CN107312003A - A kind of synthetic method for preparing the chlorine guanine of 2 amino of high-purity 6 - Google Patents
A kind of synthetic method for preparing the chlorine guanine of 2 amino of high-purity 6 Download PDFInfo
- Publication number
- CN107312003A CN107312003A CN201710552625.2A CN201710552625A CN107312003A CN 107312003 A CN107312003 A CN 107312003A CN 201710552625 A CN201710552625 A CN 201710552625A CN 107312003 A CN107312003 A CN 107312003A
- Authority
- CN
- China
- Prior art keywords
- chlorine
- amino
- purity
- guanines
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of synthetic method for preparing the chlorine guanine of 2 amino of high-purity 6, the synthetic method is with formula（II）Shown guanine be raw material, in organic solvent with Vilsmeier reagents at a temperature of 50 160 DEG C the 24h of stirring reaction 1, obtain such as formula（III）The shown chlorine guanine of 2 formamido of chloro intermediate 6, it is described such as formula（III）Shown chloro intermediate is hydrolyzed under the aqueous solution effect of alkali, isolates and purifies the formula for obtaining high-purity（I）The shown chlorine guanine of 2 amino of product 6.The present invention to the intermediate generated in course of reaction by separating, then carries out next step hydrolysis, obtains the chlorine guanine of 2 amino of product 6 of high-purity, is determined through efficient liquid phase（HPLC）Purity is up to more than 99.0%；The synthetic method yield of the present invention is good, and production cost is low, and reaction condition is gentle, and simple to operate, the three wastes are few, environmentally friendly, with larger implementary value and economic results in society.
Description
Technical field
It is more particularly to a kind of with double the present invention relates to a kind of synthetic method for preparing high-purity 2- amino -6- chlorine guanines
（Trichloromethyl）Carbonic ester（BTC）WithN,N- disubstituted amide be made Vilsmeier reagents as chlorinating agent, then with guanine
React the method for preparing 2- amino -6- chlorine guanines.
Background technology
2- amino -6- chlorine guanines are a kind of important medicine intermediates, are the general former times Lip rivers of purine biosynthesis class antiviral drugs
The important intermediate of Wei, Penciclovir and Valaciclovir, it may also be used for the synthesis of anticancer, hypotensive and anti-inflammation drugs.
At present, the synthetic route of 2- amino -6- chlorine guanines mainly has following several：
Route one：Balsiger etc.（J, Org, Chem. 1960, 25: 1573-1575.）First reported using guanine as
Raw material, unstable thioguanine is obtained with phosphoric sulfide reaction, then 2- amino -6- chlorine guanines are made with chlorine reaction,
The route yield is 61%, but environmental pollution is serious, not only poisonous and harmful especially with sulfur compound phosphoric sulfide, and smell
It is very smelly, while it is dangerous technique to carry out chlorination using chlorine, high is required to equipment and operation, in addition the thio intermediate
It is unstable so that reaction yield is relatively low；Route two：Raymond etc.（EP0203685A2）Report using guanine and trichlorine oxygen
Phosphorus is raw material, in phase transfer catalyst（Tetramethyl ammonium chloride）In the presence of, it is fast that first chlorination hydrolyzes preparation 2- amino -6- chlorine birds again
Purine, the route yield is only 30%, the value without industrialization；Route three：Japanese Sumika companies are in patent
（EP0543095A2）In report guanine first withN,N- dimethylformamide (DMF) is in POCl3In the presence of, reaction generation
2- dimethylamino methylene imino group -6- chlorine guanines, then hydrolyze and obtain 2- amino -6- chlorine guanines, total recovery is about 55%, should
Route operation is relatively complicated, and has used POCl disagreeableness to environment3Three-waste pollution is serious；Route four：Smithkline
Beecham companies（WO9407892）With 2,4,5- triamido -6- chlorine pyrimidines for raw material, 2- is prepared with triethyl orthoformate cyclization
Amino -6- chlorine guanines, total recovery is about 62%, but the prices of raw materials are expensive, are difficult to obtain, particularly preparing raw material 2,4,
The reaction time of 5- triamido -6- chlorine pyrimidines is up to 28 hours, the value without industrialization.
