* 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.
at -5 - 180℃; for 17 h; Autoclave; Inert atmosphere
In a 200 mL autoclave, 46.0 g (0.2 mol) of the first product 2-chloro-5-trichloromethylpyridine was added,on a good kettle cover, filling nitrogen 10.0MPa to maintain the pressure 5h, the reactor leak. After confirming that the kettle does not leak, empty the kettle pressure.And then the reactor was placed in an ice-salt bath for cooling. When the temperature of the kettle dropped below -5 ° C, the reactor was filled with 40.0 g (~ 2.0 mol) of anhydrous HF and the reaction was heated to 180 , the insulation reaction 12h.After completion of the reaction, the temperature was lowered to 25 ° C, and the inside of the autoclave was replaced with nitrogen for half an hour (the replaced gas was neutralized and absorbed in a 10percent aqueous solution of sodium hydroxide.)Adding the 20percent sodium hydroxide solution to the reaction solution to adjust the pH to 7 to 8, washing the mixture three times, collecting the organic phase, adding anhydrous sodium sulfate or anhydrous sodium carbonate to the organic phase for 6 hours, filtering out the solid, 2-Fluoro-5-trifluoromethylpyridine crude.(3) The crude 2-fluoro-5-trifluoromethylpyridine was put into a distillation column under reduced pressure and the boiling point was collected at 40 to 45 ° C / 11 mmHg to obtain 2-fluoro-5-trifluoromethylpyridine product 28.55g, analysis of the product measured in the 2-fluoro-5-trifluoromethyl pyridine content of 98.77percent (GC), weighing the amount of distillation and kettle residue weight, and do gas chromatography, calculated 2 - The results of the fluorination of 5-trifluoromethylpyridine were: conversion rate: 96.33percent; selectivity: 91.17percent; yield: 85.45percent.
Reference：
[1] Patent: CN106866509, 2017, A, . Location in patent: Paragraph 0030; 0032; 0044; 0046
10
[ 69045-78-9 ]
[ 52334-81-3 ]
[ 69045-82-5 ]
Reference：
[1] European Journal of Medicinal Chemistry, 1989, vol. 24, # 3, p. 249 - 258
The obtained 2-chloro-5-trichloromethylpyridine 46.2 g,After adding the catalyst, the temperature is raised to 150-160°C.Slowly dry the chlorine gas for heavy chlorination.After 6 hours of reaction, dilute the reaction solution with benzene, wash with water and dry the organic phase.After evaporating the benzene under reduced pressure,After distillation, 50.3 g of oily product was obtained.That is the intermediate 2,3-dichloro-5-trichloromethylpyridine,The yield was 90percent and the content was 95percent.
Reference：
[1] Patent: CN106748985, 2017, A, . Location in patent: Paragraph 0030; 0032; 0033; 0035
[2] Patent: CN107935920, 2018, A, . Location in patent: Paragraph 0026; 0031; 0034
14
[ 59-67-6 ]
[ 69045-78-9 ]
[ 69045-83-6 ]
Yield
Reaction Conditions
Operation in experiment
33 %Chromat.
at 210℃; for 14 h; Autoclave
EXAMPLE 7 Conversion of Nicotinic acid to a mixture of 2-chloro-5- (trichloromethyl)pyridine and 2,3-dichloro-5-(trichloromethyl)pyridine. To a 250 ml Berghof autoclave with PTFE lining was added Nicotinic acid (20g, 162 mmole) and phosphorous pentachloride (139 g, 668 mmole). The autoclave was closed and heated to 210 °C for 14 hours. During the heating an exotherm was observed around a temperature of 130 °C bringing the temperature to 190 °C and a pressure increase from 2 bar to 8 bar within 2 minutes. The heating was continued to 210 °C. After the 14 hours the pressure had increased to 37 Bar. The autoclave was cooled to room temperature, ventilated to a scrubber, opened and quantified by GC indicating a yield of 2- chloro-5-(trichloromethyl)pyridine of 33percent compared to the Nicotinic acid starting material and a yield of 2,3-dichloro-5-(trichloromethyl)pyridine 60percent.
(a) Preparation of 2-chloro-5-trichloromethylpyridine 2-Bromo-5-methylpyridine (27 g) in dry carbon tetrachloride (500 ml) was treated with dry hydrogen chloride to give the hydrochloride salt. The solid which separated was broken up and the mixture heated to reflux. Chlorine was passed through the boiling mixture for 8 hours with irradiation by an ultra-violet lamp. The mixture was then filtered and evaporated to a pale yellow liquid which solidified on cooling. This was identified as the required chloro compound by its nuclear magnetic resonance spectrum.
With hydrogenchloride; In tetrachloromethane;
(a) Preparation of 2-chloro-5-trichloromethylpyridine 2-Bromo-5-methylpyridine (27 g) in dry carbon tetrachloride (500 ml) was treated with dry hydrogen chloride to give the hydrochloride salt. The solid which separated was broken up and the mixture heated to reflux. Chlorine was passed through the boiling mixture for 8 hours with irradiation by an ultra-violet lamp. The mixture was then filtered and evaporated to a pale yellow liquid which solidified on cooling. This was identified as the required chloro compound by its nuclear magnetic resonance spectrum.
With hydrogenchloride; In tetrachloromethane;
(a) Preparation of 2-chloro-5-trichloromethylpyridine 2-Bromo-5-methylpyridine (55 g) in dry carbon tetrachloride (600 ml) was filtered and then treated with dry hydrogen chloride to give the hydrochloride salt. The solid which separated was broken up and the mixture heated to reflux. Dry chlorine was passed through the boiling mixture for 61/2 hours with irradiation by an ultra-violet lamp placed inside the reaction flask. The mixture was then cooled, filtered and evaporated to a pale yellow liquid which solidified on cooling. This was identified as the required chloro compound by its nuclear magnetic resonance spectrum.
