CN110218180A - The preparation method of 2,6- diamino -3,5- difluoro pyridine - Google Patents
The preparation method of 2,6- diamino -3,5- difluoro pyridine Download PDFInfo
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- CN110218180A CN110218180A CN201910574427.5A CN201910574427A CN110218180A CN 110218180 A CN110218180 A CN 110218180A CN 201910574427 A CN201910574427 A CN 201910574427A CN 110218180 A CN110218180 A CN 110218180A
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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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Abstract
The invention discloses a kind of preparation methods of anti-infectious new drug De Lasha star midbody 2,6-diamino -3,5- difluoro pyridine, with 2,3,5,6- ptfe pyridines as raw material, obtain 2,6- diamino -3,5- difluoro pyridine by necleophilic reaction, elimination reaction.The present invention provides a new synthetic route for antimicrobial De Lasha star intermediate, and reaction step is easy to control, of less demanding to reaction unit, can be realized stable industrialized production preparation.
Description
Technical field
The present invention relates to the preparation methods of 2,6- diamino -3,5- difluoro pyridine, belong to chemosynthesis technical field.
Background technique
Antibacterials reduce disease incident, build up health and have a very important role for fighting pathogenic infection.
But being widely used with antimicrobial, the abuse condition of antibacterials is also increasingly severe, and the drug resistance of pathogenic bacteria gradually increases
Add, the antibacterial efficacy of antimicrobial is caused constantly to decline.The infection disease as caused by drug resistance pathogen is more and more challenging, leather
Lan Shi feminine gender and the drug resistance of gram positive pathogens are continuously increased, and lead to high morbidity and mortality.In bacterial resistance
Property increased epoch, acute bacterial skin and skin infection (ABSSSI) are as clinical common one of disease, disease incidence
It is risen year by year with admission rate, and is a challenging difficult medical problem with serious complication.
De Lasha star be in June, 2017 U.S. FDA ratify it and be used to treat acute bacterial skin and skin structure infection
(ABSSSI) the novel fluoroquinolones broad spectrum antibiotic of one kind, it has anion characteristic, have in acid condition compared with
Good antibacterial activity, by inhibiting the reproduction process of DNA of bacteria, to have the function that sterilization.De Lasha star is to a large amount of height
Drug-fast bacteria shows extensive antibacterial activity, its replacement therapy drug possible as a variety of severe infections, including complexity
Property skin infection, pneumonia, endocarditis and other double infection infectious diseases.2,6- diamino -3,5- difluoro pyridine is drawn as moral
The important intermediate of Sha Xing, due to fluorine-containing and amino on its molecular structure, the exploitation of synthesis technology causes chemist
Concern.
The method reported at present for preparing 2,6- diamino -3,5- difluoro pyridine mainly has:
Method one: Journal of Fluorine Chemistry, 2009,130,461-465.Author is by 2 in document,
3,5,6- ptfe pyridine and ammonium hydroxide react 67 hours in 150 DEG C, autoclave.This method needs high temperature and pressure, has to reaction kettle
Strong corrosivity.Condition is harsher, and yield is low, is not suitable for industrialized production.
Method two: CN109251167.Author equally uses 2,3,5,6- ptfe pyridines and ammonium hydroxide to react in patent, and 30 DEG C
Confined reaction 3 hours, since ammonium hydroxide irritation and corrosivity are larger, need to react in closed unit, to reaction unit require compared with
Height is unfavorable for industrialized production.
Method three: patent WO200615194.Author is with 2,3,5,6- ptfe pyridines for raw material in patent, and first and benzylamine is raw
At N2,N6The fluoro- 2,6-diaminopyridine of dibenzyl -3,5- bis-, then hydrogenates to obtain target product 2 using 20% palladium dydroxide,
6- diamino -3,5- difluoro pyridine, this method uses expensive palladium catalyst, while needing 150- in first step reaction
170 DEG C of high temperature are not suitable for industrialized production.
The method reported from document above can see, and some reaction temperatures are high, and severe reaction conditions, some, which is used, to be compared
Expensive catalyst, there is also the low disadvantages of yield, and industrialized production still lacks a kind of simply and easily method at present,
In order to solve the problems, such as industrialized production, we further study the synthesis step of compound, find one and fit
Route used in industrial production provides a new synthetic method for domestic and international imitation medicine enterprise.
