CN105152967A - Synthesis method for medical intermediate trifluoromethyl substituted cyclohexane compound - Google Patents
Synthesis method for medical intermediate trifluoromethyl substituted cyclohexane compound Download PDFInfo
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Abstract
The invention relates to a synthesis method for a trifluoromethyl substituted cyclohexane compound shown in the following formula (III) and capable of being used as a medical intermediate. The method includes the steps that in organic solvent, in the presence of catalysts, activating agents, auxiliaries and alkali, a compound in the following formula (I) and a compound in the following formula (II) react for 8-12 hours in a stirred mode at 50-80 DEG C, and the compound in the formula (III) is obtained through after-treatment, wherein R is selected from H, C1-C6 alkyl groups, C1-C6 alkoxy groups and halogens. According to the technical scheme, through using the appropriate reaction substrate and comprehensive synergism and promotion of the catalysts, the activating agents, the auxiliaries and alkali, the target product can be obtained in a high-yield mode, and the method has good application prospects and industrialized production potentials in the technical field of organic synthesis and particularly in the technical field of medical intermediate synthesis.
Description
Technical field
The present invention relates to a kind of synthetic method of trifluoromethyl derivative, relate more particularly to a kind of synthetic method of medicine intermediate trifluoromethyl substituted cyclohexane compound, belong to organic chemical synthesis especially medicine intermediate synthesis field.
Background technology
In organic chemistry filed especially field of medicaments, trifluoromethyl is extensively present among drug molecule and agricultural formulations, is thus day by day subject to people's attention in the research of relevant trifluoromethylation reaction in recent decades, and achieves significant progress.
From the angle that valence link is formed, the method for being carried out trifluoromethylation by addition reaction is more efficiently, and this method can form unique C-CF
3key.From the nineties in 20th century, trifluoromethylation reaction has just started research and report, illustratively as described below:
GongJianchun etc. (" AlkynylationofC-HBondsviaReactionwithAcetylenicTriflones ", J.Am.Chem.Soc., 1996,118,4486-4487) reporting a kind of alkynyl trifluoromethyl sulfone compound that adopts is the reaction method of raw material, and its reaction formula is as follows:
JasonS.Xiang etc. (" MechanisticAspectsoftheC-HAlkynylationReactionofAcetylen icTriflones.DeterminationofPhenylVersusCyclohexylMigrato ryAptitudeforaVinylidineCarbene ", TetrahedronLetters, 1996,37,5269-5272) mechanism that also adopts isotope-labeled technique study alkynyl trifluoromethyl sulfone compound to react.
As mentioned above, multiple trifluoromethylation method has been disclosed in prior art.But the continuation for trifluoromethylation method is studied, and still there is necessity, this, for provide the medicine intermediate of cheapness for field of medicaments for, has very important realistic meaning.
In order to the trifluoromethylation method of development of new, present inventors studied a large amount of documents and materials, and carried out systematic Experimental Research, selection is optimized to reaction reagent, and then propose a kind of synthetic method of medicine intermediate trifluoromethyl substituted cyclohexane compound, the method route is novel, be swift in response, and reaction yield is higher, has actual application prospect widely.
Summary of the invention
In order to research and develop novel trifluoromethylation method, present inventor has performed deep research and exploration, after having paid enough creative works, thus completing the present invention.
Specifically, technical scheme of the present invention and content relate to the synthetic method of trifluoromethyl substituted cyclohexane compound shown in a kind of following formula (III) that can be used as medicine intermediate, described method comprises: in organic solvent, under catalyzer, activator, auxiliary agent and alkali exist, following formula (I) compound and following formula (II) compound stirring reaction 8-12 hour at 50-80 DEG C, described formula (III) compound is obtained through aftertreatment
Wherein, R is selected from H, C
1-C
6alkyl, C
1-C
6alkoxy or halogen.
In described synthetic method of the present invention, described C
1-C
6the implication of alkyl refers to the straight or branched alkyl with 1-6 carbon atom, such as can be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl or n-hexyl etc. in non-limiting manner.
In described synthetic method of the present invention, described C
1-C
6the implication of alkoxyl group refers to the C with above-mentioned implication
1-C
6the group obtained after alkyl is connected with Sauerstoffatom.
