CN108503590A - A kind of pyridazinone compound and its synthetic method - Google Patents
A kind of pyridazinone compound and its synthetic method Download PDFInfo
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- CN108503590A CN108503590A CN201710103140.5A CN201710103140A CN108503590A CN 108503590 A CN108503590 A CN 108503590A CN 201710103140 A CN201710103140 A CN 201710103140A CN 108503590 A CN108503590 A CN 108503590A
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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
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- 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
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- 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
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The present invention relates to a kind of pyridazinone compound and its synthetic method, the general formula of the compound is as follows：Wherein, R1For C1 C4 alkyl or halogen；R2For C1 C4 alkyl or halogen；R3For straight-chain fatty amine or cyclammonium or the third sulfydryl or fragrant methoxyl group；R4For halogen or the third sulfydryl；When preparation, haloacetyl halogen is reacted into synthesis α halo acetophenones with benzene by friedel-craft first, again with 4,5 dichloro 3 (2H) pyridazinones pass through substitution reaction synthetic intermediate, the intermediate of generation occurs substitution reaction under alkaline reagent catalysis, with nucleopilic reagent such as fatty amine or ring-shaped fat amine or propanethiol and synthesizes pyridazinone compound.Compared with prior art, the entire technological process of the present invention is simple, and favorable repeatability, raw material is simple and easy to get, applied widely, has good application prospect.
Description
Technical field
The invention belongs to organic chemical synthesis technical field, it is related to a kind of pyridazinone compound and its synthetic method.
Background technology
Pesticide (Pesticides) is primarily referred to as various diseases (pest, evil mite, line in preventing agriculture forest and husbandry from producing
Worm, pathogen, weeds and muroid) and coordinate plant growth chemicals.However, the large-scale use of traditional pesticide is to environment
The negative effect that brings and cause the drug resistance of pathogenic microorganism and pest that its application power is made to have a greatly reduced quality, if it is few with pesticide if
Harmful organism is unable to effectively preventing, often results in the agriculture underproduction, directly influences the development of national economy.
Pyridazine compound is a kind of heterocyclic compound with efficient weeding, Insecticiding-miticiding, plant growth regulating isoreactivity
Object, many kinds also have the characteristics that low toxicity, low-residual.Currently, pyridazinone compound is widely used in crop pests
And the prevention of germ, obtain the pesticide species of many commercializations.1949, Schoene and Hoffmann reported 4- hydroxyls for the first time
Radical pyridazine ketone has the characteristic of strong inhibition plant cell division, and is applied in agricultural production as plant growth regulator.
The features such as pyridazinone pesticide is active high, environmentally friendly in integrated pest control and reduces pesticide environmental pollution side
Face plays an important role, and is one of the hot spot studied both at home and abroad in recent years, with good biological activity, it has also become a kind of great
The heterocyclic compound of potentiality to be exploited and researching value.But pyridazine compound is in the long-term use, and pest and germ are to it
Drug resistance constantly enhances, it is made to be restricted in application agriculturally.
Invention content
It is an object of the present invention to overcome the above-mentioned drawbacks of the prior art and provide a kind of technological process is simple,
Pyridazinone compound applied widely.
Another object of the present invention is just to provide the synthetic method of above-mentioned pyridazinone compound.
The purpose of the present invention can be achieved through the following technical solutions：
The general formula of a kind of pyridazinone compound, the compound is as follows：
Wherein, R1For C1-C4 alkyl or halogen；R2For C1-C4 alkyl or halogen；R3For straight-chain fatty amine or cyclammonium or third
Sulfydryl or fragrant methoxyl group；R4For halogen or the third sulfydryl.
A kind of synthetic method of pyridazinone compound, this method specifically include following steps：
(1) preparation of alpha-halo acetophenone：
It by haloacetyl halogen and benzene under lewis acidic catalytic action, is reacted in ice-water bath, synthesizes alpha-halo second
Ketone；
(2) preparation of bis- chloro- 2- of 4,5- [2- (substitution) phenyl -2- oxo-ethyls] -3 (2H)-pyridazinones：
The alpha-halo acetophenone of synthesis and basic catalyst, 4,5-, bis- chloro- 3 (2H)-pyridazinones are added in solvent, passed through
Reaction synthesis 4,5- bis- chloro- 2- [2- (substitution) phenyl -2- oxo-ethyls] -3 (2H)-pyridazinones；
(3) preparation of the chloro- 5- hydroxyls -2- of 4- [2- (substitution) phenyl -2- oxo-ethyls)] -3 (2H)-pyridazinones：
By bis- chloro- 2- of 4,5- [2- (substitution) phenyl -2- oxo-ethyls] -3 (the 2H)-pyridazinones and hydroxide of synthesis
Heating reaction in a solvent, by acidification, the chloro- 5- hydroxyls -2- of synthesis 4- [2- (substitution) phenyl -2- oxo-ethyls)] -3
(2H)-pyridazinone；
(4) synthesis of pyridazinone compound：
By the chloro- 5- hydroxyls -2- of the 4- of synthesis [2- (substitution) phenyl -2- oxo-ethyls)] -3 (2H)-pyridazinones with it is electrophilic
Reagent reacts, and synthesizes pyridazinone compound.
Alpha-halo acetophenone described in step (1) includes one kind in alpha-brominated acetyl bromide or alpha-chloro chloroacetic chloride, institute
The lewis acid stated includes one kind in aluminum trichloride (anhydrous), anhydrous ferric trichloride or anhydrous zinc chloride.
The molar ratio of alpha-halo acetophenone and bis- chloro- 3 (2H)-pyridazinones of 4,5-, basic catalyst described in step (2)
For 1-2:1:1.5-1.8, the basic catalyst include sodium hydroxide, potassium hydroxide, Anhydrous potassium carbonate, natrium carbonicum calcinatum or
One kind in sodium bicarbonate.
The chloro- 5- hydroxyls -2- of 4- [2- (substitution) phenyl -2- oxo-ethyls)] -3 (2H)-pyridazinones described in step (3)
Molar ratio with hydroxide is 1:1-5, the hydroxide include one kind in sodium hydroxide or potassium hydroxide.
The chloro- 5- hydroxyls -2- of 4- [2- (substitution) phenyl -2- oxo-ethyls)] -3 (2H)-pyridazinones described in step (4)
Molar ratio with electrophilic reagent is 1:1-2, and the electrophilic reagent includes chloromethyl pyridine, benzyl chloride, 4- chlorobenzyl chlorides
Or one kind in 4- methylbenzyl chlorine.
