CN108997224B - Preparation method of 2-chloro-5-cyano nitrogen-containing six-membered heterocyclic compound - Google Patents
Preparation method of 2-chloro-5-cyano nitrogen-containing six-membered heterocyclic compound Download PDFInfo
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- 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
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Abstract
The invention provides a preparation method of a 2-chloro-5-cyano nitrogen-containing six-membered heterocyclic compound, which comprises the steps of taking a 2-hydroxy-5-bromo nitrogen-containing six-membered heterocyclic compound as a raw material, taking methanol as a solvent in the presence of a catalyst in a carbon monoxide gas atmosphere, carrying out a coupling reaction to obtain 2-hydroxy nitrogen-containing six-membered heterocyclic-5-carboxylic acid methyl ester, and then carrying out a chlorination reaction and an oxidation reaction with phosphorus oxychloride sequentially to obtain the 2-chloro-5-cyano nitrogen-containing six-membered heterocyclic compound; the preparation method of the 2-chloro-5-cyano nitrogen-containing six-membered heterocyclic compound provided by the invention has the advantages of short route, easily available raw materials, simple post-treatment method, no need of column chromatography treatment after each step of reaction, purification of the reaction product by washing and extraction of a solvent, capability of realizing amplification, industrial production, environment-friendly requirement compliance and important value for practical production.
Description
Technical Field
The invention belongs to the field of synthesis of medical intermediates, and relates to a preparation method of a 2-chloro-5-cyano nitrogen-containing six-membered heterocyclic compound.
Background
The 2-chloro-5-cyano nitrogen-containing six-membered heterocyclic compound is an important medical intermediate for preparing new drugs for treating diabetes, cancer and the like. Wherein, the 2-chloro-5-cyanopyrimidine has the CAS number of 1753-50-0 and the molecular weight of 139.54248, and the existing synthetic route mainly comprises the following two types.
The route disclosed in WO 200810611 A1 is as follows:
the raw materials of the route are high in price, low in yield and poor in reproducibility, diazotization is used, safety is poor, a large amount of wastewater is generated, cuCN is used, a large amount of copper salt waste is generated, post-treatment is complex, purification is needed through column chromatography, and production cannot be carried out in a kilogram level, so that the production efficiency is greatly limited, and industrialization is not facilitated.
Another route disclosed in US20111522952A1 is as follows:
the method discloses a route, the ring-synthesizing compound obtained after 4 steps of reaction still needs 5 steps of reaction to complete, the reaction route is long, and phosgene which is a high-toxicity substance is used in the reaction process, so that the whole yield of the route is low, the pollution is large, and the method cannot be applied to industrial production.
The existing synthetic method of 2-chloro-5-cyanopyridine takes cyanopyridine as a raw material, and the 2-chloro-5-cyanopyridine is obtained through chlorination reaction, and by-products such as 2-chloro-3-cyanopyridine and the like are inevitably generated in the chlorination process. The two substances have very similar physical and chemical properties, and the subsequent separation is very difficult, so the purity of the 2-chloro-5-cyanopyridine is difficult to improve, and the 2-chloro-5-cyanopyridine is greatly restricted as a medicinal raw material and has high cost.
CN104072414a discloses a preparation method of cyanopyridine, which comprises preparing mixed solution of picoline, ammonia and water, preheating, feeding the mixed solution and air into a fixed bed reactor filled with catalyst for catalytic ammoxidation, introducing high-temperature steam flowing out of the fixed bed reactor into cooling water, dissolving the reaction material in water, and extracting the reaction product, wherein the catalyst is composed of vanadium, iron, molybdenum, chromium, bismuth, potassium, phosphorus and carrier. However, the catalyst for preparing the cyanopyridine is complex, has high cost, and is not easy to control the generation of byproducts if the catalyst is used for preparing the chloro-substituted cyanopyridine in the subsequent process, thus being unfavorable for practical industrial production.
Therefore, how to develop a preparation method of 2-chloro-5-cyano nitrogen-containing six-membered heterocyclic compound, so as to achieve few byproducts, be suitable for industrial amplification, have important value for the production of the compound, and simultaneously provide guarantee for the production of downstream products and the reduction of the production cost of medicines.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of a 2-chloro-5-cyano nitrogen-containing six-membered heterocyclic compound, so as to facilitate industrialized mass production.
