CN105153022B - The preparation method of the pyridine sulfonamide of 3 ethylsulfonyl 2 and its intermediate - Google Patents
The preparation method of the pyridine sulfonamide of 3 ethylsulfonyl 2 and its intermediate Download PDFInfo
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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
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Abstract
The invention discloses the preparation method of the pyridine sulfonamide of 3 ethylsulfonyl 2 and its intermediate.The invention provides a kind of preparation method of the mercaptopyridine of 3 ethylsulfonyl 2, comprise the following steps：In solvent, 2,3 two b sulfonyl pyridines and sulfhydrylization reagent are subjected to nucleophilic substitution and obtain the mercaptopyridine of 3 ethylsulfonyl 2；Described sulfhydrylization reagent is the mixture or NaHS of vulcanized sodium and sulphur.The preparation method of the present invention, it is raw material to have used 2,3 cheap dichloropyridines, and reactions steps are simple, total recovery is high, greatly reduce production cost, are suitable for industrialized production.
Description
Technical field
The present invention relates to the preparation method of 3- ethylsulfonyl -2- pyridine sulfonamides and its intermediate.
Background technology
Rimsulfuron 25 be a kind of sulfonylurea efficiently, high selectivity, bud post processing low toxicity herbicide.3- ethylsulfonyls -2-
Pyridine sulfonamide is one of key intermediate for synthesizing E.I.Du Pont Company's herbicide rimsulfuron 25 (rimsulfon).
Mainly there is the synthetic method of following three kinds of 3- ethylsulfonyl -2- pyridine sulfonamides at present：
Using 2- fluorine pyridine as raw material, through ethylmercapto group substitution, sulfuryl amine obtains 3- ethylsulfonyl -2- pyridine sulfonamides again
(EP0341011)；
2nd, using tetramethoxy propane as raw material, it is condensed through ethylsulfonyl acetonitrile, hydrogen bromide acetic acid solution cyclization, sulfydryl take
After generation, chlorine and ammoniacal liquor sulfuryl amine, produce 3- ethylsulfonyl -2- pyridine sulfonamides (US5107057, modern, 2007,6
(3)：13)；
3rd, using tetramethoxy propane as raw material, it is condensed through ethylsulfonyl acetonitrile, methylphenylamine substitutes, bromination acetate hydrogen
After solution cyclization, sulfydryl substitution, chlorine and ammoniacal liquor sulfuryl amine, producing 3- ethylsulfonyl -2- pyridine sulfonamides, (Zhejiang industry is big
Learn journal, 2007,35 (5)：494th, modern, 2007,6 (3)：13).
Three of the above method is currently used three kinds of synthetic methods, but homogeneously longer to route, causes total recovery relatively low.
Method one relate to the use of expensive raw material lithium diisopropylamine (LDA) and trifluoroacetic acid, and total recovery is only
23.39%.What is more important, LDA requirement is harsh, and the requirement to operation place and consersion unit is more severe
Carve, fail large-scale industrial production in this way.
The total recovery of method two is：27.7%.It is relatively low (38.43%) that the yield of 2- bromopyridines is prepared due to this method, so
This method cost and unit consumption are higher.
The total recovery of method three is：46.58%, it is synthetic method the most frequently used at present, but synthesis step is also most, mistake
More synthesis steps certainly will increase substantial amounts of equipment cost and human cost in process of production.
Therefore, simple reactions steps, high income are found, raw material is cheap and easy to get, production cost is low, is suitable for industrialized production
The preparation methods of 3- ethylsulfonyl -2- pyridine sulfonamides be the current technical problem for being badly in need of solving.
The content of the invention
The technical problems to be solved by the invention are to overcome 3- ethylsulfonyls -2- pyridine sulfonamides in the prior art
Preparation method reactions steps are cumbersome, yield is low, cost of material is expensive, production cost is high, be not suitable for the defects of industrialized production and
Provide a kind of preparation method of 3- ethylsulfonyls -2- pyridine sulfonamides and its intermediate.The preparation method reaction step of the present invention
Rapid simple, total recovery high (reaching as high as 64.2%), raw material is cheap and easy to get, production cost is low, is suitable for industrialized production.
The invention provides a kind of preparation method of 3- ethylsulfonyls -2- mercaptopyridines, it comprises the following steps：Solvent
In, the b sulfonyl pyridines of 2,3- bis- and sulfhydrylization reagent are subjected to nucleophilic substitution and obtain 3- ethylsulfonyl -2- mercaptopyridines
；Described sulfhydrylization reagent is the mixture or NaHS of vulcanized sodium and sulphur；
The preparation method of described 3- ethylsulfonyl -2- mercaptopyridines can be such nucleophilic substitution in this area
Conventional method, particularly preferred following reaction method and condition in of the invention：
In the preparation method of described 3- ethylsulfonyl -2- mercaptopyridines, the preferred water of described solvent, amide-type are molten
One or more in agent, sulfoxide type solvents and sulfone class solvent, the mixed solvent of further preferred amide solvent and water.It is described
The preferred DMF of amide solvent (DMF) and/or 1-METHYLPYRROLIDONE (NMP).Described sulfoxide type is molten
The preferred dimethyl sulfoxide (DMSO) of agent (DMSO).The described preferred sulfolane of sulfone class solvent.The mixing of described amide solvent and water is molten
The mixed solvent of the preferred water of agent and DMF (DMF).
In the preparation method of described 3- ethylsulfonyl -2- mercaptopyridines, described solvent and described 2,3- diethyls
Sulfonyl pyridine mass values preferably 1~10, further preferred 3~6.
In the preparation method of described 3- ethylsulfonyl -2- mercaptopyridines, the preferred sulphur hydrogenation of described sulfhydrylization reagent
Sodium.
In the preparation method of described 3- ethylsulfonyl -2- mercaptopyridines, described sulfhydrylization reagent and described 2,
The molar ratio preferably 1~3 of the b sulfonyl pyridines of 3- bis-.When described sulfhydrylization reagent is the mixture of vulcanized sodium and sulphur,
The molar ratio preferably 1~1.5 of described sulphur and described vulcanized sodium.
In the preparation method of described 3- ethylsulfonyl -2- mercaptopyridines, the temperature of described nucleophilic substitution is excellent
Select 30 DEG C~150 DEG C, further preferred 110 DEG C~120 DEG C.
In the preparation method of described 3- ethylsulfonyl -2- mercaptopyridines, the process of described nucleophilic substitution can
To be monitored using the routine monitoring method (such as TLC, HPLC, NMR or GC) in this area, typically with 2,3- diethyl sulphonyl
The content (such as HPLC contents) of yl pyridines is reaction end when being less than 0.5%, the time preferably 2 of described nucleophilic substitution
Hour~8 hours, further preferred 3 hours~5 hours.
The preparation method of described 3- ethylsulfonyl -2- mercaptopyridines, it is preferred to use following steps：By 2,3- diethyl sulphonyl
The solution that yl pyridines are formed with solvent is added in the mixture that sulfiding reagent is formed with water, is warming up to 110 DEG C~120 DEG C, is entered
Row nucleophilic substitution obtains 3- ethylsulfonyl -2- mercaptopyridines.The mode of described addition is preferably added dropwise, described drop
The speed added preferably keeps system temperature at 110 DEG C~120 DEG C.The temperature of described " mixture that sulfiding reagent is formed with water "
It is preferred that 80 DEG C~90 DEG C.When described sulfiding reagent is the mixture of vulcanized sodium and sulphur, described " sulfiding reagent is formed with water
Mixture " preferably obtained using following step：At 80 DEG C~90 DEG C, sulphur powder is added in the solution formed to vulcanized sodium and water,
Insulation 1 hour~2 hours, obtain the mixture that sulfiding reagent is formed with water.
