CN104974000B - Method for di-trifluoromethylation reaction of styryl compound - Google Patents

Method for di-trifluoromethylation reaction of styryl compound Download PDF

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CN104974000B
CN104974000B CN201510412021.9A CN201510412021A CN104974000B CN 104974000 B CN104974000 B CN 104974000B CN 201510412021 A CN201510412021 A CN 201510412021A CN 104974000 B CN104974000 B CN 104974000B
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double
synthetic method
amine salt
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CN104974000A (en
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黄清东
张翔
向世明
刘金凤
黄显
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Chengdu Bai Te ten thousand closes Pharmaceutical Technology Co., Ltd
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Chengdu Bai Te Ten Thousand Closes Pharmaceutical Technology Co Ltd
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Abstract

The invention relates to a synthetic method of a compound represented by the formula (III) as shown in the description. The method comprises: in a nitrogen atmosphere and in an organic solvent, a compound with the formula (I) reacts with a compound with the formula (II) in the presence of a bi-component catalyst and a prompter to obtain the compound represented by the formula (III), wherein the formula (I) and the formula (II) are shown in the description. R is H, C1-C6 alkyl, C1-C6 alkoxy, or halogen. According to the method, a target product in a high yield is obtained by combined selection and coordination of the catalyst, the prompter, the organic solvent, and the like. The method has bright application prospects and industrial production potential in the field of organic chemical synthesis.

Description

Double (trifluoromethyl) of a kind of compound of styryl changes reaction method
Technical field
The present invention relates to a kind of 1,2- of alkene double (trifluoromethyl) changes reaction method, more particularly Double (trifluoromethyl) of being related to a kind of compound of styryl changes reaction method, belongs to organic centre Body synthesizes field.
Background technology
In organic active group, trifluoromethyl is a kind of highly useful structural modification sense Group, it possesses the ability improving lipotropy, metabolic activity and the bioavailability of compound etc., Thus receive the extensive concern in each field.
It has been reported that many plant the reaction method that relevant trifluoromethylation is modified in prior art, For example：
Before more than 20 years, Yu.M.Pustovit et al. (" Reactions of cycloalkanecarboxylic acids with SF4.I.Fluorination of cyclopropanepolycarboxylic acids with SF4”,Journal of Fluorine Chemistry, 1994,69,225-229) report one kind and adopt SF4Fluorinated cycloalkanes carboxylic acid Reaction process.
(" the Diastereoselective Synthesis of Vicinally such as Gary A.Molander Bis(trifluoromethylated)Alkylboron Compounds through Successive Insertions of 2,2,2-Trifluorodiazoethane”,Angew.Chem.Int.Ed.,2014, 53,14181-14185) disclose a kind of double (trifluoromethyl) and change alkyl boron compound and 2,2,2- tri- The insert continually reaction of fluorine aziethane, its reaction equation is as follows：
(" the AgF-Mediated Fluorinative Homocoupling of such as Gao Bing Gem-Difluoroalkenes ", Organic Letters, 2014,16,102-105) disclose one kind The β of Argentous fluoride catalysis, the coupling reaction of β-difluoro styrene derivative, its reaction equation is as follows：
Although as described above, prior art reports the method that multiple trifluoromethylations react, These reactions still suffer from some defects, such as using poisonous reagent SF4Or the conversion of material Rate is not high, or the time of reaction is longer etc., thus leading to these methods in commercial Application When there is many inconveniences.
In view of this, it is contemplated that double (trifluoromethyl) of developing a kind of distyryl compound is changed Reaction method, it is achieved thereby that the maximization of target product, and the method is relatively simple, has Good prospects for commercial application.
Content of the invention
In order to overcome many defects as indicated above, present inventor has performed in-depth study and Explore, after having paid enough creative works, thus completing the present invention.
Specifically, technical scheme and content are related to a kind of the double of distyryl compound (trifluoromethyl) changes reaction method.
More particularly it relates to a kind of synthetic method of lower formula (III) compound,
Methods described includes：Under nitrogen atmosphere with organic solvent in, in bicomponent catalyst and In the presence of accelerator, lower formula (I) compound and lower formula (II) compound react, thus obtaining Described (III) compound,
Wherein, R is H, C1-C6Alkyl, C1-C6Alkoxy or halogen.