A kind of synthetic method of pyridazinone compound, this method specifically include following steps：
(A) preparation of alpha-halo acetophenone：
It by haloacetyl halogen and benzene under lewis acidic catalytic action, is reacted in ice-water bath, synthesizes alpha-halo second
Ketone；
(B) preparation of bis- chloro- 2- of 4,5- [2- (substitution) phenyl -2- oxo-ethyls] -3 (2H)-pyridazinones：
The alpha-halo acetophenone of synthesis and basic catalyst, 4,5-, bis- chloro- 3 (2H)-pyridazinones are added in solvent, passed through
Reaction synthesis 4,5- bis- chloro- 2- [2- (substitution) phenyl -2- oxo-ethyls] -3 (2H)-pyridazinones；
(C) synthesis of pyridazinone compound：
By bis- chloro- 2- of 4,5- [2- (substitution) phenyl -2- oxo-ethyls] -3 (the 2H)-pyridazinones and nucleopilic reagent of synthesis
Reaction synthesizes pyridazinone compound.
Alpha-halo acetophenone described in step (A) includes one kind in alpha-brominated acetyl bromide or alpha-chloro chloroacetic chloride, institute
The lewis acid stated includes one kind in aluminum trichloride (anhydrous), anhydrous ferric trichloride or anhydrous zinc chloride.
The molar ratio of alpha-halo acetophenone and bis- chloro- 3 (2H)-pyridazinones of 4,5-, basic catalyst described in step (B)
For 1-2:1:1.5-1.8, the basic catalyst include sodium hydroxide, potassium hydroxide, Anhydrous potassium carbonate, natrium carbonicum calcinatum or
One kind in sodium bicarbonate.
Bis- chloro- 2- of 4,5- [2- (substitution) phenyl -2- oxo-ethyls] -3 (2H)-pyridazinones described in step (C) and parent
The molar ratio of core reagent is 1:1.5-3, and the nucleopilic reagent includes methylamine, dimethylamine, isopropylamine, n-propylamine, positive fourth
One kind in amine, morpholine, piperidines, propanethiol or isopropyl mercaptan.
Compared with prior art, haloacetyl halogen is reacted synthesis α-by synthetic method of the present invention with benzene by friedel-craft first
Halo acetophenone, then pass through substitution reaction synthetic intermediate with 4,5-, bis- chloro- 3 (2H)-pyridazinones, the intermediate of generation is in alkalinity
Under reagent catalysis, substitution reaction occurs with nucleopilic reagent such as fatty amine or ring-shaped fat amine or propanethiol and synthesizes pyridazinone derivative
Object, entire technological process is simple, and favorable repeatability, raw material is simple and easy to get, applied widely, has good application prospect.
Specific implementation mode
With reference to specific embodiment, the present invention is described in detail.
Embodiment 1
One clock pyridazinone compound, the compound molecule formula are as follows：
Wherein, R1For methyl, R2For methyl, R3For piperidyl；R4For chlorine.The synthetic method packet of the pyridazinone compound
Include following steps：
(1) synthesis of alpha-chloro acetophenone
The ortho-xylene and 74.40g (0.557mol) of 200mL are added in the 250mL three-necked flasks with drying device
Anhydrous Aluminum chloride, ice-water bath cool down, then slowly be added dropwise 60.0g (0.531mol) alpha-chloro chloroacetic chloride, be added dropwise
Afterwards, it reacts 3 hours at room temperature, stops stirring.Reaction solution is poured into the beaker equipped with 200mL ice water and is stirred, with acetic acid second
Ester extracts liquid separation, and organic phase is washed with water to neutrality, anhydrous magnesium sulfate drying.Decompression sloughs solvent and obtains white solid
76.17g, yield 78.6%,1HNMR(CDCl3,400Hz)δ:2.35 (d, 6H, J=1.6Hz), 4.71 (s, 2H), 7.27 (t,
1H),7.71(t,1H),7.75(s,1H)。
(2) synthesis of bis- chloro- 2- of 4,5- [2- (3,4- 3,5-dimethylphenyls) -2- oxo-ethyls] -3 (2H) pyridazinones
4,5-, bis- chloro- 3 (2H)-pyridazinone 9.00g (0.055mol), 11.50g are added in the there-necked flask of 250mL
It is small to react 8 at 60 DEG C by the alpha-chloro acetophenone of (0.063mol), the DMF of the potassium carbonate and 100mL of 11.40g (0.083mol)
When.It is poured into after reaction solution is cooled to room temperature in the beaker equipped with 150mL ice water, a large amount of precipitation occurs in stirring, filters, filter cake
It is washed with water three times, it is dry, obtain 12.38g, yield 72.8%, mp with ethyl acetate/ethyl alcohol recrystallization：146.4~149.7
℃,1HNMR(CDCl3,400Hz)δ:2.32 (d, 6H, J=2Hz), 5.59 (s, 2H), 7.34 (d, 1H, J=8Hz), 7.78 (d,
1H, J=8Hz), 7.82 (s, 1H), 7.85 (s, 1H).
(3) synthesis of the chloro- 5- hydroxyls -2- of 4- [2- (3,4- 3,5-dimethylphenyls) -2- oxo-ethyls] -3 (2H) pyridazinones
Bis- chloro- 2- [2- (3,4- 3,5-dimethylphenyls)-of 10.00g (0.032mol) 4,5- are added in the there-necked flask of 250mL
2- oxo-ethyls] -3 (2H) pyridazinones, the potassium hydroxide and 160mL ethylene glycol of 9.00g (0.161mol) react 6 at 100 DEG C
Hour.Reaction solution cooling is poured into the beaker of 100mL ice water, hydrochloric acid solution is added dropwise while stirring, the pH for adjusting solution is 1,
There are a large amount of precipitations, filter, washs, it is dry.It is recrystallized with ethyl acetate/methanol, obtains 7.00g white needle-like crystals.Yield
75.1%, mp：216.8~219.9 DEG C,1HNMR(CDCl3,400Hz)δ:2.35 (d, 6H, J=3.6Hz), 5.60 (s, 2H),
7.28 (t, 2H), 7.73 (d, 1H, J=7.6Hz), 7.77 (s, 1H), 7.86 (s, 1H).
