CN107652202A - A kind of synthetic method of benzamide compound - Google Patents
A kind of synthetic method of benzamide compound Download PDFInfo
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- CN107652202A CN107652202A CN201710963145.5A CN201710963145A CN107652202A CN 107652202 A CN107652202 A CN 107652202A CN 201710963145 A CN201710963145 A CN 201710963145A CN 107652202 A CN107652202 A CN 107652202A
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
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Abstract
The present invention relates to a kind of synthetic method of benzamide compound shown in lower formula (III), methods described includes：In the presence of dual-component catalyst, oxidant, Phosphine ligands and acidic materials, lower formula (I) compound and lower formula (II) compound are reacted in organic solvent, react through post processing after terminating, so as to obtain the formula (III) compoundWherein, R1For H, C1‑C6Alkyl or halogen；R2For H, C1‑C6Alkoxy or halogen.The synthetic method obtains purpose product so as to high yield, brand-new synthetic method is provided for such compound by the use of unique reactant and combined reaction system, has a good application prospect and industrial production potential.
Description
Technical field
The present invention relates to a kind of synthetic method of benzamide compound, belongs to medicine intermediate synthesis field.
Background technology
Benzamide derivatives are a kind of important branches in medicine, and benzamide class formation is often as medicine
The main of activity constructs fragment.Therefore, the synthetic method for developing benzamide compound is very necessary.
At present, the synthesis of benzamide compound is mainly that amino benzenes compounds are reacted with acetyl halide compound, from
And take off hydrogen halides and obtain purpose product.But there is the defects of certain in this method, such as need to use contaminative and corrosivity
Very strong acetyl halide compound, this causes serious negative effect to post processing, and environmental pollution is very big.
For the defect, the novel method for synthesizing of people's paraphenylene terephthalamide class compound has carried out substantial amounts of further investigation,
Such as find to be reacted to obtain by aniline compound and dibenzenyl class compound, its reaction equation is as follows：
Visible Zhiwei Wang of the synthetic method et al. (Palladium/copper tandem catalysis for
Carbon-carbon triple bond cleavage of diaryl acetylenes, Tetrahedron Letters,
56 (2015), 5449-5452) the periodical literature in.
The defects of this method, is that products collection efficiency is relatively low, can not obtain purpose product with high yield.
In order to obtain purpose product with high yield, present inventors have proposed a kind of the brand-new of benzamide compound
Synthetic method, this method is using unique reactant and combined reaction system, it is achieved thereby that the height of benzamide compound
Yield synthesizes, and provides completely new approach for the synthesis of such compound, has good application value and industrial production potential.
The content of the invention
In order to overcome many defects as indicated above and seek the brand-new synthetic method of benzamide compound, this
Inventor conducts in-depth research and explored, after enough creative works have been paid, so as to complete the present invention.
Specifically, technical scheme and content are related to benzamide compound shown in a kind of lower formula (III)
Synthetic method, methods described includes：In the presence of dual-component catalyst, oxidant, Phosphine ligands and acidic materials, following formula
(I) compound and lower formula (II) compound are reacted in organic solvent, are reacted through post processing after terminating, described so as to obtain
Formula (III) compound,
Wherein, R1For H, C1-C6Alkyl or halogen；R2For H, C1-C6Alkoxy or halogen.
In the synthetic method of the present invention, C1-C6Alkyl refers to the straight or branched alkyl with 1-6 carbon atom,
In non-limiting manner for example can be methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, n-pentyl,
Any one in isopentyl or n-hexyl etc.；And C1-C6Alkoxy is then C defined above1-C6Alkyl is direct with oxygen atom
Group obtained from being connected；Halogen is fluorine, chlorine, bromine or iodine atom.
Other technical characteristics are specifically described and limited below.
Catalyst
The dual-component catalyst is that mol ratio is 1:2 organic palladium compound and nickel acetylacetonate (Ni (acac)2)
Mixture.
Wherein, organic palladium compound is double (dibenzalacetone) palladium (Pd (dba)2), three (dibenzalacetones)
Two palladium (Pd2(dba)3), tetrakis triphenylphosphine palladium (Pd (PPh3)4), bipyridyl palladium chloride (PdCl2(Py)2), 1,5- rings it is pungent
Diene palladium bichloride (PdCl2(cod) any one in), it is most preferably double (dibenzalacetone) palladium (Pd (dba)2)。
Oxidant
The oxidant is silver trifluoroacetate, ammonium persulfate, ammonium ceric nitrate, di-t-butyl peroxide (DTBP) or 2- iodoxies
Any one in yl benzoic acid, most preferably 2- iodosobenzoic acids.
