CN107382773A - A kind of method for synthesizing 7 methoxynaphthalene acetonitriles - Google Patents
A kind of method for synthesizing 7 methoxynaphthalene acetonitriles Download PDFInfo
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- CN107382773A CN107382773A CN201710463835.4A CN201710463835A CN107382773A CN 107382773 A CN107382773 A CN 107382773A CN 201710463835 A CN201710463835 A CN 201710463835A CN 107382773 A CN107382773 A CN 107382773A
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- methoxynaphthalene
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- acetonitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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Abstract
The invention provides a kind of method for synthesizing 7 methoxynaphthalene acetonitriles, and with the dihydro naphthalene acetonitrile of 7 methoxyl group 3,4 for raw material, using DDQ as catalyst, the methoxynaphthalene acetonitrile of intermediate 7 is obtained with oxygen generation oxidation reaction in halogenated alkane solvents.Its method is succinct, and production cost is low, and reacts overall high income, and good product quality is green, is easy to industrialized production, has the great significance for popularization.
Description
Technical field
The invention belongs to organic compound synthesis technical field, in particular it relates to a kind of synthesis 7- methoxynaphthalene acetonitriles
Method.
Background technology
First antidepressants of the agomelatine as melatonin analogue, European Union ratifies the medicine and is used at present
Major depression's disease is treated, is a kind of novel antidepressant, is melatonin receptors activator and 5-T2 receptor antagonists, in maincenter god
Through active in system, be mainly used in the treatment of melatonin systemic disease, be also used for it is sleep disordered, adjust sleep wakefulness week
Phase, the Sleep architecture of patient can be adjusted in night, promotes sleep.In serious Depressive patient is treated, algebraic oriented language is beautiful to be drawn
Spit of fland shows good clinical application effect.
In the prior art, as shown in figure 1, a kind of Agomelatine disclosed in European patent EP 1564202（C）Synthesis road
Line, wherein, compound（B）7- methoxynaphthalenes acetonitrile is synthesis agomelatine important intermediate.The algebraic oriented language of existing document report
Compound in U.S. Latin synthesis（B）The synthesis of 7- methoxynaphthalene acetonitriles.Compound（A）It can be catalyzed through palladium carbon, methacrylic acid alkene
For propionic ester as hydrogen acceptor, aromatization turns to 7- methoxynaphthalene acetonitriles.But used in the patented technology substantial amounts of precious metal palladium and
Allyl acrylate, because Metal Palladium is very expensive, cause product cost higher.
In addition, as shown in figure 1, (3) pp 161-163 of Chinese Journal of Pharmaceuticals 2008,39 are reported with dichloro dicyan
Base benzoquinones（DDQ）Dehydroaromatizationof is into the method for 7- methoxynaphthalene acetonitriles, and this method used the DDQ of stoichiometry, not only
Cost is higher, and because DDQ reduzates into black, substantial amounts of black reduzate cause post processing can not in reaction solution
Extracting and demixing, and a large amount of black waste water also increase environmental protection pressure.
The content of the invention
Goal of the invention：For the deficiencies in the prior art, the invention provides one kind to synthesize 7- methoxynaphthalene acetonitriles
Method, production cost is low, and product yield is high, quality is good, green, the advantages that being easy to industrialized production.
Technical scheme：The invention provides a kind of method of synthesis 7- methoxynaphthalene acetonitriles, with 7- methoxyl group -3,4- dihydros
Naphthalene acetonitrile is raw material, and using DDQ as catalyst, the dosage of the catalyst DDQ is 7- methoxies
The 0.05-0.1 equivalents of base -3,4- dihydro naphthalene acetonitrile, intermediate is obtained with oxygen generation oxidation reaction in halogenated alkane solvents
7- methoxynaphthalene acetonitriles.The method of synthesis 7- methoxynaphthalene acetonitriles of the present invention, method is succinct, and production cost is low, only needs
Want the DDQ of catalytic amount as medium by the dihydro naphthalene acetonitrile oxidative dehydrogenation of 7- methoxyl groups -3,4- into 7- methoxynaphthalene acetonitriles, and instead
Answer overall high income.Wherein oxidative dehydrogenation mechanism is as shown in Fig. 2 by the use of oxygen as oxidant, and Main By product is water, very
It is green, have the great significance for popularization.The dosage of the catalyst DDQ is 7- methoxyl group -3,4- dihydros
The 0.05-0.1 equivalents of naphthalene acetonitrile.In the amount ranges, the progress of reaction can be effectively promoted, not only reduces cost,
And because the black product after DDQ reduction is less, extraction easily layering during post-reaction treatment, sewage is less, more environmentally friendly.
Specifically, the method for above-mentioned synthesis 7- methoxynaphthalene acetonitriles, comprises the following steps：
1）7- methoxyl group -3,4- dihydros naphthalene acetonitrile, DDQ and halogenated alkane solvents are added in reaction unit；
2）It is passed through oxygen, oxidation reaction 4-8h；
3）Reaction solution is extracted, after concentration, recrystallizes-methoxynaphthalene acetonitrile.
