CN103288718A - Preparation method of 2-chloro-5-tirfluoromethylpyridine - Google Patents
Preparation method of 2-chloro-5-tirfluoromethylpyridine Download PDFInfo
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- CN103288718A CN103288718A CN2013102612243A CN201310261224A CN103288718A CN 103288718 A CN103288718 A CN 103288718A CN 2013102612243 A CN2013102612243 A CN 2013102612243A CN 201310261224 A CN201310261224 A CN 201310261224A CN 103288718 A CN103288718 A CN 103288718A
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- VXLYOURCUVQYLN-UHFFFAOYSA-N Cc(cn1)ccc1Cl Chemical compound Cc(cn1)ccc1Cl VXLYOURCUVQYLN-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a preparation method of 2-chloro-5-tirfluoromethylpyridine. The invention provides a preparation method of 2-chloro-5-tirfluoromethylpyridine, and the preparation method comprises the following steps of: reacting 2-chloro-5-trichloromethylpyridine with hydrogen fluoride in a closed system in the presence of a catalyst to obtain the 2-chloro-5-tirfluoromethylpyridine, wherein the catalyst is antimony trioxide and/or antimony pentoxide. The invention further provides a preparation method of a compound 2, and the preparation method comprises the following steps of: reacting a compound 3 with ammonia in the presence of alkali to obtain the compound 2. The preparation method provided by the invention is cheap and liable to obtain raw materials, low in cost, few in reaction by-products, simple in post treatment, safe to operate, environment-friendly and suitable for large-scale industrial production.
Description
Technical field
The present invention relates to the preparation method of 2-chloro-5-5-flumethiazine.
Background technology
2-chloro-5-5-flumethiazine is a kind of fluorine-containing, heterocycle organic intermediate that using value is arranged very much, is to produce weedicide fluazifop and hydroxyl penta standing grain spirit, and the key intermediate of kind such as sterilant ZEN 90160.Also can be used to develop important fine-chemical intermediate simultaneously as 2,3-, two chloro-5-5-flumethiazines, 2-hydroxyl-5-5-flumethiazine, 2-hydroxyl-3-chloro-5-5-flumethiazine and 2-amino-5-5-flumethiazine etc.
The synthetic method of the 2-chloro-5-5-flumethiazine of having reported at present, mainly contains following three kinds:
One, be raw material with the 3-picoline, through superchlorination (CN1772380, CN102452977 and US2005240024) with fluoridize (GB1599123, US4567273 and US4680406) and obtain 2-chloro-5-5-flumethiazine;
Two, with the cyclopentadiene be raw material, warp and propenal condensation, again under alkaline condition with the vinyl cyanide condensation, cracking gets 4-aldehyde radical-allyl acetonitrile, again through chlorination, cyclization can get 2-chloro-5-chloromethylpyridine (CN101948424), last further chlorination and fluoridize after must 2-chloro-5-5-flumethiazine;
Three, with the benzylamine be raw material; after the propionic aldehyde condensation; after acetylize and cyclization, can get 2-chloro-5-picoline (CN102285913, US5304651, " agricultural chemicals "; 2004; 43 (10): 458-459 and " Zhejiang chemical industry "; 2005,36 (6): 19-20), get 2-chloro-5-5-flumethiazine finally by chlorination with after fluoridizing.
More than in three kinds of methods, it is raw material that method one adopts the 3-picoline, because raw materials cost is higher, so the relative method two of this operational path and method three do not have cost advantage; (0 ° of C) is low for the employed cyclopentadiene flash-point of method two, danger is bigger in the operating process, and propenal belongs to volatile hypertoxic chemical, can produce the high boiling material that 30% left and right sides viscosity has the special odor of aldehyde radical and itrile group thing greatly in the cracking process, simultaneously because this method reaction conditions is harsh relatively, whole prod production process electric energy consumption is not all possessing advantage with big aspect environmental protection, safety and the energy consumption; Though can be with the benzyl chlorine that produces in a large number as by-product recovery in the technological process of method three, but the benzyl chlorine that reclaims is except meeting occupies production site, accumulate for a long time and also may cause potential danger (CN102285913, US5304651 and " agricultural chemicals ", 2004,43 (10): 458-459).
" Zhejiang chemical industry " (2005,36 (6): 19-20) reported method has adopted phosphorus oxychloride as cyclization reagent in the cyclization step, causes having in the aftertreatment of cyclization step a large amount of phosphoric acid salt to produce, and has increased the solid useless cost of handling.
The flaorination process of reporting in the prior art (as GB1599123 and CN1342648) need to use expensive trivalent halo stibnide (GB1599123) and pentavalent halo stibnide (CN101062914), and halo stibnide cost higher, should not put for a long time, easy deliquescence, Workshop Production problems such as initiation personal security accident that feed intake easily.
Summary of the invention
Technical problem to be solved by this invention is in order to overcome preparation method's cost of material height of existing 2-chloro-5-5-flumethiazine, the cost height, reaction raw materials toxicity is big, operational hazards, byproduct of reaction is many, and Atom economy is poor, the aftertreatment difficulty, defectives such as environmental pollution is serious, and a kind of preparation method of 2-chloro-5-5-flumethiazine is provided.Preparation method of the present invention, raw material is cheap and easy to get, and cost is low, and byproduct of reaction is few, and aftertreatment is simple, operational safety, environmental friendliness is suitable for large-scale industrial production.
The invention provides the preparation method of 2-chloro-5-5-flumethiazine, it may further comprise the steps: in enclosed system, under the condition that catalyzer exists, 2-chloro-5-nitrapyrin and hydrogen fluoride are reacted, obtain 2-chloro-5-5-flumethiazine; Described catalyzer is antimonous oxide and/or antimony peroxide,
The method of the described 2-of preparation chloro-5-5-flumethiazine can be for carrying out the ordinary method of such reaction, preferred especially following reaction method and condition among the present invention in this area:
In the described method for preparing 2-chloro-5-5-flumethiazine, the per-cent of the quality of described catalyzer and described 2-chloro-5-nitrapyrin quality is preferred 0.1%～10%, and further preferred 0.1%～2%.
In the described method for preparing 2-chloro-5-5-flumethiazine, described hydrogen fluoride can be hydrogen fluoride gas or anhydrous hydrogen fluoride; Preferred 3:1～the 15:1 of mol ratio of described hydrogen fluoride and described 2-chloro-5-nitrapyrin, further preferred 3:1～5:1.
In the described method for preparing 2-chloro-5-5-flumethiazine, preferred 150 ℃～250 ℃ of the temperature of described reaction, further preferred 160 ℃～210 ℃, further preferred 180 ℃～200 ℃ again.
In the described method for preparing 2-chloro-5-5-flumethiazine, the preferred 2MPa～10MPa of the pressure of described reaction, further preferred 4MPa～6MPa.
In the described method for preparing 2-chloro-5-5-flumethiazine, the process of described reaction can adopt the conventionally test method (as GC) in this area to determine, detecting 2-chloro-5-5-flumethiazine content with GC is reaction end greater than 90%, preferred 5h～15h of reaction times, further preferred 5h～10h.
The method of the described 2-of preparation chloro-5-5-flumethiazine preferably includes following steps: in enclosed system, under the anhydrous condition, in the 2-of fusion chloro-5-nitrapyrin, add catalyzer, react with hydrogen fluoride then, obtain 2-chloro-5-5-flumethiazine; Described catalyzer is antimonous oxide and/or antimony peroxide.
In the described method for preparing 2-chloro-5-5-flumethiazine, described 2-chloro-5-nitrapyrin can adopt following method preparation, it may further comprise the steps: under the condition of light and/or initiator existence, 2-chloro-5-picoline and chlorine are reacted, obtain 2-chloro-5-nitrapyrin;
Making 2-chloro-5-5-flumethiazine according to the method for the described 2-of preparation chloro-5-5-flumethiazine again gets final product.
The employed chlorination method of described preparation 2-chloro-5-nitrapyrin can be for carrying out the ordinary method of such reaction, preferred especially following reaction method and condition among the present invention in this area:
In the described method for preparing 2-chloro-5-nitrapyrin, described reaction can be carried out in solvent or under the solvent-free condition; Be reflected at when carrying out in the solvent the preferred halogenated hydrocarbon solvent of described solvent and/or halogenated aryl hydrocarbon kind solvent when described; The preferred chlorinated hydrocarbon solvent of described halogenated hydrocarbon solvent; In the preferred methylene dichloride of described chlorinated hydrocarbon solvent, trichloromethane, tetracol phenixin and the ethylene dichloride one or more; In the preferred chlorobenzene of described halogenated aryl hydrocarbon kind solvent, orthodichlorobenzene, Meta Dichlorobenzene and the santochlor one or more; In the further preferred tetracol phenixin of described solvent, orthodichlorobenzene, Meta Dichlorobenzene and the santochlor one or more.