The preparation method of described 3- ethylsulfonyl -2- mercaptopyridines preferably includes following post-processing step：Reaction terminates
Afterwards, 70 DEG C~80 DEG C are cooled to, regulation pH value is 5.0~6.0, then is cooled to 20 DEG C~30 DEG C, is filtered, and is washed, and dries, obtains
3- ethylsulfonyl -2- mercaptopyridines.Described regulation pH preferably uses concentrated hydrochloric acid.Described concentrated hydrochloric acid can be normal in this area
Commercially available concentrated hydrochloric acid reagent is advised, the mass concentration preferably 30%~38% of described concentrated hydrochloric acid, described mass concentration refers to chlorination
The quality of hydrogen accounts for the percentage of concentrated hydrochloric acid gross mass.Described filtering, washing, drying can use the generic operation in this area
Conventional method.
The preparation method of described 3- ethylsulfonyl -2- mercaptopyridines preferably further comprises the following steps：, will in solvent
2,3- diethyl sulfide yl pyridines carry out oxidation reaction with oxidant and obtain the described b sulfonyl pyridines of 2,3- bis-；
The preparation method of the described b sulfonyl pyridines of 2,3- bis- can be the routine side of such oxidation reaction in this area
Method, particularly preferred following reaction method and condition in of the invention：
In the preparation method of the described b sulfonyl pyridines of 2,3- bis-, the preferred organic acid solvent of described solvent, institute
One or more in the preferred acetic acid of organic acid solvent, trichloroacetic acid and the trifluoroacetic acid stated, further preferred acetic acid.
In the preparation method of the described b sulfonyl pyridines of 2,3- bis-, described solvent and described 2,3- diethyl sulfenyls
The mass values of pyridine preferably 0.1~10, further preferred 0.5~5.
In the preparation method of the described b sulfonyl pyridines of 2,3- bis-, the preferred metachloroperbenzoic acid of described oxidant
(m-CPBA), hydrogen peroxide, Peracetic acid, peroxide list potassium sulfonate (Oxone), potassium permanganate or sodium hypochlorite, it is further preferably double
Oxygen water.Described hydrogen peroxide can be conventional commercial hydrogen peroxide reagent, the mass concentration preferably 20% of described hydrogen peroxide~
50%, further preferred 30%~50%.Described mass concentration refers to that the quality of hydrogen peroxide accounts for the hundred of hydrogen peroxide gross mass
Divide ratio.
In the preparation method of the described b sulfonyl pyridines of 2,3- bis-, described oxidant and described 2,3- diethyl sulfide
The molar ratio of yl pyridines preferably 4~6, further preferred 4~4.8.
In the preparation method of the described b sulfonyl pyridines of 2,3- bis-, preferably 20 DEG C of the temperature of described oxidation reaction~
85 DEG C, further preferred 70 DEG C~85 DEG C.
In the preparation method of the described b sulfonyl pyridines of 2,3- bis-, the process of described oxidation reaction can use this
Routine monitoring method (such as TLC, HPLC, NMR or GC) in field is monitored, typically containing with 2,3- diethyl sulfide yl pyridines
It is preferably 2 hours~10 hours time of the oxidation reaction described in reaction end when measuring (such as HPLC contents) less than 1%, enters one
Step preferably 2 hours~5 hours.
In the preparation method of the described b sulfonyl pyridines of 2,3- bis-, when oxidant is hydrogen peroxide, reaction preferably exists
Carried out under the conditions of catalyst is existing, the preferred manganese dioxide of described catalyst, ferric trichloride, sodium tungstate, molybdenum trioxide and molybdenum
One or more in sour ammonium, further preferred sodium tungstate.Described catalyst rubs with described 2,3- diethyl sulfide yl pyridines
That ratio preferably 0.001~0.01, further preferred 0.001~0.006, such as 0.005.
The preparation method of the described b sulfonyl pyridines of 2,3- bis- preferably uses following steps：To 2,3- diethyl sulfide yl pyridines
Oxidant is added in the mixture formed with organic solvent, oxidation reaction is carried out and obtains the b sulfonyl pyridines of 2,3- bis-；Or to
Oxidant is added in the mixture that 2,3- diethyl sulfide yl pyridines, catalyst and organic solvent are formed, oxidation reaction is carried out and obtains 2,
The b sulfonyl pyridines of 3- bis-.The mode of described addition is preferably added dropwise, and the preferred maintenance system temperature of speed of dropwise addition is no more than 70
DEG C it is defined.
The preparation method of the described b sulfonyl pyridines of 2,3- bis- is excellent to wash using following post-processing steps：After reaction terminates,
- 5 DEG C~0 DEG C is cooled to, is filtered, washing, is dried to obtain the b sulfonyl pyridines of 2,3- bis-.Described filtering, washing, drying can be with
Using the conventional method of the generic operation in this area.
The preparation method of described 3- ethylsulfonyl -2- mercaptopyridines preferably further comprises the following steps：In solvent
In, under the conditions of alkali is existing, compound 1 and ethylmercapto group reagent are subjected to nucleophilic substitution and obtain described 2,3- diethyl sulfide
Yl pyridines；
Wherein, X1For fluorine, chlorine, bromine or iodine, preferably chlorine；X2For chlorine, bromine or iodine, preferably chlorine.
The preparation method of described 2,3- diethyl sulfide yl pyridines can be the routine of such nucleophilic substitution in this area
Method, particularly preferred following reaction method and condition in of the invention：
In the preparation method of described 2,3- diethyl sulfide yl pyridines, described solvent preferred amide class solvent, sulfoxide type
One or more in solvent and sulfone class solvent, further preferred amide solvent.Described amide solvent preferred N, N- bis-
NMF (DMF), DMA (DMA), 1,3- dimethyl-imidazolinones (DMI), 1-METHYLPYRROLIDONE
(NMP) and the one or more in hexamethyl phosphoramide (HMPA), further preferred DMF (DMF) and/or
DMA (DMA).The preferred dimethyl sulfoxide of described sulfoxide type solvents (DMSO).The described preferred ring of sulfone class solvent
Fourth sulfone.
In the preparation method of described 2,3- diethyl sulfide yl pyridines, described solvent and the quality of described compound 1
Ratio preferably 1~10, further preferred 2~5.
In the preparation method of described 2,3- diethyl sulfide yl pyridines, the preferred inorganic base of described alkali；Described inorganic base
It is preferred that the one or more in sodium hydride, sodium hydroxide and potassium hydroxide, further preferred sodium hydroxide and/or potassium hydroxide.
In the preparation method of described 2,3- diethyl sulfide yl pyridines, described alkali and the mass ratio of described compound 1
Value preferably 2~3, further preferred 2~2.5.
In the preparation method of described 2,3- diethyl sulfide yl pyridines, the described preferred ethyl mercaptan of ethylmercapto group reagent.
In the preparation method of described 2,3- diethyl sulfide yl pyridines, described ethylmercapto group reagent and described compound
1 mass values preferably 2~3, further preferred 2~2.5.