In tetrachloromethane;
172 g of thus obtained 2-bromo-5-methylpyridine was dissolved in 1.3 l of carbon tetrachloride, and the system was then heated. At the time refluxing begain (at 77 C.), chlorine gas was bubbled into the system with ultraviolet light irradiation. After a lapse of 5 hours, the completion of the reaction was confirmed by gas chromatography, and the system was cooled and air was bubbled into the system to expel the unreacted chlorine. The system was washed with water several times and dried over anhydrous sodium sulfate. Then, the carbon tetrachloride was distilled off, and the system was allowed to cool. The solid crystals thus-obtained were washed with n-hexane to obtain 152 g of 2-chloro-5-trichloromethylpyridine with a melting point of 51 to 54 C.
After co-gasification of 3-methylpyridine and carbon tetrachloride, <strong>[69045-78-9]2-chloro-5-trichloromethylpyridine</strong> is obtained by reaction under a chlorine atmosphere, and fluorine is replaced with hydrogen fluoride when the catalyst is mercury oxide. The crude 2-chloro-5-trifluoromethylpyridine was obtained in a yield of not less than 85%. The crude 2-chloro-5-trifluoromethylpyridine is heated at a rate of 0.7C/min to 33C and melted. After it is placed in a cryostat, it is cooled and circulated, and the temperature is lowered at a rate of 0.07C/min. The crystals were allowed to crystallize at 22 C., recrystallization was separated, and recrystallization was performed at 30 C., sweating was repeated, and the recrystallization and sweating processes were repeated 3 times to obtain high-purity 2-chloro-5-trifluoromethylpyridine.
With hydrogen fluoride;
EXAMPLE 5 This Example describes the preparation of 2-chloro-5-trifluoromethylpyridine by a method alternative to that of Examples 1 and 4. 2-Chloro-5-trichloromethylpyridine (30.8 g) and anhydrous hydrogen fluoride (80 g) were heated for 10 hours at 200 with stirring in an autoclave. The mixture was cooled, poured on to ice, and neutralised at 0. The mixture was filtered and the residue and filtrate extracted with ether. The ether extracts were washed with water, dried, and evaporated to give an oil. This was distilled and the fraction boiling at 140-154 collected. Analysis indicated that this consisted of 2-chloro-5-trifluoromethylpyridine with some 2-fluoro-5-trifluoromethylpyridine.
With hydrogen fluoride; at 130℃;
(3) After passing chlorine gas, <strong>[69045-78-9]2-chloro-5-trichloromethylpyridine</strong> was obtained and transferred to a fluorination kettle. The mass ratio of the <strong>[69045-78-9]2-chloro-5-trichloromethylpyridine</strong> to the anhydrous hydrogen fluoride was 1:1.5. (4) adding the metered hydrogen fluoride to the fluorination tank, adding anhydrous hydrogen fluoride, heating the temperature to carry out the reaction; The reaction temperature after the temperature rise was 130 degrees. (5) The fluorination reaction material is washed with water, steam distilled, the pH is adjusted, and distilled in the press-packed rectification column to obtain a qualified 2-chloro-5-trifluoromethylpyridine product having a pH of 7.
With chlorine;pelletized catalyst TOSOH HSZ-690 HOD (SAR 203) with a silica binder; at 350℃;Gas phase;Product distribution / selectivity;
Example 2; The pelletized catalyst, TOSOH HSZ-690 HOD (SAR 203) with a silica binder, was ground to a coarse powder and screened to obtain a uniform size of 1-2 mm in diameter. A weight of 0.26 g of catalyst was charged into the reactor tube and glass wool (Pyrex) was used to secure it in place. Operating at a chlorine feed of 5 cc/min, a beta-picoline feed rate of 0.13 mg/min (10 cc/min N2 with a chiller temperature of 10 C.), the reagents were fed to the reactor at an initial temperature of 250 C. The system was initially ramped up to 325 C. and allowed to stablize. Under these conditions the product gases were 18.5% 3-trichloromethylpyridine (beta-tri ) and 65.4% beta-2-tet. When the system was allowed to stabilized at 350 C. the amount of beta-tri in the product gases was reduced to 2.6% and the conversion to beta-2-tet increased to 68.6% (see Table 2).; Example 3; The catalyst, TOSOH HSZ-690 HOD (SAR 203) with the silica binder, was sized to a uniform particle size of 1-2 mm in diameter. A weight of 0.26 g of catalyst was charged into the reactor tube and glass wool (Pyrex) was used to secure it in place. The reactor temperature was initially set to 250 C. prior to flowing chlorine at a rate of 5 cc/min. The beta-picoline feed rate was set to 0.13 mg/min (N2 flow 10 cc/min, chiller at 10 C.), while the reactor oven was ramped up to 350 C. over a one hour time period. At 350 C. the amount of beta-2-tet observed in the product gases was 65.6% (see Table 2).; Example 4; The catalyst, TOSOH HSZ-690 HOD (SAR 203) with the silica binder, was sized to a uniform particle size of 1-2 mm in diameter. A weight of 0.51 g of catalyst was charged into the reactor tube and glass wool (Pyrex) was used to secure it in place. The reactor temperature was initially set to 250 C. prior to flowing chlorine at a rate of 5 cc/min. The beta-picoline feed rate was set to 0.13 mg/min (chiller at 10 C.), with a nitrogen flow of 10 cc/min, while the reactor oven was ramped up to 350 C. over 2 hours. When the system had stabilized at 350 C. the amount of beta-2-tet observed in the product gases was 71.7% (see Table 2).; Example 5; The catalyst, TOSOH HSZ-690 HOD (SAR 203) with the silica binder, was sized to a uniform particle size of 1-2 mm. A weight of 0.51 g of catalyst was charged into the reactor tube and glass wool (Pyrex) was used to secure it in place. The reactor temperature was initially set to 250 C. prior to flowing chlorine at a rate of 5 cc/min. The beta-picoline feed rate was set to 0.25 mg/min (N2 at 10 cc/min, chiller at 20 C.), while the reactor oven was slowly ramped up to 350 C. over 2 hours. When the system had stabilized at 350 C. the amount of beta-2-tet observed in the product gases was 66.9% (see Table 2).
