CN104844523A - Synthesis method of 3-amino-6-chloropyridazine - Google Patents
Synthesis method of 3-amino-6-chloropyridazine Download PDFInfo
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- CN104844523A CN104844523A CN201510215004.6A CN201510215004A CN104844523A CN 104844523 A CN104844523 A CN 104844523A CN 201510215004 A CN201510215004 A CN 201510215004A CN 104844523 A CN104844523 A CN 104844523A
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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
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Abstract
The invention relates to a synthesis method of 3-amino-6-chloropyridazine. The synthesis method is characterized by including the following steps: taking 3,6-dichloropyridazine and ammonia water as raw materials according to a quantity ratio of 1:0.5-7.5; placing the raw materials in proper solvent for reaction at 30-180 DEG C; obtaining a pure product of 3-amino-6-chloropyridazine after purification. The synthesis method is easy-to-get in reaction raw material, reasonable in price, mild in reaction condition, easy in operation and control and simple in aftertreatment, and the product is stable in quality and high in purity.
Description
(1) technical field
The invention belongs to organic synthesis field, be specifically related to a kind of synthetic method of 3-amino-6-chlorine pyridazine.
(2) background technology
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.
The synthetic method of a kind of 3-amino-4-bromo-6-chlorine pyridazine that March 11 in 2015 announces, 3-amino-6-chlorine pyridazine (28.50g, 220mmol) is added, bromine (63.28g in 1000mL single necked round bottom flask, 396mmol), methyl alcohol and Virahol 600ml altogether.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.
3-amino-6-chlorine pyridazine is the important intermediate of organic synthesis, is mainly used in medicine intermediate, organic synthesis, organic solvent, also can be applicable to the aspects such as DYE PRODUCTION, pesticide producing and spices.This product is novel medicine intermediate, and have very large medical value, it synthesizes difficulty, and market value is expensive, lacks document and Patents report.
(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-6-chlorine pyridazine.
The present invention is achieved through the following technical solutions:
A synthetic method for 3-amino-6-chlorine pyridazine, its special character is: comprise the following steps:
With 3,6-dichloro-pyridazine and ammoniacal liquor for raw material, the ratio of the two amount of substance is 1:0.5-7.5, in suitable solvent, in 30-180 DEG C of reactions, after purifying sterling 3-amino-6-chlorine pyridazine.
The synthetic method of 3-amino-6-chlorine pyridazine of the present invention, described solvent is one or both in methyl alcohol, ethanol, methylene dichloride, DMF, acetonitrile and water.
The synthetic method of 3-amino-6-chlorine pyridazine of the present invention, in described step, purification step is evaporation concentration, recrystallization, and silica gel column chromatography is separated.
The synthetic method of 3-amino-6-chlorine pyridazine of the present invention, the charging capacity of reactant and solvent is: 3,6-dichloro-pyridazine: solvent=1:1.5-20, is more than weight ratio.
The synthetic method of 3-amino-6-chlorine pyridazine of the present invention, in described step, temperature of reaction is 30-180 DEG C, and the reaction times is 5-26 hour.
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:
3,6-dichloro-pyridazine (2.98g, 20mmol) is added, ammoniacal liquor (2.10g, 60mmol), DMF 30ml in 100mL single necked round bottom flask.Mixture in reaction flask stirring reaction 9 hours at 100 DEG C.TLC and GC determines that reaction completes.After reaction terminates, revolve and steam except desolventizing, obtain thick product, recrystallization, is separated with silica gel column chromatography and obtains straight product 3-amino-6-chlorine pyridazine, after drying, calculated yield 90.63%, purity 98.76% (GC), fusing point 207.3 DEG C-209.5 DEG C (210 DEG C, document).Nuclear magnetic resonance spectroscopy: 1H NMR (deuterated DMSO): 7.34 ppm (s, 1H), 6.84 ppm (s, 1H), 6.63 ppm (d, 2H).