In the preparation method of described 2,3- diethyl sulfide yl pyridines, preferably 50 DEG C of the temperature of described nucleophilic substitution
~130 DEG C, further preferred 80 DEG C~100 DEG C.
In the preparation method of described 2,3- diethyl sulfide yl pyridines, the process of described nucleophilic substitution can use
Routine monitoring method (such as TLC, HPLC, NMR or GC) in this area is monitored, typically with the content of compound 1 (such as
HPLC contents) be less than 0.5% when for the nucleophilic substitution described in reaction end preferably 2 hours~10 hours time, enter one
Step preferably 3 hours~5 hours.
The preparation method of described 2,3- diethyl sulfide yl pyridines preferably uses following steps：Sulfiding reagent and solvent are formed
Mixture add in the mixture that alkali and solvent are formed, react to solid and be completely dissolved, add compound 1 and organic solvent shape
Into mixture, be warming up to 80 DEG C~100 DEG C, carry out nucleophilic substitution, obtain 2,3- diethyl sulfide yl pyridines.Described
The mode of addition is preferably added dropwise.Described " adds alkali and the mixing of solvent formation by the mixture that sulfiding reagent and solvent are formed
In thing " be added dropwise the preferred maintenance reaction system of speed temperature be no more than 0~5 DEG C.It is described " add compound 1 with it is organic molten
Dosage form into mixture " be added dropwise the preferred maintenance reaction system of speed temperature be 80 DEG C~100 DEG C.
The preparation method of described 2,3- diethyl sulfide yl pyridines preferably includes following post-processing step：After reaction terminates, remove
Solvent and low-boiling by-products are removed, obtains 2,3- diethyl sulfide yl pyridines.Described removing solvent and low-boiling by-products are preferably adopted
With the mode of vacuum distillation.
The preparation method of described 3- ethylsulfonyl -2- mercaptopyridines preferably uses following route：
Present invention also offers a kind of preparation method of 3- ethylsulfonyls -2- pyridine sulfonyl chlorides, it comprises the following steps：Press
After 3- ethylsulfonyl -2- mercaptopyridines are made according to foregoing preparation method, then in a solvent, by described 3- second sulphonyl
Base -2- mercaptopyridines carry out oxidation reaction with oxidant, obtain 3- ethylsulfonyl -2- pyridine sulfonyl chlorides；
The preparation method of described 3- ethylsulfonyl -2- pyridine sulfonyl chlorides can be the normal of such oxidation reaction in this area
Rule method, particularly preferred following reaction method and condition in of the invention：
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonyl chlorides, the preferred water of described solvent and/or halo
Varsol, the mixed solvent of further preferred water and halogenated hydrocarbon solvent.The preferred chlorinated hydrocarbon of described halogenated hydrocarbon solvent
Solvent, the one or more in the preferred dichloromethane of described chlorinated hydrocarbon solvent, dichloroethanes, chloroform and carbon tetrachloride.Institute
The preferred dichloromethane of water and the mixed solvent of halogenated hydrocarbon solvent and the mixed solvent of water stated.
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonyl chlorides, described solvent and described 3- second sulphurs
The mass values preferably 1~50, further preferred 15~20 of acyl group -2- mercaptopyridines.
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonyl chlorides, the preferred sodium hypochlorite of described oxidant
Or chlorine, further preferred chlorine.
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonyl chlorides, described oxidant and described 3- second
The molar ratio preferably 1~5, further preferred 3~3.5 of sulfonyl -2- mercaptopyridines.
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonyl chlorides, the temperature of described oxidation reaction preferably -
10 DEG C~20 DEG C, preferably 0 DEG C~10 DEG C.
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonyl chlorides, the process of described oxidation reaction can be with
It is monitored using the routine monitoring method (such as TLC, HPLC, NMR or GC) in this area, typically with 3- ethylsulfonyls -2-
It is reaction end when the content (such as HPLC contents) of mercaptopyridine is less than 0.5%, the time of described oxidation substitution reaction is excellent
Select 0.5 hour~2 hours, further preferred 0.5 hour~1 hour.
When oxidant is chlorine, the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonyl chlorides is preferably using following
Step：At -5 DEG C~0 DEG C, lead to chlorine in the mixture formed to 3- ethylsulfonyl -2- mercaptopyridines and solvent, aoxidize instead
3- ethylsulfonyl -2- pyridine sulfonyl chlorides should be obtained.The preferred maintenance system temperature of speed of logical chlorine is excellent no more than 10 DEG C
- 10 DEG C~10 DEG C of choosing, further preferably -5 DEG C~10 DEG C.
3- ethylsulfonyl -2- the pyridine sulfonyl chlorides for being made described post-treated can not will directly contain 3- second sulphonyl afterwards
The organic phase of base -2- pyridine sulfonyl chlorides prepare the reaction of 3- ethylsulfonyl -2- pyridine sulfonamides.
The preparation method of described 3- ethylsulfonyl -2- pyridine sulfonyl chlorides preferably uses following route：
Present invention also offers a kind of preparation method of 3- ethylsulfonyls -2- pyridine sulfonamides, it comprises the following steps：Press
After 3- ethylsulfonyl -2- pyridine sulfonyl chlorides are made according to foregoing preparation method, then by described 3- ethylsulfonyl -2- pyridines
Sulfonic acid chloride carries out condensation reaction with ammoniacal liquor, obtains 3- ethylsulfonyl -2- pyridine sulfonamides；
The preparation method of described 3- ethylsulfonyl -2- pyridine sulfonamides can be such condensation substitution reaction in this area
Conventional method, particularly preferably following reaction method and condition in the present invention：
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonamides, described ammoniacal liquor and described 3- second sulphurs
The molar ratio preferably 1~10, further preferred 3~5 of acyl group -2- pyridine sulfonyl chlorides.Described ammoniacal liquor can be in this area
Conventional commercial ammoniacal liquor reagent, the mass concentration preferably 8%~25% of described ammoniacal liquor, described mass concentration refers to the matter of ammonia
Amount accounts for the percentage of ammonia spirit gross mass.
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonamides, the temperature of described condensation reaction preferably -
10 DEG C~20 DEG C, further preferred 0 DEG C~10 DEG C.
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonamides, the process of described condensation reaction can be with
It is monitored using the routine monitoring method (such as TLC, HPLC, NMR or GC) in this area, typically with 3- ethylsulfonyls -2-
It is reaction end when the content (such as HPLC contents) of pyridine sulfonyl chloride is less than 0.5%, the time of described condensation reaction is preferred
0.5 hour~2 hours, further preferred 0.5 hour~1 hour.
The preparation method of described 3- ethylsulfonyl -2- pyridine sulfonamides preferably uses following steps：Ammoniacal liquor is added to
In the mixture that 3- ethylsulfonyl -2- pyridine sulfonyl chlorides and organic solvent are formed, carry out condensation reaction, obtain 3- ethylsulfonyls -
2- pyridine sulfonamides；Or the mixture for forming 3- ethylsulfonyl -2- pyridine sulfonyl chlorides and organic solvent is added in ammoniacal liquor,
Condensation reaction is carried out, obtains 3- ethylsulfonyl -2- pyridine sulfonamides.Further preferred 3- ethylsulfonyl -2- pyridine sulfonyl chlorides with
The mixture that organic solvent is formed is added in ammoniacal liquor.The mode of described addition is preferably added dropwise, and the speed of dropwise addition is with keeping body
It is that temperature is defined no more than 20 DEG C, preferably 0~20 DEG C, further preferred 0~10 DEG C of system temperature.