With chlorine; at 400℃;Gas phase;Product distribution / selectivity;
Example A; This is the control run where the reactor contained glass wool (Pyrex) plugs and no catalyst. The reactor temperature was initially set to 350 C. prior to feeding chlorine at a rate of 5 cc/min. The beta-picoline feed rate was set to 0.25 mg/min (N2 at 10 cc/min, chiller at 20 C.) at the oven temperature of 350 C. When the system had stabilized the amount of beta-2-tet was only 8.7%, with the majority of the conversion going to beta-tri (65.4%). When the temperature was increased to 400 C. the amount of beta-2-tet increased to 46.1% with a reduction in beta-tri (21.5%). A fair amount of over chlorinated 2,6-dichloro-3-trichloromethylpyridine (beta-2,6-penta,12.2%) was also observed (see Table 2).
With chlorine;0.5% palladium on alumina; at 340℃;Gas phase;Product distribution / selectivity;
Example 1; The pelletized catalyst, 0.5% palladium catalyst on alumina (Harshaw Chemical Co.), was ground to a coarse powder and screened to obtain a uniform size of 1-2 mm in diameter. A weight of 0.25 g of catalyst was charged into the 0.25 reactor tube and glass wool (Pyrex) was used to secure it in place. Operating at an initial temperature of 250 C., a chlorine feed of 5 cc/min, a picoline feed rate of 0.13 mg/min (10 cc/min N2 with a chiller temperature of 10 C.), the reactor was ramped up to 340 C over about one hour. After the system stabilized at the reaction temperature of 340 C., the product gases contained 67.4% beta-2-tet (see Table 1 for conditions and Table 2 for results).
Example 1 In a 120 cc autoclave equipped with a magnetic stirrer, 2-chloro-5-trichloromethylpyridine (11.5 g), Raney nickel (1.15 g) and a 70% aqueous solution of ethylamine (32.2 g) were charged. Hydrogen gas was introduced into the autoclave to a pressure of 10 Kg/cm2, and an internal temperature was raised to 45 C. At the same temperature, the hydrogen gas was supplied under a hydrogen pressure of 5 to 12.5 Kg/cm2. The absorption of hydrogen ceased after 70 minutes from the start of hydrogen supply. After completion of reaction, the autoclave was cooled to room temperature, and the catalyst was filtrated off from the reaction mixture. The filtrate was adjusted to pH 12.9 with a 48% aqueous solution of sodium hydroxide and the filtrate was concentrated. Water was added to the concentrate, and the product was extracted with toluene twice. After phase separation, the toluene layer was concentrated to obtain a concentrate (8.0 g) containing 2-chloro-5-ethylaminomethylpyridine, which was analyzed by gas chromatography to find that a yield of 2-chloro-5-ethylaminomethylpyridine was 77%.
With sodium hydroxide; methylamine;aluminum nickel; In ethanol; water;
Example 2 In a 119.5 cc autoclave equipped with a magnetic stirrer, <strong>[69045-78-9]2-chloro-5-trichloromethylpyridine</strong> (11.5 g), ethanol (20 g), Raney nickel (1.15 g) and a 40% aqueous solution of methylamine (27.2 g) were charged. Hydrogen gas was introduced into the autoclave to a pressure of 10 Kg/cm2, and an internal temperature was raised to 45 C. At the same temperature, the hydrogen gas was supplied under a hydrogen pressure of 7 to 13 Kg/cm2. The absorption of hydrogen ceased after 95 minutes from the start of hydrogen supply. After completion of reaction, the autoclave was cooled down to room temperature, and the catalyst was filtrated off from the reaction mixture. The filtrate was adjusted to pH 12.9 with a 48% aqueous solution of sodium hydroxide and the filtrate was concentrated. Water was added to concentrate, and the product was extracted with toluene twice. After phase separation, the toluene layer was concentrated to obtain a concentrate (4.9 g) containing 2-chloro-5-methylaminomethylpyridine, which was analyzed by gas chromatography to find that a yield of 2-chloro-5-methylaminomethylpyridine was 45%.
With methylamine;aluminum nickel; In ethanol; toluene;
Example 4 In a 3000 cc autoclave equipped with a magnetic stirrer, a 40% aqueous solution of methylamine (814 g), ethanol (312 g) and Raney nickel (35 g) were charged. Hydrogen gas was introduced into the autoclave to a pressure of 3 Kg/cm2. While keeping a temperature at 30 C. or lower and supplying the hydrogen gas, a 58.8% solution of <strong>[69045-78-9]2-chloro-5-trichloromethylpyridine</strong> in toluene (589 g) was added over 40 minutes. After the addition of the solution of <strong>[69045-78-9]2-chloro-5-trichloromethylpyridine</strong>, the internal temperature was gradually raised to 40 C. At the same temperature, the hydrogen gas was supplied till the absorption of hydrogen ceased. After completion of reaction, the autoclave was cooled to room temperature, and the catalyst was filtrated off from the reaction mixture. The filtrate was analyzed by high pressure liquid chromatography to find that a yield of 2-chloro-5-methylaminomethylpyridine was 76%.
