CN110452179A - A kind of synthetic method of 2- chloro-4-methoxy -5- cyanopyrimidine - Google Patents
A kind of synthetic method of 2- chloro-4-methoxy -5- cyanopyrimidine Download PDFInfo
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- CN110452179A CN110452179A CN201910554930.4A CN201910554930A CN110452179A CN 110452179 A CN110452179 A CN 110452179A CN 201910554930 A CN201910554930 A CN 201910554930A CN 110452179 A CN110452179 A CN 110452179A
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- C07—ORGANIC CHEMISTRY
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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
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
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Abstract
The invention discloses a kind of synthetic methods of 2- chloro-4-methoxy -5- cyanopyrimidine, pass through 2, the chloro- 5- pyrimidine formyl chloride of 4- bis-, tert-butylamine and organic base reaction are made 2, the chloro- 5- pyrimidine t-butyl carboxamide of 4- bis-, 2, the chloro- 5- pyrimidine t-butyl carboxamide of 4- bis- and anhydrous methanol, 20% methanol solution of sodium methylate, which reacts, is made 2- chloro-4-methoxy -5- pyrimidine t-butyl carboxamide, after 2- chloro-4-methoxy -5- pyrimidine t-butyl carboxamide and thionyl chloride reaction, pass sequentially through ethyl acetate extraction, saturated sodium bicarbonate aqueous solution, the pernicious gases such as the sulfur dioxide and hydrogen chloride gas that are generated in saturated salt solution absorbing reaction, product is dried in anhydrous sodium sulfate, n-hexane carries out recrystallizing obtained 2- chloro-4-methoxy -5- cyanopyrimidine, compared with prior art, the invention A kind of new medicine intermediate, and yield and purity is high compared with method known in the art are not only produced, pollution is small, and technological reaction process is short.
Description
Technical field
The invention belongs to medicine intermediate field, specially a kind of synthesis side of 2- chloro-4-methoxy -5- cyanopyrimidine
Method.
Background technique
Pyrimidine ring is drug, one of most common heterocycle in natural products, and pyrimidine heterocyclic compounds are such as synthesizing
The intermediate of drug has important application in field of medicaments, is widely used in anticancer drug, the research and development of anti-AIDS drug etc.
Clinically, therefore, the preparation process for developing and optimizing such compound, has great significance, but in the prior art, doctor
The synthetic route of medicine intermediate is long, and yield is low, and toxicity is big, more serious to the damage ratio of environment, is mainly used in the present invention
The medicine intermediate of 2- chloro-4-methoxy -5- cyanopyrimidine is synthesized, 2- chloro-4-methoxy -5- cyanopyrimidine is a kind of new
Medicine intermediate, and reaction condition of the present invention is mild, technological reaction process is short, feed intake and post-process it is fairly simple, to dirt
It is simple to contaminate object processing mode, is easy to industrialization large-scale production.
Summary of the invention
It is above-mentioned to solve the purpose of the present invention is to provide a kind of synthetic method of 2- chloro-4-methoxy -5- cyanopyrimidine
The problem of synthetic route proposed in background technique is long, and yield is low, and material toxicity is big, and environmental pollution is serious.
