CN106905231A - The preparation method of 3- chloro-5-trifluoromethylpyridine class compounds and intermediate - Google Patents
The preparation method of 3- chloro-5-trifluoromethylpyridine class compounds and intermediate Download PDFInfo
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- DRJLEXZNEJBHFC-UHFFFAOYSA-N CCCC(c(cc1Cl)cnc1C#N)(F)F Chemical compound CCCC(c(cc1Cl)cnc1C#N)(F)F DRJLEXZNEJBHFC-UHFFFAOYSA-N 0.000 description 1
- YBBHJDKTEASWEP-MHPPCMCBSA-N CCOC(c1ncc(C(F)(F)[F][C@@H]2C(C)C2)cc1Cl)=O Chemical compound CCOC(c1ncc(C(F)(F)[F][C@@H]2C(C)C2)cc1Cl)=O YBBHJDKTEASWEP-MHPPCMCBSA-N 0.000 description 1
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/10—Spiro-condensed systems
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Abstract
The invention discloses a kind of 3- chloro-5-trifluoromethylpyridines class compound and the preparation method of intermediate.The preparation method of compound as shown in Equation 3 of the invention, it comprises the following steps：In the mixed solvent of organic solvent and water, in the presence of phase transfer catalyst, compound as shown in Equation 2 and metal cyanides are carried out into substitution reaction, compound as shown in Equation 3 is obtained；Further include following steps：In solvent, under fluorination reagent effect, compound as shown in Equation 1 is carried out into fluorination reaction, the compound as shown in Equation 2 is obtained；Also following steps can be further included：Under hydrogen chloride and ethanol effect, compound as shown in Equation 3 is carried out into Pinner reactions, be then hydrolyzed into ester reaction, compound as shown in Equation 4 is obtained.The preparation method low cost of 3- chloro-5-trifluoromethylpyridines class compound of the invention, production security is high, simple to operate, yield is higher, be more suitable for industrialized production.
Description
Technical field
The present invention relates to 3- chloro-5-trifluoromethylpyridine class compounds and the preparation method of intermediate.
Background technology
In terms of medicine, fluorine containing aromatic compound has very important work for a class medicine of active group
With as fluorine atom or fluoro-containing group (especially CF3Group) it is incorporated into drug molecule, its electronics effect
The distribution of intramolecule electron density should be changed with mimic effect, the acid of compound internal structure is have impact on
Alkalescence, and then its bioactivity is changed, and the fat-soluble of compound can also be improved, fluorine atom substitution
Hydrogen atom in compound, its dissolubility of class ester compounds on biomembrane is strengthened, and is promoted
Its transmission speed for absorbing in vivo, makes physiological action change, so many fluorochemicals
Than not fluorochemical on the pharmaceutical properties such as medicine, agricultural chemicals have consumption is few, toxicity is low, drug effect is high,
The strong advantage of metabolic capability.It is more next with the development and the expansion of searching medicine scope of medicament research and development technology
More medicines contain the structure of pyridine ring.Therefore the related intermediate of pyridine is used as the weight for introducing pyridine ring
Part is wanted, increasing attention, wide market is received.
3- chloro-5-trifluoromethylpyridine -2- Ethyl formates (CAS 128073-16-5), structural formula such as formula 4
It is shown, it is a kind of pyridine intermediate, there are two active groups of trifluoromethyl and ester group, it is special in many medicines
It is useful in profit or document, is a kind of drug molecule medicine for synthesizing treatment nerve degenerative diseases
Intermediate.But the few documents of synthetic route and technique or patent report of itself, and price compared with
It is high.
Following preparation method is disclosed in Chinese patent application CN 1372550A：
Although this patent reports a kind of method that can synthesize 2- cyano group -3- chloro-5-trifluoromethylpyridines,
It is the Cymag (excess) due to having used substantial amounts of DMAP (at least monovalent) and 1.5 equivalents.
DMAP expensive and it is not easily recycled, maximum problem is that DMAP can only lead in post processing
Cross plus hydrochloric acid is dissolved in water and could remove into salt, thus inevitably generate the hydrogen cyanide of severe toxicity, cause
Make post processing abnormally dangerous, particularly during industrialized production.Also, it is obtained using the method
After 2- cyano group -3- chloro-5-trifluoromethylpyridines, with reference to conventional Pinner reactions, then in conjunction with routine hydrolysis
3- chloro-5-trifluoromethylpyridine -2- Ethyl formates are prepared into ester reaction, total recovery is only 58.65%, raw material
High cost is unfavorable for industrialized production up to 917.79 yuan of (RMB)/Kg, high cost.
Following preparation method is disclosed in patent WO 2010018853：
This patent reports a kind of method that can be effectively synthesized the iodo- 5- trifluoromethyl pyridines of 2- cyano group -3-, but
Be this to synthesize 2- cyano group -3- chloro-5-trifluoromethylpyridines according to as above condition be infeasible, yield is very
It is low, and need to use the anhydrous potassium fluoride of three equivalents in reaction, it is relatively costly.
