CN104487419A - Novel pyridine derivatives and method for preparation of intermediate compound for producing sulfonylurea herbicides using the same - Google Patents
Novel pyridine derivatives and method for preparation of intermediate compound for producing sulfonylurea herbicides using the same Download PDFInfo
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- CN104487419A CN104487419A CN201380037273.7A CN201380037273A CN104487419A CN 104487419 A CN104487419 A CN 104487419A CN 201380037273 A CN201380037273 A CN 201380037273A CN 104487419 A CN104487419 A CN 104487419A
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- A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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- 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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- 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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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
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Abstract
The present invention relates to a novel method for the preparation of a key intermediate compound for producing fluoroalkylpyridine-sulfonyl urea derivatives showing superior herbicidal activity, novel pyridine derivatives used in the preparation, and a method for the preparation thereof.
Description
[technical field]
The present invention relates to the new method preparing key intermediate compound, described midbody compound for generation of the fluoroalkyl pyridine-sulfonylurea derivative of the excellent weeding activity of display, for the preparation of new pyridine derivate and for the preparation of its method.
[background technology]
Following formula 1 compound is called flucetosulfuron (flucetosulfuron), and it has excellent weeding activity (WO 2002/030921).According to the open Application Publication No.2003-335758 of JP patent, prepared by the formula 1 compound midbody compound of following formula 2:
[formula 1]
[formula 2]
A represents C
3-C
5-alkyl or C
3-C
6-cycloalkyl, or representative be unsubstituted or with being selected from C
1-C
2-alkyl and C
1-C
2the benzyl of substituting group 1-to the 5-replacement of-alkoxyl group; With
Y represents fluorine, chlorine or bromine.
In order to introduce Key residues fluorine in formula 1 compound, wherein Y is needed to be the formula 2a compound of fluorine.Formula 2a compound obtains as follows: in a solvent by Cu (II) reactant salt of formula 4 compound and formula 5 with production 2b compound, optionally in the presence of a phase transfer catalyst itself and formula 6 compound are reacted, as shown in following reaction scheme 1 subsequently.
[reaction scheme 1]
Wherein A is with defined identical above, and Y ' represents chlorine or bromine, and M represents alkaline-earth metal such as sodium, potassium and caesium.
As shown in above-mentioned reaction, only in order to fluorine is introduced basic structure and formula 2a Compound Phase with formula 4 compound just need two-step reaction.In addition, be difficult to remove completely the Cu by product that this reaction inevitably produces, and above-mentioned by product impact fluoridation subsequently, reduce its yield.The pyridyl ketone derivative of formula 4 is disclosed in US 5,354,749A1, Kevin A.Memoli, TetrahedronLett.1996,37,3617 or DE 4,304,007A1, or they can be obtained by the similarity method be adversely made up of four-step reaction disclosed in it.
Consider the problems referred to above, contriver have studied thick and fast easily for the preparation of the method for formula 2 key intermediate compound of production 1 flucetosulfuron, successfully constructs C (=O) CHYCH by single step reaction
3(Y represents fluorine, chlorine or bromine) residue introduces the method for pyridine C-2 position.Adopt the method, inventors have developed the method starting from business material and prepare target formula 2 compound, just complete the inventive method by only two-step reaction.
[summary of the invention]
[technical problem]
The object of the invention is, provide the new method for the preparation of key intermediate compound, described midbody compound is for generation of the flucetosulfuron of the excellent weeding activity of display.
Another object of the present invention is, is provided for the new pyridine derivate preparing midbody compound, and for the preparation of its method.
[solution]
Therefore, the invention provides the pyridine derivate of the following formula 3 for the preparation of flucetosulfuron.
[formula 3]
Wherein,
D represents fluorine or chlorine, or represents S-A,
A represents C
3-C
5-alkyl or C
3-C
6-cycloalkyl, or representative be unsubstituted or with being selected from C
1-C
2-alkyl and C
1-C
2the benzyl of substituting group 1-to the 5-replacement of-alkoxyl group,
E represents bromine or C (=O) CHYCH
3, and
Y represents fluorine, chlorine or bromine.
The preferred compound of above-mentioned pyridine derivate is the pyridyl ketone derivative of following formula 3a and the 2-bromopyridine derivative of following formula 3b.
[formula 3a]
Wherein,
D represents fluorine or chlorine, and
Y represents fluorine, chlorine or bromine.