To achieve the above object, the invention provides the following technical scheme: a kind of 2- chloro-4-methoxy -5- cyanopyrimidine
The synthetic method of synthetic method, the 2- chloro-4-methoxy -5- cyanopyrimidine includes following synthesis step:
1) the chloro- 5- pyrimidine formyl chloride of 2,4- bis-, tert-butylamine and organic base are mixed by weight 1:0.5-1:0.8-2, into
Row substitution reaction will obtain the chloro- 5- pyrimidine t-butyl carboxamide of 2,4- bis-, 2,4- bis- chloro- 5- pyrimidine formyls after mixture filtering washing
Chlorine is cheap, is commonly used for chemical intermediate, and tert-butylamine is soluble in ethyl alcohol, water, acetone organic synthesis raw material, common to synthesize doctor
Medicine, thiofide, insecticide, fungicide and dyestuff colorant, it is also possible to make solvent, can be used for producing rifampin, N-
Tertiary butyl -2-[4-morpholinodithio sulfenamide, special fourth ethylaminoethanol methacrylate etc., organic base is exactly to contain in molecule
The organic compound of amino, organic synthesis industry in can be used as solvent, surfactant, preservative, fungicide, catalyst and
Raw material promotes the progress of chemical reaction, carries out at 0-5 DEG C in the synthetic reaction of 2- chloro-4-methoxy -5- cyanopyrimidine
Substitution reaction is reacted at low temperature, and reaction pollution is small, is swift in response, is reduced the generation and volatilization of noxious material；
2) the obtained chloro- 5- pyrimidine t-butyl carboxamide of 2,4- bis- and methanol are mixed by weight 1:5-10 in step 1), are added dropwise
20% methanol solution of sodium methylate, and be stirred to react, temperature is 0-5 DEG C, after product filtration washing, obtains 2- after dry
Chloro-4-methoxy -5- pyrimidine t-butyl carboxamide, methanol structure is simple saturated monohydroxy alcohol, and is used as the extractant of organic matter, first
The catalyst and the raw material in pyrimidine synthetic reaction that sodium alkoxide methanol solution is a kind of organic synthesis, methanol solution of sodium methylate one
As reacted with metallic sodium and methanol, now prepare current, prevent from generating sodium hydroxide and insoluble situation occur, influence methanolic sodium methoxide
The activity of solution, 2,4- bis- chloro- 5- pyrimidine t-butyl carboxamides and 20% methanol solution of sodium methylate methanol effect under methoxy occurs
Glycosylation reaction, chlorine element generate 2- chloro-4-methoxy -5- pyrimidine t-butyl carboxamide by methoxy substitution；
3) product obtained in step 2) and thionyl chloride are mixed by weight 1:2-5, it is small heats micro- back flow reaction 3-4
When, cooling boils off thionyl chloride, and ice water is added, is extracted with ethyl acetate 2-3 times, merges organic phase, uses saturated sodium bicarbonate water
Solution is washed 1-4 times, and saturated common salt is washed 1-2 times, and anhydrous sodium sulfate dries, filters precipitation and obtains crude product, and n-hexane recrystallizes to obtain 2-
Chloro-4-methoxy -5- cyanopyrimidine product, 2- chloro-4-methoxy -5- pyrimidine t-butyl carboxamide and the reaction of thionyl chloride dehydration
It is made 2- chloro-4-methoxy -5- cyanopyrimidine mixed solution, saturated sodium bicarbonate aqueous solution is to except generating in dereaction
Sulfur dioxide gas is removed in dereaction with saturated salt solution and is generated except the by-product in dereaction after ethyl acetate extraction reaction
Hydrogen chloride gas, prevent sulfur dioxide and hydrogen chloride gas to be discharged into air and pollute environment, anhydrous sodium sulfate be used to remove
It water in reaction and will not react with 2- chloro-4-methoxy -5- cyanopyrimidine, influence the purity of product, the chloro- 4- first of 2-
Oxygroup -5- cyanopyrimidine is filtered n-hexane after obtaining crude product and is tied again to 2- chloro-4-methoxy -5- cyanopyrimidine crude product
Crystalline substance purifies 2- chloro-4-methoxy -5- cyanopyrimidine, improves the purity of product obtained.
As optimization, when the chloro- 5- pyrimidine formyl chloride of 2,4- bis-, tert-butylamine and organic base mix in step 1), to 2,4- bis-
Organic base is added in chloro- 5- pyrimidine formyl chloride, cools to 0-5 DEG C, then tert-butylamine is added dropwise.