Following preparation method is disclosed in United States Patent (USP) US 6169183：
This patent reports a kind of method that can be effectively synthesized 3- chloro-5-trifluoromethylpyridine -1- Ethyl formates.
In the method, on the one hand, due to using expensive palladium and part；In addition, reaction has used play
Poison CO gas and need high pressure, this is needed in industrial amplification process, and special high pressure is special to be set
Standby, these two aspects causes that the synthesis cost of the route is special high, security is not good, high-tension apparatus is operated
It is cumbersome；Especially, the method total recovery is 92.26%, and cost of material is up to 1001.55 yuan (RMB)
/ Kg, high cost is unfavorable for industrialized production.
Therefore, develop that low cost, production security are high, simple to operate, be more suitable for industrialized production
The preparation method of 3- chloro-5-trifluoromethylpyridine class compounds, is this area technical problem urgently to be resolved hurrily.
The content of the invention
The technical problem to be solved in the present invention is to overcome 3- chloro-5-trifluoromethylpyridines in the prior art
The preparation method expensive starting materials of class compound, production cost are high, production safety hidden danger is serious, cumbersome,
Yield is low, be unfavorable for the defects such as industrialization, and provides a kind of 3- chloro-5-trifluoromethylpyridines class compound
And the preparation method of intermediate.The preparation method of 3- chloro-5-trifluoromethylpyridines class compound of the invention into
This low, production security is high, simple to operate, yield is higher, be more suitable for industrialized production.
The invention provides a kind of preparation method of compound as shown in Equation 3, it comprises the following steps：
In the mixed solvent of organic solvent and water, in the presence of phase transfer catalyst, by chemical combination as shown in Equation 2
Thing carries out substitution reaction with metal cyanides, and compound as shown in Equation 3 is obtained；
In the substitution reaction, the organic solvent can be various having used by the such reaction routine in this area
One kind or many in machine solvent, preferably sulfoxide type solvents, sulfone class solvent, amide solvent and nitrile solvents
Kind.The preferred sulfolane of sulfone class solvent.The preferred dimethylformamide of amide solvent and/or methyl
Pyrrolidones.The preferred acetonitrile of nitrile solvents.The preferred dimethyl sulfoxide (DMSO) of sulfoxide type solvents.
In the substitution reaction, the volume mass of the organic solvent and the compound as shown in Equation 2
Preferred 1.0ml/g~the 4.0ml/g of ratio；More preferably 1.3ml/g~1.6ml/g.
In the substitution reaction, the mass values preferably 0~2.0 of the organic solvent and the water；It is more excellent
Select 1.1~1.4.
In the substitution reaction, the phase transfer catalyst can be each used by the such reaction routine in this area
Plant phase transfer catalyst, preferably quaternary ammonium salt-type phase transfer catalyst.The quaternary ammonium salt-type phase transfer catalyst
It is preferred that alkane series quaternary ammonium salt-type phase transfer catalyst.The alkane series quaternary ammonium salt refers to four of quaternary ammonium salt
Alkyl is alkyl.The preferred halide ion of acid ion of the quaternary ammonium salt, more preferably fluorine ion, chlorine from
Son, bromide ion or iodide ion.The preferred tetra-n-butyl chlorine of alkane series quaternary ammonium salt-type phase transfer catalyst
Change amine and/or tetran-butylphosphonium bromide amine；More preferably tetran-butylphosphonium bromide amine.
In the substitution reaction, the phase transfer catalyst and the compound as shown in Equation 2 mole
Ratio preferably 0.005~0.2；More preferably 0.05~0.1.
In the present invention, the metal cyanides refers to the compound that metal ion and cyanide ion are constituted.
In the substitution reaction, the metal cyanides can be various used by the such reaction routine in this area
One or more in metal cyanides, preferably Cymag, potassium cyanide, zinc cyanide and cuprous cyanide；More
It is preferred that Cymag.
In the substitution reaction, the cyanogen root in the compound as shown in Equation 2 and the metal cyanides
The molar ratio of ion preferably 1.02~2.0；More preferably 1.1~1.3.
The temperature of the substitution reaction can be the various temperature used by the such reaction routine in this area, preferably
25 DEG C~80 DEG C；More preferably 45 DEG C~50 DEG C.
In the preparation method of the compound as shown in Equation 3, the process of the substitution reaction can be used
Routine monitoring method (such as TLC, HPLC, NMR or GC) is monitored in this area, typically
As reaction end when being disappeared with the compound as shown in Equation 2, the time preferably 6 of the substitution reaction
Hour~36 hours, further preferred 20 hours~22 hours.
The preparation method of the compound as shown in Equation 3, after the substitution reaction terminates, it is preferred that
Also can further include the operation of post processing.The method and condition of described post processing can be such for this area
Post-reaction treatment conventional method and condition, preferably using following post-processing step：After reaction terminates,
Extraction, concentration, you can.The extraction and concentration can be the routine operation of the such reaction in this area.Institute
State the preferred halogenated hydrocarbon solvent of extractant of extraction；The preferred dichloromethane of halogenated hydrocarbon solvent.It is described
Preferred 8.0ml/g~the 12.0ml/g of volume mass ratio of extractant and the compound as shown in Equation 2.