In the described synthetic method of the present invention, described C1-C6The implication of alkyl refers to have The straight or branched alkyl of 1-6 carbon atom, in non-limiting manner for example can for methyl, ethyl, N-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, n-pentyl, isoamyl Base or n-hexyl etc..
In the described synthetic method of the present invention, described C1-C6The implication of alkoxyl refers to above-mentioned The described C of definition1-C6The group that alkyl is obtained after being connected with oxygen atom.
In the described synthetic method of the present invention, the implication of described halogen refers to halogen, Can be for example non-exclusively F, Cl, Br or I.
In the described synthetic method of the present invention, described bicomponent catalyst is palladium compound and three The mixture of fluorine mesylate, wherein, the mol ratio of described palladium compound and fluoroform sulphonate For 1:2-3, for example, can be 1:2、1:2.5 or 1:3.
Wherein, described palladium compound is Pd (TFA)2(palladium trifluoroacetate), Pd (PhCN)2Cl2(two (cyano group benzene) palladium chloride), Pd (acac)2(palladium acetylacetonate), Pd (PPh3)4(four (triphenyl) phosphine Palladium), Pd (dba)2(double (dibenzalacetone) palladium), Pd (OAc)2Any one in (acid chloride), Most preferably Pd (dba)2.
Wherein, described fluoroform sulphonate is copper trifluoromethanesulfcomposite, trifluoromethanesulfonic acid scandium, trifluoro Any one in methanesulfonic acid zinc or Ytterbiumtriflate, most preferably Ytterbiumtriflate.
In the described synthetic method of the present invention, described accelerator is N- normal-butyl-N- methyl piperazine Double (fluoroform sulphonyl) inferior amine salt of pyridine, 1- butyl -2,3- methylimidazole are double (fluoroform sulphonyl) Any one in inferior amine salt or double (fluoroform sulphonyl) inferior amine salt of 1- benzyl -3- Methylimidazole. Kind, most preferably double (fluoroform sulphonyl) inferior amine salt of N- normal-butyl-N- methyl piperidine.
In the described synthetic method of the present invention, described organic solvent is 1 for volume ratio:0.2 Polyethylene Glycol and the mixture of 15- crown- 5.
The consumption of described organic solvent does not have strict restriction, and those skilled in the art can be right Its consumption is suitably selected, for example, can carry out, react suitable according to making post processing be easy to The amount that profit is carried out carries out appropriately selected.
In the described synthetic method of the present invention, described formula (I) compound and formula (II) compound Mol ratio is 1:2-3, for example, can be 1:2、1:2.5 or 1:3.
In the described synthetic method of the present invention, described formula (I) compound and bicomponent catalyst Mol ratio is 1:0.05-0.09, i.e. the mole dosage of described formula (I) compound and palladium compound and three The ratio of the mole dosage sum of both fluorine mesylates is 1:0.05-0.09, for example, can be 1:0.05、 1:0.07 or 1:0.09.
In the described synthetic method of the present invention, the mol ratio of described formula (I) compound and accelerator For 1:0.2-0.3, for example, can be 1:0.2、1:0.25 or 1:0.3.
In the described synthetic method of the present invention, reaction temperature is 50-70 DEG C, for example, can be 50 DEG C, 60 DEG C or 70 DEG C.
In the described synthetic method of the present invention, the response time is 6-10 hour, for example, can be 6 Hour, 8 hours or 10 hours.
In the described synthetic method of the present invention, the post processing after reaction terminates is as follows：React Bi Hou, filters, and adjusting filtrate pH value is neutrality, is then filled with saturated sodium bicarbonate aqueous solution Divide vibration washing, add dichloromethane extraction, isolate organic faciess, more dry with anhydrous sodium sulfate Dry, concentrating under reduced pressure, residue crosses 200-300 mesh silica gel column chromatography, with volume ratio for 1:3 Petroleum ether and acetone mixture are eluent, thus obtaining described formula (III) compound.
As described above, the invention provides double (trifluoromethyl) of a kind of distyryl compound is changed instead Induction method, thus obtained trifluoromethyl replacement compound, methods described pass through catalyst, The combined selection of accelerator, organic solvent etc. and coordination, obtain purpose such that it is able to high yield and produce Thing, has a good application prospect and industrial production potential in organic chemical synthesis field.
