CN106831782A - The synthetic method of 6 chlorine imidazos [1,2 b] formic acid of pyridazine 3 - Google Patents
The synthetic method of 6 chlorine imidazos [1,2 b] formic acid of pyridazine 3 Download PDFInfo
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- CN106831782A CN106831782A CN201611038142.2A CN201611038142A CN106831782A CN 106831782 A CN106831782 A CN 106831782A CN 201611038142 A CN201611038142 A CN 201611038142A CN 106831782 A CN106831782 A CN 106831782A
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- 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 present invention relates to a kind of synthetic method of 6 chlorine imidazo [1,2 b] formic acid of pyridazine 3.N, N dimethylformamide dimethyl acetal and the chlorine pyridazine of 3 amino 6 are obtained intermediate in 40 120 DEG C of reactions, under alkali effect, in 65 140 DEG C of reactions, rotary evaporation obtains the Ethyl formate crude product of 6 chlorine imidazos [1,2 b] pyridazine 3 after concentrating, the crude product is recrystallized to give sterling, in the presence of alkali, the hydrolysis in certain solvent, reaction terminates, neutralized through hydrochloric acid, suction filtration, washing is dried to obtain the formic acid sterling of 6 chlorine imidazos [1,2 b] pyridazine 3.6 chlorine imidazos [1,2 b] formic acid of pyridazine 3 is prepared using the present invention, reaction raw materials are relatively easy to get, it is easy to operate, it is easy to control, post processing is simple, and product quality is stable, purity is high.
Description
（One）Technical field
The invention belongs to organic synthesis field, and in particular to a kind of synthesis side of 6- chlorine imidazo [1,2-b] pyridazine -3- formic acid
Method.
（Two）Background technology
6- chlorine imidazo [1,2-b] pyridazine -3- formic acid is the important intermediate of organic synthesis, is mainly used in medicine intermediate, is had
Machine synthesizes, and can also be applied to DYE PRODUCTION, the aspect such as pesticide producing and spices.Existing 6- chlorine imidazo [1,2-b] pyridazine -3- first
Acid preparation process is cumbersome, and reaction is fierce, and impurity content is high in product, yields poorly, and the reaction time is long, and cost of material is high, is unfavorable for
Enterprise competitiveness.
（Three）The content of the invention
The present invention needs the problem for solving to be directed to prior art, there is provided a kind of process is simple is reasonable, low cost, product purity
Height, is suitable to the synthetic method of laboratory and industrialized 6- chlorine imidazo [1,2-b] pyridazine -3- formic acid.
The present invention is achieved through the following technical solutions：
A kind of synthetic method of 6- chlorine imidazo [1,2-b] pyridazine -3- formic acid, it is characterized in that：Comprise the following steps：
（1）The preparation of [2- (the chloro- 3- pyridazinyls of 6-) -2- azepines vinyl] dimethylamine intermediate：
DMF dimethylacetal is both reaction raw materials and solvent, with 3- amino -6- chlorine pyridazines in 40-120
DEG C reaction is obtained [2- (the chloro- 3- pyridazinyls of 6-) -2- azepines vinyl] dimethylamine intermediate, and the intermediate is by simple post processing
Reacted for next step.
（2）The preparation of 6- chlorine imidazo [1,2-b] pyridazine -3- Ethyl formates：
Intermediate [2- (the chloro- 3- pyridazinyls of 6-) -2- azepines vinyl] dimethylamine in the presence of specific alkali, in certain solvent
In, in 65-140 DEG C of reaction, reaction terminates, and is cooled to room temperature, and ethyl acetate extraction merges organic phase, water and saturated aqueous common salt
Washing, anhydrous sodium sulfate drying obtains 6- chlorine imidazo [1,2-b] pyridazine -3- Ethyl formate crude products after rotary evaporation concentration, and this is thick
Product obtain final product sterling by recrystallization.
