CN109912454B - Synthesis method of mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile - Google Patents
Synthesis method of mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile Download PDFInfo
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Abstract
The invention belongs to the field of medical chemistry, particularly belongs to the field of organic synthesis in medical chemistry, and more particularly relates to a synthesis method of a mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile. The method comprises the steps of obtaining an intermediate compound II by reacting acetonitrile and formic ether under the action of alcohol alkali metal salt, and reacting the intermediate compound II with diethyl sulfate under the action of a phase transfer catalyst to obtain a target mixture compound I, namely a mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile. The synthesis method of the mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile disclosed by the invention has the advantages of low raw material cost, relatively mild reaction conditions, simplicity in operation, high yield and the like, and is a method suitable for industrial production and application.
Description
Technical Field
The invention belongs to the field of medical chemistry, particularly belongs to the field of organic synthesis in medical chemistry, and more particularly relates to a synthesis method of a mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile.
Background
3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile are important pharmaceutical intermediates for the synthesis of cytosine, cytosine derivatives, and precursors of vitamin B l. In recent years, as a group of patent protection period related to anti-HIV, anti-hepatitis B virus and other marketable drugs expires, the dosage of cytosine intermediate as an essential intermediate thereof increases along with the great increase of the production capacity of corresponding drugs.
Therefore, the synthesis process of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile has become a hot spot of research at home and abroad in the field at present.
At present, common methods for synthesizing a mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile at home and abroad comprise the following steps:
the first method is reported in US4525310 in 1983, and this patent document discloses a method in which acetonitrile, sodium methoxide and ethyl formate are used as raw materials, and 3-hydroxyacrylonitrile sodium salt (NaOCH ═ CHCN) is formed with CO gas under 40 to 50 atmospheres, and further etherified with ethanol hydrochloride to form 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile.
The chemical reaction formula is as follows:
the disadvantages of this process are: (1) the reaction pressure is high, and it is known that in industrial production, the pressure condition is too high, which not only obviously increases the production cost, but also has severe requirements on production conditions and production equipment, and has large potential safety hazard; (2) the raw materials are incompletely reacted, the reaction balance of different reactions is different, and in a specific reaction, after the reaction balance is achieved, the raw materials can not be further reacted to generate a product, so that a certain amount of raw materials exist in the product, the yield of the whole reaction is reduced, the subsequent purification process is influenced, the difficulty in purifying the product is increased, and the purity of the product is reduced.
The second method is reported in the publication 2012,53(7):429-431, which discloses that 1,1,3, 3-tetraethoxypropane and hydroxylamine hydrochloride are used as starting materials, isoxazole is synthesized, and then the isoxazole and diethyl sulfate are used for preparing a mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile under alkaline conditions, and the method can overcome the problem of low yield of the first method, and the total yield can reach 78%, but the 1,1,3, 3-tetraethoxypropane used as the raw material in the method is expensive and is not suitable for industrial production.
Disclosure of Invention
The invention aims to solve the technical problem of providing a novel synthesis method of a mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile, which is suitable for industrial production and application. The industrial application of the method mainly considers the following aspects: (1) the reaction conditions are relatively mild, and particularly the pressure conditions are not too high, so that the safety problem is avoided, the production cost can be reduced, and high-pressure equipment and the like are not required to be equipped; (2) the raw material cost is low; (3) the reaction yield is high; (4) the reaction process is simple and easy to operate and implement; (5) the crude product has less impurities and low purification difficulty, and a high-purity target product is easy to obtain.
In order to solve the technical problem, the invention discloses a method for synthesizing a mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile, which comprises the steps of obtaining an intermediate compound II by reacting acetonitrile and formic ether under the action of an alcohol alkali metal salt, and then reacting the intermediate compound II with diethyl sulfate under the action of a phase transfer catalyst to obtain a target compound I, namely a mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile.
The synthetic route of the method is as follows:
wherein R is1,R2Independently selected from alkyl, aryl, or aralkyl;
m is an alkali metal ion.
Further preferably, R is1,R2Independently selected from methyl or ethyl.
Further preferably, M is sodium ion or potassium ion.
Wherein the phase transfer catalyst can be any one of quaternary ammonium salt, polyethylene glycol and crown ether. And further preferably, when a crown ether is used as the phase transfer catalyst, it is preferably 15-crown-5 ether.
