CN105440042B - A kind of synthetic method of PP796 intermediates pyrimidine triazole - Google Patents
A kind of synthetic method of PP796 intermediates pyrimidine triazole Download PDFInfo
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Abstract
The invention discloses a kind of synthetic method of PP796 intermediates pyrimidine triazole, belong to methodology of organic synthesis technical field.A kind of synthetic method of PP796 intermediates pyrimidine triazole of the present invention, is for reaction raw materials with 2,3 dibromo, 2 methylpropionic acid methyl esters and guanazole, under the catalytic action of catalyst, purpose thing pyrimidine triazole is synthesized by the way that condensation reaction occurs, wherein, the reaction equation of above-mentioned condensation reaction is as follows：
Description
Technical field
The invention belongs to methodology of organic synthesis technical field, more particularly, to a kind of PP796 intermediates pyrimidine triazole
Synthetic method.
Background technology
PP796 Chineses are triazole pyrimidones, are a kind of white crystalline solids, its chemical name is 2- amino -6-
Methyl -4- n-propyls -4,5- dihydro-[1,2,4] triazole-[1,5] and pyrimidine -5- ketone, molecular formula C9H13N5O, structural formula
It is as follows：
PP796 is a kind of important organic synthesis and medicine intermediate, available for synthesizing many derived products.For example, its
It is a kind of important medical and for animals active emetic composition in medicine, it can also be used to prevent bronchial spasm and synthesis is lost weight
Medicine etc..In addition, PP796, which is alternatively arranged as antidote, is used for Rapid contact type herbicides paraquat, human body is deposited with releasing paraquat
Toxicity, so as to protect using crowd.
At present, the synthesis of PP796 is typically to use following methods in the prior art：It is former by starting of methyl methacrylate
Material, is first made dibromide through bromine addition, then carries out etherification reaction with sodium methoxide and prepare etherate 3,3- dimethoxy -2- methyl
Double methyl esters 3- methoxyl group -2- methyl methacrylates are made through catalytic pyrolysis in methyl propionate, above-mentioned etherate.Cyanamide and two sulphur
Changing carbon, condensation prepares dithioacid sodium salt in alkaline conditions, synthesizes two hydrocyanic esters, two hydrocyanic esters through methylation reaction with dimethyl suflfate afterwards
With n-propylamine after condensation reaction prepares cyanogen imido grpup-N- n-propyls-S- methyl-sulphur azepine carbonic ester, then with being hydrated hydrazine reaction
Positive third azoles is synthesized, positive third azoles carries out aldehyde contracting with benzaldehyde under catalyst action and reacts, and generates aldehyde condensates 3- benzaldehyde contracting imido
Base -5- n-propylamine base -1,2,3- triazoles；Aldehyde condensates are catalyzed ring-closure reaction generation cyclization under acid binding agent effect with double methyl esters
Thing, cyclocomplex hydrolyzes in hydrochloric acid to be sloughed benzaldehyde and obtains triazole pyrimidone PP796.But the method route is longer, take compared with
More, complex process is of high cost, and total recovery is relatively low (55%), is unsuitable for industrial production.Have relevant report to point out, triazole
Pyrimidone PP796 can directly be alkylated reaction by pyrimidine triazole and halogenopropane and prepare, more than avoiding using
Existing deficiency when method of the prior art is to prepare PP796, wherein, the structural formula of pyrimidine triazole is
Therefore, pyrimidine triazole and halogenopropane is made directly to be alkylated reaction to prepare efficiency, the gained of PP796
Can the quality of PP796 and the method be suitable for the synthesis technique that industrial production largely each depends on pyrimidine triazole.