To achieve the purpose, the invention adopts the following technical scheme:
the invention provides a preparation method of a 2-chloro-5-cyano nitrogen-containing six-membered heterocyclic compound, which comprises the steps of taking a 2-hydroxy-5-bromo nitrogen-containing six-membered heterocyclic compound as a raw material, under the existence of a catalyst, taking methanol as a solvent to perform a coupling reaction to obtain 2-hydroxy nitrogen-containing six-membered heterocyclic-5-carboxylic acid methyl ester, and then sequentially performing ammonolysis reaction, chlorination reaction and oxidation reaction with phosphorus oxychloride to obtain the 2-chloro-5-cyano nitrogen-containing six-membered heterocyclic compound;
wherein the nitrogen-containing six-membered heterocyclic ring is pyridine or pyrimidine.
When the nitrogen-containing six-membered heterocyclic ring is pyrimidine, the specific reaction route is as follows:
when the nitrogen-containing six-membered heterocyclic ring is pyridine, the specific reaction route is as follows:
the preparation method of the 2-chloro-5-cyano nitrogen-containing six-membered heterocyclic compound provided by the invention has the advantages of short route, easily obtained raw materials, simple post-treatment method, no need of column chromatography treatment after each reaction step, purification of reaction products only by washing and extracting solvents, and compared with the existing method for synthesizing the compound, which has the defects of long route, more waste materials (such as copper salt and other waste materials), high toxic substances such as phosgene and the like, and need of column chromatography purification, the method can realize amplification, carry out industrial production, has less waste materials generated in the production process, meets the environmental protection requirement, and has important value for practical production.
The preparation method provided by the invention not only provides a synthesis strategy for compounds such as cyano pyrimidine, but also provides a synthesis strategy for compounds such as methyl carboxylate, amide pyrimidine, and the like, which are intermediates generated in the reaction process.
Preferably, the catalyst is a [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex.
Preferably, the amount of methanol used is 8 to 12mL, for example, 8mL, 8.5mL, 9mL, 9.5mL, 10mL, 10.5mL, 11mL, 11.5mL, 12mL, etc., based on 1g of the 2-hydroxy-5-bromo-nitrogen-containing six-membered heterocyclic ring.
Preferably, the catalyst is used in an amount of 0.03 to 0.08g, for example, 0.03g, 0.04g, 0.05g, 0.06g, 0.07g, 0.08g, or the like, relative to 1g of the 2-hydroxy-5-bromo nitrogen-containing six-membered heterocyclic ring.
Preferably, the coupling reaction further comprises triethylamine.
Preferably, the amount of triethylamine is 1.1 to 1.3g, for example, 1.1g, 1.15g, 1.16g, 1.18g, 1.19g, 1.2g, 1.25g, 1.26g, 1.28g, 1.29g, 1.3g, or the like, based on 1g of 2-hydroxy-5-bromo nitrogen-containing six-membered heterocyclic ring.
In the invention, after the coupling reaction, the product 2-hydroxy nitrogen-containing six-membered heterocyclic-5-carboxylic acid methyl ester can be purified by using diatomite for filtration and methanol for washing, and complex post-treatment operation is not needed.
Preferably, the pressure of the coupling reaction is 0.5 to 0.8MPa, and may be, for example, 0.5MPa, 0.55MPa, 0.6MPa, 0.65MPa, 0.7MPa, 0.75MPa, 0.8MPa, or the like.
Preferably, the coupling reaction is carried out at a temperature of 100 to 110℃and may be carried out at, for example, 100℃101℃102℃103℃104℃105℃106℃107℃108℃109℃110 ℃.
In the present invention, the pressure and the temperature are controlled in the above range at the same time, so that the smooth progress of the reaction can be ensured, and the yield can be maximized. If the pressure and the temperature are too high, potential safety hazards can be generated; if the pressure and temperature are too low, the reaction time is too long, and the reaction yield is lowered.
Preferably, the coupling reaction time is 90 to 100h, and may be, for example, 90h, 91h, 92h, 93h, 94h, 95h, 96h, 97h, 98h, 99h, 100h, or the like.
Preferably, the ammonolysis reaction is: 2-hydroxy nitrogen-containing six-membered heterocyclic-5-carboxylic acid methyl ester reacts with ammonia water in methanol.
In the present invention, an amide compound is produced after the ammonolysis reaction.
Preferably, the amount of the aqueous ammonia to be used is 3.5 to 5mL, for example, 3.5mL, 3.7mL, 3.8mL, 3.9mL, 4mL, 4.2mL, 4.6mL, 4.8mL, 4.9mL or 5mL, based on 1g of the methyl 2-hydroxy nitrogen-containing six-membered heterocyclic-5-carboxylate.
