-48.5 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride; potassium carbonate; cesium fluoride; In sulfolane; | EXAMPLE 8 850 g of sulfolane, 204.3 g (3.3 mol) of potassium fluoride/cesium fluoride (9:1), 7.5 g of potassium carbonate and 20.4 g of tetra-n-octylphosphonium bromide as the phase transfer catalyst were azeotropically dried by removal of about 100 g of sulfolane by distillation (170 C.). 273.5 g (1.5 mol) of 2,3,5-trichloropyridine were then added at 190 C. and the reaction mixture was heated to 215 C. After about 2 h reflux commenced. This was maintained for 20 h, and all the substance which boiled below 3 mm Hg/140 C. was then removed from the reaction mixture by distillation. A first fraction (15.8 g) which contained 14.2 g of 5-chloro-2,3-difluoropyridine and 1.3 g of 3,5-dichloro-2-fluoropyridine (determined by GC by means of internal standard) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium nitrite; In hydrogenchloride; hexane; water; | EXAMPLE 50 2-Amino-3,5-dichloropyridine (21.0 g.) is dissolved in conc. HCl (200 ml.), then cooled with ice. To this solution, NaNO2 (48 g.) in water (60 ml.) is added slowly over 30 minutes. The reaction mixture is stirred at 0° for 1 hour and then 50° for 1 hour. The mixture is then poured into ice-water and extracted with ether. The combined extracts are washed, dried and evaporated to dryness to give yellow solid. The solid is stirred with 25percent ether/hexane and filtered. The filtrate is concentrated and washed again with 25percent ether/hexane to give 2,3,5-trichloropyridine (12 g.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 9 17.7 g of trichloroacetaldehyde, 5.3 g of acrylonitrile, 0.3 g of ruthenium(II)dichloro-tris-triphenylphosphine [T. A. Stephenson and G. Wilkinson, Inorg. Nucl. Chem., 28, 945 (1966)] and 30 ml of 3-methoxypropionitrile are heated for 2 hours at 170 C. in an enamel autoclave. After processing in a manner analogous to that described in Example 1, the yield is 10.5 g (58% of theory) of 2,3,5-trichloropyridine. 2,3,5-Trichloropyridine is obtained in likewise good yield by replacing in the above example the 3-methoxypropionitrile by butyronitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In water; dimethyl sulfoxide; benzene; | EXAMPLE 8 Preparation of Compound No. 14 (Reaction (a)) A mixture of <strong>[16063-70-0]2,3,5-trichloropyridine</strong> (18.3 g), N-[(+-)-2-(4-hydroxyphenoxy)propionyl]isoxazolidine (23.7 g) which was prepared as in Example 3, anhydrous potassium carbonate (14.5 g) and dimethylsulfoxide (200 ml) was stirred at 120 C. for 4 hours. To the reaction mixture, after cooling, were added water and benzene whereby to form two layers. The organic layer so separated was washed with 1 N aqueous sodium hydroxide solution and then with water and dried over anhydrous sodium sulfate. Removal of the solvent by a distillation in vacuo gave N-[(+-)-2-[4-(3,5-dichloro-2-pyridyloxy)phenoxy]propionyl]isoxazolidine (31.4 g) as a pale yellow crystalline solid. Recrystallization from a mixture of n-hexane/ethyl acetate yielded a white crystalline solid. m.p. 105.5-107.5 C. | |
5297.1 kg | With N-methylcyclohexylamine; In 1,2-dichloro-ethane;Large scale; | 1840.8 kg of <strong>[16063-70-0]2,3,5-trichloropyridine</strong> and 1001 kg of N-methylpiperidine,7400 kg of dichloroethane, 2343.7 kg of N- [(±) -2- (4-hydroxybenzylamino) propionyl] isoxazolidine were mixed,5297.1 kg of 99% oxaprygine was obtained. |
With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 4h; | 23.7 g of the above product, 20 g of <strong>[16063-70-0]TCP</strong>, 15 g of anhydrous potassium carbonate, and 22 ml of dimethyl sulfoxide were mixed and stirred at 120 C for 4 h.After the reaction mixture was cooled, water and benzene were layered, and the organic phase was separated and washed with 1N aqueous sodium hydroxide.After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give a pale yellow crystalline solid.Recrystallization from n-hexane-ethyl acetate gave a white crystalline solid.M.p. 105.5-107 C, the total yield was 50.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With tetrabutylammomium bromide; sodium hydroxide; zinc; In toluene; at 50℃; for 6h;Green chemistry; | Weigh 0.1 mol of pentachloropyridine dissolved in 50 ml of toluene, and then put it together with a certain amount of zinc powder, tetramethylammonium bromide and a certain concentration of sodium hydroxide in a three-section equipped with mechanical stirring, thermometer and reflux condenser. In the flask, stirring was started to raise the temperature to a certain temperature. After heating for several hours, the heating was stopped, the temperature was lowered, and the filtration was filtered. The filter cake was washed with toluene 3-4 times, the filtrate was combined, and the toluene was removed under reduced pressure to give a crude product. When the following optimized experimental conditions were employed: a NaOH solution having a concentration of 8 mol/L was used as a reaction medium, and the molar ratio of the reaction materials was n (zinc powder): n (pentachloropyridine): n (tetramethylammonium bromide) = 3.5:1:0.05, reacting at 50 C for 6 hours, after filtration and distillation under reduced pressure, the crude product of the desired product 2,3,5-trichloropyridine was obtained in a yield of 73%. |
With ammonium hydroxide; In toluene; | EXAMPLE II -- 2,3,5-Trichloropyridine To a 500 milliliter, 3-neck flask which was fitted with a reflux condenser, heater, thermometer and stirrer was added 200 milliliters (1.2 moles) of 6N ammonium hydroxide, 39.0 grams (0.60 gram atom) of zinc dust, 100 milliliters of toluene and 25.1 grams (0.1 mole) of pentachloropyridine. The pH of the mixture was 12.6. The mixture was heated to 70 C., with stirring, and held under these conditions for 35 hours. At the end of this period, the reaction mixture was cooled to 20 C. and filtered to remove insolubles. The filter cake was washed with toluene and the toluene combined with the filtrate and concentrated by distillation. Analysis indicated a 2,3,5-trichloropyridine yield of 9.39 grams (52 percent of theoretical). | |
With sodium hydroxide; zinc; In benzene; | EXAMPLE IV -- 2,3,5-Trichloropyridine Into a 5-liter fluted 3-neck flask fitted with a reflux condenser, a heater, thermometer and a stirrer was added 251.0 grams (1.0 mole) of pentachloropyridine, 500 milliliters of benzene and 1.25 liters of 8N sodium hydroxide (10 moles). The mixture was heated to ~75 C., with stirring. At this time, 260.0 grams (4.0 gram atoms) of zinc dust was added and the mixture refluxed at ~79 C. for a total reaction time of 5 hours. The pH of the reaction mixture was 14-15. At the completion of the reaction, the reaction mixture was cooled to room temperature and filtered to remove insolubles. The filter cake was washed with benzene and the benzene wash was combined with the filtrate. Gas-liquid chromatography indicated a 2,3,5-trichloropyridine content of 140.9 grams (77 percent of theoretical). |