Through retrieval, the synthetic method on pyrimidine triazole has relevant report.Such as, United States Patent (USP) US6570014B1 is disclosed
A kind of preparation method of triazolepyrimidine compounds, its reaction equation are as follows：
In above formula：Substituent R1Selected from hydrogen, C1-C10Alkyl, C3-C6Cycloalkyl, C4-C6Alkenyl；R2Selected from hydrogen, halogen, C1-
C10Alkyl, C1-C10Alkoxy；R3Selected from hydrogen, C1-C10Alkyl, C1-C4Alkoxy.With 1,2,4- triazoles -3,5- in this application
Diamines isDuring for raw material to prepare triazolepyrimidine compounds, it is necessary to first using benzaldehyde PhCHO and 1,2,4-
Triazole -3,5- diamines carries out condensation reaction to be protected to an amino in 1,2,4- triazole -3,5- diamines, makes only one
A amino participates in cyclization, the product for then needing to obtain cyclization carries out the amino of protection again through aminating reaction
Deprotection processing can just obtain pyrimidine triazole.Aldehyde is only used as protection group in this method, does not introduce final product, therefore atom passes through
Ji property is relatively poor, and production cost is higher, and its protection and deprotection reaction to amino substantially prolongs whole technique stream
Journey, technique is more complicated, and time-consuming to increase, economy substantially reduces, and the yield of pyrimidine triazole is relatively low.In addition, the method is last
Need to use a large amount of hydrochloric acid during one step aminating reaction, not only serious corrosion of equipment when causing industrialized production, and react bar
Part is difficult to control, quantity of three wastes is big, easily cause environmental pollution and increases production cost.Chinese Patent Application No. is
200610046649.2, a kind of entitled patent for the method for preparing triazolepyrimidine compounds discloses one kind and prepares three
The method of azoles pyrimidines, this application have carried out into one the synthesis technique of triazolepyrimidine compounds in formula (1)
Step is improved, and deprotection processing is carried out to amino by adding suitable catalyst in final step aminating reaction, so as to
Avoid using a large amount of hydrochloric acid, reduce equipment corrosion and environmental pollution to a certain extent.But in this application there is still a need for pair
An amino in 1,2,4- triazole -3,5- diamines is protected and deprotection processing, and technological process is still longer, can not be effective
Production cost is reduced, and the yield of triazolo pyrimidine is relatively low.And for example, prepared by the Chinese patent of Application No. 02122861.2
During triazolo pyrimidine derivative, equally also need that an amino in 1,2,4- triazole -3,5- diamines is protected and taken off using aldehyde
Protection is handled, and its deprotection hydrolysis needs uses substantial amounts of acid, and big to equipment corrosion, pollution is big.
Therefore, work out a kind of synthetic route it is short, it is time-consuming less, high income and cost is low, pollution is few pyrimidine triazole synthesis
Synthesis of the method for PP796 has great importance.
The content of the invention
1. technical problems to be solved by the inivention
Synthetic method it is an object of the invention to overcome existing pyrimidine triazole exist time-consuming more, synthesis technique complexity, into
A kind of deficiency for the shortcomings of this is higher, yield is low and environmental pollution is big, there is provided synthesis side of PP796 intermediates pyrimidine triazole
Method.The synthetic method of pyrimidine triazole in the present invention, synthesis technique is simple, the low and environmental pollution that takes short, high income, cost
It is small.
2. technical solution
To reach above-mentioned purpose, technical solution provided by the invention is：
A kind of synthetic method of PP796 intermediates pyrimidine triazole of the present invention, is with 2,3- dibromo-2-methylpropanoic acid methyl esters
Be reaction raw materials with guanazole, purpose thing pyrimidine triazole synthesized by the way that condensation reaction occurs, wherein, above-mentioned condensation reaction it is anti-
Answer formula as follows：
Further, what pyrimidine triazole synthesized concretely comprises the following steps：
Step 1: under the catalytic action of catalyst, 2,3- dibromo-2-methylpropanoic acids methyl esters and guanazole is set to have in appropriate
In solvent condensation reaction is carried out according to reaction equation (1)；
Step 2: after reaction, into reaction solution, addition extractant is extracted, and handles to obtain by liquid separation organic
Phase；
Step 3: processing is dried to the organic phase that liquid separation is handled, then obtained by rotating removing organic solvent
To pyrimidine triazole crude product；
Pyrimidine triazole sterling is obtained Step 4: obtained pyrimidine triazole crude product is recrystallized.
Further, the catalyst in the condensation reaction (1) selects the alkali metal salt of alcohol, and organic solvent is selected from first
Alcohol, ethanol, isopropanol and n-butanol, and 2,3- dibromo-2-methylpropanoic acid methyl esters and the molar ratio of guanazole and catalyst are 1:
1:2.04~4.
Further, the reaction temperature of the condensation reaction (1) is 60~120 DEG C, and the reaction time is 10~20h.
Further, the extractant in step 2 is selected from dichloromethane, chloroform, ethyl acetate, ether, isopropyl ether and first
One kind in benzene.
Further, organic phase is dried processing using anhydrous magnesium sulfate in step 3.
Further, pyrimidine triazole crude product is recrystallized using ethanol-water system in step 4, wherein ethanol and
The volume ratio of water is 1:1.
Further, the alkali metal salt of the alcohol selects sodium methoxide, potassium methoxide, sodium ethoxide or potassium ethoxide.
Further, 2, the 3- dibromo-2-methylpropanoic acid methyl esters is using methyl methacrylate and bromine as original
Material, by the way that addition reaction preparation occurs, its reaction equation is as follows：
3. beneficial effect
Using technical solution provided by the invention, compared with prior art, there is following remarkable result：
(1) synthetic method of a kind of PP796 intermediates pyrimidine triazole of the invention, is using methyl methacrylate as starting
Raw material, prepares 2,3- dibromo-2-methylpropanoic acid methyl esters through bromination addition reaction, then makes 2,3- dibromo-2-methylpropanoic acid first
Ester and guanazole direct polycondensation, by selecting suitable catalyst and reaction process parameter being optimized and controlled so that reaction
During guanazole two amino in only amino participate in condensation reaction, and another amino is then not involved in reacting so that
Can to avoid benzaldehyde or other aldehyde must be used to be protected and be deprotected operation to an amino in above-mentioned two amino,
Process route is substantially reduced, technological operation is simple, is consumed when reducing, and reduces production cost, and yield is then higher, and will not
Corrosion is produced to equipment, the harm to environment and human body is smaller, suitable for large-scale industrial production.
