CN1342648A

CN1342648A - Process for synthesizing 2-Cl-5-trifluoromethyl pyridine

Info

Publication number: CN1342648A
Application number: CN 00122987
Authority: CN
Inventors: 张伟; 徐杰
Original assignee: Dalian Institute of Chemical Physics of CAS
Current assignee: Dalian Institute of Chemical Physics of CAS
Priority date: 2000-09-13
Filing date: 2000-09-13
Publication date: 2002-04-03
Anticipated expiration: 2020-09-13
Also published as: CN1202082C

Abstract

A process for synthesizing 2-cl-5-trifluoromethyl pyridine features that 2-cl-5-methyl pyridine as raw material in the existance of organic solvent and chlorine gas and through the trigger of light radiation or initiator undergoes one-step direct chlorination to synthesize 2-Cl-5-trichloromethyl pyridine which is further uses as intermediate product to undergo one-step fluorinating reaction to synthesize 2-Cl-5-trifluoromethyl pyridine. Its advantages are high selectivity and high output rate.

Description

The method of a kind of Synthetic 2-chloro-5-5-flumethiazine

The present invention relates to close the preparation of fluorine, heterocycle organic intermediate, the method for a kind of Synthetic 2-chloro-5-5-flumethiazine is provided especially.

2-chloro-5-5-flumethiazine is a kind of fluorine-containing, crucial organic intermediate of heterocycle, in field of fine chemical such as agricultural chemicals, medicine purposes is widely arranged.US 4241213, US 4497955, US 2590279, US 5198547, EP 0557967A1 waits patent documentation to address the synthetic method of 2-chloro-5-nitrapyrin, 2-chloro-5-5-flumethiazine, but these methods all are to be raw material with the pyridine, by chlorination, fluorination step, Synthetic 2-chloro-5-5-flumethiazine; Because the yield of product is low, reaction preference is poor, the easy polymerization of reaction intermediate and coking, by product is more etc., makes industrial realization have many difficulties.

The purpose of this invention is to provide a kind of method of the 2-of preparation chloro-5-5-flumethiazine, it has highly selective, high yield.

Particular content of the present invention is as follows:

1.2-the chlorination reaction of chloro-5-picoline

With 2-chloro-5-picoline is raw material, under existence conditions such as organic solvent and chlorine, causes a step direct chlorination Synthetic 2-chloro-5-nitrapyrin by illumination or initiator.Used organic solvent can be aromatics such as chlorobenzene, dichlorobenzene, trichlorobenzene, oil of mirbane, also can be aliphatic halogenated hydrocarbons such as methylene dichloride, ethylene dichloride, trichloromethane, trichloroethane, tetracol phenixin, preferably aromatic series such as dichlorobenzene, trichlorobenzene muriate.Solvent is a 0.1-10.0 times of weight of raw material 2-chloro-5-picoline, is preferably in 1.0～5.0 times the scope.

The used initiator of chlorination reaction can be benzoyl peroxide, Diisopropyl azodicarboxylate or α, organic compound initiators such as α dihydroxyl diacetyl peroxide base trichoro-aldehyde, also mineral compound initiator such as ammonium persulfate preferably adopts organic initiators; The add-on of initiator is 0.01～0.5 times (wt.) of raw material 2-chloro-5-picoline, is preferably between 0.02～0.08 times (wt.); The feed way of initiator can evenly add according to reaction times length in batches, to guarantee that reaction system has existing of initiator in reaction process.Except using the initiator initiation reaction, also can come initiation reaction with optical radiation, used optical source wavelength can be preferably between 270～480nm in 190～700nm scope; Wavelength is during greater than 480nm, photochemical dissociation reaction difficulty, and the efficient of initiation reaction is low, and wavelength can not see through simple glass less than the UV-light of 300nm and shine on the reactant.

The temperature of chlorination reaction can be in 80 ℃～200 ℃; When temperature was lower than 80 ℃, speed of response was slow, and reaction not exclusively; After temperature of reaction was higher than 200 ℃, the by-products content that chlorination replaces on pyridine ring increased, and the principal product selectivity is low, and best temperature range is at 120 ℃～140 ℃.Under the initiator effect, react the mixture that can obtain containing 2-chloro-5-nitrapyrin in 8-12 hour.