(4) synthesis of the chloro- 5- piperidines -2- of 4- [2- (3,4- 3,5-dimethylphenyls) -2- oxo-ethyls] -3 (2H) pyridazinones
Bis- chloro- 2- of 4,5- [2- (3,4- 3,5-dimethylphenyls) -2- oxo-ethyls] -3 are added in the there-necked flask of 100mL
(2H) pyridazinone 3.00g (0.010mol), the piperidines of 1.65g (0.019mol), 2.00g (0.014mol) potassium carbonate and 50mL
DMF reacts 7 hours at 70 DEG C.Reaction solution cooling is poured into the beaker for filling 50mL ice water, a large amount of precipitations occurs in stirring, takes out
Filter, filter cake are washed with water three times, dry.It is recrystallized with ethyl acetate/methanol, obtains faint yellow solid 2.58g, yield
71.9%.mp：150.8~152.3 DEG C,1HNMR(CDCl3,400Hz)δ:1.72 (q, 6H), 2.34 (d, 6H, J=2.4Hz),
3.41(t,4H),5.54(s,2H),7.26(t,1H),7.67(s,1H),7.74(s,2H)。
Embodiment 2
One clock pyridazinone compound, the compound molecule formula are as follows：
Wherein, R1For methyl, R2For methyl, R3For morpholine, R4For chlorine.The synthetic method of the pyridazinone compound includes
Following steps：
(1) synthesis of alpha-chloro acetophenone
The ortho-xylene and 74.40g (0.557mol) of 200mL are added in the 250mL three-necked flasks with drying device
Anhydrous Aluminum chloride, ice-water bath cool down, then slowly be added dropwise 60.0g (0.531mol) alpha-chloro chloroacetic chloride, be added dropwise
Afterwards, it reacts 3 hours at room temperature, stops stirring.Reaction solution is poured into the beaker equipped with 200mL ice water and is stirred, with acetic acid second
Ester extracts liquid separation, and organic phase is washed with water to neutrality, anhydrous magnesium sulfate drying.Decompression sloughs solvent and obtains white solid
76.17g, yield 78.6%,1HNMR(CDCl3,400Hz)δ:2.35 (d, 6H, J=1.6Hz), 4.71 (s, 2H), 7.27 (t,
1H),7.71(t,1H),7.75(s,1H)。
(2) synthesis of bis- chloro- 2- of 4,5- [2- (3,4- 3,5-dimethylphenyls) -2- oxo-ethyls] -3 (2H) pyridazinones
4,5-, bis- chloro- 3 (2H)-pyridazinone 9.00g (0.055mol), 11.50g are added in the there-necked flask of 250mL
It is small to react 8 at 60 DEG C by the alpha-chloro acetophenone of (0.063mol), the DMF of the potassium carbonate and 100mL of 11.40g (0.083mol)
When.It is poured into after reaction solution is cooled to room temperature in the beaker equipped with 150mL ice water, a large amount of precipitation occurs in stirring, filters, filter cake
It is washed with water three times, it is dry, obtain 12.38g, yield 72.8%, mp with ethyl acetate/ethyl alcohol recrystallization：146.4~149.7
℃,1HNMR(CDCl3,400Hz)δ:2.32 (d, 6H, J=2Hz), 5.59 (s, 2H), 7.34 (d, 1H, J=8Hz), 7.78 (d,
1H, J=8Hz), 7.82 (s, 1H), 7.85 (s, 1H).
(3) synthesis of the chloro- 5- morpholinyls -2- of 4- [2- (3,4- 3,5-dimethylphenyls) -2- oxo-ethyls] -3 (2H) pyridazinones
Bis- chloro- 2- of the 4,5- [2- (3,4- 3,5-dimethylphenyls)-of 3.00g (0.01mol) are added in the there-necked flask of 100mL
2- oxo-ethyls] -3 (2H) pyridazinones, the morpholine of 1.68g (0.019mol), the potassium carbonate and 50mL of 2.00g (0.014mol)
DMF, react 7.5 at 80 DEG C.Reaction solution cooling to be poured into the beaker equipped with 50mL ice water, stirring precipitates, and filters,
Filter cake is washed with water three times, dry.It is recrystallized with ethyl acetate/methanol, obtains 2.64g beige crystals, yield 73.4%.
mp：209.2~241.8 DEG C,1HNMR(CDCl3,400Hz)δ:2.34 (d, 6H, J=2.8Hz), 3.44 (t, 4H), 3.86 (t,
4H),5.56(s,2H),7.27(t,1H),7.67(s,1H),7.73(s,1H)7.77(s,1H)。
Embodiment 3
One clock pyridazinone compound, the compound molecule formula are as follows：
Wherein, R1For methyl, R2For methyl, R3For n-propylamine base, R4For chlorine.The synthetic method of the pyridazinone compound
Include the following steps：
(1) synthesis of alpha-chloro acetophenone
The ortho-xylene and 74.40g (0.557mol) of 200mL are added in the 250mL three-necked flasks with drying device
Anhydrous Aluminum chloride, ice-water bath cool down, then slowly be added dropwise 60.0g (0.531mol) alpha-chloro chloroacetic chloride, be added dropwise
Afterwards, it reacts 3 hours at room temperature, stops stirring.Reaction solution is poured into the beaker equipped with 200mL ice water and is stirred, with acetic acid second
Ester extracts liquid separation, and organic phase is washed with water to neutrality, anhydrous magnesium sulfate drying.Decompression sloughs solvent and obtains white solid
76.17g, yield 78.6%,1HNMR(CDCl3,400Hz)δ:2.35 (d, 6H, J=1.6Hz), 4.71 (s, 2H), 7.27 (t,
1H),7.71(t,1H),7.75(s,1H)。
(2) synthesis of bis- chloro- 2- of 4,5- [2- (3,4- 3,5-dimethylphenyls) -2- oxo-ethyls] -3 (2H) pyridazinones
4,5-, bis- chloro- 3 (2H)-pyridazinone 9.00g (0.055mol), 11.50g are added in the there-necked flask of 250mL
It is small to react 8 at 60 DEG C by the alpha-chloro acetophenone of (0.063mol), the DMF of the potassium carbonate and 100mL of 11.40g (0.083mol)
When.It is poured into after reaction solution is cooled to room temperature in the beaker equipped with 150mL ice water, a large amount of precipitation occurs in stirring, filters, filter cake
It is washed with water three times, it is dry, obtain 12.38g, yield 72.8%, mp with ethyl acetate/ethyl alcohol recrystallization：146.4~149.7
℃,1HNMR(CDCl3,400Hz)δ:2.32 (d, 6H, J=2Hz), 5.59 (s, 2H), 7.34 (d, 1H, J=8Hz), 7.78 (d,
1H, J=8Hz), 7.82 (s, 1H), 7.85 (s, 1H).
