CN104487419B - Pyridine derivate and the method being used for producing the midbody compound of sulfonylurea herbicide with its preparation - Google Patents
Pyridine derivate and the method being used for producing the midbody compound of sulfonylurea herbicide with its preparation Download PDFInfo
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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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Abstract
The present invention relates to new for the method preparing key intermediate compound; described key intermediate compound is for producing the fluoroalkyl pyridine sulfonyl sulfonyl base urea derivative of the excellent activity of weeding of display; new pyridine derivate in preparation, and for the method preparing it.
Description
[technical field]
The present invention relates to the new method preparing key intermediate compound, described midbody compound is for producing the fluoroalkyl pyridine-sulfonylurea derivative of the excellent activity of weeding of display, for the new pyridine derivate of preparation with for the method preparing it.
[background technology]
Following formula 1 compound is referred to as flucetosulfuron (flucetosulfuron), and it has the activity of weeding (WO 2002/030921) of excellence.According to the open Application Publication No.2003-335758 of JP patent, prepared by the midbody compound of formula 1 compound following formula 2:
[formula 1]
[formula 2]
A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represent be unsubstituted or with selected from C1-C2-alkyl and C1-C2The substituted benzyl of substituent group 1-to 5-of-alkoxyl；With
Y represents fluorine, chlorine or bromine.
In order to introduce Key residues fluorine in formula 1 compound, needing wherein Y is 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 it reacted with formula 6 compound in the presence of a phase transfer catalyst, as shown in following reaction scheme 1 subsequently.
[reaction scheme 1]
Wherein A is identical with defined hereinabove, and Y ' represents chlorine or bromine, and M represents alkaline-earth metal such as sodium, potassium and caesium.
As shown in above-mentioned reaction, it is accomplished by two-step reaction only for fluorine being introduced the basic structure formula identical with formula 2a compound 4 compound.In addition, it is difficult to completely remove the Cu by-product that this reaction is inevitably generated, and the fluorination reaction that the impact of above-mentioned by-product is subsequently, reduce its yield.The pyridyl ketone derivant of formula 4 is disclosed in US 5,354,749A1, Kevin A.Memoli, TetrahedronLett.1996,37, and 3617 or DE 4,304,007A1, or they can be obtained by the similarity method being adversely made up of four-step reaction disclosed in wherein.
In view of the problems referred to above, inventor have studied the method preparing formula 2 key intermediate compound for production 1 flucetosulfuron easily thick and fast, successfully constructs C (=O) CHYCH by single step reaction3(Y represents fluorine, chlorine or bromine) residue introduces the method for pyridine C-2 position.Using the method, inventor develops and initiates from the method that business material prepares target formula 2 compound, just completes the inventive method by only two-step reaction.
[summary of the invention]
[technical problem]
It is an object of the present invention to provide new for the method preparing key intermediate compound, described midbody compound is for producing the flucetosulfuron of the excellent activity of weeding of display.
It is a further object of the invention to provide the new pyridine derivate for preparing midbody compound, and for the method preparing it.
[solution]
Therefore, the present invention is provided to prepare the pyridine derivate of the following formula 3 of flucetosulfuron.
[formula 3]
Wherein,
D represents fluorine or chlorine, or represents S-A,
A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represent be unsubstituted or with selected from C1-C2-alkyl and C1-C2The substituted benzyl of substituent group 1-to 5-of-alkoxyl,
E represents bromine or C (=O) CHYCH3, and
Y represents fluorine, chlorine or bromine.
The preferred compound of above-mentioned pyridine derivate is pyridyl ketone derivant and the 2-bromopyridine derivant of following formula 3b of following formula 3a.
[formula 3a]
Wherein,
D represents fluorine or chlorine, and
Y represents fluorine, chlorine or bromine.
[formula 3b]
Wherein,
A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represent be unsubstituted or with selected from C1-C2-alkyl and C1-C2The substituted benzyl of substituent group 1-to 5-of-alkoxyl.
The example of preferred formula 3a compound is 1-(3-fluorine pyridine-2-base)-2-fluorine acrylate-1-ketone, 1-(3-chloropyridine-2-base)-2-fluorine acrylate-1-ketone, 1-(3-chloropyridine-2-base)-2-chlorine acrylate-1-ketone and 1-(3-chloropyridine-2-base)-2-bromine acrylate-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-(tert-butylthio) pyridine and 2-bromo-3-cyclohexylthio pyridine.