In described synthetic method of the present invention, described halogen such as can be F, Cl, Br or I.
In described synthetic method of the present invention, described catalyzer is the mixture of organocopper compound and organoiron compound, and the mol ratio of wherein said organocopper compound and organoiron compound is 1:2-3, such as, can be 1:2,1:2.5 or 1:3.
Wherein, described organocopper compound is Cu (OAc)
2(venus crystals), Cu (TFA)
2(trifluoroacetic acid copper), Cu (OTf)
2(copper trifluoromethanesulfcomposite), Cu (acac)
2(acetylacetone copper) or [(CH
3cN)
4cu] PF
6any one in (phosphofluoric acid four acetonitrile copper), most preferably is [(CH
3cN)
4cu] PF
6.
Wherein, described organoiron compound is cyclooctatetraene iron tricarbonyl, ferric acetyl acetonade (Fe (acac)
3) or ferrocene in any one, most preferably be cyclooctatetraene iron tricarbonyl.
In described synthetic method of the present invention, described activator is boric acid thricyclohexyl ester.
In described synthetic method of the present invention, described auxiliary agent is boron trifluoride diethyl etherate.
In described synthetic method of the present invention, described alkali is NaOH, sodium carbonate, saleratus, sodium phosphate, morpholine, sodium ethylate, 1, any one in 4-diazabicylo [2.2.2] octane (DABCO), sodium acetate or pyridine, most preferably is DABCO.
In described synthetic method of the present invention, described organic solvent is DMF (N, dinethylformamide), any one or mixture multiple arbitrarily in DMSO (dimethyl sulfoxide (DMSO)), toluene, benzene, ethanol, acetonitrile, Virahol, PEG-200 (Macrogol 200), most preferably be the mixture of DMSO and the PEG-200 of equal-volume ratio.
Wherein, the consumption of described organic solvent strict restriction, and those skilled in the art can carry out suitable selection according to practical situation and determine, such as its consumption size is carried out and aftertreatment to facilitate reaction, is no longer described in detail at this.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and formula (II) compound is 1:1.2-1.8, such as, can be 1:1.2,1:1.5 or 1:1.8.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and catalyzer is 1:0.09-0.16, namely the mole dosage of described formula (I) compound is 1:0.09-0.16 with forming the organocopper compound of described catalyzer with the ratio of total mole dosage of organoiron compound, such as, can be 1:0.09,1:0.11,1:0.13,1:0.15 or 1:0.16.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and activator is 1:0.1-0.2, such as, can be 1:0.1,1:0.15 or 1:0.2.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and auxiliary agent is 1:0.05-0.1, such as, can be 1:0.05,1:0.07,1:0.09 or 1:0.1.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and alkali is 1:0.2-0.3, such as, can be 1:0.2,1:0.25 or 1:0.3.
In described synthetic method of the present invention, the aftertreatment that reaction terminates is specific as follows: after reaction terminates, reaction gained mixture is naturally cooled to room temperature, then adjust ph is neutral, filter, add deionized water in filtrate fully to vibrate washing, add ethyl acetate more fully to extract 2-3 time, merge organic phase, underpressure distillation, gained residue is crossed 300-400 order silica gel column chromatography and is separated, and using the chloroform of equal-volume ratio and petroleum ether mixtures as elutriant, thus obtains described formula (III) compound.
In described synthetic method of the present invention, the reaction mass of employing or reagent all prepare by prior art and/or buy use.
In sum, the invention provides a kind of synthetic method that can be used as the trifluoromethyl substituted cyclohexane compound of medicine intermediate, this technical scheme is by the use of suitable reactions substrate, and the comprehensive collaborative and facilitation effect of catalyzer, activator, auxiliary agent and alkali, thus high yield can obtain object product, have a good application prospect and industrial production potential in organic synthesis especially medicine intermediate synthesis technical field.
Embodiment
Below by specific embodiment, the present invention is described in detail; but the purposes of these exemplary embodiments and object are only used for exemplifying the present invention; not any type of any restriction is formed to real protection scope of the present invention, more non-protection scope of the present invention is confined to this.
