CN109608404A - A kind of preparation method of 4,6- dichloro pyrimidine -5- acetaldehyde - Google Patents
A kind of preparation method of 4,6- dichloro pyrimidine -5- acetaldehyde 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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Abstract
The invention discloses one kind 4, the preparation method of 6- dichloro pyrimidine -5- acetaldehyde, belong to organic chemistry filed, technical points: diethyl malonate is added in organic solvent, alkali and 2- bromomethyl -1,3- dioxolane is added, is heated to 60-70 DEG C of reaction 2-4h, it is extracted after adding water with methyl tertiary butyl ether, is evaporated methyl tertiary butyl ether and obtains intermediate one；Sodium alkoxide is added in organic alcoholic solution, adds formamidine acetate, be stirred at room temperature 30-45min be added intermediate one react 20-30h, be evaporated filtrate, with after ethyl alcohol recrystallization intermediate two；Intermediate two is added in chlorination reagent, it is heated to reflux 10-15h, it pours into ice water and is extracted with ethyl acetate, it is evaporated in the addition acid solution of intermediate three that ethyl acetate obtains and heats 2-4h, it is cooled to room temperature to adopt and be extracted with dichloromethane, it is dry using anhydrous sodium sulfate, then it is evaporated methylene chloride, petroleum ether is recrystallized to give 4,6- dichloro pyrimidine -5- acetaldehyde.The present invention reduces the risk of explosion and experimental facilities requires lower, while also meeting the requirement of batch production.
Description
Technical field
The invention belongs to organic chemistry fileds, more specifically, it relates to the preparation of one kind 4,6- dichloro pyrimidine -5- acetaldehyde
Method.
Background technique
No. CAS of 4,6- dichloro pyrimidine -5- acetaldehyde is 16019-33-3, and Chinese nickname is 2- (4,6- dichloro pyrimidine -5-
Base) acetaldehyde, its molecular formula is C6H4Cl2N2O is a kind of important chemical intermediate, while its English name are as follows: 2- (4,
6-dichloropyrimidin-5-yl) acetaldehyde, specific chemical structural formula are as follows:At present
The main method of synthesis 4,6- dichloro pyrimidine -5- acetaldehyde be according to CN108409745, WO2010/9195, WO2010/9207 and
P.1929, Nucleosides, Nucleotides and Nucleic Acids, 2004, vol.23, #12-1937 wait documents report
Road is to react to obtain intermediate B with 3- bromopropene, then close with carbonamidine using diethyl malonate or dimethyl malenate as raw material
Ring obtains intermediate C, and intermediate C obtains intermediate D after superchlorination, and intermediate D obtains target product after ozone oxidation
4,6- pyrimidine -5- acetaldehyde.Its reaction equation is as follows:
Above method main problem is the ozone oxidation in final step, it is well known that ozone oxidation reaction is one
Breakneck chemical reaction, misoperation just have risk of explosion, and need ozone generator equipment, and institute is uncomfortable in this way
For industrialization large-scale production.Therefore we have proposed a kind of methods of new synthesis 4,6- dichloro pyrimidine -5- acetaldehyde to solve
Certainly above-mentioned technical problem.
Summary of the invention
In view of the deficiencies of the prior art, the present invention intends to provide one kind 4,6- dichloro pyrimidine -5- acetaldehyde
Preparation method can not only reduce the risk exploded brought by ozonisation, and experimental facilities requirement is lower, but also meets and criticize
Measure the requirement of production.
To achieve the above object, the present invention provides the following technical scheme that the preparation of one kind 4,6- dichloro pyrimidine -5- acetaldehyde
Method, including following operating procedure:
Step 1: diethyl malonate is added in organic solvent, alkali is then added, adds 2- bromomethyl -1,3- dioxy penta
Alkane is heated to 60-70 DEG C of reaction 2-4h, adds water, three times with methyl tertiary butyl ether extraction, merges organic phase, is evaporated methyl tertiary butyl ether
After obtain intermediate one.
Step 2: sodium alkoxide is added in organic alcoholic solution, formamidine acetate is then added, it will be intermediate after stirring 30-45min
Body one is added and reacts 20-30h at room temperature, obtains product ethyl alcohol recrystallization after being evaporated filtrate, obtains intermediate two.