With sodium hydroxide; ethylenediamine;aluminum nickel; In ethanol;
Example 3 In a 119.5 cc autoclave equipped with a magnetic stirrer, <strong>[69045-78-9]2-chloro-5-trichloromethylpyridine</strong> (11.5 g), Raney nickel (1.15 g), ethylenediamine (21.0 g) and ethanol (20 g) were charged. Hydrogen gas was introduced into the autoclave to a pressure of 10 Kg/cm2, and an internal temperature was raised to 45 C. At the same temperature, the hydrogen gas was supplied under a hydrogen pressure of 7 to 11.2 Kg/cm2. The absorption of hydrogen ceased after 180 minutes from the start of hydrogen supply. After completion of reaction, the autoclave was cooled down to room temperature, and the catalyst was filtrated off from the reaction mixture. The filtrate was adjusted to pH 13.7 with a 48% aqueous solution of sodium hydroxide and the filtrate was concentrated. The concentrate was analyzed by gas chromatography to find that a yield of 2-chloro-5-(2-aminoethyl)aminomethylpyridine was 10%.
REFERENCE EXAMPLE 1 A reaction was conducted for 12 hours in the same manner as in Example 1 except that <strong>[69045-78-9]2-chloro-5-trichloromethylpyridine</strong> (0.2 mole) was replaced by 3-trichloromethylpyridine (0.2 mole). The resulting reaction mixture was analyzed by gas chromatography, which indicated that the amount of 3-cyanopyridine formed was 1% or less.
With hydrogenchloride;Zinc chloride; In N-methyl-acetamide; diethyl ether; dichloromethane; nitrobenzene;
(Method B) In 11 ml of nitrobenzene were dissolved 0.69 g of <strong>[69045-78-9]2-chloro-5-trichloromethylpyridine</strong> and 0.62 g of veratrole, to which 1 g of zinc chloride and 0.3 ml of dimethylformamide were added with stirring. After stirring at 70 C. for 12 hours, 10 ml 1N HCl was added to the reaction mixture, and the mixture was stirred at 50 to 60 C. for 30 minutes. After cooling to room temperature, the reaction mixture was extracted with dichloromethane. The extracts were dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silicagel column chromatography [eluted with a mixture solvent of dichloromethane and diethyl ether (10:1)], to give 0.56 g of 2-chloro-5-(3,4-dimethoxybenzoyl)pyridine mp 158-159 C.
The recovered organic materials include the object products as well as 20% of 2-chloro-5-fluorodichloromethylpyridine and 6.7% of 2-chloro-5-chlorodifluoromethylpyridine as intermediates and 3.8% of the unreacted <strong>[69045-78-9]2-chloro-5-trichloromethylpyridine</strong>.
The organic layer was separated, dried with MgSO4 and the solvent removed by evaporation to give 26.7 g of yellow liquid. Distillation gave 24.9 g of 95.6 percent 2,3-dichloro-5-trichloromethylpyridine (89.7 percent yield). The impurities were analyzed and found to be: 2,3,5,6-tetrachloropyridine (1.6%) 2-chloro-5-trichloromethylpyridine (1.6%) 2,3,6-trichloro-5-trichloromethylpyridine (1.2%)
26
salt of 3-methylpyridine[ No CAS ]
[ 108-99-6 ]
[ 69045-78-9 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In tetrachloromethane;
EXAMPLE 3 This Example illustrates the preparation of 2-chloro-5-trichloromethylpyridine from a salt of 3-methylpyridine. 3-Methylpyridine (15 g) in dry carbon tetrachloride (200 ml) was treated with dry HCl gas to give the hydrochloride. The oily mixture thus obtained was stirred and heated to reflux. Dry chlorine gas was bubbled into the refluxing mixture for 4 hours while illuminating it internally from the ultraviolet lamp used in Example 1. The reaction mixture was then cooled, and separated by decantation into solution and oily solid. The latter was purified, and shown to contain unreacted 3-methylpyridine salt. The former was evaporated to an oily semi-solid, which was shown by thin-layer chromatography to have the characteristics of 2-chloro-5-trichloromethylpyridine.
2-Chloro-5-trichloromethyl pyridine (18 g) and antimony trifluoride (50 g) were heated together at 140-145 C. for 1 hour. The mixture was cooled, mixed with ice and concentrated hydrochloric acid, and extracted with ether. The extracts were washed with water, dried with magnesium sulphate, and evaporated. The products from several such preparations were combined and distilled at atmospheric pressure through a short column packed with Fenske rings. The product boiling at 124-154 C. was collected and identified as 2-chloro-5-trifluoromethylpyridine. Higher boiling fractions were redistilled at a pressure of 20 mm mercury to give 2-chloro-5-difluorochloromethylpyridine, boiling at 82 to 90 C.
The liquid was found to contain 17 ppm tungsten. The solid (1.4 grams) was used to catalyze the chlorination of 187.6 grams of 2-chloro-5-trichloromethylpyridine at 200 C. and ambient pressure. In 98 hours, 77.5 weight percent of 2,3-dichloro-5-trichloromethylpyridine was obtained.
EXAMPLE 6 Hydrolysis step 5 g of 2-chloro-5-trichloromethyl pyridine was dissolved in 30 g of concentrated sulfuric acid, and the solution was heated to 110 C., whereupon hydrogen chloride gas was vigorously generated. The reaction was conducted at a temperature of from 110 to 120 C. for 2 hours. After the completion of the reaction, the reaction product was introduced into ice water, whereupon white crystals precipitated. The crystals were filtered, washed and dried to obtain 3.2 g of 6-chloronicotinic acid (yield: 94%, purity: 95%).
EXAMPLES 1 TO 5 Chlorination step To 18.2 g of 2-chloro-5-trifluoromethyl pyridine, 20 g of aluminum chloride was added in 2 hours, and they were reacted under the predetermined reaction conditions as shown in Table 1. After the completion of the reaction, the reaction product was cooled and then introduced into ice water, and the oil layer was separated by liquid separation. The solvent was removed by distillation to obtain 2-chloro-5-trichloromethyl pyridine.