Embodiment 1
Under room temperature, to in appropriate organic solvent (mixture for DMSO and the PEG-200 of equal-volume ratio), add 100mmol above formula (I) compound, 120mmol above formula (II) compound, 9mmol catalyzer (be 3mmol [(CH
3cN)
4cu] PF
6with the mixture of 6mmol cyclooctatetraene iron tricarbonyl), 10mmol activator boric acid thricyclohexyl ester, 5mmol auxiliary agent boron trifluoride diethyl etherate and 20mmol alkali DABCO, be then warming up to 50 DEG C, and stirring reaction 12 hours at such a temperature;
After reaction terminates, reaction gained mixture is naturally cooled to room temperature, and then adjust ph is neutral, filters, add deionized water in filtrate fully to vibrate washing, add ethyl acetate more fully to extract 2-3 time, merge organic phase, underpressure distillation, gained residue is crossed 300-400 order silica gel column chromatography and is separated, using the chloroform of equal-volume ratio and petroleum ether mixtures as elutriant, thus obtain above formula (III) compound, productive rate is 96.8%.
1HNMR(CDCl
3,400MHz):δ7.56(d,J＝7.4Hz,2H),7.45(dd,J＝7.4,7.4Hz,1H),7.40(dd,J＝7.4,7.4Hz,2H),3.90-3.82(m,1H),1.90-1.83(m,2H),1.80-1.72(m,2H),1.71-1.65(m,1H),1.63-1.52(m,2H),1.46-1.35(m,2H),1.34-1.23(m,1H)。
Embodiment 2
Under room temperature, to in appropriate organic solvent (mixture for DMSO and the PEG-200 of equal-volume ratio), add 100mmol above formula (I) compound, 150mmol above formula (II) compound, 12mmol catalyzer (be 3mmol [(CH
3cN)
4cu] PF
6with the mixture of 9mmol cyclooctatetraene iron tricarbonyl), 15mmol activator boric acid thricyclohexyl ester, 7mmol auxiliary agent boron trifluoride diethyl etherate and 25mmol alkali DABCO, be then warming up to 65 DEG C, and stirring reaction 10 hours at such a temperature;
After reaction terminates, reaction gained mixture is naturally cooled to room temperature, and then adjust ph is neutral, filters, add deionized water in filtrate fully to vibrate washing, add ethyl acetate more fully to extract 2-3 time, merge organic phase, underpressure distillation, gained residue is crossed 300-400 order silica gel column chromatography and is separated, using the chloroform of equal-volume ratio and petroleum ether mixtures as elutriant, thus obtain above formula (III) compound, productive rate is 96.5%.
1HNMR(CDCl
3,400MHz):δ7.48(d,J＝8.9Hz,1H),6.92(d,J＝8.9Hz,1H),3.89-3.78(m,1H),3.84(s,3H),1.91-1.82(m,2H),1.81-1.65(m,3H),1.62-1.50(m,2H),1.47-1.23(m,3H)。
Embodiment 3
Under room temperature, to in appropriate organic solvent (mixture for DMSO and the PEG-200 of equal-volume ratio), add 100mmol above formula (I) compound, 180mmol above formula (II) compound, 16mmol catalyzer (be 4.5mmol [(CH
3cN)
4cu] PF
6with the mixture of 11.5mmol cyclooctatetraene iron tricarbonyl), 20mmol activator boric acid thricyclohexyl ester, 10mmol auxiliary agent boron trifluoride diethyl etherate and 30mmol alkali DABCO, be then warming up to 80 DEG C, and stirring reaction 8 hours at such a temperature;
After reaction terminates, reaction gained mixture is naturally cooled to room temperature, and then adjust ph is neutral, filters, add deionized water in filtrate fully to vibrate washing, add ethyl acetate more fully to extract 2-3 time, merge organic phase, underpressure distillation, gained residue is crossed 300-400 order silica gel column chromatography and is separated, using the chloroform of equal-volume ratio and petroleum ether mixtures as elutriant, thus obtain above formula (III) compound, productive rate is 96.4%.