Step 3: intermediate two is added in chlorination reagent, it is then heated to reflux 10-15h, is poured into ice water, is used in combination
Ethyl acetate extraction, can be obtained intermediate three after being evaporated ethyl acetate.
Step 4: the Plus acidic solution of the intermediate three heating reaction 2-4h that step 3 is obtained, is cooled to room temperature using two
Chloromethanes extracts three times, merges organic phase, dry using anhydrous sodium sulfate, methylene chloride is then evaporated, then with petroleum ether weight
Crystallization, obtains 4,6- dichloro pyrimidine -5- acetaldehyde.
By using above-mentioned technical proposal, first by diethyl malonate and 2- bromomethyl -1,3- dioxolane organic
Reaction obtains intermediate one under the action of solution and alkali, then again closes intermediate one and formamidine acetate under the action of sodium alkoxide
Ring obtains the intermediate two of miazines；Then by intermediate two and chlorination reagent, chloro forms centre under the action of ethyl acetate
Body three, and then adds CH2Cl2With final product 4,6- dichloro pyrimidine -5- acetaldehyde is obtained after acid solution open loop.Wherein,
Total chemical equation of the step 1 to step 4 are as follows:
Above-mentioned reaction can not only reduce the risk exploded brought by ozonisation, and experimental facilities requirement is lower, but also
The requirement for meeting batch production, effectively increases yield.
Further, in step 1, the organic solution is n,N-Dimethylformamide, methanol, ethyl alcohol and tetrahydro furan
One of mutter.
By using above-mentioned technical proposal, n,N-Dimethylformamide DMF, molecular formula C3H7NO, chemical structural formula areDMF is a kind of polar aprotic solvent, its micro- smell for having chlorine, have certain hygroscopicity, and can with water, ethyl alcohol,
The majority immiscible organic solvent such as chloroform and ether, is slightly soluble in benzene.And methanol is structure saturated monohydroxy alcohol the simplest, its change
Formula is CH3OH, dissolubility is preferable, can be with water arbitrarily than miscible.Ethyl alcohol is the saturated monohydroxy alcohol with a hydroxyl, it
Chemical formula is CH3CH2OH, it is miscible with water, is miscible in most organic solvents such as ether, chloroform, glycerol.In addition, tetrahydrofuran is
Heterocycle organic compound, it is one of strongest polarity ethers, and a kind of middle polarity is used as in chemical reaction and extraction
Solvent, it is colourless transparent liquid, chemical structural formula are as follows:Thus above-mentioned N,N-dimethylformamide, first are used
Four kinds of alcohol, ethyl alcohol and tetrahydrofuran substances effectively increase the mixing between each component as organic solvent.Increase each component
Between reaction adequacy.
Further, in step 1, the alkali is potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, tertiary fourth
One of potassium alcoholate and sodium hydride.
By using above-mentioned technical proposal, potassium carbonate K2CO3It can be dissolved in water, and aqueous solution does not dissolve in ethyl alcohol, third in alkalinity
Ketone and ether.And cesium carbonate Cs2CO3It is a kind of white solid, is highly soluble in water, places rapid moisture absorption, cesium carbonate water in air
Solution is in strong basicity and can react with acid, generates corresponding cesium salt and water, and release carbon dioxide.
In addition, sodium methoxide CH3ONa is soluble easily in water, and aqueous solution can be used in medical industry, in organic synthesis in alkalinity
As condensing agent, chemical reagent, catalyst of edible oil and fat processing etc..And sodium ethoxide C2H5ONa, it is miscible with water, and meets water
After can be decomposed into sodium hydroxide and ethyl alcohol, therefore its aqueous solution is in alkalinity.
In addition, the molecular weight of sodium tert-butoxide is 96.1, molecular formula are as follows: C4H9NaO, chemical structural formula are as follows:Potassium tert-butoxide can should have the condensation, again in the mailing such as chemical industry, medicine synthesis extensively as highly basic
In the reaction such as row and open loop.And the molecular formula of potassium tert-butoxide are as follows: C4H9KO, its chemical structural formula are as follows:It is
A kind of important organic base, alkalinity are greater than potassium hydroxide, it can be as a good catalyst for transesterification, contracting
Close, reset strong polymerization, open loop and the production of heavy metal ortho esters etc..And sodium hydride NaH, it is a kind of inorganic salts, in organic conjunction
Cheng Zhong, sodium hydride are mainly used as highly basic, and wherein sodium hydride does not dissolve in organic solvent, are dissolved in molten metal sodium, therefore almost institute
There is react all in the surface of solids related with sodium hydride.