As optimization, before the chloro- 5- pyrimidine formyl chloride of 2,4- bis- in step 1), tert-butylamine and organic base mixing, first by 2,
The chloro- 5- pyrimidine formyl chloride of 4- bis- is dissolved in anhydrous chloroform, and 2,4- bis- chloro- 5- pyrimidine formyl chlorides and anhydrous chloroform are 1 by weight:
8。
As optimization, the organic base in step 1) uses triethylamine, diisopropyl ethyl amine, triisopropylamine, N, N- bis-
Methylaniline, N, N- diethylaniline, N, N- dimethyl pyrazole piperidinyl amine, pyridine, 11 carbon of 1,8- diaza-bicyclic (5,4,0)
The mixing of one of alkene -7, two rings [4.3.0] -1 and 5- phenodiazine -5- hendecene or multi-solvents.
As optimization, washing is dissolved using ethyl acetate in step 2), and saturated common salt washing is dry to use anhydrous sodium sulfate
It is dry.
As optimization, the time that is stirred to react in step 2) is 1-2 hours, and the progress of methoxylation is accelerated in stirring,
So that reaction more sufficiently and reduces the reaction time.
As optimization, the substitution reaction in step 1) is reacted 2-5 hours at 0-5 DEG C.
As optimization, temperature is controlled when 20% methanol solution of sodium methylate being added dropwise in step 2) at 0-5 DEG C, in this temperature strip
Under part, react more abundant.
It as optimization, is extracted with ethyl acetate 2-3 times in step 3), merges organic phase, use saturated sodium bicarbonate aqueous solution
It washes 2 times, saturated common salt is washed 1 time, and saturated sodium bicarbonate aqueous solution is to except the sulfur dioxide gas generated in dereaction, with full
With saline solution except the hydrogen chloride gas generated in dereaction, prevents sulfur dioxide and hydrogen chloride gas to be discharged into air and pollute ring
Border.
Reaction equation is in step 1)
Reaction equation is in step 2)
Reaction equation is in step 3)
Compared with prior art, the beneficial effects of the present invention are: a kind of synthesis of 2- chloro-4-methoxy -5- cyanopyrimidine
The purity of method, different reaction conditions, 2- chloro-4-methoxy -5- cyanopyrimidine obtained is all larger than 98%, and yield exists
Differ smaller under different reaction conditions, yield and purity are higher, and the reaction conditions such as temperature influence the yield of product
Smaller, saturated sodium bicarbonate aqueous solution is to except the sulfur dioxide gas generated in dereaction, saturated salt solution is except in dereaction
The hydrogen chloride gas of generation prevents sulfur dioxide and hydrogen chloride gas to be discharged into air and pollutes environment, reduces the dirt to environment
Dye, and present invention process is easy to operate, and entirely reacts and all carry out under cryogenic, prevents toxic and harmful substance pair
Operate the injury of human body.
Specific embodiment
Below in conjunction with the embodiment of the present invention, technical scheme in the embodiment of the invention is clearly and completely described,
Obviously, described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.Based in the present invention
Embodiment, every other embodiment obtained by those of ordinary skill in the art without making creative efforts, all
Belong to the scope of protection of the invention.
Embodiment 1:
A kind of synthetic method of 2- chloro-4-methoxy -5- cyanopyrimidine, the conjunction of the 2- chloro-4-methoxy -5- cyanopyrimidine
Include following synthesis step at method:
1) in the anhydrous chloroform for being dissolved in 800 grams to 100 grams of chloro- 5- pyrimidine formyl chlorides of 2,4- bis-, 95 grams of three second are added
Amine cools to 0 DEG C, and 38 grams of tert-butylamine is added dropwise, and 0 DEG C insulation reaction 1 hour, filters to obtain compound 2, the chloro- 5- of 4- bis- after adding
100 grams of pyrimidine t-butyl carboxamide, the purity measured is greater than 98%, yield 85%；
2) 100 grams of chloro- 5- pyrimidine t-butyl carboxamides of 2,4- bis- obtained in step 1) are dissolved in 600 milliliters of anhydrous methanol
In, it is cooled to 0 DEG C, 120 milliliters of methanol solution of sodium methylate of 20% are added dropwise, the reaction was continued at 0 DEG C 1 hour after adding, reaction
After boil off methanol, ethyl acetate dissolution, washing, saturated salt washing is dry, boils off after ethyl acetate to obtain the chloro- 4- methoxy of 2-
90 grams of t-butyl carboxamide of base -5- pyrimidine, purity is greater than 97%, yield 91%；
3) 90 grams of 2- chloro-4-methoxy -5- pyrimidine t-butyl carboxamides in step 2) are suspended in 270 grams of thionyl chloride
In, heat up micro- reflux 4 hours, and cooling boils off thionyl chloride, ice water is added, is extracted with ethyl acetate 2 times, merges organic phase, uses
Saturated sodium bicarbonate aqueous solution is washed 2 times, and saturated common salt is washed 1 time, and anhydrous sodium sulfate dries, filters precipitation and obtains crude product, n-hexane
45 grams of cyanopyrimidine of 2- chloro-4-methoxy -5- are recrystallized to obtain, purity is greater than 98%, yield 71%.