[formula 3b]
Wherein,
A represents C
3-C
5-alkyl or C
3-C
6-cycloalkyl, or representative be unsubstituted or with being selected from C
1-C
2-alkyl and C
1-C
2the benzyl of substituting group 1-to the 5-replacement of-alkoxyl group.
The example of preferred formula 3a compound is 1-(3-fluorine pyridine-2-base)-2-fluorine third-1-ketone, 1-(3-chloropyridine-2-base)-2-fluorine third-1-ketone, 1-(3-chloropyridine-2-base)-2-chlorine third-1-ketone and 1-(3-chloropyridine-2-base)-2-bromine third-1-ketone.
The example of preferred formula 3b compound is 2-bromo-3-isopropyisulfanyl pyridine, 2-bromo-3-benzylthio-pyridine, the bromo-3-of 2-(4-methoxy-benzyl) sulfenyl pyridine, the bromo-3-of 2-(uncle-butylthio) pyridine and 2-bromo-3-cyclohexylthio pyridine.
Formula 3a compound according to the present invention is prepared as follows: following formula 7 compound and n-Butyl Lithium and N, N-dimethylaminoethanol (DMAE) are reacted, then react with following formula 8 compound.
[formula 7]
[formula 8]
Wherein,
D represents fluorine or chlorine,
Y represents fluorine, chlorine or bromine, and
W represents C
1-C
4-alkoxyl group, C
1-C
4-dialkylamine or morpholine.
Formula 3b compound according to the present invention is prepared as follows: formula 10 compound and highly basic formula 11 amido lithium are reacted, then react with formula 12 electrophilic compound.
[formula 10]
[formula 11]
[formula 12]
A-S-X
Wherein,
N represents 0 or 3,
A represents C
3-C
5-alkyl or C
3-C
6-cycloalkyl, or representative be unsubstituted or with being selected from C
1-C
2-alkyl and C
1-C
2the benzyl of substituting group 1-to the 5-replacement of-alkoxyl group, and
X represents chlorine or S-A.
Particularly, when X is S-A, formula 12 compound is the di-sulphide compounds with following formula 12a symmetrical structure.
[formula 12a]
A-S-S-A
The feature of the method for formula 2 midbody compound for the preparation of flucetosulfuron produced according to the present invention is, formula 3a compound and formula 9 compound is reacted under Cu catalyzer, part, alkali and solvent exist.
[formula 3a]
[formula 9]
A-SH
[formula 2]
Wherein,
D represents fluorine or chlorine,
Y represents fluorine, chlorine or bromine, and
A represents C
3-C
5-alkyl or C
3-C
6-cycloalkyl, or representative be unsubstituted or with being selected from C
1-C
2-alkyl and C
1-C
2the benzyl of substituting group 1-to the 5-replacement of-alkoxyl group.
The feature of the another method of formula 2 midbody compound for the preparation of flucetosulfuron produced according to the present invention is, formula 3b compound and n-Butyl Lithium is reacted, and then reacts with formula 8 electrophilic compound.
[formula 3b]
[formula 8]
[formula 2]
Wherein,
W represents C
1-C
4-alkoxyl group, C
1-C
4-dialkylamine or morpholine,
Y represents fluorine, chlorine or bromine, and
A represents C
3-C
5-alkyl or C
3-C
6-cycloalkyl, or representative be unsubstituted or with being selected from C
1-C
2-alkyl and C
1-C
2the benzyl of substituting group 1-to the 5-replacement of-alkoxyl group.
After this, in more detail the present invention is described.
According to the present invention, provide two kinds of methods and method A and method B for the preparation of formula 2 midbody compound for the preparation of flucetosulfuron, depend on C (=O) CHYCH
3residue and S-A residue introduce the order of pyridine C-2 position and C-3 position respectively.
[method A]
In the first method of preparation formula 2 compound, first by C (=O) CHYCH
3residue introduces pyridine C-2 position, then S-A residue is introduced pyridine C-3 position.As raw material, formula 7 compound that can easily obtain and n-Butyl Lithium and N, N-dimethylaminoethanol (DMAE) reaction, lithium optionally to be introduced pyridine C-2 position, then reacts to produce new formula 3a compound by forming C-C key with formula 8 compound.Then, the of short duration process that formula 3a compound and formula 9 compound react can be prepared by formula 2 object compound under existing at Cu catalyzer, part, alkali and solvent.Formula 2b compound, wherein Y is chlorine or bromine, and can be converted into formula 2a compound by reacting with formula 6 compound in a solvent in the presence of a phase transfer catalyst, wherein Y is fluorine, as shown in above-mentioned reaction scheme 1.