Further, in step 2, organic alcoholic solution is in methanol, ethyl alcohol, normal propyl alcohol, isopropanol and the tert-butyl alcohol
One kind.
By using above-mentioned technical proposal, methanol, ethyl alcohol, normal propyl alcohol, isopropanol and the tert-butyl alcohol chemical formula in contain
The organic solution of hydroxyl-OH, while also there is good dissolubility, it can will be so that sodium alkoxide, formamidine acetate and intermediate one
It can sufficiently dissolve, and improve the contact area between above-mentioned each component, promote the validity of reaction.
Further, in step 2, the sodium alkoxide is one in sodium methoxide, sodium ethoxide, sodium isopropylate and sodium tert-butoxide
Kind.
By using above-mentioned technical proposal, sodium alkoxide is generally white powder, easily hydrolyzed into original pure and mild hydroxide
Sodium, sodium alkoxide meet vapor in air and become sticky quickly, while color may turn yellow color, faster and with acutely putting when heating
Heat, the compound that the hydrogen of hydroxyl is replaced by metallic sodium in alcohol molecule, sodium alkoxide is highly basic, can capture H atom shape in organic reaction
At carbanion.Above-mentioned sodium methoxide, sodium ethoxide, sodium isopropylate and sodium tert-butoxide are common sodium alkoxide, can be in step 2
Capture H atom in organic reaction and form corresponding carbanion, to be conducive to the generation of intermediate two.
Further, in step 3, the chlorination reagent is phosphorus oxychloride, thionyl chloride, phosphorus trichloride or phosphoric
One of phosphorus.
By using above-mentioned technical proposal, chlorination reagent refers to the reagent that organic matter can be made to increase chlorine atom.It is logical common
Chlorinating agent is chlorine, sulfuryl chloride (SO2Cl2) hydrochloric acid and oxidant (such as hydrogen peroxide) mixture.It sometimes can also be with phosphoric
Hydroxyl is such as replaced as the reaction of chlorine by phosphorus, thionyl chloride.The phosphorus oxychloride that uses in the present invention, thionyl chloride, phosphorus trichloride
Or phosphorus pentachloride can not only obtain the intermediate product replaced with chlorine, and the chlorination reagent being added does not influence entirely to react
It carries out, and the yield and quality that produce are higher.
Further, in step 4, the acid solution is one of concentrated hydrochloric acid, dilute hydrochloric acid and hydrobromic acid.
By using above-mentioned technical proposal, concentrated hydrochloric acid, dilute hydrochloric acid and hydrobromic acid are common acid solution, aqueous solution
In acidity, the hydrogen ion that can be provided in step 4, can not only in and be added in step 1 alkali (i.e. hydroxyl from
Son), and can also provide so that reduction obtains carbonyl C=O after ethylidene ether structure deprotection.
Further, the chemical structural formula of the intermediate one are as follows:
By using above-mentioned technical proposal, the Chinese of intermediate one is diethyl -2- ((1,3- dioxolane -2-
Base) methyl) malonic acid, it is obtained after diethyl malonate loses hydrogen in the presence of alkaliThe above-mentioned intermediate one obtained after subsequent negative electron attack 2- bromomethyl -1,3- dioxolane.
Further, the chemical structural formula of the intermediate two are as follows:
By using above-mentioned technical proposal, the Chinese of intermediate two is 5- ((1,3- dioxolane -2- base) methyl)
Pyrimidine -4,6- glycol, it is reacted by intermediate one and formamidine acetate, has obtained intermediate two after closed loop.
Further, the chemical structural formula of the intermediate three are as follows:
By using above-mentioned technical proposal, the Chinese of above-mentioned chemical structural formula is 5- ((1,3- dioxolane -2- base)
Methyl) -4,6- dichloropyridine, it is obtained after having intermediate two that chloro occurs.