Summary of the invention
The technical problem to be solved by the invention is to provide a kind of preparations of new 2,6- diamino -3,5- difluoro pyridine
Method, this method step is easy to control, condition is relatively milder and yield is higher, can be realized stable industrialized production preparation.
In order to solve the above technical problems, the technical solution adopted by the present invention are as follows:
The preparation method of one kind 2,6- diamino -3,5- difluoro pyridine passes through with 2,3,5,6- ptfe pyridines as raw material
It is obtained intermediate (I) with the necleophilic reaction of sulfonamide, (I) obtains 2,6- diamino -3,5- difluoro pyridine by elimination reaction
(II),
Synthetic route is as follows:
Wherein R is methyl, ethyl, tert-butyl, phenyl or p-methylphenyl.
Further, specifically includes the following steps:
Step 1) is that raw material in the presence of alkali, passes through parent in aprotic polar solvent with 2,3,5,6- ptfe pyridines
Nuclear reaction obtains I；
Step 2) compound I under the action of an acid, by elimination reaction obtain compound II to get.
Further, in step 1), alkali used is the mixing of one or more of potassium carbonate, cesium carbonate, triethylamine
Alkali.
Further, in step 1), solvent for use is one or more of N-Methyl pyrrolidone, DMF, DMA
Mixed solvent.
Further, in step 1), reaction temperature is 80-100 DEG C, reaction time 10-16h.
Further, in step 2), acid used is one of hydrochloric acid, sulfuric acid.
Further, in step 2), reaction dissolvent is one or more of acetic acid, ethyl alcohol, water mixed solvent, instead
Answering temperature is 0-25 DEG C, reaction time 1-2h.
Advantageous effects of the invention: the present invention provides a kind of new 2,6- diamino -3,5- difluoro pyridines
Preparation method obtains intermediate compound I by necleophilic reaction with 2,3,5,6- ptfe pyridines and sulfonamide, and intermediate compound I is in acid later
Under the action of remove RSO2Group obtains target compound, and reaction condition is milder, of less demanding to reaction unit, and second
Step elimination reaction avoid not only reducing cost, and simplify operating procedure using expensive palladium reagent, and obtain compared with
Good yield, there is presently no the methods of this synthesis 2,6- diamino -3,5- difluoro pyridine of pertinent literature report, and by pair
Nucleophilic substitution than various amine finds that, although alkyl amine can also obtain preferable yield, reaction condition all compares
It is harsher, and can generate and largely give up admittedly, post-processing is very complicated, is unfavorable for amplifying；The post-reaction treatment of sulfonamides is simple, will not
It generates and much gives up admittedly, environmentally protective, this is for researching and developing the preparation method of 2,6- diamino -3,5- difluoro pyridine and amplifying metaplasia
It produces, is of great significance.
Specific embodiment
The invention will be further described below.Following embodiment is only used for clearly illustrating technical side of the invention
Case, and not intended to limit the protection scope of the present invention.
Embodiment one:
2,3,5,6- ptfe pyridines (151g) are dissolved in 100g N-Methyl pyrrolidone, 130g potassium carbonate is slowly added to,
The N-Methyl pyrrolidone solution of tert-butyl sulfonamide (302g) is added later, a period of time is stirred at room temperature, is warming up to 40-50 DEG C
1h is reacted, then is warming up to 80-100 DEG C of reaction 10-16h.Using raw material end of reaction is controlled in liquid chromatogram (LC), stop reaction,
2400g water is added in cooling, and three times with 500g DCM extraction, organic phase adjusts pH=5-6 with 1500g 3M hydrochloric acid, and liquid separation is organic
It is mutually washed once with sodium bicarbonate solution, washing is primary, is evaporated to obtain 380g compound I (yield 99%).1H NMR(CDCl3)δ7.05
(s,1H),4.7(m,2H),1.28(m,18H)。
Embodiment two:
3L concentrated hydrochloric acid is added in compound I (one product of embodiment, 380g), 2h is reacted at room temperature, LC raw material disappears, and is added
The dilution of 1L water, stands, and obtained solid is washed, is dried to obtain crude product, is refining to obtain 136g compound II (yield with isopropanol
95%).1H NMR(CDCl3)δ7.02(s,1H),4.23(m,4H)；Mp:155-159 DEG C.
