阅读说明：本技术 一种一锅法制备吡啶类医药中间体的方法 (Method for preparing pyridine medical intermediate by one-pot method ) 是由 蒋彬 储玉平 于 2021-11-09 设计创作，主要内容包括：本发明属于医药中间体生产领域,具体公开了一种一锅法制备吡啶类医药中间体的方法,包括以下步骤：将2-氯-5-三氯甲基吡啶投入真空反应釜中,加入催化剂,设定真空度为0.01-0.1Mpa,一起加热至250-400℃后,通入过量含氟气体充分反应,降温至15-25℃以下,得到2-氯-5-三氟甲基吡啶粗品晶体；随后通过多步的水洗,降温,蒸馏结晶,获得纯度大于得到纯度大于99.8%的2-氯-5-三氟甲基吡啶。本发明所述的一锅法制备吡啶类医药中间体的方法获得的2-氯-5-三氟甲基吡啶纯度高,适合作为高品质的医药中间体原料。(The invention belongs to the field of production of medical intermediates, and particularly discloses a method for preparing pyridine medical intermediates by a one-pot method, which comprises the following steps: putting 2-chloro-5-trichloromethylpyridine into a vacuum reaction kettle, adding a catalyst, setting the vacuum degree to be 0.01-0.1Mpa, heating to 250-400 ℃, introducing excessive fluorine-containing gas for full reaction, and cooling to below 15-25 ℃ to obtain a crude product crystal of 2-chloro-5-trifluoromethylpyridine; and then washing by multiple steps of water, cooling, distilling and crystallizing to obtain the 2-chloro-5-trifluoromethylpyridine with the purity of more than 99.8 percent. The 2-chloro-5-trifluoromethylpyridine obtained by the one-pot method for preparing pyridine medical intermediates has high purity and is suitable for being used as a high-quality medical intermediate raw material.)

1. A method for preparing pyridine medical intermediates by a one-pot method is characterized by comprising the following steps:

s1, putting 2-chloro-5-trichloromethylpyridine into a vacuum reaction kettle, adding a catalyst, setting the vacuum degree to be 0.01-0.1Mpa, heating to 250-400 ℃, introducing excessive fluorine-containing gas for full reaction, and cooling to below 15-25 ℃ to obtain a crude 2-chloro-5-trifluoromethylpyridine crystal;

s2, washing the 2-chloro-5-trifluoromethylpyridine crude product crystal obtained in the step S1 by using ultrapure water at 15-25 ℃, filtering, and drying at a low temperature of 5-10 ℃ until the water content is less than 1%;

s3, cooling the 2-chloro-5-trifluoromethylpyridine crude product crystal obtained in the step S2 to-30 to-60 ℃ overnight;

s4, slowly heating the crude product of the 2-chloro-5-trifluoromethylpyridine obtained in the step S3 to 25 ℃, wherein the heating speed is 0.2-0.5 ℃/min;

s5, placing the 2-chloro-5-trifluoromethylpyridine crude product obtained in the step S4 into vacuum rectification equipment, heating and rectifying for 1-3h, and collecting reflux;

s6, carrying out programmed cooling recrystallization on the reflux obtained in the step S5, wherein the cooling speed is 1-2 ℃/min, cooling to-30 to-60 ℃, and standing overnight to obtain 2-chloro-5-trifluoromethylpyridine crude crystals;

s7, washing the crude 2-chloro-5-trifluoromethylpyridine crystal obtained in the step S6 by using ultrapure water at 15-25 ℃, filtering, and drying at a low temperature of 5-10 ℃ to obtain the 2-chloro-5-trifluoromethylpyridine with the purity of more than 99.8%.

2. The method of claim 1, wherein in step S1, the catalyst is mercuric oxide, 2-chloro-5-trichloromethylpyridine: the mol ratio of the mercuric oxide is 1000:1-10000: 1.

