CN105601483B - A kind of synthetic method of medicine intermediate 1,4- diphenyl diacetyl - Google Patents
A kind of synthetic method of medicine intermediate 1,4- diphenyl diacetyl Download PDFInfo
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
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Abstract
The present invention relates to medicine intermediate 1 shown in a kind of lower formula (III), the synthetic method of 4 diphenyl diacetyl, the described method includes in a solvent, in the presence of catalyst, containing n-donor ligand, acid compound and accelerating agent, lower formula (I) compound reacts with lower formula (II) compound, it is post-treated after reaction, so as to obtain the formula (III) compound
Description
Technical field
The present invention relates to a kind of synthetic method of dicarbonyl compound, a kind of particularly medicine intermediate that can be used as
The synthetic method of Isosorbide-5-Nitrae-diphenyl diacetyl, belongs to medicine intermediate synthesis field.
Background technology
In organic chemical synthesis field especially medicine intermediate synthesis technical field, carbonyl is a kind of with good anti-
The construction unit of activity is answered, a variety of reactions can further be occurred by carbonyl, so as to obtain different purpose products.
Wherein, diacetyl class compound is due to two carbonyls, and is synthesized in organic synthesis especially medicine intermediate
Have a good application prospect in field and potentiality, be a kind of very important midbody product.Diacetyl class knot in order to obtain
Structure, people, which synthesize it, has carried out substantial amounts of further investigation, and achieves many achievements, such as：
Chao Liu et al. people (Palladium-Catalyzed C-C Bond Formation To Construct 1,4-
Diketones under Mild Conditions, Angew.Chem.Int.Ed., 2011,50, p 7337-7341) disclosed in
A kind of synthesis of diacetyl class compound, its reaction equation are as follows：
Myron M.D.Wilde et al. (Bis (amino) cyclopropenylidenes as Organocatalysts
For Acyl Anion and Extended Umpolung Reactions, Angew.Chem.Int.Ed., 2013,50, p
A kind of method of diacetyl class compound 12651-12654) is disclosed, its reaction equation is as follows：
Xingyong Wang et al. are in " Palladium-catalyzed addition of potassium
phenyltrifluoroborate to dinitriles:Synthesis of diketone compounds ", Journal
Of Chemical Research, p.470-472 a kind of synthetic method of following cyclohexadione compounds disclosed in)：In acetic acid
Palladium catalyst, ligand 1, in the presence of 10- ferrosins and trifluoroacetic acid, formula (II) compound reacts with formula (III) compound,
The dione compounds of formula (I) are generated,
Wherein, L can be C1-C5The linker of alkylidene, but in this method diacetyl class is then obtained when L is ethylidene
Compound yield is only 57% or so, and yield is too low, still suffers from and continues improved necessity.
For diacetyl class compound as indicated above yield it is too low the defects of, present inventor has performed deeply grind
Study carefully, by the comprehensive selection of suitable catalyst, ligand, acid and organic solvent etc. with cooperateing with, so as to significantly improve product production
Rate, develops a kind of novel method for synthesizing of diacetyl class compound, has good application potential and wide industrial metaplasia
Antenatal scape.
The content of the invention
It is as described above, above-mentioned existing in the prior art as yield is too low, process is cumbersome, expensive reagents are rare in order to solve
Etc. many defects, synthesis of the present inventor for can be used as Isosorbide-5-Nitrae-diphenyl diacetyl of medicine intermediate is deeply ground
Study carefully, after a large amount of creative works are paid, so as to complete the present invention.
It is described the present invention relates to a kind of synthetic method of medicine intermediate Isosorbide-5-Nitrae-diphenyl diacetyl shown in lower formula (III)
Method include in a solvent, in the presence of catalyst, containing n-donor ligand, acid compound and accelerating agent, lower formula (I) compound with
Lower formula (II) compound reacts, post-treated after reaction, so that the formula (III) compound is obtained,
Wherein, X is alkali metal.
In the synthetic method of the present invention, X is alkali metal, may be, for example, Li, Na or K.
In the synthetic method of the present invention, the catalyst is acid chloride (Pd (OAc)2), palladium acetylacetonate (Pd
(acac)2), palladium trifluoroacetate (Pd (OTA)2), triphenylphosphine palladium chloride (Pd (PPh3)2Cl2), diethyl cyano group palladium bichloride (Pd
(CH3CN)2Cl2) or palladium bichloride (PdCl2) in any one, be preferably diethyl cyano group palladium bichloride (Pd (CH3CN)2Cl2) or chlorine
Change palladium (PdCl2), it is most preferably palladium bichloride (PdCl2)。
In the synthetic method of the present invention, the containing n-donor ligand is 2,2 '-bipyridyl, 5,5 '-dimethyl -2,2 ' -
Bipyridyl, 4,4 '-dimethyl -2,2 '-bipyridyl or 1,10- ferrosin, are most preferably 2,2 '-bipyridyl.