Above-mentioned reaction and detailed description reaction conditions are as the description of following reaction scheme.
[reaction scheme 2]
Wherein,
D represents fluorine or chlorine,
Y represents fluorine, chlorine or bromine,
W represents C
1-C
4-alkoxyl group, C
1-C
4-dialkylamine or morpholine, and
A represents C
3-C
5-alkyl or C
3-C
6-cycloalkyl, or representative be unsubstituted or with being selected from C
1-C
2-alkyl and C
1-C
2the benzyl of substituting group 1-to the 5-replacement of-alkoxyl group.
The substituting group mentioned herein has following implication.
C
3-C
5-alkyl means propyl group, sec.-propyl, butyl, the second month in a season-butyl, isobutyl-, tert-butyl, amyl group, the second month in a season-amyl group and uncle-amyl group;
C
3-C
6-cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
C
1-C
2-alkyl means methyl and ethyl; With
C
1-C
2-alkoxy means methoxy and oxyethyl group.
The people such as Fort disclose and optionally remove formula 7 Compound C-2 hydrogen and method (Eur.J.Org.Chem.2001,603 of being introduced by lithium ion; Lett.Org.Chem.2009,6,50).In reaction scheme 2 the first step, by using Fort method, by the mixture reaction of formula 7 compound and n-Butyl Lithium and N, N-dimethylaminoethanol, optionally removing C-2 position hydrogen and introducing lithium ion.Once lithium ion state intermediate is formed, its can in same reaction container directly and formula 8 electrophilic compound react, to prepare new formula 3a midbody compound.The Conventional solvents not participating in reacting can be used in this step.Preferably use and be selected from alkane such as hexane and heptane, and ether such as dimethyl ether, diethyl ether, methyl tertiary butyl ether, glycol dimethyl ether, tetrahydrofuran (THF) He one or more solvents of diox.Reactions steps can the temperature of 0 to-90 DEG C, and preferably the temperature of-20 to-90 DEG C, more preferably the temperature of-40 to-78 DEG C is carried out.Formula 8 compound commercially can obtain and maybe can be prepared as follows: the Lipase absobed conventional from corresponding organic acid or acid amides synthesis.The consumption of formula 8 electrophilic compound is 0.9 to 1.5 equivalent, preferably 1.0 to 1.1 equivalents, based on initial formula 7 compound.
In the second step, under alkali, solvent, part and Cu catalyzer exist, new formula 3a midbody compound and formula 9 compound are reacted, to carry out preparation formula 2 object compound by forming C-S key.Alkali comprises mineral alkali such as cesium carbonate, salt of wormwood, sodium bicarbonate, or organic bases such as triethylamine, pyridine and diazabicylo hendecene (DBU).Preferred alkali is cesium carbonate, salt of wormwood and triethylamine, and preferred alkali is cesium carbonate and salt of wormwood.As Cu catalyzer, cupric oxide (Cu can be used
2o), cupric iodide (CuI), cupric chloride (CuCl) and cupric bromide (CuBr).Preferred catalyzer is cupric oxide (Cu
2or cupric iodide (CuI) O).The consumption of Cu catalyzer is 0.01 to 0.5 equivalent, and preferable amount is 0.05 to 0.2 equivalent.As solvent, aprotic polar solvent such as methyl-sulphoxide (DMSO) can be used, dimethyl formamide (DMF), N,N-DIMETHYLACETAMIDE (DMAC), N-crassitude (NMP) or aromatic solvent such as benzene, toluene and dimethylbenzene.Preferred solvent is methyl-sulphoxide, dimethyl formamide, N-crassitude or toluene, and preferred solvent is methyl-sulphoxide or dimethyl formamide.Reactions steps can 0 to 60 DEG C temperature and preferably the temperature of 15 to 25 DEG C carry out.2-(ethoxy carbonyl) pimelinketone, 1,2-cyclohexane diamine or N, N dimethylamine can be used as part.