Preparation of 2-Chloro-5-trifluoromethylpyridine 23.1 g of <strong>[69045-78-9]2-chloro-5-trichloromethylpyridine</strong> and 17.9 g of antimony trifluoride were mixed in a flask equipped with a thermometer, a stirrer and a reflux condenser. The reaction was initiated immediately when the mixture was heated to 170 C., and a formed low boiling product began to be refluxed. Five minutes after the initiation of the reflux, the condenser was directed downward to distill out the refluxing product. The distillate was extracted with methylene chloride, and the extract was washed successively with 15% dilute hydrochloric acid and water and, after drying over anhydrous sodium sulfate, the washed extract was concentrated. The concentrate was distilled to obtain 8.0 g of 2-chloro-5-trifluoromethylpyridine with a boiling point of 91-93 C./80 mmHg.
23.1 g of <strong>[69045-78-9]2-chloro-5-trichloromethylpyridine</strong> and 17.9 g of antimony trifluoride were mixed in a flask equipped with a thermometer, a stirrer and a reflux condenser. The reaction was initiated immediately when the mixture was heated to 170 C., and a formed low boiling product began to be refluxed. Five minutes after the initiation of the reflux, the condenser was directed downward to distill out the refluxing product. The distillate was extracted with methylene chloride, and the extract was washed successively with 10% dilute hydrochloric acid and water and, after drying over anhydrous sodium sulfate, the washed extract was concentrated. The concentrate was distilled to obtain 8.0 g of 2-chloro-5-trifluoromethylpyridine with a boiling point of 91-93 C./80 mmHg.
With thionyl chloride; chlorine; at 75℃;Large scale;
adding pre-melted 2-chloro-5-chloromethylpyridine, through the high slot by adding thionyl chloride, Jacket steam heating, open the exhaust gas absorption system, chlorination kettle to maintain micro-negative pressure, 75 C began to pass chlorination reaction, access speed of about 15 ~ 40kg/h, with the reaction, The reaction solution gradually becomes clear from the turbidity, the chlorine speed decreases later, Gas chromatography to the end of the reaction to stop the end of chlorine, a total consumption of about 520kg of chlorine, liquid cooling, And nitrogen for half an hour to replace chlorine and hydrochloric acid gas, transferred to the solvent recovery kettle, Atmospheric distillation of dichlorosulfone distillation, recovery can be applied in the next batch of chlorination, The chlorinated material is pressurized with nitrogen gas in a stoichiometric tank for fluorination.
With phosphorus pentachloride; at 210℃; for 16h;Autoclave;
EXAMPLE 9 Preparation of 2,3-dichloro-5-(trichloromethyl)pyridine from various compounds of the formula [I]. The starting material of formula [I] (50 mmole) and PCI5 (1 or 2 eq.) was mixed in a 50 ml teflon autoclave. The autoclave was closed and heated in a 210 C warm metal block. After 16 hours the autoclave was cooled to 25 C and opened. The resulting solution was analysed by GC with results according to table 5. (trichloromethyl)pyridine In comparison, starting with the compound 2-chloro-5- (trichloromethyl)pyridine only very low conversion to the compound [II] is observed.
With phosphorus pentachloride; at 175℃; under 18751.9 - 30003 Torr; for 96h;Autoclave;
EXAMPLE 5 Conversion of Nicotinic acid to 2,3-dichloro-5-(trichloromethyl)pyridine. Using a similar setup as described in example 1, a series of experiments were carried out with 4 molar eq. of PCI5 at various temperatures and a pressure reaching between 25 and 40 bar after completion. Results are provided in table 2.
With phosphorus pentachloride; at 185℃; under 18751.9 - 30003 Torr; for 72h;Autoclave;
EXAMPLE 5 Conversion of Nicotinic acid to 2,3-dichloro-5-(trichloromethyl)pyridine. Using a similar setup as described in example 1, a series of experiments were carried out with 4 molar eq. of PCI5 at various temperatures and a pressure reaching between 25 and 40 bar after completion. Results are provided in table 2.
With phosphorus pentachloride; at 185℃; under 18751.9 - 30003 Torr; for 64h;Autoclave;
EXAMPLE 6 Conversion of Nicotinic acid to 2,3-dichloro-5-(trichloromethyl)pyridine. Using a similar setup as described in example 1, a series of experiments were carried out using various amounts of PCI5, at a temperature set at 210C, and at pressure reaching between 25 and 40 bar after completion. Results in accordance with the below table 3.
With phosphorus pentachloride; at 210℃; under 1500.15 - 27752.8 Torr; for 14h;Autoclave;
EXAMPLE 7 Conversion of Nicotinic acid to a mixture of 2-chloro-5- (trichloromethyl)pyridine and 2,3-dichloro-5-(trichloromethyl)pyridine. To a 250 ml Berghof autoclave with PTFE lining was added Nicotinic acid (20g, 162 mmole) and phosphorous pentachloride (139 g, 668 mmole). The autoclave was closed and heated to 210 C for 14 hours. During the heating an exotherm was observed around a temperature of 130 C bringing the temperature to 190 C and a pressure increase from 2 bar to 8 bar within 2 minutes. The heating was continued to 210 C. After the 14 hours the pressure had increased to 37 Bar. The autoclave was cooled to room temperature, ventilated to a scrubber, opened and quantified by GC indicating a yield of 2- chloro-5-(trichloromethyl)pyridine of 33% compared to the Nicotinic acid starting material and a yield of 2,3-dichloro-5-(trichloromethyl)pyridine 60%.
With P,P-dichlorophenylphosphine oxide; phosphorus pentachloride; at 160℃; for 5h;
General procedure: A mixture of reaction substrate (100.0 mmol), phenylphosphonic dichloride (33.0 mmol) and phosphorus pentachloride (330.0 mmol) was slowly heated to 160 C while distilled the byproduct (POCl3). Then the mixture was stirred at the same temperature for 5 hours. TLC analysis showed the reaction had been finished. The POCl3 was evaporated in vacuum and the residue was poured into ice water, and it was neutralized with saturated aqueous sodium carbonate solution, and extracted with acetic ether. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure , the obtained crude product was distilled or purified with silica gel chromatograph.
