CN110117251B - Preparation method of 4, 5-dichloro-2-hydroxypyridine - Google Patents
Preparation method of 4, 5-dichloro-2-hydroxypyridine Download PDFInfo
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- CN110117251B CN110117251B CN201810118147.9A CN201810118147A CN110117251B CN 110117251 B CN110117251 B CN 110117251B CN 201810118147 A CN201810118147 A CN 201810118147A CN 110117251 B CN110117251 B CN 110117251B
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- hydroxypyridine
- dichloro
- trichloropyridine
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- IBYSIDMKPWANMY-UHFFFAOYSA-N 4,5-dichloro-1h-pyridin-2-one Chemical compound OC1=CC(Cl)=C(Cl)C=N1 IBYSIDMKPWANMY-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- ZJKMPIAMSJCNFI-UHFFFAOYSA-N 2,4,5-trichloropyridine Chemical compound ClC1=CC(Cl)=C(Cl)C=N1 ZJKMPIAMSJCNFI-UHFFFAOYSA-N 0.000 claims abstract description 39
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 36
- 239000012074 organic phase Substances 0.000 claims abstract description 32
- 239000012043 crude product Substances 0.000 claims abstract description 23
- NKZIETIAJOSOJN-UHFFFAOYSA-N 4,5-dihydroxy-1h-pyridin-2-one Chemical compound OC1=CNC(=O)C=C1O NKZIETIAJOSOJN-UHFFFAOYSA-N 0.000 claims abstract description 22
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000000460 chlorine Substances 0.000 claims abstract description 22
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 22
- 239000002904 solvent Substances 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 238000002390 rotary evaporation Methods 0.000 claims abstract description 16
- 239000000047 product Substances 0.000 claims abstract description 11
- 239000007864 aqueous solution Substances 0.000 claims abstract description 10
- 239000002274 desiccant Substances 0.000 claims abstract description 10
- 238000010992 reflux Methods 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 8
- 239000002798 polar solvent Substances 0.000 claims abstract description 7
- 238000001953 recrystallisation Methods 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 78
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
- 239000003208 petroleum Substances 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 11
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000000741 silica gel Substances 0.000 claims description 9
- 229910002027 silica gel Inorganic materials 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000005457 ice water Substances 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 4
- 150000002894 organic compounds Chemical class 0.000 claims description 2
- 239000005416 organic matter Substances 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 8
- 238000000746 purification Methods 0.000 abstract description 3
- 239000012141 concentrate Substances 0.000 abstract 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- 238000000605 extraction Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 238000006193 diazotization reaction Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- CRRAQLWJVYODCL-UHFFFAOYSA-N 4,5-dichloropyridin-2-amine Chemical compound NC1=CC(Cl)=C(Cl)C=N1 CRRAQLWJVYODCL-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical class [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明公开了一种4,5‑二氯‑2‑羟基吡啶的制备方法，包括如下步骤：S1，向反应瓶中依次加入含氯有机物和2,4,5‑三羟基吡啶，加热回流16‑48h，浓缩、萃取，合并有机相，有机相中加入干燥剂，过滤，旋蒸除去溶剂得到2,4,5‑三氯吡啶粗品；S2，将2,4,5‑三氯吡啶粗品溶于极性溶剂中，于0‑25℃下加入NaOH水溶液，于0‑25℃下反应1h‑6h，萃取，合并有机相，有机相中加入干燥剂，过滤，旋蒸除去溶剂得到4,5‑二氯‑2‑羟基吡啶粗品；S3，将4,5‑二氯‑2‑羟基吡啶粗品重结晶得到2,4,5‑三氯吡啶纯品；本发明4,5‑二氯‑2‑羟基吡啶的制备方法中原料易得，制备过程及纯化步骤简单，便于实现工业化。The invention discloses a preparation method of 4,5-dichloro-2-hydroxypyridine, comprising the following steps: S1, adding chlorine-containing organic matter and 2,4,5-trihydroxypyridine into a reaction flask in sequence, heating under reflux for 16 -48h, concentrate, extract, combine the organic phases, add a desiccant to the organic phase, filter, and remove the solvent by rotary evaporation to obtain the crude 2,4,5-trichloropyridine; S2, dissolve the crude 2,4,5-trichloropyridine In a polar solvent, add NaOH aqueous solution at 0-25°C, react at 0-25°C for 1h-6h, extract, combine the organic phases, add a desiccant to the organic phase, filter, and remove the solvent by rotary evaporation to obtain 4,5 -dichloro-2-hydroxypyridine crude product; S3, recrystallization of 4,5-dichloro-2-hydroxypyridine crude product to obtain 2,4,5-trichloropyridine pure product; 4,5-dichloro-2 of the present invention In the preparation method of hydroxypyridine, the raw materials are easily available, the preparation process and purification steps are simple, and the industrialization is convenient.