(3) conjunction of the chloro- 5- n-propylamines base -2- of 4- [2- (3,4- 3,5-dimethylphenyls) -2- oxo-ethyls] -3 (2H) pyridazinones
At
Bis- chloro- 2- of the 4,5- [2- (3,4- 3,5-dimethylphenyls)-of 3.00g (0.010mol) are added in the there-necked flask of 100mL
2- oxo-ethyls] -3 (2H) pyridazinones, the n-propylamine of 1.14g (0.020mol), the potassium carbonate of 2.00g (0.015mol) and
The DMF of 30mL reacts 7 hours at 70 DEG C.Reaction solution is cooled to room temperature and is poured into the beaker equipped with 50mL ice water, is stirred out
Now a large amount of precipitations, filter, and filter cake is washed with water three times, dry.It is recrystallized with ethyl acetate/methanol, obtains beige crystals
2.35g.Yield 70.7%.mp：188.0~188.7 DEG C,1HNMR(CDCl3,400Hz)δ:1.04(t,3H),1.72(m,2H),
2.34 (d, 6H, J=2.4Hz), 3.32 (q, 2H), 4.81 (t, 1H), 5.55 (s, 2H), 7.26 (t, 1H), 7.65 (s, 1H),
7.74(s,1H),7.77(s,1H)。
Embodiment 4
One clock pyridazinone compound, the compound molecule formula are as follows：
Wherein, R1For methyl, R2For methyl, R3For positive third sulfydryl, R4For positive third sulfydryl.The conjunction of the pyridazinone compound
Include the following steps at method：
(1) synthesis of alpha-chloro acetophenone
The ortho-xylene and 74.40g (0.557mol) of 200mL are added in the 250mL three-necked flasks with drying device
Anhydrous Aluminum chloride, ice-water bath cool down, then slowly be added dropwise 60.0g (0.531mol) alpha-chloro chloroacetic chloride, be added dropwise
Afterwards, it reacts 3 hours at room temperature, stops stirring.Reaction solution is poured into the beaker equipped with 200mL ice water and is stirred, with acetic acid second
Ester extracts liquid separation, and organic phase is washed with water to neutrality, anhydrous magnesium sulfate drying.Decompression sloughs solvent and obtains white solid
76.17g, yield 78.6%,1HNMR(CDCl3,400Hz)δ:2.35 (d, 6H, J=1.6Hz), 4.71 (s, 2H), 7.27 (t,
1H),7.71(t,1H),7.75(s,1H)。
(2) synthesis of bis- chloro- 2- of 4,5- [2- (3,4- 3,5-dimethylphenyls) -2- oxo-ethyls] -3 (2H) pyridazinones
4,5-, bis- chloro- 3 (2H)-pyridazinone 9.00g (0.055mol), 11.50g are added in the there-necked flask of 250mL
It is small to react 8 at 60 DEG C by the alpha-chloro acetophenone of (0.063mol), the DMF of the potassium carbonate and 100mL of 11.40g (0.083mol)
When.It is poured into after reaction solution is cooled to room temperature in the beaker equipped with 150mL ice water, a large amount of precipitation occurs in stirring, filters, filter cake
It is washed with water three times, it is dry, obtain 12.38g, yield 72.8%, mp with ethyl acetate/ethyl alcohol recrystallization：146.4~149.7
℃,1HNMR(CDCl3,400Hz)δ:2.32 (d, 6H, J=2Hz), 5.59 (s, 2H), 7.34 (d, 1H, J=8Hz), 7.78 (d,
1H, J=8Hz), 7.82 (s, 1H), 7.85 (s, 1H).
(3) synthesis of 2- [2- (3,4- 3,5-dimethylphenyls) -2- oxo-ethyls] -4,5- dipropyls sulfenyl -3 (2H) pyridazinone
Bis- chloro- 2- of the 4,5- [2- (3,4- 3,5-dimethylphenyls)-of 3.00g (0.01mol) are added in the there-necked flask of 100mL
2- oxo-ethyls] -3 (2H) pyridazinones, the propanethiol of 2.28g (0.03mol), the potassium carbonate and 50mL of 2.07g (0.015mol)
DMF, reacted 7 hours at 70 DEG C.Reaction system is cooled to room temperature and is poured into the beaker equipped with 50mL ice water, stirring occurs big
Amount precipitation, filters, and filter cake is washed with water three times, dry.It is recrystallized with ethyl acetate/methanol, obtains 2.98g bronzing crystal.
Yield 78.7%.mp：78.7~83.5 DEG C,1HNMR(CDCl3,400Hz)δ:1.02(s,3H),1.11(t,3H),1.62(m,
2H), 1.79 (m, 2H), 2.34 (d, 6H, J=3.6Hz), 3.00 (t, 2H), 3.21 (t, 2H), 5.54 (s, 2H), 7.26 (t,
1H),7.67(s,1H),7.73(d,1H),7.70(s,1H)。
Embodiment 5
One clock pyridazinone compound, the compound molecule formula are as follows：
Wherein, R1For methyl, R2For methyl, R3For isopropylamine base, R4For chlorine.The synthetic method of the pyridazinone compound
Include the following steps：
(1) synthesis of alpha-chloro acetophenone
The ortho-xylene and 74.40g (0.557mol) of 200mL are added in the 250mL three-necked flasks with drying device
Anhydrous Aluminum chloride, ice-water bath cool down, then slowly be added dropwise 60.0g (0.531mol) alpha-chloro chloroacetic chloride, be added dropwise
Afterwards, it reacts 3 hours at room temperature, stops stirring.Reaction solution is poured into the beaker equipped with 200mL ice water and is stirred, with acetic acid second
Ester extracts liquid separation, and organic phase is washed with water to neutrality, anhydrous magnesium sulfate drying.Decompression sloughs solvent and obtains white solid
76.17g, yield 78.6%,1HNMR(CDCl3,400Hz)δ:2.35 (d, 6H, J=1.6Hz), 4.71 (s, 2H), 7.27 (t,
1H),7.71(t,1H),7.75(s,1H)。
(2) synthesis of bis- chloro- 2- of 4,5- [2- (3,4- 3,5-dimethylphenyls) -2- oxo-ethyls] -3 (2H) pyridazinones
4,5-, bis- chloro- 3 (2H)-pyridazinone 9.00g (0.055mol), 11.50g are added in the there-necked flask of 250mL
It is small to react 8 at 60 DEG C by the alpha-chloro acetophenone of (0.063mol), the DMF of the potassium carbonate and 100mL of 11.40g (0.083mol)
When.It is poured into after reaction solution is cooled to room temperature in the beaker equipped with 150mL ice water, a large amount of precipitation occurs in stirring, filters, filter cake
It is washed with water three times, it is dry, obtain 12.38g, yield 72.8%, mp with ethyl acetate/ethyl alcohol recrystallization：146.4~149.7
℃,1HNMR(CDCl3,400Hz)δ:2.32 (d, 6H, J=2Hz), 5.59 (s, 2H), 7.34 (d, 1H, J=8Hz), 7.78 (d,
1H, J=8Hz), 7.82 (s, 1H), 7.85 (s, 1H).