Phosphine ligands
The Phosphine ligands are the L1 or L2 of following formula,
The Phosphine ligands are preferably L1.
Acidic materials
The acidic materials are any one in acetic acid, oxalic acid, methanesulfonic acid, p-methyl benzenesulfonic acid or p-nitrophenyl sulfonic acid,
Most preferably p-methyl benzenesulfonic acid.
Organic solvent
The organic solvent is that mass ratio is 4:1 1,4- dioxane and 1- ethyl-methyl ether -3- methylimidazole tetrafluoros
The mixture of borate.
The organic solvent can be by the way that 1- ethyl-methyl ether -3- methyl imidazolium tetrafluoroborates be added to as its 4 times of quality
Isosorbide-5-Nitrae-dioxane in, be then sufficiently stirred and obtain.
Those skilled in the art can select the suitable amounts of the organic solvent according to actual conditions, such as cause reaction
It can fully carry out, and be easy to post processing etc., this is the routine techniques ability that those skilled in the art should possess, herein no longer
It is described in detail.
Parameters limit
The mol ratio of formula (I) compound and (II) compound is 1:0.4-0.8, such as can be 1:0.4、1:0.6 or
1:0.8。
The mole dosage of formula (I) compound and the organic palladium compound and levulinic for forming the dual-component catalyst
Ketone nickel (Ni (acac)2) total moles dosage ratio be 1:0.03-0.06, such as can be 1:0.03、1:0.04、1:0.05 or 1:
0.06。
Formula (II) compound and the mol ratio of oxidant are 1:1-2, such as can be 1:1、1:1.2、1:1.4、1:
1.6、1:1.8 or 1:2.
Formula (I) compound and the mol ratio of Phosphine ligands are 1:0.1-0.2, such as can be 1:0.1、1:0.15 or 1:
0.2。
Formula (II) compound and the mol ratio of acidic materials are 1:0.6-1.2, such as can be 1:0.6、1:0.8、1:1
Or 1:1.2.
The reaction temperature of the reaction is 80-120 DEG C, such as can be 80 DEG C, 90 DEG C, 100 DEG C, 110 DEG C or 120 DEG C.
The reaction time of the reaction is 14-20 hours, for example, 14 hours, 16 hours, 18 hours or 20 hours.
In the synthetic method of the present invention, the post processing is specific as follows：After reaction terminates, filter while hot, then
Filtrate is naturally cooled into room temperature and adjusts pH value as neutrality, is extracted 2-4 times with enough ethyl acetate, merges organic phase, nothing
Aqueous sodium persulfate is dried, and is filtered, and is evaporated under reduced pressure, residue crosses silica gel column chromatography, with volume ratio 1:3 ethyl acetate mixes with petroleum ether
Compound is eluted, and is collected eluent, is evaporated under reduced pressure again, so as to obtain the formula (III) compound.
As described above, the invention provides a kind of synthetic method of benzamide compound, the synthetic method passes through
The use of unique reactant and combined reaction system, purpose product is obtained so as to high yield, provided for such compound
Brand-new synthetic method, has a good application prospect and industrial production potential.
Embodiment
Below by specific embodiment, the present invention is described in detail, but the purposes of these exemplary embodiments and
Purpose is only used for enumerating the present invention, not forms any type of any restriction to the real protection scope of the present invention, more non-to incite somebody to action
Protection scope of the present invention is confined to this.
Embodiment 1
To appropriate two-component organic solvent (mass ratio 4 at room temperature:1 1,4- dioxane and 1- ethyl-methyls ether-
The mixture of 3- methyl imidazolium tetrafluoroborates) in add 100mmol on formula (I) compound, the upper formula (II) compounds of 40mmol,
6mmol dual-component catalysts (mixtures of double (dibenzalacetone) palladiums of 2mmol and 4mmol nickel acetylacetonates), 100mmol
2- iodosobenzoic acids, 20mmol Phosphine ligands L1 and 60mmol p-methyl benzenesulfonic acid, 80 DEG C are warming up to, and stirring is anti-at such a temperature
Answer 20 hours.