Embodiment 2:
A kind of synthetic method of 2- chloro-4-methoxy -5- cyanopyrimidine, the conjunction of the 2- chloro-4-methoxy -5- cyanopyrimidine
Include following synthesis step at method:
1) in the anhydrous chloroform for being dissolved in 800 grams to 100 grams of chloro- 5- pyrimidine formyl chlorides of 2,4- bis-, 65 grams of diisopropyl is added
Base ethylamine cools to 1 DEG C, and 43 grams of tert-butylamine is added dropwise, and 1 DEG C insulation reaction 1 hour, filters to obtain compound 2,4- bis- after adding
Chloro- 98 grams of 5- pyrimidine t-butyl carboxamide, the purity measured is greater than 98%, yield 83%；
2) will be 98 gram 2 obtained in step 1), the chloro- 5- pyrimidine t-butyl carboxamide of 4- bis- is dissolved in 700 milliliters of anhydrous methanol,
It is cooled to 0 DEG C, 110 milliliters of methanol solution of sodium methylate of 20% are added dropwise, the reaction was continued at 0 DEG C 1 hour after adding, and reaction terminates
Afterwards, methanol is boiled off, ethyl acetate dissolution, washing, saturated salt washing, dry, precipitation obtains the tertiary fourth of 2- chloro-4-methoxy -5- pyrimidine
86 grams of amide, purity is greater than 97%, yield 89%；
3) 86 grams of 2- chloro-4-methoxy -5- pyrimidine t-butyl carboxamides in step 2) are suspended in 200 grams of thionyl chloride
In, heat up micro- reflux 4 hours, and cooling boils off thionyl chloride, ice water is added, is extracted with ethyl acetate 2 times, merges organic phase, uses
Saturated sodium bicarbonate aqueous solution is washed 2 times, and saturated common salt is washed 1 time, and anhydrous sodium sulfate dries, filters precipitation and obtains crude product, n-hexane
41 grams of cyanopyrimidine of 2- chloro-4-methoxy -5- are recrystallized to obtain, purity is greater than 98%, yield 68%.