Embodiment 2:
3,6-dichloro-pyridazine (2.98g, 20mmol) is added, ammoniacal liquor (2.10g, 60mmol), methylene dichloride 30ml in 100mL single necked round bottom flask.Mixture in reaction flask stirring reaction 9 hours at 100 DEG C.TLC and GC determines that reaction completes.After reaction terminates, revolve and steam except desolventizing, obtain thick product, recrystallization, be separated with silica gel column chromatography and obtain straight product 3-amino-6-chlorine pyridazine, after drying, calculated yield 82.60%, purity 99.07% (GC).
Embodiment 3:
3,6-dichloro-pyridazine (14.90g, 100mmol) is added, ammoniacal liquor (10.52g, 300mmol), acetonitrile 200ml in 500mL single necked round bottom flask.Mixture in reaction flask stirring reaction 7 hours at 120 DEG C.TLC and GC determines that reaction completes.After reaction terminates, revolve and steam except desolventizing, obtain thick product, recrystallization, be separated with silica gel column chromatography and obtain straight product 3-amino-6-chlorine pyridazine, after drying, calculated yield 93.79%.
Embodiment 4:
3,6-dichloro-pyridazine (14.90g, 100mmol) is added, ammoniacal liquor (10.52g, 300mmol), DMF 200ml in 500mL single necked round bottom flask.Mixture in reaction flask stirring reaction 7 hours at 130 DEG C.TLC and GC determines that reaction completes.After reaction terminates, revolve and steam except desolventizing, recrystallization, obtains thick product, recrystallization, is separated obtains straight product 3-amino-6-chlorine pyridazine with silica gel column chromatography, after drying, and calculated yield 95.70%.
Embodiment 5:
3,6-dichloro-pyridazine (29.80g, 200mmol) is added, ammoniacal liquor (10.52g, 300mmol), DMF and acetonitrile 550ml, wherein acetonitrile 200ml altogether in 1000mL single necked round bottom flask.Mixture in reaction flask stirring reaction 6 hours at 150 DEG C.TLC and GC determines that reaction completes.After reaction terminates, revolve and steam except desolventizing, obtain thick product, recrystallization, be separated with silica gel column chromatography and obtain straight product 3-amino-6-chlorine pyridazine, after drying, calculated yield 89.25%.
Embodiment 6:
3,6-dichloro-pyridazine (2.98g, 20mmol) is added, ammoniacal liquor (0.35g, 10mmol), methylene dichloride 3.3ml in 100mL single necked round bottom flask.Mixture in reaction flask stirring reaction 26 hours at 30 DEG C.TLC and GC determines that reaction completes.After reaction terminates, revolve and steam except desolventizing, obtain thick product, recrystallization, be separated with silica gel column chromatography and obtain straight product 3-amino-6-chlorine pyridazine, after drying, calculated yield 81.42%, purity 99.00% (GC).
Embodiment 7:
3,6-dichloro-pyridazine (14.90g, 100mmol) is added, ammoniacal liquor (26.3g, 750mmol), ethanol 377ml in 500mL single necked round bottom flask.Mixture in reaction flask stirring reaction 5 hours at 78 DEG C.TLC and GC determines that reaction completes.After reaction terminates, revolve and steam except desolventizing, recrystallization, obtains thick product, recrystallization, is separated obtains straight product 3-amino-6-chlorine pyridazine with silica gel column chromatography, after drying, and calculated yield 96.70%.
Embodiment 8:
3,6-dichloro-pyridazine (14.90g, 100mmol) is added, ammoniacal liquor (26.3g, 750mmol), methyl alcohol 200ml in 500mL single necked round bottom flask.Mixture in reaction flask stirring reaction 5 hours at 85 DEG C.TLC and GC determines that reaction completes.After reaction terminates, revolve and steam except desolventizing, recrystallization, obtains thick product, recrystallization, is separated obtains straight product 3-amino-6-chlorine pyridazine with silica gel column chromatography, after drying, and calculated yield 91.42%.
Embodiment 9:
3,6-dichloro-pyridazine (14.90g, 100mmol) is added, ammoniacal liquor (10.52g, 300mmol), DMF 400ml in 500mL single necked round bottom flask.Mixture in reaction flask stirring reaction 7 hours at 180 DEG C.TLC and GC determines that reaction completes.After reaction terminates, revolve and steam except desolventizing, recrystallization, obtains thick product, recrystallization, is separated obtains straight product 3-amino-6-chlorine pyridazine with silica gel column chromatography, after drying, and calculated yield 93.70%.
