[go: up one dir, main page]

CN104803920A - 3,6-dibromopyridazide synthesis method - Google Patents

3,6-dibromopyridazide synthesis method Download PDF

Info

Publication number
CN104803920A
CN104803920A CN201510146392.7A CN201510146392A CN104803920A CN 104803920 A CN104803920 A CN 104803920A CN 201510146392 A CN201510146392 A CN 201510146392A CN 104803920 A CN104803920 A CN 104803920A
Authority
CN
China
Prior art keywords
pyridazine
reaction
dibromo
synthetic method
dihydroxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201510146392.7A
Other languages
Chinese (zh)
Inventor
耿宣平
韩猛
来新胜
曹惊涛
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shandong You Bang Biochemical Technology Co Ltd
Original Assignee
Shandong You Bang Biochemical Technology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shandong You Bang Biochemical Technology Co Ltd filed Critical Shandong You Bang Biochemical Technology Co Ltd
Priority to CN201510146392.7A priority Critical patent/CN104803920A/en
Publication of CN104803920A publication Critical patent/CN104803920A/en
Pending legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D237/00Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06Heterocyclic 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
    • C07D237/10Heterocyclic 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
    • C07D237/12Halogen atoms or nitro radicals

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a 3,6-dibromopyridazide synthesis method which comprises the following steps: using 3,6-dihydroxypyridazine and phosphorus oxybromide as raw materials for a reaction in an appropriate solvent at 0-120 DEG C; carrying out purification to obtain a pure product of 3,6-dibromopyridazide. The reaction raw materials are relatively easy to obtain and reasonable in price; the 3,6-dibromopyridazide synthesis method is mild in reaction condition, easy to operate and control, simple in post-treatment, stable in product quality and high in product purity.

