CN108675962A - One-step method green syt phthalylhydrazine - Google Patents
One-step method green syt phthalylhydrazine Download PDFInfo
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- CN108675962A CN108675962A CN201810720538.8A CN201810720538A CN108675962A CN 108675962 A CN108675962 A CN 108675962A CN 201810720538 A CN201810720538 A CN 201810720538A CN 108675962 A CN108675962 A CN 108675962A
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- phthalylhydrazine
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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
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/30—Phthalazines
- C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of one-step method green syt phthalylhydrazines：Add phase transfer catalyst in specific solvent using raw material phthalic anhydride, raw material is added dropwise under specific temperature
Description
Technical field
The invention belongs to medicine intermediate fields, and in particular to arrive one-step method green syt phthalylhydrazine.
Background technology
Phthalazines class drug is hot spot in recent years, and Phthalazines have decompression, anticonvulsion, desinsection, antitumor etc. raw
Object activity is widely used in a variety of medicine of synthesis, and phthalylhydrazine is the key intermediate Isosorbide-5-Nitrae-for preparing phthalazines class drug
The primary raw material of dichloro phthalazines, and Isosorbide-5-Nitrae-dichloro phthalazines can subsequently pass through the reactions such as substitution and cyclization, synthesize a series of phthalazines
Derivative, these derivatives gradually be used to treat the fields such as antitumor, decompression.
Phthalylhydrazine（Chemical name：2,3- dihydros-Isosorbide-5-Nitrae-phthalazine diketone）, it is that synthesis phthalazines class drug is crucial intermediate
The primary raw material of Isosorbide-5-Nitrae-dichloro phthalazines.The synthetic method of current existing phthalylhydrazine is one-step synthesis method, by raw material neighbour
Phthalic acid rising temperature for dissolving in acetic acid or ethyl alcohol, is added dropwise certain density hydration hydrazine reaction, and reaction equation is as follows.This
Reaction of atomic utilization rate is high, and in addition to phthalylhydrazine, only water generates, but the water generated is difficult to remove in solvent.Acetic acid
In shipwreck to be removed by distillation, other methods cost is too high, and in last handling process, and since acetic acid is easily waved, hair is made
It is inconvenient at severe operational environment, it is easily poisoned, there is prodigious security risk, and ethyl alcohol carries out anti-under reflux as solvent
It answers, can be because reaction temperature to be low, the reaction time is long, waste of energy, and reaction is not thorough.And the last handling process of two methods
In be required for other eluent solvents, the recycling of solvent is required for distilling, and solvent recovering rate is low.Therefore new adjacent benzene two is developed
The synthesis technology of formylhydrazine be very it is necessary to.
Invention content
The task of the present invention is with one-step method green syt phthalylhydrazine, the more current one-step method green syt of this method
The industrial method of phthalylhydrazine is easy to operate, improves production environment, improve solvent recovering rate, reduces post-processing step
Suddenly, technique is advanced, equipment is simple, energy conservation and environmental protection, it is at low cost, reduce security risk, product yield is high, purity is high and suitable
Synthetic method for industrialized production phthalylhydrazine.In order to solve the above technical problems, the present invention uses following technical side
Case：
Raw material is added in equipped with stirring, water knockout drum, the water knockout drum four-hole bottle suitable for reading equipped with condenser pipe and thermometer, solvent and
Certain density raw material is added dropwise in certain temperature in phase transfer catalyst, the water that reaction generates then is steamed, after being cooled to room temperature
Filtering, obtains phthalylhydrazine.
Reaction equation is as follows：
The raw materialAnd raw materialThe ratio between amount of substance is 1:1.0~2.5.
Water entrainer described in method is one or more of toluene, dimethylbenzene, chlorobenzene, o-dichlorohenzene, cyclohexanone, band
Aqua weight is raw material2~10 times of weight.
Phase transfer catalyst described in method is tetrabutylammonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, benzyl
Triethylammonium chloride, pyridine it is any one or several.The dosage of phase transfer catalyst is raw materialThe 0.006~0.015 of weight
Times.