Further, in step 1, weight between the diethyl malonate, alkali and 2- bromomethyl -1,3- dioxolane
Amount is than being 1:(1.5-2): (1.02-1.15)；2- bromomethyl -1,3- the dioxolane of every 1g needs that 2.5-3.5ml's is organic molten
Agent.
Further, in step 2, the weight ratio between the sodium alkoxide, formamidine acetate and intermediate one is (0.8-
1.0):(0.5-0.8):1；Organic alcoholic solution that 5-6.5ml is added is needed in the intermediate two of every 1g.
Further, in step 3, the chlorination reagent that 6-7ml is added, the centre of every 1g are needed in the intermediate two of every 1g
It needs that 5-5.5ml acid solution is added in body two.
By using above-mentioned technical proposal, preferably aforementioned proportion is tested, and can not only reduce the waste to raw material,
And its yield can also be properly increased.
In conclusion the invention has the following advantages:
1, the present invention can not only reduce the risk exploded brought by ozonisation, and experimental facilities requirement is lower, but also meets
The requirement of batch production, effectively increases yield；
2, optimize, the waste to raw material can be reduced by the ratio of optimization addition.
Detailed description of the invention
Fig. 1 is the H-NMR spectrum of intermediate one of the invention；
Fig. 2 is the H-NMR spectrum of intermediate two of the invention；
Fig. 3 is the H-NMR spectrum of product 4,6- dichloro pyrimidine -5- acetaldehyde of the invention.
Specific embodiment
Below in conjunction with each embodiment, invention is further described in detail.
Embodiment 1: the preparation method of one kind 4,6- dichloro pyrimidine -5- acetaldehyde, including following operating procedure:
Step 1: the diethyl malonate of 160g is added in the n,N-Dimethylformamide of 500mL, the carbon of 276g is then added
Sour potassium adds 2- bromomethyl -1,3- dioxolane of 167g, is heated to 60 DEG C of reaction 3h, adds the water of 100ml, with 300ml's
Methyl tertiary butyl ether extracts three times, each dosage 100ml, merges organic phase, at 60 DEG C, the vacuum degree of 0.07MPa after the completion of extraction
Under, the intermediate one of 280g can be obtained after evaporated under reduced pressure methyl tertiary butyl ether (referring to the H-NMR spectrum of Fig. 1 it is found that intermediate one
It is determined as), the chemical equation being related to are as follows:
Step 2: the sodium methoxide of 167.2g is added in the ethyl alcohol of 1.2L, the formamidine acetate of 123g, room temperature is then added
The intermediate one of 195g is added and reacts for 24 hours at room temperature by lower stirring 30min, and filtered filtrate is at 60 DEG C, 0.07MPa
Vacuum degree under, product ethyl alcohol recrystallization is obtained after evaporated under reduced pressure, obtain 99g intermediate two (referring to fig. 2 H-NMR spectrum
Figure is it is found that intermediate two is determined as), the chemical equation being related to are as follows:
Step 3: the intermediate two of 20g is added in the phosphorus oxychloride of 128ml, then 100 DEG C at a temperature of heat
Flow back 12h, pours into the ice water of 100ml, and three times with the extraction of the ethyl acetate of 300ml, each dosage 100ml, at 60 DEG C,
Intermediate three can be obtained after being evaporated ethyl acetate under the vacuum degree of 0.07MPa, the chemical equation being related to are as follows:
Step 4: the intermediate three that step 3 obtains all to be added to the concentrated hydrochloric acid heating reaction 3h of 100mL, it is down to room temperature
Afterwards three times using the methylene chloride extraction of 300ml, each dosage 100ml then merges organic phase, dry using anhydrous sodium sulfate
It is dry, methylene chloride is evaporated under 60 DEG C, the vacuum degree of 0.07MPa again after filtering removal anhydrous sodium sulfate, then with petroleum ether weight
Crystallization, H-NMR spectrum according to Fig.3, know that the product for obtaining 22g is 4,6- dichloro pyrimidine -5- acetaldehyde, the change being related to
Learn reaction equation are as follows:
Its total chemical equation entirely reacted are as follows:
The yield of the 4,6- dichloro pyrimidine -5- acetaldehyde obtained after detection is 81.2%.
