CN104761491B - The synthetic method of the iodo- 5- bromopyridines of 2- amino -3- - Google Patents

The synthetic method of the iodo- 5- bromopyridines of 2- amino -3- Download PDF

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CN104761491B
CN104761491B CN201510145900.XA CN201510145900A CN104761491B CN 104761491 B CN104761491 B CN 104761491B CN 201510145900 A CN201510145900 A CN 201510145900A CN 104761491 B CN104761491 B CN 104761491B
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amino
bromopyridines
iodo
reaction
solvent
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CN104761491A (en
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邓素曼
韩猛
来新胜
曹惊涛
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Shaanxi Youbang Biomedical Technology Co.,Ltd.
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Shandong You Bang Biochemical Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Abstract

The present invention relates to a kind of synthetic methods of 2 amino, 3 iodine, 5 bromopyridine.Using 2 amino, 5 bromopyridine and N N-iodosuccinimides as raw material, the ratio between amount of the two substance is 1:1.7 3.5, in solvent appropriate, at a temperature of 23 115 DEG C reaction generate 2 amino 3 iodine, 5 bromopyridine, it is purified after 2 amino of sterling, 3 iodine, 5 bromopyridine.The raw material of the present invention is relatively easy to get, reasonable price, while preparing without using heavy metal and corrosive gas in reaction, and reaction is mild, does not have special requirement, common corrosion resistant apparatus that can produce reflection equipment, in addition reaction condition of the present invention is moderate.