Description
Technical Field
The invention relates to the technical field of compound synthesis, in particular to a preparation method of 4, 5-dichloro-2-hydroxypyridine.
Background
Pyridine chlorides, especially 4, 5-dichloro-2-hydroxypyridine, have attracted attention as important fine chemical raw materials in various fields, including medicine, pesticide, feed, etc. The document Bioorganic & Medicinal Chemistry Letters, 19(12), 3247-3252, 2009 discloses diazotization of 2-amino-4, 5-dichloropyridine as a raw material to obtain 4, 5-dichloro-2-hydroxypyridine. The reaction formula is as follows:
the 2-amido-4, 5-dichloropyridine is expensive in price, difficult to synthesize, only suitable for laboratory research and not suitable for industrial production. In addition, the preparation process needs diazotization reaction, and the danger is high.
Therefore, there is a need to obtain a new process for the preparation of 4, 5-dichloro-2-hydroxypyridine.
Disclosure of Invention
In order to solve the problems that 2-amido-4, 5-dichloropyridine is required to be used as a raw material in the existing method for preparing 4, 5-dichloro-2-hydroxypyridine and diazotization reaction is required in the preparation process to cause high preparation cost and high danger, the invention aims to provide two new methods for preparing 4, 5-dichloro-2-hydroxypyridine, the two methods both use 2,4, 5-trihydroxypyridine as a raw material to generate a 2,4, 5-trichloropyridine intermediate, and the 2,4, 5-trichloropyridine intermediate reacts in an alkaline aqueous solution to obtain the 4, 5-dichloro-2-hydroxypyridine.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect of the present invention, there is provided a process for preparing 4, 5-dichloro-2-hydroxypyridine, comprising the steps of:
s1, sequentially adding chlorine-containing organic matters and 2,4, 5-trihydroxypyridine into a reaction bottle, heating and refluxing for 16-48h, concentrating, extracting, combining organic phases, adding a drying agent into the organic phases, filtering, and removing the solvent by rotary evaporation to obtain a crude product of the 2,4, 5-trichloropyridine, wherein the molar ratio of the chlorine-containing organic matters to the 2,4, 5-trihydroxypyridine is 5: 1;
s2, dissolving the 2,4, 5-trichloropyridine crude product in a polar solvent, adding NaOH aqueous solution at 0-25 ℃, reacting for 1-6h at 0-25 ℃, extracting, combining organic phases, adding a drying agent into the organic phases, filtering, and removing the solvent by rotary evaporation to obtain the 4, 5-dichloro-2-hydroxypyridine crude product, wherein the molar ratio of the 2,4, 5-trichloropyridine to the NaOH is 1-3: 1;
s3, recrystallizing the crude 4, 5-dichloro-2-hydroxypyridine product to obtain the pure 2,4, 5-trichloropyridine product.
Wherein the chlorine-containing organic matter in S1 is phosphorus oxychloride or thionyl chloride.
Wherein the step of adding DMF before the heating reflux in S1 is further included, wherein the volume ratio of the added DMF to the chlorinated organic compound is 1: 200.
The DMF plays a role of a catalyst, so that the chlorine-containing organic matter and the 2,4, 5-trihydroxypyridine react more completely.