Formula 3a compound preparation according to the present invention is as follows: by following formula 7 compound and n-BuLi and N, N-dimethylaminoethanol (DMAE) reacts, then reacts with following formula 8 compound.
[formula 7]
[formula 8]
Wherein,
D represents fluorine or chlorine,
Y represents fluorine, chlorine or bromine, and
W represents C1-C4-alkoxyl, C1-C4-dialkylamine or morpholine.
Formula 3b compound preparation according to the present invention is as follows: is reacted with highly basic formula 11 amido lithium by formula 10 compound, then reacts with formula 12 electrophilic compound.
[formula 10]
[formula 11]
[formula 12]
A-S-X
Wherein,
N represents 0 or 3,
A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represent be unsubstituted or with selected from C1-C2-alkyl and C1-C2The substituted benzyl of substituent group 1-to 5-of-alkoxyl, and
X represents chlorine or S-A.
Particularly, in the case of 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 method of formula 2 midbody compound for preparing flucetosulfuron produced according to the present invention is characterised by, is reacted with formula 9 compound by formula 3a compound in the presence of Cu catalyst, part, alkali and solvent.
[formula 3a]
[formula 9]
A-SH
[formula 2]
Wherein,
D represents fluorine or chlorine,
Y represents fluorine, chlorine or bromine, and
A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represent be unsubstituted or with selected from C1-C2-alkyl and C1-C2The substituted benzyl of substituent group 1-to 5-of-alkoxyl.
The another method of formula 2 midbody compound for preparing flucetosulfuron produced according to the present invention is characterised by, is reacted with n-BuLi by formula 3b compound, then reacts with formula 8 electrophilic compound.
[formula 3b]
[formula 8]
[formula 2]
Wherein,
W represents C1-C4-alkoxyl, C1-C4-dialkylamine or morpholine,
Y represents fluorine, chlorine or bromine, and
A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represent be unsubstituted or with selected from C1-C2-alkyl and C1-C2The substituted benzyl of substituent group 1-to 5-of-alkoxyl.
Hereafter, it is more fully described the present invention.
According to the present invention, it is provided that two kinds of i.e. methods A of method and method B, depend on C (=O) CHYCH for preparing formula 2 midbody compound of flucetosulfuron for preparation3Residue and S-A residue introduce pyridine C-2 position and the order of C-3 position respectively.
[method A]
In the first method of formula 2 compound, first by C (=O) CHYCH3Residue introduces pyridine C-2 position, then S-A residue is introduced pyridine C-3 position.As raw material, by readily available formula 7 compound and n-BuLi and N, N-dimethylaminoethanol (DMAE) reacts so that lithium to be selectively introduced pyridine C-2 position, then reacts with formula 8 compound with the formula 3a compound new by forming the generation of C-C key.Then, the compound of formula 2 mesh can be by preparing formula 3a compound with the of short duration process that formula 9 compound reacts in the presence of Cu catalyst, part, alkali and solvent.Formula 2b compound, wherein Y is chlorine or bromine, it is possible to being converted into formula 2a compound by reacting with formula 6 compound the most in a solvent, wherein Y is fluorine, as shown in above-mentioned reaction scheme 1.
Above-mentioned reaction and the description of the detailed description the most following reaction scheme of reaction condition.
[reaction scheme 2]
Wherein,
D represents fluorine or chlorine,
Y represents fluorine, chlorine or bromine,
W represents C1-C4-alkoxyl, C1-C4-dialkylamine or morpholine, and
A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represent be unsubstituted or with selected from C1-C2-alkyl and C1-C2The substituted benzyl of substituent group 1-to 5-of-alkoxyl.
Substituent group mentioned above has following implication.
C3-C5-alkyl means propyl group, isopropyl, butyl, sec-butyl, isobutyl group, tert-butyl, amyl group, sec-amyl group and tert-amyl group；
C3-C6-cycloalkyl means cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl；
C1-C2-alkyl means methyl and ethyl；With
C1-C2-alkoxy means methoxy and ethyoxyl.