Chlorination afterreaction mixture is by the method for underpressure distillation, purifying 2-chloro-5-nitrapyrin; The purpose of underpressure distillation is organic solvent and other impurity of removing in the reaction system; The vacuum tightness of underpressure distillation, requirement can be advisable but the still kettle temperature is no more than 180 ℃ with the certain speed distilling off solvent; Temperature is too high to cause the product coking easily.

2.2-the fluoridation of chloro-5-nitrapyrin

With intermediate product 2-chloro-5-nitrapyrin behind the chlorination purifying is raw material, and a step is fluoridized Synthetic 2-chloro-5-5-flumethiazine.Fluorination reagent can be used anhydrous HF, also can use SbF ₃, fluorination reagents such as KF, NaF; Consider to fluoridize efficient and economic factors, use anhydrous HF better, in this reaction, HF is a fluorination reagent, is again to hold agent; The add-on of HF can be about 5.0～50.0 times (mol.) of 2-chloro-5-nitrapyrin, and preferably 10-20 doubly.Fluorination reaction temperature can be between 100 ℃-250 ℃, but preferably between 150 ℃～200 ℃.When temperature of reaction was lower than 150 ℃, speed of response was slow, fluoridation is not thorough; After temperature of reaction was higher than 200 ℃, chlorosity was easily fluoridized replacement on the ring, generated by product 2-fluoro-5-5-flumethiazine.For efficient is fluoridized in raising, reaction is preferably in to add to depress to be carried out; The three power scopes of reacting can be between the 1.0-15.0MPa, and from reaction self character and industrial equipments cost consideration, reaction pressure is preferably in 4.0～10.0MPa scope.

The present invention is to be raw material with 2-chloro-5-picoline (CMP), by chlorination, fluoridize two-step reaction, the 2-chloro-5-5-flumethiazine of highly selective synthesis of high purity.Chlorination process carries out in the presence of organic solvent, removes the method for desolvating, the 2-chloro-5-nitrapyrin of synthesis of high purity by underpressure distillation; Be raw material with 2-chloro-5-nitrapyrin then, a step is fluoridized Synthetic 2-chloro-5-5-flumethiazine.Feed stock conversion height of the present invention, good reaction selectivity, intermediate polymerization and coking are few, separate easily, product purity height.

Embodiment 1.

In the reaction flask of 1L, add 2-chloro-5-picoline 164.0g (1.29mol), 1,2-dichlorobenzene 618.0g, feed nitrogen, be heated with stirring to 60 ℃, stop logical nitrogen and switch feeding chlorine, add Diisopropyl azodicarboxylate 1.0g, continue to be heated with stirring to 140 ℃, at constant temperature, logical chlorine blistering reaction.In reaction process, added one time Diisopropyl azodicarboxylate 1.0 grams every 1.5 hours.Reaction proceeds to 8 hours and begins to carry out sampling analysis later on, and after reaction 12 hours, content＞96.0% of 2-chloro-5-nitrapyrin in the reaction solution stops heating, closes the chlorine sampling valve, finishes reaction.Reaction system is cooled to 120 ℃ then, underpressure distillation removes and desolvates 1, and the 2-dichlorobenzene descends cooling after 2 hours at 0 ℃ the reactor liquid of pouring out, suction filtration, oven dry; Obtain solid 2-chloro-5-nitrapyrin 218.0g, purity 97.78% (GC); The heavy 109.3g of suction filtration raffinate, 2-chloro-5-nitrapyrin content is 45.58%.The result who calculates 2-chloro-5-trichloromethyl building-up reactions is:

Transformation efficiency: 99.33%

Selectivity: 90.39%

Yield: 89.79%

Embodiment 2.