Specific embodiment
Below by specific embodiment, the present invention is described in detail, but these are exemplary The purposes of embodiment and purpose are only used for enumerating the present invention, the not actual guarantor to the present invention Shield scope constitutes any type of any restriction, more non-is confined to protection scope of the present invention This.
Embodiment 1
Nitrogen atmosphere protection under, under room temperature to appropriate organic solvent (for volume ratio be 1:0.2 The mixture of Polyethylene Glycol and 15- crown- 5) in, add formula (I) compound on 100mmol, 2 00mmol upper formula (II) compound, 5mmol catalyst are (for 1.25mmol Pd (dba)2With The mixture of 3.75mmol Ytterbiumtriflate) and 20mmol accelerant N-normal-butyl-N- Double (fluoroform sulphonyl) inferior amine salt of methyl piperidine, then heats to 50 DEG C, and in this temperature Lower stirring reaction 10 hours.
After completion of the reaction, filter, adjusting filtrate pH value is neutrality, then uses unsaturated carbonate hydrogen Sodium water solution fully vibrates washing, adds dichloromethane extraction, isolates organic faciess, then use Anhydrous sodium sulfate drying, concentrating under reduced pressure, residue crosses 200-300 mesh silica gel column chromatography, with body Long-pending ratio is 1:3 petroleum ether and acetone mixture are eluent, thus obtain above formula formula (III) changing Compound (wherein t-Bu is the tert-butyl group), yield is 97.5%.
1H NMR(CDCl3,400MHz):δ 7.43 (d, J=8.4Hz, 2H), 7.21 (d, J =8.4Hz, 2H), 3.66-3.54 (m, 1H), 2.86-2.65 (m, 2H), 1.31 (s, 9H).
Embodiment 2
Nitrogen atmosphere protection under, under room temperature to appropriate organic solvent (for volume ratio be 1:0.2 The mixture of Polyethylene Glycol and 15- crown- 5) in, add formula (I) compound on 100mmol, 3 00mmol upper formula (II) compound, 7.5mmol catalyst are (for 2.5mmol Pd (dba)2With The mixture of 5mmol Ytterbiumtriflate) and 25mmol accelerant N-normal-butyl-N- first Double (fluoroform sulphonyl) inferior amine salt of phenylpiperidines, then heats to 60 DEG C, and at such a temperature Stirring reaction 8 hours.
After completion of the reaction, filter, adjusting filtrate pH value is neutrality, then uses unsaturated carbonate hydrogen Sodium water solution fully vibrates washing, adds dichloromethane extraction, isolates organic faciess, then with no Aqueous sodium persulfate is dried, concentrating under reduced pressure, and residue crosses 200-300 mesh silica gel column chromatography, with volume Than for 1:3 petroleum ether and acetone mixture are eluent, thus obtaining above formula formula (III) chemical combination Thing, yield is 97.3%.
1H NMR(CDCl3,400MHz):δ7.55-7.51(m,1H),7.46(s,1H), 7.28-7.23(m,2H),3.65-3.54(m,1H),2.89-2.67(m,2H).
Embodiment 3
Nitrogen atmosphere protection under, under room temperature to appropriate organic solvent (for volume ratio be 1:0.2 The mixture of Polyethylene Glycol and 15- crown- 5) in, add formula (I) compound on 100mmol, 2 50mmol upper formula (II) compound, 9mmol catalyst are (for 2.8mmol Pd (dba)2With 6. The mixture of 2mmol Ytterbiumtriflate) and 30mmol accelerant N-normal-butyl-N- first Double (fluoroform sulphonyl) inferior amine salt of phenylpiperidines, then heats to 70 DEG C, and at such a temperature Stirring reaction 8 hours.
After completion of the reaction, filter, adjusting filtrate pH value is neutrality, then uses unsaturated carbonate hydrogen Sodium water solution fully vibrates washing, adds dichloromethane extraction, isolates organic faciess, then with no Aqueous sodium persulfate is dried, concentrating under reduced pressure, and residue crosses 200-300 mesh silica gel column chromatography, with volume Than for 1:3 petroleum ether and acetone mixture are eluent, thus obtaining above formula formula (III) chemical combination Thing, yield is 97.6%.