Fort et al. disclose optionally remove formula 7 compound C-2 position hydrogen and by lithium ion introduce method (Eur.J.Org.Chem.2001,603；Lett.Org.Chem.2009,6,50).In reaction scheme 2 first step, by using Fort method, by formula 7 compound and n-BuLi and N, the mixture reaction of N-dimethylaminoethanol, optionally remove C-2 position hydrogen and introduce lithium ion.Once lithium ion state intermediate is formed, and it directly can react with formula 8 electrophilic compound, to prepare new formula 3a midbody compound in same reaction container.The Conventional solvents being not involved in reaction can be used in this step.Preferably with selected from alkane such as hexane and heptane, and one or more solvents of ether such as dimethyl ether, diethyl ether, methyl tertiary butyl ether(MTBE), dimethoxy-ethane, oxolane and dioxane.Reactions steps can be the temperature of 0 to-90 DEG C, and preferably the temperature of-20 to-90 DEG C, the temperature of more preferably-40 to-78 DEG C is carried out.Formula 8 compound can be commercially available maybe can prepare as follows: the Lipase absobed conventional from corresponding organic acid or amide 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, in the presence of alkali, solvent, part and Cu catalyst, new formula 3a midbody compound is reacted with formula 9 compound, to carry out the compound of formula 2 mesh by forming C-S key.Alkali includes inorganic base such as cesium carbonate, potassium carbonate, sodium bicarbonate, or organic base such as triethylamine, pyridine and diazabicylo hendecene (DBU).Preferably alkali is cesium carbonate, potassium carbonate and triethylamine, and preferred alkali is cesium carbonate and potassium carbonate.As Cu catalyst, it is possible to use copper oxide (Cu2O), Copper diiodide (CuI), copper chloride (CuCl) and copper bromide (CuBr).Preferably catalyst is copper oxide (Cu2Or Copper diiodide (CuI) O).The consumption of Cu catalyst is 0.01 to 0.5 equivalent, and preferable amount is 0.05 to 0.2 equivalent.As solvent, aprotic polar solvent such as dimethyl sulfoxide (DMSO) can be used, dimethylformamide (DMF), dimethyl acetylamide (DMAC), N-crassitude (NMP) or arsol such as benzene, toluene and dimethylbenzene.Preferably solvent is dimethyl sulfoxide, dimethylformamide, N-crassitude or toluene, and preferred solvent is dimethyl sulfoxide or dimethylformamide.Reactions steps can be carried out in the temperature of 0 to 60 DEG C and the temperature of preferably 15 to 25 DEG C.2-(ethoxy carbonyl) Ketohexamethylene, 1,2-cyclohexane diamine or N, N dimethylamine can act as part.
[method B]
The second method of formula 2 compound is, first S-A residue is introduced pyridine C-3 position, then by C (=O) CHYCH3Residue introduces pyridine C-2 position.As raw material, in-40 to-90 DEG C, formula 10 compound that can be readily available is reacted with highly basic formula 11 amido lithium compound in suitable solvent, so that lithium to introduce pyridine C-3 position, then react itself and formula 12 electrophilic compound to produce new formula 3b compound.Then, the compound of formula 2 mesh can be prepared by following of short duration process: through bromo-lithium exchange reactions by lithium introduction-type 3b compound C-2 position, then reacts with formula 8 electrophilic compound.
The reaction condition 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, in the case of X is S-A, formula 12 compound is the di-sulphide compounds with symmetrical structure,
Y represents fluorine, chlorine or bromine,
W represents C1-C4-alkoxyl, C1-C4-dialkylamine or morpholine, and
A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represent be unsubstituted or with selected from C1-C2-alkyl and C1-C2The substituted benzyl of substituent group 1-to 5-of-alkoxyl.