Wherein the extraction step in S1: adding ethyl acetate into the concentrated reaction solution, and washing the reaction solution for 3 times by using saturated sodium bicarbonate solution, wherein the volume ratio of the ethyl acetate to the saturated sodium bicarbonate solution is 1: 1.
Wherein the extraction step in S1: the concentrated reaction solution was poured into ice water and extracted three times with ethyl acetate.
Preferably, the step of S2 is preceded by a step of purifying the crude 2,4, 5-trichloropyridine by silica gel column.
The mobile phase in the silica gel column is a mixture of petroleum ether and ethyl acetate, wherein the volume ratio of the petroleum ether to the ethyl acetate is 8: 1.
The purification of the crude 2,4, 5-trichloropyridine can improve the yield of 4, 5-dichloro-2-hydroxypyridine, and the yield of the 4, 5-dichloro-2-hydroxypyridine obtained without purifying the crude 2,4, 5-trichloropyridine is only 70%.
Wherein the polar solvent in S2 is methanol or tetrahydrofuran, and the extractant in S2 is ethyl acetate.
Wherein the solvent selected for recrystallization in S3 is ethyl acetate: petroleum ether =1: 1.
In a second aspect of the present invention, there is provided a process for preparing 4, 5-dichloro-2-hydroxypyridine, comprising the steps of:
s1, adding dioxane and 2,4, 5-trihydroxypyridine into a reaction bottle respectively, adding a chlorine-containing organic matter under ice bath, heating and refluxing, reacting for 12-36h, concentrating, extracting, combining organic phases, adding a drying agent into the organic phases, filtering, and performing rotary evaporation to remove a solvent to obtain a crude product of the 2,4, 5-trichloropyridine, wherein the volume ratio of the dioxane to the chlorine-containing organic matter is 1.5:1, and the molar ratio of the chlorine-containing organic matter to the 2,4, 5-trihydroxypyridine is 2.5: 1;
s2, dissolving the 2,4, 5-trichloropyridine crude product in a polar solvent, adding NaOH aqueous solution to react for 1-6h, extracting, combining organic phases, adding a drying agent into the organic phases, filtering, and removing the solvent by rotary evaporation to obtain the 4, 5-dichloro-2-hydroxypyridine crude product, wherein the molar ratio of the 2,4, 5-trichloropyridine to the NaOH is 1-3: 1;
s3, recrystallizing the crude 4, 5-dichloro-2-hydroxypyridine product to obtain the pure 4, 5-dichloro-2-hydroxypyridine product.
Dioxane is used as solvent.
The preparation method is different from the preparation method in two aspects, namely, the charging sequence of the 2,4, 5-trihydroxypyridine and the chlorine-containing organic matter is different, the chlorine-containing organic matter is firstly added in the preparation method, and then the 2,4, 5-trihydroxypyridine is added in batches, and the 2,4, 5-trihydroxypyridine is firstly added in the preparation method, and then the chlorine-containing organic matter is dropwise added; secondly, the adopted raw materials are different, the preparation method only uses 2,4, 5-trihydroxypyridine and chlorine-containing organic matters in the process of preparing the intermediate 2,4, 5-trichloropyridine, and the preparation method needs to add dioxane in addition to the 2,4, 5-trihydroxypyridine and the chlorine-containing organic matters.
Although the difference exists, the 2,4, 5-trihydroxy pyridine is used as a raw material and reacts with chlorine-containing organic matters to generate a 2,4, 5-trichloropyridine intermediate, and the 2,4, 5-trichloropyridine intermediate reacts with alkaline aqueous solution to generate the 4, 5-dichloro-2-hydroxypyridine.
Wherein the chlorine-containing organic substance in S1 is phosphorus oxychloride or thionyl chloride, the step S2 further includes a step of purifying the crude 2,4, 5-trichloropyridine product through a silica gel column, the polar solvent in S2 is tetrahydrofuran or methanol, and the solvent selected for recrystallization in S3 is ethyl acetate: petroleum ether =1: 1.
Compared with the prior art, the invention has the following beneficial effects: the preparation method of the 4, 5-dichloro-2-hydroxypyridine has the advantages of easily obtained raw materials, simple preparation process and purification steps and convenience in industrialization.
