CN110845426A - Preparation method of 2-chloro-5-cyanopyrimidine compound - Google Patents
Preparation method of 2-chloro-5-cyanopyrimidine compound Download PDFInfo
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- CN110845426A CN110845426A CN201911196983.XA CN201911196983A CN110845426A CN 110845426 A CN110845426 A CN 110845426A CN 201911196983 A CN201911196983 A CN 201911196983A CN 110845426 A CN110845426 A CN 110845426A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D239/30—Halogen atoms or nitro radicals
Abstract
The invention discloses a preparation method of a 2-chloro-5-cyanopyrimidine compound, which adopts a route that cyanoacetic acid is taken as a raw material, dioxane is taken as a solvent to react under the action of N, N-dimethylformamide dimethyl acetal to generate 3- (dimethyl amino) acrylonitrile, and then the 3- (dimethyl amino) acrylonitrile is subjected to Vilsmeier reaction, addition reaction, ring closing reaction and chlorination reaction in sequence to finally obtain a finished product of the 2-chloro-5-cyanopyrimidine compound. The raw materials of the synthetic route provided by the preparation method are cheap and easy to obtain, the post-treatment is simple and easy to purify, and each step of reaction does not need column chromatography purification, so that the technical defects of long route, high raw material cost, column chromatography requirement and the like of other synthetic methods in documents in the prior art can be effectively overcome, the preparation method of the 2-chloro-5-cyanopyrimidine compound provided by the invention has great economic benefit on reduction of the medicine cost, and the preparation method is a technology which is low in cost and suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medical intermediates, and particularly relates to a preparation method of a 2-chloro-5-cyanopyrimidine compound.
Background
The 2-chloro-5-cyanopyrimidine compound is an important medical intermediate for treating cancers, has the CAS number of 1753-50-0 and the molecular weight of 139.54248, and has the following three synthetic routes described in the prior art documents.
Scheme 1: the route disclosed in WO2008110611a1 is as follows:
the synthetic route 1 has low reaction yield, expensive raw materials, heavy metal pollution, complex post-treatment and need of column chromatography, so the synthetic route is not beneficial to industrial production.
Scheme 2: the route disclosed in US20111522952a1 is as follows:
the synthetic route 2 has long reaction route, phosgene which is a highly toxic compound is used in the reaction, and the long reaction route causes low overall synthetic yield and is not beneficial to industrial production.
Scheme 3: the route disclosed in CN108997224A is as follows:
the raw materials of the synthesis route 3 are expensive, particularly the price of the palladium catalyst is continuously increased, and the increase of the raw material cost has great limitation on the industrial production.
Disclosure of Invention
The invention aims to overcome the defects in the prior art, and the invention aims to provide a preparation method of a 2-chloro-5-cyanopyrimidine compound, which is a technology with low cost and suitable for industrial production.
The invention is realized by the following technical scheme: a preparation method of a 2-chloro-5-cyanopyrimidine compound adopts a route that cyanoacetic acid is used as a raw material, dioxane is used as a solvent to react under the action of N, N-dimethylformamide dimethyl acetal to generate 3- (dimethyl amino) acrylonitrile, and then Vilsmeier reaction, addition reaction, ring closing reaction and chlorination reaction are sequentially carried out to finally obtain a finished product of the 2-chloro-5-cyanopyrimidine compound.
The preparation method of the 2-chloro-5-cyanopyrimidine compound specifically comprises the following steps:
step 1: adding 100 parts of cyanoacetic acid and 100 parts of 1, 4-dioxane into a reaction kettle, dropwise adding 168 parts of DMF-DMA, reacting for 16 hours at 20-90 ℃, after the reaction of the raw materials is finished, concentrating at 50 +/-5 ℃ until no liquid is discharged, cooling to 25 +/-5 ℃, adding 150 parts of methyl tert-butyl ether, washing once with 50 parts of saturated sodium bicarbonate, washing once with 80 parts of saturated salt water, drying with 10 parts of anhydrous sodium sulfate, and concentrating until no liquid is discharged to obtain 110 parts of 3- (dimethyl ammonia) acrylonitrile;