In reaction scheme 3 first step, react lithium introduces pyridine C-3 position by formula 10 compound and highly basic formula 11 amido lithium compound.In this reactions steps, lithium diisopropyl amido (n=0) or 2,2,6,6-tetramethyl piperidine lithiums (lithium 2,2,6,6-tetramethylpiperazide) (n=3) can act as formula 11 strong alkali compound.The Conventional solvents being not involved in reaction can be used in this step.Preferably with selected from alkane such as hexane and heptane, and ether such as dimethyl ether, diethyl ether, methyl tertiary butyl ether(MTBE), dimethoxy-ethane, oxolane, 2-methyltetrahydrofuran and one or more solvents of dioxane.Reactions steps can be the temperature of-40 to-90 DEG C, the temperature of preferably-60 to-90 DEG C, and the temperature of more preferably-78 to-90 DEG C is carried out.Once lithium ion state intermediate is formed, then it directly can react with formula 12 electrophilic compound, to prepare new formula 3b midbody compound in same reaction container.Formula 12 disulphide or sulfenyl chlorine compound can obtained commercially maybe can be by preparing (Gillis, H.M., Greene, L., Thompson, A.Synlett, 2009,112 by 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 be invariably employed for subsequent step.
In second step, the compound of formula 2 mesh can be prepared by following of short duration process: in suitable solvent, new formula 3b compound is reacted with n-BuLi, with through bromo-lithium exchange reactions by lithium introduction-type 3b compound C-2 position, then react with formula 8 electrophilic compound.The Conventional solvents being not involved in reaction can be used in this step.Preferably with selected from alkane such as hexane and heptane, with ether such as dimethyl ether, diethyl ether, methyl tertiary butyl ether(MTBE), dimethoxy-ethane, oxolane, 2-methyltetrahydrofuran and dioxane, and one or more solvents of aromatic carbon hydrate such as toluene and dimethylbenzene.Reactions steps can be the temperature of-40 to-90 DEG C, the temperature of preferably-50 to-80 DEG C, and the temperature of more preferably-60 to-78 DEG C is carried out.Once lithium is introduced C-2 position, then carries out and the reaction of formula 8 electrophilic compound in mutually synthermal in same solvent.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 formula 2 compound is new pyridine derivate.The present invention provides formula 3 compound, especially for formula 3a and the 3b compound of above-mentioned reaction scheme 2 and 3, and the method preparing it.
[formula 3]
Wherein,
D represents fluorine or chlorine, or represents S-A,
A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represent be unsubstituted or with selected from C1-C2-alkyl and C1-C2The substituted benzyl of substituent group 1-to 5-of-alkoxyl,
E represents bromine or C (=O) CHYCH3, and
Y represents fluorine, chlorine or bromine.
The pyridyl ketone derivant of formula 3a is formula 3 compound, and wherein D is fluorine or chlorine and E is C (=O) CHYCH3.It addition, the 2-bromopyridine derivant of formula 3b is formula 3 compound, 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 acrylate-1-ketone, 1-(3-chloropyridine-2-base)-2-fluorine acrylate-1-ketone, 1-(3-chloropyridine-2-base)-2-chlorine acrylate-1-ketone and 1-(3-chloropyridine-2-base)-2-bromine acrylate-1-ketone.More preferably formula 3a compound, wherein D is chlorine and Y is fluorine.
[formula 3b]
Wherein,
A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represent be unsubstituted or with selected from C1-C2-alkyl and C1-C2The substituted benzyl of substituent group 1-to 5-of-alkoxyl.
The newest formula 3b compound, wherein A is isopropyl, sec-butyl, tert-butyl, sec-amyl group, tert-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-(tert-butylthio) pyridine and 2-bromo-3-cyclohexylthio pyridine.More preferably formula 3b compound, wherein A is isopropyl, tert-butyl or benzyl.
[advantageous effects of the present invention]
New pyridyl ketone derivant according to the employing present invention or the method for 2-bromopyridine derivant, can be prepared by simple process step for producing formula 2 key intermediate of flucetosulfuron, and yield is equivalent to or is better than the yield of conventional method.
[invention pattern]
The present invention is explained in greater detail by following embodiment.But, these embodiments only illustrate the present invention, and the scope of the present invention is not limited except as.