（3）The preparation of 6- chlorine imidazo [1,2-b] pyridazine -3- formic acid：
In the presence of alkali, 6- chlorine imidazo [1,2-b] pyridazine -3- Ethyl formates hydrolysis in certain solvent, reaction knot
Beam, neutralizes, suction filtration through hydrochloric acid, and washing is dried to obtain 6- chlorine imidazo [1,2-b] pyridazine -3- formic acid sterlings.
The synthetic method of 6- chlorine imidazo [1,2-b] pyridazine -3- formic acid of the invention, step（2）Described in solvent be second
At least one of nitrile, dichloromethane, DMF, DMAC, acetic acid, ethanol, isopropanol.
The synthetic method of 6- chlorine imidazo [1,2-b] pyridazine -3- formic acid of the invention, step（2）Described in specific alkali be
Sodium acid carbonate.
The synthetic method of 6- chlorine imidazo [1,2-b] pyridazine -3- formic acid of the invention, step（1）Middle 3- amino -6- chlorine is rattled away
Piperazine：N,N-dimethylformamide dimethylacetal is 1:2-4, step（2）In, alkali：Bromoacetate is 1:1.5-3.2, the above
It is mol ratio.
The synthetic method of 6- chlorine imidazo [1,2-b] pyridazine -3- formic acid of the invention, step（3）Middle hydrolysis temperature is 20-
75℃。
The synthetic method of 6- chlorine imidazo [1,2-b] pyridazine -3- formic acid of the invention, step（3）Middle solvent be methyl alcohol or
The mixture of ethanol and water.
The synthetic method of 6- chlorine imidazo [1,2-b] pyridazine -3- formic acid of the invention, step（3）The concentration of middle hydrochloric acid is
30%。
The synthetic method of 6- chlorine imidazo [1,2-b] pyridazine -3- formic acid of the invention, step（3）Middle 6- chlorine imidazo [1,
2-b] amount ratio of pyridazine -3- Ethyl formates and alkali is 1:1.5-3.0, is more than mol ratio.
Step（1）Reaction time is 1-5 hours, step（2）Reaction time is 4-18 hours, step（3）Hydrolysis is
1-6 hours.
The synthesis technique and synthesis step of 6- chlorine imidazo [1,2-b] pyridazine -3- formic acid of the present invention are as follows：
Beneficial effects of the present invention：6- chlorine imidazo [1,2-b] pyridazine -3- formic acid is prepared using the present invention, reaction raw materials compare
It is easy to get, it is easy to operate, it is easy to control, post processing is simple, and product quality is stable, purity is high.
（Four）Specific embodiment
Embodiment 1：
3- amino -6- chlorine pyridazines are added in 250ml three neck round bottom flask（12.96g, 100mmol）, DMF
Dimethylacetal（35.75g, 300mmol）80 DEG C are reacted 4 hours, and TLC detection reactions are completed, and [2- (the chloro- 3- pyridazines of 6- are obtained
Base) -2- azepines vinyl] dimethylamine intermediate, the unnecessary DMF dimethylacetal of revolving removing.Revolving
Intermediate afterwards is poured into 500ml there-necked flasks, is added thereto to 65ml DMFs (DMF), sodium acid carbonate
（21g, 250mmol）, bromoacetate（41.75g, 250mmol）, 90 DEG C are reacted 12h, and reaction terminates, and is cooled to room temperature, are added
200ml water, then add ethyl acetate（3×150ml）, merge organic phase, wash with water（3×100ml）, then eaten with 150ml saturations
Salt water washing, anhydrous sodium sulfate drying, filtering, filtrate is concentrated to give 6- chlorine imidazo [1,2-b] pyridazine -3- Ethyl formate crude products,
The crude product ethyl acetate：N-hexane=1:3 mixed solvent recrystallizes to obtain sterling, calculated yield 76.14%, the % of purity 98.46
（HPLC）.