(3) conjunction of the chloro- 5- isopropylamine bases -2- of 4- [2- (4,5- 3,5-dimethylphenyls) -2- oxo-ethyls] -3 (2H) pyridazinones
At
In 100mL there-necked flasks, 4,5-, bis- chloro- 2- [2- (4,5- 3,5-dimethylphenyl) -2- oxygen of 2g (0.006mol) is added
Generation-ethyl] -3 (2H) pyridazinones, the isopropylamine of 0.95g (0.016mol), the K of 2.23g (0.016mol)2CO3, the DMF of 30ml,
It is reacted about 8 hours at 70 DEG C.Reaction solution to be poured into 50mL ice water, there are a large amount of precipitations in stirring, filters, and filter cake is washed with water,
It is dry.It is recrystallized with ethyl acetate/methanol, obtains product 1.42g, yield 71.3%.M.p.189.0~190.0 DEG C,
1HNMR(CDCl3,400Hz)δ：1.34 (d, 6H), 2.34 (d, 6H), 3.84 (m, 1H), 4.60 (d, 1H), 5.55 (s, 2H),
7.26 (d, 1H, J=8Hz), 7.65 (s, 1H), 7.76 (m, 2H).
Embodiment 6
One clock pyridazinone compound, the compound molecule formula are as follows：
Wherein, R1For methyl, R2For methyl, R3For n-butylamine-based, R4For chlorine.The synthetic method of the pyridazinone compound
Include the following steps：
(1) synthesis of alpha-chloro acetophenone
The ortho-xylene and 74.40g (0.557mol) of 200mL are added in the 250mL three-necked flasks with drying device
Anhydrous Aluminum chloride, ice-water bath cool down, then slowly be added dropwise 60.0g (0.531mol) alpha-chloro chloroacetic chloride, be added dropwise
Afterwards, it reacts 3 hours at room temperature, stops stirring.Reaction solution is poured into the beaker equipped with 200mL ice water and is stirred, with acetic acid second
Ester extracts liquid separation, and organic phase is washed with water to neutrality, anhydrous magnesium sulfate drying.Decompression sloughs solvent and obtains white solid
76.17g, yield 78.6%,1HNMR(CDCl3,400Hz)δ:2.35 (d, 6H, J=1.6Hz), 4.71 (s, 2H), 7.27 (t,
1H),7.71(t,1H),7.75(s,1H)。
(2) synthesis of bis- chloro- 2- of 4,5- [2- (3,4- 3,5-dimethylphenyls) -2- oxo-ethyls] -3 (2H) pyridazinones
4,5-, bis- chloro- 3 (2H)-pyridazinone 9.00g (0.055mol), 11.50g are added in the there-necked flask of 250mL
It is small to react 8 at 60 DEG C by the alpha-chloro acetophenone of (0.063mol), the DMF of the potassium carbonate and 100mL of 11.40g (0.083mol)
When.It is poured into after reaction solution is cooled to room temperature in the beaker equipped with 150mL ice water, a large amount of precipitation occurs in stirring, filters, filter cake
It is washed with water three times, it is dry, obtain 12.38g, yield 72.8%, mp with ethyl acetate/ethyl alcohol recrystallization：146.4~149.7
℃,1HNMR(CDCl3,400Hz)δ:2.32 (d, 6H, J=2Hz), 5.59 (s, 2H), 7.34 (d, 1H, J=8Hz), 7.78 (d,
1H, J=8Hz), 7.82 (s, 1H), 7.85 (s, 1H).
(3) conjunction of chloro- -3 (2H) pyridazinones of 5- n-butylamine-baseds of 2- [2- (4,5- 3,5-dimethylphenyls) -2- oxo-ethyls] -4-
At
In 100mL there-necked flasks, 4,5-, bis- chloro- 2- [2- (4,5- 3,5-dimethylphenyl) -2- oxygen of 2g (0.006mol) is added
Generation-ethyl] -3 (2H) pyridazinones, the n-butylamine of 1.25g (0.017mol), the K of 2.35g (0.017mol)2CO3, the second of 30ml
Alcohol reacts 10 hours at 70 DEG C.Reaction solution is cooled to room temperature in the ice water for pouring into 50mL, and a large amount of precipitations occurs in stirring, filters, filter
Cake is washed with water, dry.It is recrystallized with ethyl acetate/methanol, obtains product 1.83g, yield 69.0%.M.p.152.1~
200.1 DEG C,1HNMR(CDCl3,400Hz)δ:1.01 (t, 3H), 1.45 (m, 2H), 1.67 (m, 2H), 2.34 (d, 6H), 3.36
(q, 4H), 4.75 (t, 1H), 5.55 (s, 2H), 7.26 (d, 1H, J=8.0Hz), 7.66 (s, 1H), 7.74 (d, 1H J=
8.0Hz),7.78(s,1H)。
Embodiment 7
One clock pyridazinone compound, the compound molecule formula are as follows：
Wherein, R1For methyl, R2For methyl, R3For dimethylamino, R4For chlorine.The synthetic method of the pyridazinone compound
Include the following steps：
(1) synthesis of alpha-chloro acetophenone
The ortho-xylene and 74.40g (0.557mol) of 200mL are added in the 250mL three-necked flasks with drying device
Anhydrous Aluminum chloride, ice-water bath cool down, then slowly be added dropwise 60.0g (0.531mol) alpha-chloro chloroacetic chloride, be added dropwise
Afterwards, it reacts 3 hours at room temperature, stops stirring.Reaction solution is poured into the beaker equipped with 200mL ice water and is stirred, with acetic acid second
Ester extracts liquid separation, and organic phase is washed with water to neutrality, anhydrous magnesium sulfate drying.Decompression sloughs solvent and obtains white solid
76.17g, yield 78.6%,1HNMR(CDCl3,400Hz)δ:2.35 (d, 6H, J=1.6Hz), 4.71 (s, 2H), 7.27 (t,
1H),7.71(t,1H),7.75(s,1H)。
(2) synthesis of bis- chloro- 2- of 4,5- [2- (3,4- 3,5-dimethylphenyls) -2- oxo-ethyls] -3 (2H) pyridazinones
4,5-, bis- chloro- 3 (2H)-pyridazinone 9.00g (0.055mol), 11.50g are added in the there-necked flask of 250mL
It is small to react 8 at 60 DEG C by the alpha-chloro acetophenone of (0.063mol), the DMF of the potassium carbonate and 100mL of 11.40g (0.083mol)
When.It is poured into after reaction solution is cooled to room temperature in the beaker equipped with 150mL ice water, a large amount of precipitation occurs in stirring, filters, filter cake
It is washed with water three times, it is dry, obtain 12.38g, yield 72.8%, mp with ethyl acetate/ethyl alcohol recrystallization：146.4~149.7
℃,1HNMR(CDCl3,400Hz)δ:2.32 (d, 6H, J=2Hz), 5.59 (s, 2H), 7.34 (d, 1H, J=8Hz), 7.78 (d,
1H, J=8Hz), 7.82 (s, 1H), 7.85 (s, 1H).