Embodiment 1: formula 3a compound
[formula 3a]
Embodiment 1-1: preparation 1-(3-chloropyridine-2-base)-2-fluorine acrylate-1-ketone (D=chlorine, Y=fluorine)
Under nitrogen atmosphere, hexane (40mL) and N, N-dimethylaminoethanol (3.14g, 35.2mmol) are added reaction vessel and be cooled to-5 DEG C.N-BuLi (2.5M, in hexane, 70mmol) is dropped to reaction solution, and stirring mixture 1 hour and be cooled to-41 DEG C.3-chloropyridine (2.04g, 18mmol) in hexane is dropped to mixture.After addition, reactant mixture is cooled to-78 DEG C, and 2-fluorine propanoic acid morpholino amide (5.64g, 35mmol) in hexane is dropped to mixture.Stirring reactant mixture 2 hours, is then heated to-20 DEG C.Propanoic acid (9.13g, 123mmol) is dropped to mixture to terminate reaction.Reaction solution is heated to 0 DEG C.After adding water, solution with ethyl acetate extracts.The organic layer of extraction is dried over magnesium sulfate, and solvent is then distilled off.Products therefrom passes through silica gel column chromatography purification, it is thus achieved that title compound (2.29g, 68%).
1H NMR(CDCl3, 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 acrylate-1-ketone (D=fluorine, Y=fluorine)
According to the same program of embodiment 1-1, reaction 3-fluorine pyridine (1.75g, 18mmol) rather than 3-chloropyridine, it is provided that title compound (2.00g, 65%).
1H NMR(CDCl3, 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 acrylate-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) it is used as electrophilic compound rather than 2-fluorine propanoic acid morpholino amide, it is provided that title compound (1.91g, 52%).
1H NMR(CDCl3, 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: formula 3b compound
[formula 3b]
Embodiment 2-1: preparation 2-bromo-3-isopropyisulfanyl pyridine (disulfide Method)
In-20 DEG C, n-BuLi (2.5M hexane solution, 28mmol) drops to 2, oxolane (12mL) solution of 2,6,6-tetramethyl pyridines (3.94g, 28mmol), and stirs mixture about 1 hour.Reactant mixture is cooled to-78 DEG C, and to its dropping 2-bromopyridine (3.95g, 25mmol).After observing that slurry is formed, the tetrahydrofuran solution to its dropping diisopropyl disulfide compound (3.76g, 25mmol), keep temperature.After addition was complete, mixture is stirred 30 minutes extraly.It is added ethanol (2mL), and reactant mixture is heated to room temperature.Adding water with layering to mixture, organic layer is according to priority with diluted sodium hydroxide solution, water and dilute hydrochloric acid brine, distillation of then reducing pressure.Products therefrom passes through silica gel column chromatography purification, it is thus achieved that title compound (4.80g, 83%).
1H NMR(CDCl3, 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 rather than the diisopropyl disulfide compound of table 1 below, it is provided that corresponding title compound.
Table 1
Embodiment 2-6: preparation 2-bromo-3-isopropyisulfanyl pyridine (sulfenyl chlorine method)
In-20 DEG C, n-BuLi (2.5M hexane solution, 28mmol) is dropped to 2, oxolane (12mL) solution of 2,6,6-tetramethyl pyridines (3.94g, 28mmol), and stir mixture about 1 hour.Reactant mixture is cooled to-78 DEG C, and to its dropping 2-bromopyridine (3.95g, 25mmol).After observing formation slurry, hexane (4mL) solution to its dropping isopropylsulfanyl chlorine (3.10g, 28mmol), keep temperature.After addition was complete, mixture is stirred 30 minutes extraly.It is added ethanol (2mL), reactant mixture is heated to room temperature.Add water to mixture with layering, and organic layer is according to priority with diluted sodium hydroxide solution, water and dilute hydrochloric acid brine, distillation of then reducing pressure.Products therefrom passes through silica gel column chromatography purification, it is thus achieved that title compound (3.46g, 60%).
Embodiment 3: formula 2 compound (method A)
Embodiment 3-1: preparation 1-(3-Benzylsulfanyl pyridine-2-base)-2-fluorine acrylate-1-ketone
By 1-(3-chloropyridine-2-base)-2-fluorine acrylate-1-ketone (1.87g, 10mmol) it is dissolved in dimethyl sulfoxide (20mL), benzyl mercaptan (1.37g is added with to it, 11mmol), copper oxide (70mg, 0.5mmol), 2-(ethoxy carbonyl)-Ketohexamethylene (0.17g, 1mmol) with potassium carbonate (2.76g, 20mmol).It is stirred at room temperature mixture 2 hours.After the reaction was completed, it is added ethyl acetate (100mL) and water (50mL), and stirring mixture is with layering.Organic layer is according to priority with ammonia and water washing, distillation of then reducing pressure.Products therefrom passes through silica gel column chromatography purification, it is thus achieved that title compound (1.68g, 61%).