6- chlorine imidazo [1,2-b] pyridazine -3- Ethyl formates are added in 500ml single-necked flasks（11.28g,50mmol）
With methyl alcohol 50ml, NaOH（3.6g, 90mmol）It is dissolved in 100ml water, is added in reaction bulb, 25 DEG C of reactions 4 is small
When, TLC determines that reaction is completed, and pH=4 is neutralized to 30% hydrochloric acid, and suction filtration, filter cake is washed with a small amount, and is drying to obtain 6- chlorine miaows
Azoles simultaneously [1,2-b] pyridazine -3- formic acid sterlings, yield 86%.
Embodiment 2：
3- amino -6- chlorine pyridazines are added in 250ml three neck round bottom flask（12.96g, 100mmol）, DMF
Dimethylacetal（35.75g, 300mmol）80 DEG C are reacted 4 hours, and TLC detection reactions are completed, and [2- (the chloro- 3- pyridazines of 6- are obtained
Base) -2- azepines vinyl] dimethylamine intermediate, the unnecessary DMF dimethylacetal of revolving removing.Revolving
Intermediate afterwards is poured into 500ml there-necked flasks, is added thereto to 65ml acetonitriles, sodium acid carbonate（21g, 250mmol）, bromine second
Acetoacetic ester（41.75g, 250mmol）, 90 DEG C are reacted 12h, and reaction terminates, and are cooled to room temperature, add 200ml water, then add acetic acid second
Ester（3×150ml）, merge organic phase, wash with water（3×100ml）, then with 150ml saturated common salt water washings, anhydrous sodium sulfate
Dry, filtering, filtrate is concentrated to give 6- chlorine imidazo [1,2-b] pyridazine -3- Ethyl formate crude products, the crude product ethyl acetate：Just
Hexane=1:3 mixed solvent recrystallizes to obtain sterling, calculated yield 79%, the % of purity 98.70（HPLC）.
6- chlorine imidazo [1,2-b] pyridazine -3- Ethyl formates are added in 500ml single-necked flasks（11.28g,50mmol）
With methyl alcohol 50ml, potassium hydroxide（5.04g, 90mmol）It is dissolved in 100ml water, is added in reaction bulb, 25 DEG C of reactions 4 is small
When, TLC determines that reaction is completed, and pH=4 is neutralized to 30% hydrochloric acid, and suction filtration, filter cake is washed with a small amount, and is drying to obtain 6- chlorine miaows
Azoles simultaneously [1,2-b] pyridazine -3- formic acid sterlings, yield 81.42%.
Embodiment 3：
3- amino -6- chlorine pyridazines are added in 250ml three neck round bottom flask（12.96g, 100mmol）, DMF
Dimethylacetal（35.75g, 300mmol）80 DEG C are reacted 4 hours, and TLC detection reactions are completed, and [2- (the chloro- 3- pyridazines of 6- are obtained
Base) -2- azepines vinyl] dimethylamine intermediate, the unnecessary DMF dimethylacetal of revolving removing.Revolving
Intermediate afterwards is poured into 500ml there-necked flasks, is added thereto to 65ml DMAs（DMAC）, sodium acid carbonate
（21g, 250mmol）, bromoacetate（41.75g, 250mmol）, 90 DEG C are reacted 12h, and reaction terminates, and is cooled to room temperature, are added
200ml water, then add ethyl acetate（3×150ml）, merge organic phase, wash with water（3×100ml）, then eaten with 150ml saturations
Salt water washing, anhydrous sodium sulfate drying, filtering, filtrate is concentrated to give 6- chlorine imidazo [1,2-b] pyridazine -3- Ethyl formate crude products,
The crude product ethyl acetate：N-hexane=1:3 mixed solvent recrystallizes to obtain sterling, calculated yield 70.81%, the % of purity 99.00
（HPLC）.