Reacted under room temperature condition, reaction condition is gentle, simple to operate, and application cost is low, is adapted to large-scale industry should
With.
Further, the method for above-mentioned synthesis 7- methoxynaphthalene acetonitriles, it is characterised in that：Described halogenated alkane solvents
For dichloromethane or chloroform or dichloroethanes.Described halogenated alkanes solvents include but is not limited to dichloromethane, trichlorine
Methane, dichloroethanes etc..It is preferred that dichloromethane.
Further, the method for above-mentioned synthesis 7- methoxynaphthalene acetonitriles, the pressure that is passed through of oxygen is 1-3kPa.In the behaviour
Under the conditions of work, reaction is gentleer, and potential safety hazard will not be caused because of high pressure, and hypertonia easily produces other side reactions,
Product purity is caused to decline.Hypotony, the reaction time extends and easily raw material reacts incomplete.
Further, the method for above-mentioned synthesis 7- methoxynaphthalene acetonitriles, it is that alcohol-water is molten to recrystallize as recrystallization solvent
Liquid.The means re-crystallization, can effectively remove organic impurities and water-solubility impurity in dereaction, and this recrystallization solvent recrystallizes
The product purity come is higher, and content is higher.
Further, the method for above-mentioned synthesis 7- methoxynaphthalene acetonitriles, it is ethanol to recrystallize as recrystallization solvent：Water=
4:1-5:1.Ratio is reasonable, easy to use, and application cost is low.
Further, the method for above-mentioned synthesis 7- methoxynaphthalene acetonitriles, the step 3）Before extraction, reaction solution saturation
Washed in sodium bicarbonate solution.Using conveniently, make extraction complete.
Further, the method for above-mentioned synthesis 7- methoxynaphthalene acetonitriles, the step 3）After extraction, organic layer uses water again
Washing.Final products purity is high.
Further, the method for above-mentioned synthesis 7- methoxynaphthalene acetonitriles, the water are pure water.Raw material is easy to get, application
Cost is low.
Beneficial effect：Compared with prior art, the present invention has advantages below：Synthesis 7- methoxynaphthalenes of the present invention
The method of acetonitrile, method is succinct, compared with existing traditional handicraft, only using catalytic amount in synthetic method of the present invention
DDQ is as oxidative dehydrogenation medium, so cost is relatively low, and caused DDQ black reduzate is less in reaction, and post processing is simple
Convenient, post processing sewage is less in reaction, more green, and reacts overall high income, and product quality is also relatively stable,
With very high promotional value.
Brief description of the drawings
Fig. 1 is the synthetic route chart of 7- methoxynaphthalenes acetonitrile and agomelatine described in prior art；
Fig. 2 is the synthetic route chart of 7- methoxynaphthalenes acetonitrile of the present invention.
Embodiment
Below will be by several specific embodiments, the present invention is furture elucidated, these embodiments simply to illustrate that problem,
It is not a kind of limitation.
Embodiment 1
The method of synthesis 7- methoxynaphthalene acetonitriles as shown in Figure 2.150 milliliters of dichloromethane are added in 500 milliliters of pressure cookers,
19.9 grams（0.1 mole）7- methoxyl group -3,4- dihydro naphthalene acetonitriles, 1.15 grams of DDQ（0.005 mole）, it is passed through 2kPa pressure
Oxygen, at room temperature stirring reaction about 5 hours, reaction do not absorb oxygen further, and reaction stops, and reaction solution is poured into 100 milliliters and satisfied
Washed with sodium bicarbonate solution, organic layer is again with 100 milliliters of water washings, concentration of organic layers, residue with 50ml alcohol-waters=
4:1 recrystallization, obtains 18.3 grams of product 7- methoxynaphthalenes acetonitrile, purity 98.5%, yield 93%.
Embodiment 2
The method of synthesis 7- methoxynaphthalene acetonitriles as shown in Figure 2.200 milliliters of dichloroethanes are added in 500 milliliters of pressure cookers,
19.9 grams（0.1 mole）7- methoxyl group -3,4- dihydro naphthalene acetonitriles, 2.3 grams of DDQ（0.01 mole）, it is passed through the oxygen of 3kPa pressure
Gas, at room temperature stirring reaction about 4 hours, reaction do not absorb oxygen further, and reaction stops, and reaction solution is poured into 100 milliliters of saturations
Washed in sodium bicarbonate solution, organic layer is again with 100 milliliters of water washings, concentration of organic layers, residue 60ml alcohol-water=5:1
Recrystallization, obtains 17.5 grams of product 7- methoxynaphthalenes acetonitrile, purity 98%, yield 89%.
Embodiment 3
The method of synthesis 7- methoxynaphthalene acetonitriles as shown in Figure 2.100 milliliters of dichloromethane of addition in 250 milliliters of pressure cookers, 10
Gram（0.05 mole）7- methoxyl group -3,4- dihydro naphthalene acetonitriles, 2.3 grams of DDQ（0.01 mole）, the oxygen of 1kPa pressure is passed through,
Stirring reaction about 6 hours at room temperature, reaction do not absorb oxygen further, and reaction stops, and reaction solution is poured into 50 milliliters of unsaturated carbonates
Washed in hydrogen sodium solution, organic layer is again with 50 milliliters of water washings, concentration of organic layers, residue 30ml alcohol-water=4:1 ties again
Crystalline substance, obtain 9 grams of product 7- methoxynaphthalenes acetonitrile, purity 98.2%, yield 91%.