Description

A kind of synthetic method of 3,6-dibromo pyridazine
(1) technical field
The invention belongs to organic synthesis field, be specifically related to a kind of synthetic method of 3,6-dibromo pyridazine.
(2) background technology
3,6-dibromo 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 medicine intermediate is more novel, has very large using value.But lack the literature record of relevant 3,6-dibromo pyridazine.
On December 3rd, 2012, having declared with 3,6-dichloro-pyridazine is that raw material prepares 4-bromine pyridazine through four-step reaction, and concrete preparation method is as follows:
(1), get 3,6-dichloro-pyridazine and put into container, under stirring, be warmed up to 80 ~ 160 DEG C, make 3,6-dichloro-pyridazine all dissolves, and then in 3,6-dichloro-pyridazine solution, passes into chlorine, control temperature is 80 ~ 160 DEG C and carries out reaction 4 ~ 10h, after reaction terminates, reaction solution is poured in sherwood oil, and at room temperature crystallization, suction filtration, obtain 3 after drying, 4,6-trichlorine pyridazine white powder;
(2), according to 3,4, the mol ratio of 6-trichlorine pyridazine and NaOH is 1:1 ~ 5, getting in step () 3,4,6-obtained trichlorine pyridazine white powders, to join concentration be in the NaOH solution of 5 ~ 15%, reflux after heating for dissolving 4 ~ 10h at 100 DEG C, reaction solution adds HCL and adjusts pH value to be 1.0, standing post crystallization, suction filtration, again with dehydrated alcohol recrystallization, obtain 3,6-bis-chloro-4-hydroxypyridazin pale yellow powder through vacuum-drying again;
(3), by obtained for step (two) 3,6-bis-chloro-4-hydroxypyridazin powder adds in autoclave, first add anhydrous methanol fully to dissolve, then sodium hydroxide and palladium carbon catalyst is added, sealed reactor, pass into the air in hydrogen exchange reactor, then continuing to pass into hydrogen makes the pressure in reactor remain on 1.0 ~ 2.0MPa, controlling temperature of reaction is 20 ~ 80 DEG C, reaction 4 ~ 10h, reactant carries out suction filtration, by filtrate reduced in volume, use dehydrated alcohol recrystallization, drying again, obtain 4-hydroxypyridazin pale yellow powder;
In described step (three), 3, the 6-bis-chloro-4-amino pyridazine of every 1kg add 100-400g sodium hydroxide and 10-50g
Palladium carbon catalyst;
The palladium carbon catalyst of described palladium carbon catalyst to be palladium content be 5% or 10%;
(4), be 1:1 ~ 5 according to the mol ratio of 4-hydroxypyridazin and tribromo oxygen phosphorus, getting 4-hydroxypyridazin obtained in step (three) adds in tribromo oxygen phosphorus, controlling temperature of reaction is 60 ~ 120 DEG C, reaction 0.5 ~ 5h, reaction solution 60 DEG C is evaporated to dry, slow dropping frozen water, until by the thorough cancellation of tribromo oxygen phosphorus, then the strong aqua that concentration is 25% is added, solution ph is adjusted to 8.0, extract with chloroform again, get organic phase anhydrous magnesium sulfate and carry out drying, suction filtration is carried out after drying, get filtrate and put into rotatory evaporator, decompression steams chloroform, then silica gel column chromatography is carried out, use petroleum ether solvent wash-out, collect effluent liquid and carry out underpressure distillation, use hexanaphthene recrystallization again, dry, obtain 4-bromine pyridazine yellow powder.
Reactions steps is loaded down with trivial details, and raw material is not easy to obtain, and needs to improve.
(3) summary of the invention
The present invention, in order to make up the deficiencies in the prior art, provides the synthetic method of 3,6-dibromo pyridazine, and this synthetic method is simple to operate, productive rate is high, is applicable to laboratory and suitability for industrialized production.
The present invention is achieved through the following technical solutions:
A kind of synthetic method of 3,6-dibromo pyridazine, its special character is: comprise the following steps:
With 3,6-dihydroxy pyridazine and tribromo oxygen phosphorus for raw material, in suitable solvent, in 0-120 DEG C of reaction, after purifying sterling 3,6-dibromo pyridazine.
The synthetic method of 3,6-dibromo pyridazines of the present invention, in described step, reactant is 3,6-dihydroxy pyridazine and tribromo oxygen phosphorus, and charging capacity is 3,6-dihydroxy pyridazine: tribromo oxygen phosphorus=1:0.8-3, is more than mol ratio.
The synthetic method of 3,6-dibromo pyridazines of the present invention, described solvent is one or both in methylene dichloride, chloroform, ethanol, benzene, DMF, toluene and water.
The synthetic method of 3,6-dibromo pyridazines of the present invention, in described step, purification step is evaporation concentration, recrystallization, and silica gel column chromatography is separated.
The synthetic method of 3,6-dibromo pyridazines of the present invention, the charging capacity of reactant and solvent is: 3,6-dihydroxy pyridazine: solvent=1:1-10, is more than weight ratio.
The synthetic method of 3,6-dibromo pyridazines of the present invention, in described step, the reaction times is 1-30 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-dihydroxy pyridazine (1.10g, 10mmol) is added, tribromo oxygen phosphorus (5.73g, 20mmol), chloroform 8ml in 50mL single necked round bottom flask.Mixture in reaction flask stirring reaction 4 hours at 90 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 3,6-dibromo pyridazine, after drying, calculated yield 42.60%, purity 98.50% (GC), fusing point 118.5 DEG C-119.2 DEG C (117 DEG C-121 DEG C, document).Nuclear magnetic resonance spectroscopy: 1H NMR (deuterochloroform): 7.529 ppm (s, 1H).
Embodiment 2:
3,6-dihydroxy pyridazine (1.10g, 10mmol) is added, tribromo oxygen phosphorus (6.88g, 24mmol), methylene dichloride 8ml in 50mL single necked round bottom flask.Mixture in reaction flask stirring reaction 4 hours at 90 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 3,6-dibromo pyridazine, after drying, calculated yield 45.21%, purity 99.02% (GC), fusing point 118.5 DEG C-119.2 DEG C (117 DEG C-121 DEG C, document).
Embodiment 3:
3,6-dihydroxy pyridazine (5.60g, 50mmol) is added, tribromo oxygen phosphorus (28.67g, 100mmol), DMF 50ml in 250mL single necked round bottom flask.Mixture in reaction flask stirring reaction 4 hours at 90 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 3,6-dibromo pyridazine, after drying, calculated yield 43%.
Embodiment 4:
3,6-dihydroxy pyridazine (11.20g, 100mmol) is added, tribromo oxygen phosphorus (86.00g, 300mmol), ethanol 100ml in 500mL single necked round bottom flask.Mixture in reaction flask stirring reaction 4 hours at 90 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 3,6-dibromo pyridazine, after drying, calculated yield 47.25%.
Embodiment 5:
3,6-dihydroxy pyridazine (11.20g, 100mmol) is added, phosphorus oxychloride (57.34g, 200mmol), chloroform and DMF 110ml altogether in 500mL single necked round bottom flask.Mixture in reaction flask stirring reaction 4 hours at 90 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 3,6-dibromo pyridazine, after drying, calculated yield 45.28%.
Embodiment 6:
3,6-dihydroxy pyridazine (11.20g, 100mmol) is added, phosphorus oxychloride (22.94g, 80mmol), benzene 100ml in 500mL single necked round bottom flask.Mixture in reaction flask stirring reaction 15 hours at 120 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 3,6-dibromo pyridazine, after drying, calculated yield 45.96%.
Embodiment 7:
3,6-dihydroxy pyridazine (11.20g, 100mmol) is added, phosphorus oxychloride (22.94g, 80mmol), benzene 80ml, water 30ml in 500mL single necked round bottom flask.Mixture in reaction flask stirring reaction 30 hours at 0 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 3,6-dibromo pyridazine, after drying, calculated yield 45.45%.
Embodiment 8:
3,6-dihydroxy pyridazine (11.20g, 100mmol) is added, phosphorus oxychloride (22.94g, 80mmol), benzene 80ml, water 30ml in 500mL single necked round bottom flask.Mixture in reaction flask stirring reaction 1 hour at 70 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 3,6-dibromo pyridazine, after drying, calculated yield 45.45%.
Embodiment 9:
3,6-dihydroxy pyridazine (1.10g, 10mmol) is added, tribromo oxygen phosphorus (6.88g, 24mmol), methylene dichloride 1ml in 50mL single necked round bottom flask.Mixture in reaction flask stirring reaction 4 hours at 30 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 3,6-dibromo pyridazine, after drying, calculated yield 45.51%, purity 99.02% (GC), fusing point 118.5 DEG C-119.2 DEG C (117 DEG C-121 DEG C, document).
Embodiment 10:
3,6-dihydroxy pyridazine (22.4g, 200mmol) is added, phosphorus oxychloride (22.94g, 80mmol), DMF50ml, water 60ml in 500mL single necked round bottom flask.Mixture in reaction flask stirring reaction 0.4 hour at 100 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 3,6-dibromo pyridazine, after drying, calculated yield 90.1%.