In the described method for preparing 2-chloro-5-nitrapyrin, be reflected at when carrying out in the solvent when described, the ratio of the quality of the quality of described solvent and described 2-chloro-5-picoline is preferred 1～20, and more preferably 1～5.
In the described method for preparing 2-chloro-5-nitrapyrin, one or more in the preferred Diisopropyl azodicarboxylate of described initiator, phosphorus trichloride, ammonium persulphate and the benzoyl peroxide; Further preferred phosphorus trichloride and/or Diisopropyl azodicarboxylate; Preferred 300nm～the 500nm of described light wavelength.
In the described method for preparing 2-chloro-5-nitrapyrin, the ratio of the quality of the quality of described initiator and described 2-chloro-5-picoline is preferred 0.01～0.8, and further preferred 0.02～0.07.
In the described method for preparing 2-chloro-5-nitrapyrin, the preferred 3:1～10:1 of mol ratio of described chlorine and described 2-chloro-5-picoline, further preferred 3:1～5:1.
In the described method for preparing 2-chloro-5-nitrapyrin, preferred 30 ℃～180 ℃ of the temperature of described reaction, further preferred 80 ℃～150 ℃.
In the described method for preparing 2-chloro-5-nitrapyrin, the process of described reaction can adopt the conventionally test method (as GC) in this area to determine, detecting 2-chloro-5-nitrapyrin content with GC is reaction end greater than 90%, preferred reaction time 5h～20h, further preferred 5h～15h.
The method of the described 2-of preparation chloro-5-nitrapyrin preferably includes following steps: with the solution of 2-chloro-5-picoline and initiator, react with chlorine at 30 ℃～180 ℃, obtain 2-chloro-5-nitrapyrin; Perhaps, with the solution of 2-chloro-5-picoline, add initiator at 30 ℃～180 ℃, and then react with chlorine, obtain 2-chloro-5-nitrapyrin.The solvent that adopts in the solution of described 2-chloro-5-picoline and initiator is for preparing the solvent that adopts in the method for 2-chloro-5-nitrapyrin.
In the described method for preparing 2-chloro-5-nitrapyrin, described 2-chloro-5-picoline can adopt following method preparation, it may further comprise the steps: in solvent, with chlorination reagent, N, N-two substituted formamides and compound 1 react and obtain 2-chloro-5-picoline;
According to the described method for preparing 2-chloro-5-nitrapyrin, the method for the described 2-of preparation chloro-5-5-flumethiazine makes 2-chloro-5-5-flumethiazine and gets final product again; Wherein, R is selected from hydrogen, halogen (for example fluorine, chlorine, bromine or iodine) and C
1～C
3Straight or branched alkyl (for example methyl, ethyl, propyl group or sec.-propyl) in one or more, when R was a plurality of substituting group, described substituting group can be the same or different; Described N, being substituted by by C described in N-two substituted formamides
1～C
4The straight or branched alkyl replace.
The method of the described 2-of preparation chloro-5-picoline can be for carrying out the ordinary method of such reaction, preferred especially following reaction method and condition among the present invention in this area:
Compound 1 described in the present invention is the alkene of transconfiguration structure.
In the described method for preparing 2-chloro-5-picoline, one or more in the preferred halogenated hydrocarbon solvent of described solvent, halogenated aryl hydrocarbon kind solvent and the aromatic hydrocarbon solvent; The preferred chlorinated hydrocarbon solvent of described halogenated hydrocarbon solvent; In the preferred methylene dichloride of described chlorinated hydrocarbon solvent, trichloromethane, tetracol phenixin and the ethylene dichloride one or more; In the preferred chlorobenzene of described halogenated aryl hydrocarbon kind solvent, orthodichlorobenzene, Meta Dichlorobenzene and the santochlor one or more; In the preferred toluene of described aromatic hydrocarbon solvent, o-Xylol, p-Xylol and the m-xylene one or more; In the further preferred chlorobenzene of described solvent, orthodichlorobenzene, Meta Dichlorobenzene and the santochlor one or more, further preferred chlorobenzene.
In the described method for preparing 2-chloro-5-picoline, the ratio of the quality of the quality of described solvent and described compound 1 is preferred 1～10, and further preferred 1～5.
In the described method for preparing 2-chloro-5-picoline, in the preferred phosphorus oxychloride of described chlorination reagent, phosphorus pentachloride, triphosgene, trichloromethylchloroformate, phosgene, sulfur oxychloride and the oxalyl chloride one or more, in further preferred phosphorus oxychloride, phosphorus pentachloride, triphosgene, the trichloromethylchloroformate photoreactive gas one or more, one or more in further preferred triphosgene, the trichloromethylchloroformate photoreactive gas again.
In the described method for preparing 2-chloro-5-picoline, when described chlorination reagent is triphosgene, the preferred 0.6:1～2:1 of mol ratio of described chlorination reagent and described compound 1, further preferred 0.6:1～1:1; When described chlorination reagent is trichloromethylchloroformate, the preferred 1:1～2.5:1 of mol ratio of described chlorination reagent and described compound 1, further preferred 1:1～1.5:1; During other described chlorination reagents beyond described chlorination reagent is triphosgene and trichloromethylchloroformate, the preferred 2:1～5:1 of mol ratio of described chlorination reagent and described compound 1, further preferred 2:1～3:1.
In the described method for preparing 2-chloro-5-picoline, described N, being substituted by by C described in N-two substituted formamides
1～C
4The straight or branched alkyl replace described C
1～C
4Straight or branched alkyl preferable methyl, ethyl, propyl group, sec.-propyl or butyl, further preferable methyl.
In the described method for preparing 2-chloro-5-picoline, described N, the preferred N of N-two substituted formamides, dinethylformamide, N, N-diethylformamide, N, N-dipropyl methane amide, N, N-diisopropyl formamide, N, in the N-dibutyl formamide one or more, further preferred N, dinethylformamide.
In the described method for preparing 2-chloro-5-picoline, described N, the preferred 1:1～5:1 of mol ratio of N-two substituted formamides and described compound 1, further preferred 1:1～2:1.
In the described method for preparing 2-chloro-5-picoline, preferred 70 ℃～120 ℃ of the temperature of described reaction, further preferred 90 ℃～110 ℃.
In the described method for preparing 2-chloro-5-picoline, the process of described reaction can adopt the conventionally test method (as HPLC) in this area to determine, be reaction end with 2-chloro-5-picoline content greater than 85%, preferred reaction time 15h～50h, further preferred 15h～25h.
In the described method for preparing 2-chloro-5-picoline, after reaction finishes, preferable also comprise following post-processing step: be adjusted to pH9～11 with alkali, obtain compound 3 after the rectifying.Described compound 3 can continue to do the raw material of the reaction for preparing compound 2.
The method of the described 2-of preparation chloro-5-picoline preferably includes following steps: earlier with chlorination reagent and N, N-two substituted formamides react, and again with chlorination reagent and N, the reacted reaction solution of N-two substituted formamides and compound 1 react; Perhaps earlier compound 1 and chlorination reagent are reacted, with compound 1 and the reacted reaction solution of chlorination reagent and N, N-two substituted formamides react and obtain 2-chloro-5-picoline again.
The described method for preparing 2-chloro-5-picoline further preferably includes following steps: earlier with chlorination reagent and N, N-two substituted formamides react, and again with chlorination reagent and N, the reacted reaction solution of N-two substituted formamides and compound 1 react.Described chlorination reagent and N, preferred-20 ℃～30 ℃ of the temperature of the reacted reaction solution of N-two substituted formamides and compound 1 reaction, further preferred 0 ℃～20 ℃.
In the preferred step of described preparation 2-chloro-5-picoline, when adopting earlier compound 1 and chlorination reagent are reacted, again with compound 1 and the reacted reaction solution of chlorination reagent and N, when N-two substituted formamides react, described compound 1 and the reacted reaction solution of chlorination reagent and N, preferred-20 ℃～30 ℃ of the temperature of N-two substituted formamides reaction, further preferred 0 ℃～20 ℃.
The method of the described 2-of preparation chloro-5-picoline further preferably includes following steps again: with the solution of chlorination reagent, be cooled to 0 ℃～20 ℃, drip N, N-two substituted formamides, drip compound 1 then, be warming up to 70 ℃～120 ℃ and react, obtain 2-chloro-5-picoline.The solvent that adopts in the solution of described chlorination reagent is for preparing the solvent that adopts in the method for 2-chloro-5-picoline.
