CN108676005A - A kind of preparation method of high-purity 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine - Google Patents
A kind of preparation method of high-purity 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine Download PDFInfo
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- CN108676005A CN108676005A CN201810816788.1A CN201810816788A CN108676005A CN 108676005 A CN108676005 A CN 108676005A CN 201810816788 A CN201810816788 A CN 201810816788A CN 108676005 A CN108676005 A CN 108676005A
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- chloro
- purine
- methyl
- fluorophenyls
- amine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
Abstract
The invention discloses a kind of preparation methods of 6 amine of 9 [(2 chlorine, 6 fluorophenyl) methyl] 9H purine, belong to chemosynthesis technical field.Include the following steps（1）The preparation of adenine salt：Adenine, water and highly basic are added in the reactor, stirs dissolved clarification, vacuum distillation removes solvent, obtains adenine salt crude product；（2）In the reactor equipped with adenine salt crude product, after addition amides polar solvent fully dissolves, it is cooling, the reaction of 2 chlorine, 6 fluorine benzyl chloride is added, vacuum distillation after reaction removes amides polar solvent and obtains 9 [(2 chlorine, 6 fluorophenyl) methyl] 9H purine, 6 amine crude product；Fine work can be obtained by recrystallization.Preparation process of the present invention is homogeneous system, reaction condition is mild, high income；Without catalyst, raw material process is simple；Target product content obtained, purity are high, and by-products content is low.
Description
Technical field
The invention belongs to chemosynthesis technical fields.
Background technology
China is world agriculture big country, and with the development of the times, animal husbandry is played the part of more in national economy and people's lives
Carry out more important role.Throughout history long river, China's animal husbandry continue to develop, especially after reform and opening-up, achieve and look steadily throughout the world
Purpose is achieved.With advances in technology with country's support energetically, animal husbandry is towards scale, standardization, industrialization and skill
Artization is grown rapidly.Even if in the Modern Animal Husbandry of such a high standard and high-tech, there is also a variety of puzzlements, in livestock and poultry
In breeding process, livestock and poultry are threatened by a variety of diseases, and parasitic infection is exactly wherein one big threat.Parasitic infection can cause
A series of diseases of livestock and poultry, or even cause to infect between livestock and poultry, largely effect on the yield and quality of livestock and poultry.
Global animal husbandry in recent years pays high attention to the parasitic feel of the ball and contaminates influence to livestock and poultry, China also this is improved treatment with
Innovation Input, 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine are a kind of anti-parasite medicine of wide spectrum, structure
It is different from other pest-resistant drugs, with other drugs without cross resistance.With the presence of adenine ring, livestock and poultry in its primary structure
After edible, a paths are the breeding that parasite is interfered by metabolic pathway, and in addition a paths are to be turned by the metabolism of livestock and poultry
Become 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine derivatives, insect resistace enhances than active compound.
At present both at home and abroad, has relevant report prepared by 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine.Specially
Sharp US 4100159 discloses a kind of adenine and the chloro- 6 fluorine benzyl chlorides of 2- are primary raw material, and methyl tricapryl ammonium chloride is catalysis
Agent, n-hexane are solvent with water, and 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine-is prepared using two-phase stirring, reflux type
6- amine crude products, then fine work is prepared using acetic acid, water law, 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine contains in crude product
Amount is 69.9%, and the content of 3 by-products is higher, and after refining, product is white or pale yellow powder, 9- [(the chloro- 6- fluorobenzene of 2-
Base) methyl] -9H- purine -6- amine total recovery be 60.9%, 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine contain
Amount is 89%.Although the route is short, reaction is simple, and reaction is that two-phase return stirring reacts, and phase transfer catalyst need to be added, and
3 by-products that reaction generates account for relatively high, influence the receipts of final 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine
Rate, content；102532138 A of CN use same routes, 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine yields
It is similar to content to United States Patent (USP).It is raw material that patent CN 107698589A, which disclose a kind of adenine, first anti-with BOC acid anhydrides
It answers, the amino of protection 6, then carries out substitution reaction with the chloro- 6- fluoro benzyl alcohols of 2- of mesyl protection again, then hydrolyze again
To 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine, product is white or faint yellow solid, yield 79.5%,
HPLC detection levels are more than 98%.Although this method reduces the generation of 3 by-products in reaction product, yield and product content
Also it improves, but route is longer, technique is more complex, and cost is higher.