Embodiment 3:
A kind of synthetic method of 2- chloro-4-methoxy -5- cyanopyrimidine, the conjunction of the 2- chloro-4-methoxy -5- cyanopyrimidine
Include following synthesis step at method:
1) in the anhydrous chloroform for being dissolved in 800 grams to 100 grams of chloro- 5- pyrimidine formyl chlorides of 2,4- bis-, the three of 105 grams of addition are different
Propyl amine cools to 3 DEG C, and 70 grams of tert-butylamine is added dropwise, and 3 DEG C insulation reaction 1 hour, filters to obtain compound 2,4- bis- after adding
Chloro- 96 grams of 5- pyrimidine t-butyl carboxamide, the purity measured is greater than 98%, yield 81%；
2) will be 96 gram 2 obtained in step 1), the chloro- 5- pyrimidine t-butyl carboxamide of 4- bis- is dissolved in 500 milliliters of anhydrous methanol,
2 DEG C are cooled to, 100 milliliters of methanol solution of sodium methylate of 20% are added dropwise, the reaction was continued at 2 DEG C 1 hour after adding, and reaction terminates
After boil off methanol, ethyl acetate dissolution, washing, saturated salt washing, dry, precipitation obtains the tertiary butyryl of 2- chloro-4-methoxy -5- pyrimidine
83 grams of amine, purity is greater than 97%, yield 88%；
3) 83 grams of 2- chloro-4-methoxy -5- pyrimidine t-butyl carboxamides in step 2) are suspended in 240 grams of thionyl chloride
In, heat up micro- reflux 4 hours, and cooling boils off thionyl chloride, ice water is added, is extracted with ethyl acetate 2 times, merges organic phase, uses
Saturated sodium bicarbonate aqueous solution is washed 2 times, and saturated common salt is washed 1 time, and anhydrous sodium sulfate dries, filters precipitation and obtains crude product, n-hexane
38 grams of cyanopyrimidine of 2- chloro-4-methoxy -5- are recrystallized to obtain, purity is greater than 98%, yield 65%.
Embodiment 4:
A kind of synthetic method of 2- chloro-4-methoxy -5- cyanopyrimidine, the conjunction of the 2- chloro-4-methoxy -5- cyanopyrimidine
Include following synthesis step at method:
1) in the anhydrous chloroform for being dissolved in 800 grams to 100 grams of chloro- 5- pyrimidine formyl chlorides of 2,4- bis-, 75 grams of N, N- bis- is added
Methylaniline cools to 4 DEG C, and 70 grams of tert-butylamine is added dropwise, and 4 DEG C insulation reaction 1 hour, filters to obtain compound 2,4- bis- after adding
Chloro- 92 grams of 5- pyrimidine t-butyl carboxamide, the purity measured is greater than 98%, yield 78%；
2) will be 92 gram 2 obtained in step 1), the chloro- 5- pyrimidine t-butyl carboxamide of 4- bis- is dissolved in 420 milliliters of anhydrous methanol,
3 DEG C are cooled to, 105 milliliters of methanol solution of sodium methylate of 20% are added dropwise, the reaction was continued at 3 DEG C 1 hour after adding, and reaction terminates
After boil off methanol, ethyl acetate dissolution, washing, saturated salt washing, dry, precipitation obtains the tertiary butyryl of 2- chloro-4-methoxy -5- pyrimidine
81 grams of amine, purity is greater than 97%, yield 89%；
3) 81 grams of 2- chloro-4-methoxy -5- pyrimidine t-butyl carboxamides in step 2) are suspended in 200 grams of thionyl chloride
In, heat up micro- reflux 4 hours, and cooling boils off thionyl chloride, ice water is added, is extracted with ethyl acetate 2 times, merges organic phase, uses
Saturated sodium bicarbonate aqueous solution is washed 2 times, and saturated common salt is washed 1 time, and anhydrous sodium sulfate dries, filters precipitation and obtains crude product, n-hexane
40 grams of cyanopyrimidine of 2- chloro-4-methoxy -5- are recrystallized to obtain, purity is greater than 98%, yield 70%.
When organic base is triethylamine, diisopropyl ethyl amine, triisopropylamine, N, accelerine, N, N- diethyl
Aniline, N, N- dimethyl pyrazole piperidinyl amine, pyridine, 1,8- diaza-bicyclic (5,4,0) endecatylene -7, two rings [4.3.0] -1 and
When the mixing of one of 5- phenodiazine -5- hendecene or multi-solvents, can equally it be prepared according to the method for the embodiment of the present invention 1
Obtain the chloro- 5- pyrimidine t-butyl carboxamide of 2,4- bis-, and the 2- chloro-4-methoxy -5- cyanopyrimidine and 2 to 4 institute of above-described embodiment
The performance of 2- chloro-4-methoxy -5- cyanopyrimidine obtained is identical.