Embodiment 10:
3,6-dichloro-pyridazine (14.90g, 100mmol) is added, ammoniacal liquor (26.3g, 750mmol), water 100ml in 500mL single necked round bottom flask.Mixture in reaction flask stirring reaction 5 hours at 105 DEG C.TLC and GC determines that reaction completes.After reaction terminates, revolve and steam except desolventizing, recrystallization, obtains thick product, recrystallization, is separated obtains straight product 3-amino-6-chlorine pyridazine with silica gel column chromatography, after drying, and calculated yield 90.48%.
Embodiment 11:
In 1000mL single necked round bottom flask, add 3,6-dichloro-pyridazine (29.80g, 200mmol), ammoniacal liquor (10.52g, 300mmol), G & W is 500ml, wherein water 400ml altogether.Mixture in reaction flask stirring reaction 0.5 hour at 120 DEG C, is then warming up to 190 DEG C of reactions 0.4 hour.TLC and GC determines that reaction completes.After reaction terminates, revolve and steam except desolventizing, obtain thick product, recrystallization, be separated with silica gel column chromatography and obtain straight product 3-amino-6-chlorine pyridazine, after drying, calculated yield 90.25%.
Claims (5)
1. a synthetic method for 3-amino-6-chlorine pyridazine, is characterized in that: comprise the following steps:
With 3,6-dichloro-pyridazine and ammoniacal liquor for raw material, the ratio of the two amount of substance is 1:0.5-7.5, in suitable solvent, in 30-180 DEG C of reactions, after purifying sterling 3-amino-6-chlorine pyridazine.
2. the synthetic method of 3-amino-6-chlorine pyridazine according to claim 1, is characterized in that: described solvent is one or both in methyl alcohol, ethanol, methylene dichloride, DMF, acetonitrile and water.
3. the synthetic method of 3-amino-6-chlorine pyridazine according to claim 1, is characterized in that: in described step, purification step is evaporation concentration, recrystallization, and silica gel column chromatography is separated.
4. the synthetic method of 3-amino-6-chlorine pyridazine according to claim 1, it is characterized in that: the charging capacity of reactant and solvent is: 3,6-dichloro-pyridazine: solvent=1:1.5-20, is more than weight ratio.
5. the synthetic method of 3-amino-6-chlorine pyridazine according to claim 1, it is characterized in that: in described step, temperature of reaction is 30-180 DEG C, the reaction times is 5-26 hour.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0477474A (en) * | 1990-07-18 | 1992-03-11 | Takeda Chem Ind Ltd | Production of 6-amino-3-chloropyridazine |
| WO2007026623A1 (en) * | 2005-08-30 | 2007-03-08 | Sumitomo Chemical Company, Limited | Process for producing 3-amino-6-chloropyridazine |
| CN101265267A (en) * | 2008-02-04 | 2008-09-17 | 山东罗欣药业股份有限公司 | Method for preparing cefozopran hydrochloride, cefozopran hydrochloride powder injection and preparation method thereof |
-
2015
- 2015-04-30 CN CN201510215004.6A patent/CN104844523A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0477474A (en) * | 1990-07-18 | 1992-03-11 | Takeda Chem Ind Ltd | Production of 6-amino-3-chloropyridazine |
| WO2007026623A1 (en) * | 2005-08-30 | 2007-03-08 | Sumitomo Chemical Company, Limited | Process for producing 3-amino-6-chloropyridazine |
| CN101265267A (en) * | 2008-02-04 | 2008-09-17 | 山东罗欣药业股份有限公司 | Method for preparing cefozopran hydrochloride, cefozopran hydrochloride powder injection and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| DAVID C. PRYDE等: "Novel Selective Inhibitors of Neutral Endopeptidase for the Treatment of Female Sexual Arousal Disorder. Synthesis and Activity of Functionalized Glutaramides", 《J. MED. CHEM.》 * |
| 付春: "咪唑并(1, 2-b)哒嗪", 《精细与专用化学品》 * |
| 陈春光等: "咪唑并［1，2- b］哒嗪的合成", 《精细化工》 * |
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