1H NMR(CDCl3, 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: formula 2 compound (method B)
Embodiment 4-1: preparation 1-(3-isopropyl sulfanyl pyridine-2-base)-2-fluorine acrylate-1-ketone
In-70 DEG C, n-BuLi (2.5M hexane solution, 22mmol) is dropped to toluene (10mL) solution of 2-bromo-3-isopropyisulfanyl pyridine (4.72g, 20mmol), and stirs mixture 30 minutes.To 2-fluorine propanoic acid morpholino amide (3.28g, 20mmol) in its dropping toluene, keep temperature.After the reaction was completed, it is added ethanol (2mL), and reactant mixture is heated to room temperature.Organic layer with 6N hydrochlorate (9mL) and distilled water (6mL) washing, then reduces pressure and solvent is distilled off according to priority.After distillation completes, crystallize with isopropanol and normal hexane.Crystalline product is dried under a nitrogen, it is thus achieved that title compound, is white crystal (3.22g, 70%).
1H NMR(CDCl3, 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 shows the formula of being prepared by a conventional method 2 compound.
Comparing embodiment 1-1: preparation 2-cyano group-3-bromopyridine
According to being described in US 5, the method for 354,749, prepare 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-isopropyl sulfanyl pyridine
In 50 DEG C, by sodium hydride (1.64g, 41mmol), the mixture reaction of oxolane (150mL) and isopropyl mercaptan (3.12g, 41mmol) 1 hour.It is added 2-cyano group-3-bromopyridine (5.00g, 27.3mmol) obtained in comparing embodiment 1-1, reaction mixture refluxed 1.5 hours.After the reaction was completed, steam tetrahydrofuran solvent, and it is newly added water and toluene is for extracting.The organic layer of distillation extraction, then crystallizes with hexane, it is thus achieved that title compound (4.38g, 24.5mmol, 90%).
1H NMR(CDCl3, 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-isopropyl sulfanyl pyridine-2-base)-2-fluorine acrylate-1-ketone
According to the method being described in JP 2003-335758,2-cyano group-3-isopropyl 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 present invention new pyridyl ketone derivant or the method for 2-bromopyridine derivant, it is possible to by simple process step formula 2 compound, its yield is parity with or superiority over the yield of conventional method.
Claims (5)
1. the 2-bromopyridine derivative compound of following formula 3b
Wherein,
A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represent be unsubstituted or with being selected from
C1-C2-alkyl and C1-C2The substituted benzyl of substituent group 1-to 5-of-alkoxyl.
Compound the most according to claim 1, it is 2-bromo-3-isopropyisulfanyl pyridine, 2-bromine
-3-benzylthio pyridine, the bromo-3-of 2-(4-methoxy-benzyl) sulfenyl pyridine, the bromo-3-of 2-(tert-butylthio) pyrrole
Pyridine or 2-bromo-3-cyclohexylthio pyridine.
3. prepare the side of the 2-bromopyridine derivative compound of formula 3b according to claim 1
Method, it comprises the steps: to react formula 10 compound with highly basic formula 11 amido lithium, then with
Formula 12 electrophilic compound reacts
A-S-X
Wherein,
N represents 0 or 3,
A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represent be unsubstituted or with being selected from
C1-C2-alkyl and C1-C2The substituted benzyl of substituent group 1-to 5-of-alkoxyl, and
X represents chlorine or S-A.
Method the most according to claim 3, its Chinese style 12 compound is formula 12a compound
[formula 12a]
A-S-S-A
Wherein,
A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represent be unsubstituted or with being selected from
C1-C2-alkyl and C1-C2The substituted benzyl of substituent group 1-to 5-of-alkoxyl.
5. the method for formula 2 midbody compound, it is characterised in that by formula 3b compound
React with n-BuLi, then react with formula 8 electrophilic compound
Wherein,
W represents C1-C4-alkoxyl, C1-C4-dialkylamine or morpholine,
Y represents fluorine, chlorine or bromine, and
A represents C3-C5-alkyl or C3-C6-cycloalkyl, or represent be unsubstituted or with being selected from
C1-C2-alkyl and C1-C2The substituted benzyl of substituent group 1-to 5-of-alkoxyl.
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