It can be seen that, the conventional method generally existings of 2- amino -6- chlorine guanines that yield is low, environmental pollution is serious, cost is high,
The problems such as isolating and purifying difficulty, therefore, finds low environmentally friendly, cost, high income and the green syt for being easily isolated purifying
2- amino -6- chlorine guanine synthetic methods are extremely urgent.
The content of the invention
The purpose of the present invention is to overcome the shortcoming of prior art there is provided a kind of rational technology, and production safety is reliable, reaction is received
Rate is high, the chemical synthesis process for the 2- amino -6- chlorine guanines that cost is low, product is easily isolated, environmental pollution is small.
In order to solve the above technical problems, the technical solution adopted by the present invention is as follows：
A kind of synthetic method for preparing high-purity 2- amino -6- chlorine guanines, with formula（II）Shown guanine is raw material, is being had
In machine solvent with Vilsmeier reagents at a temperature of 50-160 DEG C stirring reaction 1-24h, obtain such as formula（III）Shown chloro
Intermediate 2- formamido -6- chlorine guanines, it is described such as formula（III）Shown chloro intermediate water under the aqueous solution effect of alkali
Solution, isolates and purifies the formula for obtaining high-purity（I）Shown product 2- amino -6- chlorine guanines.
Further, described Vilsmeier reagents by double (trichloromethyl) carbonic esters withN,N- disubstituted amide is in 0-
Stirring reaction 1h is made at a temperature of 10 DEG C, describedN,N- disubstituted amide is preferablyN,N- dimethylformamide,N- methyl-N-
One kind in phenyl formamide；Described double (trichloromethyl) carbonic esters withN,NThe amount ratio of the material that feeds intake of-disubstituted amide is
1：3.0.
Further, described organic solvent is one of following solvent or the mixture of more than one arbitrary proportions：Dichloro
Methane, 1,2- dichloroethanes, chloroform, chlorine benzene,toluene,xylene, ethylbenzene, nitrobenzene, dimethyl sulfoxide (DMSO),N,N- dimethyl
Formamide, preferably 1,2- dichloroethanes, toluene, dimethylbenzene, chlorobenzene；The consumption of described organic solvent is formula（II）Shown
The 16mL/g-25mL/g of raw material guanine quality.
Further, described formula（II）The amount ratio of shown raw material guanine and the material that feeds intake of Vilsmeier reagents
For 1：0.3-2.0, preferably 1：1-1.5；Described reaction temperature is preferably 86-110 DEG C；Reaction time is preferably 5-9h.
Further, the aqueous solution of described alkali is the metal hydroxides aqueous solution, the metal carbonate compound aqueous solution, metal
The carbonic acid hydride aqueous solution, preferably 1%-10% sodium hydroxides, saturated sodium bicarbonate solution.
Further, the synthetic method specifically includes following steps：
Step A：Double (trichloromethyl) carbonic esters and organic solvent are added first in three-necked flask, ice bath is cooled to 0-10 DEG C,
Then it is added dropwiseN,N- disubstituted amide, double (trichloromethyl) carbonic esters withN,NThe amount ratio for the material that-disubstituted amide feeds intake is 1：
3, after completion of dropping, continue stirring reaction 1h, obtain Vilsmeier reagents；
Step B：Formula is added in the Vilsmeier reagents that step A is obtained（II）Shown guanine, is heated to 86-110
DEG C, react 5-9h；After completion of the reaction, add and be quenched in frozen water, separate organic phase, aqueous phase adds the aqueous solution of alkali to adjust pH=3-4,
50-70 DEG C is warming up to, 1-3 h are reacted, suction filtration, washing obtains formula（III）Shown 2- formamido -6- chlorine guanine wet products；
Step C：By formula（III）Shown 2- formamido -6- chlorine guanine wet products, which are added in the aqueous solution of alkali, to be dissolved, room temperature
Lower stirring hydrolysis 3h, after reaction terminates, with acid for adjusting pH=7.5, has a large amount of solids to separate out, filters, filter cake is dried in washing
The formula of dry high-purity（I）Shown target product white solid 2- amino -6- chlorine guanines；
Its reaction equation is as follows：
Wherein：R1And R2Alkyl or phenyl or substituted phenyl for C1-C4.