(2) synthetic method of a kind of PP796 intermediates pyrimidine triazole of the invention, by joining to each technique in reaction process
Several effective control, it is possible to reduce the generation of accessory substance, is effectively ensured the purity of final gained pyrimidine triazole, improved
The follow-up using effect of pyrimidine triazole.
Embodiment
To further appreciate that present disclosure, with reference to embodiment, the invention will be further described.
Embodiment 1
A kind of synthetic method of PP796 intermediates pyrimidine triazole of the present embodiment, is with 2,3- dibromo-2-methylpropanoic acid first
Ester and guanazole are reaction raw materials, synthesize pyrimidine triazole by the way that condensation reaction occurs, it is concretely comprised the following steps：
Step 1: 78g is added into the 500mL three-necked flasks with thermometer, blender and condenser pipe at room temperature
Then (0.3mol) 2,3- dibromo-2-methylpropanoic acids methyl esters and 29.7g (0.3mol) guanazoles are added as reaction raw materials
40.5g (0.75mol) sodium methoxides are eventually adding the methanol of 200mL as solvent, make each material equal by stirring as catalyst
It can be completely dissolved in methanol and be uniformly mixed and form reaction solution, reaction solution is heated to 60 DEG C of insulation 18h, makes 2,3- bis-
Bromo- 2 Methylpropionic acid methyl esters and guanazole carry out condensation reaction to synthesize pyrimidine triazole according to the following formula：
Wherein, it using methyl methacrylate and bromine is anti-that 2, the 3- dibromo-2-methylpropanoic acid methyl esters in the present embodiment, which is,
Answer raw material to prepare, its detailed process is：
Step A, with thermometer, blender, condenser pipe, dropping funel 500mL four-hole boiling flasks in by 50g
(0.5mol) methyl methacrylate is dissolved in 60mL chloroforms, and 88g (0.55mol) liquid is added dropwise into reaction solution under condition of ice bath
Bromine, is heated to 40 DEG C by reaction solution and keeps the temperature 3h, methyl methacrylate is reacted according to the following formula with bromine：
Step B, after reaction, the NaHSO that 100mL mass fractions are 50% is added into reaction solution3Solution, stirring are quiet
Layering is put, separates organic phase, 3 extractions, the organic phase that will be obtained mutually then are carried out to the water separated using 100mL chloroforms every time
Merge.
Step C, using anhydrous magnesium sulfate as drier, processing is dried to obtained organic phase using 50g magnesium sulfate,
Magnesium sulfate drier is removed by filtration, then removes chloroform by rotating, finally obtains 129g (0.5mol) brominations addition production
Thing 2,3- dibromo-2-methylpropanoic acid methyl esters, yield 99.2%.
Step 2: being cooled to room temperature after reaction, 150mL water is added into reaction solution and is stirred, then proceed to add
Enter organic extractant to be extracted, handle to obtain organic phase by liquid separation.Dichloromethane is used in the present embodiment as extractant
Reaction solution is extracted, to ensure fully to extract, 3 extractions are carried out to reaction solution using 100mL dichloromethane every time.
It is dried, leads to as drier Step 3: adding 50g anhydrous magnesium sulfates in the organic phase handled to liquid separation
Drier is filtered to remove, then obtains pyrimidine triazole crude product by rotating removing organic solvent.
Step 4: being recrystallized using ethanol-water system to obtained pyrimidine triazole crude product, to obtain pyrimidine triazole pure
Product, the volume ratio of second alcohol and water is 1 in the present embodiment:1, total dosage of ethanol-water system is 80mL, through recrystallizing last obtain
The pyrimidine triazole sterling that purity is 98.8% amounts to 29.3g, and pyrimidine triazole yield is 59.2%.