After reaction terminates, filter while hot, filtrate is then naturally cooled into room temperature and adjusts pH value as neutrality, with enough
Ethyl acetate extracts 2-4 times, merges organic phase, anhydrous sodium sulfate drying, filters, is evaporated under reduced pressure, and residue crosses silica gel column chromatography,
With volume ratio 1:3 ethyl acetate is eluted with petroleum ether mixtures, is collected eluent, is evaporated under reduced pressure again, so as to obtain
Upper formula (III) compound, yield 93.7%.
1H NMR(DMSO-d6,400MHz):δ 10.14 (bs, 1H), 7.96 (d, J=7.2Hz, 2H), 7.65-7.48 (m,
5H), 7.22 (t, J=7.7Hz, 1H), 6.93 (d, J=7.7Hz, 1H), 2.32 (s, 3H).
Embodiment 2
To appropriate two-component organic solvent (mass ratio 4 at room temperature:1 1,4- dioxane and 1- ethyl-methyls ether-
The mixture of 3- methyl imidazolium tetrafluoroborates) in add 100mmol on formula (I) compound, the upper formula (II) compounds of 80mmol,
3mmol dual-component catalysts (mixtures of double (dibenzalacetone) palladiums of 1mmol and 2mmol nickel acetylacetonates), 200mmol
2- iodosobenzoic acids, 10mmol Phosphine ligands L1 and 120mmol p-methyl benzenesulfonic acid, are warming up to 120 DEG C, and stir at such a temperature
Reaction 14 hours.
After reaction terminates, filter while hot, filtrate is then naturally cooled into room temperature and adjusts pH value as neutrality, with enough
Ethyl acetate extracts 2-4 times, merges organic phase, anhydrous sodium sulfate drying, filters, is evaporated under reduced pressure, and residue crosses silica gel column chromatography,
With volume ratio 1:3 ethyl acetate is eluted with petroleum ether mixtures, is collected eluent, is evaporated under reduced pressure again, so as to obtain
Upper formula (III) compound, yield 93.2%.
1H NMR(DMSO-d6,400MHz):10.36 (bs, 1H), 7.96 (d, J=7.36Hz, 2H), 7.81 (d, J=
9.0Hz, 2H), 7.61 (t, J=7.36Hz, 1H), 7.55 (t, J=7.36Hz, 2H), 7.42 (d, J=9.0Hz, 2H).
Embodiment 3
For reaction equation with embodiment 1, concrete operations are as follows：
To appropriate two-component organic solvent (mass ratio 4 at room temperature:1 1,4- dioxane and 1- ethyl-methyls ether-
The mixture of 3- methyl imidazolium tetrafluoroborates) in add 100mmol on formula (I) compound, the upper formula (II) compounds of 55mmol,
5.1mmol dual-component catalysts (mixtures of double (dibenzalacetone) palladiums of 1.7mmol and 3.4mmol nickel acetylacetonates),
135mmol 2- iodosobenzoic acids, 17mmol Phosphine ligands L1 and 80mmol p-methyl benzenesulfonic acid, are warming up to 95 DEG C, and in the temperature
Lower stirring reaction 18 hours.
After reaction terminates, filter while hot, filtrate is then naturally cooled into room temperature and adjusts pH value as neutrality, with enough
Ethyl acetate extracts 2-4 times, merges organic phase, anhydrous sodium sulfate drying, filters, is evaporated under reduced pressure, and residue crosses silica gel column chromatography,
With volume ratio 1:3 ethyl acetate is eluted with petroleum ether mixtures, is collected eluent, is evaporated under reduced pressure again, so as to obtain
Formula (III) compound, yield 92.8%.
Nuclear magnetic data is not repeated to list with embodiment 1.
Embodiment 4
For reaction equation with embodiment 2, concrete operations are as follows：
To appropriate two-component organic solvent (mass ratio 4 at room temperature:1 1,4- dioxane and 1- ethyl-methyls ether-
The mixture of 3- methyl imidazolium tetrafluoroborates) in add 100mmol on formula (I) compound, the upper formula (II) compounds of 65mmol,
4.2mmol dual-component catalysts (mixtures of double (dibenzalacetone) palladiums of 1.4mmol and 2.8mmol nickel acetylacetonates),
168mmol 2- iodosobenzoic acids, 13mmol Phosphine ligands L1 and 100mmol p-methyl benzenesulfonic acid, are warming up to 112 DEG C, and in the temperature
The lower stirring reaction of degree 16 hours.