Raw material described in methodAnd raw materialRange of reaction temperature is 90 ~ 140 DEG C.
The more current industrialization process of new method of one-step method green syt phthalylhydrazine provided by the invention have with
Lower advantage：
Using one-step method green syt, atom utilization is high, and in addition to principal product, by-product is water, pollution-free.More existing industry
Production technology avoids water problem caused by solvent recovery, eliminates the link of distillation, reduces energy consumption, solvent recovery
Rate greatly improves.Production equipment is simplified, reduces operating procedure, improve production environment, reducing security risk while carrying
High product yield and purity.
Specific implementation mode
Below in conjunction with example, the invention will be further described, but the scope of protection of present invention is not limited to implement
Range described in example.
Example 1：Solvent xylene 400g is added in 1000mL is equipped with the four-hole bottle of stirring, condenser pipe and thermometer, it is former
Material118.4g（0.80 mol）, phase transfer catalyst tetrabutylammonium bromide 1.84g, be warming up to 120 DEG C or more, raw material be added dropwise
60% hydrazine hydrate 73.3g（0.088 mol）, while the azeotropic mixture of solvent xylene and the water composition of generation is steamed, divide water to nothing
After water generates, 2-3h is reacted, reaction terminates, is cooled to room temperature, cooling after the completion of reaction, filters, obtains phthalylhydrazine
125.3g, yield 96.6%, high performance liquid chromatography（HPLC）Purity 98.8%.
Example 2：Solvent xylene 400g is added in 1000mL is equipped with the four-hole bottle of stirring, condenser pipe and thermometer, it is former
Material118.4g（0.80 mol）, phase transfer catalyst benzyltriethylammoinium chloride 2.00g, be warming up to 120 DEG C or more, be added dropwise former
Material80% hydrazine hydrate 73.3g（1.17 mol）, while the azeotropic mixture of solvent xylene and the water composition of generation is steamed, divide water extremely
After anhydrous generation, 2-3h is reacted, reaction terminates, is cooled to room temperature, cooling after the completion of reaction, filters, obtains phthalylhydrazine
125.5g, yield 96.8%, high performance liquid chromatography（HPLC）Purity 99.4%.
Example 3：Solvent toluene 400g, raw material is added in 1000mL is equipped with the four-hole bottle of stirring, condenser pipe and thermometer
118.4g（0.80 mol）, phase transfer catalyst tetrabutylammonium bromide 1.84g, be warming up to 108 DEG C, raw material be added dropwise60% hydration
Hydrazine 73.3g（0.088 mol）, while the azeotropic mixture of solvent toluene and the water composition of generation is steamed, after dividing water to anhydrous generation,
2-3h is reacted, reaction terminates, is cooled to room temperature, cooling after the completion of reaction, filters, obtains phthalylhydrazine 124.6g, yield
96.1%, high performance liquid chromatography（HPLC）Purity 99.1%.
Example 4：Solvent cyclohexanone 400g is added in 1000mL is equipped with the four-hole bottle of stirring, condenser pipe and thermometer, it is former
Material118.4g（0.80 mol）, phase transfer catalyst tetrabutylammonium chloride 1.84g, be warming up to 95 DEG C or more, raw material be added dropwise
80% hydrazine hydrate, 55.6 g（0.088 mol）, while the azeotropic mixture of solvent cyclohexanone and the water composition of generation is steamed, divide water to nothing
After water generates, 2-3h is reacted, reaction terminates, is cooled to room temperature, cooling after the completion of reaction, filters, obtains phthalylhydrazine
120.7g, yield 93.1%, high performance liquid chromatography（HPLC）Purity 98.5%.