With sodium hypochlorite; sodium hydrogencarbonate; hydrazine; In propylene glycol dimethyl ether; water; | EXAMPLE VIII -- 2,3,5-Trichloropyridine A mixture was prepared containing 50.3 grams (0.2 mole) of pentachloropyridine, 20 grams (0.24 mole) of sodium bicarbonate and 6.9 grams (0.205 mole) of 95 percent hydrazine in 215 milliliters of propylene glycol methyl ether. The mixture was heated at 92 C., with stirring, for 1.5 hours. The mixture was cooled to 30 C. and 50 milliliters of propylene glycol methyl ether was added. To this mixture was added 350 milliliters of a 10 percent sodium hypochlorite solution, over a 20 minute period while the temperature of the solution was maintained at 45-50 C. At the completion of the reaction, the solution was diluted with 100 milliliters of water and extracted with hexane. The hexane extract was washed with water and the hexane evaporated off. The oily product which remained was dissolved in 250 milliliters of propylene glycol methyl ether and 20 grams of sodium bicarbonate and 6.9 grams of 95 percent hydrazine were added thereto. The mixture was heated at 92 C. for 1.5 hours and 1.0 gram of 95 percent hydrazine was added. Heating was continued for 3 additional hours and the reaction mixture was cooled to 45 C. To this mixture was added 450 milliliters of a 10 percent sodium hypochlorite solution over a 20 minute period while maintaining the reaction temperature at 45-50 C. The reaction mixture was extracted with hexane and the hexane extract was washed with water and the hexane was removed by evaporation. The crude 2,3,5-trichloropyridine product was obtained in a yield of 30.5 grams and found to be 94.6 percent pure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.1% | With 5%-palladium/activated carbon; hydrogen; potassium hydroxide; In 5,5-dimethyl-1,3-cyclohexadiene; water; at 60℃; under 4500.45 Torr; for 6h;Autoclave; | (1) 1,000 g of <strong>[2402-79-1]2,3,5,6-<strong>[2402-79-1]tetrachloropyridine</strong></strong>, 4000 g of xylene,3 g of 5% Pd / C catalyst, 380 g of potassium hydroxide, and 600 g of water were added to the autoclave.Replace 3 times with nitrogen and 3 times with hydrogen.The reaction was performed under a hydrogen atmosphere of 0.6 MPa for 6 hours;(2) Reduce the temperature to room temperature, exhaust the gas in the autoclave, and replace it with nitrogen 3 times.The reaction product is filtered, and the catalyst obtained by the filtration is recovered for use.Get an organic phase;(3) Distill the organic phase under reduced pressure at 50 C and <-0.08MPa,A pale yellow solid was obtained as 2,3,5-trichloropyridine, and the fraction was recovered for future use.The yield of the product is 99.1%, and the purity is 99.8%. |
With sodium hydroxide; In benzene; | EXAMPLE V -- 2,3,5-Trichloropyridine To a 5-liter 3-neck flask fitted with a reflux condenser, a heater, thermometer and a stirrer were added 216.9 grams (1.0 mole) of <strong>[2402-79-1]2,3,5,6-<strong>[2402-79-1]tetrachloropyridine</strong></strong>, 500 milliliters of benzene, 1.0 liter of 8N sodium hydroxide and 130.7 grams (2.0 gram atoms) of zinc dust. The pH of the mixture was 14-15 and the mixture was heated and refluxed, with stirring, for 7 hours. After completion of the reaction, the reaction mixture was cooled and filtered. The filter cake was washed with benzene and the benzene wash was combined with the filtrate. Gas-liquid chromatography of the mixture indicated a 2,3,5-trichloropyridine content of about 131.35 grams (72 percent of theoretical). By following the above procedures, additional runs showed similar yields of the 2,3,5-trichloropyridine product. Such additional runs are set forth below in Table I. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With lithium diisopropyl amide; In tetrahydrofuran; cyclohexane; | 2,3,5-Trichloro-4-formylpyridine A solution of lithium diisopropylamide (7.3 mL, 1.5 M in cyclohexane, 11 mmol) in 10 mL of dry THF under nitrogen at -78 C. was treated with <strong>[16063-70-0]2,3,5-trichloropyridine</strong> (2 g, 11 mmol) in 20 mL THF over a 30 minute period, stirred an additional 30 minutes, then methyl formate (1.4 mL, 1.3 g, 22 mmol) in 14 mL THF was added slowly to the brown solution over 15 minutes, allowed to slowly warm to room temperature and stirred overnight. The resultant dark brown solution was poured onto ice and saturated NaHCO3, extracted with ethyl acetate, washed with brine, dried (Na2SO4) and concentrated. The brown oil was flash chromatographed on silica gel with 20-33% ethyl acetate/hexane to provide the title compound (1.7 g, 74%). MS (APCI-NH3) m/e: 211 (M+H)+, 229 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) delta 10.26 (s, 1H), 8.70 (s, 1H). |
To a solution of LDA (99 mL, 197 mmol) in THF (lOOmL), was added a solution of 2,3,5- trichloropyridine (30 g, 164 mmol) in THF (200 mL) at about -78 C. The resulting reaction was stirred at about -78 C for about 1 h. Methyl formate (20 mL, 329 mmol) was added carefully to the reaction, then the mixture was stirred at about -78 C for about lh, then warmed to rt and stirred for 16 h. The reaction was poured into saturated aqueous NH4C1. The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na2S04, filtered through sintered glass funnel, and concentrated under reduced pressure to give 2,3,5- trichloroisonicotinaldehyde (26.2 g, 53 %, 70% purity). LCMS (Table 1, Method c) RT= MS m/z = 209, 211 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | To a solution of ethyl (2E) -3- [2-hydroxy-4- (2- methoxyethoxy) phenyl] acrylate (900 mg) in N,N- dimethylformamide .(15 ml) was added sodium hydride (60% in oil, 188 mg) , and the mixture was stirred at room temperature for 1 hr. 2, 3, 5-Trichloropyridine (925 mg) was added to the reaction mixture, and the. mixture was stirred at 800C for 36 hr. After cooling, water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) , and concentrated. The obtained residue was subjected to silica EPO <DP n="184"/>gel column chromatography, and eluted with ethyl acetate- hexane (1:4, v/v) . The obtained crude crystals were recrystallized from ethyl acetate-hexane to give ethyl (2E) -3- [2- [ (3, 5-dichloropyridin-2-yl) oxy] -4- (2- methoxyethoxy) phenyl] acrylate (1.01 g, yield: 72%) as colorless crystals, melting point 70.7-71.30C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | To a solution of 2-hydroxy-4- (methoxymethoxy) benzaldehyde (7.04 g)1 in N,N-dimethylformamide (50 ml) was added sodium hydride (60% in oil, 1.88 g) , and the mixture was stirred at room temperature for 30 min. 2, 3, 5-Trichloropyridine (7.40 g) were added to the reaction mixture,, and the mixture was stirred at 1100C for 14 hr. After cooling, water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSC^), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1:5, v/v) to give 2- [(3, 5- dichloropyridin-2-yl) oxy] -4- (methoxymethoxy) benzaldehyde (5.33 g, yield: 42%)' as colorless crystals.1H-NMR (300 MHz, CDCl3) delta: 3.48 (3 H, s) , 5.23 (2 H, s) , 6.85 (1 H, d, J = 2.4 Hz), 7.03 (1 H, dd, J = 9.0, 2.4 Hz), 7.82 (1 H, d, J = 2.4 Hz), ,7.92 (1 H, d, J = 9.0 Hz), 7.95 (1 H, d, J = 2.4 Hz) , 10.05 (1 H, s) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.8% | With caesium carbonate; In dimethyl sulfoxide; at 110℃; for 15h; | 96.6 g of diethyl malonate and then 196 g of cesium carbonate were added to a 300 ml solution of 50.0 g of <strong>[16063-70-0]2,3,5-trichloropyridine</strong> in 300 ml of dimethyl sulfoxide.The reaction was stirred at 110 C. for 15 hours.After completion of the reaction, the reaction solution was cooled to room temperature and then dropped into 1.2 kg of water at 5 C.After completion of the dropwise addition, the reaction solution was extracted twice with 600 ml of hexane, and then the organic layer was washed with 500 ml of water.The obtained organic layer was dried over 300 ml of saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.The obtained residue was purified by silica gel chromatography (eluent: hexane) to obtain 66.9 g of the desired product as a yellow oil (yield 79.8%). |
