CN104402828A - Synthetic method of 3-amino-4-bromo-6-chlorodiazine - Google Patents
Synthetic method of 3-amino-4-bromo-6-chlorodiazine Download PDFInfo
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- CN104402828A CN104402828A CN201410615288.3A CN201410615288A CN104402828A CN 104402828 A CN104402828 A CN 104402828A CN 201410615288 A CN201410615288 A CN 201410615288A CN 104402828 A CN104402828 A CN 104402828A
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- amino
- bromo
- chlorine pyridazine
- pyridazine
- synthetic method
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/20—Nitrogen atoms
Abstract
The invention relates to a synthetic method of 3-amino-4-bromo-6-chlorodiazine. The method comprises the following steps: reacting 3-amino-6-chlorodiazine with liquid bromine at 10-100DEG C, and purifying to obtain purified 3-amino-4-bromo-6-chlorodiazine. The method has the advantages of easily available reaction raw materials, reasonable price, mild reaction conditions, easy operation, easy control and simple post-treatment, and the above obtained product has the advantages of stable quality and high purity.
Description
(1) technical field
The present invention relates to a kind of pyridazine derivatives, be specifically related to the synthetic method of a kind of 3-amino-4-bromo-6-chlorine pyridazine.
(2) background technology
Pyridazine derivatives is widely used because of its distinctive step-down, cardiac stimulant, the physiologically active such as antiviral, anticancer in medicine, agricultural chemicals, such as, the generation of bacteria cell wall can be hindered as the antibiotic cefozopran hydrochloride of forth generation cephalosporin for injections class, the bridging action of potent blocking-up cell walls peptidoglycan, very strong avidity is had with penicillin-binding protein, β-lactamase is stablized, there is good anti-microbial activity to gram-positive microorganism, Gram-negative bacteria, be widely used in the treatment of various infection disease.3-amino-6-chlorine pyridazine is the important intermediate of synthesis Cefozopran, take maleic anhydride as starting raw material, through hydrazinolysis, halo, ammonolysis synthesis 3-amino-6-chlorine pyridazine.In order to improve biological activity and selectivity, the derivative of its structure and modification research were never interrupted.
The manufacture method of existing pyridazine derivatives is raw material mainly with 3,6-dichloro-pyridazine, mainly as follows:
(1) with 3,6-dichloro-pyridazine for raw material, react with phenols, through hydrolysis, prepare pyridazine derivatives.
(2) utilize oxygenant, with 3,6-dichloro-pyridazine for raw material, utilize phosphoryl chloride to carry out chlorination, then through hydrolysis, prepare pyridazine derivatives.
(3) with 3,6-dichloro-pyridazine for raw material, react with phenols, obtain 3-chloro-6-phenoxy group pyridazine derivatives, then, utilize oxidizing, then, carry out chlorination, hydrolysis through phosphoryl chloride, obtain pyridazine derivatives.
(4) with 3,6-dichloro-pyridazine is raw material, at 80 ~ 160 DEG C, passes into chlorine, obtain 3,4,6-trichlorine pyridazine white powder, then with NaOH solution reaction, add the palladium carbon catalyst of sodium hydroxide and 5% or 10% again, sealing, passes into hydrogen, finally adds tribromo oxygen phosphorus and prepare pyridazine derivatives.
Above-mentioned reactions steps at least will through 3 reactions steps, and the selectivity of chlorination is also low, yield not higher than 40%, as manufacture method, can not be satisfactory, need to improve.
Pyridazine derivatives 3-amino-4-bromo-6-chlorine pyridazine is as the important intermediate of multi-medicament, and it synthesizes difficulty, and market value is expensive, and pole lacks the report of document and Patents
.
(3) summary of the invention
The present invention needs the problem solved to be for prior art, and provide a kind of technique advantages of simple, cost low, product purity is high, is suitable for the synthetic method of industrialized 3-amino-4-bromo-6-chlorine pyridazine.
The present invention is achieved through the following technical solutions:
A synthetic method for 3-amino-4-bromo-6-chlorine pyridazine, its special character is: comprise the following steps:
With 3-amino-6-chlorine pyridazine and bromine for raw material, in 10-100 DEG C of reaction, after purifying sterling 3-amino-4-bromo-6-chlorine pyridazine.
The synthetic method of 3-amino-4-of the present invention bromo-6-chlorine pyridazine, the ratio of the amount of substance of 3-amino-6-chlorine pyridazine and bromine is 1:0.5-4.0.