In a preferred technical scheme, the invention further discloses that the solvent is any one of dichloromethane, tetrahydrofuran, toluene or acetonitrile or a mixed solution of two or more of the two or more of the two or the two of the two or the two of the two or the two of the two are soluble solvents. Of these, acetonitrile is particularly preferred as the solvent.
In a preferred embodiment, the molar ratio of the alcohol alkali metal salt to the formate is 1: (1-3).
Preferably, the molar ratio of the alcohol alkali metal salt to the acetonitrile is 1: (1-20).
In a preferred embodiment, the amount of the phase transfer catalyst added is 0.5-7.0 wt% of the amount of the alcohol alkali metal salt added.
In a preferred technical scheme, the molar ratio of the diethyl sulfate to the alcohol alkali metal salt is (0.5-2.0): 1.
the present inventors have unexpectedly found that, when diethyl sulfate is used as a reaction raw material, the larger the amount of diethyl sulfate added is, the better the addition amount is, which is not considered by conventional thinking, the more preferable the addition amount is, the proper amount range is controlled, that is, the molar ratio of diethyl sulfate to alcohol alkali metal salt disclosed in the present invention is (0.5 to 2.0): 1, the yield of the final target product mixture is significantly high, and the yield is reduced by too little or too much diethyl sulfate.
Further, the invention also discloses a specific process for synthesizing the mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile, which comprises the following steps:
s1: firstly, dissolving an alcohol alkali metal salt in acetonitrile, then adding formic ether under the low-temperature condition of below zero ℃, then heating a reaction system to 100-130 ℃, reacting under the atmospheric pressure condition of 1-4MPa, and cooling after the reaction is finished to obtain an intermediate product containing a compound II; preferred low temperature conditions here are-5 ℃ to 0 ℃;
s2: diluting an intermediate product containing a compound II by using a solvent, then adding a phase transfer catalyst, diethyl sulfate and organic alkali, reacting completely at 30-60 ℃, and cooling; the temperature reduction refers to naturally reducing the temperature to room temperature, generally speaking, the room temperature is 25 +/-2 ℃;
s3: filtering, taking solid, adding acetonitrile, and mixing uniformly;
s4: filtering, taking the filtrate, distilling, and taking the fraction between 100 ℃ and 105 ℃ to obtain the target product compound I, namely a mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile, wherein the distillation is preferably carried out under the reduced pressure of 8-10mm Hg.
Preferably, the atmospheric pressure condition in step S1 is 1.5-2.5 MPa.
The pressure of the gas in step S1 is a necessary condition for ensuring the reaction and is also an important factor for the yield of the product. Too high or too low a pressure adversely affects the product yield. Therefore, in the preferred interval disclosed in the present invention, the yield is significantly higher than the yield under other atmospheric conditions.
In a preferred embodiment, the organic base in step S2 is triethylamine.
The reaction conditions required by the present invention are mild, and particularly in step S1, the reaction requirements can be satisfied by designing the reactants to only require 1 to 4MPa, and in a preferred embodiment, further only requiring a pressure condition of 1.5 to 2.5MPa (reduced to 15 to 25 atmospheres). Therefore, the problems of safety, cost and the like caused by harsh reaction conditions, particularly high-pressure conditions of 40-50 atmospheric pressure are avoided. In addition, the invention creatively takes acetonitrile as raw material in the step 1, thereby the acetonitrile is taken as the raw material to participate in the reaction, and simultaneously the acetonitrile is also used as the reaction solvent, thereby the types of the raw materials can be reduced, the operation is simpler, and the acetonitrile can participate in the reactions of the two steps S1 and S2, therefore, when the acetonitrile is preferably adopted, the process is simpler for the whole reaction, and the cost is lower. In addition, in step S2, the target mixed product can be obtained in high yield by combining the phase transfer catalyst with the organic base, and the subsequent purification of the product is made simpler by controlling the reaction process, so that the target mixed product with high purity can be obtained by distillation only.
In a word, the synthesis method of the mixture of the 3-ethoxyacrylonitrile and the 3, 3-diethoxypropionitrile disclosed by the invention has the advantages of low raw material cost, relatively mild reaction conditions, simplicity in operation, high yield and the like, and is a method suitable for industrial production and application.
Detailed Description
In order that the invention may be better understood, we now provide further explanation of the invention with reference to specific examples.