With caesium carbonate; In dimethyl sulfoxide; at 110℃; for 8h; | Reference Production Example 16 A mixture of 4.56 g <strong>[16063-70-0]2,3,5-trichloropyridine</strong>, 8.80 g of diethyl malonate, 30 ml of dimethyl sulfoxide and 17.9 g of cesium carbonate was stirred for 8 hours at 110C under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, then, to this was added ice water, and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 7.45 g of the resultant residue was subjected to silica gel column chromatography, to obtain 7.08 g of diethyl (3,5-dichloro-2-pyridyl) malonate. 1H-NMR (CDCl3, TMS) delta (ppm): 1.28 (6 H, t, J=7.1 Hz), 4.28 (4 H, q, J=7.1 Hz), 5.16 (1 H, s), 7.74 (1 H, d, J=2.2 Hz), 8.45 (1 H, d, J=2.2 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 99% | With trimethylsilyl bromide; In propiononitrile; at 100℃; for 14h; | 2-bromo-3,5-dichloropyridine. A 100 mL round-bottom flask equipped with a condenser was charged with 1.82 g of compound 71 (10.0 mmol) and propiononitrile (20 mL), 3.06 g TMSBr (20.0 mmol) was slowly added to the above solution. The reaction mixture was stirred at 1000C under nitrogen for 14 hrs, then cooled to a temperature of about 250C and diluted with EtOAc (100 mL). The EtOAc layer was isolated, dried, and concentrated under reduced pressure to provide 72 as a yellowish solid (>99percent yield). |
96.8% | With hydrogen bromide; propionic acid; In water; at 80℃; | Raw material selection: 2,3,5-trichloropyridine 16g, propionic acid 60.8g, concentration 48percent hydrobromic acid aqueous solution 64g, extraction of organic solvent selected toluene, which is 100ml of toluene, water 50ml, adding liquid alkali to adjust pH, layering After the aqueous layer is extracted with a plurality of organic solvents (or ethyl acetate or toluene or cyclohexane or petroleum ether) and the organic layer is washed with water, the amount of the organic solvent and water is conventional and not limited, and the following specific process is Take toluene extraction as an example.Reaction step: in a 250 ml dry clean four-necked flask, 16 g of 2,3,5-trichloropyridine, 60.8 g of propionic acid, 64 g of hydrobromic acid aqueous solution (concentration: 48percent), and slowly heated to 80 ° C.After the addition, the temperature was kept for more than 3 hours, and the content of the raw material was determined to be less than 2percent by HPLC, and the temperature was lowered to 15 to 20 ° C, and the mixture was kept for 0.5 hour, and filtered to obtain a solid.Add 50 ml of water and 100 ml of toluene to the obtained solid, adjust the pH to 7 by adding liquid base; layer, the aqueous layer is extracted with 50 ml of toluene, the organic layer is combined, washed with 50 ml of water, layered, and the organic layer is heated at 70-80 ° C. The water was concentrated to dryness under reduced pressure to yield 19.26 g of 2-bromo-3,5-dichloropyridine, yield 96.8percent, purity 98.8percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | 1.25 g (0.029 mol) of NaH (55 %) are introduced into 30 ml of pentane. After stirring for 15 minutes under nitrogen, the solvent is removed by means of a syringe. 20 ml of absolute THF are then added and, within a period of about 5 minutes, 1.65 ml (0.028 mol) of propargyl alcohol are added dropwise at a temperature of 0C. After the addition, the ice cooling is removed, and stirring is continued for a further hour at a temperature of about 45C until the evolution of gas has ceased. Then 4.8 g (0.025 mol) of <strong>[16063-70-0]2,3,5-trichloropyridine</strong> dissolved in 5 ml of THF are added dropwise at 45C, with stirring. Then stirring is carried out for 6 hours at a temperature of 45C and for 18 hours at a temperature of 20C until gas chromatography indicates that conversion is complete. The reaction mixture is then cautiously neutralised with 1N HCI; a small amount of saturated aqueous sodium chloride is added and extraction with ethyl acetate is carried out three times in total. The combined organic phases are dried over magnesium sulfate. After filtration and after the ethyl acetate has been evaporated off, 5.0 g of 3,5-dichloro-2-(prop-2-ynyloxy)-pyridine are obtained as a light-yellow oil, which corresponds to quantitative conversion. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With palladium diacetate; potassium carbonate; triphenylphosphine; In methanol; acetonitrile; at 50℃; for 24h;Inert atmosphere; | General procedure: 2,5-dibromopyridine (0.12 g, 0.50 mmol), phenylboronic acid (67 mg, 0.55 mmol), K2CO3 (0.14 g, 1.0 mmol), Pd(OAc)2 (11 mg, 5 mol %), PPh3 (26 mg, 10 mol %) were dissolved in CH3CN/CH3OH (2:1, 6 mL). The solution was stirred at 50 C under nitrogen atmosphere for 24 h and then cooled and the solid was filtered off. The filtrate was then concentrated and the resulting crude product was dissolved in CH2Cl2 (10 mL). The solution was washed with water (10 mL*3) and brine (10 mL), and dried over sodium sulfate. Upon removal of the solvent with a rotavapor, the resulting residue was subjected to column chromatography (petroleum ether/AcOEt, 400:1) to give the desired product 3a (114 mg, 97%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.4% | Sodium hydride (60% in oil, 0.2 g, 5.5 mmol) was added to a solution of 3-hydroxy-5-methylpyrazole (0.49 g, 5.0 mmol) in DMF (10 ml) at 0C, and the mixture was stirred for 30 minutes while it was allowed to have room temperature gradually. Then, <strong>[16063-70-0]2,3,5-trichloropyridine</strong> (0.9 g, 5.0 mmol) was added, and the mixture was stirred under heating at 70C for 2 days. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (20 ml) and extracted with ethyl acetate (10 ml x 3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane = 1/7 ? 1/2), to give a white solid of 3-(3,5-dichloropyridin-2-yloxy)-5-methylpyrazole (0.7 g, yield: 57.4 %). mp: 109-111C; 1H-NMR(CDCl3, TMS, ppm): delta 2.32(s, 3H), 5.86(s, 1H), 7.77(d, J=2.3Hz, 1H), 8.03(d, J=2.3Hz, 1H), 9.40-11.50(br s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate; In N,N-dimethyl-formamide; toluene; at 100℃; | To <strong>[16063-70-0]2,3,5-trichloropyridine</strong> (25 g) were added 1-BOC-piperazine (28.13 g), potassium carbonate (37.86 g), N,N-dimethylformamide (25 mL) and toluene (50 mL), and the mixture was stirred at 100C. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (39.13 g). To 4-(3,5-dichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (6.35 g) were added palladium (II) acetate (0.46 g), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (1.71 g), potassium fluoride (9.556 g), methylboronic acid (5 g) and tetrahydrofuran (202 mL), and the mixture was refluxed under a nitrogen stream for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (5.45 g). To 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (5.45 g) were added 4N hydrogen chloride/ethyl acetate (18.2 mL) and chloroform (45.5 mL), and the mixture was stirred at room temperature. After completion of the reaction, to the reaction mixture were added water and potassium carbonate, and the mixture was extracted with ethyl acetate. The solvent was evaporated to give the title compound (3.3 g). | |