The extraction preferably first mixes reaction system with water before carrying out.During the reaction system mixes with water
Water and the compound as shown in Equation 2 the preferred 1.0ml/g~2.0ml/g of volume mass ratio.It is described
The method of the preferred distillation of concentration；The preferred vacuum distillation of distillation.
The preparation method of the compound as shown in Equation 3, preferably further comprises the following steps：Solvent
In, under fluorination reagent effect, compound as shown in Equation 1 is carried out into fluorination reaction, it is obtained described such as formula
Compound shown in 2；
The fluorination reaction is preferably carried out under the conditions of protective gas.The protective gas can be without this
The conventional protective gas in field；It is preferred that the protective gas is nitrogen.
In the fluorination reaction, the solvent can be the various solvents used by the such reaction routine in this area,
It is preferred that sulfoxide type solvents and/or sulfone class solvent.The preferred dimethyl sulfoxide (DMSO) of sulfoxide type solvents.The sulfone class
The preferred sulfolane of solvent.
In the fluorination reaction, the volume mass ratio of the solvent and the compound as shown in Equation 1
It is preferred that 1.0ml/g~5.0ml/g；More preferably 1.1ml/g~1.5ml.
In the fluorination reaction, the fluorination reagent can be the various fluorine used by the such reaction routine in this area
Change reagent, preferably metal fluoride.The metal fluoride refers to the change that metal ion is constituted with fluorine ion
Compound.The metal fluoride preferred fluorinated sodium and/or potassium fluoride；More preferably potassium fluoride.The metal fluorine
The preferred anhydrous metal fluoride of compound.
In the fluorination reaction, the molar ratio of the compound as shown in Equation 1 and the fluorination reagent
It is preferred that 1.05~2.00, more preferably 1.1~1.2.
The temperature of the fluorination reaction can be the various temperature used by the such reaction routine in this area, preferably
110 DEG C~150 DEG C, more preferably 115 DEG C~120 DEG C.
In the preparation method of the compound as shown in Equation 3, the process of the fluorination reaction can be used
Routine monitoring method (such as TLC, HPLC, NMR or GC) is monitored in this area, typically
As reaction end when being disappeared with the compound as shown in Equation 1, the time preferably 3 of the fluorination reaction
Hour~12 hours, further preferred 3 hours~5 hours.
It is preferred that the preparation method of the compound as shown in Equation 3, after the fluorination reaction terminates,
Reaction system is filtered and washed, reaction solution is obtained, the reaction solution without further work-up,
Directly carry out substitution reaction described in next step.
It is preferred that the preparation method of the compound as shown in Equation 3, after the fluorination reaction terminates,
Also can further include the operation of simple post processing.The operation of the simple post processing comprises the following steps：
By reaction system filtering, washing.The leacheate of the washing with the fluorination reaction solvent, and can be with
It is identical or different with the solvent in the reaction system.The consumption of the leacheate of the washing with it is described such as
Preferred 0.1ml/g~the 1.0ml/g of volume mass ratio of the compound shown in formula 1；More preferably
0.15ml/g~0.20ml.
The preparation method of the compound as shown in Equation 3, after the fluorination reaction terminates, it is preferred that
Also can further include the operation of post processing.The method and condition of described post processing can be such for this area
Post-reaction treatment conventional method and condition, preferably using following post-processing step：After reaction terminates,
Filtering, washing and rectifying.
The preparation method of the compound as shown in Equation 3 of the invention, it is preferred to use following reaction scheme
Carry out：
Present invention also offers a kind of preparation method of compound as shown in Equation 4, it comprises the following steps：
The compound as shown in Equation 3 is obtained according to the method described above；Then under hydrogen chloride and ethanol effect,
Compound as shown in Equation 3 is carried out into Pinner reactions, ester reaction is then hydrolyzed into, is obtained such as formula
Compound shown in 4；
In the Pinner reactions, the hydrogen chloride can participate in reaction in the way of hydrogen chloride gas,
Reaction can be participated in the form of ethanolic hydrogen chloride solution.
The preparation method of the compound as shown in Equation 4, preferably includes following steps：By the chlorination
Hydrogen and ethanol mix, and obtain the ethanol solution of hydrogen chloride, then by the ethanol solution of the hydrogen chloride with it is described
Compound as shown in Equation 3 is dissolved in the solution that organic solvent formed and is mixed.The organic solvent compared with
Be goodly alcohols solvent, one or more in aromatic hydrocarbon solvent and ether solvent.The alcohols solvent
Preferred alcohol.The preferred toluene of aromatic hydrocarbon solvent and/or dimethylbenzene.The preferred tetrahydrochysene of ether solvent
Furans and/or dioxane.The hydrogen chloride preferably mixes with the part ethanol in a gaseous form.It is described
The ethanol solution of the hydrogen chloride is molten with what remaining ethanol was formed with the compound as shown in Equation 3
Liquid be blended in when carrying out, and is preferably formed the compound as shown in Equation 3 and remaining ethanol
Solution is dropped in the mixture.The ethanol solution by the hydrogen chloride is as shown in Equation 3 with described
The solution that is formed with remaining ethanol of compound be blended in when carrying out, preferably at -5 DEG C~30 DEG C,
More preferably carried out under the conditions of 0 DEG C~5 DEG C (such as 30 DEG C).