Further, acid used is hydrochloric acid, sulfuric acid, formic acid, acetic acid etc., preferably hydrochloric acid, acetic acid in described step C.
The invention has the advantages that：
（1）The present invention to the intermediate generated in course of reaction by separating, then carries out next step hydrolysis, obtains height
The product 2- amino -6- chlorine guanines of purity, are determined through efficient liquid phase（HPLC）Purity is up to more than 99.0%.
（2）The synthetic method yield of the present invention is good, and production cost is low, and reaction condition is gentle, and simple to operate, the three wastes are few,
It is environmentally friendly, with larger implementary value and economic results in society.
Embodiment
Illustrate technical scheme, but protection scope of the present invention not limited to this with specific embodiment below.
Embodiment 1
In the 3 L three-necked flasks equipped with mechanical agitation, reflux condensing tube and thermometer, add double（Trichloromethyl）Carbonic ester
119.0 g (0.4 mol) and 1000 mL toluene, are added dropwise under ice-water bathN,NThe g of-dimethylformamide 88.0 (1.2 mol),
After completion of dropping, continue to stir 1 h, then add the g of guanine 60.0 (0.4 mol), temperature rising reflux reacts 5 h, and reaction is finished
Afterwards, it is added in frozen water and is quenched, separate organic phase, aqueous phase adds saturated sodium bicarbonate solution to adjust pH=3, is warming up to 70 DEG C of reactions 3
H, is cooled to room temperature, and suction filtration, washing obtains 2- formamido -6- chlorine guanine wet products.1H NMR (400 MHz, d6-DMSO):
δ 13.63 (s, 1H, CONH), 11.95 (s, 1H, NH), 9.32(s, 1H, CHO), 8.46(s, 1H, CH).
MS (ESI): m/z = 196.2 [M-H]-, 198.2。
Above-mentioned 2- formamidos -6- chlorine guanines are added in 500 mL saturated sodium bicarbonate solutions and dissolved, room temperature (25
DEG C) under the h of hydrolysis 3, reaction terminate after, with 35% hydrochloric acid solution adjust pH=7.5, filter, washing, filter cake is dried in vain
The g of color 2- amino -6- chlorine guanines 49.7, product yield 73.3%, HPLC detection levels 99.5%.1H NMR (400 MHz, d6-
DMSO): δ 12.81 (s, 1H, NH), 8.07 (s, 1H, CH), 6.74 (s, 2H, NH2). MS (ESI): m/
z = 168.2 [M-H]-, 170.2。
Embodiment 2
By 2- formamido -6- chlorine guanines（Preparation method be the same as Example 1）It is added to molten in the sodium hydroxide solutions of 500 mL 1%
The h of hydrolysis 1 under solution, room temperature (25 DEG C), after reaction terminates, pH=7.5 are adjusted with 10% acetic acid solution, are filtered, and washing will be filtered
Cake dries to obtain the white g of 2- amino -6- chlorine guanines 34.4, product yield 50.7%, HPLC detection levels 99.1%.
Embodiment 3
By 2- formamido -6- chlorine guanines（Prepare be the same as Example 1）It is added in the sodium hydroxide solutions of 500 mL 5% and dissolves,
The h of hydrolysis 3 under room temperature (25 DEG C), after reaction terminates, pH=7.5 are adjusted with 35% hydrochloric acid solution, are filtered, and filter cake is dried in washing
Do to obtain the white g of 2- amino -6- chlorine guanines 36.8, product yield 54.3%, HPLC detection levels 99.3%.