Invention content
For the technical problems in the prior art, the present invention provides a kind of high-purity 9- [(the chloro- 6- fluorophenyls of 2-)
Methyl] -9H- purine -6- amine preparation method, preparation process is that homogeneous system, reaction condition are mild, high income；Without catalysis
Agent, raw material process are simple；Target product content obtained, purity are high, and by-products content is low.
The preparation method of 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine, includes the following steps：
（1）The preparation of adenine salt：Be added adenine, water and metal overbase in the reactor, adenine, water and highly basic mole
Than being 1:10~40:Dissolved clarification is stirred at a temperature of 0.9~2,30~80 DEG C, 30~80 DEG C of vacuum distillations remove solvent, it is fast to obtain gland
Purine salt crude product；
（2）The preparation of 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine：In the reactor equipped with adenine salt crude product
In, 10-30 times of amides polar solvent is added under conditions of 30~100 DEG C（Molar ratio）Fully after dissolving, it is cooled to temperature-
At 10~25 DEG C, chloro- 0.9-3 times of the 6 fluorine benzyl chlorides of 2- are added（Molar ratio）, reacted 1-6 hours after addition, reaction terminates decompression
Amide solvent is distilled off and obtains 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine crude products；It is available by recrystallizing
9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine fine work.
The molar ratio of adenine, water and highly basic is 1:10~40:0.9~2.
Step（2）The dosage of middle amides polar solvent is 10~30 times of adenine mole.
Step（2）The addition of the middle chloro- 6 fluorine benzyl chlorides of 2- is 0.9~3 times of adenine mole.
Amides polar solvent is dimethylformamide and/or dimethylacetylamide, can be any one in the two,
It can also be the mixture of the two arbitrary proportion.
Highly basic is sodium hydroxide or potassium hydroxide.
The step of recrystallization is：1）Crude product is dissolved in 90-95 DEG C of acetic acid, 2）Crude product-acetic acid hot solution is added dropwise to
In 70-74 DEG C of ethyl alcohol, 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine crystal is precipitated, and 3）Turbid solution cools down, so
After filter, collect, wash, precipitate crystal.Principle;Crude product is big in hot acetic acid degree under high temperature, increases with the content of ethyl alcohol
When, solubility reduces, and by-product is with 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine in this acetic acid-ethanol system
There is also differences for middle solubility.
Or ethyl alcohol is replaced with methanol, the temperature of corresponding methanol is 55-60 DEG C.
For the present invention compared with US 4100159, advantage is that 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine is thick
9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine contents rise to 85% by 69.9% in product, 3 by-products contents by
25% is reduced to 12%, and product is white powder after refining, and 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine products are pure
Degree rises to 99% or more by 89%, and total recovery rises to 79.8% by 60.9%；And preparation process be homogeneous system, without catalyst,
Reaction condition is mild.Compared with CN 107698589A, the present invention can prepare 9- [(the chloro- 6- fluorobenzene of 2- in a reaction vessel
Base) methyl] -9H- purine -6- amine, and 0.3% is improved in yield, product purity improves 1%, and route is short, is not necessarily to catalyst, prepares
Required raw material are simple, are easy to get, simple for process, low to equipment requirement intensity, easy to operate.
The beneficial effects of the present invention are：
Preparation method preparation process of the present invention is homogeneous system, high income mild without catalyst, reaction condition；Without catalyst,
Raw material process is simple；Target product content obtained, purity are high, and by-products content is low.
Description of the drawings
Fig. 1 is the infared spectrum parsing of 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine.
Fig. 2 is the high performance liquid chromatography detection result of 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine.
Specific implementation mode
The technical solution further illustrated the present invention below by specific implementation mode.Those skilled in the art should be bright
, the embodiment, which is only to aid in, understands the present invention, should not be regarded as a specific limitation of the invention.
