A kind of synthetic method of medicine intermediate difluoromethoxy based compound
Technical field
The present invention relates to the synthetic method of a kind of halogenated compound, relate more particularly to the synthetic method of a kind of difluoromethoxy based compound that can be used as medicine intermediate, belong to organic synthesis field and medicine intermediate synthesis field.
Background technology
Halo group is the elementary cell constituting and having bioactive multi-medicament compound, for instance generally all contain halo group in enzyme inhibitor, pesticide etc.
Specifically, at drug world, the nimodipine such as containing halo group is a kind of conventional calcium antagonist, the symptom such as it can be used for treating iron-deficient cerebrovascular, migraine, slight subarachnoid hemorrhage cause cerebral vasospasm, sudden deafness, hypertension; Roflumilast is then a kind of PDE-4 inhibitor, and it can be used for treating the symptoms such as serious COPD patient bronchitis.
As can be seen here, the preparation synthetic method containing the compound of halo group class formation is Important Problems organic, pharmaceutical synthesis field institute extensive concern, to the great meaning in the field such as drug manufacture, research and development. Also just because of such important function of halo group compound, the preparation method that people have developed the multiple compound containing halo group, for instance:
YossiZafrani etc. (" Diethylbromodifluoromethylphosphonate:ahighlyefficientan denvironmentallybenigndifluorocarbeneprecursor ", Tetrahedron, 2009,65,5278-5283) reporting a kind of difluoromethyl method of phenol compound, its reaction equation is as follows:
ZhengJi etc. (" Chlorodifluoromethylphenylsulfone:anovelnon-ozone-deplet ingsubstance-baseddifluorocarbenereagentforO-andN-difluo romethylations ", Chem.Comm., 2007,5147-5151) reporting a kind of difluoromethyl method of novel phenol compound, its reaction equation is as follows:
As mentioned above, although having reported for work in prior art, multiple compounds carries out Halogenated such as the method for difluoromethyl, but it is few that the difluoromethyl reagent used in these methods also exists kind, and it is many suitable in the difluoromethylization reaction of phenolic compound under alkali condition, these factors greatly limit the difluoromethyl process of other substrate, causes that it must first be converted into certain specific precursor in pharmaceutical synthesis and just can carry out follow-up difluoromethylization reaction.
In view of this, the present inventor is intended to the synthetic method developing a kind of medicine intermediate difluoromethoxy based compound, the method can realize the efficient difluoro-methoxy of reaction substrate, thus obtaining difluoro-methoxy substituted compound with high yield, the brand-new synthetic method of such intermediate is provided for field of medicaments, it is the very valuable novel technological method of one, there is the prospect that is extremely widely applied.
Summary of the invention
For many defects of above-mentioned existence, the present inventor, after having paid substantial amounts of creative work, proposes the synthetic method of a kind of difluoromethoxy based compound that can be used as medicine intermediate through further investigation.
Specifically, the invention provides the synthetic method of difluoromethoxy based compound shown in a kind of following formula (I),
Described method includes: in a solvent, and under catalyst, organic ligand and alkali exist, formula (II) compound and formula (III) compound react, thus obtaining formula (I) compound,
Wherein, R is H, C1-C6Alkyl, benzyl, halogen or nitro.
In the described synthetic method of the present invention, C1-C6Alkyl refers to the alkyl with 1-6 carbon atom, for instance can be methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, n-hexyl etc.
In the described synthetic method of the present invention, halogen can be fluorine, chlorine, bromine or iodine.
In the described synthetic method of the present invention, described catalyst is palladium acetylacetonate (Pd (acac)2), acid chloride (Pd (OAc)2), palladium trifluoroacetate (Pd (TFA)2), three (dibenzalacetone) two palladium (Pd2(dba)3), palladium sulfate, Palladous nitrate., dichloro diamino palladium (Pd (NH3)Cl2), (1,5-cyclo-octadiene) palladium chloride (PdCl2(cod) any in), it is most preferred that for (1,5-cyclo-octadiene) palladium chloride (PdCl2(cod))��
In the described synthetic method of the present invention, described organic ligand is phosphorus-containing ligand, and it is any one in following formula L1-L3:
It most preferably is L1.
In L2 or L3, Ph represents phenyl, and t-Bu represents the tert-butyl group.
In the described synthetic method of the present invention, described alkali is any one in Sodium ethylate, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, Feldalat NM etc., it is most preferred that for sodium tert-butoxide.
In the described synthetic method of the present invention, described solvent is any one in acetonitrile, N-Methyl pyrrolidone (NMP), dioxane, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), toluene, PEG400 (PEG-400), it is most preferred that for DMSO.
In the described synthetic method of the present invention, the consumption of described solvent is not particularly limited, and those skilled in the art may select suitable consumption, reacting balance is such as made to carry out, or post processing is prone to the amount carried out, and this belongs to ordinary skill in the art means, and this is no longer going to repeat them.