From embodiment 1 to 4 as can be seen that under different reaction conditions, the purity of medicine intermediate obtained is all larger than
98%, but the yield for being different reaction condition reaction product is all different, and the result measured from experiment is it is found that in embodiment 1
In the reaction process for synthesizing 2- chloro-4-methoxy -5- cyanopyrimidine, in the different stages of reaction, the chloro- 5- of 2,4- bis- obtained is phonetic
The purity and implementation of pyridine t-butyl carboxamide, 2- chloro-4-methoxy -5- pyrimidine t-butyl carboxamide and 2- chloro-4-methoxy -5- cyanopyrimidine
Purity obtained is consistent under the reaction condition of example 2-4, and the reaction of 2- chloro-4-methoxy -5- cyanopyrimidine is synthesized in embodiment 1
Cheng Zhong, in the different stages of reaction, the chloro- 5- pyrimidine t-butyl carboxamide of 2,4- bis- obtained, the tertiary fourth of 2- chloro-4-methoxy -5- pyrimidine
The yield of amide and 2- chloro-4-methoxy -5- cyanopyrimidine than high income obtained under embodiment 2-4 reaction condition, and
For embodiment 1-4 when reaction condition is different, the purity of reaction product is all larger than 98%, and the yield variation of reaction product is little,
Saturated sodium bicarbonate aqueous solution with saturated salt solution to be removed in dereaction and be generated except the sulfur dioxide gas generated in dereaction
Hydrogen chloride gas, prevent sulfur dioxide and hydrogen chloride gas to be discharged into air and pollute environment, reduce pollution to environment, and
And operation of the present invention is convenient, and entirely reacts and all carry out under cryogenic, prevents toxic and harmful substance to operation human body
Injury.
It should be noted that, in this document, relational terms such as first and second and the like are used merely to a reality
Body or operation are distinguished with another entity or operation, are deposited without necessarily requiring or implying between these entities or operation
In any actual relationship or order or sequence.Moreover, the terms "include", "comprise" or its any other variant are intended to
Non-exclusive inclusion, so that the process, method, article or equipment including a series of elements is not only wanted including those
Element, but also including other elements that are not explicitly listed, or further include for this process, method, article or equipment
Intrinsic element.
It although an embodiment of the present invention has been shown and described, for the ordinary skill in the art, can be with
A variety of variations, modification, replacement can be carried out to these embodiments without departing from the principles and spirit of the present invention by understanding
And modification, the scope of the present invention is defined by the appended.
Claims (9)
1. a kind of synthetic method of 2- chloro-4-methoxy -5- cyanopyrimidine, it is characterised in that: the 2- chloro-4-methoxy -5- cyanogen
The synthetic method of yl pyrimidines includes following synthesis step:
1) the chloro- 5- pyrimidine formyl chloride of 2,4- bis-, tert-butylamine and organic base are mixed by weight 1:0.5-1:0.8-2, is taken
Generation reaction will obtain the chloro- 5- pyrimidine t-butyl carboxamide of 2,4- bis- after mixture filtering washing；
2) the chloro- 5- pyrimidine t-butyl carboxamide of 2,4- bis- obtained in step 1) and methanol are mixed by weight 1:5-10, is added dropwise 20%
Methanol solution of sodium methylate, and be stirred to react, temperature is 0-5 DEG C, and it is chloro- to obtain 2- after product filtration washing, after dry
4- methoxyl group -5- pyrimidine t-butyl carboxamide；
3) product obtained in step 2 and thionyl chloride are mixed by weight 1:2-5, heating reflux reaction 3-4 hours, drop
Temperature boils off thionyl chloride, and ice water is added, is extracted with ethyl acetate 2-3 times, merges organic phase, uses saturated sodium bicarbonate aqueous solution
It washes 1-4 times, saturated common salt is washed 1-2 times, and anhydrous sodium sulfate dries, filters precipitation and obtains crude product, and n-hexane recrystallizes to obtain the chloro- 4- of 2-
Methoxyl group -5- cyanopyrimidine product.