With chlorine; sodium hydroxide; at 100 - 150℃; for 12h;Inert atmosphere;
To a 500 mL three-necked round bottom flask was added 3-methylpyridine 93.0 (1.0 mol)and condenser means connected to exhaust, the use of caustic soda as scrubber liquid nitrogen with magnetic stirring upon heating to 100C, the nitrogen was stopped and chlorine gas switching, stirring and heating was continued to 150 C, a thermostat, chlorine was bubbled through the reaction.After 12 hours of reaction, the reaction was carried out. The content of 3-methylpyridine in the reaction solution was <1%. The reaction system was then cooled to room temperature, a pale yellow solid was precipitated, 200 g of ethanol was added, heated and stirred until it was completely dissolved. After the dissolution was completed, the temperature was lowered to 5C,after cooling for 2 hours, the mixture was filtered and dried to obtain 134.10 g of pure white needle-like solid 2-chloro-5-trichloromethylpyridine, 96.25% pure (GC).The filtrate was 235.04 g, and the content of 2-chloro-5-trichloromethylpyridine was 37.67%. Calculate 2-chloro-5-trichloromethylpyridine the results of the chlorination reaction were: conversion rate: 98.33%; selectivity: 95.45%; yield: 94.20%.
91.3%
With hydrogenchloride; trichlorophosphate; In water; nitrobenzene; at 100 - 140℃; for 16h;pH 4.5;Inert atmosphere;
In a four-necked flask, 10 g of 3-methylpyridine,25mL nitrobenzene and 25ml buffer solution,Dilute hydrochloric acid solution with a pH of about 4.5,At the same time 0.3g of phosphorus trichloride was added.Purged with nitrogen,Electromagnetic stirring,Warmed to 100 C,Stop the nitrogen and switch into the chlorine,Continue to heat up to 140 ,Under constant temperature, the chlorine bubbling reaction 16h,Stop heatingClose the chlorine injection valve,Purged with nitrogen,Bubble rush 1h.After the reaction mixture was distilled off under reduced pressure,Get a reddish brown oily liquid.High vacuum fractionation purification product,Collect the distillate.After extraction with trichloromethane,The combined extracts,After depressurization and desolvation,Get 19.4g light yellow oily liquid, product2-Chloro-5-trichloromethyl pyridineThe yield was 91.3%.
75.3%
With tetrachloromethane; chlorine; at 350 - 400℃; for 0.00277778h;
In a special reaction vessel,From the slow introduction of a mixture of 22.4g 3-methylpyridine and 212ml carbon tetrachloride mixed steam,Chlorine gas is introduced from the inlet port and chlorination reaction is performed at 350-400C for 10 seconds.The collected product was washed with dilute ammonia water and dried over anhydrous sodium sulfate, carbon tetrachloride was removed as an oily crude,That is the intermediate 2-chloro-5-trichloromethylpyridine,The yield was 75.3%, the yield after distillation was 50%, and the content was greater than 90%;
With tetrachloromethane; chlorine;
After co-gasification of 3-methylpyridine and carbon tetrachloride, 2-chloro-5-trichloromethylpyridine is obtained by reaction under a chlorine atmosphere, and fluorine is replaced with hydrogen fluoride when the catalyst is mercury oxide. The crude 2-chloro-5-trifluoromethylpyridine was obtained in a yield of not less than 85%.
With chlorine; In tetrachloromethane; water; at 400℃; for 4h;
Referring to Example 1, a hydrogen type ZSM-5 original powder having a silicon to aluminum ratio of 80 was replaced with a hydrogen type ZSM-5 original powder having a silicon to aluminum ratio of 230 to prepare a catalyst B. 10 g of catalyst B was taken into a cylindrical fixed bed reactor with an inner diameter of 25 mm, and the plunger pump was pumped into a solution of 3-methylpyridine in carbon tetrachloride. The mass ratio of 3-methylpyridine to carbon tetrachloride was 1: The weight hourly space velocity of 10,3-methylpyridine is 6h-1, the weight hourly space velocity of water is 3h-1, the chlorine gas flow rate is 2L/min, 3-methylpyridine, water and chlorine gas are preheated. At the same time, it is passed into a fixed bed reactor. The temperature of the fixed bed reactor is 400 C, and the reaction is carried out for 4 h. The reaction product is passed through a condenser. 2890 g of the reaction product mixture is obtained in the receiving tank. The ammonia water is adjusted to neutral, and the pear-shaped funnel is divided. The organic phase was obtained by adding 30 g of anhydrous magnesium sulfate, suction filtration, and then rotary evaporation to remove carbon tetrachloride to give white crystals as 2,3,6-trichloropyridine. After analysis and detection, the purity of 2,3,6-trichloropyridine was 94%, and the yield was 95%.
With hydrogen fluoride; at -5 - 180℃; under 75007.5 Torr; for 17h;Autoclave; Inert atmosphere;
In a 200 mL autoclave, 46.0 g (0.2 mol) of the first product 2-chloro-5-trichloromethylpyridine was added,on a good kettle cover, filling nitrogen 10.0MPa to maintain the pressure 5h, the reactor leak. After confirming that the kettle does not leak, empty the kettle pressure.And then the reactor was placed in an ice-salt bath for cooling. When the temperature of the kettle dropped below -5 C, the reactor was filled with 40.0 g (~ 2.0 mol) of anhydrous HF and the reaction was heated to 180 , the insulation reaction 12h.After completion of the reaction, the temperature was lowered to 25 C, and the inside of the autoclave was replaced with nitrogen for half an hour (the replaced gas was neutralized and absorbed in a 10% aqueous solution of sodium hydroxide.)Adding the 20% sodium hydroxide solution to the reaction solution to adjust the pH to 7 to 8, washing the mixture three times, collecting the organic phase, adding anhydrous sodium sulfate or anhydrous sodium carbonate to the organic phase for 6 hours, filtering out the solid, 2-Fluoro-5-trifluoromethylpyridine crude.(3) The crude 2-fluoro-5-trifluoromethylpyridine was put into a distillation column under reduced pressure and the boiling point was collected at 40 to 45 C / 11 mmHg to obtain 2-fluoro-5-trifluoromethylpyridine product 28.55g, analysis of the product measured in the 2-fluoro-5-trifluoromethyl pyridine content of 98.77% (GC), weighing the amount of distillation and kettle residue weight, and do gas chromatography, calculated 2 - The results of the fluorination of 5-trifluoromethylpyridine were: conversion rate: 96.33%; selectivity: 91.17%; yield: 85.45%.