[method B]
Second method of preparation formula 2 compound is, first S-A residue is introduced pyridine C-3 position, then by C (=O) CHYCH
3residue introduces pyridine C-2 position.As raw material, in suitable solvent, in-40 to-90 DEG C of formula that can easily obtain 10 compounds and highly basic formula 11 amido lithium compound react, and lithium to be introduced pyridine C-3 position, then itself and formula 12 electrophilic compound are reacted to produce new formula 3b compound.Then, formula 2 object compound can be prepared by following of short duration process: through bromo-lithium exchange reactions by lithium drawing-in system 3b Compound C-2 position, then react with formula 8 electrophilic compound.
The reaction conditions of above-mentioned reaction and detailed description is described in following reaction scheme.
[reaction scheme 3]
Wherein,
N represents 0 or 3,
X represents chlorine or S-A, and particularly, when X is S-A, formula 12 compound is the di-sulphide compounds with symmetrical structure,
Y represents fluorine, chlorine or bromine,
W represents C
1-C
4-alkoxyl group, C
1-C
4-dialkylamine or morpholine, and
A represents C
3-C
5-alkyl or C
3-C
6-cycloalkyl, or representative be unsubstituted or with being selected from C
1-C
2-alkyl and C
1-C
2the benzyl of substituting group 1-to the 5-replacement of-alkoxyl group.
In reaction scheme 3 the first step, formula 10 compound and highly basic formula 11 amido lithium compound are reacted lithium to be introduced pyridine C-3 position.In this reactions steps, lithium diisopropyl amido (n=0) or 2,2,6,6-tetramethyl piperidine lithium (lithium 2,2,6,6-tetramethylpiperazide) (n=3) can be used as formula 11 strong alkali compound.The Conventional solvents not participating in reacting can be used in this step.Preferably use and be selected from alkane such as hexane and heptane, and ether such as dimethyl ether, diethyl ether, methyl tertiary butyl ether, glycol dimethyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran He one or more solvents of diox.Reactions steps can the temperature of-40 to-90 DEG C, and the preferably temperature of-60 to-90 DEG C, more preferably the temperature of-78 to-90 DEG C is carried out.Once lithium ion state intermediate is formed, then its can in same reaction container directly and formula 12 electrophilic compound react, to prepare new formula 3b midbody compound.Formula 12 disulphide or sulfenyl chlorine compound commercial acquisition maybe can prepare (Gillis, H.M., Greene, L., Thompson, A.Synlett, 2009,112 by using conventional building-up process; Leino, R., Lonngvist, J.-E.Tetrahedron Lett.2004,8489).The consumption of formula 12 electrophilic compound is 0.9 to 1.5 equivalent, preferably 1.0 to 1.1 equivalents, based on initial formula 10 compound.Solvent for the first step can unchangeably for subsequent step.
In second step, formula 2 object compound can be prepared by following of short duration process: in suitable solvent, new formula 3b compound and n-Butyl Lithium are reacted, with through bromo-lithium exchange reactions by lithium drawing-in system 3b Compound C-2 position, then react with formula 8 electrophilic compound.The Conventional solvents not participating in reacting can be used in this step.Preferably use and be selected from alkane such as hexane and heptane, with ether such as dimethyl ether, diethyl ether, methyl tertiary butyl ether, glycol dimethyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran with diox, and one or more solvents of aromatics carbohydrate such as toluene and dimethylbenzene.Reactions steps can the temperature of-40 to-90 DEG C, and the preferably temperature of-50 to-80 DEG C, more preferably the temperature of-60 to-78 DEG C is carried out.Once lithium is introduced C-2 position, then in same solvent, carry out the reaction with formula 8 electrophilic compound in uniform temp.The consumption of formula 8 electrophilic compound is 1.0 to 1.5 equivalents, preferably 1.0 to 1.1 equivalents, based on initial formula 10 compound.
Formula 3 compound for the preparation of formula 2 compound is new pyridine derivate.The invention provides formula 3 compound, especially for formula 3a and the 3b compound of above-mentioned reaction scheme 2 and 3, and prepare its method.
[formula 3]
Wherein,
D represents fluorine or chlorine, or represents S-A,
A represents C
3-C
5-alkyl or C
3-C
6-cycloalkyl, or representative be unsubstituted or with being selected from C
1-C
2-alkyl and C
1-C
2the benzyl of substituting group 1-to the 5-replacement of-alkoxyl group,
E represents bromine or C (=O) CHYCH
3, and
Y represents fluorine, chlorine or bromine.