(3) conjunction of chloro- -3 (2H) pyridazinones of 5- dimethylamino of 2- [2- (4,5- 3,5-dimethylphenyls) -2- oxo-ethyls] -4-
At
In 100mL there-necked flasks, 4,5-, bis- chloro- 2- [2- (4,5- 3,5-dimethylphenyl) -2- oxygen of 2g (0.006mol) is added
Generation-ethyl] -3 (2H) pyridazinones, the dimethylamine of 0.73g (0.016mol), the K of 2.23g (0.016mol)2CO3, the DMF of 30ml,
It is reacted 8 hours at 70 DEG C.Reaction solution is cooled to room temperature in the ice water for pouring into 50mL, a large amount of precipitations occurs in stirring, with suction filtration, filter
Cake is washed with water, dry, is recrystallized with ethyl acetate/methanol, obtains product 1.40g.Calculated yield is 70.0%.
M.p.131.8~135.4 DEG C,1HNMR(CDCl3,400Hz)δ：(ppm):2.34 (d, 6H), 3.15 (s, 6H), 5.53 (s, 2H),
7.26 (d, 1H, J=8.0Hz), 7.66 (s, 1H), 7.73 (s, 1H, J=8.0Hz), 7.77 (s, 1H).
Embodiment 8
One clock pyridazinone compound, the compound molecule formula are as follows：
Wherein, R1For methyl, R2For methyl, 4- Chlorobenzyloxies, R4For chlorine.The synthetic method of the pyridazinone compound
Include the following steps：
(1) synthesis of alpha-chloro acetophenone
The ortho-xylene and 74.40g (0.557mol) of 200mL are added in the 250mL three-necked flasks with drying device
Anhydrous Aluminum chloride, ice-water bath cool down, then slowly be added dropwise 60.0g (0.531mol) alpha-chloro chloroacetic chloride, be added dropwise
Afterwards, it reacts 3 hours at room temperature, stops stirring.Reaction solution is poured into the beaker equipped with 200mL ice water and is stirred, with acetic acid second
Ester extracts liquid separation, and organic phase is washed with water to neutrality, anhydrous magnesium sulfate drying.Decompression sloughs solvent and obtains white solid
76.17g, yield 78.6%,1HNMR(CDCl3,400Hz)δ:2.35 (d, 6H, J=1.6Hz), 4.71 (s, 2H), 7.27 (t,
1H),7.71(t,1H),7.75(s,1H)。
(2) synthesis of bis- chloro- 2- of 4,5- [2- (3,4- 3,5-dimethylphenyls) -2- oxo-ethyls] -3 (2H) pyridazinones
4,5-, bis- chloro- 3 (2H)-pyridazinone 9.00g (0.055mol), 11.50g are added in the there-necked flask of 250mL
It is small to react 8 at 60 DEG C by the alpha-chloro acetophenone of (0.063mol), the DMF of the potassium carbonate and 100mL of 11.40g (0.083mol)
When.It is poured into after reaction solution is cooled to room temperature in the beaker equipped with 150mL ice water, a large amount of precipitation occurs in stirring, filters, filter cake
It is washed with water three times, it is dry, obtain 12.38g, yield 72.8%, mp with ethyl acetate/ethyl alcohol recrystallization：146.4~149.7
℃,1HNMR(CDCl3,400Hz)δ:2.32 (d, 6H, J=2Hz), 5.59 (s, 2H), 7.34 (d, 1H, J=8Hz), 7.78 (d,
1H, J=8Hz), 7.82 (s, 1H), 7.85 (s, 1H).
(3) synthesis of the chloro- 5- hydroxyls -2- of 4- [2- (3,4- 3,5-dimethylphenyls) -2- oxo-ethyls] -3 (2H) pyridazinones
Bis- chloro- 2- [2- (3,4- 3,5-dimethylphenyls)-of 10.00g (0.032mol) 4,5- are added in the there-necked flask of 250mL
2- oxo-ethyls] -3 (2H) pyridazinones, the potassium hydroxide and 160mL ethylene glycol of 9.00g (0.161mol) react 6 at 100 DEG C
Hour.Reaction solution cooling is poured into the beaker of 100mL ice water, hydrochloric acid solution is added dropwise while stirring, the pH for adjusting solution is 1,
There are a large amount of precipitations, filter, washs, it is dry.It is recrystallized with ethyl acetate/methanol, obtains 7.00g white needle-like crystals.Yield
75.1%, mp：216.8~219.9 DEG C,1HNMR(CDCl3,400Hz)δ:2.35 (d, 6H, J=3.6Hz), 5.60 (s, 2H),
7.28 (t, 2H), 7.73 (d, 1H, J=7.6Hz), 7.77 (s, 1H), 7.86 (s, 1H).