Example 1
In a 600ml autoclave were charged 24.50 g of sodium methoxide and 300 g of acetonitrile, the autoclave was sealed, and the mixture was ice-salted for 20 minutes, and 33.6 g of ethyl formate was sucked in. Nitrogen was introduced at 1.50 MPa. Stirring and heating to 110 ℃, keeping the temperature for reaction for 15 hours, and cooling to room temperature. A white slurry of Compound II was prepared, diluted with 200 g of acetonitrile (CAN) and added to a 1L three-necked flask and mechanically stirred. Then, 1.50 g of tetrabutylammonium bromide and 63 g of diethyl sulfate were added. 6.5 g of triethylamine is added, the temperature is raised to 40 ℃, the mixture is stirred for 10 hours at the temperature, and the temperature is reduced to the room temperature. Filtering, pulping the solid with 100 g of acetonitrile, draining, spin-drying the mother liquor at 50 ℃, and distilling to obtain a mixture I with the yield of 98.6% and the purity of 96.3%.
Example 2
In a 600ml autoclave were charged 24.50 g of sodium methoxide and 370 g of acetonitrile, the autoclave was sealed, and the mixture was ice-salted for 20 minutes, and 33.6 g of ethyl formate was sucked in. Nitrogen was introduced at 1.50 MPa. Stirring and heating to 110 ℃, keeping the temperature for reaction for 15 hours, and cooling to room temperature. The resulting compound II was obtained as a white slurry, which was diluted with 200 g of Acetonitrile (ACN) and placed in a 1L three-necked flask and mechanically stirred. Then, 1.50 g of tetrabutylammonium bromide and 63 g of diethyl sulfate were added. 6.5 g of triethylamine is added, the temperature is raised to 50 ℃, the mixture is stirred for 28 hours at the temperature, and the temperature is reduced to the room temperature. Filtering, pulping the solid with 100 g of acetonitrile, draining, spin-drying the mother liquor at 50 ℃, and distilling to obtain a mixture I with the yield of 96.5 percent and the purity of 95 percent.
Example 3
In a 600ml autoclave were charged 24.50 g of sodium methoxide and 300 g of acetonitrile, the autoclave was sealed, and the mixture was ice-salted for 20 minutes, and 100 g of ethyl formate was sucked in. Nitrogen was introduced at 1.0 MPa. Stirring and heating to 110 ℃, keeping the temperature for reaction for 15 hours, and cooling to room temperature. The resulting compound II was obtained as a white slurry, which was diluted with 200 g of Acetonitrile (ACN) and placed in a 1L three-necked flask and mechanically stirred. Then, 1.50 g of pentadecanyl pentaether and 77 g of diethyl sulfate are added. 6.5 g of triethylamine is added, the temperature is raised to 60 ℃, the mixture is stirred at the temperature overnight (more than 12 hours), and the temperature is reduced to room temperature. Filtering, pulping the solid with 100 g of acetonitrile, draining, spin-drying the mother liquor at 50 ℃, and distilling to obtain a mixture I with the yield of 96.1% and the purity of 94.8%.
Example 4
In a 600ml autoclave were charged 24.50 g of sodium methoxide and 300 g of acetonitrile, the autoclave was sealed, and the mixture was ice-salted for 20 minutes, and 33.6 g of ethyl formate was sucked in. Nitrogen was introduced at 4.0 MPa. Stirring and heating to 110 ℃, keeping the temperature for reaction for 15 hours, and cooling to room temperature. The resulting compound II was obtained as a white slurry, which was diluted with 200 g of Acetonitrile (ACN) and placed in a 1L three-necked flask and mechanically stirred. Then, 1.50 g of tetrabutylammonium bromide and 35 g of diethyl sulfate were added. 6.5 g of triethylamine is added, the temperature is raised to 40 ℃, the mixture is stirred for 10 hours at the temperature, and the temperature is reduced to the room temperature. Filtering, pulping the solid with 100 g of acetonitrile, draining, spin-drying the mother liquor at 50 ℃, and distilling to obtain a mixture I with the yield of 96.0% and the purity of 96.0%.
Example 5
In a 600ml autoclave were charged 24.50 g of sodium methoxide and 300 g of acetonitrile, the autoclave was sealed, and the mixture was ice-salted for 20 minutes, and 33.6 g of ethyl formate was sucked in. Nitrogen was introduced at 1.50 MPa. Stirring and heating to 110 ℃, keeping the temperature for reaction for 15 hours, and cooling to room temperature. The resulting compound II was obtained as a white slurry, which was diluted with 200 g of Acetonitrile (ACN) and placed in a 1L three-necked flask and mechanically stirred. Then, 1.50 g of tetrabutylammonium bromide and 140 g of diethyl sulfate were added. 6.5 g of triethylamine is added, the temperature is raised to 40 ℃, the mixture is stirred for 10 hours at the temperature, and the temperature is reduced to the room temperature. Filtering, pulping the solid with 100 g of acetonitrile, draining, spin-drying the mother liquor at 50 ℃, and distilling to obtain a mixture I with the yield of 89.0 percent and the purity of 94 percent.
