CN107382877A - A kind of synthetic method of 4 amino 2 methyl 5 (bromomethyl) pyrimidine hydrobromate - Google Patents
A kind of synthetic method of 4 amino 2 methyl 5 (bromomethyl) pyrimidine hydrobromate Download PDFInfo
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- CN107382877A CN107382877A CN201710695667.1A CN201710695667A CN107382877A CN 107382877 A CN107382877 A CN 107382877A CN 201710695667 A CN201710695667 A CN 201710695667A CN 107382877 A CN107382877 A CN 107382877A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D239/42—One nitrogen atom
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Abstract
The invention discloses a kind of synthetic method of 4 amino 2 methyl 5 (bromomethyl) pyrimidine hydrobromate, 3 methoxypropionitriles and Ethyl formate obtain formylated intermediate sodium salt A under sodium methoxide effect；Intermediate sodium salt A and dimethyl suflfate react to obtain intermediate B；Intermediate B and ethenylamidine hydrochloride are condensed to yield intermediate C；Intermediate C and hydrobromic acid react to obtain (bromomethyl) the pyrimidine hydrobromate I of 4 amino of target product, 2 methyl 5.The raw material sources of the present invention are wide, cheap, and synthetic method production operation is simple, require low to process equipment, it is not necessary to which the harsh working condition such as anhydrous and oxygen-free, high-pressure hydrogenation, reaction condition is gentle, is easy to industrial scale production；With short production cycle and technique is simple, production efficiency is higher, and production method is green, is suitable for industrialization large-scale production.
Description
Technical field
The invention belongs to organic chemistry filed, and in particular to a kind of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromic acid
The synthetic method of salt.
Background technology
4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate is a kind of important pharmaceutical intermediate, is used to tie up earliest
Raw plain B1's is fully synthetic, it can also be used to the important building block of other Advanced Drugs.Vitamin B1 is also known as thiamine, is
First B family vitamin determined.Thiamine relies on the confactor of the enzyme several enzymes relevant with energetic supersession as one, it
It is the synthesis and production of important neurotransmitter, reduces the material used in oxidative stress defence.Vitamin B1 is primarily present in
In the crust and plumule of seed, the vitamin B1 used in people is all the product of chemical synthesis at present.
Synthesis document report on 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate is less.Mainly have following
Several method：
Method one：Nineteen thirty-seven, Joseph K.C, the Robertr W of Merck ＆ Co., Inc. et al. is reported with 3- ethoxy-propionic acids
It is phonetic that ethyl ester and the formylated of Ethyl formate elder generation, hydroformylation product and ethenylamidine hydrochloride are condensed to yield 4- hydroxy-2-methyl -5- ethoxyethyls
Pyridine, pyrimidine ring flows back under the conditions of POCl3 obtains 4- Chloropyrimides, and with concentrated ammonia liquor ammonolysis reaction occurs for 4- Chloropyrimides again
4- amino-2-methyl -5- ethoxyethyl pyrimidines are obtained, finally backflow obtains target compound under hydrobromic acid acetate system.Institute
Process route is as follows：
Method two：Donaldp Picee in 1940 et al. are reported by the use of 4- amino-2-methyl -5- cyanopyrimidines as rising
Beginning raw material prepares the synthetic method of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate.4- amino-2-methyl -5- cyano group
Pyrimidine elder generation cyan-hydrolysis, obtains 4- amino-2-methyls-pyrimidine -5- formic acid, and under the conditions of the concentrated sulfuric acid methanol first occurs for pyrimidinecarboxylic acid
Esterification, obtained pyrimidine methyl esters occur hydrazinolysis and react to obtain pyrimidine formylhydrazine, formylhydrazine and benzene sulfonyl chloride reaction, obtain first
The benzene sulfonyl product of hydrazides, finally reduced to obtain 4- amino-2-methyl -5- formylpyrimidins, 4- in the basic conditions
Amino -2- methyl -5- formylpyrimidins are reduced reagent and reduce to obtain 4- amino-2-methyls -5- (methylol) pyrimidine, finally
Bromo obtains target product.Specific process program is as follows：
4- amino-2-methyl -5- cyanopyrimidines are the important intermediates of modern synthesis vitamin B1, expensive, domestic
Manufacturer is also fewer at present.The above method one and the process route of method two are tediously long, and reaction is complicated, and yield is relatively low, and cost is high
It is high, limit its application in production.