In the synthetic method of the present invention, the acid compound is boric acid, p-nitrophenyl sulfonic acid, p-methyl benzenesulfonic acid
Any one in monohydrate, benzoic acid, trifluoroacetic acid or camphorsulfonic acid, is most preferably camphorsulfonic acid.
In the synthetic method of the present invention, the accelerating agent is silver acetate or silver trifluoroacetate, is most preferably trifluoro
Silver acetate.
In the synthetic method of the present invention, the solvent is organic solvent and the mixture of water, wherein organic solvent
Volume ratio with water is 1:0.5-1.2, may be, for example, 1:0.5、1:0.7、1:0.9、1:1.1 or 1:1.2.
Wherein, the organic solvent is Isosorbide-5-Nitrae-dioxane, dimethyl sulfoxide (DMSO) (DMSO), tetrahydrofuran (THF), N, N- bis-
Any one in methylformamide (DMF) or pyridine, is most preferably tetrahydrofuran (THF).
The dosage of the solvent is not particularly limited, and those skilled in the art can be according to actual conditions, such as react
Be smoothed out, the concrete condition such as convenient post processing and suitably select and determine, this is all those skilled in the art
Routine techniques knowledge, is no longer described in detail herein.
In the synthetic method of the present invention, the molar ratio of formula (I) compound and formula (II) compound is 1:2-
3, it may be, for example, 1:2、1:2.5 or 1:3.
In the synthetic method of the present invention, the molar ratio of formula (I) compound and catalyst is 1:0.06-
0.12, it may be, for example, 1:0.06、1:0.08、1:0.1 or 1:0.12.
In the synthetic method of the present invention, the molar ratio of formula (I) compound and containing n-donor ligand is 1:0.15-
0.25, it may be, for example, 1:0.15、1:2 or 1:0.25.
In the synthetic method of the present invention, the molar ratio of formula (I) compound and acid compound is 1:1.5-
2.5, it may be, for example, 1:1.5、1:2 or 1:2.5.
In the synthetic method of the present invention, the molar ratio of formula (I) compound and accelerating agent is 1:0.08-
0.12, it may be, for example, 1:0.08、1:0.1 or 1:0.12.
In the synthetic method of the present invention, reaction temperature is 60-80 DEG C, may be, for example, 60 DEG C, 70 DEG C or 80 DEG C.
In the synthetic method of the present invention, the reaction time, there is no particular limitation, such as can be examined by liquid chromatogram
Survey the residual percentage of purpose product or raw material and determine the suitable reaction time, it typically is 20-35 it is small when, may be, for example, 20
Hour, 25 it is small when, 30 it is small when or 35 it is small when.
In the synthetic method of the present invention, post processing after reaction can be specific as follows：After reaction, by institute
It must be poured into ethyl acetate, sequentially with saturation NaHCO3Aqueous solution and saturated salt solution fully wash, and separate water-yielding stratum and organic
Layer, aqueous layer with ethyl acetate is extracted, and is merged organic layer (merging the organic layer after washing and the organic layer being obtained by extraction), is used
Anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue is purified by flash column chromatography (n-hexane/ethyl acetate), so that
Obtain the formula (III) compound.
In conclusion comprehensive selection and association of the present invention by suitable catalyst, ligand, acid compound and accelerating agent
Together, and suitable dicyandiamide solution is used, so that the yield of Isosorbide-5-Nitrae-diphenyl diacetyl is remarkably improved compared with prior art,
Have a good application prospect in organic chemical synthesis field and researching value, the synthesis for Isosorbide-5-Nitrae-cyclohexadione compounds provide
Brand-new method.
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
At room temperature, to appropriate solvent (for volume ratio 1:0.5 THF and the mixture of water) in add 100mmol on formula (I)
The upper formula (II) compound of compound, 200mmol, 6mmol catalyst PdCl2, 2,2 '-bipyridyl of 15mmol containing n-donor ligands,
150mmol camphorsulfonic acids and 8mmol accelerating agent silver trifluoroacetates, then heat to 60 DEG C, and stirring reaction 35 at such a temperature
Hour；
After reaction, gained is poured into ethyl acetate, sequentially with saturation NaHCO3Aqueous solution and saturated salt solution fill
Divide washing, separate water-yielding stratum and organic layer, aqueous layer with ethyl acetate is extracted, merge organic layer and (merge organic after washing
Layer and the organic layer being obtained by extraction), use anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue passes through flash column chromatography
(n-hexane/ethyl acetate) purifies, so that formula (III) compound is obtained, yield 88.9%.