Embodiment 4
In the 3 L three-necked flasks equipped with mechanical agitation, reflux condensing tube and thermometer, add double（Trichloromethyl）Carbonic ester
178.0 g (0.6 mol) and 1000 mL toluene, are added dropwise under ice-water bathN,NThe g (1.8 of-dimethylformamide 132.0
Mol), after completion of dropping, continue to stir 1 h, then add the g of guanine 60.0 (0.4 mol), temperature rising reflux reacts 6 h, instead
After should finishing, add and be quenched in frozen water, separate organic phase, aqueous phase adds 5% sodium hydroxide solution to adjust pH=3, be warming up to 50 DEG C instead
3 h are answered, room temperature is cooled to, suction filtration, washing obtains 2- formamido -6- chlorine guanine wet products.
Then, the hydrolysis of 2- formamidos -6- chlorine guanines is operated according to embodiment 3, obtains white 2- amino -6- chlorine birds
The g of purine 39.9, product yield 58.8%, HPLC detection levels 99.1%.
Embodiment 5
In the 3 L three-necked flasks equipped with mechanical agitation, reflux condensing tube and thermometer, add double（Trichloromethyl）Carbonic ester
119.0 g (0.4 mol) and 1500 mL toluene, are added dropwise under ice-water bathN,NThe g of-dimethylformamide 88.0 (1.2 mol),
After completion of dropping, continue to stir 1 h, then add the g of guanine 60.0 (0.4 mol), be warming up to 90 DEG C of 7 h of reaction, reacted
Bi Hou, adds and is quenched in frozen water.
Other operation be the same as Examples 1, obtain the g of 2- amino -6- chlorine guanines 48.0, and product yield 70.8%, HPLC detections contain
Amount 99.6%.
Embodiment 6
In the 3 L three-necked flasks equipped with mechanical agitation, reflux condensing tube and thermometer, add double（Trichloromethyl）Carbonic ester
178.0 g (0.6 mol) and 1000 mL toluene, are added dropwise under ice-water bathN,NThe g (1.8 of-dimethylformamide 132.0
Mol), after completion of dropping, continue to stir 1 h, then add the g of guanine 60.0 (0.4 mol), be warming up to 100 DEG C of 6 h of reaction,
After completion of the reaction, add and be quenched in frozen water.
Other operation be the same as Examples 1, obtain the g of 2- amino -6- chlorine guanines 48.7, and product yield 71.8%, HPLC detections contain
Amount 99.4%.
Embodiment 7
In the 3 L three-necked flasks equipped with mechanical agitation, reflux condensing tube and thermometer, add double（Trichloromethyl）Carbonic ester
119.0 g (0.4 mol) and 1000 mL toluene, are added dropwise under ice-water bathN- methyl-NThe g (1.2 of-phenyl formamide 162.0
Mol), after completion of dropping, continue to stir 1 h, then add the g of guanine 60.0 (0.4 mol), temperature rising reflux reacts 5 h, instead
After should finishing, add and be quenched in frozen water, separate organic phase, aqueous phase adds saturated sodium bicarbonate solution to adjust pH=3, is warming up to 70 DEG C
1 h is reacted, room temperature is cooled to, suction filtration, washing obtains 2- formamido -6- chlorine guanine wet products.
Then, the hydrolysis of 2- formamidos -6- chlorine guanines is operated according to embodiment 1, obtains 2- amino -6- chlorine guanines
44.3 g, product yield 65.3%, HPLC detection levels 99.2%.
Embodiment 8
In the 3 L three-necked flasks equipped with mechanical agitation, reflux condensing tube and thermometer, add double（Trichloromethyl）Carbonic ester
119.0 g (0.4 mol) and 1000 mL 1,2- dichloroethanes is added dropwise under ice-water bathN,NThe g of-dimethylformamide 88.0
After (1.2 mol), completion of dropping, continue to stir 1 h, then add the g of guanine 60.0 (0.4 mol), temperature rising reflux reaction 9
H, after completion of the reaction, adds and is quenched in frozen water, separates organic phase, and aqueous phase adds 5% sodium hydroxide solution to adjust pH=4, is warming up to 70
DEG C 3 h of reaction, are cooled to room temperature, suction filtration, washing obtains 2- formamido -6- chlorine guanine wet products.