The preparation method of described 3- ethylsulfonyl -2- pyridine sulfonamides preferably includes following post-processing step：Reaction knot
Shu Hou, regulation pH are 7.0~7.5, filtering, washing, dry, obtain 3- ethylsulfonyl -2- pyridine sulfonamides.Described regulation pH
It is preferred that using sulfuric acid, the mass concentration preferably 50%~80% of described sulfuric acid, described mass concentration refers to the quality of sulfuric acid
Account for the percentage of aqueous sulfuric acid gross mass.Described filtering, washing, drying can use the routine of the generic operation in this area
Method.
The preparation method of described 3- ethylsulfonyl -2- pyridine sulfonamides preferably uses following route：
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can be combined, and it is each preferably to produce the present invention
Example.
Agents useful for same and raw material of the present invention are commercially available.
The positive effect of the present invention is：The preparation method of the present invention, has used cheap 2, the 3- dichloropyridines to be
Raw material, reactions steps are simple, total recovery is high (reaching as high as 64.2%), greatly reduce production cost, are suitable for industrializing
Production.
Embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described reality
Apply among a scope.The experimental method of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product specification selects.
Embodiment 1
The DMF (DMF) of 80.00g sodium hydroxide (2.0mol) and 350g is mixed in reaction bulb
Afterwards, 0~5 DEG C is cooled to, in the case where being stirred continuously, the DMF solution (ethyl mercaptan of ethyl mercaptan is slowly added dropwise：(124.26g 2.0mol),
DMF：80g), system temperature is kept during dropwise addition at 0~5 DEG C.Drop finishes, and continues insulated and stirred 1~2 hour, until reaction bulb
Middle sodium hydrate solid is completely dissolved.System is warming up to 80~100 DEG C, be slowly added dropwise 2,3- dichloropyridines DMF solution (2,
3 dichloropyridines：134.54g (0.91mol), DMF：200g), during dropwise addition maintenance system temperature at 80~100 DEG C.Drop finishes,
Insulated and stirred 3~5 hours, is controlled in sampling, when the HPLC contents of 2,3- dichloropyridines are less than 0.5%, it is believed that reaction terminates.
After depressurizing slow desolvation and low-boiling-point substance, obtaining the 172.35g crude product of 2,3- diethyl sulfide yl pyridines, (HPLC is pure
Degree：92.0%, yield：87.5%).
Embodiment 2
112.22g potassium hydroxide (2.0mol) and 350g DMA (DMA) are mixed in reaction bulb
After conjunction, 0~5 DEG C is cooled to, in the case where being stirred continuously, the DMA solution (ethyl mercaptans of ethyl mercaptan are slowly added dropwise：124.26g
(2.0mol), DMA：80g), system temperature is kept during dropwise addition at 0~5 DEG C.Drop finishes, and continues insulated and stirred 1~2 hour, directly
Into reaction bulb, potassium hydroxide solid is completely dissolved, and produces the DMA solution of ethyl mercaptan potassium.
After 134.54g 2,3- dichloropyridines (0.91mol) are dissolved in into 200g DMA, system is warming up to 80~100
DEG C, the DMA solution of the above-mentioned ethyl mercaptan potassium prepared is slowly added dropwise, maintenance system temperature is at 80~100 DEG C during dropwise addition.Drop
Finish, insulated and stirred 3~5 hours, controlled in sampling, when the HPLC contents of 2,3- dichloropyridines are less than 0.5%, it is believed that reaction knot
Beam.
After depressurizing slow desolvation and low-boiling-point substance, obtaining the 174.88g crude product of 2,3- diethyl sulfide yl pyridines, (HPLC is pure
Degree：91.5%, yield：88.3%).
Embodiment 3
After 2,3- diethyl sulfide yl pyridines (0.20mol) prepared by 40.0g embodiment 1 are dissolved in into 80g glacial acetic acid, slowly
(described mass concentration refers to that the quality of hydrogen peroxide accounts for hydrogen peroxide to the hydrogen peroxide solution that the mass concentration that 100g is added dropwise is 30%
The percentage of gross mass), with being slowly added to for hydrogen peroxide, system temperature gradually rises, when system temperature rises to 75~80 DEG C
When, 1/3 hydrogen peroxide solution has about been added dropwise.Stop being added dropwise, system is cooled using ice bath, when system temperature is reduced to
At 70 DEG C, continue to start that remaining hydrogen peroxide solution is added dropwise, maintenance system temperature is at 70~85 DEG C during dropwise addition.Drop finishes,
70~85 DEG C are incubated 4 hours, are controlled in sampling, and now 2,3- diethyl sulfide yl pyridines HPLC contents are 7%, continue in 70~85 DEG C of guarantors
Temperature 1 hour, 2,3- diethyl sulfide yl pyridines HPLC contents are not decreased obviously.
- 5~0 DEG C is cooled to, filtering, gained filter cake makes after being washed with a small amount, and is dried in vacuo, and obtains 43.86g 2,3- bis-
B sulfonyl pyridine (HPLC purity：96.5%, yield：80.1%).
Embodiment 4
After 2,3- diethyl sulfide yl pyridines (0.20mol) prepared by 40.0g embodiment 1 are dissolved in into 80g glacial acetic acid, add
0.30g sodium tungstate (0.001mol), then be slowly added dropwise 100g mass concentration be 30% hydrogen peroxide solution (described quality
Concentration refers to that the quality of hydrogen peroxide accounts for the percentage of hydrogen peroxide gross mass), with being slowly added to for hydrogen peroxide, system temperature by
Edge up height, and when system temperature rises to 75~80 DEG C, 1/4 hydrogen peroxide solution has about been added dropwise.Stop being added dropwise, use ice bath pair
System is cooled, and when system temperature is reduced to 70 DEG C, is continued to start that remaining hydrogen peroxide solution is added dropwise, is tieed up during dropwise addition
System temperature is held at 70~85 DEG C.Drop finishes, and is incubated 4 hours at 70~85 DEG C, is controlled in sampling, now 2,3- diethyl sulfide yl pyridines contain
Measure as 2.8%, continue to be incubated 1 hour at 70~85 DEG C, 2,3- diethyl sulfide yl pyridines HPLC contents are less than 1%, it is believed that reaction knot
Beam.
- 5~0 DEG C is cooled to, filtering, gained filter cake makes after being washed with a small amount, and is dried in vacuo, and obtains 48.75g 2,3- bis-
B sulfonyl pyridine (HPLC purity：96.8%, yield：89.3%).
Embodiment 5
After 2,3- diethyl sulfide yl pyridines (0.20mol) prepared by 40.0g embodiment 1 are dissolved in into 80g glacial acetic acid, add
0.30g sodium tungstate (0.001mol), then be slowly added dropwise 50g mass concentration be 30% hydrogen peroxide solution (described quality
Concentration refers to that the quality of hydrogen peroxide accounts for the percentage of hydrogen peroxide gross mass), with being slowly added to for hydrogen peroxide, system temperature by
Edge up height, and when system temperature rises to 75~80 DEG C, 1/4 hydrogen peroxide solution has about been added dropwise.Stop being added dropwise, use ice bath pair
System is cooled, and when system temperature is reduced to 70 DEG C, is continued to start that remaining hydrogen peroxide solution is added dropwise, is tieed up during dropwise addition
System temperature is held at 70~85 DEG C.Drop finishes, and 4 hours are incubated at 70~85 DEG C.Middle control sampling, HPLC spectrograms show 2- Asias second sulphonyl
Base -3- ethylmercapto group pyridine contents are：25%, 3- Asia ethylsulfonyl -2- ethylmercapto group pyridine contents are：32%, 2,3- bis- sub- second sulphurs
Acyl pyridine content is：23%, 2,3- diethyl sulfide yl pyridines HPLC contents are 10%.Further post-processing operation is not carried out.