Nuclear magnetic resonance：1H NMR(DMSO-d6,500MHz):δ 8.03 (d, J=8Hz, 4H), 7.66 (dd, J=8Hz, 2H),
7.56 (dd, J=8HZ, 4H), 3.42 (s, 4H)；
13C NMR(DMSO-d6,125MHz):δ198.6(2C),136.6(2C),133.2(2C),128.7(4C),127.9
(4C),32.3(2C)。
Embodiment 2
Reaction equation is as follows with embodiment 1, specific operation process：
At room temperature, to appropriate solvent (for volume ratio 1:0.8 THF and the mixture of water) in add 100mmol described in formula
(I) compound, 250mmol formulas (II) compound phenyl trifluoromethanesulfonate Boratex, 9mmol catalyst PdCl2, 20mmol containing n-donor ligands 2,
2 '-bipyridyl, 200mmol camphorsulfonic acids and 10mmol accelerating agent silver trifluoroacetates, then heat to 70 DEG C, and at such a temperature
When stirring reaction 28 is small；
After reaction, gained is poured into ethyl acetate, sequentially with saturation NaHCO3Aqueous solution and saturated salt solution fill
Divide washing, separate water-yielding stratum and organic layer, aqueous layer with ethyl acetate is extracted, merge organic layer and (merge organic after washing
Layer and the organic layer being obtained by extraction), use anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue passes through flash column chromatography
(n-hexane/ethyl acetate) purifies, so as to obtain the formula (III) compound, yield 89.1%.
Nuclear magnetic data is the same as embodiment 1.
Embodiment 3
Reaction equation is as follows with embodiment 1, specific operation process：
At room temperature, to appropriate solvent (for volume ratio 1:1.2 THF and the mixture of water) in add 100mmol on formula (I)
The upper formula (II) compound of compound, 300mmol, 12mmol catalyst PdCl2, 2,2 '-bipyridyl of 25mmol containing n-donor ligands,
250mmol camphorsulfonic acids and 12mmol accelerating agent silver trifluoroacetates, then heat to 80 DEG C, and stirring reaction 20 at such a temperature
Hour；
After reaction, gained is poured into ethyl acetate, sequentially with saturation NaHCO3Aqueous solution and saturated salt solution fill
Divide washing, separate water-yielding stratum and organic layer, aqueous layer with ethyl acetate is extracted, merge organic layer and (merge organic after washing
Layer and the organic layer being obtained by extraction), use anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue passes through flash column chromatography
(n-hexane/ethyl acetate) purifies, so that formula (III) compound is obtained, yield 89.2%.
Nuclear magnetic data is the same as embodiment 1.
Embodiment 4
Reaction equation is as follows with embodiment 1, specific operation process：
At room temperature, to appropriate solvent (for volume ratio 1:1 THF and the mixture of water) in add 100mmol on formula (I)
The upper formula (II) compound of compound, 220mmol, 10mmol catalyst PdCl2, 2,2 '-bipyridyl of 18mmol containing n-donor ligands,
230mmol camphorsulfonic acids and 9mmol accelerating agent silver trifluoroacetates, then heat to 65 DEG C, and stirring reaction 25 at such a temperature
Hour；
After reaction, gained is poured into ethyl acetate, sequentially with saturation NaHCO3Aqueous solution and saturated salt solution fill
Divide washing, separate water-yielding stratum and organic layer, aqueous layer with ethyl acetate is extracted, merge organic layer and (merge organic after washing
Layer and the organic layer being obtained by extraction), use anhydrous Na2SO4Dry, negative pressure evaporation removes solvent, and residue passes through flash column chromatography
(n-hexane/ethyl acetate) purifies, so that formula (III) compound is obtained, yield 89.4%.
Nuclear magnetic data is the same as embodiment 1.
It can be seen that by above-described embodiment 1-4, when reaction system using the present invention, Isosorbide-5-Nitrae-hexichol can be obtained with high yield
Base diacetyl, improves 30% or so, yield has significantly compared with 57% yield in the above-mentioned periodical of the present inventor
Improve and improve.
Embodiment 5-24：The investigation of catalyst
Embodiment 5-8：Except by catalyst by PdCl2Replace with Pd (OAc)2Outside, other operations are constant, so as to repeat real
Embodiment 1-4 has been applied, has sequentially obtained embodiment 5-8.