Then, the hydrolysis of 2- formamidos -6- chlorine guanines is operated according to embodiment 3, obtains white 2- amino -6- chlorine birds
The g of purine 33.4, product yield 49.2%, HPLC detection levels 98.9%.
Embodiment 9
In the 3 L three-necked flasks equipped with mechanical agitation, reflux condensing tube and thermometer, add double（Trichloromethyl）Carbonic ester
119.0 g (0.4 mol) and 1000 mL 1,2- dichloroethanes is added dropwise under ice-water bathN,NThe g of-dimethylformamide 88.0
After (1.2 mol), completion of dropping, continue to stir 1 h, then add the g of guanine 60.0 (0.4 mol), temperature rising reflux reaction 5
H, after completion of the reaction, adds and is quenched in frozen water, separates organic phase, and aqueous phase adds saturated sodium bicarbonate solution to adjust pH=3, is warming up to
70 DEG C of 3 h of reaction, are cooled to room temperature, and suction filtration, washing obtains 2- formamido -6- chlorine guanine wet products.
Other operation be the same as Examples 1, obtain the g of 2- amino -6- chlorine guanines 37.9, and product yield 55.9%, HPLC detections contain
Amount 99.3%.
Embodiment 10
In the 3 L three-necked flasks equipped with mechanical agitation, reflux condensing tube and thermometer, add double（Trichloromethyl）Carbonic ester
178.0 g (0.6 mol) and 1500 mL 1,2- dichloroethanes is added dropwise under ice-water bathN- methyl-N- phenyl formamide 162.0
After g (1.2 mol), completion of dropping, continue to stir 1 h, then add the g of guanine 60.0 (0.4 mol), temperature rising reflux reaction 6
H, after completion of the reaction, adds and is quenched in frozen water.
Other operations are operated according to embodiment 3, obtain the g of 2- amino -6- chlorine guanines 34.5, product yield 50.9%, HPLC
Detection level 99.0%.
Embodiment 11
In the 3 L three-necked flasks equipped with mechanical agitation, reflux condensing tube and thermometer, add double（Trichloromethyl）Carbonic ester
119.0 g (0.4 mol) and 1500 mL dimethylbenzene, are added dropwise under ice-water bathN,NThe g (1.2 of-dimethylformamide 88.0
Mol), after completion of dropping, continue to stir 1 h, then add the g of guanine 60.0 (0.4 mol), be warming up to 90 DEG C of 7 h of reaction,
After completion of the reaction, add and be quenched in frozen water, separate organic phase, aqueous phase adds saturated sodium bicarbonate solution to adjust pH=4, is warming up to 70
DEG C 1 h of reaction, is cooled to room temperature, suction filtration, washing obtains 2- formamido -6- chlorine guanine wet products.
The hydrolysis of 2- formamido -6- chlorine guanines is operated according to embodiment 1, obtains the g of 2- amino -6- chlorine guanines 48.5,
Product yield 71.5%, HPLC detection levels 99.1%.
Embodiment 12
In the 3 L three-necked flasks equipped with mechanical agitation, reflux condensing tube and thermometer, add double（Trichloromethyl）Carbonic ester
119.0 g (0.4 mol) and 1000 mL dimethylbenzene, are added dropwise under ice-water bathN,NThe g (1.2 of-dimethylformamide 88.0
Mol), after completion of dropping, continue to stir 1 h, then add the g of guanine 60.0 (0.4 mol), temperature rising reflux reacts 5 h, instead
After should finishing, add and be quenched in frozen water, separate organic phase, aqueous phase adds 5% sodium hydroxide solution to adjust pH=4, be warming up to 70 DEG C instead
3 h are answered, room temperature is cooled to, suction filtration, washing obtains 2- formamido -6- chlorine guanine wet products.
The hydrolysis of 2- formamido -6- chlorine guanines is operated according to embodiment 1, obtains the g of 2- amino -6- chlorine guanines 52.7,
Product yield 77.7%, HPLC detection levels 99.3%.