In the described method for preparing 2-chloro-5-picoline, described compound 1 can adopt following method preparation, and it may further comprise the steps:
Step ⑴ reacts compound 2 and propionic aldehyde earlier, and the reaction solution that will react the back gained again mixes separatory with inorganic strong alkali;
Step ⑵ under the condition that organic bases exists, carries out acetylization reaction with acetylation reagent with the organic phase of step ⑴ reaction back without the aftertreatment gained, obtains compound 1;
Again according to the described method for preparing 2-chloro-5-picoline, the described method for preparing 2-chloro-5-nitrapyrin, the method for the described 2-of preparation chloro-5-5-flumethiazine makes 2-chloro-5-5-flumethiazine and gets final product, and wherein the definition of R is same as above.
The described method for preparing compound 1 can be for carrying out the ordinary method of such reaction, preferred especially following reaction method and condition among the present invention in this area:
In the step ⑴ of described preparation compound 1, preferred-20 ℃～20 ℃ of the temperature that described compound 2 and propionic aldehyde react, further preferred 0 ℃～20 ℃, further preferred 0 ℃～10 ℃ again.
In the step ⑴ of described preparation compound 1, the process of described reaction can adopt the conventionally test method (as HPLC) in this area to determine, content with the Schiff's base 4 that generates is reaction end greater than 90%, preferred 0.5h～5h of reaction times that described compound 2 and propionic aldehyde react, further preferred 0.5h～2h.
The structure of the Schiff's base 4 that described step ⑴ reaction generates is as follows:
In the step ⑴ of described preparation compound 1, described inorganic strong alkali is the conventional inorganic strong alkali that carries out such reaction in this area, and the form that described inorganic strong alkali can adopt solid form to participate in reaction or the aqueous solution participates in reaction.The preferred sodium hydroxide of described inorganic strong alkali and/or potassium hydroxide.When adopting the inorganic strong alkali of solid form, the inorganic strong alkali of described solid form preferably has the solid inorganic highly basic of water sorption; The described preferred sodium hydroxide of solid inorganic highly basic and/or potassium hydroxide with water sorption; When described inorganic strong alkali reacted with the form participation of the aqueous solution, the concentration preferred mass per-cent of the described inorganic strong alkali aqueous solution was 10%～90%, further preferred 60%～80%.Described mass percent refers to that the quality of inorganic strong alkali accounts for the per-cent of the total mass of the inorganic strong alkali aqueous solution.
In the step ⑴ of described preparation compound 1, the ratio of the quality of the quality of described inorganic strong alkali and described compound 2 preferred 0.04～0.5, further preferred 0.04～0.3.
Step ⑴ at described preparation compound 1 preferably includes following steps: described compound 2 mixes with inorganic strong alkali earlier after reacting with propionic aldehyde, stirs to make it be divided into two-phase the water that divides dereaction to generate then.Preferred 10min～2h of the time of described stirring, further preferred 0.5h～2h.
In the step ⑵ of described preparation compound 1, the preferred organic amine of described organic bases, the preferred triethylamine of described organic amine, Tri-n-Propylamine, tri-n-butylamine, diisopropyl ethyl amine, N, accelerine and N, in the N-Diethyl Aniline one or more, further preferred triethylamine.
In the step ⑵ of described preparation compound 1, the ratio of the quality of the quality of described organic bases and described compound 2 preferred 2～10, further preferred 2～5.
In the step ⑵ of described preparation compound 1, the preferred Acetyl Chloride 98Min. of described acetylation reagent and/or diacetyl oxide, further preferred diacetyl oxide.
In the step ⑵ of described preparation compound 1, the preferred 1:1～3:1 of mol ratio of described acetylation reagent and described compound 2, further preferred 1:1～1.5:1.
In the step ⑵ of described preparation compound 1, preferred 20 ℃～50 ℃ of the temperature of described acetylization reaction, further preferred 20 ℃～30 ℃.
In the step ⑵ of described preparation compound 1; the process of the acetylization reaction of described reaction can adopt the conventionally test method (as HPLC) in this area to determine; content with Schiff's base 4 was reaction end less than 0.05% o'clock, preferred reaction time 1h～10h, further preferred 1h～5h.The structure of described Schiff's base 4 is as follows:
The described method for preparing compound 1 further preferably includes following steps: step ⑴ with compound 2, is cooled to 0 ℃～5 ℃, drips propionic aldehyde, reacts, and the reaction solution that will react the back gained again mixes separatory with inorganic strong alkali;
Step ⑵ without aftertreatment gained organic phase, mixes step ⑴ reaction back with organic bases, be cooled to 0 ℃～10 ℃ and acetylation reagent and carry out acetylization reaction, obtains compound 1.
In the described method for preparing compound 1, described compound 2 can adopt following method preparation, and it may further comprise the steps: in enclosed system, under the condition that alkali exists, compound 3 and ammonia are reacted, obtain compound 2;
Again according to the described method for preparing compound 1, the described method for preparing 2-chloro-5-picoline, the described method for preparing 2-chloro-5-nitrapyrin, the method of the described 2-of preparation chloro-5-5-flumethiazine makes 2-chloro-5-5-flumethiazine and gets final product, and wherein the definition of R is same as above.
The described method for preparing compound 2 can be for carrying out the ordinary method of such reaction, preferred especially following reaction method and condition among the present invention in this area:
In the described method for preparing compound 2, described reaction can be carried out having under solvent or the solvent-free condition; When carrying out under the described condition that is reflected at solvent, one or more in described solvent preferably water, aromatic hydrocarbon solvent and the chlorinated hydrocarbon solvent, the preferred benzene of described aromatic hydrocarbon solvent and/or toluene; The preferred methylene dichloride of described chlorinated hydrocarbon solvent; In the preferred benzene of described solvent, toluene and the methylene dichloride one or more, further preferred benzene and/or toluene.
In the described method for preparing compound 2, the ratio preferred 0.5～2 of the quality of the quality of described solvent and described compound 3.
In the described method for preparing compound 2, the preferred mineral alkali of described alkali, one or more in the preferred sodium hydroxide of described mineral alkali, potassium hydroxide, yellow soda ash, sodium bicarbonate, salt of wormwood and the saleratus; Described mineral alkali can adopt the form of solid form or the aqueous solution to participate in reaction.When described mineral alkali reacts with the form participation of the aqueous solution, the concentration preferred mass per-cent of the aqueous solution of described mineral alkali is 10%～60%, further preferred 20%～50%, described mass percent refers to that the quality of mineral alkali accounts for the per-cent of total mass of the aqueous solution of mineral alkali;
In the described method for preparing compound 2, the preferred 1:1～5:1 of mol ratio of described alkali and described compound 3, further preferred 1:1～2.5:1.
In the described method for preparing compound 2, described ammonia can be ammonia, the solution that the aqueous solution of ammonia or ammonia and other organic solvents form; The aqueous solution of preferred ammonia.Described organic solvent is the organic solvent that can dissolve ammonia conventional in this area, preferred alcohols kind solvent and/or ether solvent, further preferred alcohols kind solvent, described alcoholic solvent particular methanol or ethanol; The ethanolic soln of the methanol solution of ammonia or ammonia for example.The mass percent of the aqueous solution of described ammonia preferred 15%～40%; Further preferred 15%～25%; Described mass percent refers to that the quality of ammonia accounts for the per-cent of ammonia soln total mass.
In the described method for preparing compound 2, the preferred 1:1～5:1 of mol ratio of described ammonia and described compound 3, further preferred 1:1～3:1.
In the described method for preparing compound 2, preferred 30 ℃～90 ℃ of the temperature of described reaction, further preferred 60 ℃～90 ℃.
In the described method for preparing compound 2, the preferred 0.01MPa～1.5MPa of the pressure of described reaction, further preferred 0.01MPa～0.6MPa, further preferred 0.15MPa～0.25MPa again.
In the described method for preparing compound 2, the process of described reaction can adopt the conventionally test method (as HPLC) in this area to determine, detecting the benzyl cl content with HPLC was reaction end less than 0.3% o'clock, preferred reaction time 3h～20h, further preferred 5h～10h.
In the described method for preparing compound 2, after reaction finishes, preferable also comprise following post-processing step: extraction, organic phase is adjusted to pH1～3 with acid, and water is adjusted to pH9～11 with alkali again, obtains compound 2 after the organic phase distillation.