Detailed Description
The preparation of 4, 5-dichloro-2-hydroxypyridine involves the following process route:
example 1
1) Synthesis of 2,4, 5-trichloropyridine
200mL of thionyl chloride and 0.2mol of 2,4, 5-trihydroxypyridine and 2,4, 5-trihydroxypyridine are sequentially added into a 500 mL three-neck flask in a batch manner, after all the components are added, 1 mL of DMF is added into the system, the mixture is heated to reflux and reacted for 48 hours, and the reaction is monitored by TLC to be complete. Concentrating the reacted solution at 60 deg.C, adding 300mL ethyl acetate into the concentrated solution, washing with 300mL saturated sodium bicarbonate solution for three times, combining the organic phases, adding solid Na into the organic phase2SO4Pulverizing, stirring, filtering, removing solvent from filtrate by rotary evaporation to obtain 2,4, 5-trichloropyridine crude product, purifying with silica gel column, wherein the mobile phase in the silica gel column is mixture of petroleum ether and ethyl acetateThe volume ratio of petroleum ether to ethyl acetate is 8:1, 23.4g of pure 2,4, 5-trichloropyridine is obtained, and the yield is 65%.
2) Synthesis of 4, 5-dichloro-2-hydroxypyridine
Dissolving 23.4g of 2,4, 5-trichloropyridine in 150mL of methanol, adding 50mL of 10% sodium hydroxide aqueous solution in ice-water bath, reacting for 3 hours in the ice-water bath environment, monitoring the reaction completion by TLC, taking 300mL of ethyl acetate, extracting for three times, combining organic phases after extraction, adding solid Na into the organic phase2SO4Stirring and filtering the powder, removing the solvent in the filtrate by rotary evaporation with a rotary evaporator to obtain a crude product of 4, 5-dichloro-2-hydroxypyridine, and mixing the crude product of 4, 5-dichloro-2-hydroxypyridine with ethyl acetate: recrystallization from petroleum ether =1:1 gave 19g of pure 4, 5-dichloro-2-hydroxypyridine in 90.4% yield.
Example 2
1) Synthesis of 2,4, 5-trichloropyridine
200mL of phosphorus oxychloride and 0.2mol of 2,4, 5-trihydroxypyridine and 2,4, 5-trihydroxypyridine are sequentially added into a 500 mL three-necked flask, and the mixture is heated to reflux by adopting a batch adding mode, reacted for 16 hours and monitored by TLC to finish the reaction. Concentrating the reacted solution at 60 deg.C, pouring the concentrated solution into 450mL ice water, extracting with ethyl acetate three times, each time 150mL, combining organic phases, adding solid Na into the organic phase2SO4The powder was stirred, filtered and the solvent was removed from the filtrate by rotary evaporation using a rotary evaporator to give 34.2g of crude 2,4, 5-trichloropyridine.
Nuclear magnetic data: 1H NMR (400MHz, CDCl 3): δ 7.47 (s, 1H), 8.41 (s, 1H)
2) Synthesis of 4, 5-dichloro-2-hydroxypyridine
Dissolving 34.2g of crude 2,4, 5-trichloropyridine in 200mL of tetrahydrofuran, adding 80mL of 10% sodium hydroxide aqueous solution, stirring at room temperature for 3 hours, performing TLC (thin layer chromatography) to show that the reaction is complete, extracting 300mL of ethyl acetate in three times, combining organic phases after extraction, and adding solid Na into the organic phases2SO4The powder was stirred, filtered, and the solvent was removed from the filtrate by rotary evaporation using a rotary evaporator to give 34g of 4,5-dichloro-2-hydroxypyridine crude product, and mixing the 4, 5-dichloro-2-hydroxypyridine crude product with ethyl acetate: petroleum ether =1:1, and 26.2g of pure 4, 5-dichloro-2-hydroxypyridine was obtained in a total yield of 80.3% in both steps.