1H NMR(CDCl3,400MHz):δ 7.34 (t, J=8.0Hz, 1H), 6.94-6.87 (m,2H),6.85(s,1H),3.85(s,3H),3.66-3.54(m,1H),2.84-2.67(m, 2H).
Embodiment 4-33
Embodiment 4-6：Remove and palladium compound therein is replaced with Pd (TFA)2Outward, Qi Tacao Make all same, thus embodiment 1-3 is repeated, sequentially obtain embodiment 4-6.
Embodiment 7-9：Remove and palladium compound therein is replaced with Pd (PhCN)2Cl2Outward, other Operation all same, thus embodiment 1-3 is repeated, sequentially obtains embodiment 7-9.
Embodiment 10-12：Remove and palladium compound therein is replaced with Pd (acac)2Outward, other Operation all same, thus embodiment 1-3 is repeated, sequentially obtains embodiment 10-12.
Embodiment 13-15：Remove and palladium compound therein is replaced with Pd (PPh3)4Outward, other Operation all same, thus embodiment 1-3 is repeated, sequentially obtains embodiment 13-15.
Embodiment 16-18：Remove and palladium compound therein is replaced with Pd (OAc)2Outward, other Operation all same, thus embodiment 1-3 is repeated, sequentially obtains embodiment 16-18.
Embodiment 19-21：Remove and Ytterbiumtriflate therein is replaced with copper trifluoromethanesulfcomposite Outward, other operation all sames, thus embodiment 1-3 is repeated, sequentially obtain embodiment 19-21.
Embodiment 22-24：Remove and Ytterbiumtriflate therein is replaced with trifluoromethanesulfonic acid scandium Outward, other operation all sames, thus embodiment 1-3 is repeated, sequentially obtain embodiment 22-24.
Embodiment 25-27：Remove and Ytterbiumtriflate therein is replaced with trifluoromethanesulfonic acid zinc Outward, other operation all sames, thus embodiment 1-3 is repeated, sequentially obtain embodiment 25-27.
Embodiment 28-30：It is original two kinds except bicomponent catalyst therein is substituted for consumption The one-component Pd (dba) of the total consumption of component2Outward, other operation all sames, thus repeat into Go embodiment 1-3, sequentially obtain embodiment 28-30.
Embodiment 31-33：It is original two kinds except bicomponent catalyst therein is substituted for consumption Outside the one-component Ytterbiumtriflate of the total consumption of component, other operation all sames, thus weight It is carried out a 1-3 again, sequentially obtain embodiment 31-33.
Result see table 1.
Table 1
Note：" -- " indicate Wu.
From upper table 1 data：1st, when being used one-component as catalyst, yield is equal It is significantly reduced；2nd, in palladium compound, Pd (dba)2With Ytterbiumtriflate have best Composite catalyzing effect, and the catalytic effect of other palladium compound and other fluoroform sulphonate all has Substantially reduce.Thus demonstrate, only when simultaneously using Pd (dba)2Make with Ytterbiumtriflate The excellent effect of the present invention during for bicomponent catalyst, could be obtained, can play between the two Unexpected synergism.
Embodiment 34-42
Embodiment 34-36：Remove double for N- normal-butyl-N- methyl piperidine therein (fluoroform sulphurs Acyl) inferior amine salt replaces with double (fluoroform sulphonyl) inferior amine salt of 1- butyl -2,3- methylimidazole Outward, other operation all sames, thus embodiment 1-3 is repeated, sequentially obtain embodiment 34-36.
Embodiment 37-39：Remove double for N- normal-butyl-N- methyl piperidine therein (fluoroform sulphurs Acyl) inferior amine salt replaces with outside double (fluoroform sulphonyl) inferior amine salt of 1- benzyl -3- Methylimidazole., its It operates all same, thus embodiment 1-3 is repeated, sequentially obtains embodiment 37-39.
Embodiment 40-42：In addition to accelerator therein is omitted, other operation all sames, Thus embodiment 1-3 is repeated, sequentially obtain embodiment 40-42.
Result see table 2.