Description

The synthetic method of the iodo- 5- bromopyridines of 2- amino -3-
（One）Technical field
The invention belongs to organic synthesis fields, and in particular to a kind of synthetic method of the iodo- 5- bromopyridines of 2- amino -3-.
（Two）Background technology
The iodo- 5- bromopyridines of 2- amino -3- can be used for synthetic hydroxyphenylaminopropionic acid kinase inhibitor, carry out treating cancer or anti- The only diffusion of cancer cell, including breast cancer, colon cancer, prostate cancer, lung cancer, gastric cancer, oophoroma, carcinoma of endometrium, kidney, liver Cancer, thyroid cancer, uterine cancer, cancer of the esophagus, squamous cell carcinoma, leukaemia, osteosarcoma, melanoma, spongioblastoma, at god Through cytoma；It can be used for synthesizing CRAC inhibitor, treat autoimmune disease and diseases associated with inflammation.Antimalarial can be used as The structure-activity center of drug；Effective choosing can be realized in the cell as the structure stand of mitotic kinase inhibitor Selecting property is adjusted；It is also used as Fabl inhibitor, efficiently inhibits the growth of bacterium.This product has prodigious value, synthesis Difficulty, the market price is expensive, lacks document and related patents report.
（Three）Invention content
Problem to be solved of the present invention is to be directed to the prior art, provides a kind of simple for process reasonable, at low cost, and product is pure Degree is high, is suitable for the synthetic method of the industrialized iodo- 5- bromopyridines of 2- amino -3-.
The present invention is achieved through the following technical solutions：
A kind of synthetic method of the iodo- 5- bromopyridines of 2- amino -3-, is characterized in that：Include the following steps：
Using 2- amino -5- bromopyridines and N- N-iodosuccinimides as raw material, the ratio between amount of the two substance is 1:1.7 - 3.5, in solvent appropriate, at a temperature of 23-115 DEG C reaction generate the iodo- 5- bromopyridines of 2- amino -3-, it is purified after it is pure The iodo- 5- bromopyridines of product 2- amino -3-.
The synthetic method of the iodo- 5- bromopyridines of 2- amino -3- of the present invention, solvent are ethyl alcohol, methanol, ethyl acetate, propyl alcohol, Isopropanol, dichloroethanes, dichloromethane, n,N-Dimethylformamide, one or both of tert-butyl alcohol.
The inventory of the synthetic method of the iodo- 5- bromopyridines of 2- amino -3- of the present invention, reactant and solvent is：M2- ammonia Base -5- bromopyridines：Solvent=1 m:1.8-4.5 being weight ratio.
The synthetic method of the iodo- 5- bromopyridines of 2- amino -3- of the present invention, purification step are to be concentrated by evaporation, recrystallization, silica gel Column chromatography for separation.
The synthetic method of the iodo- 5- bromopyridines of 2- amino -3- of the present invention, the solvent of recrystallization are ethyl acetate, ethyl alcohol, two Chloromethanes, n-hexane, one or both of ether substance.
The synthetic method of the iodo- 5- bromopyridines of 2- amino -3- of the present invention, reaction condition are to be reacted at a temperature of 23-115 DEG C 1-18 hour.
Beneficial effects of the present invention：The raw material of the present invention is relatively easy to get, reasonable price, while preparing and not used in reaction Heavy metal and corrosive gas, reaction is mild, does not have special requirement, common corrosion resistant apparatus that can give birth to reflection equipment Production, in addition reaction condition of the present invention is moderate, and reaction is easily controllable, and post-processing is simple, product purity etc. superiority condition, this technique It is easy to spread.
（Four）Specific implementation mode
Embodiment 1：
The mixed solvent 38ml of ethyl acetate and ethyl alcohol, ethyl acetate are added in the round bottom single-necked flask of a 100ml 15ml is inserted into thermometer, starts magnetic stirring apparatus, and the 2- amino -5- bromopyridines of 17.4g are added, and N- iodo succinyl is added Imines 39.38g reacts 18 hours under 25 DEG C of lasting stirrings.TLC and GC determines reaction 2- amino -5- bromopyridines, and the reaction was complete. Revolving removes solvent, obtains crude product, it is iodo- to be recrystallized to give net product 2- amino -3- with the mixed solvent of n-hexane and ethyl alcohol 5- bromopyridines, after dry, calculated yield 80.3%, it is 97.2% that GC, which detects purity,.Nuclear magnetic resonance spectroscopy：1HMR(CDCl3) 400MHz: δ7.98（s,1H）；δ7.66(s,1H)；δ4.96(bs,2H)
Embodiment 2：
Solvent n,N-Dimethylformamide 1006ml is added in the round bottom single-necked flask of a 2L, is inserted into thermometer and starts Magnetic stirring apparatus, and the 2- amino -5- bromopyridines of 348g are added, N- N-iodosuccinimide 994g are added, temperature is reacted at 36 DEG C The lower reaction of the lasting stirring of degree 11 hours.TLC and GC determines reaction 2- amino -5- bromopyridines, and the reaction was complete.Revolving removes solvent, obtains To crude product, the iodo- 5- bromopyridines of net product 2- amino -3- are recrystallized to give with the mixed solvent of ethyl acetate and dichloromethane, After drying, calculated yield 79.53%, it is 98.7% that GC, which detects purity,.Nuclear magnetic resonance spectroscopy：1HMR(CDCl3)400MHz: δ7.98 （s,1H）；δ7.66(s,1H)；δ4.96(bs,2H)