3. The method of claim 1, wherein in step S1, the fluorine-containing gas is hydrogen fluoride.

4. The method for preparing pyridine pharmaceutical intermediates according to claim 1, wherein the step S1 comprises the following steps:

s1, putting 2-chloro-5-trichloromethyl pyridine into a vacuum reaction kettle, adding catalyst mercuric oxide, 2-chloro-5-trichloromethyl pyridine: the molar ratio of mercury oxide is 5000: 1; setting the vacuum degree to 0.05Mpa, heating to 325 ℃, introducing excessive hydrogen fluoride-containing gas, fully reacting, and cooling to below 20 ℃ to obtain the crude 2-chloro-5-trifluoromethylpyridine crystal.

5. The method for preparing pyridine pharmaceutical intermediates according to claim 1, wherein the step S2 comprises the following steps:

s2, washing the crude 2-chloro-5-trifluoromethylpyridine crystal obtained in the step S1 by using ultrapure water at 20 ℃, filtering, and drying at a low temperature of 7 ℃ until the water content is less than 1%.

6. The method for preparing pyridine pharmaceutical intermediates according to claim 1, wherein the step S3 comprises the following steps:

s3, cooling the crude 2-chloro-5-trifluoromethylpyridine crystal obtained in the step S2 to-45 ℃ and staying overnight.

7. The method for preparing pyridine pharmaceutical intermediates according to claim 1, wherein the step S4 comprises the following steps:

s4, slowly heating the crude 2-chloro-5-trifluoromethylpyridine obtained in the step S3 to 25 ℃, wherein the heating speed is 0.3 ℃/min.

8. The method for preparing pyridine pharmaceutical intermediates according to claim 1, wherein the step S5 comprises the following steps:

s5, placing the 2-chloro-5-trifluoromethylpyridine crude product obtained in the step S4 into vacuum rectification equipment, heating and rectifying for 2h, and collecting reflux.

9. The one-pot method for preparing pyridine pharmaceutical intermediates according to claim 1, comprising the following steps:

s1, putting 2-chloro-5-trichloromethyl pyridine into a vacuum reaction kettle, adding catalyst mercuric oxide, 2-chloro-5-trichloromethyl pyridine: the molar ratio of mercury oxide is 5000: 1; setting the vacuum degree to be 0.05Mpa, heating to 325 ℃, introducing excessive hydrogen fluoride-containing gas to fully react, and cooling to below 20 ℃ to obtain 2-chloro-5-trifluoromethylpyridine crude crystals;

s2, washing the 2-chloro-5-trifluoromethylpyridine crude product crystal obtained in the step S1 by using ultrapure water at 20 ℃, filtering, and drying at a low temperature of 7 ℃ until the water content is less than 1%;

s3, cooling the crude 2-chloro-5-trifluoromethylpyridine crystal obtained in the step S2 to-45 ℃ for a night;

s4, slowly heating the crude product of the 2-chloro-5-trifluoromethylpyridine obtained in the step S3 to 25 ℃, wherein the heating speed is 0.3 ℃/min;

s5, placing the 2-chloro-5-trifluoromethylpyridine crude product obtained in the step S4 into vacuum rectification equipment, heating and rectifying for 2h, and collecting reflux;

s6, carrying out programmed cooling recrystallization on the reflux obtained in the step S5, wherein the cooling speed is 1.5 ℃/min, cooling to-45 ℃, and standing overnight to obtain 2-chloro-5-trifluoromethylpyridine crude crystals;

s7, washing the crude 2-chloro-5-trifluoromethylpyridine crystals obtained in the step S6 by using ultrapure water at 20 ℃, filtering, and drying at a low temperature of 7 ℃ to obtain the 2-chloro-5-trifluoromethylpyridine with the purity of more than 99.8%.

10. 2-chloro-5-trifluoromethylpyridine obtained by the one-pot method for preparing a pyridine pharmaceutical intermediate according to any one of claims 1 to 9.

Technical Field

The invention belongs to the field of production of medical intermediates, and particularly discloses a method for preparing pyridine medical intermediates by a one-pot method.