Embodiment 1
To equipped with blender, thermometer, dropping funel, reflux 500ml four-hole boiling flasks in, be added sodium hydroxide 8g, water
60ml, adenine 27g, are heated with stirring to 50 DEG C, and after material dissolved clarification, decompression steams solvent, to the reaction vessel for filling solid
Middle addition dimethylformamide 260ml continues to stir and be warming up to 60 DEG C after addition, maintains temperature, stirring molten to solid
Clearly, it cools to 10 DEG C hereinafter, that the mixing that is made by the chloro- 6 fluorine benzyl chlorides of 35.8g 2- and 40ml dimethylformamides is added dropwise is molten
Liquid, the reaction was continued after being added dropwise, and 2h heats and solvent dimethylformamide is removed under reduced pressure, obtain 9- [(2- after reaction
Chloro- 6- fluorophenyls) methyl] -9H- purine -6- amine crude products, 9- [(the chloro- 6- fluorophenyls of 2-) first can be obtained by Ethanol Method crystallization
Base] -9H- purine -6- amine fine work 42.7g, yield 79.8% is 99.1% through HPLC detection levels.
Embodiment 2
To equipped with blender, thermometer, dropping funel, reflux 500ml four-hole boiling flasks in, be added sodium hydroxide 8g, water
60ml, adenine 27g, are heated with stirring to 50 DEG C, and after material dissolved clarification, decompression steams solvent, to the reaction vessel for filling solid
Middle addition dimethylacetylamide 260ml continues to stir and be warming up to 60 DEG C after addition, maintains temperature, stirring molten to solid
Clearly, it cools to 10 DEG C hereinafter, that the mixing that is made by the chloro- 6 fluorine benzyl chlorides of 35.8g 2- and 40ml dimethylacetylamides is added dropwise is molten
Liquid, the reaction was continued after being added dropwise, and 2h heats and solvent dimethylacetylamide is removed under reduced pressure, obtain 9- [(2- after reaction
Chloro- 6- fluorophenyls) methyl] -9H- purine -6- amine crude products, 9- [(the chloro- 6- fluorophenyls of 2-) first can be obtained by Ethanol Method crystallization
Base] -9H- purine -6- amine fine work 40.2g, yield 75.1% is 99.1% through HPLC detection levels.
Embodiment 3
To equipped with blender, thermometer, dropping funel, reflux 500ml four-hole boiling flasks in, be added sodium hydroxide 4g, water
30ml, adenine 13.5g, are heated with stirring to 50 DEG C, after material dissolved clarification, are added what embodiment 1 was distilled to recover into reaction vessel
Dimethylformamide 100ml cools to 10 DEG C hereinafter, being added dropwise by the chloro- 6 fluorine benzyl chlorides of 17.9g 2- and 20ml dimethyl methyls
The mixed solution that amide is made into, the reaction was continued after being added dropwise, and 2h is heated and solvent dimethyl methyl is removed under reduced pressure after reaction
Amide obtains 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine crude products, and 9- [(2- can be obtained by Ethanol Method crystallization
Chloro- 6- fluorophenyls) methyl] -9H- purine -6- amine fine work 18.95g, yield 71.0% is 98.4% through HPLC detection levels.
Embodiment 4
To equipped with blender, thermometer, dropping funel, reflux 500ml four-hole boiling flasks in, be added sodium hydroxide 4g, water
30ml, adenine 13.5g, are heated with stirring to 50 DEG C, and after material dissolved clarification, pressurization steams solvent, hold to the reaction for filling solid
Dimethylacetylamide 130ml is added in device, continues to stir and be warming up to 60 DEG C after addition, maintains temperature, stirring to solid
Dissolved clarification cools to 25 DEG C, and it is molten that the mixing being made by the chloro- 6 fluorine benzyl chlorides of 17.9 g 2- and 20ml dimethylacetylamides is added dropwise
Liquid, the reaction was continued after being added dropwise, and 2h heats and solvent dimethylacetylamide is removed under reduced pressure, obtain 9- [(2- after reaction
Chloro- 6- fluorophenyls) methyl] -9H- purine -6- amine crude products, 9- [(the chloro- 6- fluorophenyls of 2-) first can be obtained by the crystallization of methanol method
Base] -9H- purine -6- amine fine work 19.9g, yield 74.4% is 98.0% through HPLC detection levels.