Embodiment 2: the preparation method of one kind 4,6- dichloro pyrimidine -5- acetaldehyde, difference from example 1 is that:
In step 1, the diethyl malonate of 155g is added in the n,N-Dimethylformamide of 500mL, the carbonic acid of 276g is then added
Potassium adds 2- bromomethyl -1,3- dioxolane of 167g, is heated to 70 DEG C of reaction 4h, adds the water of 100ml, with the first of 300ml
Three times, each dosage 100ml merges organic phase after the completion of extraction to the tertiary butyl ether extraction of base, under 40 DEG C, the vacuum degree of 0.09MPa,
The intermediate one of 270g can be obtained after evaporated under reduced pressure methyl tertiary butyl ether；Its 4,6- dichloro pyrimidine -5- acetaldehyde obtained after detecting
Yield be 80.5%.
Embodiment 3: the preparation method of one kind 4,6- dichloro pyrimidine -5- acetaldehyde, difference from example 1 is that:
It is added in the ethyl alcohol of 1.2L in step 2, by the sodium methoxide of 167.2g, the formamidine acetate of 123g is then added, stir 45min
The intermediate of 195g one is added afterwards and reacts 30h at room temperature, filtered filtrate under 40 DEG C, the vacuum degree of 0.09MPa,
Product ethyl alcohol recrystallization is obtained after evaporated under reduced pressure, obtains the intermediate two of 100g；Its 4,6- dichloro pyrimidine-obtained after detecting
The yield of 5- acetaldehyde is 79.1%.
Embodiment 4: the preparation method of one kind 4,6- dichloro pyrimidine -5- acetaldehyde, difference from example 1 is that:
In step 3, the intermediate two of 20g is added in the phosphorus oxychloride of 128ml, 15h is then heated to reflux, pours into the ice of 100ml
In water, and three times with the extraction of the ethyl acetate of 300ml, each dosage 100ml is evaporated second under 40 DEG C, the vacuum degree of 0.09MPa
Intermediate three can be obtained after acetoacetic ester；
In step 4, the intermediate three that step 3 obtains all is added to the concentrated hydrochloric acid heating reaction 4h of 100mL, is down to room temperature
Afterwards three times using the methylene chloride extraction of 300ml, each dosage 100ml then merges organic phase, dry using anhydrous sodium sulfate
It is dry, methylene chloride is evaporated under 40 DEG C, the vacuum degree of 0.09MPa again after filtering removal anhydrous sodium sulfate, then with petroleum ether weight
Crystallization, obtains the product (4,6- dichloro pyrimidine -5- acetaldehyde) of 20.5g.Its 4,6- dichloro pyrimidine -5- acetaldehyde obtained after detecting
Yield is 76.3%.
Embodiment 5: the preparation method of one kind 4,6- dichloro pyrimidine -5- acetaldehyde, difference from example 1 is that:
In step 1, the diethyl malonate of 160g is added in the tetrahydrofuran of 500mL, the reagent being added in remaining step is equal
It is operated according to the requirement of embodiment 1, the product 4 finally obtained, the yield of 6- dichloro pyrimidine -5- acetaldehyde is 73.3%.
Embodiment 6: the preparation method of one kind 4,6- dichloro pyrimidine -5- acetaldehyde, difference from example 1 is that:
In step 1, the diethyl malonate of 160g is added in the ethyl alcohol of 500mL, the reagent being added in remaining step according to
The requirement of embodiment 1 is operated, the product 4 finally obtained, and the yield of 6- dichloro pyrimidine -5- acetaldehyde is 72.5%.
Embodiment 7: the preparation method of one kind 4,6- dichloro pyrimidine -5- acetaldehyde, difference from example 1 is that:
In step 1, the diethyl malonate of 160g is added in the n,N-Dimethylformamide of 500mL, the carbonic acid of 276g is then added
Caesium, the reagent being added in remaining step are operated according to the requirement of embodiment 1, the product 4 finally obtained, and 6- dichloro is phonetic
The yield of pyridine -5- acetaldehyde is 80.1%.
Embodiment 8: the preparation method of one kind 4,6- dichloro pyrimidine -5- acetaldehyde, difference from example 1 is that:
In step 1, the diethyl malonate of 160g is added in the n,N-Dimethylformamide of 500mL, the methanol of 276g is then added
Sodium, the reagent being added in remaining step are operated according to the requirement of embodiment 1, the product 4 finally obtained, and 6- dichloro is phonetic
The yield of pyridine -5- acetaldehyde is 78.7%.