Background

Pyridine (C)₅H₅N) is a six-membered heterocyclic compound containing one nitrogen heteroatom, and is a colorless or yellowish liquid having malodor. Pyridine and its derivatives are collectively called pyridine bases, and include pyridine, 2-methylpyridine, 3-methylpyridine, 2-chloropyridine, cyanopyridine, 2-methyl-5-ethylpyridine, aminopyridine, 2-vinylpyridine, hydroxypyridine, and the like. At present, the quinolone antibacterial drugs developed and put into mass production in China mainly comprise norfloxacin, ciprofloxacin, ofloxacin, enoxacin,Lomefloxacin, fleroxacin, and the like. Wherein, the production of norfloxacin, ciprofloxacin and ofloxacin is the maximum, and accounts for about 98 percent of the total production of domestic fluoroquinolone antibacterial drugs. Quinolones are generally obtained by synthesizing fluorine-containing quinoline compounds from fluorine-containing benzene rings and condensing with piperazine (or methylpiperazine). As fluorite reserves in China are abundant, the fluorite is one of the countries with the largest output of the fluorine-containing medicaments and intermediates in the world, and more than 80 percent of fluorine-containing intermediates are supplied and exported. On the whole, the development of fluorobenzene intermediates in China is early, and the production capacity is generally surplus at present; the development of the benzotrifluoride intermediate is relatively late, and the development speed is relatively high in recent years; however, for heterocyclic aromatic compounds, especially fluorine-containing pyridines, only individual research units and manufacturers in China currently possess the synthesis technology of fluorine-containing pyridine intermediates, so that the fluorine-containing pyridine intermediates will become one of the main directions for the research and development of fluorine-containing intermediates in China in the next few years. The 2-chloro-5-trifluoromethyl pyridine is an organic intermediate with very high application value and is widely applied to the fields of pesticides, medicines, fine chemical engineering and the like. The preparation method mainly comprises the steps of using 3-methylpyridine as a raw material, firstly carrying out chlorination to obtain 2-chloro-5-trichloromethylpyridine, and then further carrying out fluorination to obtain a product, or using 3-methylpyridine as a raw material, and carrying out a fluorine chlorination reaction in the presence of a catalyst to obtain a product. The purity of the 2-chloro-5-trifluoromethyl pyridine obtained by the preparation method is generally not more than 98 percent, so that further optimization of reaction parameters and a purification method is needed, and the product purity is improved.

Disclosure of Invention

In view of the above situation, the invention discloses a method for preparing pyridine pharmaceutical intermediates by a one-pot method, which is used for preparing high-purity pyridine pharmaceutical intermediates.

The technical scheme of the invention is as follows:

a method for preparing pyridine pharmaceutical intermediates by a one-pot method comprises the following steps:

s1, putting 2-chloro-5-trichloromethylpyridine into a vacuum reaction kettle, adding a catalyst, setting the vacuum degree to be 0.01-0.1Mpa, heating to 250-400 ℃, introducing excessive fluorine-containing gas for full reaction, and cooling to below 15-25 ℃ to obtain a crude 2-chloro-5-trifluoromethylpyridine crystal;

s2, washing the 2-chloro-5-trifluoromethylpyridine crude product crystal obtained in the step S1 by using ultrapure water at 15-25 ℃, filtering, and drying at a low temperature of 5-10 ℃ until the water content is less than 1%;

s3, cooling the 2-chloro-5-trifluoromethylpyridine crude product crystal obtained in the step S2 to-30 to-60 ℃ overnight;

s4, slowly heating the crude product of the 2-chloro-5-trifluoromethylpyridine obtained in the step S3 to 25 ℃, wherein the heating speed is 0.2-0.5 ℃/min;

s5, placing the 2-chloro-5-trifluoromethylpyridine crude product obtained in the step S4 into vacuum rectification equipment, heating and rectifying for 1-3h, and collecting reflux;

s6, carrying out programmed cooling recrystallization on the reflux obtained in the step S5, wherein the cooling speed is 1-2 ℃/min, cooling to-30 to-60 ℃, and standing overnight to obtain 2-chloro-5-trifluoromethylpyridine crude crystals;

s7, washing the crude 2-chloro-5-trifluoromethylpyridine crystal obtained in the step S6 by using ultrapure water at 15-25 ℃, filtering, and drying at a low temperature of 5-10 ℃ to obtain the 2-chloro-5-trifluoromethylpyridine with the purity of more than 99.8%.