Method three：United States Patent (USP) US2016122319 discloses one kind and pressurizeed by 4- amino-2-methyl -5- cyanopyrimidines
Under the conditions of directly carry out hydro-reduction short-cut method, it is necessary to 20 kilograms of pressure could be realized, equally limit it in reality
Application in production.
It can be seen that reactions steps to be present more for process above scheme, and it is cumbersome, difficulty is isolated and purified, it is with high costs, do not meet
The defects of environmental requirement, therefore, the 4- amino that a kind of synthetic route of urgent need research and development is short, simple to operate, cost is low, green-
The new method of 2- methyl -5- (bromomethyl) pyrimidine hydrobromate.
The content of the invention
The shortcomings that it is an object of the invention to overcome prior art, there is provided a kind of 4- amino-2-methyls -5- (bromomethyl) is phonetic
The synthetic method of pyridine hydrobromate.
The purpose of the present invention is achieved through the following technical solutions：A kind of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrogen
The synthetic method of bromate, comprises the following steps：
S1.3- methoxypropionitriles and Ethyl formate obtain formylated intermediate sodium salt A under sodium methoxide effect；
S2. intermediate sodium salt A and dimethyl suflfate react to obtain intermediate B；
S3. intermediate B and ethenylamidine hydrochloride are condensed to yield intermediate C；
S4. intermediate C and hydrobromic acid react to obtain target product 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromic acid
Salt I；
Synthetic route is：
Further, it is any one in ethers, arene or alcohols that step S1, which reacts solvent for use,.Ethers is preferred
For tetrahydrofuran, methyltetrahydrofuran, ether, dioxane or isopropyl ether；Arene is preferably toluene, benzene or dimethylbenzene；
Alcohols is preferably methanol, ethanol or isopropanol.
Further, step S2 reacts solvent for use for any one in halogenated hydrocarbon or arene.Chlorinated hydrocarbon
Preferably dichloromethane, dichloroethanes, chloroform or 1,1,2,2- tetrachloroethanes；Arene is preferably toluene or benzene.
Further, it is any one in alcohols, amide-type or sulfoxide type that step S3, which reacts solvent for use,.Alcohols is preferred
For ethanol, methanol or isopropanol；
Further, it is organic acid or water that step S4, which reacts solvent for use,.Organic acid is preferably acetic acid, formic acid or propionic acid.
Further, step S1, S2 and S3 reaction temperature is 0~100 DEG C.
Further, step S4 reaction temperature is 0~150 DEG C.
The present invention has advantages below：
(1) the initiation material 3- methoxypropionitriles country of the invention has been carried out scale industrial production, can also be by more
Cheap acrylonitrile is added voluntarily to prepare, while other source chemicals of the present invention are common agents, these raw materials are easy to get, and into
This is cheap；
(2) synthetic method production operation of the invention is simple, requires low to process equipment, it is not necessary to anhydrous and oxygen-free, high pressure
The harsh working condition such as hydrogenation, reaction condition is gentle, is easy to industrial scale production；
(3) method of present invention synthesis 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate, technique is simple, production
Cycle is short, and production efficiency is higher, and production method is green, is suitable for industrialization large-scale production.