Embodiment 9: the preparation method of one kind 4,6- dichloro pyrimidine -5- acetaldehyde, difference from example 1 is that:
In step 1, the diethyl malonate of 160g is added in the n,N-Dimethylformamide of 500mL, the tertiary fourth of 276g is then added
Sodium alkoxide, the reagent being added in remaining step are operated according to the requirement of embodiment 1, the product 4 finally obtained, 6- dichloro
The yield of pyrimidine -5- acetaldehyde is 79.2%.
Embodiment 10: the preparation method of one kind 4,6- dichloro pyrimidine -5- acetaldehyde, difference from example 1 is that:
In step 1, the diethyl malonate of 160g is added in the n,N-Dimethylformamide of 500mL, the hydrogenation of 276g is then added
Sodium, the reagent being added in remaining step are operated according to the requirement of embodiment 1, the product 4 finally obtained, and 6- dichloro is phonetic
The yield of pyridine -5- acetaldehyde is 75.2%.
Embodiment 11: the preparation method of one kind 4,6- dichloro pyrimidine -5- acetaldehyde, difference from example 1 is that:
In step 1, the diethyl malonate of 160g is added in the n,N-Dimethylformamide of 500mL, the tertiary fourth of 276g is then added
Potassium alcoholate, the reagent being added in remaining step are operated according to the requirement of embodiment 1, the product 4 finally obtained, 6- dichloro
The yield of pyrimidine -5- acetaldehyde is 78.4%.
Embodiment 12: the preparation method of one kind 4,6- dichloro pyrimidine -5- acetaldehyde, difference from example 1 is that:
In step 2, the sodium ethoxide of 167.2g is added in the ethyl alcohol of 1.2L, the reagent being added in remaining step is according to implementation
The requirement of example 1 is operated, the product 4 finally obtained, and the yield of 6- dichloro pyrimidine -5- acetaldehyde is 75.1%.
Embodiment 13: the preparation method of one kind 4,6- dichloro pyrimidine -5- acetaldehyde, difference from example 1 is that:
In step 2, the sodium isopropylate of 167.2g is added in the ethyl alcohol of 1.2L, the reagent being added in remaining step is according to reality
The requirement for applying example 1 is operated, the product 4 finally obtained, and the yield of 6- dichloro pyrimidine -5- acetaldehyde is 76.6%.
Embodiment 14: the preparation method of one kind 4,6- dichloro pyrimidine -5- acetaldehyde, difference from example 1 is that:
In step 2, the sodium tert-butoxide of 167.2g is added in the ethyl alcohol of 1.2L, the reagent being added in remaining step is according to reality
The requirement for applying example 1 is operated, the product 4 finally obtained, and the yield of 6- dichloro pyrimidine -5- acetaldehyde is 74.4%.
Embodiment 15: the preparation method of one kind 4,6- dichloro pyrimidine -5- acetaldehyde, difference from example 1 is that:
In step 2, the sodium methoxide of 167.2g is added in the methanol of 1.2L, the reagent being added in remaining step is according to implementation
The requirement of example 1 is operated, the product 4 finally obtained, and the yield of 6- dichloro pyrimidine -5- acetaldehyde is 76.8%.
Embodiment 16: the preparation method of one kind 4,6- dichloro pyrimidine -5- acetaldehyde, difference from example 1 is that:
In step 2, the sodium methoxide of 167.2g is added in the normal propyl alcohol of 1.2L, the reagent being added in remaining step is according to reality
The requirement for applying example 1 is operated, the product 4 finally obtained, and the yield of 6- dichloro pyrimidine -5- acetaldehyde is 78.8%.
Embodiment 17: the preparation method of one kind 4,6- dichloro pyrimidine -5- acetaldehyde, difference from example 1 is that:
In step 2, the sodium methoxide of 167.2g is added in the tert-butyl alcohol of 1.2L, the reagent being added in remaining step is according to reality
The requirement for applying example 1 is operated, the product 4 finally obtained, and the yield of 6- dichloro pyrimidine -5- acetaldehyde is 74.7%.