The pyridyl ketone derivative of formula 3a is formula 3 compound, and wherein D is fluorine or chlorine and E is C (=O) CHYCH
3.In addition, the 2-bromopyridine derivative of formula 3b is formula 3 compound, and wherein D is S-A residue and E is bromine.
[formula 3a]
Wherein,
D represents fluorine or chlorine, and
Y represents fluorine, chlorine or bromine.
The example of preferred formula 3a compound is 1-(3-fluorine pyridine-2-base)-2-fluorine third-1-ketone, 1-(3-chloropyridine-2-base)-2-fluorine third-1-ketone, 1-(3-chloropyridine-2-base)-2-chlorine third-1-ketone and 1-(3-chloropyridine-2-base)-2-bromine third-1-ketone.More preferably formula 3a compound, wherein D is chlorine and Y is fluorine.
[formula 3b]
Wherein,
A represents C
3-C
5-alkyl or C
3-C
6-cycloalkyl, or representative be unsubstituted or with being selected from C
1-C
2-alkyl and C
1-C
2the benzyl of substituting group 1-to the 5-replacement of-alkoxyl group.
Preferably new formula 3b compound, wherein A is sec.-propyl, the second month in a season-butyl, tert-butyl, the second month in a season-amyl group, uncle-amyl group, cyclohexyl or benzyl.The example of preferred formula 3b compound is 2-bromo-3-isopropyisulfanyl pyridine, 2-bromo-3-benzylthio-pyridine, the bromo-3-of 2-(4-methoxy-benzyl) sulfenyl pyridine, the bromo-3-of 2-(uncle-butylthio) pyridine and 2-bromo-3-cyclohexylthio pyridine.More preferably formula 3b compound, wherein A is sec.-propyl, tert-butyl or benzyl.
[advantageous effects of the present invention]
According to the method adopting new pyridyl ketone derivative of the present invention or 2-bromopyridine derivative, formula 2 key intermediate for generation of flucetosulfuron can be prepared by simple process step, and yield is equivalent to or is better than the yield of ordinary method.
[invention pattern]
The present invention is explained in more detail by following embodiment.But these embodiments only illustrate the present invention, and scope of the present invention is not limited.
Embodiment 1: preparation formula 3a compound
[formula 3a]
Embodiment 1-1: preparation 1-(3-chloropyridine-2-base)-2-fluorine third-1-ketone (D=chlorine, Y=fluorine)
Under nitrogen atmosphere, hexane (40mL) and N, N-dimethylaminoethanol (3.14g, 35.2mmol) added reaction vessel and be cooled to-5 DEG C.N-Butyl Lithium (2.5M, in hexane, 70mmol) is dropped to reaction soln, and stirs the mixture 1 hour and be cooled to-41 DEG C.3-chloropyridine (2.04g, 18mmol) in hexane is dropped to mixture.After addition, reaction mixture is cooled to-78 DEG C, and 2-fluorine propionic acid morpholino amide (5.64g, 35mmol) in hexane is dropped to mixture.Stirred reaction mixture 2 hours, is then heated to-20 DEG C.Propionic acid (9.13g, 123mmol) is dropped to mixture with termination reaction.Reaction soln is heated to 0 DEG C.After adding water, solution with ethyl acetate extracts.The organic layer of extraction is dry over magnesium sulfate, and then distillation is except desolventizing.Products therefrom, by silica gel column chromatography purifying, obtains title compound (2.29g, 68%).
1H NMR(CDCl
3，δ)：8.54(dd，J＝1.2，4.3Hz，1H)，7.83(dd，J＝1.2，8.0Hz，1H)，7.42(dd，J＝4.3，8.0Hz，1H)，6.05(dq，J＝6.7，48.9Hz，1H)，1.63(dd，J＝6.7，23.8Hz，3H)
Embodiment 1-2: preparation 1-(3-fluorine pyridine-2-base)-2-fluorine third-1-ketone (D=fluorine, Y=fluorine)
According to the same program of embodiment 1-1, reaction 3-fluorine pyridine (1.75g, 18mmol) instead of 3-chloropyridine, provide title compound (2.00g, 65%).