Claims (6)

1. the synthetic method of a dibromo pyridazine, is characterized in that: comprise the following steps:
With 3,6-dihydroxy pyridazine and tribromo oxygen phosphorus for raw material, in suitable solvent, in 0-120 DEG C of reaction, after purifying sterling 3,6-dibromo pyridazine.
2. the synthetic method of 3,6-dibromo pyridazines according to claim 1, is characterized in that: in described step, and reactant is 3,6-dihydroxy pyridazine and tribromo oxygen phosphorus, and charging capacity is 3,6-dihydroxy pyridazine: tribromo oxygen phosphorus=1:0.8-3, is more than mol ratio.
3. the synthetic method of 3,6-dibromo pyridazines according to claim 1 and 2, is characterized in that: described solvent is one or both in methylene dichloride, chloroform, ethanol, benzene, DMF, toluene and water.
4. the synthetic method of 3,6-dibromo pyridazines according to claim 1 and 2, is characterized in that: in described step, purification step is evaporation concentration, recrystallization, and silica gel column chromatography is separated.
5. the synthetic method of 3,6-dibromo pyridazines according to claim 1 and 2, it is characterized in that: the charging capacity of reactant and solvent is: 3,6-dihydroxy pyridazine: solvent=1:1-10, is more than weight ratio.
6. the synthetic method of 3,6-dibromo pyridazines according to claim 1 and 2, is characterized in that: in described step, the reaction times is 1-30 hour.
CN201510146392.7A 2015-03-31 2015-03-31 3,6-dibromopyridazide synthesis method Pending CN104803920A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510146392.7A CN104803920A (en) 2015-03-31 2015-03-31 3,6-dibromopyridazide synthesis method

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510146392.7A CN104803920A (en) 2015-03-31 2015-03-31 3,6-dibromopyridazide synthesis method

Publications (1)

Publication Number Publication Date
CN104803920A true CN104803920A (en) 2015-07-29