Embodiment 13
In the 3 L three-necked flasks equipped with mechanical agitation, reflux condensing tube and thermometer, add double（Trichloromethyl）Carbonic ester
119.0 g (0.4 mol) and 1000 mL chlorobenzenes, are added dropwise under ice-water bathN,NThe g of-dimethylformamide 88.0 (1.2 mol),
After completion of dropping, continue to stir 1 h, then add the g of guanine 60.0 (0.4 mol), temperature rising reflux reacts 5 h, and reaction is finished
Afterwards, add and be quenched in frozen water, separate organic phase, aqueous phase adds 5% sodium hydroxide solution to adjust pH=3, be warming up to 60 DEG C of 3 h of reaction,
Room temperature is cooled to, suction filtration, washing obtains 2- formamido -6- chlorine guanine wet products.
The hydrolysis of 2- formamido -6- chlorine guanines is operated according to embodiment 1, obtains the g of 2- amino -6- chlorine guanines 53.1,
Product yield 78.3%, HPLC detection levels 99.5%.
Finally it should be noted that implementing to be merely illustrative of the technical solution of the present invention above to be not intended to limit the present invention, to the greatest extent
The present invention is described in detail with reference to preferred embodiment for pipe, it will be understood by those within the art that, can be to hair
Bright technical scheme is modified or equivalent substitution, and without departing from the spirit and scope of technical solution of the present invention, it all should contain
Cover in scope of the presently claimed invention.
Claims (7)
1. a kind of synthetic method for preparing high-purity 2- amino -6- chlorine guanines, it is characterised in that with formula（II）Shown bird is fast
Purine is raw material, in organic solvent with Vilsmeier reagents at a temperature of 50-160 DEG C stirring reaction 1-24h, obtain such as formula
（III）Shown chloro intermediate 2- formamido -6- chlorine guanines, it is described such as formula（III）Shown chloro intermediate is in alkali
Aqueous solution effect it is lower hydrolyze, isolate and purify the formula for obtaining high-purity（I）Shown product 2- amino -6- chlorine guanines.
2. the synthetic method according to claim 1 for preparing high-purity 2- amino -6- chlorine guanines, it is characterised in that described
Vilsmeier reagents by double (trichloromethyl) carbonic esters withN,N- disubstituted amide stirring reaction 1h systems at a temperature of 0-10 DEG C
, it is describedN,N- disubstituted amide is preferablyN,N- dimethylformamide,N- methyl-NOne kind in-phenyl formamide；Institute
Double (trichloromethyl) carbonic esters stated withN,NThe amount ratio of the material that feeds intake of-disubstituted amide is 1：3.0.
3. the synthetic method according to claim 1 for preparing high-purity 2- amino -6- chlorine guanines, it is characterised in that described
Organic solvent be one of following solvent or the mixture of more than one arbitrary proportions：Dichloromethane, 1,2- dichloroethanes, trichlorine
Methane, chlorine benzene,toluene,xylene, ethylbenzene, nitrobenzene, dimethyl sulfoxide (DMSO),N,N- dimethylformamide, preferably 1,2- dichloros
Ethane, toluene, dimethylbenzene, chlorobenzene；The consumption of described organic solvent is formula（II）The 16mL/ of shown raw material guanine quality
g-25mL/g。
4. the synthetic method according to claim 1 for preparing high-purity 2- amino -6- chlorine guanines, it is characterised in that described
Formula（II）The amount ratio of shown raw material guanine and the material that feeds intake of Vilsmeier reagents is 1：0.3-2.0, preferably 1：1-
1.5；Described reaction temperature is preferably 86-110 DEG C；Reaction time is preferably 5-9h.
5. the synthetic method according to claim 1 for preparing high-purity 2- amino -6- chlorine guanines, it is characterised in that described
Alkali the aqueous solution be the metal hydroxides aqueous solution, the metal carbonate compound aqueous solution, the metal carbonate hydride aqueous solution, preferably
1%-10% sodium hydroxides, saturated sodium bicarbonate solution.