In the described synthetic method of the present invention, the mol ratio of described formula (II) compound and formula (III) compound is 1:1.5-2.5, for instance can be 1:1.5,1:2 or 1:2.5.
In the described synthetic method of the present invention, the mol ratio of described formula (II) compound and catalyst is 1:0.02-0.05, for instance can be 1:0.02,1:0.03,1:0.04 or 1:0.05.
In the described synthetic method of the present invention, the mol ratio of described formula (II) compound and alkali is 1:2-3, for instance can be 1:2,1:2.5 or 1:3.
In the described synthetic method of the present invention, the mol ratio of described formula (II) compound and organic ligand is 1:0.04-0.08, for instance can be 1:0.04,1:0.06 or 1:0.08.
In the described synthetic method of the present invention, reaction temperature is 60-90 DEG C, for instance can be 60 DEG C, 70 DEG C, 80 DEG C or 90 DEG C
In the described synthetic method of the present invention, the response time is 3-6 hour, for instance can be 3 hours, 4 hours, 5 hours or 6 hours.
In the described synthetic method of the present invention, react the post processing after terminating as follows: after completion of the reaction, naturally cool to room temperature, Enough Dl water is added in reaction system, it is sufficiently mixed, obtain mixed liquor, then extract 2-3 time with ether, merge organic facies, drying with anhydrous sodium sulfate, removal of solvent under reduced pressure, the silica gel column chromatography of residue 200-300 order is easily separated, wherein using volume ratio be 1:1.5-3 acetone and the mixed solvent of n-butyl alcohol as eluent, thus obtaining formula (I) compound.
As mentioned above; the described method of the present invention; by the selection of suitable catalyst, organic ligand, alkali and solvent and combination; thus obtain as the difluoromethoxy based compound of pharmaceutical intermediate, field can be synthesized in organic synthesis field and medicine intermediate and there is the prospect of industrialization widely, large-scale production using high yield.
Detailed description of the invention
Below by specific embodiment, the present invention is described in detail; but the purposes of these exemplary embodiments and purpose are only used for enumerating the present invention; not the real protection scope of the present invention is constituted any type of any restriction, more non-protection scope of the present invention is limited thereto.
Wherein, the organic ligand used is above-mentioned organic ligand.
Embodiment 1
Under room temperature, in the appropriate solvent DMSO in reaction vessel, add 100mmol formula (II) compound, 150mmol formula (III) compound, 2mmolPdCl2(cod), 4mmol organic ligand L1 and 200mmol sodium tert-butoxide, be then warming up to 60 DEG C under stirring, and reaction 6 hours at such a temperature.
After completion of the reaction, naturally cool to room temperature, in reaction system, add Enough Dl water, it is sufficiently mixed, obtain mixed liquor, then extract 2-3 time with ether, merge organic facies, dry with anhydrous sodium sulfate, removal of solvent under reduced pressure, the silica gel column chromatography of residue 200-300 order is easily separated, wherein using volume ratio be 1:1.5 acetone and the mixed solvent of n-butyl alcohol as eluent, thus obtaining above formula (I) compound, yield is 98.5%.
1H-NMR(400MHz,CDCl3) ��: 6.62 (t, J=73.5Hz, 1H), 2.65 (t, J=6.0Hz, 2H), 2.44 (t, J=6.6Hz, 2H), 2.07-1.95 (m, 2H), 1.73 (s, 3H).
MSm/z:177 (M+1,100).
Embodiment 2
Under room temperature, in the appropriate solvent DMSO in reaction vessel, add 100mmol formula (II) compound, 250mmol formula (III) compound, 5mmolPdCl2(cod), 6mmol organic ligand L1 and 250mmol sodium tert-butoxide, be then warming up to 80 DEG C under stirring, and reaction 5 hours at such a temperature.
After completion of the reaction, naturally cool to room temperature, in reaction system, add Enough Dl water, it is sufficiently mixed, obtain mixed liquor, then extract 2-3 time with ether, merge organic facies, dry with anhydrous sodium sulfate, removal of solvent under reduced pressure, the silica gel column chromatography of residue 200-300 order is easily separated, wherein using volume ratio be 1:2.5 acetone and the mixed solvent of n-butyl alcohol as eluent, thus obtaining above formula (I) compound, yield is 98.2%.
1H-NMR(400MHz,CDCl3) ��: 6.47 (t, J=72.0Hz, 1H), 5.44 (s, 1H), 2.52-2.33 (m, 2H), 2.16 (m, 2H), 2.01 (m, 1H), 1.08 (d, J=6.1Hz, 3H).
MSm/z:176 (M+1,100).
Embodiment 3
Under room temperature, in the appropriate solvent DMSO in reaction vessel, add 100mmol formula (II) compound, 200mmol formula (III) compound, 4mmolPdCl2(cod), 8mmol organic ligand L1 and 300mmol sodium tert-butoxide, be then warming up to 90 DEG C under stirring, and reaction 3 hours at such a temperature.