After reaction terminates, filter while hot, filtrate is then naturally cooled into room temperature and adjusts pH value as neutrality, with enough
Ethyl acetate extracts 2-4 times, merges organic phase, anhydrous sodium sulfate drying, filters, is evaporated under reduced pressure, and residue crosses silica gel column chromatography,
With volume ratio 1:3 ethyl acetate is eluted with petroleum ether mixtures, is collected eluent, is evaporated under reduced pressure again, so as to obtain
Formula (III) compound, yield 93.9%.
Nuclear magnetic data is not repeated to list with embodiment 2.
From embodiment 1-4, synthetic method of the invention can obtain purpose product with high yield, and stability is very
It is good, products collection efficiency fluctuation very little.
Reference examples 1-4
Double (dibenzalacetone) palladiums in dual-component catalyst in embodiment 1-4 are replaced with into other organic palladiums respectively
Compound, repeat according to embodiment 1-4 same procedure, obtain reference examples 1-4, use organic palladium compound, correspond in fact
Apply example and products collection efficiency result see the table below 1：
Table 1
As can be seen here, when using other organic palladium compounds, products collection efficiency is significantly reduced.Unexpected
It is, although double (dibenzalacetone) palladium (Pd (dba)2) and three (dibenzalacetone) two palladium (Pd2(dba)3) highly similar,
But the catalytic effect of the latter will significantly reduce, this demonstrate that the unpredictability of catalyst component selection.
Reference examples 5-12
The dual-component catalyst in embodiment 1-4 is replaced with into the list that dosage is the total dosage of original dual-component catalyst respectively
One component, repeat according to embodiment 1-4 same procedure, obtain reference examples 5-12, use single catalyst, correspond in fact
Apply example and products collection efficiency result see the table below 2：
Table 2
As can be seen here, when using any single component catalyst, products collection efficiency significantly reduces, but only makes
With nickel acetylacetonate (Ni (acac)2) when reduce it is more notable.This proves to have played unexpected catalysis between two kinds of components
Synergy, so as to achieve the technique effect more more excellent than any single component.
Reference examples 13-16
Oxidant 2- iodosobenzoic acids in embodiment 1-4 are replaced with into other oxidants respectively, according to embodiment 1-4's
Same procedure repeats, and obtains reference examples 13-16, and institute see the table below using oxidant, corresponding embodiment and products collection efficiency result
3：
Table 3
As can be seen here, when using other oxidants, products collection efficiency is significantly reduced, and especially DTBP is reduced the most
Significantly, this prove oxidant not be can be with elective.
Reference examples 17-20
Phosphine ligands L1 in embodiment 1-4 is replaced with into L2 respectively, repeats according to embodiment 1-4 same procedure, obtains
To reference examples 17-20, institute see the table below 4 using Phosphine ligands, corresponding embodiment and products collection efficiency result：
Table 4
As can be seen here, Phosphine ligands L2 effect will be weaker than L1, although both structures are more or less the same, this proves part
Reaction result can unpredictably be influenceed.
Reference examples 21-24
Embodiment 1-4 middle acid substance p-methyl benzenesulfonic acid is replaced with into other acidic materials respectively, according to embodiment 1-4's
Same procedure repeats, and obtains reference examples 21-24, and institute is seen below using acidic materials, corresponding embodiment and products collection efficiency result
Table 5：
Table 5
As can be seen here, other acidic materials cause products collection efficiency to have obvious reduction, and interestingly, although to nitre
Base benzene sulfonic acid is more or less the same with p-methyl benzenesulfonic acid structure, but still has obvious reduction.This should be the Acidity with acidic materials
There is a significant relation, reaction process is more sensitive to Acidity.