Embodiment 6
By the 30.0g vulcanized sodium (purity of purchase reagent：60%, 0.23mol, described percentage refer to vulcanized sodium
Quality accounts for the percentage of sodium sulfide reagent gross mass) it is dissolved in 130g water, 80~90 DEG C are warming up to, adds 7.36g sulphur powder.
80~90 DEG C of maintenance system temperature, insulated and stirred 1 hour.
DMF solution (2, the 3- bis- ethylsulfonyl pyrroles for the b sulfonyl pyridines of 2,3- bis- being slowly dropped into prepared by embodiment 4
Pyridine：HPLC purity 96.8%, 48.13g, 0.177mol；DMF：100g).Drop finishes, and system temperature risen into 110~120 DEG C, and
4 hours are incubated at 110~120 DEG C.Controlled in sampling, when the HPLC contents of the b sulfonyl pyridines of 2,3- bis- are less than 0.5%, it is believed that
Reaction terminates.
System is cooled to 70~80 DEG C, maintains the temperature, it is 36% concentrated hydrochloric acid (described matter that mass concentration, which is slowly added dropwise,
Amount concentration refers to that the quality of hydrogen chloride accounts for the percentage of concentrated hydrochloric acid gross mass), until the pH value of system is 5.0~6.0.By system
Temperature is down to 20~30 DEG C, and insulated and stirred 1 hour, filtering, filter cake makes to be washed with a small amount, is dried in vacuo, final to obtain 44.72g
3- ethylsulfonyl -2- mercaptopyridine (HPLC purity：77.35%, yield：93.1%).
Embodiment 7
By the 18.5g NaHS (purity of purchase reagent：60%, 0.23mol, described percentage refer to vulcanized sodium
Quality account for the percentage of sodium sulfide reagent gross mass) be dissolved in 60g water, be warming up to 80~90 DEG C.It is slowly dropped into embodiment 4
DMF solution (2,3- bis- b sulfonyl pyridines of the prepared b sulfonyl pyridines of 2,3- bis-：Purity：96.8%, 48.13g,
0.177mol；DMF：100g).Drop finishes, and system temperature is risen into 110~120 DEG C, and be incubated 4 hours at 110~120 DEG C.Sampling
Middle control, when the HPLC contents of the b sulfonyl pyridines of 2,3- bis- are less than 0.5%, it is believed that reaction terminates.
System is cooled to 70~80 DEG C, maintains the temperature, it is 36% concentrated hydrochloric acid (described matter that mass concentration, which is slowly added dropwise,
Amount concentration refers to that the quality of hydrogen chloride accounts for the percentage of concentrated hydrochloric acid gross mass), until the pH value of system is 5.0~6.0.By system
Temperature is down to 20~30 DEG C, and insulated and stirred 1 hour, filtering, filter cake makes to be washed with a small amount, is dried in vacuo, final to obtain 36.92g
3- ethylsulfonyl -2- mercaptopyridine (HPLC purity：94.10%, yield：93.5%).
Embodiment 8
By the 42.7g NaHS (purity of purchase reagent：70%, 0.53mol, described percentage refer to vulcanized sodium
Quality account for the percentage of sodium sulfide reagent gross mass) be dissolved in 140g water, be warming up to 80~90 DEG C.It is slowly dropped into embodiment
DMF solution (2,3- bis- b sulfonyl pyridines of the b sulfonyl pyridines of 2,3- bis- prepared by 4：HPLC purity 96.8%,
48.13g 0.177mol；DMF：100g).Drop finishes, and system temperature is risen into 110~120 DEG C, and small in 110~120 DEG C of insulations 4
When.Controlled in sampling, when the HPLC contents of the b sulfonyl pyridines of 2,3- bis- are less than 0.5%, it is believed that reaction terminates.
System is cooled to 70~80 DEG C, maintains the temperature, it is 36% concentrated hydrochloric acid (described matter that mass concentration, which is slowly added dropwise,
Amount concentration refers to that the quality of hydrogen chloride accounts for the percentage of concentrated hydrochloric acid gross mass), until the pH value of system is 5.0~6.0.By system
Temperature is down to 20~30 DEG C, and insulated and stirred 1 hour, filtering, filter cake makes to be washed with a small amount, is dried in vacuo, final to obtain 37.16g
3- ethylsulfonyl -2- mercaptopyridine (HPLC purity：94.10%, yield：94.1%).
Embodiment 9
25.0g prepared by embodiment 7 3- ethylsulfonyl -2- mercaptopyridine (HPLC purity：94.10%,
0.116mol) it is dissolved in the mixed liquor of 180g water and 300g dichloromethane, system temperature is down to -5~0 DEG C, is slowly introducing
29.2g chlorine, lead in chlorine process and keep system temperature to be no more than 10 DEG C.After logical chlorine terminates, 0~10 DEG C of maintenance system temperature,
Insulation 0.5~1.0 hour.Controlled in sampling, when 3- ethylsulfonyl -2- mercaptopyridine HPLC contents are less than 0.5%, it is believed that chlorination
Reaction terminates.
The organic phase after chlorination is separated, is cooled to 0~10 DEG C, the ammoniacal liquor of 74.6g mass concentration 8% is slowly added dropwise
(0.35mol, described mass concentration refer to that the quality of ammonia accounts for the percentage of ammonia spirit gross mass).Drop finishes, 0~10 DEG C of guarantor
Temperature 0.5~1.0 hour.Controlled in sampling, when 3- ethylsulfonyl -2- pyridine sulfonyl chloride HPLC contents are less than 0.5%, it is believed that reaction
Terminate.The aqueous sulfuric acid that mass concentration is 50% is added dropwise, and (it is total that described mass concentration refers to that the quality of sulfuric acid accounts for sulfuric acid solution
The percentage of quality), adjust pH to 7.0~7.5.Filtering, gained filter cake use q. s. methylene chloride and water washing, vacuum respectively
Dry, obtain 25.45g 3- ethylsulfonyl -2- pyridine sulfonamide (HPLC purity：97.3%, yield：85.5%).
Embodiment 10
25.0g prepared by embodiment 7 3- ethylsulfonyl -2- mercaptopyridine (HPLC purity：94.10%,
0.116mol) it is dissolved in the mixed liquor of 180g water and 300g dichloromethane, system temperature is down to -5~0 DEG C, is slowly introducing
29.2g chlorine, lead in chlorine process and keep system temperature to be no more than 10 DEG C.After logical chlorine terminates, 0~10 DEG C of maintenance system temperature,
Insulation 0.5~1.0 hour.Controlled in sampling, when 3- ethylsulfonyl -2- mercaptopyridine HPLC contents are less than 0.5%, it is believed that chlorination
Reaction terminates.Separate the dichloromethane solution that organic phase obtains 3- ethylsulfonyl -2- pyridine sulfonyl chlorides.