In the preferable post-processing step of described preparation compound 2, solvent preferred aromatic hydrocarbons kind solvent and/or halogenated hydrocarbon solvent that described extraction is used, the preferred benzene of described aromatic hydrocarbon solvent and/or toluene; The preferred chlorinated hydrocarbon solvent of described halogenated hydrocarbon solvent, the preferred methylene dichloride of described chlorinated hydrocarbon solvent, the further preferred benzene of solvent or toluene that described extraction is used.
In the preferable post-processing step of described preparation compound 2, the preferred mineral acid of described acid, the preferred hydrochloric acid of described mineral acid and/or sulfuric acid, described hydrochloric acid is conventional commercially available hydrochloric acid reagent, described hydrochloric acid reagent is generally aqueous solution of hydrochloric acid, the mass percent of described aqueous solution of hydrochloric acid is preferred 5%～37%, and further preferred 15%～37%, described mass percent refers to that the quality of hydrogenchloride accounts for the per-cent of aqueous hydrochloric acid total mass; Described sulfuric acid is conventional commercial sulfuric acid reagent, described sulphate reagent can participate in reaction with the form of the aqueous solution of sulfuric acid, the mass percent of the aqueous solution of described sulfuric acid preferred 5%～90%, further preferred 10%～40%, described mass percent refers to that the quality of sulfuric acid accounts for the per-cent of aqueous sulfuric acid total mass.
In the preferable post-processing step of described preparation compound 2, the preferred mineral alkali of described alkali, the preferred sodium hydroxide of described mineral alkali and/or potassium hydroxide, described mineral alkali can participate in reaction with the form of its aqueous solution, when described mineral alkali reacts with the form participation of its aqueous solution, the concentration preferred mass per-cent 5%～95% of the aqueous solution of described mineral alkali, further preferred 30%～60%, described mass percent refers to that the quality of mineral alkali accounts for the per-cent of the aqueous solution total mass of mineral alkali.
In the preferable post-processing step of described preparation compound 2, described distillation can be adopted method and condition conventional in this area, preferred underpressure distillation.The temperature of described underpressure distillation and pressure can carry out choose reasonable according to boiling point and other physico-chemical properties of compound.
The described method for preparing compound 2 preferably includes following steps: in enclosed system, with compound 3 and alkali, be cooled to 5 ℃～15 ℃, dropping ammonia drips off and is warming up to 30 ℃～90 ℃ and reacts, and obtains compound 2.
The present invention also provides the preparation method of compound 2, and it may further comprise the steps: in enclosed system, under the condition that alkali exists, compound 3 and ammonia are reacted, obtain compound 2;
Wherein the definition of R is same as above.
The described method for preparing compound 2 can be for carrying out the ordinary method of such reaction, preferred especially following reaction method and condition among the present invention in this area:
In the described method for preparing compound 2, the compound 3 that described compound 3 can adopt the post-reaction treatment of preparation 2-chloro-5-picoline to obtain;
In the described method for preparing compound 2, described reaction can be carried out having under solvent or the solvent-free condition; When carrying out under the described condition that is reflected at solvent, one or more in described solvent preferably water, aromatic hydrocarbon solvent and the chlorinated hydrocarbon solvent, the preferred benzene of described aromatic hydrocarbon solvent and/or toluene; The preferred methylene dichloride of described chlorinated hydrocarbon solvent; In the preferred benzene of described solvent, toluene and the methylene dichloride one or more, further preferred benzene and/or toluene.
In the described method for preparing compound 2, the ratio preferred 0.5～2 of the quality of the quality of described solvent and described compound 3.
In the described method for preparing compound 2, the preferred mineral alkali of described alkali, one or more in the preferred sodium hydroxide of described mineral alkali, potassium hydroxide, yellow soda ash, sodium bicarbonate, salt of wormwood and the saleratus; Described mineral alkali can adopt the form of solid form or the aqueous solution to participate in reaction.When described mineral alkali reacts with the form participation of the aqueous solution, the concentration preferred mass per-cent 10%～60% of the aqueous solution of described mineral alkali, further preferred 20%～50%, described mass percent refers to that the quality of mineral alkali accounts for the per-cent of total mass of the aqueous solution of mineral alkali;
In the described method for preparing compound 2, the preferred 1:1～5:1 of mol ratio of described alkali and described compound 3, further preferred 1:1～2.5:1.
In the described method for preparing compound 2, described ammonia can be ammonia, the solution that the aqueous solution of ammonia or ammonia and other organic solvents form; The aqueous solution of preferred ammonia.Described organic solvent is the organic solvent that can dissolve ammonia conventional in this area, preferred alcohols kind solvent and/or ether solvent, further preferred alcohols kind solvent, described alcoholic solvent particular methanol or ethanol; The ethanolic soln of the methanol solution of ammonia or ammonia for example.The mass percent of the aqueous solution of described ammonia preferred 15%～40%; Further preferred 15%～25%; Described mass percent refers to that the quality of ammonia accounts for the per-cent of ammonia soln total mass.
In the described method for preparing compound 2, the preferred 1:1～5:1 of mol ratio of described ammonia and described compound 3, further preferred 1:1～3:1.
In the described method for preparing compound 2, preferred 30 ℃～90 ℃ of the temperature of described reaction, further preferred 60 ℃～90 ℃.
In the described method for preparing compound 2, the preferred 0.01MPa～1.5MPa of the pressure of described reaction, further preferred 0.01MPa～0.6MPa, further preferred 0.15MPa～0.25MPa again.
In the described method for preparing compound 2, the process of described reaction can adopt the conventionally test method (as HPLC) in this area to determine, detecting the benzyl cl content with HPLC was reaction end less than 0.3% o'clock, preferred reaction time 3h～20h, further preferred 5h～10h.
In the described method for preparing compound 2, after reaction finishes, preferable also comprise following post-processing step: extraction, organic phase is adjusted to pH1～3 with acid, and water is adjusted to pH9～11 with alkali again, obtains compound 2 after the organic phase distillation.
In the preferable post-processing step of described preparation compound 2, solvent preferred aromatic hydrocarbons kind solvent and/or halogenated hydrocarbon solvent that described extraction is used, the preferred benzene of described aromatic hydrocarbon solvent and/or toluene; The preferred chlorinated hydrocarbon solvent of described halogenated hydrocarbon solvent, the preferred methylene dichloride of described chlorinated hydrocarbon solvent, the further preferred benzene of solvent or toluene that described extraction is used.
In the preferable post-processing step of described preparation compound 2, the preferred mineral acid of described acid, the preferred hydrochloric acid of described mineral acid and/or sulfuric acid, described hydrochloric acid is conventional commercially available hydrochloric acid reagent, described hydrochloric acid reagent is generally aqueous solution of hydrochloric acid, the mass percent of described aqueous solution of hydrochloric acid is preferred 5%～37%, and further preferred 15%～37%, described mass percent refers to that the quality of hydrogenchloride accounts for the per-cent of aqueous hydrochloric acid total mass; Described sulfuric acid is conventional commercial sulfuric acid reagent, described sulphate reagent can participate in reaction with the form of the aqueous solution of sulfuric acid, the mass percent of the aqueous solution of described sulfuric acid preferred 5%～90%, further preferred 10%～40%, described mass percent refers to that the quality of sulfuric acid accounts for the per-cent of aqueous sulfuric acid total mass.
In the preferable post-processing step of described preparation compound 2, the preferred mineral alkali of described alkali, the preferred sodium hydroxide of described mineral alkali and/or potassium hydroxide, described mineral alkali can participate in reaction with the form of its aqueous solution, when described mineral alkali reacts with the form participation of its aqueous solution, the concentration preferred mass per-cent 5%～95% of the aqueous solution of described mineral alkali, further preferred 30%～60%, described mass percent refers to that the quality of mineral alkali accounts for the per-cent of the aqueous solution total mass of mineral alkali.
In the preferable post-processing step of described preparation compound 2, described distillation can be adopted method and condition conventional in this area, preferred underpressure distillation.The temperature of described underpressure distillation and pressure can carry out choose reasonable according to boiling point and other physico-chemical properties of compound.
The described method for preparing compound 2 preferably includes following steps: in enclosed system, add earlier compound 3 and alkali, be cooled to 5 ℃～15 ℃ dropping ammonia, drip off and be warming up to 30 ℃～90 ℃ and react, obtain compound 2.
The present invention also provides compound as shown in Equation 1,
Wherein, R is selected from halogen (for example fluorine, chlorine, bromine or iodine), C
1～C
3Straight or branched alkyl (for example methyl, ethyl, propyl group or sec.-propyl) in one or more, described R can be single and replace or polysubstituted, as R when being polysubstituted, the substituting group of R representative can be the same or different.