The synthetic method of 3-amino-4-of the present invention bromo-6-chlorine pyridazine, the charging capacity of reactant and solvent is: 3-amino-6-chlorine pyridazine: solvent=1:1.0-25 is more than weight ratio.
The synthetic method of 3-amino-4-of the present invention bromo-6-chlorine pyridazine, the reaction times is 2-40 hour.
The synthetic method of 3-amino-4-of the present invention bromo-6-chlorine pyridazine, described solvent is the one in methylene dichloride, ethanol, ethyl acetate, DMF, methyl alcohol and Virahol.
The synthetic method of 3-amino-4-of the present invention bromo-6-chlorine pyridazine, in described step, purification step is evaporation concentration, recrystallization, and silica gel column chromatography is separated.
Beneficial effect of the present invention: reaction raw materials compares and is easy to get, reasonable price, reaction conditions is gentle, easy handling, is easy to control, and aftertreatment is simple, and constant product quality, purity is high.
(4) embodiment
Embodiment 1:
3-amino-6-chlorine pyridazine (2.59g, 20mmol) is added, bromine (3.52g, 22mmol), methylene dichloride 20ml in 50mL single necked round bottom flask.Mixture in reaction flask stirring reaction 10 hours at 40 DEG C.TLC and GC determines that reaction completes.After reaction terminates, revolve and steam except desolventizing, obtain thick product, be separated with silica gel column chromatography and obtain straight product 3-amino-4-bromo-6-chlorine pyridazine, after drying, calculated yield 62.38%, purity 96.42% (GC), fusing point 168 DEG C-171 DEG C.Nuclear magnetic resonance spectroscopy: 1H NMR (deuterochloroform): 7.54 ppm (s, 1H), 5.50 ppm (s, 2H)
Embodiment 2:
3-amino-6-chlorine pyridazine (2.59g, 20mmol) is added, bromine (3.58g, 22.4mmol), ethyl acetate 35ml in 50mL single necked round bottom flask.Mixture in reaction flask stirring reaction 12 hours at 30 DEG C.TLC and GC determines that reaction completes.After reaction terminates, revolve and steam except desolventizing, obtain thick product, be separated with silica gel column chromatography and obtain straight product 3-amino-4-bromo-6-chlorine pyridazine, after drying, calculated yield 58.60%, purity 99.01% (GC), fusing point 168 DEG C-171 DEG C.
Embodiment 3:
3-amino-6-chlorine pyridazine (12.96g, 100mmol) is added, bromine (33.56g, 210mmol), ethanol 300ml in 500mL single necked round bottom flask.Mixture in reaction flask stirring reaction 15 hours at 25 DEG C.TLC and GC determines that reaction completes.After reaction terminates, revolve and steam except desolventizing, obtain thick product, be separated with silica gel column chromatography and obtain straight product 3-amino-4-bromo-6-chlorine pyridazine, after drying, calculated yield 72.35%.
Embodiment 4:
3-amino-6-chlorine pyridazine (12.96g, 100mmol) is added, bromine (33.56g, 210mmol), methyl alcohol 300ml in 500mL single necked round bottom flask.Mixture in reaction flask stirring reaction 20 hours at 20 DEG C.TLC and GC determines that reaction completes.After reaction terminates, revolve and steam except desolventizing, obtain thick product, be separated with silica gel column chromatography and obtain straight product 3-amino-4-bromo-6-chlorine pyridazine, after drying, calculated yield 67.97%.
Embodiment 5:
3-amino-6-chlorine pyridazine (28.50g, 220mmol) is added, bromine (52.74g, 330mmol), methyl alcohol 550ml in 1000mL single necked round bottom flask.Mixture in reaction flask stirring reaction 20 hours at 20 DEG C.TLC and GC determines that reaction completes.After reaction terminates, revolve and steam except desolventizing, obtain thick product, be separated with silica gel column chromatography and obtain straight product 3-amino-4-bromo-6-chlorine pyridazine, after drying, calculated yield 60.54%.
Embodiment 6:
3-amino-6-chlorine pyridazine (28.50g, 220mmol) is added, bromine (63.28g, 396mmol), methyl alcohol and Virahol 600ml altogether in 1000mL single necked round bottom flask.Mixture in reaction flask stirring reaction 20 hours at 20 DEG C.TLC and GC determines that reaction completes.After reaction terminates, revolve and steam except desolventizing, obtain thick product, be separated with silica gel column chromatography and obtain straight product 3-amino-4-bromo-6-chlorine pyridazine, after drying, calculated yield 73.56%.