By 74.6g mass concentration be 8% ammoniacal liquor (0.35mol, described mass concentration refer to that the quality of ammonia accounts for ammonia
The percentage of aqueous solution gross mass) 0~10 DEG C is cooled to, the temperature is maintained, the 3- ethylsulfonyls -2- of above-mentioned preparation is slowly added dropwise
The dichloromethane solution of pyridine sulfonyl chloride.Drop finishes, and 0~10 DEG C is incubated 0.5~1.0 hour.Controlled in sampling, when 3- ethylsulfonyls-
When 2- pyridine sulfonyl chloride HPLC contents are less than 0.5%, it is believed that reaction terminates.The aqueous sulfuric acid that mass concentration is 50% is added dropwise
(described mass concentration refers to that the quality of sulfuric acid accounts for the percentage of sulfuric acid solution gross mass), adjust pH to 7.0~7.5.Filtering,
Gained filter cake uses q. s. methylene chloride and water washing respectively, vacuum drying, obtains 25.82g 3- ethylsulfonyl -2- pyridine sulfonyl sulfonyls
Amine (HPLC purity：97.7%, yield：87.1%).
Claims (17)
1. a kind of preparation method of 3- ethylsulfonyls -2- mercaptopyridines, it is characterised in that it comprises the following steps：Described 3- second
The preparation method of sulfonyl -2- mercaptopyridines, using following steps：The solution that the b sulfonyl pyridines of 2,3- bis- and solvent are formed
It is added in the mixture that sulfhydrylization reagent is formed with water, is warming up to 110 DEG C~120 DEG C, carries out nucleophilic substitution and obtain 3-
Ethylsulfonyl -2- mercaptopyridines；Described sulfhydrylization reagent is NaHS；Described solvent be water, amide solvent,
One or more in sulfoxide type solvents and sulfone class solvent；The temperature of described " mixture that sulfhydrylization reagent is formed with water " is
80 DEG C~90 DEG C；
2. the preparation method of 3- ethylsulfonyls -2- mercaptopyridines as claimed in claim 1, it is characterised in that：
In the preparation method of described 3- ethylsulfonyl -2- mercaptopyridines, described amide solvent is N, N- dimethyl methyls
Acid amides and/or 1-METHYLPYRROLIDONE；
And/or
In the preparation method of described 3- ethylsulfonyl -2- mercaptopyridines, described sulfoxide type solvents are dimethyl sulfoxide (DMSO)；
And/or
In the preparation method of described 3- ethylsulfonyl -2- mercaptopyridines, described sulfone class solvent is sulfolane；And/or
In the preparation method of described 3- ethylsulfonyl -2- mercaptopyridines, described solvent and described 2,3- diethyl sulphonyl
Yl pyridines mass values are 1~10；
And/or
In the preparation method of described 3- ethylsulfonyl -2- mercaptopyridines, described sulfhydrylization reagent and described 2,3- bis-
The molar ratio of b sulfonyl pyridine is 1~3；
And/or
In the preparation method of described 3- ethylsulfonyl -2- mercaptopyridines, the time of described nucleophilic substitution is 2 hours
~8 hours；
And/or
The preparation method of described 3- ethylsulfonyl -2- mercaptopyridines includes following post-processing step：After reaction terminates, it is cooled to
70 DEG C~80 DEG C, regulation pH value is 5.0~6.0, then is cooled to 20 DEG C~30 DEG C, is filtered, and is washed, and dries, obtains 3- second sulphonyl
Base -2- mercaptopyridines.
3. the preparation method of 3- ethylsulfonyls -2- mercaptopyridines as claimed in claim 2, it is characterised in that：
In the preparation method of described 3- ethylsulfonyl -2- mercaptopyridines, described solvent and described 2,3- diethyl sulphonyl
Yl pyridines mass values are 3~6；
And/or
In the preparation method of described 3- ethylsulfonyl -2- mercaptopyridines, the time of described nucleophilic substitution is 3 hours
~5 hours；
And/or
In the step of preparation method of described 3- ethylsulfonyl -2- mercaptopyridines uses, the mode of described addition is dropwise addition,
The speed of described dropwise addition is holding system temperature at 110 DEG C~120 DEG C；
And/or
In the post-processing step that the preparation method of described 3- ethylsulfonyl -2- mercaptopyridines includes, described regulation pH is used
Concentrated hydrochloric acid.
4. the preparation method of the 3- ethylsulfonyl -2- mercaptopyridines as described in claim any one of 1-3, it is characterised in that：Institute
The preparation method for the 3- ethylsulfonyl -2- mercaptopyridines stated further comprises the steps：In solvent, by 2,3- diethyl sulfenyl pyrroles
Pyridine carries out oxidation reaction with oxidant and obtains the described b sulfonyl pyridines of 2,3- bis-；
5. the preparation method of 3- ethylsulfonyls -2- mercaptopyridines as claimed in claim 4, it is characterised in that：Described 2,
In the preparation method of the b sulfonyl pyridines of 3- bis-, described solvent is organic acid solvent；
And/or
In the preparation method of the described b sulfonyl pyridines of 2,3- bis-, described solvent and described 2,3- diethyl sulfide yl pyridines
Mass values be 0.1~10；
And/or
In the preparation method of the described b sulfonyl pyridines of 2,3- bis-, described oxidant is metachloroperbenzoic acid, dioxygen
Water, Peracetic acid, peroxide list potassium sulfonate, potassium permanganate or sodium hypochlorite；
And/or
In the preparation method of the described b sulfonyl pyridines of 2,3- bis-, described oxidant and described 2,3- diethyl sulfenyl pyrroles
The molar ratio of pyridine is 4~6；
And/or
In the preparation method of the described b sulfonyl pyridines of 2,3- bis-, the temperature of described oxidation reaction is 20 DEG C~85 DEG C；
And/or
In the preparation method of the described b sulfonyl pyridines of 2,3- bis-, the time of described oxidation reaction is small for 2 hours~10
When；
And/or
In the preparation method of the described b sulfonyl pyridines of 2,3- bis-, when oxidant is hydrogen peroxide, reacts and deposited in catalyst
Carry out under the conditions；
And/or
The preparation method of the described b sulfonyl pyridines of 2,3- bis- uses following steps：To 2,3- diethyl sulfide yl pyridines with it is organic molten
Dosage form into mixture in add oxidant, carry out oxidation reaction and obtain the b sulfonyl pyridines of 2,3- bis-；Or to 2,3- diethyls
Oxidant is added in the mixture that sulfenyl pyridine, catalyst and organic solvent are formed, oxidation reaction is carried out and obtains 2,3- diethyl sulphurs
Acyl pyridine；
And/or
The preparation method of the described b sulfonyl pyridines of 2,3- bis- uses following post-processing steps：After reaction terminates, -5 are cooled to
DEG C~0 DEG C, filter, washing, be dried to obtain the b sulfonyl pyridines of 2,3- bis-.