1H NMR(CDCl
3，δ)：8.51-8.50(m，1H)，7.60-7.54(m，2H)，6.15(dq，J＝6.7，48.9Hz，1H)，1.67(dd，J＝6.7，23.8Hz，3H)
Embodiment 1-3: preparation 1-(3-chloropyridine-2-base)-2-chlorine third-1-ketone (D=chlorine, Y=chlorine)
According to the same program of embodiment 1-1, reaction 3-chloropyridine (2.04g, 18mmol), but by 2-chloropropionate (4.78g, 35mmol) as electrophilic compound instead of 2-fluorine propionic acid morpholino amide, provide title compound (1.91g, 52%).
1H NMR(CDCl
3，δ)：8.55(d，J＝4.9Hz，1H)，7.84(d，J＝8.6Hz，1H)，7.41(dd，J＝4.3，8.0Hz，1H)，5.73(q，J＝6.7Hz，1H)，1.74(d，J＝6.8Hz，3H)
Embodiment 2: preparation formula 3b compound
[formula 3b]
Embodiment 2-1: preparation 2-bromo-3-isopropyisulfanyl pyridine (disulfide Method)
In-20 DEG C, n-Butyl Lithium (2.5M hexane solution, 28mmol) drops to tetrahydrofuran (THF) (12mL) solution of 2,2,6,6-tetramethyl pyridine (3.94g, 28mmol), and stirs the mixture about 1 hour.Reaction mixture is cooled to-78 DEG C, and 2-bromopyridine (3.95g, 25mmol) is dripped to it.After observing slurry and being formed, it is dripped to the tetrahydrofuran solution of diisopropyl disulfide compound (3.76g, 25mmol), keep temperature.After addition was complete, stir the mixture extraly 30 minutes.Ethanol (2mL) is added to it, and reaction mixture is heated to room temperature.Add water with layering to mixture, organic layer uses diluted sodium hydroxide solution, water and dilute hydrochloric acid brine, then underpressure distillation according to priority.Products therefrom, by silica gel column chromatography purifying, obtains title compound (4.80g, 83%).
1H NMR(CDCl
3，δ)：8.16(dd，J＝2.0，4.8Hz，1H)，7.58(dd，J＝2.0，7.6Hz，1H)，7.23(dd，J＝4.8，7.6Hz，1H)，3.50(m，J＝8.0Hz，1H)，1.38(d，J＝8.0Hz，6H)
Embodiment 2-2 to 2-5
According to the same program of embodiment 2-1, reaction is shown in each disulphide electrophilic compound instead of the diisopropyl disulfide compound of following table 1, provides corresponding title compound.
Table 1
Embodiment 2-6: preparation 2-bromo-3-isopropyisulfanyl pyridine (sulfenyl chlorine method)
In-20 DEG C, n-Butyl Lithium (2.5M hexane solution, 28mmol) is dropped to tetrahydrofuran (THF) (12mL) solution of 2,2,6,6-tetramethyl pyridine (3.94g, 28mmol), and stir the mixture about 1 hour.Reaction mixture is cooled to-78 DEG C, and 2-bromopyridine (3.95g, 25mmol) is dripped to it.After observing formation slurry, it is dripped to hexane (4mL) solution of isopropylsulfanyl chlorine (3.10g, 28mmol), keep temperature.After addition was complete, stir the mixture extraly 30 minutes.Ethanol (2mL) is added to it, reaction mixture is heated to room temperature.Add water to mixture with layering, and organic layer uses diluted sodium hydroxide solution according to priority, water and dilute hydrochloric acid brine, then underpressure distillation.Products therefrom, by silica gel column chromatography purifying, obtains title compound (3.46g, 60%).
Embodiment 3: preparation formula 2 compound (method A)
Embodiment 3-1: preparation 1-(3-Benzylsulfanyl pyridine-2-base)-2-fluorine third-1-ketone
By 1-(3-chloropyridine-2-base)-2-fluorine third-1-ketone (1.87g, 10mmol) be dissolved in methyl-sulphoxide (20mL), with it is added to benzyl mercaptan (1.37g, 11mmol), cupric oxide (70mg, 0.5mmol), 2-(ethoxy carbonyl)-pimelinketone (0.17g, 1mmol) with salt of wormwood (2.76g, 20mmol).At room temperature stir the mixture 2 hours.After the reaction was completed, ethyl acetate (100mL) and water (50mL) are added to it, and stirs the mixture with layering.Organic layer uses ammoniacal liquor and water washing according to priority, then underpressure distillation.Products therefrom, by silica gel column chromatography purifying, obtains title compound (1.68g, 61%).