Example 6
In a 600ml autoclave were charged 24.50 g of sodium methoxide and 300 g of acetonitrile, the autoclave was sealed, and the mixture was ice-salted for 20 minutes, and 33.6 g of ethyl formate was sucked in. Nitrogen was introduced at 1.50 MPa. Stirring and heating to 110 ℃, keeping the temperature for reaction for 15 hours, and cooling to room temperature. The resulting compound II was obtained as a white slurry, which was diluted with 200 g of Acetonitrile (ACN) and placed in a 1L three-necked flask and mechanically stirred. Then, 1.50 g of polyethylene glycol and 63 g of diethyl sulfate were added. 6.5 g of triethylamine is added, the temperature is raised to 40 ℃, the mixture is stirred for 10 hours at the temperature, and the temperature is reduced to the room temperature. Filtering, pulping the solid with 100 g of acetonitrile, draining, spin-drying the mother liquor at 50 ℃, and distilling to obtain a mixture I with the yield of 95.4% and the purity of 98%.
What has been described above is a specific embodiment of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principle of the present invention, and such improvements and modifications are also considered to be within the scope of the present invention.
Claims (10)
- A method for synthesizing a mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile, which is characterized by comprising the following steps: dissolving alcohol alkali metal salt in acetonitrile according to the molar ratio of the alcohol alkali metal salt to the acetonitrile being 1:1-20, then adding formic ether under the low temperature condition below zero, then heating a reaction system to 100-130 ℃, reacting under the atmospheric pressure condition of 1-4MPa, after the reaction is finished, cooling to obtain an intermediate product containing a compound II, and then reacting the compound II with diethyl sulfate in the solvent acetonitrile under the action of a phase transfer catalyst and organic base triethylamine to obtain a target mixture compound I, namely a mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile;the synthetic route of the method is as follows:
wherein, R1 and R2 are independently selected from methyl or ethyl;m is an alkali metal ion. - 2. The process of claim 1 for the synthesis of a mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile: and M is sodium ion or potassium ion.
- 3. The process of claim 1 for the synthesis of a mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile: the phase transfer catalyst is any one of quaternary ammonium salt, polyethylene glycol and crown ether.
- 4. The process of claim 3 for the synthesis of a mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile, characterized in that: the phase transfer catalyst is 15-crown-5 ether.
- 5. The process of claim 1 for the synthesis of a mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile: the molar ratio of the alcohol alkali metal salt to the formic ether is 1: 1-3.
- 6. The process of claim 1 for the synthesis of a mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile: the addition amount of the phase transfer catalyst is 0.5-7.0 wt% of the addition amount of the alcohol alkali metal salt.
- 7. The process of claim 1 for the synthesis of a mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile: the molar ratio of diethyl sulfate to alcohol alkali metal salt is 0.5-2.0: 1.
- 8. The process of claim 1 for the synthesis of a mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile: the method comprises the following steps:s1: firstly, dissolving alcohol alkali metal salt in acetonitrile according to the molar ratio of the alcohol alkali metal salt to the acetonitrile being 1:1-20, then adding formic ester under the low temperature condition below zero, then heating a reaction system to 100-130 ℃, reacting under the atmospheric pressure condition of 1-4MPa, and cooling after the reaction is finished to obtain an intermediate product containing a compound II;s2: diluting an intermediate product containing a compound II with acetonitrile, adding a phase transfer catalyst, diethyl sulfate and organic base triethylamine, reacting completely at 30-60 ℃, and cooling;s3: filtering, taking solid, adding acetonitrile, and mixing uniformly;s4: filtering, taking the filtrate, distilling, and taking the fraction between 100 ℃ and 105 ℃ to obtain the target product compound I, namely the mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile.
- 9. The process of claim 8 for the synthesis of a mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile, characterized in that: the distillation is 8-10mm Hg reduced pressure distillation.
- 10. The process of claim 8 for the synthesis of a mixture of 3-ethoxyacrylonitrile and 3, 3-diethoxypropionitrile, characterized in that: the atmospheric pressure condition in step S1 is 1.5-2.5 MPa.
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