6. the preparation method of 3- ethylsulfonyls -2- mercaptopyridines as claimed in claim 5, it is characterised in that：Described 2,
In the preparation method of the b sulfonyl pyridines of 3- bis-, described organic acid solvent is in acetic acid, trichloroacetic acid and trifluoroacetic acid
It is one or more；
And/or
In the preparation method of the described b sulfonyl pyridines of 2,3- bis-, described solvent and described 2,3- diethyl sulfide yl pyridines
Mass values be 0.5~5；
And/or
In the preparation method of the described b sulfonyl pyridines of 2,3- bis-, the mass concentration of described hydrogen peroxide for 20%~
50%, described mass concentration refers to that the quality of hydrogen peroxide accounts for the percentage of hydrogen peroxide gross mass；
And/or
In the preparation method of the described b sulfonyl pyridines of 2,3- bis-, described oxidant and described 2,3- diethyl sulfenyl pyrroles
The molar ratio of pyridine is 4~4.8；
And/or
In the preparation method of the described b sulfonyl pyridines of 2,3- bis-, the temperature of described oxidation reaction is 70 DEG C~85 DEG C；
And/or
In the preparation method of the described b sulfonyl pyridines of 2,3- bis-, the time of described oxidation reaction is small for 2 hours~5
When；
And/or
In the preparation method of the described b sulfonyl pyridines of 2,3- bis-, when oxidant is hydrogen peroxide and is reacted in catalyst presence
Under conditions of when carrying out, described catalyst is one in manganese dioxide, ferric trichloride, sodium tungstate, molybdenum trioxide and ammonium molybdate
Kind is a variety of；
And/or
In the preparation method of the described b sulfonyl pyridines of 2,3- bis-, when oxidant is hydrogen peroxide and is reacted in catalyst presence
Under conditions of when carrying out, the molar ratio of described catalyst and described 2,3- diethyl sulfide yl pyridines is 0.001~0.01；
And/or
In the step of preparation method of the described b sulfonyl pyridines of 2,3- bis- uses, the mode of described addition is is added dropwise, drop
The speed maintenance system temperature added is defined no more than 70 DEG C.
7. the preparation method of 3- ethylsulfonyls -2- mercaptopyridines as claimed in claim 4, it is characterised in that：Described 3- second
The preparation method of sulfonyl -2- mercaptopyridines further comprises the following steps：In a solvent, under the conditions of alkali is existing, will change
Compound 1 carries out nucleophilic substitution with second sulfhydrylization reagent and obtains described 2,3- diethyl sulfide yl pyridines；
Wherein, X1For fluorine, chlorine, bromine or iodine；X2For chlorine, bromine or iodine.
8. the preparation method of 3- ethylsulfonyls -2- mercaptopyridines as claimed in claim 7, it is characterised in that：Described 2,
In the preparation method of 3- diethyl sulfide yl pyridines, described solvent is one in amide solvent, sulfoxide type solvents and sulfone class solvent
Kind is a variety of；
And/or
In the preparation method of described 2,3- diethyl sulfide yl pyridines, described solvent and the mass values of described compound 1
For 1~10；
And/or
In the preparation method of described 2,3- diethyl sulfide yl pyridines, described alkali is inorganic base；
And/or
In the preparation method of described 2,3- diethyl sulfide yl pyridines, the mass values of described alkali and described compound 1 are 2
~3；
And/or
In the preparation method of described 2,3- diethyl sulfide yl pyridines, described ethylmercapto group reagent is ethyl mercaptan；
And/or
In the preparation method of described 2,3- diethyl sulfide yl pyridines, described ethylmercapto group reagent and described compound 1
Mass values are 2~3；
And/or
In the preparation method of described 2,3- diethyl sulfide yl pyridines, the temperature of described nucleophilic substitution is 50 DEG C~130
℃；
And/or
In the preparation method of described 2,3- diethyl sulfide yl pyridines, the time of described nucleophilic substitution is 2 hours~10
Hour.
9. the preparation method of 3- ethylsulfonyls -2- mercaptopyridines as claimed in claim 8, it is characterised in that：Described 2,
In the preparation method of 3- diethyl sulfide yl pyridines, described amide solvent is DMF, N, N- dimethylacetamides
One or more in amine, 1,3- dimethyl-imidazolinones, 1-METHYLPYRROLIDONE and hexamethyl phosphoramide；
And/or
In the preparation method of described 2,3- diethyl sulfide yl pyridines, described sulfoxide type solvents are dimethyl sulfoxide；
And/or
In the preparation method of described 2,3- diethyl sulfide yl pyridines, described sulfone class solvent is sulfolane；
And/or
In the preparation method of described 2,3- diethyl sulfide yl pyridines, described solvent and the mass values of described compound 1
For 2~5；
And/or
In the preparation method of described 2,3- diethyl sulfide yl pyridines, described inorganic base is sodium hydride, sodium hydroxide and hydrogen-oxygen
Change the one or more in potassium；
And/or
In the preparation method of described 2,3- diethyl sulfide yl pyridines, the mass values of described alkali and described compound 1 are 2
~2.5；
And/or
In the preparation method of described 2,3- diethyl sulfide yl pyridines, described ethylmercapto group reagent and described compound 1
Mass values are 2~2.5；
And/or
In the preparation method of described 2,3- diethyl sulfide yl pyridines, the temperature of described nucleophilic substitution is 80 DEG C~100
℃；
And/or
In the preparation method of described 2,3- diethyl sulfide yl pyridines, the time of described nucleophilic substitution is small for 3 hours~5
When.
10. the preparation method of 3- ethylsulfonyls -2- mercaptopyridines as claimed in claim 7, it is characterised in that：Described 2,3-
The preparation method of diethyl sulfide yl pyridines uses following steps：The mixture that sulfhydrylization reagent and solvent are formed is added into alkali and solvent
In the mixture of formation, react to solid and be completely dissolved, add the mixture that compound 1 is formed with organic solvent, be warming up to 80
DEG C~100 DEG C, nucleophilic substitution is carried out, obtains 2,3- diethyl sulfide yl pyridines；
And/or
The preparation method of described 2,3- diethyl sulfide yl pyridines includes following post-processing step：Reaction terminate after, remove solvent and
Low-boiling by-products, obtain 2,3- diethyl sulfide yl pyridines.
11. the preparation method of 3- ethylsulfonyls -2- mercaptopyridines as claimed in claim 10, it is characterised in that：Described 2,
In the step of preparation method of 3- diethyl sulfide yl pyridines uses, to be added dropwise, described " tries sulfhydrylation the mode of described addition
The mixture that agent and solvent are formed is added in the mixture that alkali is formed with solvent " speed that is added dropwise be maintenance reaction system temperature
No more than 0~5 DEG C, the speed that described " adding the mixture that compound 1 is formed with organic solvent " is added dropwise is maintenance reaction body
The temperature of system is 80 DEG C~100 DEG C；
And/or
In the post-processing step that the preparation method of described 2,3- diethyl sulfide yl pyridines includes, described removing solvent and low boiling
Accessory substance is by the way of being evaporated under reduced pressure.
12. a kind of preparation method of 3- ethylsulfonyls -2- pyridine sulfonyl chlorides, it is characterised in that it comprises the following steps：According to power
After profit requires that 3- ethylsulfonyl -2- mercaptopyridines are made in the preparation method described in 1~11 any one, then in a solvent, by described in
3- ethylsulfonyl -2- mercaptopyridines and oxidant carry out oxidation reaction, obtain 3- ethylsulfonyl -2- pyridine sulfonyl chlorides；
13. the preparation method of 3- ethylsulfonyls -2- pyridine sulfonyl chlorides as claimed in claim 12, it is characterised in that：
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonyl chlorides, described solvent is that water and/or halogenated hydrocarbon are molten
Agent；
And/or
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonyl chlorides, described solvent and described 3- ethylsulfonyls -
The mass values of 2- mercaptopyridines are 1~50；
And/or
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonyl chlorides, described oxidant is sodium hypochlorite or chlorine；
And/or
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonyl chlorides, described oxidant and described 3- second sulphonyl
The molar ratio of base -2- mercaptopyridines is 1~5；
And/or
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonyl chlorides, the temperature of described oxidation reaction for -10 DEG C~
20℃；
And/or
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonyl chlorides, the time of described oxidation reaction is 0.5 hour
~2 hours；
And/or
When oxidant is chlorine, the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonyl chlorides uses following steps：- 5
DEG C~0 DEG C, lead to chlorine into 3- ethylsulfonyl -2- mercaptopyridines and the mixture of solvent formation, carry out oxidation reaction and obtain 3-
Ethylsulfonyl -2- pyridine sulfonyl chlorides；
And/or
It is not post-treated after 3- ethylsulfonyl -2- pyridine sulfonyl chlorides described in being made directly to contain 3- ethylsulfonyl -2- pyrroles
The organic phase of pyridine sulfonic acid chloride prepare the reaction of 3- ethylsulfonyl -2- pyridine sulfonamides.