What deserves to be explained is the synthetic method of pyrimidine triazole is usually required an amino in guanazole first in the prior art
Protected using benzaldehyde or other aldehydes, condensation reaction then occurs with substituted acrylic acid derivative again, finally needs
The amino of above-mentioned protection is deprotected to obtain pyrimidine triazole through hydrolyzing again, complex operation, synthetic route is longer, raw
Produce of high cost, yield is low, and since the aldehyde of protection does not introduce final product, Atom economy is poor, further increases and is produced into
This.Therefore, inventor expect if be not required to protect the amino in guanazole and deprotection processing can synthesize pyrimidine triazole,
Technological process can be then greatly shortened, reduces production cost.But the amino in guanazole ought not be protected to synthesize pyrimidine three
During azoles, existing technological difficulties are that condensation reaction easily occurs for unprotected amino and the acrylic acid derivative of substitution, so as to lead
The generation of a large amount of side reactions is caused, makes the yield of pyrimidine triazole extremely low, and its purity is relatively low, it is impossible to meet requirement.Invention
People passes through long-term substantial amounts of experimental study, works out the synthetic method of the present embodiment finally, i.e., with 2,3- dibromo-2-methylpropanoic acids
Methyl esters and guanazole are reaction raw materials, are allowed to that condensation reaction occurs to synthesize pyrimidine triazole, and by selecting suitable catalyst kind
Class and reaction process parameter is optimized and controlled, enable to there was only an ammonia in two amino of guanazole in reaction process
Base participates in condensation reaction, and another amino is then not involved in reacting, and effectively prevent the generation of side reaction, is not required to in guanazole
Amino is protected and deprotection processing can synthesize pyrimidine triazole, and technological operation is simple, substantially reduces technological process, production
Cost is relatively low, and the yield and purity of gained pyrimidine triazole are higher, and environmental pollution is small, suitable for large-scale industrial production.
Embodiment 2
A kind of synthetic method of PP796 intermediates pyrimidine triazole of the present embodiment, is with 2,3- dibromo-2-methylpropanoic acid first
Ester and guanazole are reaction raw materials, synthesize pyrimidine triazole by the way that condensation reaction occurs, it is concretely comprised the following steps：
Step 1: 78g is added into the 500mL three-necked flasks with thermometer, blender and condenser pipe at room temperature
Then (0.3mol) 2,3- dibromo-2-methylpropanoic acids methyl esters and 29.7g (0.3mol) guanazoles are added as reaction raw materials
34.1g (0.63mol) sodium methoxides are eventually adding the methanol of 200mL as solvent, make each material equal by stirring as catalyst
It can be completely dissolved in methanol and be uniformly mixed and form reaction solution, reaction solution is heated to 70 DEG C of insulation 15h, makes 2,3- bis-
Bromo- 2 Methylpropionic acid methyl esters and guanazole carry out condensation reaction to synthesize pyrimidine triazole according to the following formula：
Wherein, it using methyl methacrylate and bromine is anti-that 2, the 3- dibromo-2-methylpropanoic acid methyl esters in the present embodiment, which is,
Answer raw material to prepare, its detailed process is：
Step A, with thermometer, blender, condenser pipe, dropping funel 500mL four-hole boiling flasks in by 50g
(0.5mol) methyl methacrylate is dissolved in 60mL chloroforms, and 88g (0.55mol) liquid is added dropwise into reaction solution under condition of ice bath
Bromine, is heated to 60 DEG C by reaction solution and keeps the temperature 2h, methyl methacrylate is reacted according to the following formula with bromine：
Step B, after reaction, the NaHSO that 100mL mass fractions are 50% is added into reaction solution3Solution, stirring are quiet
Layering is put, separates organic phase, extraction 3 times, the organic phase that will be obtained mutually then are carried out to the water separated using 100mL chloroforms every time
Merge.
Step C, using magnesium sulfate powder as drier, processing is dried to obtained organic phase using 50g magnesium sulfate,
Magnesium sulfate drier is removed by filtration, then removes chloroform by rotating, finally obtains 128g (0.49mol) brominations addition production
Thing 2,3- dibromo-2-methylpropanoic acid methyl esters, yield 98.5%.
Step 2: being cooled to room temperature after reaction, 150mL water is added into reaction solution and is stirred, then proceed to add
Enter extractant to be extracted, handle to obtain organic phase by liquid separation.Use dichloromethane as extractant to anti-in the present embodiment
Answer liquid to be extracted, to ensure fully to extract, 3 extractions are carried out to reaction solution using 100mL dichloromethane every time.
It is dried, leads to as drier Step 3: adding 50g anhydrous magnesium sulfates in the organic phase handled to liquid separation
Drier is filtered to remove, then obtains pyrimidine triazole crude product by rotating removing organic solvent；
Step 4: being recrystallized using ethanol-water system to obtained pyrimidine triazole crude product, to obtain pyrimidine triazole pure
Product, the volume ratio of second alcohol and water is 1 in the present embodiment:1, total dosage of ethanol-water system is 78mL, through recrystallizing last obtain
The pyrimidine triazole sterling that purity is 98.5% amounts to 28.5g, and pyrimidine triazole yield is 57.5%.