Enclosed system described in the present invention refers to have only energy exchange between the system and surrounding and does not have an exchange of substance, preferred autoclave.
On the basis that meets this area general knowledge, above-mentioned each optimum condition, but arbitrary combination namely get the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material be commercially available getting all.
Among the present invention, described room temperature finger ring border temperature is 10 ℃～35 ℃.
Positive progressive effect of the present invention is:
1, the synthesis technique that provides of present method is in cyclisation step, and recyclable a large amount of benzyl chlorine type aryl substitution compound, this compound can be used as raw material to be continued to apply mechanically in the synthesis technique that present method provides, thereby has reduced production cost.
2, also adopt phosgene, trichloromethylchloroformate, triphosgene etc. as cyclization reagent in the cyclization step, reduced solid useless generation in the last handling process, further reduced the cost that the three wastes are handled.
3, the present invention adopts antimonous oxide, antimony peroxide or its mixture as the catalyzer of fluorination step in fluorination step, has reduced production cost and the process safe risk that feeds intake.
4, in addition, all related processing condition of present method all compare gentle, and energy consumption cost is lower in the whole implementation of processes process.So, to compare with present bibliographical information, present method cost advantage is obvious, and institute does not have severe condition in steps, and is simple to operate, environmentally friendly, has significant social and economic benefit, is fit to suitability for industrialized production.
5, the inventive method has solved the problem that by product can't continue to utilize in the present already known processes, is a kind of method of efficient production 2-chloro-5-5-flumethiazine.
Embodiment
Mode below by embodiment further specifies the present invention, but does not therefore limit the present invention among the described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example according to ordinary method and condition, or is selected according to catalogue.
Embodiment 1
(1) step 1: N
2After testing high voltage still stopping property is qualified, in the 500mL autoclave, the mass percent that adds the benzyl chlorine of 39.2g and 80.6g successively is 32% the NaOH aqueous solution (mass percent refers to that the quality of sodium hydroxide accounts for the per-cent of the aqueous solution total mass of sodium hydroxide), be cooled to 5 ℃～15 ℃, the mass percent that adds 42.2g is 25% ammoniacal liquor (mass percent refers to that the quality of ammonia accounts for the per-cent of ammonia soln total mass), the control temperature is at 5 ℃～15 ℃ during adding, be warming up to 60 ℃ (the about 0.25MPa of still internal pressure this moment) after dripping end, behind insulation 7h under this temperature, sampling, HPLC detects the benzyl cl content less than 0.3%, determine that reaction finishes, with the toluene extraction of reaction solution with 60g * 2, merge organic phase, functional quality per-cent is that 30% hydrochloric acid (mass percent refers to that the quality of hydrogenchloride accounts for the per-cent of aqueous hydrochloric acid total mass) is transferred pH=3, gained water layer functional quality per-cent is 32% NaOH solution (mass percent refers to that the quality of sodium hydroxide accounts for the per-cent of aqueous sodium hydroxide solution total mass) accent pH=10, layering, organic layer simple distillation, about vacuum tightness 45mbar, collect about 90 ℃ cut, get benzylamine 24.2g, yield 73%, GC purity 99.2%.
(2) step 2: after the 200g benzylamine being added the four-hole boiling flask of 500mL, be cooled to 0 ℃～5 ℃, drip the propionic aldehyde of 108.3g, after dropwising, stir 1h in 0 ℃～10 ℃, sampling, the content that HPLC detects the Schiff's base of benzylamine and propionic aldehyde generation is reaction end greater than 90%, adds the 33g solid potassium hydroxide and also stirs 30 minutes, thereby tell the intermediate Schiff's base that organic phase obtains benzylamine and propionic aldehyde formation, with this Schiff's base with after the triethylamine of 900g mixes, be cooled to 0 ℃～10 ℃, drip the diacetyl oxide of 200g, dropwise back stir about 10min, be warming up to 25 ℃ of insulation 3h afterwards, sampling, HPLC detects Schiff's base content less than 0.05%, determines that reaction finishes, after the gained reaction solution removes triethylamine, underpressure distillation make triethylamine almost completely remove the thick product 350g of step 2, get this thick product of 5g, silica gel column chromatography (V (sherwood oil): V (ethyl acetate))=5:1), get step 2 straight product 3.5g(HPLC purity 99.8%, MS (EI): m/z (%): 189 (100) [M]
+), be standard model with this straight product, use external standard method conventional in this area, HPLC detects and determines that above-mentioned thick quality product content is 82.2%, thick product yield 82%.
(3) step 3: the trichloromethylchloroformate that in the four-hole boiling flask of 500mL, adds chlorobenzene and the 62.1g of 220g successively, be cooled to 0 ℃～20 ℃, drip the DMF of 22.5g, dropwise the back and stir 1h, drip above-mentioned steps two thick product 60g, be warming up to 100 ℃ of insulation 18h after dropwising, sampling, HPLC detects 2-chloro-5-picoline content greater than 85%, determine that reaction finishes, the NaOH solution (mass percent refers to that the quality of sodium hydroxide accounts for the per-cent of aqueous sodium hydroxide solution total mass) that adds the mass percent 30% of 350g, after stirring 30min, the oil reservoir rectification under vacuum obtains chlorobenzene and benzyl chlorine respectively, and benzyl chlorine continues to recover step 1 to be used as raw material, continue rectifying (vacuum tightness 7-9mbar, cut between collecting 62～68 ℃) getting 2-chloro-5-picoline 25.5g, is standard model with the analytical pure 2-chloro-5-picoline of buying, and uses the external standard method of this area routine, HPLC detects and determines that mass content is 96.8%, yield 77%.
(4) step 4: in the 500mL reaction flask, add the 2-chloro-5-picoline of 120g and the tetracol phenixin of 350g, be heated to 80 ℃, add the phosphorus trichloride of initiator 3.8g and the Diisopropyl azodicarboxylate of 1.2g, feed chlorine, continue to be heated with stirring to backflow, after reacting about 10h, sampling, GC detects 2-chloro-5-nitrapyrin content more than 90%, stops logical chlorine, and this moment, the chlorine usage quantity was 241g, remove tetracol phenixin, get 2-chloro-5-nitrapyrin 195.3g, yield 90%, GC purity 98.5% after the products obtained therefrom rectification under vacuum.
(5) step 5: after the 2-chloro-5-nitrapyrin of 231g is heated to 50 ℃ of left and right sides fusions, drop in the 1L autoclave, and then the antimonous oxide of input 2.6g, sealing autoclave, feed the hydrogen fluoride of 80g, be warming up to 180 ℃～200 ℃ (the about 4.5MPa of still internal pressure this moment), behind the insulation 7h, be cooled to 50 ℃, sampling, GC detects 2-chloro-5-5-flumethiazine content more than 90%, the venting pressure release, nitrogen purging, tail gas absorbs with alkali lye, and gained reaction solution functional quality per-cent is in 30% the sodium hydroxide solution and back (mass percent refers to that the quality of sodium hydroxide accounts for the per-cent of aqueous sodium hydroxide solution total mass), steam distillation gets 2-chloro-5-5-flumethiazine crude product, this crude product rectification under vacuum is got the pure product 141.7g of 2-chloro-5-5-flumethiazine, yield 78%, GC purity 99.8%.
Embodiment 2
(1) step 1: N
2After testing high voltage still stopping property is qualified, in the 500mL autoclave, the o-chloro benzyl chloride that adds 49.8g successively, 70.6g toluene and the mass percent of 90.3g be 40% KOH solution (mass percent refers to that the quality of potassium hydroxide accounts for the per-cent of potassium hydroxide aqueous solution total mass), be cooled to 5 ℃～15 ℃, the mass percent that adds 42.2g is 25% ammoniacal liquor (mass percent refers to that the quality of ammonia accounts for the per-cent of ammonia soln total mass), the control temperature is at 5 ℃～15 ℃ during adding, be warming up to 45 ℃ (the about 0.15MPa of still internal pressure this moment) after dripping end, behind insulation 10h under this temperature, sampling, HPLC detects o-chloro benzyl chloride content less than 0.3%, determine that reaction finishes, with the toluene extraction of reaction solution with 40g * 2, merge organic phase, use 30% hydrochloric acid to transfer pH=3, gained water layer functional quality per-cent is that 32% NaOH solution transfers the pH=10(mass percent to refer to that the quality of sodium hydroxide accounts for the per-cent of aqueous sodium hydroxide solution total mass), layering, organic layer simple distillation, about vacuum tightness 20mbar, collect about 115 ℃ cut, get o-chlorine benzylamine 33.4g, yield 76%, GC purity 99.2%.