39.13 g | With potassium carbonate; In N,N-dimethyl-formamide; toluene; at 100℃; | [0375] Preparation Example 79: Preparation of 1-(3,5-dimethylpyridin-2-yl)piperazine[0376][0377] To a mixture of <strong>[16063-70-0]2,3,5-trichloropyridine</strong> (25 g), 1-Boc-piperazine (28.13 g) and potassium carbonate (37.86 g)were added N,N-dimethylformamide (25 mL) and toluene (50 mL), and the mixture was stirred at 100C. After completionof the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by columnchromatography (hexane:ethyl acetate) to give 4-(3,5-dichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester(39.13 g). To a mixture of the obtained 4-(3,5-dichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (6.35 g),palladium(II) acetate (0.46 g), 2-dicyclohexylphosphino-2?,6?-dimethoxybiphenyl (1.71 g), potassium fluoride (9.56 g)and methylboronic acid (5 g) was added tetrahydrofuran (202 mL), and the mixture was stirred with heating under refluxfor 8 hr under a nitrogen stream. Water was added to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue waspurified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylicacid tert-butyl ester (5.45 g). The obtained 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (5.45g) was dissolved in chloroform (46 mL), 4N hydrogen chloride/ethyl acetate (18 mL) was added, and the mixture wasstirred at room temperature. After completion of the reaction, to the reaction mixture were added water and potassiumcarbonate, the mixture was extracted with ethyl acetate, and the solvent was evaporated to give the title compound (3.3 g). |
13.08 g | With potassium carbonate; In N,N-dimethyl-formamide; toluene; at 120℃; for 7h; | To a solution of <strong>[16063-70-0]2,3,5-trichloropyridine</strong> (12.1 g),1-Boc-piperazine (14.9 g)in toluene (80 mL) were added N,N-dimethylformamide (40 mL) and potassium carbonate (22 g) and the mixture was stirred at 120c for 7 hr. The reaction mixture was cooled,water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine,and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate)to give 4-(3,5-dichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (13.08 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | General procedure: To a stirred solution of 4a (74.5 g, 410 mmol) in DMF (450 mL) was added NaH (60% dispersion in oil, 19.7 g, 491 mmol) at 0 C and the mixture was stirred at the temperature for 30 min. Then 2,3-dichloro-5-(trifluoromethyl)pyridine (60.0 mL, 433 mmol) was added to the mixture, which was allowed to warm to room temperature, and stirred at room temperature for 1 h and at 50 C for 1 h. The reaction was quenched with sat. NH4Cl on ice-bath and extracted with EtOAc and the combined organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residual solid was purified by silica gel chromatography (hexane-EtOAc, 9:1 to 2:1) to give a pale-yellow solid, which was recrystallized from EtOAc/hexane to give 5a (79.0 g, 53%) as white crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With copper(l) iodide; N,N,N,N,-tetramethylethylenediamine; caesium carbonate; In dimethyl sulfoxide; at 110℃; for 24h;Inert atmosphere; | General procedure: 2,4-Dibromopyridine (0.236 g, 1 mmol) and phenol (0.094 g, 1 mmol), CuI (19.0 mg, 0.1 mmol), TMEDA (11.6 mg, 0.1 mmol), and cesium carbonate (0.65 g, 2 mmol) were placed in DMSO (5 mL). The reaction was stirred at 110 C under nitrogen atmosphere for 24 h. When the reaction mixture was cooled, the reaction mixture was filtered. The mixture was dissolved with dichloromethane (25 mL). Then the mixture was washed with brine (3×30 mL). The organic phase was dried over sodium sulfate. After evaporation of the solvent, the mixture was subjected to column chromatography with petroleum ether/ethyl acetate (20:1) as eluent to give pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.23% | With palladium diacetate; triphenylphosphine; sodium t-butanolate; In o-xylene; at 110℃; for 12h;Inert atmosphere; | Step 1: In a sealed tube, <strong>[16063-70-0]2,3,5-trichloro pyridine</strong> (8.0 g, 44mmol), 4-chloro aniline (6.17 g, 49mmol), triphenyl phosphine (1.16 g, 44 mmol) and sodium-tert-butoxide (5.09 g, 53mmol) were mixed in o-xylene (80 mL). The resulting mixture was purged with argon, added Pd(OAc)2 (0.49 g, 2.2mmol) and heated at 110 C for 12 h. After completion of the reaction, the reaction mixture was filtered through celite bed and concentrated under vacuum. The residue obtained was diluted with ethyl acetate (200 mL), washed with water, brine solution and dried over anhydrous Na2SO4. The organic phase was concentrated and purified by the column chromatography (60-120 size mesh) to get the yellow solid 3,5-dichloro-N-(4-chlorophenyl)pyridin-2-amine (7.0 g, 58.23%). LCMS: (Method B) 275 (M+H), RT. 3.69 min, 81.18% (max) 1H NMR (400 MHz, DMSO-d6) : delta 8.68 (s, 1H), 8.14 (d, J = 2.28 Hz, 1H), 8.04 (d, J = 2.32 Hz, 1H), 7.68-7.66 (m, 2H), 7.34-7.32 (m, 2H). |
58.23% | With palladium diacetate; triphenylphosphine; sodium t-butanolate; In o-xylene; at 110℃; for 12h;Sealed tube; Inert atmosphere; | Step 1 : In a sealed tube, <strong>[16063-70-0]2,3,5-trichloro pyridine</strong> (8.0 g, 44mmol), 4-chloro aniline (6.17 g, 49 mmol), triphenyl phosphine (1.16 g, 44 mmol) and sodium-te/t-butoxide (5.09 g, 53mmol) were mixed in c-xylene (80 mL). The resulting mixture was purged with argon, added Pd(OAc)2 (0.49 g, 2.2mmol) and heated at 110 C for 12 h. After completion of the reaction, the reaction mixture was filtered through celite bed and concentrated under vacuum. The residue obtained was diluted with ethyl acetate (200 mL), washed with water, brine solution and dried over anhydrous Na2S04. The organic phase was concentrated and purified by the column chromatography (60-120 size mesh) to get the yellow solid 3,5-dichloro-//-(4-chlorophenyl)pyridin-2-amine (7.0 g, 58.23%). LCMS: (Method B) 275 (M+H), RT. 3.69 min, 1H NMR (400 MHz, DMSO-d6) : delta 8.68 (s, 1H), 8.14 (d, J = 2.28 Hz, 1H), 8.04 (d, J = 2.32 Hz, 1H), 7.68-7.66 (m, 2H), 7.34-7.32 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium; potassium carbonate; In 1,4-dioxane; water; at 120℃; for 3h;Inert atmosphere; Microwave irradiation; | A mixture of dioxane and water (3:1; 20 mL) was degassed. <strong>[16063-70-0]2,3,5-Trichloropyridine</strong> (1.65 g, 9.0 mmol), N-((1 r,4r)-4-hydroxy-4-methylcyclohexyl)-4-(4,4,5,5-tetramethyl-1 3,2- dioxaborolan-2-yl)benzenesulfonamide (1.8 g, 4.6 mmol), K2003 (1.24 g, 9.0 mmol) and[1, 1-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (257 mg, 0.35 mmol) were added and the reaction mixture stirred at 120C in a microwave oven for 3 hours. The reaction mixture was concentrated, diluted with ethyl acetate and washed with water. The organic extracts were dried (Mg504) and concentrated to give a crude residue which was purified by flash column (eluent: 40 to 50% ethyl acetate in heptane). The productwas purified further by crystallisation three times (ethyl acetate I heptane) to give the title compound (284 mg, 15%).1H NMR: (400 MHz; CDCI3) O 8.59 (1H, m), 7.97 (2H, d), 7.92-7.85 (3H, m), 4.62-4.55 (1H, m), 3.38-3.28 (1H, m), 1.92-1.76 (2H, m), 1.8-1.35 (7H, m), 1.22 (3H, 5).LCMS: mobile phase A: 0.05% trifluoroacetic acid in water, mobile phase B: 0.05% trifluoroacetic acid in acetonitrile; Column: YMC ODS A, C18 (50X4.6 mm) 3uM; Flow rate: 1.2 mLlmin; Temperature: Ambient. Run time: 4.5 mm - starting solvent 20:80 B:A is increased linearly to 95:5 B:A over the first 3 mm, held at 95:5 B:A for 0.5 mm thenimmediately returned to 20:80 B:A for the last 1.5 mm. Retention time: 2.50 mi m/z415 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10.10 g | To 30.74 g of potassium tert-butoxide in 100 ml of dimethylsulfoxide, 16.72 g of nitromethane was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for another 1 hour. Then, the reaction mixture was cooled with ice again, and to the reaction mixture, 25.00 g of <strong>[16063-70-0]2,3,5-trichloropyridine</strong> in 100 ml of dimethylsulfoxide was added dropwise with stirring, and after the addition, the mixture was stirred at 70C for another 6 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, poured into 200 ml of 10% aqueous hydrochloric acid with stirring under cooling with ice and extracted with ethyl acetate (200 ml*1). The resulting organic layer was washed with water (100 ml*1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 10:90) as the eluent to obtain 10.10 g of the desired product as a pale yellow oil. 1H NMR (CDCl3, Me4Si, 300MHz) delta8.53 (d, J=2.4Hz, 1 H), 7.84 (d, J=2.4Hz, 1 H), 5.76 (s, 2H). | |