Embodiment 3
A kind of synthetic method of PP796 intermediates pyrimidine triazole of the present embodiment, it is concretely comprised the following steps：
Step 1: 78g is added into the 500mL three-necked flasks with thermometer, blender and condenser pipe at room temperature
Then (0.3mol) 2,3- dibromo-2-methylpropanoic acids methyl esters and 29.7g (0.3mol) guanazoles add 51g as reaction raw materials
(0.75mol) sodium ethoxide is eventually adding the ethanol of 180mL as solvent, each material is filled by stirring as catalyst
Divide to be dissolved in ethanol and be uniformly mixed and form reaction solution, reaction solution is heated to 78 DEG C of insulation 13h, makes 2,3- bis- bromo-
2 Methylpropionic acid methyl esters and guanazole are reacted to synthesize pyrimidine triazole according to the following formula：
Wherein, above-mentioned 2,3- dibromo-2-methylpropanoic acids methyl esters is prepared using following methods：
Step A, with thermometer, blender, condenser pipe, dropping funel 500mL four-hole boiling flasks in by 50g
(0.5mol) methyl methacrylate is dissolved in 80mL chloroforms, and 81.6g (0.51mol) is added dropwise into reaction solution under condition of ice bath
Bromine, is heated to 50 DEG C by reaction solution and keeps the temperature 2h, methyl methacrylate is reacted according to the following formula with bromine：
Step B, after reaction, the NaHSO that 100mL mass fractions are 50% is added into reaction solution3Solution, stirring are quiet
Layering is put, separates organic phase, extraction 3 times, the organic phase that will be obtained mutually then are carried out to the water separated using 120mL chloroforms every time
Merge.
Step C, using magnesium sulfate powder as drier, processing is dried to obtained organic phase using 50g magnesium sulfate,
Magnesium sulfate drier is removed by filtration, then removes chloroform by rotating, finally obtains 127.1g (0.49mol) bromination addition
Product 2,3- dibromo-2-methylpropanoic acid methyl esters, yield 97.8%.
Step 2: being cooled to room temperature after reaction, 120mL water is added into reaction solution and is stirred, then proceed to add
Enter extractant to be extracted, handle to obtain organic phase by liquid separation.Use chloroform as extractant to reaction solution in the present embodiment
Extracted, to ensure fully to extract, 3 extractions are carried out to reaction solution using 100mL chloroforms every time.
It is dried, leads to as drier Step 3: adding 50g magnesium sulfate powders in the organic phase handled to liquid separation
Drier is filtered to remove, then obtains pyrimidine triazole crude product by rotating removing organic solvent；
Step 4: being recrystallized using ethanol-water system to obtained pyrimidine triazole crude product, to obtain pyrimidine triazole pure
Product, the volume ratio of second alcohol and water is 1 in the present embodiment:1, total dosage of ethanol-water system is 80mL, through recrystallizing last obtain
The pyrimidine triazole sterling that purity is 99.0% amounts to 28.4g, and pyrimidine triazole yield is 57.3%.
Embodiment 4
A kind of synthetic method of PP796 intermediates pyrimidine triazole of the present embodiment, it is concretely comprised the following steps：
Step 1: 78g is added into the 500mL three-necked flasks with thermometer, blender and condenser pipe at room temperature
Then (0.3mol) 2,3- dibromo-2-methylpropanoic acids methyl esters and 29.7g (0.3mol) guanazoles are added as reaction raw materials
46.2g (0.66mol) potassium methoxides are eventually adding the isopropanol of 210mL as solvent, make each material by stirring as catalyst
It can be completely dissolved in isopropanol and be uniformly mixed and form reaction solution, reaction solution is heated to 80 DEG C of insulation 13h, makes 2,
3- dibromo-2-methylpropanoic acids methyl esters and guanazole are reacted to synthesize pyrimidine triazole according to the following formula：
Wherein, above-mentioned 2,3- dibromo-2-methylpropanoic acids methyl esters is prepared using following methods：
Step A, with thermometer, blender, condenser pipe, dropping funel 500mL four-hole boiling flasks in by 50g
(0.5mol) methyl methacrylate is dissolved in 60mL chloroforms, and 96g (0.6mol) liquid is added dropwise into reaction solution under condition of ice bath
Bromine, is heated to 30 DEG C by reaction solution and keeps the temperature 5h, methyl methacrylate is reacted according to the following formula with bromine：
Step B, after reaction, the NaHSO that 100mL mass fractions are 30% is added into reaction solution3Solution, stirring are quiet
Layering is put, separates organic phase, extraction 3 times, the organic phase that will be obtained mutually then are carried out to the water separated using 100mL chloroforms every time
Merge.
Step C, using magnesium sulfate powder as drier, processing is dried to obtained organic phase using 50g magnesium sulfate,
Magnesium sulfate drier is removed by filtration, then by rotate remove chloroform, finally obtain 126.1g (0.48mol) bromination adds
Into product 2,3- dibromo-2-methylpropanoic acid methyl esters, yield 97.0%.
Step 2: being cooled to room temperature after reaction, 200mL water is added into reaction solution and is stirred, then proceed to add
Enter extractant to be extracted, handle to obtain organic phase by liquid separation.Use ethyl acetate as extractant to anti-in the present embodiment
Answer liquid to be extracted, to ensure fully to extract, 3 extractions are carried out to reaction solution using 150mL ethyl acetate every time.