step 2: adding 1000 parts of solvent into a reaction kettle, adding 94 parts of N, N-dimethylformamide, cooling to 0 +/-5 ℃, dropwise adding 157 parts of oxalyl chloride, preserving heat at 0 +/-5 ℃ for 1h after adding, dropwise adding 110 parts of 3- (dimethyl ammonia) acrylonitrile, heating to room temperature and stirring for 12h after dropwise adding, concentrating at 50 +/-5 ℃ until no liquid is discharged, adding 80 parts of toluene to carry out twice, cooling to 25 +/-5 ℃, adding 800 parts of isopropanol, dissolving clear solution, adding 106 parts of acid, stirring for 1h to separate out solid, filtering, and drying a filter cake by blowing at 50 +/-5 ℃ for 10h to obtain 72 parts of brown oxalate solid;
and step 3: adding 280 parts of acetonitrile into a reaction kettle, adding 118 parts of pyridine, adding 72 parts of oxalate and 55 parts of O-methoxyisourea sulfate, heating to 80 +/-5 ℃ for reaction for 12 hours, concentrating at 50 +/-5 ℃ until no liquid is discharged, cooling to 25 +/-5 ℃, adding 260 parts of toluene and 350 parts of water, stirring, separating liquid, washing an organic phase once by using 100 parts of saturated salt water, concentrating the organic phase to 70 parts at the temperature of 60 +/-5 ℃, cooling to 25 +/-5 ℃, adding 100 parts of petroleum ether, pulping for 5 hours, filtering, and drying a filter cake by blowing at the temperature of 40 +/-5 ℃ to obtain 17.1 parts of 2-methoxy-4-cyanopyrimidine;
and 4, step 4: adding 120 parts of toluene, 17.1 parts of 2-methoxy-4-cyanopyrimidine and 19.6 parts of N, N-diisopropylethylamine into a reaction kettle, replacing 2 times with nitrogen, adding 52.7 parts of phosphorus pentachloride into five batches, heating to 100 +/-5 ℃, reacting for 16 hours, cooling to 25 +/-5 ℃, pouring the reaction liquid into 400 parts of ice water, stirring for 0.5 hour, pumping 150 parts of ethyl acetate, separating, extracting the aqueous phase once with 100 parts of ethyl acetate, combining organic phases, washing the organic phases once with 170 parts of water, 170 parts of saturated sodium bicarbonate and 170 parts of saturated salt, concentrating at 45 +/-5 ℃ until no liquid is discharged, cooling to 25 +/-5 ℃, adding 30 parts of methyl tert-butyl ether, pulping for 2 hours, filtering, and naturally drying to obtain 8.9 parts of 2-chloro-5-cyanopyrimidine.
In the step 1, 1 to 10ml, preferably 1 to 2ml of 1, 4-dioxane is added to 1g of cyanoacetic acid, and each raw material is reacted at 30 to 35 ℃ for 16 hours.
In step 2, the solvent is 1, 2-dichloroethane or dichloromethane, preferably dichloromethane, and the acid is oxalic acid, p-toluenesulfonic acid or tartaric acid, preferably oxalic acid.
In the step 3, 1.6-1.8 g of the required pyridine and 3-10 ml, preferably 4-6 ml of the required acetonitrile are relative to 1g of oxalate.
In step 4, 3.0-3.1 g of phosphorus pentachloride and 1.1-1.3 g of N, N-diisopropylethylamine are required relative to 1g of 2-methoxy-4-cyanopyrimidine.
The invention has the beneficial effects that: the raw materials of the synthetic route provided by the preparation method of the 2-chloro-5-cyanopyrimidine compound are cheap and easy to obtain, the post-treatment is simple and easy to purify, and column chromatography purification is not needed in each step of reaction.
Drawings
FIG. 1 is a synthetic process diagram of a method for preparing a 2-chloro-5-cyanopyrimidine compound of the present invention.
Detailed Description
The present invention is described in detail below with reference to the drawings and the detailed description, so that those skilled in the art can more clearly and intuitively understand the present invention and provide greater help for the synthesis of the compounds.
As shown in figure 1, the invention discloses a preparation method of a 2-chloro-5-cyanopyrimidine compound, which adopts a route that cyanoacetic acid is taken as a raw material, dioxane is taken as a solvent to react under the action of N, N-dimethylformamide dimethyl acetal to generate 3- (dimethyl amino) acrylonitrile, and then the 3- (dimethyl amino) acrylonitrile is subjected to Vilsmeier reaction, addition reaction, ring closing reaction and chlorination reaction in sequence to finally obtain a finished product of the 2-chloro-5-cyanopyrimidine compound.