Example 5：The recycling without any processing is added in 1000mL is equipped with the four-hole bottle of stirring, condenser pipe and thermometer
Solvent xylene 400g, raw material118.4g（0.80 mol）, phase transfer catalyst tetrabutylammonium bromide 1.84g, be warming up to
120 DEG C or more, raw material is added dropwise60% hydrazine hydrate 73.3g（0.088 mol）, while steaming the water group of solvent xylene and generation
At azeotropic mixture, after dividing water to anhydrous generation, react 2-3h, reaction terminates, is cooled to room temperature, cooling after the completion of reaction, takes out
Filter, obtains phthalylhydrazine 126.9g, yield 97.9%, high performance liquid chromatography（HPLC）Purity 98.7%.
Example 6：Solvent xylene 400g, raw material is added in 500mL is equipped with the four-hole bottle of stirring, condenser pipe and thermometer118.4g（0.80 mol）, phase transfer catalyst tetrabutylammonium bromide 1.84g, be warming up to 120 DEG C or more, raw material be added dropwise
60% hydrazine hydrate 73.3g（0.088 mol）, while the azeotropic mixture of solvent xylene and the water composition of generation is steamed, divide water to nothing
After water generates, 2-3h is reacted, reaction terminates, is cooled to room temperature, cooling after the completion of reaction, filters, obtains phthalylhydrazine
125.3g, yield 96.6%, high performance liquid chromatography（HPLC）Purity 98.8%.
Example 7：Solvent xylene 400g is added in 1000mL is equipped with the four-hole bottle of stirring, condenser pipe and thermometer, it is former
Material118.4g（0.80 mol）, phase transfer catalyst 4-butyl ammonium hydrogen sulfate 1.84g, be warming up to 120 DEG C or more, raw material be added dropwise60% hydrazine hydrate 73.3g（0.088 mol）, while the azeotropic mixture of solvent xylene and the water composition of generation is steamed, divide water extremely
After anhydrous generation, 2-3h is reacted, reaction terminates, is cooled to room temperature, cooling after the completion of reaction, filters, obtains phthalylhydrazine
119.8g, yield 92.4%, high performance liquid chromatography（HPLC）Purity 97.7%.
Example 8：Solvent chlorobenzene 400g, raw material is added in 1000mL is equipped with the four-hole bottle of stirring, condenser pipe and thermometer
118.4g（0.80 mol）, phase transfer catalyst tetrabutylammonium bromide 1.84g, be warming up to 120 DEG C or more, raw material be added dropwise 60%
Hydrazine hydrate 73.3g（0.088 mol）, while the azeotropic mixture of solvent xylene and the water composition of generation is steamed, divide water to without aquatic
Cheng Hou reacts 2-3h, and reaction terminates, is cooled to room temperature, cooling after the completion of reaction, filters, obtains phthalylhydrazine
114.8g, yield 88.5%, high performance liquid chromatography（HPLC）Purity 95.7%.
Example 9：Solvent o-dichlorohenzene 400g is added in 1000mL is equipped with the four-hole bottle of stirring, condenser pipe and thermometer,
Raw material118.4g（0.80 mol）, phase transfer catalyst 4-butyl ammonium hydrogen sulfate 1.84g, be warming up to 130 DEG C or more, be added dropwise former
Material60% hydrazine hydrate 73.3g（0.088 mol）, while the azeotropic mixture of solvent xylene and the water composition of generation is steamed, divide water
After to anhydrous generation, 2-3h is reacted, reaction terminates, is cooled to room temperature, cooling after the completion of reaction, filters, obtains phthalyl
Hydrazine 118.8g, yield 91.7%, high performance liquid chromatography（HPLC）Purity 98.7%.
Claims (5)
1. the present invention relates to a kind of one-step method green syt phthalylhydrazine, synthesis step is characterized in that：
Raw material is added in the four-hole bottle equipped with stirring, water knockout drum, water knockout drum installation condenser pipe suitable for reading and thermometer, solvent, phase
Transfer catalyst is warming up under certain temperature, and raw material is added dropwise, constantly the moisture that reaction generates is gone out, until anhydrous generation, reaction
After, it is down to room temperature, is then filtered, phthalylhydrazine is obtained, reaction equation is as follows：
。
2. the new synthetic method of one-step method green syt phthalylhydrazine according to claim 1, it is characterised in that：Step
In rapid, the solvent is the one or more of toluene, dimethylbenzene, chlorobenzene, o-dichlorohenzene, cyclohexanone, and weight of solvent is raw material
2~10 times of weight.