Preferably, the concentration of the aqueous ammonia is 28wt.% to 30wt.%, for example, 28wt.%, 28.4wt.%, 28.6wt.%, 28.9wt.%, 29.4wt.%, 29.6wt.%, 29.8wt.%, or 30wt.%, etc.
Preferably, the ammonolysis reaction is carried out at a temperature of 30 to 35℃and may be carried out at 30℃31℃32℃33℃34℃35℃or the like.
Preferably, the ammonolysis reaction is carried out for 90 to 100 hours, for example, 90 hours, 91 hours, 92 hours, 93 hours, 94 hours, 95 hours, 96 hours, 97 hours, 98 hours, 99 hours or 100 hours.
Preferably, the phosphorus oxychloride is used in an amount of 5 to 7mL, for example, 5mL, 5.5mL, 6mL, 6.5mL, 7mL, etc., based on 1g of the methyl 2-hydroxy nitrogen-containing six-membered heterocyclic-5-carboxylate.
In the invention, phosphorus oxychloride is used as a raw material, so that the chlorination reaction and the oxidation reaction are carried out in the same reaction, the process flow is simplified, and the reaction temperature is only required to be properly adjusted; in the prior method, as disclosed in US20111522952A1, the chlorination of the 2-position is carried out until the cyano group is finally synthesized, and the intermediate reaction route is up to 4-5 steps, so that the production cost is greatly increased, the consumed reaction time is shortened, and the industrial production is not facilitated.
Preferably, the temperature of the chlorination reaction is 50 to 55 ℃, and may be 50 ℃, 51 ℃, 52 ℃, 53 ℃, 54 ℃, 55 ℃ or the like, for example.
Preferably, the chlorination reaction time is 2 to 3 hours, and may be, for example, 2 hours, 2.1 hours, 2.2 hours, 2.3 hours, 2.4 hours, 2.5 hours, 2.6 hours, 2.7 hours, 2.8 hours, 2.9 hours, or 3 hours.
Preferably, after 2-3 hours of chlorination reaction, an acid binding agent is directly added into the reaction liquid to perform oxidation reaction.
In the reaction process of the invention, the chlorination reaction is carried out while a small part of oxidation reaction is carried out, but the oxidation reaction is slow in process, and when the chlorination reaction is basically complete, the acid binding agent is added to promote the oxidation reaction, and the oxidation reaction is dominant.
Preferably, the acid binding agent is N, N-diisopropylethylamine.
In the present invention, the addition amount of the acid-binding agent can be appropriately adjusted by those skilled in the art according to the actual reaction conditions.
Preferably, the temperature of the oxidation reaction is 75 to 85 ℃, and may be, for example, 75 ℃, 76 ℃, 77 ℃, 78 ℃, 79 ℃, 80 ℃, 81 ℃, 82 ℃, 83 ℃, 84 ℃, 85 ℃, or the like.
Preferably, the time of the oxidation reaction is 20 to 25 hours, and may be, for example, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, or the like.
Preferably, after the oxidation reaction is finished, the method further comprises the steps of cooling the reaction solution to room temperature, concentrating, extracting and washing to obtain the 2-chloro-5-cyano nitrogen-containing six-membered heterocyclic compound.
In the present invention, after the reaction is completed, the temperature is reduced to room temperature, the reaction solution is generally concentrated under reduced pressure to a proper volume, the extraction is performed by using an extractant, and then the final product is obtained by washing with an alkali solution such as sodium bicarbonate aqueous solution.
Preferably, the extraction is performed using an extractant.
Preferably, the extractant comprises any one or a combination of at least two of methyl tertiary butyl ether, petroleum ether, tetrahydrofuran or 2-methyltetrahydrofuran; methyl tertiary butyl ether is preferred.
In the invention, when methyl tertiary butyl ether is used as an extracting agent, the extracting effect is optimal, and the extracting effect of other extracting agents is poor, for example, the solubility of petroleum ether in the petroleum ether is too low, so that the product loss can be caused; and as tetrahydrofuran and the like, all raw materials and impurities have better solubility in the solvents, so that the final product contains more impurities.