Embodiment 5
To equipped with blender, thermometer, dropping funel, reflux 500ml four-hole boiling flasks in, be added sodium hydroxide 4g, water
30ml, adenine 13.5g, are heated with stirring to 60 DEG C, and after material dissolved clarification, the chloro- 6 fluorine benzyls of 17.9g 2- are added dropwise into reaction vessel
The mixed solution that chlorine, 2.56g tri-n-octyl methyl ammonium chlorides and 120ml n-hexanes are made into quickly is stirred at reflux anti-after being added dropwise
6h is answered, after reaction, solid-liquid is detached with Buchner funnel, it is thick to obtain 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine
9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine fine work 17.1g can be obtained by Ethanol Method crystallization in product, and yield is
64.2%, it is 97.2% through HPLC detection levels.
Embodiment 6
To equipped with blender, thermometer, dropping funel 500ml three-necked flasks in, sodium hydroxide 8g, water 145ml is added, gland is fast
Purine 27g, is heated with stirring to 80 DEG C, and after material dissolved clarification, decompression steams solvent, and diformazan is added into the reaction vessel for fill solid
Base formamide 160ml continues to stir and be warming up to 60 DEG C after addition, maintains temperature, stirring to solid dissolved clarification, cooling drop
Temperature is to 10 DEG C hereinafter, the mixed solution that dropwise addition is made by the chloro- 6 fluorine benzyl chlorides of 57g 2- and 70ml dimethylacetylamides, is added dropwise
The reaction was continued afterwards, and 2h heats and mixed solvent is removed under reduced pressure, obtain 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- after reaction
9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine fine work can be obtained by Ethanol Method crystallization in purine -6- amine crude products
40.9g, yield 76.1% are 99.0% through HPLC detection levels.
Embodiment 7
To equipped with blender, thermometer, dropping funel, reflux 500ml four-hole boiling flasks in, be added sodium hydroxide 4g, water
20ml, adenine 13.5g, are heated with stirring to 40 DEG C, and after material dissolved clarification, the chloro- 6 fluorine benzyls of 17.9g 2- are added dropwise into reaction vessel
The mixed solution that chlorine, 2.56g tri-n-octyl methyl ammonium chlorides and 120ml n-hexanes are made into quickly is stirred at reflux anti-after being added dropwise
6h is answered, after reaction, solid-liquid is detached with Buchner funnel, it is thick to obtain 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine
9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine fine work 17.0g can be obtained by Ethanol Method crystallization in product, and yield is
63.9%, it is 97.9% through HPLC detection levels.
Embodiment 8
To equipped with blender, thermometer, dropping funel, reflux 500ml four-hole boiling flasks in, be added sodium hydroxide 8g, water
60ml, adenine 13.5g, are heated with stirring to 60 DEG C, and after material dissolved clarification, the chloro- 6 fluorine benzyls of 17.9g 2- are added dropwise into reaction vessel
The mixed solution that chlorine, 2.56g tri-n-octyl methyl ammonium chlorides and 120ml n-hexanes are made into quickly is stirred at reflux anti-after being added dropwise
6h is answered, after reaction, solid-liquid is detached with Buchner funnel, it is thick to obtain 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine
9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine fine work 16.7g can be obtained by Ethanol Method crystallization in product, and yield is
62.5%, it is 97.1% through HPLC detection levels.
Embodiment 9
To equipped with blender, thermometer, dropping funel, reflux 500ml four-hole boiling flasks in, be added sodium hydroxide 6g, water
40ml, adenine 13.5g, are heated with stirring to 50 DEG C, and after material dissolved clarification, the chloro- 6 fluorine benzyls of 17.9g 2- are added dropwise into reaction vessel
The mixed solution that chlorine, 2.56g tri-n-octyl methyl ammonium chlorides and 120ml n-hexanes are made into quickly is stirred at reflux anti-after being added dropwise
6h is answered, after reaction, solid-liquid is detached with Buchner funnel, it is thick to obtain 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine
9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine fine work 16.6g can be obtained by Ethanol Method crystallization in product, and yield is
62.4%, it is 98.1% through HPLC detection levels.