It is dried, leads to as drier Step 3: adding 50g magnesium sulfate powders in the organic phase handled to liquid separation
Drier is filtered to remove, then obtains pyrimidine triazole crude product by rotating removing organic solvent；
Step 4: being recrystallized using ethanol-water system to obtained pyrimidine triazole crude product, to obtain pyrimidine triazole pure
Product, the volume ratio of second alcohol and water is 1 in the present embodiment:1, total dosage of ethanol-water system is 82mL, through recrystallizing last obtain
The pyrimidine triazole sterling that purity is 98.1% amounts to 30.0g, and pyrimidine triazole yield is 60.6%.
Embodiment 5
A kind of synthetic method of PP796 intermediates pyrimidine triazole of the present embodiment, its step are：
Step 1: 78g is added into the 500mL three-necked flasks with thermometer, blender and condenser pipe at room temperature
Then (0.3mol) 2,3- dibromo-2-methylpropanoic acids methyl esters and 29.7g (0.3mol) guanazoles are added as reaction raw materials
52.1g (0.62mol) potassium ethoxides are eventually adding the n-butanol of 200mL as solvent, make each material by stirring as catalyst
It can be completely dissolved in n-butanol and be uniformly mixed and form reaction solution, reaction solution is heated to 115 DEG C of insulation 10h, is made
2,3- dibromo-2-methylpropanoic acids methyl esters and guanazole are reacted to synthesize pyrimidine triazole according to the following formula：
Wherein, the preparation method of above-mentioned 2,3- dibromo-2-methylpropanoic acids methyl esters is as follows：
Step A, with thermometer, blender, condenser pipe, dropping funel 500mL four-hole boiling flasks in by 50g
(0.5mol) methyl methacrylate is dissolved in 100mL chloroforms, and 88g (0.55mol) is added dropwise into reaction solution under condition of ice bath
Bromine, is heated to 20 DEG C by reaction solution and keeps the temperature 5h, methyl methacrylate is reacted according to the following formula with bromine：
Step B, after reaction, the NaHSO that 100mL mass fractions are 80% is added into reaction solution3Solution, stirring are quiet
Layering is put, separates organic phase, extraction 3 times, the organic phase that will be obtained mutually then are carried out to the water separated using 100mL chloroforms every time
Merge.
Step C, using magnesium sulfate powder as drier, processing is dried to obtained organic phase using 50g magnesium sulfate,
Magnesium sulfate drier is removed by filtration, then by rotate remove chloroform, finally obtain 126.9g (0.49mol) bromination adds
Into product 2,3- dibromo-2-methylpropanoic acid methyl esters, yield 97.6%.
Step 2: being cooled to room temperature after reaction, 250mL water is added into reaction solution and is stirred, then proceed to add
Enter extractant to be extracted, handle to obtain organic phase by liquid separation.Use ether as extractant to reaction solution in the present embodiment
Extracted, to ensure fully to extract, 4 extractions are carried out to reaction solution using 100mL ether every time.
It is dried, leads to as drier Step 3: adding 50g magnesium sulfate powders in the organic phase handled to liquid separation
Drier is filtered to remove, then obtains pyrimidine triazole crude product by rotating removing organic solvent；
Step 4: being recrystallized using ethanol-water system to obtained pyrimidine triazole crude product, to obtain pyrimidine triazole pure
Product, the volume ratio of second alcohol and water is 1 in the present embodiment:1, total dosage of ethanol-water system is 75mL, through recrystallizing last obtain
The pyrimidine triazole sterling that purity is 99.2% amounts to 27.9g, and pyrimidine triazole yield is 56.4%.
Embodiment 6
A kind of synthetic method of PP796 intermediates pyrimidine triazole of the present embodiment, its step are：
Step 1: 78g is added into the 500mL three-necked flasks with thermometer, blender and condenser pipe at room temperature
Then (0.3mol) 2,3- dibromo-2-methylpropanoic acids methyl esters and 29.7g (0.3mol) guanazoles are added as reaction raw materials
48.6g (0.9mol) sodium methoxides are eventually adding the methanol of 180mL as solvent, make each material equal by stirring as catalyst
It can be completely dissolved in methanol and be uniformly mixed and form reaction solution, reaction solution is heated to 60 DEG C of insulation 20h, makes 2,3- bis-
Bromo- 2 Methylpropionic acid methyl esters and guanazole are reacted to synthesize pyrimidine triazole according to the following formula：
Wherein, the preparation method of above-mentioned 2,3- dibromo-2-methylpropanoic acids methyl esters is as follows：
Step A, with thermometer, blender, condenser pipe, dropping funel 500mL four-hole boiling flasks in by 50g
(0.5mol) methyl methacrylate is dissolved in 180mL dichloromethane, is added dropwise under condition of ice bath into reaction solution by 84.8g
(0.53mol) bromine, is heated to 70 DEG C by reaction solution and keeps the temperature 2h, methyl methacrylate is carried out according to the following formula instead with bromine
Should：
Step B, after reaction, the NaHSO that 100mL mass fractions are 60% is added into reaction solution3Solution, stirring are quiet
Layering is put, separates organic phase, extraction 3 times is mutually then carried out to the water separated using 100mL dichloromethane every time, is had what is obtained
Machine mutually merges.