Embodiment 7:
3-amino-6-chlorine pyridazine (2.59g, 20mmol) is added, bromine (1.6g, 10mmol), methylene dichloride 3ml in 50mL single necked round bottom flask.Mixture in reaction flask stirring reaction 40 hours at 10 DEG C.TLC and GC determines that reaction completes.After reaction terminates, revolve and steam except desolventizing, obtain thick product, be separated with silica gel column chromatography and obtain straight product 3-amino-4-bromo-6-chlorine pyridazine, after drying, calculated yield 65.118%, purity 96.48% (GC), fusing point 168 DEG C-171 DEG C.Nuclear magnetic resonance spectroscopy: 1H NMR (deuterochloroform): 7.54 ppm (s, 1H), 5.54 ppm (s, 2H)
Embodiment 8:
3-amino-6-chlorine pyridazine (0.72g, 5.6mmol) is added, bromine (3.58g, 22.4mmol), DMF113ml in 150mL single necked round bottom flask.Mixture in reaction flask stirring reaction 2 hours at 100 DEG C.TLC and GC determines that reaction completes.After reaction terminates, revolve and steam except desolventizing, obtain thick product, be separated with silica gel column chromatography and obtain straight product 3-amino-4-bromo-6-chlorine pyridazine, after drying, calculated yield 59.60%, purity 99.21% (GC), fusing point 168 DEG C-171 DEG C.
Claims (6)
1. a synthetic method for 3-amino-4-bromo-6-chlorine pyridazine, is characterized in that: comprise the following steps:
With 3-amino-6-chlorine pyridazine and bromine for raw material, in 10-100 DEG C of reaction, after purifying sterling 3-amino-4-bromo-6-chlorine pyridazine.
2. the synthetic method of 3-amino-4-according to claim 1 bromo-6-chlorine pyridazine, is characterized in that: the ratio of the amount of substance of 3-amino-6-chlorine pyridazine and bromine is 1:0.5-4.0.
3. the synthetic method of 3-amino-4-according to claim 1 and 2 bromo-6-chlorine pyridazine, is characterized in that: the charging capacity of reactant and solvent is: 3-amino-6-chlorine pyridazine: solvent=1:1.0-25 is more than weight ratio.
4. the synthetic method of 3-amino-4-according to claim 1 and 2 bromo-6-chlorine pyridazine, is characterized in that: the reaction times is 2-40 hour.
5. the synthetic method of 3-amino-4-according to claim 1 and 2 bromo-6-chlorine pyridazine, is characterized in that: described solvent is the one in methylene dichloride, ethanol, ethyl acetate, DMF, methyl alcohol and Virahol.
6. the synthetic method of 3-amino-4-according to claim 1 and 2 bromo-6-chlorine pyridazine, is characterized in that: in described step, purification step is evaporation concentration, recrystallization, and silica gel column chromatography is separated.
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| CN201410615288.3A CN104402828A (en) | 2014-11-05 | 2014-11-05 | Synthetic method of 3-amino-4-bromo-6-chlorodiazine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020057391A1 (en) | 2018-09-20 | 2020-03-26 | 周银平 | Preparation of pyridazinyl amine compound and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010100070A1 (en) * | 2009-03-02 | 2010-09-10 | F. Hoffmann-La Roche Ag | Inhibitors of bruton's tyrosine kinase |
| CN103998451A (en) * | 2011-10-20 | 2014-08-20 | 葛兰素史密斯克莱有限责任公司 | Substituted bicyclic aza-heterocycles and analogues as sirtuin modulators |
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2014
- 2014-11-05 CN CN201410615288.3A patent/CN104402828A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010100070A1 (en) * | 2009-03-02 | 2010-09-10 | F. Hoffmann-La Roche Ag | Inhibitors of bruton's tyrosine kinase |
| CN103998451A (en) * | 2011-10-20 | 2014-08-20 | 葛兰素史密斯克莱有限责任公司 | Substituted bicyclic aza-heterocycles and analogues as sirtuin modulators |
Non-Patent Citations (1)
| Title |
|---|
| ALESSANDRO STELLA ET AL: "A short and straightforward approach towards 6-amino and 6-aminoalkyl thiazolo[4,5-c]pyridazines", 《TETRAHEDRON LETTERS》, vol. 54, 24 November 2012 (2012-11-24) * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020057391A1 (en) | 2018-09-20 | 2020-03-26 | 周银平 | Preparation of pyridazinyl amine compound and application thereof |
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Application publication date: 20150311 |