With the solvent 1 that embodiment 1. dashes, the 2-dichlorobenzene uses 1,2 instead, the 4-trichlorobenzene, and the reaction times is 11 hours, other operational condition (comprising post-processing step) is identical with embodiment 1..The result obtains solid 2-chloro-5-nitrapyrin 213.2g, purity 95.5% (GC); The heavy 106.4g of suction filtration raffinate, 2-chloro-5-nitrapyrin content is 45.58%.The result who calculates 2-chloro-5-trichloromethyl building-up reactions is:

Transformation efficiency: 98.78%

Selectivity: 87.20%

Yield: 86.13%

Embodiment 3.

Initiator Diisopropyl azodicarboxylate among the embodiment 1. is removed, and (sending the light wavelength scope is 300～500nm) luminous radiation initiation reactions, and the reaction times is 12 hours, and other operational condition (comprising post-processing step) is identical with embodiment 1. to use mercury lamp instead.The result obtains solid 2-chloro-5-nitrapyrin 189.5g, purity 93.5% (GC); The heavy 116.4g of suction filtration raffinate, 2-chloro-5-nitrapyrin content is 40.56%.The result who calculates 2-chloro-5-trichloromethyl building-up reactions is::

Transformation efficiency: 97.65%

Selectivity: 77.46%

Yield: 75.64%

Embodiment 4.

Change the temperature among the embodiment 1. into 120 ℃, the reaction times is 11 hours, and other operational condition (comprising post-processing step) is identical with embodiment 1..The result obtains solid 2-chloro-5-nitrapyrin 168.2g, purity 94.40% (GC).The heavy 121.0g of suction filtration raffinate analyzes 2-chloro-5-nitrapyrin content 52.7%.The result who calculates 2-chloro-5-trichloromethyl building-up reactions is:

Transformation efficiency: 98.86%

Selectivity: 76.74%

Yield: 75.87%

Embodiment 5.

In 200 milliliters of autoclaves, add 2-chloro-5-nitrapyrin 20.0g (0.087mol), first-class kettle cover, inflated with nitrogen 10.0MPa keep-uped pressure 5 hours, to the reactor leak test; After confirming that reactor is air tight, emptying still internal pressure; Then reactor being placed cryosel to bathe cools off; When temperature in the kettle is reduced to below-5.0 ℃, in reactor, fill anhydrous hydrogen fluoride 50.0g (～2.5mol.), under agitation condition, reaction system is heated to 195 ℃, under this temperature the reaction 10 hours.

After reaction finishes, be cooled to 30 ℃, logical nitrogen replacement half an hour (gas that displaces feeds the absorption that neutralizes in the aqueous sodium hydroxide solution) is pressed into reaction solution in the frozen water of 100ml in reactor, and the sodium hydroxide solution with 20% is neutralized to about pH=10.Then, reaction mixture divides three extractions with the 100ml ether, and combining extraction liquid is washed till neutrality with deionized water; In extraction liquid, added 10 gram anhydrous sodium sulfate dryings 6 hours, filter out solids wherein, carry out air distillation again, to remove ether wherein, the liquid that obtains is under the underpressure distillation condition, collect the cut of boiling point at 80.0～81.0 ℃ (70.0mmHg), obtain 2-chloro-5-5-flumethiazine product 11.5g, analyzing the content that records 2-chloro-5-5-flumethiazine in the product is 99.60% (GC).Underpressure distillation front-end volatiles and cauldron bottom residue are merged, be weighed as 3.4g, wherein the content of 2-chloro-5-5-flumethiazine is 84.9%.The result who calculates 2-chloro-5-5-flumethiazine building-up reactions is:

Transformation efficiency: 98.8%

Selectivity: 91.9%

Yield: 91.2%

Embodiment 6.