(4) the chloro- 5- of 4- (4- Chlorobenzyloxies) -2- [2- (3,4- 3,5-dimethylphenyls) -2- oxo-ethyls] -3 (2H) pyridazines
The synthesis of ketone
4- chloro- 5- hydroxyls -2- [2- (the 3,4- dimethyl benzenes of 0.80g (0.003mol) are added in the there-necked flask of 100mL
Base) -2- oxo-ethyls] -3 (2H) pyridazinones, the 4- chlorobenzyl chlorides of 0.53g (0.003mol), the carbon of 0.57g (0.004mol)
The DMF of sour potassium and 10mL reacts 10 hours at 80 DEG C.Reaction system is cooled to room temperature and pours into the beaker equipped with 50mL ice water
In, there are a large amount of precipitations in stirring, filters, and filter cake is washed with water three times, dry.It is recrystallized with ethyl acetate/methanol, obtains white
Crystal 0.93g.Yield 74.6%.mp：173.7~212.3 DEG C,1HNMR(CDCl3,400Hz)δ:2.35(d,6H),5.33(s,
2H), 5.59 (s, 2H), 7.27 (d, 1H, J=8.8Hz), 7.43 (m, 4H), 7.73 (t, 1H), 7.76 (s, 1H), 7.85 (s,
1H)。
Embodiment 9
One clock pyridazinone compound, the compound molecule formula are as follows：
Wherein, R1For methyl, R2For methyl, R is 4- methyl benzyloxies, R4For chlorine.The synthesis of the pyridazinone compound
Method includes the following steps：
(1) synthesis of alpha-chloro acetophenone
The ortho-xylene and 74.40g (0.557mol) of 200mL are added in the 250mL three-necked flasks with drying device
Anhydrous Aluminum chloride, ice-water bath cool down, then slowly be added dropwise 60.0g (0.531mol) alpha-chloro chloroacetic chloride, be added dropwise
Afterwards, it reacts 3 hours at room temperature, stops stirring.Reaction solution is poured into the beaker equipped with 200mL ice water and is stirred, with acetic acid second
Ester extracts liquid separation, and organic phase is washed with water to neutrality, anhydrous magnesium sulfate drying.Decompression sloughs solvent and obtains white solid
76.17g, yield 78.6%,1HNMR(CDCl3,400Hz)δ:2.35 (d, 6H, J=1.6Hz), 4.71 (s, 2H), 7.27 (t,
1H),7.71(t,1H),7.75(s,1H)。
(2) synthesis of bis- chloro- 2- of 4,5- [2- (3,4- 3,5-dimethylphenyls) -2- oxo-ethyls] -3 (2H) pyridazinones
4,5-, bis- chloro- 3 (2H)-pyridazinone 9.00g (0.055mol), 11.50g are added in the there-necked flask of 250mL
It is small to react 8 at 60 DEG C by the alpha-chloro acetophenone of (0.063mol), the DMF of the potassium carbonate and 100mL of 11.40g (0.083mol)
When.It is poured into after reaction solution is cooled to room temperature in the beaker equipped with 150mL ice water, a large amount of precipitation occurs in stirring, filters, filter cake
It is washed with water three times, it is dry, obtain 12.38g, yield 72.8%, mp with ethyl acetate/ethyl alcohol recrystallization：146.4~149.7
℃,1HNMR(CDCl3,400Hz)δ:2.32 (d, 6H, J=2Hz), 5.59 (s, 2H), 7.34 (d, 1H, J=8Hz), 7.78 (d,
1H, J=8Hz), 7.82 (s, 1H), 7.85 (s, 1H).
(3) synthesis of the chloro- 5- hydroxyls -2- of 4- [2- (3,4- 3,5-dimethylphenyls) -2- oxo-ethyls] -3 (2H) pyridazinones
Bis- chloro- 2- [2- (3,4- 3,5-dimethylphenyls)-of 10.00g (0.032mol) 4,5- are added in the there-necked flask of 250mL
2- oxo-ethyls] -3 (2H) pyridazinones, the potassium hydroxide and 160mL ethylene glycol of 9.00g (0.161mol) react 6 at 100 DEG C
Hour.Reaction solution cooling is poured into the beaker of 100mL ice water, hydrochloric acid solution is added dropwise while stirring, the pH for adjusting solution is 1,
There are a large amount of precipitations, filter, washs, it is dry.It is recrystallized with ethyl acetate/methanol, obtains 7.00g white needle-like crystals.Yield
75.1%, mp：216.8~219.9 DEG C,1HNMR(CDCl3,400Hz)δ:2.35 (d, 6H, J=3.6Hz), 5.60 (s, 2H),
7.28 (t, 2H), 7.73 (d, 1H, J=7.6Hz), 7.77 (s, 1H), 7.86 (s, 1H).
(4) the chloro- 5- of 4- (4- methyl benzyloxy) -2- [2- (3,4- 3,5-dimethylphenyls) -2- oxo-ethyls] -3 (2H) rattle away
The synthesis of piperazine ketone
2- [2- (3,4- the 3,5-dimethylphenyls) -2- oxos-second of 0.80g (0.003mol) are added in the there-necked flask of 100mL
Base] chloro- -3 (2H) pyridazinones of 5- hydroxyls of -4-, the 4- methylbenzyl chlorine of 0.46g (0.003mol), the carbon of 0.57g (0.004mol)
The DMF of sour potassium and 10mL, and condensation and drying device are installed, start to stir.60~80 DEG C of oil bath, thin-layered chromatography detection are anti-
It answers, reaction in about 10 hours terminates.Reaction system is cooled to room temperature and is poured into the beaker equipped with 50mL ice water, stirring occurs a large amount of
Precipitation, is filtered with Buchner funnel, and filter cake is washed with water three times, dry.It is recrystallized with ethyl acetate/methanol, obtains 0.88g yellow
Crystal.Yield 73.9%.mp：166.6~169.5 DEG C,1HNMR(CDCl3,400Hz)δ:2.35 (d, 6H, J=3.6Hz), 2.40
(s, 3H), 5.34 (s, 2H), 5.58 (s, 2H), 7.27 (q, 3H), 7.33 (d, 2H, J=8Hz), 7.72 (t, 1H), 7.76 (s,
1H),7.88(s,1H)。
The above description of the embodiments is intended to facilitate ordinary skill in the art to understand and use the invention.
Person skilled in the art obviously easily can make various modifications to these embodiments, and described herein general
Principle is applied in other embodiment without having to go through creative labor.Therefore, the present invention is not limited to the above embodiments, ability
Field technique personnel announcement according to the present invention, improvement and modification made without departing from the scope of the present invention all should be the present invention's
Within protection domain.
Claims (10)
1. a kind of pyridazinone compound, which is characterized in that the general formula of the compound is as follows：
Wherein, R1For C1-C4 alkyl or halogen；R2For C1-C4 alkyl or halogen；R3For straight-chain fatty amine or cyclammonium or the third sulfydryl
Or fragrant methoxyl group；R4For halogen or the third sulfydryl.