The preparation method of the 2-chloro-5-cyanopyrimidine compound specifically comprises the following steps:
step 1: adding 100 parts of cyanoacetic acid and 100 parts of 1, 4-dioxane into a reaction kettle, dropwise adding 168 parts of DMF-DMA, reacting for 16 hours at 20-90 ℃, after the reaction of the raw materials is finished, concentrating at 50 +/-5 ℃ until no liquid is discharged, cooling to 25 +/-5 ℃, adding 150 parts of methyl tert-butyl ether, washing once with 50 parts of saturated sodium bicarbonate, washing once with 80 parts of saturated salt water, drying with 10 parts of anhydrous sodium sulfate, and concentrating until no liquid is discharged to obtain 110 parts of 3- (dimethyl ammonia) acrylonitrile;
step 2: adding 1000 parts of solvent into a reaction kettle, adding 94 parts of N, N-dimethylformamide, cooling to 0 +/-5 ℃, dropwise adding 157 parts of oxalyl chloride, preserving heat at 0 +/-5 ℃ for 1h after adding, dropwise adding 110 parts of 3- (dimethyl ammonia) acrylonitrile, heating to room temperature and stirring for 12h after dropwise adding, concentrating at 50 +/-5 ℃ until no liquid is discharged, adding 80 parts of toluene to carry out twice, cooling to 25 +/-5 ℃, adding 800 parts of isopropanol, dissolving clear solution, adding 106 parts of acid, stirring for 1h to separate out solid, filtering, and drying a filter cake by blowing at 50 +/-5 ℃ for 10h to obtain 72 parts of brown oxalate solid;
and step 3: adding 280 parts of acetonitrile into a reaction kettle, adding 118 parts of pyridine, adding 72 parts of oxalate and 55 parts of O-methoxyisourea sulfate, heating to 80 +/-5 ℃ for reaction for 12 hours, concentrating at 50 +/-5 ℃ until no liquid is discharged, cooling to 25 +/-5 ℃, adding 260 parts of toluene and 350 parts of water, stirring, separating liquid, washing an organic phase once by using 100 parts of saturated salt water, concentrating the organic phase to 70 parts at the temperature of 60 +/-5 ℃, cooling to 25 +/-5 ℃, adding 100 parts of petroleum ether, pulping for 5 hours, filtering, and drying a filter cake by blowing at the temperature of 40 +/-5 ℃ to obtain 17.1 parts of 2-methoxy-4-cyanopyrimidine;
and 4, step 4: adding 120 parts of toluene, 17.1 parts of 2-methoxy-4-cyanopyrimidine and 19.6 parts of N, N-diisopropylethylamine into a reaction kettle, replacing 2 times with nitrogen, adding 52.7 parts of phosphorus pentachloride into five batches, heating to 100 +/-5 ℃, reacting for 16 hours, cooling to 25 +/-5 ℃, pouring the reaction liquid into 400 parts of ice water, stirring for 0.5 hour, pumping 150 parts of ethyl acetate, separating, extracting the aqueous phase once with 100 parts of ethyl acetate, combining organic phases, washing the organic phases once with 170 parts of water, 170 parts of saturated sodium bicarbonate and 170 parts of saturated salt, concentrating at 45 +/-5 ℃ until no liquid is discharged, cooling to 25 +/-5 ℃, adding 30 parts of methyl tert-butyl ether, pulping for 2 hours, filtering, and naturally drying to obtain 8.9 parts of 2-chloro-5-cyanopyrimidine.
In the step 1, 1 to 10ml, preferably 1 to 2ml of 1, 4-dioxane is added to 1g of cyanoacetic acid, and each raw material is reacted at 30 to 35 ℃ for 16 hours.
In step 2, the solvent is 1, 2-dichloroethane or dichloromethane, preferably dichloromethane, and the acid is oxalic acid, p-toluenesulfonic acid or tartaric acid, preferably oxalic acid.
In the step 3, 1.6-1.8 g of the required pyridine and 3-10 ml, preferably 4-6 ml of the required acetonitrile are relative to 1g of oxalate.
In step 4, 3.0-3.1 g of phosphorus pentachloride and 1.1-1.3 g of N, N-diisopropylethylamine are required relative to 1g of 2-methoxy-4-cyanopyrimidine.
Finally, it should be noted that the above-mentioned contents are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, and that the simple modifications or equivalent substitutions of the technical solutions of the present invention by those of ordinary skill in the art can be made without departing from the spirit and scope of the technical solutions of the present invention.
Claims (9)
1. A preparation method of a 2-chloro-5-cyanopyrimidine compound is characterized by comprising the following steps: the preparation method of the 2-chloro-5-cyanopyrimidine compound adopts a route that cyanoacetic acid is used as a raw material, dioxane is used as a solvent to react under the action of N, N-dimethylformamide dimethyl acetal to generate 3- (dimethyl ammonia) acrylonitrile, and then the 3- (dimethyl ammonia) acrylonitrile is subjected to Vilsmeier reaction, addition reaction, ring closing reaction and chlorination reaction in sequence to finally obtain the finished product of the 2-chloro-5-cyanopyrimidine compound.
