CN106632355A - Synthesis method of 6-bromoimidazo[1,2-b]pyridazine - Google Patents
Synthesis method of 6-bromoimidazo[1,2-b]pyridazine Download PDFInfo
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- CN106632355A CN106632355A CN201611029550.1A CN201611029550A CN106632355A CN 106632355 A CN106632355 A CN 106632355A CN 201611029550 A CN201611029550 A CN 201611029550A CN 106632355 A CN106632355 A CN 106632355A
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention relates to a synthesis method of 6-bromoimidazo[1,2-b]pyridazine. The synthesis method includes subjecting 3-amino-6-bromopyridazine and a 40% chloroacetaldehyde solution, serving as raw materials, in a solvent to continuous reaction at 30-100 DEG C under the action of alkali, performing ethyl acetate extraction, water washing, anhydrous sodium sulfate drying and rotary evaporation and concentration to obtain a crude product of the 6-bromoimidazo[1,2-b]pyridazine, and recrystallizing the crude product to obtain a pure product. The synthesis method is easily available to raw materials, reasonable in price, free of heavy metals and corrosive gas in preparation reaction, mild in reaction and high in reaction yield and purity, has no special requirements on reaction equipment, and can be implemented through common corrosion-resistant equipment.
Description
（One）Technical field
The invention belongs to organic synthesis field, and in particular to and a kind of 6- bromines imidazo [1,2-b ］ synthetic method of pyridazine.
（Two）Background technology
6- bromine imidazos [1,2-b ］ pyridazine be synthesize Cefozopran important intermediate, cefozopran hydrochloride be forth generation injection
With cephalosporins, to the gram-positive bacterias such as staphylococcus and it is green take the Gram-negative bacterias such as bacillus be respectively provided with it is anti-
Bacterium acts on, and is widely used in the treatment including each section's infection disease including infection of newborn.But at present the country is with regard to 6- bromine imidazoles
And [1,2-b ］ pyridazine synthesis report it is less.Therefore 6- bromine imidazos [1,2-b ］ study on the synthesis of pyridazine has a wide range of applications
Prospect and huge market potential.
（Three）The content of the invention
It is for prior art that the present invention needs the problem for solving, there is provided a kind of process is simple is reasonable, low cost, product purity
Height, be suitable to industrialized 6- bromines imidazo [1,2-b ］ synthetic method of pyridazine.
The present invention is achieved through the following technical solutions：
A kind of 6- bromines imidazo [1,2-b ］ synthetic method of pyridazine, it is characterized in that：Comprise the following steps：
With 3- amino -6- bromines pyridazine and 40% chloroacetaldehyde solution as raw material, in a solvent, in the presence of alkali, at 30～100 DEG C
Successive reaction, Jing after ethyl acetate extraction, water washing, anhydrous sodium sulfate drying, rotary evaporation concentration 6- bromines imidazo [1,2- is obtained
B ］ pyridazine crude product, crude product solvent recrystallization obtains sterling.
The present invention 6- bromine imidazos [1,2-b ］ synthetic method of pyridazine, it is characterised in that：Solvent is water, ethanol, tertiary fourth
One or two in alcohol, DMF, methyl alcohol and isopropanol.
The present invention 6- bromine imidazos [1,2-b ］ synthetic method of pyridazine, it is characterised in that：The raw material dosage is： 3-
Amino -6- bromine pyridazines：40% chloroacetaldehyde solution：Alkali=1:1.5~2.0:1.5 or 3- amino -6- bromine pyridazines：40% chloroacetaldehyde is molten
Liquid：Alkali=1:1.5~2.0:0, it is more than mol ratio.
The present invention 6- bromine imidazos [1,2-b ］ synthetic method of pyridazine, it is characterised in that：Reactant feeds intake with solvent
Measure and be：3- amino -6- bromine pyridazines：Solvent=1：4.0 ~ 15, the above is weight ratio.