The obtained 2-chloro-5-trichloromethylpyridine 46.2 g,After adding the catalyst, the temperature is raised to 150-160C.Slowly dry the chlorine gas for heavy chlorination.After 6 hours of reaction, dilute the reaction solution with benzene, wash with water and dry the organic phase.After evaporating the benzene under reduced pressure,After distillation, 50.3 g of oily product was obtained.That is the intermediate 2,3-dichloro-5-trichloromethylpyridine,The yield was 90% and the content was 95%.
With chlorine; at 130 - 180℃; for 100h;Large scale;
2000 kg of 2-chloro-5-trichloromethylpyridine was placed in a glass-lined chlorination kettle.Then adding catalyst to the reactorThe 150kg reactor is heated with a heat transfer oil.When the temperature rises to 130 C, chlorine gas is introduced into the reactor to control the amount of chlorine.The reaction temperature was controlled at 180 C. The reaction time is usually 100 hours.After the reaction is completed, the temperature is lowered to 50 C, and the catalyst is filtered off.After the 2,3-dichloro-5-trichloromethylpyridine was metered, it was fluorinated in a fluorination kettle.
With tetrachloromethane; at 200 - 350℃; for 0.00305556h;Molecular sieve; Inert atmosphere;
40 G ZSM - 5 molecular sieve (silicon-aluminum ratio 200, strip (1 - 2 mm)) by adding [...] 60 cm, diameter of 2.4 cm cylindrical quartz tube, the upper end of the catalyst filling 10 g of inert ceramic ball (diameter 4 mm), the quartz tube using the resistance wire heating. The constant pressure in the funnel 8 g 3 - methyl pyridine and 70 g CCl4[...] 200 C flask, 2 h the raw materials of the completion of the dropping, of the 3 - methyl pyridine with CCl4The steam is N2The carrier gas to the quartz tube, N2The flow rate control in 250 ml/min. Cl2In order to 300 ml/min flow rate individually to the quartz tube with the raw material of the steam in the catalyst bed on the reaction, the reaction temperature is 350 C, time is 11 s. The reaction mixture through the receiving flask condensation, GC normalized 3 - methyl pyridine totally transformed, 3 - dichloro pyridine and isomer 47%, 2 - chloro -5 - trichloromethyl pyridine 27%, 2 - chloro -3 - trichloromethyl pyridine 4.8%, 2, 3 - dichloro -5 - trichloromethyl pyridine 11%. The purity of the purification after rectification>99% of 2 - chloro -5 - trichloromethyl pyridine, the yield of 21%.
With tetrachloromethane; at 200 - 340℃; for 0.00388889h;Molecular sieve; Inert atmosphere;
45 G of a pure silicon TS - 1 molecular sieve (spherical particles (1 - 2 mm)) is added to the long 60 cm, diameter of 2.4 cm cylindrical quartz tube, the upper end of the catalyst filling 10 g of inert ceramic ball (diameter 4 mm). The constant pressure in the funnel 8 g 3 - methyl pyridine and 70 g CCl4[...] 200 C flask, 2 h the completion of the dropping, of the 3 - methyl pyridine with CCl4The steam is N2The carrier gas to the quartz tube, N2The flow rate control in 280 ml/min. Cl2In order to 300 ml/min flow rate individually to the quartz tube with the raw material of the steam in the catalyst bed on the reaction, the reaction temperature is 340 C, time is 14 s. The reaction mixture through the receiving flask condensation, GC normalized 3 - methyl pyridine totally transformed, 3 - dichloro pyridine and isomer 18%, 2 - chloro -5 - trichloromethyl pyridine 78%, 2 - chloro -3 - trichloromethyl pyridine 0.9%, other excessive chlorinated product. The purity of the purification after rectification>99% of 2 - chloro -5 - trichloromethyl pyridine, yield is 73%.
With tetrachloromethane; at 200 - 250℃; for 0.00388889h;Molecular sieve; Inert atmosphere;
45 G of a pure silicon TS - 1 molecular sieve (spherical particles (1 - 2 mm)) is added to the long 60 cm, diameter of 2.4 cm cylindrical quartz tube, the upper end of the catalyst filling 10 g of inert ceramic ball (diameter 4 mm). The constant pressure in the funnel 8 g 3 - methyl pyridine and 70 g CCl4[...] 200 C flask, 2 h the completion of the dropping, of the 3 - methyl pyridine with CCl4The steam is N2The carrier gas to the quartz tube, N2Flow control in 280 ml/min. Cl2In order to 300 ml/min flow rate individually to the quartz tube with the raw material of the steam in the catalyst bed on the reaction, the reaction temperature is 250 C, time is 14 s. The reaction mixture through the receiving flask condensation, GC normalized 3 - methyl pyridine totally transformed, 3 - dichloro pyridine and isomer 69%, 3 - trichloromethyl pyridine and its isomer 26%, 2 - chloro -5 - trichloromethyl pyridine 2%. With the embodiment 2 compared, reduce the reaction temperature, chlorinated rate slows down, the generated 2 - chloro -5 - trichloromethyl pyridine very little.