Table 2
From upper table 2, when not using accelerator, products collection efficiency is significantly reduced, this Prove that the presence of accelerator can significantly improve products collection efficiency.And in accelerator, the positive fourth of N- Double (fluoroform sulphonyl) inferior amine salt of base-N- methyl piperidine has best facilitation effect, other rush The effect entering agent is intended to be weaker than this material.
Embodiment 43-48
Embodiment 43-45：In addition to organic solvent is replaced with single solvent Polyethylene Glycol, other Operation all same, thus embodiment 1-3 is repeated, sequentially obtains embodiment 43-45.
Embodiment 46-48：In addition to organic solvent is replaced with single solvent 15- crown- 5, other Operation all same, thus embodiment 1-3 is repeated, sequentially obtains embodiment 46-48.
Result see table 3.
Table 3
From upper table 3, the combination of organic solvent equally can have influence on products collection efficiency, wherein Only simultaneously using Polyethylene Glycol and 15- crown- 5 mixed solvent when, could obtain the present invention's Excellent effect, and when using one-component, products collection efficiency has obvious reduction.
Comparative example 1
Inventor has also investigated the response situation that substituent R is phenyl, specifically by embodiment 1 In t-Bu (tert-butyl group) replace with phenyl, other operation all sames, thus repeat to implement reality Apply example 1, obtain comparative example 1, the yield of product is only 59.6%, has and significantly reduce.
When inventor thinks that being likely due to R is phenyl, due to there occurs that conjugation makes Cloud density is increased dramatically, lead to the cloud density on the phenyl that is connected with vinyl remote Ratio is for bigger during the tert-butyl group, thus the difficulty that result in double bond addition increases.
As described above, the invention provides double (trifluoromethyl) of a kind of distyryl compound is changed instead Induction method, thus obtained trifluoromethyl replacement compound, methods described pass through catalyst, The combined selection of accelerator, organic solvent etc. and coordination, obtain purpose such that it is able to high yield and produce Thing, has a good application prospect and industrial production potential in organic chemical synthesis field.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limit this The protection domain of invention.Additionally, it will also be appreciated that after the technology contents having read the present invention, Those skilled in the art can make various changes, modification and/or modification to the present invention, all of this A little equivalent form of values equally fall within the protection domain that the application appended claims are limited.

Claims (6)

1. a kind of synthetic method of lower formula (III) compound,
Methods described includes：Under nitrogen atmosphere with organic solvent in, in bicomponent catalyst and In the presence of accelerator, lower formula (I) compound and lower formula (II) compound react, thus obtaining Described (III) compound,
Wherein, R is H, C1-C6Alkyl, C1-C6Alkoxy or halogen；
Described bicomponent catalyst is the mixture of palladium compound and fluoroform sulphonate, wherein, Described palladium compound is 1 with the mol ratio of fluoroform sulphonate:2-3；
Described palladium compound is double (dibenzalacetone) palladium；
Described fluoroform sulphonate is Ytterbiumtriflate；
Described accelerator is double (fluoroform sulphonyl) inferior amine salt of N- normal-butyl-N- methyl piperidine, Double (fluoroform sulphonyl) inferior amine salt of 1- butyl -2,3- methylimidazole or 1- benzyl -3- Methylimidazole. Any one in double (fluoroform sulphonyl) inferior amine salt；
Described organic solvent is 1 for volume ratio:0.2 Polyethylene Glycol and the mixture of 15- crown- 5.
2. synthetic method as claimed in claim 1 it is characterised in that：Described accelerator is Double (fluoroform sulphonyl) inferior amine salt of N- normal-butyl-N- methyl piperidine.
3. synthetic method as claimed in claim 1 it is characterised in that：Described formula (I) compound Mol ratio with formula (II) compound is 1:2-3.
4. synthetic method as claimed in claim 1 it is characterised in that：Described formula (I) compound Mol ratio with bicomponent catalyst is 1:0.05-0.09.
5. synthetic method as claimed in claim 1 it is characterised in that：Described formula (I) chemical combination Thing is 1 with the mol ratio of accelerator:0.2-0.3.
6. the synthetic method as described in any one of claim 1-5 it is characterised in that：Reaction Temperature is 50-70 DEG C；Response time is 6-10 hour.
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