(2) step 2: after the 265g o-chlorine benzylamine being added the four-hole boiling flask of 500mL, be cooled to 0 ℃～5 ℃, drip the propionic aldehyde of 108.3g, after dropwising, stir 1h in 0 ℃～10 ℃, sampling, the content that HPLC detects the Schiff's base of o-chlorine benzylamine and propionic aldehyde generation is reaction end greater than 90%, adds the 13g solid sodium hydroxide and also stirs 45 minutes, thereby tell the Schiff's base that organic phase obtains o-chlorine benzylamine and propionic aldehyde formation, with this Schiff's base with after the triethylamine of 900g mixes, be cooled to 0 ℃～10 ℃, drip the acetic anhydride of 200g, dropwise back stir about 10min, be warming up to 25 ℃ of insulation 3h afterwards, sampling, HPLC detects Schiff's base content less than 0.05%, determines that reaction finishes, after the gained reaction solution removes triethylamine, get the thick product 431g of step 2, get this thick product of 5g, silica gel column chromatography (V (sherwood oil): V (ethyl acetate))=5:1), get step 2 straight product 3.3g(HPLC purity 99.8%, MS (EI): m/z (%): 223 (100) [M]
+), be standard model with this straight product, use external standard method conventional in this area, HPLC detects and determines that above-mentioned thick quality product content is 80.7%, thick product yield 84%.
(3) step 3: the triphosgene that in the four-hole boiling flask of 500mL, adds chlorobenzene and the 62.1g of 300g successively, be cooled to 0 ℃～20 ℃, drip the DMF of 22.5g, dropwise the back and stir 1h, drip above-mentioned steps two thick product 71.3g, be warming up to 100 ℃ of insulation 22h after dropwising, sampling, HPLC detects 2-chloro-5-picoline content greater than 85%, determine that reaction finishes, add 30% the NaOH solution of 350g, stir 30min after, the oil reservoir rectification under vacuum obtains chlorobenzene and o-chloro benzyl chloride respectively, o-chloro benzyl chloride continues to recover step 1 to be used as raw material, and continuing rectifying (vacuum tightness 7-9mbar, collects 62～68 ℃ between cut) must 2-chloro-5-picoline 24.2g, yield 74% adopts the identical testing method of embodiment 1 step 3 to record HPLC mass content 96.8%.
(4) step 4: in the 500mL reaction flask, add the 2-chloro-5-picoline of 120g and the orthodichlorobenzene of 220g, the phosphorus trichloride that adds initiator 3.8g, under high voltage mercury lamp (300-500nm) irradiation, be heated to 145 ℃, feed chlorine, after reacting about 13h, sampling, GC detects 2-chloro-5-nitrapyrin content more than 90%, stops logical chlorine, and this moment, the chlorine usage quantity was 255g, remove orthodichlorobenzene, get 2-chloro-5-nitrapyrin 193.3g, yield 89%, GC purity 98.3% after the products obtained therefrom rectification under vacuum.
(5) step 5: after the 2-chloro-5-nitrapyrin of 231g is heated to 50 ℃ of left and right sides fusions, drop in the 1L autoclave, and then the antimony peroxide of input 3.8g, sealing autoclave, feed the hydrogen fluoride of 80g, be warming up to 180 ℃～200 ℃ (the about 4.5MPa of still internal pressure this moment), behind the insulation 9h, be cooled to 50 ℃, sampling, GC detects 2-chloro-5-5-flumethiazine content more than 90%, the venting pressure release, nitrogen purging, tail gas absorbs with alkali lye, in the sodium hydroxide solution of gained reaction solution use 30% and back (mass percent refers to that the quality of sodium hydroxide accounts for the per-cent of aqueous sodium hydroxide solution total mass), steam distillation gets 2-chloro-5-5-flumethiazine crude product, this crude product rectification under vacuum is got the pure product 151g of 2-chloro-5-5-flumethiazine, yield 83%, GC purity 99.5%
Embodiment 3
(1) N
2After testing high voltage still stopping property is qualified, in the 500mL autoclave, add successively 43.5g between the mass percent of methyl benzyl chlorine and 80.6g be 32% NaOH solution (mass percent refers to that the quality of sodium hydroxide accounts for the per-cent of aqueous sodium hydroxide solution total mass), be cooled to 5 ℃～15 ℃, the mass percent that adds 42.2g is 25% ammoniacal liquor (mass percent refers to that the quality of ammonia accounts for the per-cent of ammonia soln total mass), the control temperature is at 5 ℃～15 ℃ during adding, be warming up to 60 ℃ (the about 0.25MPa of still internal pressure this moment) after dripping end, behind insulation 9h under this temperature, sampling, methyl benzyl cl content was less than 0.3% between HPLC detected, determine that reaction finishes, with the toluene extraction of reaction solution with 60g * 2, merge organic phase, functional quality per-cent is that 30% aqueous hydrochloric acid transfers the pH=3(mass percent to refer to that the quality of hydrogenchloride accounts for the per-cent of the total mass of aqueous hydrochloric acid), gained water layer functional quality per-cent is that 32% NaOH solution transfers the pH=10(mass percent to refer to that the quality of sodium hydroxide accounts for the per-cent of aqueous sodium hydroxide solution total mass), layering, organic layer simple distillation, about vacuum tightness 25mbar, collect about 90 ℃ cut, methylbenzylamine 27.5g between getting, yield 74%, GC purity 99.3%.
(2) step 2: after methylbenzylamine between 226g being added the four-hole boiling flask of 500mL, be cooled to 0 ℃～5 ℃, drip the propionic aldehyde of 108.3g, after dropwising, stir 1h in 0 ℃～10 ℃, sampling, the content of the Schiff's base that methylbenzylamine and propionic aldehyde generated between HPLC detected be reaction end greater than 90%, adds the 13g solid sodium hydroxide and also stirs 45 minutes, thereby tell the Schiff's base of methylbenzylamine and propionic aldehyde formation between the organic phase acquisition, with this Schiff's base with after the triethylamine of 900g mixes, be cooled to 0 ℃～10 ℃, drip the acetic anhydride of 200g, dropwise back stir about 10min, be warming up to 25 ℃ of insulation 3h afterwards, sampling, HPLC detects Schiff's base content less than 0.05%, determines that reaction finishes, after the gained reaction solution removes triethylamine, get the thick product 360g of step 2, get this thick product of 5g, silica gel column chromatography (V (sherwood oil): V (ethyl acetate))=5:1), get step 2 straight product 2.2g(HPLC purity 99.8%, MS (EI): m/z (%): 203 (100) [M]
+), be standard model with this straight product, use external standard method conventional in this area, HPLC detects and determines that above-mentioned thick quality product content is 83.2%, thick product yield 79%.
(3) step 3: after in the four-hole boiling flask of 500mL, adding the orthodichlorobenzene of 280g successively, feed the phosgene of 62.1g, be cooled to 0 ℃～20 ℃, drip the DMF(N of 22.5g, dinethylformamide), dropwise the back and stir 1h, drip above-mentioned steps two thick product 64.2g, be warming up to 100 ℃ of insulation 20h after dropwising, sampling, HPLC detects 2-chloro-5-picoline content greater than 85%, determine that reaction finishes, the mass percent that adds 350g is 30% NaOH solution (mass percent refers to that the quality of sodium hydroxide accounts for the per-cent of aqueous sodium hydroxide solution total mass), behind the stirring 30min, the oil reservoir rectification under vacuum obtains orthodichlorobenzene and a methyl benzyl chlorine respectively, between methyl benzyl chlorine continue to recover step 1 and use as raw material, continuing rectifying (vacuum tightness 7-9mbar, collects 62 ℃～68 ℃ between cut) must 2-chloro-5-picoline 25.2g, yield 76% adopts the identical testing method of embodiment 1 step 3 to record HPLC mass content 96.8%.
(4) step 4: after in the 500mL reaction flask, adding the 2-chloro-5-picoline of 120g, add the phosphorus trichloride of initiator 3.8g and the Diisopropyl azodicarboxylate of 3g, under high voltage mercury lamp (300-500nm) irradiation, be heated to 140 ℃, feed chlorine, after reacting about 15h, sampling, GC detects 2-chloro-5-nitrapyrin content more than 90%, stop logical chlorine, this moment, the chlorine usage quantity was 280g, got 2-chloro-5-nitrapyrin 203.8g after the products obtained therefrom rectification under vacuum, yield 95%, GC purity 99.1%.