The mass values of the ethanol and hydrogen chloride preferably 1~2；More preferably 1.4~1.6.
In the Pinner reactions, the ethanol is preferred with the mass values of compound as shown in Equation 3
4~16；More preferably 7.5~8.5, such as 7.9 or 8.0.
The temperature and time of the Pinner reactions can be separately this area conventional institute of such reaction
Various temperature and times.
Preferably 25 DEG C~80 DEG C of the temperature of the Pinner reactions；More preferably 75 DEG C~80 DEG C.
In the preparation method of the compound as shown in Equation 4, the process of the Pinner reactions can be adopted
It is monitored, one with routine monitoring method in this area (such as TLC, HPLC, NMR or GC)
As with the compound as shown in Equation 3 disappear when as reaction end.The time of the Pinner reactions is excellent
Select 19~24 hours.The Pinner reactions are preferably carried out under agitation.
It is preferred that the Pinner reactions are reacted 3~5 hours at 25 DEG C~30 DEG C, then at 40 DEG C
Reacted at~45 DEG C 12~14 hours, finally reacted 4~6 hours at 75 DEG C~80 DEG C.
After end, the ester that is hydrolyzed into is reacted before carrying out for the Pinner reactions, preferably first will be described
The reaction system of Pinner reactions is concentrated, and then again mixes the reaction system after concentration with water.
Described to be hydrolyzed into ester reaction, the volume mass of the water and the compound as shown in Equation 3 is than excellent
Select 1~10；More preferably 2.5~3.0, such as 2.7.
The temperature for being hydrolyzed into ester reaction can be the various temperature used by the such reaction routine in this area, excellent
Select 0 DEG C~40 DEG C；More preferably 25 DEG C~30 DEG C.
In the preparation method of the compound as shown in Equation 4, the process for being hydrolyzed into ester reaction can be with
It is monitored using routine monitoring method in this area (such as TLC, HPLC, NMR or GC),
As reaction end when typically being disappeared with ammonium chloride.Preferably 1~6 hour time for being hydrolyzed into ester reaction.
The preparation method of the compound as shown in Equation 4, it is described be hydrolyzed into ester reaction terminate after, compared with
Goodly, also can further include the operation of post processing.The method and condition of described post processing can be ability
The such post-reaction treatment in domain conventional method and condition, preferably using following post-processing step：Reaction knot
Shu Hou, extraction, washing, concentration, rectifying.The preferred halogenated hydrocarbon solvent of extractant of the extraction；Institute
State the preferred dichloromethane of halogenated hydrocarbon solvent.The volume of the extractant is excellent with the ratio of the volume of the water
Elect 1~1.5 as.The extraction preferably carries out three times and merges organic phase.The washing is preferably using alkalescence
The aqueous solution is washed.The preferred sodium bicarbonate aqueous solution of alkaline aqueous solution.The sodium acid carbonate is water-soluble
The preferred saturated sodium bicarbonate aqueous solution of liquid.The washing is preferably washed till reaction system up to neutrality.The rectifying
It is preferred that rectification under vacuum.The preferred cut for collecting 120 DEG C~130 DEG C and 5mmHg~8mmHg of the rectifying.
The preparation method of the compound as shown in Equation 4, it is preferred to use following reaction scheme is carried out：
Present invention also offers a kind of preparation method of compound as shown in Equation 4, it comprises the following steps：
Compound as shown in Equation 3 is carried out into Pinner reactions, ester reaction is then hydrolyzed into, is obtained such as formula
Compound shown in 4；
The method and condition of the synthetic method of the compound as shown in Equation 4 are the same as those described above.
Present invention also offers a kind of preparation method of compound as shown in Equation 2, it comprises the following steps：
In solvent, under fluorination reagent effect, compound as shown in Equation 1 is carried out into fluorination reaction, be obtained such as formula
Compound shown in 2；
The method and condition of the synthetic method of compound as shown in Equation 2 of the invention are the same as those described above.
Present invention also offers a kind of preparation method of compound as shown in Equation 5, it comprises the following steps：
After compound as shown in Equation 4 is carried out into hydrolysis of ester group reaction, compound as shown in Equation 7 is obtained, so
The compound shown in compound as shown in Equation 7 and formula 6 is carried out into amidation process afterwards, is obtained such as formula 5
Shown compound；
The preparation method of compound as shown in Equation 5 of the present invention refers to patent WO2013148851
In 00231 section~00232 section record method.