6- chlorine imidazo [1,2-b] pyridazine -3- Ethyl formates are added in 500ml single-necked flasks（11.28g,50mmol）
With methyl alcohol 50ml, NaOH（3.6g, 90mmol）It is dissolved in 100ml water, is added in reaction bulb, 25 DEG C of reactions 4 is small
When, TLC determines that reaction is completed, and pH=4 is neutralized to 30% hydrochloric acid, and suction filtration, filter cake is washed with a small amount, and is drying to obtain 6- chlorine miaows
Azoles simultaneously [1,2-b] pyridazine -3- formic acid sterlings, yield 85.1%.
Embodiment 4：
3- amino -6- chlorine pyridazines are added in 250ml three neck round bottom flask（12.96g, 100mmol）, DMF
Dimethylacetal（35.75g, 300mmol）80 DEG C are reacted 4 hours, and TLC detection reactions are completed, and [2- (the chloro- 3- pyridazines of 6- are obtained
Base) -2- azepines vinyl] dimethylamine intermediate, the unnecessary DMF dimethylacetal of revolving removing.Revolving
Intermediate afterwards is poured into 500ml there-necked flasks, is added thereto to 30ml DMFs（DMF）, 35ml acetonitriles,
Sodium acid carbonate（21g, 250mmol）, bromoacetate（41.75g, 250mmol）, 90 DEG C are reacted 12h, and reaction terminates, is cooled to
Room temperature, adds 200ml water, then add ethyl acetate（3×150ml）, merge organic phase, wash with water（3×100ml）, then use
150ml saturated common salt water washings, anhydrous sodium sulfate drying, filtering, filtrate is concentrated to give 6- chlorine imidazo [1,2-b] pyridazine -3- first
Acetoacetic ester crude product, the crude product ethyl acetate：N-hexane=1:3 mixed solvent recrystallizes to obtain sterling, calculated yield 75.30%,
The % of purity 98.57（HPLC）.
6- chlorine imidazo [1,2-b] pyridazine -3- Ethyl formates are added in 500ml single-necked flasks（11.28g,50mmol）
With methyl alcohol 50ml, NaOH（4.0g, 100mmol）It is dissolved in 100ml water, is added in reaction bulb, 25 DEG C of reactions 4 is small
When, TLC determines that reaction is completed, and pH=4 is neutralized to 30% hydrochloric acid, and suction filtration, filter cake is washed with a small amount, and is drying to obtain 6- chlorine miaows
Azoles simultaneously [1,2-b] pyridazine -3- formic acid sterlings, yield 91%.
Embodiment 5：
3- amino -6- chlorine pyridazines are added in 250ml three neck round bottom flask（12.96g, 100mmol）, DMF
Dimethylacetal（47.66g, 400mmol）80 DEG C are reacted 3 hours, and TLC detection reactions are completed, and [2- (the chloro- 3- pyridazines of 6- are obtained
Base) -2- azepines vinyl] dimethylamine intermediate, the unnecessary DMF dimethylacetal of revolving removing.Revolving
Intermediate afterwards is poured into 500ml there-necked flasks, is added thereto to 35ml DMAs（DMAC）, 35ml acetonitriles,
Sodium acid carbonate（25.20g, 300mmol）, bromoacetate（50.10g, 300mmol）, 90 DEG C are reacted 12h, and reaction terminates, and are cooled down
To room temperature, 200ml water is added, then add ethyl acetate（3×150ml）, merge organic phase, wash with water（3×100ml）, then use
150ml saturated common salt water washings, anhydrous sodium sulfate drying, filtering, filtrate is concentrated to give 6- chlorine imidazo [1,2-b] pyridazine -3- first
Acetoacetic ester crude product, the crude product ethyl acetate：N-hexane=1:3 mixed solvent recrystallizes to obtain sterling, calculated yield 74.12%,
The % of purity 99.50（HPLC）.
6- chlorine imidazo [1,2-b] pyridazine -3- Ethyl formates are added in 500ml single-necked flasks（11.28g,50mmol）
With ethanol 50ml, NaOH（3.6g, 90mmol）It is dissolved in 100ml water, is added in reaction bulb, 25 DEG C of reactions 4 is small
When, TLC determines that reaction is completed, and pH=4 is neutralized to 30% hydrochloric acid, and suction filtration, filter cake is washed with a small amount, and is drying to obtain 6- chlorine miaows
Azoles simultaneously [1,2-b] pyridazine -3- formic acid sterlings, yield 72.09%.