Embodiment
With reference to embodiment, the present invention will be further described, and protection scope of the present invention is not limited to following institute
State：
A kind of synthetic method of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate, synthetic route are：
Embodiment 1：A kind of synthetic method of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate, including following step
Suddenly：
S1.3- methoxypropionitriles and Ethyl formate obtain formylated intermediate sodium salt A under sodium methoxide effect；Solvent for use
For tetrahydrofuran, reaction temperature is 0 DEG C；
S2. intermediate sodium salt A and dimethyl suflfate react to obtain intermediate B；Solvent for use is dichloromethane, reaction temperature
For 0 DEG C；
S3. intermediate B and ethenylamidine hydrochloride are condensed to yield intermediate C；Solvent for use is ethanol, and reaction temperature is 0 DEG C；
S4. intermediate C and hydrobromic acid react to obtain target product 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromic acid
Salt I；Solvent for use is acetic acid, and reaction temperature is 0 DEG C.
Embodiment 2：A kind of synthetic method of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate, including following step
Suddenly：
S1.3- methoxypropionitriles and Ethyl formate obtain formylated intermediate sodium salt A under sodium methoxide effect；Solvent for use
Methyltetrahydrofuran, reaction temperature are 100 DEG C；
S2. intermediate sodium salt A and dimethyl suflfate react to obtain intermediate B；Solvent for use is dichloroethanes, reaction temperature
For 100 DEG C；
S3. intermediate B and ethenylamidine hydrochloride are condensed to yield intermediate C；Solvent for use is methanol, and reaction temperature is 100 DEG C；
S4. intermediate C and hydrobromic acid react to obtain target product 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromic acid
Salt I；Solvent for use is formic acid, and reaction temperature is 150 DEG C.
Embodiment 3：A kind of synthetic method of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate, including following step
Suddenly：
S1.3- methoxypropionitriles and Ethyl formate obtain formylated intermediate sodium salt A under sodium methoxide effect；Solvent for use
For ether, reaction temperature is 10 DEG C；
S2. intermediate sodium salt A and dimethyl suflfate react to obtain intermediate B；Solvent for use is chloroform, reaction temperature
For 10 DEG C；
S3. intermediate B and ethenylamidine hydrochloride are condensed to yield intermediate C；Solvent for use is isopropanol, and reaction temperature is 10 DEG C；
S4. intermediate C and hydrobromic acid react to obtain target product 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromic acid
Salt I；Solvent for use is propionic acid, and reaction temperature is 15 DEG C.
Embodiment 4：A kind of synthetic method of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate, including following step
Suddenly：
S1.3- methoxypropionitriles and Ethyl formate obtain formylated intermediate sodium salt A under sodium methoxide effect；Solvent for use
For dioxane, reaction temperature is 20 DEG C；
S2. intermediate sodium salt A and dimethyl suflfate react to obtain intermediate B；Solvent for use is 1,1,2,2- tetrachloroethanes,
Reaction temperature is 20 DEG C；
S3. intermediate B and ethenylamidine hydrochloride are condensed to yield intermediate C；Solvent for use is amide-type, and reaction temperature is 20 DEG C；
S4. intermediate C and hydrobromic acid react to obtain target product 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromic acid
Salt I；Solvent for use is water, and reaction temperature is 25 DEG C.
Embodiment 5：A kind of synthetic method of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate, including following step
Suddenly：
S1.3- methoxypropionitriles and Ethyl formate obtain formylated intermediate sodium salt A under sodium methoxide effect；Solvent for use
For isopropyl ether, reaction temperature is 30 DEG C
S2. intermediate sodium salt A and dimethyl suflfate react to obtain intermediate B；Solvent for use is toluene, reaction temperature 30
℃；
S3. intermediate B and ethenylamidine hydrochloride are condensed to yield intermediate C；Solvent for use is sulfoxide type, and reaction temperature is 30 DEG C；
S4. intermediate C and hydrobromic acid react to obtain target product 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromic acid
Salt I；Solvent for use is acetic acid, and reaction temperature is 40 DEG C.