6. the synthetic method according to claim 1 for preparing high-purity 2- amino -6- chlorine guanines, it is characterised in that described
Synthetic method specifically includes following steps：
Step A：Double (trichloromethyl) carbonic esters and organic solvent are added first in three-necked flask, ice bath is cooled to 0-10 DEG C,
Then it is added dropwiseN,N- disubstituted amide, double (trichloromethyl) carbonic esters withN,NThe amount ratio for the material that-disubstituted amide feeds intake is 1：
3, after completion of dropping, continue stirring reaction 1h, obtain Vilsmeier reagents；
Step B：Formula is added in the Vilsmeier reagents that step A is obtained（II）Shown guanine, is heated to 86-110
DEG C, react 5-9h；After completion of the reaction, add and be quenched in frozen water, separate organic phase, aqueous phase adds the aqueous solution of alkali to adjust pH=3-4,
50-70 DEG C is warming up to, 1-3 h are reacted, suction filtration, washing obtains formula（III）Shown 2- formamido -6- chlorine guanine wet products；
Step C：By formula（III）Shown 2- formamido -6- chlorine guanine wet products, which are added in the aqueous solution of alkali, to be dissolved, room temperature
Lower stirring hydrolysis 3h, after reaction terminates, with acid for adjusting pH=7.5, has a large amount of solids to separate out, filters, filter cake is dried in washing
The formula of dry high-purity（I）Shown target product white solid 2- amino -6- chlorine guanines；
Its reaction equation is as follows：
Wherein：R1And R2Alkyl or phenyl or substituted phenyl for C1-C4.
7. the synthetic method according to claim 6 for preparing high-purity 2- amino -6- chlorine guanines, it is characterised in that step
Acid used is hydrochloric acid, sulfuric acid, formic acid, acetic acid etc., preferably hydrochloric acid, acetic acid in C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710552625.2A CN107312003A (en) | 2017-07-07 | 2017-07-07 | A kind of synthetic method for preparing the chlorine guanine of 2 amino of high-purity 6 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710552625.2A CN107312003A (en) | 2017-07-07 | 2017-07-07 | A kind of synthetic method for preparing the chlorine guanine of 2 amino of high-purity 6 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107312003A true CN107312003A (en) | 2017-11-03 |
Family
ID=60177726
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710552625.2A Pending CN107312003A (en) | 2017-07-07 | 2017-07-07 | A kind of synthetic method for preparing the chlorine guanine of 2 amino of high-purity 6 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107312003A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108084184A (en) * | 2017-12-25 | 2018-05-29 | 中山市得高行知识产权中心（有限合伙） | A kind of synthetic method of 2- amido-6-chloropurines |
| CN110627729A (en) * | 2019-10-28 | 2019-12-31 | 南京红杉生物科技有限公司 | 2-amino-6-chloropurine, and synthesis method, intermediate and application thereof |
| CN114031620A (en) * | 2021-11-30 | 2022-02-11 | 湖北省宏源药业科技股份有限公司 | Production method of high-purity 2-amino-6-chloroguanine |
| CN114437071A (en) * | 2022-01-12 | 2022-05-06 | 甘肃欣睿泽医药科技有限公司 | Process for preparing purine derivatives |
| CN114478424A (en) * | 2022-01-21 | 2022-05-13 | 浙江工业大学 | Preparation method of azlactone derivative with beta-substituted cycloalkenyl |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101139348A (en) * | 2007-09-27 | 2008-03-12 | 常州工程职业技术学院 | Method for synthesizing 2-amido-6-chloropurine |
-
2017
- 2017-07-07 CN CN201710552625.2A patent/CN107312003A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101139348A (en) * | 2007-09-27 | 2008-03-12 | 常州工程职业技术学院 | Method for synthesizing 2-amido-6-chloropurine |