As a preferred technical scheme, the preparation method provided by the invention comprises the following steps:
(1) Taking 2-hydroxy-5-bromine nitrogen-containing six-membered heterocyclic compound as a raw material, and carrying out coupling reaction for 90-100 hours under the conditions that methanol is used as a solvent and triethylamine is used as alkali under the pressure of 0.5-0.8 MPa and the temperature of 100-110 ℃ in the presence of [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex to obtain 2-hydroxy nitrogen-containing six-membered heterocyclic-5-carboxylic acid methyl ester;
(2) Carrying out ammonolysis reaction on 2-hydroxyl nitrogen-containing six-membered heterocyclic-5-carboxylic acid methyl ester and ammonia water in methanol at 30-35 ℃ for 90-100 h to obtain 2-hydroxyl nitrogen-containing six-membered heterocyclic-5-formamide; wherein the ammonia concentration is 28wt.% to 30wt.%;
(3) And (3) carrying out chlorination reaction on 2-hydroxyl nitrogen-containing six-membered heterocyclic-5-formamide and phosphorus oxychloride at 50-55 ℃ for 2-3 hours, then continuously adding an acid binding agent, adjusting the temperature to 75-85 ℃ for oxidation reaction for 20-25 hours, cooling the reaction solution to room temperature, concentrating under reduced pressure, extracting by using an extracting agent, washing to neutrality, and further concentrating to obtain the 2-chloro-5-cyano nitrogen-containing six-membered heterocyclic compound.
The purity of the product 2-chloro-5-cyano nitrogen-containing six-membered heterocyclic compound prepared by the preparation method provided by the invention is generally over 99%, while the purity of the product prepared by the prior art method is generally only about 97%. Compared with the existing method, the method provided by the invention has the advantage that the purity of the product is greatly improved.
Compared with the prior art, the invention has the following beneficial effects:
the preparation method of the 2-chloro-5-cyano nitrogen-containing six-membered heterocyclic compound provided by the invention has the advantages of short route, easily obtained raw materials, simple post-treatment method, no need of column chromatography treatment after each reaction step, and purification of reaction products by washing and extracting the solvent. In particular to the amplified production of cyanopyrimidine or cyanopyridine compounds, which has important reference value and provides a new strategy for the actual amplified production.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
Example 1
This example prepared 2-chloro-5-cyanopyrimidine by the following procedure, the reaction scheme is as follows:
(1) 26 kg of 2-hydroxy-5-bromopyrimidine, 260 liters of methanol, 30 kg of Triethylamine (TEA) and [1,1' -bis (diphenylphosphine) ferrocene were charged into an autoclave]Palladium dichloride dichloromethane Complex (Pd (dppf) Cl) 2 ) 1 kg of carbon monoxide (CO) is replaced after the addition, the pressure is 0.6MPa, the temperature is raised to 105 ℃, the reaction is carried out for 95 hours, the reaction liquid is cooled to room temperature after the raw materials are reacted completely, the filtration is carried out, a small amount of methanol is used for leaching the filter cake, the filtrate is concentrated to 60 liters, then 29wt.% ammonia water is added for 18 kg, the stirring is carried out for 4 hours at the room temperature, the filtration is carried out, 14 liters of methanol is used for leaching the filter cake, and the filter cake is dried at 55 ℃ to obtain 26 kg of 2-hydroxypyrimidine-5-carboxylic acid methyl ester.
(2) 26 kg of 2-hydroxypyrimidine-5-carboxylic acid methyl ester and 29wt.% of ammonia water 106L are added into a reaction bottle, the temperature is raised to 32 ℃ in a sealing way, the reaction is carried out for 95 hours, the raw materials are completely reacted, the filtration is carried out, 14L of methanol is used for leaching a filter cake, and then the filter cake is baked at 55 ℃ for 24 hours, so that 9 kg of 2-hydroxypyrimidine-5-formamide is obtained.
(3) 1 kg of 2-hydroxy pyrimidine-5-formamide is added into a reaction bottle, 8L of phosphorus oxychloride is slowly added, the temperature of the reaction solution is raised to 53 ℃ for 2.5 hours of reaction, 3 kg of N, N-Diisopropylethylamine (DIPEA) is slowly added, after the raw materials react for 23 hours at 80 ℃, the reaction solution is cooled to room temperature, the reaction solution is concentrated to 4.5L under reduced pressure, 5L of methyl tertiary butyl ether is used for extraction, the methyl tertiary butyl ether solution is washed to be neutral by saturated sodium bicarbonate aqueous solution, 0.6 kg of 2-chloro-5-cyano pyrimidine is obtained by concentration, and the final yield is about 26.06 percent according to the input amount of the raw materials 2-hydroxy-5-bromo pyrimidine.