Embodiment 6：
3- amino -6- chlorine pyridazines are added in 250ml three neck round bottom flask（12.96g, 100mmol）, DMF
Dimethylacetal（47.66g, 400mmol）80 DEG C are reacted 3 hours, and TLC detection reactions are completed, and [2- (the chloro- 3- pyridazines of 6- are obtained
Base) -2- azepines vinyl] dimethylamine intermediate, the unnecessary DMF dimethylacetal of revolving removing.Revolving
Intermediate afterwards is poured into 500ml there-necked flasks, is added thereto to 35ml isopropanols, 35ml acetonitriles, sodium acid carbonate（25.20g,
300mmol）, bromoacetate（50.10g, 300mmol）, 90 DEG C are reacted 12h, and reaction terminates, and are cooled to room temperature, add 200ml
Water, then add ethyl acetate（3×150ml）, merge organic phase, wash with water（3×100ml）, then washed with 150ml saturated common salts
Wash, anhydrous sodium sulfate drying, filter, filtrate is concentrated to give 6- chlorine imidazo [1,2-b] pyridazine -3- Ethyl formate crude products, the crude product
Use ethyl acetate：N-hexane=1:3 mixed solvent recrystallizes to obtain sterling, calculated yield 67.45%.
6- chlorine imidazo [1,2-b] pyridazine -3- Ethyl formates are added in 500ml single-necked flasks（11.28g,50mmol）
With ethanol 50ml, NaOH（3.6g, 90mmol）, potassium hydroxide（3.36g, 60mmol）It is dissolved in 100ml water, adds
To in reaction bulb, 25 DEG C are reacted 4 hours, and TLC determines that reaction is completed, and pH=4 is neutralized to 30% hydrochloric acid, and suction filtration, filter cake is used few
Amount water washing, is drying to obtain 6- chlorine imidazo [1,2-b] pyridazine -3- formic acid sterlings, yield 84%.
Embodiment 7：
3- amino -6- chlorine pyridazines are added in 250ml three neck round bottom flask（12.96g, 100mmol）, DMF
Dimethylacetal（200mmol）40 DEG C are reacted 5 hours, and TLC detection reactions are completed, and [2- (the chloro- 3- pyridazinyls of 6-) -2- nitrogen is obtained
Miscellaneous vinyl] dimethylamine intermediate, the unnecessary DMF dimethylacetal of revolving removing.The centre after revolving
Body is poured into 500ml there-necked flasks, is added thereto to 65ml dichloromethane, sodium acid carbonate（250mmol）, bromoacetate
（875mmol）, 65 DEG C are reacted 4h, and reaction terminates, and are cooled to room temperature, add 200ml water, then add ethyl acetate（3×150ml）,
Merge organic phase, wash with water（3×100ml）, then with 150ml saturated common salt water washings, anhydrous sodium sulfate drying, filtering, filter
Liquid is concentrated to give 6- chlorine imidazo [1,2-b] pyridazine -3- Ethyl formate crude products, the crude product ethyl acetate：N-hexane=1:3 it is mixed
Bonding solvent recrystallizes to obtain sterling, calculated yield 80%, the % of purity 98.72（HPLC）.
6- chlorine imidazo [1,2-b] pyridazine -3- Ethyl formates are added in 500ml single-necked flasks（11.28g,50mmol）
With methyl alcohol 70ml, potassium hydroxide（150mmol）It is dissolved in 110ml water, is added in reaction bulb, 75 DEG C is reacted 1 hour,
TLC determines that reaction is completed, and pH=4 is neutralized to 30% hydrochloric acid, and suction filtration, filter cake is washed with a small amount, and is drying to obtain 6- chlorine imidazoles
And [1,2-b] pyridazine -3- formic acid sterlings, yield 81.21%.