2. a kind of synthetic method of 2- chloro-4-methoxy -5- cyanopyrimidine according to claim 1, it is characterised in that: institute
When stating the chloro- 5- pyrimidine formyl chloride of 2,4- bis- in step 1), tert-butylamine and organic base mixing, first to the chloro- 5- pyrimidine formyl of 2,4- bis-
Organic base is added in chlorine, cools to 0-5 DEG C, then tert-butylamine is added dropwise.
3. a kind of synthetic method of 2- chloro-4-methoxy -5- cyanopyrimidine according to claim 2, it is characterised in that: institute
Before stating the chloro- 5- pyrimidine formyl chloride of 2,4- bis- in step 1), tert-butylamine and organic base mixing, first by the chloro- 5- pyrimidine first of 2,4- bis-
Acyl chlorides is dissolved in anhydrous chloroform, and 2,4- bis- chloro- 5- pyrimidine formyl chlorides and anhydrous chloroform are 1:8 by weight.
4. a kind of synthetic method of 2- chloro-4-methoxy -5- cyanopyrimidine according to claim 3, it is characterised in that: institute
The organic base in step 1) is stated using triethylamine, diisopropyl ethyl amine, triisopropylamine, N, accelerine, N, N- bis-
Ethyl aniline, N, N- dimethyl pyrazole piperidinyl amine, pyridine, 1,8- diaza-bicyclic (5,4,0) endecatylene -7, two rings
The mixing of one of [4.3.0] -1 and 5- phenodiazine -5- hendecene or multi-solvents.
5. a kind of synthetic method of 2- chloro-4-methoxy -5- cyanopyrimidine according to claim 1, it is characterised in that: institute
It states washing in step 2 to dissolve using ethyl acetate, saturated common salt washing is dry dry using anhydrous sodium sulfate.
6. a kind of synthetic method of 2- chloro-4-methoxy -5- cyanopyrimidine according to claim 1, it is characterised in that: institute
The time that is stirred to react stated in step 2 is 1-2 hours.
7. a kind of synthetic method of 2- chloro-4-methoxy -5- cyanopyrimidine according to claim 1, it is characterised in that: institute
The substitution reaction in step 1) is stated to react 2-5 hours at 0-5 DEG C.
8. a kind of synthetic method of 2- chloro-4-methoxy -5- cyanopyrimidine according to claim 1, it is characterised in that: institute
It states and controls temperature when 20% methanol solution of sodium methylate being added dropwise in step 2 at 0-5 DEG C.
9. a kind of synthetic method of 2- chloro-4-methoxy -5- cyanopyrimidine according to claim 1, it is characterised in that: institute
It states in step 3) and is extracted with ethyl acetate 2-3 times, merge organic phase, wash 2 times with saturated sodium bicarbonate aqueous solution, saturated salt solution
It washes 1 time.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1454210A (en) * | 2000-07-11 | 2003-11-05 | 阿斯特拉曾尼卡有限公司 | Pyrimidine derivatives |
| CN1541208A (en) * | 2001-05-30 | 2004-10-27 | 2-anilino-pyrimidine derivatives as cyclin dependent kinase inhibitors | |
| CN104755484A (en) * | 2012-10-26 | 2015-07-01 | 伊莱利利公司 | Bace inhibitors |
-
2019
- 2019-06-25 CN CN201910554930.4A patent/CN110452179A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1454210A (en) * | 2000-07-11 | 2003-11-05 | 阿斯特拉曾尼卡有限公司 | Pyrimidine derivatives |
| CN1541208A (en) * | 2001-05-30 | 2004-10-27 | 2-anilino-pyrimidine derivatives as cyclin dependent kinase inhibitors | |
| CN104755484A (en) * | 2012-10-26 | 2015-07-01 | 伊莱利利公司 | Bace inhibitors |
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| Title |
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| 韩士敏等: "《一目了然 高中化学知识表解》", 31 January 1997, pages: 168 * |
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Application publication date: 20191115 |