Nuclear magnetic data: 1H NMR (400MHz, DMSO). delta.6.67, (s, 1H), 7.88, (s, 1H)
Example 3
1) Synthesis of 2,4, 5-trichloropyridine
Adding 150mL of dioxane and 0.2mol of 2,4, 5-trihydroxypyridine into a 500 mL three-necked bottle in sequence, dropwise adding 100mL of phosphorus oxychloride in an ice bath, heating to 105 ℃, reacting for 24h, displaying complete reaction by TLC, concentrating the reaction solution at 60 ℃, adding 300mL of ethyl acetate, washing with 300mL of saturated sodium bicarbonate solution for three times, combining organic phases, adding solid Na into the organic phase2SO4The powder is stirred and filtered, the solvent in the filtrate is removed by rotary evaporation through a rotary evaporator to obtain a crude product of 2,4, 5-trichloropyridine, the crude product of 2,4, 5-trichloropyridine is purified through a silica gel column, the mobile phase in the silica gel column is a mixture of petroleum ether and ethyl acetate, wherein the volume ratio of the petroleum ether to the ethyl acetate is 8:1, 29.8g of a pure product of 2,4, 5-trichloropyridine is obtained, and the yield is 82%.
2) Synthesis of 4, 5-dichloro-2-hydroxypyridine
Dissolving 29.8g of 2,4, 5-trichloropyridine in 150mL of tetrahydrofuran, adding 70mL of 10% sodium hydroxide aqueous solution, stirring at room temperature for 3 hours, performing TLC to show that the reaction is complete, extracting three times with 300mL of ethyl acetate, combining organic phases after extraction, and adding solid Na into the organic phases2SO4Stirring and filtering the powder, removing the solvent in the filtrate by rotary evaporation with a rotary evaporator to obtain a crude product of 4, 5-dichloro-2-hydroxypyridine, and mixing the crude product of 4, 5-dichloro-2-hydroxypyridine with ethyl acetate: recrystallization from petroleum ether =1:1 gave 23.6 g of pure 4, 5-dichloro-2-hydroxypyridine in 88.1% yield.
The foregoing detailed description is given by way of example only, to better enable one of ordinary skill in the art to understand the patent, and is not to be construed as limiting the scope of what is encompassed by the patent; any equivalent alterations or modifications made according to the spirit of the disclosure of this patent are intended to be included in the scope of this patent.
Claims (9)
1. A preparation method of 4, 5-dichloro-2-hydroxypyridine is characterized by comprising the following steps:
s1, sequentially adding chlorine-containing organic matters and 2,4, 5-trihydroxypyridine into a reaction bottle, heating and refluxing for 16-48h, concentrating, extracting, combining organic phases, adding a drying agent into the organic phases, filtering, and removing the solvent by rotary evaporation to obtain a crude product of the 2,4, 5-trichloropyridine, wherein the molar ratio of the chlorine-containing organic matters to the 2,4, 5-trihydroxypyridine is 3-5:1, and the chlorine-containing organic matters in S1 are phosphorus oxychloride or thionyl chloride;
s2, dissolving the 2,4, 5-trichloropyridine crude product in a polar solvent, adding NaOH aqueous solution at 0-25 ℃, reacting for 1-6h at 0-25 ℃, extracting, combining organic phases, adding a drying agent into the organic phases, filtering, and removing the solvent by rotary evaporation to obtain the 4, 5-dichloro-2-hydroxypyridine crude product, wherein the molar ratio of the 2,4, 5-trichloropyridine to the NaOH is 1-3:1, and the polar solvent is methanol or tetrahydrofuran;
s3, recrystallizing the crude 4, 5-dichloro-2-hydroxypyridine product to obtain the pure 4, 5-dichloro-2-hydroxypyridine product.
2. The method of claim 1, wherein the step of adding DMF in S1 before the heating for refluxing, wherein the volume ratio of the added DMF to the chlorinated organic compound is 1: 200.
3. The method of claim 1, wherein the step of extracting in S1: adding ethyl acetate into the concentrated reaction solution, and washing the reaction solution for 3 times by using saturated sodium bicarbonate solution, wherein the volume ratio of the ethyl acetate to the saturated sodium bicarbonate solution is 1: 1.