1H NMR(CDCl
3，δ)：8.38(dd，J＝1.2，4.4Hz，1H)，7.74(dd，J＝1.2，8.4Hz，1H)，7.45～7.27(m，6H)，6.27(dq，J＝6.8，49.6Hz，1H)，4.16(s，2H)，1.66(dd，J＝6.8，23.6Hz，3H)
Embodiment 4: preparation formula 2 compound (method B)
Embodiment 4-1: preparation 1-(3-sec.-propyl sulfanyl pyridine-2-base)-2-fluorine third-1-ketone
In-70 DEG C, n-Butyl Lithium (2.5M hexane solution, 22mmol) is dropped to toluene (10mL) solution of 2-bromo-3-isopropyisulfanyl pyridine (4.72g, 20mmol), and stir the mixture 30 minutes.2-fluorine propionic acid morpholino amide (3.28g, 20mmol) in toluene is dripped to it, keeps temperature.After the reaction was completed, ethanol (2mL) is added to it, and reaction mixture is heated to room temperature.Organic layer uses 6N hydrochloride (9mL) and distilled water (6mL) washing according to priority, and then underpressure distillation is except desolventizing.After distillation completes, carry out crystallization with Virahol and normal hexane.Crystalline product is dry under a nitrogen, and obtaining title compound, is white crystal (3.22g, 70%).
1H NMR(CDCl
3，δ)：8.38(dd，J＝1.2，4.4Hz，1H)，7.78(dd，J＝1.2，8.4Hz，1H)，7.23(dd，J＝4.4，8.4Hz，1H)，6.25(dq，J＝8.0，48.0Hz，1H)，3.52(m，J＝8.0Hz，1H)，1.65(dd，J＝8.0，24.0Hz，3H)，1.41(d，J＝8.0Hz，3H)，1.39(d，J＝8.0Hz，3H)
Following comparing embodiment display is by ordinary method preparation formula 2 compound.
Comparing embodiment 1-1: preparation 2-cyano group-3-bromopyridine
According to being described in US 5,354, the method for 749, prepares title compound (35.7g, 195mmol, 61%) from 3-bromopyridine (50.56g, 320mmol) by two-step reaction.
Comparing embodiment 1-2: preparation 2-cyano group-3-sec.-propyl sulfanyl pyridine
In 50 DEG C, by sodium hydride (1.64g, 41mmol), the mixture reaction of tetrahydrofuran (THF) (150mL) and isopropyl mercaptan (3.12g, 41mmol) 1 hour.The 2-cyano group-3-bromopyridine (5.00g, 27.3mmol) obtained in comparing embodiment 1-1 is added to it, reaction mixture refluxed 1.5 hours.After the reaction was completed, steam tetrahydrofuran solvent, and it is newly added water and toluene for extraction.The organic layer of distillation extraction, then carries out crystallization with hexane, obtains title compound (4.38g, 24.5mmol, 90%).
1H NMR(CDCl
3，δ)：8.54(dd，J＝4.8，1.8Hz，1H)，7.84(dd，J＝8.0，1.8Hz，1H)，7.44(dd，J＝8.0，4.8Hz，1H)3.57(sep，J＝6.7，1H)，1.37(d，J＝6.7Hz，6H)
Comparing embodiment 1-3: preparation 1-(3-sec.-propyl sulfanyl pyridine-2-base)-2-fluorine third-1-ketone
According to the method being described in JP 2003-335758, the 2-cyano group-3-sec.-propyl sulfanyl (3.56g, 20mmol) obtained from comparing embodiment 1-2 prepares title compound (2.61g, 11.5mmol, 58%) by three-step reaction.
As described above, according to the method for the present invention with new pyridyl ketone derivative or 2-bromopyridine derivative, can pass through simple process step preparation formula 2 compound, its yield is parity with or superiority over the yield of ordinary method.
Claims (10)
1. for the preparation of the pyridine derived compounds of the following formula 3 of flucetosulfuron
[formula 3]
Wherein,
D represents fluorine or chlorine, or represents S-A,
A represents C
3-C
5-alkyl or C
3-C
6-cycloalkyl, or representative be unsubstituted or with being selected from C
1-C
2-alkyl and C
1-C
2the benzyl of substituting group 1-to the 5-replacement of-alkoxyl group,
E represents bromine or C (=O) CHYCH
3, and
Y represents fluorine, chlorine or bromine.