10.10 g | To 30.74 g of potassium tert-butoxide in 100 ml of dimethylsulfoxide, 16.72 g of nitromethane was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for another 1 hour. Then, the reaction mixture was cooled with ice again, and to the reaction mixture, 25.00 g of <strong>[16063-70-0]2,3,5-trichloropyridine</strong> in 100 ml of dimethylsulfoxide was added dropwise with stirring, and after the addition, the mixture was stirred at 70 C. for another 6 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, poured into 200 ml of 10% aqueous hydrochloric acid with stirring under cooling with ice and extracted with ethyl acetate (200 ml×1). The resulting organic layer was washed with water (100 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 10:90) as the eluent to obtain 10.10 g of the desired product as a pale yellow oil |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate; In N,N-dimethyl-formamide;Reflux; | To a solution of 2.78g(0.01mol) 4-(2-(5-chloro-6-ethylpyrimidin-4-ylamino)ethyl)phenol(the preparation refersto Example 3, the difference is replacing 4,5-dichloro-6-methylpyrimidine to 4,5-dichloro-6-ethylpyrimidine) and <strong>[16063-70-0]2,3,5-trichloropyridine</strong> 1.83g (0.01mol) in 30mL N,N-dimethyl formamide was added potassium carbonate 2.76g (0.02mol).The reaction mixture was heated to reflux for 4-10 hours, and monitored by TLC (Thin-Layer Chromatography) until thereaction was over, the excessive solvent was evaporated under reduced pressure. then the mixture was poured into(3x50mL) of ethyl acetate to separate the organic layer, the organic phase was washed with 50 mL of brine, dried andevaporated under reduced pressure, the residual was purified via silica column (ethyl acetate/petroleum ether (boilingpoint range 60-90C)=1:3, as an eluent) to obtain 3.50g compound 1-583 as colorless oil with yield of 83%, m.p. 53-54C.1H-NMR (300MHz, internal standard TMS, solvent CDCl3) delta(ppm): 1.26(3H, t), 2.79(2H, q), 2.96(2H, q), 3.77(2H, q),5.47(1H, t), 7.11(2H, d), 7.28(2H, d), 7.77(1H, s), 8.45(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium hydroxide; In 1,4-dioxane; water; at 80℃; for 4h; | This compound was prepared using the procedure reported by Huang et al.19. Into a 250 mL two necked flask which was equipped with magnetic stirrer was added potassium hydroxide (3 g, 53.6 mmol) dissolved in distilled water (50 mL). 2-Amino-3-hydroxypyridine (11) (4 g, 36.4 mmol) was added to the flaskand heated until it dissolved. Then <strong>[16063-70-0]2,3,5-trichloropyridine</strong> (12) (3.2 g, 18.88 mmol) in 1,4- dioxane (50 mL) was added dropby drop for 15 min. The entire mixture was refluxed for 4 h at 80 C. It was poured into a beaker and allowed to cool. Then it was filtered and the residue air dried and recrystallized with aqueous ethanol as white solid crystals of 3-chloro-1,9-diazaphenoxazine (13) (4.4 g, 72 %) with a melting point of 48 C. UV-visible (ethanol) lambdamax: 204 (log epsilon 3.01), 211.5 (logepsilon 3.02), 222.5 (log epsilon 3.05) nm. IR (KBr, numax, cm-1): 3394 (NHstret), 1650 (C=C), 1429 (C=N stretch), 1053 (C-O), 761(substituted aromatic ring). 1H NMR (400 MHz, DMSO): delta8.6 (1H, s, NH), 8.4 (1H, s, ArH), 7.6 (3H, m, Ar-H). 13C NMR (400 MHz, DMSO): delta 132.23, 130.01, 127.59, 127.01, 125.96,125.20, 124.10, 120.45, 118.20, 115.90 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With potassium hydroxide; In 1,4-dioxane; water; for 4h;Reflux; | 3-Chloro-1-azaphenoxazine (7): 3-Chloro-1-azaphenoxazine (7) was prepared according to Gulbenk et al.13. 2-Aminophenol (8) (2.0 g, 20 mmol) was placed in a 250 mL three necked flask containing potassium hydroxide (1.0 g, 30 mmol) in water (50 mL). The mixture was warmed until the materials dissolved. <strong>[16063-70-0]2,3,5-Trichloropyridine</strong> (9) (3.29 g, 16 mmol) in 1,4-dioxane (50 mL) was added in drops during a period of 15 min. The entire mixture was refluxed with stirring for 4 h. It was poured into a beaker diluted with water to the 500 mL mark and cooled. On filtering, the filtrate was chilled, filtered and the residue air dried and recrystallized from aqueous ethanol to give glistering creamy white plates of compound 7, Yield: 6.81 g, (62 %); m.p.: 37-38 C. UV-visible lambdamax (ethanol): nm 262 (log epsilon 3.50), 375 (log epsilon 3.06), 392.5 (log epsilon 3.03). IR (KBr, numax cm-1): 3381 (N-H stretch.), 3038 (aromatic C-H),1544 (C=N stretch.), 1400 (C-H bending), 1031 (C-O-C), 734 (m-substituted aromatic ring). 1H NMR (400 MHz, DMSO-d6): delta 8.4 (s, 1H), 8.7 (m, 4H) 13C NMR (400 MHz, DMSO-d6): delta 146.56, 139.03, 130.7, 129.9, 128.09, 127.91, 127.05,126.54, 125.32, 124.76, 124.02. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.7% | With potassium hydroxide; In water; N,N-dimethyl-formamide; for 4h;Reflux; | 2-Aminothiophenol (2 g, 18 mmol) was placed in the reaction flask containing potassium hydroxide (1,79 g, 44 mmol) in water (50 mL). The mixture was warmed until the material dissolved at about 85 C. 2,3,5-Trichloro-pyridine (2.97 g, 20 mmol) in DMF (50 mL) was added in drop by drop during a period of 15 min. The entire mixture was refluxed with stirring for 4 h. It was later poured into a beaker, diluted with water to the 500 mL mark and cooled, filtered and the residue recrystallized from ethanol, greenish yellow crystals of 3-chloro-1-azaphenothiazine (8) was obtained after suction filtration. Yield: 3.81 g. (99.7 %). m.p. 161-161.5 C. IR (KBr. nu max,cm-1): 3438 (N-H), 3049 (Ar-H), 1615, 1483, 1417 (C=C of aromatic ring), 1356 (aromatic 3 C-N), 1305 (aromatic 2 C-N), 1093 (C-S-C), 756 (Ar-Cl). UV-visible (ethanol) (log epsilon ): 309.2 nm (2.490), 291 nm (2.464), 360 nm (2.556). 1H NMR (CDCl3): delta = 8.2 (s, 1H), 7.8 (m. 4H), 7.4 (m, 2H), 6.8 (m. 2H), 4.2 (s, 1H). 13C NMR (CDCl3): delta 147.4, 146.9, 146.4, 135.8, 130.0, 128.6, 126.7, 126.1, 119.1, 118.8, 115.4 Analysis calculated forC11H7N2SCl: C, 56.30, H, 3.00, N, 11.90, Cl, 15.14, S, 13.65 Analysis found: C, 56.40, H, 3.01, N, 11.78, CI, 15.20, S 13.61. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Under the protection of nitrogen, into the three-necked flask, add 53g benzylamine. Then use ice-bath to cool to 3 C. Then continue to add dropwise n-propanal 28g. Control dropwise addition time to 1h. Then add dropwise in batches 13g mass concentration of 10% KOH. Add dropwise 3 time. Then allow the layers to separate. To the organic phase, add 5g mass concentration of 10% KOH. Allow to stand overnight to prepare N-propylidenebenzylamine; Into a 250 ml four-necked flask, add 68g of the above-mentioned prepared N-propylidenebenzylamine. Then add 105 ml dichloromethane and triethylamine 47g. Stir and cool to 0 C, Then continue adding dropwise chloroacetyl chloride 57g. Control the dropwise addition at 1h. Then elevate temperature to 20 C. Continue reacting for 10 min; After the reaction is finished, the deionized water washing and the mass fraction of 10% hydrochloric acid pickling and the mass concentration is 10% of sodium hydroxide caustic wash, finally by reduced pressure distillation to remove the solvent, the reaction liquid prepared, subsequently heating the reaction liquid to column chromatography separation, collection acyl compound; In a 250 ml three-necked flask, add 23g dimethylformamide and 100 ml of 1,2-dichloromethane. Then stir and cool to 0 C. Then take 5.8g triphosgene. Use 50 ml of 1,2-dichloroethane to dissolve. Then add dropwise to the three-necked flask. Control the dropwise addition at 1h. After the completion of the dropwise addition, continue adding dropwise 4.4g of above-mentioned prepared acyl compound. Heat to 55 C and stir reaction for 1h; After the completion of reaction, washing with a large amount of deionized water and collecting the organic phase, for mass fraction of 10% sodium hydroxide solution to adjust the pH to 8.0, subsequently to its hierarchical collection of the organic layer, the solvent is removed by reduced pressure distillation column chromatography separation thereof, to collect colorless transparent crystal <strong>[59782-90-0]2,3-dichloro-5-methylpyridine</strong>; 123.1g of nicotinic acid and 10 ml of <strong>[59782-90-0]2,3-dichloro-5-methylpyridine</strong> were stirred and mixed; Elevate temperature to 55 C. Then add 270g phosphorus trichloride. At 70 C, enter chlorine gas for 2h. Continue heating to 150 C. Then 600 ml ethyl acetate and 20g sodium carbonate were added to the above-mentioned solution. Then continue reaction for 2h. Dry and concentrate and then dissolve in 100 ml toluene. Heat to 80 C and slowly enter phosgene. After reacting for 2h, the sodium carbonate is used to adjust the pH to 7.0, and separating an organic layer to dry the same, subsequently prepared desolution of the 2,3-chloro-5-chloromethyl pyridine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1600 kg | With thionyl chloride; N,N-dimethyl-formamide; In toluene; at 105℃; for 7h;Reflux; Large scale; | The above-mentioned the 300 kg of 3,5-dichloro pyridine dissolves mellowly in 2000 kg in toluene, reflux removing moisture, by adding 5 kg dimethyl formamide, raising the temperature to 105 C reflux reaction water, by adding 240 kg thionyl chloride, reflux reaction 7 hours. To the clear reaction solution, by high performance liquid chromatographic monitoring solution of the dichloro pyridine sodium alcoholate in the content is 0.4%, boil off 1600 kg of toluene, cooling to 1 C, filtering, to obtain 2, 3, 5-trichloro-pyridine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate; In butanone;Reflux; | 14.8 g (0.1 mol) of 2-chloro-5-trifluoromethylpyridine was reacted with 15.96 g (0.12 mol)P-Hydroxyphenylacetonitrile was added to 200 ml of methyl ethyl ketone, and 27.60 g (0.2 mol) of potassium carbonate was added,Heating to reflux under stirring, reaction 4-10 hours, TLC monitoring reaction is completed, the solvent is evaporated under reduced pressure,And 300 ml of ethyl acetate was added thereto, followed by washing with 50 ml of each of 5% aqueous sodium hydroxide solution and saturated brine,After removal of the residue, the residue was isolated by column chromatography to give 20.29 g of a white solid, 83.0% yield |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate; In N,N-dimethyl-formamide; at 40 - 80℃; for 4h; | 0.027 mol of N-Boc ethylenediamine was added to a 150 mL reaction flask equipped with 40 mL of N, N-dimethylformamide,To this was added 3.7 g (0.027 mol) of potassium carbonate,Heating up to 40 ,A solution of 0.027 mol of N, N-dimethylformamide was commercially added dropwise with <strong>[16063-70-0]2,3,5-trichloropyridine</strong> (commercially available)15min addition is complete,The reaction was maintained at 80 C for 4 h.After the TLC monitoring reaction was complete, the reaction was poured into water, precipitated as a white solid, and filtered to give a white solid: 75% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8 kg; 1840.8 kg | To the chlorination reactor was added 25kg ferric chloride, 1000kg pyridine, 4000kg carbon tetrachloride, closed reactor, Stirring, introducing 4500kg chlorine, after the reaction, to obtain polychloropyridine.The polychloropyridine obtained in the above process was mixed with 3kg palladium carbon, 12000kg ethanol and 900kg pyridine, reacted at 80 C and 0.1MPa, and stirred till the end of the reaction to obtain 1,840.8kg 2,3,5-trichloropyridine and 8kg 2,3-dichloropyridine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(3) Using pentafluoropyridine as a raw material and DMF as a solvent, the active potassium fluoride powder is a fluorinating agent under the action of an excessive amount of nano-zinc-containing layered manganese oxide catalyst under a strong alkaline condition with a pH of 14. ,20 reaction for 20 h, filtered, and the filter cake was added to a solution of calcium chloride,2,3,5-Trichloropyridine is obtained based on a nanozinc-containing layered manganese oxide catalyst. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate; at 75℃; for 4.5h; | 1.82 g (0.01 mol) of 2-(4-hydroxyphenoxy)propionic acid and 60 mL of <strong>[16063-70-0]2,3,5-trichloropyridine</strong> were added to the reaction flask.After stirring for 10 minutes,2.76 g (0.02 mol) of potassium carbonate and 1.0 mmol of polyethylene glycol-400 were added in portions.The temperature was raised to 75 C for 4.5 h, the reaction was completed, cooled to room temperature, and the reaction solution was poured into 250 mL of ice water.Acidified to pH=2 with 10% hydrochloric acid, and the solid was precipitated with stirring, and allowed to stand.The mixture was filtered under suction to give a white solid (R,S)-2-(4-((3,5-dichloropyridin-2-yl)oxy)phenoxy)propanoic acid, 2.95 g,The purity was 95.0%, and the yield was 90.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 120℃; for 16h;Inert atmosphere; | To the solution of tert-butyl N-(2-amino-5-fluoro-phenyl)-N-methyl-carbamate (80.0 g, 333 mmol, compound A1.4) and <strong>[16063-70-0]2,3,5-trichloropyridine</strong> (66.8 g, 366 mmol, CAS: 16063-70-0) in dioxane (2.0 L) were added cesium carbonate (217 g, 666 mmol), palladium(II) acetate (3.74 g, 16.7 mmol), and BINAP ( 20.7 g, 33.3 mmol, CAS: 98327-87-8). Reaction continued at 120< SUP>o< /SUP>C for 16 h under nitrogen atmosphere. Then the reaction mixture was cooled to room temperature and diluted with EtOAc (800 mL). The precipitate was removed by filtration. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 0.2% to 5% EtOAc in petroleum ether) to give tert-butyl N-[2-[(3,5-dichloro-2-pyridyl)amino]-5-fluoro- phenyl]-N-methyl-carbamate (75 g, 58% yield). MS (ESI): 390.1 ([{< SUP>37< /SUP>Cl}M+H]< SUP>+< /SUP>), 388.1 ([{< SUP>37< /SUP>Cl+< SUP>35< /SUP>Cl }M+H]< SUP>+< /SUP>), 386.1 ([{< SUP>35< /SUP>Cl}M+H]< SUP>+< /SUP>). (0866) To the solution of tert-butyl N-[2-[(3,5-dichloro-2-pyridyl)amino]-5-fluoro-phenyl]-N- methyl-carbamate (5.0 g, 12.95 mmol) and DBU (3.94 g, 25.9 mmol, CAS: 6674-22-2) in the mixture of o-xylene (7.5 mL) and N,N-Dimethylacetamide (7.5 mL) were added palladium(II) acetate (727 mg, 3.24 mmol) and tricyclohexylphosphine tetrafluoroborate (2.38 g, 6.48 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 160C for 6 h, then cooled to room temperature and poured into water (100 mL). Then the mixture was extracted with EtOAc (200 mL) and the organic layer was collected and washed with water (50 mL) two times and brine (30 mL) two times, dried over sodium sulfate. The organic layer was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 0.5% to 20% EtOAc in dichloromethane) to give tert-butyl N-(3-chloro-6-fluoro-9H-pyrido[2,3-b]indol-8-yl)-N-methyl- carbamate (873 mg, 19.3% yield) as a yellow solid. MS (ESI): 352.1 ([{< SUP>37< /SUP>Cl}M+H]< SUP>+< /SUP>), 350.1 ([{< SUP>35< /SUP>Cl}M+H]< SUP>+< /SUP>). |
58% | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 120℃; for 16h;Inert atmosphere; | To the solution of tert- butyl N-(2-amino-5-fluoro-phenyl)-N-methyl-carbamate (80.0 g, (0277) 333 mmol, compound A1.4) and 2 , 3 ,5 -trichloropyridine (66.8 g, 366 mmol, CAS: 16063-70-0) in dioxane (2.0 L) were added cesium carbonate (217 g, 666 mmol), palladium(II) acetate (3.74 g, 16.7 mmol), and BINAP ( 20.7 g, 33.3 mmol, CAS: 98327-87-8). Reaction continued at 120 C for 16 h under nitrogen atmosphere. Then the reaction mixture was cooled to room temperature and diluted with EtOAc (800 mL). The precipitate was removed by filtration. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 0.2% to 5% EtOAc in petroleum ether) to give fe/7-butyl N-[2-[(3,5-dichloro-2-pyridyl)amino]-5-fluoro- phenyl]-N-methyl-carbamate (75 g, 58% yield). MS (ESI): 390.1 ([(37Cl}M+H]+), 388.1 (0278) ([{37Cl+35Cl }M+H]+), 386.1 ([(35Cl}M+H]+). |
58% | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 120℃; for 16h;Inert atmosphere; | To a solution of tert- butyl N-(2-amino-5-fluoro-phenyl)-N-methyl-carbamate (80 g, 333 mmol, compound A 1.4) and 2,3,5 -trichloropyridine (66.8 g, 366 mmol, CAS: 16063-70-0) in dioxane (2 L) were added cesium carbonate (217 g, 666 mmol), palladium(II) acetate (3.74 g, 16.7 mmol), and BINAP ( 20.7 g, 33.3 mmol, CAS: 98327-87-8). The reaction mixture was stirred at 120 C for 16 h under nitrogen atmosphere. After the reaction mixture was cooled back to room temperature, it was diluted with EtOAc (800 mL). The precipitate was removed by filtration and the filtrate was concentrated in vacuo, and the crude product was purified by silica gel flash chromatography (0.2% to 5% EtOAc in petroleum ether) to give intermediate fe/7-butyl N-[2-[(3,5-dichloro-2-pyridyl)amino]-5-fluoro-phenyl]-N-methyl-carbamate (75 g, 58% yield) as a white solid. MS (ESI): 390.1 ([{37C1}M+H]+), 388.1 ([{37C1+35C1 }M+H]+), 386.1 (0192) ([{35C1}M+H]+). |
58% | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 120℃; for 16h;Inert atmosphere; | To the solution of /e/7-butyl N-(2-amino-5-fluoro-phenyl)-N-methyl-carbamate (80.0 g, 333 mmol, compound A1.4) and <strong>[16063-70-0]2,3,5-trichloropyridine</strong> (66.8 g, 366 mmol, CAS: 16063-70-0) in dioxane (2.0 L) were added cesium carbonate (217 g, 666 mmol), palladium(II) acetate (3.74 g, 16.7 mmol), and BINAP ( 20.7 g, 33.3 mmol, CAS: 98327-87-8). Reaction continued at 120 C for 16 hrs under nitrogen atmosphere. Then the reaction mixture was cooled to room temperature and diluted with EtOAc (800 mL). The precipitate was removed by filtration. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 0.2% to 5% EtOAc in petroleum ether) to give /e/7-butyl N-[2-[(3,5-dichloro-2- pyridyl)amino]-5-fluoro-phenyl]-N-methyl-carbamate (75 g, 58% yield). MS (ESI): 390.1 ([{37C1}M+H]+), 388.1 ([{37C1+35C1 }M+H]+), 386.1 ([{35C1}M+H]+). |
58% | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 120℃; for 16h;Inert atmosphere; | To the solution of ferf-butyl N-(2-amino-5-fluoro-phenyl)-N-methyl-carbamate (80 g, 333 mmol, compound A1.4) and <strong>[16063-70-0]2,3,5-trichloropyridine</strong> (66.8 g, 366 mmol, CAS: 16063-70-0) in dioxane (2 L) were added cesium carbonate (217 g, 666 mmol), palladium(II) acetate (3.74 g, 16.7 mmol), and BINAP ( 20.7 g, 33.3 mmol, CAS: 98327-87-8). Reaction continued at 120 C for 16 h under nitrogen atmosphere. Then the reaction mixture was cooled to room temperature and diluted with EtOAc (800 mL). The precipitate was removed by filtration. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 0.2% to 5% EtOAc in petroleum ether) to give ferf-butyl N-[2-[(3,5-dichloro-2-pyridyl)amino]-5-fluoro- phenyl]-N-methyl-carbamate (75 g, 58% yield). MS (ESI): 390.1 ([{37C1}M+H]+), 388.1 ([{37C1+35C1 }M+H]+), 386.1 ([{35C1}M+H]+). |
190 g | To a solution of /e/ - butyl N-(2-amino-5-fluoro-phenyl)-N-methyl-carbamate (142.0 g, 0.591 mol) and <strong>[16063-70-0]2,3,5-trichloropyridine</strong> (108.0 g, 0.591 mol) in dioxane (2.0 L) was added CS2CO3 (385.0 g, 1.18 mol). The mixture was degassed with nitrogen for 2 min before Pd(OAc)2 (13.3 g, 0.059 mol) and BINAP (73.5 g, 0.118 mol) were addedunder nitrogen. After the charging was completed, the suspension was heated to 110 C and stirred for 3 h. After TLC (petrolieum ether:EtOAc = 20 : 1) showed the reaction was completed, the reaction mixture was cooled back to r.t., diluted with EtOAc (3.0 L) and filtered. The filtrate was concentrated in vacuo to give a crude product, which was purified by silica gel flash chromatography (petroleum ether:EtOAc = 500 : 1 ~ 20 : 1) to give ieri-butyl N-[2-[(3,5-dichloro-2-pyridyl)amino]-5-fluoro- phenyl]-N-methyl-carbamate (190.0 g, 83.2% yield) as a white solid. MS (ESI): 385.9 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.7% | With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 7.5h; | 40.0 g of <strong>[16063-70-0]2,3,5-trichloropyridine</strong> was dissolved in 240 g of dimethyl sulfoxide.65.2 g of methyl cyanoacetate and 75.8 g of potassium carbonate were sequentially added to the reaction solution.The reaction was stirred at 120 C. for 7.5 hours.After completion of the reaction, the reaction solution was cooled to 40 C., and 200 g of water and 114 g of 35 mass% hydrochloric acid were added to the reaction solution.The reaction was stirred at room temperature for 1 hour.The solid precipitated in the reaction solution was separated by filtration.The obtained solid was washed sequentially with 50 g of water, 50 g of normal hexane, and 100 g of diisopropyl ether, and then dried under reduced pressure to obtain 41.8 g of the desired product as a yellow solid (yield: 77.7%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.4% | 87.8 g of diethyl malonate and 179 g of cesium carbonate were added to a 300 ml solution of 50 g of <strong>[16063-70-0]2,3,5-trichloropyridine</strong> in dimethyl sulfoxide.The reaction was stirred at 100 C. for 20 hours.Thereafter, the reaction solution is cooled to room temperature and then 58.3 g of iodomethane is added.did. The reaction was stirred at the same temperature for 3 hours.After completion of the reaction, 300 ml of water was added to the reaction solution, and extracted with 300 ml of hexane.The obtained organic layer was washed with 300 ml of water, then dried over anhydrous sodium sulfate and dried, and the solvent was evaporated under reduced pressure.After 150 ml of ethanol, 150 ml of water and 79.9 g of a 48% by mass aqueous solution of sodium hydroxide were sequentially added to the obtained residue, the mixture was stirred at 60 C. for 3 hours.Thereafter, the reaction solution is cooled to room temperature, and 200 ml of the solvent is distilled off under reduced pressure.did.Heptane 150 ml was added to the obtained aqueous solution, and 35 mass% hydrochloric acid aqueous solution was added to the aqueous layer until pH became 1.After completion of the addition, the solid precipitated in the aqueous layer was separated by filtration.The resulting solid was suspended in 200 ml of water and stirred at 100 C. for 5 hours.After stirring, the aqueous solution was cooled to room temperature and extracted with 200 ml of hexane.The obtained organic layer was washed with 100 ml of water, then dried over anhydrous sodium sulfate and dried, and the solvent was evaporated under reduced