Embodiment 18: the preparation method of one kind 4,6- dichloro pyrimidine -5- acetaldehyde, difference from example 1 is that:
In step 3, the intermediate two of 20g is added in the thionyl chloride of 128ml, the reagent being added in remaining step according to
The requirement of embodiment 1 is operated, the product 4 finally obtained, and the yield of 6- dichloro pyrimidine -5- acetaldehyde is 78.7%.
Embodiment 19: the preparation method of one kind 4,6- dichloro pyrimidine -5- acetaldehyde, difference from example 1 is that:
In step 3, the intermediate two of 20g is added in the phosphorus trichloride of 128ml, the reagent being added in remaining step according to
The requirement of embodiment 1 is operated, the product 4 finally obtained, and the yield of 6- dichloro pyrimidine -5- acetaldehyde is 77.4%.
Embodiment 20: the preparation method of one kind 4,6- dichloro pyrimidine -5- acetaldehyde, difference from example 1 is that:
In step 3, the intermediate two of 20g is added in the phosphorus pentachloride of 128ml, the reagent being added in remaining step according to
The requirement of embodiment 1 is operated, the product 4 finally obtained, and the yield of 6- dichloro pyrimidine -5- acetaldehyde is 75.4%.
Embodiment 21: the preparation method of one kind 4,6- dichloro pyrimidine -5- acetaldehyde, difference from example 1 is that:
In step 4, the dilute hydrochloric acid heating reaction 3h of the 3mol/L of 100mL, remaining step is added in the intermediate three that step 3 is obtained
The reagent of middle addition is operated according to the requirement of embodiment 1, the product 4 finally obtained, the production of 6- dichloro pyrimidine -5- acetaldehyde
Rate is 78.2%.
Embodiment 22: the preparation method of one kind 4,6- dichloro pyrimidine -5- acetaldehyde, difference from example 1 is that:
In step 4, the hydrobromic acid heating reaction 3h of the 3mol/L of 100mL, remaining step is added in the intermediate three that step 3 is obtained
The reagent of middle addition is operated according to the requirement of embodiment 1, the product 4 finally obtained, the production of 6- dichloro pyrimidine -5- acetaldehyde
Rate is 72.6%.
Specific embodiment is only explanation of the invention, is not limitation of the present invention, those skilled in the art
It can according to need the modification that not creative contribution is made to the present embodiment after reading this specification, but as long as in this hair
All by the protection of Patent Law in bright scope of the claims.
Claims (10)
1. one kind 4, the preparation method of 6- dichloro pyrimidine -5- acetaldehyde, which is characterized in that including following operating procedure:
Step 1: diethyl malonate is added in organic solvent, alkali is then added, adds 2- bromomethyl -1,3- dioxy penta
Alkane is heated to 60-70 DEG C of reaction 2-4h, adds water, three times with methyl tertiary butyl ether extraction, merges organic phase, is evaporated methyl tertiary butyl ether
After obtain intermediate one；
Step 2: sodium alkoxide is added in organic alcoholic solution, formamidine acetate is then added, stirs intermediate one after 30-45min
It is added and reacts 20-30h at room temperature, obtain product ethyl alcohol recrystallization after being evaporated filtrate, obtain intermediate two；
Step 3: intermediate two is added in chlorination reagent, it is then heated to reflux 10-15h, is poured into ice water, and uses acetic acid
Ethyl ester extraction, can be obtained intermediate three after being evaporated ethyl acetate；
Step 4: the Plus acidic solution of the intermediate three heating reaction 2-4h that step 3 is obtained, is cooled to room temperature using dichloromethane
Alkane extracts three times, merges organic phase, dry using anhydrous sodium sulfate, is then evaporated methylene chloride, is then recrystallized with petroleum ether,
Obtain 4,6- dichloro pyrimidine -5- acetaldehyde.
2. a kind of preparation method of 4,6- dichloro pyrimidine -5- acetaldehyde according to claim 1, which is characterized in that in step
In one, the organic solution is one of n,N-Dimethylformamide, methanol, ethyl alcohol and tetrahydrofuran.
3. a kind of preparation method of 4,6- dichloro pyrimidine -5- acetaldehyde according to claim 1, which is characterized in that in step
In one, the alkali is one of potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and sodium hydride.