The present invention 6- bromine imidazos [1,2-b ］ synthetic method of pyridazine, it is characterised in that：The alkali is sodium acid carbonate,
One kind in NaOH, triethylamine and sodium carbonate.
The present invention 6- bromine imidazos [1,2-b ］ synthetic method of pyridazine, it is characterised in that：It is continuous anti-at 30～100 DEG C
Answer 3～16 hours.
6- bromines imidazo of the present invention [1,2-b ］ pyridazine synthesis technique and synthesis step it is as follows：
Beneficial effects of the present invention：Using the present invention prepare 6- bromine imidazos [1,2-b ］ pyridazine, reaction condition is gentle, it is easy to grasp
Make, and product quality is stable, high income, purity is high.
（Four）Specific embodiment
Embodiment 1：
3- amino -6- bromine pyridazines are added in 1000 milliliters of single port are because of bottom flask（34.8g, 200mmol), 40% chloroethene
The aldehyde aqueous solution（58.8g, 300mmol）, sodium acid carbonate（25. 2g, 300mmol ）With 200mL (158g）Ethanol.Reaction bulb
In mixture at 80 DEG C stirring reaction 7.5 hours.After reaction terminates, revolving removes solvent, adds 200mL water and 400mL
Ethyl acetate, separates organic phase, and water is mutually extracted with ethyl acetate（2×300mL）, merge and first washed with 200mL after organic phase
Wash, then with 200mL saturated common salt water washings, anhydrous Na2SO4It is dried, is filtered to remove drier, filtrate rotary evaporation removes molten
Agent obtains sepia solid, by this sepia solid with ethyl acetate：Yellow crystals, yield are obtained after n-hexane mixed solution recrystallization
72.19%, 1HNMR (400Hz, CDC13) δ: 7.13(m, 2H), 7.75(d, lH),7. 96(d, lH）.
Embodiment 2：
3- amino -6- bromine pyridazines are added in 1000 milliliters of single port are because of bottom flask（34.8g, 200mmol), 40% chloroacetaldehyde
The aqueous solution（58.8,300mmol）, triethylamine（30.36g, 300mmol ）With 200mL (158g）Methyl alcohol.In reaction bulb
Mixture stirring reaction 8.5 hours at 65 DEG C.After reaction terminates, revolving removes solvent, adds 200mL water and 400mL acetic acid
Ethyl ester, separates organic phase, and water is mutually extracted with ethyl acetate（2×300mL）, to merge and first use 200mL water washings after organic phase, then
With 200mL saturated common salt water washings, anhydrous Na2SO4It is dried, is filtered to remove drier, filtrate rotary evaporation removes solvent and obtains brown
Brown solid, by this sepia solid with ethyl acetate：Yellow crystals, yield are obtained after n-hexane mixed solution recrystallization
56.40%。
Embodiment 3：
3- amino -6- bromine pyridazines are added in 1000 milliliters of single port are because of bottom flask（34.8g, 200mmol), 40% chloroacetaldehyde
The aqueous solution（58.8,300mmol）, sodium carbonate（31.80g, 300mmol ）With 200mL (158g）Ethanol.In reaction bulb
Mixture stirring reaction 7.5 hours at 80 DEG C.After reaction terminates, revolving removes solvent, adds 200mL water and 400mL acetic acid
Ethyl ester, separates organic phase, and water is mutually extracted with ethyl acetate（2×300mL）, to merge and first use 200mL water washings after organic phase, then
With 200mL saturated common salt water washings, anhydrous Na2SO4It is dried, is filtered to remove drier, filtrate rotary evaporation removes solvent and obtains brown
Brown solid, by this sepia solid with ethyl acetate：Yellow crystals, yield are obtained after n-hexane mixed solution recrystallization
68.92%。
Embodiment 4：
3- amino -6- bromine pyridazines are added in 1000 milliliters of single port are because of bottom flask（34.8g, 200mmol), 40% chloroacetaldehyde
The aqueous solution（78.50g, 400mmol）, sodium acid carbonate（25. 2g, 300mmol ）With 200mL (158g）Ethanol.In reaction bulb
Mixture at 80 DEG C stirring reaction 7 hours.After reaction terminates, revolving removes solvent, adds 200mL water and 400mL acetic acid