In the present invention, the room temperature refers to that environment temperature is 10~35 DEG C.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can be combined, and obtain final product this
Invent each preferred embodiments.
The application quotes the full text of above-mentioned patent WO2013148851.
Agents useful for same of the present invention and raw material are commercially available.
Positive effect of the invention is：
1st, the method for the present invention is as shown in Equation 4 as raw material starts to prepare with compound as shown in Equation 1
Total recovery may be up to 65.10% during compound；And method of the present invention cost of material has compared to existing technology
Significantly reduce, can as little as 686.13 yuan (RMB)/Kg.
2nd, method of the present invention raw material is easy to get, and cost is relatively low, production security is high, simple to operate, fits
Close industrialized production.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but is not therefore limited the present invention to
Among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, according to normal
Rule method and condition, or selected according to catalogue.
Embodiment 1 (synthesis of the fluoro- 3- chloro-5-trifluoromethylpyridines of 2-)
Under the protection of nitrogen, to 2 of addition 178.7g (0.827mol) in four mouthfuls of round bottom baked bottle of 2L,
The DMSO of the chloro-5-trifluoromethylpyridines of 3- bis-, the anhydrous K F and 200mL of 57.6g (0.992mol),
The mixed liquor that will be obtained is heated to 115 DEG C~120 DEG C and is incubated 3~5 hours, is cooled to room temperature.Filtering,
And washed with the DMSO of 40mL and obtain the DMSO solution of the fluoro- 3- chloro-5-trifluoromethylpyridines of 2- and (treat
With).
Embodiment 1 ' (synthesis of the fluoro- 3- chloro-5-trifluoromethylpyridines of 2-)
Under the protection of nitrogen, to addition 17.9g (0.083mol) in four mouthfuls of round bottom baked bottle of 250mL
The chloro-5-trifluoromethylpyridines of 2,3- bis-, the aqueous KF and 20mL of 5.76g (0.099mol)
DMSO, the mixed liquor that will be obtained is heated to 115 DEG C~120 DEG C and is incubated 3~5 hours, is cooled to room temperature.
GC is surveyed in sampling, and raw material 1 all disappears, and only generates about 40% product, and generate about 53%
Dimer impurity.
Embodiment 2 (synthesis of the fluoro- 3- chloro-5-trifluoromethylpyridines of 2-)
Under the protection of nitrogen, to 2 of addition 178.7g (0.827mol) in four mouthfuls of round bottom baked bottle of 2L,
The DMSO of the chloro-5-trifluoromethylpyridines of 3- bis-, the anhydrous K F and 200mL of 57.6g (0.992mol),
The mixed liquor that will be obtained is heated to 115 DEG C~120 DEG C and is incubated 3~5 hours, is cooled to room temperature.Filtering,
And wash the DMSO solution for obtaining the fluoro- 3- chloro-5-trifluoromethylpyridines of 2- with the DMSO of 40mL,
50~55 DEG C/11mmHg cuts are collected in rectification under vacuum, obtain the chloro- 5- trifluoromethyls of the fluoro- 3- of colourless liquid 2-
Pyridine, up to 98.3%, yield reaches 93.6% to GC purity.
Embodiment 3 (synthesis of 2- cyano group -3- chloro-5-trifluoromethylpyridines)
To NaCN, 13.4 that 44.6g (0.910mol) is added in the reaction solution obtained in above-described embodiment 1
TBAB the and 200mL water of g (0.0415mol), the mixed liquor that will be obtained is stirred at 45 DEG C~50 DEG C
After mixing reaction 20~22 hours, water is added, and extracted with dichloromethane, the organic layer concentration for obtaining is steamed
Evaporate the 2- cyano group -3- chloro-5-trifluoromethylpyridines of the light yellow liquid for obtaining 127g, yield 74.3%, GC
Purity 99.33%.
About 20 milligrams of 2- cyano group -3- chloro-5-trifluoromethylpyridines are taken to be dissolved in 1 milliliter of deuterochloroform, in
Hydrogen spectrum is measured in 400000000 Bruker nuclear magnetic resonance spectrometers；According to the nuclear magnetic data of products therefrom, checking gained is produced
Product are 2- cyano group -3- chloro-5-trifluoromethylpyridines.
1H NMR(CDCl3,400MHz)：8.14(s,1H,Ar-H)；8.86(s,1H,Ar-H).
Comparative example 1 (synthesis of 2- cyano group -3- chloro-5-trifluoromethylpyridines)
Under the protection of nitrogen, to addition 17.9g (0.083mol) in four mouthfuls of round bottom baked bottle of 250mL
The chloro-5-trifluoromethylpyridines of 2,3- bis-, the anhydrous K F and 20mL of 5.76g (0.099mol)
DMSO, the mixed liquor that will be obtained is heated to 115 DEG C~120 DEG C and is incubated 3~5 hours, is cooled to room temperature.
Filtering, and washed with the DMSO of 4mL obtain the fluoro- 3- chloro-5-trifluoromethylpyridines of 2- DMSO it is molten
Liquid (stand-by).