Non-Patent Citations (3)
| Title |
|---|
| YOSHIMI HIROKAWA ET AL.: "《Synthesis and Structure–Activity Relationships of 4-Amino-5-chloro-N-(1,4-dialkylhexahydro-1,4-diazepin-6-yl)-2-methoxybenzamide Derivatives, Novel and Potent Serotonin 5-HT3 and Dopamine D2 Receptors Dual Antagonist》", 《CHEM. PHARM. BULL.》 * |
| 仝礼等: "《6-氯鸟嘌呤合成工艺的改进》", 《化学工业与工程》 * |
| 黄明旺等: "《克林霉素工艺的改进及其主要杂质形成机理的研究》", 《广东化工》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108084184A (en) * | 2017-12-25 | 2018-05-29 | 中山市得高行知识产权中心（有限合伙） | A kind of synthetic method of 2- amido-6-chloropurines |
| CN110627729A (en) * | 2019-10-28 | 2019-12-31 | 南京红杉生物科技有限公司 | 2-amino-6-chloropurine, and synthesis method, intermediate and application thereof |
| CN114031620A (en) * | 2021-11-30 | 2022-02-11 | 湖北省宏源药业科技股份有限公司 | Production method of high-purity 2-amino-6-chloroguanine |
| CN114437071A (en) * | 2022-01-12 | 2022-05-06 | 甘肃欣睿泽医药科技有限公司 | Process for preparing purine derivatives |
| CN114478424A (en) * | 2022-01-21 | 2022-05-13 | 浙江工业大学 | Preparation method of azlactone derivative with beta-substituted cycloalkenyl |
| CN114478424B (en) * | 2022-01-21 | 2023-09-26 | 浙江工业大学 | Preparation method of azlactone derivative with cycloalkenyl substituted at beta position |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107312003A (en) | A kind of synthetic method for preparing the chlorine guanine of 2 amino of high-purity 6 | |
| CN100391945C (en) | S-(-)-indolyl-2-carboxylic acid synthesizing method | |
| EP3004047B1 (en) | Compounds of '3-(5-substituted oxy-2,4-dinitro-phenyl)-2-oxo-propionic acid ester', process and applications thereof | |
| CN103435557B (en) | 5-fluorocytosine preparation method | |
| IT202000017617A1 (en) | PROCEDURE FOR THE PREPARATION OF AN INTERMEDIATE USED IN THE SYNTHESIS OF LETERMOVIR | |
| CN101333173B (en) | N-[4-(butanal-4-group)-benzoyl]-L-glutamic acid dimethyl ester compound and method for preparing pemetrexed by using the compounds | |
| CN105693748A (en) | Synthesis method of 7-amino-3-chloro-3-cephalosporin-4-carboxylic acid | |
| CN101247806A (en) | SnAr process for preparing benzimidazole compounds | |
| CN108424389A (en) | A kind of preparation method of Ivabradine impurity | |
| CN103387584B (en) | Synthetic method of 7-amino-3-chloro-3-cephem-4-carboxylic acid | |
| CN111349045A (en) | Synthetic method of lenvatinib and novel intermediate | |
| CN108623602A (en) | A method of prepare and purify and replaces Buddhist nun according to Shandong | |
| CN103664960B (en) | Pu Na is for the preparation method of Buddhist nun | |
| CN107311939B (en) | Preparation method of substituted pyrimidone derivative | |
| CN111704559A (en) | Method for preparing 2, 3-dihydro-1-oxo-1H-indene-4-carbonitrile | |
| CN101880278B (en) | One-step method for synthesizing 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline | |
| CN105330525A (en) | Preparation method of 7-hydroxy-1-indanone | |
| CN106432328B (en) | A kind of preparation method of Suo Feibuwei intermediate | |
| CN111574540B (en) | Preparation method of Degatinib | |
| CN112500379B (en) | Olaparib intermediate and preparation method of Olaparib | |
| CN102675310B (en) | Method for preparing pyrazol heteroaromatic compound | |
| CN111606929B (en) | Preparation method of Degatinib | |
| CN103936703A (en) | Preparation method of 5-oxaspiro[2,4]heptane-6-one and intermediate thereof | |
| CN109369710A (en) | A kind of 4-(methylhydroxy phosphoryl)-ALPHA-ketobutyric acid efficiently purifying technique | |
| CN108047069A (en) | A kind of preparation method of 2- amino -3- chloro benzoic ethers |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20171103 |
|
| RJ01 | Rejection of invention patent application after publication |