Embodiment 4
The method of synthesis 7- methoxynaphthalene acetonitriles as shown in Figure 2.500 milliliters of dichloromethane are added in 1000 milliliters of pressure cookers,
40 grams（0.2 mole）7- methoxyl group -3,4- dihydro naphthalene acetonitriles, 2.5 grams of DDQ, be passed through the oxygen of 3kpa pressure, stir at room temperature
Reaction about 8 hours, reaction do not absorb oxygen further, and reaction stops, reaction solution is poured into 200 milliliters of saturated sodium bicarbonate solutions
Washing, organic layer is again with 200 milliliters of water washings, concentration of organic layers, residue 100ml alcohol-water=4:1 recrystallization, obtains product
35.8 grams of 7- methoxynaphthalenes acetonitrile, purity 97.8%, yield 91%
Described above is only several embodiments of invention, it is noted that for those skilled in the art,
On the premise of inventive principle is not departed from, some improvement can also be made, these improvement also should be regarded as protection scope of the present invention.
Claims (9)
- A kind of 1. method of synthesis 7- methoxynaphthalene acetonitriles, it is characterised in that：It is original with 7- methoxyl group -3,4- dihydros naphthalene acetonitrile Material, using DDQ as catalyst, the dosage of the catalyst DDQ is 7- methoxyl group -3,4- dihydros The 0.05-0.1 equivalents of naphthalene acetonitrile, intermediate 7- methoxynaphthalene second is obtained with oxygen generation oxidation reaction in halogenated alkane solvents Nitrile.
- 2. the method for synthesis 7- methoxynaphthalene acetonitriles according to claim 1, it is characterised in that：Comprise the following steps：1）7- methoxyl group -3,4- dihydros naphthalene acetonitrile, DDQ and halogenated alkane solvents are added in reaction unit；2）It is passed through oxygen, oxidation reaction 4-8h；3）Reaction solution is extracted, after concentration, recrystallizes-methoxynaphthalene acetonitrile.
- 3. the method for synthesis 7- methoxynaphthalene acetonitriles according to claim 1 or 2, it is characterised in that：Described alkyl halide Hydrocarbon solvent is dichloromethane or chloroform or dichloroethanes.
- 4. the method for synthesis 7- methoxynaphthalene acetonitriles according to claim 2, it is characterised in that：The pressure that is passed through of oxygen is 1-3kPa。
- 5. the method for synthesis 7- methoxynaphthalene acetonitriles according to claim 2, it is characterised in that：Recrystallize molten to recrystallize Agent is ethanol-water solution.
- 6. the method for synthesis 7- methoxynaphthalene acetonitriles according to claim 5, it is characterised in that：Recrystallize molten to recrystallize Agent is ethanol：Water=4:1-5:1.
- 7. the method for synthesis 7- methoxynaphthalene acetonitriles according to claim 2, it is characterised in that：The step 3）Extraction Before, reaction solution is washed with saturated sodium bicarbonate solution.
- 8. the method for synthesis 7- methoxynaphthalene acetonitriles according to claim 2, it is characterised in that：The step 3）Extraction Afterwards, organic layer, which is washed with water, washs.
- 9. the method for the synthesis 7- methoxynaphthalene acetonitriles according to claim 5 or 6 or 8, it is characterised in that：The water is pure Water purification.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1564202A1 (en) * | 2004-02-13 | 2005-08-17 | Les Laboratoires Servier | Novel process for synthesizing and a novel crystal form of agomelatin as well as pharmaceutical preparations containing these |
| KR101179173B1 (en) * | 2007-08-03 | 2012-09-03 | 르 라보레또레 쎄르비에르 | Novel method for the synthesis of 7-methoxy-l-naphthylacetonitrile and application in the synthesis of agomelatine |
| CN106543034A (en) * | 2016-10-31 | 2017-03-29 | 苏州弘森药业股份有限公司 | A kind of method of 7 methoxynaphthalene acetonitriles of synthesis |
-
2017
- 2017-06-19 CN CN201710463835.4A patent/CN107382773A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1564202A1 (en) * | 2004-02-13 | 2005-08-17 | Les Laboratoires Servier | Novel process for synthesizing and a novel crystal form of agomelatin as well as pharmaceutical preparations containing these |
| KR101179173B1 (en) * | 2007-08-03 | 2012-09-03 | 르 라보레또레 쎄르비에르 | Novel method for the synthesis of 7-methoxy-l-naphthylacetonitrile and application in the synthesis of agomelatine |
| CN106543034A (en) * | 2016-10-31 | 2017-03-29 | 苏州弘森药业股份有限公司 | A kind of method of 7 methoxynaphthalene acetonitriles of synthesis |
Non-Patent Citations (1)
| Title |
|---|
| 唐家邓等: "阿戈美拉汀的合成", 《中国医药工业杂志》 * |
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