To NaCN the and 20mL water that 4.46g (0.091mol) is added in above-mentioned reaction solution, by what is obtained
In at 45 DEG C~50 DEG C, after 20~22 hours, HPLC is surveyed in sampling to stirring reaction to mixed liquor, and raw material 2 is complete
All disappear, only generate about 10% product, and generate substantial amounts of unknown impuritie.
Embodiment 4 (synthesis of 3- chloro-5-trifluoromethylpyridine -1- Ethyl formates)
To adding the absolute ethyl alcohol of 863g in four mouthfuls of round bottom baked bottle of 3L, and it is cooled to 0 DEG C~5 DEG C, leads to
Enter HCl gases 4~5 hours, discovery system quality of weighing stops logical HCl gases after increased 575g,
Obtain the ethanol solution of hydrogen chloride.By the chloro- 5- trifluoromethyls pyrroles of 2- cyano group -3- of 110g (0.533mol)
Pyridine is dissolved in 15g ethanol, in above-mentioned system is added dropwise at 30 DEG C, and in 30 DEG C of stirring reactions
3 hours.System is warmed up to 45 DEG C, and in 45 DEG C of stirring reactions 12 hours.System is warmed up to 75 DEG C
~80 DEG C, and in 75 DEG C~80 DEG C stirring reactions 4 hours.Ethanol is fallen in concentration, and adds 300mL water,
And in 25 DEG C~30 DEG C stirring reactions 2 hours.The system for obtaining is extracted with 3 × 300mL dichloromethane,
Merge organic layer, and washed to neutrality with 100mL saturated sodium bicarbonate aqueous solutions.Dichloromethane is fallen in concentration
Evaporating under the conditions of 120 DEG C~130 DEG C and 5mmHg~8mmHg is collected in alkane, residue rectification under vacuum
Get 118.3g colourless liquids, yield obtains 87.6%, GC purity 99.58%.
About 20 milligrams of 3- chloro-5-trifluoromethylpyridine -1- Ethyl formates are taken to be dissolved in 1 milliliter of deuterochloroform,
Hydrogen spectrum is measured in 400,000,000 Bruker nuclear magnetic resonance spectrometers；According to the nuclear magnetic data of products therefrom, checking gained
Product is 3- chloro-5-trifluoromethylpyridine -1- Ethyl formates.The total recovery of above-mentioned reaction is 65.10%.
1H NMR(CDCl3,400MHz)：1.40 (t, 3H, J=7.2Hz ,-CH3)；8.56 (q, 2H, J=
7.2Hz,-CH2),8.10(s,1H,Ar-H)；8.76(s,1H,Ar-H).
Embodiment 3 ' (synthesis of 3- chloro-5-trifluoromethylpyridine -1- Ethyl formates)
To adding the absolute ethyl alcohol of 86g in four mouthfuls of round bottom baked bottle of 250mL, and it is cooled to 0 DEG C~5 DEG C,
It is passed through HCl gases 2~3 hours, discovery system quality of weighing stops logical HCl gases after increased 37g,
Obtain the ethanol solution of hydrogen chloride.By the chloro- 5- trifluoromethyls pyrroles of 2- cyano group -3- of 11.0g (0.053mol)
Pyridine is dissolved in 2g ethanol, in above-mentioned system is added dropwise at 30 DEG C, and in 30 DEG C of stirring reactions 3
Hour.System is warmed up to 45 DEG C, and in 45 DEG C of stirring reactions 12 hours.System is warmed up to 75 DEG C
~80 DEG C, and in 75 DEG C~80 DEG C stirring reactions 4 hours.Ethanol is fallen in concentration, and adds 30mL water,
And in 25 DEG C~30 DEG C stirring reactions 2 hours.HPLC is surveyed in sampling, and the compound 3 that there is also about 10% does not have
There is reaction.
Embodiment 4 ' (synthesis of 3- chloro-5-trifluoromethylpyridine -1- Ethyl formates)
To adding the absolute ethyl alcohol of 86g in four mouthfuls of round bottom baked bottle of 250mL, and it is cooled to 0 DEG C~5 DEG C,
It is passed through HCl gases 4~5 hours, discovery system quality of weighing stops logical HCl gases after increased 57g,
Obtain the ethanol solution of hydrogen chloride.By the chloro- 5- trifluoromethyls pyrroles of 2- cyano group -3- of 11.0g (0.053mol)
Pyridine is dissolved in 2g ethanol, in above-mentioned system is added dropwise at 30 DEG C, and in 30 DEG C of stirring reactions
24 hours.HPLC is surveyed in sampling, and the compound 3 that there is also about 70% does not react.