3. the new synthetic method of one-step method green syt phthalylhydrazine according to claim 1, it is characterised in that：Step
In rapid, the phase transfer catalyst is tetrabutylammonium bromide, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, benzyl triethyl ammonium
Ammonium chloride, pyridine it is any one or several；The dosage of phase transfer catalyst is raw material0.006~0.015 times of weight.
4. the new synthetic method of one-step method green syt phthalylhydrazine according to claim 1, it is characterised in that：Step
In rapid：In step, the raw materialAnd raw materialThe ratio between amount of substance is 1:1.0~2.5.
5. the new synthetic method of one-step method green syt phthalylhydrazine according to claim 1, it is characterised in that：Step
In rapid：In step, the raw materialA concentration of 40 ~ 85%.
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Citations (5)
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|---|---|---|---|---|
| US4900844A (en) * | 1987-06-09 | 1990-02-13 | Pfizer Inc. | Intermediates for the preparation of oxophthalazinyl acetic acids having benzothiazole or other heterocyclic side chains |
| CN1523024A (en) * | 2003-09-12 | 2004-08-25 | 中国科学院上海有机化学研究所 | Macromolecule immobilized cinchonine alkaloid ligand, synthesis method and use thereof |
| CN1654458A (en) * | 2004-02-13 | 2005-08-17 | 大连绿源药业有限责任公司 | Process for preparing hexahydro pyridazine tricarboxylate |
| CN103819410A (en) * | 2014-01-26 | 2014-05-28 | 江苏新瀚有限公司 | Preparation method for (6-Chloro-pyridazino-3-yl) formic acid |
| CN108178761A (en) * | 2017-12-28 | 2018-06-19 | 安庆奇创药业有限公司 | A kind of synthetic method of Xi Gelieting |
-
2018
- 2018-07-04 CN CN201810720538.8A patent/CN108675962A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4900844A (en) * | 1987-06-09 | 1990-02-13 | Pfizer Inc. | Intermediates for the preparation of oxophthalazinyl acetic acids having benzothiazole or other heterocyclic side chains |
| CN1523024A (en) * | 2003-09-12 | 2004-08-25 | 中国科学院上海有机化学研究所 | Macromolecule immobilized cinchonine alkaloid ligand, synthesis method and use thereof |
| CN1654458A (en) * | 2004-02-13 | 2005-08-17 | 大连绿源药业有限责任公司 | Process for preparing hexahydro pyridazine tricarboxylate |
| CN103819410A (en) * | 2014-01-26 | 2014-05-28 | 江苏新瀚有限公司 | Preparation method for (6-Chloro-pyridazino-3-yl) formic acid |
| CN108178761A (en) * | 2017-12-28 | 2018-06-19 | 安庆奇创药业有限公司 | A kind of synthetic method of Xi Gelieting |
Non-Patent Citations (5)
| Title |
|---|
| ABDEL GHANY A . EL-HELBY,ET AL.: "Design, synthesis , molecular mo deling and biological evaluation of novel 2,3-d ihydrophthalaz ine-1,4-dione derivatives as potential anticonvulsa nt agents", 《JOURNAL OF MOLECULAR STRUCTURE》 * |
| MICHAEL E. PRIME，ET AL.: "Phthalaz inone Pyraz oles as Potent, Selective, and Orally Bioavaila ble Inhibitor s of Aurora-A Kinase", 《JOURNAL OF MEDICINAL CHEMISTRY ARTICLE》 * |
| 胡思前: "《有机化学》", 31 December 2015, 同济大学出版社 * |
| 赵阳，等: "6-甲基脲嘧啶合成原料和步骤的确定", 《科技资讯》 * |
| 郗英欣，白艳红: "《有机化学实验》", 28 February 2014, 西安交通大学出版社 * |
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Application publication date: 20181019 |