2. a kind of synthetic method of pyridazinone compound as described in claim 1, which is characterized in that this method specifically includes
Following steps：
(1) preparation of alpha-halo acetophenone：
It by haloacetyl halogen and benzene under lewis acidic catalytic action, is reacted in ice-water bath, synthesizes alpha-halo acetophenone；
(2) preparation of bis- chloro- 2- of 4,5- [2- (substitution) phenyl -2- oxo-ethyls] -3 (2H)-pyridazinones：
The alpha-halo acetophenone of synthesis and basic catalyst, 4,5-, bis- chloro- 3 (2H)-pyridazinones are added in solvent, it is reacted
Synthesize 4,5- bis- chloro- 2- [2- (substitution) phenyl -2- oxo-ethyls] -3 (2H)-pyridazinones；
(3) preparation of the chloro- 5- hydroxyls -2- of 4- [2- (substitution) phenyl -2- oxo-ethyls)] -3 (2H)-pyridazinones：
By bis- chloro- 2- of 4,5- [2- (substitution) phenyl -2- oxo-ethyls] -3 (2H)-pyridazinones of synthesis with hydroxide molten
Reaction is heated in agent, by acidification, the chloro- 5- hydroxyls -2- of synthesis 4- [2- (substitution) phenyl -2- oxo-ethyls)] -3 (2H)-rattle away
Piperazine ketone；
(4) synthesis of pyridazinone compound：
By the chloro- 5- hydroxyls -2- of the 4- of synthesis [2- (substitution) phenyl -2- oxo-ethyls)] -3 (2H)-pyridazinones and electrophilic reagent
Reaction synthesizes pyridazinone compound.
3. a kind of synthetic method of pyridazinone compound according to claim 2, which is characterized in that institute in step (1)
The alpha-halo acetophenone stated includes one kind in alpha-brominated acetyl bromide or alpha-chloro chloroacetic chloride, and the lewis acid includes anhydrous
One kind in alchlor, anhydrous ferric trichloride or anhydrous zinc chloride.
4. a kind of synthetic method of pyridazinone compound according to claim 2, which is characterized in that institute in step (2)
The molar ratio of the alpha-halo acetophenone stated and bis- chloro- 3 (2H)-pyridazinones of 4,5-, basic catalyst is 1-2:1:1.5-1.8, institute
The basic catalyst stated includes one kind in sodium hydroxide, potassium hydroxide, Anhydrous potassium carbonate, natrium carbonicum calcinatum or sodium bicarbonate.
5. a kind of synthetic method of pyridazinone compound according to claim 2, which is characterized in that institute in step (3)
The molar ratio of the chloro- 5- hydroxyls -2- of 4- [2- (substitution) phenyl -2- oxo-ethyls)] -3 (the 2H)-pyridazinones and hydroxide stated
It is 1:1-5, the hydroxide include one kind in sodium hydroxide or potassium hydroxide.
6. a kind of synthetic method of pyridazinone compound according to claim 2, which is characterized in that institute in step (4)
The molar ratio of the chloro- 5- hydroxyls -2- of 4- [2- (substitution) phenyl -2- oxo-ethyls)] -3 (the 2H)-pyridazinones and electrophilic reagent stated
It is 1:1-2, and the electrophilic reagent includes in chloromethyl pyridine, benzyl chloride, 4- chlorobenzyl chlorides or 4- methylbenzyl chlorine
It is a kind of.
7. a kind of synthetic method of pyridazinone compound as described in claim 1, which is characterized in that this method specifically includes
Following steps：
(A) preparation of alpha-halo acetophenone：
It by haloacetyl halogen and benzene under lewis acidic catalytic action, is reacted in ice-water bath, synthesizes alpha-halo acetophenone；
(B) preparation of bis- chloro- 2- of 4,5- [2- (substitution) phenyl -2- oxo-ethyls] -3 (2H)-pyridazinones：
The alpha-halo acetophenone of synthesis and basic catalyst, 4,5-, bis- chloro- 3 (2H)-pyridazinones are added in solvent, it is reacted
Synthesize 4,5- bis- chloro- 2- [2- (substitution) phenyl -2- oxo-ethyls] -3 (2H)-pyridazinones；
(C) synthesis of pyridazinone compound：
4,5-, bis- chloro- 2- [2- (substitution) phenyl -2- oxo-ethyls] -3 (2H)-pyridazinones of synthesis are reacted with nucleopilic reagent,
Synthesize pyridazinone compound.
8. a kind of synthetic method of pyridazinone compound according to claim 7, which is characterized in that institute in step (A)
The alpha-halo acetophenone stated includes one kind in alpha-brominated acetyl bromide or alpha-chloro chloroacetic chloride, and the lewis acid includes anhydrous
One kind in alchlor, anhydrous ferric trichloride or anhydrous zinc chloride.
9. a kind of synthetic method of pyridazinone compound according to claim 7, which is characterized in that institute in step (B)
The molar ratio of the alpha-halo acetophenone stated and bis- chloro- 3 (2H)-pyridazinones of 4,5-, basic catalyst is 1-2:1:1.5-1.8, institute
The basic catalyst stated includes one kind in sodium hydroxide, potassium hydroxide, Anhydrous potassium carbonate, natrium carbonicum calcinatum or sodium bicarbonate.
10. a kind of synthetic method of pyridazinone compound according to claim 7, which is characterized in that institute in step (C)
The molar ratio of bis- chloro- 2- of 4,5- [2- (substitution) phenyl -2- oxo-ethyls] -3 (the 2H)-pyridazinones and nucleopilic reagent stated is 1:
1.5-3, and the nucleopilic reagent includes methylamine, dimethylamine, isopropylamine, n-propylamine, n-butylamine, morpholine, piperidines, propanethiol
Or one kind in isopropyl mercaptan.
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| WO2022258992A1 (en) * | 2021-06-10 | 2022-12-15 | Universitetet I Oslo | Pyridazinones for the treatment or prevention of hypertension |
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| CN1493564A (en) * | 2003-08-05 | 2004-05-05 | 中国农业大学 | Pyridazinyl ketone derivative having insect growth regulation activity and its preparation method |
| CN102432546A (en) * | 2011-11-29 | 2012-05-02 | 上海工程技术大学 | Pyridazinone compound and synthetic method thereof |
| CN103694179A (en) * | 2013-12-04 | 2014-04-02 | 上海工程技术大学 | Bishydrazide compound and preparation method thereof |
| CN103980268A (en) * | 2014-04-29 | 2014-08-13 | 上海工程技术大学 | Thiadiazole compound and synthesis method thereof |
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| CN1493564A (en) * | 2003-08-05 | 2004-05-05 | 中国农业大学 | Pyridazinyl ketone derivative having insect growth regulation activity and its preparation method |
| CN102432546A (en) * | 2011-11-29 | 2012-05-02 | 上海工程技术大学 | Pyridazinone compound and synthetic method thereof |
| CN103694179A (en) * | 2013-12-04 | 2014-04-02 | 上海工程技术大学 | Bishydrazide compound and preparation method thereof |
| CN103980268A (en) * | 2014-04-29 | 2014-08-13 | 上海工程技术大学 | Thiadiazole compound and synthesis method thereof |
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| WO2022258992A1 (en) * | 2021-06-10 | 2022-12-15 | Universitetet I Oslo | Pyridazinones for the treatment or prevention of hypertension |
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