Embodiment 8：
3- amino -6- chlorine pyridazines are added in 250ml three neck round bottom flask（12.96g, 100mmol）, DMF
Dimethylacetal（35.75g, 300mmol）120 DEG C are reacted 1 hour, and TLC detection reactions are completed, and [2- (the chloro- 3- pyridazines of 6- are obtained
Base) -2- azepines vinyl] dimethylamine intermediate, the unnecessary DMF dimethylacetal of revolving removing.Revolving
Intermediate afterwards is poured into 500ml there-necked flasks, is added thereto to 100ml DMF, sodium acid carbonate（21g, 250mmol）, bromine second
Acetoacetic ester（41.75g, 250mmol）, 140 DEG C are reacted 5h, and reaction terminates, and are cooled to room temperature, add 200ml water, then add acetic acid second
Ester（3×150ml）, merge organic phase, wash with water（3×100ml）, then with 150ml saturated common salt water washings, anhydrous sodium sulfate
Dry, filtering, filtrate is concentrated to give 6- chlorine imidazo [1,2-b] pyridazine -3- Ethyl formate crude products, the crude product ethyl acetate：Just
Hexane=1:3 mixed solvent recrystallizes to obtain sterling, calculated yield 79.5%, the % of purity 98.70（HPLC）.
6- chlorine imidazo [1,2-b] pyridazine -3- Ethyl formates are added in 500ml single-necked flasks（11.28g,50mmol）
With methyl alcohol 50ml, potassium hydroxide（5.04g, 90mmol）It is dissolved in 100ml water, is added in reaction bulb, 20 DEG C of reactions 6 is small
When, TLC determines that reaction is completed, and pH=4 is neutralized to 30% hydrochloric acid, and suction filtration, filter cake is washed with a small amount, and is drying to obtain 6- chlorine miaows
Azoles simultaneously [1,2-b] pyridazine -3- formic acid sterlings, yield 81.98%.
Embodiment 9：
3- amino -6- chlorine pyridazines are added in 250ml three neck round bottom flask（12.96g, 100mmol）, DMF
Dimethylacetal（35.75g, 300mmol）80 DEG C are reacted 4 hours, and TLC detection reactions are completed, and [2- (the chloro- 3- pyridazines of 6- are obtained
Base) -2- azepines vinyl] dimethylamine intermediate, the unnecessary DMF dimethylacetal of revolving removing.Revolving
Intermediate afterwards is poured into 500ml there-necked flasks, is added thereto to 20ml acetic acid, 60ml ethanol, sodium acid carbonate（21g,
250mmol）, bromoacetate（41.75g, 250mmol）, 90 DEG C are reacted 18h, and reaction terminates, and are cooled to room temperature, add 200ml
Water, then add ethyl acetate（3×150ml）, merge organic phase, wash with water（3×100ml）, then washed with 150ml saturated common salts
Wash, anhydrous sodium sulfate drying, filter, filtrate is concentrated to give 6- chlorine imidazo [1,2-b] pyridazine -3- Ethyl formate crude products, the crude product
Use ethyl acetate：N-hexane=1:3 mixed solvent recrystallizes to obtain sterling, calculated yield 77.8%, the % of purity 98.14（HPLC）.
6- chlorine imidazo [1,2-b] pyridazine -3- Ethyl formates are added in 500ml single-necked flasks（11.28g,50mmol）
With methyl alcohol 50ml, potassium hydroxide（5.04g, 90mmol）It is dissolved in 100ml water, is added in reaction bulb, 40 DEG C of reactions 2 is small
When, TLC determines that reaction is completed, and pH=4 is neutralized to 30% hydrochloric acid, and suction filtration, filter cake is washed with a small amount, and is drying to obtain 6- chlorine miaows
Azoles simultaneously [1,2-b] pyridazine -3- formic acid sterlings, yield 81.31%.
