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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- pyridazine
- chlorine
- formic acid
- chlorine imidazo
- synthetic method
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 21
- 239000000460 chlorine Substances 0.000 title abstract description 14
- 229910052801 chlorine Inorganic materials 0.000 title abstract description 14
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 title abstract description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 title abstract 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 title abstract 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 title abstract 4
- 235000019253 formic acid Nutrition 0.000 title abstract 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 59
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 28
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000012043 crude product Substances 0.000 claims abstract description 22
- 238000005406 washing Methods 0.000 claims abstract description 13
- 239000003513 alkali Substances 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 238000000967 suction filtration Methods 0.000 claims abstract description 12
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000007062 hydrolysis Effects 0.000 claims abstract description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 7
- 239000000047 product Substances 0.000 claims abstract description 6
- 238000012805 post-processing Methods 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 238000002390 rotary evaporation Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 39
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 238000001035 drying Methods 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 229920002554 vinyl polymer Polymers 0.000 claims description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 11
- 239000012074 organic phase Substances 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 235000002639 sodium chloride Nutrition 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims 1
- NGODILSACSTEDJ-UHFFFAOYSA-N N1=NC=CC=C1.[Cl] Chemical compound N1=NC=CC=C1.[Cl] NGODILSACSTEDJ-UHFFFAOYSA-N 0.000 abstract 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- 238000001514 detection method Methods 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 9
- 239000002585 base Substances 0.000 description 8
- KDPAWGWELVVRCH-UHFFFAOYSA-M bromoacetate Chemical compound [O-]C(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-M 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000012046 mixed solvent Substances 0.000 description 8
- RUUOPSRRIKJHNH-UHFFFAOYSA-N pyridazine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=N1 RUUOPSRRIKJHNH-UHFFFAOYSA-N 0.000 description 8
- 150000003851 azoles Chemical class 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 5
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000002253 acid Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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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