Embodiment 6：A kind of synthetic method of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate, including following step
Suddenly：
S1.3- methoxypropionitriles and Ethyl formate obtain formylated intermediate sodium salt A under sodium methoxide effect；Solvent for use
For toluene, reaction temperature is 40 DEG C；
S2. intermediate sodium salt A and dimethyl suflfate react to obtain intermediate B；Solvent for use is benzene, reaction temperature 40
℃；
S3. intermediate B and ethenylamidine hydrochloride are condensed to yield intermediate C；Solvent for use is ethanol, and reaction temperature is 40 DEG C；
S4. intermediate C and hydrobromic acid react to obtain target product 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromic acid
Salt I；Solvent for use is water, and reaction temperature is 55 DEG C.
Embodiment 7：A kind of synthetic method of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate, including following step
Suddenly：
S1.3- methoxypropionitriles and Ethyl formate obtain formylated intermediate sodium salt A under sodium methoxide effect；Solvent for use
For benzene, reaction temperature is 50 DEG C；
S2. intermediate sodium salt A and dimethyl suflfate react to obtain intermediate B；Solvent for use is dichloromethane, reaction temperature
For 50 DEG C；
S3. intermediate B and ethenylamidine hydrochloride are condensed to yield intermediate C；Solvent for use is amide-type, and reaction temperature is 50 DEG C；
S4. intermediate C and hydrobromic acid react to obtain target product 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromic acid
Salt I；Solvent for use is acetic acid, and reaction temperature is 65 DEG C.
Embodiment 8：A kind of synthetic method of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate, including following step
Suddenly：
S1.3- methoxypropionitriles and Ethyl formate obtain formylated intermediate sodium salt A under sodium methoxide effect；Solvent for use
For dimethylbenzene, reaction temperature is 60 DEG C；
S2. intermediate sodium salt A and dimethyl suflfate react to obtain intermediate B；Solvent for use is 1,1,2,2- tetrachloroethanes,
Reaction temperature is 60 DEG C；
S3. intermediate B and ethenylamidine hydrochloride are condensed to yield intermediate C；Solvent for use is ethanol, and reaction temperature is 65 DEG C
S4. intermediate C and hydrobromic acid react to obtain target product 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromic acid
Salt I；Solvent for use is formic acid, and reaction temperature is 80 DEG C.
Embodiment 9：A kind of synthetic method of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate, including following step
Suddenly：
S1.3- methoxypropionitriles and Ethyl formate obtain formylated intermediate sodium salt A under sodium methoxide effect；Solvent for use
For methanol, reaction temperature is 70 DEG C；
S2. intermediate sodium salt A and dimethyl suflfate react to obtain intermediate B；Solvent for use is dichloroethanes, reaction temperature
For 65 DEG C；
S3. intermediate B and ethenylamidine hydrochloride are condensed to yield intermediate C；Solvent for use is isopropanol, and reaction temperature is 70 DEG C；
S4. intermediate C and hydrobromic acid react to obtain target product 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromic acid
Salt I；Solvent for use is water, and reaction temperature is 100 DEG C.
Embodiment 10：A kind of synthetic method of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate, including it is following
Step：
S1.3- methoxypropionitriles and Ethyl formate obtain formylated intermediate sodium salt A under sodium methoxide effect；Solvent for use
For ethanol, reaction temperature is 80 DEG C；
S2. intermediate sodium salt A and dimethyl suflfate react to obtain intermediate B；Solvent for use is toluene, reaction temperature 0
~80 DEG C；
S3. intermediate B and ethenylamidine hydrochloride are condensed to yield intermediate C；Solvent for use is sulfoxide type, and reaction temperature is 75 DEG C；
S4. intermediate C and hydrobromic acid react to obtain target product 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromic acid
Salt I；Solvent for use is formic acid, and reaction temperature is 120 DEG C.