Step C, using magnesium sulfate powder as drier, processing is dried to obtained organic phase using 50g magnesium sulfate,
Magnesium sulfate drier is removed by filtration, then removes dichloromethane by rotating, finally obtains to obtain 128.0g (0.49mol) bromine
Change addition compound product 2,3- dibromo-2-methylpropanoic acid methyl esters, yield 98.5%.
Step 2: being cooled to room temperature after reaction, 150mL water is added into reaction solution and is stirred, then proceed to add
Enter extractant to be extracted, handle to obtain organic phase by liquid separation.Use isopropyl ether as extractant to reaction in the present embodiment
Liquid is extracted, and to ensure fully to extract, 3 extractions are carried out to reaction solution using 150mL isopropyl ethers every time.
It is dried, leads to as drier Step 3: adding 50g anhydrous magnesium sulfates in the organic phase handled to liquid separation
Drier is filtered to remove, then obtains pyrimidine triazole crude product by rotating removing organic solvent；
Step 4: being recrystallized using ethanol-water system to obtained pyrimidine triazole crude product, to obtain pyrimidine triazole pure
Product, the volume ratio of second alcohol and water is 1 in the present embodiment:1, total dosage of ethanol-water system is 83mL, through recrystallizing last obtain
The pyrimidine triazole sterling that purity is 98.6% amounts to 29.8g, and pyrimidine triazole yield is 60.3%.
Embodiment 7
A kind of synthetic method of PP796 intermediates pyrimidine triazole of the present embodiment, its step are：
Step 1: 78g is added into the 500mL three-necked flasks with thermometer, blender and condenser pipe at room temperature
Then (0.3mol) 2,3- dibromo-2-methylpropanoic acids methyl esters and 29.7g (0.3mol) guanazoles are added as reaction raw materials
64.8g (1.2mol) sodium methoxides are eventually adding the n-butanol of 210mL as solvent, make each material by stirring as catalyst
It can be completely dissolved in n-butanol and be uniformly mixed and form reaction solution, reaction solution is heated to 120 DEG C of insulation 10h, is made
2,3- dibromo-2-methylpropanoic acids methyl esters and guanazole are reacted to synthesize pyrimidine triazole according to the following formula：
Wherein, the preparation method of above-mentioned 2,3- dibromo-2-methylpropanoic acids methyl esters is as follows：
Step A, with thermometer, blender, condenser pipe, dropping funel 500mL four-hole boiling flasks in by 50g
(0.5mol) methyl methacrylate is dissolved in 150mL carbon tetrachloride, is added dropwise under condition of ice bath into reaction solution by 84.8g
(0.53mol) bromine, is heated to 70 DEG C by reaction solution and keeps the temperature 2h, methyl methacrylate is carried out according to the following formula instead with bromine
Should：
Step B, after reaction, the NaHSO that 100mL mass fractions are 40% is added into reaction solution3Solution, stirring are quiet
Layering is put, separates organic phase, extraction 3 times is mutually then carried out to the water separated using 100mL carbon tetrachloride every time, is had what is obtained
Machine mutually merges.
Step C, using magnesium sulfate powder as drier, processing is dried to obtained organic phase using 50g magnesium sulfate,
Magnesium sulfate drier is removed by filtration, then removes carbon tetrachloride by rotating, finally obtains to obtain 128.0g (0.49mol) bromine
Change addition compound product 2,3- dibromo-2-methylpropanoic acid methyl esters, yield 98.3%.
Step 2: being cooled to room temperature after reaction, 150mL water is added into reaction solution and is stirred, then proceed to add
Enter extractant to be extracted, handle to obtain organic phase by liquid separation.Use toluene as extractant to reaction solution in the present embodiment
Extracted, to ensure fully to extract, 4 extractions are carried out to reaction solution using 80mL dichloromethane every time.
It is dried, leads to as drier Step 3: adding 50g anhydrous magnesium sulfates in the organic phase handled to liquid separation
Drier is filtered to remove, then obtains pyrimidine triazole crude product by rotating removing organic solvent；
Step 4: being recrystallized using ethanol-water system to obtained pyrimidine triazole crude product, to obtain pyrimidine triazole pure
Product, the volume ratio of second alcohol and water is 1 in the present embodiment:1, total dosage of ethanol-water system is 83mL, through recrystallizing last obtain
The pyrimidine triazole sterling that purity is 98.6% amounts to 29.8g, and pyrimidine triazole yield is 60.3%.