Family

ID=53689159

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510146392.7A Pending CN104803920A (en) 2015-03-31 2015-03-31 3,6-dibromopyridazide synthesis method

Country Status (1)

Country Link
CN (1) CN104803920A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110903248A (en) * 2019-12-25 2020-03-24 郑州华赞医药科技有限公司 Synthesis method of 5-chloro-4-aminopyridazine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN86104837A (en) * 1985-06-14 1986-12-31 伊莱利利公司 Fungicidal pyrisazines
CN102924386A (en) * 2012-12-03 2013-02-13 洛阳师范学院 Industrial preparation method of 4-bromopyridazine
CN104447569A (en) * 2014-11-05 2015-03-25 定陶县友帮化工有限公司 Method for synthetizing 3,6-dichloropyridazine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN86104837A (en) * 1985-06-14 1986-12-31 伊莱利利公司 Fungicidal pyrisazines
CN102924386A (en) * 2012-12-03 2013-02-13 洛阳师范学院 Industrial preparation method of 4-bromopyridazine
CN104447569A (en) * 2014-11-05 2015-03-25 定陶县友帮化工有限公司 Method for synthetizing 3,6-dichloropyridazine

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110903248A (en) * 2019-12-25 2020-03-24 郑州华赞医药科技有限公司 Synthesis method of 5-chloro-4-aminopyridazine
CN110903248B (en) * 2019-12-25 2023-04-07 郑州华赞医药科技有限公司 Synthesis method of 5-chloro-4-aminopyridazine

Similar Documents

Publication Publication Date Title
Tang et al. An efficient synthesis of polysubstituted pyrroles via copper-catalyzed coupling of oxime acetates with dialkyl acetylenedicarboxylates under aerobic conditions
CN102924386B (en) Industrial preparation method of 4-bromopyridazine
CN102212046A (en) Catalytic system for synthesizing 5-hydroxymethylfurfural by dehydration of sugar or polysaccharide
CN112028809B (en) A kind of preparation method of 3-amino-4-phenylselenyl maleimide compound
CN104803920A (en) 3,6-dibromopyridazide synthesis method
CN109912579B (en) Preparation method of 2, 2-disubstituted tetrahydrofuran derivative
CN101638352B (en) A kind of preparation method of aryl-substituted nitrogen heterocyclic compound
Li et al. Efficient synthetic route to bisaryl ketones via copper-catalyzed C–C triple bonds cleavage
CN103275027A (en) Synthesis method of alpha-keto amide compound
Lv et al. Palladium-catalyzed enol/enolate directed oxidative annulation: functionalized naphthofuroquinone synthesis and bioactivity evaluation
CN106883192B (en) The synthetic method of the benzoic acid derivative of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl modification
CN110627754A (en) A kind of method utilizing continuous flow microchannel reactor to prepare 2-oxo-2-furyl acetic acid
CN103102243A (en) Method for preparing chlorotoluene
Chen et al. Unusual transformation of 4-hydroxy/methoxybenzylic alcohols via CC ipso-substitution reaction using proton-exchanged montmorillonite as media
CN103709174A (en) One-step synthesis method of 6-bromo-3H-oxazolo [4,5-b] pyridine-2-ketone
CN102924473A (en) Preparation method of 2-chlorine-7-iodothieno[3,2-D] pyrimidine
CN104910154A (en) 3-Bromo-6-chloro-imidazo [1,2-a] pyridine synthetic method
Bellezza et al. Aza-Diels–Alder reaction of Danishefsky's diene with immines catalyzed by porous α-zirconium hydrogen phosphate and SDS under solvent-free conditions
CN102030757B (en) Synthesis process of methoxsalen
CN116082131A (en) One-pot method for synthesizing 1-indanone compound method
Axelsson et al. An improved palladium (II)-catalyzed method for the synthesis of aryl ketones from aryl carboxylic acids and organonitriles
CN103554040A (en) Preparation method of deferasirox derivative
CN104151283A (en) Method for catalytically synthesizing 12-aryl-8,9,10,12-tetrahydrobenzo[alpha]xanthenes-11-one derivative
CN106674162B (en) Preparation method of 2, 5-furan diformaldehyde
CN104844523A (en) Synthesis method of 3-amino-6-chloropyridazine

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
EXSB Decision made by sipo to initiate substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication

Application publication date: 20150729

RJ01 Rejection of invention patent application after publication