Embodiment 11：A kind of synthetic method of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate, including it is following
Step：
S1.3- methoxypropionitriles and Ethyl formate obtain formylated intermediate sodium salt A under sodium methoxide effect；Solvent for use
For isopropanol, reaction temperature is 90 DEG C；
S2. intermediate sodium salt A and dimethyl suflfate react to obtain intermediate B；Solvent for use is dichloroethanes, reaction temperature
For 90 DEG C；
S3. intermediate B and ethenylamidine hydrochloride are condensed to yield intermediate C；Solvent for use is methanol, and reaction temperature is 85 DEG C；
S4. intermediate C and hydrobromic acid react to obtain target product 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromic acid
Salt I；Solvent for use is water, and reaction temperature is 135 DEG C.
Experimental example 1：A kind of synthetic method of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate, including following step
Suddenly：
S1. 1 liter of toluene and 140 grams of sodium methoxides, stirring suspension are added into 2 liters of there-necked flasks；First is slowly added dropwise into system
Acetoacetic ester/3- methoxypropionitriles (200 grams/200 grams) mixed solution, is dripped off for 4 hours.It is added dropwise in the system of being slowly heated to warm
For 48~50 DEG C, the temperature stirring reaction is maintained 24 hours.0 DEG C is cooled to, filtering, filter cake is eluted with q. s. toluene, obtained
Solid obtains 255 grams of off-white powder, yield 80% in 50 DEG C of dryings；
S2. 100 grams of 500 milliliters of dichloroethanes and upper step product are added into 1 liter of there-necked flask, stirring suspension, is slowly added dropwise
112 grams of dimethyl suflfate, process control system temperature is added dropwise and is less than 25 DEG C, slow heating is added dropwise and is warming up to interior temperature as 50
DEG C, thermotonus 16-24 hours are maintained, TLC determines reaction end.Room temperature is down to after completion of the reaction, adds three second thereto
About 20 grams of regulation system pH=8-9 of amine.Filtering, filtrate are collected, and the pH of saturated common salt water washing to organic phase is neutral, anhydrous sulphur
Sour sodium is dried, and is filtered to remove drier, 95 grams of the give light yellow oil that filtrate decompression is concentrated to dryness, yield 100%；
S3. 95 grams of 400 grams of absolute ethyl alcohol and sodium methoxide are added into 1 liter of there-necked flask, stirs lower addition ethenylamidine hydrochloride 142.5
Gram, it is slowly heated to 50 DEG C and stirs 2 hours, 95 grams of methylate is walked in addition, continues to be heated to system back flow reaction 8-16
Hour, TLC determines reaction end.Room temperature is down to after completion of the reaction, is filtered, and filtrate pressurization is concentrated to dryness to obtain semi-solid crude product.To
80 grams of ethyl acetate is added in crude product, system dissolving clarification is heated to, adds 140 grams of petroleum ether while hot, a large amount of solids separate out, drop
Temperature crystallization, filtering, dry 55.5 grams of cyclization product, yield 45%；
S4. added into 1 liter of single port bottle and walk 10 grams of cyclization product, be slowly added to 50 milliliters of 33%HBr/HOAc solution,
System is to slowly warm up to 100 DEG C, maintains thermotonus 8-16 hours, TLC determines reaction end.Add while hot after completion of the reaction
Enter acid 2 grams of activated carbon, stirring is filtered after 30 minutes, and filtrate pressurization is concentrated to dryness, and adds 30 milliliters of absolute ethyl alcohol, cooling knot
Crystalline substance, filtering, dry 14.2 grams of target product, yield 83%.