1HNMR(CDCl
3,400MHz):δ7.52(s,1H),7.439(d,J＝7.9Hz,1H),7.436(d,J＝7.7Hz,1H),7.35(dd,J＝7.9,7.6Hz,1H),3.88-3.78(m,1H),1.91-1.81(m,2H),1.80-1.65(m,3H),1.64-1.52(m,2H),1.47-1.23(m,3H)。
Embodiment 4
Under room temperature, to in appropriate organic solvent (mixture for DMSO and the PEG-200 of equal-volume ratio), add 100mmol above formula (I) compound, 130mmol above formula (II) compound, 15mmol catalyzer (be 5mmol [(CH
3cN)
4cu] PF
6with the mixture of 10mmol cyclooctatetraene iron tricarbonyl), 18mmol activator boric acid thricyclohexyl ester, 6mmol auxiliary agent boron trifluoride diethyl etherate and 23mmol alkali DABCO, be then warming up to 60 DEG C, and stirring reaction 11 hours at such a temperature;
After reaction terminates, reaction gained mixture is naturally cooled to room temperature, and then adjust ph is neutral, filters, add deionized water in filtrate fully to vibrate washing, add ethyl acetate more fully to extract 2-3 time, merge organic phase, underpressure distillation, gained residue is crossed 300-400 order silica gel column chromatography and is separated, using the chloroform of equal-volume ratio and petroleum ether mixtures as elutriant, thus obtain above formula (III) compound, productive rate is 96.1%.
1HNMR(CDCl
3,400MHz):δ7.52(d,J＝7.6Hz,1H),7.36(dd,J＝7.6,7.6Hz,1H),7.26(d,J＝7.6Hz,1H),7.21(dd,J＝7.6,7.6Hz,1H),3.93-3.84(m,1H),2.48(s,3H),1.90-1.82(m,2H),1.81-1.75(m,2H),1.73-1.66(m,1H),1.64-1.55(m,2H),1.44-1.24(m,3H)。
Embodiment 5-24
Embodiment 5-8: remove the [(CH in catalyzer
3cN)
4cu] PF
6replace with Cu (OAc)
2outward, other operation is all constant, thus is repeated embodiment 1-4, obtains embodiment 5-8.
Embodiment 9-12: remove the [(CH in catalyzer
3cN)
4cu] PF
6replace with Cu (TFA)
2outward, other operation is all constant, thus is repeated embodiment 1-4, obtains embodiment 9-12.
Embodiment 13-16: remove the [(CH in catalyzer
3cN)
4cu] PF
6replace with Cu (OTf)
2outward, other operation is all constant, thus is repeated embodiment 1-4, obtains embodiment 13-16.
Embodiment 17-20: remove the [(CH in catalyzer
3cN)
4cu] PF
6replace with Cu (acac)
2outward, other operation is all constant, thus is repeated embodiment 1-4, obtains embodiment 17-20.
Embodiment 21-24: except replacing with except ferric acetyl acetonade by the cyclooctatetraene iron tricarbonyl in catalyzer, other operation is all constant, thus is repeated embodiment 1-4, obtains embodiment and obtains embodiment 21-24.
Embodiment 25-28: except replacing with except ferrocene by the cyclooctatetraene iron tricarbonyl in catalyzer, other operation is all constant, thus is repeated embodiment 1-4, obtains embodiment and obtains embodiment 25-28.
Embodiment 29-32: except catalyzer is replaced with the one-component [(CH that consumption is the total consumption sum of original two kinds of components
3cN)
4cu] PF
6outward, other operation is all constant, thus is repeated embodiment 1-4, obtains embodiment and obtains embodiment 29-32.
Embodiment 33-36: except catalyzer being replaced with one-component cyclooctatetraene iron tricarbonyl that consumption is the total consumption sum of original two kinds of components, other operation is all constant, thus is repeated embodiment 1-4, obtains embodiment and obtains embodiment 33-36.
The results are shown in following table 1.
Table 1
"--" represents not exist.
As can be seen here, in organocopper compound, [(CH
3cN)
4cu] PF
6there is best effect; In organoiron compound, cyclooctatetraene iron tricarbonyl has best effect.Also can find out, when being used alone [(CH simultaneously
3cN)
4cu] PF
6or during cyclooctatetraene iron tricarbonyl, products collection efficiency has and significantly reduces significantly.This proves to only have and uses [(CH simultaneously
3cN)
4cu] PF
6with the mixture of cyclooctatetraene iron tricarbonyl as catalyzer, just good result of the present invention can be obtained.