Further, in the above one-pot method for preparing pyridine pharmaceutical intermediates, in step S1, the catalyst is mercuric oxide, 2-chloro-5-trichloromethylpyridine: the mol ratio of the mercuric oxide is 1000:1-10000: 1.

Further, in the above one-pot method for preparing a pyridine pharmaceutical intermediate, in step S1, the fluorine-containing gas is hydrogen fluoride.

Further, in the above one-pot method for preparing pyridine pharmaceutical intermediates, the step S1 specifically includes:

s1, putting 2-chloro-5-trichloromethyl pyridine into a vacuum reaction kettle, adding catalyst mercuric oxide, 2-chloro-5-trichloromethyl pyridine: the molar ratio of mercury oxide is 5000: 1; setting the vacuum degree to 0.05Mpa, heating to 325 ℃, introducing excessive hydrogen fluoride-containing gas, fully reacting, and cooling to below 20 ℃ to obtain the crude 2-chloro-5-trifluoromethylpyridine crystal.

Further, in the above one-pot method for preparing pyridine pharmaceutical intermediates, the step S2 specifically includes:

s2, washing the crude 2-chloro-5-trifluoromethylpyridine crystal obtained in the step S1 by using ultrapure water at 20 ℃, filtering, and drying at a low temperature of 7 ℃ until the water content is less than 1%.

Further, in the above one-pot method for preparing pyridine pharmaceutical intermediates, the step S3 specifically includes:

s3, cooling the crude 2-chloro-5-trifluoromethylpyridine crystal obtained in the step S2 to-45 ℃ and staying overnight.

Further, in the above one-pot method for preparing pyridine pharmaceutical intermediates, the step S4 specifically includes:

s4, slowly heating the crude 2-chloro-5-trifluoromethylpyridine obtained in the step S3 to 25 ℃, wherein the heating speed is 0.3 ℃/min.

Further, in the above one-pot method for preparing pyridine pharmaceutical intermediates, the step S5 specifically includes:

s5, placing the 2-chloro-5-trifluoromethylpyridine crude product obtained in the step S4 into vacuum rectification equipment, heating and rectifying for 2h, and collecting reflux.

Further, the method for preparing the pyridine pharmaceutical intermediate by the one-pot method comprises the following steps:

s1, putting 2-chloro-5-trichloromethyl pyridine into a vacuum reaction kettle, adding catalyst mercuric oxide, 2-chloro-5-trichloromethyl pyridine: the molar ratio of mercury oxide is 5000: 1; setting the vacuum degree to be 0.05Mpa, heating to 325 ℃, introducing excessive hydrogen fluoride-containing gas to fully react, and cooling to below 20 ℃ to obtain 2-chloro-5-trifluoromethylpyridine crude crystals;

s2, washing the 2-chloro-5-trifluoromethylpyridine crude product crystal obtained in the step S1 by using ultrapure water at 20 ℃, filtering, and drying at a low temperature of 7 ℃ until the water content is less than 1%;

s3, cooling the crude 2-chloro-5-trifluoromethylpyridine crystal obtained in the step S2 to-45 ℃ for a night;

s4, slowly heating the crude product of the 2-chloro-5-trifluoromethylpyridine obtained in the step S3 to 25 ℃, wherein the heating speed is 0.3 ℃/min;

s5, placing the 2-chloro-5-trifluoromethylpyridine crude product obtained in the step S4 into vacuum rectification equipment, heating and rectifying for 2h, and collecting reflux;