Embodiment 10
To equipped with blender, thermometer, dropping funel 500ml three-necked flasks in, sodium hydroxide 8g, water 125ml is added, gland is fast
Purine 27g, is heated with stirring to 80 DEG C, and after material dissolved clarification, decompression steams solvent, and diformazan is added into the reaction vessel for fill solid
Base formamide 80ml continues to stir and be warming up to 60 DEG C after addition, maintains temperature, stirring to solid dissolved clarification, cools
To 10 DEG C hereinafter, the mixed solution being made by the chloro- 6 fluorine benzyl chlorides of 40g 2- and 60ml dimethylformamides is added dropwise, after being added dropwise
The reaction was continued, and 2h heats and solvent dimethylformamide is removed under reduced pressure, obtain 9- [(the chloro- 6- fluorophenyls of 2-) first after reaction
Base] -9H- purine -6- amine crude products, 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine can be obtained by Ethanol Method crystallization
Fine work 41.2g, yield 77.1% are 99.1% through HPLC detection levels.
Claims (6)
1. a kind of preparation method of 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine, it is characterised in that：Including following
Step（1）The preparation of adenine salt：Adenine, water and highly basic are added in the reactor, stirs dissolved clarification at 30~80 DEG C, 30~80
DEG C vacuum distillation remove solvent, obtain adenine salt crude product；（2）In the reactor equipped with adenine salt crude product, 30~100 DEG C
Under conditions of be added after amides polar solvent fully dissolve, be cooled to temperature -10~25 DEG C, the chloro- 6 fluorine benzyl chlorides of 2- be added and react
1~6 hour, vacuum distillation after reaction removed amides polar solvent and obtains 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H-
Purine -6- amine crude products；9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine fine work can be obtained by recrystallization.
2. the preparation method of 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine according to claim 1, special
Sign is：The molar ratio of adenine, water and highly basic is 1:10~40:0.9~2.
3. the preparation method of 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine according to claim 1, special
Sign is：Step（2）The dosage of middle amides polar solvent is 10~30 times of adenine mole.
4. the preparation method of 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine according to claim 1, special
Sign is：Step（2）The addition of the middle chloro- 6 fluorine benzyl chlorides of 2- is 0.9~3 times of adenine mole.
5. the preparation method of 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine according to claim 1, special
Sign is：Amides polar solvent is dimethylformamide and/or dimethylacetylamide.
6. the preparation method of 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine according to claim 1, special
Sign is：Highly basic is sodium hydroxide or potassium hydroxide.
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| CN201810816788.1A CN108676005A (en) | 2018-07-24 | 2018-07-24 | A kind of preparation method of high-purity 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine |
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| CN201810816788.1A CN108676005A (en) | 2018-07-24 | 2018-07-24 | A kind of preparation method of high-purity 9- [(the chloro- 6- fluorophenyls of 2-) methyl] -9H- purine -6- amine |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4100159A (en) * | 1977-02-07 | 1978-07-11 | Merck & Co., Inc. | Process for preparation of 9-(2,6-dihalobenzyl)adenines |
| CN102532138A (en) * | 2012-02-17 | 2012-07-04 | 曾明华 | Synthesis method of anticoccidial drug adprin |
| CN103992322A (en) * | 2014-05-20 | 2014-08-20 | 安徽农业大学 | Synthesis method of anticoccidial drug fluoroadenine |
| CN107698589A (en) * | 2017-10-16 | 2018-02-16 | 浙江金伯士药业有限公司 | A kind of novel preparation method of Adprin |
-
2018
- 2018-07-24 CN CN201810816788.1A patent/CN108676005A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4100159A (en) * | 1977-02-07 | 1978-07-11 | Merck & Co., Inc. | Process for preparation of 9-(2,6-dihalobenzyl)adenines |
| CN102532138A (en) * | 2012-02-17 | 2012-07-04 | 曾明华 | Synthesis method of anticoccidial drug adprin |
| CN103992322A (en) * | 2014-05-20 | 2014-08-20 | 安徽农业大学 | Synthesis method of anticoccidial drug fluoroadenine |
| CN107698589A (en) * | 2017-10-16 | 2018-02-16 | 浙江金伯士药业有限公司 | A kind of novel preparation method of Adprin |
Non-Patent Citations (1)
| Title |
|---|
| I. SHINKAI等: "Phase‐transfer catalysis in the N‐benzylation of adenine", 《JOURNAL OF HETEROCYCLIC CHEMISTRY》 * |
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Application publication date: 20181019 |
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