Embodiment 5 ' (synthesis of 3- chloro-5-trifluoromethylpyridine -1- Ethyl formates)
To adding the absolute ethyl alcohol of 86g in four mouthfuls of round bottom baked bottle of 250mL, and it is cooled to 0 DEG C~5 DEG C,
It is passed through HCl gases 4~5 hours, discovery system quality of weighing stops logical HCl gases after increased 57g,
Obtain the ethanol solution of hydrogen chloride.By the chloro- 5- trifluoromethyls pyrroles of 2- cyano group -3- of 11.0g (0.053mol)
Pyridine is dissolved in 2g ethanol, in above-mentioned system is added dropwise at 30 DEG C, and in 30 DEG C of stirring reactions 3
Hour.System is warmed up to 45 DEG C, and in 45 DEG C of stirring reactions 12 hours.HPLC is surveyed in sampling, also
The compound 3 for having about 30% does not react.
Embodiment 5 (synthesis of compound as shown in Equation 5)
By obtained 3- chloro-5-trifluoromethylpyridines -1- Ethyl formates in embodiment 3, according to patent
WO201314885100231 sections~00232 section method of record, prepare compound 5, reaction equation is as follows：
Wherein compound 5 has good pharmaceutical activity, treats nerve degenerative diseases.
Claims (10)
1. a kind of preparation method of compound as shown in Equation 3, it is characterised in that it includes following step
Suddenly：In the mixed solvent of organic solvent and water, in the presence of phase transfer catalyst, will be as shown in Equation 2
Compound carries out substitution reaction with metal cyanides, and compound as shown in Equation 3 is obtained；
2. preparation method as claimed in claim 1, it is characterised in that：
In the substitution reaction, the organic solvent is sulfoxide type solvents, sulfone class solvent, amide solvent
With one or more in nitrile solvents；
And/or, in the substitution reaction, the body of the organic solvent and the compound as shown in Equation 2
Product mass values are 1.0ml/g~4.0ml/g；
And/or, in the substitution reaction, the organic solvent is 0~2.0 with the mass values of the water；
And/or, in the substitution reaction, the phase transfer catalyst is quaternary ammonium salt-type phase transfer catalyst；
And/or, in the substitution reaction, the phase transfer catalyst and the compound as shown in Equation 2
Molar ratio be 0.005~0.2；
And/or, in the substitution reaction, the metal cyanides be Cymag, potassium cyanide, zinc cyanide and
One or more in cuprous cyanide；
And/or, in the substitution reaction, in the compound as shown in Equation 2 and the metal cyanides
Cyanide ion molar ratio be 1.02~2.0；
And/or, the temperature of the substitution reaction is 25 DEG C~80 DEG C；
And/or, the time of the substitution reaction is 6 hours~36 hours.
3. preparation method as claimed in claim 2, it is characterised in that：
The sulfone class solvent is sulfolane；
And/or, the amide solvent is dimethylformamide and/or methyl pyrrolidone；
And/or, the nitrile solvents are acetonitrile；
And/or, the sulfoxide type solvents are dimethyl sulfoxide (DMSO)；
And/or, in the substitution reaction, the body of the organic solvent and the compound as shown in Equation 2
Product mass values are 1.3ml/g~1.6ml/g；
And/or, in the substitution reaction, the organic solvent is 1.1~1.4 with the mass values of the water；
And/or, the quaternary ammonium salt-type phase transfer catalyst is alkane series quaternary ammonium salt-type phase transfer catalyst；
And/or, in the substitution reaction, the phase transfer catalyst and the compound as shown in Equation 2
Molar ratio be 0.05~0.1；
And/or, in the substitution reaction, in the compound as shown in Equation 2 and the metal cyanides
Cyanide ion molar ratio be 1.1~1.3；
And/or, the temperature of the substitution reaction is 45 DEG C~50 DEG C；
And/or, the time of the substitution reaction is 20 hours~22 hours.
4. preparation method as claimed in claim 3, it is characterised in that：The alkane series quaternary ammonium salt
Class phase transfer catalyst is tetra-n-butyl ammonium chloride and/or tetran-butylphosphonium bromide amine.
5. the preparation method as any one of Claims 1 to 4, it is characterised in that：It is described such as formula 3
The preparation method of shown compound, further includes following steps：In solvent, under fluorination reagent effect,
Compound as shown in Equation 1 is carried out into fluorination reaction, the compound as shown in Equation 2 is obtained；
6. preparation method as claimed in claim 5, it is characterised in that：
The fluorination reaction is carried out under the conditions of protective gas；
And/or, in the fluorination reaction, the solvent is sulfoxide type solvents and/or sulfone class solvent；
And/or, in the fluorination reaction, the volume matter of the solvent and the compound as shown in Equation 1
Amount ratio is 1.0ml/g~5.0ml/g；
And/or, in the fluorination reaction, the fluorination reagent is metal fluoride；
And/or, in the fluorination reaction, the compound as shown in Equation 1 rubs with the fluorination reagent
Your ratio is 1.05~2.00；
And/or, the temperature of the fluorination reaction is 110 DEG C~150 DEG C；
And/or, the time of the fluorination reaction is 3 hours~12 hours；
And/or, the preparation method of the compound as shown in Equation 3, after the fluorination reaction terminates,
Reaction system is filtered and washed, reaction solution is obtained, the reaction solution without further work-up,
Directly carry out substitution reaction described in next step.