Embodiment 9-12：Except by catalyst by PdCl2Replace with Pd (acac)2Outside, other operations are constant, so as to repeat
Embodiment 1-4 is implemented, sequentially obtains embodiment 9-12.
Embodiment 13-16：Except by catalyst by PdCl2Replace with Pd (OTA)2Outside, other operations are constant, so as to repeat
Embodiment 1-4 is implemented, sequentially obtains embodiment 13-16.
Embodiment 17-20：Except by catalyst by PdCl2Replace with Pd (PPh3)2Cl2Outside, other operations are constant, so that
Repetition implements embodiment 1-4, sequentially obtains embodiment 17-20.
Embodiment 21-24：Except by catalyst by PdCl2Replace with Pd (CH3CN)2Cl2Outside, other operations are constant, so that
Repetition implements embodiment 1-4, sequentially obtains embodiment 21-24.
The result is shown in table 1 below.
Table 1
It can be seen from the above that in all catalyst, PdCl2With Pd (CH3CN)2Cl2With best catalytic effect (and
PdCl2Effect is best)；Other catalyst cause yield to be greatly lowered, or even to be less than yield of the prior art (this
Products collection efficiency is that 57%), more even can not obtain product in the above-mentioned periodical literature of inventor (see embodiment 17-20).
Embodiment 25-40：The investigation of containing n-donor ligand
Embodiment 25-28：Except containing n-donor ligand replaced with 5 by 2,2 '-bipyridyl, 5 '-dimethyl -2, outside 2 '-bipyridyl,
Other operations are constant, so as to repeat to implement embodiment 1-4, sequentially obtain embodiment 25-28.
Embodiment 29-32：Except containing n-donor ligand replaced with 4 by 2,2 '-bipyridyl, 4 '-dimethyl -2, outside 2 '-bipyridyl,
Other operations are constant, so as to repeat to implement embodiment 1-4, sequentially obtain embodiment 29-32.
Embodiment 33-36：Except containing n-donor ligand is replaced with outside 1,10- ferrosins by 2,2 '-bipyridyl, other operations are not
Become, so as to repeat to implement embodiment 1-4, sequentially obtain embodiment 33-36.
Embodiment 37-40：Outside by containing n-donor ligand 2,2 '-bipyridyl is omitted, other operations are constant, so as to repeat
Embodiment 1-4 is implemented, sequentially obtains embodiment 37-40.
The result is shown in table 2 below.
Table 2
It can be seen from the above that in all ligands, 2,2 '-bipyridyl has a best effect, and 5,5 '-dimethyl -2,2 '-connection
Pyridine and 4,4 '-dimethyl -2,2 '-bipyridyl can also obtain the yield higher than 80%, and 1,10- ferrosin is (in the prior art
In the above-mentioned periodical literature of the present invention or patent application, for other dione compounds in addition to Isosorbide-5-Nitrae-diketone, then 1,10- is luxuriant and rich with fragrance
Hello quinoline can obtain be higher than 80% good yield) and without containing n-donor ligand when can not then obtain product.
Embodiment 41-60：The investigation of acid compound
Embodiment 41-44：In addition to acid compound is replaced with boric acid by camphorsulfonic acid, other operations are constant, so that
Repetition implements embodiment 1-4, sequentially obtains embodiment 41-44.
Embodiment 45-48：In addition to acid compound is replaced with p-nitrophenyl sulfonic acid by camphorsulfonic acid, other operations are not
Become, so as to repeat to implement embodiment 1-4, sequentially obtain embodiment 45-48.
Embodiment 49-52：In addition to acid compound is replaced with p-methyl benzenesulfonic acid monohydrate by camphorsulfonic acid, so that weight
Embodiment 1-4 is implemented again, sequentially obtains embodiment 49-52.
Embodiment 53-56：In addition to acid compound is replaced with benzoic acid by camphorsulfonic acid, other operations are constant, from
And repeat to implement embodiment 1-4, sequentially obtain embodiment 53-56.
Embodiment 57-60：In addition to acid compound is replaced with trifluoroacetic acid by camphorsulfonic acid, other operations are constant,
So as to repeat to implement embodiment 1-4, embodiment 57-60 is sequentially obtained.
The result is shown in table 3 below.
Table 3
It can be seen from the above that in all acid compounds, camphorsulfonic acid has best effect, and other acid cause yield
Significantly reduce, especially with boric acid when is only<2%.And in the prior art (such as above-mentioned periodical literature or patent application)
In have best effects trifluoroacetic acid, but can only obtain the products collection efficiency of 21.8-22.6%.