Experimental example 2：A kind of synthetic method of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate, including following step
Suddenly：
S1. 1 liter of toluene and 140 grams of sodium methoxides, stirring suspension are added into 2 liters of there-necked flasks；First is slowly added dropwise into system
Acetoacetic ester/3- methoxypropionitriles (200 grams/200 grams) mixed solution, is dripped off for 4 hours.It is added dropwise in the system of being slowly heated to warm
For 48~50 DEG C, the temperature stirring reaction is maintained 24 hours.0 DEG C is cooled to, filtering, filter cake is eluted with q. s. toluene, obtained
Solid obtains 269 grams of off-white powder, yield 85% in 50 DEG C of dryings；
S2. 100 grams of 500 milliliters of dichloroethanes and upper step product are added into 1 liter of there-necked flask, stirring suspension, is slowly added dropwise
112 grams of dimethyl suflfate, process control system temperature is added dropwise and is less than 25 DEG C, slow heating is added dropwise and is warming up to interior temperature as 50
DEG C, thermotonus 16-24 hours are maintained, TLC determines reaction end.Room temperature is down to after completion of the reaction, adds three second thereto
About 20 grams of regulation system pH=8-9 of amine.Filtering, filtrate are collected, and the pH of saturated common salt water washing to organic phase is neutral, anhydrous sulphur
Sour sodium is dried, and is filtered to remove drier, 95 grams of the give light yellow oil that filtrate decompression is concentrated to dryness, yield 100%；
S3. 95 grams of 400 grams of absolute ethyl alcohol and sodium methoxide are added into 1 liter of there-necked flask, stirs lower addition ethenylamidine hydrochloride 142.5
Gram, it is slowly heated to 50 DEG C and stirs 2 hours, 95 grams of methylate is walked in addition, continues to be heated to system back flow reaction 8-16
Hour, TLC determines reaction end.Room temperature is down to after completion of the reaction, is filtered, and filtrate pressurization is concentrated to dryness to obtain semi-solid crude product.To
80 grams of ethyl acetate is added in crude product, system dissolving clarification is heated to, adds 140 grams of petroleum ether while hot, a large amount of solids separate out, drop
Temperature crystallization, filtering, dry 61.7 grams of cyclization product, yield 50%；
S4. added into 1 liter of single port bottle and walk 50 grams of cyclization product, be slowly added to 250 milliliters of 33%HBr/HOAc solution,
System is to slowly warm up to 100 DEG C, maintains thermotonus 8-16 hours, TLC determines reaction end.Add while hot after completion of the reaction
Enter acid 10 grams of activated carbon, stirring is filtered after 30 minutes, and filtrate pressurization is concentrated to dryness, and adds 150 milliliters of absolute ethyl alcohol, cooling knot
Crystalline substance, filtering, dry 73 grams of target product, yield 85%.
Experimental example 3：A kind of synthetic method of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate, including following step
Suddenly：
S1. 2.5 liters of toluene and 350 grams of sodium methoxides, stirring suspension are added into 5 liters of there-necked flasks；It is slowly added dropwise into system
Ethyl formate/3- methoxypropionitriles (500 grams/500 grams) mixed solution, is dripped off for 4 hours.It is added dropwise in the system of being slowly heated to
Temperature is 48~50 DEG C, maintains the temperature stirring reaction 24 hours.0 DEG C is cooled to, filtering, filter cake is eluted with q. s. toluene, obtained
Solid in 50 DEG C of dryings, obtain 690 grams of off-white powder, yield 87%；
S2. 500 grams of 2.5 liters of dichloroethanes and upper step product are added into 5 liters of there-necked flasks, stirring suspension, sulphur is slowly added dropwise
560 grams of dimethyl phthalate, process control system temperature is added dropwise and is less than 25 DEG C, slow heating is added dropwise and is warming up to interior temperature as 50 DEG C,
Thermotonus 16-24 hours are maintained, TLC determines reaction end.Room temperature is down to after completion of the reaction, adds triethylamine about thereto
20 grams of regulation system pH=8-9.Filtering, filtrate are collected, and the pH of saturated common salt water washing to organic phase is neutral, anhydrous sodium sulfate
Dry, be filtered to remove drier, 470 grams of the give light yellow oil that filtrate decompression is concentrated to dryness, yield 100%；
S3. 190 grams of 800 grams of absolute ethyl alcohol and sodium methoxide are added into 1 liter of there-necked flask, stirs lower addition ethenylamidine hydrochloride 285
Gram, it is slowly heated to 50 DEG C and stirs 2 hours, 190 grams of methylate is walked in addition, continues to be heated to system back flow reaction 8-16
Hour, TLC determines reaction end.Room temperature is down to after completion of the reaction, is filtered, and filtrate pressurization is concentrated to dryness to obtain semi-solid crude product.To
80 grams of ethyl acetate is added in crude product, system dissolving clarification is heated to, adds 300 grams of petroleum ether while hot, a large amount of solids separate out, drop
Temperature crystallization, filtering, dry 135.8 grams of cyclization product, yield 55%；
S4. added into 1 liter of single port bottle and walk 100 grams of cyclization product, be slowly added to the milli of 33%HBr/HOAc solution 500
Rise, system is to slowly warm up to 100 DEG C, maintains thermotonus 8-16 hours, TLC determines reaction end.Take advantage of after completion of the reaction
Heat adds acid 20 grams of activated carbon, and stirring is filtered after 30 minutes, and filtrate pressurization is concentrated to dryness, and adds 30 milliliters of absolute ethyl alcohol, drop
Temperature crystallization, filtering, dry 149 grams of target product, yield 87%.