4. The method of claim 1, wherein the step of extracting in S1: the concentrated reaction solution was poured into ice water and extracted three times with ethyl acetate.
5. The method of claim 1, wherein the step of S2 is preceded by a step of purifying the crude 2,4, 5-trichloropyridine by a silica gel column.
6. The method of claim 1, wherein the extractant in S2 is ethyl acetate.
7. The method according to claim 1, wherein the solvent selected for recrystallization in S3 is ethyl acetate: petroleum ether is 1: 1.
8. A preparation method of 4, 5-dichloro-2-hydroxypyridine is characterized by comprising the following steps:
s1, adding dioxane and 2,4, 5-trihydroxypyridine into a reaction bottle respectively, adding chlorine-containing organic matters under ice bath, heating and refluxing, reacting for 12-36h, concentrating, extracting, combining organic phases, adding a drying agent into the organic phases, filtering, and removing the solvent by rotary evaporation to obtain a crude product of the 2,4, 5-trichloropyridine, wherein the volume ratio of the dioxane to the chlorine-containing organic matters is 1.5:1, the molar ratio of the chlorine-containing organic matters to the 2,4, 5-trihydroxypyridine is 2.5:1-1.8, and the chlorine-containing organic matters are phosphorus oxychloride or thionyl chloride;
s2, dissolving the 2,4, 5-trichloropyridine crude product in tetrahydrofuran or methanol, adding NaOH aqueous solution to react for 1-6h, extracting, combining organic phases, adding a drying agent into the organic phases, filtering, and removing the solvent by rotary evaporation to obtain the 4, 5-dichloro-2-hydroxypyridine crude product, wherein the molar ratio of the 2,4, 5-trichloropyridine to the NaOH is 1-3: 1;
s3, recrystallizing the crude 4, 5-dichloro-2-hydroxypyridine product to obtain the pure 4, 5-dichloro-2-hydroxypyridine product.
9. The method of claim 8, wherein the step of S2 is preceded by the step of purifying the crude 2,4, 5-trichloropyridine by a silica gel column, wherein the solvent selected for recrystallization in S3 is ethyl acetate: petroleum ether is 1: 1.
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| CN201810118147.9A CN110117251B (en) | 2018-02-06 | 2018-02-06 | Preparation method of 4, 5-dichloro-2-hydroxypyridine |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1676516A (en) * | 2004-03-29 | 2005-10-05 | 朱小平 | Novel method for industrially preparing trichloropyridine sodium alcoholate |
| CN102993236A (en) * | 2012-06-05 | 2013-03-27 | 湖北仙隆化工股份有限公司 | Synthesizing method of active compound of chlorpyrifos |
| WO2014151142A1 (en) * | 2013-03-15 | 2014-09-25 | Constellation Pharmaceuticals, Inc. | Modulators of methyl modifying enzymes, compositions and uses thereof |
| CN104529880A (en) * | 2014-11-28 | 2015-04-22 | 南京红太阳生物化学有限责任公司 | Synthesis method of 2,3-dichloropyridine |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1676516A (en) * | 2004-03-29 | 2005-10-05 | 朱小平 | Novel method for industrially preparing trichloropyridine sodium alcoholate |
| CN102993236A (en) * | 2012-06-05 | 2013-03-27 | 湖北仙隆化工股份有限公司 | Synthesizing method of active compound of chlorpyrifos |
| WO2014151142A1 (en) * | 2013-03-15 | 2014-09-25 | Constellation Pharmaceuticals, Inc. | Modulators of methyl modifying enzymes, compositions and uses thereof |
| CN104529880A (en) * | 2014-11-28 | 2015-04-22 | 南京红太阳生物化学有限责任公司 | Synthesis method of 2,3-dichloropyridine |
Non-Patent Citations (1)
| Title |
|---|
| Pyridones as glucokinase activators: Identification of a unique metabolicliability of the 4-sulfonyl-2-pyridone heterocycle;Jeffrey A.Pfefferkorn et al.;《Bioorganic & Medicinal Chemistry Letters》;20090503;第19卷(第12期);第3247-3252页 * |
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