4. a kind of preparation method of 4,6- dichloro pyrimidine -5- acetaldehyde according to claim 1, which is characterized in that in step
In two, organic alcoholic solution is one of methanol, ethyl alcohol, normal propyl alcohol, isopropanol and tert-butyl alcohol.
5. a kind of preparation method of 4,6- dichloro pyrimidine -5- acetaldehyde according to claim 1, which is characterized in that in step
In two, the sodium alkoxide is one of sodium methoxide, sodium ethoxide, sodium isopropylate and sodium tert-butoxide.
6. a kind of preparation method of 4,6- dichloro pyrimidine -5- acetaldehyde according to claim 1, which is characterized in that in step
In three, the chlorination reagent is one of phosphorus oxychloride, thionyl chloride, phosphorus trichloride or phosphorus pentachloride.
7. a kind of preparation method of 4,6- dichloro pyrimidine -5- acetaldehyde according to claim 1, which is characterized in that in step
In four, the acid solution is one of concentrated hydrochloric acid, dilute hydrochloric acid and hydrobromic acid.
8. one kind 4 described in any one of -3 according to claim 1, the preparation method of 6- dichloro pyrimidine -5- acetaldehyde, feature
It is, in step 1, weight ratio is 1:(1.5- between the diethyl malonate, alkali and 2- bromomethyl -1,3- dioxolane
2): (1.02-1.15)；2- bromomethyl -1,3- the dioxolane of every 1g needs the organic solvent of 2.5-3.5ml.
9. a kind of preparation method of 4,6- dichloro pyrimidine -5- acetaldehyde according to claim 1 or 4 or 5, which is characterized in that
In step 2, the weight ratio between the sodium alkoxide, formamidine acetate and intermediate one is (0.8-1.0): (0.5-0.8): 1；Often
Organic alcoholic solution that 5-6.5ml is added is needed in the intermediate two of 1g.
10. one kind 4 described according to claim 1 or 6 or 7, the preparation method of 6- dichloro pyrimidine -5- acetaldehyde, which is characterized in that
In step 3, the chlorination reagent that 6-7ml is added is needed in the intermediate two of every 1g, needs that 5- is added in the intermediate two of every 1g
5.5ml acid solution.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103524423A (en) * | 2013-09-18 | 2014-01-22 | 苏州乔纳森新材料科技有限公司 | Preparation method of 4,6-dichloropyrimidine-5-acetaldehyde |
| CN103554035A (en) * | 2013-10-29 | 2014-02-05 | 苏州乔纳森新材料科技有限公司 | Preparation method of 4,6-dihalogenated pyridine-5-aldehyde |
| WO2018237134A1 (en) * | 2017-06-23 | 2018-12-27 | San Diego State University Research Foundation | Atropisomerism for enhanced kinase inhibitor selectivity |
-
2019
- 2019-01-12 CN CN201910028887.8A patent/CN109608404A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103524423A (en) * | 2013-09-18 | 2014-01-22 | 苏州乔纳森新材料科技有限公司 | Preparation method of 4,6-dichloropyrimidine-5-acetaldehyde |
| CN103554035A (en) * | 2013-10-29 | 2014-02-05 | 苏州乔纳森新材料科技有限公司 | Preparation method of 4,6-dihalogenated pyridine-5-aldehyde |
| WO2018237134A1 (en) * | 2017-06-23 | 2018-12-27 | San Diego State University Research Foundation | Atropisomerism for enhanced kinase inhibitor selectivity |
Non-Patent Citations (4)
| Title |
|---|
| CHRISTOPHE AÏSSA: "Improved Julia-Kocienski Conditions for the Methylenation of Aldehydes and Ketones", 《J. ORG. CHEM.》 * |
| HAIFENG TANG，ET AL.: "Discovery of MK-7145, an Oral Small Molecule ROMK Inhibitor for the Treatment of Hypertension and Heart Failure", 《ACS MED. CHEM. LETT.》 * |
| TERRENCE L. SMALLEY, ET AL.: "Synthesis and evaluation of novel heterocyclic inhibitors of GSK-3", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| YU-LIU ZHANG，ET AL.: "An improved synthesis of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine", 《CHEMISTRY OF HETEROCYCLIC COMPOUNDS》 * |
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