Embodiment 3：
The 7500ml of ethyl alcohol is added in the reaction kettle of a 10L, is inserted into thermometer and starts mechanical agitator, and be added N- N-iodosuccinimide 12375g are added in the 2- amino -5- bromopyridines of 3828g, anti-in the case where 40 DEG C of reaction temperatures persistently stir It answers 9 hours.TLC and GC determines reaction 2- amino -5- bromopyridines, and the reaction was complete.Revolving removes solvent, obtains crude product, uses acetic acid The mixed solvent of ethyl ester and ethyl alcohol is recrystallized to give the iodo- 5- bromopyridines of net product 2- amino -3-, after dry, calculated yield It is 97.4% that 86.4%, GC, which detect purity,.Nuclear magnetic resonance spectroscopy：1HMR(CDCl3)400MHz: δ7.98（s,1H）；δ7.66(s, 1H)；δ4.96(bs,2H)
Embodiment 4：
The mixed solvent 20004ml of tetrahydrofuran and dichloroethanes, tetrahydrofuran are added in the reaction kettle of a 50L 12000ml is inserted into thermometer and starts mechanical agitator, and the 2- amino -5- bromopyridines of 5742.2g are added, and N- iodo fourths are added Imidodicarbonic diamide 23760g reacts 7 hours in the case where 53 DEG C of reaction temperatures persistently stir.TLC and GC determines reaction 2- amino -5- bromine pyrroles The reaction was complete for pyridine.Revolving removes solvent, obtains crude product, net product is recrystallized to give with the mixed solvent of ethyl acetate and ethyl alcohol The iodo- 5- bromopyridines of 2- amino -3-, after dry, calculated yield 81.5%, it is 98.3% that GC, which detects purity,.Nuclear magnetic resonance spectroscopy：1HMR (CDCl3)400MHz: 1HMR(CDCl3)400MHz: δ7.98（s,1H）；δ7.66(s,1H)；δ4.96(bs,2H)
Embodiment 5：
Mixed solvent 43.3L, the tetrahydrofuran 18L of tetrahydrofuran and dichloroethanes are added in the reaction kettle of a 100L, It is inserted into thermometer, starts magnetic stirring apparatus, and the 2- amino -5- bromopyridines of 7830.5g are added, N- N-iodosuccinimides are added 21262.5g reacts 5.5 hours in the case where 95 DEG C of reaction temperatures persistently stir.TLC and GC determines that reaction 2- amino -5- bromopyridines are anti- It should be complete.Revolving removes solvent, obtains crude product, net product 2- is recrystallized to give with the mixed solvent of ethyl acetate and n-hexane The iodo- 5- bromopyridines of amino -3-, after dry, calculated yield 78.93%, it is 98.7% that GC, which detects purity,.
Nuclear magnetic resonance spectroscopy：1HMR(CDCl3)400MHz: 1HMR(CDCl3)400MHz: δ7.98（s,1H）；δ7.66 (s,1H)；δ4.96(bs,2H).
Embodiment 6：
Methanol 43L is added in the reaction kettle of a 100L, is inserted into thermometer, starts magnetic stirring apparatus, and be added N- N-iodosuccinimide 15230g are added, in the case where 64 DEG C of reaction temperatures persistently stir in the 2- amino -5- bromopyridines of 7830.5g Reaction 0.7 hour.TLC and GC determines reaction 2- amino -5- bromopyridines, and the reaction was complete.Revolving removes solvent, obtains crude product, uses The mixed solvent of dichloromethane, ether is recrystallized to give the iodo- 5- bromopyridines of net product 2- amino -3-, after dry, calculated yield It is 98.1% that 87.4%, GC, which detect purity,.
Embodiment 7：
Tert-butyl alcohol 43L is added in the reaction kettle of a 100L, is inserted into thermometer, starts magnetic stirring apparatus, and be added N- N-iodosuccinimide 13560g are added, in the case where 84 DEG C of reaction temperatures persistently stir in the 2- amino -5- bromopyridines of 7830.5g Reaction 0.5 hour.TLC and GC determines reaction 2- amino -5- bromopyridines, and the reaction was complete.Revolving removes solvent, obtains crude product, uses Diethyl ether recrystallization obtains the iodo- 5- bromopyridines of net product 2- amino -3-, and after dry, calculated yield 87.9%, GC detects purity and is 98.0%。

Claims (2)

1. a kind of synthetic method of the iodo- 5- bromopyridines of 2- amino -3-, it is characterised in that：Include the following steps：
Using 2- amino -5- bromopyridines and N- N-iodosuccinimides as raw material, the ratio between amount of the two substance is 1:1.7-3.5, In solvent appropriate, at a temperature of 23-115 DEG C reaction generate the iodo- 5- bromopyridines of 2- amino -3-, it is purified after sterling 2- ammonia The iodo- 5- bromopyridines of base -3-, solvent are ethyl alcohol, methanol, ethyl acetate, propyl alcohol, isopropanol, dichloroethanes, dichloromethane, N, N- The inventory of dimethylformamide, one or both of tert-butyl alcohol, reactant and solvent is：m2- amino -5- bromopyridines：mSolvent=1:1.8- 4.5, it is weight ratio, purification step is to be concentrated by evaporation, recrystallization, silica gel column chromatography separation, and the solvent of recrystallization is acetic acid second Ester, ethyl alcohol, dichloromethane, n-hexane, one or both of ether substance.
2. the synthetic method of the iodo- 5- bromopyridines of 2- amino -3- according to claim 1, it is characterised in that：Reaction condition is 1-18 hour is reacted at a temperature of 23-115 DEG C.
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