1 H NMR(300MHz,CDCl 3 ):δ8.94(2H,s)。
MS(m/z)＝139.0,141.0。
Example 2
This example prepared 2-chloro-5-cyanopyridine by the following procedure, the reaction scheme is as follows:
(1) 26 kg of 2-hydroxy-5-bromopyridine, 208 liters of methanol, 28.6 kg of triethylamine, 0.78 kg of [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex are added into an autoclave, carbon monoxide is replaced after the addition, the pressure is 0.5MPa, the temperature is raised to 100 ℃, the reaction time is 90 hours, after the raw materials react completely, the reaction solution is cooled to room temperature, the filtration is carried out, a small amount of methanol is used for leaching a filter cake, the filtrate is concentrated to 50 liters, then 28wt.% ammonia water is added for 18 kg, stirring is carried out for 3 hours at room temperature, the filtration is carried out, 13 liters of methanol is used for leaching the filter cake, and the filter cake is dried at 50 ℃ to obtain 24 kg of 2-hydroxypyridine-5-carboxylic acid methyl ester.
(2) 24 kg of 2-hydroxypyridine-5-carboxylic acid methyl ester and 100L of 28wt.% ammonia water are added into a reaction bottle, the temperature is raised to 30 ℃ in a sealing way, the reaction is carried out for 90 hours, the raw materials are completely reacted, the filtration is carried out, 13L of methanol is used for leaching a filter cake, and then the filter cake is baked for 20 hours at 50 ℃ to obtain 8.1 kg of 2-hydroxypyridine-5-formamide.
(3) 1 kg of 2-hydroxypyridine-5-formamide is added into a reaction bottle, 7.2 liters of phosphorus oxychloride is slowly added, the temperature of the reaction solution is raised to 50 ℃, 3.2 kg of N, N-diisopropylethylamine is slowly added, the reaction is carried out for 20 hours at 75 ℃, after the raw materials react completely, the reaction solution is cooled to room temperature, the reaction solution is concentrated to 4 liters under reduced pressure, 5.3 liters of methyl tertiary butyl ether is used for extraction, the methyl tertiary butyl ether solution is washed to be neutral by saturated sodium bicarbonate aqueous solution, 0.52 kg of 2-chloro-5-cyanopyridine is obtained by concentration, and the final yield is about 20.34 percent according to the input amount of the raw materials 2-hydroxy-5-bromopyridine.
1 H NMR(300MHz,CDCl 3 ):δ8.72(1H,d,J＝2.1Hz),δ7.95(1H,dd,J＝8.4,2.4Hz),δ7.51(1H,d,J＝8.4Hz)。
MS(m/z)＝138.0,140.0。
Example 3
This example prepared 2-chloro-5-cyanopyrimidine by the following procedure, the reaction scheme is as follows:
(1) 26 kg of 2-hydroxy-5-bromopyrimidine, 312 liters of methanol, 33.8 kg of triethylamine, 2.08 kg of [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex are added into an autoclave, carbon monoxide is replaced after the addition, the pressure is 0.8MPa, the temperature is raised to 110 ℃, the reaction is carried out for 100 hours, after the raw materials react completely, the reaction solution is cooled to room temperature and filtered, a small amount of methanol is used for leaching a filter cake, the filtrate is concentrated to 70 liters, then 30wt.% ammonia water is added for 18 kg, stirring is carried out for 5 hours at room temperature, filtering is carried out, 15 liters of methanol is used for leaching the filter cake, and the filter cake is dried at 60 ℃ to obtain 25.5 kg of 2-hydroxypyrimidine-5-carboxylic acid methyl ester.
(2) 26 kg of 2-hydroxypyrimidine-5-carboxylic acid methyl ester and 106 liters of 30wt.% ammonia water are added into a reaction bottle, the temperature is raised to 35 ℃ in a sealing way, the reaction is carried out for 100 hours, the raw materials are completely reacted, the filtration is carried out, 15 liters of methanol is used for leaching a filter cake, and then the filter cake is baked at 60 ℃ for 25 hours, so that 8.8 kg of 2-hydroxypyrimidine-5-formamide is obtained.