Ethyl ester, separates organic phase, and water is mutually extracted with ethyl acetate（2×300mL）, to merge and first use 200mL water washings after organic phase, then
With 200mL saturated common salt water washings, anhydrous Na2SO4It is dried, is filtered to remove drier, filtrate rotary evaporation removes solvent and obtains brown
Brown solid, by this sepia solid with ethyl acetate：Yellow crystals, yield are obtained after n-hexane mixed solution recrystallization
69.30%。
Embodiment 5：
3- amino -6- bromine pyridazines are added in 1000 milliliters of single port are because of bottom flask（34.8g, 200mmol), 40% chloroacetaldehyde
The aqueous solution（58.8,300mmol）With 200mL (158g）Ethanol.Mixture in reaction bulb stirring reaction 7 at 80 DEG C is little
When.After reaction terminates, saturation NaHCO is used3Solution is neutralized to pH=8, adds 400mL ethyl acetate, separates organic phase, water phase
(2 × 300mL is extracted with acetic acid ethyl ester）, merge and 200mL water washings are first used after organic phase, then washed with 200mL saturated common salts
Wash, anhydrous Na2SO4It is dried, is filtered to remove drier, filtrate rotary evaporation removes solvent and obtains sepia solid, this sepia is consolidated
Body ethyl acetate：Yellow crystals, yield 79.63% are obtained after n-hexane mixed solution recrystallization.
Embodiment 6：
3- amino -6- bromine pyridazines are added in 1000 milliliters of single port are because of bottom flask（34.8g, 200mmol), 40% chloroacetaldehyde
The aqueous solution（58.8,300mmol）With 300mL water.Mixture in reaction bulb stirring reaction 7 hours at 80 DEG C.Reaction knot
Shu Hou, uses saturation NaHCO3Solution is neutralized to pH=8, adds 400mL ethyl acetate, separates organic phase, and water mutually uses acetic acid ethyl ester
Extraction (2 × 300mL）, to merge and first use 200mL water washings after organic phase, then with 200mL saturated common salt water washings, it is anhydrous
Na2SO4It is dried, is filtered to remove drier, filtrate rotary evaporation removes solvent and obtains sepia solid, by this sepia solid acetic acid
Ethyl ester：Yellow crystals, yield 64.9% are obtained after n-hexane mixed solution recrystallization.
Embodiment 7
3- amino -6- bromine pyridazines are added in 1000 milliliters of single port are because of bottom flask（34.8g, 200mmol), 40% chloroacetaldehyde
The aqueous solution（58.8g, 300mmol）, triethylamine（300mmol ）And 522gDMF.Mixture in reaction bulb is stirred at 100 DEG C
Mix reaction 7 hours.After reaction terminates, revolving removes solvent, adds 300mL water and 500mL ethyl acetate, separates organic phase, water
Mutually it is extracted with ethyl acetate（2×300mL）, to merge and first use 200mL water washings after organic phase, then use 200mL saturated aqueous common salts
Washing, anhydrous Na2SO4It is dried, is filtered to remove drier, filtrate rotary evaporation removes solvent and obtains sepia solid, and this is brown
Color solid with ethyl acetate：Yellow crystals, yield 70.18% are obtained after n-hexane mixed solution recrystallization.
Embodiment 8
3- amino -6- bromine pyridazines are added in 1000 milliliters of single port are because of bottom flask（34.8g, 200mmol), 40% chloroacetaldehyde
The aqueous solution（58.8g, 300mmol）, NaOH（300mmol ）With the 300g tert-butyl alcohols.Mixture in reaction bulb is at 90 DEG C
Lower stirring reaction 6 hours.After reaction terminates, revolving removes solvent, adds 300mL water and 400mL ethyl acetate, separates organic
Phase, water is mutually extracted with ethyl acetate（2×300mL）, merge and 200mL water washings are first used after organic phase, then eaten with 200mL saturations
Salt water washing, anhydrous Na2SO4It is dried, is filtered to remove drier, filtrate rotary evaporation removes solvent and obtains sepia solid, by this
Sepia solid with ethyl acetate：Yellow crystals, yield 72.18% are obtained after n-hexane mixed solution recrystallization.