Embodiment three:
2,3,5,6- ptfe pyridines (151g) are dissolved in 100g DMF, 130g potassium carbonate is slowly added to, benzene is added later
The DMF solution of sulfonamide (314g) is stirred at room temperature a period of time, is warming up to 40-50 DEG C of reaction 1h, then is warming up to 80-100 DEG C instead
Answer 10-13h.Raw material end of reaction to be controlled in LC, stops reaction, 2400g water is added in cooling, three times with the extraction of 500g ethyl acetate,
Organic phase 1500g 3M hydrochloric acid adjusts pH=5-6, liquid separation, and organic phase is washed once with sodium bicarbonate solution, and washing is primary, anhydrous
Sodium sulphate is dry, is evaporated to obtain 412g compound I (yield 97%).1H NMR(CDCl3)δ7.07(s,1H),7.68-7.60(m,
4H),7.87(m,2H),7.99-7.90(m,4H),4.9(m,2H)。
Example IV:
The 500mL concentrated sulfuric acid is added in compound I (three product of embodiment, 412g), 1h is reacted at room temperature, LC raw material disappears,
It is slowly added to 1L saturated sodium carbonate solution, 1L ether is extracted twice, and merges organic phase, washing, salt washing, vacuum distillation obtains thick
Product are refining to obtain 139g compound II (yield 96%) with isopropanol.1H NMR(CDCl3)δ7.02(s,1H),4.23(m,4H)；
Mp:155-159 DEG C.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, without departing from the technical principles of the invention, several improvement and deformations can also be made, these improvement and deformations
Also it should be regarded as protection scope of the present invention.
Claims (7)
1. one kind 2, the preparation method of 6- diamino -3,5- difluoro pyridine, characterized in that with 2,3,5,6- ptfe pyridines as former
Material, is obtained intermediate (I) by the necleophilic reaction with sulfonamide, and (I) obtains 2,6- diamino -3,5- difluoro by elimination reaction
Pyridine (II),
Synthetic route is as follows:
Wherein R is methyl, ethyl, tert-butyl, phenyl or p-methylphenyl.
2. the preparation method of 2,6- diamino -3,5- difluoro pyridine according to claim 1, characterized in that specifically include
Following steps:
Step 1) with 2,3,5,6- ptfe pyridines be raw material, it is in the presence of alkali, anti-by nucleophilic in aprotic polar solvent
It should obtain I；
Step 2) compound I under the action of an acid, by elimination reaction obtain compound II to get.
3. the preparation method of 2,6- diamino -3,5- difluoro pyridine according to claim 1, it is characterized in that in step 1),
Alkali used is one or more of potassium carbonate, cesium carbonate, triethylamine mixed base.
4. the preparation method of 2,6- diamino -3,5- difluoro pyridine according to claim 1, characterized in that in step 1),
Solvent for use is one or more of N-Methyl pyrrolidone, DMF, DMA mixed solvent.
5. the preparation method of 2,6- diamino -3,5- difluoro pyridine according to claim 1, characterized in that in step 1),
Reaction temperature is 80-100 DEG C, reaction time 10-16h.
6. the preparation method of 2,6- diamino -3,5- difluoro pyridine according to claim 1, characterized in that in step 2),
Acid used is one of hydrochloric acid, sulfuric acid.
7. the preparation method of 2,6- diamino -3,5- difluoro pyridine according to claim 1, characterized in that in step 2),
Reaction dissolvent is one or more of acetic acid, ethyl alcohol, water mixed solvent, and reaction temperature is 0-25 DEG C, and the reaction time is
1-2h。
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| CN201910574427.5A CN110218180B (en) | 2019-06-28 | 2019-06-28 | Preparation method of 2, 6-diamino-3, 5-difluoropyridine |
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