(5) step 5: after the 2-chloro-5-nitrapyrin of 231g is heated to 50 ℃ of left and right sides fusions, drop in the 1L autoclave, and then the antimony peroxide of input 3.0g and the antimonous oxide of 1.0g, sealing autoclave, feed the hydrogen fluoride of 80g, be warming up to 180 ℃～200 ℃ (the about 4.5MPa of still internal pressure this moment), behind the insulation 7.5h, be cooled to 50 ℃, sampling, GC detects 2-chloro-5-5-flumethiazine content more than 90%, the venting pressure release, nitrogen purging, tail gas absorbs with alkali lye, and gained reaction solution functional quality per-cent is in 30% the sodium hydroxide solution and back (mass percent refers to that the quality of sodium hydroxide accounts for the per-cent of aqueous sodium hydroxide solution total mass), steam distillation gets 2-chloro-5-5-flumethiazine crude product, this crude product rectification under vacuum is got the pure product 156g of 2-chloro-5-5-flumethiazine, yield 85%, GC purity 99.5%.
Claims (22)
1. the preparation method of a 2-chloro-5-5-flumethiazine is characterized in that may further comprise the steps: in enclosed system, under the condition that catalyzer exists, 2-chloro-5-nitrapyrin and hydrogen fluoride are reacted, obtain 2-chloro-5-5-flumethiazine; Described catalyzer is antimonous oxide and/or antimony peroxide,
2. the preparation method of 2-chloro-5-5-flumethiazine as claimed in claim 1 is characterized in that:
The preparation method of described 2-chloro-5-5-flumethiazine may further comprise the steps: in enclosed system, under the anhydrous condition, in the 2-of fusion chloro-5-nitrapyrin, add catalyzer, react with hydrogen fluoride then, obtain 2-chloro-5-5-flumethiazine; Described catalyzer is antimonous oxide and/or antimony peroxide;
The mass percent of the quality of described catalyzer and described 2-chloro-5-nitrapyrin is 0.1%～10%; The mol ratio of described hydrogen fluoride and described 2-chloro-5-nitrapyrin is 3:1～15:1; The temperature of described reaction is 150 ℃～250 ℃; The pressure of described reaction is 2MPa～10MPa.
3. the preparation method of 2-chloro-5-5-flumethiazine as claimed in claim 2, it is characterized in that: the per-cent of the quality of described catalyzer and described 2-chloro-5-nitrapyrin quality is 0.1%～2%; The mol ratio of described hydrogen fluoride and described 2-chloro-5-nitrapyrin is 3:1～5:1; The temperature of described reaction is 160 ℃～210 ℃; The pressure of described reaction is 4MPa～6MPa.
4. as the preparation method of each described 2-chloro-5-5-flumethiazine of claim 1～3, it is characterized in that: described 2-chloro-5-nitrapyrin adopts following method preparation: under the condition of light and/or initiator existence, 2-chloro-5-picoline and chlorine are reacted, obtain 2-chloro-5-nitrapyrin;
Again according to right with require 1～3 each described preparation method to prepare 2-chloro-5-5-flumethiazine to get final product.
5. the preparation method of 2-chloro-5-5-flumethiazine as claimed in claim 4 is characterized in that:
The method of the described 2-of preparation chloro-5-nitrapyrin may further comprise the steps: with the solution of 2-chloro-5-picoline and initiator, react with chlorine at 30 ℃～180 ℃, obtain 2-chloro-5-nitrapyrin; Perhaps, with the solution of 2-chloro-5-picoline, add initiator at 30 ℃～180 ℃, and then react with chlorine, obtain 2-chloro-5-nitrapyrin.
6. the preparation method of 2-chloro-5-5-flumethiazine as claimed in claim 4 is characterized in that:
In the described method for preparing 2-chloro-5-nitrapyrin, described being reflected in the solvent or under the solvent-free condition carried out; Described initiator is one or more in Diisopropyl azodicarboxylate, phosphorus trichloride, ammonium persulphate and the benzoyl peroxide; Described light wavelength is 300nm～500nm; The ratio of the quality of the quality of described initiator and described 2-chloro-5-picoline is 0.01～0.8; The mol ratio of described chlorine and described 2-chloro-5-picoline is 3:1～10:1; The temperature of described reaction is 30 ℃～180 ℃; Be reflected at when carrying out in the solvent when described, described solvent is halogenated hydrocarbon solvent and/or halogenated aryl hydrocarbon kind solvent.
7. the preparation method of 2-chloro-5-5-flumethiazine as claimed in claim 6, it is characterized in that: in the method for the described 2-of preparation chloro-5-nitrapyrin, described halogenated hydrocarbon solvent is the chlorinated hydrocarbon solvent; Described chlorinated hydrocarbon solvent is one or more in methylene dichloride, trichloromethane, tetracol phenixin and the ethylene dichloride; Described halogenated aryl hydrocarbon kind solvent is one or more in chlorobenzene, orthodichlorobenzene, Meta Dichlorobenzene and the santochlor; The ratio of the quality of the quality of described initiator and described 2-chloro-5-picoline is 0.02～0.07; The mol ratio of described chlorine and described 2-chloro-5-picoline is 3:1～5:1; The temperature of described reaction is 80 ℃～150 ℃.
8. the preparation method of 2-chloro-5-5-flumethiazine as claimed in claim 4 is characterized in that:
Described 2-chloro-5-picoline adopts following method preparation: in solvent, with chlorination reagent, N, N-two substituted formamides and compound 1 react and obtain 2-chloro-5-picoline;
Preparing 2-chloro-5-5-flumethiazine according to the described preparation method of claim 4 again gets final product;
Wherein, R is selected from hydrogen, halogen and C
1～C
3The straight or branched alkyl in one or more; Described N, being substituted by by C described in N-two substituted formamides
1～C
4The straight or branched alkyl replace.
9. the preparation method of 2-chloro-5-5-flumethiazine as claimed in claim 8 is characterized in that:
When R was halogen, described halogen was fluorine, chlorine, bromine or iodine;
When R is C
1～C
3The straight or branched alkyl time, described C
1～C
3The straight or branched alkyl be methyl, ethyl, propyl group or sec.-propyl;
As described N, being substituted by by C described in N-two substituted formamides
1～C
4Straight or branched alkyl when replacing, described C
1～C
4The straight or branched alkyl be methyl, ethyl, propyl group, sec.-propyl or butyl.
10. the preparation method of 2-chloro-5-5-flumethiazine as claimed in claim 8, it is characterized in that: in the method for the described 2-of preparation chloro-5-picoline, described solvent is one or more in halogenated hydrocarbon solvent, halogenated aryl hydrocarbon kind solvent and the aromatic hydrocarbon solvent; Described chlorination reagent is one or more in phosphorus oxychloride, phosphorus pentachloride, triphosgene, trichloromethylchloroformate, phosgene, sulfur oxychloride and the oxalyl chloride; When described chlorination reagent was triphosgene, the mol ratio of described chlorination reagent and described compound 1 was 0.6:1～2:1; When described chlorination reagent was trichloromethylchloroformate, the mol ratio of described chlorination reagent and described compound 1 was 1:1～2.5:1; During other described chlorination reagents beyond described chlorination reagent is triphosgene and trichloromethylchloroformate, the mol ratio of described chlorination reagent and described compound 1 is 2:1～5:1; Described N, N-two substituted formamides are N, dinethylformamide, N, N-diethylformamide, N, N-dipropyl methane amide, N, N-diisopropyl formamide, N, one or more in the N-dibutyl formamide; Described N, the mol ratio of N-two substituted formamides and described compound 1 is 1:1～5:1; The temperature of described reaction is 70 ℃～120 ℃.
11. the preparation method of 2-chloro-5-5-flumethiazine as claimed in claim 10 is characterized in that: in the method for the described 2-of preparation chloro-5-picoline, described halogenated hydrocarbon solvent is the chlorinated hydrocarbon solvent; Described chlorinated hydrocarbon solvent is one or more in methylene dichloride, trichloromethane, tetracol phenixin and the ethylene dichloride; Described halogenated aryl hydrocarbon kind solvent is one or more in chlorobenzene, orthodichlorobenzene, Meta Dichlorobenzene and the santochlor; Described aromatic hydrocarbon solvent is one or more in toluene, o-Xylol, p-Xylol and the m-xylene; When described chlorination reagent was triphosgene, the mol ratio of described chlorination reagent and described compound 1 was 0.6:1～1:1; When described chlorination reagent was trichloromethylchloroformate, the mol ratio of described chlorination reagent and described compound 1 was 1:1～1.5:1; During other described chlorination reagents beyond described chlorination reagent is triphosgene and trichloromethylchloroformate, the mol ratio of described chlorination reagent and described compound 1 is 2:1～3:1; Described N, the mol ratio of N-two substituted formamides and described compound 1 is 1:1～2:1; The temperature of described reaction is 90 ℃～110 ℃.