A kind of synthetic method of PP796 intermediates pyrimidine triazole of the present invention, using methyl methacrylate as starting material,
First pass around bromination addition reaction and obtain 2,3- dibromo-2-methylpropanoic acid methyl esters, be then catalyzed with alkali metal salt of the guanazole in alcohol
Under carry out reaction generation pyrimidine triazole.The synthetic method only makes one by adding appropriate catalyst and control to reaction process
A amino participates in condensation reaction, another is not involved in reacting, and broken needs to protect one of amino using aldehyde in tradition
Shield and the viewpoint of deprotection, have the advantages that route is short, technique simply, high income, cost is low, pollution is few, be suitable for industrializing
Production.
Claims (7)
- A kind of 1. synthetic method of PP796 intermediates pyrimidine triazole, it is characterised in that：It is with 2,3- dibromo-2-methylpropanoic acids Methyl esters and guanazole are reaction raw materials, and purpose thing pyrimidine triazole is synthesized by the way that condensation reaction occurs, wherein, above-mentioned condensation reaction Reaction equation it is as follows：The reaction temperature of the reaction is 60~120 DEG C, and the reaction time is 10~20h, and the catalyst selects sodium methoxide, methanol Potassium, sodium ethoxide or potassium ethoxide, and 2,3- dibromo-2-methylpropanoic acid methyl esters and the molar ratio of guanazole and catalyst are 1:1:2.04 ~4.
- A kind of 2. synthetic method of PP796 intermediates pyrimidine triazole according to claim 1, it is characterised in that：Its is specific Step is：Step 1: under the catalytic action of catalyst, make 2,3- dibromo-2-methylpropanoic acids methyl esters and guanazole appropriate organic molten In agent condensation reaction is carried out according to reaction equation (1)；Step 2: after reaction, into reaction solution, addition extractant is extracted, and handles to obtain organic phase by liquid separation；Step 3: processing is dried to the organic phase that liquid separation is handled, then obtained by revolving removing organic solvent phonetic Pyridine triazole crude product；Pyrimidine triazole sterling is obtained Step 4: obtained pyrimidine triazole crude product is recrystallized.
- A kind of 3. synthetic method of PP796 intermediates pyrimidine triazole according to claim 2, it is characterised in that：Described Organic solvent is selected from methanol, ethanol, isopropanol and n-butanol.
- A kind of 4. synthetic method of PP796 intermediates pyrimidine triazole according to claim 2, it is characterised in that：Step 2 In one kind in dichloromethane, chloroform, ethyl acetate, ether, isopropyl ether and toluene of extractant.
- A kind of 5. synthetic method of PP796 intermediates pyrimidine triazole according to claim 2, it is characterised in that：Step 3 It is middle organic phase to be dried processing using anhydrous magnesium sulfate.
- A kind of 6. synthetic method of PP796 intermediates pyrimidine triazole according to claim 2, it is characterised in that：Step 4 Middle that pyrimidine triazole crude product is recrystallized using ethanol-water system, wherein the volume ratio of second alcohol and water is 1:1.
- A kind of 7. synthetic method of PP796 intermediates pyrimidine triazole according to claim 3, it is characterised in that：Described 2,3- dibromo-2-methylpropanoic acid methyl esters be using methyl methacrylate and bromine as raw material, by occur addition reaction prepare, Its reaction equation is as follows：
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3773949A (en) * | 1969-08-14 | 1973-11-20 | Ici Ltd | Certain s-triazolo(1,5-a)pyrimidines for preventing bronchospasm or reducing body fat |
| CN1537853A (en) * | 2003-06-18 | 2004-10-20 | 上海汉飞生化科技有限公司 | Synthesis method of 2-amino-6-methyl-5-oxo-4-normal propyl-5-triazole [1,5-alpha] pyrimidine |
| WO2015012328A1 (en) * | 2013-07-24 | 2015-01-29 | 武田薬品工業株式会社 | Heterocyclic compound |
-
2016
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3773949A (en) * | 1969-08-14 | 1973-11-20 | Ici Ltd | Certain s-triazolo(1,5-a)pyrimidines for preventing bronchospasm or reducing body fat |
| CN1537853A (en) * | 2003-06-18 | 2004-10-20 | 上海汉飞生化科技有限公司 | Synthesis method of 2-amino-6-methyl-5-oxo-4-normal propyl-5-triazole [1,5-alpha] pyrimidine |
| WO2015012328A1 (en) * | 2013-07-24 | 2015-01-29 | 武田薬品工業株式会社 | Heterocyclic compound |
Non-Patent Citations (2)
| Title |
|---|
| 2-取代氨基-6-甲基-5-氧代-4-正丁基-4,5-二氢-1,2,4-三氮唑并[1,5-a]嘧啶类衍生物的合成;张欢欢，等;《有机化学》;20081231;第28卷(第4期);第680-684页，尤其参见其第681页合成路线2，第682页第1.2.3节 * |
| HSAB Driven Chemoselectivity in Alkylation of Uracil Derivatives. A High Yielding Preparation of 3-Alkylated and Unsymmetrically 1,3-Dialkylated Uracils.;Augusto Gambacorta，等;《Tetrahedron》;19991231;第55卷;第12615-12628页 * |
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