2. The process for producing a 2-chloro-5-cyanopyrimidine compound according to claim 1, wherein: the preparation method of the 2-chloro-5-cyanopyrimidine compound specifically comprises the following steps:
step 1: adding 100 parts of cyanoacetic acid and 100 parts of 1, 4-dioxane into a reaction kettle, dropwise adding 168 parts of DMF-DMA, reacting for 16 hours at 20-90 ℃, after the reaction of the raw materials is finished, concentrating at 50 +/-5 ℃ until no liquid is discharged, cooling to 25 +/-5 ℃, adding 150 parts of methyl tert-butyl ether, washing once with 50 parts of saturated sodium bicarbonate, washing once with 80 parts of saturated salt water, drying with 10 parts of anhydrous sodium sulfate, and concentrating until no liquid is discharged to obtain 110 parts of 3- (dimethyl ammonia) acrylonitrile;
step 2: adding 1000 parts of solvent into a reaction kettle, adding 94 parts of N, N-dimethylformamide, cooling to 0 +/-5 ℃, dropwise adding 157 parts of oxalyl chloride, preserving heat at 0 +/-5 ℃ for 1h after adding, dropwise adding 110 parts of 3- (dimethyl ammonia) acrylonitrile, heating to room temperature and stirring for 12h after dropwise adding, concentrating at 50 +/-5 ℃ until no liquid is discharged, adding 80 parts of toluene to carry out twice, cooling to 25 +/-5 ℃, adding 800 parts of isopropanol, dissolving clear solution, adding 106 parts of acid, stirring for 1h to separate out solid, filtering, and drying a filter cake by blowing at 50 +/-5 ℃ for 10h to obtain 72 parts of brown oxalate solid;
and step 3: adding 280 parts of acetonitrile into a reaction kettle, adding 118 parts of pyridine, adding 72 parts of oxalate and 55 parts of O-methoxyisourea sulfate, heating to 80 +/-5 ℃ for reaction for 12 hours, concentrating at 50 +/-5 ℃ until no liquid is discharged, cooling to 25 +/-5 ℃, adding 260 parts of toluene and 350 parts of water, stirring, separating liquid, washing an organic phase once by using 100 parts of saturated salt water, concentrating the organic phase to 70 parts at the temperature of 60 +/-5 ℃, cooling to 25 +/-5 ℃, adding 100 parts of petroleum ether, pulping for 5 hours, filtering, and drying a filter cake by blowing at the temperature of 40 +/-5 ℃ to obtain 17.1 parts of 2-methoxy-4-cyanopyrimidine;
and 4, step 4: adding 120 parts of toluene, 17.1 parts of 2-methoxy-4-cyanopyrimidine and 19.6 parts of N, N-diisopropylethylamine into a reaction kettle, replacing 2 times with nitrogen, adding 52.7 parts of phosphorus pentachloride into five batches, heating to 100 +/-5 ℃, reacting for 16 hours, cooling to 25 +/-5 ℃, pouring the reaction liquid into 400 parts of ice water, stirring for 0.5 hour, pumping 150 parts of ethyl acetate, separating, extracting the aqueous phase once with 100 parts of ethyl acetate, combining organic phases, washing the organic phases once with 170 parts of water, 170 parts of saturated sodium bicarbonate and 170 parts of saturated salt, concentrating at 45 +/-5 ℃ until no liquid is discharged, cooling to 25 +/-5 ℃, adding 30 parts of methyl tert-butyl ether, pulping for 2 hours, filtering, and naturally drying to obtain 8.9 parts of 2-chloro-5-cyanopyrimidine.
3. A process for preparing a 2-chloro-5-cyanopyrimidine compound according to claim 2, characterized in that: in the step 1, 1 to 10ml of 1, 4-dioxane is reacted with 1g of cyanoacetic acid at 30 to 35 ℃ for 16 hours.
4. A process for preparing a 2-chloro-5-cyanopyrimidine compound according to claim 2, characterized in that: in the step 2, the solvent is 1, 2-dichloroethane or dichloromethane, and the acid is oxalic acid, p-toluenesulfonic acid or tartaric acid.
5. A process for preparing a 2-chloro-5-cyanopyrimidine compound according to claim 2, characterized in that: in the step 3, 1.6-1.8 g of required pyridine and 3-10 ml of required acetonitrile are relative to 1g of oxalate.
6. A process for preparing a 2-chloro-5-cyanopyrimidine compound according to claim 2, characterized in that: in the step 4, 3.0-3.1 g of phosphorus pentachloride and 1.1-1.3 g of N, N-diisopropylethylamine are required relative to 1g of 2-methoxy-4-cyanopyrimidine.
7. A process for preparing a 2-chloro-5-cyanopyrimidine compound according to claim 3, characterized in that: in the step 1, the amount of 1, 4-dioxane is 1 to 2ml relative to 1g cyanoacetic acid.
8. The process for producing a 2-chloro-5-cyanopyrimidine compound according to claim 4, wherein: in the step 2, the solvent is dichloromethane, and the acid is oxalic acid.
9. The process for producing a 2-chloro-5-cyanopyrimidine compound according to claim 5, wherein: in the step 3, 4-6 ml of acetonitrile is required relative to 1g of oxalate.
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