Reference examples 25-28
Two-component organic solvent in embodiment 1-4 is replaced with into single component Isosorbide-5-Nitrae-dioxane respectively, according to embodiment
1-4 same procedure repeats, and obtains reference examples 25-28, uses acidic materials, corresponding embodiment and products collection efficiency result
It see the table below 6：
Table 6
As can be seen here, when adding 1- ethyl-methyl ether -3- methyl imidazolium tetrafluoroborates, reaction effect can be significantly improved
Fruit, this should be caused by both combinations have a more preferable solvent effect.
Summary, the invention provides a kind of synthetic method of benzamide compound, the synthetic method passes through
The use of unique reactant and combined reaction system, purpose product is obtained so as to high yield, provided for such compound
Brand-new synthetic method, has a good application prospect and industrial production potential.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to the protection model of the limitation present invention
Enclose.In addition, it should also be understood that, after the technology contents of the present invention have been read, those skilled in the art can make each to the present invention
Kind change, modification and/or variation, all these equivalent form of values equally fall within the guarantor that the application appended claims are limited
Within the scope of shield.
Claims (10)
1. the synthetic method of benzamide compound, methods described include shown in a kind of lower formula (III)：In double-component catalyst
In the presence of agent, oxidant, Phosphine ligands and acidic materials, lower formula (I) compound and lower formula (II) compound are in organic solvent
Reacted, reacted through post-processing after terminating, so as to obtain the formula (III) compound,
Wherein, R1For H, C1-C6Alkyl or halogen；R2For H, C1-C6Alkoxy or halogen.
2. synthetic method as claimed in claim 1, it is characterised in that：The dual-component catalyst is that mol ratio is 1:2 have
Machine palladium compound and nickel acetylacetonate (Ni (acac)2) mixture；
Wherein, organic palladium compound is double (dibenzalacetone) palladium (Pd (dba)2), three (dibenzalacetone) two palladium
(Pd2(dba)3), tetrakis triphenylphosphine palladium (Pd (PPh3)4), bipyridyl palladium chloride (PdCl2(Py)2), 1,5- cyclo-octadiene
Palladium bichloride (PdCl2(cod) any one in), it is most preferably double (dibenzalacetone) palladium (Pd (dba)2)。
3. synthetic method as claimed in claim 1 or 2, it is characterised in that：The oxidant is silver trifluoroacetate, persulfuric acid
Any one in ammonium, ammonium ceric nitrate, di-t-butyl peroxide (DTBP) or 2- iodosobenzoic acids, most preferably 2- iodoxies
Benzoic acid.
4. the synthetic method as described in claim any one of 1-3, it is characterised in that：The Phosphine ligands are the L1 or L2 of following formula,
The Phosphine ligands are preferably L1.
5. the synthetic method as described in claim any one of 1-4, it is characterised in that：The acidic materials are acetic acid, oxalic acid, first
Any one in sulfonic acid, p-methyl benzenesulfonic acid or p-nitrophenyl sulfonic acid, most preferably p-methyl benzenesulfonic acid.
6. synthetic method as claimed in claim 5, it is characterised in that：Mole of formula (I) compound and (II) compound
Than for 1:0.4-0.8.
7. the synthetic method as described in claim any one of 1-6, it is characterised in that：The mole dosage of formula (I) compound
Organic palladium compound and nickel acetylacetonate (Ni (acac) with forming the dual-component catalyst2) the ratio of total moles dosage be
1:0.03-0.06。
8. the synthetic method as described in claim any one of 1-7, it is characterised in that：Formula (II) compound and oxidant
Mol ratio is 1:1-2.
9. the synthetic method as described in claim any one of 1-8, it is characterised in that：Formula (I) compound and Phosphine ligands
Mol ratio is 1:0.1-0.2.
10. the synthetic method as described in claim any one of 1-9, it is characterised in that：Formula (II) compound and acid
The mol ratio of matter is 1:0.6-1.2.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105481767A (en) * | 2016-01-13 | 2016-04-13 | 高廷梅 | Synthesis method of quinoline amide compounds |
| CN106083636A (en) * | 2016-06-22 | 2016-11-09 | 尹磊 | A kind of synthetic method of arylamides |
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- 2017-10-17 CN CN201710963145.5A patent/CN107652202A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105481767A (en) * | 2016-01-13 | 2016-04-13 | 高廷梅 | Synthesis method of quinoline amide compounds |
| CN106083636A (en) * | 2016-06-22 | 2016-11-09 | 尹磊 | A kind of synthetic method of arylamides |
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