7. preparation method as claimed in claim 6, it is characterised in that：
The protective gas is nitrogen；
And/or, in the fluorination reaction, the sulfoxide type solvents are dimethyl sulfoxide (DMSO)；
And/or, in the fluorination reaction, the sulfone class solvent is sulfolane；
And/or, in the fluorination reaction, the volume matter of the solvent and the compound as shown in Equation 1
Amount ratio is 1.1ml/g~1.5ml；
And/or, in the fluorination reaction, the metal fluoride is sodium fluoride and/or potassium fluoride；
And/or, in the fluorination reaction, the compound as shown in Equation 1 rubs with the fluorination reagent
Your ratio is 1.1~1.2；
And/or, the temperature of the fluorination reaction is 115 DEG C~120 DEG C；
And/or, the time of the fluorination reaction is 3 hours~5 hours.
8. a kind of preparation method of compound as shown in Equation 4, it is characterised in that it includes following step
Suddenly：According to the preparation method any one of claim 1~7 be obtained as described in change as shown in Equation 3
Compound；Then under hydrogen chloride and ethanol effect, compound as shown in Equation 3 is carried out into Pinner reactions,
Then ester reaction is hydrolyzed into, compound as shown in Equation 4 is obtained；
9. preparation method as claimed in claim 8, it is characterised in that：
The preparation method of the compound as shown in Equation 4, comprises the following steps：By the hydrogen chloride and
Ethanol mix, obtain the ethanol solution of hydrogen chloride, then by the ethanol solution of the hydrogen chloride with described such as formula
Compound shown in 3 is dissolved in the solution that organic solvent formed and is mixed；
And/or, in the Pinner reactions, the mass values of the ethanol and hydrogen chloride are 1~2；
And/or, in Pinner reaction, the mass ratio of the ethanol and compound as shown in Equation 3
Be worth is 4~16；
And/or, the temperature of the Pinner reactions is 25 DEG C~80 DEG C；
And/or, the time of the Pinner reactions is 19~24 hours；
And/or, the Pinner reactions are carried out under agitation；
And/or, described to be hydrolyzed into ester reaction, the volume matter of the water and the compound as shown in Equation 3
Amount is than being 1~10；
And/or, the temperature for being hydrolyzed into ester reaction is 0 DEG C~40 DEG C；
And/or, the time for being hydrolyzed into ester reaction is 1~6 hour.
10. preparation method as claimed in claim 8, it is characterised in that：The Pinner reactions exist
Reacted at 25 DEG C~30 DEG C 3~5 hours, then reacted 12~14 hours at 40 DEG C~45 DEG C, finally existed
Reacted 4~6 hours at 75 DEG C~80 DEG C.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110498767A (en) * | 2019-09-26 | 2019-11-26 | 重庆医药高等专科学校 | The synthetic method of the chloro- 2- cyanopyridine of 3,5- bis- |
| CN112390746A (en) * | 2020-11-03 | 2021-02-23 | 内蒙古佳瑞米精细化工有限公司 | Method for inhibiting generation of 2-cyano-3-chloro-5-trifluoromethylpyridine precursor impurity |
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| CN1372550A (en) * | 1999-09-07 | 2002-10-02 | 阿方蒂农科有限公司 | Process for the preparation of 2-cyanopyridines |
| CN1778794A (en) * | 2004-11-19 | 2006-05-31 | 姜堰市康鹏农化有限公司 | Method for synthesizing 2-chloro-5-trifluoromethylpyridine |
| WO2010018853A1 (en) * | 2008-08-13 | 2010-02-18 | 石原産業株式会社 | Pyridyl-triazolopyrimidine derivative or salt thereof, and harmful organism control agent comprising the same |
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- 2015-12-23 CN CN201510981601.XA patent/CN106905231A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1372550A (en) * | 1999-09-07 | 2002-10-02 | 阿方蒂农科有限公司 | Process for the preparation of 2-cyanopyridines |
| CN1778794A (en) * | 2004-11-19 | 2006-05-31 | 姜堰市康鹏农化有限公司 | Method for synthesizing 2-chloro-5-trifluoromethylpyridine |
| WO2010018853A1 (en) * | 2008-08-13 | 2010-02-18 | 石原産業株式会社 | Pyridyl-triazolopyrimidine derivative or salt thereof, and harmful organism control agent comprising the same |
| JP2010065026A (en) * | 2008-08-13 | 2010-03-25 | Ishihara Sangyo Kaisha Ltd | Pyridyl-triazolopyrimidine derivative or salt of the same, and noxious organism remover containing them |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110498767A (en) * | 2019-09-26 | 2019-11-26 | 重庆医药高等专科学校 | The synthetic method of the chloro- 2- cyanopyridine of 3,5- bis- |
| CN112390746A (en) * | 2020-11-03 | 2021-02-23 | 内蒙古佳瑞米精细化工有限公司 | Method for inhibiting generation of 2-cyano-3-chloro-5-trifluoromethylpyridine precursor impurity |
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