Claims (7)
1. a kind of synthetic method of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate, it is characterised in that including following
Step：
S1.3- methoxypropionitriles and Ethyl formate obtain formylated intermediate sodium salt A under sodium methoxide effect；
S2. intermediate sodium salt A and dimethyl suflfate react to obtain intermediate B；
S3. intermediate B and ethenylamidine hydrochloride are condensed to yield intermediate C；
S4. intermediate C and hydrobromic acid react to obtain target product 4- amino-2-methyls -5- (bromomethyl) pyrimidines hydrobromate I；
Synthetic route is：
2. a kind of synthetic method of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate as claimed in claim 1, its
It is characterised by, step S1 reaction solvent for use is any one in ethers, arene or alcohols.
3. a kind of synthetic method of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate as claimed in claim 1, its
It is characterised by, step S2 reaction solvent for use is any one in halogenated hydrocarbon or arene.
4. a kind of synthetic method of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate as claimed in claim 1, its
It is characterised by, step S3 reaction solvent for use is any one in alcohols, amide-type or sulfoxide type.
5. a kind of synthetic method of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate as claimed in claim 1, its
It is characterised by, step S4 reaction solvent for use is organic acid or water.
6. a kind of synthetic method of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate as claimed in claim 1, its
It is characterised by, step S1, S2 and S3 reaction temperature is 0~100 DEG C.
7. a kind of synthetic method of 4- amino-2-methyls -5- (bromomethyl) pyrimidine hydrobromate as claimed in claim 1, its
It is characterised by, step S4 reaction temperature is 0~150 DEG C.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109651261A (en) * | 2019-01-11 | 2019-04-19 | 江苏快达农化股份有限公司 | The method of one pot process 4- amino -2,5- dimethoxypyridin |
| CN109651260A (en) * | 2018-12-22 | 2019-04-19 | 山东国邦药业股份有限公司 | A kind of preparation method of 4- amino -5- methoxy -2- propyl pyrimidine |
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| US3211778A (en) * | 1961-05-18 | 1965-10-12 | Merck & Co Inc | Method for preparing acrylonitrile derivatives |
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| US3211778A (en) * | 1961-05-18 | 1965-10-12 | Merck & Co Inc | Method for preparing acrylonitrile derivatives |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109651260A (en) * | 2018-12-22 | 2019-04-19 | 山东国邦药业股份有限公司 | A kind of preparation method of 4- amino -5- methoxy -2- propyl pyrimidine |
| CN109651261A (en) * | 2019-01-11 | 2019-04-19 | 江苏快达农化股份有限公司 | The method of one pot process 4- amino -2,5- dimethoxypyridin |
| CN109651261B (en) * | 2019-01-11 | 2022-05-20 | 江苏快达农化股份有限公司 | Method for synthesizing 4-amino-2, 5-dimethoxypyrimidine by one-pot method |
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