Claims (9)
1. a kind of synthetic method of 6- chlorine imidazo [1,2-b] pyridazine -3- formic acid, it is characterised in that：Comprise the following steps：
（1）The preparation of [2- (the chloro- 3- pyridazinyls of 6-) -2- azepines vinyl] dimethylamine intermediate：
DMF dimethylacetal is both reaction raw materials and solvent, with 3- amino -6- chlorine pyridazines in 40-120
DEG C reaction is obtained [2- (the chloro- 3- pyridazinyls of 6-) -2- azepines vinyl] dimethylamine intermediate, and the intermediate is by simple post processing
Reacted for next step.
（2）The preparation of 6- chlorine imidazo [1,2-b] pyridazine -3- Ethyl formates：
Intermediate [2- (the chloro- 3- pyridazinyls of 6-) -2- azepines vinyl] dimethylamine in the presence of specific alkali, in certain solvent
In, in 65-140 DEG C of reaction, reaction terminates, and is cooled to room temperature, and ethyl acetate extraction merges organic phase, water and saturated aqueous common salt
Washing, anhydrous sodium sulfate drying obtains 6- chlorine imidazo [1,2-b] pyridazine -3- Ethyl formate crude products after rotary evaporation concentration, and this is thick
Product both obtain sterling by recrystallization.
（3）The preparation of 6- chlorine imidazo [1,2-b] pyridazine -3- formic acid：
In the presence of alkali, 6- chlorine imidazo [1,2-b] pyridazine -3- Ethyl formates hydrolysis in certain solvent, reaction knot
Beam, neutralizes, suction filtration through hydrochloric acid, and washing is dried to obtain 6- chlorine imidazo [1,2-b] pyridazine -3- formic acid sterlings.
2. the synthetic method of 6- chlorine imidazo [1,2-b] pyridazine -3- formic acid according to claim 1, it is characterised in that：Step
Suddenly（2）Middle solvent is acetonitrile, dichloromethane, DMF, DMAC, acetic acid, ethanol, at least one of isopropanol.
3. the synthetic method of 6- chlorine imidazo [1,2-b] pyridazine -3- formic acid according to claim 1 and 2, its feature exists
In：Step（2）The specific alkali is sodium acid carbonate.
4. the synthetic method of 6- chlorine imidazo [1,2-b] pyridazine -3- formic acid according to claim 1 and 2, its feature exists
In：Step（1）Middle 3- amino -6- chlorine pyridazines：N,N-dimethylformamide dimethylacetal is 1:2-4, step（2）In, alkali：Bromine
Ethyl acetate is 1:1.5-3.2, is more than mol ratio.
5. the synthetic method of 6- chlorine imidazo [1,2-b] pyridazine -3- formic acid according to claim 1 and 2, its feature exists
In：Step（3）Middle hydrolysis temperature is 20-75 DEG C.
6. the synthetic method of 6- chlorine imidazo [1,2-b] pyridazine -3- formic acid according to claim 1 and 2, its feature exists
In：Step（3）Middle solvent is the mixture of methyl alcohol or ethanol and water.
7. the synthetic method of 6- chlorine imidazo [1,2-b] pyridazine -3- formic acid according to claim 1 and 2, its feature exists
In：Step（3）The concentration of middle hydrochloric acid is 30%.
8. the synthetic method of 6- chlorine imidazo [1,2-b] pyridazine -3- pyridine carboxylic acids according to claim 1 and 2, its feature
It is：Step（3）Middle 6- chlorine imidazo [1,2-b] pyridazine -3- Ethyl formates are 1 with the amount ratio of alkali:1.5-3.0, be more than
Mol ratio.
9. the synthetic method of 6- chlorine imidazo [1,2-b] pyridazine -3- pyridine carboxylic acids according to claim 1 and 2, its feature
It is：Step（1）Reaction time is 1-5 hours, step（2）Reaction time is 4-18 hours, step（3）Hydrolysis is 1-6
Hour.
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