14. the preparation method of 3- ethylsulfonyls -2- pyridine sulfonyl chlorides as claimed in claim 13, it is characterised in that：
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonyl chlorides, described halogenated hydrocarbon solvent is chlorinated hydrocarbon
Solvent；
And/or
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonyl chlorides, described solvent and described 3- ethylsulfonyls -
The mass values of 2- mercaptopyridines are 15~20；
And/or
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonyl chlorides, described oxidant and described 3- second sulphonyl
The molar ratio of base -2- mercaptopyridines is 3~3.5；
And/or
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonyl chlorides, the temperature of described oxidation reaction is 0 DEG C~10
℃；
And/or
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonyl chlorides, the time of described oxidation reaction is 0.5 hour
~1 hour；
And/or
When oxidant is chlorine, in the step of preparation methods of described 3- ethylsulfonyl -2- pyridine sulfonyl chlorides uses, lead to chlorine
The speed of gas is that maintenance system temperature is no more than 10 DEG C.
15. a kind of preparation method of 3- ethylsulfonyls -2- pyridine sulfonamides, it is characterised in that it comprises the following steps：According to power
After profit requires that 3- ethylsulfonyl -2- pyridine sulfonyl chlorides are made in preparation method described in 1~14, then by described 3- ethylsulfonyls -
2- pyridine sulfonyl chlorides carry out condensation reaction with ammoniacal liquor, obtain 3- ethylsulfonyl -2- pyridine sulfonamides；
16. the preparation method of 3- ethylsulfonyls -2- pyridine sulfonyl chlorides as claimed in claim 15, it is characterised in that：
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonamides, described ammoniacal liquor and described 3- ethylsulfonyls -
The molar ratio of 2- pyridine sulfonyl chlorides is 1~10；
And/or
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonamides, the temperature of described condensation reaction for -10 DEG C~
20℃；
And/or
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonamides, the time of described condensation reaction is 0.5 hour
~2 hours；
And/or
The preparation method of described 3- ethylsulfonyl -2- pyridine sulfonamides uses following steps：Ammoniacal liquor is added to 3- second sulphonyl
In the mixture that base -2- pyridine sulfonyl chlorides are formed with organic solvent, condensation reaction is carried out, obtains 3- ethylsulfonyl -2- pyridine sulphurs
Acid amides；Or the mixture for forming 3- ethylsulfonyl -2- pyridine sulfonyl chlorides and organic solvent is added in ammoniacal liquor, is condensed
Reaction, obtains 3- ethylsulfonyl -2- pyridine sulfonamides；
And/or
The preparation method of described 3- ethylsulfonyl -2- pyridine sulfonamides includes following post-processing step：After reaction terminates, regulation
PH is 7.0~7.5, filtering, washing, dries, obtains 3- ethylsulfonyl -2- pyridine sulfonamides.
17. the preparation method of 3- ethylsulfonyls -2- pyridine sulfonyl chlorides as claimed in claim 16, it is characterised in that：
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonamides, described ammoniacal liquor and described 3- ethylsulfonyls -
The molar ratio of 2- pyridine sulfonyl chlorides is 3~5；
And/or
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonamides, the mass concentration of described ammoniacal liquor for 8%~
25%, described mass concentration refers to that the quality of ammonia accounts for the percentage of ammonia spirit gross mass；
And/or
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonamides, the temperature of described condensation reaction is 0 DEG C~10
℃；
And/or
In the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonamides, the time of described condensation reaction is 0.5 hour
~1 hour；
And/or
In the step of preparation method of described 3- ethylsulfonyl -2- pyridine sulfonamides uses, the mode of described addition is drop
Add, the speed of dropwise addition is to keep system temperature to be defined no more than 20 DEG C；
And/or
In the post-processing step that the preparation method of described 3- ethylsulfonyl -2- pyridine sulfonamides includes, described regulation pH is adopted
With sulfuric acid, the mass concentration of described sulfuric acid is 50%~80%, and described mass concentration refers to that the quality of sulfuric acid accounts for sulfuric acid water
The percentage of solution gross mass.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510586851.3A CN105153022B (en) | 2015-09-16 | 2015-09-16 | The preparation method of the pyridine sulfonamide of 3 ethylsulfonyl 2 and its intermediate |
Applications Claiming Priority (1)
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1349505A (en) * | 1999-05-14 | 2002-05-15 | 住友精化株式会社 | Process for preparing tribomomethylsulfonylphyridine |
| WO2008021491A2 (en) * | 2006-08-16 | 2008-02-21 | Achillion Pharmaceuticals, Inc. | Method for synthesis of 8-alkoxy-9h-isothiazolo[5,4-b]quinoline-3,4-diones |
| WO2008131415A1 (en) * | 2007-04-23 | 2008-10-30 | Achillion Pharmaceuticals, Inc. | 4-substituted-1h-isothiazolo[5,4-b][1,4]oxazino[2,3,4-ij]quinoline-7,8(2h,9h)-diones and related compounds as anti-infective agents |
| WO2013096785A1 (en) * | 2011-12-21 | 2013-06-27 | Achillion Pharmaceuticals, Inc. | 2-substituted-thienoquinolones and related compounds as anti-infective agents |
-
2015
- 2015-09-16 CN CN201510586851.3A patent/CN105153022B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1349505A (en) * | 1999-05-14 | 2002-05-15 | 住友精化株式会社 | Process for preparing tribomomethylsulfonylphyridine |
| WO2008021491A2 (en) * | 2006-08-16 | 2008-02-21 | Achillion Pharmaceuticals, Inc. | Method for synthesis of 8-alkoxy-9h-isothiazolo[5,4-b]quinoline-3,4-diones |
| WO2008131415A1 (en) * | 2007-04-23 | 2008-10-30 | Achillion Pharmaceuticals, Inc. | 4-substituted-1h-isothiazolo[5,4-b][1,4]oxazino[2,3,4-ij]quinoline-7,8(2h,9h)-diones and related compounds as anti-infective agents |
| WO2013096785A1 (en) * | 2011-12-21 | 2013-06-27 | Achillion Pharmaceuticals, Inc. | 2-substituted-thienoquinolones and related compounds as anti-infective agents |
Non-Patent Citations (2)
| Title |
|---|
| bis-Alkylsulfonylpyridines;S. G. Woods，等;《J. Heterocyclic Chem.》;19840228(第21期);第97-101页 * |
| 除草剂砜嘧磺隆的合成研究;谭晓军，等;《精细化工中间体》;20050630;第35卷(第3期);第26-27页 * |
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