Temperature among the embodiment 4. is changed to 180 ℃, and other operational condition comprises that post-processing step is identical with embodiment 4..Obtain 2-chloro-5-5-flumethiazine 10.8g, purity 98.9% (GC).Underpressure distillation front-end volatiles and cauldron bottom residue are merged, be weighed as 4.2g, wherein the content of 2-chloro-5-5-flumethiazine is 60.3%.The result who calculates 2-chloro-5-5-flumethiazine building-up reactions is:

Transformation efficiency: 98.8%

Selectivity: 86.5%

Yield: 85.5%

Claims

1, the method for a kind of Synthetic 2-chloro-5-5-flumethiazine is characterized in that this method comprises the steps:

(1) 2-chloro-5-nitrapyrin is synthetic

With 2-chloro-5-picoline is raw material, under organic solvent and chlorine existence condition, causes a step direct chlorination Synthetic 2-chloro-5-nitrapyrin by illumination or initiator;

Used organic solvent is the aromatics of chlorobenzene, dichlorobenzene, trichlorobenzene, oil of mirbane, or the aliphatics hydrochloric ether of methylene dichloride, ethylene dichloride, trichloromethane, trichloroethane, tetracol phenixin, the add-on of solvent is a 0.1-10.0 times of weight of raw material 2-chloro-5-picoline;

The temperature of chlorination reaction is in 80 ℃～200 ℃;

Chlorination afterreaction mixture is by the method purifying 2-chloro-5-nitrapyrin of underpressure distillation;

(2) 2-chloro-5-5-flumethiazine is synthetic

With intermediate product 2-chloro-5-nitrapyrin behind the chlorination purifying is raw material, and a step is fluoridized Synthetic 2-chloro-5-5-flumethiazine;

Fluorination reagent is anhydrous HF, SbF ₃, KF, NaF, add-on is 5.0～50.0 times of moles of 2-chloro-5-nitrapyrin; Fluorination reaction temperature is between 100 ℃～250 ℃; The reaction pressure scope is between 1.0-15.0MPa.

2, press the method for the described Synthetic 2 of claim 1-chloro-5-5-flumethiazine; it is characterized in that: the used initiator of chlorination reaction is benzoyl peroxide, Diisopropyl azodicarboxylate or α; the organic compound initiator of α dihydroxyl diacetyl peroxide base trichoro-aldehyde; or the mineral compound initiator of ammonium persulfate, the add-on of initiator is 0.01～0.5 times of weight of raw material 2-chloro-5-picoline.

3, press the method for the described Synthetic 2 of claim 2-chloro-5-5-flumethiazine; it is characterized in that: the used initiator of chlorination reaction is an organic compound; add-on is that 0.02～0.08 times of used initiator of reaction of raw material 2-chloro-5-picoline is benzoyl peroxide, Diisopropyl azodicarboxylate or α; the organic compound initiator of α dihydroxyl diacetyl peroxide base trichoro-aldehyde, the add-on of initiator are 0.02～0.08 times of weight of raw material 2-chloro-5-picoline.

4, by the method for the described Synthetic 2 of claim 1-chloro-5-5-flumethiazine, it is characterized in that: when coming initiation reaction with optical radiation, used optical source wavelength is in 190～700nm scope.

5, by the method for the described Synthetic 2 of claim 4-chloro-5-5-flumethiazine, it is characterized in that: used optical source wavelength is between 270～480nm.

6, by the method for the described Synthetic 2 of claim 1-chloro-5-5-flumethiazine, it is characterized in that: used organic solvent is aromatic series muriates such as dichlorobenzene, trichlorobenzene, and the add-on of solvent is 1.0～5.0 times of weight of raw material 2-chloro-5-picoline.

7, by the method for the described Synthetic 2 of claim 1-chloro-5-5-flumethiazine, it is characterized in that: chlorination reagent is an anhydrous HF, and the add-on of HF is a 10-20 times of mole of 2-chloro-5-nitrapyrin.

8, by the method for the described Synthetic 2 of claim 1-chloro-5-5-flumethiazine, it is characterized in that: the temperature of chlorination reaction is between 120 ℃～140 ℃; Fluorination reaction temperature is between 150 ℃～200 ℃, and reaction pressure is between 4.0～10.0Mpa.

9, by the method for the described Synthetic 2 of claim 1-chloro-5-5-flumethiazine, it is characterized in that: vacuum distillation temperature is no more than 180 ℃.