2. compound according to claim 1, it is the pyridyl ketone derivative of following formula 3a
[formula 3a]
Wherein,
D represents fluorine or chlorine, and
Y represents fluorine, chlorine or bromine.
3. compound according to claim 2, it is 1-(3-fluorine pyridine-2-base)-2-fluorine third-1-ketone, 1-(3-chloropyridine-2-base)-2-fluorine third-1-ketone, 1-(3-chloropyridine-2-base)-2-chlorine third-1-ketone or 1-(3-chloropyridine-2-base)-2-bromine third-1-ketone.
4. compound according to claim 1, it is the 2-bromopyridine derivative of following formula 3b
[formula 3b]
Wherein,
A represents C
3-C
5-alkyl or C
3-C
6-cycloalkyl, or representative be unsubstituted or with being selected from C
1-C
2-alkyl and C
1-C
2the benzyl of substituting group 1-to the 5-replacement of-alkoxyl group.
5. compound according to claim 4, it is 2-bromo-3-isopropyisulfanyl pyridine, 2-bromo-3-benzylthio-pyridine, the bromo-3-of 2-(4-methoxy-benzyl) sulfenyl pyridine, the bromo-3-of 2-(uncle-butylthio) pyridine or 2-bromo-3-cyclohexylthio pyridine.
6. prepare the method for formula 3a pyridyl ketone derivative compound according to claim 2, it comprises the steps: following formula 7 compound and n-Butyl Lithium and N, N-dimethylaminoethanol (DMAE) to react, and then reacts with following formula 8 compound
[formula 3a]
[formula 7]
[formula 8]
Wherein,
D represents fluorine or chlorine,
Y represents fluorine, chlorine or bromine, and
W represents C
1-C
4-alkoxyl group, C
1-C
4-dialkylamine or morpholine.
7. prepare the method for the 2-bromopyridine derivative compound of formula 3b according to claim 4, it comprises the steps: formula 10 compound and highly basic formula 11 amido lithium to react, and then reacts with formula 12 electrophilic compound
[formula 3b]
[formula 10]
[formula 11]
[formula 12]
A-S-X
Wherein,
N represents 0 or 3,
A represents C
3-C
5-alkyl or C
3-C
6-cycloalkyl, or representative be unsubstituted or with being selected from C
1-C
2-alkyl and C
1-C
2the benzyl of substituting group 1-to the 5-replacement of-alkoxyl group, and
X represents chlorine or S-A.
8. method according to claim 7, its Chinese style 12 compound is formula 12a compound
[formula 12a]
A-S-S-A
Wherein,
A represents C
3-C
5-alkyl or C
3-C
6-cycloalkyl, or representative be unsubstituted or with being selected from C
1-C
2-alkyl and C
1-C
2the benzyl of substituting group 1-to the 5-replacement of-alkoxyl group.
9. for the preparation of the method for formula 2 midbody compound preparing flucetosulfuron, it is characterized in that, under Cu catalyzer, part, alkali and solvent exist, formula 3a compound and formula 9 compound are reacted
[formula 3a]
[formula 9]
A-SH
[formula 2]
Wherein,
D represents fluorine or chlorine,
Y represents fluorine, chlorine or bromine, and
A represents C
3-C
5-alkyl or C
3-C
6-cycloalkyl, or representative be unsubstituted or with being selected from C
1-C
2-alkyl and C
1-C
2the benzyl of substituting group 1-to the 5-replacement of-alkoxyl group.
10., for the preparation of the method for formula 2 midbody compound preparing flucetosulfuron, it is characterized in that, formula 3b compound and n-Butyl Lithium are reacted, then react with formula 8 electrophilic compound
[formula 3b]
[formula 8]
[formula 2]
Wherein,
W represents C
1-C
4-alkoxyl group, C
1-C
4-dialkylamine or morpholine,
Y represents fluorine, chlorine or bromine, and
A represents C
3-C
5-alkyl or C
3-C
6-cycloalkyl, or representative be unsubstituted or with being selected from C
1-C
2-alkyl and C
1-C
2the benzyl of substituting group 1-to the 5-replacement of-alkoxyl group.
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| MALLET, M.，等: "Homotransmetalation of 2- or 4-bromo-3-halopyridines with butyllithium. Mechanism of the telesubstitution of bromine", 《TETRAHEDRON》, vol. 42, no. 8, 31 December 1986 (1986-12-31), pages 2253 - 2262 * |
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