s6, carrying out programmed cooling recrystallization on the reflux obtained in the step S5, wherein the cooling speed is 1.5 ℃/min, cooling to-45 ℃, and standing overnight to obtain 2-chloro-5-trifluoromethylpyridine crude crystals;

s7, washing the crude 2-chloro-5-trifluoromethylpyridine crystals obtained in the step S6 by using ultrapure water at 20 ℃, filtering, and drying at a low temperature of 7 ℃ to obtain the 2-chloro-5-trifluoromethylpyridine with the purity of more than 99.8%.

Further, the 2-chloro-5-trifluoromethylpyridine is prepared by the method for preparing the pyridine medical intermediate by the one-pot method.

Compared with the prior art, the invention has the following beneficial effects:

the invention discloses a method for preparing pyridine medical intermediates by a one-pot method. 2-chloro-5-trichloromethylpyridine is used as a raw material, an important medical intermediate 2-chloro-5-trifluoromethylpyridine is obtained by a one-step method, the steps are simple, the reaction is rapid, the purification steps are elaborately set, the purity of the finally obtained 2-chloro-5-trifluoromethylpyridine is more than 99.8%, and the 2-chloro-5-trifluoromethylpyridine can be used for preparing high-quality medicines.

Drawings

FIG. 1 is a molecular formula of 2-chloro-5-trifluoromethylpyridine according to the present invention.

Detailed Description

The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The reagents or instruments used in the examples of the present invention are not indicated by manufacturers, and are all conventional reagent products available from commercial sources.

Example 1

A one-pot method for preparing pyridine pharmaceutical intermediates shown in figure 1 comprises the following steps:

s1, putting 2-chloro-5-trichloromethyl pyridine into a vacuum reaction kettle, adding catalyst mercuric oxide, 2-chloro-5-trichloromethyl pyridine: the molar ratio of mercuric oxide is 1000:1, the vacuum degree is set to be 0.01Mpa, after the mercuric oxide and the mercuric oxide are heated to 250 ℃, excessive hydrogen fluoride is introduced for full reaction, and the temperature is reduced to 15 ℃ to obtain a crude product crystal of 2-chloro-5-trifluoromethylpyridine;

s2, washing the 2-chloro-5-trifluoromethylpyridine crude product crystal obtained in the step S1 by using ultrapure water at 15 ℃, filtering, and drying at a low temperature of 5 ℃ until the water content is less than 1%;

s3, cooling the crude 2-chloro-5-trifluoromethylpyridine crystal obtained in the step S2 to-30 ℃ for a night;

s4, slowly heating the crude product of the 2-chloro-5-trifluoromethylpyridine obtained in the step S3 to 25 ℃, wherein the heating speed is 0.2 ℃/min;

s5, placing the 2-chloro-5-trifluoromethylpyridine crude product obtained in the step S4 into vacuum rectification equipment, heating and rectifying for 1h, and collecting reflux;

s6, carrying out programmed cooling recrystallization on the reflux obtained in the step S5, wherein the cooling speed is 1 ℃/min, cooling to-30 ℃, and standing overnight to obtain 2-chloro-5-trifluoromethylpyridine crude crystals;

s7, washing the crude 2-chloro-5-trifluoromethylpyridine crystal obtained in the step S6 by using ultrapure water at 15-25 ℃, filtering, drying at 5 ℃ to obtain 2-chloro-5-trifluoromethylpyridine, wherein the purity is 99.84% and the yield is 92% by HPLC detection.