12. the preparation method as each described 2-chloro-5-5-flumethiazine of claim 8～11, it is characterized in that: the method for preparing 2-chloro-5-picoline may further comprise the steps: with the solution of chlorination reagent, be cooled to 0 ℃～20 ℃, drip N, N-two substituted formamides, drip compound 1 then, be warming up to 70 ℃～120 ℃ and react, obtain 2-chloro-5-picoline;
In the described method for preparing 2-chloro-5-picoline, after reaction finishes, also comprise following post-processing step: be adjusted to pH9～11 with alkali, obtain compound 3 after the rectifying; The structural formula of described compound 3 is as follows:
Wherein, the definition of R is as described in claim 8 or 9.
13. the preparation method of 2-chloro-5-5-flumethiazine as claimed in claim 8 is characterized in that:
In the method for preparing 2-chloro-5-picoline, described compound 1 adopts following method preparation, and it may further comprise the steps:
Step ⑴ reacts compound 2 and propionic aldehyde earlier, and the reaction solution that will react the back gained again mixes separatory with inorganic strong alkali;
Step ⑵ under the condition that organic bases exists, carries out acetylization reaction with acetylation reagent with the organic phase of step ⑴ reaction back without the aftertreatment gained, obtains compound 1;
Prepare 2-chloro-5-5-flumethiazine according to the described preparation method of claim 8 again and get final product, wherein the definition of R is as described in claim 8 or 9.
14. the preparation method of 2-chloro-5-5-flumethiazine as claimed in claim 13, it is characterized in that: the method for preparing compound 1 may further comprise the steps: step ⑴ is with compound 2, be cooled to 0 ℃～5 ℃, drip propionic aldehyde, react, the reaction solution that will react the back gained again mixes separatory with inorganic strong alkali;
Step ⑵ without aftertreatment gained organic phase, mixes step ⑴ reaction back with organic bases, be cooled to 0 ℃～10 ℃ and acetylation reagent and carry out acetylization reaction, obtains compound 1;
In the step ⑴ of described preparation compound 1, described compound 2 is-20 ℃～20 ℃ with the temperature that propionic aldehyde reacts; Described compound 2 is 0.5h～5h with the reaction times that propionic aldehyde reacts; Described inorganic strong alkali is sodium hydroxide and/or potassium hydroxide; The ratio of the quality of the quality of described inorganic strong alkali and described compound 2 is 0.04～0.5;
In the step ⑵ of described preparation compound 1, described organic bases is organic amine; The ratio of the quality of the quality of described organic bases and described compound 2 is 2～10; Described acetylation reagent is Acetyl Chloride 98Min. and/or diacetyl oxide; The mol ratio of described acetylation reagent and described compound 2 is 1:1～3:1; The temperature of described acetylization reaction is 20 ℃～50 ℃.
15. the preparation method of 2-chloro-5-5-flumethiazine as claimed in claim 14 is characterized in that: in the step ⑴ of described preparation compound 1, described compound 2 is 0 ℃～20 ℃ with the temperature that propionic aldehyde reacts; Described compound 2 is 0.5h～2h with the reaction times that propionic aldehyde reacts; The ratio of the quality of the quality of described inorganic strong alkali and described compound 2 is 0.04～0.3;
In the step ⑵ of described preparation compound 1, described organic amine is triethylamine, Tri-n-Propylamine, tri-n-butylamine, diisopropyl ethyl amine, N, accelerine and N, one or more in the N-Diethyl Aniline; The ratio of the quality of the quality of described organic bases and described compound 2 is 2～5; The mol ratio of described acetylation reagent and described compound 2 is 1:1～1.5:1; The temperature of described acetylization reaction is 20 ℃～30 ℃.
16. the preparation method as each described 2-chloro-5-5-flumethiazine of claim 13～15, it is characterized in that: in the method for preparing compound 1, described compound 2 adopts following method preparation, it may further comprise the steps: in enclosed system, under the condition that alkali exists, compound 3 and ammonia are reacted, obtain compound 2;
Prepare 2-chloro-5-5-flumethiazine according to the described preparation method of claim 13 again and get final product, wherein the definition of R is as described in claim 8 or 9.
17. the preparation method of 2-chloro-5-5-flumethiazine as claimed in claim 16 is characterized in that: in the described method for preparing compound 2, the compound 3 that described compound 3 obtains for the post-reaction treatment of preparation 2-chloro-5-picoline;
In the described method for preparing compound 2, described being reflected under solvent or the solvent-free condition carried out; Described alkali is mineral alkali; The mol ratio of described alkali and described compound 3 is 1:1～5:1; In the method for preparing compound 2, ammonia is ammonia, the solution that the aqueous solution of ammonia or ammonia and other organic solvents form; The mol ratio of described ammonia and described compound 3 is 1:1～5:1; The temperature of described reaction is 30 ℃～90 ℃; The pressure of described reaction is 0.01MPa～1.5MPa; When carrying out under the described condition that is reflected at solvent, described solvent is one or more in water, aromatic hydrocarbon solvent and the chlorinated hydrocarbon solvent.
18. the preparation method of 2-chloro-5-5-flumethiazine as claimed in claim 17 is characterized in that: in the described method for preparing compound 2, described aromatic hydrocarbon solvent is benzene and/or toluene; Described chlorinated hydrocarbon solvent is methylene dichloride; Described mineral alkali is one or more in sodium hydroxide, potassium hydroxide, yellow soda ash, sodium bicarbonate, salt of wormwood and the saleratus; Described mineral alkali adopts the form of solid form or the aqueous solution to participate in reaction; When described mineral alkali participated in reaction with the form of the aqueous solution, the concentration of the aqueous solution of described mineral alkali was that mass percent is 10%～60%, and described mass percent refers to that the quality of mineral alkali accounts for the per-cent of total mass of the aqueous solution of mineral alkali; Described ammonia is the aqueous solution of ammonia, and the mass percent of the aqueous solution of described ammonia is 15%～40%; Described mass percent refers to that the quality of ammonia accounts for the per-cent of the aqueous solution total mass of ammonia; The mol ratio of described alkali and described compound 3 is 1:1～2.5:1; The mol ratio 1:1 of described ammonia and described compound 3～3:1; The pressure of described reaction is 0.01MPa～0.6Mpa.
19. the preparation method of 2-chloro-5-5-flumethiazine as claimed in claim 18 is characterized in that: when described mineral alkali reacted with the form participation of the aqueous solution, the concentration of the aqueous solution of described mineral alkali was that mass percent is 20%～50%.
20. the preparation method of a compound 2 is characterized in that may further comprise the steps: in enclosed system, under the condition that alkali exists, compound 3 and ammonia are reacted, obtain compound 2;
Wherein the definition of R is as described in claim 8 or 9; Each reaction conditions is as claim 16～19 as described in each.
21. a compound as shown in Equation 1,
Wherein, R is selected from halogen and C
1～C
3The straight or branched alkyl in one or more.
22. compound as shown in Equation 1 as claimed in claim 21 is characterized in that:
When R was halogen, described halogen was fluorine, chlorine, bromine or iodine;
When R is C
1～C
3The straight or branched alkyl time, described C
1～C
3The straight or branched alkyl be methyl, ethyl, propyl group or sec.-propyl.
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| CN104529789A (en) * | 2014-12-04 | 2015-04-22 | 苏州市玮琪生物科技有限公司 | Synthetic process of 3,5-dichloro-alpha,alpha-dimethyl benzylamine |
| CN105330592A (en) * | 2015-11-23 | 2016-02-17 | 上海晋景化学有限公司 | Preparation method of 2-chloro-5-picoline |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000034215A1 (en) * | 1998-12-10 | 2000-06-15 | Occidental Chemical Corporation | METHOD OF MAKING α-CHLORO-α,α-DIFLUORO AROMATIC COMPOUNDS |
-
2013
- 2013-06-26 CN CN201310261224.3A patent/CN103288718B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000034215A1 (en) * | 1998-12-10 | 2000-06-15 | Occidental Chemical Corporation | METHOD OF MAKING α-CHLORO-α,α-DIFLUORO AROMATIC COMPOUNDS |
Non-Patent Citations (1)
| Title |
|---|
| 陈娇领等: "2-氯-5-三氟甲基吡啶的合成", 《浙江化工》, vol. 36, no. 6, 31 December 2005 (2005-12-31), pages 19 - 20 * |
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