Embodiment 37-44
Embodiment 37-40: except being omitted by activator, other operation is all constant, thus is repeated embodiment 1-4, obtains embodiment and obtains embodiment 37-40.
Embodiment 41-44: except being omitted by auxiliary agent, other operation is all constant, thus is repeated embodiment 1-4, obtains embodiment and obtains embodiment 41-44.
The results are shown in following table 2.
Table 2
As can be seen here, the existence of activator or auxiliary agent, all can significantly improve the productive rate of product, and when lacking any one, productive rate all will be caused to have obvious reduction, this demonstrate that the necessity and importance that use activator and auxiliary agent.
Embodiment 45-52
Except using following Different Alkali, other operation is all constant, thus the different embodiment of correspondence and carried out embodiment 45-52, use alkali, corresponding embodiment and products collection efficiency to see the following form 3.
Table 3
The data of 1-4 are visible in conjunction with the embodiments, and as alkali, DABCO has best effect, and other alkali all causes products collection efficiency to have obvious reduction.
Embodiment 53-60
Except using single organic solvent different in following table, other operation is all constant, thus the different embodiment of correspondence and obtain embodiment 53-60, the single organic solvent used, corresponding embodiment and products collection efficiency see the following form 4.
Table 4
As can be seen here, when using single organic solvent, products collection efficiency all has obvious reduction, even if when being used alone DMSO or PEG-200, productive rate is also remarkable in productive rate during use DMSO and PEG-200 mixed solvent, and the mixture of this both proof has best solvent effect.
In sum, the invention provides a kind of synthetic method that can be used as the trifluoromethyl substituted cyclohexane compound of medicine intermediate, this technical scheme is by the use of suitable reactions substrate, and the comprehensive collaborative and facilitation effect of catalyzer, activator, auxiliary agent and alkali, thus high yield can obtain object product, have a good application prospect and industrial production potential in organic synthesis especially medicine intermediate synthesis technical field.
Should be appreciated that the purposes of these embodiments is only not intended to for illustration of the present invention limit the scope of the invention.In addition; also should understand; after having read technology contents of the present invention, those skilled in the art can make various change, amendment and/or modification to the present invention, and these all equivalent form of values fall within the protection domain that the application's appended claims limits equally.
Claims (10)
1. the synthetic method of trifluoromethyl substituted cyclohexane compound shown in a following formula (III), described method comprises: in organic solvent, under catalyzer, activator, auxiliary agent and alkali exist, following formula (I) compound and following formula (II) compound stirring reaction 8-12 hour at 50-80 DEG C, described formula (III) compound is obtained through aftertreatment
Wherein, R is selected from H, C
1-C
6alkyl, C
1-C
6alkoxy or halogen.
2. synthetic method as claimed in claim 1, it is characterized in that: described catalyzer is the mixture of organocopper compound and organoiron compound, the mol ratio of wherein said organocopper compound and organoiron compound is 1:2-3.
3. synthetic method as claimed in claim 1 or 2, is characterized in that: described activator is boric acid thricyclohexyl ester.
4. the synthetic method as described in any one of claim 1-3, is characterized in that: described auxiliary agent is boron trifluoride diethyl etherate.
5. the synthetic method as described in any one of claim 1-4, it is characterized in that: described alkali is NaOH, sodium carbonate, saleratus, sodium phosphate, morpholine, sodium ethylate, 1, any one in 4-diazabicylo [2.2.2] octane (DABCO) or sodium acetate, most preferably is DABCO.
6. the synthetic method as described in any one of claim 1-5, is characterized in that: the mol ratio of described formula (I) compound and formula (II) compound is 1:1.2-1.8.
7. the synthetic method as described in any one of claim 1-6, is characterized in that: the mol ratio of described formula (I) compound and catalyzer is 1:0.09-0.16.
8. the synthetic method as described in any one of claim 1-7, is characterized in that: the mol ratio of described formula (I) compound and activator is 1:0.1-0.2.
9. the synthetic method as described in any one of claim 1-8, is characterized in that:, the mol ratio of described formula (I) compound and auxiliary agent is 1:0.05-0.1.
10. the synthetic method as described in any one of claim 1-9, is characterized in that: the mol ratio of described formula (I) compound and alkali is 1:0.2-0.3.
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