After completion of the reaction, naturally cool to room temperature, in reaction system, add Enough Dl water, it is sufficiently mixed, obtain mixed liquor, then extract 2-3 time with ether, merge organic facies, dry with anhydrous sodium sulfate, removal of solvent under reduced pressure, the silica gel column chromatography of residue 200-300 order is easily separated, wherein using volume ratio be 1:3 acetone and the mixed solvent of n-butyl alcohol as eluent, thus obtaining above formula (I) compound, yield is 98.6%.
1H-NMR(400MHz,CDCl3) ��: 7.26-7.13 (m, 5H), 6.58 (t, J=73.3Hz, 1H), 3.69 (s, 2H), 2.67 (t, J=6.1Hz, 2H), 2.46-2.38 (m, 2H), 2.15-1.97 (m, 2H).
MSm/z:252 (M+1,100).
Embodiment 4-24: the investigation of catalyst
Embodiment 4-6: respectively by the PdCl in embodiment 1-32(cod) Pd (acac) is replaced with2, other operation is all constant, and implements embodiment 4-6.
Embodiment 7-9: respectively by the PdCl in embodiment 1-32(cod) Pd (OAc) is replaced with2, other operation is all constant, and implements embodiment 7-9.
Embodiment 10-12: respectively by the PdCl in embodiment 1-32(cod) Pd (TFA) is replaced with2, other operation is all constant, and implements embodiment 10-12.
Embodiment 13-15: respectively by the PdCl in embodiment 1-32(cod) Pd is replaced with2(dba)3, other operation is all constant, and implements embodiment 13-15.
Embodiment 16-18: respectively by the PdCl in embodiment 1-32(cod) replacing with palladium sulfate, other operation is all constant, and implements embodiment 16-18.
Embodiment 19-21: respectively by the PdCl in embodiment 1-32(cod) replacing with Palladous nitrate., other operation is all constant, and implements embodiment 19-21.
Embodiment 22-24: respectively by the PdCl in embodiment 1-32(cod) Pd (NH is replaced with3)Cl2, other operation is all constant, and implements embodiment 22-24.
Concrete outcome is shown in table 1 below.
Table 1: the impact of catalyst
From upper table 1, when using other palladium catalyst, all causing that productivity significantly reduces, this proves PdCl2(cod) there is best catalytic effect.
Embodiment 25-33: the investigation of organic ligand
Embodiment 25-27: respectively the phosphorus-containing ligand L1 in embodiment 1-3 is replaced with L2, other operation is all constant, and implements embodiment 25-27.
Embodiment 28-30: respectively the phosphorus-containing ligand L1 in embodiment 1-3 is replaced with L3, other operation is all constant, and implements embodiment 28-30.
Embodiment 31-33: respectively the phosphorus-containing ligand L1 in embodiment 1-3 is replaced with triphenylphosphine, other operation is all constant, and implements embodiment 31-33.
Concrete outcome is shown in table 2 below.
Table 2: the impact of phosphorus-containing ligand
From upper table 2, when using other phosphorus-containing ligand, all causing that productivity significantly reduces, even if using the triphenylphosphine very similar with L1, its productivity also significantly reduces, and thus demonstrates L1 and has best concerted catalysis effect.
Embodiment 34-39: the investigation of alkali
Except adopting different alkali, being carried out example 34-39 with the same way of embodiment 1-3 respectively, used alkali, corresponding relation and products collection efficiency are shown in table 3 below.
Table 3: the impact of alkali
From upper table 3, the kind of alkali has significant impact for final result, and wherein sodium tert-butoxide has best effect, even if the potassium tert-butoxide very similar with it, its productivity also has significant reduction (being reduced to 88.4% by 98.2%).
Embodiment 40-45: the investigation of solvent
Except adopting different solvents, being carried out example 40-45 with the same way of embodiment 1-3 respectively, used solvent, corresponding relation and products collection efficiency are shown in table 4 below.
Table 4: the impact of solvent
From upper table 4, the kind of solvent has a degree of impact for final result, and wherein DMSO has a best solvent effect, and all decreases to some degree of other solvent.
As mentioned above, the invention provides the synthetic method of a kind of difluoromethoxy based compound that can be used as medicine intermediate, the method is by the mutually collaborative of suitable catalyst, organic ligand, alkali and solvent and/or combination, it is achieved thereby that the efficient difluoro-methoxy of reaction substrate, difluoro-methoxy substituted compound can be obtained with high yield, provide the brand-new synthetic method of such intermediate for field of medicaments, be the very valuable novel technological method of one, there is the prospect that is extremely widely applied.
Should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limit the scope of the invention. In addition; it is also contemplated that; after the technology contents having read the present invention, the present invention can be made various change, amendment and/or modification by those skilled in the art, and all these equivalent form of value falls within the application appended claims protection defined equally.