pressure to obtain 28.67 g of the desired product as a yellow oil (yield 59.4%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 5h; | 767 mg of ethyl 2-cyanopropionate and then 833 mg of potassium carbonate were added to a solution of 500 mg of <strong>[16063-70-0]2,3,5-trichloropyridine</strong> in 5 ml of dimethyl sulfoxide.The reaction was stirred at 100 C. for 5 hours.After completion of the reaction, the reaction solution was cooled to room temperature, 10 ml of water was added, and the mixture was partitioned with 20 ml of ethyl acetate.The obtained organic layer is concentrated under reduced pressure, and the obtained residue is purified by silica gel chromatography (ethyl acetate: hexane = 1: 2)Thus, 270 mg of the desired product was obtained as a colorless oil (yield 49%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium fluoride; tetrakis(triphenylphosphine) palladium(0); In toluene; at 100℃; for 5h; | At room temperature, <strong>[16063-70-0]2,3,5-trichloropyridine</strong> (20 g, 109 mmol) and 2-methoxyphenylboronic acid (21.5 g, 141.7 mmol) are added to a 2-neck flask.Pd (PPh 3) 4 (5.04 g, 5.67 mmol) and potassium fluoride (15.8 g, 272.5 mmol) are added.After addition of 300 ml of toluene, the mixture was stirred at 100 C for 5 hours. After completion of the reaction, the solution is filtered through silica.Column chromatography after solvent removal (MC: Hexane = 1: 1)After purification, an oil type transparent compound S-1 (32.6 g, yield 90%) was obtained. |
90% | With potassium fluoride; tetrakis(triphenylphosphine) palladium(0); In toluene; at 100℃; for 5h; | <strong>[16063-70-0]2,3,5-trichloropyridine</strong> (20 g, 109 mmol) at room temperature,2-methoxyphenolboronic acid (methoxyphenylboronic acid) (21.5g, 141.7 mmol)Into a 2-neck flask.Pd (PPh3) 4 (5.04 g, 5.67 mmol)Potassium fluoride (15.8 g, 272.5 mmol)Add.After addition of 300 ml of toluene, the mixture was stirred at 100 C for 5 hours.After completion of the reaction, the solution is filtered through silica.Column chromatography after solvent removal (MC: Hexane = 1: 1)After purification, oil type transparent compound S-1 (32.6 g, yield 90%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With potassium fluoride; tetrakis(triphenylphosphine) palladium(0); In toluene; at 100℃; for 5h; | At room temperature, <strong>[16063-70-0]2,3,5-trichloropyridine</strong> (20 g, 109 mmol) and 3-bromo-2-methoxyphenylboronic acid (50.3 g, 218 mmol) are added to a 2-neck flask. Pd (PPh 3) 4 (3.78 g, 3.27 mmol) and potassium fluoride (8.7 g, 218 mmol) are added. After addition of 400 ml of toluene, the mixture was stirred at 100 C for 5 hours. After completion of the reaction, the solution is filtered through silica. Purification by column chromatography (MC: Hexane = 1: 4) after solvent removal is followed by column chromatography (EA: Hexane = 1: 4). After removing the solvent, oil type Compound S-9 (12.34 g, Yield 34%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With potassium tert-butylate; palladium diacetate; triphenylphosphine; In o-xylene; at 120℃;Inert atmosphere; | A mixture of <strong>[16063-70-0]2,3,5-trichloropyridine</strong> (I), 2.50 g, 13.7 mmol), triphenylphosphine (0.719 g, 2.74 mmol), potassium f-butoxide (1 .85 g, 16.4 mmol) and palladium(ll) acetate (0.308 g, 1.37 mmol) was dissolved in dry o-xylene (25.0 ml.) under argon and was treated with aniline (1 .25 ml_, 13.7 mmol) while stirring. The dark brown solution was stirred at 120 C overnight. The suspension was filtered through a pad of Celite and the filter was washed with ethyl acetate (20.0 ml_). The filtrate was evaporated, the obtained residue was dissolved in ethyl acetate (20.0 ml.) and washed twice with brine (10 ml_). The organic layer was dried over sodium sulfate, filtered and the solvent was removed under vacuum. The residue was purified via flash chromatography (silica, gradient: 100% n-hexane -> n- hexane/ethyl acetate 95/5 v/v. The product was obtained as yellow oil (1.449 g, 43%). 1H-NMR (200 MHz, CDCI3) d 8.09 (d, J = 2.3 Hz, 1 H), 7.66 - 7.53 (m, 3H), 7.43 - 7.30 (m, 2H), 7.15 - 7.02 (m, 1 H), 6.96 (s, 1 H). 13C-NMR (50 MHz, CDCI3) d 149.8, 144.3, 139.3, 136.4, 129.1 , 123.3, 121 .0, 120.1 , 1 16.2. TLC-MS (ESI+): Calculated 238.01 for CnH8CI2N2. Measured 238.8 for [M+H]+. HPLC: tR = 9.32 min, purity: 99.8% (254.4 nm), 96.6% (230.4 nm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: potassium fluoride; tetramethlyammonium chloride / 1-methyl-pyrrolidin-2-one / 4 h / 150 °C / Inert atmosphere 2: water / 4 h / 60 °C / Inert atmosphere 3: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 25 h / 50 °C 4: methanol / 24 h / Reflux 5: hydrogenchloride / water / 42 h / 102 - 104 °C | ||
Multi-step reaction with 5 steps 1: neat (no solvent) / 130 °C 2: Isopropyl acetate / 10 h / 80 °C 3: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 25 h / 50 °C 4: methanol / 24 h / Reflux 5: hydrogenchloride / water / 42 h / 102 - 104 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: potassium fluoride; tetramethlyammonium chloride / 1-methyl-pyrrolidin-2-one / 4 h / 150 °C / Inert atmosphere 2.1: water / 4 h / 60 °C / Inert atmosphere 3.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 25 h / 50 °C 4.1: methanol / 24 h / Reflux 5.1: hydrogenchloride / water / 42 h / 102 - 104 °C 6.1: 1,1'-carbonyldiimidazole / dimethyl sulfoxide / 1 h / 45 °C 6.2: 2.5 h / 20 °C 7.1: sodium hydroxide; tetrahydrofuran / tetrahydrofuran / 2 h / 20 °C | ||
Multi-step reaction with 7 steps 1.1: neat (no solvent) / 130 °C 2.1: Isopropyl acetate / 10 h / 80 °C 3.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide / 25 h / 50 °C 4.1: methanol / 24 h / Reflux 5.1: hydrogenchloride / water / 42 h / 102 - 104 °C 6.1: 1,1'-carbonyldiimidazole / dimethyl sulfoxide / 1 h / 45 °C 6.2: 2.5 h / 20 °C 7.1: sodium hydroxide; tetrahydrofuran / tetrahydrofuran / 2 h / 20 °C | ||
Multi-step reaction with 7 steps 1.1: potassium fluoride; tetramethlyammonium chloride / 1-methyl-pyrrolidin-2-one / 4 h / 0.15 °C / Inert atmosphere 2.1: water; tert-butyl methyl ether / 4 h / 0.6 °C / Inert atmosphere 3.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; N,N-dimethyl-formamide / 25 h / 50 °C 4.1: methanol; toluene / 24 h / Reflux 5.1: water; hydrogen bromide / 20 h / Reflux 6.1: 1,1'-carbonyldiimidazole / dimethyl sulfoxide / 1 h / 45 °C 6.2: 2.5 h / 20 °C 7.1: sodium hydroxide / tetrahydrofuran / 2 h / 20 °C |
Multi-step reaction with 7 steps 1.1: neat (no solvent) / 130 °C 2.1: Isopropyl acetate; N,N-dimethyl acetamide / 90 °C 3.1: potassium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; N,N-dimethyl-formamide / 25 h / 50 °C 4.1: methanol; toluene / 24 h / Reflux 5.1: water; hydrogen bromide / 20 h / Reflux 6.1: 1,1'-carbonyldiimidazole / dimethyl sulfoxide / 1 h / 45 °C 6.2: 2.5 h / 20 °C 7.1: sodium hydroxide / tetrahydrofuran / 2 h / 20 °C | ||
Multi-step reaction with 4 steps 2: hydrogenchloride 4: hydrogenchloride; sodium hydroxide | ||
Multi-step reaction with 4 steps 2: hydrogenchloride 4: hydrogenchloride; sodium hydroxide | ||
Multi-step reaction with 4 steps 2: hydrogenchloride 4: hydrogenchloride; sodium hydroxide | ||
Multi-step reaction with 4 steps 2: hydrogenchloride 4: hydrogenchloride; sodium hydroxide |
Tags: 16063-70-0 synthesis path| 16063-70-0 SDS| 16063-70-0 COA| 16063-70-0 purity| 16063-70-0 application| 16063-70-0 NMR| 16063-70-0 COA| 16063-70-0 structure
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P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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