Embodiment 9
3- amino -6- bromine pyridazines are added in 1000 milliliters of single port are because of bottom flask（34.8g, 200mmol), 40% chloroacetaldehyde
The aqueous solution（58.8g, 300mmol）, sodium carbonate（300mmol ）With 500g isopropanols.Mixture in reaction bulb is at 85 DEG C
Stirring reaction 3 hours.After reaction terminates, revolving removes solvent, adds 300mL water and 400mL ethyl acetate, separates organic phase,
Water is mutually extracted with ethyl acetate（2×300mL）, to merge and first use 200mL water washings after organic phase, then use 200mL saturated common salts
Water washing, anhydrous Na2SO4It is dried, is filtered to remove drier, filtrate rotary evaporation removes solvent and obtains sepia solid, by this palm fibre
Brown solid ethyl acetate：Yellow crystals, yield 78.24% are obtained after n-hexane mixed solution recrystallization.
Claims (6)
1. a kind of 6- bromines imidazo [1,2-b ］ synthetic method of pyridazine, it is characterised in that：Comprise the following steps：
With 3- amino -6- bromines pyridazine and 40% chloroacetaldehyde solution as raw material, in a solvent, in the presence of alkali, at 30～100 DEG C
Successive reaction, Jing after ethyl acetate extraction, water washing, anhydrous sodium sulphate are dried, rotary evaporation is concentrated 6- bromines imidazo [1,2- is obtained
B ］ pyridazine crude product, crude product solvent recrystallization obtains sterling.
2. 6- bromines imidazo according to claim 1 [1,2-b ］ synthetic method of pyridazine, it is characterised in that：Solvent is molten
Agent is one or two in water, ethanol, the tert-butyl alcohol, DMF, methyl alcohol and isopropanol.
3. 6- bromines imidazo according to claim 1 and 2 [1,2-b ］ synthetic method of pyridazine, it is characterised in that：Reactant
It is with the inventory of solvent：3- amino -6- bromine pyridazines：Solvent=1：4.0 ~ 15, the above is weight ratio.
4. 6- bromines imidazo according to claim 1 and 2 [1,2-b ］ synthetic method of pyridazine, it is characterised in that：The original
Expect that consumption is：3- amino -6- bromine pyridazines：40% chloroacetaldehyde solution：Alkali=1:1.5~2.0:1.5, it is more than mol ratio.
5. 6- bromines imidazo according to claim 1 and 2 [1,2-b ］ synthetic method of pyridazine, it is characterised in that：The alkali
It is sodium acid carbonate, the one kind in NaOH, triethylamine and sodium carbonate.
6. 6- bromines imidazo according to claim 1 and 2 [1,2-b ］ synthetic method of pyridazine, it is characterised in that：30～
100 DEG C of successive reactions, 3～16 hours.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115557954A (en) * | 2022-11-11 | 2023-01-03 | 上海泰坦科技股份有限公司 | Preparation method of 6-bromo- [1,2,4] triazolo [4,3-b ] pyridazine |
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2016
- 2016-11-22 CN CN201611029550.1A patent/CN106632355A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115557954A (en) * | 2022-11-11 | 2023-01-03 | 上海泰坦科技股份有限公司 | Preparation method of 6-bromo- [1,2,4] triazolo [4,3-b ] pyridazine |
| CN115557954B (en) * | 2022-11-11 | 2024-06-11 | 上海泰坦科技股份有限公司 | Preparation method of 6-bromo- [1,2,4] triazolo [4,3-b ] pyridazine |
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Application publication date: 20170510 |