With chlorine; In tetrachloromethane; at 400℃; for 4h;
10 g of catalyst B was taken into a cylindrical fixed bed reactor with an inner diameter of 25 mm, and the plunger pump was pumped into a solution of 3-methylpyridine in carbon tetrachloride. The mass ratio of 3- methylpyridine to carbon tetrachloride was 1: The weight hourly space velocity of 10,3-methylpyridine is 6h, the chlorine gas flow rate is 2L/min, and the 3-methylpyridine and chlorine gas are vaporized by the preheating tube and then passed into the fixed bed reactor. The fixed bed reactor is used. The temperature was 400 C, the reaction was carried out for 4 h, the reaction product was passed through a condenser, and 2987 g of the reaction product mixture was obtained in a receiving tank. The ammonia solution was added to adjust to neutrality, and the pear-shaped funnel was separated to obtain an organic phase. 30 g of anhydrous sulfuric acid was added to the organic phase. Magnesium is dehydrated, suction filtered, and then rotary evaporated to remove carbon tetrachloride to give a pale yellow liquid. After analysis and detection, the product is a mixture of 2-chloro-5-trichloromethylpyridine, 2,3-dichloro-5-trichloromethylpyridine and 2,3,6-trichloropyridine, respectively. 77%, 16%, 7%. It is indicated that it is difficult to remove trichloromethyl group under the reaction conditions in the absence of water
As a further technical solution, the 3-methylpyridine and chlorine gas are reacted by heating 3-methylpyridine and chlorine gas at a molar ratio of 1:15 to above 200 C, and entering the shallow chlorination reactor in a gas phase. The reaction is carried out at 355 C to obtain a reaction mixed gas, and then the reaction mixed gas is introduced into the quenching tower. The excess chlorine gas and a small portion of the hydrogen chloride gas are separated by a separation column and returned to the shallow chlorination reactor, and the 2-column is obtained at the bottom of the quenching tower. -5-Dichloromethylpyridine, 2-chloro-5-trichloromethylpyridine, 2-chloro-3-trichloromethylpyridine liquid phase incubation, continuous distillation, separation, respectively for 2-chloro-5 - Dichloromethylpyridine, 2-chloro-5-trichloromethylpyridine, 2-chloro-3-trichloromethylpyridine for storage.
A 2-chloro-5-trichloromethylpyridine distillation purification method,Add 15.6 g of crude 2-chloro-5-methylpyridine,0.1g methyl ethyl ketone peroxide,50mL of o-dichlorobenzene, pass in nitrogen, stir at 150r / min for 10min, increase the temperature to 80 C, stop nitrogen flow and switch in the chlorine gas, continue to increase the temperature to 142 C, under constant temperature, chlorine gas bubbling reaction. An additional 0.07 g of methyl ethyl ketone peroxide was added every 2 hours. After 20 hours of reaction, the heating was stopped, the introduction of chlorine gas was stopped, the introduction of nitrogen gas was bubbled, and the chlorine was bubbled for 1 hour. The product obtained was recrystallized from anhydrous ethanol and then dried under vacuum to obtain 2-chloro-5-trichloromethylpyridine as a white solid.As a further technical solution, the separation in the separation and elution is performed by column chromatography using silica gel GF254.As a further technical solution, the composition of the eluent used for the elution in the separation and elution is V (ethyl acetate): V (petroleum ether) = 1:20.
With ammonium hydroxide; 5%-palladium/activated carbon; hydrogen; In acetic acid methyl ester; water; at 55 - 60℃; under 6000.6 Torr; for 7h;Autoclave;
Step 1: Put 1500 g of methyl acetate in a high pressure reaction kettle, and put 1000 g of <strong>[69045-78-9]2-chloro-5-trichloromethylpyridine</strong>, 3 g of Pd / C catalyst, and 420 g of ammonia water at a mass concentration of 25% into the high pressure reaction kettle. And 400 g of pure water, first replacing the air in the autoclave with nitrogen for 3 times, and then passing in hydrogen to replace the nitrogen for 3 times;Step 2: Continue to introduce hydrogen until the hydrogen pressure in the high-pressure reactor is 0.8 MPa, and the reaction is carried out at a temperature of 55 C. to 60 C. for 7 hours under a pressure of 0.8 MPa in the reactor, and the temperature is reduced to room temperature after the reaction is completed;Step 3: Discharge the hydrogen in the autoclave after the temperature drop in Step 2, and replace it with nitrogen 3 times;Step 4: Under the condition of a pressure of 0.2 MPa, pressurize the solid-liquid mixture in the autoclave after the nitrogen replacement in the third step of the filter press to obtain a filter cake and a filtrate;Step 5: Allow the filtrate described in step 4 to separate into the aqueous phase and the organic phase, remove the aqueous phase to obtain an organic phase; intermittently sample during the reaction, and analyze the conversion of <strong>[69045-78-9]2-chloro-5-trichloromethylpyridine</strong> by gas chromatography 98%, reaction stopped;Step 6. Place the organic phase in step 5 in an evaporator and evaporate at 100 C for 5 hours to obtain organic solvent vapor and crude product.Step 7. Distill the crude product under reduced pressure to obtain 2-chloro-5-chloromethylpyridine; the pressure of the vacuum distillation is -0.095 MPa, and the time of the vacuum distillation is 6 hours;Step 8. Condensing and recovering the organic solvent vapor in Step 6 at a temperature of -5 C to 0 C to obtain a recovered organic solvent, and recycling the recovered organic solvent for recycling.Step Nine, recovering the filter cake of Step IV to obtain a recovered catalyst.In this example, the yield of 2-chloro-5-chloromethylpyridine was 88.6%, and the gas chromatographic purity of 2-chloro-5-chloromethylpyridine was 98.8%. The number of times was 6 and the yield and purity of 2-chloro-5-chloromethylpyridine were basically unchanged during the cycle application.
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