Embodiment 61-68：The investigation of accelerating agent
Embodiment 61-64：In addition to accelerating agent is replaced with silver acetate by silver trifluoroacetate, other operations are constant, so that
Repetition implements embodiment 1-4, sequentially obtains embodiment 61-64.
Embodiment 65-68：In addition to accelerating agent silver trifluoroacetate is omitted, other operations are constant, so as to repeat real
Embodiment 1-4 has been applied, has sequentially obtained embodiment 65-68.
The result is shown in table 4 below.
Table 4
It can be seen from the above that when without using accelerating agent, products collection efficiency significantly reduces (but still being significantly higher than the prior art).And
When using silver trifluoroacetate as accelerating agent, then products collection efficiency has a significant improvement, but it was unexpectedly determined that even with
The very similar silver acetate of silver trifluoroacetate, its to yield improvement also be significantly lower than silver trifluoroacetate improvement (but
Still it is significantly higher than the prior art).
Embodiment 69-92：The investigation of solvent
Embodiment 69-72：In addition to the THF in solvent is replaced with Isosorbide-5-Nitrae-dioxane, other operations are constant, so that weight
Embodiment 1-4 is implemented again, sequentially obtains embodiment 69-72.
Embodiment 73-76：In addition to the THF in solvent is replaced with DMSO, other operations are constant, so as to repeat to implement
Embodiment 1-4, sequentially obtains embodiment 73-76.
Embodiment 77-80：In addition to the THF in solvent is replaced with DMF, other operations are constant, so as to repeat to implement
Embodiment 1-4, sequentially obtains embodiment 77-80.
Embodiment 81-84：In addition to the THF in solvent is replaced with pyridine, other operations are constant, so as to repeat to implement
Embodiment 1-4, sequentially obtains embodiment 81-84.
Embodiment 85-88：In addition to solvent is replaced with single solvent THF by the mixture of THF and water, other operations are not
Become, so as to repeat to implement embodiment 1-4, sequentially obtain embodiment 85-88.
Embodiment 89-92：In addition to solvent is replaced with single solvent water by the mixture of THF and water, other operations are not
Become, so as to repeat to implement embodiment 1-4, sequentially obtain embodiment 89-92.
The result is shown in table 5 below.
Table 5
Note：" NR " represents not react
It can be seen from the above that in the organic solvent constituent of composition solvent, THF has best effect；And have when using other
During solvent component, then yield, which drastically reduces, can not even react；It can also be seen that when THF or water is used alone, production
Rate significantly reduces, and can not even react.All these demonstrate only while use THF and the mixture conduct of water
Solvent, method of the invention could obtain best technique effect.
In conclusion can clearly be found out by above-mentioned all embodiments, when applying the method according to the invention, pass through specific catalysis
The selection of agent, ligand, acid compound and accelerating agent and solvent, can overcome the yield of cyclohexadione compounds in the prior art
The defects of too low, can obtain purpose product with high yield, in organic chemical synthesis field especially medicine intermediate synthesis neck
Domain 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 the present invention each
Kind change, modification and/or variation, all these equivalent forms equally fall within the guarantor that the application the appended claims are limited
Within the scope of shield.
Claims (6)
1. the synthetic method of Isosorbide-5-Nitrae-diphenyl diacetyl shown in a kind of lower formula (III), the described method includes in a solvent, in catalysis
In the presence of agent, containing n-donor ligand, acid compound and accelerating agent, lower formula (I) compound reacts with lower formula (II) compound,
It is post-treated after reaction, so that the formula (III) compound is obtained,
Wherein, X K；
The catalyst is palladium bichloride；
The containing n-donor ligand is 2,2 '-bipyridyl；
The acid compound is camphorsulfonic acid；
The accelerating agent is silver trifluoroacetate；
The solvent is organic solvent and the mixture of water, and the wherein volume ratio of organic solvent and water is 1:0.5-1.2, it is described to have
Solvent is tetrahydrofuran.
2. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound is rubbed with formula (II) compound
You are than being 1:2-3.
3. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound and the molar ratio of catalyst are
1:0.06-0.12。
4. synthetic method as claimed in claim 1, it is characterised in that：The molar ratio of formula (I) compound and containing n-donor ligand
For 1:0.15-0.25.
5. synthetic method as claimed in claim 1, it is characterised in that：Mole of formula (I) compound and acid compound
Than for 1:1.5-2.5.
6. such as claim 1-5 any one of them synthetic methods, it is characterised in that：Formula (I) compound and accelerating agent
Molar ratio is 1:0.08-0.12.
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