(3) 1 kg of 2-hydroxy pyrimidine-5-formamide is added into a reaction bottle, 13 kg of phosphorus oxychloride is slowly added, the temperature of the reaction solution is raised to 55 ℃, 3.3 kg of N, N-diisopropylethylamine is slowly added, the reaction is carried out for 25 hours at 85 ℃, after the raw materials are reacted completely, the reaction solution is cooled to room temperature, reduced pressure is concentrated to 5 l, 4.8 l of methyl tertiary butyl ether is used for extraction, the methyl tertiary butyl ether solution is washed to be neutral by saturated sodium bicarbonate aqueous solution, 0.58 kg of 2-chloro-5-cyano pyrimidine is obtained by concentration, and the final yield is about 24.63 percent according to the input amount of the raw materials 2-hydroxy-5-bromo pyrimidine.
1 H NMR(300MHz,CDCl 3 ):δ8.94(2H,s)。
MS(m/z)＝139.0,141.0。
Example 4
This example differs from example 1 only in that the coupling reaction in step (1) was carried out at a pressure of 0.3MPa and a temperature of 80℃and the remainder were the same as in example 1, to finally obtain 0.52 kg of 2-chloro-5-cyanopyrimidine.
Example 5
This example differs from example 1 only in that after the reaction in step (3) is completed, tetrahydrofuran is used for extraction, and the remainder is the same as example 1, and 0.45 kg of 2-chloro-5-cyanopyrimidine product is finally obtained.
From a comparison of examples 4 and 5 with example 1, it is understood that the present invention provides a preparation method in which the pressure must be controlled within a reasonable range and extraction with methyl t-butyl ether is required in the final post-reaction treatment step, which would otherwise result in a reduced yield of the product.
The applicant states that the present invention is illustrated by the above examples as a process for preparing the 2-chloro-5-cyano nitrogen-containing six-membered heterocyclic compound of the present invention, but the present invention is not limited to the above detailed process, i.e., it does not mean that the present invention must be carried out depending on the above detailed process. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
Claims (7)
1. A method for preparing a 2-chloro-5-cyano nitrogen-containing six-membered heterocyclic compound, the method comprising:
(1) Taking 2-hydroxy-5-bromine nitrogen-containing six-membered heterocyclic compound as a raw material, and carrying out coupling reaction for 90-100 hours under the conditions that methanol is used as a solvent and triethylamine is used as alkali under the pressure of 0.5-0.8 MPa and the temperature of 100-110 ℃ in the presence of [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex to obtain 2-hydroxy nitrogen-containing six-membered heterocyclic-5-carboxylic acid methyl ester;
(2) Carrying out ammonolysis reaction on 2-hydroxyl nitrogen-containing six-membered heterocyclic-5-carboxylic acid methyl ester and ammonia water in methanol at 30-35 ℃ for 90-100 h to obtain 2-hydroxyl nitrogen-containing six-membered heterocyclic-5-formamide; wherein the ammonia concentration is 28wt.% to 30wt.%;
(3) Carrying out chlorination reaction on 2-hydroxyl nitrogen-containing six-membered heterocyclic-5-formamide and phosphorus oxychloride at 50-55 ℃ for 2-3 hours, then continuously adding an acid binding agent, adjusting the temperature to 75-85 ℃ for oxidation reaction for 20-25 hours, then cooling the reaction solution to room temperature, concentrating under reduced pressure, extracting by using an extracting agent, washing to neutrality, and further concentrating to obtain the 2-chlorine-5-cyano nitrogen-containing six-membered heterocyclic compound;
wherein the nitrogen-containing six-membered heterocyclic ring is pyridine or pyrimidine;
the acid binding agent is N, N-diisopropylethylamine.
2. The process according to claim 1, wherein the amount of methanol used is 8 to 12mL relative to 1g of the 2-hydroxy-5-bromo-nitrogen-containing six-membered heterocyclic ring.
3. The preparation method according to claim 1, wherein the [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex is used in an amount of 0.03 to 0.08g relative to 1g of the 2-hydroxy-5-bromo nitrogen-containing six-membered heterocycle.
4. The process according to claim 1, wherein the amount of triethylamine is 1.1 to 1.3g based on 1g of the 2-hydroxy-5-bromo nitrogen-containing six-membered heterocyclic ring.
5. The process according to claim 1, wherein the amount of the aqueous ammonia is 3.5 to 5mL relative to 1g of the methyl 2-hydroxy nitrogen-containing six-membered heterocyclic-5-carboxylate.
6. The method according to claim 1, wherein the phosphorus oxychloride is used in an amount of 5 to 7mL relative to 1g of the methyl 2-hydroxy nitrogen-containing six-membered heterocyclic-5-carboxylate.
7. The method of claim 1, wherein the extractant is methyl tert-butyl ether.
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