Example 2

A one-pot method for preparing pyridine pharmaceutical intermediates shown in figure 1 comprises the following steps:

s1, putting 2-chloro-5-trichloromethyl pyridine into a vacuum reaction kettle, adding catalyst mercuric oxide, 2-chloro-5-trichloromethyl pyridine: the molar ratio of mercury oxide is 5000: 1; setting the vacuum degree to be 0.05Mpa, heating to 325 ℃, introducing excessive hydrogen fluoride-containing gas, fully reacting, and cooling to 20 ℃ to obtain 2-chloro-5-trifluoromethylpyridine crude crystals;

s2, washing the 2-chloro-5-trifluoromethylpyridine crude product crystal obtained in the step S1 by using ultrapure water at 20 ℃, filtering, and drying at a low temperature of 7 ℃ until the water content is less than 1%;

s3, cooling the crude 2-chloro-5-trifluoromethylpyridine crystal obtained in the step S2 to-45 ℃ for a night;

s4, slowly heating the crude product of the 2-chloro-5-trifluoromethylpyridine obtained in the step S3 to 25 ℃, wherein the heating speed is 0.3 ℃/min;

s5, placing the 2-chloro-5-trifluoromethylpyridine crude product obtained in the step S4 into vacuum rectification equipment, heating and rectifying for 2h, and collecting reflux;

s6, carrying out programmed cooling recrystallization on the reflux obtained in the step S5, wherein the cooling speed is 1.5 ℃/min, cooling to-45 ℃, and standing overnight to obtain 2-chloro-5-trifluoromethylpyridine crude crystals;

s7, washing the crude 2-chloro-5-trifluoromethylpyridine crystal obtained in the step S6 by using ultrapure water at 20 ℃, filtering, and drying at a low temperature of 7 ℃ to obtain the 2-chloro-5-trifluoromethylpyridine with the purity of 99.92% and the yield of 93% through detection.

Example 3

A one-pot method for preparing pyridine pharmaceutical intermediates shown in figure 1 comprises the following steps:

s1, putting 2-chloro-5-trichloromethyl pyridine into a vacuum reaction kettle, adding catalyst mercuric oxide, 2-chloro-5-trichloromethyl pyridine: the molar ratio of mercuric oxide is 10000:1, the vacuum degree is set to be 0.1Mpa, after the mercuric oxide and the mercuric oxide are heated to 400 ℃, excessive hydrogen fluoride is introduced to fully react, and the temperature is reduced to 25 ℃ to obtain a crude product crystal of 2-chloro-5-trifluoromethylpyridine;

s2, washing the 2-chloro-5-trifluoromethylpyridine crude product crystal obtained in the step S1 by using ultrapure water at 125 ℃, filtering, and drying at a low temperature of 10 ℃ until the water content is less than 1%;

s3, cooling the crude 2-chloro-5-trifluoromethylpyridine crystal obtained in the step S2 to-60 ℃ for a night;

s4, slowly heating the crude product of the 2-chloro-5-trifluoromethylpyridine obtained in the step S3 to 25 ℃, wherein the heating speed is 0.5 ℃/min;

s5, putting the 2-chloro-5-trifluoromethylpyridine crude product obtained in the step S4 into vacuum rectification equipment, heating and rectifying for 3 hours, and collecting reflux;

s6, carrying out programmed cooling recrystallization on the reflux obtained in the step S5, wherein the cooling speed is 2 ℃/min, cooling to-60 ℃, and standing overnight to obtain 2-chloro-5-trifluoromethylpyridine crude crystals;

s7, washing the crude 2-chloro-5-trifluoromethylpyridine crystal obtained in the step S6 by using ultrapure water at 15-25 ℃, filtering, drying at 10 ℃ to obtain the 2-chloro-5-trifluoromethylpyridine with the purity of 99.87% and the yield of 91% by HPLC detection.

From the above examples, it can be seen that the method for preparing pyridine pharmaceutical intermediates disclosed by the invention uses 2-chloro-5-trichloromethylpyridine as a raw material to obtain the important pharmaceutical intermediate 2-chloro-5-trifluoromethylpyridine by a one-step method, the steps are simple, the reaction is rapid, the purification steps are elaborately set, and the finally obtained 2-chloro-5-trifluoromethylpyridine has a purity of more than 99.8%, and can be used for preparing high-quality drugs.

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.